Oxidative N-dealkylation reactions by oxoiron(IV) complexes of nonheme and heme ligands

Article abstract of DOI:10.1021/ic0614014

Nonheme and heme iron monooxygenases participate in oxidative N-dealkylation reactions in nature, and high-valent oxoiron(IV) species have been invoked as active oxidants that effect the oxygenation of organic substrates. The present study describes the first example of the oxidative N-dealkylation of N,N-dialkylamines by synthetic nonheme oxoiron(IV) complexes and the reactivity comparisons of nonheme and heme oxoiron(IV) complexes. Detailed mechanistic studies were performed with various N,N-dialkylaniline substrates such as para-substituted N,N-dimethylanilines, para-chloro-N-ethyl-N- methylaniline, para-chloro-N-cyclopropyl-N-isopropylaniline, and deuteriated N,N-dimethylanilines. The results of a linear free-energy correlation, inter- and intramolecular kinetic isotope effects, and product analysis studied with the mechanistic probes demonstrate that the oxidative N-dealkylation reactions by nonheme and heme oxoiron(IV) complexes occur via an electron transfer-proton transfer (ET-PT) mechanism.

Full text of DOI:10.1021/ic0614014

Inorg. Chem. 2007, 46, 293−298
Oxidative N-Dealkylation Reactions by Oxoiron(IV) Complexes of
Nonheme and Heme Ligands
Kasi Nehru, Mi Sook Seo, Jinheung Kim,* and Wonwoo Nam*
Department of Chemistry, DiVision of Nano Sciences, and Center for Biomimetic Systems,
Ewha Womans UniVersity, Seoul 120-750, Korea
Received July 27, 2006
Nonheme and heme iron monooxygenases participate in oxidative N-dealkylation reactions in nature, and high-
valent oxoiron(IV) species have been invoked as active oxidants that effect the oxygenation of organic substrates.
The present study describes the first example of the oxidative N-dealkylation of N,N-dialkylamines by synthetic
nonheme oxoiron(IV) complexes and the reactivity comparisons of nonheme and heme oxoiron(IV) complexes.
Detailed mechanistic studies were performed with various N,N-dialkylaniline substrates such as para-substituted
N,N-dimethylanilines, para-chloro-N-ethyl-N-methylaniline, para-chloro-N-cyclopropyl-N-isopropylaniline, and deuteriated
N,N-dimethylanilines. The results of a linear free-energy correlation, inter- and intramolecular kinetic isotope effects,
and product analysis studied with the mechanistic probes demonstrate that the oxidative N-dealkylation reactions
by nonheme and heme oxoiron(IV) complexes occur via an electron transfer−proton transfer (ET−PT) mechanism.
Introduction
nuclear nonheme oxoiron(IV) complexes bearing tetradentate
N4 and pentadentate N5 and N4S ligands were synthesized
and studied in a variety of oxidation reactions, including
alkane hydroxylation, olefin epoxidation, and the oxidation
of PPh3, sulfides, and alcohols.5,6
Metalloenzymes with heme and nonheme iron active sites
participate in many metabolically important oxidative trans-
formations by activating dioxygen in biological reactions.1,2
In the catalytic cycles of dioxygen activation by the enzymes,
high-valent oxoiron(IV) species have been invoked as the
key intermediates that effect the oxygenation of organic
substrates.1,2 For example, oxoiron(IV) porphyrin π-cation
radicals are believed to carry out the oxygenation reactions
in cytochromes P450 (CYP 450).1 Similarly, nonheme
oxoiron(IV) species are invoked as the active oxidants in
nonheme iron enzymes.2 In biomimetic studies, reactivities
of oxoiron(IV) porphyrin π-cation radicals and oxoiron(IV)
porphyrins have been investigated in hydrocarbon oxidations
as chemical models of CYP 450.1,3,4 Very recently, mono-
The oxidative N-dealkylation of N,N-dialkylamines by
CYP 450 and their model compounds has been intensively
(3) (a) Groves, J. T.; Haushalter, R. C.; Nakamura, M.; Nemo, T. E.;
Evans, B. J. J. Am. Chem. Soc. 1981, 103, 2884. (b) Gross, Z.; Nimri,
S. Inorg. Chem. 1994, 33, 1731. (c) Goh, Y. M.; Nam, W. Inorg.
Chem. 1999, 38, 914. (d) Song, W. J.; Ryu, Y. O.; Song, R.; Nam,
W. J. Biol. Inorg. Chem. 2005, 10, 294.
(4) Nam, W.; Park, S.-E.; Lim, I. K.; Lim, M. H.; Hong, J.; Kim, J. J.
Am. Chem. Soc. 2003, 125, 14674.
(5) (a) Rohde, J.-U.; In, J.-H.; Lim, M. H.; Brennessel, W. W.; Bukowski,
M. R.; Stubna, A.; Mu¨nck, E.; Nam, W.; Que, L., Jr. Science 2003,
299, 1037. (b) Kaizer, J.; Klinker, E. J.; Oh, N. Y.; Rohde, J.-U.;
Song, W. J.; Stubna, A.; Kim, J.; Mu¨nck, E.; Nam, W.; Que, L., Jr.
J. Am. Chem. Soc. 2004, 126, 472. (c) Kim, S. O.; Sastri, C. V.; Seo,
M. S.; Kim, J.; Nam, W. J. Am. Chem. Soc. 2005, 127, 4178. (d)
Klinker, E. J.; Kaizer, J.; Brennessel, W. W.; Woodrum, N. L.; Cramer,
C. J.; Que, L., Jr. Angew. Chem., Int. Ed. 2005, 44, 3690. (e) Oh, N.
Y.; Suh, Y.; Park, M. J.; Seo, M. S.; Kim, J.; Nam, W. Angew. Chem.,
Int. Ed. 2005, 44, 4235. (f) Sastri, C. V.; Seo, M. S.; Park, M. J.;
Kim, K. M.; Nam, W. Chem. Commun. 2005, 1405. (g) Sastri, C. V.;
Park, M. J.; Ohta, T.; Jackson, T. A.; Stubna, A.; Seo, M. S.; Lee, J.;
Kim, J.; Kitagawa, T.; Mu¨nck, E.; Que, L., Jr.; Nam, W. J. Am. Chem.
Soc. 2005, 127, 12494. (h) Bukowski, M. R.; Koehntop, K. D.; Stubna,
A.; Bominaar, E. L.; Halfen, J. A.; Mu¨nck, E.; Nam, W.; Que, L., Jr.
Science 2005, 310, 1000. (i) Park, M. J.; Lee, J.; Suh, Y.; Kim, J.;
Nam, W. J. Am. Chem. Soc. 2006, 128, 2630. (j) Sastri, C. V.; Oh,
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* To whom correspondence should be addressed. E-mail: jinheung@
ewha.ac.kr (J.K.), wwnam@ewha.ac.kr (W.N.).
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Schlichting, I. Chem. ReV. 2005, 105, 2253. (c) Meunier, B.; de Visser,
S. P.; Shaik, S. Chem. ReV. 2004, 104, 3947.
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10.1021/ic0614014 CCC: $37.00
Published on Web 12/02/2006
© 2007 American Chemical Society
Inorganic Chemistry, Vol. 46, No. 1, 2007 293

Nehru et al.
Scheme 1. Proposed ET-PT and HAT Mechanisms in Oxidative N-Demethylation by [(Porp)+•FeIVdO]+
FeIVdO]2+ (6a),5b [(TMC)FeIVdO]2+ (6b),5a and (TPFPP)-
FeIVdO (6c)4 (see Figure 1 for the structures of iron
complexes).15 We now provide experimental evidence that
the N-dealkylation of N,N-dialkylanilines by the nonheme
and heme oxoiron(IV) complexes occurs via a rate-limiting
ET coupled with a proton transfer (PT) mechanism.
Chart 1
Results and Discussion
The oxidative N-dealkylation reactions were investigated
with nonheme and heme oxoiron(IV) complexes generated
in situ, and the oxoiron(IV) complexes, 6a-c (Figure 1),
were prepared by the literature methods (see the Experi-
mental Procedures). Upon the addition of 20 equiv of para-
methyl-N,N-dimethylaniline (p-Me-DMA) to the solutions
of 6a-c at 15 °C, the intermediates reverted back to their
starting iron complexes, showing pseudo-first-order decay
as monitored by a UV-vis spectrophotometer (Figure 2a
for 6a and Supporting Information Figures S1a and S2a for
6b and 6c, respectively). Pseudo-first-order fitting of the
kinetic data allowed us to determine kobs values for the
reactions of 6a-c [kobs ) 5.8 × 10-2 s-1 for 6a (2 mM), 4.7
× 10-2 s-1 for 6b (2 mM), and 1.1 × 10-1 s-1 for 6c (2 ×
10-2 mM)], and product analysis of the resulting solutions
revealed that para-methyl-N-methylaniline (p-Me-MA) was
produced as a major product with the concurrent formation
of CH2O in all of the reactions (>80% based on the
intermediates generated) (eq 1). The pseudo-first-order rate
constants increased proportionally with the p-Me-DMA
concentration, leading us to determine second-order rate
constants (Table 1, column of k2; Figure 2b for 6a; and
Supporting Information Figures S1b and S2b for 6b and 6c,
respectively). The second-order rate constants indicate that
the oxoiron(IV) porphyrin complex, 6c, is much more
reactive than the nonheme oxoiron(IV) complexes, 6a and
6b, but that the reactivities of 6a and 6b are similar. The
latter result implies that the mechanism of the oxidative
N-dealkylation is different from that of the oxo transfer from
investigated over the past two decades.1a,7 High-valent
oxoiron(IV) porphyrin π-cation radicals are considered as a
common oxidant in the N-dealkylation reactions, but two
different mechanisms, such as an electron transfer-proton
transfer (ET-PT) and a hydrogen atom transfer (HAT)
(Scheme 1),7 have often been proposed on the basis of
mechanistic studies using para-substituted N,N-dimethyl-
anilines (1),8 para-chloro-N-ethyl-N-methylaniline (2),9 para-
chloro-N-cyclopropyl-N-isopropylaniline (3),10 and deuteri-
ated N,N-dimethylanilines (4 and 5) (Chart 1).8,9,11 The
oxidative N-dealkylation has also been reported in the
reactions of nonheme iron enzymes and synthetic nonheme
iron complexes.12,13 For example, the Escherichia coli AlkB
protein has been known to play an important role in alkylated
DNA damage repair, and a nonheme oxoiron(IV) species
has been proposed as an active oxidant.12 In our ongoing
efforts to understand the chemical properties of mononuclear
nonheme and heme oxoiron(IV) complexes in oxidation
reactions,4,5 we have investigated oxidative N-dealkylation
reactions of the aforementioned mechanistic probes14 with
nonheme and heme oxoiron(IV) complexes, such as [(N4Py)-
(6) (a) Balland, V.; Charlot, M.-F.; Banse, F.; Girerd, J.-J.; Mattioli, T.
A; Bill, E.; Bartoli, J.-F.; Battioni, P.; Mansuy, D. Eur. J. Inorg. Chem.
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44, 9592.
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J. P. J. Am. Chem. Soc. 1998, 120, 10762. (b) Baciocchi, E.;
Lanzalunga, O.; Lapi, A.; Manduchi, L. J. Am. Chem. Soc. 1998, 120,
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1993, 268, 1546.
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2001, 123, 8502. (b) Bhakta, M. N.; Wimalasena, K. J. Am. Chem.
Soc. 2002, 124, 1844. (c) Shaffer, C. L.; Harriman, S.; Koen, Y. M.;
Hanzlik, R. P. J. Am. Chem. Soc. 2002, 124, 8268. (d) Bhakta, M. N.;
Hollenberg, P. F.; Wimalasena, K. J. Am. Chem. Soc. 2005, 127, 1376.
(11) (a) Manchester, J. I.; Dinnocenzo, J. P.; Higgins, L.; Jones, J. P. J.
Am. Chem. Soc. 1997, 119, 5069. (b) Dinnocenzo, J. P.; Karki, S. B.;
Jones, J. P. J. Am. Chem. Soc. 1993, 115, 7111.
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Y.; He, C. J. Am. Chem. Soc. 2003, 125, 8730. (c) Trewick, S. C.;
Henshaw, T. F.; Hausinger, R. P.; Lindahl, T.; Sedgwick, B. Nature
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2002, 419, 178.
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Lippard, S. J. J. Am. Chem. Soc. 2001, 123, 4611.
Figure 1. Iron(II) complexes used in this study
294 Inorganic Chemistry, Vol. 46, No. 1, 2007

N-Dealkylation Reactions by Oxoiron(IV) Complexes
Table 1. Kinetic Data and Product Yields Obtained in Oxidative
N-Dealkylation of N,N-Dialkylanilines by Nonheme and Heme
Oxoiron(IV) Complexesa
c
f
g
intermediateb k2 (M-1 s-1
)
Fd
-2.2 15 ( 2
[88:6]
-2.6 10 ( 2
[80:8]
-3.3 16 ( 3
[82:5]
2a/2be
(kH/kD)inter (kH/kD)intra
6a
6b
6c
1.4 ( 0.1
1.2 ( 0.1
3.0 ( 0.3
2.4 ( 0.3
2.8 ( 0.3
4.9 ( 0.5
3.6 ( 0.5
4.2 ( 0.4
(3.0 ( 0.2)
× 104
a Reactions were run at least in triplicate, and the data reported represent
the average of these reactions. b Intermediates were prepared as described
in the Experimental Procedures. c Figure 2b and Supporting Information
Figures S1b and S2b. d Figure 2c, Table 2, and Supporting Information Fig-
ures S1c and S2c. e Product ratios of 2a to 2b. Numbers in brackets are
percent yields of 2a and 2b. f The observed kH and kD values were
determined kinetically in the reactions of p-Me-DMA and p-Me-DMA-d6,
respectively, and the KIE values were calculated by dividing kH by kD. See
Supporting Information Figure S5. g The KIE values were determined from
product analysis of reaction solutions of 5 with LC-ESI MS, and the ratios
were calculated by dividing the relative abundance of para-methyl-N-tri-
deuteromethylaniline (p-Me-MA-d3, 5a) by para-methyl-N-methylaniline
(p-Me-MA, 5b) (see eq 3 in the text). See Supporting Information Figure
S6.
Figure 2. Reactions of [(N4Py)FeIVdO]2+ (6a) with N,N-dialkylanilines
in CH3CN at 15 °C. (a) UV-vis spectral changes of 6a (2 mM) upon
addition of 20 equiv of p-Me-DMA (40 mM). Inset shows absorbance traces
monitored at 695 nm. (b) Plot of kobs against p-Me-DMA concentration to
determine a second-order rate constant. (c) Hammett plot of log kobs against
Table 2. Rate Constants Determined in the Reactions of 6a-c with
Various p-X-N,N-Dimethylanilines (1)a,b
σp of p-X-N,N-dimethylanilines. (d) Plot of log kobs vs E0 of para-
ox
substituted N,N-dimethylanilines.
kobs (s-1
)
Eoox (vs SCE, V)c
6a
6b
6c
nonheme oxoiron(IV) complexes to organic substrates (i.e.,
2e--oxidation reactions) since it has been demonstrated
previously that 6a is a much stronger oxidant than 6b in the
oxygenation of organic substrates such as alkanes, alcohols,
and sulfides.5
X
σp
OMe -0.28
Me
H
0.52
0.69
0.76
0.84
0.92
1.15
1.3
1.1 × 10-1 8.8 × 10-2 ndd
-0.14
5.8 × 10-2 4.7 × 10-2 1.1 × 10-1
1.7 × 10-2 1.6 × 10-2 ndd
0
F
0.15
0.26
0.7
1.3 × 10-2 1.4 × 10-2 1.7 × 10-2
7.6 × 10-3 4.9 × 10-3 4.7 × 10-3
1.0 × 10-3 2.6 × 10-4 1.7 × 10-4
5.0 × 10-4 1.5 × 10-4 1.5 × 10-4
Br
CN
NO2 0.81
a Reactions were run at least in triplicate, and the data reported represent
the average of these reactions. b Rate constants, kobs, were determined by
pseudo-first-order fitting of UV-vis spectral changes monitored at 695 nm
for 6a, 820 nm for 6b, and 547 nm for 6c. Reaction conditions: substrates
(20 equiv to the intermediates) were added to the intermediates (2 mM for
6a and 6b and 2 × 10-2 mM for 6c) in CH3CN at 15 °C. c Data are from
ref 17. d Not determined.
We then investigated the mechanism of the oxidative
N-dealkylation by 6a-c with the mechanistic probes, 1-5
(see Chart 1). First, the electronic effect of substrates was
examined with para-substituted N,N-dimethylanilines (1),8
and we have observed a significant influence of the electron-
donating ability of the para-substituents on the reaction rates
(Table 2). By plotting the rates as a function of σp of the
para-substituents, a good linear correlation was obtained with
large negative Hammett F values, and all substituents fit the
Hammett plot well (Table 1, column of F; Figure 2c for 6a;
and Supporting Information Figures S1c and S2c for 6b and
6c, respectively). Further, the plot of log kobs against the one-
electron oxidation potentials of DMAs (E°ox) afforded a good
linear correlation with large negative slopes, such as -3.3
for 6a, -4.0 for 6b, and -5.0 for 6c (Figure 2d for 6a and
Supporting Information Figures S1d and S2d for 6b and 6c,
respectively). These results indicate that no change of
mechanism occurs depending on the electron-richness of
substrates. Further, the large negative Hammett F values
determined kinetically in the present study are suggestive
of a rate-limiting electron transfer from DMA to the oxo-
iron(IV) species (Scheme 1, pathway ET) (vide infra).8,16 It
should be noted that such a large negative F value was
observed by the kinetic analysis in the oxidative N-
II
demethylation with a Cu2 -O2 adduct,16 but much smaller F
values were reported by analyzing products in the oxidative
N-demethylation of para-substituted DMAs by iron(III)
porphyrin complexes and iodosylbenzene (PhIO) under
catalytic conditions.8b,8c Furthermore, a bell-shaped type
dependence of reaction rates on the E°ox of para-substituted
DMAs and a less sensitive substituent effect on the reaction
rates have been observed in the reactions of cumylperoxyl
radical and para-substituted DMAs, in which HAT rather
than ET-PT from substrates to the cumylperoxyl radical was
proposed as a rate-determining step.17 In the CYP 450 model
with a rate-limiting electron-transfer step, a large negative
(14) We have observed the polymerization of N,N-dialkylanilines in some
cases. Thus, para-substituted N,N-dialkylanilines were used to avoid
the polymerization occurring at the para-position: Venkataramanan,
N. S.; Kuppuraj, G.; Rajagopal, S. Coord. Chem. ReV. 2005, 249, 1249.
(15) Abbreviation used: TMC, 1,4,8,11-tetramethyl-1,4,8,11-tetraazacy-
clotetradecane; N4Py, N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)-
methylamine; TPFPP ) meso-tetrakis(pentafluorophenyl)porphinato
dianion.
(16) Shearer, J.; Zhang, C. X.; Hatcher, L. Q.; Karlin, K. D. J. Am. Chem.
Soc. 2003, 125, 12670.
(17) Fukuzumi, S.; Shimoosako, K.; Suenobu, T.; Watanabe, Y. J. Am.
Chem. Soc. 2003, 125, 9074.
Inorganic Chemistry, Vol. 46, No. 1, 2007 295

Nehru et al.
Scheme 2. Products Formed in the ET-PT and HAT Mechanisms
slope (approximately -8) was observed when the reaction
rates were plotted against the oxidation potential of para-
substituted DMAs.8a
and heme oxoiron(IV) complexes proceeds via an ET
pathway (Scheme 2, pathway ET).
Finally, the inter- and intramolecular kinetic isotope effect
(KIE) values were determined with deuteriated para-methyl-
N,N-dimethylanilines such as para-methyl-N,N-di(trideutero-
methyl)aniline (p-Me-DMA-d6, 4) and para-methyl-N-(tri-
deuteromethyl)-N-methylaniline (p-Me-DMA-d3, 5). The
intermolecular KIE values were measured kinetically (Table
1, column of (kH/kD)inter; Supporting Information Figure S5
showing time traces for the determination of kH and kD
values), whereas the intramolecular KIE values were obtained
by a product analysis method (eq 3) (Table 1, column of
(kH/kD)intra; Supporting Information Figure S6 for product
analysis for the determination of kH/kD values). The inter-
and intramolecular KIE values in Table 1 are fully consistent
with the proposed rate-limiting ET-PT mechanism, on the
basis of the previous results reported in a number of
N-dealkylation reactions by CYP 450 and biomimetic
compounds.8,9,16,19 If the N-dealkylation occurs via a HAT
mechanism, a much higher KIE value would be expected.18,20
Indeed, a KIE value of 50 was reported in both alkane
hydroxylation and alcohol oxidation reactions by 6a, in which
a hydrogen atom abstraction from substrates by 6a was
proposed as a rate-determining step.5b,5e Further, as we have
shown previously, the similar reactivities of 6a and 6b
exclude the possibility of the HAT mechanism. In addition,
the observation that the inter- and intramolecular KIE values
are greater than 1 implies that the first ET process is not
kinetically isolated but coupled with the following PT
process.9b In other words, the oxidative N-dealkylation
reactions may occur via a concerted proton-coupled electron
transfer (PCET) process,21 but more detailed investigations
are needed to establish the PCET mechanism in the oxoiron-
The rate-limiting ET-PT process was further supported
from the N-dealkylation of 2 by 6a-c, in which N-
demethylation was greatly favored over N-deethylation (eq
2).9 The product ratios of 2a to 2b were high in all of the
reactions (Table 1, column of 2a/2b and Supporting Infor-
mation Figure S3 for product analysis). The preference of
the deprotonation of the methyl group over the ethyl
methylene in the step of the proton transfer from the aminium
radical to the (L)FeIVdO species (see the PT step in Scheme
1) was rationalized with a high acidity of the methyl proton
as compared to the ethyl one (i.e., pKa values of N,N-
dimethylaniline and N,N-diethylaniline are 5.15 and 6.56,
respectively).9 If the N-dealkylation initiates via a HAT
mechanism (Scheme 1, pathway HAT), the formation of a
deethylated product, 2b, would be a preferred pathway owing
to a weak methylene C-H bond strength (i.e., ∼3 kcal/mol
less than the methyl C-H bond strength), and a low product
ratio of 2a to 2b would be observed (e.g., a ratio of 0.5 in
the reaction of a tert-butoxy radical with amines).18 Conse-
quently, the high ratios of 2a to 2b observed in the present
study rule out the possibility of a rate-limiting HAT pathway
for the oxidative N-dealkylation reactions.
Additional support for the ET-PT mechanism was
obtained by carrying out the oxidation of para-chloro-N-
cyclopropyl-N-isopropylaniline (3) by 6a-c; compound 3a
(and the ring-opened product) is the product(s) of N-
decyclopropylation resulting from an ET pathway, whereas
3b is the product of N-deisopropylation resulting from a HAT
pathway (Scheme 2).10,19 In the present study, we have
observed that 3a was the predominant product with the
formation of a trace amount of 3b in the reactions of 6a-c
(∼90% yield based on the intermediates generated) (Sup-
porting Information Figures S4 for product analysis), sup-
porting our conclusion that the N-dealkylation by nonheme
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L., Jr.; Fukuzumi, S. Angew. Chem., Int. Ed. 2000, 39, 398. (b)
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2006, 128, 6075. (b) Rhile, I. J.; Mayer, J. M. J. Am. Chem. Soc.
2004, 126, 12718. (c) Mayer, J. M.; Rhile, I. J. Biochim. Biophys.
Acta 2004, 1655, 51. (d) Lebeau, E. L.; Binstead, R. A.; Meyer, T. J.
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296 Inorganic Chemistry, Vol. 46, No. 1, 2007

N-Dealkylation Reactions by Oxoiron(IV) Complexes
Scheme 3. Proposed Mechanism in Oxidative N-Demethylation by
Nonheme Fe(IV)-oxo Intermediates
N-cyclopropyl-N-isopropylaniline (3) was prepared by condensing
para-chloro-N-cyclopropylaniline28 with acetone, followed by
sodium cyanoborohydride reduction.29 para-Methyl-N,N-di(trideu-
teriomethyl)aniline (p-Me-DMA-d6, 4) and para-methyl-N-(trideu-
teriomethyl)-N-methylaniline (p-Me-DMA-d3, 5) were prepared by
alkylating either p-toluidine or N-methyl-p-toluidine with CD3I.11b
The purities of the compounds were checked with 1H NMR spectra.
Caution: Perchlorate salts are potentially explosive and should
be handled with great care.
Instrumentation. UV-vis spectra were recorded on a Hewlett-
Packard 8453 spectrophotometer equipped with OptostatDN variable-
temperature liquid-nitrogen cryostat (Oxford Instruments) or with
a circulating water bath. LC-ESI MS spectra were collected on a
Finnigan Surveyor Integrated HPLC systems (PDA detector and
LC pump) connected with Thermo Finnigan (San Jose, CA) LCQ
Advantage MAX quadrupole ion trap instrument. The separation
of products was achieved by on-column injection to a Hypersil
GOLD column (5 µm, 4.6 × 250 mm) using a CH3CN/H2O (3:1)
eluent at a flow rate of 1 mL/min, at the spray voltage 4.8 kV and
the capillary temperature at 250 °C. All products m/z correspond
to [M + 1]+. Product analysis for the oxidation of N,N-dialkyl-
anilines was performed on DIONEX Pump Series P580 equipped
with a variable wavelength UV-200 detector (HPLC). GC and
GC-MS analyses were with an Agilent Technologies 6890N gas
chromatograph (GC) and a Hewlett-Packard 5890 II Plus gas
chromatograph interfaced with Hewlett-Packard model 5989B mass
spectrometer (GC-MS). 1H NMR spectra were recorded on a Bruker
250 spectrometer. All spectra were recorded in CDCl3 using TMS
as an internal standard.
Reactions of Nonheme and Heme Oxoiron(IV) Complexes
with N,N-Dimethylanilines. In general, reactions were run at least
in triplicate, and the data represent average of these reactions. All
reactions were followed by monitoring spectral changes of reac-
tion solutions with a UV-vis spectrophotometer. Nonheme oxo-
iron(IV) complexes, 6a and 6b,5a,5b were prepared by reacting
Fe(N4Py)(ClO4)2 (2 mM) with excess solid PhIO and Fe(TMC)-
(OTf)2 (2 mM) with 1.2 equiv of PhIO (2.4 mM, diluted in 50 µL
of CH3OH), respectively, in a 1 cm UV cuvette in CH3CN (2 mL)
at ambient temperature. Oxoiron(IV) porphyrin, 6c, was prepared
by adding 4 equiv of m-CPBA (8 mM, diluted in 10 µL of
CH3CN) into a solution containing Fe(TPFPP)Cl (2 mM) and H2O
(3 µL) in a solvent mixture (0.1 mL) of CH2Cl2 and CH3CN (1:3)
at ambient temperature,4 and then the resulting solution was diluted
with CH3CN. The final concentration of 6c was 0.02 mM. Then,
appropriate amounts of N,N-dialkylanilines were added into the UV
cuvette, and spectral changes of the oxoiron(IV) complexes were
directly monitored with a UV-vis spectrophotometer. Rate con-
stants, kobs, were determined by pseudo-first-order fitting of the
decrease of absorption bands at 695 nm for 6a, 820 nm for 6b,
and 547 nm for 6c.
(IV) reactions. In the CYP 450 model system, the observation
of high KIE values in a rate-limiting ET-PT mechanism
was interpreted that there is a competition between back
electron transfer from (Porp)FeIVdO to the nitrogen radical
cation (i.e., a reverse reaction of the ET step in Scheme 1)
and H-atom transfer from the nitrogen radical cation to
(Porp)FeIVdO (i.e., the PT step in Scheme 1).8a
In summary, we have reported the first example of the
oxidative N-dealkylation of N,N-dialkylanilines by nonheme
and heme oxoiron(IV) complexes generated in situ. Mecha-
nistic studies performed with various probes such as para-
substituted N,N-dimethylanilines, para-chloro-N-ethyl-N-
methylaniline, para-chloro-N-cyclopropyl-N-isopropylani-
line, and deuteriated N,N-dimethylanilines (see structures in
Chart 1) provided strong evidence that the N-dealkylation
reactions proceed via a rate-limiting ET followed by a PT
process (Schemes 1 and 3 for mechanisms of heme and
nonheme oxoiron(IV) reactions, respectively). The relative
reactivities of nonheme and heme oxoiron(IV) complexes
were briefly discussed in the present study, but more detailed
investigations are needed to understand the exact role of
ligand structures in controlling the reactivities of nonheme
and heme oxoiron(IV) complexes in the oxidative N-
dealkylation reactions.22
Experimental Procedures
Starting Materials. All chemicals obtained from Aldrich
Chemical Co. were the best available purity and used without further
purification unless otherwise noted. Solvents were dried according
to published procedures23 and distilled under Ar prior to use. Iron-
(II) complexes such as Fe(TMC)(OTf)2‚2CH3CN and Fe(N4Py)-
(ClO4)2‚CH3CN were prepared in a glovebox by literature
methods.5a,24 Iodosylbenzene was prepared by a literature method.25
m-Chloroperbenzoic acid (m-CPBA) was purified by washing with
phosphate buffer (pH 7.4) and then water, followed by drying under
reduced pressure. Fe(TPFPP)Cl and CD3I were obtained from
Aldrich. para-Methoxy-N,N-dimethylaniline was prepared by react-
ing para-anisidine with para-formaldehyde followed by sodium
cyanoborohydride reduction.26 para-Chloro-N-ethyl-N-methylaniline
(2) was obtained by coupling para-bromochlorobenzene with
N-ethylmethylamine in the presence of Pd2(dba)3 and BINAP (2,2′-
bis(diphenylphosphino)-1,1′-binaphthyl) as catalysts.27 para-Chloro-
Product Analysis for the Oxidation of N,N-Dialkylanilines
by Oxoiron(IV) Complexes. Reaction solutions of oxoiron(IV)
intermediates (2 mM) were prepared as described above. Then, 20
equiv of N,N-dialkylanilines (40 mM) was added to the reaction
solutions. Product analysis was performed by injecting reaction
solutions directly into HPLC, LC-ESI MS, GC, and/or GC-MS (see
Figures S3 and S4). Product yields were determined by comparison
with standard curves of known authentic samples.
(22) (a) Decker, A.; Solomon, E. I. Angew. Chem., Int. Ed. 2005, 44, 2252.
(b) de Visser, S. P. J. Am. Chem. Soc. 2006, 128, 9813.
(23) Purification of Laboratory Chemicals; Armarego, W. L. F.; Perrin,
D. D., Eds.; Pergamon Press: Oxford, 1997.
(24) Lubben, M.; Meetsma, A.; Wilkinson, E. C.; Feringa, B.; Que, L., Jr.
Angew. Chem., Int. Ed. 1995, 34, 1512.
In the reaction of para-methyl-N-(trideuteriomethyl)-N-methy-
laniline (p-Me-DMA-d3, 5), p-Me-DMA-d3 (40 mM) was added
(25) Organic Syntheses; Saltzman, H.; Sharefkin, J. G., Eds.; Wiley: New
York, 1973; Vol. V, p 658.
(26) Gribble, G. W.; Nutaitis, C. F. Synthesis 1987, 709.
(27) Teuten, E. L.; Leoppky, R. N. Org. Biomol. Chem. 2005, 3, 1097.
(28) Cui, W.; Leoppky, R. N. Tetrahedron 2001, 57, 2953.
(29) Leoppky, R. N.; Elomari, S. J. Org. Chem. 2000, 65, 96.
Inorganic Chemistry, Vol. 46, No. 1, 2007 297

Nehru et al.
to reaction solutions containing oxoiron(IV) complexes (2 mM).
After 30 min, the resulting solutions were passed through a short
silica-gel column. Product analysis was then performed with HPLC
for product yields and LC-ESI MS for product ratios. The deuterium
compositions in para-methyl-N-methylaniline were analyzed by the
relative abundances of m/z ) 122 for para-methyl-N-methylaniline
and m/z ) 125 for para-methyl-N-(trideuteromethyl)aniline (see
Figure S6).
Program (W.N.), the Korea Research Foundation (KRF-
2005-217-C00006 to M.S.S.), and the SRC/ERC program
of MOST/KOSEF (R11-2005-008-00000-0 to J.K.).
Supporting Information Available: Additional kinetic and
spectroscopic data and product analysis (Figures S1-S6). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This research was supported by
MOST/KOSEF through the Creative Research Initiative
IC0614014
298 Inorganic Chemistry, Vol. 46, No. 1, 2007