5784 J. Am. Chem. Soc., Vol. 120, No. 23, 1998
Baciocchi et al.
and e then follow, as in the ET mechanism. Additional support
to this conclusion came from the observation that the deproto-
nation of N,N-dimethylaniline radical cations (an essential step
in the ET mechanism) exhibits a kinetic deuterium isotope effect
profile significantly different from that actually found in the
cytochrome P450 induced reactions. Moreover, subsequent
work showed that the kinetic deuterium isotope effect profile
as a mechanistic probe could also be applied as well to other
cytochrome P450 induced hydroxylation reactions involving
substrates different than N,N-dimethylanilines.4
Iron porphyrins are well recognized chemical models of
cytochrome P450 capable of mimicking most reactivity aspects
of this enzyme, including the N-dealkylation of tertiary amines.1d,5
Indeed, the active oxidant, in the oxidations catalyzed by iron
tetraarylporphyrins, is an iron oxo complex, formed by the
reaction of an oxygen donor with the iron porphyrin (eq 1, where
P now indicates the synthetic porphyrin and SO is an oxygen
donor), structurally similar to the one involved in cytochrome
P450 induced reactions.1a,6 It would therefore seem reasonable,
even though by no means certain, to expect that the two systems
also share the main mechanistic features.
effect profile. Our main aim was that of reaching definitive
conclusions on the mechanism of these reactions, at the same
time testing the actual validity of the isotope effect profile as a
mechanistic probe.
In this paper we report on an investigation of the PhIO
promoted oxidation of a number of 4-substituted N,N-dimethyl-
anilines, catalyzed by tetrakis(pentafluorophenyl)porphyrin
iron(III) chloride (FeTPFPPCl). FeTPFPPCl is a significantly
more efficient catalyst than FeTPPCl,9 which has allowed us
to conveniently investigate a wide range of substituted N,N-
dimethylanilines. On the other hand, its reduction potential is
higher than that of FeTPPCl.10 Therefore, if an ET mechanism
is operating with FeTPPCl, a fortiori it should operate with
FeTPFPPCl.
Results
The reactions of a number of 4-X substituted N,N-dimethyl-
anilines (X ) MeO, Me, Br, H, CF3, CN, NO2) with PhIO in
the presence of FeTPFPPCl were studied in CH2Cl2. In most
experiments 100 µmol of substrates were reacted with PhIO
(50 µmol) and FeTPFPPCl (2 µmol) in CH2Cl2 (1 mL). In all
cases, clean N-demethylation was observed with the formation
of the corresponding N-methylaniline. Dimerization products,
if present, were formed in negligible amounts.
P-FeIII + SO f +•P-FeIVdO + S
(1)
This, however, would not be the case if the conclusions by
Dinnocenzo and Jones are correct. Accordingly, the available
information on the reaction selectivity of the oxidation of N,N-
dimethylanilines by tetraphenylporphyrin iron(III) chloride
(FeTPPCl), using iodosylbenzene (PhIO) as the oxygen source,5c,d
appears more in line with the ET mechanism reported in Scheme
1 than with the HAT mechanism proposed by Dinnocenzo and
Jones for the N-dealkylations promoted by cytochrome P450.2
Moreover, it should be noted that Lindsay Smith and co-workers
proposed an ET mechanism for the N-dealkylation of N,N-
dimethylbenzylamines induced by FeTPPCl and PhIO.7 Since
the oxidation potentials of N,N-dimethylanilines8a are signifi-
cantly lower than those of N,N-dimethylbenzylamines,8b it would
seem reasonable to expect that the ET mechanism also holds
for the former substrates. Thus, if these conclusions are correct,
we are faced with the following dilemma: either the biomimetic
and enzymatic oxidative N-dealkylation of N,N-dimethylanilines
react by different mechanisms or the kinetic deuterium isotope
effect profile is not a reliable mechanistic probe to distinguish
ET from HAT mechanisms.
Intramolecular kinetic deuterium isotope effects, (kH/kD)intra
,
were determined by reacting 4-X-substituted N-trideuterio-
methyl-N-methylanilines (X ) MeO, Me, H, Br, CN, NO2) with
PhIO and FeTPFPPCl, under the same conditions as above. At
the end of the reaction, the formed CH2O and CD2O were
converted into the corresponding dimedone adducts and the ratio
of the two adducts was measured by GC-MS. In some cases,
(kH/kD)intra was also determined by measuring the molar ratio
between the 4-X-N-trideuteriomethylaniline and the 4-X-N-
methylaniline produced in the reaction, by GC-MS. Intermo-
lecular kinetic deuterium isotope effects, (kH/kD)inter, were
obtained in competitive experiments by reacting an equimo-
lecular mixture of 4-X-N,N-bis(trideuteriomethyl)aniline and the
corresponding N,N-dimethylaniline with PhIO and the iron
porphyrin. For these experiments, the concentration of the two
substrates was always at least 10 times larger than that of the
product N-methylanilines. In this case too, at the end of the
reaction, CH2O and CD2O were reacted with dimedone and the
ratio of the dimedone adducts measured by GC-MS. All values
of kH/kD are reported in Table 1.
In view of the great general interest toward the development
of mechanistic probes to distinguish HAT and ET mechanisms,
we felt it worthwhile to obtain further information on the
mechanism of the oxidation of N,N-dimethylanilines induced
by synthetic iron porphyrins by using a number of mechanistic
criteria, including the intramolecular kinetic deuterium isotope
The relative reactivity of the 4-X-N,N-dimethylanilines was
determined in competitive experiments, by reacting couples of
substrates with FeTPFPPCl and PhIO. Since the two substrates
were in excess with respect to the oxidant, the relative reactivity
was determined by the molar ratio of the two formed N-
methylanilines, which was measured by GC. The relative
reactivity values for the various N,N-dimethylanilines, with
respect to X ) H (kX/kH), are reported in Table 2. When the
log(kX/kH) values are plotted against the substituent constants
σ+, the good (r2 ) 0.98) correlation shown in Figure 1 is
obtained, which allows us to calculate a F+ value of - 0.88.
The data of Table 2 were also fitted to the Rehm-Weller
(4) Manchester, J. I.; Dinnocenzo, J. P.; Higgins, L. A.; Jones, J. P. J.
Am. Chem. Soc. 1997, 119, 5069-5070.
(5) (a) Bruice, T. C.; Shannon, P. J. Am. Chem. Soc. 1981, 103, 4580-
4582. (b) Miyata, N.; Kiuchi, H.; Hirobe, M. Chem. Pharm. Bull. 1981,
29, 1489-1492. (c) Dicken, C. M.; Lu, F.-L.; Nee, M. W.; Bruice, T. C. J.
Am. Chem. Soc. 1985, 107, 5776-5789. (d) Mori, T.; Santa, T.; Higuchi,
T.; Mashino, T.; Hirobe, M. Chem. Pharm. Bull. 1993, 41, 292-295.
(6) (a) Meunier, B. Chem. ReV. 1992, 92, 1411-1456. (b) Groves, J. T.;
Haushalter, R. C.; Nakamura, M.; Nemo, T. E.; Evans, B. J. J. Am. Chem.
Soc. 1981, 103, 2884-2886.
(7) (a) Lindsay Smith, J. R.; Mortimer, D. N. J. Chem. Soc., Chem.
Commun. 1985, 64-65. (b) Lindsay Smith, J. R.; Mortimer, D. N. J. Chem.
Soc., Perkin Trans. 2 1986, 1743-1749.
(8) (a) Parker, V. D.; Tilset, M. J. Am. Chem. Soc. 1991, 113, 8778-
8781. (b) A cyclic voltammogram of N,N-dimethylaniline in MeCN/Bu4-
NBF4 gave an Ep value of 1.09 V vs SCE (we thank Dr. Patrizia Gentili
for performing this experiment).
(9) (a) Chang, C. K.; Ebina, F. J. Chem. Soc., Chem. Commun. 1981,
778-779. (b) Bartoli, J. F.; Brigaud, O.; Battioni, P.; Mansuy, D. D. N. J.
Chem. Soc., Chem. Commun. 1991, 440-442.
(10) Grinstaff, M. W.; Hill, M. G.; Birnbaum, E. R.; Schaefer, W. P.;
Labinger, J. A.; Gray, H. B. Inorg. Chem. 1995, 34, 4896-4902.