Mechanistic insight into the aromatic hydroxylation by high-valent iron(IV)-oxo porphyrin π-cation radical complexes

Article abstract of DOI:10.1021/jo070557y

(Chemical Equation Presented) Mechanistic studies of the aromatic hydroxylation by high-valent iron(IV)-oxo porphyrin π-cation radicals revealed that the aromatic oxidation involves an initial electrophilic attack on the π-system of the aromatic ring to p

Full text of DOI:10.1021/jo070557y

SCHEME 1
Mechanistic Insight into the Aromatic
Hydroxylation by High-Valent Iron(IV)-oxo
Porphyrin π-Cation Radical Complexes
Min-Jung Kang,† Woon Ju Song,† Ah-Rim Han,†
Young S. Choi,‡ Ho G. Jang,*,‡ and Wonwoo Nam*,†
Department of Chemistry, DiVision of Nano Sciences, and
Center for Biomimetic Systems, Ewha Womans UniVersity,
Seoul 120-750, Korea, and Department of Chemistry and
Center for Electro & Photo ResponsiVe Molecules,
Korea UniVersity, Seoul 136-701, Korea
wwnam@ewha.ac.kr; hgjang@korea.ac.kr
ReceiVed April 1, 2007
mechanism of the aromatic hydroxylation has been proven to
be quite complex, as shown in the proposed mechanisms of the
aromatic ring hydroxylation by high-valent iron(IV)-oxo por-
phyrin π-cation radicals (the so-called Compound I) (Scheme
1). Early studies concluded that the hydroxylation of aromatic
compounds occurs via an arene oxide formation (Scheme 1,
pathway A).4 More recent experimental evidence, however, has
revealed that the aromatic oxidation does not proceed via the
epoxide intermediate formation but occurs via the generation
of a tetrahedral radical or cationic σ-complex (Scheme 1,
pathway B).5 Very recently, density functional theory (DFT)
calculations of aromatic hydroxylation by Compound I have
shown that the aromatic ring activation involves an initial
electrophilic attack on the π-system of the aromatic ring to
produce a radical or cationic species (Scheme 1, pathway B).6,7
The evidence for the formation of radical cations by direct
electron abstraction from aromatic compounds is still ambiguous
(Scheme 1, pathway C),8 but DFT calculations do not support
the electron-transfer mechanism.6 The hydrogen abstraction
mechanism has been ruled out on the basis of experimental
results, including a small kinetic isotope effect (KIE) value
despite the high bond dissociation energy of aromatic C-H
bonds, and computational calculations (Scheme 1, pathway
D).6,9,10
Mechanistic studies of the aromatic hydroxylation by high-
valent iron(IV)-oxo porphyrin π-cation radicals revealed that
the aromatic oxidation involves an initial electrophilic attack
on the π-system of the aromatic ring to produce a tetrahedral
radical or cationic σ-complex. The mechanism was proposed
on the basis of experimental results such as a large negative
Hammett F value and an inverse kinetic isotope effect. By
carrying out isotope labeling studies, the oxygen in oxygen-
ated products was found to derive from the iron-oxo
porphyrin intermediates.
Aromatic hydroxylation is an important chemical process in
enzymatic reactions, as evidenced by the detoxification processes
and drug metabolism by Cytochromes P450, nonheme iron
mono- and dioxygenases, and copper enzymes.1-3 The aromatic
hydroxylation has been extensively investigated over the past
three decades in Cytochromes P450 and iron porphyrin models,
with the intention of understanding their reaction mechanisms
and developing artificial catalysis that can be used in drug
synthesis and biodegradation of environmental pollutants.1 The
Since the previously proposed mechanisms were based on
experimental results obtained under catalytic conditions and with
an assumption that Compounds I were generated as reactive
species in the catalytic reactions, we have investigated the
aromatic hydroxylation by generating high-valent iron(IV)-oxo
porphyrin π-cation radicals and using the intermediates directly
(4) (a) Jerina, D. M.; Daly, J. W. Science 1974, 185, 573-582. (b) Jerina,
D. M.; Daly, J. W.; Witkop, B.; Zaltzman, P.; Udenfriend, S. J. Am. Chem.
Soc. 1968, 90, 6525-6527.
† Ewha Womans University.
‡ Korea University.
(1) (a) de Montellano, P. R. O. Cytochrome P450: Structure, Mechanism,
and Biochemistry, 3rd ed.; Kluwer Academic/Plenum Publishers: New
York, 2005. (b) Meunier, B.; de Visser, S. P.; Shaik, S. Chem. ReV. 2004,
104, 3947-3980. (c) Meunier, B. In Biomimetic Oxidations Catalyzed by
Transition Metal Complexes; Imperial College Press: London, 2000; pp
171-214.
(5) (a) Vannelli, T.; Hooper, A. B. Biochemistry 1995, 34, 11743-11749.
(b) Korzekwa, K. R.; Swinney, D. C.; Trager, W. F. Biochemistry 1989,
28, 9019-9027. (c) Burka, L. T.; Plucinski, T. M.; MacDonald, T. L. Proc.
Natl. Acad. Sci. U.S.A. 1983, 80, 6680-6684.
(6) De Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2003, 125, 7413-
7424.
(2) (a) Solomon, E. I.; Brunold, T. C.; Davis, M. I.; Kemsley, J. N.;
Lee, S.-K.; Lehnert, N.; Neese, F.; Skulan, A. J.; Yang, Y.-S.; Zhou, J.
Chem. ReV. 2000, 100, 235-349. (b) Fitzpatrick, P. F. Biochemistry 2003,
42, 14083-14091. (c) Costas, M.; Mehn, M. P.; Jensen, M. P.; Que, L., Jr.
Chem. ReV. 2004, 104, 939-986. (d) Nam, W. Acc. Chem. Res., published
online May 2007, http://dx.doi.org/10.1021/ar700027f.
(3) (a) Lewis, E. A.; Tolman, W. B. Chem. ReV. 2004, 104, 1047-1076.
(b) Land, E. J.; Ramsden, C. A.; Riley, P. A. Acc. Chem. Res. 2003, 36,
300-308.
(7) (a) Bathelt, C. M.; Ridder, L.; Mulholland, A. J.; Harvey, J. N. J.
Am. Chem. Soc. 2003, 125, 15004-15005. (b) Bathelt, C. M.; Ridder, L.;
Mulholland, A. J.; Harvey, J. N. Org. Biomol. Chem. 2004, 2, 2998-3005.
(8) (a) Sato, H.; Guengerich, F. P. J. Am. Chem. Soc. 2000, 122, 8099-
8100. (b) Riley, P.; Hanzlik, R. P. Xenobiotica 1994, 24, 1-16.
(9) Hanzlik, R. P.; Ling, K.-H. J. J. Am. Chem. Soc. 1993, 115, 9363-
9370.
(10) Shiota, Y.; Suzuki, K.; Yoshizawa, K. Organometallics 2005, 24,
3532-3538.
10.1021/jo070557y CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/10/2007
J. Org. Chem. 2007, 72, 6301-6304
6301

FIGURE 2. Hammett plot of log krel against σp of para-X-substituted
benzenes. The krel values were calculated by dividing k2 of para-X-
benzene by k2 of benzene.
the kinetic data allowed us to determine the kobs value to be
3.0(3) × 10-3 s-1 (Figure 1a, inset). The pseudo-first-order rate
constants increased proportionally with benzene concentration,
thus leading us to determine a second-order rate constant to be
1.0(1) × 10-1 M-1‚s-1 (Figure 1b). Activation parameters for
the benzene hydroxylation was determined by plotting first-
order-rate constants measured at different temperatures (183-
208 K) against 1/T (Figure 2c); the activation enthalpy and
entropy values were calculated to be ∆H‡ ) 4.6(3) kcal‚mol-1
and ∆S‡ ) -29(2) cal‚mol-1‚K-1, respectively. Product analysis
of the benzene hydroxylation with GC and GC-MS revealed
that benzoquinone was produced as a major product (vide infra).
We then investigated the electronic effect of benzene substrate
on reaction rates, by carrying out the reactions of 1 with various
para-X-substituted benzenes at -80 °C. The second-order rate
constants were determined under the conditions described above
but with different concentrations depending on their relative
reactivities (Supporting Information, Figure S2). The data in
Table S1 (Supporting Information) indicate that the electron-
donating ability of the para substituents influences the reaction
rate significantly. By plotting the second-order rates as a function
of σp of the para substituents, a good linear correlation was
obtained with a large negative Hammett F value of -8.0 (Figure
2), indicating an unusually high charge separation and electro-
philic nature in the transition state of the benzene oxidation by
iron(IV)-oxo porphyrin π-cation radical species. Further, such
a large negative F value of -8.0 suggests the generation of a
cationic species rather than a radical species in the transition
state (see Scheme 1).6
It is worth noting that Hammett F values reported previously
in the catalytic oxidation of aromatic compounds by Cytochrome
P450 and iron(III) porphyrins are much smaller (F value of -1)
than the value determined kinetically with iron(IV)-oxo por-
phyrin π-cation radicals generated in situ.8b,12 Further, it is of
interest to compare Hammett F values obtained in the aromatic
hydroxylation and olefin epoxidation reactions.11,13,14 In olefin
epoxidations, F values of -1.8 and -1.9 were reported in the
competitive epoxidation of para-substituted styrenes by 1 and
in the kinetic studies of para-substituted styrenes by
[(TMP)+•FeIV(O)]+ (TMP ) meso-tetramesitylporphinato di-
anion), respectively.11,13 Such a large difference between the F
FIGURE 1. (a) UV-vis spectral changes of 1 (1.5 mM) upon addition
of 100 equiv of benzene in CH2Cl2 at -80 °C. Inset shows absorbance
traces monitored at 660 nm. (b) Plot of kobs against benzene concentra-
tion to determine a second-order rate constant at -80 °C. (c) Plot of
first-order-rate constants against 1/T to determine activation parameters.
in kinetic studies of aromatic hydroxylation under stoichiometric
conditions. In this work, we have observed a large negative
Hammett F value in the reactions of para-substituted benzenes
and inverse KIE. By carrying out 18O-labeling experiments, the
oxygen in oxygenated products was found to derive from the
iron-oxo porphyrin intermediates. To the best of our knowledge,
this study provides the first mechanistic details of aromatic
hydroxylation investigated with high-valent iron(IV)-oxo por-
phyrin π-cation radicals generated in situ.
A high-valent iron(IV)-oxo porphyrin π-cation radical com-
plex, [(TPFPP)+•FeIV(O)]+ (1) (TPFPP ) meso-tetrakis(pen-
tafluorophenyl)porphinato dianion) (Supporting Information,
Figure S1 for the structure of iron porphyrins),11 was prepared
by treating Fe(TPFPP)(CF3SO3) with m-chloroperbenzoic acid
(m-CPBA) in CH2Cl2 containing a small amount of CH3CN at
-80 °C. Upon addition of benzene to the solution, the
intermediate reverted back to the starting iron porphyrin complex
and showed pseudo-first-order decay as monitored by a UV-
vis spectrophotometer (Figure 1a). Pseudo-first-order fitting of
(12) Khavasi, H. R.; Safari, N. J. Mol. Catal. A: Chem. 2004, 220, 127-
(11) We have shown very recently that iron(IV)-oxo porphyrin π-cation
radicals prepared from their triflate iron porphyrins favor aromatic ring
oxidation over C-H hydroxylation and that CH3CN, which was used as a
co-solvent in reaction solutions, might be coordinated as an axial ligand
trans to the iron-oxo group: Song, W. J.; Ryu, Y. O.; Song, R.; Nam, W.
J. Biol. Inorg. Chem. 2005, 10, 294-304.
132.
(13) Groves, J. T.; Watanabe, Y. J. Am. Chem. Soc. 1986, 108, 507-
508.
(14) (a) Traylor, T. G.; Xu, F. J. Am. Chem. Soc. 1988, 110, 1953-
1958. (b) Lindsay Smith, J. R.; Sleath; P. R. J. Chem. Soc., Perkin Trans.
2 1982, 1009-1015.
6302 J. Org. Chem., Vol. 72, No. 16, 2007

TABLE 1. Kinetic Isotope Effect in the Hydroxylation of
Aromatic Compounds by High-Valent Iron(IV)-oxo Porphyrin
π-Cation Radical Complexesa
SCHEME 2
benzene
hydroxylation by 1
toluene
hydroxylation by 2
naphthalene
hydroxylation by 3
rate constantb
rate constantb
rate constantb
(10-1 s-1
)
(10-3 s-1
)
(10-2 s-1
)
C6H6
0.8
C6D6 kH/kD C7H8
1.0 0.8 1.8
C7D8 kH/kD C10H8 C10D8 kH/kD
2.2 0.82 0.8 0.8
1
a Reactions were done with [(TDCPP)+•FeIV(O)]+ (1.5 mM) and
substrates (15 mM for benzene, 150 mM for toluene, and 15 mM for
naphthalene) in CH2Cl2 at -80 °C. Rate constants are averaged by three
determinations.
values of aromatic hydroxylation and olefin epoxidation is
attributable to the involvement of a more polar species in the
transition state of aromatic hydroxylation, as Shaik and co-
workers proposed in theoretical studies that a major difference
between benzene hydroxylation and olefin epoxidation is the
appearance of a cationic pathway in the case of benzene,
whereas radicalar-only pathways operate in the case of ole-
fins.6,15
Kinetic isotope effect (KIE) was also investigated kinetically
in the hydroxylation of undeuterated and deuterated aromatic
compounds by high-valent iron(IV)-oxo porphyrin π-cation
radicals, such as in the reactions of benzene and deuterated
benzene by 1, toluene and deuterated toluene by
[(TDFPP)+•FeIV(O)]+ (2) (TDFPP ) meso-tetrakis(2,6-difluo-
rophenyl)porphinato dianion), and naphthalene and deuterated
naphthalene by [(TDCPP)+•FeIV(O)]+ (3) (TDCPP ) meso-
tetrakis(2,6-dichlorophenyl)porphinato dianion) (Table 1). The
calculated kH/kD value of ∼0.8 indicates an inverse KIE in the
aromatic ring oxidation reactions; the observation of the inverse
KIE is consistent with the sp2-to-sp3 hybridization change during
the addition of an electrophilic iron-oxo species to the sp2 center
of aromatic ring to form a σ adduct.5a,6,9,16 Further, the inverse
KIE rules out the hydrogen abstraction mechanism;9 large KIE
values ranging from 5 to 14 are observed in C-H bond
activation by high-valent iron(IV)-oxo porphyrin π-cation
radicals,17 and we have reported a KIE value of 14 in
cyclohexane hydroxylation by 1 at -80 °C.11
Finally, the source of oxygen in oxygenated products was
investigated by carrying out isotope labeling studies in the
hydroxylation of toluene by 18O-labeled [(TPFPP)+•FeIV(18O)]+
(1-18O) at -80 °C. To increase the accuracy of product analysis,
the catalytic hydroxylation of toluene by [FeIII(TPFPP)]+ and
PhIO was carried out in the presence of H218O at 25 °C. By
analyzing the reaction solution with GC and GC-MS, we found
that 2-methylbenzoquinone was produced as a major product
(70% based on catalyst) with the formation of small amounts
of 2- and 4-methylphenol (less than 5% based on catalyst) and
that the percentages of M, M + 2, and M + 4 products were 9,
40, and 50%, respectively (Scheme 2).18 The formation of
quinone products has been well documented in aromatic
hydroxylation reactions catalyzed by metalloporphyrins,19-21
and a mechanism has been proposed in which two metal-oxo
complexes are needed for the formation of one quinone
product.19,20 The observation of the significant amount of 18O-
incorporation into the quinone product indicates that the source
of the oxygen in the product is the iron-oxo porphyrin complex.
However, since the product was not fully 18O-labeled, we
checked the percent of 1-18O generated in the labeled H218O
experiments by carrying out the catalytic epoxidation of
cyclohexene by [FeIII(TPFPP)]+ and PhIO under the identical
conditions of the toluene hydroxylation.22 In the latter experi-
ment, we found that cyclohexene oxide contains 75% 18O,
indicating that 75% of 1 is labeled by 18O. In control experi-
ments, we checked that the oxygen of 2-methylbenzoquinone
does not exchange with H218O under the conditions. Further,
the product formed in the hydroxylation of toluene under 18O2
atmosphere did not contain 18O, demonstrating that O2 is not
involved in the toluene hydroxylation. Furthermore, the oxida-
tion of phenol and o-cresol by 1 afforded only trace amounts
of benzoquinone and 2-methylbenzoquinone, respectively,
proposing that two high-valent metal-oxo molecules are simul-
taneously involved in producing the quinone products in the
oxidation of aromatic compounds.19a
In summary, we have reported mechanistic details of aromatic
hydroxylation investigated kinetically with high-valent iron(IV)-
oxo porphyrin π-cation radicals generated in situ. On the basis
of the experimental results of a large Hammett F value and an
inverse KIE, we have proposed that the aromatic oxidation
involves an initial electrophilic attack on the π-system of the
aromatic ring to produce a tetrahedral radical or cationic
σ-complex (Scheme 1, pathway B). We have also demonstrated
(18) When we checked the percent of 1-18O generated in the labeled
H218O experiments by carrying out the catalytic epoxidation of cyclohexene
with [FeIII(TPFPP)]+ and PhIO under the identical conditions of the toluene
hydroxylation, we found that cyclohexene oxide contains 75% 18O. This
result indicates that 75% of 1 is 18O-labeled.
(19) (a) Song, R.; Sorokin, A.; Bernadou, J.; Meunier, B. J. Org. Chem.
1997, 62, 673-678. (b) Sorokin, A.; Meunier, B. Eur. J. Inorg. Chem. 1998,
1269-1281.
(20) Higuchi, T.; Satake, C.; Hirobe, M. J. Am. Chem. Soc. 1995, 117,
8879-8880.
(21) Khavasi, H. R.; Davarani, S. S. H.; Safari, N. J. Mol. Catal. A:
Chem. 2002, 188, 115-122.
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Soc. 2001, 123, 3037-3047. (b) de Visser, S. P.; Ogliaro, F.; Sharma, P.
K.; Shaik, S. J. Am. Chem. Soc. 2002, 124, 11809-11826.
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(17) (a) Kumar, D.; de Visser, S. P.; Sharma, P. K.; Cohen, S. Shaik, S.
J. Am. Chem. Soc. 2004, 126, 1907-1920 and references therein. (b) Iyer,
K. R.; Jones, J. P.; Darbyshire, J. F.; Trager, W. F. Biochemistry 1997, 36,
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Soc. 1994, 116, 9375-9376. (c) Lee, K. A.; Nam, W. J. Am. Chem. Soc.
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J. Org. Chem, Vol. 72, No. 16, 2007 6303

treating PhIO (10 mM, diluted in 50 µL CH3OH) with H218O (10
µL, 0.52 mmol, 95% 18O enriched), into a reaction solution
containing Fe(TPFPP)(OTf) (2 mM) and toluene (0.2 M) in a
solvent mixture (0.5 mL) of CH2Cl2 and CH3CN (200:1) at 25 °C.
Then, the reaction mixture was stirred for 0.5 h and directly
analyzed by GC-MS. 16O and 18O compositions in 2-methylben-
zoquinone were analyzed by the relative abundances of the
following mass peaks: m/z ) 122 (M), 124 (M + 2), and 126 (M
+ 4) for 2-methylbenzoquinone (see Scheme 2). The reaction
procedures for cyclohexene epoxidation were the same as described
for the toluene hydroxylation, and the 16O and 18O compositions
in cyclohexene oxide were determined by the relative abundances
of the mass peaks at m/z ) 83 and 97 for 16O and m/z ) 85 and 99
for 18O.
unambiguously that the oxygen in oxygenated products derives
from the iron-oxo intermediates, not from molecular oxygen.
Experimental Section
Kinetic Studies and Product Analysis. In general, high-valent
iron(IV)-oxo porphyrin π-cation radicals were prepared by adding
1.3 equiv of m-CPBA (2 mM, diluted in 50 µL of CH2Cl2) to
reaction solutions containing their corresponding iron(III) porphyrin
triflates (1.5 mM) in a solvent mixture (0.5 mL) of CH2Cl2 and
CH3CN (200:1) in a 0.1-cm UV cell at -80 °C. Then, appropriate
amounts of substrates (diluted in 100 µL CH2Cl2) were added to
the UV cell, and spectral changes of the intermediate were directly
monitored by a UV-vis spectrophotometer. Rate constants, kobs
,
were determined by pseudo-first-order fitting of the decrease of
absorption bands at 660 nm for 1, 665 nm for 2, and 680 nm for
3. All the rate constants are averages of at least three determinations.
Product analysis was performed by injecting reaction solutions
directly into GC and GC-MS. Product yields were determined by
comparison with standard curves of known authentic samples and
decane as an internal standard. The source of oxygen in oxy-
genated products was determined by preparing 18O-labeled
[(TPFPP)+•FeIV(18O)]+ (1-18O) and using the intermediate directly
in the hydroxylation of toluene. To increase the accuracy of the
product analysis, the hydroxylation of toluene was performed under
catalytic conditions by adding PhI18O, which was prepared by
Acknowledgment. This research was supported by the
Creative Research Initiative Program of MOST/KOSEF (to
W.N.) and the Korea University Grant (to H.G.J.).
Supporting Information Available: General experimental
conditions, Figure S1 for the structure of iron(III) porphyrin
complexes, and Figure S2 for the determination of second-order
rate constants. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO070557Y
6304 J. Org. Chem., Vol. 72, No. 16, 2007