Catalytic C-H Bond Oxidation Using Dioxygen by Analogues of Heme Superoxide

Article abstract of DOI:10.1021/acs.inorgchem.9b03767

Heme active sites are capable of oxidizing organic substrates by four electrons using molecular oxygen (heme dioxygenases), where a dioxygen (O₂) adduct of heme (Fe^III-O₂^-) acts as the primary oxidant, in contrast to monooxygenases, where high-valent species are involved. This chemistry, although lucrative, is difficult to access using homogeneous synthetic systems. Over the past few years using a combination of self-assembly and in situ resonance Raman spectroscopy, the distribution of different reactive intermediates formed during the electrochemical reduction of oxygen has been elucidated. An Fe^III-O₂^- species, which is the reactive species of dioxygenase, is an intermediate in heterogeneous electrochemical O₂ reduction by iron porphyrins and its population, under electrochemical conditions, may be controlled by controlling the applied potential. Iron porphyrins having different axial ligands are constructed on a self-assembled monolayer of thiols on an electrode, and these constructs can activate O₂ and efficiently catalyze the dioxygenation of 3-methylindole and oxidation of a series of organic compounds having C-H bond energies between 80 and 90 kcal mol^-1 at potentials where Fe^III-O₂^- species are formed on the electrode. Isotope effects suggest that hydrogen-atom transfer from the substrate is likely to be the rate-determining step. Axial thiolate ligands are found to be more efficient than axial imidazoles or phenolates with turnover numbers above 60000 and turnover frequencies over 60 s^-1. These results highlight a new reaction engineering approach to harness O₂ as a green oxidant for efficient chemical oxidation.

Full text of DOI:10.1021/acs.inorgchem.9b03767

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Article
Catalytic C−H Bond Oxidation Using Dioxygen by Analogues of
Heme Superoxide
Manjistha Mukherjee and Abhishek Dey*
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ABSTRACT: Heme active sites are capable of oxidizing organic substrates
by four electrons using molecular oxygen (heme dioxygenases), where a
dioxygen (O2) adduct of heme (FeIII-O2•−) acts as the primary oxidant, in
contrast to monooxygenases, where high-valent species are involved. This
chemistry, although lucrative, is difficult to access using homogeneous
synthetic systems. Over the past few years using a combination of self-
assembly and in situ resonance Raman spectroscopy, the distribution of
different reactive intermediates formed during the electrochemical reduction
•−
of oxygen has been elucidated. An FeIII-O2 species, which is the reactive
species of dioxygenase, is an intermediate in heterogeneous electrochemical
O2 reduction by iron porphyrins and its population, under electrochemical
conditions, may be controlled by controlling the applied potential. Iron
porphyrins having different axial ligands are constructed on a self-assembled
monolayer of thiols on an electrode, and these constructs can activate O2 and efficiently catalyze the dioxygenation of 3-methylindole
and oxidation of a series of organic compounds having C−H bond energies between 80 and 90 kcal mol−1 at potentials where FeIII-
O2•− species are formed on the electrode. Isotope effects suggest that hydrogen-atom transfer from the substrate is likely to be the
rate-determining step. Axial thiolate ligands are found to be more efficient than axial imidazoles or phenolates with turnover numbers
above 60000 and turnover frequencies over 60 s−1. These results highlight a new reaction engineering approach to harness O2 as a
green oxidant for efficient chemical oxidation.
1. INTRODUCTION
Utilization of dioxygen (O2) as a green oxidant for useful
chemical transformations has been a long-time pursuit of the
scientific community.1−6 In nature, metalloenzymes like heme
dioxygenases (HDOs; Figure 1A)7,8 and cytochrome P450
(cytP450; Figure 1B)9−11 have evolved to utilize O2 to oxidize
a wide variety of organic substrates playing key roles in several
biochemical processes. These metalloenzyme active sites can
activate oxygen controllably to generate reactive intermediates,
which act as the oxidants9,11,12 (Figure 2). In HDOs, the
oxygen-bound heme iron(III) superoxide (P[FeIII-O2•−],
where P represents the porphyrin ring) species reacts with
the substrate7 (Figure 1A). In cytP450, a resting ferrous active
site binds oxygen, and utilizing two electrons and two protons
generates a highly reactive species known as compound I,
Figure 1. Schematic representation of the active intermediates of (A)
indole 2,3-dioxygenase, (B) cytP450 monooxygenase, (C) intradiol
catechol dioxygenase, and (D) a synthetic model for HAT from a
which has a ferryl center bound to a porphyrin radical-cation
species P+[FeIVO]. In cytP450, a FeIII-OOH species, which
precedes compound I, is also proposed to be an active oxidant
pendant quinol system by iron superoxide species.
involved in alkene epoxidation (Figure 1C).13−15
The chemistry community has been pursuing emulating this
Received: December 29, 2019
elegant chemistry for several decades.16−18 Activation of
oxygen by small-molecule ferrous complexes outside the
protein environment to oxidize organic substrates has proven
to be challenging.19−22 This is primarily due to two reasons.
First, the generation of high-valent intermediates like
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process (Figure 2).35 A ferric porphyrin is first reduced to a
ferrous porphyrin as the applied potential is lowered below the
thermodynamic reduction potential of the iron porphyrin
[E°(FeIII/II) in Figure 2]. The ferrous porphyrin binds O2,
generating a FeIII-O2•− species, which is the reactive species in
HDOs and has been detected and characterized in solution in
spectroelectrochemical experiments.36 The FeIII-O2•− species is
then further reduced as the applied potential if further lowered
to a FeIII-OOH species (Figure 2), which is known as
compound 0 in heme enzymes. This reduction step is either a
proton-coupled electron-transfer (PCET) or a electron-trans-
fer proton-transfer (ETPT) pathway depending on the nature
of the axial ligand, solvent, and distal environment.37,38 Again,
depending on the nature of the axial ligand and distal structure
of the porphyrin, the FeIII-OOH species can lead to either a
FeIVO (compound II) or a P+FeIVO (compound I)
species, which are accumulated on the electrode during steady-
state O2 reduction.39−42 The oxygen-derived species that
accumulate on the electrode are chemically the same as the
reactive oxidants in different heme enzymes (Figure 2). The
electrochemical approach of generating these reactive species is
advantageous because these different species are separated by
the thermodynamic potential, which can be controlled by
externally applying the requisite potential.
Figure 2. Schematic representation of the intermediates involved in
oxygen reduction and their reactivity in both enzyme and synthetic
systems.
compound I from oxygen requires controlled delivery of
electrons and protons; while deftly engineered in metal-
loenzymes, it is challenging to control in most synthetic
constructs.3,23,24 Second, the reaction of O2 with ferrous
complexes generates reactive oxygen species like superoxide
and hydroxyl radicals and the corresponding ferric com-
plexes.25,26 While these radicals are unselective oxidants,27 the
end product ferric species do not react with O2, thereby
jeopardizing catalysis.3 Early efforts to chemically regenerate
the active reduced metal form by an external reducing agent to
obtain catalysis resulted in the nonspecific oxidation of both
styrene and cyclohexane with very limited turnovers.28
Recently, photocatalysis has been utilized to regenerate the
reactive species, and it has been proven that photogeneration
of the reactive intermediate occurs via a free-radical path-
Using this approach, thiolate-bound iron porphyrins,
immobilized on self-assembled monolayers (SAMs) of thiols
on gold electrodes, demonstrated monooxygenase activity,
where the two electrons required for it were supplied from the
electrode.43 Catalytic hydroxylation of aliphatic C−H bonds
having a bond dissociation energy of ≥100 kcal mol−1 using O2
as an oxidant was demonstrated with a turnover number
(TON) of >20000, and a 100% 18O2-incorporated product
indicated that molecular oxygen was the source of the oxygen
atom. High-valent intermediates such as compound I
(P+FeIVO in Figure 2) generated during oxygen reduction
could be utilized to oxidize organic substrates in these
electrochemical analogues of the cytP450 system. Normally,
such high-valent intermediates formed during electrochemical
O2 reduction are reduced by rapid electron transfer (ET) from
the electrode, which in these cases is generally held at cathodic
potentials. When the rate of ET was controlled by controlling
the chain length of the thiols used to form the SAM, these
intermediates could be used to oxidize inert C−H bonds
catalytically. These recent developments raise the possibility of
way.29,30 In very rare cases, FeIII-O2 has been found to be
•−
capable of oxidizing organic substrates in a controllable
manner.31−33 A recent example is the two-electron oxidation
of a quinol group appended to the porphyrin ring by FeIII-O2
•−
species (Figure 1D) via two consecutive hydrogen-atom-
transfer (HAT) steps.34 The above few cases represent two-
electron oxidation of the substrate and not four-electron
oxidation typical of dioxygenases. In dioxygenases, all four
electrons required to reduce O2 are obtained from an organic
substrate, which, in turn, gets oxidized by four electrons and
incorporates the oxygen atoms. Such reactivity utilizing O2 as a
four-electron oxidant is yet to be demonstrated in synthetic
heme systems.
harnessing the reactivity of FeIII-O2 species at potentials
•−
where the FeIII-O2 species may exist. In this manuscript,
•−
catalytic chemical oxidation of organic substrates by four
electrons is achieved using molecular oxygen as the oxidant.
•−
The oxidant, a FeIII-O2 species, is generated electrochemi-
cally on SAM-covered gold electrodes by the reaction of O2
with iron(II) porphyrins having different axial ligands (e.g.,
thiolate, phenolate, and imidazole). Apart from indoles, a series
of substrates having C−H bond dissociation free energies
(BDFECH) of less than 90 kcal mol−1 could be oxidized with
turnover number (TON) and turnover frequency (TOF)
greater than 60000 and 60 s−1, respectively. Isotope effects,
18O2 labeling, and the effect of the applied potential suggest
that HAT by a FeIII-O2•− species is likely to be the key step in
catalysis.
The regeneration of a reactive ferrous form can also be, in
principle, achieved electrochemically. Such attempts are
complicated by the fact that the application of a cathodic
potential to iron porphyrins (to reduce them) in the presence
of O2 leads to the electrochemical reduction of oxygen. While
•−
intermediates such as FeIII-O2 and P+FeIVO can be
envisaged to be involved in the process, it has not been clear
as to how to access these species controllably using O2. Very
recently, the electrochemical reduction of O2 using iron
porphyrin complexes in conjunction with in situ resonance
Raman spectroscopy has led to the development of a general
understanding of the mechanism for the oxygen reduction
2. RESULTS
2.1. Oxidation of Substrates. Iron porphyrin having a
hydrophobic distal site like iron “picketfence” porphyrin,17
B
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Figure 3. (A) Schematic representation of the heterogeneous electrode system used, where L stands for different axial ligands such as imidazole
(md), phenolate (OPh−), and thiolate (RS−). FeIII/II cyclic voltammograms in the absence of O2 (solid line; scan rate 1 V s−1) and the
electrocatalytic O2 reduction current (dashed line; scan rate 50 mV s−1) for (B) imidazole-, (C) phenolate-, and (D) thiolate-ligated FePf in a 100
mM pH 7 phosphate buffer.
FePf, is attached to imidazole, phenolate, and thiolate terminal
headgroups of thiols thinly dispersed in a SAM on gold
electrodes (Figure 3A, where R = o-pivolylacetamidophenyl) as
described earlier.44 In the absence of oxygen, these electrodes
show reversible FeIII/II processes at −202, −217, and −250 mV
versus Ag/AgCl (saturated KCl) for phenolate-, imidazole-,
and thiolate-ligated FePf, respectively (parts C, B, and D of
Figure 3, respectively). In the presence of oxygen in a pH 7
buffer solution, these show electrochemical oxygen reduction,
which has been investigated in detail.35,40,44,45 When 3-
methylindole, a modified indole dioxygenase substrate, is
Figure 4. Oxidation of (A) 3-methylindole and (B) toluene by FeIII-
O2 with different axial ligands.
taken in the buffer solution used for oxygen reduction reaction
and a constant potential of −300 mV versus Ag/AgCl
(saturated KCl) is applied in a bulk electrolysis experiment,
N-(2-acetylphenyl)formamide (Figure 4A and Figures S.3 and
S.4) is found during product analysis, which is the product of a
dioxygenase reaction, suggesting that the electrochemical
activation of O2 provides access to dioxygenase reactivity in
this construct. The same reactivity is observed irrespective of
the axial ligand used (i.e., thiolate, phenolate, and imidazole).
Having observed the oxidation of 3-methylindole, a convenient
substrate has to be chosen to understand the reactivity of the
oxidant produced during electrochemical oxygen reduction in
detail [rate, kinetic isotope effect (KIE), 18O incorporation,
•−
suggested that the BDFEOH value of FeIII-O2H bond is 83.9
kcal mol−1. Accordingly, toluene (BDFECH of 89 kcal mol−1) is
chosen as a substrate to investigate the reactivity of these
systems. In this case, a four-electron-oxidized product of
toluene, benzaldehyde, is detected as the main product with
TONs as high as 6.1 × 104 and TOFs as high as 67.93 s−1 for
the thiolate-bound FePf complex (Table 1). Thus, the
construct developed here can catalyze the reaction PhCH3 +
O2 → PhCHO + H2O efficiently at room temperature and in
an aqueous medium (Figure 4B). Along with benzaldehyde,
minor amounts of benzyl alcohol are also observed, suggesting
that the reaction proceeds via benzyl alcohol as an
intermediate.
•−
etc.]. Recently, an FeTPP-based FeIII-O2 species has been
demonstrated to perform HAT from a covalently attached
pendant quinol having a BDFEOH of 80 kcal mol−1 (Figure
1D).34 Accompanying density functional theory calculations
C
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species could not be achieved with axial imidazole and
phenolate ligations (Table 1, rows 8 and 9) using this approach
in the same potential range of −100 to −500 mV versus Ag/
AgCl (saturated KCl).
Table 1. TONs, TOFs, the Maximum TON Possible for
Monooxygenase Reaction (TONM), and the Ratio of TON
and TONM (μ) for the Products Obtained after the
Oxidation of Substrates by Differently Ligated FePf
Complexes
2.2. Quantification of the Faradaic Efficiency. Mono-
oxygenase activity (R−H + O2 + 2H+ + 2e− → R−OH + H2O)
requires two electrons from the electrode per substrate
oxidized. Thus, if an electrolysis experiment consumes a total
charge Q, the moles of the product obtained can be at most Q/
nF, where F is a Faraday constant of 96500 C mol−1. For a
monooxygenase-type reaction, the maximum possible TON
(TONM in Table 1, column 6) can be estimated from the total
charge consumed using this formula, where n = 2. For example,
as demonstrated recently, a compound I type species is formed
during oxygen reduction by iron porphyrins with axial thiolate
ligands at cathodic potentials that can hydroxylate and
epoxidize organic substrates via a cytP450-like monooxygenase
activity.43 It was observed that the ratio of the actual TON and
TONM(defined henceforth as μ; section S.8) was always <1
because some of the electrons are consumed as a result of a
competing oxygen reduction reaction, which does not lead to
product formation (Table 1, column 7). For a dioxygenase-
type reaction or a four-electron oxidation of an organic
substrate, the reactive ferrous form is regenerated at the end of
the cycle and μ can be theoretically infinite.48,49 However,
when attached to an electrode and dipped in an aqueous
solution, there is always a competing oxygen reduction reaction
and hydrolysis of the intermediates involved (e.g., FeIII-OOH),
which consumed electrons.43 In such a case, the experimentally
observed μ can be expected to be more than 1 (n = 2) but not
infinite. Note that while the competing oxygen reduction is
expected to reduce the efficiency of the dioxygenase activity,
the active ferrous species can be regenerated at the electrode at
the applied cathodic potential and help to reinstate catalysis.
Quantification of the oxidation product of toluene,
benzaldehyde, reveals that the yields in these cases, where
the applied potential is held in the kinetically controlled region
of the oxygen reduction reaction, are substantially higher than
what monooxygenase activity would allow (TONM in Table 1),
necessarily implying an oxidation mechanism that does not
require regeneration of the active ferrous form at the end of the
catalytic cycle, i.e., a four-electron oxidation by O2. The ratio of
actual TON and TONM, μ, is ≫1 for almost all substrates
where BDFECH is <89 kcal mol−1. For stronger C−H bonds as
well as the epoxidation of styrene, oxidation is only observed
with an axial thiolate ligand, akin to cytP450, having μ < 1 for
reasons explained before. A μ of 22 in the case of thiolate-
bound FePf implies that there are 22 turnovers for the four-
electron oxidation of toluene to benzaldehyde before the iron
center needs to be reduced by the electrode. Radical-chain
reactions like Russel termination and Gif reactions can also
lead to excess substrate oxidation but are rescinded based on
product distribution and isotope effects that are discussed
below. The TON and TOF are higher for the thiolate-ligated
porphyrin relative to the imidazole- and phenolate-ligated
porphyrins. Moreover, the amount of oxidized product
increases ∼5 times when the aqueous electrolyte, containing
0.2 mM dissolved O2, is saturated with O2 (∼1 mM),
consistent with a dioxygenation-type four-electron oxidation of
the substrate (Figure S.7 and Table S.3). Thus, 18O
incorporation, very high μ values, and dependence of the
rate on the concentration of oxygen in the solution imply that a
four-electron oxidation of the substrate is catalyzed by iron
a
b
c
L is the axial ligand. TON is the turnover number. Turnover
frequency (TOF) averaged over the entire duration of the experiment.
d
e
Maximum turnover expected from monooxygenase reactivity. The
ratio of TON and TONM.
The incorporation of molecular O2 in the product is
confirmed by labeling experiments using 18O2. While the
benzyl alcohol produced is 100% labeled with 18O, the
benzaldehyde produced is not because the rate of exchange of
a
18O-labeled aldehyde oxygen with unlabeled water is ∼105
M−1 s−1 in buffered solutions.46 Recently, 18O2 incorporation
in aldehyde in unlabeled water was established by reducing it
in situ to the corresponding alcohol using NaBH4.47 In the
presence of NaBH4, the 18O-labeled benzaldehyde produced
immediately gets reduced to labeled benzyl alcohol and the
alcoholic oxygen atom thus produced does not get further
exchanged.47 Thus, the electrochemical oxygen reduction is
performed in a 18O2-saturated buffer in the presence of toluene
and excess NaBH4. This resulted in a substantially greater
amount of 18O-labeled benzyl alcohol (Figure S.8) than that
produced without labeled oxygen. The excess 18O-labeled
benzyl alcohol is obtained from the reduction of 18O-labeled
benzaldehyde produced via oxidation of toluene with 18O-
labeled molecular oxygen. The total yields of benzaldehyde are
lower for axial imidazole and phenolate ligands relative to that
for an axial thiolate ligand (Table 1, rows 1−3). A series of
substrates, including benzyl alcohol, benzaldehyde, and
cinnamaldehyde, could be oxidized by molecular oxygen
using the same approach. These substrates all have BDFEC−H
< 89 kcal mol−1 (Table 1, rows 4−6). However, stronger C−H
bonds of cyclohexane or epoxidation of styrene by a FeIII-O2
•−
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Figure 5. μ of benzadehyde obtained as a function of the applied potential for (A) imidazole-, (B) phenolate-, and C) thiolate-bound FePf in a pH
7 buffer solution at room temperature.
porphyrins using a molecular oxygen by four electrons, where
substrate oxidation is reduced substantially at this potential,
with μ approaching the monooxygenation limit of <1. At these
potentials, O2 is already reduced by two electrons to generate
peroxide species or FeIVO/P+FeIVO species (produced
after O−O bond cleavage) and, hence, μ approaching a value
<1 is expected.
2.4. ET Rate. In case a high-valent intermediate like
compound I or II generated during O2 reduction is the oxidant,
increasing the rate of ET from the electrode to the catalyst by
altering the chain length of the thiol reduces the yield of the
oxidized product.43 For example, when compound I generated
during O2 reduction is used to oxidize cyclohexane to
cyclohexanol in thiolate-bound FePf, μ decreases rapidly as
the rate of ET from the electrode to catalyst is enhanced by
decreasing the chain length of thiols used to construct the
SAM. In contrast, the yield of benzaldehyde from toluene
oxidation is determined to be almost independent of the ET
rate from the electrode, suggesting that the majority of
oxidation occurs via a dioxygenase-type reactivity that does not
require ET from the electrode during catalytic turnover (Table
2).
•−
FeIII-O2 is a reactive intermediate formed upon binding of
O2 to the ferrous porphyrin produced on the electrode. The
population of a FeIII-O2•− species on an electrode is potential-
dependent because this species is further reduced to a FeIII-
OOH species in the process of O2 reduction and that
automatically requires the product distribution to be potential-
dependent as well.
2.3. Effect of the Applied Potential. The extent of four-
electron-oxidized product produced during constant potential
electrolysis reactions, expressed in μ (section S.8), is quantified
at different applied potentials for FePf bound to axial
imidazole, phenolate, and thiolate ligands. In all of these
cases, the maximum yield is obtained at potentials where the
FeIII-O2 species is likely most abundant on the electrode
•−
(Figure 5), i.e., at the potential-dependent kinetic region of the
electrocatalytic current where ET is the rate-determining step
(rds). This is the potential region where the rate of O2
reduction is limited by the reduction of FeIII-O2 via ET
•−
from the electrode.38 At more negative applied potentials
[−500 mV vs Ag/AgCl (saturated KCl)], surface-enhanced
resonance Raman spectroscopy coupled to rotating disk
electrochemistry experiments have indicated the presence of
FeIII-OOH (major) and FeIVO species (minor); i.e., the
Apart from four-electron oxidation of these substrates by
oxygen, it is also possible that oxidation occurs via a radical-
chain reaction where a substrate radical reacts with oxygen in
the medium. There are two possible pathways: (a) Russel
FeIII-O2 species has been further reduced.35 The extent of
•−
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proposed FeIII-O2•−, FeIII-OOH, and FeIVO intermediates
were all characterized using resonance Raman and electron
paramagnetic resonance spectroscopy.34 The KIEs are
consistent with the HAT being the rds as proposed.
Table 2. Changes in μ with Changes in the ET Rate
The proposed mechanism requires the FeIVO species to
complete the second two-electron oxidation. While imidazole-
and phenolate-bound FeIVO species are known to be stable
at neutral pH,55 thiolate-bound FeIVO species have pKa >
956 and are protonated at pH 7. Similarly, a thiolate-bound
FeIII-OOH is prone to heterolysis. While protonation of FeIV
O would compete with HAT from the monooxygenated
substrate, protonation of FeIII-OOH would compete with its
rebound (Figure 6) to the substrate radical. However, the
bulky pivolyl groups in FePf create a hydrophobic pocket that
disfavors water binding to the iron. This is evident from the
fact that the resonance Raman data of thiolate-bound FePf
show that it is five-coordinate even in an aqueous environment,
unlike thiolate-bound iron porphyrins without the bulky
pivolyl groups, which, as the resonance Raman data show,
form wate-bound six-coordinate low-spin species.57 Similarly,
protonation of FeIII-OOH by bulk water during O2 reduction
or monooxygenation, for example, has a KSIE of 13.43
Accordingly, when an iron porphyrin with two pivolyl groups
is used, FehPf (Figure S.11), the benzadehyde produced is
reduced substantially and μ values are reduced to 12.4 relative
to 22.8 in FePf because of the greater access of water to the
active site, causing more O2 reduction and monooxygenase
activity, consistent with the proposed mechanism.
termination;50 (b) Gif reaction. Russel termination would
result in a 1:1 ratio of the aldehyde and alcohol, which is not
the case here. Gif reaction would require the formation of a
Fe−C bond and has a minimal KIE. The formation of a Fe−C
bond would inhibit oxygen binding to the iron, which would,
in turn, inhibit O2 reduction, contrary to the experimental
results. Thus, neither of these radical mechanisms fits the
product profile and KIE (see below) obtained here.
2.5. Isotope Effects. These reactions were performed with
toluene-d8 to estimate the KIE. The axial thiolate, phenolate,
and imidazole ligands produce KIEs of 5, 9, and 12,
respectively (Table 3 and Figure S.9). These formidable
Table 3. KIE and KSIE for Toluene Oxidation with
Differently Ligated FePf
The low KIE and high KSIE suggest that, for thiolate-bound
FePf, the rds is not likely to be HAT by a FeIII-O2 species
•−
because a HAT step does not have a water involved.
Alternatively, considering the high pKa of a thiolate-bound
FeIVO, it is possible that the basic FeIVO abstracts the
proton from the benzyl alcohol produced from toluene,
followed by hydride abstraction from the resultant alkoxide
(Figure 7A). A similar mechanism for benzyl alcohol oxidation
to benzaldehyde has been proposed for basic FeVO
supported by a tetraamidate ligand.58 Because the proton of
benzyl alcohol, which sits atop of the active site cavity, is
rapidly exchangeable with the solvent (faster than the time
scale of these reactions) but the benzylic C−H is not, such a
rds will show both KIE and KSIE as observed here.
Consistently, KSIE is not observed when benzyl alcohol is
used as the substrate for thiolate-bound FePf, where benzoic
acid is the major product (forms benzylbenzoate in situ). This
is because the first two-electron oxidation of benzyl alcohol will
lead to benzaldehyde (Figure 7B), which does not have an
exchangeable proton and hence no KSIE.
KIEs for the axial imidazole and phenolate ligands suggest that
HAT is the rds in these reactions. This rds is likely to be HAT
.−
from toluene to the FeIII-O2 intermediate formed during O2
reduction on the electrode.51−54 Because these reactions are
performed in aqueous solvents, the solvent kinetic isotope
effects (KSIEs) are measured (Figure S.10). Consistent with a
HAT mechanism, neither axial phenolate nor imidazole ligands
have any KSIEs. The axial thiolate ligand exhibits a KSIE of 4,
which along with a weak KIE may imply a different rds. Note
that a monooxygenase reaction by the thiolate-bound FePf
complex exhibited a KSIE of 13 because the proton-assisted
heterolytic O−O bond cleavage of FeIII-OOH was involved.43
3. MECHANISM OF ACTION
The proposed mechanism suggests that the same reactivity,
in principle, should be attainable under homogeneous
conditions under both single turnover conditions (starting
with ferrous porphyrins) and homogeneous electrocatalytic
conditions. Accordingly, cyclic voltammetry (CV) of FePf with
N-methylimidazole in the presence of O2 and toluene shows a
large electrocatalytic current at potentials where the iron is
reduced to its ferrous state (section S.14 and Figure S.12).
This current, which is absent in the presence of O2 alone,
On the basis of the experimental observations, a mechanism of
•−
action for the observed reactivity can be proposed. A FeIII-O2
species performs the first HAT from the substrate, forming a
FeIII-OOH species and a substrate radical. The FeIII-OOH
rebounds via homolytic cleavage of the O−O bond to form a
hydroxylated substrate and FeIVO. The FeIVO, being a
better oxidant than FeIII-O2•−, performs another HAT from the
two-electron-oxidized substrate, and via a final rebound, it
forms the four-electron-oxidized substrate, regenerating the
FeII reactive state, which can enter another catalytic cycle. The
corresponds to the oxidation of toluene by the FeIII-O2
•−
ability of FeIII-O2 to perform two consecutive HATs from a
•−
species formed, and benzaldehyde and benzoic acid are indeed
detected by gas chromatography/mass spectrometry (GC/
MS).
substrate, as proposed here, was recently established using an
iron porphyrin bearing a pendant quinol group.34 The
F
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Figure 6. Proposed mechanism of oxidation of toluene to benzaldehyde by O2 catalyzed by FePf covalently attached to the electrode via axial
ligands.
Figure 7. Proposed mechanism for the second oxidation of (A) benzyl alcohol, produced from toluene, and (B) benzaldehyde, produced from
benzyl alcohol with thiolate-bound FePf.
room temperatures and in water solvent. The combination of
the self-assembly of an active site atop an electrode and
knowledge of the detailed mechanism of O2 reduction by iron
porphyrins immobilized on the electrode allowed control over
the species present on the electrode using an applied potential,
4. CONCLUSION
In summary, the catalytic oxidation of benzylic C−H bonds by
iron porphyrins using O2 could be demonstrated with TONs
and TOFs as high as ∼60000 and ∼60 s−1, respectively, at
G
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diluent shown in Table 4. All of these linkers were prepared using the
reported procedure.44 In each case, the diluent used was C8SH, except
for the cases where the ET control reactivity was measured. For both
C4SH and C10SH diluents, the SAM solutions were prepared using
the same diluent and linker (SHC11SH) ratio that was used for SAM
solutions containing a C8SH diluent. Freshly cleaned gold wafers were
rinsed with triple-distilled water and ethanol, purged with N2 gas, and
immersed in the depositing solution for 48 h.
5.4. Attachment of the Catalyst to the Electrode. Gold wafers
immersed in the deposition solution were taken out before the
experiments and rinsed with ethanol followed by triple-distilled
deionized water and then dried with N2 gas. The wafers were then
inserted into a plate material evaluating cell (ALS Japan). Catalysts
were dissolved in chloroform. For attachment of FePf (Figure 9) to
thereby harnessing a dioxygenase-type reactivity likely via a
•−
proposed FeIII-O2 species. The rds for this reaction, as
indicated by KIE and KSIE, is HAT by FeIII-O2 for axial
•−
imidazole and phenolate ligands, while for an axial thiolate
ligand, it is likely to be hydride transfer to a thiolate-bound
FeIVO from a benzyl alcohol formed in situ. These results
not only open up new reaction engineering approaches for
harnessing a green oxidant like O2 for useful chemical
oxidations but also offer direct insight into the role of axial
ligands in tuning the reactivity of FeIII-O2•− species, which are
proposed to be formed during electrochemical oxygen
reduction and are ubiquitous in nature in all heme oxidases
and oxygenases.
5. EXPERIMENTAL SECTION
5.1. Materials. All reagents were of the highest grade
commercially available and were used without further purification.
Octanethiol (C8SH), butanethiol (C4SH), decanethiol (C10SH),
potassium hexafluorophosphate (KPF6), benzyl alcohol, benzalde-
hyde, cinnamaldehyde and 3-methylindole were purchased from
Sigma-Aldrich. Disodium hydrogen phosphate dihydrate (Na2HPO4·
2H2O) was purchased from Merck. Triethylamine (Et3N) and toluene
were purchased from Spectrochem India Ltd. Isotopic labeled O2 was
purchased from Berry Associates, West Milford, NJ. Gold wafers were
purchased from Platypus Technologies [1000 Å of gold on 50 Å of a
titanium adhesion layer on top of a silicon(III) surface].
5.2. Instrumentation. All electrochemical experiments were done
using CH Instruments (model CHI700E electrochemical analyzer).
The bipotentiostat, reference electrodes [Ag/AgCl (saturated KCl)],
and Teflon plate material evaluating cell (ALS Japan) were purchased
from CH Instruments. All qualitative and quantitative experiments
were done using GC/MS. For this, an Agilent 7890B GC system with
a 5977A MS detector was used.
Figure 9. Catalysts used in the work with FePf.
the ImdC11SH linker, the electrode surface was immersed in a CHCl3
solution of the catalyst for about 1.5 h. For the SHC11SH and
OPhC11SH linkers, the electrode surfaces were immersed first in Et3N
for 10 min and then in the FePf solution for 2.5 h (Scheme 1). After
the respective times, the surfaces were thoroughly rinsed with
chloroform, ethanol, and triple-distilled water before electrochemical
catalysis. Thiolate ligation was characterized by CV, X-ray photo-
electron spectroscopy,43 and resonance Raman spectroscopy (section
S.1). Phenolate and imidazole ligations were characterized using CV
and resonance Raman spectroscopy44 (section S.1).
5.5. CV Experiments. All CV experiments were done in pH 7
buffer (unless otherwise mentioned) containing 100 mM Na2HPO4·
2H2O and 100 mM KPF6 (supporting electrolyte) using a platinum
wire as the counter electrode and Ag/AgCl (saturated KCl) as the
reference electrode.
5.3. Construction of the Electrode. Cleaning of the gold wafers
was performed electrochemically by sweeping several times between
1.7 V and −300 mV versus Ag/AgCl (saturated KCl) in 0.5 M
H2SO4. SAM solutions were prepared using the concentration ratio of
the linkers (SHC11SH, OPhC11SH, and ImdC11SH; Figure 8) and
5.6. Oxidation of the Substrates. The substrates used here were
toluene, benzyl alcohol, benzaldehyde, cinnamaldhyde, and 3-
methylindole. Phosphate buffer solutions (pH 7) were saturated
with these substrates by adding 2 drops of ethanol to the suspension
of these organic molecules in water, followed by vigorous shaking of
the previously mentioned suspension. The use of ethanol increases
the solubility of the organic substrates in aqueous buffer. The mixture
was allowed to settle and separated using a separating flask. The
aqueous layer was extracted, and electrocatalysis was done as reported
before.43 Electrochemical analyses were performed with this aqueous
solution (Figure S.1). Electrolysis was performed at a constant
potential of −300 mV [vs Ag/AgCl (saturate KCl)] with this solution
for 15 min. The potential dependence of the oxidation reaction was
evaluated by performing electrolysis experiments at several potentials
between −100 and −500 mV versus Ag/AgCl (saturated KCl) and
analyzing the products. Product analysis represents the average of 3−5
individual experiments. The CV data collected after bulk electrolysis
(Figure S.1.A) indicate the extent of decay of the catalysts during
electrolysis. After the electrochemical experiments, the resultant
aqueous electrolytes containing reactants and products were extracted
with chloroform (CHCl3). The CHCl3 layer was dried and
evaporated, and the product left behind was subjected to GC/MS
analysis (Figure S.2). Note that ethanol, used here to make the
substrates more soluble in water, acts as a competing substrate in this
reaction because acetaldehyde was detected by GC. However, the
amount is low because of its higher solubility in water and lesser
affinity for the hydrophobic electrode surface. For toluene oxidation
with differently ligated FePf, electrolysis was done in this potential
Figure 8. (A−C) Linker molecules SHC11SH, ImdC11SH, and
OPhC11SH, respectively. (D) Diluent molecule (n = 1, 5, and 7
respectively for C4SH, C8SH, and C10SH).
Table 4. SAM Solution Preparation Ratio
linker
mole fraction of the linker
total concentration (mM)
ImdC11SH
OPhC11SH
SHC11SH
0.2
0.2
0.2
0.4
0.4
3
H
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a
Scheme 1. Schematic Representation of the Construction of Bioinspired Electrodes
a
The catalyst, iron porphyrin, was attached on top of the SAM-coated gold electrode.
range, and in Table 1, the maximum values of TON, TOF, and μ were
ACKNOWLEDGMENTS
■
reported for each of the axial ligands. Control experiments without
axial ligands were also done to confirm that the axially ligated iron
porphyrin is responsible for oxidation of the substrates (section S.5
and Figure S.5).
The work is supported by the Department of Science and
Technology, Government of India (Grant SERB/EMR-
0008063).
5.7. Estimation of TON and TOF. The amount of oxidized
product was determined by GC (Figure S.2). In order to do that, the
areas of the peaks of pure samples of different known concentrations
were determined and plotted against the known concentrations of the
samples. This plot represents the calibration plot for that particular
sample (Figure S.6). The amount of the oxidized product, outlined
above, was actually quantified by using the respective calibration plot.
CV experiments were used to calculate the amount of catalyst on the
electrode surface (Table S.2). The ratio of the number of moles of
product formed and number of moles of catalyst depicts the TON.
TON divided by the reaction time gives the TOF of the overall
reaction.
5.8. Estimation of KIE and KSIE. To measure KIE for toluene
oxidation, toluene-d8 was used as the substrate. The deuterated
substrate was dissolved in aqueous buffer, and catalysis was performed
as mentioned above with the catalyst attached to the electrode. For
KSIE measurement, instead of pH 7 phosphate buffer, pD 7 buffer
with the same concentration of electrolyte was used, and the
substrates were saturated in this buffer to perform catalytic reactions
with the modified electrode. In both cases, the products were
quantified by GC/MS, and then the amounts were compared with the
products obtained for the substrates stated above.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.9b03767.
■
sı
Control experiments and additional CV data (PDF)
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AUTHOR INFORMATION
Corresponding Author
Abhishek Dey − School of Chemical Science, Indian Association
for the Cultivation of Science, Kolkata 700032, India;
orcid.org/0000-0002-9166-3349; Email: icad@iacs.res.in
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Author
Manjistha Mukherjee − School of Chemical Science, Indian
Association for the Cultivation of Science, Kolkata 700032,
India; orcid.org/0000-0001-6550-6262
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
I
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