The α-effect in reactions of sp-hybridized carbon atom: Michael-type reactions of 1-aryl-2-propyn-1-ones with primary amines

Article abstract of DOI:10.1021/jo050624t

Second-order rate constants (k_N) have been measured for the Michael-type reaction of 1-(X-substituted phenyl)-2-propyn-1-ones (2a-f) with a series of primary amines in H₂O at 25.0 ± 0.1 °C. A linear Bronsted-type plot with a small β_nuc value (β_nuc = 0.30) has been obtained for the reactions of 1-phenyl-2-propyn-1-one (2c) with non-α-nucleophile amines. Hydrazine is more reactive than other primary amines of similar basicity (e.g., glycylglycine and glycine ethyl ester) and results in a positive deviation from the linear Bronsted-type plot. The reactions of 2a-f with hydrazine exhibit a linear Hammett plot, while those with non-α-nucleophile amines give linear Yukawa-Tsuno plots, indicating that the electronic nature of the substituent X does not affect the reaction mechanism. The α-effect increases as the substituent X in the phenyl ring of 2a-f becomes a stronger electron-donating group. However, the magnitude of the α-effect for the reactions of 2a-f is small (e.g., k^Nhydrazine/k_N ^{glycylglycine} = 4.6-13) regardless of the electronic nature of the substituent X. The small β_nuc has been suggested to be responsible for the small α-effect. A solvent kinetic isotope effect (e.g., k_N^H2O/k_N^D2O = 1.86) was observed for the reaction with hydrazine but absent for the reactions with non-α-nucleophile amines. The reactions with hydrazine and other primary amines have been suggested to proceed through a five-membered intramolecular H-bonding structure VI and a six-membered intermolecular H-bonding structure VII, respectively. The transition state modeled on VI can account for the substituent dependent α-effect and the difference in the solvent kinetic isotope effect exhibited by the reactions with hydrazine and other primary amines. It has been proposed that the β_nuc value is more important than the hybridization type of the reaction site to determine the magnitude of the α-effect.

Full text of DOI:10.1021/jo050624t

The r-Effect in Reactions of sp-Hybridized Carbon Atom:
Michael-Type Reactions of 1-Aryl-2-propyn-1-ones with Primary
Amines
Ik-Hwan Um,* Eun-Ju Lee, Jin-Ah Seok, and Kyung-Hee Kim†
Department of Chemistry, Ewha Womans University, Seoul 120-750, Korea
ihum@mm.ewha.ac.kr
Received March 31, 2005
Second-order rate constants (kN) have been measured for the Michael-type reaction of 1-(X-
substituted phenyl)-2-propyn-1-ones (2a-f) with a series of primary amines in H2O at 25.0 ( 0.1
°C. A linear Brønsted-type plot with a small ânuc value (ânuc ) 0.30) has been obtained for the
reactions of 1-phenyl-2-propyn-1-one (2c) with non-R-nucleophile amines. Hydrazine is more reactive
than other primary amines of similar basicity (e.g., glycylglycine and glycine ethyl ester) and results
in a positive deviation from the linear Brønsted-type plot. The reactions of 2a-f with hydrazine
exhibit a linear Hammett plot, while those with non-R-nucleophile amines give linear Yukawa-
Tsuno plots, indicating that the electronic nature of the substituent X does not affect the reaction
mechanism. The R-effect increases as the substituent X in the phenyl ring of 2a-f becomes a
stronger electron-donating group. However, the magnitude of the R-effect for the reactions of 2a-f
is small (e.g., kNhydrazine/kNglycylglycine ) 4.6-13) regardless of the electronic nature of the substituent
X. The small ânuc has been suggested to be responsible for the small R-effect. A solvent kinetic
isotope effect (e.g., kNH O/kND O ) 1.86) was observed for the reaction with hydrazine but absent for
the reactions with non-R-nucleophile amines. The reactions with hydrazine and other primary
amines have been suggested to proceed through a five-membered intramolecular H-bonding
structure VI and a six-membered intermolecular H-bonding structure VII, respectively. The
transition state modeled on VI can account for the substituent dependent R-effect and the difference
in the solvent kinetic isotope effect exhibited by the reactions with hydrazine and other primary
amines. It has been proposed that the ânuc value is more important than the hybridization type of
the reaction site to determine the magnitude of the R-effect.
2
2
Introduction
dynamic stability of the reaction product,6-9 and dif-
ferential solvation effect.2a,10-14 Many factors have been
The term R-effect was given to the abnormally en-
hanced nucleophilicity exhibited by nucleophiles possess-
ing one or more nonbonding electron pairs at the position
adjacent to the nucleophilic site.1 Numerous studies have
been performed to account for the cause of the R-effect.2
Some theories suggested as the cause of the R-effect
include destabilization of the ground-state through elec-
tron repulsion between the nonbonding electron pairs,3
stabilization of the transition state,4,5 enhanced thermo-
reported to influence the magnitude of the R-effect, e.g.,
4-6,9
solvent,2a,10-14 ânuc
,
basicity of nucleophiles,11 and
hybridization type of the electrophilic center.4,15,16
(3) Ibone-Rassa, K. H.; Edwards, J. O. J. Am. Chem. Soc. 1962, 84,
763-768.
(4) (a) Buncel, E.; Chuaqui, C.; Wilson, H. J. Org. Chem. 1980, 45,
3621-3626. (b) Buncel, E.; Chuaqui, C.; Wilson, H. J. Am. Chem. Soc.
1982, 104, 4896-4900.
(5) (a) Hoz, S. J. Org. Chem. 1982, 47, 3545-3547. (b) Buncel, E.;
Hoz, S. Tetrahedron Lett. 1983, 24, 4777-4780. (c) Hoz. S.; Buncel, E.
Tetrahedron Lett. 1984, 25, 3411-3414.
† Present address: Department of Chemistry & Biochemistry,
University of Notre Dame, Notre Dame, IN.
(1) Edwards, J. O.; Pearson, R. G. J. Am. Chem. Soc. 1962, 84, 16-24.
(2) Reviews: (a) Buncel, E.; Um, I. H. Tetrahedron 2004, 60, 7801-
7825. (b) Buncel, E.; Hoz, S. Isr. J. Chem. 1985, 26, 313-319. (c)
Grekov, A. P.; Veselor, V. Y. Usp. Khim. 1978, 47, 1200-1230. (d) Fina,
N. J.; Edwards, J. O. Int. J. Chem. Kinet. 1973, 5, 1-26.
(6) (a) Dixon, J. E.; Bruice, T. C. J. Am. Chem. Soc. 1971, 93, 3248-
3254. (b) Dixon, J. E.; Bruice, T. C. J. Am. Chem. Soc. 1971, 93, 6592-
6597. (c) Dixon, J. E.; Bruice, T. C. J. Am. Chem. Soc. 1972, 94, 2052-
2056.
(7) Palling, D. J.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 4869-
4876.
10.1021/jo050624t CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/16/2005
7530
J. Org. Chem. 2005, 70, 7530-7536

R-Effect in Reactions of sp-Hybridized Carbon Atom
SCHEME 1
The role of solvent on the R-effect has been reported
to be significant.2a,10-14 DePuy et al. have found that
HOO- exhibits no enhanced reactivity compared with
OH- in the gas-phase reactions with methyl formate,10a
while Wolfe et al. have calculated that HOO- and FO-
do not exhibit the R-effect.10b Similarly, we have recently
shown that the R-effect is strongly dependent on the
solvent composition for the nucleophilic substitution
reaction of 4-nitrophenyl acetate and related esters.2a,12,13
The ânuc value4-6,9 and the basicity of nucleophiles11,17
have also been reported to be important to determine the
magnitude of the R-effect. The R-effect has been shown
to be small or absent for reactions in which the ânuc value
is small4-6,9 or for reactions with highly basic R-nucleo-
philes.11,17 However, the type of hybridization of the
electrophilic center has been suggested to dominate the
magnitude of the R-effect. A small or even no R-effect was
observed for reactions at sp3-hybridized carbon atoms,
while the R-effect for reactions at sp2-hybridized carbon
atoms was generally reported to be ca. 102.4,15 Buncel et
al. showed that HOO- and hydrazine 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 reactions with methyl
sulfates.4 Fountain et al. found a similar result for the
reaction at sp3-hybridized carbon atoms with benzohy-
droxamate anions and hydroxylamine.15 On the other
hand, the largest R-effect was observed in the reaction
at an sp-hybridized carbon atom. For example, HOO- was
reported to be 20000-60000 times more reactive than
OH- toward the sp-hybridized carbon of benzonitriles in
50% aqueous acetone or in H2O.16
We have recently found an unexpectedly small R-effect
for the reactions at an sp-hybridized carbon atom of
3-butyn-2-one (1).18 Hydrazine and methoxylamine ex-
hibited positive deviations from the Brønsted-type plot.
However, the degree of deviation from the linear Brøn-
sted-type plot was not significant; i.e., hydrazine and
methoxylamine were found to be only 11 and 8.4 times
more reactive than the corresponding normal nucleo-
philes glycylglycine and trifluoroethylamine, respec-
tively.18 Such a small R-effect was considered to be quite
surprising for the reactions at an sp-hybridized carbon
atom.
(8) Morris, J. J.; Page, M. I. J. Chem. Soc., Perkin Trans. 2 1980,
84, 220-224.
(9) (a) Bernasconi, C. F.; Murray, C. J. J. Am. Chem. Soc. 1986,
108, 5251-5257. (b) Bernasconi, C. F.; Leyes, A.; Eventova, I.;
Rappoport, Z. J. Am. Chem. Soc. 1995, 117, 1703-1711. (c) Bernasconi,
C. F.; Stronach, M. J. Org. Chem. 1991, 56, 1993-2001.
(10) (a) DePuy, C. H.; Della, E. W.; Filley, J.; Grabowski, J. J.;
Bierbaum, V. M. J. Am. Chem. Soc. 1983, 105, 2481-2482. (b) Wolfe,
S.; Mitchell, D. J.; Schlegel, H. B.; Minot, C.; Eisenstein, O. Tetrahedron
Lett. 1982, 23, 615-618. (c) Evanseck, J. D.; Blake, J. F.; Jorgensen,
W. L. J. Am. Chem. Soc. 1987, 109, 2349-2353.
(11) (a) Terrier, F.; Le Guevel, E.; Chatrousse, A. P.; Moutiers, G.;
Buncel, E. Chem. Commun. 2003, 600-601. (b) Buncel, E.; Cannes,
C.; Chatrousse, A. P.; Terrier, F. J. Am. Chem. Soc. 2002, 124, 8766-
8767. (c) Moutiers, G.; Le Guevel, E.; Cannes, C.; Terrier, F.; Buncel,
E. Eur. J. Org. Chem. 2001, 17, 3279-3284. (d) Moutiers, G.; Guevel,
E.; Villien, L.; Terrier, F. J. Chem. Soc., Perkin Trans. 2 1997, 7-10.
(e) Terrier, F.; Moutiers, G.; Xiao, L.; Guevel, E.; Guir, F. J. Org. Chem.
1995, 60, 1748-1754. (f) Laloi-Diard, M.; Verchere, J. F.; Gosselin,
P.; Terrier, F. Tetrahedron Lett. 1984, 25, 1267-1268.
Thus, for a more systematic investigation, we have
extended our study to the reactions of 1-(X-substituted
phenyl)-2-propyn-1-ones (2a-f) with a series of primary
amines in H2O, as shown in Scheme 1. In the present
paper, we report the effect of substituent X on the R-effect
together with a plausible cause of the small R-effect found
in the reactions at the sp-hybridized carbon atoms of 1
and 2a-f.
Results and Discussion
(12) (a) Um, I. H.; Buncel, E. J. Am. Chem. Soc. 2001, 123, 11111-
11112. (b) Um, I. H.; Hong, J. Y.; Buncel, E. Chem. Commun. 2001,
27-28. (c) Um, I. H.; Lee, E. J.; Buncel, E. J. Org. Chem. 2001, 66,
4859-4864. (d) Um, I. H.; Buncel, E. J. Org. Chem. 2000, 65, 577-
582. (e) Um, I. H.; Yoon, H. W.; Lee, J. S.; Moon, H. J.; Kwon, D. S. J.
Org. Chem. 1997, 62, 5939-5944. (f) Tarkka, R. M.; Buncel, E. J. Am.
Chem. Soc. 1995, 117, 1503-1507. (g) Buncel, E.; Um, I. H. J. Chem.
Soc., Chem. Commun. 1986, 8, 595.
(13) (a) Um, I. H.; Lee, E. J.; Buncel, E. J. Org. Chem. 2001, 66,
4859-4864. (b) Um, I. H.; Park, Y. M.; Buncel, E. Chem. Commun.
2000, 1917-1918. (c) Um, I. H.; Yoon, H. W.; Lee, J. J.; Moon, H. J.;
Kwon, D. S. J. Org. Chem. 1997, 62, 5939-5944.
(14) (a) Limb, J. K.; Jeon, S. E.; Lee, S. E.; Um, I. H. Bull. Korean
Chem. Soc. 2002, 23, 1263-1267. (b) Um, I. H. Bull. Korean Chem.
Soc. 1990, 11, 173-175.
(15) (a) Fountain, K. R.; Felkerson, C. J.; Driskell, J. D.; Lamp, B.
D. J. Org. Chem. 2003, 68, 1810-1814. (b) Fountain, K. R.; Tady, D.
B.; Paul, T. W.; Golynskiy, M. V. J. Org. Chem. 1999, 64, 6547-6553.
(c) Fountain, K. R.; Patel, K. D. J. Org. Chem. 1997, 62, 4795-4797.
(d) Fountain, K. R.; Dunkin, T. W.; Patel, K. D. J. Org. Chem. 1997,
62, 2738-2741. (e) Fountain, K. R.; White, R. D.; Patel, K. D.; New,
D. G.; Xu, Y. B.; Cassely, A. J. Org. Chem. 1996, 61, 9434-9436. (f)
Fountain, K. R.; Hutchinson, L. K.; Mulhearn, D. C.; Xu, Y. B. J. Org.
Chem. 1993, 58, 7883-7890.
(16) (a) Wiberg, K. B. J. Am. Chem. Soc. 1955, 77, 2519-2522. (b)
McIsaac, J. E., Jr.; Subbaraman, J.; Mulhausen, H. A.; Behrman, E.
J. J. Org. Chem. 1972, 37, 1037-1041. It is noted that HO- is not
appropriate for the reference nucleophile of HOO- since their basicity
is not similar.
(17) Aubort, J. D.; Hudson, R. F. J. Chem. Soc., Chem. Commun.
1970, 937-938.
The enaminones (3) formed from the reactions of 2a-f
with non-R-nucleophile amines were stable under the
kinetic conditions, while those from the reactions with
hydrazine reacted further to yield 3-(X-substituted phe-
nyl)pyrazoles. All of the reactions obeyed pseudo-first-
order kinetics. Pseudo-first-order rate constants (kobsd
)
were calculated from the slope of the linear plots of ln-
(A∞ - At) vs time. The plots of kobsd vs amine concentration
were linear passing through the origin. Generally, five
different concentrations of amines were used to deter-
mine second-order rate constants (kN) from the slope of
the linear plots of kobsd vs amine concentration. Correla-
tion coefficients of the plots were usually higher than
0.9995. It is estimated from replicate runs that the
uncertainty in the rate constants is less than (3%. The
second-order rate constants determined in this way are
summarized in Tables 1 and 2.
r-Effect in Reaction at sp-Hybridized Carbon
Atom. As shown in Table 1, the reactivity of amines
toward 2c increases as the amine basicity increases. The
(18) Um, I. H.; Lee, J. S.; Yuk, S. M. J. Org. Chem. 1998, 63, 9152-
9153.
J. Org. Chem, Vol. 70, No. 19, 2005 7531

Um et al.
TABLE 1. Summary of Second-Order Rate Constants
for the Michael-Type Reactions of
1-Phenyl-2-propyn-1-one (2c) with Primary Amines in
H2O at 25.0 ( 0.1 °C
â-methoxy-R-nitrostilbene, and benzylidenemalonodial-
dehyde), Bernasconi et al. have found that the R-nucleo-
philes such as hydrazine, methoxylamine, and semicar-
barzide exhibit no R-effect for the nucleophilic attack
process.9 In all cases, the k1 values for these R-nucleo-
philes show good linear Brønsted-type correlations with
those for the other primary amines with a ânuc value of
ca. 0.2.9 On the other hand, the rate constants for the
reverse process (k-1) are markedly depressed for the
reaction with these R-nucleophiles. As a result, these
R-nucleophiles exhibit positive deviations from the linear
plots of log k1/k-1 vs amine basicity. Bernasconi et al.
have suggested that the small ânuc value is responsible
for the absence of the R-effect for the k1 process.9 Dixon
and Bruice have found a similar result for the addition
reactions of primary amines including hydrazine and
methoxylamine to malachite green, i.e., the reaction with
a small ânuc value exhibits a small R-effect and vice
versa.6a,b Clearly, these studies suggest that the ânuc value
is an important factor to determine the magnitude of the
R-effect.
a
no.
amines
pKa
kN/M-1s-1
1
2
3
4
5
6
7
8
ethylamine
10.63
9.76
9.50
9.34
8.25
8.10
7.75
5.70
1.33
glycine
1.13
ethanolamine
benzylamine
glycylglycine
hydrazine
glycine ethyl ester
trifluoroethylamine
0.703
1.22
0.595
4.41
0.466
0.0407
a pKa taken from: Jencks, W. P.; Regenstein, J. In Handbook
of Biochemistry, 2nd ed.; Sober, H. A., Ed.; Chemical Rubber
Publishing Co.: Cleveland, OH, 1970; p J-203. Gilchrist, M.;
Jencks, W. P. J. Am. Chem. Soc. 1968, 90, 2622-2237.
The ânuc value determined is 0.30 for the reactions of
2c with primary amines in this study. We have reported
a similar ânuc value (0.32) for the corresponding reactions
of 1, in which the R-effect found is 11.18 Edwards et al.
have also reported a small R-effect for the substitution
reactions of ClCN (another sp-hybridized carbon atom)
with primary amines including hydrazine.19 The nucleo-
philic substitution reactions of ClCN with primary amines
proceed by C-Cl bond scission. They have found that the
R-effect kNhydrazine/kNglycine amide ) 18, while ânuc ) 0.36 for
the substitution reactions at the sp-hybridized carbon
atom.19 Thus, one might suggest that the small ânuc value
is mainly responsible for the small R-effect found in the
present and the previous reactions of the sp-hybridized
carbon atoms. This argument is consistent with the
proposal by Bruice, Buncel, and Hoz that the R-effect
should decrease as the ânuc value decreases.2b,4-6 In fact,
Dixon and Bruice have experimentally shown that the
R-effect (kNhydrazine/kNglycylglycine) decreases linearly with
decreasing ânuc value for nucleophilic substitution reac-
tions of 17 different substrates with hydrazine and
glycylglycine (or glycine amide).6c Dependence of the
R-effect on the ânuc value has also been found for the
reactions of carbon-, sulfur-, and phosphorus-centered
esters with anionic nucleophiles, e.g., butan-2,3-dione
monoximate (Ox-) and 4-chlorophenoxide (ClPhO-) as an
R- and a reference normal nucleophile, respectively.12b We
have recently reported that the R-effects (kOx-/kClPhO-) are
300, 200, and 40 in the reaction of 4-nitrophenyl acetate
(CdO), benzenesulfonate (SO2), and diphenylphosphinate
(PdO), respectively, while the ânuc value decreases from
0.64 to 0.54 and 0.21 in accordance with decreasing the
R-effect.12b Thus, one can suggest that the ânuc value is a
more important factor than the type of hybridization of
the reaction site to determine the magnitude of the
R-effect.
FIGURE 1. Brønsted-type plot for the Michael-type reactions
of 1-phenyl-2-propyn-1-one (2c) with primary amines in H2O
at 25.0 ( 0.1 °C. The identity of the points is given in Table 1.
effect of amine basicity on reactivity is illustrated in
Figure 1. As shown, the second-order rate constant kN
increases linearly with increasing the pKa of the conju-
gate acid of all the amines studied except hydrazine,
which exhibits a positive deviation from the linear
Brønsted-type plot. One can estimate from Figure 1 that
hydrazine behaves like a primary amine with a pKa value
of 11.8 rather than its actual pKa value of 8.10. The
positive deviation exhibited by hydrazine is diagnostic
for an R-effect. However, the R-effect in the present
system (e.g., kNhydrazine/kNglycylglycine) is only ca. 7.4, which
is quite small for the reaction at an sp-hybridized carbon
atom, since the R-effect has often been reported to be
about 10, 102, and 103-104 for reactions at the sp3, sp2,
and sp-hybridized carbon atom, respectively.4,15,16
Effect of Substituent on Reaction Mechanism. To
obtain further information about the effect of substitu-
ents on the R-effect, the study has been extended to the
reactions of 1-(X-substituted phenyl)-2-propyn-1-ones
In the addition reactions of primary amines to acti-
vated CdC bonds (e.g., benzylidene Meldrum’s acid,
(19) Edwards, J. O.; Erstfeld, T. E.; Ibne-Rasa, K. M.; Levey, G.;
Moyer, M. Int. J. Chem. Kinet. 1986, 18, 165-180.
7532 J. Org. Chem., Vol. 70, No. 19, 2005

R-Effect in Reactions of sp-Hybridized Carbon Atom
TABLE 2. Summary of Second-order Rate Constants for the Michael-type Reactions of 1-(X-Substituted
phenyl)-2-propyn-1-ones (2a-f) with Primary Amines in H2O at 25.0 ( 0.1 °C
kN/M-1 s-1
X
hydrazine
ethylamine
glycylglycine
trifluoroethylamine
R-effecta
2a, p-OMe
2b, p-Me
2c, H
2d, p-Cl
2e, p-CN
2f, m-NO2
3.43
0.615
0.984
1.33 (1.46)b
1.83
0.267
0.0174
13
4.13
0.466
0.0280
8.9
7.4
6.5
4.6
4.6
4.41 (2.42)b
5.54
9.90
9.66
0.595 (0.660)b
0.855
2.17
2.11
0.0407 (0.0384)b
0.0532
0.152
0.138
4.36
4.28
a R-Effect ) kNhydrazine/kN
.
b The data in parentheses are the second-order rate constants for the reactions run in D2O.
glycylglycine
thionobenzoates.23 In all cases, the points for π-electron-
donating substituents (e.g., X ) 4-MeO, 4-Me) exhibited
negative deviations from the linear Hammett plots, and
the degree of deviation was more significant for the
stronger EDG. Traditionally, such a nonlinear Hammett
plot has been interpreted as a change in the rate-
determining step (RDS). However, we have attributed
such a negative deviation to stabilization of the ground
state through resonance interaction between the π-elec-
tron donating substituent and the carbonyl (or sulfonyl)
group as shown in the resonance structures I and II.20-23
Stabilization of the ground state through resonance
interaction is also possible in the present system as
illustrated by the resonance structures III and IV. This
argument can be confirmed by the fact that the Yukawa-
Tsuno plots shown in Figure 3 exhibit excellent linear
correlation. Thus, one can suggest that the negative
deviation shown by 2a is not due to a change in the RDS
or reaction mechanism but stabilization of the ground
state by resonance is responsible for the nonlinear
Hammett plots.
FIGURE 2. Hammett plots for the Michael-type reactions of
1-(X-substituted phenyl)-2-propyn-1-ones (2a-f) with primary
amines in H2O at 25.0 ( 0.1 °C. The identity of the points is
given in Table 2.
(2a-f) with hydrazine and three other primary amines.
As shown in Table 2, the second-order rate constant
increases as the substituent X changes from an electron-
donating group (EDG) to an electron-withdrawing group
(EWG) for all of the amines studied including hydrazine.
The effect of substituent X on the reactivity is illustrated
in Figure 2.
The Hammett plot for the reaction with hydrazine
exhibits a good linearity. However, the corresponding
Hammett plot for the reactions with the other primary
amines shows poor correlation, i.e., the point for the
substrate having a π-electron donor substituent (e.g., X
) 4-MeO) exhibits a negative deviation from the linear
Hammett plots. This result is similar to the nonlinear
Hammett plots found for the aminolyses of aryl X-
substituted benzoates20 and benzenesulfonates21 and
alkaline hydrolyses of aryl X-substituted benzoates22 and
log(kX/kH) ) F{σo + r(σ+ - σo)}
(1)
The r value in the Yukawa-Tsuno equation (eq 1)
represents the extent of resonance contribution.24 Equa-
tion (1) becomes the Hammett equation when r ) 0 or
the Brown-Okamoto equation when r ) 1. The r value
determined is ca. 0.55 ( 0.1 for the reactions of 2a-f
with the non-R-nucleophile amines. This accounts for the
result that the Yukawa-Tsuno plots exhibit much better
linear correlation than the corresponding Hammett or
Brown-Okamoto plots, in which σ or σ+ constants alone
(21) (a) Um, I. H.; Hong, J. Y.; Kim, J. J.; Chae, O. M.; Bae, S. K. J.
Org. Chem. 2003, 68, 5180-5185. (b) Um, I. H.; Chun, S. M.; Chae, O.
M.; Fujio, M.; Tsuno, Y. J. Org. Chem. 2004, 69, 3166-3172.
(22) Um, I. H.; Han, H. J.; Ahn, J. A.; Kang, S.; Buncel, E. J. Org.
Chem. 2002, 67, 8475-8480.
(23) Um, I. H.; Lee, J. Y.; Kim, H. T.; Bae, S. K. J. Org. Chem. 2004,
69, 2436-2441.
(24) (a) Tsuno, Y.; Fujio, M. Adv. Phys. Org. Chem. 1999, 32, 267-
385. (b) Tsuno, Y.; Fujio, M. Chem. Soc. Rev. 1996, 25, 129-139. (c)
Yukawa, Y.; Tsuno, Y. Bull. Chem. Soc. Jpn. 1959, 32, 965-970.
(20) (a) Um, I. H.; Kim, K. H.; Park, H. R.; Fujio, M.; Tsuno, Y. J.
Org. Chem. 2004, 69, 3937-3942. (b) Um, I. H.; Min, J. S.; Ahn, J. A.;
Hahn, H. J. J. Org. Chem. 2000, 65, 5659-5663. (c) Um, I. H.; Chung,
E. K.; Lee, S. M. Can. J. Chem. 1999, 77, 659-666.
J. Org. Chem, Vol. 70, No. 19, 2005 7533

Um et al.
FIGURE 4. Plots showing dependence of the R-effect on the
electronic nature of the substituent X for the reactions of 1-(X-
substituted phenyl)-2-propyn-1-ones (2a-f) and 4-nitrophenyl
X-substituted benzoates (inset) with hydrazine and glycylgly-
cine in H2O at 25.0 ( 0.1 °C. The identity of the points is given
in Table 2. The data for the reactions of the benzoate system
were taken from ref 25.
FIGURE 3. Yukawa-Tsuno plots for the Michael-type reac-
tions of 1-(X-substituted phenyl)-2-propyn-1-ones (2a-f) with
ethylamine (Y), glycylglycine (O), and trifluoroethylamine (b)
in H2O at 25.0 ( 0.1 °C. The identity of the points is given in
Table 2.
are used. Thus, one can suggest that the electronic nature
of the substituent X does not affect the reaction mecha-
nism on the basis of the linear Yukawa-Tsuno plots.
Effect of Substituent on the r-Effect. As shown in
Table 2, the R-effect for the reactions of 2a-f increases
as the substituent X changes from a strong EWG to a
strong EDG. The effect of the substituent on the R-effect
is illustrated in Figure 4. One can see that the R-effect
exhibits a linear correlation with the electronic nature
of the substituent X. However, the magnitude of the
R-effect for the reactions at the sp-hybridized carbon is
small regardless of the electronic nature of the substitu-
ent X (e.g., the R-effect of only 4.6-13). To achieve an
R-effect of 103-104, the largest R-effect suggested for the
reaction of an sp-hybridized carbon atom,16 the σ value
should be at least ca. -6.7. However, such a σ value is
practically impossible.
with hydrazine. As the substituent X in the benzoyl
moiety changes from an EWG to an EDG, more negative
charge would develop at the oxygen atom of the carbonyl
bond, which enables a stronger H-bonding interaction
(more stabilization of the transition state) and results
in the increasing R-effect trend shown in the inset of
Figure 4.
Dependence of the R-effect on the electronic nature of
substituents has also been reported for the reactions of
4-nitrophenyl X-substituted benzoates with primary
amines including hydrazine.25 As shown in the inset of
Figure 4, the R-effect of the benzoate system also
increases as the substituent X changes from a strong
EWG to a strong EDG. We have explained the increasing
R-effect trend through the intramolecular general acid/
base catalysis modeled on V, which is one of the first
explanations to account for the R-effect exhibited by NH2-
NH2, HONH2, HOO-, etc.2b-d,26 Such an intramolecular
H-bonding interaction is possible only for the reactions
The importance of the structure V has been neglected
because MeONH2 cannot form such a transition state but
it has often exhibited a large R-effect.2b-d Since the origin
of the R-effect exhibited by NH2NH2 and MeONH2 is not
necessarily the same, we propose a transition state
modeled on VI to account for the substituent dependent
R-effect.27 Hydrazine can stabilize the transition state
through the five-membered intramolecular H-bonding
(26) (a) Hess, R. A.; Hengge, A. C.; Cleland, W. W. J. Am. Chem.
Soc. 1997, 119, 6980-6983. (b) Jencks, W. P. J. Am. Chem. Soc. 1958,
80, 4585-4588. (c) Epstein, J.; Demek, M. M.; Rosenblatt, D. H. J.
Org. Chem. 1956, 21, 796-797.
(25) Um, I. H.; Chung, E. K.; Lee, S. M. Can. J. Chem. 1998, 76,
729-737.
7534 J. Org. Chem., Vol. 70, No. 19, 2005

R-Effect in Reactions of sp-Hybridized Carbon Atom
interaction. As the substituent X in the phenyl ring of
2a-f changes from a strong EWG to a strong EDG, the
developing negative charge would be more localized at
the 2-carbon atom of 2a-f. Then, the intramolecular
H-bonding interaction would be stronger and the transi-
tion state VI can be more stabilized. On the contrary, as
the substituent X becomes a strong EWG, the negative
charge at the 2-carbon atom would be delocalized to the
carbonyl group, which would result in a decrease in both
the H-bonding interaction and the transition state sta-
bilization. This argument can account for the substituent
dependent R-effect shown in Figure 4.
be destabilized by the electron repulsion between the
adjacent nonbonding electrons or by other reasons, the
difference in the ground-state energy between hydrazine
and glycylglycine should be constant, since they were
used as the R and the reference normal nucleophile for
all the reactions of 2a-f in this study. Thus, if the
difference in the ground-state energy were responsible
for the R-effect, the magnitude of the R-effect should have
been about the same regardless of the electronic nature
of the substituent X in the present system. However, our
result shows that this is not the case. Accordingly, one
can suggest that destabilization of the ground-state
energy cannot be the cause of the substrate dependent
R-effect shown in Figure 4. This argument is consistent
with the conclusion drawn by Buncel and Hoz that
ground state destabilization will contribute only slightly,
if at all, to the manifestation of R-effects.5b
The transition state VI can also explain the solvent
kinetic isotope effect (KIE) determined in this study. As
shown in Table 2, the second-order rate constant (kN) for
the reactions with non-R-nucleophile amines is almost
D2O
the same in H2O and in D2O, i.e., kNH O/kN
) 1.0 (
2
Stabilization of transition state through aromatic28 or
radicaloid5 character, and/or intramolecular H-bonding
interaction,25,26 has been suggested as an origin of the
R-effect. In the preceding section, we have suggested that
the transition state for the reaction with hydrazine is
stabilized through the intramolecular H-bonding struc-
ture VI. However, one can expect that the transition state
stabilizing effect would be significant only for the system
in which the ânuc value is large. Since the ânuc values are
very small for the reactions of 1 and 2a-f, the effect of
transition state stabilization through the structure VI
cannot be significant. This argument is consistent with
the small R-effect found in this and previous reactions
at the sp-hybridized carbon atoms (e.g., 1, 2a-f, and
ClCN). Thus, one can suggest that stabilization of the
transition state through the structure VI is responsible
for the increasing R-effect trend shown in Figure 4, but
the effect of transition state stabilization is not significant
due to the small ânuc value.
0.1, while the reactivity of hydrazine decreases signifi-
cantly in D2O, i.e., kNH O/kN
) 1.82. The absence of
D2O
2
solvent KIE suggests that the proton transfer occurs after
the RDS for the reactions with the non-R-nucleophile
amines, while the solvent KIE of 1.82 for the reaction
with hydrazine indicates that the proton transfer occurs
at the RDS. The difference in the solvent KIE is consis-
tent with the proposal that the reactions of 2a-f with
hydrazine proceed through the transition state VI. In this
model, the proton transfer can occur through the in-
tramolecular H-bonding at the RDS. However, such an
intramolecular H-bonding structure is not possible for the
reactions with non-R-nucleophile amines. Instead, one
might suggest a six-membered intermolecular H-bonding
structure VII for the reactions with the non-R-nucleophile
amines. This model would be better than a four-
membered intramolecular H-bonding structure VIII.
Thus, the proton transfer from the nitrogen atom to the
2-carbon atom of 2a-f would occur after the RDS through
the intermediate modeled on VII on the basis of the
absence of solvent KIE for these reactions with non-R-
nucleophiles.
Conclusions
The present study has allowed us to conclude the
following: (1) The Brønsted-type plot for the reactions
of 2c with primary amines is linear with a ânuc value of
0.30. Hydrazine exhibits a positive deviation from the
linear Brønsted-type plot but the R-effect is very small
(e.g., kNhydrazine/kNglycylglycine ) 7.4). (2) The electronic nature
of the substituent X does not influence the reaction
mechanism for the reactions of 2a-f, but the R-effect
increases as the substituent X becomes a stronger EDG.
(3) The reactions with hydrazine and other primary
amines have been suggested to proceed through a five-
membered intramolecular H-bonding structure VI and
a six-membered intermolecular H-bonding structure VII,
respectively. The transition state modeled on VI can
account for the substituent dependent R-effect and the
difference in the solvent KIE exhibited by the reactions
with hydrazine and other primary amines. (4) The small
ânuc value has been suggested to be responsible for the
small R-effect found in the reactions of 1 and 2a-f. (5)
We propose that the ânuc value is a more important factor
than the hybridization type of the reaction site to
determine the magnitude of the R-effect.
Origin of Small r-Effect. Nucleophilic reactivity is
determined by the free energy gap between the ground
state and the transition state of the reaction. One might
suggest that R-nucleophiles exhibit enhanced reactivities
(the R-effect) by destabilizing their ground state and/or
by stabilizing their transition state. It has often been
suggested that the ground state of R-nucleophiles is
destabilized.2 In fact, from a calorimetric study, we have
recently shown that the R-nucleophile (butan-2,3-dione
monoximate) is ca. 4 kcal/mol less solvated than its
reference normal nucleophile (4-chlorophenoxide) in
H2O.12d Although the ground state of hydrazine might
(27) A reviewer has suggested to note that “This transition state
leads to the formation of a zwitterion. While ylides of second row
elements are common, this one may be of a too high energy.”
(28) Liebman, J. F.; Pollack, R. M. J. Org. Chem. 1973, 38, 3444-
3445.
J. Org. Chem, Vol. 70, No. 19, 2005 7535

Um et al.
Product Analysis. The enaminones (3) from the reactions
with non-R-nucleophile amines were identified by means of
their UV-vis and 1H NMR spectra. 1H NMR studies have
shown that the enaminones exist as the cis-isomer exclusively
in CD3Cl but as 1:1 mixture of cis- and trans-isomers in CD3-
OD. The measurement of 1H NMR spectra in H2O was not
possible due to the low solubility of the reaction products. An
intramolecular H-bonding structure IX has been suggested to
be responsible for the cis-isomer in the aprotic solvent.31 (See
Experimental Section
Materials. 1-(X-substituted phenyl)-2-propyn-1-ones (2a-
f) were readily prepared from oxidation of the corresponding
carbinols,29 which were obtained from the reactions of X-
substituted benzaldehydes with ethynylmagnesium bromide
in dried diethyl ether as reported in the literature.30 Their
1
purity was checked by means of melting points and H NMR
spectra (Supporting Information). Doubly distilled water was
further boiled and cooled under nitrogen just before use.
Amines and other chemicals used were of the highest quality
available.
1
the H NMR spectra in the Supporting Information.)
Kinetics. The kinetic studies were performed with a UV-
vis spectrophotometer equipped with a constant temperature
circulating bath to keep the temperature of the reaction
mixture at 25.0 ( 0.1 °C. The reactions were followed by
monitoring the appearance of the enaminone (3) at a fixed
wavelength corresponding to the maximum absorption (see
Tables S2-S33 in the Supporting Information). All of the
reactions were carried out under pseudo-first-order conditions
in which the concentration of the amines was at least 20 times
greater than that of 2a-f. The amine stock solution of ca. 0.2
M was prepared in a 25.0 mL volumetric flask by adding
2 equiv of amine hydrochloride to 1 equiv of standardized
NaOH solution (or by adding 2 equiv of free amine to 1 equiv
of standardized HCl) in order to obtain a self-buffered solution
under nitrogen just before use and transferred by gas-
tight syringes. The detailed kinetic conditions and results
are summarized in Tables S2-S33 in the Supporting Informa-
tion.
The reactions of 2a-f with hydrazine also produced the
enaminones initially, but they reacted further to yield the ring
closed products, 3-(X-substituted phenyl)pyrazoles (4), under
the kinetic conditions as reported.32
Acknowledgment. We are grateful for the financial
support from the Korea Science and Engineering Foun-
dation (KOSEF-R01-2004-10279).
Supporting Information Available: Table S1 for melting
points (determined in the present study and reported in the
literatures) of 2a-f. Tables S2-S33 for kinetic conditions and
results. 1H NMR spectra of 1-(4-cyanophenyl)-2-propyn-1-one
(2e), 3-(benzylamino)-1-(4-methylphenyl)-prop-2-en-1-one (in
CDCl3 and CD3OD), and 3-phenylpyrazole. This material is
available free of charge via the Internet at http://pubs.acs.org.
(29) Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. L.
J. Chem. Soc. 1946, 39-45.
JO050624T
(30) (a) Bagley, M. C.; Dale, J. W.; Ohnesorge, M.; Xiong, X.; Bower,
J. J. Comb. Chem. 2003, 5, 41-44. (b) McMullen, C. H.; Stirling, C. J.
M. J. Chem. Soc. 1966, 1221-1223. (c) Jones, E. R. H.; McCombie, J.
T. J. Chem. Soc. 1942, 733-735. (d) Hennion, G. F.; Murray, W. S. J.
Am. Chem. Soc. 1942, 64, 1220-1222. (e) Froning, J. F.; Hennion, G.
F. J. Am. Chem. Soc. 1940, 62, 653-655.
(31) Tripathi, V. K.; Venkataramani, P. S. J. Chem. Soc., Perkin
Trans. 1 1979, 36-41.
(32) Zelenin, K. N.; Tugusheva, A. R.; Yakimovich, S. I.; Alekseev,
V. V.; Zerova, E. V. Chem. Heterocycl. Compd. 2002, 38, 668-676.
7536 J. Org. Chem., Vol. 70, No. 19, 2005