First N-alkyl heterolysis of tertiary benzamides in neutral conditions

Article abstract of DOI:10.1016/S0040-4039(00)01555-0

Tertiary benzamides 1-4 bearing a tricyclopropylmethyl substituent were synthesized and found to undergo rapid alkyl-nitrogen heterolysis at pH 7. X-Ray diffraction structural data for these amides revealed that their ability to give N-alkyl fission was not induced by the pyramidalization of the nitrogen atom, in contrast to what has been observed in the case of N-acyl cleavage (hydrolysis). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01555-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8781–8785
First N-alkyl heterolysis of tertiary benzamides in neutral
conditions
Nicolas Auzeil,a Alain Tomas,b Maurice-Bernard Fleurya and Martine Largerona,*
aLaboratoire de Chimie Analytique et Electrochimie, associe´ au CNRS,
Faculte´ des Sciences Pharmaceutiques et Biologiques, Universite´ Rene´ Descartes, 4, Avenue de l’Observatoire,
75270 Paris Cedex 06, France
bLaboratoire de Cristallographie et RMN Biologiques, associe´ au CNRS,
Faculte´ des Sciences Pharmaceutiques et Biologiques, Universite´ Rene´ Descartes, 4, Avenue de l’Observatoire,
75270 Paris Cedex 06, France
Received 4 September 2000; accepted 12 September 2000
Abstract
Tertiary benzamides 1–4 bearing a tricyclopropylmethyl substituent were synthesized and found to
undergo rapid alkyl-nitrogen heterolysis at pH 7. X-Ray diffraction structural data for these amides
revealed that their ability to give N-alkyl fission was not induced by the pyramidalization of the nitrogen
atom, in contrast to what has been observed in the case of N-acyl cleavage (hydrolysis). © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: amides; cleavage reactions; kinetics; X-ray crystallography.
A considerable effort has been expended to understand the mechanisms of hydrolysis of the
amide bond, in both acidic and basic media.1 The carbonyl oxygen atom of the amide group is
universally believed to be the preferred site of protonation in planar amides. However, in the
case of distorted amides, the strong pyramidalization of the nitrogen atom favors N-protona-
tion, which is suggested to play a key role in enzyme-mediated hydrolysis of twisted amides.2–7
So far, little attention has been paid to the competitive N-alkyl fission of strained N-alkyl-
amides, probably because of the drastic conditions of both temperature and pH necessary for
the reaction, conditions which were considerably different from physiological ones.8–10 However,
we have recently shown that tertiary pyridinecarboxamides or related benzamides bearing a
tert-butyl substituent, suffered a facile alkyl-nitrogen cleavage under unusually mild conditions
(room temperature, dilute aqueous sulfuric acid solutions), subsequently to O-protonation of
the amide group.11 Replacing the tert-butyl substituent with the tricyclopropylmethyl group, we
* Corresponding author. Fax: 33-1-43-29-05-92; e-mail: largeron@pharmacie.univ-paris5.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01555-0

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found that the amide portion became extremely sensitive towards N-alkyl heterolysis, so that it
occurred even in the neutral pH region.
In this paper, we wish to report the first alkyl-nitrogen heterolysis in a neutral medium of
tertiary benzamides bearing a tricyclopropylmethyl substituent. We provide both rate constants
and activation parameters for N-alkyl fission, as well as X-ray diffraction structural data for
benzamides 1–4, in order to establish the relationship between the degree of amide distortion
and the susceptibility towards N-alkyl heterolysis.
At pH 7 and 25°C, tertiary benzamides 1–3 afforded, in nearly quantitative yields, the
corresponding secondary amides 5–7, along with the tricyclopropylcarbinol 8, by N-alkyl
1
cleavage of the amide (Scheme 1). The kinetics was investigated using high-field H NMR
spectroscopy following a procedure previously reported.11 The apparent first-order rate constant
of the alkyl-nitrogen heterolysis was determined with 2, in neutral medium. In the 5.0–7.5 pH
range, the log kobs vs pH profile was a straight line whose slope was 0.94, a result in agreement
with a kinetic law of the type: v=kobs[amide]=k[amide][H3O+], which can be explained in terms
of a full initial protonation of the amide oxygen atom.12 Moreover, comparison of the rate
constant values measured for compounds 1–3, at pH 7 and 25°C, indicated that the reaction rate
decreased in the presence of an electron-withdrawing substituent at the 4-position of the phenyl
ring and, conversely, increased in the presence of an electron-donating substituent. Thus, a
15-fold decrease in kobs was noted in passing from compound 1 (kobs=35.3×10−5 s−1) to
compound 2 (kobs=2.3 10−5 s−1), while the rate constant for N-alkyl heterolysis of compound 3
was too fast to be measured, under the same experimental conditions. Of particular note,
introduction of methyl groups at the 2- and 6-positions of the phenyl ring blocked the
alkyl-nitrogen heterolysis (compound 4).
Scheme 1.
Activation parameters13 also supported the reaction scheme. The small positive DS" value
was as expected for a substrate exhibiting a unimolecular process.10 It is known that distortion
of an amide causes a shift from O- to N-protonation, which is accompanied by a marked
decrease in the DH" values, from 100 to 20 kJ mol−1, while the DS" values are generally large

8783
and negative (about −150 J mol−1 K−1).3,6,14 According to the data reported,13 it could be
deduced that the distortion caused by both the tricyclopropylmethyl and methyl substituents
would not be sufficiently severe to provoke a shift from O- to N-protonation. This was further
substantiated by the results of X-ray crystallographic study.
Benzamides 1, 2 and 4 yielded crystals suitable for structure determination (Fig. 1). In
contrast, we were unable to obtain satisfactory crystals of 3 for X-ray crystallographic analysis,
due to its high reactivity which gave N-alkyl heterolysis on standing. While the most precise
description of molecular distortion was obtained from the analysis of the atomic positions
proposed by Dunitz and Winkler,15 a qualitative feel for the distortion can be derived from the
tilt and twist angles as defined by Brown.5 We especially wanted to know whether the significant
acceleration of N-alkyl heterolysis, observed with benzamides 1–3, arose from twisting the
N-lone pair out of conjugation, the tilting which was achieved on N-pyramidalization, or some
combination of the two deformations. Selected bond distances and angles for benzamides 1, 2
and 4 are collected in Table 1.16 N-p-Nitrobenzoylpyrrolidine was added for comparison with
benzamide 2, as it was anticipated to have a planar amidic unit, or very nearly so.17,18 X-Ray
crystallographic data for 1-aza-2-adamantanone was also reported since this is the extreme case
of a twisted amide, in which overlap of the lone pair of the nitrogen atom with the p system of
the carbonyl group is prevented by the rigid geometry of the tricyclic compound.19
Figure 1. Perspective views of 2 and 4. Atoms are represented by Gaussian ellipsoids at the 50% probability level.
Hydrogen atoms are omitted for clarity. (Atom numbering is for crystallographic purposes only and does not
correspond to naming of the compound)
Results reported in Table 1 indicate that, in all cases, benzamides contained a planar amidic
unit, as characterized by summation of the three valence angles around N11 (roughly 360°) and
by the low value found for the tilt angle which never exceeded 4°.2,5 Moreover, the molecules
displayed bond distances within normal limits for planar amides.18 So, it could be deduced that
the great reactivity of benzamides 1–3 did not correlate with N-pyramidalization. Interestingly,
the difference between non-reactive benzamide 4 and highly reactive compounds 1–3 stemmed
from changes in the twist angle, which markedly increased from 2 to roughly 20° (Table 1), a
value which remains moderate when compared with that of 1-aza-2-adamantanone, the extreme
case of twisted amide (90°). Whether such a twisting deformation was important in terms of
increasing the susceptibility of benzamides 1–3 towards N-alkyl heterolysis was somewhat
difficult to appreciate, as the distortion in these molecules also provoked a substantial torsion

8784
Table 1
Selected structural parameters for benzamides 1, 2 and 4
r (N11ꢀC7) Angle hd (°) Angle around Twist anglee (°) Tilt anglee (°)
,
(A)
N11 (°)
1a
1.355(3)
1.356(3)
1.357(2)
1.354(3)
55.2(2)
56.7(2)
50.2(2)
89.0(2)
–
359.5(2)
360.3(2)
359.9(2)
359.7(2)
359.3
18.8(2)
18.5(2)
20.0(2)
2.0(2)
6.1
3.4(2)
4.1(2)
1.7(2)
2.6(2)
2
4
(N-p-Nitrobenzoyl)pyrrolidineb 1.337
3.7
1-aza-2-Adamantanonec
1.475
–
325.7
90.5
f
a Two crystallographically independent molecules in unit cell.
b Reference 18.
c Reference 19.
d Angle h between the plane of the amide and that of the phenyl ring.
e Reference 5.
f This value was not mentioned.
angle h between the amide plane and that of the phenyl ring (Table 1). Note, that according to
kinetic results, h did not affect transmission of substituent effects at the 4-position of the phenyl
ring, as orbitals twisted out of the plane in the ground state could become coplanar in the
localized excited state.20 In the case of non-reactive benzamide 4, for which h was found to be
maximal (89°), it could be conceivable that the steric crowding exerted by 2- and 6-methyl
substituents forced the planar amidic unit out of the plane of the phenyl ring, even in the
localized excited state.21 Then, interruption of p-electron conjugation between the amidic
portion and the phenyl ring would be responsible for the lack of reactivity observed. Consistent
with this hypothesis, it could be remembered that, in the previously studied benzamide series,11
N-cyclohexyl-N-tert-butylsalicylamide has been found to be the best candidate for N-alkyl
heterolysis, due to intramolecular hydrogen bonding that rendered coplanar the NꢀC(O) moiety
and the 2-hydroxyphenyl ring.
In summary, we have evidenced, in neutral medium, the first N-alkyl cleavage reaction of
tertiary benzamides. Using X-ray crystallographic analysis, we have shown that the ability of
these amides to give N-alkyl fission is not induced by N-pyramidalization, contrary to what is
observed in the case of N-acyl cleavage (hydrolysis). It remains to be confirmed whether the
propensity of N-tricyclopropylbenzamides to form the tricyclopropylium ion intermediate may
account for their improved N-alkyl heterolysis, compared to that of N-tert-butyl analogues,11
since the most stable carbonium ion shows the onset of N-alkyl cleavage in the lowest acidity.
Further work to underpin this proposal is currently in progress in our laboratory.
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8785
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3
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109.16(2), i=92.04(2), k=99.32(2)°, V=801.7(2) A , Dc=1.302 g cm−3, F(000)=336, v=0.721 mm−1. 2743
3
,
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−3
,
1.028 for 279 refined parameters. The residual electron density shows no features up to 0.205 e A and down to
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,
b=7.692(3), c=17.059(6) A, h=90.00, i=90.72 (3), k=90.00°, V=1767(1) A , Dc=1.118 g cm−3, F(000)=648,
v=0.519 mm−1. 2893 reflections were measured. Final wR2=0.2195, R1=0.066 (2284 reflections with I>2|(I))
and a goodness-of-fit=1.108 for 285 refined parameters. The residual electron density shows no features up to
3
,
,
−3
−3
,
,
0.361 e A and down to −0.191 e A
.
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.