Nonheme iron complex-catalyzed efficient alcohol oxidation by t-BuOOH with N-hydroxyphthalimide (NHPI) as co-catalyst: Implication of high valent iron-oxo species

Article abstract of DOI:10.1016/j.ica.2016.06.038

Two iron catalysts ([Fe(bpc)Cl₂][Et₄N] (1a) and [Fe(Me₂bpb)Cl₂][Et₃NH] (1b)) displayed efficient catalysis in oxidation of various alcohols to the corresponding carbonyl products using t-BuOOH as an oxidant in the presence of N-hydroxyphthalimide (NHPI) under mild conditions. 1a having an electron-withdrawing group showed a little better catalytic activity than that of 1b with an electron-donating group. The mechanistic studies through Hammett plot, deuterium isotope effect, and the use of 2-methyl-1-phenylprop-2-yl hydroperoxide (MPPH) as a mechanistic probe suggested that the reactive oxidants responsible for the alcohol oxidation possibly involved Fe^IV[Formula presented]), and phthalimide N-oxyl radical [Formula presented]. On the other hand, the presence of imidazole increased the heterolytic cleavage of Fe-OOR intermediate to form Fe^V[Formula presented] species and accelerated its [Formula presented] bond cleavage rate. In particular, the formation of Fe^V[Formula presented] intermediate via the heterolytic cleavage of Fe-OOR species in the presence of imidazole in the catalytic oxidation systems of nonheme iron complexes with t-BuOOH was substantialized, for the first time, to the best of our knowledge.

Full text of DOI:10.1016/j.ica.2016.06.038

Accepted Manuscript
Nonheme iron complex-catalyzed efficient alcohol oxidation by t-BuOOH with
N-hydroxyphthalimide (NHPI) as co-catalyst: Implication of high valent iron-
oxo species
Jeong Mi Bae, Myoung Mi Lee, Seul Ah Lee, Sun Young Lee, Kwon Hee Bok,
Jinheung Kim, Cheal Kim
PII:
S0020-1693(16)30348-6
http://dx.doi.org/10.1016/j.ica.2016.06.038
ICA 17129
DOI:
Reference:
Inorganica Chimica Acta
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Revised Date:
Accepted Date:
3 February 2016
9 May 2016
28 June 2016
Please cite this article as: J.M. Bae, M.M. Lee, S.A. Lee, S.Y. Lee, K.H. Bok, J. Kim, C. Kim, Nonheme iron
complex-catalyzed efficient alcohol oxidation by t-BuOOH with N-hydroxyphthalimide (NHPI) as co-catalyst:
Implication of high valent iron-oxo species, Inorganica Chimica Acta (2016), doi: http://dx.doi.org/10.1016/j.ica.
2016.06.038
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Nonheme iron complex-catalyzed efficient alcohol oxidation by t-BuOOH
with N-hydroxyphthalimide (NHPI) as co-catalyst: Implication of high
valent iron-oxo species
Jeong Mi Bae,a Myoung Mi Lee,a,* Seul Ah Lee,a Sun Young Lee,a Kwon Hee Bok,a
Jinheung Kim,b Cheal Kima,*
a Department of Fine Chemistry and Department of Interdisciplinary Bio IT Materials, Seoul
National University of Science and Technology, Seoul 139-743, Korea. Fax: +82-2-973-
9149; Tel: +82-2-970-6693; E-mail:ohno801126@nate.com and chealkim@seoultech.ac.kr
bDepartment of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750,
Korea
Abstract: Two iron catalysts ([Fe(bpc)Cl2][Et4N] (1a) and [Fe(Me2bpb)Cl2][Et3NH] (1b)
displayed efficient catalysis in oxidation of various alcohols to the corresponding carbonyl
products using t-BuOOH as an oxidant in the presence of N-hydroxyphthalimide (NHPI)
under mild conditions. 1a having an electron-withdrawing group showed a little better
catalytic activity than that of 1b with an electron-donating group. The mechanistic studies
through Hammett plot, deuterium isotope effect, and the use of 2-methyl-1-phenylprop-2-yl
hydroperoxide (MPPH) as a mechanistic probe suggested that the reactive oxidants
responsible for the alcohol oxidation possibly involved FeIV=O species, alkoxy radical (RO.),
and phthalimide N-oxyl radical (PINO.). On the other hand, the presence of imidazole
increased the heterolytic cleavage of Fe-OOR intermediate to form FeV=O species and
accelerated its O-O bond cleavage rate. In particular, the formation of FeV=O intermediate
via the heterolytic cleavage of Fe-OOR species in the presence of imidazole in the catalytic
oxidation systems of nonheme iron complexes with t-BuOOH was substantialized, for the
first time, to the best of our knowledge.
Keywords: nonheme iron complexes, alcohol oxidation, high-valent iron-oxo species, tert-
butyl hydroperoxide, imidazole, N-hydroxyphthalimide.
1

1. Introduction
Efficient and selective oxidation of alcohols to their corresponding carbonyl compounds
is an essential transformation in organic synthesis because the target compounds, which can
be gained directly in one-pot sequences, are significant precursors for many chemicals [1].
Most catalytic methods for oxidation of alcohols have been designed utilizing various
transition metals such as Pd [2], Cu [3], Co [4], Ru [5], and Au [6]. Unfortunately, these
transition metals cause disadvantages, such as expensive reagents, high reagent loadings and
generation of a lot of toxic heavy metal waste [7]. To overcome these problems, more
efficient, cheaper, and greener oxidation processes have been recently developed in both
industry and academia [1g-h,8]. In these processes, iron is an attractive candidate because it
is readily available, inexpensive, abundant in nature and less toxic compared to the other
transition metals [9]. However, not many reports have been published to-date on alcohol
oxidation with iron-based complexes [10]. Moreover, some iron-based catalysts exhibit
selectivity and reactivity only toward a few types of substrates. Thus, iron-based catalysts,
with high selectivity and efficiency for alcohol oxidation are still in great demand.
Peroxides, such as hydrogen peroxide (H2O2) or tert-butyl hydroperoxide (t-BuOOH)
have been preferred more as environmentally friendly oxidation systems due to their non-
toxic reaction products [11], than the systems employing toxic oxidants such as MCPBA,
PhIO, CrO3. Additionally, the peroxides are cheaper and readily available [12]. However, t-
BuOOH is not so much recognized as a promising oxidant, which is possibly because its
reaction with nonheme iron complexes affords non-specific products. The non-specific
products are formed by FeIV=O species and tert-butoxy radical, which are produced from the
homolytic O-O bond cleavage of Fe-OOR species. Therefore, one of the important goals of
bioinorganic chemists is to produce FeV=O species from the reactions of t-BuOOH and
nonheme iron catalysts, which would show specific hydrocarbon oxidations. To the best of
our knowledge, FeV=O species that is generated from the reaction of nonheme iron(III)
complexes with t-BuOOH has not been reported until now.
NHPI was first used by Masui as an efficient electron carrier in the electrochemical
oxidation of alcohols [13]. Subsequently, Ishii et al. found that NHPI can also catalyze
efficiently aerobic oxidation of various organic substrates to oxygen-containing compounds
under non-electrochemical conditions [13c]. They explained that PINO. radical, which was
2

derived from NHPI can abstract a hydrogen atom from the C-H bond and improve the
reaction rates and selectivities [14].
Meanwhile, we reported epoxidation of olefins in excess by m-chloroperbenzoic acid
(MCPBA) as terminal oxidant with two amide-based nonheme iron complexes
([Fe(Me2bpb)(H2O)] and [Fe(bpc)(H2O)]) [15]. However, these two iron catalysts were less
efficient for alcohol oxidation, because they were not robust enough to carry out the C-H
bond activation of alcohols at alcohol to MCPBA ratio of 1:1. In order to improve the
efficiency of alcohol oxidation with the above two iron complexes and to observe possible
iron-oxo species from the reaction of the nonheme iron complexes with t-BuOOH, we
planned to replace the strong oxidant MCPBA with a combination of environmentally
friendly and mild oxidant t-BuOOH and NHPI as a co-catalyst.
In this paper, we report efficient oxidation of alcohols to their corresponding carbonyl
compounds with t-BuOOH catalyzed by two iron complexes (1a and 1b, see Scheme 1) in the
presence of NHPI as a co-catalyst. Moreover, the reaction mechanism for the alcohol
oxidation reactions will be discussed based on the product analysis, such as Hammett plot,
kinetic isotope effect (KIE) study, and the use of MPPH as a mechanistic probe. Under the
same conditions, in particular, the presence of FeV=O species was proposed in the presence of
imidazole, which has not been reported earlier from the reactions of t-BuOOH with nonheme
iron complexes.
2. Results and Discussion
Optimized conditions for alcohol oxidation: In order to find the optimized conditions for
the most efficient alcohol oxidation, we conducted the oxidation of cyclohexanol with t-
BuOOH using imidazole or/and NHPI as co-catalyst in the presence of iron complexes under
various reaction conditions as shown in Table 1. CH3CN was found to be the best solvent for
the reactions. The control experiments indicated that presence of both the iron catalyst and
NHPI was absolutely necessary for efficient alcohol oxidation (entries 1-9 in Table 1 and
Figure S1). Cyclohexanol was oxidized effectively to the corresponding ketone in the highest
yield only in presence of both the iron catalysts and NHPI (87.1% for 1a and 87.3% for 1b,
entries 6 and 8) under various reaction conditions. Under anaerobic conditions, the yields for
cyclohexanol oxidation with catalysts 1a and 1b were almost identical to those obtained in
3

the aerobic systems (entries 6 vs 7 and 8 vs 9), indicating that O2 was little involved in the
alcohol oxidation reaction. Switching to imidazole from NHPI gave worse oxidation results
(entries 4 vs 6 and 5 vs 8), although its presence made the reaction time faster from 7 h to
0.17 h. On the other hand, presence of both NHPI and imidazole reduced the product yield to
half (compare entries 6 vs 10 and 8 vs 11). Next, we examined the stability of catalysts 1a
and 1b during the catalytic reactions. In the presence of imidazole, most of 1b, with electron-
donating groups (-CH3), decomposed at the end of the reaction (Figure S2(b)), while 1a, with
the electron-withdrawing groups (-Cl), decomposed to a lesser extent (Figure S2(a)). These
observations might be consistent with small amounts of products as shown in entries 4 and 5
of Table 1. In presence of NHPI, 1a and 1b seemed to be robust (Figure S3). Therefore, we
may observe high yield of the products. On the other hand, in the presence of both NHPI and
imidazole, little 1a and some of 1b decomposed (Figure S4) and these results seemed to be
consistent with the reduced yields of the products that were observed in the reactivity study
(entries 10 and 11 in Table 1). Another possibility for the reduced yields of the products in
the presence of imidazole is that t-BuOOH also acts as a substrate toward a potential oxidant
FeV=O species generated from heterolytic cleavage of Fe-OOR intermediate [16].
Oxidation of various alcohols catalyzed by iron complexes: As the most efficient results
for the alcohol oxidation were obtained under the condition of entries 6 and 8 in Table 1, the
oxidation reaction of various alcohols with t-BuOOH was carried out under those conditions
and the results are shown in Table 2. With complex 1a, cyclic alcohols such as cyclopentanol
and cycloheptanol were oxidized to the corresponding ketones showing excellent yields (70.5%
and 100%; entries 1 and 2), with conversions ranging from 83.3 to 100%. In the case of
benzyl alcohol (entry 3), the benzaldehyde (45.4%) was a major product along with moderate
amounts of benzoic acid (22.4%), which was generated from further oxidation of
benzaldehyde. Secondary alcohol, viz. sec-phenethyl alcohol, produced the corresponding
ketone with a good yield (93.5%, entry 4). cis-2- and trans-2-Methylcyclohexanols were
almost quantitatively converted to the corresponding ketones, while trans-2-
methylcyclohexanol took a longer reaction time (14 h) than cis-2-methylcyclohexanol
because of steric hindrance (entries 5 and 6). endo-Norborneol showed a higher activity than
exo-norborneol (100% vs 57.9%, entries 7 and 8). A linear aliphatic primary alcohol, 1-
4

octanol, was converted to the corresponding aldehyde (1.7%, entry 9), which underwent
further oxidation to the corresponding carboxylic acid (14.4%). Linear aliphatic secondary
alcohols such as 2-hexanol, 3-hexanol and 2-octanol were oxidized smoothly to the
corresponding ketones in high yields (entries 10, 11 and 12). Complex 1b showed a little
lower efficiency than 1a (Table 2). These results demonstrated that the substitution of an
electron withdrawing group -Cl on the ligand enhanced its reactivity toward alcohol oxidation
than an electron-donating group -CH3, which was similar to the results observed in the olefin
epoxidation systems using [Fe(Me2bpb)(H2O)] vs [Fe(bpc)(H2O)] complexes [15c].
Competitive experiments of sec-phenethyl alcohol and para-substituted sec-phenethyl
alcohols for Hammett plot: To further investigate the electronic influence of the substituents
on the reaction rate, we carried out the competitive oxidation between sec-phenethyl alcohol
and equivalent amounts of para-substituted sec-phenethyl alcohols by iron complexes with t-
BuOOH in the presence of NHPI. The ρ values were determined to be -0.44 for 1a (Figure 1)
and -0.40 for 1b (Figure S5). The negative ρ values indicated the electrophilic character of
the reactive intermediates responsible for the alcohol oxidation. In addition, the two similar ρ
values implied that both 1a and 1b possibly catalyzed alcohol oxidation via the same reaction
mechanism. These ρ values are smaller than those reported for the oxidation of phenethyl
alcohols using P-450 enzymes (-1.19 and -1.41) [17] and iron porphyrin complex
[(F20TPP)FeCl] (F20TPP = tetrakis(pentafluorophenyl)porphyrin) (-1.34) [18].
Kinetic isotope effect (KIE) study on competitive oxidation of benzyl alcohol and
deuterated benzyl alcohol by t-BuOOH in the presence of iron complexes: Since the
kinetic isotope effect had been extensively used as a mechanistic probe in alkane
hydroxylation by both P-450 enzymes and metalloporphyrin models [18,19], we studied
intermolecular competitive alcohol oxidation of benzyl alcohol and benzyl alcohol-d7 by t-
BuOOH in presence of the two iron catalysts. These reactions were performed in presence of
excess substrate because further oxidation of benzaldehyde, derived from benzyl alcohol, to
benzoic acid obstructed the determination of the exact KIE value. Thus, reliable KIEs were
obtained from the formation ratio of both benzaldehyde and deuterated benzaldehyde as the
only product in these competitive experiments.
5

Alcohol oxidation by only NHPI without any catalyst showed a kH/kD value of 2.3 (yield:
less than 10% after 1 day, entry 1, Table 3), indicating a typical radical type of alcohol
oxidation by PINO. [20]. The kH/kD for benzyl alcohol oxidation by t-BuOOH with iron
catalysts and without both imidazole and NHPI afforded 5.1 for 1a and 4.8 for 1b (entries 2
and 3, Table 3). We assumed that the reactive species under entries 2 and 3 might be FeIV=O
species and tert-butoxy radical and will be discussed later. The KIE values for catalysts 1a
and 1b in the presence of imidazole without NHPI were found to be 3.5 and 3.8, respectively
(entry 4 and 5). These values were almost identical to those of a corresponding hydrogen
abstraction reaction by the tert-butoxy radical (entry 10) and by the combination of an
iron(III) porphyrin complex [(F20TPP)FeCl] with MCPBA [18]. The KIE values for catalysts
1a and 1b in the presence of NHPI without imidazole were determined to be 6.3 and 5.8,
respectively (entries 6 and 7). These results suggested that FeIV=O, t-BuO. radical, and PINO.
radical species might be involved in alcohol oxidation and will also be discussed in details
later. In the presence of both imidazole and NHPI, the KIE values were 6.7 for 1a and 6.3 for
1b, which were the highest among all the reactions tested in this study. Based on these results,
it can be concluded that hydrogen atom abstraction from C-H bonds was involved in the rate-
determining step, and that the reactive species responsible for the alcohol oxidation under
each reaction condition of Table 3 might be different.
Analysis of the O-O bond cleavage products from the alcohol oxidation reactions by
MPPH in the presence of iron complexes: Previously, MPPH had been used a mechanistic
probe to distinguish between heterolytic and homolytic cleavage of alkyl hydroperoxide O-O
bond [21]. As shown in Scheme 2, if the O-O bond of the Fe-alkylperoxo intermediate (FeIII-
OOC(O)R, 2) is heterolytically cleaved, it can generate 2-methyl-1-phenylprop-2-ol
(MPPOH (5)) as a heterolytic cleavage product and FeV=O species (3, pathway (a) of Scheme
2) responsible for the alcohol oxidation. On the other hand, homolysis of the O-O bond can
afford the FeIV=O intermediate (4) and alkoxy radical, which can form benzyl radical and
acetone via a fast β-scission cleavage (2.2 x 108 s-1) (pathway (b) of Scheme 2). This benzyl
radical is then converted to benzyl alcohol (6), benzaldehyde (7), and toluene (8) [21a,d,22].
We investigated the oxidation of sec-phenethyl alcohol with MPPH as a mechanistic
probe in the presence of iron catalysts (Table 4). The oxidation results for catalyst 1ashowed
6

5.7% of MPPOH as a heterolytic cleavage product, whereas 69.6% of benzaldehyde and 11.1%
of benzyl alcohol as homolytic cleavage products without imidazole and NHPI (entry 1). The
yield of acetophenone as the product was 14%. This result demonstrated that the intermediate
Fe-OOR species formed from the reaction of iron(III) complex with MPPH was cleaved as
6.5% heterolysis and 93.5% hemolysis. Before we were confident about the completion of the
oxidation reaction, we carried out another control experiment to determine whether MPPH
was completely consumed by catalyst 1a during the reaction period (10 h). Therefore, in the
duplicate experiment PPh3 was added into the reaction mixture after the given reaction time
(entry 2), because it is well known that alkyl hydroperoxides react quickly with PPh3 to give
the corresponding alcohols [23]. The product analysis of entries 1 and 2 in Table 4 showed
nearly identical product distributions, suggesting that MPPH decomposed completely during
the alcohol oxidation reactions within the given reaction time. Next, we carried out the same
oxidation reaction of sec-phenethyl alcohol with MPPH in the presence of imidazole, and the
results showed 12.4% of the heterolytic product, whereas 73.1% and 9.0% of the homolytic
products (entry 5), indicating a 13.0% heterolytic and 87.0% homolytic cleavage of Fe-OOR
species. These results suggested that a certain amount of heterolytic cleavage product from
Fe-OOR species, viz. FeV=O species, could be formed in the presence of imidazole, which
was not ever reported from the reactions of t-BuOOH with nonheme iron complexes. In the
presence of NHPI, 1.2% of MPPOH and 98.2% of benzaldehyde were obtained (entry 9),
surprisingly, suggesting that the homolytic cleavage of Fe-OOR species occurred exclusively.
In the presence of both imidazole and NHPI, 14.0% of MPPOH and 73.3% of benzaldehyde
were formed (entry 13), indicating 16.0% heterolytic and 84.0% homolytic cleavage of the
Fe-OOR species. The highest heterolytic cleavage portion was observed under these
conditions. These results indicated that the heterolytic cleavage of the iron(III)-alkylperoxo
species could occur in the catalytic reactions of nonheme iron(III) complexes with t-BuOOH
under a certain condition, for example, in the presence of imidazole. Similar results were also
obtained for 1b (entries 3-4, 7-8, 11-12, 15-16, Table 4), indicating that both catalysts 1a and
1b possibly catalyze alcohol oxidation via the same reaction mechanism.
Imidazole effect on the alcohol oxidation: Imidazole had been reported as a co-catalyst in
hydrocarbon oxidation reactions in literatures dealing with iron and manganese porphyrin
7

complexes [24-29]. Labeque and Marnett studied the effects of imidazole on olefin
epoxidation by heme iron complexes with t-BuOOH [30], and found that the presence of
imidazole enhanced the yields of epoxide. Based on these results, they proposed that
imidazole might act as a general base catalyst to promote heterolytic cleavage of an O-O
bond [26-31]. We also investigated the influence of imidazole in our catalytic oxidation of
alcohols. As shown in the entries 2 and 3 vs 4 and 5 of Table 1, the presence of imidazole
reduced the reaction time from 10 h to 0.17 h with no change in the yield of products. The
presence of imidazole with NHPI also reduced the reaction time from 7 h to 1 h (entries 6 and
8 vs 10 and 11), although in this case the product yields were reduced to half. Under the same
condition, in Table 4 are shown the alcohol oxidation results due to the effect of imidazole on
the cleavage mode of alkyl hydroperoxide O-O bond using MPPH as the oxidant. As shown
in entries 1 and 3 vs 5 and 7, imidazole enhanced the heterolytic O-O bond cleavage of Fe-
OOR intermediate almost twice that of the one without imidazole. Moreover, the presence of
imidazole with NHPI increased the heterolytic O-O bond cleavage percent 5 to 16 times
(entries 9 and 11 vs 13 and 15). These results demonstrated that imidazole not only
accelerated the O-O bond cleavage rate of Fe-OOR species but also affected the ratio
between homolytic and heterolytic O-O bond cleavage. In particular, the enhancement of the
heterolytic cleavage of Fe-OOR species by imidazole in the catalytic oxidation systems of
nonheme iron complexes with t-BuOOH was evidenced, for the first time, to the best of our
knowledge.
In order to observe the proposed reactive intermediates FeIII-OOC(O)R, Fe(V)=O, and
Fe(IV)=O, we used the spectroscopic instruments such as EPR and ESI-mass. As shown in
Table 1, all the reaction times are so long from 0.17 to 10 h. Therefore, we assumed that it
was not easy to trap the reactive intermediates directly by utilizing the spectroscopic
instruments, because the sufficient amounts of the intermediates could not be accumulated.
These observations led us to concentrate only on the fastest reaction (entries 10 and 11 in
Table 1) under the conditions which the iron complexes are stable to some degree during the
catalytic reaction. First, we carried out EPR experiments to trap the proposed reactive
intermediates, but could not observe any reactive species. Next, we used ESI-mass instrument,
and was able to observe a possible Fe(V)=O species in the presence of both NHPI and
imidazole (under entry 10 condition in Table 1), as shown in Fig. S6. The negative-ion mass
8

spectrum indicated that the peak at m/z = 598.87 was assignable to [(bpc)Fe(V)=O + OH- + 3
solvents]- [calcd, 598.98] intermediate.
Mechanism: Based on all of our results, the most plausible mechanisms for the alcohol
oxidation reaction by nonheme iron complexes 1a and 1b with alkyl hydroperoxides are
illustrated in Scheme 3. The iron(III) complex reacted with alkyl hydroperoxides to form
iron(III)-alkylperoxide intermediate 2, which underwent a homolytic O-O bond cleavage
almost exclusively to produce FeIV=O species 4 and t-butoxy radical (pathway a). These two
reactive species might not be efficient for alcohol oxidation, because the ketones obtained
under the reaction conditions were in low yields. Interestingly, the presence of imidazole
increased the heterolytic O-O bond cleavage of Fe-OOR intermediate twice, although the
yields of the ketone remained almost unchanged (pathway b). We assumed that the low
ketone yield might be due to self-destruction of the iron complexes by FeV=O species 3
formed from the heterolytic O-O bond cleavage of Fe-OOR intermediate in the presence of
imidazole (Figure S2). Instead of imidazole, the presence of NHPI caused homolysis
cleavage exclusively of the O-O bond in Fe-OOR to achieve efficient alcohol oxidation
(pathway c). These results led us to propose that both FeIV=O species 4 and alkoxy radical
generated from the homolytic O-O bond cleavage of the intermediate Fe-OOR 2 oxidized
NHPI to PINO. radical via hydrogen abstraction reaction (Scheme 4). The resulting PINO.
radical then abstracted the hydrogen atom of the C-H bond of cyclohexanol to produce the
cyclohexanol radical. Finally, FeIV=O, alkoxy radical and PINO. radical oxidized the
cyclohexanol radical to the corresponding cyclohexanone (Scheme 5).
Therefore, the FeIV=O, alkoxy radical and PINO. radical probably acted as key reactive
intermediates responsible for alcohol oxidation under this condition. Lastly, the presence of
both imidazole and NHPI enhanced the heterolysis (up to 16%) of the O-O bond in Fe-OOR
intermediate, with reduced yields of ketone products (pathway d in Scheme 3). We presumed
that the reduced ketone products might be attributed to some self- destruction of the iron
complexes by FeV=O intermediate (Figure S4). Nevertheless, some iron complexes were still
alive, which afforded half amounts of yields.
3. Conclusion
9

We have conducted efficient oxidations of a variety of alcohols catalyzed by the iron
complexes and t-BuOOH as environmentally friendly terminal oxidant in the presence of
NHPI. Various alcohols were converted to the corresponding ketones efficiently under our
catalytic system. 1a was found to be a little better catalyst for alcohol oxidation than 1b. The
active oxidants in these systems were proposed to be FeIV=O, alkoxy radical and PINO.
radical, as indicated by KIE (kH/kD) and Hammett study, as well as the use of MPPH as an
oxidant. On the other hand, imidazole not only accelerated the O-O bond cleavage rate of Fe-
OOR species but also affected the ratio between the homolytic and heterolytic O-O bond
cleavage. Therefore, it was proposed that an FeV=O might exist in the presence of imidazole
in the catalytic oxidation systems of nonheme iron complexes with t-BuOOH. Our future
work will focus on (1) further exploring the biologically relevant reactivity of the iron (III)
complex/t-BuOOH systems, and (2) obtaining further spectroscopic evidence for the FeV=O
species described herein.
4. Experimental Section
General: Alcohols, ketones, carboxylic acids, anhydrous acetonitrile, dodecane, t-BuOOH,
imidazole and NHPI were purchased from Aldrich Chemical Co. and were used without
further purification. MPPH was synthesized according to the literature method [21a].
[Fe(bpc)Cl2][Et4N] (1a) and [Fe(Me2bpb)Cl2][Et3NH] (1b) were obtained from the previous
study [15].
Instruments: Product analyses for alcohol oxidation and MPPH experiment were conducted
by using a DS6200 gas chromatograph equipped with a FID detector of Donam instrument
Co. and a 30 m capillary column (Hewlett-Packard, DB-5 or HP-FFAP).
Catalytic alcohol oxidations by t-BuOOH in the presence of iron complexes: t-BuOOH
(0.075 mmol) was added to a mixture of substrate (0.05 mmol), iron complex (1.0x10-3
mmol), imidazole (0.01 mmol), NHPI (0.02 mmol), and solvent (CH3CN; 1 mL). The
o
mixture was stirred for the given time at 50 C. Each reaction was monitored by GC/MS
analysis of 20 µL aliquots withdrawn periodically from the reaction mixture. Dodecane was
used as an internal standard to quantify the yields of products and conversions of substrates.
10

All reactions were run at least in triplicate, and the average conversions and product yields
have been presented. Conversions and product yields were calculated with respect to
substrates.
Competitive reactions of sec-phenethyl alcohol and para-substituted sec-phenethyl
alcohols for Hammett plot: To a mixture of sec-phenethyl alcohol (0.025 mmol), para(X)-
substituted phenethyl alcohol (X = -OCH3, -F, -Br and -CF3, 0.025 mmol), NHPI (0.02
mmol), catalysts 1a or 1b (1.0 x 10-3 mmol), and solvent (CH3CN, 1 mL) was added t-
BuOOH (0.04 mmol). The mixture was stirred for 7 h at 50 oC. The amounts of sec-phenethyl
alcohols before and after the reactions were measured by GC/MS analysis of 20 µL aliquots
withdrawn periodically from the reaction mixture. The relative reactivities were calculated
using the following equation: kx/ky = log(Xf/Xi)/log(Yf/Yi) where Xi and Xf are each initial
and final concentration of para-substituted sec-phenethyl alcohols and Yi and Yf are each
initial and final concentration of sec-phenethyl alcohol [18].
KIE study on competitive oxidation of benzyl alcohol and deuterated benzyl alcohol by
t-BuOOH in the presence of iron complexes: This reaction was performed in presence of
excess substrate to avoid further oxidation of the benzaldehyde, derived from benzyl alcohol,
to benzoic acid which inhibits the determination of the exact KIE value. Moreover, in order
to improve the accuracy in measuring the amount of deuterated benzyl alcohol product, a 1:6
mixture of benzyl alcohol and deuterated benzyl alcohol was used. The reaction procedure: t-
BuOOH (0.075 mmol) was added to a mixture of benzyl alcohol (0.1 mmol) and benzyl-d7-
alcohol (0.6 mmol), imidazole (0.01 mmol), NHPI (0.02 mmol), catalysts 1a or 1b (1.0x10-3
o
mmol), and solvent (CH3CN, 1 mL). The mixture was stirred for the given time at 50 C.
Reaction conversion was monitored by GC/MS analysis of 20 µL aliquots withdrawn
periodically from the reaction mixture. All the reactions were run at least in triplicate and the
average KIE values have been presented.
Analysis of the O−O bond cleavage products from the oxidation reactions of substrates
by MPPH in the presence of iron complexes: MPPH (0.02 mmol) was added to a mixture
of substrate (0.05 mmol), imidazole (0.01 mmol), NHPI (0.02 mmol), catalysts 1a or 1b
(1.0x10-3 mmol), and solvent (anhydrous CH3CN, 1 mL). The mixture was stirred for the
11

o
given time at 50 C. In order to check whether MPPH was decomposed completely within a
given reaction time, PPh3 in the duplicate experiment was added into the reaction mixture
after the given reaction time. Each reaction was monitored by GC/MS analysis of 20 µL
aliquots withdrawn periodically from the reaction mixture. All reactions were run at least in
triplicate, and the average conversions and product yields have been presented. Conversions
and product yields were based on MPPH.
Acknowledgements
Basic Science Research Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Technology (NRF-
2014R1A2A1A11051794 and NRF-2015R1A2A2A09001301) are gratefully acknowledged.
Supplementary data
Supplementary data related to this article can be found at http: //
12

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18

Scheme 1. Structures of iron(III) complexes.
19

Scheme 2. Possible degradation pathways of MPPH by iron complexes.
20

Scheme 3. Plausible mechanisms for the alcohol oxidation by iron complexes with MPPH
(Based on Table 4).
21

Scheme 4. Possible alcohol oxidation mechanism for the pathway (c) in Scheme 3.
22

Scheme 5. Termination of the cyclohexanol radical by the active oxidants.
23

Table 1. Oxidation of cyclohexanol catalyzed by iron complexes 1a and 1b with t-BuOOH in
the absence or/and presence of imidazole and NHPI at 50 oC.a
Cyclohexanolb
Reaction
time
(h)
Entry
Catalyst
imidazole
NHPI
Conversion
(%)
Yield
(%)
1
No
1a
24
10
10
0.17
0.17
7
No
No
Yes
No
1.3 1.2
10.2 1.6
14.6 2.8
12.1 1.7
14.1 0.3
89.5 2.2
90.4 3.9
91.3 2.1
90.4 4.3
57.5 0.7
55.2 1.4
trace
2
9.5 0.3
3
No
No
13.7 0.4
10.2 0.1
10.8 0.3
87.1 4.6
89.4 2.2
87.3 4.6
89.0 5.3
46.4 3.2
52.9 2.0
1b
1a
4
Yes
Yes
No
No
5
No
1b
1a
6
Yes
Yes
Yes
Yes
Yes
Yes
7
1ac
1b
1bc
1a
7
No
8
7
No
9
7
No
10
1
Yes
Yes
11
1
1b
a
Reaction conditions: cyclohexanol (0.05 mmol), catalyst (1.0x10-3 mmol), imidazole (0.01
mmol), NHPI (0.01mmol), t-BuOOH (0.075 mmol), and solvent (1 mL, CH3CN). b Based on
substrate. c Under anaerobic conditions with N2 atmosphere.
24

Table 2. Oxidation reaction of various alcohols catalyzed by iron complexes 1a and 1b with t-BuOOH in the presence of NHPI at 50 oC.a
1a b
1b b
Entry
Substrate
Product
Conversion (%)
Yield (%)
70.5
Conversion (%)
Yield (%)
68.3
1
2
3
cyclopentanol
cycloheptanol
benzyl alcohol
cyclopentanone
cycloheptanone
benzaldehyde
benzoic acid
83.3
100
82.8
100
100
89.0
96.2
45.4
75.8
53.6
22.4 (44.8) c
93.5
8.2 (16.4) c
87.2
4
5
6
7
8
9
sec-phenethyl alcohol
cis-2-methylcyclohexanol
trans-2-methylcyclohexanol
endo-norborneol
acetophenone
100
98.7
91.8
100
100
87.4
90.5
96.9
54.0
53.6
2-methylcyclohexanone
2-methylcyclohexanone
norcamphor
85.3
76.7
80.5
80.0
100
94.5
exo-norborneol
norcamphor
61.4
55.4
57.9
51.5
1-octanol
octanal
1.7
1.9
octanoic acid
2-hexanone
14.4 (28.8) c
86.8
10.9 (21.8) c
86.8
10
11
12
2-hexanol
3-hexanol
2-octanol
89.3
94.4
88.4
87.7
92.2
85.9
3-hexanone
91.0
90.3
2-octanone
85.8
85.2
a
Reaction conditions: alcohols (0.05 mmol), catalyst (1.0x10-3 mmol), NHPI (0.01 mmol), t-BuOOH (0.075 mmol), and solvent (1 mL,
b
c
CH3CN). Reaction time was 7 h. Based on substrate.
aldehyde to the corresponding carboxylic acids.
Yields in parenthesis are considered the further oxidation of the first oxidation
25

Table 3. Kinetic isotope effects on oxidation of benzyl alcohol/benzyl-d7 alcohol by iron
complexes 1a and 1b with t-BuOOH at 50 oC.a
Reaction
Entry
Catalyst
time
(h)
Imidazole
NHPI
kH/kD
Reference
24
1
2
3
4
5
6
7
8
9
No
1a
1b
1a
1b
1a
1b
1a
1b
No
No
Yes
No
2.3 0.2
this work
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this work
this work
10
10
0.17
0.17
7
5.08 0.3
4.78 0.0
3.49 0.2
3.75 0.0
6.26 0.0
5.72 0.0
6.67 0.1
6.31 0.2
No
No
Yes
Yes
No
No
No
Yes
Yes
Yes
Yes
7
No
1
Yes
Yes
1
t-butoxy
10
-
-
3.6
19c
radical
a
Reaction conditions: benzyl alcohol (0.1 mmol), benzyl-d7 alcohol (0.6 mmol), catalyst
(1.0x10-3 mmol), imidazole (0.01 mmol), NHPI (0.01 mmol), t-BuOOH (0.075 mmol), and
solvent (1 mL, CH3CN).
26

Table 4. Yield of products derived from 2-methyl-1-phenylprop-2-yl hydroperoxide (MPPH) mediated by iron complexes 1a and 1b in the
presence of sec-phenethyl alcohol at 50 oC.a
Heterolysisd,e
Homolysisd,e
Yieldd (%)
PPh3
Reaction
time
(h)
Entry
Catalyst
Imb
NHPI
Hetero/Homo
(mM)c
MPPOH
aldehyde
ol
acetophenone
1
2
10
10
10
10
0.3
0.3
2
No
No
No
No
0
100
0
0.07 (6.5/93.5)
0.10 (9.1/90.9)
0.07 (6.5/93.5)
0.08 (7.4/92.6)
0.15 (13.0/87.0)
0.16 (13.8/86.2)
0.10 (9.1/90.9)
0.12 (10.7/89.3)
0.01 (1.0/99.0)
0.02 (2.0/98.0)
0.03 (3.0/97.0)
0.04 (4.0/96.0)
0.19 (16.0/84.0)
0.23 (18.7/81.3)
0.18 (15.3/84.7)
0.20 (16.7/83.3)
5.7 0.7
8.3 0.8
6.3 0.2
6.9 0.3
12.4 0.1
12.4 0.6
6.8 0.7
7.8 1.0
1.2 0.9
2.4 0.3
3.0 0.4
4.1 0.7
14.0 0.2
16.7 0.6
14.1 0.2
15.3 1.4
69.6 3.3
69.6 1.6
80.3 4.1
79.3 2.8
73.1 2.1
68.1 0.2
67.8 2.6
63.2 1.1
98.2 1.3
98.4 1.4
93.5 0.3
91.3 0.8
73.3 5.9
72.1 4.4
77.4 1.5
76.4 3.0
11.1 3.3
10.8 0.7
7.7 0.1
6.2 0.4
9.0 0.5
8.1 1.3
1.2 1.2
0.0
14.1 0.2
15.6 0.2
11.0 1.2
9.5 0.5
1a
3
1b
1a
1b
1a
1b
1a
1b
No
No
4
No
No
100
0
5
Yes
Yes
Yes
Yes
No
No
4.3 0.2
6
No
100
0
3.9 0.1
7
No
8.9 0.1
8
2
No
100
0
8.1 0.9
9
7
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
0.0
52.7 0.9
55.0 0.2
53.5 0.6
51.7 0.3
28.0 0.5
27.5 0.4
33.2 4.0
36.5 2.4
10
11
12
13
14
15
16
7
No
100
0
0.0
7
No
4.5 0.7
3.2 2.1
0.0
7
No
100
0
4
Yes
Yes
Yes
Yes
4
100
0
0.0
4
0.0
4
100
0.0
a Reaction conditions: sec-phenethyl alcohol (0.05 mmol), catalyst (1.0x10-3 mmol), imidazole (0.01 mmol), NHPI (0.01 mmol), MPPH (0.02
b
mmol), and solvent (1 mL, CH3CN). Im = imidazole. In order to confirm whether MPPH was completely consumed or not, PPh3 was
c
d
e
added into the reaction solution after the reaction finished. Based on MPPH. MPPOH, aldehyde, and ol indicate 2-methyl-1-phenyl-2-
propanol, benzaldehyde, and benzyl alcohol, respectively.
27

Figure Caption
Figure 1. Hammett plot for selective reactivities of sec-phenethyl alcohol to para-substituted
sec-phenethyl alcohols by 1a with t-BuOOH in the presence of NHPI.
28

Figure 1.
29