Unraveling structure-reactivity relationships in SNV reactions: Kinetics of the reactions of methoxybenzylidenemalononitrile, 2-(methylthiobenzylidene)- 1,3-indandione, 2-(benzylthiobenzylidene)-1,3-indandione, and methyl β-methylthio-α-nitroci

Article abstract of DOI:10.1021/ja003536t

The kinetics of the title reactions were determined in 50% DMSO-50% water (v/v) at 20 °C; n-BuS^-, HOCH₂CH₂S^-, and MeO₂CCH₂S^- were used as thiolate ions. The reactions with the th

Full text of DOI:10.1021/ja003536t

J. Am. Chem. Soc. 2001, 123, 2155-2164
2155
Unraveling Structure-Reactivity Relationships in SNV Reactions:
Kinetics of the Reactions of Methoxybenzylidenemalononitrile,
2-(Methylthiobenzylidene)-1,3-indandione,
2-(Benzylthiobenzylidene)-1,3-indandione, and Methyl
â-Methylthio-R-nitrocinnamate with OH- and Thiolate Ions in
Aqueous DMSO
Claude F. Bernasconi,*,† Rodney J. Ketner,† Mark L. Ragains,† Xin Chen,‡ and
Zvi Rappoport‡
Contribution from the Department of Chemistry and Biochemistry, UniVersity of California,
Santa Cruz, California 95064, and the Department of Organic Chemistry,
The Hebrew UniVersity of Jerusalem, Jerusalem 91904, Israel
ReceiVed September 28, 2000
Abstract: The kinetics of the title reactions were determined in 50% DMSO-50% water (v/v) at 20 °C;
n-BuS-, HOCH2CH2S-, and MeO2CCH2S- were used as thiolate ions. The reactions with the thiolate ions
gave rise to two separate kinetic processes. The first refers to rapid, reversible attachment of RS- to the substrate
leading to a tetrahedral intermediate (kR1 S, kRS), the second to the conversion of the intermediate to products
-1
(kR2 S). In most cases all of the rate constants (k1RS,kRS, and kR2 S) could be determined. In combination with
-1
results from previous studies, a detailed discussion regarding the effects of activating substituents and leaving
groups on rate and equilibrium constants as well as on intrinsic rate constants is presented. The reaction with
OH- only allowed a determination of kO1 H for nucleophilic attack on the substrate; in this case the tetrahedral
intermediate remains at steady-state levels under all conditions.
Introduction
and derivatives carrying other leaving groups (4-LG) such as
OAr, OCH2CF3, SR, with thiolate ions,2b oxyanions,3 and amine
nucleophiles.4 More recently, studies of the reactions of thiolate
ions and oxyanions with derivatives of Meldrum’s acid, 5-LG
(LG ) MeO, SMe), which also allow direct detection of the
corresponding intermediates, have been reported.5 A major
Nucleophilic vinylic substitution (SNV) reactions of a leaving
group (LG) on substrates activated by electron-withdrawing
groups (X,Y) proceed by a two-step mechanism that involves
a tetrahedral intermediate (2), eq 1.1 An important benchmark
in the mechanistic investigations of these reactions was the
discovery of the first example, the reaction of â-methoxy-R-
nitrostilbene (4-OMe) with thiolate ions in 50% DMSO-50%
water, where the corresponding intermediate (2) was directly
observable by UV spectroscopy.2 This opened up the possibility
of measuring the rate constants for each individual step (kN1 u,
kN-u1, and kN2 u) and hence of developing a more detailed
understanding of structure-reactivity relationships in these
reactions. Initially this research focused on reactions of 4-OMe
conclusion that has emerged from these studies is that there is
an unusually complex interplay of numerous factors that
influence reactivity in these systems. These factors include
inductive/field and resonance effects of the activating groups,
π-donor effects of the leaving group, steric effects, anomeric
effects,6 polarizability effects, and others. Even though some
(3) (a) Bernasconi, C. F.; Schuck, D. F.; Ketner, R. J.; Weiss, M.;
Rappoport, Z. J. Am. Chem. Soc. 1994, 116, 11764. (b) Bernasconi, C. F.;
Schuck, D. F.; Ketner, R. J.; Eventova, I.; Rappoport, Z. J. Am. Chem.
Soc. 1995, 117, 2719.
(4) (a) Bernasconi, C. F.; Leyes, A. E.; Rappoport, Z.; Eventova, I. J.
Am. Chem. Soc. 1993, 115, 7513. (b) Bernasconi, C. F.; Leyes, A. E.;
Eventova, I.; Rappoport, Z. J. Am. Chem. Soc. 1995, 117, 1703.
(5) (a) Bernasconi, C. F.; Ketner, R. J.; Chen, X.; Rappoport, Z. J. Am.
Chem. Soc. 1998, 120, 7461. (b) Bernasconi, C. F.; Ketner, R. J.; Brown,
S. D.; Chen, X.; Rappoport, Z. J. Org. Chem. 1999, 64, 8829. (c) Bernasconi,
C. F.; Ketner, R. J.; Chen, X.; Rappoport, Z. Can. J. Chem. 1999, 77, 584.
(6) In the present context, the anomeric effect7 refers to the stabilization
exerted by the geminal oxygen atoms,8 e.g., in dialkoxy adducts.
† University of California.
‡ The Hebrew University.
(1) For reviews, see: (a) Rappoport, Z., AdV. Phys. Org. Chem. 1969,
7, 1. (b) Modena, G. Acc. Chem. Res. 1971, 4, 73, (c) Miller, S. I.
Tetrahedron 1977, 33, 1211. (d) Rappoport, Z. Acc. Chem. Res. 1981, 14,
7; 1992, 25, 474. (e) Rappoport, Z. Recl. TraV. Chim. Pays-Bas 1985, 104,
309. (f) Shainyan, B. A. Usp. Khim. 1986, 55, 942.
(2) (a) Bernasconi, C. F.; Fassberg, J.; Killion, R. B., Jr.; Rappoport, Z.
J. Am. Chem. Soc. 1989, 111, 6962. (b) Bernasconi, C. F.; Fassberg, J.;
Killion, R. B., Jr.; Rappoport, Z. J. Am. Chem. Soc. 1990, 112, 3169.
10.1021/ja003536t CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/14/2001

2156 J. Am. Chem. Soc., Vol. 123, No. 10, 2001
Bernasconi et al.
recognizable patterns are emerging, a comprehensive under-
standing of the relative importance of the various factors is not
yet at hand.
emalononitrile (8-OMe) with OH-, n-BuS-, HOCH2CH2S-, and
One feature that needs further investigation is the influence
of the activating groups on the relative thermodynamic and
kinetic stabilities of the intermediates. This influence not only
depends on the inductive/field and resonance effects of X and
Y, but also on steric interactions between these groups and with
the groups attached to the tetrahedral carbon. The comparison
of the reactions of 4-OMe and 5-OMe with HOCH2CH2S-
illustrates the point. The equilibrium constants, KR1 S, for the
formation of the respective intermediates are 2.57 × 104 M-1
for 5-OMe5a and 7.65 × 103 M-1 for 4-OMe,2 respectively,
that is, KR1 S(5-OMe)/KR1 S(4-OMe) ) 3.4. This small ratio does
not appear to reflect the relative electron-withdrawing strength
of the activating groups. If the pKa values of the respective
carbon acids, CH2XY, that is, Meldrum’s acid (pKa ) 4.70)9,10
and phenylnitromethane (pKa ) 7.93)9,11 were taken as relative
measures for the electron-withdrawing effects of the respective
activating groups, one might have expected a K1(5-OMe)/K1-
(4-OMe) ratio of ∼2 × 103. The attenuation of the electronic
effect of the Meldrum’s acid moiety in 5-OMe must be the
result of more severe steric crowding in the intermediate derived
from 5-OMe than in the one derived from 4-OMe. This
conclusion is supported by the fact that for HOCH2CH2S-
addition to the sterically less bulky 4-H and 5-H the KR1 S(5-H)/
KR1 S(4-H) ratio of 6612,13 is substantially higher than the
KR1 S(5-OMe)/KR1 S(4-OMe) ratio.
MeO2CCH2S- in 50% DMSO-50% water, the same solvent
used in previous investigations. We also report a more limited
study of the reaction of 2-(benzylthiobenzylidene)-1,3-indan-
dione (6-SCH2Ph) with HOCH2CH2S-.
On the basis of the pKa values of the respective carbon acids,
that is, 6.35 for 1,3-indandione,9,15 5.95 for CH2(NO2)CO2Me,9,16
and 10.21 for CH2(CN) 2,9,17 the electron-withdrawing strength
of the activating groups in 6-SMe, 6-SCH2Ph, and 7-SMe is
expected to be somewhere between that in 4-OMe and 5-OMe,
implying that the respective intermediates in the reaction with
thiolate ions should be observable. This prediction is borne out
by our results. For 8-OMe, the electron-withdrawing effect is
expected to be much smaller and perhaps too small to allow
accumulation of the intermediate. However, it will be shown
that even for 8-OMe the intermediate in the reactions with
thiolate ions accumulates to detectable concentrations because
the relatively weak electron-withdrawing effect of the two cyano
groups is offset by reduced steric crowding in the intermediate.
On the other hand, in the reaction of the various substrates with
OH- no intermediate could be observed.
Results
General Features. All reactions were conducted in 50%
DMSO-50% water (v/v) at 20 °C, at an ionic strength of 0.5
M maintained with KCl. Pseudo-first-order conditions were
applied throughout, with the nucleophile as the excess compo-
nent. Rates were measured by standard spectrophotometric
procedures, mostly in a stopped-flow spectrophotometer.
Reaction with OH- and Water. For the reactions of 6-SMe,
6-SCH2Ph, and 8-OMe with OH- only one kinetic process was
observed. It corresponds to the conversion of the substrate to
the hydrolysis product, for example, 9a T 9b for the reaction
of 6-SMe and 6-SCH2Ph, without accumulation of the inter-
Another interesting observation refers to the rate constants
of intermediate formation, kR1 S, in the above reactions with
HOCH2CH2S-; they are 3.90 × 102 M-1 s-1 for 4-OMe2 and
4.40 × 104 M-1 s-1 for 5-OMe,5a that is, k1(5-OMe)/k1(4-OMe)
) 1.13 × 102. The fact that the k1(5-OMe)/k1(4-OMe) ratio is
substantially larger than the K1(5-OMe)/K1(4-OMe) ratio
indicates that the intrinsic rate constant14 for the reaction of
4-OMe is lower than that for the reaction of 5-OMe. This
reduction of the intrinsic rate constant is the result of a greater
resonance contribution to the stabilization of the intermediate
derived from 4-OMe (more on this below).
mediates, 10. The kinetic results are consistent with eq 2
In the present paper we report a study of the reactions of
2-(methylthiobenzylidene)-1,3-indandione (6-SMe), methyl â-me-
thylthio-R-nitrocinnamate (7-SMe), and methoxybenzyliden-
kobsd ) kO1 H[OH-]
(2)
with kO1 H being the rate constant for nucleophilic attack by
OH- (see Discussion). The kO1 H values are summarized in
Table 1.
(7) (a) Kirby, A. G. The Anomeric Effect and Related Stereoelectronic
Effects of Oxygen; Springer-Verlag: Berlin, 1983. (b) Schleyer, P. v. R.;
Jemmis, E. D.; Spitznagel, G. W. J. Am. Chem. Soc. 1985, 107, 6393.
(8) (a) Hine, J.; Klueppl, A. W. J. Am. Chem. Soc. 1974, 96, 2924. (b)
Wiberg, K. B.; Squires, R. R. J. Chem. Thermodyn. 1979, 11, 773. (c)
Harcourt, M. P.; More O’Ferrall, R. A. Bull. Soc. Chim. Fr. 1988, 407.
(9) In 50% DMSO-50% water at 20 °C, the solvent used in all the
reactions reported here.
(10) Bernasconi, C. F.; Oliphant, N. Unpublished results.
(11) Bernasconi, C. F.; Kliner, D. A. V.; Mullin, A. S.; Ni, J. X. J. Org.
Chem. 1988, 53, 3342.
(12) Bernasconi, C. F.; Killion, R. B., Jr. J. Am. Chem. Soc. 1988, 110,
7506.
For the reaction of 7-SMe with OH- biphasic kinetics was
observed. This is attributed to 7-SMe consisting of a mixture
of E and Z isomers. The kO1 H value reported in Table 1 refers to
the faster of the two processes which accounts for most of the
absorbance change and hence reflects the reaction of the major
(Z) isomer.
In the case of 8-OMe the rate of reaction with water was
also determined. These experiments were performed in HCl
(13) Bernasconi, C. F.; Ketner, R. J. J. Org. Chem. 1998, 68, 6266.
(14) For a reaction with a rate constant k1 (barrier ∆Gq) in the forward
1
(15) Bernasconi, C. F.; Paschalis, P. J. Am. Chem. Soc. 1986, 108, 2969.
(16) Bernasconi, C. F.; Brown, S. D. Unpublished results.
(17) Bernasconi, C. F.; Zitomer, J. L.; Fox, J. P.; Howard, K. A. J. Org.
Chem. 1984, 49, 482.
and k-1 (∆Gq-1) in the reverse direction the intrinsic rate constant, ko
(intrinsic barrier ∆Gq), is defined as ko ) k1 ) k-1 (∆Gq )∆Gq ) ∆Gq
)
o
o
1
-1
where the equilibrium constant K1 ) 1 (∆Go ) 0).

Structure-ReactiVity Relationships in SNV Reactions
J. Am. Chem. Soc., Vol. 123, No. 10, 2001 2157
Figure 1. Plots of koI bsd (9) and koIIbsd (b) versus [RS-] for the reaction
of 6-SMe with HOCH2CH2S-.
solutions and acetate buffers. Under these conditions kobsd
corresponds to kH1 O for nucleophilic attack by water. At the
2
buffer concentrations used ([AcO-] e 10-2 M), no general base
catalysis was observed. For the other substrates, the rate of
hydrolysis by water is extremely slow with half-lives of >(.)-
10 days, and hence no attempts at determining kH1 O values
2
were made.
Reaction with Thiolate Ions. A. 6-SMe and 6-SCH2Ph.
This reaction is characterized by two kinetic processes. The first
is rapid, with kIobsd values in the range of about 2 to 100 s-1; it
represents the disappearance of the substrate and formation of
the respective intermediate. A representative plot of koI bsd
versus [RS-] is shown in Figure 1. The slope and intercept
afford kR1 S and kRS, respectively (eq 3).
-1
kIobsd ) k1RS[RS-] + kRS
(3)
-1
The second kinetic process is slow, with kIoIbsd values ranging
from about 0.01 to 0.5 s-1; it corresponds to formation of the
II
obsd
products. A representative plot of k
versus [RS-] is in-
cluded in Figure 1; it is consistent with eq 4, where KR1 S ) k1RS/
RS
k
is the equilibrium constant for the first step.
-1
KR1 SkR2 S[RS-]
1 + KR1 S[RS-]
II
obsd
k
)
(4)
The various kinetic parameters obtained from these experi-
ments are summarized in Table 2. For the reactions of 6-SMe
with n-BuS- and of 6-SCH2Ph with HOCH2CH2S- the intercept
RS
-1
according to eq 3 was too small to afford an accurate k
value, and hence kRS was obtained as k1RS/K1RS, with KR1 S being
-1
determined via eq 4. In the reaction of 6-SMe with HOCH2CH2S-
RS
-1
an approximate k value could be determined via eq 3, but the
value obtained as kR1 S/K1RS appears to be more reliable and will
be adopted. For the reaction of 6-SMe with MeO2CCH2S- the
intercept according to eq 3 was quite large and could be
determined with good precision; in this case there is excellent
agreement between this kR-S1 value and that obtained as kR1 S/KRS
.
-1
7-SMe. The reaction of 7-SMe with the three thiolate ions
showed a similar pattern as the reactions of 6-SMe or
6-SCH2Ph, that is, a fast process corresponding to the formation
of the intermediate (eq 3) and a slow one for the formation of
the product (eq 4). With n-BuS- and HOCH2CH2S- as the
nucleophile, the intercept according to eq 3 was indistinguishable

2158 J. Am. Chem. Soc., Vol. 123, No. 10, 2001
Bernasconi et al.
Table 2. Rate and Equilibrium Constants for the Reactions of Vinylic Substrates with HOCH2CH2S- and OH- in 50% DMSO-50% Water at
20 °C, µ ) 0.5 M (KCl)
a This work. b Reference 2b. c Reference 5a. d Reference 5c. e Bernasconi, C. F.; Garc´ıa, J., unpublished results. f Reference 12. g Ketner, R. J.
Ph.D. Thesis, University of California, 1997; p 628. h Reference 13. i Bernasconi, C. F.; Laibelman, A.; Zitomer, J. L. J. Am. Chem. Soc. 1985, 107,
6563. j Based on kR1 S for n-BuS- and assuming ânnuc ) 0.14, see text.
stopped-flow range and k1RS, and kRS could be obtained for this
reaction.
from zero, and even with MeO2CCH2S- the intercept provided
at best an approximate value for kR-S1. An accurate determina-
tion of KR1 S was not possible because at the low [RS-] needed
to make KR1 S[RS-] < 1 the reaction amplitudes were very
small which led to difficulties in obtaining reproducible results.
For the reaction with HOCH2CH2S-, K1RS[RS-] was still
>(.)118 at [RS-] ) 10-4 M, implying that KR1 S g 5 × 104
8-OMe. For the reactions of 8-OMe with HOCH2CH2S- and
MeO2CCH2S- only the slow process (koIIbsd) could be observed
kinetically. This is because kIobsd is too fast and outside the
stopped-flow range. Hence, only KR1 S and k2RS could be deter-
mined (eq 4) for these reactions. On the other hand, for the
reaction with n-BuS-, the first kinetic process was within the
-1
Discussion
Detectability of Intermediates. As elaborated upon else-
where,2b two conditions are necessary for an intermediate to
accumulate to detectable levels. One is that the equilibrium for
conversion of reactants to the intermediate is favorable (“ther-
modynamic condition,” eq 5); the other is that the rate of forma-
tion of the intermediate must exceed its rate of conversion to
products (“kinetic conditions”); for eq 1 this would require eq 6.
M-1
.
KN1 u[Nu-] g 1
kN1 u[Nu-] g kN2 u
(5)
(6)
II
obsd
(18) According to eq 4, k
≈ KR2 S for k1RS[RS-] . 1.

Structure-ReactiVity Relationships in SNV Reactions
J. Am. Chem. Soc., Vol. 123, No. 10, 2001 2159
Table 3. Brønsted ânnuc Values and Intrinsic Rate Constants (log
These conditions are met for the reactions of 6-SMe,
6-SCH2Ph, 7-SMe, and 8-OMe with the thiolate ions used in
this study, but not for the reactions of the same substrates with
OH-. This is reminiscent of our earlier findings for the reactions
of 4-OMe, 4-SPr, 4-OMe and 5-SMe with thiolate2,5a,5c ions
and OH-.5a,c,19
kRo S) for the Reaction of Thiolate Ions with Various Vinylic
Substrates in 50% Me2SO-50% Water at 20 °C, µ ) 0.5 M (KCl)
Previous analysis of the reasons why no intermediate is
detectable in the reactions with OH- is likely to apply to the
reactions of the present study as well, that is, even though the
thermodynamic condition is probably met in each case, it is
the kinetic condition of eq 6 that is not met.5a,c,19 This has been
attributed to the availability of additional pathways for the
conversion of the intermediate to products. One such pathway
involves the conjugate base of the intermediate, that is, 11-
which is in rapid acid-base equilibrium with 11 (eq 7). The
negative charge provides extra push to the expulsion of the
leaving group, leading to faster product formation. Another
pathway is intramolecular acid catalysis of leaving-group
departure by the OH proton in 11. In view of the strong
sensitivity of MeO- departure to acid catalysis,3b,5c this pathway
is probably mainly important when LG ) MeO; for LG ) MeS
it may be less important, reflecting the weaker sensitivity of
MeS departure to acid catalysis.5b
Structure-Reactivity Relationships. Table 3 provides a
summary of rate and equilibrium constants for the reaction of
HOCH2CH2S- with the substrates of the present investigation
as well as those of previous studies. HOCH2CH2S- has been
chosen as representative thiolate ion nucleophile because it is
the only one for which rate and equilibrium constants are
available for most compounds.
A. KR1 S as Function of the Activating Groups. One would
expect that, barring other factors, KR1 S should increase with
increasing electron-withdrawing strength of X,Y. The pKa values
of the corresponding carbon acids, CH2XY, may be taken as
an approximate measure of this electron-withdrawing effect
which includes both an inductive and resonance component.
For the four substrates without a nucleofuge (4-H, 5-H, 6-H,
and 8-H), there is in fact a good linear correlation between log
a This work. b Reference 2b. c Reference 5a. d Reference 5c. e Ber-
nasconi, C. F.; Garc´ıa, J., unpublished results. f Reference 12. g Ketner,
R. J. Ph.D. Thesis, University of California, 1997; p 628. h Reference
13. i log kPoT refers to alicylic amines as the proton acceptors; values
taken from ref 27. j Assumed value, see text. k Reference 16.
Me), and (NO2,Ph). The small steric effect with X,Y ) (CN,-
CN) must be the reason the intermediates in the reactions of
8-OMe with thiolate ions accumulate to detectable levels despite
the relatively weak electron-withdrawing effect of the cyano
groups.
Another indication of the importance of the steric effect is
the relatively low KR1 S value for 4-SPr. It is reflected in the
KR1 S(4-OMe)/KR1 S(4-SPr) ratio (730) being much larger than
the KR1 S(5-OMe)/KR1 S(5-SMe) ratio (77.4) and can be attributed
to the larger leaving group (n-PrS vs MeS). This reasoning is
based on the expectation that the (unknown) KR1 S value for
4-SMe would be substantially larger than for 4-SPr; it would
result in a KR1 S(4-OMe)/KR1 S(4-SMe) ratio that is smaller rather
KR1 S (RS- ) HOCH2CH2S-) and -pKCH XY (Figure 2, O) with
2
a
a slope of 1.11 ( 0.05. On the other hand, for substrates with
LG ) MeO or MeS the correlation is poor (Figure 2, b and
4).
An important factor leading to the poor correlations appears
to be steric crowding in the intermediates. When LG ) H this
steric effect is minimal, but it becomes important for LG )
MeO and even more so for the larger MeS.20 Assuming that all
of the scatter in Figure 2 is due to steric effects, one concludes
that it is most pronounced for X,Y ) MA,23 quite small for
X,Y ) (CN,CN), and intermediate for X,Y ) ID,23 (NO2,CO2-
(19) Bernasconi, C. F.; Fassberg, J.; Killion, R. B., Jr.; Schuck, D. F.;
Rappoport, Z. J. Am. Chem. Soc. 1991, 113, 4937.
(20) ES (MeO) ) -0.55, ES (MeS) ) -1.07;21 νef (MeO) ) 0.36, νef
(MeS) ) 0.64.22
(21) Unger, S. H.; Hansch, C. Prog. Phys. Org. Chem. 1996, 12, 91.
(22) Charton, M. Stud. Org. Chem. 1991, 42, 629.
(23) MA ) Meldrum’s acid moiety, ID ) 1,3-indandione moiety.

2160 J. Am. Chem. Soc., Vol. 123, No. 10, 2001
Bernasconi et al.
Figure 3. Plots of log kR1 S versus log K1RS (RS- ) HOCH2CH2S-)
generated by varying X,Y. O, LG ) H; b, LG ) MeO; 4, LG ) MeS
(see Table 2 for identification of specific compounds).
Figure 2. KR1 S(RS- ) HOCH2CH2S-) as function of X,Y. Plots of
log K1RS versus -pKaCH XY. O, LG ) H; b, LG ) MeO; 4, LG ) MeS
2
(see Table 2 for identification of specific compounds).
than larger than the K1RS(5-OMe)/KR1 S(5-SMe) ratio because
the MA23 derivatives are inherently more sensitive to steric
effects than the (NO2,Ph) derivatives.
B. KR1 S as Function of the Leaving Group. The relative
order in KR1 S is H . OMe > SMe, irrespective of the
activating groups. A major factor responsible for this order is
steric crowding in the intermediate which follows the order MeS
> MeO . H.20 The π-donor effect of the MeO and MeS groups,
which stabilizes the substrate, contributes to the reduction in
KR1 S for these substrates, especially for LG ) MeO.24 The fact
that KR1 S is smaller for LG ) MeS than for MeO, despite the
smaller π-donor effect of the MeS group, shows that the steric
factor is dominant; the somewhat stronger electron-withdrawing
inductive effect of MeO versus MeS26 probably contributes to
making KR1 S larger for LG ) MeO than for MeS. A more
detailed discussion of these effects can be found elsewhere.5c
C. Dependence of kR1 S on the Activating Group. Plots of
logkR1 S vs logK1RS (RS- ) HOCH2CH2S-) generated by vary-
ing X,Y are shown in Figure 3 for LG ) H(O), MeO (b) and
MeS (or n-PrS in one case) (4). The correlations are poor or
nonexistent, especially so for LG ) MeO where kR1 S for the
dicyano derivative is unusually high considering the low K1RS
value. The lack of a good correlation indicates that the intrinsic
barriers (∆Gqo) or intrinsic rate constants (kRo S)14 depend greatly
on the activating groups, with kRo S being particularly high for
X,Y ) CN,CN, intermediate for X,Y ) MA and ID and low
for X,Y ) (NO2,CO2Me) and (NO2,Ph). One may determine
approximate log kRo S values from the Brønsted plots of log kR1 S
versus log KR1 S (variation of thiolate basicity) discussed below.
These intrinsic rate constants are included in Table 3. The
dependence of log kRo S on substrate for a given LG appears to
be mainly governed by resonance effects of the X,Y groups
but there is also a strong dependence on LG for a given X,Y
which must include π-donor and steric effects.
Figure 4. Plots of log kRo S (RS- ) HOCH2CH2S-) versus log kPT. O,
o
LG ) H; b, LG ) MeO; 4, LG ) MeS (n-PrS for 4-SPr; see Table
3 for identification of specific compounds).
principle of nonperfect synchronization (PNS), according to
which any product stabilizing factor whose development at the
transition state lags behind bond changes, lowers the intrinsic
rate constant.27 In proton transfers from CH2XY, where steric
effects play a minor role, the differences between the intrinsic
rate constants are in fact dominated by the resonance effect (log
kPoT in Table 3) and follow the order (CN,CN) (≈7.0) . MA
(3.9) > ID (3.1) > (CO2Me,NO2) (2.3) . (Ph,NO2) (-0.25).
The only anomaly is that kPoT (CO2Me,NO2) . kPT(Ph,NO2)
o
which can be attributed to the kPoT-enhancing inductive/field
effect of the CO2Me group.16,28
For the nucleophilic addition of thiolate ions to the substrates
summarized in Table 3, log kRo S follows the same qualitative
order as logkPoT but there are some important quantitative
differences. This is best appreciated by inspection of plots of
logkRo S vs log kPoT (Figure 4). (1) The slopes of these plots are
substantially less than unity: 0.32 ( 0.06 for LG ) H, 0.40 (
0.03 for LG ) MeO, 0.56 ( 0.17 for LG ) MeS (LG ) n-PrS
for 4-SPr). This reduced sensitivity to resonance effects implies
Specifically, with respect to X,Y, its resonance effect is
expected to lower kRo S. This is because in reactions that lead to
resonance stabilized products the transition state is always
imbalanced in the sense that resonance development lags behind
bond formation. This reduction in kRo S is a manifestation of the
(27) (a) Bernasconi, C. F. Acc. Chem. Res. 1987, 20, 301. (b) Bernasconi,
C. F. Acc. Chem. Res. 1992, 25, 9. (c) Bernasconi, C. F. AdV. Phys. Org.
Chem. 1992, 27, 119.
(24) σR (MeO) ) -0.43, σR (MeS) ) -0.15.25
(25) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165.
(26) σF (MeO) ) 0.30, σF (MeS) ) 0.20.25
(28) A similar situation exists for PhCOCH2NO2.29

Structure-ReactiVity Relationships in SNV Reactions
J. Am. Chem. Soc., Vol. 123, No. 10, 2001 2161
a smaller transition-state imbalance than for the proton transfers.
The major reason for the reduced imbalances has been attributed
to the fact that the pro-carbanionic carbon of the vinylic
substrates is sp2 hybridized. This facilitates π-overlap with the
X,Y groups and charge delocalization at the transition state and
reduces the ko-lowering PNS effect.27c,30 In contrast, proton
transfer from CH2XY requires rehybridization of the R-carbon
from sp3 to sp2, a feature that adds to the delay in charge
27c,30
delocalization and leads to a large PNS effect in ko.
(2) The logkRo S values for the reactions with LG ) MeO and
MeS are much lower than with LG ) H, especially for LG )
MeS. There are two factors that contribute to this result. One is
the π-donor effect of the MeO and MeS groups. The π-donor
resonance stabilization of the respective substrates must follow
the usual pattern of resonance effects, that is, its loss at the
transition state is ahead of bond formation which results in a
reduction of kRo S.27 In view of the stronger π-donor effect of
the MeO group, this factor should affect the reactions of the
MeO derivatives more strongly than those of the MeS deriva-
tives. However, since the observed kRo S values are lower for LG
) MeS than for LG ) MeO, there must be an additional factor
that reduces kRo S more for the MeS than for the MeO deriva-
tives. This additional factor appears to be the steric effect.
Specifically, the results are consistent with a kRo S-lowering
PNS effect27 arising from a development of the steric effect
that is ahead of bond formation. This conclusion agrees with
an earlier one that was based on a much more limited set of
data.5c Whether steric effects always develop ahead of bond
formation in chemical reactions is unclear though; recent results
referring to the reaction of thiolate ions with quinone methide
reported by Richard et al.31 suggest that there are cases where
steric effects lag behind bond formation.
Figure 5. Brønsted plots for the reactions of thiolate ions with 6-SMe.
O, log KR1 S; 0, log k1RS; 4, log kRS
.
-1
Table 4. Brønsted Coefficients for the Reactions of 6-SMe,
7-SMe, and 8-OMe with Thiolate Ions
6-SMe
7-SMe
8-OMe
0.16 ( 0.18 0.28 ( 0.03 ∼0.13a
ânuc ) d log kRS/dpKaRSH
1
âlg ) d log kRSH/dpKaRSH
-0.58 ( 0.15 -0.67
-1
âeq ) d log KRS/dpKaRSH
0.74 ( 0.04 0.92
0.24 ( 0.22 0.27
-0.76 ( 0.22 -0.73
0.43 ( 0.02
0.96 ( 0.05
1
n
ânuc ) d log kR1 S/d log K1RS
b
∼0.14
∼-0.86
0.13c
n
RS
âlg) d log k /d log K1RS
b
-1
âpush ) d log kRS/dpKaRSH
2
a ânuc and âlg assumed to be the averages of the respective ânuc and
âlg values for the reactions of 4-OMe and 5-OMe with thiolate ions.
b From plots of log kR1 S vs log K1RS and log kRS vs log KR1 S, respectively.
-1
c Based on n-BuS- and MeO2CCH2S- only, see text.
(3) For the reactions of the MeS derivatives there is
considerable scatter in the plot of logkRo S versus logkoPT. Part of
this scatter may be attributed to experimental uncertainty in the
ko values which most likely is larger than their standard
deviation. A major source of this uncertainty is related to the
Brønsted plots (see below) from which the kRo S values were
evaluated. Another potential source of the scatter is the same
steric effect that leads to lower kRo S values for the MeS
derivatives as a family. Specifically, the fact that kRo S for the
Meldrum’s acid derivative is not higher than kRo S for the
indandione derivative may be a reflection of the greater steric
effect with the former substrate.
D. K1RS, kR1 S, kRS, and k2RS as Function of pKRa SH. Brønsted
-1
plots of logKR1 S, logk1RS, logkRS, and logk2RS versus pKRa SH, with
-1
pKRa SH referring to the acidity of the thiol, are shown in Figure
5 for the reactions of 6-SMe and 7-SMe. The various Brønsted
coefficients as well as the intrinsic rate constants, kRo S, obtained
by extrapolation are reported in Table 4 (ânnuc values, including
those for previously studied systems, are also reported in Table
3). For 8-OMe, kR1 S could only be determined for n-BuS-, and
hence no experimental ânuc or âlg could be obtained. The ânuc
value reported in Table 4 is an estimate and corresponds to the
average value for the reactions of 4-OMe and 5-OMe with
thiolate ions; this value, in conjunction with âeq which was
experimentally accessible, yields an approximate ânnuc from
which an approximate log kRo S was obtained.
Figure 6. Brønsted plots for the reactions of thiolate ions with 7-SMe.
O, log KR1 S; 0, log k1RS; 4, log kRS
.
-1
For the reactions with 6-SMe and 8-OMe, there are enough
data to examine the dependence of kR2 S on pKaRSH (Figures 6
and 7). For 6-SMe, there is an excellent correlation which yields
âpush ) 0.43; âpush reflects the developing π-donor effect of the
RS group in the product. For 8-OMe, the correlation is poor.
One possible interpretation of the poor correlation is that the
point for n-BuS- is deviant. This would imply that the dashed
line in Figure 7 is correct, yielding a ânuc ) 0.51 which is close
to the value obtained for 6-SMe. An alternative view is that it
is the point for HOCH2CH2S- which is deviant (solid line); in
this case one obtains âpush ) 0.13.
(29) Bernasconi, C. F.; Montan˜ez, R. L. J. Org. Chem. 1997, 62, 8162.
(30) (a) Bernasconi, C. F. Tetrahedron 1989, 45, 4017. (b) Bernasconi,
C. F.; Renfrow, R. A. J. Org. Chem. 1994, 59, 5404.
(31) Toteva, M. M.; Richard, J. P. J. Am. Chem. Soc. 2000, 122,
11073.

2162 J. Am. Chem. Soc., Vol. 123, No. 10, 2001
Bernasconi et al.
thiolate ion addition, koRS, are much higher than those for OH-
addition, kOo H. There are two major factors that contribute to
the large kRo S/kOo H ratios. One is solvation of the nucleophile
and the requirement that its partial desolvation, as it enters the
transition state, is ahead of bond formation.27,31 This results in
a ko-lowering PNS effect. Because solvation of OH- is much
stronger than that of thiolate ions,33 this leads to a stronger
reduction of kOo H than of koRS. The other factor is that the soft-
soft interactions34 between the thiolate ion and the substrates
enhance kRo S, provided that these interactions develop ahead of
bond formation (another PNS effect), which is a reasonable
assumption.12
For a given LG, there is a dependence of the kR1 S/k1OH ratios
on the X,Y groups that essentially parallels the corresponding
dependence of KR1 S/K1OH. The trend is a decrease in both ratios
in the order (Ph,NO2) > ID > MA > (CN) 2 for LG ) H, (CN)2
> (Ph,NO2) > MA for LG ) MeO, and (Ph,NO2) > ID > MA
> (CO2Me,NO2) for LG ) MeS. These trends mainly reflect
the greater sensitivity of the HOCH2CH2S- reaction to steric
crowding in the adduct and corresponding transition states.
Figure 7. Plot of log k2RS versus pKRa SH for the reactions of 6-SMe (O)
and 8-OMe (b).
Despite a reviewer’s comment that the first interpretation
should not be discarded, we believe that the second interpretation
is more attractive. This is because there is no plausible
interaction mechanism that can explain the negative deviation
of the point for n-BuS- but there is a mechanism that can
rationalize the positive deviation of the point for HOCH2CH2S-.
This mechanism is intramolecular acid catalysis of MeO-
departure by the OH group of the SCH2CH2OH moiety (11).
Conclusions
(1) For the reactions of 6-SMe, 6-SCH2Ph, 7-SMe, and
8-OMe the conditions necessary for the direct observation of
the intermediate (eqs 5 and 6) are met with Nu ) RS- but not
with Nu ) OH-. In the latter case it is probably eq 6 that is not
met because additional pathways enhance the rate for conversion
of the intermediate to products.
(2) The equilibrium constants for HOCH2CH2S- addition to
substrates with LG ) H correlate well with the corresponding
-pKCa H XY, but the correlation between logK1RS and -pKCa H XY
is poor when LG ) MeO or MeS. This is the result of a
reduction of KR1 S by steric hindrance which varies depending
on the bulk of X,Y. There is also a reduction of KR1 S by the
π-donor effect of the leaving groups but it is outweighed by
the steric effect.
2
2
This catalysis is only observed with 8-OMe but not with 6-SMe
because alkoxide ion departure is very sensitive to acid catalysis
while thiolate ion departure is not.5b A similar observation has
been reported for the reaction of HOCH2CH2S- with 5-OMe
and interpreted in the same way.5a
Whether the small âpush value for the reaction of 8-OMe is
the result of an unusually early transition state or a consequence
of a relatively small π-donor effect of the RS groups in this
case cannot be ascertained without a âpush value for the
unavailable equilibrium constant of the kR2 S step. In view of the
relatively weak electron-withdrawing effect of the C(CN)2
moiety, the π-donor effect of the RS group is likely to be smaller
than that with the 1,3-indandione derivatives.
(3) The intrinsic rate constants for thiolate ion addition, kRo S,
as function of X,Y decrease in the order (CN,CN) > MA J ID
> (CO2Me,NO2) > (Ph,NO2), mainly reflecting the kRS-reduc-
o
ing PNS effect of increasing π-acceptor strength of X,Y.
Compared to kPoT for deprotonation of CH2XY, the PNS effect
is attenuated because the pro-carbanionic carbon in vinylic
substrates is sp2 hybridized.
(4) For a given X,Y, the order in kRo S is LG ) H > MeO >
MeS. This order reflects reductions in kRo S by the π-donor and
steric PNS effects of MeO and MeS, with the steric effect being
dominant.
(5) For the reactions of 6-SMe and 8-OMe, âpush values for
leaving-group expulsion could be determined from a correlation
of logkR2 S with pKaRSH. With HOCH2CH2S- as the nucleophile,
kR2 S for the reaction of 8-OMe is abnormally high, probably
because of intramolecular acid catalysis by the OH group.
(6) Nucleophilic attack by OH- is much slower than by
HOCH2CH2S-. This is mainly the combined result of lower
intrinsic rate constants for the OH- reaction caused by the PNS
effect of early desolvation of the nucleophile and the enhanced
Rate Constants for HO- Addition (k1OH). The k1OH values
obtained in this study along with those for some other substrates
are summarized in Table 2. The table also lists the kR1 S values
for the reactions with HOCH2CH2S- and log(k1RS/k1OH). The
most notable observation is that in all cases the reaction with
OH- is substantially slower than the reaction with HOCH2CH2S-,
despite the higher basicity of OH-, with log(k1RS/k1OH) ranging
from 1.9 to 5.4. In trying to understand this result it is useful to
include a comparison of the respective equilibrium constants.
Experimental KO1 H values are only available for compounds
with LG ) H. However, for those substrates where an
equilibrium constant for CF3CH2O- addition is known
(KR1 O),3a KO1 H was estimated as 1.8 × 103K1RO based on the KO1 H
/
(32) (a) Hupe, D. J.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 451. (b)
Jencks, W. P.; Brant, S. R.; Gandler, J. R.; Fendrich, G.; Nakamura, C. J.
Am. Chem. Soc. 1982, 104, 7054.
(33) (a) Parker, A. J. Chem. ReV. 1969, 69, 1. (b) Bordwell, F. G.;
Hughes, D. L. J. Org. Chem. 1982, 47, 3224. (c) Taft, R. W. Prog. Phys.
Org. Chem. 1983, 14, 247.
KR1 O ratio for 5-H and essentially reflects the pKa difference
between water and CF3CH2OH.
In all cases the k1RS/k1OH ratios are much larger than the KR1 S/
KO1 H ratios. This indicates that the intrinsic rate constants for
(34) Pearson, R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827.

Structure-ReactiVity Relationships in SNV Reactions
J. Am. Chem. Soc., Vol. 123, No. 10, 2001 2163
Table 5. Experimental Conditions for the Kinetic Experiments with Thiolate Ions
RS-
pH
[RSH] M
[RS-]
M
na
6-SMe (4-5 × 10-5 M)b
1.8 × 10-4-8.6 × 10-3
1.3 × 10-3-1.5 × 10-1
8.6 × 10-3-4.9 × 10-3
n-BuS-
11.08-12.08
10.45
9.04
8.14 × 10-4-4.17 × 10-2
9.8 × 10-4-1.2 × 10-1
1.4 × 10-2-8.3 × 10-2
14
12
7
HOCH2CH2S-
MeO2CCH2S-
6-SCH2Ph (1.0 × 10-4 M)b
4.8 × 10-3-9.3 × 10-2
HOCH2CH2S-
10.45
3.5 × 10-3-7.3 × 10-2
8
7-SMe (4-8 × 10-5 M)c
1.1 × 10-3-8.6 × 10-3
2.9 × 10-3-6.4 × 10-2
1.3 × 10-2-4.9 × 10-2
n-BuS-
11.08-12.08
9.08-10.72
7.50-9.04
5.2 × 10-4-4.1 × 10-2
9.4 × 10-5-9.1 × 10-2
1.5 × 10-3-8.3 × 10-2
7
8
HOCH2CH2S-
MeO2CCH2S-
8-OMe (4.0 × 10-5 M)d
3.0 × 10-4-6.3 × 10-3
1.3 × 10-3-1.5 × 10-1
3.7 × 10-4-1.8 × 10-2
n-BuS-
11.76-12.31
10.47
9.80
1.0 × 10-4-5.2 × 10-2
9.8 × 10-4-1.2 × 10-1
3.6 × 10-3-1.7 × 10-1
12
12
10
HOCH2CH2S-
MeO2CCH2S-
I
II
I
a Number of runs. kobsd and kobsd monitored at 350 nm (n-BuS-), 360 nm (HOCH2CH2S-), and 340 nm (MeO2CCH2S-), respectively. kobsd
b
c
II
monitored at 350 nm (n-BuS-, HOCH2CH2S-) and 340 nm (MeO2CCH2S-); k
monitored at 360 nm (HOCH2CH2S-). d Monitored at 300 nm
obsd
(n-BuS-, koI bsd) and 350 nm (kII , n-BuS-, HOCH2CH2S-, and MeO2CCH2S-).
obsd
kRo S for the thiolate ion reaction due to early development of
soft-soft interactions.
124.30, 126.53, 129.03, 129.39, 134.33, 134.90, 134.98, 140.42, 140.66,
173.92, 187.07, 191.64. MS (EI, 70 eV): m/z (%) 280 (M+, 100), 265
(M - CH3, 26), 233 (M - SCH3, 37).
2-(Benzylthiobenzylidene)-1,3-indandione (6-SCH2Ph). A mixture
of NaH (20 mg) and benzylmercaptan (0.25 mL) in dry ether (1 mL)
was stirred at rt under argon for 12 h. DMSO (5 mL) was then added
to dissolve the sodium salt. One hundred milligrams (0.36 mmol) of
13 was added to the mixture, and the solution was stirred further at rt
for 30 min. After workup as described for 6-SMe the crude product
was purified by chromatography on silica gel 60 using ethyl acetate/
petroleum ether (1:5) as eluent to afford 0.13 g (98%) of a yellow liquid.
Anal. Calcd for C23H16O2S: C, 77.50; H, 4.52; S, 9.00. Found: C,
Experimental Section
Materials. 2-(Methylthiobenzylidene)-1,3-indandione (6-SMe) and
its benzyl analogue (6-SCH2Ph) were prepared according to eq 8.
1
77.21; H, 4.67; S, 8.61. H NMR (CDCl3, 300 MHz) δ 3.68 (s, 2H),
a. 2-Benzoyl-1,3-indandione (12). This compound was prepared
by the method of Kilgore.35 The crude product was recrystallized from
methanol, mp 110-111 °C (lit.35 109-110 °C). 1H NMR (CDCl3, 300
MHz) δ 7.50-7.56 (m, 2H), 7.60-7.66 (m, 1H), 7.70-7.79 (m, 2H),
7.83-7.91 (m, 2H), 8.14-8.17 (m, 2H).
7.06-7.10 (m, 2H), 7.17-7.25 (m, 5H), 7.47-7.52 (m, 3H), 7.63-
7.74 (m, 3H), 7.88-7.91 (m, 1H). 13C NMR (CDCl3) δ 35.57, 122.96,
123.36, 124.52, 127.52, 128.07, 129.04, 129.06, 129.55, 129.69, 134.89,
134.93, 134.96, 135.58, 141.03, 141.31, 172.31, 186.92, 191.09.
Methyl â-methylthio-r-nitrocinnamate (7-SMe) was prepared
according to eq 9.
b. 2-(Chlorobenzylidene)-1,3-indandione (13). A mixture of 12
(1.0 g, 4.0 mmol), phosphorus oxychloride (4 mL) and N,N-diethyl-
aniline (3 mL) was stirred at 75 °C for 45 min. The mixture was then
cooled to rt, 20 g of ice was added slowly followed by aqueous HCl
(5%, 15 mL), and the mixture was filtered, giving 0.85 g of a red solid
which was washed with cold water. The crude product was purified
by chromatography on silica gel 60 with ethyl acetate/petroleum ether
(2:8) as eluent, giving 0.45 g (42%) of yellow needles, mp 160-161
°C (lit.36 145-147 °C). Anal. Calcd for C16H9O2Cl: C, 71.51; H, 3.35;
Cl, 13.22. Found: C, 71.77; H, 3.33; Cl, 13.70. 1H NMR (CDCl3, 300
MHz) δ 7.45-7.60 (m, 5H), 7.76-7.85 (m, 2H), 7.88-7.91 (m, 1H),
8.01-8.05 (m, 1H). MS (EI, 70 eV): m/z (%) 268, 270 (M+, 35Cl,
37Cl, 64, 21), 267 (M+ - 1, 100), 233 (M+ - Cl, 38), 205 (22), 179
(31). IR (Nujol, KBr): ν (cm-1) 1692 (s), 1602 (m), 1570 (s), 1463,
1258, 1210.
c. 2-(Methylthiobenzylidene)-1,3-indandione (6-SMe). A mixture
of 13 (0.27 g, 1.0 mmol) and NaSMe (0.22 g, 3.1 mmol) in dry DMSO
(7 mL) was stirred at rt for 3 h. Fifteen milliliters of water was then
added, and the mixture was stirred for 10 min and then extracted with
ether, washed with water, and dried (Na2SO4). After removal of the
solvent, 0.19 g (67%) of yellow solid was obtained. It was purified by
chromatography on silica gel 60 with ethyl acetate/petroleum ether (2:
8) as eluent to afford 0.16 g (54%) of the pure product, mp 150-151
°C. Anal. Calcd for C17H2O2S: C, 72.83; H, 4.31; S, 11.44. Found:
a. Methyl â-Iodo-r-nitrocinnamate (15). Nitrogen dioxide gas was
bubbled into a solution containing methyl phenylpropiolate (14) (8.00
1
g, 0.05 mol, H NMR (CDCl3, 400 MHz) δ 3.79 (s, 3H), 7.31-7.35
(m, 2H), 7.39-7.43 (m, 1H), 7.52-7.55 (m, 2H)) and iodine (14.05 g,
0.55 mol) in dry ether (300 mL) until complete disappearance of 14
according to TLC. The unused excess of iodine was washed with 5%
aqueous Na2S2O3 solution. The yellow ether layer was separated,
washed with water, and dried (Na2SO4), and after removal of the
solvent, the crude product was purified by chromatography on silica
gel 60, eluting with petroleum ether/EtOAc (9:1) to afford 13.82 g
(83%) of the desired product 15 with differing Z/E isomer ratios. It
was recrystallized from petroleum ether to afford the pure (E) isomer,
and the pure (Z) isomer could be obtained from the mixture on
recrystallization with petroleum ethers/ether (9:1).37
b. Methyl â-Methylthio-r-nitrocinnamate (7-SMe). A solution of
15 (E/Z: 10:2.7, 1.0 g, 3.0 mmol) and NaSMe (Aldrich, 95%, 0.31 g,
4.2 mmol) in 45.0 mL of dry DMSO was stirred at rt for 1.0 h. The
mixture was poured into 15.0 mL of water and stirred for another 5
min and then extracted with ether (25 mL × 3), washed with water
(20 mL × 3), and dried (Na2SO4). After removal of the solvent, 0.67
g of a yellow oil was obtained. Chromatography on silica gel 60 using
petroleum ether/EtOAc (17:3) eluent, gave 0.50 g (yield, 66.3%) of a
1:2 ratio of E/Z isomers as a yellow solid, mp 57-63 °C. Anal. Calcd
1
C, 72.97; H, 4.38; S, 10.98. H NMR (CDCl3, 300 MHz) δ 1.99 (s,
3H), 7.13-7.18 (m, 2H), 7.45-7.55 (m, 3H), 7.63-7.74 (m, 3H), 7.89-
7.92 (m, 1H). 13C NMR (CDCl3, 100.6 MHz) δ 15.80, 122.78, 123.21,
(35) Kilgore, L. G.; Ford, J. H.; Wolfe, W. C. Ind. Eng. Chem. 1942,
34, 494.
(36) Korchevin, N. A.; Usova, T. L.; Vasilev, A. V.; Dorofeev, I. A.;
Usov, V. A.; Voronkov, M. Zh. Org. Khim. 1986, 22, 580 (Russ.); Chem.
Abstr. 1986, 106, 119416n.
(37) Data for the pure isomers, which were not studied here, will be
given elsewhere.

2164 J. Am. Chem. Soc., Vol. 123, No. 10, 2001
Bernasconi et al.
for C11H11O4NS: C, 52.16; H, 4.38; N, 5.53; S, 12.66. Found: C, 51.98;
H, 4.36; N, 5.53; S, 12.37. When the reaction was conducted in DMSO
(2.5 mL) at rt for 1.0 h starting from a 3.0:0.11 E/Z isomer mixture
(10 mg) of 15 with NaSMe (∼5 mg) the product was obtained as a
1.1:1.0 ratio of the E/Z isomers.
containing the malononitrile, methanol, and acetic anhydride were
distilled at 18 mm up to 92 °C, and the remaining brown oil (2.8 g)
solidified on standing. Chromatography on dry silica gel, using 4:6
petroleum ether:AcOEt mixture and then AcOEt gave 8-OMe in the
first fraction as colorless crystals, mp 90-91 °C (2 g, 24%). 1H NMR
(CDCl3) δ 3.92 (3H, s, Me), 7.47-7.65 (5H, m, Ph). Anal. Calcd for
C11H8N2O: C, 71.73, H, 4.38; N, 15.20. Found: C, 71.44; H, 4.55; N,
15.33.
1H NMR (CDCl3, 400 MHz) E isomer: δ 1.84 (s, 3H), 3.88 (s, 3H),
7.17-7.26 and 7.42-7.52 (m, 5H); Z isomer: δ 1.88 (s, 3H), 3.51 (s,
3H), 7.17-7.26 and 7.42-7.52 (m, 5H).
Several attempts to separate the mixture to the pure isomers by
recrystallization from petroleum ether, ether, petroleum ether/ether, and
petroleum ether/EtOAc mixture failed and always ended with a mixture
containing the E- and Z-7-SMe, the two major isomers. Notably, in
addition to them, there are always two other minor side products
Methodology. Preparation of solutions, pH measurements, recording
of spectra, kinetic measurements, and data analysis were performed
using the general methods described before.3a
Kinetic Data. Rate constants for the reactions with OH-, k1OH, were
obtained from the slope of plots of kobsd versus [KOH]; typically kobsd
was measured at 5-6 concentrations ranging from 0.01 to 0.2 M. For
1
displaying H NMR signals at δ 2.77 (s, 3H), 3.64 (s, 3H), and 2.80
the reactions with thiolate ions the conditions under which kIobsd and
(s, 3H), 3.95 (s, 3H), which sometimes became considerably larger on
standing in CDCl3 at rt or during purification by chromatography or
by recrystallization. Consequently, 7-SMe seems to be unstable.
Melting points at different isomer ratios are: E/Z 1.0:1.9, mp 57-
60 °C; E/Z 1.0:1.7, mp 61-63 °C; E/Z 1.0:1.5, mp 72-73 °C.
Methoxybenzylidenemalononitrile (8-OMe) was prepared by the
condensation of trimethyl orthobenzoate and malononitrile. A solution
of malononitrile (3 g, 45 mmol) and trimethyl orthobenzoate (9.9 g,
49 mmol) in acetic anhydride (15 mL) was refluxed for 6 h. Fractions
II
obsd
k
were determined are summarized in Table 5.
Acknowledgment. This research was supported by Grant
CHE-9734822 from the National Science Foundation (C.F.B.)
and a grant from the U.S.-Israel Binational Science Foundation
(Z.R.)
JA003536T