Selective oxygenation of unactivated C-H bonds by dioxygen: Via the autocatalytic formation of oxoiron(v) species

Article abstract of DOI:10.1039/d0cc03071f

Selective catalytic oxygenation of unactivated C-H bonds for a series of substrates by dioxygen using iron complexes was performed without the use of a co-reductant. Mechanistic studies indicate that the reaction proceeded via the autocatalytic formation of an oxoiron(v) intermediate, which brings high regioselectivity and stereoretention.

Full text of DOI:10.1039/d0cc03071f

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Selective oxygenation of unactivated C-H bonds by dioxygen via
an autocatalytic formation of oxoiron(V) species
Received 00th January 20xx,
Accepted 00th January 20xx
Bittu Chandra,a Puja De a and Sayam Sen Gupta* a
DOI: 10.1039/x0xx00000x
Selective catalytic oxygenation of unactivated C-H bonds for a for comparison of oxygenation reactions by O2 using various
series of substrates by dioxygen using iron complexes without the iron complexes). Recently, Fukuzumi and coworkers have
use of co-reductant. Mechanistic studies indicate that the reaction shown iron(III)-(TAML) catalyzed cyclohexene oxidation by
proceeded via an autocatalytic formation of
intermediate which brings in high regioselectivity and the reaction was selective towards the formation of
oxoiron(V) dioxygen via an oxoiron(V) autocatalyzed reaction.5 Although
stereoretention.
cyclohexenone, the substrate scope was limited to
hydrocarbons having only weak C-H bonds (BDE < 85
kcal/mol). Our group has synthesized biuret modified Fe-TAML
complex, [Et4N]2[(bTAML)FeIII-Cl] (1a); [bTAML= biuret
modified tetramido macrocyclic ligand] which reacts with
chemical oxidants (mCPBA or NaOCl)6a,6b or photochemically
generated oxidant, [{RuIII(bpy)3}Cl3]6c,6d to form a room
temperature stable oxoiron(V) intermediate, which can oxidize
3o C-H bonds with very high selectivity. We have also
subsequently demonstrated that axially water-bound complex
[Ph4P][(bTAML)FeIII-OH2] (1b) in dichloromethane reductively
activates O2 to form the corresponding dimeric species
[{(bTAML)FeIV}2O]2- (2), which oxidizes alkenes to their
corresponding epoxides.7 The reductive activation of O2 was
proposed to form the oxoiron(V) intermediate, which then led
to the formation of 2 after comproportionation with 1b. Since
oxoiron(V) intermediates were shown to be formed via
autocatalytic processes using hydrocarbons with weak C-H
bonds like cyclohexene,5 we were interested in exploring if
such methods could be utilized for the selective oxidation of
unactivated 3o C-H bonds in hydrocarbons. Herein, we report
selective oxygenation of a series of hydrocarbons having
unactivated 3o C-H bonds or benzylic C-H bonds by a molecular
iron complex, and O2 via formation of oxoiron(V) species,
[(bTAML)FeV(O)]- (3) in aerated acetone solvent. We believe
this is the first report on the selective oxygenation of
hydrocarbons having unactivated 3o C-H bonds by O2 via an
autocatalytic formation of oxoiron(V) to date.
The development of iron complexes that selectively oxidize
industrially useful organic molecules containing unactivated C-
H bonds to their corresponding alcohols or ketones using only
dioxygen remains a challenge. Synthesis of such complexes
would mimic the natural iron-containing oxygenases1, e.g.,
cytochrome P4501b, methane monooxygenase1c, and
naphthalene dioxygenase1d among others that activate O2,
leading to the formation of high-valent oxoiron intermediates
which catalyze the oxidation reaction. Perhalogenated metal
porphyrins, such as Fe(TFPPBr8)Cl, are remarkably active and
robust catalysts for the oxidation of alkanes under mild
conditions.2 Mechanistic studies indicate that the reaction is
not biomimetic, but proceeds via the radical chain
autoxidation process. The role of the metal complex is limited
to the catalytic decomposition of hydroperoxides to produce
the oxygenated alcohol and/or ketone. This results in the
formation of significant C-C bond scission in several substrates
to produce undesired by-products. Subsequently, iron(II)
complexes of bispidine ligands have been used for the
oxidation of hydrocarbons with O2 via an autocatalytic radical
chain pathway.3 The reaction was shown to generate non-
heme oxoiron(IV) complex, which displayed very poor
selectivity (cis/trans = 4.4:2 plus other side products for cis-
dimethylcyclohexane) and TON (~10) for hydrocarbon
oxidation. Other non-heme iron(II) complexes such as
[Fe(N4Py)]2+ and [Fe(Bn-TPEN)]2+ are not known for C-H bond
oxidation4a whereas [Fe(TMC)]2+ exhibits activity towards C-H
bonds having BDE < 80 kcal/mol4b, although they are known to
form oxoiron(IV) species via O2 activation4c (see ESI†, Table S1;
a. Department of Chemical Sciences, Indian Institute of Science Education and
Reasearch Kolkata, Mohanpur, West Bengal 741246, India. Email
sayam.sengupta@iiserkol.ac.in
:
† Footnotes relating to the title and/or authors should appear here.
Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
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Scheme 1 Oxygenation of hydrocarbons (RH) by 1a/1b/1c using dioxygen via
the formation of [(bTAML)FeV(O)]- in aerated acetone at room temperature.
the ketone product with good TON (Table 1; entries 7 and 8).
The formation of ketone as the main product was attributed to
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DOI: 10.1039/D0CC03071F
the over oxidation of the hydroxylated product, which was
formed first during the oxygenation reaction (cyclohexanol
oxidation by [(bTAML)FeV(O)]- has been reported to be ~350
times faster than cyclohexane oxidation10).
Our initial studies involved incubation of complex 1b (0.10
mM) and adamantane (0.10 M) in aerated acetone solvent at
room temperature for 20 h. Adamantane was chosen as a
model substrate having four 3o C-H (BDE = 96.5 kcal/mole8)
and twelve 2o C-H bonds (BDE = 98.5 kcal/mole8). After 30 min
to 1 h of incubation (depending on whether we use bottle
grade or rigorously purified substrate and solvent), a slow
color change from orange (color of 1b) to pale green was
observed, which with time slowly changed to blue-black. After
20 h, the reaction mixture was filtered through an alumina
plug and analyzed by gas chromatography-mass spectroscopy
(GC-MS). Product analysis indicated the formation of 10 mM 1-
adamantanol and 1 mM of 2-adamantanone (10:1), which
corresponds to a 3o:2o regio-selectivity of 25:1 and a TON of
110. The selectivity for 3° C-H bonds, although lower than
what is observed for chemically synthesized oxoiron(V)-
bTAML,6 is much higher than classical autooxidation processes
(HO· typically affords values near 2, while tBuO· initiated
reactions exhibit values around 10).9a The selectivities are
comparable to other high-valent oxoiron intermediates
reported in the literature.9b When the same reaction was
carried out with 1a, the selectivity and TON were unchanged,
while for 1c, the TON increased to 120 (Table 1; entry 1).
When the reactions were carried out in the absence of O2, no
colour change was observed for 12 h. Besides, as expected, no
formation of 1-adamantanol or 2-adamantanone was
observed. These data strongly indicated that both Fe-bTAML
and O2 were involved, and the reaction likely proceeded
through a high-valent oxoiron intermediate.
Table 1 Catalytic oxygenation of alkanes by 1a and 1c using dioxygen in aerated
acetone solvent at room temperature.
TON
1a
Yielda
Entry
Substrate
Products
1c
OH
O
106
120
96%
1.
3o : 2o = 25 : 1
b
OH
OH
58
70
27
91%
71%
2.
cis : trans = 25 : 1
c
OH
OH
3.
18
trans : cis = 20 : 1
OH
OH
H
H
d
4.
75
116
84%
H
H
cis : trans = 8 : 1
O
O
O
O
22
33
97%
90%
5.
6.
OH
H
H
O
OH
124
162
A : K = 1 : 1.1
O
Next, cis-1,2-dimethylcyclohexane (cis-DMCH, 3o C-H BDE =
93.9 kcal/mole8), trans-1,2-dimethylcyclohexane (trans-DMCH,
3o C-H BDE = 97.4 kcal/mole8) and cis-decalin (3o C-H BDE =
93.5 kcal/mole8) were explored as substrates. In case of cis-
1,2-dimethylcyclohexane, 3o hydroxylated products with
stereoretention (cis/trans = 25:1) and 3o to 2o regioselectivity
(22:1) was achieved (Table 1; entry 2). On the other hand,
trans-1,2-dimethylcyclohexane showed much less reactivity
under similar reaction condition, although good
stereoselectivity is maintained (Table 1; entry 3). For cis-
decalin, hydroxylation at 3o position (17:1 selectivity over 2°)
7.
8.
120
195
184
252
94%
97%
A : K = 1 : 17
O
A : K = 1 : 35
Reaction conditions: Complex 1a/1c (0.1 mM), substrate (0.1 M) in aerated acetone
solvent at room temperature for 20 hours; TON = moles of product/moles of catalyst;
TON (within 10% error) values were determined in GC-MS. aYields are based on
converted starting material. b(3o:2o = 22:1) ; c(3o:2o = 3:1) ; d(3o:2o = 17:1). A/K denotes
alcohol/ketone.
We next proceeded to understand the origin of the
selectivity, which typically indicates the formation of high-
valent oxoiron intermediates. The colour change observed
during the course of the reaction was monitored using UV-Vis
spectroscopy. In the initial period (30 - 60 min), a decrease in
the peak at 357 nm (λmax of 1a) was observed together with
the appearance of peaks at 441 nm and 613 nm, with an
isosbestic point at 399 nm. This change in absorption spectra
corresponded to the colour change from orange to green
observed initially. The UV-Vis spectrum of the green species is
identical to the well-characterized FeV(O) species,
[(bTAML)FeV(O)]- (3, abbreviated as FeV(O)),6 that was
independently synthesized using equimolar amounts of 1a and
mCPBA/NaOCl.6a The maximum yield of FeV(O) species formed
occurred and
a cis/trans ratio of 8:1 exhibits the
stereoretentive nature of the reaction (Table 1; entry 4).
Oxidation of cedryl acetate, a natural product derivative of
cedrol, having a very rigid structure with five 3o C-H bonds,
afforded regioselective hydroxylated product but with lower
TON (Table 1; entry 5).
Lastly, substrates having activated C-H bonds (benzylic 3o
and 2o C-H bonds) such as ethylbenzene (EB), cumene, and
diphenylmethane (DPM) were explored by using the same
optimized conditions. For cumene, 2-phenyl-2-propanol and
acetophenone were obtained as the major products (ratio
1:1.1) (Table 1; entry 6). The oxidation reactions of
ethylbenzene and diphenylmethane by O2 primarily afforded
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DPM). Additionally, the length of the induction period was not fully
was determined to be > 85% based on the extinction
coefficient. Further, ESI-Mass of the green species in acetone
revealed a prominent ion peak at the mass to charge ratio, m/z
429.0724 (calculated 429.0730) (ESI†, Fig. S2), which
confirmed the formation of FeV(O). On similar lines, the
formation of [(NO2-bTAML)FeV(O)]- from 1c, adamantane, and
O2 was also observed in UV-Vis (ESI†, Fig. S3).
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reproducible for the same substrate and depended upon the purity
DOI: 10.1039/D0CC03071F
of the substrate and solvent (acetone) used. Similar observations
have been reported for the autocatalytic formation of oxoiron(IV)
complexes from iron(II) bispidine complexes before.3 An increment
in the induction period was observed with rigorously purified cis-
DMCH (see ESI†, Fig. S4a). Aged bottle grade hydrocarbons
probably contain a small amount of hydroperoxides, which initiate
the radical reaction. Acetone, when stored for a long time, shows
the formation of the aldol product, diacetone alcohol, which can
decrease induction times (ESI†, Fig. S4b). For all kinetic studies,
rigorously purified hydrocarbons and acetone were used.
Since the initial results pointed to the operation of radical
pathways, FeV(O), alkyl hydroperoxide, and a spin trapping agent,
DMPO (5,5′-dimethyl-1-pyrroline N-oxide) were added to observe
their effects on the induction time. The addition of a catalytic
amount of FeV(O) to the aerated solution of 1a (0.10 mM) and
substrate (0.1 M) led to a reduction in the induction period (ESI†,
Fig. S5). The acceleration of the sigmoidal generation of FeV(O)
upon the addition of a catalytic amount of FeV(O) was also
observed. A similar reduction in the induction period was also
observed upon increasing the concentration of substrate and
t
addition of a catalytic amount of cumyl hydroperoxide (or BuOOH)
at the start of the reaction (ESI†, Fig. S6 and S7). These results are
indicative of the radical chain mechanism.
Fig. 1 UV−Vis absorption spectral changes observed in the oxygenation of 1a (0.10 mM)
with O2 in the presence of adamantane (0.1 M) in aerated acetone solvent at 298 K.
We hypothesized two possible pathways to explain the formation of
FeV(O): (i) The reductive activation O2 at Fe(III) center of 1a followed
by H atom abstraction from the substrate (RH) by the superoxido
species (FeIV-OO·) and successive homolysis of the hydroperoxido
species (FeIV-OOH) (see scheme 2A). (ii) The operation of an
autocatalytic
radical
chain
mechanism
leading
to
alkylhydroperoxide, which would react with 1a to form FeV(O) (see
Fig. 2 UV-Vis time profiles at 613 nm for the reaction of (a) 1a (0.1 mM) with different
substrate (0.1 M) and (b) 1a (0.1 mM) and DPM (0.1 M) in the presence of DMPO (0 to
20% w.r.t 1a) in aerated acetone at 298 K.
On the other hand, addition of a catalytic amount of a spin trapping
agent, DMPO, to an aerated acetone solution 1a (0.10 mM) and
substrate (O.1 M) resulted in a significant increase in the induction
period, which increased with increasing concentration of the DMPO
(Fig. 2b). Such effective trapping of the chain carrier radical (alkyl
peroxyl radical or alkoxyl radical) by DMPO also supports the
involvement of a radical chain pathway during the formation of
FeV(O).
Based on the above observations, we propose a reaction
mechanism involving the catalyst (1a/1b/1c), dioxygen, and
substrate (alkanes, RH) (scheme 3). The radical chain reaction
initiates with the H-atom abstraction of the substrate to form
substrate radical (R·) (initiation step A). The initial formation of
substrate radical might involve either H-atom abstraction by
FeV(O) which might be formed via the FeIII catalyzed reductive
O2 activation (as shown in scheme 2A) or by the reaction of the
substrate molecule with O2 before catalyst addition12. Once
the radical is formed, it readily reacts with O2 to form the
alkylperoxyl radical, ROO· (B). The alkylperoxo radical can
either (i) abstract the H-atom from another molecule of the
substrate to generate the alkylhydroperoxide, ROOH, or (ii)
Scheme 2 Formation of oxoiron(V) species via (A) reductive activation of O2 vs (B)
autocatalytic radical chain mechanism.
scheme 2B). The kinetic traces for the formation of FeV(O) at 613
nm showed sigmoidal curve having a substantial lag phase with all
the substrates (Fig. 2a). This sigmoidal nature of the curve is very
distinctive of a radical chain mechanism where an induction period
is required.11
The induction period for the formation of FeV(O) increases with the
bond dissociation energies (BDE) of C-H bond for the substrates
used. This implies that the initiation step (H atom abstraction) of
the radical chain reaction consumes more time for substrates with
higher BDE C-H (e.g. cis-DMCH) than those with lower BDE (e.g.
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compared to 70:1 for adamantane) indicates that additional free-
form the alkoxyl radical (RO·) via bimolecular self-reaction (via
C). Both these alkoxy and peroxy radical are capable of chain
propagation. For substrates with strong C-H bonds like
adamantane, propagation through the alkoxyl radical is more
plausible since it is a much stronger oxidant then the
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radical autooxidation pathways are also operational.
DOI: 10.1039/D0CC03071F
S. S. G. acknowledges SERB, New Delhi (Grant no EMR/2017/
003258), and IISER-Kolkata (‘‘Start-up Grant’’) for funding. B.
Chandra acknowledges UGC-New Delhi for his fellowship and P. De
acknowledges CSIR-New Delhi for her fellowship.
t
corresponding alkylperoxyl radical (ΔHBDE of BuO-H is 105
kcal/mol in comparison to 87 kcal/mol for tBuOO-H).9b If ROOH
formed, it can convert FeIII to FeV(O) via the “shunt pathway’’.
Conflicts of interest
There are no conflicts to declare.
t
In fact, BuOOH or cumyl hydroperoxide can cleanly generate
FeV(O) from FeIII (ESI†, Fig. S8). Interestingly, the formation
FeV(O) does not proceed via the µ-O-FeIV (2) dimer, as has
2
been observed in CH3CN (ESI†, Fig. S9). The FeV(O) finally
formed can abstract the H-atom to form iron(IV)-hydroxo (FeIV-
OH) intermediate and substrate radical (R·), which in turn can
either combine to produce the selective oxygenated product
(ROH) via rebound mechanism. The analysis of the UV-Vis
spectra for longer time period shows periodic formation and
disappearance of the FeV(O), which supports this hypothesis
(ESI†, Fig. S10). There is another possibility of the formation of
FeV(O) via D pathway, which can lead to the formation of FeIV-
OR, which was detected by mass spectroscopy (ESI†, Fig. S11).
Such monomeric Fe(IV) intermediates are dead ends and are
incapable of catalyzing further oxidation reaction. The
regioselectivity in adamantane oxidation and the
stereoretention in cis-DMCH oxidation support the rebound
mechanism to some extent. It is essential to mention that
formation of these radicals may involve additional pathways,
such as the reductive activation of O2 with Fe-bTAML. In fact,
reductive activation of O2 with Fe-bTAML leading to the
formation of FeV(O), has been postulated in more hydrophobic
solvents like CH2Cl2.7
Notes and references
1
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Scheme 3 Proposed autocatalytic radical chain mechanism for the oxygenation of
alkanes in presecne of 1a/1b/1c and dioxygen.
In conclusion, the selective catalytic oxidations of 3o C-H bonds
for a series of substrates containing unactivated C-H bonds,
including the natural product cedryl acetate by dioxygen using the
iron complexes 1a and 1c have been achieved. The reaction
required no usage of any stoichiometric co-reductant. With
substrates having activated C-H bonds, TON’s up to 250 was
observed. Mechanistic studies indicate that the reaction proceeded
via an autocatalytic radical chain mechanism. The selectivity
observed for the hydrocarbon oxidation is uncharacteristic of
typically free radical autooxidation of hydrocarbons. With Fe-
bTAML complexes 1a and 1c, the formation of the FeV(O)
intermediate bring in the high regioselectivity and stereoretention
for the oxidation reactions, which has not been observed to date
with other iron-based complexes. However, reduction in selectivity
in comparison to stoichiometric oxidations by FeV(O) (25:1
7
8
9
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