Direct evidence for oxygen-atom exchange between nonheme oxoiron(IV) complexes and isotopically labeled water

Article abstract of DOI:10.1002/anie.200353497

Rates of exchange: Evidence that non-heme oxoiron(IV) complexes exchange their oxygen atoms with H₂¹⁸O was obtained for the first time, by monitoring electrospray ionization mass spectral changes of the oxoiron(IV) species. The oxyge

Full text of DOI:10.1002/anie.200353497

Angewandte
Chemie
Nonheme Iron Complexes
Direct Evidence for Oxygen-Atom Exchange
between Nonheme Oxoiron(iv) Complexes and
Isotopically Labeled Water**
Mi Sook Seo, Jun-Hee In, Sun Ok Kim, Na Young Oh,
Jongki Hong, Jinheung Kim,* Lawrence Que, Jr.,* and
Wonwoo Nam*
The establishment of the involvement of high-valent iron-oxo
intermediates in the catalytic cycles of heme and nonheme
iron monooxygenases and their model compounds has been
an important goal in mechanistic enzymology and bioinor-
ganic chemistry.[1,2] These highly reactive and unstable
intermediates are often difficult to characterize directly;
therefore, 18O-labeled water experiments have frequently
been carried out to obtain indirect insight into the nature of
the reactive intermediates involved in the catalytic oxygen-
ation reactions.[3–5] Since metal-oxo species can in principle
exchange their oxygen with labeled water prior to oxo
transfer to organic substrates (Scheme 1),[3] the incorporation
of labeled 18O from H218O into oxidation products has been
Scheme 1. Proposed mechanism for 18O-incorporation from H218O into
products in metal-catalyzed oxygenation reactions.
[*] Prof. Dr. J. Kim
Department of Chemical Technology
Changwon National University, Kyungnam 641-773 (Korea)
Fax: (+82) 55-283-6465
E-mail: jinkim@sarim.changwon.ac.kr
Prof. Dr. L. Que, Jr.
Department of Chemistry and Center for Metals in Biocatalysis
University of Minnesota, Minneapolis, Minnesota 55455 (USA)
Fax: (+1) 612-624-7029
E-mail: que@chem.umn.edu
Dr. M. S. Seo, J.-H. In, S. O. Kim, N. Y. Oh, 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)232-772-384
E-mail: wwnam@ewha.ac.kr
Dr. J. Hong
Hazardous Substance Research Team
Korea Basic Science Institute, Seoul 136-701 (Korea)
[**] This research was supported by the Ministry of Science and
Technology of Korea through Creative Research Initiative Program
(W.N.), the KOSEF (R02–2003-000-10047-0 to W.N.), and the NIH
(GM-33162 to L.Q.). We also thank KOSEF and NSF for stimulating
this international cooperative research effort.
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.200353497
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2417

Communications
considered as evidence for the participation of high-valent
metal-oxo intermediates in oxygen-atom transfer reactions.
However, the mechanisms of oxygen exchange between high-
valent metal-oxo species and H218O are not well understood.
For example, the rate of oxygen exchange has not yet been
directly measured in enzymes and biomimetic systems.[6]
A
mechanism involving oxo-hydroxo tautomerism has been
proposed by Meunier and co-workers for heme models[3,4f]
but may not be generally applicable to nonheme models. The
recent isolation and unexpected stability of nonheme oxoir-
on(iv) complexes[7] provide us with an unprecedented oppor-
tunity to investigate mechanisms of oxygen exchange in
nonheme iron models. Herein, we report the first direct
evidence of 18O exchange between nonheme oxoiron(iv)
complexes and H218O, and the determination of activation
parameters for the 18O exchange reactions.
The addition of H2O2 to a reaction solution containing
[Fe(TMC)(OTf)2] (TMC = 1,4,8,11-tetramethyl-1,4,8,11-tet-
raazacyclotetradecane, OTf = CF3SO3), thioanisole, and a
small amount of H218O in CH3CN at 108C produced a
green-colored solution with an absorption maximum wave-
2+
length lmax at 820 nm, thus indicating that [(TMC)FeIV O]
=
(1) is generated in this reaction.[7a] After the intermediate
reverted back to the starting [Fe(TMC)]2+ complex (t1/2
ꢀ
70 s),[8] analysis of the reaction solution with GC and GC/
MS revealed that methyl phenyl sulfoxide[9] was obtained as a
major product (ꢀ 80% yield based on the amount of H2O2
used) and 54% of the oxygen in the sulfoxide product derived
from the labeled water. The 18O-incorporation from H218O
into the sulfoxide product was found to increase linearly with
the increase of 18O% in the water (Figure 1).[4f] Since the
Figure 2. ESI-MS spectral changes of 1 (left) and of 2 (right) upon the
addition of H218O (20 mL) to reaction solutions containing in situ-gen-
erated 1 and 2 (2 mm) at 108C.
477.3) decreased, whereas the mass peak corresponding to
[FeIV(18O)(TMC)(OTf)]+ (m/z = 479.2) increased. By plotting
the percentages of 18O in 1 against the incubation time, we
were able to determine a pseudo-first-order rate constant
k
obs = 1.5(3) ” 10À3 sÀ1 at 108C (Figure 3a). The rate of oxygen
exchange increased concomitantly with the amount of H218O
in the reaction mixture, affording a second rate constant k2 of
5.4(6)mÀ1 sÀ1 (Figure 3b). We also found that the rate of
oxygen exchange was retarded as the reaction temperature
lowered. By determining the rates from 283 to 308 K, we
obtained activation parameters of DH° = 4.1(6) kcalmolÀ1
and DS° = À57(8) calmolÀ1 KÀ1 (Figure 3c).
Much to our surprise, we also observed 18O exchange with
2+
[(N4Py)FeIV O]
(2) (N4Py = N,N-bis(2-pyridylmethyl)-
=
bis(2-pyridyl)methylamine), a complex with a pentadentate
ligand.[7c] As with 1, this exchange could easily be monitored
by the decrease of the mass peak corresponding to
[FeIV(16O)(N4Py)(ClO4)]+ (m/z = 538.1) and the increase of
the mass peak corresponding to [FeIV(18O)(N4Py)(ClO4)]+
(m/z = 540.1) upon the addition of H218O to a reaction
solution of 2 (Figure 2). The pseudo-first-order rate constant
was determined to be kobs = 1.7(3) ” 10À3 sÀ1 at 108C (Sup-
porting Information). As observed in the reactions of 1, the
rate of oxygen-atom exchange between 2 and H218O increased
concomitantly with the amount of H218O in the reaction
mixture, affording a second rate constant k2 of 4.8(5) mÀ1 sÀ1
(Supporting Information). The rate of oxygen-atom exchange
was faster at higher temperature, and analysis of the rates of
oxygen-atom exchange from 283 to 308 K afforded activation
Figure 1. Plot of 18O (%) in methyl phenyl sulfoxide against H218O
(vol%) in water. See Experimental Section for detailed reaction proce-
dures.
oxygen atom of methyl phenyl sulfoxide does not exchange
with H218O under the reaction conditions, the observed 18O-
incorporation from H218O demonstrates that 1 is generated as
a reactive species in the reaction of [Fe(TMC)]2+ and H2O2,
and that 1 exchanges its oxygen atom with H218O before the
oxo group of 1 is transferred to thioanisole (see Scheme 1).[3–5]
This observation led us to monitor oxygen-atom exchange
between 1 and H218O directly with electrospray ionization
mass spectrometry (ESI-MS).[7,10,11] Figure 2 shows that upon
the addition of H218O to a reaction solution of 1, the mass
peak corresponding to [FeIV(16O)(TMC)(OTf)]+ (m/z =
parameters
of
DH° = 4.0(6) kcalmolÀ1
and
DS° =
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Chemie
Scheme 2. Proposed oxo–hydroxo tautomerism mechanisms for 18O exchange in
a) heme and b) nonheme iron models.
of the N4Py ligand and the way it wraps around the iron
center does not permit binding of a water molecule trans to
the oxo atom (see the proposed structure of 2 in Figure 2).
Despite these constraints, H218O exchanges readily with the
iron-oxo units of 1 and 2, with very similar activation barriers
(see above). We are thus compelled to propose an alternative
to the oxo–hydroxo tautomerism mechanism, in which
oxygen exchange occurs via a twofold symmetric cis-dihy-
droxoiron(iv) transition state that is formed by coordination
of a water molecule to the iron center adjacent to the oxo
group (Scheme 2b). The unusual geometry of the proposed
intermediate is similar to that associated with h2-peroxoiron
complexes.[11,12] Indeed the fact that such a side-on peroxo
complex has been characterized for [FeIII(N4Py)] complex[12a]
is a strong argument for this proposed transition state.
In summary, we report the first direct evidence for
oxygen-atom exchange between nonheme oxoiron(iv) com-
plexes and H218O, and the first direct measurement for the
rates and activation parameters for the 18O-exchange reac-
tions. Oxygen-atom exchange in nonheme oxoiron(iv) models
is proposed to occur not through the trans oxo-hydroxo
tautomerism pathway proposed in high-valent metal-oxo
porphyrins but by a variant that involves a cis-dihydroxoir-
on(iv) transition state.
Figure 3. a) Plot of ln [[FeIV(18O)(TMC)]] against incubation time for
the oxygen-atom exchange between 1 and H218O (20 mL) at 108C.
b) Plot of kobs against the amounts of H218O for the oxygen-atom
exchange between 1 and H218O at 258C. c) Determination of activation
parameters for the oxygen exchange of 1 with H218O (20 mL). See
Experimental Section for detailed reaction procedures.
À57(8) calmolÀ1 KÀ1, which are quite similar to those
obtained for 1 (Supporting Information).
Experimental Section
General: H218O (95% 18O-enriched) was purchased from ICON
Services Inc. (Summit, NJ, USA). UV/Vis spectra were recorded on a
Hewlett Packard 8453 spectrophotometer equipped with an Optostat
variable-temperature liquid-nitrogen cryostat (Oxford instruments)
or a circulating water bath. Electrospray ionization mass spectra were
collected on a Thermo Finnigan (San Jose, CA, USA) LCQ Deca XP
Plus and Advantage quadrupole ion trap instrument. Product
analyses were performed on a Hewlett-Packard 5890 II Plus gas
chromatograph interfaced with Hewlett-Packard model 5989B mass
spectrometer.
How do nonheme oxoiron(iv) complexes exchange their
oxygen atoms with labeled water? For high-valent metal-oxo
porphyrin species, the prevailing exchange pathway is
through the oxo–hydroxo tautomerism mechanism proposed
by Meunier and co-workers,[3,4f] which entails the binding of
labeled water trans to the oxo group and then tautomerization
of this species to a symmetric trans-dihydroxoiron(iv) inter-
mediate that scrambles the label (Scheme 2a). This pathway
clearly cannot be operative for 1 and 2, since such a symmetric
trans-dihydroxoiron(iv) species cannot be attained for these
nonheme complexes. The crystal structure of 1 shows that the
top and bottom of the TMC ligand, unlike for the planar
porphyrin ligands, are not equivalent; in fact all four N-
methyl groups point away from the oxo group.[7a] Thus,
although it is conceivable for labeled water to bind trans to
the oxo group by displacement of the bound acetonitrile
ligand, a symmetric trans-dihydroxoiron(iv) transition state
cannot be obtained. In the case of 2, the pentadentate nature
Oxidation of thioanisole by Fe(TMC)(OTf)2 and H2O2: This
reaction was run at least in duplicate under air, by monitoring the UV/
Vis spectral changes of reaction solutions. The addition of H2O2
(6 mm, diluted in 20 mL CH3CN) into a 1 cm UV cuvette containing
[Fe(TMC)(OTf)2] (6 mm), thioanisole (0.12m), and H218O (0.12 mL,
95% 18O) in CH3CN (3 mL) at 108C resulted in the formation of a
green species, [(TMC)FeIV O]
. After the green intermediate
2+
=
reverted back to the starting [Fe(TMC)]2+ complex, the reaction
solution was directly analyzed by GC and GC/MS. The 16O and 18O
compositions in thioanisole oxide were analyzed by the relative
abundances of m/z = 125 and 140 for 16O and m/z = 127 and 142 for
18O.
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Isotope labeling studies with oxoiron(iv) complexes and H218O:
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Complexes 1 and 2 were prepared by treating [Fe(TMC)(OTf)2]
(2 mm) and [Fe(N4Py)(ClO4)2] (2 mm), respectively, with 1 equivalent
of peracid (peracetic acid for 1 and m-chloroperbenzoic acid for 2) in
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distribution patterns of 1 before and after addition of labeled water
were provided with the bars representing the calculated isotope
distributions (Supporting Information).
2+
[8] In the absence of thioanisole, [(TMC)FeIV O]
decayed
=
extremely slowly (t1/2 ~ 5 h).
[9] A trace amount (< 2%) of methyl phenyl sulfone was also
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Keywords: enzyme models · iron · oxidation · oxo ligands ·
oxygen
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