Tuning the reactivity of FeV(O) toward C-H bonds at room temperature: Effect of water

Article abstract of DOI:10.1021/ic502535f

The presence of an Fe^V(O) species has been postulated as the active intermediate for the oxidation of both C-H and C=C bonds in the Rieske dioxygenase family of enzymes. Understanding the reactivity of these high valent iron-oxo intermediates,

Full text of DOI:10.1021/ic502535f

Article
pubs.acs.org/IC
Tuning the Reactivity of FeV(O) toward C−H Bonds at Room
Temperature: Effect of Water
Kundan K. Singh,† Mrityunjay k. Tiwari,‡ Munmun Ghosh,† Chakadola Panda,† Andrew Weitz,§
Michael P. Hendrich,§ Basab B. Dhar,† Kumar Vanka,‡ and Sayam Sen Gupta*,†
†Chemical Engineering Division, CSIR-National Chemical Laboratory, Pune 411008, India
‡Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory, Pune 411008, India
§Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, Pennsylvania 15213, United States
S
* Supporting Information
ABSTRACT: The presence of an FeV(O) species has been
postulated as the active intermediate for the oxidation of both
C−H and CC bonds in the Rieske dioxygenase family of
enzymes. Understanding the reactivity of these high valent
iron−oxo intermediates, especially in an aqueous medium,
would provide a better understanding of these enzymatic
reaction mechanisms. The formation of an FeV(O) complex at
room temperature in an aqueous CH3CN mixture that
contains up to 90% water using NaOCl as the oxidant is
reported here. The stability of FeV(O) decreases with
increasing water concentration. We show that the reactivity of FeV(O) toward the oxidation of C−H bonds, such as those in
toluene, can be tuned by varying the amount of water in the H2O/CH3CN mixture. Rate acceleration of up to 60 times is
observed for the oxidation of toluene upon increasing the water concentration. The role of water in accelerating the rate of the
reaction has been studied using kinetic measurements, isotope labeling experiments, and density functional theory (DFT)
calculations. A kinetic isotope effect of ∼13 was observed for the oxidation of toluene and d8-toluene showing that C−H
abstraction was involved in the rate-determining step. Activation parameters determined for toluene oxidation in H2O/CH3CN
mixtures on the basis of Eyring plots for the rate constants show a gain in enthalpy with a concomitant loss in entropy. This
points to the formation of a more-ordered transition state involving water molecules. To further understand the role of water, we
performed a careful DFT study, concentrating mostly on the rate-determining hydrogen abstraction step. The DFT-optimized
structure of the starting FeV(O) and the transition state indicates that the rate enhancement is due to the transition state’s
favored stabilization over the reactant due to enhanced hydrogen bonding with water.
temperature using biuret-modified Fe−TAML7 and mCPBA
INTRODUCTION
■
in CH3CN.8 FeV(O) was characterized by UV−vis, X-band
Metalloenzymes use oxidants like O2 and H2O2 to catalyze
electron paramagnetic resonance (EPR), Mossbauer, and high
̈
oxidation reactions that exhibit exquisite substrate specificity
and selectivity and operate under mild conditions through
inherently “green” processes.1 Examples of such catalysts
include cytochrome P450 and peroxidases, enzymes that use
an iron(IV) oxoporphyrin radical cation intermediate to
catalyze the oxidation of various organic substrates selectively
and efficiently.2 Other non-heme-based monooxygenases, such
as α-KG dioxygenase, catalyze the oxidation of C−H bonds by
an FeIV(O) intermediate.3 In the Rieske dioxygenase family of
enzymes, FeV(O) has been postulated to be the active
intermediate reactive species for carrying out oxidation of
both C−H and CC bonds.4 Although several models of
FeIV(O) intermediates have been synthesized, and their
reactivity for oxidizing C−H bonds has been studied in detail,5
very few studies have explored the reactivity of FeV(O) toward
the oxidation of C−H bonds.6
resolution mass spectrometry (HR-MS). It has also been shown
to catalyze the oxidation of C−H bonds with abstraction of the
hydrogen atom being the rate-determining step. Because the
iron monooxygenase reactions occur in water,2d it is important
to understand the effect of water on the rate of reaction for the
oxidation of C−H bonds by FeV(O). Water has been shown to
play a critical role during oxidation of organic substrates in
heme-containing enzymes such as cytochrome P450.9 The
formation of FeIV(O) by Fe−TAML in water has been
previously reported.10 In this Article, we verify the stability of
FeV(O) in H2O/CH3CN mixtures containing up to 90% water.
The effect of water on the reactivity of FeV(O) during C−H
activation has also been studied both experimentally and
theoretically. We also report that the rate of oxidation of
Recently, we reported for the first time the quantitative
Received: October 17, 2014
formation of a well-defined FeV(O) complex at room
© XXXX American Chemical Society
A
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Mossbauer Spectroscopy. 57Fe-enriched 1 was prepared
following the procedure used for the synthesis of 1; in this case,
57FeCl3 was used in place of 56FeCl2 (70% yield). The corresponding
57Fe-enriched 2 (2 mM) was quantitatively prepared by reacting 1 with
2 equiv of NaOCl in an ice bath; spectra were recorded at 4.2 K. The
isomer shift was reported relative to the Fe metal. Simulation of the
toluene with FeV(O) in an H2O/CH3CN mixture is enhanced
up to 60-fold, likely attributable to preferential stabilization of
the transition state during C−H abstraction due to hydrogen
bonding with water molecules.
̈
Mossbauer spectra was calculated with least-squares fitting using the
program SpinCount and the standard spin Hamiltonian (eq ii).
̈
Scheme 1. Formation of FeV(O) Species in an H2O/CH3CN
Mixture and Its Reaction toward Toluene
H = βBgS + SDS + SAI − g b B
n
e
n
eQV
zz [3Iz − I(I + 1) + η(Ix − Iy )]
2
2
2
I +
(ii)
12
Preparation of FeV(O) (2) in Different H2O/CH3CN Mixtures.
NaOCl (1.1 equiv) was added to a 1 × 10−4 M solution of biuret-
modified Fe−TAML (1) in different H2O/CH3CN mixtures (10, 30,
50, 70, and 90% water); UV−vis spectra of FeV(O) (2) were recorded
at 25 °C.
Stability of FeV(O) (2) in Different H2O/CH3CN Mixtures. The
rate constant (k5/4,3) (Table 1) for the spontaneous reduction of FeV
Table 1. Stability and Reactivity of the FeV(O) Intermediate
for Toluene Oxidation in Various H2O/CH3CN Mixtures
EXPERIMENTAL METHODS
■
Materials. Biuret-amide-modified Fe−TAML (1) was synthesized
as we have previously reported.7 57FeCl2 was purchased from Trace
Sciences International Corporation (Canada). Aqueous sodium
hypochlorite (reagent grade, Aldrich, available chlorine 4.00−4.99%)
was used as received and quantified by iodiometry. Acetonitrile
(HPLC grade, Aldrich) was used after passing through an activated
neutral alumina column. D2O (99.9 atom % D) was used as received
(Aldrich). 18O-enriched water (98%) was procured from the Shanghai
Research Institute of Chemical Industry (China). Deionized water was
used to make all of the stock solutions for the reaction and kinetic
runs. Toluene (Aldrich, 99.8%) was passed through activated neutral
alumina and distilled prior to use. All reactions were carried out
without any special precautions under atmospheric conditions unless
otherwise specified.
percentage of water in the
H2O/CH3CN mixture (%)
stability
reactivity
yield (%
benzaldehyde)
(k5/4,3, s−1
)
(k2, M−1 s−1
)
<1
10
30
50
60
70
90
2.4 × 10−5
2.8 × 10−5
3.1 × 10−5
6.5 × 10−5
7.6 × 10−5
1.1 × 10−4
3.2 × 10−4
0.27
0.31
0.47
1.4
23
21
19
20
20
20
5.2
19.6
to FeIV/FeIII in H2O/CH3CN mixtures at 25 °C was measured by the
initial rate approach. The quantitative formation of FeV was carried out
by adding 1.1 equiv of NaOCl in solution to 1. The rate of
spontaneous reduction of FeV to FeIV/FeIII was monitored by
measuring the decrease in absorbance at 613 nm (λmax for FeV).
Linear correlation of the initial rate against [FeV] was found, which
indicated first-order dependency on FeV (i.e., rate = k5/4,3[FeV]).
Reactivity of FeV(O) (2) toward Toluene Oxidation. Kinetics
were monitored in either kinetic mode or scanning spectral kinetics
mode of the spectrophotometer using a 1.0 cm quartz cell at 375 nm
(the isosbestic points of FeIV and FeIII species) at 25.0 °C.12 All of the
kinetic experiments were carried out in H2O/CH3CN mixtures where
the percentage of water present varied as required per experiment.
During kinetic measurements, the concentration of the FeV(O)
complex (10−4 M) was kept constant while the substrate concentration
was varied. A pseudo-first-order rate constant (kobs) was calculated at
the isosbestic wavelength by nonlinear curve fitting [At = Aα − (Aα −
General Instrumentation. X-band EPR spectra were recorded on
a Bruker 300 spectrometer equipped with an Oxford ESR-910 liquid
helium cryostat. For both instruments, the microwave frequency was
calibrated with a frequency counter and the magnetic field with an
NMR gaussmeter. Mossbauer spectra were recorded with two
̈
spectrometers using a Janis Research Super Vari-temp Dewar. UV−
vis spectral studies were carried out using an Agilent diode array 8453
spectrophotometer with an attached electrically controlled thermostat.
Gas chromatography (GC) was performed on a PerkinElmer Arnel
Clarus 500 instrument equipped with a hydrogen flame ionization
detector; BP20 columns (polar) (12 m × 0.53 mm × 1 μm) were used
with helium as the carrier gas at a flow rate of 1 mL min−1. GC-MS
was performed on an Agilent 5977A mass selective detector interfaced
with an Agilent 7890B gas chromatograph using an HP-5ms capillary
column (30 m × 0.32 mm × 0.25 μm, J&W Scientific). HR-MS was
performed in a Thermo Scientific Q-Exactive Orbitrap analyzer using
an electrospray ionization source connected with a C18 column (150
m × 4.6 mm × 8 μm).
A0)e(−k t)] and was in good agreement with the rate constant value
obs
(within 5% error). The resulting kobs values correlated linearly with the
substrate concentration to give the second-order rate constant k2
(Table 1).
EPR Spectroscopy. The sample for EPR analysis was prepared by
adding 10 μL of 40 mM NaOCl to 190 μL of 2 mM biuret-modified
Fe−TAML (1) in an ice bath; the spectrum was taken at 21 K. The
signal was quantified relative to a Cu−EDTA spin standard. A
modulation frequency of 100 kHz was used for the EPR spectra. The
EPR simulation software (SpinCount) was written by one of the
authors.11 The software diagonalizes the spin Hamiltonian (eq i),
where S is the total spin of the complex (unless explicitly stated
otherwise), and the parameters have the usual definitions. The
quantitative simulation was a least-squares fit of the experimental
spectra generated with consideration for the intensity factor, which
allows for the computation of simulated spectra at a specified sample
concentration.
Product Quantification. Gas chromatography (GC) was used for
product quantification. Excess substrate (100 μL, 10−1 M) was added
to a freshly prepared 1 mL solution of 2 (generated by the reaction of
1 (10−4 M) and NaOCl (1.1 × 10−4 M)) at room temperature under
an argon atmosphere. After completion of the reaction (determined by
UV−vis spectroscopy), the internal standard bromobenzene was
added, and the reaction mixture was immediately passed through an
alumina column. Product (% yield) was quantified by GC using the
calibration curve obtained with authentic benzaldehyde and
bromobenzene.
Computational Methods. All of the minima and transition states
reported in this study were fully optimized at the density functional
theory (DFT)-UB3LYP/6-31G*, LANL2DZ (Fe) level of theory13
using the Gaussian09 suite of quantum chemical programs.14 The
H = βBgS + SDS + SAI
(i)
e
B
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Figure 1. (A) UV−vis spectral changes of 1 (10−4 M) (orange) upon the addition of 0.5 equiv of NaOCl (5 × 10−5 M) in CH3CN, forming the μ-
Oxo-FeIV dimer species (violet). Addition of another 0.5 equiv of NaOCl (5 × 10−5 M) to the preformed μ-Oxo-FeIV dimer species produces the
spectrum of FeV(O) (2, green). (B) UV−vis spectra of FeV(O) in different H2O/CH3CN mixtures. (C) EPR spectra of FeV(O) (2) in acetonitrile (2
mM) at 21 K. Black = experimental, red = simulated. (D) Mossbauer spectra of 57Fe-enriched [FeV(O)] ([2]) in acetonitrile (2 mM) at 4.2 K. The
̈
solid lines are spectral simulations.
stationary points on the potential energy surface were characterized by
evaluating the vibrational frequencies. The transition states were
characterized by a single imaginary frequency. The zero point
vibrational energy corrections and thermal corrections were applied
to the “bottom-of-the-well” values to obtain values for the Gibbs free
energy at 298.15 K.
The experimental results suggest that the solvent plays a vital role in
the rate-determining step, as the hydroxylation reaction of toluene by
[FeV(O)(biuret−TAML)]− is favored by increasing the polarity of the
solvent. The electrostatic effect of the solvent dielectric on the reactive
species was determined by full geometry optimizations at the
UB3LYP/6-31G*, LANL2DZ (Fe) level of theory in the dielectric
continuum of acetonitrile and water using the conductor-like
polarizable continuum model.15 Charge stabilization through hydro-
gen-bonding interactions with explicitly added water molecules was
studied by spotting the water-bound reactants, transition states, and
intermediates in the gas phase for the rate-determining hydrogen
abstraction step. This solvent model has recently been employed in
several DFT studies.16
Recent literature suggests that improved treatment of hydrogen
bond interactions could be achieved with the M06 functional.17
Therefore, single point energies were calculated at the ROM062X/6-
31G*, LANL2DZ (Fe) level of theory for the species involved in the
rate-determining step (RDS) for UB3LYP-optimized structures. These
energy values have better concurrence with the experimental findings.
All of the values reported at the ROM062X/6-31G*, LANL2DZ (Fe)
level of theory are single point energies. To have a fair comparison
between UB3LYP and ROM062X energies, only the electronic energy
values describing the effect of the solvent have been reported in this
Article. All assessments on the role of the solvent are thus made on the
basis of their relative electronic energy values.
All of the energies were calculated with respect to optimized
structures with all of the reactants at a finite distance from each other.
This approach is purported to minimize errors in the computation of
the translational entropy in determining the relative free energy values.
Intermediates were optimized by keeping FeIV(OH) and the toluene
radical together in the relative vicinity of each other in one structure.
The same strategy was employed for obtaining the optimized
geometries of the final product. Such strategies have been employed
in the recent past in other computational reports.18
RESULTS AND DISCUSSION
■
Water-soluble NaOCl (household bleach) was used as an
oxidant for the formation of FeV(O). NaOCl has been used as a
co-oxidant for a variety of metal-catalyzed oxidation reactions,
such as olefin epoxidation.19 Addition of NaOCl to 1 showed
the same UV−vis spectral features (Figure 1A) previously
observed using mCPBA in organic media (with both 0.5 and
1.1 equiv of oxidant). The EPR and Mossbauer spectra (Figure
̈
1C and D, respectively) of this species determined by the
addition of 1.1 equiv of NaOCl to 1 are similar to the spectra of
the FeV(O) species we reported previously.8 The g tensors of
the species observed in the X-band EPR spectra from our
previous study were 1.983, 1.935, and 1.726 with mCPBA as
C
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Figure 2. (A) First-order rate constant k5/4,3 varies with water concentration. Inset shows initial rate vs [FeV(O)]. (B) Second-order rate constant k2
for toluene oxidation vs the percentage of water content in the H2O/CH3CN mixture.
the oxidant and are 1.977, 1.888, and 1.720 in the present work
using NaOCl as the oxidant. Spin quantification of the observed
signal indicated quantitative conversion of 1 to the FeV(O)
points of FeIII and FeIV interconversions (345 and 375 nm) at
25 °C, as has been shown before.8 The reaction was studied for
different H2O/CH3CN mixtures (10, 30, 50, 60, and 70%
H2O). The pseudo-first-order rate constant was determined
species. The Mossbauer spectra showed a single quadrupole
̈
doublet with an isomer shift of −0.45 mm/s and quadrupole
splitting of 4.27 mm/s for the FeV(O) species, which are within
the error compared to the parameters of the species from
mCPBA.8
from nonlinear curve fitting of the absorbance relative to time
obst)
data using the equation At = Aα − (Aα − A0)e(−k
and
exhibited good agreement with rate constant values within 5%
error. The kobs correlated linearly with the toluene concen-
tration (Figure SI 2, Supporting Information), and the second-
order rate constant k2 (M−1 s−1) was calculated from the slope
of the straight line that passed through the origin (Table 1,
Figure 2B). At the end of the reaction, the parent FeIII complex
was quantitatively regenerated as was observed from the UV−
vis spectra (peak at 356 nm; Figure SI 3, Supporting
Information) and HR-MS (m/z = 413.0716; Figure SI 4,
Supporting Information). After completion of the reaction,
product identification was carried out by GC-MS (Figure SI 5,
Supporting Information) and HR-MS (Figure SI 6, Supporting
Information). The results showed that benzaldehyde was
formed, and the yield was quantified by GC to be ∼20−23%
(theoretically, only 25% is expected because toluene oxidation
to benzaldehyde is a four electron process and 50% of FeV(O)
comproportionates with 1). The UV−vis scanning kinetics
study showed that the starting FeV(O) species changed to the
diamagnetic μ-Oxo-FeIV dimer species, which gradually
regenerated parent FeIII complex 1 (Figure SI 3, Supporting
Information). In all of the different H2O/CH3CN composite
mixtures (10 to 70%), the rate of toluene oxidation (kobs) was
much faster than the spontaneous reduction of FeV(O). The
variation in k2 values indicated that the reactivity of FeV(O)
increased with water concentration. Initially, the rate enhance-
ments were modest, but it increased significantly when the
water concentration exceeded 50%. At 70% water, k2 was
around 60-fold higher than that in 100% CH3CN. Such an
increase in the rate of oxidation of aromatic hydrocarbons by
RuV(O) has been previously reported by Meyer et al.22
We then proceeded to evaluate the formation of FeV(O) in
H2O/CH3CN mixtures by monitoring its characteristic spectra
through UV−vis spectroscopy. It was observed that in H2O/
CH3CN mixtures with 10, 30, 50, 70, and 90% water, the
spectral characteristics were identical to that of fully
characterized FeV(O) in acetonitrile medium (Figure 1B).
Formation of 2 in a 30:70 H2O/CH3CN mixture was also
confirmed by HR-MS spectra (Figure SI 1 in the Supporting
Information). At 100% water, the spectrum of FeV(O) was not
observed; instead, a violet species was observed whose UV−vis
spectrum was similar to that of the μ-Oxo-FeIV dimer
species.8,12,20 The EPR spectrum of complex 2 in 50:50
H2O/CH3CN showed a species characteristic of the S = 1/2
species of FeV(O).21 The slight difference observed from the
spectrum in pure CH3CN may be due to hydrogen bonding of
water with the FeV(O) complex, as has been proposed below.
We then proceeded to evaluate the stability of the FeV(O)
complex as a function of increasing water concentration. The
stability was measured by monitoring the spontaneous self-
reduction of FeV to FeIV/FeIII at room temperature using UV−
vis spectroscopy at 613 nm (characteristic band of the FeV(O)
species). The initial rate of decay at 613 nm displayed first-
order dependency with respect to FeV(O), and the first-order
rate constant (k5/4,3, s−1) was determined from the slope of the
fitted straight line (Figure 2, Table 1). It was observed that the
stability of FeV(O) decreased with increasing water concen-
tration. At 90:10 H2O/CH3CN, the rate constant k5/4,3 was 10-
fold higher than that observed in 100% CH3CN. This is likely
due to the attack of water molecules on FeV(O), as we have
recently proposed while studying photochemical water
oxidation using 1.21 However, the stability at 70:30 H2O/
CH3CN was only 4 times lower than that in 100% CH3CN, and
the self reduction was much slower than what we observed for
toluene oxidation by FeV(O) in 100% CH3CN.8 We therefore
proceeded to evaluate the rate of toluene oxidation in H2O/
CH3CN mixtures with the water concentration varied from <1
to 70% (Table 1).
The role of H2O during C−H abstraction was then
investigated. First, the direct role of water, such as its attack
on the benzylic carbon of toluene to facilitate C−H bond
cleavage, was investigated. Toluene oxidation was performed
using a 50:50 H218O/CH3CN mixture so that the direct attack
of H218O on the benzylic carbon would lead to the exclusive
formation of 18O-benzaldehyde. However, the percentage of
18O incorporation (calculated on the basis of the relative
abundance of 16O and 18O in the product by GC-MS) was
found to be only 20%. This 18O-incorporated product was
likely the result of (a) exchange of H218O with product
The ability of FeV(O) to facilitate toluene oxidation was
studied under pseudo-first-order conditions at the isosbestic
D
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benzaldehyde via the formation of a gem-diol and (b) oxygen
atom exchange between FeV(O) (2) and H218O leading to the
formation of small amounts of FeV(18O), which would lead to
the incorporation of 18O-benzaldehyde.23 The absence of
exclusive 18O-benzaldehyde formation indicates that direct
attack of water is unlikely. Next, the kinetics of C−H
abstraction was studied in mixed H2O/CH3CN solvents to
evaluate if they differed from the kinetics in pure CH3CN that
we have reported previously. Kinetic isotope effects (KIE) of 13
and 9 for the oxidation of toluene/toluene-d8 in 50:50 and
70:30 H2O/CH3CN (Figure SI 7, Supporting Information),
respectively, were observed. This value is similar to the value
determined for pure CH3CN (KIE of 9).8 This observation
suggests that the rate-determining step in 50:50 H2O/CH3CN
involves C−H abstraction, as has been reported for pure
CH3CN.8 Further, a similar rate enhancement was also
observed with 2,3-dimethylbutane, suggesting that this
phenomenon was not limited to only toluene (Figure SI 8,
Supporting Information). To further understand the role of
water, the solvent kinetic isotope effect (SKIE) was evaluated
with varying D2O/CH3CN mixtures as the solvent for toluene
oxidation. A constant SKIE (kH O/CH CN/kD O/CH CN) value of
Figure 3. Plot of ln(k2/T) vs 1/T for toluene oxidation in 100%
CH3CN and in 70:30 H2O/CH3CN in the temperature range of 283−
300 K.
addition of water. The gain in enthalpy with a concomitant loss
in entropy points to the formation of an ordered transition state
involving water molecules. To more comprehensively under-
stand the role of water in the reaction kinetics, we performed a
careful density functional theory (DFT) study, concentrating
mostly on the rate-determining hydrogen abstraction step.24
All of the stationary points were fully optimized at the DFT-
UB3LYP/6-31G*, LANL2DZ (Fe) level of theory.13−15 The
complete gas-phase energy profile clearly indicates that the
intermediate with the quartet spin state is more stable than the
doublet (Figure 4A and Table SI 3 in the Supporting
Information). This result is further confirmed by the separate
optimization of intermediate complex [FeIV(OH)]− in singlet
and triplet spin states in both the gas phase and in an
acetonitrile solvent. The triplet is stabilized by more than 15.0
kcal mol−1 compared to the singlet. The energy values are
summarized in Table SI 4 of the Supporting Information.
Because the reaction is favored by increasing the polarity (i.e.,
by increasing the relative concentration of water), we envisaged
that water could affect the barrier through two separate
mechanisms: by direct active participation in hydrogen
abstraction (ruled out by the experimental kinetic isotope
study) or by favored stabilization of the rate-determining
transition state over that of the reactant.
2
3
2
3
1.4−1.5 was observed in (H2O/D2O)/CH3CN mixtures with
10, 30, 50, and 70% H2O or D2O (Table 2 and Figure SI 9 in
the Supporting Information), indicating the likely involvement
of hydrogen bonding in the transition state.
Table 2. SKIE Values [k2(H2O)/k2(D2O)] of FeV(O) for
Toluene Oxidation in Various Mixtures of H2O and D2O in
CH3CN
H2O or D2O
(%)
k2 in H2O
k2 in D2O
k2(H2O)/
k2(D2O)
(M−1 s−1
)
(M−1 s−1
)
10
30
50
70
0.31
0.47
1.4
0.21
0.33
0.91
14.0
1.5
1.4
1.5
1.4
19.6
To have a better understanding of the transition state,
variable-temperature (283−300 K) kinetic measurements
(Table SI 1, Supporting Information) were performed for
toluene oxidation to determine the activation parameters
(Table 3, Figure 3) on the basis of Eyring plots for the rate
Two possible means for the differential stabilization of the
transition state and reactant with increasing concentrations of
water were investigated: (a) a bulk solvation effect (macro-
solvation) through the solvent dielectric and (b) a solute−
solvent interaction through hydrogen bonding interactions
(microsolvation). Only a marginal decrease in the rate-
determining barrier (RDB) was obtained by changing the
dielectric of the medium (Table SI 5, Supporting Information)
from acetonitrile to pure water, which suggests that bulk
solvation has a nominal effect on the rate enhancement with
increasing water concentrations. On the other hand, micro-
solvation through the explicit consideration of one and two
water molecules was found to be the primary reason for the
decreased RDB (Figure 4B and Table SI 6 in the Supporting
Information). A clear decrease in the rate-determining barrier
(by 9.3 kcal mol−1) at the ROM062X level, which is known to
provide better treatment of hydrogen bonds,17 upon the
inclusion of one explicit water molecule, and a further decrease
of 2.8 kcal mol−1 upon the inclusion of a second explicit water
molecule corroborate the experimental findings.
Table 3. Thermodynamic Parameter (ΔH°, ΔS°, and ΔG°)
Values for Toluene Oxidation in CH3CN and in a 70:30
H2O/CH3CN Mixture in the Temperature Range of 283−
300 K
ΔH° (kJ mol−1
)
ΔS° (J K−1
)
ΔG° (kJ mol−1
)
CH3CN (100%)
69.3
51.1
−25.3
−49.2
61.7
36.4
70:30 H2O/CH3CN
constants. According to the activation parameters for toluene
oxidation in CH3CN (ΔH° = 69.3 kJ mol−1, TΔS° = −7.6 kJ
mol−1, 300 K) and 70:30 H2O/CH3CN (ΔH° = 51.1 kJ mol−1,
TΔS° = −14.7 kJ mol−1, 300 K), the 60-fold increase in the
reaction rate is mainly controlled by the favorable activation
enthalpy terms (ΔH° gain of 18 kJ mol−1). In contrast, the
contribution of the activation entropy terms (ΔS° loss of 7 kJ
mol−1) to the transition states is negative upon the addition of
water. Because the enthalpic gain is 3 times that of the entropic
loss, a favorable ΔG° leads to rate acceleration upon the
E
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Article
Figure 4. (A) Gas-phase free energy profile for the hydroxylation of toluene by 2 at the UB3LYP/6-31G*, LANL2DZ (Fe) level of theory. Violet
and black colors represent energy profiles at S = 3/2 and S = 1/2 spin states, respectively. All of the values are in kcal mol−1. (B) Electronic energy
profile for the rate-determining step of toluene hydroxylation catalyzed by 2. All of the values correspond to gas-phase data. Values outside and inside
the parentheses correspond to the ROM062X/6-31G*, LANL2DZ (Fe) and UB3LYP/6-31G*, LANL2DZ (Fe) levels of theory, respectively. Black,
green, and yellow colors represent the energy profile with zero, one, and two explicitly added water molecules, respectively. (i, ii, and iii) UB3LYP
optimized transition state structures for the hydrogen atom abstraction rate-determining step (RDS) with zero, one, and two explicitly added water
molecules, respectively. Hydrogen atoms not involved in the reaction coordinate are removed for clarity. All of the values are in kcal mol−1. All
atom−atom distances are in Å.
Our calculations show that water is capable of making a
hydrogen bond with the oxo group of the FeV(O) complex. At
the same time, the FeV(O) complex exhibits other hydrophilic
hydrogen bonding interactive sites, as well those that can
compete with the oxo group. However, the increasing
concentration of water enhances the possibility of Fe(oxo)−
water interactions. It also increases the chance of having more
water in the active site of the FeV(O) complex. Careful
examination of the water-bound reactant structures implies that
the Fe−O bond length increases with an increase in the
number of water molecules hydrogen bonded with the oxo
group in the active site of FeV(O) (2) (Table SI 7 and Figure SI
10, Supporting Information). An increase of 0.053 Å in the Fe−
O bond length upon the inclusion of two explicit water
molecules in the reactant structure suggests that the increasing
concentration of water leads to a decrease in the Fe−O bond
order of FeV(O) (Table SI 7, Supporting Information). This
means that the bond dissociation energy of the Fe−O bond
decreases. We also know that elongation of a chemical bond is
associated with a decrease in the overlap of the involved
orbitals, which usually causes weakening (and thus destabiliza-
tion) of the chemical bond, and thus makes the bond (and
eventually the molecule via that bond) more prone to
dissociation upon chemical attack. On the other hand, we can
see that the Fe−O bond is elongated upon consideration of
explicit water molecules in the transition state structures as well.
However, this elongation decreases upon the addition of
additional explicit water molecules (0.12, 0.092, and 0.087 Å for
zero, one, and two explicit water molecules, respectively, with
respect to the corresponding reactants). The extent of
elongation of the Fe−O bond in the transition state compared
to that of the corresponding reactants can be directly correlated
with the barrier according to the “extended activation strain
model” proposed by Jong et al.25 This model proposes that
smaller deformation in the structure of the involved species
results in less strain energy, which leads to a lower activation
barrier. We should also note that the Fe−O bond in the
equilibrium geometry of the reactant with two explicitly added
water molecules is significantly longer than in the bare reactant,
which causes the strain energy to increase to a lesser extent as
this bond expands in the activated complex compared to that of
the bare reactant without any explicit water included. Hence,
the smaller difference between the transition state and reactant
geometries, as well as the change that occurs when the Fe−O
bond has been weakened significantly by solute−solvent
interactions through hydrogen bonding upon the inclusion of
F
DOI: 10.1021/ic502535f
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
explicit water molecules, together leads to a smaller barrier and
an enhanced rate of reaction. This indicates that the bond
dissociation energy of the Fe−O bond should decrease. A
theoretical study on a related FeIII(O) system by Borovik et al.
confirms that the bond dissociation energy of the Fe−O bond
decreases upon the inclusion of hydrogen bonds from solvent
water.26 Their study further supports the notion that the Fe−O
bond length increases upon the inclusion of explicit water
molecules. They have also shown that the increase in bond
length is associated with a decrease in the percentage of
covalent character of the Fe−O bond. This suggests that the
ionic character of the Fe−O bond in the transition state should
be greater as the Fe−O bond becomes distended. This
elongation is 0.12 Å in the structure without consideration of
explicit water. The greater ionic character of the Fe−O bond
explains the stronger hydrogen bonding with water in the
transition state relative to that of the reactant.
ACKNOWLEDGMENTS
■
S.S.G. acknowledges DST, New Delhi (Grant EMR/2014/
000106) for funding. M.P.H. acknowledges NIH Grant
GM077387 and NSF Grant CHE1126268 for support. K.K.S.,
M.K.T., M.G., and C.P. acknowledge CSIR (Delhi) for their
fellowships. B.B.D. also acknowledges CSIR for his SRA
position. S.S.G. and M.G. thank Professor T. J. Collins for
hosting M.G. at Carnegie Mellon University.
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* Supporting Information
HR-MS spectra, GC-MS traces, kinetic traces, UV−vis spectral
kinetics, KIEs, optimized reactant structures, DFT data, and xyz
coordinates for all stationary points of the optimized structures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Corresponding Author
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Notes
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