Chem 201804225

DOI: 10.1002/chem.
201804225 Review
& Materials Science
Nonconjugated Hydrocarbons as Rigid-Linear Motifs: Isosteres for

Material Sciences and Bioorganic and Medicinal Chemistry
Gemma M. Locke, Stefan S. R. Bernhard, and Mathias O. Senge*[a]
Dedicated to Professor Philip E. Eaton
Chem. Eur. J. 2019, 25, 4590 – 4647 4590 T 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Review
Abstract: Nonconjugated hydrocarbons, like bicyclo[1.1.1]- manner. In this Review article, recent developments and
pentane, bicyclo[2.2.2]octane, triptycene, and cubane are a usages of these special, rectilinear systems are discussed.
unique class of rigid linkers. Due to their similarity in size Furthermore, we focus on covalently linked, nonconjugated
and shape they are useful mimics of classic benzene moie- linear arrangements and discuss the physical and chemical
ties in drugs, so-called bioisosteres. Moreover, they also fulfill properties and differences of individual linkers, as well as
an important role in material sciences as linear linkers, in their application in material and medicinal sciences.
order to arrange various functionalities in a defined spatial
1. Introduction cyclo[2.2.2]octane (BCO) and triptycene (Figure 1). In particular,

the use of triptycene as a molecular rotor has received much
Arranging functionalities in a linear fashion enables the altera- interest, propelled by the Nobel prize in chemistry for molecu-
tion of the distance between functionalities without affecting lar machines awarded in 2016.[4]
the overall geometry of the molecule, and this is of high im- This Review aims at identifying the origins of rigid-linear-ali-
portance in medical and material sciences. This can be achiev- phatic hydrocarbons and their use in functional materials,
ed with nonconjugated rigid hydrocarbons (NRHs) which share while tying together the chemistry, differences and commonal-
three main features for their usage in biological and material ities between these groups and outlining the missing compo-
sciences: 1) they are rigid, that is, all conformational changes nents of those dormant groups. While there are many aspects
are frozen; 2) they are linear, where the arrangement of the dif- that govern the structural composition and behavior of a com-
ferent functionalities happens in a defined spatial manner, in pound, such as quantum mechanics (e.g., London dispersion),
this case a 1808 fashion; 3) they are nonconjugated, as the this review will focus solely on the physical bond connections
formal sp3-hybridized carbon center interrupts electronic com- within the four selected NRH linkers, taking a structural engi-
munication (even though this is only partially true, as will be neering viewpoint.
discussed in detail vide infra).
Over the years, linear linking has been a classic field of para-
substituted benzenes and alkynes, due to the plethora of well- 2. General Aspects
established cross-coupling reactions.[1] Recently however, cer-
2.1. Bicyclo[1.1.1]pentane (BCP)
tain other hydrocarbons, such as cubane or bicyclo[1.1.1]pen-
tane (BCP) have begun to draw attention due to their remark- Bicyclo[1.1.1]pentane (BCP) is the smallest member of bicyclic
able properties.[2, 3] Besides these highly strained, rather unusu- bridged alkanes. It was first synthesized by Wiberg et al. in
al hydrocarbons more common moieties are in use, such as bi- 1964 (Scheme 1).[5, 6] The synthesis was achieved by an anti-
Markovnikov addition of hydrogen bromide to methylenecy-
clobutane 1, followed by hydrolysis of the methylester 2 and
decarboxylative bromination in the presence of mercury(II)ox-
ide. The final ring-closure was achieved by a Wurtz reaction of
the dibromide 3 in dioxane to form BCP 4.
Figure 1. Nonconjugated rigid hydrocarbons (NRHs).
[a] G. M. Locke, Dr. S. S. R. Bernhard, Prof. Dr. M. O. Senge Scheme 1. Synthesis of BCP according to Wiberg et al.[5]
School of Chemistry, SFI Tetrapyrrole Laboratory
Trinity Biomedical Sciences Institute, Trinity College Dublin
The University of Dublin, 152–160 Pearse Street, Dublin 2 (Ireland)
E-mail: [email protected] Different approaches for the synthesis of substituted and un-
The ORCID identification number(s) for the author(s) of this article can be substituted BCPs are known in the literature.[7] The methods in-
found under: https://doi.org/10.1002/chem.201804225. volve cyclizations, ring-expansions, and ring-contractions.
T 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. Today, most chemistry of the BCP scaffold arises from the
This is an open access article under the terms of Creative Commons Attri-
bridged [1.1.1]propellane intermediate 6 by utilizing strain
bution NonCommercial License, which permits use, distribution and repro-
duction in any medium, provided the original work is properly cited and is relief as the main driving force. Usually the generation of the
not used for commercial purposes. reactive [1.1.1]propellane intermediate is carried out according
Chem. Eur. J. 2019, 25, 4590 – 4647 www.chemeurj.org 4591 T 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Review
at the bond critical point,[16] as a positive Laplacian was evi-

dent.[17] A positive Laplacian usually is interpreted as a typical
signature of charge shift bond, a bond in which the covalent–
ionic resonance energy is the main factor.[18]
Scheme 2. Preparation of [1.1.1]propellane 6. In addition, systematic theoretical studies of the 1J(13C–13C) nu-
clear spin–spin coupling of the bridgehead–bridgehead carbon
atoms reflected strong through-cage electronic interactions,
to an optimized and improved procedure developed by Szei- but with higher p-character of the central bond.[19] The invert-
mies and co-workers that employs the tetrahalide 5 as the ed carbon geometry of the bridgehead–bridgehead bond, no
starting material (Scheme 2).[8] The term propellane was first matter of the actual bond character itself–which most likely
coined by Ginsburg et al. in 1966, to trivialize the lengthy will stay unrevealed–still tests current theoretical calculations
names tricyclic systems require.[9] of energy and bond lengths (Table 1).[20] Further information
The molecular structure of the parent BCP hydrocarbon about BCP and related propellanes can be found in other very
shows some notable peculiarities. Electron diffraction in the comprehensive reviews.[3, 7, 22]
vapor phase confirmed the symmetric shape (D3h) and shows
one of the shortest nonbonded carbon–carbon interactions (in-
terbridgehead distance of 1.845[10]/1.874 a[11]). This 1,3-non-
bonded repulsion of the bridgehead carbon atom leads to a
destabilization of the BCP cage in the ground state. Moreover,
it even is considered to be one major aspect of the overall ring Gemma Locke obtained her BSc in Medicinal
strain.[12] The inverted tetrahedral geometry of BCP is repre- Chemistry at Trinity College Dublin (TCD) in
2014. During this time, she did a three-month
sented by the high strain energy of 68 kcal mol@1 (Table 1).[13]
internship in the University of North Carolina
at Chapel Hill (UNC), working on N-centered
radicals under the supervision of Prof. Dr. Erik
Table 1. Physical properties of bicyclo[1.1.1]pentane. Alexanian. She is currently a PhD student
under the mentorship of Prof. Dr. Mathias O.
Molecular formula C5H8 Senge carrying out research on electron-trans-
[7] fer mimics with both cubane and triptycene
boiling point [8C] 36
porphyrin complexes.
appearance colorless clear liquid
decomposition [8C][21] > 280
heat of formation [kcal mol@1] [13]
51
strain energy [kcal mol@1][13] 68
C1@C2 bond length [a] 1.545[10]/1.557[11] Dr. Stefan Berhard studied chemistry at the
C@H bond length [a] 1.100[10]/1.109[11] Johannes Gutenberg-University Mainz, Germa-
bridgehead distance [a] 1.845[10]/1.874[11] ny. He completed his doctoral studies on the
synthesis of optically active crinine-type alka-
loid precursors under the supervision of Prof.
Udo Nubbemeyer in 2015. In the same year
he joined the group of Prof. Dr. Mathias O.
Decreasing the electron density of the relevant orbitals, for
Senge at the Trinity College Dublin as a post-
example, by the introduction of electron-withdrawing substitu- doctoral researcher. His current research is fo-
ents at the bridgehead, leads to a reduction of the 1,3-non- cused on cross-coupling chemistry with highly
bonding repulsion and a shorter distance between the bridge- strained alkanes and the functionalization of
porphyrins.
head carbon atoms.[14] Interestingly, this repulsion is further re-
lieved by the introduction of an internal carbon–carbon bond,
an unexpected stability of [1.1.1]propellane. Due to the high s-
Mathias O. Senge, Dipl.-Chem., MA, Dr rer.
character, the intercaged carbon–carbon bonds are very short nat., FTCD, studied chemistry and biochem-
(according to Bent‘s rule).[15] Therefore, the true character of istry in Freiburg, Amherst, Marburg, and Lin-
the central inverted bridgehead–bridgehead bond still remains coln. After a PhD from the Philipps Universit-t
enigmatic (Scheme 3). A refined electron density analysis of Marburg (1989) and postdoctoral studies with
K. M. Smith at UC Davis he received his habili-
[1.1.1]propellane by intense synchrotron primary radiation tation in Organic Chemistry in 1996 from the
measurements revealed significant electron density, which is Freie Universit-t Berlin. From 1996 on he was
characteristic of a covalent bond, but no charge accumulation a Heisenberg fellow at FU Berlin and UC
Davis and held visiting professorships in
Greifswald and Potsdam. In 2002 he was ap-
pointed Professor of Organic Chemistry at the
Universit-t Potsdam and since 2005 holds the
Chair of Organic Chemistry at Trinity College
Dublin. He was the recipient of fellowships from the Studienstiftung des Deut-
schen Volkes, the Deutsche Forschungsgemeinschaft, and Science Foundation
Scheme 3. Valence bond structures for the internal bond in [1.1.1]propel- Ireland (Research Professor 2005–2009).
lane.
Review
2.2. Bicyclo[2.2.2]octane (BCO)
The first synthesis of bicyclo[2.2.2]octane (BCO) 10 was achiev-

ed by Alder and Stein in 1934 (Scheme 4).[23] They utilized their
Figure 2. Conformation of BCO.
prior findings, a Diels–Alder reaction, for the generation of the
analysis of substituted derivatives gave clear indication that

the stable conformation is indeed the eclipsed D3h one.[29, 34]
The measured bond distances and angles are in good agree-
ment with the theoretical considerations of Gleicher and
Scheme 4. Synthesis of bicyclo[2.2.2]octane. Schleyer, both supporting the D3h-symmetry.[35]
The high melting of BCO is attributed to the dense, approxi-
mately spherical packing (Table 2).
bridged bicyclo[2.2.2]octane-2-carbaldehyde 8.[24] After ozono-
lysis of the enolacetate to ketone 9, they were able to reduce
the corresponding semicarbazide to the parent hydrocarbon Table 2. Physical properties of bicyclo[2.2.2]octane.
10.
Molecular Formula C8H14
In comparison to the fairly stable [1.1.1]propellane, the cor-
[36]
responding [2.2.2]propellane 12 is only of minor importance boiling point [8C] 116 (5 mbar)
melting point [8C][23] 169–170
for further synthetic modifications. The first synthesis of the heat of formation [kcal mol@1][15] @24.3
unsubstituted parent hydrocarbon was achieved by Wiberg strain energy [kcal mol@1][15] 7.4
et al. in 1974.[25] However, the pure material could not be iso- C1@C2 bond length [a][a] 1.542[29]
lated and was trapped as the addition product of chlorine 13 C2@C3 bond length [a][a] 1.544[29]
C1@C4 distance [a][a,b] 2.597 a[29]
(Scheme 5). The [2+ +2]-cycloreversion to the 1,4-dimethylenecy-
[a] Data in reference to the 1,4-dicarboxylic acid derivative, since no data
for the parent compound is available. [b] Bridgehead-to-bridgehead dis-
tance.
2.3. Triptycene and barrelene

Highly related to the BCO system is the triple benzannulated
tripycene, the simplest representative of the so-called ipty-
cenes.[37, 38] Triptycene—named after “triptych” (t1&ptucon
Greek. “threefold”), a painting or book with three leaves hinged
on a common axis—was first synthesized by Bartlett et al. in
1942 (Scheme 6).[39] A Diels–Alder reaction was used to install
the threefold geometry, by reacting anthracene 16 with qui-
Scheme 5. Synthesis of [2.2.2]propellane.
none in refluxing xylene. The final defunctionalization of the
quinone intermediate was obtained by isomerization, oxidation
to the corresponding quinone 17, substitution with hydroxyl-
clohexane 14 proceeds at low temperatures by the singlet rad- amine hydrochloride, and a subsequent reduction to the di-
ical. Interestingly, the opposite approach, populating the triplet amine 18. The bis-diazoniumtriptycene was afforded through
state via irradiation, can also be used to generate [2.2.2]propel-
lane 12. Again, the reactive intermediate was trapped by the
addition of bromine to give 11.[26]
Both experiments proved earlier predictions regarding the
instability of the [2.2.2]propellane system through calculations
by Stohrer and Hoffmann.[27] The actual conformation of BCO
was a topic of a long discussion during the 1960s.[28, 29] The
large heat of hydrogenation from bicyclo[2.2.2]octene to bicy-
clo[2.2.2]octane, was interpreted by Turner et al. as proof for a
twisted D3-structure,[30] in accordance with previous strain-mini-
mization calculations by Hendrickson (Figure 2).[31] In contrast,
the analysis of IR, Raman, and microwave spectra indicated an
eclipsed conformation with D3h-symmetry.[32] Due to a forma-
tion of a large super-cell with a complex diffraction pattern,
the preferred conformation could not be proven.[33] Only the Scheme 6. Synthesis of triptycene according to Bartlett et al.[39]
Review
diazotization with sodium nitrite and reduction of the corre-

sponding chloride in the presence of potassium hydroxide and
palladium on calcium carbonate, to yield triptycene 19. This
synthetic route enabled access to a series of substituted BCO
derivatives, to study the nucleophilic substitution at the
bridgehead carbon center and thus investigate the reactivity
of structures, which cannot undergo the Walden inversion.[40, 41]
A further insight into the chemistry of those bridgeheads will
be given at a later stage. Up to now, using a Diels–Alder reac-
tion with anthracene derivatives is still the most valid method
for the introduction of functionalities in the bridgehead posi-
tions, especially with the usage of aryne coupling partners,
generating the (functionalized)-triptycene unit in a single
step.[42] Scheme 8. Reactivity and photochemistry of barrelene.
The missing link from BCO to triptycene is bicyclo[2.2.2]octa-
2,5,7-triene, the so-called barrelene 24. Its first synthesis was
achieved by Zimmerman and Paufler in 1960 (Scheme 7).[43] phase shift, a characteristic phe-
nomenon for Mçbius-type aromat-
ic structures (Figure 3).[47, 48]
However, the chemistry and re-
activity of 24 indicate a rather non- Figure 3. Barrelene as a
aromatic behavior. Hydrogenation Mçbius aromatic system.
of the double bonds results in the
saturated BCO 10 (Scheme 8).
Thereby, comparison to other hydrocarbons suggests a desta-
bilization of about 10 kcal mol@1 due to angular strain.[49] The
addition of bromine leads to a transannular bond formation
yielding 25, showing typical nonaromatic behavior as well.[47]
Despite its theoretical interest, little use of barrelene 24 as a
Scheme 7. Synthesis of barrelene by Zimmerman et al.[43]
building block is reported in the literature.[50] The existence of
the even more bizarre propellene analogue, [2.2.2]propella-
Coumalic acid 20 was decarboxylated over copper at 650 8C triene, is a topic of speculation and for now remains at the
to a-pyrone 21. Afterwards the labile diene was heated under realms of theoretical chemists.[51]
reflux with two equivalents of methyl vinyl ketone, generating
the bicyclo[2.2.2]octene 22 skeleton in a double Diels–Alder re-
2.4. Cubane
action with loss of carbon dioxide. Generation of the bis-
oxime, and a subsequent second-order Beckmann rearrange- Cubane 37, a constitutional isomer to barrelene (C8H8) 24, was
ment under alkaline conditions of the bis-tosylate, yielded the synthesized in 1964 by P. E. Eaton and T. W. Cole.[52, 53] Despite
diamine 23. Exhaustive methylation and Hofmann elimination its fascinating simple structure of eight methine units in per-
of the quaternary ammonium salts led to the introduction of fect cubic arrangement, this synthesis is considered a mile-
the two missing double bonds, finalizing the synthesis of bar- stone of organic chemistry,[54] challenging the concept of
relene 24. carbon hybridization. Cubane was considered impossible due
The photochemical isomerization of barrelene represents to the significant deviation in geometry of each carbon atom
one of the most fundamental and general photoprocesses; a from the tetrahedral angle (109.58 of sp3-carbon vs. 908 in a
di-p-methane rearrangement is observed which initiated differ- cubic arrangement).[55] Its high strain notwithstanding, cubane
ent general mechanistic discussions (Scheme 8).[44, 45] shows a remarkable high thermal stability; due to the lack of
Different pathways are observed depending on the presence orbital symmetry-allowed ring opening, the thermal rearrange-
of an additional photosensitizer. Direct irradiation results in a ment does not occur below 200 8C.[56]
photochemical isomerization to cyclooctatetraene 30 by the Eaton’s original synthesis of the carbon skeleton of cubane
intramolecular [2++2]-cycloadduct 29. In the presence of a suit- 37 is still the basis of most practical approaches to install the
able photosensitizer, the triplet excited state reacts with the caged structure.[57] Just two cycloadditions, a diastereoselective
diradical 28 a. Ring-opening of the cyclopropane intermediate Diels–Alder reaction, and a subsequent [2+ +2]-photocyclization,
to the stabilized allylradical 28 b results in the subsequent for- are necessary to setup the backbone of cubane, which then
mation of semibullvalene 31.[46] Consideration of the bond can undergo a double ring contraction under Favorskii condi-
structure, according to Heckel’s rule, suggests barrelene 24 is tions (Scheme 9).[53]
an aromatic compound. Although the p-bonds are not copla- Other approaches to generate substituted cubanes, make
nar, the p orbitals show some homoconjugative overlap with a use of [2+
+2]-cycloadditions of substituted tricy-
Review
Table 3. Physical properties of cubane.
Molecular formula C8 H 8
shape[64, 65] Oh point group
appearance transparent, rhombic crystals[64]
decomposition [8C][66] > 220
density [g cm@3][62] 1.29
heat of formation [kcal mol@1] [67]
144
strain energy [kcal mol@1][68] 161.5
Scheme 9. Eaton and Cole’s synthesis of the cubane core.[53, 57] DIPB = 1,4-di- C@C bond lengths [a][63] 1.571
isopropylbenzene; NBS = N-bromosuccinimide. C@H bond lengths [a][63] 1.109
C1@C4 distance [a][62] 2.72
clo[4.2.0.02,5]octa-3,7-diene derivatives 38, a method not suit-

able for unsubstituted cubanes, due to the large separation of prehensive reviews[2, 62, 69] and book chapters,[70] each delivering
the involved p-orbitals (3.05 a), the sizeable difference in strain a unique view onto chemistry‘s platonic body par excellence.
energy between the educt and product, and a dominance of
through-bond interaction, as p + lies above p@ for both sets of
MOs (Scheme 10).[58] Dissimilarly to the quite stable [1.1.1]pro- 3. Physical Properties
To understand the different chemical behavior during the syn-
thesis and the resulting properties of the NRHs a closer look
into some specific physical detail is necessary. This chapter
identifies common trends and differences from a physical per-
spective between the different groups and combines it with
additional information about the specific bond situation given
for the individual linker motif.
3.1. Size and dimension

Scheme 10. Persubstituted cubanes. The structural properties of the NRHs have been studied by X-
ray diffraction, electron diffraction and other types of spectros-
copy. Even though the geometry for each linker is linear, there
pellane, the reaction of 1,4-diiodocubane 39 with tert-butyl-
is a remarkable variety in size and, therefore, in the length of
lithium, is proposed to have three plausible reactive intermedi-
the linker unit (Figure 4). While acetylene 26 is rather small
ates, the cubane-diyl 40 a, the “cubane-propellane” 40 b, and
with a C@C distance of 1.20 a,[71] the size increases gradually
the cubane–diene 40 c (Scheme 11).[59] Due to an orbital mis-
from BCP 4 (1.85 a),[10] to BCO 10 (2.60 a),[29] to triptycene 19
(2.61 a),[72] to cubane 37 (2.72 a),[73] which is very close to the
largest representative benzene 27 (2.79 a).[74]
The highly strained BCP system is influenced the most by
electronic and steric effects. Different substituents on the
bridgehead positions alter the internal C@C distance. This
Scheme 11. Reactive intermediates in the synthesis of compound 36.
match the long length of the internal bond would be rather

weak and calculations could rule out the likelihood of a
“cubane-propellane” intermediate and strengthen the possibili-
ty of a singlet diradical species.[60, 61] The cubane–diene inter-
mediate 40 c, a supposedly excellent dienophile, could not be
quenched in the presence of Diels–Alder dienes.
Due to the unusual structure of cubane its physical proper-
ties are quite different from other hydrocarbons (Table 3). The
perfect cubic arrangement of the carbon atoms results in an
octahedral point group Oh, with a high density of
1.29 g cm@3.[62] The carbon–carbon distance of 1.571 a is slight-
ly longer than in unstrained alkanes (1.54 a) and in cyclobu-
tane (1.55 a).[63] Further information can be deduced in com- Figure 4. Bond length and internal C@C distance for the bridgehead carbon
atoms.
Review
ed triptycene 19 and BCO 10 show the expected chemical

shifts,[81] the degree of s-character is already significantly
higher compared to cyclohexane.[82] This effect further increas-
es for BCP 4 and cubane 37.[83, 84] Here the formal bond situa-
tion is closer to sp2 than to sp3. The extraordinary s-character
of the exocyclic C@H-orbitals in cubane, and, therefore, the p-
rich character of the cage C@C-orbitals, are further reflected in
the high acidity of the C@H bond.[85, 86] The kinetic acidity of
Figure 5. Substitution effects on internal C@C bond length of BCP-deriva-
tives. cubane is 6.6 V 10@4 that of benzene and 6.3 V 104 that of cyclo-
hexane.[86] This result is quite similar to other strained hydro-
carbons, for example, the kinetic acidity for cyclopropane is
effect is contributed to the increased s character of the exocy- 7.1 V 104 that of cyclohexane, and both, cyclopropane and
clic bond (Bent’s rule[15]) and is even visible in the oligoBCP cubane, have a similar degree of hybridization (32 vs. 31 %).[87]
compounds 41 and 42, so-called n-staffanes (Figure 5). Here,
the distance between the two bridgehead carbon atoms in-
3.2.1. Electronic communication
creases with the amount of additional BCP-monomer units.[75]
The same effect results in rather long internal distances for An important characteristic of the different linker units is the
alkyl- and aryl-substituted BCPs.[76] On the other hand, the op- efficacy of electronic communication within the carbon scaf-
posite effect occurs in quaternary pyridinium salts 43.[77] Here fold (“through-bond”) and the bridgehead-bridgehead carbons
the very short nonbonding contact of 1.80 a, is almost as short (“through-space”). A highly effective approach to investigate
as the longest observed direct C@C-bond is long (1.70 a).[78] those influences is the acidity of linear-substituted carboxylic
acids (Table 4). The acidity of BCP acid 46 a (pKa = 5.63) and
3.2. Bond considerations, electronic communication, and

ring strain Table 4. Acidity of linear-substituted hydrocarbons.[a]
Bridgehead hybridization and distances are not only important

for the electronic communication of linear attached functional- Linker
ities of the target molecule, they also indicate the reactivity of
the compound. 1H and 13C NMR shifts and coupling constants pKa for X 46 47 48 49
are a powerful tool to determine the formal character of a a H 5.63 H 6.54 H 5.20 H 5.94
b F 4.84 CH3 6.50 CH3 5.23 CO2H 5.43
bond.[79] The chemical shifts for unstrained hydrocarbons like
c Cl 4.69 Cl 5.72 Cl 4.67 CO2Me 5.40
acetylene 26, benzene 27 and cyclohexane 45 are referred d CF3 4.75 CF3 5.79 Br 4.67 Br 5.32
here as standards (Figure 6).[80] Within those molecules the
[a] Values were determined in EtOH/H2O v/v (1:1).[88–90]
carbon–hydrogen coupling represents the classic hybridization
(50 % = sp, 33 % = sp2, 25 % = sp3). A different situation occurs
for the nonconjugated-linear linkers. While the rather unstrain-
cubane acid 49 a (pKa = 5.94) is significantly higher compared
to unstrained BCO acid 47 a (pKa = 6.54), as a result of the in-
creased electronegativity (s-character) of the exocyclic carbon
bonding orbitals relative to BCO.[88] In addition, there is a clear
correlation of bridgehead–bridgehead distance and the influ-
ence of the substituent. The short bridgehead–bridgehead dis-
tance within the BCP derivatives leads to a strong influence of
the substituent.
This effect can be further demonstrated by the position of
the substituent: 3-substituted BCO acids show less influence
compared to 4-substituted ones, since the effect of the bridge-
head–bridgehead interaction is missing.[91] Wiberg could show
that the effects of the different substituents for bicyclic carbox-
ylic acids result from a field effect.[91] This inductive/field effect
was shown to have a linear-dependence on the acidity of the
compound and the C@X dipole. The electronic effects in 4-sub-
stituted cubane carboxylic acids can even be utilized to illus-
trate substituent effects in cyclobutanes, which are otherwise
Figure 6. NMR and hybridization data for bridgehead carbon atoms; the s-
character is calculated via Mueller and Pritchard’s empirical relationship: too weak to be detected.[92] Irngartinger et al. could determine
% s = 1/5 J(C@H).[79] the different carbon–carbon bond lengths within the cubane
Review
skeleton, depending on the substituent present in the 4-posi- The p-MOs of 1,3-diethynylbicyclo[1.1.1]pentane 50 showed
tion.[93] Again, a closer look into the strong 1,3-nonbonding in- a remarkable split of about 0.67 eV and similar effects occurred
teractions between bridgehead carbon atoms is necessary for for the 1,3-dibromo[1.1.1]pentane 51 (0.72 eV) and the extend-
the BCP cage system. As mentioned above, the short inter- ed 3,3’-dibromo-1,1’-bis(BCP) 52 (0.45 eV). These effects are not
bridgehead distance (1.80–1.98 a) leads to repulsion of the as strong as the conjugation effect for butadiene 53 (2.5 eV) or
back lobes of the exocyclic hybrid orbitals, and is considered the homoconjugation effect of norbornadiene 54 (0.86 eV), but
to be a main contributor to the overall strain energy of the still show the good relay effect. Recent measurements and cal-
system.[12, 14] culations even showed the possibility to tweak the orbital-
A very valuable method to illustrate the effects of electronic splitting energy with additional substituents on the carbon
communication between two separated electronic systems is cage, for example, hexafluorination led to further enhance-
photoelectron spectroscopy (PE). According to Koopman‘s the- ment.[99] Quantum chemical calculations for diethynyl[n]staf-
orem the first ionization energy of a molecular system is equal fanes, with 1 , n , 5, predict a long-range interaction of
to the negative energy of the HOMO.[94] The effects of direct 0.04 eV over a distance of 18 a for the longest staffane (n =
interactions (through-space) and mediated interactions via the 5).[100] A further hint for the strong through bond-coupling
s-skeleton (through-bond) can be directly observed in the PE within the BCP-skeleton is shown by electron transmission
spectra. The assignment of the absorption energies to the ac- spectroscopy (ETS) studies done by Schafer et al.[101] They de-
cording molecular orbitals (MO) can be quite challenging, due termined the p*-splitting of the acetylenic p*-orbitals in 1,3-di-
to different effects (Jahn–Teller effect, spin-orbit coupling for ethynylbicyclo[1.1.1]pentane 50 to be 1.1 eV. This results com-
heavy heteroatoms, vibrational fine structure, etc.). However, plement the findings of Gleiter et al.,[98] showing a strong
semiempirical models for molecules consisting of the first and through-bond coupling of the p*-orbitals, facilitated by the s/
second row atoms have been used with great success and are s*-skeleton of the linker.
a helpful tool within the assignment of the MOs. The corre- In conclusion, both spectroscopic methods, PE and ETS, clas-
sponding splitting of the ionization energies with the assigned sified the BCP bridging unit as an excellent mediator for elec-
MOs (DIn) represents the degree of interaction. Initial studies tron transfer, not only for radical cations (PE) but also for radi-
on cubane,[95] cubane derivatives,[96] and BCO derivatives[97] cal anions (ETS). On the other hand, cubanes and BCO would
showed only very small splitting, characteristics for only a very be prime linkers in terms or electronic resistors, since little
feeble interaction of the linked systems. A different picture communication occurs via the s-skeleton. Recent literature
was observed for BCP derivatives. Here a rather strong splitting offers detailed theoretical studies,[102] discussing influences and
of linked systems occurs (Figure 7).[98] consequences of electron-transfer systems containing noncon-
jugated hydrocarbon linkers, but little experimental data.
3.2.2. Ring strain

Unusual bonding situations are exemplified by the strain
energy of the particular systems. Usually the overall ring strain
is a combination of various parameters: 1) Baeyer strain[103] or
angle strain (deformation of bond angle); 2) Pitzer strain[104] or
conformational strain (torsional eclipsing interactions);
3) Prelog strain[105] or transannular strain (van der Waals interac-
tions of transannular atoms). For example, the angle strain, the
Figure 7. Orbital energy splitting.[98] deviation from the tetrahedral angle of 109.58, is higher in cy-
clopropane than that in cyclobutane (Table 5). The strain
Table 5. Heat of combustion and strain energy of cycloalkanes.
Compound Heat of combustion DHc Heat of formation DHf Strain energy[15] Strain energy per C@C bond
[kcal mol@1] [kcal mol@1] [kcal mol@1] [kcal mol@1]
cyclopropane (C3H6) 505.8[106] 12.7[106] 27.7[15] 9.1
cyclobutane (C4H8) 656.0[92] 6.8[107] 26.3[15] 6.6
cyclohexane (C6H12) 943.8[108] 29.8[108] 0.4[15] 0.1
BCP (C5H8) N/D[a] 51 (calcd)[109] 68.0[15] 11.3
cubane (C8H8) 1155.2[67] 142.7[67] 161.5[68] 13.5
BCO (C8H14) 1195.5[110] 23.6[110] 7.4 0.8
triptycene 2409.1[111] 76.8[111] 7.0[111] 0.8
[a] N/D = not determined.
Review
energy of cubane is about six times the amount of cyclobu-

tane, which represents the sum of the six “cyclobutane faces
of the cube”. But compared to the ring strain per carbon–
carbon bond, cubane has double the amount of cyclobutane.
The deviation is even higher when the strain energy is calculat-
ed per number of carbon atoms (cubane & 20.2 kcal vs. butane
& 6.6 kcal). However, one should be aware, that the concept of
ring strain has its intrinsic limitations, for example, in terms of
chemical stability. The less-strained isomer is not always the
most stable one. In addition, cubane and BCP are relatively
stable compounds, even though highly strained. But neverthe-
less, the concept of ring strain is still very valuable and can be Figure 8. Approximate solvolysis rate of brominated bridgeheads and cation
applied for a better interpretation of chemical reactivity.[112] An stabilization effect.
interesting example is the correlation of ring strain with the

ability of the molecule to act as a hydrogen bond donor; the
higher the strain, the more acidic the C@H bond.[113] While cation formed seems to neglect all known cation-rationales,
many of these strained hydrocarbons are thermodynamically such as the geometry is far from flat and hyperconjugation
unstable, due to their deviation from standard sp3 geometry, would result in a very strained cubenelike structure, an ex-
they possess remarkable kinetic stability. For example, cubane treme example of a pyramidalized olefin.[118@121] This remark-
is thermodynamically unstable (DHf = 144 kcal mol@1), and able effect can be explained by additional stabilization through
highly strained (SE = 161.5 kcal mol@1), but it is capable of with- delocalization of the positive charge along the surrounding
standing temperatures of up to 220 8C (Table 5).[66] BCP also carbon–carbon bonds (resonance stabilization). In addition, fur-
contains notable kinetic stability, as it is shown to withstand ther hyperconjugation, vicinal through bond sCaCb !p* could
temperatures greater than 280 8C.[21] BCO and triptycene are be the reason for the notable stability of the cubane cation.[122]
notably less strained (SE = 7.4 and 7, respectively) with heats of Furthermore, Eaton et al. pointed out another consideration:
formation of 23.6 and 76.8 kcal mol@1. the internuclear line between the individual carbon bonds rep-
resents a false picture of the actually bent bond (“banana
bond”),[123] since the endocyclic interorbital angle is rather 101–
3.3. Bridgehead cations, anions, radicals and radical-cations
1048 than 908,[124] reducing the actual pyramidalization
In terms of chemical reactivity and stability other important angle.[122] Further influences on the solvolysis rate are reported
factors have to be considered. How does the rigid scaffold for substituted cubanes. While electron-withdrawing groups at
behave in reactive intermediates? How stable are the accord- the g-position slow down solvolysis, electron-donors at the b-
ing bridgehead cations or anions? Is the homolysis of the position accelerate it.[116, 120, 125] So far no skeletal rearrangement
carbon–hydrogen bond possible, and how stable is the corre- is observed for the cubane cation, and only recent calculations
sponding bridgehead radical? Which intermediates will break showed a possible pathway for the cage-opening via the
the rigid cage-like structure and rearrange to more stable cuneyl cation. The rate-determining barrier for ring opening of
products? In this chapter those questions will be answered 25.3 kcal mol@1 highlights the kinetic persistence of this unusu-
from a rather physical point of view; examples concerning the al cation.[126]
actual reactivity and chemistry will be discussed in detail in Originally the first synthesis of triptycene by Bartlett et al.
Chapter 4. was conducted to compare the stabilizing effect of benzene
rings on the rigid, tied-back orientation in triptycene with the
triptycenyl cation.[39, 40, 41] In triptycene, the p-system is fixed in
3.3.1. Bridgehead cations
an orthogonal orientation relative to the developing p-orbital;
The short nonbonding contact in BCP allows for the fast solvo- therefore, no overlap/stabilization is possible. Leaving groups
lysis of halosubstituted BCP, despite the expected high strain at the bridgehead position do not show the usual substitution
of the resulting carbocation intermediates (Figure 8).[114] Gener- chemistry since it cannot be flattened and as the backside is
ally the positive charge of carbocations is stabilized in planar shielded by the other bridgehead carbon atom.[127] Shielding
geometries, but this cannot occur at the pyramidalized bridge- even occurs at the front side of the molecule, and for the
head positions of BCP.[115] Due to the close nonbonding con- triple benzylic-like position in 9-bromomethyltriptycene, due
tact, a rather strong transannular stabilization of the develop- to the peri-type steric hindrance of the cationic center and the
ing BCP cation can be observed.[116] The fast solvolysis rate of adjacent aromatic hydrogen atoms (Figure 9).[128]
BCP also enables relief from ring strain, which can be observed Another unique property of the cubane core is the instability
by the presence of solely the rearranged substituted-cyclobu- of the cubylcarbinyl cation, as the positive charge next to the
tane products.[117] cubane skeleton usually leads to rapid rearrangement to the
The cubane cage, on the other hand, is very stable toward homocubyl derivatives, as was observed for cubylmethyl alco-
skeletal rearrangement and the solvolysis rate is about 1015 hols 55. Originally described by T. W. Cole in his Ph.D. disserta-
times faster than originally calculated, even though the cubyl tion with Eaton 1966 (Scheme 12),[129] modern calculations sug-
Review
Figure 9. Nucleophilic substitution on 9-substituted triptycenes.
Figure 10. Experimental gas-phase acidities (DHa), electron affinities (EA),

and bond dissociation energy (BDE). All values in kcal mol@1; parenthetical
values are results of G3 computations.[132, 137, 140]
bond.[141] The homolytic bond dissociation energy (BDE), re-

flecting the stability and the ease of formation of the alkyl radi-
cal, follows the predicted order for the stability of the radicals.
Scheme 12. Cubylcarbinyl cation rearrangement.
The anionic intermediates are of greater importance for the
functionalization than the cationic counterparts. This is espe-
gest a mechanism via the homocubyloxonium ion 56 a, for the cially due to the wide variety of organometallic coupling and
Wagner–Meerwein-type rearrangement.[130] exchange reactions.
3.3.2. Bridgehead anions 3.3.3. Bridgehead radicals

Ample research has been conducted to determine the stability As for the bridgehead carbocations, the geometry for bridge-
of the highly basic hydrocarbon anions.[131] A general method head radicals is quite different from other more flexible sys-
is the preparation in the gas phase in the presence of fluoride tems. The rigid core results in a permanent pyramidal confor-
anions (DePuy reaction).[132, 133] The kinetic acidity can be deter- mation, far from the favored planar conformation. Also, in
mined by mass spectrometry (flowing afterglow[134] or ion cy- comparison to the planar tert-butyl radical, which shows rapid
clotron resonance[135]) with a method developed by DePuy inversion, the conformation is locked within the inflexible cage
et al.[136] The thermodynamic relationship of the homolytic structure. The orientation of the SOMO and the tied back
bond dissociation energy (BDE), gas-phase acidities (DHa), the carbon atoms result in less distinctive stabilization effects
ionization energy of hydrogen (IE(H) = 313.6 kcal mol@1),[137] and (Figure 11). Hyperconjugative delocalization or b-scission of
the electron affinity (EA) is given by the following equation,
representing the thermodynamic cycle [Eq. (1)].[138]
BDEðR-HÞ ¼ DHa ðRHÞ @ IEðHC Þ þ EAðRC Þ ð1Þ
Strictly speaking, Equation (1) is only valid for localized Figure 11. a) Hyperconjugative delocalization; b) definition of dihedral angle
anions and radicals, and resonance delocalization only plays a V.
minor role in stabilizing these intermediates.[139] In general, the
acidities and bond dissociation energies of hydrocarbons are
influenced by the hybridization of the according orbital. The bridgehead carbon atoms lead to high-energy bridgehead al-
higher the s-character, or the J(C@H), the higher the kinetic acidi- kenes (anti-Bredt[142] alkenes). Consequently, the reduced steric
ty of the hydrocarbon (low values of DHa) (Figure 10). shielding of the exposed bridgehead radicals, in combination
This can be seen in the high kinetic acidities of BCP 60 and with the alleviated hyperconjugation, results in a much higher
cubane 37. The high s-character increases the acidity, as seen reactivity in comparison to “normal” tertiary carbon radicals.[143]
when compared to BCO 10, CP 58, and tBu 59. But due to the But despite their high reactivity, the half-lives for all bridge-
higher transannular interaction between the back lobes of the head-radicals are long enough to study their properties with
bridgehead carbon orbitals, the effect for BCP is partly mitigat- spectroscopic methods.
ed. This effect can be illustrated by adding an electronegative The highest hyperconjugation of the b-hydrogen atoms is
substituent, for example, chlorine, at position 3 of BCP. The en- observed for a parallel orientation to the SOMO (dihedral
ergetically low-lying s* orbitals of the halogen–carbon bonds angle V = 08). The strength of this effect can be seen in EPR
can be populated, leading to a longer carbon–halogen spectra in the hyperfine splitting (hfs) (Figure 12). A significant
Review
3.3.4. Bridgehead radical cations
Examples of radical cations for the rigid hydrocarbons currently

under review, in the literature are limited. Although, one prom-
inent example from the work of the Schreiner group with the
cubane radical cation 37C + should be noted (Scheme 14).[152]
Scheme 14. The two rearrangement pathways for the cubane radical cation.
Figure 12. Rate of formation and EPR data.[144, 146, 149, 150]
Both experimental ((photo)chemical oxidation of cubane 37C +

factor of the stabilization within the tert-butyl radical comes in acetonitrile) and computational (DFT and MP2) techniques
from the hyperconjugation with the b-hydrogens (hfs = 22.9 were employed to investigate the rearrangement of the
G). Within the bridgehead-systems only cubane shows a minor cubane radical cation 37C + . Two rearrangement pathways are
contribution of the b-hydrogens (hfs = 12.4 G),[144] which is at- possible for this radical cation. While the barriers are almost
tributed to the optimum overlap with a dihedral angle of V = equivalent for the isomerization of 37C + to the cuneane radical
08.[145] Remarkable for the BCP-radical is the unusual strong cation 37 aC + (pathway A) and for the C@C bond fragmentation
coupling with the g-hydrogen atoms (hfs = 69.9 G).[146] Again, to the secocubane-4,7-diyl radical cation 37 bC + (pathway B)
this effect is owed to the very small bridgehead–bridgehead (DH* @1
0 = 7.8 and 7.9 kcal mol , respectively), pathway B is fa-
distance within the BCP-radical of only 1.74 a,[147] reflecting a vored, as the rearrangement of 37 bC + to the more stable syn-
large through-space contribution; this is a notable difference tricyclooctadiene radical cation 62C + has a low-energy barrier
in length when compared to the neutral BCP-species of and terminates with the cyclooctatetraene radical cation 30C + .
1.845 a. In addition, three identical pathways through the In contrast, cuneane 37 aC + is oxidized exclusively to semibull-
carbon–skeleton with an ideal trans-arrangement are available valene 31 aC + , as a barrier of 35.7 kcal mol@1 prohibits the ex-
for an enhanced through-bond communication.[148] pansion of 31 aC + to 30C + .
The triptycene radical on the other hand shows no interac-
tion with the opposite bridgehead substituent. Even if a fluo-
rine atom is placed on the other bridgehead carbon atom, no
measurable coupling is observed between the radical and the 4. Reactivity and Manipulation of the Bridge-
opposite atom. This indicates that the actual through-space head Carbon Center
coupling for BCO[150] and cubane, which share similar bridge-
4.1. Limitations of the carbon skeleton–stability and rear-
head–bridgehead distances (2.60 and 2.72 a, respectively), is
rangements of cubane and BCP
an insignificant effect. Further investigation on related systems
confirmed that a through-space coupling mechanism is only The carbon-skeleton of triptycene and BCO—both unstrained
valid for distances below 2.1 a.[151] The strong hyperfine split- linker systems—are nearly indestructible under normal reaction
ting in the BCO and cubane systems is, therefore, only attribut- conditions. However, BCP and cubane bear a vast amount of
ed to the through-bond interactions.[149] Even though bridge- strain energy in their cage structure. Certain reaction condi-
head radicals are highly reactive, ring opening via b-scission tions are able to crack the kinetically stable skeleton and lead
was only observed for the BCP-radical at elevated tempera- to thermodynamically more stable products. Due to the high
tures and is, therefore, regarded as kinetically disfavored. The activation energy (Ea) the thermal stability of BCP is remarkably
kinetic barrier was determined to be higher than 26 kcal mol@1 high so that the isomerization to 1,4-pentadiene 61 only takes
(Scheme 13).[146] In terms of reactivity and stabilization the radi- places at elevated temperatures (Scheme 15).[7, 21] Similarly in
cal approach is one of the most reliable approaches for the fur- cubane, the activation energy (Ea = 43 kcal mol@1) of the rate-
ther functionalization of those strained hydrocarbons. The utili-
ty of radical intermediates is discussed in detail below.
Scheme 13. Allowed radical rearrangement of BCP. Scheme 15. Thermal isomerization of BCP and cubane.
Review
determining step for a homolytical C@C-bond cleavage, during

the rearrangement to cyclooctatetraene 30 provides only limit-
ed relief in the overall strain, hence the thermal ring opening
only occurs at higher temperatures.[153]
Another option to release some strain energy is a metal-cat-
alyzed s-bond rearrangement. In the presence of AgI or PdII, in-
sertion into the carbon–carbon bond of cubane occurs
(Scheme 16 a).[154] A rearrangement of the cubane skeleton
Scheme 17. Kinetics of cubylcarbinyl radical 67.
Scheme 16. Rearrangement of cubane (a,b,c) and [1.1.1]propellane (d) skele-

tons.
yields the stable cuneane 63 (lat. cuneus = wedge). A similar re-

arrangement is observed in the presence of Li cations or pro-
tons (Scheme 16 b).[155] Rhodium(I) complexes rapidly insert
into the carbon–carbon bond of cubanes in an oxidative addi-
tion style. The intermediate five-membered metallacycle 66 is
rearranged to the more staple tricyclodiene 62
Scheme 18. Kinetics of BCP-carbinyl radical.
(Scheme 16 c).[156] The corresponding BCP-skeleton shows no
related reactivity. Only in the case of the very strained bridged
[1.1.1]propellane, a comparable ring opening in the presence Further release of ring strain can be induced by ring expan-
of transition metals occurs (Scheme 16 d).[157] sion. Carbene generation adjacent to the ring skeleton leads to
Despite the stability of the cubane radical, different effects remarkable anti-Bredt olefins. The BCP(phenyl)ketone was used
are observed for radicals adjacent to the caged ring system. to generate the carbene from the according diazo compound
The cubylcarbinyl radical 69, generated by the photolysis of 78. After refluxing, the existence of the very strained bridge-
the corresponding N-hydroxy-2-pyridinethione ester 70 head olefin 80 was verified with the addition product of etha-
(“Barton ester”),[158] does not show the 1,2-shift to homocubyl nol (Scheme 19).[157] For cubane the situation is even more ex-
radical 71, which was found for the analogous cubylcarbinyl ceptional; the corresponding homocubene 84, generated from
cation (Scheme 17).[159, 160] Instead a very fast ring opening the adjacent carbene 83, is regarded as one of the most twist-
occurs (kR = 2 V 1010 s@1). From there different isomers 73 a, ed anti-Bredt olefins up to date.[162] The existence of the homo-
73 b, and the mixture of diastereomeric trienes 74 a and 74 b cubene 84 was confirmed by trapping experiments.[163] Later,
are isolated with a distribution correlated to their rate forma-
tion. Due to the low lifetimes (10–35 ps), rearrangement pro-
cesses are predominant over diffusion-controlled bimolecular
trapping within the cubane system. Again a similar process is
observed for BCP-carbinyl radical 76 a. Even at low tempera-
tures, the radical readily rearranges by a b-scission.[161] In pres-
ence of a PhSH as a hydrogen donor the photochemical de-
composition of the BCP-Barton ester 75 yields a product ratio
of about 3 to 1 76/77 (Scheme 18).[151]
Scheme 19. Ring expansion via carbene insertion.
Review
even more remarkably, Eaton et al. could show with 13C-label- tions (Scheme 23). A similar mechanism was observed under
ing that the homocubene 84 rearranges reversibly to the ho- pure thermal conditions and at elevated temperatures during
mocubylidene 85.[164] Further studies on the equilibrium be- Grubbs-metathesis.[170] The final product after a cascade of cy-
tween the homocubene and the homocubylidene were con- cloreversions and cycloadditions is the stable 4-vinyl-trans-b-io-
ducted by Chen et al. and the equilibrium constant was as- dostyrene 103.
signed to be close to unity at room temperature.[165]
Certain other reaction conditions are able to crack the kinet-
ically stable cubane framework. In the presence of palladium-
on-charcoal Stober et al. observed a stepwise hydrogenation
of the strained skeleton.[166] The scission of the first ring leads
to the secocubane 86. Every further hydrogenation step, from
secocubane to nortwistbrendane 87 and from nortwistbren-
dane to BCO 10, releases about 50 kcal mol@1 of strain energy
(Scheme 20).[167] The order of hydrogenation proceeds as ex-
pected; the least stable/the longest bond is hydrogenated
first.
Scheme 20. Stepwise hydrogenation of cubane.

Scheme 23. Ring opening of cubanyl 97 to 4-vinyl-trans-b-iodostyrene 103.
The presence of an anionic charge at the carbon atom vici- 4.2. Functionalization of bridgehead linkers
nal to the cubane skeleton 89 leads to degradation of the ring
4.2.1. BCP chemistry
system 90. Deprotonation at the a-position of an acceptor
system 88 a or 88 b results in the two diene products 92 and A general approach for the functionalization of BCP utilizes the
93 (Scheme 21).[168] A similar instability is observed for cubyl- reactivity of the internal bond in [1.1.1]propellanes 6. This
bond can be opened either by an anionic, radical, or a cationic
pathway. Generally the cationic pathway leads to ring opening
of the BCP scaffold (Scheme 24), while in the case of
cubane,[59–61] BCO,[26] and triptycene no chemistry of the inter-
nal bond is utilized.
Scheme 21. Cubane skeleton decomposition in the presence of lithium di-

isopropylamide (LDA).
methyl alcohol 94. Slight acidic conditions induce a homoketo-

nization reaction yielding cyclobutene 96 (Scheme 22).[159] Scheme 24. Functionalization of [1.1.1]propellane.
The polymerization of a [1.1.1]propellane derivative 104 was

first achieved through the anion-induced ring opening of BCP
with lithium–organic initiators such as tert-butyllithium and
phenyllithium.[171] The central sigma bond is opened leading to
Scheme 22. Ring opening of cubylmethyl alcohol in slightly acidic condi-
a rigid rod structure 105 with a degree of polymerization
tions.
greater than 20 units (Scheme 25).
Conversely, nonpolymeric reactions can be carried out with
A very interesting ring-opening mechanism of the cubane 6, such as the radical addition of different thiols to the strained
core was observed during the attempts to polymerize the carbon–carbon bond of 6 to form BCP-thioether compounds
iodo-vinyl cubane 97.[169] The partial positive charge in the vici- 106.[172] This reaction proceeds by a radical chain process with
nal position 98 leads to a sequence of skeletal bond migra- high functional group tolerance and few byproducts in yields
Review
with this method. The multicomponent reaction involves a

concerted mechanism starting with a radical addition, followed
by cleavage of the central bond then radical trapping, allowing
the C@C bond to form simultaneously with the C@N bond on
the BCP scaffold. Methyl carbazate was used as a methoxycar-
bonyl radical precursor, while di-tert-butyl azodicarboxylate
was utilized as the radical acceptor for the intermediary 3-sub-
stituted BCP-radical, this radical intermediate is kinetically
stable allowing the formation of the C@N bond over BCP oligo-
merization. The optimized conditions for this reaction were
found to be a combination of tert-butyl hydroperoxide (TBHP)
and (phthalocyaninato)iron(II) (Fe(Pc)) (cat.) with the inorganic
base Cs2CO3 in MeCN at @20 8C for 1 h.
As has been observed and noted before, the most strained
C@C bond present in 6 is the central C@C bond that has a
bond energy of & 60 kcal mol@1. The energy of the “spring-
loaded” C@C and C@N bonds was harnessed to develop a syn-
thetic route to BCP amines 110.[177] The turboamide
(Bn2NMgCl·LiCl) was reacted with propellane on a > 100 g
scale to afford the amine in a 54 % yield over two steps. Inert
conditions are required while the reaction is run from 0 to
60 8C and allowed to react for 16 h. The HCl salt was then pre-
cipitated once the dibenzyl group was removed. A large
number of BCP amines were synthesized through this method.
A significant body of work has also been carried out with
the reaction of various Grignard reagents and 6 to form 1,3-di-
functionalized BCP products.[178] This was first seen with work
performed by the Szeimies group in which various 1,3-bisaryl/
alkylarylBCP compounds 111 were synthesized through the re-
action of 6 with different Grignard reagents to form alkyl/aryl
Scheme 25. Poly[1.1.1]propellane, addition of a Grignard reagent to
magnesium halides. These intermediates could then undergo
[1.1.1]propellane and radical carboamination of [1.1.1]propellane.
coupling reactions with bromoarenes in the presence of
[PdCl2(dppf)] to form the 1,3-difunctionalized products in
between 16 and 90 %. All reactions were performed at room modest yields between 21–49 %, with minimum reaction times
temperature in the absence of any catalysts and with short re- of 48 h.[76] Following on from this, 1,3-disubstituted BCP deriva-
action times of 15 min. tives were synthesized from 6 by an alternative route. Organyl
Carboamination was also achieved by reaction with 6. Di- iodides were reacted with 6 by radical addition reactions; then
tert-butyl-1-(BCP)hydrazine-1,2-dicarboxylate 107 was synthe- a halogen–lithium exchange was performed followed by either
sized through the reaction of 6 with di-tert-butyl azodicarbox- transmetallation with zinc chloride or the addition of a
ylate and phenylsilane in the presence of tris(2,2,6,6-tetrameth- Grignard reagent to open up access to a variety of 3-substitut-
yl-3,5-heptanedionato)manganese(III) [Mn(dpm)3].[173] It had ed BCP-1-magnesium and -zinc derivatives. The zinc derivative
been previously shown that [1.1.1]propellane can have a simi- was then used in coupling reactions with various alkenyl, aryl,
lar reactivity profile to that of olefins.[8] Furthermore, it was and biaryl halides and triflates using either [NiCl2(dppe)],
demonstrated that H@N can be added across olefins by a free- [Pd(PPh3)4], or [PdCl2(dppf)] catalysts to give a number of 1,3-
radical mechanism in manganese-catalyzed hydrohydrazination disubstituted BCP derivatives 111. Moderate yields were ob-
reactions.[174] Coupling these results together enabled the de- tained and long reaction times of three to seven days were re-
velopment of this reaction that traps the 1-BCP radical, under quired for the corresponding BCP magnesium species.
similar conditions with an azodicarboxylate. 1-BCP-amine 108 Similarly, arylmagnesium halides were again reacted with 6
was then accessed through BOC deprotection to give 1-BCP- and the resulting BCP magnesium intermediates were
hydrazine that was then reduced to the product. This synthetic quenched with ethyl chloroformate to give the corresponding
route proved to be superior in terms of scalability, yield, safety, ethyl esters 112 in 60–92 % yields.[179] Yields were significantly
and cost when compared with previously reported routes in higher for the arylmagnesium halides that had electron-donat-
the syntheses of 1-bicyclo[1.1.1]pentylamine.[175] ing groups (EDG) (74–92 %) than those with electron-withdraw-
Following this, a one-pot radical carboamination of 6 was ing groups (EWG) (47–61 %). This result is logical due to the in-
developed under mild conditions to afford multifunctionalized creased nucleophilicity of the EDG Grignard reagents. The opti-
BCP derivatives 109 in gram-scale quantities.[176] Notably, the mum reaction conditions for the first step involved two equiv-
synthetically useful 3-substituted BCP-amines can be accessed alents of the Grignard reagent, heating to 100 8C with 6 for
Review
45 min to 3 h. The reaction was then quenched with four

equivalents of ethyl chloroformate at @78 8C. Alternatively as
seen before, the BCP magnesium intermediates undergo a
transmetallation reaction with ZnCl2 that then allowed for Ne-
gishi cross-coupling with various aryl or heteroaryl halides
(Ar’X) to give 1,3-bisarylated BCP derivatives 113 in good
yields. Negishi cross-coupling conditions were carried out with
the catalyst [PdCl2(dppf)]·CH2Cl2 ; only a 40 8C temperature was
required for coupling with aryl iodides, whereas a higher tem-
perature of 65 8C was necessary to access coupling with het-
eroaryl bromides and chlorides as electrophiles to provide
BCPs bearing various heterocyclic ring systems in 49–91 %
yields. More sensitive groups such as a nitriles or esters are tol-
erated under these conditions.
Recent work has also shown the applicability of alkyl iodide
substitution with 6 to form iodoalkyl BCP products 114.[180]
These compounds are achieved under mild conditions using
10 mol % of the Lewis acid triethylborane at room temperature
and the reaction is often completed within 15 min. Important-
ly, in the absence of triethylborane, no product formation was
observed in the dark or light, highlighting its necessity. Also
noteworthy was the absence of any staffane byproducts from
the reaction.
Scheme 26. Functionalization of the bridgehead carbon in triptycenes;

solv. = solvent.
4.2.2. Triptycene chemistry

4.2.3. Functionalization of the BCO scaffold
9-Bromotriptycene 115 has been utilized by many groups to
further functionalize triptycene at the 9-position. This is most A wide variety of chemistry is available for the functionalization
commonly executed through halogen–lithium exchange reac- of the BCO scaffold. For example, 1,4-dibromoBCO 125 a can
tions (Scheme 26). This was first carried out in the 1970s, when be accessed from the conversion of two carboxylic acid groups
trimethyl-9-triptycenyl tin 117 a was synthesized by quenching in 124 by the radical Hunsdiecker reaction (Scheme 27).[189, 190]
the 9-lithiotriptycene intermediate 116 with tri- Here the silver salts of the carboxylic acids react with the or-
methyltinchloride.[181] Following this trimethyl-9-triptycenyl tin ganic halide, and decarboxylation followed by the radical re-
117 a was utilized to access dimethyl-9-triptycenyl tin hydride
117 b. This was achieved by a bromination reaction followed
by the reduction of tin with LiAlH4.[182] Additionally, when 9-
lithiotriptycene was quenched with formaldehyde, the tripty-
cene carbaldehyde 117 c was formed.[183] 9-Triptycene pheneth-
yl selenide 118 was prepared from 9-bromotriptycene again
through the use of a lithium–halogen exchange reaction and
quenched with diphenyl diselenide to form the product in a
75 % yield.[184, 185] Moreover, 9-lithiotriptycene 116 was reacted
with a series of metals such as GaCl3, AlCl3, and InBr3 to form
the complexes, [(tript)GaCl2(THF)] 119 a, [(tript)AlCl2(OEt2)]
119 b, and [(tript)InBr(m-Br)2Li(OEt2)2] 119 c, in which tript = 9-
triptycenyl.[186]
Iodine and chlorine were also introduced at the 9-position
of triptycene. Iodination was achieved by Bartlett by the radi-
cal-induced decomposition of ditriptycenoyl peroxide 120 at
80 8C in the presence of I2 to give compound 121.[187] Chlorina-
tion was observed when 9-N-(acyloxy)phthalimide triptycene
122 and 1,4-diazaBCO (DABCO) were irradiated for 3 h with a
100 W high pressure Hg lamp in a solution of [tBuOH-CCl4-H2O
(53:42:5, v/v)] resulting in the decarboxylated chloride product Scheme 27. BCO chemistry at the bridgehead position. PCC = pyridinium
123 in 59 %.[188] chlorochromate. See ref. [192] for further information.
Review
Scheme 28. Redox-active ester chemistry. DMAc = dimethylacetamide; BTMG = 2-tert-butyl-1,1,3,3-tetramethylguanidine.
combination of BCOC and BrC results in the desired product. A popular and versatile method has arisen that allows for
Moreover, the use of aluminum foil and a catalytic amount of the attachment of a variety of different functional groups di-
bromine in methyl iodide allows for the efficient conversion to rectly to many of the bulky alkyl groups of interest in this
1,4-diiodoBCO 125 b, whereas Fenton conditions enable the review, that is, BCP, BCO, and cubane. These methods, as devel-
FGI to the 1,4-dihydroBCO species 126. Friedel–Crafts arylation oped by Baran’s group involve the cross-coupling of redox-
reactions have also be utilized to access 1,4-diaryl BCO 127 active esters, derived from alkyl carboxylic acids, with organo-
compounds from 1,4-dibromo BCO 125 through the use of metallic species and employ single-electron transfer to achieve
AlCl3 and the chlorinated aryl group.[191] the desired coupled compounds (Scheme 28). The mechanism
4-Methoxy BCO-1-carboxylic acid 128 was utilized to access for the majority of these reactions involves a single-electron-
a series of difluoroethylene BCOs 130 a–j.[192] Several different transfer (SET) mechanism, which circumvents the need for oxi-
functional-group interconversion reactions were performed at dative addition of a transition-metal into the carbon–halogen
the bridgehead carbon atom of BCO to access groups, such as bond, which can often be detrimental for the stability of the
NO2, CN, CF3, COOCH3, F, Cl, OCH3, C6H5, CH3, and C(CH3)3 strained alkyl groups under discussion.
129 a–j. Following this the carboxylic acid moiety, at the oppo- The alkyl redox-active ester 136 has been shown to success-
site bridgehead carbon atom, was reduced and subsequently fully couple with organozinc and organomagnesium species
oxidized to the corresponding aldehyde to allow for the final using an Fe-based catalyst system, such as [Fe(acac)3] (acac =
reaction with LiCF2P(O)(OC2H5)2 thus enabling access to a series acetylacetone) and the dppBz ligand to attach phenyl groups
of 1,1-difluoro-2-(4-substituted-bicyclo[2.2.2]oct-1-yl)ethenes to cubane 137, BCO 137 a, and BCP 137 b;[196] while the forma-
130 a–j. tion of alkyl boronic acids and esters can also be achieved
Another example of BCO chemistry uses 1-bromoBCO 131 a through the use of the alkyl redox-active esters. The catalytic
in direct reductive cross-coupling reactions with allylic acetates system of NiCl·6 H2O and MgBr2·OEt2 is employed to couple
through the use of a CoBr2/Mn catalyst system and an acetoni- the redox-active ester with lithiated bis(pinacolato)diboron.[197]
trile/pyridine solvent mixture. A variety of compounds includ- The boronic acid can then be accessed by reacting the ester
ing 1-allyl BCO 132 were synthesized through this method in product with boron trichloride. This method was successfully
reasonable yields within 4–6 h.[193] The BCO scaffold was suc- applied to synthesize methyl 4-(pinacolboron)cubane-1-carbox-
cessfully alkylated from 1-bromo-4-methyl BCO 131 b by using ylate 138 and methyl 4-(pinacolboron)BCO-1-carboxylate
the corresponding Grignard reagent to synthesize 1-methyl-4- 138 a.
pent-1-yl BCO 133.[194] Similarly, Friedel–Crafts alkylation was On the other hand, alkyl boronic acids and esters can also
also employed to alkylate 1-chloro-4-methylBCO 131 c by be produced through photoinduced decarboxylative boryla-
using AlMe3 to form 1,4-dimethyl BCO 134.[192] 4-Methyl-1-(2- tion of carboxylic acids as developed by Aggarwal and co-
phenylethynyl) BCO 135 was synthesized from 1-iodo-4-meth- workers.[198] This method does not use transition-metal catalysis
ylBCO 131 d through reaction with silver(I) phenylacetylide in but instead utilizes light to initiate the radical combination of
anhydrous pyridine under argon at 150 8C in 31 % yield. How- the N-hydroxyphthalimide ester derivative with the diboron re-
ever, these reaction conditions were only successful for this agent bis(catecholato)diboron. This reaction was used with
compound, as attempts to react silver(I) phenylacetylide with both cubane, BCO, and BCP scaffolds 138, 139 a,and 139 b, re-
1,4-diiodoBCO and methyl 4-iodoBCO-1-carboxylate failed.[195] spectively, to form their boronic ester derivatives, in moderate
to good yields.
Review
Scheme 29. Examples of organic transformations with cubane and classic cubane carbonyl chemistry. IBDA = iodobenzene I,I-diacetate.
A method for decarboxylative alkynylation was the target of carboxylation mechanism (Scheme 29).[204] This was achieved
further investigations. Again a redox-active alkyl ester was uti- through the use of hypervalent Phl(OAc)2-CCl4-I2 and with irra-
lized to react with either an alkynyl Grignard reagent using an diation of the compound. The iodocubane products were
iron catalyst or a lithiated-alkynylzinc species with a nickel cat- achieved in 80–90 % yields. Phenylcubane 150 was first ob-
alyst. Unfortunately, this approach was not successful for any tained from the transformation of fluorocubane 149, when it is
of the tertiary bulky cagelike alkyl groups 141 in this Review, reacted with benzene and boron trifluoride in toluene in a
that is, those derived from BCP, BCO, and cubane.[199] In addi- Friedel–Crafts type reaction.[205] After 30 min, a 40 % yield of
tion, decarboxylative alkenylation of a variety of groups can be phenylcubane was achieved as the sole product.
used as well. Here, a redox-active alkyl ester is coupled with an Much chemistry has been reported based on work with car-
alkenylzinc reagent in the presence of [Ni(acac)2] and a bipyri- bonyl cubanes. Dimethyl cubane-1,4-dicarboxylate 151 was
dine ligand. Methyl 4-(propen-2-yl)BCO-1-carboxylate 142 was transformed into a variety of different functional groups from
prepared in a 42 % yield through this method.[200] reactions with the ester functional group. Triazole 152 a, oxa-
Most recently, redox active esters have been employed to zole 152 b, thiazole 152 c, imidazole 152 d, pyrazole 152 e,
synthesize sp3-rich(fluoro)alkylated scaffolds.[201] This is made benzimidazol 152 f, pyridine 153 a, isoxazole 153 b, and imid-
possible through modular radical cross-coupling with sulfones azole 153 c functionalities were all introduced through classic
in the presence of [Ni(acac)2] followed by the reaction with (4- carbonyl transformations.[206]
fluorophenyl)zinc chloride. This method was shown to be ap- To access cubane for use in palladium cross-coupling reac-
plicable with the BCO scaffold 143. Copper catalysis and pho- tions a series of chemically distinct, highly strained, activated
toredox catalysis were coupled together to develop a new cubane scaffolds were synthesized (Scheme 30). This was
method to incorporate alkyl substrates by sp3 C@N bond for- achieved by using iodinated cubane derivatives 154 to opti-
mation.[202] This strategy involves the reaction between alkyl mize lithium–halogen exchange reactions.[207] Boron 155 a,
carboxylic acids, such as BCO 144 and BCP 145 (via in situ io- phosphorus 155 b, tin 155 c, silicon 155 d, sulfur 155 e, and
donium activation) and N-nucleophiles. N-BCO and N-BCP alkyl 155 f groups were attached to the cubane scaffold with
products, 146 and 147, respectively, can be achieved in high this method. The optimum conditions found for the metal–hal-
yields at room temperature from 5 to 60 min when irradiated ogen exchange reaction allowed for the generation of the lithi-
with light while activated by an iridium catalyst and in the ated intermediate through the reaction of cubanyl iodide 154
presence of copper. The reaction proceeds via single-electron with two equivalents of tBuLi at @78 8C in THF for 1 h. The re-
transfer pathways and opens a new avenue to C@N bond for- action mixture was then allowed to warm to room tempera-
mations that uses alkyl carboxylic acids over alkyl halides as ture after two equivalents of the relevant R@X reagent were
the coupling partner. Further details of these types of reactions added. These electrophilic cubanes were then investigated for
can be found in the recent review entitled “Decarboxylation as their use in Suzuki–Miyaura, Negishi, and Stille cross-coupling
the key step in C@C bond-forming reactions”.[203] reactions with various halogenated phenyl groups, but all cou-
pling reactions proved unsuccessful.
To avoid transition-metal-facilitated oxidative addition direct-
4.2.4. Cubane chemistry
ly onto the cubane core an ethynyl bond was introduced. So-
Cubanyl chemistry has evolved over the years to increase its nogashira cross-coupling reactions with ethynylcubane 156
applicability in modern day synthesis. Work in the 80s showed and different halogenated aromatic groups proved successful
how a cubanyl carboxylic acid group 47 a could be trans- due to the presence of this spacer. As a result, a variety of
formed to an iodide 148 by a hypervalent iodine oxidative de- ethynyl-linked cubane products were obtained, showing the
Review
Scheme 30. Expanded cubane chemistry. 9-BBN = 9-borabicyclo[3.3.1]nonane.
first example of cubane stability in the presence of palladium line derivative provided the best results.[208] It was hypothe-
catalysts.[208] Conditions for this reaction were optimized for sized that the ligand affects the rate-determining step of the
the coupling of 1-iodo-4-ethynylcubane 156 a with various catalytic cycle, that is, the reductive elimination of the cubane
halogenated substituted aryl groups. These conditions involve and aryl residue from the nickel center. Yields were achieved of
the reaction of a 0.1 m concentration of cubane 156 a with over 50 % with this method with very electron-rich aryl moie-
three equivalents of the aryl halide, in the presence of ties and unfunctionalized aryl groups that could be coupled
[Pd(PPh3)4] (10 mol %) and CuI (30 mol %) in NEt3 under argon smoothly. This is a two-fold increase over previously reported
for 16 h. The highest yield observed was 90 % when cubane yield of 25 % for the iron-catalyzed coupling.[196] But most excit-
156 a was coupled with ethyl 4-iodobenzoate. Also, the first ingly, the first example of a directly coupled cubanyl porphyrin
ever example of a porphyrin attached to a cubane was achiev- was obtained.
ed with this method under copper-free Sonogashira conditions Additional chemistry with cubane can be observed such as
in a 51 % yield. Sonogashira conditions were also employed for the nickel-catalyzed Barton decarboxylation and Giese radical
coupling reactions of 1,4-diethynylcubane with various por- conjugate addition reactions.[209] These reactions were rein-
phyrins. Monosubstituted products were achieved in yields up vestigated to simplify the required conditions and widen the
to 83 %. scope of the reactions. In each case N-hydroxyphthalimide
The direct attachment of aryl groups, namely porphyrins (NHPI) based redox-active esters were utilized and a thermally
onto the cubane core was still a synthetic target for us, so a initiated Ni-catalyzed radical formation was carried out. Subse-
different approach was sought to achieve this as palladium- quent trapping with either a hydrogen atom source (PhSiH3) or
catalyzed cross-coupling chemistry failed due to the instability an electron-deficient olefin in the case of 159 and 160, respec-
of the cubane core in presence of palladium. A single-electron- tively, led to the two products of interest. The former route re-
transfer mechanism was chosen, as it circumvents the require- sulted in the decarboxylated cubane product in 77 % yield
ment for the oxidative addition of the transition metal onto while the latter route gave the alkylated cubanyl product in
the cubane core by instead utilizing the cubyl radical which is 56 % yield. Additionally, an interrupted Barton decarboxylation
rather stable. Moreover, the versatility of redox-active esters reaction can be used to synthesize simple sulfinate salts 161
used for decarboxylative cubane-aryl cross-coupling had been from readily available carboxylic acids 47 b.[210] The carboxylic
seen by work performed by the Baran group, which supported acid is transformed to acyl chloride, then reacted with 1-hy-
SET as a viable method for cubanyl porphyrin coupling. Firstly, droxypyridine-2-thione, followed by illumination with light,
optimization of the nickel-catalyzed cubane-aryl coupling was then exposure to ruthenium trichloride and sodium periodate
carried out by looking at five major contributing factors: 1) sol- to form the sulfone product. Addition of sodium ethoxide
vent, 2) temperature, 3) concentration, 4) Ni source, and 5) allows for the conversion to the sulfinate salt. The cubanyl sul-
ligand. The ligand was identified as the main contributing pa- fone product was achieved in 42 % and the salt in 95 %.
rameter and results showed that the very electron-deficient
4,4’-functionalized bipyridines, especially the rigid phenanthro-
Review
5. Applications of Rigid-Linear Linkers in Elec-

tron-Transfer Systems
There is an increasing need to discover more efficient methods
to harvest energy and, as is often the case, we can look to
nature as the supreme example of how to maximize this pro-
cess. As a result many artificial molecular devices have been
made for solar energy conversion by acting as photosynthetic Figure 14. Naphthalene systems with various small molecule chromophores
mimics.[211] During photosynthesis, in order to absorb and and BCO linkers.
transfer solar energy effectively the antenna chlorophylls in
photosynthetic bacteria are organized as noncovalent macro-
rings in a spatially defined manner (Figure 13).[212] Therefore, molecule, thus indicating a correlation between distance and
transmission. The molecules were synthesized over a series of
steps starting from 1,4-dichloroBCO; the two chromophores
were attached sequentially, the donor moiety by an aromatic
alkylation and, more challengingly, the acceptor units by lithi-
um–halogen exchange reactions.
Following the successful identification of the most efficient
Figure 13. Basic overview of the electron-transfer mechanism occurring in donor and acceptor moieties in the rigid linker system seen in
photosystems during photosynthesis. 163 b, the effect of inserting an aromatic ring in between two
BCO scaffolds was investigated.[214] a-Substituted naphthalene
was implemented as the donor group and an acetyl or benzoyl
for electron-transfer systems, it is crucial to have the correct group acted as the acceptor groups in the phenylene-bridged
geometry, conformation and spatial arrangement of the molec- system 164. Results showed that transmission of singlet excita-
ular building blocks in these photochemical systems.[212c–f] In tion proved to be less efficient compared to the previously
order to achieve this, rigid-linear isolating linkers (among studied rods. D-Density determinations were employed to de-
others) are required to provide defined structures and fixed re- scribe the distribution of electronic excitation in these systems
giochemical arrangements similar to those seen in nature. and to see what was controlling energy transmission. These
Work began in this area as early as the 1980s with small or- determinations showed that while most of the excitation
ganic chromophores, and has progressed to larger multipor- energy is located in the terminal chromophores, some is dis-
phyrin complexes.[213] The majority of systems seen in literature tributed in the BCO units, indicating the presence of through-
are linked with either BCO, triptycene or BCP. Synthetic meth- bond energy transfer. Evidence also showed that energy trans-
ods employed to achieve these complexes ranges from substi- fer is mainly through-bond for the short rods but when the
tution reactions to transition-metal-catalyzed cross-coupling rod is lengthened Fçrster through-space transfer can be ob-
methodologies such as Suzuki, Sonogashira, and Stille reac- served.
tions. In 1995, the Langmuir–Blodgett technique was used to ad-
vance research into artificial molecular devices for solar energy
conversion.[215] The BCO linker was utilized for its ability to ar-
5.1. Small-organic acceptor–donor systems
range the functional moieties in a controlled manner across
One of the first examples of an electron-transfer system, mod- the films in the molecular device and to separate the chromo-
eled with a linear-rigid linker was seen in the 1980s which uti- phores at a fixed distance. b-Substituted naphthalene was
lized BCO as the linker.[213] The [2.2.2] rods consisted of one or used as the sensitizer (S) and ferrocene as the electron-donor
two BCO moieties with different chromophores attached to (D) 165. Both moieties were attached to the BCO scaffold via
the bridgehead carbon atoms. a-Naphthyl 162 and b-naphthyl Friedel–Crafts alkylation. Further studies into the dynamics of
163 were used as the donor groups while the energy acceptor the S–D dyads have yet to be published.
units consisted of acetyl, benzoyl, or cyclohexanecarbonyl moi- Fçrster resonance energy transfer (FRET) is used to indicate
eties (Figure 14). the molecular proximity of light-absorbing and fluorescent
Emission was observed by both the donor and the acceptor structures.[216] FRET was utilized to investigate if energy transfer
moieties upon excitation of the donor chromophore, with the occurs when chromophores are arranged orthogonally to one
ratio depending on the system. The rates of intramolecular another. The BCO scaffold was chosen to allow for this specific
energy transfer and the decay exhibited by the bridgehead arrangement and the chromophore selected was perylene bis-
groups were determined using single-photon counting. The imide 166 (Figure 15). Pump-probe spectroscopy, chemical var-
most rapid transmission was seen with 163 b, in which the b- iation, and calculations were executed, which unexpectedly
naphthyl group was the donor group while benzoyl was the showed energy transfer in the dyad with near-unit quantum
most efficient acceptor. Additionally, the shorter rod length efficiency. However, further experimentation showed that this
showed quicker transmission, due to the simple dipole–dipole was due to a break in the orthogonal arrangement, owing to
coupling that is aided by excitation transmission through the thermally populated ground-state vibrations that allow for
Review
Figure 16. Small molecule chromophores for electron-transfer studies.

Figure 15. Photochromic systems to investigate Fçrster resonance energy
transfer (FRET).
p-Phenylene, methyl-substituted p-phenylene and BCO were

multiple transition dipole moment orientations showing the employed as linkers to determine the torsional dependence of
pivotal role vibrational motion plays in energy transfer process- donor–acceptor systems when they are mediated by the s/p-
es. Further investigations with the transition density cube ap- systems of a bridging linker.[219] BCO, which possesses the
proach indicated that while chromophores are orthogonally ar- “Aviram–Ratner” diode bridge, can be used to evaluate Js and
ranged Coulombic interactions do not contribute to electronic Hs explicitly in the absence of any p-contributions to the ex-
coupling. The perylene bisimide was attached to the BCO change and electronic coupling. A semiquinone (Zn-SQ) donor
linker via an amide condensation reaction. and a nitronylnitroxide (NN) acceptor 169 were used in the D–
BCP was also utilized as a rigid linker to study FRET between B–A system. CASSCF calculations gave results consistent with
the fluorophore 1,5-dimethoxy-9,10-di(phenylethynyl)anthra- that of the exchange coupling parameter, showing that the s-
cene (donor) and different substituted thiophene acceptor superexchange, mediated by a saturated BCO bridge, is equiv-
units 167.[3, 217] Its short C1–C3 distance makes it a unique linker, alent to the predicted s-superexchange through a p-phenyl-
allowing two conjugated chromophores to be in close proximi- ene ring perpendicular to both SQ and NN. Furthermore, there
ty while not allowing any significant p-conjugation. A suggest- is no measurable hybridization-dependent difference in the
ed application for the BCP dyad is use in (rewritable) data stor- magnitude of the s-contribution to the superexchange, as the
age media, where fluorescence can be reversibly switched “on” carbon atoms are sp2 for the phenylene ring and sp3 for the
and “off”, depending on the state of the photochromic part. BCO bridge. Additionally, no measurable difference is observed
Encouragingly, results showed quantitative resonance energy owing to the three @CH2CH2@ s-pathways for BCO, compared
transfer between the excited state of the fluorophore and the to para-phenylene’s two pathways.
closed form of the photochromic units. However, when the The effect of sequential addition of p-bridges in the form of
photochromic units were substituted with methoxy groups benzene rings to the BCO scaffold (to eventually form tripty-
their photostability is reduced compared to methyl groups, cene 171 was investigated with respect to the electron transfer
which may limit their use in fatigue-resistant optical switches. rates.[220] A 4-(pyrrolidin-1-yl)phenyl electron donor and 10-cya-
To synthesize these compounds Sonogashira methodologies noanthracen-9-yl electron acceptor were attached via alkyne
were followed to introduce the anthracene fluorophore to the linkages to the scaffold and used as the model system 170.
BCP linker and a lithium reaction was employed to attach the Previous studies have proven the existence of the Marcus in-
photochromic units. verted region through the use of saturated spacer groups,
The efficient conversion of light to storable electric or chem- whereas the advantage of p-bridges are that they maintain
ical energy was investigated with a phenothiazineanthraqui- closer energetic resonance between the p-systems of the D
none dyad 168, connected via BCO (Figure 16).[218] The photo- and A group conveying electronic communication. But surpris-
induced charge separation of the dyad was determined ingly, it was shown, by Natural Bond Orbital (NBO) analysis,
through the use of picosecond and nanosecond transient ab- that the additional p-pathways played no role in the electron
sorption and time-resolved ESR spectroscopies. A long-lived transfer. Furthermore, no effect was seen from the changes in
charge separated (CS) state was observed in the dyad upon ex- the s-system because of shifting hybridization, despite the pre-
citation of the anthraquinone (AQ) donor chromophore, as AQ dictions of photoelectron spectra.
acts as a triplet photosensitizer. Time constants of 1.3 ns and 1,4-Bis(p-cyanophenyl)BCO 172 and 1-benzoyl-4-(a-naph-
1.0 ms were found of the formation and the decay of the CS thyl)BCO 162 b, amongst other compounds, were synthesized
state, respectively. Owing to the formation of the CS state via for energy and electron-transfer studies,[221] to investigate
the triplet mechanism, time-resolved ESR showed spin polari- whether electrons can be transferred, upon electron excitation,
zation for all the emission signals. The dyad was synthesized through a saturated hydrocarbon insulator (Figure 17). BCO
via Pd cross-coupling methodologies. was selected for the scaffold as it provides a symmetrical and
Review
teraction,[226] and all were shown to decay exponentially with

molecular length. To measure the decay constant of the ex-
change, the effect of the magnetic field on the electron trans-
fer and the splitting of the molecular orbital was studied. Dif-
ferent rod lengths were used with the nitroxide biradicals and
the complexes were measured through the simulation of the
ESR spectra. Results showed that the exchange interaction de-
creased with the decay constant, indicating that the spin–spin
exchange interaction between neutral radicals has a decay
Figure 17. Electric rods linked by BCO units. constant similar to the molecular conductance. The diradicals
were synthesized using 1,4-dibromoBCO as an intermediate. A
series of steps afforded diformyl intermediates that enabled
accessible framework dissuading the approach of orbitals from access to the desired nitronyl nitroxide derivatives following
separate p-systems.[222] The introduction of a single electron reaction with 2,3-bis(hydroxyamino)-2,3-dimethylbutane sulfate
into one aromatic ring of the symmetrical diaryl derivatives led and oxidation by sodium periodate.
to radical anions in which the odd electron was localized in Calculations were used to determine the suitability of organ-
one of the two aromatic rings. This result was hypothesized to ic molecular systems in a single molecular spin-pump
be due to a tunneling problem from a single potential energy device.[227] As they are well spaced and energetically separated,
barrier in the bicyclic ring structure. In contrast, singlet energy biradicals with triplet state singly occupied molecular orbitals
transfer was observed from the naphthyl to the benzoyl (SOMOs) are proposed for such devices. Different candidates
moiety in compound 162 b, and triplet transfer from benzoyl were designed and computationally studied through density
to naphthyl. A dipole–dipole mechanism is involved in the sin- functional theory, all of which employed bis(nitronyl nitroxide)
glet transfer, while the triplet–triplet transfer suggests that a based biradicals, including a complex with two fused propel-
close approach may not be necessary. A sodium–potassium lane units 176 (a purely theoretical compound) as the bridging
alloy was used to introduce the electron and ESR spectroscopy unit. It was estimated that the proposed molecular structures
of monoradical anions was used to determine whether the will operate as spin-pumps using harmonic magnetic fields in
electron was delocalized over one or both rings. the MHz regime and optical fields in the IR to visible light
Following this, rodlike linear units consisting of four BCO regime.
units (173 and 174) were synthesized and a series of excitation To effectively study electron transfer, practical devices re-
and electron-transfer studies were carried out.[223] The reason quire vectorial energy or electron transfer over long distances.
for the longer rods was to investigate “through-space” electron Moreover, the geometry of the system must be rigidly defined
transfer as the previous rods all showed only singlet and triplet to compare with the predictions made for energy and electron
“through-bond” transfers. Results showed that both singlet transfer.[228] A novel bridging ligand 1,4-bis[2-(2,2’-bipyridine-5-
and triplet through-bond energy transfer were occurring. To yl)ethynyl]BCO 177 (b-Z-b) was synthesized with two bipyri-
synthesize the longer rods a new synthetic approach was re- dine units (b) that are separated by the rigid 1,4-diethynylBCO
quired. Sodium–potassium coupling was implemented to (Z) spacer. The ligands were then employed to construct
achieve these systems by radical dimerization of the bridge- mono- and dinuclear complexes of RuII and OsII and investigat-
head free radicals. ed for electron-transfer studies (Figure 19).[229] Light excitation
To investigate the decay constant of p-phenylene, oligophe- of the Ru-based unit followed by a very efficient (> 90 %)
nylene molecular rods bearing the BCO moiety were synthe- energy transfer to the sensitized Os-based unit was observed
sized with two nitronyl nitroxide radicals 175 (Figure 18).[191] in the heterometallic [(bpy)2Ru(b-Z-b)Os(bpy)2]4 + complex,
Owing to its rigid p-conjugated structure, oligo(p-phenylene) overcoming the long metal–metal distance. The key step in
can be used to query molecular conductance. The decay con- the synthesis of the 177 complex connected the diformylBCO
stant has been obtained for molecular conductance,[224] the to the dipyridyl units via a Wadsworth–Emmons reaction
rate of electron transfer,[225] and the magnitude of exchange in- giving the (E,E) dimer.
Low temperatures are a hindrance in the utilization of elec-
tron transfer for practical applications, as the process is
blocked when the solvent freezes. It can be seen that in the
rodlike dinuclear complex {(ttp)Ru(tpy-ph-BCO-ph-
tpy)Os(ttp)}4 + (RuOs) 178 an electron-transfer process occurs
that is independent of temperature and the state of the sol-
vent (ttp = p-tolyl-tpy, tpy = terpyridine, ph = 1,4-phenylene).[230]
The RuOs complex 178 is a rigid-rodlike linear species owing
to the ph-BCO-ph spacer. At high temperatures, the lumines-
cent excited-state lifetime is the same for RuOs as Ru, showing
Figure 18. Nitroxide biradicals for the theoretical investigation of decay con- that the dinuclear complex energy transfer is too slow to com-
stants and use in light-induced spin-pump devices. pete with intrinsic Ru-based deactivation. At low temperatures
Review
Figure 19. Ru2 + complexes linked by BCO that were used to investigate long-range energy transfer.
energy transfer occurs from the Ru center to the Os center, molecular rotary motor. This concept is based on the transport
shown through observations in which the Ru luminescence is of electrons between two electrodes by electroactive groups
quenched while sensitization of the Os- based luminescence attached to a central rotatable core.[234] The ultimate goal is to
occurs. In the RuOs complex, the critical temperature for when study the molecule between the two electrodes of a nanojunc-
the energy-transfer rates for Ru-based intrinsic deactivation tion to test its applicability as a molecular machine.
and Ru!Os are identical is 184 K. It was found that over the In light-harvesting systems, amongst other electron-transfer
temperature range 90–200 K, the Ru!Os energy transfer rate processes, M(N-N)2n + complexes have become an area of much
in {(ttp)Ru(tpy-ph-bco-ph-tpy)Os(ttp)}4 + is 5.2 V 106 s@1 (20 %). interest, in which M is a second or third transition-row metal
Therefore, energy transfer is neither affected by temperature ion such as RuII, ReI, or OsII.[235] RuII and ReI act as photosensitiz-
changes nor by the state of the solvent, which is fluid at T > ers and are modulated by the donor- or acceptor groups of
110 K and frozen below that temperature. the coordinated N-N ligands, such as 2,2’-bipyridine (bpy) or
To study long-range electron transfer in TiO2 semiconductor 1,10-phenanthroline (phen) (Figure 20).
nanoparticle thin films, a tripodal RuII–polypyridyl complex 179 Different triptycene spacers of varying oxidation states were
was synthesized with a BCO bridge.[231] The BCO moiety was employed to make Ru2 + and Os2 + complexes 182–184, allow-
chosen to investigate the role of conjugation in the bridge. ing the spacer to act as a redox-active switching unit and en-
1,3,5,7-Tetraphenyladamantane derivatives, containing three abling the quinone spacer to potentially control energy and
CO2Me anchoring groups, were used to anchor the molecule electron-transfer reactions in between two complexed metal
to the TiO2 film while the Ru complex with bpy ligands was centers.[236] Key steps in the synthesis of these complexes were
employed as the sensitizer. Sonogashira methodologies were the Diels–Alder reactions to form the triptycene scaffold and
utilized to attach the different moieties to the BCO bridge. the lithium–halogen exchange reactions used to connect the
Through the use of theoretical calculations the role of BCO RuII moieties to the diformyltriptycene. The ratio between the
as an electronic insulator was evaluated by a comparison of relative emission of (Ru-bmb-Ru), (Ru-btb-Ru), and (Ru-bqb-Ru)
the electronic coupling parameter (Vab) of 1,4-bis(ferrocenyl)- was found to be 3.7:2:1. The highest emission was found for
benzene and 1,4-bis(ferrocenyl)BCO 180. DFT was used to opti- the bmb ligand due to the donor effect of the methoxy-sub-
mize geometries and extended Heckel calculations were em- stituents, whereas the lowest emission was seen for the bqb
ployed to calculate Vab by the dimer splitting method. Results system as the emission is strongly quenched by the quinone
of the calculations showed a 12-fold decrease in electronic moiety. Owing to the quinones redox active properties emis-
coupling with the BCO derivative (Figure 20).[232] sion tuning can be obtained. The electronic energy level is
Following this, a potential star-shaped molecular motor 181 positive enough for the quinone moiety, in the metal complex
was synthesized that incorporates the BCO fragment.[233] The Ru–bqb–Os, to act as a quencher for the Ru-based 3CT excited
molecule is based on a ruthenium complex that bears a tripo- state as is shown by the lack of phosphorescence seen from
dal stator functionalized with ester groups to be anchored the Os-based 3CT level.
onto oxide surfaces. These motors contain ferrocenyl electroac-
tive groups and the cyclopentadienyl (Cp) rotor connected
5.2. Porphyrin systems
through the insulating spacer BCO. The known 1,4-disubstitut-
ed BCO is a good candidate, as it has a rigid saturated back- Porphyrins have been employed as more accurate photosyn-
bone enabling it to maintain linearity and rigidity in the arms thetic mimics due to their similarity in structure and electronics
of the motor. This is an example of an electrically fueled, single with the chlorophyll pigments in plants[212] and due to the
Review
Figure 20. Star-shaped molecular motor and triptycene-linked electron-transfer systems.
many advances in their synthesis, structural understanding, of a semiempirical method. The edge to edge distances of the
and functionalization.[237] In 1984, the first porphyrin photosyn- BCO and biBCO systems 185 and 186 were found to be 10
thetic model with a linear-rigid linker was published. The link and 14 a, respectively. It was predicted in these systems that
between electron tunneling and distance was investigated by hole transfer would dominate, resulting in a significant differ-
extending the length between two chromophores with addi- ence between the rate of decay for the forward electron trans-
tional BCO linkers (Figure 21).[238] Due to the employment of fer compared with that of the reverse electron transfer over
the rigid BCO linker, the dependence of variables such as dis- distance. Results indicate that the symmetry of the donor and
tance, orientation, and the energy gap between donor and ac- acceptor orbitals relative to the BCO linker orbitals determines
ceptor molecules in electron-transfer processes can be more the energy dependence on it to mediate the donor–acceptor
effectively studied. The electronic energy for photosynthetic interactions. Also, for every additional BCO unit added it was
model compounds, linked by BCO, containing a porphyrin and expected that the forward rate from the singlet excited state
quinone unit in 185 and 186, was calculated through the use will slow by a factor of 1500, whereas the reverse rate will only
decrease by a factor of 60.
To effectively mimic photosynthesis, the ability to control
the ratio of the rates for charge separation and recombination
is key in creating long-lived charge separated states, which is
necessary for efficient electron-transfer processes. Marcus
theory was used to further understand these rates in electron-
transfer reactions on a series of electron donor–acceptor sys-
tems with push–pull chromophores as electron acceptors.[239] A
zinc(II) porphyrin (ZnP) electron donor connected via a rigid
phenylene–ethynylene–phenylene (PEP)BCO linker to different
anilino-substituted multicyanobutadienes or extended tetra-
cyanoquinodimethane analogues 187 was synthesized
(Figure 21). First reduction potentials were obtained, and cou-
pled with other results, showed that the extent of ZnP fluores-
cence quenching correlates with the strength of the electron
acceptor. This finding indicates that a rational tuning of the
Figure 21. Monoporphyrin BCO-linked systems as photosynthetic mimics. photophysical properties by the push–pull chromophores as
Review
electron acceptors is possible. The computed Marcus curves To further understand the factors that control the depend-
showed that the charge-recombination kinetics in the inverted ence of ET rates on the distance between the electron-donor
region was greatly affected by enhancing the electron-vibra- and the -acceptor, a series of (ZnII–FeIII) 5,10,15,20-tetraarylme-
tion couplings, due to the conformationally highly fixed push– talloporphyrin dimers 189, with a variety of different linkers, in-
pull acceptor chromophores. X-ray crystal structure data cluding BCO, were synthesized and the kinetics of their PET re-
showed well-defined systems holding the acceptor and donor activity were measured.[241] Through the use of fluorescence
moieties at fixed distances with edge-to-edge distances of lifetime measurements, the electronically excited states of the
around 17 a with little spectral overlap between the porphyrin zinc porphyrin to the bis(imidazole)iron porphyrin cation could
and acceptor moieties. It can be deduced from this data that if be determined. Results showed that when the distance was in-
electron transfer is occurring by a through-bond mechanism creased by 13 a the rate of electron-transfer only decreased by
the likelihood of Fçrster resonance energy transfer is greatly a factor of 165 indicating a small reduction of the electronic
reduced. coupling with distance. Selective nucleophilic aromatic substi-
It is of great interest to generate long-lived ion pair (IP) tution of the para-fluorine atoms in tetra-arylporphyrins was
states via singlet radical ion pair states to effectively mimic effi- employed in the synthesis of the molecular building blocks.
cient charge separation (CS) in a photosynthetic reaction This method allowed for a wide variety of systematic modifica-
center (RC). Strategies based on multicomponent donor–actions such as type and length of spacer, metal center, and
ceptor systems that require multistep electron-transfers offer redox-potential difference between donor and acceptor. A
great possibilities in achieving this goal. With this in mind, con- single zinc(II) or one iron(III) atom can be inserted after the
formationally constrained triads 188 were synthesized consist- synthesis of the symmetrical porphyrin dimer (Figure 23).
ing of a metal-free porphyrin (H2P), a zinc porphyrin (ZnP) and Further studies involving porphyrin-based donor–bridge–ac-
1,4:5,8-naphthalenetetracarboximide (NIm) (Figure 23).[240] The ceptor (D–B–A) systems aimed to find the triplet excited-state
porphyrin moieties are bridged by four different aromatic deactivation of a gold porphyrin (AuP) (Figure 24).[242] 1,4-Di-
spacers one of which is BCO-1,4-diylbis(1,4-phenylene). Pico- ethynyl-BCO was utilized as a saturated linker to explore
second excited-state dynamics were studied with these sys- whether electrons/electron holes can be transferred within the
tems using picosecond time-resolved transient absorption dimer 190 between AuP and ZnP. As a comparison, 1,4-diethy-
spectroscopy. Results showed that long-lived ion pair states of nylbenzene (BB) and 1,4-diethynylnaphthalene (NB) were de-
the triads (ZnP) + -(H2P)-(NIm)@ were observed upon photo-exci- rived as conjugated linkers. The porphyrins are separated by
tation by charge separation between the (H2P)* and NIm fol- 19 a, edge-to-edge, so a direct (through-space) exchange
lowed by a hole-transfer reaction from the (H2P) + to the ZnP. mechanism was not predicted. Results showed no quenching
The rates of this hole transfer were used to determine quan- of AuP that is, no hole transfer, when the conjugation in the
tum yields of the formation of long lived ion-pair states system is broken due to the BCO linker. While long-range hole
(Figure 22). transfer from AuP to ZnP occurs on the nanosecond time scale
at room temperature in the dimers connected by fully-conju-
gated bridging chromophores (NB and BB).
A similar porphyrin scaffold was used to investigate effects
on the photophysical processes in the donor–bridge–acceptor
(D–B–A) systems through studies of the acceptor spin state.[243]
Again, 1,4-diethynyl-BCO, -BB and -NB were the linkers investi-
gated. In this system 191, FeP acts as the acceptor while ZnP
acts as the donor. FeP is modulated from iron(II) to low-spin
iron(III) by the coordination of an imidazole ligand. In previous
such systems, the high-spin FeIIIP significantly enhances the in-
tersystem crossing in the ZnP, as the dominating deactivation
Figure 22. Energy-level diagram of artificial photosynthetic-bisporphyrin
model 188 (ZnP = zinc(II) porphyrin, H2P = free base porphyrin, pathway for the singlet excited zinc porphyrin. But this process
NIm = 1,4:5,8-naphthalenetetracarboximide; cf. Figure 23). is only a minor contribution to the quenching of the low-spin
Figure 23. BCO-linked porphyrin dimers.
Review
Figure 24. BCO-linked bisporphyrin systems as photosynthetic mimics.
iron(III); instead the major photophysical process that is occur- as for the construction of supramolecular assemblies and giant
ring is a long-range electron transfer on the picosecond time- molecules. Furthermore, in the last decade, the mechanical
scale allowing intersystem crossing to occur at its “normal” properties of wheels, vehicles, rotors, and motors have been
rate. EPR and UV/Vis measurements were used to prove the vigorously studied. Molecular machines and rotors are seen in
change from iron’s high-spin state to low-spin state upon imid- all living organisms and possess vital roles in many biological
azole coordination. Steady-state and time-resolved fluores- processes from cell division, motility and muscle contraction to
cence measurements were used to measure total quenching supporting cellular metabolism, vesicle and neuronal transport,
efficiencies for the excited states of the zinc porphyrin donors. as well as signaling and energy processing in cellular mem-
Again an analogous porphyrin-based donor–bridge–accept- branes.[245] As a result of the impressive flexibility and efficiency
or (D-B-A) system 192 with a 1,4-diethynyl-BCO spacer was in- observed in these biological nanomachines, much experimen-
vestigated, this time to find out the contributions towards sin- tal effort has been invested to develop artificial molecular de-
glet energy transfer from Fçrster and Dexter mechanisms.[244] A vices that can be used in areas such as medicine, nanotechnol-
clear distinction between the two mechanisms can be seen ogy and material science.
when the inert BCO-linker is used. This so-called superex-
change mechanism for singlet energy transfer has been shown 6.1. Rods
to make a significant contribution to the energy transfer rates
6.1.1. Liquid crystals
in several D–B–A systems and its D–A distance as well as D–B
energy gap dependencies have been studied. In each system, Liquid crystals (LCs) are largely known for their use in LCDs,
the acceptor is a free base porphyrin and the donor consists of namely liquid-crystal displays that are incorporated into many
a zinc porphyrin with/without a coordinated pyridine ligand. everyday electronic devices such as electric wrist-watches. A
Complementary results were obtained for the energy-transfer nematic LC is a transparent liquid that can cause the polariza-
processes in these BCO-bridged porphyrin D–B–A systems with tion of light due to its crystal-like organization, and how much
both experimental and theoretical methods. Results highlight- the light is polarized can in turn be modulated through the ap-
ed that the singlet energy transfer contribution is relatively plication of electric current. LCDs are made from nematic,
similar from both Coulombic (Fçrster) and through-bond su- smectic A or C materials. The LC phases are usually comprised
perexchange mechanisms and that the relative contributions of molecules containing a rigid core with flexible substituents
do not vary with the D–A distance. The distance-dependence to for an extended rod. The mesogenic rigid cores provide the
was shown to be approximately exponential for through-bond anisotropic interactions, required to form the LC state and are
coupling for singlet energy transfer. thought to modulate the properties of the materials while the
substituents lower the melting point of the molecule.[246]
It is rare that thermotropic LC phases are found in single-
6. Applications of Rigid-Linear Linkers in
ring compounds as they often crystallize before forming a
Molecular Rods and Rotors
mesophase. But these compounds, especially with simple alkyl
Aliphatic rigid linkers are seen throughout material chemistry, substituents, are desirable for their potential to reduce the vis-
from areas such as molecular rods and rotors to metal organic cosity of nematic mixtures while not affecting the devices op-
frameworks (MOFs). Molecular rods first became of interest erating range.[247] Additionally, studies with these simplified
due to their applications in electron and energy transfer stud- structures reduce the number of variables so the actual ring
ies, their use in liquid crystals and polymer chemistry, as well effect on mesogenic behavior can be assessed. Simple nonpo-
Review
lar compounds with homostructural cores were employed

using the BCO moiety.[246] Previous studies with two-ringed
structures showed inconsistencies in their structure–property
relationship and it was thought to be due to conformational
preferences and intramolecular dynamics of the two-ring com-
pounds taking precedence over the relative sizes of the cores
rings.
The dipentyl- and diheptyl-BCO derivatives 193 and 194
were synthesized and studied in the pure state and in binary
mixtures with a nematic host and they were found to exhibit a
monotropic nematic phase (Figure 25).[246] This the first exam-
Figure 26. Various BCO-based liquid crystals exhibiting wide-range nematic

phases.
Figure 25. BCO-based liquid crystals.

A group of 33 4-n-alkylphenyl-4-n-alkyl-BCO-1-carboxylates
201–202 were synthesized and were shown to possess many
nematic phases that exist up to high temperatures and have
ple of a single-ring hydrocarbon and opens up possibilities to higher clearing points when compared with cyclohexane and
find low-temperature thermotropic phases for other single-ring benzyl derivatives.[252] Moreover, they exhibited moderate vis-
structures. A comparison of single- and two- ring structures cosity, low birefringence, and low dielectric anisotropy in the
showed that ring stereochemistry might be influencing the sta- nematic phase. But the most significant features of these ester
bility of the liquid crystals, but further studies are necessary mixtures with cyanobiphenyls is the sharpness, and low tem-
with larger rods to confirm this. 4-pentyl-BCO-1-carboxylic acid perature dependence of the threshold voltage, and the low
was utilized to synthesize these compounds, firstly a lithium– tendency for injected smectic properties. For all BCO deriva-
halogen exchange reaction was employed to form the butyl tives, although the nematic-isotropic transition temperatures
ketone, followed by a reduction to form the desired alkylated (TN-1) may vary for different functional groups, what remains
product 193. constant is the higher TN-1 values obtained for BCO compared
Previous nematic materials used for LCDs have several unde- with cyclohexane and benzene analogues.[253]
sirable properties associated with them such as coloration and The relationship between LC stability and molecular confor-
chemical and/or photochemical instability, which are attributed mational effects has been show through empirical data.[254] The
to the central linking unit between the two benzene rings in data suggests the increased flexibly in the molecule leads to
the compounds, such as cyano-substituted stilbenes and decreased phase stability owing to a lower dynamic aspect
Schiff’s bases, azo and azoxy compounds. The removal of ratio and lower packing density in the liquid crystalline phase.
these aromatic linking through the replacement of a benzene These trends can be observed in homologous series, where in-
ring by a cyclohexane ring not only allowed for mesogens creased chain length results in decreased clearing temperature
with lower melting points, but often they had higher clearing for high-temperature materials.[255] A series of isostructural
points too.[248] While these results provided a range of stable compounds containing p-carborane, BCO and benzene were
nematogens of high positive dielectric anisotropy, ever increas- synthesized to investigate the effect that different phenyl/alkyl
ing demands require LCs capable of wider ranges in func- connecting groups have on the mesogenic properties of LCs
tion.[249] using thermal and optical methods.[256] Results showed the
The BCO scaffold had previously been shown to be detri- order for mesophase stability in the series as (Alk)CH2CH2@<
mental to the LC properties.[189] However, a series of mono- (Alk)OOC@< (Alk)CH2O@< (Alk)COO@. Different tests aimed to
and diester BCO molecules displayed higher nematic to iso- distinguish what factor caused the impact of the structural ele-
tropic liquid transition temperatures than analogous materials ments BCO, benzene etc. on phase stabilization but none
such as phenylene rings and cyclohexane rings (Figure 26).[250] could be identified. Instead, it is proposed that a combination
1,4-Disubstituted-BCOs 195–200 were synthesized with three of conformational properties of structural elements, such as
types of ester from BCO carboxylic acids and phenols. This their relative sizes, and electronic properties of the benzene
series of LCs provided a new range of colorless, chemically and ring bearing the substituent, dictate mesogenic properties.
photochemically stable compounds that consisted of nematic A common way to modulate aromatic cores in LC systems is
phases with low birefringence and high positive dielectric ani- through fluoro substitution. Fluorine substituents can reduce
sotropy. Friedel–Crafts alkylation reactions were employed to melting without total elimination of liquid crystal phase due to
attach the aromatic units to the brominated BCO moiety, fol- its small atom size and high electronegativity that modulate
lowed by a functional interconversion on the brominated aro- the physical properties of the molecule.[257] A variety of linear-
matic for a cyano group.[251] ly-BCO-connected LC were synthesized with fluorine-substitut-
ed benzenes incorporated in different positions of the meso-
Review
Figure 27. Investigation of the mesogenic and dielectric properties of lateral-

ly fluorinated three-ring mesogens.
genic core 203–204 (Figure 27).[258–260] Results showed that

when fluorine atoms were incorporated at the end or in the
middle of the mesogenic core a decrease of melting and clear-
ing point values was observed which either reduced the inter-
val of the mesophase or removed the LC phase completely de-
pending on the location and number of fluorine atoms. Key
steps to the synthesis of these compounds involve the reac-
Figure 28. BCP liquid crystals.
tion of a BCO copper reagent with the iodinated bicyclic aro-
matic units.
The fluorinated BCO derivative 205 and benzene LCs 212, benzene and cyclohexane derivatives and as expected the
showed that upon fluorination nematic behavior was eliminat- BCP analogue showed strong destabilization in the smectic
ed for both compounds while their SmC and SmA phases were phases and much lower clearing temperatures.[262]
enhanced and for the BCO derivative induced SmA, smectic I
(SmI) and smectic F (SmF) phases were observed.[258] The key
6.1.2. Structural chemistry and crystal engineering
step in the synthesis of compound 205 involved the reaction
of the BCO alcohol, 4-(3,4-difluorophenyl)bicyclo[2.2.2]octan-1- Crystal engineering utilizes intermolecular interactions to con-
ol, with 1,3-difluoro-5-propylbenzene in the presence of H2SO4. struct crystal structures from molecular components into reoc-
The interest to incorporate BCP into LCs first began as it was curring patterns; understanding the relationship between mo-
hypothesized to increase the thermal stability of the mesogen lecular structure and crystal structure is imperative for its suc-
and improve other mechanical properties.[8] Research has cess. Identification of specific functional groups that allow for
shown BCP to contribute to both low- and high-order predictable and persistent robust synthons is required to reach
phases,[261] although in general, thermal stabilities of the liquid- the target crystal structure. Carboxylic acids are strong donor–
crystalline phases are lower than other analogous compounds. acceptor functionalities that allow for hydrogen bonding with
It has also been shown that BCP is far inferior to BCO, benzene other weak donors and acceptor moieties. There are two dis-
and cyclohexane rings at stabilizing nematic phases. This is tinct conformations that occur when carboxylic acid moieties
thought to be due to low rotational barriers and thus high hydrogen bond, notably syn-planar or anti-planar. As a result
conformational mobility of the bridgehead substituents.[262] of these two conformations, there are four possible ways that
BCP has been attached directly to the other rings such as in functionalities interlink, the most dominant is the syn-syn cen-
207 and 208, but also via ester linkages such as in 206 and trosymmetric dimer. The other possible catemers known to
209 and ethylene bonds (Figure 28). When directly attached to form are of the type syn-syn, anti-anti, and the rare alternating
an aromatic ring BCP compounds behave similarly to BCO ana- syn-anti (Figure 29 a,b).
logues albeit with much lower clearing points. Conversely, A series of 4-substituted-1-cubanecarboxylic acids were syn-
when connected between two aromatic groups mesophase thesized with interesting crystallization patterns that indicate
stability is undermined and only low-transition temperatures their potential for crystal engineering.[266] Within this family of
are observed.[263] When BCP is connected to the aromatic rings compounds, the unusual catemers of the syn-anti-conforma-
via an ester link the mesogenic properties slightly improves tion are frequently observed, specifically in the cases for which
again. On the other hand, when BCP is connected directly to X = Cl, Br, I, or CO2Me. The reoccurrence of this rare conforma-
aliphatic substituents 211 or via an ester link 209 relatively tion is attributed to the stabilization between C@H···O and cu-
high-phase stabilities are observed and almost exclusively in banyl C@H bonds caused by the high acidity of the cubanyl
the highly-ordered smectic phases. In order for [n]staffanes to protons. In this orientation the halogen atoms can be seen to
exhibit liquid-crystalline phases, a minimum of three BCP units fill the centrosymmetric voids that are present due to the rest
are required,[264] whereas with BCO only one unit is required of the packing, thus stabilizing the whole crystal structure.
for the nematic phase and two for the smectic phase[246, 265] To Moreover, when X = CO2Me cyclic patterns are formed, and in
further cement BCP unsuitability as a LC component, a com- cases for which the substituent is too small that is, X = H, too
parison between a known polymer was performed with BCP big, for example, X = Ph, or when it has a specific hydrogen-
Review
sterically demanding shallow glide conformation. This confor-

mation is further reinforced by the C@H···O hydrogen bond
from an acidic cubyl C@H group (Figure 30 c). Furthermore,
there is an increased ability for cubane to form C@H···H@C
bonds, explaining its high melting point. This ability is attribut-
ed to the large C@C-H pyramidality angle of the interacting hy-
drogen atoms present due to the tertiary and restricted nature
of the carbon atoms.[269]
Remarkable not only because of its aesthetic curiosity, the
structure of fullerene-cubane heteromolecular crystals with C60
and C70 fullerenes were shown to form high-symmetry molecu-
lar crystals with cubane due to the topological molecular rec-
ognition that occurs between the complementary surfaces of
the fullerene and cubane molecules (Figure 31).[270] These com-
Figure 29. Different hydrogen-bonding interactions for 1,4-substituted

cubane carboxylic acids.
bonding preference of its own X = CONH2 the catemer no

longer forms and instead dimer formation is seen (Figure 29 c–
e).
Following this work, an additional study was carried out that
further showed how the C@H bond of cubane is activated
toward hydrogen-bond formation and its ability to support a Figure 31. Fullerene–cubane heteromolecular crystals Reproduced with per-
crystallographic framework with stabilizing C@H···O bonds.[267] mission from ref. [270]. Copyright Nature Springer 2005.
This was demonstrated in an alternative way with a series of
primary cubane carboxamides, which investigated the N@H···O
hydrogen bonds in amides.[268] The usual motif observed for pounds were prepared by evaporating a 1:1 mixture of ful-
primary carboxamides is the centrosymmetric dimer with syn- lerenes and cubanes. In these crystals static cubane acts as a
oriented N@H groups, similar to the carboxylic acid dimer, bearing between the rotating fullerene molecules by occupy-
while the anti-oriented N@H groups form either a linear pat- ing the octahedral voids of the face-centered-cubic (fcc) struc-
tern with or without a glide plane (shallow-glide motif). The tures. The rotation of fullerenes around the static cubane
motif without the glided plane characteristically has succeed- occurs by a “rotor-stator”-phase between 140 and 470 K,
ing molecules that are related by 5.1 a translation (Figure 30 a). whereas below 140 K a phase transition to orthorhombic ori-
ented phase occurs.[271]
6.1.3. Other rods

Polymerization of BCP enables access to rigid molecular rods
that show restricted rotation along the rod axis. BCP polymers
213–216 can be synthesized using either radical[272, 273] or
anionic initiators,[274] but also from the unsubstituted [1.1.1]pro-
pellane which polymerizes spontaneously. Additionally,
Grignard reagents can be coupled via palladium catalysis to
produce symmetrically disubstituted [2]staffanes 217. The suc-
cess of this homocoupling hinges on the presence of bromo-
Figure 30. Amide hydrogen-bonding motifs.
methane, a byproduct from the first step of the BCP synthesis,
as it enables the oxidation of Pd to PdII.[3, 275] Another series of
When a linear pattern without a glide plan occurs in combina- different [n]staffanes were synthesized with combinations of
tion the dimer motif the commonly occurring translational BCP with BCO 218 and cubane 219 moieties (Figure 32). Sub-
ribbon synthon is formed (Figure 30 b). Notably, the primary stituents were added at the end of the oligomers, such as
cubane carboxamides have been shown not to utilize the @CO2CH3, @n-C4H9, @C6Hs, @Br, @I, and @SCOCH3.[273] A compari-
ribbon motif, because the cubane skeleton is too big for the son was made of these straight rods and spool-like connectors
5.1 a translation motif, thus encouraging formation of the less as a molecular-size civil engineering equivalent to a child’s
Review
Figure 32. Molecular rods that exhibit restricted rotation along the rod axis.
“Tinkertoy” play set which is essentially a toy construction set.

These “mixed” staffanes have approximately equal separations, Figure 33. Terminal mono- and bidentate binding sites, star-shaped struc-
as BCO and cubane have similar lengths. The use of these moi- tures used as trigonal and tetragonal connectors.
eties in rod structures also enables a 2 a increment relative to
a parent [n]staffane so they can also be utilized for rod exten-
sion applications. Synthesis of the compounds was initially per- tential applications of these rodlike molecules include use as
formed by radical induced oligomerization from the highly re- liquid crystals, use in electron-transfer reaction studies, and use
active tricyclo[1.1.1.0]pentane intermediate with either itself or as noncollapsible nanosized molecules (Figure 34).
1,4-diiodocubane.[60, 273] Further methods were developed to
symmetrically couple bridgehead-BCP bromides and iodides
via the oxidation of bridgehead-cuprates with lithium re-
agents.[276]
Carborane was also connected to the BCP moiety either di-
rectly or via two ethynyl bonds enabling the construction of a
new type of rodlike structure 220 and 221, respectively. Its ap-
plication as a molecular rotor is also apparent as both cages
have free-rotation around the axial-linking bond. Sonogashira
methodologies were employed to attach the substituents to
1,3-diethynylBCP to form 221, overcoming the possible rear- Figure 34. Rodlike molecules with BCO and cubane linkers.
rangement of the bicyclopentane cage that occurred in many
other cases.[277]
As an expansion of the Tinkertoy tool box, different rods A method for the synthesis of alkynylcubanes was devel-
and connectors have been used to construct large molecular oped to expand currently available nanoarchitectures.[280] Ter-
structures and connectors. 1,3-diethynyl-BCP has been used to minal and substituted alkynylcubanes were synthesized
synthesize 1,3,5- and 1,2,4,5-substituted benzene derivatives through the nBuLi-promoted elimination of halogen atoms
222 and 223, which are linked by BCP to the bipyrimidyl termi- from 1,1-dibromovinylcubanes followed by quenching with the
ni, as trigonal or tetragonal connectors for the construction of desired electrophile, while dimerization and cross-coupling re-
large molecular structures. Sonogashira methods were actions of various diethynylcubanes afforded longer rods 225.
employed to link the units in a convergent synthesis Directly-linked cubane polymers were also synthesized form-
(Figure 33).[278] ing rode-like structures with very poor solubility.[62, 281] The syn-
The synthesis of rodlike molecules was achieved using Kolbe thesis was performed with cubyllithium and 1,4-diiodocubane
electrolysis enabling a shorter, less labor intensive method to to afford the oligomers 226 through successive halogen-ex-
access rigid noncollapsible nanosize spacer units.[279] Kolbe change equilibrium reactions. Termination of the reaction
electrolysis works by joining two carboxylic acids bearing alkyl occurs with a halogen–metal exchange. The longest rod ob-
groups in the a-position. Previous examples included only tained by this method was 15 a, in which each cubane contrib-
simple alkyl groups, whereas now the method has been ex- utes ~ 4.15 a. The application of this method can be extended
panded to include the highly branched BCO scaffold 224. Po- by trapping the lithiocubane intermediate with various com-
Review
pounds such as phenanthrene-9,10-epoxide, followed by a de- held together by chemical bonds. The rotator has the smaller
hydration reaction to form the product 227. moment of inertia while the stator has the largest.
Due it its very rigid 3D structure, cubane offers opportunities Hexagonal tris(o-phenylenedioxy)cyclotriphosphazene (TPP)
to make a variety of new materials, including polymers. The was employed as a host to investigate the behavior of dipolar
first cubanyl polymer was achieved by the metathesis polymer- rotor assemblies that acted as guests.[286] A variety of different
ization of the 1,4-bis(homoallyl)cubane 228. Addition of 3,6-disubstituted pyridazines were synthesized including 3,6-
Schrock’s molybdenum catalyst enabled the production of an bis(3-methylbicyclo[1.1.1]pent-1-yl)-
oligomer with an average of 6.2 repeat units per chain pyridazine 232 (Figure 36). It was
(Figure 35).[282] seen that the BCP compound
formed hexagonal bulk inclusion
compounds with TPP and that the
Figure 36. BCP rotor.
in-plane lattice parameters for the
hexagonal phases increased with
the size of the end group, which in
turn controlled the energy barriers for rotation of the pyrid-
azine dipole. Overall it was shown that through a combination
of molecular design and optimal positioning of the rotor mole-
cules in the host material, a dramatic lowering of rotational
barriers can be achieved. Key steps in the synthesis of 232 in-
cluded a Grubbs metastasis reaction to connect the two BCP
moieties by a double bond. The introduction on the pyridazine
ring was achieved by the reaction of hydrazine with the bridg-
ing 1,4-diketone moiety, followed by its subsequent aromatiza-
tion with Pd/C.
Bis{[4-(4-pyridyl)ethynyl]bicyclo[2.2.2]oct-1-yl}buta-1,3-diyne
233 was synthesized containing two 1,4-diethynyl-BCO rotators
Figure 35. Cubane polymers. linked by a diyne fragment (Figure 37). Sonogashira methodol-
ogies were employed to link the BCO and pyridine moieties.[287]
Solubility of these oligomers posed a problem as it inhibited

the synthesis of longer length chains. Poor solubility was
thought to be due to the hindered free-rotation of the poly-
mer chain because of the steric bulk of cubane, thus leading
to the precipitation and premature terminate of the polymeri-
zation reaction. Different functionalities were incorporated into
the chain to overcome this problem such as amide linkages
229 with aromatic diamines and it was found that chains up
to & 20 units could be obtained.[283] Additionally, tethering
cubane to a polymer backbone 230 was carried out to increase
its free-rotation and thus increase its entropy and, in lieu, its
solubility. Ring-opening metathesis polymerization of cubane-
tethered norbornene monomers was employed to obtain poly-
Figure 37. Ethynyl-linked mixed molecular rotors.
mer chains of up to ~ 143 units.[284]
Polymerization reactions were also employed to synthesize a
double-stranded ladderphane 231 containing cubane ester Unique features were observed for this compound as it con-
linkers by ring-opening metathesis polymerization (ROMP) of tains two Brownian rotators with different activation energies
bisnorbornene monomers (Figure 35).[285] The ladderphanes and as it self assembles into a 1D crystalline array with space
were prepared through self-assembly, forming an ordered pat- inversion symmetry. The dynamic equilibrium of the BCO
tern similar to that seen in a double-stranded DNA helix. rotors was investigated and evidence was found showing pairs
of adjacent rotors in adjacent molecules rubbing against each
other just like two cog wheels that are in direct contact with
6.2. Rotors one another in a microscopic clockwork.
In this polymorph, the motion is highly correlated, whereas,
6.2.1. Molecular rotors
in contrast, another polymorph was observed in which half of
Molecular rotors are described as molecules containing two the rodlike molecules appear to be shifted with respect to
parts that can easily rotate relative to each other. The parts their closest neighbors. This translation disconnects the cog-
can either be interlocked such as rotaxanes and catenanes or wheel-like pairs of rotators in the lattice in such a way that
Review
their motion becomes uncorrelated. In both polymorphs, this

motion takes place independent of mutations in the preferred
rotators and of the “mutamer”-induced second harmonic gen-
eration.[288] Remarkably, alternating the speed of crystallization
controls which polymorph is formed. Faster recrystallization re-
sults in the first polymer while a slower process forms the
more thermodynamically stable shifted second polymorph en-
abling the coglike motion to be switched on and off. A poten-
tial application of these molecules includes molecular optome-
chanical switches.
1,4-Bis{3-[(trimethylsilyl)ethynyl]bicyclo-[1.1.1]pent-1-yl}buta-
1,3-diyne 234 was also synthesized in a control experiment uti-
lizing two BCP moieties instead of the two BCO units
(Figure 37).[289] The BCP units can rotate but are achiral so pro-
duce no second-order optical response. They self-assemble by
C@H···N hydrogen bonds in a crystalline array similar to the
BCO derivative, but the rotor–rotor interactions are weaker as
they do not rub against each other as often so no coglike
motion is observed. At thermodynamic equilibrium the same
Figure 38. Triptycene rotors.
type of correlated gearing motion is occurring for both deriva-
tives, but the BCP derivative has a much smaller difference in
energy between the low-energy gearing relaxation process the design and synthesis of molecular machines”.[294] The interest
and a higher-energy gear-slipping relaxation process. in functional molecular machines first began in the nineties
As unsymmetric rotators with a 1,4-diethynyl-BCO core are when the real time rotation of an ATP synthase macromolecu-
needed for engineering crystalline arrays of functional molecular motor was observed.[295] The synthetic aim of this field of
lar rotors, new methods to expand and improve the available study involves the synthesis of miniature man-made mechani-
synthesis with this moiety were investigated.[290] Protecting cal devices on the nanoscale. For this to be successful the mo-
groups of the acetylene bonds such as carbinol were utilized tions of the molecular machine must be controllable, the sur-
to give the 2-methyl-3-butyn-2-ol moiety that is desirable for face the molecule is on must be suitable as must the external
its polar character, ability to sustain orthogonal functionaliza- stimuli that is necessary to provide the energy for move-
tion and easy removal. This enabled the BCO moiety to be un- ment.[296]
symmetrically functionalized to allow for compound 236 and A solid-state molecular rotor with a large triptycene rotator
homocoupled by Glaser-coupling methodologies to give com- 240 was synthesized, up to three times larger than previous
pound 235. Vastly improved yields were obtained with this phenylene rotators (Figure 38).[297] This expanded triptycene ro-
strategy and a larger diversity of polyrotors has been made tator was found to be functional due to its volume conserving
available. The mixed rotor 237 was synthesized using Sonoga- system. Experiments revealed that mechanical functions in
shira methodologies to expand the library of asymmetrically solids can be attained for larger molecules by suitable molecu-
substituted BCO derivatives. The key step to connect the BCP lar design. The key step in the synthesis was a Diels–Alder re-
and BCO units employed Cadiot–Chodkiewicz cross-cou- action with benzyne and functionalized 9,10-diethynylanthra-
pling.[291] cene to form the triptycene moiety followed by deprotection
Initially bis(9-triptycenyl)X-type molecules were investigated of the ethynyl protons and Sonogashira reactions to give 240.
for their use in dynamic gearing. The triptycene moieties are A series of molecular machines have been synthesized that
connected by single atoms/groups (X = CH2, NH, O, SiH2, Ph, S) employ triptycene as the molecular wheels with various aro-
producing nonlinear compounds. While these compounds are matic and unsaturated backbone connectors, for example, trip-
outside the scope of this review, they are some of the first ex- tycene with a butadiyne linker 241 (Figure 39). A macroscopic
amples of compounds in this class. It was seen that the barrier wheelbarrow 242 was synthesized with triptycene wheels that
heights for gear slipping are dependent on the connecting X theoretically could rotate in the same direction, with a large
group.[292] Following this, the use of three consecutive bonds polycyclic aromatic backbone, two 3,5-di-tert-butylphenyl
was investigated to see if the angle and/or distance between ‘legs’, and two 4-tert-butylphenyl ‘handles’ that underwent ma-
the two 9-triptycenyl groups would vary significantly, effecting nipulation with the tip of the microscope.[298] Attached to a
the tightness of gearing in these systems. A cis-vinylene group Cu(100) surface, unfortunately, no lateral motion of the wheel-
was employed as the connecting group to synthesize cis-1,2- barrow was observed upon stimulation with the STM tip due
bis(9-triptycenyl)ethylene 239 through the hydrogenation of a to the aromatic rings of triptycene strongly physisorbing by
ethynyl linker 238 (Figure 38).[293] parallelization to the metal surface causing deformation. The
Work with molecular machines was first pioneered and de- synthesis of this molecule involved multiple Knoevenagel-
veloped by Jean-Pierre Sauvage, Sir J. Fraser Stoddart, and Ber- Diels–Alder reaction sequences with an a-diketo fragment to
nard L. Feringa, who were awarded the 2016 Nobel prize “for build the dibenzopyracene chassis. The triptycene moieties
Review
Figure 40. A crystalline rotor.
transition at 145 K. The switching mechanism of the rotational

barriers and the frequency of associated rotational motion in
this system were investigated through the deliberate use of
halogen- and hydrogen-bonding. Observations showed that
the reversible change is caused by a squeezing of the rotators’
C@Hrotator···Istator hydrogen bond cloud across the C@Istator···Istator@C
halogen bond. Moreover, second-harmonic generation from
this material has been observed, showing the advantages of
using polarized light to probe the torsional degree of freedom
of chiral helix blades, in addition to symmetry and dimension-
ality of large collections of chiral rotors in the solid state.
6.2.2. Molecular gyroscopes

There is a growing need for organic materials that have tun-
able transmittance, refraction, polarization, and color for use in
communication technologies. While current research in this
area originates from polymer and liquid crystal chemistry, a
new concept has emerged in which photonics materials are
constructed using dipolar units that can reorient rapidly under
the influence of electric, magnetic, and optical stimuli. These
new molecular architectures are expected to function similarly
to macroscopic compasses and gyroscopes.
Figure 39. Molecular machines with triptycene wheels. A facile synthesis has been developed for molecular rotors
made up of ethynyltriptycenes linked together by various aro-
matic groups such as 1,4-phenylene 245 a, 1,4-biphenyl 245 b,
were attached in the last step using classic Sonogashira condi- 9,10-anthracenylene 245 c, and 2,7-pyrenylene 245 d
tions. (Figure 41).[302] The dibromoarenes are coupled with ethynyl
Triptycene enables the entire functionalized molecule to triptycenes through Sonogashira reactions. Semiempirical cal-
move easily on the surface by its rolling motion. System 243 culations were conducted on these materials with the AM1
was the first ever synthesized nanovehicle, with the two tripty- method and results suggested that an essentially frictionless
cene wheels linked along a butadiyne axel, that enabled the rotation about triptycene–alkyne and aryl–alkyne single bonds
molecule to have almost free-rotation and maintained a linear
geometry.[71, 300] Synthesized over three steps from 9-bromoan-
thracene, 9-ethynyltriptycene was then dimerized using Glaser-
Hay methods to give the diethynyltriptycene wheel dimer.[299]
The molecule was sublimed onto a Cu(110) surface and wheel
rotation was induced and observed for the first time using a
STM tip. Typically, only one triptycene wheel was observed
moving while the other stayed stationary, so further molecules
were investigated to see if both wheels could simultaneously
be activated.
The molecular rotor 244 was synthesized in crystalline arrays
with a 1,4-diethynyl-BCO core that acts as a neutral, soluble
spacer for the design of halogen-bonded metallic conductors
and superconductors.[301] It was found that the dynamics of the
system was affected by the environment it was in, which in-
duced phase transitions (Figure 40). 1,4-Bis[(2,4,6-trifluoro-3,5-
diiodophenyl)ethynyl]BCO 244, synthesized by Sonogashira
methodologies, changes back and forth across a reversible Figure 41. Molecular compasses and gyroscopes.
Review
should be occurring in gas phase. Rapid rotation was also ob- molecular machines based on amphidynamic crystals with iner-
served also in the solution phase from a dynamically averaged tial rotors.
1
H and 13C NMR spectra. Amphidynamic crystals have strong translational interactions
A convergent synthesis was reported to prepare molecular that are separate from internal rotational motions which are
gyroscopes in which para-phenylene rotors linked by triple thermally activated in the solid-state.[307, 308] The role of intramo-
bonds to methyl-substituted triptycenes act as pivots and en- lecular interactions, vibrations, coupling, and flexibility of dif-
capsulating frames. 1,4-Bis[2-(2,3,6,7,12,13-hexamethyl-10-alkyl- ferent segments were investigated using extensive rigid-body
9-triptycenyl)ethynyl]benzenes 246 were prepared from 2,3-di- molecular dynamics simulations and simple phenomenological
methyl-1,3-butadiene by using Diels–Alder cycloaddition and a arguments. Cubane 249 and BCO 250 analogues with 1,4-trityl
Sonogashira reactions to attach the three units. Different trip- substitutions were model systems (Figure 42).[309] Results sug-
tycenes with methyl, propyl, and benzene substituents at the gest that the flexibility and size of a molecular rotor, alongside
bridgehead C10-position were employed to synthesize a varie- intramolecular interactions within the rotator and stator,
ty of molecular gyroscopes. The best results were observed strongly affect their crystal packing structure, energies and ro-
with small methyl and propyl electron donating substituents tational behavior. Ordered crystalline phases that have speci-
at C10 over the larger benzene group. Also, results suggest for fied free volume for rotations of the central group are seen
free movement around the phenylene axis to occur as low as when there are strong interactions are present in the stator
100 K, illustrating a relatively efficient gyroscopic motion.[303] To segments. Increased flexibility in the stator leads to increased
further improve upon the solubility and dynamic properties of disorder in the system, drastically affecting rotational dynamics
the 1,4-phenylene linked triptycene molecular gyroscopes the due to increased interactions with the local environment. Fur-
unsymmetric triptycenyl-trityl stator 247 was prepared. This thermore, the theoretical results obtained correlate with exper-
compound retains the relatively high melting point of the two imental data that suggested that rotational barriers are gener-
symmetric structures, while achieving the other aforemen- ally larger for less symmetric rotator groups and that electro-
tioned properties. The unsymmetric molecule was synthesized static effects might be not very important.
again through the use of Pd0-catalyzed cross-coupling with
1,4-diiodobenzene.[304] 6.2.3. Molecular gears
The target of amphidynamic crystals (otherwise known as
6.2.3.1. Molecular spur gears
molecular gyroscopes) is to obtain a molecule that rotates
close to its moment of inertia. A molecular rotor with a high The correlated motion of macroscopic mechanical devices can
symmetry order was synthesized with a BCO rotator linked to be mimicked on the microscopic level through designed mo-
rigid mestranol fragments.[305, 306] The compound was synthe- lecular gears that consist of two or more rotators in one mole-
sized in a one-pot, three-step coupling reaction between 1,4- cule. The most widely synthesized gears are spur gears which
diethynyl-BCO and mestrone with perfect diastereoselectivity hold the two rotors parallel to one another at the axes and
and good overall yields. Isomorphous crystals were formed have straight-teeth relative to the axes. For a gearing mimic to
with the benzene derivative of 248, but were not observed for be successful, it is essential to have the gear axes mounted on
the BCO rotator due to disorder in the packing (Figure 42). a rigid base in the same direction. Triptycene is a popular
choice for molecular gearing due to its D3h symmetry, a resem-
blance to a macroscopic gearwheel.
9-(2-Indenyl)-triptycene was dimerized to investigate wheth-
er the free-rotation around the indenyl-triptycene bond that
occurs in the monomer could be affected or inhibited.[310] The
sterically congested size and shape of the dimer 251 deter-
mined the orientation of the triptycene blades (Figure 43). In
the solid state, the C2-symmetry of the whole molecule is
broken due to the intermeshing of the pairs of triple paddle-
wheels and rotation is restricted. In solution C2-symmetry is re-
stored, as seen by the gear-like rapid contra-rotation of the
triptycene paddlewheels when it is dissolved. The racemic
dimer 2,2’-bis(9-triptycenyl)-1,1’-biindenyl 251 was formed
through the lithiation and subsequent oxidation of 9-(2-inden-
Figure 42. Amphidynamic crystals of molecular rotors. yl)triptycene.
Spur gears were synthesized with either an anthracene 252
or naphthalene 253 base and two triptycene rotors connected
NMR experiments showed that the BCO has a relatively low ac- by two acetylene shafts to diminish steric interactions between
tivation energy barrier allowing it to achieve a high average the two moieties. These molecular structures were compared
site exchange rate at ambient temperatures which is notable to investigate the orientation of the two gear shafts and the
due to the large size of BCO. These results suggest the applica- meshing of rotor moieties.[311] Results showed that tuning the
bility of BCO derivatives in ultrafast responsive materials and orientation of the two rotors was possible by varying the base
Review
Figure 44. Triptycenyl spur gears with nitrogen-aromatic linkers and a metal-
locene molecular gear.
of the triptycene ligands. The linear-to-helical conformational

switching, which is triggered by complexation/decomplexa-
tion, thus enables reversible control the intermeshed and de-
meshed states. Key steps in the synthesis include a Diels–Alder
reaction with a functionalized anthracene to form the tripty-
cene unit, an aldol condensation to attach an acceptor substi-
tuted olefin to the triptycene which was then converted to the
Figure 43. Triptycenyl spur gears. final product 255 through reaction with 2,6-diacetylpyridine.
The air-stable (9-triptycenylethynylcyclopentadienyl)(tetra-
phenylcyclobutadiene)cobalt complex 256 was synthesized as
component, and that the best system was achieved with the the first example of a metallocene-containing molecular gear,
anthracene base 252. There are two mechanisms of rotation in an effort to expand the number of teeth in the system over
possible when two triptycene rotors are connected in a spur the commonly used 3-toothed bitriptycene systems.[314] Addi-
gear. Firstly, the desired gear rotation can occur when the two tionally, this is an example of a molecular gear employing non-
wheels rotate in opposite directions, causing the “cogs” to equal gearing ratios. There is a low energy barrier to rotation
turn. In the second mechanism, gear slippage is seen when about the metal fragment in the complex and it is described
conrotation is observed, that is, rotation of the wheels in the as analogous to a low friction ball-bearing. 1H NMR studies
same direction causing the cogs to not interact. DFT calcula- were carried out on the system and, although independent ro-
tions showed that the optimum transition state for geared rotation of the individual triptycene and metallocene rotors
tation is structure GR1 where the barrier to gear slippage is cannot be quantifiably ruled out, it is strongly supported due
higher making gear rotation the preferred mechanism. Keys to results from previous studies that show bridgehead-substi-
steps in the synthesis involved Sonogashira coupling of 9-ethy- tuted triptycenes to have a very high threefold torsional barri-
nyltriptycene with the corresponding diiodoacenes. er.[315] Thus, it can be deduced that in order to avoid free-rota-
The gearing behavior of two parallel triptycene groups was tion a low energy-correlated gearing mechanism between the
further investigated using derivatives of 4,4-bis(triptycen-9-yl- two intermeshing cogs of the four and three toothed metallo-
ethynyl)bisbenzimidazole, including the first desymmetrized cene gear is occurring. The cobalt complex 256 was synthe-
spur gear 254 (Figure 44).[312] DFT calculations were employed sized from sodium carbomethoxy-cyclopentadienylide and key
that showed a preference for geared rotation over gear slip- steps in the synthesis include a cross-coupling reaction with 9-
page. Key steps in the synthesis involved a Sonogashira reac- iodoanthracene and a cycloaddition reaction with benzyne.
tion to attach the acetylene triptycenes to 4,4-dibromo-2,2-bis-
benzimidazole (BBI) and treatment of the free BBI nitrogen
6.2.3.2. Molecular multigear systems
atoms with excess 1-bromo-2-chloroethane to form the six-
membered ring. A cyclic multigear system 257 was synthesized with four 9,10-
The linear quinquepyridine (QPY) foldamer was connected triptycene units connected to four 1,2-phenylene units via
to two triptycene molecules at the second and fourth pyridine ethynyl linkers. This macrocycle was achieved through succes-
rings (in order to reversibly control the gearing system) form- sive Sonogashira reactions with 9,10-diethynyltriptycene deriv-
ing a molecular spur gear 255 (Figure 44).[313] Control was es- atives and diiodobenzene. DFT calculations showed the tripty-
tablished by the complexation and decomplexation of AgI to cene units to be intermeshed with one another via p···p and
the pyridine ligands. Upon complexation with a metal, mono- CH···p interactions. Despite this, all triptycene units in the tetra-
nuclear helical complexes are formed preventing the rotation mer rotated in a correlated and frictionless manner, regardless
Review
pliances, or from nature such as muscles and flagellae. For ex-

ample, in a vehicle the ability to stop by the use of a brake is
often as important as acceleration. On the molecular level,
spontaneous free-rotation around a single bond is continuous.
By reversibly coordinating a metal to a designed compound at
a remote site, a conformational change occurs in the molecule
restricting movement around the single bond, thus functioning
as a molecular brake.
Triptycene has been shown to function as a three-toothed
gear in the compound 259 (Figure 47).[318] It spins rapidly
around the bridgehead C@C bond that connects it with the di-
Figure 45. Quadruple triptycene gears.
of the continuous interactions between the gear units. 1H NMR

showed rapid rotation of the system, even at low temperatures
(Figure 45).[316]
6.2.3.3. Molecular turnstiles

A family of metal-mediated molecular turnstiles 258 was syn-
thesized with various methyl-substituted triptycene rotors con-
nected to two stators with pyridyl binding sites (Figure 46).[317]
Figure 47. Ion-regulated molecular brake.
pyridyl moiety. Upon coordination of a Hg2 + ion to the dipyrid-

yl moiety, the free-rotation around this bond is inhibited, en-
abling it to act as a braking system in the molecule 259 a. The
complex was accessed easily through two palladium-catalyzed
biaryl coupling reactions, the first to attach the two pyridine
moieties and the second a Stille coupling with 9-
Figure 46. Molecular turnstiles regulated by metal ions. (Me3Sn)anthracene. The final reaction to form the triptycene
scaffold involved a cycloaddition reaction with benzyne.
The longer triply-fused pyridine arene unit was also investi-
The methyl groups were introduced into the triptycene rotor gated for its use as a molecular brake 260.[319] Observations
to investigate the effect that increased rotor size has on the showed that upon coordination of Hg2 + , Zn2 + , and Pd2 + ions,
closed-state formation. In addition, metal-ion coordination was or even upon covalently bonding the two nitrogen units to-
investigated for close-state formation. It was observed that gether by a two-carbon bridge 260 a–d, rotation was still ob-
free-rotation occurs in the system at room temperature but in served in the system, even at temperatures as low as @120 8C.
the presence of either Pd2 + or Ag + rotation is restricted, by An analogy for what is happening in this system was suggest-
metal coordination at the pyridyl sites. The closed-state of the ed to be similar to a fastening a playing card to a child’s bike
system is only observed at reduced temperatures upon Ag + and the card becoming continuously dislodged by each pass-
coordination showing that it is the binding of metal ions to ing spoke.
the pyridyl group that determines the closed-state not the size A device that only allows rotation in one direction is com-
of the rotor. In this manner the bistability of molecular turn- monly known as a ratchet. The most basic components of a
stiles can be regulated allowing for potential applications in ratchet consist of a toothed ratchet wheel, a pawl to enforce
the construction of functional molecular devices. unidirectional rotation of the ratchet wheel, and a spring that
holds the pawl in place. Triptycene substituted with a helicene
such as in 261 was investigated for its use as a molecular
6.2.3.4. Molecular brake and ratchet
ratchet (Figure 48).[320] The triptycene acts as the ratchet wheel
The operation of machines is governed mainly by brakes and while the helicene is used as the pawl and spring. At room
motors, whether they are man-made, such as vehicles and ap- temperature rotation is frozen around the triptycene/helicene
Review
molecular brake was designed where protonation of [{h6-2-(9-

triptycenyl)indene}Cr(CO)3] 266 a notably increased the barrier
of rotation of the triptycene paddlewheel by causing a hapto-
tropic migration (h6 !h5) of the bulky metal carbonyl fragment
onto the adjacent five-membered ring (Figure 49).[322] Depro-
Figure 49. A ferrocenyl kaleidoscope.
Figure 48. Covalent regulated molecular brake.
tonation reversed this process. 9-(3-Indenyl)anthracene was

single bond. The molecule uses chemical energy to activate ro- synthesized using Heck conditions to couple indene with 9-
tation and a thermally induced isomerization reaction to bromoanthracene; the triptycene product was achieved
achieve unidirectional intramolecular rotary motion. When R = through a Diels–Alder reaction with benzyne.
H there is a plane of symmetry in the molecule 261 a, prevent- An electrochemically driven redox approach was then inves-
ing it to function as a unidirectional ratchet. While when R = tigated aiming at more widespread applicability. 9-Ferrocenyl-
Me 261 b symmetry is broken in the system but NMR studies triptycene 267 by and 9,10-diferrocenyltriptycene 267 ay were
indicated that the triptycene rotates equally in both directions. synthesized. Results showed that the diferrocenyl species
The helicene where R = H is more seen as a friction brake that exists as slowly interconverting meso and racemic rotamers
inhibits, but does not completely prevent, spontaneous rota- that occur in a stepwise manner suggesting its suitability for
tion of the triptycene. Continuing the friction braking action is use as a molecular dial, as they can rotate only one position at
required to fully prevent anticlockwise rotation. a time. The different forms of the rotamer are temperature-in-
Theoretically unidirectional motion is achieved by reversibly dependent implying that they are energetically equivalent.[323]
introducing a tether between the two units to energetically To expand upon these results the triptycene moieties were
favor one of the two possible rotation directions. To make the functionalized with di-tert-butyl groups affording 2,6-di-tert-
triptycene/helicene molecule suitable for use as a molecular butyl-9,10-diferrocenyltriptycene 267 ax, breaking the three-
ratchet, modifications were made to each unit. An amino fold symmetry of the triptycenyl framework. This was achieved
group was added to triptycene and an oxypropan-1-ol unit through the cycloaddition of benzyne to 9,10-diferrocenyl-2,6-
was added to the tip of the helicene unit (Figure 48).[321] When di-tert-butylanthracene. Results showed six slowly interconvert-
carbonyl dichloride is added to a solution of 262, the chemical ing rotamers in solution that are almost equivalent in energy.
energy provided lowers the energy barrier of clockwise rota- Steric interactions of the tert-butyl groups were shown to con-
tion thereby increasing its likelihood of occurring. This unidi- trol the barriers between rotamers.[324]
rectional rotation is ultimately caused by the asymmetric skew
of the helicene coupled with monosubstituted triptycene, pro-
6.2.4. Metalorganic frameworks (MOFs)
ducing nonidentical energy surfaces for clockwise and anti-
clockwise rotation. To synthesize 262 palladium cross-coupling Metal–organic frameworks (MOFs) have a wide range of appli-
was implemented, anthracene was functionalized at the 9-posi- cations from gas storage and sensors, to catalysis and medi-
tion with a benzaldehyde derivative, a cycloaddition reaction cine. Made from combinations of metallic clusters and organic
with benzyne and the anthracene produced the triptycene linkers, MOFs offer tunable pore sizes that can accommodate a
unit, followed by a Horner–Wittig reaction then to afford the range of different-sized molecules, from small molecular hydro-
“helicene” unit. gen to larger molecules such as proteins.[325] In particular,
Internal rotations can be induced chemically or photochemi- MOFs with small pore sizes can incorporate certain molecules
cally resulting in unidirectional rotations and controlled molec- without the need for intermolecular interactions between the
ular brakes or gyroscopes. This phenomenon can ultimately be guest species. In contrast, the majority of MOFs require func-
utilized for molecular machines or switches. An organometallic tional groups capable, mainly, of hydrogen bonding in order
Review
Figure 50. Triptycene-based MOFs.
to encapsulate the desired molecules.[326] Rigid organic ligands, reliable formation of the 3D MOF whereas interpenetrated 3D
usually those containing aromatic units or spacers, are em- frameworks have a tendency to form in other rodlike pillaring
ployed in the construction of MOFs, although, as is outlined in ligands such as those containing bipyridine in terephthal-
this section, rigid-aliphatic linkers can also be implemented.[327] ates.[330] Potential applications of this MOF include uses in the
MOFs can be utilized in the pursuit of potential artificial mo- field of sensing and energy transfer on the micro- and nano-
lecular machines. A set of pillared paddlewheel MOFs were scales in fluid media.
prepared containing 9,10-bis(4-pyridylethynyl)triptycene with A 1,3,5-trisubstituted benzene was coupled with triptycene
the purpose to act simultaneously as a pillar and molecular ro- to incorporate rigid arms with two carboxylic acid moieties at
tator 268, three axially substituted dicarboxylate linkers of the end of the chain. A MOF 271 was then created by com-
varying lengths and steric bulk were also employed plexing the triptycene system with CuO.[331] This complex was
(Figure 50).[328] Changing the linker from benzene to a biphenyl studied computationally to investigate the effect triptycene
and then a triptycene moiety, 268 a, 268 b, and 268 c, showed has on methane adsorption properties. Calculations of meth-
2-fold, 4-fold, and no catenation, respectively, when crystalized ane adsorption properties were performed with Grand Canoni-
from DMF, in correlation to the amount of space available in cal Monte Carlo simulations and showed favorable results
their 2D frames. Tight packing is observed for the two catenat- when compared to known MOFs of a similar structure and top-
ed structures while the triptycene derivative shows no contacts ology. It was showed that the methane adsorption uptake was
between pillars and linkers in the lattice. Rotation is occurring significantly enhanced on a volumetric basis with this complex
in this compound via a Brownian three-fold jumping mecha- 271.
nism and, as there are no steric interactions in this molecule, it Terephthalic acid is one of the most commonly reported
is suggested that the confined DMF molecules in the lattice spacers in MOF constructions, although it has several draw-
cause the rotation. A hydrodynamic model was used to esti- backs, such as solid-state transparency only between 350 and
mate a four orders of magnitude greater viscosity of the DMF 800 nm. To extend transparency in the UV domain (below
MOF compared with that of the bulk liquid and this has been 320 nm) BCO 124 was employed as a terephthalic acid replace-
compared to the consistency of honey. The viscosity changes ment in a MOF construction 272 a along with ZnII as both are
allow an opportunity to analyze the dynamics of fluids under expected to have a higher transparency (Figure 51 i and ii).[327]
tight confinement at variable temperatures. A classic MOF-5,10 was prepared, with BCO 124 instead of
(Triptycenedicarboxylato)zinc MOFs 270 were prepared and terephthalic acid, and Zn4O clusters that arranged the moieties
constructed with paddle wheel secondary building units con- into a cubic network with BCO 124 on the edges and the zinc
taining different axial ligands.[329] 3D frameworks were made by cluster on the vertices. The BCO moiety was found to retain
a pillaring approach as triptycene paddlewheels 269 reliably the rigidity of the structure while removing aromaticity, thus
form layers with zinc nitrate. By employing different ligands, increasing transparency, making it highly suitable for the prep-
such as bis(4-pyridyl)-s-tetrazine 270 a and bis(4-pyridyl)-dime- aration of transparent metal–organic frameworks (TMOFs). The
thoxy-p-phenylenedivinylene 270 b, the functionalities of the TMOF was synthesized with high reproducibility, a good yield,
MOFs were modified. Guest-exchange behavior, microporosity, and was formed by self-assembly.
luminescence, and stability were investigated for these MOFs. The density functional based tight-binding method was
In was seen that the presence of 2D triptycene allowed for the used to compute the properties of an isoreticular series of
Review
Figure 51. Towards a “transparent MOF” showing, metal-view (i) and ligand-view (ii). DEF = N,N’-diethylformamide. View of molecular tunnel formation (iii).
Nax = axial nitrogen atoms; Neq = equatorial nitrogen atoms.
metal–organic frameworks (IRMOFs).[332] Again, Zn4O clusters 7. Application of Rigid-Linear Linkers in Small
are arranged in a cubic network composed this time of Molecule Drugs
cubane-1,4-dicarboxylic acid 36 or triptycene-9,10-dicarboxylic
acid 269 on the edges and the metal cluster on the vertices Over the years bioisosteres have been implemented in drug
forming 272 b and 272 c (Figure 51 i and ii). Results showed all design and development to overcome problems associated
MOFs to be energetically stable semiconductors or insulators with potential drug candidates. At the late stage of drug devel-
and that unsymmetric linkers caused marked distortions in the opment, the utilization of bioisosteres is often the only viable
zinc-oxo carboxylato rings while symmetric linkers show little option. Pharmacokinetic properties (PK) such as bioavailability,
or no influence on the geometry. solubility, metabolic stability, and toxicity limit a drugs’ applica-
Atomic charges with similar values are observed for the free tion even though good potency and selectivity may be ob-
building blocks and the solid MOFs, except those seen with served in vitro. Alternatively, bioisosteres have been employed
linking oxygen atoms as they change when going from the simply to expand the scope of a family of compounds but also
free linker to the MOF. This knowledge could allow for the cre- to investigate structure–activity relationships (SAR).
ation of materials for hydrogen storage and optical applica- Benzene bioisosteres have been investigated most exten-
tions amongst other applications. sively in the literature, but several examples of bioisosteres for
Layered double hydroxides (LDHs) are a class of claylike ethynyl, cyclohexane rings, adamantane, and tert-butyl and
anionic nanoscale minerals consisting of [Mg(OH)2]-like layers methyl groups have also been reported. Linear-aliphatic-rigid
in which trivalent ions have replaced ordinarily divalent cations linkers are ideal replacements for these functional groups as
to form positively charged sheets.[333] A cubane MOF was con- they can maintain the structure of the drug that is often crucial
structed when cubane-1,4-dicarboxylate (cubane-dc) anions to activity, offer metabolic stability when enzymatic action dra-
were incorporated into a Zn2Al LDH inorganic host. This was matically reduces the half-life of a drug, and increase the lipo-
achieved through means of the coprecipitation method, with philicity of a drug that may be required to cross the blood–
solutions of ZnII and AlIII nitrate salts and an alkaline solution of brain-barrier. Moreover, BCP has been shown to increase the
cubane-dc. DOS calculations computed with the DFT method aqueous solubility of a drug,[336] and, alongside cubane[337] and
and the molecular orbital models showed a redshift in the BCO, has been proven to increase the selectivity and potency
spectrum of the large intercalated cubane-dc anions with a for specific receptors.
subsequent lower band energy gap than that of Zn-Al-NO3-
LDH, which is a much smaller anion.[334]
The singly metal–metal-bonded complex [Rh2(cis-DAniF)2-
7.1. Aromatic bioisosteres
(CH3CNeq)4(CH3CNax)2](BF4)2 (DAniF = N,N’-di-p-anisylformamidi-
nate) was assembled with (Et4N + )2(Carb2@), in which Carb2@ is A popular option to overcome problems with the design and
the dicarboxylate anion of BCP and cubane 273 and 274, re- development of drug candidates is the use of bioisosteres.
spectively, amongst other groups to form square complexes Due to its ubiquity in most drug molecules benzene is often
(Figure 51 iii). In crystal form these complexes stack forming in- chosen as a target for bioisosteric
finite tunnels which can be closed to allow for the encapsula- manipulation.[338] Chosen for its ri-
tion of solvent molecules.[335] gidity, unique electronics and syn-
thetic accessibility, benzene is
known to be one of the leading
Figure 52. A visual concept of
causes for compound attrition in cubane as a benzene bioisos-
drug discovery (Figure 52).[339] tere.
Review
Figure 53. Arylated cubane, BCO, and BCP as para-benzene bioisosteres.

Figure 54. Synthesis and antifolate evaluation of the aminopterin analogue
with a BCO ring in place of the benzene ring.
For example, the effect of substitution of the B ring of the

diaryl amine system 275 was investigated (Figure 53).[340] Tradi- While the cause of Alzheimer’s disease (AD) is unknown,
tional bioisosteres, such as fluorobenzene and pyrimidine were contributors to the development of the disease have been
trialed first but seemed to be ineffective at overcoming com- identified as b-amyloid peptide (Ab) chains of 40–42 amino
pound attrition. Following this, the BCP moiety was incorporat- acids. Activated by secretases (b and g), APP (b-amyloid pre-
ed to give 276. This involved a new five-step synthetic route cursor protein) releases b-amyloids into the plasma and the
from commercially available starting materials with an overall cerebrospinal fluid.[345] It is the aggregation of these peptides
yield of 32 %. This is an improvement over the original seven- into oligomers and plaques that is thought to contribute to
step synthesis which had a yield of 14 % and incorporated the the diseases progression. g-Secretase is an attractive drug
use of the corrosive hydrazoic acid reagent.[341] The key step in- target as it regulates the solubility of the AB fragments by con-
volved a novel, potentially versatile method using metal-free trolling their length. The main obstacle drug design must over-
homolytic alkylation. come is the selectivity for the APP enzyme over the Notch sig-
To improve the quality of imaging reagents and modify the naling protein which is involved in the differentiation and pro-
physiochemical properties of different drug candidates BCP liferation of many different cell types.[346] A previously identi-
280, BCO 279, and cubane 278 were utilized as benzene bio- fied g-secretase inhibitor (GSIs) BMS-708 282, showed excellent
isosteres for biarylcarboxy compounds to develop methods for antagonist activity.[347] To improve upon the potency of the
use in more complex systems.[342] The success of a bioisostere flurobenzene compound 282, a BCP derivative 282 a was
is dependent on the role the aromatic group it is replacing has made with subnanomolar g-secretase inhibitory potency in
in the overall molecule. If the para-substituted arene of the vitro and a robust pharmacological response in vivo. Moreover,
drug molecule influences the conformation of the molecule or the BCP analogue showed increased aqueous solubility, passive
has a role in the pharmacophore (e.g., p–p staking)—an ali- permeability, and oral bioavailability in mouse studies (Fig-
phatic bioisostere will not be effective. It was shown that BCP ure 55).[336a]
improves aqueous solubility by at least 50-fold and markedly Initially a therapeutic target for the treatment of atheroscle-
decreases nonspecific binding (NSB).[124] On the other hand, rosis, Lipoprotein-associated phospholipase A2 (LpPLA2) has
BCO increased the lipophilicity of the molecules but did not also been shown to have a role in Alzheimer’s disease.[348] The
show the same benefits regarding NSB or solubility. Cubane inhibitor darapladib 283 has been developed to combat the
showed improvements for both parameters. These results con-
firm the potential advantages of both BCP and cubane motifs
as bioisosteric replacements for optimizing para-substituted
benzene derivatives.
N-(4-{[(2,4-Diamino-6-pteridinyl)methyl]amin}BCO-1-carbon-
yl)-l-glutamic acid 281 a was synthesized and tested for antifo-
late activity (Figure 54).[343] Methotrexate (MTX) is a clinically
used antitumor agent and has also seen application against
psoriasis and rheumatoid arthritis.[344] MTX acts as a difolate re-
ductase (DHFR) antagonist, inhibiting the production of folic
acid in tumor cells that regulates cell division, DNA/RNA syn-
thesis and repair and protein synthesis. The central benzene
ring was replaced in 281 by BCO to improve selective uptake
and activity in tumor cells. Results showed that although spa-
tial requirements are met a 740-fold reduction in potency was
observed. This is one of the few examples of BCO as a benzene
bioisostere reported in the literature, suggesting that more de-
sirable effects are observed with BCP and cubane analogues. Figure 55. Analogues of the g-secretase inhibitor smd-1 and the LpPLA2 in-
hibitor Darapladib.
Review
adverse effects associated with LpPLA2, such as myocardial in- Utilized against a variety of leukemias,[358] commercially avail-
farction or ischemic stroke (Figure 55).[349] Darapladib has been able Gleevec, the mesylate salt of Imatinib 286 (Im-1)
shown to have good potency and lipophilicity while maintain- (Figure 57), is one of the first synthetic tyrosine kinase inhibi-
ing artificial membrane permeability. But, unfortunately, the in- tors (TKI). Im-1 has a high density of aromatic rings and high
hibitor has a suboptimal physicochemical profile, with a high
molecular weight, low aqueous solubility, and high property
forecast indices (PFI); a risk indicator of developability.[350] But
through the substitution of the suboptimal benzene ring with
a BCP moiety 283 a, the PK profile of the drug was improved
while maintaining potency.[351] This drug was synthesized over
a number of steps, the key transformation involved a dichloro-
carbene insertion into a bicyclo[1.1.0]butane system.
Great interest has been shown in resveratrol 284 due to its
wide range of therapeutic properties, such as antioxidant, anti-
cancer, antidiabetic, or cardioprotective (Figure 56).[352] Yet, its
application is hindered by its poor bioavailability.[353] Studies
Figure 57. The ABL1 kinase inhibitor Imatinib and its bicyclo[1.1.1]pentyl an-
alogue.
lipophilicity resulting in partial solubility only in neutral aque-

ous media. The free-base Im-1 was utilized as a model system
for evaluating the biopharmaceutical properties (e.g., ABL1
kinase inhibitory activity, cytotoxicity).[336b] Some of the excess
aromatic systems were substituted with sp3 structural motifs,
including BCP and cubane moieties, which add increased
Figure 56. BCP benzene analogues. three-dimensionality and rigidity.
For the BCP analogue 286 a, an 80-fold increase in aqueous
solubility was observed over the parent compound, although
have shown this is due to its rapid first-pass metabolism to there was reduced potency against the target ABL1 kinase and
glucuronide and sulfate conjugates.[354] Routine manipulation thus therapeutic effects were not conserved. The cubane ana-
of the 4-OH of the phenolic ring would be carried out to over- logue 286 b also showed an increased solubility, exhibited the
come this, but previous literature warned against this, as it highest inhibitory activity against ABL1 kinase, and the most
would be detrimental to activity.[355] As an alternative to over- potent cytotoxicity against cancer cell lines K562 and SUP-B15,
come these problems the BCP moiety was employed as a bio- but this is still lower than the parent compound. The discrep-
isostere 284 a for the phenolic ring.[356] Results showed superior ancy between reduced inhibitory potency of the cubane ana-
in vivo PK properties over the parent compound and offered logue and the high cytotoxic potency suggests that an addi-
reason to proceed with biological testing. Compound 284 a tional biological target(s) is being accessed by this molecule. A
was synthesized over six steps from the monoester monocar- novel convenient synthesis of Im-1 was described where the
boxylic acid BCP, the key step employing a Wittig reaction to bioisosteres were attached through amide condensation reac-
connect the BCP moiety with the benzene diol. tions.
Another benzene bioisostere used was BCP 285 a, as an al- In the early 90s Eaton postulated that cubane would be an
ternative to a current Wnt inhibitor 285 (which stops Wnt, a ideal isostere for benzene due to their similarity in size and
family of proto-oncogenes, encoding secreted signaling pro- shape (Figure 52).[62, 119] Various molecules were synthesized to
teins that are involved in oncogenesis) (Figure 56).[357] This was test the applicability of this hypothesis with applications in
done to test and see if the benzene ring is merely a spacer or cancer therapeutics, AD medication and pain management.[74]
whether other electronic effects come into play. The synthesis The histone deacetylase inhibitor SAHA 287 (suberanilohy-
was achieved from commercially available monocarboxylic acid droxamic acid),[359] used for the treatment of cutaneous T-cell
monoesterBCP, attaching the pyridine unit through homolytic lymphoma (CTCL) was the first molecule investigated
alkylation and the second moiety through an amide condensa- (Figure 58). Tumor cell line inhibition studies showed both
tion. Interestingly, biological evaluation showed no inhibitor SAHA and the cubane analogue 287 a had similar potencies in
activity of the BCP derivative in the Wnt-reporter assay indicat- tumor cell inhibition, but SAHA’s toxicity was slightly greater
ing that the benzene ring is more than just a spacer and that towards NFF primary cells.
its unique combination of electronic, stereoelectronic, and Previous studies showed significantly increased neurite out-
steric effects may be crucial for its 1,4-substituents in 285. growth in PC12 neural precursor cells derived from a rat pheo-
chromocytoma upon administration of the neotrophic drug le-
Review
broad spectrum activity (Figure 59). However, bacterial resist-

ance is always an ongoing problem. An alternative quinolone
analogue 291 was prepared with a tert-butyl group at the N-1
position.[363] Following this, a BCP analogue 292 was synthe-
sized, replacing the tert-butyl group.[362] This compound
showed enhanced activity against gram-positive aerobic bacte-
ria and anaerobic organisms, relative to that of ciprofloxacin.
Moreover, time-kill kinetic studies revealed that BCP 292 is ex-
tremely potent against ciprofloxacin-resistant Staphylococcus
aureus.
The tert-butyl groups of Bosentan and Vercirnon were also
replaced with BCP groups to increase metabolic stability and
other physiochemical affects. Bosentan is used for the treat-
ment of pulmonary arterial hypertension[364] while Vercirnon
Figure 58. Cubane benzene bioisosteres. was developed for the treatment of inflammatory bowel dis-
ease.[365] Each compound has a para-substituted tert-butylben-
zene sulfonamide unit and straightforward synthesis makes
teprinim.[360] The treatment of PC12 cells with either leteprinim them ideal candidates for tert-butyl isostere studies. All the
288 or the cubane analogue 288 a were both ineffective in the BCP derivatives 293 and 294 were shown to remain biological-
absence of nerve growth factor (NGF). But upon administration ly active and in the Bosentan series an even higher potency
together the differentiation capacity of the cubane analogue was observed with IC50 values compared with that of the
was remarkably better than the parent compound. parent drug.[366] Additionally, all data on metabolic stability, sol-
The third compound targeted was the nonselective sodium- ubility, logP, pK, and permeability showed the applicability of
ion channel blocker benzocaine 289,[361] a widely used local an- BCP as a viable alternative to tert-butyl groups.
esthetic. Adult male rats were used to test the effect of the To expand the synthetic viability of incorporating BCP into
cubane 289 a and parent analogues, through injection of the drug molecules a new method involving the reaction of
drugs and application of an acute noxious heat stimulus at the “spring-loaded” strained C@C and C@N molecules with amines
source of injection. Results showed the same local anesthetic was developed, enabling the inclusion of BCP at any point in
efficacy of both drugs in this model. Other examples of the synthesis. A series of structurally diverse tertiary BCP-con-
cubane as a bioisosteres are outlined in the publication.[74] taining amines was synthesized, including derivatized drugs
Overall results showed the applicability of cubane as a ben- such as maprotiline and amoxapine (Figure 60).[367]
zene bioisostere.
7.2. Aliphatic bioisosteres

Alternatively to acting as a benzene bioisosteres, BCP can also
be implemented as tert-butyl substitute due to its small con-
strained size. While tert-butyl is widely employed as a motif in
medicinal chemistry it can affect the properties of the mole-
cule causing drawbacks such as increased lipophilicity and en-
hanced metabolism rates.[362] From the family of fluoroqui-
nones, Ciprofloxacin 290 is a potent antibacterial drug with
Figure 60. Bioisosteres based on bicyclo[1.1.1]pentan-1-amine.
A novel class of heat shock protein 90 (Hsp90) antagonists

was discovered by high-throughput screening and a SAR study
was carried out to investigate their properties.[368] Of interest
here are the BCP-containing moieties which acted as bulky
amide substituents. The BCP-containing compound 300
showed cytochrome P450 inhibition, but unwanted off-target
Figure 59. BCP-substituted tert-butyl bioisosteres. effects were also noted and in animal tumor models potent ef-
Review
ficacy was observed along with other desirable pharmaceutical

properties. Likewise, BCP moieties have been installed in sever-
al different compounds from a JAK inhibitor 295, to an atypical
PKC inhibitor 296, a tricyclic antidepressant 297, a tropomyo-
sin related kinase inhibitor 298, and an antibacterial agent
299. These molecules are a part of different series that have
been developed by Cephalon, Pfizer, Bristol–Myers–Squibb
amongst others as lead compounds in drug trials.[3]
Alternatively to the benzene and tert-butyl isosteres already
discussed, the ethynyl group was replaced by a BCP unit, as it
is closer to BCP in length than the benzene ring. Tazarotene
Figure 62. Cubane analogues of N-methyl groups and adamantane.
301 used in the treatment of psoriasis, acne and sun damaged
skin and 2-methyl-6-(phenylethynyl)pyridine (MPEP) 302 a
mGluR5 antagonist were selected for investigation The ATP gated P2X7 receptors (P2X7R) have been indicated
(Figure 61).[369] The central ethynyl bond in both compounds to have a role in neurodegenerative diseases[371] and chronic
pain modulation.[372] To improve the properties of a current
adamantyl benzamide drug 305, the replacement of the ada-
mantane moiety with cubane 306 was carried out and it was
hoped that 306 could be used as a diagnostic probe (when ra-
diolabeled) for in vivo molecular imaging whilst maintaining
the activity of the drug.[373] This allowed for the first time to
image P2X7R expression in disease and disease progression.
Cubanyl compounds 306 a–c possessed favorable P2X7R antag-
onistic properties when tested on rat spinal cord microglia
cells. In addition, the cubane analogues 306 a–c showed in-
creased lipophilicity, allowing the drug easier access across the
Figure 61. BCP bioisosteres of internal alkynes. blood–brain barrier to be used as potential PET radioligands.
Unfortunately, results of receptor profiling studies indicated
that none of the compounds of 306 or 305 exhibited apprecia-
were replaced with a BCP unit so that the pharmacokinetic ble binding to the many neuroreceptor subtypes assayed.
and physicochemical properties of these analogues could be Commercially available dimethyl 1,4-cubanedicarboxylate was
investigated; but results proved unfavorable.[175] To synthesize utilized to synthesize the product over a series of steps, em-
these compounds various arylmagnesium halides were employing an amide condensation to connect the aryl ring.
ployed to ring-open [1.1.1]propellane. The bisarylated BCPs Inhibition of DGAT-1 is a popular target for the treatment of
301 a and 302 a were obtained through transmetallation reac- obesity and other elements of the metabolic syndrome as it is
tions with ZnCl2 and Negishi cross-coupling with aryl and het- involved in the final step of triacylglycerol synthesis.[374] A
eroaryl halides. series of pyrazido[4,5-b][1,4]oxazine derivatives were published
The opioid activity of morphinoids has been linked to the by Japan Tobacco and Tularik companies.[375] Of particular inter-
nature of their nitrogen substituents. Examples in the literature est was compound 307, shown to be a potent and selective
show that the N-methyl group in morphine 303 can be re- DGAT-1 inhibitor but with toxic metabolites (Figure 63).[376] Re-
placed by a variety of electron-rich aliphatic compounds to placement of the cyclohexane ring with sterically bulky, but
create potent morphine antagonists such as cubylmethylnalor- electronically similar BCO groups 308 was carried out to in-
phine, Naloxone, Naltrexone, and Nalbuphine (Figure 62). In- crease steric crowding around the carboxylic group to limit
spired by this, cubane was employed as an alternative bioisos-
tere to morphine through the replacement of the methyl
group, as it is electronically comparable[370] due to its endocy-
clic orbitals that are rich in p-character. The N-cubylmethyl de-
rivatives of morphine and oxymorphone, N-cubylmethylnor-
morphine 303 a and N-cubylmethylnoroxymorphone 304 were
shown to be more potent ligands at the m and k opioid recep-
tors than morphine and oxymorphone, respectively. However,
while compound 303 a was shown to have moderate narcotic
antagonism activity it was much weaker than its N-allyl ana-
logue Naloxone. This reduction in potency is hypothesized to
be due to the disfavorable steric interactions of the larger
cubane scaffold.
Figure 63. BCO analogues of cyclohexane linkers.
Review
metabolism.[377] Compound 308 a proved to be a potent and 315 a and 316 a both showed subnanomolar potency at the 5-
selective inhibitor of the enzyme DGAT-1, with a superior PK HT1A receptor. The C@I bond was found to be stable both in
profiles and a further optimization of 307, resulted in the for- vivo and in vitro. Unfortunately, poor brain uptake of the
mation of BCO 309 with the replacement of bicyclic pyrazi- drugs was observed resulting in low concentrations in the
do[4,5-b][1,4]oxazine with a pyrazine moiety, to give an in- brain, especially in the hippocampus where large volumes of
creased potency at the hDGAT1 receptor amongst other desir- the target receptor are located, making these derivates unsuit-
able physiochemical properties. The cyclohexane and BCO de- able for SPECT. Fluorinated derivatives were also prepared for
rivatives were both synthesized, but the former proved most the cubyl and BCO analogues 315 b and 316 b, respectively.[383]
promising as a future drug candidate.[378] Good potency at the receptor was observed and this time with
The covalent Bruton’s Tyrosine Kinase (BTK) inhibitor Ibruti- high selectivity for the 5-HT1A R rich regions of the brain but
nib 310 is currently approved for mantle cell lymphoma and the major drawback seen with this analogue was the in vivo
chronic lymphocytic leukemia (Figure 64).[379] However, ana- enzymatic defluorination of the drug, deactivating the radio
ligand.
7.3. Additional uses of rigid scaffolds in medicinal chemistry

Collectively the risk factors visceral adiposity, diabetes, dyslipi-
demia, and hypertension make up the metabolic syndrome
and the incidence of cardiovascular disease is greatly increased
when they occur together and intracellular cortisol is thought
to be the cause.[384] The enzyme 11b-hydroxysteroid dehydro-
genase type 1 (11b-HSD1) plays an integral role in the regula-
tion of cortisol activation, thus making it a therapeutic
target.[385] Heteroaryl substituted bicyclo[2.2.2]octyltriazoles are
potent and selective 11b-HSD1 inhibitors with excellent phar-
macokinetic profiles.[386] Owing to this, compound 317 was
synthesized and proved to be a very efficient cortisone inhibi-
tor, but with high clearance rate and low bioavailability
(Figure 65). The main metabolite was formed as a result of oxi-
Figure 64. Novel BTK inhibitors and potential SPECT ligands.
logues were shown to inhibit adenosine uptake (AdU) causing

undesirable CV effects.[380] To avoid these adverse effects opti-
mization of the drug 310 was carried out by substituting the Figure 65. Various rigid linker scaffolds.
cyclohexane ring for cubane, BCO, and BCP.[381] The cubane
311 and BCP 313 analogues showed reduced human whole
blood (hWB) potency, whereas the BCO 312 analogue exhibit- dation at the w-1 position of the 5-carbon alkyl chain. Further
ed excellent potencies at the desired receptors but was poorly experiments were conducted, replacing the chain with various
selective for AdU. The addition of an ethoxy group onto the heterocycles, resulting in compound 318 that was shown to
central benzene ring of the compound 312 b resulted in the have high selectivity of 1800 fold for HSD1 over HSD2, with
retention of good potency while reducing adenosine uptake good cortisone inhibition. Moreover, the compound possesses
activity. But unfortunately, a high metabolic clearance was ob- a very high bioavailability and was selected as a lead com-
served for this compound making further optimization neces- pound and patented by Merck.[387]
sary before it can be effective. One of the first examples in medicinal chemistry that em-
5-HT1A receptor ligands derived from 314 (WAY-100635) ployed cubane as a scaffold for medicinal drugs was seen in
were made that replaced the peripheral cyclohexane group of 1971, when the compound was found to possess antiviral
314 with various halogenated bridge-fused ring systems such properties, especially towards the influenza virus.[388] Later on,
as cubane 315 and BCO 316.[382] The iodinated analogues in the 90s Dipivaloylcubane 320 and diphenylcubane 321
Review
were proposed as cubanyl drugs which displayed moderate are needed to see if its potency was affected. Owing to a more
antitumor activity and anticancer activity, respectively. In these similar size, cubane makes a more suitable bioisostere for ben-
compounds cubane was shown to increases the lipophilicity of zene, thus ACUDA 323 c was prepared.[395] However, when
the compound allowing easier movement across cell mem- tested with the mGlu1 ligand 323 c only weak activity was ob-
branes and to possess minimal toxicity. Additionally, 322 was served and a nine-fold decrease in activity was observed com-
shown to have applications in aorta relaxation and calcium pared to BCP 323 b. This was attributed to the increase in
channel blocking. volume of the 3D cube, suggesting that cubane represents the
upper limit for the steric accessibility of the mGlu1 binding
7.4. Amino Acids site. Interestingly, while BCP 323 b has higher activity, ACUDA
323 c was shown to have remarkable selectivity, enabling it to
7.4.1. Glycine and alanine mGluR1 antagonists
be devoid of any effect at mGluR5, while under the same con-
Activated by synaptic release of l-glutamic acid 323, metabo- dition BCP 323 b acts as a partial mGluR5 agonist. A BCO
tropic glutamate (mGlu) receptors consist of eight (currently group was also incorporated into CPG framework 323 f, ex-
known) mGlu receptor subtypes that have been classified into panding the family of linear-rigid scaffolds employed. Unfortu-
three groups. Group I contains mGlu1 and mGlu5, which are nately though, testing in AV-12 cells showed that the non-nat-
positively coupled to phospholipase C (PLC) and mGlu1 has ural amino acid was inactive against human mGluR1 and
been linked to the cause and accentuation of post-ischemic mGluR5.
neuronal damage.[389] Thus, mGlu1 antagonists are potential To further ascertain the influence that the distance between
therapeutic agents in the treatment of CNS disorders such as the two pharmacophore groups plays and, additionally, to
ischemia, stroke, head trauma and Alzheimer’s disease.[390] Car- quantify the importance of the distal carboxylate group, the
boxyphenylglycines (CPGs) have been shown to be selective synthesis of BCP 323 h ((S)-TBPG) was carried out, characterized
mGlu1 antagonists over glutamate ionotropic receptors[391] and by the tetrazole moiety replacement of the carboxyl group.[396]
optimizations of this drug category resulted in benzene ana- This substitution compensated for the shorter distance of the
logues; S-4CPG 323 a, S-4C3HPG 323 d, and (+ +)M4CPG 323 g BCP-based moiety compared with that of the “standard” S-
which have all been shown to inhibit mGlu1 activity, albeit 4CPG. A 2.5-fold reduction in potency was observed at mGluR1
with drawbacks such as low potency and activation of the when compared with than the parent compound but it was
mGlu2 receptor subtypes (Figure 66).[392] While the coplanarity found to be devoid of affinity for the mGluR5 subtype. The re-
duction in activity was thought to be due to the reduced acidi-
ty of the tetrazole ring compared with the carboxylate and/or
due to the different hydrogen bonding geometry of the com-
pound. The tetrazole moiety was attached through the cyclo-
addition of tri-n-butyltin azide (nBu3SnN3) with a nitrile group.
Further studies were performed to investigate the influence
the introduction of lipophilic moieties in the 2’-position of the
core of (S)-CBPG 323 b would have on potency and selectivi-
ty.[397] Two chloro groups were introduced at the 2’-position of
the BCP of both stereoisomers and a racemate of a mono-
chloro BCP group was also synthesized, namely (R)-dichloroBCP
323 I, (S)-dichloroBCP 323 j, and chloroBCP 323 k. Functional
assays showed that all compounds had antagonist activity at
group I receptor subtypes but were unselective, working at
both mGlu1 and mGlu5 receptors. Docking studies showed
Figure 66. mGluR1 antagonists. that the antagonistic behavior observed was due to the pres-
ence of disfavored van der Waals interactions in the binding
site which arise because of a different orientation the drugs
between the a-amino acidic and the w-carboxy functionalities, take compared to the native (S)-glutamate.
introduced by the benzene moiety, is generally accepted to be To obtain a new class of acidic amino acids with specific ac-
a crucial feature of the CPG, whether it has other contributions tivities at excitatory amino acid (EAA) receptors, the w-carbox-
to activity was unknown. SAR studies carried out on the cur- ylate moiety of glutamic acid 323 (l-Glu) was substituted with
rent S-4CPG antagonist involved the substitution of the ben- a w-phosphonate group. The most potent example of a selec-
zene ring with different saturated, rigid hydrocarbons, such as tive mGluR3 agonist is l-AP4 324 a (Figure 67).[398] A first-choice
BCP, BCO, and cubane.[393, 394] strategy to achieve subtype selectivity often is conformational
BCP 323 b was shown to have good potency at the mGlu1 constraining and previous research with 4-PPG 324 b showed
receptor and little activity at the other subtypes in both in it to be a potent group III selective agonist. In search for new
vitro and in vivo tests, indicating that the benzene ring is not group III ligands to enable further characterization of this
of importance when linearity and rigidity are maintained. BCP family of receptors, a BCP bioisosteric replacement approach
is considerably shorter than an aromatic ring, so further tests was employed.[399a] Stereoselective Ugi condensations were
Review
7.4.2. Other natural amino acid derivatives
Fibrinolysis is a natural process that occurs in the body to pre-

vent the build-up and thus harmful effect of blood clots. Pri-
mary fibrinolysis involves the normal rate of breakdown for
blood clots while the rate of secondary fibrinolysis is excessive,
leading to severe bleeding. Previous potential inhibitors
are analogous amino acids -aminocaproic acid (EACA),
p-aminomethylbenzoic acid (PAMBA), and trans-4-
aminomethylcyclohexanecarboxylic acid.[400] Their proposed
mode of action is the inhibition of the proteolytically active
enzyme plasmin from plasminogen. These drugs were mostly
glycine derivatives and it was thought that the maximum anti-
fibrinolytic activity would be achieved once the optimum dis-
tance between amino and carboxyl moieties was obtained.
Figure 67. mGlu3 agonists. Thus, different rigid spacers, such as cubane and BCO, were in-
vestigated to test this theory. The non-natural BCO amino acid
325 b showed more activity than any molecules previously re-
employed to synthesize the two isomers (2R)- and (2S)-phos- ported and, in addition, it was shown to be orally available,
phono-BCP-glycine 324 c and 324 d, which are potent agonists and without major toxicity (Figure 68). Linearity was also
at group III mGluRs, while inactive at mGluR1 receptors and proven to be important as a decrease in activity was seen with
only weakly active at mGluR2. Interestingly, they had opposite
effects at mGluR2; the S-enantiomer acted as a weak antago-
nist, whereas (R)-PBPG 324 c was a weak agonist. Within group
III receptors (S)-PBPG 324 d exhibited a selective profile for
mGluR4, with a 16-fold potency at this receptor subtype over
mGluR6, whereas the R-enantiomer showed no distinction. Al-
though an increased potency over l-AP4 was not achieved,
this increased selectivity will hopefully allow more to be
learned about the mGluR4.
Additional BCP amino acid derivatives were synthesized, in-
cluding (2S)- and (2R)-carboxyBCPalanines 324 e and 324 f,
which are elongated versions of (2S)- and (2R)-CBPG 323 b and
323 e, for which the distance between the pharmacophoric
groups is increased by homologation of the carbon backbone
at the amino functionality. Also (2S)- and (2R)-carboxymeth-
ylBCPglycines 324 g and 324 h were prepared, for which the
distal carboxylate is the functionality elongated and, finally,
Figure 68. Various amino acid non-natural analogues.
(2S)- and (2R)-phosphonomethylBCPglycines 324 i and 324 j
were synthesized through the substitution with a w-phospho-
nate group of the elongated w-carboxylate group.[399b] the comparable non-linear bicyclo[3.2.2]nonane analogue. Con-
The biological profiles of the six new compounds were ex- versely, the cubane derivative 325 a did not show superior ac-
amined at both ionotropic glutamate receptors and recombi- tivity to previous examples, this was thought to be due to the
nant mGluRs subtypes through binding experiments. The most protruding protons from the unoccupied corners of the cube.
interesting results were obtained for the NMDA receptor. Out In an effort to synthesize pharmaceutically relevant cubane
of the w-carboxylate derivatives the (R)-enantiomers (R)-CBPA derivatives,[206] a series of novel cubane-containing amino acids
324 f and (R)-homoCBPG 324 h had the highest potency and were prepared. Initial cubane-containing amino acids synthe-
good selectivity being completely inactive at the other iGluRs sized were cubane-containing carboxyglycine 325 a (R = H)[401]
and mGluRs. But the highest affinities for NMDA were ob- and its derivatives (R = Me, CH2CHAr2), accessed by the Strecker
served for the w-phosphonate derivatives, while still maintain- method (Figure 68). Reports were also made of the synthesis
ing high degrees of selectivity. (R)-homoPBPG 324 j had the of the cubane-containing glycine derivative 325 i using the
highest potency of them all and has the potential to be a lead Ellman method. But cubane-containing glycine 325 itself still
compound for the NMDA receptor. remained unreported.[402] The first successful synthesis of cu-
banyl 325 was finally achieved using readily accessible cubane
precursors, while cubane-containing alanine 325 c could only
be prepared after developing conditions for the hydrogenation
of the unsaturated precursor. Furthermore, the synthesis of
Review
cubane-containing b-aminopropanoic acid 325 d and cubane- lipid interactions. At different hydrophobic positions of the
containing N-Bn-protected b-alanine 325 e was described. KIGAKI sequence, CF3-Bpg 326 was incorporated either as an l-
These b-amino acids are of interest as previous b-amino acids or a d-enantiomer. The 19F-labeled sequence showed that al-
have shown resistance to proteolysis[403] and form stable and though d-epimers are known for having higher aggregation
highly structured b-peptides.[404] A Mitsunobu C@C bond-form- thresholds than the l-epimers, aggregation was seen in both
ing reaction was employed to synthesize the b-amino acids (Figure 69).
and the addition of a lithium amide to an a,b-unsaturated
ketone.[401]
A number of different tyrosine 325 h and phenylalanine
325 g derivatives have also been reported in the litera-
ture.[124, 356] BCP analogues of these natural amino acids were
made to elucidate conformational and electronic effects in Figure 69. 3-(Trifluoromethyl)bicyclopent-[1.1.1]-1-yl glycine (CF3-Bpg).
peptides. The BCP-containing glycine derivative was synthe-
sized through the homologation of a carboxylic acid, followed
by a Strecker reaction, in eight steps.[124] The BCP-containing To investigate its use as a synthetic probe, the 19F-labeled
tyrosine analogue was accessed from the BCP aldehyde by a amino acid 3-(trifluoromethyl)BCPglycine 327 a (CF3-Bpg = 3-
Wittig reaction to form an a,b-unsaturated ester, this group (trifluoromethyl)bicyclopent-[1.1.1]-1-yl-glycine) was synthe-
was then transformed into a diazo derivative by using hydro- sized (Figure 70).[412] The presence of the nonconjugating BCP
hydrazination conditions.[356]
7.4.3. 19F-labeled amino acids

The 19F isotope is of great interest in 19F NMR labeling due to
its high sensitivity, its wide range of chemical shifts, the ab-
sence of biological background signals, and its strong dipolar
interactions.[405] Often in NMR applications fluorine-labeled l-a-
amino acids (FAAs) act simply as a qualitative probe to sense
changes in the local environment. Only recently, FAAs have
been incorporated into membrane-bound peptides to deter-
mine the orientational limitations of the peptide and the in-
teratomic distances required between amino acids through the
use of solid-state 19F NMR spectroscopy.[406, 407] Information can
be gained from these studies such as the conformation, align-
ment, and dynamic behavior in a lipid bilayer under quasi-
native conditions of membrane active peptides. In order for
the 19F label to be successful strict guidelines must be adhered Figure 70. 19F NMR labels for peptide studies.
to. Firstly, the 19F label must be conformationally restrained at
a defined position close to the aminocarboxylic moiety. Fur-
thermore, it must be compatible with the synthesis of the pep- linker reduced electronic transmission across the amino acid as
tide and lastly the peptide must not have its structure or its compared to an aromatic ring, leading to less racemization.[89]
function altered. Furthermore, the loss of HF is avoided as in the CF3-Ala deriva-
To slow down the aggregation of peptides into b-sheeted tive 327 b, as is the low reactivity of the aminocarboxylate
assemblies, the stereochemistry of a single amino acid can be moiety 327 c as a result of steric hindrance, under solid-phase
changed from the d- to the l-enantiomer through substitution. peptide synthesis conditions (SPPS). CF3-Bpg 327 a resembles
This seemingly simple change can cause significant effects in a amino acids Ile and Leu most closely in size and lipophilicity,
system altering its conformational and thus functional and bio- while it is also suitable as a Met, Phe or Trp isostere in terms of
logical properties. The amphiphilic membrane-active model shape and steric volume, although lacking the aromaticity of
peptide [KIGAKI]3-NH2, is used to investigate this effect of the Trp and Phe. When compared with previously used phenylgly-
reversal of an amino acids stereochemistry, as it is known to cine derivative 327 e, parameters show that CF3-Bpg is closest
form amyloid-like fibrils.[408, 409] This peptide has been shown to to the natural nonpolar amino acids. To confirm the proposed
exhibit potent activity against various bacteria compared to and calculated properties of CF3-Bpg, the new FAA was incor-
that of amphiphilic a-helices.[410] Notably, even with one-third porated in the 21-mer sequence of the antimicrobial peptide
of the amino acids in the form of the d-enantiomer in the PGLa 328.[406, 407] Previous FAA 327 f racemized completely
KIGAKI sequence a b-sheeted conformation was still predomi- under the SPPS conditions when used to produce PGLa, while
nant.[411] Different functional assays of this peptide have been the synthetic peptides containing CF3-Bpg contained only one
investigated to deduce whether aggregation plays a role in diastereoisomer, as shown by HPLC/MS. Additionally, the bio-
various biologically relevant functions that involve peptide– logical activity of these peptides was tested using bacterial-
Review
growth inhibition assays and no change was noted from the

activities observed with the wild-type peptide, implying that
the introduction of CF3-Bpg was not detrimental to activity.
Moreover, circular dichroism showed that there were no distor-
tions in the peptides that could have been caused by the new
unit. The labeled peptides were also arranged mechanically
into phospholipid bilayers and behaved compatibly with the
known a-helical conformation further showing 327 a (CF3-Bpg)
suitability as a 19F labeling unit for solid-state 19F NMR spectros-
copy.[408, 413]
Significant work has been done on CF3 analogues of various
amino acids, whereas monofluorinated labels that allow superi-
or[414] intra- and intermolecular distance measurements have
received less attention.[415, 416] Previously, examples, such as
327 d and 327 e have shown serious drawbacks, these prob- Figure 71. 19F-Labeled peptide.
lems also occur in the case of alkyl 327 d, which has no rigidity
in its structure resulting in ambiguous analysis of the NMR
data obtained owing to its conformational flexibility. This limi- change (CODEX) experiment was used to validate the pro-
tation was overcome with aromatic 327 e as the position of posed label for 19F–19F distance measurements.[418] The intra-
the 19F atom is fixed, but when replacing aliphatic amino acids molecular 19F–19F distance was found to be approximately 8 a,
(Ala, Val, Ile, Leu) extensive racemization during peptide syn- which is much closer in value to the expected distance of 7.5–
thesis is observed. Thus, to overcome these problems, BCO 8.0 a in an ideal helix than the 6.6 a value obtained for
was utilized to synthesize the new aliphatic 19F-substituted BCO.[419] The slightly longer distance can be explained by the
amino acid (4-fluoroBCO)glycine 327 f.[416] Unfortunately, race- minor distortion seen of the a-helix in CD, but nevertheless F-
mization was still observed with the BCO derivative, although Bpg 327 g can still be effectively used as a label to measure in-
only partially, resulting in the two epimeric peptides 327 h/ terspin distances.
327 i upon synthesis with SPPS. The key transformation in the
synthesis of the amino acid 327 f was a decarboxylative fluori-
7.4.4. Non-natural peptides
nation of an aliphatic carboxylic acid with XeF2 in C6F6.
Following on from this research, an alternative to BCO 327 f To increase the metabolic stability and bioavailability of pep-
was sought to overcome the reduced reactivity of the amino tides, additional non-natural amino acids have been incorpo-
acid caused by its increased lipophilicity and steric bulk when rated into peptides. Adamantane-substituted peptides have
compared to natural aliphatic amino acids.[416] Hence, 3-fluoro- been shown to enhance the peptides ability to penetrate bio-
BCP-glycine (F-Bpg, 327 g) was prepared, a smaller, while still logical membranes, and they have been investigated for their
rigid and nonconjugated core, that allows for an increased ac- anti-tumor[420] and antimicrobial activities.[421] With structural
tivity of the bioisostere in SPPS (Figure 70). The interatomic similarities to adamantane, cubane-based derivatives are also a
distances in membrane-active peptides were determined by viable option for non-natural amino acids. The first cubane-
solid-state 19F NMR spectroscopy, made possible with F-Bpg based amino acid synthesized for its neuroprotective proper-
327 g as it avoids the problems associated with the previous ties was 4-carboxylcubylglycine 325 a.[394] As unfunctionalized
FAAs. Calculations showed that the smaller BCP unit was closer cubane is a closer mimic of hydrophobic amino acids such as
in likeness to the natural Leu/Ile than all other 19F labels in leucine, isoleucine, and phenylalanine, cubane derivative 325 i
terms of size and lipophilicity. was synthesized, as were the dipeptide derivatives 329 a–c
F-Bpg 327 g was incorporated into the antimicrobial peptide bearing cubane residues in place of side chains (Figure 72).[402]
PGLa 328 from the skin of Xenopus laevis, to evaluate the po- Due to the high sensitivity of the vinylcubane unit, initial at-
tential of the label in detecting the F···F contacts tempts to prepare a cubane-based alanine derivative via the
(Figure 71).[417] Manual SPPS was employed to synthesize the corresponding dehydroalanine were unsuccessful. However,
polypeptide and encouragingly no degradation, low reactivity, the successful synthesis of a cubane-based glycine derivative
or racemization of F-Bpg was observed.[402] The peptide was re- and cubane-substituted dipeptides 329 a–c in diastereomer-
constituted in 1,2-dimyristoyl-sn-glycero-3-phosphocholine ically pure form was achieved upon the addition of lithiated
(DMPC) bilayers and gave the expected two 19F resonances in cubane to a (R,S)-glyoxylate sulfinimine.
the 19F NMR spectrum. CD spectroscopy of the labeled peptide C@H activation was utilized to achieve an efficient synthesis
showed slight deviation from the wild-type peptide in its a- of N14-desacetoxytubulysin H (Tb1) and pretubulysin D, along-
helical character, probably caused by the destabilization of the side the derivatives tubulysin BCP 330 a and cubane 330 b.[422]
helix near the labeled sites. Overall CD showed the presence of The synthesized compounds were biologically evaluated with
a mostly a-helical-labeled peptide in the membrane mimicking an array of cancer cell lines. Notable results included the novel
environment and, albeit with reduced activity, the 19F peptide BCP analogue Tb14 330 a, which showed high potencies
remained antimicrobial. A center band only detection of ex- against certain cell lines such as uterine sarcoma and human
Review
In recent years, peptides have emerged as promising novel

antibiotics due to their wide applicability against a broad spec-
trum of pathogens. Toxicity, instability and high production
costs are big obstacles for the practical implementation of
large peptides. To overcome these issues, smaller antibacterial
peptides with adequate metabolic stability are required. While
few examples are known in the literature, N-acetylated hexa-
peptides such as Ac-RRWWRF-NH2 have been identified.[424] The
size, shape, and character of the side chains influence the anti-
microbial effect, as does cyclization of the peptide through re-
ducing the likelihood of proteolysis.
To investigate the influence of lipophilic, nonaromatic amino
acid side chains on antimicrobial and hemolytic activity a
number of corresponding linear and cyclic peptides were syn-
thesized that contain non-natural amino acids with a BCP
moiety.[425] Linear and cyclic hexapeptides of the type Arg-Arg-
Xaa-Yaa-Arg-Phe 334 containing the BCP amino acid 333 as a
replacement for two tryptophan residues were prepared by
SPPS (Figure 74). Results showed that the antimicrobial effect
Figure 72. Non-natural peptides.
embryonic kidney cell line. These highly potent cytotoxic com-

pounds have application as antibody–drug conjugates and
other drug delivery systems for personalized targeted cancer
chemotherapies.
One of the first examples of amino acids containing a BCP
moiety are 2-(3’-substituted-BCP)glycines 331 (Figure 73).[393, 396]
Figure 73. A BCP peptide.
Inspired by this work, four derivatives of 3-aminoBCP-1-carbox-

ylic acid 331 a–d were prepared to act as rigid analogues of 4- Figure 74. BCP and BCO antimicrobial peptides.
aminobutyric acid, which has been shown to act as a neuro-
transmitter in the brain.[423] These analogues were then incor-
porated into linear and cyclic peptides using solution chemis- of the non-natural peptides markedly increased due to the
try and solid-phase techniques. Moreover, the sequences for presence of the bulky and hydrophobic BCP amino acids con-
the BCP peptide 332 were derived from the neuropeptide firming the importance of having hydrophobicity in the hexa-
cholecystokinine (CCK), to be used as a ligand for the CCK-B peptides. Unexpectedly, cyclization was detrimental to the ac-
subreceptor in the brain that acts as neurotransmitter and neu- tivity of the BCP-substituted derivatives, likely due to its high
romodulator. The shortest natural CCK fragment that exhibits a global hydrophobicity eliminating the activity-enhancing effect
high affinity for the CCK-B receptor is the C-terminal CCK-4 of cyclization-induced amphipathicity.[426] The chiral BCP amino
that has the sequence Trp-Met-Asp-Phe. Classic coupling meth- acid was synthesized over nine steps from the tetrahalide; key
ods as well as by solid-phase techniques were employed to steps involved addition of a Grignard reagent to from the BCP
synthesize the peptide. scaffold and an asymmetric Strecker reaction to form two gly-
cinonitriles.
Review
One of the significant areas of antibiotic resistance involves

Gram-positive skin and soft-tissue infections. GE2270, an isolat-
ed thiopeptide-based natural product was found to inhibit the
prokaryotic chaperone elongation factor Tu (EF-Tu).[427] The an-
tibiotic profile was remarkable, with minimum inhibitory con-
centrations below 1 mg mL@1 but drawbacks included low Figure 76. Scope of distances within the 1808 void.
water solubility and instability of the macrocycle. Hence, in
order to increase the intrinsic aqueous solubility and improve
the cellular antibacterial activity, a variety of linkers, spacers, enter the stage, spanning a full range of different angles and
and termini, including the BCO spacer, were examined to fur- distances. The family of bicyclic [x.y.z]-hydrocarbons seems to
ther chemically stabilize the 4-aminothiazole macrocyclic be perfect candidates for a wide spectrum of angles and dis-
335.[428] SAR results showed improvements in the solubility and tances (Figure 77). With x, y, z in the range of 1 to 3, this group
efficacy profiles over previous analogues and GE2270 although covers a range from 2.01 to 3.02 a, and a geometrical arrange-
the cyclohexane derivative proved to be more effective than ment from 132 to 1778.
the rigid BCO counterpart.
Hepatitus C virus (HCV) is a positive-stranded RNA virus that
causes several serious liver conditions such as liver cirrhosis,
chronic hepatitis, and hepatocellular carcinoma.[429] A potential
therapeutic target for the treatment of HCV is the HCV NS5A
protein as it plays a critical role in regulating HCV replica-
tion.[430, 431] The first-in-class HCV NS5A inhibitor Daclatasvir
336[432] contains a C2-symmetric biphenyl bisimidazole motif,
and a biphenyl central unit (Figure 75). Alternative rigid bio-
Figure 77. Different angles and distances within the [x.y.z]-hydrocarbon

series. Estimated values assuming standard bond angles and length, for non-
specific functional groups.
The potential for various orientations becomes even more

complicated and exciting with the introduction of more than
two functional groups. New geometric arrangements and iso-
mers can be realized to generate desired functions. Expanding
Figure 75. HCV NS5A inhibitors. on this, a four-fold substituted system, with a tetrahedrane-like
shape, would even introduce a new chiral opportunity. Chiral
adamantane or cubane-systems seem to be ideal candidates
isosteres, such as the BCO analogue 337, were employed to to explore the tetrahedral space and progress has already
improve the pharmacokinetic properties of the compound.[433] been made in this area, with the synthesis of tetrahalogenated
Results showed good solubility and potency at the target. Ad- asymmetric adamantane[434] and cubane[435] (Figure 78).
ditionally, the BCO derivative 337 possessed good bioavailabil- Implementing the use of multidimensional arrays with Chau-
ity and high concentrations in liver tissues and saw increased vin‘s concept of carbomers,[436] is a logical process to achieve
solubility compared with the parent compound. The 10- to 20- the various linker lengths and geometries. A “cubamere”, the
fold less reduction in potency relative to Daclatasvir 336 sug-
gests that the biphenyl unit may be interacting with the NS5A
protein and not just merely acting as a spacer.
8. Perspective of Linkers
The systems we have presented all share the common theme
of being linear and disubstituted, ranging from bridgehead-to-
bridgehead distances of 1.85 a in BCP to 2.79 a in cubane
(Figure 76).
With regards to rigidity, being able to arrange functional
groups in a spatial defined manner, many other hydrocarbons Figure 78. The tetrahedral space.
Review
nonconjugated counterpart to Feldman‘s tetraethynylmeth-

ane[437] is just one thinkable structure with unexplored proper-
ties. Like the tetraethynylmethane, the synthesis of the corre-
sponding cubamer would be a remarkable challenge, but with
promising possibilities (Figure 79). In addition, just like the ple-
Figure 81. Shape-shifting bullvalene as a dynamic chemical sensor.
A few more examples focus on reversible carbon–carbon

bond formations without the presence of heteroatoms are cat-
alyzed olefin[442] or alkyne metathesis[443] or cycloadditions,[444]
as shown below (Scheme 31).[445] These systems are interesting
since they combine the rigidness of their arrangement with
Figure 79. Expanding methane from carbomers to cubamers.
the flexible control of their formation.
thora of polyacetylenic linked molecules and their triumphal

procession in material chemistry,[438] their nonconjugated coun-
terparts would build the bridge over unknown waters for
many desirable functions. Again, there is no set limit to the tet-
rahedral space as well, many different polysubstituted linker
systems being possible (Figure 80): Octasubstituted BCP with a
trigonal bipyramidal motif (6 + 2), octadodecasubstituted trip-
tycene (4 + 4 + 4 + 2), or even an octasubstituted cubane with
eight different substituents.
Scheme 31. Dynamic covalent C@C bond formations.
9. Conclusions
Figure 80. Possible geometrical arrangements of different substituents (indi- In this Review article, the chemistry and applications of differ-
cated by different colors) for key framework molecules. ent, rigid, nonconjugated, linear hydrocarbons are highlighted.
It is hoped that this comprehensive study compiles the rele-
vant information about BCP, BCO, triptycene, and cubane into
A rather futuristic approach lies within utilizing rigid linker a “handbook” to provide chemists with the knowledge re-
systems in a dynamic fashion–order and turmoil in one mole- quired to select an appropriate hydrocarbon, depending on
cule. One might need molecules to be arranged in a certain their unique needs, whether it be for electron-transfer studies,
geometry, but would it not be even more covetable to use a MOF or liquid crystal constructions, molecular rotors or rods,
dynamic, covalent approach? Breaking and mending bonds, bioisosteres or drug motifs. What is more, the relevance of
but still in a defined conformational and, therefore, geomet- these systems has been long overlooked and disregarded be-
rical distinct fashion. This would create the possibility to use cause of their different chemistry when compared to the omni-
the rigid, but still flexible conformation of the linker molecules present benzene or acetylene motifs; thus, their chemistry has
to cope with the specialties of the environment. One could been highlighted once more. We hope this Review inspires
imagine a linker which can adjust the overall geometric ar- chemists to develop new and expanding methodologies to
rangement of the pharmacophores, to specifically fit into a access these molecules. The use of these unique scaffolds[446]
protein binding pocket? Current work utilizing this shape shift- will leave their shadow-existence once more robust cross-cou-
ing approach was presented by the Bode group.[439] They incor- pling methodologies (sp3-sp, sp3-sp2, sp3-sp3) have been devel-
porated a single 13C-label into the bullvalene backbone and oped. Nevertheless, the already prepared systems show highly
were able to differentiate dissimilar polyols by small changes interesting and unique properties in diverse areas, from bioi-
in the chemical shift and intensities (Figure 81).[440] With the re- sosteres to rigid rods. The rapid development within recent
cently developed method by the Fallon group, disubstituted years clearly shows the rising interest in these hydrocarbons
bullvalenes are easily available now and their computational with many more fascinating developments emerging.
network analysis is a useful tool to understand the energetic Naturally, there are more compounds that fulfill the require-
landscape of the various isomers.[441] ments of this Review article, such as the rigid-linear hydrocar-
Review
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DOI: 10.1002/chem.

& Materials Science

Nonconjugated Hydrocarbons as Rigid-Linear Motifs: Isosteres for

1. Introduction cyclo[2.2.2]octane (BCO) and triptycene (Figure 1). In particular,

Figure 1. Nonconjugated rigid hydrocarbons (NRHs).

at the bond critical point,[16] as a positive Laplacian was evi-

2.2. Bicyclo[2.2.2]octane (BCO)

The first synthesis of bicyclo[2.2.2]octane (BCO) 10 was achiev-

analysis of substituted derivatives gave clear indication that

2.3. Triptycene and barrelene

diazotization with sodium nitrite and reduction of the corre-

Table 3. Physical properties of cubane.

clo[4.2.0.02,5]octa-3,7-diene derivatives 38, a method not suit-

3.1. Size and dimension

match the long length of the internal bond would be rather

ed triptycene 19 and BCO 10 show the expected chemical

3.2. Bond considerations, electronic communication, and

Bridgehead hybridization and distances are not only important

3.2.2. Ring strain

Table 5. Heat of combustion and strain energy of cycloalkanes.

[a] N/D = not determined.

energy of cubane is about six times the amount of cyclobu-

interesting example is the correlation of ring strain with the

Figure 9. Nucleophilic substitution on 9-substituted triptycenes.

Figure 10. Experimental gas-phase acidities (DHa), electron affinities (EA),

bond.[141] The homolytic bond dissociation energy (BDE), re-

3.3.2. Bridgehead anions 3.3.3. Bridgehead radicals

BDEðR-HÞ ¼ DHa ðRHÞ @ IEðHC Þ þ EAðRC Þ ð1Þ

3.3.4. Bridgehead radical cations

Examples of radical cations for the rigid hydrocarbons currently

Both experimental ((photo)chemical oxidation of cubane 37C +

determining step for a homolytical C@C-bond cleavage, during

Scheme 17. Kinetics of cubylcarbinyl radical 67.

Scheme 16. Rearrangement of cubane (a,b,c) and [1.1.1]propellane (d) skele-

yields the stable cuneane 63 (lat. cuneus = wedge). A similar re-

Scheme 20. Stepwise hydrogenation of cubane.

Scheme 21. Cubane skeleton decomposition in the presence of lithium di-

methyl alcohol 94. Slight acidic conditions induce a homoketo-

The polymerization of a [1.1.1]propellane derivative 104 was

with this method. The multicomponent reaction involves a

45 min to 3 h. The reaction was then quenched with four

Scheme 26. Functionalization of the bridgehead carbon in triptycenes;

4.2.2. Triptycene chemistry

Scheme 28. Redox-active ester chemistry. DMAc = dimethylacetamide; BTMG = 2-tert-butyl-1,1,3,3-tetramethylguanidine.

Scheme 30. Expanded cubane chemistry. 9-BBN = 9-borabicyclo[3.3.1]nonane.

5. Applications of Rigid-Linear Linkers in Elec-

Figure 16. Small molecule chromophores for electron-transfer studies.

p-Phenylene, methyl-substituted p-phenylene and BCO were

teraction,[226] and all were shown to decay exponentially with

Figure 20. Star-shaped molecular motor and triptycene-linked electron-transfer systems.

Figure 23. BCO-linked porphyrin dimers.

Figure 24. BCO-linked bisporphyrin systems as photosynthetic mimics.

lar compounds with homostructural cores were employed

Figure 26. Various BCO-based liquid crystals exhibiting wide-range nematic

Figure 25. BCO-based liquid crystals.

Figure 27. Investigation of the mesogenic and dielectric properties of lateral-

genic core 203–204 (Figure 27).[258–260] Results showed that

sterically demanding shallow glide conformation. This confor-

Figure 29. Different hydrogen-bonding interactions for 1,4-substituted