Mechanistic insight into alcohol oxidation by high-valent iron-oxo complexes of heme and nonheme ligands

Article abstract of DOI:10.1002/anie.200500623

(Chemical Equation Presented) Iron-mediated oxidation: High-valent iron(IV)-oxo complexes of heme and nonheme ligands are generated in situ and are used in mechanistic studies of alcohol oxidation (see scheme). It is proposed that the oxidation of alcohols occurs by an α-CH hydrogen atom abstraction followed by electron transfer. Porp = porphyrin.

Full text of DOI:10.1002/anie.200500623

Angewandte
Chemie
Reaction Mechanisms
Mechanistic Insight into Alcohol Oxidation by
High-Valent Iron–Oxo Complexes of Heme and
Nonheme Ligands**
Na Young Oh, Yumi Suh, Mi Joo Park, Mi Sook Seo,
Jinheung Kim,* and Wonwoo Nam*
High-valent iron–oxo species are frequently invoked as the
key intermediates in the catalytic oxidation of organic
substrates by heme and nonheme iron mono-oxygenases.[1,2]
In the case of heme-containing enzymes such as cyto-
chromes P450, oxoiron(iv) porphyrin p-cation radicals have
been proposed as active oxidants that effect a number of
oxidation reactions, which include alkane hydroxylation,
olefin epoxidation, and alcohol oxidation.[1] Indeed,
a
number of synthetic oxoiron(iv) porphyrin p-cation radicals
have been prepared and used in mechanistic studies of alkane
hydroxylation and olefin epoxidation.[3] In mononuclear
nonheme iron enzymes, oxoiron(iv) intermediates have
been unveiled very recently in enzymatic and biomimetic
reactions.[4–6] The mononuclear nonheme oxoiron(iv) species
have been well-characterized with various spectroscopic
techniques and with X-ray crystallography and were shown
to be active in a variety of oxidation reactions such as alkane
hydroxylation, olefin epoxidation, and the oxidation of
sulfides and PPh3.[4–6]
The oxidation of alcohols to the corresponding carbonyl
compounds is an important chemical process in industrial and
[*] N. Y. Oh,+ Y. Suh,+ M. J. Park, Dr. M. S. Seo, Prof. Dr. J. Kim,
Prof. Dr. W. Nam
Department of Chemistry
Division of Nano Sciences and Center for Biomimetic Systems
Ewha Womans University
Seoul 120-750 (Korea)
Fax: (+82)2-3277-4441
E-mail: jinheung@ewha.ac.kr
wwnam@ewha.ac.kr
[+] These authors contributed equally to this work.
[**] This research was supported by the Ministry of Science and
Technology of Korea through Creative Research Initiative Program.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500623
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Communications
biological reactions.[7,8] Thus, tremendous effort has been
devoted to developing environmentally benign catalysis and
bioinspired oxidation reactions. In the latter case, the
oxidation of alcohols by synthetic copper complexes has
been intensively investigated as chemical models of galactose
oxidase (GOase).[9,10] It has been also shown that cyto-
chromes P450 and their model compounds are able to
catalyze the oxidation of alcohols,[11,12] although mechanistic
details of iron-complex-mediated alcohol oxidation have
never been investigated with in situ generated intermediates
of oxoiron(iv) porphyrin p-cation radicals. In the present
work, we carried out alcohol oxidation reactions with
spectroscopically well characterized oxoiron(iv) porphyrin
+
+
+
p-cation radicals, [(tdcpp)C FeIV O] (1a) and [(tmp)C FeIV
=
=
Scheme 1. Structures of heme and nonheme ligands of the iron
complexes 1a–d used in this study.
O]+ (1b),[13] and mononuclear nonheme oxoiron(iv) com-
plexes, [(tpa)FeIV O]2+ (1c)[5b] and [(N4Py)FeIV O]2+ (1d)[5c]
(see Scheme 1 for structures of heme and nonheme
ligands).[14] To the best of our knowledge, this study provides
the first mechanistic details of alcohol oxidation with
oxoiron(iv) complexes generated in situ, which bear heme
and nonheme ligands.
=
=
decay as monitored by a UV/Vis spectrophotometer (see
Figure 1a for 1d and Supporting Information for 1a–c).
Pseudo-first-order fitting of the kinetic data allowed us to
determine kobs values for the reactions of 1a–d (Table 1; kobs is
the observed rate constant), and product analysis of the
resulting solutions with HPLC and GC revealed that benzal-
dehyde was produced with high yields in all of the reactions
(> 70% based on the intermediates generated; Scheme 2).
The pseudo-first-order rate constants increased propor-
tionally with benzyl alcohol concentration, thus leading us to
determine second-order rate constants (see Table 1, Fig-
ure 1b, and Supporting Information). We then determined
activation enthalpy, entropy, and Gibbs energy (DH°, DS°,
The high-valent iron–oxo complexes were prepared by
using reported methods (see Supporting Information), and
kinetic studies with benzyl alcohol were performed at differ-
ent temperatures due to the different reactivity of the
oxoiron(iv) complexes in the oxidation reactions; reaction
temperatures were À1008C for 1a, À608C for 1b, À408C for
1c, and 08C for 1d. Upon adding 25 equivalents of benzyl
alcohol to the solutions of 1, the intermediates reverted back
to the starting iron complexes and showed pseudo-first-order
Figure 1. Reactions of 1d with benzyl alcohols at 08C. a) UV/Vis spectral changes of 1d (2 mm) upon addition of 25 equivalents of benzyl alcohol
(50 mm, interval 300 s, A=absorbance). Inset shows absorbance traces monitored at 695 nm. b) Plot of kobs against the concentration of benzyl
alcohol to determine a second-order rate constant. c) Plot of first-order rate constants against 1/T to determine activation parameters.
d) Hammett plot of logkrel against substituent constants sp of benzyl alcohols. The krel values were calculated by dividing kobs of para-X-benzyl
alcohol by kobs of benzyl alcohol.
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Table 1: Kinetic parameters determined in the oxidation of benzyl alcohol by oxoiron(iv) complexes of
classical KIE values indicate that
heme and nonheme ligands.[a]
heme and nonheme oxoiron inter-
mediates activate alcohols exclu-
sively by hydrogen atom abstrac-
tion from the a-CH of benzyl
Intermediate[b]
T [oC]
kobs [10À3 sÀ1
]
k2 [10À1 mÀ1 sÀ1 [c]
]
DG°
kH/kD
1[f]
[e]
[kcalmolÀ1 [d]
]
1a
1b
1c
1d
À100
À60
À40
0
6.9Æ0.3
3.5Æ0.2
5.5Æ0.3
1.4Æ0.1
1.7Æ0.2
11Æ1
16Æ2
16Æ2
20Æ2
21Æ3
À0.39
À0.43
À0.06
À0.07
>20 [g]
58Æ5
48Æ4
À
alcohol and that C H bond cleav-
0.84Æ0.03
1.2Æ0.1
age is the rate-determining step in
the alcohol oxidation.[10a,c,17–19]
Consistent with this mechanism,
0.31Æ0.02
[a] See Supporting Information for detailed reaction procedures. [b] Intermediates were prepared as
described in the Supporting Information. [c] k2 is the second-order rate constant, see Figure 1b and
Supporting Information. [d] Data of DH° and DS° are reported in Figure 1c and Supporting
Information. [e] Data of kH and kD are listed in Supporting Information; kH is the rate constant obtained
with C6H5CH2OH, kD is the rate constant obtained with C6D5CD2OH. [f] See Figure 1d and Supporting
Information. 1=Hammett reaction constant. [g] The kD value was similar to the natural decay of 1b,
which indicates that the kH/kD value should be greater than that reported. See the kD value and the rate of
natural decay of 1b in Supporting Information.
studies
with
para-substituted
benzyl alcohols reveal that the
reaction rates are not greatly influ-
enced by the electron-withdrawing
and electron-donating ability of the
para substituents and that plotting
the rates as a function of sp of the
substituents affords small Ham-
mett 1 values (see Table 1, Figure 1d, and Supporting
Information). It is of interest to note that Hammett 1 values
obtained in the reactions of GOase and its model compounds
are small (e.g., ꢀ À0.1)[17,18] and that the Hammett 1 values
of synthetic oxoiron(iv) porphyrin p-cation radicals, 1a and
1b, are similar to those reported in cytochrome P450 enzymes
(e.g., ꢀ À0.4).[11]
Scheme 2. Oxidation of benzyl alcohol by high-valent iron–oxo
complexes of heme and nonheme ligands.
We then studied cyclobutanol oxidation with the oxo-
iron(iv) species, as the substrate has been often used as a
mechanistic probe to distinguish a one-electron versus a two-
electron process in alcohol oxidation by high-valent transi-
tion-metal oxidants.[21] For example, if cyclobutanone is
produced predominantly, then the reaction occurs by hydro-
gen atom abstraction followed by an electron transfer (i.e., a
two-electron process, see Scheme 3, pathway A). If a carbon
and DG°) for the benzyl alcohol oxidation with 1 by plotting
first-order-rate constants determined at different temper-
atures against 1/T (see Table 1, Figure 1c, and Supporting
Information). Taking into consideration that the reactions
were performed at different temperatures, we find the kinetic
and activation parameters indicate that the relative reactiv-
ities of oxoiron(iv) complexes are in the order of 1a > 1b >
1c > 1d. The greater reactivity of oxoiron(iv) porphyrin p-
cation radicals compared to nonheme oxoiron(iv) complexes
is rationalized with the higher oxidation state of the iron
center in oxoiron(iv) porphyrin p-cation radicals (i.e., the
formal oxidation states of FeV and FeIV in oxoiron(iv)
porphyrin p-cation radical and nonheme oxoiron(iv) species,
respectively).[15] In the case of oxoiron(iv) porphyrin p-cation
radicals, it has been well documented that the reactivity of
electron-deficient iron porphyrins is greater than that of
electron-rich iron porphyrins.[16] It has been also shown that
the reactivity of nonheme oxoiron(iv) species is dependent on
the ligand architecture,[5a–c] and the results presented herein
demonstrate that 1c is more reactive than 1d in alcohol
oxidation.
Scheme 3. Oxidation of cyclobutanol by heme and nonheme
oxoiron(iv) complexes.
radical formed by hydrogen atom abstraction of cyclobutanol
escapes from the solvent cage, a ring-opened product, 4-
hydroxybutyraldehyde, is formed (Scheme 3, pathway B).[21a]
In the present study, when the oxidation of cyclobutanol was
carried out with two oxoiron(iv) complexes, 1a and 1c, we
found that cyclobutanone was formed exclusively (80–90%
yields; see Supporting Information), thus demonstrating that
the alcohol oxidation by heme and nonheme oxoiron(iv)
complexes proceeds by a two-electron process (Scheme 3,
pathway A). A similar observation was reported in the
oxidation of cyclobutanol by FeIVO2+ in aqueous solution.[21a]
Finally, the oxidation of benzyl alcohol was carried out
The kinetics of benzyl alcohol oxidation have also been
measured with [D7]-deuterated benzyl alcohol (C6D5CD2OH)
À
to investigate the C H kinetic isotope effect (KIE). The KIE
values determined were large in all of the reactions (see
Table 1 and Supporting Information), and such large KIE
values have also been observed in GOase[17] and its mod-
els[10a,c,18] as well as in the oxidation of benzyl alcohol by high-
valent ruthenium-oxo complexes[19] and hydrogen atom
abstraction reactions by the iron(iv) intermediates of mono-
iron Taurine/a-Ketoglutarate Dioxygenase (TauD)[4b] and
diiron methane monooxygenase enzymes.[20] The large, non-
with an 18O-labeled oxoiron(iv) complex, [(N4Py)FeIV 18O]2+
=
([18O]1d), to understand whether the final step of the alcohol
oxidation is the dehydration of a gem-diol intermediate or
hydride transfer in the solvent cage to yield a carbonyl
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product (Scheme 4). We therefore prepared [18O]1d by
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=
Scheme 4. Proposed mechanism for the oxidation of alcohol by heme
and nonheme oxoiron(iv) complexes.
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We have also reported mechanistic details of alcohol oxida-
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valent iron–oxo complexes of heme and nonheme ligands.
The reactivity of heme and nonheme oxoiron(iv) complexes
has been briefly compared as well. Finally, we have proposed
a plausible mechanism for alcohol oxidation by heme and
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alcohols occurs by an a-CH hydrogen atom abstraction
followed by electron transfer (Scheme 4, pathways A and C).
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Received: February 21, 2005
Published online: June 2, 2005
Keywords: alcohols · enzyme models · iron · oxidation ·
.
reaction mechanisms
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N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)me-
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