Mechanistic insights into the oxidation of substituted phenols via hydrogen atom abstraction by a cupric-superoxo complex

Article abstract of DOI:10.1021/ja503105b

To obtain mechanistic insights into the inherent reactivity patterns for copper(I)-O₂ adducts, a new cupric-superoxo complex [(DMM-tmpa)Cu^II(O₂^?-)]⁺ (2) [DMM-tmpa = tris((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amine] has been synthesized and studied in phenol oxidation-oxygenation reactions. Compound 2 is characterized by UV-vis, resonance Raman, and EPR spectroscopies. Its reactions with a series of para-substituted 2,6-di-tert-butylphenols (p-X-DTBPs) afford 2,6-di-tert-butyl-1,4-benzoquinone (DTBQ) in up to 50% yields. Significant deuterium kinetic isotope effects and a positive correlation of second-order rate constants (k₂) compared to rate constants for p-X-DTBPs plus cumylperoxyl radical reactions indicate a mechanism that involves rate-limiting hydrogen atom transfer (HAT). A weak correlation of (k_BT/e) ln k ₂ versus E_ox of p-X-DTBP indicates that the HAT reactions proceed via a partial transfer of charge rather than a complete transfer of charge in the electron transfer/proton transfer pathway. Product analyses, ¹⁸O-labeling experiments, and separate reactivity employing the 2,4,6-tri-tert-butylphenoxyl radical provide further mechanistic insights. After initial HAT, a second molar equiv of 2 couples to the phenoxyl radical initially formed, giving a Cu^II-OO-(ArO') intermediate, which proceeds in the case of p-OR-DTBP substrates via a two-electron oxidation reaction involving hydrolysis steps which liberate H₂O₂ and the corresponding alcohol. By contrast, four-electron oxygenation (O-O cleavage) mainly occurs for p-R-DTBP which gives ¹⁸O-labeled DTBQ and elimination of the R group.

Full text of DOI:10.1021/ja503105b

Article
pubs.acs.org/JACS
Open Access on 06/22/2015
Mechanistic Insights into the Oxidation of Substituted Phenols via
Hydrogen Atom Abstraction by a Cupric−Superoxo Complex
Jung Yoon Lee,† Ryan L. Peterson,† Kei Ohkubo,‡ Isaac Garcia-Bosch,† Richard A. Himes,†
Julia Woertink,§ Cathy D. Moore,† Edward I. Solomon,*,§ Shunichi Fukuzumi,*,‡
and Kenneth D. Karlin*,†
†Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, United States
‡Department of Material and Life Science, Graduate School of Engineering, and ALCA, Japan Science and Technology Agency (JST),
Osaka University, Suita, Osaka 565-0871, Japan
§Department of Chemistry, Stanford University, Stanford, California 94305, United States
S
* Supporting Information
ABSTRACT: To obtain mechanistic insights into the inherent
reactivity patterns for copper(I)−O2 adducts, a new cupric−
superoxo complex [(DMM-tmpa)CuII(O2•−)]+ (2) [DMM-
tmpa = tris((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-
amine] has been synthesized and studied in phenol
oxidation−oxygenation reactions. Compound 2 is characterized
by UV−vis, resonance Raman, and EPR spectroscopies. Its
reactions with a series of para-substituted 2,6-di-tert-butyl-
phenols (p-X-DTBPs) afford 2,6-di-tert-butyl-1,4-benzoquinone
(DTBQ) in up to 50% yields. Significant deuterium kinetic
isotope effects and a positive correlation of second-order rate constants (k2) compared to rate constants for p-X-DTBPs plus
cumylperoxyl radical reactions indicate a mechanism that involves rate-limiting hydrogen atom transfer (HAT). A weak
correlation of (kBT/e) ln k2 versus Eox of p-X-DTBP indicates that the HAT reactions proceed via a partial transfer of charge
rather than a complete transfer of charge in the electron transfer/proton transfer pathway. Product analyses, 18O-labeling
experiments, and separate reactivity employing the 2,4,6-tri-tert-butylphenoxyl radical provide further mechanistic insights. After
initial HAT, a second molar equiv of 2 couples to the phenoxyl radical initially formed, giving a CuII−OO−(ArO′) intermediate,
which proceeds in the case of p-OR-DTBP substrates via a two-electron oxidation reaction involving hydrolysis steps which
liberate H2O2 and the corresponding alcohol. By contrast, four-electron oxygenation (O−O cleavage) mainly occurs for p-R-
DTBP which gives 18O-labeled DTBQ and elimination of the R group.
has been detected in the gas phase,2 hinted at in coordination
INTRODUCTION
■
chemistry studies3 or discussed computationally.4 Among them,
the mononuclear species such as cupric−superoxide (A and B),
cupric hydroperoxide (C), and copper oxyl (D) species all have
been considered as highly reactive intermediates which likely
participate in overall reaction sequences occurring in copper
enzyme biotransformations.5
Investigation of the structure and reactivity of various CuI/O2
adducts (Chart 1), those derived from the reaction of reduced
Chart 1
They may hydroxylate the substrate C−H bond in copper
enzymes such as peptidylglycine-α-hydroxylating mono-
oxygenase (PHM) and dopamine-β-monooxygenase (DβM)6
or initiate O−H oxidation in copper oxidases such as galactose
oxidase (GO)6a,7 or copper amine oxidase (CAO).6a,8 From
relatively recent experimental and computational studies, the
[CuII(O2•−)]+ (A or B) moiety has been declared as the
reactive intermediate which effects C−H9,10 or O−H7,8
hydrogen atom transfer (HAT) reactions. Relevant to this is
an X-ray crystallographic study on a PHM derivative, which
ligand−copper(I) complexes with molecular oxygen (dioxy-
gen), occurs in large part due to their critical roles in
metalloenzymes.1 Monocopper complexes A−C or dinuclear
species E−G, or their analogues, have been discovered, and
insights into their electronic structural characteristics and 3-D
structures have been obtained.1 Formally high-valent species D
Received: August 27, 2013
© XXXX American Chemical Society
A
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reveals a dioxygen-derived species assigned as an end-on bound
cupric−superoxo species (B) (also discussion below).11 As is
relevant to part of the GO catalytic cycle, recent experimental
studies support a mechanism wherein O2 binding to this fully
reduced copper ion affords a cupric−superoxo species (Figure
1), and that this mediates the oxidation of the ligated tyrosine
Chart 2
stable end-on bound superoxo−copper(II) complex, we found
that 2,6-di-tert-butylphenol derivatives (p-X-DTBP; X = OMe,
tBu, H) were oxidized to 2,6-di-tert-butyl-1,4-benzoquinone
(DTBQ) (Scheme 1).
Figure 1. Reduction of molecular oxygen in galactose oxidase (GO).
See Supporting Information (Figure S1a) for fuller details.
Scheme 1
residue resulting in the formation of a cupric hydroperoxide
species (C) plus phenoxyl radical.7c Hydrolysis leads to the
release of hydrogen peroxide, the observed stoichiometric O2
reduction product in the overall mechanism.
With this background, one of the research goals that we have
recently been emphasizing is on the chemistry of cupric−
superoxo complexes. It is critical to elucidate chemical/physical
properties, spectroscopic characteristics, and reactivity toward
substrates possessing C−H or O−H bonds. An understanding
of such aspects is critical in order to fully elucidate
fundamentals involved in oxidative processes and the reduction
of dioxygen by copper centers in chemical systems or at the
active sites of metalloenzymes.
In this report, we describe the chemistry of a new
[CuII(O2•−)]+ complex and a detailed investigation into its
reactions with phenolic substrates. As discussed above, the net
hydrogen atom abstraction reaction from a phenol derivative is
directly relevant to the enzyme chemistry in GO. Similar
reactivity occurs in CAO, where a cupric−superoxo species is
thought to undergo a proton-coupled electron transfer (PCET)
process converting TPQSQ (2,4,5-trihyroxyphenylalanine semi-
quinone) to TPQIMQ, the one-electron oxidized iminoquinone
form (Supporting Information Figure S1b).8 As mentioned,
phenols can undergo oxidation by two pathways, both resulting
in formation of the neutral phenoxyl radical and transfer of a
hydrogen atom to the oxidant (eq 1). Mechanistically, the
process can occur by PCET12 or hydrogen atom transfer, and
these are fundamentally important reactions occurring in many
biological systems.
We herein describe a detailed study employing a new
electron-rich ligand supporting the cupric−superoxo complex,
[(DMM-tmpa)CuII(O2•−)]+ (2) (Scheme 1), which is capable
of mediating this chemistry for a large series of p-X-DTBP (X =
alkoxy/alkyl) substrates. We provide decisive kinetic evidence
supporting cupric−superoxo complex-mediated HAT as the
rate-limiting step in phenol O−H bond activation and two-
and/or four-electron reduction of molecular oxygen (vide
infra). There are three possible reaction pathways in the overall
hydrogen atom transfer from p-X-DTBP to [CuII(O2•−)]+: (1)
electron transfer (ET) followed by proton transfer (PT); (2)
PT followed by ET; and (3) concerted ET and PT. The former
two pathways correspond to PCET processes, whereas the third
one (i.e., concerted ET and PT) corresponds to a direct HAT
process. The mechanistic conclusions are drawn by several
corroborating studies employing physical measurements
leading to (i) kinetic isotope effect (KIE) determination, (ii)
correlation of the relative reactivity for hydrogen atom
abstraction using cumylperoxyl radical (4) as a mechanistic
benchmark, (iii) comparison of the rate dependences in the
phenol oxidations by 2 and 4 on the one-electron oxidation
potentials of the p-X-DTBPs, and (iv) activation parameters
determined from the reaction kinetics. We also discuss the
experimental results from product analysis showing that either
overall two-electron oxidation or four-electron oxygenation of
the p-X-DTBPs can occur; the results depend on the identity of
the substituent X. Detailed pathways leading to the products
observed are proposed.
ArOH → ArO• + H•
(1)
Osako et al.13 previously investigated phenol (and C−H)
oxidation chemistry using binuclear complexes of the type (μ-
η2:η2-peroxo)dicopper(II) (F) and/or bis(μ-oxo)dicopper(III)
(G). For a series of phenols, kinetic/mechanistic studies
demonstrated that these oxidations proceeded via PCET rather
than HAT. However, studies on the reactivity of mononuclear
CuI/O2 species are scarce, and in fact, no detailed mechanistic
investigations have been described. Only recently have ligand
design and synthetic methodologies better allowed for the
formation of discrete [CuII(O2•−)]+ adducts, making it possible
for the systematic investigation into their inherent chemical and
physical properties, along with substrate reactivity.14
EXPERIMENTAL SECTION
■
General Considerations. All materials used were of commercially
available reagent quality unless otherwise stated. Acetone was distilled
from Drierite under argon atmosphere. Tetrahydrofuran (THF) and 2-
methyltetrahydrofuran (MeTHF) inhibitor-free were purchased from
Sigma-Aldrich and distilled under argon from sodium/benzophenone
prior to use. Pentane was distilled under argon over CaH2. Acetonitrile
was purified via passage through a double alumina column solvent
purification system from Innovative Technologies, Inc. Di-tert-butyl
Furthermore, the investigation into exogenous phenolic
substrate O−H oxidation by [CuII(O2•−)]+ complexes has
been limited to the report of product yields for a few phenol or
catechol substrates. Thus, utilizing the tripodal tetradentate
ligand NMe2-tmpa (Chart 2), which forms a low-temperature
B
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1
peroxide was purchased from Nacalai Tesque Co., Ltd. and purified by
chromatography through alumina which removes traces of the
hydroperoxide. Cumene was purchased from Tokyo Chemical
Industry Co., Ltd. Air-sensitive compounds were synthesized and
transferred under an argon atmosphere using standard Schlenk
techniques and stored in an MBraun glovebox filled with N2.
[CuI(CH3CN)4]B(C6F5)4 was synthesized as previously reported.15
2,4,6-Tri-tert-butylphenoxyl radical (tBu3ArO•) was synthesized
following a procedure reported in the literature16 and characterized
with UV−vis absorption band at 384 and 402 nm and sharp EPR
signal at g = 2.00. Elemental analyses were performed by Desert
p-OCH2CH3-DTBP: H NMR (CDCl3) δ 6.758 (s, 2H), 4.757 (s,
1H), 4.02−3.95 (q, 2H, J = 6.9 Hz), 1.43 (s, 18H), 1.419−1.372 (t,
3H, J = 6.9 Hz); 13C NMR (CDCl3) δ 151.83, 147.66, 137.17,
111.262, 63.80, 34.576, 30.22, 15.10; FAB-MS calcd M+ = 250.19328,
found 250.19312.
1
p-OCD2CD3-DTBP: H NMR (CDCl3) δ 6.758 (s, 2H), 4.757 (s,
1H), 4.02−3.95 (q, 2H, J = 6.9 Hz), 1.43 (s, 18H), 1.419−1.372 (t, 3H
J = 6.9 Hz); 13C NMR (CDCl3) δ 151.83, 147.66, 137.17, 111.262,
63.80, 34.576, 30.22, 15.10; FAB-MS calcd M+ = 255.22466, found
255.22453.
1
p-OCD3-DTBP: H NMR (CDCl3) δ 6.766 (s, 2H), 4.773 (s, 1H),
1.43 (s, 18H); H NMR (CDCl3) δ 3.759 (s); 13C NMR (CDCl3) δ
2
1
Analytics, Tucson, AZ. The H NMR spectrum was measured on a
152.41, 147.68, 110.53, 34.57, 30.18; FAB-MS calcd M+ = 239.19696,
found 239.19629.
2
Bruker 300 MHz or a Bruker 400 MHz spectrometer. H NMR was
2
recorded on the broad-band coil on a 300 MHz instrument with H
p-OCH2CF3-DTBP: 1H NMR (CDCl3) δ 6.86 (s, 2H), 4.975(s, 1H),
4.40−4.316 (q, 2H, J = 8.4 Hz), 1.49 (s, 18H); 13C NMR (CDCl3) δ
150.64, 149.17, 137.49, 129.14−118.082 (q, J = 278 Hz) 112.19,
67.71−66.316 (q, J = 35.3 Hz), 34.59, 30.121; 19F NMR δ 74.61−
74.67 (t, J = 8.5 Hz); FAB-MS calcd M+ = 304.16501, found
304.16607.
resonance at 46 MHz. Chemical shifts are reported in parts per million
downfield against TMS or residual solvent signals unless otherwise
specified. Benchtop low-temperature UV−vis experiments were carried
out on a Cary bio-50 spectrophotometer equipped with a Unisoku
USP-203A cryostat using a 1 cm modified Schlenk cuvette. EPR
measurements were performed on a Bruker X-band EPR 5 mm quartz
EPR tubes (Willmad). Electrospray ionization (ESI) mass spectra were
acquired using a Finnigan LCQDeca ion-trap mass spectrometer
equipped with an electrospray ionization source (Thermo Finnigan,
San Jose, CA). Sulfur dioxide (SO2, gas) was prepared by mixing
sodium metabisulfite-saturated water and diluted sulfuric acid solution
(Figure S2). 2,4,6-Tri-tert-butyl-4-hydroperoxycyclohexa-2,5-dienone
p-OMPP-DTBP (2-Methyl-1-phenylpropan-2-yloxy): 1H NMR
(CDCl3) δ 7.332−7.31 (m, 5H), 6.778 (s, 2H), 4.931 (s, 1H),
2.989 (s, 2H), 1.431 (s, 18H), 1.235 (s, 6H); 13C NMR (CDCl3) δ
149.82, 147.18, 138.50, 136.15, 130.77, 127.83, 126.19, 120.88, 79.83,
48.85, 34.27, 30.28, 30.25, 26.23; FAB-MS calcd M+ = 354.25588,
found 354.25570.
was prepared as in the literature17 and characterized by H NMR
Preparation of 2H-O-2,6-Di-tert-butyl-4-methoxyphenol. A
Schlenk flask containing 1.25 g of p-OMe-DTBP and a stir bar was
dissolved in 20 mL of freshly distilled THF. The sample was then
chilled to −78 °C and 1.1 equiv of n-butyllithium dissolved in pentane
was slowly added to the solution. The solution was allowed to react at
low temperature for 30 min, after which 1.4 mL of D2O was added to
the solution in ∼150 μL portions. The solution was slowly allowed to
warm to room temperature and the solvent removed in vacuo, yielding
a white precipitate. The desired phenol was extracted from the flask by
the addition of ∼20 mL of freshly distilled pentane, and the resulting
pentane solution was filtered through a plug of Celite. The pentane
was removed in vacuo, yielding the desired product as a white solid.
The sample was stored in the glovebox, and the 2H content was
assessed by the absence of the RO−H proton resonance at ∼4.8 ppm.
2H content was determined to be >98%.
1
spectroscopy.
Ligand Synthesis. DMM-tmpa [tris((4-methoxy-3,5-dimethyl-
pyridin-2-yl)methyl)amine] ligand utilized in this report was
synthesized following a procedure described in the literature.18
2-Phthalimidomethyl-4-methoxy-3,5-dimethylpyridine: TLC on
1
alumina (1:1 = EtOAc/hexane), Rf = 0.63; H NMR (CDCl3) δ 8.05
(s, 1H), 7.89−7.86 (dd, 2H, J = 4 Hz), 7.72−7.70 (dd, 2H, J = 4 Hz),
4.93 (s, 2H), 3.75 (s, 3 H), 2.31 (s, 3H), 2.17 (s, 3H); FAB-MS calcd
MH+ = 297.12392, found 297.12352.
(4-Methoxy-3,5-dimethylpyridin-2-yl)methanamine: TLC on alu-
1
mina (95:5 = DCM/MeOH), Rf = 0; H NMR (CDCl3) δ 8.16 (s, 1
H), 3.87 (s, 2H), 3.71 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H), 1.98 (br s,
2H).
DMM-tmpa: TLC on alumina (95:5 = DCM/MeOH), Rf = 0.29;1H
NMR CDCl3 δ 8.18 (s, 3H), 3.74 (s, 6H), 3.65 (s, 9H), 2.22 (s, 9H),
1.61 (s, 9H); 1H NMR (acetone-d6) δ 8.16 (s, 3H), 3.68 (s, 9H), 3.67
(s, 6H), 2.21 (s, 9H), 1.62 (s, 9H); FAB-MS calcd MH+ = 465.28657,
found 465.28582.
Redox Potentials of para-Substituted 2,6-Di-tert-butyl-
phenols (p-X-DTBPs). The redox potentials were measured by
second harmonic AC voltammetry (SHACV) in CH3CN containing
−
0.10 M Bu4N+PF6 as a supporting electrolyte using an ALS-630B
electrochemistry analyzer with a three-electrode setup consisting of a
platinum disk working electrode, platinum wire counter electrode, and
a Ag/AgNO3 reference electrode. The voltammograms are plotted
against the [Fe(Cp)2]+/0 potential which was measured as an external
standard. The E0 values (vs Ag/AgNO3) were converted to those
versus the [Fe(Cp)2]+/0 (Fc/Fc+) potential which was measured as an
external standard. All electrochemical measurements were carried out
at 25 °C under argon atmosphere. Scans were run at 4 mV s−1.
Synthesis of [(DMM-tmpa)CuI(CO)]B(C6F5)4 (1). This complex
was synthesized in a manner very similar to that for the previously
reported complex [(NMe2-tmpa)CuI(CO)]B(C6F5)4.21 A 100 mL
Schlenk flask containing a stir bar, 100 mg of DMM-tmpa, and 195 mg
of [CuI(CH3CN)4]B(C6F5)4 was evacuated and the flask purged with
argon on the vacuum line. To this reaction flask was attached a Claisen
adapter fitted with two air-free addition funnels consisting of ∼50 mL
of THF and ∼125 mL of pentane, respectively. The argon line was
replaced with a carbon monoxide (CO) line, and the resulting
solutions were deaerated with briskly flowing CO(g) for 20 min.
Approximately, 10 mL of the CO-saturated THF solution was used to
dissolve the ligand and copper salt. The yellow solution was allowed to
stir for ∼5 min under a positive pressure of CO. The CO-saturated
pentane was added to the THF solution, resulting in the solution
turning cloudy and an oil settling to the bottom of the flask. Excess
solvent was decanted off under a CO(g) atmosphere and the resulting
4-Bromo-2,6-di-tert-butyl-2,5-cyclohexadienone: The preparation
of 4-bromo-2,6-di-tert-butyl-2,5-cyclohexadienone was accomplished
using a modified published procedure:19 1H NMR (CDCl3) δ 6.77−
6.75 (d, 2H), 5.38−5.36 (t, 1H), 1.24 (s, 9H); 13C NMR (CDCl3) δ
185.05, 143.74, 136.60, 77.31.
Synthesis of para-Alkoxyl-2,6-di-tert-butylphenols (p-OR-
DTBPs). Selected phenols were synthesized from adapted published
procedures.20 A 22 mL vial was charged with 810.7 mg of silver triflate
and a magnetic stir bar. To this vial was added 10 mL of the
corresponding alcohol (RO-H). If needed, a minimal amount of
dimethylethanol (DME) was used to dissolve the silver salt. To this
solution was rapidly added 900 mg of 4-bromo-2,6-di-tert-butyl-2,5-
cyclohexadienone dissolved in 2.5 mL of DME, resulting in the
immediate formation of a precipitate and the solution to turn yellow.
After 3 min, the solution was poured into a 50 mL solution containing
∼1 g of NaSH. The organics were separated by extraction four times
with 50 mL portions of pentane. This pentane solution was dried over
sodium sulfate and filtered using a 0.45 μm filter. The pentane was
removed by vacuum, and the phenol was purified by flash
chromatography using silica gel eluting with 0−2.5% gradient of
EtOAc/petroleum ether. The phenols were isolated as pale yellow to
white solids, and the purity was checked by NMR and GC−MS. If
necessary, phenols were crystallized from petroleum ether. Phenol
purity for kinetic analysis was >95%. The yields of phenols varied
according to substituent but were typically 25−70%.
1
oil dried under vacuum, yielding a white solid (70% yield): H NMR
C
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(acetone-d6) δ 8.39 (s, 3H), 4.13 (s, 6H), 3.82 (s, 9H), 2.29 (s, 9H),
2.24 (s, 9H). Cu−CO stretch 2085 cm−1 in CH3CN. Anal. Calcd: C,
50.56; H, 2.94; N, 4.54. Found: C, 50.96; H, 2.95; N, 4.52). Note: The
use of the CO adduct of the copper(I) complex is required in order to
prevent disproportionation. The counteranion, B(C6F5)4, is utilized for
better solubility of the superoxo−copper(II) complex and products
derived from its reactions at very low temperatures.
100 mL of a Hamilton gastight syringe equipped with a three-way
valve and needle outlet. After 2 was fully formed, three Ar/vacuum
purge cycles were applied to remove excess dioxygen and a stock
solution of substrates was added to the solution. When the reaction
ended, the Schlenk cuvette was taken out to be warmed at room
temperature. The solvent was removed in vacuo, redissolved in 300 μL
of the solvent, and transferred in a GC−MS vial. Then 1 μL was
injected into the GC−MS.
Generation of [(DMM-tmpa)CuII(O2•−)]B(C6F5)4 (2) and
Reaction with p-X-DTBP Derivatives. Kinetic Measurements. In
the glovebox, 0.27 mM solution of [(DMM-tmpa)CuI(CO)]B(C6F5)4
(1) was prepared in a 2.5 mL acetone solvent mixture (10% MeTHF),
and the 1 cm Schlenk cuvette was sealed with a rubber septum. Out of
the glovebox and at room temperature, the solution was immediately
purged for 15 s with CO(g) using a long syringe needle. The solution
was then cooled to the appropriate temperature (−100 to −85 °C),
and dioxygen was gently bubbled through the solution. Clean
isosbestic conversion to 2 was obtained within 15 min as monitored
by UV−vis spectroscopy.21 This green intermediate was stable for
hours at −90 °C. Phenol oxidation reactions were initiated by the
addition of a stock solution of phenol to the fully generated 2 after
three Ar/vacuum purge cycles. Pseudo-first-order rate plots were
performed by observing the disappearance of a 409 nm band to obtain
plots of ln[(A − Af)/(Ai − Af)] versus time (seconds), which were
found to be linear for three or more half-lives. {General notes: (i)
Complex 2 is stable for an hour at −90 °C in acetone, as judged by any
absorbance loss at λmax = 409 nm. This “lifetime” is well beyond times
needed for kinetic studies. (ii) The superoxo complex 2 can also be
generated in other solvents such as THF or MeTHF, but it is less
stable than in acetone. (iii) If CO(g) is not present in excess in the
initial solution of 1 (in 10% MeTHF/acetone at −90 °C), the
binuclear peroxodicopper(II) species [{(DMM-tmpa)CuII}2(μ-1,2-
O22−)]2+ readily forms upon addition of O2. (iv) Further, this
dicopper species is formed when higher concentrations of 1 (>1 mM)
are employed in the generation of the 2, thus confining the range of
concentrations used in all of the studies described. (v) Superoxo
complex 2 does slowly decay with warming to above −85 °C; however,
[{(DMM-tmpa)CuII}2(μ-1,2-O22−)]2+ is not the product.}
2
OR Product Analysis Using H NMR. Reactions were performed
using a 0.75 mM solution of [(DMM-tmpa)CuI(CO)] B(C6F5)4 (1)
in acetone. The [(DMM-tmpa)CuII(O2•−)]B(C6F5)4 (2) was
generated in a similar fashion described above at −95 °C. After
oxygenation, a solution containing 5 equiv of p-OR-DTBP (OR =
OCD3 or OCD2CD3) and benzene-d6 (as internal reference) was
added to the NMR tube. The sample was loaded to the spectro-
photometer at low temperature and the spectrum recorded. After
which, the sample was removed from the instrument, allowed to be
warmed to room temperature, and the spectrum of the solution
recorded.
Oxidation of Phenols by the Cumylperoxyl Radical (4). Kinetic
measurements were performed on a JEOL X-band spectrometer (JES-
ME-LX) at 183 K. Typically, photoirradiation of an oxygen-saturated
acetone solution containing di-tert-butyl peroxide (1.0 M) and cumene
(1.0 M) with a 1000 W mercury lamp resulted in formation of
cumylperoxyl radical (g = 2.0156) which could be detected at low
temperatures. The g values were calibrated by using a Mn2+ marker.
Upon cutting off the light, the decay of the EPR intensity was recorded
with time. The decay rate was accelerated by the presence of p-X-
DTBPs (1.0 × 10−2 M). Rates of hydrogen transfer from p-X-DTBPs
to PhCMe2OO• were monitored by measuring the decay of the EPR
signal of PhCMe2OO• in the presence of various concentrations of p-
X-DTBPs in acetone at 183 K. Pseudo-first-order rate constants were
determined by a least-squares curve fit using a personal computer. The
first-order plots of ln (I − I∞) versus time (I and I∞ are the EPR
intensity at time t and the final intensity, respectively) were linear for
three or more half-lives with the correlation coefficient, ρ > 0.99. In
each case, it was confirmed that the rate constants derived from at least
five independent measurements agreed within an experimental error of
5%.
Quantification of 2,6-Di-tert-butyl-1,4-benzoquinone with Gas
Chromatography−Mass Spectrometry (GC−MS). A Schlenk flask
was charged with 10 mL of 0.25 mM acetone solution of [(DMM-
tmpa)CuI(CO)]B(C6F5)4 (1) in the glovebox, and out of the
glovebox, the solution was immediately purged with CO(g) at room
temperature. The solution was then cooled to the −90 °C acetone/
liquid nitrogen cooling bath, and dioxygen was gently bubbled through
the solution to generate [(DMM-tmpa)CuII(O2•−)]B(C6F5)4 (2).
After 2 was fully formed, three Ar/vacuum purge cycles were applied
to remove excess dioxygen, and a stock solution of substrates (1−50
equiv) was added to the solution. When the reaction ended, the
Schlenk flask was warmed to room temperature. (Note: we also
analyzed solutions quenched at low temperature by addition of SO2,
but the results and yields of reactions were not affected). The solvent
was removed in vacuo, redissolved in 300 μL of the solvent, and
transferred in a GC−MS vial with addition of 0.8 μmol of naphthalene
as a standard. Then 1 μL was injected into the GC−MS. The area ratio
was converted to mole ratio to quantify the yield of DTBQ by using a
standard curve. All GC−MS experiments were carried out and
recorded using a Hewlett-Packard 6890 series gas chromatograph
system equipped with 5973N mass selective detector. The GC−MS
conditions for the product analysis were as follows: injector port
temperature = 250 °C; column temperature = initial temperature = 80
°C; initial time = 2 min; final temperature = 280 °C; final time = 2
min; gradient rate = 10 °C/min; flow rate = 14.2 mL/min; ionization
voltage = 1.3 kV.
Hydrogen Peroxide Quantification. Detection of H2O2 as a
product has been performed with CH3CN-saturated NaI solution as in
a recent report.22 First, 2.5 mL of a 0.6 mM solution of [(DMM-
tmpa)CuII(O2•−)]B(C6F5)4 (2) was generated in a Schlenk cuvette in
a typical way. After the reaction with p-X-DTBP was ended, the
solution was taken out and warmed to room temperature. Then, 70 μL
of solution was added into 2.0 mL of a CH3CN-saturated NaI solution
at room temperature in the darkness. The UV−vis spectrum of this
−
solution displayed the formation of triiodide (I3 ) at 362 nm, and the
yield was calculated by comparing with a standard H2O2 solution of
known concentrations. 2,4,6-Tri-tert-butyl-4-hydroperoxycyclohexa-
2,5-dienone was also found to oxidize the iodide ion.
Attempt To Detect Formaldehyde. The detection of the
formaldehyde was accomplished spectrophotometrically via an
aqueous-based Nash assay.23 The Nash reagent was prepared by
dissolving 7.5 g of ammonium acetate, 100 μL of 2,4-pentadione, and
150 μL of acetic anhydride in 50 mL of water. Eight milligrams of
[(DMM-tmpa)CuI(CO)]B(C6F5)4 (1) was dissolved in 5 mL of
acetone and transferred to a Schlenk flask, capped with a rubber
septum, and bubbled with CO(g) for ∼30 s. This reaction vesicle was
put in a −95 °C acetone bath. The formation of [(DMM-
tmpa)CuII(O2•−)]B(C6F5)4 (2) was achieved by O2 displacement for
∼10 min at which time 7.4 mg of para-methoxy-2,6-di-tert-butylphenol
dissolved in 200 μL of acetone was added to the solution. The reaction
was allowed to react at −95 °C for 45 min at which time the reaction
was quenched at low temperature with SO2(g). The solution was
allowed to be warmed to room temperature, and a 250 μL aliquot of
the reaction solution was added to a vial charged with 2 mL of the
Nash reagent cocktail. The reaction mixture was capped, sealed, and
heated to 60 °C for 90 min at which time the absorbance at 413 nm
was recorded.
18O-Labeling Experiments. A Schlenk cuvette was charged with 2.5
mL of 1 mM acetone solution of [(DMM-tmpa)CuI(CO)]B(C6F5)4
(1) in the glovebox, and out of the glovebox, the solution was
immediately purged with CO(g) at room temperature. The solution
was then cooled to the −90 °C, and 18O2 was gently bubbled through
the solution to generate [(DMM-tmpa)CuII(O2•−)]B(C6F5)4 (2)
monitored by UV−vis spectroscopy. 18O2 (Icon 6393) was prepared in
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Attempt To Detect Isobutylene. The attempt for detecting
isobutylene (gas) as one of the products was performed by using
GC−MS. An isobutylene-saturated acetone solution was injected as an
authentic standard, and it could be easily detected by GC−MS.
However, when the reaction solution was tested, there was no
evidence of isobutylene. We attribute this to the low concentrations
(maximum 1 mM) used for reaction.24
Resonance Raman Spectroscopy. Resonance Raman spectra were
recorded on a Princeton Instruments ST-135 back-illuminated CCD
detector and on a Spex 1877 CP triple monochromator with 1200,
1800, and 2400 grooves/mm holographic spectrograph gratings.
Excitation was provided by a Coherent I90C-K Kr+ ion laser (λex = 407
nm). The spectral resolution was <2 cm−1. Spectra were recorded at 5
mW power at the sample, and the samples were cooled to 77 K in a
quartz liquid nitrogen finger Dewar (Wilmad). Baseline spectra were
collected using ground, activated charcoal. Isotopic substitution was
achieved by oxygenating with 18O2 (Icon, Summit, NJ).
RESULTS AND DISCUSSION
■
Spectroscopic Characterization of [(DMM-tmpa)-
CuII(O2•−)]+ (2). There exist three structurally characterized
cupric−superoxo complexes. One is a synthetic complex from
Fujisawa−Kitajima with a side-on η2-bound O2•− fragment. It is
a ground-state singlet species (S = 0) and from resonance
Raman spectroscopy νO−O = 1043 cm−1.25 There is also the
already mentioned case of the PHM protein X-ray structure,
considered to have the CuII(O2•−) formulation and end-on
bound O2 fragment.11 The physical properties of this species
within the protein are still lacking. Closely related to our own
case here, 2, is the now very well-known complex from
Sundermeyer and Schindler,26 [(TMG3tren)CuII(O2•−)]+
(TMG3tren = (1,1,1-tris[2-[N2-(1,1,3,3-tetramethyl-
guanidino)]ethyl]amine), with analogous tripodal tetradentate
ligand, and end-on superoxo binding (∠Cu−O−O = 123°) (X-
ray structure, Figure 2) with νO−O = 1120 cm−1 (Δ18O2 = −63
Figure 3. (a) Absorption spectra of 1 (0.27 mM) and 2 after addition
of O2(g) in acetone (10% MeTHF) at 183 K. (b) Resonance Raman
spectra of 2 (0.7 mM) measured in MeTHF (λex = 407 nm). Red,
16O2; blue, 18O2.
and 1030 M−1 cm−1, respectively. This complex is EPR silent
(Figure S3). Complex 2 is stable enough (t1/2 > ∼3 h; −90 °C)
to investigate its reactivity toward external substrates.
Compared to the parent tmpa ligand (without any pyridyl
substituents) CuII−superoxo complex, which can only be
observed as a fleeting intermediate at −128 °C in MeTHF,29
the electron-donating groups on the DMM-tmpa ligand (as also
for NMe2-tmpa; Chart 2)21 provide significant electron density
to the copper center, resulting in stabilization of [(ligand)-
CuII(O2•−)]+ species.
Figure 2. Structural representation of [(TMG3tren)CuII(O2•−)]+.26
Resonance Raman spectra of [(DMM-tmpa)CuII(O2•−)]+
(2) (λex = 407 nm) reveal two dioxygen isotope-sensitive
vibrations (Figure 3b). An O−O vibration is observed at 1121
cm−1, which shifts to 1058 cm−1 (Δ18O2 = −63 cm−1) upon
18O2 substitution. An additional isotope-sensitive vibration
attributed to the Cu−O stretch occurs at 474 cm−1 (Δ18O2 =
−18 cm−1). These parameters closely match those for
[(TMG3tren)CuII(O2•−)]+ and other cupric−superoxo com-
plexes with tripodal tetradentate N4 ligands.21,27,30
cm−1). The electronic structure of this molecule has been
delineated by Solomon and co-workers,27 and the molecule
possesses a triplet ground state with ferromagnetically coupled
spins on both the Cu(II) ion and superoxo fragment. In fact,
the finding of a triplet ground state for cupric−superoxo
complexes possessing tripodal tetradentate ligands is general.28
Based on the physical properties of [(DMM-tmpa)-
CuII(O2•−)]+ (2), as described here, it has a physical and
electronic structure very similar to that of [(TMG3tren)-
CuII(O2•−)]+. Complex 2 was generated in acetone and/or
MeTHF at −90 °C via displacement of CO(g) by bubbling O2
gas through a solution of [(DMM-tmpa)CuI(CO)]+ (1); a
further discussion of why/how this procedure is employed, with
references, is given in the Experimental Section. Thus, 2 has
been presently characterized by UV−vis and resonance Raman
spectroscopies. The absorption spectrum of this green colored
complex is shown in Figure 3a, and three primary absorption
bands are observed: 409, 587, and 743 nm with ε = 4250, 1100,
Reactivity of [(DMM-tmpa)CuII(O2•−)]+ (2) toward
para-Substituted 2,6-Di-tert-butylphenols. As mentioned
in the Introduction, the broader perspective for why the present
study was undertaken is that our general knowledge of
[CuII(O2•−)]+ reactivity is very limited. There are a few highly
interesting examples of C−H oxidation reaction (vide infra),
and as also indicated, we provided initial descriptions of phenol
oxygenation (giving benzoquinones) with both [(NMe2-
tmpa)CuII(O2•−)]+ (Chart 2)21 and [(TMG3tren)CuII(O2•−)]+
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Table 1. Phenol BDE’s, Redox Potentials (Eox), Second-Order Rate Constants (183 K) for p-X-DTBP Phenol Oxidations by 2
and 4 and Reaction Yields (See Figure S10 for Kinetics Details)
a
c
d
d
BDE (kcal mol−1
)
Eox, V (vs Fc/Fc+)
k2 of 2 (M−1 s−1
)
k2 of 4 (M−1 s−1
)
DTBQ yield (%)
49
C
substituent (X)
OCH2CH3
0.532
0.526
0.496
0.585
0.614
0.805
0.81
24
714
520
513
58
OCH3
79.6
23
OCD3
21
OR
OCH3, −OD
2.1
b
OMPP
0.84
0.81
0.042
0.027
0.023
0.010
0.008
350
329
185
160
152
44
OCH2CF3
CH3
80.1
80.0
CH2CH3
sec-butyl
CH3, −OD
tert-butyl
H
0.875
0.884
0.896
0.927
1.074
R
82.3
106
38
82.7
NR
a
b
c
Bond dissociation energy in DMSO.31 OMPP = 2-methyl-1-phenylpropan-2-yloxy. These were determined from SHACV measurements; see
d
Experimental Section. The experimental error is 0.01 V. The experimental error is 5%.
(Figure 2).32 At first, we planned to employ either or both of
these complexes for detailed phenol oxidation/oxygenation
reactivity studies but found them to have a very narrow range of
substrates that could be oxidized (in terms of O−H BDE), and
even where oxidation occurred, the reactions were exceptionally
slow (Figure S4), thus not amenable to kinetic investigations, as
compared to what we find here for reactions of complex 2. A
very simple analysis and conclusion would be that the superoxo
moiety in [(NMe2-tmpa)CuII(O2•−)]+, with its very electron-
releasing pyridyl p-NMe2 substituents, is less electrophilic than
the superoxo complex in 2, with its pyridyl p-OMe substituents.
As to how this translates to reactivity of phenols with varying
O−H BDE, we can judge from the BDE values of substrates in
Table 1 that the BDE of the Cu−OOH complex must be larger
than 79.6 kcal mol−1 but smaller than 82.7 kcal mol−1. Initial
survey of reaction of 2 with a variety of phenols indicated that
the kinetic studies and product analyses were viable for a good
range of phenols, both p-alkoxy-2,6-di-tert-butylphenols (p-OR-
DTBP) and p-alkyl-2,6-di-tert-butylphenols (p-R-DTBP)
(Table 1).
Kinetic and Thermodynamic Studies. Demonstration
of Hydrogen Atom Transfer Chemistry. Kinetic isotope
labeling studies on the oxidation of the two phenol substrates
p-OMe-DTBP and p-Me-DTBP by [(DMM-tmpa)-
CuII(O2•−)]+ (2) were performed under pseudo-first-order
conditions at 183 K by following the disappearance of the 409
nm band, as shown in Figure 4a.33 In both cases, the decay
behavior observed fits to a first-order kinetics and yields an
observed rate constant (kobs) which was linear with respect to
the substrate concentration, as shown in Figure 4b. A second-
order rate constant (k2) of 23 M−1 s−1 was obtained for the
oxidation of proteo p-OMe-DTBP. Using a substrate which had
been subjected to deuterium (2H−O) exchange (see
Experimental Section), a significant deceleration of the reaction
rate was observed, yielding a second-order rate constant of 2.1
M−1 s−1. Thus, a primary kinetic isotope effect (KIE) of 11 was
obtained. Using p-Me-DTBP, a lower but significant KIE of 4.2
was observed based on the determination of k2 = 4.2 × 10−2
and 1.0 × 10−2 M−1 s−1 obtained for the oxidation of the
proteo- and deuterium-labeled phenols, respectively. Thus, it
appears that the oxidations of both the p-alkoxy-DTBP and p-
alkyl-DTBP by 2 occur via a rate-limiting O−H activation
event.
Comparison of KIEs to Other Metal−Superoxo-Mediated
Oxidations. There have been no prior reports of O−H KIEs by
cupric−superoxo complexes. However, primary KIEs of 10.6
and 10.9 are reported for the C−H activation of hippuric acid
and dopamine by PHM and DBM, respectively,34 thought to be
effected by a protein cupric−superoxide moiety.6b,10 In a
bioinspired synthetic system, a value of 12.1 was reported for
the oxidation of BNAH (1-benzyl-1,4-dihydronicotinamide) for
the PV-tmpa [bis(pyrid-2-ylmethyl) ([6-(pivalamido)pyrid-2-
yl]methyl)amine] cupric−superoxo complex.30 A lower magni-
tude of 4.1 was reported for the intramolecular benzylic C−H
oxidation of a phenethyl ligand arm in a chelated copper(II)−
superoxo complex reported by Itoh and co-workers.35 In
addition, this value (KIE = 12) is approximately equal to what
is observed for the oxidation of a water-soluble trisubstituted
phenol by a chromium−superoxo described by Bakac and co-
workers.36 All of these results are consistent with the substrate
activation via homolytic O−H bond cleavage.
Cumylperoxyl Radical (4) Plus Phenol Substrate HAT
Reactions for Comparison. To provide further evidence that
hydrogen atom transfer is the rate-determining step in these
reactions, we studied the same substrates with cumylperoxyl
radical (4); the latter is known to effect “pure” HAT chemistry
with phenols (and N,N-dimethylanilines).13,37 This hydrogen
atom acceptor reacts with phenols to yield cumene hydro-
peroxide and phenoxyl radical; here, we wished to compare the
behavior of 4 with phenols to that of the reactions of [(DMM-
tmpa)CuII(O2•−)]+ (2) and phenols (Scheme 2). Thus, to
understand the relationship between second-order rate
C
constants for 2 (k2) and 4 (k2 ) (Table 1), the reaction of
the whole series of substrates with 2 and 4 has been explored
monitoring the chemistry with the use of UV−vis and EPR
spectroscopies, respectively (see Experimental Section). A large
KIE value (KIE = 9.0) was observed for hydrogen atom transfer
from p-OMe-DTBP to 4, as shown in Figure S5. The k2 values
C
display a linear correlation with k2 , which further indicates that
HAT is involved in the rate-limiting step of phenol oxidations
by 2 (Figure 5). If the rate-determining step was to be pure
HAT, as in case of 4, the slope would be 1. The larger slope
observed (=4.85) from the plot obtained indicates that some
degree of contribution of partial transfer of charge is also
involved in the rate-determining step for 2 plus phenol
reactions.
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C
Figure 5. Correlation between log k2 of 2 and log k2 of 4 with p-X-
DTBPs. Slope is 4.85.
Rate Constant (k2) Correlation to Phenol Redox Potentials
? We also considered possible relationships between the
second-order rate constants for the reaction of [(DMM-
tmpa)CuII(O2•−)]+ (2) with phenols (k2) and substrate redox
potentials. In fact, k2 values for the reactions increase with
decreasing the redox potentials, that is, with increasing driving
force of electron transfer from phenols to 2. The plot of (kBT/
e) ln k2 versus Eox exhibits a linear correlation with a negative
slope = −0.29, as shown in Figure 6. By contrast, for the case of
Figure 4. (a) UV−vis spectral changes observed by addition of p-Et-
DTBP (20 mM) to 2 (0.27 mM) in acetone (10% MeTHF) at 183 K;
kobs = 5.73 × 10−4 s−1. (b,c) Plots of kobs values against the
concentrations of substrates (circles) and deuterated 2H−O substrates
(squares) for p-OMe-DTBP (b) and p-Me-DTBP (c) to determine
second-order rate constants and KIEs.
Figure 6. Plots of (kBT/e) ln k2 for the reactions of p-X-DTBPs with 2
(squares) and 4 (circles) against the one-electron oxidation potentials
(Eox) of substrates. The slopes are −0.29 and −0.05, respectively.
C
Scheme 2
cumylperoxyl radical (4), the plot of (kBT/e) ln k2 versus Eox
exhibits a much weaker dependence on the Eox values, and the
slope is only −0.05. Although the bond dissociation energy
(BDE) of p-X-DTBP is known to decrease by electron-
donating substituents,38 the difference in BDE between OCH3
and tert-butyl group is only 2.7 kcal mol−1, which is equivalent
to 0.12 eV, whereas the difference in Eox between OCH3 and
tert-butyl group is 0.40 eV (Table 1). Based on thermochemical
cycles,37 the difference in BDE (ΔBDE) is given by eq 2.
ΔBDE = eΔEox + kBTΔpKa
(2)
where ΔpKa is the difference in the pKa values of p-X-DTBP•+
and entropy changes are neglected. The pKa value becomes
smaller with increased Eox value, and the constant BDE value
(eq 2) indicates that an increase in the Eox value is partially
canceled by a decrease in the pKa value. Such cancellation may
be the reason why the BDE value is much less sensitive to
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electron-donating substituents in Table 1 as compared to the
Eox value.
Mechanistic Considerations. There are three possible
reaction pathways in the apparent hydrogen atom transfer
from p-X-DTBP to [CuII(O2•−)]+: (1) electron transfer
followed by proton transfer, (2) PT followed by ET; and (3)
concerted ET and PT (Scheme 3). The observation of large
Activation Parameters and Comparisons. The rates of the
[(DMM-tmpa)CuII(O2•−)]+ (2) + p-X-DTBP reactions were of
course temperature-dependent. However, we could only
examine a narrow temperature range, as colder (than 173 K)
conditions involved solution freezing, while self-decomposition
of 2 was too extensive when warming above 188 K. Also, the
slow self-decomposition precluded the generation of good
quality data except for the fastest reaction, that being with the
p-OMe-DTBP substrate. Nevertheless, an Eyring plot devel-
oped from data between 173 and 188 K for this substrate
yielded activation parameters as follows: ΔH⧧ = 3.6 0.6 kcal
mol−1 and ΔS⧧ = −32 3 cal mol−1 K−1 (Figure S6). The large
negative activation entropy suggests that the rate-determining
step involves a well-ordered transition state.
Scheme 3
Although no comparable activation parameters for p-X-
DTBP oxidation by cupric−superoxide or other Cu−oxygen
complexes have been reported, there are a few values measured
for oxidation of phenol derivatives by various other metal ion
complexes, including CuIII, RuVI, MnV, and RuIII (Table 2).42
Table 2. Kinetic Parameters in Various Metal Complexes
Plus Phenol Oxidation Reactions
ΔH⧧
ΔS⧧
reactants
(kcal mol−1
)
(cal mol−1 K−1
)
KIEs in Figure 4 indicates that PT should be involved in the
rate-determining step. In such a case, PT should be the rate-
determining step following the ET equilibrium, which is
endergonic, in the electron transfer/proton transfer (ET/PT)
pathway (1).39 In this case, the observed second-order rate
constant (k2) is given by eq 3.
a
CuII−O2
p-OMe-DTBP
3.6 0.6
8.3 1.1
11.3 0.8
6.3 1.4
1.6 0.2
−32
−27
−14
−35.6 2.3
−36
3
3
2
•−
Cu(III)42a
Ru(VI)42b
Mn(V)42c
Ru(III)42d
2,4-DTBP
phenol
2,4-DTBP
p-tBu-DTBP
2
a
This work.
k2 = kpKet
(3)
Except for the case of the reaction of a RuIII-pterin complex,
which was concluded to involve PCET, all other cases are
stated as involving HAT in the rate-limiting step. In particular,
the HAT reaction of a manganese(V)−oxo corrolazine complex
plus 2,4-di-tert-butylphenol (2,4-DTBP) affording MnIV(OH)
plus 2,4-di-tert-butylphenoxyl radical gives both ΔH⧧ and ΔS⧧
values close to those obtained from our reaction of 2 and p-
OMe-DTBP.
where kp is the rate constant of proton transfer from p-X-
DTBP•+ to [CuII(O22−)]0 and Ket is the ET equilibrium
constant between p-X-DTBP and [CuII(O2•−)]+ (Ket ≪ 1).
Because the Brønsted slope of kp is between 0 and 0.5 for an
exergonic proton transfer reaction,40 and the slope of the plot
of (kBT/e) ln Ket versus Eox is −1.0, the predicted slope of a
plot of (kBT/e) ln k2 versus Eox is between −0.5 and −1.0.
In the case of the PT/ET pathway (2), PT should also be the
rate-determining step followed by fast ET. In this case, the
slope of the plot of (kBT/e) ln k2 versus Eox is positive because
an increase in the Eox value with electron-withdrawing
substituents results in an decrease in the pKa value (more
acidic) when the proton transfer from p-X-DTBP to
[CuII(O2•−)]+ becomes thermodynamically more favorable.
The observed negative slope (−0.29) clearly rules out the PT/
ET pathway. Although the ET/PT pathway affords the negative
slope of a plot of (kBT/e) ln k2 versus Eox is between −0.5 and
−1.0, the observed slope (−0.29) is less negative than −0.5. In
the case of the concerted ET/PT pathway (one-step hydrogen
atom transfer), the slope is −0.05 as observed for hydrogen
atom transfer from p-X-DTBP to 4. The smaller slope than
expected for transfer of a full unit of charge has been reported
to result from only partial transfer of charge in hydrogen atom
transfer reactions from hydrogen donors to the triplet excited
state of benzophenone.41 Thus, it is most likely that hydrogen
transfer from p-X-DTBP proceeds via a partial transfer of
charge rather than an ET/PT pathway in which a full unit of
charge is transferred. Thus, more electron-deficient ligands may
be required in order to increase the hydrogen transfer reactivity
of [CuII(O2•−)]+ by facilitating charge transfer from p-X-DTBP
to [CuII(O2•−)]+.
KIE Temperature Dependence? We also investigated the
temperature dependence of the KIE values for the reaction with
deuterated p-OMe-DTBP (Table 3, Figure S6). While the
Table 3. Temperature Dependence on the KIEs of the HAT
Reactions from p-OMe-DTBP to [(DMM-
tmpa)CuII(O2•−)]+ (2)
kH (M−1 s−1
)
kD (M−1 s−1
)
kH/kD
173 K
178 K
183 K
188 K
11
14
23
26
1.0
1.2
2.1
2.7
11
12
11
10
temperature range is again limited, the results suggest there is
no temperature dependence on the magnitude of the primary
KIEs. Thus, the Arrhenius pre-exponential factor for the phenol
O−H and O−D isotopically labeled analogues remains
essentially constant as a function of temperature. This behavior
is consistent with a substrate oxidation mechanism involving
classical rate-limiting H atom abstraction.43
Summary of the Kinetic−Thermodynamic Studies. As
detailed above, our in-depth studies are consistent with the
H
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Scheme 4. Proposed Pathways for [CuII(O2•−)]+ Reactivity with p-OMe-DTBP or p-tBu-DTBP Substrates Leading to Observed
a
Products
a
See text for detailed descriptions of direct/indirect evidence or literature support for the individual reaction steps or intermediates described. EPR
spectra observed for (A ≡ A′) (from mixing 2 and p-X-DTBP at −90 °C), for LCuII−OH(H) (observable at room temperature and refreezing to
record EPR spectra) are indistinguishable; see Figure S7 and caption.
conclusion that the cupric−superoxo complex [(DMM-tmpa)-
CuII(O2•−)]+ (2), as a kind of prototype for the initial adducts
formed in chemical or biological CuI/O2 interactions, reacts
with p-OMe-DTBP (and the other phenols) via a HAT
oxidative mechanism. Likewise, as mentioned above, rate-
limiting HAT occurs for the galactose oxidase active site special
Tyr, but PCET in CAO has been suggested by Klinman7c and
Roth.8 In relevant C−H bond activation by [CuII(O2•−)]+
species, Klinman and Blackburn reported C−H bond cleavage
in N-benzoylglycine by PHM having large intrinsic isotope
effects.34a They also demonstrated hydrogen tunneling as
occurring in PHM with a lack of a temperature dependence of
an intrinsic isotope effect on the C−H bond cleavage of the
substrate hippuric acid.44 As also mentioned, Itoh and co-
workers reported intramolecular C−H hydroxylation (HAT)
by a cupric−superoxo species supported by tridentate ligand
possessing a distorted tetrahedral geometry.35a
temperature UV−vis (new d−d bands) and EPR (EPR silent to
EPR active) spectroscopies reveal that a new mononuclear CuII
complexes has formed, but NMR spectroscopy suggests that no
quinone has yet formed and only starting extra phenol is
present. However, warming of these initial reaction solutions to
room temperature followed by NMR and GC−MS analyses
indicates that up to 50% yields of 2,6-di-tert-butyl-1,4-
benzoquinones form (Scheme 1). An 18O-labeling experiment
(see Experimental Section) where 2 was generated using 18O2
gas revealed that no 18O was incorporated into the DTBQ. This
is explained below; only the overall two-electron oxidation of
the substrate phenol takes place, while hydrogen peroxide and
alcohol products are also formed. The fate of the initial para-
2
OR fragment, after warming, was identified by H(D)-labeling
experiments using p-OCD3/OCD2CD3-DTBP substrates (Fig-
ure S9). In each case, the product detected was the
corresponding alcohol (methanol and ethanol), not the
oxidized form (formaldehyde and acetaldehyde). The inorganic
product is a mononuclear copper(II) complex [(DMM-
tmpa)CuII-(OH(H))]+/2+, and H2O2 is produced (∼50%
yield), as determined by EPR/UV−vis spectroscopy (see
Figures S7, S8, and S13) and iodometric titration, respec-
tively.45
Product Analyses and Further Mechanistic Insights.
Phenol Oxidations Lead to Benzoquinone Products. As
described above in detail, the initial products generated after
rate-limiting hydrogen atom transfer occurs are presumed to be
a [(DMM-tmpa)CuII(OOH)]+ (3) and a para-X-2,6-di-tert-
butylphenoxyl radical (Scheme 2). Such a phenoxyl radical
would possess distinctive λmax = 384 and 402 nm absorptions
and exhibit a sharp g ∼ 2.0 EPR spectroscopically detectable
signal. However, neither of these spectroscopic signals could be
observed. Thus, qualitative and quantitative product analyses
were carried out, allowing us to understand and build up the
proposed overall mechanism and stoichiometry of the reactions
observed. In fact, for all phenolic substrates, benzoquinones are
produced. As mentioned above, reactions of 2 with p-OR-
DTBP and p-R-DTBP proceed via different pathways, two-
electron oxidation and four-electron oxygenation, respectively,
and these further aspects of the overall chemistry are now
detailed.
Proposed Pathway for [CuII(O2•−)]+ (2) Reaction with p-
OR-DTBP Substrates (Scheme 4). Initially, a hydrogen atom is
transferred from the phenol to [CuII(O2•−)]+ as the (low-
temperature) rate-determining step, where [CuII(OOH)]+ and
the corresponding phenoxyl radical form (Scheme 4, step i).
The [CuII(OOH)]+ intermediate would “hydrolyze”, giving
H2O2 and [CuII(OH)]+ (Scheme 4, step iii) (upon warming to
room temperature). Strong support for this claim comes from
our independent generation of authentic complex
[CuII(OOH)]+ (3) and demonstration that it releases H2O2
(which was directly identified) and forms the hydroxide
complex, [CuII(OH)]+. This was identified as the Cu product
by matching EPR and UV−vis spectroscopic data with
authentically generated compounds (see Supporting Informa-
tion). The formation of the eventual benzoquinone and other
products is explained by (a) fast radical−radical coupling
reaction of the newly generated ArO• moiety and a second
equiv [CuII(O2•−)]+, affording a peroxy CuII−OO-(ArO′)
Reaction of [(DMM-tmpa)CuII(O2•−)]+ (2) with p-Alkoxy-
2,6-di-tert-butylphenols (p-OR-DTBPs). All synthetic reactions
were carried out by mixing excess phenol substrate with 2 at
−90 °C. The cryogenic solutions were interrogated by UV−vis,
NMR, and EPR spectroscopies. As described for the initial
kinetics of the system (vide supra), 2 rapidly disappears. Low-
I
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species A (Scheme 4, step ii); (b) then this reacts with solvent
water to give B, which eliminates the alcohol (RO−H) derived
from the p-OR-DTBP substrate (step iv). {Note: if this
hydrolysis step involved CuII−OOH rather than CuII−OO−
(ArO′) bond cleavage, then the corresponding hydroperoxo
intermediate C (HOO−(ArO′)) (Scheme 5) forms, rather than
Scheme 6
Scheme 5
vis monitoring), and the Cu(II) EPR spectrum previously
observed for the [(DMM-tmpa)CuII(OH(H))]+/2+ product
appears. The yield of DTBQ was 98%, and a 70−80% 18O
incorporation into the DTBQ product was observed. Thus, the
t
2 + Bu3ArO• occurs with a 1:1 stoichiometry (Scheme 4, step
ii), and this then supports the [CuII(O2•−)]+/phenol = 2:1
overall stoichiometry. In contrast to the case of p-OR-DTBP,
the oxygen incorporated into the oxidized product (DTBQ)
obtained from the reaction of p-R-DTBP with 2 originates from
2 via O−O bond cleavage followed by the elimination of the
oxidized R group (Scheme 4, step v).
Minor Reaction Pathway Contributing to p-R-DTBP
Oxidation. If the reaction of [(DMM-tmpa)CuII(O2•−)]+ (2)
our postulated B with HO−(ArO′) formulation. However, C
would be incapable of producing methoxide/methanol plus
benzoquinone, our observed products. If C or CuII−peroxo
derivative A were to form, CH2O would be produced
(Scheme 5), but none was observed (Experimental Section).}
Kinetic aspects for quinone formation were not investigated in
detail, as this step occurs later, with warming of the reaction
solutions (also see Experimental Section).
t
with p-R-DTBP (or that of 2 + Bu3ArO•) occurred only via
step v (Scheme 4), the product solution should not oxidize
iodide since no H2O2 would have been generated. However, we
observed 20−30% of triiodide absorption band formation when
testing for peroxide. We explain this by invoking the “minor”
step vi, where hydrolysis of A′ occurs giving 2,4,6-tri-tert-butyl-
4-hydroperoxycyclohexa-2,5-dienone (C′), which (i) does
oxidize iodide ion (see Experimental Section) and (ii) slowly
converts to DTBQ (at room temperature) but (iii) fully
converts to DTBQ in the GC−MS experiment.
Reaction of [(DMM-tmpa)CuII(O2•−)]+ (2) with p-Alkyl-2,6-
di-tert-butylphenols (p-R-DTBPs). For the case where the para-
substituent is an alkyl group like tert-butyl, the reaction of p-R-
DTBP plus [(DMM-tmpa)CuII(O2•−)]+ (2) proceeds differ-
ently, via an overall four-electron substrate oxygenation. In the
initial reaction, steps i and ii proceed analogously, producing
the CuII−OO−(ArO′) species A′ (Scheme 4). This, however,
can undergo a tert-butyl substituent oxidation via elimination of
isobutylene, then directly giving the DTBQ and Cu(II)
products observed (Scheme 4, step v).46 Isobutylene or
tBuOH (=isobutylene + H2O) elimination from tert-butyl-
substituted phenols under oxidative conditions is well
precedented.47 We, however, were not able to detect
isobutylene as a product.24,48
Precedent and Comparison with Cobalt and Nickel−
Superoxide Phenol Oxidations. In the overall process
involving reaction of the p-X-DTBP, steps i and ii (top line;
Scheme 4), a second molar equiv of [(DMM-tmpa)CuII(OH)]+
and H2O2 is produced, all consistent with the identity and
yields of products obtained and thus the reaction stoichiometry.
Nishinaga and co-workers, in classical studies of the reactions of
[CoIII(O2•−)]+ (formed from CoII and O2), also observed this
same reaction stoichiometry, involving two [CoIII(O2•−)]+
moieties with one phenol substrate. Further, Nishinaga’s work
provides precedent for the proposed (Scheme 4) reaction of
[(DMM-tmpa)CuII(O2•−)]+ (2) with the initially generated
phenoxyl radical intermediate;51 Nishinaga51b also obtained a
cobalt peroxy species CoIII−OO−(ArO′), and its X-ray
structure for a para-tBu phenol substrate (Scheme 7). Further,
in order to explain the products observed in very recent
investigations by Driess and co-workers,52 involving phenol
reactions with a new [NiII(O2•−)]+ complex, an intermediate
analogous to A′ was proposed to form from p-R-DTBP (R = H,
As can be seen from Scheme 4 (step v), the product DTBQ
in the [(DMM-tmpa)CuII(O2•−)]+ (2) plus p-R-DTBP
substrate reaction should have one of its O atoms derived
from molecular oxygen (derived from 2). Indeed, this appears
to be the case. The reaction of p-tBu-DTBP with 2 provides for
a quantitative yield of DTBQ (based on the stoichiometry of
two molecules of 2 per one mole of phenol substrate). For 18O-
labeled 2 (derived from 1 plus 18O2), reaction with p-tBu-DTBP
affords a 40% of 18O-incorporated DTBQ (GC−MS). The
smaller isotope incorporation yield than expected may result
from the 18O−16O exchange reaction with water because
carbonyl compounds are known to undergo oxygen exchange
reactions with water, catalyzed by acids or bases.49
t
Me, Bu) substrates.
Prior Computational Study of [CuII(O2•−)]+ Reaction with
2,6-Di-tert-butylphenol (p-H-DTBP) Leading to a 2,6-Di-tert-
butyl-1,4-benzoquinone. In 2009, based on DFT calculations,
Guell et al.53 proposed a mechanism (Scheme 8) of p-H-DTBP
̈
[CuII(O2•−)]+ (2) Coupling with 2,4,6-Tri-tert-butylphenoxyl
Radical. A set of experiments that provides further and strong
support for our mechanistic picture of the chemistry comes
from reacting [(DMM-tmpa)CuII(O2•−)]+ (2) with isolated
oxidation by a cupric−superoxide complex close analogue of 2,
[(NMe2-tmpa)CuII(O2•−)]+ (see Introduction), which differs
considerably from what we have found and proposed in the
present study (Scheme 4). They suggest HAT occurs at the
first step (as we observe), but then it is suggested that the
LCuII−OOH species formed undergoes Cu−OOH homolytic
cleavage and the hydroperoxyl radical thus formed attacks the
t
tBu3ArO• (Scheme 6). The addition of 1 equiv of Bu3ArO• to
2 was monitored by UV−vis and EPR spectroscopies. A fast
reaction occurs;50 the intermediate 2 quickly disappears (UV−
J
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Article
DTBP substrates, and the observed activation parameters for
the reaction. The hydrogen atom transfer from p-X-DTBPs
proceeds via a partial transfer of charge rather than a complete
transfer of charge in the ET/PT pathway. The qualitative and
quantitative product analyses and reactivity study carried out
with the 2,4,6-tri-tert-butylphenoxyl radical (tBu3ArO•) reacting
with 2 allowed us to build the case for the proposed overall
stoichiometry of reaction and, furthermore, the detailed
mechanism. Two moles of copper(II)−superoxo species are
required to oxidize para-substituted 2,6-di-tert-butylphenols to
2,6-di-tert-butyl-1,4-benzoquinones. It is found that the reaction
of 2 toward para-alkoxy-2,6-di-tert-butylphenol proceeds via
two-electron oxidation with hydrolysis, while reaction with
para-alkyl-2,6-di-tert-butylphenol proceeds via a process involv-
ing four-electron oxygenation chemistry.
Scheme 7
This study contributes significantly to our understanding of
the fundamental chemistry and oxidative capabilities of initial
copper(I)−dioxygen adducts, such as cupric−superoxide
complexes. As described in the Introduction, CuII(O2
)
•−
Scheme 8
species are implicated in reactions with both C−H and O−H
containing substrates, and the latter biomimetic chemistry was
the focus of attention here. The supporting ligand is well-
known to modulate the structural, electronic structure/
bonding, as well as the reactivity nature of copper complexes,
here with O2-derived fragments bound to the copper ion. Thus,
future efforts will include the generation of CuII(O2
)
•−
complexes with rather differing supporting ligands to explore
the range of reactivity possible for such primary copper−
dioxygen adducts.
ASSOCIATED CONTENT
* Supporting Information
■
S
Reaction schemes for copper proteins, synthetic details, EPR
spectra, additional kinetic data and NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
phenoxyl radical, overall leading to copper(I) and hydroperoxy
organic compound. This C−O bond formation process is
described as the rate-determining step. Then, the resulting
copper(I) facilitates O−O homolytic cleavage, forming a
hydroxyl radical plus a copper(II)−O−ArO′ complex. The
last step involves HAT (or PCET) from the ring to hydroxyl
radical, leading to the formation of copper(I), a water molecule,
and DTBQ. Thus, their overall chemistry is formally a catalytic
reaction (regenerating copper(I), to react again with more O2
to give the cupric−superoxo species), with different stoichiom-
etry than we observed and a different rate-determining step as
mentioned. However, we should point out that the substrate
used in their calculations was p-H-DTBP, a perhaps rather
special case compared to the series of substrates we examined
(Table 1). In fact, we find that p-H-DTBP is unreactive toward
[(DMM-tmpa)CuII(O2•−)]+ (2).
AUTHOR INFORMATION
■
Corresponding Authors
edward.solomon@stanford.edu
fukuzumi@chem.eng.osaka-u.ac.jp
karlin@jhu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NIH (E.I.S., DK31450; K.D.K.,
GM28962), JSPS (S.F., 20108010; K.O., 23750014,
26620154, 26288037), and JST (S.F., ALCA) for financial
support of this research.
CONCLUSION
■
REFERENCES
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step and the rate-determining-step for the oxidation of p-X-
DTBPs. The key observations supporting this were the finding
of a large deuterium kinetic isotope effect, a good correlation
with reactivity of the cumylperoxyl radical toward the same
substrates, comparison of the rate dependences in the phenol
oxidations on the one-electron oxidation potentials of the p-X-
■
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