Spectroscopic and kinetic evidence for an accumulating intermediate in an SNV reaction with amine nucleophiles. Reaction of methyl β-methylthio-α-nitrocinnamate with piperidine and morpholine

Article abstract of DOI:10.1021/jo062602s

(Chemical Equation Presented) A spectroscopic and kinetic study of the reaction of methyl β-methylthio-α-nitrocinnamate (4-SMe) with morpholine, piperidine, and hydroxide ion in 50% DMSO/50% water (v/v) at 20 °C is reported. The reactions of 4-SMe with pi

Full text of DOI:10.1021/jo062602s

Spectroscopic and Kinetic Evidence for an Accumulating
Intermediate in an SNV Reaction with Amine Nucleophiles. Reaction
of Methyl â-Methylthio-r-nitrocinnamate with Piperidine and
Morpholine
Claude F. Bernasconi,*,† Shoshana D. Brown,† Irina Eventova,‡ and Zvi Rappoport‡
Department of Chemistry and Biochemistry, UniVersity of California, Santa Cruz, California 95064, and
Department of Organic Chemistry, The Hebrew UniVersity of Jerusalem, Jerusalem 91904, Israel
bernasconi@chemistry.ucsc.edu
ReceiVed December 18, 2006
A spectroscopic and kinetic study of the reaction of methyl â-methylthio-R-nitrocinnamate (4-SMe) with
morpholine, piperidine, and hydroxide ion in 50% DMSO/50% water (v/v) at 20 °C is reported. The
reactions of 4-SMe with piperidine in a pH range from 10.12 to 11.66 and those with morpholine at pH
12.0 are characterized by two kinetic processes when monitored at λmax (364 nm) of the substrate, but by
only one process when monitored at λmax (388) nm of the product. The rate constants obtained at 388 nm
were the same as those determined for the slower of the two processes at 364 nm. These rate constants
refer to product formation, whereas the faster process observed at 364 nm is associated with the loss of
reactant to form an intermediate. In contrast, for the reaction of 4-SMe with morpholine at pH 8.62 the
rates of product formation and disappearance of the substrate were the same, i.e., there is no accumulation
of an intermediate. Likewise, the reaction of 4-SMe with OH- did not yield a detectable intermediate.
The factors that allow the accumulation of intermediates in certain SNV reactions but not in others are
discussed in detail, and structure-reactivity comparisons are made with reactions of piperidine and
morpholine with other highly activated vinylic substrates.
Introduction
The nucleophilic vinylic substitution (SNV) on substrates
activated by electron-withdrawing groups is a stepwise process
as shown in eq 1 for the reaction with an anionic nucleophile;
X and Y are the activating substituents and LG- is the leaving
group.1 Early kinetic studies provided mainly indirect evidence
for the stepwise nature of the reaction, but more recently several
systems were found where the intermediate actually accumulates
to detectable levels, allowing an experimental determination of
the individual rate constants k1, k-1, and k2.2 Some notable
examples are the reactions of 1-OMe,3,4 1-SMe,4 2-OMe,5
† 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. (e)
Rappoport, Z. Recl. TraV. Chim. Pays-Bas 1985, 104, 309. (f) Shainyan,
B. A. Usp. Khim. 1986, 55, 942. (g) Rappoport, Z. Acc. Chem. Res. 1992,
25, 474.
(2) Bernasconi, C. F.; Ketner, R. J.; Ragains, M. L.; Chen, X.; Rappoport,
Z. J. Am. Chem. Soc. 2001, 123, 2155.
10.1021/jo062602s CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/04/2007
3302
J. Org. Chem. 2007, 72, 3302-3310

SNV Reaction with Amine Nucleophiles
2-SMe,5 3-OMe,2 and 4-SMe2 with thiolate ions as well as some
only cases involving such amines studied so far, have yielded
detectable intermediates, although paradoxically the reaction of
1-OMe with the much more weakly basic methoxyamine (pKa
) 4.70) and N-methylmethoxyamine (pKa ) 4.67) did allow
the direct observation of T-A.9
other substrates.2
The reason why the intermediates in the reactions of 1-OMe
and 2-SMe with strongly basic amines were undetectable is not
that the thermodynamic condition was not met-it was amply
met-it is the kinetic condition that remained elusive. This is
because leaving group departure is strongly accelerated by the
electronic push from the nitrogen lone pair in T-A,9 leading to
transition state stabilization that results from the developing
product resonance (eq 5).
There are two requirements for an intermediate such as TN-u
to become detectable. The first is that the equilibrium of the
first step is favorable, i.e., (k1/k-1)[Nu-] ) K1[Nu-] > (.) 1
(“thermodynamic condition”). The second is that the formation
of T-Nu is faster than its conversion to products, i.e., k1[Nu-] >
(.) k2 (“kinetic condition”). The first condition can be met by
a combination of a strong nucleophile and strongly electron-with-
drawing substituents, whereas for the second condition there is
the additional requirement that LG- is a sluggish leaving group.
All of the above-mentioned examples meet both requirements.
For the reactions with amine nucleophiles the mechanism
involves additional steps due to the acidic nature of the initially
formed zwitterionic intermediate as shown in eq 2; the
The reason why T-A was observed in the reaction of 1-OMe
with weakly basic amines is that the push shows a much stronger
dependence on amine basicity (âpush ) 0.71)9 than the nucleo-
philic addition step (ânuc ) 0.25).9 This means that the reduced
nucleophilic reactivity resulting from the lower basicity is more
than offset by the decreased acceleration of the product forming
step.
In this paper we report spectroscopic and kinetic evidence
that in the reaction of methyl â-methylthio-R-nitrocinnamate
(4-SMe) with piperidine and morpholine T-A accumulates to
detectable levels under certain conditions. This is the first
observed example of a nucleophilic vinylic substitution by
strongly basic amines that leads to such intermediate accumula-
tion. We also report kinetic data on the hydrolysis of 4-SMe in
basic solution.
Results
General Features. The synthesis of 4-SMe led to a mixture
of E and Z isomers with an E/Z ratio of 0.5. Attempts at
separating the mixture were unsuccessful. Our results suggest
that the reactivities of the two isomers are very similar and do
not lead to complications such as biphasic kinetics.
kA3 H[R′R′′NH+2 ] term refers to general acid (AH)-catalyzed
The reaction of 4-SMe with piperidine and morpholine leads
to 4-Pip and 4-Mor, respectively. Both 4-Pip and 4-Mor have
leaving group departure by the protonated amine, while k3H O
2
1
been thoroughly characterized, including H NMR, 13C NMR,
refers to noncatalyzed or water-catalyzed loss of the leaving
group. In this case the conditions for detectability of either one
or both intermediates (TA(, T-A) are given by eq 3 (thermody-
namic condition) and eq 4 (kinetic condition), respectively:6
MS, an X-ray crystallographic structure of 4-Pip, and UV data.10
(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. B.; Brown,
S. D.; Chen, X.; Rappoport, Z. J. Org. Chem. 1999, 64, 8829. (c) Berna-
sconi, C. F.; Ketner, R. J.; Chen, X.; Rappoport, Z. Can. J. Chem. 1999,
77, 584.
(K1 + K1K(a /aH+)[R′R′′NH] > (.) 1
(3)
(6) Usually a pH higher than pK(a is required; under such conditions eqs
k1[R′R′′NH] > (.) {K(a /(Ka( + aH+)}(kH O
+
2
3 and 4 simplify to (K1K(/aH )[R′R′′NH] > (.) 1 and k1[R′R′′NH] >
+
3
a
(.) k3H O + k3AH[R′R′′NH2+].
2
kA3 H[R′R′′NH+2 ]) (4)
(7) Bernasconi, C. F.; Fassberg, J.; Killion, R. B., Jr.; Rappoport, Z. J.
Org. Chem. 1990, 55, 4568.
Interestingly, the reactions of neither 1-OMe7 nor 2-SMe8 with
strongly basic amines such as piperidine or n-butylamine, the
(8) (a) Bernasconi, C. F.; Ali, M.; Nguyen, K.; Ruddat, V.; Rappoport,
Z. J. Org. Chem. 2004, 69, 9249. (b) Ali, M.; Biswas, S.; Rappoport, Z.;
Bernasconi, C. F. J. Phys. Org. Chem. 2006, 19, 647.
(9) (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.
(10) Beit-Yannai, M.; Chen, X.; Rappoport, Z. J. Chem. Soc., Perkin
Trans. 2 2001, 1534.
(3) Bernasconi, C. F.: Fassberg, J.; Killion, R. B., Jr.; Rappoport, Z. J.
Am. Chem. Soc. 1989, 111, 6862.
(4) Bernasconi, C. F.; Fassberg, J.; Killion, R. B., Jr.; Rappoport, Z. J.
Am. Chem. Soc. 1990, 112, 3169.
J. Org. Chem, Vol. 72, No. 9, 2007 3303

Bernasconi et al.
FIGURE 1. Time-resolved spectra of the reaction of 4-SMe with
morpholine at pH 8.62 and [morpholine] ) 0.20 M; time intervals 20
s.
FIGURE 3. Reaction of 4-SMe with morpholine at pH 8.76: (O)
k3o6b4sd; (b) k388
.
obsd
(11.02). In this case the absence of sharp isosbestic points
indicates the presence of at least one non-steady-state intermedi-
ate. A similar behavior was observed when the reaction with
morpholine was run in a triethylamine buffer at pH 11.96 or in
a KOH solution at pH 12.0, again suggesting the presence of a
non-steady-state intermediate (spectra not shown).
Kinetics. The spectra shown in Figure 1 for the reaction with
morpholine suggest that the rate of product formation measured
at 388 nm should be the same as the rate of disappearance of
the reactant determined at 364 nm. Plots of the observed pseudo-
388
obsd
364
obsd
first-order rate constants, k
and k , versus morpholine
concentration at pH 8.76 shown in Figure 3 confirm this
expectation.11 The situation is different at pH 12.0; here product
formation is slower than loss of reactant, as expected on the
basis of the spectral observations. Kinetic measurements at 388
nm provided rate constants for product formation, k3ob8s8d. Ki-
netic measurements at 364 nm yielded two rate constants:
k3o6b4sd(R) for the fast loss of reactant associated with a decrease
in absorption and k3ob6s4d(P) for the slower rate of product
formation associated with a small increase in absorption.
Because the absorbance changes associated with k3ob6s4d(P) were
smaller than the ones associated with k3ob8s8d, the data obtained at
388 nm are deemed somewhat more reliable. Figure 4 shows
FIGURE 2. Time-resolved spectra of the reaction of 4-SMe with
piperidine at pH 11.0 and [piperidine] ) 0.19 M; time intervals 20 s.
The latter show λmax in acetonitrile at 274/388 nm for 4-Pip
and at 275/386 nm for 4-Mor, respectively.
388
364
plots of k
and k (R) versus morpholine concentration.
obsd
obsd
Slower rates of product formation compared to the rate of
substrate loss were also observed for the reaction with piperidine
at several pH values. Figures S1 and S2 in Supporting
364
Information12 show representative plots of k (R) versus
All reactions were conducted in 50% DMSO/50% water
(v/v) at 20 °C and an ionic strength of 0.5 M maintained with
KCl. The kinetic experiments were conducted under pseudo-
first-order conditions with 4-SMe as the minor component.
Reaction of 4-SMe with Morpholine and Piperidine. UV/
vis Spectra. When the reaction with morpholine was conducted
at a pH close to the pKa of the morpholinium ion (8.72), there
was a clean transformation of reactants to products. This is
apparent from Figure 1, which shows two sharp isosbestic points
in the time-resolved UV/vis spectra taken at pH 8.62. It implies
that none of the two assumed intermediates (T(A and TA-)
accumulates to detectable levels, i.e., they behave as steady state
intermediates.
obsd
piperidine concentration, and Figures S3 and S412 show corre-
sponding plots of k3ob8s8d; for reasons explained in Discussion,
the latter data are plotted versus piperidinium ion rather than
piperidine concentration. As with the morpholine reaction, rates
of product formation could also be determined at 364 nm, but
388
obsd
the k
values are again deemed more reliable than the
k3o6b4sd(P) values because of smaller absorbance changes and also
because the separation between k3ob6s4d(R) and k364 (P) was not
obsd
very large.
388
obsd
364
(11) The k
values are slightly larger than the k
values, which we
obsd
attribute to experimental error; if there was a slight accumulation of an
388
obsd
364
obsd
As shown in Figure 2, the situation is different for the reaction
with piperidine at a pH close to the pKa of the piperidinium ion
intermediate one would expect k
to be smaller than k
.
(12) See Supporting Information paragraph at the end of this paper.
3304 J. Org. Chem., Vol. 72, No. 9, 2007

SNV Reaction with Amine Nucleophiles
FIGURE 4. Reaction of 4-SMe with morpholine at pH 12.0: (O)
k3o6b4sd(R); (b) k388
.
FIGURE 5. Reaction of 4-SMe with piperidine. Plots according to
eq 9: (O) 364 nm; (b) 388 nm.
obsd
Hydrolysis of 4-SMe. Rates of hydrolysis were measured in
KOH solutions ranging from 0.01 to 0.35 M. The reaction was
monitored by following the disappearance of the substrate at
306 and 364 nm. The pseudo-first-order rate constants are
linearly dependent on [KOH] (Figure S5)12 and are consistent
with eq 6:
for our purposes eqs 7 and 8 are adequate. The situation
described by eqs 7 and 8 pertains to the reaction of 4-SMe with
piperidine under all conditions examined in this study and to
the reaction with morpholine at pH 12.0 in KOH solutions and
at pH 11.96 in dilute triethylamine buffers.
The plots of k3ob6s4d(R) versus amine concentration do not
(
kobsd ) kH O + kOH[OH-]
(6)
+
yield well-defined intercepts, suggesting that the k-1aH /(Ka +
2
+
aH ) term is negligible. The slopes of these plots provide k1
values; the fact that for the piperidine reaction these slopes are
essentially pH-independent (Table S1)12 supports our interpreta-
tion in terms of eq 7.
The slope yielded kOH ) 0.415 ( 0.011 M-1 s-1 from the data
obtained at 364 nm and kOH ) 0.343 ( 0.011 M-1 s-1 at 306
nm. The former is deemed more reliable because the absorbance
changes at 364 nm were much larger than those at 306 nm.
The intercepts of these plots were too small to yield a reliable
388
364
The plots of k
or k (P) also have negligible intercepts,
obsd
obsd
indicating that the water catalyzed leaving group departure
(kH3 O) is negligible compared to the ammonium ion catalyzed
2
value for kH O
.
2
conversion of T-A to products. The pH dependence of the
slopes of these plots examined for the piperidine reaction show
a nonlinear increase with increasing pH (Table S2);12 a plot of
The hydrolysis reaction is followed by two kinetic processes
on much slower time scales; they lead to unidentified products
and were not further investigated.
slope-1 versus aH according to eq 9 is shown in Figure 5; it
+
yields kA3 H ) (4.05 ( 0.98) × 10-2 M-1 s-1 and pK(a ) 11.08
( 0.12 at 364 nm, and kA3 H ) (4.88 ( 2.85) × 10-2 M-1 s-1
and pK(a ) 11.30 ( 0.22 at 388 nm.
Discussion
Interpretation of Kinetic Data. Under the conditions where
one or both intermediates are detectable, the fast process refers
to the reversible formation of T(A and TA-, while the slower
process refers to the conversion of T-A (in fast equilibrium with
aH
+
1
slope-1
)
+
(9)
kA3 H K(a kA3 H
T(A) to products. Hence k364 (R) is approximated by eq 7 and
obsd
388
obsd
364
obsd
k
) k (P) are approximated by eq 8:
For the morpholine reaction conducted at pH 12.0 we
can safely assume pH . pKa( since in similar situations
one always finds pK(a (piperidine) - pKa( (morpholine) ≈
pKAa H (piperidine) - pKaAH (morpholine).3,4,13 Hence eq 8
aH
K(a + aH
+
k3o6b4sd(R) ) k1[R′R′′NH] + k-1
(7)
+
simplifies to eq 10. The kA3 H value determined from the slope
Ka(
k
(kH3 O + k3AH[R′R′′NH2+])
388
obsd
364
obsd
364
obsd
2
of k (P) is 2.08 ( 0.23 M-1 s-1
.
) k (P) )
K(a + aH
+
(8)
388
obsd
k
) k364 (P) ) kA3 H[R′R′′NH2+]
(10)
obsd
We use the term “approximated” because the time separation
For the reaction of 4-SMe with morpholine at pH 8.76 there
between the fast and slow process was, in most cases,
significantly less than a factor of 10 and as low as a factor of
3 or 4, especially for the reaction with piperidine at pH 10.12
and 10.30. This leads to some kinetic coupling between the two
processes and reduces the accuracy of the kobsd values. However,
is no intermediate accumulation, and hence the steady state
364
obsd
388
applies and k
) k
are given by eq 11.
obsd
(13) Bernasconi, C. F. Tetrahedron 1989, 45, 4017.
J. Org. Chem, Vol. 72, No. 9, 2007 3305

Bernasconi et al.
388
obsd
364
TABLE 1. Summary of Kinetic Parameters for the Reactions of
4-SMe with Piperidine, Morpholine, and OH- in 50% DMSO/50%
Water (v/v) at 20 °C
k
) k
)
obsd
kA3 HK(
a [R′R′′NH] +
KAa H
kH3 OK(a
2
[OH-]
364 nm
388 nm
average
Kw
piperidine (pKAa H ) 11.02)
k1
[R′R′′NH] (11)
[OH-]
kA3 HK(
a [R′R′′NH] +
KAa H
kH3 OK(a
2
k1, M-1 s-1 (9.63 ( 1.55) × 10-2a
9.63 × 10-2
kA3 H, M-1 s-1
(4.05 ( 0.98) × 10-2 (4.88 ( 2.85) × 10-2 4.46 × 10-2
k-1
+
Kw
k1/kAH
2.16
11.19
3
pK(a
11.08 ( 0.12
11.30 ( 0.22
364
obsd
388
The plots of k
and k
(Figure 3) show some upward
obsd
morpholine (pKAa H ) 8.72)
k1, M-1 s-1 (1.71 ( 0.17) × 10-2b
1.71 × 10-2
2.08
curvature, which is consistent with catalysis by morpholine at
low concentrations and arises from the (kA3 HKa(/KaAH)[R′R′′NH]
term in eq 11. As the morpholine concentration increases, the
curvature decreases. These results imply that at low amine
concentration the relationship of eq 12 holds with the (kA3 HKa(/
KAa H)[R′R′′NH] term being dominant.14
kA3 H, M-1 s-1
2.08 ( 0.23
k1/kAH
8.22 × 10-3
3
pK(a
≈8.88c
OH-
k1, M-1 s-1
0.415 ( 0.011
0.415
a Average from slopes at six pH values (Table S1). b Average from slopes
at two pH values (Table S1). c Estimated as pKa( (mor) ≈ pKa((pip) -
pKAa H(pip) + pKAa H(mor).
kA3 HK(
a [R′R′′NH] +
KAa H
kH3 OK(a
Kw
2
[OH- ] j k-1
(12)
to the intrinsic rate constants15 for the proton transfer from these
carbon acids (5, 6, and 7) to secondary alicyclic amines. The
pKCa H values may be regarded as an approximate measure of
the relative thermodynamic stabilities of the respective inter-
At the higher concentrations the decrease in the upward
curvature means that either eq 13 or eq 14 holds.
(kA3 HK(a /KaAH)[R′R′′NH] J k-1
(kA3 HK(a /KaAH)[R′R′′NH] . k-1
(13)
(14)
mediates; the log kPT values serve as rough indicators of the
°
relative intrinsic rate constants for nucleophilic attack on the
respective vinylic substrates, except for possible distortions by
other effects as will be discussed below. The following points
are noteworthy:
We prefer the former interpretation, because if eq 14 were
valid, it would imply that eq 11 reduces to eq 15 and that the
slope of the quasi linear portion of the plots in Figure 3 are
equal to k1.
(1) In the reactions of 4-SMe with piperidine and morpholine,
leaving group departure catalyzed by the respective protonated
amine (kA3 H) is the dominant pathway while the noncatalyzed
or water-catalyzed pathway (kH3 O) is negligible. The k3AH(mor)/
2
388
obsd
364
obsd
k
) k
) k1[R′R′′NH]
(15)
kA3 H(pip) ratio of 48.9, which corresponds to a Brønsted R )
0.73, suggests a transition state where proton transfer is well
advanced. The dominance of the kA3 H pathway is reminiscent of
the reaction of 2-SMe8a with piperidine where kA3 H is 433-fold
However, these slopes are ∼7.0 × 10-3 M-1 s-1 at 364 nm
and ≈8.2 × 10-3 M-1 s-1 at 388 nm, respectively; they are
smaller than the k1 value of (1.71 ( 0.17) × 10-2 M-1 s-1
determined at pH 12.0. Hence, the condition of eq 14 has not
been reached.
larger than kH3 O, but different from the situation in the reaction
2
of 1-OMe with amines where it is the kH3 O pathway that is
2
dominant.7,9 The fact that the reactions with the MeS- leaving
group are more sensitive to acid catalysis than the reaction with
the MeO- leaving group is counterintuitive because the meth-
oxide ion is more basic than the methylthiolate ion and usually
reactions involving oxyanions as leaving groups are more prone
to acid catalysis than those involving thiolate ions.17 A possible
explanation for the absence of significant acid catalysis of MeO-
expulsion from T-A derived from 1-OMe lies in the very strong
electronic push (eq 5) that prevails in the noncatalyzed MeO-
Summary of Rate Constants and Comparisons with Other
Systems. Table 1 provides a summary of the kinetic parameters
obtained in this study. Note that the k1, kAH, and pKa( values
3
for the piperidine reaction are associated with relatively large
experimental uncertainties; as pointed out earlier, this is most
likely the result of coupling between the fast and slow processes
that leads to inaccuracies in the kobsd values. The parameters
summarized in Table 2 allow comparisons to be made among
reactions of similar substrates with the same nucleophiles. Table
2 includes the pKCa H values of the respective parent carbon
expulsion (k3H O, ânuc ) 0.71). This makes the kH3 O step
competitive with the acid-catalyzed pathway because the
transition state of the acid-catalyzed pathway is probably too
crowded for the optimal coplanarity required for an effective
push to apply. In the reactions of 2-SMe and 4-SMe there is
2
2
acids (5, 6, and 7, respectively) and log kPT values, which refer
°
(15) The intrinsic rate constants refer to rate constants that have been
interpolated or extrapolated from Brønsted plots to ∆pKa + log(p/q) ) 0
where ∆pKa ) pKAH - pKaCH is the difference between the pKa values of
a
the protonated amines and the carbon acids, respectively, and p and q refer
to statistical factors.16
(16) Keeffe, J. R.; Kresge, A. J. In InVestigation of Rates and Mechanisms
of Reactions; Bernasconi, C. F., Ed.; Wiley-Interscience: New York, 1986;
Part 1, p 747.
(17) Bernasconi, C. F.; Ketner, R. J.; Brown, S. D.; Chen, X.; Rappoport,
Z. J. Org. Chem. 1999, 64, 8829.
(14) Since for the piperidine reaction the kA3 H pathway is dominant over
the kH3 O pathway, the same must be true for the morpholine reaction,
2
especially since the morpholinium ion should be a stronger acid catalyst
than the piperidinium ion.
3306 J. Org. Chem., Vol. 72, No. 9, 2007

SNV Reaction with Amine Nucleophiles
TABLE 2. Comparison of Kinetic Parameters of the Reactions of 4-SMe with the Reactions of 1-OMe and 2-SMe
a Reference 7. b Reference 31. c Bernasconi, C. F.; Kliner, D. A. V.; Mullin, A. S.; Ni, J. X. J. Org. Chem. 1988, 53, 3342. d Bernasconi, C. F.; Pe´rez-
Lorenzo, M.; Brown, S. D. Unpublished results. e Reference 8a. f Estimated, see ref 8a. g Reference 5c. h Bernasconi, C. F.; Oliphant, N. Unpublished results.
i pKa of parent carbon acid; see text. j kPoT is the intrinsic rate constant for proton transfers from parent carbon acid; see text.
already too much crowding even at the transition state of the
non-catalyzed reaction because of the large size of the MeS
group. This leads to a reduction of the push in the kH3 O step.
2
We shall return to these points when dealing with the question
of why T-A is observable in the reaction of 2-SMe with
piperidine and morpholine but not in the reaction of 1-OMe
with the same amines.
(2) The pK(a (pip) value for 4-SMe is somewhat higher than
is strongest in the case of 10, intermediate in the case of 9, and
weakest for T(A derived from 8. This implies that anionic
that for 2-SMe, presumably because the O2NCCO2Me
moiety is somewhat less electron-withdrawing than the
carbonyl oxygens are better hydrogen acceptors than anionic
nitro group oxygens. A possible reason for this is that there is
repulsion between the positive charges on the ammonium
C(COO)2C(CH3)2 moiety, as suggested by the respective pKCH
a
values (Table 2). This contrasts with the much lower pK(a (pip)
value for 1-SMe. In order to develop some understanding of
this contrast it is useful to look at the pK(a values of the
piperidine adducts of olefinic substrates such as 8, 9, and 10
that lack a leaving group. Two factors influence these pKa(
nitrogen and the nitrogen of the nitro group that (partially)
offsets the stabilizing effect of hydrogen bonding.
Turning to the pK(a values of T(A derived from 1-OMe,
2-SMe, and 4-SMe (Table 2), we note the following. For 1-OMe
there is a reduction by 2 pK units relative to that for 8, which
may be accounted for by the electron-withdrawing inductive
effect of the MeO group. In 2-SMe the degree of reduction
relative to the pK(a of 9 is unknown but probably less than 2
pK units since the MeS group is less electron-withdrawing than
the MeO group.24 The pKa( of 4-SMe (11.19) hence fits in well
with the notion that there is substantial intramolecular hydrogen
bonding in T(A derived not only from 2-SMe but also from
4-SMe and that this hydrogen bonding is most likely to the
carbonyl oxygen of the ester group rather than to an oxygen of
the nitro group.
values. One is the electron-withdrawing strength of the activating
substituents, which is strongest in the case of 9, weakest in the
case of 10 (the pKaCH of acetylacetone is 9.1218,23), and
intermediate in the case of 8. The second and more important
factor is intramolecular hydrogen bonding between the am-
monium ion and the negative oxygens exemplified by 11. This
hydrogen bond reduces the acidity of the ammonium ion and
(3) In comparing 4-SMe to 2-SMe one would expect that
4-SMe should be less reactive toward nucleophilic attack than
2-SMe because the higher pKCa H suggests a lower electrophi-
licity or lower stability of the respective intermediates and
the lower log kPT implies a lower rate constant even if the
°
stabilities of the respective intermediates were the same. The
(18) In 50% DMSO/50% water (v/v) at 20°C.
(19) Bernasconi, C. F.; Renfrow, R. A. J. Org. Chem. 1987, 52,
3035.
(20) In water at 25°C.
(22) Bernasconi, C. F.; Kanavarioti, A. J. Am. Chem. Soc. 1986, 108,
7744.
(21) Bernasconi, C. F.; Murray, C. J. J. Am. Chem. Soc. 1986, 108,
5251.
(23) Bernasconi, C. F.; Bunnell, R. D. Isr. J. Chem. 1985, 26, 420.
(24) σF(OMe) ) 0.30; σF(SMe) ) 0.20.25
J. Org. Chem, Vol. 72, No. 9, 2007 3307

Bernasconi et al.
fact that k1(OH-) for 4-SMe (0.415 M-1 s-1) is only marginally
lower than for 2-SMe (0.634 M-1 s-1) indicates that other
factors must be important. One such factor may be π-donation
by the MeS group in the substrate (12 and 13). According to
in the reactions of 1-OMe or 2-SMe with strongly basic amines
because only the thermodynamic condition (eq 3) but not the
kinetic condition (eq 4) is met. However, in the reaction of
4-SMe with piperidine, TA( and T-A do accumulate to detectable
levels and so does T-A in the reaction of 4-SMe with morpho-
line at high pH. Furthermore, in the reaction of 1-OMe with
the much less basic amines methoxyamine and N-methyl-
methoxyamine, T-A could also be observed directly.9
These contrasting observations are related to an important
difference between the reactions of 4-SMe and 1-OMe with
amines: In the reaction of 1-OMe the dominant pathway for
the conversion of T-A to products is the water-catalyzed leaving
the pKCa H values (Table 2) the electron-withdrawing effect
of the C(COO)2C(CH3)2 moiety is stronger than that of the
O2NCCO2Me moiety, which probably translates into a stronger
π-donor effect in the Meldrum’s acid derivative. Since π-dona-
tion stabilizes the substrate this will lead to a larger reduction
in reactivity of 2-SMe than of 4-SMe.
group departure (kH3 O), whereas in the reaction of 4-SMe it is
2
the acid-catalyzed pathway (kA3 H) that is dominant. Hence in
the reaction of 1-OMe the strong electronic push (âpush ) 0.71)
becomes a determining factor regarding the detectability of an
intermediate. Specifically, the strong push leads to kH3 O(pip) .
2
kH3 O(mor) . kH3 O (MeONHMe) and, coupled with the small
2
2
(4) In contrast to the k1(OH) values, the k1(pip) and k1(mor)
values for 4-SMe are substantially lower than for 2-SMe: 39-
fold for k1(pip) and 29-fold for k1(mor), respectively. A possible
explanation of this is that the transition state of the amine
reactions is stabilized by intramolecular hydrogen bonding
between the developing ammonium ion and the developing
negative charge, which is akin to the intramolecular hydrogen
bond in the fully developed T(A. The results suggest that this
hydrogen bond and thus the transition state stabilization is
stronger in the reaction of 2-SMe than in the reaction of 4-SMe.
Such stronger hydrogen bonding could arise if charge develop-
ment on the nitrogen were more advanced at the transition state
of the reaction of 2-SMe. The larger ânuc value (0.41) for the
reaction of 2-SMe compared to that of 4-SMe (0.33) is
consistent with this notion. A larger steric effect in the reaction
of 4-SMe may also contribute to the difference in the rates;
even though such a steric effect would probably not discriminate
between the k1(OH-) values due to the small size of the
nucleophile, such discrimination is more plausible for k1(pip)
and k1(mor) because of the bulkiness of the amines.
ânuc (0.25), to (k1/kH O)(pip) < (k1/kH O)(mor) < (k1/kH O)-
2
2
2
3
3
3
(MeONHMe). This explains why intermediates derived from
less basic amines are more easily detectable than those derived
from more basic amines.
In the reactions of 4-SMe the electronic push apparently plays
a minor role if any; this can be seen from the fact that
kA3 H(mor) ) 2.08 M-1 s-1 is considerably larger than kA3 H(pip)
) 4.25 × 10-2 M-1 s-1 and is reflected in R ) 0.73 for acid
catalysis.30 The larger k3AH(mor) value coupled with k1(pip) >
k1(mor) yields (k1/kAH)(pip) . (k1/kAH)(mor), i.e., here in-
3
3
creased basicity of the amine enhances the detectability of the
intermediate. This explains why T-A accumulates to detectable
levels with strongly basic amines and that T-A derived from
piperidine is more easily detectable than T-A derived from
morpholine.
Regarding the reaction of 2-SMe with piperidine and mor-
pholine, not enough information is available to pinpoint the
reasons why the respective intermediates were not observable.
For one, under conditions where nucleophilic attack is not rate-
limiting, ammonium ion catalyzed leaving group departure is
rate-limiting only for the piperidine reaction, whereas for the
morpholine reaction deprotonation of T(A was found to be rate-
limiting.8a
(5) On the basis of the pKCa H and log kPT values, one would
°
have expected 1-OMe to be much less reactive than 4-SMe or
2-SMe, but this is not the case. The main factor responsible for
the higher than expected reactivity of 1-OMe is the replacement
of the MeS group with the MeO group. In reactions with bulky
nucleophiles such as secondary amines the smaller MeO group
leads to a strong reduction in steric crowding at the transition
state.2 This appears to be the main reason why k1(pip) and k1-
(mor) for 1-OMe are higher than the respective rate constants
for 4-SMe. The enhanced electron-withdrawing inductive effect
of the MeO group over the MeS group24 should also contribute
to the higher rates for 1-OMe, although the stronger π-donor
effect of the MeO group26 would probably offset this factor.
For the reaction with OH-, steric effects should play a much
smaller role. However, here the anomeric effect27 is responsible
for the relatively high k1(OH) value for 1-OMe relative to that
for 4-SMe and 2-SMe.
Why Is the Intermediate in the Reaction with Hydroxide
Ion Not Detectable? There is no evidence that the presumed
intermediate in the reaction of 4-SMe with OH-, 14, ac-
cumulates to detectable levels. This finding is consistent with
observations made earlier in the hydrolysis of 1-OMe,31
(28) (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.
(29) (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.
(30) The âpush value cannot possibly be larger than 1 - R ) 1 - 0.73
) 0.27; a âpush value of 0.27 would imply a “true” R value for acid catalysis
of 1.0, which is unlikely.
Why Is the Intermediate Detectable in the Reactions with
Piperidine and Morpholine? As stated in the Introduction,
there is no accumulation of any intermediates to detectable levels
(25) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165.
(26) σR(OMe) ) -0.43; σR(SMe) ) -0.15.25
(27) In the present context, the anomeric effect28 refers to the stabilization
exerted by geminal oxygen atoms,29 e.g., in dialkoxy or alkoxyhydroxy
adducts.
(31) Bernasconi, C. F.; Fassberg, J.; Killion, R. B., Jr.; Schuck, D. F.;
Rappoport, Z. J. Am. Chem. Soc. 1991, 113, 4937.
3308 J. Org. Chem., Vol. 72, No. 9, 2007

SNV Reaction with Amine Nucleophiles
2-OMe,32 2-SMe,33 3-OMe2, and other highly activated sub-
strates. As with these earlier examples, it is the kinetic rather
than the thermodynamic condition that is not met. As observed
before,31,33 this is because conversion of 14 to products is
unusually fast due to the availability of additional pathways.
One such pathway involves rapid deprotonation of the OH
group, generating the dianionic form of two intermediate, 15,
which expels the leaving group much more rapidly than the
monoanionic form because of the extra push. The other pathway
involves intramolecular acid catalysis of leaving group departure
by the OH group.
k1(OH) value for 1-OMe is also higher than expected. Here the
main factor appears to be the anomeric effect; because of the
small size of the nucleophile, the smaller steric effect is probably
of minor importance.
Experimental Section
The synthesis of 4-SMe involved the conversion of methyl
phenylpropiolate (16) to methyl â-iodo-R-nitrocinnamate (4-I) (eq
16) followed by substitution of the iodo group by the MeS group
(eq 17).
Conclusions
(1) The reaction of 4-SMe with piperidine and morpholine
is the first example of an SNV reaction with moderately to
strongly basic amine nucleophiles where the intermediate
accumulates to detectable levels. The only other SNV reaction
involving amine nucleophiles that has allowed a direct observa-
tion of the intermediate is that of 1-OMe with methoxyamine
and N-methylmethoxyamine, but these are weakly basic amines;
in the reaction of the same substrate with morpholine or
piperidine T-A is a nonobservable steady state intermediate.
(2) The reason why for 4-SMe it is easier to detect the
intermediate in its reactions with highly basic amines whereas
for 1-OMe T-A is more easily observed in reactions with
weakly basic amines is the fact that leaving group departure in
the former reactions is catalyzed by the respective protonated
Synthesis of 4-I. Dinitrogen tetraoxide (2.6 mL, 0.04 mmol) was
transferred by a stream of dry argon to a solution containing methyl
1
phenylpropiolate [(8 g, 0.05 mol; H NMR (CDCl3) δ: 3.84 (3H,
s, OMe), 7.36-7.39 (2H, m, Ph), 7.43-7.45 (1H, m, Ph), 7.57-
7.59 (2H, m, Ph)] and iodine (20 g, 0.08 mol) in dry ether (300
mL) during 5 h at room temperature. The solution was then stirred
for 40 h at room temperature. To the dark red solution was slowly
added a 5% aqueous Na2S2O3 solution (6 × 250 mL) until the iodine
color had completely disappeared. The organic phase was washed
with water (2 × 100 mL) and dried (MgSO4). Evaporation of the
solvent left a mixture of a solid and an oil (15 g, 90%).
amine but not in the latter. This leads to (k1/kAH)(pip) . (k1/
After washing with cold petroleum ether, a yellow solid (10 g),
mp 98-104 °C, was obtained. An additional amount was obtained
from the washing solution. The product was separated into the E
and Z isomers by crystallization from petroleum ether or CHCl3
and gave 99% Z isomer, 1% E isomer in the best case. It was
obtained as the pure isomer from chromatography over silica
column using 90% petroleum ether, 40-60 °C, 10% EtOAc eluent,
followed by crystallization from petroleum ether. Two consecutive
crystallizations from petroleum ether gave pure E-isomer. Data for
E-isomer: yellow crystals, mp 119-120 °C. 1H NMR (CDCl3) δ:
3.94 (3H, s, OMe), 7.28-7.45 (5H, m, Ar); (DMSO-d6) δ: 3.89
(3H, s, OMe), 7.29-7.47 (5H, m, Ar). MS: m/z (relative abundance
%, assignment) 333 (8, M), 305 (3, M - CO), 176 (3, M - I -
NO), 160 (29, M - I - NO2), 129 (100, M - PhI), 105 (45, PhCO),
103 (4, PhCO - 2H), 102 (31, PhCO - 3H), 77 (14, Ph). Anal.
Calcd for C10H8O4IN: C, 36.06; H, 2.42; N, 4.21. Found: C, 35.94;
H, 2.38; N, 4.12. Data for Z-isomer: yellow crystals, mp 65-
65.5 °C. 1H NMR (CDCl3) δ: 3.63 (3H, s, MeO), 7.30-7.42 (5H,
m, Ph); (DMSO-d6) δ: 3.56 (3H, s, OMe), 7.29-7.50 (5H, m, Ar).
MS: m/z (relative abundance %, assignment) 333 (6, M), 305 (2,
M - COO, 228 (s), 176 (3, M - I - NO), 160 (19, M - I -
NO2), 129 (100, M - Ph - I), 105 (63, PhCOO, 103 (5, PhCO -
2H), 77 (25, Ph). Anal. Calcd. for C10H8O4IN: C, 36.06; H, 2.42;
N, 4.21. Found: C, 36.27; H, 2.38, N, 4.27. Both pure isomers
decompose on standing in DMSO-d6.
3
kA3 H)(mor) in the reactions of 4-SMe, but because âpush > ânuc
,
to (k1/kH O)(pip) < (k1/kH O)(mor) < (k1/kH O)(MeONHMe) in
2
2
2
3
3
3
the reactions of 1-OMe.
(3) No intermediate could be observed in the reaction of
4-SMe with OH-. This is because the acidic properties of the
hydroxyl group of the intermediate provide additional pathways
for the loss of the leaving group.
(4) The pK(a values of T(A from the reaction of 4-SMe are
consistent with the pKa( of T(A from the reaction of 2-SMe with
piperidine and considerably higher than the pK(a values of the
respective amine adducts of 1-OMe. This is because of strong
intramolecular bonding in the former and weak intramolecular
hydrogen bonding in the latter; the reduced electron-withdrawing
effect of the MeS group compared to that of the MeO group
also contributes to the difference.
(5) The expectation, based on the pKCa H and log kPT values,
°
that k1(OH) for 4-SMe should be significantly lower than for
2-SMe is not met. A possible reason is weaker π-donation by
the MeS group in 4-SMe due to the stronger electron-
withdrawing effect of the (COO)2C(CH3)2 group. On the other
hand, the k1(pip) and k1(mor) values for 4-SMe are substantially
lower than for 2-SMe. Stronger transition state stabilization by
intramolecular hydrogen bonding in the reactions of 2-SMe is
the likely cause for this finding.
Synthesis of 4-SMe. To a solution of a 5:1 E/Z mixture of 4-I
(999 mg, 3 mmol) in acetonitrile (150 mL) was added the sparingly
soluble sodium methylthiolate (252 mg, 3.6 mM). The turbid
mixture was stirred for 4 h at room temperature until a precipitate
was formed. Water (100 mL) was added, most of the MeCN was
evaporated, and the residue was extracted with CHCl3 (3 × 100
mL). The CHCl3 solution was dried (MgSO4) and filtered, and
evaporation of the solvent left a crude yellow oil (600 mg, 79%),
(6) The main reason why the k1(pip) and k1(mor) for the
reactions of 1-OMe are higher than the respective rate constants
for 4-SMe and higher than expected based on the pKCa H and
log kPT values is the reduced steric crowding at the transition
1
°
higher field H NMR (CDCl3) δ 1.84 (E), 1.88 (Z) (2s, MeS, E/Z
state when the MeS group is replaced by a MeO group. The
ratio ) 0.7, 29%), which contained a large percentage of the
precursor methyl propiolate. The mixture was chromatographed over
a silica column using 85% petroleum ether 40-60 °C/15% EtOAc
as eluent. This ester was the main product eluted in the first
fractions.
(32) Bernasconi, C. F.; Ketner, R. J.; Chen, X.; Rappoport, Z. J. Am.
Chem. Soc. 1998, 120, 7461.
(33) Bernasconi, C. F.; Schuck, D. F.; Ketner, R. J.; Weiss, M.;
Rappoport, Z. J. Am. Chem. Soc. 1994, 116, 11764.
J. Org. Chem, Vol. 72, No. 9, 2007 3309

Bernasconi et al.
Middle fractions were mixtures of the propiolate ester and E-
and Z-4-SMe. The last fractions were mixtures of E- and Z-4-SMe.
Crystallization from petroleum ether gave a white solid (54 mg),
mp 73-4 °C with E/Z ratio of 0.5. 1H NMR (CDCl3) δ: 1.84 (E),
1.88 (Z) [3H, 2s, MeS], 3.51 (Z), 3.88 (E) [3H, 2s, MeO], 7.20-
7.48 [5H, m, Ar], E/Z ca. 0.5. MS: m/z (relative abundance %,
assignment) 253 (7, M), 223 (5, M - NO), 221 (4, M - S), 174
(9, M - MeS - MeOH), 160 (23, M - MeS - NO2), 148 (14, M
- CO2Me - NO2), 133 (M - CO2Me - NO2 - Me), 130 (10, M
- Ph - NO2), 129 (M - Ph - MeS), 105 (100, PhCO), 102 (21,
PhCO, 3H), 77 (38, Ph). Anal. Calcd for C11H11NO4S: C, 52.16;
H, 4.38; N, 5.53. Found: C, 52.06, H, 4.33, N, 5.50.
Additional fractions gave 13 mg of E/Z of ca. 0.7 and 28 mg of
E/Z ca. 1.25, mp 90-91 °C. Altogether, 100 mg of E- and Z-4-
SMe (13.5%) was obtained. No attempt to optimize the yield was
made. Attempts to separate further the E- and Z-isomers by
crystallization from petroleum ether, CHCl3, and CH2Cl2 or by
chromatography on silica gave in each experiment a different E/Z
composition and separation was not achieved. The ratios were
temperature- and solvent-dependent, e.g., E/Z ) 1.1 (CDCl3), 0.7
(DMSO-d6). A sample with E/Z ) 0.7 in DMSO-d6 at room
temperature gave an E/Z ratio of 0.5 after 26 h at room temperature.
Other Materials. Piperidine, morpholine, and triethylamine were
distilled over sodium metal in an argon atmosphere. Solutions of 2
M KOH and 2 M HCl were prepared using Baker Dilut-it cartridges.
DMSO was distilled over CaH2.
Methodology. Preparation of solutions, pH measurements,
recording of spectra, kinetic measurements, and data analysis were
performed using general methods described previously.33
Acknowledgment. This research was supported by Grants
CHE-9734822 and CHE-0446622 from the National Science
Foundation (CFB), and a grant from the U.S.-Israel Binational
Science Foundation (ZR).
Supporting Information Available: Figures S1-S4 (kinetic
data) and Tables S1-S2 (kinetic parameters). This material is
available free of charge via the Internet at http://pubs.acs.org.
JO062602S
3310 J. Org. Chem., Vol. 72, No. 9, 2007