O2 activation and selective phenolate ortho hydroxylation by an unsymmetric dicopper μη1: η1-peroxido Complex

Article abstract of DOI:10.1002/anie.200906749

Unusual reactivity: A novel unsymmetric dicopper complex gives rise to the unsymmetric species 1-O₂ having a μ-η¹: η¹ -O₂ binding mode and reactivity patterns not previously observed for symmetric analogues. It is unreactive in oxygen atom transfer reactions, but it can selectively bind phenolate and mediate its Ortho hydroxylation, thereby demonstrat-ing a conceptually different tyrosinase model with exquisite selectivity. (Figure Presented)

Full text of DOI:10.1002/anie.200906749

Communications
DOI: 10.1002/anie.200906749
À
O O Activation
O2 Activation and Selective Phenolate ortho Hydroxylation by an
Unsymmetric Dicopper m-h1:h1-Peroxido Complex**
Isaac Garcia-Bosch, Anna Company, Jonathan R. Frisch, Miquel Torrent-Sucarrat,
Mar Cardellach, Ilaria Gamba, Mireia Gꢀell, Luigi Casella,* Lawrence Que, Jr.,* Xavi Ribas,*
Josep M. Luis,* and Miquel Costas*
Understanding the intimate details of O2 activation at metal
sites is of interest because of the relevance of such reactions in
biological and technological processes.[1] Of particular rele-
vance is uncovering basic chemical principles and mecha-
nisms for taming the high oxidizing potential of the O2
molecule into highly selective oxidative transformations,
especially those involving the selective hydroxylation of
Figure 1.
C H bonds.
(CuIII2(m-O)2) cores show electrophilic character, and can
mediate tyrosinase-like phenolate ortho-hydroxylation reac-
tions.[3] The latter reactivity has never been observed for end-
on Cu2O2 species; therefore its possible biological relevance
has been ignored so far.
The rich and subtle chemistry exhibited by Cu2O2 cores
makes unsymmetric options interesting. Actually, Cu2O2
species in systems containing distinct copper sites have been
rarely observed.[2b] Herein we describe a novel dicopper
complex based on a heptadentate ligand that gives rise to an
unsymmetric N3CuIIN4CuII(m-h1:h1-O2) core, which hitherto
exhibits reactivity patterns not observed for symmetric
analogues. This nonsymmetric peroxide species shows an
exquisite selectivity in its oxygen atom transfer reactivity. It
performs the selective intermolecular ortho hydroxylation of
a phenolate, but fails to oxidize many common oxophilic
substrates.
À
For the particular case of dicopper sites, three basic Cu2O2
core structures have been widely described as arising from the
interaction of discrete CuI complexes and O2 (Figure 1).[2]
Each specific Cu2O2 core determines particular spectroscopic
and chemical properties:[2b,c] whereas end-on trans-CuII -
2
(m-h1:h1-O2) species exhibit nucleophilic and basic behavior,
side-on CuII (m-h2:h2-O2) and bis-m-oxido dicopper(III)
2
[*] I. Garcia-Bosch, Dr. A. Company,[+] M. Cardellach, Dr. X. Ribas,
Dr. M. Costas
Departament de Quꢀmica, Universitat de Girona
Campus de Montilivi, 17071 Girona, Catalonia (Spain)
E-mail: xavi.ribas@udg.edu
miquel.costas@udg.edu
J. R. Frisch, Prof. L. Que, Jr.
Department of Chemistry and Center for Metals in Biocatalysis
University of Minnesota, 207 Pleasant Street SE
Minneapolis, MN 55545 (USA)
Reaction of m-XylN3N4 with [CuI(CH3CN)4X] (X =
CF3SO3, PF6, ClO4) in acetonitrile affords the unsymmetric
dinuclear copper(I) complex [CuI2(m-XylN3N4)](X)2 (1-X;
Figure 2). For comparative purposes, [CuI2(m-XylN4N4)]-
(ClO4)2 (2-ClO4) was also prepared. Crystallographic charac-
terization of 1-CF3SO3 reveals that the copper ion bound to
the tridentate arm adopts a highly distorted T-shape geom-
etry, whereas the copper ion bound to the tetradentate arm
has a distorted trigonal-pyramidal geometry, with structural
parameters nearly superimposable with those of the two
tetracoordinated copper ions in 2-ClO4.[4]
E-mail: larryque@umn.edu
Dr. M. Torrent-Sucarrat
Institut de Quꢀmica Avanꢁada de Catalunya, IQAC–CSIC
Catalonia (Spain)
Dr. I. Gamba, Prof. L. Casella
Department of General Chemistry, University of Pavia
27100 Pavia (Italy)
E-mail: bioinorg@unipv.it
Dr. M. Gꢂell, Dr. J. M. Luis
Institut de Quꢀmica Computacional, Universitat de Girona
Catalonia (Spain)
E-mail: josepm.luis@udg.edu
josepm.luis@udg.edu
[+] Present address:
Acetone solutions of 1-X at À908C react with O2 within
seconds to form a red-brown species [Cu2(O2)(m-XylN3N4)]2+
(1-O2), characterized by a visible band at 478 nm (e =
7800mÀ1 cmÀ1), and a broad shoulder between 575 and
700 nm (Figure 3). The visible spectrum of 1-O2 is intermedi-
Institut Chemie, Technische Universitꢃt Berlin (Germany)
[**] This work was supported financially by MCYT of Spain (projects
CTQ2006-05367/BQU and CTQ2009-08464/BQU to M.C.), by the
U.S. NIH (grant GM38767 to L.Q.), and by the Italian MIUR (Prin
project to L.L.). I.G.B and A.C. thank MICINN for PhD grants. M.T.-
S. thanks the CSIC for the JAE-DOC contract. We thank STR-UdG for
technical support. M.C. also thanks the Generalitat Catalunya for an
ICREA-Academia award and for project 2009 SGR-637.
ate between those of Itohꢀs proposed CuII (m-h1:h2-O2)
2
species[5] and reported CuII (m-h1:h1-O2) complexes.[2b,6] UV/
2
Vis monitoring of this reaction shows an isosbestic point at
414 nm indicating the clean transformation of 1-CF3SO3 into
1-O2 without accumulation of any intermediate species. 1-O2
is stable for hours at À908C, but it decomposes within seconds
when warmed to room temperature.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906749.
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Chemie
and 520 cmÀ1 [D18O2-16O2 = 45 and 22 cmÀ1, respectively],
À
À
characteristic of O O and Cu O stretching vibrations of an
end-on CuII2(m-h1:h1-O2) species.[2b] Excitation profiles indi-
cate that the two vibrations are in resonance with the lower
energy band, and no features resulting from a CuII2(m-h2:h2-
O2) species were observed. Experiments with mixed labeled
À
O2 (Figure 3 bottom, inset C) showed a n(O O) region with
three isotopomeric peaks at frequencies that suggest insensi-
tivity of the bound O2 to the unsymmetrical nature of the
ligand.[7]
In contrast, symmetric complex 2-ClO4 reacts at À908C in
acetone to form a different metastable purple species, 2-O2,
which is characterized by two intense UV/Vis bands at lmax
=
500 nm (e = 5000mÀ1 cmÀ1) and 635 nm (e = 3300mÀ1 cmÀ1),
typical of an end-on trans-CuII (m-h1:h1:O2) species.[2b] The O2-
2
binding mode was confirmed by the resonance Raman spectra
of a frozen 2-O2 solution, collected with laser excitation at
488 nm (see the Supporting Information), which shows a
À1
À
characteristic resonance-enhanced n(O O) band at 826 cm
[D18O2-16O2 = 44 cmÀ1]. The fact that both 1-O2 and 2-O2 give
À
rise to n(O O) features of nearly the same frequency strongly
suggests that the dioxygen moiety is bound in the same
Figure 2. Top: Chemical diagram of 1-X (left) and 2-ClO4 (right).
Bottom: Ellipsoid diagrams (30% probability) of the cationic parts of
1-CF3SO3 (left) and 2-ClO4 (right). H atoms were omitted for clarity.
fashion in the two complexes. Because of the high energy of
the n(O O) stretching frequency,[2b] and because a m-h1:h2-O2
À
binding mode is unlikely for 2-O2,[8] we favor a m-h1:h1-O2
mode for both O2 adducts.
The reactivities of 1-O2 and 2-O2 with different substrates
were explored (Schemes 1 and 2). 1-O2 and 2-O2 rapidly and
quantitatively react with CF3CO2H releasing H2O2 (99%
yield, see the Supporting Information). Titration experiments
reveal that both reactions are complete with 1 equivalent of
H+ (per Cu), and no other intermediate species are detected
when substoichiometric amounts of H+ are added. 1-O2 and 2-
O2 react neither with thioanisole, styrene, triphenylmethane,
nor with electron donors such as ferrocene. Thermal decom-
position of 1-O2, by warming up acetone solutions to room
temperature, in the presence of large excess of toluene
(1000 equiv), did not cause toluene oxidation.[9] The addition
of PPh3 (10 equiv) to 1-O2 and 2-O2 at À908C induces fast O2
release (t1/2 ꢀ 5 min) without formation of OPPh3.[10] In sum,
all the above observations suggest that 1-O2 and 2-O2 are not
electrophilic oxidants, and typically react like other end-on
trans-CuII (m-h1:h1-O2) complexes.[11]
2
However, substantial differences arise when the reactions
of 1-O2 and 2-O2 with benzaldehydes are studied. 2-O2 reacts
with benzaldehydes to generate the corresponding benzoic
acids in quantitative yields. Kinetic analyses of the reactions
were performed by using UV/Vis methods to monitor the
decay of the spectral features of 2-O2. The 2-O2 decay rate can
be fitted to single exponential processes, and the measured
kobs values are linearly dependent on substrate concentration
(see the Supporting Information). Reaction of 2-O2 against a
series of para-substituted benzaldehydes was studied and the
corresponding decay rate constants were extracted by using
UV/Vis methods to monitor the reactions. Plotting the decay
rate of 2-O2 against the corresponding Hammett substituent
constants (s+) affords a linear correlation which gives a
1 value of 1.4 (R2 = 0.98, see the Supporting Information),
consistent with a nucleophilic oxidizing species that attacks
Figure 3. Top: UV/Vis spectra for the reaction of 1-CF3SO3 with O2 in
acetone at À908C to form 1-O2. Bottom: Resonance Raman spectra
(lex =488 nm) of frozen acetone solutions of 1-O2 from 16O2 (A), 18O2
(B), and 18O16O (C).
To gain insight into the peroxido binding mode of 1-O2,
resonance Raman spectra of frozen samples of 1-O2 were
obtained. Laser excitation at 488 nm (Figure 3 bottom, insets
A and B) gives rise to two resonance-enhanced peaks at 832
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À0.6 (R2 = 0.98, see the Supporting Information),
consistent with an electrophilic oxidizing species that
attacks the aromatic ring in the rate-determining step
of the reactions. In line with this reactivity, no
catechol product was formed when electron-poor
phenolates (X = CN, NO2, and CO2Me) were used as
substrates. In contrast, substrate hydroxylation does
not appear to be only determined by the electron-
releasing nature of the substrate because the elec-
tron-rich, sterically more demanding 2,4-di-tert-butyl-
catecholate was neither hydroxylated nor oxidized to
the corresponding diphenol coupled product. We
conclude that hydroxylation occurs exclusively for
non-electron-poor, sterically unhindered phenolate
substrates. Furthermore 1-O2 differs from any other
CuII (m-h1:h1-O2) intermediate in its capacity to carry
2
Scheme 1. Schematic representation of selected reactivity exhibited by 1-O2 and
2-O2. (N.R.=no reaction).
out electrophilic arene hydroxylation.[2c] We propose
that the difference in the reactivity of 1-O2 and any
the carbonyl moiety. In contrast, 1-O2 fails to react with
benzaldehyde. Thus we conclude that 1-O2 is unreactive in
oxygen atom transfer reactions to common substrates which
are either electrophilic or nucleophilic in nature.
previously reported end-on CuII2(m-h1:h1-O2) species (includ-
ing 2-O2) stems from the possibility that phenolate can
initially bind at the N3Cu site, as proposed in a symmetric
m-xylyl-bridged bis-tridentate CuII (m-h2:h2-O2) system.[3b]
2
Strikingly, addition of p-Cl-C6H4ONa (3 equiv, Scheme 2)
to a solution of 1-O2 at À908C causes rapid conversion into a
Indeed, in the present example, the substrate binding event
can be understood as playing a selective peroxide-activation
role, since 1-O2 by itself lacks oxygen atom transfer reactivity.
The selective oxygen atom transfer reactivity exhibited by
1-O2 was additionally substantiated by DFT computational
methods.[12] The computed structure of 1-O2 (see the Sup-
short-lived (t1/2 ꢀ 1 min) yellow-brown species 3Cl (lmax
=
470 nm, e > 6000mÀ1 cmÀ1, see the Supporting Information).
The resemblance in the UV/Vis spectral features of 1-O2 and
3
Cl strongly suggests that the CuII2(m-h1:h1-O2) core is retained,
but the instability of 3Cl has thus far precluded its Raman
characterization. Surprisingly, after complete decomposition
of the 3Cl species, acidic work-up and subsequent HPLC/MS
analyses show the formation of p-chlorocatechol in 39% yield
with respect to 1-O2. Similar addition of p-chlorophenolate to
2-O2 causes fast bleaching of its spectral features, without
accumulation of any intermediate species, and without any
sign of phenolate ortho hydroxylation.
porting Information) reveals a CuII (m-h1:h1-O2) complex with
2
a Cu···Cu distance of 4.31 ꢁ and structural parameters in
good agreement with a crystallographically characterized
example.[13] We have also found that the CuIII2(m-O)2 isomer is
36.8 kcalmolÀ1 higher in energy.[12] In addition, attempts to
perform geometry optimizations on side-on CuII (m-h2:h2-O2)
2
isomeric cores proved unsuccessful.[14] Therefore, consistent
with the experimental observations, the end-on CuII2(m-h1:h1-
O2) is the most stable species.[14–16] Phenolate binding to 1-O2
retains the CuII2(m-h1:h1-O2) core as the most stable isomer (in
agreement with our formulation of 3X based on its UV/Vis
spectrum), and causes an elongation of the Cu···Cu distance
up to 4.50 ꢁ. Interestingly, the phenolate p system is adjacent
to the peroxide oxygen atom bound to the other Cu in 3Me
(Figure 4), offering a plausible pathway for a s* electrophilic
attack of the peroxide moiety on the aromatic ring.[17] Most
remarkably, the computed activation barrier for this reaction
is only 14.7 kcalmolÀ1, and no intermediates regarding the
Kinetic analysis indicates that the decay of 3Cl is a first-
order process. The analogous species 3X (X = F, Me, H, and
OMe) were generated by the addition of 3 equivalents of p-X-
C6H4ONa to 1-O2 at À908C in acetone, and their correspond-
ing UV/Vis decay rates were fitted to a single exponential
function by nonlinear regression methods. Product analysis
after 3X (X = F, Me, H, and OMe) decomposition reveals that
the corresponding catechol is formed in 34%, 34%, 36%, and
14% yields, respectively. A Hammett plot (log (kobs) for 3X
versus s+) affords a linear correlation which gives a 1 value of
isomerization to side-on CuII (m-h2:h2-O2) or CuIII2(m-
2
O)2 cores are found along this attack, thereby strongly
suggesting that the trans end-on peroxido core is a
À
competent species for executing the aromatic C H
hydroxylation event.[12]
In conclusion, our study of O2 activation at a novel
asymmetric dicopper complex 1-O2 has hitherto
uncovered reactivity patterns thus far not observed
for symmetric analogues. 1-O2 is basically unreactive
in oxygen atom transfer reactions. However, it has an
available coordination site that selectively binds
phenolate and mediates its ortho hydroxylation,
Scheme 2. Reaction of 1-O2 with the sodium salt of para-substituted phenolate.
therefore functionally mimicking tyrosinase through
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[4] CCDC 755536 (1CF3SO3) and 755537 (2ClO4) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
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[5] Y. Tachi, K. Aita, S. Teramae, F. Tani, Y. Naruta, S. Fukuzumi, S.
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[8] Bis-tetradentate ligands most often give rise to m-h1-h1 isomers:
Figure 4. Stationary points along the reaction pathway of the ortho hy-
droxylation of para-methyl phenolate into 4-methyl catechol from 3Me
.
a unique pathway. Furthermore, coordination of the pheno-
late substrate turns on the unprecedented electrophilic
reactivity of the asymmetric end-on trans-peroxido core.
The combined experimental and computational evidence
indicate that the ortho hydroxylation of a phenolate by a
Cu2O2 species can occur by adjacent binding of phenolate and
O2 at a common N3Cu site without requiring the peroxido to
be side-on bound, thus offering a conceptually new under-
standing of O2 activation at dicopper sites.
see [2b] and references within.
II
[9] Aliphatic C H oxidation of toluene mediated by Cu 2(m-h1:h1-
À
O2) species has been recently reported: a) H. R. Lucas, L. Li,
A. A. Narducci Sarjeant, M. A. Vance, E. I. Solomon, K. D.
Karlin, J. Am. Chem. Soc. 2009, 131, 3230 – 3245; b) C. Wꢄrtele,
O. Sander, V. Lutz, T. Waitz, F. Tuczek, S. Schindler, J. Am.
Chem. Soc. 2009, 131, 7544 – 7545.
[10] 1H and 31P NMR spectra of the final mixture are identical to
those observed after mixing 1ClO4 and 10 equivalents PPh3 in
CD3CN under argon. See the Supporting Information for details.
[11] P. P. Paul, Z. Tyeklar, R. R. Jacobson, K. D. Karlin, J. Am. Chem.
Soc. 1991, 113, 5322 – 5332.
[12] DFT geometries were optimized at the B3LYP level in junction
of the SDD basis set and associated ECP for Cu, 6-311G(d) basis
set for the atoms bond to Cu, and 6-31G basis set for the other
atoms, as implemented in the Gaussian 03 program (see the
Supporting Information). The energies were additionally refined
by single-point calculations using cc-pVTZ basis set for Cu and
the atoms bond to Cu, and cc-pVDZ basis set for the other
atoms. Final free energies given in this work include energies
computed at the B3LYP/cc-pVTZ&cc-pVDZ//B3LYP/SDD&6-
311G(d)&6-31G level of theory together with zero-point ener-
gies, thermal corrections, and entropy calculated at the B3LYP/
SDD&6-311G(d)&6-31G level. The same qualitative results
were also obtained with the BLYP and OPBE methods.
[13] Z. Tyeklꢅr, R. R. Jacobson, N. Wei, N. N. Murthy, J. Zubieta,
K. D. Karlin, J. Am. Chem. Soc. 1993, 115, 2677 – 2689.
Experimental Section
See the Supporting Information for the full experimental details for
the synthesis, spectroscopic, and crystallographic characterization of
1-X (X = CF3SO3, PF6, ClO4) and 2-ClO4, the experimental proce-
dures for the generation, characterization, and reactivity studies of
1-O2 and 2-O2, and the computational details on the DFT calculations.
Received: November 30, 2009
Published online: February 28, 2010
Keywords: bioinorganic chemistry · dioxygen ligands ·
.
À
O O activation · oxidation
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[15] For recent computational studies evaluating CuII2(m-h1:h2-O2)
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C. Nꢆther, C. C. Wꢄrtele, M. C. Holthausen, S. Schindler, F.
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Shiota, K. Yoshizawa, J. Am. Chem. Soc. 2008, 130, 16890 –
16897.
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[16] Because of the energy proximity of the asymmetric CuII2(m-h1:h2-
O2) species (+ 1 kcalmolÀ1), we have also considered its ability
to bind phenolate, and found that upon phenolate coordination
the species also converts into a CuII2(m-h1:h1-O2) core.
[3] a) S. Itoh, H. Kumei, M. Taki, S. Nagatomo, T. Kitagawa, S.
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