The reactivity of well defined diiron(III) peroxo complexes toward substrates: Addition to electrophiles and hydrocarbon oxidation

Article abstract of DOI:10.1016/S0968-0896(98)00270-3

The reactivity of previously reported peroxo adducts [Fe(μ-O₂)(μ-L)(O₂CPhCy)₂(1-Bu-Im)₂] (1), and [Fe(μ-O₂)(μ-L)(O₂CPhCy)₂(py)₂] (2), where L is a dinucleating ligand based on the m-xylylenediamine bis(Kemp's triacid imide), toward a variety of substrates is described. These studies were performed to probe the electronic properties of 1 and 2 and evaluate their potential as selective hydrocarbon oxidants. Compound 1 is nucleophilic at -77°C, reacting with phenols and carboxylic acids to liberate hydrogen peroxide, whereas the less electron-rich pyridine analogue 2 is unreactive toward both reagents. By contrast, neither reacts at -77°C with electrophilic reagents such as olefins or triphenylphosphine, or with weak hydrogen atom donors such as dimethylbenzylamine. When solutions of 1 are warmed to room temperature in solvents such as THF, toluene, and cyclopentane, mixtures of alcohol and ketone products derived from the solvent are formed. A detailed investigation of cyclopentane oxidation strongly points to a radical autoxidation pathway. These results are discussed in the context of the selective hydroxylation chemistry that occurs at the carboxylate-bridged diiron centers in soluble methane monooxygenase. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(98)00270-3

Bioorganic & Medicinal Chemistry 7 (1999) 763±772
The Reactivity of Well De®ned Diiron(III) Peroxo Complexes
Toward Substrates: Addition to Electrophiles and Hydrocarbon
Oxidation
Daniel D. LeCloux, Amy M. Barrios and Stephen J. Lippard*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Received 17 September 1998; accepted 6 October 1998
AbstractÐThe reactivity of previously reported peroxo adducts [Fe(m-O2)(m-L)(O2CPhCy)2(1-Bu-Im)2] (1), and [Fe(m-O2)(m-L)
(O2CPhCy)2(py)2] (2), where L is a dinucleating ligand based on the m-xylylenediamine bis(Kemp's triacid imide), toward a variety
of substrates is described. These studies were performed to probe the electronic properties of 1 and 2 and evaluate their potential as
selective hydrocarbon oxidants. Compound 1 is nucleophilic at 77 ꢀC, reacting with phenols and carboxylic acids to liberate
hydrogen peroxide, whereas the less electron-rich pyridine analogue 2 is unreactive toward both reagents. By contrast, neither reacts
at 77 ꢀC with electrophilic reagents such as ole®ns or triphenylphosphine, or with weak hydrogen atom donors such as dimethyl-
benzylamine. When solutions of 1 are warmed to room temperature in solvents such as THF, toluene, and cyclopentane, mixtures
of alcohol and ketone products derived from the solvent are formed. A detailed investigation of cyclopentane oxidation strongly
points to a radical autoxidation pathway. These results are discussed in the context of the selective hydroxylation chemistry that
occurs at the carboxylate-bridged diiron centers in soluble methane monooxygenase. # 1999 Elsevier Science Ltd. All rights reserved.
Introduction
elucidation of the biological O2-activation mechanisms
and of developing practical hydrocarbon oxidation
catalysts.
The selective and ecient catalytic oxidation of hydro-
carbon substrates under mild conditions continues to be
a challenging goal for the synthetic chemist.1±8 In Nat-
ure, obligate methanotrophic bacteria carry out one of
the most dicult reactions of this kind, the conversion
of methane to methanol under ambient conditions (eq
(1)), by utilizing a soluble9±11 or particulate12,13 methane
monooxygenase (sMMO or pMMO).
The current state of knowledge regarding these systems,
including structural, spectroscopic, and mechanistic
information, is described in detail elsewhere;9,14±16
therefore, only a brief synopsis is provided here. Oxy-
genated intermediates have been characterized for
sMMO10,17,18 and RNR-R219±23 by combining stopped-
¯ow and rapid freeze quench methodologies with a
variety of spectroscopic techniques. Both sMMOH and
RNR-R2 react with O2 in their diiron(II) forms to
a€ord a diiron(III) peroxo species as the ®rst detected
intermediate. For sMMO, this unit converts to a di-
iron(IV) species, designated intermediate Q. It is inter-
mediate Q or a closely related derivative which reacts
with alkane substrates. Studies with radical clock24 and
chiral alkane25 probes have provided compelling evi-
dence against a hydrocarbon oxidation mechanism
involving discrete substrate radicals. In RNR-R2, the
peroxo intermediate converts to an oxo-bridged di-
iron(III)(IV) unit, X, possibly through a diiron(IV)
intermediate like sMMO-Q. Intermediate X abstracts a
hydrogen atom from a nearby tyrosine to yield a cata-
lytically viable tyrosyl radical.
‡
‡
CH4 ‡ O2 ‡ NADH ‡ H ! CH3OH ‡ H2O ‡ NAD
ꢀ1†
The soluble form houses a carboxylate-bridged diiron
center in its hydroxylase component (sMMOH), the site
of methane oxidation. This protein is a member of a
class of non-heme diiron enzymes which carry out a
variety of selective hydrocarbon oxidative processes.9,11
A closely related enzyme is ribonucleotide reductase,
which reacts with O2 at a diiron(II) center in its R2
subunit (RNR-R2) to generate a tyrosyl radical which
in turn assists in the catalytic reduction of ribonucleo-
tides. We seek to prepare functional synthetic models
of these systems, with the dual goals of aiding in the
Much e€ort has been expended to mimic the oxidation
chemistry of these non-heme iron enzymes. Iron(III)
Key words: Biomimetic reactions; oxygen; oxygenation.
*Corresponding author. Tel.: +1-1617-253-1892; fax: +1-617-258-8150.
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(98)00270-3

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D. D. LeCloux et al. / Bioorg. Med. Chem. 7 (1999) 763±772
complexes have been treated with either hydrogen per-
oxide26±30 or tert-butyl hydroperoxide31±33 to generate
an active oxidant. Modest selectivities for alcohol27,31 or
ketone27,28 product have been observed in some cases.
Careful examination has shown, however, that most of
these oxidative systems operate through non-biomi-
metic, autoxidation pathways involving freely di€using
alkyl radicals.30,33±39 One exception may be a stereo-
speci®c and presumably non-radical catalytic system
composed of an Fe(II) tris(2-pyridylmethyl)amine
complex and H2O2.26
line techniques at room temperature unless otherwise
noted.
Physical measurements
NMR spectra were recorded on a Bruker AC-250 or
Varian XL-300 spectrometer. FTIR spectra were re-
corded on a BioRad FTS-135 FTIR spectrometer.
GC and GC/MS
Analyses were carried out on a HP-5970 gas chromato-
graph connected to a HP-5971 mass analyzer. Alltech
Econo-cap EC-WAX capillary columns of dimensions
(15 mÂ0.53 mmÂ1.2 mm) and (30 mÂ0.25 mmÂ0.25 mm)
were used for GC and GC/MS studies, respectively,
except for triphenylphosphine and triphenylphosphine
oxide, which were assayed with a HP-101 (12 mÂ0.2 mm
Â0.2 mm) capillary column. The following method was
used to e€ect nearly all separations: initial temperature
=50 ꢀC; initial time=10 min; temperature ramp=
50 200 ꢀC at 10 deg/min. The products were identi®ed
by comparing their retention times and mass spectral
patterns to those of authentic standards. Integrations
were acquired by FID detection run in parallel to mass
spectrometry by using an HP-3393 integrator. FID
response calibration constants were measured by running
calibration curves with authentic samples and an internal
standard, either cyclopentanone or cyclohexanone.
By contrast, the reactivity of discrete, well de®ned di-
iron(III) peroxo complexes derived from iron(II) pre-
cursors and O2 is essentially unexplored. Given that
sMMO utilizes a reductive O2 activation pathway, it
is desirable to track an oxidation reaction in a model
system from the dioxygen binding step, to formation of
a high valent oxidant, and ®nally through the substrate
oxidation event. Such a study would provide invaluable
information for comparison with the enzyme and may
spawn the development of practical hydrocarbon oxi-
dation catalysts. Moreover, this approach may shed
light on the composition, structure, and reactivity of
intermediates postulated for synthetic iron oxidation
systems. In the present article we provide a complete
analysis of the reactivity of diiron(III) peroxo com-
plexes derived from the m-xylylenediamine bis(Kemp's
triacid)imide (H2XDK) ligand system.40
For kinetic isotope or 18O2 labeling studies, the ratio of
isotopomers was determined by mass spectral integra-
tion of each parent ion. The integration response was
assumed to be identical for the isotopomers.
Experimental
General considerations
The complexes [Fe2(m-O2)(m-PXDK)(m-O2CPhCy)(O2-
CPhCy)(Bu-Im)2] (1) and [Fe2(m-O2)(m-BXDK)(m-O2-
CPhCy)(O2CPhCy)(py)2] (2) were prepared from O2 and
the appropriate diiron(II) precursors at 77 ꢀC accord-
ing to an established procedure.40 Authentic samples
of 3,30,5,50-tetra-tert-butyl-1,10-bi-2,20-phenol,41 cyclo-
pentyl-hydroperoxide,42 and 2-hydroxytetrahydro-
furan,43 were synthesized according to the literature
Low-temperature UV±vis spectroscopy
Spectra were recorded on a HP8452A diode array
spectrophotometer by using a custom manufactured
immersion dewar, equipped with a 3 mL cell (1-cm
pathlength) with quartz windows connected to a 14/20
female joint via a 10-cm long glass tube. A temperature
of 77 ꢀC was maintained with a dry ice/acetone bath
and monitored with a Sensortek Model BAT-12 ther-
mocouple thermometer.
1
methods, and their purity was con®rmed by H NMR
and/or GC and GC/MS analyses. The presence of
hydrogen peroxide was detected by using EM Quant1
peroxide test strips, catalog number 10011-1, which
were purchased from EM Science. Dioxygen (99.994%,
Boc gases) was dried by passing the gas stream
through a column of Drierite. Labeled dioxygen (95%
18O2), toluene, and THF were purchased from Cam-
bridge Isotope Laboratories, Inc. The solvents were
vacuum transferred from Na/benzophenone ketyl. All
other reagents were procured from commercial sources
and used as received unless otherwise noted. THF,
cyclopentane, toluene, pentane, and Et2O were distilled
from sodium benzophenone ketyl under nitrogen.
Cyclopentane, isopentane, 1-hexene, and cyclohexene
were distilled from sodium under nitrogen. Dichloro-
methane, 1,2-dichloroethane, and pyridine were dis-
tilled from CaH2 under nitrogen. All air sensitive
manipulations were carried out either in a nitrogen ®lled
Vacuum Atmospheres drybox or by standard Schlenk
Resonance Raman spectroscopy
Raman data were acquired by using a Coherent Innova
90 Kr+ laser with an excitation wavelength of 647.1 nm
and 65 mW of power. A 0.6-m single monochromator
(1200 grooves/mm grating), with an entrance slit of
100 mm, and a liquid nitrogen cooled-CCD detector
(Princeton Instruments, Inc.) were used in a standard
backscattering con®guration. A holographic notch ®lter
(Kaiser Optical Systems) was used to attenuate Ray-
leigh scattering. Spectra of all samples were collected
in toluene solution at 77 ꢀC with the same custom-
manufactured dewar used to acquire low-temperature
UV±vis spectra. Solute concentrations were made as high
as possible depending on the solubility of the reduced
sample, ꢁ20 mM in the best cases, to ensure an optimal
signal-to-noise ratio. High vacuum line techniques were

D. D. LeCloux et al. / Bioorg. Med. Chem. 7 (1999) 763±772
765
used to transfer 18O2 and to manipulate the resulting
samples. A total of 1000 scans each with a 3 sec expo-
sure time were collected for each sample. Raman shifts
were calibrated with toluene as an internal standard.
The data were processed by using CSMA software
(Princeton Instruments, Inc. Version 2.4A) on a Gate-
way 2000 computer, and the resulting ASCII ®les were
processed with Kaleidagraph (Abelbeck Software).
rubber septum. All sample volumes were 5.0 mL. Per-
oxo complex 1 was generated in the usual manner at
77 ꢀC.40 It was stable for at least several hours at this
temperature, as judged by UV±vis spectroscopy, which
a€orded identical traces in all the solvents. For ther-
molysis reactions carried out under argon, the peroxo
solution was degassed by carrying out three vacuum/Ar
purge cycles and three freeze±pump±thaw cycles with
liquid nitrogen, and then back®lling with 1 atm of Ar
prior to warming. Warming to room temperature over
5 min was accomplished by removing the reaction vessel
from the dry ice/acetone bath. Warming over 2 h was
carried out by removing the excess dry ice from the
cooling bath while keeping the ¯ask or UV±vis cell in
contact with the bath. Solutions incubated at low tem-
perature for longer time periods were placed in a 85 ꢀC
refrigerator. After addition of an internal standard, the
crude reaction mixtures were examined directly by GC
and GC/MS analyses.
Synthetic methods: General procedures for stoichiometric
reactions of 1 or 2 at 77 ꢀC
All reactions were monitored by low-temperature UV±
vis spectroscopy. The dewar was equipped with a stir
bar and loaded in the drybox with 5.0 mL of a 0.50±
1.0 mM solution of the diiron(II) precursor of 1 or 2.
The apparatus was topped with a rubber septum,
brought out of the drybox, placed under a positive N2
pressure, and cooled to 77 ꢀC with a dry ice acetone
bath. A spectrum was recorded, and then the sample
was subjected to a gentle purge of O2 at atmospheric
pressure for 15 s. After this time the peroxo complex 1
or 2 had formed to completion, as judged by the blue
color which developed and the known second order rate
constants for the oxygenation reactions. Excess O2 was
removed with a 5 min Ar purge of the solution. Another
spectrum was recorded, and then 200 mL of the test
reagent solution was added dropwise to a stirred solu-
tion of the peroxo complex, taking care not to allow the
peroxo solution to warm above 77 ꢀC. For the CO2
reactions, the gas was bubbled gently through the
solution of the peroxo complex over ꢁ30 s. CAUTION:
Owing to the low temperature, this procedure introduces a
large excess of CO2 to the solution, and therefore con-
siderable caution should be taken when venting the solu-
tion upon warming so as to not build up a dangerous
pressure level. The resulting mixture was allowed to stir
for 15±30 s, by which time a homogenous solution had
formed. Additional spectra were recorded, and the
reaction was monitored by the decay of the peroxo-to-
iron charge transfer band. The quantities of reagents
and solvent used for each reaction are listed in Table 1.
Intermolecular kinetic isotope measurements
Peroxo complex samples (1.0 mM) were prepared in
equimolar quantities of perdeutero or protio solvents, to
a total volume of 5.0 mL. Thermolyses were carried out
over 5 min as described above, and the crude reaction
mixtures were analyzed by GC/MS.
Results and Discussion
Reactions of peroxide complexes 1 and 2 at 77 ꢀC
The electronic spectra of the 1-alkylimidazole and pyr-
idine complexes 1 and 2 were used to monitor their
reactivity toward three classes of substrates: oxygen-
atom acceptors, electrophiles/acids, and weak H-atom
donors. Such a comparative analysis has been used pre-
viously to characterize transition metal peroxo com-
plexes, where the reactivity pattern of the peroxide
ligand depends on the Lewis acidity of the metal ion and
the mode of peroxo coordination.44±46 In general, early
transition metal ions in high oxidation states render
coordinated peroxide ligands electron de®cient such
that they typically undergo oxygen-atom transfer reac-
tions to acceptors such as phosphines and ole®ns.46,47
These reactions become more favored thermodynamically
General procedures for solvent oxidation studies
Samples were prepared in the immersion dewar des-
cribed above or in a round bottom ¯ask sealed with a
Table 1. A summary of reagents and solvents used for the stoichiometric reactions
Reagents
Reagent quantity
Peroxo complex
Quantity of diiron(II)
precursor (mg, mmol)
Solvent (5.0 mL)
Triphenylphosphine
2-Cyclohexen-1-one
Dimethylbenzylamine
2,4-Di-tert-butylphenol
2,4-Di-tert-butylphenol
Phenol
Penta¯uorophenol
2,4,6-Tri-tert-butylphenol
1-Phenylcyclohexylcarboxylic acid
CO2
6.0 mg, 23 mmol
6.0 mg, 23 mmol
10 mL, 66 mmol
1.0 mg, 4.9 mmol
1.0 mg, 4.9 mmol
0.5 mg, 5.3 mmol
0.7 mg, 3.5 mmol
5 mL, 5 mmol
1.0 mg, 4.7 mmol
Excess
Excess
1.4 mg, 4.4 mmol
0.8 mg, 4.4 mmol
1
1
1
1
2
1
1
1
1
1
2
1
1
5.0, 3.3
6.5, 4.3
10, 6.6
7.4, 4.9
7.0, 4.1
6.8, 4.5
4.8, 3.2
6.4, 4.2
6.5, 4.3
7.4, 4.9
7.0, 4.1
6.0, 4.0
6.0, 4.0
THF
THF
Et2O
THF
CH2Cl2
THF
THF
Cyclopentane
Toluene
Et2O
CO2
Pentamethylferrocene
Cobaltocene
CH2Cl2
THF
THF

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D. D. LeCloux et al. / Bioorg. Med. Chem. 7 (1999) 763±772
as the substituents bound to the reacting substrate
functionality are more electron releasing. By contrast,
low-valent, late-metal peroxo adducts usually behave as
nucleophiles, undergoing addition reactions to electro-
philes such as CO2, acyl chlorides, or electron-de®cient
ole®ns.46 In addition, these electron rich peroxo adducts
will react with acids to a€ord hydroperoxo complexes
or they may react with an additional acid equivalent to
liberate H2O2. Peroxo complexes may also display radi-
cal character and react with weak hydrogen atom donors
such as isopropyl C±H48,49 and phenolic O±H44,45 bonds.
Peroxo O±O bond cleavage may occur prior to hydro-
gen atom abstraction in these reactions, as has been
demonstrated in a related bis(m-oxo)dicopper system.50±52
Moreover, the distinction between nucleophilic/basic
versus radical peroxo character can be probed with
phenols since deprotonation usually leads to phenoxide
coordination,46 whereas hydrogen atom abstraction
provides a phenoxyl radical. With appropriate substitu-
tion of the aryl ring, such a species can be identi®ed as
the 2,20-biphenol-coupled product.44,53
peroxo adducts 1 or 2, a result which suggests that
they have little or no electrophilic character. Similarly,
exposure of either peroxo complex to the weak H-atom
donor dimethylbenzylamine a€orded no reaction.
Treatment of the 1-butylimidazole peroxo complex 1
with 1.0 equiv of 2,4-di-tert-butylphenol resulted in a
color change from purple to deep royal blue within 30 s.
By contrast, pyridine analogue 2 did not react with the
phenol under similar conditions. The optical spectrum
of the 1+phenol reaction product persists for >2 h at
77 ꢀC, but decays rapidly (<1 min) upon warming to
room temperature (Fig. 1). No 2,20-biphenol coupled
product was detected by GC/MS, as judged by com-
parison of the product chromatogram to that of pure
2,20-biphenol, but H2O2 was qualitatively identi®ed.
These facts, coupled with the metastable nature of the
product and the resemblance of its UV±vis spectrum to
that of 1, suggested that a diiron(III) phenoxide±hydro-
peroxide complex might have been formed through
deprotonation of the phenol with the diiron(III)-bound
peroxide. The resulting charge transfer band at 620 nm
(e=1400 M 1 cm 1) is considerably red-shifted from
those of known hydroperoxo complexes, however, such
as [FeIII(N4Py)(OOH)(MeCN)](ClO4)2(lmax=458 mn,
e=1100 M 1 cm 1, where N4Py=N,N-bis(2-pyridyl-
methyl)-N-bis(2-pyridyl)methylamine)54 and [Fe(TPA)
(OOH)](ClO4)]2+ (lmax=538 nm, eꢁ1000 M 1 cm 1),
where TPA=tris(2-pyridylmethyl)amine).26 Moreover,
Stoichiometric reactions were conducted by generating
peroxo complex 1 or 2 in solution at 77 ꢀC, followed
by thorough removal of excess O2 with Ar purge/
dynamic vacuum cycles and then addition of the
reagent. Reactions were monitored by UV-vis spectro-
scopy. These studies are summarized in Scheme 1. No
reaction with triphenylphosphine was observed for
Scheme 1.

D. D. LeCloux et al. / Bioorg. Med. Chem. 7 (1999) 763±772
767
Figure 1. Electronic absorption spectra of 1 in THF at 77 ꢀC (A,
0.98 mM), 1.0 equiv of 2,4-di-tert-butylphenol added (B, lmax
=
620 nm, e=1400 M 1 cm 1), ®ve traces qualitatively tracking the decay
of the phenol product upon thermolysis from 77 ꢀC to room tem-
perature (C), and the decomposition product at room temperature (D).
reactions with less electron-rich phenols such as the
parent compound and penta¯uorophenol exhibited
UV±vis bands blue-shifted from that obtained for the 2,4-
di-tert-butylphenol product (C6H5OH: lmax=546 nm,
1
e=2100 M 1 cm 1; C6F5OH: lmax=460 nm, e=3300 M
cm 1). Both of these observations make it more likely
that the product UV±vis feature is due to a phenoxide-
to-iron(III) charge transfer.
Figure 2. Resonance Raman spectra obtained with 647-nm excitation
at 77 ꢀC on ¯uid toluene solutions of [Fe2(16O2)(PXDK)(O2CPh-
Cy)2(Bu-Im)2] (A, top spectrum), 1-16O2+1.1 equiv of 2,4-di-tert-
butylphenol (A, bottom spectrum), [Fe2(18O2)(PXDK)(O2CPhCy)2-
(Bu-Im)2] (B, top spectrum), 1-18O2+1.1 equiv of 2,4-di-tert-butyl-
phenol (B, bottom spectrum). Peaks marked with an asterisk and
those o€ scale are due to toluene.
Resonance Raman studies were conducted to probe
further the fate of the peroxide complex 1 upon treat-
ment with 2,4-di-tert-butylphenol. Peroxo species were
prepared with 16O2 or 18O2, and each was treated with
1.1 equiv of the phenol. Spectra before and after the
reaction are displayed in Figure 2. For the 16O2 sample,
the n(16O±16O) band at 864 cm
disappears almost
1
completely upon addition of the phenol, and two new
bands appear at 750 and 913 cm 1. The n(18O±18O) band
also diminishes when phenol is added, as judged by the
narrowing and shifting of a peak at ꢁ825 cm 1, which is
composed of the peroxo band and one arising from
toluene.40 The same two new peaks observed when
phenol was added to the 16O2 sample also appear in the
18O2 spectrum at identical energies, indicating that nei-
ther can be ascribed to a hydroperoxide or peroxide
species. These features are therefore assigned to coordin-
ated phenoxide ligand vibrations which are resonance
enhanced by a charge transfer band to iron. A new
n(O±O) band may have been obscured by the toluene
peaks, but none was observed after performing solvent
subtraction procedures.
values for protonated 1-butylimidazole (6.95) and pyr-
idine (5.25) compared to phenol (9.89)55 makes proton
transfer to a dissociated nitrogen instead of the peroxo
ligand highly improbable.
Two other proton donors were investigated to probe
further the character of the peroxide ligands in 1 and 2.
Treatment of 1 with 1.1 equiv of 2,4,6-tri-tert-butylphe-
nol a€orded no reaction, as judged by UV±vis spectros-
copy. Apparently proton transfer does not occur in this
case because the sterically encumbered phenol cannot
access the peroxide ligand. Alternatively, the deproto-
nated phenol may be too hindered to bind to the iron
center(s). A carboxylic acid was used to determine whe-
ther a hydroperoxo complex could be stabilized by an
additional hindered carboxylate ligand and to see whe-
ther the less basic pyridine peroxo complex 2 could be
protonated with a stronger acid. Treatment of peroxo
complex 1 with 1.1 equiv of 1-phenylcyclohexylacetic
acid was accompanied by decomposition at 77 ꢀC
within 15±30 s (Fig. 3), yielding intractable products upon
work up at room temperature. As with all the phenol
reactions with 1, H2O2 was detected qualitatively in the
crude decomposition mixtures. Peroxo 2 was completely
unreactive toward the carboxylic acid, an outcome
Irrespective of the identity of the initial metastable pro-
ducts, this set of experiments demonstrate that 1
behaves as a basic, and not a hydrogen atom abstract-
ing, peroxo species. The fact that 2 does not react at all
with 2,4-di-tert-butylphenol further supports this con-
clusion. Compared to pyridine, the more basic 1-alkyl-
imidazole groups impart additional electron density to
the iron centers in 1, which is in turn transmitted to the
peroxide ligand. Moreover, the di€erence in the pKa

768
D. D. LeCloux et al. / Bioorg. Med. Chem. 7 (1999) 763±772
reaction was observed with ferrocene or pentamethyl-
ferrocene, but treatment with cobaltocene induced rapid
decay of the peroxo UV±vis band (Fig. 5). The cobalto-
cenium cationic product could not be identi®ed because
intense features in the higher energy visible region
dominated the spectrum. Assuming that cobaltocene
donates an electron to the peroxo complex in a 1:1
stoichiometry, then the reduction potential of 1 can be
estimated to be between those of Cp2Fe and cobalto-
cene,
0.59 and
1.33 mV versus Cp2Fe+/Cp2Fe,
respectively.57 This value is consistent with the stability
of the diiron(III) peroxo species toward hydrogen atom
donors, notwithstanding the issue of proton anity,
since reduction of one of the Fe(III) ions would have to
accompany hydrogen atom transfer to the peroxo
ligand. Moreover, it provides at least a partial explana-
tion as to why peroxo species 1 deprotonates 2,4-di-tert-
butylphenol instead of abstracting a hydrogen atom
from this reagent.
Figure 3. Electronic absorption spectra of 1-16O2 in toluene at 77 ꢀC
(A, 0.86 mM), after 1.1 equiv of HO2CPhCy was added (B), and the
reduced complex (1) prior to addition of 16O2 at 77 ꢀC (C).
Thermolysis reactions leading to solvent oxidation
which further illustrates the di€erent electronic proper-
ties imparted to the peroxo ligands solely by the choice
of N-donor.
Solutions of peroxo complexes 1 or 2 rapidly decay
when warmed above ꢁ 65 ꢀC, changing from purple or
midnight blue, respectively, to an orange brown color
which is characteristic of m-oxo diiron(III) complexes.
Several mechanisms could account for this decay. The
most well documented such reaction in diiron(III) peroxo
chemistry is a bimolecular decomposition accompanied
by extrusion of 0.5 equiv of O2 per diiron complex,
a€ording oxo-bridged diiron(III) products.58,59 Such a
process could not entirely account for the decomposi-
tion of 1 or 2, however, because manometric studies
indicated either that O2 was not released during the
decay or that, in solvents such as THF and CH2Cl2, up
to an additional equivalent of dioxygen was con-
sumed.40 Such a result might be explained a priori by
ligand oxidation, but a thorough 1H NMR, IR, and
GC/MS analysis of the organic components revealed
no oxidized ligands following acid decomposition and
extraction of the resulting products. Instead, solvent
oxidation products were identi®ed in the reaction
Electrophilic reagents were examined to probe the
nucleophilicity of the peroxo complexes. Exposure of 1
at 77 ꢀC to a large excess of CO2 resulted in decay of
the peroxide-to-iron charge transfer band within 15 s
(Fig. 4). As with other peroxo complexes that react with
CO2,44,46 this reaction probably generates a peroxy-
carbonate species which decomposes to an iron(III)
carbonate complex(es), although nothing tractable was
isolated from the reaction mixture. Consistent with the
protonolysis studies, 2 was unreactive toward CO2 over
the course of 2 h as determined by UV±vis spectroscopic
monitoring of the reaction. Neither 1 nor 2 was reactive
toward 2-cyclohexen-1-one, a less potent electrophile
that reacts with some nucleophilic peroxo complexes.56
Finally, the behavior of 1 toward reductants was exam-
ined to obtain an estimate of its reduction potential. No
Figure 5. Electronic absorption spectrum of 1 in THF at 77 ꢀC (A,
0.79 mM), 11 traces qualitatively tracking the decay of the peroxo
upon addition of 1.1 equiv of Cp2Co (B), and the product mixture at
77 ꢀC (C).
Figure 4. Electronic absorption spectrum of 1 in Et2O at 77 ꢀC (A,
0.98 mM), seven traces qualitatively tracking the decay of the peroxo
upon addition of CO2 at 77 ꢀC (B), and the product mixture at
77 ꢀC (C).

D. D. LeCloux et al. / Bioorg. Med. Chem. 7 (1999) 763±772
769
mixtures for several di€erent solvents. A detailed ana-
lysis of those reactions for 1 was undertaken because its
butyl and propyl groups render it soluble in a wide
variety of hydrocarbons.
A key to understanding this chemistry is provided by
the product distribution for each substrate. For cyclo-
hexene, only allylic oxidation products were produced
in appreciable quantities. This result contrasts with that
for sMMO,60,61 and early transition metal peroxo47 or
terminal oxo complexes,62 which all a€ord the epoxide
as the major or exclusive product in reactions with ole-
®ns. For oxidations with 1 at saturated C±H bonds,
ketones are favored over alcohol products, whereas
sMMO a€ords alcohols exclusively.60,61
Table 2 summarizes the results of this initial survey,
which de®ned the scope of the oxidation process. Sub-
strates with particularly weak C±H bonds,55 such as
THF (92 kcal/mol), cyclohexene (allylic C±H=85 kcal/
mol), and toluene (85 kcal/mol), a€orded g-buty-
rolactone and 2-hydroxytetrahydrofuran, 2-cyclohexen-
1-ol, 2-cyclohexen-1-one, and cyclohexene oxide, and
benzaldehyde, respectively, in modest yields based on 1.
1,2-Dichloroethane, identi®ed qualitatively as a product
of peroxo decay in CH2Cl2 solutions, was presumably
formed by C±Cl bond homolysis. Solvents with high
C±H bond strengths, such as isopentane (95 kcal/mol)
and pentane (98 kcal/mol), were completely unreactive.
Cyclopentane, which has an intermediate C±H bond
strength (94.5 kcal/mol), a€orded a small amount of
product.
To investigate the mechanism in more detail, we chose
to focus on cyclopentane oxidation. This solvent is
readily puri®ed and not susceptible to autoxidation in
air for months at room temperature. Cyclohexene and
THF, on the other hand, autoxidize after ꢁ12 h in air in
the absence of radical inhibitors, judging by GC/MS.
From a practical standpoint its higher C±H bond
strength makes cyclopentane a more attractive target.
Table 3 lists a series of conditions designed to probe the
oxidation mechanism of cyclopentane. The results for
entries 1±3 reveal that yields of ketone and alcohol are
una€ected by the warming rate, reaction atmosphere, or
peroxo concentration; in each case the same small
quantities of ketone and alcohol formed in a 2.5:1 ratio.
When decomposed reaction mixtures were allowed to
stand in air for extended periods of time (entries 6±8),
however, a slow but steady production of additional
product resulted, as determined by analyzing aliquots
of the reaction mixture by GC/MS on a daily basis.
After three weeks the total yield of oxidized products
based on the original amount of 1 was 250%, but the
ketone:alcohol ratio remained invariant over this time
period. The latter observation suggests that the entire
oxidation process proceeds through a common mechan-
ism, from the initial warming of the peroxo solution
through prolonged incubation in air at room tempera-
ture. An aliquot of the long-term reaction was removed
after 1 day (entry 8) and treated with a 50-fold excess of
2,4,6-tert-butylphenol, which completely quenched pro-
duct formation. Moreover, when solutions of 1 were
warmed in the presence of 1.0 equiv of this phenol, with
which it does not react at 77 ꢀC (vide supra), no oxi-
dized products were observed either immediately after
the reaction or upon standing in air for several days.
Table 2. A survey of solvent oxidation reactions mediated by peroxo
1
Solvent
Products (% yield based on 1)
CH2Cl2
An intermolecular kinetic isotope e€ect (KIE) was not
measured for cyclopentane oxidation because the per-
deutero isotopomer is prohibitively expensive. Instead,
we carried out measurements using THF and toluene
as solvents, which a€orded kH/kD values of 6.2 and
7.8, respectively. These values may be compared to
the intramolecular KIE values of 2±3 for Gif cyclo-
hexane and adamantane oxidations,63 and 1.0 for
sMMO.24
No reaction
No reaction
The ability of phenol to quench product formation
indicates that a free radical, non-metal based autoxida-
tion mechanism is most likely occurring for this system.
An example of such a mechanism is illustrated by eqs
(2)±(5) for oxidation at a secondary carbon atom.46 This
well known hydrocarbon oxidation process is initiated by
No reaction

770
D. D. LeCloux et al. / Bioorg. Med. Chem. 7 (1999) 763±772
Table 3. Cyclopentane oxidation reactions carried out with peroxo 1 under a set of experimental conditions designed to probe the mechanism
Entry
atm
Temp. (ꢀC)/Heating rate
Concn (mM)
Additives (equiv)
None
Yield (%)
-one
-ol
1
2
3
4
5
6
7
8
Ar or O2
77!rt over 5 min
77!rt over 2 h
1.2
1.2
1.2
0.12
11.2
1.2
5
5
2
2
85 for 3 days
77!rt over 5 min
5
2
5
2
77!rt over 5 min
5
2
Ar or O2, then air
Ar or O2
77!rt over 5 min then rt, 24 h
77!rt over 5 min then rt, 3 weeks
77!rt over 5 min then rt, 3 weeks
77!rt over 5 min
10
170
10
0
4
80
4
2,4,6-t-Bu-phenol (10) after 24 h
2,4,6-t-Bu-phenol (10)
PPh3 (1.0)
9
10
11
0
77!rt over 5 min
5
2
77!rt over 5 min
HO2CPhCy (10) or H2O (10)
5
2
Initiation InÁ‡R2CH2 ! InH ‡ R2CHÁ
Propagation R2CHÁ‡O2 ! R2CHOOÁ
ꢀ2†
ꢀ3†
ꢀ4†
peroxo sample was also warmed in the presence of
10 equiv of PPh3 to trap any cyclopentylhydroperoxide
that might have formed, a reaction which would a€ord
triphenylphosphine oxide and alcohol. This procedure
neither changed the overall yield nor altered the
ketone:alcohol ratio, suggesting that if the hydroper-
oxide is formed it decomposes exceedingly rapidly.
R2CHOOÁ‡R2CH2 ! R2CHÁ‡R2CHOOH
Perhaps the most interesting issue for this system is the
role of 1 in the autoxidation chemistry. For reactions
conducted under Ar, the peroxo is presumably the
source of free O2, some of which could be released
upon warming. In addition, it is highly probable that a
metal-bound oxygen species is involved in the initiation
step. One possibility would be direct hydrogen atom
abstraction by the diiron(III) peroxide, a€ording a
Fe(II)Fe(III) hydroperoxo complex and an alkyl radical
(eq (9)). The former could then eliminate a hydroxyl
radical and a (m-oxo)diiron(III) product (eq (10)).
Termination 2R2CHOOÁ ! R2CO4CR2
! R2CHOH ‡ RꢀCO†R ‡ O2
ꢀ5†
hydrogen atom abstraction to generate an alkyl radical,
which is trapped with dioxygen. The resulting alkyl
peroxy radical then reacts with another equivalent of
substrate, and the chain is propagated. Chain termina-
tion occurs when two alkyl peroxy radicals combine,
and the resulting species rearranges to a€ord dioxygen,
ketone, and alcohol. Decomposition of the resulting
alkyl hydroperoxide to ketone and alcohol can be
catalysed by iron salts via a Haber±Weiss cycle (eqs
(6) and (7)).62,64 The resulting alkoxy radical reacts
with substrate to yield alcohol (eq (8)), and the alkyl
peroxy radical can decompose as indicated in eq (5).
‰FeI2IIꢀm O2†ꢀXDK†ꢀO2CPhCy†2ꢀBu Im† Š ‡ C5H10
2
Â
Ã
! FeIIFeIIIꢀOOH†ꢀXDK†ꢀO2CPhCy†2ꢀBu Im†
2
‡C5H9Á
(9)
FeꢀII† ‡ R2CHOOH ! R2CHOÁ‡FeIIIꢀOH† ꢀ6†
Â
Ã
Ã
FeIIFeIIIꢀOOH†ꢀXDK†ꢀO2CPhCy†2ꢀBu Im†
2
Â
! FeI2IIꢀm O†ꢀXDK†ꢀO2CPhCy†2ꢀBu Im† ‡OHÁ
2
FeIIIꢀOH† ‡ R2CHOOH ! R2CHOOÁ‡FeII ‡ H2O
ꢀ7†
ꢀ10†
This particular sequence of events is unlikely, however,
since 1 displays no propensity to abstract a hydrogen
atom from even weak H-atom donors such as phenol
(O±H bond strength= 88 kcal/mol).55 Alternatively, the
peroxo complex may convert to a new intermediate
upon warming that is capable of performing the hydro-
gen atom abstraction reaction. Perhaps a dioxodi-
iron(IV) species forms having the same formal metal
oxidation states as sMMO-Q but exhibiting a much
di€erent pattern of reactivity (eq (11)). More likely
perhaps is a bimolecular decay, whereby some of the
R2CHOÁ‡R2CH2 ! R2CHÁ‡ROH
ꢀ8†
1
The reaction mixtures were analyzed by H NMR and
GC/MS to determine whether a signi®cant concentra-
tion of cyclopentylhydroperoxide builds up over the
1
course of the extended reactions. No H NMR reso-
nances or GC/MS peaks attributable to this species
were identi®ed upon comparing the data to that
obtained for a pure sample prepared independently. A

D. D. LeCloux et al. / Bioorg. Med. Chem. 7 (1999) 763±772
771
peroxo complex releases O2 upon warming, and the
Conclusions
resulting reducing equivalents are then used to activate
diiron(III) peroxide to e€ect Fenton chemistry, per-
haps with trace water serving as a proton source to
generate a hydroxyl radical (eq (12)).
The reactivity properties of diiron(III) peroxo com-
plexes 1 and 2 have been fully elucidated. These adducts
behave as nucleophilic/basic peroxides, exhibiting no
tendency to serve as oxygen atom donors, even for potent
acceptors such as triphenylphosphine. The 1-butylimi-
dazole ligands in 1 enhance the nucleophilicity/basicity of
the peroxo ligand compared to the pyridine analogue
probably because imidazole is a better s-donor. This
greater electron density at the iron centers would be
transmitted to the peroxo ligand. Thermolysis of the
peroxo adducts in a variety of media results in solvent
oxidation, providing ketone and alcohol products in
modest yields based on the complex. A detailed analysis
of cyclopentane oxidation provided evidence for a radical
chain autoxidation mechanism, a reaction manifold
which does not mimic the hydrocarbon oxidation chem-
istry of sMMO. Future e€orts are aimed at preparing
diiron(III) peroxo complexes having carboxylate-bridged
structures that facilitate conversion to a Q-type unit to
allow access to the enzymatic hydroxylation pathway.
‰FeI2IIꢀm O2†ꢀXDK†ꢀO2CPhCy†2ꢀBu Im† Š
2
O
O bond
homolysis!Á ‰FeIVꢀO†2ꢀXDK†ꢀO2CPhCy†2ꢀBu Im† Š
2
2
C5H9
! C5H9Á
ꢀ11†
Â
Ã
FeI2IIꢀm O2†ꢀXDK†ꢀO2CPhCy†2ꢀBu Im†
2
Â
Ã
Á
FeIIꢀXDK†ꢀO2CPhCy†2ꢀBu Im†
*
)
ꢀ12†
2
2
j
! OHÁ‡FeꢀIII† Products
‡
1;H
An important conclusion to be drawn from these cyclo-
pentane oxidation studies is that, despite having gener-
ated a stoichiometrically accurate model of the Hperoxo
intermediate, we have not accessed the manifold of
reactivity used by the diiron centers in sMMO in terms
of substrate scope, product selectivity, or the oxidation
mechanism. A similar diiron(III) peroxo adduct has
been suggested as a key intermediate in iron(III)-cata-
lyzed hydrocarbon oxidations with H2O2,27 but these
systems also lack sMMO selectivity and radical path-
ways have been implicated.30,37 Conversely, studies of
the enzyme with radical clock substrate probes and
chiral ethane have provided evidence against a discrete
radical intermediate.24,25 Hence, for a functional model
system to duplicate the chemistry of sMMO, metal-
based oxidants which abstract hydrogen from a sub-
strate without concomitantly forming a carbon±oxygen
bond must be avoided. Not only might such a reaction
lead to undesired radical chain autoxidation chemistry,
but it would also imply that the model has not matched
the composition and structure of the key enzymatic
oxidant.
Acknowledgements
This work was supported by grants from the National
Science Foundation and AKZO Corp. We thank A. M.
Valentine, D. P. Steinhuebel, and J. D. Du Bois for
many helpful discussions.
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