Olefin-dependent discrimination between two nonheme HO-Fev=O tautomeric species in catalytic H2O2 epoxidations

Article abstract of DOI:10.1002/chem.200802597

A study was conducted to demonstrate olefin-dependent discrimination of two nonheme HO-Fe^v=O tautomeric species in catalytic H₂O ₂ epoxidations. Mechanistic studies were carried out under the condition of excess of olefin to minimize over-oxidation reactions and all reactions for the study were carried out under a N₂ atmosphere to prevent auto-oxidation process due to presence of O₂. It was observed that the diol/epoxide (D/E) ration for these reaction was dependent on the specific olefin and ranged from 3/2 (cyclooctene) to 6/1 (1-octene). The oxidation of cyclooctene using H₂¹⁸O₂ revealed that only 28% of the oxygen atoms in the epoxide derived from H ₂O₂. Mechanistic results suggested that HO-Fe ^v=O oxidant need to be labeled before its reaction with substrates.

Full text of DOI:10.1002/chem.200802597

COMMUNICATION
DOI: 10.1002/chem.200802597
V
ꢀ
Olefin-Dependent Discrimination between Two Nonheme HO Fe =O
Tautomeric Species in Catalytic H2O2 Epoxidations
Anna Company,[a] Yan Feng,[c] Mireia Gꢀell,[b] Xavi Ribas,[a] Josep M. Luis,[b]
Lawrence Que, Jr.,*[c] and Miquel Costas*[a]
Nonheme iron oxygenases are emerging as versatile bio-
logical catalysts for a number of oxidative processes with
biomedical, environmental, and technological implications.[1]
Their heme counterparts are commonly taken as precedents
for their chemistry.[2] In the heme paradigm, O O heterolyt-
ꢀ
ic cleavage of an FeIII OOH intermediate affords a high-
ꢀ
valent metal–oxo species that acts as the oxidant for the re-
action (Scheme 1). Although nonheme iron oxygenases are
Scheme 1.
Scheme 2.
less well understood, evidence has accumulated in the last
few years that high-valent iron–oxo species are also involved
V
[5]
ꢀ
dations occur via a high-valent HO Fe =O species. We
have also shown that 1 is an excellent olefin oxidation cata-
lyst, affording large turnover numbers (TNs) of epoxide and
cis-dihydroxylation products with unprecedented efficiency
(Scheme 2, bottom).[6,7] Surprising mechanistic insights into
these reactions are described in the present work, which
show a reaction mechanism that does not conform to the
canonical heme oxygenase paradigm.
in some of their catalytic pathways.[3] Furthermore,
a
number of synthetic model complexes have been de-
scribed.[4]
We have recently described that [FeACTHNUTRGNEUNG
(OTf)2(Me2PyTACN)]
(1) (OTf=CF3SO3, Scheme 2) is a stereoselective alkane hy-
droxylation catalyst in combination with H2O2, and that oxi-
Mechanistic studies were run under conditions of a large
excess of olefin to minimize overoxidation reactions and
also due to limitations imposed by the use of isotopically la-
beled compounds (vide infra). All the reactions were run
under a N2 atmosphere to avoid autooxidation processes
due to the presence of O2. In a typical experiment, 10 equiv
of H2O2 (70 mm solution in CH3CN) were delivered by sy-
ringe pump together with 1000 equiv of H2O over a period
of 30 min into an acetonitrile solution containing 1 equiv of
the iron catalyst 1 (final concentration=1 mm) and the spe-
cific alkene (0.05–1m). In all olefin oxidation reactions ex-
plored (Table 1), mixtures of cis-diol and epoxide were ob-
tained with modest to excellent efficiency in the conversion
of H2O2 into products (3.9 to 7.8 TN, maximum TN=9.5).
The diol/epoxide (D/E) ratio observed in these reactions
was dependent on the specific olefin, and it ranges from 3/2
[a] Dr. A. Company, Dr. X. Ribas, Dr. M. Costas
Departament de Quꢀmica. Universitat de Girona
Campus de Montilivi, 17071, Girona (Spain)
Fax : (+34)972-41-81-50
E-mail: miquel.costas@udg.edu
[b] M. Gꢁell, Dr. J. M. Luis
Institute of Computational Chemistry
Universitat de Girona
Campus de Montilivi, 17071, Girona (Spain)
[c] Y. Feng, Prof. Dr. L. Que, Jr.
Department of Chemistry and Center for Metals in Biocatalysis
University of Minnesota
207 Pleasant Str SE Mpls, MN, 55545 (USA)
Fax : (+1)612-624-7029
E-mail: larryque@umn.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802597.
Chem. Eur. J. 2009, 15, 3359 – 3362
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3359

Table 1. Olefin oxidation reactions catalyzed by iron catalysts 1–3 (1 mm)
in the presence of 1m H218O under N2.
and terminal olefins afforded epoxides with 69ꢁ6% of the
oxygen from water, while the level of water incorporation in
trans-disubstituted olefins was 33ꢁ3%. For comparison, ep-
oxidation reactions of cis-2-heptene, trans-2-heptene, and 1-
octene catalyzed by 2 and 3 exhibited a level of water incor-
poration into epoxide products that was substrate-independ-
ent, 11ꢁ1% for 2 and 22ꢁ1% for 3. Lastly, because of the
high extent of label incorporation observed for 1-catalyzed
epoxidations, the dependence of label incorporation on sub-
strate concentration could be investigated (Table 1). Inter-
estingly, no dependence was found, demonstrating that label
exchange must be faster than the substrate oxidation step
and does not compete with it.
We considered different options to rationalize the unex-
pectedly high level of water incorporation into the epoxide
products for most of the olefins studied. The possibility that
a radical cation intermediate was initially formed and subse-
quently trapped by water was discarded, because the in-
volvement of a substrate radical species with a significant
lifetime was inconsistent with the high retention of configu-
ration observed for the epoxidation and cis-dihydroxylation
Cat. Substrate
Cat:Ox:S[a] D[b]/E[c]
16O18O[d,f] 18O[e,f]
1
1
1
1
1
1
1
1
1
1
2
2
2
3
3
3
1-octene
1:10:1000
1:10:1000
1:10:1000
1:10:1000
1:10:1000
1:10:770
1:10:250
1:10:50
6.3/1.1
85
64
30
35
32
64
67
70
69
65
75
11
11
12
22
23
21
trans-2-octene
trans-3-octene
trans-4-octene
cis-2-heptene
cis-2-heptene
cis-2-heptene
cis-2-heptene
cyclooctene
2.6[g]/1.3 77
3.7[g]/1.6 80
3.7[g]/2.1 74
3.0[h]/1.2 77
3.5[h]/1.8 87
3.3[h]/1.5 81
3.5[h]/1.5 83
1:10:1000
4.7/3.1
2.0/1.8
2.3/0.9
88
91
96
2-methyl-2-heptene 1:10:50
1-octene
1:10:1000
1:10:1000
1:10:1000
1:10:1000
1:10:1000
1:10:1000
trans-2-heptene
cis-2-heptene
1-octene
trans-2-heptene
cis-2-heptene
1.8[g]/1.8 95
1.5[h]/2.3 95
2.9/0.5
75
2.1[g]/2.6 70
1.8[h]/0.7 66
[a] Catalyst:H2O2:substrate. See Supporting Information for experimental
details. [b] cis-diol[8] (TN). [c] Epoxide (TN). [d] Percentage of diol
16O18O-labeled. See Supporting Information for experimental details.
[e] Percentage of epoxide 18O-labeled. [f] Remaining product is exclusive-
ly 16O-labeled. [g] 95% threo-vic-diol. [h] 95% erythro-vic-diol.
of cis-2-heptene (97% cis-epoxide and 95% erythro-vic-diol,
V
ꢀ
(cyclooctene) to 6/1 (1-octene). Oxidation of cis-2-heptene
by 1 was syn-stereospecific and afforded 3.5 TN of diol
(95% erythro-vic-diol)[8] and 1.8 TN of epoxide (97% cis).
Insight into the olefin oxidation mechanisms was obtained
by means of isotopic labeling with H218O2 and H218O. Studies
of the oxidation of cyclooctene using H218O2 indicated that
only 28% of the oxygen atoms in the epoxide derived from
H2O2. Complementary experiments carrying out the oxida-
tion in the presence of H218O (1000 equiv) showed 65% in-
corporation of oxygen atoms from water into the epoxide.
On the other hand, 88% of the cis-diol product contained
one oxygen atom derived from H2O2 and one oxygen atom
from H2O. Oxidation of cyclooctene under analogous condi-
tions as a function of the amount of H218O added to the re-
action mixture showed that the fractions of labeled epoxide
and cis-diol increased linearly with [H218O] at lower concen-
trations but reached a plateau at higher concentrations (see
Figure S1 in the Supporting Information), indicative of a sat-
uration behavior. These data strongly implicate a reversible
water binding step (Scheme 3) prior to the generation of the
species responsible for olefin oxidation.[9]
respectively). The possibility that the HO Fe =O oxidant
became doubly labeled by rapid, multiple intermolecular ex-
changes with H218O prior to its attack of the olefin substrate
was also eliminated, because epoxide and cis-diol[8] are
formed in parallel, and doubly labeled cis-diol[8] product was
not observed under any studied conditions.
These experiments led us to several mechanistic conclu-
sions. First, the only oxidant in this catalytic system is the
HO Fe =O species. Were its Fe OOHACTHNUTRGEN(UNG OH2) precursor
also an oxidant, no label incorporation from water would
occur in this pathway, so the extent of label incorporation
from water into products would have been observed to de-
crease with increasing substrate concentration. Furthermore,
oxo–hydroxo tautomerism of the HO Fe =O oxidant must
V
III
ꢀ
ꢀ
V
ꢀ
be fast relative to substrate oxidation to explain the lack of
a substrate-concentration dependence on the extent of 18O
label incorporation from water. This conclusion suggests
that the HO Fe =O oxidant must be fully labeled prior to
V
ꢀ
its reaction with either substrate and that the different ex-
tents of label incorporation are a result of specific interac-
tions between substrate and oxidant. Support for this latter
notion was found in the competitive oxidation of cis-2-hep-
tene and trans-2-octene in the presence of H218O
(Scheme 4). Interestingly, cis-2-heptene was found to be
Much more surprising were labeling results for epoxida-
tions catalyzed by 1, in which all epoxides showed a much
higher incorporation of oxygen atoms from water (30–75%)
than found for [Fe
N
2ACHTUNGTNER(NUNG TPA)]
(2) and [Fe(OTf) CHTUNGTRENNUNG
G
(3) (Table 1). Indeed, the activi-
ty of 1 is unprecedented as
water is the main source of
oxygen atoms in the epoxida-
tion of most of the substrates
studied. In addition, the extent
of label incoporation depended
on the nature of the olefin. cis-
Disubstituted,
trisubstituted, Scheme 3.
3360
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3359 – 3362

Olefin-Dependent Discrimination
COMMUNICATION
The accumulated labeling results for olefin epoxidation
reactions catalyzed by 1 present a new twist in the reactivity
of the high-valent species (OA and OB). Despite the large
differences in the degree of label incorporation (30–75%,
Table 1), these values in fact translate into only small differ-
ences in energy, comparable to those associated with chiral
discrimination. Catalyst 1 may give rise to the novel labeling
V
ꢀ
results we observe because the two HO Fe =O oxidants
Scheme 4.
(OA and OB), though inequivalent, are quite close to each
other in energy (Scheme 5). According to this mechanistic
roughly five times more reactive than trans-2-octene, but
cis-2-heptene oxide incoporated 63% label, while trans-2-
octene epoxide incorporated only 34%, values similar to
those observed in the absence of the other olefin. In other
words, the faster reacting substrate incorporated more water
than the less reactive substrate. Thus the catalytic behavior
of 1 differs from that described for iron and manganese por-
phyrin catalysts, in which oxo–hydroxo tautomerism com-
petes with substrate oxidation by the high-valent species.[2,12]
In this porphyrin scenario the reactivity of a specific sub-
strate is inversely related to the level of water incorporation
into products. Clearly, a different mechanistic picture arises
from our results.
scenario, a C2-symmetric complex such as 3 should give rise
V
ꢀ
to symmetrically equivalent HO Fe =O species OA and OB,
and consequently, the level of water incorporation into
products must be substrate independent. This is indeed what
is observed in Table 1; olefin oxidations catalyzed by 3
afford epoxides incorporating 22ꢁ1% of oxygen from
water.
The mechanistic scenario arising from this study may be
related to aspects of the catalytic cycle of the a-KG-depen-
dent Cyt-C3 halogenase,[3e] in which two high-spin FeIVO(X)
(X=Cl or Br) intermediates have been characterized by
rapid-freeze–quench Mçssbauer experiments and found to
ꢀ
be directly responsible for the C H activation event. The
Scheme 5 shows a proposed mechanism for the action of 1
relative proportions of these two high-valent isomers remain
constant along the reaction coordinate, suggesting that fast
interconversion between them precedes substrate oxidation.
Indeed, the presence of nonequivalent cis-binding sites is a
common structural characteristic of a number of nonheme
iron oxygenases,[1] and therefore the interplay between two
isomerically related high-valent species may be a rather
common yet unexpected feature of their oxygen activation
chemistry, substantially different from heme systems. The
current study serves as a synthetic precedent for this novel
mechanistic feature and it calls into question the canonical
description of oxygenase action.[16]
where FeIIIOOH
ACHTUNGTRENNUNG(OH2) isomer PA is more populated than
isomer PB.[13] PA then undergoes rate-determining O O
bond cleavage and rapid oxo–hydroxo tautomerism to form
OA and OB prior to olefin attack. The subsequent reactions
of OA and OB occur at rates dependent on the structure of
the olefin substrate, that is, kA ¼ kB. Support for this pro-
posal is obtained by DFT calculations which indicate that
isomer PA is energetically favored over PB by 2 kcalmolꢀ1,
and the transition state of the heterolytic O–O cleavage of
PA to form OA is favored with respect to PB lysis by 4 kcal
molꢀ1.[14,15] As demonstrated by the H218O labeling experi-
ments presented above, trans-disubstituted olefins incorpo-
rate half as much label from H218O as cis-disubstituted, tri-
substituted, and terminal olefins. This difference indicates
that trans olefins prefer to react with OA (oxo group not la-
beled), whereas the other olefins react preferentially with
OB (oxo group labeled).
ꢀ
Experimental Section
Reaction conditions for catalysis: In a typical reaction, a 70 mm H2O2 so-
lution (0.36 mL, 25 mmol; diluted from a 35% H2O2 aqueous solution) to-
gether with H2O (45 mL, 2500 mmol) in CH3CN was delivered by syringe
pump over 30 min at 258C under N2 to a vigorously stirred CH3CN solu-
tion (2.14 mL) containing the iron catalyst (2.5 mmol) and the substrate
(2500 mmol). The final concentrations of the reagents were 1 mm iron cat-
alyst (1, 2, or 3), 10 mm H2O2, 1m H2O, and 1m substrate. After syringe
pump addition, the resulting solution was stirred for another 10 min. Ad-
dition of acetic anhydride (1 mL) together with 1-methylimidazole
(0.1 mL) afforded the esterification of the diol products. After the mix-
ture had been stirred for 15 min at room temperature, ice was added and
the mixture was stirred for about 30 min. Biphenyl or naphthalene (inter-
nal standard) was added at this point and the mixture was extracted with
CHCl3 (2 mL). The organic layer was washed with H2SO4 1m (2 mL), sa-
turated aqueous NaHCO3 (2 mL), and H2O (2 mL), dried with MgSO4,
and subjected to GC analysis. The organic products were identified by
comparison with authentic compounds.
Isotope labeling studies: Reaction catalytic conditions using H218O: In a
typical reaction, a 70 mm H2O2 solution (0.29 mL, 20 mmol; diluted from
a 35% H2O2 aqueous solution, 64 mmol H216O) in CH3CN together with
H218O (40 mL, 2000 mmol H218O) was delivered by syringe pump over
Scheme 5.
Chem. Eur. J. 2009, 15, 3359 – 3362
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3361

M. Costas, L. Que, Jr. et al.
30 min at 258C under N2 to
a
vigorously stirred CH3CN solution
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(1.71 mL) containing the iron catalyst (2.0 mmol) and the substrate
(2000 mmol). The final concentrations of reagents were 1 mm iron catalyst
(1, 2, or 3), 10 mm H2O2, 1m H218O/32 mm H216O, and 1m substrate. After
syringe pump addition, the resulting solution was stirred for another
10 min. The reaction solutions were treated with 1-methylimidazole
(0.1 mL) and acetic anhydride (1 mL) to esterify the diol products follow-
ing the experimental procedure described above. The products were ana-
lyzed by GC and GC-MS.
Reaction catalytic conditions using H218O2:
(0.29 mL, 20 mmol; diluted from
a
70 mm H218O2 solution
a
2% H218O2 aqueous solution,
2100 mmol H216O) in CH3CN was delivered by syringe pump over 30 min
at 258C under N2 to a vigorously stirred CH3CN solution (1.71 mL) con-
taining the iron catalyst (2.0 mmol) and cyclooctene (2000 mmol). The
final concentrations of reagents were 1 mm iron catalyst (1), 10 mm
H218O2, 1m H2O, and 1m cyclooctene. After syringe pump addition, the
resulting solution was stirred for another 10 min. The reaction solutions
were treated with 1-methylimidazole (0.1 mL) and acetic anhydride
(1 mL) to esterify the diol products following the experimental procedure
described above. The products were analyzed by GC and GC-MS.
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Full experimental data as well as details for the analysis of the isotopic
labeling studies are provided as Supporting Information.
[8] For simplicity, the cis-diol term will be used in this manuscript to
refer to the diol product resulting from a stereospecific cis-dihydrox-
ylation reaction.
[9] a) K. Chen, M. Costas, J. Kim, A. K. Tipton, L. Que, Jr., J. Am.
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Acknowledgements
Financial support from MCYT of Spain through project CTQ2006–05367/
BQU to M.C., and from the US Department of Energy (DE-FG02–
03ER15455) to L.Q. is gratefully acknowledged. A.C. and M.G. thank
MEC for PhD grants. The authors also thank Rahucat for a gift of 1,4,7-
tri(p-toluensulfonyl)-1,4,7-triazacyclononane.
Keywords: bioinorganic chemistry
nonheme oxygenases · oxidation · reaction mechanisms
· enzyme catalysis ·
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[13] Note that if peroxide binding and/or O–O breakage in species PA
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[14] DFT geometries were optimized at the B3LYP level in junction of
the LANL2DZ basis set with associated ECP for Fe as implemented
in the Gaussian 03 program. The energies were further refined by
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Received: December 10, 2008
Published online: February 19, 2009
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Chem. Eur. J. 2009, 15, 3359 – 3362