Complexes of Urea

Chem. Rev.
2004, 104, 1047−1076 1047
Reactivity of Dioxygen−Copper Systems

Elizabeth A. Lewis and William B. Tolman*
Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455
Received July 9, 2003
Contents
1. Introduction 1047
1.1. Background 1047
1.2. Scope 1049
2. Reactivity of Cu(I) Complexes with O2 1049
2.1. Overview 1049
2.2. Formation of 1:1 Cu/O2 Adducts 1051
2.3. Reactions of 1:1 Cu/O2 Adducts to Yield 1054
Higher Nuclearity Complexes
3. Isomerism between µ-η2:η2-Peroxo- and 1059
Bis(µ-oxo)dicopper Complexes
4. Alternate Syntheses of Copper−Dioxygen and 1061
Related Complexes
5. Intramolecular Reactions of Copper−Dioxygen 1061
Complexes Elizabeth A. Lewis grew up in Pembrokeshire, Wales, and obtained her
Bachelor’s degree in Chemistry from the University of York, UK in 1996.
5.1. Arene Hydroxylations and Related Reactions 1061 She then received a Master’s degree from Dalhousie University, Nova
5.2. N-Dealkylations and Benzylic Oxidations 1063 Scotia (with Robert L. White) in 1998 and a Ph.D. from the University of
5.3. Other Intramolecular Ligand Oxidations 1066 York, UK (with John R. Lindsay Smith and Paul H. Walton) in 2002. After
this time, she moved to the University of Minnesota and joined the group
6. Intermolecular Reactions of Copper−Dioxygen 1068 of William B. Tolman as a postdoctoral researcher focusing on the
Complexes synthesis of novel Cu/O2 species. She is currently a Welcome Trust
7. Perspective and Conclusion 1072 postdoctoral research fellow at the University of Hull, UK, with Stephen
8. Acknowledgments 1072 J. Archibald, investigating Cu complexes for medical applications.
9. References 1072
1. Introduction
1.1. Background
Copper proteins that bind and/or activate dioxygen
perform a variety of critical biological functions.1-3
These include O2 transport (hemocyanin, Hc),4 aro-
matic ring oxidations (tyrosinase, Tyr,5 catechol
oxidase, CO,6 and quercetin 2,3-dioxygenase, QDO7-9),3
the biogenesis of neurotransmitters and peptide
hormones (dopamine β-monooxygenase, DβM,10 and
peptidylglycine R-amidating monooxygenase,
PHM11,12),2 hydrogen peroxide generation (galactose William B. Tolman is a Distinguished McKnight University Professor of
and glyoxal oxidases, GAO and GLO),13-18 iron ho- Chemistry at the University of Minnesota, Twin Cities. He obtained his
meostasis (ceruloplasmin3 and Fet3p19-21), and meth- B.A. from Wesleyan University in 1983 and subsequently worked in the
ane oxidation (particulate methane monoxygenase, laboratory of Prof. K. Peter C. Vollhardt at the University of California,
pMMO),22-25 among others (Table 1).16,26-42 Post- Berkeley, for his Ph.D. (1987). After a postdoctoral stint in the laboratory
translational synthesis of organic cofactors also may of Prof. Stephen J. Lippard at the Massachusetts Institute of Technology,
he joined the faculty at the University of Minnesota in 1990. Current
involve the reaction of dioxygen with copper protein research activities range from synthetic modeling of metalloprotein active
active sites.43 Usually, the chemical pathway tra- sites to the development and mechanistic study of catalysts for the
versed by these various proteins involves the reaction synthesis of biodegradable polymers from renewable resources.
of reduced Cu(I) centers with dioxygen to yield an
adduct or intermediate species, which subsequently
* To whom correspondence should be addressed. Phone: 612-625- reacts with substrate. Despite such fundamental
4061. E-mail: [email protected]. FAX: 612-624-7029. commonality, diverse mechanisms of action are pos-
10.1021/cr020633r CCC: $48.50 © 2004 American Chemical Society
Published on Web 01/13/2004
1048 Chemical Reviews, 2004, Vol. 104, No. 2 Lewis and Tolman
Table 1. Copper Proteins that Bind and/or Activate Dioxygen

no. Cu ions
involved in
protein (abbreviation) O2 activation reaction performed selected lead refs
amine oxidase (AO) 1 aldehydes and H2O2 from primary amines 2, 16, 26-28
galactose oxidase (GAO) 1 aldehydes and H2O2 from alcohols 2, 13-16
glyoxal oxidase (GLO) 1 carboxylic acids and H2O2 from aldehydes 2, 17, 18
dopamine β-monooxygenase (DβM) 2 (uncoupled)a hydroxylation of dopamine to yield epinephrine 2, 10
peptidylglycine R-amidating 2 (uncoupled)a hydroxylation at R-position of glycine 2, 11, 12
monooxygenase (PHM)
quercetin 2,3-dioxygenase (QDO) 1 oxidative ring opening of quercetin 7-9
hemocyanin (Hc) 2 reversible binding of O2 1, 3, 4
tyrosinase (Tyr) 2 hydroxylation of aromatic ring 3, 5
catechol oxidase (CO) 2 oxidation of catechol to o-quinone 3, 6
methane monoxygenase (MMO) b hydroxylation of methane to methanol 22-25
ammonia monoxygenase (AMO) b oxidation of ammonia to hydroxylamine 3, 29, 30
multicopper oxidasesc 3 1, 3, 31
laccase (Lc) 3 oxidative coupling of catechols 32-34
ascorbate oxidase (AO) 3 oxidation of ascorbate 35
ceruloplasmin (Cp) 3 oxidation of Fe(II) to Fe(III) 36
Fet3 3 oxidation of Fe(II) to Fe(III) 37, 38
phenoxazinone synthase (POS) 3 oxidative coupling of aminophenols 39, 40
cytochrome c oxidase 1 (+ Fe)) establishment of membrane proton gradient 41, 42
a
These proteins contain two copper ions separated by ∼11 Å, but it is unclear if one or both activates dioxygen. b Nuclearity
of the O2 activating copper sites is unclear. c Only selected examples of multicopper oxidases are listed; for more complete discussion,
see refs 1 and 3.
Figure 1. Aspects of the mechanisms proposed for (a) GAO and GLO,44 (b) DβM,47 (c) Tyr,1,3 and (d) the multicopper
oxidases.53 The symbol “N” refers to a histidine imidazolyl group. Axial ligands in (c) and all protein ligands in (d) are
omitted for clarity. Reversible O2 binding in Hc occurs according to the top O2 coordination step in (c); CO activity is
postulated be similar to the last step in (c).1,3,49
sible because of the varied protein active site struc- binding of O2 to the reduced Cu(I) form yields a
tures (nuclearities, ligands, geometries) and types of Cu(II)-superoxide, which has yet to be observed
transformations promoted. through spectroscopic means. Subsequent internal
To illustrate this point, selected aspects of proposed hydrogen atom (or proton coupled electron) transfer
catalytic mechanisms are drawn in Figure 1 for is suggested to yield a (tyrosyl radical)Cu(II)-
representative examples of proteins that contain hydroperoxide, from which H2O2 evolves to yield the
active sites with nuclearities ranging from 1 to 3 active form identified by spectroscopy that oxidizes
copper ions. In Figure 1a is shown a proposed substrate. Intermediates formulated as Cu(II)-OOH,
pathway by which the active Cu(II)-tyrosyl radical Cu(II)-O2-, and Cu(II)-O•/Cu(III)dO have been pro-
form of GAO (and GLO) is formed.44 In the first step, posed for PHM and DβM on the basis of kinetic
Reactivity of Dioxygen−Copper Systems Chemical Reviews, 2004, Vol. 104, No. 2 1049
evidence (Figure 1b).2,45-47 Despite much study of literature covered extends to summer 2003. The
these enzymes, however, many mechanistic questions spectroscopy and structures (including theoretical
remain, including ones concerning how these putative descriptions) of the various types of adducts that have
oxidants are formed48 and which is (are) responsible been characterized to date are discussed in the
for attacking the substrate C-H bond.45-47 A (µ-η2: preceding article in this issue.90 We divide our
η2-peroxo)dicopper(II,II) unit has been identified discussion as follows. First, we consider the kinetics
conclusively in Hc,3,4 Tyr,3 and CO6,49 (Figure 1c). and thermodynamics of the reactions of O2 with
Substrate accessibility appears to determine the fate Cu(I) complexes that lead to discrete adducts and
of this unit, such that in Hc (no substrate access) only related complexes. Second, interconversions among
reversible O2 binding occurs, but in Tyr and CO specific isomeric complexes that result from Cu(I)/
wherein substrate can approach and/or bind to the O2 reactions are discussed. Alternate synthetic routes
Cu2O2 moiety, an aromatic ring is hydroxylated and/ to Cu/O2 species are then presented. Finally, we
or a catechol(ate) is converted to an ortho-quinone. evaluate the mechanisms of the reactions of Cu/O2
The Tyr hydroxylation mechanism shown (Figure 1c) species with endogenous and exogenous substrates.
involving direct electrophilic attack of the peroxo unit Although there are many examples of oxidation
onto the aromatic ring is supported by recent experi- reactions catalyzed by Cu complexes in the literature,
mental50 and theoretical results.51 Finally, an un- in this review we focus on the formation and reactiv-
usual mixed-valent tricopper-hydroperoxo structure ity of Cu/O2 complexes that are well-defined through
has been suggested as a reactive intermediate in spectroscopic studies and/or X-ray crystal structure
reduction of O2 to H2O by the multicopper oxidases analyses.
(Figure 1d).52-54 Taken together, and despite being
described only briefly, these examples demonstrate 2. Reactivity of Cu(I) Complexes with O2
the diversity of structures and pathways proposed for
Cu/O2 species in proteins; more comprehensive mecha- 2.1. Overview
nistic analyses of many of the biological systems
listed in Table 1 are presented in various re- Early kinetic studies on reactions of Cu(I) com-
views.1-6,11,13,16,43 plexes with O2 implicated formation of Cu/O2 adducts,
Among the central chemical issues to be addressed but evidence was lacking for the unambiguous iden-
to understand the function of the copper proteins tification of these often thermally unstable species.
listed in Table 1, those that center on the geometry, For example, the kinetics of autoxidation of Cu(I)
electronic structure, interconversions, and substrate complexes of substituted imidazoles in aqueous ac-
reactivity of the Cu/O2 adducts or intermediates have etonitrile showed competing one- and two-electron O2
attracted the most attention, particularly by scien- reduction pathways.91,92 It was argued that the
tists who examine small molecule models with which existence of the former route provided indirect evi-
detailed physicochemical and mechanistic insights dence for formation of an unstable 1:1 Cu/O2 adduct
may be obtained.55 Thus, stimulated by the fascinat- in solution. Because clear spectroscopic or structural
ing biological systems, as well as by relevance to support for such hypotheses was unavailable, early
many copper-promoted transformations in homoge- experimental approaches generally focused on pre-
neous56,57 and heterogeneous catalysis,58,59 extensive paring more readily isolated and characterized com-
studies of the reaction of Cu(I) complexes with O2 plexes with endogeneous bridging ligands that might
have been performed. In large part, these studies model O2 interactions (e.g., N3-, RO-).62
have attempted to address questions such as: How Since these initial studies, the understanding of
does O2 coordinate to the copper ion, and what are Cu/O2 systems has improved dramatically as a result
the kinetics and thermodynamics for O2 binding? of a combination of technological advances (e.g., CCD
How do supporting ligands (topology, electronic prop- detectors for X-ray crystallography and Raman spec-
erties) influence the structure and stability of the troscopy, instrumentation for low-temperature stopped
species derived from the Cu(I)/O2 reaction? How do flow kinetics measurements), the use of low-temper-
these species react (what are the mechanisms?)? ature sample handling methods, and the judicious
What are the most important geometric and/or application of ligand design principles.93,94 A number
electronic structural features for controlling their of discrete copper-dioxygen and related species have
reactivity? As discussed below, through detailed been stabilized sufficiently for characterization using
kinetics and other mechanistic studies of synthetic a wide variety of ligands (Chart 1, listed in order of
copper compounds, studies aimed at answering these discussion in the text; structural motifs are sum-
questions have provided fundamental chemical in- marized in Chart 2). A key research objective has
sights of value for understanding copper protein been to unravel the mechanism(s) by which these
function. species form; toward this end, the kinetics of the
oxygenations of Cu(I) complexes have been examined
1.2. Scope extensively. Due to the typically quite rapid rates of
Cu(I)/O2 reactions and the thermal instability of the
There are many reviews describing different as- resulting complexes, the development of low temper-
pects of Cu/O2 adduct formation, characterization, ature stopped-flow kinetic techniques and the ap-
and subsequent reactivity toward substrates.60-89 In plication of numerical methods and factor analysis
this article, we provide an overview of the kinetic, to interpret the data collected from these experiments
thermodynamic, and mechanistic features of Cu/O2 have been particularly useful for unraveling oxygen-
adduct formation and subsequent reactivity. The ation pathways.95-98 As a result, the individual steps
Chart 1
Chart 1 (continued)
Chart 2 Scheme 1
observed to date, differences in details are often

significant, and reflect important influences of sup-
porting ligand structure on the dioxygen activation
mechanism.
It is important to appreciate that while kinetic and
thermodynamic parameters are of critical importance
in understanding the reactivity of model Cu(I) com-
plexes with O2 they do not provide information about
the nature of O2 binding to the metal center(s)
(although sometimes specific intermediates may be
leading to the formation of well-defined Cu/O2 species more logical mechanistically). Spectroscopic and, if
have now been elucidated for a range of different possible, structural data are required to complement
systems and their kinetic and thermodynamic pa- kinetic information and provide a complete mecha-
rameters determined.99-101 nistic representation. Finally, it is worth noting a
warning99 against establishing mechanistic argu-
We discuss these results within the context of a
ments on the sole basis of a comparison of kinetic
general mechanistic framework shown in Scheme 1.
and equilibrium constants at a given temperature
According to this scheme, dioxygen initially binds to
because these can sometimes be very misleading; use
a Cu(I) center to form a 1:1 Cu/O2 adduct (process
of activation and thermodynamic parameters is pre-
A). This adduct usually, but not always, reacts with
ferred.
a second Cu(I) complex to form one or more binuclear
Cu2O2 species (process B). Further reaction with LCu-
(I) can occur to give trinuclear or tetranuclear ad-
2.2. Formation of 1:1 Cu/O2 Adducts
ducts (not shown). While this general picture ad- Most commonly, 1:1 Cu/O2 adducts have been
equately encompasses the oxygenation pathways implicated in stopped-flow kinetic studies as short-
lived intermediates on the pathway to well-defined tion (k-1) were observed for the more sterically
2:1 Cu/O2 complexes.95,97,100,102-117 Broadly speaking, hindered BQPA (4) system relative to its TMPA (1)
three kinetic situations have been identified. In some and TMPAE (3) congeners. Less favorable ∆Sq values
cases (e.g., complexes supported by TMPA (1),102-106 for both processes for the BQPA (4) case (by ∼50 J
4R-TMPA (2a-d),105 TMPAE (3),107 BQPA (4),104 D1 K-1 mol-1) underly its slower reactions. On the other
(5),111 or Me6tren (6)96,97,108,109), the rates of formation hand, increased rate constants for O2 association and
and decay of the intermediate 1:1 adduct are such greater stabilization of 1:1 Cu/O2 complexes (larger
that both processes may be monitored and the K1 at low temperature and more negative ∆H°
intermediate may be observed spectroscopically. In values) than seen for (TMPA)Cu(I) were noted in
other instances, formation of the initial 1:1 adduct cryogenic stopped-flow kinetics studies of systems
is slow and rate-determining, with fast subsequent supported by Me6tren (6), 2L (11) and 4-R-TMPA (2c,
trapping of this adduct by an additional Cu(I) center R ) OMe or 2d, R ) NMe2). For Me6tren (6), a more
that prevents observation of the 1:1 complex (e.g., than 4-fold increase in oxygenation rate at low
with LRR′ (7),115,116 m-XYLiPr4 (8),115 p-XYLiPr4 (9),115 temperature (183 K) compared to the TMPA (1)
or i-Pr4dtne (10)115,117). For both scenarios, kinetic and complex may be traced to a more favorable ∆Hq1 (by
thermodynamic parameters for 1:1 adduct formation ∼15 kJ mol-1) that is only partially offset by a more
(k1, k-1, K1) may be determined. Finally, there are negative ∆Sq1 (by ∼60 J mol-1 K-1). A redox influ-
instances in which the equilibrium for binding of O2 ence was cited109 as a possible rationale for this
to a single Cu site is reached very rapidly, which difference in oxygenation kinetics, whereby the poly-
prevents determination of k1 and k-1 values (e.g., for pyridyl ligation of TMPA (1) better stabilizes Cu(I)
TMPA (1) or 4-OMe-TMPA (2c) in THF,105 2L (11),118 than the more electron donating alkylamines of
AN or MeAN (12a,b),114 HPy2Me (13b),119 or N4Py2 Me6tren (6), resulting in faster formation of the
(14b)112) and/or leads to kinetics that are second order Cu(II)-superoxide complex for the latter.
in the starting Cu(I) complex due to slow, rate-
An analogous electronic effect was identified and
controlling trapping of a putative 1:1 adduct (e.g.,
HPy2Phe (13c)113 or HPy1Et,Bz (15a)120). In fact, through more rigorously separated from possible steric influ-
ences in a detailed kinetic study comparing the
the use of particularly sterically bulky supporting
TMPA (1) system with derivatives substituted at the
ligands, reaction of a 1:1 adduct with a second Cu(I)
remote 4-position on the pyridyl rings, 4-R-TMPA
complex may be prevented completely. This strategy
(2a-d).105 For the cases in which R is strongly
has facilitated spectroscopic characterization of 1:1
electron donating (2c, R ) OMe or 2d, R ) NMe2),
Cu/O2 complexes104,105 and, in a few instances, has
faster rates of oxygenation and increased stabiliza-
enabled them to be isolated as solids (TptBu,Me
tion of the 1:1 Cu/O2 adduct were observed. These
(16d),121,122 1L (17),123 H(R2LiPr2) (18a, R ) tBu; 18b,
differences were attenuated when the kinetics were
R ) Me124,125)). Note that in one case, an X-ray crystal
studied in EtCN solvent, which binds strongly to
structure of a 1:1 Cu/O2 adduct126 was later reas-
Cu(I) and competes with O2 coordination. When more
signed127 as a Cu(II)-hydroxide complex, presumably
weakly coordinating THF was used as solvent, much
derived from a decomposition process.128,129
faster 1:1 Cu/O2 adduct formation was observed for
Selected kinetic and thermodynamic parameters TMPA (1). Indeed, in a recent study using a “flash-
for 1:1 Cu/O2 adduct formation are compared in Table and trap” technique to examine the oxygenation rate
2. Some general similarities are evident among of [(TMPA)Cu(I)THF]+ derived from photolysis of
systems supported by different N-donor ligands. [(TMPA)Cu(I)CO]+, extraordinarily high k1 values
Thus, activation enthalpies for oxygenation (∆Hq1) of (greater than for reduced iron heme complexes),130 a
Cu(I) complexes of tris(pyridyl)methylamines (TMPA correspondingly small ∆Hq1 value and a negative
(1), TMPAE (3), BQPA (4)) and of triazacyclononanes ∆Sq1 were measured (Table 2) that were consistent
(LiPr3 (7b), m-XYLiPr4 (8), i-Pr4dtne (10)) fall within with direct attack of O2 onto the Cu site with
a relatively narrow range (30-40 kJ mol-1), with an essentially no interference from solvent.106 The elec-
exception being the TMPA (1) system studied by flash tronic effects of the remote 4-substituents in the
photolysis (discussed below).106 Unfavorable activa- systems supported by 4-R-TMPA (2a-d) also were
tion entropies generally are observed (-62 to ca. 0 J enhanced in THF solvent. These effects correlate
K-1 mol-1), consistent with loss of degrees of freedom nicely with the basicity of the 4-substituted pyridines
upon binding of O2. The thermodynamics for 1:1 and the (4-R-TMPA)Cu(I)/(II) complex redox poten-
adduct formation are similar for most of the tris- tials measured by cyclic voltammetry in CH3CN; the
(pyridyl)methylamine systems (at 183 K, K1 ) 102- electron donating substituents increase pyridyl ring
103 M-1), and feature comparably favorable reaction basicity, decrease the Cu(II)/(I) reduction potentials,
enthalpies (∆H° ∼ -30 kJ mol-1) and unfavorable and increase the rate of oxygenation and thermo-
reaction entropies (∆S° ∼ -125 J K-1 mol-1) that dynamic stability of the 1:1 Cu/O2 adducts. Similar
preclude observation of the adducts at room temper- correlations, in particular between redox potentials
ature. and O2 binding thermodynamics, are known for iron
Notwithstanding the aforementioned general simi- and cobalt complexes.101,131 Interestingly, when ac-
larities, interesting differences in kinetic and ther- etone was used as solvent, a significant shift in the
modynamic parameters for 1:1 adduct formation have oxygenation mechanism was identified (Scheme 2).
been identified among systems that vary with respect In acetone, the Cu(I) precursor was shown to be
to supporting ligand structure or solvent medium. dimeric from independent conductivity and NMR
For example, slower O2 association (k1) and dissocia- evidence; related dimeric structures had also been
Table 2. Selected Kinetic and Thermodynamic Parameters for the Formation of 1:1 Cu/O2 Adducts upon Low Temperature Oxygenation of Cu(I) Complexesa
thermo-
activation activation dynamic
parameters parameters parameters
ligand solvent k1b (k1)c k-1b (k-1)c K1d (K1)c ref
TMPA (1) EtCN (1.18 ( 0.01) × 104 ∆Hq ) 31.6 ( 0.5 15.9 ( 0.1 ∆H ) 61.5 ( 0.5
q
(7.42 ( 0.04) × 102 ∆H° ) -29.8 ( 0.2 105
∆Sq ) 10 ( 3 ∆Sq ) 118 ( 3 ∆S° ) -108 ( 1
THF g2 × 106 (7 ( 3) × 105 ∆H° ) -41 ( 2 105
∆S° ) -112 ( 9
THFe 1.5 × 108 (293 K) ∆Hq ) 7.62 240 (193 K) ∆Hq ) 58 6.5 × 105 (193 K) ∆H° ) -48.5 106
∆Sq ) -45.1 ∆Sq ) 105 ∆S° ) -140
4OMe-TMPA (2c) EtCN (1.93 ( 0.04) × 104 ∆Hq ) 30.5 ( 0.6 1.11 ( 0.06 ∆Hq ) 62.2 ( 0.7 (1.73 ( 0.08) × 104 ∆H° ) -31.8 ( 0.4 105
∆Sq ) 8 ( 3 ∆Sq ) 100 ( 3 ∆S° ) -93 ( 2
TMPAE (3) EtCN (8.2 ( 0. 4) × 103 ∆Hq ) 31 ( 5 29 ( 2 ∆Hq ) 63 ( 5 (2.84 ( 0.09) × 102 ∆H° ) -32 ( 1 106
∆Sq ) 5 ( 29 ∆Sq ) 132 ( 29 ∆S° ) -127 ( 3
BQPA (4) EtCN 18 ( 1 ∆Hq ) 30 ( 2 (6.1 ( 0.7) × 10 -3
∆Hq ) 65 ( 4 (2.9 ( 0.3) × 10 3
∆H° ) -35 ( 6 104
∆Sq ) -53 ( 8 ∆Sq ) 72 ( 19 ∆S° ) -125 ( 27
D1 (5) EtCN (1.63 ( 0.01) × 104 ∆Hq ) 20 ( 1 8.0 ( 0.2 ∆Hq ) 55 ( 1 (2.03 ( 0.04) × 103 ∆H° ) -35.3 ( 0.4 106
∆Sq ) -53 ( 6 ∆Sq ) 76 ( 6 ∆S° ) -129 ( 2
Me6tren (6) EtCN (9.5 ( 0.4) × 104 ∆Hq ) 17.1 ( 0.6 (7.0 ( 0.3) × 10-2 ∆Hq ) 62.0 ( 0.6 (1.35 ( 0.04) × 106 ∆H° ) -44.9 ( 0.2 109
∆Sq ) -52 ( 3 ∆Sq ) 76 ( 3 ∆S° ) -128 ( 1
LiPr3 (7b) acetone 0.191 (193 K) ∆Hq ) 37.2 ( 0.5 115,116
∆Sq ) -62 ( 2
m-XYLiPr4 (8) acetone 2.46 (193 K) ∆Hq ) 39.4 ( 0.5 115
∆Sq ) -30 ( 2
i-Pr4dtne (10) acetone 1.87 (193 K) ∆Hq ) 39.4 ( 0.1 115,117
∆Sq ) -32.0 ( 0.4
Chemical Reviews, 2004, Vol. 104, No. 2 1053

2
L (11) THF (3 ( 1) × 1010 ∆H° ) -69 ( 1 118
∆S° ) -177 ( 4
a
All data from cryogenic stopped-flow kinetics measurements except where indicated; the rate and equilibrium constants are for process A in Scheme 1. Except for [(BQPA)Cu]+
and [2LCu], the 1:1 Cu/O2 adducts are short-lived intermediates only. Solvent coordination is likely in many of the complexes, but is not shown for clarity. b Units are M-1 s-1, with
values at 183 K unless noted otherwise. c Units are kJ mol-1 (∆Hq, ∆H°) or J K-1 mol-1 (∆Sq, ∆S°). d Equal to k1/k-1; units are M-1, with values at 183 K unless noted otherwise.
e
Data obtained using “flash-and-trap” method, whereby the carbon monoxide complex was flash-photolyzed and the trapping of the intermediate THF complex by O2 was measured.
Scheme 2 parameters for the individual steps that result from

ligand structural disparities and/or solvent effects
(Table 3). A µ-η1:η1-peroxodicopper product is the
thermodynamically most stable species (vs the 1:1
precursor) for TMPA (1), TMPAE (3), BPQA (19), and
Me6tren (6). As for the 1:1 Cu/O2 adducts described
above for TMPA (1) and 4-substituted derivatives
(2a-d), the peroxo species are more stable when THF
is used as solvent (e.g., for TMPA (1), ∆H° (β ) K1K2)
) -77 kJ mol-1 in EtCN vs. -94 kJ mol-1 in THF)
noted for other multidentate ligand systems.132,133 and when the ligand is more electron donating (4-
Kinetic data for the system supported by 4-tBu- OMe-TMPA, 2c). On the other hand, the replacement
TMPA (2b) were interpreted to indicate binding of of a pyridyl arm in TMPA (1) to yield the more
O2 to one Cu(I) ion in the dimer to yield a mixed- hindered BPQA (19) results in decreased stability.
valent Cu(I)Cu(II) superoxo species. Subsequent Substituting a second pyridyl group in TMPA with a
reaction with another dicopper(I) complex to afford quinolyl group introduces sufficient steric bulk (BQPA,
a tetracopper peroxo intermediate (a precedented 4) to make the initial 1:1 Cu/O2 adduct the thermo-
motif; section 4)134,135 was suggested to precede cleav- dynamic product, rather than the µ-η1:η1-peroxodi-
age and reaction with a second O2 molecule to yield copper complex. Analogous, yet less drastic destabi-
the final 2:1 Cu/O2 product. lization of the 2:1 Cu/O2 complex supported by
Even greater enhancement of the stability of a 1:1 Me6tren (6) relative to its 1:1 precursor also has been
adduct was observed for 2L (11); 2LCuO2 is remark- attributed to steric effects. Other ligand effects on
ably more stable than the adducts supported by other Cu/O2 reaction kinetics are more subtle, such as the
tetradentate tripodal ligands by virtue of a signifi- finding that the Cu(I) complex of PMEA (20), which
cantly more negative reaction enthalpy (K1 ) 3 × 1010 differs from TMPA only by virtue of one additional
M-1 at 183 K corresponding to a ∼108-fold enhance- methylene spacer in one pyridylmethyl arm, yields
ment relative to TMPA (1), ∆H° ) -69 ( 1 kJ a µ-η1:η1-peroxo species directly (without an observ-
mol-1).117 The negative charge provided by 2L (11) able intermediate) that is unstable toward irrevers-
may be construed as a basis for this result, through ible decomposition.136
stabilization of the Cu(II) state of the adduct. An Similar to the aforementioned case of BQPA (4),
alternative rationale may be considered in which initial binding of O2 to the Cu(I) of 2L (11) in THF
differences in O2 coordination modes are invoked, but gives rise to a thermodynamically stable 1:1 Cu/O2
while there is resonance Raman spectroscopic evi- adduct that subsequently evolves to a relatively
dence in favor of η2-O2 coordination in 2LCuO2, the unstable µ-η1:η1-peroxo species that is only observed
mode of binding in the other tetradentate ligand by spectroscopy under conditions when sub-stoichio-
systems is not known. metric O2 is used. In the presence of excess O2, the
peroxo species is only detected in steady-state con-
2.3. Reactions of 1:1 Cu/O2 Adducts to Yield centrations with a small equilibrium constant, indi-
Higher Nuclearity Complexes cating that the overall equilibrium eq 1 lies to the
left. The enormous difference in relative stabilities
With only a few exceptions, initially formed 1:1 Cu/
(also alluded to above, section 2.2) of the 1:1 and 2:1
O2 complexes generally react rapidly to yield 2:1 (and
complexes supported by TMPA (1) and 2L (11) is
sometimes higher nuclearity) species that in many
reflected by the reaction enthalpies associated with
cases exhibit thermodynamic stability sufficient for
K1 and K2. For TMPA (1), ∆H°2 is more negative
detailed characterization. The most commonly ob-
(favorable) than ∆H°1, but the situation is reversed
served products contain µ-η1:η1-peroxo-, µ-η2:η2-per-
for 2L (11), where ∆H°2 is rather small (-25 kJ
oxo-, or bis(µ-oxo)dicopper cores (Chart 2), the struc-
mol-1). In an alternative comparison, at 223 K for
tural and spectroscopic features of which have been
TMPA (1) K1/K2 ) 4.0 × 10-5, whereas for 2L (11)
well defined.61-90 In the following discussion, we first
this ratio is 3.8 × 103, a ∼108 fold difference.
consider the reactions of monocopper(I) complexes
with O2 that follow the pathway in Scheme 1 to yield
2:1 Cu/O2 species. We then discuss the formation of 2 2LCuO2 a [(2LCu)2(O2)] + O2 (1)
such species from dicopper(I) precursors comprising
dinucleating supporting ligands, for which less clear Oxygenation rate data are available for mono-
evidence for prior 1:1 adduct generation is typically nuclear Cu(I) complexes of the tridentate ligands
available. Finally, mechanistic aspects of the forma- LRR′ (7a-g),115,116 (Ln)3tacn (21a-c),137 AN (12a),114
tion of 3:1 Cu/O2 species are presented. MeAN (12b),114 HPy2Me (13b),119 HPy2Phe (13c),113 and
Stopped-flow kinetic studies of the reactions of H
Py1Et,Phe (22a),120 which yield µ-η2:η2-peroxo and/or
mononuclear Cu(I) complexes of the tetradentate bis(µ-oxo)dicopper complexes. For the Cu(I) complex
tripodal ligands TMPA (1),102-104 4R-TMPA (2a-d),105 of LiPr3 (7b) in acetone, both types of isomeric dicopper
TMPAE (3),105 BPQA (19),104 BQPA (4),104 Me6tren complexes form in parallel according to the simple
(6),96,97,108,109 and 2L (11)118 generally support similar rate law eq 2.115,116
pathways for the formation of 2:1 Cu/O2 products via
trapping of 1:1 adducts by unreacted Cu(I) species,
but with significant differences in thermodynamic rate ) k[(LiPr3Cu)+][O2] (2)
Table 3. Selected Kinetic and Thermodynamic Parameters for the Formation of 2:1 Cu/O2 Adducts upon Low Temperature Oxygenation of Cu(I) Complexesa
activation activation thermodynamic
parameters parameters parameters
ligand solvent k2b (k2)c k-2b (k-2)c K2d (K2)c ref
TMPA (1) EtCN (1.34 ( 0.02) × 104 ∆Hq ) 22.6 ( 0.1 (2.0 ( 0.2) × 10-5 ∆Hq ) 69.8 ( 0.6 (6.7 ( 0.7) × 108 ∆H° ) -47.2 ( 0.6 105
∆Sq ) -38.6 ( 0.6 ∆Sq ) 51 ( 3 ∆S° ) -89 ( 2
THF (1.0 ( 0.2) × 105 ∆Hq ) 17.5 ( 0.1 2 × 10-6 ∆Hq ) 70 ( 4 5 × 1010 ∆H° ) -53 ( 4 105
∆Sq ) -50 ( 1 ∆Sq ) 32 ( 14 ∆S° ) -82 ( 14
4OMe-TMPA (2c) EtCN (1.85 ( 0.01) × 104 ∆Hq ) 20.59 ( 0.06 (8 ( 2) × 10-6 ∆Hq ) 69 ( 1 (2.4 ( 0.7) × 109 ∆H° ) -49 ( 1 105
∆Sq ) -46.7 ( 0.3 ∆Sq ) 40 ( 5 ∆S° ) -87 ( 5
TMPAE (3) EtCN 15.2 ( 0.5 ∆Hq ) 21 ( 1 (2.1 ( 0.4) × 10 -5
∆Hq ) 66 ( 1 (7 ( 2) × 10 5
∆H° ) -45 ( 1 106
∆Sq ) -43 ( 3 ∆Sq ) 33 ( 5 ∆S° ) -76 ( 6
BQPA (4) EtCN (2.0 ( 0.2) × 103 ∆H° ) -15 104
∆S° ) -20
Me6tren (6) EtCN (1.53 ( 0.04) × 104 ∆Hq ) 17.0 ( 0.2 (5.8 ( 0.9) × 10-5 ∆Hq ) 63.7 ( 0.8 (1.4 ( 0.7) × 108 ∆H° ) -46.7 ( 0.9 109
∆Sq ) -67.9 ( 0.9 ∆Sq ) 26 ( 3 ∆S° ) -94 ( 3
D1 (5) EtCN 35.1 ( 0.5 ∆Hq ) 37 ( 1 (3.9 ( 0.3) × 10-1 ∆Hq ) 37 ( 1 90 ( 7 ∆H° ) 0.5 ( 0.6 106
∆Sq ) -9 ( 2 ∆Sq ) -49 ( 3 ∆S° ) 40 ( 3
2LCu (11) THF (8.7 ( 0.2) × 103 (213 K) ∆Hq ) 22.9 ( 0.4 19 ( 9 (213 K) ∆Hq ) 48 ( 12 (5 ( 2) × 103 (213 K) ∆H° ) -25 ( 12 118
∆Sq ) -40 ( 0.2 ∆Sq ) 6 ( 53 ∆S° ) -46 ( 53
AN (12a) CH2Cl2 (2.7 ( 0.1) × 104 e ∆Hq ) -9.9 ( 0.6 (1.02 ( 0.07) × 106 f ∆H° ) -24 ( 1 114
∆Sq ) -210 ( 3 ∆S° ) -14 ( 6
MeAN (12b) CH2Cl2 (6.9 ( 0.7) × 102 e ∆Hq ) -27 ( 3 (7.6 ( 0.6) × 10-2 f ∆H° ) -28 ( 2 114
∆Sq ) -335 ( 16 ∆S° ) -61 ( 12
H
Py2Me (13b) CH2Cl2 (1.91 ( 0.03) × 104 (253 K)e ∆Hq ) -0.7 ( 1 (5.9 ( 0.3) × 105 f ∆H° ) -89 ( 3 119
∆Sq ) -164 ( 4 ∆S° ) -240 ( 9
HPy2Phe (13c) THF 11 ( 1 (193 K) ∆Hq ) 19.3 ( 0.4 113
∆Sq ) -91.6 ( 2.0
Chemical Reviews, 2004, Vol. 104, No. 2 1055

BPQA (19) EtCN (1.5 ( 0.8) × 10-4 ∆Hq ) 61 ( 3 (1.7 ( 0.2) × 1010 f ∆H° ) -69 ( 2 104
∆Sq ) 19 ( 10 ∆S° ) -181 ( 5
HPy1Et,Phe
(22a) acetone g ∆Hq ) 25.3 ( 1.1 120
∆Sq ) -22.8 ( 6.0
a All data from cryogenic stopped-flow kinetics measurements. Except where noted, the rate and equilibrium constants are for process B in Scheme 1. Solvent coordination is likely
in many of the complexes, but is not shown for clarity. b Units are M-1 s-1, with values at 183 K unless noted otherwise. c Units are kJ mol-1 (∆Hq, ∆H°) or J K-1 mol-1 (∆Sq, ∆S°).
on ) k2K1),
d Equal to k /k ; units are M-1, with values at 183 K unless noted otherwise. e No discernible 1:1 Cu/O intermediate; reported rate constant is interpreted as composite (k
2 -2 2
with units M-2 s-1. f A composite, overall equilibrium constant, with units M-2. g Not reported.
This rate law and the similarity of the activation Scheme 3

parameters to those of the system supported by
BQPA (4, Table 2) support 1:1 adduct formation as
rate-limiting, with all subsequent steps leading to the
final product mixture being fast. As described below
(section 3), the data are also consistent with rapid
equilibration between the isomeric 2:1 Cu/O2 prod-
ucts. Dendrimer size influences the oxygenation rates
of the Cu(I) complexes of (Ln)3tacn (21a-c), the rate
constant for (L2)3tacn (21a, k ) 1.39 M-1 s-1) being
2 orders of magnitude larger than for (L3)3tacn (21b,
k ) 1.3 × 10-2 M-1 s-1).137 Complete shielding of the
Cu(I) sites by (L4)3tacn (21c) prevents oxygenation plexes comprising dinucleating ligands, although the
entirely. The Cu(I) complexes of AN (12a) and MeAN kinetics are sometimes more complicated and 1:1
(12b) in CH2Cl2 yield either a bis(µ-oxo)- or a species are less readily observable for these systems.
µ-η2:η2-peroxodicopper complex, respectively.114 Both For example, consider the complexes of the series
reactions are reversible, lack observable intermedi- m-XYLiPr4 (8),115 p-XYLiPr4 (9),115 and i-Pr4dtne
ates, and are characterized by negative activation (10),115,117 where the structural attributes of the
enthalpies and large negative activation entropies linker bridging the triazacyclononane moieties
(Table 3). These data have been interpreted to signficantly influences the oxygenation mechanism
indicate a rapid, left-lying preequilibria involving a (Scheme 4). For i-Pr4dtne (10) in which a short
1:1 Cu/O2 intermediate, eq 3. Similar results were ethylene linker tethers the macrocycles, bis(µ-oxo)-
communicated for the system comprising HPy2Me dicopper complex formation proceeds with kinetics
(13b), although in this case kinetic and spectroscopic similar to that observed for LiPr3 (7b), such that initial
data indicate that the product is a mixture of 1:1 adduct formation is rate-determining and subse-
equilibrating µ-η2:η2-peroxo and bis(µ-oxo) species.119 quent 2:1 adduct formation is fast. Similar rate-
Irreversible formation of a µ-η2:η2-peroxo complex was determining 1:1 Cu/O2 complex formation ensues
observed with HPy2Phe (13c) as supporting ligand, and with m-XYLiPr4 (8) and p-XYLiPr4 (9), but for the
a second-order dependence on the Cu(I) precursor former the nature of the final product depends on the
concentration on the rate of product formation was initial concentration of the dicopper(I,I) precursor,
determined.113 Similar kinetics were observed for bis- such that the µ-η2:η2-peroxo core predominates under
(µ-oxo)dicopper complex formation upon oxygenation dilute conditions and the bis(µ-oxo) unit is favored
of the Cu(I) complex of the bidentate ligand HPy1Phe at high concentration. Only bis(µ-oxo) core formation
(22a).120 The results for both systems were inter- is seen with p-XYLiPr4 (9). These results were inter-
preted to indicate rate-controlling reaction between preted to indicate a competition between intra-
a Cu(I) complex and O2 to yield a 1:1 adduct formed molecular and intermolecular dioxygen activation
in a rapid preequilibrium. pathways (Scheme 4). An intramolecular path is
geometrically possible with m-XYLiPr4 (8), and be-
LCu + O2 a LCuO2 cause of the steric constraints of the m-xylyl bridge
that enforce relatively large intermetal separations,
(L ) AN (12a), MeAn (12b), HPy2Me (13b)) (3) the µ-η2:η2-peroxo motif is favored relative to the
isomeric bis(µ-oxo) core. At higher concentrations for
Because of equilibria such as that shown in eq 3 m-XYLiPr4 (8), and under all conditions for p-XYLiPr4
and the usually rapid trapping of 1:1 adducts (process (9), intermolecular species predominate, and bis(µ-
B, Scheme 1), the stepwise synthesis of 2:1 Cu/O2 oxo) core formation becomes favored because closer
species by the sequential reaction of a 1:1 adduct with approach of the metal ions is enabled (e.g., because
a second Cu(I) complex, which by itself could react of loss of the bridge geometric constraint operative
with O2, is generally not possible. However, this route in the intramolecular adduct of m-XYLiPr4 (8)).
was made feasible by the discovery that the 1:1 Cu/ Related competition between intra- and inter-
O2 adduct supported by Me2LiPr2 (18a) is stable in molecular paths occurs with the dicopper system
solution at low temperature in the absence of O2.124,125 supported by D1 (5).111 Through a detailed analysis
Thus, after removal of excess O2, (Me2LiPr2)CuO2 was of the stopped flow kinetic data, the effects of the
treated with the Cu(I) complexes of Me2LMe2 (18c),125 ethylene linker in D1 (5) on the activation and
Me4pda (23a),125 LMe3 (7a),125 or LiPr3 (7b)138 to yield thermodynamics of dioxygen binding were assessed.
the “asymmetric” bis(µ-oxo) complexes with different Not surprisingly, the linker has no discernible effect
supporting ligands on each copper center (Scheme 3). on the initial O2 binding reaction, as indicated by
These products were identified by UV-vis and reso- similar ∆H°1 and ∆S°1 values for the TMPA (1) and
nance Raman spectroscopy, as well as by X-ray D1 (5) systems. However, the µ-η1:η1-peroxo complex
crystallography in one instance. The success of this formation process (k2) for D1 (5) is characterized by
stepwise approach for the synthesis of such 2:1 Cu/ a significantly (∼70 J K-1 mol-1) more favorable
O2 complexes provides precedence for broader poten- entropy of activation and a less favorable ∆Sq for the
tial applications, such as the preparation of mixed back reaction (k-2) than for TMPA (1). As a result,
metal species (e.g., [(Me2LiPr2)Cu(O)2ML]n+). the reaction entropy for µ-η1:η1-peroxo formation is
The overall pathway in Scheme 1 also generally more favorable for D1 (5) by ∼140 J K-1 mol-1. On
applies to oxygenation reactions of dicopper com- the other hand, this entropic stabilization of the 2:1
Scheme 4
Scheme 5 tion (∆Vq) of -15 ( 2.5 cm3 mol-1 for the oxygenation
(k1) of the system with R ) H (24a) in acetone.149 For
R ) MeO (24b), NMR studies indicate that at low
temperature the substituent interacts with the
Cu(I) centers resulting in formation of a complex that
is unsuitable for O2 binding to yield the µ-η2:η2-peroxo
unit. A similar effect in the fluoro-substituted system
(24d) is thought to explain anomalies in thermo-
dynamic and kinetic data for adduct formation com-
pared to the other systems. The cyano- substituted
system (24e) does form the 2:1 Cu/O2 adduct at low
temperature, but an interfering photochemical reac-
tion prevents the process from being followed spec-
trophotometrically so no kinetic or thermodynamic
data can be obtained. Comparing the cases in which
R ) NO2 (24f) versus R ) tBu (24c), activation
enthalpies for O2 dissociation are lower and overall
Cu/O2 species by the tether linking the N donors in reaction enthalpies for peroxo complex formation are
D1 (5) is offset by enthalpic destabilization (i.e., less favorable for the nitro-subsituted system. Two
strain) that is reflected in a higher ∆Hq2, a lower possible explanations have been offered for the ap-
∆H-2q
, and a correspondingly decreased enthalpic parently stronger binding of O2 to the dicopper
driving force (∆H° more positive by almost 50 kJ complex when the remote R group is more electron-
mol-1) compared to the TMPA (1) case. Relief of donating.140 According to one hypothesis, direct in-
enthalpic strain is accomplished through inter- teraction of the electrophilic Cu2O2 core with the
molecular adduct formation (oligomerization), as seen arene ring (as proposed for the mechanism of ring
for the m-XYLiPr4 (8) system. hydroxylation, section 5.1) is suggested to result in
Potentially tridentate bis(pyridyethyl)amine or simi- differential stabilization of the peroxo complex when
lar donor groups are linked in R-XYL-H (24a-f),139,140 R is varied. A second suggestion is that there are
R-XYL-O- (24g),139,141 D (25),142 UN-O- (26b),143,144 differences in the stabilities of the conformations of
PD (27a),145 N4Py2 (14b),112 MEPY22PZ (28),146 and the dicopper(I) complex and/or the intermediate 1:1
dendrimer 29,147 and the variable tethers also influ- Cu/O2 adduct for the differently substituted ligands
ence the Cu/O2 reactivity, albeit apparently without (cf. the flexibility of the benzylic linkages) that
the complication of competition between intra- and somehow influence the kinetic parameters.
intermolecular paths.148 With one exception (24b, R A related argument invoking differences in confor-
) OMe), the series of related complexes [(R-XYL-H)- mational flexibility was invoked to explain the ∼103-
Cu2]2+ (ligands 24a,c-f, R ) H, tBu, F, CN, NO2) fold weaker binding of O2 at 195 K to the dicopper(I)
yield µ-η2:η2-peroxo species upon low-temperature complex of 30 relative to [(XYL-H)Cu2]2+, in which
oxygenation (Scheme 5).139,140 By varying the remote identical xylyl groups link different N-donors (benz-
substituent (R1 in the drawing of the ligand in Chart imidazolyl vs pyridyl).150 Entropic stabilization con-
1 and Scheme 5) the influence of changes in the ferred by the MEPY22PZ ligand (28) also was cited
electronic properties of the spacer could be investi- to rationalize the room-temperature stability of its
gated systematically (Table 4). In general, the activa- µ-η1:η1-peroxo complex.146 Similar arguments were
tion enthalpies for initial O2 binding are low (<10 presented to explain the enhanced stability (relative
kJ mol-1) but are offset by significantly negative to irreversible decay) of the peroxo complexes sup-
activation entropies. Studies at high pressure reported by BPL2 (31, t1/2 ∼ 50 min at 298 K) relative
vealed a correspondingly negative volume of activa- to BPL (32, t1/2 ∼ 15 s at 250 K),151 and by N2tripy
Scheme 6
All data from cryogenic stopped-flow kinetics measurements, CH2Cl2 solvent. The rate and equilibrium constants are for the processes denoted in the respective Schemes 5-7.
Solvent coordination is likely in many of the complexes, but is not shown for clarity. b Units are M-1 s-1, with values at 183 K unless noted otherwise. c Units are kJ mol-1 (∆Hq, ∆H°)
or J K-1 mol-1 (∆Sq, ∆S°). d Equal to k1/k-1; units are M-1, with values at 183 K unless noted otherwise. e Values measured at 195 K. f Equilibration with O2 in <5 ms. g A and B refer
139,140
ref
140
140
140
150
139
112
Table 4. Selected Kinetic and Thermodynamic Parameters for the Formation of 2:1 Cu/O2 Adducts upon Low Temperature Oxygenation of Dicopper(I)
∆S° ) -250 ( 20
∆S° ) -156 ( 10
∆S° ) -101 ( 19
thermodynamic
∆S° ) -196 ( 6
∆S° ) -159 ( 4
∆S° ) -192 ( 2
∆S° ) -165 ( 8
∆H° ) -62 ( 1
∆H° ) -74 ( 4
∆H° ) -52 ( 3
∆H° ) -53 ( 1
∆H° ) -66 ( 1
∆H° ) -28 ( 3
∆H° ) -58 ( 2
parameters
(K1)c
(4.5 ( 0.4) × 102

(7 ( 3) × 107
(33, t1/2 ) 25.5 h at 298 K) compared to tripy (34,
K1d
2.6 × 107
9.6 × 107
3.3 × 106
5.9 × 106
1.4 × 104
6.5 × 108
observable only at low temperature).152

In the oxygenation of the dicopper(I) complex of
to data corresponding to kA1 or KA1 and kB1 or KB1 , respectively (Scheme 7). h Not reported, but may be calculated from k1 and K1.
XYL-O- (24g), where a phenolate links the two
Cu(I) ions, an asymmetrically disposed peroxide
bridge is proposed to form (Scheme 6).139,141 A similar
adduct forms upon oxygenation of the complex sup-
∆Sq ) 110 ( 20
∆Sq ) 90 ( 10
ported by UN-O- (26b), but it is more stable, such

∆Sq ) -8 ( 4
parameters
∆Hq ) 70 ( 1
∆Hq ) 83 ( 4
∆Hq ) 81 ( 3
∆Hq ) 59 ( 1
∆Sq ) 50 ( 6
activation
that it may be isolated as a solid.143 One-electron

(k-1)c
oxidation of this adduct yields a species formulated

as a unique dicopper-superoxide, which also may be
accessed by direct low-temperature oxygenation of
the mixed-valence precursor [(UN-O-)Cu(I)Cu-
(II)]2+.144 For XYL-O- (24g), dioxygen is bound re-
versibly and too rapidly for kinetic data to be
(1.5 ( 0.4) × 10-5
(1.8 ( 0.2) × 10-5
obtained, even at 173 K, but overall thermodynamic

(5 ( 2) × 10-6
(3 ( 1) × 10-6
data for O2 binding are in line with other systems,

k-1b
7.8 × 10-5
including R-XYL-H (24a-f). The increase in the rate

of binding of O2 relative to the complexes of R-XYL-H
is proposed to arise from preorganization of the
h
h
system in a conformation suitable for 2:1 complex

formation (k1 in Table 4). Greater electron donation
by the phenolate moiety also could be a basis for the
∆Sq ) -162 ( 18
increased oxygenation rate.

∆Sq ) -146 ( 1
∆Sq ) -140 ( 1
∆Sq ) -167 ( 1
∆Hq ) 9.1 ( 0.3
∆Hq ) 6.4 ( 0.1

∆Sq ) -66 ( 1
∆Sq ) -70 ( 9
parameters
∆Hq ) 8.2 ( 1
activation
∆Hq ) 29 ( 1
∆Hq ) 18 ( 2
The linker in N4Py2 (14b) is significantly more

∆Hq ) 0 ( 3
(k1)c
flexible than the xylyl bridges in R-XYL-H (24a-f)

and XYL-O- (24g), and as a result a more compli-
cated reaction scheme for oxygenation of [(N4Py2)-
Cu2]2+ is observed (Scheme 7).112 Two peroxodicopper
species form in parallel, the µ-η1:η1 (end-on) complex
A, which is characterized by UV-vis spectroscopic
features similar to those of [(TMPA)2Cu2(O2)]2+, and
B: (8.5 ( 0.2) × 103
A: (1.1 ( 0.1) × 104
the µ-η2:η2 (side-on) compound B. Species B is ther-

(4.9 ( 0.2) × 102
modynamically favored relative to A, as indicated by

the overall reaction enthalpies of -58 versus -28 kJ
k1b
mol-1, respectively (Table 4). However, the kinetic

9.3 ( 0.3
385 ( 5
109 ( 2
data rule out sequential formation of B directly from

>106 f
A, and require the intermediacy of either the starting

1.1
dicopper(I) complex or a transient 1:1 adduct (“Tr”).

The complex Tr is not observed, but is thought to be
a steady-state intermediate formed in a rapid pre-
NO2-XYL-H (24f)
tBu-XYL-H (24c)
equilibrium because (a) the formation of the initial

F-XYL-H (24d)
XYL-O- (24g)
peroxo species A occurs with an activation enthalpy

N4Py2 (14b)g
XYL-H (24a)
complex
Complexesa
of zero and (b) it is unlikely that 2:1 Cu/O2 adduct

formation proceeds in synchronous fashion. It is
noteworthy that both A and B form more quickly
30ae
than the peroxo complex supported by R-XYL-H (24a;

a
compare k1 values in Table 4). This result has been

Scheme 7
interpreted to indicate that increased rates of O2 species by a Cu(I) complex was obtained in experi-
adduct formation may result from greater flexibility ments performed at lower concentrations of starting
in a dinucleating ligand.100 Cu(I) compound (e.g., 0.2 mM), where UV-vis spec-
The effect of the linker in a dinucleating ligand troscopy indicated that a mixture of bis(µ-oxo)-
system was explored in studies of the O2 reactivity dicopper and bis(µ3-oxo)tricopper products formed.
of a dicopper(I) complex of L3(Py2)2 (35), which Addition of more starting Cu(I) complex to these
contains a substrate receptor between bis(pyridyl- mixtures resulted in conversion of the dicopper to the
ethyl)amine chelates.153 Complexes of L1Py2 (36) and tricopper species, and a second-order rate constant
L2(Py2)2 (37) were studied for comparison. Although for this reaction was determined (3.4 ( 0.2 × 102 M-1
detailed kinetics data for the oxygenations are not s-1 at 179 K).
available, pseudo-first-order rate constants for the
formation of 2:1 Cu/O2 species obtained at 188 K 3. Isomerism between µ-η2:η2-Peroxo- and
revealed faster oxygenations of [(L3(Py2)2)2Cu2]2+ (kobs Bis(µ-oxo)dicopper Complexes
) 3.41 × 103 s-1) and [(L2(Py2)2)2Cu2]2+ (kobs ) 23 ×
103 s-1) than [(L1Py2)Cu]+ (kobs ) 2.56 × 102 s-1). Interconversion of the isomeric µ-η2:η2-peroxo- and
These results were interpreted to support intra- bis(µ-oxo)dicopper cores represents a possible path-
molecular adduct formation for the dinucleating way for the reversible making and breaking of the
ligand systems. dioxygen O-O bond in a dimetal system. As such, it
is relevant to a variety of biological and other
Finally, species of higher nuclearity than two have processes, such as aerobic oxidations, catalytic de-
been targeted to model O2 activation at the tricopper composition of NO to N2 and O2,162 and photo-
active sites of the multicopper oxidases. One strategy synthetic O2 evolution.163 Initially discovered for the
involves building multinucleating ligand scaffolds system supported by LiPr3 (7b, Scheme 8),116 the
designed to preorganize N-donor groups so that three process has been identified for a number of other
or more metal centers are collected in close proximity. complexes of N-donor ligands and has been the
While several such scaffolds have been con- subject of numerous theoretical studies.164-171 A key
structed,154-157 to date none have led to well-charac- finding from theory is that the reaction involves a
terized Cu/O2 adducts.158 However, a few 3:1 Cu/O2 continuous diabatic correlation of occupied orbitals,
adducts have been prepared by using simple biden- analogous to symmetry-allowed pericyclic reac-
tate ligands with substituents featuring minimized tions.164
steric bulk (see a recent review89 for discussion of this
steric issue). Thus, a bis(µ3-oxo)tricopper(II,II,III) Scheme 8
complex was reported upon low-temperature oxygen-
ation of the Cu(I) complex of Me4Cyda (38a) at
concentrations > 10 mM.159,160 Reaction of an initially
formed bis(µ-oxo)dicopper compound with a third
Cu(I) precursor is a reasonable pathway for tricopper
complex formation, but supporting mechanistic evi-
dence is lacking for this system. An analogous
product was recently reported for the oxygenation of The existence of a rapid equilibrium between [(LiPr3-
the Cu(I) complex of HPy1Me,Me (15c), and in this case Cu)2(µ-η2:η2-O2)]2+ and [(LiPr3Cu)2(µ-O)2]2+ in solution
mechanistic data for the process were obtained.161 was postulated on the basis of several lines of
When a 5.0 mM solution of [(HPy1Me,Me)Cu(O3SCF3)] evidence.116,172 As noted above, stopped-flow kinetics
in acetone was oxygenated, the rate of formation of data showed that the oxygenation of [LiPr3Cu(MeCN)]+
the tricopper species showed a first-order dependence in acetone obeys a rate law that is first order with
on the copper(I) complex concentration, indicating respect to the concentrations of O2 and Cu(I) complex
that 1:1 Cu/O2 formation is rate-determining and that (eq 2). These data indicate that formation of a 1:1
subsequent additions of Cu centers are fast. Direct adduct is rate determining, even though such an
support for the trapping of a bis(µ-oxo)dicopper adduct is not observed. The observed products in
acetone are a ∼4:1 mixture of the µ-η2:η2-peroxo and is available. The most important factor controlling
bis(µ-oxo) complexes, and each forms at the same rate which of the two isomers is favored appears to be
over a range of temperatures (190-223 K). A mech- interligand substituent steric interactions in the
anism consistent with these data involves fast reac- dicopper complexes, which differ significantly in their
tion of the initially formed 1:1 adduct with a Cu(I) intermetal separations, ∼3.6 Å for the peroxo vs ∼2.8
starting complex to yield a rapidly equilibrating Å for the bis(µ-oxo).70,85 A consensus view is that the
mixture of the peroxo and bis(µ-oxo) isomers. In more compact bis(µ-oxo) core is inherently more
further support of this equilibrium, reversible tem- stable in most instances, but can be disfavored when
perature-dependent shifts of their ratio in dilute THF supporting ligand substituents are of sufficient size
solution were identified, and thermodynamic param- to result in prohibitive interligand steric clashes. For
eters were determined: ∆H° ) 4 kJ mol-1 and ∆S° example, copper(I) complexes of triazacyclononane
) 25 J mol-1 K-1. Also consistent with the existence ligands with substituents that are less sterically
of the equilibrium, solvent influences the ratio of the demanding than iPr (e.g., LBn3 (7c)175 or LMe3 (7a)173)
isomers, with the peroxo favored in CH2Cl2 and the yield bis(µ-oxo) cores only. Similar steric effects were
bis(µ-oxo) favored in THF. Importantly, the isomer found for the Cu/O2 chemistry with HPy1Et,Bz (15a)
ratios were shifted immediately in solvent mixing and MePy1Et,Bz (15c), which exclusively yielded bis-
experiments. (µ-oxo) and peroxo cores, respectively.120,176 In addi-
Other systems for which direct evidence supporting tion, comparison of Keq () [peroxo]/[bis(µ-oxo)]) values
facile equilibration of the peroxo and bis(oxo) isomers across the series of bidentate diamine supporting
has been obtained are those supported by the biden- ligands revealed the size of the substituents to be the
tate diamines R2R′2eda (39) and R2R′2pda (23)89,173,174 most important determining factor [cf. Keq(iPr2Me2-
and the tridentate ligand HPy2Me (13b).119,171 For the pda, 23b) > Keq(Me4pda, 23a)].174 The size of the
diamines, ratios of peroxo and bis(µ-oxo) isomers that ligand chelate ring also was found to be important,
are dependent on supporting ligand structure, sol- as indicated by the trend Keq(iPr2Me2pda, 23b) > Keq-
vent, counteranion, and temperature were observed. (iPr2Me2eda, 39b) and the finding that the iPr3tacd
With one exception (see below), a rapid equilibrium system (40, with one more methylene spacer than
for each diamine-supported system was indicated by LiPr3, 7b) yields the peroxo isomer only.168 Through
the finding that the relative amounts of the isomers structural analysis of Cu(I) precursors and theoretical
in THF, acetone, or CH2Cl2 varied reversibly with calculations, the basis for the chelate ring effect for
changes in temperature. Changing the counterion in the latter example was argued to be greater inter-
select cases also shifted the product ratio.89 For the ligand steric conflict resulting from the conforma-
system ligated by tBu2Me2eda (39a), thermodynamic tional preferences of the larger macrocyclic ligand.
parameters associated with Keq () [peroxo]/[bis(µ- Other ligand geometric effects on the relative
oxo)]) in CH2Cl2 were estimated to be ∆H° ∼ 3 kJ stabilities of the isomers have been identified. One
mol-1 and ∆S° ∼ 8 J mol-1 K-1, similar to the LiPr3 is proposed to be the Neq-Cu-Neq bite angle for
case discussed above. Oxygenation kinetics data for bidentate ligands, with smaller values favoring the
the tridentate HPy2Me (13b) system also were inter- bis(µ-oxo) structure because of angular dependencies
preted to support rapid equilibration between peroxo of Cu and O orbital interactions (evaluated by
and bis(µ-oxo) isomers, both of which were observed theoretical calculations).170 A related effect concerns
by various spectroscopic means in solution and in the the internal bite angles in tridentate ligands, such
solid state (including as a compositionally disordered that a propensity to support a square pyramidal
X-ray crystal structure).119,171 copper ion geometry correlates with greater stability
The combined data for all of the above systems of the dicopper(III) core of the bis(µ-oxo) form.165,168
support a very low barrier for the interconversion of The nature of the linkers in binucleating ligands also
the peroxo and bis(µ-oxo) isomers that have rather influences peroxo/bis(µ-oxo) stability. For example,
similar thermodynamic stabilities. A higher barrier peroxo formation is inhibited for the system sup-
has been observed in one case, the tBu2Me2eda (39a) ported by iPr4dtne (10), in which the short ethylene
system in MeTHF solvent,174 where decomposition of tether prohibits attainment of the requisite long
the peroxo isomer is significantly faster than the bis- (∼3.6 Å) intermetal separation.117 Conversely, the
(µ-oxo) complex. The indicated slow equilibration intramolecular adducts formed for the m-XYLiPr4 (8)
between the two isomers in this instance has enabled and N2tripy (33) systems are peroxos in large part
the differential reactivity of the two isomers to be because the geometric constraints of the linkers
examined (section 6). Sluggish conversion of a peroxo prohibit the short (∼2.8 Å) intercopper distance of
to a bis(µ-oxo) species with MePy1Et,Bz (15c) also has the bis(µ-oxo) isomers (cf. Scheme 4).115,152 More
been invoked on the basis of kinetic data for an recently, hydrogen bonding was found to preferen-
intramolecular C-H bond activation reaction (section tially stabilize the peroxo isomer when the secondary
5).113,161 diamine supporting ligand tBu2H2eda (39d) was
Insights into the basis for the relative thermo- used.177 This result is particularly noteworthy in view
dynamic stabilities of the two isomers have come both of the fact that the more hindered tBu2Me2eda (39a)
from studies of the above systems in which an yields mixtures of both isomers.
equilibrium between them has been identified, from Finally, electronic effects on the relative stabilities
theoretical calculations,164-171 and from analysis of of the isomers have been identified from a comparison
the nature of the products observed in other oxygen- of Raman spectral data for the oxygenated species
ations for which no direct evidence for equilibration ligated by the series of ligands RPy2Me (R ) H (13b),
MeO (41a), Me2N (41b)), which present identical Scheme 9

steric influences but variable electron donating abil-
ity due to the different para-substituents on the
pyridyl rings.178 Greater electron donation was shown
to result in the relative stabilization of the bis(µ-oxo)
core, in line with what one would expect from the
higher oxidation state of its copper centers.
4. Alternate Syntheses of Copper−Dioxygen and

Related Complexes
Treatment of Cu(II) starting materials with H2O2
in some instances has been shown to yield the same
Cu/O2 species that form upon oxygenation of Cu(I) Several 2:1 Cu2OOR (R ) H, alkyl, or acyl) com-
precursors (analogous to the “shunt” pathway in plexes have been prepared, by reaction of 1 equiv of
heme-iron chemistry).179 For example, a µ-η2:η2- H+ or an acylating agent (m-ClC6H4C(O)Cl) to a
peroxo complex supported by TpiPr2 (16b) may be peroxodicopper species supported by XYL-O- (24g)
accessed from low-temperature oxygenation of a Cu- or UN-O- (26b),143,191,192 by oxygenation of the
(I) precursor or from the reaction of its bis(µ-hydroxo)- dicopper(I) complex of the protonated ligand UN-
dicopper(II) complex with H2O2.180 In another illus- OH,143 or by addition of H2O2 to [(XYL-O-)Cu2-
tration, a novel and quite thermally stable 4:1 Cu/ (OH)]2+.191,192 In each case, a µ-1,1-hydroperoxo or
O2 complex featuring a µ4-peroxo unit may be prepared acylperoxo derivative was produced.
either by exposure of a basic MeOH solution of HL1
(42a) and Cu(I) salt to O2, or by addition of H2O2 (or 5. Intramolecular Reactions of Copper−Dioxygen
catechol + O2) to a mixture of HL1 (42a), a Cu(II) Complexes
salt, and NEt3 in MeOH.134,135 Similar µ4-peroxo
complexes may be prepared using HL2 (42b) or HL3 With few exceptions,146,152,193-195 copper-dioxygen
(42c). Evidence has also been cited to suggest that complexes are stable in solution for reasonable
the µ4-peroxo compounds may be accessed by addition periods (hours) only at low temperature (< -40 °C).
of H2O2 (or catechol + O2) to (µ4-oxo)tetracopper Warming usually causes decomposition, typically to
species.135 Cu(II) complexes via processes involving intramo-
Reactions of Cu(II) compounds with H2O2 or ROOH lecular oxidation of a supporting ligand. Although
(R ) alkyl or acyl group), sometimes in the presence such processes are inherently destructive and thus
of base, also have led to isolable hydro-, alkyl-, or may be undesired from the point of view of catalyst
acylperoxo complexes that are of great interest due development, detailed mechanistic studies are none-
to their relevance to postulated reactive intermedi- theless worthwhile for providing fundamental mecha-
ates (e.g., CunOOH moieties) in copper oxidase and nistic information relevant to the reactivity of Cu/O2
oxygenase catalytic cycles.1-3 Mononuclear (1:1) species in enzymatic and other catalytic systems.
CuOOR (R ) H, alkyl, or acyl) complexes have been Indeed, significant insights into the pathways by
prepared via this route using the supporting ligands which Cu/O2 species attack organic moieties have
TpiPr2 (16b),181-183 HPy2tBu (13n),184 HPy2Net2 (13o),185 been obtained from experimental and theoretical
HPy2NEtAm (13p),185 BPPA (43a),186 TMPA (1),187 assessments of intramolecular ligand oxidations.
RPy2MeIm (44a-c, R ) H, Me, Me ),188 2-dimethylimi-
2
dazole,187 and HPy2BzO (13k),187 and Py′2PhS (45).189 5.1. Arene Hydroxylations and Related Reactions
The last example in which thioether coordination to A commonly observed reaction of 2:1 Cu/O2 adducts
copper is implicated is particularly noteworthy be- is the hydroxylation of a m-xylyl linker in a dinucle-
cause of specific relevance to the MetHis2Cu site in ating ligand (Scheme 10). Interest in this reaction
peptidylglycine- and dopamine β-monooxygenas-
es.2,11,12 Mechanistic information on the formation Scheme 10
and reactivity of 1:1 CuOOH species was provided
by stopped-flow studies of the reaction of H2O2 in the
presence of NEt3 with Cu(II) complexes of HPy2PhePh
(13m), HPy2Phe (13c), and TEPA (46, 0.2 mM) at 183
K in MeOH.190 Saturation kinetics for both substrates
(H2O2 and NEt3) were recorded, consistent with the
path for formation of a 1:1 CuOOH compound C has been stimulated by its relevance to the activity
shown in Scheme 9. For the system supported by of tyrosinase, in which a coupled dicopper active site
HPy2PhePh (13m), the 1:1 complex underwent a slower
converts phenols to catechols and/or orthoquino-
first-order reaction (rate independent of [H2O2] or nes.3,5,196,197 The most detailed mechanistic under-
[NEt3]; k2 ) 1.6 ( 0.1 s-1) to a species tentatively standing of the xylyl hydroxylation process has come
assigned as a novel monocopper(II) η2-peroxide (D in from studies of the set of compounds [(R-XYL-H)-
Scheme 9). This species then decayed to the µ-η2:η2- Cu2]2+ (ligands 24a-c,e,f, R ) H, OMe, tBu, CN, or
peroxo complex [(HPy2PhePh)2Cu2(O2)]2+ at higher con- NO2).139,140,149,198,199 Reaction of these complexes with
centrations (2.0 mM) of Cu(II) starting material via O2 at room-temperature results in the formation of
a second-order process (k3 ) 2.6 ( 0.1 × 102 M-1 s-1). [(R-XYL-O)Cu2(OH)]2+ (Scheme 11), with both of the
Scheme 11 Scheme 12
newly introduced O atoms derived from O2 (and not

H2O) as determined from experiments using 18O2. On
the basis of kinetic and spectroscopic studies per-
formed at low temperature (section 2.3), the reactive
intermediate has been identified as the 2:1 Cu/O2
adduct [(R-XYL)Cu2(O2)]2+. The lifetime of this ad-
duct is increased when R is electron withdrawing,
enabling characterization by resonance Raman spec-
troscopy for the case R ) NO2 (24f).199 Only peaks
corresponding to µ-η2:η2-peroxo species were observed
and an upper limit for the amount of bis(µ-oxo) ideal orientation and close proximity to the aromatic
isomer present in 4 mM solutions was calculated to ring may explain its high reactivity and lack of
be ∼0.13%. Thus, while it is conceivable that the sensitivity toward changes in the ring substituents.
hydroxylating species is either the observed µ-η2:η2- This notion is supported by the results of high
peroxo compound or a small amount of bis(µ-oxo) pressure kinetic studies that yielded a relatively
formed in a rapid preequilibrium, the latter would small and negative volume of activation ∆Vq (k2) of
have to be a ∼1000 times more reactive hydroxylat- -4.1 ( 0.7 cm3 mol-1, interpreted to indicate minimal
ing agent than the former. The results of theoretical geometrical rearrangement during attack of the
calculations have been interpreted to indicate that peroxo at the xylyl ring.149 Theoretical calculations
this reactivity order is unlikely to be correct,199 and that provide an orbital picture for this process have
stereochemical considerations further support the been described.199,201
µ-η2:η2-peroxo as the hydroxylating agent in this Further experimental support for an electrophilic
system (see below). pathway involving a carbocationic intermediate was
The mechanism proposed for xylyl ring hydroxy- provided by the results of oxygenations of systems
lation by the µ-η2:η2-peroxo intermediate involves with methyl-substituted rings, [(XYL-Me)Cu2]2+ and
electrophilic attack onto the arene π system to yield [(Me2XYL-Me)Cu2]2+ (ligands 24h and 24i; Scheme
a carbocation intermediate (Scheme 11). Subsequent 12).202,203 Hydrolytic workup of the reactions of these
proton transfer and rearomatization yields the final complexes with O2 yielded the indicated phenols,
product. Several pieces of evidence support this path. secondary amines, and formaldehyde. A key proposed
The lack of a kinetic isotope effect when the hydrogen step in the mechanism of these reactions involves a
at the hydroxylated position is replaced by deuterium 1,2-methyl migration (“NIH shift”) in a cationic
is consistent with rate-controlling attack onto the π cyclohexadienyl intermediate analogous to that pos-
system.139 The possible involvement of radicals is not tulated for the hydroxylations discussed above.
supported by the kinetic analysis or the fact that The reaction of the dicopper(II) complex of XYL-H
radical traps have no effect on the Cu/O2 adduct (24a) with H2O2 also resulted in ring hydroxyla-
decay rate. Consistent with the peroxo acting as an tion.204 Notably, the kinetics were pH dependent and
electrophile, a decrease in hydroxylation rate con- indicated a second-order dependence on the dicopper-
stants (k3) and an increase in ∆Hq values with the (II) complex, suggesting a tetracopper intermediate
electron withdrawing power of the R substituents or transition state. It was proposed that a (µ-1,1-
was observed, reflected by a negative Hammet F ) hydroperoxide)dicopper species forms and that a
-2.1 at 193 K.140 On the other hand, the magnitude second dicopper(II) complex acts as a Lewis acid to
of F is small compared to those typical for electro- activate the hydroperoxide for electrophilic aromatic
philic aromatic substitutions.200 Possible explanations substitution. In a related ligand system with benz-
offered for this modest F value are that (a) k3 is a imidazolyl instead of pyridyl donors (30a), double
composite rate constant, incorporating several of the hydroxylation occurs upon reaction of its dicopper-
steps involved in the overall transformation, or (b) (II) complex with H2O2 (Scheme 13).205 On the basis
the µ-η2:η2-peroxo group is so reactive an electrophile of the results of a mechanistic study, attack of a (µ-
that it is relatively insensitive to electronic changes 1,1-hydroperoxide)dicopper intermediate at the 5-po-
in the aromatic ring. Although it appears unlikely sition was proposed, with functionalization of the
that the peroxo unit is intrinsically so reactive, its 2-position occurring subsequently.
Scheme 13 Scheme 14
In addition to the aforementioned XYL series (24), all of these systems indicates that ligand structure
the reactivity of dicopper(I) complexes of numerous influences the course of the oxygenation processes,
other xylyl-linked dinucleating ligands (30 and 47- and that proper disposition of a bridging peroxo unit
51, as well as a trinucleating analogue158) has been is one prerequisite for xylyl hydroxylation. Still, the
examined, and some undergo arene hydroxylation bases for many of the ligand structural effects (cf.
upon treatment of their dicopper(I) complexes with variation of N-donors) remain obscure.
O2. In most instances, however, little is known about Intramolecular hydroxylations of ligand pyridyl
the factors that affect the observed reactivity or the rings have been reported, in one case upon treatment
nature of the Cu/O2 species involved.206-219 The of a Cu(I) complex of HPy2Phe (13c) with iodosylben-
nature of the N-donors is important, as indicated by zene221 and in another via reaction of the Cu(I)
the fact that hydroxylation occurs for XYL (24) complex of PyIso (52) with O2.222 Mechanistic data
systems comprising solely pyridyl donors, but not for for these reactions are not available.
the analogous ligands with various other N-hetero- Decomposition of bis(µ-oxo)dicopper complexes sup-
cyles (30), which instead yield products resulting ported by PhPyNEt2 (53) resulted in phenyl ring
from four-electron reduction of O2 (e.g., bis(hydroxo)- hydroxylation (Scheme 14), providing precedence for
dicopper(II) complexes).206,220 On the other hand, for the notion that a bis(µ-oxo) core is a possible oxidant
the series of Schiff base ligands 47a-j, xylyl hy- in tyrosinase even though it has not been ob-
droxylation is observed for X ) 2-pyridyl (47a), served.74,223 On the other hand, even though no
2-imidazolyl (47b), 5-imidazolyl (47c), or 2-benzimi- indication of the presence of a µ-η2:η2-peroxo isomer
dazolyl (47d).207 Interestingly, when methoxy sub- was found in Raman spectra for the synthetic system,
stituents are incorported into the 2- (site of hydrox- hydroxylation by a small, undetectable amount of
ylation) and 5-position of the xylyl linker (47e, X ) such an isomer in rapid equilibration with the bis-
2-pyridyl), oxidative demethylation of the 2-methoxy (µ-oxo) form could not be ruled out. In any case, an
group occurs.208,209 For the histidine donor series 47f- electrophilic aromatic substitution pathway like that
j, when they are N-methylated (47h and 47i) hy- delineated for the XYL (24) system was supported
droxylation occurs, but not when the histidines have by the lack of a H/D kinetic isotope effect and the
H or CO2Me substituents (47f and 47g), unless protic finding that the rate and overall yield of hydroxyla-
solvents are used.210 In the latter cases, the ratio of tion were inversely correlated with the electron
arene hydroxylation to four-electron O2 reduction withdrawing capability of phenyl ring substituents.
may be increased by addition of small amounts of
acid, implying the intermediacy of a hydroperoxo 5.2. N-Dealkylations and Benzylic Oxidations
adduct. Oxygenation of the dicopper(I) complex of the
tetra-Schiff base ligand 48 results in hydroxylation A commonly observed result of decomposition of
of one of the xylyl rings,212-215 but four-electron O2 Cu/O2 complexes and of room-temperature oxygen-
reduction occurs instead in an analogous system 47 ation of Cu(I) compounds is intramolecular oxidation
with furan instead of xylyl linkers.216 The unsym- of C-H bonds that are “activated” due their position
metrical relatives of the XYL series, UN (26a)217 and R to an amine donor and/or to a phenyl ring. For the
UN2 (50),218 also undergo hydroxylation (albeit more former, the result is oxidative N-dealkylation to yield
sluggishly), and a µ-η2:η2-peroxo intermediate was a secondary amine and an aldehyde or ketone, a
identified at low temperature for the former. Simi- process well-studied (yet still mechanistically con-
larly, hydroxylation of m-XYLiPr4 (8) occurs upon troversial) for heme-iron oxidants, such as cyto-
decomposition of its intramolecular (µ-η2:η2-peroxo)- chrome P450.224,225 Such N-dealkylations have been
dicopper complex,115 but the intermolecular bis(µ-oxo) observed for copper systems supported by LR3 (7a-
species of this ligand that is formed in parallel c, R ) Me, iPr, Bn),173,175,226 iPr4dtne (10),117 m-
(Scheme 4) reacts differently (N-dealkylation, section and p-XYLiPr4 (8 and 9),115 (Ln)3tacn (21a-c),137
5.2). Hydroxylation of the aromatic ring in the R2R′2Cyda (38a-c),173 HPy1Et,Bz (15a),176 MePy1Et,Bz
tridentate ligand 51 occurs upon treatment of its (15c),176 D (25),142 L2(Py2)2 (37),153 L3(Py2)2 (35),153
Cu(I) complex with O2, despite the entirely different Me2TMPA (43b),227 and Me3TMPA (43c).228 Available
disposition of the xylyl unit compared to the afore- activation parameters for these processes are listed
mentioned binucleating ligands.219 Consideration of in Table 5. A mechanistic study of the decomposition
Table 5. Activation Parameters and Kinetic Isotope Effects for Intramolecular Ligand Degradation Reactions of
Cu/O2 Species
type of O2 activation KIE
ligand complex/solvent reaction parametersa (298 K)b ref
LMe3 (7a) bis(µ-oxo)/CH2Cl2 N-dealkylation ∆HqH ) 53 ( 2 173
∆SqH ) -75 ( 4
LiPr3 (7b) bis(µ-oxo)c/THF N-dealkylation ∆HqH ) 55 ( 2 11 226
∆SqH ) -57 ( 5
∆HqD ) 62 ( 2
∆SqD ) -54 ( 5
LBn3 (7c)d bis(µ-oxo)/CH2Cl2 N-dealkylation ∆HqH ) 58 ( 2 25 226
∆SqH ) -41 ( 5
∆HqD ) 63 ( 2
∆SqD ) -50 ( 5
iPr
4dtne (10) bis(µ-oxo)/CH2Cl2 N-dealkylation ∆HqH ) 56 ( 2 16 117
∆SqH ) -59 ( 5
∆HqD ) 68 ( 2
∆SqD ) -42 ( 5
(L2)tacn (21b) bis(µ-oxo)/CH2Cl2 N-dealkylation ∆HqH ) 60 137
∆SqH ) -23
(L3)tacn (21c) bis(µ-oxo)/CH2Cl2 N-dealkylation ∆HqH ) 62 137
∆SqH ) -39
Me4Cyda (38a) bis(µ-oxo)/CH2Cl2 N-dealkylation ∆HqH ) 56 ( 2 173
∆SqH ) -100 ( 4
Me2Et2Cyda (38b)e bis(µ-oxo)/CH2Cl2 N-dealkylation ∆HqH ) 52 ( 2 2.3 173
∆SqH ) -95 ( 4
∆HqD ) 55 ( 2
∆SqD ) -92 ( 5
HPy1Et,Bz (15a) bis(µ-oxo)/CH2Cl2 N-dealkylation ∆HqH ) 55 ( 1 5.6 176
∆SqH ) -31 ( 4
∆HqD ) 67 ( 2
∆SqD ) -5 ( 8
MePy1Et,Bz
(15c) bis(µ-oxo)/CH2Cl2 N-dealkylation ∆HqH ) 31 ( 1 1 176
∆SqH ) -121 ( 4 (270 K)
∆HqD ) 41 ( 2
∆SqD ) -84 ( 12
LiPr2Py (54) 1,2-peroxo/CH3CN amidation ∆HqH ) 53 ( 2 2.5 ( 0.5f 232
∆SqH ) -96 ( 8
HPy2Et,Phe µ-η2:η2-peroxo/THF
(22a) benzylic hydroxylation ∆HqH ) 28.1 ( 1.0 1 113
∆SqH ) -155 ( 5 (254 K)
∆HqD ) 40.3 ( 1.3
∆SqD ) -107 ( 6
HPy1Et,Phe
(22a) bis(µ-oxo)/acetone benzylic hydroxylation ∆HqH ) 39.1 ( 0.4 1.7 120
∆SqH ) -72.6 ( 1.9
∆HqD ) 52.8 ( 0.5
∆SqD ) -31.1 ( 2.3
i-Bu3CY (57) bis(µ-oxo)/CH2Cl2 aliphatic hydroxylation ∆HqH ) 42.2 ( 1.8 242
∆SqH ) -62 ( 10
a Values of ∆Hq and ∆Sq reported in units of kJ mol-1 and J mol-1 K-1, respectively. Subscripts “H” and “D” refer to values
obtained from rate measurements with ligands perprotiated or perdeuterated, respectively, at the position adjacent to the N
atom (the carbon that is oxidized). b KIE ) kH/kD, calculated from the activation parameters (except where noted). c Major species
present, but minor amount of µ-η2:η2-peroxo complex probably present as well. d Values corrected from those provided in ref 173,
which were inadvertently calculated from the Arrhenius (ln k vs T-1) instead of the Eyring (ln(k/T) vs T-1) plots. e Values calculated
from Eyring plot provided as Supporting Information in ref 173. Note that only the R positions on the ethyl substituents (and not
the methyl substituents) were perdeuterated, so the H/D KIE may not be fully expressed in the data provided. f Directly measured
value at 243 K (activation parameters for deuterated ligand not available).
of the bis(µ-oxo)dicopper complex supported by LBn3 with C-H bond breaking in the rate-determining
serves as an illustrative example (Scheme 15).226 step. In addition, crossover and double labeling
Labeling studies with 18O2 show that the O atom in experiments have been performed to show that the
the aldehyde or ketone originates from the bis(µ-oxo) bis(µ-oxo) core is responsible for O transfer during
core. Decay of the bis(µ-oxo)dicopper complex obeys the N-dealkylation process and not 1:1 Cu/O frag-
first-order kinetics and exhibits a large KIE when ments in equilibrium with the dimeric species. A
deuterium is introduced R to the nitrogen, consistent Hammett study of the decomposition reaction of a
Scheme 15
series of para-substituted LBn3 systems 7c-f gave a

F value of -0.4,229 which is similar to those measured
for benzylic hydrogen atom abstractions by free
radicals230 and indicative of electrophilic character
for the bis(µ-oxo)dicopper core. The electrophilicity
is postulated to arise from a low-lying LUMO+1
Figure 2. Calculated stucture of the transition state for
orbital having dominant lobes extending from the the hydrogen atom abstraction step in the intramolecular
bridging oxygen atoms.164 On the basis of the experi- N-dealkylation depicted in Scheme 15.231 Figure reprinted
mental evidence, a mechanism for the N-dealkylation with permission from ref 85. Copyright 2002 Wiley Inter-
process was proposed (Scheme 15). According to this science.
hypothesis, hydrogen abstraction from the R-CH bond
generates a carbon centered radical that is then measured for the LiPr3 system (Table 5), selective
quickly trapped by a hydroxyl group in a mechanism deuteration of the isopropyl groups in m-XYLiPr4-d28
akin to the paradigmatic cytochrome P450 “rebound” (8-d28) shifts the reactivity of the system toward
path.179 Alternatively, C-H bond scission and O atom benzylic C-H rather than isopropyl C-D bond scis-
transfer may occur simultaneously in a concerted sion. Moreover, N-dealkylation of the bis(µ-oxo) com-
mechanism (not shown). Both pathways result in the plex supported by iPr4dtne (10) is quantitative and
formation of a carbinolamine species that decomposes completely regioselective, giving rise only to products
to give the secondary amine and aldehyde or ketone derived from cleavage of an isopropyl group and not
as the final products. Strong preferential support for from scission of the ethyl linker, again consistent
the hydrogen atom abstraction pathway has been with the differing proximity of their respective C-H
provided by the results of integrated molecular bonds to the reactive oxo unit.117
orbital molecular mechanics electronic structure Both the bis(µ-oxo) and µ-η2:η2-peroxo complexes
calculations, which revealed a relatively late transi- supported by HPy1Et,Bz (15a) and MePy1Et,Bz (15c),
tion state structure featuring C- - -H and H- - -O respectively, decompose to give products resulting
distances of 1.310 and 1.217 Å, respectively (Figure from N-dealkylation, but with different kinetic pa-
2).231 rameters.176 While the bis(µ-oxo) complex decomposi-
Analogous mechanisms appear to be followed in tion exhibits a large KIE (33 at 218 K; 5.6 at 298 K)
N-dealkylations of other systems. Thus, for example, and activation parameters similar to those observed
decomposition of bis(µ-oxo) complexes of R2R′2Cyda for the LBn3 system (7c, Table 5), a much smaller KIE
(38a-c) occurs via hydrogen atom abstraction from (∼1 at 270 K) and quite different activation param-
the R-CH bonds of the R/R′ substituents, with relative eters (Table 5) were measured for decay of the peroxo
rates that correlate with the relevant C-H bond complex of MePy1Et,Bz (15c). The latter results were
strengths (e.g., -CH3 < -CH2CH3).173 As noted interpreted to indicate that slow isomerization to a
previously (section 2.3) products of oxygenation of bis(µ-oxo) isomer occurred prior to C-H bond attack,
[(m-XYLiPr4)Cu2]2+ and [(p-XYLiPr4)Cu2]2+ differ, the similar to the path suggested for benzylic hydroxy-
former yielding both intramolecular µ-η2:η2-peroxo lation by the µ-η2:η2-peroxo complex of HPy2Phe (13c,
and intermolecular bis(µ-oxo) species but the latter see below).86,113
only intermolecular bis(µ-oxo) species (Scheme 4). While reaction of the dicopper(I) complex of the
These species decay via different paths as well; the binucleating ligand D (25b) with O2 at 273 K results
µ-η2:η2-peroxo hydroxylates the bridging xylyl group in oxidation of the central N atom to an N-oxide, the
(section 5.1), but the intermolecular bis(µ-oxo) species same reaction run at ambient temperature for longer
decompose through N-dealkylation of the ligand times (> 12 h) resulted in N-dealkylation via hy-
isopropyl groups.115 The regioselectivity of the bis(µ- droxylation of one of the methylene carbons adjacent
oxo) core attack at the isopropyl rather than the to the central nitrogen.142 The reactive species re-
benzylic C-H groups in these complexes is proposed sponsible for these transformations is not known,
to be controlled by geometric constraints, where the however, because both the N-oxidation and N-dealky-
former lie in the equatorial coordination position near lation reactions require reaction times significantly
the reactive oxo moiety. In keeping with a structural longer than the lifetime of the µ-η2:η2-peroxo complex
explanation and the significant H/D KIE values spectroscopically observed at 193 K (section 2.3).
Scheme 16 Scheme 17
ligand that had been hydroxylated at a iPr methine

position. This type of substituent functionalization
is similar to those observed for various TpiPr2 (16b)
complexes of metal ions other than Cu, such as Co
or Mn.236,237 In addition to decomposing via an
N-dealkylation pathway, the bis(µ-oxo) complex sup-
ported by Me3TMPA (43c) also yielded a ligand in
Activation of a C-H bond R to an N donor also
which a methyl substituent had been oxidized to a
occurs upon decomposition of the µ-1,2-peroxo com-
carboxylate, with both O atoms derived from the bis-
plex supported by the tetradentate tripodal ligand
(µ-oxo) core.228 An autoxidation path involving an
LiPr2Py (54), but oxidation to an amide occurs instead
alcohol intermediate was ruled out by the observation
of N-dealkylation (Scheme 16).232 A mechanism was
of no carboxylate product upon treatment of the
proposed in which the C-H activation step is pre-
alcohol (Me3TMPA with one Me replaced by CH2OH)
ceded by a rate-controlling unimolecular isomeriza-
with Cu(II), Et3N, and O2. Similar derivatization of
tion, speculated to yield a µ-η2:η2-peroxo species in
Me3TMPA was observed upon decay of its bis(µ-oxo)-
which a pyridyl group is not bound. The requirement
dinickel(III) complex.238 Finally, it is likely that 2:1
for such an isomerization was based on the combined
Cu/O2 adducts are involved in hydroxylations of
observations of (a) first-order kinetics for peroxo HPy2Ind (13l) and CalixNPy2 (55), but such species
complex decay, with a negative activation entropy
were not identified in these cases.233,234 It is note-
(Table 5) that argues against cleavage into mono-
worthy that for the oxidation of HPy2Ind (13l) (a) a
mers, and (b) a relatively low H/D KIE (2.5 at 243
large KIE (11 at 298 K) supports rate-determining
K) for experiments involving isotope substitution at
benzylic C-H bond cleavage, and (b) hydroxylation
the methylene group that is oxidized.
is regio- and stereoselective, with deuterium labeling
Intramolecular hydroxylation of benzylic positions
studies showing retention of configuration.233
not adjacent to N-donor atoms to yield alcohol
Intramolecular hydroxylation of unactivated ali-
functional groups has been observed upon decay of
phatic C-H bonds of ligand substituents in copper
Cu/O2 species supported by HPy2Phe(X) (13c-f),86,113
H complexes has been reported,239-241 and in one in-
Py1Et,Ph (22a-e),120 HPy2Ind (13l),233 CalixNPy2 (55),234
stance the nature of the oxidizing Cu/O2 intermediate
and P(3-R-5-iPrIm)3 (56a and 56b, R ) iPr or Et).235
was identified.242 Oxygenation of the Cu(I) complex
These reactions are of particular interest due to their
of i-Bu3CY (57) yielded a bis(µ-oxo)dicopper species,
resemblence to the benzylic hydroxylation catalyzed
identified by UV-vis and Raman spectroscopy, which
by dopamine β-monooxygenase.2,11,12 For the case of
H upon warming decomposed to yield a bis(alkoxo)-
Py2Et,Phe(X) (22a-e), the hydroxylated product forms
dicopper complex resulting from hydroxylation at the
upon decay of a µ-η2:η2-peroxo species identified by
substituent carbon β to the secondary amine donor
spectroscopy, but, similar to the situation noted above
atom (Scheme 18). An intramolecular hydrogen atom
for LiPr2Py (54) and MePy1Et,Bz (15c), kinetic data (Table
abstraction mechanism similar to those proposed for
5) were interpreted to indicate that isomerizaton to
N-dealkylations (see above) was implicated by the
a bis(µ-oxo) species occurred prior to attack at the
first-order kinetics and the activation parameters
benzylic C-H bond (Scheme 17). For example, a low
(Table 5).
KIE was measured (1.7 at 233 K, extrapolated to 1
at 254 K), and the rate of decay of the peroxo
compound was found to be relatively insensitive to
5.3. Other Intramolecular Ligand Oxidations
para substitution of the aromatic ring.113 Direct Inspired by the structure and function of galactose
attack at the benzylic position by an observable bis- oxidase (GAO), which catalyzes the two-electron
(µ-oxo) species was shown for the system supported redox reaction in eq 4 via cycling between Cu(I)/
by HPy1Et,Phe (22a),120 as supported by a large KIE phenol(ate) and Cu(II)/phenoxyl radical states (Fig-
for bis(µ-oxo) decay (35 at 193 K) and a F value of ure 1a),13-15 several research groups have examined
-1.48 from a Hammett study, both of which are the aerobic oxidation of alcohols to aldehydes or
similar to values obtained for N-dealkylation of LBn3 ketones using Cu(II)/phenolate and/or -phenoxyl
(7c) upon decay of its bis(µ-oxo) complex.226 In radical precursors.243,244 Of particular relevance to the
another example, the reversibly formed µ-η2:η2-peroxo current discussion are studies in which evidence is
complex of P(3,5-iPrIm)3 (56a) decomposed to yield presented for involvement of a Cu/O2 intermediate
Scheme 18 Table 6. Selected Kinetic Parameters for the

Oxygenolysis of Cu-Flavonolate Complexesa
activation
parameters
complex kb (k) Fc ref
[Cu(fla)2] (1.57 ( 0.08) ∆H ) 53 ( 6
q
-0.63 253
× 10-2 d ∆Sq ) -138 ( 11
[Cu(PPh3)2(fla)] (4.16 ( 0.48) ∆Hq ) 102 ( 7 -1.32 252
× 10-3 e ∆Sq ) -13 ( 21
[Cu(phen)(fla)2] (9.50 ( 0.60) ∆Hq ) 79 ( 16 -1.03 257
× 10-2 ∆Sq ) -40 ( 44
[Cu(bpy)(fla)2] (2.40 ( 0.10) 257
× 10-2
[Cu(Me4eda)- (2.00 ( 0.10) 257
(fla)2] × 10-2
a
All data from kinetics measurements in DMF solvent. The
rate and equilibrium constants are for the processes denoted
in Scheme 19. Structures of the abbreviated ligands are shown
in Chart 1, where fla ) 58, phen ) 59, bpy ) 60, and Me4eda
in the intramolecular generation of Cu/phenoxyl ) 39e. b Second-order rate constants (units are M-1s-1) mea-
sured at 353 K unless noted otherwise. c Hammett F value
radical species (the reactant responsible for alcohol determined from the rate constants k for flavonolate deriva-
oxidation) concomitant with the ejection of H2O2. tives with R ) OCH3, CH3, H, and Cl. d Measured at 373 K.
Copper(I) intermediates have been implicated in e
Measured at 363 K.
several aerobic alcohol oxidation systems,122,245 but
in only one instance with supporting ligand 1L (17) ester, H, Scheme 19).246-257 Shown in Scheme 19 are
has a Cu/O2 species been identified, [(1LH3)Cu(O2)- two related pathways for the reaction of a Cu(II)-
NEt3].122 This complex was formulated as a (η1- flavonolate, which were suggested on the basis of the
superoxo)copper(II) species on the basis of UV-vis results of mechanistic studies for several systems,
and FTIR spectroscopy. Interestingly, it equilibrates most notably [Cu(fla)2],253 [Cu(PPh3)2(fla)],252 and
with H2O2 and an isolable Cu(II)-phenoxyl radical [Cu(L)(fla)2] (L ) Me4eda (39e), phen (59), bpy
compound that is capable of oxidizing benzyl and (60)).257 Both mechanisms involve a prior rapid
ethyl alcohol. This process apparently involves H preequilibrium (with a small Keq) between the
atom or proton coupled proton transfers to the CuO2 Cu(II)-flavonolate and a redox isomer, a Cu(I)-fla-
unit that may be intramolecular, but the details have vonoxyl radical, in a process like that which is well
yet to be elucidated. established for simple catecholate/semiquinone com-
plexes of metal ions.258-261 Rate-determining binding
RCH2OH + O2 a RCHO + H2O2 (4) of O2 to the Cu(I) center is then postulated to occur,
consistent with the observation of overall second-
Copper-dioxygen species have been implicated in order kinetics (first order in complex and in O2),
studies of intramolecular oxidative C-C bond cleav- negative entropies of activation, and negative Ham-
age reactions of Cu-flavonolate (fla, 58) complexes mett F values when the substituent R is varied (Table
that model the monocopper active site of the enzyme 6). In subsequent fast steps, intramolecular coupling
quercetin 2,3-dioxygenase.7-9 Several Cu(I and II)- of the bound superoxide and the flavonoxyl radical
flavonolate compounds have been shown to react with is proposed to yield a trioxometallocycle (E), which
O2, typically at elevated temperatures, to yield carbon then rearranges to form an endoperoxide (F) or an
monoxide and a depside (phenolic carboxylic acid oxetane (G). Both intermediates would break down
Scheme 19
to yield a C-C bond cleaved product, the former by results clearly demonstrate a disparity in reactivity
a pathway analogous to the Criegee-type rearrange- between the end-on (nucleophilic) and side-on (elec-
ments of peroxides that have been cited for other trophilic) peroxides in the dicopper complexes. Sev-
metal-dioxgenase reaction mechanisms (cf. nonheme eral rationales for this disparity have been offered.
iron)262 and the latter in a route established for A steric argument has been suggested,62 which is
organic oxetanes that yields 2-benzoatophenylgly- based on the hypothesis that because substrate
oxylic acid and is accompanied by chemilumines- attack on the peroxide moiety occurs along the O-O
cence.263 Indeed, the two routes are distinguished by bond axis it would be inhibited when approach along
the presence or absence of light emission during the the O-O bond vector is blocked by the bulk of the
reaction; chemiluminescence was observed for the supporting ligand; such blocking would be decreased
faster reacting [Cu(phen)(fla)2], implicating G, but in a µ-η2:η2-peroxide compound. In an alternative
not for the more sluggish complexes [Cu(fla)2] or [Cu- argument based on simple valence bond consider-
(PPh3)2(fla)], which were thus suggested to react via ations, µ-η2:η2-peroxo coordination requires three
F. These mechanistic differences obviously are re- bonds to each O atom, and therefore may, in part,
lated to the nature of the supporting ligand, but it is be responsible for partial positive charge being as-
not yet clear how, and none of the intermediates in sociated with these atoms (i.e., electrophilic charac-
the overall mechanism have been observed. ter).264 More quantitative insights were obtained from
a detailed theoretical study of the relationship be-
6. Intermolecular Reactions of Copper−Dioxygen tween the electronic structure of peroxo adducts and
Complexes their observed reactivity toward substrates.3,201,265 A
key finding was that electron donation from the
While intramolecular ligand oxidations by Cu/O2 peroxide π* orbital into a Cu(II) d orbital (π*σ
complexes have provided important insights into interaction) is greater in the side-on bonded case,
fundamental reactivity issues, the reactions of such which corresponds to decreased electron density
complexes with exogenous substrates are particularly (greater electrophilic character) at the peroxide ligand.
relevant to enzyme catalysis. Comparative studies of A further observation is that the side-on adduct
structurally varied Cu/O2 compounds have revealed exhibits an additional bonding interaction where the
notable differences in reactivity with added sub- σ* orbital of the peroxide acts as a π-acceptor, thus
strates and have led to detailed understanding of leading to an overall weakening of the O-O bond.
oxidation mechanisms, both in synthetic and biologi-
cal systems. Further subtleties become evident upon comparing
In a landmark study,264 the reactivity with exoge- the reactivity of µ-η2:η2-peroxides with different N-
neous reagents of three different 2:1 Cu/O2 adducts donor ligands, such as N4Py2 (14b) and TpMe2 (16c),
that share similar pyridyl-amine N-donor ligation the cores of which adopt “bent butterfly” and planar
was compared: (a) [(TMPA)2Cu2(O2)]2+, comprising geometries, respectively.264,266 Unlike [(N4Py2)Cu2-
a trans-µ-η1:η1-peroxide with ligand 1, (b) [(XYLO-)- (O2)]2+, PPh3 is not oxidized but displaces the bound
Cu2(O2)]+, with an asymmetrically bound end-on O2 in [(TpMe2)2Cu2(O2)] to form the Cu(I)-PPh3 adduct.
peroxide and ligand 24g (Scheme 6), and (c) [(N4Py2)- Similar reactivity is exhibited by the TpiPr3 (16b)
Cu2(O2)]2+, with ligand 14b and a “bent” µ-η2:η2- analogue.180 It is only possible to oxidize cyclohexene
peroxo ligand (Scheme 7, B). It was concluded that under aerobic conditions with the TpMe2 (16c) system
the end-on η1-peroxides in the TMPA (1) and XYLO- and the O atoms in the product are derived from
(24g) complexes are nucleophilic in character. Thus, exogenous O2, not the peroxo moiety. Phenols and
for example, addition of 1 equiv of HBF4, HPF6 or an catechols are oxidatively coupled under anaerobic
acylating agent (m-ClC6H4C(O)Cl) to [(XYLO-)- conditions, as observed for the N4Py2 (14b) system.
Cu2(O2)]+ yielded µ-1,1-hydroperoxo or acylperoxo The different geometries of the two side-on peroxo
derivatives, respectively, as noted above (section adducts may well explain their varying reactivity
4).191,192 Hydrogen peroxide was evolved upon treat- toward substrates, although other differences such
ment of [(XYLO-)Cu2(O2)]+ and [(TMPA)2Cu2(O2)]2+ as overall charge (2+ vs neutral) and ligand-based
with excess protic acid. Both complexes also reacted steric bulk may be contributing factors; more detailed
readily with CO2 at low temperature to yield putative study is required before drawing any strong conclu-
peroxycarbonate (CO42-) species that decayed to sions. It is noteworthy that the presumably planar
isolable carbonate complexes. Triphenylphosphine µ-η2:η2-peroxo complex supported by the secondary
was not oxidized and instead displaced the peroxide diamine tBu2H2eda (39d) converts PPh3 to OPPh3
ligand to yield Cu(I)-PPh3 complexes. Phenols be- stoichiometrically and, in unprecedented fashion,
haved as a source of H+ ions resulting in the genera- oxidizes benzyl alcohol to benzaldehyde and benzyl-
tion of H2O2 and phenoxodicopper(II) systems. amine to benzonitrile.177
In contrast, the “bent” µ-η2:η2-peroxide in [(N4Py2)- The reactions of (µ-η2:η2-peroxo)dicopper complexes
Cu2(O2)]2+ acts as an electrophile. No reaction was with phenols, phenolates, and catechols have at-
observed with acyl chlorides and only low yields tracted particular attention because of direct rel-
(<15%) of H2O2 were obtained upon treatment of the evance to the catalytic transformations of tyrosinase
complex with excess HPF6. No reaction occurred with and catechol oxidase (Figure 1b),3,5,196,197,267 for which
CO2, but PPh3 was converted to OPPh3 upon warm- strong spectroscopic evidence has been provided for
ing of the complex. Rather than donating a proton, the intermediacy of this 2:1 Cu/O2 structural mo-
2,4-di-tert-butylphenol was oxidized to its dihydroxy- tif.3,268 Phenol or catechol oxidations have been shown
biphenyl radical coupling product. These and other to be performed by a variety of copper complexes in
the presence of O2, although specific data that would Scheme 20

shed light on the nature of Cu/O2 intermediates in
the reactions are generally lacking.269-278 In reactions
in which an exogenous phenol is hydroxylated in the
ortho position (as in tyrosinase), a µ-η2:η2-peroxo
species has been observed and shown to be directly
involved in a few instances.150,177,279,280 Addition of
sodium 4-carbomethoxyphenolate to the µ-η2:η2-per-
oxo complexes formed upon low-temperature oxygen-
ation of the dicopper(I) complex of 30a150 and the
monocopper(I) complex of L-6Ph (61) yielded the
corresponding ortho-catecholate. In the latter case,280
no quinone or dimers arising from C-C or C-O
coupling reactions were identified. On the basis of
kinetic results, a mechanism involving rapid hy-
droxylation after reversible generation of the spec-
troscopically observed µ-η2:η2-peroxo complex was
proposed, and an alternative path involving pheno- Scheme 21
late coordination to the Cu(I) complex prior to hy-
droxylation was ruled out. In separate experiments
with [(30a)Cu2]2+, prior phenolate coordination was
shown to yield hydroxylated product upon oxygen-
ation,276 so it is less clear with the system supported
by 30a that the peroxo species reacts directly with
added phenolate. It has also been suggested that in
this system quinone rather than catechol is the direct
reaction product.269 This view is controversial,281 and
has been both supported196 and refuted50 in studies
of tyrosinase.
In another example in which phenolate hydroxy-
lation occurs, the µ-η2:η2-peroxo complex supported
by the secondary diamine tBu2H2eda (39d) reacts Direct treatment of well-defined Cu/O2 adducts
with 2,4-di-tert-butylphenolate at 193 K to generate with catechols have revealed radical-based reaction
3,5-di-tert-butylcatechol and 3,5-di-tert-butyl-1,2-ben- pathways. As noted above, µ-η2:η2-peroxo complexes
zoquinone in a 1:1 ratio.177 The overall yield was of N4Py2 (14b) and TpMe2 (16c) oxidatively couple
∼80%, assuming that quinone formation from the catechols via radical processes; under excess O2 the
phenolate requires 2 equiv of the peroxo complex latter complex also generates the corresponding
(with no formation of Cu(I)). quinone.266 In a related transformation, addition of
3,5-di-tert-butylcatechol to the µ-η2:η2-peroxo complex
Extensive mechanistic information on phenolate
capped by LiPr3 (7b) afforded a mononuclear Cu(II)-
hydroxylation by a discrete Cu/O2 species is available
semiquinonato complex (Scheme 21).282 Because of
for the conversion of the series of phenolates p-X-
the demonstrated propensity of this µ-η2:η2-peroxo
C6H4OLi to the corresponding catechols upon reaction complex to isomerize to its bis(µ-oxo) isomer, it is not
with the µ-η2:η2-peroxo complex supported by HPy2Bz-d2 clear which species reacts with catechol. In support
(13j-d2, deuterated at the benzylic position to inhibit of the possible involvement of the bis(µ-oxo) form in
competing intramolecular benzylic oxidation) at low this reaction are (a) the known ability of bis(µ-oxo)
temperature (178 K).86,279 In this case, only catechols complexes to abstract hydrogen atoms from phenols
were observed; no quinone or C-C/C-O coupling (see below) and (b) the finding that the bis(µ-oxo)
products were identified. The loss of the µ-η2:η2- compound supported by LBn3 (7c), a ligand that does
peroxo spectroscopic features in the presence of not appear to yield a µ-η2:η2-peroxo isomer, reacts
excess phenolate followed pseudo-first-order kinetics, analogously with catechols to form Cu(II)-semiquinon-
and plots of the kobs values as a function of [p-X-C6H4- ato products.282 In contrast, the bis(µ-oxo) complex
OLi] revealed saturation behavior indicative of re- supported by the bidentate ligand Me4pda (23a)
versible coordination of the phenolate to the µ-η2:η2- quantitatively yields the corresponding quinone upon
peroxo complex prior to ring hydroxylation (Scheme reaction with 3,5-di-tert-butylcatechol.283
20). Comparison of association constants (Kf) and Bis(µ-oxo) complexes are generally proficient at
hydroxylation rate constants (kox) determined from what appear to be hydrogen atom abstraction reac-
double reciprocal plots as a function of the nature of tions, as illustrated by their reactions with phenols,
the para substituent X showed little effect on Kf, but which yield phenoxyl radicals or products derived
revealed a clear influence on kox, such that greater therefrom. Hydrogen atom abstraction from sub-
electron donation increased the hydroxylation rate strates such as 1,4-cyclohexadiene or 9,10-dihydroan-
constant. No H/D isotope effect on kox was discerned. thracene that have weak C-H bonds has also been
Overall, these data support an electrophilic aromatic observed in several instances, although the nature
substitution pathway for the kox step (Scheme 20). of the oxidant in these studies is unclear. In one case
Scheme 22 Scheme 23
(with HPy2Me, 13b), equilibration between bis(µ-oxo)

and µ-η2:η2-peroxo cores obfuscates matters,119,171
while in another (with HPy1Et,Bz-d2, 15a-d2, deuter-
ated at the benzylic positions) a second-order depen-
dence of the rate of oxidation of 10-methyl-9,10-
dihydroacridine on the concentration of a bis(µ-oxo)
species was observed.284 A provocative hypothesis
invoking generation of a more oxidizing (µ-oxo)(µ-oxyl notion comes from (a) the lack of a dependence of the
radical)dicopper(III) intermediate via disproportion- rate of phenol oxidation by cumylperoxyl radicals
ation of the bis(µ-oxo) complex was put forth in order (which react via hydrogen atom transfer, HAT) on
to rationalize the kinetics data (Scheme 22). Interest- the substrate redox potential (Figure 3), (b) observa-
ingly, even though the bis(µ-oxo) complex of Me4pda tion of modest KIE values (ArOH/D) between 1.2 and
(23a) abstracts hydrogen atoms readily from phenols, 1.6 that are similar to those previously reported for
it does not appreciably oxidize 1,4-cylohexadiene or other PCET processes,286 and (c) independent DFT
9,10-dihydroanthracene.283 calculations that indicate a preference for PCET over
In a recent detailed analysis of the one-electron HAT in phenol oxidations.287
oxidation of phenols by Cu/O2 species, the kinetics Intriguing ligand electronic effects on the reactivity
of the reactions of the µ-η2:η2-peroxo complex of of Cu/O2 species with a variety of exogeneous sub-
H
Py2Bz-d2 (13j-d2) and the bis(µ-oxo) complex of strates were revealed in studies of the mixture of
H
Py1Et,Bz-d2 (15a-d2) with phenols of varying redox µ-η2:η2-peroxo and bis(µ-oxo) complexes that result
potentials were compared.285 Marcus plots of the upon oxygenation of the Cu(I) complexes of RPy2Me
second-order rate constants (Figure 3) were linear (R ) H (13b), OMe (41a), Me2N (41b)).178 A wide
with slopes (-0.7) more negative than the value of range of oxidation reactions were reported, including
-0.5 predicted for rate-limiting ET (under the as- ones not seen previously for any other characterized
sumption that the driving force is significantly smaller Cu/O2 complex, such as the conversions of THF to
than the reorganization energy). These data were 2-hydroxytetrahydrofuran, methanol to formalde-
interpreted to support a proton coupled electron hyde, and N,N′-dimethylaniline to methylaniline and
transfer (PCET) pathway. Further support for this formaldehyde. Yields and reaction rates generally
increased when the most electron-donating support-
ing ligand was used (R ) Me2N, 41b). An increased
bis(µ-oxo):µ-η2:η2-peroxo isomer ratio also correlates
with greater electron donation by the ligand (section
3), but this ratio difference probably is not the sole
basis for the reactivity trend due to likely rapid
equilibration of the isomers under the reaction condi-
tions. Greater mechanistic insight into the oxidative
dealkylation of N,N′-dimethylaniline was recently
provided288 by a comparison of intra- and intermo-
lecular KIEs for reactions of the series of complexes
of RPy2Me (R ) H (13b), OMe (41a), Me2N (41b)) with
N-trideuteriomethyl-N′-methylaniline (KIEintra) or
mixtures of N,N′-dimethylaniline and N,N′-hexadeu-
teriodimethylaniline (KIEinter) with various para-
substituents.289 On the basis of the results, a di-
chotomy between hydrogen atom transfer (HAT) and
Figure 3. Marcus plots for the oxidation rates (k2) of electron transfer/proton transfer (ET/PT) pathways
phenols (numbered 1-10) of variable redox potentials
(E°ox) by (A) the µ-η2:η2-peroxo complex of HPy2Bz-d2 (13j-
was proposed (Scheme 23), wherein the parent sys-
d2), (B) the bis(µ-oxo) complex of HPy1Et,Bz-d2 (15a-d2), and tem reacted by ET/PT but the systems ligated by
RPy2Me (R ) OMe (41a) or Me N (41b)) followed both
(C) cumylperoxyl radical. Figure reprinted with permission 2
from ref 285. Copyright 2003 American Chemical Society. pathways depending on the para-substituent of the
Scheme 24 Scheme 25
substrate. For electron-donating substituents MeO

and Me, the reaction was suggested to involve rate-
limiting ET, but HAT was proposed to become rate
determining as the substituents become more elec-
tron withdrawing (H and CN).
A number of studies suggest that binding of sub-
strates to available coordination positions of Cu/O2
complexes (as in the phenolate oxidations by the (µ3-oxo)tricopper(II,II,III) complex supported by
H
peroxo complex supported by HPy2Bz-d2 (13j-d2) de- Py1Me,Me (15b).161 The tricopper compound acts as
scribed above) may be a generally important mecha- a two-electron oxidant to yield the coupled bis-phenol
nistic feature in oxidation reactions. Thus, [(Me4- dimer, a bis(µ-hydroxo)dicopper(II,II) species, and
pda)2Cu2(µ-O)2]2+ oxidizes alcohols to aldehydes or [(HPy1Me,Me)Cu]+ (Scheme 25). Two intermediates
ketones and benzylamine to benzonitrile in reactions were identified by UV-vis spectroscopy (I and J).
that are postulated to involve coordination to copper The rate of decay of the tricopper starting material
followed by deprotonation and then oxidation.283 displays a first-order dependence on its concentration
Support for the capability for substrate to coordinate and on that of the phenol (k1 ) 0.46 ( 0.02 M-1 s-1
to a Cu(III) center was provided by (a) EXAFS data at 183 K, Scheme 25). Since the more hindered
that implicate ClO4- binding to this complex and (b) substrate 2,4,6-tri-tert-butylphenol did not react,
an X-ray crystal structure of a related bis(µ-oxo) phenol coordination is implicated in the generation
compound [(Me2LMe2)(Me4pda)Cu2(µ-O)2]O3SCF3 of intermediate I. The slower conversion to interme-
(Me2LMe2 ) 18b) that shows CF3SO3- coordination diate J displayed substrate saturation kinetics (K )
to the Cu ligated by Me4pda (23a).125 Direct kinetic 44.6 ( 2.2 M-1 and k2 ) 9.5 ( 0.5 × 10-3 s-1 at 203
evidence for substrate coordination was provided in K), supporting substrate coordination in this step as
studies of the oxidation of thioethers to sulfoxides by well, and leading to the overall mechanistic postulate
the bis(µ-oxo) complex supported by HPy1Et,Bz-d2 (15a- outlined in Scheme 25. Further work is required to
d2).290 The kinetic data support rapid binding of delineate the structures of I and J.
thioether followed by slower oxidation (Scheme 24), Protonation or acylation of peroxo copper species
which is suggested to involve direct oxygen atom appears to enhance their O-atom transfer reactivity.
transfer instead of electron transfer on the basis of This has been demonstrated by observation of facile,
a relatively small dependence of the rate constant on stoichiometric conversion of PPh3 to OPPh3 and/or
the substrate oxidation potential for a range of R2S to R2SO by hydro- and acylperoxo complexes
thioethers (value of -0.94 for the slope of log k2 vs supported by TpiPr2 (16b),181,182 XYL-O- (24g),191,192
E0ox).291 UN-O- (26b),143 TMPA (1),187 1,2-dimethylimida-
The significance of substrate coordination has been zole,187 and HPy2BzO (13k).187 In most cases, copper-
stressed in a comparative study of the reactivity of (II) complexes with hydroxo- or carboxylate ligands,
isomeric bis(µ-oxo) and µ-η2:η2-peroxo dicopper com- respectively, were isolated from the reactions. De-
plexes of tBu2Me2eda (39a) that equilibrate unusually tailed mechanistic information on these reactions are
slowly, [(tBu2Me2eda)2Cu2(µ-O)2]2+ and [(tBu2Me2- not available, although an analysis of O-O and
eda)2Cu2(O2)]2+.174 The µ-η2:η2-peroxo isomer reacts Cu-O bond scission pathways in reactions of TpiPr2-
more readily than the bis(µ-oxo) with PPh3 to yield CuOOH(R) complexes using spectroscopic and theo-
OPPh3, but the bis(µ-oxo) is more efficient at oxida- retical methods has been presented.183 A key conclu-
tively coupling 3,5-di-tert-butylphenol. These results sion is that O-O homolysis or heterolysis in these
implicate reactivity differences intrinsic to the iso- complexes is energetically disfavored because of
meric structure of the dicopper core, although other thermodynamic instability of the resulting Cu(III/IV)-
results suggest that accessibility of substrate to a oxo species. Further studies of supporting ligand
copper center is just as critical. Thus, while the bis- effects on these energetics are needed.
(µ-oxo) complex supported by iPr2Me2eda (39b, un- Coupling of inter- and intramolecular reactivity has
contaminated by measurable amounts of its peroxo been reported for the reaction of the 2:1 Cu/O2 adduct
isomer) is incapable of oxidizing PPh3, that supported supported by the ligand PD (27a) with dimethyl-
by the much less hindered Me4pda (23a) produces formamide (DMF, Scheme 26).82,145 The product
OPPh3 in high yield. contains a hydroxylated arene linker and formate
Substrate coordination to a Cu center has also been derived from hydrolysis of DMF, with both atoms
implicated by the results of kinetic data obtained for from O2 incorporated (one in the arene and the other
the reaction of 2,4-di-tert-butylphenol with the bis- in formate) as shown by a 18O-isotope labeling experi-
Scheme 26 conclusions drawn for its involvement in particular

biological processes, work on the peroxo/bis(µ-oxo)
equilibrium should continue to influence interpreta-
tions of studies of O2 activation by a variety of
synthetic compounds and/or proteins, including those
that incorporate metal ions other than Cu, such as
Fe,292 Mn,293 Co,294,295 and Ni.238,294,296 Finally, it is
important to emphasize that the peroxo/bis(µ-oxo)
equilibrium is just one of many possible dynamic
transformations that may occur as O2 is manipulated
by metal sites for attack at organic substrates (cf.
Schemes 7 and 16), and further elucidation of such
processes is eagerly awaited.
Detailed insights into the mechanisms of intra- and
intermolecular oxidations by well-characterized Cu/
O2 compounds have been obtained in several in-
stances. Notable in this regard are the investigations
of m-xylyl hydroxylations and N-dealkylations by
ment. Initial nucleophilic attack of the 2:1 Cu/O2
peroxo and bis(µ-oxo)dicopper species, respectively,
adduct at the DMF carbon was suggested as one
described in sections 5.1 and 5.2. Mechanistic un-
possible reaction pathway, but mechanistic data are
derstanding is less well-developed for intermolecular
lacking.
reactions of Cu/O2 species, which display variable
reactivity that depends on Cu/O2 adduct and sup-
7. Perspective and Conclusion porting ligand properties in ways that in many
respects are difficult to fathom. An illustrative un-
Enormous research efforts over the past several resolved issue concerns the bases for one- vs two-
decades have borne fruit, insofar as our understand- electron redox chemistry by dicopper species (e.g.,
ing has deepened of the detailed mechanisms by radical abstractions vs O-atom transfers) and for
which copper complexes bind and activate dioxygen. PCET vs HAT pathways. Addressing the nature of
Through cryogenic stopped-flow studies of the oxy- elementary reaction steps in oxidations by discrete
genation of Cu(I) compounds, critically important Cu/O2 complexes is thus a fertile area for future
kinetic and thermodynamic information has been study, with success most likely to depend on the
obtained. A notable general finding concerns the synergistic application of experimental and theoreti-
typical thermodynamic instability of Cu/O2 adducts, cal approaches.
which may be traced to a negative reaction entropy A survey of the field also reveals the preponderance
that offsets the favorable enthalpy for O2 binding. of systems comprising two copper ions, reflecting a
One strategy for enhancing adduct stability is to particular thermodynamic preference with the ligands
manipulate the unfavorable entropy term by control- used to date that has arguably played a role in
ling the conformational flexibity of dinucleating leading researchers to focus their efforts on such
ligands. Putting this notion into practice is not species. Particular interest on dicopper compounds
without pitfalls, however, such as enthalpic destabi- also has been motivated by their relevance to the
lization that can accompany imposition of conforma- well-characterized proteins hemocyanin, tyrosinase,
tional control,99,100 and other approaches such as and catechol oxidase. Fewer mono-, tri-, or tetra-
protecting supporting ligands from intramolecular nuclear Cu/O2 compounds have been studied, and it
oxidative attack may also be required.194,195 To date, would appear that ingenious synthetic approaches
Cu/O2 adducts that exhibit room-temperature stabil- will be required to access a diverse array of such
ity are rare,146,152,193-195 but others are sure to be species for comparative studies and to inhibit the
discovered. formation of the generally more favored dicopper
Processes by which Cu/O2 adducts interconvert and cores. Particular impetus for future research aimed
O-O bonds are broken and formed are especially at these types of molecules is provided by the
important to understand if enzymatic mechanisms established significance in oxygenase and oxidase
of dioxygen activation are to be deconvoluted. The enzymes of active sites with one or three (or more)
peroxo/bis(µ-oxo) equilibration in dicopper compounds copper ions. Unresolved questions centered on how
is an illustrative example, and examination of the O2 is activated by these enzymes should inspire
factors that control the relative stability of the two synthetic efforts for years to come.
isomeric cores continues to be informative, as do
efforts to dissect their relative reactivities toward 8. Acknowledgments
exogenous substrates in order to develop new and
useful oxidation reagents and to understand the We thank the coauthors cited in the references
nature of the oxidants involved in biological catalysis. from our laboratory for their extensive efforts, and
Whether or not the peroxo/bis(µ-oxo) interconversion the NIH (GM47365) for financial support.
is important in specific copper proteins, such as in
tyrosinase, is a matter of active debate, and we note 9. References
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Chem. Rev.

2004, 104, 1047−1076 1047

Reactivity of Dioxygen−Copper Systems

Received July 9, 2003

Table 1. Copper Proteins that Bind and/or Activate Dioxygen

observed to date, differences in details are often

Chemical Reviews, 2004, Vol. 104, No. 2 1053

Scheme 2 parameters for the individual steps that result from

Chemical Reviews, 2004, Vol. 104, No. 2 1055

This rate law and the similarity of the activation Scheme 3

(4.5 ( 0.4) × 102

observable only at low temperature).152

ported by UN-O- (26b), but it is more stable, such

that it may be isolated as a solid.143 One-electron

oxidation of this adduct yields a species formulated

(1.8 ( 0.2) × 10-5

obtained, even at 173 K, but overall thermodynamic

data for O2 binding are in line with other systems,

including R-XYL-H (24a-f). The increase in the rate

system in a conformation suitable for 2:1 complex

increased oxygenation rate.

∆Hq ) 6.4 ( 0.1

The linker in N4Py2 (14b) is significantly more

flexible than the xylyl bridges in R-XYL-H (24a-f)

the µ-η2:η2 (side-on) compound B. Species B is ther-

modynamically favored relative to A, as indicated by

mol-1, respectively (Table 4). However, the kinetic

data rule out sequential formation of B directly from

A, and require the intermediacy of either the starting

dicopper(I) complex or a transient 1:1 adduct (“Tr”).

equilibrium because (a) the formation of the initial

peroxo species A occurs with an activation enthalpy

of zero and (b) it is unlikely that 2:1 Cu/O2 adduct

than the peroxo complex supported by R-XYL-H (24a;

compare k1 values in Table 4). This result has been

MeO (41a), Me2N (41b)), which present identical Scheme 9

4. Alternate Syntheses of Copper−Dioxygen and

newly introduced O atoms derived from O2 (and not

series of para-substituted LBn3 systems 7c-f gave a

ligand that had been hydroxylated at a iPr methine

Scheme 18 Table 6. Selected Kinetic Parameters for the

the presence of O2, although specific data that would Scheme 20

(with HPy2Me, 13b), equilibration between bis(µ-oxo)

substrate. For electron-donating substituents MeO

Scheme 26 conclusions drawn for its involvement in particular

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