Electron-transfer mechanism in the N-demethylation of N,N-dimethylanilines by the phthalimide-N-oxyl radical

Article abstract of DOI:10.1021/jo0503916

The reactivity of the phthalimide N-oxyl radical (PINO) toward the N-methyl C-H bond of a number of 4-X-substituted N,N-dimethylanilines (X = OMe, OPh, CF₃, CO₂Et, CN) has been investigated by product and kinetic analysis. PINO was generated in CH₃CN by reaction of N-hydroxyphthalimide (NHPI) with Pb(OAc)₄ or, for the kinetic study of the most reactive substrates (X = OMe, OPh), with tert-butoxyl radical produced by 266 nm laser flash photolysis of di-tert-butyl peroxide. The reaction was found to lead to the N-demethylation of the N,N-dimethylaniline with a rate very sensitive to the electron donating power of the substituent (ρ⁺ = -2.5) as well as to the oxidation potential of the substrates. With appropriately deuterated N,N-dimethylanilines the intermolecular and intramolecular deuterium kinetic isotope effects (DKIEs) were measured for some substrates (X = OMe, CO₂Et, CN) with the following results. First, intramolecular DKIE [(k_H/k_D) _intra] was found to be always different and higher than intermolecular DKIE [(k_H/k_D)_inter]; second, no intermolecular DKIE [(k_H/k_D)_inter = 1] was observed for X = OMe, whereas substantial values of (k_H/k _D)_inter were exhibited by X = CO₂Et (4.8) and X = CN (5.8). These results, while are incompatible with a single step hydrogen atom transfer from the N-C-H bond to the N-oxyl radical, as proposed for the reaction of PINO with benzylic C-H bonds, can be nicely interpreted on the basis of a two-step mechanism involving a reversible electron transfer from the aniline to PINO leading to an anilinium radical cation, followed by a proton-transfer step that produces an α-amino carbon radical. In line with this conclusion the reactivity data exhibited a good fit with the Marcus equation and a λ value of 37.6 kcal mol^-1 was calculated for the reorganization energy required in this electron-transfer process. From this value, a quite high reorganization energy (> 60 kcal mol^-1) is estimated for the PINO/NHPI(-H)^- self-exchange reaction. It is suggested that the N-demethylated product derives from the reaction of the α-amino carbon radical with PINO to form either a cross-coupling product or an α-amino carbocation. Both species may react with the small amounts of H₂O present in the medium to form a carbinolamine that, again by hydrolysis, can be eventually converted into the N-demethylated product.

Full text of DOI:10.1021/jo0503916

Electron-Transfer Mechanism in the N-Demethylation of
N,N-Dimethylanilines by the Phthalimide-N-oxyl Radical
Enrico Baciocchi,*,† Massimo Bietti,‡ Maria Francesca Gerini,†,§ and Osvaldo Lanzalunga*,†,§
Dipartimento di Chimica, Universita` degli Studi di Roma “La Sapienza”, P. le A. Moro, 5,
I-00185 Rome, Italy, Istituto CNR di Metodologie Chimiche (IMC-CNR), Sezione Meccanismi di Reazione,
P. le A. Moro, 5, I-00185 Rome, Italy, and Dipartimento di Scienze e Tecnologie Chimiche,
Universita` “Tor Vergata”, Via della Ricerca Scientifica, I-00133 Rome, Italy
enrico.baciocchi@uniroma1.it; osvaldo.lanzalunga@uniroma1.it
Received March 2, 2005
The reactivity of the phthalimide N-oxyl radical (PINO) toward the N-methyl C-H bond of a number
of 4-X-substituted N,N-dimethylanilines (X ) OMe, OPh, CF3, CO2Et, CN) has been investigated
by product and kinetic analysis. PINO was generated in CH3CN by reaction of N-hydroxyphthal-
imide (NHPI) with Pb(OAc)4 or, for the kinetic study of the most reactive substrates (X ) OMe,
OPh), with tert-butoxyl radical produced by 266 nm laser flash photolysis of di-tert-butyl peroxide.
The reaction was found to lead to the N-demethylation of the N,N-dimethylaniline with a rate
very sensitive to the electron donating power of the substituent (F+ ) -2.5) as well as to the oxidation
potential of the substrates. With appropriately deuterated N,N-dimethylanilines the intermolecular
and intramolecular deuterium kinetic isotope effects (DKIEs) were measured for some substrates
(X ) OMe, CO2Et, CN) with the following results. First, intramolecular DKIE [(kH/kD)intra] was
found to be always different and higher than intermolecular DKIE [(kH/kD)inter]; second, no
intermolecular DKIE [(kH/kD)inter ) 1] was observed for X ) OMe, whereas substantial values of
(kH/kD)inter were exhibited by X ) CO2Et (4.8) and X ) CN (5.8). These results, while are incompatible
with a single step hydrogen atom transfer from the N-C-H bond to the N-oxyl radical, as proposed
for the reaction of PINO with benzylic C-H bonds, can be nicely interpreted on the basis of a
two-step mechanism involving a reversible electron transfer from the aniline to PINO leading to
an anilinium radical cation, followed by a proton-transfer step that produces an R-amino carbon
radical. In line with this conclusion the reactivity data exhibited a good fit with the Marcus equation
and a λ value of 37.6 kcal mol-1 was calculated for the reorganization energy required in this
electron-transfer process. From this value, a quite high reorganization energy (>60 kcal mol-1) is
estimated for the PINO/NHPI(-H)- self-exchange reaction. It is suggested that the N-demethylated
product derives from the reaction of the R-amino carbon radical with PINO to form either a cross-
coupling product or an R-amino carbocation. Both species may react with the small amounts of
H2O present in the medium to form a carbinolamine that, again by hydrolysis, can be eventually
converted into the N-demethylated product.
Introduction
these systems the active oxidant is the phthalimide
N-oxyl radical (PINO),5,6,12 which has stimulated research
aimed at obtaining quantitative information on the
reactivity of this radical toward a variety of C-H bonds.
The studies carried out so far have concerned the C-H
bonds of alkylaromatics, benzylic alcohols and benz-
aldehydes.5,6,12-19 In addition, more recently also the
reactivity of PINO toward the phenolic O-H bond has
N-Hydroxyphthalimide (NHPI) in combination with
metal and nonmetal cocatalysts is a very efficient catalyst
for the mild oxidative functionalization of alkanes and
alkylaromatics.1-11 There is general consensus that in
† Universita` degli Studi di Roma “La Sapienza”.
‡ Universita` “Tor Vergata”.
§ Istituto CNR di Metodologie Chimiche (IMC-CNR).
(1) Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.; Iwahama,
T.; Nishiyama, Y. J. Org. Chem. 1995, 60, 3934-3935.
(2) Iwahama, T.; Sakaguchi, S.; Nakayama, K.; Nishiyama, Y. J.
Org. Chem. 1996, 61, 4520-4526.
10.1021/jo0503916 CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/18/2005
5144
J. Org. Chem. 2005, 70, 5144-5149

N-Demethylation of N,N-Dimethylanilines
been investigated by our group.20 A classical hydrogen
atom transfer (HAT) mechanism has been suggested for
the reaction of PINO with benzylic C-H bonds, whereas
for the reaction with phenols, a proton coupled electron
transfer (PCET) process seemed more in line with the
experimental results.
We have now found that PINO is also very reactive
toward the methyl C-H bond of N,N-dimethylanilines
(DMAs) promoting the oxidative N-demethylation of the
substrate, a reaction of great chemical and biological
importance which has attracted particular attention in
recent years.21-34 Herein, we wish to report a detailed
kinetic investigation of this process, where, for the first
time, PINO generation has also been accomplished by
the laser flash photolysis technique that has made
possible the study of very reactive substrates.
The reactivity of a number of 4-X-substituted N,N-
dimethylanilines (1-5) was studied and the intermolecu-
lar and intramolecular deuterium kinetic isotope effects
were also determined. The results led to the very
interesting conclusion that the reaction of PINO with
DMAs behaves differently from the previously investi-
gated systems, involving an electron-transfer mechanism.
(3) Ishii, Y.; Yoshino, Y.; Hayashi, Y.; Iwahama, T.; Sakaguchi, S.;
Ishii, Y. J. Org. Chem. 1997, 62, 6810-6813.
(4) Wentzel, B. B.; Donners, M. P. J.; Alsters, P. L.; Feiters, M. C.;
Nolte, R. J. M. Tetrahedron 2000, 56, 7797-7803.
(5) Ishii, Y.; Sakaguchi, S.; Iwahama, T. Adv. Synth. Catal. 2001,
343, 393-427.
(6) Minisci, F.; Recupero, F.; Pedulli, G. F.; Lucarini M. J. Mol.
Catal. A 2003, 204-205, 63-90.
(7) Saha, B.; Nobuyoshi, K.; Espenson, J. H. J. Phys. Chem. A 2004,
108, 425-431.
Results
For product studies, the PINO radical was generated
in CH3CN by reaction of NHPI with Pb(OAc)4 as previ-
ously described15,20 and was allowed to react with DMAs
1-5 at 25 °C. At the end of the reaction, after workup,
GC-MS and 1H NMR analysis indicated that the corre-
sponding N-methylanilines were formed as the major
reaction products in relatively low yields (from 12% to
20% referred to the starting material) probably because
part of PINO is used in the competitive dimerization
reaction. Formation of CH2O was also detected by its
conversion into the dimedone adduct. When 1H NMR
analysis of the reaction mixture was performed before
work-up, two additional singlets at 5.2-5.3 ppm and 3.1-
3.2 ppm (relative intensity ) 2:3) were observed. These
singlets were reasonably assigned (see the Experimental
Section) to a cross-coupling product of PINO and the
R-aminomethyl radical formed by the PINO-induced
hydrogen abstraction from the N-Me group of the sub-
strate. Evidently, this adduct is converted during workup
into the N-demethylated product (vide infra), as the above
signals were absent in the final mixture. We made some
attempts to isolate this intermediate, which, however,
were unsuccessful because it was unstable during the
chromatographic isolation procedure, always decompos-
ing into the N-methylaniline and NHPI.
The same reactions were carried out with the anilines
1, 3, and 5 where a single N-methyl group was replaced
by a N-trideuteriomethyl group, that allowed us to
determine the product (intramolecular) deuterium isotope
effects (kH/kD)intra by measuring, by GC-MS analysis, the
molar ratio between N-trideuteriomethylaniline and N-
methylaniline produced in the reaction. In line with the
hydrogen abstraction process, in all cases we observed
substantial values of (kH/kD)intra, as listed in the last
column of Table 1.
(8) Minisci, F.; Recupero, F.; Cecchetto, A.; Gambarotti, C.; Punta,
C.; Paganelli, R.; Org. Process Res. Dev. 2004, 8, 163-168.
(9) Yang, G.; Ma, Y.; Xu, J. J. Am. Chem. Soc. 2004, 126, 10542.
(10) Yang, G.; Zhang, Q.; Miao, H.; Tong, X.; Xu, J. Org. Lett. 2005,
7, 263-266.
(11) Rajabi, F.; Clark, J. H.; Karimi, B.; Macquarrie, D. J. Org.
Biomol. Chem. 2005, 3, 725-726.
(12) Ueda, C.; Noyama, M.; Ohmori, H.; Masui, M. Chem Pharm.
Bull. 1987, 35, 1372-1377.
(13) Minisci, F.; Punta, C.; Recupero, F.; Fontana, F.; Pedulli, G. F.
J. Org. Chem. 2002, 67, 2671-2676.
(14) Koshino, N.; Cai, Y.; Espenson, J. H. J. Phys. Chem. A 2003,
107, 4262-4267.
(15) Koshino, N.; Saha, B.; Espenson, J. H. J. Org. Chem. 2003, 68,
9364-9370.
(16) Amorati, R.; Lucarini, M.; Mugnaini, V.; Pedulli, G. F.; Minisci,
F.; Recupero, F.; Fontana, F.; Astolfi, P.; Greci, L. J. Org. Chem. 2003,
68, 1747-1754.
(17) Minisci, F.; Recupero, F.; Cecchetto, A.; Gambarotti, C.; Punta,
C.; Faletti, R.; Paganelli, R.; Pedulli, G. F. Eur. J. Org. Chem. 2004,
109-119.
(18) Annunziatini, C.; Gerini, M. F.; Lanzalunga O.; Lucarini, M.
J. Org. Chem. 2004, 69, 3431-3438.
(19) Cai, Y.; Koshino, N.; Saha, B.; Espenson, J. H. J. Org. Chem.
2005, 70, 238-243.
(20) Baciocchi, E.; Gerini, M. F.; Lanzalunga O. J. Org. Chem. 2004,
69, 8863-8866.
(21) Miwa, G. T.; Walsh, J. S.; Kedderis, G. L.; Hollenberg, P. F. J.
Biol. Chem. 1983, 258, 14445-14449.
(22) Heimbrook, D. C.; Murray, R. I.; Egeberg, K. D.; Sligar, S. G.;
Nee, M. W.; Bruice, T. C. J. Am. Chem. Soc. 1984, 106, 1514-1515.
(23) Burka, L. T.; Guengerich, F. P.; Willard, R. J.; Macdonald, T.
L. J. Am. Chem. Soc. 1985, 107, 2549-2551.
(24) Macdonald, T. L.; Gutheim, W. G.; Martin, R. B.; Guengerich,
F. P. Biochemistry 1989, 28, 2071-2077.
(25) Dinnocenzo, J. P.; Karki, S. B.; Jones, J. P. J. Am. Chem. Soc.
1993, 115, 7111-7116.
(26) Karki, S. B.; Dinnocenzo, J. P.; Jones, J. P.; Korzekwa; K. R. J.
Am. Chem. Soc. 1995, 117, 3657-3664.
(27) Guengerich, F. P.; Yun, C.-H.; Macdonald, T. L. J. Biol. Chem.
1996, 271, 27321-27329.
(28) Chen, H.; de Groot, M. J.; Vermeulen, N. P. E.; Hanzlik, R. P.
Guengerich, F. P.; Yun, C.-H.; Macdonald, T. L. J. Org. Chem. 1997,
62, 8227-8230.
(29) Manchester, J. L.; Dinnocenzo, J. P.; Higgins, L. A.; Jones, J.
P. J. Am. Chem. Soc. 1997, 119, 5059-5070.
(30) Baciocchi, E.; Lanzalunga, O.; Lapi, A.; Manduchi, L. J. Am.
Chem. Soc. 1998, 120, 5783-5787.
The kinetics of the reactions of DMAs 1-5 with PINO
were studied in CH3CN at 25 °C. With the less reactive
substrates 1-3, PINO was generated as in the products
study, and its decay was followed spectrophotometrically
at 380 nm (λMAX).12 The spontaneous slow decay of PINO
was strongly accelerated in the presence of DMAs 1-3,
following clean first-order kinetics in the presence of an
(31) Goto, Y.; Watanabe, Y.; Fukuzumi, S.; Jones, J. P.; Dinnocenzo,
J. P. J. Am. Chem. Soc. 1998, 120, 10762-10763.
(32) Shearer, J.; Zhang, C. X.; Hatcher, L. Q.; Karlin, K. D. J. Am.
Chem. Soc. 2003, 125, 12670-12671.
(33) Fukuzumi, S.; Shimoosako, K.; Suenobu, T.; Watanabe, Y. J.
Am. Chem. Soc. 2003, 125, 9074-9082.
(34) Bhakta, M. N.; Hollenberg, P. F.; Wimalasena, K. J. Am. Chem.
Soc. 2005, 127, 1376-1377.
J. Org. Chem, Vol. 70, No. 13, 2005 5145

Baciocchi et al.
TABLE 1. Substrate Oxidation Potentials and Kinetic Data for the Reaction of PINO with 4-X-Substituted
N,N-Dimethylanilines in CH3CN at 25 °C
b
b,d
substrate
E° a
kHb (M-1s-1
)
kDb,c (M-1s-1
)
(kH/kD)inter
(kH/kD)intra
1 (X ) CN)
1.29e
1.25g
1.21h
0.80g
0.69e
4.5(4) × 102 f
1.4(1) × 103 f
3.5(4) × 103 f
3.0(3) × 105 i
3.7(4) × 106 i
77(5)f
n.d.
5.8(5)
n.d.
4.8(5)
n.d.
1.0(2)
10.5(5)
n.d.
9.6(5)
n.d.
5.8(5)
2 (X ) CF3)
3 (X ) CO2C2H5)
4 (X ) OC6H5)
5 (X ) OCH3)
7.3(8) × 102 f
n.d.
3.7(3) × 106 i
a V vs NHE in CH3CN. b The number in parentheses represents the error in the last digit. c Determined using 4-X-C6H4N(CD3)2 as
substrate. d Determined by product analysis of the oxidation of 4-X-C6H4N(CH3)(CD3). e Reference 37. f Determined spectrophotometrically.
g Calculated by the correlation of the oxidation potential of 4-X-substituted N,N-dimethylanilines vs Hammett σ+ values. Reference 37.
h Reference 38. i Determined by laser flash photolysis.
FIGURE 1. Transient absorption spectra measured 200 ns
FIGURE 2. Time-resolved absorbance measured at 380 nm
(filled circles), 640 ns (empty circles), 2 µs (filled triangles),
after laser excitation of a solution of di-tert-butyl peroxide (1.0
6.3 µs (empty triangles), and 20 µs (filled squares) after laser
M) and NHPI (10 mM) in CH3CN in the absence (a) or in the
excitation of a solution of di-tert-butyl peroxide (0.5 M) and
presence (b) of 4-CH3O-C6H4N(CH3)2 (0.4 mM).
NHPI (0.6 mM) in CH3CN.
mined by measuring the rate constants for the deuterium
abstraction reaction (kD) from 4-CN-C6H4N(CD3)2, 4-CO2-
excess of substrate. With the more reactive DMAs 4 and
5, the laser flash photolysis technique was used. PINO
Et-C6H4N(CD3)2, and 4-CH3O-C6H4N(CD3)2, respectively
was produced by hydrogen atom abstraction from NHPI
(see Figures S1, S3, and S5 in the Supporting Informa-
by the tert-butoxyl radical generated by 266 nm laser
flash photolysis of di-tert-butyl peroxide in CH3CN at 25
tion). All of the kinetic data are collected in Table 1.
°C. The time-resolved spectrum obtained in a laser pho-
tolysis experiment carried out with a solution of di-tert-
Discussion
From the results presented above, it appears that
PINO is able to promote the N-demethylation of DMAs
by a process involving a hydrogen transfer from the
N-CH3 group to PINO. It can also be concluded that such
a transfer does not occur by a classical free radical
hydrogen abstraction mechanism (as suggested for the
PINO reactions with benzylic C-H bonds)5,6,12-20 as
substantial differences are observed between inter- and
intramolecular deuterium kinetic isotope effects (Table
1), a situation inconsistent with a single-step mecha-
nism.30,32
A two-step mechanism (Scheme 1, paths a and b),
involving a reversible electron transfer from the substrate
to PINO in the first step, is a reasonable hypothesis that
is supported by several lines of evidence.
First, the reactivity data reported in Table 1 show that
the reaction rate is very sensitive to the electron donating
power of the substituent as well as to the oxidation
potential of the substrates, increasing as the former
increases and the second becomes lower. Good linear
correlations are obtained by plotting log kH against the
substituent σ+ constants (F+ ) -2.5, r2 ) 0.987) and the
butyl peroxide (0.5 M) and NHPI (0.6 mM) is reported in
Figure 1, where it can be observed that the absorption
that appears 200 ns after the laser pulse (filled circles),
due to the tert-butoxyl radical,35 is replaced after 20 µs
(filled squares) by the absorption due to PINO (λMAX )380
nm).12 An isosbestic point can be identified at λ ) 355 nm.
The PINO signal is stable on the millisecond time scale,
but, in the presence of an excess of 4 or 5,36 a much faster
decay of PINO is observed that follows first-order kinetics
(Figure 2).
From the observed pseudo-first-order rate constants
(kobs) plotted against the substrate concentration (see
Figures S1-S5 in the Supporting Information), the
second-order rate constants (kH) for the hydrogen abstrac-
tion reaction of compounds 1-5 with PINO were calculat-
ed. With the DMAs 1, 3, and 5, the intermolecular deu-
terium kinetic isotope effect (kH/kD)inter was also deter-
(35) Tsentalovich, Y. P.; Kulik, L. V.; Gritsan, N. P.; Yurkovskaya,
A. V. J. Phys. Chem. A 1998, 102, 7975-7980; Baciocchi, E.; Bietti,
M.; Salamone, M.; Steenken, S. J. Org. Chem. 2002, 67, 2266-2270.
(36) From the initial ∆OD we can estimate that the PINO concen-
tration is about 0.03 mM.
5146 J. Org. Chem., Vol. 70, No. 13, 2005

N-Demethylation of N,N-Dimethylanilines
consistent with the occurrence of an electron-transfer
step, a decisive support in this respect comes from the
observation that the intermolecular DKIE decreases on
going from electron-withdrawing to electron-donating
substituents.27 Accordingly, (kH/kD)inter is 5.8 with 1 (CN),
4.8 with 3 (CO2Et), and 1.0 (no DKIE!) with 5 (OMe).40
This trend, when coupled with the observation that
intramolecular DKIEs [(kH/kD)intra] are always different
and higher than (kH/kD)inter, is a strong evidence in favor
of a mechanism where the electron transfer from DMA
to PINO is reversible and is followed by a proton-transfer
step (Scheme 1, paths a and b).27,30,31
According to this mechanism, any NHPI(-H)-/DMA+•
pair formed in the first step can partition either toward
the product by proton transfer (kb) or the initial reactants
(k-et). The value of (kH/kD)inter will therefore depend on
the ratio of the rate constants of the back electron
transfer (k-et) to that of the proton transfer (kb).31 With
5, the electron transfer is exergonic (the reduction
potential of PINO is 0.92 V vs NHE41). It is therefore
reasonable to suggest that since the back electron
transfer will be rather slow, k-et may be much smaller
than kb. It follows that the electron-transfer step is rate
determining and no intermolecular DKIE is observed. On
the other hand, as expected, the product intramolecular
DKIE is substantial as it originates from the deprotona-
tion step. Conversely, the radical cations formed from 3
and 1 will be much less stable (their formation is
endergonic), hence larger values of k-et are expected.
Thus, it is plausible that the deprotonation step too may
contribute to determine the reaction rate leading to
FIGURE 3. Dependence of the bimolecular rate constants of
PINO with N,N-dimethylanilines 1-5 in CH3CN at 25 °C upon
the Hammett σ+ constants (a) and on the oxidation potential
(b).
SCHEME 1
substantial values of (kH/kD)inter.
42 Nevertheless, it has to
be noted that not even with 1 and 3 does the deprotona-
tion step become completely rate determining since a
large difference between (kH/kD)inter and (kH/kD)intra is still
present in both cases.
Very interestingly, a pattern of results very close to
ours [decrease of (kH/kD)inter by increasing the electron
donating power of the substituent and different values
of (kH/kD)inter and (kH/kD)intra] were obtained by Watanabe
et al. in the N-demethylation of DMAs catalyzed by high
valent metal-oxo species OdFeIVTMP•+ (TMP ) 5,10,-
15,20-tetramesitylporphyrin dianion).31 In this case too,
the results were interpreted with a mechanism involving
a reversible electron transfer from the aniline to OdFeIV-
TMP•+.43 The similar mechanism of the reaction of DMAs
with PINO and OdFeIVTMP•+ is further supported by the
observation that both reactions exhibit a linear depen-
dence of the rate constants kH upon the substrate
oxidation potential with similar slopes, -5.9 for PINO
and -7.76 for OdFeIVTMP•+.
oxidation potentials of the DMAs (slope ) -5.9, r2
0.983), as shown in Figure 3. Clearly, these observations
indicate a transition state characterized by a substantial
development of positive charge.39
Whereas the substituent effects on the rate as well as
the strong rate dependence on the E° values are certainly
)
In line with an electron-transfer mechanism is also the
quite satisfactory fit (Figure 4) obtained when the PINO
(40) Secondary isotope effects are likely obscured by the error limit.
(41) Gorgy, K.; Lepretre, J.-C.; Saint-Aman, E.; Einhorn, C.; Ein-
horn, J.; Marcadal C.; Pierre, J.-L. Electrochim. Acta 1998, 44, 385.
(42) Of course, substituents also influence the rate of the second
step. However, the effect on the electron-transfer step should be much
more important, as also shown by the observed electronic effects of
the substituents.
(43) Actually, for this reaction Watanabe et al. assumed that the
radical cation undergoes a hydrogen atom transfer and not a proton-
transfer reaction. At present, we cannot exclude that such a possibility
occurs also in our case, the radical cation reacting with PINO to form
an R-amino carbocation that can either be converted into the carbino-
lamine or react with the N-hydroxyphthalimide anion, produced in step
a, to give the adduct (Scheme 1).
(37) Parker, V. D.; Tilset, M. J. Am. Chem. Soc. 1991, 113, 8778-
8781.
(38) Renaud, R. N.; Stephens, C. J.; Brochu, G. Can. J. Chem. 1984,
62, 565-569.
(39) Actually, the kinetic data correlate better with the σ rather than
with the σ+ constants (F ) -4.2, r2 ) 0.997), that probably indicates
that the partial positive charge in the transition state should be mainly
localized on the nitrogen atom and not on the aromatic ring.
J. Org. Chem, Vol. 70, No. 13, 2005 5147

Baciocchi et al.
tramolecular reorganization energy (λi) was calculated by
the method proposed by Nelsen46 and Larsson.47 The
energy of the optimized radical was calculated (E1). By
adding an electron to the radical freezing its geometry
the energy E2 was calculated. Then the energy of the
optimized anion was calculated (E3) and by removing an
electron to the anion freezing its geometry the energy
was calculated (E4). The difference E2 - E3 is the λi for
the anion and the difference E1 - E4 is the λi for the
radical. The sum of these two reorganization energies is
the total λi. A rather low value was found (8.2 kcal mol-1
)
as expected, indicating that most of the reorganization
energy must involve the reorganization of the solvent.
Finally, concerning the pathway by which the R-amino
carbon radical, formed in path b of Scheme 1, is converted
into the N-demethylated aniline, a possibility is the
reaction with PINO to form the cross-coupling product
(Scheme 1, path c). This adduct can react with the small
amounts of H2O present in the solvent and form a
carbinolamine that is then converted into the N-methy-
laniline (path f) and CH2O, detected as its dimedone
adduct. However, it is also possible that in part the
R-amino carbon radical is oxidized to a carbocation by
PINO. The reaction of the carbocation with H2O may lead
to the carbinolamine (paths d and e) and then to the final
product.
FIGURE 4. Diagram of ln kH vs ∆G°′ for the reactions of
4-substituted N,N-dimethylanilines with PINO. The solid
circles correspond to the experimental values; the curve is
calculated by nonlinear least-squares fit to the Marcus equa-
tion with Z ) 6 × 1011.
reactivity data were treated according to the Marcus
equation44 (eq 1, where ∆Gq is the activation free energy
for the electron-transfer step (path a), ∆G°′ is the
standard free energy for the same step corrected for the
electrostatic interaction arising from the charge variation
in the reactants upon electron transfer,45 and λ is the
reorganization energy).
Conclusions
PINO reacts with the N-Me C-H bonds of N,N-
dimethylanilines in CH3CN, leading ultimately to the
formation of the N-demethylated product. The rates of
this process resulted very sensitive to the electronic
effects of substituents (F+ ) -2.5) as well as the E° values
of the substrates. The intermolecular and intramolecular
deuterium kinetic isotope effects (DKIEs) were measured
for some substrates (X ) OMe, CO2Et, CN) and two
important results were obtained. First, intramolecular
DKIE [(kH/kD)intra] was always different and higher than
intermolecular DKIE [(kH/kD)inter]; second, no intermo-
lecular DKIE [(kH/kD)inter ) 1] was observed for X ) OMe,
whereas substantial values of (kH/kD)inter were exhibited
by X ) CO2Et (4.8) and X ) CN (5.8). These results, while
are incompatible with a single step hydrogen atom
transfer from the N-C-H bond to the N-oxyl radical, can
be nicely interpreted on the basis of a two-step mecha-
nism involving a reversible electron transfer from the
aniline to PINO leading to an anilinium radical cation,
followed by a proton-transfer step, that produces an
R-amino carbon radical (Scheme 1, paths a and b).
Moreover, a good fit was obtained by applying the Marcus
equation to the reactivity data with a λ value of 37.6 kcal/
mol for the reorganization energy required in the electron-
transfer process. From this value, a quite high reorga-
nization energy (>60 kcal mol-1) is estimated for the
PINO/PINO(-H)- self-exchange reaction.
2
λ
4
∆G°′
λ
∆Gq ) 1 +
(1)
(
)
From the nonlinear least-squares fitting, a λ value of
37.6 kcal mol-1 was calculated for the reorganization
energy required in the transfer of one electron from DMA
to PINO. Since the reorganization energy for the DMA+•/
DMA self-exchange reaction is rather low (<15 kcal
mol-1),24 a substantial reorganization energy (>60 kcal
mol-1) can be calculated for the PINO/NHPI(-H)- self-
exchange reaction. Such a high value is not surprising
since significant reorganization energies are generally
observed for the electron-transfer reactions of oxygen
centered radicals.33 In this respect, it is interesting to
note that Fukuzumi et al. have recently reported a λ
value as high as 160 kcal mol-1 for the C6H5C(CH3)2OO•/
C6H5C(CH3)2OO- self-exchange reaction.33 Such a high
value might explain why peroxyl radicals react with N,N-
dimethylanilines by a hydrogen atom transfer mecha-
nism and not by an electron-transfer mechanism, al-
though their reduction potential (0.89 V vs NHE)33 is not
much different than that of PINO.41
To better understand the origin of the reorganization
energy for the PINO/NHPI(-H)- self-exchange reaction,
DFT calculations at the B3LYP/6-311G** level of theory
were performed to estimate the energy required for the
adjustment in nuclear geometry needed to convert PINO
into its anion (Supplementary Information). The in-
Summing up, the mechanism of the reaction of PINO
with DMAs appears to be different from the one (hydro-
(46) Nelsen, S. F.; Blackstock, S. C.; Kim, Y. J. Am. Chem. Soc. 1987,
109, 677-682.
(47) Klimkans, A.; Larsson, S. Chem Phys. 1994, 189, 25-31. For
more recent applications of the method, see: Hutchison, G. R.; Ratner,
M. A.; Marks, T. J. J. Am. Chem. Soc. 2005, 127, 2339-2350.
Amashukeli, X.; Gruhn, N. E.; Lichtenberger, D. L.; Winkler, J. R.;
Gray, H. B. J. Am. Chem. Soc. 2004, 126, 15566-15571.
(44) Marcus, R. A. Annu. Rev. Phys. Chem. 1964, 15, 155. Eberson,
L. Electron-Transfer Reactions in Organic Chemistry; Springler Ver-
lag: Berlin Heidelberg, 1986; Chapter 3.
(45) ∆G°′ values and the details of their calculation are reported in
the Supporting Information.
5148 J. Org. Chem., Vol. 70, No. 13, 2005

N-Demethylation of N,N-Dimethylanilines
solution in the cuvette (substrate concentration in the range
0.2-2 mM) and the absorbance change was monitored at 380
nm. For all the substrates investigated each kinetic trace
obeyed a first-order kinetic. Second-order rate constants were
obtained by the plot of the observed rate constant kobs vs the
substrate concentration. It was verified that the self-decom-
position of PINO, generated by the oxidation of NHPI (0.30
mM) with Pb(OAc)4 (0.03 mM) in CH3CN (at 25 °C under
argon) was slow enough to allow the study of the reaction of
PINO with the N,N-dimethylanilines.
Laser Flash Photolysis Experiments. Laser flash pho-
tolysis experiments were carried out with a laser kinetic
spectrometer using the fourth harmonic (266 nm) of a Q-
switched Nd:YAG laser. A 3 mL Suprasil quartz cell (10 mm
× 10 mm) was used for all the experiments. Argon-saturated
CH3CN solutions containing di-tert-butyl peroxide (1.0 M),
N-hydroxyphthalimide (10 mM), and dimethylanilines 4-5
(0.1-1.0 mM) were used. All the experiments were carried out
at T ) 25 ( 0.5 °C under magnetic stirring. Rate constants
were obtained by monitoring the change of absorbance at 380
nm and by averaging three to five values. Each kinetic trace
obeyed a first-order kinetic and second-order rate constants
were obtained by the plot of the observed rate constant kobs vs
the substrate concentration.
DFT Calculations. All computations were performed with
the Gaussian 98 program49 using the three-parameter hybrid
functional B3LYP50 with the 6-311G** basis set.51 Such
functional was chosen because it is reported to yield accurate
geometries and reasonable energies.52 Harmonic vibrational
frequencies were calculated at B3LYP/6-311G** level to
confirm that optimized structures correspond to local minima.
Spin contamination due to states of multiplicity higher than
the doublet state was negligible, the value of the S2 operator
was, in all cases, well within 5% of the expectation value for
a doublet (0.75). The atomic charges and unpaired electron
spin densities were calculated using the Mulliken population
analysis.
gen atom transfer) found to be operating in the reactions
of this radical with a variety of benzylic C-H bonds.
However, it should be noted that, with respect to the
benzylic systems, N,N-dimethylanilines are characterized
by generally lower oxidation potentials (that makes
electron transfer more favorable) and higher BDEs of the
scissile C-H bond (that makes the hydrogen atom
transfer less favorable).48 Both factors may be at play in
causing the mechanistic changeover on passing from
benzylic systems to N,N-dimethylanilines.
Experimental Section
Product Analysis. The substrate (0.080 mmol) in 10 mL
of CH3CN, Pb(OAc)4 (0.022 mmol) in 3 mL of 1% CH3COOH
in CH3CN, and NHPI (0.052 mmol) in 3 mL of CH3CN were
separately degassed with argon for 20 min. By mixing the
solutions of NHPI and Pb(OAc)4, the PINO was generated and
added to the solution of the substrate under argon. The
reaction mixture was stirred at 25 °C for 10 min. The solvent
was then removed under reduced pressure and the residue was
treated with dilute HCl, then neutralized with NaOH 2 N. The
mixture was then extracted with CH2Cl2 and the collected
organic extracts were dried over anhydrous Na2SO4 and
analyzed by GC-MS and 1H NMR. With all the substrates
the major product was the corresponding N-methylaniline
(comparison with authentic specimens). The yields, however,
were rather small (from 12% to 20% referred to the starting
material) probably because part of PINO is used in the
competitive dimerization reaction.12,19 1H NMR analysis of the
reaction mixture carried out before the workup showed two
additional singlets at 5.2-5.3 ppm and 3.1-3.2 ppm (the
position depends on the substituent in the aniline), with
relative intensity ) 2:3. These singlets can be reasonably
assigned to the cross-coupling product of PINO and the
R-aminomethyl radical (shown in Scheme 1); in particular, a
singlet at 5.2-5.3 ppm can be predicted for the methylene
group of this adduct on the basis of the additive effect of the
C6H4(CO)2NO and C6H5N(CH3) substituents on the shielding
constant. Moreover, the singlet at 3.1-3.2 ppm can be at-
tributed to the N-methyl group of the adduct being slightly
shielded with respect to the substrate N-methyl groups by the
effect of the CH2ON(CO)2C6H4 substituent. Attempts to isolate
this adduct were unsuccessful because it was unstable during
the chromatographic isolation procedure, always decomposing
into the N-methylaniline and NHPI. Formation of CH2O was
detected by its dimedone adduct. In this case 10 mL of water
and 10 mL of CH2Cl2 were added to the reaction mixture at
the end of the reaction. Then the aqueous layer was incubated
with 3 mL of a 0.2 M dimedone solution in 0.2 M NaOH at
room temperature. Then dilute HCl was added dropwise until
the mixture became acidic. The dimedone adduct was extracted
with CH2Cl2 and analyzed by GC-MS (m/z ) 292). Product
(intramolecular) deuterium isotope effects (kH/kD)intra were
determined, by GC-MS analysis, as the ratio of the corrected
signal intensities of the N-trideuteriomethylanilines and N-
methylanilines (m/z 135 and 132 in the oxidation of 4-cyano-
N-methyl-N-trideuteriomethylaniline; m/z 182 and 179 in the
oxidation of 4-ethoxycarbonyl-N-methyl-N-trideuteriomethy-
laniline; m/z 140 and 137 in the oxidation of 4-methoxy-N-
methyl-N-trideuteriomethylaniline).
Acknowledgment. Financial support from the Min-
istero dell’Istruzione dell’Universita` e della Ricerca
(MIUR) is gratefully acknowledged. We thank Prof.
Basilio Pispisa and Dr. Lorenzo Stella for the use and
assistance in the use of a LFP equipment.
Supporting Information Available: Instrumentation,
materials, synthesis of N,N-dimethylanilines, N,N-bis(trideu-
teriomethyl)anilines, and N-methyl-N-trideuteriomethyla-
nilines, dependence of kobs on the concentration of N,N-
dimethylanilines 1-5, calculation of ∆G°′ values, and computa-
tional data of PINO and NHPI(-H)-. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0503916
(49) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A., Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle,
E. S.; Pople, J. A. Gaussian 98, revision A.7; Gaussian, Inc.: Pitts-
burgh. PA, 1998.
(50) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter
1988, 37, 785-789. Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
(51) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; J. Wiley & Sons: New York, 1987.
(52) Curtiss, L. A.; Raghavachari, K.; Redfern, P. C.; Pople J. A. J.
Chem. Phys. 1997, 106, 1063-1079. Arulmozhiraja, S.; Sato, T.; Yabe,
A. J. Comput. Chem. 2001, 22, 923-930. Kraka, E.; Cremer D. J.
Comput. Chem. 2001, 22, 216-220. Johnson, W. T. G.; Cramer C. J.
J. Am. Chem. Soc. 2001, 123, 923-928.
Spectrophotometric Kinetic Studies. PINO was gener-
ated by the oxidation of NHPI (0.30 mM) with Pb(OAc)4 (0.03
mM) in CH3CN at 25 °C and under an argon atmosphere. A
solution of the substrate (1-3) was added into the PINO
(48) McMillen, D. F.; Golden, D. M. Annu. Rev. Phys. Chem. 1982,
33, 493-532. 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, 2003.
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