Frontiers in Polymer Chemistry (Chemical Reviews v.101, N.12, S
Frontiers in Polymer Chemistry (Chemical Reviews v.101, N.12, S
Frontiers in Polymer Chemistry (Chemical Reviews v.101, N.12, S
nism of folding, formation of 3-dimensional structure, ture and dynamics of molecular, macromolecular, and
functions, and properties at the level of sophistication supramolecular systems. Finally, Ungar and Zeng
displayed by the natural compounds. Hill, Mio, discuss the use of linear, branched, and cyclic model
Prince, Hughes, and Moore provide a very compre- compounds prepared mostly by iterative methods in
hensive review that discusses for the first time all the elucidation of the polymer crystallization mech-
classes of biological and nonbiological foldamers. On anism by using the most advanced X-ray diffraction
related topics, Nakano and Okamoto detail the methods.
synthesis and properties of helical polymers. This Although I completely agree with the following
theme is further developed by Cornelissen, Rowan, statement made by one of the pioneers of the field of
Nolte, and Sommerdijk in their analysis of chiral polymer science: “...there is no substitute for reading
architectures from macromolecular building blocks. every reference, cited-second-hand citations are in-
Both in biological and nonbiological macromol- credibly unreliable...” (Morawetz, H. Polymers. The
ecules the intramolecular folding process is deter- Origins and Growth of a Science; Wiley: New York,
mined by a combination of primary structure and 1985), I hope that our readers will find that the out-
noncovalent directional and nondirectional interac- standing work done by the authors mentioned above
tions. Most recently, combinations of various nonco- will provide an excellent and state of the art report
valent interactions were also used to self-assem- for the Frontiers in Polymer Chemistry at the begin-
ble supramolecular polymers in which the repeat ning of the 21st century. The field of polymer chem-
units are interconnected via noncovalent rather than istry was born at the interface between many disci-
covalent bonds. The field of supramolecular poly- plines and today is more interdisciplinary than ever.
mers is reviewed by Brunsveld, Folmer, Meijer, and Finally, I express my great appreciation for the
Sijbesma. cooperation on this thematic issue to all contributing
Progress in the field of chemical and biological authors and reviewers and to the Editorial Office of
sciences is continually impacted by the development Chemical Reviews.
of novel methods of structural analysis. Sheiko and
Möller review a field that started to develop only in
the past several years, i.e., visualization of biological Virgil Percec
and synthetic macromolecules including individual Roy & Diana Laboratories,
macromolecules and their motion on surfaces with Department of Chemistry,
the aid of scanning force microscopy (SFM). Brown University of Pennsylvania,
and Spiess analyze the most recent advances in solid- Philadelphia, Pennsylvania 19104-6323
state NMR methods for the elucidation of the struc- CR000885X
Chem. Rev. 2001, 101, 4013−4038 4013
regarded as only oligomers by synthetic polymer (3) viscosity or light scattering data giving informa-
scientists. tion on the shape and size of an entire molecule, (4)
A helix is a chiral structure; that is, right- and left- chiroptical properties [optical activity, circular dichro-
handed helices are nonidentical mirror images. Hence, ism (CD)] when the helix has an excess screw sense,
if one of the two helices is selectively synthesized or (5) X-ray diffraction data for fiber samples of poly-
induced for a polymer, the polymer may be optically mers, (6) microscopic observation, or (7) single-crystal
active even if it contains no configurationally chiral X-ray analysis.
group in the side chain or the main chain. Although the last method generally gives the surest
There are basically two types of helical structures. information on molecular conformation, it has limita-
One is a rigid helix having a stable existence at room tions in that it is only applicable to oligomers and
temperature, while the other is a dynamic helix in polymers uniform in terms of molecular weight
which helix reversals can readily move along a including proteins but not to polydisperse real poly-
polymer chain at room temperature. The average mers and that it reveals only the structure in the
length of a one-handed helical sequence can be very solid state. In most cases, one or more of these
long for some polymers. In the former case, one may methods (1-7) have been chosen to support the
expect to obtain an optically active polymer with an presence of helical structures. Hence, the structural
excess of a screw sense through the polymerization proof in the studies reviewed in this paper may not
process using a chiral initiator or catalyst. This kind be necessarily perfect in establishing helical struc-
of polymerization is interesting and important in the tures. In the following sections, the topics are clas-
field of polymer synthesis and has been called helix- sified in terms of the chemical structure of the
sense-selective polymerization. The first helix-sense- polymers.
selective polymerization was achieved from the mono-
mer triphenylmethyl methacrylate, leading to a II. Helical Polymers
nearly 100% one-handed helical polymer during
polymerization with a chiral anionic initiator.13 A. Polyolefins
We published a review paper in this journal The isotactic polyolefins prepared using a Ziegler-
entitled “Asymmetric Polymerization” in 1994 which Natta catalyst form a helical conformation in the
encompassed this aspect of helical polymer synthesis solid state (crystalline regions).11,38,42 This helical
in addition to the other types of polymerization in structure persists in solution, but because of fast
which chirality is introduced during the polymeriza- conformational dynamics, only short segments of the
tion process.34 There have been several other review helix exist among disordered conformations. When
papers on asymmetric polymerization and chiral an isotactic polyolefin is prepared from an optically
polymers.35-40 On the other hand, if the energy active monomer having a chiral side group, the
barrier is low enough to allow rapid helix inversion polymer shows the characteristic chiroptical proper-
at room temperature, one cannot expect to obtain a ties which can be ascribed to a helical conformation
stable one-handed helical polymer but may expect to with an excess helicity.12,43-46 The chiroptical proper-
induce a prevailing helical sense with a small amount ties arise in this case predominantly from the helical
of chiral residue or stimulant. The existence of this conformation of the backbone.
type of polymer was most clearly demonstrated with Because polyolefins do not absorb light in the
poly(alkyl isocyanate)s.23,41 accessible UV range, CD spectroscopy, which is a
In the present paper, in addition to the helical powerful tool for studying the chiral structure of
polymers with a screw-sense excess, those in a polymers, could not be used for these vinyl-derived
completely racemic form will also be discussed. polymers. Hence, the chiral structures were eluci-
Following up on the types of polymers discussed in dated in terms of optical rotatory dispersion. For
our last review, newer publications that appeared example, isotactic poly[(S)-3-methyl-1-pentene] (1)
since 1994 will be mainly reviewed here. Moreover,
in addition to the “classical” helical polymers consist-
ing of monomeric units connected to each other
through covalent bonds, polymeric aggregates having
a helical form in which their constituent units
interact through weaker forces have been reported
lately. This type of aggregate will also be covered.
Furthermore, although a helical conformation stable shows a larger specific rotation than the correspond-
in solution was the theme of our last review, some ing monomer.12,43-46 The optical activity of the poly-
newer polymers and aggregates whose helical struc- mer increased with its decreasing solubility and
tures were proposed in the solid phase (liquid crys- increasing melting point, which are related to the
tals, suspensions) are also included this time. isotacticity of the polymer, but decreased as the
The method and accuracy of proving the presence temperature of the measurement increased (Table
of a helical structure varies depending on the type 1).44 This relation between isotacticity and optical
of study and the structure of the polymer. Structural rotation means that the helical conformation may
questions can be addressed by (1) various methods become imperfect when configurational disorders
based on computer calculations or observations of take place in the main chain. In addition, in the
molecular models, (2) achiral spectroscopic evidence conformation of the polyolefin, right- and left-handed
(NMR spectra, absorption spectra, X-ray diffraction), helical segments are considered to be separated
4016 Chemical Reviews, 2001, Vol. 101, No. 12 Nakano and Okamoto
benzene 1200 ( 100. e Determined by a Kofler melting point apparatus. f Determined by the X-ray method. g Determined by the
capillary method. h Referred to one monomeric unit. i Monomer optical purity 91%. l Monomer optical purity 89%. m (10%.
n
Reprinted with permission from ref 44. Copyright 1963 Wiley-VCH.
mers were designed so that their ester linkage is helical conformation, with the polymer still exhibiting
more durable toward methanolysis than that of poly- optical activity in the salt form. Poly(3PyDBSMA)
(TrMA). This design had been introduced for diphen- also formed a salt with n-butyl iodide.
yl-2-pyridylmethyl methacrylate (D2PyMA, 15).63-65
The durability of the ester linkage is an important 3. Poly(triphenylmethyl methacrylate) Analogues:
feature of the helical polymethacrylates when they Free-Radical Polymerization
are used as chiral packing materials for HPLC. Poly- As discussed so far in this section, the helical
(TrMA) is known to slowly decompose and lose its polymethacrylates are synthesized predominantly
helical structure by reaction with methanol, which using anionic polymerization techniques. However,
is a good solvent for a chiral separation experi- recently, more versatile, inexpensive, and experi-
ment.14-16 The methanolysis rates of these monomers mentally simple free-radical polymerization has been
are shown in Table 3 with the data for TrMA. The proved to be an alternative, effective way to prepare
results indicate that the pyridyl-group-containing helical polymethacrylates from some monomers. Al-
monomers are more durable than TrMA, suggesting though the stereochemical control of radical polym-
that the monomers will afford helical polymers more erization is generally more difficult compared with
resistant to methanolysis than poly(TrMA). that in other types of polymerization,69 an efficient
Stereoregulation in the anionic polymerization of method would make it possible to synthesize helical,
D3PyMA and PB2PyMA using organolithium-chiral optically active polymers having functional side
ligand complexes was more difficult than that of chains by direct radical polymerization without using
TrMA reasonably because the coordination of the protective groups. In the radical polymerization of
pyridyl group to Li+ cation competes with the effec- bulky methacrylates, helix-sense selection is gov-
tive complexation of a chiral ligand to Li+ cation. Sp erned by the chirality of a monomer itself or an
and DDB that are effective in controlling the TrMA additive.
polymerization13,52 resulted in rather low specific Although most of the bulky methacrylates de-
rotation values, and only PMP led to the polymers scribed so far give isotactic polymers by radical
showing a relatively high optical activity [poly- polymerization as well as by anionic polymerization
(D3PyMA),59 [R]365 +708°; poly(PB2PyMA),60 [R]365 at low temperatures, the isotactic specificity of the
+1355°]. However, in contrast, the polymerization of radical polymerization is generally lower than that
2PyDBSMA61 and 3PyDBSMA62 was much more in the anionic polymerization.70 However, 1-phen-
readily controlled using Sp, DDB, and PMP as yldibenzosuberyl methacrylate (PDBSMA, 16)71-73
ligands. The bulky and rigid fused ring systems in
these monomers may prevent the side-chain-Li+
coordination.
The polymers obtained from D3PyMA and
P2BPyMA have a less stable helix than that of poly-
(TrMA).59,60 Their helical conformation undergoes
helix-helix transition, leading to a decrease in the
screw-sense excess as observed for the single-handed
helical poly(D2PyMA).66
Helical copolymers of some of the monomers dis- and its derivatives, 2PyDBSMA61 and 3PyDBSMA,62
cussed in this section with TrMA have been synthe- afford nearly completely isotactic polymers by radical
sized.67 polymerization regardless of the reaction conditions.
The optically active polymers obtained from A possible polymer structure of isotactic poly(PDB-
D3PyMA, PB2PyMA, 2PyDBSMA, and 3PyDBSMA SMA) is shown in Figure 3 in which the polymer has
show chiral recognition ability toward some racemic an approximately 7/2-helical conformation. The high
compounds in chiral HPLC or chiral adsorption isotactic specificity implies that the obtained polymer
experiments, though the ability was generally lower is an equimolar mixture of completely right- and left-
than that of poly(TrMA).16,59-62 handed helical molecules, suggesting that introduc-
Quaternary salt formation with alkyl iodides was tion of a nonracemic chiral influence to the polym-
studied using the optically active poly(D3PyMA) and erization reaction could result in the production of a
poly(3PyDBSMA).68 The polymers were found to form single-handed helical, optically active polymer with
a quaternary salt by reaction with CH3I in CHCl3. an almost complete isotactic structure.
Upon salt formation, poly(D3PyMA) lost its helical This concept was realized in the radical polymer-
conformation and optical activity probably due to ization of PDBSMA using optically active initiators
electrostatic repulsion between the charged side DMP (17) and CMBP (18), chain-transfer agents
groups, whereas poly(3PyDBSMA) maintained the NMT (19) and MT (20), and solvents including
Synthetic Helical Polymers Chemical Reviews, 2001, Vol. 101, No. 12 4019
(+)-2F4F2PyMA ([R]365 +28°) afforded polymers with group, is an example. The helical conformation was
a relatively low mm content and a low optical activity first found in the solid state by the X-ray analysis of
either by the anionic polymerization with DPEDA- oriented fiber samples. The conformation was them
Li in THF at -78 °C (mm/mr/rr ) 70/30/∼0, [R]365 confirmed visually by scanning force micrography. In
-82°) or by the radical polymerization in toluene contrast to the polymethacrylates discussed in the
using (i-PrOCOO)2 at 40 °C (mm/mr/rr ) 54/27/19, preceding section, the polymers are likely to form a
[R]365 -2°).89 The monomer design of 2F4F2PyMA helical conformation regardless of the main chain
was not as effective as that of PPyoTMA in control- configuration. A similar conformational control has
ling the polymerization stereochemistry. been realized also with polystyrene derivatives hav-
(1-Methylpiperidin-4-yl)diphenylmethyl methacry- ing a dendritic side group.
late (MP4DMA, 29) has been revealed to afford Helix-sense-selective anionic polymerization of acry-
highly isotactic, helical polymers by radical polym- lates TrA (32) and PDBSA (33)97,98 and acrylamides
including the series of N,N-diphenylacrylamides99-104
(34) have been investigated using (+)-PMP, (-)-Sp,
36, respectively), the optical activity is considered to is reasonably due to a conformational transition
be based on an excess helicity because the rotation allowed only in solution.
was lost when the polymers were converted to the An optically active polystyrene derivative, 40 ([R]25365
methyl esters. -224° to -283°), was prepared by anionic and radical
catalyses.113 The one synthesized through the anionic
polymerization of the corresponding styrene deriva-
tive using BuLi in toluene seemed to have a high
stereoregularity and showed an intense CD spectrum
whose pattern was different from those of the mono-
mer and a model compound of monomeric unit 41.
In contrast, polymer 42 and a model compound, 43,
elucidated, a helical structure has been verified by The polymer 53, bearing a chiral side group, showed
NMR and crystallographic analyses of the uni- much larger optical activity ([R]D -81° to -94°) than
form oligomers separated by chromatographic tech- a model compound of the monomeric unit.125a,b
niques.29,118 A helical conformation has also been
proposed for poly(trifluoroacetaldehyde) (48) and E. Polyisocyanides
poly(tribromoacetaldehyde) (49).119,120
Optically active 44 partially resolves trans-stilbene 1. Polymers of Monoisocyanides
oxide121 and separates several aromatic compounds122 Polyisocyanides having a 4/1-helical conformation
when used as an HPLC stationary phase. 44 also (54) are obtained by the polymerization of chiral
partially resolves isotactic polymers of (R)-(+)- and isocyanide monomers.17,126 An optically active poly-
(S)-(-)-R-methylbenzyl methacrylate.123 isocyanide having a chirality due to the helicity was
first obtained by chromatographic resolution of poly-
2. Other Polyaldehydes (tert-butyl isocyanide) (poly-55) using optically active
Optically active poly(3-phenylpropanal) ([R]25365 poly[(S)-sec-butyl isocyanide] as a stationary phase,
-33° to -56°) (50) is obtained by the anionic polym- and the polymer showing positive rotation was found
erization of 3-phenylpropanal (51) using the com- to possess an M-helical conformation on the basis of
plexes of Sp with ethylmagnesium bromide (EtMgBr) CD spectral analysis.127,128 Details of the helical
structure of polyisocyanides have been discussed on
the basis of theoretical and experimental analyses.19-21
Optically active polymers having an excess helicity
can be prepared by the polymerization of bulky
isocyanides using chiral catalysts. Catalysts effective
for helix-sense-selective polymerization include Ni-
and n-octylmagnesium bromide (OctMgBr).124 The (CNR)4(ClO4)/optically active amine systems,128 the
optical activity may be based on a predominant Ni(II) complexes 56-58,129 and the dinuclear complex
single-handed helical conformation. Reaction of the containing Pd and Pt which has a single-handed
initiator with 51 gives an ester (52) and the (3- oligomeric isocyanide chain (59).130 By the polymer-
phenylpropoxy)magnesium bromide-Sp complex ization of 55 using Ni(CN-But)4(ClO4)/(R)-(+)-C6H5-
through the Tishchenko reaction (Figure 7). The CH(CH3)NH2, an M-helical polymer with an ee of
62% can be synthesized,128 and complex 58 converts
55 to a levorotatory polymer with 69% ee.129 The
complex 59 is obtained by oligomerization of m-(l)-
menthoxycarbonylphenyl isocyanide with Pt-Pd di-
Polymer 108 having a chiral side chain possesses (folding of the molecule) causes the hypochromicity
a helical conformation with a predominant helicity in acetonitrile. The absorption spectral pattern also
due to the effect of the side groups. The predominant differs depending on the solvent. Intermolecular
helicity was reversed by the interaction with (R)- interaction was ruled out by the spectral studies at
various concentrations, and the helical structure was
supported by the 1H NMR measurement, which
showed a remarkable upfield shift of the aromatic
protons, an indication of overlap of the phenylene
groups.
Oligomers 112195 and 113196 having chiral groups
in the main or side chain have an excess helicity. A
112 analogue having a flexible chiral group in place
of the binaphthyl group has also been reported.197
mandelic acid (helix-helix transition), while (S)- Although the exact values of the helical-sense excess
mandelic acid only slightly affected the conformation are not known, the chiral oligomers show the char-
of the polymer. The diastereomeric acid-base inter- acteristic CD bands in acetonitrile, which are not
action causes the conformational transition.190 Com- seen in chloroform.
plexes of 108 with R2Zn effectively catalyze the
asymmetric alkylation of benzaldehyde.191
The poly(phenylacetylene) derivatives discussed
here are considered to be molecular probes for chiral-
ity detection of various chiral molecules.
As another example of a helical polyacetylene, the
single-handed helical polyacetylene fibril, whose
structure was studied by SEM, was prepared by the
polymerization of acetylene within a chiral nematic
liquid crystalline phase.192
2. Polyphosphazene
Helicity induction was also realized for polyphos-
phazene derivative 109 using (R)-1-phenethylamine
(110) as the chiral additive.193
tional calculation.213 The NMR analysis of a trimer isocyanates, which has been interpreted by the
having a chiral group at the chain terminal suggested sergeants and soldiers theory.41
that two diastereomeric conformers existed, which A regioregular polymer, 129, having chiral mono-
may be right- and left-handed helical ones. meric units has been synthesized. This polymer does
not show CD absorption in chloroform, a good solvent.
models indicated that either configuration can yield acid yields an optically active polyaniline derivative.
a similar helical structure. The polymer shows intense CD bands as a film
In addition to the polymers described above, the deposited on an electrode.233 The polymer is soluble
polysilanes having aromatic side groups222,225 and the in NMP, CHCl3, DMF, DMSO, and MeOH, and the
copolymers of a chiral monomer and an achiral polymer also showed a CD absorption in solution
monomer224-228 have been shown to adopt a helical probably based on a chiral main chain conformation
conformation. A water-soluble, helical polysilane such as a helix. A film made by spin-coating a
having an ammonium moiety has also been pre- mixture of polyaniline with camphorsulfonic acid also
pared.229 showed strong CD absorptions that may be based on
Furthermore, a helix-helix transition was found a helical conformation of the main chain.233c The
for polysilane 132 and some copolymers having a 3,7- electopolymerization method has been applied to the
dimethyloctyl group as a chiral group.230 In the synthesis of an optically active polypyrrole which may
stereomutation of 132 in an isooctane solution, the have a helical conformation.234
ratio of right- and left-handed helices depends on A polyaniline film prepared by doping an emeral-
temperature and is 1/1 at -20 °C. dine base with optically active CSA showed a CD
spectrum. Even after dedoping, the film exhibited CD
bands which were different in pattern from those of
the original dedoped film, suggesting that a chiral
conformation such as a helix remains in the polymer
chain. The dedoped film exhibited chiral recognition
ability toward phenylalanine.235
By anionic polymerization using t-BuOK, an opti-
cally active, binaphthyl-based carbonate monomer
(135) gives polymer poly-135, which has a single-
handed 41-helical conformation.236 An analogous poly-
mer has been synthesized from a biphenyl-based
An excess helicity was induced not only by the monomer, 136.237,238
chirality of the side chain but also by the terminal
group. 133 shows the CD absorptions based on an
excess helicity at 85K in an isopentane/methylcyclo-
hexane matrix.231
(149) in which the molecules are stacked along their helical chirality within the aggregate. Moreover, an
helix axes has been proposed. aggregate consisting of 8% chiral 152a and 92%
achiral 152b also showed CD absorptions whose
intensity was comparable with that of the spectrum
of the 152a aggregate. This means that a small
amount of 152a incorporated into an aggregate
consisting mostly of 152b can induce an excess
helicity in the aggregate.
V. Acknowledgments
We are grateful to Ms. Kiyoko Ueda (Nagoya
University) and Mr. Toru Yade (NAIST) for their
assistance in preparing the manuscript.
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Chem. Rev. 2001, 101, 3869−3892 3869
Myongsoo Lee, born in 1960, received a bachelor degree in Chemistry Wang-Cheol Zin received his Ph.D. degree from the University of Cincinnati
from Chungnam National University, Korea, in 1982 and his Ph.D. degree in 1983 and did postdoctoral work at Stanford University before joining
in Macromolecular Science from Case Western Reserve University, the Korea Research Institute of Chemical Technology as a senior
Cleveland, in 1992. In the same year, he became a postdoctoral fellow researcher. He is Professor of Materials Science and Engineering at the
at University of Illinois, Urbana-Champaign. In 1993, he was a senior Pohang University of Science and Technology since 1986. His research
research scientist at Korea Research Institute of Chemical Technology focuses on the self-organization of rod-coil block molecules and phase
where he worked in the field of π-conjugated systems. In 1994, he joined relationship in block copolymers and polymer blends.
the Faculty of Chemistry at Yonsei University, Korea, where he is presently
Associate Professor of Chemistry. His current research interests include function of the volume fraction of one component f
synthetic self-organizing macromolecules, controlled supramolecular and the product χN, where χ is the Flory-Huggins
architectures, and organic nanostructured materials. interaction parameter and N is the degree of polym-
erization.33 A predicted stable microstructure in-
cludes lamellae, hexagonally packed cylinders, body-
centered cubic spheres, close-packed spheres, and
bicontinuous cubic network phases with Ia3d sym-
metry (Figure 1).
Byoung-Ki Cho was born in Daejeon, Korea, in 1971 and studied Chemistry
at Yonsei University, Korea. After receiving his B.S. degree in 1996, he
joined the research group of Professor Myongsoo Lee, Yonsei University,
where he received his Ph.D. degree in 2001. His graduate research
focused on supramolecular organization based on organic rod building
blocks. During his graduate study, he received research excellence award Figure 1. Phase diagram for a structurally symmetric
in Yonsei University and graduate fellowship granted by Seo-Am coil-coil block copolymer (Lam ) lamellae, Hex ) hexago-
Foundation. Dr. Cho is currently a postdoctoral associate at Cornell nally packed cylinders, QIa3h d ) bicontinuous cubic with
University, Ithaca. h d symmetry, QIm3h m ) body-centered cubic, CPS ) close
Ia3
packed sphere).
tent length and whose end to end distance scales Including both rod and block characters, Semenov
linearly with the number of monomer units. and Vasilenco (SV) have initiated a theoretical study
Rod-coil block copolymers have both rigid rod and on the phase behavior of rod-coil block copolymers.12
block copolymer characteristics. The formation of In their study, SV only considered the nematic phase
liquid crystalline nematic phase is characteristic of and smectic A lamellar phases where rods remain
rigid rod, and the formation of various nanosized perpendicular to the lamellae. The smectic phase has
structures is a block copolymer characteristic. A either a monolayer or bilayer structure. In the
theory for the nematic ordering of rigid rods in a following study, Semenov included the smectic C
solution has been initiated by Onsager and Flory,28,29 phases, where the rods are tilted by an angle theta
and the fundamentals of liquid crystals have been to the lamellar normal.13,14 The model also included
reviewed in books.30,31 The theoretical study of coil- a weak phase in which lamellar sheets containing the
coil block copolymer was initiated by Meier,32 and the rigid rod were partly filled by flexible coil. For free
various geometries of microdomains and micro phase energy calculations, SV introduced four main terms:
transitions are now fully understood. A phase dia- ideal gas entropy of mixing, steric interaction among
gram for a structurally symmetric coil-coil block rods, coil stretching, and unfavorable rod-coil inter-
copolymer has been theoretically predicted as a actions. The ideal gas entropy of the mixing term is
Supramolecular Structures from Rod−Coil Block Copolymers Chemical Reviews, 2001, Vol. 101, No. 12 3871
associated with the spatial placement of the junction minimize free energy. The main disadvantage of
point of rod-coil molecules. To find the steric inter- forming the hockey puck relative to lamellae is the
action energy term of the rods SV used the lattice creation of an extra surface, for which they pay a
packing model (Flory lattice approach). Coil stretch- surface energy penalty. WF, following the SV ap-
ing arises from the constraint of the density unifor- proach, included the hockey puck micelle phase in
mity, and it restricts the number of possible confor- the phase diagram by comparing the free energy of
mations of flexible coil in the structured system. The micelle to that of the lamellar structures (Figure 3).
Flory-Huggins interaction parameter measures un-
favorable rod-coil interaction energy. The schematic
phase diagram calculated shows various phases as
a function of the volume fraction of the flexible
component f, the product χN and the ratio ν of the
characteristic coil to rod dimensions. In rod-coil
block copolymers, the shape of the phase diagram is
affected by the ratio ν. It was also shown that the
nematic-smectic transition is a first-order transition,
while the smectic A-smectic C transition is a continu-
ous second-order transition.
Williams and Fredrickson proposed the hockey
puck micelle (one of the nonlamellar structure) where
the rods are packed axially to form finite-sized
cylindrical disk covered by coils (Figure 2).15 They Figure 3. Phase diagram including the hockey puck and
lamellae phases. The phases are (I) bilayer lamellae, (II)
monolayer lamellae, (III) bilayer hockey pucks, (IV) mono-
layer hockey pucks, and (V) incomplete monolayer lamellae.
Log(ν3χ) is plotted against λ. λ ) φ/(1 - φ) where φ is the
volume fraction of the coil. ν ) κ/λ and κ ) Na2/L2 where
the coil part is assumed to consist of N segments with a
mean-square separation between adjacent segments of 6a2,
and L is the rod length. χ is the Flory-Huggins interaction
parameter.
Scheme 1
of coil-rod-coil triblock copolymers in a selective Very recently, low molecular weight block copoly-
solvent of low molecular weight. mers consisting of poly(γ-benzyl-L-glutamate) with
degrees of polymerization of 10 or 20 and polystyrene
III. Rod−Coil Copolymers Based on Helical Rods with degree of polymerization of 10 were synthesized
by Klok, Lecommandoux, and a co-worker (Scheme
Polymers with a stiff helical rodlike structure have 1).44 The coil block was synthesized by conventional
many advantages over other synthetic polymers living anionic polymerization initiated by sec-butyl-
because they possess stable secondary structures due lithium followed by end capping with 1-(3-chloropro-
to cooperative intermolecular interactions. An ex- pyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopen-
ample of polymers with helical conformation is tane. Acid-catalyzed hydrolysis produced a primary
polypeptides in which the two major structures amine functionalized oligostyrene with a degree of
include R-helices and β-sheets. The R-helical second- polymerization of 10. The resulting primary amine
ary structure enforces a rodlike structure, in which functionalized polystyrene was then used as a mac-
the polypeptide main chain is coiled and forms the roinitiator for the polymerization of γ-benzyl-L-
inner part of the rod.18 This rodlike feature is glutamate N-carboxyanhydride to produce the
responsible for the formation of the thermotropic and polypeptide block. The length of the polypeptide
lyotropic liquid crystalline phases. Polypeptide mol- segment was controlled by the molar ratio of the
ecules with R-helical conformation in the solution are N-carboxyanhydride monomer to the primary amine
arranged with their long axes parallel to each other
macroinitiator. In this way, two different rod-coil
to give rise to a nematic liquid crystalline phase.
copolymers consisting of polystyrene with the degree
However, even long chain polypeptides can exhibit a
of polymerization of 10 and polypeptide containing
layered supramolecular structure, when they have
either 10 or 20 γ-benzyl-L-glutamate repeating units
a well-defined chain length. For example, the mono-
were prepared.
disperse poly(R,L-glutamic acid) prepared by the
bacterial synthetic method assembles into smectic Both the rod-coil polymers were observed to
ordering on length scales of tens of nanometers.39,40 exhibit thermotropic liquid-crystalline phases with
Incorporation of an elongated coillike block to this assembled structures that differ from the lamellar
helical rod system in a single molecular architecture structures. Incorporation of a polypeptide segment
may be an attractive way of creating new supramo- into a polystyrene segment was observed to induce a
lecular structures due to its ability to segregate significant stabilization of the R-helical secondary
incompatible segment of individual molecules. The structure as confirmed by FT-IR spectra. However,
resulting rod-coil copolymers based on a polypeptide small-angle X-ray diffraction patterns indicated that
segment may also serve as models providing insight R-helical polypeptides do not seem to assemble into
into the ordering of complicated biological systems. hexagonal packing for the rod-coil copolymer with
High molecular weight rod-coil block copolymers 10 γ-benzyl-L-glutamate repeating units. The amor-
consisting of a polypeptide connected to either a phous character of the polystyrene coil is thought to
polystyrene or a polybutadiene were thoroughly frustrate a regular packing of the R-helical fraction
studied by Gallot et al.18,41-43 These rod-coil copoly- of the short polypeptide segments. Increasing the
mers were observed to self-assemble into lamellar length of the polypeptide segment to a DP of 20 gives
structures with a uniform thickness even though the rise to a strong increase in the fraction of diblock
polypeptide blocks are not monodisperse. Further- copolymers with R-helical polypeptide segment. By
more, one of these studies that involved hydrophobic- studying this block copolymer with small-angle X-ray
hydrophilic polypeptide rod-coil copolymers with coil analysis, a 2-D hexagonal columnar supramolecular
volume fractions ranging between approximately 25 structure was observed with a hexagonal packing of
and 45% showed that the rods are tilted 15-70° in the polypeptide segments adopting an 18/5 R-helical
the lamellae and that the tilt angle increased with conformation with a lattice constant of 16 Å. The
water content.43 In all these studies, the polypeptide authors proposed a packing model for the formation
segments in these block copolymers have an R-helix of the “double-hexagonal” organization (Figure 4). In
conformation. this model, the rod-coil copolymers are assembled
Supramolecular Structures from Rod−Coil Block Copolymers Chemical Reviews, 2001, Vol. 101, No. 12 3873
Scheme 4
3876 Chemical Reviews, 2001, Vol. 101, No. 12 Lee et al.
Scheme 5
Supramolecular Structures from Rod−Coil Block Copolymers Chemical Reviews, 2001, Vol. 101, No. 12 3877
Chart 1
Chart 2
Figure 12. (a) TEM image of nanoribbons formed in dichloromethane. (b) Schematic representation of supramolecular
nanoribbon by self-assembly of dendron rod-coil molecules. (Reprinted with permission from ref 61. Copyright 2001
American Chemical Society).
Supramolecular Structures from Rod−Coil Block Copolymers Chemical Reviews, 2001, Vol. 101, No. 12 3879
structural change in the melt state of this rod-coil PPO repeating units self-assemble into a supramo-
system was observed with variation in the coil length lecular honeycomb-like layered structure, in which
as determined by a combination of techniques con- perforations are filled by coil segments. When cast
sisting of differential scanning calorimetry (DSC), from dilute CHCl3 solution onto a carbon support
optical polarized microscopy, and X-ray scattering. film, honeycomb-like supramolecular structure was
Rod-coil molecules with 7 and 8 propylene oxide observed, as revealed by transmission electron mi-
units exhibit layered smectic C and smectic A phases, croscopy (TEM), in which coil perforations are packed
while rod-coil molecules with 10 to 15 repeating on a hexagonal symmetry with distances between
units exhibit an optically isotropic cubic phase. This perforations of approximately 10 nm (Figure 14a).
structure was identified by the X-ray scattering Electron diffraction patterns revealed very well-
method to be a bicontinuous cubic phase with Ia3d oriented, single crystal-like reflections associated
symmetry. Further increasing the coil length induces with the a*b* reciprocal plane of a rectangular lattice,
a hexagonal columnar mesophase as in the case of indicating that the rod segments are aligned axially
the molecules with 15 to 20 repeating units (Figure with their preferred direction with respect to the
13). Organization of the rod-coil molecules into a plane normal of the layer. Small-angle X-ray diffrac-
cross sectional slice of a cylinder for cubic and tion pattern showed a number of sharp reflections
columnar phases is thought to give rise to a aromatic that are indexed as a 3-dimensional hexagonal
core with approximately square cross section taking structure (Figure 14b). On the basis of these results
into account the calculation based on the lattice as well as density measurements, the supramolecular
parameters and densities. The sizes and periods of structure was proposed to be a honeycomb-like
these supramolecular structures are typically in a crystalline layer of the rod segments with in-plane
range of less than 10 nm. hexagonal packing of coil perforation as illustrated
Supramolecular structures of rod-coil diblock mol- in Figure 15. The consequent layers were suggested
ecules consisting of more elongated rod segment and to be stacked in ABAB arrangement to generate
PPO coil segment (11) were also investigated by the 3-dimensional order. The diameters of perforation
authors (Chart 3).66 In these rod-coil molecules, the sizes were estimated to be approximately 6.5 nm as
rod segment consists of two biphenyl and a phenyl confirmed by TEM, SAXS, and density measure-
group connected through ester linkages. Thus, the ments. These dimensions are comparable to those to
tendency of this system to self-organize into layered Bacillaceae in which pores with regular size are
structures at a given rod volume fraction was ex- organized predominantly into a hexagonal lattice.
pected to be stronger than that of the rod-coil system Thus, this system might provide access to an excel-
containing only two biphenyl units as the rod block. lent model for exploring biological processes in su-
These rod-coil molecules with 22 (11a) and 34 (11b) pramolecular materials.
3880 Chemical Reviews, 2001, Vol. 101, No. 12 Lee et al.
Chart 4
Figure 15. Schematic diagram for the honeycomb-like layer formed by the rod segments of rod-coil molecule 11b.
(Reprinted with permission from ref 65. Copyright 2001 American Chemical Society).
Supramolecular Structures from Rod−Coil Block Copolymers Chemical Reviews, 2001, Vol. 101, No. 12 3881
Chart 5
Figure 18. Schematic diagram of self-assembly of 13c into a supramolecular bundle and the subsequent formation of the
body-centered tetragonal lattice. (Reprinted with permission from ref 67. Copyright 2000 American Chemical Society).
3882 Chemical Reviews, 2001, Vol. 101, No. 12 Lee et al.
Chart 6
Figure 19. Schematic representation for the formation of
(a) lamellar of the (rod-coil)1, (b) 2-D rectangular of the
(rod-coil)2, and (c) hexagonal columnar of the (rod-coil)3.
(Reprinted with permission from ref 70. Copyright 2001
American Chemical Society).
Scheme 7
Scheme 8
Scheme 9
Chart 7
Supramolecular Structures from Rod−Coil Block Copolymers Chemical Reviews, 2001, Vol. 101, No. 12 3887
Scheme 10
Figure 29. SFM image of nonspherical micelles formed quently coupled with oligo(phenylene vinylene) con-
by rod-coil triblock copolymer 27. (Reprinted with permis- taining a vinyl end functional group to yield final
sion from ref 104. Copyright 1998 American Chemical rod-coil copolymers (29) with larger conjugated block
Society). (Chart 8). These rod-coil copolymers were observed
Chart 8 to have remarkable self-assembling properties, and
long cylindrical micelles are formed. TEM and AFM
studies showed that the core of the micelles formed
by 29 with n ) 45 and m ) 6 has a diameter of about
8-10 nm and is composed of a conjugated block
surrounded by a poly(ethylene oxide) coil block
(Figure 31).
Jenekhe et al. reported on the self-assembling
behavior of rod-coil diblock copolymers consisting of
poly(phenylquinoline) as the rod block and polysty-
rene as the coil block (Scheme 11).107,108 The rod-
coil copolymers (30) were prepared by condensation
reaction of ketone methylene-terminated polystyrene
and 5-acetyl-2-aminobenzophenone in the presence
of diphenyl phosphate. The degree of polymerization
of the conjugated rod block in the rod-coil copolymers
was controlled by the stoichiometric method. These
strategy by first coupling with poly(ethylene oxide) block copolymers were found to self-assemble into
coil block with a oligo(phenylene vinylene) followed fascinating supramolecular structures, although the
by coupling of the functionalized rod-coil copoly- rod block might not be monodisperse. For example,
mer.106 The resulting block copolymer was subse- a rod-coil copolymer consisting of poly(phenylquino-
3888 Chemical Reviews, 2001, Vol. 101, No. 12 Lee et al.
Scheme 11
Chart 9
3890 Chemical Reviews, 2001, Vol. 101, No. 12 Lee et al.
Scheme 13
Scheme 14
covalent linkage of the amphiphilic segments, seg- (22) Bates, F. S.; Schulz, M. F.; Khandpur, A. K.; Föster, S.; Rosedale,
J. H.; Almdal, K.; Mortensen, K. Faraday Discuss., Chem. Soc.
regation does not lead to macroscopic separation. 1994, 98, 7.
Instead, it results in the formation of different (23) Khandpur, A. K.; Förster, S.; Bates, F. K.; Hamley, I. W.; Ryan,
regions which are separated by interfaces at a mo- A. J.; Bras, W.; Almdal, K.; Mortensen. K. Macromolecules 1995,
28, 8796.
lecular scale. This amphiphilic feature allows rod- (24) Fredrickson, G. H.; Liu, A. J.; Bates, F. S. Macromolecules 1994,
coil copolymers to construct low dimensional ionic 27, 2503.
conductive nanomaterials as well as ordered nano- (25) (a) Matsen, M. W.; Schick, M. Macromolecules 1994, 27, 4014.
(b) Milner, S. T. Macromolecules 1994, 27, 2333.
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It would be of interest to synthesize rod-coil 7070.
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Chem. Rev. 2001, 101, 3819−3867 3819
Scott M. Grayson (left) was born in 1974 in St. Louis, Missouri. He studied
at Tulane University in New Orleans and graduated summa cum laude
with a BS in Chemistry in 1996. After completing his M.Phil. in
Archaeological Chemistry at the University of Bradford (Bradford, U.K.),
under the guidance of Prof. Carl Heron, he returned to the US to pursue
doctoral studies in chemistry. He is presently researching the applications
of dendritic architectures with Professor Jean M. J. Fréchet at the University
of California, Berkeley.
Jean M. J. Fréchet (right) obtained his first degree at the Institut de Chimie
et Physique Industrielles (now CPE) in Lyon, France, and Ph.D. degrees
at SUNY−CESF and Syracuse University. Following academic appoint-
ments at the University of Ottawa (1973−1986) and Cornell University
(1987−1996), he joined the department of chemistry at the University of
California, Berkeley. Fréchet is a member of the National Academy of
Science, the National Academy of Engineering, and the American Academy
of Arts and Sciences. His research is concerned with functional polymers
from their design and synthesis to their applications.
B. Applications
Because of their well-defined, unique macromo-
lecular structure, dendrimers are attractive scaffolds
for a variety of high-end applications. Their highly
branched, globular architecture gives rise to a num-
ber of interesting properties that contrast those of
linear polymers of analogous molecular weight.35-39
When compared to linear analogues, dendrimers
demonstrate significantly increased solubility35,36 that
can be readily tuned by derivatizing the periphery,40
and they also exhibit very low intrinsic viscosities.11,37
Unlike linear polymers, properly designed high gen-
eration dendrimers exhibit a distinct “interior” that
is sterically encapsulated within the dendrimer,
enabling applications as unimolecular container mol-
ecules.41 For example, Meijer et al. have described
an elegant “dendritic box” that can encapsulate
various small organic molecules and control their
release by modifying the steric crowding of the
dendritic periphery.42 Synthetic approaches have
been developed that allow the functionalization of
both the interior and exterior of these versatile
macromolecules enabling them to operate as transi-
tion state catalysts with high turnover.43 The encap-
sulation of function28 provided by dendrimers has
been utilized in a variety of light-harvesting,44 emis-
sion,44 and amplification45 functions. Among many
other applications under consideration, the use of
dendrimers as components in drug or gene delivery
is the object of numerous current studies.46-54
C. Synthetic Approaches
Two complementary general approaches, the di-
vergent and the convergent, have been used for the
synthesis of dendrimers.15,17
1. Divergent Approach
The divergent approach, arising from the seminal
work of Tomalia and Newkome, as well as the
branched model work of Vögtle, initiates growth at
what will become the core of the dendrimer and
continues outward by the repetition of coupling and
activation steps (Figure 2). Reaction of the peripheral Figure 2.
functionalities of the core with the complementary
reactive group of the monomer introduces a new
latent branch point at each coupling site and results venting uncontrolled hyperbranched polymerization.
in an increase in the number of peripheral function- After driving the first coupling reaction to completion,
alities (Figure 2: coupling step). The peripheral these latent functionalities can be activated to afford
functionalities on each monomer are designed to be a new layer of peripheral groups capable of coupling
inert to focal monomer functionality, thereby pre- to additional monomer (Figure 2: activation step).
3822 Chemical Reviews, 2001, Vol. 101, No. 12 Grayson and Fréchet
2. Convergent Approach
The convergent method, first reported by Hawker
and Fréchet in 1989-1990,9,10,65 initiates growth from
what will eventually become the exterior of the
molecule (Figure 3), and progresses inward by cou-
pling end groups to each branch of the monomer
(Figure 3: coupling step). After completion of the
coupling, the single functional group located at the
focal point of the wedge-shaped dendritic fragment,
or dendron, can be activated (Figure 3: activation
step). Coupling of this activated dendron to each of Figure 3.
the complementary functionalities on an additional
monomer unit affords a higher generation dendron.
After sufficient repetition of this process, these den- decreases exponentially as the generation number
drons can be attached to a polyfunctional core increases. Since coupling yields are not quantitative
through their focal point to form a globular multi- and purification results in some losses, the mass of
dendron dendrimer. Although again an iterative the sample decreases with each additional genera-
synthesis, the convergent route strongly contrasts its tion. In addition, because the coupling reaction occurs
divergent counterpart since it involves only a small at the focal point of the growing dendron, the
number of reactions per molecule during the coupling preparation of very large dendrimers (typically above
and activation steps. the sixth generation) is complicated by steric inhibi-
Although the molecular weight of the dendron is tion, resulting in decreased yields.
effectively doubled at each coupling step, the contri- As mentioned earlier, each activation and coupling
bution of the monomer to the mass of the product step in the convergent synthesis requires only a very
Convergent Dendrons and Dendrimers Chemical Reviews, 2001, Vol. 101, No. 12 3823
Scheme 1
Figure 5.
prevented elimination side reactions that frequently relatively readily accessed and exhibit the chemical
accompany nucleophilic displacements. Similarly, stability associated with ether linkages.
optimization of the activation step from a benzylic The versatility of this Williamson type convergent
alcohol to the benzylic bromide ensured that this dendritic synthesis can be witnessed by the number
reaction could be achieved with consistently high of variations (Figure 6) reported on the original
yields. These considerations mandated our initial
choice of monomer 1 in order to provide excellent
yields and regioselectivity during its activation and
coupling reactions.
A clear limitation of the convergent growth is
observed when pursuing the synthesis at very high
generation number, as steric constraints begin to
hinder the coupling step. For example, in the poly-
(benzyl ether) synthesis depicted in Scheme 1, the
yields obtained during the coupling reactions for the
first four generations are consistently near 90%, but
drop to 85% at the fifth generation coupling step and
to 78% at the sixth. All of the dendrons from genera-
tion one through six can also be effectively coupled
to a tris(phenolic) core 13 to form tridendron den-
drimers 14-20, though an analogous steric effect
causes a slight reduction in yields for the larger
dendrimers (Scheme 2).
Scheme 2
Figure 6.
3. Poly(phenylene) Dendrimers
Two other convergent syntheses including that of
a family poly(1,3,5-phenylene) dendrimers132,133 were
reported by Miller and Neenan shortly after that of
the poly(benzyl ether) dendrimer.10 Preparation of
these polyphenylenes (Scheme 4) and their fluori-
Scheme 4
Scheme 6 Scheme 7
Scheme 8 Scheme 9
These procedures generally maintain the versatility The “hypermonomer” approach, applies the concept
and product monodispersity offered by the traditional of multistage growth to the monomer itself. Instead
convergent method, but reduce the number of linear of assembling dendrons one generation at a time,
synthetic steps required to access larger dendritic hypermonomers contain two or more layers of branch-
materials. ing units, enabling the addition of multiple genera-
tions during each coupling step. Although the cou-
pling and activation steps may involve reactions
1. Multigenerational Coupling: Hypercores, identical to those used with traditional monomers,
Hypermonomers, and Double Exponential Growth
the number of individual coupling reactions per
Fréchet and co-workers developed the “hypercore” growth step increases exponentially with the genera-
approach in order to improve the yields of sterically tion of the hypermonomer, requiring the use of very
inhibited high-generation coupling reactions. The efficient coupling chemistry.
goal of this approach is to couple convergently Wooley et al. first demonstrated this approach
synthesized dendrons to the periphery of a dendritic (Scheme 11) by utilizing a second generation hyper-
core that already contained layers of branching units. monomer, 109, consisting of two layers of branch
Using the standard convergent approach, first, sec- points.216 The carboxylic acid terminated hypermono-
ond, and third generation dendrimers were con- mer allowed the facile synthesis of the fifth genera-
structed with 4,4-bis(4′-hydroxyphenyl)pentanol as tion dendron 112 from the first generation benzyl
the flexible repeat unit.87 The benzyl ether periphery bromide 2 in just three reaction steps. L’abbé and
of these dendrimers could be removed via hydro- co-workers 217,218 later introduced silyl-protected sec-
genolysis (Scheme 10) to expose 6, 12, or 24 phenolic ond and third generation hypermonomers 113 and
114, to enable the accelerated synthesis of the poly-
Scheme 10
(benzyl ether) dendrons initially reported by Hawker
and Fréchet (Scheme 12). tert-Butyldiphenylsilyl
protecting groups were selected for the periphery
because they could withstand the conditions required
for hypermonomer synthesis, yet could be readily
cleaved with fluoride ions. The deprotection step is
followed by an immediate in situ coupling to dendritic
benzylic bromides to produce dendrons up to the fifth
generation in greater than 80% yield.
The final development in multigeneration growth
was proposed by Moore and co-workers in 1995 and
takes direct advantage of both divergent and conver-
gent techniques.219 Dubbed “double exponential den-
drimer growth”, this procedure requires a monomer
with orthogonally masked focal and peripheral func-
tionalities. The first generation dendron can be modi-
fied either at the focal point, to obtain the activated
dendron, or at the periphery, to yield the first gen-
eration monomer. Coupling of the monomer and acti-
vated dendron yields a second generation dendron,
which may likewise be activated at either the focal
point or the periphery. Coupling of the resultant acti-
vated second generation dendrons to the second gen-
eration hypermonomer affords a fourth generation
dendron. Each successive repetition of these three
groups. In a second stage of growth the dendritic steps (dendron activation, monomer activation, and
polyols were utilized as multigenerational “hyper- coupling) leads to a doubling of the generation
cores” capable of coupling with the benzylic bromide number.
functionalities of Fréchet-type dendrons. As a result, To demonstrate this approach (Scheme 13), Moore
coupling of the third generation hypercore 107 with and co-workers selected compound 115, containing
24 fourth generation dendritic bromides 8 afforded the orthogonal focal triazene protecting group and
the seventh generation dendrimers 108 in a 61% two TMS-protected alkynes, to initiate their synthe-
yield. This so-called “double stage convergent” ap- sis. Conversion of its focal point to an iodo functional-
proach not only provides access to dendrimers with ity afforded the activated first generation dendron
chemically differentiated internal and external repeat 116, while removal of the TMS protecting groups
units, but it also provides a more rapid and less yielded the activated first generation monomer 117.
demanding route to very large dendritic molecules. Coupling of monomer 116 with 2 equiv of dendron
This approach has also been employed by Neenan 117 yielded the second generation dendron 118.
and Miller, to enable the synthesis of a third genera- Subsequent halogenation of its focal point or depro-
tion poly(phenylene) dendrimer,133 and by Xu et al. tection of its periphery yielded 119 and 120 respec-
in the synthesis of a fourth generation phenylacety- tively, the two reactants necessary to produce the
lene dendrimer.215 fourth generation dendron 121. Attempts to continue
Convergent Dendrons and Dendrimers Chemical Reviews, 2001, Vol. 101, No. 12 3831
Scheme 11
Scheme 13 Scheme 14
Scheme 15
2. Orthogonal Syntheses
The other accelerated approach for dendrimer syn-
thesis, the orthogonal approach, involves convergent
growth with two different monomers. The monomers, monomers 3,5-diisocyanatobenzyl chloride, 131, and
an AB2 and a CD2 must be carefully selected such 3,5-dihydroxybenzyl alcohol, 1. Although this ap-
that the focal functionalities of each individual mono- proach enabled a one-pot, two-step synthesis of the
mer will only react with the periphery of the other third generation poly(ether carbamate) dendron 133,
monomer (B couples only with C and D only with A) difficulties in purification prohibited further growth.
thus removing the need for activation reactions. As Zimmerman and co-workers were the first to report
Convergent Dendrons and Dendrimers Chemical Reviews, 2001, Vol. 101, No. 12 3833
Scheme 17
Scheme 19
Scheme 21 Scheme 22
Figure 8.
encapsulation of their reactive sites.253,254,259,263 A vents, the solvatochromic shift in the absorption
substantial contribution to the field of dendritic spectra appeared to change drastically between the
porphyrins and phthalocyanines has also been made third and fourth generations, confirming that only
by the groups of Diederich269-272 and Koboyashi268,273 large dendrimers are capable of efficiently shielding
using the divergent approach. their core from the exterior environment. Devadoss
In the following section, a variety of convergently et al. reported a similar shift in the fluorescence
prepared dendrimers will be discussed in the general spectra between the fourth and fifth generations,
context of their applications. Given the focus of this utilizing the characteristic charge transfer in poly-
review, such a classification is quite appropriate since (phenylacetylene) dendrimers having a 2,5-dimethox-
it is the application that dictates the design of the yphenylethyne focal point.275 In other studies, tryp-
dendrimer and hence its synthesis. tophan cores were used to evaluate the nature of
hydrogen bonding within the interior of the den-
1. Environmentally Responsive Cores: Dendritic Probes drimer,276 rubicene cores were incorporated to deter-
Because high generation dendrimers can sterically mine the hydrodynamic volume of dendrimers in
encapsulate the core from the external environment, different solvents,277 and paramagnetic,278 or isotope
the interior is expected to exhibit a unique microen- labeled279 cores were utilized in conjunction with
vironment. The ability to tune this environment may nuclear magnetic resonance to probe dendritic con-
eventually provide a synthetic mimic of enzymatic formation.
catalysis or biological binding events, but initial Vögtle and co-workers have also explored the steric
investigations have focused on the incorporation of demands and flexibility of the Fréchet-type dendrons
responsive core moieties designed to help elucidate by comparing the rate of rotaxane dethreading
the complex nature of the dendritic molecules them- between the dendritic stoppers and traditional rigid
selves. For example, Hawker et al. coupled the anion stoppers.280 The dendritic rotaxanes were prepared
of 4-(N-methylamino)-1-nitrobenzene to Fréchet-type by Williamson ether coupling reaction between a
dendritic bromides (Figure 9) yielding 175, a solva- bulky alkoxide and a dendritic bromide. Dethreading
tochromic probe to elucidate the internal polarity of rates and computer modeling suggested that the
the dendrimer.274 When measured in nonpolar sol- steric requirements of the second generation dendron
3838 Chemical Reviews, 2001, Vol. 101, No. 12 Grayson and Fréchet
Scheme 23
Figure 9.
2. Chiral Cores
Figure 10.
The structural purity of convergent dendrimers has
provided a unique opportunity to study chirality in The inclusion of Fréchet-type dendrons around
synthetic macromolecules.197,198,281 A wide variety of stereogenic cores such as (3R,4S,5R)-3,5-dihydroxy-
poly(aryl ether) dendrimers have been prepared with 4-hydroxymethyl-2,2-dimethylhexane,288,289 (1R,2S)-
chiral cores, using the Williamson ether coupling 2-amino-1-phenyl-1,3-propanediol,290 2,5-anhydro-D-
reaction. The effect of dendritic substitution on the mannitol,291 and TADDOL292 produced the opposite
chiral properties of a core molecule depend primarily effect. As the generation number of the attached
on the origin of its chirality. Dendritic analogues of dendrons increased, the molar optical rotation of
the axially chiral molecule binaphthol 176 were these materials generally decreased. This trend is
prepared by the Williamson ether coupling of Fré- believed to result from perturbation of the chiral
chet-type dendritic bromides to the phenols of 1,1′- conformation by the bulky dendrons.86
bi-2-naphthol (Figure 10). Increasing the size of Meijer and co-workers have prepared an interest-
dendritic substituents produces an increasingly nega- ing set of molecules with chirality that originates
tive value for the molar optical rotation.282-284 Cir- from dendrons of different generation radiating from
cular dichroism has determined that this effect an otherwise achiral pentaerythritol core.293-295 Un-
results from an expansion of the dihedral angle fortunately, attempts to resolve the racemic products
Convergent Dendrons and Dendrimers Chemical Reviews, 2001, Vol. 101, No. 12 3839
Figure 13.
Figure 14.
7. Redox-Active Cores
As with chromophores, the steric encapsulation of
a dendrimer core can be utilized to prevent intermo-
lecular interactions between redox active sites. A
number of different redox active core moieties have
been investigated, including, iron-sulfide clus-
ters,93,94 bis(terpyridine)iron(II) complexes,92 tris-
(bipyridine)ruthenium(II) complexes,330 zinc porphy-
rins,252 oligothienylenevinylenes,331 fullerenes,236,332
ferrocenes,333-336 oligothiophenes,322 oligonaphtha-
lenes,337 and 4,4′-bipyridinium.338
Following the early cyclic voltammetry (CV) studies
by Fréchet and co-workers with dendrimer-encap-
sulated fullerenes235 168 and Chow et al. with den-
dritic bis(terpyridine)iron(II) complexes 186 (Figure
16),92 a number of groups have reported the insulat-
ing effect of dendritic structures on redox active
sites.93,236,252,322,330-333,339 Gorman et al. were the first
to report the dendritic encapsulation (Figure 17) of
inorganic clusters 187. These molecules were syn-
Photoresponsive dendrimers are of interest because thesized by a ligand exchange reaction where al-
the properties of these materials can be readily kanethiols on a (Fe4S4(S-t-Bu)4)2- cluster were re-
modified by an external stimulus. These initial stud- placed by dendritic aromatic thiols.93 As demonstrated
ies have verified that the inclusion of photoactive with other encapsulated redox sites, the irrevers-
moieties into dendritic systems does not adversely ibility of electron transfer increases with dendrimer
affect their photochemical response and can enable size because the active core moiety becomes more
changes in the overall macromolecular structure. insulated from the electrodes and other redox sites.
Comparison of the CV data of the poly(phenylacety-
6. Fluorescent Cores lene) and the poly(benzyl ether) dendrimers sug-
Dendrimers have also been attached to fluorescent gested that more rigid poly(phenylacetylene) struc-
cores in order to modify the properties of the dye. The ture led to more efficient redox site encapsula-
Convergent Dendrons and Dendrimers Chemical Reviews, 2001, Vol. 101, No. 12 3843
B. Linear−Dendritic Copolymers
Figure 17.
Because linear and dendritic polymers have very
tion.340 Noteworthy redox active dendrimers prepared different physical properties and intermolecular in-
via the divergent approach have been reported by teractions, copolymers of these two macromolecular
Diederich269-272 and Newkome.341 architectures are expected to exhibit interesting
Kaifer and co-workers designed an interesting behavior. Gitsov et al. first synthesized these poly-
molecular device that exhibits a pH dependency on meric hybrids by reacting one or both hydroxyl
3844 Chemical Reviews, 2001, Vol. 101, No. 12 Grayson and Fréchet
Figure 19.
termini of poly(ethylene glycol) (PEG) chains with with two poly(benzyl ether) benzyl bromides,365 by
dendritic bromides.357,358 Subsequent studies of PEG atom transfer radical polymerization (ATRP) of sty-
with one and two terminal dendrons, as well as a four rene initatied by a dendritic benzyl bromide,366,367 by
armed-star PEG with four dendritic end groups, a nitroxide mediated “living” radical polymeriza-
190,359,360 revealed that these materials change con- tion,367,368 and by ring opening polymerization of
formation depending on their interactions with sol- lactones with a dendritic alcohol.369,370
vent (Figure 19). 1H NMR verified that in nonpolar
solvents the linear PEG chains collapse, enabling the C. Dendronized Linear Polymers
nonpolar dendritic blocks to shield them from ener-
getically unfavorable interactions with solvent. In Dendronized, or dendritic-grafted linear polymers,
polar solvents, the system minimizes its free energy are linear polymers that bear pendant dendrons
by “inverting” so that the collapsed nonpolar den- along the repeat units. Although there have been a
drons are shielded from solvent allowing the sur- few reports of divergently prepared dendronized
rounding PEG chains to form the interface between materials,138,371,372 the majority of the research in this
the molecule and the solvent.359,361,362 In addition, field has focused on the convergent approach. Re-
these amphiphilic materials exhibited the ability to cently, the convergent synthesis of these materials
solubilize polyaromatic compounds, including fuller- has been optimized, and their preparation has been
enes, without a critical micelle concentration (CMC).363 reviewed extensively elsewhere.373-375 The salient
Amphiphilic linear-dendritic block copolymers can examples are, however, briefly mentioned below.
also be utilized to modify surface properties. When
1. Macromonomer Approach
used with a cellulose substrate or even a more hydro-
phobic poly(ethylene terephthalate) film, the PEG- The “macromonomer approach” refers to the po-
poly(benzyl ether) dendron copolymers self-assemble lymerization of a monomer that is functionalized with
at the surface, increasing its hydrophilicity.364 a dendron. The first attempts to make these com-
Linear-dendritic copolymers have also been syn- pounds via the convergent approach were reported
thesized by capping a “living” polystyrene dianion by Hawker and Fréchet and utilized a fourth genera-
Convergent Dendrons and Dendrimers Chemical Reviews, 2001, Vol. 101, No. 12 3845
Scheme 26
“coupling to” approach, on the other hand, the initial dendron attached. Dynamic light scattering data
linear polymer may be prepared with a well-defined suggested that the sterically bulky high generation
length and polydispersity, but the attachment of Fréchet-type dendrons produced small aggregates,
dendrons is prone to incomplete reaction. while the smaller dendrons led to larger aggre-
gates.422
D. Self-Assembly of Dendritic Cores Columnar aggregation was investigated by Aida
and co-workers, who attached Fréchet-type dendrons
Self-assembled macromolecular structures are of
to a tert-butoxycarbonyl-(L)-tyrosinyl-(L)-alanine focal
particular interest because of their ability to reorga-
group.423 In moderately nonpolar organic solvents,
nize in response to changes in their environment
hydrogen-bonding interactions between the peptide
(concentration, solvent, pH, etc.)415,416 Zimmerman
segments led to the formation of a gel for dendrons
and co-workers417,418 first demonstrated the hydrogen-
of the second and third generations. Cross-polarized
bond mediated self-assembly of dendritic cores (Fig-
microscopy and scanning electron microscopy re-
ure 22) in 1996. The rigid bis(isophthalic acid)
vealed the presence of fibril bundles, on the order of
1 µm. Such ordering was not seen in the parent
peptide or the first generation dendron. The gel could
be rapidly dissolved by addition of a small percentage
of DMSO into the solvent.
Dendritic self-assembly has also been reported in
a number of inorganic systems.45,92,327,329,353,424-426
Seminal studies in this area were carried out by
Balzani and co-workers utilizing the self-assembly
of polypyridine-type ligands around transition
metals.427-430 These materials are considered beyond
the scope of this review, as their preparation does
not follow a strictly convergent methodology. How-
ever, more recently, convergent self-assembly utiliz-
ing polypyridine ligands around a transition metal
core has been reported by the Chow,92 Balzani, De
Cola, and Vögtle groups.329 Plevoets et al. designed
a dendrimer consisting of three Fréchet-type den-
drons bearing focal bipyridine units arranged around
a ruthenium core.329,330 In aerated solution the ru-
thenium core with higher generation dendrons ex-
hibited longer luminescence lifetime because the
dendritic wedges protected the core from dioxygen
quenching. The self-assembly of Fréchet-type den-
drons bearing a focal carboxylate group (Figure 23)
around a series of lanthanide metals, 202-204, was
Figure 22.
E. Surface-Bound Dendrons
The control of surface chemistry has become in-
creasingly important as numerous device and mate-
rial properties are controlled by surfaces and inter-
faces. For example, surface patterning is the founda-
tion of lithography, and its implications in fields such
as microlelectronics or microfluidics are profound.
The synthetic and functional versatility of den-
drimers as well as their defined shape has made
them attractive molecules for surface modification.431
Gorman and co-workers first reported the attachment
of dendrons to a solid surface. Using dendrons with
a focal thiol substituent91 they were able to assemble
monolayers of first, second, or third generation den-
drons on a gold surface.432 Zhang and co-workers
prepared similar monolayers of thiol substituted
dendrons adsorbed onto silver and gold films and
studied the modified surfaces in detail with scanning
tunneling microscopy.433,434 Light-harvesting den-
dritic antennas can also be self-assembled onto the
surface of silicon wafers providing a synthetically less
demanding approach toward constructing chro-
mophore arrays for energy transfer applications.435
Recently, Tully et al. demonstrated that dendrons
could be applied onto surfaces as single, uniform
layers with potential for high-resolution nanolithog-
raphy through molecular level addressing. Both
covalent and ionic (Scheme 27) approaches were
investigated for the attachment of poly(aryl ether)
dendrons onto the surface of a silicon wafer. The
covalent dendritic monolayers were attached via a
silyl chloride functionalized linker, 205, capable of
reacting with the surface silanol groups of the
wafer.436 Ionically bound monolayers could also be
prepared by treating an aminopropyl functionalized
silicon surface with a dendron bearing a single
carboxylic acid functionality at its focal point, 207,
while stronger surface attachment was achieved
using dendrons bearing multiple carboxylate func- homogeneous thin dendrimer monolayer remaining
tionalities.437 Both the covalently and the ionically in unpatterned areas of the wafer surface proved
bound dendritic monolayers could be patterned using resistant to etching with aqueous HF, which removed
scanning probe lithographic techniques, affording the oxidized pattern and etched a positive tone trench
raised SiO2 features in the patterned areas. The into the underlying silicon. At present, this approach
Convergent Dendrons and Dendrimers Chemical Reviews, 2001, Vol. 101, No. 12 3849
to nanolithography is not limited by the properties containing vinyl groups,308,452 organoruthenium moi-
of the dendritic materials but rather by the imaging eties,453-455 ferrocenyl groups,456 TADDOL catalytic
tools available. Both the size of the tip, which far sites,457 concave pyridine units,458,459 liquid crystalline
exceeds that of a dendrimer, and the very low end groups,240 and chromophores.44,79-81,329,460,461 Simi-
throughput of the single-tip scanning probe instru- lar approaches have been employed to incorporate tri-
ment prevent this approach from realizing its ulti- arylamine,120 oligo(ethylene glycol),462,463 tetrathiaful-
mate single-molecule addressing potential. valene (TTF),464-466 saccharide,467-469 fullerene,426,470,471
and ferrocene169,472 moieties onto the periphery of
other dendritic backbones.
IV. Modification of the Periphery
Modification of the dendritic periphery is of par- B. Introduction of End Groups after Completion
ticular interest because this portion of the dendrimer of Dendritic Growth
acts as the primary interface with the external
environment. As might be expected, the functional- In the post modification route, the peripheral
ities at the periphery dominate the solubility proper- functionality is masked or remains unreactive during
ties of the molecule as the generation of the den- convergent growth, to be modified in a subsequent
drimer increases.35,40 Although both NMR438 and reaction. This approach allows the eventual incorpo-
molecular dynamic439 studies have suggested that the ration of end groups that may be incompatible with
end groups of some dendritic systems are capable of the generation growth steps. However, these trans-
“backfolding” toward the core, other studies clearly formations suffer from the same complications as the
indicate that backfolding is not predominant in many divergent synthesis; in the case of larger dendrimers,
dendritic systems.13,440 Being related to free-energy the multiplicity of end group transformations re-
that controls interactions between chain-ends, repeat quires the careful optimization of synthetic and
unit, and general environment (solvent), backfolding purification techniques.
can be controlled by changing the design of the Numerous examples of postsynthetic modifications
dendrimer.13,440 In fact, in a systematic comparison at the dendritic periphery have been explored. In
between analogous linear, hyperbranched, and den- early work, Hawker et al. investigated the hydro-
dritic polymers, Wooley et al. demonstrated that the genolysis and subsequent modification of benzyl-
chain ends of the poly(aryl ester) dendrimers were protected poly(aryl ester) dendrimers473 and later the
sufficiently accessible to be quantitatively modified, saponification of Fréchet-type dendrimers with p-
unlike the analogous functionalities of linear or methyl benzoate end groups to afford an anionic
hyperbranched structures.35 carboxylated periphery.41 The isophthalate ester end
There are two possible approaches toward incor- groups proved to be especially versatile (Scheme 28)
poration of functionality at the periphery: the at-
tachment of the desired end group before initiating Scheme 28
the dendritic synthesis, or modification of the exist-
ing peripheral groups after completion of the syn-
thesis.
Scheme 29 Scheme 30
Scheme 31
ethylene glycol chains261,262,303,334,483 to impart water ment.46 Kono et al. studied the concepts of covalent
solubility on the corresponding dendrimers. Hawker drug loading and targeting by attaching folate or
et al. demonstrated the first convergent synthesis of methotrexate residues to Fréchet-type dendrons via
dendritic unimolecular micelles,41 using molecules diacylhydrazine linkages.484 The water solubility of
with a spherical amphiphilic architecture (Scheme these materials could be improved by attachment of
31) analogous to that reported by Newkome in a poly(ethylene glycol) chain to the focal point of the
divergent systems.57 Saponification of ester-termi- dendron.
nated Fréchet-type dendrimer 224, afforded a den- The ability to drastically alter dendritic solubility
drimer with a polycarboxylate periphery and pH- by modification of the end groups also makes con-
dependent solubility.41 The polycarboxylate 225 vergent dendrons attractive materials for nanolithog-
also exhibited micellelike solubilization of polycyclic raphy. As photolithographic resolution approaches
aromatic hosts (e.g., pyrene). These structures have the size regime of linear polymers, the compact,
been dubbed “unimolecular micelles” because, unlike “pixellike,” globular conformation of the dendrimer
traditional micelles, their covalently bound structure is expected to provide better resolution than longer
is not subject to disaggregation below a certain linear polymer chains. Tully et al. have reported the
concentration threshold. Piotti et al. later utilized preparation of tert-butyloxycarbonyloxy (t-BOC) pro-
these micellar properties to design efficient macro- tected dendrimers 228, spun cast onto silicon wafers
molecular nanoreactors 226 and 227 (Scheme 32), for use as dendritic photoresists (Scheme 33).485
that used the polarity difference between the den- Imaging was achieved by activation of a photoacid
drimers’ interior and exterior to drive the reactants generator where the polymeric film was exposed to
toward the internal catalytic sites while simulta- e-beam lithography, leading to removal of the t-BOC
neously expelling the products to prevent catalyst protecting groups and producing the base-soluble
inhibition.43 poly-phenol dendrimer 229. Developing with aqueous
Because convergent dendrons exhibit a multiplicity base removed the exposed regions of the resist, while
of peripheral groups together with a single reactive development with organic solvents remove the un-
focal point, providing for easy orthogonal function- exposed polymer, enabling access to complementary
alization and control of solubility, they represent an images with feature sizes well below 100 nm.
ideal scaffold for drug delivery applications.53 Fréchet Dendrimers can also serve as a scaffold for energy
and co-workers recently investigated the incorpora- transfer between chromophores,44 a useful step to-
tion of drug moieties by both encapsulation and ward the goal of efficient light-harvesting and arti-
covalent attachment. Liu et al. designed a water- ficial photosynthesis. Although a number of studies
soluble “unimolecular micelle” consisting of a den- have demonstrated the ability of dendritic repeat
dritic polyether structure fitted with peripheral units to act as an antenna,119,257,428,429,486,487 funneling
oligo(ethylene glycol) chains. The macromolecule energy toward the core, attachment of dye groups to
could encapsulate 11 wt % of the model drug in- the periphery of an “insulating” dendritic structure
domethacin and exhibited a slow sustained release (Figure 24) has enabled Fréchet and co-workers to
of this drug when placed in an aqueous environ- carry out a more systematic study of the energy
3852 Chemical Reviews, 2001, Vol. 101, No. 12 Grayson and Fréchet
Scheme 32
transfer in these dendritic systems.80,488,489 The well- and oligothiophenes have been investigated,81 verify-
defined dendrimer architecture enables a multiplicity ing the generality of this approach. In addition,
of donating chromophores at the periphery and an Chrisstoffels et al. have investigated the energy
acceptor chromophore at the focal point to be fixed transfer between dye-labeled dendrons assembled
within the distance range required for efficient För- onto a silicon substrate, and verified that the energy
ster energy transfer. In addition, the irradiation of transfer and amplification phenomena could also be
multiple donating chromophores around a single observed within monolayers.435 Pioneering work by
acceptor amplifies the emission of the focal acceptor Moore and co-workers on a different approach utiliz-
due to the highly efficient energy transfer that occurs ing a layered convergent structure119,486 rather than
within these molecules.488 A variety of systems with end-functionalized dendrons is discussed in a later
different chromophores, including coumarin dyes 230 section.
Convergent Dendrons and Dendrimers Chemical Reviews, 2001, Vol. 101, No. 12 3853
Scheme 33
Figure 25.
Figure 24.
first reported the design and synthesis of a dendritic
LED (Figure 25) in 1996. The incorporation of tri-
arylamine groups on the periphery 231 improved the
hole injection process, lowering the onset voltage
required to operate the devices. In separate work,
Freeman et al. showed that if the dendrimers are
designed to provide sufficient site isolation of their
core, intermolecular energy transfer is inhibited
enabling simultaneous emission from different core
chromophores.461,490 As a result, the color of emission
from the device may be tuned by simply adjusting
the ratio between different “site-isolated” dendritic
Figure 26.
chromophores.
The nature of dendritic self-assembly processes, also be tuned by modification of the periphery. After
and therefore the resulting overall architecture, can investigating the tubular self-assembly of first gen-
3854 Chemical Reviews, 2001, Vol. 101, No. 12 Grayson and Fréchet
A. Layered Copolymers
Layered copolymers contain two or more types of
repeat units that are segregated in a layerwise
fashion in the final dendritic product (Figure 29a).
Since both the divergent and convergent syntheses
progress by the stepwise addition of layers, both
procedures can theroretically access these hybrid
structures. However, with the notable exception of
Balzani and co-workers, who have divergently pre-
pared dendrimers containing concentric layers of
transition metals connected through multidentate
oligopyridine ligands,427,430 and preliminary studies
by Dvornic et al., 524 layer copolymers have been
predominantly investigated through the convergent
growth approach. The first synthesis of a layered
dendritic copolymer (Scheme 34) was reported by
Scheme 34
Figure 30.
B. Segmented Copolymers
Segmented copolymers are hybrids in which con-
trasting repeat units are segregated into wedge-
shaped regions (Figure 29b). The convergent ap-
proach is ideally suited to create these structures
because each growth reaction may be stopped after
the first of two possible coupling reactions by using
an excess of monomer. After isolating the singly
coupled product, the remaining active functionality
of the monomer may be coupled to a dendron with a
chemically different backbone (Figure 5). This hybrid
coupling strategy produces a dendron composed of
two contrasting wedges. Because growth in the
divergent synthesis proceeds outward from the core,
it is difficult to control the multiple reactions of the
surface groups with enough precision to access these
architectures. Only through the application of pro-
tecting group chemistry have representative mol-
ecules of this type been accessed via the divergent
methodology, but these approaches are not generally
applicable.528-530
The first report of such architectures by Hawker
and Fréchet, was again based on the poly(benzyl
ether) and poly(benzyl ester) repeat units as con-
trasting dendritic components525 (Scheme 35). The
second generation Fréchet-type dendritic bromide 4
reacted with an excess of the poly(benzyl ester)
monomer 238 to afford the singly coupled product
243. The remaining phenol of 243 was coupled by a
DCC-mediated esterification to the second generation
poly(benzyl ester) carboxylic acid 244, yielding the
unsymmetrical hybrid dendron 245. After activation
of the focal point, three of these dendrons could be
coupled to a trisphenolic core to yield dendrimer 247
with three pairs of hybrid ester-ether dendritic
wedges. An analogous approach was utilized by Chow
and co-workers during the preparation of dendritic
copolymers with alternating D and L chiral seg-
ments.99,100,526 Although the structures of the seg-
mented block copolymers are often represented in two
dimensions, implying Cn symmetry, the flexibility
within the repeat units enables considerable confor-
mational variations.
The synthesis of surface copolymers entails the
same methodology as the segment copolymers, except
the two contrasting dendrons differ only in the groups.441 Dendrimers were also synthesized that
identity of their end groups.443 This technique was contained benzyl ether end groups in one hemisphere
developed to access hemispherically segregated sur- and methyl esters in the other. Saponification of the
face copolymers. Wooley et al. described the prepara- esters produced the dendritic amphiphile 249 that
tion of dendrimers in which one of the hemispheres demonstrated micellar properties (Scheme 36). Be-
contained p-cyanophenyl electron-withdrawing groups, cause of the well-segregated polar and nonpolar
and the other traditional 3,5-bis(benzyloxy)phenyl regions within the dendrimer, these structures are
electron-donating groups. The resulting dendrimer believed to orient themselves at the interface between
was shown to have a strong dipole due to its globular hydrophilic and hydrophobic solvents.41 Pesak and
shape and the structural segregation of different end Moore used a similar approach to investigate the
3858 Chemical Reviews, 2001, Vol. 101, No. 12 Grayson and Fréchet
Scheme 36
Scheme 37 Scheme 38
Scheme 40
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Chem. Rev. 2001, 101, 3661−3688 3661
Contents
I. Introduction 3661
A. Background 3661
B. Scope of Review 3662
II. Historical Perspective 3662
III. Nitroxide-Mediated Living Free Radical 3663
Polymerizations
A. Bimolecular Process 3664
B. Unimolecular Initiators 3664
IV. Nitroxides Development 3665
V. Approaches to Alkoxyamines 3667
VI. Mechanistic and Kinetic Features 3669
A. Nitroxide Exchange 3669
B. Additives 3671 Tonny Bosman (left) was born in Nijmegen, The Netherlands, in 1970
C. Chain End Degradation 3671 and studied chemistry at the University of Nijmegen. His undergraduate
research (1994) was done in the group of Roeland Nolte concerning chiral
D. Elucidation of Living Nature 3672 mesogenic phthalocyanines after which he undertook his Ph.D. with Bert
E. Emulsion and Related Processes 3673 Meijer at Eindhoven University of Technology (1999) in the area of dendritic
VII. Toward New Materials 3673 molecules and functional materials. He is currently undertaking postdoctoral
A. Molecular Weight Control 3673 research at the IBM Almaden Research Center with Jean Fréchet and
Craig Hawker on combinatorial/high-throughput chemistry and its applica-
B. Telechelic Polymers 3673 tion to developing new methods in living free radical procedures.
C. Block Copolymers 3674 Eva Harth (center) was born in Cologne, Germany and studied chemistry
D. Random Copolymers 3678 at the University of Bonn and the University of Zurich, Switzerland under
VIII. Complex Macromolecular Architectures 3680 the supervision of Prof. A. Vasella, ETH Zurich, where she worked on
A. Star and Graft Polymers 3680 the synthesis and application of glycosylidene fullerenes derivatives. In
1994 she joined the group of Prof. K. Muellen at the MPI for Polymer
B. Hyperbranched and Dendritic Structures 3681 Research in Mainz, obtaining her Ph.D. in 1998 for work in the area of
IX. Surface-Initiated Polymerizations 3683 fullerene adducts and polymers. She is currently undertaking postdoctoral
X. Outlook 3685 research at the IBM Almaden Research Center focusing on the
development of new living free polymerization techniques and novel
XI. Acknowledgments 3686 approaches to nanoscopic materials.
XII. Note Added after ASAP 3686 Craig Hawker (right) was born in Toowoomba, Australia, in 1964. He
XIII. References 3686 received a B.Sc. degree in chemistry from the University of Queensland
in 1984 and a Ph.D. degree in bio-organic chemistry from the University
of Cambridge in 1988 under the supervision of Prof. Sir Alan Battersby.
I. Introduction Jumping into the world of polymer chemistry, he undertook a postdoctoral
fellowship with Prof. Jean Fréchet at Cornell University from 1988 to 1990
A. Background and then returned to the University of Queensland as a Queen Elizabeth
II Fellow from 1991 to 1993. He is currently a Research Staff Member at
At first glance, radical polymerization may be the IBM Almaden Research Center and an investigator in the NSF Center
considered a mature technology with millions of tons for Polymer Interfaces and Macromolecular Assemblies and was recently
of vinyl based homo- and copolymers being produced awarded the 2001 Carl S. Marvel Award in Creative Polymer Science.
annually. This perception of maturity is based on the His research has focused on the interface between organic and polymer
chemistry with emphasis on the design, synthesis, and application of
fact that free radical polymerization is so widely used unusual macromolecular structures in microelectronics and nanotechnology.
industrially and in research laboratories for the
synthesis of a wide variety of polymeric materials. It is therefore surprising that the study of radical
This widespread adoption is due to its versatility, polymerization has witnessed a renaissance in terms
synthetic ease, and compatibility with a wide variety of both synthetic possibilities and mechanistic un-
of functional groups, coupled with its tolerance to derstanding in recent years. One of the driving forces
water and protic media. These features make possible for this renaissance has been the growing demand
the development of emulsion and suspension tech- for functionalized, well-defined materials as building
niques, which greatly simplifies the experimental set blocks in nanotechnology applications. In the prepa-
up and has led to wide commercial adoption. ration of well-defined macromolecules, traditional
10.1021/cr990119u CCC: $36.00 © 2001 American Chemical Society
Published on Web 10/25/2001
3662 Chemical Reviews, 2001, Vol. 101, No. 12 Hawker et al.
B. Scope of Review
This review covers the scientific literature from
1980 to the present concerning nitroxide-mediated
living free radical polymerization. Strategies for
controlling polymeric structure and macromolecular
architecture will be discussed in detail with special
emphasis placed on the synthesis of functionalized propagating radical 2 can undergo monomer addition
polymers. Other important synthetic considerations followed by recombination with a primary sulfur
such as the design of nitroxides with improved radical, 3, to give a dormant species, 4, it may also
performance and the development of new synthetic undergo chain transfer to the initiator itself. As
approaches to alkoxyamine initiators will be exam- opposed to conventional free-radical polymerization,
ined in an effort to provide a basis for future develop- which results in chain termination, even at low
ment in the field. While mechanistic and kinetic conversion, this technique provides rudimentary
details of the polymerization process will be exam- characteristics of typical living systems, such as a
ined, for a more detailed treatment the reader is linear increase in molecular weight with conversion.
directed to the review article by Fischer in this issue.7 In addition, the monofunctional, or R,ω-bifunctional
Similarly, the relationship between nitroxide-medi- chains, can be considered as telechelic polymers,
ated and other living free radical techniques, such giving the possibility to prepare block copolymers.
as atom transfer radical polymerization (ATRP) and Nevertheless, other features of a true living system
radical addition, fragmentation and transfer (RAFT) such as accurately controlled molecular weights and
will be discussed and examples given for each of these low polydispersities could not be obtained since a thio
novel techniques; however, for an in depth analysis, radical, 3, can also initiate polymerization. As will
the reader is directed to the review by Sawamoto in be discussed below, one of the primary requirements
this thematic issue.8 for a mediating radical is that it undergoes reversible
termination of the propagating chain end without
II. Historical Perspective acting as an initiator. Subsequently, a wide range of
stabilized radicals has been examined as mediating
The first detailed attempt to use initiators that radicals for the development of a living free radical
control radical polymerization of styrene and methyl system.11-13 As with the preliminary iniferter work
methacrylate was reported by Werrington and To- of Otsu, they suffer from incomplete control over both
bolsky in 1955.9 However, the specific dithiuram the initiation and reversible termination steps and
disulfides that were employed lead to high transfer lead to poorly controlled polymerizations; however,
constants, which resulted in retardation of the po- their structures do point to interesting features that
lymerization. This promising concept was subse- may be relevant in the future development of this
quently overlooked for close to 30 years until the use technology (Figure 1). Delocalized systems, the pres-
Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3663
Figure 1.
ence of heteroatoms and in many examples, steric the desired initiating species and growth should occur
hindrance all play key roles in determining the in a living fashion, allowing a high degree of control
success of the mediating radical. Of particular note over the entire polymerization process with well-
to the nitroxide work described below, is the ability defined polymers being obtained.
of radicals such as the verdazyl and borinate deriva- The identity of the mediating radical, R•, is critical
tives to control the polymerization of methacrylates. to the success of living free radical procedures and a
The tendency of the radical species in these examples variety of different persistent, or stabilized radicals
to abstract R-hydrogens is obviously decreased for have been employed. These range from (arylazo)oxy,14
methacrylate polymerizations when compared to substituted triphenyls,15 verdazyl,16 triazolinyl,17 ni-
nitroxides and an understanding of the difference troxides,18 etc. with the most widely studied and
between these systems may permit the design of certainly most successful class of compounds being
improved nitroxides for methacrylate polymerization. the nitroxides and their associated alkylated deriva-
tives, alkoxyamines. Interestingly, the development
III. Nitroxide-Mediated Living Free Radical of nitroxides as mediators for radical polymerization
Polymerizations stems from pioneering work into the nature of
standard free radical initiation mechanisms and the
The pioneering iniferter work provided the basis desire to efficiently trap carbon-centered free radi-
for the development of LFRP and it is interesting to cals. Solomon, Rizzardo, and Moad were able to
note the similarity between the iniferter mechanism demonstrate that at the low temperatures typically
outlined in Scheme 1 and the general outline of a associated with standard free radical polymeriza-
successful living free radical mechanism (Scheme tions, 40-60 °C, nitroxides such as 2,2,6,6-tetram-
2). In this general mechanism, the reversible termi- ethylpiperidinyloxy (TEMPO), 5, reacted at near
diffusion controlled rates with carbon-centered free
Scheme 2 radicals, 6, generated from the addition of initiating
radicals, 7, to vinyl monomers.19 The resulting
alkoxyamine derivatives, 8, were essentially stable
at these temperatures and did not participate in the
reaction further, thus acting as radical traps (Scheme
3).
Scheme 3
A. Bimolecular Process
The second seminal contribution which demon-
strated to a wide audience that living free radical
polymerizations are a viable synthetic methodology
was a report from the group of Georges at XEROX
describing the preparation of low polydispersity
polystyrene.21 The key feature of this work was the
preparation of high molecular weight, low polydis-
persity materials. By increasing the temperature to
130 °C and conducting the polymerizations in bulk,
a system comprising benzoyl peroxide, 9, and a stable
nitroxide, TEMPO (5), in a molar ratio of 1.3:1, gave
polystyrene derivatives, 10, by a living process in
which the molecular weight increased in a linear
fashion with conversion (Scheme 4). Even more
B.Unimolecular Initiators
While successful, the poorly defined nature and
unknown concentration of the initiating species in the
bimolecular process prompted the development of a
single molecule initiating system which would permit
control over molecular weight, architecture, etc.
Borrowing the concept of well-defined initiators from
living anionic and cationic procedures, unimolecular
initiators for nitroxide-mediated living free radical
polymerizations have been developed.28,29 The struc-
ture of these initiators was based on the alkoxyamine
startling were the polydispersity values for 10 (PDI functionality that is present at the chain end of the
) 1.2-1.3), which were significantly lower than the growing polymer during its dormant phase. The C-O
theoretical lower limit for a free radical process of bond of the small molecule alkoxyamine derivative
1.5 and the typical values of ca. 2.0 for free radical 11 is therefore expected to be thermolytically un-
systems. At these elevated temperatures the C-ON stable and decompose on heating to give an initiating
bond becomes unstable, releasing the nitroxide which radical, i.e., the R-methylbenzyl radical 12 as well
can now act as a polymerization mediator, not as an as the mediating nitroxide radical 5 in the correct
inhibitor as they are low temperatures, hence their 1:1 stoichiometry (Scheme 5). Following initiation the
use by Solomon to trap polymerization intermediates. polymerization would proceed as described previous
While this original work by the XEROX group for the bimolecular case to give the polystyrene
displays many of the fundamental aspects of a living derivative 13.
Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3665
Scheme 6
as styrenics, leading to alkoxyamines suitable for use produce very few unwanted side products, which
as initiators in living free radical procedures. While greatly facilitates isolation and purification.
the mechanism for the Jacobsen epoxidation of olefins
is still controversial, a substantial body of evidence VI. Mechanistic and Kinetic Features
has been accumulated that supports direct attack of
the olefin at the oxomanganese center to generate a A. Nitroxide Exchange
radical intermediate followed by collapse to give the
desired epoxide.91 It is anticipated that a similar The key kinetic feature of nitroxide-mediated living
mechanism is involved during the synthesis of free radical polymerization is the operation of a
alkoxyamines with evidence suggesting that an in- special kinetic phenomenon, termed the persistent
termediate organomanganese derivative, 35, is in- radical effect. Fischer has developed the equations
volved, which on reduction with sodium borohydride for the polymerization rates and for the polydisper-
gives the alkoxyamine 36 (Scheme 13). The advan- sities of the resulting polymers that have been shown
to effectively model LFRP.92,93 In the initial stages
Scheme 13 of the polymerization, a small fraction of the initiat-
ing radicals 37 formed from decomposition of the
unimolecular initiator 38 undergo radical-radical
coupling. This leads to a terminated small molecule
or oligomer, 39, and the resulting elimination of two
initiating radicals. At this early stage of the polym-
erization, this is a facile reaction since the diffusing
radicals are sterically not congested and the reaction
medium is not viscous. However, by its nature, the
mediating radical, or persistent radical, 40 does not
undergo coupling and so a small increase in the
overall concentration of 40 relative to the propagat-
ing/initiating radical 37 occurs. This increased level
of 40 is self-limiting since a higher concentration
leads to more efficient formation of the dormant chain
end 41 and a decrease in the amount of radical-
radical coupling (Scheme 14). This interplay between
Scheme 14
Scheme 17
Scheme 18
Scheme 19
tion is a direct result of having the functional groups groups allows block copolymers to be prepared in at
built into the initiator, coupled with the necessity for least four different ways. As shown in Scheme 19,
no functional group transformations at the chain vinyl block copolymers can be prepared in a tradi-
ends. It should also be realized that functional group tional sequential fashion by the polymerization of one
interconversions are possible based at the propagat- monomer followed by a second monomer (reaction 1).
ing chain end on alkoxyamine chemistry and a Alternatively, a functionalized alkoxyamine can be
number of groups have exploited this in the design used to terminate polymerization of an initial mono-
of telechelic systems.112-115 mer under conditions other than living free radical.
The alkoxyamine-terminated macromolecule can then
C. Block Copolymers be used as a macroinitiator to prepare block copoly-
One of the primary driving forces behind the mers. The interesting feature of this process is that
interest that living radical procedures have received it permits the facile introduction of a functional group
in recent years is the ability to prepare block copoly- or chromophore at the junction point between the two
mers. Not only may existing block copolymers be blocks (reaction 2). In reaction 3, a dual, or double-
prepared more efficiently and in some case with a headed, initiator is prepared which has both an
greater degree of control, but also novel block copoly- alkoxyamine initiating fragment and an initiating
mers, which were not accessible using existing tech- group for a different polymerization contained in the
niques, may also be prepared. The synthetic versa- same molecule. Depending on the compatibility of the
tility associated with alkoxyamine initiators and the initiating groups, the polymerization processes and
ability to introduce a wide variety of functional the desired structure of the block copolymer, the
Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3675
order of polymerization can be varied to give the decreased, leading to reduced radical coupling and a
desired block copolymer. Finally, a preexisting tele- more controlled polymerization.
chelic polymer can be mono- or difunctionalized with The second strategy for nonvinylic block copolymer
the appropriate alkoxyamine to give a macroinitiator formation involves the combination of living free
from which a vinyl block can be grown under living radical techniques with other polymerization pro-
radical conditions. While not an extensive list of all cesses either to form linear block copolymers or graft
possible procedures, the multitude of synthetic strat- systems. All of these processes take advantage of the
egies that have currently been explored for nitroxide- compatibility and stability of alkoxyamines and their
mediated living radical procedures does give an associated nitroxide-mediated polymerization proce-
indication of the extreme versatility in block copoly- dures with a wide range of reaction conditions. For
mer formation which is possible using this novel example, this permits the alkoxyamine initiating
technique. To give a greater insight into the myriad group to be copolymerized into a poly(olefin) back-
possibilities, a list of linear block copolymers that bone under metallocene conditions169 or into a vinyl
have been prepared using nitroxide-mediated pro- backbone under anionic170 or normal free radical
cesses is detailed in Table 2 and a number of actual conditions.171 The latter is an interesting application
examples discussed below.116-172 of the specificity of nitroxide-mediated living free
As discussed above, one synthetic strategy relies radical polymerizations. Since the cleavage of the
on the coupling of a functionalized alkoxyamine with C-ON bond is thermally activated, reactions at lower
a telechelic or mono-functional nonvinylic polymer to temperatures (ca. <80 °C) can be performed without
give a macroinitiator. This macroinitiator can then any initiation occurring from the alkoxyamine group/
be used in standard living free radical procedures. s. Therefore normal free radical polymerizations,
Such an approach is best illustrated by the prepara- ATRP, and RAFT procedures can be performed in the
tion of poly(ethylene glycol)-based block copoly- presence of alkoxyamines. Subsequent activation of
mers129,136,150,167 by initial reaction of a mono-hydroxy the alkoxyamine permits the facile synthesis of graft
terminated poly(ethylene glycol) with sodium hydride and block copolymers.
followed by the chloromethyl-substituted alkoxyamine The synthetic versatility associated with combining
36. The PEG-based macroinitiator (PDI ) 1.05-1.10) different polymerization techniques can also be dem-
61 can then be used to polymerize a variety of vinyl onstrated by the preparation of poly(caprolactone)-
monomers, such as styrene, to give amphiphilic block b-(styrene) copolymers by a combination of living ring
copolymers, 62, which have accurately controlled opening polymerization with nitroxide-mediated free
molecular weights and very low polydispersities, radical procedures using a hydroxy-substituted alkoxy-
1.05-1.10 (Scheme 20).167 The extremely low poly- amine as a dual, or double-headed, initiator, 63.173
The primary alcohol is used as the initiating group
Scheme 20 for the ring opening polymerization of caprolactone
to give the alkoxyamine-terminated macroinitiator
64, which can then be used to initiate the living
polymerization of styrene to afford the well-defined
block copolymer 65. Alternatively, the alkoxyamine
group of 63 can be used to initiate the polymerization
of styrene, and in turn, the hydroxy-terminated
polystyrene 66 allows the ring opening polymeriza-
tion to be initiated from the hydroxy group to give
the analogous block copolymer 65 (Scheme 21). The
significant feature of this approach is that either
sequence of living polymerizations gives the same
polymeric structure, the ultimate choice being dic-
tated primarily by the block copolymer composition.
In a similar vein, Sogah has combined living free
radical polymerization with the cationic ring opening
of oxazolines, and anionic ring opening into the same
multifunctional initiator. This trifunctional system
has been shown to be highly effective leading to well-
defined block copolymers and can even be combined
into a one-pot, one-step block copolymerization by
simultaneous free radical and either cationic ring
opening or anionic ring opening procedures.174
The advantages of living free radical polymeriza-
tions are not restricted to the synthesis of block
copolymers, which contain a nonvinylic block/s, i.e.,
dispersities may be due to the use of a macroinitiator caprolactone. The compatibility with functional groups
in contrast to typical small molecule initiators. In the and the inherent radical nature of the process also
latter case, mobility and reactivity of the initiating permits significant progress to be made in the
radicals is high leading to radical-radical coupling. synthesis of block copolymers based solely on vinyl
For the macroinitiator, diffusion and reactivity is monomers. While a number of these structures can
3676 Chemical Reviews, 2001, Vol. 101, No. 12 Hawker et al.
Table 2. Structure of Monomer Employed in the Synthesis of Block Copolymers by Nitroxide Mediated Living
Free Radical Procedures
Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3677
sion to give the block copolymer 71, analysis of which D. Random Copolymers
revealed the expected increase in molecular weight,
while the polydispersity remained very low (PD. ) One of the major advantages of living radical
1.06-1.19) and there were no detectable amount of procedures compared to living anionic or cationic
unreacted starting poly(acrylate) block (Scheme 23). polymerizations is the ability to prepare well-defined
random copolymers. In traditional anionic or cationic
Scheme 23 procedures, there are numerous problems which
normally preclude the successful synthesis of random
copolymers. For example, reactivity ratios can be
extremely large in anionic systems, and so true
random copolymerizations do not occur and blocky
structures are obtained. Alternatively, the polymer-
ization conditions for one monomer or functional
group are not compatible with the second monomer
and an uncontrolled polymerization is obtained. This
lack of synthetic versatility has prompted numerous
groups to examine the synthesis of well-defined
random copolymers via living radical techniques.
While early work with TEMPO did demonstrate that
random copolymers can be prepared under nitroxide-
mediated conditions the inability to control the
homopolymerization of monomers other than styrene
limited the range of monomer units and possible
The radical nature of nitroxide-mediated processes random copolymer structures.31,174,180 With the advent
also allows novel types of block copolymers to be of second-generation nitroxides, such as 17, the realm
prepared in which copolymers, not homopolymer, are of well-defined random copolymers have been dra-
employed as one of the blocks. One of the simplest matically opened. For example, while the homopo-
examples incorporate random copolymers124 and the lymerization of methacrylates does not give controlled
novelty of these structures is based on the inability polymers, random copolymers of methacrylates with
to prepare random copolymers by living anionic or up to 90 mol % of methacylate incorporation can be
cationic procedures. This is in direct contrast to the prepared in a living fashion.38 The actual rationale
facile synthesis of well-defined random copolymers for this stark contrast is not known at the moment
by nitroxide-mediated systems. While similar in and deserves further study since it may provide
concept, random block copolymers are more like insights into controlling H-abstraction and in turn
traditional block copolymers than random copolymers methacrylate polymerization in these systems. The
in that there are two discrete blocks, the main ultimate aim of these studies would be to develop a
difference being one or more of these blocks is living polymerization of methacrylates that leads to
composed of a random copolymer segment. For ex- well-defined materials, one of the major challenges
ample, homopolystyrene starting blocks can be used in this general area.
to initiate the copolymerization of styrene and 4-vi- The finding that the reactivity ratios for monomers
nylpyridine to give a block copolymer consisting of a under living free radical conditions are essentially
polystyrene block and a random copolymer of styrene the same as under normal free radical conditions is
and 4-vinylpyridine as the second block.166 also fundamentally important. As a consequence of
this, random copolymers prepared by living free
The potential for these materials can be better radical processes are different on a molecular level
appreciated if the synthesis and application of the to those prepared by normal free radical methods,
functionalized block copolymer 72 is considered. An even though they may appear the same on the
initial random copolymer of methyl acrylate and macroscopic level (Scheme 25). In the case of tradi-
glycidyl methacrylate, 73, is prepared by nitroxide- tional free radical polymerization, continuous initia-
mediated living free radical polymerization and then tion leads to chains initiating and terminating at
used to initiate the polymerization of isoprene leading different stages of the polymerization. Therefore,
to the random block copolymer 72 (Scheme 24). The chains that are initiated and terminated at low
design of these macromolecules incorporates a ran- conversion experience a different monomer feed
dom block which is not only miscible with thermoset- ratio compared to chains initiated later in the po-
ting epoxies, but also can undergo reaction leading lymerization. The polymerization product is therefore
to covalent linking between the copolymer micro- a complex mixture of random copolymers with dif-
structure and the cross-linked epoxy resin. The ferent monomer compositions and different molecular
polyisoprene block is immiscible and so drives the weights. For living radical systems, all chains are
formation of a nanoscopic phase separated structure initiated at the same time and grow at approximately
and leads to modification of the physical and me- the same rate, as a consequence all of the growing
chanical properties of the thermosetting epoxy. The chains experience the same change in monomer
facile synthesis of 72, which combines reactive epoxy concentrations. As a result the random copolymers
functionalities with both a block and random copoly- have approximately the same composition coupled
mer structure, demonstrates the far reaching poten- with a low dispersity of molecular weights. This is
tial of living radical procedures. depicted graphically in Scheme 25; however, it should
Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3679
Scheme 24
Scheme 27
ability of coupling also increases. For example, a (Scheme 29).187a One interesting facet of this polym-
mixture of styrene and p-chloromethylstyrene can be erization is that the hyperbranched polystyrene
polymerized under “living” free radical conditions to derivatives contain numerous initiating centers. These
give a well-defined linear copolymer, 79, with con- numerous initiating centers have been used to form
trolled molecular weight and low polydispersity (ca. a unique class of star macromolecules in which the
1.10-1.25). Reaction of 79 with the sodium salt of central core is a highly functionalized hyperbranched
the hydroxy functionalized unimolecular initiator polymer. Subsequently, Fréchet187b and Matyjasze-
then gives the desired polymeric initiator 80 which wski188 have applied a similar technique to the
is a precursor to a variety of graft copolymers, 81.185 preparation of hyperbranched polystyrene derivatives
At average grafting densities of greater than six by the homopolymerization of p-chloromethylstyrene
initiating sites per backbone, chain-chain coupling using ATRP conditions, though the actual structure
becomes apparent by GPC, and at densities greater of the materials obtained seems to be variable.189
than 15, it is a major process (Scheme 28). The synthesis of these highly branched star poly-
mers has recently attracted much interest and a
B. Hyperbranched and Dendritic Structures variety of simplified approaches have been reported.
As demonstrated by Fréchet186 in the development While Yang190 has discussed the use of mediating
of self-condensing polymerizations, the ability to form nitroxides, which contain a polymerizable double
reactive unimolecular initiators, such as 82, opens bond and therefore lead to branch points, the major-
up a number of avenues to unusual macromolecular ity of work has centered on the coupling, or knitting
architectures that are either difficult, or impossible, together, of preformed linear chains by reaction with
to prepare using traditional free radical chemistry cross-linkable monomers, a technique which has been
or living anionic procedures. In the case of the extensively used in anionic and cationic procedures.
styrenic derivative 82, a propagating center and an One of the attractive features of this approach, which
initiating center are combined in the same molecule is unique to living radical systems, is that the start-
to effectively create a self-condensing monomer, ing linear chains, 85, can be isolated, characterized
which is similar to AB2 monomers used for the and stored before subsequent coupling. Additionally,
preparation of hyperbranched and dendritic macro- a variety of different chains in terms of molecular
molecules by condensation chemistry. Homopolym- weight, composition, etc. can be copolymerized to-
erization of 82 under “living” free radical conditions gether to give heterogeneous star-block copoly-
was shown to lead to initial formation of dimers, mers.191,192 The basic strategy is outlined in Scheme
trimers, etc. and eventually hyperbranched macro- 30, and involves the preparation of alkoxyamine
molecules, 83, with the kinetics of growth resembling terminated linear chains 84 and subsequent coupling
a step-growth polymerization even though the po- of these dormant chains with cross-linking agents
lymerization occurs by a free radical mechanism such as divinylbenzene or a bis(maleimide) deriva-
3682 Chemical Reviews, 2001, Vol. 101, No. 12 Hawker et al.
Scheme 28
Scheme 29 Scheme 30
dendritic initiator 87. Hybrid dendritic-linear block be different to the more traditional small molecule
copolymers, 88, with well-controlled molecular weights nitroxides.
and low polydispersities are then obtained by the This building block, or modular approach to the
reaction of 87 with a variety of styrenic monomers synthesis of complex macromolecular architectures
or comonomer mixtures under living free radical can be taken a step further in the rapid synthesis of
polymerization conditions (Scheme 31).161,195,196 Simi- combburst, or dendritic graft copolymers by a tandem
“living” free radical approach.185,199,200 The underlying
Scheme 31
strategy in this novel approach to highly branched
linear polymers is that each layer, or generation, of
linear polymers is prepared by “living” free radical
procedures and the initiating groups are either
present during the polymerization or introduced in
a post-polymerization functionalization step. In this
way very large, highly branched combburst copoly-
mers can be prepared in a limited number of steps
using mild reaction conditions. As shown in Scheme
32 the initial linear backbone 89 is prepared by
nitroxide-mediated “living” free radical polymeriza-
tion of a mixture of styrene and p-chloromethyl
styrene. At this stage the polymerization mechanism
can be switched from nitroxide mediated to atom
transfer “living” free radical conditions to give graft
copolymers or TEMPO based initiating groups can
be introduced by reaction of the numerous chlorom-
ethyl groups with the sodium salt of 63 to give the
polymeric initiator 91. A second layer, or generation,
of reactive chloromethyl groups can be introduced on
the grafted arms 92 by a second copolymerization of
styrene and p-chloromethylstyrene. This functional-
ized graft copolymer can again be used as a complex
polymeric initiator for ATRP polymerization that
introduces a third layer of linear polymer chains, 93.
In analogy with the divergent growth approach to
dendritic macromolecules, this stepwise functional-
ization/growth strategy can be continued to give
larger and larger combburst macromolecules and the
mild reaction conditions permit a wide variety of
monomer units and functional groups to be used.
The versatility associated with nitroxide-mediated
polymerizations, in terms of both monomer choice
and initiator structure, also permits a wide variety
of other complex macromolecular structures to be
prepared. Sherrington201 and Fukuda202 have exam-
ined the preparation of branched and cross-linked
structures by nitroxide-mediated processes, signifi-
cantly the living nature of the polymerization permits
subtlety different structures to be obtained when
lar structures can also be prepared using ATRP compared to traditional free radical processes. In
chemistry and in this case the initiating group is addition, a versatile approach to cyclic polymers has
simply a focal point chloromethyl, or bromomethyl been developed by Hemery203 that relies on the
functionality.197 While the majority of examples synthesis of nonsymmetrical telechelic macromol-
involve the dendrimer being attached to the initiator, ecules followed by cyclization of the mutually reactive
there is a single instance where it is attached to the chain ends. In a similar approach, Chaumont has
mediating radical. Interestingly, in the case198 where prepared well-defined polymer networks by the cross-
the dendritic block is attached to the nitroxide, the linking of telechelic macromolecules prepared by
molecular weights and polydispersities for the block nitroxide-mediated processes with bifunctional small
copolymers are not as well controlled as in the case molecules.204
where the dendrimer is attached to the initiating
fragment. This difference may be due to the increased
steric bulk of the dendritic nitroxide which would be
IX. Surface-Initiated Polymerizations
expected to decrease its mobility and hence ability The stability of alkoxyamine initiators is not only
to control the polymerization. While a detailed study a major synthetic advantage when compared to more
has not been performed this result may have impor- traditional living polymerization procedures but it
tant implications especially for complex, functional- also permits opportunities in the area of surface
ized nitroxides whose diffusion characteristics may modification. In analogy with the work that has
3684 Chemical Reviews, 2001, Vol. 101, No. 12 Hawker et al.
Scheme 32
subsequently been done in the area of ATRP, func- of nanotechnology. Two examples that capture this
tionalized alkoxyamines were the first example of promise are the preparation of functionalized macro-
living radical initiators, prepared and attached to a porous monoliths for advanced chromatographic sepa-
variety of surfaces and subsequently used to grow rations and the design of “Rasta-resins”. The latter
covalently attached polymer chains. The living nature are especially interesting as ultrahigh capacity sup-
of the polymerization provides an unprecedented ports for combinatorial chemistry which not only
ability to control the structure, density, functionality, utilize the increased functionality or amplification
etc. of the surface attached polymer chains and has afforded by the surface-initiated polymerization con-
rapidly become an area of significant importance and cept (one initiating site leads to numerous reactive
growth.205 Numerous studies have appeared demon- functional groups) but takes advantage of the more
strating the ability to control the degree of polymer- “solution-like” environment of the functional groups
ization or thickness of the grafted polymer chains, attached to the solvated polymer chains when com-
achieve low polydispersities and prepare block co- pared to functionalities at a solid-liquid interface or
polymers. The covalent nature of the surface attach- in a cross-linked resin.208,209 Similar strategies can
ment also allows either the living free radical initia- be performed on alternate particulate substrates such
tors themselves to be patterned or the resulting as silica205 or carbon black210 or via ATRP tech-
polymer brushes to be patterned (Figure 6).206,207 This niques.211
allows the surface chemistry and topology of the The potential for surface-initiated polymerizations
polymer brush to be controlled and this ability to using nitroxide-mediated living free radical proce-
control the placement and structure of vinyl polymer dures is perhaps best illustrated by the direct syn-
chains is an indication of the tremendous potential thesis of dispersed nanocomposities by Sogah and
that both nitroxide-mediated and atom transfer living Giannelis.212 In this approach the synthetic versatil-
free radical polymerizations show in the general area ity of the alkoxyamine group is again exploited to
Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3685
Figure 6. Interaction of a water droplet with 200 micron features of a patterned polymer brush prepared by surface-
initiated polymerization. The unusual wetting profile is due to preferential interaction of the water droplet with the poly-
(acrylic acid) brush domains (light) and complete non-wetting of the hydrophobic poly(tert-butyl acrylate) domains (dark).
prepare the quaternary amine salt 94 which due to to be developed in order to make block copolymer
its chemistry can intercalate readily into the inter- formation a routine procedure for the nonexpert. If
gallery spaces of a silicate or inorganic matrix. These these challenges can be overcome the industrial
“anchored” alkoxyamine groups can now be used to appeal of nitroxide-mediated living free radical pro-
initiate the polymerization of a vinyl monomer such cedures will increase significantly, while also provid-
as styrene leading to a dispersed silicate nanocom- ing an extremely powerful synthetic technique for the
posite. The advantages of this novel approach are synthesis of vinyl based polymers.
that the intercalation of small initiating species such The power of living free radical procedures as
as 94 is orders of magnitude faster than for similar synthetic tools in polymer science can be better
chain end functionalized polystyrene derivatives. In appreciated by considering the potential advantages
addition, critical polymer characteristics such as when compared to traditional techniques such as
molecular weight and polydispersity are controlled anionic polymerization. The ability to accommodate
while block or random copolymer formation is pos- functional groups and diverse families of monomers
sible (Scheme 33). permit block, random, and gradient copolymers to be
prepared without complicated, multistep reaction
X. Outlook schemes. Complex macromolecular architectures can
Even though the first reports of a successful living also be prepared, however, the low occurrence of
radical process leading to high molecular weight radical-radical coupling reactions does place restric-
(>30 000), low polydispersity (1.1-1.2) materials tions on the number of propagating arms per mac-
were published in 1993 the impact on the field of romolecule. The radical nature of the polymerization
polymer chemistry has been immense, opening up process does limit the ability to control the stereo-
possibilities in both polymer synthesis and polymer chemistry; no evidence has been currently presented
physics that until recently were either prohibitively to indicate that living free radical processes can lead
difficult or impossible. The development of nitroxide- to tacticity control. Presumably the generation of a
mediated living free radical polymerizations as an planar radical at the propagating chain end during
important synthetic tool has been extremely rapid each monomer addition step is the key step in this
and poses exciting possibilities for the future. How- loss of stereochemical control.
ever, there are a number of issues that must be Another significant advantage of living free radical
addressed to enable the continued evolution of this procedures is the stability of the initiating species.
new technique. A greater understanding of the In the case of nitroxide-mediated processes, the above
relationship between nitroxide/alkoxyamine struc- discussion clearly demonstrates that a variety of
ture and polymerization efficiency needs to be devel- chemical transformations can be performed with no
oped. Specifically, mediating nitroxides or strategies deleterious effect on the initiating ability of the
must be developed which allow the polymerizations alkoxyamine initiator. Not only does this significantly
to be conducted at lower temperatures (ca. 60-80 °C) improve the ability to prepare chain end labeled
in shorter time periods (2-5 h) and with higher macromolecules but also permits initiating fragments
conversions (ca. 99%+). It is also highly desirable to to be introduced at various surfaces, interfaces, chain
further increase the range of monomers that can be ends of dendrimers, along the backbone of a linear
polymerized under living conditions, prime candi- polymer chain, etc. As more and more effort is
dates are methacrylates and vinyl acetate based devoted to controlling structure and function on the
monomers. Finally a complete understanding of block nanometer scale, the role of well-defined polymeric
copolymer formation, reinitiation efficiency, etc. needs materials with controlled size, dispersity and func-
3686 Chemical Reviews, 2001, Vol. 101, No. 12 Hawker et al.
XIII. References
(1) Moad G.; Solomon D. H. The Chemistry of Free Radical Polym-
erization, Pergamon: Oxford, England, 1995.
(2) Quirk, R. P.; Kinning, D. J.; Fetters, L. J. Comprehensive
Polymer Science; Aggarwal, S. L. Ed.; Pergamon Press: London,
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(3) Sawamoto M.; Kamigaito M. CHEMTECH 1999, 29, 30-38.
(4) Malmstrom, E. E.; Hawker, C. J. Macromol. Chem. Phys. 1998,
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(5) Matyjaszewski, K. Controlled radical polymerization; Matyjas-
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(169) Stehling, U. M.; Malmstrom, E. E.; Waymouth, R. M.; Hawker, (202) Ide, N.; Fukuda, T. Macromolecules 1999, 32, 95.
C. J. Macromolecules 1998, 31, 4396. (203) Lepoittevin, B.; Perrot, X.; Masure, M.; Hemery, P. Macromol-
(170) Tsoukatos, T.; Pispas, S.; Hadjichristidis, N. Macromolecules ecules 2001, 34, 425.
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Chem., Int. Ed. Engl. 1997, 36, 270. (205) Husseman, M.; Malmström, E. E.; McNamara, M.; Mate, M.;
(172) Bosman, A. W.; Fréchet, J. M. J.; Hawker, C. J. Polym. Mater. Mecerreyes, D.; Benoit, D. G.; Hedrick, J. L.; Mansky, P.; Huang,
Sci. Eng. 84, 376, 2001. E.; Russell, T. P.; Hawker, C. J. Macromolecules 1999, 32, 1424.
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Veregin, R. P. N. Macromolecules 1997, 30, 2228; Bouix, M.; (209) Lindsley, C. W.; Hodges, J. C.; Filzen, G. F.; Watson, B. M.;
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R. F.; Malmstrom, E. E.; Ito, H.; Hawker, C. J. Organic Thin CR990119U
Chem. Rev. 2001, 101, 3893−4011 3893
Roger Adams Laboratory, Departments of Chemistry and Materials Science & Engineering, The Beckman Institute for Advanced Science and
Technology, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801; Department of Chemistry, Macalester College, 1600 Grand Avenue,
St. Paul, Minnesota 55105; and 3M Adhesive Technology Center, 3M Center, 201-3N-04, St. Paul, Minnesota 55144
Thus, the motivation for developing new chain in solution, the structures of which are stabi-
molecules that adopt ordered solution conformations lized by a collection of noncovalent interactions
can be stated as an attempt to gain deeper insight between nonadjacent monomer units. There
into the fitness of nature’s biomacromolecules and to are two major classes of foldamers: single-
identify new polymers that perform functions that stranded foldamers that only fold (peptidomi-
are, at least in part, outside of those seen in nature. metics and their abiotic analogues) and mul-
Toward these goals, chemists have endeavored to tiple-stranded foldamers that both associate
intentionally generate unnatural oligomeric se- and fold (nucleotidomimetics and their abiotic
quences that take on well-defined conformations in analogues). Before discussing this definition in
solution. This subject has come to be known as the detail, let us briefly reconsider high molecular weight
field of foldamers.3 This review covers the literature biomacromolecules. We imagine that a foldamer will
relevant to foldamers, as specified below, through not be a very good mimic of a biomacromolecule. In
July 2001. Progress to date has been encouraging, other words, there is something beyond foldamers.
and the field is developing rapidly as demonstrated This “something” is perhaps a high molecular weight
by the various architectures that have been gener- polymer that consists of a collection of foldamers, just
ated, schematically represented in Figure 1. Yet, as proteins can be viewed as a collection of secondary
today we are still far from producing high molecular structures. To clearly distinguish a foldamer, as
weight polymers that mimic the sophistication of defined above, from this higher molecular weight
biomacromolecules, either in form or function. “something”, we suggest the term tyligomer. Tyligo-
A foldamer has previously been defined as “any mer is derived from tyligos, meaning “to fold”, and
polymer with a strong tendency to adopt a specific, meros, meaning “part” (i.e., a structure consisting of
compact conformation”.4 Upon inspection of the folded parts). Thus, foldamer relates to an element
literature, we thought this definition was in need of of secondary structure, in the same way that tyligo-
clarification. First, the “foldamers” described in the mer relates to a tertiary or quaternary conformation.
literature are not polymers; they are oligomers. Let us now examine our definition in detail, since
Second, the word “compact” is ambiguous and in- this has been used to limit the scope of this review.
vokes high molecular weight globular proteins, unlike First, a foldamer is a chain molecule, meaning that
the smaller segments of secondary structure typical there will almost certainly be a regularly repeating
of this area. Third, a crucial aspect of chain confor- motif within the backbone. Second, foldamers are of
mation is its dynamic character, which in the case oligomeric (not polymeric) size, consistent with the
of foldamers is manifested in the context of folding recent literature. Third, the verb in our definition is
and unfolding. Specifically, the “folding reaction” is “to fold”, which conveys the dynamic character of
the process that transforms the conformationally conformation, i.e., the folding reaction. Oligomers
disordered oligomer into a conformationally ordered where no folding reaction can occur, such as heli-
state, which corresponds to a small set of nearly cenes,5,6 cannot be considered foldamers (Figure 2a).
congruent conformations. The folding reaction also assumes that the associa-
Our definition of a foldamer is any oligomer tion of multiple foldamer strands involves a similar
that folds into a conformationally ordered state type of entropy loss as folding. Fourth, when folded,
3896 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
suggest that descriptions involving the verb “fold” present in the folded state or not. There are, however,
should be reserved for conformationally defined chain several issues unique to tyligomers which mirror the
molecules and not be used for polymeric mixtures. more complex issues of the long-standing protein
For example, a compact polymeric micelle certainly folding problem34 and which will be treated below.
exists in multiple lowest energy conformations but Since a goal of the field is to endow synthetic
should not be considered to adopt folded conforma- foldamers, and eventually tyligomers, with the struc-
tions. tural (and functional) specificity reminiscent of fold-
Overall, it is the purpose of this article to present ing biopolymers, the theoretical models that describe
a thorough review of foldamer research contained these phenomena should be considered.
within our definition. A survey of what is involved To rationally design a foldamer, it will be necessary
in the generation of foldamers is in order first, to understand the properties of known foldamers,
followed by a discussion of specific contributions to which are those secondary-structure domains of
the field of foldamers. sequence-specific biopolymers that have been meta-
bolically synthesized by living organisms, i.e., pro-
II. Generating FoldamerssDesign, Synthesis, teins, nucleic acids, and oligosaccharides. Each of
Purification, and Characterization these biopolymers derives its function from a confor-
mationally well-defined folded state, which for pro-
The foundation for foldamer research was laid in teins is usually called the “native state”.30 The
the early 20th century, during the rise of modern process of going from a large ensemble of extended
synthetic polymer chemistry,31 molecular biology, and conformations to this folded state is called the folding
more recently through supramolecular chemistry.16 reaction,35 and elucidating the general mechanism of
Upon examination of these disciplines, it becomes this reaction involves the identification of the critical
clear why and how modern foldamer research has thermodynamic and kinetic parameters. It will then
evolved into a stimulating scientific field. It is hoped be instructive to relate these parameters to the
that the lessons learned in the roots of the foldamer properties of unnatural synthetic oligomers that can
field can be brought to bear upon the problems of be adjusted by the synthetic chemist.
designing, creating, and evaluating foldamers and, Three issues shared with the field of protein folding
eventually, biomimetic tyligomers. Before reviewing must be dealt with to make the design of foldamers
the current state of the field of foldamers, a summary possible: foldability, structure prediction (reverse
of various aspects impacting foldamer design will be engineering), and designability (forward engineer-
presented. ing). The first of these refers to an individual chain’s
ability to fold to a unique structure or a set of closely
A. Foldamer Design related structures; a chain that does so efficiently is
Since the initial use of the term “foldamer” in said to have a high foldability. The second issue deals
1996,32 the field has witnessed several design ap- with the ab initio determination of the folded state
proaches. We begin by clarifying the context in which structure given the primary sequence structure. The
we use the word “design”. Our use of this word will third issue, designability, refers to the number of
be in the same sense as “building a house”schoosing these chains that will fold to a particular structure
raw materials, mapping out the blueprint for the of interest; a folded structure that can be formed by
structure, constructing the necessary subunits into many different, highly foldable sequences is said to
the final framework, and performing interior decora- have a high designability. By the very nature of their
tion. Gellman’s daunting steps4 to generate useful length, short oligomeric chains participate in rela-
foldamers echoes this analogy: determining novel tively short-range intrachain contacts and as a result
backbones that can fold, developing efficient synthetic usually form structurally simple folded states that
methods and integrating chemical function. Of course, are straightforward to design. Longer chains are
it is presumptuous for the authors to profess knowl- capable of folding into structures with very long-
edge of how published foldamers were initially con- range interactions, making design more difficult
ceived. Rather, we intend to detail the logical thought because of the large number of potential contacts. The
processes that must necessarily be considered in the foldability of tyligomers has been treated analytically
generation of a successful foldamer.33 and by simulations of simple models. Although some
progress has been made, the best methods for ab
The broad philosophical foundations of foldamer
initio determination of a long sequence’s folded
design draw on concepts developed over the past
structure have been worked out in essentially taxo-
decades in the fields of polymer physics, condensed
nomic ways for the most well-studied biopolymer,
matter physics, and, in particular, biophysics. It is
proteins.36,37 Designability has been investigated but
evident that oligomeric foldamers are not large or
only for very simple systems. The fundamental idea
complex enough to form anything other than simple,
that emerges from these models is that some struc-
secondary structures such as helices or sheets. A
tures are much more designable than others.
clear logical next step in the field would be to design
larger, more complex chain molecules capable of 1. The General Folding Problem
folding into truly tertiary structures or structures
having long-range intrachain energetic interactions.4 Consider an oligomer or polymer chain consisting
The designs of both simple and complex systems of N monomer units, each having ω torsionally
share many features, and much of the discussion accessible conformations. The parameter ω is de-
below will be general whether tertiary structure is pendent on the rigidity of the chain backbone and is
3898 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
equivalent to the number of minima on a Ramachan- contacts or unfavorable chain-solvent forces. For
dran-like surface for the backbone repeat unit. This oligomers containing residues that are poorly sol-
chain has ωN accessible conformations, neglecting vated, collapse to a set of compact conformations can
those conformations that are inaccessible as a con- occur before the folded state is populated. In a
sequence of the chain folding back upon itself in a protein, the minimization of the solvophobic force
sterically prohibitive manner (the so-called excluded- between apolar residues and polar solvent, namely,
volume conformers). This simple calculation gives an water, lowers the free energy of the protein-solvent
overestimation of the total number of conformations system and is the primary driving force for col-
but does accurately reflect the magnitude of the lapse.40,41 This collapse minimizes the unfavorable
number of states. For polypeptides, ω has been solvation interactions and maximizes whatever fa-
determined to be between 2 and 3.38 The exponential vorable intrachain interactions exist, typically involv-
ωN rapidly becomes very large with increasing chain ing electrostatic and van der Waals forces. There is
length, to the point of being unimaginably large for usually a gain in entropy for the solvent, since a
a chain that would be capable of performing any sort higher degree of solvent ordering around the chain
of chemically or biologically significant function. As segment is required to solvate solvophobic segments
mentioned previously (Figure 2), oligomers may than would be required to solvate solvophilic seg-
appear to be folded but in fact lack a folding reaction ments. The solvophobic collapse is then caused by a
because ω is roughly equal to 1. Such oligomers have free energy gradientshaving both entropic and en-
very few minima on their overall potential energy thalpic originsstoward states whose structures have
surface, since ωN is very small for all values of N. a minimum of solvophobic segment-solvent contacts.
For an oligomer to populate a small subset of the In the absence of any bias toward an energetically
ωN conformations, this folded state, F, must have an preferred folded state, this collapse will result in a
energy that is much lower than the unfolded state, random ensemble of compact conformations. For a
U. This must be the case if the lowest energy chain that is able to fold reliably to a single folded
conformations are able to dominate the equilibrium state, the mechanism of folding is essentially a
mixture of conformers. The thermodynamics of the question of how the system loses entropy en route to
folding reaction are controlled by two main factors. the folded state. Two mechanisms of efficient overall
The unfolded state must lose the conformational entropy loss can be imagined. Initial collapse to the
entropy present in its much larger conformational ensemble of compact conformations could be followed
by a search through that ensemble to find the folded
ensemble in order to realize the enthalpic gain
state or the collapse could take place concurrently
present in the folded state. Multistranded systems
with the formation of folded structure. Both types of
are more complex since they must also lose some
behavior are observed for real biopolymers,42 and a
translational and rotational entropy upon association
general picture of oligomer folding must take both
as well as chain conformational entropy. Yet, their
scenarios into account.
thermodynamics are similar. The thermodynamic
properties observed in biological folding reactions can Especially for long chains capable of tertiary struc-
be reproduced by a simple model having a single ture formation, it should also be noted that not every
folded structure separated from U by an energy gap, sequence that has a nondegenerate global minimum
illustrated in more detail below. To reach its lowest spontaneously folds to a unique state. A parallel can
energy state, an oligomer will have to maximize its be drawn between the folding process and the con-
favorable energetic interactions and minimize those densation of individual molecules during crystalliza-
that are unfavorable, including both intrachain and tion or the condensation of atoms to form clusters.
chain-solvent interactions. The existence of an op- Just as there are some solid materials that crystallize
timized set of unfavorable and favorable contacts in quite efficiently, there are those that do not relax to
the folded state has been called the “minimally their global thermodynamic minimum but form
frustrated” state.39 glasses instead.43,44 These glasses are formed when
the entropy loss occurs faster than the loss of energy
Noncovalent interactions involve much weaker and or equivalently when the barriers to interconversion
reversible interactions than covalent linkages, which between different conformations begin to dominate
allows for the exploration of many chain conforma- the kinetics of relaxation. Likewise, well-designed
tions during the folding reaction. The net strength tyligomers efficiently find their folded state, while
of the nonadjacent contacts that determine the most random sequences do not fold to a unique
thermodynamics of folding are essentially the differ- structure but rather merely collapse to a ‘molten
ences between the strengths of the chain-chain and globule’ state or a unimolecular glass.
the solvent-chain interactions. Undoubtedly, if sol- What then is required of a chain to fold reliably?
vent-chain contacts are stronger than chain-chain Does the chain have a minimum energy state that is
contacts, the molecule will not fold; such is the case much lower in energy than the rest of the unfolded
in denaturing solvents. A subtle balance then exists conformations U? If so, is this folded state thermo-
in solvent-foldamer interactions; the solvent must dynamically accessible from U at temperatures and
solvate the molecule without competing for nonad- other conditions that allow characterization and
jacent contacts while providing the chain with an perhaps function? For longer chains capable of many
environment in which to undergo the folding reaction. more contacts and potentially tertiary structure, is
The formation of unique, folded structures requires this transition kinetically accessible? Beyond predict-
the presence of favorable nonadjacent chain-chain ing the existence of a folding reaction, what do the
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3899
( )
consists of a chain of different residue types that are P(F)
constrained to the points of a lattice. Nonadjacent ∆Gfolding ) -kT ln Keq ) -kT ln )
interactions are accounted for by assigning energies P(U)
to neighboring lattice points occupied by residues + kT ln 3 (3)
that are not adjacent in the sequence.
Varying degrees of heterogeneity can be modeled Alternatively, the free energy of folding can be
by including any number of residue types and as- derived by considering the ∆H and ∆S of the reaction.
signing energy values to the different pairs of neigh- The enthalpy change is clearly . The loss of entropy
boring nonbonded residues. In the simplest version can be calculated by taking the sum of the loss of
of the model (the so-called HP model) a two-letter entropy of each chain segment. As each segment has
alphabet is employed, where H represents a solvo- ω conformations available, the sum of the entropy
phobic monomer and P represents a polar, or solvo- lost over the whole N-long chain is approximately -k
philic, residue. The choice of a two-letter code reflects ln(ωN) or -kN ln ω. At constant pressure and volume,
and models the importance of the solvophobic col- it then follows that the free energy change is given
lapse of proteins as a key step in the folding process. by eq 4.
Lattices with 2-D square, 3-D cubic, and even 2-D ∆G ) ∆H - T∆S
hexagonal geometries have been employed by differ-
ent groups; some of this work will be described in ∆G ) + kTN ln ω (4)
later sections. An excellent review of these models
by Chan and Dill46 describes the picture they have It should be noted that this formulation has been
provided of biopolymer folding. used to experimentally estimate the entropy lost per
Consider the tetramer toy model (TTM),46 which chain segment and thus the average number of
is a 2-D square lattice chain consisting of two types conformations available to each residue. Eq 4
of monomers, H and P (Figure 3). This is perhaps suggests that there exists a folding temperature at
the simplest model that still captures many of the which the population is evenly divided between
3900 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
the folded structure if the system is to fold on a the energy gap is already enhanced by the high
reasonable time scale. symmetry of secondary structures. For instance,
It is conceivable that the unreasonably long search helices offer a minimally frustrated way of packing
time predicted by Levinthal could be reduced by side chains to avoid unfavorable van der Waals forces
decreasing the number of conformations involved in while maximizing some favorable intrachain con-
the random search. Discarding the conformations tacts, often hydrogen bonds. Small helices and sheets
whose chains fold back on themselves and are are thus well-designed folders, because of the smooth-
therefore sterically disallowed reduces the number ness of the FES and their energy gaps. Their thermo-
of conformers from 1060 to 1043 for a 2-D square lattice dynamics are very similar to those for the golf-course
100-mer,50,51 a number that still requires an unreal- model, as reflected in the similarity in the overall
istic amount of search time.52 topology of the two funnels.
If, however, the number of compact structures 2. Foldamers: Secondary Structure
(those present after a solvophobic collapse) is con- Since many of the foldamers described in this
sidered, the size of the search drops further to 1017 review have helical folded structures, the FES as well
conformers,53 a much smaller number but one that as the thermodynamics and kinetics of folding to a
is still too large for a truly random search to approxi- helical geometry will be considered in some detail.
mate real folding times. While the collapsed ensemble It should be noted that sheets, having regions of
is still too large, it should be noted that the process segments of the same dihedral angles, are themselves
of collapse reduces both the entropy and enthalpy of helices or bundles of two or more interacting helices.
the system. This suggests a possible solution to As a result, the mechanism of sheet folding is related
Levinthal’s paradox. Certain FESs can be described to that for helices. It involves potential cooperativity
as funnels in which the energy generally decreases in two dimensions, both along the strand and be-
as the structure more closely resembles that of the tween strands.55,56 As it is slightly more complicated,
folded state. Just as importantly, this lowering of the it will not be treated in detail.
energy is accompanied by a concurrent loss of en- a. Folding of Helices: Thermodynamics of the
tropy. That is, the width of the funnel narrows and Helix-Coil Model. Since the FES that describes
the energy goes down as the folded state is ap- helix folding, the smooth funnel, is topographically
proached. Tyligomers must have FESs that are similar to that of the golf-course landscape, it rep-
funnel-like, such that the overall free energy gradient resents a cooperative transition. There exists one
favors movement of the system toward the folded transition between the higher energy unfolded state
state from any starting geometry or point of the and the lower energy folded state. The statistical
multidimensional FES. thermodynamics of the helix-coil transition were
e. The Funnel Picture. For those systems with first described by Zimm and Bragg57 as a one-
FESs resembling that in Figure 5c, that is, rugged dimensional problem. Cooperative phase transitions
surfaces with many deep minima and no single can be described in terms of a nucleation/propagation
dominant folded state, any cooling will simply result model,58 a description of which follows.
in relaxation to the nearest well. If the temperature Consider an oligomer that forms a helix with Ni
becomes low enough, the interconversion between segments per turn, again with ω conformations
these traps, or other deep minima structurally dis- available to each chain segment. If the favorable
tinct from the folded state, will become very slow, intrachain contacts each contribute an energy to
even if one state is lower in energy than all the rest. the system (usually called H because a hydrogen
Such conditions would lead to the observation of non- bond is often responsible), the change in entropy and
Arrhenius kinetics, as is observed for some polypep- energy for each step of helix formation can be
tides.54 When this interconversion is slowed to the considered. Since each conformational choice along
point that it is effectively nonexistent, a glass transi- the chainshelical or nonhelicalsis dependent only
tion has taken place. At this point, it becomes very on the immediately previous step, the problem is
unlikely that the folding reaction, or indeed any essentially one-dimensional. That is, the free energy
further progress toward a global minimum structure, change of a residue as it progresses from a random-
will proceed any further. Most folding biopolymers coil geometry to that of the helix is dependent only
lie between the two extremes of the flat, rugged on the state of its neighbors. Figure 6 shows ∆H (∆E)
landscape and the smooth funnel, thereby exhibiting and ∆S for the coil-to-helix change for a segment
a range of thermodynamic and kinetic behaviors. adjacent to a helical segment and to a coil segment.
For systems with smooth funnel FESs such as that Each situation involves the loss of kB ln(ω) confor-
in Figure 5b, a cooling of the system will lead mational entropy. Only when Ni + 1 adjacent helix
smoothly and rapidly to a relaxation to the bottom segments are formed does the system gain the
of the funnel. Such is the case for reliably folding interaction energy. Thus, for the first Ni coil-to-helix
helical oligomers. Again, small oligomers are more steps, there is a total loss of entropy of NikB ln(ω)
likely to have smooth funnels because shorter chains but no gain in energy; this is called the nucleation of
have fewer nonadjacent interactions that can con- helix formation. Once this helix nucleation has oc-
tribute to ruggedness. The FES of an oligomer can curred, each subsequent conversion of a segment
be considered as a small section of a polymer’s FES from coil to helix geometry, i.e., propagation, involves
that immediately surrounds the folded state. Thus, the loss of kB ln(ω) entropy and a gain of energy .
the only ruggedness present in the oligomer FES will The free energy change in going from a random coil
be that present near the folded state. Additionally, to a helix where n is the number of segments in the
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3903
Figure 6. Helix-coil transition. (top) The initiation and propagation steps and their attendant changes in enthalpy and
entropy. (lower left) The free energy of folding as a function of chain length, and (lower right) the sharpness of the transition
as a function of chain length.
helix minus the number required to form the first structure of the segments, but since it is a free energy
turn is given by eq 6 and is plotted in the lower left it may also be changed by the environmental factors
of Figure 5. over which the free energy is evaluated. For instance,
if the interaction arises from a solvophobic force, it
∆Gn ) ∆Gnuc + n(∆Gprop) ) can be made stronger by making the solvent more
NikT ln ω + n(kT ln ω - ) (6) polar. Likewise, a hydrogen bond interaction can be
made stronger by making the solvent less polar or
weaker by adding competitive, protic solvents. Chang-
There is a free energy cost upon folding until the ing the net strength of the intrachain interactions
chain reaches a length at which the enthalpic gain shifts the folding temperature; this is the principal
of the intrachain interactions outweighs the entropic underlying solvent denaturation experiments. Rather
cost of constraining the chain in the folded conforma- than changing the temperature while keeping
tion. It can then be seen that a cooperative transition constant, the reverse may be done in order to see the
takes place when the change in free energy between transition.
helix and coil states becomes negative at the folding
temperature, Tf (eq 7). The sharpness of this transi- Foldamers that adopt helical conformations are
tion is dependent on the number of residues required reliable folders because they lie on a smooth funnel
for initiation, as can be seen from eq 2 and is shown FES. The folding to these highly symmetrical struc-
in the lower right of Figure 6. tures can be described by the two parameters and
ω, both of which can be controlled by the foldamer
n chemist in the design of the oligomer.
Tf ) (7) b. Folding of Helices: Kinetics. Since helices
(Ni + n)k ln ω
have experimentally been shown to fold on a time
scale in the milliseconds to microseconds,59,60 there
These quantities are often cast in the form of an
do not seem to be serious kinetic issues that must be
equilibrium constant, with σ and s representing the
considered in their design. This is consistent with a
equilibrium constants for the nucleation and propa-
smooth-funnel FES, with little ruggedness to slow the
gation steps, respectively (eq 8)
progress of the system down the funnel to the folded
state. There is some evidence that the little rugged-
Keq ) e-∆G/kT ) e-Nilnω(e/kT e-lnω)n ) σsn (8) ness present does lead to the presence of folding
intermediates for some helices,61,62 and in some cases
where σ ) ω-Ni and s ) e/kTω-1. the pathways between these intermediates can be
Zimm and Bragg showed that the fraction of enumerated,63 but in general the folding should be
segments in a helical conformation exhibits a sharp rapid enough that (a) changes in the design will make
cooperative transition as s is increased, which is only small differences in the absolute folding rates
equivalent to increasing the interaction energy or and (b) small helices with a thermodynamic propen-
decreasing the temperature. The interaction energy sity to fold will do so rapidly enough to demonstrate
is designed into the system based on the chemical ideal foldamer properties.
3904 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 8. Energy spectra (density of states) for several in Figure 8 are taken into account, it is possible to
3-D 27-mer HP heteropolymers and the fraction of MC runs imagine a system that becomes trapped in a non-
which resulted in folding. Larger energy gaps lead to native state, below the glass transition temperature,
greater foldability. (Adapted from ref 48.) even if the folded state lies far below the trap. The
kinetics and thermodynamics of rugged folding fun-
compact homopolymer conformations69 and suggests nels have been analyzed by Wolynes and co-workers73
that the formation of highly symmetric secondary using a random energy model (REM) developed by
structures is not sequence-specific nor only a property Derrida.74 The large number of states and pathways
of reliable folders. The existence of these locally between the states complicates a complete, explicit
organized low-energy structures suggests a self- analysis of the free energy surface but is well-suited
similarity of the FES that enhances its funnel-like to a statistical description.
shape even if helices or sheets that are not present The key assumption of the generalized random
in the folded state are formed during folding. energy model is that the energies of any two confor-
Similar studies were performed on 3-D 27-mer HP mations are independent of each other. This leads to
heteropolymers,48 but because of the much larger a distribution of states that can be described as a
number of possible conformations, the sequence space Gaussian function. This approximation can be made
was sampled randomly. The likelihood of folding for less stringent by assuming that there will be some
several randomly generated sequences was evaluated correlation of energies, which will be dependent on
by measuring the number of random Monte Carlo the proximity of the two conformations to the folded
steps required for the sequence to find the folded structure. This similarity measure, called Q, is a
state.70-72 Figure 8 represents the energy spectra of function of certain internal geometrical coordinates
several of these sequences and the folding efficiency, of the foldamer that describe the folded state, such
which was measured as the fraction of MC runs that as those between nonbonded residues that become
led to folding. Each individual line represents an proximate after folding. The rugged funnel, shown
individual conformation and its height the energy of in Figure 5e, is intermediate between the completely
that structure. Degeneracy of conformations is rep- rugged surface, shown in Figure 5c, and the smooth
resented by the dense packing of states, which appear funnel, shown in Figure 5b. The parameter Q on the
as regions of solid continuum. It can be seen that rugged funnel roughly indicates the energy of a
although each of the sequences had a nondegenerate conformation arising from the smooth funnel com-
ground state, only those with a large energy gap were ponent. The closer Q is to 1, the more the conforma-
reliable folders. Again, this indicates that a large tion resembles the folded state and the lower the
energy gap, which will be referred to below as δEs, energy will be in general. Within each strata of Q on
between the native state and the rest of the non- the funnel, however, the energy level distribution will
native states is at least necessary if a chain is to fold. be given by a Gaussian function, in that it represents
b. The REM Analysis of the Rugged Funnel. the smooth funnel component of the FES (Figure 9).
It has been noted that the stability gap alone does This density of states, or the probability that a given
not indicate whether a polymer will fold. If the state will have a structure parameter Q and an
barriers to interconversion between the states shown energy E, is given by eq 9. Here E(Q) is the average
3906 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
P(Q,E) )
1
x2π∆E2(Q)
exp -{ [E - E(Q)]2
2∆E2(Q) } (9)
x
∆E2(Q)
x
Tf δEs 2k
Tg(Q) ) (13) ≈ (14)
2kSo(Q) Tg ∆E So
Below this temperature, the system becomes It should be noted that reducing the ruggedness
trapped as the barriers to interconversion between measure (∆E)2 to zero gives the same result as that
states become thermodynamically insurmountable. obtained for the smooth funnel that models the
The larger the roughness of the surface, represented folding of a helix. The possibility of another transi-
by the width of the Gaussian that describes the tion, the glass transition, reveals the complexity
energy distribution function, the higher this Tg possible in the tyligomer folding mechanism. Tyligo-
occurs. Thus, the roughness of the surface can be mers with particularly smooth FESs may never
identified as another parameter that determines the encounter this second-order phase transition and
foldability of a chain because it is this roughness that exhibit simple and cooperative Arrhenius kinetics. As
determines how likely the chain is to become frozen the ruggedness is increased, the likelihood of encoun-
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3907
kinetically accessible from the unfolded ensemble. simulations have demonstrated that not all struc-
The rigorous approach is to simulate the folding tures are equally designable. An exhaustive enu-
funnel, which involves determining the energy gap meration of all of the possible 3 × 3 3-D lattice two-
and the ruggedness. Finding the magnitude of the letter alphabet structures and sequences was per-
energy gap requires the identification of the global formed.102 All of the sequences that had a high
minimum, the folded structure, which has been foldability were considered, and it was found that
proven in information theory to be an NP-hard there were some structures to which many sequences
problem. That is, there does not exist an algorithm folded and some structures to which no sequences
with a difficulty and average time of completion that folded. Earlier studies of 2-D lattices revealed the
scales polynomially with the size of the problem. same result.103 These structures that kept turning
Thus, essentially the only way to ensure location of up were considered to have a high “designability”. If
the global minimum is to exhaustively search all of one were to try to design a sequence that would fold
phase space, a prohibitively long procedure for the to such a structure, one’s chances of success would
reasons that Levinthal illustrated. However, algo- be relatively high. Additionally, such structures are
rithms have been developed that stand a very good more stable to mutations of the sequence and can be
chance of locating the global minimum, often taking considered more evolutionarily robust.
advantage of the properties of funnels just as real Since there are some structures that are easier to
biopolymers do. Once the global minimum has been design than others, their nature and structural
found as a likely candidate for the folded structure, properties should be considered. These highly design-
the gap can be measured by comparing its energy to able 3-D lattice structures have high symmetry and
the energies of the next lowest lying states. While often have high proportions of secondary structure-
the presence of a sizable gap does not guarantee like motifs.104,105 Thus, there seems to be a correlation
folding behavior, it does favor it, and the presence of between those structures that are highly designable
degenerate states that are not similar in structure and the highly foldable sequences that fold into them.
would be sufficient to screen out a polymer sequence These design principals must be tested for the
as a folding candidate. backbones and structural motifs that are described
The characteristics of the funnel can also be below. We must first learn to design synthetic fol-
measured, and given a knowledge of the ruggedness damers that will simply fold before we can learn to
and slope as a function of Q, the free energy can be design tyligomers that are endowed with the same
determined for each strata of the funnel by the specific functionality found among the biopolymers.
equations given above.100,101 This can be accomplished
by sampling the FES using Monte Carlo algorithms B. Foldamer Synthesis and PurificationsThe
or by sampling during molecular dynamics simula- Chemistry of Oligomers
tions. Once enough structures are sampled for each
As discussed in the Introduction, one goal is the
strata of the funnel, a plot of the free energy as a
generation of high molecular weight tyligomers with
function of Q can be made, which is very reminiscent
discrete chain lengths and primary sequences. Yet,
of a potential energy diagram of the type used to
chemists’ inability to prepare high molecular weight
picture the mechanisms of small molecule reactions.
substances in pure, monodisperse form precludes
Tf and Tg can also be determined from this simulation
data and the likelihood of folding evaluated. their current study. Thus, the field is currently
restricted to the size regime of oligomers. Even here
d. Designing Tyligomeric Folded Structures. the synthetic challenges are significant. It has been
It may be enough to simply show that a single stated, “despite much methodological progress, the
structure can be obtained; if the goal is simply to synthesis and purification of monodisperse oligomers
design a chain that folds, this is sufficient. However, often remains quite tedious.”106 Three approaches to
designing tyligomers that are capable of carrying out heteromeric chain molecules have been developed:
certain functions such as binding or catalysis will step-by-step, iterative, and polymeric growth. Step-
involve the much more complicated task of designing by-step growth is the extension of a chain one
heteropolymers that fold to specific folded structures. monomer at a time and allows for high sequence
Forward engineering is much easier if one knows the control at the cost of slow chain growth. Iterative
rules of design, which can be learned from extensive approaches permit more rapid chain lengthening,
reverse engineering. There has been some progress especially through split pool divergent/convergent
made on the reverse engineering of proteins, that is, methods, while imposing some limits on sequence
the ab initio prediction of protein structure given the control.107 For instance, an orthogonally diprotected
amino acid sequence. Unfortunately, most of this dimer, A-B, can be coupled to a tetramer, A-B-A-
progress has been specific to the polypeptide chemical B, doubling chain length but limiting sequence vari-
system and, as such, is parametrized for these ability. Solid-phase methodologies in foldamer syn-
particular biopolymers. Some theoretical work on this thesis have utilized both step-by-step and iterative
problem has been done, as well as lattice simulations, growth.107-111 The third approach, polymeric growth,
but there are few results that can guide the foldamer provides rapid but statistical chain lengthening to a
designer at present. heteropolymeric mixture with minimal control over
The forward engineering problem may be even length or sequence and, therefore, has been avoided
more difficult for real systems, but there has been for the generation of foldamers. Though modifications
some illuminating work done using lattice models of polymeric growth methodologies to narrow chain-
that helps to identify the challenges involved. Lattice length distribution have been proposed, a reliable
3910 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Table 1. Foldamer-Specific Characterization Techniques, Possible Secondary Structure Data Thereof, General
References Regarding Their Usage, and a Representative Reference, Structure, and Type of Foldamer from Each
Field
3912 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
structure of the backbone repeat unit, thereby casting IV. Peptidomimetic Foldamers
a reasonably wide net of coverage. For these reasons,
we partitioned the literature into peptidomimetics, The field of peptidomimetics aims at mimicking
nucleotidomimetics, and abiotic variations of each. peptide structure through substances having con-
trolled spatial disposition of functional groups. Pep-
D. General Scope tidomimetics have general features analogous to their
parent structure, polypeptides, such as amphiphilic-
Our foremost criterion for inclusion of specific ity. They have been developed, to a large extent, for
examples from foldamer research in this section is the purpose of replacing peptide substrates of en-
as follows: was conformational analysis performed zymes or peptide ligands of protein receptors.128-133
on the molecules in question through studies on Peptidomimetic strategies include the modification
discrete oligomers? We chose “interesting examples” of amino acid side chains, the introduction of con-
from the literature to demonstrate the basic charac- straints to fix the location of different parts of the
ter of foldamer research and have been as exhaustive molecule,134 the development of templates that induce
as possible within this definition of the field. Ad- or stabilize secondary structures of short chains,135,136
the creation of scaffolds that direct side-chain ele-
ditionally, we limited our treatment of more extensive
ments to specific locations, and the modification of
areas to suit the length of this review. While many
the peptide backbone. Of these strategies, systematic
of the following might technically fit our definition
backbone modificationssstructural alterations of the
of foldamers, they will not be covered here: oligo(R- repeat unitsare most relevant to the field of foldam-
amino acid)s, oligo(deoxy)ribonucleotides, simple ers. Backbone modifications may involve isosteric or
ligand-metal complexes, non-oligomeric synthetic isoelectronic exchange of units or the introduction of
receptors,114-119 non-oligomeric chemosensors,120-123 additional fragments. Efficient monomer prepara-
transition-metal-assembled three-dimensional cyclic tions and repetitive synthetic methods for oligomer
nanostructures124 and two-dimensional grids,125 hy- constructions have recently been developed for many
drogen-bonded networks and tapes,118 supramolecu- biologically inspired, unnatural chain molecules.137
lar polymers,33,126 dendrimers,127 and oligomers To summarize progress to date on these systems and
mentioned in the Introduction. We will also not be structurally organize them, a family tree of peptido-
inspecting the abundance of molecules that adopt mimetic backbones is shown in Figure 13, organized
helical conformations only in the solid state, as this from left-to-right by the number of atoms separating
defies our definition of having discrete solution peptide (or peptide-like) units and top-to-bottom by
structure. the functional group classes.
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3913
Figure 16. Oligo(pyrrolinone) backbones linked through the 2,5- and 3,5-positions. The correlation between the 3,5-
linked pyrrolin-4-ones and R-peptide β-strands. The S(6) hydrogen-bonding interaction is indicated in red. N-Methylated
3,5-linked pyrrolin-4-one sequence 1 adopts a helical conformation in the solid state and in solution.
Figure 20. Examples of β-amino acid homopolymers from racemic lactams and the conformational preferences as
rationalized in 1968 by Bestian.189
disubstituted monomer produced a highly stable, on sample preparation, two types of helical structures
insoluble backbone, while the corresponding erythro- were found in the solid state. Fibers pulled from a
disubstituted monomer resulted in a polymer that concentrated solution of chloroform showed hexago-
was much more soluble and had lower thermal nal packing, while chloroform solutions precipitated
decomposition. This was explained189 by the prefer- with ethanol produced a tetragonal crystal habit.
ence for antiperiplanar (ap) torsion angles with the Systematic consideration of the possible helical con-
threo isomer and hence extended chains in this case, formations (Figure 21) led to four models. The tet-
while the erythro isomer was more prone to adopt ragonal crystal was initially thought to consist of a
synclinal (sc) torsion angles. Although detailed struc- right-handed helix in which 4 residues are present
tural studies were not performed, powder X-ray in one turn and hydrogen bonding involves a 20-
diffraction and IR spectroscopic studies supported membered ring. On the other hand, the hexagonal
these assertions. Solubility was a serious problem crystal was initially thought to consist of a left-
that hampered these early investigations. handed helix in which 13 residues are present in 4
In 1984, Fernández-Santı́n et al. reported199 that turns and H-bonding occurs through a 16-membered
poly(S-βAspOiBu), the poly-β-peptide first described ring. Helical conformations were also believed to be
by Yuki,195 does indeed exist in helical conformations stable in helicogenic solvents. Solvent denaturation
when fibers are spun or films are cast from chloro- experiments followed by 1H NMR and solution vis-
form solutions. This work claimed to be the first cosity showed evidence202 of a helix-coil transition
report of helical conformations in a polyamide back- similar to that seen in helical poly(γ-benzyl-L-
bone other than chains of R-amino acids. Depending glutamate).203 However, experimental evidence204 and
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3919
molecular modeling studies205-207 now strongly sup- resembles aspects of protein secondary structure, but
port a right-handed 14-helix (similar to that origi- overall it is quite unpredictable.213
nally proposed by Applequist188) in the hexagonal Although many fewer cyclic β-peptides have been
crystal and a right-handed 18-helix in the tetragonal crystallographically examined in comparison to R-pep-
crystal. Predictions based on matching calculated and tides, a similar conclusion can be made: many of the
observed CD spectra, however, while qualitatively
observed conformations hint at features found in
consistent with helical conformations, are unable to
distinguish between the possible helical conforma- β-peptide oligomers and polymers. For example,
tions.208 systematic studies on cyclic oligomers that incorpo-
rated β-amino acids have revealed that these units
Studies with other poly(β-L-aspartate)s demon- readily adopt turned motifs.214-218 Using molecular
strate that these polymers not only adopt conforma- models, Pavone et al. hypothesized214 that cyclic
tional patterns that are similar to poly(R-amino peptide oligomers containing the β-HGly dipeptide
acids), but that they exhibit greater conformational sequence are able to adopt conformations that permit
versatility. The range of conformations now include
transannular H-bonds between the amide groups of
extended chain structures, arranged as antiparallel
the β-HGly residue. To test this idea and its general-
packings that come about by stretching poly(R-
ity, a variety of cyclic peptides were synthesized and
methyl-β-L-aspartate) films in boiling water.209 In
their crystal structures obtained. Indeed, many turn
solution, the helix-coil conformational transition is
types were observed depending on the number of
a phenomenon common to the whole family of poly-
β-peptide residues, their placement in the sequence,
(R-alkyl-β-L-aspartates).210 The ordered conformation
is responsive to environmental factors such as tem- and the total number of residues in the cyclic
perature and solvent in much the same way as for structure. As a representative example, the structure
poly(R-peptides). of the S(13)S(10)219 containing cyclo-(L-Pro-L-Pro-L-
Phe-β-HGly-β-HGly) is shown in Figure 22.215 A
Methods for the facile preparation of high molec- transannular H-bond between the carbonyl of the
ular weight poly(β-homopeptides) are not common β-HGly and the N-H of Phe is clearly evident.
and limited to specific cases such as poly(R-alkyl-β- Starting from the H-bond donor and tracing through
aspartates). By analogy to the preparation of poly- the β-HGly dipeptide segment to the H-bond acceptor
(R-homopeptides) by ring opening polymerization of (i.e., the thick bonds in Figure 22), it can be seen that
R-amino acid-N-carboxyanhydrides, Cheng and 13 atoms are involved in the H-bond circuit. The
Deming recently attempted to polymerize β-amino
second hydrogen bond circuit involves 10 atoms
acid-N-carboxyanhydrides using either NaOtBu or a
tracing from donor to acceptor through the L-Pro-L-
nickel amido amidate complex as the initiator.211 The
Pro segment. It can be seen from Figure 14 that the
molecular weights achieved were generally low
CR-Cβ bonds of both β-HGly units adopt a gauche
(8 e degree of polymerization e 20) due to precipita-
(i.e., sc) dihedral angle to form corners of the covalent
tion of these poorly soluble macromolecules. The
ring and to orient the H-bond donor and acceptor for
benzyl carbamate-protected oligo(β-homolysine)
adopted a helical conformation in hexafluoro-2-pro- transannular interaction. An example of a crystal-
panol (HFIP). In direct analogy to poly(R-homo- lographically characterized macrocycle that incorpo-
lysine),212 the deprotected oligo(β-homolysine) exists rates a β3-substituted residue is also shown in Figure
in a disordered conformation at low pH due to 22.220 The interesting features of this pentapeptide
electrostatic repulsion. As the pH was raised from are the S(12)S(10) transannular H-bond interaction,
10 to 11.2, a strong Cotton effect was observed, the cis amide conformation, and the sc torsion about
suggesting a transition to a helical conformation. This the CR-Cβ bond (Figure 22). A similar dihedral
transition was shown to be reversible. A similar pH- arrangement is found in many of the β3-peptide
induced transition was found for oligo(β-homo- oligomers as noted below.
glutamate) in aqueous solution. These examples show Seebach and co-workers studied macrocycles com-
that polymerizations can be used as a rapid screening posed entirely of β-amino acid residues.221,222 Three
method to bypass the slow and tedious step-by-step different stereoisomeric tetracycles of β-HAla were
preparation of oligomers. synthesized by cyclization of their pentafluorophenyl
c. β-Peptide Oligomers. Systematic studies on esters. The ease with which β-cyclopeptides were
cyclic oligomers and small β-peptides have provided formed relative to R-cyclopeptides of similar size was
valuable insight into the conformational preferences noted as a tendency for the β-peptide backbone to
of their long-chain linear counterparts. This approach favorably adopt turn structures.221,223 Poor solubility
has been extensively used to study conformations in and high melting points characterized the physical
R-peptides,213 where a wide variety of folded forms properties of these compounds. Their solid-state
has been observed. The geometric constraints in structures, as shown in Figure 23, were determined
cyclic structures greatly reduce the conformational by refinement of powder X-ray data.222 It can be seen
degrees of freedom, thus making it possible to observe that the CdO and N-H bonds are approximately
turns and noncovalent interactions that may other- oriented in a direction perpendicular to the average
wise not be present in small linear analogues. The macrocyclic plane (Figure 23). This in turn leads to
shapes of R-peptides have been described as sinusoi- tubular stacks held strongly together by inter-
dal, saddle, elongated loop, disk, pleated sheet, and molecular C(4) H-bond chains. These H-bond ar-
helical. The general conclusion from crystallographic rangements qualitatively resemble the intramolecu-
studies with small R-peptides is that the folding lar H-bonding motifs in helical β-peptide oligomers.
3920 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 22. Crystal structures of cyclo(L-Pro-L-Pro-L-Phe-β-HGly-β-HGly)215 showing H-bond patterns and another
cyclopentapeptide.220 The β-peptide segments involved in S(13)S(10) and S(12)S(10) transannular H-bonds are rendered
as thick cylinders. Newman projections about the CR-Cβ bonds of the β-amino acid residues show a sc conformational
preference.
Figure 23. Chemical and crystal structures of three different stereoisomeric tetracycles of β-HAla.222
While the studies of Pavone and others with cyclic contribute to a next-nearest-neighbor S(11) H-bond-
peptide oligomers showed that next-nearest-neighbor ing motif (Figure 24).
amides can engage in H-bonding interactions, the It is interesting to consider whether intramolecular
contribution of cyclic constraints raises the question H-bonding interactions or the dihedral preferences
of whether such interactions could readily occur in of the β-peptides dictate the conformations of these
acyclic systems. In 1992, the crystal structure of the short β-peptides. Although this is difficult to decon-
linear tripeptide t-Boc-Aib-Aib-β-HGly-NHMe (where volute from X-ray structures, the importance of
Aib is R-aminoisobutyric acid) was reported, showing torsional bias can be inferred from the crystal struc-
that intramolecular H-bonding interactions form ture of the β-tripeptide t-Boc-β3-HVal-β3-HAla-β3-
even in short chains void of macrocyclic constraints.224 HLeuOMe reported by Seebach in 1996 (Figure
The sc dihedral about the CR-Cβ bond together with 25).223 No intramolecular H-bonds were observed in
the sharp bend at the Aib CR carbon form corners that 3; yet, it is apparent that one of the β-peptide
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3921
Figure 25. Crystal structure of the β-tripeptide t-Boc-β3-HVal-β3-HAla-β3-HLeuOMe (3) reported by Seebach223 showing
an intrinsic preference for a turned conformation. Two of the β-peptide residues are rendered as thick cylinders. The
Newman protections about the CR-Cβ bonds for these residues are shown, indicating the apparent preference of the β3-
substituted residue bearing the bulky substituents to adopt a sc conformation while the residue with the smaller methyl
substituents takes on an ap conformation.
3922 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
were conducive to nearest-neighbor hydrogen bond- structures in protic solvents.227 Given the seemingly
ing. It should be noted that following Gellman’s greater flexibility of β-peptides, one might expect that
studies, the special case of β-peptides synthesized even longer stretches of β-peptide oligomers would
from 1-(aminomethyl)cyclopropanecarboxylic acids be required before stable helices form. However, this
was reported in which nearest-neighbor H-bonding turns out not to be the case. As hinted from the
interactions are observed.226 Hyperconjugation be- observations highlighted above, short β-peptide back-
tween the cyclopropane σ orbitals and the π* orbital bones are poised to adopt ordered conformations. In
of the CdO bond impart preference for the bisected 1996, two groups independently reached this conclu-
or s-cis conformation. This together with bond angle sion: short β-peptide oligomers form surprisingly
deformations caused by the cyclopropyl substituent stable helices in solution and the solid state.32,223
provide sufficient backbone constraints to induce Seebach221,228,229 approached the problem from the
nearest-neighbor S(8) H-bonding, as seen in the context of amide analogues of oligo-(R)-3-hydroxybu-
crystal structures of the β-peptide dimer and trimer tanoates (i.e., oligo-HBs) to address the question of
(Figure 26). whether replacing the oxygen in the HB backbone
d. Helical Secondary Structures in Oligo- with the N-H hydrogen bond donor would stabilize
meric β-Peptides. i. Background and General Con- helical conformations analogous to those observed for
siderations. At least 15 R-amino acid residues are oligo-HBs.230,231 Gellman4 studied hydrogen bonding
required for formation of stable R-helix secondary in model amides and on the basis of their previous
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3923
Figure 27. Side and top views of ca. one turn of the 14-helix extracted from the crystal structure of Gellman’s trans-
ACHC hexamer.239 A single S(14) H-bond circuit in the peptide backbone has been rendered as thick cylinders. Additionally,
one residue has been rendered as a space-filling model to provide a frame of reference between the two views and to more
clearly show the spatial relationship between cyclohexyl groups.
results predicted225 that β-peptide oligomers could ized sequences were also investigated.234 It is increas-
adopt long-range conformational order. ingly clear that functionalization with polar append-
Prompted by questions that arose from structural ages can have a dramatic impact on the secondary
modification of oligo-HBs,221,229 Seebach’s group in- structure.235 Extension to γ-peptides (see below),236,237
vestigated homologues of natural L-amino acids, which were shown to adopt a stable right-handed
beginning with a hexapeptide H-(β3-HVal-β3-HAla- helix, gave the surprising result that of the three
β3-HLeu)2-OH. The above-mentioned hexamer is backbones, the R-peptides are the least prone to adopt
considered as a β3-peptide since all of the side chains stable secondary structures.
are in the 3-position. The particular sequence se- Gellman’s approach focused on conformationally
lected is reminiscent of the arrangements observed rigidified residues that limited the degrees of freedom
in the dimer-forming leucine zipper region of DNA about the CR-Cβ bond, with the intention of observ-
binding proteins,232 and the fragment Val-Ala-Leu ing ordered conformations from the fewest possible
has previously been used as a building block to study residues. They approached the design of helical
the influence of R,R-disubstituted amino acids on oligomeric β-peptides with the aid of systematic
peptide conformation.233 The apolar side chains af- molecular modeling studies.32 The candidates were
forded β-peptide sequences that were soluble in selected from β-amino acids in which the backbone
organic solvents. In subsequent studies, functional- carbons were embedded into carbocycles containing
3924 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 28. Circular dichroism spectra of four different β-peptide sequences in methanol: black,241 blue,239 green,273 and
red.249
three, four, five, or six atoms. Both cis and trans ring possible 14-membered ring H-bonds were present in
stereochemistries were considered, and for the cis- the solid state.32,239 In solution, the β-peptides were
containing peptides, both orientations of the ring with established to be monomeric under the conditions
respect to the helix were examined. Helical confor- used for NMR and CD studies.240 Amide proton NH/
mations were modeled for each of these 12 different ND exchange experiments suggested that in metha-
sequences using the six smallest H-bonded cyclic nol the hexamer adopts a very stable intramolecu-
patterns: the 12-, 16-, and 20-helix corresponding to larly hydrogen-bonded conformation, presumably the
H-bonds from carbonyls to N-H groups in the C- 14-helix. A solution structure for the trans-ACHC
terminal direction and the 10-, 14-, and 18-helices hexamer based on NMR-derived constraints was
corresponding to H-bonds from carbonyls to N-H in hampered by severe overlap of signals in the CRH and
the N-terminal direction (Figure 21). Molecular me- CβH regions in this case.240 The CD spectrum in
chanics studies of the resulting 72 structures led to methanol shows a single peak above 200 nm with a
the conclusion that the 14-helical form of trans-2- maximum at 217 nm (Figure 28). The intensity at
aminocyclohexanecarboxylic acid (trans-ACHC) would the maximum increased as the chain lengthened,
be the most stable among these hypothetical helices. presumably the result of a growing population of the
These studies also predicted that trans-2-amino- 14-helical state.239 This behavior was suggested to be
cyclopentanecarboxylic acid (trans-ACPC) would adopt an indication that the 14-helix formation involves a
the 12-helix,238 a surprising result in that there had cooperative process (see below).
been no example of this conformation in the β-peptide As predicted computationally, the trans-ACPC oli-
field. As mentioned below, both of these structure gomers revealed a different type of helical conforma-
types were observed as predicted. tion in both solution and the solid state. Crystal
The helical conformations of Gellman’s oligomers structures of the trans-ACPC hexamer and octamer
were firmly established by a battery of experimental displayed the 12-helical conformation (Figure 29).238,241
techniques. The crystal structure of the trans-ACHC The spectral data of the ACPC oligomers in solution
hexamer (Figure 27) revealed that all four of the are consistent with the crystallographic observations.
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3925
Figure 29. Side and top views of ca. one turn of the 12-helix extracted from the crystal structure of Gellman’s trans-
ACPC hexamer.241 A single S(12) H-bond circuit in the peptide backbone has been rendered as thick cylinders. Additionally,
a residue has been rendered as a space-filling model to provide a frame of reference between the two views and to more
clearly show the spatial relationship between cyclopentyl groups.
Circular dichroism spectra of the ACPC oligomer the 12-helical conformation.242 In pyridine-d5, the
series in CH3OH vary significantly with chain length. ACPC hexamer and octamer displayed sufficient 1H
While the trimer and tetramer show no maxima NMR dispersion to afford solution structures calcu-
above 200 nm, the CD pattern of the pentamer and lated from NMR-derived distance constraints.240 The
hexamer begin to converge and the magnitude of the NMR-determined conformations of these oligomers
Cotton effect increases as the chain lengthens. This were similar to the conformations found from crystal-
behavior is interpreted as an increasing population lography. Correlations established by NOE data were
of the 12-helical conformation with increasing chain observed for all CβH(i)-NH(i+2) proton pairs along
length, reflecting cooperativity in the 12-helix forma- the backbone as expected for a fully formed 12-helix.
tion. The CD spectrum of the ACPC hexamer is However, the data suggested the lack of a high degree
clearly distinct from the 14-helical β-peptides (Figure of conformational order in the chain ends, indicative
28), displaying a maximum around 207 nm and a of fraying.
minimum at 222 nm. The observed CD spectrum The switch in H-bonded patterns for the ACHC and
agrees well with theoretical spectral predictions for ACPC β-peptides teaches that foldamer conforma-
3926 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 30. Data from the crystal structure of the ACPC hexamer show that the five internal torsions within each of the
six cyclopentyl residues are superimposed on the cyclopentyl pseudorotation circuit as revealed in a correlation plot of φi
vs φ3.
tions can be controlled by small residue changes, a variable, taking on a range of values from 7.3° to
concept not common to R-peptides. It is interesting 41.2°. Traversing along the helical backbone from one
to understand what specific residue-based changes ring to the next, no obvious pattern in dihedral values
bring about this conformational switch. The internal emerges, which is somewhat surprising given the
ring torsion across the CR-Cβ bond in the ACHC regular backbone conformation. In addition to the
hexamer varies little among the six residues, span- noted variability in φ1, the ring substituents deviate
ning the range from -55.0° to -58.8°. In contrast to significantly from the nearly ideal gauche conforma-
cyclohexyl rings, five-membered carbocyclics are tion of ACHC. The greater flexibility about φ1 and
considerably more flexible. The coupling of small the deviation from gauche geometry are apparently
bond angle deformations to internal rotational angles the major factors responsible for the tighter 12-helix
gives rise to an equipotential energy surface known in ACPC oligomers.
as the pseudorotation circuit.243,244 The five internal Recently, β-peptide oligomers from cis-substituted
dihedral angles, φi, are highly correlated to one oxetane rings have been synthesized and studied.247
another because of geometric restrictions from ring Molecular modeling and NMR NOE data in CDCl3
constraints. This correlation is apparent in a plot of and C6D6 on the hexamer have identified a helical
φi vs any one of the internal angles (e.g., φ3), whereby secondary structure stabilized by four S(10) H-
elliptical paths of the pseudorotation circuit connect bonding interactions. Although S(10)-stabilized turns
equipotential points between torsional extremes of are known in β-peptides,248,249 this is the first example
(42° (Figure 30).245,246 From the crystal structure of of the repetition of this pattern to generate a 10-helix.
ACPC hexamer, the five internal torsions within each Thus, while the cyclopentane and cyclohexane β-ami-
of the six cyclopentyl residues are superimposed on no acid oligomers adopt the 12- and 14-helix, respec-
the cyclopentyl pseudorotation circuit in Figure 30. tively, and S(8) interactions produce a ribbon struc-
It can be seen that nearly all of the ring dihedrals ture in cyclopropane-based β-peptides,226 the cis-
conform very well to the cyclopentane pseudorotation oxetanes take on the intermediate S(10) H-bond ring
circuit. Only rings 3 and 6 show minor deviations size, giving a consistent trend. These latest results
from the expected correlations, suggesting either a build on the general theme, previously mentioned,
slight deformation away from ideality or possibly that foldamer conformations are sensitive to small
limitations in the X-ray refinement of these two rings. residue changes. Finally, it should be mentioned that
In great contrast to the ACHC case, the CR-Cβ furanose250 and pyranose251 carbopeptoids having a
torsional angles (φ1) in ACPC are significantly more β-amino acid repeating unit are under development,
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3927
Figure 32. β-Peptides with β-HCys residues to demonstrate the side-chain relationship in sequences prone to adopt the
14-helix conformation through disulfide formation.
adopt regular secondary structure in MeOH and that secondary structure. Specifically, a sequence contain-
the extent of secondary structure formation is maxi- ing the 3-aminopropanoyl unit (β-HGly, i.e., loss of
mal once four residues are in place.260 On the basis single methyl side chain) gave a CD spectrum that
of the β-tripeptide crystal structure, 1H NMR cou- became highly dependent on solvent. In MeOH the
pling constants, and assumptions based on confor- CD spectrum of the β-HGly mutant was character-
mational analysis, Seebach proposed a 103 right- istic of the 14-helix, while in 1:1 MeOH:H2O an
handed helix for the (S)-β3-homoproline chain. This entirely different and yet uncharacterized pattern
extended conformation is a further example that emerged. These results pointed to a strongly biased
illustrates how the preferred backbone conformation torsional potential energy surface for β-peptides
around the central CR-Cβ bond dominates the sec- bearing side chains in the 2 or 3 position.252 This is
ondary structure of β-peptides. consistent with the subsequent observation that the
Seebach’s helical molecular model led his group to helix to random conformation transition in β-peptides
test how variations in backbone constitution and is a noncooperative process.234
stereochemical modifications stabilized or destabi- A series of mutants having stereochemical varia-
lized the secondary structure.252 Incorporation of a tions in the central β-amino acid position revealed
single amino acid residue into the center of the additional information (Table 3). According to See-
original β3-hexapeptide HVal-HAla-HLeu-HVal-HAla- bach’s original model,223 the short pitch of the β-pep-
HLeu-OMe sequence generated a series of single tide helix and the equatorial orientation of the side
point mutations (Table 2). As predicted by Seebach’s chains with respect to the helical axis both place
model,223 many relatively minor structural changes limits on substitution patterns that can sustain the
to the central residue were incompatible with the 14- helical secondary structure (Figure 35). Thus, lateral
helix, resulting in sequences that did not show the non-H-substituents in the 2- and 3-positions on the
characteristic CD pattern of the 14-helix. These 3-amino acid residues of the helix were predicted not
included N-methylation (i.e., an N-Me β-amino acid), to interfere with the secondary structure, while axial
replacement of NH by O (i.e., a β-depsipeptide), and ones were expected to disrupt the helix. This is borne
removal of the CH2 group (an R-amino acid). These out by the data in Table 3.252 Incorporating a single
observations suggested that proper dihedral angles, mismatched residue in the central position of the
H-bonding, and a periodic backbone are necessary in β-heptadepsipeptide caused the CD pattern to disap-
order to maintain conformational integrity. The pear, while detailed NMR and CD data confirm the
absence of side-chain substituents on the central helical structure in mutants that have lateral sub-
β-amino acid residue also destabilized the helical stituents. The geminal dimethyl mutant is also
3930 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Table 3. Single Residue Mutants Used To Probe How Substituents on the β-Peptide Effect the 14-Helix
Conformation252
Table 4. β-Peptide Amino Acid Sequences Probing the Effects of Stereochemistry and Substitution of the 14-Helix
Conformation
Figure 36. sc and ap conformations about the CR-Cβ bond of β-amino acid residues. Schematic depiction of the electrostatic
considerations that favor the sp conformation.
and like-β2,3 disubstituted residues, promotes helical repeat units, the critical nucleus size generally cor-
or turn conformations. The ap conformation, favored responds to a chain length of at least one turn.
for unlike-β2,3 disubstituted residues, promotes an Experimental observations268,269 on helix-forming
extended, strand-like structure (vide infra). Gemi- R-peptides are in good agreement with theory, al-
nally disubstituted residues have no preferred con- though a deeper understanding of the specific inter-
formation about the CR-Cβ bond, although axial actions responsible for this cooperativity is still
positions in a helical conformation would destabilize developing.258,270,271
a 14-helix (Figure 35). For β-peptide secondary structures, cooperative
iii. Cooperativity. Cooperative conformational order formation has been investigated in various ways. One
results from multiple noncovalent interactions be- test of cooperativity involves examining the onset of
tween nonadjacent chain segments. A critical chain conformational order as a function of chain length.
length and sigmoidal transitions are the hallmarks The earliest study of this sort for discrete β-peptide
of cooperative ordering mechanisms. In the specific oligomer appears to date back to 1979 on poly(S-
case of helical conformations, this behavior can be βAspOiBu).198 However, at that time the structure
understood265-267 as resulting from a minimum num- of the ordered conformation was not understood.
ber of residues required to nucleate stable helix Clues about cooperativity in forming the 14-helix
propagation. Since the propagating helix is stabilized with β-peptides can be found from CD studies. Figure
by noncovalent interactions between nonadjacent 37 shows a plot of CD intensity (normalized per
3932 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Table 5. Role of Sequence Variation and End Groups on the Solution Conformation of β-Peptides
a On the basis of CD spectra in MeOH. b Trifluoroacetate salt. c Also based on NMR structure determination.
H-bonding pattern between next neighbors. This is contributed to the discovery of stable secondary
an example of residue-controlled or substituent- structures from β-peptides in aqueous solution. Some
induced turn formation, and it illustrates how the of the oligomers examined for this purpose can be
monomer’s torsional potential energy surface can be found in Figure 38. To enhance water solubility,
biased to regulate backbone conformation. β-peptides containing polar serine and lysine side
The 12/10 secondary structure was rationalized on chains were synthesized and studied.253,280 While in
the basis of solvophobic interactions.249 Whereas the MeOH these oligomers exhibited the CD profile
14-helix conformation of the β2-alternating-β3 se- typical of the 14-helix, in aqueous solution fewer of
quence does not provide close interactions between the oligomers studied maintained this pattern. Those
side chains in successive turns, in the 12/10-helix that did exhibit spectral characteristics of the 14-
they are directly atop one another. Solvophobic helix in water did so with much reduced intensity.
interactions with the terminal protecting groups Moreover, in both organic as well as aqueous sol-
explained why the protected forms were more prone vents, the presence of a large number of neighboring
to adopt the 12/10-helix. In the unprotected form, the cationic side chains destabilizes the secondary struc-
dipole moment of the 14-helix may add stability ture, consistent with the well-known behavior of poly-
through charge-pole interactions.234,249 An alterna- (R-homolysine).212 It was concluded that oligomers
tive rationalization is one that illustrates negative with neutral serine-derived side chains have a smaller
design principles. Whereas many patterns of alkyl helix-disrupting effect in water than the charged
substitution disrupt the 14-helix, they only cause lysine derivatives. However, β-peptides that are
mild destabilization of the 12/10-helix pattern.185 hydroxylated in the R-position appear to be void of
Thus, it is possible to destabilize (i.e., design away) helical secondary structure.235
the 14-helix in favor of the 12/10-helix. Regardless To reduce the disruptive consequences of several
of interpretation, in 1997, when Seebach’s group charged groups, β-peptide sequences having just one
communicated their initial findings on the β2-,β3-co- polar side chain (either homoglutamate or homo-
oligomers, it became apparent from this work 248 and lysine) were studied by Gung and Zou (Figure 38).281
the related studies by Gellman238 that the β-peptides However, these heptamers were poorly soluble in
are likely to have a high degree of variability in water. Heptamers bearing two β-HGlu or one β-HGlu
secondary structure type. and a C-terminal aspartate (D-Asp) were synthesized
v. Water-Soluble β-Peptide Foldamers. Following next and found to be soluble in water up to concen-
earlier observations,278,279 Seebach’s initial paper on trations from ca. 5 to more than 15 mM (without
β-peptide oligomers showed that this backbone is significant aggregation). However, in going from
remarkably resistant to proteolytic digestion and, MeOH to H2O, the helical content decreased as
hence, potentially useful as a candidate for new judged by CD, and no NOE cross-peaks characteristic
drugs.223 Consequently, there has been considerable of the 14-helix were observed in water. It is interest-
activity on the development of β-peptides that are ing to note however, that the peptide sequence with
both highly water soluble and conformationally struc- the D-Asp C-terminus gave considerably greater CD
tured in aqueous solution. Several groups have intensity at 216 nm than the sequence differing by
3934 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
of a wide range of side chains onto the APC unit.285 two cysteine side chains and incorporated these into
Despite the change in the geometry of the five- β-hexa- and β-heptapeptides (Figure 38). Ionic side
membered ring upon sulfonylation, the 12-helix chains were excluded on the basis of their tendency
persists, although somewhat more tightly wound. to destabilize the 14-helix conformation. Deprotection
Seebach further pursued the design of water- of the thiol groups resulted in cyclic disulfide forma-
soluble helical β-peptides based on sequences having tion in the case of cysteine-containing sequences. To
minimal conformational constraints.286 Following on study the CD contribution of the disulfide chromo-
their observation that like-2,3-disubstituted β-amino phore, the carbocyclic analogue was also prepared.
acids increase the stability of the 14-helix conforma- All of these sequences including the hexapeptide
tion, they prepared monomers carrying two serine or showed a CD spectrum in H2O characteristic of the
3936 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 40. Crystal structures of β-peptides sequences with antiparallel and parallel β-sheetlike structures.201 The backbone
is rendered in thick cylinders. Newman projections show representative CR-Cβ dihedral angles in the ap conformation.
14-helix. Whereas the hexapeptide without confor- markedly on the concentration of added electrolyte.
mational restriction gave no NOE cross-peaks indi- A plot of CD intensity versus the square root of NaCl
cating little helical content in water, the heptapep- molality is approximately sigmoidal, with a midpoint
tide containing the cyclic disulfide showed NOEs near 0.4 M (according to Debye-Hückel theory, the
characteristic of the 14-helix. The low intensity of energy of electrostatic interactions between ions
these cross-peaks suggested that only partially heli- scales as the square root of [NaCl]).
cal conformations, or a mixture of helical and non- vi. Biological Activity of β-Peptide Foldamers. The
helical chains, exist for this sequence under these availability of conformationally structured, water-
conditions. soluble β-peptide sequences, together with their
The successful development of water-soluble β-pep- known stability and resistance to enzymatic degrada-
tides having helical conformations from sequences tion,289,290 has led to some early observations regard-
that do not contain any constrained monomers was ing the biological activity of this oligomer class.
achieved using salt-bridge stabilization strategies Seebach and co-workers designed cyclic β-peptides
(Figure 38). This approach was realized indepen- containing only four residues that bind to the soma-
dently by Seebach287 and DeGrado.288 Both of these tostatin receptor with micromolar affinity (Figure
studies showed, by NMR and CD methods, that 39).291 Hexa-, hepta-, and nonameric β-peptides car-
electrostatic interactions between the side chains of rying one to seven water-solubilizing groups have
acyclic β-amino acids produce a well-defined 14-helix also been shown to be inhibitors of small intestinal
in aqueous media. Since charged groups resulted cholesterol and fat adsorption.292 A correlation was
from deprotonated acidic and protonated basic resi- found between the ability of β-peptides to form an
dues, the stability of the helical conformation was amphipathic 14-helix in MeOH and their inhibitory
expected to be pH dependent. Indeed, the CD inten- effect. DeGrado293,294 and Gellman295 used similar
sity was shown to reach a maximum at an interme- designs in mimicking natural membrane-active pep-
diate value of pH in which the salt bridge would exist. tide toxins and antibiotics. A strong correlation exists
DeGrado showed that the CD intensity depends among the sequences studied between the helical
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3937
Figure 43. Hydrazino peptide backbones and a diagram showing the many possible intrastrand H-bond interactions in
this backbone.
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3939
ary structures by systematic studies on discrete have been investigated in solution and the solid state.
oligomers. However, unlike the poly-β-peptides for In chloroform, IR and 1H NMR studies reveal that
which helical structures have been clearly estab- the intramolecular H-bond preference is for S(14)
lished,199,202 firm conclusions about the conforma- rings involving the terminal carbamate CdO accep-
tional preferences of homopolymers of γ-peptides tor. This produces a turn-like motif that is also found
appear not to have been resolved. From the results in the crystal structures. However, in the solid state
of ORD measurements, Rydon suggested a helical a fairly long intramolecular S(12) H-bond interaction
structure for the neutral form of poly-γ-D-glutamic is formed by utilizing one of the SdO acceptors. Here
acid.318 Two left-handed helical models were pro- the carbamate carbonyl is tied up in a much shorter
posed, both of which invoked three repeats per turn. intermolecular H-bond interaction. Although a com-
The models differed as to whether S(17) or S(19) pact intramolecular H-bond fold is present in solu-
hydrogen-bonded interactions were involved.318 Ka- tion, the lack of involvement of the SdO bond in all
jtár and Bruckner synthesized oligo-γ-L-glutamic of the oligomers studied calls into question the
acids from dimer to heptamer and showed that the potential of this backbone to form long-range second-
ORD signal increases linearly with the chain length, ary structures.
suggesting that the polymer takes on a random In 1998, two reports appeared simultaneously
conformation.316 However, there appears to be no showing that in contrast to this expectation, γ-pep-
resolution to the question of whether these polymers tide sequences form remarkably stable helical con-
are helical or conformationally random.192,320 formations in solution.236,237 The Seebach group de-
The added torsional degrees of freedom in γ-amino scribed a γ4-hexapeptide analogue of the sequence
acids321,322 might be expected to promote conforma- H(-Val-Ala-Leu)2-OH with L-configuration. Al-
tionally disordered chains. Yet, just as for β-peptides, though the CD spectra did not reveal patterns
this intuitive view does not hold for the γ-peptides characteristic of secondary structure, conformational
either. As stated by Seebach et al., “the surprising analysis by NMR in either pyridine or methanol
difference between the natural R-, and the analogous revealed a right-handed helix with S(14) H-bonds
β- and γ-peptides is that the helix stability increases from the CdO of residue i to the H-N of residue i+3
upon homologation of the residues.”237 and ca. 2.6 residues per turn. Molecular models of
The first report demonstrating that chain mol- this conformation suggested that the side chains are
ecules based on γ-amino acids form regular secondary oriented approximately perpendicular to the helical
structure appeared in 1992.323 This work targeted the axis, the H-bonds lie along the helix axis with the
discovery of new classes of protein-like substances dipole moment oriented from the N- to C-terminus,
with alternative backbones. These oligomers were and the CR-Cβ and Cβ-Cγ bonds adopt (+)-sc con-
considered to be vinylogous polypeptides since an (E)- formations for this right-handed helix.
ethenyl unit was inserted into each repeat unit to Hanessian studied the solution structure of tetra-,
rigidify the backbone. To restrict rotation about the hexa-, and octa-γ-peptide analogues of the sequence
Cβ-Cγ bond and extend the backbone into sheetlike (-Ala-Val-).236 All three of these γ4-peptides derived
conformations, an R-methyl substituent was initially from L-amino acids adopted stable right-handed
examined. For this particular substitution pattern, helical conformations in solution. The helical param-
allylic A1,3 strain was expected to drive the γ-hydro- eters were identical to those found by the Seebach
gen to lie in the plane of the enamide. This confor- group: 2.6 residues per turn stabilized by S(14)
mational preference was borne out in a dipeptide H-bonds. Temperature-dependent chemical shifts
which crystallized into a two-stranded antiparallel suggested that these intrastrand interactions are
sheet; however, longer oligomers failed to form higher strong. As also noted by Seebach, CD did not reveal
order sheetlike structures. Removal of the R-methyl a pattern diagnostic of secondary structure. The
substituent led to vinylogous peptides that organized obvious but important lesson from these reports is
into long stacks of parallel sheets as revealed by that CD cannot be used alone as a means of screening
X-ray crystallography. To favor antiparallel align- for secondary structure.
ment, a Pro-Gly dipeptide turn was inserted between
Figure 44 compares the 14-helix of the β- and
a pair of vinylogous amino acids. 1H NMR data
γ-peptides.325 It is interesting that both backbones
supported the existence of an intramolecular H-bond
between the N-H and OdC on the two ends, sug- prefer H-bond patterns involving 14 atom rings.
gesting the preference of this secondary structure in Obviously these patterns originate differently for the
solution. A peptide sequence which consisted of a two constitutions. In the case of β-peptides, the S-
vinylogous amino acid, the Pro-Gly turn, and a γ2,3- (14) H-bond results from the N-H of residue i-2
amino acid exhibited a helical conformation that being donated to the carbonyl of residue i. In the case
contained 10- and 12-membered H-bond rings. of the γ-peptides, the N-H of residue i is donated to
Two years later, a family of sulfur-containing the carbonyl of residue i+3. As a result, with L-amino
γ-peptide mimics was reported.306,324 This backbone acids there is a reversal of helix sense, the β-peptide
is linked by the sulfonamide group as a replacement adopting an M-helix and the γ-peptide adopting the
for the peptide bond. Being derived from γ-amino- P-helix (as do R-peptides). The direction of the dipole
R,β-unsaturated sulfonic acids, these oligomers have moment is reversed too. Thus, for the β-peptide, the
come to be known as vinylogous sulfonamidopeptides, dipole is oriented from the C-terminus to the N-
closely related to the vinylogous peptides described terminus, while for the γ-peptide, it runs from the
above. Protein-like side chains added to the γ-carbon N-terminus to the C-terminus (as with R-peptides).
gave chiral monomers. The folding patterns of short Many substituent patterns and stereoisomers are
oligomers ranging from the dimer to the tetramer possible for γ-amino acids, but as of yet, these have
3940 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 49. Structures and proposed H-bonding patterns of the 316 and 422 helix for sialooligomers.
3942 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
that sterically interferes with H-bond formation. In tionship exists between adjacent units. Simple mod-
contrast to the β-turns found for the cis-linked eling suggests a helical structure, stabilized by
furanoses, trans-linked furanose oligomers give a intrastrand N-Hi‚‚‚OdCi-3 H-bonds. The conforma-
much different secondary structure. In initial reports tional preference appeared stronger for octamer than
that only studied chain lengths up to the tetramer, the tetramer since the tetramer has only one stabiliz-
however, it appeared that no stable secondary struc- ing H-bond. A related octamer in which the protect-
tures in the trans isomer could be observed.362 1H ing groups were removed was studied and found to
NMR was used to study the solution conformation give a strong Cotton effect at 216 nm in methanol
of a trans-linked octamer. At this chain length, it was and TFE.363
apparent that a new secondary structure had emerged. Fleet’s carbopeptoids are closely related to the oligo
In contrast to the backbones derived from cis-isomers, tetrahydrofuran amino acid sequence used in the
long-range NOEs between sugar ring protons were gramicidin-like peptide developed and studied by
observed. A repeating pattern of NOEs was detected Koert and co-workers.364 These oligo-THF peptides
along the backbone, indicating that a regular rela- (Figure 52) were inserted into synthetic lipid bilayer
3944 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 54. Drawing of the proposed helical conformation of oligomer 11 (n ) 8), where R ) Sn-Pr. Side (bottom left) and
top (bottom right) view of the space-filling model of the crystal structure of pyridine-pyrimidine oligomer 11 (n ) 8) in a
helical conformation.
consistent with an increasing number of stacked The helical conformation of these oligomers was
aromatic rings. characterized in the solid state by using X-ray
The creation of a chiral, helical structure from crystallography. Shorter oligomer 11 (n ) 5) was
polyheterocyclic strands resulted in a racemic mix- found to pack in a centrosymmetric cell that con-
ture of M and P forms. By using variable temperature tained an enantiomeric pair of oligomers.378 In addi-
NMR and the diastereotopic R-thiomethylene pro- tion, the helices were found to stack on top of one
tons, it was possible to determine the barrier to the another creating long channels in the void space of
the helix interior. The octamer of 11 was also
helical inversion process. A value of k ) 85 s-1 at 251
determined to pack in a helical confirmation in the
K and a free energy of activation of ∆Gq ) 12.3
solid-state (Figure 54).379 In this case, a unit cell was
kcal‚mol-1 was determined for shorter oligomer 11
found to contain two molecules of only one twist
(n ) 8).377 In an analogous fashion, these values were sense, thereby creating a chiral channel from an
determined for two of the longer oligomers 11 (n ) achiral molecule. Spontaneous chiral resolution oc-
5) (k ) 85 s-1 at 250 K and ∆Gq ) 12.4 kcal‚mol-1) curs concomitantly with crystallization. In both cases
and 11 (n ) 12) (k ) 86 s-1 and ∆Gq ) 13.6 a helical pitch of 3.75 Å was determined along with
kcal‚mol-1).379 The comparable activation free ener- an internal void space from ∼2.5 to 3 Å. The high
gies led to the proposal that the racemic helical degree of solid-state organization led the authors to
conformation interconverted via a stepwise folding propose that these systems may have interesting
mechanism (Figure 55).379 Interestingly, while this electronic features, when compared to linear molec-
interconversion is certainly dynamic, there is no ular wires.
evidence to indicate that these oligomers undergo the
folding reaction (i.e., that they can unfold). The 2. Pyridine−Pyrimidines with Hydrazal Linkers
racemization between the M and P helical conforma- The previous design method has been shown to be
tions was proposed to go through an intermediate, highly effective for obtaining well-defined conforma-
partially unfolded conformation (Figure 55, interme- tions in solution. However, the synthesis of the
diate B). Furthermore, no spectroscopic evidence was oligomers described above was challenging. In an
offered to show that the oligomers exist in completely attempt to overcome this limitation, Lehn et al.
unfolded conformations. described the synthesis and study of oligomers that
3946 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
3. Pyridine−Pyridazines
Alternative attempts at creating well-defined heli-
cal conformations from polyheterocyclic strands have
Figure 56. The transoid-transoid to transoid-cisoid
equilibrium and structure of pyridine-pyrimidine oligo- recently been reported by Lehn et al.382 The same
mers with hydrazal linkers 12 (n ) 1, 3). design criteria as that used for the previously studied
systems was used except that an isomeric pyridine-
are more amenable to stepwise synthesis while still pyridazine repeat unit was employed (Figure 57). The
taking advantage of selective torsions around adja- synthesis of oligomer 13 was accomplished by using
cent pyridine-pyrimidine bonds.381 The system is a similar procedure to the pyridine-pyrimidine het-
still based on the preference of 2,2′-bipyridine to eronuclear strands.378 It was proposed that 13 would
adopt a transoid conformation in solution (Figure 53). yield a hexagonal, helical structure with 12 rings per
However, the middle portion of the oligomer back- turn and a central cavity of ∼25 Å (determined by
bone contains a hydrazal group, which replaces the molecular modeling). The helical conformation of 13
pyridine fragment of the previously studied oligo- in solution was characterized by large upfield shifts
mers. When R-substituted N-heterocycles are used, of the proton resonances for the terminal pyridine
the transoid-transoid conformation (Figure 56) is rings. The chemical shifts of all aromatic resonances
preferred over others (transoid-cisoid shown for were found to be highly concentration dependent,
comparison) for several reasons. These include the suggesting that a large amount of intermolecular
minimization of secondary steric and electronic in- aggregation was occurring at increased concentra-
teractions, the increased amount of aromatic stacking tions. Vapor-pressure osmometry measurements
that occurs when the imine is in the transoid- showed an apparent molecular weight approximately
transoid conformation, and the conformational rigid- twice that of the oligomer, indicating a high amount
ity and planarity through conjugation. The synthesis of self-aggregation. Solutions of 13 in dichloromethane
of the desired oligomers 12 (n ) 1, 3) (Figure 56) and pyridine resulted in gel formation with micro-
remained somewhat difficult but was simplified by structures that consisted of helical substructures as
having the hydrazal condensation as the final step. evidenced by electron microscopy (Figure 58). It was
The helical conformation was characterized by determined that the fibers had an approximate
NMR spectroscopy and X-ray crystallography. Both diameter of 80 Å, most likely being composed of two
oligomers displayed 1H NMR consistent with a helical or three bundles of helical stacks. Due to the large
conformation as evidenced by the upfield shift of the size of the cavity, it was proposed that the system
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3947
2. Guanidines
Oligo(guanidinium) strands form a stacked ar-
rangement by using a combination of aromatic stack-
ing interactions and the preferred conformation of a
charged backbone.383-387 These systems are based on
the conformational preference of a charged N,N′-
diphenylguanidine group in solution (Figure 59).383
Figure 57. Drawing of the proposed helical conformation By using a combination of 1H NMR spectroscopy and
of oligomer 13, where R ) Sn-Pr. X-ray crystallography, it was determined in a N,N′-
diphenyl-N,N′-dimethylguanidine model system that
the cisoid-cisoid conformation is predominant over
the alternative conformations in water and other
polar, aprotic solvents. The guanidium moiety was
incorporated into water-soluble, longer length oligo-
mers (14-17) containing three and five aromatic
rings linked at both the meta- and para-positions.
The conformation of the oligomers in solution was
characterized by NMR spectroscopy and X-ray crys-
tallography. All four oligomers were found to adopt
a helical conformation in both solution and the solid-
state (Figure 59). X-ray crystallography showed that
the dihedral angle between face-to-face phenyl rings
was ca. 30° for the meta-substituted oligomers (14
and 15) and slightly smaller for the para-substituted
oligomers (16 and 17). These findings were somewhat
surprising since the parallel structure had been
calculated to be less favorable than other conforma-
Figure 58. Freeze-fracture electron micrograph of com-
pound 13 in (a) dichloromethane and (b) pyridine showing
tions. The meta-substituted oligomers pack in a chiral
fiber network formation with helical textures.382 Scale bar conformation in the solid state with both enantio-
represents 100 nm. (Reprinted with permission from ref meric forms present in a 1:1 ratio. NMR spectroscopy
382. Copyright 2000 Wiley-VCH.) showed that the oligomers exist predominantly as
layered structures in both organic solvents and water
self-organized into extended molecular channels with as evidenced by the upfield shifting of the aromatic
a fairly large opening of ∼8 Å, potentially useful as protons inside the layers when compared to the
functional polymeric materials for ion-active devices terminal phenyl rings. These NOE measurements
requiring internal functionalization with metal co- confirmed the existence of stacked, parallel layers.
ordinating groups. These oligomers and others in One possible application of this system is as a
their class have yet to show tolerance for groups polyintercalator targeting the minor groove of DNA.386
present on the inside of the helical cavity. The lack
of evidence for an unfolded state makes it unclear 3. Aedamers
whether these oligomers exhibit a folding reaction Another system composed primarily of aromatic
which may be important when dynamic cavity as- rings was reported by Iverson and Lokey.388 These
sembly/disassembly is desired. structures take advantage of the stacking propensi-
ties of the aromatic electron donor-acceptor interac-
C. Backbones Utilizing Solvophobic Interactions tions (aedamers) of covalently linked subunits. For
the electron-deficient aromatic rings, 1,4,5,8-naph-
1. Qualification thalenetetracarboxylic diimide rings were employed
The preceding section of abiotic, single-stranded and 1,5-dialkoxynaphthalene rings were used for the
oligomers employed aromatic stacking to stabilize the electron-acceptor rings. Crystal structures of model
folded conformation. The following backbones utilize compounds were used to help determine the location
solvophobic interactions, and in some of these cases, for linking the aromatic rings with the correct length
these stacking contacts occur between adjacent mono- of the tethering unit389 between the rings. A series
3948 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 59. Transoid-transoid, transoid-cisoid, and cisoid-cisoid equilibrium and structure of aromatic oligo-
(guanidinium)s.
of oligomers (18-20) was synthesized by solid-phase 19 (n ) 1, 2, 3, 4) was synthesized and studied. These
methods using L-aspartic acid as the linker, which oligomers are comparable to the initially reported
helped promote solubility in water and minimized system388 except for the linkages between the aro-
intermolecular aggregation (Figure 60). matic rings and the presence of only electron-accept-
In these initial studies, absorption and NMR ing aromatic rings. In these compounds, a lysine
spectroscopy studies were used to probe the confor- linkage was employed which helped to improve the
mation of the oligomers in water. The shorter oligo- electrostatic interactions with DNA. A variety of
mer 18 (n ) 1) was found to have to have absorption techniques showed that the oligomers are inter-
maxima identical to a solution of the model com- calated into the major groove of DNA (based on steric
pounds, indicating the lack of a folded conformation preferences) in a cooperative fashion. While these
of the aromatic rings. Solutions of the longer oligo- results do not necessarily involve the study of fol-
mers 18 (n ) 2, 3) showed an 18 nm red shift damers, they demonstrate that the conformation of
suggesting that at least two aromatic rings were these oligomers in solution can be used to design a
stacked. NMR studies confirmed the formation of a better system for application toward more natural,
collapsed conformation as evidenced by diastereotopic biological systems.
methylene hydrogens, presumably resulting from Aedamers have also been shown to have potential
restricted rotation on the NMR time scale, along with applications in the area of molecular sensors.391
the observation of NOE signals between hydrogens Aedamer 20 was synthesized in the hope of mimick-
on adjacent aromatic rings indicating a stacked ing the leucine zipper motif found in peptide systems.
conformation. These results showed that oligomers This was attempted by creating an oligomer that
of sufficient length adopt pleated structures in solu- would have one side lined by a hydrophobic unit
tion (Figure 61) and supported the idea that donor- (leucine) and the other side by a hydrophilic unit
acceptor interactions alone can be used to create well- (aspartic acid). Instead of adopting the desired leu-
defined conformations in an aqueous environment. cine zipper, it was determined by UV-Vis, NMR, and
One potential application of the aedamer systems dynamic light scattering that 20 intramolecularly
is in the area of polyintercalating molecules for folds in solution and undergoes an increase in
DNA.390 For these studies, a new series of oligomers intermolecular aggregation. Furthermore, it was
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3949
4. Cyclophanes
Differently substituted N-benzyl phenylpyridinium
cyclophanes have been used as models to probe the
solvent effects of face-to-face aromatic stacking
(Figure 63).392-395 A variety of R groups, both electron-
donating and -withdrawing, were explored to mea-
sure the aromatic-aromatic stacking interactions.
Recently, longer chains with up to five aromatic rings
suggest collapsed conformations in aqueous solution,
with open conformations in chloroform.396
Investigations into the construction of larger
cyclophanes397-403 proceeded through the generation
of linear oligomers of tetrasubstituted aryl moieties
linked through tosylated aminomethyl groups.
Through iterative synthesis, chain lengths up to the
Figure 61. General schematic representation of a second- nonamer401 were obtained and crystal structures for
ary structural element based on donor-acceptor interac- pentamer 21 revealed stacked, molecular ribbons
tions. (Figure 63). Although detailed spectroscopic studies
and folding transitions through either solvent or
found that upon heating above 80 °C, 1.5 mM thermal denaturation were not demonstrated, these
aqueous solutions of 20 undergo an irreversible structures have similar conformations to previously
conformational change (Figure 62). At room temper- described aedamers. In chloroform, 1H NMR showed
atures, solutions of 20 are red wine colored. Upon that the S-shaped folded conformation is the preor-
heating, the aedamers begin to unfold and expose the ganized structure before cyclization to the macro-
hydrophobic backbones to solution leading to an cycles.398,399 Extensions of this backbone have in-
uncolored, presumably tangled aggregate. It was cludedtheincorporationofp-phenylrings,403 pyridines,401
further found that the transition was induced by the and biphenyl groups,402 as well as the use of thioether
addition of preformed aggregate to solutions of oli- linkages.397,403
gomer 20. This behavior was compared by the
authors to the behavior of triple-helix collagen. It was 5. Side Chain−Backbone Interactions
proposed that the color change (red wine to colorless) a. Oligo(thiophene)s. Recently, oligothiophenes
could therefore be used as a temperature sensor with chiral p-phenyl-oxazoline side chains were
3950 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 62. Proposed scheme for the conversion of amphiphilic aedamer 20 to a tangled aggregate state upon heating.
(Adapted from ref 391.)
Figure 63. Cyclophanes discussed in the text. (top) Substituted N-benzyl phenylpyridinium bromides. (bottom) Part of
the crystal structure of the [3.3]meta-cyclophane pentamer 21.399 Side chains have been omitted for clarity.
Figure 67. (a) Molar extinction coefficient (303 nm) versus oligomer length n for oligomer series 22 in chloroform (black,
squares) and acetonitrile (red and blue, circles). The lines are linear fits to the data; for acetonitrile, the fits are for n )
2-8 (red) and n ) 10-18 (blue). (b) The average chemical shift δA versus chain length n for oligomer series 22 in chloroform
(CDCl3, squares) and acetonitrile (CD3CN, circles). The curves are drawn only as guides to the eye. All the spectra in
chloroform and those of n ) 4, 6, 8 in acetonitrile did not change upon dilution; the spectra of n ) 10, 12, 14, 16, 18 in
acetonitrile were measured at ca. 10 µM.
3952 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 73. Structures of various oligo(m-phenylene ethynylene)s used to bias the twist sense of the helical conformation.
3954 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 74. Plots of UV-Vis (top), fluorescence (middle), and circular dichroism spectra (bottom) of oligomers 24 (n ) 6)
through 24 (n ) 18) in chloroform (left) and acetonitrile (right).
to the main chain could only occur once order is tional uniqueness of the backbone. At high chloro-
present in the backbone. form compositions (but still helical as judged by UV)
By monitoring the CD signal as a function of there are possibly a large number of energetically
volume percent chloroform in acetonitrile, it was only similar, helical-like backbone conformations that
at high acetonitrile compositions that a Cotton effect interconvert rapidly. Here, the analogy can also be
was observed (Figure 75). On the basis of this made to the compact, denatured state of proteins.416
observation it is plausible that ordering of the sol- Regardless of which of these explanations is correct,
vated side chains, a process that lags behind helix the transfer of chirality appeared to be a highly
formation, is the mechanism by which chirality is cooperative process that required a progression of
transferred to the backbone. This is analogous to the conformational order beyond the initially formed
molten globular state of proteins, a state in which helical state. These results showed that the side
the peptide backbone possesses a nativelike confor- chains played more than just a solubilizing role in
mation while having disordered side chains.414,415 An these conformationally ordered oligomers.
alternative way to explain the observed transition All members of oligomer series 24 were fully
behavior is to consider the dynamics and conforma- substituted with chiral side chains, not allowing the
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3955
Figure 77. Plot of ∆314 vs mole % chiral octadecamer 24 (n ) 18) for solutions of varying amounts chiral and achiral 23
(n ) 18) octadecamers in different concentrations of water/acetonitrile (v/v). All spectra were recorded in solutions with a
total oligomer concentration of 3.3 µM. The dotted lines are the expected signals that should arise upon dilution of a
sample only containing only chiral octadecamer. The solid line is the least-squares linear fit of the chiral octadecamer
dilution data (top left, correlation coefficient ) 0.998).
Figure 82. Chemical structures of m-phenylene ethynylene oligomeric hosts 30-32 used in binding small molecule guests
(R ) -CO2(CH2CH2O)3CH3).
3958 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 83. Space-filling model of the 1:1 minimum energy complex of 30 and (-)-R-pinene determined by a Monte Carlo
search in which the position and orientation of R -pinene within the helix cavity was varied. Top and side views are shown.
Figure 86. (a) Schematic diagram illustrating the binding of a rodlike guest to helical oligomers of differing lengths. The
cavity height is determined by the oligomer length. (b) Solvent-exposed surface of the oligomer cavity (s) and the rodlike
guest (- - -) in a complexed state as a function of cavity height. The total amount of solvent-exposed surface (s) shows a
minimum that predicts a cavity length with the highest affinity for the rodlike guest. (c) Minimized structure of 23 (n )
18) with 39 determined by a Monte Carlo docking algorithm.
Figure 89. Schematic diagram illustrating the aggregation behavior of m-phenylene ethynylene oligomers over a range
of concentrations. In dilute solution, the oligomers can exist in a random or helical conformation. At increased concentrations
they associate intermolecularly, possibly in an extended lamellar-type fashion or as tubular and hexagonal helical stacks.
upon binding of the first molecule. An examination packs in 2D sheets. Job’s method confirmed the 1:1
of concentrated solutions in hydrocarbon solvents by stoichiometry of the complex in solution.449,450 Pen-
optical and electron microscopy revealed the presence tamer 53, which can bind 2 equiv of isophthalic acid
of entangled fibers. This behavior was attributed to in solution (stoichiometry determined by Job’s
the intermolecular aggregation of the helical confor- method449,450), was also examined by X-ray structural
mation 52, similar to previously described systems.382 studies. Eight H-bonds were revealed corresponding
These results show that the proper use of intermo- to the planar configuration of the complex (Figure
lecular interactions between a host and guest mol- 95). Overall, these results show that the binding of
ecule can template helical conformations and higher a guest can modulate the conformation of its respec-
ordered structures in solution. tive host and that extending the host backbone can
b. Phenylene-Pyridine-Pyrimidine Ethynyl- result in multisite foldamer receptors.452
ene Backbones Templated by Isophthalic Acid.
Moore and co-workers reported a phenylene ethynyl- E. Backbones Utilizing Metal Coordination
ene-based isophthalic acid receptor that can be
extended to a dual-site complex.451 While this system 1. Overview
does not utilize aromatic stacking to adopt a planar Up to this point in the review, foldamer structures
conformation, it does employ the rigidity of a phenyl- primarily stabilized by hydrogen bonding and aro-
acetylene backbone to properly bind its guest via matic-aromatic stacking have been considered. At
H-bonding. Cocrystallization of the precursor trimer the same time, a significant amount of work has been
and isophthalic acid gives single crystals of a complex conducted on chains that fold upon binding ionic
suitable for X-ray structure determination. The re- species, especially coordination of metal ions, termed
sulting complex clearly displays four H-bonds and helicates.453 The folding reaction of these backbones
3964 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 95. Crystal structure of a trimeric receptor with two molecules of bound isophthalic acid.
Figure 97. All-transoid solution conformation of qtpy, and the all-cisoid coordinated form.
Figure 98. Two different single-stranded qpy helicates in two different Re oxidation states. Crystal structures are shown
for each.
Figure 99. Solution equilibrium of a dinuclear qpy Zn(II) helicate containing a bridging hydroxide.
however, adopt helical conformations upon metal In the Re(I) helicate, the dinuclear coordination mode
coordination and demonstrate various folded archi- in the S-shaped conformation is adopted in order to
tectures, although becoming increasingly insoluble alleviate steric hindrance in alternative complex-
with longer lengths. Recent approaches that incor- ations (as well as to accommodate the geometric
porate 4-tert-butyl phenyl469 and n-propylthio side preferences of the CO ligands) with the dihedral
chains470 greatly aid in solublizing these oligomers. angles between the central ring and the bipy frag-
The ability of metal ions to optimize their coordi- ments opening up to 110° and 112°. 1H NMR con-
nation sphere while minimizing their geometric firmed that the solid-state conformations of both
constraints results in the ability to selectively coor- complexes were retained in solution. Similarly, a
dinate to preferred segments within a chain molecule. single-stranded 6,6′′′′-dimethyl-qpy chain binds two
This is a powerful supramolecular construct for
Zn(II) ions (bridged by a hydroxyl group) and two
foldamers whose level of architectural control has not
acetate species. In the solid state, bipy and tpy
been fully exploited. For instance, with Re(III),
quinquepyridine (qpy) (n ) 5) adopts a mononuclear, oligomer segments bind separately in order to ideally
all-cisoid helical complex (also observed in a [Ag(qpy)]- match steric constraints and satisfy the coordination
[PF6] complex471) (Figure 98). With Re(I), one of two spheres of the Zn(II) ions (Figure 99).473 In solution,
isolated crystals was determined to be the dinuclear the central pyridine coordinates to either of the Zn(II)
helicate where the metal ions partition the oligomer ions in a dynamic equilibrium as evidenced by 1H
into two bipy segments, leaving the central pyridine NMR. With sexipyridines (spy), Eu(III) forms a
uncoordinated.472 With Re(III), the helical conforma- monohelical, 10-coordinate complex through torsional
tion occurs by interannular twists in the backbone adjustments in the backbone to minimize chain end
to assuage steric interactions between the termini. interactions,474 while with Pd(II), spy coordinates to
3966 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 100. Structures of cyano-substituted oligo(m-phenylene ethynylene)s and a space-filling model of 54 coordinated
to two Ag+ ions. Side chains have been omitted for clarity.
to their role as precursors in the generation of natural In general, DNA strands adopt unique conforma-
products such as macrocyclic porphryins. Sessler and tions upon association through interstrand contacts.
co-workers synthesized fully conjugated hexapyrrin On the other hand, not only does RNA form duplex
with four n-propyl side chains. Crystallization of the structures, but also single chains also commonly fold
dihydrochloric acid salt of this foldamer showed the through intrastrand interactions into complex sec-
chain to lie in a completely planar conformation, ondary structures such as hairpins and loops.487 Prior
where one chloride ion rests in each of the two clefts to duplex formation, single-stranded oligonucleotides
generated in the “S” shape. This configuration allows show significant conformational preorganization. This
each of the anions to engage in three hydrogen bonds, preorganization is a result of phosphates in the
where one is ionic in character. The dihydrochloric backbone linearly extending the oligonucleotide chain
acid salt was the only analogue generated that through electrostatic repulsion (similar to polyanionic
packed in this way. Data gained from NOE spectros- polymer backbones31) and base-stacking interactions
copy confirmed that the prevalent solution-phase that align the backbone into an expanded state.488
conformation was also planar. Yet, the presence of Upon duplex formation, realignment of the oligo-
an overlapped helix could not be ruled out given that nucleotide backbone proceeds at an entropic cost in
no new cross-peaks could be observed by this method order to maximize the enthalpic gain from intra- and
for such a conformation. interstrand base interactions within the double helix,
thus refining the overall conformation through base
VI. Nucleotidomimetic Foldamers pairing. The recognition selectivity is primarily a
function of the interstrand base-pairing interactions
A. Overview shown in Figure 102. Exhaustive conformational
Although the oligomer systems described thus far analysis of the furanose ring in oligonucleotide
have involved only single chain folding reactions, the backbones has revealed several preferred puckered
field of foldamers is not limited to this definition. In states due to the flexibility of the five-membered ring;
fact, the scope of foldamers extends to multistrand these ring conformations are seen in DNA and RNA
assemblies where oligomer chains associate and fold sequences (Figure 103).487,489 In double-stranded (ds)
through noncovalent intermolecular interactions be- complexes, RNA backbones primarily adopt the 3′-
tween strands. Within this field, nucleotidomimetics endo A-type conformation whereas DNA (d) back-
aim at improving the understanding of natural bones adopt both the A- and 2′-endo B-type confor-
oligonucleotides,478 seeking insight on the origins of mations (Figure 104). These conformations influence
life,479-481 and on the development of antisense the tilting of the nucleobases; the B-type conforma-
(targeting mRNA) and antigene (targeting the major tion orients the bases perpendicular to the helical
groove of double-stranded DNA) agents.482-486 These axis, while the bases of the A-type conformation are
approaches involve correlating structural modifica- inclined ca. 14-20° to the axis.490 The resulting
tion of the backbone and the nucleobases with con- duplex architectures are stabilized through Watson-
formational changes in the chain and the stability of Crick (WC) base-pairing and have information-rich
the generated duplexes. Conformational changes are surfaces both in the major groove, where oligonucle-
measured directly by NMR and other structurally otides can bind through Hoogsteen (H) pairing to
determinant techniques or indirectly by thermal form triple-helical assemblies, and the minor groove,
denaturation using classic UV melting curves. which contains sites for small molecule interac-
To our knowledge, the literature has not completely tions.487
connected these structures with foldamers since the
The successful design of an oligonucleotide folda-
motivation for research in this area derives primarily
mer will be evaluated in two ways: first, the ability
from generating stable supramolecular complexes.
Because of this, studies of nucleotidomimetic foldam- of the foldamer to adopt backbone conformations that
ers can best be summarized as “research on foldam- promote base interactions, both pairing and stacking,
ers” where the folding reaction is implied but not the by their intra- or intermolecular stability and, second,
central focus as it has been with peptidomimetic and the demonstration of attributes such as cooperativity
single-stranded abiotic foldamers. From the perspec- and base selectivity that provide insight into the
tive of the foldamer field, nucleotidomimetics aim to folding reaction. This survey will primarily focus on
ascertain the interdependence between sugar-back- backbone modifications of the carbohydrate, linkage,
bone conformations and the strength of interstrand and nucleobases (for reviews, see refs 486 and 491),
interactions. That is, given the variety of sequence- and to a lesser extent foldamers that bind in the
dependent pairing motifs and complex-induced con- minor groove of oligonucleotide duplexes. On the
formations possible in natural oligonucleotides, it is whole, nucleotidomimetic foldamers are robust. This
of interest to determine how variation of the back- behavior is perhaps a fundamental property of re-
bone affects the mode and selectivity of strand peating, polyelectrolyte chain molecules. They can
association. Examples described herein can afford an tolerate a variety of modifications within the back-
expanded conceptualization for the construction of bone while retaining their duplex stability primarily
novel foldamer complexes while at the same time due to a well balanced set of supramolecular inter-
approach the field from the point of view of chain actions that, most importantly, includes electrostatic
folding and association. Just as with peptidomimetic repulsion. It is worth mentioning that thermal de-
foldamers, nucleotidomimietics are approached naturation data provided in this discussion is system
through a top-down design, and therefore, the success specific, and therefore, comparisons can only be made
of structural modification is often ascertained by to isostructural systems studied under identical
direct comparison to their biological counterparts. conditions.
3968 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 102. Common nucleotide base-pairing motifs and acronyms used throughout this section.
Figure 107. Alternative oligonucleotide backbones investigated with aldohexoses (CH2O)n (n ) 4, 5, or 6). Bold indicates
backbone bonds.
and ζ from 180° to -170° to preserve the proper chair Duplexes of p-RNA having strands of opposite
conformation of the ring for pairing interactions chirality form through alternative base-pairing modes
(confirmed from UV melting curves of duplexes). This such as reverse Watson-Crick (RWC) pairing.532 The
is believed to be a result of minimized steric inter- noncanonical bases, isoguanine (isoG) and 5-methyl-
actions between the phosphate linkage, the equato- isocytosine (5-Me-isoC), that have the potential to
rial hydrogens on ribopyranose (distances increase participate in RWC pairing with homo-G and -C
about 1 Å), and increased interstrand stacking through strands were incorporated into L- and D-p-RNA
decreased base distances (from over 4 to ca. 3.5 Å). strands. Both homochiral (D/D) and heterochiral (L/
These results suggest that the backbone realignment D) duplexes of homomeric strands were compared, in
is a consequence of the intermolecular association. terms of melting curves, to determine the degree of
Observed χ values ranged from -120° to -135° specificity dictated by the backbone stereochemistry.
within the sequence, while the terminal G residue Strands of D-p-isoGn and D-p-Cn (n ) 6 and 8) did not
had a much lower χ value indicating higher confor- show any self-pairing or duplex formation under the
mational lability at this position. Proton exchange given conditions, while duplex formation was ac-
experiments and molecular-dynamics simulations complished using the L-p-isoGn with D-p-Cn (n ) 6
supported WC pairing throughout the duplex and a and 8). The isoG bases promote RWC pairing with C
rapid opening and closing of the terminal base pairs. in this duplex, allowing for proper co-linear orienta-
Interstrand NOEs confirmed an antiparallel orienta- tion of the strands. Other p-RNA mixtures were
tion resulting in the inclination of the base pair from shown to form L/D but not D/D duplexes most likely
the backbone by an angle of 35° and 45°, suggesting through the RWC pairing mode, though pairing
that interstrand base interactions should be favorable assignments in the case of D- and L-p-isoGn remain
for purine-purine and purine-pyramidine stacking uncertain since mixing curves showed aggregate
but not between two pyramidines. In addition, an formation. The p-RNA chains of opposite chirality
inter-pyranose distance between 3.6 and 4.0 Å was pair inefficiently as evidenced by the lower melting
calculated, producing a translational step of 6.5-6.9 temperatures of duplexes formed from mixing homo-
Å along the backbone and a pitch of ca. 110 Å, chiral D-p-RNAs with complementary L-p-RNAs. This
incorporating 18-19 monomers per turn. enantioselectivity, as well as the observed pairing
Through oligomerization of β-D-ribopyranosyl phos- selectivity (WC only), is believed to be due to the more
phoramidite derivatives526,527 by automated synthesis conformationally restrained p-RNA backbone. It has
and purification by HPLC, adenine (A) and uracil (U) only four flexible bonds (as opposed to six in DNA)
containing p-RNA octamers were initially synthe- due to the three large substituents occupying equa-
sized and characterized to ascertain the stability of torial positions. Furthermore, the more constrained
the duplexes formed.528 Although self-pairing A8 phosphodiester linkages connect to secondary carbons
duplexes have formed in other alternative oligonucle- on the ring, whereas DNA linkages attach to a
otides,529 p-A8 remains as a single strand under these primary carbon (5′) allowing for greater flexibility.
conditions, indicating that alternative pairing inter- Finally, the alignment of the nucleobases as a
actions are disfavored due to the topological backbone consequence of the backbone conformation promotes
constraints in this pairing mode, thus enhancing the antiparallel interstrand interactions through WC
oligomer’s pairing selectivity. The WC paired duplex base-pairing only, since H and reverse-Hoogsteen
formed from a 1:1 mixture of p-A8 and p-U8 revealed (RH) pairing disfavor the preferred co-linear chain
concentration-dependent and reversible UV melting orientation. This study demonstrates the ability of
curves, temperature-dependent CD spectra, and com- p-RNAs to form duplexes with the same or opposite
position-dependent UV absorptions with a minimum sense of chirality backbones, depending on the spe-
at a 1:1 stoichiometry. The self-complementary octa- cific nucleobases used.
mers, p-A4U4, p-U4A4, p-(AU)4, and p-(UA)4, show In order to mimic RNA architectures and their
duplex formation by self-pairing in an antiparallel conformational diversity, a necessary secondary struc-
orientation.530 Additionally, the higher melting tem- ture is the hairpin turn, a sequence-dependent
perature of the p-A4U4 duplex in comparison to the structure promoted by intramolecular base pairing
natural RNA oligomer indicates an increased stabil- over interstrand interactions. Investigations of hair-
ity through stronger base-pairing interactions. This pin formation in a series of self-complementary
is attributed to the smaller entropic cost of organiza- p-RNA base sequences studied at low concentrations
tion necessary to form the p-RNA duplex since the (3 µM) with a central p-T2 segment resulted only in
quasi-linear rigid chain is preorganized for the proper duplex formation while with three T bases competi-
WC pairing orientation. Other nucleobases incorpo- tive duplex formation was observed in melting curves
rated into p-RNAs for duplex formation studies at higher concentrations.533 Only at the critical length
include guanine (G), cytosine (C), isoguanine (isoG), of four T bases did the oligonucleotide show a similar
2,6-diaminopurine (Dp), and thymine (T).531 In a Tm at both concentrations, indicating a stabilized
chain-length study, UV and CD spectra confirmed hairpin. Furthermore, hairpin p-RNAs synthesized
that p-Gn (n ) 6, 8, and 10) exist as single strands with a noncomplementary base (A or C) at either the
at ambient temperature (as do the p-isoG8 and p-Dp8 2′- or 4′-end supported the expectation, from modeling
strands). In equimolar mixtures of oligo-p-Gn and of p-RNA duplexes,525 that a dangling base at the 2′-
oligo-p-isoGn (n ) 6 and 8), duplex formation proceeds end would stabilize the structure through interstrand
through purine-purine WC pairing showing higher stacking of the two terminal bases with purine-
thermal stability than DNA sequence analogues. purine contacts leading to greater stability than
3972 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 111. Two idealized conformations of the homo-DNA backbone. Conversion from A to B occurs through a 120°
rotation about R and γ of the phosphodiester linkage.
ents of the hexose chair conformation in equatorial (2′-eq, 3′-eq) (Figure 107).521 The presence of these
positions (Figure 111). A much looser orientation of hydroxyls causes intrastrand steric repulsion in the
base pairs was observed through a range of adopted duplex conformation that disrupts WC base pairing,
χ torsions in addition to extensive fluctuations in encourages purine-purine RH self-pairing in allo
base-pair distances, deviation from coplanarity, and and altro backbones, and leads to sequence-depend-
a base-stacking distance of ca. 4.5 Å. ent and lower Tm values than for RNA. For the self-
In general, homo-DNA duplexes demonstrate a complementary sequence CGCGAARRCGCG (R ) U
pairing priority of G-C > A-A ∼ G-G > A-T where in allo and altro backbones, T in DNA and homo-
G-C and A-T pair through the WC motif while RH DNA), no duplex formation was observed for allo and
pairing occurs in A-A and G-G dd-sequences.529 altro backbones at room temperature (though Tm
Through a chain-length study on dd-An (n ) 3-6), values increased at lower pH) in great contrast to
self-paired duplexes showed increasing UV melting both DNA and homo-DNA. The inclusion of hydroxyls
temperatures with increasing chain length (for n ) in the hexopyranosyl backbones must induce the
3, no Tm; n ) 4, Tm < 12 °C; n ) 5, Tm ) 32 °C; n ) backbone to adopt conformations that disfavor the
6, Tm ) 43 °C) and increasing concentrations (from folded state necessary for ideal base pairing in the
4.9 to 92 µM, ∆Tm ) 15 °C), sigmoidal hypochromicity duplex.
curves (dependent on [NaCl]; where [NaCl] ) 15 mM Other variants of hexoses include 2,4- and 3,4-
to 1.5 M, ∆Tm ) 9 °C), and temperature-dependent dideoxyhexopyranosyl backbones542,543 and have simi-
CD spectra. Self-complementary dd-(AT)n (n ) 3-6) lar connectivities to iso-DNAs but incorporate meth-
duplexes showed high stability with melting curves ylene groups into the ring between the C1-C2 and
ca. 30-40 °C higher than in the corresponding DNA C2-C3 connections. With one to four multiple-T
duplexes. Though the self-paired duplex (dd-A6)2 substitutions of either modified monomer into DNA
persisted when mixed with the complementary dd- 13-mers, the 3,4-backbone destabilized the duplex
T6, the self-pairing dd-G6 could be disrupted with dd- with complementary d-A13 to a higher extent than
C6 to form the heterostranded complex. Further the 2,4-modification, although these heteromeric
investigations into the pairing properties of dd-purine duplexes retain cooperative transitions. The effect on
sequences revealed WC pairing between dd-(G)n/dd- the duplex with the 3,4-connectivity is similar to the
(isoG)n and dd-(Dp)n/dd-(xanthines)n (X) while dd- results obtained with homo-DNA. Homomeric 2,4-T13
(isoG)n and dd-(Dp)n oligomers self-pair through RH oligomers were unable to form duplexes with the
motifs.541 Overall, sequence discrimination is lower complementary DNA.
in homo-DNA than DNA due to the linear orientation
of the strands, inefficient base-stacking, and the 2. Backbones with C2′-Base Connectivities
conformational rigidity of the hexose ring which leads a. Isonucleosides. Another modification of deoxy-
to a preorganization of the single strand and de- nucleotides involved the repositioning of the base-
creases the conformational entropic cost of duplex sugar connection from the C1- to the C2-position to
formation. afford 1,4-anhydro-2-deoxy-D- and -L-arabinitol,544
ii. Other Hexoses. In homo-DNA as in DNA, hy- dubbed isonucleosides (Figure 112). In 14-mer strands
droxyl groups are not present as they are in RNA with homo-T bases, D-arabinitol formed slightly less
and the pyranosyl backbones described thus far. stable duplexes with d-A14 (∆Tm ) -5.9 °C) than with
Further investigations into hexopyranosyl (6′f4′) d-T14, while L-arabinitol was unable to complex with
backbones incorporated 2′- and 3′-hydroxyl groups in this complement.545 Addition of a methylhydroxyl
β-allo (2′-eq, 3′-ax), β-altro (2′-ax, 3′-ax), and β-gluco moiety to the C1′-position of the D-arabinitol gener-
3974 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 124. Crystal structure of a peptide nucleic acid duplex (left).901 For clarity, one strand is colored yellow and the
other uses conventional atom colors: PNA2-DNA triplex (right).710 Four chains are shown. The DNA chains are colored
yellow and blue. The DNA sequence is 5′-(GAAGAAGAG)-3′. The PNA chains are colored red and green. The PNA sequence
is H2N-(CTCTTCTTC-His-Gly-Ser-Ser-Gly-His-CTTCTTCTC)-CO2H.
Figure 131. β-Strands and β-sheets incorporating the artificial amino acid Hao.
peptide β-sheet formation and nucleotide base pairing dimerization depends on the association strength of
as seen in DNA. The majority of these systems the sequence-selective algorithm.
establish a sequence of H-bond donors (D) and Nowick and co-workers described β-strands and an
acceptors (A) through heterocyclic amide- or urea- artificial β-sheet that form strong, H-bonded dimers
linked monomers. Through both theoretical774,775 and in CDCl3.157,773 To prevent indefinite association
experimental776 work, determination of association typical of β-strands, the unnatural amino acid “Hao”
constants for triply hydrogen-bonded complementary was designed to allow H-bonding on only one edge of
complexes were shown to be highly dependent on the a β-strand mimic (Figure 131).155,157 Hao is an amimo
D/A sequence, with the strongest complexation oc- acid based upon hydrazine, 5-amino-2-methoxyben-
curring between all-D and all-A strands, while mixed zoic acid, and oxalic acid constituents. This peptido-
or alternating D/A sequences showed weaker associa- mimetic building block maps onto a tripeptide seg-
tions due to repulsive secondary electrostatic inter- ment and hence can be considered as an η-peptide.
1H NMR chemical shift data, NOE studies, and
actions. Higher levels of complexity can be achieved
in moieties capable of D/A tautomerization and intra- dilution experiments indicated that the peptide de-
molecular H-bonding in addition to intermolecular rivative 60 strongly dimerized in pure CDCl3 with
association.777,778 Through these motifs, differentia- an association constant of ca. 106 M-1. As expected,
tion between competitive self- versus complementary the association constant was considerably lower upon
3984 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 132. Oligo(arylamide)s complexed through self-complementary ADAD and AADD duplexes and a complementary
ADAADA/DADDAD strand.
addition of 10% MeOH. An artificial sheet was speculated to be a result of decreasing intermolecular
constructed in which the Hao unit was attached to stacking interactions. Self-association of both 63 and
one end of Nowick’s previously described molecular 64 could produce dimers stabilized by four H-bonding
scaffold while to the other end an R-tripeptide was interactions. The self-complexation association con-
connected. This structure resulted in an artificial stant for 64 was determined to be approximately
β-sheet that dimerized in solution via the H-bond 4 × 104 M-1 compared to the lower limit 63:64
donors and acceptors on the top edge.773 association constant of 9 × 107 M-1. Recent studies
Arylamide oligomers with various D/A sequences showed that mismatches in the AD sequence lead to
have been recently investigated by Gong et al.445,446 a conformational rearrangement of the backbone
Quadruply H-bonded complexes, 61:61 and 62:62, driven by steric interactions that resulted in >40
with D/A sequences DADA and DDAA, respectively, times lower duplex stability as evidenced by isother-
were shown by 1H NMR and X-ray studies to dimer- mal titration calorimetry.779
ize through self-complementarity from two dimeric A system capable of two-state conformational
strands (Figure 132). The association constant of switching has been produced from two complemen-
62:62 was determined to be marginally more stable tary naphthyridinyl urea oligomers (Figure 133).780
than 61:61 (6 × 104 M-1 vs 4 × 104 M-1) even though Both linear molecules 65 and 66 form associated
more favorable electrostatic interactions exist with structures through intramolecular H-bonding by
62. Although some torsional flexibility exists in both rotation about the arylamide bonds. In frame-shifted
foldamers, these H-bonded duplexes form readily (relative to 66) monoaromatic 65, the folded confor-
through both intra- and intermolecular H-bonds to mation is observed to intermolecularly associate to
adopt planar, β-sheetlike structures. Extension of produce oligomeric species (of unknown n) through
these preliminary studies to trimeric oligomer lengths noncooperative association at all concentrations. At
enabled the formation of self-complementary planar low concentrations, the bent form of 66 associates to
duplexes stabilized by six H-bonding interactions.446 form dimer 67, while at higher concentrations the
The two symmetric heterotrimers, 63 and 64, have extended conformation of 66 dimerizes to 68. Upon
two and four intramolecular H-bonding interactions mixing of 66 and 65, a complementary complex 69
and D/A sequences of DADDAD and ADAADA, self-assembles with the extended, planar conforma-
respectively. Preorganization through intramolecular tions of both molecules at all concentrations. This
H-bonding interactions predispose these oligomers to occurs since the association constant for the forma-
planar, extended conformations, exposing sequence tion of 69 is greater than either of the duplexing
sites for intermolecular association. NOESY experi- modes.
ments under complexing conditions (i.e., CDCl3) Bis-2-ureido-4[1H]-pyrimidinones are capable of
confirmed the close interstrand proximity of the self-associating into a duplex structure stabilized by
methylene groups. Slight downfield shifting of a NH eight H-bonding interactions with 70 that are adap-
signal in 64 upon dilution (100 to 10 µm) was tive through a keto-enol tautomerization (Figure
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3985
Figure 133. Intra- and intermolecular pairing modes for DDAADD and AADDAA strands.
134).781 In 70, two D/A sequences, the keto DDAA and stacking and intermolecular H-bonding where crys-
the enol ADAD, are possible through proton transfer tals obtained from DMF revealed two possible syn
and a switch in the intramolecular H-bonding by a coplanar orientations in the solid-state while crystals
N-C rotation in the urea moiety. X-ray analysis of grown from CHCl3 showed anti or helical orienta-
crystals revealed pyrimidinone aromatic-aromatic tions. NOE and 2D-ROESY experiments revealed
3986 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 136. Self-complementary oligomer in a zipper structure. Dotted lines indicate edge-face aromatic-aromatic
interactions.
mM) indicate the presence of a single species as shifting of several of the aromatic signals and an
evidenced by a single set of sharp 1H NMR signals. X-ray crystal structure from DMSO/CH3CN showed
Aromatic stacking as demonstrated by the upfield the expected helical conformation.
3988 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 138. Series of oligo(pyridylamide)s capable of forming single- and double-stranded helices.
Figure 140. M and P helical conformations of double helicates from a dimer with a chiral ligand.
Figure 141. Head-to-head and head-to-tail conformations of double helicates from substituted qtpy ligands.
octahedral coordinations incorporate only six of the (1R,1R)-(+)-R-pinene-terminated strand was also
seven pyridines in the backbone, leading to strand synthesized and proved to form the M helicate after
slipping in solution.470 To design out this molecular crystallization. The origin of selectivity arose from
motion, 1,3-phenylene monomers incapable of coor- interactions of the pinene end groups with the
dinating to the metal ions have been used to replace pyridine ligands in the backbone. Additionally, the
the central positions in qpy,798 spy,799 and septipy800 Cu(I) helicates from this ligand formed in solution
strands, thereby dividing the chain into localized with 98.7% de, and after crystallization, again only
coordinating segments. Alkynyl linkages have also the P helix was isolated. Qpty strands with thioethyl
been incorporated into oligopyridine backbones pro- side chains and a methyl end group at the 4′-position
moting helicate formation by maintaining the rigidity were reacted with Cu(I) to produce a 3:2 mixture of
of the backbone while decreasing interstrand steric the head-to-head (HH) and head-to-tail (HT) configu-
interactions.801,802 rations, as evidenced by 1H NMR (Figure 141).806
Helicate duplexes incorporating symmetric oligo- Variation of the side chain and the end group by
mers do not possess strand directionality, unlike systematically incorporating bulkier groups at these
(3′f5′) oligonucleotide duplexes. To enhance archi- positions revealed no increased selectivity when
tectural control of these assemblies, the covalent groups such as ethyl or tert-butyl were employed as
attachment of chiral end groups, either through the the end group while the thioethyl side chain re-
incorporation of fused moieties or attachment through mained.807,808 In the absence of a side chain, the tert-
single bonds to terminal chain ends, has been ex- butyl-terminated quaterpyridine helicate formed the
plored. Qpty strands incorporating fused chiral (1S)- parallel HH configuration exclusively. All other cases
(-)-R-pinene end groups formed M and P helical resulted in a mixture of HH and HT with the HH
complexes with Ag(I) (Figure 140). 803-805 Diastereo- configuration preferred. It was speculated that this
meric excess in these complexes can shed light on the preference was dependent on the electronic character
effect of interstrand steric interactions on the ther- of the side chain and the resulting helical pitch due
modynamics of helicate formation. It was found in to steric interactions between intrastrand substitu-
CH3CN that a 0.024:1.0 ratio (95.3% de) of complexes tions at either the side chain or end group. Constable
formed. Upon crystallization, only the major isomer and co-workers809-811 utilized a terpyridine ligand
was isolated which was identified as the P helix. The coupled to (1S)-(-)-borneol at one terminus to impart
3990 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 142. Solvent effects on the formation of helicate structures from a terpy strand. Head-to-tail double-stranded
helicates obtained from borneol-terminated terpy ligands.
asymmetry in the helicate complex (Figure 142).809 oligopyridine-based chains that can adopt ideal, less
Since this strand lacks a C2-symmetric axis, four constrained coordination geometries within helicate
possible helicate isomers may be realized. Molecular assemblies. One of the most thoroughly investigated
modeling studies revealed that the HH isomers are systems involves the incorporation of methyl(methoxy)
much higher in energy due to steric repulsion of the ether linkages between bipy or terpy segments.
borneol units. Reaction of the ligands with [Cu- Initial chain-length studies showed these modified
(MeCN)4][PF6] formed a 6.5:1 ratio of two unidenti- oligomers of varying length (n ) 3-5) form homo-
fied components in CH3CN by 1H NMR, presumably stranded helicates with Cu(I)812 (Figure 143) and
the two diastereomers of the HT configurations. Ag(I)813 in CH3CN.814 To investigate self-recognition
Crystallization of this mixture produced only the selectivity, a mixture of 2 equiv of the dimer, 1 equiv
major isomer, which was shown to be the (S)(S)-(M)- of the tetramer, and 3 equiv of Cu(I) produced only
HT by X-ray analysis. It is unclear why the M helix the homostranded complexes, demonstrating the
was favored over the P helix. With Ag(I), the equi- preference for homostranded complexation.815 Further-
librium between the mononuclear complex and the more, a mixture of all four oligomers, upon addition
dinuclear helicate could be shifted by the choice of of Cu(I), also formed only the homostranded double-
solvent.810 Acetonitrile solutions favored the mono- helical structures after reaching equilibrium. Given
nuclear complex through competitive solvent coordi- the lack of heterostranded complexes, this system
nation, while less coordinating solvents such as demonstrates length dependence and multinuclearity
methanol and nitromethane favored the helical du- matching in the self-recognition process. This ex-
plex, as confirmed by both 1H NMR and CD. ample further reveals the sensitivity of the associa-
tion to alignment mismatches. Self-organization in
2. Linked Oligopyridines the assembly of these strands has been shown to be
cooperative.816,817 The attachment of thymine-
a. Ether-Linked Oligopyridines. The incorpora- nucleoside side chains to these oligopyridine strands
tion of flexible linkages within the backbone provides produced a double helicate with nucleosides extend-
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3991
Figure 144. Heterostranded heterotopic double-stranded helicates from tpy-bipy-tpy and bipy-tpy-bipy trimers.
Figure 145. Heteronuclear double-stranded helicates from trimers incorporating bipy and tpy ligands.
ing out from the ionic interior,818,819 an architecture systematic look at bipy/phen mixed trimers involved
similar to one once proposed as the structure of the synthesis of bipy3, bipy-phen-bipy, phen-bipy-
DNA.820 phen, and phen3 trimers complexed with Cu(I) and
A variety of heteromeric oligopyridine-based strands Ag(I) (Figure 147).823 The homooligomeric phen se-
have been synthesized and complexed into helicates quence formed a double-stranded helicate with Cu(I),
to assess the impact of non-bipy ligands on self- although a mixture of helicate complexes resulted
assembly. Two trimeric oligomer strands incorporat- upon addition of Ag(I). An excess of Ag(I) shifted the
ing a bipy-tpy-bipy and a tpy-bipy-tpy oligomer equilibrium toward the double-helical complex com-
were generated and complexed with pentacoordinate- pletely. The heterotopic strand of phen-bipy-phen
preferring Cu(II) ions (Figure 144).821 Only the formed double-stranded helicates with both Cu(I) and
heterotopic, heterostranded helicate was obtained Ag(I), indicating that the central unit in the ligand
after crystallization. These structures are reminis- may influence the stability of the helicate through
cent of DNA base matching in that the two separate steric interactions.
strands encoded with complementary ligands form To probe heterostranded helicate formation, mix-
into a single complex through segment matching. tures of these four ligands under helicate-forming
Upon addition of 2 equiv of Cu(I) and 1 equiv of conditions were tested (Figure 148). It was found that
Fe(II), both bipy-tpy-bipy and bipy-bipy-tpy oligo- whether the ligands were mixed prior to ion addition
mers formed homostranded, heteronuclear helicates or helicate solutions were mixed together, the hetero-
(Figure 145). Phen segments, having similar struc- stranded helicates were thermodynamically favored
ture and denticity to bipys but lacking torsional providing statistical (1:2:1) helicate distributions.
flexibility, have also been incorporated into these Further investigation into the role of the central unit
oligomers, and double-stranded helicates were formed in double-stranded helicates from trimers allowed
from Cu(I), Ag(I), and Zn(II) (Figure 146).822 A more determination of binding affinity by cyclic voltam-
3992 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 151. Homo- and heterostranded helicates from two different bipy strands.
methyl groups extend outward to minimize steric into two discrete homostranded helicates: a double-
repulsions. Rigid, chiral bridges such as spirobisin- stranded, tetrahedral Cu(I) complex with the ether-
danol or dimethylbiphenic acid, tethering two bipy3 linked strand and a triple-stranded, octahedral Ni(II)
oligomers, can effectively bias the twist sense of a complex incorporating the alkyl-linked strand. No
Cu(I) helicate by dictating the absolute configuration heterostranded species were observed by 1H NMR or
of the strands through more rigid constraints (Figure ESI-MS. Here, the end groups of the strands, as well
150).826,827 as the nature and length of the linker group between
b. Alkyl-Linked Oligopyridines. With the suc- the ligands endow the oligomer with structural
cess of the ether-linked bipy helicates, other linkages information that directs the self-assembly process.
involving ethyl- and ethylene-linked bipy trimers The power of self-recognition processes in the forma-
were explored.828 Oligomers incorporating the alkene tion of highly organized structures is clear in this
spacer did not produce a discrete double-stranded case: 11 chemical components of four types (two
helicate with Cu(I) as evidenced by 1H NMR, due to organic oligomers and two transition-metal ions)
the lack of flexibility in the backbone. On the other combine to form two discrete supramolecular species.
hand, the ethyl-linked strands were effectively in- At the same time, the ether-linked bipy3 and the
corporated into the complex. An imine linker has also ethyl-linked tpy3 oligomers formed a heterostranded
been utilized to form double-stranded helicates with
helicate which was able to form through complex-
Cu(I) and Ag(I).829 When the alkyl- and ether-linked
ation with Cu(II) (Figure 153).832 Although the Cu-
oligomers were mixed under helicate-forming condi-
(II) ion prefers a pentacoordinate geometry, trigonal
tions to test for recognition, a mixture of homo- and
bipyramidal and square pyramidal coordination are
heterostranded complexes was formed in a ratio of
both possible. In this case, the central copper coor-
2:2:1 (Figure 151). At equilibrium, the homostranded
dination adopted a trigonal bipyramidal geometry
helicate is favored over the heterostranded helicate,
deviating from the statistical distribution, presum- while the terminal ends of the strands coordinate to
ably due to the electrostatic attraction between the the terminal copper through square pyramidal ori-
oxygen and Cu(I) ions and the lower flexibility of the entations as evidenced by X-ray analysis. This occurs
ethyl linker. Furthermore, ethyl-linked bipy3 strands since the steric demands at the termini are not as
formed triple-helical complexes with Ni(II),830 while stringent as the central segments.
ethyl-linked tpy3 complexed with Fe(II) produced When the ethyl-linked bipy3 oligomer was com-
double-stranded helicates,831 where both complexes bined with an equimolar quantity of FeCl2 in ethyl-
formed through octahedral coordination geometries. ene glycol at 170 °C, a pentameric circular helicate
To test the self- vs nonself-recognition selectivity was exclusively produced (Figure 154).833 This com-
between the ether and alkyl bipy strands, Cu(I) and plex is believed to form from templation by the Cl-
Ni(II) where added to a mixture of these two oligo- counterion. Further investigations into this system
mers (Figure 152).815 These trimers self-assembled with a variety of counterions revealed a second
3994 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 152. Formation of only homostranded helicates from a mixture of two different bipyridine trimers. Crystal structure
of the Ni(II) triple-stranded helicate with the alkyl-linked trimers is shown.878
circular helicate, the hexameric complex, in which the accelerated the dissociation of the metal complexes.
counterion is believed to also bind in the central In this case, a 2:1 ratio of the circular vs the linear
cavity.834,835 When a hexanuclear circular helicate Ni(II) species was obtained after a period of 4 days,
prepared using FeSO4 was heated in the presence of at which point strand decomposition became a factor.
Cl-, 1H NMR and ES-MS analysis revealed the shift Hence, the additional flexibility of the alkyl linkage
to the pentameric circular helicate exclusively. This within the backbone provides the torsional freedom
indicates that the Cl- ion can selectively template in the chain necessary to adopt a variety of confor-
the pentameric assembly from the equilibrating mations within the various helicate complexes.
mixture of complexes. Investigations into the mech-
anism of this circular helicate formation revealed 3. Pyridine Analogues
that the kinetic product of this reaction is the linear A variety of helicates incorporating pyridine-based
triple-stranded helicate, which over the course of 24 analogues have been described in the literature
h reassembles into the thermodynamic product, the including methylene-linked benzimidazoles837 and
pentameric circular helicate.836 Similar results were their derivatives,838-840 bis(phenyloxazolinyl)pyri-
obtained with the use of NiCl2 under conditions that dines,841,842 bis(pinene-bpy) ligands,843 and bis-imino-
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3995
Figure 153. Formation of heterostranded helicates from a bipy trimer and terpy trimer.
quinolines.844,845 While these ligands effectively form mismatching could only be compensated by higher
helicates with a variety of metal ions, we do not order strand incorporation. Variable temperature 1H
consider them as foldamers since it is difficult to NMR studies revealed a dynamic rearrangement
envision how their chain lengths may be easily involving a twist sense reversal within these triple
extended, a similar criteria that was used for ruling helicates wherein one or more strands pass through
out many of the receptor systems. Since they do not a meso state in which the strands adopt a parallel,
satisfy our criteria for foldamers, we will not discuss fully extended conformation.851,852 Related dimeric
them further (some of these systems have been catecholamides form triple-helical complexes with
discussed in recent reviews457). However, dipyrro- either Ti(III) or Ga(III). Yet, upon the addition of
methene oligomers, structurally isomorphous to the Me4N+, these complexes are intercoverted to a tetra-
phytochromobilins,846 have been recently shown to hedral cluster in order to provide the necessary cavity
form double-stranded helicates with Zn(II) and Co(II), space to accommodate the cationic guest (Figure
where a hexameric strand complexes to Zn(II) in a 157).853,854
3:2 ratio (Figure 155).847 The oligomers have also Self-recognition processes have also been demon-
been extended to incorporate alkyl spacers of varying strated to coincide with template-driven helicate
length.848,849 formation.855 Dimeric catechol-derived strands, previ-
ously shown to bind Li+ 856,857 or Na+ 858 within triple-
4. Catecholates stranded helicates, were synthesized with methylene
Catecholates also have the ability to form helicates and ethylene spacers, and the mixtures were coor-
when complexed to gallium and titanium metal dinated to “Ti(IV)” in the presence of different
ions.455,457 Investigations into the effect of spacer carbonate bases to form triple-stranded helicates.
length (and the distance between the metal ions) on When the helicate was prepared using Na2CO3, only
self-recognition were conducted with catecholamide the homostranded species were observed. Upon ad-
ligands.850 Ditopic ligands with three different aro- dition of Li2CO3, both homostranded species were
matic spacers were synthesized and complexed with observed along with a heterostranded species (2
Ga(III) to form triple-helical structures (Figure 156). methylene + 1 ethylene strand). When K2CO3 was
A 1:1:1 mixture of the three ligands with Ga(III) used, the ethylene strands formed dinuclear helicates
provided only the homostranded helicates as evi- while the methylene bridged ligands formed indis-
denced by 1H NMR and ESI-MS. The authors argue tinguishable higher oligomeric species. Interestingly,
that the self-recognition process is a combination of when 1:1 mixtures of the bases were utilized, only
effects whereby the helicate structure is favored over the homostranded helicates formed. It is worth
polymeric structures due to an entropic driving force mentioning that a nonaromatic backbone has also
disfavoring the polymeric structure, the rigid spacers been incorporated into a double-stranded helicate.859
disfavoring heterostranded helicate formation, and
the presence of an energetic drive to fully saturate D. Multistranded Receptors
the coordination sphere of Ga(III). In this mixture, Foldamer duplex receptors that assemble through
the lack of flexibility in the spacer promotes forma- multimodal interactions have been developed in order
tion of only the homostranded helicates, since spatial to generate supramolecular host assemblies for
3996 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 154. Penta- and hexameric cyclic helicates formed through host-guest templation. The crystal structure of the
pentameric complex is shown.
molecular recognition of small organic guests.114,860 two oligomer chains, a metal ion, and an organic
This has been accomplished through the use of guest. In this way, the metal-coordinating segments
heterotopic strands with metal-coordinating ligands are conformationally restricted in the complex while
and D/A segments such that self-assembly occurs the D/A segments have the torsional flexibility to
through multiple, noncovalent interactions between potentially accommodate structurally diverse guests.
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3997
Figure 156. Homostranded helicates from catecholate strands with three different spacers.
Figure 157. Formation of a triple-stranded helicate and a tetrahedral cluster from catecholate dimers.
These architectures are more commonly referred to 84, or 85, no shift in the equilibrium was observed
as artificial receptors while at the same time fitting though shifts in the NMR indicated H-bonding inter-
under the categorization of foldamer duplexes since actions between 80 and the guests. However, with
they adopt their unique conformations through these the addition of 86, the proportions of the free ligands
noncovalent interactions and form similar architec- were shifted to 48% of 80 and 52% of 81 through
tures as described in the previous two sections on simultaneous H-bonding between two strands and
multistranded abiotic foldamers. this bridging guest. When similar Pd(II) complexes
In a series of experiments aimed at guest-induced formed with 80 and 81 (where R ) H) in 5% DMSO
equilibrium shifting of metal-coordinated assemblies, in CHCl3, a square-planar coordination geometry
bis(carboxamidobipyridine) ligands with tBu 80 (R ) arranges the strands in a coplanar orientation,
Me or H) and with DAD H-bonding caproylpyridyl thereby suggesting a planar, rigid guest could pos-
81 (R ) Me or H) peripheral groups were complexed sibly shift the equilibrium toward the host-guest
with Cu(I) and Pd(II) ions to form double-stranded, assembly. Binding of the guest shows the ability of
tetracoordinate complexes (Figure 158).861 Through each guest to enhance the formation of complexes,
the addition of complementary (ADA) guests with as indicated by the proportions of ligands involved
varying degrees of flexibility (82-86) in the presence in complexes determined by 1H NMR. Guest 82 is
of 80 and 81 (both R ) Me), a shift in the equilibrium capable of concurrently H-bonding to each strand and
from the 80:80 to the 81:81 complex was promoted stabilizing the 81:81:Pd(II) complex (even enhancing
through H-bonding in the guest assembly. Guests 82 the shift at lower temperatures).
and 84 are rigid, while 83, 85, and 86 have various
numbers of single bonds, which increases their E. Foldamer−Oligomer Interactions
torsional flexibility. With 0.5 equiv of Cu(I), 80 As the final section of this review, we wish to
(1 equiv) and 81 (1 equiv) formed distorted tetra- present more advanced examples of foldamer archi-
hedral complexes in chloroform, and by 1H NMR, the tectures that lay the foundation for the development
degree of uncomplexed ligand was determined to be of backbones capable of homo- or heterostranded
27% of 80 and 73% of 81. Upon addition of 82, 83, foldamer-foldamer interactions seen with natural
3998 Chemical Reviews, 2001, Vol. 101, No. 12 Hill et al.
Figure 158. Multistranded receptor formation through H-bonding and metal coordination.
systems (i.e., protein-protein or protein-DNA in- guanidinium and formyl termini that shows prefer-
teractions). This requires two structurally different ential binding to AT-rich sequences in 1:1 and 2:1
backbones to associate through recognition processes stoichiometries with ds-DNA (in antiparallel orienta-
embedded in the surfaces of their folded conforma- tions) (Figure 159). NMR studies have determined
tions. To date, natural systems that adopt secondary that in a distamycin-A:d(CGCGAATTCGCG)2 com-
structures and template the association and folding plex, two of the pyrroles (Py) remain planar while
of small oligomers (or segments of homomorphous the third ring rotates to conform to the minor groove
backbones) have only been accomplished. These are twist.870 The first chain-length studies (n ) 1-6) on
best described as foldamer-oligomer interactions and modified distamycins effectively demonstrated the
provide insight into this next step within the fol- ability to extend the minor groove sequence recogni-
damer field. tion of small oligomeric molecules.871,872 Through
1. Minor Groove Binding Oligomers incorporation of imidazoles (Im)873 and hydroxypyr-
roles (Hp)874 into lexitropsin oligomers, pairing rules
Major groove binding of oligonucleotide variants for minor groove binding have been ascertained: Py/
through triplex formation has been discussed in Im targets C-G, Py/Hp targets A-T, Hp/Py targets
terms of stability and sequence selectivity. The T-A, and Im/Py targets G-C.875 Since lexitropsin
folding reaction considered here is one in which backbones cannot effectively coil around oligonucleo-
complexation induces conformational order in an tide duplexes at chain lengths higher than five,
unstructured oligomer. Yet, no nonnucleotidomimetic incorporated β-alanine units add flexibility to the
foldamers have been demonstrated to target the oligomer and also enhance sequence recognition.876
major groove,862 suggesting the potential of this Linking of lexitropsin oligomers by γ-butyric acid
unexplored area. However, the minor groove of DNA
tethers allow the 2:1 binding mode to become a
duplexes offers crucial sites for noncovalent supra-
unimolecular process, thereby enhancing affinity by
molecular recognition, as demonstrated by recent
ca. 100.877 A single substitution of imidazole for
X-ray crystal structures of DNA polymerase:ds-
DNA complexes.863-865 Although studies aimed at pyrrole in a lexitropsin hairpin structure showed a
elucidating protein-oligonucleotide interactions are decrease in affinity of 2 orders of magnitude, demon-
currentlybeinginvestigatedwithnucleotidomimetics,866-868 strating the efficient mismatch discrimination in
we limit our discussion here to members of the these oligomers.878 This field has expanded exponen-
lexitropsin and duocarmycin antibiotics, which have tially, primarily due to the work of the Dervan group,
shown considerable progress in adapting these sys- since the development of solid-phase synthetic meth-
tems for more complex sequence recognition. odologies.879 Since this field has been thoroughly
a. Lexitropsins. The lexitropsin class of natural reviewed elsewhere,875,880-883 here we only mention
oligo(N-methylpyrrolecarboxamide)s, isolated from the lexitropsins to draw their connection to the field
streptomyces strains,869 binds in the minor groove of of foldamers; that is, they adopt their unique confor-
duplexed DNA through a combination of van der mations by undergoing a folding reaction through
Waals’ contacts, H-bonding, hydrophobic, and electro- complexation with the ds-DNA minor groove. Hence,
static interactions. Distamycin-A is a crescent- conformational stability is derived by intermolecular
shaped, amide-linked N-methylpyrrole oligomers with noncovalent interactions.
A Field Guide to Foldamers Chemical Reviews, 2001, Vol. 101, No. 12 3999
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Chem. Rev. 2001, 101, 3793−3818 3793
Enzymatic Polymerization
Shiro Kobayashi,* Hiroshi Uyama, and Shunsaku Kimura
Department of Materials Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 606-8501, Japan
Shiro Kobayashi was born in Himeji, Japan, in 1941. He received his Shunsaku Kimura was born in Kyoto, Japan in 1954. He received his
B.S. (1964), M.S. (1966, Professor J. Furukawa), and Ph.D. (1969, B.S. (1976), M.S. (1978), and Ph.D. (1982, Professor Y. Imanishi) degrees
Professor T. Saegusa) degrees from Kyoto University. He spent his from Kyoto University. He joined the Department of Polymer Chemistry,
postdoctoral period (1969−1971, Professor G. A. Olah) at Case Western Kyoto University, as Research Associate (1981), Lecturer (1992), and
Reserve University, Cleveland, OH. In 1972, he joined the Department of Associate Professor (1993). He moved to the Department of Materials
Synthetic Chemistry, Kyoto University, as Research Associate. In 1986, Chemistry, Kyoto University (1996), and in 1999 he was appointed Full
he was appointed Full Professor at the Department of Applied Chemistry, Professor. He spent his postdoctoral career (1982−1984, 1986, Professor
Tohoku University. He moved to the Department of Materials Chemistry, R. Schwyzer) at ETH-Zurich, Switzerland. He received the Award of the
Kyoto University, in 1997. He has received several awards, such as the Society of Polymer Science, Japan, in 1999. He currently serves as
Chemical Society of Japan Award for Young Chemists (1976), the Award Associate Editor for Polymer Journal. His main interests are polymer
of the Society of Polymer Science, Japan (1987), the Distinguished supramolecular chemistry, peptide engineering, and optoelectronics
Invention Award (1993), the Cellulose Society of Japan Award (1996), devices.
the Humboldt Research Award, Germany (1999), the Award of the
Chemical Society of Japan (2001), and the Award of the “Hattori-Hokokai” respective enzymes are given in Table 1. Here,
Foundation, Japan (2001). He has been a foreign member of the enzymatic polymerizations are described according
Northrhine Westfalian Academy of Science, Germany, since 1999. He to the nature of catalyst enzymes.
currently serves as Regional Editor and/or (Executive) Advisory Board
Member for 14 international journals including Macromolecules and Table 1. Classification of Enzymes and in Vitro
Biomacromolecules. His main interests are enzymatic catalysis in polymer Production of Typical Polymers Catalyzed by
synthesis, bio- and biorelated polymers, new polymerizations and reaction Respective Enzymes
mechanisms, and functional and high-performance polymer materials.
enzymes typical polymers
oxidoreductases polyphenols, polyanilines, vinyl polymers
transferases polysaccharides, cyclic
oligosaccharides, polyesters
hydrolases polysaccharides, polyesters,
polycarbonates, poly(amino acid)s
lyases
isomerases
ligases
II. Oxidoreductases
In living cells, various oxidoreductases play an
important role in maintaining the metabolism of
living systems. Most of oxidoreductases contain low-
valent metals as the catalytic center. In vitro enzy-
matic oxidoreductions have afforded functional or-
Hiroshi Uyama was born in Kobe, Japan, in 1962. He received his B.S. ganic materials.1 Recently, some oxidoreductases
(1985) and M.S. (1987) degrees from Kyoto University. In 1988, he joined
the Department of Applied Chemistry, Tohoku University, as Research
such as peroxidase, laccase, and bilirubin oxidase
Associate. He obtained Ph.D. degree under the direction of Professor have received much attention as catalyst for the
Shiro Kobayashi in 1991. He moved to the Department of Materials oxidative polymerizations of phenol and aniline de-
Chemistry, Kyoto University, in 1997. In 2000, he was appointed Associate rivatives to produce novel polyaromatics.
Professor of the same department. He was honored as the recipient of
the Award of the Society of Polymer Science, Japan, for the Outstanding A. Peroxidases
Paper published in the Polymer Journal in 1995 and the Chemical Society
of Japan Award for Young Chemists in 1997. 1. Oxidative Polymerization of Phenol Derivatives
only some natural polymers but also a variety of Peroxidase catalysis is an oxidation of a donor to
unnatural polymers. Thus, the target macromol- an oxidized donor by the action of hydrogen peroxide,
ecules for the enzymatic polymerization have been liberating two water molecules. Horseradish peroxi-
polysaccharides, polyesters, polycarbonates, poly- dase (HRP) is a single-chain β-type hemoprotein that
(amino acid)s, polyaromatics, vinyl polymers, etc. All catalyzes the decomposition of hydrogen peroxide at
the enzymes are generally classified into six groups, the expense of aromatic proton donors. HRP is a Fe-
and typical polymers produced with catalysis by containing porphyrin-type structure and is well-
Enzymatic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3795
Scheme 4 Scheme 5
A novel photoactive azopolymer, poly(4-phenyl- Model complexes of peroxidase were used as cata-
azophenol), was synthesized using HRP catalyst. The lysts for the oxidative polymerization of phenols.
polymer exhibited reversible trans to cis photoi- Hematin, a hydroxyferriprotoporphyrin, catalyzed
somerization of the azobenzene group with a long the polymerization of p-ethylphenol in an aqueous
relaxation time.49 Hydroquinone mono-oligo(ethylene DMF.63 Iron-N,N′-ethylenebis(salicylideneamine)
glycol) ether was polymerized by HRP in aqueous 1,4- (Fe-salen) showed high catalytic activity for oxida-
dioxane. The film prepared from a mixture of the tive polymerization of various phenols.64 The first
lithiated polyphenol and poly(ethylene glycol) (PEG) synthesis of crystalline fluorinated PPO was achieved
showed high ionic conductivities (4 × 10-5 S/cm).50 by the Fe-salen-catalyzed polymerization of 2,6-
Phenolic copolymers containing fluorophores (fluo- difluorophenol. Cardanol was polymerized by Fe-
roscein and calcein) were synthesized using SBP salen to give a cross-linkable polyphenol in high
catalyst and used as an array-based metal-ion sen- yields.
sor.51 Selectivity and sensitivity of metal sensing were
controlled by changing the polymer components. A 2. Oxidative Polymerization of Aniline Derivatives
combinatorial approach for screening of specific metal Aniline and its derivatives were oxidatively polym-
ions was examined. erized by peroxidase catalyst. HRP catalyzed the
In vitro synthesis of lignin, a typical phenolic polymerization of aniline in aqueous organic solvents
biopolymer, has been attempted by the HRP-cata- to produce the polymer with a complicated structure
lyzed terpolymerization of p-coumaryl alcohol, co- in low yields.65 The resulting polymer showed good
niferyl alcohol, and sinapyl alcohol (14:80:6 mol %) third-order nonlinear optical properties.66
in extremely dilute aqueous solutions at pH 5.5.52 The addition of templates enabled the enzymatic
Dialysis membrane method was applied to the po- production of conducting polymers with well-defined
lymerization of coniferyl and sinapyl alcohols, yield- structure.67 In using sulfonated polystyrene (SPS) as
ing insoluble polymeric materials.53 Coniferyl alcohol a template, the resulting polymer was soluble in
was polymerized by HRP in an aqueous acetone to water and the conductivity reached 5 × 10-3 S/cm
give the insoluble polymer.54 In the presence of a without doping. Besides SPS, a strong acid surfactant
small amount of lignin component, the molecular (sodium dodecylbenzenesulfonic acid) or poly(vi-
weight distribution became much broader than that nylphosphonic acid) provided a suitable local tem-
in the absence of lignin.55 HRP catalyzed the polym- plate environment leading to the formation of con-
erization of soluble oligomeric lignin fragments to ducting polyaniline.
yield insoluble polymeric precipitates.56 HRP-catalyzed polymerization of o-phenylenedi-
Peroxidase-catalyzed grafting of polyphenols on amine in an aqueous 1,4-dioxane gave a soluble
lignin was performed by HRP-catalyzed polymeriza- polymer with a molecular weight of 2 × 104.68 NMR
tion of p-cresol with lignin in the aqueous 1,4-dioxane analysis showed the formation of the polymer con-
or reverse micellar system.57 Phenol moiety in lignin sisting of an iminophenylene unit. From p- and
was reacted with p-cresol to produce a lignin-phenol m-isomers, the polymer with well-defined structure
copolymer with a branched and/or cross-linked struc- was not obtained.69 HRP-catalyzed polymerization of
ture. The product was highly insoluble in common 4,4′-diaminoazobenzene gave a new photodynamic
organic solvents. polyaniline derivative containing an azo group.70
Various aniline derivatives, p-aminobenzoic acid,71
The peroxidase-catalyzed reaction of low-molecular
p-aminophenylmethylcarbitol,72 2,5-diaminobenzene-
weight coal (molecular weight ≈ 4 × 103) was
sulfonate,73 and p-aminochalcones,74 were polymer-
performed in a mixture of DMF and buffer.58 The
ized by peroxidase catalyst. Monolayer of aniline/p-
resulting product was partly soluble in DMF, and the
hexadecylaniline prepared by LB technique at the
DMF-soluble part had a larger molecular weight than
air-water interface was polymerized through HRP
that of the starting substrate.
catalysis to give polymeric monolayer.24
Peroxidase catalysis also induced the depolymer- A new class of polyaromatics was synthesized by
ization of enzymatically obtained polyphenols.59 For- peroxidase-catalyzed oxidative copolymerization of
mation of HRP compound III intermediate may be phenol derivatives with anilines. In the case of a
related to the onset of the depolymerization. Fur- combination of phenol and o-pheneylenediamine, FT-
thermore, the polyphenols were reported to be sub- IR analysis showed the formation of the correspond-
jected to biodegradation, although the degradation ing copolymer.75
proceeded slowly.60
HRP was used as catalyst for cross-linking of 3. Polymerization of Vinyl Monomers
peptides (soy proteins and wheat gliadin).61 Tyrosine Some oxidoreductases have been reported to induce
residues of the proteins were subjected to the enzy- polymerization of vinyl monomers. A novel initiating
matic oxidative coupling, yielding a network of pep- system for vinyl polymerization, HRP/hydrogen per-
tide chains. The treatment increased the tensile oxide/β-diketones such as acetylacetone, was dem-
strength of the materials. onstrated in which the catalytic action of HRP
Lignin-degradating manganese(II) peroxidase was generates carbon radical, a real initiating species,
used as catalyst for the oxidative polymerization of from hydrogen peroxide and β-diketone through an
various phenol derivatives such as guaiacol, o-cresol, oxidoreductive pathway (Scheme 6).76 Hydrophobic
and 2,6-dimethoxyphenol in the aqueous organic monomers, styrene77 and methyl methacrylate
solvents.62 (MMA),78 were also polymerized by this initiating
Enzymatic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3799
Scheme 6
Scheme 7
system in a mixture of water and tetrahydrofuran.
The polymer from MMA had syndiotactic diad frac-
tions ranging from 0.82 to 0.87.78 Manganese peroxi-
dase catalyzed the acrylamide polymerization in the
presence of acetylacetone.79
B. Laccases
Laccases having a Cu active site catalyze the
oxidative coupling of phenols. Laccases derived from catechol ring proceeded using PCL catalyst to give
Pycnoporus coccineus (PCL) and Myceliophthore were the cross-linked film showing excellent dynamic
active for the polymerization of syringic acid to give viscoelasticity.84
PPO with a molecular weight up to 1.8 × 104 (Scheme A novel system of enzymatic polymerization, i.e.,
2).27,80 Enzymatic synthesis of PPO was also achieved a laccase-catalyzed cross-linking reaction of new
from 2,6-dimethylphenol using PCL catalyst.26 The urushiol analogues for the preparation of “artificial
polymerization of 1-naphthol using laccase from urushi”, was demonstrated (Scheme 7).85 Single-step
Trametes versicolor (TVL) proceeded in aqueous synthesis of the urushiol analogues having ester
acetone to give the polymer with a molecular weight group was achieved by using lipase as catalyst. These
of several thousands.81 compounds were cured in the presence of laccase
Coniferyl alcohol was polymerized by laccase cata- catalyst under mild reaction conditions without use
lyst. The polymerization behavior depended on the of organic solvents to produce the cross-linked poly-
origin of the enzyme. PCL and laccase from Coriolus meric film. Properties of the film are comparable to
versicolar showed high catalytic activity to give the those of natural urushi with a high gloss surface and
dehydrogenative insoluble polymer, whereas very low dynamic viscoelasticity (Figure 1).
catalytic activity was observed in laccase from Rhus Laccase catalyzed the polymerization of acrylamide
vernicifera Stokes.54 The increase of the molecular in water.86 The high molecular weight polymer was
weight was observed in the treatment of soluble
lignin using TVL catalyst.82
Urushi is a Japanese traditional coating showing
excellent toughness and brilliance for a long period.
The main important components of urushi are “uru-
shiols”, whose structure is a catechol derivative
directly linked to unsaturated hydrocarbon chains
consisting of a mixture of monoenes, dienes, and
trienes at the 3- or 4-position of catechol.83 Film-
forming of urushiols proceeds under air at room
temperature without organic solvents; hence, urushi
seems to be very desirable for coating materials from
an environmental standpoint. In vitro enzymatic
hardening reaction of catechol derivatives bearing an Figure 1. Dynamic viscoelasticity of artificial urushi from
unsaturated alkenyl group at the 4-position of the urushiol analogue having a linolenic acid group.
3800 Chemical Reviews, 2001, Vol. 101, No. 12 Kobayashi et al.
C. Other Oxidoreductases
Bilirubin oxidase (BOD), a copper-containing oxi-
doreductase, catalyzes the oxidative polymerization
of aniline and 1,5-dihydroxynaphthalene. The polym-
erization of aniline in a buffer solution in the pres-
ence of BOD-adsorbed solid matrix gave the poly-
aniline film containing the active enzyme.88 The film
was electrochemically reversible in its redox proper-
ties in acidic aqueous solution. In the BOD-catalyzed
polymerization of 1,5-dihydroxynaphthalene in aque-
ous organic solvents, the insoluble polymer was
formed.89 The polymer films exhibited a wide band
from 300 to 470 nm in their UV spectrum, indicating
the formation of a long π-conjugated structure. The
polymer treated with HClO4 showed an electrocon-
ductivity of 10-3 S/cm.
Tyrosinase (polyphenol oxidase, a copper-contain-
ing monooxygenation enzyme) was used as catalyst
for the modification of natural polymers. Phenol
moiety-incorporated chitosan derivatives were sub- formation of cross-linked product was observed in the
jected to tyrosinase-catalyzed cross-linking, yielding polymerization of acrylamide in the presence of
stable and self-sustaining gels.90 Tyrosinase also bisacrylamide catalyzed by xanthine oxidase, chloro-
catalyzed the hybrid production between the modified peroxidase, and alcohol oxidase.99
chitosan and proteins.
The enzymatic treatment of chitosan in the pres- III. Transferases
ence of tyrosinase and phenol derivatives produced
new materials based on chitosan.91 During the reac- Transferases are enzymes transferring a group
tion, unstable o-quinones were formed, followed by from one compound (generally regarded as donor) to
the reaction with the amino group of chitosan to give another compound (generally regarded as acceptor).
the modified chitosan. The tyrosinase-catalyzed modi- For example, a glycosyl group as donor is transferred
fication of chitosan with phenols dramatically altered to an alcohol as acceptor to form a glycosidic bond
rheological and surface properties of chitosan. The and an acyl group as donor to an alcohol as acceptor
modification with chlorogenic acid onto chitosan giving rise to an ester bond. Several transferases such
conferred the water solubility of chitosan under basic as phosphorylases and synthases have been found to
conditions.92 A new water-resistant adhesive was be effective for catalyzing in vitro synthesis of
developed by the tyrosinase-catalyzed reaction of 3,4- polysaccharides and polyesters. It is to be noted,
dihydroxyphenethylamine and chitosan.93 Poly(4- however, that some of the in vitro reactions below,
hydroxystyrene) was modified with aniline by using such as cellulose, chitin, hyaluronic acid, and poly-
tyrosinase catalyst.94 The incorporated ratio of aniline ester syntheses, catalyzed by the respective syn-
into the polymer was very low (1.3%). thases are occurring in a manner similar to biosyn-
Tyrosinase catalyzed the oxidative coupling of thetic pathways in vivo. Such reactions are then not
soluble lignin fragments to give the insoluble poly- in the category of enzymatic polymerization in a strict
mer.56 Tyrosinase model complexes catalyzed the sense of its definition but are probably instructive to
regioselective oxidative polymerization of phenols, readers.
leading to the formation of aromatic polyethers with
well-defined structure.95-97 The reaction at the un- A. Glycosyltransferases
substituted ortho positions did not take place, in
sharp contrast to the polymerization by a Cu-amine 1. Phosphorylases
catalyst system.25 From 4-phenoxyphenol95 and 2,5- A phosphorylase catalyzes in vitro production of
dimethylphenol,96 crystalline PPO derivatives were amylose (poly-R(1f4)-D-glucopyranose) and its de-
formed (Scheme 8). The polymer from the latter rivatives. Amylose was synthesized from D-glucosyl
monomer possessed a melting point higher than 300 phosphate as a substrate monomer and malto-oligo-
°C, a class of super engineering plastics.96 A “radical- mers with a minimum length of four glucosyl resi-
controlled” reaction mechanism is proposed for the dues as a primer by using potato phosphorylase
high regioselectivity. (Scheme 9).100 The reaction proceeded analogously to
Glucose oxidase initiated the vinyl polymerization a living polymerization to form amyloses having
in the presence of Fe2+ and dissolved oxygen.98 The relatively uniform chain lengths. Branched polymers
Enzymatic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3801
Scheme 9 Scheme 10
Scheme 11 Scheme 12
Scheme 15
Enzymatic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3805
Scheme 17
Scheme 18
Scheme 16
Scheme 19
syl fluorides including 6-substituted derivatives as was notably more effective than hydrolysis activity.145
activated donors. The acceptor subsite of the mutant All these instances show the possibility that gly-
of Cel7B accommodated various mono- and disaccha- cosidases can be converted to glycosynthase by single
rides. Notably, the polymerization occurred in a substitution at the active site, which suppresses the
phosphate buffer (pH 7.0). hydrolysis activity of glycosidases. At the same time,
T4 lysozyme belongs to family 19 chitinases, which however, the nucleophilic attack of aglycon at the
show inversion of the anomeric configuration accord- acceptor site to the anomer carbon should be signifi-
ing to the single displacement hydrolysis mecha- cantly promoted in these mutants. This molecular
nism.143 Thr26 is located at the R side of the substrate mechanism remains to be solved.
and functions as a general acid in cooperation with
carboxylic acid nearby. The substitution of Thr26 B. Lipases
with His converted the lysozyme from an inverting
to a retaining enzyme.144 This altering can be ex- Lipase is an enzyme which catalyzes the hydrolysis
plained by the nucleophilic property of His to yield a of fatty acid esters normally in an aqueous environ-
glycosyl enzyme intermediate. Upon point mutation, ment in living systems. On the other hand, some
the mutant showed transglycosylation activity, which lipases are stable in organic solvents and can be used
Enzymatic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3807
Scheme 20 Scheme 21
Scheme 23 Scheme 24
weight. Lipase CA- or MM-catalyzed polycondensa- acid and diethyl adipate did not afford the polymeric
tion of dimethyl succinate and 1,6-hexanediol in materials, indicating the high polymerizability of bis-
toluene quickly attained the equilibrium (the conver- (enol ester) toward lipase catalyst. In the enzymatic
sion of methyl ester moiety was ca. 50%); however, polymerization of divinyl adipate or divinyl sebacate
Mn of the product was very low (ca. 300).195 The with R,ω-glycols with different chain lengths, lipases
equilibrium was shifted by elimination of methanol CA, MM, PC, and PF showed high catalytic activity
with nitrogen bubbling, leading to an increase of toward the polymerization.200 A combination of divi-
conversion (>99%) and of the polymer molecular nyl adipate, 1,4-butanediol, and lipase PC afforded
weight (Mn ≈ 3 × 103). Formation of cyclic oligomers the polymer with Mn ≈ 2 × 104. The yield of the
with DP from 2 to 20 as byproduct was observed, and polymer from divinyl sebacate was higher than that
their yield depended on the monomer structure and from divinyl adipate, whereas the opposite tendency
concentration and reaction temperature. The ring- was observed in the polymer molecular weight. The
chain equilibrium was observed, and the molar polyester formation was observed in various organic
distribution of the cyclic species obeys the Jacobson- solvents, and among them, diisopropyl ether gave the
Stockmayer equation. best results. The polymerization also proceeded in
The molecular weight greatly increased when a bulk by using lipase CA as catalyst.
vacuum was used in the polymerization using diacids In the case of polyester synthesis from divinyl
or dialkyl esters as monomer; removal of the formed esters, hydrolysis of the vinyl end group partly took
water or alcohols resulted in a shift of the equilibrium place, resulting in the limitation of the polymer
toward the product polymer. In the lipase MM- growth.201 A mathematical model showing the kinet-
catalyzed polymerization of sebacic acid or its ethyl ics of the polymerization predicts the product com-
ester with 1,4-butanediol in hydrophobic solvents of position. On the basis of these data, a batch-stirred
high boiling points such as diphenyl ether and reactor was designed to minimize temperature and
veratrole under vacuum, Mw of the product polymer mass-transfer effects.202 The efficient enzymatic pro-
reached higher than 4 × 104, although a long reaction duction of polyesters was achieved using this reactor;
time (>1 week) was required.196 poly(1,4-butylene adipate) with Mn ≈ 2 × 104 was
In lipase-catalyzed esterifications and transesteri- synthesized in 1 h at 60 °C.
fications, esters of halogenated alcohols, typically Ester copolymers were synthesized by lipase-
2-chloroethanol, 2,2,2-trifluoroethanol, and 2,2,2- catalyzed copolymerization of lactones, divinyl esters,
trichloroethanol, have been used often, owing to an and glycols.203 Lipases CA and PC showed high
increase of the electrophilicity (reactivity) of the acyl catalytic activity for this copolymerization, yielding
carbonyl and avoiding significant alcoholysis of the ester copolymers with Mn higher than 1 × 104. 13C
products by decreasing the nucleophilicity of the NMR analysis showed that the resulting product was
leaving alcohols. The enzymatic synthesis of bio- not a mixture of homopolymers but a copolymer
degradable polyesters from the activated diesters was derived from the monomers, indicating that two
achieved under mild reaction conditions.197 The po- different modes of polymerization, ring-opening po-
lymerization of bis(2,2,2-trichloroethyl) glutarate and lymerization and polycondensation, simultaneously
1,4-butanediol at room temperature in diethyl ether take place through enzyme catalysis in one pot to
gave the polyesters with Mn ≈ 8 × 103. The polym- produce ester copolymers.
erization of bis(2,2,2-trichloroethyl) adipate and 1,4- Another approach based on the irreversible process
butanediol using PPL catalyst proceeded in a super- was performed by using bis(2,3-butanedione mon-
critical fluoroform solvent to give the polymer with oxime) alkanedioates as diester substrate.204 Lipase
Mw of several thousands.198 By changing the pressure, MM efficiently produced the polymer with Mn up to
the low-dispersity polymer fractions were separated. 7.0 × 103.
Vacuum technique was applied to shift the equi- Cyclic anhydrides and polyanhydrides were used
librium forward by removal of the activated alcohol as starting substrate for enzymatic production of
formed.196,199 In the enzymatic polycondensation of polyesters. A new type of enzymatic polymerization
bis(2,2,2-trifluoroethyl) sebacate and aliphatic diols, involving lipase-catalyzed ring-opening poly(addi-
lipases CR, MM, PC, and PPL produced the polymer tion-condensation) of cyclic acid anhydride with
with Mw of more than 1 × 104 and lipase MM showed glycols was demonstrated.205 The polymerization of
the highest catalytic activity. In the PPL-catalyzed succinic anhydride with 1,8-octanediol using lipase
reaction of bis(2,2,2-trifluoroethyl) glutarate with 1,4- PF catalyst proceeded at room temperature to give
butanediol in veratrole or 1,3-dimethoxybenzene, the the polyester. The enzymatic reaction of poly(azelaic
periodic vacuum method increased the molecular anhydride) and glycols using lipase CA catalyst also
weight (Mw ≈ 4 × 104). produced the polyesters in which glycols are appar-
Enol esters have been shown to be good acylating ently inserted into poly(azelaic anhydride).206
reagents in lipase-catalyzed reactions, since the leav- Polymerization of oxiranes with succinic anhydride
ing unsaturated alcohol irreversibly tautomerizes to proceeded in the presence of PPL catalyst.207 Under
an aldehyde or a ketone, leading to the desired appropriate conditions, Mw reached 1 × 104. During
product in high yields (see also Scheme 25). Thus, the polymerization, the enzymatically formed acid
the enzymatic polymerization using divinyl adipate group from the anhydride may open the oxirane ring
and 1,4-butanediol was first demonstrated in 1994;200a to give a glycol, which is then reacted with the
the reaction proceeded in the presence of lipase PF anhydride or acid by lipase catalysis, yielding poly-
at 45 °C. Under similar reaction conditions, adipic esters.
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Chem. Rev. 2001, 101, 3581−3610 3581
The Persistent Radical Effect: A Principle for Selective Radical Reactions and
Living Radical Polymerizations
Hanns Fischer*
Physikalisch-Chemisches Institut, Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
Contents
I. Introduction 3581
II. Early References and Basic Kinetics 3583
A. Non-Polymeric Systems 3583
1. Leading Observations 3583
2. Theoretical Description 3584
3. Experimental Verifications 3586
B. Polymer Systems 3587
1. Leading Observations 3587
2. Theoretical Description 3589
3. Experimental Verifications 3592
III. Reactions Exhibiting the Persistent Radical Effect 3594
A. Uncatalyzed and Photochemical Organic and 3594
Metal−Organic Reactions Hanns Fischer, born 1935, started his carreer at the Technical University
1. Photochemical Reactions Involving NO 3594 Darmstadt, Germany, and obtained his Ph. D. (1963) and Habilitation
2. Thermal Reactions Involving Persistent 3594 (1966) working at the Deutsches Kunststoff-Institut mostly on polymer-
and Semipersistent Organic Radicals related transient carbon-centered free radicals with ESR, NMR and CIDNP.
After leading a physicochemically oriented division of this Institute, a period
3. Reactions Involving the Reversible 3596 at Carnegie-Mellon University, Pittsburgh, and lecturing in Darmstadt, he
Cleavage of Weak Metal−Carbon Bonds became Associate (1969) and then full Professor (1971) for Physical
B. Catalyzed Organic Reactions 3596 Chemistry at the University of Zürich, Switzerland. There, he continued
1. Catalyzed Kharasch Additions and 3596 his work on transient organic free radicals, their structure, reaction
Related Reactions mechanisms, and reaction kinetics in liquid solutions employing ESR,
2. Photocatalysis 3597 CIDNP, optical spectroscopy, and muon spin rotation. He has authored
about 240 original publications, several reviews, and two books and edits
C. Reactions in Polymer Systems 3597 a large series of tables on radical properties and kinetics in Landolt-
1. Nitroxide-Mediated Systems 3597 Börnstein. Honors include the Centenary Medal and Lectureship of the
2. Mediation by Other Persistent Radicals 3599 Chemical Society London and the Silver Medal of the International EPR
Society. He retires in 2001 but intends further research on the topic of
3. Organo−Cobalt Complex Mediated 3600 this review.
Systems
4. Atom Transfer Radical Polymerization 3600 covered that lead to a highly dominant and unusually
IV. Theoretical Methods and Special Cases of Living 3601 selective formation of the cross-reaction products of
Radical Polymerizations these radicals. The usual transient radical self-
A. The Basic Reaction Mechanism 3601 terminations are virtually absent, although chain
B. Initial Excess of Persistent Species in Living 3603 processes are not involved. This remarkable phenom-
Radical Polymerizations enon was seldom explained, although it has a quite
C. Decay or Removal of Persistent Species in 3605 simple basis.
Living Radical Polymerizations Consider the mechanism of Scheme 1, where
D. Instantaneous Radical Formation 3606 transient R• and persistent radicals Y• are formed
V. Concluding Remarks 3607 simultaneously with equal rates from the same or
different precursors (1, 2). Then, from the usual
VI. Acknowledgment 3607
radical-radical reactions (3, 4) one obtains R-Y as
VII. References and Notes 3608 highly dominant product.
Scheme 1
I. Introduction
From time to time reactions involving both tran-
sient and persistent radical intermediates were dis-
Offhand, one may be surprised. Intuitively, one However, one may reason now that one will not
could expect equal concentrations of R•and Y•, be- find a marked lifetime prolongation if the equilibrium
cause the radicals are formed with equal rates, and constant is above a critical limit. Actually, a too small
therefore, the products R-Y and R-R should be rate constant of the back-reaction must lead to a fast
formed in the statistical ratio of 2:1. However, this and complete conversion of R-Y to the final products
is not the case, except during a very short initial R-R and Y•. Also, the self-termination of the tran-
period. The simple cause is that the transient radicals sient radicals never ceases completely. Therefore, a
R• disappear by their self-termination (4) and by the true stationary state does not exist, and for the given
cross-reaction, whereas by definition the persistent reaction mechanism, the radical concentrations will
radicals Y• do not self-terminate but disappear only always depend on time. Moreover, the apparent
by the cross-reaction.1 Hence, every self-termination equilibrium and the lifetime prolongation of R-Y are
event of R• (3) causes a buildup of excess Y•, and this only of transient nature, because at sufficiently long
buildup continues as the time goes on. The perma- times one must always find only self-termination
nently increasing concentration of Y• accelerates the products and persistent radicals.
cross-reaction at the expense of the self-termination A technically important situation arises when the
(4). This reaction never stops completely but attains transformation of R• to R′• occurs by addition to a
lower and lower levels. Hence, R-Y becomes the suitable monomer, M; the resulting product R′-Y )
main product. In fact, a dynamic equilibrium is R-M-Y itself undergoes the fragmentation (5),
reached where the rate of the cross-reaction matches R-M• undergoes further monomer addition, and the
that of the radical generation (1, 2). This leads to the process continues. This mechanism is displayed in
following general conclusions: Scheme 3, where n g 0 denotes the number of
(1) If the transient and persistent radicals are monomer units that are contained in the radical and
formed with equal rates, one always expects the product species.
highly dominant formation of their cross-reaction
products, be it R-Y formed by the combination (3), Scheme 3
products such as R(-H) and Y-H arising from a
disproportionation, or ions such as R+ and Y- result-
ing from a charge-transfer between R• and Y•.
(2) If the transient radicals R• transform rapidly
into other transient radicals R′•, for example by
fragmentation, rearrangement, addition to an unsat-
urated molecule, atom or group transfer, or by any
other reaction, then the cross-reaction products be- Carbon-centered radicals derived from the low
tween R′• and Y• become dominant. The transforma- molecular compounds R-Y and from the longer chain
tion of Y• to another persistent Y′• leads to the molecules Rn-Y have similar structures and reac-
selective formation of R-Y′. tivities, and therefore,
(3) During the reactions, the concentration of the (6) one expects a polymerization without termina-
persistent species Y• increases to a much higher level tion,2 which is characterized by a transient equilib-
than the concentrations of the transient radicals R• rium between the dormant polymer Rn-Y and the
or R′•. radicals.
Yet, these statements leave open questions. How (7) The dormant polymer is living in the sense that
persistent must Y• be to cause this effect, and are it grows until the monomer is depleted, and that it
equal formation rates really necessary? We answer can grow on after additional monomer feed as in an
them later and first consider Scheme 2. ionic living polymerization.3 The final degree of
polymerization is determined by the initial concen-
Scheme 2 trations of the monomer and of the radical precursor
R0-Y, and the formation of block copolymers is
possible.
(8) One further obtains a controlled growth of the
polymer if the characteristic time for the reversible
dissociation is sufficiently short in comparison with
monomer conversion, that is, if all chains start to
The two radicals are now produced by the revers- grow practically together.2
ible dissociation of a common precursor R-Y but However, one may again suspect that this will hold
undergo the same reactions as in Scheme 1, other- only under favorable kinetic circumstances.
wise. Now, the above argumentation suggests: So far, we have introduced the concept of what is
(4) The lifetime of the radical precursor R-Y is now called the “persistent radical effect” without
markedly prolonged because it is permanently re- giving specific examples or theoretical proof for its
generated, and the dynamic equilibrium between the existence. Further, we have indicated that there may
radical generation and the cross-reaction acts like the be stringent conditions for its occurrence in real
chemical equilibrium of the reversible decay. chemistry. This review further elucidates the phe-
(5) A rapid transformation of R• into R′• leads again nomenon, but it is restricted to the most important
mainly to R′-Y, if the formation of this product is aspects and to illustrative chemical systems. The
irreversible, and a transformation of Y• to another next section shows how the main ideas have been
persistent Y′• leads again to R-Y′. developed over the years in order to explain specific
The Persistent Radical Effect Chemical Reviews, 2001, Vol. 101, No. 12 3583
observations, and it reveals the fundamental kinetic Thus, “penta-p-biphenylethane gave only two percent
conditions for basic reaction schemes. Then, we list of s-tetra-p-biphenylethane after being heated for two
a larger variety of examples from organic,4 metal- hours in o-dichlorobenzene at 100 °C, the original
organic, and polymer chemistry and close with an compound being recovered in 87% yield.” However,
outline of an appropriate theoretical analysis and its the solutions developed the characteristic color of
application to further cases of practical interest. triarylmethyl radicals, and this agreed with the much
Today, the subject is far from being mature. There faster conversion under oxygen. The authors con-
are probably many more experimental manifestations cluded that in the absence of oxygen, “the dissociation
of the effect than we are aware of, and there may be of pentaarylethanes is a reversible reaction in which
more kinetic peculiarities and variants. This is the the position of the equilibrium is practically entirely
reason we neither present a completely comprehen- in favor of the pentaarylethane”. They also knew that
sive description of all pertinent experimental findings diarylmethyl radicals but not triarylmethyl radicals
nor a complete theory. Moreover, the particular dimerize irreversibly under their experimental condi-
subfield of living radical polymerizations involving tions and, hence, that in these systems diarylmethyl
the effect has become of practical importance. Hence, radicals are transient and triarylmethyl radicals are
in the past few years, a large number of publications persistent species. Obviously, the cross-coupling be-
and patents have been published on this topic. These tween these is strongly favored.
are covered in more detail in other parts of this issue, To explain these observations the authors wrote
and here, we discuss only those aspects that are “Now, the irreversible formation of an extremely
important for the operation of the persistent radical small amount of s-tetraethylethane (by coupling,
effect in living polymerizations. Scheme 4) results in a corresponding increase in the
equilibrium concentration of triarylmethyl radicals;
II. Early References and Basic Kinetics as a result the concentration of diarylmethyl radicals
is reduced to such an extent that their association is
A. Non-Polymeric Systems practically stopped.” Moreover, “The formation of
every molecule of s-tetraarylethane decreases the
1. Leading Observations rate of formation of the next molecule.” They also
To our knowledge, Bachmann et al.5 were the first clearly noticed the unusual character of the apparent
who stated the correct reason for the unusual prefer- dissociation equilibrium because “the concentration
ence for unsymmetrical coupling reactions in systems of triarylmethyl radicals is always much greater than
involving persistent and transient radicals as early the concentration of diarylmethyl radicals,” and “this
as 1936. They had prepared phenyl- and p-biphenyl precluded measurements of the extent of the equi-
carrying pentaarylethanes and studied their stability. librium from the color”, that is, the triarylmethyl
In oxygenated o-dichlorobenzene solutions containing concentration. Finally, they noted that “it should be
pyrogallol as hydrogen donor, all compounds decom- borne in mind, however, that a pentaarylethane
posed quantitatively at 100 °C within a few minutes solution is an unstable system which in infinite time
to triarylmethyl and diarylmethyl hydroperoxides. would disproportionate completely into hexaaryle-
Various experiments ensured that the primary dis- thane (“triarylmethyl radicals” would be more ap-
sociations to triarylmethyl and diarylmethyl radicals propriate) and s-tetraarylethane.” These are the
were followed by very fast additions of these radicals features of a persistent radical effect following Scheme
to oxygen and by the consecutive very fast hydrogen 2.
abstractions of the resulting peroxyradicals from The second thoughtful description was given by
pyrogallol (Scheme 4). Hence, the rates of conversion Perkins.6 He explained the unusual product distribu-
were equal to the rates of dissociation of the pen- tions of phenylations of aromatic compounds when
taarylethanes. phenylazotriphenylmethane is used as thermal phen-
Surprisingly at first, the pentaarylethanes were yl radical generator. Scheme 5 provides an example.
much more stable under oxygen-free conditions. It had been found7 that benzene solutions yield 1,4-
dihydro-4-triphenylmethylbiphenyls as major prod-
Scheme 4 ucts besides biphenyl and triphenylmethane, and “a
particular feature of this scheme is the absence of
dimerization and disproportionation of the interme-
Scheme 5
3584 Chemical Reviews, 2001, Vol. 101, No. 12 Fischer
kc[R][Y] 2(kc/ktR)[Y]/[R]
s) )
ktR[R]2/2 + ktY[Y]2/2 1 + (ktY/ktR)([Y]/[R])2
(12)
Differentiation with respect to the auxiliary variable
[Y]/[R] yields the maximum of s for [Y]/[R] ) (ktR/
ktY)1/2. Use of this relation and eqs 10 and 11 for the
stationary state and subtraction of the resulting
equations 13 and 14 yields rR ) rY:
and
Figure 1. Computed time dependencies of the concentra-
tion of the transient (R•) and the persistent radicals (Y•)
d[Y]/dt ) 0 ) rY - kc(ktR/ktY)1/2[R]2 - ktR[R]2 (14) for [Y]0 ) [R]0 ) 0, a common radical generation rate r )
10-6 M s-1, ktR ) kc ) 109 M-1 s-1, and different ratios ktY/
Hence, the maximum selectivity does occur in fact ktR in a log-log representation. The log-log representation
for equal formation rates of the two radicals, as was enhances the visualization of the different time regimes.
implied in the discussions of Schemes 1 to 3 and as
is valid for the mechanisms of Schemes 4-7. Re- representation.12 Such log-log representations are
stricting the further discussion to the case rR ) rY ) unusual, but they are needed here and in the follow-
r at the moment and using [Y]/[R] ) (ktR/ktY)1/2 and ing because they allow one to clearly visualize the
eq 12 provide different time regimes. The interpretation of the time
evolution is straightforward. For all ratios of the self-
kc termination constants, both radical concentrations
smax ) (15) first increase linearly with time, [R] ) [Y] ) rt. When
(ktRktY)1/2 the rate of the terminations become approximately
equal to the rate of radical generation, [R] attains a
Now, if Y• were as transient as R•, one would have maximum, in times of milliseconds to seconds for
approximately ktR ) kc ) ktY, which gives smax ) 1. usual rate constants. Thereafter, the concentration
This leads to the statistical product distribution [PR]: of the transient radical decreases, and the excess of
[Pc]:[PY] ) 1:2:1. However, for a persistent Y• with a the persistent species builds up. For nonzero self-
small self-termination constant ktY , kc ≈ ktR one termination of the persistent radical, both radical
obtains smax . 1.14 For instance, if the rate constant concentrations reach stationary states. For ktY ) 0,
for the self-termination of Y• were ktY ) 103 M-1 s-1 however, [R] continues to decrease and [Y] continues
and the other rate constants diffusion controlled, kc to increase. After the maximum of [R], log [R] and
) ktR ≈ 109 M-1 s-1 in nonviscous liquids, the log [Y] depend linearly on time. They show slopes of
selectivity would become smax ≈ 1000, and this means different signs but equal magnitude. For ktY ) 0, this
99.9% cross-reaction. Hence, the selectivity increases holds forever, and it is observed also for a nonzero
with decreasing self-termination rate constant of the ktY before the stationary states are reached. The
persistent species; however, this species need not be magnitudes are smaller than 1, that is, in this regime
infinitely long-lived. Further, one notes that [Y]/[R] the time dependencies of both radical concentrations
) (ktR/ktY)1/2 implies [Y] . [R] for ktR . ktY, that is, are weak. Empirically, the slopes give [Y] ∼ t1/3 and
the large excess of the persistent radical. Moreover, [R] ∼ t-1/3, and such time dependencies are very
for ktY , kc ≈ ktR the self-termination terms on the unusual in chemical kinetics. Furthermore, one finds
right-hand sides of eqs 13 and 14 are much smaller empirically that the concentrations obey the dynamic
than the cross-reaction term. This proves the exist- equilibrium eq 16.
ence of a dynamic equilibrium A rigorous derivation of the unusual time depend-
encies and of eq 16 for ktY ) 0 was first found for the
kc[R][Y] ) r (16) reversible radical generation of Scheme 2 with the
restriction ktR ) kc,15 which was removed subse-
for which the rate of radical generation is nearly
quently.16,17 The mathematical method will be out-
completely balanced by the rate of the cross-reaction.
lined in section IV. For the mechanism of Scheme 8,
Our treatment explained the experimental results
with equal radical formation rates and ktY ) 0, it
of Huber et al.10 and Kraeutler11 quantitatively.12
provides for the radical concentrations at sufficiently
However, it is not strictly applicable when Y• does
long times18
not self-terminate at all because [Y]/[R] and s diverge
to infinity for ktY f 0. Actually, in this case and for
[R] ) (r/3kcktR)1/3 t-1/3 and
equal rates of radical generation, eqs 10 and 11 have
no stationary state solution except for infinite time, [Y] ) (3ktRr2/kc2)1/3t1/3 (17)
where [Y] goes to infinity and [R] becomes zero.
Figure 1 shows computed time evolutions of the They fulfill the dynamic equilibrium relation (16).
radical concentrations for [Y]0 ) [R]0 ) 0, a common For the reversible radical generation of Scheme 2
radical generation rate r ) 10-6 M s-1, ktR ) kc ) 109 and ktY ) 0, the unusual time dependencies [Y] ∼
M-1 s-1, and different ratios ktY/ktR in a log-log t1/3 and [R] ∼ t-1/3 and the large excess of [Y] over [R]
3586 Chemical Reviews, 2001, Vol. 101, No. 12 Fischer
Scheme 11
Scheme 12 Scheme 13
Scheme 14
izations with essentially constant radical concentra- nitroxide-mediated processes are unconveniently
tions, no steady-state approximation is possible. small, even at temperatures as high as 130 °C, and
Whereas the patent stressed the controlled forma- this is so because the persistent radical effect leads
tion of oligomers and low molecular weight polymers, to very low transient radical concentrations.
Georges et al. showed in 1993 that moderate molec- Using di-tert-butylnitroxide (DBNO)-based initia-
ular weight (50 000 au) polystyrenes with low poly- tors (1 in Scheme 12), Catala et al.34 observed that
dispersity indices (1.20) can be obtained by nitroxide- the polymerization rate of styrene is independent of
mediated polymerizations at around 120 °C.30 Instead the initiator alkoxyamine concentration. This is
of using alkoxyamines as initiators, they employed unusual in radical polymerizations, and Matyjasze-
a 1.2:1 ratio of the nitroxide radical TEMPO (Scheme wski et al.35a first pointed out in this case that the
10, and 3 in Scheme 12) and dibenzoyl peroxide in styrene polymerization rate is governed by the au-
styrene and preheated the reaction mixture to 95 °C toinitiation of the monomer that creates additional
for a short time. Under these conditions, benzoyloxy propagating species. These authors also published
radicals first add to styrene. The coupling of the illuminating simulations on the nitroxide-mediated
adduct radicals with TEMPO provides unimeric process.35b The autoinitiation of styrene then may
alkoxyamines that initiate the polymerization at the have led to the renewed idea36 to add a slowly
higher temperature. As expected for a stepwise decomposing conventional initiator to the systems.
growth, the degree of polymerization increases fairly This had already been realized by Otsu.24 Sparingly
linearly with conversion. It was also noticed that a applied, it accelerates the polymerizations apprecia-
larger initial excess of the persistent species de- bly without deteriorating the livingness and the
creased the polydispersity at the expense of a slower control to untolerable extents.36
polymerization rate. Later work showed, among other The facile and reversible dissociation of cobalt-
results, that the concentration of the persistent carbon bonds to give a persistent cobalt-derived and
nitroxide increases during the polymerization, be- a transient alkyl radical was discussed already in
cause of the ongoing termination, that the rate of connection with Schemes 7 and 9. In 1994, it was first
polymerization can be increased considerably by a utilized by Wayland et al.37 in living and controlled
slow removal of the excess nitroxide, that these polymerizations of methyl acrylate. Using (tetramesi-
controlled polymerizations display no gel effect, and tylporphyronato)cobalt neopentyl and variants thereof
that they can be extended to aqueous-phase poly- in benzene solution at 60 °C provided only oligomers
merizations and also to the formation of polystyrene- for small ratios of monomer to complex, but for ratios
polybutadiene, -polyisoprene and -polyacrylate block of 2500:1, polymers with Mn ) 150 000 and about
copolymers.31 70% conversion were achieved. The molecular weight
The technical potential of the work of Rizzardo et increased linearly with conversion, and the polydis-
al.27-29 and Georges et al.30,31 stimulated further persity index was as low as 1.1-1.3. Livingness of
research along similar lines by many other groups. the polymer, that is, the fidelity of the porphyrina-
We mention here only a few principally important tocobalt end group of the polymer chains, was dem-
and early results. By an elegant crossover experiment onstrated by the formation of block copolymers of
using model polystyrene alkoxyamine derivatives, methyl and butyl acrylate. Wayland knew of the
Hawker et al.32 demonstrated the occurrence of the earlier publications on the persistent radical effect12,21
reversible cleavage. The prolongation of the alkoxy- and interpreted his findings in terms of Scheme 3.
amine lifetime during the reactions became evident The addition of polyhaloalkanes and related halo-
from the apparent decay times reported for 1-phen- genated compounds to alkenes can occur via a clas-
yl-1-(2′,2′,6′,6′-tetramethylpiperidine-1′-oxyl)ethane sical radical chain process (Scheme 13), which is often
(phenethyl-TEMPO) by Priddy et al.33a of about 150 called the Kharasch reaction.38 In 1961, Minisci et
min in trichlorobenzene at 140 °C and by Hawker et al.39 and Asscher and Vofsi40 discovered that this
al.33b of about 5 min in styrene at 123 °C. In the latter reaction is catalyzed by transition metal ions in their
case, the addition of the 1-phenethyl radical to lower valent state such as Cu+ and Fe2+, and they
styrene prevents the regeneration of the parent formulated the mechanism in Scheme 14. The ca-
compound, of course. Further, it was often noticed talysis of the additions by simple metal salts or
that the polymerization rates obtained in many complexes such as Cu(I)-2,2′-bipyridyl41a and ruthe-
The Persistent Radical Effect Chemical Reviews, 2001, Vol. 101, No. 12 3589
nium(II) tris(triphenylphosphine) (RuCl2(PPh3)3)41b ATRP, the dormant chains carry halogen atoms as
found many organic synthetic applications. It was end groups. Alone and freed from the catalyst they
often stated that the intermediacy of freely diffusing will not initiate new polymerizations, but they revive
carbon-centered radicals is unlikely in these pro- upon addition of the same or another catalyst.
cesses, because the normal termination products are Therefore, in a looser sense we will consider these
absent. However, the transition metal ions and their processes also as “living” polymerizations. By “con-
complexes are persistent, and Scheme 14 involves the trolled” we mean a polymerization for which the
simultaneous formation of a persistent species and number-average degree of polymerization (XN) and,
a transient radical. Hence, the operation of the hence, the number-average molecular weight of the
persistent radical effect is a much more likely cause polymer increase linearly with monomer conversion
for the virtual absence of the self-termination reac- and for which XN ideally reaches the ratio of the
tions. initial monomer and initiator concentrations at full
Monoadditions are usually carried out with about monomer conversion. These are the characteristics
1:1 ratios of the organic halide and the alkene and of a polymerization without termination.2 If, in ad-
very small catalyst concentrations. When lower halide/ dition, all chains start in a time period that is short
alkene ratios are used, telomer formation is impor- compared to the overall conversion time, that is,
tant. Hence, for small halide concentrations, high practically at the same time, one obtains a narrow
polymers may be obtained, and this is supported by Poisson chain length distribution. Then, the polydis-
Otsu’s experiments26 with Ni(0) powders. persity index develops as PDI ) MW/MN ) XW/XN )
The first real success along these lines was achieved 1 + 1/XN and decreases with increasing conversion
in 1995 by Sawamoto et al.,42 Matyjaszewski et al.,43 to values close to one.2
and Percec et al.44 The first group used RuCl2(PPh3)3 “Livingness” and “control” go parallel in many ionic
as catalyst and CCl4 as initiating halide in a 1:2 ratio, processes, but this need not always be so. Actually,
added methylaluminum bis(2,6-di-tert-butylphen- in the radical polymerizations, the dissociation of the
oxide) to activate the initiator C-Cl bonds, and dormant chains or the activating halogen transfer
employed methyl methacrylate as monomer solvent. may be so slow that considerable conversion occurs
Nearly 90% conversion was achieved at 60 °C in before these reactions have occurred at least once.
about 4 h.42 Matyjaszewski employed Cu(I)Cl-2,2′- Then, one expects the formation of a polymer with a
dipyridyl (1:3) as catalyst and 1-chloro-1-phenyl- large “living” fraction but little “control”. On the other
ethane (1) as initiator and found 90% conversion of hand, if the time for appreciable monomer conversion
styrene in about 3 h at 130 °C.43 The polymerization overlaps with the final reaction stage where the
of styrene was also addressed by Percec et al.,44 who termination processes dominate, one may find prod-
used the same catalyst as Matyjaszewski but diverse ucts with a large degree of “control” but little “liv-
aromatic sulfonyl chlorides as initiators. All authors ingness”.
amply demonstrated the livingness of the resulting The theoretical exploration of living radical poly-
polymers and the controlled nature of the process merizations has been approached by numerical simu-
with molecular weights increasing with conversion lations of conversion rates and molecular weight
and low polydispersities. In comparison to Otsu’s distributions. Several methods have been devel-
earlier attempt,26 their success is presumably due to oped.15,17,29,35,46,47 Such simulations provide consider-
the more homogeneous reaction conditions following able insight into the inner working of the mecha-
from the use of metal complexes. Since the addition nisms and can reproduce the experimental findings.
of haloalkanes to alkenes involves atom transfer Yet, they are not of general value, because they hold
steps, Matyjaszewski termed the new method “atom only for the specific kinetic parameters employed in
transfer radical polymerization” (ATRP).43 In terms the individual cases. For the analysis of polymeriza-
of polymerization rates and generality, ATRP ap- tion data, analytical equations are more helpful, and
pears to be the most versatile variant of living radical their derivations also reveal the fundamental kinetic
polymerizations based on the persistent radical effect aspects. Such derivations address the time depen-
today. dence of the radical concentrations, of the monomer
conversions, and of the evolution of the molecular
2. Theoretical Description weight distributions, and they have mainly been
Before entering the kinetic treatment of living worked out by Fukuda et al. and by our group.
radical polymerizations based on the persistent radi- Before giving some results, it must be stressed that
cal effect, it is necessary to define the terms “living” all equations have been derived and will be valid only
and “controlled” radical polymerization as used in for ideal cases, especially only for chain length
this review, because a unified terminology has not independent rate constants and in the absence of any
yet evolved and conflicting views have been ex- reactions besides those considered explicitly. Further,
pressed.45 In the sense of Szwarc,3 we call a polymer they imply mathematical approximations. Both re-
“living” that, after formation and isolation, can grow strictions can lead to deviations of the experimental
upon further monomer feed and that can be used to data from the theoretical results. Yet, such deviations
build block copolymers. The dormant chains formed do not disprove the equations, unless it is demon-
in nitroxide and cobalt-complex-mediated polymer- strated that the preconditions of the derivations are
izations carry end groups that provide transient strictly fulfilled by the chemical systems under study.
radicals upon dissociation to which monomer can add. In our work,15-17 we have mainly concentrated on
Hence, these processes are properly “living”. In polymerizations that follow Schemes 3 and 11. Dis-
3590 Chemical Reviews, 2001, Vol. 101, No. 12 Fischer
( )
K[I]0 1/3
[M] ) [M]0e-3/2kp t2/3 or
3kt
( )
[M]0 1/3
3 K[I]0
ln ) kp t2/3 (22)
[M] 2 3kt
( )
πkp3[I]0 1/2
[M]0 - [M] [I]0
XN ) (24) PDI∞ ) 1 + + (27)
[I]0(1 - e-kdt) [M]0 kdkckt
( ) [ ( ) ]
0
and as predicted by eqs 22, 24, and 25.
πkp3[I]0 1/2
K[I]0 1/6
The livingness of the polymer is also easily calcu-
erf (3kp)1/2 t1/3 (25)
kdkckt 3kt lated because the number of dead chains is practi-
cally equal to the number of the released persistent
If the dissociation of the initiator occurs well before species, which is known from eq 18. Further, the
the conversion (kdt . 1), all chains start to grow analytical solutions provide conditions for the rate
practically together at zero time. Then eq 24 provides constants that should allow a successful living and
the desired linear increase of MN with the conversion controlled polymerization.17 First, we may want the
and the control by the initial initiator concentration. concentration fraction of the dead polymer products
The PDI decreases with increasing XN, time, and [P]/[I]0 at the large monomer conversion of 90% to
The Persistent Radical Effect Chemical Reviews, 2001, Vol. 101, No. 12 3591
()
on K but on kd (24) and on the product kdkc (27). [M]0 r 1/2
ln ) kp t (34)
The optimum values of kd and kc depend on the [M] kt
propagation constant (kp), the termination constant
(kt), and the attempted degree of polymerization as for a conventional polymerization with a constant
through [I]0. For a given set of these latter param- initiation rate (23). This is so because the additional
eters one finds a range for kd and kc in which a living radical generation stops the permanent decrease of
and controlled polymerization should be observed. the transient radical concentration that occurs in its
This is illustrated by the diagram shown in Figure absence (eq 18) and keeps the radical concentration
5, which was constructed with the aid of eqs 28-30. constant at a higher level. Therefore, in comparison
Here, point A corresponds to the rate constants to the absence of any additional initiation, the
leading to Figure 4, that is, to a process yielding 90% conversion rate is markedly enhanced.
conversion in 5.55 h for a monomer with kp ) 5000 Recently, we explored the effects of the additional
M-1 s-1, an average degree of polymerization XN ) initiation in detail, and found that the conditions (20)
100, a polydispersity index of 1.2, and 5% dead for the existence of the equilibrium (19) must again
3592 Chemical Reviews, 2001, Vol. 101, No. 12 Fischer
obtains
1 2
PDI0 ) 1 + + (38)
XN kdt
The different numerical factors (eqs 26 and 28) are
due to the different time dependencies of the radical
concentrations. Equation 38 has also been derived by
Fukuda et al.36b by a purely probabilistic method, and
it is generally valid for a constant concentration of
growing chains.
Theoretical work has also been devoted to examine
the influence of reactions that interrupt the often
repeated cycles of radical formation (activation) and
Figure 6. ln([M]0/[M]) versus time for a polymerization cross-termination to dormant species (deactivation).
with additional initiation and different ratios r/kd[I]0. Solid For the nitroxide- and the cobalt-mediated systems,
lines are from numerical calculations and circles from the such reactions are the formation of R(-H) and YH
analytical equations. Parameters: kd ) 3 × 10-3 s-1, kc ) by a usual radical disproportionation, which competes
5 × 107 M-1 s-1, kt ) 108 M-1 s-1, kp ) 2000 M-1 s-1, [I]0
) 0.1 M, [M]0 ) 10 M. with the coupling of R• and Y• or by a direct
fragmentation of R-Y to the hydroxylamine or a
be fulfilled.50 Equations 33 are valid if [R]s ) xr/kt hydridocobalt complex and the alkene.22,33a,35,47,51-57
. K, that is, the equilibrium constant must be rather Even rather small fractions of these processes limit
small, because the radical concentrations should the maximum conversion and stop the polymerization
normally not exceed 10-8 M. Further, a good control prematurely in nearly indistinguishable ways, be-
and the livingness of the resulting polymer require cause they lead to an exponential decay of the
that the rate of the cross-reaction to dormant chains dormant species. Before the end of conversion this
largely exceeds that of the self-termination to dead does not affect the linear dependence of XN on
products. This provides r , kd[I]0, which means that conversion and causes only minor increases of the
the rate of the additional initiation must be small polydispersity.57 To some extent the deteriorating
compared to the cleavage rate of the dormant species. effect of these reactions can be compensated by the
In practice, a ratio r/kd[I]0 ) 0.01 yields an about 10- rate enhancement through an additional initiation.50
fold rate enhancement under retention of most of the Another aspect49 is the initial presence of persistent
livingness and control, but larger initiation rates species in nonzero concentrations [Y]0, and it will be
should not be used if the polymer should be living at discussed more closely in section IV. In the absence
high conversion. of any additional initiation, the excess [Y]0 at first
Figure 6 shows calculated polymerization rates ln- levels the transient radical concentration to an equi-
([M]0/[M]) for various ratios r/kd[I]0. Even for very librium value [R]s ) K[I]0/[Y]0. This is smaller than
small ratios of r and kd[I]0, rather large rate enhance- that found without the initial excess and lowers both
ments are obtained. Moreover, the time dependence the initial conversion rate and the initially large PDI.
of ln([M]0/[M]) becomes linear. Since some additional Further, it provides a linear time dependence of ln-
initiation by impurities or autoinitiation may always ([M]0/[M]), which is directly proportional to the equi-
occur, the nonlinear behavior for the ideal case of librium constant. Later in the reaction course, [Y]
Figure 3 may be difficult to observe in actual poly- may exceed [Y]0 because of the self-termination, then
merizations, unless kd[I]0 is sufficiently large. [R] is given by eq 18. If there is additional radical
The expressions for the evolution of the degree of generation, the first stages will eventually be re-
polymerization and the polydispersity index for po- placed by a second stationary state that was de-
lymerizations in the stationary state of constant scribed above. Further effects are expected from a
radical concentrations are50 decay or an artificial removal of the persistent species
that increases the concentration of the transient
[M]0 - [M] radicals and the polymerization rate (see section IV).
Xn ) (35) Radical transfer reactions to polymer, monomer, or
[I]0(1 - e-kdt) + rt initiator have not yet been incorporated in the
( )
analytical treatments.
kp 2-C 1 ATRP utilizes a bimolecular radical formation
PDI ) (1 - e-kdt + rt/[I]0) 1 + [R] + reaction (Scheme 14). Apart from this, the rate
kd s C XN
(36) equations are similar to those holding for the uni-
molecular cases, and therefore, the theory should be
Here, C is the fractional monomer conversion. If one similar. It is not yet far developed, but for equal
has kdt . 1 and rt , [I]0 at the time of observation, initial concentrations of catalyst and initiating halide,
eq 36 reduces to the equations given above should also hold for ATRP
with kd[I]0 replaced by ka[Cat]0[RHal]0.16
1 kp 2-C
PDI ) 1 + + [R]s (37) 3. Experimental Verifications
XN kd C
Stringent quantitative verifications of the analyti-
and for small conversions, C ≈ kp[R]st , 1, one cal equations should confirm the reaction orders with
The Persistent Radical Effect Chemical Reviews, 2001, Vol. 101, No. 12 3593
III. Reactions Exhibiting the Persistent Radical although these products have occasionally been ob-
Effect served. The photooximation of alkanes with NOCl
follows essentially the same course and has industrial
A. Uncatalyzed and Photochemical Organic and importance (Scheme 16).
Metal−Organic Reactions Scheme 16
The persistent radical effect must always play a
role when transient and persistent radicals are
formed with equal or nearly equal rates. It leads to
the formation of the mutual reaction products in high
yields and to the virtual absence of the self-termina-
tion reactions. In the few examples given earlier, the
persistent species were radicals and transition metal
complexes, but other reaction partners such as mo-
lecular ions and even normal molecules may take
their place. Furthermore, the phenomenon can also
work with other transient species, such as carbenes,
nitrenes, and molecules in electronically excited 2. Thermal Reactions Involving Persistent and
states. A literature search would probably reveal a Semipersistent Organic Radicals
large variety of diverse reactions that exhibit the
effect to some degree, although this went unnoticed, Scheme 17 displays several radicals with lifetimes
so far. Here, we restrict the survey to evident cases. exceeding about 1 h in oxygen-free liquid solutions
A few of the reactions have even been designed to and at ambient temperature. Many of them have
exploit the persistent radical effect in synthesis. been isolated in pure form.71 Their stability has
electronic and steric reasons. It is favored by the
1. Photochemical Reactions Involving NO absence of β-hydrogen atoms, which would facilitate
disproportionation. As shown before, the persistent
There are a variety of photochemical reactions radical effect can also be observed for radicals that
involving free nitrous oxide (NO) as persistent radi- are not extremely persistent. Therefore, it is impor-
cal. Often there is an initial fragmentation, as tant to notice that the lifetimes of all types of radicals
presented in Scheme 6 for N,N-dimethyl-N-nitro- can be adjusted by proper substitution. 1 Comprehen-
samine. One example is the Barton reaction of nitrite sive compilations of the magnetic properties72 and of
esters (Scheme 15). It allows the functionalization of the reactivities73 of radicals are available in the
methyl groups in steroids and utilizes an intermedi- Landolt-Boernstein series. They reveal that a large
ate 1,5-hydrogen atom migration, which converts the variety of radicals are persistent enough for eventual
initially formed oxygen-centered radical to a carbon- synthetic applications using the effect.
centered species.69 The selecting influence of triphenylmethyl radicals
Similar reactions occur with N-nitrosoamines R2- on product distributions has already been discussed
NNO and N-nitrosoamides RCO(R′)NNO.70 Apart in earlier sections, and additional examples are found
from the intramolecular hydrogen atom transfer,
diverse intramolecular radical additions (cyclizations) Scheme 17
and other rearrangements have also been used to
obtain cross-reaction products between NO and the
radicals resulting from the transformation of the
primarily formed R• to another radical R′•.69,70 Giving
evidence for the persistent radical effect, the yields
of the desired products are large and those of the self-
termination of the transient intermediates are low,
Scheme 15
The Persistent Radical Effect Chemical Reviews, 2001, Vol. 101, No. 12 3595
Scheme 18 Scheme 20
Scheme 19
Scheme 23 Scheme 26
Table 1. Rate and Equilibrium Constants for the Reversible Dissociation of Polymeric Alkoxyamines and Low
Molecular Model Compounds, Frequency Factors, and Activation Energies of Dissociations
alkoxyamine,
Schemes 12, 30 T/°C kd/s-1 Ad/s-1 Ea,d/kJ mol-1 kc/M-1 s-1 K/M ref
3-(TEMPO)-polystyryl 125 0.0016 3× 1013 124 7.6 × 107 2.1 × 10-11 48, 49
125 0.00052 ≈1 × 108 ≈1 × 10-11 31
120 ≈0.001 35
3-1-phenylethyl 120 0.00052 2.5 × 1014 133 2.5 × 108 2.1 × 10-12 62, 63
120 0.00045 5 × 1013 128 105
1-(DBNO)-polystyryl 120 0.042 3.8 × 1014 120 48, 49
1-phenylethyl 120 0.014 2.2 × 1014 122 62
1-poly-tert-butylacrylate 120 0.001 48, 49
1-1-tert-butoxycarbonylethyl 120 0.0011 1.2 × 1014 128 62
6-polystyryl 130 ≈0.0032 ≈6 × 106 5.2 × 10-10 23
6-1-phenylethyl 120 0.0027 1 × 108 2.7 × 10-11 62, 63
8-(DEPN)-polystyryl 125 0.0034 1 × 1014 121 5.7 × 105 1.9 × 10-8 65
120 0.011 2 × 1015 130 6 × 10-9 59
120 48, 49
8-1-phenylethyl 120 0.0055 1.9 × 1014 125 4.6 × 106 1.2 × 10-9 62, 63
8-poly-n-butylacrylate 120 0.0071 1.7 × 1015 130 4.2 × 107 1.7 × 10-10 59
8-1-tert-butoxycarbonylethyl 120 0.003 3.5 × 1014 128 62
The Persistent Radical Effect Chemical Reviews, 2001, Vol. 101, No. 12 3599
model compounds, a clustering around 2 × 1014 s-1 CH(CH3)CO2CH3. It is ascribed to the concerted
was observed. These frequency factors are remark- alkene elimination, which is also known for TEMPO-
ably small since for molecular dissociations into fairly alkyl compounds.81,112 However, for TEMPO-
large groups values much larger than 1015 s-1 are CH(CO2CH3)CH2C(CH3)2C6H5, the fraction of the side
usual.111 Obviously, nearly the whole bond dissocia- reaction is again low (fD ≈ 1%), so TEMPO-
tion energy is needed to reach the transition state of CH(CH3)CO2CH3 is not a good model for TEMPO-
the cleavage while little entropy is gained. Further, terminated acrylates. Nevertheless, one may specu-
we note that the cleavage is favored by polar solvents, late that side reactions contribute to the difficulties
external and internal hydrogen bonding, strong steric encountered with TEMPO-mediated acrylate poly-
congestion around the NO group, increasing CNC merizations, because they are virtually absent for
bond angles, and electron-donating groups on the DEPN (8) based systems.112 Similarly, the nitroxide
nitroxide moiety.82,104 9 exhibits a much better end group fidelity than
The rate constants for the coupling of carbon- TEMPO in styrene and acrylate polymerizations.114
centered radicals with nitroxides (Table 1) range from The irreversible decay of the dormant alkoxamine
6 × 105 M-1 s-1 to about 108 M-1 s-1, and they vary chains stops the monomer conversion rather abruptly
more than the cleavage rate constants. Many studies at the time t ) 1/fDkd. For methyl methacrylate
on small radicals have shown that the rate constants polymerizations this stop has been observed, and it
are generally lower than diffusion controlled values has been demonstrated that it is caused by a consid-
and depend very little on temperature.63,108,109 In erable fraction of cross-disproportionation between
some cases even negative activation energies have the nitroxide and the propagating radicals.51,97,112
been found, whereas the rate constants with small Unfortunately, the factors governing disproportion-
positive activation energies often revealed unusually ation-to-combination ratios in radical-radical reac-
small frequency factors. This is rationalized by a tions are not well understood up to now, but stereo-
nearly barrierless cross-coupling reaction, where the electronic effects are certainly very important.112
location of the transition state is governed by entropy. Hence, one cannot yet predict a nitroxide structure
Support for this explanation is the anticorrelation of that will allow living methacrylate polymerizations
the cleavage of alkoxyamines and the coupling rate up to large conversions.
constants for systems with the same basic structures Recently, it has been found that the elimination of
but different substitutions.63 the hydroxylamine from a nitroxide-capped polymer
occurs particularly facilely upon the controlled
In total, alkoxyamine systems with large cleavage monoaddition of maleic anhydride and maleimide
(activation) rate constants tend to show small cou- derivatives under the creation of a very useful
pling (deactivation) rate constants. This provides functional end group, that is, the often detrimental
large equilibrium constants that increase the conver- side reactions can also be put to good use.115
sion rates. It must not deteriorate the control since A complete mechanism of the nitroxide-mediated
this depends on kd and the product kdkc. In compari- polymerizations must also take further reactions into
son, the more recently introduced nitroxides 6, 8, and account. For the case of TEMPO + styrene, Scaiano
9 provide larger equilibrium constants than e.g. 3 et al. showed that the nitroxide radical can add
(TEMPO). For acrylate-derived radicals, the equilib- directly to the monomer.116 It can also abstract a
rium constants are usually smaller than for styryl hydrogen atom from the Mayo dimer117 and possibly
type radicals, and this may, at least in part, explain from the polystyryl chains.116 In addition, hydroxyl-
the failure of TEMPO-regulated acrylate polymeriza- amines can act as hydrogen donors for the propagat-
tions. However, judging from model studies,62,63 this ing radicals and retard the polymerization.118 Quan-
reason does not apply for methacrylates. titative assessments of the importance of these
Reactions that convert the alkoxyamines to hy- reactions are still missing, but the practical experi-
droxylamines and alkenes can strongly limit the ence with living radical polymerizations points against
monomer conversion. These are either usual radical strong deteriorating influences.
disproportionations between the nitroxide and the
propagating radicals or concerted alkoxyamine de- 2. Mediation by Other Persistent Radicals
cays. Both pathways lead to an exponential decrease Most of the living radical polymerizations using
of the concentration of the dormant chains with rate organic radicals as regulating persistent species
constant kdec ) fDkd, where fD is the fraction of the involved nitroxides. Exceptions are triphenylmethyl
side reaction concurring with radical coupling of and other carbon-centered radicals in the early work
alkoxyamine decay.57 kdec can be measured from the of Otsu and Braun.24,25 More recently, Chung showed
decay of the dormant alkoxyamine chains under that borinate radicals 10 formed by the thermal
nonscavenging conditions, and its relation with kd cleavage of in situ generated alkyl boryl peroxides
provides fD. From data of Fukuda et al. one can (Scheme 31) can be employed to control methacrylate
deduce fD ) 0.4% for a TEMPO-polystyryl compound
and fD ) 1.1% for a di-tert-butylnitroxide-poly-tert- Scheme 31
butylacrylate macroinitiator both at 120 °C.53,55 Simi-
lar small values of fD hold for TEMPO-cumyl (Scheme
10),22 TEMPO-1-phenylethyl,112 and a better mimetic
compound for TEMPO-polystyryl.113 In these cases,
fD probably represents the usual radical dispropor-
tionation. A much larger fD ≈ 25% holds for TEMPO-
3600 Chemical Reviews, 2001, Vol. 101, No. 12 Fischer
imine . aryl imine > arylamine,134 and tris(2- general and can be applied to many cases. We start
(dimethylamino)ethyl)amine seems to be one of the with the minimum mechanism given in Scheme 3
most efficient ligands.124 and the assumptions stated earlier. The concentra-
Atom transfer polymerizations are often subject to tions of the radicals R•and Y• obey
problems arising from solubility, the initial presence
of metal ions in the higher oxidation state, multiple d[R]/dt ) kd[I] - kc[R][Y] - kt[R]2 (39)
complex equilibria, and a variety of side effects.137-139
Quite often, diverse broken reaction orders are d[Y]/dt ) kd[I] - kc[R][Y] (40)
observed with respect to catalyst and initiator, and
they are difficult to analyze.140 Nevertheless, with the By stoichiometry, they are related by [I]0 - [I] ) [Y]
methods outlined above for nitroxides, some quanti- ) [R] + [P]. Hence, [I] can be expressed by [Y], and
tative data for the reversible radical formation steps the concentration [P] of the termination products is
were obtained. practically equal to the concentration of the persis-
Table 2 shows results for polymeric and low mo- tent species [Y].
lecular model systems. If one takes the second-order According to the rate equations (39 and 40), both
radical formation into account and assumes 0.1 M radical concentrations increase at first linearly with
concentrations of initiator and catalyst, the atom time as [R] ) [Y] ) kd[I]0t, and they attend a
transfer favors the radical formation (activation) stationary state only at infinite time, where [Y]∞ )
more than the alkoxyamine dissociation. On the other [P]∞ ) [I]0 and [R]∞ ) 0, that is, when the initiator is
hand, the cross-reaction rate constants kc and kdeact fully converted to persistent radicals and unreactive
show similar orders of magnitude for both types of products. To find the intermediate behavior and the
reactions. This explains the generally shorter reac- dynamic equilibrium, we cast the rate equations into
tion times for the metal-catalyzed systems. In model simpler forms by using reduced variables and pa-
studies Matyjaszewski et al.134 found that the rate rameters
constant kact for radical formation from Cu(I) com-
plexes and organobromides increases with decreasing [R] [Y] kc[I]0 kt[I]0
reduction potential of the complex and can be tuned F) η) τ ) kdt a ) b)
[I]0 [I]0 kd kd
by the choice of the ligand. This is also known in
(41)
organic synthesis (see above) and it points to an
activation-controlled forward reaction. The authors and the definition x̆ ) dx/dτ. This yields
also noticed an anticorrelation between kdeact and kact,
that is, larger rate constants for the radical formation F̆ ) 1 - η - aFη - bF2 (42)
parallel the smaller rate constants for the reverse
reaction. The same holds for the nitroxide-based η̆ ) 1 - η - aFη (43)
systems, and it may indicate an entropy-controlled
deactivation. If this is generally true, one expects only Obviously, the kinetics are determined by two pa-
weak or even negative temperature dependencies of rameters, a and b, only. It is thus sufficient to solve
kdeact. the differential equations in terms of a and b and
then go back to the real concentrations and times via
IV. Theoretical Methods and Special Cases of the relations 41.
The parameters a and b depend on [I]0, and the
Living Radical Polymerizations rate constants and their magnitudes can be esti-
mated. In polymerizations, one often aims at average
A. The Basic Reaction Mechanism degrees of polymerization of 100-1000 for an initial
In this section we summarize a method for the monomer concentration of about 10 M (bulk). Hence,
quantitative treatment of living radical polymeriza- one uses [I]0 ) 10-2-10-1 M. For small radicals R•
tions involving the persistent radical effect. It is quite and low viscosities, the termination constant is
Table 2. Rate and Equilibrium Constants for the Reversible Bromine Atom Transfer Reaction of Polymeric and
Low Molecular Model Compounds with Cu-Complexes. For Ligand Structures, See Scheme 33
initiator or dormant chain catalyst T/°C kact/M-1 s-1 kdeact/M-1 s-1 K ref
poly(methyl methacrylate)-Br CuBr/(4,4-di-n-heptyl-2,2-bipyridine)2 100 7 × 10-7 124
ethylisobutyrate-Br CuBr/TERPY 35 1.5 132
CuBr/BPOA 35 0.3 132
CuBr/DPIP 35 0.1 132
polystyryl-Br CuBr/(4,4-di-n-heptyl-2,2-bipyridine)2 110 0.45 1.1 × 107 3.9 × 10-8 64, 131
90 2 × 10-8 64, 131
1-bromoethylbenzene CuBr/TERPY 35 0.42 4.1 ×105 a 132
CuBr/BPOA 35 0.066 3.3 × 106 a 132
CuBr/DPIP 35 0.014 3.1 × 106 a 132
poly(methyl acrylate)-Br CuBr/(4,4-di-n-heptyl-2,2-bipyridine)2 90 1.2 × 10-9 131
methyl proprionate-Br CuBr/(4,4-di-n-heptyl-2,2-bipyridine)2 60 0.065 92
CuBr/TERPY 35 0.41 132
CuBr/BPOA 35 0.014 132
CuBr/DPIP 35 0.011 132
a 75 °C.
3602 Chemical Reviews, 2001, Vol. 101, No. 12 Fischer
usually kt ≈ 109 M-1 s-1, and it reduces to 107-108 increase along the first diagonal, the trajectory bends
M-1 s-1 for long chains. For the special case of up and crosses the isocline η2 vertically. Thereafter,
alkoxyamines, the cross-coupling rate constants are F decreases and η continues to increase. The trajec-
in the range kc ) 105-108 M-1 s-1, and kd ranges from tory cannot cross η2 a second time, since it must do
10-5 to 1 s-1 for reaction temperatures around 120 so vertically in the direction of increasing η. It cannot
°C (Table 1). This places a between 103 and 1014 and cross the isocline η1 either, since it must do so
b between 105 and 1014. Hence, a and b are always horizontally in the direction of decreasing F. There-
large compared to 1, and one also expects a2/b . 1 fore, after the first crossing, the trajectory is confined
for most individual cases. to the region between the two isoclines. This region
The system of nonlinear differential equations 42 is very narrow for the chosen parameters. Staying
and 43 has no closed solution. Our analysis starts between the isoclines, the trajectory finally ap-
from an investigation of the possible trajectories of proaches the final point. The maximum of F is on
the point (F(τ),η(τ)) in the two-dimensional phase isocline η2. Therefore, F is limited to values below F
plane spanned by the variables F and η. These are ) 1/xb.
limited by stoichiometry to values between 0 and 1. In the log-log representation of the phase diagram,
Moreover, from eqs 42 and 43 one has the dynamic equilibrium relation 19 (kc[R][Y] )
kd[I]0) or aFη ) 1 appears as a straight line with slope
η̆ ) F̆ + bF2 (44) -1. It starts at (F, η) ) (1/a, 1), and it is practically
identical to η1 for F > 1/a. The trajectory must closely
For the given initial conditions this implies that η g follow η1, and hence, there is a time range where the
F for all times. Hence, all trajectories are in the plane equilibrium relation is certainly valid. With increas-
(0,1) × (0,1), start at the origin (0,0) along the first ing 1/a, the equilibrium line shifts to the right. It will
diagonal and then deviate positively therefrom. Set- not be reached at all when 1/a becomes close to b-1/2.
ting η̆ ) 0 and F̆ ) 0 in eqs 42 and 43 yields the Consequently, one condition for the existence of the
singular point (0,1) at infinite time. equilibrium is a2/b . 1. Further, because F < 1, one
In the intermediate time regime, the evolution of has b g 1, and this implies the third condition a . 1
the trajectories follows from the behavior of isoclines, by combination with the first. With the definitions
where the time derivatives of the dynamic variables 41, this yields eqs 20.
are individually zero, namely isocline η1(F), where F̆ In the transition region between the initial and the
) 0, and isocline η2(F), where η̆ ) 0. From eqs 42 and equilibrium regime, the details of the time evolutions
43 these are are complicated.17 However, for the equilibrium
regime where aFη ) 1, the integration of eq 44 leads
1 1 - bF2 to eqs 18.17 These solutions are obeyed until η
η1(F) ) and η2(F) ) (45)
1 + aF 1 + aF approaches 1 and F approaches 1/a, and this happens
at the approximate time t ) [I]0/3K2kt. For nitroxide-
The isoclines divide the phase plane into regions based systems with a large equilibrium constant, K
of different signs of the time dependencies of F and ) 10-8 M (Table 1), a rather small initiator concen-
η, as is indicated in Figure 9 in a log-log representa- tration, [I]0 ) 10-2 M and kt ) 108 M-1 s-1, the
tion. Consequently, any trajectory can cross the equilibrium, and that is also the persistent radical
isocline η1 only horizontally and in the direction of effect, lasts for about 90 h, and it is entered at rather
decreasing F, and it can cross the isocline η2 only short times of at most seconds.17
vertically in the direction of increasing η. Further, Polymerizations are studied typically in time ranges
η2 crosses the line η ) 0 at the maximum F ) 1/xb, between 100 s and 30 h, that is, in the equilibrium
and both isoclines approach the final point (0,1) with regime. Therefore, for polymerizing systems, one can
the same slope. use eq 20, insert it into the rate equation of the
Figure 9 also shows a computed trajectory for the monomer consumption (21), integrate, and obtain eq
parameters (a, b) ) (108, 108). After the initial 22. The further derivation of the control involves the
calculation of the moments mk of the chain length
distribution and of their time dependencies.
≈
mk ) ∑ nk([In] + [Pn] + [Rn]) k ) 0, 1, 2
n)1
initiator, the transient radicals, and the products that fraction but little “control”.17 The latter situation
do not contain monomer units. It seems reasonable corresponds to parameters close to point B in Figure
to assume and is borne out by numerical calculations 5 and has been observed for monomers with large
that [I0] decays exponentially because R0• immedi- propagation constants kp. A counterstrategy is to add
ately adds to the monomer. For the same reason, [R0] some persistent species before the reactions, and
and [P0] are small compared to [I0]. Thus, one has this has been used both in nitroxide-mediated
systems59,65,96,141-143 and in ATRP.130 Actually, and
especially in ATRP, traces of persistent species may
[I0] ) [I]0e-kdt and m0 ) [I]0(1 - e-kdt) (47) always be present as impurities. The initial excess
[Y]0 first levels the transient radical concentration
to the equilibrium value130 [R]s ) K[I]0/[Y]0, and this
For the moments m1 and m2, we derived the kinetic is smaller than the radical concentration without the
equations16 initial excess of the persistent species. Therefore, the
conversion rate it lowered, and one obtains a linear
time dependence of ln([M]0/[M]).
dm1 d[M]
)- (48) In a closer examination,50 we cover only radical
dt dt formation (activation) by bond cleavage and cases for
which the conditions (20) for the dynamical equilib-
dm2 d[M] rium are fulfilled. The initial presence of the persis-
)- + 2kp[M]m1(R) (49)
dt dt tent species leads to the stoichiometry relations [I]0
- [I] ) [Y] - [Y]0 ) [R] + [P]. A comparison with the
earlier relations [I]0 - [I] ) [Y] ) [R] + [P] suggests
where m1(R) ) ∑∞n)1 n[Rn]. By integration of eq 48 a new time-dependent variable, namely, the persis-
and use of eq 47, one obtains the number-average tent radical concentration that arises only from the
degree of polymerization XN ) m1/m0 (24). To calcu- initiator, [Y] - [Y]0. Consequently, the appropriate
late m2 and the polydispersity index PDI ) m0m2/ new reduced variable η̃ is now defined by η̃ ) ([Y] -
m12, one also needs m1(R). It enters the kinetic [Y]0)/[I]0, and one has η ) η̃ + η0.
equation for the first moment of I.16 The kinetic equations become
condition a2/b . 1. The isoclines intersect the F-axis 10. It is entered at the time t0 ) 1/kc[Y]0, where [R]
at obeys [R] ) kd[I]0t0 ) K[I]0/[Y]0, and this is in the
millisecond region. After the long time t1 ) [Y]03/3K2-
F1 ) 1/aη0 and [I]02kt, eqs 19 hold, then [R] decreases proportionally
to t-1/3. While [R] is constant, [Y] - [Y]0 takes the
F2 ) (aη0/2b)(x1 + 4b/(aη0)2 - 1) (56) same value as [R] at first, then it increases linearly
with time. Finally, for t . t1, [Y] - [Y]0 increases
and these intersections nearly coincide if η0 . xb/a. proportionally to t1/3.
For the present parameters this holds for η0 . 10-4, Analytical solutions that cover both the intermedi-
and is fulfilled for η0 ) 10-2, as seen in Figure 10. ate and the final time regimes are also available.
The isoclines are also again superimposed in a region Equation 44 is independent of the initial conditions
where they satisfy the equilibrium relation aη̃F ) 1. and can be integrated using the combined equilibri-
Figure 10 also displays trajectories. As before, they um relation a(η̃ + η0)F ) 1. As for η0 ) 0,16 this yields
start along the first diagonal, cross isocline η̃2, and an implicit equation for the time dependence of η,
remain confined to the region between η̃2 and η̃1, which leads to the approximate solution
thereafter. For the small η0 ) 10-6, the first stage of
the time evolution is directly followed by the equi- [Y] ) (3ktK2[I]02(t - t0) + [Y]03)1/3 + K[I]0/[Y]0
librium regime aη̃F ) 1, that is, the trajectory is not (57)
at all influenced by the initial presence of the
persistent species. For η0 ) 10-2, there is an inter- Apart from the small last term, it has been given
mediate region where F is constant. Here, one has earlier by Fukuda et al.49
aη0F ) 1, and aη̃F ) 1 is reached only later. In this With [R] given by [R]s ) K[I]0/[Y]0 before the time
case, and more generally for η0 . xb/a, the two t1 and by eq 18 thereafter, the rate equation for the
regimes can be combined to a(η̃ + η0)F ) 1, that is, monomer consumption (21) integrates to
the usual equilibrium relation 19.
It is important to notice that for a sufficiently large [M]0 [I]0
ln ) kpK t for t < t1 (58a)
excess of the persistent species η0 . xb/a, the [M] [Y]0
intermediate region where F is constant and one has
aη0F ) 1 does exist even if the dynamic equilibrium and to
( )
19 does not hold in the absence of the excess [Y]0.
[M]0 [I]0 1/3
Hence, in such unfavorable cases, one can drive the 3 K[I]0
system to equilibrium by a deliberate addition of the ln ) kpK t1 + k p (t2/3 - t12/3)
[M] [Y]0 2 3kt
persistent radical and, consequently, to control.
for t > t1 (58b)
Figure 11 shows the radical concentrations [R] and
[Y] - [Y]0 versus time in a log-log representation
These relations reveal that the additional persis-
for the same parameters a and b as used for Figure
tent species has no influence on the conversion rate
10 and, specifically, for kd ) 10-3 s-1, kc ) 107 M-1
if [Y]0 < (3K[I]0kt/kp)1/2, whereas 90% conversion
s-1, kt ) 108 M-1 s-1, and [I]0 ) 0.1 M. A too small
occurs before t1 if [Y]0 > (3 ln(10)K[I]0kt/kp)1/2. For a
initial excess [Y]0 ) 10-7 M has no effect on the time
monomer with a large propagation constant of kp )
evolution (compare Figure 1 for ktY ) 0). For the
20 000 M-1 s-1, and kd ) 10-3 s-1, kc ) 107 M-1 s-1,
larger [Y]0 ) 10-3 M, the short time increase of [Y]
kt ) 108 M-1 s-1, and [I]0 ) 0.1 M, the first condition
- [Y]0 and [R] (Figure 10) is followed by a regime
holds for [Y]0/[I]0 < 0.004, that is, 0.4% initial
where [R] is constant at [R] ) K[I]0/[Y]0. This corre-
persistent species, and the second for [Y]0/[I]0 > 0.006,
sponds to the vertical part of the trajectory in Figure
or 0.6%. Since one often applies persistent radical
concentrations that are a few percent of the initiator
concentration,59,65,96,130,141-143 the second situation is
met in practice. Then, eq 58a holds, that is, the
polymerization index increases linearly with time and
depends on the equilibrium constant. Of course, the
conversion is retarded. From the previous equations
one obtains the ratio between the times for 90%
monomer conversion and the ratio of the unreactive
products with and without the initial excess of the
persistent species as
t90([Y]0)3
) [Y]0(kp/2 ln(10)K[I]0kt)1/2 )
t90([Y]0 ) 0) 2
Figure 11. Time dependence of the reduced radical 3 [P]90([Y]0 ) 0)
concentrations in a log-log representation for different (59)
4 [P]90([Y]0)
reduced excess concentrations η0 of the persistent species.
Parameters a and b as used for Figure 10, and specifically
kd ) 10-3 s-1, kc ) 107 M-1 s-1, kt ) 108 M-1 s-1, and [I]0 ) For the parameters used above, this yields an about
0.1 M. Circles are added according to the analytical 50-fold reduction of the unreactive products for 1%
equations. excess of the persistent species at the expense of an
The Persistent Radical Effect Chemical Reviews, 2001, Vol. 101, No. 12 3605
Y• f X + R• (61)
with rate constant kY.
Initially, only the initiator I shall be present. This
leads to the stoichiometry relations [I]0 - [I] ) [Y] +
[X] ) [R] + [P] - [X]. Obviously, one needs to consider
now three time-dependent variables, and the rate
equations are
Figure 12. Average degrees of polymerization XN and d[R]/dt )
polydispersity indices as functions of conversion for a fast
propagating monomer in the absence and in the presence kd([I]0 - [Y] - [X]) - kc[R][Y] + kY[Y] - kt[R]2
of an initial reduced excess concentration η0 of the persis-
tent species. Parameters as used for Figure 11, and kp ) d[Y]/dt ) kd([I]0 - [Y] - [X]) - kY[Y] - kc[R][Y]
20000 M-1 s-1, [M]0 ) 10 M. Circles are added according
to the analytical equations.
d[X]/dt ) kY[Y]
increase of the conversion time by a factor of 30. In
ATRP systems, the effects are less drastic.66 Using the reduced variables (41) and, in addition, ξ
In the derivation of the moments one has now to ) [X]/[I]0 and d ) kY/kd yields
consider the reformation of the initiator I0 by coupling
of R0 with the excess Y•, which competes with the F̆ ) 1 - η - ξ - aFη + dη - bF2 (62a)
addition of R0• to the monomer. This leads to a η̆ ) 1 - η - ξ - aFη - dη (62b)
reduction of the effective decay rate constant of I0 by
the probability factor β ) kp[M]0/(kp[M]0 + kc[Y]0), so ξ̇ ) dη (62c)
that the zeroth moment is now given by m0 ) [I]0(1
- e-βkdt). The other equations for the moments are In the three-dimensional phase space (F,η,ξ) the
not changed by the presence of [Y]0. Therefore, XN is isoclines η1(F) and η2(F) are now surfaces that inter-
given by eq 24 with kd replaced by βkd. sect at
In most cases, the excess [Y]0 leads to a constant
radical concentration [R]s ) K[I]0/[Y]0 during the 2dη ) bF2 (63)
polymerization. Insertion into eq 51, integration, and
use of the definition provide the polydispersity index Figure 13 displays these isoclines for ξ ) 0 and for
the parameters kd ) kY ) 3 × 10-3 s-1, kc ) 5‚107
( )
kp[I]0 2 - C M-1 s-1, kt ) 108 M-1 s-1, and [I]0 ) 0.1 M, which
1
PDI ) (1 - e-βkdt) 1 + + (60) obey the conditions 20. It also shows the projection
kc[Y]0 C X N of a trajectory onto the plane (F,η,0). As before, after
crossing η2, the trajectory is confined to the space
For small conversions but sufficiently long times, this between the isoclines. At first, it behaves like the
reduces to eq 38. trajectory in Figure 9. ξ is very small in this regime
Figure 12 shows the beneficial effects of 5% excess and can be obtained by integrating eq 62c with η
persistent species on the control of the chain length
distribution for a rather fast living polymerization
that shows little control without the excess, because
the parameters are close to point B in Figure 5. Of
course, the much better control is obtained at the
expense of a strong retardation of the monomer
conversion that amounts to a factor of 150. For fast
polymerizations and parameters close to point C in
Figure 5, one expects control but little livingness for
large conversions, and in this case the improvement
requires quite large initial nitroxide concentrations.50
( )
polydispersity indices as functions of conversion in the
2kYK[I]0 1/3 absence and in the presence of a decay of the persistent
[R] ) (1 - t/t1) and species. Parameters as used for Figure 11, and kp ) 5000
kt M-1 s-1, [M]0 ) 10 M.
(
K2[I]02kt
)
1/3
sion times in slow living radical polymerizations by
[Y] ) (1 - t/t1)2 (65) the removal of these species through additives or a
kY
built-in instability.31,118
Figure 14 shows the concentrations of all species
in a log-log-representation as functions of time for D. Instantaneous Radical Formation
the parameters given above. As qualitatively ex- In all examples discussed so far, the transient and
pected, the decay of Y• leads to an intermediate the persistent species were continuously generated.
stationary state of the radical concentrations. This Now, we consider the behavior when both radicals
state is entered at the time t0 ) 1/6kY, and for kY ) are initially present and then react without further
3 × 10-3 s-1, this is at t0 ) 56 s. It breaks down at generation by the cross-reaction of R• with Y• and by
the much larger time t1 ≈ 1.2 × 107 s ) 3300 h. This the self-terminations. This initial situation may be
may seem surprising, because the natural lifetime created by a pulse photolysis of suitable precursor
of Y• is only 1/kY ) 330 s. The explanation is that molecules. The first theoretical treatment was given
the unstable persistent species is present in this form by O’Shaughnessy et al.,144 and the resulting equa-
only for a small fraction of time and stays essentially tions were later used to determine cross-reaction
incorporated in the dormant chains where it does not constants in the photocatalysis reaction of polyoxo-
decay. This time fraction is approximately equal to tungstates (Scheme 29).94
[Y]/[I]0 ) 0.1% for the region where [Y] is constant In the simplest case, the self-termination of the
(Figure 14). persistent species is absent, and the rate equations
Figure 15 displays the average degrees of polym- are
erization and polydispersities expected without and
with the decay of the persistent radical and for the d[R]/dt ) - kc[R][Y] - kt[R]2 (66)
parameters given above. The control remains satis-
factory, even for the large decay constant kY. On the d[Y]/dt ) - kc[R][Y] (67)
other hand, the time for 90% conversion is reduced
by a factor of about 6. The fraction of unreactive
with the initial concentrations [R]0 and [Y]0. Accord-
products increases by a factor of 5 but remains small
ing to eq 66, the transient species always reach [R]∞
(4%). This confirms the strategy to shorten conver-
) 0 at infinite time. Insertion into eq 67 does not
provide a value for [Y]∞. However, one can guess that
the self-termination of R• may lead to leftover Y• and
that this will depend on the initial concentrations and
the rate constants.
To solve the problem, one combines eqs 66 and 67
to
d[R] kt [R]
)1+ (68)
d[Y] kc [Y]
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Chem. Rev. 2001, 101, 4071−4097 4071
Supramolecular Polymers
L. Brunsveld, B. J. B. Folmer, E. W. Meijer,* and R. P. Sijbesma
Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands
ment of neighboring donor and acceptor sites is an bonding units based on 2-ureido-4[1H]-pyrimidinones
additional factor which significantly affects the (DDAA), which dimerize in chloroform with an as-
strength of the complexation. This phenomenon was sociation constant of Kdim ) 6 × 107 M-1.30,31 The
first recognized for the association of linear arrays supramolecular polymers that were developed using
of 3 hydrogen-bonding sites (Figure 3); whereas these hydrogen-bonding units will be discussed in
complexes between the common ADA-DAD (1-2) detail below. Zimmermann and co-workers have
motif exhibit an association constant of around 102 reported a very stable self-complementary quadruple
M-1 in chloroform, this value is around 104 M-1 in hydrogen-bonding unit (7), depicted in Figure 4, in
complexes with a DAA-DDA (3-4) motif, while AAA which all tautomers can dimerize via quadruple
and DDD arrays (5-6) exhibit association constants hydrogen bonds.
exceeding 105 M-1. Detailed calculations by Jorgen- There is ample opportunity for developing new
son24,25 showed that this effect is due to differences multiple hydrogen-bonding units for use in supramo-
in secondary interactions between these motifs. In lecular polymers with novel, attractive features, such
the complexes, diagonally opposed sites repel each as ease of synthesis, insensitivity to tautomeriza-
other electrostatically when they are of the same kind tion,28 and stronger association by using arrays of 6
(both donor or both acceptor), whereas disparate sites bonds32 or 8 hydrogen bonds.33 The use of heteroaro-
attract each other. In the DDD-AAA motif the matic compounds as multiple hydrogen-bonding units
number of attractive secondary interactions is maxi- for self-assembly has recently been reviewed.34
mized, and in the ADA-DAD motif the number of Application of hydrogen-bonding units as associat-
repulsive interactions is at its largest. ing end-groups in difunctional or multifunctional
Very stable complexes can be obtained when qua- molecules results in the formation of supramolecular
druple hydrogen-bonding units are employed.26-30 polymers with varying degrees of polymerization
Aspects of multiple hydrogen-bonding units that are (DP). The early examples of hydrogen-bonded su-
of special importance with respect to application in pramolecular polymers rely on units, which associate
supramolecular polymers are the self-complementa- using single, double, or triple hydrogen bonds that
rity of DADA and DDAA arrays and the possibility all have association constants below 103 M-1. In
of tautomerism. The latter may lead to loss of isotropic solution, the DP of these polymers is ex-
complexation when complementarity is lost, or when pected to be low. In the liquid crystalline state,
a DDAA array tautomerizes to a DADA array with however, the interactions are stabilized by excluded
a higher number of repulsive secondary interactions. volume interactions, and the DP is much higher.
We have reported on self-complementary quadruple Examples of linear supramolecular polymers based
H-bonding units based on mono-ureido derivatives on weak hydrogen-bonding interactions assisted by
of diamino-triazines29 (DADA-array) with a dimer- liquid crystallinity or phase separation will be treated
ization constant of Kdim ) 2 × 104 M-1 and hydrogen- below, followed by a discussion of supramolecular
Supramolecular Polymers Chemical Reviews, 2001, Vol. 101, No. 12 4075
Figure 4. Hydrogen-bonding unit 7 that dimerizes via quadruple hydrogen bonding without regard to tautomeric form.
polymers based on strong hydrogen-bond interactions bonded groups via an imide group. Because of the
that persist in the isotropic state (melt or solution). increased molecular rigidity, the system is not ther-
motropic liquid crystalline, but a lyotropic liquid
B. Hydrogen Bonding Enforced by Liquid crystalline phase is observed in apolar solvents, that
Crystallinity is birefringent and highly viscous.
A number of supramolecular liquid crystalline
The first hydrogen-bonded supramolecular poly- polymers based on a single hydrogen bond have been
mers all showed liquid crystallinity, although the reported. Incorporation of single hydrogen-bonding
separate components making up these polymers units is synthetically more straightforward than
displayed a narrow liquid crystalline regime or no those with triple hydrogen bonds, and, particularly,
liquid crystallinity at all. The liquid crystalline phase the single hydrogen bond between a pyridyl unit and
in the supramolecular polymer is stabilized by the carboxylic acids has been utilized frequently in su-
increased aspect ratio of aggregates compared to the pramolecular liquid crystalline polymers (LCP’s).46-50
constituent molecules. There is a strong cooperativity The complexation between a pyridyl unit and a
between association and the induction of the liquid carboxylic acid is stronger than carboxylic acid
crystalline phase, because anisotropy in the liquid dimerization; a Ka value of approximately 500 M-1
crystal strongly enhances the degree of polymeriza- was estimated for the pyridyl/carboxylic acid com-
tion of the hydrogen-bonded molecules.35 Liquid plex.47 Kato and Fréchet have described a variety of
crystalline supramolecular polymers are unique in self-assembled side-chain liquid crystalline polymers
the respect that they combine the potential to exhibit (SLCPs), with various backbones.48,49 Polyacrylates
the electrooptical properties associated with low- and polysiloxanes functionalized with pendant ben-
molar-mass liquid crystals with the benefit of the zoic acids display stabile mesophases upon self-
good mechanical properties of conventional poly- assembly with stilbazoles. The reverse principle has
mers.36 Odijk,37,38 van der Schoot,39 and Ciferri40 been employed for the formation of supramolecular
developed a theoretical basis for the relation between liquid crystalline polyurethanes.50 Furthermore, the
chain growth and orientation in supramolecular stability of the induced mesophase has been enlarged
liquid crystals. by employing the double hydrogen bond between
The group of Lehn is recognized to be the first to benzoic acids in the polymer main-chain and 2-(acyl-
develop a supramolecular main-chain polymer. By amino)pyridines.51,52
triple hydrogen bonding between difunctional diami- Utilization of the single hydrogen bond between
nopyridines (8) and difunctional uracil (9) derivatives pyridine and benzoic acids in SLCP’s has been a
(Figure 5) supramolecular polymer chains were formed source of inspiration for other groups in the develop-
(10).41,42 The 1:1 mixture of 8 and 9 exhibits liquid ment of main-chain supramolecular polymers based
crystallinity over a broad temperature window, on diacids and dipyridines.53-56 Supramolecular rod-
whereas, in contrast, the pure compounds are solids coil polymers have been developed by assembly of
which melt in an isotropic liquid without displaying 4,4′-bipyridines and telechelic polypropylene oxide
a liquid crystalline phase. Because of the chirality of with benzoic acid end-groups, which show highly
the tartaric acid spacer used, the fibers observed by ordered liquid crystalline phases.57 The use of tartaric
electron microscopy showed biased helicity.43 Lehn acid derivatives in combination with bipyridine units
and co-workers expanded the scope of supramolecular resulted in the formation of hydrogen-bonded, chiral
polymers by the development of rigid rod polymers main-chain LCP’s, as has been shown by circular
(11, Figure 5).44,45 In these polymers, a rigid 9,10- dichroism measurements, optical microscopy, and
dialkoxyanthracene core connects the hydrogen- X-ray data.58,59
4076 Chemical Reviews, 2001, Vol. 101, No. 12 Brunsveld et al.
Figure 5. Liquid crystalline supramolecular polymers developed by Lehn, based on triple hydrogen bonds: from chiral,
tartaric acid based monomers (10) and from rigid monomers (11).
A columnar mesophase has been used by the group Hydrogen bonding between pyridine units in a
of Percec for the creation of hydrogen-bonded su- tetrafunctional compound (12) and benzoic acid units
pramolecular polymers.60,61 The phase separation of in difunctional compounds (13, Figure 6), resulted in
the apolar side groups of substituted benzamides the formation of reversible ladder-like polymers (14)
with the core of the molecule accounts for the self- or networks (15). These materials are liquid crystal-
assembly into a cylindrical structure in which hy- line, and the large drop in material properties above
drogen bonding acting along the columnar axis occurs the isotropisation temperature demonstrates that,
and stabilizes the column. also here, the interplay between association and
Next to side-chain LCPs and main-chain LCPs, liquid crystallinity is instrumental in the process of
supramolecular networks were obtained by complex- polymerization.63 DSC studies on these networks
ation of bipyridines with polyacrylates containing reveal a memory effect, resulting in a consistent
decrease of crystallinity as the time the material is
pendant benzoic acid groups. In a related approach,
in the isotropic state increases.64
Kato and Fréchet have studied supramolecular net-
works based on low-molecular-weight components, in C. Hydrogen Bonding Enforced by Phase
which a trifunctional benzoic acid derivative was Separation
combined with a difunctional pyridine derivative.62
The methodology of increasing the strength of a
The hierarchy of the LC-phase that was formed
relatively weak hydrogen-bond interaction by (crys-
turned out to be dependent on the flexibility of the
talline) domain formation is frequently encountered
trifunctional compound used. in chain extension of conventional polymers, and is
Although chain extension based on single hydrogen in principle analogous to the enforcement of associa-
bonding is observed, supramolecular materials based tion in the liquid crystalline phase. Lillya et al. has
on this interaction, in most aspects, resemble small shown that by end-capping of poly-THF with benzoic
molecules more than they resemble polymers. Only acid functionalities, the material properties improve
the triple hydrogen-bonded supramolecular polymers significantly due to the formation of large crystalline
reported by Lehn show some typical polymer proper- domains of the hydrogen-bonded units.65 Further-
ties, such as the ability to draw fibers from the melt. more, end capping of poly(dimethylsiloxane)s with
By using multifunctional low-molecular-weight build- benzoic acid groups has been reported to result in a
ing blocks, Griffin was able to obtain materials that change in polymer properties upon functionalization.
exhibited polymer-like properties.63 However, the change in properties seems to be less
Supramolecular Polymers Chemical Reviews, 2001, Vol. 101, No. 12 4077
Figure 6. Formation of a linear ladder-type supramolecular polymer (14) or a hydrogen-bonded network (15) based on
the single hydrogen bond between a pyridine unit and a benzoic acid unit.
Figure 7. Formation of a supramolecular network by hydrogen bonding between phenylurazole units and subsequent
formation of ordered clusters.
remarkable than the results obtained with poly- ses,75-81 dielectric spectroscopy82,83, deuteron-NMR,84
THF.66 On the basis of detailed FTIR spectroscopy and IR spectroscopy85-87 were used to analyze the
and viscosimetry studies, a quantitative model for the properties of these materials.
chain length and weight distribution of the function- Although the strength of association between units,
alized polysiloxane in solution was described by which assemble by only a single or double hydrogen
Bouteiller et al.67 These associative polymers with bond, is low, chain extension by these synthetically
hydrogen-bonded groups, either telechelic or in the accessible units is a versatile tool for gaining a
side-chains, are of considerable interest for numerous significant improvement in material properties. A
applications, such as rheology modifiers, adhesives, modest degree of polymerization in combination with
adsorbents, coatings, surfactants, and stabilizers, physical interchain interactions by means of domain
because of the reversibility of interactions in the formation results in high-molecular-weight assem-
chain and between chains.68 Particularly, Stadler blies with improved material properties. Without
made an impressive contribution to this field by domain formation, or when low-molecular-weight
studying the properties of polybutadienes function- building blocks are used, a very high degree of
alized with hydrogen-bonded phenylurazole units (16, polymerization, and consequently a high association
Figure 7).69-87 constant, is required, as will be discussed in the
Because of their reversible chain extension and the following section.
subsequent formation of small crystalline domains,
the functionalized polymers exhibit properties typical D. Strong Dimerization of Multiple
for thermoplastic elastomers. At low temperatures Hydrogen-Bonding Units
the hydrogen-bond interaction contributes to the
properties comparable to covalent interactions, where- The number of supramolecular polymers based on
as at high temperatures these interactions disappear very strong multiple hydrogen-bonded units is rela-
and the materials exhibit flow behavior typical for a tively small because of the increased synthetic efforts
low-molecular-weight polymer. DSC,72,73 light and required for the synthesis of the monomers. Intrigu-
X-ray scattering,71,74 dynamical mechanical analy- ing architectures such as nanotubes88 are obtained
4078 Chemical Reviews, 2001, Vol. 101, No. 12 Brunsveld et al.
Figure 9. Nanorods based on the cyclic hydrogen-bonding motif of cyanuric acid and melamine in bifunctional calixarene
derivatives 18 and 19. (Reprinted with permission from ref 106. Copyright 1999 American Chemical Society.)
when bifunctional compounds with cyclic arrays of of an azobenzene unit, resulted in a system that can
hydrogen-bonding sites are used. Ghadiri has studied be switched between intramolecular dimerization and
nanotubes that self-assemble from cyclic peptides linear polymer formation by UV light.98,99 The cyclic
(17). These tubes can be considered reversible poly- peptides were shown to self-assemble in membranes
mers because of their multiple-hydrogen bonding. On to form trans-membrane ion channels,100 whose ori-
the basis of earlier work by De Santis89 and Toma- entation in the membrane has been studied in detail
sic,90 cyclic peptides were designed, composed of an with different IR techniques.101 The nanotubes have
even number of alternating d- and l-amino acids, been used in size-selective ion-sensing on self-as-
which assemble into extended linear stacks through sembled monolayers.102 Tubular assemblies based on
hydrogen bonding between the flat ring-shaped pep- hydrogen bonding between cyclic β-peptides, have
tides (Figure 8).91-102 been reported by Seebach,103 and by Ghadiri who
These nanotubes were found to be very robust and showed that these related structures also self-as-
turned out to be stable to a wide range of pH and semble to form membrane-spanning ion channels.104
solvents, as well as to physical stress.94 From variable Stable peptide nanotubes have been obtained by
temperature studies in chloroform, Ghadiri and co- using the hydrogen-bond formation between urea
workers concluded that the dimeric form was favored groups in cysteine based macrocycles.105
over the monomer by 23 kJ mol-1, and they postu- The groups of Reinhoudt106 and of Whitesides107
lated that this gain in stabilization energy would be have reported independently on the formation of
additive as the number of assembled rings in- supramolecular “nanorods” based on the well-known
creased.95 The association constant is dependent on cyanuric acid-melamine motif. These hydrogen-
the peptide residue used and is around 2500 M-1. By bonded polymeric rods are composed of parallel
selective backbone N-methylation the self-assembly cyanuric acid-melamine rosettes (Figure 9).
of the peptides is limited to the formation of Both groups employed the same rationale: the self-
dimers.96,97 Subsequently linking of two of the N- assembly of dimelamine derivative with a dicyanu-
methylated peptides by a short spacer results again rate derivative in which the spatial distance between
in the formation of linear reversible polymers, this the two cyanurate units is different from the distance
time with the direction of chain growth perpendicular between the two melamine units. It was anticipated
to the direction of hydrogen bonding. A clever com- that this mismatch prevented the formation of a
bination of this approach with the photoisomerization closed disklike assembly and induced the formation
Supramolecular Polymers Chemical Reviews, 2001, Vol. 101, No. 12 4079
Figure 10. Bifunctional calixarene derivative 20 and a cartoon-like representation of its polymerization induced by small
molecules.
of polymeric entities. A 1:1 mixture of dimelamine long alkyl chains, chloroform solutions develop liquid
(18) and dicyanurate (19) resulted in a viscous crystallinity.112
solution, indicating that high-molecular-weight ag- Although these supramolecular polymers possess
gregates were formed. The nature of the aggregates intriguing new properties, synthetic barriers hamper
was further investigated by NMR spectroscopy, gel extensive study of the mechanical properties of these
permeation chromatography (GPC), and transmission materials. The supramolecular polymers discussed
electron microscopy (TEM). above are the products of multistep synthesis, and it
The group of Rebek Jr. has developed an ingenious is a daunting task to prepare sufficient amounts of
way to form supramolecular polymers by utilizing the material for evaluations such as melt-rheological
hydrogen bonding between urea functionalized calix- experiments and tensile testing. The development of
arenes (Figure 10).108-112 These calixarenes had been the ureidopirimidinone functionality, a synthetic very
shown to form very stable dimeric capsules which accessible quadruple hydrogen-bonding unit with a
bind a solvent molecule inside their cavity. Associa- very high association constant, has helped enor-
tion of bifunctional molecules consisting of two co- mously to open the way to complete exploration of
valently connected calixarene moieties (20) results all aspects of supramolecular polymers.
in the formation of “polycaps”. The association be-
tween the monomers is based upon hydrogen bonding E. Ureidopyrimidinone-Based Polymers
in cooperation with complexation of a small guest;
the polymerization of the assembly is driven by The ureidopyrimidinone unit can be made in a one-
encapsulation of small guests such as benzene. Solu- step procedure from commercially available com-
tions of these molecules in o-dichlorobenzene show pounds,29,31 and it dimerizes with an association
polymer-like rheological behavior, with a strong constant of 6 × 107 M-1 in CDCl3. Difunctional
concentration-dependent viscosity.111 The physical compounds (21), possessing two of these ureidopy-
integrity of the noncovalent assemblies under shear rimidinone units, form very stable and long polymer
was demonstrated by the observation of strong chains in solution as well as in the bulk (Figure
normal forces in rheometry experiments. The “poly- 11).113,114
caps” can be drawn into fibers with a tensile strength Dissolving a small amount of this low-molecular-
in the order of 108 Pa.109 Networks from tetrafunc- weight compound (21) in chloroform results in a
tional molecules in solution display a stronger elastic solution with a high viscosity. It can be calculated
component in their rheological behavior, and they that polymers with chain lengths of the order of 106
have complicated time dependent properties such as Da can be formed when highly purified monomers
shear thickening. When the “polycaps” are fitted with are used. The presence of monofunctional impurities
4080 Chemical Reviews, 2001, Vol. 101, No. 12 Brunsveld et al.
Figure 12. Light-induced depolymerization of UPy-based supramolecular polymers. Concept (a); and compounds used
(b).
is expected to lead to a dramatic reduction in DP, or solutions of conventional polymers. Similar to the
because they will act as “chain stoppers”. In fact, behavior in the melt, solution viscosities of UPy-
deliberate addition of small amounts of monofunc- based supramolecular polymers are also strongly
tional compounds (22) results in a sharp drop in temperature-dependent. Recently a very surprising
viscosity, proving the reversibility and unidirection- inversion of the normal temperature-dependence of
ality of association. The reversibility of the linkages the solution viscosity was observed in solutions of
between the building blocks is instrumental in the preorganized difunctional compounds (24), which
development of materials that change their proper- form a mixture of linear polymer chains and cyclic
ties in response to environmental changes, so-called dimers (Figure 13).116 The thermodynamic param-
‘smart materials’. Application of a light-sensitive eters of this equilibrium are such that polymerization
monofunctional compound (23) yielded a material is favored at higher temperatures. As a result, the
from which the degree of polymerization in solution viscosity of a 145 mM chloroform solution of the
could be tuned by UV irradiation (Figure 12).115 compound was observed to increase by a factor of 3.9
Although the supramolecular polymers based on when the temperature was increased from 255 to 323
bifunctional ureidopyrimidinone derivatives in many K. Entropy-driven polymerizations are rare, and the
ways behave like conventional polymers, the strong unexpected effect in this system is the first time it
temperature dependence of their mechanical proper- was observed in a reversible synthetic system.
ties really sets them apart from macromolecular The quadruple hydrogen-bonded unit has been
polymers. At room temperature, the supramolecular further employed in the chain extension of telechelic
polymers show polymer-like viscoelastic behavior in polysiloxanes,117 poly(ethylene/butylenes), polyethers,
bulk and solution, whereas at elevated temperatures polyesters, and polycarbonates.118 In these com-
liquid-like properties are observed. These changes are pounds, the material properties were shown to im-
due to a 3-fold effect of temperature on the reversible prove dramatically upon functionalization, and ma-
polymer chain. Because of the temperature depen- terials were obtained that combine many of the
dence of the Ka value of UPy association, the average mechanical properties of conventional macromol-
DP of the chains is drastically reduced at elevated ecules with the low melt viscosity of organic com-
temperatures. Simultaneously, faster dynamics of the pounds. This strategy can be seen as closing the gap
scission-recombination process leads to faster stress between polymers and oligomers by taking the best
relaxation in an entangled system. These two effects of both worlds. Especially in the field of conjugated
occur in addition to the temperature-dependent stress polymers for plastic electronic devices, expectations
relaxation processes that are also operative in melts for future applications of this strategy are high.119
Supramolecular Polymers Chemical Reviews, 2001, Vol. 101, No. 12 4081
Figure 14. Self-assembly of discotic molecules with the different aggregates given as a function of concentration.
Very recently, Coates et al. used a vinyl-substituted flexible side-chains. The core generally consists of a
Upy-unit to be part of an olefin polymerization using planar aromatic system, whereas the side-chains are
the Brookhart catalyst. With small amounts of Upy- usually flexible alkyl chains.122 This anisotropy gen-
units incorporated, the polyolefins showed thermo- erates thermotropic liquid crystalline mesophases, as
plastic elastomeric properties.120 was first discovered in 1977. The structural proper-
The reversibility of supramolecular polymers adds ties make discotic molecules highly suitable for the
new aspects to many of the principles that are known formation of supramolecular polymers in solution.
from condensation polymerizations. A mixture of The strong π-π (or arene-arene) interactions of their
different supramolecular monomers, for example, will cores make discotics prone to aggregate in either
yield copolymers, but it is extremely simple to adjust polar or apolar solvents, forming rodlike or wormlike
the copolymer composition instantaneously by adding polymers. Because of the polarizability and good
an additional monomer. Moreover, the use of mono- intermolecular contact of the planar aromatic system
mers with a functionality of three or more, will give attractive intermolecular stacking interactions occur.
rise to a network formation. However, in contrast to In polar or in very apolar solvents the π-π stacking
condensation networks, the “self-healing” supramo- may be strengthened significantly by solvophobic
lecular network can reassemble to form the thermo- interactions. In this section we will use the general
dynamically most favorable state, thus forming denser term arene-arene interactions, but it should be noted
networks.121 that solvophobic effects are generally stronger than
Although the “virtual” molecular weight and life- π-π stacking.
time of supramolecular polymers and networks based Actually, discotic liquid crystals are the only type
on strong hydrogen-bonding functionalities is ex- of liquid crystals able to form linear architectures,
tremely high, low creep resistance is an intrinsic i.e., supramolecular polymers, in dilute solution by
property of these materials that may limit future means of these stacking interactions. Other types of
applications. Strong interchain interactions, espe- liquid crystals have ordering interactions of the same
cially in crystalline domains, may be employed to order of magnitude in at least two dimensions. This
tackle this problem and may lead to thermoplastic
gives rise to gels at appreciable concentration, i.e.,
elastomers with enhanced processability. With the
uncontrolled growth of the aggregates, whereas at
facile synthetic accessibility of these self-complemen-
lower concentrations the intermolecular interactions
tary Upy-units at hand it is expected that many novel
are generally too weak to generate polymeric archi-
materials properties can be obtained, and multiple
tectures.
hydrogen bonding between repeating units offers an
ideal motive for supramolecular polymers, both in In discotics, the interdisk stacking interaction is
solution and in the solid state. several orders of magnitude stronger than the inter-
columnar interactions, because of the phase separa-
V. Supramolecular Polymers Based on Discotic tion induced by the side-chains whose van der Waals
interactions are much weaker. Generally, long poly-
Molecules mers are obtained via discotics that have strong and
Discotic molecules are ditopic structures with a specific intermolecular interactions, either via a large
disc-shaped core and a periphery of a number of aromatic core or via additional specific intermolecular
4082 Chemical Reviews, 2001, Vol. 101, No. 12 Brunsveld et al.
interactions such as hydrogen bonding. Moreover, the triphenylene 25d resulted in a broadening of the
combination of two or more interactions accounts for UV-Vis spectrum and an increase of the absor-
the formation of highly ordered columns. Only at bance.127
higher concentrations, the intercolumnar interactions Ringsdorf and co-workers have shown that triphen-
become prominent, and superstructure formation or ylenes can form alternating donor-acceptor su-
gelation occurs followed by the liquid crystalline pramolecular polymers in solution by doping them
phase in the bulk. An illustrative picture displaying with equimolar amounts of electron acceptors.128,129
the self-assembly of discotic molecules into supramo- Supramolecular polymers formed in this manner
lecular polymers is given in Figure 14. allow for electron transfer perpendicular to the
In this section we will discuss those discotic mol- molecular planes upon excitation of the chromophores,
ecules that have been shown to form supramolecular i.e., unidirectional charge-transport through the col-
polymers. For information concerning discotic liquid umn.130 The formation of these donor-acceptor pairs
crystals in general, their synthesis, behavior, and is favored in apolar solvents. In more polar solvents
applications the reader is referred to review the the triphenylenes alone do not polymerize and con-
literature.122 The mechanical properties of the su- sequently donor-acceptor polymers with low DP are
pramolecular polymers from discotic liquid crystalline formed.
molecules are not particularly interesting and have
not been studied in detail, therefore, these properties The “loose” way of stacking of the triphenylenes
will not be covered here. It should be noted, however, was shown by the absence of a Cotton effect in
that because of the strong intermolecular interac- circular dichroism (CD) experiments for chiral tri-
tions, the thermotropic mesophases of discotics gen- phenylene 25e in heptane.131 Even though this chiral
erally show much better mechanical properties than molecule does form a supramolecular polymer, the
those of calamitics, illustrating the beneficial proper- side-chain chirality is not expressed in the column:
ties of strong unidirectional interactions. Because the a phenomenon typical for molecules arranged in an
specific interactions between the disks in the rigid- unordered assembly. Mixing of achiral alkoxytriph-
rod supramolecular polymers often gives rise to well- enylene 25d with a bulky chiral electron acceptor
defined architectures, we will discuss the architec- derived from (-)-menthol 3,5-dinitrobenzoate (26) did
tures of these supramolecular polymers in more introduce supramolecular chirality in the columns.127
detail. The sterically demanding “bulky” menthol group
intercalates in the alkyl side-chains of the triph-
This section is divided into three parts. The first
enylene and induces a noncooperative helical twist
part, section A, deals with rodlike polymers formed
by the arene-arene interactions. In the second part into the columns (Figure 15), resulting in an induced
(B) discotics will be discussed for which unidirectional CD effect in the chromophore of the triphenylene.
hydrogen bonding is the driving force for supramo- Triphenylenes provided with nonionic di(ethylene
lecular polymerization. Finally, section C will deal oxide) side-chains (25f)132-134 or with ionic alkyl
with supramolecular polymers formed by a combina- chains (25g)135 form supramolecular polymers in
tion of arene-arene interactions and hydrogen bond- water.136 The arene-arene interactions of the aro-
ing. matic cores allow for the formation of columnar
“micelles”. At low concentrations the columns are
A. Arene−Arene Interactions relatively short, and the solutions are isotropic. At
higher concentrations the longer columns interact
1. Triphenylenes and lyotropic mesophases are formed.133 Computer
simulations showed that in the isotropic solution the
Alkoxy substituted triphenylenes (25a-e) were
polymerization of the discotics is driven by solute-
among the first discotic molecules shown to be liquid
solute attraction and follows the theory of isodesmic
crystalline.123,124 A large variety of different triphen-
linear aggregation; the association constants for
ylenes has been synthesized and their thermotropic
dimerization, trimerization, and etc., are equal and
mesomorphism has been studied in great detail.122
the DP of the column thus can easily be tuned by
The aromatic core of triphenylenes is relatively small;
nevertheless, polymerization of triphenylenes (25a- concentration and temperature.137,138 At higher con-
c) does occur in deuterated hexadecane as shown centrations the sizes of the columns are influenced
with small angle neutron scattering (SANS).125 At low by their neighbors, the columns align, and the DP
concentrations the DP is small, but at higher con- rises rapidly.
centrations (10-3 M) rodlike polymers are observed. Fluorescence studies have shown that the radiative
The intercore distance was determined to be ∼6 Å, a lifetime of 25f increases upon increasing DP, sug-
value significantly larger than the stacking distance gesting that the mobile excitons move through the
of ∼3.5 Å in the liquid crystalline state. This result supramolecular polymers and relax at their ends.139
indicates that the molecules are loosely stacked, most Insertion of electron acceptors between the triphen-
probably due to the absence of specific intermolecular ylenes accounts for the formation of longer polymers
interactions. Furthermore, the triphenylenes are and increases the order within the column. An X-ray
highly mobile and undergo both lateral and rotational diffraction ring with a diffraction spacing of 3.5 Å
translation, similar to that in the liquid crystalline indicates a short intermolecular distance, a feature
state.126 The supramolecular polymerization of tri- not present for undoped samples.140 A chiral electron
phenylenes was also visualized using optical tech- acceptor resulted in the formation of a cholesteric
niques. Increase of the concentration of a solution of mesophase.
Supramolecular Polymers Chemical Reviews, 2001, Vol. 101, No. 12 4083
Figure 15. (a) Apolar (25a-e) and polar (25f-g) triphenylenes and electron acceptor (-)-menthol 3,5-dinitrobenzoate
(26). (b) Helical columns based on the donor-acceptor system as studied by Schuster.
Figure 17. Liquid crystalline disc-shaped helicene 30 and its mode of association into helical columns. (Reprinted with
permission from ref 189. Copyright 2000 John Wiley & Sons, Inc.)
terparts are not helical.163 The helicity of this ag- their rigid cores renders these columns helical (Fig-
gregate could be “turned off” by the addition of ure 17).172 The high DP at high concentrations in
potassium salt, overruling the twist imposed by the dodecane results in an increase of the viscosity and
chiral side-chains, with the ion-dipole coordination an increase of the Cotton effect as observed with CD
of potassium ions to two crown ether rings of two spectroscopy. The helical supramolecular polymer
different phthalocyanines. The unwinding of the gives rise to a stronger expression of chirality,
helical aggregate results in a nonassociating achiral because the intrinsic shape of the helicenes generates
dimer. In contrast, the supramolecular chirality of a tight “intertwined” fit. More detailed measurements
covalent polymer 28b remains present upon the have been performed on columns formed by a non-
addition of potassium ions, illustrating the ease of liquid crystalline helicene.173-175 These supramolecu-
tuning the properties of supramolecular polymers via lar polymers have been proven to be extremely
external stimuli.164 promising systems for second-order nonlinear optics.
Providing phthalocyanines with chiral bulky heli- They form highly organized Langmuir-Blodgett
cenes at the periphery (29) also results in helical films in which the chiral polymeric organization
aggregates.165 Aggregation in chloroform occurs upon makes the second-order NLO susceptibility approxi-
addition of ethanol as was observed with UV-Vis mately 30 times larger for the nonracemic material
spectroscopy, while CD spectroscopy revealed the than for the racemic material with the same chemical
helical nature of the columnar aggregates. Calcula- structure.176
tions have indicated that two phthalocyanines need
to be rotated to allow a favorable intermolecular 4. m-Phenylene Ethynylene Oligomers
distance of 3.4 Å, because of the bulky helicenes. As Whereas helicene 30 studied by Katz172 is helical
such, phthalocyanines provided with racemic heli- under all conditions, the m-phenylene ethynylene
cenes cannot stack in such a defined manner, because oligomers studied by Moore are flexible and can
of the steric hindrance of the racemic side groups. reversibly fold into helices. Depending on the sub-
Aggregation of a smaller analogue of 29, a triphen- stitution pattern, the oligomers fold either into
ylene-based porphyrazine, has been shown to occur lamellae (31a)177 or into column-forming helices
as well.166 (31b)178 in the liquid crystalline state (Figure 18). In
Polymerization of phthalocyanines in water occurs solution the oligomers can be directed to fold from a
for derivatives substituted with oligo(ethylene oxide) random coil into a helix.179,180 Increasing the polarity
side-chains (27c).167,168 In the lyotropic mesophases by addition of water (a nonsolvent for the backbone)
in water supramolecular polymers are present, and results in the polymerization of the helices in helical
a comparative aggregation study between tetraphen- columns.181 The polymerization of the oligomers is a
ylporphyrins and phthalocyanines proved the polym- cooperative process: a chiral oligomer 31c creates a
erization of the phthalocyanines to be stronger.168 The homochiral platform for an achiral oligomer 31a to
strong arene-arene interactions and the flatness of stack and thus amplifies its chirality to the achiral
the aromatic core in the phthalocyanines causes them oligomer. Also, apolar m-phenylene ethynylene oli-
to aggregate more strongly, also mediated by the gomers 31d fold into helices.182 Because of the
additional hydrophobic effect. strongly favored arene-arene interactions in apolar
Porphyrins are close analogues to the phthalocya- solvents, the helical folding coincides with stabilizing
nines, and ionic porphyrins can be considered to fall stacking of the oligomers into helical columnar
into the class of the chromonics (vide infra), however, polymers, giving a strong and time-dependent en-
nonionic porphyrins also have been shown to ag- hancement of the Cotton effect.
gregate.168 Also, porphyrins are mainly forming dimers Cyclic m-phenylene ethynylene oligomers 32 adopt
in solution,169,170 although aggregation into larger a completely flat conformation (Figure 19) and form
aggregates such as fibers has been shown.171 Within highly stable thermotropic mesophases due to strong
the aggregates the molecules are rotating freely, but π-π stacking of the cores.183 These arene-arene
use of additional interactions such as intermolecular interactions also induce polymerization in solution.184
hydrogen bonding hinders the rotation and generates The DP depends heavily on the nature of the sub-
chiral aggregates.171 stituents on the macrocycle.185 Planarity is a strict
requirement for polymerization as the DP is strongly
3. Helicenes suppressed for nonplanar macrocycle 33.186 Butadiyne
Nonracemic helicene 30 has been shown to form bridged macrocycles with benzenes (34) or with
supramolecular polymers, and the helical shape of pyridines (35), the larger analogues of the m-phen-
Supramolecular Polymers Chemical Reviews, 2001, Vol. 101, No. 12 4085
Figure 18. m-Phenylene ethynylene oligomers as studied by Moore (a), that fold from a random coil in good solvents into
helices and columns in poor solvents and into lamellae or hexagonally packed columns in the solid state (b). (Reprinted
with permission from ref 178. Copyright 2000 American Chemical Society.)
Figure 20. Pyridine-pyridazine oligomer 36 studied by Lehn and its proposed mode of aggregation into columns and
superstructures. (Reprinted with permission from ref 190. Copyright 2000 John Wiley & Sons, Inc.)
ylene ethynylene macrocycles, have been shown to also subsequently self-assemble to form fibers at
form columnar polymers as well.187,188 higher concentrations.191 The controlled use of exter-
nal stimuli and programmed intermolecular interac-
5. Other Systems tions illustrates the power to generate and direct
Folding into helices189 and subsequent polymeri- supramolecular polymers.
zation of the helices into columns and larger archi- Ringsdorf showed a nice example of confinement
tectures (Figure 20) is observed for pyridine- of supramolecular polymers.192 In cyclohexane, hexa-
pyridazine oligomers (36).190 Similar to the m-phen- cinnamoyl azacrown 37 self-assembles to form su-
ylene ethynylene oligomers 31, these flexible oligo- pramolecular columnar polymers. The periphery of
mers adopt a helical conformation because of pro- photopolymerizable groups forms cross-links via pho-
grammed intramolecular interactions. At higher tocycloaddition and allows the pre-assembled su-
concentration the polymers self-assemble to give pramolecular polymer to be transferred into a rodlike
helical fibers, which were visualized with electron covalent polymer (Figure 21). Performing the reaction
microscopy. Upon binding of cyanuric acid, oligo- on molecularly dissolved molecules gives rise to a
isophthalamides fold to a helical disk, and these disks randomly cross-linked polymer with a lower DP.
4086 Chemical Reviews, 2001, Vol. 101, No. 12 Brunsveld et al.
Figure 21. Hexa-cinnamoyl azacrown with polymerizable side-chains 37 as studied by Ringsdorf, and the photopolym-
erization into covalent columns in solution.
Figure 22. Examples of drug and dye molecules forming chromonic mesophases in water.
As early as 1986, the aggregation in solution of an induce a strong increase in the viscosity of the
alkyl modified 2,6,2′,6′-tetraphenyl-[4,4′]-bipyran- solution, and the dynamic properties of these ag-
ylidene was shown, and the self-assembly was related gregates leads to rheological behavior typical for
to its thermotropic mesomorphism.193 The addition entanglement networks.199 The observations have
of the more polar solvent methanol to methylene indicated that chromonics are suited as simple model
chloride induces aggregation into J aggregates. As systems for a broader and deeper insight into the
the nonliquid crystalline compound without the side- principles of flow.
chains does not aggregate, it might be concluded that
the self-assembly is, in this case, not dominated by B. Hydrogen Bonding
the aggregation of the aromatic core. Self-assembly
via aggregation of the side-chains occurs, which is Section V-A has dealt with the formation of
fundamentally different from the previously dis- supramolecular polymers by nonspecific arene-arene
cussed polymers, and generally leads to 3-dimension- stacking, which generally results in irregular or
al growth. “loose” stacking. The use of additional steric interac-
tions in these structures allowed for a control over
A variety of smaller discotic molecules have been
supramolecular order or helicity. In this section we
shown to form lyotropic mesophases in either alkane
will discuss columnar supramolecular polymers formed
solvents or water. These discotics range from alkyl-
by the more specific intermolecular hydrogen bonds.
oxydibenzopyrenes194 and hexaesters of hexahydroxy-
benzene and -cyclohexane195 to metallo-discogens.196 The main body of work on columnar hydrogen-
bonded architectures has been performed on 1,3,5-
6. Chromonics benzene triamides (41), which are C3-symmetric
molecules consisting of a single benzene ring and 3
Discotic molecules provided with oligo(ethylene side-chains connected via amide bonds.200,201 The
oxide) side-chains form supramolecular polymers in molecules arrange themselves in columns via 3-fold
water. If the discotics are provided with ionic groups intermolecular hydrogen bonding as proven by X-ray
the compounds are known as chromonics (for ex- diffraction202 and infrared spectroscopy. The weak
amples see 38-40, Figure 22).197,198 Even though arene-arene interactions of the single central ben-
chromonics are crystalline and do not form supramo- zene group are subordinate to the strong 3-fold
lecular polymers in the solid state, we mention them hydrogen bonding. For packing reasons, the inter-
briefly here because of their practical importance and molecular hydrogen bonds rotate out of the plane,
widespread occurrence. A large body of work, dating thus inducing helicity in the columns. Achiral com-
back to the early part of the 20th century, has been pounds 41a-d form an equimolar mixture of left- and
performed on these compounds, and the reader is right-handed helical columns, but the homochiral
referred to review articles for detailed informa- side-chains of chiral discotic compound 41e introduce
tion.197,198 The most common chromonics are drugs an energy difference between left and right-handed
and dyes, which explains the early recognition of columns and bias the helicity.203 Figure 23 shows the
their aggregation. Their self-assembly in water makes formation of the helical columnar polymers by the
them a highly important type of lyotropic liquid polymerization of 41d in a cartoon-like presenta-
crystal, as it influences their performance. The tion.202
molecules first self-assemble, isodesmic, into su- The helical rigid-rod polymers have a high DP even
pramolecular rodlike polymers, followed by the for- in very dilute solution (10-6 M in hexane), due to
mation of lyotropic mesophases. The rodlike polymers their large association constant (5‚108 L/mol). When
Supramolecular Polymers Chemical Reviews, 2001, Vol. 101, No. 12 4087
Figure 23. (a) 1,3,5-Benzene trisamides that form columns in apolar solvents via 3-fold intermolecular hydrogen bonding;
(b) solid state arrangement of the helical columns; (c) graphical representation of the helical hydrogen-bonded columns.
(Reprinted with permission from ref 202. Copyright 1999 Royal Society of Chemistry.)
Figure 24. Small discotics that form columnar polymers via intermolecular hydrogen bonding.
chiral (41e) and achiral (41c) molecules are blended C. Arene−Arene Interactions and Hydrogen
mixed columns are formed, and, surprisingly, only Bonding
one chiral disk (on average) on every 200 achiral
Although hydrogen bonds can be employed for the
disks is enough to bias the helicity of a complete
creation of highly ordered columns (section V-B),
columnar polymer for one helicity. These results are
their use is highly limited to apolar solvents. In
analogous to those obtained in chiral polymers with
contrast, arene-arene interactions allow for supra-
covalent bonds in the main chain204 and are explained
molecular polymer formation in a large variety of
by a strong intracolumnar cooperative effect via
solvents, but without positional control (section V-A).
directional hydrogen bonding in polymers with a very
Thus, the combination of arene-arene interactions
high DP. At higher concentrations, the long columns
and hydrogen-bonding should allow for formation of
gelate the solvent via lateral intercolumnar interac-
highly ordered supramolecular polymers with high
tions,200,201 reminiscent of the behavior of rigid-rod
DP in solvents as desired. In this section we discuss
covalent polymers such as polyaramides and poly(γ-
such supramolecular polymers. Hydrogen bonding
benzyl-L-glutamate).205
has been utilized both for the formation of the discotic
Cis-1,3,5-cyclohexanetricarboxamides (42) are an- entity itself and as a tool to control the order within
other example of discotic molecules assembling in the columns. Furthermore, the occurrence of hydro-
columns via intermolecular hydrogen bonding (Figure gen bonds allows for a controlled hierarchical growth
24).206 Because of the cis arrangement of the amides, of the well-defined columns, and subtle tuning of the
all three can participate in the uni-directional hy- interactions can be achieved by selection of solvent
drogen bonding. Depending on the type of solvent, type.
the compound either gelates the solvent or forms a
transparent viscoelastic fluid. No mention is made 1. Guanine and Pterine Derivatives
of the presence of helicity in the columnar aggregates The most impressive work on self-assembling chiral
or at a microscopic level, in contrast to the trans-1,2- discotics has been performed on guanine- and pter-
diaminocyclohexane derived gelators (43), which form ine-related molecules by Gottarelli, Spada, and co-
chiral supercoiled structures observable with electron workers.210 These molecules organize in lamellae in
microscopy.207 the solid state,211,212 but form disc-shaped tetramers
Aggregation via hydrogen bonding and formation in solution via intermolecular hydrogen bonding. The
of columns and lyotropic liquid crystals and gels has subsequent stacking of the disks into helical columns
also been described for benzenehexamine derivatives has been most elaborately studied. The system is of
44208 that assemble via 6-fold intermolecular hydro- interest because of its strong similarities to DNA and
gen bonding, and for tris(stearoylamino)triphenyl- other biopolymers.213,214
amine 45209 that assembles via 3-fold intermolecular Oligomeric deoxyguanosines 46 all assemble into
hydrogen bonding. columns in water.215 Using SANS, the average length
4088 Chemical Reviews, 2001, Vol. 101, No. 12 Brunsveld et al.
Figure 25. (a) Deoxyguanosine oligomers 46 and folic acid 47 and their mode of self-assembly in tetramers; (b) mode of
aggregation of eight d(GpGpApGpG) molecules. First, self-assembly in “barrels” occurs, followed by stacking of these “barrels”
in columns. (Reprinted with permission from ref 222. Copyright 1995 Royal Society of Chemistry.)
of the columns (DP) of freshly prepared samples was intensity of the Cotton effect was followed as a
determined to be around 6 nm at a concentration of function of temperature, indicating the amount of
1% in D2O.210 Increase of the temperature resulted chirality present in the columns. In water a single
in loss of the cylindrical aggregates. When the sodium melting transition was detected, whereas in the
salt is used, subsequent cooling does not result in the presence of salt two melting transitions were visible,
re-formation of the cylindrical polymers. In contrast, indicating hierarchical assembly.221
use of the potassium salt does allow for reversible Gottarelli, Davis, and co-workers have prepared
self-assembly. The addition of extra potassium salt apolar guanosine derivatives 48a and b for study in
even increases the DP; it binds to the inner carbonyls organic solvents. In dilute solution in the presence
of the G-tetramer and stabilizes the tetramer.216 of potassium ions, disc-shaped structures are
The formation of lyotropic liquid crystalline mes- formed.222 In chloroform compound 48b is molecu-
ophases by a deoxyguanosine derivative in water was larly dissolved, but upon contact of the organic layer
reported in 1988,217 after which this behavior was with an aqueous layer containing potassium salts,
found for other monomers and oligomers of deoxy- 48b extracts the potassium into the organic layer.
guanosine phosphate.218 The microscopic textures An octameric potassium complex is formed, consist-
observed show the presence of cholesteric and hex- ing of two stacked G-quartets between which a
agonal phases at lower and higher concentrations, potassium ion is sandwiched via interactions with the
respectively. The polymeric columns are formed in a carbonyls of the guanosines (Figure 26).223,224 Upon
hierarchical manner: first a well-defined “barrel” is the addition of more salt the octamers polymerize
formed by the assembly of four oligodeoxyguanosine into a columnar architecture. In this polymer potas-
oligomers, and then these “barrels” stack on top of sium ions and G-quartets alternate in the stacking.225
one another to give the columns (Figure 25 b).210,215 The Cotton effect observed for the polymer indicates
This stepwise self-assembly process was elucidated a helical columnar nature. Apart from the formation
using CD experiments, which revealed two melting of octamers, the formation of decamers has also been
transitions. Furthermore, it was shown that forma- observed.226
tion of the liquid crystalline phase depends on the Compound 48b was shown to display enantiose-
amount of electrostatic repulsive interactions from lectivity in the extraction of chiral potassium salts
the phosphate groups and the hydrophilic/hydropho- from water into the organic phase.227 The supramo-
bic balance. lecular polymer possesses a homochiral helical ar-
Not only guanosine, but also pterine derivatives, chitecture onto which one of the anionic enantiomers
give rise to supramolecular polymers in water.219 preferentially binds. Intriguingly, for some of the
Similar to the guanosines, folic acid 47 assembles in anions the octamer and polymer show opposite
disc-shaped tetramers in water. Addition of sodium selectivity, illustrating the difference in supramo-
or potassium salts aids the tetramerization and lecular chirality of the two. Furthermore, the polymer
induces the aggregation into columns.220 At the is capable of inducing a Cotton effect in the achiral
relatively high concentration of 4%, w/w, these col- potassium N-(2,4-dinitrophenyl)glycinate. The use of
umns have an average DP of 9 disks. Melting these polymers as artificial ion channels is currently
experiments performed in water and upon the addi- under investigation, as the apolar side-chains would
tion of salt showed very interesting results. The allow incorporation into a membrane.224,228 Also,
Supramolecular Polymers Chemical Reviews, 2001, Vol. 101, No. 12 4089
Figure 27. (a) Monofunctional ureidotriazines 49 and 51 and the mode of association of 49 via quadruple hydrogen bonding
in a disk and stacking of the disks in columns lacking positional order; (b) bifunctional ureidotriazines 50 and 52 and the
helical columns formed by these molecules in which the disks are positionally ordered.
4090 Chemical Reviews, 2001, Vol. 101, No. 12 Brunsveld et al.
Figure 28. Extended -core discotic 53 built up via intermolecular hydrogen bonding.
Figure 29. (a) C3-symmetrical disc-shaped molecules 54 and 55 with achiral and chiral side-chains; (b) a cartoon
representation of the propeller-like conformation attained by the C3-symmetrical molecular; and (c) formation of helical
columns by the propellers. (Reprinted with permission from ref 237. Copyright 2000 American Chemical Society.)
columnar aggregate of the chiral disks 53a, the enough to obtain helical polymers of one helicity
chirality of the side-chains induces a bias in the exclusively. This experiment shows that there is a
helicity of the supramolecular assembly. “Sergeant high energetic penalty for helix reversal within the
and soldiers” measurements204 were performed and polymer. Lateral interactions between the supramo-
showed that there is no amplification of chirality from lecular polymers arise at higher concentrations and
53a to 53b; the induction of helicity in columns of result in the formation of a lyotropic liquid crystalline
53 is a noncooperative process. gel.234 Because of the chiral propeller-like conforma-
tion of the molecules, the columns have a dipole
4. C3-Symmetrical Discotic Molecules moment along their axes, which allows alignment
Molecules that have the best potential for a high and switching of the columns in the gel by an electric
degree of polymerization and for the creation of a field.
well-defined architecture in all solvent types need to Polar, water-soluble analogues 55 of these C3-
have a large aromatic core, as well as structuring symmetrical molecules have also been studied, and
intermolecular hydrogen-bonding interactions. Disc- they have been shown to form helical columns in a
shaped molecules 54 and 55 feature these require- variety of polar solvents.235,236 A stepwise association
ments. Discotic molecules 54232 form polymeric struc- process is observed when alcohol solutions of 55 are
tures with a rigid-rod character and large DP in very cooled. The molecules first polymerize into achiral
dilute solution (10-6 M in hexane), due to their large columns with a small DP governed by their generic
(108 L/mol) association constant.233 The aggregation arene-arene interactions. Subsequently, these achiral
of the disks is a cooperative process; the molecules columns become helical via a phase transition (Figure
attain a chiral, propeller-like conformation (Figure 30) and a strong growth spurt of the DP occurs,
29) and the conformation of subsequent monomers rendering a DP > 1000.237 During this transition,
is biased toward a propeller with the same handed- specific intermolecular hydrogen-bonding interac-
ness. The optimized stacking interactions result in tions occur that order the molecules in a helical
a helical column. The chirality placed in the side- fashion in addition to the arene-arene stacking. In
chains of 54b accounts for the formation of homo- water, the helicity of the columns is similarly lost at
chiral columns via the transfer of the side-chain higher temperatures, but polymerization is main-
chirality into the supramolecular helical polymer. tained. Because of the increased strength of the
Using “sergeant and soldiers” experiments204 for arene-arene interactions and lower critical solution
mixtures of 54a and 54b, the presence of only one temperature (LCST) of the side-chains in water at
disk with chiral side-chains per 80 achiral disks is higher temperature, long columns remain even at 90
Supramolecular Polymers Chemical Reviews, 2001, Vol. 101, No. 12 4091
Figure 32. Bifunctional metal complexating 57 and its mode of polymerization upon addition of Cu+.
Figure 34. Formation of coordination polymers from porphyrin 59 and two chain stoppers 60.
Figure 35. Polymerization via interactions between bifunctional ammonium compounds and bifunctional crown ether
derivatives.
groups” of DPH fit into the cavity of β-cyclodextrin, gregates on graphite confirmed their nanotube ar-
and the cavity of γ-cyclodextrin can accommodate chitecture.
three phenyl groups. Binding of the phenyl groups The specific inclusion of adamantyl groups in
of one DPH molecule in two different cyclodextrin β-cyclodextrin in aqueous environments has been
cavities (Figure 36), results in polymeric aggregates used as binding interaction between adamantyl end-
with an estimated length of 20 β-cyclodextrins, or capped poly(ethylene oxide)263,264 or polyester and a
20-35 γ-cyclodextrins, based on light scattering cyclodextrin polymer. Even though the formation of
results. Scanning tunneling microscopy of the ag- linear chain extended structures was not specifically
4094 Chemical Reviews, 2001, Vol. 101, No. 12 Brunsveld et al.
Figure 37. Supramolecular polymer materials created with the ureidopyrimidone unit. (Reprinted with permission from
ref 118. Copyright 2000 John Wiley & Sons, Inc.)
studied - polyfunctionality of the cyclodextrin poly- such as low strength of the supramolecular gels and
mer gives rise to network architectures - the highly their phase transitions, gives them a low added-value
defined 1:1 stoichiometry of the interaction and its with respect to covalent polymers as construction
reversibility make this an interesting system. Inter- materials. However, their strong π-π interactions
action between the two polymers has been demon- within a column lead to high electronic mobilities, a
strated through dynamic light scattering and viscos- property that is essential in the development of
ity measurements. The limiting value of the relaxation plastic transitors and photovoltaics.265,266 Coordina-
time in light scattering measurements (230 ms) was tion polymers and a number of other approaches
suggested to be related to the lifetime of the inclusion show the versatility of the supramolecular polymer
of adamantyl groups in the cyclodextrin cavity. approach.
Finally, an important conclusion that arises after
VII. Conclusions and Outlook discussing the literature on supramolecular polymers
relates to the fact that these polymers are also
Roughly fifteen years after the first experiments interesting systems to be used by polymer theorists
toward supramolecular polymers (monomeric units to verify a number of polymer theories. The thermo-
held together by specific directional secondary inter- dynamic nature of the supramolecular polymers
actions), it can be concluded that a new research area enables the study of these systems without the
is added to the field of polymer science. The progress kinetic constraints that are normally involved in the
in supramolecular chemistry has paved the way to study of macromolecules. The future, however, will
assembling small molecules into polymer arrays: show the scope and limitations of this new field of
structures that possess many of the well-known supramolecular polymers. We foresee a bright future,
properties of “traditional” macromolecules. Because and it is now clear that the status of supramolecular
of the reversibility in the bonding, these supramo- polymers has grown from scientific curiosities into
lecular polymers are under thermodynamic equilib- systems with technological relevance.
rium, and their properties can be adjusted by exter-
nal stimuli. In this review we have analyzed three
different classes of supramolecular polymers, in VIII. Acknowledgments
which hydrogen-bonded systems have been shown to We acknowledge the many contributions of and
be technologically relevant, having surpassed the discussions with our colleagues Jef Vekemans, Anja
state of being merely scientific curiosities. A large Palmans, Felix Beijer, Ronald Lange, and Ky Hirsch-
variety of applications is foreseen to be feasible, berg. The research presented has been supported by
especially as this approach can also be used for the the Eindhoven University of Technology, DSM Re-
modification of telechelic oligomers or to modify search, and The Netherlands Organization for Chemi-
existing polymers. But also, the possibility to tune cal Research (CW), with financial aid from The
the properties by simple copolymer formation due to Netherlands Organization for Scientific Research
just mixing monomers seems very attractive, whereas (NWO), the National Research School Combination
hybrids between blocks of macromolecules and su- Catalysis (NSRC-C), and the Dutch Polymer Insti-
pramolecular polymers are easy to prepare. There- tute.
fore, novel thermoplastic elastomers, superglues,
hotmelts, and tunable polymeric materials are within IX. References
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Chem. Rev. 2001, 101, 4039−4070 4039
Jeroen J. L. M. Cornelissen started to study chemistry in 1992 at the Roeland J. M. Nolte received his Ph.D. in physical organic chemistry from
University of Nijmegen, from which he graduated in 1996 after working the University of Utrecht (1973), where he stayed and became Assistant
on conducting polymers (in the group of E. W. Meijer, Eindhoven University Professor and then Associate Professor. In 1981, he was a visiting scientist
of Technology) and substrate-selective catalysis (in the group of Roeland at UCLA in the group of Donald J. Cram. In 1987, he moved to the
J. M. Nolte). In the latter group, he subsequently performed his Ph.D. University of Nijmegen and became Professor of Organic Chemistry, and
research on chiral architectures from polymers and block copolymers of since 1994 he has also been Professor of Supramolecular Chemistry at
isocyanopeptides. Since June 2001 he has been working as a postdoctoral the Eindhoven University of Technology. His principal research interest
fellow at the IBM Almaden Research Center in San Jose, CA. is supramolecular chemistry, focusing on the design of catalysts and
polymeric materials.
Figure 1. Top: Structures and CPK models of regioisomeric phospholipid analogues. Bottom: (a, b) TEM micrographs of
aggregates of 2. (a) Right-handed helices. (b) Superhelices formed by further assembly of the helices shown in (a). Inset:
freeze-fractured replica of the superhelix. (c) Schematic representation of the superhelical winding.
as to how building blocks at the monomeric level will in the backbones of the resulting cylindrical polymer
be built into the polymer chains. Together with other architectures above a critical degree of polymeriza-
molecular information embedded in the monomers, tion (>20 for styrene, >15 for methacrylate).22,23
it will dictate how polymer chains will fold and, The double helix of DNA exemplifies Nature’s
ultimately, interact with neighboring chains to form ability to construct complex chiral structures in an
well-defined polymeric architectures. aqueous medium by making use of both hydrogen-
The aggregation of small chiral molecules can be bonding and hydrophobic interactions. Inspired by
used not only as a guideline for the construction of this phenomenon, Sijbesma and Meijer used dimeric
chiral polymer structures; the following examples building blocks equipped with 4-fold hydrogen-bond-
show that it may also be directly applied to generate ing units to obtain true polymeric structures in
polymer architectures, e.g., by serving as a template solution based on supramolecular interactions. By the
for the organization of macromolecules into larger interplay between the stacking of the aromatic
structures, to organize amphiphilic monomers, or hydrogen-bonding units and the incorporated enan-
even to form polymeric strands based on strong tiomerially pure solubilizing side chains, they were
supramolecular interactions. able to generate helical self-assembled polymeric
Lipid molecules with specific ligands or binding architectures in organic solvents as well as in aque-
sites for selected protein templates have been dem- ous media (Figure 3b,c).24
onstrated to direct the organization of these proteins 2. Foldamers: Oligomers with a Preferred
into tubular structures with an outer shell consisting Helical Conformation. With the design of polymers
of a crystalline layer of biomacromolecules packed in with well-defined secondary and tertiary structures
a perfect helical arrangement.18 Helical polymer as the ultimate goal, researchers have taken up the
architectures can also be obtained from chiral lipids task of identifying and synthesizing new structural
and surfactants carrying polymerizable groups which elements that contain the information required for
can be fixed by photopolymerization as has been the programmed folding of molecular chains. This has
reviewed by O’Brian et al.19 Already in 1985, Yager, led to the development of a class of compounds
Schoen, and co-workers reported on polymerized lipid generally referred to as “foldamers” and defined by
tubes comprising helically folded bilayer sheets.20 Gellman as polymers “with a strong tendency to
More recently Percec et al. demonstrated the control adopt a specific compact conformation”.25 Essential
over the backbone conformation of different polymers in the design of foldamers is the identification of new
through the programmed self-assembly of monomers backbones with well-defined structural preferences,
(Figure 3a).21 The polymerization of styrenes and and foldamers are thus further defined as oligomers
methacrylates equipped with tapered gallic acid- of modest length that in solution display such a
derived monodendrons induces a helical conformation specific conformational preference. As the two most
4042 Chemical Reviews, 2001, Vol. 101, No. 12 Cornelissen et al.
Figure 2. Hierarchical organization in the aggregation of an amphiphilic imidazole-containing gluconamide in the presence
of copper(II) ions.
common structural elements found in Nature are (amino acid)s probably are the most simple example
helices and β-sheets, the realization of their synthetic of how structural information in the polymer back-
equivalents has been adopted as a research target bone can dictate the folding of the molecules in a
by a large number of scientists.26 In this review, we predefined manner. Some of these polymers, e.g.,
will limit ourselves to examples in which the research poly(benzyl glutamate), have now been sythesized in
has concentrated on systems with homogeneity in the a true polymer approach by the ring-opening reaction
backbone since a polymer approach may be applied of N-carboxyanhydride monomers (see also section
to these materials and we will not go into the fields III.A).27 The preference of these poly(R-amino acid)s
of polypeptide synthesis and peptidomimetics. Poly- 4 (Chart 1) for the R-helix and the 3/10-helical
Chiral Architectures from Macromolecular Building Blocks Chemical Reviews, 2001, Vol. 101, No. 12 4043
Chart 1
Chart 2
Chiral Architectures from Macromolecular Building Blocks Chemical Reviews, 2001, Vol. 101, No. 12 4045
Figure 4. (a) Synthesis of oligo(m-phenyleneethynylene)s containing a chiral binaphthyl group. (b) Structure of oligo-
(m-phenyleneethynylene)s with optically active ethylene oxide side chains. (c) Same as (b) but with cyano groups that
allow the binding of metal ions.
molecules exhibit a large degree of conformational themselves into a long tubular structure with an in-
flexibility due to the fact that rotation is possible ternal diameter of 8 Å. These fibers display a helical
around the ethynylene linkers, which allows switch- twist and stretch out over several micrometers.53
ing between the transoid and cisoid states, the latter
of which leads to a helical conformation. The aromatic III. Chiral Macromolecules: Secondary Structure
backbone bears pendant oligo(ethylene oxide) chains
to ensure solubility in a large variety of solvents, and A chiral organization within a macromolecule in
oligomers consisting of up to 18 repeat units were most cases is present as a helical conformation of the
prepared. To obtain a helical bias, initially binaphthyl polymeric backbone. In the 1950s, it was first recog-
groups were incorporated into the backbone of the nized that the polymerization of substituted olefins
oligomers;47 later chiral side chains were used.48 By could lead to the formation of macromolecules with
equipping every second phenylene group with a cyano a helical conformation.54 Experimental evidence for
group on the free meta position, silver ions could be the existence of such a structure in solution was first
bound into the interior of these foldamers, which reported in 1960 by Pino and Lorenzi55 and later also
aided the stability of the helices49 (Figure 4). by others.56,57 The properties of these helical macro-
Metal ion complexation has been used to direct the molecules are highly dependent on the helix inversion
helical folding of many oligomeric compounds. The barrier. The screw sense of one particular strand is
resulting complexes are known as helicates and have stable at room temperature when this helical inver-
been reviewed by Williams,50 and by Piguet et al.51 sion barrier is high (g∼85 kJ‚mol-1), whereas the two
The group of Lehn has demonstrated how by screw senses may be in equilibrium when the inver-
careful design oligomeric strands 14 (Chart 2) of sion barrier is lower.58 In the case of nonchiral side
alternating pyridine and pyrimidine can fold into chains, the left- and right-handed helices are enan-
helical structures using the geometry of the mol- tiomers, having equal free energies. When the poly-
ecules, without the further need of specific directing mer contains chiral side chains, the helices are
forces or agents.52 In their design, they used the fact diastereomers and consequently have different free
that when these aromatic building blocks are linked energies (Figure 5). Polymers with low helix inversion
at the appropriate positions the preference for a barriers have dynamic properties which can be used
transoid conformation automatically leads to a helical to build chiral architectures that respond to interac-
structure. When pyridazines 15 (Chart 2) are used tions with small molecules, light, or subtle changes
instead of pyrimidine groups, the helices organize in monomer composition or temperature as will be
4046 Chemical Reviews, 2001, Vol. 101, No. 12 Cornelissen et al.
Chart 3
Chart 4
Chart 5
activity, a helical conformation was proposed.88 The Scheme 1. (Left) Synthesis of Polyaniline by
optical rotation and ellipticity of the related polymer Electropolymerization in the Presence of an
21 (Chart 5) prepared using the [Rh(nbd)Cl]2 cata- Optically Active Acid and (Right) Structure of
lyst were much higher than those prepared by a Oxazoline-Containing Polythiophene 29
MoOCl4-Bu4Sn catalyst, which produces a much
more irregular macromolecular chain.89 In a more
extended investigation, a similar comparison was
made for a variety of poly(propiolic ester)s with other
chiral substituents.90 It was concluded that the
appearance of intense CD effects, originating from a
helical backbone conformation, corresponded with a
large band gap energy (ca. 3.2 eV). Furthermore, the
introduction of bulky substituents into the polymers
was found to enhance the persistence length of the
single-handed helix, leading to an increase in the Many papers have appeared on the synthesis and
magnitude of the Cotton effects and optical rotations. characterization of other chiral-conjugated polymers
Conformational studies in solution were undertaken for possible applications in, among others, membrane
to elucidate the helical structure of poly(propiolic resolution of racemates,105 enantioselective HPLC,106
ester)s.91 The chiroptical properties of copolymers of and asymmetric catalysis.107 Remarkably, only for a
21 and 22 (Chart 5) were found to be strongly related relatively small number of these chiral π-conjugated
to the enantiomeric excess of the monomer of 21, polymers, which have been reviewed by Pu,108 the
which suggested that these polymers had a long strong optical activity in the π-π* transition is
helical persistence length. In contrast, the copolymer ascribed to the presence of a secondary structure, i.e.,
of 23 and 24 had random-coil character when the (R)- to a helical conformation of the polymer backbone in
24 (Chart 5) content was 60%. solution. Most of them only display helicity in an
aggregated form. In fact, apart from the polyacety-
A number of optically inactive polyacetylenes were lenes, the aforementioned foldamers, and “binaph-
prepared by Yashima and others to study the induc- thyl-based polymers” (see section B), only a few
tion of helicity upon their complexation of an optically examples of conjugated polymers with a helical main
active compound in organic solvents, in thin films, chain exist. Main chain helicity has been reported
and in water.92 In the case of aliphatic polyacetylene for one substituted poly(phenylenevinylene),109 for an
derivatives, a helical conformation was only induced oligo(β-pyrole),110 for a cyclophane analogue of poly-
in 25 (Chart 5) when this polymer was complexed (p-phenylene), and for polyanilines.111,112
with mandelic acid.93 Poly(arylacetylene)s substituted A special feature of the polyanilines (28) is the fact
with optically active pendant groups adopt a helical that they are prepared by electrochemical polymer-
backbone conformation.94-96 Using optically inactive ization in the presence of a chiral dopant (Scheme
poly[(4-carboxyphenyl)acetylene] (26) (Chart 5), a CD 1). Polymers prepared in the presence of enantio-
spectrum could be induced upon complexation of meric counterions give rise to CD spectra with
chiral amines97 and amino alcohols in DMSO solu- completely different signs. These signals are lost
tions and in films.98 Interestingly, the sign and shape completely upon deprotonation of the polymer. This
of the induced CD effect was found to depend on the suggests that the helicity is maintained by hydrogen-
stereochemistry, bulkiness, degree of substitution bonding and/or electrostatic interactions with the
(primary, secondary, or tertiary), and absolute con- counterions.
figuration of the amines. Nonlinear correlations were Another very interesting class of chiral conjugated
found between the enantiomeric purity of the com- polymers, which has been explored by Swager and
plexing agents and the observed ellipticity, and co-workers,113 comprises macromolecules in which the
between the concentration of the chiral amines and monomeric units are equipped with receptor groups.
the amount of helicity induced in the macromol- Binding of analyte molecules leads to changes in the
ecules. Poly[(4-dihydroxyborophenyl)acetylene]99 and folding of the polymers and consequently to changes
poly(arylacetylene)s bearing an amine group100 have in their electrooptical properties, allowing them to
been used in the chirality assignment of carbohy- act as effective sensors for a variety of different
drates and steroids, and carboxylic acids, respec- analytes. Surprisingly, only one example has been
tively. Polymer 27 (Chart 5) in DMSO solution exists reported in which the binding of the guest leads to a
as a right-handed helix, but it reverses handedness change in the helical conformation of the reporter
upon the addition of mandelic acid.101 For 26, the polymer. The regioregular polythiophene 29 (see also
induced helicity can be “memorized” when the opti- section IV) bearing chiral oxazoline-derived side
cally active amine is replaced by various achiral groups only gives rise to a CD effect in poor solvents
amines. Although this helicity is self-repairing, small such as alcohols. However, exposure to copper(II) ions
structural changes in the achiral component strongly in a good solvent such as chloroform gives rise to a
influence the efficiency of helix retention.102 Further- strong Cotton effect in the CD spectrum of the
more, helical polyacetylenes with pendant lactose polymer which was attributed to the induction of a
side groups have been applied for the molecular helical conformation in the polythiophene back-
recognition of lectin,103 and derivatives bearing (R)- bone.114
(1-phenylethyl)carbamoyl groups have been used as 3. Polysilanes. Polysilanes are linear polymers of
a chiral stationary phase for HPLC.104 silicon in which the σ-electrons in the polymer
4050 Chemical Reviews, 2001, Vol. 101, No. 12 Cornelissen et al.
Scheme 2. Wurtz Coupling of Enantiopure Dichlorosilanes and the Structure of the Resulting Chiral
Polymers
backbone are delocalized. This σ-conjugation gives uents, a preference for a dihedral angle of 150° was
rise to electronic properties that allow for possible found which corresponds to a 7/3-helix, a structure
applications as electroluminescent, nonlinear optical, which is remarkably similar to the one proposed for
lithographic, and semiconductor materials.115 Since the solid-state structure of poly(di-n-butylsilane) and
polysilanes are electroactive main chain polymers, poly(di-n-pentylsilane).118-120 By the introduction of
the properties of these macromolecules are strongly enantiopure substituents in the dialkyldichlorosilane
related to the substituents on silicon. Not only the monomers, polysilanes can be prepared displaying a
direct electronic effects of substitution but also its preferred handedness of the helical backbone (Scheme
indirect effect on the conformation of the polymer 2).121,123-127 This backbone chirality can also be
backbone, along which conjugation occurs, affects the induced by using terminal chiral substituents as was
optoelectronic properties of these polymers.116 demonstrated for oligosilanes with isopropyl side
The parent polysilane chain is extremely flexible, groups.122 In a detailed study by Fujiki, it was
and for tetrasilane, the energy barriers between the demonstrated that the optoelectronic properties of
gauche-gauche and gauche-anti rotation were cal- such helical polymers are directly related to their
culated to be only 6.3 ( 0.8 and 2.9 + 0.4 kJ·mol-1, conformational properties, since the folding of the all-
respectively.117 For permethylated silanes, still no silicon backbone affects the effective conjugation
distinct conformational preferences could be deter- length.123 Fujiki synthesized a large number of chiral
mined; however, for the more bulky n-hexyl substit- polysilanes using the Würtz synthesis (Scheme 2) and
Chiral Architectures from Macromolecular Building Blocks Chemical Reviews, 2001, Vol. 101, No. 12 4051
Figure 12. (a) Structure of poly[((S)-3,7-dimethyloctyl)(3-methylbutyl)silane]. (b) Energy diagram showing the double-
well shape. (c) CD and UV spectra of both screw senses. (d) Schematic representation of the two helical forms. (Reprinted
with permission from ref 129. Copyright 2000 American Chemical Society.)
4052 Chemical Reviews, 2001, Vol. 101, No. 12 Cornelissen et al.
Figure 13. (a) CD and UV/vis spectra of optically active doped poly(methylphenylsilane). (b) Calculated energy diagram
of this polymer. (Reprinted with permission from ref 131b. Copyright 2000 American Chemical Society.)
Scheme 4. Synthesis of Polyguanidines via the suggest that a helical conformation can also be
Polymerization of Carbodiimines induced in this polyphosphazene.
Isotactic vinyl polymers often possess a helical
conformation in the solid state; however, without
bulky substituents present (vide infra) in solution at
room temperature, helix-helix reversal takes place
fast and no optical activity is observed. Ortiz and
Kahn reported a borderline case in which a non-
bonded interaction between the monomers leads to
the formation of isotactic 39 (Chart 7) by anionic
polymerzation at -78 °C. Optically active polymers
can be isolated, but in solution the proposed one-
handed helicity is lost in less than 1 h.148 An intrigu-
TFA.141 Remarkably, the hydrogen bonds in 33 and ing class of polymers formed by polycondensation of
34 are weaker in thin films than in solution, although diboronic acid and chiral tetraalcohols has been
XRD measurements pointed to a hexagonal arrange- studied by Mikami and Shinkai and is exemplified
ment of the macromolecules, suggesting that also in by polymer 40 (Chart 7). In this D-mannitol-based
this case they possess a rodlike structure.142 polymer, the noncovalent intramolecular interaction
between the amines and the boron atoms imposed a
An interesting class of rigid helical polymers is sp3-hybridization on boron, which, according to cal-
obtained by the polymerization of carbodiimides culations, results in a helical conformation of the
(Scheme 4). These polymers, referred to as poly- macromolecule.149
guanidines, can be prepared by using titanium(IV)
complexes143 and both copper(I) and copper(II) amid- B. Helical Polymers Having High Helix Inversion
inate complexes144 as catalysts. The chiroptical prop-
erties of polyguanidines have been investigated using
Barriers
35 and 36 as examples, the former, in contrast to the 1. Sterically Restricted Poly(methacrylate
latter, being optically active. Surprisingly, the optical ester)s. It was recognized by Okamoto and co-
rotation of 35 directly after polymerization was workers150 that the anionic polymerization of tri-
comparable to that of the monomer, but changed sign phenylmethyl methacrylate (TrMA, 41) (Chart 8) at
and increased significantly upon annealing at el- low temperature in the presence of an optically active
evated temperatures. It was found that a kinetically initiator results in the formation of an isotactic,
controlled structure is formed during polymerization, optically active polymer. The helical conformation of
which changes to the thermodynamically controlled the backbone in these macromolecules is the result
helical one upon annealing (for this process Ea ) 26.8 of steric interactions between the bulky trityl groups,
( 1.3 kJ‚mol-1). This process was catalyzed by acid, as was shown by the loss of optical activity upon their
and addition of optically active camphorsulfonic acid conversion to methyl ester groups. This class of bulky
to 37 (Chart 7) resulted in an excess of one helical
sense from an initially racemic mixture of macro- Chart 8
molecular helices.145
Studies performed by Carriedo et al. indicated that
the spirocyclic phosphazene polymer 37 can adopt a
helical conformation in solution.146 Yashima et al.
subsequently investigated the chiroptical response of
38 (Chart 7) upon complexation with (R)-R-phenyl-
ethylamine in DMSO.147 The resulting optical rota-
tion and its response to changes in temperature
Chart 7
4054 Chemical Reviews, 2001, Vol. 101, No. 12 Cornelissen et al.
Table 1. Asymmetric Polymerization of TrMA with (-)-Sp, (+)-DDB, and (+)-PMP-FiLi Complexes in Toluene at
-78 °Ca
B/Hb-insoluble part
time yield c
yield [R]25Dd [θ] × 10
e -4
[θ]e × 10-5 tacticityg
initiator (h) (%) (%) (deg) (235 nm) (210 nm) DPf Mw/Mnf (%), mm
(i)-Sp-FiLi 24 99 82 +383 +9.42 +2.32 60 1.31 >99h
(+)-DDB-FiLi 24 100 93 +344 +8.45 +1.86 47 1.10 >99h
(+)-PMP-FiLi 3 100 94 +334 +7.78 +1.76 39 1.12 >99h
a
Reprinted with permission from ref 153. Copyright 1992 American Chemical Society. Conditions: TrMA, 1.0 g; toluene, 20
mL; [TrMA]/[Li] ) 20. b A mixture of benzene and hexane (1:2, v/v). c CH3OH ) insoluble part. d c ) 0.5 (tetrahydrofuran). e The
CD spectrum was measured in tetrahydrofuran at ca. 25 °C. Units: cm2 dmol-1. f Determined by GPC of poly(MMA) derived from
poly(TrMA). g Determined by 1H NMR of poly(MMA) derived from poly(TrMA). h The signals due to the racemo sequence were
found only in the termination end.
Chart 9
experiments, the activation energy (Ea) and the rate tion of the catalytic center, and also allows interaction
of transition from one helical conformation to the of substituents on the conjugated segments with the
other one were determined to be 68.6 kJ‚mol-1 and metal. These modifications allow tuning of the cata-
3.9 s-1 at 20 °C, respectively.161 lytic properties and have led to the finding of good
4. Binaphthyl-Based Polymers. Molecules that chemical yields and excellent enantioselectivities in,
derive their chirality from their molecular geometry, e.g., the asymmetric reduction of aldehydes and the
e.g., helicenes, can be used to construct architectures epoxidation of R,β-unsaturated ketones. By synthe-
in which the chirality of the individual molecules is sizing copolymers containing alternating BINOL and
amplified and perpetuates over long distances (see BINAP groups, a mixed Ru(III)-Zn(II) catalyst was
also section II).162 Katz et al. have prepared oligomers prepared (51). This catalyst was able to perform an
with more than one helical turn based on bissalicyl- asymmetric tandem reaction involving a diethylzinc
aldimine.163 The helical conformation of these mol- addition to acetylbenzaldehyde and the subsequent
ecules has a marked effect on their optical properties; catalytic hydrogenation of the product to form the
i.e., very intense absorption bands and CD effects corresponding diol in chemical yields larger than 99%
were observed compared to those of the low-molec- and with diastereoselectivities of 75-87%.
ular-weight parent compounds. Extending this con- On the basis of the same principles, Pu et al. have
cept further, higher-molecular-weight materials have synthesized a chiral dendritic compond (52) (Chart
been obtained via the linking of conjugated segments 10) which shows fluorescence quenching upon bind-
with optically active 1,1′-binaphthyl groups as was ing of amino alcohols. An enantioselective response
reported and recently reviewed by Pu.108 Pu et al. was observed on addition of a number of amino
have used binaphthyl linkers to connect a large alcohols; the most significant effect was obtained with
variety of conjugated molecules such as arylene- phenylalaninol.165
ethynylenes, phenylenevinylenes, polythiophenes, 5. Polyisocyanides. Polymers of isocyanides have
oligophenylenes, and oligoethynylenes (e.g., 49) (Chart the exceptional feature that every carbon atom in the
9). In the cases where the linkers contain phenyl main chain is provided with a substituent (Scheme
groups, meta as well as para substitution has been 6). It was already proposed by Millich166 that these
used. In the former case, this leads to the introduc- macromolecules would have a helical conformation
tion of an extra turn in the polymer backbone, as the result of a restricted rotation around the single
whereas, in the latter case, the turns are exclusively bonds constituting the polymeric backbone. Until
due to the binaphthyl groups. The resulting materials Nolte’s report on the applicability of Ni(II) as a
have a rigid helical comformation and can be applied catalyst for the polymerization of isocyanides, routes
to anchor catalytic complexes based on Al(III) and toward polyisocyanides were limited.167 This transi-
Zn(II) via the hydroxy groups on their naphthyl tion-metal catalyst allowed the polymerization of the
units.164 The twist in the backbone of the polymer sterically demanding poly(tert-butyl isocyanide) (53),
molecules can be tuned by connecting the conjugated which subsequently could be resolved by chromatog-
segments either via the 3,3′-positions or via the 6,6′- raphy into the left- and the right-handed helical
positions (50) (Chart 9). Connection at the 3,3′- forms using poly[(S)-sec-butyl isocyanide] as the
positions provides better control over the conforma- stationary phase.168 These experiments confirmed the
4056 Chemical Reviews, 2001, Vol. 101, No. 12 Cornelissen et al.
Table 2. Molecular Weight Characteristics of Selected According to this theoretical analysis, polymer 54,
Polymersa which only is moderately sterically restricted, may
yield adopt two helical structures with different dihedral
monomer catalyst conditions (%) Mn Mw/Mn angles.
tert-C4H9NC 58 N2, neat 100 2200 1.03 Huige and Hezemans179,180 have performed exten-
C6H5CH(CH3)NC NiCl2 N2, H2O 75 13220 1.45 sive molecular mechanics calculations using the
C6H5CH(CH3)NC NiCl2 air, H2O 100 7420 1.64 consistent force-field method on various oligo- and
C6H5CH(CH3)NC 58 N2, toluene 100 24000 1.15
polyisocyanides. The hexadecamer of tert-butyl iso-
a Reprinted with permission from ref 171. Copyright 1992
cyanide was calculated to have a helical middle
American Chemical Society. section and disordered ends. The dihedral angle
NdCsCdN in the middle section was found to be
reaction will appear faster than a first-order reaction, 78.6°, and the number of repeat units per helical turn
due to the lack of rate dependence on monomer was 3.75. The latter number is in agreement with
concentration. The differences in transition state circular dichroism calculations using Tinoco’s exciton
were examined by determination of thermodynamic theory (3.6-4.6) and De Voe’s polarizability theory
activation parameters by performing an Eyring analy- (3.81). The molecular mechanics calculations further
sis of the rate constants.173 More kinetic data have predicted that the less bulky polymers 56 and 57
been reported by Deming and Novak investigating form helical polymers as well, whereas a disordered
substituent effects on the monomer174 and by Hong structure was calculated for poly(methyl isocyanide)
and Fox using functional isocyanides.175 An in-depth (55).
discussion of the mechanistic parameters based on Clericuzio et al. recently published ab initio and
these results is beyond the scope of this review, and molecular mechanics studies on octameric oligoiso-
for this we refer to the work cited.176 cyanides. These calculations, in contrast to the
The conformation of polyisocyanides has been the aforementioned ones, showed the so-called syndio
subject of several computational studies. Using the conformation to be the minimum-energy geometry
extended Hückel theory, Kollmar and Hoffmann although the 4/1 conformation was recognized as a
showed that repulsion between the lone pairs of the local minimum (Figure 14).181 The obtained set of
imino groups in a polyisocyanide chain favors a data was used to tentatively explain some of the
departure from a planar structure.177 Similar repul- features in the UV/vis, CD, and 13C NMR spectra of
sive effects are known to be operative in polyketones compounds prepared by Salvadori’s182 and Green’s
as was reported by Cui and Kertesz, who found a new groups.183 Regarding properties such as optical ab-
type of helical Peierls-like distortion for polyketone sorptions at long wavelengths, low intensity of the
and polyisocyanide. They suggested that as a result CD bands, and the chemical shift dispersion of
of the existence of partially filled crossing bands a backbone carbon atom resonances, the calculations
helical structure is formed.178 Calculations by Koll- were found to fit the experimental results. Neverthe-
mar and Hoffman on the series of polymers 53-55 less, the outcome of the calculations is the thermo-
indicated that steric effects are more important than dynamic minimum conformation of the polymer
electronic effects in determining the polymer struc- backbone, whereas the polymerization is kinetically
ture. For the hypothetical polymer 55, a broad range controlled, possibly leading to a different conforma-
of helical conformations was predicted, in contrast tion. However, if the helix inversion barrier is not
to 53 for which the authors proposed a rigid 4/1-helix. too high, the 4/1-helix imposed during the polymer-
4058 Chemical Reviews, 2001, Vol. 101, No. 12 Cornelissen et al.
Chart 11
Second, the rate constants for propagation were structure of the monomer of 71a served as a reference
virtually identical no matter whether the monomer point (Table 3).
that was incorporated had the same or the opposite The hydrogen bonds are formed between the amide
chirality as the one constituting the initiating oligo- carbonyl groups in side chains n and the amide NH
mer. This suggests thermodynamic rather than ki- groups in side chains n + 4 (Figure 15). In the case
netic control over the helical sense, which contradicts of the tripeptide-derived polyisocyanide 72, a similar
the high helix inversion barrier previously proposed β-sheet-like hydrogen-bonding arrangement was
for helical polyisocyanides. However, the observation found. This chiral architecture, based on secondary
of a nonlinear relation between the optical purity of interactions, represents a mimic of the naturally
the isocyanide and the induced helical sense in the occurring β-helices, which are recently discovered
polymer201 (majority rules concept) confirms this sug- structural motifs in proteins.208 The additional in-
gestion. These observations indicate that factors teractions between the side chains stabilize the
other than steric interactions may be operative dur- helical conformation of these polymers, leading to an
ing the synthesis of these particular polyisocyanides. enhanced rigidity. This rigidity was reflected, for
Nonsteric helix-stabilizing effects have recently
been reported for peptide-derived polyisocyanides.
Polymers built from di- and tripeptide-based iso-
cyanides containing different functional groups have
been synthesized as protease mimics (Chart 12; 68-
70).202-204 More recently compounds 71 and 72 (Chart
12) were synthesized to investigate the effect of this
hydrogen bonding between side chains on the con-
formational properties of the polymer backbone.205-207
IR and 1H NMR studies in which the amide NH
characteristic bands and signals of the monomer were
compared with those of the polymer showed the
involvement of the side-chain amide groups in well-
defined arrays of hydrogen bonds along the polymeric Figure 15. Schematic representation of the hydrogen-
backbone. In these studies the single-crystal X-ray bonding array in peptide-derived polyisocyanide 71b.
4060 Chemical Reviews, 2001, Vol. 101, No. 12 Cornelissen et al.
Chart 13
example, in the well-defined hexagonal organization glycoproteins. Hong and Fox175 synthesized block
of the molecules in the solid state as well as in the copolymer 74 (Chart 13) with a rigid backbone to
formation of a lyotropic liquid crystalline phase in spatially organize chromophores and quencher groups
concentrated CHCl3 solution. Similar to the unfolding to study directional electron transfer and energy
of proteins, the disruption of the hydrogen bonds in migration.211 Excimer formation, which is a complica-
the polymers proceeds in a cooperative fashion as tion observed in flexible polymeric systems, is de-
could be monitored by CD spectroscopy.202 Although pressed, and long-living charge-separated states are
not recognized at that time, some of the intriguing observed. Both features are in line with the rigid
physical properties of polyisocyanides 68-70 synthe- character of the polymer, despite the absence of
sized in the early 1980s, e.g., pKa values which limiting steric interactions close to the backbone
strongly deviate from those of amino acids and very imine groups. Extensive nonlinear optical studies
intense Cotton effects, can now be explained by the have been performed by Persoons and co-work-
presence of an intramolecular chain of hydrogen ers212,213 on 75 (Chart 13) and related compounds.214-216
bonds between the peptide side groups. Second-harmonic light was generated by Langmuir-
Hasegawa et al. reported on glycosylated poly- Blodgett films of these polyisocyanides but not by
(phenyl isocyanide)s primarily to study the recogni- spin-coated or -cast films. This NLO activity probably
tion of lectins by these polymers,209 as well as the results from a side-chain orientation realized at the
adsorption and self-organizing properties of these air-water interface. In solution the orientational
polymers (in particular 73) (Chart 13) on a hydro- correlation between the side-chain chromophores led
philic surface.210 Molecular dynamics calculations to unexpectedly high first hyperpolarizabilities (ex-
indicated that also in this case additional stabiliza- ceeding 5000 × 10-30 eu). The breaking of centro-
tion of the helical backbone by hydrogen bonding symmetry, which is required for a second-order
between side-chain residues takes place. Due to the nonlinear response, could be attributed to the con-
high saccharide density along the rigid polyiso- sistent angle of ∼60° these chromophores make with
cyanide backbone, the binding affinity of lectins was the axis of the helical backbone, rather than to the
approximately 100 times lower than for flexible helical organization itself.
Chiral Architectures from Macromolecular Building Blocks Chemical Reviews, 2001, Vol. 101, No. 12 4061
Chart 16 Chart 17
Chart 18
Chart 19
Figure 21. Transmission electron micrographs showing the formation of (a) vesicles, (b, c), micellar fibers, and (d)
superhelices from a PEO-PMPS block copolymer (105).
preliminary communication, the formation of vesicles been addressed include the conformational dynamics
was reported in pure water (Figure 21a).287 In a later of the helicity and their effect on the (photo)physical
paper,133 it was described that the aggregation be- properties of the polymers, the induction of helicity
havior of this amphiphilic polymer can be tuned by in the polymer chain, the influence of kinetics on the
dispersing it in water-THF mixtures of varying macromolecular secondary structure, and the use of
composition. Below water concentrations of 40% (v/ multiple interactions in the hierarchical organization
v) no aggregates were found. Electron microscopy of macromolecules to well-defined supramolecular
demonstrated the presence of micellar rods in mix- assemblies.
tures containing 40-80% (v/v) water (Figure 21b,c). It is evident that mastering the organization of
In solvent mixtures containing more than 80% water, macromolecules is essential for the generation of
helices (Figure 21d)133 with both left- and right- materials with sophisticated properties. Since poly-
handed screw pitch were observed. Given the multi- mers with a permanent and precisely defined helical
block nature of the polymer and the polydispersity structure allow the generation of well-defined chiral
of the PMPS blocks, it is unlikely that the helical superstructures, it is our contention that this class
superstructures arise from preferential aggregation of macromolecules provides the route toward a better
of PMPS segments with identical screw senses. A understanding of the principles underlying the gen-
cooperative process was assumed to occur in which eration of functional polymeric materials with ter-
the handedness of the initial PMPS segment(s) tiary structure from synthetic building blocks with
determine(s) the handedness of the subsequent PMPS a known secondary structure. In the future, these
segments assembling in the same aggregate, such principles may be extrapolated to understand and
that a chiral architecture is formed by hierarchical ultimately predict also the assembly processes taking
assembly of these dynamic helical macromolecules. place between macromolecules with a more dynamic
backbone conformation, ultimately allowing their
V. Conclusions and Outlook application for the construction of advanced poly-
meric materials and devices.
On the way from molecular to macromolecular and
supramolecular chemistry, researchers have realized VI. Acknowledgments
increasingly complex functional materials; however,
We thank The Netherlands Organization for Sci-
these still lag behind compared to highly sophisti-
entific Research (NWO) for financial support of
cated macroscopic architectures with precise and
J.J.L.M.C.
predefined structure that are encountered in biologi-
cal systems. In this review, we have summarized the
first steps chemists have taken toward the construc- VII. References
tion of macromolecular architectures with defined (1) Rowan, A. E.; Nolte, R. J. M. Angew. Chem., Int. Ed. 1998, 37,
63-68.
three-dimensional structures. In the past decade, (2) Feiters, M. C.; Nolte, R. J. M. In Advances in Supramolecular
polymers with defined secondary structure mimick- Chemistry. Vol. 6. Chiral Self-assembled Structures of Bio-
ing one or more aspects from biological systems have molecules and Synthetic Analogues; Gokel, G. W., Ed.; JAI Press
Inc.: Stamford, CT; Vol. 6, pp 41-156.
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organization of synthetic macromolecules that have structure, they will not be included in this review. For an
Chiral Architectures from Macromolecular Building Blocks Chemical Reviews, 2001, Vol. 101, No. 12 4067
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Chem. Rev. 2001, 101, 4099−4123 4099
Figure 2. Height image of L,L-PIAA molecules on mica as measured by tapping mode SFM. The histogram shows
distribution of the apparent lengths of the adsorbed molecules.
Figure 4. (a) SF micrograph of DNA molecules deposited on mica from a physiological solution. (b) Mean-square end-
to-end distance, 〈R2〉, as a function of the DNA contour length measured in different buffer solutions. The continuous line
represents the 〈R2〉 evaluated from eq 2 for a DNA persistent length of 53 nm.79
[ lp
〈R20〉 ) 2lpL 1 - (1 - e-L/lp)
L ] (2)
the molecules in solution.
At low concentrations from 0.5 to 2 nM, the
molecules are adsorbed onto mica as single species
The Kratky-Porod formula may be not applicable as shown in Figure 4a. Figure 4b shows a plot of
for long molecules with L . lp, for which excluded 〈R20〉 as a function of the contour length L. Both
volume interactions should be taken into account. parameters were measured directly from the SFM
Intramolecular excluded volume effects result from micrographs. Assuming that the molecular conforma-
repulsion between segments within the same mol- tion was not perturbed by excluded volume interac-
ecule, which can cause an increase of the end-to-end tions between molecular segments as well as by
distance. These effects are particularly strong for 2D interactions between the segments and the substrate,
systems, which demonstrate an increased density of Rivetti et al. used the Kratky-Porod formula to
segments and do not permit the chain crossings. Both determine a persistence length of 53 nm.79 The data
methods require complete visualization of a statisti- were in good agreement with those obtained by
cal ensemble of single molecules in order to determine electron microscopy and gel electrophoresis.139 For
the length L, the angle Θ, and the end-to-end the molecules adsorbed on mica, the crossover of the
distance 〈R20〉. In addition, they assume the observa- perturbed and unperturbed regimes was found at
tion of molecules in their natural state, in which contour lengths of about 1000 nm (ca. 20 times the
molecules are not constrained and freely fluctuate persistence length). Therefore, evaluation by the
around their equilibrium conformation. Kratky-Porod formula (eq 2) is limited to
The concurrent effects of adsorption, solvent evapo- DNA molecules whose length is shorter than 1000
ration, and capillary forces can, however, lead to nm.
kinetically trapped conformations (see below). The The effect of excluded volume repulsion on the
question arises whether and under what conditions molecular conformation was investigated for long
an equilibrium 2D conformation can be achieved. DNA molecules in an aqueous environment by fluo-
Optimum conditions were reported for DNA mol- rescence optical microscopy. Figure 5a shows fluo-
ecules deposited on mica.78 In water, mica is nega- rescence images of λ-phage DNA fragments bound to
tively charged; and therefore, mica repels negatively a glass-supported cationic lipid membrane in 10 mM
charged DNA molecules. When divalent cations, such HEPES buffer. Since the observed molecules were
as Mg2+, Mn2+, Co2+, and Ca2+, are adsorbed, the much longer than the persistence length, the ex-
surface charge is inverted. Thus, DNA adhesion can cluded volume effects resulted in the coil expansion.
be promoted if deposition is done from a buffer Figure 5b depicts the log-log representation of the
solution containing divalent cations.108 Because the radius of gyration as a function of the number of base
divalent cations and thus the adhesion sites can pairs for a set of molecules that consist of 880, 6141,
diffuse along the surface, the deposition process was 14 953, and 26 528 base pairs.140 The scaling expo-
assumed to allow equilibration rather than being nent for the 2D-confined molecules was found to be
dominated by kinetic trapping effects. A typical ν ) 0.79 ( 0.04. This experimental value is in good
example is a 0.5 nM DNA solution in a pH 7.4 buffer agreement with the theoretical prediction ν ) 3/4 for
with NaCl (10 mM) and MgCl2 (2 mM). In this case, self-avoiding statistical chains in two dimensions141
the adsorption of DNA molecules from solution is and consistent with a persistence length lp of 50 nm.
controlled by diffusion. A diffusion coefficient of D ) For individual DNA molecules in solution, the scaling
5.5 × 10-8 cm2/s was found using the formula ns/n0 exponent was determined to ν ) 3/5.142
Visualization of Macromolecules Chemical Reviews, 2001, Vol. 101, No. 12 4103
Figure 5. Static scaling analysis of single DNA molecules. (a) Fluorescence micrograph of λ-phage DNA cut by the
restriction enzyme BbrPI. (b) The log-log plot of the averaged radius of gyration of DNA fragments as a function of fragment
length in number of base pairs N(bp). The straight line fits the scaling Rg ∝ Nv, with ν ) 0.79 ( 0.04.140
Figure 6. (a) STM image of C36H74 alkane on graphite.143 (b) Head-to-tail-coupled poly(3-dodecylthiophene) in the HOPG/
liquid (1,2,4-trichlorobenzene) interface 20 × 20 nm.145
2.2. Structural Effects by Specific Interactions Figure 6b shows the ordering of polythiophene mol-
with the Substrate ecules with alkyl side chains along the crystal-
lographic axes of the graphite.145 Formation of highly
Absence of surface interactions that effect the ordered monolayers follows from the epitaxial-like
conformation of the macromolecules is, however, not orientation of the hydrocarbon chains with respect
the rule. Below we will discuss examples of how the to the graphite lattice.
molecular conformation can be effected by specific
interaction with the substrate. Obviously, one cannot Also, relatively long polymer molecules can be
regard the apparent persistence length of the ad- extended and aligned by specific adsorption of the
sorbed molecules as a characteristic value for the side groups with the substrate. Detailed studies of
chain flexibility. the molecular conformation affected by adsorption on
Spectacular pictures of adsorbed chain molecules a solid substrate have been possible with so-called
have been obtained for n-alkanes on graphite where monodendron-jacketed polymers.41,146-148 Scheme 1
the carbon chains were oriented according to the depicts two examples of monodendron-jacketed mac-
3-fold symmetry of the graphite (Figure 6a). The romolecules: 14-ABG-PS carries three monoalkoxy-
orientation of the main chain has been explained by benzyl ether groups per monomer unit, whereas the
the close matching between the repeat length le ) stronger branched 3,4,5-t-3,4,5-PS monomer is sub-
2.54 Å of a -(CH2-CH2)- sequence in all-trans stituted by three trisalkoxybenzyl ether groups and
planar zigzag conformation and the crystallographic has a 2 times larger molecular mass.149
spacing a ) 2.46 Å of the graphite surface.143,144 Figure 7 shows an SF micrograph of 14-ABG-PS
Also, interactions of the side chains with the on graphite together with a cartoon of the molecular
substrate can cause alignment of adsorbed molecules. structure.147 The macromolecules are arranged in
4104 Chemical Reviews, 2001, Vol. 101, No. 12 Sheiko and Möller
Figure 7. SFM micrograph of 14-ABG-PS molecules on HOPG prepared by spin casting of a solution in cyclopentane
(c ) 0.1 mg/mL). Individual molecules aligned parallel to the substrate and bent at characteristic angles of 60° and 120°
to follow the 6-fold symmetry of graphite.147
Scheme 1
straight segments with bends of a characteristic move the molecules or molecular parts along the
angle of 60° and 120°. Also, in this case the ordering substrate and to cause aggregation of individual
of the macromolecules is explained by an epitaxial molecules into monolayers.
adsorption of the alkyl tails of the monodendron side Another example for wormlike synthetic macro-
groups on highly oriented pyrolytic graphite, HOPG. molecules is depicted in Figure 10. The SFM images
Specific interaction of the side chains with the show poly(methyl methacrylate) brush molecules that
substrate has been verified by STM studies on adsorbed as extended threats on a flat mica surface.
monolayers of the monodendrons.148 The backbone consists of methacrylate units, each of
It has also been possible to observe how the chains which is grafted by a methyl methacrylate side
adsorb originally in a coiled conformation and how chain.151 The molecular properties are summarized
they expand subsequently to the ordered pattern. in Table 1.
Figure 8 shows a series of SFM images of a polyox- Neglecting the interaction with the substrate, the
norbornene substituted by the same dendron groups overall conformation of the brush molecule is con-
as in the case of 14-ABG-PS after different times for trolled by the repulsion and excluded volume of the
adsorption.148 Besides the increase in surface cover- densely grafted side chains. Thus, the spatial demand
age, one observes the relaxation within minutes. of the side chains results in bending rigidity and
On mica, the 14-ABG-PS polymer did not show any prevents the collapse of a brush molecule to a dense
particular order (Figure 9). Only a short-range ori- globule. Yet, in contrast to DNA, where the segmen-
entational order of densely packed cylinders was tal conformation, i.e., the rotational angles of the
observed. bonds in the backbone, is fixed to a large extent, the
The dense arrangement of the chains points to the brush molecules possess a flexible backbone. Thus,
action of other forces that can control the molecular the brush acquires rigidity on the length scale of it’s
conformation of adsorbed macromolecules in addition thickness or larger, but the conformation within short
to the interaction with the substrate. Capillary forces segments of the backbone can be disordered similar
and dewetting during evaporation of the solvent can to that in a coil molecule. The monodendron-jacketed
cause condensation and dense packing of the mol- polymers depicted in Figures 7-9 can be regarded
ecules in monolayer patches,147,148,150 For large mol- as an intermediate case, where the rigidity of the
ecules with a diameter of ca. 5 nm, capillary forces backbone conformation is caused not only by the
are in the range of a few nN, which is sufficient to bulkiness but also by self-assembly of the side chains
Visualization of Macromolecules Chemical Reviews, 2001, Vol. 101, No. 12 4105
Figure 8. (a-c) A series of SFM micrographs was measured after adsorption of polyoxanorbornene DP100 from THF
solution with concentration 0.001 mg/mL on mica during different times. The adsorption time is indicated by arrows in d,
representing dependence of the coverage on the time for different polyoxanorbornenes (9) DP 100, (b) DP 200, (2) DP
400.148
Table 1. Molecular Characterization of the PMMA Brushes Depicted in Figure 5151
length of side chainsa total molecular weightb contour length (SFM)c Lw/Ln length/monomer (SFM)
2410 g/mol 1.08 × 107 g/mol 367 nm 1.3 0.07 ( 0.1 nm
a
MALDI-TOF. b Small angle light scattering. c Lw ) (∑niLi2)/(∑niLi).
Figure 10. (a) Molecular brushes with poly(methyl methacrylate) side chains were adsorbed on mica and annealed above
the glass transition temperature T ) 105 °C for 24 h. (b) The undulated structures in higher magnification images
demonstrate the tendency of the brush molecules to contraction via the buckling mechanism. The height of the molecules
was determined to be 2 nm and the width 16 ( 2 nm.
PMMA brush molecules in THF solution.151 Also, in free energy of excluded volume interaction.156-159
this case, the monomer length h ) 0.081 ( 0.008 nm
indicated an axial contraction compared to the fully F(R,h) R2
stretched all-trans conformation. The coincidence of ) + |τ|2Rh - |τ|2N (3)
kBT N
the experimentally determined values for h in dilute
solution and for the dry adsorbed molecules might
be regarded as an indication that the axial contrac- Here N is the number of monomer units in the side
tion of a densely grafted brush molecule does not chains and R is their end-to-end distance. In a
depend strongly on the quality of the solvent. It must, uniformly collapsed brush below the Θ point, the
however, be noted that adsorption of the side chains, binary interactions are attractive and the polymers
i.e., their confinement to a 2D conformation, can density ∝ |τ|. The thickness of the collapsed brush
cause significant stretching compared to the uncon- scales as R ∝ (N/h|τ|)1/2. The axial tension is given
fined brush (see below). Thus, an axial contraction by
caused by decreasing solvent quality or in a dry brush
might well be compensated by stretching due to dF/kBT
partial adsorption of the side chains. That this is in f/kBT ) - = (|τ|h2)-1 - |τ|3/2(N/h)1/2 (4)
dh
fact the case is indicated by the remarkable buckling
of the brush conformation observed in Figure 10b. The degree of stretching of the side chains and the
Buckling can be explained by a transformation where extensional force on the backbone decreases with
the molecules first contract as the solvent evaporates decreasing grafting density and decreasing solvent
and then expand axially as the side chains start to qualityτ (i.e., increasing |τ|).
adsorb tightly. Buckling is typical for confined aniso- If the backbone is not stiff but flexible, an eventu-
tropic systems when the strain cannot be released ally resulting negative axial tension can be partly
completely, such as thin films, microtubuli, and released by contraction, i.e., variation of the effective
nanotubes.153-155 grafting density h. Moreover, under the condition of
The driving force for the axial contraction was a fixed monomer density N/(R2h) = |τ|, minimization
elucidated by O. Borisov by scaling analysis of a of the total elastic free energy of the collapsed brush
linear brush molecule.156 Because of the dense sub- has been shown to result to156
stitution, the side chains get stretched. Stretching of
the side chains with respect to the Gaussian dimen-
h(τ) = h(τΘ(|τ|/|τΘ|)-1/3
sion leads to conformational entropy loss. Thus, if the
grafting density h-1 is fixed, the cylindrical brush
experiences an extensional axial force of entropic R(τ) = R(τΘ(|τ|/|τΘ|)-1/3 (5)
origin. In a bad solvent or in air when the brush is
collapsed, a negative contribution to the axial force with τΘ corresponding to the onset of the side chain
has to be taken into account due to the excess collapse.
interfacial energy of the brush. The interfacial energy The detailed analysis156 demonstrated that the
per unit area is proportional to τ2, where τ describes onset of the side chain collapse is shifted toward the
the quality of the solvent given by the relative range of poorer solvent conditions compared to that
deviation from the Θ point, τ ) (T - Θ)/Θ. The free in an individual chain of length N. Both the side
energy per side chain, F, in a collapsed brush chains and the backbone remain extended at τ e τΘ
comprises the elastic penalty for extension of a side with respect to the Gaussian dimensions for densely
chain, the excess free energy of the interface, and the grafted brushes, and the length of a dense brush is
Visualization of Macromolecules Chemical Reviews, 2001, Vol. 101, No. 12 4107
Figure 11. (a) SFM micrograph of single 14-ABG-PS molecules on HOPG, and (b) suggested conformation of monodendron-
jacketed linear chains.146
Table 2. Molecular Dimensions and Length Per almost complete stretching of the backbone with
Monomer Unit of 14-ABG-PS, 3,4,5-t-3,4-PS, and lSFM) 2.3 Å.
3,4,5-t-3,4,5-PS from SFM Micrographs and SEC and
SLS Data146,147 Clearly, also the monodendron-jacketed polysty-
renes are contracted in length compared to the full
polymers
contour length. For 14-ABG-PS it must be noted,
14-ABG-PS 3,4,5-t-3,4-PS 3,4,5-t-3,4,5-PS however, that the coincidence of the length per
M,a g/mol 1194 1612 2140 monomer unit in the adsorbed and the hexagonal
Mw,c 106 g/mol 1.1 1.2 2.0 columnar mesophase has to be considered to occur
Mw/Mn 2.6 2.6 2.2 by chance. As discussed for Figure 7, the molecular
a,c Å 52.1 41.4 47.7
lXDR,d Å 0.8 1.8 2.0
conformation of 14-ABG-PS is significantly affected
lSFM,e Å 1.2 1.9 2.3 by the interaction with the substrate.146-148 Certainly
a Molecular weight of the monomer unit. b Molecular weight
such an interaction with the substrate will be a factor
of the polymers determined by size exclusion chromatography
that changes the segmental conformation and does
in tetrahydrofuran using a light scattering detector. c Column not only align the molecular segments in a straight
diameter determined by X-ray diffraction measurement in the line. In this case, the length per monomer unit results
columnar mesophase. d X-ray spacing along the column axis from the interplay between the interfacial and in-
per repeat unit of the main chain as determined for the tramolecular interactions. Constraint of the tightly
columnar mesophase in bulk. e Length of the cylindrical
molecules per repeat unit of the main chain determined from adsorbed side chains to the surface plane causes
the SFM micrographs as lSFM ) M‚Ln/Mn. extension of the backbone, while aggregation of
desorbed side chains favors contraction.
predicted to depend only weakly on the solvent 2.3. Metastable Tertiary Structures by Local
conditions within the regime of a poor solvent.
Contraction and Twisting
Also, in the case of the monodendron-jacketed
macromolecules, the chain length-per-repeat unit lSFM It is obvious that the conformation of adsorbed
) Ln/DPn could be evaluated from the molecular molecules can be far from equilibrium if the adsorp-
length in comparison with the independently deter- tion process has been fast and irreversible. In this
mined degree of polymerization DPn. Figure 11 case, the molecules do not have time to sample the
depicts an SFM image of single 14-ABG-PS molecules whole assembly of thermodynamic states and get
deposited on the surface of highly oriented pyrolytic trapped kinetically at the contact sites. Yet, there are
graphite.146,147 The 5 nm thick molecular threads are distinct kinetic pathways that give rise to the forma-
aligned parallel to the substrate plane. Table 2 tion of peculiar tertiary structures in connection with
summarizes the molecular dimensions and the values the axial contraction and local twisting. An example
of the length per monomer unit, lSFM, for three discussed above is the buckling of the PMMA brushes
monodendron-jacketed polystyrenes with three, six, in Figure 10. Another example is demonstrated in
and nine terminal alkyl chains per dendron, respec- Figure 12. Here 14-ABG-PS molecules are depicted
tively. that were deposited by fast spin coating on mica.147
The value of lSFM ) 1.2 Å for 14-ABG-PS is in good The molecules were adsorbed randomly without
agreement with the stacking period in the columnar interfacial ordering effects, and quick evaporation of
hexagonal mesophase that was obtained from the the solvent caused underwinding or overwinding of
macroscopic density and the X-ray periodicity of the the molecules, i.e., significant torsional strain is
columnar packing. This value is almost 2 times less evidenced by the observation of supercoils, so-called
than the length l0 ) 2.5 Å expected for a fully plectonemes (from the Greek meaning “braided
extended main chain in an all-trans planar zigzag string”).161
conformation. In contrast, 3,4,5-t-3,4,5-PS with the The drawing of a monodendron-jacketed chain in
sterically more demanding side groups demonstrated Figure 11 indicates that axial contraction is enabled
4108 Chemical Reviews, 2001, Vol. 101, No. 12 Sheiko and Möller
Figure 12. SFM micrographs of (a) 14-ABG-PS on mica147 and (b) twisted ribbon structure of polypeptide β-sheets.164
The plectoneme conformation is caused by the backward folding of the torsionally stressed molecules. Insert in a depicts
a plectoneme supercoil.
by local winding up of the backbone. Regular helix pares the lengths of pnBuA brushes with different
formation is highly unlikely because of the atactic numbers of nongrafted MMA monomers. One can see
stereostructure and was also not observed in the that less densely grafted brushes undergo stronger
mesophase state.160 However, axial contraction must axial contraction of the main chain. When the aver-
clearly be linked to local twisting. Thus, the observed age length of the MMA sequences became larger than
supercoiling is a way of releasing torsional stress.162,163 four monomeric units, the observed length per mono-
To the best of our knowledge, the supercoil formation mer unit decreased significantly. This value is re-
of the monodendron-jacketed polystyrene is one of the markably similar to the length lk ∼ 12 Å of the
first observations of a defined tertiary structure in statistical (Kuhn) segment of PMMA.
synthetic polymers. While in biomolecules the ter- In addition to the visualization of the molecular
tiary structures are typically stabilized by specific contour, topographic and phase contrast SFM en-
interactions between side groups, the supercoil of the abled clear resolution of the fine molecular structure.
monodendron-jacketed polymers is metastable. Even- Figure 14 shows SFM micrographs of single brush
tually, annealing offered a path for the stress relax- molecules, where one can easily distinguish both the
ation and led to vanishing of the supercoil conforma- backbone and the tightly adsorbed side chains. For
tion.147 Figure 12b shows a similar conformation example, white contours in the height micrograph
observed for a polypeptide.164 (Figure 14b) correspond to the backbone wrapped by
nonadsorbed side chains, while the grayish areas
2.4. Microscopic Structure of Adsorbed between the white threads demonstrate the hairy
Macromolecules structure of the adsorbed segments of the side chains.
How adsorption of the side chains to a flat sub- The molecules in Figure 14a,b differ in the degree of
strate effects the backbone conformation has been polymerization of the side chains as DPn ) 52 ( 10
observed in further microscopic detail for brush and DPn )10 ( 2, respectively. This difference was
molecules with a methacrylate backbone and poly- readily detected by SFM. The brushes in Figure 14a
(n-butyl acrylate) side chains. These poly(n-butyl show a thicker corona of side chains around the
acrylate) brushes were prepared by living radical backbone compared to the brush in Figure 14b.
grafting from a multifunctional macromolecular ini- The distance between the backbones in densely
tiator.38 The synthetic approach allowed observation packed monolayers, like the one shown in Figure 14b,
of the same batch of molecules without (macroinitia- increases linearly with the number-average degree
tor) and with poly(n-butyl acrylate) side chains of polymerization of the side chains, D ∼ DPn. The
(brush). distance is, however, significantly larger than the
After adsorption on mica, the SFM length of the number-average length of a fully extended side chain,
brush molecules corresponded to an almost fully l0 ) DPn × 2.5 Å. These observations suggest that
extended backbone approaching the trans zigzag the absolute distance between adsorbed brushes is
conformation (Figure 13b). In contrast, the apparent not determined by the number-average length of the
length of the macroinitiator, which was scanned by side chains but it is controlled by a small fraction of
SFM prior to grafting, was 2 times shorter than the longer side chains.
contour length of the main chain (Figure 13a). Extension and stiffening of the backbone because
The extension of brush molecules is caused by of the tight adsorption of the side chains are con-
excluded volume repulsion of the 2D-adsorbed side nected with a significant loss of entropy. A certain
chains. Therefore, the length of adsorbed brushes decrease in the entropy by bending of the backbone
should also depend on the grafting density. Copoly- without changing the degree of adsorption of the side
mer brushes with a random sequence of methyl chains can, however, be enabled by an uneven
methacrylate and poly(n-butyl acrylate)-substituted distribution of the side chains between the two sides
methacrylate units were prepared with different of the backbone. On the concave side of the bend, the
compositions, i.e., grafting densities. Table 3 com- space available per side chain is increased compared
Visualization of Macromolecules Chemical Reviews, 2001, Vol. 101, No. 12 4109
Figure 13. (Top) Preparation of PBA brushes by grafting from the macroinitiator using ATRP.38 (Bottom) Single molecules
of the macroinitiator (a) and PBA brushes (b) adsorbed on mica were visualized by tapping-mode SFM. Clearly, the grafting
of long side chains led to almost full extension of the backbone approaching the contour length L ) N‚l0, where l0 ) 0.25
nm is the monomer length of a hydrocarbon chain in the all-trans conformation.
Table 3. Axial Contraction of pnBuA brushes as a Function of the Grafting Density
polymer MMA, % DPn, side chains DPn, backbone Ln, nm lm ) Ln/DPn, nm
homopolymer 0 35 567 123 0.22 ( 0.2
copolymer 1 35 58 477 120 0.25 ( 0.2
copolymer 2 56 42 637 127 0.2 ( 0.2
copolymer 3 77 32 710 116 0.16 ( 0.2
to the straight conformation. Thus, for these chains favored could be obtained in the case of the brushes
and the backbone, bending yields an increased con- with poly(n-butylacrylate), PBA, side chains. The low
figurational entropy. glass transition temperature of PBA (Tg ) -54 °C)
Computer simulations demonstrated that such an favors fast equilibration upon thermal annealing. The
uneven distribution of the side chains leads to bend- sample in Figure 17a was prepared by spreading a
ing.165 Scaling analysis showed that the uneven side dilute solution of the PBA brush molecules in CHCl3
chain distribution and bending is favorable in par- on water (Langmuir trough). The surface pressure
ticular for long side chains and lower grafting densi- was increased to obtain a condensed film that was
ties (Figure 15). In the case of an isolated single then transferred onto a mica substrate. Similar to
chain, bending can furthermore reduce the line Figure 13, the backbones were predominantly ex-
tension, in the optimum case by formation of a spiral tended. This indicates a rather even distribution of
structure.166,167 the side chains to the one and the other side as it
Indeed, bending and even spiral conformations might be expected for fast adsorption at the substrate
were observed for PMMA brush molecules that were surface. When the film on mica was, however, an-
deposited from a solution in THF.165,167 This is shown nealed for 48 h at 120 °C, considerable coiling of the
by the SFM micrograph in Figure 16. Nevertheless, molecules occurred as shown in Figure 17b.
the situation in Figure 16 is a snapshot of a situation Summarizing the evidence from Figures 13-15 and
that emerged upon evaporation of the solvent and 17, it results that the backbone conformation of the
does not represent an equilibrium conformation. brush molecule is strongly effected by the adsorption
Clear experimental evidence that the coiling of and side distribution of the grafts. The most impor-
brushes on solid substrates is thermodynamically tant contribution is the repulsion between the ad-
4110 Chemical Reviews, 2001, Vol. 101, No. 12 Sheiko and Möller
Figure 14. Molecular brushes with poly(n-butyl acrylate) side chains of different degrees of polymerization: (a) n ) 52
and (b) n ) 10.
Figure 15. Calculation of the free energy of a brush molecule with asymmetrically distributed side chains as a function
of the bending curvature (DPside chains ) 100, ∆1 ) 4, ∆2 ) 8, one side chain per two backbone units).
Figure 16. (a) SFM micrograph of PMMA brushes lying flat on the mica surface. The arrows show one of the typically
observed conformationss2D helices of tightly winded cylindrical brushes. (b) Zoomed image of molecule 3 in part a. (c)
Typical snapshot of the simulated 2d bottle-brush structure consisting of the 128-segment main chain and the 4-segment
side chains grafted at σ ) 1 and φ ) 0.1.
sorbed side chains that leads to the extension of the the persistence length must depend on the grafting
whole brush molecule. Hence, the conformation and density and the fractions of the adsorbed and de-
Visualization of Macromolecules Chemical Reviews, 2001, Vol. 101, No. 12 4111
Figure 17. SF micrograph of a condensed film of poly(n-butylacrylate) brushes, DP side chain ) 60: (a) transferred from
water onto mica and (b) after annealing at 120 °C for 48 h.
Figure 18. (Left) SFM images of poly(n-butylacrylate) brushes with varying degree of polymerization, n, of the poly(n-
butylacrylate) side chains on mica (spin cast samples). (Right) Persistence length of a molecular brush as a function of the
side chain length n. The continuous line describes the power function lp∝ n2.7 and the points experimental values from
SFM.167
sorbed side chains. While tightly adsorbed side chains dependence of lp on the length of the side chains can
favor extension of the backbone, desorbed side chains be described by a power function nR with R varying
favor the coiling process. between 2 and 3 (see Figure 18, right).
The dependence of the persistence length lp on the The theoretical analysis has been verified experi-
fraction of the adsorbed side chains Θ has been mentally. The SFM images in Figure 18 depict the
derived from scaling analysis168 contour of four poly(n-butylacrylate) brushes differing
in the degree of polymerization of the poly(n-butyl-
(φx) n + (1 -x φ) n
5 3 3 acrylate) side chains. All four molecules were pre-
lp = (6)
pared by grafting from the same macroinitiator
sample. Clearly, the extension and straightening of
where x ) L/(a‚N) denotes the degree of longitudinal the molecules improved with the side chain length.
contraction which denotes the effective grafting The diagram in Figure 18 (right) gives a fit of the nR
density. dependency to experimental values. The resulting
The degree of contraction was evaluated by mini- exponent R ) 2.7 ( 0.2 is indicative of a relatively
mization of the free energy of the adsorbed brush. large fraction of adsorbed side chains as expected for
Three contributions were considered: the elastic strong interaction between the polar acrylates and
energy of the main and side chains, the interfacial the polar mica surface.
energy, and the mixing entropy between adsorbed Because the adsorption of the side chains is such
and desorbed chains.168 The persistence length varies a strong factor in controlling the macromolecular
with the side chain length with a cubic power conformation, not only the length of side chains but
dependence lp = n3 in the strong adsorption regime also their composition is of great importance. This
(φ, x ≈1) and with a square dependence lp = n2in the can be demonstrated by comparing the structures for
weak adsorption regime (φ ≈ 0, x = n-1/3). The the brush molecules with poly(n-butylacrylate) side
4112 Chemical Reviews, 2001, Vol. 101, No. 12 Sheiko and Möller
Figure 19. AFM micrographs of four different polymers adsorbed on mica: (a) single molecules of macroinitiator pBPEM,
(b) monolayer of homopolymer pBPEM-graft-pnBuA brush, (c) monolayer of pBPEM-graft-(pnBuA-block-pS) brush, and
(d) single molecules of pBPEM-graft-(pS-block-pnBuA) brush.169
chains and poly(styrene)-block-poly(n-butylacrylate) brush with an inner pnBuA and an outer polystyrene
side chains, respectively. While the n-butylacrylate block (pBPEM-g-(pnBuA-b-PS)), and (iv) the inverse
units interact strongly with a polar substrate like structure with an inner polystyrene and an outer
mica, there is a much weaker adsorption of the pnBuA block (pBPEM-g-(pS-b-pnBuA)) have been
styrene units and correspondingly of a polystyrene prepared. Because all molecules have been prepared
brush.169 Diblock side chains offer the possibility to from the same macroinitiator, they have the same
distinguish between adsorption effects of the inner length, DPbackbone ) 514. Due to the consequential
polymer segment, adjacent to the backbone, and the addition of the blocks, the side chains vary in length.
outer side chain tail. Figure 19 shows SFM images of the four polymers
Brushes with diblock side chains have been pre- that have been deposited by spin casting from THF
pared by the same concept as illustrated in Figure solution on freshly cleaved mica. In each case, single
13. In this case either a polystyrene block or a poly- molecules are resolved lying flat on the substrate.
(n-butylacrylate) block was grafted first by atom One clearly recognizes distinct differences in the 2D
transfer polymerization, ATRP, on a poly(2-bro- conformation, which can be attributed to the different
mopropanoyl ethyl methacrylate), pBPEM, on which adsorption behavior of the side chains. The images
in a second step the other monomer was polymerized allowed one to measure the length of the macro-
as the second block.169 Table 4 summarizes the molecules and to evaluate the contraction of the
molecular structure of the corresponding polymers, backbone relative to the contour length of the fully
i.e., (i) the macroinitiator or mere backbone molecule extended main chain.
(pPBEM) from which (ii) a brush with pnBuA ho- The length of the brush molecules per monomer
mopolymer side chains (pBPEM-g-pnBuA), (iii) a unit of the backbone, lm, was evaluated from the
Visualization of Macromolecules Chemical Reviews, 2001, Vol. 101, No. 12 4113
Figure 20. SFM micrographs of single molecules of pBPEM-graft-(pnBuA-block-pS) brushes. The cross sectional profiles
(c and d) were drawn perpendicular and parallel to the molecular contour along the dotted lines in a and b, respectively.
The scheme explains the necklace morphology upon looking at the molecule from the edge (e) and from the side (f).
images and compared to lmax ) 0.25 nm for all-trans driving force might be found in entropically favorable
conformation of an aliphatic chain (Table 4). For the coiling and in reduced unfavorable contacts between
pnBuA brush, the length lm ) 0.22 nm indicates the pS and pnBuA blocks as well as between pS and
almost complete stretching of the backbone as shown air. While the PS segments form clusters, the pnBuA
before (Figure 14, Table 3). The pnBuA-b-pS brushes chain fragments remain tightly adsorbed on the
with a pnBuA core and a pS shell demonstrated substrate. This interpretation is consistent with the
similar extension to lm ) 0.20 nm. In contrast, a intermolecular distances D measured in Figure 20b,c.
significantly shorter monomer length lm ) 0.16 nm,
was determined for the inverted structure, i.e., pS- 3. Manipulated Conformational Transitions of
b-pnBuA with a pS core and a pnBuA shell. The axial Adsorbed Macromolecules
contraction is consistent with the more globular Conformational transitions and the corresponding
conformation of the coiled up molecule morphology stimuli response of macromolecules provide funda-
of the brush molecules in Figure 19d compared to mental means for the molecular assembly and func-
those in Figure 19b,c. As might be expected, the tion of biological systems.1-7 Establishing a likewise
stretching and straightening of the brush molecules control factor in the field of synthetic macromolecules
are predominantly controlled by the adsorption of the is recognized as a major challenge in nanotechnology.
side chain segments near the backbone. According to theoretical considerations, the transi-
The extended block-copolymer brush in Figure 19c tion between the state of an expanded coil and a
exhibited well defined periodic undulations in thick- compact globule can be discrete, depending on the
ness. This is seen in further detail in the enlarged nature of the interaction and the chain flexibility.170
images in Figure 20a,b. A thin corona of the tightly Equilibrium coexistence of two conformations of
adsorbed chain segments is depicted surrounding the single macromolecules as an unambiguous criterion
undulated backbone of the single molecule of pnBuA- for a first-order transition171-174 has been clearly
b-pS in Figure 20a. The cross-sectional profiles in observed only in the case of relatively large DNA
Figure 20d,c were recorded along the molecular molecules.174 However, the peculiar branching topol-
backbone and perpendicular to it, respectively. After ogy in dendrimers, block-copolymer micelles, and
correction for the radius (R ∼ 8 nm), the diameter of cylindrical brushes provides a unique means to
the globuli forming the necklace-like string and their introduce the competitive interactions necessary for
separation was determined from the image to be d a conformational transition.168,175-177 In the following
) 5 ( 1 nm and δ ) 15 ( 2 nm, respectively. it will be shown that coexistence between an ex-
A tentative interpretation of the undulations is tended and a globular conformation can occur in the
presented in Figure 20e,f: In contrast to the pnBA case of poly(n-butyl acrylate) brush molecules168 and
chains that adsorb flatly, the pS tails in the block- be visualized in detailed resolution on a significantly
copolymer brushes tend to aggregate to clusters. The smaller length scale than possible in the case of DNA.
4114 Chemical Reviews, 2001, Vol. 101, No. 12 Sheiko and Möller
Figure 21. Conformations of cylindrical brushes upon adsorption on a surface: (a) extended chain, (b) globule.
Table 5. Molecular Characterization of the PBPEM
Macroinitiators and the Corresponding PBA Brushes
by Multiangle Laser Light Scattering Size Exclusion
Chromatography (MALLS-SEC) and Static Light
Scattering (SLS)168
macroinitiator brush
,a
polymer Mw g/mol Mw/Mn Nb Mw,c g/mol Mw/Mnd nLSe
A 2.2 × 105 1.3 641 4.6 × 106 1.1 46
B 1.6 × 105 1.3 453 1.6 × 106 1.2 20
C 1.8 × 105 1.4 490 1.4 × 106 1.3 15
a By MALLS-SEC using dn/dc)0.084 (error bar 5%). b Num-
As discussed above, the conformation of molecular determined by size exclusion chromatography and
brushes at an interface is determined by the interac- light scattering in dilute solution.
tion of the side chains with the substrate and entropic Owing to the amphiphilic nature of n-butyl acrylate
flexibility of both the side chain and the flexible groups, the pnBA brushes spread on a water surface.
backbone. The stretched backbone conformation of Figure 22 shows a π-A isotherm (surface pressure
pnBA brushes depicted in Figures 13, 14, 17, and 18 versus monolayer area per BA residue) for polymer
is enabled by a large number of energetically favor- A with the longest side chains. Corresponding to the
able surface contacts. One can envision a transition low glass transition temperature, Tg ) -54 °C,
to a globular conformation if the interaction strength compression of the PBA brushes was fully reversible
is reduced and coiling becomes entropically favored as expected for equilibrium spreading. The pressure
at the expense of the surface contacts. Since the onset occurred at about 35 Å2 and rose until a critical
energy and the entropy contribution vary differently area of 22 Å2, at which the pressure leveled off at
with respect to contact area and interaction strength, 19.5 mN/m. The plateau between 22 and 13 Å2 was
the brushes can undergo a transition at a critical followed by a second plateau with a distinct increase
interaction strength at which the free energies of the in pressure from 19.5 to 21 mN/m. The linear
stretched and collapsed state become equal. Such a extrapolation of the isotherm to zero pressure gave
transition may occur upon changing thermodynamic the area a0 ) 28 ( 1 Å2, which is consistent with the
variables, e.g. solvent quality and temperature, or monomer area of 29.3 Å2 measured for linear PBA.
under the effect of an external field. Thus, instead The values indicate that practically all BA monomer
of variation of the interfacial energies, the number units are in contact with the water surface, whereby
of surface contacts available per molecule or side the butyl tails are oriented toward air perpendicular
chain can be altered by reducing or expanding the to the surface. The plateau between 22 and 13 Å2 is
surface area per molecule as done experimentally on remarkable and indicates a structural transition
a Langmuir trough. In this case the free energies of within the monofilm.
the extended and collapsed state become equal at a The molecular structures at the different stages of
critical surface pressure, at which point the brushes compression were visualized by SFM on samples that
can undergo a transition. The concept is schemati- were transferred onto a mica substrate while the
cally depicted in Figure 21 and has been realized in pressure was kept constant. Figure 23 shows such a
experiment with pnBA brush molecules.168 series of SFM micrographs obtained at different
Table 5 lists the molecular structure parameters compression.
of three different pnBA brush molecules basically In each micrograph, the brush molecules were
differing in the length of the side chains, which were clearly resolved individually. At areas above 22 Å2
Visualization of Macromolecules Chemical Reviews, 2001, Vol. 101, No. 12 4115
Figure 23. SFM micrographs of monolayers of pnBA brushes (sample A in Table 5) transferred on mica at different
degrees of compression: (a) 30 Å2, (b) 23 Å2, (c) 21 Å2, (d) 17 Å2, (e) 13 Å2, (f) 30 Å2 (after expansion).168
the molecular cylinders retained their stretched chains. Since the free energies of these two confor-
conformation but became packed increasingly dense. mations depend in an opposite way on the interaction
The wormlike entities in Figure 23a, b mark the strength, the variation of either the area available
contour of the backbone and represent the extended per molecule A or the spreading parameter S ) γ1 -
brush molecules as depicted in Figure 21a. The space γ12 - γ2 can cause a discontinuous first-order transi-
between is occupied by the fraction of the side chains tion from one state to the other. The results of the
which are tightly adsorbed. The fundamental collapse evaluation are summarized in Figure 24, where the
of the wormlike structure predicted above was ob- fraction of adsorbed side chain units is plotted
served in the transition zone between 22 and 13 Å2. against the surface pressure and the critical surface
The SFM images in Figure 23c-e demonstrate that pressure Sc is plotted against the inverse length of
the molecules became more flexible and coiled, while the side chains 1/n.
at the same time a significant decrease in length is Switching between two distinct conformations has
observed. The round spots in Figure 23c-e are been observed also for spherical branched particles
assigned to single molecules which collapsed to a such as block copolymer micelles. Block copolymers
pancake-like or nearly globular structure as il- of poly(styrene) and poly(N-alkyl-4-vinylpyridinium
lustrated in Figure 21b. As the number of chains in iodide) were aggregated to micelles with a polysty-
Figure 23a and number of globuli in Figure 23e was rene core and a poly(N-alkylpyridinium iodide) co-
fairly equal, it was concluded that the molecular rona. These micelles could be spread on water from
collapse is accompanied by desorption of the side a solution in CHCl3 and compressed to a monofilm170
chains from the water surface and is occurring in first (Figure 25b). Due to the amphiphilicity of the N-
as an intramolecular collapse and only in a later alkylpyridinium iodides, the poly(pyridinium iodide)
stage by intermolecular aggregation as the collapsed block gets adsorbed in a 2D conformation with the
molecules get piled up. n-alkyl groups pointing to the air. Upon lateral
The observed conformational transition was ana- compression of the condensed monofilm of surface
lyzed theoretically assuming partial desorption of the micelles, also in this case, a distinct phase transition
side chains under compression, i.e., upon variation was observed upon lateral compression as the corona
of the spreading parameter.168 The total free energy chains got desorbed from the water/air interface
F ) F2D 3D
el + Fel + Fs + Fmix (Fel ) elastic contribution
(Figure 25a). The transition was particularly pro-
to the free energy, Fs ) surface energy of the brush, nounced in the case of longer chains, i.e., n-octyl
Fmix ) mixing entropy of the side chains) was pyridinium groups. The cooperative desorption/col-
minimized with respect to two independent vari- lapse is consistent with recent X-ray reflectivity
ables: the fraction of adsorbed 2D chains, φa, and the data.178
relative contour length of the brush, L/aN. Above a
critical length of the side chains, the free energy has 4. Motility of Molecules
two minima, i.e., (i) the extended brush with a large
fraction of adsorbed side chains and (ii) the collapsed So far we have encountered two particular features
globuli with a smaller fraction of adsorbed side of the conformation of brush molecules adsorbed on
4116 Chemical Reviews, 2001, Vol. 101, No. 12 Sheiko and Möller
Figure 24. Phase transition from the extended coil to a globule state as found by scaling analysis. The transition is
caused by lowering the surface pressure below a certain critical value Sc at which the fraction of adsorbed monomers
φa ) N2D/N undergoes discrete changes (a). Hereby, the Sc depends critically on the side chain length (b).168
Figure 25. Surface pressure-area/molecule isotherms of Langmuir films (a) of (PS)260(RPVP+I-)240, where the P4VP
block was quaternized with different n-alkyliodides R ) C1, C4, C6, C10. Metal-shadowed TEM micrographs (b) of the LB
films of P(S260-b-VP71/C10I) deposited on a carbon-coated surface at 2 mN/m from a pure water surface.178
a flat surface. These are (i) the observation that the lecular motility and the development of molecular
brush gets stretched as the side chains get confined motors. Complex protein molecules such as kinesin,
to a 2D layer upon adsorption and (ii) the observation myosin, and dynein are examples of molecular motors
that the 2D brush winds up if the side chains get from biology. These molecules can undergo directed
distributed unevenly between the two faces of the movement along cytoskeletal filaments based on
backbone. Both effects provide an intriguing access coordinated conformational changes which lead to
to stimulated molecular action. For example, if we periodic adsorption and detachment of molecular
assume a tightly adsorbed brush molecule with two fragments on the filament surface.179-183 The move-
different side chains whose mutual interaction pa- ment occurs via a sequence of elementary steps which
rameter can be switched from attractive to repulsive are driven by ATP hydrolysis,184 but the steps can
by an external field, such a molecule can undergo a take place stochastically and some of them are
stimulated transition from an extended (even distri- directed backward.185 Respectively, two models have
bution of side chains) to a curled conformation been proposed to explain the motion of motor pro-
(uneven distribution of the side chains). Yet, we teins: single-step directed motion and the biased
cannot propose a realistic concept for such a system. Brownian ratchet model.184,185 In the latter case an
However, a molecular rod-coil actuator appears to anisotropic ratchet potential is turned off and on.
be much more feasible based on the experiments This way the Brownian motion of a particle can be
summarized in Figures 21-25. Besides the variation transformed into a directed motion.186
of the surface pressure used in the experiment in
Figure 22, stimulated adsorption/desorption of a In the following we want to discuss, first, experi-
brush molecule can, in principle, be achieved by a ments on the motility of brush molecules based on
number of means, e.g., photoisomerization of suitable stimulated desorption/adsorption. The stimulation is
groups in the side chains, by mechanical interaction effected by the tip of a scanning force microscope as
with the tip of a scanning probe microscope, or by the molecules are probed. Essential questions are
changes of the temperature. The latter means have whether this can cause mobility different from Brown-
the advantage that isolated molecules can be ad- ian motion but also different from dragging of the
dressed also in contrast to the isothermal compres- molecules. For comparison, we summarize results on
sion of a monofilm. the dragged motion of a λ-phage DNA through an
Ultimately, a stimulated molecular action like the entangled solution and the Brownian motion of DNA
stretch-coiling transition can form a basis for mo- molecules adsorbed on a fluid lipid membrane.
Visualization of Macromolecules Chemical Reviews, 2001, Vol. 101, No. 12 4117
Figure 26. (a) Tiled series of images showing tube deformation and stress recovery in a concentrated polymer solution.
The times for images are 0, 0.3, 1.6, 2.3, 3.0 s. (b) Comparison of the relaxation of a 17 mm molecule linearly stretched to
full extension at 80 mm/s in (O) concentrated polymer solution and in (b) pure solvent.65
4.1. Dragged Motion of λ-DNA One can also analyze the rotational relaxation of
the adsorbed molecules.140 Figure 27a shows a time
Recent developments of optical trapping and fluo- sequence of a single molecule with an overlay of the
rescent labeling techniques allowed detection and unit vector u(t) defined as the direction of the longer
probing of single molecules.65,142 To test the dragged principal axis of the gyration tensor. An instanta-
motion and relaxation of a single macromolecule, the neous polymer configuration may be described by an
end of a fluorescently labeled λ-phage DNA was ellipse, and therefore, the simplest conformational
chemically linked to a latex bead and dragged by change is the rotational motion of an ellipse. The time
means of optical tweezers through an entangled correlation function of u(t) decays exponentially
solution of nonlabeled molecules at velocities from 5 where τr denotes the rotational relaxation time,
to 100 µm/s. As the test chain was pulled or relaxed 〈u(t)u(0)〉 ∝ exp(-t/τr).
through the concentrated polymer solution, it closely As shown in Figure 27c, the rotational relaxation
followed the path of the bead (Figure 26a). The time varies as a power of length, τr ∝ Nµ with µ )
motion through the entanglement network was shown 2.6 ( 0.4. The experimental result is in remarkable
to be much different from the motion in a viscous agreement with the scaling behavior of the rotational
Newtonian fluid, where the chain moved in a direc- relaxation τr ∝ N1+2ν with µtheory ) 2.5, which follows
tion perpendicular to its contour. As the bead was from the Rouse model and the Flory exponent v )
rapidly moved away from the loop, tension in the 3/4.189
chain increased and the loop was pulled tight. When
the bead stopped, the loop recovered to the original
size.
4.3. Stimulated Motion of Monodendron-Jacketed
Polymers
4.2. Brownian Motion of Adsorbed λ-Phage DNA The observation that a macromolecular brush gets
As discussed before for the example in Figure 5, stretched as the side chains get adsorbed on a flat
DNA chains are confined to two dimensions but are surface provides a means to stimulate molecular
free to diffuse laterally if they get adsorbed to a fluid motility by desorption of the brush molecule or a
lipid membrane. The microscopy experiments of the segment of it. If the molecule is in a subsequent
fluorescence-labeled molecules also allowed direct period allowed to relax to the adsorbed stretched
analysis of the chain dynamics, self-diffusion of the state it will eventually do a step forward. This is
molecules, and conformational relaxation as a func- depicted schematically in Figure 28 as a sort of a
tion of the chain length.140 With the exception of a creep motion. Here, the desorbed state might be
number of molecules that showed anomalous diffu- characterized as an excited state whose formation
sion attributed to surface defects, the overall motion requires input of energy. In the case that the struc-
was described by the mean-square displacement ture of the surface and of the molecule favor relax-
linear in time: 〈|Rcm(t) - Rcm(0)|2〉 ) 4Dt. The diffu- ation into a distinct direction, i.e., in the case of an
sion coefficient Dcm (center of mass) decreases in- asymmetric potential, the motion of the molecule can
versely proportional to the length of the polymer as be become directed.
predicted for the dynamical scaling of the Rouse The examples shown in Figures 7, 8, and 11 of the
model, DRouse ∼ N-1, in the absence of hydrodynamic monodendron-jacketed polymers adsorbed on HOPG
interaction.187,188 Fitting of the experimental data demonstrated that these macromolecules orient along
yielded Dcm ∼ N0.95(0.06 (Figure 27b). Hence, the 2D the main axes of graphite. Thus, relaxation by
diffusion is substantially different from DNA three- adsorption according to the scheme in Figure 28 will
dimensional self-diffusion in bulk, where long-ranged be directed along these axes, either forward or
hydrodynamic interaction plays a dominant role.142,189 backward. In particular, if the desorption effects only
4118 Chemical Reviews, 2001, Vol. 101, No. 12 Sheiko and Möller
Figure 27. Dynamical scaling of DNA confined to the surface of a supported lipid membrane. (a) Time sequence (∆t ) 30
s) of a DNA molecule diffusing on a cationic lipid membrane. The image on the right depicts an overlay of 16 images: time
average yields a smeared fluorescence distribution. (b) Scaling behavior of the self-diffusion coefficient of the center of
mass D with the number of base pairs. (c) Scaling behavior of the rotational relaxation time τr with the number of base
pairs.140
Figure 28. Creep motion by contraction upon desorption Figure 29. Chemical structure and phase transitions of
and subsequent stretching upon adsorption of an abstract 12-ABG-4EO-PMA.
molecular object.
a segment of the molecule as depicted in Figure 28, crystal phase to a hexagonal columnar state φh has
it will keep some memory of its original orientation been found at 42 °C. Axial extension by ca. 7% has
toward the substrate and eventually follow this line. been found by X-ray upon transition from the crys-
The examples of the pnBA brushes in Figures 14 and talline to the hexagonal phase.160
23 have demonstrated that the transition between Similar to the other monodendron-jacketed poly-
the stretched and the coiled conformation is particu- mers discussed above, also 12-ABG-4EO-PMA or-
larly pronounced for comb or brush molecules with ders along the main axes of HOPG upon adsorption.
long side chains that adsorb tightly. Combination of Figure 30 shows on the right side a scanning force
both structural features might, thus, be expected to micrograph with a number of single molecules that
allow a creeping step in a preferred direction. have been deposited from dilute solution on HOPG.
Figure 29 depicts the molecular structure of a A scanning force microscope equipped with a tem-
polymethacrylate where each monomer unit has been perature cell enabled in-situ monitoring of the motion
substituted by a tris(p-undecyloxybenzyloxo)benzoate of the single molecules and small molecular clusters
unit via a tetraethylenglycol spacer. From the mol- at elevated temperature.190 The diagram on the left
ecules, which we have been able to study so far, this side of Figure 30 depicts the traces of the molecules
is the structure that suits the model best. For the that were recorded by imaging the sample within
bulk structure a transition from a low-temperature intervals of 4 h 20 min over a period of 12 h at 35
Visualization of Macromolecules Chemical Reviews, 2001, Vol. 101, No. 12 4119
Figure 30. Random walk of single molecules as observed in situ by tapping-mode SFM at 35 °C.
Figure 31. Persistent motion of a small cluster of five 14ABG-4EO-PMA molecules along the terrace of HOPG at 40 °C.
The width of each image corresponds to 486 nm.
°C. The motion patterns are consistent with a random ecules: (i) The diffusion becomes faster upon raising
walk, i.e., a mean square displacement linear in time, the temperature; (ii) smaller molecules or clusters of
〈∆R2〉 ) 4Dt. Evaluation of the time dependencies a few molecules exhibit a higher mobility then larger
yielded diffusion coefficients for each molecule, e.g., ones, (iii) within certain time intervals the molecules
for the five molecules/clusters marked by the num- appear to be tight to yet unknown obstacles on the
bers in Figure 30, the following diffusion coefficients substrate, so that they can only sway around, (iv)
were obtained: D(1) ) 0.01 nm2/s; D(2) ) 0.09 nm2/ some molecules move along a distinct line that is
s; D(3) ) 1.7 nm2/s; D(4) ) 0.04 nm2/s; D(5) ) 0.06 probably a defect in the surface structure of HOPG,
nm2/s. Within the accuracy of the evaluation proce- e.g., a grain boundary, (v) molecules can show an
dure ((0.02 nm2/s) the following trends could be de- increased mobility characterized by a diffusion coef-
duced from the observation of more than 100 mol- ficient that is 10-20 times larger than the average
4120 Chemical Reviews, 2001, Vol. 101, No. 12 Sheiko and Möller
Figure 32. Time variation of (a) the displacement and (b) cluster size during its motion on HOPG at 46 °C. The in-situ-
measured SFM micrographs depict momentary shape and inner structure of the cluster including packing of the molecules
at different intervals after the motion starteds8, 16, and 28 min.
value (see 3 in Figure 30). The two latter observations ordered to a less-ordered structure and vice versa.
can be seen as an indication that the motion can be Systematic variation of the tapping parameters have
guided by the substrate and eventually switch for demonstrated further that the well-ordered structure
some time to a higher “gear”. This, however, will formed after relaxation can be disordered by the
require a mechanism other than Brownian motion. interaction with the probing tip. This occurs without
That the motion can, indeed, change significantly direct displacement of the cluster of molecules. A
was observed for larger clusters of a number of quantitative and more detailed study of this phe-
molecules at further elevated temperature. Figure 31 nomenon is still in progress.
shows a series of six micrographs captured during a
time period of 1 h at a temperature of 46 °C. One 5. Synopsis
can clearly see that a small cluster consisting of ca.
five molecules moves steadily along the terrace of the The examples discussed above demonstrate that
HOPG substrate. The motion started at 46 °C and the complex architecture of hyperbranched and brush-
continued for 60 min until the cluster got trapped in like macromolecules can lead to properties and
the gusset formed by two terraces on the HOPG characteristics in the molecular conformation that
surface. are not known for linear macromolecules. Competing
Besides the remarkable directionality of the mo- effects at different length scales result in very
tion, the images demonstrate also a periodic variation peculiar ordering and transformations. The not yet
of the cluster from an elongated to a circular shape. proven model of a molecular motion demonstrates
The diagrams in Figure 32 depict the time depen- how the interplay of the different interactions and
dence of the displacement and the cluster size. Until elastic forces might be exploited for creating a mo-
the cluster was finally trapped, the speed remained lecular walker. While on one hand the adsorption of
fairly constant, as can be seen from the constant slope the molecules on a flat surface is necessary to
in Figure 32a. The oscillatory variation of the cluster perform SFM studies on macromolecules with mo-
area and shape is shown in the graph in Figure 32b. lecular resolution, the surface interaction also causes,
The motion can be explained according to the on the other hand, a perturbation that can be
coarse model depicted in Figure 28. Although the manipulated in very specific ways. Here we proposed
actual cause of the motility remains unknown, local that the localized interaction of the probing tip of a
perturbations of the molecular structure are believed scanning probe microscope can be exploited to stimu-
to be caused by the mechanical contact with the late macromolecules to move according to their
scanning tip.190 Clearly, the SFM images shown in particular relaxation modes. Other means to apply
Figure 32 demonstrate an alternation form a more- an external field can be considered such as photo-
Visualization of Macromolecules Chemical Reviews, 2001, Vol. 101, No. 12 4121
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Chem. Rev. 2001, 101, 4157−4188 4157
Learning Polymer Crystallization with the Aid of Linear, Branched and Cyclic
Model Compounds
Goran Ungar*,†,‡ and Xiang-bing Zeng†
Department of Engineering Materials, University of Sheffield, Sheffield S1 3JD, U.K., and Venture Business Laboratory, University of Hiroshima,
Higashi-Hiroshima, Japan
Contents
I. Introduction 4157
II. Lamellar Structure and Chain Conformation 4158
A. Early Studies 4158
B. Integer Folded (IF) Forms 4159
C. Noninteger Folded (NIF) Form 4160
D. Fold- and End-Surface 4163
E. Chain Tilt 4166
F. Cyclic Oligomers 4168
G. Oligomers with Specific Endgroups 4169
H. Monodisperse Block Copolymers 4170
I. Branched Oligomers 4171
J. Binary Mixtures 4173
III. Crystallization Process and Morphology 4175 Goran Ungar obtained his first degree and masters degree from the
A. Stepwise Growth Rate vs Temperature 4175 University of Zagreb, Croatia. In 1979, he obtained his Ph.D. from
Gradient University of Bristol, England. His thesis was on radiation effects in
polymers, under the supervision of Professor Keller. After spending several
B. Crystallization Rate Minima and Negative 4175 years at Ru]er Bošković Institute in Zagreb and at University of Bristol,
Order Kinetics he moved in 1989 to University of Sheffield where he now holds the post
C. Crystallization and Morphology 4178 of Reader in the Department of Engineering Materials. His research
D. Lamellar Thickening 4181 interests are crystalline polymers, structure, and physical properties of
E. Implications for Polymer Crystallization 4182 liquid crystal polymers, liquid crystals, and supramolecular assemblies.
Theory
IV. Conclusions 4185
V. List of Symbols and Abbreviations 4186
VI. Acknowledgments 4186
VII. References 4186
I. Introduction
It is now universally accepted that polymers with
reasonably flexible chains crystallize as thin lamellae
with chain folding (see schematic drawing in Figure
1). A crystalline lamella is the basic morphological
unit which, in the case of melt-crystallized polymers,
is the building block of larger structures such as
spherulites, row-structures, transcrystalline layers, Xiangbing Zeng was born in 1971, P. R. China. He graduated in 1992
etc. The reason that polymer crystals are thin is from the University of Science and Technology of China. He received his
entirely kinetic; a thin crystal grows faster than a M. S. degree in condensed matter physics in 1995 at the Institute of
thick one, as the addition of short straight stretches Physics, Chinese Academy of Sciences. He received his Ph.D. degree in
2001 at the University of Sheffield. He studied lamellar structures in pure
of flexible chains presents a lower entropic barrier and mixed long chain n-alkanes and derivatives under the supervision of
than the addition of long extended chains. Folding Dr. G. Ungar. He is working as a Research Assistant in the Department
is a necessary accompaniment to lamellar morphol- of Engineering Materials, University of Sheffield. His main research interests
are polymer crystal structure, scattering methods, polymer crystallization
* To whom correspondence should be addressed. Phone: (44) 114 and polymer physics.
222 5457. Fax: (44) 114 222 5943. E-mails: [email protected].
† Department of Engineering Materials. ogy. Thus, it is kinetics driven, unlike the folding in
‡ Venture Business Laboratory. proteins, which is thought to be thermodynamically
10.1021/cr990130u CCC: $36.00 © 2001 American Chemical Society
Published on Web 11/20/2001
4158 Chemical Reviews, 2001, Vol. 101, No. 12 Ungar and Zeng
fundamental polymer parameters such as equilibri- librium melting temperature of an ideal polymer
um melting point and ultimate elastic modulus of a crystal, though fundamentally important in crystal-
polymer. lization, cannot be determined directly. Instead, it is
Raman spectra of certain crystalline polymers and often obtained by extrapolation to infinite chain
their oligomers show a series of identifiable LAM length of melting points of a series of extended-chain
bands in the low-frequency region, corresponding to oligomers. Early extrapolations were based on the
symmetrical longitudinal backbone vibration modes. presumption that both the enthalpy and entropy of
In the simplest approach, the stem is considered as fusion were linear in the number of repeat units n
a continuous elastic rod, the frequency of the vibra- per chain.48,19 However, in their analysis of melting
tion being35 points of alkanes C11H23 to C100H202, Flory and Vrij12
suggested that a nonlinear term R lnn be included
j E 1/2
νj ) ()
2ls F
(1) in the entropy of fusion to account for the “unpairing”
of chain ends upon melting of the crystal. Their
extrapolation leads to a 4 K increase in the equilib-
where E is Young’s modulus of the chain, F the rium melting point of polyethylene (from 414.5 to
density, and j the vibration order (only odd orders 418.5 K), but the quality of fit was hardly improved
are Raman active). The fact that LAM frequency is compared with previous equations19 as pointed out
inversely proportional to the straight stem length ls by Wunderlich.13 The validity of the term R lnn is
makes this a valuable technique for studying polymer supported by studies on PEO fractions,49 while
morphology. Extended chain monodisperse oligomers evidence for it is not clear in long-chain ketones.50
are ideal for testing eq 1,36-38 and finding the value The melting points of long alkanes with 150 < n <
of E, since ls ) L. Although eq 1 has been commonly 390 were found to be consistently lower than pre-
used in the past, weak interlamellar forces result in dicted by Flory’s theory.31,33 This has been discussed
an upward shift of ν. Thus according to Strobl et al.,39 in terms of the premelting effect.51 Assuming a
who studied alkanes CnH2n+2 with 33 e n e 94, constant entropy change due to premelting, Carlier
et al. found a linear relationship between the melting
2236j 2.2 points Tm of oligomers and the value (lnn + C)/n
νj ) + (2)
n - 1.6 j where C is a constant.52 These authors have carried
out extrapolations for polyethylene (11 < n < 390),
The associated elastic modulus of polyethylene is E poly(tetrafluoroethylene) (5 < n < 24), poly(methyl-
) 290 GPa. However, the critical test of eq 2 is in eneoxide) (4 < n < 22), poly(ethylene oxide), poly-
the ls f ∞ region. The results for long extended-chain (etheretherketones) (PEEK, 1 < n < 4), and poly-
alkanes up to C294H590 were at variance with eq 2 and (phenylene sulfide) (PPS, 1 < n < 7). Studies of
obeyed the simple ν1 f ∝ 1/n law, with ν f 0 as ls f melting points of folded-chain PEO fractions have
∞ and with E ) 350 GPa.40,41 Recent experiments shown that, for a given fold length l, the melting point
point to end-surface disorder as a possible cause of increases with increasing total chain length L, i.e.,
the discrepancy. In the longest pure alkanes, very with increasing number of folds per chain.53 End- and
slow crystallization from the melt is needed in order fold-surface free energies for PEO were derived.
to create a highly ordered end-surface; this was found These parameters were also derived for polyethyl-
to result in higher ν than the more rapid crystalliza- ene,54,55 using melting point data for different IF
tion.42 Furthermore, alkane mixtures give lower ν forms of n-alkanes.33 Melting points of monodisperse
than pure alkanes. The above discrepancy is thus linear and cyclic oligo(oxyethylenes) were found to
possibly due to the lack of surface order in the longest be in general agreement with the Flory-Vrij expres-
alkanes used in previous studies. That surface dis- sion, provided “segment” and “repeat unit” were
order has a noticeable effect is also borne by the appropriately defined.126
observation by Khoury et al.43 that the LAM fre-
quency of n-C36H74 and n-C94H190 is affected by end C. Noninteger Folded (NIF) Form
group packing; the effect was attributed to differences
in methyl end group interaction. While mature alkane crystals show a strong ten-
While the interlamellar forces in n-alkanes are dency for integer folding, when melt crystallization
weak and their contribution to the LAM frequencies was monitored in real time by SAXS using synchro-
is small, in systems with strongly interacting chain tron radiation, it was found that below the extended-
ends the effect can be very pronounced.44 For ex- chain growth temperature region the initial lamellar
ample, while in n-alkanes, the ratio ν3/ν1 is around periodicity l was a noninteger fraction of L, even after
2.8, quite close to 3 as expected from eq 1, ν3/ν1 is correcting for tilt.56 It corresponded to a fold length
only 2.1-2.3 for monodisperse oligo(oxyethylenes) between L and L/2 and was dependent on crystal-
and PEO fractions.45,46 In PEO fractions, this effect lization temperature Tc and time. These “noninteger
makes it difficult to distinguish between LAM-3 of folded” (NIF) lamellae subsequently transformed
the extended chain conformation and LAM-1 of the isothermally by thickening to extended-chain or, at
once folded chain, and peak assignment must be lower Tc, by “thinning” to once-folded (F2) chain
made with caution. The helical conformation of PEO lamellae with hairpin chain conformation. In Figure
accounts for its low elastic modulus (25 GPa), as 5a the real-time SAXS recording of isothermal crys-
obtained from LAM frequencies.47 tallization of C246H494 shows the rapid emergence of
Linear oligomers have been used extensively in the NIF marked by the strong first-order peak. This is
determination of polymer melting points. The equi- followed by its demise and concurrent replacement
Learning Polymer Crystallization Chemical Reviews, 2001, Vol. 101, No. 12 4161
( )
ness, with added loops rather than cilia forming the
la la noncrystalline phase responsible for high SAXS
Q) 1 - (∆η)2 (3)
l l intensity. Electron density reconstruction may help
Learning Polymer Crystallization Chemical Reviews, 2001, Vol. 101, No. 12 4163
Table 1. Parameters of Inter-crystalline Layer for Extended (E) and Once-Folded (F2) Chain Long Alkanes
Derived from SAXS
integral width of
electron deficiency width of interlayer from interlayer (la)
temp per unit area of κ assuming noncrystalline (from Fourier
sample form (°C) interlayer, κ (electron Å-2)a density ) 0.85 g cm-3 (Å)a synthesis) (Å)
C194H390 or C198H398
melt-crystallized E rt 0.66 13 15b
120 26b
solution-cryst F2 rt 0.40 8 17c
C246H494
melt-crystallized E rt 0.66 13 26b
122 32b
F2 rt 0.73 14.5 18c
linear polyethylene
melt-crystallized rt 2.4 48
a Using absolute intensity SAXS data.76 b From ref 75. c From ref 77.
folded n-alkanes and cycloalkanes at room temper- Small ring oligomers of several other polymers
ature). Low-temperature spectra of cycloalkanes have have been synthesized, and their crystal structures
not been reported. The calculated energy of a model determined. Thus, relevant to the industrially im-
{110} fold (20.4 kJ/mol) is somewhat higher than that portant cyclic impurities in poly(ethylene terephtha-
of a {100} fold (16.3 kJ/mol).115 This is consistent with late) (PET), the structures of the low-temperature129
the smaller rings being monoclinic and larger rings and the high-temperature130 modifications of cyclic
orthorhombic. It would appear that stem packing PET trimer have been determined. The structure of
favors the orthorhombic form while folds favor the cyclic dimer of poly(butylene terephthalate) (PBT)
monoclinic form. has also been determined131 in order to help under-
A detailed solid-state 13C NMR study on c-(CH2)12, stand a mechanically induced polymorphic transition
c-(CH2)24, and c-(CH2)36 has been carried out resulting in the parent polymer. Limited crystallization work
in the assignment of chemical shifts for a number of has been done on the otherwise extensively studied
rotational isomeric sequences in alkanes.117 Chemical cyclic oligosiloxanes;132 the object was “cold crystal-
shifts for carbons at the center of sequences gtgg, gttg, lization” near the glass transition temperature.
ggtt, tggt, gttt, and tttt were identified. The assign- Cyclic main-chain liquid crystal oligomers have
ments were based on low temperature spectra, since been shown to display a number of crystalline poly-
at higher temperatures the cycloalkanes investigated morphs in addition to smectic and nematic phases.133
transform into highly conformationally disordered These collapsed rings have rigid mesogens in their
crystals with a pseudohexagonal structure.118,119 In “stems” while folds form selectively in the flexible
terms of enthalpy and entropy, as well as number of spacer. Significant difference between even and odd-
nonplanar conformers, this “mesophase” is closer to membered rings are seen, particularly where the
the melt than to the ordered crystal. It has therefore flexible spacer is short.
been compared to the high-pressure hexagonal meso-
phase in polyethylene, rather than to the “rotator” G. Oligomers with Specific Endgroups
phase in linear alkanes with n e 40.120
Prior to the synthesis of long n-alkanes in 1985,
Even in the largest cyclic alkane synthesized, the narrowest molecular weight distribution achieved
c-(CH2)288, only the “extended” ring conformation has in paraffinoid chain systems in the 100-400 C-atom
been observed, i.e., the two stems constituting the range was R,ω-dicarboxylic acids produced by selec-
collapsed ring did not fold further.31 tive oxidation of solution-grown polyethylene single
Cyclic PEO has been prepared in two ways: (a) crystals. Nitric acid or ozone treatments134 were
with narrow PEO fractions as starting material, applied to remove the fold layer, and the length of
using ring closure Williamson reaction121,122 and (b) the remaining alkanoic diacid was determined by the
as monodisperse rings, effectively large unsubstituted thickness of the original crystalline layer; this, in
crown ethers.123-126 The largest monodisperse ring turn, could be controlled by the choice of crystalliza-
prepared and used in crystallization studies was c-E27 tion or annealing temperature. The carboxylic end
(E ) CH2CH2O), or 81-crown-27. In the latter case, groups have also been reduced, resulting first in R,ω-
the two stems of the collapsed ring were found to dibromoalkanes and, finally, alkanes. While crystal-
have the same helical tgt conformation and the same lization studies on alkanes thus produced have not
monoclinic subcell as linear PEO chains.125 In con- been reported, both the long diacids and dibromides
trast, smaller rings show a different crystal struc- showed only continuous change of long spacing with
ture.124 The boundary was found to lie between c-E16 crystallization temperature.134
and c-E18.126 The melting points of the ring com- Most linear oligomers can be regarded as having
pounds were significantly higher than those of their “special” end-groups, and as stated at the beginning,
linear analogues, an effect attributed to a decreased one of the reasons for synthesising long alkanes was
melting entropy. the similarity of end groups with the bulk of the
Rings prepared from commercial PEO fractions had chain. In a number of studies of PEO fractions, which
Mn up to 10000 (equivalent to c-E227).122 SAXS and are normally OH-terminated, methoxy-terminated
Raman LAM measurements showed that for Mn ) equivalents (MPEO) were also examined for com-
6000 such cyclic polymers crystallize as collapsed parison. Thus, it was found that crystallization is
rings forming layers, as in the case of the large crown more rapid in MPEO compared to that in PEO and
ethers and cycloalkanes (see Figure 21a). However, that the same is true for subsequent transformation
the cyclic polymer of Mn ) 10 000 crystallized in a of NIF into IF forms.34 OH groups show a degree of
folded conformation when cooled from its melt at hydrogen bonding, as evidenced by IR spectroscopy.
moderate rates. That is to say, each stem of the The self-diffusion coefficient of MPEO in the melt was
collapsed ring was folded again in two (see Figure found by spin-echo NMR measurements to be higher,
21b). When the Mn ) 10 000 sample was crystallized by a factor of 1.17, than that of PEO, although the
slowly at a high temperature, the conformation of the activation energies were the same.
extended collapsed ring (Figure 21a) was obtained. There has been some evidence from TEM135 and
A Raman study has shown that LAM-1 frequencies Raman45 that hydroxy-terminated PEO fractions
of cyclic PEOs in the range 1000 < Mn < 3000 are form double-layer crystals, but doubts have been
only 1.8 times higher than those of their linear expressed subsequently.38 End-group interaction in
counterparts.127 This is in contrast with cycloalkanes, low-molecular weight PEO fractions certainly has a
where the LAM-1 frequency of c-(CH2)n is nearly pronounced effect on LAM frequency. The following
exactly twice that of linear CnH2n+2.128 two linear relationships were found between the
4170 Chemical Reviews, 2001, Vol. 101, No. 12 Ungar and Zeng
frequency of LAM-1 mode (in cm-1) and reciprocal Figure 23. SAXS traces (Lorentz corrected intensities vs
q) of n-C191H385COOH recorded during cooling an already
chain length (in Å):38 partially crystallized sample at 0.3 °C/min from 132 to 112
°C. Bragg spacings corresponding to the observed peak
PEO: ν1 ) 1161.1 L-1 positions, recording temperatures and diffraction orders of
the bilayer phase are marked (from ref 137 by permission
of American Chemical Society).
MPEO: ν1 ) 1094.7 L-1
Table 3. Comparison of Melting Points of the Two Lamellar Forms of n-Alkanoic Acid C191H393COOH with Those
of Integer Forms of Alkanes C194H390 and C390H782 (ref 138)
compd form Tm (°C) form Tm (°C)
C194H390 extended 126.2 ( 0.3
C191H393COOH monolayer 130.0 ( 0.5 bilayer 131.9 ( 0.3
C390H782 once-folded 129.0 ( 0.3 extended 132.0 ( 0.3
Figure 25. Schematic drawing of different lamellar amorphous layer (Figure 25b). At low Tc, another
structures observed in asymmetric methyl-branched alkane semicrystalline form is obtained. Here lc is smaller
C191H383CH(CH3)C99H199 (a); (b) semicrystalline form ob- and is determined by the length of the shorter arm.
tained at high Tc; (c) double layer crystalline form obtained As shown in Figure 25d, the extended shorter arm
from panel b on cooling; (d) semicrystalline form obtained and part of the longer arm may contribute to the
at low Tc; (e) triple layer crystalline form obtained from crystalline layer, with the remainder of the long arm
panel d on cooling. Chain tilt is neglected in this and Figure
26, for simplicity (from ref 151). staying in the amorphous layer.
When either of the semicrystalline forms of the
asymmetric alkane are cooled, they transform to a
believed to be due to the initial preference for double-layer and a triple-layer crystalline structure,
“correct” chain attachment dictated by the exclusion respectively. These 1-d superlattices are described as
of the branch to the lamellar surface. ABAB... and ABAABA... stacks of crystalline layers
The above butyl-branched alkane was studied by as depicted in Figure 25, panels c and e. Note that
solid-state 13C NMR, alongside its linear analogue the structure in Figure 25e is related to the mixed
C198H398, to establish the solid-state diffusion coef- integer “folded-extended” structure in some pure
ficient.150 Both alkanes were in the once-folded form. n-alkanes (Figure 7c) and in binary mixtures of long
The progressive saturation experiments have shown n-alkanes (Section II.J, Figure 30b).
that the longitudinal relaxation of magnetization is Y-shaped alkane C120H241CH(C61H123)C119H239, which
consistent with a solid state chain diffusion process. has two long and one shorter arm (Figure 26a), has
Reptation and one-dimensional diffusion models were also been prepared105 and investigated.151 A semi-
demonstrated to satisfactorily represent the data. crystalline structure was found in the high-temper-
The addition of the branch to the alkane chain was ature region, with the crystalline layer thickness
shown to result in a decrease in the diffusion coef- being determined by the length of the long arms.
ficient, which ranged from 0.0918 nm2 s-1 for the From the thickness of the amorphous layer la it was
linear chain to 0.016 nm2 s-1 for the branched chain. concluded that some molecules have both their long
These diffusion coefficients are consistent with those arms crystallized, but others have only one crystal-
of polyethylene. lized, the other two remaining in the amorphous
Asymmetrically methyl-branched alkane C191H383- layer (see Figure 26b). A double layer crystalline
CH(CH3)C99H199 (Figure 25a), synthesized recently,105 superstructure is formed in a transition on subse-
has been studied by real-time SAXS.151 The com- quent cooling, with one layer containing only long
pound can be crystallized in two different semicrys- arms of the molecules and the other layer containing
talline forms, depending on crystallization temper- both extended short arms and folded long arms (see
ature Tc. Electron density reconstruction has shown Figure 26c).
that in each case the structure consists of alternating From the observations on branched PEO and
crystalline and amorphous layers with respective alkanes more general conclusions can be drawn about
thicknesses lc and la (lc + la ) l). In the first form, the overcrowding problem at the crystalline-amor-
obtainable only at high Tc, the longer arm of the phous interface in polymers and about the mecha-
alkane crystallizes as extended chain, while the nism of chain deposition during crystal growth. Thus,
shorter arm remains as a cilium, contributing to the e.g., although for the Y-shaped alkane the energeti-
Learning Polymer Crystallization Chemical Reviews, 2001, Vol. 101, No. 12 4173
Figure 32. Temperature dependence of growth rate GH for the creation of the two new surfaces either side
of {010} faces of single crystals and GR of spherulites for of the single-stem nucleus; here b is the chain width
five low molecular weight fractions and a polymer of PEO and σ the side surface free energy. For polymer
(from ref 28 by permission of John Wiley & Sons.). crystals of fixed fold length l, the slope dG/d(∆T)
should be constant within the limited temperature
thickness of the basic layer unit is determined by the interval that is accessible for studying.184 Indeed,
length of the shorter C122H246 chain.61 when plotted on a linear scale, the growth rates G
vs ∆T dependence in Figure 32 does not deviate much
III. Crystallization Process and Morphology from linearity for a given m.185 However, linear G vs
∆T is also consistent with the alternative polymer
A. Stepwise Growth Rate vs Temperature crystallization theory, the so-called “roughness-pin-
Gradient ning theory” of Sadler.185,186 According to this theory,
the difference between nucleation and growth of
Studies on PEO fractions in the molecular weight molecular layers on the growth face is negligible and
range between 1500 and 12 000 have shown28 that the growth surface is rough rather than smooth (see
the slope of the increasing crystal growth rate with Section III.E).
supercooling dG/d(∆T) increases sharply at a series On closer scrutiny the crystal growth data for PEO
of specific crystallization temperatures Tcm (m ) 1, fractions deviated somewhat from those expected
2, 3, ...). These mark the transitions between the from secondary nucleation theory; there were depar-
growth of crystals with m-1 and m folds per chain. tures from linearity of G vs ∆T near the Tcm transi-
Figure 32 shows the temperature dependence of the tion temperatures,185-188 and the value of σ derived
growth rate from the melt normal to the {010} lateral from the kinetics was unrealistically low.187
face for five low molecular weight fractions and a
polymer (note the log rate scale). The breaks in the B. Crystallization Rate Minima and Negative
slope at Tcm are particularly pronounced in low Order Kinetics
molecular weight fractions and are completely lost
in the polymer. The existence of such sharp increases Crystallization rate experiments on monodisperse
in dG/d(∆T) is, at least qualitatively, entirely predict- n-alkanes have shown a rather different picture. Not
able by the secondary nucleation theory once quan- only is there a sharp increase in dG/d(∆T) at the
tization of lamellar thickness is accepted.18 The transition between extended and once-folded (or NIF)
supercoolings at which growth transitions occur, crystallization mode (Tm)1c ) but the dG/d(∆T) gradi-
relative to the melting point of extended chains, are ent actually becomes negative as Tm)1c is approached
given by from above.18 This was found to occur both in crystal-
lization from melt189 and from solution,190 and it
2σe(∞)Tm applies both to crystal growth and primary nucle-
∆Tcm )
∆hf (mm+ 1)/[(m L+ 1) - δ] (5) ation.191 Figure 34 shows the way G passes through
a maximum and reaches a sharp minimum at the
Here σe(∞) is the fold-surface free energy for L ) ∞, transition from extended to once-folded chain crystal
and ∆hf is heat of fusion. δ is a small constant, growth of C198H398 from solution for two different
reflecting the fact that some finite supercooling is concentrations.192 The rate minimum at Tm)1 c has
required for crystal growth (see Section III.E). Equa- been observed in a number of alkanes from C162H326
tion 5 can be used for the determination of accurate to C294H590.193-196 In alkane C294H590, where crystal-
σe(∞) for the parent polymer. lization rate from solution is sufficiently low for
According to the secondary nucleation theory, Tm)2
c to be accessible, a crystallization rate mini-
polymer crystals grow by deposition of layers of stems mum has been observed between the once-folded and
on the side surface of the lamella183 (see Figure 33). twice-folded growth intervals.197 A weak minimum
Each new layer needs to be nucleated (“secondary” at Tm)1
c has also been reported in melt-crystalliza-
or surface nucleation), after which it spreads com- tion of a methyl-terminated PEO fraction.198
paratively rapidly. The main barrier to secondary The negative dG/d(∆T) observed in alkanes has
nucleation is the excess side surface free energy 2blσ been attributed to an effect termed “self-poisoning”.189
4176 Chemical Reviews, 2001, Vol. 101, No. 12 Ungar and Zeng
be explained by most theories. Thus, e.g., the free Several significant developments in polymer crys-
energy barrier is roughly linear in l in both LH theory tallization theory have been made more recently, e.g.,
()2lbσ), as well as in the fine-grain theories of Point the two-dimensional nucleation and sliding diffusion
and Sadler (-sT ) kT ln(w)-1, where w = pn, p being theory of Hikosaka,231 the two-stage crystallization
the number of conformers per segments and n the model by Strobl,232 and a number of simulation
number of segments in a stem; hence -sT ∝ n ∝ l). studies have been carried out and are in progress.
Experimental results on monodisperse model poly- Past and future experiments on model compounds
mers therefore provide much needed further tests for will undoubtedly benefit these developments.
the theories. The self-poisoning minimum in particu-
lar can be regarded as one of the key probes, IV. Conclusions
alongside the δl catastrophe and the curved crystal
faces. As it happens, in the course of their rate Research on model compounds and sharp oligomer
equation analysis Sadler and Gilmer included in their fractions has already had a profound effect on our
investigation a model with certain energetically understanding of polymer crystallization and mor-
preferred stem lengths and indeed observed minima phology. The availability of monodisperse polymers
in growth rate vs ∆T.199 Since no such effect had been removes the dependence of this field of science on
observed at the time, the work remained unpublished essentially impure multicomponent experimental
until the experimental results on alkane C246H494 systems. It also helps close the gap between polymer
became available.189 The subsequent theoretical and science and mainstream chemistry and physics.
simulation analysis of the ∆T 200 and concentration192 The list of achievements made possible with the
dependencies of alkane growth rate was based on aid of model compounds includes (1) discovery of
Sadler’s model. In our opinion, only fine grain theo- integer folding, stepwise lamellar thickening, crystal
ries can describe the minimum. An attempt to growth rate transitions, separation of the effects of
interpret it in terms of the coarse-grain LH theory230 temperature and crystal thickness in crystallization
had to resort to highly unusual Arrhenius-type terms kinetics; (2) visualization and elucidation of the
and could be disputed on other grounds.210 The topology of lamellar thickening, taking advantage of
chances are that Point’s model might also predict the the enhanced quantized thickness contrast; (3) ob-
minimum if applied to monodisperse chains; up to servation and structural characterization of transient
now, this has not been tested. However, it is almost noninteger folding and of the subsequent transfor-
certain that neither the roughness-pinning theory nor mations, new insights into primary chain deposition,
Point’s model would predict crystal shapes correctly, ciliation, and subsequent rearrangements, of rel-
the former because it fails to distinguish between evance to secondary crystallization in polymers; (4)
nucleation and growth. On the other hand, Point’s new 1-D superlattices in mixed long chains, unex-
original fine-grain treatment would not be able to pected stability of semicrystalline structures, and
explain the minimum in v, such as that in Figure 42, experimental determination of the extent of over-
because it only applies to nucleation and not to crowding at the crystal-amorphous surface; (5) the
growth of new layers. role of cilia in pure and binary systems, the effect on
As mentioned in Section III.C, the fact that the lamellar branching and spherulite growth; (6) the
temperature dependence of crystal habits in polyeth- discovery of self-poisoning and its unusual conse-
ylene is an almost exact reversal of that in alkanes quences for crystallization kinetics, the resolution of
approaching the rate minimum is an indication that the effect on the deposition of the first and subse-
self-poisoning is present in crystallization of the quent stems, discovery of poisoning by shorter chains,
polymer and that it is more pronounced at higher the likely effect of self-poisoning on crystallization
temperatures. Figure 43 tentatively describes the row and morphology of polymers; (7) elucidation of the
of stems normal to a self-poisoned surface in a nature of the fold surface and end surface, determi-
polymer crystal. The situation is the same as that nation of the spectral bands due to folds (IR, Raman,
envisaged by Sadler. However, Figure 43 could NMR), and new insights into chain tilt and surface
equally apply to a layer of stems parallel to the disorder; (8) improved understanding of the effect of
surface, in which case it would describe retardation chain length and lamellar thickness on melting point
in v, a case not considered by Sadler. Paradoxically, and Raman LAM frequency, derivation of improved
it is the exact shape of rounded crystals of alkanes values for equilibrium melting point and Young’s
and polyethylene that point indirectly to poisoning modulus of polymer chains; (9) better understanding
of polymer crystal faces and the similarity with of end-group effects and bilayer formation; and (10)
Sadler’s model. However, we now know that this of the effect of specific chemical defects and short and
model was conceived by mistakenly associating the long branches on the crystallization process and the
rounding with nonnucleated growth. At this juncture, resulting structure.
it would appear that a synthesis of Sadler’s model There is ample scope for future research. For
and the nucleation theory could come close to ex- example, new monodisperse oligomers are currently
plaining most experimental observations in polymers being contemplated, notably aromatic and model
as well as in monodisperse model compounds. A biopolymers. Deuterium-labeled long alkanes are
similar outcome may potentially be expected from being studied by neutron scattering and NMR. Fold
Point’s theory, extended to include fine-grain treat- surfaces of IF crystals, devoid of amorphous over-
ment of layer completion. layer, may be amenable to studies by different
4186 Chemical Reviews, 2001, Vol. 101, No. 12 Ungar and Zeng
surface techniques. Primary nucleation and high- (2) Keller, A. In Sir Charles Frank: An Eightieth Birthday Tribute;
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Chem. Rev. 2001, 101, 4125−4155 4125
quantum (DQ) MAS experiment,34 it has recently As has been stressed above, an important aspect of
been demonstrated that the semiquantitative infor- this review is to highlight the importance of 1H solid-
mation about specific proton-proton proximities state NMRsthis is reflected in the chosen applica-
yielded by rotor-synchronized 2D spectra allows the tions, which illustrate the valuable structural infor-
differentiation between distinct hydrogen-bonding mation gained on account of the marked sensitivity
structures21 as well as the identification of particular of the 1H chemical shift to hydrogen-bonding and
aromatic π-π packing arrangements.22,24 Moreover, aromatic π-π effects. In addition, the ability to probe
it has further been shown that an analysis of rotor- dynamic events, such as the making and breaking
encoded 1H DQ MAS spinning-sideband patterns35,36 of hydrogen bonds as well as guest mobility in a
enables the quantitative determination of the inter- supramolecular complex, is demonstrated.
nuclear distance for a well-isolated pair of aromatic
protons in a hexabenzocoronene derivative in the II. Improving the Resolution in 1H Solid-State
solid phase as well as the order parameter of the NMR
liquid-crystalline (LC) phase.22 In addition, attention
has focused on the development of methods suitable Table 1 lists the NMR-active nuclei (i.e., those with
for the measurements of heteronuclear dipolar cou- I > 0) of most relevance for organic solids, together
plings between protons and other spin I ) 1/2 nuclei
(i.e., 1H-13C and 1H-15N).37-40 Table 1. Properties of the NMR-Active Nuclei of Most
Relevance for Organic Solids
As indicated by the opening paragraphs, the em-
nucleus I γ/107 rad T-1 s-1 natural abundance/%
phasis of this review is on advanced solid-state NMR
1H
experiments suitable for providing insight into the 1/2 26.8 99.99
2H
1 4.1 0.02
mechanisms of self-assembly which are of much 13C
1/2 6.7 1.10
relevance in modern polymer science. As such, we 14N 1 1.9 99.63
restrict our attention to the spin I ) 1/2 nuclei found 15
N 1/2 -2.7 0.37
in organic solids, in particular, 1H and 13C, and focus 17O 5/2 -3.6 0.04
19F
on recently developed, i.e., within the last 10 years, 1/2 25.2 100.00
solid-state NMR methods that probe the structural
29Si
1/2 -5.3 4.67
31P
1/2 10.8 100.00
and dynamic information inherent to the dipolar
coupling. Importantly, we will show that 1H NMR of
rigid solids is now feasible. with their nuclear spin quantum numbers, their
We note that the considerable progress made in magnetogyric ratios (γ), and natural abundances.46
solid-state NMR of half-integer quadrupolar nuclei, The low natural abundance of the nuclei 2H, 13C, 15N
e.g., 23Na, 27Al, and 17O, as a consequence of the explains why selective isotopic labeling is successful
introduction of the MQMAS experiment by Frydman in these cases. Moreover, the central importance of
and Harwood in 1995,41 falls outside the scope of this protons in solution-state NMR is evident from Table
review. In addition, it is to be remembered that the 1: a near 100% natural abundance is combined with
NMR experiments we describe are equally applicable the highest magnetogyric ratio (and hence best
to biological molecules; indeed, much of the recent sensitivity) of all naturally occurring nuclei. It is,
development of solid-state NMR methodology, e.g., however, exactly this combination that makes solid-
the experiments for determining torsional angles,16,17 state 1H NMR problematic.
has been stimulated by the considerable interest in The dipolar coupling constant, D, defining the
biological systems. Reviewing the biological applica- dipolar coupling between two nuclei is given by
tions is, however, not an aim of this review, although
a few relevant examples will be mentioned. To (µ0/4π)pγIγS
D) (1)
further specify the scope of this article, as far as the r3
probing of dynamics is concerned, we will only
consider methods suitable for probing fast processes. where r denotes the internuclear separation. The
Thus, recently developed methods, such as one- dependence of D on the product of the magnetogyric
dimensional exchange spectroscopy by sideband al- ratios of the two nuclei means that the dipolar
ternation (ODESSA),42 time-reverse ODESSA,43 and coupling constant for two 1H nuclei is a factor of
centerband-only detection of exchange (CODEX),44,45 approximately 16 times larger than that for a pair
which are capable of probing slower dynamics (time of 13C nuclei at the same separation. As an example,
scales ranging from milliseconds to seconds), will not the 1H-1H D in a CH2 group (assuming r ) 0.18 nm)
be discussed. is 20 kHz, which is about twice the typically encoun-
To give an outline of the structure of the review, tered chemical shift range (15 ppm) at today’s largest
the main body is divided into two parts: first (in solid-state NMR magnets (corresponding to 1H Lar-
sections II-IV), the NMR experiments will be intro- mor frequencies of 700-800 MHz), and is much
duced, and, second (in sections V-VIII), specific larger than the through-bond J couplings which
applications will be described, which illustrate what characterize solution-state spectra.
structural and dynamic insight can be provided. A major difference between the through-space
These specific applications can be considered to be dipolar and through-bond J couplings is that the
case studies, which illustrate how a particular system former is an anisotropic rather than an isotropic
can be approached experimentally, with the meth- interaction. This means that the dipolar coupling
odology being extendable to other organic systems. between a pair of nuclei depends on the orientation
4128 Chemical Reviews, 2001, Vol. 101, No. 12 Brown and Spiess
of the internuclear vector with respect to the direction as the other anisotropic interactions. To achieve high
of the static magnetic field, B0. Specifically, the resolution, the solid-state NMR spectroscopist would
dipolar coupling is proportional to (3 cos2θ - 1), like to mimic this averaging process. First, we note
where θ is the angle between the internuclear vector that anisotropic interactions such as the dipolar
and the B0 direction. For a powdered sample, there coupling between a pair of nuclei, the CSA, and the
is a uniform distribution of orientations, and thus the first-order quadrupolar interaction all have an ori-
NMR spectrum consists of a superposition of many entation dependence that can be represented by a
lines, corresponding to the different dipolar couplingss second-rank tensor.8-10 For such interactions, rather
such a powder spectrum is referred to as being than requiring an isotropic motion, a physical rota-
anisotropically broadened.8-10 tion of the sample around an axis inclined at an angle
In organic solids, protons are ubiquitous, and an of arctan(x2) ) 54.7°, the so-called magic angle, to
extensive network of dipolar-coupled protons existss the external magnetic field suffices.49,50 That this is
in so-called spin-counting experiments, clusters of so can be understood by considering that sample
over 100 dipolar-coupled protons can be identified.47,48 rotation around a single axis leads to the components
As shown in Figure 1, the static 1H NMR spectrum perpendicular to the rotation axis being zero on
of a typical organic solid is simply a broad featureless average, and only the component parallel to the
hump. The striking difference to the corresponding rotation axis remains nonzero on average. Thus, in
1H solution-state NMR spectrum is evident. It should
a powdered sample, for any orientation of, e.g., the
be stressed that the problem in the former case is internuclear vector for a pair of dipolar-coupled spins,
not a lack of information, but rather there is es- rotation around an axis yields an “average orienta-
sentially an overload, such that the net effect is the tion” parallel to the axis of rotation. Under MAS, this
virtual loss of all information. The challenge facing parallel component has an anisotropic frequency
the solid-state NMR spectroscopist is then how can equal to zero for all cases, and the anisotropic
experiments be designed that combine high-resolu- broadening is averaged to zero for all crystallite
tion, i.e., a recovery of the chemical shift resolution, orientations.
with the preservation of the valuable information A familiar example of the application of MAS is 13C
inherent to the anisotropic interactions, i.e., for 1H NMR, where the combination of 1H-13C cross-polar-
NMR, the structural and dynamic information inher- ization (CP)51,52 with MAS, CP MAS NMR53, is
ent to the dipolar coupling. routinely used to investigate a wide range of systems.
Under the application of high-power proton decou-
A. Magic-Angle Spinning pling, the dominant anisotropic broadening is the
CSA; in this case, as illustrated by the simulated
On account of its angular dependence, molecular spectra in Figure 2, the static line shape breaks up
motion leads to an averaging of the dipolar coupling; into a centerband and spinning sidebands, whose line
as will be shown later, determining the reduction in widths are narrow and independent of νR. A full
the dipolar coupling allows the identification of mathematical treatment of MAS and anisotropic
particular dynamic processes. The extreme case is interactions can be found in, e.g., refs 8, 9, 54, and
found in solution, where fast isotropic tumbling of 55.
the molecules leads to the averaging to zero of the The effect of MAS on a dipolar-coupled multiproton
line broadening due to the dipolar couplings as well network is quite different. Figure 3 shows the effect
NMR for Elucidation of Structure and Dynamics Chemical Reviews, 2001, Vol. 101, No. 12 4129
homogeneous dipolar broadening, with MAS being sample volume is restricted by the application of a
required to deal with the CSA. static magnetic field gradient and a selective pulse.75
Recently, Hafner and Spiess have shown that In the first applications of the FSLG technique,
CRAMPS experiments employing a basic multiple- homonuclear 1H decoupling was employed to remove
pulse sequence (WHH-4 or variants thereof)58 at a the perturbing effects of the dipolar-coupled proton
moderately fast νR (10-15 kHz) can deliver a line network such that, for example, the spinning-side-
narrowing corresponding to that achievable by the band patterns in a 13C MAS spectrum directly reflect
conventional CRAMPS approach, with a particular the heteronuclear 13C-1H dipolar couplings.71,72 In
advantage being that the method is comparatively addition, Levitt et al. presented a modified FSLG
insensitive to experimental imperfections.65-67 As sequence, which, by the incorporation of acquisition
reflected in the naming of this approach as multiple- windows, allowed the direct recording of high-resolu-
pulse assisted MAS, such experiments represent a tion 1H spectra.73 Of more importance, however, has
shift in philosophy in that both MAS and the multiple- been the subsequent incorporation of the method into
pulse sequence “attack” the dipolar broadening; the a number of experiments that achieve high-resolution
latter can be considered to “clean up” the residual in an indirect 1H dimension, i.e., in cases where the
dipolar broadening, which remains as a consequence FSLG irradiation does not need to be combined with
of the insufficiency of the used νR. direct acquisition (in this respect, the FSLG method
can be termed a windowless decoupling method). For
The success of the multiple-pulse assisted MAS example, FSLG decoupling is an integral part of the
approach requires some thought concerning the 1H-13C correlation experiments presented by de Groot
synchronization of the duration of each cycle of the and co-workers31 and Emsley and co-workers,32 which
multiple-pulse sequence, τC, with the rotor period: will be described later.
For the CH3 group in L-alanine, the smallest line Recently, Vega and co-workers have presented a
width (full-width at half-maximum height, fwhmh) phase-modulated Lee-Goldburg experiment (PMLG)
of about 250 Hz (for comparison, the fwhmh under experiment, in which only the phase of a series of
MAS at 35 kHz is 750 Hz)20 is obtained for a plateau adjacent pulses is changed, i.e., ω1 remains con-
of τC/τR values between 0.2 and 0.3.68 It has been stant.76,77 In an ingenious reinterpretation of the LG
shown that, using zero-order average Hamiltonian concept, the zero-order term in the average Hamil-
theory,59,69 favorable synchronization conditions can tonian can be shown to vanish when the modulation
be identified by a straightforward graphical ap- of the pulse phase described by
proach.67 The quasi-static regime is not a prerequisite
for the success of multiple-pulse assisted MAS; for φ(t) ) ωPMLGt (2)
example, a marked line narrowing has been observed
for a benzoxazine dimer using WHH-4 at 35 kHz, satisfies the condition:
where τC/τR equals 1.5.21 It is to be noted that a
homonuclear decoupling method does not only re- |ωPMLG| ) ω1/x2. (3)
move the dipolar broadening, it also scales the
isotropic chemical shift scale; all fwhmh’s quoted here An LG irradiation unit has a duration corresponding
are those measured in a “corrected” spectrum where to a 2π rotation of the proton magnetization about
the normal ppm values of the different resonances the effective field, i.e.,
have been restored.
τLG ) x(2/3)(2π/ω1). (4)
An alternative means by which homonuclear 1H
decoupling can be achieved is the Lee-Goldburg Thus, the angle through which the rf precesses in
experiment, in which the offset of the 1H rf irradia- each LG unit is given by
tion is set equal to ω1/x2, where ω1 is the inherent
nutation frequency of the pulse (|ω1| ) |γ B1|, where RLG ) |ωPMLG|τLG ) 207.8° (5)
B1 is the rf field strength), such that, in the vector
model picture of NMR, the spins rotate around an If the sign of ωPMLG is negated between alternate LG
effective field tilted away from the static magnetic units, the symmetrization required to ensure the
field direction by the magic angle.70 In this way, the removal of odd-order terms in the dipolar average
zero-order average dipolar Hamiltonian vanishes. Hamiltonian is achieved. To demonstrate the feasi-
The decoupling performance is significantly enhanced bility of the PMLG sequence, Vinogradov et al
in the frequency-switched Lee-Goldburg (FSLG) ex- employed a 2D experiment in which a high-resolution
periment, which involves breaking up the continuous 1H dimension, incorporating PMLG decoupling, is
rf irradiation into a series of 2π rotations of the correlated with 1H acquisition, with only moderate
proton magnetization about the effective field, with MAS (10-15 kHz) providing line narrowing in the
a switch between the two LG conditions (ω1/x2 direct dimension. The resulting resolution obtained
accompanied by a simultaneous shift in the phase by for a sample of malonic acid is illustrated in Figure
π at the end of each segment.71-73 The better perfor- 4.76
mance of the FSLG method is a consequence of the Using Lee-Goldburg based decoupling methods, a
setting to zero of all odd-order terms in the dipolar fwhmh of 150-170 Hz has been reported for the
average Hamiltonian on account of the introduced aliphatic 1H resonances in L-alanine78sthis is dem-
symmetry. The FSLG method has been found to onstrated in part c of Figure 5, where, for comparison,
function well for a νR between 10 and 16 kHz,74 with the (a) static and (b) MAS (νR ) 30 kHz) spectra are
a further marked improvement being possible if the also shown. The spectrum in Figure 5c was recorded
NMR for Elucidation of Structure and Dynamics Chemical Reviews, 2001, Vol. 101, No. 12 4131
broadening but rather by the inherent range of signal is amplitude modulated in t1.5,80 Sign discrimi-
chemical shifts associated with a sample, which is nation can be restored in the F1 dimension by the
not perfectly crystalline. TPPI87 or States-TPPI88 method, which for the evolu-
tion of DQC in t1, in both cases, involves incrementing
the phases of all excitation pulses by 45° after
III. Homonuclear 2D Double-Quantum NMR recording each t1 point.
Spectroscopy
The previous section has been devoted to methods A. The Excitation of Homonuclear DQC
that seek to achieve line narrowing in solid-state 1H
NMR by reducing the homogeneous broadening due In the solid state, the first 1H MQ experiments
to the extended homonuclear proton-proton dipolar were performed on static samples by Baum et al.;47,48
coupling network. Such line narrowing is obviously as mentioned above, these elegant experiments allow
essential to allow the resolution of distinct reso- the determination of the size of spin clusters by
nances. However, this is achieved at the expense of monitoring the time development of MQC, with
the loss of the valuable structural and dynamic average Hamiltonian theory having been used to
information inherent to the dipolar coupling. A specially design the excitation and reconversion
method is, therefore, required which, in addition to sequences. In contrast to the homonuclear decoupling
achieving high resolution, allows the accessing of the methods discussed in the previous section where it
information inherent to the dipolar coupling. One was necessary to ensure that the dipolar terms in the
such method is two-dimensional 1H-1H DQ MAS average Hamiltonian vanish, in this case the aim is
spectroscopy,34,83 with the key to the DQ approach the generation of a DQ Hamiltonian, HXX - HYY. In
lying in the fact that the creation of a DQ coherence a MQ experiment, it is not enough to simply excite
(DQC) relies on the existence of a dipolar coupling the MQC, attention must be paid to the careful
between two protons. reconversion of the MQC back to the initial state,
In solution-state NMR, many important experi- usually longitudinal magnetization, from which di-
ments incorporate the creation and evolution of MQ rectly observable transverse magnetization can be
coherence (MQC).5,6,84-86 Since MQC cannot be di- created by a single 90° rf pulse. For the spin-counting
rectly detected, experiments that follow the evolution experiments due to Baum et al.,47,48 a reconversion
of a MQC are inherently at least two-dimensional. sequence which is the apparent time reversal of that
This is the case with 1H-1H DQ MAS spectroscopy. used for excitation was employed, such that the
Figure 7 shows a corresponding pulse sequence and destructive interference of the many MQCs is pre-
coherence transfer pathway diagram: first, a DQC vented.
is excited, which subsequently evolves during an For the excitation of DQC under MAS, the interfer-
incremented time period t1; the DQC is then con- ence with the sample rotation must be considered,
verted into observable single-quantum (SQ) coher- as was the case for the CRAMPS experiment dis-
ence (SQC), which is detected in the acquisition cussed in the previous section. In particular, if a
period, t2. To select the desired coherence transfer sequence designed for a static MQ experiment is used
pathways, e.g., only DQC during t1, a phase cycling without modification, the excitation (and reconver-
scheme is employed.79,80 Pure absorption-mode two- sion) time is limited to τR/2, since the rotor modula-
dimensional line shapes are ensured by the selection tion causes the action of the pulse sequence in the
of symmetric pathways such that the time-domain second half of the rotor period to be the time reversal
of that which occurred in the first half of the rotor
period. Starting with the suggestion of Meier and
Earl,89,90 who simply proposed the phase switching
of the static sequences used by Baum et al.,47,48 every
half rotor period to prevent the process of self-time-
reversal, many different approaches have been pre-
sented that allow excitation (and reconversion) times
of one or more rotor periods. Such pulse sequences
that counteract the effect of MAS are referred to as
recoupling methods,11,12 examples that have been
used in homonuclear DQ MAS NMR spectroscopy
include BABA,91 C7,92 DRAMA,93 DRAWS,94 and
HORROR.95 We note that Levitt and co-workers have
recently introduced a very helpful classification
Figure 7. Pulse sequence and coherence transfer pathway
system, based on symmetry principles, which covers
diagram for a 1H DQ MAS experiment using the BABA such sequences.96,97
recoupling sequence for the excitation and reconversion of Much of the considerable effort that has been
DQCs. The rectangular blocks represent pulses of flip angle devoted to the optimization of recoupling sequences
90°, with the choice of the phases being described in, e.g., for the excitation and reconversion of homonuclear
ref 25. If the t1 increment is set equal to a rotor period, a
rotor-synchronized two-dimensional spectrum is obtained,
DQC has been motivated by the desire to probe weak
while reducing t1, and hence increasing the DQ spectral dipolar couplings, e.g., between two specific 13C
width, leads to the observation of a DQ MAS spinning- labels. For 1H DQ MAS NMR of rigid solids, where
sideband pattern. the dipolar couplings under consideration are usually
NMR for Elucidation of Structure and Dynamics Chemical Reviews, 2001, Vol. 101, No. 12 4133
quite large, the demands imposed on the recoupling spin pair, it can be shown that the efficiency of DQC
sequence are less severe. Moreover, to enable a νR of excitation is directly proportional to the dipolar
30+ kHz to be used to obtain a sufficient line coupling constant, D.83,99 (In this respect, a short
narrowing, it is important that the method is robust. recoupling time, τrcpl, corresponds to the case where
In this respect, in our laboratory, we find that the sin(Dτrcpl) ) Dτrcpl). Since the reconversion to SQC
BABA sequence, although it does not deliver the efficiency has the same dependence, the integrated
maximum amount of DQC, is a good candidate. As intensity of the DQ peaks due to a given DQC, in this
shown in Figure 7, BABA, which derives its name limiting case, is proportional to D2. The inverse cubed
from the presence of back-to-back pulses, consists of dependence of D on the internuclear distance, r,
segments of duration half a rotor period, where an between the two nuclei means that the DQ peak
evolution period is bracketed by two 90° pulses, with intensity is inversely proportional to r6. Therefore,
the phases of the pulses in adjacent segments being by a simple inspection of which peaks are present in
shifted by 90°. This shifting of the phases achieves a a rotor-synchronized 1H DQ MAS spectrum, and,
negation of the spin-part of the DQ Hamiltonian, often more importantly, which are absent, much
which exactly compensates the negation of the spatial insight is obtained into proton-proton proximities.
part caused by MAS. Modified two- and four-τR For example, in Figure 8a, only two of the six possible
versions of the BABA sequence have also been types of DQ peaks (see Figure 8b) are observed, which
presented, which provide compensation with respect is consistent with the structural arrangement shown
to offset and pulse imperfections.98 A fuller account in Figure 8c. (As discussed in section VIIB, in this
of the operation of BABA and other recoupling particular case, the inequivalence of the aromatic
sequences is found in, e.g., refs 67 and 83. protons A, B, and C is a consequence of intermolecu-
lar ring current effects.) The reliability of such a
B. Rotor-Synchronized 2D DQ MAS Spectra semiquantitative approach has been clearly demon-
strated for cases where an X-ray single-crystal struc-
The two-dimensional DQ MAS experiment can be ture is available to corroborate the proton-proton
performed in two distinct ways. We consider first proximity information provided by 1H DQ MAS
spectra recorded in a rotor-synchronized fashion in spectra.21,24,29 It should be noted that an advantage
t1, i.e., the t1 increment is set equal to one rotor of the DQ approach over a spin diffusion experi-
period, τR. In this way, all spinning sidebands in F1 ment9,100 in which a mixing time is inserted between
can be considered to fold back onto the centerband two SQ evolution periods is that an auto (i.e., AA)
position. The appearance of a rotor-synchronized 2D peak is only observed if there is a close proximity of
1 two protons; in the spin diffusion experiment, strong
H DQ MAS spectrum is illustrated in Figure 8. Since
the DQ frequency corresponding to a given DQC is auto peaks are seen for all resonances regardless of
simply the sum of the two SQ frequencies, DQCs whether there is a close proximity.
between like (AA) and unlike (AB) spins can, in Later in this review, examples will be presented
general, be distinguished in that, in the former case, where rotor-synchronized 1H DQ MAS spectra pro-
a single peak at (2νA, νA) is observed, while, in the vide both structural and dynamic insight. The method
latter case, two peaks at (νA + νB, νA) and (νA + νB, is, however, not restricted to 1H NMR, for example,
31P-31P DQ MAS spectra of inorganic phosphates and
νB) are observed. [The notation (ν1, ν2) refers to a DQ
peak centered at ν1 and ν2 in the F1 and F2 dimen- glasses have also been presented.101-105 In addition,
sions, respectively.] Nielsen et al. have presented a 13C-13C DQ MAS
To a first approximation, which is fully valid in the experiment,106 using which C-C connectivities of the
limit of short recoupling times and for an isolated alkyl backbone can be established, thus, allowing the
Figure 8. (a) A representative rotor-synchronized 1H DQ MAS spectrum. (b) A schematic representation showing the
positions of the six possible DQ peaks; the observed AB and CC peaks (filled circles) imply the proton-proton proximities
indicated in (c). As discussed in section VIIB, in this particular case, the inequivalence of the aromatic protons A, B, and
C is a consequence of intermolecular ring current effects. (Reproduced with permission from ref 24. Copyright 2000 Elsevier.)
4134 Chemical Reviews, 2001, Vol. 101, No. 12 Brown and Spiess
Figure 10. (a-c) Simulated 1H DQ MAS spinning-sideband patterns for an isosceles triangle arrangement of three spins,
where the (D/2π)s for spins A & B, A & C, and B & C are 15.5, 8.9, and 8.9 kHz (corresponding to distances of 0.198, 0.238,
and 0.238 nm), respectively. Spins A & B are on resonance, while spin C is 4 kHz off resonance. The sideband patterns are
detected at spin B; in this way, for each sideband order, the left- and right-hand peaks correspond to DQCs between spins
B & C and A & B, respectively. Numerical density matrix simulations, assuming infinitely short radio frequency pulses,
were performed for uncompensated BABA recoupling sequences of duration one, two, and four rotor periods at MAS
frequencies of 15, 30, and 60 kHz in (a), (b), and (c), respectively. (d) and (e) Spectra generated using the analytical time-
domain formula for an isolated spin pair, eq 6, with (D/2π)s of (d) 8.9 and (e) 15.5 kHz, for a BABA recoupling sequence
of duration two rotor periods at a MAS frequency of 30 kHz. The same Gaussian line-broadening was applied for all spectra.
(Reproduced with permission from ref 30. Copyright 2001 American Chemical Society.)
by De Paul et al., 31P DQ MAS spinning-sideband Gregory et al. were able to determine the relative
patterns are dominated by the CSA, such that it is orientation of 13C CSA tensors from an analysis of
13C DQ MAS spinning-sideband patterns obtained
not possible to extract information about phosphorus-
phosphorus proximities.116 In addition, we note that using the DRAWS recoupling method.117
NMR for Elucidation of Structure and Dynamics Chemical Reviews, 2001, Vol. 101, No. 12 4137
Figure 14. A comparison of three HETCOR spectra of naturally abundant L-tyrosine‚HCl recorded under as far as possible
equivalent conditions using (a) the FSLG-decoupled CP (Figure 11), (b) the MAS-J-HMQC (Figure 12), and (c) the REPT-
HSQC (Figure 13) experiments. Above each spectrum, the 13C skyline projection as well as the Fourier transformation of
the first slice (t1 ) 0) of the 2D data set is shown, while below each spectrum the 1H skyline projections are shown. The
spectra were recorded at a 1H Larmor frequency of 500 MHz; the improvement in resolution at a Larmor frequency of 700
MHz for the REPT-HSQC experiment is shown as a dashed line. (Reproduced with permission from ref 125. Copyright
2001 Academic Press.)
scaling factor is 1/x3 ) 0.58, although, experimen- 13) experiments are presented in Figure 14panels a,
tally the precise scaling factor must be calibrated. b, and c, respectively. The 1H line widths (fwhmh)
The experiments also differ with respect to the type for the FSLG-decoupled spectra are approximately
of coherence that evolves during t1: in Figure 11, 1 ppm as compared to over 3 ppm for the REPT-
normal 1H transverse magnetization is present, while HSQC experiment (this does reduce to about 2 ppm
in the other two cases, heteronuclear spin modes are at a 1H Larmor frequency of 700 MHz). Moreover,
created, namely, heteronuclear MQC and hetero- Lesage and Emsley have recently shown that a
nuclear SQC for the techniques in Figures 12 and fwhmh of only 150 Hz (0.3 ppm) can be obtained in
13, respectively. The analogy to the well-known a HETCOR spectrum of a sample of L-alanine re-
solution-state heteronuclear single-quantum correla- corded at a 1H Larmor frequency of 500 MHz using
tion (HSQC)127 and heteronuclear multiple-quantum a MAS-J-HSQC experiment.131 In this respect, the
correlation (HMQC)128 experiments (dilute-spin, e.g., experiments with homonuclear 1H decoupling are
13C, detected) is to be noted. We will return to the superior. However, in using only very-fast MAS, it
differences between the heteronuclear spin modes has been argued that the REPT-HSQC experiment
later. In all experiments, TPPM 1H decoupling129 is is more robust.
applied during 13C acquisition; the better perfor- The principal motivation in recording a 1H-13C
mance of TPPM over conventional continuous wave HETCOR experiment is the determination and iden-
decoupling under fast MAS has been explained tification of the 1H chemical shifts of the protons
recently in terms of the requirement to reintroduce bound to particular carbons. For the relatively small
the homonuclear 1H dipolar network to suppress the organic molecules of relevance in modern polymer
broadening due to the cross term between the het- chemistry, most of the 13C chemical shifts can usually
eronuclear dipolar coupling and the 1H CSA.97,130 be assigned by reference to the solution-state spec-
1H-13C HETCOR spectra obtained for a sample of trum. (This is, of course, to be contrasted with the
L-tyrosine‚HCl at a 1H Larmor frequency of 500 MHz larger systems of importance in biology. A discussion
using the FSLG-decoupled CP (Figure 11), the MAS- of the various assignment approaches available for
J-HMQC (Figure 12), and the REPT-HSQC (Figure such systems, e.g., the 13C-13C correlation experi-
NMR for Elucidation of Structure and Dynamics Chemical Reviews, 2001, Vol. 101, No. 12 4139
ments discussed at the end of section IIIB, is beyond have shown that fast MAS alone at a νR of at least
the scope of this review.) For correlation methods 12 kHz provides sufficient proton dipolar decoupling
based on the dipolar coupling, it is necessary to such that relatively reliable 1H-13C dipolar couplings
ensure that the observed peaks are then not due to can be extracted. Very-fast MAS should be avoided
close through-space proximities. In this respect, the since the higher-order spinning sidebands become too
REPT method is better than CP, although it is to be weak to allow a reliable fitting.39
noted that van Rossum et al. have recently presented Alternatively, in a modification of the original SLF
a HETCOR experiment employing LG-CP (see dis- method, Hohwy et al. have presented a sophisticated
cussion in the following subsection).40 This problem experiment in which a pulse sequence is applied
is obviously avoided by utilizing through-bond J during t1 which actively recouples the weak hetero-
couplings. It could be expected that the necessity for nuclear dipolar coupling while decoupling the homo-
relatively long excitation periods on account of the nuclear 1H-1H dipolar coupling.38 Instead of giving a
small size of the J couplings would cause significant spinning-sideband pattern, a powder line shape is
sensitivity losses. However, for the examples pre- obtained in the indirect dimension. It is shown that
sented, the observed signal-to-noise is impressive; for this experimental approach allows the accurate de-
example, the successful recording of a 1H-15N MAS- termination of both N-H distances as well as the
J-HMQC spectrum with 15N at natural abundance H-N-H bond angle in a NH2 group. Another state-
has even been presented.124 Finally, we note that the of-the-art method that has recently been proposed
existence of methods based on both dipolar and J involves performing CP from 1H to 13C with the rf
couplings opens up the possibility for distinguishing pulse on the 1H channel fulfilling the Lee-Goldburg
through-bond connectivities and through-space prox- condition discussed earlier.40 The suppression of the
imities on a medium- to long-range, such that insight homonuclear 1H dipolar couplings means that a LG-
into intermolecular packing arrangements is pro- CP signal builds up in an oscillatory manner, reflect-
vided. In this way, the two approaches are compli- ing coherent heteronuclear transfer. The Fourier
mentary in a similar way to the case of the COSY transformation of such build-up curves yields powder
and NOESY5,6 solution-state NMR experiments. spectra with marked singularities from the separa-
tion of which the heteronuclear dipolar coupling can
B. The Quantitative Determination of be determined.
Heteronuclear Dipolar Couplings In direct analogy to the homonuclear DQ MAS
experiment, if the t1 increment in the REPT pulse
A major advantage of solid-state NMR is that sequences is not set equal to τR, a spinning-sideband
localized molecular motions can be quantitatively pattern rotor-encoded by the heteronuclear dipolar
probed by the measurement of site-specific anisotro- coupling is obtained.33,37,125 In Figures 13 and 16, two
pic NMR coupling parameters.9,132 In particular, the alternative implementations of the REPT experiment
determination of the 1H-13C dipolar coupling for are presented, which can be seen to differ as to where,
directly bonded C-H pairs can provide much insight with respect to t1, the second and third 90° pulses
into, e.g., aromatic ring flips. The development of are applied. In both cases, the evolution of transverse
very-fast MAS and new homonuclear 1H decoupling 1H magnetization, -I , under the heteronuclear di-
y
methods has led to a recent resurgence of interest in polar coupling gives at the end of the first REDOR
methods seeking to probe dynamics by the determi- recoupling period a heteronuclear SQC, 2IxSz. In the
nation of heteronuclear one-bond dipolar couplings. REPT-HSQC experiment in Figure 13, there are no
Figure 15 presents the pulse sequence for a general pulses before the start of the t1 period; as illustrated
separated local field (SLF) experiment.133-136 The in the previous subsection, this variant is suitable
basic principle of the SLF technique is that a spin- for a HETCOR experiment, since only 1H transverse
ning-sideband pattern, from which the heteronuclear magnetization evolves during t1.
dipolar coupling can be extracted, is obtained in the
indirect dimension for each resolved resonance in the
direct dimension, i.e., the dipolar interaction is
separated from the chemical shift interaction. In the
original SLF papers, a homonuclear decoupling
method is applied in t1, but recently McElheny et al.
In Figure 16, a 1H 90° pulse is applied before t1 to sections are all designed for application to powdered
give a state of heteronuclear dipolar order, 2IzSz, samples, i.e., there is no requirement for a single
which does not evolve under either the 1H or 13C crystal. The ability of solid-state NMR to provide
chemical shift during t1. This experiment is suitable structural information about partially ordered samples
for recording rotor-encoded spinning-sideband pat- will be demonstrated in this section. In this respect,
terns without any distortions from chemical shift we note that the analysis of solid-state NMR spectra
evolution. It is referred to as REPT-HDOR (hetero- obtained for samples where it was not possible to
nuclear dipolar order rotor encoding). In most cases, prepare a single crystal suitable for X-ray diffraction
the loss of chemical shift information in the 1H is greatly aided by the existence of X-ray or neutron
dimension is not a problem. An advantage of the single-crystal structures of related systems.
REPT-HDOR approach is that it is only necessary Solid-state NMR is also not redundant for the case
to record the t1 signal for one τR; the acquired signal where it is possible to prepare a single-crystal suit-
can then be catenated and multiplied by a weighting able for an X-ray analysis, since structure determi-
function to introduce an artificial line broadening nation by single-crystal X-ray diffraction methods,
before Fourier transformation. The heteronuclear being based on the diffraction of X-rays by electrons,
REPT spinning-sideband patterns for a heteronuclear is not well suited to the localization of lighter atoms.
spin pair are identical to those shown in Figure 9 for This is of particular relevance with regard to the
DQ MAS of a homonuclear spin pair except for a localization of hydrogen-bonded protons, in which
factor of 1.5 which reflects the difference in the case a neutron diffraction study is to be preferred.138
homonuclear and heteronuclear dipolar Hamilto- It should be noted, though, that neutron diffraction
nians. is not the perfect solution: as well as the requirement
If a 13C 90° pulse is applied before t1 a hetero- for both larger crystals and very expensive facilities,
nuclear MQC, 2IxSx, is obtained. Indeed, this REPT- the investigation of protons is complicated by their
HMQC experiment is described in the original pa- large incoherent cross section, such that deuteration,
per.33 The disadvantage in this case is that, to record which may cause a change in the hydrogen-bonding
a HETCOR experiment, a 180° pulse must be applied arrangement, is often required. Thus, solid-state
in the center of t1 to refocus the 13C chemical shift NMR methods that can provide interproton and
evolution. Note the presence of such a pulse in the proton-heteroatom distance constraints, by means
MAS-J-HMQC experiment in Figure 12. The inclu- of which the localization of the important protons in
sion of this 180° pulse leads to a timing problem;125 the single-crystal structure can be refined, are of
however, Lesage and Emsley have recently shown much value.
that the insertion of a 180° pulse in the center of t1 In addition, solid-state NMR is well-suited to an
leads to a better resolution in a HSQC experiment investigation of polymorphism. In this respect, it is
on account of the refocusing of the heteronuclear J to be remembered that, when selecting single crystals
and residual dipolar couplings.131 Finally, it should suitable for a diffraction study, it could happen that
be mentioned that a related set of experiments, minor crystalline forms, which may less readily form
termed dipolar heteronuclear multiple-spin correla- single crystals, are missed. For example, using a
tion (DIP-HMSC), have recently be described, which modified version139,140 of the magic-angle turning
also incorporate REDOR recoupling but begin with (MAT)141 experiment, which allows the separation of
13C transverse magnetization created by a CP step.137 13C CSA tensor spinning-sideband patterns, Harper
pairs, and the clear difference in the ethyl spectrum pattern for the SQ resonance at 10 ppm, corresponding to
therefore indicates an alternative packing arrange- the hydrogen-bonded protons. (Reproduced with permission
ment. from Figures 4 and 5 of ref 153. Copyright 2000 American
Chemical Society.)
A consideration of the basic structure of the benz-
oxazine dimer reveals that the observation of both
forward interpretation of spectra that typically re-
the strong AC peak and the absence of the CC peak
quire less than 1 h of measuring time. The recording
for the ethyl dimer can be explained if one of the
of 1H DQ MAS spinning sideband patterns usually
aromatic rings is flipped such that instead of pairs
requires a significantly longer measuring time (8-
of hydrogen-bonded dimers there exist hydrogen-
12 h). However, as illustrated by the following
bonded chains as shown in Figure 17e. In addition,
examples, the extra investment is often rewarded by
this alternative packing arrangement gives rise to a
additional important structural information.
close proximity of the O-H‚‚‚O proton and the
N-ethyl chain. The resulting cross-peak between the As noted above, the presence of centerband and
O-H‚‚‚O proton and the ethyl-chain CH2 protons even-order sideband intensity in a 1H DQ MAS
(BD) is, indeed, clearly seen in the DQ MAS spectrum spectrum arises from the evolution during t1 of a
of the ethyl dimer (Figure 17c). DQC, due to a particular two spins, under dipolar
couplings to other spins. In an elegant use of this
A further example of the utility of rotor-synchro-
phenomenon, Shantz et al have shown how the
nized 1H DQ MAS NMR spectra is the investigation
observation of an intense centerband in the 1H DQ
of the change in the quadruple hydrogen-bonding
MAS spinning-sideband pattern for the SQ resonance
arrangement formed by dimers of 2-ureido-4-pyrimi-
at 10 ppmssee Figure 18 sproves that at least three
done units upon a keto to enol tautomerism. 83,152 The
silanol protons are engaged in hydrogen bonding
ability of monomers incorporating two and three of
within the defect sites in an all-silica ZSM-12 zeo-
these units to self-assemble into linear polymers and
lite.153
reversible networks, respectively, was noted in the
Introduction.2 In an additional related example fo- The simulated spinning-sideband patterns for a
cusing on ionic intermolecular interactions, Rod- model three-spin system presented in Figure 10
riguez et al. have presented 2D rotor-synchronized demonstrated that at a very-fast νR, i.e., 30+ kHz,
1
H DQ MAS spectra that prove the intimate contact the evolution during t1 of a DQC under perturbing
of the two polymers, poly(sulfonated styrene) (PSS) dipolar couplings to other spins is suppressed, such
and poly(diallyldimethylammonium chloride) (PDAD- that the intensity of the centerband and even-order
MAC), in both a polyelectrolyte complex and thin self- sidebands is usually weak. In addition, Figure 10
assembled PSS/PDADMAC multilayers on silica col- showed that the effect of a perturbing dipolar cou-
loids.26 pling on the odd-order spinning-sideband pattern
generated by the RRE mechanism for the DQC
corresponding to the dominant D is small, such that
B. 1H DQ MAS NMR Spinning-Sideband Patterns it is possible, for a multispin system, to determine
The rotor-synchronized 1H DQ MAS experiment the dominant D, and hence the shortest proton-
can be considered to be a workhorse method; valuable proton distance, to a high degree of accuracy. As an
semiquantitative insight is provided by the straight- explicit example of this, consider the hydrogen-
NMR for Elucidation of Structure and Dynamics Chemical Reviews, 2001, Vol. 101, No. 12 4143
Figure 21. (a, c) 1H (700.1 MHz) DQ MAS NMR spinning-sideband patterns obtained for the NH1 hydrogen-bonded
resonances of bilirubin, 2, (see Figure 20b) at a MAS frequency of 30 kHz. BABA recoupling sequences of duration (a) two
or (c) three τR were used for the excitation and reconversion of DQCs. The corresponding best-fit simulated three-spin 1H
DQ MAS spinning-sideband patterns are presented in (b) and (d). (Reproduced with permission from ref 30. Copyright
2001 American Chemical Society.)
is strong evidence that the intramolecular hydrogen- extracted by solid-state NMR to those determined by
bonding arrangement shown in Figure 19 persists. neutron diffraction studies.136,158 The corresponding
On this basis and considering the intensities of the best-fit simulated three-spin spinning-sideband pat-
respective DQ peaks, the SQ resonances at 9.1 and terns are shown in Figure 21b,d. The analysis also
13.9 ppm can be assigned to the pyrrole NH and yields a distance between the lactam NH and car-
carboxylic acid OH protons, respectively. boxylic acid OH protons of 0.230 ( 0.008 nm (corre-
In Figure 21 a and c, 1H (700.1 MHz) DQ MAS sponding to a perturbing D of 9.9 ( 1.0 kHz) and an
spinning-sideband patterns obtained for the lactam H-H-H angle of 122 ( 4°snote that the precision
(at 10.8 ppm) NH resonances of bilirubin, with τrcpl of these values is less than for the case of the shortest
equal to (a) two and (c) three rotor periods at a νR ) proton-proton distance.
30 kHz are shown. In the rotor-synchronized 1H DQ
MAS spectrum in Figure 20b, in addition to the VII. Aromatic π−π Interactions and Ring-Current
intense NH-NH DQ peaks, weaker DQ peaks due Effects
to DQCs involving the OH and aliphatic protons are
observed. An inspection of the spectra in Figure 21 In addition to hydrogen-bonding effects, the 1H
reveals the existence of spinning sidebands due to chemical shift is very sensitive to the ring currents
all these different DQCs; note that the DQ peak for associated with aromatic moieties.159 In comparison
the NH-NH pair is at the second-to-left position. to the solution state, where isotropic molecular
In ref 30, a protocol is presented whereby the tumbling means that such effects are only seen for
dominant D, and hence the shortest proton-proton unusual intramolecular geometries,160 in the solid
distance, can be determined by finding the best fit state, the protons are exposed to the ring currents
simulated three-spin spectra on the basis of a com- due to other nearby through-space aromatic moieties,
parison of the extracted integrated experimental be they intra- or intermolecular. However, it is only
sideband intensities with those in the simulated with the renewed interest in methods offering high
spectra. In this way, the distance between the lactam resolution 1H solid-state spectra that the widespread
and pyrrole NH protons in bilirubin is determined importance of ring current effects in the solid-state
to be 0.186 ( 0.002 nm (corresponding to a dominant is being appreciated. It should be noted that ring
D of 18.5 ( 0.5 kHz), proving an exceptionally close current effects are not restricted to 1H NMRsit will
approach of two protons being noncovalently bonded be shown below that shifts of the order of 1 ppm are
to the same atom. The accuracy is better than what also observed in the 13C dimension. However, the
can be reliably expected from a standard X-ray effects are much more pronounced in 1H NMR on
structural analysis. We note that, at this degree of account of the small chemical shift range and the
accuracy, the different effects of vibrational averaging usual location of the protons in “exposed” parts of the
should be considered, when comparing distances molecule.
NMR for Elucidation of Structure and Dynamics Chemical Reviews, 2001, Vol. 101, No. 12 4145
Figure 22. A representation of the aggregation shifts, i.e., the difference between the chemical shift in the aggregate
(i.e., the solid state) and in the monomer (i.e., in solution), as determined for the 1H and 13C nuclei in a uniformly 13C
enriched bacteriochlorophyll (BChl) c in intact chlorosomes of Chlorobium tepidum, using 2D 1H-13C and 3D 1H-13C-13C
dipolar correlation spectroscopy at a magnetic field of 14.1 T. Circles correspond to upfield changes upon aggregation with
the size of the circle indicating the magnitude of the change. The different representations in I and II correspond to the
experimental observation of two separate components. (Reproduced with permission from ref 162. Copyright 2001 American
Chemical Society.)
Figure 26. The solid-state packing arrangement of 4@5, as determined by an X-ray single-crystal investigation.171 Large
white, large black, and small white circles represent nitrogen, carbon, and hydrogen atoms, respectively. In (b), (c) and
(d), views through the naphthalene, inner benzene and outer benzene rings, respectively, are shown. The distance from
Hb to the center of the inner benzene ring is 260 pm (view (c)) as opposed to 404 pm to the middle of the naphthalene unit
(view (b)) and 314 pm to the center of the outer benzene ring (view (d)). Specific carbon and hydrogen atoms are labeled
according to the above chemical structure. (The notation xa refers to the quaternary carbon between carbons x and x+1.)
(Reproduced with permission from ref 29. Copyright 2001 Wiley.)
current effects then allows the clear assignment of Table 2. Comparison of the 1H Chemical Shifts (in
the two separate peaks at 13C chemical shifts of 129.6 ppm) for 4@5 Determined by NMR Experiments and
ab Initio Calculations29
and 128.7 ppm in Figure 25b to the guest CHs
(labeled 5a and 5b), with the corresponding 1H solution-state solid-state ab initio ab initio
NMR NMR (monomer) (dimer)
chemical shifts being 5.6 and 2.0 ppm, respectively.
The pair of cross-peaks at a DQ frequency of 7.6 Ha (guest) 3.5 5.6 5.5 5.2
ppm in Figure 25a can thus be identified as being Hb (guest) 3.5 2.0 2.5 2.1
H2,3,14,15 6.4 4.9 6.6 5.5-5.6
due to two neighboring guest CH protons. It is further other arom 7.0-7.2 7.1-7.2 7.2-8.0 6.9-7.7
interesting to note that two distinct host aromatic Hbridgehead 4.1 3.8a 3.9-4.2 3.3-4.0
1H resonances can be resolved in both the 1H DQ
H25,28b 2.4 2.0-3.8a 2.2 2.1
MAS and 1H-13C REPT-HSQC spectra: the 13C peak H26,27b 2.5 0.6-2.3a 2.0-2.1 0.4-1.0
at 124.4 ppm (4ar(1)) can be assigned to the meta a
These 1H chemical shifts were determined from the alkyl
pair of carbons of the outer benzene ring (2, 3, 14, region of the 1H-13C correlation spectrum (not shown). b Note
and 15), with the corresponding 1H chemical shift that the two protons in each CH2 group are inequivalent.
being 4.9 ppm (4arII). From Figure 25b, the other
aromatic protons have, within the experimental the two guest aromatic protons experience the ring
resolution, the same chemical shift of 7.1 ppm (4arI). currents due to the host to different degrees. More-
In this way, the observation of diagonal 1H DQ peaks over, from Figure 26a, the end pair of aromatic
at 13.8 and 10.0 ppm, as well as shoulders corre- protons can be seen to be directed into the ring
sponding to DQ cross-peaks at 12.0 ppm can be current due to the naphthalene unit of the next host,
explained. explaining the 4arII resonance.
The observed experimental features can be quali- As was the case with the HBC-C12 example
tatively understood by reference to the structure of discussed above, ab initio quantum chemical calcula-
4@5, which is known from an X-ray single-crystal tions were carried out, thus providing a fully quan-
analysis.171 In Figure 26a, the side-by-side arrange- titative interpretation of the experimental results.
ment of two 4@5 complexes is displayed, while Table 2 presents the experimental solution- and solid-
Figures 26b, 26c, and 26d show views through the state 1H chemical shifts obtained by quantum chemi-
different host aromatic moieties. It is apparent that cal calculations (for details, see ref 29) for a single
NMR for Elucidation of Structure and Dynamics Chemical Reviews, 2001, Vol. 101, No. 12 4149
in N,N-bisarylformamidines178 or a phenylenedi-
amine.179 In this subsection, we will show that the
resolution routinely achievable in 1H solid-state NMR
methods allows the making and breaking of hydrogen
bonds to be directly probed.
Consider the hexabenzocoronene (HBC) derivative,
2, 5, 8, 11, 14, 17-hexa[10-carboxydecyl]hexa-peri-
hexabenzocoronene, 6, (henceforth referred to as
Figure 31. Extracted columns from 1H (500.1 MHz) DQ MAS spectra of HBC-C12, 3, showing the DQ spinning sideband
patterns for (a) the aromatic protons at 8.3 ppm in the solid phase (T ) 333 K), and (b) the aromatic protons at 6.2 ppm
in the LC phase (T ) 386 K). In each case, best-fit spectra, generated according to the spin-pair expression in eq 6, are
shown (shifted to the left to allow a better comparison) as dotted lines. A spinning frequency, νR, equal to 35 and 10 kHz
was used for the solid and LC phases, respectively, with the two rotor-period compensated BABA recoupling sequence
being used for the excitation and reconversion of DQCs in both cases. In (a), additional peaks corresponding to DQCs
between aromatic and residual undeuterated R-carbon protons are marked by *. The insets to the right of the experimental
spectra show the sensitivity of the spinning-sideband patterns to the product Dτrcpl. (Reproduced with permission from ref
22. Copyright 1999 American Chemical Society.)
Finally, we note that an analysis of 1H-13C spinning- As stated in section V, solid-state NMR should not
sideband patterns obtained using the REPT-HDOR be considered as a replacement for the established
experiment (see Figure 16) has also been used to diffraction methods. Instead, the two methods should
provide evidence of restricted dynamics in a shape- be thought of as being complementary, since they
persistent polyphenylene dendrimer.184 have much to offer each other. For example, as
discussed in section VIIB, the existence of a single-
IX. Conclusions crystal X-ray structure for unsubstituted HBC al-
lowed a qualitative interpretation of the observed 1H
In this review, we have demonstrated that the DQ MAS spectrum of HBC-C12, where it was not
advanced solid-state NMR methods existing today possible to obtain a single-crystal suitable for an
are well placed to provide answers to the structural X-ray analysis. The symbiosis between 1H solid-state
and dynamic questions of relevance in modern poly- NMR and X-ray single-crystal methods was further
mer chemistry. In particular, the further develop- well illustrated by the case of bilirubin in section VIB,
ment of high-resolution 1H solid-state NMR methods where an X-ray single-crystal structure exists. On
has opened up the possibility of routinely directly one hand, the reliable establishing of the heteroatom
probing hydrogen-bonding and aromatic π-π inter- positions facilitated the assignment of the observed
actions. It is to be emphasized that only 10-20 mg peaks in the 1H DQ MAS spectrum. On the other
of a powdered as-synthesized sample is required, i.e., hand, it was shown that an analysis of 1H DQ MAS
there is no need for synthetically demanding selective spinning-sideband patterns allowed the determina-
isotopic labeling or a single crystal. Moreover, the tion of the distance between two hydrogen-bonded
potential applications of solid-state NMR are not protons to a precision of ( 0.002 nm; since structure
restricted to the many examples given in the previous determination by single-crystal X-ray diffraction
sections: in our laboratory, for example, preliminary methods, being based on the diffraction of X-rays by
results have been obtained that provide insight into electrons, is not well suited to the localization of
proton conduction in imidazole-based materials as lighter atoms, the ability of solid-state NMR to
well as the local order and dynamics in the cylindrical provide distance constraints, which can be used in
macromolecules synthesized by Percec and co-work- the optimization of a crystal structure, in particular,
ers, which were mentioned in the introduction. the very relevant hydrogen-bonded part, is of much
Solid-state NMR spectroscopy should certainly not importance.
be used in isolation. For example, when a new sample In section VII, the value of a combined experimen-
is to be investigated, we insist, in our laboratory, on tal and theoretical approach, incorporating the ab
receiving assigned 1H and 13C solution-state NMR initio calculation of 1H chemical shifts, was illus-
spectra (except, of course, for cases where the sample trated. First, in section VIIB, it was stated that the
is insoluble). An example of the importance of this is calculation of 1H chemical shifts for model HBC
provided by the 1H-13C correlation spectrum of the oligomers allowed the quantitative assignment of the
host-guest complex in Figure 25b, where the assign- experimental observation of three aromatic reso-
ment of the guest resonances is based on the known nances in HBC-C12 to a specific packing arrange-
solution-state 13C chemical shifts and the compara- ment. Moreover, in section VIIC, the ability to
tive insensitivity of 13C chemical shifts to through- identify the importance of intra- and intercomplex
space aromatic ring currents. interactions as well as the role of the separate
In addition, if dynamic processes are to be inves- aromatic moieties was discussed. The advances in
tigated, it is very useful if differential scanning computing power as well as the development of
calorometry (DSC) curves can be first obtained, so methodology means that the use of quantum chemi-
that the temperatures at which phase transitions cal calculations of NMR parameters in the interpre-
occur are known in advance. Moreover, when carry- tation of experimental results will become ever more
ing out variable temperature studies of organic solid, popular.
it is important to be aware of the fact that the It should not be forgotten that the development of
observed behavior, in terms of, e.g., phase transition advanced solid-state NMR methodology is an area of
temperatures and NMR spectra, can differ signifi- ongoing active research. For example, as evidenced
cantly depending on whether the solid phase formed by section II, various groups are pursuing the goal
from solution or from a LC phase or melt. It is, of reducing the 1H solid-state NMR line width ever
therefore, necessary to see both the first and subse- further. Moreover, the utility of the 1H DQ MAS
quent DSC heating curves; a clear example of this method would be much enhanced if homonuclear
phenomenon is described in ref 25. Furthermore, we decoupling methods, which, as illustrated by Figure
note that, in our experience, different batches of a 5, yield a striking improvement in the 1H line width
material, synthesized by the same procedure, can as compared to very-fast MAS, could be incorporated
give slightly different solid state 1H NMR spectra, in a robust and artifact-free manner. It is to be hoped
even though the purity of the material as determined that the problems of significant spectral artifacts
by standard methods, e.g., solution-state NMR, is encountered in an earlier attempt to combine 1H DQ
judged to be the same. This is particularly the case MAS spectroscopy with the multiple-pulse assisted
for hydrogen-bonded systems, and thus it seems that MAS approach20 can be overcome. To conclude, it is
solid-state NMR is able to distinguish subtly different envisaged that solid-state NMR can become as highly
packing arrangements, suggesting potential quality- valuable to the chemist as solution-state NMR is
control applications. today.
4154 Chemical Reviews, 2001, Vol. 101, No. 12 Brown and Spiess
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Spiess, H. W. Angew. Chem., Int. Ed. Engl. 1999, 38, 3039.
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Masami Kamigaito was born in 1965 in Nagoya, Japan. He received his Mitsuo Sawamoto, born in Kyoto, Japan (1951), received his B.S. (1974),
B.S. and M.S. degrees and Ph.D. degree in polymer chemistry from Kyoto M.S. (1976), and Ph.D. (1979) degrees in polymer chemistry from Kyoto
University in 1993 under the direction of Professor Toshinobu Higashimura. University under the direction of Toshinobu Higashimura. After postdoctoral
After postdoctoral research with Professor Mitsuo Sawamoto, he joined research with Joseph P. Kennedy at the Institute of Polymer Science,
the faculty at Kyoto University in 1995, where he is now Associate The University of Akron, Akron, OH (1980−81), he joined the faculty of
Professor of Polymer Chemistry. In 1997−1998, he was a visiting scientist the Department of Polymer Chemistry, Kyoto University, in 1981 as a
under Professor Robert M. Waymouth at Stanford University. He is the research instructor. He was promoted to Lecturer (1991), to Associate
recipient of the 1999 Award for the Encouragement of Research in Polymer Professor (1993), and to Professor (1994), his current position, of the
Science of the Society of Polymer Science, Japan, and the 2001 Arthur same department. Sawamoto also serves as one of the three Editors of
K. Doolittle Award of the ACS PMSE Division. His research interests the Journal of Polymer Science, Part A: Polymer Chemistry (1995−
include metal catalysis for precision polymer synthesis, particularly living present) and as an Editorial Advisory Board member of Macromolecular
cationic and radical polymerization. Chemistry and Physics, the Journal of Macromolecular Science, Chemistry,
and e-Polymers, and is the recipient of the 1991 Award of the Society of
Polymer Science, Japan, the 1998 Divisional Award of the Chemical
Society of Japan, the 2001 Aggarval Lectureship in Polymer Science,
Cornell University, and the 2001 Arthur K. Doolittle Award of the ACS
PMSE Division. With more than 250 articles and reviews, his research
interest covers living radical and cationic polymerizations, precision polymer
synthesis, and the chemistry of radical and carbocationic reaction
intermediates.
as (meth)acrylates and other functional derivatives.3-6 (eq 6) have most extensively been studied, probably
Similar proliferation has recently occurred in other due to the high controllability, the wide applicability,
polymerizations, including cationic,7-9 coordination,10 and the relatively easy access to the catalysts and
ring-opening,11 and ring-opening metathesis,12 for other components to be employed.
which precise reaction control had been considered
difficult for some time. In this regard, living radical
polymerization has been among the most challenging
frontiers in precision polymer synthesis and polymer
chemistry.
from the conventional radical polymerization that a dormant carbon-halogen bond at a polymer ter-
involves a metal-assisted formation of the initiating minal via a one-electron redox reaction of the metal
radical species via irreversible redox processes, al- center. In this process, the metal center attacks the
though the initiating system for the latter also halogen at the chain end and is oxidized via a single
consists of two components, a metal complex and an electron transfer followed by halogen abstraction,
organic halide.34,35 In these examples, except for a thus generating a growing radical species. Sooner or
few,36,37 the control of molecular weights and MWDs later, the oxidized metal center donates the halogen
is generally difficult. The use of effective telomers can therein back to the radical growing species, along
also make the control of molecular weights better in with reduction of the metal center, before or after the
low molecular weight regions. However, the control- propagation reaction between the radical and mono-
lability is much better for the recently developed mer. The lower oxidation state of the metal center
systems with reversible activation. A few reviews [e.g., Ru(II)] should be more stable than its higher
dealing with comparison between the new and the counterpart [e.g., Ru(III)] so as to establish an
old metal-catalyzed systems are also available.30,38 extremely low concentration of the radical species as
This review covers mainly the scientific literature well as a fast reversible reaction with the halogen.
that has appeared in relevant journals until early This set of reactions, i.e., the activation/cleavage
2001 concerning the metal-catalyzed (or atom- of a carbon-halogen bond, the formation of a radical
transfer) living radical polymerization. The word species, the repetitive addition (propagation) of the
“living” employed here simply refers to polymeriza- radical species to the monomer, and the regeneration
tions that provide control over the molecular weights, of the carbon-halogen bond, are called the Kharasch
the molecular weight distributions, and the chain end or ATRA reactions. There are various metal com-
reactivity as do other living polymerizations. Its plexes active for these reactions, as have been utilized
definition and use criteria, along with the word in organic synthesis. Indeed, some of the metal
“controlled”, are still under discussion and have complexes active for living radical polymerization
recently been discussed elsewhere.39 Thus, the dis- were originally developed for the small-molecule
cussion on the difference between these words is not reactions, but along with the recent advances in
to be treated here. polymerization, new and more active complexes have
The review roughly consists of two parts, the scope emerged, too. Although there are still no consistent
and design of initiating systems followed by precision rules for designing catalysts, there have been several
polymer synthesis. The former will treat the scope papers dealing with the relationships between the
of metal catalysts, initiators, and monomers along metal center, catalyst structure, or ligand and their
with polymerization mechanisms. The latter will catalytic activities.53,54 In general, it is suggested that
focus on the precision synthesis of various polymers the catalytic activity increases with increasing elec-
with controlled structures and interesting properties tron density of the metal center or with decreasing
or functions, such as block, end-functionalized, star, redox potential of the complex, because, upon the
and other architecturally well-defined polymers. Other onset of radical generation, the catalyst should give
reviews are also available, comprehensive,31,40-44 and one electron to the halide terminal. The following
relatively short,45-52 dealing with the recent develop- sections will focus on the transition-metal catalysts
ments of the field. employed for living radical polymerization.
1. Ruthenium
II. Design of the Initiating Systems This group 8 transition metal was one of the first
whose complexes [RuCl2(PPh3)3 etc., Ph ) C6H5] were
The initiating systems for the metal-catalyzed demonstrated to induce living radical polymeriza-
living radical polymerizations consist of a metal tion.27 Among the various oxidation states of ruthe-
complex (or catalyst) and an initiator; the former nium complexes (-2 to +6), the divalent form with
allows the generation of radical species from the phosphine ligands has effectively been employed for
latter or the dormant polymer terminal. The choice the metal-catalyzed living radical polymerization as
of the metals and the initiators according to the well as Kharasch addition reactions (Figure 1). The
monomer structures is crucial for controlling radical dichloride RuCl2(PPh3)3 (Ru-1) was the first complex
polymerizations. The rate and control of the polym- employed for the metal-catalyzed living radical po-
erization can also be increased by the addition of lymerization of methyl methacrylate (MMA) in con-
other compounds or by changing solvents. This first junction with CCl4 as an initiator in the presence of
part will deal with the design of the initiating a metal alkoxide such as MeAl(ODBP)2 (ODBP ) 2,6-
systems from the viewpoint of various components, di-tert-butylphenoxy) as an additive.27 In toluene at
i.e., metal complex catalysts, initiators, monomers, 60 °C, the polymerization proceeded homogeneously
additives, and solvents, as well as the relevant to give polymers with molecular weights that were
reaction mechanisms. controlled by the feed ratio of monomer to initiator
and relatively narrow MWDs (Mw/Mn ≈ 1.3). The
A. Transition-Metal Catalysts radical nature of the polymerization was suggested
by inhibition of the polymerization on addition of a
One of the most important components in the radical scavenger or inhibitor such as galvinoxyl and
metal-catalyzed living radical polymerization is the 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO).27,55 The
transition-metal complex. As a catalyst, the complex tacticity of the polymers was similar to that prepared
induces reversible activation (homolytic cleavage) of in conventional radical systems.27
3694 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
The ruthenium-catalyzed polymerization was fur- borate-based complex (Ru-8), isoelectronic to 18-
ther improved by using CHCl2COPh and Al(O-i-Pr)3 electron half-metallocene-type complexes, also in-
in place of CCl4 and MeAl(ODBP)2, respectively, duced living radical polymerization of MMA either
resulting in very narrow MWDs (Mw/Mn ) 1.1) of with or without additives, where the rates and
poly(MMA).56 This complex can also be applicable for molecular weights were not changed on addition of
styrene polymerization in conjunction with an iodo Al(O-i-Pr)3.53
initiator to give relatively narrow MWDs (Mw/Mn ≈ A series of p-cymene-based ruthenium dichloride
1.2).57 A similar PPh3-based ruthenium(II) hydride complexes (Ru-9) with various phosphines and re-
(Ru-2) is more active than the chloride Ru-1, thus lated two-electron-donor ligands was synthesized and
inducing faster polymerizations.58 The hydride com- used for the radical polymerizations of several mono-
plex is still active at 30 °C to give polymers with mers as well as Kharasch addition reactions.63,64
narrow MWDs (Mw/Mn ≈ 1.2). A ruthenium complex Controlled polymerizations were achieved with basic
with an ionic phosphine ligand (Ru-3), which is and bulky phosphine or arsenic ligands (L ) PCy3,
soluble in water or methanol, catalyzes homogeneous P(i-Pr)3, P(c-C5H9)3, PPhCy2, AsCy3, PCy2CH2CH2-
living radical polymerization of 2-hydroxyethyl meth- CH2C6H5). Among them, the tricyclohexylphosphine
acrylate (HEMA) in methanol;59 no protection of the complex (L ) PCy3) is most active and efficient in
hydroxyl group is required for HEMA. giving well-controlled molecular weights and narrow
Among a series of the 18-electron half-metallocene- MWDs (Mw/Mn ≈ 1.1) for methacrylates.63 In con-
type ruthenium complexes (Ru-4, Ru-5, and Ru-6), trast, less basic or less bulky phosphine-, pyridine-,
the indenyl derivative Ru-5 led to the fastest living isocyanide-, and antimony-based ligands led to less
radical polymerization of MMA.60 In this case, addi- efficient and/or less controlled polymerizations. Simi-
tives such as aluminum alkoxides are not necessary lar complexes carrying benzene (Ru-10) or tetralin
for controlled polymerization. However, addition of (Ru-11) can also be employed; the activity decreased
an amine such as n-Bu2NH dramatically increased in the order p-cymene > benzene > tetralin.65
the rate to complete the polymerization in 5 h at 100 A complex with a bridged ligand with arene and
°C without broadening the MWDs.61 phosphine can be obtained via release of the p-
Though less active, the Cp* complex Ru-6 is a cymene ligand from Ru-9 (L ) PCy2CH2CH2CH2C6H5)
versatile catalyst, which enables living radical poly- on heating to 120 °C, but it was significantly less
merizations of three different types of monomers, i.e., active than the precursor Ru-9 (L ) PCy2CH2CH2-
MMA, styrene, and methyl acrylate (MA), in conjunc- CH2C6H5), which induces efficient living radical po-
tion with a chloride initiator and Al(O-i-Pr)3. The lymerization.65 The activation process of these arene-
initiating system with Ru-6 gives controlled molec- based 18-electron complexes is thus release of arene
ular weights and narrow MWDs (Mw/Mn ) 1.1-1.2) ligands, which results in active and coordinatedly
for all the monomers in toluene at 80 °C without unsaturated 12-electron complexes.
changing the initiator and reaction conditions ac- A series of so-called Grubbs ruthenium-carbene
cording to the monomers.62 The catalytic activity of complexes (Ru-12) can mediate living radical polym-
these half-metallocene-type complexes increased in erization of MMA and styrene to afford controlled
the order Ru-4 < Ru-5 < Ru-6; namely, the lower the polymers with narrow MWDs (Mw/Mn ≈ 1.2).63,66 The
redox potential of the complex, the faster the polym- polymerization apparently proceeds via a radical
erization.53 Another half-metallocene-type ruthenium mechanism, as suggested by the inhibition with
complex with 16-electrons (Ru-7) is more active than galvinoxyl. For example, a novel ruthenium-carbene
Ru-6, because the former has a vacant site that can complex (Ru-13) carries a bromoisobutyrate group
interact with a halogen at the polymer terminal and can thus not only initiate but also catalyze living
without release of phosphine ligand.62 A trispyrazolyl radical polymerization of MMA without an initiator.67
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3695
Matyjaszewski and has subsequently been applied the CuBr/L-1 system by adding 10% DMF, while the
to a wide range of monomers. The first system MWDs were relatively broad (Mw/Mn ) 1.4-1.8).88
consists of CuCl and 2,2′-bipyridine (L-1) ligand, A difficulty in isolation and clarification of the
coupled with 1-phenylethyl chloride as an initiator.28 active Cu(I)-bipyridine complexes was overcome
Though a heterogeneous system, the polymers had with the use of a silyl-containing bipyridyl ligand (L-
controlled Mn, in direct proportion to monomer con- 6), which generates an ionic complex (Cu-1) on
version up to 100000 amu, and narrow MWDs (Mw/ mixing with an equimolar amount of CuBr.89,90 The
Mn < 1.5). The Cu(I)/L-1 system also proved effective complex as well as an equimolar mixture of CuBr and
for other monomers such as MA. The use of CuBr L-6 showed levels of control similar those with L-3
and a bromide initiator narrows the MWDs of poly- and CuBr. An active Cu(I) species with bipyridine-
styrene and poly(MA) (Mw/Mn ≈ 1.1), while broader type ligands presumably has a tetrahedral 18-
MWDs (Mw/Mn ≈ 1.4) were obtained for poly(MMA).84 electron species, as suggested for the similar com-
In an effort to solubilize the catalyst, long-chain plexes isolated after the polymerization of MA with
alkyl groups on the 4,4′-positions of bipyridine were L-4.91,92
introduced. Typical ligands in this line include L-2, A Cu(II) complex with a bipyridine-type ligand (Cu-
L-3, and L-4. Homogeneous polymerizations have 4) is effective in the controlled polymerization of
been achieved with L-385 and L-486 independently and styrene and acrylates in the presence of Al(O-i-Pr)3,
almost simultaneously by two research groups. The which most probably serves as a reducing agent of
polymerizations proceeded faster than the heteroge- Cu(II) into Cu(I).93,94 A fluoroalkyl-substituted bipy-
neous ones to give polystyrene of very narrow MWDs ridine ligand (L-7) was also employed in supercritical
(Mw/Mn ) 1.05). A longer alkyl chain substituent (L- carbon dioxide for the polymerization of fluorinated
5) is similarly efficient.87 Alternatively, homogeneous acrylates and methacrylates.95 Similar pyridine-
polymerization of styrene can be achieved even with based bidentate ligands, 1,10-phenanthroline and its
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3697
as well as deactivation of the Re(V) complex via (Merrifield resin) such as SL-2 and SL-3 also resulted
interaction with TEMPO. The system can equally be in uncontrolled polymerizations of acrylates, meth-
employed for acrylate polymerizations, although the acrylates, and styrene. A better control can be
MWDs are broader (Mw/Mn ) 1.6-1.8).142 achieved with the use of SL-4 for a mixture of CuBr2
There is also a report on the use of a Re(I) complex and CuBr in the polymerization of MA, where the
(Re-2) in 1,2-dichloroethane at 50 °C, where the molecular weights became closer to the calculated
increase of molecular weights with conversion was values, and the MWDs became narrower (Mw/Mn )
observed in the MMA polymerization.143 Due to the 1.6-2.0).145 The residual copper in the reaction
absence of initiator, the solvent presumably serves mixture was estimated about 3% of the initial amount,
as a supplier of the initiating radical species. The which indicates that the metal was effectively bound
radical nature of the polymerization was suggested to the resin.
from the copolymerization behavior of MMA and The use of another supported ligand such as SL-5
styrene. on silica gels and polystyrene resins induced con-
trolled radical polymerization of MMA, resulting in
8. Molybdenum narrower MWDs (Mw/Mn ) 1.5-1.6), although the
A group 6 metal complex can be a candidate as a molecular weights were higher than the calculated
catalyst for radical polymerization because of its values.146,147 Block copolymerization and the reuse of
variable oxidation states, despite its sensitivity to air the catalysts have also been achieved. Physically
and protic compounds. A lithium molybdate(V) com- adsorbed catalysts obtained by mixing silica gels or
plex (Mo-1) can polymerize styrene in conjunction amino-functionalized silica gels with CuBr in the
with benzyl chloride in toluene at 80 °C to yield presence of free ligands gave narrower MWDs (Mw/
polystyrene with relatively broad MWDs (Mw/Mn ) Mn ) 1.3-1.4) but resulted in coloring of the solution
1.5-1.7).144 The initiation efficiency was low (∼10%), due to free copper complexes.
and decomposition of the complex was observed. A ruthenium complex (Ru-1) can also be supported
on a silica gel such as SL-6.148 The ruthenium-
9. Immobilized Catalysts catalyzed MMA polymerization gave controlled mo-
lecular weights, closer to the calculated values, and
Immobilized catalysts have been studied in metal-
narrow MWDs (Mw/Mn ) 1.5-1.7). Block copolymer-
catalyzed living radical polymerization for, in part,
ization as well as the reuse of the catalysts is
easy removal of the catalysts from the products. In
possible. The polymerization was faster in the pres-
most examples, the catalytic metal centers are at-
ence of SL-6 than in the absence, most probably due
tached to solid supports, such as silica gel and
to the effects of amines as additives as will be
polystyrene beads, via spacers and/or coordinating
discussed below (section II.D). The residual ruthe-
ligands (Figure 7). The central metals thus far
nium in the reaction mixture was estimated to be
employed include copper and ruthenium.
about 10% of the initial feed.
A similar, physically bound CuBr catalyst on a
silica gel support (L-29) was also employed for MMA
polymerization.149 The polymers had narrow MWDs
(Mw/Mn ≈ 1.3), but the molecular weights were higher
than the calculated values. The recycled catalysts
have a lower activity but lead to better control of
molecular weights; i.e., the Mn agreed well with the
calculated values, and the MWDs were narrower (Mw/
Mn ≈ 1.2). The physically supported catalysts were
further employed for the synthesis of end-function-
alized polymers.150 When physically supported silica
gel catalysts are packed into a continuous column
reactor, a controlled polymerization is possible.151
In contrast, unsupported catalysts can be removed
by precipitation of polymers,152 passing through an
alumina column,152 or using an absorbant,27 but
complete removal is difficult. The use of ion-exchange
resins was investigated and seems more practical.153
Figure 7. Ligands for immobilized catalysts.
Another efficient method for catalyst removal is to
use special ligands or catalysts such as L-26115 and
Several silica-based materials such as silica gels, Ru-3,59 which can be removed with the use of fluoro
silica powder, and fumed silica (Aerosil) were em- solvents and water, respectively. Ionic liquid can also
ployed as supports for CuBr by modification of their be employed for catalyst removal (section II.E.5).
surface as in SL-1.145 Thus, for instance, bulk polym-
erization of styrene was investigated but resulted in
polymers of uncontrolled molecular weights and
B. Initiators
broad MWDs (Mw/Mn ) 2-10) due to the slow The role of the initiator in metal-catalyzed living
deactivation or initiation of the growing radical radical polymerization is to form an initiating radical
species relative to propagation. Organic polymer- species via homolytic cleavage of its labile bond such
supported ligands on a cross-linked polystyrene as C-halogen by the metal catalysts. In most cases,
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3701
the dissociated halogen or its equivalent is subse- monomers and metal complexes. There have been
quently reattached to the propagating radical chain some papers discussing various halide initiators in
end to give a dormant species. The initiator is thus the metal-catalyzed living polymerization.154,155
chosen so that the initiation occurs fast and is
quantitative, with the dormant polymer chain end 1. Haloalkanes
being stable during the polymerization. This means Carbon tetrachloride (I-1) was the first initiator
that the initiator should be carefully selected in employed for the metal-catalyzed living radical po-
accordance with the structure and reactivity of the lymerization of MMA in conjunction with Ru-1.27 The
monomers and metal complexes. Mn values increase with conversion and are controlled
Most of the initiators thus far successfully em- by the molar ratio of monomer to initiator. They
ployed are organic halides with a potentially active agree with the calculated values assuming that one
carbon-halogen bond, which can easily generate a molecule of CCl4 generates one living polymer chain,
radical species through electronic and steric effects but become smaller at the later stages of the poly-
of their substituents (Figure 8). These organic halides merizations. Despite CCl4 being a chain-transfer
therefore possess surplus halogens or conjugated agent or a telomer in free radical polymerization, no
substituents such as allyl, aryl, carbonyl, and cyano evidence is found to suggest such reactivity in the
groups for stabilization of the generated radical metal-mediated processes; the initiator is quantita-
species by the inductive and/or resonance effects. tively consumed during the early stages. A similar
However, in some cases, an extensive stabilization result was also obtained in the Cu(I)-catalyzed MMA
of the initiating radical may disturb its addition to polymerizations.156,157
the monomer and thus result in slow initiation, which Another possible problem is that such polyhalogen
causes uncontrolled molecular weights and/or broad compounds may act as multifunctional initiators to
MWDs. An organic halide, the structure of which is give telechelic or star polymers. The initiating moiety
similar to that of the dormant chain end of the thus involved midchain (---CCl2---) may also induce
polymer, is preferentially used so that the activity side reactions, and in fact the lower Mn at the latter
of the carbon-halogen bond in the initiator is similar stages of the polymerizations of MMA is due to the
to that of the dormant polymer terminal. generation of new polymer chains via chain trans-
Halogens (X) in the initiators (R-X) include chlo- fer.156 CCl4 can be also employed for other metal
rine, bromine, and iodine, where the reactivity of the complexes such as Fe,70 Ni,132 Pd,137 and Rh138,140 as
C-X bond increases in the order Cl < Br < I, but well as other monomers such as styrene84 to give
the stability of the C-X bond decreases vice versa. well-controlled molecular weights and relatively nar-
Chlorides and bromides have thus been widely row MWDs (Mw/Mn ) 1.3).
employed. A series of 1,1,1-trichloroalkanes (I-2 to I-6) were
The following summarizes various initiators in examined as initiators for the Cu(I)-catalyzed poly-
terms of their structures, focusing on available merizations of styrene,158 MMA,156 and MA.156 These
3702 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
polychloroalkanes are efficient initiators to give larly suited for controlling polymerizations of sty-
controlled molecular weights and narrow MWDs (Mw/ renes. The first example of the controlled radical
Mn ) 1.1-1.7; narrowness depending on the initia- polymerization of styrene indeed involves I-13 (X )
tors and monomers), with most of them serving as Cl) and CuCl/L-1, where the Mn increased in direct
bifunctional initiators. In contrast, CHCl3 (I-2) is not proportion to monomer conversion and agreed well
a good initiator in the Ru-1-based system probably with the calculated values in a molecular weight
due to the low activity or the high redox potential of range from 4000 to 100000.28 The relatively broad
the ruthenium complex relative to the copper cata- MWDs with the chloride I-13 (X ) Cl) are improved
lyst.154 1,1-Dichloroalkanes such as CH2Cl2 and CH3- by using the bromide counterpart I-13 (X ) Br) for
CCl2CH3 and monochloroalkanes such as C4H9Cl are CuBr/L-4 (Mw/Mn ≈ 1.5 vs 1.1).84,85
totally inactive with Cu(I) and Ru(II) complexes.84,154,156 The activity of the carbon-halogen bonds of I-13
A haloalkane with mixed halogens (I-7) led to living (X ) Cl, Br) as well as I-12 (X ) Br) in the Cu(I)/L-3
polymerization of methacrylates, acrylates, and acryl- system was examined by monitoring the capping of
amides when coupled with ruthenium and nickel the generated radical species by TEMPO in toluene-
complexes.133,135,159,160 The weak C-Br bond is pref- d8.163 The activation energy of the C-X bonds de-
erentially activated, while multifunctional initiation creased in the order I-13 (X ) Cl) > I-12 (X ) Br) >
is possible. However, CCl3Br is the initiator of choice I-13 (X ) Br), which would reflect the rate of
if obtaining narrow MWDs is desired without paying initiation and thereby the MWDs of the produced
attention to monomer structures. polymers. The bromo initiator I-13 (X ) Br) can be
The use of perfluoroalkyl iodides I-8 and I-9 and also employed with iron complexes such as Fe-271 and
iodoform (I-10) was also studied in the Ru(II)- and a mixture of FeBr2 and a nitrogen- or phosphine-
Cu(I)-based systems for styrene and MA.57,142 Fine based ligand74 to give polystyrene with narrow MWDs
control of molecular weights and MWDs was attained (Mw/Mn ) 1.1-1.2). The chloride I-13 (X ) Cl) and
for the former monomer, although an iodine-transfer the bromide I-13 (X ) Br) are not suited for the
mechanism could not be totally ruled out. styrene polymerization with ruthenium (Ru-1), giving
broader MWDs [Mw/Mn > 2 (X ) Cl), ≈ 1.9 (X ) Br)]
2. Allyl Halides while the molecular weights were controlled with the
Allyl radical is relatively stable due to the conjuga- latter.57 However, the iodide I-13 (X ) I) gives
tion of a vinyl group with the carbon-centered radical. controlled molecular weights and narrower MWDs
Allyl chloride and bromide (I-11, X ) Cl, Br) were (Mw/Mn ≈ 1.5) in conjunction with Ru-1. The use of
thus employed as initiators for controlled radical an iodide complex such as Re-1 is preferred with such
polymerization of styrene in conjunction with CuCl/ an iodide initiator to avoid halogen-exchange reac-
L-1 and CuBr/L-1, respectively.161 The molecular tions, and polystyrenes with narrower MWDs (Mw/
weights agreed well with the calculated values as- Mn ≈ 1.2) are produced.141
suming the formation of one living polymer chain per Radical species can be generated more easily from
initiator and increased in direct proportion to mono- benzhydryl chloride (I-14), carrying two phenyl groups.
mer conversion. The MWDs were narrower with This compound induced the radical polymerization
bromide than with chloride (Mw/Mn ≈ 1.2 vs 1.3). of MMA catalyzed by CuCl/L-4 to give narrow MWDs
(Mw/Mn ) 1.1-1.2),164 although it should be added
3. (Haloalkyl)benzenes slowly into the mixture to suppress bimolecular
A series of (haloalkyl)benzenes (I-12 to I-15) were termination of the initiating radical spceis.155 Intro-
extensively examined and proved effective specifically duction of an additional chlorine at the R-position,
for polymerizations of styrene and its derivatives, due as in I-15, is effective in narrowing MWDs in the Cu-
to the benzyl radical being similar to the growing (I)-catalyzed polymerization of styrene and MMA.165
radical chain ends therein. Among them, benzyl It serves as a bifunctional initiator for the former and
chloride (I-12, X ) Cl), which forms a primary a monofunctional initiator for the latter.
radical, has the strongest carbon-halogen bond, but
4. Haloketones
induces the controlled radical polymerization of
styrene with CuCl/L-1 in the bulk at 130 °C.84 The As described above, radical formation is favored by
MWD is slightly broader than that obtained with introducing an electron-withdrawing and conjugating
CCl4 under similar conditions, due to the slow initia- substituent in the R-position relative to the C-halo-
tion (Mw/Mn ) 1.45 vs 1.30). A similar slow initiation gen bonds. A series of haloketones (I-16 to I-18)
was observed for benzyl bromide (I-12, X ) Br) in proved effective especially in Ru(II)- and Ni(II)-
the polymerization of styrene with CuBr/L-4, while mediated living radical polymerizations of MMA. The
the MWDs were quite narrow (Mw/Mn ) 1.2).162 This PMMA obtained with trichloro- (I-16) and dichlo-
initiator can also be employed with the CuCl/L-4 pair roketones (I-17) in the presence of Ru-1 had con-
for MMA to give relatively narrow MWDs (Mw/Mn ≈ trolled Mn in direct proportion to monomer conver-
1.3); note that this system involves halogen exchange sion, in good agreement with the calculated values,
between the initiator/dormant end and the metal and narrow MWDs (Mw/Mn ) 1.1-1.2).56 A similar
catalyst (section II.F.5). living polymerization is possible with more active
1-Phenylethyl halides (I-13, X ) Cl, Br, I), adducts Ru(II) complexes such as Ru-258 and Ru-5.60 The
of styrene and the corresponding hydrogen halide, controllability of polymerizations with I-17 is supe-
can be considered as a unimer of the dormant C-X rior to that with CCl4 when coupled with Ru-1, while
terminal of polystyrene, and thus they are particu- it serves as a bifunctional initiator.154 A monofunc-
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3703
tional bromoketone (I-18) is specifically effective in copper,84,100 and nickel132-136 complexes to give well-
nickel-catalyzed living radical polymerizations of controlled molecular weights and narrow MWDs (Mw/
MMA.132,135,136 However, haloketones are generally Mn ) 1.1-1.5). Similarly, I-24 (X ) Br) is suitable
too reactive for the copper-catalyzed homogeneous for styrene and acrylates with ruthenium,60 iron,73
systems and result in uncontrolled polymerizations copper,84 and nickel catalysts.135 An iodoester (I-24,
probably due to the reduction of the electrophilic X ) I) was specifically employed with iodo complexes
radical species into anions by the highly active Cu(I) of Re and Fe to initiate living radical polymerization
catalysts.155 of styrenes and acrylates, where it performs as a
better initiator than other iodides such as I-13 (X )
5. Haloesters I) and I-21 (X ) I).72,73,141,142,169 In contrast, the
Relative to haloketones, haloesters have been suc- chloride versions such as (CH3)2C(CO2CH3)Cl are
cessfully employed with a wider range of metal poor initiators for MMA, although they can be
complexes, including Ru, Fe, Cu, Ni, etc. A less regarded as a unimer of PMMA with a C-Cl dormant
electron-withdrawing ester group can moderately terminal.170 The problem with the chloride initiators
activate the carbon-halogen bond and does not make can be overcome with a dimer type of initiator, i.e.,
the resulting radical too electrophilic. This type of MMA dimers capped with chlorine (I-25, X ) Cl),
initiator can be more versatile for various monomers which achieves fast initiation catalyzed by Ru-1 to
including styrenes, methacrylates, acrylates, etc. by give well-controlled molecular weights and narrower
careful design of their structures. Some specific MWDs (Mw/Mn ≈ 1.3). This is most probably due to
examples follow. electronic and/or steric effects. The former is related
to the electron-deficient R-carbon atom, which is
Trichloroacetate I-19 and dichloroacetate I-20 can
suggested by the lower-field 13C NMR chemical shifts
be employed for the Ru-1-mediated living radical
relative to that in the unimer I-24, while the latter
polymerization of MMA to give narrow MWDs (Mw/
factor is related to the so-called back strain effect,
Mn ≈ 1.2), where the latter seems to be monofunc-
which makes the dissociation of the C-Cl bond easier
tional.56,154
during the rehybrdization of the R-carbon from sp3
A series of R-halopropionates (I-21 and I-22, X ) to sp2, thus relieving steric hindrance. When coupled
Cl, Br), model compounds of the dormant polymer with Ru-6, the dimer initiator is highly versatile and
terminal of acrylates, are suitable for not only acry- can be employed for not only MMA but also styrene
lates but also styrenes and acrylamides. Ethyl 2-chlo- and MA to give narrow MWDs under the same
ropropionate (I-21, X ) Cl) was employed for the conditions (Mw/Mn ) 1.1-1.2) as describe above.62 A
controlled radical polymerizations of MA and styrene similarly higher reactivity of the dimer-type com-
catalyzed by CuCl/L-1 to afford relatively narrow pound was observed for the bromide version I-25 (X
MWDs (Mw/Mn ≈ 1.5).84 A better controlled polym- ) Br), which can be employed for MMA with Ru-1170
erization of MA is achieved with the bromides I-21 and Ni-3.60,135
and I-22 (X ) Br) in conjunction with CuBr/L-1 to
The malonate-type initiator I-26 can generate a
give narrower MWDs (Mw/Mn ≈ 1.2).84 A similar
stabilized initiating radical rapidly and can be em-
result was obtained with the combination of I-23 and
ployed for the living radical polymerization of MMA
CuBr/L-1 for the polymerization of styrene.166 A
with Ru-1154 and Fe-170 to afford narrow MWDs (Mw/
nickel-based system with Ni-2 and I-21 (X ) Br) gave
Mn ≈ 1.2) but slightly higher Mn values than the
another controlled polymerization of nBA.134 The
calculated values. Control of molecular weights for
iodide compound I-21 (X ) I) is specifically effective
PMMA is achieved with the I-26/CuBr/L-4 system,
in conjunction with an iodide complex such as Re-1
while no polymerizations occurred with CH(CO2-
to induce controlled polymerization of styrene.141
Et)2Br.155
R-Halopropionates are generally less suitable for
MMA polymerization due to the low reactivity of their A compound such as I-27, which possesses one
C-X bonds compared with that of the dormant ester and one phenyl group adjacent to the chlorine
methacrylate terminal, due to the difference in the atom, induces controlled polymerization of both MMA
reactivity of secondary and tertiary halides.154 How- and styrene in the presence of CuBr/L-1.171 The
ever, the use of a halogen-exchange method for I-21 initiation occurs faster than with I-21 (X ) Cl) and
(X ) Br) and CuCl/L-1 improves MMA polymeriza- CH2ClCO2C2H5, both of which have no phenyl sub-
tion to give controlled molecular weights and narrow stituent. A bromide (I-28) with a similar structure
MWDs (Mw/Mn ) 1.2-1.4), where a less reactive proved effective in the CuBr/L-24-mediated polym-
chlorine-capped dormant species is generated after erization of MMA.149
the initiation.167 Controlled polymerization of N,N-
dimethylacrylamide has been achieved with I-22 (X
6. Haloamides
) Cl) in conjunction with CuCl in toluene at 20 °C.168 Bromides with N,N-alkylamide groups (I-29 and
2-Bromoisobutyrate I-24 (X ) Br), a unimer model I-30) can be good initiators for acrylamides. They
of poly(methacrylate) with a dormant C-Br terminal, were employed for the Ru-catalyzed polymerization
is more versatile for various monomers such as of N,N-dimethylacrylamide (DMAA) to give con-
methacrylates, acrylates, and styrenes; various metal trolled molecular weights and broad MWDs (Mw/Mn
complexes including Ru, Fe, Cu, and Ni can be ≈ 1.6).160 In contrast, the chloride version CH3CH-
employed in this case. Living or controlled radical (CONMe2)Cl failed to give controlled molecular
polymerization of MMA was successfully done with weights,160 and similar halides without alkyl substit-
I-24 (X ) Br) coupled with ruthenium,56 iron,70,71 uents on the amide nitrogens, such as CH3CH-
3704 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
(CONH2)X (X ) Cl, Br), do not lead to controlled observed when compared with that of bromoisobu-
polymerization of DMAA.172 tyrate [I-24 (X ) Br)]/CuBr/L-9 in p-xylene.179
Perfluoroalkanesulfonyl halides I-35 and I-36 in-
7. Halonitriles duced controlled polymerization of styrene and MMA
Halonitriles I-31 (X ) Cl, Br), unimer models of in the presence of copper catalysts, although the
halogen-capped dormant poly(acrylonitrile), are spe- initiation efficiency is lower.177 With the alkanesulfo-
cifically employed for the polymerization of acrylo- nyl halides I-35 and I-36, decomposition by loss of
nitrile with copper halides. Controlled molecular SO2 from the initial sulfonyl radical occurs to give a
weights and narrow MWDs (Mw/Mn ) 1.1-1.4) are perfluoroalkyl radical, which then adds to the mono-
achieved.173,174 The strong electron-withdrawing cy- mer to initiate the polymerization.
ano group facilitates the formation of the initiating The use of arenesulfonyl halides was also investi-
radical, and may thus be employed for other mono- gated for the ruthenium-catalyzed polymerization of
mers such as MMA with Fe catalysts74 and styrene MMA.180 Living polymers are indeed attained, where
with CuCl/L-1.84 the R-end group (Fn ≈ 1.0) and the MWDs are
controlled (Mw/Mn ) 1.2-1.5), whereas the Mn values
8. Sulfonyl Halides were higher than the calculated values due to low
Sulfonyl halides, particularly arenesulfonyl ha- initiation efficiency (Ieff ≈ 0.4).
lides, can afford radical species much faster than
carbon halides by the assistance of a metal complex 9. Conventional Radical Initiators
and efficiently add to olefins with little dimerization Another route to the metal-catalyzed living or
of sulfonyl radicals in comparison to carbon-centered controlled radical polymerization is through initia-
radicals. Another feature of the compounds is that tion by a conventional radical initiator (A-A) such
there is little effect of the substituents on the rate of as AIBN in conjunction with a metal complex
addition to an olefin. These properties make sulfonyl [Mn+1Xn+1Lm] at a higher oxidation state, for example,
halides an efficient and “universal” series of initiators CuCl2/L-1 (Scheme 4). This system is sometimes
for the metal-catalyzed living radical polymerizations
of various monomers including methacrylates, acry- Scheme 4. Reverse-Type Metal-Catalyzed Living
lates, and styrenes (Figure 9).152,175-177 Radical Polymerization
with the Ru(II)-Cp* complex (Ru-6) in the presence copper-based system, consisting of I-31 (X ) Cl, Br),
of Al(O-i-Pr)3 in toluene at 80 °C.62 CuX (X ) Cl, Br), and L-1 in ethylene carbonate at
A series of substituted styrenes (M-19 to M-27) 45-65 °C.173,174 The Mn is controlled up to 30000,
were polymerized with the I-13 (X ) Br)/CuBr/L-1 keeping relatively narrow MWDs (Mw/Mn < 1.5). The
system in diphenyl ether at 110 °C to give controlled end-group analysis showed some loss of the terminal
Mn that increased in direct proportion to monomer halogen most probably due to the reduction of the
conversion.206 The polymerization rate was faster growing radical by CuX to form the corresponding
with more electron-withdrawing substituents due to polymer anion that subsequently deactivates quickly.
the increase of monomer reactivity and the carbon-
halogen bond in the dormant species. The MWDs of 6. Acrylamides
the polymers with electron-donating substituents (M- Polymerizations of acrylamides were investigated
24 and M-25) were relatively broad (Mw/Mn ) 1.4- with several systems based on copper and ruthenium.
1.7). Introduction of a strongly electron-donating The system with Ru-1 and a bromide initiator such
substituent such as a methoxy group gave only as I-29 in the presence of Al(O-i-Pr)3 induced quan-
oligomers, probably because of the formation of titative polymerizations of M-36 in toluene at 60-
cationic propagating species via the heterolysis of the 80 °C to give polymers of controlled molecular
dormant C-Br. weights and relatively broad MWDs (Mw/Mn ≈ 1.6).160
Though not in the late-transition-metal family, a In contrast, molecular weight control is difficult with
rhenium complex is applicable for both electron- a chloride initiator. The copper-based systems are
donating (M-24) and -withdrawing (M-22) groups to applicable, but the polymerization strongly depends
give well-controlled molecular weights and narrow on the initiators, copper halides, ligands, tempera-
MWDs (Mw/Mn ) 1.2-1.3).169 Living radical polym- tures, and solvents. Namely, in some cases the
erization of 4-acetoxystyrene (M-28) was reported polymerizations were not quantitative due to side
with the use of a copper-207 or iron-based169 system. reactions such as cyclization and loss of terminal
The acetoxy groups in the polymers can be removed halogens.117,168,172 Among them, I-22 (X ) Cl)/CuCl/
after the polymerization to form poly(p-vinylphenol) L-32 induced the best controlled polymerization in
with controlled molecular weights.208 Copolymeriza- toluene at 20 °C to give narrow MWDs (Mw/Mn )
tions of M-29 or M-30 with styrene were studied with 1.1-1.2), though limited to 80% conversion.168 Simi-
the copper-based systems to give well-controlled lar controlled polymerizations were also feasible for
copolymers.209 Rhenium (Re-1) and iron (Fe-5) com- M-37 and M-38 with the same initiating system.168
plexes induced polymerization of M-30 in conjunction Unsubstituted acrylamide (M-39) was polymerized
with I-24 (X ) I) to give controlled molecular weights with CuCl/L-1 in conjunction with benzyl chloride
but relatively broader MWDs (Mw/Mn ≈ 1.8) due to I-12 (X ) Cl) or with a surface-confined initiator in
side reaction of its benzyl group.169 Controlled po- DMF at 130 °C.216-218 The polymers obtained with
lymerization of a silyl-substituted styrene (M-31) was I-12 were analyzed by matrix-assisted laser desorp-
also achievable.210 4-(Chloromethyl)styrene (M-32), tion-ionization time-of-flight mass spectrometry
which has a reactive C-Cl bond in the unit, is (MALDI-TOF-MS), which showed monomodal MWDs,
polymerized with the copper-based systems to pro- but there was no detailed analysis of the polymer.
duce a hyperbranched or linear polymer depending The polymer obtained by the surface initiation had
on the conditions.211-213 This will be discussed later narrow MWDs (Mw/Mn ) 1.1-1.3).
in Precision Polymer Synthesis (section III.I).
7. Other Monomers
4. Vinylpyridines
Via metal catalysis, cyclic monomers such as N-
Metal-catalyzed living radical polymerizations of substituted maleimides M-40, M-41, and M-42 do not
vinylpyridines were investigated with the copper- homopolymerize but can copolymerize with vinyl
based systems. One of the difficulties in the polym- monomers, among which alternating copolymers can
erization is a decrease of catalytic activity imposed be obtained with styrene via a radical mechanism.
by the coordination of the monomers by the metal The I-13 (X ) Br)/CuBr/L-1 system induced alternat-
complex. Controlled radical polymerization of 4-vi- ing copolymerizations with styrene to give controlled
nylpyridine (M-33) was achieved by an initiating molecular weights and narrow MWDs (Mw/Mn ) 1.1-
system consisting of a strong binding ligand such as 1.4) in the bulk or anisole at 80-110 °C.219-222
L-32 and a chloride-based system [I-13 (X ) Cl)/ A bicyclic monomer containing a maleate ester unit
CuCl] in 2-propanol at 40 °C.214 The Mn increased in (M-43) undergoes a very slow 2,6-addition polymer-
direct proportion to monomer conversion, and the ization with I-12 (X ) Cl)/CuCl/L-1 in the bulk at
MWDs were narrow (Mw/Mn ) 1.1-1.2). In contrast, 130 °C to afford narrow MWDs (Mw/Mn ≈ 1.2) (11%
2-vinylpyridine (M-34) can be polymerized in a conversion in 2 weeks).223 Enchainment of this mono-
controlled way with chlorine-capped polystyrene as mer to the chlorine-terminated polystyrene increases
an initiator and the CuCl/L-1 pair in p-xylene at 140 the decomposition temperature of the polymer.
°C.215 Block copolymers with narrow MWDs (Mw/Mn Ring-opening living radical polymerization was also
) 1.1-1.2) were obtained therein. reported for M-44, where the I-23/CuBr/L-1 system
gave polymers with controlled molecular weights and
5. Acrylonitrile
narrow MWDs in the bulk at 120 °C.224 However,
A good control of molecular weights and MWDs unlike in conventional radical polymerization, the
was accomplished for this monomer (M-35) with a content of the ring-opened units is not 100% but
3708 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
varies from 38% to 67% depending on the conditions. MMA, and EA were possible with an organic bromide
Cationic polymerizations concurrently occur, which and CuBr2 in the presence of Al(O-i-Pr)3.93,94
can be suppressed by the addition of pyridine. The addition of aluminum compounds was initially
As pointed out, living radical polymerization of less intended to increase the monomer reactivity via
conjugated monomers such as vinyl acetate has not coordination to its carbonyl group or to increase the
been achieved yet. However, irreversible activation reactivity of the terminal group via the coordination
of the carbon-halogen bond in CCl4 with Fe(OAc)2/ of the terminal carbonyl group.27 However, this
L-24 generates trichloromethyl radical to induce possibility proved less probable, because strong Lewis
radical polymerization of vinyl acetate via the radical acids such as SnCl4 were not effective in a similar
telomerization mechanism.225 The molecular weights acceleration.227 There was no increase in the halogen-
can be controlled by the molar ratio of monomer to exchange rate in the model reaction between I-24 (X
CCl4 although the MWDs were broad in the usual ) Br) and Ru-1 on addition of Al(O-i-Pr)3, while
radical telomerization (Mw/Mn ≈ 1.8). under similar conditions the polymerization rate was
Polymerization of ethylene is one of the most clearly increased relative to that of the additive-free
important unsolved problems in metal-catalyzed liv- system.170 Possible interactions between the added
ing radical polymerization. This is due to the dif- Al(O-i-Pr)3 and monomer, terminal group, and ru-
ficulty of the activation of the primary carbon- thenium complex were investigated with the use of
halogen bond. The unpolymerizable nature of ethylene kinetics, NMR, and cyclic voltamometry.227 These
can be utilized for the end-functionalization of studies suggest that the added metal compounds
PMMA with a terminal CH2CH2Br group (section most probably interact with the metal catalysts in
III.B.2).226 their higher oxidation states, or increase the concen-
trations of radical species out of the coordination
spheres, resulting in smooth redox reactions. Further
D. Additives studies are required to clarify these interesting
Metal-catalyzed living or controlled radical poly- features of metal-mediated radical processes.
merizations can generally be achieved with initiating Zerovalent metals such as Cu(0) and Fe(0) can
systems consisting of an organic halide as an initiator effectively reduce CuBr2 and FeBr3 into active CuBr
and a metal complex as a catalyst or an activator as and FeBr2, respectively, to dramatically increase the
described above. However, these polymerizations are polymerization rate.129 For example, addition of Cu-
slow in most cases due to low concentration of the (0) to the polymerization mixture of MA with I-22 (X
radical species, as required by the general principle, ) Br)/CuBr/L-4 in the bulk at 90 °C increased the
the dormant-active species equilibria, for living radi- rate by about 10 times; i.e., the reaction reached 97%
cal polymerization (see the Introduction). conversion in 570 min without additives, whereas
A promising solution for this inherent problem is 96% in 55 min in the presence of Cu(0). This is
the use of additives. Some additives are needed for attributed to the removal of a small amount of Cu-
acceleration and/or better control of the polymeriza- (II) species generated via irreversible termination of
tions. These additives most probably can effectively the growing or the initiating radical species. A similar
reduce the metal species in higher oxidation states fast polymerization is possible with CuBr2 in the
or form more efficient catalysts via coordination. presence of Cu(0). This allows the controlled radical
Metal alkoxides such as Al(O-i-Pr)3 are employed polymerization even in the presence of oxygen or
for the ruthenium-, iron-, nickel-, rhenium-, and without purification of the monomer, where Cu(0)
copper-catalyzed polymerizations and are effective in and Fe(0) can reduce the generated Cu(II) and Fe-
increasing the polymerization rate as well as nar- (III) species into active Cu(I) and Fe(II), respec-
rowing the MWDs of the produced polymers. In fact, tively.230 The I-13 (X ) Br)/CuBr2/Cu(0)/L-4 system
the use of such additives can be found in the first induced a fast polymerization of unpurified styrene
examples of metal-catalyzed living radical polymer- at 110 °C to reach 90% conversion within 2 h.
ization. Thus, for the mild catalyst Ru-1, MeAl- Controlled molecular weights and narrow MWDs are
(ODBP)2 was added to achieve a faster and quanti- available even when the polymerization is performed
tative polymerization of MMA with CCl4 in toluene in ampules sealed in air. However, no polymerization
at 60 °C.27 A trialkoxide [Al(O-i-Pr)3] is less active occurred open to air.
as an additive but more effective in controlling the Phenols usually serve as radical inhibitors in
molecular weights and MWDs than MeAl(ODBP)2.56,198 conventional radical polymerization but can enhance
Other metal alkoxides such as Ti(O-i-Pr)4 and Sn(O- the polymerizations of MMA with I-21 (X ) Br)/CuBr/
i-Pr)4 induce faster polymerizations of MMA with L-9 (R ) n-Pen).231 For example, on addition of 10
Ru-1 than Al(O-i-Pr)3, while the controllability is equiv of 2,6-di-tert-butyl-4-methylphenol with respect
lower.227 Aluminum acetylacetonate [Al(acac)3] is an to initiator ([I-21]:[CuBr]:[L-9]:[phenol] ) 1:3:1:10),
alternative mild additive that does not induce an the conversion increased from 55% to 75% in 4 h in
ester-exchange reaction between the ester group and xylene at 90 °C without any changes in the MWDs.
the monomer or monomer units in the polymer chain, Similar effects were observed for 4-methoxyphenol,
which might occur with aluminum alkoxides.228 These phenol, and 2,6-di-tert-butylphenol.231-233 No inhibi-
metal alkoxides are also effective for other complexes tion but enhancement of the polymerization by the
such as Fe-3,72 Ni-2,133 Re-1,141 and CuBr/L-1.229 Al- addition of phenols may suggest that the growing
(O-i-Pr)3 can even make the Cu(II) species active, species is different from that in conventional radical
where the controlled polymerizations of styrene, polymerization. However, phenols do not act as
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3709
inhibitors even for some conventional free radical the catalysts but also acceleration and better control
(meth)acrylate polymerizations as suggested else- of the polymerization. Due to the radical nature of
where.155 An explanation is that the added phenols the polymerizations, even protic solvents such as
substitute nitrogen-based ligands on copper catalysts alcohol and water can be employed. Some of these
to increase the catalytic activity, which is suggested solvents, e.g., toluene, are known as chain-transfer
by the isolation of methanol-coordinated catalysts234 agents, but the effects of potential chain-transfer
and NMR analysis of the mixture of catalysts and agents have not yet been examined well in metal-
phenols.233 catalyzed living radical polymerizations.
Benzoic acid also increases the polymerization rate
with copper catalysts, most probably via displace- 1. Aprotic Polar Solvents
ment of the nitrogen ligand and creation of a coor- Aprotic polar solvents thus far employed in metal-
dination site on the metal.235 Similarly, carboxylate catalyzed polymerizations include dimethoxybenzene
salts such as sodium benzoate and acetate have (DMB), diphenyl ether (DPE), ethylene carbonate,
remarkable effects on rate enhancement.107 Addition acetonitrile, N,N-dimethylformamide (DMF), and
of sodium benzoate, 4 equiv with respect to CuCl, to acetone, among others. Most of them are employed
I-32 (Y ) OCH3)/CuCl/L-1 enhances the polymeriza- for copper catalysts because of their low solubility.
tion rate of nBMA 2.4 times in diphenyl ether at 120 For well-solubilized Ru(II), Ni(II), and Fe(II) com-
°C, where the reaction reaches 90% conversion in 1 plexes with phosphine or other ligands, such an
h. The MWDs were still narrow. A similar rate additional precaution is not necessary, and toluene
enhancement was observed with a mixture of para- or other relatively nonpolar solvents have mostly
substituted benzoic acids and metal carbonates M2- been used.
CO3 (M ) Cs, K, Na, Li). These are due to in situ
formation of cuprous carboxylate that has higher Unsubstituted 2,2′-bipyridine (L-1) cannot com-
activity as described above (section II.A.3). pletely solubilize copper halide in the bulk or non-
The ruthenium-catalyzed living radical polymer- polar solvents, and thus the polymerization systems
izations provide good cases for considerable accelera- are heterogeneous as described above. Various sol-
tion by the addition of alkylamines.61,236 For example, vents were thus investigated in the polymerization
on addition of n-butylamines to the polymerization of nBA with I-22 (X ) Br)/CuBr/L-1, and ethylene
of MMA with I-25 (X ) Cl)/Ru-1 in toluene at 80 °C, carbonate proved effective in fast and homogeneous
the rate was increased dramatically. Time for 75% living polymerizations.239 Relative to the heteroge-
conversion: 269 h (no additive) > 29 h [Al(Oi-Pr)3] neous systems, these reactions give polymers of
> 17 h (n-Bu3N) > 9 h (n-Bu2NH) > 4 h (n-BuNH2). narrower MWDs. This is due to the increased solubil-
n-Bu3N and n-Bu2NH gave narrow MWDs (Mw/Mn ity of the copper complex and/or to the change in the
) 1.2) and controlled molecular weights, similarly to structure of the copper species (known to form a
Al(O-i-Pr)3, but broad MWDs were obtained with dimeric species in organic media) into a monomeric
n-BuNH2 (Mw/Mn ≈ 1.8). These added amines most form. Similar effects were observed for DMF and
probably coordinate to the ruthenium complex to acetone in tert-butyl acrylate (tBA) polymerizations
produce more active complexes, as suggested by NMR with I-22 (X ) Br)/CuBr/L-24.202 Styrene polymeri-
analysis of amine/Ru(II) catalyst mixtures. An in- zation with I-13 (X ) Cl)/CuCl/L-1 at 130 °C became
creased catalytic activity was also observed on addi- homogeneous in the presence of a limited amount of
tion of silica gel supported amine ligands.148 DMF (∼10% v/v) to give polymers with well-con-
trolled molecular weight up to 40000.88 Copper-based
In the heterogeneous systems based on Cu2O/L-1
systems with bipyridines, such as R-Cl/CuCl/L-4, are
and Cu(0)/L-1, phase-transfer catalysts such as C(CH2-
not suited for controlling methacrylate polymeriza-
OCOPh)4 and poly(ethylene glycol) can increase the
tion in the bulk or in nonpolar solvents, but are
rate and control the polymerization more precisely.107
effective in DPE solvent, where monomeric copper
Rate enhancement can also be achieved by irradia- species may form.107,126,164,178,240 Acetonitrile is another
tion of visible light.237 The polymerization of MMA choice of solvent in some Cu-catalyzed polymeriza-
with I-17/CuCl/L-1 in toluene at 80 °C in the dark tions.93,112,167,241
ceased around 40% conversion, but under irradiation
of visible light, the polymerization became quantita- In the homogeneous MMA polymerization with
tive. This is due to a photochemical effect on the I-32 (Y ) CH3)/CuBr/L-9 (R ) n-Pen), the rate
inner-sphere complex between the catalyst and the increased in the order xylene < DMB < DPE,179
dormant alkyl chloride. probably due to the differences in the dielectric
constant and coordination ability of the solvents.
With the homogeneous Ru-1 catalyst, the polymeri-
E. Solvents zation of MMA was faster in a polar solvent such as
Metal-catalyzed living radical polymerizations may CH2Cl2 than in toluene.159 A more detailed analysis
be carried out either in solution or in the bulk. on solvent effects was carried out by end-capping a
Importantly, unlike conventional free radical polym- polymer radical with hydroxyl-TEMPO, where the
erization, the Trommsdrof or gel effect is absent in radical intermediate was generated from bromide
these living processes in the bulk.238 For the solution macroinitiators via CuBr/L-4 catalyst.242 A polar
processes, nonpolar or less polar solvents are em- solvent such as butyl acetate increases the radical-
ployed, such as toluene, xylene, and benzene. Polar generation rate from poly(acrylate)s but not from
solvents are sometimes employed for not only solu- polystyrene. On the other hand, no rate increase was
bilizing the monomers, the produced polymers, and found for both macroinitiators in DMF, which is
3710 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
considered not only a polar solvent but also a the polymerization was heterogeneous due to the
coordinating ligand. hydrophobicity of the initiator.248
A similar effect of water was observed in the iron- nm even without sonication.184,255 There were no
catalyzed polymerization of styrene.76,250 An iron effects of the size and number of particles on the
complex is less stable in water than ruthenium and polymerization rate.252 It is suggested that the nucle-
thus considered difficult to use as an active catalyst ation mechanism in the reverse atom-transfer emul-
in such an aqueous suspension system. For example, sion radical polymerization is different from that in
FeBr2(PPh3)2 (Fe-1, X ) Br; Figure 2) rapidly decom- the conventional processes, because of the lack of
poses upon exposure to water. However, a Cp-based formation of high molecular weight polymers during
iron complex (Fe-3; Figure 2) proved effective in the early stages.255
living radical suspension polymerizations of acrylates Another aqueous heterogeneous polymerization
and styrene to give narrow MWDs (Mw/Mn ) 1.1- was recently reported for the precipitation polymer-
1.2).250 These polymerizations are also clearly faster ization of MMA and styrene complexed with methy-
than those in organic media under otherwise similar lated β-cyclodextrin.256 The polymerization was car-
conditions. ried out in water with I-21 (X ) Br)/CuBr/L-4 to give
Nickel (Ni-1) and palladium (Pd-2) complexes were polymers with controlled molecular weights and
employed for suspension polymerization of MMA in relatively narrow MWDs (Mw/Mn ) 1.3-1.8). Ini-
the presence of a small amount (1-5 wt %) of tially, the reaction mixture was homogeneous with
sorbitane monooleate poly(ethylene glycol) (20) (Tween the hydrophilic cyclodextrin-complexed MMA, but
80) as a surfactant.132,137 The obtained polymer had sooner or later it became heterogeneous due to the
controlled molecular weights and moderate MWDs formation of water-insoluble polymers.
(Mw/Mn ) 1.4-1.7) similarly to those obtained in
toluene, although there was no detailed analysis on 5. Other Special Solvents
the size of the particles. Apart from water, supercritical carbon dioxide
Detailed studies were performed on the copper- (scCO2) is an environmentally friendly solvent and
catalyzed suspension or emulsion polymerizations.249 currently attracts much attention as a medium for
Living or controlled emulsion radical polymerization organic reactions and polymerizations. The solvent
of nBMA can be achieved in the presence of nonionic was also employed for the copper-catalyzed radical
poly(oxyethylene)-based surfactants such as Brij 97, polymerizations of fluorinated (meth)acrylates with
Brij 98, and Tween 20 with the I-21 (X ) Br)/CuBr/ the I-22 (X ) Br)/CuCl initiating system in the
L-3 or L-4 system.249,251,252 The Mn increased in direct presence of Cu(0) and bipyridine-based ligands such
proportion to monomer conversion up to 5 × 104 (Mw/ as L-1, L-4, and L-7.95 A fluorinated ligand (L-7)
Mn ) 1.1-1.2). The particle sizes are around 1000- induced a homogeneous polymerization without any
4000 nm, suggesting a suspension, but can be re- visible precipitation to give polymers with controlled
duced to about 300 nm with the use of hexadecane molecular weights. This system is equally applicable
as a cosurfactant along with ultrasonication.249,252 for random and block copolymerizations between the
Surfactants largely affect the polymerizations. fluorinated monomers and MMA. Dispersion polym-
Anionic surfactants such as sodium dodecyl sulfate erization of MMA was also conducted in scCO2 with
adversely affect the control of molecular weights and poly(perfluorinated acrylate)s as dispersants to form
MWDs, whereas poly(ethylene glycol) facilitates mo- PMMA with controlled molecular weights and rela-
lecular weight control but leads to coagulation.251 tively narrow MWDs (Mw/Mn ) 1.4).
Water-soluble or more hydrophilic ligands such as The use of fluorous solvents or ligands leads to so-
L-1, L-24, L-32, and L-9 (R ) CH2CH2CHPh2) are called fluorous biphasic conditions, where at an
detrimental to the control of molecular weights due ambient temperature two phases separate, the phases
to unfavorable partioning of the Cu(II) species into becoming miscible at a higher temperature. This
water.249,251,253 Other monomers such as MMA, nBA, permits the homogeneous polymerization at high
and styrene can also be polymerized with the copper- temperatures, and the facile separation of products
based systems in emulsion to give polymers with from the catalysts under ambient conditions. A
controlled molecular weights and MWDs.249,251,253 fluorous biphasic system consisting of I-24 (X ) Br),
Random and block copolymerizations of these CuBr, and L-26 was employed for polymerizations
monomers were also investigated with ruthenium, of MMA in an equivolume mixture of (perfluorometh-
iron, and copper catalysts and gave successful results yl)cyclohexane and toluene.115 The polymerization
depending on the conditions.110,250,254 proceeded most likely in a homogeneous phase to give
The so-called reverse atom-transfer radical po- polymers with controlled molecular weights and
lymerization is feasible in aqueous emulsion too. narrow MWDs (Mw/Mn ) 1.2-1.3). They are easily
This system enables the formation of initiating isolated from the organic phase as a colorless glassy
radical species in the water phase with the use of solid with a minimum contamination of copper. It is
water-soluble initiators such as I-39, I-40, and I-41 also reported that the catalysts, largely remaining
as in conventional emulsion radical polymeriza- in the fluorous phase, can be recycled for second and
tion.184,249,252,255 The copper-catalyzed emulsion radical third polymerizations without loss of catalytic activ-
polymerization of nBMA afforded polymers with ity.
narrow MWDs (Mw/Mn ) 1.1-1.4), but the Mn values Another special class of solvent, ionic liquids such
were much higher than the calculated values due to as 1-butyl-3-methylimidazolium hexaflurorophos-
the termination between the initiating radicals in the phate, was used for the polymerization of MMA with
aqueous phase.184,255 The emulsions are relatively I-24 (X ) Br)/CuBr/L-9 (R ) n-Pr), which proceeded
stable and their particle sizes are around 100-300 even at 30 °C, reached 90% conversion within 5 h,
3712 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
and gave polymers with narrow MWDs (Mw/Mn ) However, TEMPO may also deactivate the metal
1.3-1.4).257 The products are easily removed by complexes to form inactive metal species in higher
washing with toluene, while the catalyst is highly oxidation states instead of giving the C-TEMPO
soluble in the ionic liquid and can be reused. terminal.141 A similar inhibition by these compounds
was also observed for living anionic polymerizations
F. Mechanisms and group-transfer polymerizations of MMA, both of
which proceed via an anionic mechanism.263 Alter-
The metal-catalyzed living polymerizations most
natively, some of the phenols, which are scavengers
probably proceed via a carbon-centered radical spe-
in conventional radical polymerizations of styrene,
cies reversibly generated from a carbon-halogen
can increase the polymerization rate as mentioned
terminal (dormant species) and a metal catalyst. The
above (section II.D).231 Though these inhibition effects
radical nature of the polymerizations has been sug-
cannot completely prove radical-growth mechanisms
gested by several facts and observations, some of
for the metal-catalyzed living polymerizations, they
which were already discussed above. This part deals
are at least consistent with the proposed pathways.
with the analysis of the polymerizations based on
various methods and apparatuses for mechanistic 2. Stereochemical Structures
investigation. Short overviews on the mechanistic
studies are also available.258-262 The stereochemistry of polymers, in general, pro-
vides useful information about the polymerization
1. Radical Scavengers mechanism by which they are formed. More specif-
One of the most useful methods to determine a ically in the metal-catalyzed living radical polymer-
polymerization mechanism is to examine the effects ization, it has been anticipated that the proposed
of additives or potential terminating agents (scaven- mechanism via metal-assisted reversible radical gen-
gers or quenchers). Since the beginning of develop- eration (cf. Scheme 3) might induce different and/or
ment of metal-catalyzed living radical polymeriza- better stereochemical control than in the classical
tion, therefore, terminating experiments have been radical counterpart, in which the growing end is a
carried out extensively, and they were particularly really “free” radical. The anticipation originates from
important at that time, because combinations of the fact that the oxidized metal catalyst, with the
haloalkanes and transition-metal catalysts do not halogen from the dormant species, might reside in
automatically warrant radical-growth mechanisms. close vicinity to the resulting radical end, inducing a
As potential terminators, two classes of compounds situation reminiscent of ion pair growing species in
have primarily been employed: protic compounds ionic polymerizations where the counterions exert a
such as water and alcohols, and radical scavengers strong influence on the stereochemistry of propaga-
such as galvinoxyl, 1,1-diphenyl-2-picrylhydrazyl tion.
(DPPH), and TEMPO. Namely, there are well-known Surprisingly or not, the tacticity of PMMA ob-
terminators for anionic and radical growing species, tained with various metals including Ru,27,56,58,63
respectively, and their use was based on the fact that Cu,28,84,97,100,102,103,116,232,263 Fe,70,80 Ni,132,133 Pd,137 and
the monomers employed in the early-phase develop- Rh138 was almost the same (almost atactic, slightly
ment were primarily MMA and styrene, which po- syndiotactic) as the tacticity of those obtained with
lymerize by both mechanisms. conventional radical initiators such as AIBN under
It was soon realized that almost all of the metal- similar conditions. The triad ratio of rr:mr:mm as
catalyzed living processes are not quenched by the determined by 13C NMR is usually 58:38:4 and does
protic compounds but clearly by the radical scaven- not change even with the use of chiral and/or bulky
gers, and this phenomenon was the case for such ligands.103,116 These results may exclude a coordina-
metal catalysts as ruthenium,29,55,56,58,63,66 copper,28 tion mechanism and suggest a radical nature. How-
nickel,132,133,135 rhodium,138 and rhenium.141 The carbon- ever, the stereochemical structure alone is not strong
centered radical most probably reacts with these evidence for the radical polymerization because, for
scavengers (Y) to produce a dead polymer chain end example, group-transfer polymerization, basically via
with inactive covalent C-Y or C-H bond or unsatur- an anionic mechanism, results in a stereo structure
ated carbon-carbon double bond. of PMMA similar to those for free radical processes.263
The first set of quenching experiments has been
3. Copolymerizations
reported for the Ru-mediated polymerization of
MMA,27,55 and the Kyoto group observed the reaction Monomer reactivity ratios in copolymerization and
is immune to methanol and alcohol but is quantita- copolymer structures can also give insight into the
tively terminated with galvinoxyl, DPPH, and TEMPO mechanism of the polymerizations. As observed with
added in 5-10-fold molar excess over the initiator. ruthenium205 and copper,264,265 MMA-styrene and
End-group analysis on the quenched products re- related copolymerizations turned out to be “living” if
vealed that the terminating moieties are not attached initiated with the metal catalysts effective for the
to the growing end; rather exo-olefins result via corresponding homopolymerizations. Besides these
hydrogen abstraction from the MMA’s R-methyl synthetic aspects to be covered later in this review
group. (section III.D), the results also give some insight into
On the other hand, the formation of C-Y bonds the reaction mechanisms. With a ruthenium catalyst
was observed in the copper-catalyzed model reactions (Ru-1), MMA and styrene were copolymerized at
between the isolated polymers or model compounds varying monomer feed ratios.205 The products were
such as I-13 and TEMPO or hydroxy-TEMPO.163,242 true copolymers, as evidenced by single MWD profiles
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3713
by size-exclusion chromatography (SEC) and a set of the halogens at a dormant polymer terminal ex-
heteroenchainment NMR signals, among others. The change with those in a metal catalyst.154,155,170,196,272,273
MWDs were fairly narrow, clearly narrower than According to the proposed homolytic cleavage mech-
those from the corresponding AIBN-initiated samples, anism (Scheme 3), the halogen-exchange reaction
and the Mn was directly proportional to the total proceeds via abstraction of (one of) the terminal
weight (overall conversion) of the consumed mono- halogens by the metal catalyst followed by return of
mers. All these findings demonstrate that the copoly- one of the halogens on the metal species onto the
mers are living. growing radical center; thus, the process presumably
Equally important, the two comonomers were po- occurs via a radical intermediate.
lymerized in parallel, with MMA consumption slightly In a typical example, the MMA dimers I-25 were
faster, and the copolymer composition curve shows employed as authentic terminal models for PMMA.170
a shallow S-shaped profile, similar but not identical NMR readily distinguishes chlorine replacement at
to those for the textbook examples of free radical the bromine ends in I-25. Taking this advantage, the
MMA/styrene copolymerization. Thus, once again, Kyoto group examined the halogen-exchange reac-
the observation is consistent with some radical tions by treating I-25 (X ) Br) and Ru-1 in NMR
growth in the metal catalysis, and their difference sample tubes, mimicking the radical-generation pro-
from a conventional radical copolymerization is not cess of their Ru(II)-mediated living polymerizations.
deniable but not conclusive. Almost immediately after mixing the two components
Kinetic analyses were done for several copper- followed by heating to the polymerization tempera-
catalyzed copolymerizations of MMA/nBMA,263 nBA/ ture, the chloride version of I-25 (X ) Cl) was clearly
styrene,264,266 and nBA/MMA.267 All these studies detected by NMR, and it increasingly predominated,
show that there were no significant differences in demonstrating that the bromine end is rapidly re-
reactivity ratio as well as in monomer sequence placed (exchanged) by the chlorine in the metal
between the copper-catalyzed and conventional radi- catalyst.
cal polymerizations. Only a difference was observed Another interesting aspect of the model reactions
in the copolymerizations between MMA and ω-meth- has been reported for copper-mediated processes.273
acryloyl-PMMA macromonomers where the reactivity Thus, optically active methyl 2-bromopropionate was
of the latter is higher in the metal-catalyzed poly- mixed with a CuCl catalyst, and the reaction was
merizations.267 However, this can be ascribed not to followed by NMR and polarimetry. The latter analy-
the different nature of the propagating species but sis showed, as in solvolysis, that the model quickly
to the difference in the time scale of monomer undergoes racemization; i.e., the halogen on the
addition or other factors. Simulation has also been chiral carbon dissociates and recouples.
applied for the copolymerization study.268 The degrees of the exchange reactions depend on
several factors, the central metals, the ligands, the
4. EPR structures of the terminal groups, and the reaction
One of the most effective and direct ways to prove conditions. The absence of carbon-metal species,
a radical mechanism is to detect the radical inter- which would form via oxidative addition of the metal
mediate by electron paramagnetic resonance (EPR), complexes into the carbon-halogen bonds, also ex-
but this approach has not been fruitful yet for the cludes the coordination mechanism.
detection due to the low concentrations of the radical 6. MS
species or other factors. The polymers and their terminal groups (R and ω)
EPR was indeed applied to the copper-catalyzed in metal-mediated living radical polymerizations
radical polymerization of styrene, MA, and have been analyzed by modern mass spectrometry,
MMA.162,269-271 Invariably, it was difficult to detect particularly MALDI-TOF-MS,100,125,173,174,197,239,244,274-277
any radical growing species because of the low time-of-flight static secondary ion mass spectrometry
concentrations of the radical species, but just specif- (TOF-SSIMS),278,279 and electrospray ionization mass
ically for copper, the accumulated paramagnetic Cu- spectrometry (ESIMS).172,277,280 All these analyses
(II) species was generated via radical termination. support the existence of fairly stable carbon-halogen
This indicates that 3-6% of the initially added Cu- terminals.
(I) catalyst is converted into the Cu(II) counterpart The MALDI-TOF-MS spectra of the obtained poly-
during the polymerization (especially its initial stage). mers basically show only one series of peaks sepa-
5. NMR rated exactly by the mass of each monomer. The
observed mass of each peak agrees well with the
In the mechanistic study of metal-catalyzed living theoretical one, which possesses one initiator frag-
polymerization, this method has thus far been uti- ment at the R-end and one halogen terminal group
lized primarily for analysis of model reactions to at the ω-end in each polymer chain (with a single
uncover the interaction between a metal catalyst and degree of polymerization) (Scheme 3). The observed
a carbon-halogen dormant end.170,176 Typical models isotopic distribution was in excellent agreement with
for the dormant end include R-haloesters, such as the simulated profile based on the neutral abundance
alkyl haloisobutyrate and MMA dimer halides I-25 of 2H, 13C, etc.197 In some cases, laser irradiation of
(Figure 8) (for methacrylate), alkyl 2-halopropionate the samples leads to partial or complete loss of the
(for acrylate), and R-phenylethyl halide (for styrene). terminal halogens during the analysis depending
NMR analysis of model reactions for the polymer- on the polymer structures and analytical condi-
izations and polymer terminal groups revealed that tions.197,239,244,276 In other cases, MS analysis in turn
3714 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
reveals that some polymers suffer from halogen loss the radical species is thus estimated to be very low,
during polymerizations.172,174,275 between 10-8 and 10-7 mol/L, which may minimize
bimolecular termination.
7. CV The kinetic parameter for the radical dissociation
The correlation between the physical parameters of a carbon-halogen terminal was obtained with the
of the catalysts and their catalytic activity will clarify use of an isolated polystyrene with a terminal C-Br
polymerization mechanisms. The redox potential of bond in the presence of a copper catalyst and a
the metal complexes is certainly among these pa- conventional radical initiator with a long half-
rameters, because metal-assisted living radical po- life.282,283 The result was compared with that of low
lymerization is triggered by oxidation of the metal molecular weight compounds of similar carbon-
complex; i.e., a single electron is transferred from the halogen bonds.163 The second-order rate constant of
metal to a dormant carbon-halogen terminal. The the model compound I-13 (X ) Br), an effective
redox potential was thus measured for ruthenium,53,227 initiator for styrene, is comparable to that of the
iron,73 and copper54 complexes by cyclic voltammetry polymer terminal. Alternatively, rate constants can
(CV). These studies basically indicate that a complex be obtained by using a combination of nitroxide-
with a lower redox potential induces a faster revers- exchange reactions and HPLC analysis.242
ible cleavage (activation) of a carbon-halogen ter- Computer simulations were also done for these
minal and, in turn, generates more radical species. polymerizations although the details are omitted in
For example, among half-metallocene-ruthenium this review.284-287
complexes (Ru-4, -5, and -6 in Figure 1) the redox
potential decreases in the order Ru-4 > Ru-5 > Ru- 9. Other Mechanistic Analyses
6, and the halogen exchange rate follows the same While the radical nature of the metal-catalyzed
order (Ru-6 gives the fastest).53 polymerizations seems to be generally accepted, there
However, there is no definite correlation between still remains a question whether the propagating
the polymerization rate and the redox potential, radical species therein is the same in nature as the
partly because a higher concentration of the radical “free radicals” in the conventional systems. The
species may lead to a higher probability of bimolecu- metal-assisted radical formation most probably pro-
lar termination and a higher concentration of per- ceeds through an inner-sphere electron transfer from
sistent radical species.54,261 Another possibility of side the metal to the carbon-halogen terminal as re-
reaction is due to the reduction of the radical into ported in Kharasch addition reactions.288,289 The
an anion with metal complexes with extremely low resulting radical species may temporarily be confined
redox potential. An appropriate range for the redox in the coordination sphere of the complex in a higher
potential of the metal catalysts was suggested be- oxidation state. The confined situation or environ-
tween -0.3 and +0.6 V (versus NHE) for living ment might exert some effects on the polymerization
radical polymerization.54 such as suppression of bimolecular termination.
Although this possibility was suggested for some
8. Kinetics systems around the time when the metal-catalyzed
Kinetic analysis of metal-catalyzed radical polym- systems were discovered,27,100,132 there is still no
erization was extensively performed for homogeneous strong supporting evidence.290 In this aspect, the lack
copper-based systems.123,164,176,281 Almost invariably, of stereoregulation (see above) is particularly frus-
the polymerization follows a first-order kinetics with trating.
respect to the monomer, initiator, and copper(I) If similar radical species are involved in both living
halide as expected from the proposed mechanism; i.e., and conventional polymerizations, it follows that the
the reaction between the monomer and the radical metal-assisted growing species may suffer from side
species, which is generated via the Cu(I)-catalyzed reactions prone to free radical systems, however well
activation of the carbon-halogen terminal, originated suppressed in the living systems. This then deter-
from the initiator. Addition of Cu(II) species retards mines the lifetime of the growing end as well as the
the polymerization by shifting the equilibrium be- maximum molecular weights to be achieved therein.
tween the covalent and radical species. However, the The highest molecular weights are still below 106
polymerization kinetics were not simple inverse first with all the reported living systems.
order with respect to the initial copper(II) halide Side reactions such as termination and transfer
concentration due to the persistent radical effect, were investigated in the polymerizations of sty-
which resulted in an increase in Cu(II) concentration rene,291 acrylates,292 and methacrylates.293 The oc-
during the initial stages of the polymerization.123,164,281 currence of thermally initiated radical polymeriza-
This also indicates the presence of irreversible bimo- tions was observed in the copper-catalyzed styrene
lecular termination reactions, prone to the radical polymerization, while the resulting polymer chain
polymerizations. The equilibrium constants for the can be converted into the dormant polymer terminal
activation/radical dissociation process are calculated via abstraction of halogens from the persistent metal
on the assumption that the absolute propagation rate radical in higher oxidation states.294
constant in the metal-catalyzed polymerization is the The effects of chain-transfer agents such as oc-
same as that in the conventional free radical pro- tanethiol on copper-catalyzed polymerizations are
cesses, and the values vary with the monomers from similar to those on conventional radical polymeriza-
10-9 to 10-7 and increase in the order acrylates < tions.295 These may also mean little difference among
styrene < methacrylates.123,176 The concentration of the growing species generated from the carbon-halo-
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3715
gen terminals and in conventional radical systems. as we have already seen in this review, this advan-
Another interesting observation is that a simul- tage is apparently passed on to the metal-catalyzed
taneous metal-catalyzed and nitroxide-mediated liv- living polymerizations. This in turn leads to direct
ing radical polymerization of styrene is possible via polymerization of functionalized monomers and the
fast scrambling of terminal halogen and TEMPO synthesis of pendant functionalized polymers of well-
groups to form a single type of polymer chains.296 defined structure and molecular weights without
These suggest, in part, that a key to metal- tedious protection and deprotection processes. These
catalyzed radical polymerizations might be the per- functional groups include not only hydroxyl, amino,
sistent radical effect,15,297,298 as pointed out for ni- and amido groups but also ionic and other special
troxide-mediated systems. More detailed mechanistic groups, which are, in most cases, introduced directly
studies are required. into methacrylates, acrylates, and styrenes as sub-
stituents. Figure 12 is a nearly complete inventory
III. Precision Polymer Synthesis of functionalized monomers for which metal-mediated
One of the most distinguishable characteristics of living radical polymerizations have been reported.
the metal-catalyzed living radical polymerization is A hydroxyl-functional monomer, HEMA (FM-1),
that it affords polymers with controlled molecular can be polymerized in a controlled way with several
weights and narrow MWDs from a wide variety of transition-metal complexes including ruthenium,59
monomers under mild conditions even in the presence copper,241,243 and nickel311 in the bulk and in alcohols.
of a protic compound such as water. This permits the In view of the relatively broad MWDs of the products
synthesis of a vast number of polymers with con- (Mw/Mn ) 1.3-1.8), further optimization of the reac-
trolled structures such as end-functionalized poly- tion conditions is needed, although the catalyst and
mers, block copolymers, star polymers, etc., where the growing terminal keep the activity during the
they are widely varied in comparison with those polymerizations. Better-controlled polymerizations of
obtained by other living polymerizations. This is a protected form of HEMA with a trimethylsilyl
primarily due to the tolerance to various functional group (FM-2) were also conducted with ruthenium,
groups and the polymerizability/controllability of copper, and nickel.243,312 2-Hydroxylethyl acrylate
various vinyl monomers as mentioned above. (FM-3), an acrylate with a hydroxyl group, can be
This section is thus directed to precision polymer polymerized with the I-22 (X ) Br)/CuBr/L-1 system
synthesis with the use of metal-catalyzed living in the bulk and in water to give narrow MWDs (Mw/
radical polymerizations. In this synthetic aspect, Mn ) 1.2-1.3) where the polymerization is faster and
numerous reviews are available already. 219,265,299-310 better controlled in the bulk.244 Its protected version
(FM-4) was polymerized with I-22 (X ) Br)/CuBr/
A. Pendant-Functionalized Polymers L-24 in the bulk to give similarly narrow MWDs (Mw/
Radical polymerization, in general, is more tolerant Mn ≈ 1.2).313 Soluble in organic media, these silyloxy-
of polar functionality than its ionic counterpart, and protected monomers (FM-2 and FM-4) can be effec-
3716 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
tively employed for block or random copolymerizations Polymers containing sugar moieties, so-called gly-
with aliphatic methacrylates.243,312,313 copolymers, have been attracting attention as bio-
Amino- and amido-functionalized monomers can compatible materials. Some of them have been ob-
also be polymerized directly with metal catalysts. tained by the polymerization of FM-21321 and FM-
Living radical polymerization of 2-(dimethylamino)- 22322 with CuBr-based initiating systems. Their block
ethyl methacrylate (FM-5) was achieved with I-31 (X copolymerizations with styrene are also feasible as
) Br)/CuBr/L-29 in dichlorobenzene at 50 °C.314 Its described below (section III.C.1).
ammonium salt (FM-6) was polymerized from the Metal-catalyzed living radical polymerization can
surface of a cross-linked polystyrene latex with CuBr/ be further extended to multifunctional nucleoside-
L-1 in water at 80 °C to generate hydrophilic shells, containing monomers. Examples are silyl-protected
although there were no data for polymer molecular monomers with uridine (FM-23) or adenosine (FM-
weight.248 As described above (section II.C.6), (meth)- 24) groups, both of which can be polymerized with a
acrylamides with at least their amido protons un- combination of a bromide initiator, CuBr, and L-9 (R
protected (FM-7, FM-8, and FM-9) can be polymer- ) n-Pen) or L-32 homogeneously in toluene (Mw/Mn
ized with copper-based systems,117,168,217,218 but a ) 1.1-1.4).323
further optimization seems to be necessary. Side-chain liquid-crystalline polymers with con-
Ionic monomers carrying a carboxylate salt, such trolled molecular weights have been obtained by the
as FM-10200 and FM-11,247 can be polymerized with polymerization of FM-25 with I-22 (X ) Br)/CuBr/
a water-soluble bromide initiator in conjunction with L-3 in the bulk at 100 °C, to examine the thermo-
CuBr and L-1 in aqueous media to give moderately tropic transition as a function of the MWD.324 Second-
controlled molecular weights and MWDs (Mw/Mn ) order nonlinear optical materials with branched
1.2-1.3). The reaction media should be kept under structure were prepared by the copper-catalyzed
alkaline conditions (pH 8-11) to avoid loss of the radical polymerization of FM-26 and FM-27 using
catalytic activity; seemingly free acid functions in the hyperbranched poly[4-(chloromethyl)styrene] as a
monomers and/or polymers are detrimental. multifunctional initiator.325
A methacrylic monomer with polyhedral oligomeric
Perfluoroalkyl (meth)acrylates FM-12 and FM-15
silsesquioxanes (FM-28) as a pendant group can be
have been polymerized homogeneously in scCO2 with
polymerized with I-24 (X ) Br)/CuBr/L-32 in toluene
copper catalysts/fluorinated ligand systems, but the
(Mw/Mn ) 1.14).326 Block and star copolymers of this
MWDs of the products are not reported due to the
partially inorganic monomer with MA and nBA are
lack of appropriate analytical methods.95 Other flu-
expected to function as new hybrid materials.
orinated monomers (FM-13 and FM-14) were used
for block copolymerization with styrene and acrylates
with CuBr/L-1 in the bulk under heterogeneous B. End-Functionalized Polymers
conditions.315 As in other living polymerizations, metal-catalyzed
Epoxy and lactone groups seem to remain intact living radical processes can be employed for the
under the conditions for metal-catalyzed living radi- synthesis of end-functionalized polymers. To this end,
cal polymerization. Therefore, glycidyl acrylate (FM- there are two general methods, i.e., a functional init-
16) can be exclusively polymerized via the vinyl iator method and an end-capping method, and both
moiety with I-22 (X ) Br)/CuBr/L-4 in the bulk at are indeed applicable therein. In the former, living
90 °C to high conversion (Mw/Mn ≈ 1.2).316 Statistical radical polymerization is initiated with a function-
copolymers of styrene and FM-17, an epoxy-function- alized organic halide initiator coupled with a metal
alized styrene, with controlled molecular weights catalyst to form polymers with an R-end (head)
were obtained with a CuBr-based system at 100 °C, functionality. In the latter, a metal-catalyzed living
whereas a similar reaction with TEMPO gave prod- radical polymerization is terminated with a function-
ucts of bimodal MWDs that might come from the high alized quencher that in turn introduces an ω-end
reaction temperature (124 °C).317 An acrylate with (tail) functionality. An alternative method for ω-end
-caprolactone can be polymerized with I-21 (X ) Br)/ functionalization is to transform a stable carbon-
Ni-2 in the bulk at 90 °C to result in polymers with halogen ω-terminal via polymer reactions. Examples
controlled molecular weights (Mw/Mn ) 1.1-1.3).318 of these approaches will be discussed below.
Methacrylates with pendant oxyethylene units
(FM-19) were polymerized in a controlled way with
1. R-End-Functionalized Polymers
metal catalysts in the bulk or in water. The catalytic Taking advantage of the tolerance of living radical
systems include a bromide initiator coupled with Ni-2 polymerization for functional groups, a variety of
for n ) 2 (bulk, 80 °C)319 and CuCl for n ) 7-8.246,320 functionalized initiators have been designed. A gen-
The latter polymerization proceeded very fast in eral way is to attach a functional group to a halogen
aqueous media at 20 °C to reach 95% conversion in compound such as a haloester, (haloalkyl)benzene,
30 min and gave very narrow MWDs (Mw/Mn ) 1.1- haloalkane, or sulfonyl halide. Most of the functional
1.3). The fast reaction is attributed to the formation groups therein are insulated from the initiation
of a highly active, monomeric copper species com- moiety via a spacer to avoid possible side reactions,
plexed by the oxyethylene units. A statistical copo- as shown in Figure 13, where entries are grouped in
lymerization of FM-19 (n ) 7-8) and FM-20, a terms of the intended R-functionalities.
methacrylate with a oligo(propylene oxide) pendant For instance, hydroxyl-functionalized initiators
group, led to hydrophilic/hydrophobic copolymers (FI-1 to FI-6) were employed for living radical po-
with narrow MWDs (Mw/Mn ) 1.2).320 lymerization of MMA,134,139,156,157,274,327 MA,280 nBA,134
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3717
tBA,328 styrene,280,329 and sodium methacrylate.200 has been employed for MMA/CuBr/L-1.327 Simpler
Note that for these no protection of the protic function initiators such as FI-5134,139 and FI-6156,157 are com-
is required, in sharp contrast to similar initiators for mercially available and applied to MMA, nBA, and
ionic living polymerizations. Initiator FI-1 generates styrene with CuBr/L-1 or L-4 as well as Ni-2,
an HEMA radical and thus is applied to MMA with although the plural carbon-halogen bonds therein
CuBr/L-9 (R ) n-Pr) in xylene at 90 °C; near complete might cause multiple initiations.
attachment of the R-end function has been shown by Carboxyl groups were also introduced at the R-end
MALDI-TOF-MS.274 This initiator can also be em- of poly(methacrylate)s134,235,320 and polystyrene330,331
ployed for sodium methacrylate200 and tBA.328 An by using unprotected and protected initiators. 2-Bro-
acrylate version FI-2 is for MA with CuBr/L-4, but moisobutyric acid (FI-7) was employed for MMA
the initiation efficiency for styrene is reported to be coupled with CuBr/L-9 (R ) n-Pen)235 and with Ni-
lower (Ieff ≈ 0.7) due to side reactions upon initia- 2134 to give narrow MWDs (Mw/Mn ) 1.1-1.3) but Mn
tion.280 In contrast, a nearly quantitative initiation values higher than the calculated values. This un-
was achieved with FI-3 in the styrene polymerization protected initiator, on the other hand, has poor
with CuBr/L-1.329 A chloride FI-4 is another interest- efficiency (Ieff ) 0.10) for styrene, probably because
ing initiator that can generate a radical doubly of the intramolecular cyclization into a γ-butyrolac-
stabilized by a carbonyl and a phenyl substituent and tone after addition of one styrene unit.330 Protection
3718 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
of the acid function by trimethylsilyl (FI-8), tert- ciency.120,150 Vinyl ether derivatives FI-37 and FI-38
butyldimethylsilyl (FI-9), or tert-butyl (FI-10) groups can initiate living polymerizations of styrene, meth-
leads to improved initiation efficiencies (ca. 0.6, 0.8, acrylates, and acrylates with copper catalysts from
and 1.0, respectively). Benzoic acid initiators with a their halogen moiety, though carefully selected reac-
well-separated halogen (FI-11 and FI-12) afforded tion conditions are required.150,336 Thus, the vinyl
well-defined polystyrenes with narrow MWDs at ether double bonds are susceptible to radical addition
relatively high initiation efficiencies (Ieff ≈ 0.7); thus, at higher conversions to result in bimodal MWDs and
rigid aromatic spacers may help.330 Similar results termination. Interestingly, vinyl acetate groups can
were obtained with protected initiators such as FI- be introduced at the R-end of polystyrenes and poly-
13 and FI-14.331 Salt-type initiators FI-15 and FI-16 (methacrylate)s by using FI-39337 and FI-40,246,247,320
are specifically employed for the aqueous-phase po- because they only poorly copolymerize with styrene
lymerization of hydrophilic monomers such as FM- and methacrylates even under radical conditions.
19 (Figure 12).320 Macromonomers for ring-opening polymerizations
Nitrogen-containing groups such as amine, aniline, can be obtained from FI-41328 and FI-42312 for tBA
amide, pyrrole, and pyridine are also available for and MMA.
the functional initiator method. A bromoester with An azo bromoester bifunctional compound FI-43
a dimethylamino group (FI-17) was used in aqueous induces a living polymerization of nBA with a highly
media for oligo(ethylene glycol) methacrylate (FM- active catalytic system (CuBr/L-32) at 30 °C from the
19) (Mw/Mn ≈ 1.4).246,320 Poly(tBA)328 and polysty- latter function alone.338 The low temperature allows
rene331 with terminal amide functions were prepared the azo group to elude concurrent thermal dissocia-
with FI-18 and FI-19, respectively. The pyrrole- tion (<0.5%). The obtained polymers of narrow
containing initiator FI-20 induced living radical MWDs were employed for block copolymerization
polymerization of methacrylates, acrylates, and sty- with vinyl acetate at 90 °C.
rene with Ni-2 or CuBr/L-1, giving macromonomers End-functionalized polymers with relatively long
for electrochemical polymerization.319 The 2,2′-bipy- hydrophilic segments can be prepared from an
ridine unit in FI-21 and FI-22 is to attach binding initiator (FI-44) with oligo(oxyethylene glycol)
sites onto polystyrene332 and poly(MMA),333 respec- units.200,246,247,320 Initiators FI-45 to FI-50 are for
tively, for macroligand chelation with Ru and other other functionalities of special interest. For example,
metal cations. A series of 4-substituted-phenyl 2-bro- the pyrenyl group in FI-45 can become a tag for
moisobutylates (FI-23) with amino, nitro, and alde- distinguishing the end-functionalized polymers from
hyde groups, etc. were successfully employed for nonfunctionalized byproducts and was used in simul-
MMA with CuBr/L-9 (R ) n-Oct) (Mw/Mn ) 1.1-1.2; taneous metal-catalyzed and nitroxide-mediated liv-
Ieff ) 0.8-1.0).199 ing radical polymerizations of styrene.296 Biologically
Thiols also provide good binding points toward a related functions such as oligosaccharide,339 choles-
metal surface such as gold for the synthesis of terol,340,341 and nucleosides323 are incorporated in FI-
polymer brushes, etc. A protected initiator (FI-24) 46 to FI-49 for CuBr/L-9 (R ) n-Pen or n-Oct),
gave thiol-functionalized PMMA with Ni-2 as a whereas FI-50 (with CuBr/L-1) is to introduce a C60
catalyst.334 The thiophene-capped PMMA from FI- or fullerene terminal.342
25 can be employed as a macromonomer for electro- In addition to the carbon-centered radical initia-
chemical copolymerization with pyrrole,335 as with tors, arenesulfonyl halides are simple and efficient
those from FI-20 (see above). functionalized initiators by introducing a variety of
A series of poly(chloroalkyl ester)s (FI-26 to FI-28) functional termini; conjugation between the aryl and
can be employed for styrene polymerization with the sulfonyl groups is absent (FI-51 to FI-58; Figure
CuCl/L-1 to give polymers with ester groups at the 14).175 Typically, a series of monosubstituted deriva-
R-end.158 Benzyl bromides FI-29317 and FI-30328 are tives (FI-51) are commercially available and afford
another possibility for R-end functionalization. hydroxyl, carboxyl, nitro, and halo groups in living
Multiple halogen compounds FI-31158 and FI-32328
seem interesting to attest the chemoselectivity of
transition-metal catalysis, and the CF3- and the
aromatic bromide therein, respectively, remain intact
during the living polymerizations to afford R-end
functions, though their utility might be limited.
End-functionalized polymers with polymerizable
groups such as double bonds and heterocycles of
course provide macromonomers; allyl, vinyl ester,
vinyl ether, lactone, and epoxy are examples of such
a category whose R-ends are not susceptible or have
little susceptibility to metal-catalyzed radical polym-
erization. As discussed above, for example, allyl
chloride and bromide (FI-33 and FI-34) are effective
initiators to be used for styrene with CuCl and CuBr
catalysts,161 while allyl compounds with remote halo-
gens such as FI-35 and FI-36 allow the polymeriza- Figure 14. Sulfonyl halide and conventional radical
tion of methacrylates with high initiation effi- functional initiators.
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3719
2. ω-End-Functionalized Polymers
In contrast to the frequent use of the initiator
method and the wide variety of available functional
initiators, the end-capping method is not as fre-
quently employed, primarily because of the difficulty
in selective and quantitative quenching radical po-
lymerization, particularly in the metal-catalyzed
living systems involving dormant halogen species.
This stems from several factors: the extremely low
concentration of the radical species relative to the
dormant species, the highly stable dormant carbon-
halogen bond, and the limited availability, thus far,
of suitable quenchers that can add to the growing
carbon radical without deteriorating the metal com-
plex catalyst. However, with the use of selected
compounds, the halogen terminal can be converted
into functional groups via metal-catalyzed radical
reactions or other reactions.
Metal-catalyzed end-capping via a radical mecha-
nism can be carried out either by in situ quenching
of the polymerization or by the reaction of isolated
halogen-capped polymers. Mostly the same quencher
may be used for both methods. Despite the less
frequent applications, however, a wide variety of
quenching end-capping agents have been reported
(EC-1 to EC-15) (Figure 15). Most of these compounds
have a vinyl group that can add to a polymer
terminal under metal-catalyzed conditions to form
much less reactive carbon-halogen bonds or unsat-
urated groups via release of low molecular weight
halogen compounds.
The first of these are silyl enol ethers EC-1 with a
phenyl group or R-(silyloxy)styrenes. They can ef-
fectively quench the ruthenium-catalyzed living radi-
cal polymerization of MMA to give the ω-end-
functionalized PMMA with a ketone group with high
end functionality (Fn ≈ 1.0).293,344 The method is also
useful to attach an aromatic ω-end group not only
for end-functionalization (via the substituent on the
ring) but also for end-group analysis (via the aromatic
protons). The quenching reaction is considered to Figure 15. End functionalization of carbon-halogen
proceed via addition of the growing radical to the terminals.
vinyl group of EC-1 to generate another radical
terminal that is stabilized by the R-phenyl group, In contrast, silyl enol ethers with an R-alkyl group
followed by elimination of the trimethylsilyl group (R-silyloxy vinyl ethers) proved less efficient, indicat-
with the chlorine at the polymer terminal (or on the ing the stability of the resultant silyloxyl radicals is
metal center) due to their high affinity toward among the critical factors in designing good quench-
halogens (Scheme 5). The quenching is quantitative ers of this class. These are due to the degree of the
and selective, and proceeds faster with an electron- affinity of the PMMA radical toward the vinyl groups
donating substituent (X; OCH3 > H > F > Cl) on the in the quenchers. This silyl enol ether capping is
phenyl group of EC-1 and at its higher concentration. applicable for copper-catalyzed polymerizations [with
3720 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
Scheme 5. Quenching of Metal-Catalyzed Living styrene and poly(nBA), which have no R-methyl
Radical Polymerization with Silyl Enol Ethers substituent, can be displaced into the carbon-
TEMPO terminal via the copper-catalyzed reaction
with EC-6.242
Allyl compounds (CH2dCH-CH2R) without good
radical leaving groups react with the growing radical
in the metal-catalyzed polymerizations to result in
an inactive carbon-halogen terminal (---CH2-CHX-
CH2R). Thus, the reaction is, formally, an addition
of alkyl halide (the halogen-capped growing end)
across an olefin. For example, copper-catalyzed radi-
cal polymerizations of MA280 and MMA327 were
quenched with allyl alcohol (EC-7) to generate a
EC-1 (X ) OSiMe3)], in the reported examples, β-bromo alcohol terminal. A similar reaction was
carried out on isolated PMMA. The quenching has reported with EC-8327 and EC-9.346 Ethylene (EC-10)
been carried out, not in situ, but on isolated PMMA cannot polymerize with the metal-based radical
samples.226 The trimethylsilyloxy group at the 4-posi- systems but can react with the terminal carbon of
tion can be also converted into the phenol function. isolated halogen-capped PMMA in the presence of
An interesting application of the silyl enolate CuBr and L-9 (R ) n-Oct) to yield a primary bromide
capping reaction has been developed by Percec, who end quantitatively.226 Similarly, a single unit of
coined the capping agents “TERMINI” (irreversible maleic anhydride (EC-11) can be introduced to poly-
terminatior multifunctional initiator).345 This refers styrene and PMMA.226,348 Even one unit of divinyl-
to a “protected functional compound able to quanti- benzene (EC-12) can be attached quantitatively at a
tatively terminate a living polymerization and, after low temperature (25 °C), where the homopolymer-
deprotection, to quantitatively reinitiate the same or izations are suppressed.226 However, the end-capping
a different living polymerization in more than one yield with benzyl acrylate (EC-13), a more reactive
direction”. Typical TERMINI agents are designed to monomer, cannot exceed 62%.226 An interesting ap-
possess one silyl enolate function for quenching (as plication of these one-step olefin additions is found
in Scheme 5) and two or more protected sulfonyl with EC-14 to attach a C60 end (35% yield).349
chlorides for subsequent multiple initiation of metal- Almost all metal-catalyzed living polymerizations
catalyzed living radical polymerization. Obviously give polymers capped with halogens that are stable
from this design the TERMINI method is applicable after the usual workup. These terminal halogens
for the efficient and well-defined synthesis of den- would be undesirable, because they may lower the
drimers and their libraries, along with other poly- polymer’s thermal stability. Dehalogenation by tribu-
mers of complex and multibranched architectures. tyltin hydride (EC-15) is of importance in this respect
The silyl enolate quenching process (Scheme 5) is, and effectively works for the bromide terminals in
in principle, similar to addition fragmentation reac- polystyrene, PMMA, and poly(MA) in the presence
tions as well as the more recent reversible addition of copper catalysts.277
fragmentation chain transfer (RAFT; see also eq 9),18 An alternative method for ω-end functionalization
in that all three involve an initial addition of the is to transform the terminal halide by ionic reactions.
growing radical across a reactive vinyl group that Thus, nucleophilic substitution was examined with
carries both a radical-stabilizing group (a phenyl and compounds EC-16 to EC-23. For example, an amino
an ester) and a good (radical) leaving group. The alcohol (EC-16) in DMSO at room temperature gives
difference among them is whether the released radi- polystyrene with hydroxyl groups.280,350 However, an
cal via fragmentation is capable of reinitiating radical amino alcohol with a longer spacer (EC-17) should
polymerization (e.g., capable in RAFT, incapable in be employed for poly(MA) to avoid multiple alcohol
the silyl enolate capping). functionalities.280
Allyltri-n-butylstannane (EC-2) similarly termi- Transformation into azide groups was achieved for
nates the copper-catalyzed polymerization of MA to polystyrene, poly(MA), and poly(nBA) with the use
give allyl-functionalized polymers via elimination of of sodium azide (EC-18)351-353 or trimethylsilyl azide
the stannyl group accompanying the bromine origi- (EC-19)161,351,354 in the presence of tetrabutylammo-
nated from the dormant polymer terminal.346 Allyl nium fluoride. The azide groups can be further
ω-end PMMA was obtained also by the copper- converted into amino (-NH2) groups by treatment
catalyzed reaction between allyl bromide (EC-3) and with PPh3/H2O351 or LiAlH4.354 The reaction between
the isolated bromine-capped PMMA, although the the azide end group in polystyrene and C60 was also
functionalization was 57%.226 Another allyl derivative examined.353
(EC-4) similarly leads to methacrylate-based macro- Nucleophilic substitution with the phenolate anion
monomers quantitatively in the presence of Cu(0).347 derived from EC-20 and K2CO3 induced 30% substi-
The same poly(methacrylate)-based macromono- tution, along with elimination of hydrogen bro-
mer can be obtained via the TEMPO (EC-5)-promoted mide.331 Phosphonium groups can be introduced at
elimination of hydrogen and bromine from the iso- the polystyrene and poly(MA) terminal via reaction
lated bromine-ended PMMA in the presence of CuBr/ with EC-21,355 and methyl groups with Me3Al (EC-
L-9 (R ) n-Pr), though the functionality was 78%.226 22).356 An allyl terminal is obtained also via an ionic
In contrast, the carbon-bromine bond in the poly- pathway, where the polystyryl carbocation generated
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3721
from the chlorine terminal polystyrene in the pres- Block copolymers between alkyl or related meth-
ence of TiCl4 reacts with allyltrimethylsilane (EC- acrylates (B-1,132,198,357 B-2,198 and B-3115,146,148) were
23).356 The allyl terminal was further transformed prepared via the ruthenium-, copper-, and nickel-
into epoxy and alcohol. catalyzed living radical polymerizations. These block
copolymers can be synthesized both via sequential
C. Block Copolymers living radical polymerizations and via the living
radical polymerization initiated from isolated poly-
One of the most important applications of living
mers. For example, the ruthenium-catalyzed sequen-
polymerization is obviously block copolymerization.
tial living radical polymerization of MMA followed
Block copolymers are usually obtained via sequential
by nBMA affords AB block copolymers B-1 with
living polymerization of a monomer followed by
narrow MWDs (Mw/Mn ) 1.2), which can be extended
another. This is also true for the metal-catalyzed
further into ABA block copolymers B-2 with similarly
living radical polymerization, which permits synthe-
narrow MWDs (Mw/Mn ) 1.2).198 Star block copoly-
sis of a wide variety of block copolymers and appar-
mers with B-1 as arm chains were similarly synthe-
ently is more versatile than other living polymeriza-
sized but with multifunctional initiators.357
tions. Another way is the use of isolated halogen-
capped polymers as macroinitiators, taking advantage Block copolymers between alkyl acrylates such as
of the stability of the dormant carbon-halogen B-4,358 B-5,202,203 and B-6,203 on the other hand, have
terminal even toward air and moisture. The proce- been synthesized by the macroinitiator methods
dure for the former method is apparently simpler mostly with copper catalysts. Star block copolymers
than the latter because the reaction can be done in with a soft poly(MA) core and a hard poly(isobornyl
one pot. However, the problem therein is contamina- acrylate) shell were synthesized by using multifunc-
tion of the first monomer’s unit(s) in the second tional initiators.358 Poly(tBA) segments in B-5 and
segments, because the second monomer is often B-6 can be converted into hydrophilic poly(acrylic
added before the complete consumption of the first acid).203 Block copolymers between p-methylstyrene
monomer to avoid side reactions at high conversion. and styrene (B-7) were also prepared by the rhenium-
The synthetic strategy for a wider variety of block catalyzed living radical polymerization in conjunction
copolymers is to combine the metal-catalyzed living with an alkyl iodide initiator.169
radical and other living polymerizations. This can be Block Copolymers between Different Fami-
accomplished by the introduction of a potentially lies of Monomers. Block copolymers among differ-
active carbon-halogen bond into the polymers ob- ent families of monomers (e.g., methacrylate/acrylate)
tained commercially or by some living processes. can be efficiently prepared by metal-catalyzed radical
This section discusses the block copolymer synthe- polymerizations (Figure 17). Though widely feasible,
ses by these two approaches, and Figures 16-25 give the synthesis often calls for specific care, and in
comprehensive lists of reported block copolymers. particular the initiating systems including terminal
halogens, metals, and ligands should be carefully
1. Block Copolymers via Sequential Metal-Catalyzed selected so that they are effective for both monomers
Living Radical Polymerization in different families. For the macroinitiator method,
A wide variety of block copolymers can be obtained in contrast, the catalysts for the first and the second
by the metal-catalyzed living radical polymerizations, polymerizations should not be necessarily the same.
which are now applicable to numerous monomers. Most of the block copolymers consisting of meth-
Most of them are block copolymers prepared from acrylates and acrylates (B-8 to B-12) have been
methacrylates, acrylates, and styrenes; combinations prepared via macroinitiator methods. AB- and BA-
are therefore within the same family or between type block copolymers of MMA and MA (B-876,135,359
different families. and B-9359) were prepared with nickel, copper, and
Block Copolymers between the Same Family iron catalysts. Due to the higher activity of the
of Monomers. Block copolymers derived from the carbon-halogen terminals in poly(methacrylate)s
same family of monomers (Figure 16) are obtained than in poly(acrylate)s, block copolymerization from
relatively easily, because the two monomers can PMMA is successfully performed via both sequential
normally be polymerized with common initiating and macroinitiator methods, where the controllability
systems and under similar reaction conditions. seems better in the copper-based system. Similar
3722 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
results were also obtained for B-10.135,138,359 In con- ments caused by the lower activity of the C-Br ter-
trast, for BA-type block copolymers from MA, halogen- minal of poly(nBA).363 The use of halogen-exchange
exchange reactions from C-Br into C-Cl terminals methods with the copper-based systems can narrow
(see above) should be employed so that the initiation the MWDs of the ABA block copolymers.359,360,364
from the less active dormant terminal of acrylates The MMA/styrene block copolymers of both AB and
can be quantitative and faster.359 This method gave BA types (B-13 and B-14) were synthesized with
B-9 with fairly narrow MWDs (Mw/Mn ) 1.15) with- copper and iron catalysts, although the MWDs were
out contamination of homopoly(MA). A similar block slightly broader (Mw/Mn ) 1.4-1.5) than those of the
copolymer with nBA and MMA (B-11) can be pre- other block copolymers.76,94,241,365
pared by the same method.360 A wider range of acrylate/styrene block copolymers
ABA-type block copolymers B-12 with a hard have been prepared by copper catalysts, partially
PMMA as the outer segment (A) and a soft poly(nBA) because the homopolymerizations of both monomers
as the inner segment (B) are expected as all-acrylic can be controlled with common initiating systems.
thermoplastic elastomers. Examples of B-12 have Both AB- (B-15 to B-17)202,230,254,366,367 and BA-type
been prepared with copper and nickel catalysts via (B-18 to B-21)28,112,169,230,366,368,369 block copolymers
bifunctional initiation.359-364 Unfortunately, the co- were obtained from macroinitiators prepared by the
polymers by R-Br/Ni-2 via the macroinitiator method copper-based systems. The block copolymerizations
were reported to be inferior as thermoplastic elas- can also be conducted under air230 and under emul-
tomers to those by living anionic polymerizations. A sion conditions with water.254 Combination of the Re-
possible reason is the presence of short PMMA seg- and Ru-mediated living radical polymerizations in
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3723
2. Block Copolymers via Combination of Other (Living) utilized for isoprene as in B-64.374 Such macroinitia-
Polymerizations tors induced living radical polymerization of meth-
acrylates, acrylates, and styrene in the presence of
Block copolymers can be prepared by combination the copper catalysts to give block copolymers with
of metal-catalyzed living radical polymerization and narrow MWDs (Mw/Mn ) 1.1-1.2). The use of ethyl-
other polymerizations. Namely, polymers with car- ene oxide for quenching the living anionic polymer-
bon-halogen terminals may be synthesized by some ization of styrene followed by treatment with SOCl2
living polymerization, and the product is further used resulted in a carbon-chlorine terminal for a subse-
to initiate living radical polymerization in the pres- quent polymerization of 2-vinylpyridine (B-61).215
ence of transition-metal catalysts. Therefore, this A transformation method can introduce some func-
method is essentially a variant of the macroinit- tional groups at the junction as in B-63, which bear
iator method discussed above. Such carbon-halogen a fluorescent dye between the polyisoprene and
terminals can be obtained by transformation of the polystyrene segments.375 The preparation is based on
polymer terminal with some reagents or by use of quenching the living anionic polymerization of iso-
halogenated initiators for the first-step living polym- prene with 1-(9-phenanthryl)-1-phenylethylene fol-
erization. In some cases, there is no need for the lowed by addition of excess R,R′-dibromo-p-xylene,
transformation since the first-step polymerization which affords a C-Br terminal effective for the
also proceeds via similar carbon-halogen chain ends copper-catalyzed radical polymerization of styrene.
as in living cationic polymerization (see below). Cationic Vinyl Polymerization. Living cationic
Reviews on block copolymer synthesis based on mech- polymerizations, in general, are based on the revers-
anism transformation are available elsewhere.301,302 ible activation and heterolytic dissociation of carbon-
Another method is based on initiation of other halogen terminals by a Lewis acid.7-9 Despite the
polymerizations from the polymers prepared by living difference in the activation processes, some of the
radical polymerization as macroinitiators. The fol- carbon-halogen bonds obtained in living cationic
lowing sections give specific examples. polymerization can be used as an initiating site for
Anionic Vinyl Polymerization. The carbanionic metal-catalyzed living radical polymerization without
terminals in living anionic polymerization can be any modification. Figure 20 shows block copolymers
transformed into carbon-halogen bonds suited for obtained in this way.
radical generation. The backbones utilized thus far The polystyrene obtained by living cationic polym-
for this approach include polystyrene (B-58 to erization with R-Cl/Lewis acid possesses a carbon-
B-62)215,374 and polyisoprene (B-63 and B-64),374,375 chlorine terminal that is subsequently used for the
although the former segment can also be prepared living radical polymerizations of acrylates and meth-
by the living radical polymerization (Figure 19). acrylates to give block copolymers such as B-65 to
For B-58 to B-60 and B-62, the polystyryllithium B-67.376-378
terminal was converted into a bromide by the reac- Chlorine-capped polyisobutylene, prepared via cat-
tion with styrene oxide followed by treatment with ionic polymerization, was also used as a macroini-
2-bromoisobutyryl bromide.374 The same method is tiator for the copper-catalyzed radical polymeriza-
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3725
copper-catalyzed radical polymerizations from poly- B-90 and B-91, respectively.390 Another route coupled
(THF) macroinitiators obtained with 2-bromopropio- with cationic ring-opening polymerizations is ac-
nyl bromide and silver triflate.387 complished for polymer B-92 with the use of a
The ABA-type block copolymers B-86 to B-88 were hydroxyl-functionalized initiator with a C-Br ter-
synthesized via termination of telechelic living poly- minal, where the OH group initiates the cationic
(THF) with sodium 2-bromoisopropionate followed by polymerizations of 1,3-dioxepane in the presence of
the copper-catalyzed radical polymerizations.387 A triflic acid.329 Poly(ethylene oxide)-based block co-
similar method has also been utilized for the syn- polymers B-93 are obtained by living anionic polym-
thesis of 4-arm star block polymers (arm B-82), where erization of ethylene oxide and the subsequent trans-
the transformation is done with β-bromoacyl chloride formation of the hydroxyl terminal into a reactive
and the hydroxyl terminal of poly(THF).388 The BAB- C-Br terminal with 2-bromopropionyl bromide, fol-
type block copolymers where polystyrene is the lowed by the copper-catalyzed radical polymerization
midsegment were prepared by copper-catalyzed radi- of styrene.391
cal polymerization of styrene from bifunctional initia- Living ring-opening polymerization of -caprolac-
tors, followed by the transformation of the halogen tone with aluminum alkoxide or alkylaluminum can
terminal into a cationic species with silver perchlo- be combined with nickel-catalyzed living radical po-
rate; the resulting cation was for living cationic lymerization for the synthesis of linear and dendri-
polymerization of THF.389 A similar transformation mer-like star block copolymers B-94 to B-98.139,392-394
with Ph2I+PF6- was carried out for halogen-capped Such block copolymers were first synthesized via
polystyrene and poly(p-methoxystyrene), and the living radical polymerization with CBr3CH2OH, where
resultant cationic species subsequently initiated cat- the C-Br bond is a radical initiating site and the
ionic polymerization of cyclohexene oxide to produce hydroxyl group is for the subsequent ring-opening
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3727
nyl bromide. The telechelic bisbromide was subse- tween a telechelic polystyrene with terminal maleic
quently employed for the copper-catalyzed block anhydride units and a commercially available poly-
polymerization of styrene or nBA to give B-110 and (ethylene glycol methyl ether) gave B-128.348
B-111, respectively.398 A polysilylene-based block Polysiloxane-based ABA-type block copolymers
copolymer (B-112) was synthesized similarly from a B-129 can be prepared from commercially available
telechelic polysilane macroinitiator with benzyl chlo- poly(dimethylsiloxane) as a stating material followed
ride terminals.399 Another block copolymer (B-113) by functionalization and the subsequent copper-
consisting of a fluorene unit in the midsegment was catalyzed radical polymerization of styrene.409
obtained by two-step polymerizations, the Ni(0)-
mediated condensation polymerization of 2,7-dibromo- D. Random Copolymers
9,9-dihexylfluorene and the Ni(II)-mediated living A distinctive advantage of radical polymerization
radical polymerization of MMA after the transforma- is that a variety of monomer pairs can readily be co-
tion of the telechelic terminals.400 polymerized into true random/statistical copolymers.
Polystyrene B-114401 and poly(acrylate) B-115402 A mixture of two monomers that can be homopo-
are connected to a dendrimer at its focal core. These lymerized by a metal catalyst can be copolymerized
are prepared with dendrimer-type macroinitiators as in conventional radical systems. In fact, various
with a benzyl bromide at the focal point, from which pairs of methacrylates, acrylates, and styrenes have
are initiated the copper-catalyzed living radical po- been copolymerized by the metal catalysts in random
lymerizations of styrene and acrylates, respectively. or statistical fashion, and the copolymerizations
For B-114, various functional groups (R) were intro- appear to also have the characteristics of a living
duced into the periphery. process. The monomer reactivity ratio and sequence
Commercially Available Polymers. Modifica- distributions of the comonomer units, as discussed
tion of terminal groups for block copolymer synthesis already, seem very similar to those in the conven-
can be applied to commercially available end-func- tional free radical systems, although the detailed
tionalized polymers although most of them are pro- analysis should be awaited as described above. Apart
duced by living anionic polymerization. Thus, some from the mechanistic study (section II.F.3), the metal-
of the block copolymers shown in Figure 25 were catalyzed systems afford random or statistical co-
already described above. polymers of controlled molecular weights and sharp
Hydroxyl-capped poly(ethylene-co-butylene), a so- MWDs, where, because of the living nature, there are
called Kraton, was converted into a macroinitiator almost no differences in composition distribution in
via esterification with 2-bromopropionyl chloride, and each copolymer chain in a single sample, in sharp
then employed for the block copolymerizations of contrast to conventional random copolymers, in which
styrene and p-acetoxystyrene (B-116 and B-117).403 there is a considerable compositional distribution
A similar method is utilized for B-118 to B-121 where from chain to chain. Figure 26 shows the random
the esterification is with 2-bromoisobutyroyl bro- copolymers thus prepared by the metal-catalyzed
mide.341 A commercially available polybutadiene is living radical polymerizations.
also employed for B-122 via a similar transformation There are several examples of random copolymers
into the chloroacetyl group.404 of methacrylates (R-1 to R-3). MMA/nBMA copolym-
Poly(oxyethylene) units can be introduced by using erization was carried out with a copper catalyst, but
commercially available poly(ethylene oxide)s and the products were of low molecular weight because
poly(ethylene glycol)s via esterification of the termi- this study was directed to mechanistic studies.263
nal hydroxyl groups with appropriate acyl halides. Random copolymers of MMA and nBMA (R-1) were
Various AB- (B-123 and B-124) and ABA-type (B- also obtained in emulsion (Mw/Mn ) 1.2-1.3).254 Two
125 and B-126) block copolymers were thus pre- monomers were consumed almost simultaneously to
pared,171,327,405-408 along with a poly(propylene oxide)- give a random or statistical distribution of repeat
based version (B-127).404 The polymer coupling be- units along the chains. Copolymerization of MMA
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3729
narrow MWDs (Mw/Mn ) 1.1-1.2) because the sys- G. Telechelic and Star Polymers
tems are effective in controlling homopolymerizations
of both styrene and nBA.264 The R-Cl/CuCl system Telechelic and star polymers can be obtained by a
also gave R-13 although the MWDs became slightly so-called multifunctional initiator method where
broader (Mw/Mn ) 1.3-1.4).366 metal-catalyzed living radical polymerizations are
Other methacrylate-based copolymers are also pos- initiated from halogen compounds with plural reac-
sible with acrylamide (R-14)370 and maleimide (R- tive carbon-halogen bonds. This method can give
15),410 which can be prepared by ruthenium and multiarmed or star polymers with a predetermined
copper catalysts, respectively. Both copolymers have number of arms that corresponds to the number of
amide groups randomly distributed in the PMMA the carbon-halogen bonds in the initiator. Numerous
chains. polyhalogen compounds are accessible and synthe-
sized from various polyfunctional compounds as
E. Alternating Copolymers summarized in Figures 27 and 28, where the arm
numbers may be varied between 2 and 12.
Alternating copolymers can be obtained from the Another route to synthesizing star polymers by
monomers that cannot homopolymerize alone but can living polymerization involves the use of multifunc-
copolymerize in conjunction with the appropriate tional end-capping agents, but this method is not
monomers. As described above, N-substituted male- suited for metal-catalyzed radical polymerizations, at
imides copolymerize with styrene in this fashion in least so far, due to the lack of universal and conve-
the presence of copper catalysts to give alterna- nient terminating agents, as described above (section
ting copolymers with controlled molecular weights III.B.2).
(Mw/Mn ) 1.1-1.2). The substituents in the male- The third method is based on a polymer-linking
imides include 2-acetoxylethyl, phenyl, and cyclo- reaction where the liner polymers are obtained by
hexyl groups.219-222 the living radical polymerization with divinyl com-
pounds. This can afford star polymers with a rela-
F. Gradient Copolymers tively large number of arms, up to several hundred
Another type of copolymer with controlled composi- per molecule, while the number of arms by definition
tion or sequence distribution is a gradient copolymer, involves a statistical distribution in a single sample.
in which the repeat-unit composition (sequence)
changes along a backbone; i.e., “A” units are pre- 1. Telechelic Polymers with Bifunctional Initiators
dominant, for example, near the R-end, and their Halogen compounds with two reactive carbon-
abundance continuously decreases, while “B” units halogen bonds can be bifunctional initiators for
increasingly predominate near the ω-end. Such poly- metal-catalyzed living radical polymerizations to give
mers can be prepared by metal-catalyzed radical telechelic polymers. The effective bifunctional initia-
polymerization; two methods are known so far: One tors include MI-1 to MI-26 with various spacers
method is based on the automatic formation of a between the initiating sites.
gradient composition due to an inherent monomer R,R′-Dichloro-p-xylene (MI-1, X ) Cl) is a bifunc-
reactivity difference, and the other is based on tional initiator for the copper-catalyzed living radical
continuous addition of a second monomer at a con- polymerization of styrene to give telechelic polymers
trolled rate into a polymerizing solution of the first with controlled molecular weights and narrow MWDs
monomer. The former is exemplified in the copoly- (Mw/Mn ) 1.45).84 The bromide version of MI-1 (X )
mers obtained of MMA and nBA.411 Although they Br) is more versatile and gives telechelic polymers
are considered random copolymers, detailed analysis of stryene,84,315,348 MA,84,315 nBA,315 and p-acetoxysty-
indicates that there is a gradient structure therein. rene207 with narrow MWDs (Mw/Mn ) 1.1-1.3). The
The latter method was applied for pairs of styrene/ telechelics are further employed as macroinitiators
nBA and styrene/acrylonitrile. The physical proper- for ABA-type block copolymers. The copper-catalyzed
ties of the copolymers were studied in comparison to radical polymerization of MMA with MI-2 gave
those of other copolymers. polymers with narrow MWDs (Mw/Mn ) 1.2) but in
Another copolymer with compositional change along low initiation efficiency (Ieff ) 0.13).412 The obtained
the chains is an ABC-type block/random copolymer PMMA possesses one anthracene unit in the middle
that consists of three segments, each of which is a of the polymer backbone. R,R-Dichlorotoluene (MI-
copolymer of the two monomers with a different 3) serves as a bifunctional initiator for the copper-
composition. A mixture of styrene/MMA (3:1 molar catalyzed radical polymerization of styrene, while it
ratio) was polymerized with the ruthenium-based works as a monofunctional version for MMA polym-
systems, and two portions of MMA were sequentially erization due to the low reactivity of the second C-Cl
added at varying styrene conversions.205 The styrene/ bond after the initiation.165A haloketone, dichloroac-
MMA sequential compositions from the R- to the etophenone (MI-4), induces living radical polymeri-
ω-end in the final products with relatively narrow zation of MMA in the presence of ruthenium catalysts
MWDs (Mw/Mn ≈ 1.5) are about (3:1)-(1:1)-(1:4). to give polymers with extremely narrow MWDs (Mw/
These interesting experiments show not only that the Mn ≈ 1.1).56 As it turned out, both of the carbon-
Ru-catalyzed MMA/styrene copolymerization is in chlorine bonds in the initiator initiate living polym-
fact living irrespective of the initial monomer com- erization.154
position, but also that the reaction might lead to new Ester-type bifunctional initiators can readily be
copolymers differing from statistical or gradient prepared by a reaction of dialcohols or diphenols with
derivatives. β-haloacyl halides. For example, bis(dichloroacetate)s
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3731
such as MI-5 and MI-6 serve as a bifunctional Telechelic PMMA can be obtained from MI-13 with
initiator for MMA in the presence of Ru-1 and Al- Ni-2 as a catalyst.414 Anthrathene-labeled polysty-
(acac)3 to give telechelic PMMA with controlled rene can be synthesized with the copper-catalyzed
molecular weights and narrow MWDs (Mw/Mn ) 1.3- polymerizations initiated with MI-14; the aromatic
1.4). In contrast to dichloroacetophenone (see above), tag or probe is located near the midpoint of a polymer
one dichloroacetate unit serves as a monofunctional chain.415 Dibromoacetates MI-15 and MI-16 are com-
initiator in the ruthenium catalysis (Ru-1).228 An- mercially available and effective for methacrylates,
other chloride-type bifunctional initiator (MI-7) af- acrylates, and styrene with nickel and copper cata-
fords telechelic polystyrene in the presence of copper lysts.134,256,360-362 The resultant telechelic polymers
catalysts.171 Bromoesters MI-8 and MI-9 derived from have been subsequently employed for the synthesis
ethylene glycol were employed for acrylate and of various ABA triblock copolymers.
styrene with copper catalysts.313,326,358,359,368,389,413 These Functional groups can also be introduced in the
telechelic polymers can further be employed as spacer units. Bifunctional initiators with bipyridine
bifunctional macroinitiators for ABA block copoly- units such as MI-17 and MI-18 induced the living
mers.313,326,359,368,389 The obtained telechelic polysty- radical polymerizations of styrene and MMA, respec-
renes can produce polymer network gels by a copper- tively, with copper catalysts to give polymers that
mediated linking reaction with divinylbenzene.413 A carry a coordination site at the middle of the
series of bromoesters (MI-10 to MI-12), derived from chain.87,333 These polymers can be connected together
diphenols and 2-bromoisobutyroyl bromide, are ef- into star polymers with a ruthenium cation at the
fective in the copper-mediated living radical poly- core, where the arm numbers are varied among three,
merizations of various acrylates and styrene (Mw/Mn four, five, and six in combination with the polymers
≈ 1.1).263 A chloroester (MI-10, X ) Cl) gave similar obtained from the monofunctional initiator with a
polymers with slightly broader MWDs (Mw/Mn ≈ 1.2). bipyridine unit (FI-21 and FI-22; Figure 13).416 A
3732 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
modified method for the coupling reaction with the (MI-38) from the same tetraol can be employed for
metal center can also afford heteroarm star polymers methacrylates and styrene polymerization.343
consisting of polystyrene and PMMA chains.417 The Another tetrafunctional ester (MI-36) is the small-
bifunctional initiator complexed with ruthenium est number of a series of dendrimer-type initiators
prior to the polymerization (MI-19) is also effective such as MI-46 and MI-53 for 6- and 12-arm star
in the copper-catalyzed polymerization.87,333 polymers, respectively.414,419,420 These initiators in-
Bifunctional initiators with oligophenylenes as a duce the living radical polymerizations of MMA with
rigid spacer unit (MI-20 and MI-21) generate rigid/ Ni-2 to give the corresponding multiarmed polymers
flexible triblock copolymers of styrene.418 with controlled molecular weights although the arm
Disulfonyl halides such as MI-22 to MI-26 are number with MI-53 is slightly lower than 12 due to
effective bifunctional initiators for various monomers incomplete initiation from all the carbon-bromine
including methacrylates, acrylates, and styrenes, bonds.
because the sulfonyl halide part, as pointed out for A series of calixarene-core-type initiators (MI-40,
their monofunctional versions, can induce fast initia- MI-47, and MI-51) were prepared and employed for
tion without a bimolecular termination reaction the radical polymerizations of MMA, styrene, and
between the sulfonyl radicals.240,343 tBA. Ruthenium catalysts357 were first employed, and
copper catalysts are equally effective.421,422 PMMA
2. Star Polymers with Multifunctional Initiators obtained with the dichloroacetate version of MI-40
Halogen compounds with more than two reactive had narrow MWDs (Mw/Mn ) 1.1-1.2) and controlled
carbon-halogen bonds afford star polymers, the arm numbers of arms, which were ascertained by the
number of which is defined by the number of the scission of arms from the cores after the polymeriza-
initiating sites, whereas the arm length therein is tions.357
determined simply from the initial molar ratio of The star polymers obtained with the bromoester-
monomer to initiator. The multifunctional initiator type calixarene-based initiators were analyzed by
method gave various star polymers with 3 (MI-27 to SEC equipped with a multiangle laser light scatter-
MI-33), 4 (MI-34 to MI-42), 5 (MI-43), 6 (MI-44 to ing (MALLS) detector. The arm numbers were well
MI-50), 8 (MI-51 and MI-52), and 12 arms (MI-53 controlled (close to the initiator’s functionality),
and MI-54). although the octafunctional initiator MI-51 induced
A benzyl bromide-type initiator (MI-27) was uti- star-star coupling in the styrene-polymerization at
lized for the copper-catalyzed synthesis of 3-armed conversions higher than 20%.421 A similar series of
poly(acrylate)s with mesogen units as side-chain tetra-, hexa-, and octafunctionalized initiators with
groups.324 The effect of molecular architecture on the calixarene cores were synthesized for sulfonyl chlo-
thermotropic behavior was compared with the cor- ride versions (MI-41, MI-48, and MI-52) and em-
responding linear polymers in both living and con- ployed for copper-catalyzed MMA polymerizations.343
ventional polymerizations. Carbosilane-based dendritic bromoesters MI-39
Haloester-type trifunctional initiators are obtained and MI-54 are also effective as multifunctional
from triols by a method similar to those for bifunc- initiators for 4- and 12-arm star PMMA with narrow
tional haloesters. 3-arm star polymers of MMA are MWDs (Mw/Mn ) 1.1-1.2).423 However, star-star
obtained with dichloroacetates MI-28 and MI-29, for coupling was observed with the use of MI-54.
which Ru-1 and Al(acac)3 are employed.228 The poly- A pentafunctionalized initiator can be obtained
mers have controlled molecular weights and narrow from esterification of β-D-glucose, and star PMMA
MWDs. Similarly, MI-30 and MI-31 with copper with 5 arms are obtained.340 Inorganic cores, other
catalysts gave 3-arm star polymers of styrene, acry- than silicon, can also be employed such as the
lates, and methacrylates; suitable copper catalysts cyclotriphosphazene (MI-44 and MI-45), which gives
vary with each monomer.199,326,358,368 The obtained 6-arm polymers from styrene, acrylates, and meth-
star polymers can be further transformed into star acrylates.303,358 Tetra- (MI-42)87,332 and hexafunction-
block copolymers comprised of hydrophilic/hydropho- alized initiators (MI-4987,332 and MI-50424) with a
bic368 or organic/inorganic326 segments by block co- ruthenium center can be also employed for the radical
polymerizations of other monomers. polymerizations of styrene and MMA in the presence
Trisulfonyl chlorides MI-32 and MI-33 are also of appropriate catalysts such as copper, ruthenium,
efficient in the copper-catalyzed radical polymeriza- and nickel.
tion of methacrylates and styrene (Mw/Mn ) 1.1- Other multifunctional initiators include star poly-
1.4).343 The polystyrene arms can be cleaved from the mers prepared from initiators via living radical or
core with a base, giving polymers (arms) whose other living polymerizations. In particular, all of the
molecular weights are about 1/3 of the original. star polymers via metal-catalyzed living polymeri-
Tetra(bromomethyl)benzene (MI-34) was employed zation, by definition, carry a halogen initiating site
for alternating radical copolymerization of styrene at the end of each arm, and thus they are potentially
and N-cyclohexylmaleimide to give controlled molec- all initiators. Thus, star-block copolymers with three
ular weights and narrow MWDs (Mw/Mn ) 1.2- polyisobutylene-block-PMMA arms and four poly-
1.4).221 Another benzyl halide initiator (MI-37) with (THF)-block-polystyrene or poly(THF)-block-polysty-
a cyclosiloxane core induced styrene polymerization rene-block-PMMA were synthesized via combination
(Mw/Mn ) 1.16).358 An ester-type initiator (MI-35) is of living cationic and copper-catalyzed living radical
effective in the copper-catalyzed radical polymeriza- polymerizations.381,388 Anionically synthesized star
tion of nBA.358 A tetrafunctional sulfonyl chloride polymers of -caprolactone and ethylene oxide have
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3733
hydroxy groups at their terminal, which can be L-24 as a ligand, up to 85-90% yield. The linking
transformed into C-Br bonds. The functionality of reaction of a poly(tBA) with a bromide terminal was
C-Br bonds to be introduced thereby can be either also possible with divinylbenzene, whereas the other
mono-, bi-, or tetrafunctional, and thus one can two divinyl compounds led to side reactions.328 The
increase the initiating sites on the transformation. yield of star polymers can be increased up to 95%
With the use of this method, the arm numbers of with the use of additives. The R-end-functionalized
PMMA chains can be increased up to 24 arms.393 This linear polymers afford surface-functionalized star
method can also afford miktoarmed PEO-block- polymers with various functional groups such as
(polystyrene)2 and (polystyrene)2-block-PEO-block- alcohols, amines, epoxides, and nitriles.
(polystyrene)2 H-type copolymers.391
H. Comb and Graft Copolymers
3. Star Polymers by Linking Reaction
Comb and graft copolymers were also prepared by
As in known in anionic and other living polymer- metal-catalyzed living radical polymerizations. There
izations, star polymers with a large number of arms are two methods available for the synthesis, one of
(>10) can be prepared conveniently by a linking which is via the metal-catalyzed radical polymeriza-
reaction of linear polymers with divinyl compounds. tion of macromonomers in the absence or the pres-
Similar to the synthesis of block copolymers (section ence of comonomers (“grafting through” method), and
III.C.1), there are two ways for the synthesis by the other is via graft polymerization from the reactive
metal-catalyzed radical polymerizations, where the carbon-halogen bonds attached to the main chains
linking reaction is done via sequential addition of the (“grafting from” method). In contrast to ionic living
divinyl compounds into the polymerization mixture polymerizations, there have been no reports on the
after the almost completion of the vinyl monomers, use of “grafting onto” method, partly due to the lack
or via isolation of halogen-capped monofunctional of efficient ω-end capping agents as described above
linear polymers followed by linking reaction in the (section III.B.2).
presence of the metal catalysts and the divinyl
compounds. The former method may involve incor- 1. Comb Polymers
poration of the first vinyl monomer units (remaining Comb or densely grafted polymers are defined as
at the first stage) in the cores while the latter is free polymers that have at least one polymeric chains per
from such contamination though more cumbersome monomer unit of the main chain, and Figure 29
than the first. Also, the former one can be carried shows examples obtained by metal-catalyzed living
out in a one-pot reactor. radical polymerization. Comb polymers possess physi-
The sequential-addition method was systematically cal properties similar to those of star polymers in
employed for the ruthenium-catalyzed living radical solution.
polymerization of MMA followed by in situ linking
reaction with various dimethacrylates and related
bifunctional monomers.425 The yields of star polymers
depend on several factors such as halogens at the
polymer terminal and the spacer-unit structure
(length and rigidity) in the linking agents, where
chloride terminals and a soft aliphatic or a rigid long
aromatic spacer are favorable. The best yield reached
93%. The arm number of the star-polymers was also
determined form the molecular weights measured by
static light scattering or by SEC coupled with MALLS.
In an example, about 20 arms of PMMA chains were
linked together into one star polymer. Divinyl com-
pounds with amide and alcohol groups form core-
functionalized star polymers with 20-640 PMMA
arms in the ruthenium-catalyzed living radical po-
lymerization of MMA.426 In particular, bisacrylamides
are good linking agents, and they give interesting
star polymers in the core of which a large number of Figure 29. Comb polymers.
amide functions are embedded.
The copper-based system gave star polymers con- Combination of a living ionic polymerization and
sisting of polystyrene and poly(tBA) arms by the a metal-catalyzed radical polymerization also leads
linking reaction of isolated linear polymers.328,427 The to comb polymers, where both the molecular weights
linking reaction of Br-terminated polystyrenes was of the arm and main-chain polymers are well con-
examined with three divinyl compounds, divinylben- trolled. PMMA with poly(vinyl ether) arm polymers
zene, 1,4-butanediol diacrylate, and ethylene glycol of controlled molecular weights (C-1) were prepared
dimethacrylate with CuBr/L-1 catalyst.427 The first by the copper-catalyzed radical polymerization of
agent gave soluble star polymers, while the acrylate methacrylate-capped macromonomers carrying a poly-
and methacrylate versions resulted in insoluble gels, (isobutyl vinyl ether), which were obtained by living
attributed to star-star coupling. The formation of star cationic polymerization with a methacryloxy-capped
polymers with divinylbenzene can be accelerated with end-functionalized initiator.428 Comb polymers with
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3735
poly(oxyethylene glycol) with varying molecular Another dual living polymerization of MMA and
weights between 400 and 2000 were also obtained -caprolactone in the presence of HEMA gave graft
by the copper-catalyzed radical polymerizations of the copolymers with poly(-caprolactone) as branches (G-
corresponding macromonomers.319,320,429 However, this 5) because the hydroxyl group in HEMA serves as
method is not always suitable for high molecular an initiating site for -caprolactone.392 A similar graft
weight macromonomers because the polymerization structure is obtained in graft polymerization of
suffers from incomplete conversion and limits the ethylene oxide from the hydroxyl group.393
degree of polymerization of the main-chain units. The metal-catalyzed copolymerization from carbon-
Another method is based on the metal-catalyzed halogen bonds in the main chain can be employed
polymerization from carbon-halogen bonds in the widely for graft polymer synthesis. A combination of
main-chain units, which was applied for the synthesis nitroxide-mediated and copper-catalyzed living radi-
of C-3 and C-4.430 For C-3, the main chain polymers cal polymerizations, for example, gives graft copoly-
with controlled molecular weights were prepared via mers G-6, where the main chain is prepared by the
the copper-catalyzed radical polymerization of tri- former.432 The chlorobenzyl unit in the copolymer is
methylsilyl-protected HEMA followed by the trans- not active during the polymerization but, upon copper
formation of the silyloxyl group into 2-bromoisobu- catalysis, it can initiate living radical polymerizations
tyrate. The pendant C-Br bonds were subsequently of styrene and methacrylates.
activated by the copper catalysts to polymerize A similar well-defined graft copolymer consisting
styrene and nBA. A more direct way is employed for of polystyrene main chain and branches (G-7) can be
C-4; i.e., via conventional radical polymerization of prepared simply via repetition of copper-catalyzed
2-[(2-bromopropinonyl)oxy]ethyl acrylate followed by living radical polymerizations.209 Thus, the synthesis
the copper-catalyzed graft polymerization of styrene starts with the copolymerization of styrene and
and nBA from the C-Br substituent. p-(acetoxymethyl)styrene or p-(methoxymethyl)sty-
2. Graft Polymers rene, followed by bromination of the substituent into
the benzyl bromide moiety, which then initiates the
Various graft copolymers were synthesized by
copper-catalyzed radical polymerization of styrene to
metal-catalyzed radical polymerizations, as detailed
give graft polymers with 8-14 branches.
in Figure 30. Most of them were from random
copolymerization of a macromonomer with a low A combination of metallocene-catalyzed syndiospe-
molecular weight comonomer. cific styrene polymerization and the metal-catalyzed
In a study, copper-catalyzed radical copolymeriza- radical polymerization affords various graft copoly-
tion of nBA and methacryloxy-capped poly(MMA) mers consisting of syndiotactic polystyrene main
was compared with conventional radical copolymer- chains (G-8).433 The reactive C-Br bonds (7-22%
ization.267,431 The graft copolymers G-1 obtained with content) were generated by bromination of the poly-
copper catalysts are more homogeneous in terms of styrene main chain with N-bromosuccimide in the
MWD (Mw/Mn ≈ 1.6 vs 3) and the number of side presence of AIBN.
chains. This is attributed to diffusion control being Another graft copolymer with polystyrene seg-
less important in the metal-catalyzed radical polym- ments in main chain is derived from the triblock
erization, where the growing radical species is rapidly copolymers of polyisobutylene and poly(p-methylsty-
converted into the dormant covalent species. rene) prepared by living cationic copolymerizations
There are several examples of graft copolymers (G-9).434 The grafting point was generated by the
obtained from macromonomer prepared by the metal- bromination of the p-methyl groups into benzyl
catalyzed polymerizations. Conventional radical co- bromide, which are then employed for the copper-
polymerization of N-vinylpyrrolidione and vinyl catalyzed polymerization of styrene and p-acetoxy-
acetate-capped polystyrene synthesized with copper styrene. A similar graft copolymer (G-10) can be
catalysts gave graft copolymers G-2, which formed obtained from a commercially available polymer
hydrogels in water.337 Electrochemical copolymeri- (EXXPRO) consisting of isobutylene, p-methylsty-
zation of pyrrole and thiophene-capped poly(MMA) rene, and p-(bromomethyl)styrene units.265,435 The
affords G-3.335 mechanical properties of the graft copolymers were
A graft copolymer consisting of poly(-caprolactone) also investigated. Another commercial product, poly-
as main chain and PMMA as branches was also (styrene-block-ethylene-co-propylene) (Kraton 147)
synthesized by ring-opening copolymerization of -ca- with 29.0 wt % styrene units, is also used as a
prolactone and -caprolactone-capped PMMA mac- backbone.436 About 6.4 mol % chloromethylated sty-
romonomer; the macromonomer was prepared by a rene units are first introduced by chloromethylation,
nickel catalyst.312 The obtained graft copolymers have which then initiates graft polymerization of ethyl
relatively narrow MWDs (Mw/Mn ) 1.3-1.4) because methacrylate to give the products G-11.
both the polymerizations are living. There are two A polyolefin-based graft copolymer such as G-12
other ways for the preparation; one is graft polym- is prepared from a commercially available EPDM
erization of MMA from the C-Br moiety in the rubber (Vistollon 2727).437 The allyl group is partially
pendant groups of poly(-caprolactone), and the other converted into allyl bromide moiety, and living radi-
is simultaneous or dual living polymerization of cal polymerization of MMA initiated therefrom with
MMA and -caprolactone in the presence of a func- copper catalysts. Graft copolymers of polyethylene (G-
tionalized -caprolactone with C-Br bond (FI-41). 13) were synthesized from commercially available
Both the methods afford similar products with nar- poly(ethylene-co-glycidyl methacrylate) as a starting
row MWDs. material, the epoxy groups of which were esterified
3736 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
with chloroacetic acid and 2-bromopropionic acid into Graft polymers with a poly(vinyl chloride) backbone
the reactive carbon-halogen bonds.438 The function- and various branches (G-14) were obtained from the
alized polymers then initiate the copper-catalyzed copolymer of vinyl chloride and 1 mol % vinyl
radical polymerizations of styrene and MMA to afford chloroacetate.439 Glass transition temperature (Tg) of
arm polymers with controlled lengths. the copolymer with nBA decreases with increasing
Metal-Catalyzed Living Radical Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3737
content of nBA. A more direct and simple way for where addition of CuBr2 is needed to decrease the
poly(vinyl chloride)-based graft copolymers is to use concentrations of the radical species generated from
the allyl chloride and tertiary chloride units as the monomers.443 Under appropriate conditions, nearly
structural defects in the base polymers for the ideal self-condensing vinyl polymerizations proceed.
initiating moiety in the metal-catalyzed living radical The obtained polymer was a viscous solid with a
polymerization.440 This method can afford various subambient Tg (-11 °C). Detailed kinetic and mecha-
graft copolymers G-15, which was characterized by nistic studies were carried out to determine the
SEC, NMR, DSC, and film preparation. difference in reactivity among the C-Br bonds in
Hybrid graft copolymers having silicon-based poly- terminals and side chains.212,444,445 Similar meth-
mer backbones were also prepared by the metal- (acrylic) hyperbranched polymers were prepared from
mediated radical polymerizations of styrene. The H-3 and H-5 while the products with H-4 were most
phenyl groups of poly[(methylphenyl)silylene] were likely linear polymers. 446
bromomethylated and then employed as the grafting The self-condensing copper-catalyzed polymeriza-
points of polystyrene (G-16).294,441 Polysiloxane can tion of macromonomer of poly(tBA) with a reactive
be employed also as a backbone (G-17) by introduc- C-Br bond (H-6) affords hyperbranched or highly
tion of benzyl chloride units into the pendant vinyl- branched poly(tBA).447 Copolymerization of H-1 and
functionalized poly(dimethylsiloxane).409 N-cyclohexylmaleimide induced alternating and self-
condensing vinyl polymerization.448 The residual
I. Hyperbranched Polymers C-Cl bond was further employed for the copper-
In vinyl polymerization, hyperbranched polymers catalyzed radical homopolymerization of styrene to
can be obtained from the monomers that have an give star polymers with hyperbranched structures.
initiating group along with a vinyl group (Figure 31). Hyperbranched polymers of H-1 further serve as a
complex multifunctionalized macroinitiator for the
copper-catalyzed polymerization of a functional mono-
mer with polar chromophores to yield possible second-
order nonlinear optical materials.325
The graft copolymers with poly(H-1) arms have
multiple carbon-halogen bonds that can initiate
copper-catalyzed radical polymerization to give highly
branched dendrigraft polymers.432 The products with
styrene or nBMA had relatively narrow MWDs
because each chain was prepared by living polymer-
ization.
A combination of other polymerization pathways
also results in some hyperbranched structures. Mul-
tifunctional hydroxyl groups in polyglycerol with
hyperbranched structure, prepared by anionic po-
lymerization of glycidol, were esterified with 2-bro-
moisobutyroyl bromide and then employed as a
hyperbranched multifunctional macroinitiator for the
Figure 31. Monomers for hyperbranched polymers. copper-catalyzed radical polymerization of MA to give
products with 45-55 poly(MA) arms.449
The self-condensing vinyl polymerization, which was Another method for hyperbranched polymers is
initially developed for living cationic polymeriza- based on a simultaneous or dual living polymeriza-
tion,442 is also applicable for metal-catalyzed living tion such as metal-catalyzed radical and ring-opening
radical polymerizations. ionic polymerizations.311 In this method, copolymer-
For example, p-(chloromethyl)styrene (H-1) was izations of HEMA and H-7 are carried out in the
employed for copper-catalyzed self-condensing vinyl presence of Ni-2 and Sn(Oct)2, where the C-Br bond
polymerizations.211 The hyperbranched structure was in H-7 serves as an initiating point for the nickel-
supported by the fact that the molecular weight catalyzed radical polymerization of HEMA and the
measured by SEC was lower than those by viscosity OH group in HEMA for the tin-catalyzed ring-
and light scattering. The average number of branches opening polymerization of H-7. The products had
per polymer chain was estimated to be 25. In con- hyperbranched structures, similarly to those obtained
trast, another paper reported that the reaction condi- in self-condensing vinyl polymerizations. Addition of
tions should be changed for the synthesis of hyper- MMA and/or -caprolactone into the system gave
branched structure.213 A high catalyst-to-monomer looser hyperbranched structures.
ratio around 0.1-0.3 should be employed to minimize
the formation of linear polymers due to the difference
in reactivity between the primary and the secondary
J. Polymer Brushes
benzylic halide sites. The residual carbon-halogen Polymer brushes can be obtained by metal-medi-
bonds were transformed into functional groups such ated living radical polymerization from the initiator
as cyano, ester, thioether, and imide to generate moiety confined to the surface of a substrate via
multifunctionalized hyperbranched polymers. spacers. The surface-initiated living polymerization
Acrylic hyperbranched polymers are obtained by can control the thickness and the density of brushes;
the copper-catalyzed radical polymerizations of H-2, the former is regulated by brush’s chain length and
3738 Chemical Reviews, 2001, Vol. 101, No. 12 Kamigaito et al.
Another example is the copper-catalyzed surface- the polymerizations, bromide-type initiator frag-
initiated radical polymerization of MMA from S-7 at ments S-10 and S-11 were attached to the surface
room temperature without addition of free initiator. and initiated the homopolymerization or copolymer-
The molecular weights and MWDs of the polymers izations. A higher loading of the polymers was
were directly measured after removing the brushes observed with S-11 than S-10.
from the surface. For example, the surface with 40
nm thickness had Mn of 68900 and MWDs of 1.45. A 5. Polymer Latex
high graft density (180 Å2/chain) and decreased Organic compounds such as polystyrene latexes
surface roughens (0.54 nm) were observed. This were also used as substrates for the surface-initiated
method is free from solution and thermal polymer- radical polymerizaiton.248 Reactive C-Br bonds (S-
izations due to the absence of free initiators and a 12) were introduced at the surface via radical emul-
low polymerization temperature, which permits a sion copolymerization of styrene and 2-(2-bromopro-
simple washing step without Soxhlet extraction. pionyloxy) ethyl methacrylate in the presence of
divinylbenzene under selected conditions. The surface-
3. Silica Particle and Bead initiated polymerization of hydrophilic monomers
Surface-initiated living radical polymerization is such as FM-3 and FM-6 resulted in hydrophilic shell
also applied for spherical surfaces such as silica and hydrophobic core latexes.
nanoparticles and beads.
Spherical silica nanoparticles, with an average IV. Conclusions
diameter of 70 nm, modified with the initiator moiety
(S-8) were employed for the copper-mediated radical This paper has provided, we believe, a comprehen-
polymerization of styrene.457 The diameter of the sive, up-to-date, critical, and objective review on the
particles and the molecular weights of the obtained discovery and the subsequent fast development of
polymers increased with conversion. For example, the living radical polymerizations catalyzed by transi-
average diameter of the particles obtained at 58.8% tion-metal complexes in the period from 1994 to early
monomer conversion was increased to 188 nm, where 2001. These metal-catalyzed living radical polymer-
the Mn and MWDs of the arm polymers were 26500 izations have rapidly been developing since their
and 1.33, respectively. Given a narrow size distribu- discovery in 1994, and the scope of applicable mono-
tion (<10%), the nanoparticles within the film do- mers, metal catalysts, and initiators has been ex-
mains were observed to pack into hexagonal arrays. panding. Their advantages include versatility toward
A smaller silica nanoparticle with 14 nm was em- a variety of monomers, feasibility in a wide range of
ployed also for the copper-catalyzed radical polym- reaction conditions, and relatively easy access to the
erization of styrene initiated with S-9.458 materials. This permits many researchers to use the
systems for the precision synthesis of various poly-
Silica microspheres (∼3 µm) with initiating moiety
mers with controlled architectures.
(S-8) induced the copper-catalyzed radical polymer-
ization of benzyl methacrylate to form polymer layers As in many other fields of science, however, these
on the surface.459 The thickness of polymer shell can extensive developments have also elicited a number
be increased to 550-600 nm, where the Mn and of interesting and challenging problems that are still
MWDs of the arm polymers were 26500 and 1.26, waiting for solutions and answers. These may include
respectively. Removal of the core silica by chemical the kinetics and mechanism of the polymerizations,
etching gave uniform hollow polymer microspheres. the nature of the true growing intermediates that are
considered to associate with the metal catalyst (e.g.,
4. Silica Gel and Silica Capillary are they really radicals identical or similar to those
in classical “free” radical polymerizations?), the guid-
Organic polymer layer on the surface of silica gels ing principles for designing metal catalysts, and the
or porous silica can modify the surface to increase “novel” polymers that can be synthesized by the
the resistance of the silica surface to basic com- metal-based systems but cannot be by other (living)
pounds. radical polymerizations. In addition to these prob-
The first example of the surface-initiated metal- lems, future research efforts will therefore be directed
catalyzed radical polymerization was reported for toward the development of more efficient and versa-
acrylamide from the initiator moiety S-8 attached to tile catalyst systems for various monomers including
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Chem. Rev. 2001, 101, 3611−3659 3611
Alexei A. Gridnev*
DuPont Performance Coatings, 2401 Grays Ferry Avenue, Philadelphia, Pennsylvania 19146
Steven D. Ittel*
DuPont Central Research and Development, Experimental Station, Wilmington, Delaware 19880-0328
Steve Ittel was born in Hamilton, OH (1946), and received his B.S. degree
in Chemistry from Miami University in 1968. After two years of studying
photochemical smog in the greater New York City area for the USPHS,
he attended Northwestern University, where he received his Ph.D. degree
in Inorganic Chemistry in 1974 with Jim Ibers. Joining DuPont’s Central
Research, he was involved in the elucidation of fluxional processes in
five- and seven-coordinate inorganic complexes. After work on C−H
activation, diamagnetic and paramagnetic agostic M−H−C interactions,
and cyclohexane oxidation, he moved to research management. Never
straying far from the scientific edge, he has been involved in small molecule The catalytic chain-transfer (CCT) process displays
catalysis including hydrocarbon oxidation, fluoro-organometallic chemistry, all of the features characteristic of typical, uncata-
and olefin hydrocyanation. The molecules started getting larger as his lyzed chain transfer other than taking place at a rate
interests turned toward elastomeric polypropylene, catalytic chain transfer competitive with chain propagation. Thus, the rate
in free-free-radical radical polymerizations, and most recently ethylene
polymerization with polar comonomers. He has over 100 publications and
of polymerization at low conversions is independent
patents and a book to his credit. Another interest, having both technical of the concentration of the cobalt porphyrin (Figure
and aesthetic aspects, is the nurture and styling of a collection of about 1) while the molecular weight, Mh n, decreases linearly
100 bonsai. by over 2 orders of magnitude with increasing
concentration of cobalt catalyst (Figure 2). As ex-
terminators is often employed.3 Thus, compounds pected for a typical polymerization, the rate of
such as thiols will react with a growing polymer polymerization increases linearly with the square
chain to yield a thiol-terminated species.4,5 In this root of the concentration of the azo initiator and no
instance, there would be only one polymer chain per polymerization occurs in the absence of the initiator.
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3613
Free-radical polymerizations of bulk monomers are The same species has been observed in the spon-
subject to the gel effect or Trommsdorff effect.16 taneous polymerization of MMA, but its yield is
Figure 1 also indicates that CCT suppresses the gel limited to at most 50% because it arises from dispro-
effect. Because the resulting product is lower in portionation of two radical chains.24 In low productiv-
molecular weight, the viscosity of the polymerizing ity polymerizations, some product derived from the
medium is not as high at a given degree of conver- initiating radical could be observed, but in high
sion. Thus, the observed sharp maxima in the rates conversion polymerizations, it appeared that virtually
of polymerization at time τ can be used as a quanti- all of the product molecules were initiated with a
tative measure of the chain-transfer constant of hydrogen atom and terminated with an olefinic end
CCT.17 At 60 °C in a bulk polymerization of MMA group. This polymeric product can be formed in the
initiated with 0.04 mol/L AIBN, the following empiri- presence of cobalt porphyrin only by hydrogen trans-
cal equation relates the chain-transfer constant of fer from the R-methyl group of methacrylate end unit
CCT, kC, to the concentration of cobalt catalyst, LCo, of the propagating radical to monomer. The turn-over
in mol/L and the time of maximum polymerization number of this reaction was calculated to be at least
rate, τ, in minutes18 106, while selectivity is virtually quantitative.2,25,26
It is the quantitative nature of the double bond
400 formation that makes this new product useful in a
) 3.6 - lg(kC[LCo]) (1) number of applications. It is interesting that the
τ
isomeric compound, 4, is not observed in the reaction
The linearity of this relationship is demonstrated in mixture even though it is more stable thermodynami-
Figure 3. Any deviation from linearity from eq 1 cally.27
indicates complications in the course of the polym-
erization. The complications are typically catalyst
poisoning or polymerization retardation (see section
3.6).
The cobalt porphyrin, PorCo, was recovered from
the product by flash chromatography and reused
several times without any detectable change in
molecular structure, clearly indicating the catalytic
3614 Chemical Reviews, 2001, Vol. 101, No. 12 Gridnev and Ittel
The kinetic preference for 3 could be attributed to species into focus. For example, the lower solvent
steric screening of the internal methylene protons content required to meet low VOC constraints for
near the tertiary carbon center through their interac- paints34 brings renewed interest in low-viscosity
tion with the large planar porphyrin molecule. oligomers that can be cured during or shortly after
Styrene lacks a methyl group on the propagating application.35,36 Highly structured pigment dispers-
radical, so chain termination must lead to a different ants for paints and other applications are often based
type of product. A thorough analysis has led to the upon block copolymers37 accessible through mac-
conclusion that the product is terminated exclusively romonomers, and ink-jet printers require sophisti-
by a trans substituted olefinic group.28 For example, cated polymer formulations to achieve the very
the trimer is 5. rigorous set of demands placed upon those systems.38
The Mayo equation is often used to determine
chain-transfer constants.39 Cs is determined from
measurements of DPn over a range of [S]/[M] with
the provison that DPn0 remains constant throughout
the range evaluated.40,41 A plot of 1/DPn versus
[S]/[M] yields a straight line with a slope of Cs and
intercept of DPn0. Catalytic chain transfer obeys the
Mayo equation well for DPn of 20 and higher. When
DPn is less than 20, there is an apparent deviation
from linearity for DPn versus the concentration of the
One of the most striking features of CCT is the cobalt catalyst. This phenomenon was observed for
exceptionally fast rate at which it takes place. The methacrylate.14 It appears that at low molecular
molecular weight of a polymer can be reduced from weights or high catalyst concentrations, the catalyst
tens of thousands to several hundred utilizing con- is loosing activity (Figure 4).
centrations of cobalt catalyst as low as 100-300 ppm
or ∼10-3 mol/L. The efficiency of catalysis can be
measured as the ratio between the chain-transfer
coefficients of the catalyzed reaction versus the
noncatalyzed reaction. The chain-transfer constant
to monomer, CM, in MMA polymerization is believed
to be approximately 2 × 10-5.29 The chain-transfer
constant to catalyst, CC, is as high as 103 for porphy-
rins and 104 for cobaloximes. Hence, improved ef-
ficiency of the catalyzed relative to the uncatalyzed
reaction, CC/CM, is 104/10-5 or 109. This value for the
catalyst efficiency is comparable to many enzymati-
cally catalyzed reactions whose efficiencies are in the
range of 109-1011.18 The rate of hydrogen atom
transfer for cobaloximes, the most active class of CCT
catalysts to date, is so high that it is considered to
be controlled by diffusion.5,30-32 Indeed, kC in this case Figure 4. Dependence of the average chain-transfer
is comparable to the termination rate constant.33 constant on the number-average degree of polymerization.
The very high rates of catalytic chain transfer Data are taken from ref 14.
finally made it practical to prepare low molecular
weight oligomers by free-radical polymerization. The This unusual behavior was detected for measure-
chemistry of low molecular weight oligomers was ments of polydispersity as well. While polydispersity
relatively unexplored for several reasons. Previous is close to 2 for DPn > 20 as expected for free-radical
routes to oligomers involved complicated and un- polymerizations in which there is a high level of chain
pleasant chemistry or were very expensive. Thiol transfer,40,42 the polydispersity index decreases to
chain termination required high levels of chain- values approaching 1.1-1.2 for DPn < 10. To explain
transfer agents, leaving high levels of toxic or mal- this unusual behavior for CC, low MMA oligomers
odorous residues. It is also possible to obtain low were separated into fractions by HPLC43 and CC was
molecular weight species by utilizing high levels of calculated for each individual radical, CC(n). The
initiator, but in addition to being expensive, high resulting dependence of CC(n) on DP is shown in
levels of azo initiators can lead to toxic cross-coupling Figure 5.
products. Living polymerizations required high levels CC(n) stays unchanged for DP values down to 6, and
of initiator or catalysts because each initiator leads then it starts to diminish rapidly. CC by definition is
to only one macromonomer, making them com- an “average” term, and as a result, it does not change
mercially unattractive when low molecular weights as rapidly with decreasing degree of polymerization
are required. A further reason was that the main as does CC(n). Having determined CC(n) for each “n”,
objective of polymer science had generally been the one can now plot the calculated dependence of CC
synthesis of high molecular and even ultrahigh against DPn. The calculated dependence does not
molecular weight species, primarily to improve me- correlate well with the earlier results.14 In fact,
chanical properties. Recent changes in industrial evidence that indicates that CC decreases with in-
requirements have brought lower molecular weight creasing chain length has been reported.44,45 A viable
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3615
1 1 kC[LCo]
) + (3)
DPn DPn0 kP[M]
Figure 6. Dependence of the extinction coefficient and
relative index of refraction of low MMA oligomers on the
degree of polymerization. M is monomer, and DPn and DPn0 are the number-
average degree of polymerization corresponding to
these parameters for MMA dimers differ from those those obtained with and without chain-transfer agent.
of high polymer by over 50% with smaller differences In an extreme, at elevated levels of an active catalyst
for higher oligomers. For example, if a solvent with (for example kC ) 107 L/mol‚s and [LCo] ) 0.01 mol),
a refractive index close to that of MMA dimer is used the calculated DPn can be less than 1, clearly an
in the analysis, errors can be substantial. In an impossible situation. Hence, the Mayo equation in its
extreme example, the use of toluene for the analysis standard form is not applicable for many cases of
would give inverse peaks for all of the low oligomers CCT when low oligomers are being prepared. Rede-
while high polymer would give a positive peak. Some termination of the dependence of the number-average
moderate oligomers would be invisible to the analy- degree of polymerization on the concentrations of
3616 Chemical Reviews, 2001, Vol. 101, No. 12 Gridnev and Ittel
monomer and CCT catalyst concentration in the lyst.61 Discussion of the absolute propagation rate
short-chain approximation gives eq 452 constants of small radicals is not related directly to
the purpose of this review, but there are two points
1 1 kC[LCo] worth making.
) + (4)
DPn - 2 DPn0 kP[M] First, the chain-transfer coefficient, kC, is almost
independent of radical lengths despite the array of
For high polymer, eq 4 is indistinguishable from eq claims in the literature.44-47 Thus, kC of the meso-
3. For the case of intensive CCT, when the MW of tetraphenyl derivative of Co-porphyrin with the
the resulting product is low, eq 4 can be reduced to dimeric MMA radical is 2.8 × 106 L/mol‚s versus 2.4
eq 5 × 106 L/mol‚s for high polymer. As a result, CC
decreases with DPn because CC ) kC/kP. The reason
kP[M] that kC is independent of the size of the radical is
DPn ) 2 + (5) not clear. CCT seems to be diffusion controlled, and
kC[LCo] the large size and required orientation of the por-
There also arises an interesting semantic issue. phyrin molecule may be controlling. It cannot be
Equation 5 indicates that product lower than the excluded that the rate of CCT is determined by the
dimer cannot be obtained by CCT. Clearly, the actual rate of formation of intermediate species such as a
degree of polymerization is quantized in units of one caged radical pair. In the latter case with low
and DP1 is called “starting material”. Nonetheless, molecular weight species, one might observe length
at high levels of an active catalyst, starting monomer dependence of the kC for highly active CCT catalyst,
is frequently converted to radical and then back to like cobaloximes.
“monomeric product” before addition of a second The second significant point is that propagation in
monomer can occur. At DPn < 12-15, deviation from the presence of the cobalt catalyst occurs by a free-
the linear dependence of DPn on the concentration radical mechanism, not by a coordination polymeri-
of catalytic chain-transfer agent are observed as zation mechanism described by eqs 7-9 as suggested
expected.14 At the same time, the polydispersity (if in some publications.2,62-64
this is a meaningful term) narrows and becomes
dependent upon DPn according to eq 6 LCo - Rn + M f LCo - Rn+1 (7)
Table 1. Effect of Substituents on MMA CCT Activity Table 2. Influence of Cobaloximes 6 Substituents on
for Cobaloximes 6a, 7b and 8 CCT Activity in Styrenea77
compound X1 X2 A or E E (base) CC ref compound X1 X2 A E (base) CC
6a Me Me Me H2O <50 77 6a Me Me Me H2O <4
6b -(CH2)4- Et H2O <50 77 6d Me Me NO2 Py <4
6c Me Me CN Py <50 77 6e Ph Ph CN Py <4
6d Me Me NO2 Py <50 77 6g Me Me Cl Py 450
6e Ph Ph CN Py <50 77 6n -(CH2)4- Cl Py 300
6f Ph Ph Et H2O <50 77 6q Ph Ph Cl Py 350
6g Me Me Cl Py 5 000 77 6r Ph Ph Cl P(Ph)3 500
6h Me Me I Py 1 000 77 a
6i Me Me CNS Py 4 000 77 Bulk styrene, 60 °C.
6j Me Me sec-Bu H2O 13 000 77
6k Ph Ph CNS Py 25 000 77
6l Me COOEt Cl Py 12 000 77 ing science and art. Choosing the optimal testing
6m Me COMe Cl Py 25 000 77 conditions is crucial for getting reliable results. Side
6n -(CH2)4- Cl Py 4 000 77 reactions can both mask and mimic CCT so that
6o R-furyl R-furyl Cl Py 100 000 77 considerable judgment is required. The results of
6p Ph Ph Cl H2O 25 000 77 polymerization in the presence of cobalt chelates
6q Ph Ph Cl Py 30 000 77
6r Ph Ph Cl P(Ph)3 100 000 77 depend on temperature, solvent, pH, the sterics and
6s Me Me Py Py 2 100 78 electronics of the chelating ligand, the presence of
6se Me Me Py Py 700 79 additional ligands, and the monomer chosen. Minute
6t Me Me NEt3 NEt3 1 600 78 concentrations of impurities, particularly oxygen,75,76
6u Me Me PPh3 PPh3 4 100 78 in the reaction media or even in the tested complex
6u Me Me PPh3 PPh3 20 000 44
7a Cl 11 000 77
may corrupt the results. The issue of polymerization
7b ClO4 <50 77 conditions will be discussed later in section 3.7 and
7c NO3 <50 77 to a lesser extent in other sections. Redox or other
8ac Me Me 11 000 77 reactions in the polymerization media, changes in the
8bd Ph Ph 66 000 77 rate constants due to presence of solvents, and other
a Run in bulk MMA at 60 °C. b Measured in MMA:methanol phenomena can lead to reduction of MW in the
) 7:3 v/v at 60 °C. c MMA:methanol ) 7:3 v/v. d MMA: absence of CCT. One generally expects a profound
methanol ) 7:3 v/v + 1% Py. e MMA:methanol ) 1:1 v/v. effect, so when CC < 50, the presence of CCT can be
questionable. This is not to say that cobalt chelates
relative bond-breaking energetics requires quantum with CC < 50 are not CCT catalysts, but confirmation
mechanics, and until recently, few calculations have requires additional investigation.
been attempted because of their large size. Semiem- Unless otherwise mentioned in the text, all scout-
pirical models have been important in the discussion ing for CCT reported here was carried out at 60 °C
of the balance between steric and electronic effects in MMA or in a methanol solution of MMA if LCo
in B12 reactions,70 but they are not effective for the was not directly soluble in monomer. AIBN was used
determination of equilibrium structures. DFT calcu- as the azo initiator because peroxides often decom-
lations are expected to provide higher accuracy. pose or poison the cobalt complexes.
Calculation of nuclear quadrapole couplings of simple The best known CCT catalysts are cobaloximes
coenzyme B12 models without a planar framework having the general structures 6, 7, 8, and 9.77-81 Data
proved to be reasonable.71 The B3LYP method has on their catalytic activities in MMA and styrene
been used to evaluate the equilibrium structures of polymerizations are presented in Tables 1 and 2,
corrin models with different axial alkyl groups.72 The respectively.
equilibrium structures of methyl B12 and adenosyl B12
have a different electronic structure for the two Co-C
bonds. The HOMO energy is higher in AdoB12 than
in MeB12, favoring homolytic cleavage because of the
5′-deoxyadenosyl group that induces more electron
density on cobalt. This may explain part of the
homolysis heterolysis dichotomy. Comparison of the
computational geometries with experimental re-
sults73 suggests two very different reaction coordi-
nates for the two coenzymes related to competitive
heterolysis or homolysis of the two respective Co-C
bonds.74 Unfortunately, these studies invoke chemical
and structural differences that are not available to
the catalysts in CCT.
2. Catalysts
2.1. Catalyst Screening
Testing new compounds for catalytic chain-transfer
activity in free-radical polymerizations is an interest-
3618 Chemical Reviews, 2001, Vol. 101, No. 12 Gridnev and Ittel
As a result of the ready availability of required tant on a commercial scale that the compounds can
starting material and smooth, well-developed syn- be stored and handled by chemical operators without
theses,82 the cobaloximes 6-8 served as convenient special precautions.97-100
models for understanding how axial ligands and It is difficult to compare the activities of the
substituents on the macrocyclic ligand affected the H-bridged cobaltII oximes with their BF2-bridged
catalytic behavior of these CoII species.83 There are counterparts because of their increased sensitivity to
some advantages to using the CoIII-alkyl versions of
oxygen. The in situ preparation of cobaltII oximes in
these catalysts.84 The macrocyclic ligand in co-
radical polymerization of MMA has been described.79
baloximes is an almost perfectly planar structure
Making such cobaloximes in situ requires methanol,
carrying a formal double negative charge. The hy-
drogen bonding between the two monoanionic cova- pyridine, or other solvents to dissolve the starting
lent halves of the equatorial ligand is sufficient to materials, and as a result, the concentrations of the
confer considerable structural rigidity and chemical monomers are 70% or less in the final solution. In
stability.85-88 The complexes are able to withstand one example, the data indicate CC ≈ 700 for Py-
strong acids89,90 and even Grignard reagents.91 In (dmgH)2CoII,79 which is substantially less than that
deuterium oxide solutions, replacement of the bridg- of the cobaltIII oximes shown in Table 1. A second
ing hydrogen atom with deuterium is slow even in approach for in situ synthesis is to use starting
the presence of bases or acids.92,93 This stability materials such as cobalt 2-ethylhexanoate that are
allows the catalysts to be employed in aqueous soluble in MMA, thereby making additional solvent
systems as well as organic media.94 unnecessary.101
The axial ligands can be divided into two groups. Traditional methods of handling air-sensitive ma-
Group A comprises monoanionic ligands that result terials102 are generally appropriate for making co-
in an oxidation state of three in cobalt. These may baltII dioximes because cobaloximes of the type
be the anions resulting from acido ligand (for instance E(dmgH)2CoII tend to dimerize and precipitate from
chloride) or may be alkyls. The hydride ligand would methanol solutions. Thus, (PPh3)(dmgH)2CoII-CoII-
also fall into this category and plays an important (dmgH)2(PPh3) was synthesized and tested in bulk
role in the catalytic chemistry, but in general, they MMA to give a relatively unusual result. The cata-
have not been observed directly. Electron-donating lytic activity of such LCo depends on the concentra-
ligands, E, are neutral, Lewis base ligands which are tion and ranges from CC ) 800 to CC ) 20 000.44 The
coordinatively bound and are not involved in the reasons for such a distribution of CC values will be
oxidation state of the cobalt. From a practical point detailed later. At this point it is sufficient to indicate
of view, E ligands, particularly water, are often that the catalytic activities of cobaloximes 6-8
present in the catalysts employed for CCT, but they depend very much on axial ligands of the A type and
are often unspecified. much less on substituents in the equatorial ligand
and ligand of the E type. The latter two may change
2.2. Cobalt Catalyst Activities the chain-transfer constant 2- to 4-fold, while ligands
of the A type may reduce CC by orders of magnitude.
As shown in the Table 1, the activities of co-
The A ligands giving the highest activities are
baloximes 6 can vary by more than 3 orders of
halides, especially chloride. E type ligands tend to
magnitude.77-81,95,96 Ligands of class A showed no
increase CC with increasing ligand strength as one
catalytic activity when A ) primarily alkyl, CN, or
NO2 (entries 6a through 6f). When A is halogen, may see in Table 1 (phosphines > py > H2O).78 The
pseudohalogen, or secondary alkyl (entries 6g-6k), same results were observed in porphyrins, although
the resulting cobaloximes are potent chain-transfer the effect is smaller than in cobaloximes perhaps due
catalysts. Variation of substituents on the dioximate to a larger “electron pool”.
moieties (entries 6L-6o) changes the CCT chain- When cobaloximes, 9, with a BF2-bridging
transfer constants severalfold. The presence of ligands ligand,103,104 were first reported as CCT catalysts,105,106
of the E type (entries 6p-6r) also cause variations they quickly became the CCT catalysts of
of severalfold, and it seems at first glance that CC choice.44,107-117 They are often introduced into the
increases with the strength of their ligand field. reaction mixture as either CoII or CoIII-alkyl species.
For charged cobaloximes such as 7, the choice of It is presumed that the CoIII-alkyl species are
the A ligand is crucial (Table 1). Differences in this quickly and quantitatively reduced to CoII in situ.77,118
catalytic activities of these cobaloximes with chloride Data on their activity are reported in Table 3.
and other acido ligands range over 3 orders of Substituents in the cobaloximes 9 have a slight effect
magnitude. CobaltIII oximes 8 with no A ligands are on the catalytic activity but more surprising is the
among the most active. These observations are dependence of CC on solvents employed for the
consistent for both MMA and styrene as monomer polymerizations (see Tables 2 and 3). In one case the
(Table 2). dependence of CC on solvent was traced to impurities,
Cobaloximes with structure 9 have a BF2 bridge presumably acids, in butanone.115 Freshly distilled
rather than the more usual hydrogen atom bridge butanone does not reduce the CCT chain-transfer
between the two dioxime moieties. Such a modifica- constant. In another case CC was found to be depend-
tion leads to better stability of the cobaltII oximes ent upon impurities in the initiator.76 Regardless of
toward oxidation by oxygen by air. While of little the origin of the solvent effect, the existence of such
consequence in an academic laboratory, it is impor- an effect makes it difficult to extrapolate observations
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3619
made in solution polymerizations in the presence of polymerization,115 a value 20-30 less than CC in
9 or the subset of complexes polymerization of methacrylates. This is similar to
that observed for cobaloximes, 6 (Table 1), and for
cobalt porphyrins, although in the last case the
kinetic picture is more complex. Interestingly, the
rate of CCT in styrene polymerization has been
shown to be light dependent.125 The rate was found
to be less that 100 in the dark but increases to a
maximum value of CC ) 5000 under UV irradiation.
The value of CC was also found to be dependent upon
the initiator concentration, decreasing with higher
initiator levels. Apparently, UV irradiation homo-
lyzes the CoIII-C bond formed by addition of styrene
to emulsion or suspension polymerizations reported radical to the CoII.
in Table 3.119
In cobaloximes 6-8 it could be concluded that Viscosity of the medium can also play a role in the
electron-withdrawing groups (EWG) increase CC. kinetics due to the importance of diffusion in the
Compare, for example, entries 6g, 6L-o, 8a, and 8b observed rate constants. In the bulk radical polym-
in Table 1. Table 3 does not afford the same conclu- erization of 2-phenoxyethyl methacrylate, thiol chain-
sion. transfer reagents operate at rates close to those
For cobaloxime 9a, chain-transfer constants ob- observed for MMA while the rate of CCT catalyzed
tained using the new CLD techniques of rate constant by 9a is an order of magnitude slower (2 × 103 at 60
calculations40,122 were CC ) 25 000 for MMA and CC °C) than that of MMA.5 The thiol reactions involve a
) 660 for styrene polymerization at 60 °C.123,124 In chemically controlled hydrogen transfer event,
other cobaloximes, a reverse trend was observed, with whereas the reaction of methacrylate radicals with
electron-donating substituents (entries 9e-h in Table cobalt are diffusion controlled. The higher bulk
3) increasing activity while EWG (entries 9i-L in viscosity of the 2-phenoxyethyl methacrylate has a
Table 3) led to a decrease relative to hydrogen (9c, significant influence on the transfer rate.
Table 3). The data of Table 3 can be explained by the The chain-transfer reaction is essentially un-
presence of the strong EWG, BF2, in cobaloximes 9.97 changed in going from bulk polymerization to toluene
The electron-withdrawing group reduces electron solution.30 In the low-viscosity medium, supercritical
density on cobalt to the extent that the lone electron CO2, chain transfer was found to be significantly
on CoII behaves less like a free radical. Electron- enhanced by an order of magnitude (108 L mol-1 s-1)
donating substituents in the equatorial ligands of 9 compared with toluene or bulk MMA as a medium.
help to restore the free-radical properties of the cobalt Again, the results are consistent with a diffusion-
atom, while additional EWG in the equatorial ligand controlled rate-determining step.30 However, another
exacerbate the electron density problem on cobalt. report indicates no enhancement of chain transfer in
This explanation leads to the conclusion that some supercritical CO2.126 This discrepancy may be the
value of electron density on the cobalt atom is result of the necessity of using different catalysts in
required for optimal hydrogen atom abstraction dur- the two media.
ing CCT. While on the subject of polymerization media, there
The effect of solvents on the properties of BF2- is also a report of CCT in ionic liquids.127 1-Butyl-3-
bridged cobaloximes in methacrylate CCT carries methylimidazolium hexafluorophosphate is a room-
over to polymerization of styrene. Thus, for co- temperature ionic liquid. Although such liquids have
baloximes 9 in the polymerization of styrene, CC ) been found to be excellent solvents for a number of
500 in butanone120 while CC ) 1400 in bulk.115 chemical transformations, there are few reports of
Cobaloxime 9c showed CC ) 700 in bulk styrene polymerizations.128 Nonetheless, CoII-mediated cata-
3620 Chemical Reviews, 2001, Vol. 101, No. 12 Gridnev and Ittel
Table 4. (Continued)
a In many instances, there were unspecified axial ligands present. B Cobalamin substituents not shown. c Catalytic inhibition
in L/mol‚sec. d Irradiated with sunlamp. Temperature is unknown. e In MMA/DMF ) 9:1 at 60 °C. f LRP initiators.
lytic chain transfer has been observed in the radical ditional experiments to confirm that the reduction
polymerization of MMA. in molecular weight is actually due to CCT rather
Polymerization of MMA both thermally and pho- than other reactions including noncatalytic chain
tochemically in the ordered media, cholesteryl oleyl transfer. As a reasonable indication of the accuracy
carbonate and cholesteryl 2-ethylhexyl carbonate, of the chain-transfer constant measurements, the CC
were studied in the presence and absence of cobalt of compound 30 (salcomine) was found to range from
tetraphenylporphyrin. The percentage conversion <50 to 150.
and molecular weight were lowered in the presence It is clear that a core of four nitrogen atoms in the
of CoTPP for thermal polymerizations. In photopo- coordination center is crucial for active CCT. Re-
lymerizations, the percentage conversion was high placement of two nitrogen atoms with oxygen (23-
and the molecular weights were low.129 26, 29-31) or sulfur (28) essentially shuts down the
In the photodecomposition of polystyrene-bound ability of LCo to abstract hydrogen from free radicals.
cobaloximes, the polymer chain decreases the mobil- Compound 28 is particularly interesting because of
ity of bis(dimethylglyoximato)pyridinecobalt(L) and the similarity of molecular structure of this chelate
increases the probability of recombination of L and to cobalt phthalocyanines, which are known to be
a radical fixed on the polymer chain. Retardation of good CCT catalysts.
the dissociation resulted in a larger equilibrium The influence of axial ligands on cobalt dimethylg-
constant for the polymeric system than that for the lyoxime complexes holds for these other ligands.
analogous monomeric system.130 Axial ligands that preclude CCT by cobaloximes (e.g.,
Table 4 presents CC for a variety of catalysts other CN) also interfere with the ability of cobalamin 10
than cobaloximes that have been tested in MMA to react with radicals. When hydroxyl is the A ligand
radical polymerizations.101,109,131-136 In addition, the on cobalamin (11), it does not interfere with hydrogen
following values have been reported: MMA, CC ) transfer. Halogen, pseudohalogen, and carboxylic
from 3 × 105 to 2.4 × 105 (from 40 to 70 °C, 9a);31 acids are “good” ligands. Somewhat surprisingly, in
and CC ) 1.9 × 104, kCo ) 1.6 × 106 M-1 s-1 (60 °C, 34, NO3- is also “good” for CCT while in cobaloximes
9c).5 Where data at several temperatures are avail- such ligands resulted in the absence of catalytic
able, CC is relatively independent of temperature activity.
because kP and kCo change at approximately the same The presence of four nitrogen atoms coordinated
rate. in the equatorial plane in LCo does not guarantee
It is clear that cobalt catalysts 10-44 are much noticeable catalytic properties. It would be of interest
less active than cobaloximes, generally by 2 orders to determine the factors that control activity. One
of magnitude. It is concluded that the hydrogen explanation suggests that only low-spin LCo can be
transfer reaction is not diffusion controlled in their CCT catalysts.109 Thorough investigation indicated,
case. This difference in reactivity also suggests that however, that this could be a necessary but is not a
some of the trends found for cobaloximes may not sufficient condition. For example, CCT catalysts such
work for other cobalt chelates. Unfortunately, there as cobaltII oximes bearing either H or BF2 bridges
have been few studies to this end. Most of the values have the same magnetic moment, µ ) 1.8-2.1, as
of CC in Table 4 were calculated having only one or noncatalysts 16, 19, 20, and 23.140,141 An empirical
two points on the Mayo dependence. For cases when observation ascribes catalytic properties to all LCo
CC < 50, it is usually necessary to carry out ad- that have four nitrogen atoms coordinated in the
3622 Chemical Reviews, 2001, Vol. 101, No. 12 Gridnev and Ittel
equatorial coordination plane which are incorporated Scheme 1. Atomic Planes of 15 from
into an extended system of conjugated π-bonds. The Crystallographic Data, Showing the
equatorial plane may be either open C-shaped or Four-Membered r-Plane, the Aromatic
closed O-shaped. Planarity of the macrocycle is Six-Membered β-Planes, and the Five-Membered
γ-Planes
important.131,132 Cobalamin 10 represents such a
structure. It has four nitrogen atoms in an O-shaped
π-conjugated system.
The active LCo complexes indicated above can be
used to test this theory. Porphyrins and phthalocya-
nines have an O-shaped system which has a more
extended π-system than that in cobalamins, but it
does not provide a substantial increase in reactivity.
It should be noted that the hydrogen bonds of the
cobaloxime catalysts are essentially as effective as In radically polymerized MMA, LCo 16 does not
π-bonds in continuing the effects of delocalization catalyze hydrogen transfer to monomer but instead
around the macrocyclic ring. This effect has been catalyzes a termination reaction. This conclusion was
noted elsewhere.142 Catalyst 11 comprises an O- reached by comparison of DPn versus the decrease
shaped π-system. Replacement of one π-bond with a in rate of polymerization. As mentioned in the
σ-bond in the analogue 13 significantly affects the Introduction, CCT catalysts do not change the rate
catalytic properties since both complexes retain their of polymerization. In the case of 16, the rate of
O-shape with π-conjugation. Additional replacement polymerization and DPn decrease linearly with con-
of π-bonds with σ-bonds leads to a complete loss of centration of 16 with a stoichiometric coefficient of
catalytic properties as chelates 13, 20, or 21 indicate. inhibition >4. The steric encumbrance of chelate 15
Chelate 22, cannot be a CCT catalyst because of the represents an intermediate case between 14 and 16
absence of interaction between the two π-systems. since it has only two methyl groups instead of four
Chelate 34 is an exception; its molecular structure in 16. Since these methyl groups may twist, only one
is similar to 21 and 13, but it catalyzes chain transfer benzene ring twists slightly from the γ-planes, and
with a measurable rate. A possible explanation of this complex 16 generally retains the C-shape of the
phenomenon will be provided in section 3.7. π-conjugation. As a result, 16 shows the properties
of a CCT catalyst but its CC is lower than that of 14
As with cobaloximes, substituents on the equatorial or 34.
ligand have only a moderate effect on the value of Complexes 35-39 also support this conclusion.
CC for the complexes in Table 3. The same is true for Catalyst 35 has a planar, C-shaped system of π-con-
substituents on cobalt porphyrins, 1 and 45-51 jugation. The three-carbon bridges between the NH
(Table 4). For tetrakis(pentafluoroethylphenyl)- and other coordinated nitrogens provide adequate
porphyrin-CoII the substituent effect is not clear. The flexibility in coordination so that the entire equatorial
fluorinated porphyrin works moderately for the po- ligand is planar. Chelates based on [14]-annulenes
lymerization of MMA in supercritical CO2 with chain- are known to exist as strictly planar structures, while
transfer constant CC ) 550 at 60 °C.126 Unfortu- bigger/longer ligands, like chelate 39, can exist in
nately, no data on the chain-transfer constant in bulk different conformations. Chelates 37 and 38 are not
polymerization are available, so that it is not clear effective catalysts for CTC due to the shortening of
whether this reduced value of CC is the result of the bridge between the two nitrogen atoms from
solvent or the presence of a strong EWG such as three carbon atoms to two. The two neighboring five-
pentafluorophenyl in the porphyrin macrocycle. Simi- membered rings do not support a planar structure,
lar experiments with 9c (Table 2) led to CC ) 378 000, so that the cobalt and the coordinated nitrogen atoms
which is 20 times higher than in bulk MMA or in in these chelates cannot form a perfect plane. A
organic solvents.30 We may conclude at this point that planer molecule cannot be formed at all in the case
additional experiments are required with different of 37 with only 12 atoms in the macrocyclic ligand.
catalysts to allow us to make reliable conclusions. The observed structures of 37, 38, and 39 are
Complexes 13-15 provide interesting additional reflected in their chain-transfer constants: catalytic
information on the influence of substituents. Cata- activity decreases with increasing nonplanarity of the
lytic activity gradually decreases with increasing structure in the series 35 > 39 > 38 . 37.
steric interference between the protons of the methyl Additional understanding of the role of π-conjuga-
groups and the benzylic ring. This steric interference tion is provided by cobaloximes 6-8 and other CCT
is so high that complex 16 is substantially twisted catalysts with hydrogen bonds which complete the
so that the macrocycle is not planer but rather is macrocycle (i.e., 32 and 33). The common feature
“saddle-shaped”. According to the crystal structure, shared by a π-bond and these hydrogen-bonded
cobalt and the four nitrogen atoms are laying in an systems is their ability to delocalize their electron
approximate plane (R), while the aromatic rings (β) density.131,132 Resonance isomers with different bond-
are above the coordination plane, and the wings γ ing of the H or BF2 bridges to the oxygen atoms allow
are twisted below this plane (Scheme 1). The dihedral the electrons to delocalize around the equatorial
angle between the planes β and γ is 43°.147,148 As a plane as shown in Scheme 2.
result of the substantial nonplanarity of the molecule, A necessity for a delocalized ring current in CCT
chelate 16 behaves differently from its planar catalysts explains the requirement that the equato-
analogues.149-152 rial ligand be flat. Chelate 17 would have been a good
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3623
Rn and R1 correspond to the polymeric and mono- is the bimolecular disproportionation reaction, eq
meric radicals respectively, M is monomer, LCo is a 16.173-178
cobaltII chelate, [LCo‚‚‚Rn] is an intermediate com-
plex, and Pn) is oligomer or polymer with a terminal 2LCoH f 2LCoII + H2 (16)
double bond. Although eq 10 has been observed on
numerous occasions, catalyst regeneration (eq 11) is
more problematic. It is unlikely that a monomer like The chain-transfer constant of about 105 L/mol s172,175
methacrylate would abstract a hydrogen atom from makes it difficult to study the properties of (DH)2CoH.
a coordinated metal alkyl. It would be expected that Equation 16 is reversible, and under basic conditions
hydrogen atom abstraction could be from the R-posi- the equilibrium is shifted to the left. LCoH complexes
tion, but rearrangement to a coordinated olefin that are weakly acidic and are dissociated easily according
could be dissociated is possible.158 This mechanism, to eq 17.
deemed to be unlikely, has been explicitly tested and
found lacking.124 LCoH + Base f LCoI- + H+‚Base (17)
A second proposed mechanism of the CCT was
based upon a Michaelis-Menton-type mechanism.12 Equations 16 and 17 are known not only for co-
This mechanism is typical of enzymatic catalysis,159 baloximes, but also for other cobalt chelates as well.
and the rates of CCT have been compared to those Thus, the addition of bases stabilizes LCoH in its
of enzymes. It requires the formation of a complex anionic form, slowing the disproportionation reaction
between the catalyst and the monomer (eq 12). The in eq 16. The anion which is formally LCoI- behaves
propagating radical then reacts with the complex (eq as a supernucleophile in SN2 reactions, reacting with
13) to transfer a hydrogen atom to the monomer. a wide variety of substrates such as acetylenes,
olefins, alkyl chlorides, or alkyl bromides.181,182 The
kM
LCo + M 98 [LCoM] (12) high reactivity of the LCoI- complex together with
eq 16 at times makes it difficult to distinguish
ktr whether LCoH or LCoI is the species responsible for
[LCoM] + Rn 98 LCo + R1 + Pn) (13) a particular reaction. In many cases both LCoI and
LCoH are present in the reaction media simulta-
There is little support for the mechanism expressed neously.
by eqs 12 and 13. MMA is able to form a π-complex
Very stable CoI chelate complexes are obtained
with cobalt porphyrins,160 but the chain-transfer
from phthalocyanine ligands (for example, 44 and
constant for its formation (1.8 L/mol s) is not high
71).
and is much smaller than the observed CCT chain-
transfer constants. If the mechanism of eqs 12 and
13 is correct, then reduced concentrations of mono-
mer should disfavor formation of LCoM, resulting in
a decrease in the rate of CCT. The chain-transfer
constant of the chain transfer is independent of the
concentration of monomer.14,52 The mechanism ex-
pressed by eqs 12 and 13 will not be considered
further.
A third reaction scheme (eq 14 and 15) encom-
passes what is the currently accepted mechanism.
This scheme was suggested simultaneously with eqs
10 and 12 and calls for the formation of the cobalt
hydride, LCoH, as an intermediate species.161,162
kc
Rn + LCo 98 Pn) + LCoH (14)
kr
LCoH + M 98 LCo + R1 (15)
effect is similar to the range (1.9-3.3) of kinetic its.161 The failure to observe LCoH called into ques-
isotope effects observed for hydrogen atom abstrac- tion its role as an intermediate species in CCT.
tion from a variety of substrates by different metallo- The addition of LCoH to olefinic double bonds is
radicals.198-201 It seems reasonable to conclude that well documented in the chemistry of cobaloximes.
hydrogen atom abstraction in CCT occurs by the Because LCoH has the ability to dissociate to H+ and
three-centered intermediate illustrated in eq 18 LCoI-, both the hydride and CoI- form of the cobalt
chelate must be considered in any system where
LCo + Rn f [LCo‚‚‚H-Rn] f LCoH + Pn) (18) LCoH can be obtained.
The anionic chelates LCoI are highly reactive
The kinetic isotope effect would be expected to be nucleophiles, in some cases called supernucleophiles
smaller or zero if the rate-limiting step involved a for their reactivity.214 They readily replace halogen
concerted β-hydride elimination.202 atoms in alkylhalides,214,215 transalkylate phos-
Another reaction of radicals with CoII chelates phates,216 add to aldehydes,217 and add to double
known to occur at diffusion rates is recombination bonds.218 The fragmentation of haloalkylurethanes in
(eq 19). the presence of LCoI was proposed to go through
π-olefinic intermediates, but radical chemistry is
k19 more likely.219 The large body of CoI-chelate chem-
LCo + Rn 98 [LCo-Rn] (19) istry has been reviewed elsewhere, and we refer the
reader to available surveys.43,163,220-225
In the case of vitamin B12, eq 19 is well investigated For the purposes of this review, it is important to
and its rate constant k19 ) 4 × 109 L/mol‚s for recognize the dual nature of cobalt macrocycle com-
primary radicals.203 Comparison of this value with plexes. Both species, LCoIIIH and LCoI, can add to
the rate constant for methyl radical dimerization of double and triple bonds forming alkyl and alkenyl
∼1010 L/mol‚s191 indicates that eq 19 proceeds at cobalt chelates but the products are different. The
diffusion-controlled rates. Newer approaches may CoIII hydride reaction occurs in a Markovnikov ad-
provide greater accuracy in the measurement of rates dition while LCoI provide anti-Markovnikov products.
of recombination of free radicals, providing a better It is believed that eqs 21 and 22 explain the differ-
understanding of hydrogen atom abstraction (eq ence.
18).205
The ratio between the rates of parallel eqs 18 and
19 is an issue of practical importance. Cobalt chelates
may be good capping agents in living radical polym-
erization, LRP.206,207 This requires that eq 19 be
reversible and the forward and backward (eq 20)
rates be approximately equal.
These conditions have been met in a number of Substituents X and Y are electron-withdrawing
systems yielding living radical polymerizations at groups. For olefins with strong EWG like CN, the
moderate temperatures.207-213 For successful LRP, eq formation of π-complexes (73) was observed.226
18 should not occur at all and eq 19 is required. For
the CCT technologies of this review, the rate of eq
18 should be more than competitive with eq 19,
though a low equilibrium level of formation of LCo-R
is not detrimental. In addition to choice of proper
temperature, solvent, and monomer, the molecular
structure of LCo has proven to be the most important
factor in achieving effective LRP or CCT. Those LCo
Strong bases (pKa > 11) also convert alkyl co-
that are not effective for CCT should be screened for
baloximes and alkyl cobalamins into π-complexes
LRP, though there are many means by which both
such as 73. This is usually followed by further
reactions can fail.
decomposition to olefins and alkanes. The stability
of complexes such as 73 depends very much upon X
3.3. Hydrogen Atom Addition and the nature of the axial ligand in the cobalt
Hydrogen atom transfer from the hydride form of chelate.98,218,227-230 Strong nucleophiles such as RS-
the catalyst to monomer (eq 15) is relatively unex- or CN- can cause decomposition of LCo-R as well.98,231
plored in comparison with the initial reaction in the Under the normal conditions of radical polymeriza-
catalytic cycle, hydrogen atom abstraction from the tion, Markovnikov organocobaloxime should form
growing radical. This is despite the fact that the two whenever the hydride, LCoH, appears in the polym-
reactions are essentially the microscopic reverse, erization mixture. If 1,2-vinylidene monomers are
because the substituents on the organic fragment are being polymerized, then thermally unstable tert-
relatively removed from the metal center. Early alkyl-cobaloximes are obtained. These species are
investigations of CCT were frustrated by the fact that expected to undergo homolytic Co-C cleavage to yield
concentrations of LCoH were below detection lim- tertiary radicals.
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3627
An alternative mechanism calls for hydrogen atom escaped the cage to propagate polymerization in
transfer by the reverse of eq 14 with no organome- solution. The suggestion was confirmed by employing
tallic intermediates. Attempts to distinguish between perhydro azo initiator and MMA-d8. The unsaturated
these two possible pathways of hydrogen addition molecule 2,5-dihydrofuran was added to trap the
employed deuterium labeling. Stereoselectivity in the intermediate. As expected, the isolated tetrahydro-
addition of LCoH to double and triple bonds was furanyl cobalt complex was deuterated in the cis-
observed. Early work indicated Co-D cis addition to vinyl position. Unexpectedly, MMA-d8 was discovered
olefins and acetylenes.232 Later experiments showed to be a highly efficient deuterium donor. A 2-fold
excess of MMA relative to LCo was enough to convert
LCoH into a LCoD before reaction with dihydrofuran.
Using these methods, the results shown in Figure 8
It was clear that rapid hydrogen/deuterium ex- The reaction proceeds well even in the presence of a
change was occurring in a radical cage236 involving 100-fold excess of MMA-d8 to generate the label. The
LCoH/LCoD and MMA before the monomeric radical addition of the cobalt deuteride to 1-hexyne or
3628 Chemical Reviews, 2001, Vol. 101, No. 12 Gridnev and Ittel
5-hexynenitrile displays Markovnikov regioselectivity nated vinyl would be expected to be higher for
and trans (anti) stereoselectivity. The high conversion sterically hindered porphyrins that favor homolytic
of the CoII to vinyl cobaltIII porphyrins allowed dissociation, but this does not fit the observations.
labeling using AIBN-d12 as a source of (TAP)CoD. An alternative unimolecular mechanism would in-
Unexpectedly, the incorporation of deuterium into the volve a concerted 1,3-hydrogen shift, but it is difficult
axial vinyl substituent on cobalt was dependent upon to explain why a relatively remote terminal group of
the concentration of the acetylene, with only 40 the axial ligand would have an effect on the rate of
atom-% trans-vinylic deuterium addition at 0.04 M isomerization as observed. The decrease in the rate
1-hexyne increasing systematically to 90 atom-% at of isomerization for a coordinating nitrile substituent
1 M. The deuterium content of the product increased versus a noncoordinating methyl substituent is ex-
during the course of a reaction at fixed acetylene plained by a bimolecular catalyzed reaction as in eq
concentration with no deuterium incorporation at the 30.
cis-vinylic site occurring during these experiments.
The unaccounted deuterium was lost to an unknown
side reaction. The presence of a large excess of
exchangeable MMA-d8 overcame the unknown reac-
tion and provided a high level of deuterium incorpo-
ration in the trans-vinyl position. In some cases,
isomerization (eq 27) of the initial product was
observed.
Experiments with model compounds demonstrated hydride and its isomeric form in which the hydrogen
the exceptional importance of the π-system in mol- atom is located on one of the ligand nitrogen atoms.257
ecules involved in chain-transfer catalysts. Cobalt Hydrides of cobalt chelates are known to be less
chelates without planar, extended conjugated π-sys- stable than those of rhodium, so it is likely that a
tems are not active in chain-transfer catalysis.132 One hydrogen atom would undergo migration from cobalt
possible explanation of this could be the necessity of to ligand at rates faster than those in rhodium
hydrogen atom migration from cobalt to ligand dur- phthalocyanine. Mechanisms based upon these in-
ing the catalysis. Disruption of the conjugation by the termediates or transition states are plausible alter-
hydrogen atom migration should be less in an ex- natives to the caged radical pair, though the inter-
tended π-system. mediates would have to be very short-lived because
Concerted insertion of an olefin into a CoH bond the rates of the catalytic chain transfer are so high.
or its microscopic reverse, β-hydride elimination, Rapid, reversible migration of the hydrogen atom
involves the intermediate species 77. between cobalt and ligand could be responsible for
the poor stereoselectivity of cobalt hydride addition
to the double bond of cyclopentene at low tempera-
tures when thermal isomerization of the Co-C ad-
duct is known to be negligible.208 If a Co-H transfer
is not stereoselective and a ligand hydrogen atom
transfer is stereoselectively cis, then the overall
stereoselectivity of cyclopentene addition to LCoIIIH
would reflect the ratio between the concentrations
the isomers, CoH, and LH.
An important feature of the LH form of the hydride
is that it contains a CoIII bearing a very open
The availability of only one coordination site due to coordination site for reaction with nucleophiles.
the large rigid equatorial ligand of the cobalt por- There are several publications on the unusual reac-
phyrin macrocycle would appear to make such an tion of “naked” cobaltIII in porphyrins with acetylenes
intermediate unlikely. Viewed as a transition state and olefins.256h-j,258 This could also explain the trans
with a large component of C-H bond formation, the addition of the hydrides to acetylenes. A charge-
Co-C bond formation would occur later in the transfer intermediate in the reaction of the LH
process. In the extreme of complete C-H bond isomer with an acetylene or alkene could explain the
formation prior to Co-C formation, the intermediate difference in behavior of substituted versus unsub-
is indistinguishable from a radical mechanism. stituted olefins. If the above explanation is correct,
The cobalt-hydride intermediate has not been then it would require essential equality between the
isolated and is virtually undetected. Cobalt hydride energies of the Co-H and L-H complexes. Param-
reaction with an olefin by first migrating the hydro- eters such as solvent properties could shift the
gen atom from cobalt to a porphyrin nitrogen atom equilibrium concentrations of the two isomers of the
(78) or carbon atom (79) is precedented by the hydrides, leading to apparently different results in
isomerization of a benzylcobalt chelate. In that case, the same reaction and explain poor reproducibility
the benzyl migrates reversibly from the cobalt to the in stereoselectivities.232,233
carbon atom of the equatorial ligand.253 The role of protic intermediates was recognized in
the very earliest work on hydridocobaltIII chelate
reactions.259 In basic solutions, H/D exchange was
relatively fast, while neutral or acidic conditions
reduced the rate significantly.230,260 The chemistry is
associated with hydridocobaltIII and the deprotonated
anionic complex which is formally cobaltI. Under
basic conditions, the regiochemistry is reversed with
acrylonitrile giving the primary alkyl, CoIIICH2CH2-
CN.
Caution is required in extrapolating the conclu-
It is also reported that alkyl groups in N-substi- sions from one particular set of reactants and condi-
tuted Ni and Pd corroles can migrate from pyrrolic tions to other closely related systems. The chimeric
nitrogen to the β-carbon atom of the pyrrolic ring.254 nature of CoH, reacting as a free-radical or an ionic
The intermediate is also precedented by complexes species, can depend both on the nature of the equato-
bearing partially hydrogenated cobaloxime ligands rial ligand and on the trans substituents, particularly
produced by exposure of the complexes to molecular if migration of the hydrogen atom over the surface
hydrogen.177 Migration of organic substituent from of the equatorial ligand plays a role in the insertion
metal to nitrogen and addition of acetylenic substrate reaction. In this case, the structure of the equatorial
to both metal and macroligand have been reported ligand rather than the redox potential of the metal
in several dozen publications.255,256 Support for a center may control the course of the reaction.
possible role for hydrogen atom migration from the The addition of double bonds to hydridocobaltIII
metal atom to a macrocyclic ligand is provided by the chelates is clearly dependent on the structure of
coexistence of a normal rhodium phthalocyanine organic substrate. Generally, electron-withdrawing
3630 Chemical Reviews, 2001, Vol. 101, No. 12 Gridnev and Ittel
substituents promote cis addition while electron- Table 7. CCT in Polymerizationa of Bulk Styrene
donating substituents lead to loss of selectivity in the Catalyzed by Porphyrins 80144
reaction. It is likely that olefins and acetylenes react substituent, phenyl-Z bond length
with CoH by different mechanisms and parallel entry Z CC (nm)
reactions may occur.261 80a (50)b H 2150 0.108
80b OMe 1530 0.135
3.5. Living Radical Polymerizations 80c Me 1000 0.152
80d Cl 610 0.170
The phenomenon of living polymerization is ob- 80e Br 550 0.185
served whenever propagation and reversible termi- a
Bulk MMA, 60 °C. b 4-Anisyl.
nation are significantly faster than any process for
irreversible termination. The primary route of ter- example. The difference between 16, where π-delo-
mination in free-radical polymerizations is bimolecu- calization was interrupted, and ortho-substituted
lar in nature. If the persistent radical effect can be phenyls in the macrocycle is that they force the
employed to reduce the instantaneous concentration phenyl to be perpendicular to the macrocycle plane,
of active radicals in solution at a given time, then positioning the ortho-substituents directly above or
bimolecular termination can be greatly reduced. This below the plane of the macrocycle. This creates a
is done by establishing an equilibrium between active steric obstruction to the propagating radical as reac-
and dormant radicals. The resulting polymerization tion with the cobalt center takes place.
is living in that Mn increases in direct proportion to Porphyrin molecules provide a good example of this
the conversion of monomer. The molecular weight effect.144 In Table 7, a clear connection between the
distribution in resulting living radical polymerization size of the ortho substituents and the chain-transfer
(LRP) is narrow, and it is possible to prepare a constant, CC, is observed. The electronic effects of the
number of desirable polymer architectures such as substituents are less important because methyl and
block copolymers and end-functional polymers. chloro have similar CC but significantly different
Under certain conditions, some poor CCT catalysts electronic effects. According to X-ray data, porphyrins
are potentially good candidates for living radical such as 80 are so restricted in rotation of the phenyl
polymerizations, LRP, if the factor limiting the CCT rings that four atropo-isomers can be easily separated
is formation of a stable metal alkyl species, LCoIII- by preparative chromatography.
R, which removes active cobaltII from the reac-
tion.262-264 This stable species is not an intermediate
in the CCT reaction but rather represents a side
reaction.123 This has been observed for a variety of
olefins, actually allowing isolation of the CoIII-
alkyls262 and determination of the Co-C bond
strengths and kinetics of Co-C bond homolysis of
several of these species.265-269 The strong ring cur-
rents of porphyrins and phthalocyanines270 make the
use of NMR spectroscopy particularly advantageous.
In many cases involving catalysts 48-59, retardation
of polymerization was observed, thereby complicating
the overall mechanistic picture. Retardation has also
been reported for porphyrin complexes of metals
other than cobalt, with the retardation increasing in The substituents, Z, can be located both below and
the order Zn ≈ Ni < Pd < Cu ≈ Mn ≈ Cr.17 This above the plane. Both sides of the porphyrin plane
retardation indicates that these porphyrin complexes are equivalent, so the purely statistical ratio between
may participate in other reactions with the propagat- concentrations of the atropo-isomers (above the plane/
ing radical including LRP since retardation is an below the plane)s(0/4):(1/3):(2/2)sis 1:4:3. About 12%
inherent feature of LRP,271 but additional experi- of all the porphyrin molecules will have one com-
ments are required to discover the origin of the pletely unsubstituted side (the other side being
retardation. This effect may sometimes be referred tetrasubstituted) having the same steric exposure as
to as the “persistent radical effect”.272-276 an unsubstituted porphyrin. Experimentally, the
In selected cases, it is possible to convert effective methoxy-substituted porphyrin displayed 8% of the
CCT catalysts to species suitable for LRP by incor- (0/4) atropo-isomer, which is very close to the ex-
porating special substituents into the design of the pected value based upon populations of active species
equatorial ligand. Above, we demonstrated that sub- alone.277 Hence, it would be expected that at most
stituents usually have little effect on CCT chain- 10% of the ortho-substituted phenyl porphyrins 80
transfer constants. These limited effects are generally could provide full activity regardless of the size of the
deemed to be electronic in nature. There are several Z-substituents. The concentration of atropo-isomers
special instances of ortho-substituted phenyl substit- (1/3) and (2/2) are approximately equal, so if the (2/
uents having a substantial influence on CC. Ortho- 2) isomer completely blocks radical approach, then
substitution on phenyls can play a significant role CC should be about one-half of that of the unsubsti-
by preventing the phenyl rings from being coplanar tuted porphyrins. From Table 7, one may conclude
with the macrocycle through steric interactions such that having one methyl or one methoxy group is not
as those discussed above with chelate 16 as an enough to block the cobalt reaction with the propa-
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3631
was reported.253 The benzyl radical is involved in an Table 8. MMA Chain-Transfer Constantsa of Reaction
equilibrium between cobalt and carbon-centered ad- 37 for Different Cobaloximes296
ducts. catalyst substituents axial ligands K E (M-1 s-1)
Oxygen may substantially reduce the catalytic 6h CH3 CH3 I Py 120
activity of porphyrin CCT catalyst.75 First, the peroxo 6g CH3 CH3 Cl Py 200
radical, RnO2• forms as in eq 32. 6i CH3 CH3 CNS Py 200
6n -(CH2)4- Cl Py 280
6p Ph Ph Cl H2O 520
O2 + •Rn f •O2Rn (35) 6q Ph Ph Cl Py 700
6r Ph Ph Cl P(Ph)3 2800
6o R-furyl R-furyl Cl Py 1200
The peroxo radical then oxidizes the cobalt porphyrin 6m CH3 COCH3 Cl Py 800
with the formation of several products with a rate 6l CH3 COOC2H5 Cl Py 1300
constant of 7000 M-1 s -1, typical for peroxo radicals a
Bulk MMA, 60 °C, [AIBN] ) 0.04 M.
in their reaction with cobaltII complexes. In addition
to the alkylperoxoCoIII-porphyrin, 92, in eq 36, there
is concomitant formation of a Por′Co species in which CoIII-cobaloxime (eq 37), a carbon-centered free
the porphyrin ligand has been modified. radical is required for reduction.187
RnO2• + PorCoII f PorCoIII-O2Rn + Por′Co (36) LCoIII-A + •Rn f LCoII + products (37)
Reaction of the porphyrin ligand leads to degradation The reduction can be effected by either MMA-
of the Soret band and reduction of ring current in propagating radicals or other tertiary radicals such
NMR spectra after prolonged polymerization in the as those provided by the decomposition of azo initia-
presence of air.75 The concentration of Por′Co species tors. The reduction in eq 34 is autoaccelerated,
increases with time during a polymerization, possibly indicating involvement of LCoH, most likely through
because of multiple reactions of peroxo radicals with eq 38.304
the porphyrin macrocycle. LCoH + LCo-A f 2LCo + HA (38)
The BF2-bridged cobaloximes probably behave simi-
larly to cobalt porphyrins, but detailed studies are Unaccelerated rate constants of the reduction in eq
not available. The H-bridged cobaloximes are more 37 are several orders of magnitude less than kCo (see
reactive toward oxidation than cobalt porphyrins or Table 8).
phthalocyanines; their CoII complexes are oxidized The CoII complexes obtained by eq 38 may interact
immediately by dioxygen upon contact. The increased with other products of the reaction such as HCl.
oxygen stability of CoIII BF2-bridged complexes ex- While cobalt porphyrins are generally unaffected by
plains why they are preferred for industrial applica- counterions and byproducts, cobaloximes show com-
tions. The alkyl-CoIII-cobaloximes, where the alkyl plicated patterns of reactivity. When CoIII-Cl co-
radical is more stable than methyl, decompose at baloxime catalysts are re-isolated after catalysis,
elevated temperatures to yield the active CoII deriva- stoichiometric chloride is obtained despite the conclu-
tives. Studies indicate that the oxidized CoIII species sion that the catalysts had passed through a CoII,
are reduced by propagating PMMA radicals.77,188,303,304 halide-free state. For CoIII-Cl cobaloxime catalysts,
When the monoanionic ligand, A, is halogen in a there is an induction period defined stoichiometrically
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3635
lyst decomposition. Cobalt porphyrins and cobalt a variety of monomer for which chain-transfer con-
phthalocyanines are much more stable under basic stants are available or could be calculated. In keeping
pH and in the presence of free radicals than co- with patent strategies, many additional monomers
baloximes. Thus, the CoI phthalocyanine that forms are mentioned in patents but are not exemplified.
by reduction by free radicals in amides is very stable, Nonetheless, the monomers that have been studied311
being stored in a sealed glass ampule for 1 year range from simple alkyl methacrylates to highly
without any change of its characteristic blue-green reactive species such as glycidyl methacrylates, 2-iso-
color. The more rapid decomposition of dioximates of cyanatoethyl methacrylates, or methacrylic acid80
CoI is on a time frame comparable with polymeriza- and to biologically derived materials such as 2-meth-
tions (0.06-2% min-1).188 acryloxyethyl phosphoryl choline, glycerol monom-
In conclusion, there are a variety of processes that ethyl methacrylate, or 3-O-methacryloyl-1,2:5,6-di-
can affect CCT by increasing or, more often, reducing O-isopropylidene-D-glucofuranose.312
the rate of the chain transfer by affecting the catalyst. Several CCT catalysts are soluble in MMA but
Some of them are more pronounced at the beginning insoluble in the resulting polymer.318 Interestingly,
of polymerization, while others are become more when these CCT catalysts are added to frontal
significant at the end. The most common is the polymerizations, they are carried in the polymeriza-
reversible or irreversible poisoning of CCT catalysts tion front, decreasing the molecular weight through-
by peroxides because it is difficult to reduce the out the resulting polymer.
concentration of peroxides in the monomer to com- In addition to standard methacrylates, it has been
monly used levels of catalyst (100 ppm or less). This possible to extend CCT to carbohydrate-based sys-
is why erratic results on catalytic activity of cobalt tems.319
chelates in CCT are not uncommon. Employment of
low-conversion reactions (like 2-4%) makes testing 4.1.1. Di- and Trimethacrylates
results especially vulnerable. These side reaction can Dimethacrylate monomers and polymethacrylate
often be recognized by deviation from linearity of eq monomers must be discussed separately from other
1, but such careful investigation is not the norm. methacrylates because of their ability to cross-link
under normal free-radical polymerization conditions.
4. Monomers for CCT Even at very low conversion, less than 1%, they
produce completely cross-linked polymers that cannot
4.1. Methacrylates be solvent-swollen and are insoluble. CCT agents
reduce molecular weight and thereby move the ge-
Methacrylates are the monomers most commonly lation point to a much higher degree of conversion,
utilized in CCT, and MMA seems to be the monomer though CCT cannot prevent gelation completely.320
against which all comparisons are made. It was Hyperbranched polymers were synthesized by di-
discussed extensively in the section on catalysts. In rect free-radical polymerization of ethylene glycol
addition to the methyl ester, many other methacry- dimethacrylate monomer in the presence of a CCT
late esters are mention in the literature. Table 9 lists catalyst. The free-radical homopolymerization of di-
vinyl monomers is thought to selectively yield trimer
Table 9. CCT Chain-Transfer Constantsa for Different 96,321,322 though previous work on oligomer distribu-
Methacrylates5,126,313-317 tions would indicate that this is unlikely.
ester group CC catalyst ref
PhOC2H4- 2000 9c 5
(MeO)3SiC3H6- 27000 ( 1200 9a 313
[Me3SiO]3SiC3H6- 7500 ( 1400 9a 313
lauryl 20000 ( 1400 9a 313
3-(N-triazolyl)-4-hydroxyphenyl- 4000 ( 200 9a 313
Me2NC2H4- 4400 ( 600 9ab 314
(N-phthalimidoyl)C2H4- 500 9ac 315
methyl 1300 52d 126
methyl 34000 9c 316
ethyl 26000 9c 316
butyl 16000 9c 316
methyl 2400 1 317
butyl 670 1 317 Polymerization of the trimers then leads to cascade
hexyl 430 1 317 branching, ultimately yielding soluble hyperbranched
heptyl 250 1 317
octyl 250 1 317 polymers instead of the insoluble networks obtained
nonyl 150 1 317 in the absence of the CCT catalyst. Terminating
decyl 110 1 317 polymerization at moderate conversion provides highly
hexadecyl 130 1 317 reactive hyperbranched methacrylate. As mentioned
hydroxyethyl 1120 9ae 312
glycerol monomethyl 958 9ae 312 above, there is some similarity between living radical
methacrylic acid 1058 9ae 312 polymerization and polymerizations carried out with
a Polymerization conducted at 60 °C in neat monomer unless high levels of CCT catalyst. Both processes preclude
otherwise indicated. b 70 °C in neat monomer. Catalytic ter- rapid chain growth by periodically interrupting chain
mination is observed. c Chain-transfer constant calculated on growth. As a result, molecular weight tracks mono-
the basis of the article data. 80 °C; 30% in toluene. Catalytic mer conversion to a greater extent than it would in
termination is observed. d 50% monomer in supercritical CO2. the absence of CCT. The oligomerization results in
e In water.
polymers with very low intrinsic viscosity.323-325 The
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3637
molecular weight and intrinsic viscosity of the hy- This product is then further grafted with glycidyl
perbranched polymers indicated that the average methacrylate.
molecular weight ranged from a few thousand to
more than 40 000. The reaction provides an alterna- 4.1.2. Emulsion Polymerization
tive to the complex, multistep, routes to dendritic and The kinetics of solution polymerizations involving
starlike polymers. The superior physicochemical and CCT are not substantially different from bulk poly-
molecular properties of star and dendrimer poly- merizations. An initial report that toluene as a
mers326 are believed to justify their very complex solvent led to reduced catalysis rate336 seems to be
technology, but the cascading polymerization pro- unfounded.124
vides polymers that meet the requirements for many Emulsion polymerization is an attractive route for
commercial applications where such perfection is not making polymer compositions without solvent or with
required.36,327-329 minimal amount of organic solvent.32,94,337-340 CCT in
In a similar report utilizing triethylene glycol emulsion polymerization may provide narrower poly-
dimethacrylate, the polymer was described as a dispersity relative to noncatalytic chain-transfer
linear polyester.330 Again, this description is probably agents.339
incomplete, though it is possible at high catalyst Starved-feed emulsion polymerization can be con-
loadings to prepare methacrylic dimers. Under ideal ducted without emulsifiers if suitable comonomers
conditions, this would lead to the linear, unsaturated and procedures are utilized.341 Polymerization of a
polymer 97. water-soluble methacrylate like HEMA in the pres-
ence of a CCT agent is carried out initially. The
resulting HEMA oligomer is further copolymerized
with hydrophobic monomers so that the resulting
diblock copolymer serves as a surfactant (see, for
instance, sections 5.3 and 5.4). During the cross-
linking process, all of this surfactant is incorporated
into the polymer backbone and is thus immobilized,
This was a single example with minimal charac- overcoming the problem of residual surfactant in the
terization. A more direct approach to the polyester final product.
involves transesterification of the dimer with neo- In contrast to solution polymerization, emulsion
pentyl glycol to oligomers and chain extension with polymerization is more complex.119 Monomer feeding
diacids and glycols.331 These species are effective can be crucial in obtaining the desired molecular
pigment binders in paints. weight.342 The partitioning coefficient of the CCT
agent between phases is another key factor.343,344 The
Oligomerization of ethyleneglycol diethacrylate, solubility of the cobaloxime catalysts can be regulated
EGEtA, provided polyester by radical polymerization by the size of substituents on the equatorial ligand.
according to Scheme 8.332 Bis(dimethylglyoximato)- The distribution coefficient for water/MMA drops
CoIII(benzil)(Py) as a CCT catalyst reduced the mo- sharply from 0.4 to 0.05 when the substituents in the
lecular weight of the resulting polymer. No rate equatorial ligand change from methyl to ethyl in 9.
constants were determined. The authors surprisingly Further increase of the substituent alkyl group does
observed that the yield of the oligomer increases with not change this ratio substantially.120
the concentration of the CCT catalyst. A similar Generally, efficiency of CCT catalysis drops in
dependence was found in AMS oligomerization and emulsion polymerization. The following values of
was attributed to minimization of bimolecular ter- CCT chain-transfer constants may be compared with
mination by rapid capture of the dimer radicals by solution and bulk polymerization: CCMMA ) 1100 M-1
CCT catalysts.333 Related branched macromonomers s-1, CCEMA ) 640 M-1 s-1, CCn-BMA ) 520 M-1 s-1,
were also prepared by copolymerization of methyl CC2-EHMA ) 400 M-1 s-1 (75 °C, water, 9a).342 In
methacrylate with 1,6-hexanediol dimethacrylate in miniemulsion polymerization, the choice of catalyst
the presence of R-methylstyrene dimer as a molecular depends on the choice of initiator (see Table 10).345
weight control (see section 5.1).334 Azo initiators provide good catalyst activity in both
Branched polymers can also be obtained by copo- solution and miniemulsion polymerizations, while the
lymerization of MMA with dimethacrylates based peroxide initiator K2S2O8 substantially decreases the
upon the condensation product of hexamethylenedi- efficiency of molecular weight reduction by 9a. The
isocyanate with two hydroxyethyl methacrylates.335 results in Table 10 may be explained by the ability
3638 Chemical Reviews, 2001, Vol. 101, No. 12 Gridnev and Ittel
Table 10. Comparison of Miniemulsion (65 °C) and transfer constant CAMSd of 0.29 at 110 °C.353 Although
Bulk (60 °C) Polymerization345 AMSd has been known to be a good molecular weight
CC control agent for decades, commercially feasible
initiator catalyst miniemulsion bulk methods for its manufacture have become available
only recently. Most are based upon cationic polym-
AIBN 9a 21 000 24 000
AIBN 9c 11 000 14 000 erization. The major objective is to avoid internal
K2S2O8 9 830 Freidel-Crafts substitution to give the indane prod-
K2S2O8 9c 12 000 uct a in Scheme 9. This reaction is the major reason
cationic polymerization is not used for commercial
of potassium dipersulfate to oxidize the CCT catalyst polymerization of styrene or its derivatives.
when it is in the water phase. Since the 9c catalyst To minimize the indane, 99, formation, dimeriza-
is less soluble in water than 9a catalyst, it is less tion was conducted in two-phase systems containing
susceptible to oxidation poisoning. In the case of 9c, toluenesulfonic acid,354 sulfuric acid,355,356 electro-
the peroxy radicals react with monomer rather than philic transition-metal complexes,357 the polymeric
with the catalyst. More details on oxidative catalyst solid-state acid Nafion,358,359 metal oxide solid-state
poisoning were given in section 3.7. catalysts such as tungstophosphoric acid,360 various
zeolites,361,362 mixed oxides,363 and montmorillonite
4.2. Methacrylonitrile clay in the presence of organic solvents.364,365 The
major limitation of the cationic approach, however,
Methacrylonitrile is a slow polymerizing monomer is the unavoidable formation of internal isomer 100.
under conditions of CCT, and it yields oligomer with Since isomer 100 is inert in radical polymerization,
a double-bond end group similar to methacrylates (eq the lower the content of isomer 100, the higher
40). The resulting oligomeric products have a stron- activity of the 98 mixture. Even in the very best
ger tendency to copolymerize with additional mono- cases, its presence is never less than 5-15%.
mer and thus be incorporated into subsequent poly-
CCT also can be employed to synthesize 98.366
mer chains than do MMA oligomers.139
Temperatures over 150 °C facilitate the process. A
process yielding undetectable levels (probably, <0.2%)
of isomer 99 in the final AMSd, 98, provides a high-
quality process for AMS dimerization.367 Apparently,
the “ceiling temperature” of the dimer of AMS is
This tendency is presumably the result of the much higher than that of AMS polymer. The mono-
smaller size of the nitrile group relative to the ester meric radical obtained in reaction with LCoH is
group, so that reaction of LCoH with MAN oligomer capable of adding one or two monomeric units but
is more competitive with that of the monomer. The then sterics reduce the value of the propagation rate
chain-transfer constant CC is not known for the constant, thereby preventing further radical growth.
polymeric MAN radical, but for the MAN dimer The decrease in propagation rate constant improves
radical, the rate coefficient for CCT kC is 8 × 105 M-1 the efficiency of any chain-terminating reactions. As
s-1 (at 60 °C with TAPCoII).346 emphasized earlier,61 low MW polymer chemistry is
significantly different from that of high polymer.
4.3. r-Methyl Styrene Many concepts and equations well established for
conventional polymer science may encounter serious
A major limitation of R-methylstyrene in free- limitations when used to describe oligomers with
radical polymerizations is its very low ceiling tem- DP < 6.
perature of 61 °C.347 As a result, AMS is utilized
commercially only in radical copolymerization. None- 4.4. Styrene
theless, it is among the most active CCT monomers
with CC ) 9 × 105 at 50 °C for 9a as CCT catalyst.348 While there is a considerable body of research on
This value is relatively unchanged at 40 °C. This high CCT polymerizations of styrene itself, there are no
value reflects the low kP ) 1.7 M-1 s-1 so that kC ) reports of CCT in polymerizations of substituted
5 × 105 M-1 s-1. styrenes. In the case of styrene as well as in the case
AMS dimer, AMSd (98), is useful as a radical of other vinylic monomers bearing no methyl group
addition-fragmentation-chain-transfer radical adjacent to the propagating radical, CCT always
(RAFT) agent,349-352 which is covered later. In the provides oligomers with an exclusively trans config-
polymerization of styrene, AMSd is as active as uration of the double bond.28,368 Because there is no
methacrylate trimers and tetramers with a chain- abstractable methyl hydrogen atom, the only site for
Scheme 9. Cationic Oligomerization of r-Methylstyrene
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3639
Scheme 10. Back-Biting in Growing Acrylate of a CCT catalyst.389 The Markovnikov hydrogen
Chains atom addition normally observed in CCT requires
that one methyl group should start each polymer
molecule and each should be terminated by one
vinylic end. In the case of acrylamide, the theoretical
number of vinylic hydrogen atoms was observed but
expected resonances attributable to CH3-CH at the
head of the chain were absent.
It cannot be excluded that the back-biting depicted
in Scheme 10 could be responsible for the observed
absence of methyl proton.389 Scheme 10 would leave
most of the dead polymer molecules without methyl
end groups. The chemical shifts of the vinylic protons
in the resulting oligo-acrylamides are at 5.75 and 6.25
ppm, which is similar to the methacrylate end group
of polyBA which has been terminated by back-biting.
In oligo-acrylates produced by CCT, the vinylic
protons have resonances at 6.8 and 5.85 ppm.383 The
mechanism of Scheme 11 in acrylate polymerization
requires additional study.
There is a cationic analogue of Scheme 11 when
N-vinyl carbazole polymerization was induced by
poly(vinyl chloride)-bound dimethylglyoxime com-
plexes of CoII, NiII, and even CuII (Scheme 12).390
fragmentation. The net result of the back-biting is
the formation of oligomer with a terminal double Scheme 12. Cationic Route to Macromonomers
bond of a “methacrylate moiety” with vinylic proton
resonances at 6.2 and 5.5 ppm.383 When the polym-
erization of acrylic acid is conducted at temperatures
above 225 °C, the resulting oligomers have a DP
below 50.388 The products are useful as detergent
additives and for subsequent polymerization.
Originally the reaction in Scheme 10 was discov-
ered at temperatures approaching 240 °C,388 which
are close to the ceiling temperature of acrylates. More
recently it was demonstrated that this process is
relatively independent of temperature and can be
observed as low as 90 °C. Thus, the polymerization
of acrylates in the presence of CCT may result in a
mixture of vinyl-terminated products.
Another “side reaction” in the polymerization of
acrylates could be the anti-Markovnikov addition of The polymerization shown in Scheme 12 was ob-
Co-H to the olefinic double bond. This reaction served at room temperature and explains the sto-
shown in Scheme 11 was suggested to explain the ichiometric formation of vinylidene end groups. This
absence of any methyl group in the polymer backbone reaction seems to be a cationic polymerization rather
of acrylamide radically polymerized in the presence than an example of CCT.
Finally, Scheme 10 is a good example that interest-
Scheme 11. Proposed Mechanism to Explain ing chemistry remains to be found even in well-
Poly(acrylamide) Structure studied polymerization systems. In addition to acry-
lates, substantial back-biting occurs even in radically
polymerized styrene.383 Despite the long-standing
utilization of acrylates in radical polymerization, the
reaction shown in Scheme 10 was overlooked.
4.6. Acrylonitrile
Investigation of CCT homopolymerization of acry-
lonitrile is difficult as a result of the insolubility of
polyAN even at low molecular weight. Copolymeri-
zation with styrene was reported.297,371 Addition of
minor quantities of amines (about 3%) was shown to
have a positive synergetic effect on CCT at 60 °C (bis-
(diphenylglyoximatoCoII(Py)Cl, AIBN). The role of
amines is possibly to labilize the Co-C bond with
formation of a π-complex instead.
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3641
This reinitiation is of commercial interest in a added under starved-feed conditions. Such an ap-
number of circumstances. In preparation of low proach would minimize the percentage of chains
oligomers by CCT, large quantities of dimer are initiated with the conventional monomer.
formed, but dimer is often less attractive than the An attempt to polymerize 2-methyl-2-butenenitrile,
other oligomers for reasons of activity and volatility. MBN, by first isomerizing to methylenebuteronitrile
Dimer could be distilled out of the higher oligomers (eq 46) led to isomerization instead (eq 47).
and combined with additional monomer in the oli-
gomerization process to be converted to higher mo-
lecular weight species. An extruder-based process for
synthesis of lower macromonomers would involve
recycle of monomer.107 In addition, it is possible to
react the dimers or oligomers of one monomer with
a second monomer, thereby forming block copoly-
mers. The resulting polymers would be a complex
mixture with homopolymer of the new monomers, but Heating an E/Z ) 1:2 mixture of MBN isomers in
there are some applications where this would not be the presence of AIBN and a cobalt catalyst results
a complication. in the reverse composition of E and Z isomers, 2:1,
in 2 h.
Extension of macromonomer reinitiation led to
copolymerizations with “nonpolymerizable mono-
mers”.399-401 Methacrylate oligomers cannot be ho-
mopolymerized due to the steric bulk of the substit-
uents at what would be the radical center. Thus, they
are subject only to reinitiation under CCT conditions. Without cobalt chelate and azo initiator there was
There are many other olefinically unsaturated species no change. Oligomerization (eq 48) also occurs, but
which do not undergo homopolymerization or copo- the rate is several orders of magnitude slower.
lymerization with normal free-radical monomers.402
These can by represented by the tetrasubstituted
olefin in eq 45, though more often the desired olefin
is 1,2-disubstituted.
Table 12. Copolymerization Chain-Transfer CCT monomers. Monomers that form secondary
Constants, CC, for Selected Catalysts radicals or do not possess methyl substituents are
composition catalyst generally considered to be poor CCT monomers.430
MMA BA St 39b 39c 5s These include MA, styrene, acrylonitrile, and vinyl
acetate. Copolymerization of the good CCT monomers
10 0 0 1200 3500 630
9 1 0 1000 560 184 with poor CCT monomers in the presence of a CCT
8 1 1 700 500 200 catalyst leads initially to oligomers terminated after
5 5 0 440 130 31 the incorporation of a good CCT monomer. Thus, in
Calculated from ref 135.
general, the mixed oligomers will contain a terminal
methylene unit. For example, copolymerization of
methyl acrylate with R-methylstyrene mixture in the
nature of monomers.431 The catalysts in Table 12 presence of a CCT catalyst leads initially to oligomers
were prepared in situ rather than under optimized with a terminal double bond.374 As shown in Scheme
conditions, making the results a questionable com- 13, the most frequent product will be oligomers of
bination of solubilities, formation rate constants, and
chain-transfer constants. Nonetheless, the effects in Scheme 13. Illustrative Products in Methyl
copolymerizations presented in Table 12 are typical. Acrylate Copolymerization with r-Methylstyrene:
Addition of butyl acrylate or styrene lowers the E ) CO2Me
effective CC, and the reduction can be significant.
In a copolymerization of styrene and methyl meth-
acrylate under CCT conditions, the fraction of un-
saturated styrene end groups is proportional to the
fraction of styrene in the monomer feed.368 Due to
the stability of styrene radicals, the relative fraction
of propagating styrene radicals is large over the
whole range of monomer feed compositions.432,433 This
feature complicates the determination of radical
reactivity ratios but may be compensated for by
measuring the average transfer rate coefficient as a
function of monomer feed composition.
Measurement of reactivity ratios under normal
free-radical and CCT polymerization conditions in-
dicates that CCT is a modified free-radical polymer-
ization as expected.434 The reactivity ratios for MMA
and butyl methacrylate were used as a mechanistic
probe. Reactivity ratios were 1.04 and 0.81 for
classical anionic polymerization, 1.10 and 0.72 for
alkyllithium/trialkylaluminum initiated polymeriza- methyl acrylate terminated with an R-methylstyrene
tion, 1.76 and 0.67 for group transfer polymerization, moiety, 109. The methyl acrylate radical is highly
0.98 and 1.26 for atom transfer radical polymeriza- reactive but spends much of its time coordinated to
tion, 0.75 and 0.98 for CCT, and 0.93 and 1.22 for the cobalt catalyst.
classical free-radical polymerization. These ratios Insertion of a single AMS leads to a relatively
suggest that ATRP and CCT proceed via radical stable radical with an appreciable lifetime. Because
propagation. AMS is an effective CCT monomer, generating a
The composition of CCT copolymerization products growing radical with an available methyl C-H bond,
has been explored in a more complete manner utiliz- CCT occurs with high probability, producing struc-
ing matrix-assisted laser desorption/ionization time- ture 109 that has a terminal double bond that is
of-flight (MALDI-TOF) mass spectrometry.435 The reactive toward poor CCT monomers. The unsatur-
bivariate distributions of monomer composition and ated species, 109, is a copolymerizable monomer that
chain length were determined for a series of copoly- can be incorporated into an additional growing
mers of MMA and butyl methacrylate (BMA) pro- polymer chain forming a branch point. Incorporation
duced by CCT. The relationship between the distri- of 109 again leads to a relatively stable radical
butions of copolymers and the kinetics of the copoly- species, but unlike AMS incorporation, it does not
merization reactions was derived using the terminal provide a readily accessible methyl at the radical
copolymerization model.436,437 The reactivity ratios, center, so continued propagation is the most likely
CCT coefficients, and initiator selectivities were rMMA outcome. Early in the polymerization this is an
) 1.09 and rBMA ) 0.77, CCMMA ) 17 900 and CCBMA unlikely event, but as the other monomers are
) 6150, and SMMA ) 0.535, respectively. The reactiv- depleted, the relative molar concentration of 109
ity ratios for these polymerizations by 1H NMR (rMMA increases, leading ultimately to a substantial portion
) 0.75 and rBMA ) 0.98) were in general agreement. of branched product, 110. At high conversion, the
Monomers that form tertiary radicals bearing concentrations of AMS, MA, 109, and 110 become
methyl substituents are generally considered to be similar and a complicated dendritic structure emerges.
good CCT monomers. These include MMA, AMS, and The ultimate product has been described by structure
methacrylonitrile.311 In addition, dienes can be good 111, where the R1 and R2 substituents are typically
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3645
carboalkoxy, phenyl, or cyano and where Z is typi- polymerization while the concentration of terminally
cally methyl. unsaturated macromonomers is steadily increasing.
These varying concentrations favor the formation of
highly branched polymer at high conversion.
The product may be of more complex structure if
more than two monomers are utilized. For example,
if nonhomopolymerizable monomers as described
above402 are included at the beginning of the polym-
erization, the final product would have them on the
periphery of the branched structure. Feeding the
polymerization with different monomers would pro-
vide additional flexibility to this “arms-first” ap-
proach of making hyperbranched polymers.
Batch polymerizations of styrene, MMA, and 2-hy-
droxyethyl methacrylate carried out in the presence
of either dodecanethiol or 9c indicate that the overall
In addition, Z can be described by 112. When Z is
rates of polymerization do not differ significantly in
methyl, structure 111 would be a simple random
the two systems.438 The molecular weight distribution
copolymer of the poor monomer bearing only R1,
of the polymer formed in the presence of the thiol
terminated by the good comonomer bearing a methyl
becomes increasingly broad, whereas the 9c-medi-
and R2. Interestingly, Z can be a single branch 112
ated polymerization produces a relatively uniform
when it contains only methyl as Z, but 112 can also
product during the course of the reaction. The
contain additional branches again defined by 112,
polymer product formed with 9c was found to be
building into a highly branched system.
slightly less stable thermally than the product formed
The entire process relies upon elevated tempera-
by the thiol, presumably a result of the unsaturated
tures to destabilize any CoIII-alkyls and high catalyst
end groups.
concentrations such that ample CoII is available. This
To prepare water-soluble polymers employing CCT,
also leads to relatively low molecular weights for the
it is necessary to modify the polymerization condi-
initial products. It also helps that the susceptibilities
tions.312,439 Use of a standard batch reaction leads to
of the two monomers to CCT are significantly differ-
hydrolysis of catalyst, changing the catalyst level over
ent and that the concentration of the good CCT
the course of the polymerization, yielding a mixture
monomer is high. Unbranched structures are favored
of products and poor control of the reaction. A feed
by low conversion, while high conversion favors
or starved-feed process that adds catalyst over the
reinsertion and high branching. The low molecular
course of the reaction maintains a constant catalyst
weight and resulting higher concentration of oligo-
level and high conversion. The approach can be
mers favors reincorporation and branching.
applied to a range of monomers such as methacrylic
Scheme 13 may be generalized by describing A-type
acid, 2-aminoethyl methacrylate hydrochloride, 2-hy-
monomers311 and B-type monomers.430 A-type mono-
droxyethyl methacrylate, 2-methacryloxyethyl phos-
mers provide chain termination and branching. The
phoryl choline, glycerol monomethyl methacrylate,
A monomers would stay mostly in the branching
and 3-O-methacryloyl-1,2:5,6-di-O-isopropylidene-D-
point. Because B-type monomers are not nearly as
glucofuranose.
effective for CCT, they are generally not the ultimate
group in resulting macromonomers. Nonetheless,
they are capable of copolymerizing both with the A 5. Applications of CCT Products
monomers and with the olefinically terminated mac- In general, the products of CCT are utilized in
romonomers. Thus, they incorporate oligomers and further chemistry, but there are some applications
monomers into higher polymer. In Scheme 13 one can where they are employed directly. For instance, CCT
understand how the structure of the final product catalysts may be used directly in the preparation of
depends on the relative concentration of oligomers, emulsions for electrophotographic toners.340 The re-
A monomers, B monomers, and cobalt catalyst. In sulting emulsions are more stable than those ob-
Table 13, the results of butyl acrylate copolymeriza- tained with thiol chain-transfer reagents. They may
be combined directly with suspensions of black or
Table 13. Batch Polymerization of BA:MMA (4 v/v
mixture at 90 °C)a colored pigments and precipitated to yield toners of
narrow particle size. Apparently there may be occa-
time (h) 1.5 3 7 22
sions where highly bimodal molecular weight distri-
percent conversion 12 24 55 93 butions are desired for toner applications, and then
Mn 540 640 890 2300 the CCT catalyst is added partway through the
PDI 2.08 2.08 7 2.8
polymerization.440,441 Alternatively, the CCT catalysts
a A 50% solution in 1,2-dichloroethane, [VAZO-88] ) 2 g/L;
may be employed directly in the casting composition
[cobaloxime 8] ) 0.25 g/L. for thermoformable sheet compositions, lowering
viscosities and improving toughness of the final sheet
tion with 20% MMA are presented. goods.442
Because MMA is incorporated into polymer chains For some application sensitive to color, it may be
more rapidly, the concentration of MMA decreases necessary to decolorize some macromonomers. The
steadily relative to BA during the course of the process used is dependent on the properties of the
3646 Chemical Reviews, 2001, Vol. 101, No. 12 Gridnev and Ittel
macromonomer and the catalyst used in its prepara- for dimer, 0.19 for trimer, 0.31 for tetramer, and 0.21
tion.443,444 While most polymerizations are carried out for mixed higher oligomers with an average DP of
in batch reactions or starved-feed reactions, continu- 24. The transfer constants demonstrated only a small
ous reactors can also be employed.445 temperature dependence and no variation with con-
Ethylene-vinyl alcohol copolymers are important version. There was no discernible retardation in the
oxygen barrier resins for the food packaging industry, rate of polymerization. A reduced yield of polymer
and aesthetics of the packaging films are important. was observed. In bulk polymerizations with conver-
The role of R-methylstyrene dimer added to ethyl- sions greater than 10%, the reduced yield was at-
ene-vinyl acetate copolymers after polymerization tributed to the absence of the gel (Trommsdorff)
but before saponification is difficult to understand. effect. The results are interpreted in terms of the
Nonetheless, the resulting polymers have the advan- addition-fragmentation mechanism for chain trans-
tages of good melt extrusion stability and drawdown fer shown in Scheme 14.457
resistance resulting in films without streaking.446 In
addition, they have good interlayer adhesiveness and Scheme 14. Mechanism of
gas barrier properties. Addition-Fragmentation Chain Transfer
5.1. Reduction of MW
Federal requirements to produce increasingly lower
VOC paints34 have been a significant driver of CCT
technology.447 Telechelic polymers and other func-
tional systems are used as low-viscosity reactive
cross-linkers,35 and pigment dispersants.37
A good example of cross-linking utilizing low mo-
lecular weight oligomers involves poly(ortho esters)
and isocyanates.448 Oligomers of hydroxyethyl meth-
acrylate provide multiple hydroxyl groups for reac-
tion of trimethyl orthoformate and hexamethylene
diisocyanate trimer, in the presence of a sulfonate
catalyst, to give a product with flowability for ap-
plication but which cures to give good weatherability
and adhesion. Similar systems are useful for the
electrodeposited underlayer used for corrosion resis-
tance in automotive finishes.449
The MMA dimer, 113, readily prepared by CCT, is Thermal degradation of the oligomers as a model
not homopolymerizable; this is attributed to the steric for the transfer process indicates that the process is
constraints imposed by the steric bulk appended to homolytic bond cleavage and not a retro-ene reac-
the R-position.450 Interestingly, the isomeric olefin tion.458
114 can be polymerized to low molecular weight,451 MMA oligomers are effective chain-transfer agents
and the less hindered species 115 is readily polym- in a variety of copolymerizations.337,459-461 If the
erized to higher molecular weight,452 though in both dimer of hydroxyethyl methacrylate is employed as
cases fragmentation chain transfer is observed. In a chain-transfer agent in MMA polymerization, the
copolymerization with MMA, 114 acts as a chain- resulting product is an R,ω-telechelic polymer.462 It
transfer agent. was noted that the chain-transfer constant was
dependent upon the concentration of the dimer.
Emulsion copolymerization of MMA oligomer which
was essentially trimer with butyl methacrylate,
2-ethylhexyl methacrylate, hydroxyethyl methacry-
late, methacrylamide, and methacrylic acid gave a
All three species are copolymerizable with styrene. latex with average particle diameter of over 100 nm
The three species were prepared in interesting solid- and a molecular weight reduced significantly from
state dimerizations involving their salts and mixed that which would have been obtained without the
salts.453-455 trimer.337 The dimer of methacrylic acid is useful for
Attempted copolymerizations of MMA oligomers control of molecular weight in emulsion polymeriza-
with MMA were relatively unsuccessful. Rather, the tions.463
MMA oligomers served as chain-transfer agents. The Other dimers that have been employed are those
chain-transfer activities of a series of MMA oligomers of methacrylic acid and its anhydride,464 ethyl meth-
were evaluated in MMA polymerizations over the acrylate, methacrylonitrile, and R-methylstyrene.465,466
temperature range 45-100 °C.456 The transfer con- The cross dimers of these monomers with each other
stants were determined by analysis of the chain as well as with MMA were also found to be effective,
length distributions of the resulting polymers as a with those species containing R-methylstyrene being
function of macromonomer concentration. The MMA particularly effective.
dimer was substantially less effective as a chain- The dimer of R-methylstyrene is useful in control-
transfer agent than the MMA trimer or the higher ling molecular weight in polystyrene manufac-
macromonomers. At 60 °C, the constants were 0.013 ture.467,468 The control of molecular weight with
Catalytic Chain Transfer Chemical Reviews, 2001, Vol. 101, No. 12 3647
malodorous sulfur compounds is particularly impor- tions. Polymers for automotive finishes typically
tant in room-temperature-curable hand lay-up mold- contain methyl methacrylate, butyl methacrylate,
ing and spray-up molding applications.469 In dental and glycidyl methacrylate. Incorporation of AMS
adhesives which are cured by UV irradiation, the dimer into one of these polymerizations yields poly-
presence of R-methylstyrene dimer controls harden- mers of the proper molecular weight which are free
ing time and the heat of polymerization.470 from the odor problems associated with thiol chain-
Polymers incorporating AMS dimer are utilized in transfer agents.483,484 Formulation into a powder
a number of aspects of paper making. It is desirable coating gave a product with little yellowing.
to maintain as much of the fiber from the paper pulp Formulation of poly(vinyl chloride) into sheet goods
as possible in the paper rather than in the waste- is often beset with color problems. The kneading
water. These polymers must demonstrate thickening process takes place in the presence of dibutyltin
at low shear ratio and good flowability at high shear maleate to initiate cross-linking reactions. The pres-
ratio. A copolymer of Et acrylate, methacrylic acid, ence of AMS dimer in the kneading process leads to
and poly(ethylene glycol) acrylate palmityl ether less yellowing and better thermal stability for the
prepared utilizing AMS dimer in a chain-transfer PVC sheet.485
polymerization performed well as a fiber retention
agent.471 To enhance the surfactant properties of AMS dimer was used to prepare a macromonomer
these polymers, other useful monomers include sul- of 2-ethylhexyl methacrylate. Copolymerization of the
fonates of vinyl-terminated polyalkyleneglycols and resulting macromonomer with butyl acrylate and
vinyl-terminated alkylpolyalkylene glycols. Surface acrylic acid gave a polymer backbone with Tg less
properties of the paper are particularly important in than 10 °C that is useful in adhesive applications.486
printing, and the molecular weight of latex polymers The adhesive is better than the same composition
containing acrylamide, acrylic acid, acrylonitrile, made without the intermediacy of the macromono-
butadiene, itaconic acid, MMA, and styrene are mer.
controlled with AMS dimer.472 Control of molecular weight and branching can also
After the paper making process is complete, latexes be an issue in the preparation of ABS (acrylonitrile,
that are useful as binders for the application of clays butadiene, styrene) rubbers. AMSd is employed to
or CaCO3 to paper for printing paper may be pre- lower molecular weight, and the functional end
pared using the dimer of AMS. In a typical formula- groups may be reincorporated into the polymer to
tion, styrene, butadiene, Me methacrylate, and acry- yield branching.487
lonitrile were emulsion polymerized in the presence In the copolymerization of difunctional acrylics to
of AMS dimer to obtain a copolymer latex.473 Surpris- prepare cross-linked amorphous glasses for lenses,
ingly, the AMS dimer was used in combination with it is useful to control molecular weight utilizing the
tert-dodecylmercaptan, so there may have been some AMS dimer. For instance, copolymerization of diallyl
residual odor. Unsaturated carboxylic acids, such as isophthalate, dibutyl maleate, and diethyleneglycol
acrylic acid, or sulfonic acids, such as 2-ethylsulfonyl bis(allyl carbonate) in the presence of AMSd in a
acrylate, or unsaturated amides, such as acrylamide, mold gave a lens showing good refractive index,
are also useful, providing the polarity necessary in transparency, and impact resistance.488 Similar re-
these applications.474 sults are obtained for metal-containing optical coat-
The dimer of AMS is used in the preparation of ings based upon neodymium in di(2-methacryloyl-
waterborne coatings.475 When used to control molec- oxyethyl)phosphate, mono(2-methacryloyloxyethyl)-
ular weight in copolymerizations of diacetone acry- phosphate, methacrylic acid, and phenoxyethyl acry-
lamide, acrylic acid, MMA, MA, and BA with a Na late. The resulting antiglare coatings are very mois-
vinylsulfonate copolymer ammonia salt, the resulting ture resistant.489
waterborne coating shows good gloss and excellent
The compound 3,9-divinyl-2,4,8,10-tetraoxaspiro-
resistance against water, salt-spray, and blistering.
[5.5]undecane together with a peroxide is utilized in
Similar systems are utilized for can coatings.476 When
the polymers are going to be used in food applica- the cross-linking or curing of polyethylene for wire
tions, it is particularly important that they be low and cable applications. Addition of 2,4-diphenyl-4-
odor. Therefore, it is useful to replace mercaptans methyl-1-pentene (AMSd) inhibits scorch or prema-
with AMS dimer.477 ture cross-linking of the polymer, presumably through
interception of the radicals.490
Polymerization of N,N-dimethylaminopropylacry-
lamide with AMS dimer gave a polymer useful in the Apparently, AMSd is also useful in the reduction
preparation dispersant polymers for black pigmented of the molecular weight of waste polymer.491 Heating
inks for ink-jet applications.478-481 In one, the polym- polystyrene foam pieces recycled from food packaging
erization was initiated with 2,2′-azobis(2-methylpro- materials at 160 °C for 1 h in the presence of AMSd
pioamidine) dihydrochloride in a water-2-propanol reduced the Mn from approximately 70 000 to 10 000.
mixture, and it is likely that the spent catalyst was The mode of action is unknown, but it is presumed
extracted into the aqueous phase.478 The inks dem- that AMS radicals are generated and abstract hy-
onstrate good storage stability. Imide and urea func- drogen atoms from the polystyrene backbone, result-
tionalities are also incorporated into polymers for ing in chain cleavage.
dispersants utilizing CCT technology.482 In a more esoteric application, the dimers are
Powder coatings are an important step toward the useful in the study of free-radical chemistry through
lowering of volatile emissions from painting opera- trapping experiments.351,352
3648 Chemical Reviews, 2001, Vol. 101, No. 12 Gridnev and Ittel
5.2. Macromonomers for Graft Copolymers ing multiblock copolymers can be neutralized to form
ionomeric networks.
In some instances, the macromonomers synthe- Graft acrylic polyols for two-component polyure-
sized by CCT can be copolymerized with acrylics to thane coatings can be prepared by free-radical copo-
form comb copolymers. While β-scission predominates lymerization of MMA, BMA, BA, acrylic acid, HEMA,
in copolymerizations with methacrylates, acrylates and PMMA macromonomers.505 The polymers offer
and styrene give both incorporation to yield comb an advantage over conventional resins with respect
copolymers and β-scission.492 Products of this type to the application/appearance of coatings as well as
have been thoroughly characterized by a variety of the final film properties. Some of these advantages
spectroscopic techniques. When high levels of CCT were higher solids and a better control of the coating
macromonomers are employed, it is possible to go rheology, an increase in the cross-linking reactivity
beyond the comb structure and obtain more highly of the polyols with polyisocyanate, and improvement
branched polymers.493 in film toughness. The change in the morphological
In a more specific example, macromonomer com- structure of the films under tensile stress was of
posed of n-butyl methacrylate and methacrylic acid particular interest.
prepared by CCT was copolymerized with n-butyl
In an alternative approach, chloride-containing
acrylate containing a small portion of methyl meth-
polymers such as styrene-co-chloromethylstyrene
acrylate.341 Comparison to the equivalent copolymer
were grafted with MMA by initiating from the chloro
made with a macromonomer prepared with a thiol
groups with chlorocobaloxime.506,507 Similar reaction
chain-transfer agent demonstrated that the CCT
had been noted under photochemical conditions, but
macromonomer formed a copolymer while the thiol
the reactions can also be run thermally. The mech-
macromonomer did not. When these compositions
anism is unclear, but improved polymerization in the
were cured using trifunctional isocyanates, they were
presence of zinc as a reducing agent suggests that
useful as both clear and pigmented automotive
CoI may have been involved. Polymerization was also
finishes.
initiated from halide donors such as chloroform or
Dispersions of organic or inorganic particles that trichloroethane without the reducing agent.
are insoluble in the liquid vehicle are stabilized by
polymeric dispersants. These dispersants are usually
structured polymeric systems (random, block, or
5.3. RAFT
graft) having at least one segment that is soluble in RAFT (reversible addition-fragmentation transfer)
the vehicle and at least one segment that is insoluble polymerization is gaining popularity as an alternative
in the vehicle and having an affinity for the particle. to living polymerizations for the synthesis of narrow
They have improved stability when the insoluble molecular weight or structured polymers.508-514 Early
segment contains cross-linkable groups. One or both work in the area demonstrated that the methacrylate
segments can be prepared by CCT.494-495 oligomers synthesized by CCT can be employed in
Core-shell microgels can be prepared utilizing the RAFT process,512,515 as can dimers of R-methyl-
CCT macromonomers496 and self-stabilized cross- styrene prepared cationically.350 Today, RAFT tech-
linked latexes.497-501 nology is dominated by the use of thiocarbonylthio
Methyl methacrylate macromonomers were copo- compounds and the term RAFT has come to imply
lymerized to provide a hydrophobic graft on an the use of these compounds. The RAFT process, very
otherwise hydrophilic polymer.502,503 Such systems similar to that shown in Scheme 14, involves a series
are useful in the preparation of soft contact lenses. of reversible addition-fragmentation steps.508,509 Ad-
Hydrophobic methyl methacrylate macromonomers dition of a propagating radical to an MMA oligomer
were synthesized by CCT and subsequently copoly- gives an adduct radical which can fragment to form
merized with any of the hydrophilic monomers N,N- terminated polymeric chain and a new radical. The
dimethylacrylamide, 2-hydroxyethyl acrylate, or N-vi- reaction of the new radical with a monomer (M)
nyl-2-pyrrolidone by γ-radiation to yield xerogels. The results in a new propagating radical. Subsequent
copolymerization was confirmed by NMR analyses addition-fragmentation steps allow a dynamic equi-
and by subsequent aqueous extraction of the result- librium to be established between the active propa-
ant copolymers. On swelling in deionized water, gating radicals and dormant polymer such that there
hydrogels were formed that had significantly higher is an equal probability of growth for all chains,
Young’s moduli than hydrogels based on random resulting in an apparent living polymerization and
copolymers of equivalent composition a narrow molecular weight distribution.
Polar polyacrylamide with well-defined nonpolar CCT of benzyl methacrylate leads to a mixture of
polystyrene grafts (PAM-g-PSt) was synthesized via poly(benzyl methacrylate) macromonomers from which
macromonomer technique.504 The resulting am- the dimer macromonomer could be isolated.516 When
phiphilic polymers exhibit good emulsifying proper- the benzyl dimer is used as a RAFT chain-transfer
ties. Interestingly, when PAM-g-PSt was blended agent, PMMA with R- and ω-terminal benzyl meth-
with PMAA grafted with PMMA, an intermolecular acrylate units is obtained. Catalytic hydrogenation
complex membrane was formed. The permeability of of the R,ω-benzyl terminal methyl methacrylate
the membrane is controlled reversibly by changing polymer results in the evolution of toluene and
the pH value, making it a chemical valve. formation of R,ω-dicarboxyl functional telechelic
Oligomers of acrylic acid having a DP below 50 are PMMA.
useful as detergent additives and boosters.388 When When it is important that surfactants utilized in
employed in subsequent polymerizations, the result- free-radical emulsion polymerization not be free to
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Chem. Rev. 2001, 101, 3747−3792 3747
I. Introduction
Immediately after the discovery of the living char-
acter1 of anionic polymerization,2 polymer chemists
started synthesizing well-defined linear homopoly-
mers and diblock copolymers with low molecular
10.1021/cr9901337 CCC: $36.00 © 2001 American Chemical Society
Published on Web 11/21/2001
3748 Chemical Reviews, 2001, Vol. 101, No. 12 Hadjichristidis et al.
Marinos Pitsikalis received his B.Sc. and Ph.D. from the University of Hermis Iatrou received his B.Sc. and Ph.D. from the University of Athens,
Athens, Greece in 1989 and 1994, respectively. His postdoctoral research Greece, in 1989 and 1993, respectively. He did postdoctoral research at
was done at the University of Alabama at Birmingham, with Prof. J. W. the Institute of Material Science in the Center of Nuclear Science in Juelich,
Mays (1995−1996). Since 1998, he has been a Lecturer at the Industrial Germany, with Prof. Dr. Dieter Richter (1994−1995), and University of
Chemistry Laboratory, Department of Chemistry, University of Athens. Alabama at Birmingham, with Prof. Jimmy Mays (August 1997−February
He has been a Visiting Scientist at the University of Milano, Italy (March 1998). He has been a Research Associate at the University of Athens
1991); University of Alabama at Birmingham (September−October 1993); since 1998. He has published 30 papers in refereed scientific journals
Max Plank Institute for Polymer Science, Germany (August 1994); National and made 27 announcements at international scientific conferences.
Institute for Standards and Technology (December 1995); and IBM
Almaden Research Center (February 1995). He has published 35 papers
in refereed scientific journals and made 30 announcements at international
scientific conferences.
initiators, due to the strong aggregation effects. The high dilution to obtain a stable microgel suspension.
steric hindrance effects, caused by the high segment These microgels, which were covered by living anionic
density, causes excluded volume effects. sites, were subsequently used as multifunctional
Use of Multifunctional Linking Agents. This initiators to polymerize styrene, isoprene, or buta-
method involves the synthesis of living macroanionic diene. A slight variation was adopted by Funke.17,18
chains and their subsequent reaction with a multi- The polymerization of DVB was initiated by living
functional electrophile, which acts as the linking poly(tert-butylstyryl)lithium chains having low mo-
agent. It is the most efficient way to synthesize well- lecular weights in order to avoid the solubility
defined star polymers, because there can be absolute problems arising from the strong association of the
control in all the synthetic steps. The functionality carbon-lithium functions in the nonpolar solvent.
of the linking agent determines the number of the Rempp et al. synthesized poly(tert-butyl acrylate)16
branches of the star polymer, provided that the (PtBuA) and poly(ethylene oxide)19 (PEO) stars, ac-
linking reaction is quantitative. The living arms can cording to Scheme 2.
be isolated and characterized independently along
with the final star product. Consequently, the func- Scheme 2
tionality of the star can be measured directly and
with accuracy. Disadvantages of the method can be
considered the sometimes long time required for the
linking reaction and the need to perform fractionation
in order to obtain the pure star polymer, since in
almost all cases a small excess of the living arm is
used in order to ensure complete linking.
Use of Difunctional Monomers. In this method
a living polymer precursor is used as initiator for the
polymerization of a small amount of a suitable
difunctional monomer, such as divinylbenzene (DVB)
or ethyleneglycol dimethacrylate (EGDM).3,11,12 Mi-
crogel nodules of tightly cross-linked polymer are
formed upon the polymerization. These nodules serve
as the branch point from which the arms emanate. The synthesis of the PtBuA stars was performed
The functionality of the stars prepared by this in the polar solvent tetrahydrofuran (THF) to mini-
method can be determined by molecular weight mize the strong association effects, using naphtha-
measurements on the arms and the star product, but lene lithium to polymerize the DVB. DVB polymer-
it is very difficult to predict and control the number ization was initiated by electron-transfer instead of
of arms. The number of branches incorporated in the by addition. The polymerization of the tBuA was
star structure is influenced by many parameters. The carried out at -55 °C in the presence of LiCl and
most important is the molar ratio of the difunctional after the active centers have been reacted with a
monomer over the living polymer. The functionality suitable amount of 1,1-diphenylethylene (DPE) to
of the star increases by increasing this ratio. Other reduce their nucleophilicity. It was found that the
parameters that influence the number of branches mole ratio [DVB]:[Li+] should vary between 1.5 and
are the chemical nature (polystyrene, polydiene etc.), 2.5 to obtain a stable microgel suspension. The
the concentration and the molecular weight of the molecular weight of the branch cannot be measured
living polymer chain, the temperature and the time directly but can be calculated from the ratio of the
of the reaction, the rate of stirring, the composition monomer consumed during the polymerization over
of the isomers in the case of DVB (ratio of m, o, and the total Li concentration. The products were char-
p isomers), etc. Another disadvantage of this proce- acterized by size exclusion chromatography (SEC)
dure is that the final products are characterized by and light scattering (LS). The results showed the
a distribution in the number of the arms incorporated existence of broad molecular weight distributions and
into the star structure. Consequently, the number of even multimodal peaks. The formation of a rather
the arms determined experimentally by molecular small amount of aggregates was obtained in most
weight measurements is an average value. It is cases. It was removed by filtration or centrifugation.
obvious that although this method is technologically The molecular characteristics of the final products
very important and can be applied on an industrial and the calculated molecular weight of the branches
scale, it is less suitable for the preparation of well- revealed the existence of large numbers of arms,
defined stars. ranging from 22 to 1300.
Recent advances in all three methodologies devel- For the synthesis of the PEO stars, potassium
oped for the synthesis of star polymers will be naphthalene was used to generate the multifunc-
presented in the following sections. tional initiator. The molar ratio [DVB]:[K+] was less
than 3 in all cases. The functionalities of the stars,
1. Multifunctional Initiators. as determined by LS measurements, were also rather
The use of DVB as a multifunctional initiator was large, ranging from 5 to 219.
initially demonstrated by Burchard et al.13,14 and was Alternatively, PEO stars were synthesized using
later developed by Rempp and his collaborators.15,16 cumylpotassium to polymerize DVB and thus prepare
DVB was polymerized by butyllithium in benzene at the polyfunctional initiator.20 The products exhibited
3750 Chemical Reviews, 2001, Vol. 101, No. 12 Hadjichristidis et al.
Scheme 4
Scheme 6
pends on the steric requirements of the linking agent theoretical value were obtained in all cases. However,
and the living macromolecular chain end. The linking extended periods of time were needed for complete
efficiency can be improved by separating the Si-Cl linking reactions, and fractionation was required to
groups by spacers, such as methylene groups, and/ eliminate excess arm (purposely added) and low
or by end-capping the living chains with a few units molecular weight impurities.
of butadiene in order to reduce the steric hindrance The validity of the chlorosilane linking agents for
and facilitate the linking reaction. Under these the synthesis of star polymers was reevaluated
conditions, well-defined stars have been prepared recently using NMR41 and matrix-assisted laser
with functionalities ranging from 3 up to 18.31-37 desorption/ionization time-of-flight mass spectrom-
Recent advances in the synthesis of pure carbosilane etry (MALDI-TOF MS)42 techniques. Polyisoprene
dendrimers led to the preparation of linking agents (PI) and polybutadiene (PBd) stars having low arm
with functionalities as high as 128.38 These dendrim- molecular weights (M ∼ 103) and functionalities
ers were successfully used for the synthesis of PBd ranging between 3 and 64 were prepared. It was
stars having 32, 64, and 128 branches.39,40 The observed that for stars having 16 or less arms, the
products were characterized by SEC, membrane structural quality with respect to the polydispersity
osmometry (MO), vapor pressure osmometry (VPO), and the functionality agrees very well with the
and LS, and their dilute solution properties were theoretical values. For stars having theoretically 32
extensively studied in the framework of several and 64 arms, the average functionalities of the
theoretical models. Low molecular weight distribu- chlorosilane linking agent was found to be 31 and
tion polymers having functionalities close to the 60, respectively, whereas the number of arms of the
Complex Polymers by Living Anionic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3753
Scheme 7
B. Star−Block Copolymers
changing the steric hindrance of the living chain end. Star-block copolymers are star polymers in which
The functionality could be also controlled by the each arm is a diblock (or a triblock) copolymer. They
stoichiometry of the reaction between the living can be prepared by all the methods reported earlier.
polymers and the C60. However, it was impossible to The best way involves the linking reaction of a living
selectively incorporate one or two chains per C60 diblock copolymer, prepared by sequential anionic
molecule. polymerization of the two monomers, with a suitable
In polar solvents, such as THF a different situation linking agent. Using this method and chlorosilane
was observed. During the reaction of a living poly- linking agents, Fetters and collaborators synthesized
styrylpotassium with C60 in THF, a two-electron star-block copolymers (PS-b-PI)n, where n ) 4, 8, 12,
transfer was initially observed followed by the addi- 18.53,54 An example is given in Scheme 12. Well-
tion of four chains, according to Scheme 11. When defined structures of low polydispersities were ob-
the living PS chain was end-capped with 2-vinyl- tained.
pyridyl or 1,1-diphenylethyl groups, the number of Scheme 12
the linked chains was reduced to 3 and 0, respec-
tively, showing that both the reactivity and the
bulkiness of the end group play an important role in
this reaction.
Scheme 11
Using the same method Storey et al. prepared ionic
star-block copolymers.55,56 Styrene was oligomerized
followed by the polymerization of butadiene. The
living diblock copolymer was subsequently linked
with methyltrichlorosilane to provide a three-arm
star-block copolymer of styrene and butadiene.
Hydrogenation of the diene blocks and sulfonation
of the styrene blocks produced the desired ionic star-
3. Use of Difunctional Monomers block structure having ionic outer blocks and hydro-
phobic inner blocks, as depicted in Scheme 13.
Several star polymers have been prepared by
reacting living polymers with DVB. The method has Scheme 13
been applied in the past for the synthesis of PS48,49
and polydiene50 stars. Rather narrow molecular
weight distribution PS stars were obtained when the
[DVB]:[PSLi] ratio was varied from 5.5 to 30 and the
corresponding functionality was between 13 and 39.
Similar behavior was obtained for polydiene stars
when the [DVB]:[PDLi] ratio was from 5 to 6.5 and
the functionality of the star was varied between 9
and 13. In other cases, broad distributions were
observed, caused by the large distribution of the
functionalities of the stars prepared by this method.
More recently, PMMA stars were prepared by C60 was also employed for the synthesis of star-
reacting living PMMA chains with ethylene glycol block copolymers.47 Living PS-b-P2VP diblocks, hav-
dimethacrylate (EGDM).51 The polymers were char- ing short P2VP chains, were prepared by sequential
acterized by SEC, LS, and viscometry. It was found anionic polymerization in THF. These living diblocks
that well-defined polymers can be prepared when the were reacted with a suspension of C60 in THF, leading
arm molecular weight was rather high (e.g. Mw ) to the formation of a three-arm star-block copolymer
40 000). It seems that this high molecular weight is (Scheme 14). The corresponding reaction with the
necessary to prevent intercore and gelation reactions living PS homopolymer results in the formation of a
from taking place. four-arm star. The lower reactivity of the 2VP anion
EGDM was also reacted with isotactic living PMMA seems responsible for this behavior. The SEC analy-
chains obtained using tert-butylmagnesium bromide sis showed that the product had a broad molecular
as initiator in the presence of 1,8-diazabicyclo[5.4.0]- weight distribution, indicating that a mixture of stars
undec-7-ene.52 A star polymer with a number of arms with different functionalities was obtained.
estimated between 20 and 30 was synthesized. SEC DVB was used to prepare a multifunctional initia-
connected with LS and viscometry detectors was used tor from which the polymerization of styrene was
to characterize the sample. Similar reaction using initiated, followed by the polymerization of ethylene
syndiotactic living PMMA chains, obtained with the oxide. Quite broad polydispersities were reported for
initiator system t-BuLi/R3Al, failed to give star these star-block copolymers, due to the random
Complex Polymers by Living Anionic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3755
The excess of the PSB arm was removed by fraction- possibility of preparing end-functionalized asym-
ation. Detailed characterization results by SEC, MO, metric stars after reaction of the growing living
and LS revealed that well-defined structures were branches A′ with suitable electrophilic compounds.
obtained. Using this method asymmetric stars of the type
The method was also applied in the synthesis of (PSA)n(PSB)n were prepared.77 Living PS chains were
asymmetric PBd75 and PI76 stars. When the molec- obtained by s-BuLi initiation and reacted with a
ular weight of the PI chain that was reacted with the small amount of DVB to give a living star polymer.
excess silane was less than 5.5 × 103, the formation The anionic sites of the star core were subsequently
of the coupled byproduct could not be avoided, due used to initiate the polymerization of a new quantity
to the low steric hindrance of the living PI chain end. of styrene. This initiation step was accelerated by the
The byproduct was removed by fractionation. The addition of a small quantity of THF. It was revealed
stars were characterized by SEC, MO, and LS, by SEC analysis that high molecular weight species
showing that the desired structures having low were also present, probably due to the formation of
polydispersities were efficiently prepared. linked stars. These structures can be obtained when
ii. Divinylbenzene Method. As already dis- living anionic branches of one star react with the
cussed, when appropriate living polymer chains react residual double bonds of the DVB-linked core of
with a small amount of DVB, a star polymer is another star.
formed consisting of a highly cross-linked polydi- iii. Diphenylethylene Derivative Method. The
vinylbenzene core from which the arms emanate. method is based on the use of 1,1-diphenylethylene
This is actually a living star since the core carries derivatives that are nonhomopolymerizable mono-
anionic centers. The number of these active sites is mers. Rich chemistry was developed, leading to the
theoretically equal to the number of the arms of the formation of several types of asymmetric stars. Quirk
star. Subsequent addition of a new monomer results reacted living PS chains with either 1,3-bis(1-phenyl-
in the growth of new arms from the core and ethenyl)benzene, (MDDPE) or 1,4-bis(1-phenyleth-
therefore the formation of an asymmetric star of the enyl)benzene (PDDPE), according to Scheme 24.
type AnA′n can be achieved, if the molecular weight
Scheme 24
of the original chains is different than that obtained
by the chains formed in the second step. This general
procedure is depicted in Scheme 23.
Scheme 23
Scheme 25 Scheme 27
Scheme 28 Scheme 29
vacuum technique was employed to ensure the for- the polymers were hydrogenated, transforming the
mation of products that are characterized by high PI branches to poly(ethylene-alt-propylene) and the
degrees of chemical and compositional homogeneity. d-PBd to partially deuterated polyethylene.
This was tested using several techniques such as Miktoarm stars of the general type B(A-b-B)2,
SEC, MO, LS, differential refractometry, and NMR where A is PI and B is PS, were prepared,96 according
spectroscopy. to Scheme 36. The living PI arm was reacted with
In a more recent study, a series of (d-PS)(PI)2 stars,
where d-PS is deuterated PS, was prepared by the Scheme 36
same technique.93 No difference was obseved by using
the deuterated arm compared to the PS(PI)2 stars.
A similar study concerning the synthesis of (d-PBd)-
(PBd)2 stars containing a deuterated PBd arm was
also reported.94 Both kinds of arms have almost the
same molecular weight, and consequently, the only
difference was that one of them was labeled with
deuterium.
Miktoarm stars of the type (d-PBd)(PI)2 and PI(d-
PBd)2 were synthesized according to the reaction
Schemes 34 and 35, respectively.95 A different ap- an excess of the linking agent to give the dichloro
end-capped macromolecular linking agent followed,
Scheme 34
after the removal of the excess silane, by the addition
of the living diblock copolymer PS-b-PILi. The char-
acterization data showed that polymers of high
chemical and compositional homogeneity were formed.
Very recently the development of the controlled
anionic polymerization of hexamethylcyclotrisiloxane
(D3) led to the synthesis of a PDMS(PS)2 miktoarm
star,97 according to Scheme 37. A benzene:THF (50:
50 v/v) solution of the living PDMS arm was added
proach was adopted for the synthesis of the (d-PBd)- Scheme 37
(PI)2 star. Instead of incorporating the different arm
first (d-PBd in this case), the two living PI chains
were reacted with methyltrichlorosilane in a stoichio-
metric ratio of 2:1. To avoid the formation of the
three-arm PI star, the living PI chains were end-
capped with a few units of styrene to increase the
steric hindrance of the living end. In the case of the
PI(d-PBd)2 star, the more common procedure was
adopted. The living PI arm was reacted first with the
linking agent. Due to the low molecular weight of the
PI chain and the reduced steric hindrance of its living
end, the polymer was end-capped with one unit of
DPE. This method proved to be efficient to avoid the
formation of coupled byproducts. Well-defined stars
were obtained in both cases, as revealed by extensive
molecular characterization results. In the final step
Scheme 35
Complex Polymers by Living Anionic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3763
slowly into a large excess of methyltrichlorosilane, deuterated [(d-PBd)(PBd)3].94 The product was stud-
leading to the formation of the monoadduct product. ied by SEC, MO, and LS.
The macromolecular linking reagent thus formed was As in the case of the B(A-b-B)2 stars, the B(A-b-
then reacted with living PS chains that were previ- B)3 structures were also prepared, A being PI and B
ously end-capped with D3. This capping reaction was being PS.96 SiCl4 was the linking agent in that case,
necessary to avoid the backbiting side reactions of and well-defined polymers were also obtained.
the very reactive PSLi anion to the PDMS arm and A different strategy was applied by Tsiang for the
to facilitate the linking. THF was also added to synthesis of (A-b-B)B3 stars, where A is PS and B is
accelerate the linking reaction. PBd.100 The living chains B were reacted with the
A different approach was adopted by Eisenberg et SiCl4 in a molar ratio 3:1, followed by the addition of
al.98 for the synthesis of P2VP(PS)2 miktoarm stars, the living A-b-B chains. However, the control of the
where P2VP is poly(2-vinylpyridine). Methyldichloro- first step was rather limited, since not only the
silane (CH3SiCl2H) was used as linking agent to desired B3SiCl but also the byproducts B2SiCl4 and
produce the two-arm PS star. Living P2VP was B4Si were formed. This behavior was observed due
reacted with allyl bromide to give an end-function- to the absence of steric hindrance of the living PBd
alized polymer carrying a terminal vinyl group. In chain end. It is obvious that this method is very
the last step a hydrosilylation reaction of the Si-H demanding regarding the stoichiometric control of the
group of the two-arm star with the end-double bond reagents. It seems more appropriate in this case to
of the P2VP chain produced the desired structure incorporate the living A-b-B arm first and then to add
(Scheme 38). Rather high molecular weight distribu- the other three arms.
iii. AnB (n > 3) Miktoarm Star Copolymers.
Scheme 38 The synthesis of PSPI5 miktoarm stars101 was ac-
complished by the reaction sequence outlined in
Scheme 40. Living PS was reacted with the hexafunc-
Scheme 40
Scheme 43
The order of linking of the various arms to the was deuterated polystyrene (dPS). The higher mo-
linking agent is crucial for the success of the synthe- lecular weight PI branch was introduced first, fol-
sis. The less sterically hindered chain end, namely lowed by the slow stoichiometric addition (titration)
the PBdLi, has to be incorporated last, whereas the of the living dPS chains. The lower molecular weight
most sterically hindered, namely the PSLi, at the PI branch was incorporated at the end of the proce-
titration step. Extensive characterization data for the dure.
arms, the intermediate, and the final product con- A different approach was employed for the syn-
firmed that the ABC star was characterized by high thesis of (PI)(PS)(PMMA) miktoarm star terpoly-
structural and compositional homogeneity. mers,111,112 as outlined in Scheme 45. It is well-known
The same methodology was adopted for the syn- that the reaction between living PMMA chains with
thesis of the (PS)(PI)(P2VP) miktoarm star terpoly- Si-Cl bonds fails to give the linked product. There-
mer.109 The monofunctional linking agent (PI)(PS)- fore, after the monofunctional macromolecular link-
Si(CH3)Cl was synthesized in benzene solution. ing agent (PI)(PS)Si(CH3)Cl was formed, it was
Benzene was then evaporated and the linking agent reacted with a dilute solution containing a stoichio-
was dissolved in THF, followed by the addition of the metric amount of a difunctional initiator, synthesized
living P2VPLi chains, prepared in THF at -78 °C. by the reaction between DPE and Li. According to
The linking was conducted at -78 °C to avoid side this procedure, one of the active centers of the
reactions with the living P2VP chains. Well-defined difunctional initiator was linked to the remaining Si-
stars were prepared as shown by the extensive Cl bond, whereas the other one was used to initiate
molecular weight characterization data given in this the polymerization of MMA, resulting in the forma-
study. tion of the desired product. It is obvious that the
A (PI)(PS)(PDMS) miktoarm star terpolymer was PMMA branches cannot be isolated and character-
synthesized by the same method.97 The (PI)(PS)Si- ized independently. This method is very demanding,
(CH3)Cl macromolecular linking agent was prepared and extreme care has to be taken for the control of
as previously mentioned, followed by the addition of the different reaction steps. It was found that during
the living PDMSLi chains to give the desired product. the synthesis of the difunctional initiator a large
Also in this case a well-defined polymer with narrow amount of the monofunctional byproduct (as high as
molecular weight distribution was obtained. ∼30%) was also obtained. This byproduct does not
The same route was adopted for the synthesis of interfere with the synthesis of the ABC star, since it
asymmetric AA′B star polymers.110 The two A arms reacts with the macromolecular linking agent (PI)-
were PIs having different molecular weights, and B (PS)Si(CH3)Cl to give the terminated PS-b-PI diblock,
3766 Chemical Reviews, 2001, Vol. 101, No. 12 Hadjichristidis et al.
which can be removed by fractionation. Nevertheless, rene was initiated with s-BuLi, except in the case of
it reduces the yield of the desired product and makes the PSnPEOn stars, where cumyl potassium was used.
the control of its composition more difficult. Despite After the formation of the living PS star the SEC
these difficulties, well-defined structures were ob- analysis showed that a considerable part (as high as
tained. 15%) of the PS chains was not incorporated in the
vi. ABCD Miktoarm Star Quaterpolymers. star structure, mainly due to accidental deactivation.
Only one example of the synthesis of ABCD mikto- When the second monomer was a (meth)acrylate, the
arm star quaterpolymers is reported in the litera- active sites were first capped with one unit of DPE
ture.104 It consists of four different arms, PS, PI, PBd, to reduce their nucleophilicity. The final stars usually
and poly(4-methylstyrene) (P4MeS). A step by step had n values between 4 and 20.
incorporation of the branches was adopted in this An important feature of this method is that the
case, as shown in Scheme 46. The synthetic proce- second-generation branches growing from the living
core are living and therefore are susceptible to end-
Scheme 46
functionalization reactions or can be potentially used
to initiate the polymerization of another monomer,
leading to the formation of a An(B-b-C)n structure.
All the drawbacks of the method reported earlier in
the discussion concerning the asymmetric stars and
the use of DVB as a multifunctional initiator apply
in this case as well. The poor control over the
structural parameters (n values, composition, molec-
ular weights of the B chains), the inability to inde-
pendently characterize the B arms, and the existence
of a distribution in the number of arms within the
same sample indicate that the products have rather
dure involved two titration steps. Therefore, the order poor molecular and compositional homogeneity.
of linking of the different branches plays an essential 3. Diphenylethylene Derivative Method
role in controlling the reaction sequence. PS was
chosen to react first with an excess of SiCl4, followed The DPE derivative methods are based on the
after the evaporation of the excess silane by the slow procedures developed by Quirk and Hirao, as was
stoichiometric addition of the living P4MeS chains previously reported in the case of the asymmetric
in order to form the difunctional linking agent (PS)- stars. The first procedure relies on the use of either
(P4MeS)SiCl2. A second titration step was then 1,3-bis(1-phenylethenyl)benzene (MDDPE) or 1,4-bis-
performed with the addition of the living PI chains (1-phenylethenyl)benzene (PDDPE), whereas the sec-
to form the monofunctional linking agent (PS)- ond relies on the formation of macromonomers car-
(P4MeS)(PI)SiCl. The fourth arm, namely PBdLi, was rying DPE end groups with methoxymethyl moieties
added in the last step to give the desired product. that can be transformed to chloromethyl groups.
Complete linking was observed in all the reaction Other specific methods have also been developed
steps by SEC. Combined characterization results utilizing DPE derivatives for the synthesis of mik-
from several methods revealed that a well-defined toarm stars. The discussion given in the case of the
star was produced. asymmetric stars concerning the advantages and
limitations of the methods apply here as well. The
2. Divinylbenzene Method recent achievements using this methodology will be
The DVB method can be applied for the synthesis presented in the following paragraphs.
of miktoarm stars of the type AnBn in a similar i. A2B Miktoarm Star Copolymers. A2B mikto-
manner as in the case of the asymmetric AnA′n stars. arm stars, where A is PS and B is PI or PtBuMA,
It is a three-step procedure starting from the syn- were synthesized by Hirao et al.116,117 according to
thesis of the living chains A. These living chains the reaction in Scheme 47. Living PS chains were
initiate the polymerization of a small quantity of reacted with a 1.2-fold excess of 1,1-[bis(3-methoxy-
DVB, leading to the formation of a living star polymer methylphenyl)]ethylene in THF at -78 °C for 1 h.
carrying within its core a number of active sites equal Only the monoadduct product was obtained under
to the number of arms that have contributed to its these conditions. The end-methoxymethyl groups
formation. During the third step, these active sites were then transformed to chloromethyl moieties by
are used to polymerize the monomer B, thus produc- reaction with BCl3 in CH2Cl2 at 0 °C for 2 h. NMR
ing the miktoarm star AnBn. studies showed that this transformation reaction goes
This method for the synthesis of miktoarm stars to completion. The macromolecular linking agent was
was first reported by Funke17,18 and then extended then carefully purified by repeated precipitation and
and improved by Rempp et al.10 In all cases published freeze-drying from benzene solution and then reacted
in the literature, the A arms are PS chains, whereas with living PILi or PtBuMALi chains to give the
a variety of B chains has been used such as desired products. A small amount (5%) of the dimeric
PtBuMA, PtBuA, PEO, P2VP, and PEMA58,113-115. product was observed by SEC analysis. It was
Special care was given to the synthesis of amphiphilic proposed that this byproduct is obtained by the Li-
stars carrying both hydrophobic and either cationic Cl exchange and/or electron transfer reactions. SEC
or anionic branches. The polymerization of the sty- and NMR methods have been only used for the
Complex Polymers by Living Anionic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3767
Scheme 47 Scheme 48
Scheme 51
Complex Polymers by Living Anionic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3769
Scheme 53
was shown that this methodology is very powerful product was isolated by silica gel thin-layer chroma-
with respect to the variety of structures that can be tography. The epoxide group was then hydrolyzed
obtained, and it offers the possibility to prepare even under acidic conditions to give the ω-dihydroxyl-
more complex products. However, this multistep functionalized PS. The pure product was obtained by
procedure is time-consuming and extra care is needed silica gel chromatography. The hydroxyl groups were
to avoid the presence of side reactions. The formation reacted with cesium metal in THF at room temper-
of byproducts was minimized by the choice of reaction ature for 5 h to give the cesium alkoxides, which were
conditions, leading to the formation of well-defined subsequently used as initiators for the polymerization
products. The exclusive use of low molecular weight of propylene oxide. The crude product contained 36
arms poses questions about the efficiency of the wt % of the desired PS(PPO)2 star and 64 wt % of
method when higher molecular weight arms, having PPO homopolymer, as a result of chain transfer to
more sterically hindered chain ends, are used. the PPO monomer. The homopolymer was removed
by fractionation in a methanol/water mixture. Only
4. Synthesis of Miktoarm Stars by Other Methods SEC and 1H NMR analysis were given, making it
difficult to prove that the final product contains two
Several other specific methods have been reported equal PPO arms.
in the literature for the synthesis of miktoarm stars. Star polymers carrying one poly(2-vinylnaphtha-
Usually they do not have general applicability, but lene) (PVN) and several PS arms were prepared by
most of them lead to products that cannot easily be Takano et al.127 according to Scheme 57. (4-Vinyl-
obtained by the more general methods described
earlier. Therefore, these techniques are valuable tools Scheme 57
in polymer synthesis.
A miktoarm star copolymer carrying one PS arm
and two poly(propylene oxide) arms126 was prepared
by the method given in Scheme 56. Living PS chains
were end-capped with one unit of DPE, to reduce the
reactivity of the chain end, followed by the addition
of epichlorohydrin to produce the epoxide function-
alized polymer. It was shown by SEC analysis and
chemical titration that the epoxide content of the
final product was 95 wt %. The desired functionalized
Scheme 56
59). The PBd backbones were synthesized by anionic PS, PS-g-PI, and PS-g-PMMA comb-shaped polymers
polymerization in benzene, resulting in PBds with with well-defined molecular characteristics (Scheme
high 1,4-addition (1,2-addition was lower than 10%). 61). The PS-g-PMMA graft copolymers were found
Postpolymerization catalytic hydrosilylation using to decompose in proton-containing media, while they
(CH3)2SiHCl was used for introduction of chlorosilane were stable in organic solvents.
groups, preferentially at the 1,2-double bonds. Fi- Anionically prepared and subsequently hydro-
nally, a linking reaction between living polystyrene silylated PBds were also used for the formation of
anions and the Si-Cl groups of the PBd backbone PBd-g-poly(sodium methacrylate) graft copolymers.134
gave poly(Bd-g-S) graft copolymers with randomly The precursors were PBd-g-poly(tert-butyl meth-
placed single PS branches. When HSiCl2CH3 was acrylate) graft copolymers. These were prepared by
used in the hydrosilylation step, difunctional branch- reaction of the hydrosilylated PBd backbone with
ing sites were introduced in the backbone. Subse- living PtBuMA anions end capped with tert-butyl
quent reaction with excess PSLi afforded graft co- 4-vinylbenzoate. This modification of the living end
polymers with randomly distributed double PS proved to be necessary, since in this way the expected
branches (PBd-g-PS2). Characterization of the final C-silylation stable product is obtained instead of the
products showed that they possessed a high degree O-silylated one, when uncapped living PtBuMA is
of molecular weight and compositional homogeneity. used. Hydrolysis of the graft copolymers followed by
By the same synthetic scheme, PBd comb polymers neutralization with sodium hydroxide yielded the
were prepared, and after catalytic hydrogenation, amphiphilic analogues.
well-defined graft polyethylenes were obtained132 Ruckenstein and Zhang presented the synthesis of
(Scheme 60). amphiphilic graft copolymers with poly(methacrylic
acid) hydrophilic backbones and hydrophobic PS side
Scheme 60 chains.135 The precursors of the backbones were
random copolymers of 1-(ethoxy)ethyl methacrylate
(EEMA) and glycidyl methacrylate (GMA) prepared
by anionic copolymerization of the two monomers.
These copolymers had narrow molecular weight and
composition polydispersities as well as predetermined
molecular weights and compositions. The amount of
GMA in the copolymers determines the number of
grafting sites in the backbone, and it was kept low
Ruckenstein and Zhang reported that the anionic
in all cases. In the next step a predetermined amount
copolymerization of 4-(vinylphenyl)-1-butene with
of a solution of living PSLi was added to the solution
styrene in toluene/THF at -40 °C gives well-defined
of the living backbone, resulting in a rapid reaction
polymers,133 since under these experimental condi-
between PSLi active chain ends and the epoxy groups
tions the vinylic double bond is selectively polymer-
of GMA in the backbone. Unreacted epoxy groups
ized. The copolymers were subjected to hydrosilyl-
were neutralized by 1,1-diphenylhexyllithium. The
ation for the introduction of Si-Cl groups at the
final graft copolymers had relatively narrow molec-
olefinic double bonds. These groups were used as
grafting sites for the linking of PSLi, PILi, and
Scheme 62
PMMALi living chains in order to synthesize PS-g-
Scheme 61
Complex Polymers by Living Anionic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3773
ular weight distributions. The EEMA units were then pared by reaction of poly(m-bromomethylstyrene)
subjected to hydrolysis, and the desired amphiphilic with PSLi end-capped with DPE.
comblike copolymers were obtained (Scheme 62). It Partially chloromethylated or bromomethylated
is characteristic that no excess of PSLi was used in anionically prepared polystyrenes have been used for
this work, introducing another way of controlling the the preparation of several graft copolymers contain-
number of grafted chains per backbone through ing PS backbones and PI,43 P2VP,45,139 P4VP,140
control of the stoichiometry between potential graft- PtBuMA,45 and PEO141,142 branches. Some of these
ing sites and number of living side chains. copolymers are precursors for amphiphilic graft
Using the same methodology, PMMA-g-PS and copolymers (Scheme 64).
poly(allyl methacrylate)-g-Ps graft copolymers were Scheme 64
prepared.136 In all cases GMA was anionically co-
polymerized with the appropriate methacrylic mono-
mer in order to produce the backbone of the graft. In
the case of poly(allyl methacrylate)-g-PS, the allylic
groups of allyl methacrylate were converted to hy-
droxyl groups by hydroboration-oxidation reaction,
giving amphiphilic graft copolymers with hydrophilic
backbones and hydrophobic branches. Reaction of
GMA homopolymers with a PSLi, PILi, and PSLi/
PILi mixture resulted in the formation of PGMA-g-
PS, PGMA-g-PI, and PGMA-g-(PS,PI) graft copoly-
mers.137
Hirao and Ryu synthesized PS graft copolymers
with one side chain in almost every monomeric
unit.138 They used anionically synthesized poly (m-
(tert-butyldimethylsilyl)oxystyrene)s as precursors
for the preparation of m-halomethylstyrenes by reac- Watanabe et al. reported the synthesis of P2VP-
tion with BCl3, (CH3)SiCl/LiBr, and (CH3)SiCl/NaI g-PS and P2VP-g-PI copolymers.143 The P2VPs used
for the introduction of Cl, Br, and I, respectively. The as the backbones were prepared by anionic poly-
transformation reactions were quantitative. The halo- merization. After thorough purification for complete
methylstyrenes, having well-defined molecular weights removal of terminating impurities, these homopoly-
and low molecular weight polydispersities, were mers were directly reacted with living PILi and PILi
subsequently used as backbones for the preparation to give the desired graft copolymers (Scheme 65). The
of comb-shaped polymers. Reaction of the highly final products had narrow molecular weight distribu-
reactive benzyl halides with living PSLi chains in tions. No grafting was observed when the side chains
THF gave the aforementioned PS combs (Scheme 63). were end-capped with DPE.
The final products, isolated after fractionation, were
similar in respect to their molecular characteristics Scheme 65
with the polymer obtained when living PSLi was
coupled with poly(m-chloromethylstyrene) at -78 °C
or diphenylethylene-capped PSLi at -40 °C. Reaction
times were shorter in the former case, due to the
higher reactivity of PSLi. PS combs were also pre-
Scheme 63
B. “Grafting From”
In the “grafting from” method, after the prepara-
tion of the backbone, active sites are produced along
the main chain that are able to initiate the poly-
merization of the second monomer(s). Polymerization
of the second monomer results in the formation of
branches and the final graft copolymer. The number
of branches can be controlled by the number of active
sites generated along the backbone, assuming that
each one of them initiates the formation of one
branch. Obviously, the isolation and characterization
of each part of the graft copolymer in this case is
almost always impossible. Knowledge of precursor
molecular characteristics is limited to the backbone.
Isolation of the branches can be achieved only in
some cases and usually involves selective chemical
decomposition of the backbone, e.g., ozonolysis of
polydiene backbone in poly(diene-g-styrene) graft
copolymers.133 Following this methodology, several
3774 Chemical Reviews, 2001, Vol. 101, No. 12 Hadjichristidis et al.
graft copolymers were synthesized by the use of mers are oligomeric or polymeric chains that have a
anionic polymerization. polymerizable end group. In this case, the macro-
Anionic active sites can be generated by metalation monomer comprises the branch of the copolymer and
of allylic, benzylic, or aromatic C-H bonds, present the backbone is formed in situ. The number of
in the backbone, by organometallic compounds, such branches per backbone can be generally controlled
as s-BuLi, in the presence of strong chelating agents by the ratio of the molar concentrations of the
that facilitate the reaction. The metalation of poly- macromonomer and the comonomer. Several other
dienes with s-BuLi in the presence of N,N,N′,N′- factors have to be considered. Among them the most
tetramethylethylenediamine (TMEDA) presents a important one is the copolymerization behavior of the
representative example.144-146 macromonomer and the comonomer forming the
Metalation of PI and PBd by this procedure and backbone. Depending on the reactivity ratios, r1 and
subsequent polymerization of styrene led to the r2, of the reacting species, different degree of ran-
formation of PI-g-PS and PBd-g-PS copolymers with domness can be achieved, with respect to the place-
well-defined molecular characteristics144-148 (Scheme ment of the branches. Since macromonomer and
66). comonomer incorporation in the graft copolymer can
vary in the course of the copolymerization reaction
Scheme 66 due to changes in the concentration of the two
compounds in the mixture, different kinds of graft
copolymers are formed as a function of time. Phase
separation can also occur in these systems, due to
the formation of the copolymers, leading to increased
compositional and molecular weight heterogeneity of
the final product.
PS macromonomer formation by anionic polymer-
ization has been described in several cases.150-153 In
one of them styrene was polymerized by s-BuLi, and
In another approach, PMMA-g-poly(β-butyrolac- once the monomer has been consumed completely, a
tone) copolymers were synthesized using the “graft- slight excess of ethylene oxide was added.150 The
ing from” technique.149 Anionically polymerized PMMA oxirane end-capped living polymer is then reacted
was treated with the 18-crown-6 complex of potas- with methacryloyl chloride to give a PS macromono-
sium hydroxide in toluene, resulting in an macro- mer with a methacrylate type polymerizable end unit.
molecular initiator (Scheme 67). The average number If the oxirane end-capped living polymer is reacted
with benzyl bromide (or chloride), PS macromonomer
Scheme 67 with a styrenic polymerizable end unit is produced.
Alternatively, living PS was end-capped with 1,1-
diphenylethylene and then reacted with vinyl benzyl
bromide (chloride). In a similar way, living PMMALi
anions can be end-capped with methacryloyl chloride
or vinyl benzyl bromide (chloride) by direct reaction.
These macromonomers were used, after complete
removal of protonic impurities, in subsequent anionic
copolymerization with MMA or styrene to give the
corresponding PMMA-g-PMMA, PMMA-g-PS, and
PS-g-PS comb-shaped polymers (Scheme 68). Direct
polymerization of the macromonomers results in the
formation of polymacromonomers, i.e., graft copoly-
mers with a side chain on every backbone mono-
of grafting sites per macroinitiator was determined mer.154
by reaction of the modified PMMA with benzyl Graft copolymers of St and Is, with trifunctional
bromide and subsequent characterization of the or tetrafunctional branching points, situated equi-
copolymer. The carboxylate active groups formed
were used as initiating sites for the anionic poly- Scheme 68
merization of β-butyrolactone in THF at room tem-
perature. The grafting process was followed by 1H
NMR and the final copolymers, obtained after ter-
mination with methyl iodide, were characterized by
SEC, VPO, and NMR. The grafting efficiency was
determined to be high and the density of the grafting
sites could be controlled easily.
C. “Grafting Through”
In the grafting through method, preformed macro-
monomers are copolymerized with another monomer
in order to produce the graft copolymer. Macromono-
Complex Polymers by Living Anionic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3775
Scheme 69 Scheme 70
Scheme 72
temperature in THF using cumylcesium as initiator Ruckenstein et al. reported the preparation of
followed by the addition of styrene. Living PILi was PMMA-b-(PGMA-g-PS) and PMMA-b-(PGMA-g-PI)
then allowed to react with the vinylsilyl groups of block-graft copolymers, where PGMA is poly(glycidyl
the VS block, giving the final graft copolymer (Scheme methacrylate).137 The PMMA-b-PGMA diblock was
71). Detailed characterization of the polymers ob- obtained first by anionic polymerization through
tained by SEC, osmometry, and ultracentrifugation sequential addition of monomers. Then living PSLi
techniques proved their high molecular weight and and PILi chains were linked to the diblock backbone
compositional homogeneity, as well as their desired by reaction with the glycidyl groups of the GMA
architecture. block. Molecular characterization of the final prod-
ucts confirmed the intended architecture and rela-
The synthesis of block-graft copolymer containing
tively narrow molecular weight distributions.
styrene, hydroxystyrene, and ethylene oxide of the
types PS-b-(PHS-g-PEO) and PS-b-(PHS-g-PEO)-b-
PS, where PHS is poly(p-hydroxystyrene), has been V. r,ω-Branched Architectures
reported.158 The ABA triblock copolymer comprising
the backbone was synthesized by a three-step se- By the use of anionic polymerization and controlled
quential addition of monomers i.e., styrene and p-tert- chlorosilane chemistry, the exact placement of the
butoxystyrene (the precursor to hydroxystyrene). The side chains along the backbone is possible. Using this
PBS blocks were converted to poly(p-hydroxystyrene), combination, H- and super-H-shaped copolymers
by reaction with hydrogen bromide. The OH groups were synthesized. In the case of H-shaped copoly-
thus formed were transformed to potassium alkoxide mers,159 living PSLi and MeSiCl3 were reacted in a
groups by reaction with cumyl potassium or 1,1- ratio SiCl:Li ) 3:2.1. Due to the sterically hindered
diphenylethylene potassium. The resulting macro- PSLi anion, only two Cl atoms were substituted,
molecular initiators were used for the polymerization resulting in a PS dimer having an active Si-Cl bond
of EO, forming the branches of the block-graft-block at the center. The macromolecular linking agent was
copolymers (Scheme 72). Molecular characterization reacted with a difunctional PI chain (the connector),
of the products by SEC and osmometry indicated that synthesized using the difunctional initiator derived
they possessed narrow molecular weight distributions from MDDPE and s-BuLi in benzene solution and in
and predictable molecular weights and compositions. the presence of lithium-tert-butoxide, giving the
Complex Polymers by Living Anionic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3777
Scheme 73 Scheme 76
Scheme 77
Scheme 78 Scheme 79
Scheme 80
Pi ) (3/2π)3/2ve/〈r2〉3/2
Pe ) (NAc/M)ve
light scattering, and this was attributed to the lower
where NA is Avogadro’s number, c the concentration hydrodynamic volume that is expected for a cyclic
of the polymer, and M the molecular weight. The polymer when compared to the corresponding linear
concentration at which the intra- and intermolecular material.
reaction are equally likely is given by Roovers et al.169 synthesized cyclic PS under high-
vacuum conditions by using naphthalene sodium as
cequal ) [(3/2π)/〈r2〉]3/2M/NA a difunctional initiator. The polymerization solvent
was a mixture of THF:benzene in a ratio of 1:1 (v/v).
This equation shows that (a) the more dilute the The linking agent was dichlorodimethylsilane, and
polymer solution, the more probable the cyclization the linking reaction was performed in cyclohexane
over the polycondensation is, and (b) at the same at room temperature, which is close to θ conditions
molecular weight, double the concentration (higher for PS (Scheme 82). Although the procedure has been
yield) can be used for heterodifunctional than for questioned by some authors due to the higher pos-
homodifunctional polymers. The practical strategies sibility of forming permanent “knots”, no clear evi-
used for the preparation of cyclic copolymers will be dence of this conjecture has been forthcoming. Roovers
presented below. synthesized a series of cyclic PSs having molecular
weights (2.0-55) × 104 g/mol. The separation of the
A. Cyclic Homopolymers from Precursors with Scheme 82
Homodifunctional Groups
Many different linking agents and functional groups
have been proposed for the synthesis of cyclic poly-
mers using homodifunctional groups. However, the
general strategy followed by most authors is similar
and can be outlined as follows:
(a) preparation of a monodisperse R,ω-homodifunc-
tional living polymer,
(b) reaction of the living polymer with a homodi-
functional linking agent,
and (c) fractionation for purification of the cyclic
polymer.
In all cases a high dilution of the linking reaction
was used in order to increase the yield of cyclization.
1. Cyclic Homopolymers
Hild et al.168 prepared ring polystyrenes under
argon atmosphere by reacting R,ω-dipotassium poly-
styrene, synthesized by potassium naphthalenide,
with dibromo-p-xylene in a mixture of THF:benzene
or cyclohexene in a ratio 1:1 (v/v) (Scheme 81). The
addition of the reagents was made by using two
dropping funnels. After fractional precipitation, the
yield of the synthetic procedure was between 30%
and 46%. The apparent molecular weight obtained
by SEC was about 20% lower than that obtained by
Complex Polymers by Living Anionic Polymerization Chemical Reviews, 2001, Vol. 101, No. 12 3781
Scheme 83 Scheme 85
Scheme 86 Scheme 88
Scheme 90
al.175,176 Styrene was polymerized by lithium naph- under high dilution conditions (Scheme 86). The
thalenide initiator at -78 °C in THF, followed by the purity of the cyclic copolymers was investigated by
polymerization of hexamethylcyclotrisiloxane (D3). 1H NMR, 29Si NMR, and FTIR. The lack of SiOH or
The resulting R,ω-living triblock PDMS-PS-PDMS SiCl groups in the final copolymers was a direct
was cyclized with dichlorodimethylsilane at 5-10 °C indication of the high purity of the cyclics. However,
due to the backbiting reaction of the living PDMS
Scheme 91 under the conditions used for the cyclization reaction,
the quality of the cyclics is questionable. In the same
Scheme 92
3784 Chemical Reviews, 2001, Vol. 101, No. 12 Hadjichristidis et al.
Scheme 95
The smaller the ring fraction in the copolymer, the tion reaction was performed in a 0.5% solution of
more difficult the separation. Insufficient character- linear precursor by using 1,2-bis(methyldichlorosilyl)-
ization results were given. ethane (Scheme 92). Although the final product was
Antonietti et al.183 synthesized bicyclic PS homo- proved to have double the molecular weight, suf-
polymers. They prepared difunctional PS initiated by ficient characterization results to prove the architec-
sodium naphthalene in THF at -40 °C. The cycliza- tures claimed were not presented.
3786 Chemical Reviews, 2001, Vol. 101, No. 12 Hadjichristidis et al.
Scheme 97
the presence of cyclic PS. The polymerization of techniques for synthesizing polymers with well-
2-vinylpyridine was performed in THF by using defined molecular characteristics and the more dif-
lithium naphthalenide as initiator. The cyclization ficult to characterize them. Many synthetic ap-
reaction was performed at room temperature at proaches have been presented for the preparation of
relatively high concentration of cyclic PS in order to hyperbranched polymers, mainly by polycondensa-
increase the possibility of the formation of catenanes tion reactions.191,192 In most cases the resulting
(Scheme 96). The catenanes were isolated from the polymers exhibited high molecular and compositional
side products and cyclic PS homopolymer by treating polydispersity, and their molecular architectures
the crude product with cyclohexane, which is a poor could not be exactly defined. Even so, their properties
solvent for P2VP, and methanol, which is poor solvent were very interesting, and therefore these polymers
for PS. Indications for the formation of the catenanes can be used in many technological applications. Here
were obtained only by NMR spectroscopy. several synthetic approaches to the synthesis of
hyperbranched polymers by anionic polymerization
VII. Hyperbranched Architectures will be presented.
Branched polymers have physical properties dis- Gauthier et al.193 prepared highly branched ar-
tinct from their linear analogues, both in solution and borescent graft copolymers of PS and poly(ethylene
in the melt. However, the more complicated the oxide). Their synthetic approach involved the reaction
structure, the more difficult the development of of living PS end-capped with DPE with chlorometh-
3788 Chemical Reviews, 2001, Vol. 101, No. 12 Hadjichristidis et al.
Scheme 100
1,2-PBd block is short, followed by coupling with an mediate polymers was performed by SEC and static
appropriate chlorosilane linking agent, depending on light scattering. It was found that an average number
the desired number of arms. After isolation of the star of 29 arms of poly(R-methylstyrene) was attached to
by fractional precipitation, the double bonds of the each initial poly(4-methylstyrene) block. The intrinsic
1,2-PBd were hydrosilylated in order to incorporate viscosity of the hyperbranched copolymers was meas-
-Si(CH3)Cl2 or -Si(CH3)Cl, followed by reaction with ured, and the g′ values were calculated.
living PBd or P2VP chains (Scheme 98). Recently Hasan et al.195 synthesized hyperbranched
Ishizu et al.194 synthesized hyperbranched macro- copolymers by using a dendritic type initiator. Low
molecules that resemble dendrimers. The synthetic molecular weight living PS chains were reacted with
approach involved the preparation of poly(4-methyl- a mixture of vinylbenzyl chloride or 4-(chlorodimeth-
styrene-b-PS-b-poly(4-methylstyrene) triblock copoly- ylsilyl)styrene and styrene in a molar ratio 1:10. The
mer by using naphthalene lithium as difunctional living ends of polystyrene chains can polymerize the
initiator. The 4-methyl groups of the terminal blocks styrene monomer and at the same time can react
were metalated with s-BuLi/tetramethylethylenedi- with the -SiCl or -CH2Cl group of the or 4-(chloro-
amine (TMEDA) complex in a molar ratio of 1:2. After dimethylsilyl)styrene or vinylbenzyl chloride, as shown
removal of the excess s-BuLi by repeated precipita- in Scheme 100. A dendritic type initiator is obtained
tion of the living polymer and transfer of supernatant for polymerization of either styrene or isoprene. The
solution to another flask under high vacuum condi- weak point of this approach is that the positions of
tions, the polymer was dissolved in THF and was the grafting points of the macromolecular initiator
used as the initiator of R-methylstyrene at -78 °C. are randomly distributed along the PS chains. More-
After the polymerization of R-methylstyrene, a small over, the number of the linear PS or PI chains cannot
amount of 4-methylstyrene was added. The procedure be controlled. The molecular weight of the resulting
of metalation of the R-methyl groups and polymeri- polymer was characterized by SEC coupled with
zation of R-methylstyrene can be repeated many multiangle laser light scattering. In the case of the
times to form a dendritic type hyperbranched poly- copolymers, the composition was determined by 1H
mer (Scheme 99). The characterization of the inter- NMR.
3790 Chemical Reviews, 2001, Vol. 101, No. 12 Hadjichristidis et al.
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