Oxidative ortho C-C coupling of 4-ethylphenol by dual substrate activation at a bioinspired dicopper complex - Trapping of an unusual oligophenolic Cu 6 species

Article abstract of DOI:10.1002/chem.200900424

A study was conducted to demonstrate oxidative ortho C-C coupling of 4-ethylphenol (HOPh^Et-4) by dual substrate activation at a bioinspired dicopper complex trapping of an oligophenolic Cu₆ Species. It was demonstrated that the HOPh<

Full text of DOI:10.1002/chem.200900424

DOI: 10.1002/chem.200900424
ꢀ
Oxidative ortho C C Coupling of 4-Ethylphenol by Dual Substrate
Activation at a Bioinspired Dicopper Complex—Trapping of an Unusual
Oligophenolic Cu6 Species
Angelina Prokofieva,[a, b] Sebastian Dechert,[a] Christian Große,[a]
George M. Sheldrick,[a] and Franc Meyer*[a]
Oxidative phenol coupling is a valuable transformation
and is of great importance in the synthesis of natural prod-
ucts or polymeric materials for resin and coating technolo-
gies.[1] Inter alia, oligomeric compounds derived from para-
cresol were shown to have interesting antioxidant effects
and antimicrobial properties.[2] These properties are strongly
dependent on the presence of hydroxyl groups in the skele-
ton of the oligomeric or polymeric phenolic products, and
catalysts that selectively mediate the ortho–ortho coupling
of para-substituted phenols are thus required. Enzymatic
phenol dehydropolymerization mostly relies on oxidoreduc-
tases that contain iron or copper within their active sites.[3]
Even though our mechanistic understanding of the reactivity
patterns of biological copper-containing oxidases is increas-
ing rapidly, successful application of this knowledge to the
development of bioinspired synthetic oxidase systems is still
in its infancy.[4,5] Chemically the oxidative ortho-coupling
leading to the formation of aryl–aryl bonds is usually ach-
ieved with strong oxidants such as FeCl3 or hypervalent
iodine reagents. Many stoichiometric or catalytic methods
have meanwhile been developed that work well for sterical-
ly hindered phenols or 2-naphthol derivatives.[6] Simple phe-
nols such as para-cresol, however, are usually poor sub-
strates because of a lack of regioselectivity, giving not only
the desired ortho–ortho linkages but also polycyclic by-prod-
ucts that result from ortho–para coupling with subsequent
1,4-addition (Pummererꢀs ketone).[7] Template-directed ap-
proaches using tetraphenoxyborates in electrochemical pro-
cesses have recently been developed to overcome these
problems.[8] In a conceptually related approach, major prog-
ress towards the enantioselective coupling of 2-naphthol has
been achieved with bimetallic systems that use a dual activa-
tion mechanism at dicopper or divanadium complexes.[9,10]
Highly preorganized bimetallic systems that can simultane-
ously bind and activate two phenol substrates in a way that
favors the desired ortho–ortho coupling appear to be prom-
ising scaffolds in this respect.
We have recently reported that a pyrazolate-based bioin-
spired dicopper(II) complex (1H)[11] binds 2,4,6-trimethylphe-
nol (TMP) within its bimetallic pocket and catalyzes the se-
ꢀ
lective benzylic para-C H activation of this ortho-substitut-
ed substrate under aerobic conditions, producing stilbene-
quinone.[12] Using the related complex 1Ph (Figure 1)[11] we
now found that the ortho-unsubstituted substrate 4-ethyl-
phenol (HOPhEt-4) preferentially undergoes C C coupling in
ꢀ
the ortho-positions to yield the respective 2,2’-biphenol 22
[a] Dr. A. Prokofieva, S. Dechert, Dipl.-Chem. C. Große,
Prof. Dr. G. M. Sheldrick, Prof. Dr. F. Meyer
Institut fꢁr Anorganische Chemie, Georg-August Universitꢂt
Tammannstrasse 4, 37073 Gçttingen (Germany)
Fax : (+49)551-393063
E-mail: franc.meyer@chemie.uni-goettingen.de
[b] Dr. A. Prokofieva
New address: CAT Catalytic Center, ITMC
RWTH-Aachen Worringerweg 1, 52074 Aachen (Germany)
Figure 1. ORTEP plot (30% probability thermal ellipsoids) of the molec-
ular structure of the dication 1Ph (see the Supporting Information for de-
tails).[11] Nitrate anions are not shown.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900424.
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Chem. Eur. J. 2009, 15, 4994 – 4997

COMMUNICATION
and minor amounts of the corresponding 2,2’,6’,2’’-terphenol
23 (Scheme 1).
now at 783 nm). This suggests that upon addition of base
the binding equilibrium shifts towards the coordination of
two anionic phenolates within the bimetallic pocket. The
UV/Vis spectrum then gradually changes and the intensity
of the copper(II) d–d band decreases when this solution is
stored under ambient conditions (Figure 2, spectrum d),
Addition of the substrate HOPhEt-4 to a solution of 1Ph (as
the perchlorate salt) in MeCN results in drastic color
ꢀ
which reflects the progress of the C C coupling reaction.
Raman spectroscopy (488 nm excitation) was applied to
probe the electronic structures of the copper/substrate spe-
cies (Figure 3). The reaction mixture of 1Ph and HOPhEt-4
Et-4
Scheme 1. Oxidative ortho C C coupling of HOPh mediated by 1Ph
.
ꢀ
changes and the appearance of an intense absorption at
458 nm, assigned to a phenolate ! copper(II) CT transition
(Figure 2, spectrum b). No significant shift of the copper(II)
Figure 3. Raman spectrum of the reaction mixture (1Ph and HOPhEt-4
after addition of one equivalent of KOtBu) in MeCN; lex =488 nm; s de-
notes solvent peak.
shows features characteristic for a phenolate coordinated to
ꢀ
ꢀ
copper(II), with bands at 1167 (C H bending), 1253 (C O
[13]
stretching), 1501, and 1603 cmꢀ1 (C C stretching). These
ꢀ
bands remain unchanged upon addition of base, confirming
that the ground state of the active species is best described
as a copper(II) bis(phenolate) complex.
Low-temperature EPR spectra of frozen solutions of
either 1Ph or the reaction mixture containing 1Ph and
HOPhEt-4 show weak signals characteristic for exchange-cou-
pled systems with an S=0 ground state. When one equiva-
lent of KOtBu was added and the reaction mixture kept
under anaerobic conditions, a more intense axial spectrum
developed, suggesting the formation of a mixed-valent
CuICuII species (presumably valence-localized on the EPR
time scale; see the Supporting Information). Formation of
some 2,2’-biphenol 22 under these conditions could be con-
firmed by GC-MS.
Figure 2. UV/Vis spectra of the reaction mixture in MeCN: a) solution of
1
addition of one equivalent of KOtBu to the solution (b); d) after storing
the reaction mixture with one equivalent of KOtBu for 24 h.
Ph; b) a few seconds after addition of HOPhEt-4; c) a few seconds after
d–d band at 983 nm is observed, suggesting simple replace-
ment of MeOH by the phenolic substrate within the bimet-
allic pocket. The spectrum remains unchanged for several
hours, indicating that this copper(II)–phenolate species is
1
unreactive. H NMR analysis of the reaction mixture after
24 h and after passing the solution over a silica column (to
separate off all copper species) revealed the starting phenol
HOPhEt-4 as the only organic material, while GC-MS analy-
sis shows the presence of trace amounts of 22. Addition of
one equivalent of base (KOtBu) to the reaction mixture of
1Ph and HOPhEt-4 leads to a significant shift of the LMCT
band to lower energy, with a new maximum at 483 nm, con-
current with an increase in the intensity of this band
(Figure 2, spectrum c). The copper(II) d–d transition hardly
changes in intensity, but shifts to higher energy (maximum
Slow diffusion of Et2O into a reaction mixture containing
1Ph, HOPhEt-4, and one equivalent of KOtBu under aerobic
conditions led to formation of black crystals of a new com-
plex 3. Its high-resolution (HR) ESI mass spectrum suggest-
ed that 3 is composed of two pyrazolate-derived ligand scaf-
folds, six copper ions, and two molecules of the deprotonat-
ed terphenol 23 (calcd for the doubly charged cation
A
(ClO4)ꢀ]2+: 1224.22790 m/z; found: 1224.23 m/z; see
ACHTUNGTRENNUNG
the Supporting Information). The structure of 3 was eluci-
dated by single-crystal X-ray diffractometry. The moderate
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F. Meyer et al.
quality of the structure determination (due to the presence
of disordered solvent molecules for which no satisfactory
model for the disorder could be found) does not allow any
detailed discussion of individual bond parameters, but clear-
ly reveals the topology and constitution of this unique com-
plex.[14] Its central Cu6O6 core is shown in Figure 4, and a
schematic drawing of the overall structure of the cation of 3
is given in Figure 5.
bridging towards the central Cu1); and iii) the resulting 2,2’-
biphenols and 2,2’,6’,2’’-terphenols are good chelate ligands,
and extraction of the metal ions from the original copper
complex (leading to catalyst deactivation) has to be consid-
ered when new catalysts for oxidative phenol coupling are
developed.
ESI mass spectrometry (vide supra) confirms that the
hexaACTHUNRTGNEUNGcopper complex 3 is also present in solution. Its UV/Vis
spectrum in the solid state (diffuse reflectance) shows three
bands at lmax 1039, 633, and 427 nm, which are in good
agreement with the different coordination spheres of the
copper ions found in the crystal structure (d–d band at
1039 nm for copper ions in trigonal-bipyramidal environ-
ment (Cu2), d–d band at 633 nm typical for copper(II) in
square-planar coordination (Cu1)). The band at 427 nm is
assigned to the phenolate ! copper(II) CT transition.[15]
The UV/Vis spectrum of a solution of 3 in MeCN shows d–d
bands at 972 and 732 nm, indicating that both types of cop-
per(II) ions are still present, but that the complex undergoes
some structural changes upon dissolution.
The combined spectroscopic and structural findings sug-
gest to assume that the ortho–ortho coupling occurs via a
LMCT excited copper(I) phenoxide state when two of the
phenolic substrate molecules are bound in close proximity
within the bimetallic pocket of the LPhCu2 scaffold derived
from 1Ph (Figure 6). In this constrained environment with
Figure 4. Molecular structure of the central Cu6O6 core of complex 3;
part of the aromatic rings and backbones of the capping ligands are omit-
ted for clarity.
Figure 5. Schematic representation of the hexanuclear complex 3.
Figure 6. Possible intermediate A for the ortho–ortho coupling reaction
from an LMCT excited state (left) and side products 2CO and 2CC (right).
The hexanuclear complex 3 consists of a dicopper core
that is spanned by two terphenolato ligands (derived from
23) and is capped by two LPhCu2 entities. The two central
copper(II) ions (Cu1) are found in distorted square-planar
{O4} environment, whereas the four outer metal ions (Cu2)
are still hosted in the tetradentate ligand compartments of
LPh and are five-coordinate, with O atoms from the terphe-
nolato units completing the {N4O} coordination spheres.
Apart from its unprecedented structure, 3 is of interest for
several reasons because of its isolation directly from the re-
action mixture: i) it confirms that ortho–ortho coupling of
the substrate HOPhEt-4 is mediated by 1Ph in the presence of
base, likely via coordination of the phenolate substrate to
the LPhCu2 platform; ii) inspection of the capping units lends
support for our conclusions from the spectroscopic findings,
namely that two anionic phenolates can be bound to the two
copper ions of the LPhCu2 scaffold within the bimetallic
pocket (in 3 the phenolates after ortho–ortho coupling are
dual activation of the two substrates, ortho–ortho coupling is
the favored reaction path. However, GC-MS analysis of the
reaction mixture from which the hexacopper complex 3 was
isolated revealed that two further isomers of 22 with the
same mass (m/z 242) are formed as side products, presuma-
co
bly the common ortho C O dimer 2 and the tricyclic 2cc (a
ꢀ
structural analogue of Pummererꢀs ketone) that results from
ꢀ
ortho–para C C coupling with subsequent 1,4-addition. Ter-
phenol 23 (m/z 362) found in 3 is detected only in traces in
the reaction mixture, while higher oligomers are not ob-
served.
In conclusion, preferred ortho–ortho coupling of a simple
phenolic substrate has been achieved via a dual activation
mechanism in which both substrates are bound within the
bimetallic binding pocket of a highly preorganized dicop-
per(II) complex featuring bioinspired imidazole-N ligation.
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Oligophenolic Cu6 Species
COMMUNICATION
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Acknowledgements
This work was supported by the DFG (International Research Training
Group GRK 1422 “Metal Sites in Biomolecules: Structures, Regulation
and Mechanisms”; see www.biometals.eu) and the Fonds der Chemischen
Industrie. A.P. is grateful to the Daimler Benz-Foundation for a PhD fel-
lowship.
[11] 1H and 1Ph only differ by the backbone substituent at the pyrazolate-
C4: H for 1H (ligand LH) and Ph for 1Ph (ligand LPh). The structure
of 1a has been described in: A. Prokofieva, A. I. Prikhod’ko, E. A.
Enyedy, E. Farkas, W. Maringgele, S. Demeshko, S. Dechert, F.
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of 1Ph, of the new pyrazolate ligand LPh, and of the X-ray crystallo-
graphic structure determination of 1Ph are provided in the Support-
ing Information.
Keywords: bioinspired catalysis
·
copper
·
dinuclear
complexes · phenol coupling · pyrazole ligands
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Received: February 16, 2009
Published online: April 2, 2009
Chem. Eur. J. 2009, 15, 4994 – 4997
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www.chemeurj.org
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