Nucleophilic Reactivities of Carbanions in Water: The Unique Behavior of the Malodinitrile Anion

Article abstract of DOI:10.1021/ja036838e

The kinetics of the reactions of nine carbanions 1a-i, each stabilized by two acyl, ester, or cyano groups, with benzhydrylium ions in water were investigated photometrically at 20 °C. Because the competing reactions of the benzhydrylium ions with water and hydroxide ions are generally slower, the second-order rate constants of the reactions of the benzhydrylium ions with the carbanions can be determined with high precision. The rate constants thus obtained can be described by the Ritchie equation, log(k/k₀) = N ₊ (eq 1), which allows us to calculate Ritchie N+ parameters for a series of stabilized carbanions, for example, malonate, acetoacetate, malodinitrile, etc., and compare them with those of other n-nucleophiles in water (hydroxide, amines, azide, thiolates, etc.). Because the Ritchie relationship (eq 1) is a special case of the more general relationship log k = s(N + E) (eq 4), the reactivity parameters N and s for the carbanions 1a-i can also be calculated and compared with the nucleophilic reactivities of a large variety of n-, π-, and σ-nucleophiles, including reactivities of carbanions in dimethyl sulfoxide. While the acyl and ester substituted carbanions are approximately 3 orders of magnitude less reactive in water than in dimethyl sulfoxide, the malodinitrile anion (1i) shows almost the same reactivity in both solvents. Correlations between the nucleophilic reactivities of carbanions with the pK_a values of the corresponding CH acids reveal that the malodinitrile anion (1i) is considerably more nucleophilic than was expected on the basis of its pK_a value. This deviation is assigned to the exceptionally low Marcus intrinsic barriers of the reactions of the malodinitrile anion (1i).

Full text of DOI:10.1021/ja036838e

Published on Web 09/27/2003
Nucleophilic Reactivities of Carbanions in Water: The Unique
Behavior of the Malodinitrile Anion
Thorsten Bug and Herbert Mayr*
Contribution from the Department Chemie der Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstrasse 5-13 (Haus F), D-81377 Mu¨nchen, Germany
Received June 23, 2003; E-mail: Herbert.Mayr@cup.uni-muenchen.de
Abstract: The kinetics of the reactions of nine carbanions 1a-i, each stabilized by two acyl, ester, or
cyano groups, with benzhydrylium ions in water were investigated photometrically at 20 °C. Because the
competing reactions of the benzhydrylium ions with water and hydroxide ions are generally slower, the
second-order rate constants of the reactions of the benzhydrylium ions with the carbanions can be
determined with high precision. The rate constants thus obtained can be described by the Ritchie equation,
log(k/k0) ) N+ (eq 1), which allows us to calculate Ritchie N+ parameters for a series of stabilized carbanions,
for example, malonate, acetoacetate, malodinitrile, etc., and compare them with those of other n-nucleophiles
in water (hydroxide, amines, azide, thiolates, etc.). Because the Ritchie relationship (eq 1) is a special
case of the more general relationship log k ) s(N + E) (eq 4), the reactivity parameters N and s for the
carbanions 1a-i can also be calculated and compared with the nucleophilic reactivities of a large variety
of n-, π-, and σ-nucleophiles, including reactivities of carbanions in dimethyl sulfoxide. While the acyl and
ester substituted carbanions are approximately 3 orders of magnitude less reactive in water than in dimethyl
sulfoxide, the malodinitrile anion (1i) shows almost the same reactivity in both solvents. Correlations between
the nucleophilic reactivities of carbanions with the pKa values of the corresponding CH acids reveal that
the malodinitrile anion (1i) is considerably more nucleophilic than was expected on the basis of its pKa
value. This deviation is assigned to the exceptionally low Marcus intrinsic barriers of the reactions of the
malodinitrile anion (1i).
carbanions in DMSO.4 As in our previous investigations,
benzhydrylium ions were employed as reference electrophiles
(Table 1), which allows us to link the data obtained in this
investigation to the reactivity scales of uncharged π-nucleo-
philes5 and hydride donors.6,7 For the determination of the
nucleophilicity parameters of the tertiary carbanions 1d and 1h
Introduction
Ritchie’s discovery that the rates of the reactions of stabilized
carbocations and diazonium ions with a large variety of
nucleophiles can be described by the so-called “constant
selectivity relationship” (eq 1) led to the conclusion that
nucleophilicity is an intrinsic property of the reagents, dependent
on the medium but independent of the nature of the reaction
partner.1
(3) (a) Bates, R. B.; Ogle, C. A. In Carbanion Chemistry-ReactiVity and
Structure Concepts in Organic Chemistry; Hafner, K., Lehn, J.-M., Rees,
C. W., Schleyer, P. v. R., Trost, B. M., Zahradnik, R., Eds.; Springer-
Verlag: Berlin, 1983; Vol. 17. (b) Buncel, E.; Durst, T. ComprehensiVe
Carbanion Chemistry, pts. A, B, and C; Elsevier: New York, 1980, 1984,
1987. (c) Snieckus, V. AdVances in Carbanion Chemistry; JAI: Greenwich,
1992, 1996; Vols. 1 and 2. (d) Heathcock, C. H.; Winterfeldt, E.; Schlosser,
M. In Modern Synthetic Methods - Topics in Carbanion Chemistry;
Scheffold, R., Ed.; VHCA and VCH: Basel and Weinheim, 1992. (e)
Trofimov, B. A. J. Heterocycl. Chem. 1999, 36, 1469-1490. (f) Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 3, Chapter 1.1-1.7. (g) Fleming, F. F.; Shook,
B. C. Tetrahedron 2002, 58, 1-23. (h) Beak, P.; Reitz, D. B. Chem. ReV.
1978, 78, 275-316.
(4) (a) Lucius, R.; Mayr, H. Angew. Chem. 2000, 112, 2086-2089; Angew.
Chem., Int. Ed. 2000, 39, 1995-1997. (b) Lucius, R.; Loos, R.; Mayr, H.
Angew. Chem. 2002, 114, 97-102; Angew. Chem., Int. Ed. 2002, 41, 91-
95.
(5) (a) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-77.
(b) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem.-Eur. J. 2003, 9,
2209-2218. (c) Bug, T.; Hartnagel, M.; Schlierf, C.; Mayr, H. Chem.-
Eur. J. 2003, 9, 4068-4076.
(6) (a) Funke, M.-A.; Mayr, H. Chem.-Eur. J. 1997, 3, 1214-1222. (b) Mayr,
H.; Basso, N.; Hagen, G. J. Am. Chem. Soc. 1992, 114, 3060-3066. (c)
Mayr, H.; Lang, G.; Ofial, A. R. J. Am. Chem. Soc. 2002, 124, 4076-
4083.
log(k/k0) ) N+
(1)
log k0 ) electrophile-dependent parameter
N+ ) nucleophile-dependent parameter
A large variety of nucleophiles, for example, amines, alcohols,
alkoxides, thiolates, have been characterized in this way.2
Remarkably, cyanide was the only carbon nucleophile investi-
gated by Ritchie, despite the fact that carbanions are the
nucleophiles of greatest interest to organic chemists.3 We have
now determined the nucleophilic reactivities of carbanions in
water each stabilized by two cyano, ester, or keto groups, and
we compare the results with Ritchie’s N+ values of heteronu-
cleophiles as well as with the nucleophilic reactivities of these
(1) (a) Ritchie, C. D. Acc. Chem. Res. 1972, 5, 348-354. (b) Ritchie, C. D.
Can. J. Chem. 1986, 64, 2239-2250.
(2) See refs 10-25 in ref 1b.
(7) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf,
B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem.
Soc. 2001, 123, 9500-9512.
9
12980
J. AM. CHEM. SOC. 2003, 125, 12980-12986
10.1021/ja036838e CCC: $25.00 © 2003 American Chemical Society

Nucleophilic Reactivities of Carbanions in Water
A R T I C L E S
Table 1. Electrophilicity Parameters E, and log k0 Values of the
Reference Electrophiles Employed for Determining the
Nucleophilicities of the Carbanions 1a-i
Table 3. Second-Order Rate Constants of the Reactions of the
Carbanions 1a-i with Benzhydrylium Tetrafluoroborates
-
(2a-e)-BF4 in Water at 20 °C and Listing of the Characterized
Products
a In water from ref 8. b From ref 7. c From ref 4b. d In DMSO from ref
9.
Table 2. Rate Constants of the Reactions of Benzhydrylium
Tetrafluoroborates with Water and OH- in Water
k1Ψ,W/s-1
k2,OH /L mol-1 s-1
−
electrophile
2a
2b
2c
2d
2e
2.6 × 10-2 a
5.57 × 10-3 b
2.20 × 10-3 b
1.31 × 102 b
4.85 × 101 b
2.36 × 101 c
1.08 × 101 b
2.16b
a From ref 11. b From ref 8. c Calculated with N and s from ref 8 and eq
4.
in DMSO, the quinone methides 2f and 2g were used as
additional electrophiles, as in previous kinetic investigations of
carbanions in DMSO (Table 1).4a
Results
Preparative Investigations. The reactions of the carbanions
1 with the benzhydrylium salts 2-BF4 in water produce the
a Yields not optimized. b Uncertain value; see text.
-
[1:1] addition products 3. As shown in Table 3, reaction products
electrophile 2 concentration (eq 2).
of the combinations of the carbanions 1a-i with one or two of
-
the benzhydrylium salts 2a-e-BF4 have been isolated and
-d[2]/dt ) k1Ψ,obs[2]
(2)
characterized as described in the Supporting Information.
In all reactions of the benzhydrylium ions with carbanions
in water, competing reactions of the carbocations with hydroxide
and water have to be considered. The observed pseudo-first-
order rate constants k1Ψ,obs reflect the reaction of the electrophile
-
-
-
with the carbanion (k1Ψ,C ), OH (k1Ψ,OH ), and water (k1Ψ,W
)
Kinetic Investigations. All reactions reported in this Article
followed second-order kinetics, first order with respect to the
carbanion 1a-i concentration and first order with respect to
electrophile 2a-g concentration. Because the carbanions 1a-i
were usually employed in excess over the carbocations, their
concentration can be considered to be constant, resulting in
pseudo-first-order kinetics with an exponential decay of the
(eq 3).
k1Ψ,obs ) k1Ψ,C- + k1Ψ,OH- + k1Ψ,W
(3)
) k2,C-[C-] + k -[OH-] + k
2,OH
1Ψ,W
k
1Ψ ) k1Ψ,obs - k2,OH-[OH-] ) k -[C-] + k
(3.1)
2,C
1Ψ,W
9
J. AM. CHEM. SOC. VOL. 125, NO. 42, 2003 12981

A R T I C L E S
Bug and Mayr
Table 5. pKa Values of the Conjugate CH Acids of the
Carbanions 1a-i in Water and DMSO
pK (DMSO) −
a
carbanion
dimedone (1a)
Meldrum’s acid (1b)
acetylacetone (1c)
3-methylacetylacetone (1d)
ethyl cyanoacetate (1e)
ethyl acetylacetate (1f)
diethyl malonate (1g)
diethyl methylmalonate (1h)
malodinitrile (1i)
pK (H O)
pK (DMSO)
pK (H O)
a
2
a
a
2
5.3a
4.8a
11.2b
7.3b
5.9
2.5
4.3
4.3
1.9
3.5
3.5
5.6
9.0c
13.3d
15.1f
13.1h
14.2b
16.4d
18.7d
11.1d
10.8e
11.2g
10.7i
12.9c
13.1j
11.2c
-0.1
a From ref 23. b From ref 24. c From ref 12. d From ref 25. e From ref
26. f From ref 27. g From ref 28. h From ref 29. i From ref 30. j From ref
13.
-
Figure 1. Determination of the second-order rate constant k2,C ) 12.9 L
mol-1 s-1 for the reaction of 2e with deprotonated dimedone (1a) in water
at 20 °C.
Scheme 1. Reaction of the Tertiary Carbanion 1h with the
Quinone Methide 2f in DMSO
Table 4. Second-Order Rate Constants of the Reactions of the
Carbanions 1d,h with the Electrophiles 2e-BF4 and 2f,g in DMSO
-
at 20 °C and Listing of the Characterized Products
a Yields not optimized.
[C-] is the concentration of the carbanion, which was
generated from the CH acid with KOH. The concentrations of
the carbanions [C-] and of the hydroxide [OH-] are calculated10
from [OH-]0, [CH acid]0, and pKa as described on p S12 of the
methylmalonate in water has not been determined experimen-
tally, the value of 13.1 calculated by ACD Software was
employed.13 Because of the lack of independent confirmation,
the resulting k2,C and N values for 1h should be considered as
less reliable.
-
-
Supporting Information. With the already published k2,OH
values8 (Table 2) and the calculated concentrations [OH-], the
-
partial pseudo-first-order rate constants k1Ψ,OH can be calcu-
Rate constants for the reactions of the carbanions 1a-i with
electrophiles in water are given in Table 3.
lated.
-
To compare the nucleophilicities of all carbanions from Table
3 in water with the corresponding data in DMSO, it was
necessary to complete the previously published data set in
DMSO4b by determining the nucleophilic reactivities of 1d and
1h in this solvent (Table 4). Scheme 1 shows the isolated
addition product 3hf which was obtained from the quinone
methide 2f and the tertiary carbanion 1h in DMSO.
The slopes of the plots (k1Ψ ) k1Ψ,obs - k1Ψ,OH ) (eq 3.1)
versus [C-] correspond to the second-order rate constants k2,C
,
-
as shown in Figure 1 and in the Supporting Information. The
intercepts, which correspond to the reactions of the benzhydryl-
ium ions with water, are negligible, in accord with the directly
measured reactivities toward water listed in the middle column
of Table 2. As explicitly shown in the Supporting Information,
only in some experiments with 1h does k1Ψ,OH reach an order
of magnitude similar to that of k1Ψ,C , while in all other cases
k1Ψ,OH , k1Ψ,C with the consequence that usually k1Ψ
k1Ψ,obs
-
Discussion
-
Figure 2 shows that the reactions of the carbanions 1a-i with
benzhydrylium ions follow Ritchie’s eq 1, not worse and not
better than the nucleophiles initially studied by Ritchie.1
The N+ values in water for the carbanions 1a-i (Figure 3),
which correspond to the abscissa of Figure 2, have been
calculated from the Ritchie correlation (eq 1) using the log k0
values8 listed in Table 1.
-
-
≈
.
The pKa values for the conjugate CH acids of 1a-f and of
1i have repeatedly been determined in the literature and agree
within (0.2 units in pKa. Because of the high acidities of these
compounds (pKa e 11.2, see Table 5), the errors in calculated
-
carbanion concentrations as well as in k2,C and N resulting from
These N+ values can be compared with N+ of other
nucleophiles determined by Ritchie.1 It is remarkable that the
the uncertainties of pKa are negligible. For diethyl malonate,
we used a pKa value of 12.912 which is consistent with other
data, with the consequence that the resulting N value can also
be considered as reliable. Because the pKa value for diethyl
(11) McClelland, R. A.; Kanagasabapathy, V. M.; Banait, N. S.; Steenken, S.
J. Am. Chem. Soc. 1989, 111, 3966-3972.
(12) Albert, A.; Serjeant, E. P. The Determination of Ionization Constants: A
Laboratory Manual, 3rd ed.; Chapman and Hall: London, 1984; pp 137-
160.
(13) From SciFinder Scholar 2002: Calculated using Advanced Chemistry
Development (ACD) Software Solaris V4.67 (1994-2003 ACD).
(8) Minegishi, S.; Mayr, H. J. Am. Chem. Soc. 2003, 125, 286-295.
(9) Lucius, R. Dissertation, Ludwig-Maximilians-Universita¨t Mu¨nchen, 2001.
(10) Evans, A. G.; Hamann, S. D. Trans. Faraday Soc. 1951, 47, 34-40.
9
12982 J. AM. CHEM. SOC. VOL. 125, NO. 42, 2003

Nucleophilic Reactivities of Carbanions in Water
A R T I C L E S
Figure 4. Correlation of the rate constants (20 °C) for the reactions of the
carbanions 1a-i with the benzhydrylium tetrafluoroborates (2a-e)-BF4
in water toward the electrophilicity parameters E.
-
Figure 2. Analysis of the rate constants for the reactions of benzhydrylium
ions with the carbanions 1a-i in water according to the Ritchie formalism
(eq 1). Data for OH- and n-PrNH2 are from ref 8. Each correlation line
corresponds to one benzhydrylium ion: b (2a), O (2b), 2 (2c), 0 (2d), 9
(2e).
eq 4, which differs from eq 1 by an additional parameter, the
nucleophile-specific slope parameter s.
log k(20 °C) ) s(N + E)
s ) nucleophile-specific slope parameter
(4)
N ) nucleophilicity parameter
E ) electrophilicity parameter
Because eq 1 is a special case (s ) constant) of the more
general relationship (4), eq 4 has recently been employed for
linking Ritchie’s nucleophilicity parameters to the nucleophi-
licity scales for π-systems and hydride donors.8 It has previously
been discussed that eq 4 is equivalent to log k ) Nu + sE with
Nu ) sN; for practical reasons, however, it is preferable to use
the nucleophilicity parameters N instead of Nu.18
In analogy to previous investigations,7 we have plotted the
rate constants of the reactions of the carbanions 1a-i with the
benzhydrylium ions 2a-e in water against the corresponding
electrophilicity parameters E. The reactivity parameters N and
s as defined by eq 4 were then derived (Figure 4).
While the nucleophilicity sequences expressed by N+ (Figure
2) and by N (Figure 4) are similar, the two scales are not
perfectly proportional to each other: While N+ (eq 1) reflects
the averaged relative reactivities of the nucleophiles toward the
electrophiles investigated in this work, N (eq 4) reflects the
extrapolated reactivity order of nucleophiles toward variable
Figure 3. Comparison of the N+ values in water for the carbanions 1a-i
with those of other nucleophiles. N+ of PhS-, EtS-, N3-, BH4-, and OH-
from ref 1b; N+ of SO32-, HOO-, n-PrNH2, CF3CH2O-, and HONH2 from
ref 8.
(14) (a) Mayr, H.; Schneider, R.; Schade, C.; Bartl, J.; Bederke, R. J. Am. Chem.
Soc. 1990, 112, 4446-4454. (b) Mayr, H.; Schneider, R.; Irrgang, B.;
Schade, C. J. Am. Chem. Soc. 1990, 112, 4454-4459. (c) Mayr, H.;
Schneider, R.; Grabis, U. J. Am. Chem. Soc. 1990, 112, 4460-4467. (d)
Mayr, H. Angew. Chem. 1990, 102, 1415-1428; Angew. Chem., Int. Ed.
Engl. 1990, 29, 1371-1384. (e) Irrgang, B.; Mayr, H. Tetrahedron 1991,
47, 219-228. (f) Roth, M.; Schade, C.; Mayr, H. J. Org. Chem. 1994, 59,
169-172. (g) Mayr, H.; Hartnagel, M. Liebigs Ann. Chem. 1996, 2015-
2018.
carbanions of dimedone (1a) and Meldrum’s acid (1b), the least
reactive carbanions of this series, are considerably more reactive
than OH- in water (Figure 3). The thiolate anions (EtS- and
PhS-) are more nucleophilic than most carbanions of this series,
only exceeded by the malodinitrile anion (1i).
Numerous investigations of the reactions of carbocations with
π-nucleophiles (alkenes,14 arenes15) and hydride donors (si-
lanes,6b,16 stannanes,17 aminoboranes,6a unsaturated hydrocarbons6c)
have shown that Ritchie’s two-parameter eq 1 is insufficient to
properly describe the rate constants of all of these reactions.5a,18
Excellent correlations were obtained, however, by employing
(15) (a) Mayr, H.; Bartl, J.; Hagen, G. Angew. Chem. 1992, 104, 1689-1691;
Angew. Chem., Int. Ed. Engl. 1992, 31, 1613-1615. (b) Gotta, M. F.; Mayr,
H. J. Org. Chem. 1998, 63, 9769-9775.
(16) Basso, N.; Go¨rs, S.; Popowski, E.; Mayr, H. J. Am. Chem. Soc. 1993, 115,
6025-6028.
(17) Mayr, H.; Basso, N. Angew. Chem. 1992, 104, 1103-1105; Angew. Chem.,
Int. Ed. Engl. 1992, 31, 1046-1048.
(18) (a) Mayr, H.; Patz, M. Angew. Chem. 1994, 106, 990-1010; Angew. Chem.,
Int. Ed. Engl. 1994, 33, 938-957. (b) Mayr, H.; Patz, M.; Gotta, M. F.;
Ofial, A. R. Pure Appl. Chem. 1998, 70, 1993-2000. (c) Mayr, H.; Kuhn,
O.; Gotta, M. F.; Patz, M. J. Phys. Org. Chem. 1998, 11, 642-654.
9
J. AM. CHEM. SOC. VOL. 125, NO. 42, 2003 12983

A R T I C L E S
Bug and Mayr
Figure 6. Plot of the nucleophilicity parameter N versus pKa of the
corresponding acids of the carbanions 1a-i (water, 20 °C).
Figure 5. Comparison of the nucleophilicity and slope parameters (N/s)
for the carbanions 1a-i in water and in DMSO. (a) Data are from ref 4b.
b Uncertain value; see text.
(hypothetical) electrophiles which react with rate constants of
1 L mol-1 s-1 (log k ) 0). As discussed previously,8 the N
parameters thus derived can be employed for a direct comparison
with the reactivities of nucleophiles which do not follow eq 1,
for example, alkenes and arenes.
Figure 7. Plot of the nucleophilicity parameter N versus pKa of the
corresponding acids of the carbanions 1a-i (DMSO, 20 °C).
and in DMSO (Table 5).22 All other CH acids of this investiga-
tion are significantly more acidic in water than in DMSO.
The reactivity parameters N of the carbanions 1a-i in water
determined in this work and the corresponding pKa values can
be used for correlations between reactivity and Brønsted
basicity.31 Good correlations may be expected because the
nucleophiles are of the same type (carbanions)32 and the
nucleophile-specific slope parameters s according to eq 4 differ
only slightly (0.50 e s e 0.69, H2O). Both correlations of N
versus pKa, in water (Figure 6) as well as in DMSO (Figure 7),
are of poor quality, however.
The deprotonated malodinitrile (1i), in particular, is consider-
ably more reactive in both solvents than expected on the basis
of its pKa value. Thus, the malodinitrile anion is again unique.
Because Figures 6 and 7 correlate nucleophilicity toward
carbon with basicity toward protons, one cannot a priori exclude
a thermodynamic origin for this observation. Ru¨chardt had
indeed reported that the destabilizing inverse anomeric effect
The rate constants for the reactions of carbanions with
benzhydrylium ions in water (Table 3) are from 1 to 3 orders
of magnitude smaller than the corresponding values in DMSO
(Figure 5).4b We assign these differences predominantly to
different carbanion solvation and not to carbocation solvation
because similar solvent effects are observed for the reactions
of carbanions with benzhydrylium ions and quinone methides.
Thus, the reaction of ethyl cyanoacetate (1e) with the benzhy-
drylium ion 2e and with the neutral electrophiles 2f,g is 5 times
slower in methanol than in DMSO.19
Figure 5 shows that the nucleophilicity parameters N of all
carbonyl and ester stabilized carbanions are about 2-4 units
smaller in water than in DMSO, corresponding to rate ratios
k(DMSO)/k(H2O) of 102-104. Hydrogen bonding to the nega-
tively charged oxygen atoms may account for the lower
reactivities of these carbanions in water.
However, the deprotonated malodinitrile (1i) behaves differ-
ently. It possesses nearly the same N parameter in water and in
DMSO. The small reactivity difference toward the electrophile
2e (k(DMSO)/k(H2O) ) 12) is due to the difference in the slope
parameter s. The remarkably small influence of the solvent on
the nucleophilicity of the malodinitrile anion 1i is in accord
with the small degree of charge delocalization in cyano
substituted carbanions,20,21 which results in little hydrogen bond
stabilization and identical pKa values of malodinitrile in water
(22) Bernasconi, C. F.; Bunnell, R. D. J. Am. Chem. Soc. 1988, 110, 2900-
2903.
(23) Feith, B.; Weber, H.-M.; Maas, G. Chem. Ber. 1986, 119, 3276-3296.
(24) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
(25) Bordwell, F. G.; Harrelson, J. A., Jr.; Satish, A. V. J. Org. Chem. 1989,
54, 3101-3105.
(26) Pearson, R. G.; Mills, J. M. J. Am. Chem. Soc. 1950, 72, 1692-1694.
(27) Arnett, E. M.; Maroldo, S. G.; Schilling, S. L.; Harrelson, J. A. J. Am.
Chem. Soc. 1984, 106, 6759-6767.
(28) Dale, J.; Morgenlie, S. Acta Chem. Scand. 1970, 24, 2408-2418.
(29) Bordwell, F. G.; Branca, J. C.; Bares, J. E.; Filler, R. J. Org. Chem. 1988,
53, 750-782.
(19) Phan Thanh, B.; Mayr, H., unpublished results.
(30) Eidinoff, M. L. J. Am. Chem. Soc. 1945, 67, 2072-2073.
(31) Brønsted, J. N.; Pedersen, K. Z. Phys. Chem. 1924, 108, 185-235.
(32) Bordwell, F. G.; Cripe, T. A.; Hughes, D. L. In Nucleophilicity; Harris, J.
M., McManus, S. P., Eds.; American Chemical Society: Washington, DC,
1987.
(20) Wiberg, K. B.; Castejon, H. J. Org. Chem. 1995, 60, 6327-6334.
(21) (a) Richard, J. P.; Williams, G.; Gao, J. J. Am. Chem. Soc. 1999, 121,
715-726. (b) Abbotto, A.; Bradamante, S.; Pagani, G. A. J. Org. Chem.
1993, 58, 449-455.
9
12984 J. AM. CHEM. SOC. VOL. 125, NO. 42, 2003

Nucleophilic Reactivities of Carbanions in Water
A R T I C L E S
Scheme 2. Effect of Methyl Substitution on the Geminal
Experimental Section
Interaction of Two Ester or of Two Cyano Groupsa
Materials. Water was distilled and passed through a Milli-Q water
purification system. Dimethyl sulfoxide (DMSO, Fluka, puriss., stored
over molecular sieve, H2O e 0.01%) and acetonitrile (Fluka, for HPLC,
g99.9%) were used without further purification.
Benzhydrylium tetrafluoroborates7 and quinone methides9,42 were
prepared as described.
Potassium salts of diethyl methylmalonate and 3-methylacetylacetone
were synthesized in analogy to literature reports.9,27
Potassium hydroxide was purchased as an aqueous solution (Merck,
c ) 0.1 M ( 0.1%; Aldrich, c ) 0.5073 M (volumetric standard)).
Meldrum’s acid (Acros, 98%), dimedone (Acros, 99%), diethyl
malonate (Fluka, g99%), ethyl cyanoacetate (Fluka, g99%), malo-
dinitrile (Lancaster, 99%), ethyl acetoacetate (Fluka, g99%), acetylace-
tone (Merck, g99.5%), diethyl methylmalonate (Fluka, g99%), and
3-methylacetylacetone (Fluka, g99+%) were from commercial sources.
Liquids were distilled before use. Solids were used without further
purification.
a Gas-phase thermochemical data are from ref 33 (nitrile) and ref 35
(esters). Values correspond to ∆fH0 in kJ mol-1
.
of geminal nitrile groups is attenuated by the presence of alkyl
groups.33 The magnitude of this effect is given by ∆rH° of the
isodesmic reaction in Scheme 2, which indicates that the
replacement of the methylene protons by methyl groups
stabilizes malodinitrile only slightly more than methyl mal-
onate.34 The small value of ∆rH° in Scheme 2 excludes
differences between carbon and proton basicities of malodinitrile
and malonic ester anions as the origin for the exceptionally high
nucleophilicity of the malodinitrile anion.
One has to assume, therefore, that the intrinsic barrier for
the reaction of the malodinitrile anion (1i) is significantly lower
than that for the other carbanions of this study. This conclusion
is in accord with Bernasconi’s report that the malodinitrile anion
(1i) undergoes Michael additions with lower intrinsic barriers
than most other carbanions.36 The well-known fact that cyano-
carbons differ from most CH acids in the sense that their proton-
transfer reactions are almost “normal” in the Eigen sense37,38
again indicates low intrinsic barriers.21a Both phenomena have
been attributed to the small degree of resonance stabilization
in the malodinitrile anion21,39 which results in little transition
state imbalance40 of its reactions with electrophiles. Bernasconi’s
“Principle of Nonperfect Synchronization”38,41 which relates the
magnitudes of intrinsic barriers with the degree of resonance
stabilization of the reagents has previously been used to explain
the high intrinsic reactivity of the malodinitrile anion with
Michael acceptors as well as its fast proton-transfer reactions.
Analogous rationalizations can be used to explain the exception-
ally high reactivity of the malodinitrile anion toward carboca-
tions.
Kinetics. The reactions of benzhydrylium ions with carbanions were
studied in aqueous solution and in DMSO, whereas the reactions of
quinone methides were only studied in DMSO. The rates of the
reactions of the colored electrophiles with the carbanions 1a-i were
measured photometrically. In aqueous solutions, all carbanions were
generated by treatment of the corresponding acids with KOH. The
reactions in DMSO were carried out with stock solutions of the
potassium salts of the CH acids.
For slow reactions (τ1/2 > 10 s), the decrease of the absorbances of
the benzhydrylium ions was measured in a thermostated flask with an
immersion UV-vis probe using a working station as already
described.14b,43 We used a J&M TIDAS diode array spectrophotometer
which was controlled by Labcontrol Spectacle software and connected
to a Hellma 661.502-QX quartz Suprasil immersion probe (5 mm light
path) via fiber optic cables and standard SMA connectors. The
temperature of solutions during all kinetic studies was kept constant
(20 ( 0.2 °C) by using a circulating bath thermostat and monitored
with a thermocouple probe that was inserted into the reaction mixture.
Fast reactions (τ1/2 < 10 s at 20 °C) were studied with a stopped-
flow spectrophotometer system (Hi-Tech SF-61DX2 spectrophotometer
controlled by Hi-Tech Kinet Asyst2 software) as described previ-
ously.7,44 The kinetic runs were initiated by mixing equal volumes of
solutions of the carbanion and the electrophile. Carbanion concentrations
higher than the electrophile concentration were employed, resulting in
pseudo-first-order kinetics with an exponential decay of the electrophile.
First-order rate constants were obtained by least-squares fitting of the
absorbance data (averaged from at least four kinetic runs at each
nucleophile concentration) to the single-exponential At
exp(-k1ψ,obst) + C.
) A0
We have thus shown on a statistical basis that pKa values are
poor guides for predicting nucleophilic reactivities of carbanions
and that the exceptional high nucleophilicity of malodinitrile
anion (1i) is found in water as well as in DMSO.
In the cases of the weak CH acids 1g and 1h, the concentration of
the corresponding carbanion is smaller than that of the electrophiles.
The exponential decays of the electrophile concentrations indicate,
however, the constancy of [C-], implying that the deprotonation of
the CH acid used in large excess is fast as compared to the reaction of
the benzhydrylium cations with carbanion and hydroxide.
(33) Beckhaus, H.-D.; Dogan, B.; Pakusch, J.; Verevkin, S.; Ru¨chardt, C. Chem.
Ber. 1990, 123, 2153-2159.
(34) Thermodynamic data for the exchange of only one methyl group are not
available.
(35) Verevkin, S.; Dogan, B.; Beckhaus, H.-D.; Ru¨chardt, C. Angew. Chem.
1990, 102, 693-695; Angew. Chem., Int. Ed. Engl. 1990, 29, 674-676.
(36) Bernasconi, C. F.; Zitomer, J. L.; Fox, J. P.; Howard, K. A. J. Org. Chem.
1984, 49, 482-486.
(37) (a) Eigen, M. Angew. Chem. 1963, 75, 489-508; Angew. Chem., Int. Ed.
Engl. 1964, 3, 1-19. (b) Hojatti, M.; Kresge, A. J.; Wang, W. H. J. Am.
Chem. Soc. 1987, 109, 4023-4028. (c) For the analogous behavior of HCN,
see: Bednar, R. A.; Jencks, W. P. J. Am. Chem. Soc. 1985, 107, 7117-
7126.
Because of the poor solubility of the benzhydrylium tetrafluorobor-
ates in water, it was necessary to employ up to 1.6% (v/v) of acetonitrile
as a cosolvent for the kinetic investigations in water. In previous work
with other anionic nucleophiles, it has already been shown that the
small amount of acetonitrile does not affect the observed rate con-
stants.8
(38) Bernasconi, C. F. Acc. Chem. Res. 1992, 25, 9-16.
(39) Richard, J. P.; Amyes, T. L.; Toteva, M. M. Acc. Chem. Res. 2001, 34,
981-988.
(40) Jencks, D. A.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 7948-7960.
(41) (a) Bernasconi, C. F. Acc. Chem. Res. 1987, 20, 301-308. (b) Bernasconi,
C. F. Tetrahedron 1989, 45, 4017-4090. (c) Bernasconi, C. F. AdV. Phys.
Org. Chem. 1992, 119-238.
(42) Evans, S.; Nesvadba, P.; Allenbach, S. (Ciba-Geigy AG), EP 744392, 1996
[Chem. Abstr. 1997, 126, 46968v].
(43) Dilman, A. D.; Ioffe, S. L.; Mayr, H. J. Org. Chem. 2001, 66, 3196-
3200.
(44) Mayr, H.; Ofial, A. R. Einsichten - Forschung an der LMU Mu¨nchen
2001, 20, 30-33.
9
J. AM. CHEM. SOC. VOL. 125, NO. 42, 2003 12985

A R T I C L E S
Bug and Mayr
In some experiments with electrophile 2a in water, small quantities
of benzenesulfonic acid were added to avoid the reaction of 2a with
water prior to mixing the solutions of the reactants.
Supporting Information Available: Syntheses and charac-
terization of the products 3 of the reactions of carbanions 1 with
electrophiles 2. Tables containing the concentrations and rate
constants of the individual kinetic experiments (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Dedicated to Professor Manfred T. Reetz
on the occasion of his 60th birthday. We thank Stefanie
Mugrauer for performing experiments with 1a and 1b and
Clemens Schlierf for preparative investigations. Financial sup-
port by the Deutsche Forschungsgemeinschaft and the Fonds
der Chemischen Industrie is gratefully acknowledged.
JA036838E
9
12986 J. AM. CHEM. SOC. VOL. 125, NO. 42, 2003