Fe2+-catalyzed heterolytic RO-OH bond cleavage and substrate oxidation: A functional synthetic non-heme iron monooxygenase system

Article abstract of DOI:10.1021/ja0286268

The reaction of [Fe₂²⁺(H₂Hbamb)₂(N-MeIm)₂], [1], a binuclear, non-heme iron complex, with 2-methyl-1-phenylprop-2-yl hydroperoxide (MPPH) shows that [1] induces heterolytic cleavage of the peroxy O-O

Full text of DOI:10.1021/ja0286268

Published on Web 03/06/2003
Fe2+-Catalyzed Heterolytic RO-OH Bond Cleavage and Substrate Oxidation:
A Functional Synthetic Non-Heme Iron Monooxygenase System
Trina L. Foster and John P. Caradonna*
Department of Chemistry, Boston UniVersity, Boston, Massachusetts 02215
Received September 20, 2002; E-mail: caradonn@bu.edu
Scheme 1
Nature has evolved a variety of strategies to utilize O2 for the
controlled oxidation of organic molecules.1,2 The formal incorpora-
tion of an oxygen atom into unactivated C-H bonds typically
requires the use of transition metal centers in either the reduction
of dioxygen to peroxide and/or in the formation of the reactive
intermediate responsible for the oxidation reaction.1,3,4 Two fun-
damental mechanistic features observed in both mono- and binuclear
non-heme iron-dependent monooxygenase pathways are (i) the
heterolytic O-O bond cleavage of an iron coordinated peroxide
ligand and (ii) the subsequent tightly coupled transfer of one oxygen
atom to substrate for each equivalent of dioxygen/peroxide con-
sumed.3,5 Despite significant advances in our understanding of the
structural, spectroscopic, and mechanistic issues of iron-based
enzymatic alkane oxidation processes, the development of synthetic
analogue systems that parallel key steps in the biological oxidation
of hydrocarbons is still a major challenge.6 Although synthetic ferric
mono- and binuclear model systems are reported to hydroxylate
organic substrates in the presence of dioxygen or peroxides, studies
implicate the significant involvement of oxygen-based free radical
chemistry initiated by the homolytic cleavage of the peroxy O-O
bond. We have previously reported the ability of a synthetic
binuclear ferrous compound, [Fe22+(H2Hbamb)2(N-MeIm)2], 17
(Figure 1), to catalyze the hydroxylation of alkanes, arenes, and
sulfides in the presence of oxygen atom donor (OAD) molecules.8
Herein, we report (i) the ability of 1 to induce heterolytic cleavage
of the alkyl hydroperoxide 2-methyl-1-phenylprop-2-yl hydroper-
oxide (MPPH) and (ii) the ability of 1 to efficiently catalyze the
oxidation of phenyl methyl sulfide and cyclohexane using MPPH
as the source of oxygen atom.
Table 1. Product Distributions for the Cleavage of MPPH by Iron
Complexes
products
products
heterolytic cleavagea,b
homolytic cleavagea,c
mass
species
%
T. N.
%.
T. N.
balanced
[Fe2+,Fe2+], 1
85 ( 1 44 ( 1
0 ( 0
0
101 ( 2
99 ( 1
[Fe3+,Fe3+], 2
0 ( 0
0 ( 0
0
0
37 ( 1 19 ( 1
µ-oxo-[Fe3+,Fe3+], 3
34 ( 2 17 ( 1 101 ( 2
a All reactions were performed with an excess of peroxide (52:1
MPPH(5.21 mM):iron complex(0.10 mM)) under strict anaerobic conditions
in MeOH for 6 h. Turnover numbers are corrected for nonmetal-catalyzed
products. b 1-Methyl-2-phenyl-propan-2-ol. c Phenyl methyl ether, bibenzyl,
benzyl alcohol and benzaldehyde were observed in a 50:10:7:1 ratio. Other
possible products, including toluene and benzoic acid, were below levels
of detection. d Quantitative analyses were performed by gas chromatographic
methods using chlorobenzene as internal standard.
hours. MPPH showed equivalent stability in the absence of metal
complexes; GC analyses and iodometric titration10 showed the
absence of either homolytic or heterolytic cleavage for a period
of 15 h. Parallel control reactions (absence of catalysts) were used
to correct for nonmetal-mediated peroxide cleavage. Total mass
balance of the parent peroxide and the various cleavage products
at the end of 6 h was obtained by GC analyses and iodiometric
titrations. The effect of iron core oxidation state on MPPH cleavage
pathway is dramatically shown in Table 1. After 6 h (room temper-
ature), approximately 90% of the initial [MPPH] (45 turnovers)
reacted with 1 by the heterolytic pathway to yield 2-methyl-1-
phenyl-propan-2-ol; any iron-induced homolytic cleavage products
formed were below our limits of detection. These data directly
contrast the results obtained with the [Fe3+,Fe3+] complex 2 (19
turnovers) and with the µ-oxo-[Fe3+,Fe3+] complex 3 (17 turnovers),
where only homolytic cleavage products (phenyl methyl ether,
bibenzyl, benzyl alcohol) of MPPH were observed. Peroxide activity
assays performed at the end of each reaction showed the appropriate
concentration of unreacted MPPH.10 Free Fe2+ and Fe3+ ions
supported only homolytic cleavage (22 and 31 turnovers, respec-
tively) under equivalent conditions, suggesting that the electronic
environment generated by the H2Hbamb2- ligand is important for
heterolytic cleavage chemistry to occur. Neither free H4Hbamb nor
Figure 1. Structures of ligand and iron complexes.
The use of MPPH as a mechanistic probe to distinguish
homolytic versus heterolytic cleavage of alkyl hydroperoxide O-O
bonds is well established.6 The rapid â-scission process (kâ ) 2 ×
108 s-1) resulting in formation of the benzyl radical following
homolytic cleavage of the peroxy O-O bond allows the clear
differentiation between modes of metal-mediated peroxide cleavage
(Scheme 1).
The reactions of excess MPPH9 (5.21 mM) in the presence
of either [Fe2+,Fe2+], 1, [Fe3+,Fe3+], 2, or µ-oxo-[Fe3+,Fe3+], 3
([complex] ) 0.10 mM), were investigated under strict anaerobic
conditions using MeOH as solvent. All iron complexes were stable
under the reaction conditions in the absence of MPPH for over 12
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J. AM. CHEM. SOC. 2003, 125, 3678-3679
10.1021/ja0286268 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Product Distributions of Catalytic Atom Transfer
Scheme 2
Reactions
equivalents products
equivalents
MPPH used
mass
balance (%)
substratea
sulfoxide/alcohol
sulfone/aketone
thioanisole
cyclohexane
524
239
500 ( 13
230 ( 30
11 ( 2
5 ( 1
98 ( 2
97 ( 3
a All reactions were run in DMF/CH2Cl2 (30/70) which were freshly
distilled and degassed several times prior to use (Fe:MPPH:Ph-S-Me -
1:596:6011, Fe:MPPH:C6H12-1:600:2500); reaction time ) 6 h).
Li2(H2Hbamb) ligand catalyzed MPPH cleavage. The catalytic
reaction of 1 with MPPH was facilitated by MeOH, which reacted
quantitatively with the iron-based intermediate to form formalde-
hyde during peroxide turnover.11 The absence of a suitable substrate
(solvent) led to formation of diamagnetic µ-oxo-[Fe3+,Fe3+], 3
(EPR silent, νas Fe-O-Fe ) 840 cm-1), resulting from collapse of
the reactive intermediate formed by the 1:1 interaction of MPPH
and the diferrous core of 1.
for subsequent oxygen atom transfer to substrate. Heterolytic
cleavage of the peroxide argues against the possibility of freely
diffusing radicals being responsible for the oxidative chemistry that
is observed. This fulfills an essential requirement for modeling
oxygenases, which proceed exclusively via a heterolytic pathway
in order to avoid the formation of biologically damaging hydroxy
radicals. Furthermore, the observed tight coupling between hetero-
lytic cleavage of the alkyl peroxide and the transfer of an oxygen
atom to an organic substrate (reaction efficiency >99%) models
the chemistry exhibited at the active site of iron-based mono-
oxygenases where one oxidized substrate is generated per equivalent
of O2 consumed. Studies designed to define both the scope and
mechanism of the substrate oxidation reactions are underway.
The above data can be explained by the formal transfer of an
oxygen atom obtained from the heterolytic cleavage of MPPH to a
ferrous center in 1, resulting in a two-electron oxidation of the
electronic structure of 1 (Scheme 2). The subsequent intermediate
can be viewed as an [Fe2+,Fe4+dO] T [Fe2+,Fen+{O}•] species
where the latter electronic description is meant to convey the
potential for unpaired electron density on either the diamide or
terminal oxo ligands. This intermediate may also collapse to a
µ-oxo-[Fe3+,Fe3+] dimer which in itself is inert as an oxygen atom
transfer catalyst. The data also suggest that while the ligand system
is capable of stabilizing an Fe4+ intermediate species generated from
heterolysis of the Fe2+-OOR species, it is unable to afford the Fe5+
species that would result from heterolysis at an Fe3+-OOR center.
Catalytic oxygen atom transfer reactions utilizing PhSMe and
cyclohexane (C-H bond strength ∼ 95 kcal/mol)12 as substrates
are summarized in Table 2. In each case, phenyl methyl sulfoxide
(500 turnovers) and cyclohexanol (230 turnovers) were initially
formed prior to the production of phenyl methyl sulfone (11
turnovers) and cyclohexanone (5 turnovers). Parallel control reac-
tions showed negligible product formation (e10 turnovers) in the
absence of catalyst, suggesting the primary role of an iron-based
oxidant. Tight coupling between MPPH O-O bond cleavage and
the oxygen atom transfer process is demonstrated by quantitatively
comparing the levels of 2-methyl-1-phenylpropan-2-ol with equiva-
lents of product (sulfoxide or alcohol). The results indicate the high
efficiency of MPPH utilization (99 ( 1%) and that only heterolytic
cleavage of MPPH occurs during catalysis. The data in Table 2
also establish that the ferrous centers in 1 return to their reduced
states at the end of each cycle (Scheme 2). Adventitious oxidation
of 1 or collapse of the intermediate to the µ-oxo-[Fe3+,Fe3+] dimer
would result in an iron complex population that would facilitate
homolytic cleavage of the alkyl peroxide O-O bond, leading to
detection of MPPH products based on the reactivity of the benzyl
radical. The observed absence of these species only allows for a
lower bound for the partitioning of productive versus nonproductive
processes (g500:1) during catalysis.
Acknowledgment. Financial support for this research was
provided in part by the U.S. Department of Energy, Office of Basic
Energy Sciences (ER14279) and by NIH (GM61208). We thank
FMC Corporation for the generous gift of 70% H2O2.
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(7) Abbreviations: H4Hbamb, 2,3-bis(2-hydroxybenzamido)2,3-dimethyl-
butane; [Fe2+,Fe2+], Fe22+(H2Hbamb)2(N-MeIm)2; [Fe3+,Fe3+], [Fe2+3+(H2-
Hbamb)2(N-MeIm)2](I-); µ-oxo-[Fe3+,Fe3+], µ-oxo-[Fe23+(H2Hbamb)2(N-
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(9) MPPH was prepared according to literature procedures via the classical
alcohol/H2O2 route at 40 °C using 70% H2O2 (FMC Corporation).13 The
resulting MPPH was then extracted with Et2O. CAUTION: Distillation
of the MPPH/ether solution resulted in an explosion! This step was
replaced by solvent removal under a stream of N2. The crude peroxide
was recrystallized from n-pentane at 20 °C, affording pure crystalline
MPPH in >80% isolated yield. NMR and mass spectroscopic (parent ion
MW: 166.2) characterizations gave reported results. Active MPPH levels,
measured by iodiometric titrations, showed 100% peroxide activity.
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These data demonstrate the ability of reduced binuclear 1 to act
as an efficient catalyst for the heterolytic cleavage of MPPH and
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