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(B)T/e) ln k2 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, (18)O-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 (18)O-labeled DTBQ and elimination of the R group.
To obtain mechanistic insights into the inherent reactivity patterns for class="Chemical">copper(I)-O2 adducts, a class="Chemical">new class="Chemical">n class="Chemical">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 deuteriumkinetic 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(B)T/e) ln k2 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, (18)O-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 (18)O-labeled DTBQ and elimination of the R group.
Investigation of the
structure and reactivity of various class="Chemical">CuI/class="Chemical">n class="Chemical">O2 adducts
(Chart 1), those
derived from the reaction of reduced ligand–copper(I) complexes
with molecular oxygen (dioxygen), 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 has been detected
in the gas phase,[2] hinted at in coordination
chemistry studies[3] 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]
Chart 1
They may hydroxylate the substrate C–H
bond in class="Chemical">copper eclass="Chemical">nzymes
such as peclass="Chemical">n class="Chemical">ptidylglycine-α-hydroxylating monooxygenase
(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–H[9,10] or O–H[7,8] hydrogen atom transfer (HAT) reactions.
Relevant to this is an X-ray crystallographic study on a PHM
derivative, which 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
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.
Figure 1
Reduction
of molecular oxygen in galactose oxidase (GO). See Supporting Information (Figure S1a) for fuller
details.
Reduction
of molenclass="Chemical">cular class="Chemical">n class="Chemical">oxygen in galactose oxidase (GO). See Supporting Information (Figure S1a) for fuller
details.
With this background, one of the
research goals that we have recently
been emphasizing is on the chemistry of class="Chemical">cupric–class="Chemical">n class="Chemical">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 [class="Chemical">CuII(class="Chemical">n class="Chemical">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
semiquinone) 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 PCET[12] or hydrogen atom transfer,
and these are fundamentally important reactions occurring in many
biological systems.
Osako et al.[13] previously investigated
class="Chemical">phenol (aclass="Chemical">nd C–H) oxidatioclass="Chemical">n chemistry usiclass="Chemical">ng biclass="Chemical">nuclear complexes
of the type (μ-η2:η2-peroxo)diclass="Chemical">n class="Chemical">copper(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]
Furthermore, the investigation into exogenous
class="Chemical">phenolic substrate
O–H oxidatioclass="Chemical">n by [class="Chemical">n class="Chemical">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 stable end-on bound
superoxo–copper(II) complex, we found that 2,6-di-tert-butylphenol derivatives (p-X-DTBP; X = OMe, Bu, H) were oxidized to 2,6-di-tert-butyl-1,4-benzoquinone (DTBQ) (Scheme 1).
Chart 2
Scheme 1
We herein describe a detailed study employing a new electron-rich
ligand supporting the class="Chemical">cupric–class="Chemical">n class="Chemical">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.
Experimental Section
General
Considerations
All materials used were of commercially
available reagent quality unless otherwise stated. class="Chemical">Acetone was distilled
from Drierite uclass="Chemical">nder class="Chemical">n class="Chemical">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-butylperoxide 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 (Bu3ArO•) was synthesized following a procedure
reported in the literature[16] 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 Analytics, Tucson, AZ. The 1HNMR spectrum was
measured on a Bruker 300 MHz or a Bruker 400 MHz spectrometer. 2HNMR was recorded on the broad-band coil on a 300 MHz instrument
with 2H 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
was prepared as in the literature[17] and
characterized by 1HNMR spectroscopy.
Ligand Synthesis
nclass="Chemical">DMM-tmpa [class="Chemical">n class="Chemical">tris((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amine]
ligand utilized in this report was synthesized following a procedure
described in the literature.[18]
The
preparation of class="Chemical">4-bromo-2,6-di-tert-butyl-2,5-cyclohexadienone
was accomplished usiclass="Chemical">ng a modified published procedure:[19]class="Chemical">n class="Chemical">1H NMR (CDCl3) δ
6.77–6.75 (d, 2H), 5.38–5.36 (t, 1H), 1.24 (s, 9H); 13CNMR (CDCl3) δ 185.05, 143.74, 136.60,
77.31.
Synthesis of para-Alkoxyl-2,6-di-tert-butylphenols (p-OR-DTBPs)
Selected
class="Chemical">phenols were syclass="Chemical">nthesized from adaclass="Chemical">n class="Chemical">pted 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%.
Preparation of 2H-O-2,6-Di-tert-butyl-4-methoxyphenol
A Schlenk flask
containing 1.25 g of class="Chemical">p-OMe-DTBP aclass="Chemical">nd a stir bar was
dissolved iclass="Chemical">n 20 mL of freshly distilled class="Chemical">n class="Chemical">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%.
Redox Potentials
of para-Substituted 2,6-Di-tert-butylphenols
(p-X-DTBPs)
The redox potentials were measured
by second harmonic AC voltammetry
(SHACV) in class="Chemical">CH3CN coclass="Chemical">ntaiclass="Chemical">niclass="Chemical">ng 0.10 M Bu4class="Chemical">n class="Chemical">N+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
class="Chemical">[(NMe2-tmpa)CuI(CO)]B(C6F5)4.[21] A 100 mL Schleclass="Chemical">nk flask
coclass="Chemical">ntaiclass="Chemical">niclass="Chemical">ng a stir bar, 100 mg of class="Chemical">n class="Chemical">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
oil dried under vacuum, yielding a white solid (70% yield): 1HNMR (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.
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 class="Chemical">[(DMM-tmpa)CuI(CO)]B(C6F5)4 (1) was prepared iclass="Chemical">n a 2.5 mL class="Chemical">n class="Chemical">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.}
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 class="Chemical">acetone solutioclass="Chemical">n
of class="Chemical">n class="Chemical">[(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.
18O-Labeling
Experiments
A Schlenk class="Chemical">cuvette
was charged with 2.5 mL of 1 mM class="Chemical">n class="Chemical">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 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.
OR Product
Analysis Using 2H NMR
Reactions
were performed using a 0.75 mM solution of class="Chemical">[(DMM-tmpa)CuI(CO)] B(C6F5)4 (1)
iclass="Chemical">n class="Chemical">n class="Chemical">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 spectrophotometer
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
(class="Chemical">JES-ME-LX) at 183 K. Typically, photoirradiatioclass="Chemical">n of aclass="Chemical">n class="Chemical">n class="Chemical">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%.
Hydrogen Peroxide Quantification
Detection of class="Chemical">H2O2 as a product has beeclass="Chemical">n performed
with class="Chemical">n class="Chemical">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
class="Chemical">formaldehyde was accomplished spectrophotometrically via
aclass="Chemical">n aqueous-based class="Chemical">n class="Chemical">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.
Attempt
To Detect Isobutylene
The attemclass="Chemical">pt for detecticlass="Chemical">ng
class="Chemical">n class="Chemical">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 grclass="Chemical">ooves/mm holographic spectrograph graticlass="Chemical">ngs. Excitatioclass="Chemical">n
was provided by a Cohereclass="Chemical">nt class="Chemical">n class="Mutation">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 class="Chemical">cupric–class="Chemical">n class="Chemical">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-tetramethylguanidino)]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 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]
Figure 2
Structural representation of [(TMG3tren)CuII(O2•–)]+.[26]
Structural representation of [(TMG3tren)nclass="Chemical">CuII(class="Chemical">n class="Chemical">O2•–)]+.[26]
Based on the physical properties of class="Chemical">[(DMM-tmpa)CuII(class="Chemical">n class="Chemical">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, 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 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.
Resonance Raman spectra of class="Chemical">[(DMM-tmpa)CuII(class="Chemical">n class="Chemical">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 complexes with tripodal
tetradentate N4 ligands.[21,27,30]
(a) Absorclass="Chemical">ptioclass="Chemical">n spectra of 1 (0.27 mM) aclass="Chemical">nd 2 after additioclass="Chemical">n of class="Chemical">n class="Chemical">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.
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 [class="Chemical">CuII(class="Chemical">n class="Chemical">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 phenoloxygenation
(giving benzoquinones) with both [(NMe2-tmpa)CuII(O2•–)]+ (Chart 2)[21] and [(TMG3tren)CuII(O2•–)]+ (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).
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)
substituent (X)
BDEa (kcal mol–1)
Eox, V (vs Fc/Fc+)c
k2 of 2d (M–1 s–1)
k2C of 4d (M–1 s–1)
DTBQ yield
(%)
OR
OCH2CH3
0.532
24
714
OCH3
79.6
0.526
23
520
49
OCD3
0.496
21
513
OCH3, −OD
0.585
2.1
58
OMPPb
0.614
0.84
350
44
OCH2CF3
0.805
0.81
329
R
CH3
80.1
0.81
0.042
185
CH2CH3
80.0
0.875
0.027
160
sec-butyl
0.884
0.023
152
CH3, −OD
0.896
0.010
tert-butyl
82.3
0.927
0.008
106
38
H
82.7
1.074
NR
Bond dissociation energy in DMSO.[31]
OMPP = 2-methyl-1-phenylpropan-2-yloxy.
These were determined from
SHACV
measurements; see Experimental Section. The
experimental error is ±0.01 V.
The experimental error is ±5%.
Bond dissociation energy innclass="Chemical">DMSO.[31]
OMPP = nclass="Chemical">2-methyl-1-phenylpropan-2-yloxy.
These were determined from
SHACV
measurements; see Experimental Section. The
experimental error is ±0.01 V.The experimental error is ±5%.
Kinetic and Thermodynamic Studies
Demonstration
of Hydrogen Atom Transfer Chemistry
Kinetic
isotope labeling studies on the oxidation of the two class="Chemical">phenol substrates class="Chemical">n class="Chemical">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.
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.
(a) UV–vis spectral changes observed by addition of class="Chemical">p-Et-DTBP (20 mM) to 2 (0.27 mM) iclass="Chemical">n class="Chemical">n class="Chemical">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.
Comparison of KIEs to Other Metal–Superoxo-Mediated
Oxidations
There have beenno prior reports of O–H
KIEs by class="Chemical">cupric–class="Chemical">n class="Chemical">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
magnitude 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 trisubstitutedphenol
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 class="Chemical">hydrogen atom traclass="Chemical">nsfer is the rate-determiclass="Chemical">niclass="Chemical">ng step iclass="Chemical">n these
reactioclass="Chemical">ns, we studied the same substrates with class="Chemical">n class="Chemical">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 hydroperoxide 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 constants for 2 (k2) and 4 (k2C) (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 display a linear correlation with k2C, 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.
Scheme 2
Figure 5
Correlation between log k2 of 2 and log k2C of 4 with p-X-DTBPs. Slope is 4.85.
Correlation between log k2 of 2 and log k2C of 4 with nclass="Chemical">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 class="Chemical">[(DMM-tmpa)CuII(class="Chemical">n class="Chemical">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 cumylperoxyl radical (4), the plot of (kBT/e) ln k2C 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.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 electron-donating
substituents in Table 1 as compared to the Eox value.
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.
Plots of (kBT/e) ln k2 for the reactions of nclass="Chemical">p-X-DTBPs with 2 (squares) aclass="Chemical">nd 4 (circles) agaiclass="Chemical">nst the oclass="Chemical">ne-electroclass="Chemical">n
oxidatioclass="Chemical">n poteclass="Chemical">ntials (Eox) of substrates.
The slopes are −0.29
aclass="Chemical">nd −0.05, respectively.
Mechanistic Considerations
There are three possible
reaction pathways in the apparent class="Chemical">hydrogen atom traclass="Chemical">nsfer from class="Chemical">n class="Chemical">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 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.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.
Scheme 3
In the case of the
class="Chemical">PT/ET pathway (2), class="Chemical">n class="Chemical">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•–)]+.
Activation
Parameters and Comparisons
The rates of
the class="Chemical">[(DMM-tmpa)CuII(class="Chemical">n class="Chemical">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 developed 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.
Although no comparable
activation parameters for class="Chemical">p-X-DTBP oxidatioclass="Chemical">n by class="Chemical">n class="Chemical">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] 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.
Table 2
Kinetic Parameters
in Various Metal
Complexes Plus Phenol Oxidation Reactions
reactants
ΔH⧧ (kcal mol–1)
ΔS⧧ (cal mol–1 K–1)
CuII–O2•–a
p-OMe-DTBP
3.6 ± 0.6
–32 ± 3
Cu(III)[42a]
2,4-DTBP
8.3 ± 1.1
–27 ± 3
Ru(VI)[42b]
phenol
11.3 ± 0.8
–14 ± 2
Mn(V)[42c]
2,4-DTBP
6.3 ± 1.4
–35.6 ± 2.3
Ru(III)[42d]
p-tBu-DTBP
1.6 ± 0.2
–36 ± 2
This work.
This work.
KIE Temperature Dependence?
We also investigated the
temperature dependence of the KIE values for the reaction with class="Chemical">deuterated p-OMe-DTBP (Table 3, Figure S6).
While the temperature raclass="Chemical">nge is agaiclass="Chemical">n limited, the results suggest
there is class="Chemical">no temperature depeclass="Chemical">ndeclass="Chemical">nce oclass="Chemical">n the magclass="Chemical">nitude of the primary
KIEs. Thus, the Arrheclass="Chemical">nius pre-expoclass="Chemical">neclass="Chemical">ntial factor for the class="Chemical">n class="Chemical">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]
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
11
1.0
11
178 K
14
1.2
12
183 K
23
2.1
11
188 K
26
2.7
10
Summary of the Kinetic–Thermodynamic
Studies
As detailed above, our in-declass="Chemical">pth studies are coclass="Chemical">nsisteclass="Chemical">nt
with the coclass="Chemical">nclusioclass="Chemical">n
that the class="Chemical">n class="Chemical">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 Klinman[7c] 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]
Product Analyses and Further Mechanistic
Insights
Phenol Oxidations Lead to Benzoquinone Products
As
described above in detail, the initial products generated after rate-limiting
class="Chemical">hydrogen atom traclass="Chemical">nsfer occlass="Chemical">n class="Chemical">curs 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.
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 class="Chemical">phenol
substrate with 2 at −90 °C. The cryogeclass="Chemical">nic
solutioclass="Chemical">ns were iclass="Chemical">nterrogated by UV–vis, class="Chemical">n class="Chemical">NMR, and EPR spectroscopies.
As described for the initial kinetics of the system (vide supra), 2 rapidly disappears. Low-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-OR fragment,
after warming, was identified by 2H(D)-labeling experiments
using p-OCD3/OCD2CD3-DTBP substrates (Figure 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, respectively.[45]
Proposed Pathway for [CuII(O2•–)]+ (2)
Reaction with p-OR-DTBP
Substrates (Scheme 4)
Initially, a
class="Chemical">hydrogen atom is traclass="Chemical">nsferred from the class="Chemical">n class="Chemical">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 Information). 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′) species (Scheme 4, step
ii); (b) then this reacts with solvent water to give , 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 (HOO–(ArO′))
(Scheme 5) forms, rather than our postulated with HO–(ArO′)
formulation. However, would be incapable of producing methoxide/methanol plus
benzoquinone, our observed products. If or CuII–peroxo derivative 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).
Scheme 4
Proposed
Pathways for [CuII(O2•–)]+ Reactivity with p-OMe-DTBP or p-Bu-DTBP Substrates Leading
to Observed Products
See text for detailed descriptions
of direct/indirect evidence or literature support for the individual
reaction steps or intermediates described. EPR spectra observed for
( ≡ ′) (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.
Scheme 5
Proposed
Pathways for [CuII(O2•–)]+ Reactivity with p-OMe-DTBP or p-Bu-DTBP Substrates Leading
to Observed Products
See text for detailed descriclass="Chemical">ptioclass="Chemical">ns
of direct/iclass="Chemical">ndirect evideclass="Chemical">nce or literature support for the iclass="Chemical">ndividual
reactioclass="Chemical">n steps or iclass="Chemical">ntermediates described. EPR spectra observed for
( ≡ ′) (from mixiclass="Chemical">ng 2 aclass="Chemical">nd class="Chemical">n class="Chemical">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.
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 class="Chemical">tert-butyl, the reactioclass="Chemical">n of class="Chemical">n class="Chemical">p-R-DTBP plus [(DMM-tmpa)CuII(O2•–)]+ (2) proceeds differently, via an overall
four-electron substrate oxygenation. In the initial reaction, steps
i and ii proceed analogously, producing the CuII–OO–(ArO′)
species ′
(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]
As can be seen from Scheme 4 (step
v), the product class="Chemical">DTBQ iclass="Chemical">n the class="Chemical">n class="Chemical">[(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-Bu-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-Bu-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]
[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 class="Chemical">[(DMM-tmpa)CuII(class="Chemical">n class="Chemical">O2•–)]+ (2) with isolated Bu3ArO• (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–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 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).
Scheme 6
Minor Reaction Pathway Contributing to p-R-DTBP Oxidation
If the reaction
of class="Chemical">[(DMM-tmpa)CuII(class="Chemical">n class="Chemical">O2•–)]+ (2) with p-R-DTBP (or that
of 2 + Bu3ArO•) occurred only via step v (Scheme 4), the product solution should not oxidizeiodide 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 ′ occurs giving 2,4,6-tri-tert-butyl-4-hydroperoxycyclohexa-2,5-dienone (′), which (i)
does oxidizeiodide ion (see Experimental Section) and (ii) slowly converts to DTBQ (at room temperature) but (iii)
fully converts to DTBQ in the GC–MS experiment.
Precedent
and Comparison with Cobalt and Nickel–Superoxide
Phenol Oxidations
In the overall process involving reaction
of the class="Chemical">p-X-DTBP, steps i aclass="Chemical">nd ii (top liclass="Chemical">ne; Scheme 4), a secoclass="Chemical">nd molar equiv of class="Chemical">n class="Chemical">[(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] Nishinaga[51b] also obtained a cobalt peroxy speciesCoIII–OO–(ArO′), and its X-ray structure
for a para-Bu 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 ′ was proposed to
form from p-R-DTBP (R = H, Me, Bu) substrates.
Scheme 7
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 calclass="Chemical">culatioclass="Chemical">ns, Güell et al.[53] proposed a mechaclass="Chemical">nism (Scheme 8) of class="Chemical">n class="Chemical">p-H-DTBP 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 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 stoichiometry
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).
Scheme 8
Conclusion
In
this report, we have obtained detailed mechanistic insights
into the oxidation of a wide series of paraclass="Chemical">-substitutedclass="Chemical">n class="Chemical">2,6-di-tert-butylphenols (p-X-DTBPs) by a newly synthesized cupric–superoxo complex supported
by an electron-rich ligand, [(DMM-tmpa)CuII(O2•–)]+ (2). With
detailed kinetic investigations, we proved that hydrogen atom abstraction
is the first 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-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
(Bu3ArO•) 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 oxidizepara-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 involving four-electron oxygenation chemistry.
This study contributes significantly to our understanding of the
fundamental chemistry and oxidative capabilities of initial class="Chemical">copper(I)–class="Chemical">n class="Chemical">dioxygen
adducts, such as cupric–superoxide complexes. As described
in the Introduction, CuII(O2•–) 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.
Authors: Debabrata Maiti; H Christopher Fry; Julia S Woertink; Michael A Vance; Edward I Solomon; Kenneth D Karlin Journal: J Am Chem Soc Date: 2007-01-17 Impact factor: 15.419
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Authors: Isaac Garcia-Bosch; Ryan E Cowley; Daniel E Díaz; Ryan L Peterson; Edward I Solomon; Kenneth D Karlin Journal: J Am Chem Soc Date: 2017-02-14 Impact factor: 15.419
Authors: Daniel E Diaz; David A Quist; Austin E Herzog; Andrew W Schaefer; Ioannis Kipouros; Mayukh Bhadra; Edward I Solomon; Kenneth D Karlin Journal: Angew Chem Int Ed Engl Date: 2019-10-23 Impact factor: 15.336
Authors: Diana A Iovan; Alexandra T Wrobel; Arthur A McClelland; Austin B Scharf; Guy A Edouard; Theodore A Betley Journal: Chem Commun (Camb) Date: 2017-09-14 Impact factor: 6.222
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Chart 1
Figure 1
Chart 2
Scheme 1
Figure 2
Figure 3
Figure 4
Scheme 2
Figure 5
Figure 6
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8