Selective C-H Bond Oxidation Catalyzed by the Fe-bTAML Complex: Mechanistic Implications

Article abstract of DOI:10.1021/acs.inorgchem.7b00453

Nonheme iron complexes bearing tetradentate N-atom-donor ligands with cis labile sites show great promise for chemoselective aliphatic C-H hydroxylation. However, several challenges still limit their widespread application. We report a mechanism-guided development of a peroxidase mimicking iron complex based on the bTAML macrocyclic ligand framework (Fe-bTAML: biuret-modified tetraamido macrocyclic ligand) as a catalyst to perform selective oxidation of unactivated 3° bonds with unprecedented regioselectivity (3°:2° of 110:1 for adamantane oxidation), high stereoretention (99%), and turnover numbers (TONs) up to 300 using mCPBA as the oxidant. Ligand decomposition pathways involving acid-induced demetalation were identified, and this led to the development of more robust and efficient Fe-bTAML complexes that catalyzed chemoselective C-H oxidation. Mechanistic studies, which include correlation of the product formed with the Fe^V(O) reactive intermediates generated during the reaction, indicate that the major pathway involves the cleavage of C-H bonds by Fe^V(O). When these oxidations were performed in the presence of air, the yield of the oxidized product doubled, but the stereoretention remained unchanged. On the basis of ¹⁸O labeling and other mechanistic studies, we propose a mechanism that involves the dual activation of mCPBA and O₂ by Fe-bTAML, leading to formation of the Fe^V(O) intermediate. This high-valent iron oxo remains the active intermediate for most of the reaction, resulting in high regio- and stereoselectivity during product formation.

Full text of DOI:10.1021/acs.inorgchem.7b00453

Article
pubs.acs.org/IC
Selective C−H Bond Oxidation Catalyzed by the Fe-bTAML Complex:
Mechanistic Implications
Munmun Ghosh,† Santanu Pattanayak,† Basab B. Dhar,‡ Kundan K. Singh,† Chakadola Panda,†
and Sayam Sen Gupta*,§
†Chemical Engineering Division, CSIR, National Chemical Laboratory, Pune 411008, India
‡Department of Chemistry, Shiv Nadar University, Gautam Buddha Nagar, Uttar Pradesh 201314, India
§Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur 741246, India
S
* Supporting Information
ABSTRACT: Nonheme iron complexes bearing tetradentate
N-atom-donor ligands with cis labile sites show great promise
for chemoselective aliphatic C−H hydroxylation. However,
several challenges still limit their widespread application. We
report a mechanism-guided development of a peroxidase
mimicking iron complex based on the bTAML macrocyclic
ligand framework (Fe-bTAML: biuret-modified tetraamido
macrocyclic ligand) as a catalyst to perform selective oxidation
of unactivated 3° bonds with unprecedented regioselectivity
(3°:2° of 110:1 for adamantane oxidation), high stereo-
retention (99%), and turnover numbers (TONs) up to 300
using mCPBA as the oxidant. Ligand decomposition pathways
involving acid-induced demetalation were identified, and this
led to the development of more robust and efficient Fe-bTAML complexes that catalyzed chemoselective C−H oxidation.
Mechanistic studies, which include correlation of the product formed with the FeV(O) reactive intermediates generated during
the reaction, indicate that the major pathway involves the cleavage of C−H bonds by FeV(O). When these oxidations were
performed in the presence of air, the yield of the oxidized product doubled, but the stereoretention remained unchanged. On the
basis of 18O labeling and other mechanistic studies, we propose a mechanism that involves the dual activation of mCPBA and O2
by Fe-bTAML, leading to formation of the FeV(O) intermediate. This high-valent iron oxo remains the active intermediate for
most of the reaction, resulting in high regio- and stereoselectivity during product formation.
donor ligands with cis labile sites (FeN4) have shown great
promise.26−28 Using H2O2 as an oxidant, these complexes
catalyzed the intermolecular aliphatic C−H oxidation of 3° and
2° sites of complex organic substrates in a preparative scale with
predictable selectivity using steric, electronic, and stereo-
electronic rules that govern site selectivity.26−33
In the catalytic oxidation of alkanes, high regioselectivity is
obtained as a result of the formation of high-valent iron oxo
intermediates [either oxoiron(IV), i.e., FeIV(O), or oxoiron(V),
i.e., FeV(O)], which abstracts a hydrogen to form a carbon-
based radical that “rebounds” to the one-electron-reduced
FeOH species to produce the alcohol product.11,34,35 The
generation of FeV(O) via heterolytic cleavage of the O−O bond
is essential to achieve high regioselectivity during C−H bond
oxidation (•OR formed during homolytic cleavage, reduces the
regioselectivity significantly). In fact, for FeN4 complexes,
mechanistic studies have demonstrated that binding of both
H2O2 and acetic acid to the cis labile sites leads to water/
INTRODUCTION
■
A major challenge in synthetic organic chemistry is the
development of reagents for the chemoselective oxidation of
alkyl C−H bonds in complex natural products under mild
conditions.1−3 Such methodologies would reorient biomimetic
natural product synthesis because polar hydroxyl groups can
alter the biological properties of natural products and advance
early-stage drug discovery.4 Both metal- and non-metal-
mediated chemistries that oxidize unactivated alkyl C−H
bonds have been identified.5−8 Studies of metal-catalyzed
transformations have focused extensively on biomimetic
methods involving synthetic or bioinspired models of
CytP450 and Rieske dioxygenase, enzymes that hydroxylate
unactivated C−H bonds with very high selectivity and fast
rates.9,10 Numerous iron complexes, including heme11−14 and
related systems (e.g., corroles15−17 and phthalocyanines18) and
nonheme19−25 iron complexes, have been used for the
oxidation of aliphatic C−H bonds with a variety of oxidants,
including dioxygen (O2), hydrogen peroxide (H2O2), m-
chloroperbenzoic acid (mCPBA), and iodosylbenzene. Among
them, nonheme iron complexes bearing tetradentate N-atom-
Received: February 19, 2017
© XXXX American Chemical Society
A
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carboxylic acid-assisted heterolytic cleavage of the O−O bond
to generate a FeV(O)(OAc) intermediate36,37 similar to the
proposed reactive intermediate of the enzyme Rieske
dioxygenase.38,39 In another report, heterolytic cleavage of the
O−O bond in the pentacoordinated complex [(dpaq)-
FeIIIOOH] (dpaq = 2-[bis(pyridin-2-ylmethyl)]amino-N-qui-
nolin-8-ylacetamidate) leads to the selective catalytic oxidation
of aliphatic C−H bonds.21,40 These FeV(O) intermediates,
which bear neutral N-atom-donor ligands, are extremely
electrophilic. This makes them very reactive toward aromatic
rings that get preferentially hydroxylated over unactivated
aliphatic C−H bonds.41 Such a lack of tolerance for aromatic
groups in addition to the lower selectivity of 3° C−H bonds
over 2° C−H bonds limits their widespread application.26,27,31
We hypothesized that the formation of a FeV(O) intermediate
with much-reduced electrophilicity during the hydroxylation of
C−H bonds would yield reactions with greater substrate scope
and higher selectivity.
Interestingly, a 2-fold increase in the yield of the oxidized
product under aerobic conditions was observed. Isotope-
labeling experiments indicate a cooperative mechanism that
involved dual activation of both mCPBA and O2 by 1a, leading
to the formation of FeV(O) as the active oxidant for most of the
reaction.
EXPERIMENTAL SECTION
■
Materials. (Et4N)2[(bTAML)FeIII(Cl)] (1a) and NO2-substituted
Fe-bTAML (1b) were synthesized by our previously reported
methodology.43,44,45a m-Chloroperbenzoic acid (mCPBA; Aldrich,
77%) was purified by an established methodology.46 Acetonitrile
(LC-MS Chromasolv grade, Aldrich) was passed through an activated
neutral alumina column and used thereafter. 18O2 was received from
Icon (Isotopes) Services Inc. 18O-enriched water (98%) was procured
from the Shanghai Research Institute of Chemical Industry (China).
All of the substrates (Aldrich, 99.8%, or TCI India) were used as
received unless otherwise stated, and their purity was checked by gas
chromatography (GC).
We have recently reported the formation of a room-
temperature-stable FeV(O) from a FeIII complex bound to a
biuret-modified tetraamido macrocyclic ligand (bTAML;
Scheme 1). Upon the addition of mCPBA to
General Instrumentation. UV−vis spectral studies were carried
out using an Agilent diode-array 8453 spectrophotometer with an
attached electrically controlled thermostat. GC was performed on a
PerkinElmer Arnel Clarus 500 instrument equipped with a hydrogen
flame ionization detector; HP5 columns (polar; 12 m × 0.32 mm ×
1.0 μm) were used with helium as the carrier gas at a flow rate of 1 mL
min−1. GC−mass spectrometry (MS) was performed on a Thermo
Scientific ISQ QD mass spectrometer attached with a Thermo
Scientific TRACE 1300 gas chromatograph using an HP-5 ms capillary
column (30 m × 0.32 mm × 0.25 μm; J&W Scientific) with helium as
the carrier gas. High-resolution MS (HR-MS) was performed in a
Thermo Scientific Q-Exactive Orbitrap analyzer using an electrospray
ionization (ESI) source connected with a C18 column (150 m × 4.6
mm × 8.0 μm). GC−MS method: oven temperature program, 22 min;
initial temperature, 50 °C, hold for 1.00 min; ramp 1, 12 °C min−1 to
270 °C, hold for 2.67 min; injector temperature, 230 °C; detector
temperature, 280 °C
Scheme 1. Schematic Presentation for the Generation of 2a
from 1a and 1b
(Et4N)2[(bTAML)FeIIICl] (1a), the peroxide-bound iron(III)
complex (FeIIIOOR) undergoes heterolytic O−O cleavage to
form the corresponding FeV(O) quantitatively, which oxidizes
unactivated alkyl C−H bonds selectively with fast rates via C−
H abstraction.42 The starting iron(III) complex is quantitatively
regenerated after the reaction. For the oxidation of a
hydrocarbon such as cis-DMCY with FeV(O) under single-
turnover conditions, high diastereoselectivity is observed, which
indicates that the “rebound” process is operational. In addition,
the high regioselectivity obtained toward the oxidation of 3°
C−H bonds of adamantane and cis-DMCY implies a strong σ-
donor ability of the N atoms, rendering FeV(O) much less
electrophilic than their corresponding complexes bearing
neutral N-atom-donor ligands such as the FeN4 complex. We
presumed that the ability of 1a to quantitatively generate
FeV(O) without concomitant formation of oxygen-based
radicals and its capacity to selectively cleave unactivated alkyl
C−H bonds with high regioselectivity and diastereoselectivity
would facilitate catalytic chemoselective alkane oxidations.
We herein report the mechanism-guided design of 1b, a
nitro-substituted analogue of the previously reported complex
1a that can affect the selective oxidation of sp3 C−H bonds
with the oxidant mCPBA over methylenic C−H bonds under
catalytic conditions. For adamantane oxidation, turnover
numbers (TONs) of >140 were achieved together with very
high selectivity for 3° C−H bonds over 2° C−H bonds of
110:1. For the oxidation of cis-DMCY, 99% stereoretention was
observed in the hydroxylated product. A thorough investigation
of the reaction mechanism revealed the involvement of FeV(O)
as the key intermediate during the oxidation reaction.
Single-Turnover Conditions. A 1.2 × 10−4 M (1.2 equiv)
mCPBA solution was added to 500 μL of an acetonitrile solution of 1
× 10−4 M 1a. The color of the solution changed from yellow to green;
UV−vis studies indicated the formation of [(bTAML)FeV(O)]− (2a).
Substrates of 5 × 10−2 M [500 equiv; cis-dimethylcyclohexane (cis-
DMCY), adamantane, and cis-decalin] were added to the solution at
room temperature. Immediately, the solution color changed from
green to violet to yellow. The products were identified by GC−MS
and quantified by GC.
Catalytic Conditions. Study of Substrate Oxidation by 1a or 1b
Using the Iterative Addition of mCPBA in Small Aliquots of 5 or 25
equiv with Respect to the Catalyst. The oxidation of adamantane and
1,2-DMCY was examined using this methodology. The reactions were
performed in pure CH3CN, CH3CN/H2O, or CH3CN/H2O/K2HPO4
as solvents with or without the exclusion of O2 at room temperature.
In the presence of O2, reactions were performed in CH3CN/H2O/
K2HPO4 as the solvent. In general, 5 equiv of mCPBA was added at a
time to the reaction mixture of 500 μL of solvent containing 1a (0.1
mM, 0.2 mol %, 1 equiv) and excess substrate (50 mM, 500 equiv).
After the disappearance of the color characteristic of FeV(O) (green
for 2a and violet for 2b), an aliquot was removed from the reaction
mixture and analyzed by UV−vis, GC, and GC−MS. This process of
adding mCPBA in aliquots of 5 equiv was repeated several times until
the color of the reaction mixture bleached out and turned colorless. At
the end of the reaction, the reaction mixture was also analyzed by ESI-
MS. Before analysis using GC and GC−MS, anhydrous Na2SO4 was
first added to the reaction mixture and subsequently filtered through a
plug of silica. For catalyst 1b, a similar procedure was followed with 25
equiv of oxidant.
Determination of the Kinetic Isotope Effect (KIE) under Catalytic
Conditions. Equimolar amounts of 10−2 M adamantane and
adamantane-d16 were added to 500 μL of a solution of 1b (0.1
mM) in 80% CH3CN−20% H2O/K2HPO4. A solution of mCPBA in
B
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CH3CN (2.5 mmol, 25 equiv) was added to the solution at room
temperature under a dinitrogen atmosphere. Upon the addition of
oxidant, the color of the reaction mixture changed to violet [an
indication of formation of the FeV(O) reactive intermediate 2b], which
upon stirring for an additional 2 min reformed the starting yellow
solution of 1b. At this point, the products obtained from the oxidation
of adamantane and adamantane-d16 were identified by GC−MS and
quantified from GC.
Reaction with N-Bromosuccinimide (NBS) and Bromotrichloro-
methane (BrCCl3). 2a (10−4 M, 500 μL) was prepared under an argon
atmosphere as described earlier. To this solution was added 100 equiv
of a radical scavenger (NBS or BrCCl3). After 10 min, the product of
the reaction was identified by GC−MS.
RESULTS AND DISCUSSION
■
Catalytic Oxidation of C−H Bonds with 1a. To
understand the mechanism of catalytic C−H bond oxidation,
1a was evaluated as a catalyst (0.2 mol %, 1 equiv) in 500 μL of
acetonitrile at room temperature with the exclusion of O2.
Adamantane (50 mM, 500 equiv), containing 12 2° and 4 3°
C−H bonds, was used as a substrate to study the
regioselectivity of C−H oxidation. When excess H2O2 was
used as the oxidant (up to 100 equiv), no product was observed
Figure 1. (A) Oxidation of adamantane with 1a or 1b with iterative
mCPBA addition in cycles. Each cycle represents the addition of 5
equiv (for 1a) and 25 equiv (for 1b) of a mCPBA solution in 500 μL
of CH3CN. The reaction used 1a in CH3CN under N2. Orange:
Spectra of 1a at the start of the reaction. Green: Spectra observed after
the first addition of 5 equiv of mCPBA (cycle 1) that is characteristic
of FeV(O). Red: Spectra of the bleached reaction mixture at the end of
the 20th cycle (10−2 M mCPBA). (B) Amounts of 1-adamantanol and
2-adamantanone formed upon an increase in the addition of mCPBA,
as quantified by GC. (C) Reaction using 1b in 1 mL of a CH3CN−
20% H2O/K2HPO4 solvent system under a dinitrogen atmosphere.
Red: Spectra of 1b at the start of the reaction. Purple: Spectra
observed after the addition of 25 × 10−4 M mCPBA (cycle 1) that is
characteristic of FeV(O). UV−vis spectra of the reaction mixture at the
end of 10 cycles (orange), 16 cycles (orange-yellow), 24 cycles
(yellow), and 50 cycles (green). Each cycle represents 25 equiv of the
addition of mCPBA. (D) Amounts of 1-adamantanol and 2-
adamantanone formed upon the increasing addition of mCPBA, as
quantified by GC.
t
for adamantane. With BuOOH (tert-butyl hydroperoxide,
TBHP) as the oxidant (up to 100 equiv), 1-adamantanol and
2-adamantanone were formed in equal proportions (yield ∼5%;
Figure S1A). A similar mixture of products indicating oxidation
at the 3° and 2° C−H bonds with equal efficacy was also
observed when decalin was used as the substrate (yield ∼5%;
Figure S1B). Such a lack of regioselectivity between the 3° and
2° C−H bonds in adamantane/decalin during oxidation
indicates the operation of a radical pathway when TBHP was
used as an oxidant. By contrast, when the same amount of
mCPBA was used, 1-adamantanol was the major product with
minor amounts of 2-adamantanone (1-ol:2-one mol % ratio =
23:1; 3°:2° selectivity of 69:1 based on the statistical correction
for the number of C−H bonds). We presume that the apparent
differences in the efficacy of these three oxidants are linked to
their ability to form a high-valent iron oxo intermediate, as was
reported for heme and nonheme systems in the literature.34 To
inspect the difference among three different oxidants, UV−vis
studies were carried out. The addition of H2O2 (even up to 10
equiv) to 1a did not lead to any formation of FeV(O). Upon the
addition of 5 equiv of TBHP to 1a at 0 °C, a transient
formation of FeV(O) was observed, which decayed immedi-
ately, possibly because of a subsequent reaction with TBHP.47
The reaction of TBHP leads to the generation of oxygen-
adamantane, possibly due to catalyst decomposition, prompted
us to study the progress of the reaction upon the addition of
mCPBA in small aliquots of 5 × 10−4 M (5 equiv). We,
therefore, employed a reaction protocol in which the oxidation
of adamantane was initiated by the addition of mCPBA (5 ×
10−4 M) to a solution of 1a (10−4 M, 0.2 mol %) and substrate
(5 × 10−2 M) with an exclusion of O2 in 500 μL of CH3CN.
After every 90 s, a further aliquot of 5 equiv of mCPBA was
added; this aliquot addition was continued until the color of the
solution completely bleached out (Figure 1A). The time
window of 90 s was chosen to observe the change of the green
color in solution after the addition of mCPBA [indicating the
formation of FeV(O)] to a violet/blue solution, indicating the
formation of a mixture of the starting iron(III) and monomeric
iron(IV) complexes (Figure S3). The progress of the reaction
was monitored by analyzing the reaction mixture before and
after each aliquot of mCPBA addition by GC−MS (for product
determination) and UV−vis (to determine reactive intermedi-
ates). For adamantane, at the end of the reaction (when the
solution became colorless, the reaction time was 30 min), the
product consisted of only 1-adamantanol (3.6%) and 2-
adamantanone (0.15%), indicating a TON and a 3°:2°
selectivity of 10 and ∼69:1, respectively, which remained
t
centered radicals such as BuO•, resulting in a low 3°:2° ratio
typical of radical reactions.47,48 However, the addition of 1.2
equiv of mCPBA (1.2 × 10−4 M) to 1a in 500 μL of CH3CN
led to the quantitative formation of FeV(O) (2a) from 1a
(Scheme 1 and Figure 1A) through an O-atom-transfer
reaction, as reported by us;42 hence, mCPBA was used as the
oxidant of choice for exploring subsequent catalytic reactions.
The addition of 10−2 M (100 equiv) mCPBA to a solution of
adamantane (5 × 10 −2 M, 500 equiv) and 1a (10−4 M, 0.2 mol
%, 1 equiv) in 500 μL of CH3CN led to a visible color change
from orange to green, indicating formation of the FeV(O)
intermediate. With time, the intensity of the green color
decreased, and the solution became colorless, indicating
decomposition of the catalyst. Although 1-adamantanol and
minor amounts of 2-adamantanone (1-ol:2-one was 23:1; 3°:2°
selectivity of 69:1; Figure S2) were formed (GC yield, ∼2%;
TON, 5−10; reaction time, 10 min), this low conversion of
C
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constant over the course of the reaction (Figure 1B). To check
whether there was any product formation, 10 equiv of mCPBA
was added for another 5 min, but there was no considerable
increment of the product yield observed. Next, cis-DMCY was
chosen as a substrate probe to determine the stereoselectivity,
which upon oxidation with FeV(O) can form either (1R,2R or
1S,2S)-1,2-dimethylcyclohexanol or (1R,2S or 1S,2R)-1,2-
dimethylcyclohexanol due to epimerization.49 Using the same
oxidant addition protocol as that described for adamantane
oxidation, the predominant product formed upon the oxidation
of cis-DMCY was (1S,2R or 1R,2S)-1,2-dimethylcyclohexanol
(3b) in ∼5% yield (reaction time, 30 min; Figure S4). The
amount of trans product obtained due to epimerization was
<3%, indicating >97% stereoretention under the reaction
conditions.
Finally, cyclohexane was chosen as a substrate to probe the
efficacy of 1a/mCPBA toward the oxidation of 2° C−H bonds
in the absence of 3° C−H bonds. The oxidation of cyclohexane
was expected to be much slower from single-turnover
experiments, and hence aliquots of 5 equiv of mCPBA were
added after a time span of 5 min. Initially, the formations of
both cyclohexanol and cyclohexanone were observed at a ratio
of 9:1 (Figure S5).42 This ratio, however, continued to decrease
with consecutive cycles, and after completion of 15 equiv of
mCPBA addition, the ratio was 3.5:1, with an overall yield of
∼2% (TON, 5; reaction time, 30 min). The rapid decrease in
A/K, leading to the formation of cyclohexanone, was expected
because the rate of cyclohexanol-to-cyclohexanone (k2 ∼ 7.9
M−1 s−1) conversion by FeV(O) was estimated to be ∼400
times faster than the rate of cyclohexane-to-cyclohexanol
oxidation (0.02 M−1 s−1).50 The significantly reduced reactivity
of 1a toward cyclohexane demonstrates that our catalyst is a
weak oxidant for methylenic C−H bonds, as observed for
adamantane oxidation (Figure 1B).
Although the oxidation of hydrocarbons containing 3° C−H
bonds with 1a and mCPBA under anaerobic conditions yielded
excellent regio- and stereoselectivity, the measured yields and
TONs were very low. Because single-turnover experiments with
preformed FeV(O) yielded the near-quantitative product, it was
hypothesized that, during catalytic oxidation, catalyst degrada-
tion took place over the course of the reaction. Hence,
understanding the catalyst degradation pathway could provide
insight into improving the TONs and the overall yield of the
reaction. The progress of the catalytic oxidation of adamantane
with 1a and mCPBA (added in aliquots of 5 equiv) was studied
using UV−vis and MS. The UV−vis studies indicated that the
first addition of 5 equiv of mCPBA to 1a (10−4 M, 0.2 mol %)
and substrate (5 × 10−2 M, 500 equiv) in 500 μL of CH3CN
led to the appearance of peaks at 613 and 441 nm
[characteristic of FeV(O); 2a], which, upon progression of
the reaction, decreased and subsequently led to the appearance
of a major peak at 381 nm (characteristic of 1a; Figure S3A). In
the sixth cycle (each cycle representing the addition of 5 equiv
of mCPBA), UV−vis observations indicated a mixture of
iron(III) and monomeric iron(IV) (the monomeric FeIVCl,
synthesized independently, has a characteristic UV−vis peak at
545 nm; Figures S3B and S6B). The formation of monomeric
iron(IV) complexes are rationalized via protonation (from the
m-chlorobenzoic acid byproduct from mCPBA) of the
corresponding μ-(FeIV)2O complex, formed due to very fast
comproportionation of FeV(O) with iron(III) (Figure S6A).
The absorbance of FeV(O) and iron(III) at the beginning and
end of subsequent cycles decreased with an increase in the cycle
number. At the end of the 20th cycle (the addition of 10−2
mCPBA), the reaction mixture was completely bleached out
(Figure 1A). ESI-MS analysis of the bleached reaction mixture
revealed the presence of the free ligand, indicating that the
complex had degraded hydrolytically (Figure S7).
M
The hydrolytic instability of Fe-TAML toward protic acids
was studied earlier in which the first step involved the attack of
H+ on the N atom of the Fe−N bond.43,51 The kinetic displays
of Fe-TAML and Fe-bTAML show first- and third-order
dependencies of H+ on the rate of degradation. Although FeIII-
bTAMLs are significantly more stable to acids than the
prototype Fe-TAMLs (∼103 times), they degrade when the pH
is lowered below 2.43 We first hypothesized that m-
chlorobenzoic acid formed as a byproduct from mCPBA-
induced demetalation of 1a. To test this hypothesis, 10−2
M
equiv of m-chlorobenzoic acid in 500 μL was added to 1a, but
this did not change the UV−vis spectrum of 1a, indicating that
the above assumption was likely not true. In contrast, an
addition of excess mCPBA (10−2 M) to 1a or in situ generated
2a resulted in the immediate degradation of the catalyst, leading
to the formation of a free ligand. Preliminary experiments
indicate that the (i) rate of catalyst decomposition increases
with increasing oxidant concentration and (ii) oxidants that are
less acidic (e.g., mCPBA vs perbenzoic acid) show slower
degradation rates (Figures S8 and S9). One of the possibilities
could involve coordination of the peracid to the in situ
generated 2a (Figure S10), followed by an intramolecular
proton transfer, leading to demetalation. Detailed investigations
are underway to elucidate the mechanism of catalyst
deactivation by mCPBA.
The improvement of TONs would thus require modification
of the structure of the catalyst framework to improve the
hydrolytic stability of Fe-bTAML. Changes in the TAML
framework that can dramatically improve the hydrolytic
stability under operational conditions have been elaborated
by Collins et al.51,52 It has been shown that the introduction of
electron-withdrawing substituents such as the −NO2 group in
the aromatic “head” part of TAML can enhance the hydrolytic
stability of Fe-TAMLs.53 A similar strategy was employed by us
to generate a second-generation Fe-bTAML in our quest to
improve the catalytic performance of a Fe-bTAML/mCPBA
system toward C−H bond oxidation.
Catalytic C−H Bond Oxidation with 1b. The hydrolytic
instability of 1a during the catalytic oxidations was improved
upon modification of the ligand framework of catalyst 1a to
generate catalyst 1b, which has a −NO2 group present in the
aromatic ring of 1a. Complex 1b also quantitatively forms the
FeV(O) reactive intermediate 2b at room temperature (Figures
1C and S11).54 Complex 1b is hydrolytically more stable
toward H+-catalyzed demetalation in water than the related 1a
by ∼500-fold (Table S1).45 In CH3CN, complex 2b was found
to be more stable in the presence of excess mCPBA by ∼100-
fold (Figures S9 and S10). Furthermore, the presence of an
electron-withdrawing group increases the FeV(O)/FeIV(O)
redox potential, which, in turn, increases its reactivity toward
the C−H bond by at least 20-fold.45 Moreover, the solvent
system was changed to 80% CH3CN−20% H2O, and 100 equiv
of 1 M K2HPO4 was added as a base to neutralize the acidity
generated from formation of the byproduct m-chlorobenzoic
acid. The reaction protocol employed was similar to that used
for 1a and involved the addition of mCPBA (25 × 10−4 M) in
aliquots with the exclusion of O2 in a 1 mL solvent system.
With 0.2 mol % (10−4 M) 1b, a 15-fold increase in the yield of
D
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1-adamantanol (yield, 29%; reaction time, 30 min; 20 cycles)
was found (TON of 140; 3°:2° ratio = 110:1; Figure 1D, Table
1, and Figure S12). The observed 3°:2° selectivity remained
Table 1. Catalytic Oxidation of Bench-Marked Substrates
a
with Varying Catalysts and Solvents
conditions
1a (0.2
1b (0.2
1b (0.2
mol %)
mol %)
mol %)
1b (0.2 mol %)
CH3CN/20%
buffer, air
CH3CN/ CH3CN/ CH3CN/20%
substrate
Ar
Ar
buffer, Ar
adamantane
(3°/2°)
(yield %)
69:1 (∼2) 85:1
110:1 (29)
60:1 (60)
(∼10)
cis-DMCY (% 97% (∼5) 98%
99% (38)
98% (70−75)
RC) (yield
%)
a
A 97% retention of configuration (RC) indicates cis-DMCY-to-cis-
DMCY-OH conversion, 0.2 mol % catalyst was used in catalytic
oxidation, 30/20 indicates a 1-ol-to-2-one ratio, and Ar indicates an
argon atmosphere.
constant throughout the reaction (Figure 1D). When the same
reaction was performed in the absence of the base (K2HPO4),
the amount of 1-adamantanol obtained was only 12% (reaction
time, 30 min). A study of this reaction via UV−vis revealed that
the amount of iron(III) regenerated successively decreased after
each cycle of the reaction initiated by mCPBA addition (Figure
1C), which correlated positively with the amount of product
formed in each successive cycle (Figure S13). At the end of the
reaction, the catalyst solution became colorless, with no
observable spectra, due to demetalation of the complex (Figure
1C). ESI-MS studies of this spent reaction mixture revealed a
peak at m/z 405.15, indicating the presence of a free ligand
(Figure S14). For oxidation of cis-DMCY (3a), the
predominant product formed was (1S,2R or 1R,2S)-1,2-
dimethylcyclohexanol (3b) with >98% stereoretention (Figure
S15A). In comparison, the oxidation of cis-DMCY with 1a and
mCPBA under similar conditions (80% CH3CN−20%
K2HPO4/H2O) resulted in the formation of cis-dimethylcyclo-
hexanol with ∼10% yield (in only CH3CN, the yield was ∼5%)
and >97% stereoretention (Table 1). The higher yields
obtained for 1b led us to use this for further experiments.
Catalytic C−H Bond Oxidation with 1b in Aerobic
Conditions. The unprecedented chemoselectivity of the
bTAML catalyst (1a) encouraged us to study the oxidation
reaction under ambient conditions to determine if the catalyst
could be used for the hydroxylation of hydrocarbons at a
preparative scale. Under aerobic conditions, the oxidation of
adamantane with 0.2 mol % 1b yielded 57% 1-adamantanol and
3% 2-adamantanone (total yield of 60%) and a 3°:2° ratio of
60:1 (Figure 2A). This represents a 2-fold increase in the yield
of 1-adamantanol (from 30% to 57%) and a ∼4-fold increase of
2-adamatanone (0.8% to 3%). This increased yield was
accompanied by a resulting loss of 3°:2° selectivity (from
110:1 to 60:1). With cis-DMCY, the stereoselectivity did not
change (>98%) and the yield was 70−75% (Table 1 and Figure
S15B). To better understand the effect of O2, the reactions
were performed in the presence of 18O2. GC−MS analysis of
the reaction mixture indicated ∼80% incorporation of 18O in 2-
adamantanone and 38% incorporation in 1-adamantanol, which
is slightly lower than the increase in the reaction yield in the
presence of O2 (Figure S16). However, even after a 2-fold
reduction of the 3°:2° selectivity, the selectivity was still higher
Figure 2. (A) TONs and regioselectivity for the oxidation of
adamantane with 1b/mCPBA in the presence (green column) and
absence of air (black column). (B) Oxidation of adamantane with 2b
in 1 mL of CH3CN/H2O−K2HPO4 using an iterative 25 × 10−4
M
mCPBA addition protocol under aerobic conditions. The correlation
of the products adamantanol + adamantanone formed (TON from
GC) with iron(III) regenerated (via a ESI-MS study) in each cycle is
presented.
(60:1) than that of most iron complexes reported to date.24
The incorporation of 18O from 18O2 in the product is typically
indicative of free-radical autooxidation (see the discussion later
on the incorporation of 18O2 in a “mechanistic study”). Such an
increase in the product yield was also observed in the single-
turnover experiments upon the reaction of adamantane with
preformed FeV(O), where a 2-fold increase in the amount of
adamantanol and adamantanone was obtained. Single-turnover
experiments with FeV(O) in the presence of 18O2 revealed
<40% incorporation of the 18O label in adamantanol (Table
S2). These results suggest that, in the presence of O2,
adamantane oxidation performed either with 2b under single-
turnover conditions or under catalytic conditions with 1b/
excess mCPBA shows a similar increase in yield and a decrease
in the regioselectivity of the product(s) compared to those in
anaerobic conditions (Table S2). With 1a we also performed
the reaction under similar conditions, leading us to very fast
bleaching of the color and resulting in ∼5% yield for
adamantane. This conclusively guided us to carry out further
reactions with 1b.
Mechanistic Outlook. According to our study, we believe
that binding of mCPBA to the FeIII center of 1a/1b leads to the
formation of the acylperoxoiron(III) species, which then
cleaves heterolytically to generate FeV(O) and m-chlorobenzoic
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acid.42 FeV(O), a very competent oxidant, cleaves the C−H
bond via H-atom abstraction, as we demonstrated previously.42
Several lines of evidence strongly suggest that catalytic reactions
are indeed metal-based and predominant pathways of the
reaction through FeV(O) species:
quantification), and UV−vis studies58 indicated a positive
correlation between the iron(III) recovered after each cycle
with a gradual increase in the TON of the oxidized product
(Figure 2B). It indicates that free-radical pathways, if at all
operative, are not the dominant pathways and the oxidation
reaction involves FeV(O) as reactive intermediate.
(i) The use of isotopically labeled H218O as a cosolvent (80%
CH3CN and 20% H218O) leads to the incorporation of 38%
18O in the product 1-adamantanol. The incorporation of the
18O label can be assigned to exchange of the oxygen label in
FeV(16O) upon the addition of H218O (Figure S17).
Experiments on the oxidation of adamantane with 1b/
mCPBA in the presence of O2 indicate an increase in the yield
of 1-adamantanol and 2-adamantanone from 30% to 57% and
from 0.8% to 3%, respectively, in comparison to that of
anaerobic conditions. This would mean that, in the presence of
O2, an additional pathway is operative that can account for 27%
1-adamantanol and 2.2% 2-adamantanone (Figure 2A). On the
basis of these results and 18O2 experiments described earlier,
the possibility of the adamantyl radical reacting with O2, leading
to a free-radical chain reaction, arises (“non-rebound” process).
However, it should be noted that the regioselectivity observed
in this O2-mediated pathway (27% 1-adamantanol and 2.2% 2-
adamantanone) corresponds to a 3°:2° selectivity ratio of 36:1,
which is not indicative of a free-radical autooxidation process.
In fact, such a high selectivity is indicative of the involvement of
high-valent iron oxo intermediates (this regioselectivity is
greater than ∼30, which is typically observed for iron
complexes12,21,36 that operate through iron oxo intermediates).
To gain a better understanding of the effect of O2 on C−H
oxidations, stereoselectivity was used as a tool by studying the
hydroxylation of cis-DMCY by 1b/mCPBA. It was shown
earlier that, for the rebound process, stereoretention was
observed, leading to the formation of the cis isomer (1S,2R or
1R,2S)-1,2-dimethylcyclohexanol as the only product.59 For
non-rebound processes, which involve escape of the cis-DMCY
radical from the solvent cage, epimerization is faster than its
subsequent reaction with O2, leading to formation of the trans
product.49 The oxidation of cis-DMCY by 1b/mCPBA in the
presence of O2 yielded the cis isomer (1S,2R or 1R,2S)-1,2-
dimethylcyclohexanol as the major product, and the yield
increased 2-fold in comparison to reactions performed in the
absence of O2 [under single-turnover conditions with the
FeV(O) complex 2b, a similar 1.6-fold increase in the product
yield was observed]. Surprisingly, the stereoselectivity of cis-
DMCY remained unchanged at 99%, indicating again that the
O2-dependent pathway does not involve radical-based autoox-
idation reactions such as the reaction of long-lived 3° radicals
with O2. These results point out that, under aerobic conditions,
a high-valent iron oxo compound, formed from the interaction
of O2 and FeIII-bTAML, remains the active oxidant for this
additional pathway.
(ii) The very high regioselectivity and stereoretention
observed in the oxidation of adamantane and cis-DMCY are
similar under both catalytic and single-turnover reaction
conditions involving FeV(O). For example, the regioselectivities
obtained for adamantane with FeV(O) of 1a and 1b were
determined to be 69:1 and 110:1, respectively, under single-
turnover and catalytic conditions (Table 1). cis-DMCY yielded
a 43% hydroxylated product showing 98% stereoretention,
which was similar to that found under single-turnover
conditions (97%; Table S2).
(iii) The KIE for the oxidation of adamantane and
adamantane-d16 was estimated to be ∼5 for 1b, which is
reminiscent of oxidation involving iron oxo species. In contrast,
the KIE for adamantane oxidation involving oxygen-centered
55
·
radical is low; for OH, the value is ∼2.
(iv) Upon oxidation of adamantane, the decrease in the yield
of 1-adamantanol upon each successive addition of 25 equiv of
the mCPBA aliquot correlated well with the decrease in
iron(III) regeneration during the progression of the reaction
(Figures 2B and S13).
(v) The absence of any significant amounts of chloroben-
zene, an indicator of mCPBA-mediated free-radical autoox-
idation, indicates the involvement of a metal oxo intermediate
(Figure S18).
(vi) Oxidation of adamantane by 1b and mCPBA was carried
out in the presence of NBS. No change was observed in the
amount of 1-adamantanol formed, and no bromoadamantane
formation was observed upon NBS addition.56
All of the above evidences indicate that, in the absence of O2,
oxidation of C−H bonds by 1b and mCPBA is predominantly
metal-based and involves H-atom abstraction from a C−H
bond by FeV(O) formed in situ. The radical formed
subsequently reacts with FeIVOH via a “rebound” mechanism
to afford the hydroxylated product (Figure S19). As the
reaction progresses, the catalyst slowly decomposes via a
hydrolytic pathway, leading to demetalation, and ligand is
observed as the major product
FeIII-TAMLs have been shown to activate O2 to generate the
dimeric μ-oxo-(FeIV)2 quantitatively.60 We have recently shown
that this dimer is competent to oxidize olefins61 to the
corresponding epoxides, although their reaction with unac-
tivated C−H bonds is kinetically very slow. We propose that
C−H abstraction by FeV(O) and the subsequent “rebound”
lead to the formation of FeIII-bTAML having either no axial
ligation or a weakly coordinated solvent molecule (Figure 3).
This coordinatively unsaturated iron(III) could potentially bind
to O2 and get subsequently converted to the μ-oxo-(FeIV)2
dimer as shown in Figure 3. Such rapid formation of the μ-oxo-
(FeIV)2 dimer from coordinatively unsaturated iron(III) has
been studied by us in nonpolar organic solvents such as
dichloromethane or dichlorobenzene.62 The μ-oxo-(FeIV)2
dimer can either react with excess mCPBA to get converted
to the starting FeV(O) or react with alkanes directly to produce
Under aerobic conditions, a significant increase in the yield
of hydroxylated products has typically indicated the operation
of both “rebound” (described above for reactions performed
with the exclusion of O2) and “non-rebound” pathways. Such
observations were recently reported for reactions of nonheme
FeIV(O) with C−H bonds.12,35,57 For the non-rebound process,
the carbon radical formed upon C−H abstraction by FeV(O) is
expected to react with O2 to form an alkylperoxo radical, which
would subsequently initiate a free-radical chain reaction. We
first proceeded to ascertain whether FeV(O)-mediated C−H
abstraction was still operative in the presence of O2 because this
step would be common to both the rebound and non-rebound
pathways. We, therefore, monitored, quantified, and correlated
the amount of oxidized product formed and the iron(III)
complex recovered during each progressive cycle of mCPBA
addition. HR-MS (for 1b quantification), GC−MS (product
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Article
bonds in adamantane are manifested in the very high
regioselectivity observed.
CONCLUSION
■
In conclusion, we reported the mechanism-guided development
of a nitro-substituted Fe-bTAML complex for the efficient
hydroxylation of unactivated 3° C−H bonds.58 This catalyst,
which is a functional mimic of peroxidases, is structurally very
different from other iron complexes based on the Fe−N4
framework reported previously. A thorough investigation of
the reaction mechanism revealed the involvement of FeV(O) as
the key intermediate during the oxidation reaction. We were
able to correlate the generation of FeV(O), recovery of
iron(III), and product formation during the reaction involving
an iterative mCPBA addition-based reaction protocol. In the
presence of O2, a 2-fold increase in the product is observed with
minimal changes in the regioselectivity and stereoretention of
the reaction. We proposed a mechanism that involves the dual
activation of mCPBA and O2 by Fe-bTAML, leading to the
ultimate formation of a FeV(O) intermediate. Because FeV(O)
remains the active intermediate for most of the reaction, the
selectivity is mostly unaffected. Thus, Fe-bTAML complexes
display great promise in the quest to develop reagents for
chemoselective oxidation of alkyl C−H bonds in complex
natural products under mild conditions, as was recently
demonstrated.58 We believe that further changes can be
incorporated into the ligand framework to obtain even more
active catalysts that can use cheap oxidants such as sodium
hypochlorite or O2 instead of the more expensive mCPBA.
Such efforts are now underway in our laboratory.
Figure 3. Probable reaction pathway of 2b in the presence of oxygen.
hydroxylated products. In such a scenario, part of the O atom
incorporated in the product was obtained from O2 (Figure 3).
Because the diiron(IV) complex was not competent for
oxidation of unactivated C−H bonds under the time scale of
the reaction, this pathway was not incorporated in the proposed
mechanism. We believe that excess mCPBA present in the
reaction mixture oxidized the diiron(IV) complex to FeV(O) (a
fast process reported by us earlier61), which subsequently
oxidized the C−H bond. It is possible that alternative
mechanisms to explain the stereoretention and regioselectivity
during oxidations in the presence of O2 exist, and further
mechanistic studies are needed to assign the exact mechanisms
conclusively.
Finally, it is worth commenting on the very high
regioselectivity observed for the Fe-bTAML complexes during
adamantane oxidation in comparison to other complexes such
as [(TPP)Fe-Cl] reported earlier.24 The 48:1 selectivity
observed for 3° C−H bonds over 2° C−H bonds during
adamantane oxidation by iron porphyrin reported by Groves et
al.11 is lower than the 110:1 regioselectivity observed for the Fe-
bTAML complex (1b). This high selectivity of the Fe-bTAML
complexes can be explained by understanding the nature of the
transition state during C−H abstraction by FeV(O). The nature
of the transition state was used earlier to explain the higher
selectivity of a bromine radical (Br•) over a chlorine radical
(Cl•) toward C−H bonds in alkanes. For example, the relative
rates for abstraction of a 3° and 2° hydrogen in alkane by Cl• is
6:4, while that for the corresponding Br• is 95:1; hence,
bromination is much more selective. This is explained by the
fact that the bond dissociation energy of H−Cl being much
higher compared to that of H−Br leads to an “early transition
state”, where there is very little radical character developing on
the carbon in the transition state during H-atom abstraction. In
contrast, abstraction of the H atom by Br• being an
endothermic reaction leads to a “late transition state”, where
there is a lot of radical character on carbon in the transition
state.63 For Fe-bTAML, the tetraanionic nature of the ligand
makes FeV(O) much less electrophilic than most complexes,
which bear neutral ligands. In fact, the bond dissociation energy
(FeIVOH) value determined for the FeV(O) complexes of
bTAML (∼99 2 kcal/mol)45b,c is comparable to the C−H
BDE of adamantane. This leads to the formation of a “late
transition state” during the C−H abstraction process, and the
inherent differences in the bond strength of 3° and 2° C−H
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.7b00453.
GC and GC−MS characterization of various oxidized
products, UV−vis absorption and ESI-MS spectra of
different intermediates, plot of the initial rate of
degradation of 2a, resonance Raman spectra of 2b, and
additional experimental information (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: sayam.sengupta@iiserkol.ac.in (S.S.G.).
■
ORCID
Sayam Sen Gupta: 0000-0002-3729-1820
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.S.G. acknowledges SERB Grant EMR/2014/0016 for
funding. S.S.G. acknowledges Dr. Abhishek Dey and Atanu
Rana with their help regarding resonance Raman measure-
ments, which was funded by SERB Grant SERB/2013/IC-25.
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DOI: 10.1021/acs.inorgchem.7b00453
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
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DOI: 10.1021/acs.inorgchem.7b00453
Inorg. Chem. XXXX, XXX, XXX−XXX