A Biomimetic Mechanism for the Copper-Catalyzed Aerobic Oxygenation of 4-tert-Butylphenol

Article abstract of DOI:10.1021/acs.inorgchem.5b01297

Controlling product selectivity during the catalytic aerobic oxidation of phenols remains a significant challenge that hinders reaction development. This work provides a mechanistic picture of a Cu-catalyzed, aerobic functionalization of phenols that is selective for phenoxy-coupled ortho-quinones. We show that the immediate product of the reaction is a Cu(II)-semiquinone radical complex and reveal that ortho-oxygenation precedes oxidative coupling. This complex is the resting state of the Cu catalyst during turnover at room temperature. A mechanistic study of the formation of this complex at low temperatures demonstrates that the oxygenation pathway mimics the dinuclear Cu enzyme tyrosinase by involving a dinuclear side-on peroxodicopper(II) oxidant. Unlike the enzyme, however, the rate-limiting step of the ortho-oxygenation reaction is the self-assembly of the oxidant from Cu(I) and O₂. We provide details for all steps in the cycle and demonstrate that turnover is contingent upon proton-transfer events that are mediated by a slight excess of ligand. Finally, our knowledge of the reaction mechanism can be leveraged to diversify the reaction outcome. Thus, uncoupled ortho-quinones are favored in polar, coordinating media, highlighting unusually high levels of chemoselectivity for a catalytic aerobic oxidation of a phenol. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.inorgchem.5b01297

Article
pubs.acs.org/IC
A Biomimetic Mechanism for the Copper-Catalyzed Aerobic
Oxygenation of 4-tert-Butylphenol
Mohammad S. Askari,† Kenneth Virgel N. Esguerra,‡ Jean-Philip Lumb,*,‡ and Xavier Ottenwaelder*,†
†Department of Chemistry and Biochemistry, Concordia University, Montreal, QC H4B 1R6, Canada
‡Department of Chemistry, McGill University, Montreal, QC H3A 0B8, Canada
S
* Supporting Information
ABSTRACT: Controlling product selectivity during the
catalytic aerobic oxidation of phenols remains a significant
challenge that hinders reaction development. This work
provides a mechanistic picture of a Cu-catalyzed, aerobic
functionalization of phenols that is selective for phenoxy-
coupled ortho-quinones. We show that the immediate product
of the reaction is a Cu(II)−semiquinone radical complex and
reveal that ortho-oxygenation precedes oxidative coupling. This
complex is the resting state of the Cu catalyst during turnover
at room temperature. A mechanistic study of the formation of this complex at low temperatures demonstrates that the
oxygenation pathway mimics the dinuclear Cu enzyme tyrosinase by involving a dinuclear side-on peroxodicopper(II) oxidant.
Unlike the enzyme, however, the rate-limiting step of the ortho-oxygenation reaction is the self-assembly of the oxidant from
Cu(I) and O2. We provide details for all steps in the cycle and demonstrate that turnover is contingent upon proton-transfer
events that are mediated by a slight excess of ligand. Finally, our knowledge of the reaction mechanism can be leveraged to
diversify the reaction outcome. Thus, uncoupled ortho-quinones are favored in polar, coordinating media, highlighting unusually
high levels of chemoselectivity for a catalytic aerobic oxidation of a phenol.
of the enzyme’s active site that recreate the characteristic μ-
η2:η2-peroxodicopper(II) oxidant (P, Scheme 1b). Upon
exposure to stoichiometric quantities of sodium, lithium, or
tetrabutylammonium phenolate salts, these complexes achieve
ortho-oxygenation, with the proposed catecholatodicopper(II)
complex C as the reaction’s end point. This leads to catechols
or quinones after acidic workup.9−12 If neutral phenols are used
instead of phenolates, ortho-oxygenation is not observed, and
products of C−C coupling predominate,11f,13 except in one
recent intramolecular case.14 This has led to the generally
accepted view that deprotonation of the phenol must precede
the formation of a discrete Cu-phenolate complex, which
ensures selective oxygen-atom transfer (OAT) via an inner-
sphere mechanism.4b,15 (In this Article, we use the expression
“ortho-oxygenation” for the bulk reaction and “OAT” for the
specific mechanistic step where the oxygen atom is transferred
to the substrate.) Likewise, deprotonation of the phenol
substrate is believed to occur during the ortho-oxygenation by
tyrosinase, where the suitable base is either a histidine residue
or an activated water or hydroxide molecule near the enzyme’s
active site.7a,16
INTRODUCTION
■
Selective aerobic oxidations are fundamentally important to the
chemical industry due to the abundance of molecular oxygen
(O2) and the sustainable source of energy provided by its
reduction.1 Despite significant growth in this field, the
application of aerobic oxidations to phenols, which are
ubiquitous feedstock chemicals, remains underdeveloped due
to issues of selectivity.1b,2 With few exceptions,3,4 catalytic
aerobic oxidations of phenols generate phenoxyl radicals that
undergo nonselective C−C dimerization or oxidation to the
para-quinone, limiting their synthetic utility (Scheme 1a).1b,2
To avoid radical-based reactions, the overwhelming majority of
phenolic oxidations used in synthesis employ stoichiometric
amounts of a terminal oxidant other than O2 but do so at the
expense of atom- and step-efficiency.5
A remarkable example of a selective catalytic aerobic
oxygenation of phenols is mediated by the dinuclear Cu
enzyme tyrosinase. This enzyme converts L-tyrosine into L-
dopaquinone (Scheme 1b) in the first and rate-limiting step of
the ubiquitous biosynthesis of melanin pigments.6 Its
fundamental importance for life and its unique reactivity have
made tyrosinase the focal point of mechanistic investigations
and biomimicry, which have provided considerable insight into
factors that govern selectivity in the aerobic oxidation of
phenols.7 More generally, these studies have been fundamen-
tally important in elucidating the speciation of Cu(I) and O2 in
the presence of a vast array of amine ligands.8 Of particular
relevance to tyrosinase and melanogenesis are synthetic mimics
The requirement of a phenolate in order to achieve selective
OAT has prompted several groups to employ triethylamine
(Et3N, 2 equiv per substrate) as a buffer for catalytic reactions
starting from the phenol.8c,10e,h,12b,17 Deprotonation of the
Received: June 9, 2015
© XXXX American Chemical Society
A
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Scheme 1. (a) Selectivity Issues upon Oxidation/
Oxygenation of Phenols and (b) Simplified Mechanism of
the o-Oxygenation of L-Tyrosine by Tyrosinase during
Scheme 2. This Paper’s Study
a
Melanogenesis
catalytic system finds origin in the stoichiometric experiments
of Mirica, Stack, and Solomon (Scheme S1a), whose
mechanistic investigations on the ortho-oxygenation of 2,4-di-
tert-butylphenolate provide important spectroscopic signatures
of the intermediates involved in O2 activation and OAT when
DBED is used as the ligand.9,18 In spite of this precedent, the
relevance of these intermediates to a catalytic transformation
that employs a phenol, as opposed to a phenolate, is unproven
(see Scheme S1 for details). Herein, we bridge the gap between
stoichiometric experiments and catalytic conditions and provide
spectroscopic and kinetic support for a tyrosinase-like
mechanism under conditions that are relevant to catalysis.
RESULTS AND DISCUSSION
■
Fast Oxygenation to a Cu(II)−Semiquinone. At the
outset of our work, we monitored the conversion of 1 into 2 by
in situ UV−visible spectroscopy. Thus, introduction of O2 into
a CH2Cl2 mixture composed of 1, 4% CuPF6, and 8% DBED at
25 °C4a results in the rapid formation of the purple DBED−
Cu(II)−semiquinone radical complex 3 (λmax = 545 nm) along
with the product ortho-quinone 2 (λmax = 426 nm) (Figure 1).
a
Key: μ-η2:η2-peroxodicopper(II) (P) and μ-catecholato-μ-
hydroxodicopper(II) (C) intermediates. The nature of the base in
the active site is still debated.
phenol in situ affords the necessary phenolate for oxygenation,
along with the conjugate acid Et3NH+, which is thought to be
suitably acidic to protonate C. Drawing mechanistic con-
clusions under these reaction conditions is complicated,
however, because of a pronounced background oxygenation
of the phenol with Et3N, Cu, and O2 alone (i.e., catalytic
oxygenation is observed in the absence of a biomimetic
ligand).4a,b Since these previous examples have not demon-
strated that a P species can form in the presence of Et3N and a
phenol, it is unclear to what extent independent character-
ization of P10c,h,17c,d relates to catalytic conditions in which P
must self-assemble in the presence of all reaction components.
Moreover, previous catalytic systems, whether Et3N- or
phenolate17e-based, produce more than one product or do
not proceed to complete substrate conversion, which interferes
with a mechanistic analysis.
Figure 1. In situ UV−vis spectroscopic monitoring under catalytic
conditions: CH2Cl2, 25 °C, 30.7 mM 1, 4% CuPF6, 8% DBED, 1.0
mm path length. Inset: time profiles of the absorbances at 413 and 545
nm, with main absorbing species at these wavelengths.
In 2014, one of our groups reported a catalytic aerobic ortho-
oxygenation of phenols that addresses many of these
complications.4a It is catalytic in all components, uses a single
amine to adjust the reaction pH and ligate Cu, and provides a
single product at complete conversion. Thus, oxidation of 4-
tert-butylphenol, 1, in the presence of 4 mol % of [Cu-
(CH3CN)4](PF6) (CuPF6) and 5−8 mol % of N,N′-di-tert-
butylethylenediamine (DBED) affords coupled ortho-quinone 2
in isolated yields greater than 95% on a multigram scale
(Scheme 2). This uniquely simple set of conditions, wherein a
single amine additive is used to mediate both O2 activation and
proton transfer, is ideal for mechanistic investigations. This
The structure of 3 was confirmed by an independent
synthesis,19 mass spectrometry, and X-ray crystallography
(Figures S1−S4, Supporting Information). Complex 3 remains
at a near-steady-state concentration (>95% of the total [Cu]) as
long as the reaction turns over to form 2 (Figure 1a, inset).
Time profiling of all species in solution during turnover
reveals that the formation of complex 3 is the fastest observable
process at room temperature (Figure 2). A small amount of
uncoupled 4-tert-butyl-ortho-quinone 4 is observed along with 3
and remains at a concentration of ∼9% of [1]0 throughout
B
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evidenced by the complete conversion of 1 to 2 when 5 mol %
of 3 is used as the only source of Cu, along with an additional 5
mol % of DBED.
Mechanistic Proposal for the ortho-Oxygenation. The
selective formation of Cu(II)−semiquinone 3 from phenol 1 at
low temperatures enabled us to study the mechanism of ortho-
oxygenation in the absence of the oxidative coupling. A
plausible mechanism for this transformation at −80 °C is
provided in Scheme 4 and forms the basis for the ensuing
discussion.
Scheme 4. Proposed Mechanism for the o-Oxygenation of
Phenol 1 to Cu(II)−Semiquinone Complex 3 at −80 °C
Figure 2. Concentrations of absorbing species during the reaction of
Figure 1, deduced by fitting UV−vis spectra at various time points
(e.g., Figure S3). The y-axis is scaled to the maximum concentration of
each species, i.e., [3]max = [5]max = [CuPF6]0, [4]max = [1]0, and [2]max
= 0.5[1]0. Thus, each point in the graph gives the yield of each species.
turnover (Figure 2).20 As the concentration of 2 increases, its
corresponding Cu(II)−semiquinone complex 5 is observed.
Quinones 2 and 4 are in equilibrium with their Cu(II)−
semiquinone complexes, 3 and 5, respectively, with stronger
binding observed between DBED−Cu(I) and the more
electron-deficient quinone 4 (Scheme 3 and Figures S5 and
a
Scheme 3. DBEDCu(I)−Quinone Binding Constants
*Step 4 produces one molecule of a Cu(I) complex, but two are
required in step 1.
Kinetic Measurements and Isotopic Labeling. To
probe the initial stages of the mechanism, the formation of 3
was analyzed using stopped-flow kinetic experiments at −80
°C. The initial rate of the reaction shows a second-order
dependence on [CuPF6] (Figures 3 and S10), which is
consistent with the two-step formation of a dinuclear species,
a
The Cu(I) complex was prepared by mixing DBED and [Cu-
(CH3CN)4](PF6) in a 1:1 ratio. Thus, a total of 4 equiv of CH3CN is
present in solution.
S6). Complex 3 is the predominant Cu species until the
concentration of 2 approaches 50%, at which point the
concentration of complex 5 grows. Subsequent decay of 5
(and 3) is consistent with its dissociation and subsequent
oxidation of DBED−Cu(I) to the spectrally innocuous bis(μ-
hydroxo)dicopper(II) complex,21 which does not recoordinate
the quinones. We have previously demonstrated that this
Cu(II)−hydroxide dimer can re-enter the catalytic cycle, such
that its formation does not preclude catalysis.4c
The conversion of 3 into 2 is the rate-limiting sequence of
the reaction at 25 °C, and it does not proceed at −78 °C. When
the reaction is run at −78 °C, 3 is the only visible species, and it
forms quantitatively with respect to the starting amount of Cu.
Upon warming to 25 °C, turnover proceeds and 2 forms in
96% NMR yield, indicating that 3 is a competent intermediate.
Complex 3 is also a suitable precatalyst for the reaction, as
Figure 3. Dependence of the initial rate of formation of 3 on [CuPF6]
= 0.1−1.5 mM, [1] = 2.5 mM, [DBED]/[CuPF6] = 1.1 in CH2Cl2 at
−80 °C.
C
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as expressed in eqs 1 and 2.22 This provides the first kinetic
support for a dinuclear mechanism of O2 activation under
biomimetic ortho-oxygenation conditions.
+
DBEDCu+ + O2 = DBEDCuO2
(1)
+
2+
DBEDCuO2 + DBEDCu+ = DBED2Cu2O2
(2)
The substrate does not participite in the rate-limiting step of
the reaction. With a [DBED]/[CuPF6] ratio maintained at 1.1,
no significant changes in the initial rate were observed upon
varying [1] (Figure S12), suggesting a zeroth order dependence
on substrate concentation. This result is consistent with the
absence of a kinetic isotope effect (KIE) when isotopically
labeled 4-tert-butyl-2-deuterophenol (1HD) or 4-tert-butyl-2,6-
dideuterophenol (1DD) is used instead of 1 (Figure S13). These
results create an important distinction with Mirica’s stoichio-
metric experiments using a preformed P species and suggest
that the rate of self-assembly of the dinuclear Cu oxidant (O2
activation) is rate-determining under catalytically relevant
conditions at −80 °C.
The OAT event that converts 1 into 3 was probed via
product analysis in the −78 °C reaction of 1HD, where
competition is present between a C−H and a C−D bond at the
ortho positions of the phenol (Table S2). In this case, we
observed an intrinsic KIE of 0.87(3), which is consistent with
previously reported values using tyrosinase23 or synthetic9,11e,f
mimics6d,24 and supports a mechanism of C−O bond formation
via electrophilic aromatic substitution. Following OAT, a fast
proton migration of the ortho H/D atom aromatizes the
substrate and leads to bridged catecholate C, in line with
previous mechanistic hypotheses (e.g., Scheme 1b; see below
for additional discussion).
Figure 4. Intermediates in the oxygenation of 1 to 3. Oxygenation at
−115 °C of a MeTHF solution containing 1 (24.85 mM), 4% CuPF6,
and 5% DBED. (i, black) Solution before introducing O2. (ii, red)
Spectrum after oxygenating for 3 min, indicating the presence of P and
O. (iii, green) Spectrum after 91 min under O2, indicating a ∼4:1
mixture of C (800 nm) and 3 (545 and 900 nm). (iv, orange)
Warming up to −78 °C under O2 shows the conversion of C to >90%
3.
Intermediates in the Oxygenation. The second-order
dependence in Cu supports a dinuclear mechanism for O2
activation that is consistent with the mechanism of tyrosinase
and previous work by Mirica, Stack, and Solomon with the
DBED ligand (Scheme S1a).9 To gain insight into the
structures of the key dinuclear intermediates, we monitored
the oxygenation of a solution composed of 1, 4% CuPF6, and
5% DBED at −115 °C in 2-methyltetrahydrofuran (MeTHF).
This generates a solution with an intense feature at 353 nm,
possessing a small shoulder at 418 nm (Figure 4i→ii, and
Figure S8).8a The same spectral features are observed upon the
oxygenation of a 1:1 mixture of CuPF6 and DBED in the
absence of phenol (Figure S9),18 indicating the formation of a
∼5:1 mixture of rapidly interconverting8a P and O species.26
Within minutes, the reaction, which contains phenol and a
small excess of DBED per Cu, evolves to a 1:4 mixture of 3 and
a species we tentatively assign as a catecholatohydroxodicopper-
(II) complex, C (λmax = 800 nm, Figure 4iii and Figure S10).9b
The assignment of C is supported by its independent synthesis
from preformed P and 2.5 equiv of 4-tert-butylphenolate
according to literature.9b The UV−visible spectrum of the
obtained species is comparable to that reported by Mirica et al.
with 2,4-di-tert-butylphenolate (Figure 5iii and Figure S10)27
and so is its reactivity (release of 3 upon addition of 2.5 equiv
of H+ from H2SO4).9
Figure 5. Closing the catalytic cycle: cleavage of C. P is formed by
oxygenating a 1:1 solution of DBED/CuPF6 in THF at −78 °C (i →
ii). Addition 2.51 equiv of sodium 4-tert-butylphenolate (per P) under
N2 leads to the formation of C (iii). Addition of 2.54 equiv of
DBEDH(PF6) forms 1 equiv of 3 with respect to P (iv). More details
are provided in the Supporting Information.
dissociation of C occurs rapidly at −78 °C, 3 forms
quantitatively relative to the total Cu concentration.
The P, C, and 3 intermediates are analogous to those
observed under Mirica’s stoichiometric experiments, but the
absence of a visible intermediate between P and C is an
important distinction. Whereas Mirica et al. observed a
transient bis(oxo)phenolato complex A upon addition of 2,4-
di-tert-butylphenolate to P at −115 °C (Scheme S1),9b we do
not observe an A species under our catalytically relevant
conditions (Figure 4i→iii). An A species is also absent when
the oxygenation of 1 is performed using its sodium phenolate
under conditions identical to those reported by Mirica (Figure
5ii→iii). We attribute this difference to a much faster OAT
when the starting phenol lacks a 2-tert-butyl substituent.
Protonation of C and Catalyst Regeneration. The key
step that enables catalyst turnover is the cleavage of C to 3 by
Upon subsequent warming to −78 °C, the reaction mixture
affords 3 in >90% yield with respect to the starting amount of
CuPF6 (Figure 4iv). This percentage proves that the
spectroscopically silent Cu species that forms upon cleavage
of dinuclear C to mononuclear 3 can re-enter the oxygenation
cycle to form additional 3 (details below). Since the
D
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redox tautomerization of the catecholate and the two Cu(II)
centers of the dinuclear complex. Since this process is triggered
by protonation of the hydroxide bridge,9b stoichiometric
oxidations using phenolate salts cannot close the catalytic
cycle of ortho-oxygenation. Under catalytic conditions,
deprotonation of neutral phenol 1 by uncoordinated DBED
(DBED is in excess of Cu) affords the mild acid DBEDH+.
DBEDH+ is a suitably strong acid to protonate C and release 3
along with a colorless Cu(I) species that is capable of re-
entering the ortho-oxygenation cycle. We demonstrate this
explicitly by the synthesis of C from P and the sodium
phenolate of 1 at −78 °C (Figure 5iii). Subsequent addition of
DBEDH(PF6) (prepared separately) affords 1 equiv of
mononuclear 3 per dinuclear C (Figure 5iv), along with a
Cu-containing species, X, which is spectroscopically silent.
Species X can re-enter the oxygenation cycle, as demonstrated
in Figure 6. Thus, the reaction of 1 (2 equiv) with preformed P
phenolate to make C (steps 2 and 3). Protonation of dicopper
species C by DBEDH+ releases 3 and Cu(I) complex X, which
re-enters the oxygenation cycle (step 4). At −78 °C, complex 3
is kinetically inert and requires higher temperatures to
oxidatively couple with 1 to afford 2. Upon formation of the
more electron-rich quinone 2, DBED−Cu(I) is more easily
released from the intermediate semiquinone 5 and can either
re-enter the catalytic cycle or oxidize to the bis(μ-hydroxo)-
dicopper(II) species.
The absence of a KIE between 1 and 1DD and the zeroth
order dependence on [1] indicate that the OAT step is not
rate-limiting at −80 °C. Instead, the rate of ortho-oxygenation is
dependent on the formation of P, which requires the self-
assembly of O2 and two molecules of DBED−Cu(I). This is
distinct from the oxygenation of phenols catalyzed by
tyrosinase, which rapidly forms P due to the colocalization of
the two Cu(I) centers. The inverse intramolecular isotopic
effect observed with 1HD (0.87) is consistent with an
electrophilic aromatic substitution being the product-determin-
ing step. Whether OAT proceeds via a discrete Cu−phenolate
species like A or by direct attack of the electron-rich aromatic
ring onto the oxygen atom of P remains unclear, but efforts are
underway to distinguish between these two possibilities.
Diverting the Course of the Dearomatization Reac-
tion. The involvement of 3 in the formation of coupled ortho-
quinone 2 at higher temperatures (25 °C) creates an
opportunity to divert the course of the reaction to uncoupled
ortho-quinone 4 by simply changing the solvent from CH2Cl2
to acetonitrile (CH3CN). The coordinating ability of CH3CN
can reverse the equilibrium position between 3 and 4 (Scheme
3) in favor of 4 (Figure S7). Thus, conducting the catalytic
reaction in pure CH3CN affords a 1:1 mixture of quinones 2
and 4 at 25 °C (Table 1, entry 2) and a 1:4 mixture at −40 °C
a
Table 1. Diversification of the Reaction Outcome
Figure 6. Closing the catalytic cycle: fate of the released Cu. (i) P
species −85 °C in CH2Cl2 under N2. (ii) Addition of 1 and a catalytic
amount of DBED rapidly forms 3 (56% of the total [Cu]). (iii) After
O2 is reintroduced, 3 grows to 100% of the total [Cu]. More details are
provided in the Supporting Information.
(1 equiv) under N2 at −85 °C in the presence of a catalytic
quantity of DBED (20% per Cu) rapidly forms 1 equiv of 3
from every starting P (Figure 6ii). If O2 is introduced at this
point, all remaining Cu present in solution is rapidly converted
into 3 (Figure 6iii), confirming that X is suitable for additional
turnover to 3. The demonstration that X promotes additional
conversion of 1 into 3 closes the cycle of ortho-oxygenation and
provides an explicit demonstration that the cleavage of C
releases a catalytically competent Cu species.10e
Discussion on the Mechanism. The visualization of P in
the presence of a large excess of phenol under conditions that
retain selectivity for ortho-oxygenation is noteworthy since P
species are known to react with phenols via radical-based
pathways.13 In the absence of a small excess of DBED with
respect to CuPF6, preformed P does not react with 1 at −80
°C, and 1 is recovered after workup, as is the case with 2,4-di-
tert-butylphenol.18 This strongly suggests that the ortho-
oxygenation must proceed through the phenolate and under-
scores the importance of a slight excess of DBED per Cu for
turnover. Consistent with the second-order dependence of the
rate on [CuPF6],22 our mechanistic proposal at −80 °C
(Scheme 4) begins by assembling P from DBED−Cu(I) and
O2 (step 1), which then reacts with the in situ generated
b
yield (%)
CuPF6
DBED
entry
(mol %)
(mol %)
solvent
T (°C)
2
4
6
c
1
4
4
8
8
CH2Cl2
CH3CN
CH3CN
CH2Cl2
CH2Cl2
25
98
52
18
0
0
0
0
c
2
25
47
76
82
c
3
4
8
−40
−78
−78
0
c
4
100
100
110
110
0
d
5
0
0
c
81
a
b
Reactions performed on 1 mmol of phenol. Isolated yields. Workup
with 10% NaHSO4. Saturated Na2S2O4 workup. See Supporting
Information for experimental details.
d
(entry 3). Under these conditions, we do not observe 3 by
UV−visible spectroscopy, which suggests that CH3CN
coordination to Cu(I) promotes the release of 4 faster than
oxidative coupling with 1 to afford 2. This scenario constitutes
an important proof of principle that the ortho-oxygenation
reaction can be performed in isolation of oxidative coupling,
which is attractive for synthetic applications.
If complete selectivity for 4 is desired, the oxygenation of 1
can be carried out at −78 °C in CH2Cl2 with 1 equiv of CuPF6
and 1.1 equiv of DBED, which results in the quantitative
E
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probe having a 1.0 mm path length. The probe was immersed in the
solution inside a custom-made Schlenk flask. Temperature was
maintained with external cooling baths: acetone/dry ice (−75 °C
inside the solution), acetone/liquid nitrogen (−85 °C), pentane/liquid
nitrogen (−115 °C). Spectra for mixtures or evolving solutions are
reported in apparent ε, that is, molar extinction coefficients with
respect to the total Cu concentration.
formation of 3. Subsequent exposure of 3 to either acidic or
reductive conditions affords uncoupled ortho-quinone 4 (entry
4) or catechol 6 (entry 5), respectively. Semiquinones related
to 3 have been popularized as noninnocent ligands for late
transition metals,28 but they have not been explored as strategic
intermediates for synthesis. To our knowledge, this is the first
synthesis of a semiquinone−metal complex directly from a
phenolthese complexes are typically formed by inner-sphere
reaction between a low-valent metal and an ortho-quinone.28
This is also the first illustration that semiquinone−metal
complexes are viable precursors to either free ortho-quinones or
catechols, setting the stage for their development into strategic
intermediates for synthesis.
Low-temperature stopped-flow experiments were carried out in the
Departement de Chimie at the Universite de Montreal on a Hi-Tech
́ ́ ́
CSF-61DX2 instrument (TgK Scientific) equipped with a diode-array
detector over the 300−700 nm range. The UV−vis cuvette
(pathlengths of 1.5 or 10 mm) was cooled by immersion in an
ethanol bath cooled with liquid N2. Syringe 1 was filled with a CH2Cl2
solution containing 1, DBED, and CuPF6 in desired concentrations
that was prepared in an MBraun Labmaster glovebox. Syringe 2 was
filled with CH2Cl2 that was O2-saturated at atmospheric pressure and
room temperature. Concentrations were corrected for the 2-fold
dilution upon mixing. Initial rates were calculated by measuring the
tangent of the growth of the absorbance at 545 nm at the initial stage
of the reaction (150 ms after mixing) and using ε545(3) = 4100 M−1
cm−1.
CONCLUSIONS
■
Building upon the stoichiometric studies by Mirica, Solomon,
and Stack,9 we establish that (1) the tyrosinase-like P species is
indeed a viable oxidant under catalytic conditions and in the
presence of excess phenol, (2) ortho-oxygenation under
catalytic conditions requires deprotonation of the phenol, and
(3) DBED is a suitable buffer to mediate proton transfer
between 1 and C. In this sense, the ortho-oxygenation pathway
under DBED/CuPF6 conditions is very similar to that of
tyrosinase, which proceeds through a P species, exhibits phenol
deprotonation, and requires protonation of C for substrate
release.6,7 However, the formation of Cu(II)−semiquinone 3
marks an important point of divergence from tyrosinase. In the
enzyme, both Cu atoms are retained in the protein-constrained
active site following ortho-oxygenation.6a,d,7a This constraint
enforces the release of the relatively unstable L-dopaquinone,
which is prone to polymerization.29 By contrast, our reaction
attenuates the reactivity of the ortho-quinone by keeping it
bound to Cu as a partially reduced semiquinone radical. Our
work marks an important extension of mechanistic data
acquired under stoichiometric conditions at cryogenic temper-
atures to a catalytic transformation that is conducted at room
temperature on a gram scale. This provides a mechanistic
framework from which to explore the aerobic dearomatization
of phenols, a reaction that holds significant promise for
synthesis, but for which few selective catalytic aerobic systems
have been developed.
Intramolecular competition experiments on 1HD were carried out on
solutions containing 52 mM 1HD, 52 mM CuPF6, and 58 mM DBED
in CH2Cl2 at −78 °C under 2 atm O2 for 4 h. Reductive workup with
Na2S2O4 yielded the catechols. The ratios of 6 (major) to 5-tert-butyl-
3-deuterocatechol (6D, minor) were measured by GC-MS on an
Agilent 7890A GC with a HP 140915-433A column and an Agilent
5975C VL MSD (EI, 70 eV). Details are in Table S2.
Independent synthesis of 3.19 3(PF6): To a solution of DBED
(51.8 mg, 0.30 mmol, 1.1 equiv) and CuPF6 (100 mg, 0.27 mmol, 1
equiv) in 4 mL of THF was added a solution of 4-tert-butylquinone (4,
48.5 mg, 0.30 mmol, 1.1 equiv) in 1 mL of THF with stirring. The
color of the solution immediately changed from light pink to deep
purple. The solution was stirred for 2 h at 25 °C under N2. The
solution was then filtered through Celite and added to 15 mL of
stirring pentane precooled to −35 °C, upon which a purple solid
precipitated. The solid was collected, washed with 2 mL of Et2O and 2
× 2 mL of pentane, and dried under vacuum for 24 h. Yield: 110 mg,
75%. UV−vis, CH2Cl2, 25 °C, λ/nm (ε/M−1 cm−1): 230 (6,380), 300
(9,000), 359 (1,910), 545 (3,500), 915 (1,300). Elemental analysis
(mol %): expected for C20H36N2O2F6PCu·0.9CH3CN·1.8H2O: C,
42.62; H, 6.94; N, 6.61; found C, 42.75; H, 6.90; N, 6.61. Structural
analysis of weakly diffracting crystals showed the same structure as that
for the 3(SbF6) structure below, with the exception of smaller unit cell
−
−
dimensions and a disordered PF6 instead of SbF6 .
3(SbF6): This compound was prepared similarly using [Cu-
(CH3CN)4](SbF6) as the copper source. Crystals suitable for X-ray
diffraction studies were grown by slow layered diffusion of pentane
into a CH2Cl2 solution of the complex at −30 °C in the glovebox.
3(SbF6) was only used for structural characterization. For all solution
EXPERIMENTAL SECTION
■
Chemicals and solvents were purchased from Sigma-Aldrich, Alfa
Aesar, or Strem Chemicals. Inhibitor-free solvents were dried using a
MBraun SPS 800, transferred to an inert-atmosphere glovebox
(MBraun Labmaster, <1 ppm of O2 and H2O, filled with a dry N2
atmosphere), further degassed under vacuum, and stored over
activated molecular sieves (4 Å). tert-Butylphenol 1 was purified by
double recrystallization from CH2Cl2/hexanes. N,N′-Di-tert-butylethy-
lenediamine (DBED) was distilled over CaH2 under N2 and stored in
the glovebox. The copper(I) salt [Cu(CH3CN)4](PF6), abbreviated
CuPF6, was purchased from commercial sources or made via a
literature procedure.30 [Cu(CH3CN)4](SbF6) was prepared via the
same method but using HSbF6 instead of HPF6. All copper(I)
complexes were stored inside the glovebox.
−
experiments, the PF6 salt was used.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.5b01297.
X-ray data for 3 (CCDC-950162) (CIF)
Experimental and kinetic details, spectroscopic character-
ization of intermediates (PDF)
Unless otherwise noted, reactions were performed in oven-dried
glassware under a positive pressure of nitrogen using standard
synthetic inert-atmosphere techniques. Bulk oxidation reactions were
setup in the glovebox in 25-mL Radley tubes equipped with a Teflon-
coated stir bar. The reaction vessels were then connected to a cylinder
of O2, purged three times with O2, and then overpressurized to +1.0
atm.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: jean-philip.lumb@mcgill.ca.
*E-mail: dr.x@concordia.ca.
UV−visible spectra were recorded on a B&W Tek iTrometer
equipped with fiber-optic cables connected to a Hellma full-quartz dip-
F
DOI: 10.1021/acs.inorgchem.5b01297
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Chem. Soc. 2001, 123, 6708−6709. (c) Battaini, G.; Carolis, M. D.;
Monzani, E.; Tuczek, F.; Casella, L. Chem. Commun. 2003, 726−727.
(d) Palavicini, S.; Granata, A.; Monzani, E.; Casella, L. J. Am. Chem.
Soc. 2005, 127, 18031−18036. (e) Rolff, M.; Schottenheim, J.; Peters,
G.; Tuczek, F. Angew. Chem., Int. Ed. 2010, 49, 6438−6442. (f) Citek,
C.; Lyons, C. T.; Wasinger, E. C.; Stack, T. D. P. Nat. Chem. 2012, 4,
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Funding
Financial support was provided by the Natural Sciences and
Engineering Council of Canada, the Fonds de Recherche du
Quebec−Nature et Technologies and the Centre de Chimie
́
Verte et Catalyse (Quebec).
Notes
The authors declare no competing financial interest.
́ ́
Goos, A.; Rubhausen, M.; Troeppner, O.; Ivanovic-Burmazovic, I.;
̈
Wasinger, E. C.; Stack, T. D. P.; Herres-Pawlis, S. Angew. Chem., Int.
Ed. 2013, 52, 5398−5401.
ACKNOWLEDGMENTS
■
We are grateful to Prof. Hein Schaper and Prof. Garry Hanan
(Universite
(11) For examples of phenolate oxygenations by well-characterized
Cu−O2 complexes other than P, see: (a) Company, A.; Palavicini, S.;
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de Montrea
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and glovebox equipment. M.S.A. acknowledges NSERC for a
PGS-D scholarship.
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DOI: 10.1021/acs.inorgchem.5b01297
Inorg. Chem. XXXX, XXX, XXX−XXX