Selective benzylic C-C coupling catalyzed by a bioinspired dicopper complex

Article abstract of DOI:10.1039/b718162k

A highly preorganized bioinspired dicopper complex with imidazole ligation catalyzes the selective benzylic para-C-H activation of 2,4,6-trimethylphenol under aerobic conditions, yielding either the stilbenequinone or 4-methoxymethyl-2,6-dimethylphenol depending on the solvent used. The Royal Society of Chemistry.

Full text of DOI:10.1039/b718162k

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Selective benzylic C–C coupling catalyzed by a bioinspired dicopper
complexw
Angelina Prokofieva, Alexander I. Prikhod’ko, Sebastian Dechert and
Franc Meyer*
Received (in Cambridge, UK) 23rd November 2007, Accepted 2nd January 2008
First published as an Advance Article on the web 28th January 2008
DOI: 10.1039/b718162k
A highly preorganized bioinspired dicopper complex with
imidazole ligation catalyzes the selective benzylic para-C–H
activation of 2,4,6-trimethylphenol under aerobic conditions,
yielding either the stilbenequinone or 4-methoxymethyl-2,6-di-
methylphenol depending on the solvent used.
(phenylene)ether (PPE), an important engineering thermo-
plastic.9
Some pyrazolate-based dinuclear copper complexes similar
to 1 are highly active catalysts for this polymerization, with
activities depending on the particular ligand systems em-
ployed.10 In contrast, the bioinspired complex 1, when reacted
with DMP, was found to selectively yield the alternative C–C
coupled product 3,30,5,50-tetramethyl-4,40-diphenoquinone
(DPQ). In order to rationalize that particular selectivity, we
employed the para-alkylated derivative TMP as a potential
substrate. When catalyst 1 is treated with an excess of TMP in
MeCN–CH2Cl2 at ambient conditions, the fully oxidized C–C
coupled product 3,30,5,50-tetramethylstilbene-4,40-quinone
(TMSQ) is obtained as the major product with yields up to
65% after 24 h (Scheme 1). Oxidative coupling at the benzylic
position of alkylated phenols such as TMP is quite delicate
and usually requires a large amount of strong oxidant.11 Few
systems are hitherto known to selectively catalyze that trans-
formation, and mechanistic insight is scarce.12
Biological type 3 dicopper sites are fascinating models for the
synthetic chemist and may serve as blueprints for the devel-
opment of new bioinspired synthetic copper catalysts for
selective oxidation or oxygenation chemistry.1 Prominent ex-
amples of those metalloenzymes are tyrosinase (Tyr) and
catechol oxidase (CO), which mediate the ortho-hydroxylation
of phenolic substrates to catechols (Tyr)2 and the subsequent
oxidation of catechols to ortho-quinones (Tyr and CO).3 In
order to emulate such synergetic metal ion reactivity in a
preorganized bimetallic system, we have recently prepared a
new pyrazole-based ligand with imidazole-containing side
arms that can host two copper ions at a distance of around
4 A (1, Fig. 1).4 Although not strictly analogous to the
biological sites where the proximate copper ions are ligated
by three N-bound histidine residues, 1 was anticipated to
enable cooperative substrate transformations in a bioinspired
approach. Its labile MeOHꢀ ꢀ ꢀOMe bridge allows rapid bind-
ing and activation of substrates within the bimetallic pocket.5
Here we show that 1 catalyzes the selective oxidative functio-
nalization of 2,4,6-trimethylphenol (TMP) at the para methyl
group, in particular the benzylic C–C coupling to give stilbe-
nequinones, and we provide some first mechanistic insights.
TMP derivatives functionalized at the 4-position are im-
portant organic compounds, both for industrial purposes and
fundamental research studies.6 Copper-mediated oxidations of
TMP with dioxygen usually lead to oxygenated products such
as 4-hydroxy-3,5-dimethylbenzaldehyde,7 and just recently a
catalytic version has been reported for this benzylic C–H
activation with a binuclear dicopper species suggested as a
key intermediate.8 Bimetallic mechanisms are also being dis-
cussed for a related copper-catalyzed reaction, the oxidative
C–O coupling of 2,6-dimethylphenol (DMP) to give poly-
Turn over numbers (TON) for the present reaction increase
linearly with TMP concentration (see ESIw), and a 5 : 1 (TMP :
1) ratio has been used for further mechanistic studies. Since the
methanolate bridge in 1 serves as an internal base, no addition
of co-catalyst is required. When left standing in air without
stirring, TMSQ forms as dark red crystals from the reaction
mixture.13 In the presence of methanol, 4-methoxymethyl-2,6-
dimethylphenol (MDP) is obtained as the main product
(Scheme 1).
In order to get a first insight into the mechanism of this
catalytic process, the reaction was followed by means of UV-
Vis, NMR and EPR spectroscopy. The electronic spectrum of
1 in MeCN–CH2Cl2 shows a band at 989 nm (e = 269 L molꢁ1
cmꢁ1) with a shoulder at 724 nm, corresponding to d–d
transitions of CuII ions in a trigonal bipyramidal ligand
environment. Within the first few minutes after addition of
TMP, the reaction mixture becomes red and a relatively
Institut fur Anorganische Chemie, Georg-August-Universitat,
¨
¨
Tammannstrasse 4, D-37077 Gottingen, Germany. E-mail:
¨
franc.meyer@chemie.uni-goettingen.de; Fax: (+49)-551-393063;
Tel: (+49)-551-393012
w Electronic supplementary information (ESI) available: Experimental
section including EPR studies. Crystal data for 20. See DOI: 10.1039/
b718162k
Fig. 1 Schematic representation of catalyst 1.
Chem. Commun., 2008, 1005–1007 | 1005
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Scheme 1 Oxidative C–C coupling of TMP and 1,6-nucleophilic
addition of MeOH catalyzed by 1.
Scheme 2 Key intermediate 2 and initial benzylic C–C coupling of
TMP to give TMBB and the mixed-valent CuICuII intermediate 3.
intense band appears at lmax = 495 nm (e E 1500 L molꢁ1
cmꢁ1), while the ligand field band shifts to 960 nm (Fig. 2).
These spectral changes are attributed to coordination of TMP
within the bimetallic pocket of 1 to give the key intermediate
2 (Scheme 2).
Assignment of the red color to a phenolate - CuII LMCT
transition is corroborated by the trend in lmax for differently
substituted phenols: adducts between 1 and the less electron
rich substrates DMP and 4-tert-butylphenol give rise to
(d (O1ꢀ ꢀ ꢀO2) = 2.583(6) A). The exchange of methanolate
in 1 for a PFP anion in 20 causes only slight changes in the
coordination spheres of the five-coordinate Cu ions (tCu =
0.80/0.73 in 20 versus 0.88 in 14), but the PFP adduct appears
to be stabilized by p–p stacking between the C6F5-ring and one
imidazole unit of the ligand side arms (interplane distance
3.88 A, angle 4.51, with the imidazole ring containing N11
and N12).
Formation of TMSQ from the solution of the red inter-
mediate 2 begins after a relatively long initiation period (1.5 h),
at which point the absorption band of the product occurs at
440 nm (e E 96 000 L molꢁ1 cmꢁ1). When the reaction of 1
and TMP is performed under anaerobic conditions in a glove
box, the initially observed intense LMCT band again gradu-
ally disappears within several hours to give a yellow-green
solution. Only traces (less than 0.1%) of TMSQ are observed
under these conditions (Fig. 2, spectrum (c)). Work-up of the
reaction mixture reveals that the C–C coupled but non-oxi-
dized 4,40-dihydroxy-3,30,5,50-tetramethylbibenzyl (TMBB) is
formed as the sole product (Scheme 2; see ESI for complete
characterizationw). Formation of TMBB represents a 1eꢁ
oxidation per TMP substrate. Since the yield of TMBB formed
under anaerobic conditions is consistent with a stoichiometric
1 : 1 reaction between 1 and TMP, the dicopper complex 1
should thereby be semi-reduced to its mixed-valent CuICuII
state (3). This is consistent with the decrease in intensity of the
CuII d–d transition upon formation of TMBB (Fig. 2, spectra
(a) and (c)). Further evidence comes from X-band EPR
LMCT bands that are shifted hypsochromically with lmax
=
472 nm and 455 nm, respectively. The assignment is further
confirmed by Raman spectroscopy, which has proven parti-
cularly useful for elucidating the structural and electronic
properties of copper-phenolate complexes.14,15 Excitation into
the LMCT band of 2 results in a spectrum that is very similar
to those of other CuII-phenolate systems (Fig. 3), with char-
acteristic resonance-enhanced modes at, inter alia, 1237 cmꢁ1
(n7a, C–O stretching) and 1607 cmꢁ1 (n8a, Cortho–Cmeta ring
stretching).15
Structural information about the proposed key intermediate
2 comes from the crystallographic characterization of a model
complex 20 that was obtained from the reaction of 1 with
pentafluorophenol (PFP)—a phenol that is not prone to
oxidation (Fig. 4).z As anticipated, the PFP anion is bound
to only one of the two CuII ions (Cu1) and forms a strong
intramolecular H-bond to the MeOH molecule that is coordi-
nated to the adjacent Cu2 within the bimetallic pocket
Fig. 2 UV-Vis spectra of the reaction mixture (initial concentrations
of 1: 0.005 mol Lꢁ1; TMP: 0.025 mol Lꢁ1; solvent: MeCN–CH2Cl2
4 : 6 v/v): (a) solution of 1; (b) few minutes after addition of TMP (red
solution of 2); (c) 48 h after addition of TMP under anaerobic
conditions (yellow-green solution; the asterisk denotes traces of
TMSQ; see text for explanation).
Fig. 3 Resonance Raman spectrum of the red solution of key
intermediate 2 in MeCN (RT, lex = 488 nm, solvent signals are
subtracted).
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(possibly short-lived) CuI-phenoxide radical species in the key
step, spectroscopic data support a CuII-phenolate ground state
description for the red intermediate 2. While mechanistically
distinct from the type 3 dicopper sites (which shuttle between
the CuIICuII and CuICuI states without involvement of 1eꢁ
radical chemistry), some new cooperative two-centre reactivity
has resulted from the present bioinspired approach. Cu-
mediated formation of MDP from TMP in the presence of
methanol has previously been suggested to proceed via 1,6-
nucleophilic addition of methanol to a quinone methide
intermediate,8 which would require an initial 2eꢁ transfer that
is not observed here. Further studies are now directed at
elucidating details of the electronic structure of 2, the activa-
tion of dioxygen by the mixed-valent species 3 with the
possible generation and involvement of superoxide, and finally
a full mechanistic understanding of the various reaction steps.
Fig. 4 ORTEP plot (30% probability thermal ellipsoids) of the
structure of 20. For the sake of clarity all hydrogen atoms except H2
have been omitted. Cu1ꢀ ꢀ ꢀCu2 4.309(1) A; see ESIw for other atom
distances and angles.
Notes and references
z Crystal data for 20 are given in the ESIw.
CCDC 659295. For crystallographic data in CIF format see DOI:
10.1039/b718162k
spectroscopy (see ESIw): 1 is EPR silent at 15 K but at 50 K
shows a broad absorption around 3000 G with a weak half-
field signal, characteristic of an exchange-coupled antiferro-
magnetic dicopper(II) system (J = ꢁ35.3 cmꢁ1 was derived
from SQUID data4). In contrast, the spectrum of the frozen
yellow-green solution containing 3 recorded at 15 K shows a
typical axial EPR spectrum for a single CuII, suggesting that 3
is a valence-localized CuICuII species on the EPR time scale.
Furthermore, spectral parameters for 3 are very similar to
those of a CuICuII compound prepared independently from
the pyrazolate/imidazole-based ligand and each one equivalent
of a CuI and CuII salt (gII = 2.25, g> = 2.06, |AII| = 157 G,
|A>| = 20 G).
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Obviously, molecular oxygen is not involved in the initial
C–C coupling, but only in subsequent re-oxidation of the semi-
reduced dicopper complex and transformation of TMBB to
the final product TMSQ. Control experiments show that
TMBB itself is not oxidized to TMSQ in air, but it is rapidly
oxidized upon exposure to air in the presence of catalyst 1.
In conclusion, a highly preorganized dicopper complex has
allowed the development of a new catalytic procedure for the
para C–H activation of TMP with aerial dioxygen as the
oxidant. Selective formation of either TMSQ or MDP is
achieved depending on the solvent used. The reaction proceeds
through initial coordination of TMP to the dicopper site,
followed by benzylic C–C coupling that leads to TMBB as
the first product. The resulting semi-reduced CuICuII species is
then re-oxidized by dioxygen to revive catalyst 1. A model
complex for the first key intermediate, featuring a coordinated
and strongly hydrogen-bonded phenolate within the bimetallic
pocket, has been isolated and structurally characterized.
Whereas the benzylic C–C coupling of TMP to give TMBB
may suggest a radical-based process and involvement of a
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