Catalysis of Anilide Ethanolysis
J . Org. Chem., Vol. 63, No. 19, 1998 6479
conclude therefore that cleavage of anilides 1 and 3 not
only occurs in ethanol solution according to the same
mechanism proposed by Schowen et al.5 for the metha-
nolysis reaction, but also that the positions of the proton
in the two valence isomeric transition states are very
similar in the two solvents.
expulsion of the amine leaving group had been considered
in papers by earlier workers,13,3a but it was not until 1992
that Suh et al.14 reported convincing evidence of the
general acid role of a Cu(II)-bound water molecule in
amide hydrolysis. The results reported in this paper add
to the above evidence and point to general acid catalysis
by a metal-bound solvent molecule in the expulsion of
the amine leaving group as a fundamental mode of
catalysis by metal ions in amide cleavage reactions.
Furthermore, they widen considerably the scope of s-
block metal ions as efficient catalysts of acyl transfer
processes.15 Finally, the very finding that a barium or
strontium ion is still catalytically active after complex-
ation to a crown ether proved to be useful in the
construction of more elaborate catalysts with esterase
and amidase activity capable of substrate recognition in
which the catalytic site was provided by a crown ether
complexed alkaline-earth metal ion. The results of this
investigation will be reported in due time.
Interpretation of metal ion influences on solvent
isotope effects in terms of variations in transition state
structure requires at least a rough knowledge of metal
ion induced variations in the secondary contributions. We
note (Table 2) that the isotope effect in the ethanolysis
of phenyl acetate, that is devoid of primary contributions,
is remarkably insensitive to the presence of either the
barium ion or its complex with 18C6. This finding
provides a strong indication that the magnitude of
secondary contributions is hardly affected by the metal
ion.12 By this hypothesis the primary contribution to the
solvent isotope effect in the ethanolysis of 1 is signifi-
cantly reduced by both the barium ion and its crown
complex to a value of ca. 2 or even less, whereas it is left
substantially unchanged in the ethanolysis of 3.
Exp er im en ta l Section
Application of Thornton’s reacting bond rules with the
aid of the diagram of Figure 2 provides a rationale for
the above conclusions. Addition of barium ion (or its
crown complex) stabilizes corner P relative to R because
the metal ion binds more strongly to the ethoxide than
to the tetrahedral intermediate on account of the more
basic character of the former. Furthermore, the metal
ion strongly stabilizes corner Q because it can favorably
interact with the two oxide ions, but has a minor
influence on the energy of corner S. Thus, addition of
the metal ion should move the transition state for
mechanism a from *a along the reaction coordinate
toward R and, to a much larger extent, perpendicular to
the reaction coordinate toward Q. The net result ex-
pected is a new transition state structure at *a′. Com-
pared to *a, the new structure has a greater degree of
proton transfer to nitrogen which, in line with observa-
tions, causes a decrease in the primary contribution to
the solvent isotope effect. When a similar reasoning is
applied to transition state *b, a relatively minor change
along the reaction coordinate toward R and little or no
change perpendicular to the reaction coordinate are
predicted. The degree of proton transfer to nitrogen in
the new position *b′ is so close to that in *b that any
variation in the primary contribution to the solvent
isotope effect should be hardly noticeable, which is again
in line with experimental findings.
Amides 14 (mp 27.6-28.1 °C; lit.4 mp 26-28 °C), 216 (mp
68-69 °C; lit.16 mp 68-69 °C), and 34 (mp 73.5-74 °C; lit.4
mp 70.5-72.5 °C) were prepared according to standard
literature procedures. Spectrophotometric rate measurements
were carried out in the thermostated cell compartment of a
diode array spectrometer. Reactions in EtOH and EtOD were
determined successively within a short time interval for each
compound. Each measurement was carried out in duplicate.
Errors in the (kEtOH/kEtOD) quantities are on the order of 0.01-
0.02. HPLC rate measurements were carried out on a liquid
chromatograph fitted with a UV-vis detector operating at 230
nm. Samples of the reaction mixture were withdrawn at time
intervals, quenched with dilute hydrobromic acid, and sub-
jected to HPLC analysis after addition of a known amount of
the internal standard (4-methylanisole). Analyses were car-
ried out on a Supelcosil LC-18-DB column (25 cm × 4.6 mm
i.d.; particle size 5 µm) with 55:45 (v/v) MeOH (30 mM sodium
1-heptanesulfonate)-H2O (30 mM sodium 1-heptanesulfonate
and 8.0 mM H3PO4/50 mM NaH2PO4 buffer, pH ) 3) as mobile
phase, at a flow rate of 0.65 mL/min. The mobile phase was
prepared daily and stored at 4 °C when not used. Other
materials, apparatus, and techniques were as reported previ-
ously.1,2
Ack n ow led gm en t. The authors greatly acknowl-
edge financial contributions from MURST, from CNR
(Progetto Strategico Tecnologie Chimiche Innovative),
and from the HCM program of EU.
J O972102M
Con clu d in g Rem a r k s
(13) Gensmantel, N. P.; Proctor, P.; Page, M. I. J . Chem. Soc., Perkin
Trans. 2 1980, 1725.
(14) Suh, J .; Park, T. H.; Hwang, B. K. J . Am. Chem. Soc. 1992,
114, 5141.
The possible involvement of a metal-coordinated sol-
vent (water) molecule as general acid catalyst in the
(12) This is understandable if the metal-ethoxide pair has the
structure of a solvent-separated ion pair, where at least the first
solvation sphere of the ethoxide is substantially unchanged compared
with the free ion. Tight pairing of the barium cation to the ethoxide
would presumably result in a reduction of the number of ethanol
(15) Cacciapaglia, R.; Mandolini, L. Chem. Soc. Rev. 1993, 22, 221;
Cacciapaglia, R.; Mandolini, L. In Molecular Design and Bioorganic
Catalysis; Wilkox, C. S., Hamilton, A. D., Eds.; Kluwer Academic
Publishers: Dordrecht, 1996, pp 71-86; see also: Stanton, M. G.;
Gagne´, M. R. J . Am. Chem. Soc. 1997, 119, 5075.
(16) Biechler, S. S.; Taft, R. W. J r., J . Am. Chem. Soc. 1957, 79,
4927.
molecules hydrogen bonded to the latter and, consequently, in
substantial increase in the (kEtOH/kEtOD quantity.
a
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