An unexpectedly small α-effect in nucleophilic attack at sp-hybridized carbon: Michael-type additions of primary amines to 3-butyn-2-one

Full text of DOI:10.1021/jo9816459

9152
J . Org. Chem. 1998, 63, 9152-9153
An Un exp ected ly Sm a ll r-Effect in
Nu cleop h ilic Atta ck a t sp -Hybr id ized Ca r bon :
Mich a el-Typ e Ad d ition s of P r im a r y Am in es to
3-Bu tyn -2-on e
Ik-Hwan Um,* J ung-Sook Lee, and Sung-Min Yuk
Department of Chemistry, Ewha Womans University,
Seoul 120-750, Korea
Received August 17, 1998
The term R-effect was given to the abnormally enhanced
reactivity shown by nucleophiles having one or more non-
bonding electron pairs at the position R to the nucleophilic
center.1 Numerous studies have been performed to investi-
gate the cause of the R-effect,2 and some suggested origins
of the R-effect are as follows: (a) ground-state destabilization
of the nucleophile,3 (b) stabilization of the transition state,4
(c) enhanced thermodynamic stability of reaction products,5
and (d) differential solvent effect.6,7
F igu r e 1. Brønsted-type plots for the addition reactions of
primary amines to 3-butyn-2-one in H2O at 25.0 °C: 1, methoxyl-
amine; 2, (trifluoroethyl)amine; 3, glycine ethyl ester; 4, hydrazine;
5, glycylglycine; 6, benzylamine; 7, ethanolamine; 8, glycine; 9,
ethylamine.
The magnitude of the R-effect (kR-Nu/knormal-Nu) has been
while the largest R-effect was observed in the reaction at
an sp-hybridized carbon atom.12,13 For example, HOO- is
20000-60000 times more reactive than HO- toward the sp-
hybridized carbon of benzonitriles in 50% aqueous acetone12
or in H2O.13
Until now, the reaction at the sp-hybridized carbon atom
was limited to the reaction at the CtN group in benzoni-
triles.12,13 Reaction at CtC bonds by R-nucleophiles has
never been studied. In this paper, we report the first results
for the addition reactions of a series of primary amines
including R-effect amines to the activated acetylene, 1, as
shown in the following equation. Our aim was to probe the
magnitude of the R-effect with this sp-hybridized electro-
phile, 1.
reported to be influenced by many factors, e.g., solvent,6,7
â
nuc value,8 basicity of nucleophiles,9 and hybridization type
of the electrophilic center.10-13 Among them, the hybridiza-
tion type of electrophilic centers has been suggested to
dominate the magnitude of the R-effect; i.e., the magnitude
of the R-effect increases significantly with increasing “s”
character of the carbon atom at the reaction center.10-13
A
small or no R-effect has been observed for reactions at sp3-
hybridized carbons.10,11 Buncel showed that HOO- and NH2-
NH2 are 5.7-11 and 3.0-5.2 times more reactive than the
corresponding normal nucleophiles HO- and glycylglycine,
respectively, in the methyl group transfer reaction with
methyl sulfates.10 Recently, Fountain also observed small
R-effects (kR-Nu/knormal-Nu ) 2-11) for the reaction at an sp3-
hybridized carbon atom with hydroxamate anions and
hydroxylamine.11 By comparison, the R-effect for reactions
at sp2-hybridized carbons was generally reported to be ∼102,
* To whom correspondence should be addressed. Tel.: (822) 360-2349.
Fax: (822) 360-2844. E-mail: ihum@mm.ewha.ac.kr.
(1) Edwards, J . O.; Pearson, R. G. J . Am. Chem. Soc. 1962, 84, 16-24.
(2) Reviews: (a) Buncel, E.; Hoz, S. Isr. J . Chem. 1985, 26, 313-319. (b)
Grekov, A. P.; Veselov, V. Y. Usp. Khim. 1978, 47, 1200-1230. (c) Fina, N.
J .; Edward, J . O. Int. J . Chem. Kinet. 1973, 5, 1-26.
Figure 1 shows the Brønsted-type plot for the addition
reaction of the amines to 1. As shown, the reactivity of
amines increases generally with an increase in their basicity,
except for hydrazine and methoxylamine. These two amines
are more reactive than the other amines of similar basicity,
resulting in positive deviations from the linear Brønsted-
type plot. These positive deviations are diagnostic for the
R-effect. However, the magnitude of the R-effect in the present
(3) Ibone-Rassa, K. H.; Edwards, J . O. J . Am. Chem. Soc. 1962, 84, 763-
768.
(4) Buncel, E.; Chuaqui, C.; Wilson, H. J . Org. Chem. 1980, 45, 3621-
3626.
(5) Herschlag, D.; J encks, W. P. J . Am. Chem. Soc. 1990, 112, 1951-
1956.
(6) (a) Um, I. H.; Chung, E. K.; Lee, S. M. Can. J . Chem. 1998, 76, 729-
737. (b) Um, I. H.; Yoon, H. W.; Lee, J . S.; Moon, H. J .; Kwon, D. S. J . Org.
Chem. 1997, 62, 5939-5944. (c) Um, I. H.; Oh, S. J .; Kwon, D. S.
Tetrahedron Lett. 1995, 36, 6903-6906. (d) Um, I. H.; Lee, G. J .; Yoon, H.
W.; Kwon, D. S. Tetrahedron Lett. 1992, 33, 2023-2026. (e) Buncel, E.; Um,
I. H. J . Chem. Soc., Chem. Commun. 1986, 595.
system is surprisingly small for the reaction at an sp-
2NH2
hybridized carbon atom, e.g., kNH
/ kglycylglycine ) 11 and
kMeONH / k
) 8.4, R-effects comparable to those of sp3
CF3CH2NH2
2
reaction systems. Clearly, the present result suggests that the
R-effect is not always large for the reaction at the sp-
hybridized carbon atom.
(7) DePuy, C. H.; Della, E. W.; Filley, J .; Grabowski, J . J .; Bierbaum, V.
M. J . Am. Chem. Soc. 1983, 105, 2481-2482.
Bruice and Dixon have demonstrated that the magnitude
of the R-effect is strongly dependent on the magnitude of
ânuc for a variety of reactions of carboxylic esters with
hydrazine and glycylglycine; i.e., the R-effect decreases with
decreasing ânuc value.8a Similarly, Bernasconi has observed
no R-effect for the addition reaction of primary amines
including NH2NH2 and MeONH2 to Meldrum’s acid, systems
in which the ânuc value is 0.22.8b The ânuc value in the present
reaction has been calculated to be 0.32. Therefore, at least
in part, the small ânuc value is considered to be responsible
for the small R-effect observed in the present system.
It has often been suggested that the thermodynamic
R-effect is more important than the kinetic R-effect for
(8) (a) Dixon, J . E.; Bruice, T. C. J . Am. Chem. Soc. 1971, 93, 6592-
6597. (b) Bernasconi, C. F.; Murray, C. J . J . Am. Chem. Soc. 1986, 108,
5251-5257. (c) Palling, D. J .; J encks, W. P. J . Am. Chem. Soc. 1984, 106,
4869-4876.
(9) (a) Moutiers, G.; Guevel, E.; Villien, L.; Terrier, F.J . Chem. Soc.,
Perkin Trans. 2, 1997, 7-10. (b) Terrier, F.; Moutiers, G.; Xiao, L.; Guevel,
E.; Guir, F. J . Org. Chem. 1995, 60, 1748-1754. (c) Terrier, F.; MacCormack,
P.; Kizilian, E.; Halle, J . C.; Demerseman, P.; Guir, KF.; Lion, M. J . Chem.
Soc., Perkin Trans. 2, 1991, 153-158.
(10) Buncel, E.; Chuaqui, C.; Wilson, H. J . Am. Chem. Soc. 1982, 104,
4896-4900.
(11) (a) Fountain, K. R.; Dunkin, T. W.; Patel, K. D. J . Org. Chem. 1997,
62, 2738-2741. (b) Fountain, K. R.; Hutchinson, L. K.; Mulhearn, D. C.;
Xu, Y. B. J . Org. Chem. 1993, 58, 7883-7890.
(12) Wiberg, K. B. J . Am. Chem. Soc. 1955, 77, 2519-2522.
(13) McIsaac, J . E. J r.; Subbaraman, J .; Mulhausen, H. A.; Behrman, E.
J . J . Org. Chem. 1972, 37, 1037-1041.
10.1021/jo9816459 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/12/1998

Communications
J . Org. Chem., Vol. 63, No. 25, 1998 9153
reactions with nitrogen nucleophiles.8 Morris and Page have
shown that the R-effect in hydrazinolysis of benzylpenicillin
can be dissected into a 15-fold increase in the rate constant
but, importantly, a 350-fold increase in the equilibrium
constant for formation of the addition intermediate.14 Simi-
larly, J encks found a small R-effect for reactions involving
nitrogen nucleophiles when nucleophilic attack is the rate-
determining step (RDS) but a large R-effect when nucleo-
philic attack occurs before the RDS,8c indicating that the
magnitude of the R-effect is dependent on the RDS. Conse-
quently, it is necessary to investigate the reaction mecha-
nism for the present system.
not via either TS I or TS III. On the other hand, the R-effect
nucleophiles, NH2NH2 and MeONH2, exhibit a primary KIE;
i.e., the KIE value (kH O/kD O) has been calculated to be 2.00
and 2.30 for MeONH2 and NH2NH2, respectively. The
primary KIE clearly suggests that the N-H bond cleavage
occurs at the RDS,17 and therefore, the reaction of these two
R-effect amines with 1 would proceed via either TS I or TS
III but not via TS II. However, one cannot differentiate TS
I from TS III on the basis of this KIE value alone.
2
2
Useful information about reaction mechanisms can be
inferred from the magnitude of the ânuc value. The magni-
tude of ânuc values for various aminolyses has been reported
to decrease sharply from 0.8 ( 0.1 to 0.2 ( 0.1 as the RDS
changes from a rate-determining breakdown of the addition
intermediate to a rate-determining attack of the amine to
form the addition intermediate.18-20 The ânuc value has been
calculated to be 0.30 for the reaction of 1 with NH2NH2 and
MeONH2. Although this value includes the uncertainty
inherent in a two point analysis, the magnitude is fairly
small as in the corresponding reactions with the non-R-effect
amines (Figure 1). If the reaction proceeded via TS III, in
which bond formation between the nucleophile and the
substrate is fully advanced, one would have expected a
significantly large ânuc value. Therefore, the small ânuc value
obtained in the present system suggests that the reaction
with these R-effect amines proceeds via TS I but not via TS
III.
Although the TS structure for the reaction with the
R-effect amines appears to be different from the one for the
reaction with non-R-effect amines (TS I vs TS II), the attack
of amines occurs at the RDS for both systems. As mentioned
previously, the R-effect has generally been found to be small
for aminolyses in which the attack of amines is rate limiting.
Therefore, one might attribute the small R-effect observed
in the present reaction system to either the difference in
the transition-state structure (TS I vs TS II) or the nature
of the RDS (rate-limiting amine attack for both systems).8c
Alternatively, the small ânuc value may dictate a small
R-effect. Clearly, differentiation of these possibilities awaits
further study on other acetylenic systems.
Addition reactions of amines to activated acetylenes have
been reported to produce E and Z enamines. The E/Z isomer
ratio has been suggested to be influenced by many factors
such as solvent, structure of acetylenes and amines, con-
centration of amines, etc.15,16 However, in our present study,
no detectable Z isomer was observed in the 1H NMR
spectrum of the reaction mixture. Besides, the plots of kobs
vs amine concentration were linear for all the amines studied
in the present system, indicating absence of general base
catalysis by the amine. Therefore, three different reaction
pathways would be suggested, i.e., a one-step concerted
mechanism with a transition state (TS) structure similar to
TS I or stepwise processes with an intermediate modeled
on 2. The latter mechanism can have two different transition
state structures; i.e., TS II represents the transition-state
structure in the rate-determining formation of the interme-
diate 2, and TS III applies to the rate-determining proton
transfer from the intermediate 2 to yield the product.
TS structures I and III are favored by the fact that only
the E isomer is produced. In these mechanisms, one might
expect to see a large primary kinetic isotope effect (KIE),
since the N-H bond cleavage is involved in the RDS.
However, the rate of reaction of 1 with non-R-effect amines
in H2O was found to be almost identical with the one in D2O
Ack n ow led gm en t. This research was supported by
Korea Science and Engineering Foundation (KOSEF 981-
0303-017-2) and by a grant for the promotion of scientific
research in women’s universities.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and kinetic data (Tables 1-10) (6 pages).
(kH O/kD O ) 1.00 ( 0.04). Therefore, one can suggest that
the reaction of 1 with these amines proceeds via TS II but
2
2
J O9816459
(14) Morris, J . J .; Page, M. I. J . Chem. Soc., Perkin Trans. 2, 1980, 220-
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(17) Koh, H. J .; Kim, S. I.; Lee, B. C.; Lee, I. J . Chem. Soc., Perkin Trans.
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