Acid-catalyzed breakdown of alkoxide and thiolate ion adducts of benzylidene Meldrum's acid, methoxybenzylidene Meldrum's acid and thiomethoxybenzylidene Meldrum's acid

Article abstract of DOI:10.1021/jo991041k

A kinetic study of the acid-catalyzed loss of alkoxide and thiolate ions from alkoxide and thiolate ion adducts, respectively, of benzylidene Meldrum's acid (1-H), methoxybenzylidene Meldrum's acid (1-OMe), and thiomethoxybenzylidene Meldrum's acid (1-SMe) is reported. The reactions appear to be subject to general acid catalysis, although the catalytic effect of buffers is weak and the bulk of the reported data refers to H⁺-catalysis. α-Carbon protonation and, in some cases, protonation of one of the carbonyl oxygens to form an enol compete with alkoxide or thiolate ion expulsion. This rendered the kinetic analysis more complex but allowed the determination of pK(a) values and of proton-transfer rate constants at the α-carbon. In conjunction with previously reported data on the nucleophilic addition of alkoxide and thiolate ions to the same Meldrum's acid derivatives, rate constants for nucleophilic addition by the respective neutral alcohols and thiols could also be calculated. Various structure-reactivity relationships are discussed that help define transition-state structures. Comparisons with similar reactions of alkoxide ion adducts of β-alkoxy-α-nitrostilbenes provide additional insights.

Full text of DOI:10.1021/jo991041k

J . Org. Chem. 1999, 64, 8829-8839
8829
Acid -Ca ta lyzed Br ea k d ow n of Alk oxid e a n d Th iola te Ion Ad d u cts
of Ben zylid en e Meld r u m ’s Acid , Meth oxyben zylid en e Meld r u m ’s
Acid a n d Th iom eth oxyben zylid en e Meld r u m ’s Acid
Claude F. Bernasconi,*,† Rodney J . Ketner,† Shoshana D. Brown,† Xin Chen,‡ and
Zvi Rappoport‡
Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, and
Department of Organic Chemistry, The Hebrew University of J erusalem, J erusalem 91904, Israel
Received J une 29, 1999
A kinetic study of the acid-catalyzed loss of alkoxide and thiolate ions from alkoxide and thiolate
ion adducts, respectively, of benzylidene Meldrum’s acid (1-H), methoxybenzylidene Meldrum’s acid
(1-OMe), and thiomethoxybenzylidene Meldrum’s acid (1-SMe) is reported. The reactions appear
to be subject to general acid catalysis, although the catalytic effect of buffers is weak and the bulk
of the reported data refers to H+-catalysis. R-Carbon protonation and, in some cases, protonation
of one of the carbonyl oxygens to form an enol compete with alkoxide or thiolate ion expulsion.
This rendered the kinetic analysis more complex but allowed the determination of pKa values and
of proton-transfer rate constants at the R-carbon. In conjunction with previously reported data on
the nucleophilic addition of alkoxide and thiolate ions to the same Meldrum’s acid derivatives,
rate constants for nucleophilic addition by the respective neutral alcohols and thiols could also be
calculated. Various structure-reactivity relationships are discussed that help define transition-
state structures. Comparisons with similar reactions of alkoxide ion adducts of â-alkoxy-R-
nitrostilbenes provide additional insights.
In tr od u ction
One aspect of these reactions which has not received
much attention is the acid-catalyzed breakdown of the
intermediate, either toward products or toward reactants.
These processes are shown in eq 2 for the 1-OMe/RSH
We have been engaged in a research program aimed
at improving our understanding of structure-reactivity
relationships in nucleophilic vinylic substitution reactions
(SNV)1 that proceed by the addition-elimination mech-
anism. Our focus has been on reactions where the
intermediate accumulates to detectable levels and allows
a direct kinetic determination of the individual steps in
the mechanism.2 In such systems much more can be
learned about the factors that determine reactivity than
is possible when the intermediate remains at steady-state
levels.
system; note that in this case the microscopic reverse of
the H+-catalyzed breakdown of the intermediate toward
reactants is solvent-assisted nucleophilic attack by the
protonated nucleophile. The possibility of buffer catalysis
will be brought up later.
The processes shown in eq 2 can be studied in experi-
ments where the intermediate is first generated by the
reaction of the vinylic substrate with the anionic nucleo-
phile (Nu-) RS- in this case) in basic solution and then
Recent examples are the reactions of methoxyben-
zylidene Meldrum’s acid, 1-OMe,3 and thiomethoxyben-
zylidene Meldrum’s acid 1-SMe,4 with alkoxide and
thiolate ion nucleophiles. The mechanistic scheme is
(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.
illustrated in eq 1 for the reaction of 1-OMe with a
(2) (a) Bernasconi, C. F.; Fassberg, J .; Killion, R. B., J r.; Rappoport,
Z. J . Am. Chem. Soc. 1989, 111, 6862. (b) Bernasconi, C. F.; Fassberg,
J .; Killion, R. B., J r.; Rappoport, Z. J . Am. Chem. Soc. 1990, 112, 3169.
(c) Bernasconi, C. F.; Leyes, A. E.; Rappoport, Z.; Eventova, I. J . Am.
Chem. Soc. 1993, 115, 7513. (d) Bernasconi, C. F.; Schuck, D. F.;
Ketner, R. J .; Weiss, M.; Rappoport, Z. J . Am. Chem. Soc. 1994, 116,
11764. (e) Bernasconi, C. F.; Leyes, A. E.; Eventova, I.; Rappoport, Z.
J . Am. Chem. Soc. 1995, 117, 1703. (f) Bernasconi, C. F.; Schuck, D.
F.; Ketner, R. J .; Eventova, I.; Rappoport, Z. J . Am. Chem. Soc. 1995,
117, 2719.
(3) Bernasconi, C. F.; Ketner, R. J .; Chen, X.; Rappoport, Z. J . Am.
Chem. Soc. 1998, 120, 7461.
(4) Bernasconi, C. F.; Ketner, R. J .; Chen, X.; Rappoport, Z. Can. J .
Chem. 1999, 77, 584.
thiolate ion.
† University of California.
‡ The Hebrew University.
10.1021/jo991041k CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/26/1999

8830 J . Org. Chem., Vol. 64, No. 24, 1999
Bernasconi et al.
subjected to reaction with an acidic solution. This yields
kH-1 and k2H; k1NuH can be obtained as kN1 uH ) K1NuH k-H1
with KN1 uH being the equilibrium constant for NuH
addition and related by KN1 uH ) KN1 u KNa uH to the known
equilibrium constant for Nu- addition3,4 and the acidity
constant of NuH (KNa uH). Such a study is now reported
for the acid-catalyzed breakdown of alkoxide and thiolate
ion adducts of 1-OMe and 1-SMe, as well as the corre-
sponding adducts of benzylidene Meldrum’s acid, 1-H.5
These latter reactions serve as reference points that allow
an assessment of the effect of the methoxy in 1-OMe and
thiomethoxy groups in 1-SMe on the reactivity of the
respective systems.
Resu lts
Gen er a l F ea tu r es. All kinetic experiments were
performed in 50% DMSO-50% water (v/v) at 20 °C and
conducted under pseudo-first-order conditions, with the
substrates/adducts as the minor component. The adducts
were generated in situ by reaction of a given substrate
with a basic solution of the respective alkoxide or thiolate
ion. In the case of 1-H, the adducts were quite stable;
with 1-OMe and 1-SMe, solutions of the respective
adducts started to decompose within a few minutes,
either as a result of conversion to substitution products
or hydrolysis of the substrate3,4 that is in equilibrium
with the adduct. This made it imperative to initiate the
reaction with acid immediately after the adduct had been
generated. The reactions were monitored spectrophoto-
metrically, exploiting the large differences in the UV
spectra between the intermediates and the reactants or
products.3-5
F igu r e 1. Reactions of 1-(H,OR)- with HCl. Plots of kofabsstd vs
[H+]. 9, R ) Me; b, R ) HCtCCH2.
1-H. A. Alk oxid e Ion Ad d u cts. The adducts, 1-(H,-
OR)- with R ) H, CH3, HCtCCH2, and CF3CH2, were
investigated. When a solution of 1-(H,OR)- was added
F igu r e 2. Reaction of 1-(H,OCH2CF 3) with HCl. Plot of
slow
vs [H+] according to eq 9.
to an HCl solution, two kinetic processes were observed.
The first is associated with partial recovery of 1-H and
k
obsd
fast
obsd
catalyzed RO- departure, k-H1[H+]) and 1-(H,OR)H (pro-
tonation on carbon, kpH[H+]). Under conditions where
is quite fast. Plots of k
vs [H+] are shown for two
cases in Figure 1; the plot for 1-(H,OMe)- is also
representative for 1-(H,OH)-, while the plot for 1-(H,-
OCH2C≡CH)- is also representative for 1-(H,OCH2CF3)-.
The second, slower, process completes the recovery of
(k-1 + kp )[H+] . k-HpO, kobsd is given by eq 4. The very
H
H
fast
2
fast
obsd
k
) (kH-1 + kHp )[H+]
(4)
1-H. For the reaction of 1-(H,OH)- and 1-(H,OMe)-,
slow
obsd
k
is pH-independent between [H+] ) 0.0012-0.16 M,
fast
obsd
small intercepts in the plots of k
vs [H+] for the
whereas for 1-(H,OCH2C≡CH)- and 1-(H,OCH2CF 3)-,
reactions of 1-(H,OMe)- (Figure 1) and 1-(H,OH)- (plot
not shown) indicate that this condition is met over nearly
the entire range of [H+]. However, in the reactions of
1-(H,OCH2C≡CH)- (Figure 1) and 1-(H,OCH2CF 3)-
(not shown), the intercepts are not negligible, indicating
slow
obsd
k
depends non-linearly on [H+]. Figure 2 shows a
representative plot.
These results can be understood on the basis of eq 3.
that the relationship (kH-1 + kpH)[H+] . k-Hp2O is not valid.
fast
obsd
In these cases the expression for k
becomes quite
complex,6 although the slope of these plots may still be
approximated by eq 5.
slope ≈ kH-1 + kHp
The individual k-H1 and kHp values (Table 1) were
(5)
The fast process corresponds to reaction of 1-(H,OR)- with
the hydronium ion, which leads to a mixture of 1-H (acid-
(5) Bernasconi, C. F.; Ketner, R. J . J . Org. Chem. 1998, 63, 6266.
obtained by combining the slopes (eq 5) with eq 6

Acid Catalysis of Meldrum’s Acid Derivatives
J . Org. Chem., Vol. 64, No. 24, 1999 8831
Ta ble 1. Ra te Con sta n ts for H+-Ca ta lyzed RO- Dep a r tu r e fr om 1-(H,OR)- a n d Ca r bon P r oton a tion of 1-(H,OR)- a n d
p KCa H Va lu es of 1-(H,OR)H
kpH
kH-p
k-1
k-1
2O
H
H
a
b
a
e
RO-
pKRa OH
M-1 s-1
s-1
pKCa H
pKCa H
M-1 s-1
M-1 s-1
d
e
HO-
17.3
17.2
15.2
14.0
(1.83 ( 0.01) × 104
(1.27 ( 0.02) × 104
(5.46 ( 0.08) × 103
(2.63 ( 0.12) × 103
37.2 ( 2.4
50.4 ( 1.8
47.0 ( 0.8c
39.9 ( 1.8c
2.69 ( 0.03
2.40 ( 0.03
2.06 ( 0.02
1.82 ( 0.03
(1.33 ( 0.07) × 105
(6.25 ( 0.11) × 104
(5.77 ( 0.09) × 103
(2.11 ( 0.10) × 103
MeO-
HCtCCH2O-
CF3CH2O-
2.34 ( 0.04
1.87 ( 0.04
(5.57 ( 0.39) × 103
(1.40 ( 0.09) × 103
From k
(eqs 4 and 5 combined with eq 6). From kobsd (eq 8). c From plateau at high [H+]. pKCa H ) -log(k-pO/kpH) with kHp from
fast
obsd
slow
H2
a
b
d
fast
2O
k
(eqs 4 and 5 combined with eq 6) and kH-p from kslow (eq 8). e From koslboswd (eq 9).
obsd
obsd
Ta ble 2. Ra te Con sta n ts for H+-Ca ta lyzed RS- Dep a r tu r e fr om 1-(H,SR)- a n d Ca r bon P r oton a tion of 1-(H,SR)- a n d
p KCa H a n d p KOa H Va lu es of 1-(H,SR)H
kpH
M-1 s-1
kH-p
s-1
kH-p
s-1
k-1
M-1 s-1
2O
2O
H
a
d
e
RS-
pKRa SH
11.40 1.39 ( 0.08 ∼2.55
pKOa H
pKCa H
pKCa H
a
b
c
n-Bu-
MeS-
2.07 ( 0.03 (1.90 ( 0.42) × 104
52 ( 40 162 ( 43 28.3 ( 1.0
≈11.0
1.27 ( 0.08
2.09 ( 0.22 2.03 ( 0.03 (1.68 ( 0.34) × 104 135 ( 38 156 ( 43 17.9 ( 0.8
HOCH2CH2S-
MeO2CCH2CH2S-
MeO2CCH2S-
10.56 1.11 ( 0.06
10.40 1.13 ( 0.05
8.83 0.99 ( 0.06
1.90 ( 0.09 1.90 ( 0.04 (1.31 ( 0.15) × 104 166 ( 18 165 ( 39
6.62 ( 0.99
2.61 ( 0.10
0.17 ( 0.04e
1.89 ( 0.11 1.80 ( 0.03 (1.07 ( 0.17) × 104 139 ( 19 168 ( 38
1.50 ( 0.09
(0.93 ( 0.13) × 104 291 ( 19 232 ( 41
fast
obsd
CH
H2
H
2O
fast
slow
H
2O
slow
From k
(eq 11). pKa ) -log(k-pO/kpH) with kpH and k-p from k
(eq 11). c From kobsd (eq 12). k-p ) KaCH kpH with KaCH from k
a
b
d
o
b
s
d
o
b
s
d
(eq 14). e Calculated from eq 14 with KCa H from kfast
.
obsd
Ta ble 3. Su m m a r y of Ra te Con sta n ts for Sp on ta n eou s (k-1) a n d H+-Ca ta lyzed
(kH-1) Br ea k d ow n of 1-(H,OR)- a n d 1-(H,SR)-, for Nu cleop h ilic Ad d ition of ROH a n d RSH to
1-H (kN1 u H), a n d Oth er Releva n t P a r a m eter s
H
k-1
k-1
M-1 s-1
kH-1/k-1
kN1 uH
M-1 s-1
b
c
f
e
nucleophile
pKNa uH
s-1
M-1
pH (50)d
KN1 uH
1-(H,OR)-
H2O
17.33a
17.2
1.57 × 10-7
2.35 × 10-6
4.71 × 10-4
3.25 × 10-3
1.33 × 105
6.25 × 104
5.67 × 103 g
1.75 × 103 g
8.47 × 1011
2.66 × 1010
1.20 × 107
5.38 × 105
11.93
10.42
7.08
5.43 × 10-8 h
j
7.10 × 10-3 i
j
MeOH
HCtCCH2OH
CF3CH2OH
15.2
5.26 × 10-8
2.98 × 10-4
14.0
5.73
6.43 × 10-8
1.13 × 10-4
1-(H,SR)-
n-BuSH
MeSH
HOCH2CH2SH
MeO2CCH2CH2SH
MeO2CCH2SH
11.40
≈11.0
10.56
10.40
8.83
4.25 × 10-5
2.68 × 10-4
3.21 × 10-4
3.35 × 10-3
28.3
17.9
6.62
2.61
0.17
6.66 × 105
5.82
2.34
66.2
2.47 × 104
8.13 × 103
5.07 × 101
4.39
3.91
1.71
1.45
1.86
3.14
9.80
4.85
0.66
Based on pKw ) 15.89; Halle´, J .; Gaboriaud, R.; Schaal, R. Bull. Soc. Chim. Fr. 1970, 2047. Reference 5. c This work. pH for which
a
b
d
kH-1[H+] ) k-1
.
e K1NuH ) KN1 u KNa uH with K1NuH from ref 5. f k1NuH ) K1NuH k-H1
.
Average of the two values reported in Table 1. Obtained by
g
h
dividing observed KN1 uH by [H2O]. Using K1
) 5.43 × 10-8 to define kN1 uH as bimolecular rate constant. Not experimentally
NuH
i
j
measurable in 50% DMSO-50% water.
slow
tion that k
is independent of [H+]. Equation 8 can be
kH-1
kH-1 + kHp
∆ODfast
∆ODtotal
obsd
H2O
)
(6)
solved for k
which is the only unknown.
-p
For the HCtCCH2 and CF3CH2 derivatives, 1-(H,OR)-
cannot be considered a steady-state intermediate except
at the high end of the [H+] range, i.e., where ksolboswd
reaches a plateau (Figure 2). This plateau corresponds
to eq 8. At low [H+] the acid-base equilibrium between
1-(H,OR)- and 1-(H,OR)H no longer favors 1-(H,OR)-
H. If this proton transfer is treated as a rapid equilibrium
where ∆ODfast refers to the change in absorbance associ-
ated with the fast process and ∆ODtotal refers to the
absorbance change corresponding to total recovery of 1-H.
Note that in conjunction with the known5 equilibrium
constant, KN1 uH, for eq 7, kN1 uH for nucleophilic attack on
and kH-1 as the rate-limiting step, we may approximate
KN1 uH
slow
1-H + ROH y z 1-(H,OR)- + H+
(7)
obsd
-p
k
by eq 9, with KCa H ) kH2O/kHp being the acidity
KCa HkH-1[H]+
KCa H + [H+]
1-H by ROH can be obtained as KN1 uH k-H1 (Table 3).
slow
obsd
In regards to the slow process, for 1-(H,OH)- and
1-(H,OMe)- it represents conversion of 1-(H,OR)H to
k
)
(9)
1-H via 1-(H,OR)- as a steady-state intermediate, with
slow
obsd
constant of 1-(H,OR)H. A least-squares curve fit of the
k
given by eq 8. This is consistent with the observa-
slow
obsd
plots of k
vs [H+] according to eq 9 yields k-H1 and
KCa H. As can be seen from the results summarized in
Table 1, the kH-1 values obtained from eq 9 are in good to
excellent agreement with those obtained from eqs 5 and
6; there is also good agreement between the KCa H values
H2O
-p
k
kH-1
slow
obsd
k
)
(8)
kHp kH-1
fast
obsd
slow
obsd
obtained from k
and k
in the case of 1-(H,-
(6) Bernasconi, C. F. Relaxation Kinetics; Academic Press: New
York, 1976; Chapter 3.
OCH2CF 3)H but a somewhat larger discrepancy for the

8832 J . Org. Chem., Vol. 64, No. 24, 1999
Bernasconi et al.
F igu r e 3. Reaction of 1-(H,SR)- (R ) MeO2CCH2CH2) with
F igu r e 4. Reaction of 1-(H,SR)- (R ) MeO2CCH2CH2) with
fast
slow
HCl. Plot of k
vs [H+] according to eq 11.
HCl. Plot of k
vs [H+] according to eq 12.
obsd
obsd
fast to be measurable on the stopped-flow time scale and
propargyl derivative. In view of the approximations that
underlie eqs 5 and 9 in this case, though, the discrepancy
is remarkably small.
acts as a rapid pre-equilibrium preceding protonation on
fast
obsd
carbon. Based on eq 10, k
is given by eq 11; a non-
B. Th iola t e Ion Ad d u ct s. The adducts, 1-(H,SR )-
with R ) CH3, n-Bu, HOCH2CH2, MeO2CCH2CH2, and
MeO2CCH2, were investigated. J ust as is the case for
KOa HkHp [H+]
KOa H + [H+]
fast
obsd
H2O
-p
k
)
+ k
(11)
linear least-squares fit yields the KOa H, kpH and kH2O
-p
values summarized in Table 2.
The slow process can be understood based on Scheme
1 in which both proton transfer equilibria are rapidly
established on the time scale of the conversion of 1-(H,-
slow
obsd
SR)- to 1-H; k
is given by eq 12.
1-(H,OR)-, reaction of 1-(H,SR)- with HCl leads to two
kinetic processes. However, only the second, slower
process brings about recovery of 1-H; there is no increase
in absorbance at 325 nm (λmax of 1-H) associated with
the first, faster process, which simply leads to protonation
of the adduct. There are also important differences in the
kinetic results for the thiolate adducts compared to the
KOa HKCa H
k
)
(k-1 + kH-1[H+])
slow
obsd
KOa HKCa H + (KaOH + KaCH)[H+]
(12)
We shall first discuss the results for 1-(H,SR)- with
R ) n-Bu, Me, HOCH2CH2, and MeO2CCH2CH2 for which
alkoxy adducts.
slow
obsd
vs [H+] are as shown in Figure 4. These
fast
obsd
the plots of k
Figure 3 shows a plot of k
vs [H+] for the reaction
plots are consistent with k-1 , kH-1[H+] which reduces
of 1-(H,SCH2CH2CO2Me)-; it is representative for the
eq 12 to eq 13 at low [H+] and to eq 14
fast process with all five adducts. The second reaction is
several orders of magnitude slower. Figure 4 displays a
slow
obsd
slow
k
) kH-1[H+]
(13)
(14)
plot of k
vs [H+] for the reaction of the same adduct,
obsd
which is also representative for R ) n-Bu, CH3, HOCH2-
CH2, and MeO2CCH2CH2. With R ) MeO2CCH2 no
satisfactory data could be obtained at [HCl] < 0.1 M
KOa HKCa H
slow
obsd
k
)
kH-1
KOa H + KCa H
because the absorbance changes were too small; at [HCl]
slow
obsd
at high [H+]. The k-H1 and KCa H values obtained by fitting
the data to eq 14 are summarized in Table 2. For the
MeS, HOCH2CH2S, and MeO2CCH2CH2S derivatives the
) 0.1-0.5 M k
was measurable and showed no
dependence on [H+].
We offer the following interpretation. The fast process
is consistent with eq 10 where protonation occurs both
KCa H values obtained from kfast (as pKaCH ) -log(kH2O
/
-p
obsd
kHp )) and from kslow are in remarkably good agreement.
obsd
However, for the n-BuS derivative the agreement is poor.
This is not surprising because of the very large uncer-
H2O
-p
tainty in the k
value used to calculate pKCa H in this
H2O
case. For this reason k
calculated as KCa HkpH with
-p
slow
obsd
pKCa H from k
will be taken as the correct value for the
on carbon and oxygen; the protonation on oxygen is too
n-BuS derivative.

Acid Catalysis of Meldrum’s Acid Derivatives
J . Org. Chem., Vol. 64, No. 24, 1999 8833
Sch em e 1
Sch em e 2
For the MeO2CCH2S derivative the absence of data for
slow
k
at low [H+] precludes a determination of pKCa H and
obsd
kH-1, although it seems clear that the kslow values at [H+]
obsd
) 0.1-0.5 M are consistent with eq 14. Using pKaCH
obtained from kofabsstd, eq 14 can be solved for k-H1 as the
only unknown.
J ust as for the reaction of 1-(H,OR)-, the k-H1 values
allow calculation of kN1 uH ) K1NuH k-H1 (Table 3) for
nucleophilic attack on 1-H by RSH because the equilib-
rium constants for thiol addition, KN1 uH, are known from
a previous study.5
A referee has raised the possibility of a competing
pathway which converts 1-(H,SR)Henol directly into 1-H.
This would add a term to eq 12 to yield eq 15 with k′
-1
Sch em e 3
KOa HKCa H
KOa HKCa H + (KaOH + KaCH)[H+]
KCa H[H+]
kobsd
)
(k-1 + kH-1[H+]) +
k′ (15)
-1
KOa HKCa H + (KaOH + KaCH)[H+]
being the rate constant for direct conversion of 1-(H,-
SR)Henol to 1-H. Hence what is reported as kH in Table
-1
2 would take on the meaning of kH-1 + k′ /KaOH. For the
-1
k′ pathway to contribute equally to the reaction as the
-1
kH-1 pathway, the relationship k′ ) KOa H k-H1 would have
-1
to hold. Because the KOa H values are on the order of
0.05-0.1 (Table 2) this would require k′ to be not less
-1
quenching of any of these adducts with HCl generated
one fast kinetic process followed by one or two much
slower reactions. The slow processes were shown to
represent the previously reported3,4 hydrolysis of the
respective products of the fast process, i.e., 1-OMe, 1-OR,
or 1-SR (see Schemes 2-4).
than 5-10% of kH-1. In view of the absence of a negative
charge on 1-(H,SR)Henol which in 1-(H,SR)- provides the
main driving force of the reaction, such a high value for
k′ seems unlikely.
-1
1-OMe a n d 1-SMe. Alk oxid e a n d Th iola t e Ion
Ad d u cts. The following adducts were investigated: 1-(O-
Me,OR)- with R ) CH3, HCtCCH2, and CF3CH2;
1-(OMe,SR)- with R ) n-Bu, CH3, HOCH2CH2, MeO2-
CCH2CH2, and MeO2CCH2; and 1-(SMe,SMe)-. The
fast
obsd
For the fast process, plots of k
vs [H+] are curved
in most cases, as shown in Figure 5 for two representative
examples. This observation is consistent with concurrent
H+-catalyzed loss of both leaving groups from the respec-
tive intermediate; protonation on carbon acts as a fast
pre-equilibrium, which is the cause of the downward
curvature in the plots (Figure 5). This is shown in
Schemes 2, 3, and 4, respectively, for the various cases.
Note that in Scheme 4 a statistical factor of 2 is

8834 J . Org. Chem., Vol. 64, No. 24, 1999
Bernasconi et al.
Sch em e 4
1-SR (t1/2 ≈ 68.7 h).4,8 The change in absorbance at 270
nm that resulted from this hydrolysis provided a measure
of the amount of 1-OMe that had been generated in the
reaction of 1-(OMe,SR)- with HCl. This allowed a
determination of the kH2 /k-H1 ratios and in conjunction
with kH-1 + kH2 afforded k-H1 and kH2 individually (Table 4).
The large experimental uncertainty associated with the
kH-1 values is the result of the rather small amounts of
1-OMe formed in the reaction.
For the reactions shown in Scheme 2 with R * CH3
the above methodology could not be used to determine
kH-1 and kH2 individually. HPLC analysis, which was
successfully applied for such purpose in the reactions of
acid with alkoxide ion adducts of â-methoxy-R-
nitrostilbene,2f could not be used here either because the
hydrolysis of 1-OR and 1-OMe is too fast (t1/2 ) 23 s for
1-OMe and shorter for 1-OR). However, for the case R
) CH3, kH ) kH2 could be obtained just as is the case for
-1
the reaction of Scheme 4.
A few selected experiments were also conducted in
acetate buffers ranging in pH from 4.7 to 6.8. The adducts
subjected to this study were of the type 1-(OMe,SR)-
with R ) n-Bu, MeO2CCH2CH2, and MeO2CCH2. Buffer
catalysis was weak at [AcOH] e 0.04 M and typically
amounted to less than 7% increase in kobsd at the highest
concentration.
F igu r e 5. Reactions of 1-(OMe,OMe)- (O) and 1-(SMe,SMe)-
fast
(b) with HCl. Plots of k
vs [H+] according to eq 15
obsd
(1-(OMe,OMe)-) or eq 16 (1-(SMe,SMe)-).
included to render the kH-1 value comparable to k-H1 in
Scheme 3 when making structure-reactivity compari-
Discu ssion
sons.
fast
obsd
Mech a n ism of Acid Ca ta lysis. Acid catalysis of
alkoxide ion departure from addition complexes between
electrophiles and alkoxide or hydroxide ions has fre-
quently been observed.2b,9-11 These reactions are typically
subject to general acid catalysis. The weak catalysis of
MeO- departure from 1-(OMe,SR)- by acetic acid and
results reported previously for the reactions of 1-(H,OR)-
(R ) HCtCCH2 and CF3CH2) with Et3NH+ 5 also indicate
general acid catalysis. This kind of catalysis has generally
been interpreted in terms of a concerted mechanism12
with a transition state such as 2 shown for the break-
The expression for k
for Schemes 2 and 3 is given
by eq 15, and for Scheme 4 it is given by eq 16.
KCa H
KCa H + [H+]
k
)
(kH-1 + kH2 )[H+]
(15)
(16)
fast
obsd
KCa H
fast
obsd
k
) 2
kH-1[H+]
KCa H + [H+]
Non-linear least-squares fit of the data to eqs 15 and 16
yielded kH-1 + k2H (Schemes 2 and 3) and k-H1 (Scheme 4),
respectively. In cases where curvature is strong, a value
for KCa H was also obtained; in situations where the
curvature is weak, no KaCH values are reported because
of large experimental uncertainty.
In the reactions described by Scheme 3 the spectra of
the solutions at the end of the reaction showed that the
main species formed was 1-SR (λmax ) 335 nm4,7), with
smaller amounts of 1-OMe (λmax ) 272 nm).3 This implies
kH2 > kH-1. Because of considerable overlap of the spectra
of 1-SR and 1-OMe, no precise kH2 /k-H1 ratio could be
determined from an analysis of these spectra. However,
kH2 /kH-1 ratios were obtained by exploiting the fact that
1-OMe hydrolyzes much more rapidly (t1/2 ≈ 23 s)3 than
down of 1-(H,OR)- catalyzed by a buffer acid BHν+1 and
3 for H3O+ as the catalyst.14 Evidence presented below
(8) t1/2 ≈ 68.7 h refers to the hydrolysis of 1-SMe.
(9) J encks, W. P. Chem. Rev. 1985, 85, 511 and numerous references
therein.
(10) (a) Bernasconi, C. F. Tetrahedron 1989, 45, 4017 and numerous
references therein. (b) Bernasconi, C. F.; Fassberg, J . J . Am. Chem.
Soc. 1994, 116, 514.
(11) Bernasconi, C. F.; Fassberg, J .; Killion, R. B., J r.; Schuck, D.
F.; Rappoport, Z. J . Am. Chem. Soc. 1991, 113, 4937.
(12) This mechanism is usually referred to as a class n mechanism.13
(13) J encks, W. P. Chem. Soc. Rev. 1981, 10, 345.
(7) λmax is virtually independent of the R group.

Acid Catalysis of Meldrum’s Acid Derivatives
J . Org. Chem., Vol. 64, No. 24, 1999 8835
Ta ble 4. Ra te Con sta n ts for H+-Ca ta lyzed RO- a n d RS- Dep a r tu r e fr om Va r iou s Ad d u cts a n d
p KCa H Va lu es of Som e Ad d u cts
kH-1 + kH2
kH-1
k2H
adduct
1-(OMe,OMe)-
pKNa uH
M-1 s-1
M-1 s-1
M-1 s-1
pKCa H
17.2a
(1.77 ( 0.05) × 105
(3.02 ( 0.08) × 104
(4.02 ( 0.40) × 103
(1.97 ( 0.40) × 105
(7.55 ( 0.10) × 104
(3.39 ( 0.10) × 104
(8.85 ( 0.25) × 104
1.97 ( 0.03
(-MeOH)
1-(OMe,OCH2C≡CH)-
1-(OMe,OCH2CF 3)-
1-(OMe,SBu )-
15.2a
14.0a
11.40b
1.78 ( 0.02
1.18 ( 0.10
(2.7 ( 0.8) × 104
(-BuSH)
(1.70 ( 0.48) × 105
(-MeOH)
1-(OMe,SMe)-
≈11.0b
10.56b
(8.9 ( 2.0) × 103
(-MeSH)
(7.00 ( 0.30) × 104
(-MeOH)
1-(OMe,SCH2CH2OH)-
(5.9 ( 1.1) × 103
(-HOCH2CH2SH)
(2.80 ( 0.26) × 104
(-MeOH)
1-(OMe,SCH2CH2CO2Me)-
1-(OMe,SCH2CO2Me)-
10.40b
8.83b
(2.81 ( 0.45) × 104
(6.83 ( 1.31) × 103
(2.2 ( 0.7) × 103
(-MeO2CCH2SH)
(5.80 ( 0.20) × 102
(-MeSH)
(4.6 ( 2.0) × 103
(-MeOH)
1-(SMe,SMe)-
≈11.0b
(1.16 ( 0.04) × 103
a
b
NuH ) ROH. NuH ) RSH.
Ta ble 5. Su m m a r y of Ra te Con sta n ts for Sp on ta n eou s (k-1) a n d H+-Ca ta lyzed (k-H1 a n d
kH2 ) Br ea k d ow n of 1-(OMe,OMe)- a n d 1-(OMe,SR)-, for Nu cleop h ilic Ad d ition of MeOH a n d RSH to 1-OMe
(kN1 u H), a n d Oth er Releva n t P a r a m eter s
k-1
kH-1
kH-1/k-1
a
pKNa uH
s-1
M-1 s-1
M-1
pH (50)c
KN1 uH
d
Nu
MeOH
n-BuSH
HOCH2CH2SH
MeO2CCH2SH
17.2
6.1 × 10-6 g
8.85 × 104 g
2.7 × 104
5.9 × 103
2.2 × 103
1.45 × 1010
6.84 × 104
3.45 × 103
1.57 × 102
10.2
4.83
3.54
2.20
11.40
10.56
8.83
0.395
6.77 × 10-7
7.08 × 10-7
2.53 × 10-6
1.71
14.0
kN1 uH
M-1 s-1
k2
s-1
k2H
kH/k2
e
a
b
2
Nu
M-1 s-1
M-1
pH (50) f
n-BuSH
HOCH2CH2SH
MeO2CCH2SH
1.83 × 10-2
4.18 × 10-3
5.57 × 10-3
1.11 × 10-4
1.7 × 105
2.8 × 104
4.6 × 103
1.5 × 109
9.18
8.11
2.16 × 10-4
1.3 × 108
H
Reference 3. This work. c pH for which k-1 [H+] ) k-1
.
KN1 uH ) K1Nu KNa uH with K1Nu from ref 3. e k1NuH ) K1NuH k-H1
.
f pH for which
a
b
d
H
k2 [H+] ) k2. Statistically corrected.
g
suggests that, at least for 3, proton transfer to the RO
group is more advanced than C-O bond cleavage, as
represented by the position of the transferred proton and
the placement of a partial positive charge on the RO
oxygen in 3. Note that by virtue of the principle of
microscopic reversibility, 2 and 3 are also the transition
states for general base-catalyzed and water-catalyzed,
respectively, nucleophilic attack by the neutral alcohol.
Acid catalysis of thiolate ion departure or its micro-
scopic reverse, addition of thiols, has not been reported
as often. Examples include the reactions of PhS-/PhSH
with 1-chloro-2,4,6-trinitrobenzene in methanol-water
mixtures15 and with 7-halogeno-4-nitrobenzofurazan16 in
methanol and the reactions of HOCH2CH2S-/HOCH2CH2-
SH with the tri-p-anisylmethyl cation in water.17 It is
likely that the mechanism is the same as for the alcohol
reactions.
catalysis can be detected. This pH range is determined
by the kH-1/k-1 ratios, with k-1 referring to spontaneous
loss of the leaving group. The acid-catalyzed process
contributes 50% to the overall rate when kH-1[H+]/k-1
)1. From the kH-1/k-1 ratios summarized in Table 3 (1-
(H,OR)- and 1-(H,SR)-) and Table 5 (1-(OMe,SR)-) we
can deduce that acid catalysis contributes 50% to the rate
at much higher pH values for alkoxide than for thiolate
ion loss (“pH(50)” columns in Tables 3 and 5).18 Hence,
unless experiments are conducted at rather low pH, acid
catalysis remains undetected. The lower kH-1/k-1 ratios
for thiolate ion departure are the combined result of a
lower sensitivity to acid catalysis due to the lower proton
basicity of thiolate compared to alkoxide ions and the
higher rate constants for spontaneous loss (k-1) of thiolate
compared to alkoxide ions.
Kin et ic a n d Th er m od yn a m ic St a b ilit ies of 1-
(OMe,SR )- vs 1-(H,SR )- a n d of 1-(OMe,OMe)- vs
1-(H,OMe)-. The k-H1 values for the H+-catalyzed loss of
thiolate ions are substantially larger for 1-(OMe,SR)-
(Table 5) than for 1-(H,SR)- (Table 3), with
kH-1(1-OMe,SR)-/kH-1(1-H,SR)- ratios ranging from ca.
The reason why acid catalysis of thiolate ion departure
or its microscopic reverse has not been reported as
frequently as for alkoxide ion or OH- expulsions is
related to the narrower pH range within which such
(14) As pointed out by a referee, the H3O+-catalyzed reaction could
alternatively be stepwise, involving pre-equilibrium protonation of the
leaving group by H3O+ followed by carbon-heavy atom bond cleavage.
We prefer the concerted mechanism (3) because of its similarity to the
mechanism of buffer catalysis.
103 to 104. This largely reflects the much smaller equi-
librium constants, KN1 uH, for RSH addition to 1-OMe
(Table 5) compared to 1-H (Table 3), with KN1 uH(1-OMe)/
(15) Forlani, L. J . Chem. Res. (S) 1992, 376.
(16) de Rosso, M. D.; Di Nunno, L.; Florio, S.; Amorese, A. J . Chem.
Soc., Perkin Trans. 2 1980, 239.
(18) A similar approach to this problem has been discussed by
J ensen and J encks19 for the acid-catalyzed hydrolysis of benzaldehyde
O,S-acetals. We are indebted to a referee for pointing this out.
(17) Ritchie, C. D.; Gandler, J . R. J . Am. Chem. Soc. 1979, 101, 7318.

8836 J . Org. Chem., Vol. 64, No. 24, 1999
Bernasconi et al.
F igu r e 6. Brønsted plots for the reaction 1-H + RSH a 1-(H,-
F igu r e 7. Brønsted plots for the reactions 1-OMe + RSH r
1-(OMe,SR)- + H+ f 1-SR + MeOH. O, kH-1; 9, kH2 .
SR)- + H+. b, k1NuH (NuH ) RSH); O, kH-1
.
Ta ble 6. Br øn sted Coefficien ts
KN1 uH(1-H) ratios ranging from ca. 3 × 10-7 to 8 × 10-7 20
.
parameter
1-H
1-OMe
The main reasons for the much smaller equilibrium
constants for 1-OMe are the greater steric crowding in
the adduct and the ground-state stabilization of 1-OMe
by the π-donor effect of the methoxy group, as discussed
in more detail elsewhere.3,4
ROH as Nucleophiles
ânuc ) d log kNuH/dpKaROH
ca. 0.35a,b
0.46 ( 0.04a
1
âlg ) d log kH-1/dpKaROH
“â” ) d log(kH-1 + k2H)/dpKRa OH
0.50 ( 0.09a
For 1-(OMe,OMe)- the k-H1 value (8.85 × 104 M-1 s-1
,
RO- as Nucleophiles
Table 5) is very nearly the same as kH-1 ) 6.25 × 104 M-1
s-1 for 1-(H,OMe)- (Table 3). This is consistent with the
equilibrium constants, KN1 uH, for MeOH addition to
1-OMe (KN1 uH ) ca. 1.7 × 10-9, Table 5)21 being much
less depressed compared to KN1 uH for MeOH addition to
1-H (K1NuH ) ca. 5 × 10-8, Table 3)22 than is the case in
the reactions with thiols. As discussed in detail else-
where,3 the relatively high equilibrium constants for the
addition of oxygen nucleophiles to 1-OMe is in large
measure the result of anomeric stabilization of the adduct
by the geminal alkoxy groups.23,24
ânuc ) d log kNu/dpKaROH
ca. 0.23c
ca. -0.81c
0.51d
-0.97d
1
âlg ) d log k-1/dpKROH
a
RSH as Nucleophiles
ânuc ) d log kNuH/dpKaRSH
0.75 ( 0.11a
0.85 ( 0.07a
ca. 0.7a
0.35 ( 0.13a
0.58 ( 0.14a
1
âlg ) d log kH-1/dpKaRSH
âpush ) d log kH2 /dpKaRSH
RS- as Nucleophiles
ânuc ) d log kNu/dpKaRSH
0.17c
-0.72c
0.17d
-0.59d
0.75d
d
1
âlg ) d log k-1/dpKRSH
a
âpush ) d log k2/dpKRSH
a
This study. Based on two points only. c Reference 5. Ref-
a
b
Br øn sted Coefficien ts. Figures 6 and 7 show some
representative Brønsted plots, and Table 6 gives a
summary of all Brønsted â values determined in this
study, including some previously determined ones for the
reactions of RO- and RS-. The fact that all âlg values for
acid-catalyzed leaving group departure (kH-1) are posi-
tive indicates a transition state which, relative to the
adduct, is destabilized by electron-withdrawing R groups.
This implies a buildup of positive charge on the leaving-
group atom, which must be the result of a transition-
state imbalance9,25,26 where proton transfer from H3O+
erence 3.
to the departing group has made more progress than
C-O or C-S bond cleavage (see 3).
In the direction of nucleophilic attack by ROH or RSH
(k1NuH), the ânuc values are also positive, just as âlg for
kH-1, consistent with transition state 3 which, relative to
the reactants, is being destabilized by electron-withdraw-
ing R groups. Incidentally, a consequence of both âlg and
ânuc being positive is that KN1 uH depends little on the R
group.
(19) J ensen, J . L.; J encks, W. P. J . Am. Chem. Soc. 1979, 101, 1476.
(20) Note that the K1NuH(1-OMe)/KN1 uH(1-H) ratios are the same as
the KN1 u(1-OMe)/K1Nu(1-H) ratios because K1NuH ) K1Nu Kw.
The positive âlg values for acid-catalyzed leaving-group
expulsion contrast with the negative âlg values for
spontaneous departure of RO- and RS- (k-1). These latter
values reflect the buildup of negative charge on the
leaving-group atom at the transition state (4, X ) O or
S). In the direction of nucleophilic attack by RO- or RS-
(21) K1NuH for 1-(OMe,OMe)- estimated as the average of KN1 uH for
1-(OMe,OCH2C≡CH)- and 1-(OMe,OCH2CH3)-.
(22) K1NuH for 1-(H,OMe)- estimated as the average of KN1 uH for
1-(H,OR)- with R ) H, HCtCCH2, and CF3CH2.
(23) (a) Kirby, A. G. The Anomeric Effect and Related Stereoelectronic
Effects of Oxygen; Springer-Verlag: Berlin, 1983. (b) Schleyer, P. v.
R.; J emmis, E. D.; Spitznagel, G. W. J . Am. Chem. Soc. 1985, 107,
6393.
(24) (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.

Acid Catalysis of Meldrum’s Acid Derivatives
J . Org. Chem., Vol. 64, No. 24, 1999 8837
Ta ble 7. Ra te Con sta n ts for th e Sp on ta n eou s (k-1, k2) a n d H+-Ca ta lyzed
(kH-1, k2H) Colla p se of RO- Ad d u cts of â-Alk oxy-r-n itr ostilben esa ,b
a
b
In 50% Me2SO-50% water at 20 °C (µ ) 0.5 M KCl); ref 2f. The various âpush and âlg values were obtained from comparisons of pairs
of rate constants. For example, âpush ) 0.24 refers to a comparison of k-1 for the loss of CF3CH2O- from 6-(OCH2CF 3)2- with that from
6-(OMe,OCH2CF 3)-, i.e., it is a measure of the increased push by the MeO group compared to the CF3CH2O group. c Statistically corrected.
(kN1 u) the ânuc values are “normal,” i.e., positive, a conse-
quence of partial loss of the negative charge on RX- when
entering the transition state.
Table 6 reports a âpush value (0.58) for the H+-catalyzed
MeO- loss from 1-(OMe,SR)-. This value comes from a
plot of log kH2 vs pKRa SH, i.e., it is the group left behind
that is varied while the leaving group is constant. The
positive value of âpush is the result of an electronic push
by the π-donor effect of the RS group, which leads to
resonance stabilization in the incipient product (5).
groups.28 The stronger acidifying effect of a thio group
compared to an alkoxy group is even more apparent when
comparing the pKCa H values of 1-(OMe,SMe)H (1.18)
with those of 1-(OMe,OMe)H (1.97) and 1-(OMe,-
OCH2CtCH)H (1.78). This is probably the result of the
greater polarizability of the sulfur compared to the
oxygen substituents. Sulfur substituents on the R-carbon
of carbanions are known to exert a strong stabilizing
effect;30,31 our results suggest that even in the â-position
there is still a modest stabilizing effect.
Com p a r ison s w ith RO- Ad d u cts of â-Alk oxy-r-
n itr ostilben es. It is instructive to compare the rate
constants for the collapse of 1-(OMe,OR)- with the
corresponding rate constants for the collapse of simi-
lar adducts derived from â-alkoxy-R-nitrostilbenes,
specifically, 6-(OMe)-2 , 6-(OMe,OCH2CF 3)-, and 6-
(OCH2CF 3)-2 .2f They are summarized in Table 7.
For the reaction of the 1-(OMe,OR)- adducts (R * Me)
only the sum of kH-1 and k2H and not the individual rate
constants could be determined. A plot of log(kH-1 + k2H) vs
pKRa OH (not shown) yields a slope “â” ) 0.50 ( 0.09
(Table 6). This is a reasonable value because kH-1 is
expected to decrease with decreasing pKRa OH (positive
âlg) as is the case for ROH departure from 1-(H,OR)- (âlg
) 0.46) and kH2 is also expected to decrease with de-
creasing pKRa OH (positive âpush), as in the case of MeOH
departure from 1-(OMe,SR)- (âpush ) 0.58).
p KCa H Va lu es. The pKCa H values of the 1-(H,OR)H
complexes range from 1.82 to 2.69 (Table 1), for the 1-(H,-
SR)H complexes from 1.80 to 2.07, for the 1-(OMe,OR)-
H complexes from 1.78 to 1.97 (Table 4), while the pKaCH
of 1-(OMe,SMe) is 1.18 (Table 4). These pKCa H values
are considerably lower than the pKCa H of Meldrum’s acid
(4.70),27 indicating that the electron-withdrawing effect
of the PhCH(OR), PhCH(SR), PhC(OMe)OR, and PhC-
(OMe)SMe moieties is substantial, and apparently reflect
stabilization of the carbanion. The trend toward lower
pKCa H values with decreasing pKNa uH of the nucleophile is
a manifestation of the same phenomenon.
It is noteworthy that the pKCa H values for the alkoxide
and thiolate ion complexes derived from 1-H are quite
similar to each other or even slightly lower for the
thiolate ion adducts, despite the stronger electron-
withdrawing inductive/field effect of RO compared to RS
The following points are noteworthy. (1) The kH-1/k-1
ratio of 1.45 × 1010 M-1 for 1-(OMe)-2 is about the same
as for 6-(OMe)2- (1.86 × 1010 M-1), but the absolute
values of k-1 and k-H1 for 1-(OMe)-2 are more than 200-
fold higher than for 6-(OMe)-2 . As pointed out
elsewhere,2f the fact that the absolute values of k-1 are
higher for 1-(OMe)-2 than for 6-(OMe)-2 is particularly
remarkable because 1-(OMe)-2 is thermodynamically
more favored relative to its precursor (1-OMe) than 6-
(OMe)-2 relative to â-methoxy-R-nitrostilbene. The rea-
(28) The σF values for MeO and MeS are 0.30 and 0.20, respec-
tively.29
(29) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(30) For reviews, see (a) Price, C. C.; Oae, S. Sulfur Bonding; Ronald
Press: New York, 1962. (b) Cram, D. J . Fundamentals of Carbanion
Chemistry; Academic Press: New York, 1965; pp 71-84. (c) Eliel, E.
L.; Hartmann, A. A.; Abatjoglou, A. G. J . Am. Chem. Soc. 1974, 96,
1807. (d) Bordwell, F. G.; Bares, J . E.; Bartmess, J . E.; Drucker, G. F.;
Gerhold, J .; McCollum, G. J .; Van der Puy, M.; Vanier, N. R.;
Matthews, W. S. J . Org. Chem. 1977, 42, 326.
(25) J encks, D. A.; J encks, W. P. J . Am. Chem. Soc. 1977, 99, 7948.
(26) 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.
(31) Bernasconi, C. F.; Kittredge, K. W. J . Org. Chem. 1998, 63,
1944.
(27) Bernasconi, C. F.; Oliphant, N., unpublished results.

8838 J . Org. Chem., Vol. 64, No. 24, 1999
Bernasconi et al.
son for the higher kinetic reactivity of 1-(OMe)-2 is that
the intrinsic rate constant32 is higher. This is because
resonance plays a lesser role26 in the stabilization of 1-
(OMe)-2 and similar adducts derived from Meldrum’s
acid than in the case of 6-(OMe)-2 and analogues. (2)
The âlg and âpush values based on two-point comparisons
reported in Table 7 follow the same qualitative patterns
seen for the Meldrum’s acid derivatives. In particular,
the âlg values for spontaneous loss of RO- are large
negative numbers (-0.97 for 1-OMe vs -0.82 and -1.06
for the nitrostilbene derivatives) but positive for H+-
catalyzed RO- loss (“â” ) 0.50 for 1-OMe vs 0.35 and
0.26 for the nitrostilbene derivatives), while âpush is
positive in all cases. Apparently, the relative reactivities
governed by the change of leaving groups (âlg) or groups
that are left behind (âpush) are not affected in a major way
by the changes in the intrinsic rate constants.
on the R-carbon, as indicated in exaggerated form in 7.
Hence the stabilization of this charge resulting from the
polarizability of the sulfur is relatively more effective
than the stabilization of the more remote delocalized
charge in the carbanions.33
It should be noted that the enhancement of the
intrinsic rate constant for the thiolate ion adducts
relative to the alkoxide ion adducts of 1-H is rather
modest because the RS groups are one carbon removed
from the R-carbon. In cases where the RS group is on
the R-carbon, the effect is considerably larger.31
p KOa H of 1-(H,SR)Hen ol. In strongly acidic solution,
rapid protonation of one of the carbonyl oxygens of 1-(H,-
SR)- or 1-(H,OR)- to form an enol (eq 10), acts as a pre-
equilibrium step that precedes protonation on carbon
P r oton -Tr a n sfer Ra te Con sta n ts. Rate constants for
the proton-transfer reactions of eq 17 are summarized
kpH
1-(H,XR)- + H3O+ y z 1-(H,XR)H + H2O (17)
H
O
(kHp ) and acid-catalyzed RS- expulsion (k-H1). In the case
2
k-p
of 1-(H,SR) the pKOa H of the enol could be determined
fast
obsd
because the plot of k
vs [H+] levels off (pH < pKOa H
)
in Table 2 for X ) O and Table 3 for X ) S. Some of these
rate constants are subject to a relatively large experi-
fast
before k
becomes too large for stopped-flow measure-
obsd
ments (Figure 5). For 1-(H,OR)- no such leveling could
be observed within the limits of the stopped-flow tech-
nique, and hence pKOa H was inaccessible.
mental uncertainty. For example, this can be seen from
H2O
-p
the large standard deviations for k
in the reaction of
1-(H,SR)H and the fact that two methods of determining
H2O
-p
The pKOa H values of 1-(H,SR)Hen ol are about 0.7-0.8
log units lower than the pKCa H values (Table 3) and show
a similar dependence on pKRa SH of the thiol as the pKCa H
values. In comparison, the pKOa H value of the enol form
of Meldrum’s acid (2.48)35,36 is 2.35 log units lower than
the pKaCH (4.83).35,36 The smaller difference between
these k
values yield different values. In the case of
H2O
1-(H,OR), the k
values may be subject to systematic
-p
errors that are much larger than the standard deviations.
This is because they were obtained by solving eq 8, which
contains two rate constants that may have their own
H2O
-p
systematic errors. This may explain why k
for the
alkoxide ion adducts does not show the expected trend
pKOa H and pKCa H implies that the enolization equilibrium
constants, which are given by eq 18, are larger for 1-(H,-
toward lower values with increasing pKaCH
.
For these reasons and also because the pKCa H ranges
are quite small, one cannot expect to obtain meaningful
Brønsted coefficients for these reactions and none are
reported. The same is true for the intrinsic rate constants,
(k0),32 that are usually determined by suitable extrapola-
tion of the Brønsted plots.26 Nevertheless, the fact that
KCa H
KOa H
[enol]
KE )
)
(18)
[ester]
SR)H (0.15-0.20) than for Meldrum’s acid (4.47 ×
10-3).35,36 This indicates a stabilization of the enol and/
or a destabilization of the ester form by the PhCH(SR)
substituent. Our results are consistent with reports that
the enolization constants of â-diketones are generally
enhanced by electron-withdrawing substituents on the
R-carbon,37 an enhancement that has been attributed to
a destabilization of the keto form due to increased
positive charge on the carbonyl carbons.37
for a given pKaCH, both kHp and kH2O are about 3- to 4-fold
-p
higher for the sulfur compared to the oxygen compounds
indicates that the intrinsic rate constant for the sulfur
complexes is higher than that for the oxygen complexes
by a similar factor.
The higher intrinsic rate constants for the sulfur
complexes may be attributed to the same polarizability
effect that is responsible for the acidity of 1-(H,SR)H that
is higher than what is expected on the basis of the
inductive/field effect of the RS group. As discussed in
much more detail elsewhere,31 an enhancement of the
intrinsic rate constant will occur if the stabilization of
the transition state by the polarizability effect is dispro-
portionately strong relative to that of the fully developed
carbanion 1-(H,SR)-. This is likely to be the case,
because in the deprotonation of carbon acids that lead
to resonance-delocalized carbanions, the delocalization
has typically made little progress at the transition state.26
This implies that the negative charge is mainly localized
Con clu sion s
(1) Thiolate ion departure is much less sensitive to H+-
catalysis than alkoxide ion departure, as reflected in
much smaller kH-1/k-1 and kH/k2 ratios for the former.
2
This is the result of the lower basicity of the thiolate ions,
(33) This is true for the inductive/field effect as well, but the degree
to which the transition state benefits more from the polarizability factor
relative to the carbanion is larger because the polarizability effect falls
off more rapidly with distance than does the inductive/field effect.34
(34) Taft, R. W.; Topsom, R. D. Prog. Phys. Org. Chem. 1987, 16, 1.
(35) Eigen, M.; Ilgenfritz, G.; Kruse, W. Chem. Ber. 1965, 98, 1623.
(36) In water at 25 °C.
(32) For a reaction with a forward rate constants kf and a reverse
rate constant kr the intrinsic rate constants, k0, is defined as k0 ) kf )
kr when K ) kf / kr ) 1 (∆G0 ) 0).
(37) Toullec, J . In The Chemistry of Enols; Rappoport, Z., Ed.; Wiley
& Sons: New York, 1990; p 323.

Acid Catalysis of Meldrum’s Acid Derivatives
J . Org. Chem., Vol. 64, No. 24, 1999 8839
which leads to reduced acid catalysis (kH-1, k2H) but
enhanced spontaneous departure (k-1, k2).
known trends according to which enolization constants
of â-diketones are generally enhanced by electron-
withdrawing substituents on the R-carbon.
(2) H+-catalyzed loss of RS- from 1-(OMe,SR)- is much
faster than from 1-(H,SR)-, reflecting the larger ther-
Exp er im en ta l Section
modynamic driving force (smaller KN1 uH) for expulsion of
thiolate ion from 1-(OMe,SR)- compared to 1-(H,SR)-.
The H+-catalyzed loss of MeO- from 1-(OMe,OMe)- is
about the same as for loss from 1-(H,OMe)-, reflecting
comparable thermodynamic driving forces, i.e., similar
Ma ter ia ls. Benzylidene Meldrum’s acid (1-H), methoxy-
benzylidene Meldrum’s acid (1-OMe), and thiomethoxyben-
zylidene Meldrum’s acid (1-SMe) were available from previous
studies.3-5 DMSO was refluxed over CaH2, distilled under
vacuum, and stored under dry argon. All other organic
reagents, salts, and solvents were purchased from Aldrich or
Fischer Chemicals. The thiols were distilled prior to use, and
â-mercaptoethanol was distilled under vacuum. 2,2,2-Trifluo-
roethanol and propargyl alcohol were distilled and stored
under nitrogen or argon. Methanol, glacial acetic acid, and KCl
were used as received. Standardized solutions of HCl and KOH
were prepared from Baker “Dilut-its.” Millipore water was
used for all experiments.
In Situ Gen er a tion of th e An ion ic Ad d u cts. Solutions
of the desired adduct of 1-OMe, 1-SMe, or 1-H were prepared
by adding microliter amounts of the substrates to a methanol
solution containing the buffered nucleophile. KOMe was used
as the base in preparing the nucleophile buffer. Microliter
amounts of the adduct-containing solutions were then added
to 50% DMSO-50% water solutions, which were used in
stopped-flow experiments. The final amount of methanol was
typically <1% of the solvent. Solutions of the adduct had a
limited lifetime and had to be freshly prepared before each
experiment.
KN1 uH values.
(3) The âlg values for H+-catalyzed RO- or RS- depar-
ture are positive and imply an imbalanced transition
state where proton transfer from H3O+ to the departing
group is ahead of C-O or C-S bond cleavage. The
positive âpush values are the result of an electronic push
by the π-donor effect of the group left behind, which leads
to resonance stabilization in the incipient product.
(4) The âlg and âpush values are comparable to those
found earlier for the nitrostilbene systems. However, the
absolute rate constants for adduct collapse of the Mel-
drum’s acid derivatives are higher than those for the
nitrostilbene derivatives because of the diminished role
played by resonance effects in the adducts, which leads
to higher intrinsic rate constants.
(5) The pKCa H values of the various adducts are much
lower than the pKCa H of Meldrum’s acid, indicating that
the negative charge in the adducts is stabilized by the
PhCH(OR), PhCH(SR), PhC(OMe)OR, and PhC(OMe)-
SMe groups. The effect is stronger with RS-containing
groups, suggesting that the polarizability of sulfur con-
tributes to the stabilization of the negative charge. The
higher proton-transfer rate constants for the sulfur-
containing adducts can also be attributed to the polar-
izability effect of sulfur.
Rea ction Solu tion s, p H Mea su r em en ts, a n d Kin etic
Exp er im en ts. The procedures described before3,5 were fol-
lowed. All kinetic determinations were made in an Applied
Photophysics DX.17MV stopped-flow apparatus.
Ack n ow led gm en t. This research was supported by
Grants CHE-9307659 and CHE-9734822 from the Na-
tional Science Foundation (C.F.B.) and a grant from the
U.S.-Israel Binational Science Foundation, J erusalem
(Z.R.).
(6) The enol content of 1-(H,SR)H is significantly
higher than that of Meldrum’s acid, consistent with
J O991041K