A Tricopper(I) Complex Competent for O Atom Transfer, C-H Bond Activation, and Multiple O2 Activation Steps

Article abstract of DOI:10.1021/acs.inorgchem.8b00921

Oxygenation of a tricopper(I) cyclophanate (1) affords reactive transients competent for C-H bond activation and O atom transfer to various substrates (including toluene, dihydroanthracene, and ethylmethylsulfide) based on ¹H NMR, gas chromatography/mass spectrometry (MS), and electrospray ionization (ESI)/MS data. Low product yields (<1%) are determined for C-H activation substrates (e.g, toluene, ethylbenzene), which we attribute to competitive ligand oxidation. The combined stopped-flow UV/visible, electron paramagnetic resonance, ESI/MS, ¹H NMR, and density functional theory (DFT) results for reaction of 1 with O₂ are consistent with transient peroxo- and di(oxo)-bridged intermediates. DFT calculations elucidate a concerted proton-coupled electron transfer from toluene to the di(μ-oxo) intermediate and subsequent radical rebound as the C-H activation mechanism. Our results support a multicopper oxidase-like mechanism for O₂ activation by 1, traversing species similar to the coplanar Cu₃O₂ unit in the peroxy and native intermediates.

Full text of DOI:10.1021/acs.inorgchem.8b00921

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
A Tricopper(I) Complex Competent for O Atom Transfer, C−H Bond
Activation, and Multiple O2 Activation Steps
Brian J. Cook,†,§ Gianna N. Di Francesco,†,§ Matthew T. Kieber-Emmons,‡ and Leslie J. Murray*,†
†Center for Catalysis and Florida Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville,
Florida 32611-7200, United States
‡Department of Chemistry, University of Utah, Salt Lake City, Utah 84112-0850, United States
S
* Supporting Information
ABSTRACT: Oxygenation of a tricopper(I) cyclophanate (1)
affords reactive transients competent for C−H bond activation and
O atom transfer to various substrates (including toluene,
1
dihydroanthracene, and ethylmethylsulfide) based on H NMR,
gas chromatography/mass spectrometry (MS), and electrospray
ionization (ESI)/MS data. Low product yields (<1%) are
determined for C−H activation substrates (e.g, toluene, ethyl-
benzene), which we attribute to competitive ligand oxidation. The
combined stopped-flow UV/visible, electron paramagnetic reso-
1
nance, ESI/MS, H NMR, and density functional theory (DFT)
results for reaction of 1 with O2 are consistent with transient
peroxo- and di(oxo)-bridged intermediates. DFT calculations
elucidate a concerted proton-coupled electron transfer from
toluene to the di(μ-oxo) intermediate and subsequent radical rebound as the C−H activation mechanism. Our results support
a multicopper oxidase-like mechanism for O2 activation by 1, traversing species similar to the coplanar Cu3O2 unit in the peroxy
and native intermediates.
of reported model compounds from that of the enzymatic
systems. With this consideration in mind, the steric constraints
imposed by our cyclophane ligand can likely enforce the desired
coplanar orientation of O2 binding. To that end, we report the
INTRODUCTION
■
Dioxygen activation by multicopper oxidases (MCOs) couple
dioxygen reduction to water with a number biochemical
processes, including substrate oxidation and selective ion
transport.1,2 The diverse reactivity of copper−dioxygen adducts
arising from similar active-site structures has inspired ongoing
work to replicate this reactivity in model compounds. In
particular, the potential for copper complexes to function as
catalysts for C−H bond functionalization and dioxygen
reduction have applications in green synthesis and in fuel
cells.3 The tricopper(I) state of MCOs is proposed to react
with O2 to arrest at a peroxide-bridged transient (PI) and
requires a further one e−/H+ reduction to complete O2 bond
scission to yield the native intermediate (NI; Figure 1).1a,5
Contrastingly, no synthetic tricopper−dioxygen adduct arrests
at the peroxide state, although stable peroxo−dicopper(II)
species and those in equilibrium in the di(μ-oxo) congeners
have precedent (Figure 1).7 These tricopper compounds are
capable of H atom abstraction from substrates (e.g., phenols) or
O atom transfer to phosphines. Density functional theory
(DFT) studies on MCOs indicates that O2 binds coplanar with
the Cu3 plane, whereas the O···O vector is orthogonal to the
Cu3 plane in model compounds.5,6d,8
I
oxygenation of a Cu3 cyclophanate, 1, in which the
macrobicycle enforces an MCO-like O2 coordination to the
metal ions.2a,3b,6b,d,9 Oxygenated transients 1·O2 are competent
for C−H activation of C−H bonds of substrates such as 9,10-
dihydroanthracene and toluene and O atom transfer to styrene
and ethylmethyl sulfide. DFT calculations on this system point
to a covalent [Cu3(μ3-O)(μ2-O)]3+ cluster as one likely reactive
intermediate. These in silico studies point to a favorable H
atom abstraction from PhMe followed by radical rebound to
afford the alcohol product. In addition, the initial metal
complex product of O atom transfer is identified as a μ3-
oxotricopper(II/II/I) complex, which can react with an
additional equivalent of O2. Our results higlhight the
importance of O2 orientation as a key factor in dictating the
reactivity of multimetallic species.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were prepared under a
dinitrogen atmosphere in an Innovative Technologies glovebox and
then transferred to a Schlenk line. Unless otherwise explicitly stated, all
The consequence of O2 orientation relative to the metal
centers on bond activation remains poorly understood. Our
hypothesis is that the orientation of the O2 fragment relative to
the tricopper plane is a key element differentiating the reactivity
Received: April 5, 2018
© XXXX American Chemical Society
A
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package. All accessories were supplied by TgK Scientific. Absorbance
measurements were conducted with a Xe or quartz−tungsten lamp
with either a diode array (multiwavelength data) or a photomultiplier
(single wavelength data) detector. In addition to the solvent drying
procedure reported above, solvents used in these experiments were
also stirred over NaK for 24 h prior to use. Instrument lines were
rinsed with a dilute solution of sodium benzophenone ketyl in THF
and then extensively with anhydrous and anaerobic THF or n-hexane.
Solutions of 1·N2 in THF (1.1 mM) or 1′ in n-hexane (0.66 mM)
were prepared in the glovebox and then loaded onto the stopped-flow
instrument using gastight syringes (Hamilton Laboratory Products).
Dioxygen-saturated THF and n-hexane were prepared by vigorously
sparging an aliquot of the particular solvent (∼15 mL) for 30 min with
UHP O2 on a vacuum/inert gas manifold, and the O2-saturated solvent
was then transferred to the stopped-flow instrument using Hamilton
gastight syringes. Data were collected at −80 °C for n-hexanes, and the
spectra were fit using a three-exponential, four-component kinetic
model as described elsewhere.13 For the 490 nm single-wavelength
data set, data were truncated to 4 ms−1.0 s for fitting purposes to
account for instrument dead time and downstream decay products,
which could not be fit reliably. For the 630 nm single-wavelength data
set, data were truncated to 4−200 ms for fitting purposes to account
for instrument dead time and downstream decay products.
EPR Spectroscopy. A solution of 1·N2 in toluene (1.5 mM, ∼1
mL) was transferred to a quartz tube inside of a dinitrogen-filled
glovebox. The tube was capped with a Teflon valve, removed from the
glovebox, and placed under N2 on a vacuum manifold. The solution
was then degassed by three freeze−pump−thaw cycles, after which the
tube was placed in CO2(s)/isopropranol bath. After the sample had
thawed under vacuum, tube was refilled with O2 and then flash frozen
after ∼10 s using liquid nitrogen. The sample tube was then evacuated,
flame-sealed, and stored at 77 K. Electron paramagnetic resonance
(EPR) spectra were collected on a Bruker Elexsys E580 with a Bruker
4116DM resonator maintained at 5 K with a liquid helium-cooled
cryostat. Data were collected in perpendicular mode from 50 to 7050
G with the following parameters: power = 0.633 mW; frequency =
9.407 GHz; modulation frequency = 100.00 kHz; modulation
amplitude = 10.00 G; and gain = 60 dB. In parallel mode, from 50
to 7050 G with the following parameters: power = 2.00 mW;
frequency = 9.410 GHz; modulation frequency = 100.00 kHz;
modulation amplitude = 10.00 G; and gain = 60 dB.
Synthesis of 2. In a typical synthesis, 35.0 mg (0.0391 mmol) of
Cu3OL35 was dissolved in 10 mL of THF and added to a 50 mL
round-bottom Schlenk flask with a Teflon screw-cap seal valve. This
was attached to a Schlenk line and degassed with three consecutive
freeze−pump−thaw cycles to remove dissolved gases. The flask was
then backfilled with UHP O2 and allowed to thaw to room
temperature. The reaction was allowed to stir vigorously for 30 min
under static O2, which resulted in a color change from dark yellow to
dark maroon. After this color change was complete, volatiles were
removed from the reaction vessel under reduced pressure to yield the
final product as a dark purple solid. 1H NMR (300 MHz, THF-d8, 298
K): δ (ppm), 129.0(br, 12H), −18.4(s, 18H), −30.9(s, 3H). Other
ligand-derived signals could not be reasonably assigned. Attenuated
total reflectance (ATR) IR (cm−1): 2959(m), 2925(m), 2868(m),
1550(s), 1522(m), 1469(m), 1434(s), 1405(vs), 1373(m), 1331(m),
1237(w), 1066(w), 1014(w), 730(m).
Figure 1. Proposed mechanism for O2 reduction by multicopper
oxidases traverses peroxo- and a (μ-hydroxo)(μ3-oxo)tricopper
transients abbreviated PI and NI (top).1 The active site of laccase
from Steccherinum murashkinskyi (PDB ID: 5MIB) with Cu ions
depicted as green spheres and the proteinaceous ligands as sticks
(bottom, left). Crystallographically characterized di(μ3-oxo)tricopper
compounds synthesized by reaction of monocopper(I) complexes of
the depicted ligands and dioxygen.4,6
solvents and reagents were purchased from Sigma-Aldrich. Solvents
were dried using an Innovative Technologies solvent purification
system and stored over activated 3 Å molecular sieves inside the
dinitrogen-filled glovebox. Ultra High Purity (UHP) O2 was purchased
from AirGas. Deuterated solvents were purchased from Cambridge
Isotope Laboratories (CIL) and purified according to reported
procedures for the proteo-solvents and then stored over activated 3
Å molecular sieves under inert atmosphere.10 NMR spectra were
1
collected on a Varian Inova operating at 500 MHz for H, equipped
with a three-channel 5 mm indirect detection probe with z-axis
gradients. All chemical shifts are reported in parts per million and
1
referenced to tetramethylsilane for H. Electrospray ionization (ESI)
mass spectrometry (MS) was conducted in positive mode by direct
injection using a manual injector, which fed into a constant flow of
anhydrous air-free solvent, and then into an Agilent 6120 TOF
spectrometer. The following ESI and MS conditions were used: gas
temperature = 350 °C and fragmentation voltage = 120 V. Gas
chromatography (GC) analyses were conducted using a Varian CP-
3800 gas chromatogram using a flame ionization detector (FID) and
equipped with a J&W Scientific DB-35MS capillary column, 0.5 μm,
30 m × 0.53 mm. Samples were run on a Thermo Scientific Trace
DSQ GC-MS in EI mode using a 30 m Stabliwax-DA column using a
temperature profile starting with a hold at 50 °C for 2 min followed by
a ramp to 175 °C at 6°/min and then a second temperature ramp to
250 °C at 15°/min. Retention times were measured for the substrates
and potential oxidation products using commercially available
compounds and loaded on to the GC column with a 10:1 split and
a 0.1 μL (90 mM in tetrahydrofuran (THF)) sample injection.
[H(DMF)][OTf] (DMF = dimethylformamide) was prepared as
described previously.11 Deuterated 9,10-dihydroanthrancene (d4-
DHA), the ligand H3L, and tricopper complex 1, were synthesized
as reported previously.9b,c,12
H2O2 Quantification by Iodometric Titration. Adapted from a
previously reported procedure.26 Under N2, 15.8 mg (0.0174 mmol)
of 1·N2 was dissolved in 50 mL of C6H5F (concentration = 0.349
mM), and 9.0 mg (0.0101 mmol) of 2 was dissolved in 25 mL of
C6H5F (0.407 mM). These were then transferred 20 mL scintillation
vials were fitted with 14/20 rubber septa containing 5 mL of solution
each. For 1·N2, a Schlenk line connected to UHP O2 was purged for 5
min to replace atmosphere. Under positive pressure of O2, each
septum seal was pierced with a needle to allow O2 flow, which caused
an immediate color change from pale orange to brown. After 5 s, 1.0
mL of 17.5 mM [H(DMF)]OTf in MeCN was used to quench,
bringing the total volume to 6.0 mL, for a final analyte concentration
of 0.291 mM (1·N2) and 0.336 mM (2). The final reaction mixture
Stopped-Flow UV/Visible Spectroscopy. Experiments were
performed with a TgK Scientific CSF-61DX2 cryogenic stopped-flow
instrument in single-mixing mode using the Kinetic Studio v.4 software
B
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and 630 nm are consistent with reported CunO2 species.14,21
A430 and A630 kinetic traces were complex, and we were unable
to simulate the data with two- or three-sequential elementary
step mechanisms. We then re-examined this reaction using 1
synthesized under Ar (1′), which lacks the 505 nm band of 1·
N2, to better resolve ΔA490 and ΔA630 (Figures S3, S5, and S7).
1′ can be quantitatively converted to 1·N2 upon exposure to
N2, supporting 1′ as Cu3L (Figures S3 and S4). Reaction of 1′
with O2 in n-hexane at −80 °C results in similar increases in
A490 and A630 as with 1·N2 (Figure 2). A430 and A630 data are
best modeled using an A → B → C → D scheme (Figure 2
inset and Figures S7−S12). The employed model is consistent
with the profiles of A630 versus A490 (specifically, the initial
maximization time for A630 differs from that for A490). As a
caveat, however, the initial 0.28 absorption change within the
instrument dead time, and the gradual persistent absorption
was then freeze-pumped-thawed once more. The reaction mixture (0.2
mL) was added to a 1 cm quartz cuvette, and to this was added 1.8 mL
of a 0.3 M NaI solution in MeCN, for a final concentration of 0.0291
mM Cu3(N2)L. Since 1·N2 has a ligand-based absorption that overlaps
with I3− (λmax = 361 nm, ε = 22 000 M−1 cm−1), a control of 1·N2 + O2
+ [H(DMF)]OTf was used as a background (see Figures S42 and
S43). From the five trials, a total of 94.5 14.8% (1·N2) and 52.3
9.5% (2) yield of H2O2.
Oxidation of Hydrocarbons and Ether. To a solid portion of 1·
N2 (0.028 mmol, 25 mg) in a 20 mL vial was added an aliquot of a
THF solution of either styrene (1.6 mL, 0.87 M), toluene (1.5 mL,
0.94 M), ethylbenzene (1.7 mL, 0.82 M), diethyl ether (1.4 mL, 0.95
M), hexanes (1.8 mL, 0.80 M), cyclohexane (1.5 mL, 0.94 M), or
cyclohexene (28 μL, 0.055 M). This solution was then diluted with
THF to give a final reaction volume of 3 mL with concentrations of 9.2
mM for 1·N2 and 460 mM for the given substrate. The vial was sealed
with a septum and removed from the glovebox. UHP dioxygen was
then introduced to the headspace of the vial for ∼5 s. The reaction was
then removed from the manifold and stirred overnight under a static
atmosphere, after which the reaction was opened to air, filtered
through diatomaceous earth, and the filtrate was used for GC/MS
measurements. Oxidation reactions using 18O2 were prepared as
described above. Reaction mixtures were injected splitless with either a
0.5 or 1 μL sample injection volume for UHP O2 or 18O2, respectively.
Oxidation of Ethylmethylsulfide and 9,10-Dihydroanthra-
cene. A 50 mL pear-shaped Schlenk flask equipped with a
poly(tetrafluoroethylene) (PTFE)-coated magnetic stir bar was
charged with 1·N2 (25 mg, 0.028 mmol), and either ethylmethylsulfide
(0.5 mL, 5.53 mmol)/0.5 mL of THF, 9,10-dihydroanthracene (DHA;
73 mg, 0.40 mmol)/1.0 mL of THF, or d4-DHA (31 mg, 0.17 mmol)/
1.0 mL of THF. Naphthalene was included as a gas chromatography
(GC) internal standard (14.1 mg, 0.11 mmol). The flask was then
removed from the glovebox and placed under Ar on a vacuum
manifold. The reaction mixture was degassed by repeated freeze−
pump−thaw cycles and cooled to −78 °C (CO2/isopropanol). The
flask was then filled with 1 atm of UHP oxygen gas or 18O2, and the
vessel remained under a static atmosphere at −78 °C for 15 min. An
aliquot was removed and then injected into the ESI/MS instrument.
After the aliquot was removed and with the temperature maintained at
−78 °C, all volatiles from the reaction flask were removed under
reduced pressure, which required ∼20 min. The solid residue was
1
transferred to the glovebox, and H NMR spectra were recorded in
either d-toluene or d-dichloromethane.
Computational Methods. Density functional theory (DFT)
calculations were performed in Gaussian09 Version D.01.15 A model
of the dinitrogen complex 1 was built from crystallographic
coordinates and optimized as the neutral singlet with the BP86
functional. Ahlrich’s triple-ζ basis set with polarization (tzvp)16 was
used on Cu, O, and N atoms, and split valence with polarization
(svp)17 was used on C and H atoms. The oxygenated products and
reaction trajectory were computed analogously. Analytical frequency
calculations were performed on all complexes to ensure stationary
points on the potential energy surface had been reached, and no
imaginary frequencies were found. Single-point energy calculations
were performed with the b3lyp functional18 within the unrestricted
formalism with an ultrafine integration grid as implemented in
Gaussian09. These single-point calculations included solvation using
the polarizable continuum model with the solvent parameters of THF.
The overall Gibbs free energy was determined as the sum of the
solvated b3lyp SCF energy and the thermal corrections from the
analytical frequency calculations. Mulliken populations were determed
using QMForge,19 and molecular orbitals were visualized with Lumo.20
Figure 2. Stopped-flow UV/visible absorption data for reaction of 0.33
mM 1′ in n-hexane with O2-saturated n-hexane at −80 °C monitored
by diode array (top) and at 490 and 630 nm only (bottom). A rapid
increase in absorption is observed within the instrument dead time
considering the spectrum of the compound in the absence of O2 (---,
top) and the first spectrum collected after mixing. A630 has an initial
maximum evident at ∼200 ms (vertical red dashed line), whereas A490
maximizes at ∼1.0 s (vertical black dashed line). Both A490 and A630 are
well-modeled with a sequential three-step kinetic model over the 4−
1000 ms time domain.
RESULTS AND DISCUSSION
■
Monitoring reaction of 1·N2 with O2 in THF at −78 °C by
stopped-flow (SF) UV/visible spectroscopy, we observe an
initial rapid decay at λmax = 505 nm (<100 ms) followed by
absorption increases at λmax = 490 and 630 nm (Figures S1 and
S2). ΔA505 may arise from N2 dissociation, and those at 490
C
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increases out to long reaction times (>40 min) required
truncation of the data sets (4 ms−1.0 s). Our absorption
maxima are comparable to ligand-to-metal charge-transfer
bands at 480 nm reported for PI and Chan’s tricopper−
dioxygen intermediate(s).3c,5a,22 Our A490 and A630 data agree
with reported spectral differences between peroxo- and di(μ-
oxo)-dicopper compounds.21a,b,23 Thus, we tentatively assign B,
C, and D as an initial O2 adduct, a peroxo-bridged transient,
and a di(μ-oxo)tricopper cluster, respectively. To evaluate if
simpler reaction outcomes could be achieved (e.g., a stable
infinite absorption value), product mixtures from reaction of 1·
N2 with 1 equiv of O2 were examined by 1H NMR
spectroscopy, revealing three products, two of which are as-
yet-identified: Cu3OL,35 a diamagnetic C2v symmetric species,
and a paramagnetic product (Figure S36).
Attempts to probe the O−O bond order spectroscopically
for 1·O2 species were unsuccessful. Absorptions assignable to
O−O stretching modes for a peroxide transient were
unobservable by stopped-flow infrared (SF-IR) or in Raman
spectra on frozen samples using 16O2 or 18O2. We note that
vibrational data on PI have not been reported, albeit due to
protein absorption and fluorescence.24 X-band EPR spectra
recorded on 1·O2 revealed absorptions at 3244 G and ∼1570 G
in perpendicular and parallel mode (Figure S13). These spectra
are comparable to those for triplet di(μ-oxo)tricopper(II/II/
III) clusters.6d,a,25 However, the intensity ratio of the half-field
versus the g ≈ 2 signals for 1·O2 is significantly smaller than
previously reported. We speculate that this discrepancy arises
from di- and tricopper decomposition products (e.g., ligand
oxidation) present in the reaction mixture, which agrees with
MS data (vide infra). Finally, the H2O2 content of oxygenated
samples of 1·N2 measured using the iodometric method was 95
15% (Figure S42).26 Taken together, these results support
O2 activation by 1·N2 to the peroxide, if not more reduced
states.
Figures S14−S17). Similar carbonyl products have been
observed for oxidation of the relevant substrates and attributed
to overoxidation or rearrangement under reaction or GC
conditions.27 The low yields are expected, as oxidation of ligand
benzylic positions is likely competitive with hydrocarbon
oxidation. Consistently, the product yield improves substan-
tially for the more readily oxidized EtSMe. We attempted to
characterize ligand products in the absence of substrates but
1
observed intractable complex mixtures by GC/MS and H
NMR (Figures S29 and S30). MS data on products from
reactions of 1·N2 and styrene or toluene using 18O2 were
shifted by 2 mass units, confirming that the incorporated O
atom is O2-derived (Figures S18−S21). Scrambling of the 18O
label is observed in the products, but similar results are
reported for other copper and related systems.28 Oxidation
products were not observed with cyclohexane, hexane, pentane,
or diethyl ether as the substrates.
Thus, we estimate the oxidizing power of 1·O2 intermediates
as 88.5 kcal/mol (bond dissociation energy (BDE) of PhCH3),
although the expected competitive ligand oxidation complicates
this analysis.29 For DHA oxidation, the predominant ion
envelopes in ESI/MS data are well-simulated to a mixture of
[Cu3O2L+H]+ and [Cu3O21L+2H]+ (Figure S32), and
anthracene was observed by H NMR (Figure S31). If d4-
DHA is used, resonances for d2-anthracene and a parent ion
consistent with [Cu3O2L+D]+, which suggests H atom
abstraction (HAA), are observed in the product mixtures by
1H NMR and ESI/MS, respectively (Figures S35 and S34).
This result, however, is not unambiguous, as the mass is within
5 ppm of that for [Cu3O2L+2H]+. For EtSMe oxidation, ions
corresponding to [Cu3O2L]+, [Cu3O2L+H]+, [Cu3OL]+,
[Cu3OL+H]+, and [EtS(O)Me+M]+ (M = Li+, Na+, K+)
were observed in ESI/MS data (Figures 3 and S26). An ion
We subsequently probed the reactivity pattern of 1·O2
transients. GC data on oxygenated mixtures of 1·N2 solutions
premixed with various substrates evidenced O atom transfer
(OAT) and C−H activation, albeit in low yield (Table 1,
Table 1. Yields of Oxidation Products
Figure 3. High-resolution ESI/MS(+) data from the oxygenation
reaction of 1·N2 in the presence of EtSMe. Each isotopic pattern is
best simulated as a combination of [M]+ and [M + H]+ with m/z =
895.3047 assigned to [Cu3OL]+ and [Cu3OL+H]+, m/z = 910.2942 as
[Cu3O2L]+ and [Cu3O2L+H]+, and m/z = 928.3004 as [Cu3O2L
+H2O]+ and [Cu3O2L+H3O]+.
envelope consistent with a dicopper species is also assignable;
however, similar envelopes are also present in MS data for
other purified tricopper complexes,9a,35 suggesting potential
demetalation under analysis conditions. Using 18O2 for EtSMe
oxidation affords ions with m/z values consistent with
[Cu316/18OL]+ and [Cu316/18OL+H]+, and [Cu316/18O2L]+ and
[Cu316/18O2L+H]+. Similar to our GC/MS results, incorpo-
a
b
c
1
On the basis of [1·N2]. Determined by GC. Determined by H
NMR.
D
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ration of the O atom label is also not nearly quantitative for the
copper products; the cause of this scrambling remains under
investigation. Resonances corresponding to Cu3OL are also
implying that geometric and electronic structures are reliable,
whereas the relative thermodynamics between species should
be used with caution.30
1
evident in H NMR spectra of EtSMe and DHA oxidation
The relatively short O−O distance of 1.45 Å in 3 reflects
minimal back-bonding from the unique Cu(II) ion into the O2
σ* orbital as is typically observed in side-on adducts to Cu.
Consequently, this orbital, which would be the acceptor orbital
for potential H atom abstraction, is unactivated, as the O2 σ*
orbital is high in energy. Analysis of the unoccupied orbitals of
34the lower energy isomer of 4revealed a highly covalent
[Cu3O2]3+ core (Table S3), with three copper-based orbitals
(241α, 240β, and 241β) and an unoccupied O orbital on the
μ2-O donor (62.0% O, Figure 5). This unoccupied predom-
reactions (Figures S24, S25, and S31).35 We conclude then that
1 exhibits mono-oxygenase-like reactivity leading to C−H bond
activation and OAT as potential reaction pathways.
Given the complexity of our reaction kinetics, we challenged
our assumption that Cu3OL is a terminal product of O2
activation by 1. Cu3OL does not effect OAT (e.g., Me3P)
and is unreactive toward O atom donors (e.g., PhIO). Exposure
of a d8-THF solution of Cu3OL to O2 at −78 °C results in
complete consumption of Cu3OL to yield a paramagnetic
species, 2 (λmax = 488 nm, Figure S39). 2 is unstable under an
O2 atmosphere, precipitating a brown solid after ∼2 h (Figure
S40), but it can be isolated if the reaction is degassed.
1
Oxidation products are identifiable in H NMR spectra of
reactions of isolated 2 with DHA (Figure S45) but are
undetected for reactions with toluene, ethylbenzene, or styrene.
Assuming quantitative conversion of Cu3OL to 2, the H2O2
yield of 52(10)% by iodometric titration on samples of 2
(Figure S43) hint at a peroxo-bridged bis[Cu3OL] species
analogous to our bis(triiron) compound.12b Another possible
formula assignment for 2 is superoxo-adduct of Cu3OL, which
cannot be excluded by our data. Taken together, 1 can react
with multiple equivalents of O2 in the presence of substrates.
To our knowledge, the ability of the product cluster of a mono-
oxygenase reaction to react with dioxygen in the absence of
additional reducing equivalents is unprecedented.
Geometry optimization of a dinitrogen-for-dioxygen sub-
stituted 1·N2 affords two stationary points: a peroxotricopper-
(I/II/II) species (3) at −18.1 kcal/mol and a (μ-oxo)(μ3-
oxo)tricopper(II/III/III) intermediate (4) at −22.9 kcal/mol
(Figure 4). Notably, the Cu3O2 is planar in both 3 and 4, as
Figure 5. Unoccupied frontier molecular orbitals of 4. The orbital
depicted as a red line is comprised of significant out-of-plane radical O
p character.
inantly O-centered orbital has out-of-plane p character,
indicative of a highly electrophilic O atom. One could,
3
therefore, describe the [Cu3O2]3+ core of 4 as a (μ-oxyl)(μ3-
oxo)tricopper(II) species.
To evaluate the mechanism of C−H activation, a toluene
3
molecule was docked into the structure of 4 near the μ2-O
atom to afford the stationary point (Figure S51, 4·Tol). Using
the maximum along a linear transit for H-abstraction from CH3
of toluene to the μ2-O of 34 as an initial guess of the transition
state (TS), we obtained an optimized TS with C···O and H···O
distances of 2.56 and 1.27 Å, respectively. This evolves to a (μ-
hydroxo)(μ3-oxo)tricopper(II) species and a benzyl radical (5·
R·, Figure S50). Whereas the μ2-O bears radical character
resides in an orbital of out-of-plane p-character, the H atom
2
2
acceptor orbital is of in-plane O p + Cu dx −y character and
3
equivalent to orbital 241β in 4 (Figure S5 and Table S3).
Inspection of the molecular orbitals of the TS reveals that
electron and proton transfer are simultaneous, consistent with a
concerted proton−electron transfer. Subsequent radical re-
bound is favorable (−33.6 kcal/mol versus 5·R·), yielding
PhCH2OH and Cu3OL (Figure S51). From examination of the
two-dimensional (2D) potential energy surface of C−O bond
making versus O−Cu bond breaking for this rebound, the step
is essentially barrierless (Figure S50), suggesting that
accumulation of 5 and benzyl radical dimerization are
disfavored.
Figure 4. Reaction profile for 1 with O2. N2 dissociation and O2
coordination are favored, leading to a peroxo- (3) and a di(μ-oxo)-
tricopper intermediates (4).
proposed for PI. The calculated energy separations between the
S = 0 and 1 states of 3 and 4 (namely, 13, 33, 14, 34) are small,
suggesting an equilibrium mixture, and are consistent with
complexity of the kinetic data above. These results are evocative
of reversible O−O bond cleavage in dicopper−dioxygen
adductsa known pathological case for energetics by DFT
In our proposed mechanism for O2 activation and substrate
oxidation by 1, coplanar coordination of O2 to the Cu3 centers
E
DOI: 10.1021/acs.inorgchem.8b00921
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
results in peroxo-and di(μ-oxo)-tricopper transients, with the
former being analogous to PI in MCOs (Scheme 1). The
reported by Chan and co-workers is a terminal unreactive
species. This deviation likely originates from the difference in
ligand donor strength; the anionic β-diketiminate arms of our
cyclophane afford a more electron-rich tricopper cluster as
compared to the neutral donors in Chan’s ligand.
Scheme 1
Regarding our low yields for OAT to hydrocarbon substrates,
we surmise that intramolecular ligand oxidation is competitive
with exogenous substrate bond activation. As noted above, the
ligand presents four benzylic C−H bonds in the locale for
substrate approach. The 2 orders of magnitude increase in
product yield with EtSMe as the substrate as compared to
toluene or DHA is consistent with our assertion. More
pointedly, this increase in yield of the oxidized products leads
to a concomitant increase in the formation of Cu3OL and
thereby supports our proposed mechanism; that is, 1·O2, which
could be either a peroxo or di(μ-oxo) transient, is indeed the
initial active oxidant and not a low-yield minor component in
the reaction mixture.
CONCLUSION
■
In conclusion, we report that 1·O2 transients are competent for
OAT to hydrocarbon C−H bonds through an HAA
mechanism. Our kinetic, spectroscopic, and DFT analyses are
consistent with transient peroxo- and/or di(μ-oxo) species as
the likely identity of these reactive species. In addition, the
product cluster of OAT, Cu3OL, is itself reactive toward
dioxygen, presenting a unique instance in which the product of
a mono-oxygenase reaction retains reactivity toward O2. Future
studies aim to trap reactive species and enhance ligand stability
toward oxidation.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.8b00921.
perpendicular alignment of the O···O vector with respect to the
β-diketiminates differs from reported di(μ-oxo)tricopper
compounds and decreases metal-O2 backbonding, which we
attribute to the observed reactivity differences.6d,8 Although we
cannot exclude HAA or hydride abstraction by 3, we note that
HAA is rare for peroxo-bridged dicopper complexes and that
Et2O oxidation is not observed despite its lower heterolytic
BDE versus PhMe.13,31 Importantly, our results parallel O2
reduction by MCOs, as the μ2-oxide is the favored site of formal
H atom transfer in both systems, hinting at similar electronic
structure in both.32 Whereas NI is protected from reaction with
adventitious substrates within the enzyme active site, our NI-
like species undergoes a rebound reaction with a previously
generated substrate radical.33
Although dioxygen−copper transients are well-known for
HAA, intermolecular O atom transfer coupled to C−H
activation remain uncommon. Tricopper complexes facilitate
OAT to triphenylphosphine, mediate phenol oxidation, and
ligand oxidation.7a,d−k,21a,34 Maji et al. reported oxygenated Cu3
transients competent for acetonitrile hydroxylation and catalytic
oxidation of methane, which is the only example of C−H
activation by a tricopper system to our knowledge.3d,22 We do
not observe activation of C−H bonds stronger than that of
toluene, suggesting that oxidation of these substrates is not
accessible kinetically (e.g., rate of ligand oxidation is
competitive). OAT to substrates in both systems is proposed
to arise from a di(μ-oxo) tricopper transient, with the μ2-O
bearing oxyl or oxene character and being the H atom acceptor
from substrates. Our system here diverges from that of Chan
and co-workers in the reactivity of the μ3-O tricopper species.
Cu3OL is reactive toward O2 with the downstream oxygenated
transient being competent for HAA from DHA, whereas that
■
S
Data from experiments including diode array absorbance
1
changes, H NMR spectra, A490 versus time plots, gas
chromatograms, mass spectra, ESI/MS spectra, ATR-IR
spectra, calculated (TD-DFT) UV−visible spectra,
optimized Cartesian coordinates (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: murray@chem.ufl.edu.
ORCID
Matthew T. Kieber-Emmons: 0000-0002-6357-5579
Leslie J. Murray: 0000-0002-1568-958X
■
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
L.J.M.: Univ. of Florida departmental instrumentation award
(NSF CHE-1048604), ACS Petroleum Research Fund (ACS-
PRF 52704-DNI3), and NSF CHE-1464876. G.N.D.: Univ. of
Florida, College of Liberal Arts and Sciences Graduate
Research Fellowship. The content of this publication is solely
the responsibility of the authors and does not necessarily
represent the official views of NIGMS or NIH. Computational
F
DOI: 10.1021/acs.inorgchem.8b00921
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Inorganic Chemistry
Article
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time was provided by the Extreme Science and Engineering
Discovery Environmentsupported by NSF ACI-1053575
(TG-CHE130047)and the Center for High Performance
Computing at the Univ. of Utah. The authors thank R. Ferreira
1
(UF), for help collecting H NMR data on 1′, and Dr. K. M.
Light for preliminary calculations.
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DOI: 10.1021/acs.inorgchem.8b00921
Inorg. Chem. XXXX, XXX, XXX−XXX