Catalytic aerobic oxidation of phenols to ortho-quinones with air-stable copper precatalysts

Article abstract of DOI:10.1039/c5dt00822k

A range of air-stable copper species was examined for catalytic activity in the catalytic aerobic transformation of phenols into ortho-quinones. Efficient catalysis was obtained with commercially available copper(ii) acetate. The stability of all constitu

Full text of DOI:10.1039/c5dt00822k

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Catalytic aerobic oxidation of phenols to ortho-
quinones with air-stable copper precatalysts†
Cite this: DOI: 10.1039/c5dt00822k
M. S. Askari,a L. A. Rodríguez-Solano,a A. Proppe,a B. McAllister,a J.-P. Lumbb and
Received 26th February 2015,
Accepted 13th March 2015
X. Ottenwaelder*a
DOI: 10.1039/c5dt00822k
www.rsc.org/dalton
A range of air-stable copper species was examined for catalytic
activity in the catalytic aerobic transformation of phenols into
ortho-quinones. Efficient catalysis was obtained with commercially
available copper(II) acetate. The stability of all constituents before
mixing makes for a practical process that advances previously
reported copper(I)-based oxygenations.
Due to their ability to activate oxygen (O2), CuI complexes are
involved in a vast array of aerobic oxidations.1 In particular,
the Cu-catalyzed oxygenation of phenols into ortho-quinones
has been extensively investigated because it is prevalent in bio-
synthesis and because it converts a readily available feedstock
into a versatile, synthetically useful electrophile.2 The quintes-
sential example of such a reaction is the conversion of L-tyro-
sine into L-dopaquinone by the type-III Cu monooxygenase
tyrosinase in the first step of melanin biosynthesis
(Scheme 1a).3 The resting (met) state of tyrosinase is a hydro-
xido CuII2 dimer that requires reduction to the O2-reactive CuI2
(deoxy) state for phenol oxygenation to occur.3 While replicat-
ing a tyrosinase-like oxygenation is synthetically desirable, the
reactivity between CuI, O2 and phenols outside a protein active
site is plagued by competitive radical pathways that erode
selectivity for ortho-oxygenation.1 Progress has been made
towards bio-inspired metal complexes that can emulate the
reaction of tyrosinase,4 although most reactions employ stoi-
chiometric amounts of a Cu complex5,6 or feature catalytic
cycles that have poor turn-over, yield, or unfavourable reaction
conditions.7 Consistent throughout these studies has been the
use of Cu in the +1 oxidation state together with non- or
weakly coordinating anions,8 which are thought to be require-
ments for selective O2 activation and ortho-oxygenation.
Scheme 1 (a) Mechanism of tyrosinase. The side chains of tyrosine
(phenol), L-dopa (catechol) and dopaquinone (o-quinone) are omitted
for clarity. (1): Monophenolase activity, (2,3) diphenolase activity. Reac-
tion (3) also represents an activation pathway from the met to the deoxy
form. (b) Conversion of 4-tert-butylphenol 1 into o-quinone 2 under
Lumb’s conditions.9 CuPF6 is [CuI(CH3CN)4](PF6).
quinones that is catalytic in all reaction components
(Scheme 1b).9 Typical conditions involve stirring a solution of
phenol for 4 hours under 2 atm O2 in the presence of 4 mol%
of [CuI(CH3CN)4](PF6) and 5 mol% of N,N′-di-tert-butylethy-
lenediamine (DBED). Under these conditions, DBED is thought
to play the role of ligand to CuI, which promotes selective O2
activation as a peroxo Cu dimer6 similar to that in oxy-tyrosi-
nase, as well as a base to generate a phenolate in situ.10 The
present work extends these conditions to a more practical and
air-stable CuII precatalyst. We reveal that catalytic ortho-oxygen-
ation is possible from a range of Cu species, including those
with oxidation states and coordinating counteranions that are
not traditionally employed in biomimetic studies.
Recently, the Lumb group reported an efficient method for
the aerobic conversion of phenols into functionalized ortho-
aDepartment of Chemistry and Biochemistry, Concordia University, Montreal,
QC H4B 1R6, Canada. E-mail: dr.x@concordia.ca
bDepartment of Chemistry, McGill University, Montreal, QC H3A 0B8, Canada
†Electronic supplementary information (ESI) available: Synthetic details, solvent
screen, UV-vis experiments. CCDC 1051251 and 1051252. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c5dt00822k
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Table 1 Screening of Cu precatalystsa
As a point of departure, we investigated the fate of Cu
during the standard reaction of 4-tert-butylphenol 1, which is
converted into coupled ortho-quinone 2 in the presence of O2,
[CuI(CH3CN)4](PF6) and DBED. Recovered Cu at the end of this
reaction is in the form of the well-known [(DBED)CuII-
(µ-OH)2CuII(DBED)](PF6)2 complex, 3, as confirmed by IR spec-
troscopy and crystallization.† This air-stable product, which
can be independently prepared by exposing a 1 : 1 mixture
of DBED:[CuI(CH3CN)4](PF6) to air or O2,11 is reminiscent of
the CuII dimer in met-tyrosinase. We were thus drawn by
the prospect that 3 could re-enter the catalytic cycle in a
manner that resembles the activation of met-tyrosinase, which
must be reduced from CuII to CuI prior to ortho-oxygenation
(Scheme 1a). Thus, using a 2.5 mol% of 3 (i.e. 5 mol% Cu) and
an additional 5 mol% DBED (10 mol% total), phenol 1 is con-
verted into 2 in 67% yield after 4 hours. This result is surpris-
ing since, to our knowledge, it represents the first example of
a synthetic CuII pre-catalyst that functions in an ortho-
oxygenation.
Conversion (%) [yield(s) (%)]b
Entry Cu species
Time No MSc
+ MSc
CuI species
1
2
3
4
5
6
7
8
9
[CuI(CH3CN)4](PF6)
[CuI(CH3CN)4](TfO)
4 h
4 h
100 [89, 11]d
100 [76, 7]d
100 [92]
25 [10]
100 [95, 5]d
100 [86, 7]d
[CuI(CH3CN)3.5](MsO) 4 h
—
17 [7]
—
—
—
CuI(AcO)
CuICl
4 h
4 h
4 h
4 h
4 h
3 d
94 [58]
CuIBr
CuII
[<30]e
[<10]e
CuICN
CuI2O
60 [33]
96 [74]
43 [28]
—
Cu0 species
10
Cu0, wire
3 d
22 [22]
97 [88]
—
—
11
Cu0, activated powder 3 d
CuII species
12
[(DBED)CuII(µ-OH)2-
4 h
97 [67]
100 [93]
CuII(DBED)](PF6)2, 3f
CuII(AcO)2·H2O
13
14
15
16
17
18
19
20
21
22
23
24
25
4 h
4 h
8 h
98 [97]
94 [75]
98 [85]
98 [85]
100 [91]
43 [8]
89 [89]
92 [84]
—
92 [72]
—
CuII(AcO)2·MeCN
CuII(AcO)2·MeCN
Although 3 is not an ideal precatalyst due to its poor solubi-
lity and the necessity to synthesize it from a reactive CuI pre-
cursor, this result demonstrates that phenol o-oxygenations
can be carried out by air-stable CuII precatalysts. This
prompted us to investigate additional Cu salts with a range of
oxidation states and counteranions using the 1 → 2 model
reaction (Table 1). Several reactions were also tested in the
presence of molecular sieves, as the inclusion of a desiccant
was shown to improve conversion and yield.9,12 In most cases,
however, the effect of the molecular sieves was minimal.
Among the CuI species that were probed (Table 1, entries
[CuII(DBED)(AcO)2], 4f 4 h
CuII(HCO2)2·4H2O
CuII(TfO)2
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
3 d
—
CuII(TfO)2·4H2O
CuII(BF4)2·6H2O
CuII(acac)2
100 [84, 3]d
7 [4]
100 [86, 3]d
12 [12]
2 [2]
—
13 [7]
CuIICl2·2H2O
CuIIBr2
77 [54]
e
—
CuII(SO4)·5H2O
CuIIO
10 [1]
0
—
—
a Conditions: 0.666 mmol 1, 5% Cu, 10% DBED, 6 mL CH2Cl2 (0.1 M),
2 atm O2, 25 °C. Work-up: 10% NaHSO4(aq.) and extraction with
CH2Cl2. b NMR conversion of 1 and yield of 2 calculated by NMR using
hexamethylbenzene as internal standard. c MS = 4 Å molecular sieves;
200 mg per mmol of 1 when used. d The first value is the yield of 2, the
second is the yield of 4-tert-butyl-o-quinone. e Reaction is not clean,
noninterpretable NMR spectrum. f Only 5% extra DBED was added to
adjust [DBED]total to 10% of [1].
−
1–9), those with weakly coordinating anions such as PF6 or
sulfonates displayed varying levels of catalytic activity whereas
insoluble species (entries 4–9) were generally poor at initiating
the reaction. Exceptions are CuICl, CuICN and CuI2O, but
these precatalysts lead to low selectivity. Interestingly, insolu-
ble CuI2O required an induction period of days during which
no reaction was observed. Similarly, metallic Cu0 (entries 10
and 11) is catalytically competent after an induction period of
3–4 days, at which point catalysis begins and complete conver-
sion is reached within a few hours. This induction pheno-
menon with Cu0 or CuI2O suggests that turnover requires a
soluble catalyst (likely a CuI species) formed by slow self-
assembly under reaction conditions.
coordinating ability/basicity of the counteranion is not a deci-
sive factor.
The reactivity of CuII(OAc)2·H2O as
a precatalyst was
explored in several solvents that ranged in polarity, hydrogen-
bonding capability and miscibility with water (Table S2†).
Acetonitrile was found to promote the conversion of 1 to 2 in
good yields, but the insolubility of 2 in this solvent led us to
choose CH2Cl2 as the optimal solvent. While CuII(OAc)2·H2O is
itself insoluble in CH2Cl2, addition of DBED creates a clear
blue solution within a few minutes, i.e. the active Cu species is
in the same phase as the substrate for efficient initiation of
catalysis. The soluble species is the discrete, neutral
[CuII(DBED)(AcO)2] complex, 4, which is also an efficient pre-
catalyst when preformed outside the reaction mixture (Table 1,
entry 16). The crystal structure of 4 (Fig. 1) shows a distorted
tetrahedral structure about the CuII ion. The 49° angle
between the CuN2 and CuO2 planes likely results from the
large steric demands of the tert-butyl substituents, as is the
case in 3† and other DBED–CuII complexes.10,11,13
A survey of CuII species (entries 12–25) revealed that com-
mercially available Cu(OAc)2·H2O is one of the most efficient
precatalysts. Other carboxylates or hydrated sulfonates are
also efficient, whereas non-hydrated CuII(TfO)2 or CuII(acac)2
are very poor at catalyzing the reaction. The discrepancy
between CuII(TfO)2·4H2O (84% yield) and CuII(TfO)2 (8% yield)
is unexpected given the fact that water is a reaction by-product
and is detrimental to the yield at long reaction times.9 Poor
catalysis is obtained with insoluble Cu salts such as
CuII(BF4)2·6H2O or CuII(SO4)·5H2O, while the completely inso-
luble CuIIO is inefficient even after several days. From the
results included in Table 1, we conclude that good solubility of
the Cu precursor leads to more efficient catalysis and that the
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Fig. 1 ORTEP representation at 50% ellipsoid probability of 4 at 293 K.
Hydrogen atoms removed for clarity, except on N atoms. i: 1 − x, y, 1/2 −
z. Selected bond lengths and angles: Cu1–O1 = 1.9272 Å, Cu1–N1 =
2.0281 Å. O1–Cu1–O1 = 87.19°, O1–Cu1–N1 = 146.61°, N1–Cu1–N1 =
87.18°.
The conversion of 1 into 2 was monitored by UV-vis spec-
troscopy to probe for reaction intermediates. With CuII(OAc)2·
H2O, the spectra evolved from the initial light burgundy
color of the CuII-1-DBED mixture to the orange color of 2
without detectable intermediacy of strongly colored species
Scheme 2 Yields of coupled ortho-quinone for various substrates.
Conditions: 1 mmol phenol, 5% CuII(OAc)2·H2O, 10% DBED, 10 mL
CH2Cl2 (0.1 M), 2 atm O2, 4 h, 25 °C. Work-up: 10% NaHSO4(aq.) or
0.1 M HCl and extraction with CH2Cl2. NMR yields calculated using
(Fig. S2†). In contrast, CuII(TfO)2·4H2O led to the observation hexamethylbenzene as internal standard. a Noninterpretable NMR spec-
of ca. 80% (with respect to [Cu]) of CuII-semiquinone complex
trum. Reaction carried out with 200 mg of 4 Å molecular sieves (<5%
yield without molecular sieves). b Ar = 2-phenylphenyl.
5 (Fig. 2), which is the same intermediate as in the reaction
mediated by [CuI(CH3CN)4](PF6).10 This suggests that the CuII-
promoted reaction enters the same catalytic cycle as the CuI-
hydrogen atoms (12–13), presumably due to the ease with
which the corresponding ortho-quinones undergo tautomeriza-
promoted reaction, at least with non-coordinating counter-
anions. While more work is warranted to probe the conversion
of the air-stable CuII precatalyst into an O2-reactive CuI catalyst,
tion. The reaction does not proceed for phenols possessing
strongly electron-withdrawing substituents (14, 0% conver-
sion). Electron-rich phenols and 2-naphthol produce intract-
several hypotheses can be proposed based on literature pre-
cedent. These include disproportionation of a CuII–phenolate
into CuII–phenoxyl and CuI,14 or in situ reduction of CuII by
able mixtures of products (8, 9, 17), in stark contrast to their
CuI-mediated reactions. Based on the substantially lower oxi-
catechol impurities in the starting phenol,‡ which is akin to
dation potentials of these substrates compared with 1,15 we
the accepted activation of met-tyrosinase (Scheme 1a).
The catalytic efficiency of the DBED:CuII(OAc)2·H2O system
attribute this discrepancy to the ease of outer-sphere oxi-
dations of these phenols into phenoxyl radicals by CuII at the
with various substrates (Scheme 2) is generally comparable to
that of CuI,9 and displays similar limitations. Thus, low yields
outset of the reaction.
are consistently observed for phenols that possess benzylic
Conclusions
In summary, catalytic aerobic ortho-oxygenation of phenols is
possible from a range of Cu precatalysts possessing 0, +1 or +2
oxidation states, as well as coordinating and non-coordinating
counteranions. Solubility of the Cu precatalyst is essential for
good reaction performance, as illustrated with the in situ for-
mation of the neutral [DBEDCuII(OAc)2] complex. This species
provides an attractive starting point for additional reaction
optimization and to probe the mechanism of CuII reduction
under the reaction conditions.
Acknowledgements
Fig. 2 In situ UV-visible monitoring of the reaction of 1 (50 mM) with
5% CuII(OTf)2·4H2O and 10% DBED, CH2Cl2 under 1.1 atm O2 during the
The authors belong to the CCVC-CGCC (Centre for Green
Chemistry and Catalysis, Québec). We thank Andrew Dalton
first 220 s. Complete spectra in Fig. S3.† Final yield of 2 was 98%.
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(Concordia) and Laurène Petitjean (McGill) for experimental
help. Funding was provided by a team grant from FRQNT
(Fonds de Recherche du Québec – Nature et Technologies) and
individual Discovery grants from NSERC (Natural Sciences and
Engineering Council of Canada) (XO and JPL). We are grateful
to NSERC for graduate scholarships (MSA) and USRAs (AP,
BMA). We acknowledge the CCVC-CGCC for awards (MSA, AP)
and the Canadian Inorganic Chemistry Exchange program
(BMA).
L. Santagostini and R. Ugo, Inorg. Chem., 1996, 35, 7516–
7525; E. Monzani, L. Quinti, A. Perotti, L. Casella,
M. Gullotti, L. Randaccio, S. Geremia, G. Nardin,
P. Faleschini and G. Tabbì, Inorg. Chem., 1998, 37, 553–562;
Y.-T. Cheng, H.-L. Chen, S.-Y. Tsai, C.-C. Su, H.-S. Tsang,
T.-S. Kuo, Y.-C. Tsai, F.-L. Liao and S.-L. Wang, Eur. J. Inorg.
Chem., 2004, 2004, 2180–2188.
6 L. M. Mirica, D. J. Rudd, M. A. Vance, E. I. Solomon,
K. O. Hodgson, B. Hedman and T. D. P. Stack, J. Am. Chem.
Soc., 2006, 128, 2654–2665; L. M. Mirica, M. Vance,
D. J. Rudd, B. Hedman, K. O. Hodgson, E. I. Solomon and
T. D. P. Stack, Science, 2005, 308, 1890–1892; B. T. Op’t
Holt, M. A. Vance, L. M. Mirica, D. E. Heppner,
T. D. P. Stack and E. I. Solomon, J. Am. Chem. Soc., 2009,
131, 6421–6438.
Notes and references
‡To the levels of detection of NMR and ESI-MS, we were unable to observe cate-
chol as a contaminant in the phenol starting material.
7 M. Réglier, C. Jorand and B. Waegell, J. Chem. Soc., Chem.
Commun., 1990, 1752–1755; L. Casella, M. Gullotti,
R. Radaelli and P. Di Gennaro, J. Chem. Soc., Chem.
Commun., 1991, 1611–1612; M. Rolff, J. Schottenheim,
G. Peters and F. Tuczek, Angew. Chem., Int. Ed., 2010, 49,
6438–6442; A. Hoffmann, C. Citek, S. Binder, A. Goos,
M. Rübhausen, O. Troeppner, I. Ivanović-Burmazović,
E. C. Wasinger, T. D. P. Stack and S. Herres-Pawlis, Angew.
Chem., Int. Ed., 2013, 52, 5398–5401; C. Wilfer,
P. Liebhäuser, H. Erdmann, A. Hoffmann and S. Herres-
Pawlis, Eur. J. Inorg. Chem., 2015, 2015, 494–502.
8 X. Ottenwaelder, D. J. Rudd, M. C. Corbett, K. O. Hodgson,
B. Hedman and T. D. P. Stack, J. Am. Chem. Soc., 2006, 128,
9268–9269; Y. Funahashi, T. Nishikawa, Y. Wasada-Tsutsui,
Y. Kajita, S. Yamaguchi, H. Arii, T. Ozawa, K. Jitsukawa,
T. Tosha, S. Hirota, T. Kitagawa and H. Masuda, J. Am.
Chem. Soc., 2008, 130, 16444–16445.
1 S. E. Allen, R. R. Walvoord, R. Padilla-Salinas and
M. C. Kozlowski, Chem. Rev., 2013, 113, 6234–6458.
2 J. Zakzeski, P. C. A. Bruijnincx, A. L. Jongerius and
B. M. Weckhuysen, Chem. Rev., 2010, 110, 3552–3599;
S. Yamamura, The Chemistry of Phenols, John Wiley & Sons,
Ltd., West Sussex, UK, 2003; S. Quideau, D. Deffieux and
L. Pouységu, Comprehensive Organic Synthesis II, Elsevier,
Amsterdam, 2nd edn, 2014.
3 E. I. Solomon, D. E. Heppner, E. M. Johnston,
J. W. Ginsbach, J. Cirera, M. Qayyum, M. T. Kieber-
Emmons, C. H. Kjaergaard, R. G. Hadt and L. Tian, Chem.
Rev., 2014, 114, 3659–3853.
4 L. M. Mirica, X. Ottenwaelder and T. D. P. Stack, Chem.
Rev., 2004, 104, 1013–1046; E. A. Lewis and W. B. Tolman,
Chem. Rev., 2004, 104, 1047–1076; M. Rolff,
J. Schottenheim, H. Decker and F. Tuczek, Chem. Soc. Rev.,
2011, 40, 4077–4098.
9 K. V. N. Esguerra, Y. Fall and J.-P. Lumb, Angew. Chem., Int.
Ed., 2014, 53, 5877–5881.
10 M. S. Askari, J.-P. Lumb and X. Ottenwaelder, in
preparation.
11 L. M. Mirica and T. D. P. Stack, Inorg. Chem., 2005, 44,
2131–2133.
12 K. V. N. Esguerra, Y. Fall, L. Petitjean and J.-P. Lumb, J. Am.
Chem. Soc., 2014, 136, 7662–7668.
13 P. Verma, J. Weir, L. Mirica and T. D. P. Stack, Inorg. Chem.,
2011, 50, 9816–9825.
14 Y. Shimazaki, S. Huth, A. Odani and O. Yamauchi, Angew.
Chem., Int. Ed., 2000, 39, 1666–1669.
15 F. G. Bordwell and J. Cheng, J. Am. Chem. Soc., 1991, 113,
1736–1743; T. Osako, K. Ohkubo, M. Taki, Y. Tachi,
S. Fukuzumi and S. Itoh, J. Am. Chem. Soc., 2003, 125,
11027–11033.
5 L. Santagostini, M. Gullotti, E. Monzani, L. Casella,
R. Dillinger and F. Tuczek, Chem. – Eur. J., 2000, 6, 519–
522; S. Itoh, H. Kumei, M. Taki, S. Nagatomo, T. Kitagawa
and S. Fukuzumi, J. Am. Chem. Soc., 2001, 123, 6708–6709;
G. Battaini, M. D. Carolis, E. Monzani, F. Tuczek and
L. Casella, Chem. Commun., 2003, 726–727; C. Citek,
C. T. Lyons, E. C. Wasinger and T. D. P. Stack, Nat. Chem.,
2012, 4, 317–322; J. Matsumoto, Y. Kajita and H. Masuda,
Eur. J. Inorg. Chem., 2012, 2012, 4149–4158; S. Herres-
Pawlis, P. Verma, R. Haase, P. Kang, C. T. Lyons,
E. C. Wasinger, U. Flörke, G. Henkel and T. D. P. Stack, J.
Am. Chem. Soc., 2009, 131, 1154–1169; S. Mandal,
J. Mukherjee, F. Lloret and R. Mukherjee, Inorg. Chem.,
2012, 51, 13148–13161; P. Capdevielle and M. Maumy,
Tetrahedron Lett., 1982, 23, 1577–1580; L. Casella,
E. Monzani, M. Gullotti, D. Cavagnino, G. Cerina,
Dalton Trans.
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