Angewandte
Chemie
substituents on the aromatic ring. The effect was remarkable
with solvolysis of the p-nitrobenzyl substrate complete in
minutes (entry 2), even proceeding efficiently at 188C
(entry 3). Linear free-energy analysis against Hammett sÀ
values confirmed that a resonance-stabilized partial negative
charge accumulates at the a-C during the solvolysis (1À = 2.6).
To probe whether activation was specific to a-aryl amides,
a range of acetamides bearing electron-withdrawing substitu-
ents (R’) at the a-position (Table 2) were then tested for
methanolytic reactivity. The diisopropyl amides 1a–d were
deviation from planarity. Thus even in these most hindered
examples, the ground-state structures “measure” as normal
amides and their exceptional reactivity does not arise from
the dominant “ketonic” character[6] found in strained lactams.
Variable temperature NMR data provided an important
clue in the analysis of the trend in proton switch/methanolysis
rates. In the less reactive compounds, for example the N,N-
diisopropyl amides 1, the signals are analogous to those
observed in all typical amides, where there is a high energetic
barrier to cis–trans interconversion of N-substituents, because
À
of the resonance decoupling that arises during N CO
rotation. However, for the other amides in the series, the
Table 2: The effect of a-substituent (R’) and steric hindrance (R2) on the
methanolytic half-life of acetamides.
À
barriers to N CO rotation decrease substantially as the
nitrogen center becomes more crowded, until at the stage of
the highly reactive TMP amides 4, the barrier is much less
than half that found in a regular amide[13] The reduced
À
energetic cost of N CO torsion presumably arises because
steric decompression can partially compensate for the reso-
nance decoupling that results. In other words, unlike lactams
where resonance decoupling is enforced, these new systems
À
are able to twist about the N CO bond more freely than
normal amides, and thus generate a transiently decoupled
system.
NR2
(T [8C])
t1/2 [min][a]
a
t1/2 [min][a]
b
t1/2 [min][a]
c
t1/2 [min][a]
d
1.0ꢀ105[b]
1.7ꢀ104[d]
0.5ꢀ102[e]
2.2[f,g]
1.9ꢀ105[c]
2.7ꢀ104
0.7ꢀ102
8
0.6ꢀ105
2.1ꢀ104
4.0ꢀ102
23
1.9ꢀ105[c]
0.5ꢀ104
3.8ꢀ102
3.4ꢀ102
A mechanism that incorporates all of these observations is
outlined in Figure 1. In cases where R is unhindered, the
planar amide is conventional and inert because of the
conformational rigidity afforded by the classical bonding
picture. As the R groups are increased in steric bulk, a flatter
1 (708C)
2 (508C)
3 (508C)
4 (188C)
[a] Based on conversion (1H NMR) or isolated yield through first-order
solvolytic decay. [b] a-CH/D t1/2 =2 h at 218C. [c]ꢀ1% conversion/48 h.
[d] a-CH/D t1/2 =51 min at 218C. [e] a-CH/D t1/2 =9 s at 218C. [f] a-CH/
D t1/2 =3 min at À108C. [g] t1/2 =48 min at 38C.
stable, undergoing only trace conversion at reflux for 48 h. On
moving to the more hindered amides 2 and 3, a significant
increase in reactivity was observed, most notable in the cases
of the phenylsulfonyl 3a and cyano 3b substituted examples.
However, once again it was the TMP derivatives 4a–d that
showed exceptional reactivity, and with the phenyl sulfonyl
derivative 4a quantitative ester formation (> 99% isolated
yield) occurred in minutes at room temperature.
Analysis of the kinetics[11] of methanolysis of the a-sulfone
acetamide series 1a–4a in CD3OD revealed that H/D
exchange of the protic solvent with the a-carbon proceeded
102–103 times faster than methanolysis. A key observation is
that through the series (1a–4a) the two processes are linked,
thus as the activation barrier to a-CH/D exchange decreases,
so does the barrier for methanolysis.[12] In other words, the
bulkier the substituents at N, the faster the reversible proton
switch occurs. This might be envisaged as arising from an
increasing level of amide distortion, and thus “ketonic”
character, as the steric bulk increases. However, none of the
amides studied showed any significant difference in their IR
stretching frequency (around 1640 cmÀ1) or 13C NMR chem-
ical shift (159.8–164.5 ppm) to that expected for classic planar
amides. This conclusion was reinforced by an X-ray crystallo-
graphic study (see the Supporting Information) in which it is
evident that the amide moieties in 1a, 2a, and 3a have a
typical planar structure, and that even 4a only has a small
Figure 1. Model for the roles of steric hindrance (NR2) and electron-
withdrawing a-substituent (R’) in neutral methanolysis through elimi-
nation.
À
energy surface for N CO torsion (KR) allows a greater extent
of transient nitrogen pyramidalization. The concomitant
increase in N-basicity in this minor population then accel-
erates nucleophile-mediated proton switch[12] (KPS) to rever-
sibly generate a zwitterion, Figure 1. Build-up of negative
charge at the a-carbon is accommodated by the electron-
withdrawing group (X, Table 1, 1À = 2.6 and R’, Table 2) and
[11]
elimination (kelim
)
of the neutral hindered amine, acceler-
ated by steric decompression, then generates a transient
ketene.[14]
Angew. Chem. Int. Ed. 2012, 51, 548 –551
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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