Reaction of N,N-Dimethylanilines with dpph•
SCHEME 1
might represent a reliable criterion to distinguish ET from HAT
mechanisms, no rate accelerating effect by the metal cation being
expected in the latter case.19
Clearly, the occurrence of an ET mechanism in the reaction
of N-Me-AcrH2 with dpph• is somewhat surprising because this
mechanism is thermodynamically unfavored with respect to the
HAT mechanism. Accordingly, the ET step is endergonic by
21
almost 13 kcal mol-1
,
whereas the BDEs reported above
the formed phenolate anion, can operate. With phenolic antioxidant
of low ionization potential, an ET step followed by proton transfer
(ET-PT)14 may also be envisaged, and accordingly, this possibility
has been recently suggested for the reaction of dpph• with a vitamin
E model in MeOH.15 This proposal, however, has been strongly
challenged.13 Clearly, under the conditions where SPLET or ET
mechanism work, dpph• may no longer be a good model of peroxyl
radicals reactivity.10
indicate that the HAT mechanism is practically thermoneutral.
Thus, it would appear that either dpph• has an intrinsic reactivity
much higher in ET than in HAT processes or the HAT
mechanism is strongly retarded by steric effects so that the ET
mechanism can take over.22
We have found that dpph• can promote the N-demethylation
of N,N-dimethylanilines (DMAs), a process that certainly
involves the cleavage of a methyl C-H bond (vide infra). The
Much less information is available for the reactivity of dpph•
BDE of this bond is around 90-92 kcal mol-1 23 (much higher
,
toward C-H bonds, probably because the N-H bond dissocia-
16
tion energy (BDE) in dpph-H is 79.6 kcal mol-1
,
and one
than that of the 9-C-H bond in N-Me-AcrH2), and at the same
time, the reduction potentials of DMAs radical cations24 are of
the same order of magnitude or lower than that of N-Me-
AcrH2+•. Thus, if dpph• reacts with N-Me-AcrH2 by an ET
mechanism, it would seem very reasonably to anticipate that
the same mechanism should also hold in the corresponding
reaction with the DMAs.
can predict a significant reactivity of dpph• only toward
substrates with relatively weak C-H bonds. Recently, it has
been shown that dpph• reacts efficiently with N-methyl-9,10-
dihydroacridine (N-Me-AcrH2) to form the N-methylacridinium
cation (N-Me-AcrH+) in a process involving the 9-C-H bond.17
This process might well involve a HAT mechanism as the
18
9-C-H BDE is as low as 80 kcal mol-1
.
However, it was
We felt that a study aimed at testing this prediction would
be certainly warranted because the use of dpph• in the assesse-
ment of the relative reactivity of antioxidants requires reliable
information about the respective scopes of HAT (CPET),
SPLET, or ET-PT mechanisms for this radical as well as the
possible differences between processes involving cleavage of
C-H bonds and processes involving cleavage of O-H bonds.
It should be also considered that there is a continuous interest
for the mechanistic aspects of the oxidative N-demethylation
of tertiary methylamines induced by free radical species, a
process of high biological interest.25
In this paper we report on a kinetic study of the N-
demethylation reaction of a number of 4-X-substituted-N,N-
dimethylanilines (1, X ) H; 2, X ) CH3; 3, X ) OC6H5; 4, X
) OCH3) promoted by dpph• in MeCN. Substituent and solvent
effects have been determined together with the intra- and
intermolecular deuterium kinetic isotope effects (DKIEs). The
kinetic effect of Mg2+ (Mg(ClO4)2) has also been investigated.
found that the reaction rate is increased by addition of Mg2+
,
and on this basis, it was suggested that the reaction of dpph•
with N-Me-AcrH2 most likely takes place by an ET mechanism
where a radical cation is first formed that is then deprotonated
(Scheme 1).
The observed rate increase was attributed to the stabilization
by Mg2+ of dpph- formed in the electron transfer step (eq 1 of
Scheme 1). It was also suggested that the kinetic effect of Mg2+
(4) The transfer of a hydrogen atom formally involves the transfer of an
electron and a proton. When electron and proton are transferred to the same
center in the same step, we generally speak of HAT mechanism. Very recently,
however, DFT theoretical calculations5–7 have shown that quite energetically
different situations can arise depending on whether the same or different sets of
orbitals are involved in the transfer of the proton and the electron. In the former
case, the mechanism continues to be designated as HAT; in the latter case, the
process is described as a proton coupled electron transfer (PCET) or a concerted
proton electron transfer (CPET). Theoretical calculations8 have also shown that
both HAT and CPET pathways are possible for the reaction of dpph• with phenols.
It should, however, be noted that Huynh and Meyer9 have expressed some
reservation on the distinction discussed above. According to these authors, the
CPET terminology should be strictly reserved to when proton and electron are
transferred to orbitals located in well separated sites.
Results
(5) Mayer, J. M.; Hrovat, D. A.; Thomas, J. L.; Borden, W. T. J. Am. Chem.
Soc. 2002, 124, 11142–11147.
For product studies, a solution of N,N-dimethyl-p-toluidine
(6) DiLabio, G. A.; Ingold, K. U. J. Am. Chem. Soc. 2005, 127, 6693–6699.
(7) DiLabio, G. A.; Johnson, E. R. J. Am. Chem. Soc. 2007, 129, 6199–
6203.
and dpph• (4:1 molar ratio) in CH3CN was stirred for 3 h at 25
1
°C under argon. After workup, GC-MS and H NMR analysis
(8) Katarina, N. M. J. Mol. Struct.: THEOCHEM 2007, 818, 141–150.
(9) Huynh, M. H. V.; Meyer, J. M. Chem. ReV. 2007, 107, 5004–5064.
(10) Foti, M. C.; Daquino, C.; Geraci, C. J. Org. Chem. 2004, 69, 2309–
2314.
(19) For other application of this criterion, see: Nakanishi, I.; Miyazaki, K.;
Shimada, T.; Ohkubo, K.; Urano, S.; Ikota, N.; Ozawa, T.; Fukuzumi, S.;
Fukuhara, K. J. Phys. Chem. A 2002, 106, 11123–11126. Nakanishi, I.; Fukuhara,
K.; Shimada, T.; Ohkubo, K.; Iizuka, Y.; Inami, K.; Mochizuchi, M.; Urano, S.;
Itoh, S.; Miyata, N.; Fukuzumi, S. J. Chem. Soc., Perkin Trans. 2 2002, 1520–
1524. The effect can concern metal cations other than Mg2+ (ref 20)
(20) Fukuzumi, S.; Shimoosako, K.; Suenobu, T.; Watanabe, Y. J. Am. Chem.
Soc. 2003, 125, 9074–9082, and references therein.
(11) Litwinienko, G.; Ingold, K. U. J. Org. Chem. 2004, 69, 5888–5896.
(12) Litwinienko, G.; Ingold, K. U. J. Org. Chem. 2005, 70, 8982–8990.
(13) Litwinienko, G.; Musialik, M. Org. Lett. 2005, 7, 4951–4954.
(14) (a) Wright, J. S.; Johnson, E. R.; Di Labio, G. A. J. Am. Chem. Soc.
2001, 123, 1173–1183. (b) Leopoldini, M.; Marino, T.; Russo, N.; Toscano, M.
J. Phys. Chem. A 2004, 108, 4916–4922. (c) Leopoldini, M.; Pitarch, I. P.; Russo,
N.; Toscano, M. J. Phys. Chem. A 2004, 108, 92–96.
(21) The reduction potential of dpph• is 0.24 V vs SCE and that of N-Me-
17
+•
AcrH2 is 0.8 V vs SCE, both values taken in MeCN.
(15) Nakanishi, I.; Kawashima, T.; Ohkubo, K.; Kanazawa, H.; Inami, K.;
Mochizuchi, M.; Fukuhara, K.; Okuda, H.; Ozawa, T.; Itoh, S.; Fukuzumi, S.;
Ikota, N. Org. Biomol. Chem. 2005, 3, 626–629.
(22) In a more recent study, however, the reaction of N-Me-AcrH2 with dpph•
has been assumed to take place by a HAT mechanism.3
(23) Dombrowski, G. W.; Dinnocenzo, J. P.; Farid, S.; Goodman, J. L.;
Gould, I. R. J. Org. Chem. 1999, 64, 427–431. Luo, Y.-R. Handbook of Bond
Dissociation Energies in Organic Compounds; CRC Press LLC: Boca Raton,
FL, 2003.
(16) Mahoney, L. R.; Mendenhall, G. D.; Ingold, K. U. J. Am. Chem. Soc.
1973, 95, 8610–8614.
(17) Fukuzumi, S.; Tokuda, Y.; Chiba, Y.; Greci, L.; Carloni, P.; Damiani,
E. J. Chem. Soc., Chem. Commun. 1993, 1575–1577.
(24) Parker, V. D.; Tilset, M. J. Am. Chem. Soc. 1991, 113, 8778–8781.
(25) Karki, S. B.; Dinnocenzo, J. P.; Jones, J. P.; Korzekwa, K. R. J. Am.
Chem. Soc. 1995, 117, 3657–3664.
(18) Ru¨chardt, C.; Gerst, M.; Ebenoch, J. Angew. Chem., Int. Ed. Engl. 1997,
36, 1406.
J. Org. Chem. Vol. 73, No. 11, 2008 4111