Opening the CoIII,IV2(μ-O)2Diamond Core by Lewis Bases Leads to Enhanced C-H Bond Cleaving Reactivity

Article abstract of DOI:10.1021/jacs.0c07294

The high-valent diiron(IV) intermediate Q is the key oxidant that cleaves strong C-H bonds of methane in the catalytic cycle of soluble methane monooxygenase (sMMO). sMMO-Q was previously reported as a bis-μ-oxo FeIV2(μ-O)2 diamond core but was recently described to have an open core with a long Fe···Fe distance. We recently reported a high-valent CoIII,IV2(μ-O)2 diamond core complex (1) that is highly reactive with sp3 C-H bonds. In this work, we demonstrated that the C-H bond cleaving reactivity of 1 can be further enhanced by introducing a Lewis base X, affording faster kinetic rate constants and the ability to cleave stronger C-H bonds compared to 1. We proposed that 1 first reacts with X in a fast equilibrium to form an open core species X-CoIII-O-CoIV-O (1-X). We were able to characterize 1-X using EPR spectroscopy and DFT calculations. 1-X exhibited an S = 1/2 EPR signal distinct from that of the parent complex 1. DFT calculations showed that 1-X has an open core with the spin density heavily delocalized in the CoIV-O unit. Moreover, 1-X has a more favorable thermodynamic driving force and a smaller activation barrier than 1 to carry out C-H bond activation reactions. Notably, 1-X is at least 4 orders of magnitude more reactive than its diiron open core analogues. Our findings indicate that the diamond core isomerization is likely a practical enzymatic strategy to unmask the strong oxidizing power of sMMO-Q necessary to attack the highly inert C-H bonds of methane.

Full text of DOI:10.1021/jacs.0c07294

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Opening the CoIII,IV2(μ-O)2 Diamond Core by Lewis Bases Leads to
Enhanced C−H Bond Cleaving Reactivity
Yan Li, Suhashini Handunneththige, Jin Xiong, Yisong Guo,* Marat R. Talipov,* and Dong Wang*
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ABSTRACT: The high-valent diiron(IV) intermediate Q is the key
oxidant that cleaves strong C−H bonds of methane in the catalytic
cycle of soluble methane monooxygenase (sMMO). sMMO-Q was
previously reported as a bis-μ-oxo FeIV2(μ-O)2 diamond core but was
recently described to have an open core with a long Fe···Fe distance.
We recently reported a high-valent CoIII,IV2(μ-O)2 diamond core
complex (1) that is highly reactive with sp3 C−H bonds. In this work,
we demonstrated that the C−H bond cleaving reactivity of 1 can be
further enhanced by introducing a Lewis base X, affording faster kinetic
rate constants and the ability to cleave stronger C−H bonds compared
to 1. We proposed that 1 first reacts with X in a fast equilibrium to
form an open core species X−CoIII−O−CoIV−O (1-X). We were able
to characterize 1-X using EPR spectroscopy and DFT calculations. 1-X
exhibited an S = 1/2 EPR signal distinct from that of the parent
complex 1. DFT calculations showed that 1-X has an open core with the spin density heavily delocalized in the CoIV−O unit.
Moreover, 1-X has a more favorable thermodynamic driving force and a smaller activation barrier than 1 to carry out C−H bond
activation reactions. Notably, 1-X is at least 4 orders of magnitude more reactive than its diiron open core analogues. Our findings
indicate that the diamond core isomerization is likely a practical enzymatic strategy to unmask the strong oxidizing power of sMMO-
Q necessary to attack the highly inert C−H bonds of methane.
core interacts with a Lewis base to form an open core species
with a terminal FeIV=O moiety.15−17 The open core species
exhibited a million-fold rate enhancement for C−H bond
activation.17
INTRODUCTION
■
The diiron active site in nonheme metalloenzyme soluble
methane monooxygenase (sMMO) activates dioxygen and
produces a high-valent diiron(IV) intermediate Q, one of
nature’s strongest oxidants, to cleave inert C−H bonds of
methane (bond dissociation energy, BDE = 105 kcal/mol) and
selectively form the hydroxylated product methanol.1,2 It has
become frontier research in recent years to investigate the
nature of sMMO-Q using spectroscopic, computational and
biomimetic/bioinspired approaches.1 The structure of sMMO-
Q was previously described as a bis-μ-oxo bridged FeIV2(μ-O)2
diamond core based on evidence obtained from Mossbauer
spectroscopy, X-ray absorption spectroscopy (XAS), and
resonance Raman spectroscopy.3−6 However, recent work by
DeBeer et al. using high-energy-resolution fluorescence
detected X-ray absorption spectroscopy (HERFD XAS) argued
against the diamond core assignment and claimed that sMMO-
Q has an open core structure with a long Fe···Fe distance of
∼3.4 Å.7,8
Very recently, we reported a novel high-valent CoIII,IV2(μ-
O)2 diamond core complex (1) supported by neutral
tetradentate tris(2-pyridylmethyl)amine (TPA) ligand (struc-
ture shown in Figure 2).18 Complex 1 has a short Co···Co
distance of 2.78 Å and an S = 1/2 ground state having spin
delocalization on both cobalt centers. Notably, 1 is highly
reactive with hydrocarbons and cleaves sp3 C−H bonds 3−5
orders of magnitude faster than diiron and dimanganese
diamond core analogues. In this work, we demonstrated that
the C−H bond cleaving reactivity of 1 can be further enhanced
by introducing a Lewis base X, affording faster kinetic rate
constants and the ability to cleave stronger C−H bonds up to
96 kcal/mol compared to 1. We proposed that 1 first reacts
Received: July 7, 2020
A number of studies by Nam, Goldberg, and others have
shown that the reactivities of synthetic mononuclear iron-oxo
and manganese-oxo complexes can be tuned by neutral or
anionic axial ligands in both heme and nonheme systems.9−14
Furthermore, recent studies of a high-valent FeIII,IV2(μ-O)2
model complex showed that the bis-μ-oxo bridged diamond
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with X in a fast equilibrium to form an open core species X−
CoIII−O−CoIV−O (1-X). We were able to measure the
equilibrium constant for this reaction and trap 1-X for its
characterization by electron paramagnetic resonance (EPR)
spectroscopy. 1-X exhibited an S = 1/2 EPR signal with clearly
detectable 59Co nuclear hyperfine splittings at the X-band
frequency, which is distinct from that of the parent diamond
core complex 1. Furthermore, DFT calculations showed that 1-
X is an open core species where the CoIII−X (X = F) and
CoIV−O moieties are preferably in a trans configuration. The
unpaired spin is heavily delocalized in the CoIV−O unit,
providing the terminal oxygen with a partial radical character.
According to our calculations, 1-X has a more favorable
thermodynamic driving force and a smaller activation barrier
than 1 to carry out C−H bond activation reactions, making 1-
X a much stronger oxidant both thermodynamically and
kinetically. Notably, 1-X is million-fold faster than 1 to oxidize
ethylbenzene and is at least 4 orders of magnitude more
reactive than its diiron open core analogues to oxidize other
substrates. Our findings indicated that the diamond core
isomerization is likely a practical enzymatic strategy to unmask
the strong oxidizing power of sMMO-Q necessary to attack the
highly inert C−H bonds of methane.
RESULTS AND DISCUSSION
■
As we previously reported, the Co2III,IV(μ-O)2 diamond core
complex 1 is able to cleave sp3 C−H bonds as strong as those
in ethylbenzene (BDE = 87 kcal/mol) with a second-order rate
constant k2 = 0.025(2) M−1 s−1 measured at −60 °C. In order
to study the effect of Lewis bases, we first selected the fluoride
ion (F−, pKa = 3.17 in water) for our investigations. The
addition of 1 equiv of F− (0.15 mM) into the methanol
solution of 1 at −60 °C causes a 3-fold increase for the self-
decay rate constant of 1 from 0.008 to 0.022 s−1, suggesting
that there is an interaction between 1 and F−. In the presence
of F−, 1 reacts with excess ethylbenzene in a pseudo-first-order
fashion with the reaction kinetics monitored at the character-
istic 480 nm chromophore (Figure S1). No other intermediate
was observed to form in the course of the reaction. As shown
in Figure 1A, for each F− concentration studied, the measured
pseudo-first-order rate constant kobs is linearly dependent on
the concentration of ethylbenzene, indicating that the reaction
is first-order with respect to the substrate. Moreover, the k2
value (indicated by the slope of each linear plot in Figure 1A,
see also Table S1) for ethylbenzene oxidation becomes higher
when the concentration of F− increases. With 5 equiv of F−
present (0.75 mM), a 12-fold rate enhancement (0.31(3) M−1
s−1) was observed. At a fixed ethylbenzene concentration, the
reaction rate is linearly dependent on the concentration of F−
added (Figure S2), suggesting that the reaction is first-order
for F−. Thus, the reaction exhibited first-order dependence on
all three reactants. For each F− concentration studied, an H/D
kinetic isotope effect (KIE) in the range 4−10 was determined
using deuterated ethylbenzene as the substrate (Figures S3−S5
and Table S1), indicating that the cleavage of a C−H bond is
the rate-determining step in the oxidation of ethylbenzene.
Quantification of the oxidation product(s) of ethylbenzene by
GC-MS indicated the formation of primarily acetophenone
(34% yield, Table S2) and a trace amount of 1-phenylethanol,
accounting for ∼60−70% of the oxidizing equivalents used
after correcting for the formation yield of 1 (typically ∼70%).
No fluorinated product was observed. We further designed
competitive experiments to measure H/D KIEs for ethyl-
Figure 1. (A) Plots of kobs as a function of the substrate concentration
for ethylbenzene oxidation by 0.15 mM 1 in the presence of no F−
(black), 0.15 mM F− (red), 0.45 mM F− (blue), and 0.75 mM F−
(green) obtained in MeOH at −60 °C. The lines represent the best
linear fittings. (B) Plot of log k2(PhMe) as a function of the pKa of the
Lewis base for toluene oxidation by 1 in the presence of 1 equiv of the
selected Lewis base in MeOH at −60 °C, fitted to a saturation curve.
benzene oxidations by reacting 1 with a 1:1 mixture of PhEt
and PhEt-d10 in the presence of a different amount of F− and
analyzing the ratio of the nondeuterated/deuterated acetophe-
none. As shown in Table S1, the KIE values obtained in this
method are consistent with those directly measured from
kinetic rate constants.
We further extended our investigations to other Lewis bases
−
with an increased basicity including NO2 (pKa = 3.29 for a
−
conjugate acid, all pKa values in water), N3 (pKa = 4.72),
pyridine (pKa = 5.3), CN− (pKa = 9.2), and OH− (pKa = 13.8).
Notably, substrates having C−H bonds stronger than 87 kcal/
mol such as toluene (BDE = 90 kcal/mol) can be oxidized by 1
in the presence of only 1 equiv (0.15 mM) of any Lewis base
from this group studied. As shown in Figure 1B, the log k2 for
toluene oxidation exhibits a saturation behavior as a function of
the pKa of the Lewis base used. This observation suggests that
at a fixed Lewis base concentration the maximum oxidizing
power of 1 can be reached when the basicity of the Lewis base
used is higher than the threshold pKa ≈ 4. When deuterated
toluene was used as the substrate, slower reactions were
observed, and H/D KIEs in the range 1.6−10 were determined
(1.1−10.8 from substrate competitive experiments, Figures
S6−S11 and Table S1), indicating that the rate-determining
step for toluene oxidation is the cleavage of its C−H bond. For
all Lewis bases studied, only oxygenated products (benzyl
alcohol and benzaldehyde) were observed in the product
analysis (Table S2). No functionalized product was identified.
B
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With the introduction of a Lewis base having pKa > 4 such as
N3 in a stoichiometric amount (1 equiv, 0.15 mM), 1 is able
of varied concentrations into the solution of 1. We selected
pyridine (py) as the Lewis base for this study because of its
high enough basicity and high solubility in methanol even at
−80 °C. For each pyridine concentration studied, we
monitored the immediate decrease of the 480 nm band after
the addition of the pyridine solution, recorded its absorbance
after a well-mixed solution was obtained but before significant
self-decay was observed, and used it to calculate the percentage
of the remaining 1 in the solution after the equilibrium is
established. As clearly shown in Figure 3, the fraction of the
−
to access strong C−H bonds up to those in methanol (BDE =
96 kcal/mol). A solvent KIE of 1.6 was determined using
deuterated methanol as the solvent (Figure S12), suggesting
that the self-decay of 1 in the presence of N3− is to oxidize the
solvent methanol. In addition, tetrahydrofuran (THF, BDE =
92 kcal/mol) is oxidized to γ-butyrolactone and 2-hydroxyte-
trahydrofuran in a yield of 20% and 16%, respectively, with a
rate of 0.085(4) M−1 s−1 and an H/D KIE of 5.4 (Figure S13).
Furthermore, the rate for ethylbenzene oxidation by 1 in the
−
presence of 1 equiv (0.15 mM) of N3 exhibits a 30-fold
increase as compared to the one by 1 only (Figure S14). Figure
2 shows that the log k2′ (k2′ = k2/the number of equivalent
Figure 3. Plot of the percentage of the remaining 1 (initial
concentration 0.15 mM) in titration experiments as a function of
the concentration of pyridine added into the solution of 1, fitted using
a reciprocal model (red curve, see the SI for more details).
Figure 2. (A) Plots of log k2′ as a function of the C−H bond strength
for substrate oxidations by 1 (black squares, data from ref 10) and 1 +
0.15 mM N3− (red squares) in MeOH at −60 °C, and HO−FeIII−O−
FeIV=O in 3:1 CH2Cl2/MeCN at −80 °C (blue squares, data from ref
9). The lines represent the best linear fittings. The red star represents
remaining 1 becomes smaller as the pyridine concentration
increases, as expected. The titration data can be nicely fitted
using a reciprocal model, allowing Keq = 0.31(4) M−1 to be
obtained (see the Supporting Information for more details).
Such a small Keq value confirms that the equilibrium indeed
disfavors the formation of 1-X; for example, ∼3.2 M pyridine is
required in order to obtain a 50% formation yield of 1-X.
Under our typical experimental conditions for C−H bond
oxidation (Lewis base concentration < 0.1 M), 1-X is only
formed in a yield of < 3%. Furthermore, the saturation
behavior of the toluene oxidation rate as a function of the
Lewis base pKa (Figure 1B) strongly suggests that the Keq
values for Lewis bases having pKa > 4 are quite similar.
−
the predicted rate for DHA oxidation by 1 + 0.15 mM N3 . Inset:
schematic structure of the CoIII,IV2(μ-O)2 diamond core complex 1
studied in this work.
hydrogen in the substrate) correlates linearly with the strength
−
of the C−H bond being cleaved for 1 + N3 with a slope of
−0.34. This slope is twice as big as the one observed for 1
without any added Lewis base in our previous work (−0.17).18
The different sensitivity of the reaction rates to the C−H bond
strength for these two systems (1 + N3 vs 1), as well as the
The formation of a high-valent open core species X−CoIII−
O−CoIV−O (1-X) is of particular fundamental interest;
therefore, we spent significant effort trying to trap this highly
reactive intermediate for spectroscopic characterizations. Our
attempt to obtain its UV−vis spectrum was unsuccessful. Also,
based on the Keq value measured, it is unlikely that 1-X can be
obtained in high yields for characterization using X-ray
absorption spectroscopy. Alternatively, we sought to inves-
tigate 1-X using EPR spectroscopy. For similar considerations
as in our titration experiments, pyridine was selected as the
Lewis base for this study. X-band EPR spectra of samples
containing 1 or 1-py are shown in Figure 4. The spectrum of 1
(Figure 4A) generated upon one-electron oxidation of 1 mM
Co2III(μ-O)2 precursor is identical to that reported previously
and represents ∼70% formation yield of the Co2III,IV(μ-O)2
diamond core species.18 Upon the addition of a large excess
pyridine (0.1 and 0.3 M, respectively, for the spectra obtained
in Figure 4B,C), a new feature was found to develop at g ∼
2.15 with clearly visible hyperfine splittings due to the 59Co
nuclear spin (I = 7/2, natural abundance 100%). We assign this
−
fact that 1 + N3− is able to cleave C−H bonds stronger than 87
kcal/mol, strongly indicates that a new species, 1-X, that is
more powerful than the diamond core complex 1 in cleaving
sp3 C−H bonds is generated upon the interaction of a Lewis
base X with 1.
We hypothesized that 1-X is an open core species X−CoIII−
O−CoIV−O, as analogous to the diiron system.15,17 The
conversion between 1 and 1-X must be a fast equilibrium that
disfavors the formation of 1-X because (1) C−H bond
cleavage is the rate-determining step, and (2) the formation of
a detectable intermediate assignable to 1-X was not observed
on the UV−vis spectroscopy regardless of the identity and the
amount of the Lewis base added. We noticed that the
previously reported diiron open core species show only an
absorption at ∼400 nm but also lack intense and well-defined
features in the visible to near-IR region.15,17 On the other
hand, the intense absorption of 1 at 480 nm provides a
convenient way to measure the equilibrium constant Keq for
the conversion between 1 and 1-X upon titrating a Lewis base
C
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spectrum shown in Figure 4A from that of Figure 4C always
yielded an unreasonable sharp line shape at g ∼2 resonance
(see Figure S16). Instead, a more reasonable spectrum of 1-py
was obtained by subtracting the spectrum in Figure 4B from
that of Figure 4C, which is shown in the bottom panel of
Figure 4. To ensure a reliable spectral simulation, we simulated
this difference spectrum (Figure 4D) together with the original
spectrum in Figure 4C (shown also in Figure 4E together with
its simulation). For the spectrum in Figure 4C, we included the
parameters for describing both 1 and 1-py. The parameters for
1 were fixed at the published values.18 In this way, the
simulation reproduced the spectral features representing 1-py
nicely (see Figure S17 for additional simulation results). To
further illustrate the quality of the simulation, particularly the
hyperfine splitting features, we took derivatives on both the
spectrum and the corresponding simulation (effectively the
second derivative to the absorption spectrum) shown in Figure
4E and overlaid them together in Figure 4F. It shows that all
the hyperfine splitting features are well reproduced by the
simulation. The parameters obtained to describe the EPR
signal of 1-py are g1 = 2.09, g2 = 2.08, and g3 = 2.03, together
with two different 59Co A tensors (detailed parameters are
listed in the Figure 4 caption), indicating that 1-py is an S = 1/
2 species. The difference in the magnitude of the principle
components in the two 59Co A tensors (e.g., the magnitude of
the largest component of one tensor is ∼120 MHz, while of the
other tensor is ∼50 MHz) suggests that the spin density is
more localized on one of the two Co sites of 1-py. This is
different from the diamond core complex 1, where the spin
density is equally distributed on both Co centers with two
identical A tensors (see Table S5 for the comparison of the
experimentally determined and DFT predicted parameters).18
We then turned to DFT calculations to investigate the
structure of 1-X (X = F). Geometry optimization at the BP86/
6-31G(D) + PCM(methanol) level provided low-spin ground
states for both the diamond core complex 1 and the fluorine-
bound open core complex 1-F. 1-F can exist in cis and trans
isomeric forms, where the trans isomer is more stable than the
cis isomer by 10.92 kcal/mol (Figure 5A,B). The calculated
Co−O and Co−F distances for these two isomers are highly
similar (Table S3). Interestingly, it was previously reported
that the trans open core species was also the most stable
isomer for the diiron analogue (5.2 kcal/mol more stable than
the cis isomer) supported by the same TPA ligand and with
fluoride as the Lewis base.15
Figure 4. X-band EPR spectra of 1 and 1-py. Top panel: EPR
spectrum of (A) complex 1; (B) a sample containing 1-py obtained
by treating complex 1 with 0.1 M pyridine; (C) a sample containing
1-py obtained by treating complex 1 with 0.3 M pyridine. Bottom
panel: (D) difference spectrum between spectra C and B from the top
panel (red), representing the EPR signal of 1-py, and the
corresponding simulation (black); (E) the same spectrum shown in
C of the top panel (yellow) and the corresponding simulation (black)
including the spectral components of 1-py and 1; (F) 2nd derivative
relative to the absorption spectrum of spectrum E (yellow) and its
corresponding simulation (black). The simulation parameters for 1-py
are g = [2.09, 2.08, 2.03], σg = [0.015, 0.004, 0.003], A1(59Co) = [120,
70, 90] MHz, A2(59Co) = [20, 50, 40] MHz. For 1, the published
simulation parameters are used (ref 18). The measurement conditions
are microwave frequency 9.64 GHz, microwave power 2 μW,
modulation frequency 100 kHz, modulation amplitude 1 mT, and
temperature 16 K.
Of particular interest is the CoIV−O moiety in trans-1-F
where a terminal oxygen atom is bound to the Co(IV) center.
The calculated CoIV−O bond length of 1.74 Å is apparently
longer than the one computed for the diiron analogue (1.64
Å)15 and those measured experimentally for FeIV=O
complexes19,20 and the only structurally characterized CoIII=O
species (1.68 Å)21 but is shorter than a CoIV−O single bond.22
Such a distance indicates that the CoIV−O bond order is less
than two but greater than one, and the oxygen atom has
significant radical character. A recently characterized mono-
nuclear CoIV−O species by Nam and coauthors showed a
similar CoIV−O distance of 1.72 Å.23 Supporting this notion is
the calculated spin population of trans-1-F (Figure 5C, Table
S4), which shows that the spin density is largely distributed
and delocalized on Co(IV) (+0.50 a.u.) and the terminal
oxygen atom (+0.35 a.u.), suggesting that in trans-1-F the
terminal oxygen has a partial radical character.
feature to 1-py. The relative ratio of the signal intensities at g ∼
2.15 vs g ∼2 increases as the amount of pyridine added to the
solution becomes higher, indicating that the conversion of 1 to
1-py is positively dependent on the concentration of pyridine
in the solution. This observation is consistent with the model
of fast equilibrium between 1 and 1-py described above. We
also measured the EPR spectrum of a sample containing 1
treated with F− (Figure S15), which is highly similar to those
of the samples treated with pyridine but showed a lower
concentration of EPR active species. Therefore, we focused our
discussion on the samples treated with pyridine.
We then performed spectrum subtraction to reveal the EPR
signal associated with 1-py. The direct subtraction of the
D
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Figure 5. (A, B) BP86/6-31G(D) + PCM(methanol) optimized structures for F−CoIII−O−CoIV−O (1-F) in the (A) trans and (B) cis forms.
Bond lengths are shown in Å for the selected bonds. (C) Spin density plot of trans-1-F. (D, E) Schematic depiction of the SCF potential energy
changes for the transformations (D) 1 → 2 and (E) 1-F → 2-F and the structures of the corresponding reactants, transition states, and products.
Pink, green, red, blue, and gray colors are used to depict Co, F, O, N, and C atoms, respectively. Hydrogen atoms are omitted for clarity in panels
A−C.
We also calculated the EPR parameters for both the
diamond core (1) and open core (1-X, X = F, py) complexes
(Tables S5−S7). The calculated g factors are in reasonable
agreement with experimental values for both species (See
Tables S5−S7 and discussions in the SI for more details).
Furthermore, DFT predicted A values (for 1-py, A1(59Co) =
[158, −150, 100] MHz, A2(59Co) = [18, 0, −9] MHz) are in
modest agreement with experiment but successfully repro-
duced the pattern observed in EPR measurements.22,24−26
Specifically, the diamond core complex 1 showed that the two
cobalt centers have almost identical spin populations,
indicating that 1 is a spin-delocalized species. On the other
hand, the principal components of the two 59Co A tensors
calculated for complex 1-py differ in the magnitude, which is
consistent with those obtained by EPR simulations and implies
that the spin density is present more on one cobalt site than
the other due to the fact that these cobalt centers have a
different chemical environment. Therefore, DFT calculations
support our assignment that 1-X is an open core dicobalt-
(III,IV) species.
We further calculated the transition states of the C−H bond
cleavage reactions by both 1 and 1-F in order to better
understand the reaction mechanism. According to calculations,
conversion of 1 to CoIII(μ-O)(μ−OH)CoIII (2) by the
hydrogen atom abstraction from toluene is energetically
unfavorable with the enthalpy change of +17.71 kcal/mol
(Figure 5D). The activation energy for the transformation 1 →
2 was computed to be 28.71 kcal/mol thus indicating the
unlikelihood of this reaction at a low temperature. This result
is consistent with experimental observations that 1 is unable to
cleave the C−H bond of toluene. In contrast, the hydrogen
atom transfer from toluene to 1-F with the formation of F−
CoIII−O−CoIII−OH (2-F) has an enthalpy change of only
+1.24 kcal/mol, which is 16.47 kcal/mol lower in energy than
that of a similar transformation 1 → 2. The complex 2-F also
shows a cis/trans isomerism, with the cis isomer being more
stable by 2.85 kcal/mol due to a hydrogen bond interaction
between the CoIII−F and CoIII−OH moieties (Figure 5E). For
the transformation 1-F → 2-F, the computed activation energy
was found to be 15.11 kcal/mol, which is 13.60 kcal/mol lower
than that for the transformation 1 → 2 (Figure 5E). Similar
calculations using the hydroxide ion instead of the fluoride ion
showed that the conversion of HO−CoIII−O−CoIV−O (1-
OH) to HO−CoIII−O−CoIII−OH (2-OH) upon reacting with
toluene has an enthalpy change of +4.53 kcal/mol and an
activation barrier of 16.03 kcal/mol, which is lower in energy
by 13.18 and 12.68 kcal/mol, respectively, than the conversion
of 1 to 2 in the first pathway (Figure S18). Similar results were
obtained using a different density functional B3LYP (see the SI
for details). Thus, the DFT calculations suggest that the
presence of a Lewis base can both increase the thermodynamic
driving force and lower the activation barrier of the hydrogen
atom transfer from a substrate to the dicobalt complex.
Based on our calculations, the electronic spin density
appears to contribute to the high-reactivity of trans-1-F.
While the spin density of 1 is equally distributed on the Co2(μ-
O)2 diamond core, the spin density of trans-1-F is primarily
localized on Co(IV) (+0.50 a.u.) and the terminal oxygen
atom (+0.35 a.u.), thus displaying a significant radical character
on the terminal oxygen atom (Figure 5C, Table S4).
Therefore, hydrogen atom abstraction by the terminal oxygen
in trans-1-F is much more feasible than 1 due to the
completion of the octet during the reaction.27 Our calculations
further show that the highest occupied molecular orbital
(HOMO) of trans-1-F (Figure S19) is higher in energy
(−4.377 eV) as compared with the HOMO of 1 (−5.374 eV),
making trans-1-F a higher-energy hydrogen atom abstractor
than 1. Therefore, trans-1-F should have a more favorable
E
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thermodynamic driving force and a smaller activation barrier
than 1 to carry out C−H bond activation reactions.
We propose a reaction mechanism shown in Scheme 1 that
summarizes our experimental and computational findings. The
rates are still far below the one at the saturation level. Within
this range of [X], Keq[X] ≪ 1, so eq 1 can be simplified as eq
2:
rate = KeqkC−H[X][1][substrate]
(2)
Scheme 1. Proposed Mechanism for C−H Bond Oxidation
by 1 in the Presence of a Lewis Base X
Under pseudo-first-order conditions
kobs = KeqkC−H[X][substrate]
(3)
Equation 3 is consistent with our observations that the
measured kobs is linearly dependent on the concentrations of
the Lewis base (Figures S2 and S18) and the substrate (Figures
S3−S14). For each substrate, the k2 value determined is the
product of Keq, kC−H, and [X] (eq 4).
k2 = KeqkC−H[X]
(4)
kC−H can then be obtained by rearranging eq 4. For those
measurements using a Lewis base having pKa > 4 (Keq = 0.31
M−1) with a known concentration (typically [X] = 0.15 mM,
see Table S1)
kC−H = k2/(Keq[X]) = 2.15 × 104k2
(5)
interaction of the Co2III,IV(μ-O)2 diamond core complex 1 with
a Lewis base X produces a X−CoIII−O−CoIV−O open core
species 1-X in a fast equilibrium, which strongly disfavors the
formation of 1-X. For Lewis bases having pKa > 4, a small
equilibrium constant Keq = 0.31 M−1 was determined.
Although present in only a small amount, 1-X is capable of
cleaving a C−H bond of the substrate in a rate-determining
step with an intrinsic second-order rate constant kC−H, generating
a one-electron reduced species X−CoIII−O−CoIII−OH and a
carbon radical. The oxygen rebound then yields the alcohol
product, which can be further overoxidized to form the ketone
product. For such a kinetic model that includes a fast
equilibrium preceding a rate-determining step, the overall
reaction rate should follow saturation kinetics, as expressed in
eq 1:
As clearly shown by eq 5, the intrinsic rate constant kC−H for
each substrate oxidation by 1-X is 4 orders of magnitude
higher than the k2 value measured. For example, kC−H = 1.7 ×
104 M−1 s−1 for ethylbenzene oxidation by 1-X was calculated
according to eq 5. Compared to the rate of 0.025 M−1 s−1 by
complex 1, the rate enhancement upon opening up the
diamond core is about a million-fold. For toluene, THF, and
methanol, the corresponding kC−H values are 6.2 × 103, 1.8 ×
103, and 8.6 M−1 s−1 (Table 1).
Our results revealed that the dicobalt open core species 1-X
is a much stronger oxidant than its diiron analogues supported
by the same TPA ligand. As shown in Table 1, in the presence
−
of only 0.15 mM N3 , the rate for ethylbenzene oxidation
(0.78(3) M−1 s−1) at −60 °C is more than 3 orders of
magnitude higher than that (2 × 10−4 M−1 s−1) of FeIII,IV2(μ-
O)2 at −30 °C in the presence of 1 M H2O.16 Furthermore,
the predicted DHA oxidation rate constant by 1-X is ∼2700
M−1 s−1 by extrapolating the linear fitting of the BDE plot to
78 kcal/mol (Figure 2). This rate is too fast to be measured
experimentally but should be about 2 orders of magnitude
higher than that (28 M−1 s−1) of HO−FeIII−O−FeIV=O and 8-
fold higher than that (360 M−1 s−1) of CH3O−FeIII−O−
FeIV=O.17 In addition, 1-X oxidizes THF at a rate (0.085(4)
M−1 s−1) similar to that of HO−FeIII−O−FeIV=O (0.03 M−1
s−1).17 As described above, these rates are expected to increase
KeqkC−H[X][1][substrate]
1 + Keq[X]
kC−H[X][1][substrate]
rate =
=
1
+ [X]
Keq
(1)
where [X], [1], and [substrate] are the concentrations of the
Lewis base X, complex 1, and the substrate, respectively. A
saturated rate constant should be expected at high enough
Lewis base concentrations. However, in our system, the
reaction rates start to become too fast to be measured
accurately when gradually increasing [X]. These measurable
Table 1. Comparison of Second-Order Rate Constants (M−1 s−1) for Substrate Oxidations by Diamond Core and Open Core
Diiron and Dicobalt Complexes
substrate
complex
FeIII,IV2(μ-O)2
DHA
10−5
1.5
2.8 × 101
3.6 × 102
2.7 × 103
PhEt
PhMe
1.2 × 10−4
THF
MeOH
ref
a
a
2 × 10−4
2.5 × 10−2
16
18
17
16
1
HO−FeIII−O−FeIV=O
3 × 10−2
CH3O−FeIII−O−FeIV=O
b
7.8 × 10−1
1.7 × 104
2.9 × 10−1
6.2 × 103
8.5 × 10−2
1.8 × 103
1.2 × 10−3
8.6
this work
this work
−
1 + 0.15 mM N3
c
1-X
a
b
c
In the presence of 1 M H2O. Estimated by extrapolating the linear fitting of the BDE plot shown in Figure 2. The rates for 1-X (kC−H) are
−
calculated using the equation kC−H = k2/(Keq[X]), where k2 values are measured at a known [X] (such as 0.15 mM N3 ). Keq = 0.31 M−1 for Lewis
bases having pKa > 4.
F
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Article
further when the Lewis base is present in a higher
concentration. Using the calculated kC−H values of 1-X for an
estimate, 1-X is at least 4 orders of magnitude more reactive
than its diiron analogues.
important breakthrough in our effort aiming to develop more
effective bioinspired approaches for C−H bond activation.
These findings are insightful for understanding the diiron(IV)
intermediate sMMO-Q. Together with a similar rate enhance-
ment reported previously for the diiron open core analogues,
we suggest that the diamond core isomerization to release a
thermodynamically and kinetically more potent oxidant is a
practical strategy to target a specific substrate with highly inert
C−H bonds and to avoid unnecessary damage to other
enzymatic residues.
Lewis bases have been shown in a number of studies to be
capable of modulating C−H bond activation, electron transfer,
and oxygen atom transfer reactivities for high-valent mono-
nuclear metal-oxo complexes in both heme and nonheme
systems.9−14 Upon coordinating to the metal center cis or trans
to the oxo group, these Lewis bases tune both the geometric
and electronic structures of the metal-oxo moieties and
subsequently impact their redox properties and reactivities
without altering the identities of these metal-oxo oxi-
dants.13,14,28,29 In contrast, for high-valent dinuclear diamond
core complexes described for iron15−17 and cobalt (present
work), the interaction of a Lewis base with the dinuclear
species changes the nature of the oxidant from the bis-μ-oxo
bridged diamond core to an open core with a terminal metal-
oxo moiety. This conversion appears to have a greater effect on
the C−H bond activation reactivities for these dinuclear
diamond core complexes (106-fold rate enhancement)
compared to the mononuclear counterparts (up to 104 fold
rate enhancement).12,13
The characterization of 1-X, an open core species with a
terminal CoIV−O moiety, by EPR spectroscopy and DFT
calculations is promising. As predicted by classic bonding
theory,30,31 such CoIV−O species should be highly reactive.
Our observation that 1-X is able to access strong sp3 C−H
bonds at −60 °C with fast intrinsic rate constants is in
accordance with such theoretical prediction. This high
reactivity for an oxocobalt species has only been reported in
the gas phase32 but has yet to be observed for mononuclear
CoIV−O and CoIII=O complexes that have been characterized
in the condensed phase to date.21,23,33,34
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c07294.
■
sı
Experimental methods, computational details, and addi-
tional data and figures including absorbance spectra, kobs
plots, X-band EPR spectra, difference spectra, sche-
matics, and structures (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Yisong Guo − Department of Chemistry, Carnegie Mellon
University, Pittsburgh, Pennsylvania 15213, United States;
orcid.org/0000-0002-4132-3565; Email: ysguo@
andrew.cmu.edu
Marat R. Talipov − Department of Chemistry and
Biochemistry, New Mexico State University, Las Cruces, New
Mexico 88003, United States; orcid.org/0000-0002-
7559-9666; Email: talipovm@nmsu.edu
Dong Wang − Department of Chemistry and Biochemistry,
Center for Biomolecular Structure and Dynamics, University
of Montana, Missoula, Montana 59812, United States;
orcid.org/0000-0002-6370-1942; Email: dong1.wang@
umontana.edu
Our findings are thus insightful for a better understanding of
the high-valent diiron(IV) intermediate Q in sMMO. The
attack of a highly inert C−H bond of methane directly by a
diamond core species is unlikely. Instead, a thermodynamically
and kinetically more potent open core species can be formed
by the core isomerization equilibrium when necessary, for
example, when the appropriate substrate is present. The level
of the oxidizing power can be further tuned by the degree of
such equilibrium. This is an excellent strategy to achieve
substrate specificity and to avoid attacking residues having
weaker C−H bonds.
Authors
Yan Li − Department of Chemistry and Biochemistry, Center
for Biomolecular Structure and Dynamics, University of
Montana, Missoula, Montana 59812, United States;
orcid.org/0000-0002-2623-0475
Suhashini Handunneththige − Department of Chemistry and
Biochemistry, New Mexico State University, Las Cruces, New
Mexico 88003, United States; orcid.org/0000-0001-
5257-8013
Jin Xiong − Department of Chemistry, Carnegie Mellon
University, Pittsburgh, Pennsylvania 15213, United States;
orcid.org/0000-0001-7443-0554
CONCLUSION
■
We have shown in the current study that the C−H bond
cleaving reactivity of the CoIII,IV2(μ-O)2 diamond core complex
1 can be dramatically enhanced when introducing a small
amount of moderate or strong Lewis base into the solution of
1. The interaction of 1 with a Lewis base opens up the
diamond core through core isomerization equilibrium to
generate an open core species 1-X, which was characterized
by EPR spectroscopy and DFT calculations as an S = 1/2
dicobalt(III,IV) species with a terminal CoIV−O moiety. The
equilibrium strongly disfavors the formation of 1-X, with an
equilibrium constant Keq = 0.31 M−1 determined for Lewis
bases having pKa > 4. 1-X is a much stronger oxidant than 1 to
(1) afford million-fold rate enhancement for ethylbenzene
oxidation and (2) cleave stronger C−H bonds up to 96 kcal/
mol. Moreover, 1-X is at least 4 orders of magnitude more
reactive than its diiron analogues. Our results thus represent an
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c07294
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support of this work was provided by the Center for
Biomolecular Structure and Dynamics CoBRE (Grant
NIGMS P20GM103546) and the University of Montana
(Y.L. and D.W.). M.R.T. and S.H. were supported by New
Mexico State University. The computational part of this work
was supported by the Extreme Science and Engineering
Discovery Environment (XSEDE) TG-CHE170004. J.X. and
G
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Article
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Y.G. acknowledge the support from NSF (CHE-1654060) and
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