Biomimetic alcohol oxidations by an iron(III) porphyrin complex: Relevance to cytochrome P-450 catalytic oxidation and involvement of the two-state radical rebound mechanism

Article abstract of DOI:10.1039/b414603d

The systematic oxidation reactions of a wide range of alcohols have been carried out by using an iron porphyrin complex in order to understand their relation to cytochrome P-450 enzymes and to have a practical application to organic synthesis. The iron porphyrin complex catalyzed efficiently alcohol oxidation to the respective carbonyl compound via a high-valent iron-oxo porphyrin intermediate ((Porp)Fe=O⁺). Several mechanistic studies such as isotope ¹⁸O labeling, deuterium isotope effect, linear free energy relationship, and ring-opening of radical clock substrate, have suggested that the alcohol is oxidized by a sequence of reactions involving an a-hydroxyalkyl radical intermediate and oxygen rebound to form the gem-diol, dehydration of which yields the carbonyl compounds. Moreover, it has been proposed that a two-state reactivity mechanism can also be adopted for alcohol oxidation reactions in iron porphyrin model systems as exhibited by P-450 enzymes.

Full text of DOI:10.1039/b414603d

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F U L L P A P E R
Biomimetic alcohol oxidations by an iron(III) porphyrin complex:
relevance to cytochrome P-450 catalytic oxidation and involvement
of the two-state radical rebound mechanism
a
a
a
a
b
Jung Hee Han, Sang-Kun Yoo, Jin Soo Seo, Sung Jin Hong, Seok Kyu Kim and
a
Cheal Kim*
a
Department of Fine Chemistry, Seoul National University of Technology, Seoul, 139-743,
Korea. E-mail: chealkim@snut.ac.kr; Fax: +82-2-973-9149; Tel: +82-2-970-6693
b
Department of Chemistry, Yeong Nam University, Daegu, 120-750, Korea
Received 21st September 2004, Accepted 17th November 2004
First published as an Advance Article on the web 30th November 2004
The systematic oxidation reactions of a wide range of alcohols have been carried out by using an iron porphyrin
complex in order to understand their relation to cytochrome P-450 enzymes and to have a practical application to
organic synthesis. The iron porphyrin complex catalyzed efficiently alcohol oxidation to the respective carbonyl
+
compound via a high-valent iron-oxo porphyrin intermediate ((Porp)Fe=O ). Several mechanistic studies such as
1
8
isotope O labeling, deuterium isotope effect, linear free energy relationship, and ring-opening of radical clock
substrate, have suggested that the alcohol is oxidized by a sequence of reactions involving an a-hydroxyalkyl radical
intermediate and oxygen rebound to form the gem-diol, dehydration of which yields the carbonyl compounds.
Moreover, it has been proposed that a two-state reactivity mechanism can also be adopted for alcohol oxidation
reactions in iron porphyrin model systems as exhibited by P-450 enzymes.
Introduction
reaction catalyzed by 1 occurs immediately after peroxybenzoic
acid addition, compared with gradual direct oxidation. This
system has shown high catalytic activities for the oxidation of
non-activated and activated alcohols under mild conditions as
shown in Table 1. Secondary alcohols were easily converted
to the corresponding ketones in excellent yields and reaction
selectivity was over 97% in all cases. Cyclic alcohols such as
cyclopentanol, cyclohexanol and cyclooctanol were oxidized to
the corresponding ketones in good yields (entries 1–3), whereas
sterically hindered alcohols such as trans-2-methylcyclohexanol
and exo-norborneol were less efficiently oxidized to ketones
under this system (compare entries 4 and 5, and entries 6
and 7). Linear aliphatic secondary alcohols were also smoothly
converted to the corresponding ketones in good yields (entries
Cytochrome P-450 enzymes catalyze aliphatic and aromatic
hydroxylation, N-, O-, and S-oxidation and dealkylation, olefin
epoxidation, and alcohol oxidation. While many of the mech-
1
anistic details of P-450 enzymes remain obscure, the product-
determining steps catalyzed by the oxidizing species, iron-oxo
2
and iron-hydroperoxo, are particularly unclear. A number of
biomimetic systems have also been developed to model the
3
reactivity of P-450 enzymes. Although metalloporphyrins were
found to catalyze the biomimetic oxidations such as olefin
epoxidation, alkane hydroxylation, sulfide oxidation, etc., and
their reaction mechanisms have been intensively investigated,
their biomimetic alcohol oxidation has not yet been reported,
4
to our knowledge. Therefore, we have studied the systematic
8
–11). While the saturated aliphatic secondary alcohols could
oxidation of a wide range of alcohols catalyzed by iron porphyrin
in order to understand their relation to cytochrome P-450
enzymes and to investigate their practical application to organic
synthesis. Herein, we have reported for the first time that an
iron porphyrin complex catalyzes efficiently alcohol oxidation
to the carbonyl compound by a sequence of reactions involving
an a-hydroxyalkyl radical intermediate and oxygen rebound to
form the gem-diol, dehydration of which yields the carbonyl
compounds. Moreover, we have proposed that a two-state
reactivity mechanism can be also adopted for alcohol oxidation
be oxidized to the corresponding ketones selectively in high
yields, further oxidation of the aldehydes, derived from primary
alcohols such as benzyl alcohol, 1-hexanol, and 1-octanol, to the
respective carboxylic acid was observed (entries 12–14). In com-
petition experiments, primary alcohols were oxidized faster than
secondary alcohols (e.g. 1.5 times for 1-hexanol vs. 3-hexanol)
and cis-2-methylcyclohexanol was 4 times more reactive (due to
steric hindrance) than trans-2-methylcyclohexanol.
Recently, the P-450-catalyzed oxidation mechanism has in-
voked much interest in chemists and bioinorganic chemists in
the areas of reactive species, iron-oxo vs. iron-hydroperoxo, and
reactions in this iron porphyrin model system as shown in P-
5
4
50 enzymes, based on several mechanistic studies such as
2
C–H bond activation, concerted vs. radical rebound. Since we
1
8
isotope O labeling, deuterium isotope effect, linear free energy
relationship, and ring-opening of radical clock substrate.
have also been interested in the oxidation mechamism, we have
18
carried out several mechanistic studies, isotope O labeling,
deuterium isotope effect, linear free energy relationship, and
ring-opening of radical clock substrate, to understand and
compare the alcohol oxidation mechanism of the iron porphyrin
model system and the P-450 enzyme.
Results and disscusion
We used m-chloroperbenzoic acid (MCPBA) as the oxidant
and iron porphyrin, [(F20TPP)FeCl] (tetrakis(pentafluoro-
phenyl)porphinatoiron chloride, 1), as the catalyst for the oxida-
tion of alcohols. To a mixture of substrate (0.0175 mmol), iron
1
8
Isotopically labeled water (H O) experiments have been
2
well established as useful mechanistic probes in testing the
involvement of high-valent metal oxo intermediates in metal-
−
3
6
18
porphyrin 1 (1 × 10 mmol), and solvent (CH
2
Cl
2
/CH
3
CN =
mediated oxygen atom transfer reactions. When labeled O is
18
1
/1, 0.5 mL) was added MCPBA (0.035 mmol). The mixture was
found to be incorporated from H O into oxygenated products,
2
stirred for 10 min at room temperature. We confirmed that direct
alcohol oxidation was negligible, because the oxygen transfer
a high-valent metal oxo complex is proposed as an oxygenating
species, since the intermediate exchanges its oxygen atom with
4
0 2
D a l t o n T r a n s . , 2 0 0 5 , 4 0 2 – 4 0 6
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5

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a
Table 1 Oxidation reaction of various alcohols catalyzed by 1 with MCPBA
b
c
Entry
1
Substrate
Product
Conversion (%)
Yield (%)
90.7
88.6
97.1
71.0
80.8
86.3
2
3
4
5
6
99.8
77.4
99.4
83.0
62.6
85.2
7
84.7
92.9
70.5
85.8
8
9
91.1
86.3
88.8
71.8
1
1
0
1
86.3
72.8
d
1
1
1
2
3
4
55.4
67.1
64.8
1.3 (41.1)
d
1.5 (29.1)
d
6.4 (35.5)
1
1
5
6
81.4
93.4
70.2
90.6
a
Reaction conditions: see Experimental section for detailed experimental procedures. All reactions were run at least in triplicate, and the data
b
reported represent the average of these reactions. Amount of the starting alcohol consumed during the reaction; based upon the starting alcohols.
c
d
Amount of the carbonyl product formed during the reaction; based upon the starting alcohols. The numbers in parentheses indicate the yields of
the corresponding carboxylic acids.
labeled water prior to oxygen atom transfer to organic substrates.
Therefore, we have conducted the oxidation of cyclohexanol
by 1 and MCPBA in the presence of 200 equiv excess of
amounts due to solvent exchange. We have also performed the
labeled water experiments by varying the amounts of labeled
water present during alcohol oxidation by iron porphyrin and
1
8
18
H
2
O to substrate. As the results show in Table 2, 22% of
MCPBA and found that the amounts of O incorporated into
1
8
the oxygen in the cyclohexanone product came from H
2
O
the carbonyl decreased as the concentration of labeled water in
the reaction mixture decreased (entries 2 and 3). The dependence
(
entry 1), suggesting that a high-valent iron-oxo porphyrin
1
8
intermediate was generated as a reactive species in the reactions
of the iron porphyrin and MCPBA as proposed in cytochrome
of O-incorporation on the concentration of labeled water
can be explained by the relative rates of oxygen atom transfer
and oxygen exchange as previously demonstrated by Meunier,
7
P-450 enzymes. A control experiment with cyclohexanone in
1
8
6
H
2
O under the same conditions showed incorporation of trace
Groves, Nam, and co-workers.
D a l t o n T r a n s . , 2 0 0 5 , 4 0 2 – 4 0 6
4 0 3

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18
18
a
Table 2 Percentage of O-incorporated from H
2
O into cyclohexanone formed during cyclohexanol oxidation by 1 and MCPBA
18
18
Entry
Amount of cyclohexanol/M
Amount of H
2
O/M
O in cyclohexanone (%)
1
2
3
0.01
0.01
0.01
2.08
1.04
0.52
21.9 ± 2.0
9.5 ± 1.0
4.8 ± 1.0
a
Reaction conditions: see Experimental section for detailed experimental procedures. All reactions were run at least in duplicate, and the data reported
represent the average of these reactions.
1
8
hydrogen abstraction reaction by the tert-butoxy radical,8c thus
implying that alcohol oxidation by 1 proceeds by a common,
hydrogen atom transfer mechanism. In addition, the P-450 have
The incorporation of the oxygen atom of H O into cyclo-
2
hexanone suggests two possible reaction mechanisms in the
oxidation of alcohol by the high-valent iron-oxo species. As
the proposed oxidation mechanisms show in Scheme 1, both of
the pathways A and B form a common gem-diol intermediate,
dehydration of which gives the carbonyl product. The pathway
A is a direct insertion from the iron-oxo species into the C–H
bond. Pathway B involves stepwise oxidation of the alcohol to
an a-hydroxy carbinyl radical via hydrogen-atom abstraction,
followed by oxygen rebound. The other possible pathways
including a common carbonium intermediate, generated by
hydride transfer or hydrogen atom abstraction followed by
electron transfer, can be excluded based on the labeling extent
7,8c
also shown a value of 2.8, a lower limit for the intrinsic isotope
effect,8 indicating that P-450, iron porphyrin, and tert-butoxy
radical oxidize alcohols to the carbonyl products by the same
reaction mechanism as suggested by Jones et al.8
c
c
In order to further investigate the electrophilic character of
the high-valent iron-oxo species, we carried out competitive
experiments of the oxidation of para-substituted phenethyl
alcohols to para-substituted acetophenones in this system. A
Hammett treatment of the data gave a good correlation against
+
r
and the slope of the Hammett plot, q, was determined to
1
8
of O of the cyclohexanone. If the two pathways are allowed,
the content of O of the product should always be close to 50%
irrespective of the varying amounts of labeled water because
be −1.34 (see Fig. 1; correlation coefficient = 0.95). This is very
1
8
close to the values −1.19 and −1.41 obtained from the oxidation
7
of phenethyl alcohols by P-450 enzymes, supporting, again, the
1
8
H
2
O exists at a large excess compared to the oxidant, the source
conclusion that P-450 and iron porphyrin oxidize alcohols to
carbonyl products by the same reaction mechanism.
1
6
of the O atom.
Scheme 1 Proposed mechanism for alcohol oxidation by the high-
valent iron-oxo species.
To distinguish pathway B from pathway A, we have examined
the kinetic isotope effect (KIE) that has been used extensively
as a mechanistic probe in alkane hydroxylation by both P-450
8
enzymes and metalloporphyrin models. Jones et al. recently
found that the k
H
/k values of P-450-mediated H-atom abstrac-
D
Fig. 1 Hammett plot for relative reactivities of para-substituted
tion from several substrates are nicely correlated with those
of H-atom abstraction by the tert-butoxy radical, providing
evidence for a common H-atom abstraction mechanism.8 In
addition, Shaik et al. have supported the concept of Jones’s
KIE by using density functional theory calculations that the
hydrogen abstraction reaction by the tert-butoxy radical models
phenethyl alcohols to phenethyl alcohol.
c
Cyclopropyl-substituted alkanes have been frequently used
as a mechanistic probe for radical intermediate vs. direct
insertion because their ring-opening rates vary according to
9
10
the bond activation in C–H hydroxylation by P-450 enzymes.
their substituents. We have chosen the commercially available
Since the fact that the tert-butoxy radical oxidation of substrates
falls on the same line as the benzyl alcohol in isotope effect
profiles can be taken as evidence that the alcohol oxidations
also proceed by a hydrogen atom transfer mechanism, we
have carried out intermolecular competitive alcohol oxidation
cyclopropylmethyl carbinol for this study. The rate constants for
the ring opening of the secondary cyclopropylmethyl carbinyl
radical and the tertiary a-methylcyclopropylmethyl carbinyl
8
8
−1
radical were reported as 0.70 × 10 and 0.88 × 10 s at
◦
11
37 C, respectively, but the ring opening rate for the a-
hydroxycyclopropylmethyl carbinyl radical derived from the
cyclopropylmethyl carbinol is not available. However, this is
not a matter for concern, because this alcohol oxidation
occurs in open solution and the radical generated by the high-
valent iron-oxo can move freely, not in the compact active-site
like P-450. This means that the ring opening rate of the a-
hydroxycyclopropylmethyl carbinyl radical is actually the same
with benzyl alcohol and benzyl alcohol-d . This reaction was
8
carried out in the presence of an excess of substrate, since
further oxidation of the benzaldehyde, derived from benzyl
alcohol, to benzoic acid prevents the determination of the
exact KIE value. When 70 equiv excess of a mixture of benzyl
alcohol (0.1 mmol) and deuterated benzyl alcohol (0.6 mmol)
compared to MCPBA (0.01 mmol) was used, benzaldehyde
and deuterated benzaldehyde were exclusively obtained with
trace amounts of benzoic acid and deuterated benzoic acid,
producing a reliable KIE value (see the Experimental section
for more details). The kinetic isotope effect for benzaldehyde
formation by 1 and MCPBA was determined to be 3.3 ± 0.3
which is virtually equal to that (3.6 ± 0.4) of a corresponding
9
−1
as the diffusion-controlled rate (≈10 s ), the radical escape
rate from the solvent cage. Keeping this idea in mind, we have
examined the oxidation reaction of cyclopropylmethyl carbinol
with our catalytic system to measure the rebound rate constant,
if possible (Table 1, entry 16). The reaction produced exclusively
the unrearranged product, cyclopropylmethyl ketone, without
4
0 4
D a l t o n T r a n s . , 2 0 0 5 , 4 0 2 – 4 0 6

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any ring-opened products. This result also suggests two scenarios
like Scheme 1: (1) pathway A; direct C–H bond insertion by the
high-valent iron-oxo and (2) pathway B; rebound mechanism
with a high rebound rate constant (>10 s ) greater than the
diffusion-controlled rate.
Packard Model 5989B mass spectrometer or a Donam Systems
6200 gas chromatograph equipped with a FID detector using
30 m capillary column (Hewlett-Packard, HP-1, HP-5, and
Ultra 2).
1
1
−1
We prefer, again, the pathway B rebound mechanism that can
be explained by a two-state reactivity mechanism as proposed
by Shaik et al. In the two-state mechanism, there will be a
Catalytic alcohol oxidations by 1 with MCPBA
5
To a mixture of substrate (0.0175 mmol), iron porphyrin 1 (1 ×
−
3
10
mmol), and solvent (CH
2
Cl
2
/CH
3
CN = 1/1, 0.5 mL) was
preference for the low-spin path, because the low-spin path
has a slightly lower bond activation barrier than the high-spin
path. Based on a comparison of the properties of the high-spin
transition and the low-spin transition state, this preference will
increase when the substrate becomes a better electron donor.
Therefore, alcohol oxidation will follow the low-spin path,
increasing the ratio of unrearranged to rearranged products,
because the C–H bond of the alcohol is weaker than the normal
added MCPBA (0.035 mmol). The mixture was stirred for 10 min
at room temperature. Reaction conversion was monitored by
GC/Mass analysis of 20 lL aliquots withdrawn periodically
from the reaction mixture. All reactions were run at least
three times and the average conversion and product yields are
presented. Conversion yields were based on the consumption of
the starting alcohols.
12
alkane, and thus is a better electron donor. Density functional
theory also shows that as both the substrate and its hydrogen-
abstracted radical become better electron donors, the amount
of radical rearrangement will decrease quite quickly.5 The a-
hydroxyalkyl radical species generated from hydrogen atom
abstraction of the alcohol substrate by high-valent iron-oxo is
a better electron donor due to the lower ionization energy than
the alkyl radical obtained from alkanes, resulting in the a-
hydroxyalkyl radical also following the barrierless low-spin path
for the rebound step. Consequently, as both the alcohol and
the corresponding a-hydroxyalkyl radical become better electron
donors, the rebound rate constant will increase and virtually no
rearrangement could be detected. Therefore, it might be more
difficult to observe the rearranged products derived from the
a-hydroxyalkyl radical in alcohol oxidation by iron porphyrins
and P-450 enzymes.
Competitive alcohol oxidations by 1 with MCPBA
In a competitive reaction of 1-hexanol and 3-hexanol, an
excess of substrates was used, because the product of 1-
hexanol, 1-hexanal, underwent further oxidation to 1-hexanoic
c
acid. To a mixture of 1-hexanol (0.125 mmol) and 3-hexanol
−3
(
0.125 mmol), iron porphyrin 1 (1 × 10 mmol), and sol-
13
vent (CH
(
2
Cl
2
/CH
3
CN = 1/1, 0.5 mL) was added MCPBA
0.01 mmol). The mixture was stirred for 10 min at room
temperature. Reaction conversion was monitored by GC/Mass
analysis of 20 lL aliquots withdrawn periodically from the
reaction mixture. All reactions were run at least three times
and the average conversion and product yields are presented.
Reaction conditions for the competitive reaction of cis-2- and
trans-2-methylcyclohexanol were the same as described above
except that 0.02 mmol of each substrate was used instead of
0
.125 mmol.
Conclusion
1
8
18
O-labeled H
2
O experiments
We have studied the systematic oxidations of a wide range
of alcohols catalyzed by the iron porphyrin complex in order
to understand and compare the alcohol oxidation mecha-
nism by an iron porphyrin model system and P-450 enzymes
and reported for the first time that an iron porphyrin com-
plex catalyzes efficiently alcohol oxidation to the carbonyl
To a mixture of cyclohexanol (0.005 mmol), 1 (0.001 mmol), and
H
dried solvent mixture (0.5 mL) of CH Cl and CH CN (1 : 1)
was added MCPBA (0.0025 mmol). The reaction mixture was
stirred for 2 min at room temperature and then directly analyzed
1
8
18
2
O (5–20 lL, 95% O enriched, Aldrich Chemical Co.) in a
2
2
3
1
6
18
compound via a high-valent iron-oxo porphyrin intermediate
by GC/Mass. The O and O composition in cyclohexanone
were determined by the relative abundance of mass peaks at
+
(
(Porp)Fe=O ). In addition, several mechanistic studies such
1
8
16
18
as isotope O labeling, deuterium isotope effect, linear free
energy relationship, and ring-opening of radical clock substrate,
and application of two-state reactivity mechanism led us to
conclude that an a-hydroxyalkyl radical intermediate is involved
in the oxidation of alcohols by this iron porphyrin complex as
m/z = 99 for O and m/z = 101 for O. All reactions were run
at least three times and the average values are presented.
Kinetic isotope effect for the benzyl alcohol oxidation by 1 with
MCPBA
7,14
proposed in cytochrome P-450 enzymes
and that pathway
This reaction was carried out in the presence of an excess of
substrate, since further oxidation of the benzaldehyde, derived
from benzyl alcohol, to the benzoic acid prevents the determi-
nation of the exact KIE value. Moreover, in order to improve
the accuracy for measuring the amount of deuterated benzyl
alcohol product, a 1 : 6 mixture of benzyl alcohol and deuterated
benzyl alcohol was used. The reaction conditions are as follows:
To a mixture of benzyl alcohol (0.1 mmol), deuterated benzyl
B in Scheme 1 best describes the oxidation of alcohols by
Fe(porp)/MCPBA. Moreover, this catalytic system might have
a practical application to organic synthesis.
Experimental
Materials
−
3
[
(F20TPP)FeCl] (tetrakis(pentafluorophenyl)porphinatoiron
alcohol (0.6 mmol), iron porphyrin 1 (1 × 10 mmol), and
chloride) (1) was purchased from Aldrich Chemical Co. Methy-
lene chloride and acetonitrile were purchased from Aldrich
Chemical Co. and used without further purification. All chem-
icals obtained from Aldrich Chemical Co. were of the best
available purity and were used without further purification
solvent (CH Cl /CH CN = 1/1, 0.5 mL) was added MCPBA
2
2
3
(0.01 mmol). The mixture was stirred for 10 min at room
temperature. Reaction conversion was monitored by GC/Mass
analysis of 20 lL aliquots withdrawn periodically from the
reaction mixture. All reactions were run at least three times and
the average KIE value is presented.
1
8
18
unless otherwise indicated. MCPBA (65%) and H
enrichment) were purchased from Aldrich.
2
O (95% O
Competitive reactions of phenethyl alcohol and para-substituted
phenethyl alcohols for Hammett plot
Instrumentation
1
8
Product analyses for the alcohol oxidation and O incorporation
of cyclohexanone were performed on either a Hewlett-Packard
5
To a mixture of phenethyl alcohol (0.01 mmol) and para-
(X)-substituted phenethyl alcohol (0.01 mmol, X = -OCH
3
,
, -F, and -Br), iron porphyrin 1 (1 × 10− mmol), and
3
890 II Plus gas chromatograph interfaced with a Hewlett-
-CH
3
D a l t o n T r a n s . , 2 0 0 5 , 4 0 2 – 4 0 6
4 0 5

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solvent (CH
2
Cl
2
/CH
3
CN = 1/1, 0.5 mL) was added MCPBA
T. Higuchi, Y. Urano, K. Kikuchi and T. Nagano, J. Inorg. Biochem.,
2000, 82, 127–132; (q) F. Hino and D. Dolphin, Chem. Commun.,
(
0.01 mmol). The mixture was stirred for 10 min at room temper-
1
999, 629–630; (r) M. W. Nee and J. R. Lindsay Smith, J. Chem.
ature. The amounts of alcohol before and after the reactions were
determined by GC. The relative reactivities were determined
Soc., Dalton Trans., 1999, 3373–3377; (s) K. Weitzerbin, J. G. Muller,
R. A. Jameton, G. Pratviel, J. Bernadou, B. Meunier and C. J.
Burrows, Inorg. Chem., 1999, 38, 4123–4127; (t) Z. Gross and S. Ini,
J. Org. Chem., 1997, 62, 5514–5521; (u) R. J. Balahura, A. Sorokin,
J. Bernadou, B. Meunier and C. J. Burrows, Inorg. Chem., 1997, 36,
3488–3492.
using the following equation: k
where X and X are the initial and final concentrations of
substituted phenethyl alcohols and Y and Y are the initial
x
/k
y
= log(X
f
/X
i
)/log(Y
f
/Y )
i
i
f
i
f
15
and final concentrations of phenethyl alcohol.
4
5
In epoxidation of allylic alcohols by iron porphyrin complex [(TD-
CPP)FeCl] with PhIO, Adam et. al. reported that, only in the case
of 4-hydroxy-2-pentene, a small amount of ketone was formed with
epoxide as a major product: W. Adam, V. R. Stegmann and C. R.
Saha-Moller, J. Am. Chem. Soc., 1999, 121, 1879–1882.
Acknowledgements
This work was supported by the Korea Research Foundation
DP0270).
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