Kinetics of the reactions of methoxybenzylidene Meldrum's acid with thiolate ions, alkoxide ions, OH-, and water in aqueous DMSO. Detection and kinetic characterization of the S(N)V intermediate

Article abstract of DOI:10.1021/ja9743102

The nucleophilic vinylic substitution (S(N)V) reactions of methoxybenzylidene Meldrum's acid (5-OMe) follow the common two-step mechanism involving a tetrahedral intermediate. With thiolate and alkoxide ions, this intermediate is shown to accumulate to detectable levels and a detailed kinetic study allowed the determination of the rate constants of the various elementary steps. With OH^- as the nucleophile, the intermediate cannot be observed; it is shown that this is the result of the intermediate rapidly breaking down to products by a pathway not available in the reactions with the thiolate or alkoxide ions. Comparison of structure-reactivity data for the reactions of 5-OMe with those of benzylidene Meldrum's acid (5-H) and β-methoxy-α-nitrostilbene (4-OMe) reveal a complex interplay of steric effects, π-donor and π-acceptor resonance effects, and anomeric effects.

Full text of DOI:10.1021/ja9743102

J. Am. Chem. Soc. 1998, 120, 7461-7468
7461
Kinetics of the Reactions of Methoxybenzylidene Meldrum’s Acid
with Thiolate Ions, Alkoxide Ions, OH-, and Water in Aqueous
DMSO. Detection and Kinetic Characterization of the SNV
Intermediate
Claude F. Bernasconi,*,† Rodney J. Ketner,† Xin Chen,‡ and Zvi Rappoport‡
Contribution from the Department of Chemistry and Biochemistry of the UniVersity of California,
Santa Cruz, California 95064, and Department of Organic Chemistry, the Hebrew UniVersity of Jerusalem,
Jerusalem 91904, Israel
ReceiVed December 22, 1997. ReVised Manuscript ReceiVed May 11, 1998
Abstract: The nucleophilic vinylic substitution (SNV) reactions of methoxybenzylidene Meldrum’s acid (5-
OMe) follow the common two-step mechanism involving a tetrahedral intermediate. With thiolate and alkoxide
ions, this intermediate is shown to accumulate to detectable levels and a detailed kinetic study allowed the
determination of the rate constants of the various elementary steps. With OH- as the nucleophile, the
intermediate cannot be observed; it is shown that this is the result of the intermediate rapidly breaking down
to products by a pathway not available in the reactions with the thiolate or alkoxide ions. Comparison of
structure-reactivity data for the reactions of 5-OMe with those of benzylidene Meldrum’s acid (5-H) and
â-methoxy-R-nitrostilbene (4-OMe) reveal a complex interplay of steric effects, π-donor and π-acceptor
resonance effects, and anomeric effects.
It is well established that nucleophilic vinylic substitutions
(SNV) of a leaving group (LG) on substrates moderately or
strongly activated by electron-withdrawing groups (X, Y)
proceed by a stepwise mechanism via intermediate 2 (eq I).1
MeONHMe4a and MeONH2,4 of 4-SR (R ) ZCH2CH2; Z )
Me, HO, MeO2C) with thiolate ions2b and the reaction of
4-OCH2CF3 with CF3CH2O- and HOCH2CH2S- 3b also led to
intermediates that accumulated to detectable levels.
However, extensive recent work revealed several substitutions
of nonactivated systems which were interpreted as single-step
concerted substitutions, thus increasing the need for more clear-
cut examples where the intermediate has been unequivocally
observed.5,6 Thus far, all detectable intermediates were derived
from nitrostilbenes, where X, Y ) Ph, NO2 provide unusually
effective stabilization of the intermediate, as implied by the high
acidity of PhCH2NO2 (pKa ) 7.93 in 50% Me2SO-50% H2O7).
In exploring other types of strongly activated vinylic substrates
that might lead to a detectable intermediate we have now
investigated the reaction of methoxybenzylidene Meldrum’s acid
(5-OMe) with RS-, RO-, OH-, and H2O in 50% DMSO-50%
(I)
The first direct spectrophotometric detection of 2 was reported
in 1989 for the reaction of â-methoxy-R-nitrostilbene (4-OMe)
with thiolate ions in 50% Me2SO-50% H2O (v/v).2 Besides
providing the most compelling evidence for the two-step
mechanism and the existence of 2, its direct observation allowed
a determination of the rate constants kN1 u, kNu, and k2Nu in eq I.
-1
Subsequently, the reactions of 4-OMe with MeO-,3 CF3CH2O-,3
† 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, 6862. (b) J. Am. Chem. Soc. 1990, 112, 3169.
(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.
H2O (v/v), henceforth abbreviated as 50% DMSO. Since the
pKa of Meldrum’s acid is 4.70 in 50% DMSO,8 the chances to
observe the intermediate seemed as good as in the reactions of
4-OMe or 4-SR. This is confirmed below.
(4) (a) Bernasconi, C. F.; Leyes, A. E.; Rappoport, Z.; Eventova, I. J.
Am. Chem. Soc. 1993, 115, 7513. (b) Ibid. 1995, 117, 1703.
S0002-7863(97)04310-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/21/1998

7462 J. Am. Chem. Soc., Vol. 120, No. 30, 1998
Bernasconi et al.
Table 1. Summary of Rate and Equilibrium Constants for the Reactions of 5-OMe and 5-H with Various Nucleophiles in 50% DMSO-50%
Water (v/v) at 20 °C, µ ) 0.5 M
Nu
-1
Nu (pKNa uH
)
kN1 u, M-1 s-1
k
, s-1
KN1 u, M-1
kN2 u, s-1
5-OMe
n-BuS- (11.40)
(6.70 ( 0.10) × 104
(4.40 ( 0.02) × 104
(4.43 ( 0.11) × 104
(2.40 ( 0.09) × 104
(5.41 ( 0.13) × 102
(4.61 ( 0.16) × 103
(1.09 ( 0.03) × 103
(2.98 ( 0.08) × 10-2a
0.395 ( 0.016
1.71 ( 0.05
2.00 ( 0.19
14.0 ( 0.7
(1.70 ( 0.09) × 105
(2.57 ( 0.09) × 104
(2.22 ( 0.26) × 104
(1.71 ( 0.15) × 103
(1.11 ( 0.04) × 10-4
(2.16 ( 0.14) × 10-4
(1.98 ( 0.17) × 10-5
HOCH2CH2S- (10.56)
MeO2CCH2CH2S- (10.40)
MeO2CCH2S- (8.83)
HO- (17.33)
MeO- (17.2)b
(1.22 ( 0.32) × 10-5
(1.06 ( 0.04) × 10-3
(1.60 ( 0.20) × 10-2
HCtCCH2O- (15.2)c
CF3CH2O- (14.0)
H2O (-1.44)
(4.35 ( 0.95) × 106
(6.81 ( 1.60) × 104
5-Hd
HOCH2CH2S- (10.56)
HO- (17.33)
1.44 × 107
1.80 × 103
2.09 × 104
2.68 × 10-4
1.45 × 10-7
4.38 × 10-3
5.38 × 1010
1.17 × 1010
4.77 × 106
CF3CH2O- (14.0)
a First-order rate constant (s-1). b pKa of MeOH estimated as discussed in ref 3a. c pKa of HCtCCH2OH is estimated; see text. d From ref 12.
and water, respectively (see below), i.e., kOH ) kOH and kH O
)
2
1
kH1 O (eq I and Table 1).
2
At pH >2, the hydrolysis product is anion 6-, displayed as
its two resonance forms 6a- and 6b-. Its structure was identical
(by HPLC) to an authentic sample of 6-. At pH <2, the UV
spectrum of the hydrolysis product starts to undergo a batho-
chromic shift from λmax ) 285 to 299 nm at pH 0.3, indicating
protonation of 6-. The λmax suggests protonation on oxygen,
giving 5-OH rather than 6. The spectrophotometrically deter-
mined pKa of 5-OH is 1.06 ( 0.03.
Reaction of 5-OMe with Thiolate Ions. Upon rapid mixing
of solutions of 5-OMe and a thiolate buffer (n-BuS-,
HOCH2CH2S-, and MeO2C(CH2)nS-, n ) 1, 2), a fast reaction
was observed on the stopped-flow time scale, with pseudo-first-
order rate constants proportional to [RS-] (Figure 2S).9 Due
to rapid hydrolysis of 5-OMe, it was difficult to obtain
Figure 1. (a) Time-dependent spectra showing the hydrolytic conver-
sion of 5-OMe to 6- in neutral 50% DMSO-50% water solution at 20
°C. Scans taken every 5 s for 90 s. [5-OMe]o ) 7.0 × 10-5 M. (b)
Spectrum of the protonated form of the hydrolysis product, 5-OH, in
strongly acidic HCl solution (pH ≈0).
Results
meaningful spectral data about the species formed in the reaction
between 5-OMe and RS-. However, a clean spectrum was
generated by conducting the reaction in MeOH, where hydroly-
sis is not an issue, and then injecting this solution into 50%
DMSO. This spectrum is shown in Figure 2 (spectrum b) along
with that of 5-OMe (spectrum a) and of 5-SR (spectrum d).
The blue-shifted λmax of spectrum b indicates loss of conjugation
with the CdC bond which is consistent with the intermediate
7-(OMe,SR). This implies that the kinetic results refer to eq 2
Reaction of 5-OMe with H2O and OH-. Hydrolysis of
5-OMe is quite fast, even in neutral or acidic solution where
t1/2 is ∼23 s. Figure 1 shows spectral changes associated with
the hydrolysis reaction. Its kinetics was measured in 0.01-0.2
M KOH solutions, acetate buffers (pH 5.78-6.78), and HCl
solutions (pH 0.3-3.0). No significant buffer catalysis was
observed. The rate-pH profile is shown in Figure 1S of the
Supporting Information.9 The observed pseudo-first-order rate
constant was fitted to eq 1. No intermediate accumulated and
kR1 S
5-OMe + RS- y z 7-(OMe,SR)
(2)
kobsd ) k + kOH[OH-]
(1)
RS
k
H2O
-1
kOH and kH O represent rate-limiting nucleophilic attack by OH-
kobsd
) kR1 S[RS-] + kRS
(3)
-1
2
k1[RS-].
(5) For recent references summarizing earlier work, see: (a) Okuyama,
T.; Takino, T.; Sato, K.; Oshima, K.; Imamura, S.; Yamataka, H.; Asano,
T.; Ochiai, M. Bull. Chem. Soc. Jpn. 1998, 71, 243. (b) Beit-Yannai, M.;
Rappoport, Z.; Shainyan, B.; Danilevich, Y. S. J. Org. Chem. 1997, 62,
8049.
(6) For recent theoretical work, see: (a) Glukhovstsev, M. N.; Pross,
A.; Radom, L. J. Am. Chem. Soc. 1994, 116, 5961. (b) Lucchini, V.;
Modena, G.; Pasquato, L. J. Am. Chem. Soc. 1995, 117, 2297.
(7) Bernasconi, C. F.; Kliner, D. A. V.; Mullin, A. S.; Ni, J. X. J. Org.
Chem. 1988, 53, 3342.
and kobsd is given by eq
3
with k-1
,
kR1 S values are reported in Table 1.
Reaction of 7-(OMe,SR) with AcOH Buffers. Since eq 2
RS
-1
favors 7-(OMe,SR), k could not be obtained from the above
RS
kinetic experiments. Instead, k was determined by generat-
ing 7-(OMe,SR) in MeOH and then injecting it into AcOH
-1
(9) See paragraph concerning Supporting Information at the end of this
paper.
(8) Bernasconi, C. F.; Oliphant, N., unpublished results.

Reactions of Methoxybenzylidene Meldrum’s Acid
J. Am. Chem. Soc., Vol. 120, No. 30, 1998 7463
Figure 3. Conversion of 7-(OMe,SR) (R ) n-Bu) to 5-OMe and 5-SR
according to eq 7 in BuSH/BuS- buffers at pH 11.10 in 50% DMSO-
Figure 2. Spectra of various species derived from 5-OMe, [5-OMe]o
) 7.0 × 10-5 M. (a) 5-OMe in CH3CN; (b) 7-(OMe,SR) with R )
HOCH2CH2 in 50% DMSO-50% water; (c) 7-(OMe,OR) with R )
CF3CH2 in 50% DMSO-50% water; (d) 5-SR with R ) HOCH2CH2
in 50% DMSO-50% water.
50% water at 20 °C. kobsd given by eq 8, which simplifies to kobsd
)
kR2 S at high [RS-].
treating KR1 S as an unknown in a curve fit to eq 8. At high
[RS-], the KR1 S[RS-] term becomes quite large, especially with
buffers in 50% DMSO. Under these conditions, the [RS-] in
the more basic thiolate ions and eq 8 simplifies to kobsd
)
the solution is very small and in eq 3, kRS . k1RS[RS-]. kobsd
kR2 S, as is apparent from Figure 3.
-1
was determined at pH of 5.5-6.7 (or 7.10 for R ) n-Bu) at
When R ) HOCH2CH2, HPLC analysis allowed 5-SR to be
separated from 6-; the UV spectrum of 5-SR was virtually
identical to that of an authentic sample of 5-SMe.10
∼10-3 to 4 × 10-2 M [AcOH]. Buffer dependence was
+
insignificant. A slight dependence on aH according to eq 4
Reaction of 5-OMe with RO-. For the reaction of 5-OMe
with CF3CH2O- and HCtCCH2O-, kobsd was determined in
the stopped-flow apparatus. It strongly depends on [RO-], and
the UV spectrum of the species formed (c in Figure 2) is
consistent with 7-(OMe,OR); the spectrum was obtained after
generating 7-(OMe,OR) in MeOH and injecting it into 50%
DMSO in order to avoid contamination by 6-. Hence, the
kinetic data refer to eq 9. One difference between the reactions
kobsd ) k-RS1 + kRSHaH
(4)
+
-1
RS
k
+ kR-S1HaH+
-1
7-(OMe,SR)
8 5-OMe + RS- (RSH) (5)
implies acid-catalyzed loss of RS- (eq 5). Only when R )
n-Bu was this dependence strong enough to allow determination
RSH
of a k
value (1.9 × 105 M-1 s-1). The k-RS1 values are
-1
reported in Table 1.
kR1 O[RO ]
-
Collapse of 7-(OMe,SR) to Products. The intermediate to
5-OMe + RO- y
z 7-(OMe,OR)
(9)
products conversion is much slower than the kR1 S and kRS steps
RO
k
-1
-1
and should, in principle, be measurable by following formation
of 5-SR, eq 6, under conditions that favor 7-(OMe,SR) over
of RS- and RO- is that RO- is slower, and at low [RO-], OH--
promoted hydrolysis of 5-OMe competes. Hence, kobsd is given
kR2 S
RO
7-(OMe,SR) 8 5-SR + MeO- (MeOH)
(6)
by eq 10; k is negligible under the experimental conditions.
-1
5-OMe in eq 2. However, even then a competition by substrate
hydrolysis affects the rate of 5-SR formation. This is due to
the interconnectedness of the various processes shown in eq 7;
kobsd ) k1RO[RO-] + kOH[OH-]
(10)
Plots of kobsd - kOH[OH-] vs [RO-] yield the kR1 O values
reported in Table 1 (cf. Figure 3S9). For CF3CH2O-, the
[CF3CH2O-] was corrected for the homoassociation constant
(Kassoc ) 1.8 M-1).3a
Reaction of 7-(OMe,OR) with Et3N Buffers. 7-(OMe,OR)
generated in MeOH was injected into Et3N buffers in 50%
DMSO, pH 10.5. The dimethoxy adduct, 7-(OMe,OMe), was
-
kH2O + kOH[OH ]
KR1 S[RS ]
kR2 S
-
6- 7
5-OMe y
z 7-(OMe,SR) 8 5-SR
(7)
note that on the time scales of the hydrolysis and the kR2 S step
the equilibrium of the reaction of 5-OMe with RS- is rapidly
established and hence KR1 S replaces kR1 S and kRS. kobsd for the
-1
RO
-1
concurrent formation of 6- and 5-SR is given by eq 8.
kobsd ) k
(11)
K1RS kR2 S[RS-] + kH O + kOH[OH-]
2
included in these experiments. Under these conditions, kobsd is
given by eq 11; for [Et3NH+] ) 0.007-0.065 M buffer catalysis
kobsd
)
(8)
1 + KR1 S[RS-]
was negligible. Equation 11 is valid even though kR1 O[RO-] is
RO
-1
A representative plot of kobsd vs [RS-] according to eq 8 is
shown in Figure 3. Equation 8 can be solved for the unknown
kR2 S; in view of the highly accurate KR1 S values determined from
not negligible compared to k because, under the reaction
conditions, k1OH[OH-] . kR1 O[RO-]. Hence, 5-OMe formed by
(10) Bernasconi, C. F.; Ketner, R. J.; Chen, X.; Rappoport, Z.,
unpublished observations.
the kR1 S/kRS ratios, this procedure gives a more reliable kR2 S than
-1

7464 J. Am. Chem. Soc., Vol. 120, No. 30, 1998
Bernasconi et al.
the loss of RO- from 7-(OMe,OR) cannot revert back to
7-(OMe,OR) since it is immediately hydrolyzed.
Why Are No Intermediates Detectable in the Hydrolysis
Reactions? On the basis of the kR1 O values for RO- addition
to 5-OMe one would expect kO1 H for OH- addition to be very
high. If the K1OH/K1RO ratio (R ) CF3CH2) ) 2.45 × 103 for
5-H12 can serve as a guide, KO1 H for 5-OMe may be e1.7 × 108
Discussion
Detection of Intermediate and Kinetic Analysis. Our major
objective was to try to detect the SNV intermediate in the
reaction of 5-OMe with nucleophiles and to determine the rate
constants of eq 1. On the basis of the evidence above, the
corresponding intermediates were shown to accumulate to
detectable levels in the reactions with RS- and RO- but not in
those with OH- or H2O. All rate constants (kNu,kNu,kN2 u) were
1
-1
determined for three RS- ions, while only kN1 u and kNu could be
-1
measured for the reactions with one RS- and the RO-.
Why the intermediate was not always observed, and only
partial kinetic analysis was sometimes possible when it was
detectable, is best understood by considering the rate and
equilibrium constants summarized in Table 1. Three conditions
must be met simultaneously for the intermediate to accumulate
to detectable levels.2b (1) The equilibrium of the first step must
be favorable, eq 12. (2) The intermediate must be formed faster
M-1; i.e., the conditions of eq 12 are amply met. Using the
RO
statistically corrected k for MeO- expulsion from 5-(OMe,-
-1
OMe) (6.1 × 10-6 s-1) as approximation for the collapse rate
constant of 7-(OMe,OH) to 5-OH, one obtains kO1 H/k2OH ≈ 5.41
× 102/6.1 × 10-6 ) 8.87 × 107 M-1. This easily meets the
condition of eq 13 even at relatively low pH.
Since the condition of both eqs 12 and 13 is met, 7-(OMe,-
OH) is not detectable because there must be other pathways
that convert it to products that are considerably faster than the
kO2 H step and not available for the collapse of the intermediates
in the reactions with RS- or RO-. One such pathway is a direct
intramolecular acid-catalyzed conversion of 7-(OMe,OH) to 6-
and MeOH via transition state 8. The other involves equilibrium
deprotonation of 7-(OMe,OH) to 7-(OMe,O)-, which accelerates
formation of 6- due to the “push” provided by the O- group.
Our results require that either one or both of these additional
pathways cause the fast product formation in basic solution.
The fast conversion of 7-(OMe,OH) also implies that the
nucleophilic addition is rate limiting for the overall reaction,
KN1 u[Nu-] J 1
(12)
(13)
kN1 u[Nu-]/kN2 u J 1
than it converts to products, eq 13. (3) The kN2 u value must be
low enough to allow detection of the intermediate, e.g., by
conventional or stopped-flow spectrophotometry. The third
condition is met for all our reactions. As to the first, K1Nu
)
1.71 × 103 to 4.35 × 106 M-1 for reactions where the
intermediate was observed, indicating that mostly eq 12 does
not even require very high [Nu-]. The least favorable case is
the reaction with MeO2CCH2S- for which [RS-] ) 5.85 × 10-4
M is needed. Similarly, where data are available, the second
i.e., kOH ) kOH. Arguments similar to those discussed before13
1
suggest that for the water reaction, too, nucleophilic addition is
rate limiting; i.e., kH O ) kH O
.
2
condition is amply met since always kN1 u/k2Nu > 2 × 108 M-1
.
2
1
The hydrolysis product is present as the anion 6- at pH >1
but at pH <1 it is protonated (pKa ) 1.06). The red shift (Figure
1) indicates oxygen rather than carbon protonation; i.e., enol
5-OH is thermodynamically more stable than ketone 6 and pKa-
(6) < pKa(5-OH). This is reasonable since the CH pKa of 10
It is safe to assume that the kN1 u/k2Nu ratio for the reaction of
5-OMe with MeO2CCH2S- is in the same range and hence
kN2 u should, in principle, be experimentally accessible. How-
ever, kN2 u values could not be determined due to the fast
hydrolysis of 5-OMe which becomes the major pathway in eq
7; i.e., in eq 8 KR1 S kRS[RS-] < kH O + kOH[OH-] even at high
2
2
[RS-].
The absence of kN2 u values in the reactions of 5-OMe with
RO- has a similar origin. The complete reaction scheme is
shown in eq 14. In the reaction of 7-(OMe,OR) with Et3N
–
10
10
-
kH2O + kOH[OH ]
kR1 O[RO ]
-
6- 7
5-OMe y
z
RO
k
-1
kR2 O
7-(OMe,OR) 8 5-OR + MeO- (MeOH) (14)
–
4-OH
9
9
buffers, the intermediate may partition into both 5-OMe and
in water is 2.95,14 and anion stabilization in 6- is far greater
than in 10-. This contrasts with 9-, the hydrolysis product of
4-OMe, which is protonated on carbon to form 9 rather than
4-OH.13
Structure-Reactivity Relationships. (A) Formation of the
Intermediate. Comparison between 5-OMe and 5-H. Table
1 summarizes rate and equilibrium constants for the reactions
of 5-OMe and 5-H.12 We focus attention on the nucleophiles
5-OR with kobsd ) kRO + k2RO. However, we expect that k2RO
,
-1
kR-O1 since MeO- is a much worse nucleofuge than RO- and the
push provided by the RO group left behind (kR2 O step) is
RO
weaker than that by the MeO group left behind in the k
-1
step.11 On mixing 5-OMe with RO-, depletion of 7-(OMe,-
OR) via hydrolysis of 5-OMe is faster than its conversion to
products and hence kR2 O, again, remains inaccessible.
(11) The statistically corrected rate constant for MeO- expulsion from
(12) Bernasconi, C. F.; Ketner, R. J. J. Org. Chem., in press.
(13) Bernasconi, C. F.; Fassberg, J.; Killion, R. B., Jr.; Schuck, D. F.;
Rappoport, Z. J. Am. Chem. Soc. 1991, 113, 4937.
(14) Bernasconi, C. F.; Leonarduzzi, G. D. J. Am. Chem. Soc. 1980,
102, 1361.
7-(OMe,OMe), 0.5 × 1.22 × 10-5 s-1, is 170-fold lower than k-RO1 for
HCtCCH2O- expulsion from 7-(OMe,OR) and 2600-fold lower than
RO
-1
k
for CF3CH2O- expulsion. Because of the reduced push, kR2 O for
7-(OMe,OR) should be even lower than 0.5 × 1.22 × 10-5 s-1
.

Reactions of Methoxybenzylidene Meldrum’s Acid
J. Am. Chem. Soc., Vol. 120, No. 30, 1998 7465
HOCH2CH2S-, CF3CH2O-, and HO- used with both substrates.
The following features are noteworthy.
(1) For addition of HOCH2CH2S-, both KRS and k1RS are
1
much smaller for 5-OMe than 5-H, with KR1 S(5-OMe)/
KR1 S(5-H) ) 4.78 × 10-7 and k1RS(5-OMe)/kR1 S(5-H) ) 3.06 ×
10-3, respectively. The most important factors that may affect
the relative reactivity of 5-OMe and 5-H toward nucleophiles
are steric crowding in the intermediate, reactant stabilization
by π-donation (11), the inductive/field effect of the OMe group,
Figure 4. Brønsted plots for the reactions of 5-OMe with thiolate ions.
b, log KR1 S; 2, log k1RS; 9, log kRS
.
-1
and anomeric stabilization15 of the intermediate. The first two
factors should reduce KR1 S and kR1 S for 5-OMe relative to 5-H,
and the third and fourth factors should increase them, although
the anomeric effect is probably only significant with RO-
nucleophiles. The lower rate and equilibrium constants for
5-OMe compared to 5-H are thus ascribed to the combined
contributions of the π-donor and steric effects which more than
offset the inductive/field and anomeric effects. Similar results
have been reported for the reactions of 4-OMe and R-nitrostil-
bene (4-H) with RS-.2b,18
(2) The kR1 O and K1RO values for CF3CH2O- addition to
5-OMe are somewhat smaller than for addition to 5-H:
kR1 O(5-OMe)/k1RO(5-H) ) 5.22 × 10-2, K1RO(5-OMe)/KR1 O(5-H)
) 1.42 × 10-2. These ratios are much larger than for the
HOCH2CH2S- reaction; i.e., replacing H with MeO is less
detrimental than in the thiolate reaction. This is attributed to a
combination of reduced steric hindrance, by the smaller nu-
cleophilic atom, and to a strong stabilization of the intermediate
and transition state by the anomeric effect.15
Figure 5. Brønsted plots for the reactions of 5-OMe with alkoxide
ions and OH-. b, log K1RO; 2, log k1RO; 4, log k1OH; 9, log kRO
.
-1
(3) kH1 O is slightly lower for OH- addition to 5-OMe than to
5-H: kH1 O(5-OMe)/kH1 O(5-H) ) 0.30. This ratio is very similar
to the kR1 O(5-OMe)/kR1 O(5-H) ratio for CF3CH2O- (0.0522)
discussed above and reflecting again the reduced steric effect
compared to the thiolate reactions, combined with the anomeric
effect.
Table 2. Brønsted Parameters and Intrinsic Rate Constants for the
Reactions of Thiolate and Alkoxide Ions with 5-OMe and 5-H
parameter
5-OMe
5-Hc
RS- as Nucleophiles
0.17 ( 0.01
ânuc
â1g
âeq
0.17
-0.72
0.89
0.19
-0.81
-0.59 ( 0.04
0.76 ( 0.05
(B) Brønsted Parameters and Intrinsic Rate Constants.
Brønsted plots for the reaction with RS- are shown in Figure
4, for the reaction with RO-, including OH-, in Figure 5. The
Brønsted parameters are summarized in Table 2, which includes
corresponding parameters for 5-H and normalized Brønsted
coefficients and intrinsic rate constants. The former were
obtained as the slopes of plots (not shown) of log kN1 u vs log
n
a
0.22 ( 0.01
ânuc
n
a
-0.78 ( 0.01
â1g
âpush
0.75b
log kRo S
3.66 ( 0.03
5.17
RO- as Nucleophiles
ânuc
â1g
âeq
0.51b
0.23
-0.81
1.03
0.22
-0.79
KN1 u (ânnuc) and of log kNu vs log K1Nu (âlng); this gives more
-0.97 ( 0.01
1.48b
-1
accurate values than ânuc/âeq and âlg/âeq, respectively. The
0.34b
n
a
intrinsic rate constants, defined as kN0 u ) k1Nu ) kNu when
ânuc
-1
-0.66b
n
a
â1g
KN1 u ) 1 were obtained by suitable extrapolation of the log
kN1 u vs log KN1 u plots. The following points are of interest.
1.49d
2.86
log kRo O
a ânnuc and ân1g obtained from plots of log k1 and log k-1, respec-
tively, vs log K1; see text. b No standard deviation given because â is
based on two points only. c Reference 12. d No standard deviation given
(15) In the present context, the anomeric effect16 refers to the stabilization
exerted by geminal oxygen atoms,17 e.g., in dialkoxy adducts such as
7-(OMe,OR).
(16) (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.
(17) (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.
(18) Bernasconi, C. F.; Killion, R. B., Jr. J. Am. Chem. Soc. 1988, 110,
7506.
because log kRo O is based on two points only.
(1) âeq for RS- addition to 5-OMe and to 5-H is <1,
indicating that carbon and proton basicities of RS- are not quite
proportional. This is a common pattern in reactions of RS-
with electrophilic vinylic substrates.2a,18 The ânuc (ânnuc) values
for the RS- reactions are quite small and the âlg (âlng) values

7466 J. Am. Chem. Soc., Vol. 120, No. 30, 1998
Bernasconi et al.
RS
-1
which have been “corrected” for differences in the equilibrium
constants arising from different degrees of π-donor, inductive/
field, steric, and anomeric effects on reactants and intermediates
in the various reactions. Hence, if at the transition state these
factors were proportional to bond formation (i.e., a “balanced”
transition state), the intrinsic rate constants should be the same
for all the systems. Their differences indicate “imbalanced”
transition states.20c,25 Specifically, the loss of resonance stabi-
lization of 5-OMe resulting from the π-donor effect is expected
to be farther ahead than bond formation at the transition state.26
The principle of nonperfect synchronization (PNS)27 then
predicts depressed k0RS and kR0 O for 5-OMe relative to 5-H. The
greater steric crowding in the intermediates derived from 5-OMe
may also lower kR0 S and k0RO if the steric effect develops ahead
of bond formation at the transition state.28 There are indications
that steric effects develop early.26c The large intrinsic rate
constant differences for the reactions of 5-OMe and 5-H are
consistent with a steric contribution.
for the reverse reaction (k ) is quite large. This suggests a
transition state with relatively little charge transfer and hence
presumably little bond formation,19 as is typical for this type of
reactions.2a,18
(2) The Brønsted coefficient for the reaction of 5-OMe with
RO- is considered approximate for two reasons. (i) ânuc
,
ânnuc, ân , and âeq are based on two points only (HCtCCH2O-
lg
and CF3CH2O-) because kRO and KR1 O for MeO- addition is
1
not measurable in DMSO/H2O and the negatively deviating OH-
point is not a member of the RO- family (cf. (5) below).
RO
-1
However, k for R ) Me was measurable and hence âlg is
based on three k’s. (ii) The unknown pKa values of HCtCCH2-
OH and MeOH in 50% DMSO had to be estimated.22 Despite
these uncertainties, a comparison of the Brønsted parameters
in the RO- reactions of 5-H and 5-OMe (Table 2) is meaningful
because they were obtained similarly and potential uncertainties
should cancel. We note that ânuc and especially âeq is
substantially larger in the reaction of 5-OMe: âeq is ∼0.45 unit
higher than with 5-H. The exalted ânuc and âeq values for
5-OMe may possibly result from the anomeric effect provided
that stabilization of the resonance structure 13b by stronger
(5) The ko values for the RO- reactions are all substantially
smaller than for the corresponding RS- reactions, i.e., log
k0RO ) 1.49 vs log k0RS ) 3.66 with 5-OMe, and log kR0 O ) 2.86
vs kR0 S ) 5.15 with 5-H. The stronger solvation of RO- than
29,30
of the RS-
undoubtedly contributes to this result. The
partial desolvation of the nucleophile which is typically ahead
of bond formation at the transition state30,31 depresses log ko
more for the RO- reactions. The negative deviation of kO1 H for
OH- addition to 5-OMe from the Brønsted line defined by
CF3CH2O- and HCtCCH2O- (Figure 5) reflects the same
30,32
electron-donating R groups more than offsets the destabilization
of 13a. This would lead to a net stabilization of 7-(OMe,OR)
phenomenon: OH- solvation exceeds RO- solvation
making kO0 H even lower than kR0 O
.
A second factor that may increase ko for the RS- reactions18
is the greater polarizability of the RS- ions which is the major
reason their carbon basicity is generally unusually high relative
to their proton basicity.33,34 In Pearson’s35 terminology, the
reaction of RS- with the vinylic substrate leads to a favorable
soft-soft interaction, compared with a less favorable hard-
soft interaction in the reaction of RO-. If one assumes that the
soft-soft interaction runs ahead of bond formation at the
transition state, the PNS predicts an increase in kR0 S.
(6) The potential contribution by the anomeric effect to log
kN0 u in the reaction of RO- with 5-OMe is insignificant since
the differences, log kR0 S - k0RO are essentially substrate inde-
pendent, i.e., log k0RS - log kR0 O ) 5.17-2.86 ) 2.3 for 5-H
and 3.66-1.49 ) 2.17 for 5-OMe.
with increasing electron donation by R and translate into âeq
>
1.
(3) The kR2 S values for MeO- departure from 7-(OMe,SR) in
the reactions of 5-OMe with RS- increase on increasing
pKRa SH
.
Based only on the two points for MeO2CCH2-
CH2S-and n-BuS-, âpush ) d log k2RS/dpKRa SH ) 0.75. This
value is not precise but is clearly .0. The push results from
the developing resonance in the product (12) which becomes
stronger with increasing basicity of the RS group. The k2RS
value for HOCH2CH2S-, which is larger than kRS for the other
2
two RS-, does not fit into this correlation. This may be
attributed to intramolecular hydrogen-bonding assistance by the
OH group (cf. 14).
(4) The intrinsic rate constants for nucleophilic addition to
5-OMe (log kR0 S ) 3.66, log kR0 O ) 1.49) are substantially
lower than for addition to 5-H (log kR0 S ) 5.15, log k0RO
)
(24) (a) Marcus, R. A. Annu. ReV. Phys. Chem. 1964, 15, 155. (b) Marcus,
R. A. J. Phys. Chem. 1968, 72, 891.
(25) Jencks, D. A.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 7948.
(26) (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.
2.86).23 Intrinsic rate constants are purely kinetic quantities24
(19) This is the traditional interpretation of ânuc or ân 20 However, the
.
nuc
use of ânuc or ânnuc as a measure of transition-state structure has been
questioned.21.
(27) The PNS states that if the development of a product-stabilizing factor
lags behind bond changes or charge transfer at the transition state, ko is
reduced. The same is true if the loss of a reactant-stabilizing factor runs
ahead of bond changes or charge transfer. For product-stabilizing factors
that develop early or reactant-stabilizing factors that are lost late, ko is
enhanced.26.
(20) (a) Leffler, J. E.; Grunwald, E. Rates and Equilibrium of Organic
Reactions, Wiley: New York, 1963; p 128. (b) Kresge, A. J. In Proton-
Transfer Reactions; Caldin, E. F., Gold, V., Eds.; Wiley: New York, 1975;
p 179. (c) Jencks, W. P. Chem. ReV. 1985, 85, 511.
(21) (a) Johnson, C. D. Tetrahedron 1980, 36, 3461. (b) Pross, A. J.
Org. Chem. 1984, 49, 1811. (c) Bordwell, F. G.; Hughes, D. L. J. Am.
Chem. Soc. 1985, 107, 4737.
(28) In the context of the PNS,27 steric crowding is a product-destabilizing
factor which depresses ko if it develops ahead of bond formation.
(29) (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.
(22) The pKa values of HCtCCH2OH and CF3CH2OH in H2O are 13.55
and 12.37, respectively (Ballinger, P.; Long, F. A. J. Am. Chem. Soc. 1960,
82, 795), while the pKa of CF3CH2OH in 50% DMSO-50% H2O is 14.0.3a
Assuming identical pKa(50% DMSO) - pKa(H2O) for HCtCCH2OH and
CF3CH2OH (1.63), we estimate pKa of 15.2 for HCtCCH2OH in 50%
DMSO-50% H2O. Using similar arguments, a pKa of 17.2 has been
estimated for MeOH.3a
(30) Jencks, W. P.; Brant, S. R.; Gandler, J. R.; Fendrich, G.; Nakamura,
C. J. Am. Chem. Soc. 1982, 104, 7054.
(31) Hupe, D. J.; Jencks. W. P. J. Am. Chem. Soc. 1977, 99, 451.
(32) Kresge, A. J. Chem. Soc. ReV. 1973, 2, 475.
(33) Sander, E. G.; Jencks, W. P. J. Am. Chem. Soc. 1968, 90, 6154.
(34) Hine, J.; Weimar, R. D., Jr. J. Am. Chem. Soc. 1965, 87, 3387.
(35) Pearson, R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827.
(23) Even though the uncertainty in ânnuc for the reaction of 5-OMe with
RO- implies an uncertainty in log ko of perhaps as much as (0.5 log unit,
clearly kRo O(5-OMe) < kRo O(5-H).

Reactions of Methoxybenzylidene Meldrum’s Acid
J. Am. Chem. Soc., Vol. 120, No. 30, 1998 7467
smaller than ∆log kP0T, in line with the pattern that the PNS
effect of delayed resonance development is weaker in nucleo-
philic additions to PhCHdCXY than in deprotonation of
RCHXY-type acids.26c,37 A major reason for this attenuation
is that in PhCHdCXY CR is already sp2-hybridized, which
reduces the imbalance.26c,37 Another is steric hindrance in the
intermediate carbanion which precludes it from achieving full
planarity and hence from maximizing the resonance effect.
Table 3. Comparison of Rate and Equilibrium Constants for the
Reactions of 5-OMe and 4-OMe with Selected Nucleophilesa
parameters
5-OMe
4.70d
4-OMe
7.93e
log(5-OMe/4-OMe)i
3.23j
0.53
2.04
1.53
1.35
1.50
4.15
0.83
3.33
2.50
3.04
2.89
3.10
pKCa H
b
2.57 × 104
4.40 × 104
1.71
7.65 × 103
3.90 × 102 f
5.10 × 10-2 f
9.6 × 10-6 f
2.16f
KR1 S, M-1
kR1 S, M-1 s-1
RS
-1
k
, s-1
2.16 × 10-4
kR2 S, s-1
log kRo S
3.66
3.90d
-0.25e
Conclusions
log kPoT
c
9.81 × 104
1.57 × 103
1.60 × 10-2
1.49
1.45 × 104 g
KR1 O, M-1
(1) Stabilization of the intermediate in the reactions of 5-OMe
with RS-, RO-, and OH- is sufficient to render the equilibrium
of the first step favorable. With RS- and RO-, conversion of
the intermediate to products is also slow enough to permit its
direct observation. With OH- the acidity of the OH group in
the intermediate provides faster pathways to products, rendering
the intermediate undetectable.
(2) Comparison of rate and equilibrium constants for nucleo-
philic addition to 5-OMe and 5-H reveals the strong role played
by steric crowding in 7-(OMe,SR) and 7-(OMe,OR), by the
π-donor effect of the methoxy group on the stabilization of
5-OMe and by the anomeric effect in stabilizing (7-OMe,OR)
and 7-(OMe,OH).
0.73g
kR1 O, M-1 s-1
5.03 × 10-5 g
RO
-1
k
, s-1
≈-1.55g
log kRo O
5.41 × 102
6.91 × 10-1 h
kO1 H, M-1 s-1
2.98 × 10-2
2.37 × 10-5 h
kH1 O
2
a RS- ) HOCH2CH2S-; RO- ) CF3CH2O-. b pKaCH refers to
Meldrum’s acid and PhCH2NO2, respectively. c PT, proton transfer from
Meldrum’s acid and PhCH2NO2, respectively, to secondary alicyclic
amines. d Reference 8. e Reference 7. f Reference 2. g Reference 3a.
h Reference 13. i log(5-OMe/4-OMe) refers to ∆log KR1 S ) log
KR1 S(5-OMe) - log KR1 S(4-OMe), ∆log k1RS ) log kR1 S(5-OMe) - log
kR1 S(4-OMe), etc. j pKaCH(PhCH2NO2) - pKCH(Meldrum’s acid).
a
(3) The intrinsic rate constants are lower for addition to
5-OMe than to 5-H, due to the loss of the π-donor effect of the
MeO group being ahead of bond formation at the transition state.
There may also be a steric contribution to the lowering of ko.
(4) The intrinsic rate constants for nucleophilic addition to
5-OMe are higher than for addition to 4-OMe. This reflects
the fact that for the reactions of 5-OMe resonance makes a much
smaller contribution to the stability of the intermediate than in
the reactions of 4-OMe.
(5) MeO- departure from 7-(OMe,SR) is subject to a
significant push by the RS group left behind due to the
developing resonance in the product (12). With R ) HOCH2-
CH2, intramolecular assistance of MeO- departure leads to an
enhanced kR2 S value.
(C) Comparison with the Nitrostilbene System. In Table
3 equilibrium and rate constants and intrinsic rate constants are
compared for the reactions of 5-OMe and 4-OMe. The
following features are of interest.
(1) The equilibrium constants for HOCH2CH2S- and
CF3CH2O- addition are somewhat higher for 5-OMe than for
4-OMe (∆log K1RS ) 0.53, ∆log KR1 O ) 0.83).36 This reflects
the stronger electron-withdrawing effect of the cyclic diester
moiety of 5-OMe compared to the phenylnitro moiety of 4-OMe.
However, the ∆log K1 are much smaller than the ∆pKCH of
a
3.23 between Meldrum’s acid and PhCH2NO2. The rather small
∆log K1 values probably reflect the more severe steric crowding
in the intermediate derived from 5-OMe which depresses its
KR1 S and KR1 O more than for 4-OMe. This is consistent with the
much smaller ∆log KR1 S for the comparison between 5-OMe
and 4-OMe than between 5-H and 4-H (0.53 vs 3.812) where
steric crowding should be weaker, and with the smaller ∆log
KR1 S ) 0.53 than ∆log KR1 O ) 0.83 for the bulkier sulfur
nucleophile.
Experimental Section
Materials. Methoxybenzylidene Meldrum’s acid (5-OMe) was
prepared by reacting a mixture of 1.6 g (11 mmol) of Meldrum’s acid
with 10 g (55 mmol) of trimethyl orthobenzoate for 24 h at 75 °C
under nitrogen. The excess ester was distilled off at 58-62 °C (12
mmHg). Recrystallization of the brown residue from CHCl3-petroleum
ether (bp 60-80 °C) gave white crystals (33% yield), mp 155-6 °C
(dec). Anal. Calcd for C14H14O5: C, 64.11; H, 5.38. Found: C, 63.82;
H, 5.29. 1H NMR (CD2Cl2) δ 1.70 (6H, s, CH3), 3.69 (3H, s, CH3O),
7.50 (5H, m, Ph). Hydroxybenzylidene Meldrum’s acid (5-OH) was
prepared by hydrolyzing 5-OMe in a 2:1 (v/v) DMSO-H2O mixture
in the presence of 0.3 M NaOH. After 2 h, the solution was poured
into water, acidified with HCl, and extracted with ether. The ether
was evaporated, and the white solid obtained was recrystallized from
ether, giving a white powder, mp 114° (dec): 1H NMR (DMSO-d6)
δ1.76 (6H, s, CH3), 7.50 (5H, m, Ph); IR 2300-2800 cm-1 (br, OH).
All other materials were commercial and purified as described
before.12 Reaction solutions were prepared and pH measurements were
performed as described earlier.12
(2) The rate constants for HOCH2CH2S- and CF3CH2O-
addition to 5-OMe are substantially higher than for addition to
4-OMe (∆log kR1 S ) 2.04, ∆log kR1 O ) 3.33). These ∆log
kR1 S and ∆log kR1 O values are larger than the corresponding
∆log KR1 S and ∆log KR1 O values; i.e., the kinetic advantage of
the reactions of 5-OMe over those of 4-OMe exceeds the
RS
-1
RO
-1
thermodynamic advantage. Likewise, the k and k values
are higher for 5-OMe despite the smaller equilibrium constants
RS
-1
RO
-1
(∆log k ) 1.53, ∆log k ) 2.50). This arises from higher
intrinsic rate constants for the reactions of 5-OMe than for the
reactions of 4-OMe (∆log kR0 S ) 1.50, ∆log k0RO ≈ 3.04).
The main reason ko is higher for reactions of 5-OMe is that
resonance contributes less to the stability of the intermediates
than in the reaction of 4-OMe. Since resonance development
lags behind bond formation at the transition state,27 ko for the
4-OMe should be lower. This resembles the deprotonation
In Situ Generation of T-(OMe,SR) and T-(OMe,OR). 5-OMe
was added to an excess of RSH/RS- or ROH/RO- buffers prepared in
MeOH by reacting the respective RSH or ROH with KOMe. The
solutions were quite stable and allowed the taking of absorption spectra
of the respective intermediate. They also were used to measure the
rate of decomposition of the intermediates by injecting small volumes
into the appropriate buffer in 50% DMSO.
behavior of Meldrum’s acid and PhCH2NO2 (∆log k0PT
)
4.15). However, ∆log kR0 S and ∆log kR0 O are substantially
(36) For the definition of ∆log KR1 S, ∆log K1RO, ∆log K1RS, etc., see
footnote i in Table 3.
(37) Bernasconi, C. F. Tetrahedron 1989, 45, 4017.

7468 J. Am. Chem. Soc., Vol. 120, No. 30, 1998
Bernasconi et al.
Product Analysis. Products were analyzed on a Hewlett-Packard
1090M HPLC system. Best separations were achieved with an Alltech
Altima 5 µm, 4.6 mm × 250 mm C18 column, with the following
gradient system: (solvent A) 0.02 M phosphate buffer, pH 6.0; (solvent
B) 40% MeCN; (solvent C) 80% MeCN. From 0 to 1 min, 100% A;
from 1 to 20 min, gradient from 100% A to 100% B; from 20 to 23
min, 100% B; from 23 to 28 min, 100% C. The flow rate was 1.5
mL/min; the effluent was monitored at 255, 285, and 335 nm.
Spectra, pKa of 5-OH and Kinetic Measurements. UV spectra
were obtained on a Hewlett-Packard 8452A diode array spectropho-
tometer. The pKa of 5-OH was determined by standard spectropho-
tometric methodology. Reactions with kobsd < 10-2 s-1 were monitored
on a Perkin-Elmer Lambda 2 spectrophotometer. For reactions with
kobsd > 10-2 s-1, the measurements were performed on an Applied
Photophysics DX.17MV stopped-flow apparatus. Due to the rapid
hydrolysis of 5-OMe, the substrate (in MeCN) was only added a few
seconds prior to firing the stopped-flow apparatus.
Acknowledgment. This research was supported by Grant
CHE-9307659 from the National Science Foundation (C.F.B.)
and a grant from the U.S.-Israel Binational Science Foundation,
Jerusalem (Z.R.). We thank Mrs. Ettie Joseph for preliminary
synthetic work.
Supporting Information Available: Figures 1S-3S (3
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