793 1
Mechanisms for Enforced General Acid Catalysis of the Addition of Thiol Anions to Acetaldehyde1 H. F. Gilbert and W. P. Jencks* Contribution No. I 1 75 f r o m the Graduate Department of Biochemistry, Brandeis University, Waltham. Massachusetts 021 54. Receiued March 28, 1977
Abstract: General acid catalysis of the addition of the anion of methyl mercaptoacetate to acetaldehyde exhibits a disappearance or decrease of catalysis at high acid concentrations that is evidence for a change in rate-determining step, a metastable intermediate, and a kinetically significant proton transfer step that traps the intermediate. This catalysis by trapping is enforced by the short lifetime of the anionic addition intermediate, T- (k-1 = 4 X IO7 s-’). The more stable intermediates formed from more basic thiol anions exhibit no catalysis and catalysis is enforced for all less stable intermediates. The Brpsted plot for catalysis by trapping is consistent with an “Eigen curve” for proton transfer. However, the Brvnsted plot for catalysis of the addition of pentafluorobenzenethiol anion (pK = 2.7) has a slope, (Y = 0.26, that is inconsistent with a trapping mechanism and is attributed to catalysis by hydrogen bonding in a preassociation mechanism. Catalysis of the addition ofp-methoxybenzenethiol anion (pK = 6.5) appears to proceed through both mechanisms concurrently, depending on the acidity of the catalyst. Rate and equilibrium constants for the individual steps of the reactions are consistent with the proposed mechanisms. Catalysis by trapping proceeds through a late transition state with complete S-C bond formation (Pnuc= 1 .O), whereas catalysis by hydrogen bonding to carboxylic acids involves an early transition state (P,, N 0.2). It is shown that the importance of general acid catalysis by hydrogen bonding, relative to the uncatalyzed reaction and to catalysis by trapping, is inversely dependent on the lifetime of the addition intermediate. The value of (Y increases with decreasing basicity of the attacking thiol increases with decreasing acidity of the catalyzing acid according to the relationship ba/-bpKnuc = bonuc/ anion and, , @, ~ P K H= A 1/c2 = 0.026. There is also an increase in Pnucwith decreasing thiol anion basicity that probably reflects a later, more basic transition state which forms a stronger hydrogen bond to the catalyzing acid.
T h e addition of thiol anions to acetaldehyde (eq 1) is a relatively simple reaction that serves to illustrate how different mechanisms of catalysis of addition to the carbonyl group a r e related to the lifetime of the addition intermediate and the basicity of the carbonyl oxygen atom in the transition state.
Tkh k-h
It has been shown previously that the addition of basic thiol anions exhibits no detectable general acid catalysis,2 whereas the addition of weakly basic anions of aromatic thiols and thioacetic acid is subject to general acid catalysis with a Brfnsted CY ,- 0.2 (the value of CY = 0.2 for thiol anion attack corresponds t o p = 0.8 for the reverse, base-catalyzed breakdown of the h e m i t h i ~ a c e t a l )This . ~ catalysis has been shown to involve true general acid catalysis rather than the kinetically equivalent specific acid-general base catalysis. T h e mechanism of catalysis was originally described as being in some sense “concerted”, in order to distinguish it from stepwise catalysis by a trapping m e ~ h a n i s mHowever, .~ it is better described as catalysis in which there has been partial proton transfer from a catalyst that is present in the transition state for attack of the thiol anion. The experiments described here were initiated because it was noticed that the estimated rate constants for the proton transfer steps of the catalyzed reactions a r e close to the observed rate constants. This suggested that the proton transfer steps themselves might become kinetically significant or that reaction pathways might exist that avoid the diffusion-controlled proton transfer step, so that it appeared desirable to investigate the relationships between proton transfer, catalysis, and the lifetime of the intermediate anionic addition compound, T-. The reversible addition of thiols is a n unusually simple system because there is no requirement for protonation of t h e sulfur atom before its expulsion from the addition compounds, so that the rate and equilibrium constants for the individual steps of the overall reaction may readily be calculated from experimental data. In particular, the rate constant k-1 for the breakdown of T-, the anion of the hemithioacetal formed from methyl mercaptoacetate and acetaldehyde (eq 2), was calcu-
I I
RS-C-OH
+ -OH
(2)
TH
lated from the estimated pK of the h e m i t h i o a ~ e t a land ~ , ~ the known rate constant for its hydroxide ion catalyzed breakdown3 and was found to be similar to the rate constant kh for proton abstraction from water by T- to give TH. This suggested that proton abstraction from water ( k h ) is partly rate determining in this reaction and that catalysis of this proton transfer by added buffer acids should increase the observed reaction rate. The results reported here confirm this prediction and show how the progressively decreasing lifetimes of intermediates formed from thiol anions of decreasing basicity lead first to catalysis by trapping and then to catalysis by hydrogen bonding to the developing negative charge on the carbonyl oxygen atom in the transition state through a preassociation mechanism. An additional, unanticipated finding is that the Brpnsted coefficient, CY,for catalysis by hydrogen bonding increases with decreasing pK of the attacking thiol anion. The simplest explanation of this result is that it is a consequence of a later, more basic transition state with weak nucleophiles. It has been shown previously that catalysis of the addition of methoxyamine to substituted benzaldehydes occurs through concurrent mechanisms of trapping by general acids and direct catalysis of the addition step by the proton and that the relative importance of these mechanisms for amine additions is determined by the lifetime of the addition intermediate.6 The concurrent existence of general acid catalysis by trapping and by hydrogen bonding has been observed for the addition of weakly basic carbanions to substituted acetaldehydes.’ Evidence for catalysis of the addition of weakly basic amines to p-chlor~benzaldehyde~ and formaldehydes by a preassociation
Gilbert, Jencks
/
Addition of Thiol Anions to Acetaldehyde
7932 mechanism has been reported and general acid catalysis of these reactions may also involve hydrogen bonding or “concerted” catalysis. Some of the results described here have been summarized in preliminary reports.g.10
Experimental Section
10%.
Materials. Reagent grade inorganic salts were used without further purification. Organic reagents were redistilled or recrystallized except
for trifluoroethanol, methoxyethanol (Aldrich “Gold Label”, 99+%), and acetic acid. After distillation, solutions of trifluoroacetone hydrate were found to contain traces of a strongly acidic impurity ( 9.2 are less effective catalysts than the acids in group 2. Approximate rate constants for catalysis by the trapping mechanism, k H A = klk,/k-1, were obtained from the data a t buffer concentrations below 0.2 M by correcting the observed rate constants for the change in ratedetermining step, as described in the Experimental Section, and a r e summarized in Table 111. Addition of Aromatic Thiols to Acetaldehyde. T h e pH-rate profiles for the addition of p-methoxybenzenethiol and pentafluorobenzenethiol to acetaldehyde (Figure 4) show that the pH-independent reaction, which corresponds to the protoncatalyzed addition of thiol anion, becomes more important for
*t 02
0
04
M
f C/ACIT Figure 5. General acid catalysis of the addition ofp-methoxybenzenethiol anion to acetaldehyde at 25 O C and ionic strength 1.O M by chloroacetate 70%acid, pH 1.94. buffers. (e),30% acid, pH 2.64; (O),
weakly basic thiols, as has been observed p r e v i ~ u s l y T . ~h e attack of the thiol anion is catalyzed by buffer acids with no inGilbert, Jencks
/
Addition of Thiol Anions to Acetaldehyde
7938 Table V. Acid-Catalyzed Addition of 3,4-Dichlorobenzenethiol Anion to Acetaldehyde at 25 OC, Ionic Strength 1.0 M
Acid H3O+ Cyanoacetic Boric Hexafluoro-2-propanol Water a
Total buffer, M
pH
0-0.4 0-0.4 0-0.2 0-0.2
2.01 2.69 4.14" 4.1 5"
of points
10-4kCa,, M-2~-1
6 5 5
120 13fl
5 5
2.0 2.3 0.0026
NO.
6
pH maintained with 0.01 M acetic acid buffer, 25% base.
Table VI. Acid-Catalyzed Addition of p-Nitrobenzenethiol Anion to Acetaldehyde at 25 OC, Ionic Strength 1.0 M (KCI)
Acid H30+ Cyanoacetic Chloroacetic Methoxyacetic 4cetic Boric Hexafluoro-2-propanol Water
Total buffer, M
0-0.1 0-0.1
of points
NO.
pH
4.42b 4.34b
5 8
10-4kcat, M-2~-1
Discussion Catalysis by Trapping. There is no detectable general acid catalysis of the addition of basic thiol anions to acetaldehydes2 T h e thermodynamically favorable removal of a proton from hemithioacetals by hydroxide ion in the reverse direction (k-h, Scheme I) occurs with a diffusion-controlled rate constant of k - h = l o i oM-l s - I . ~ Since the observed rate constant for the hydroxide ion catalyzed breakdown of the hemithioacetal of ethanethiol,* 7.3 X lo7 M-I s-l, is smaller than this, the proton transfer step is fast, and the rate-determining step of the breakdown reaction is the expulsion of the thiol anion from the anion of the addition intermediate, T-, with the rate constant k-1 (Scheme I). The proton transfer step in the forward direction involves the abstraction of a proton from water by Tand the rate constant for this step, k h , may be calculated from k-h and the equilibrium constant for t h e proton transfer, according to (17)
kh = k-hKw/KTH
20" 2.3" 1.9" 1.4" 0.65" 0.13 0.19
in which K T H is the acid dissociation constant of the hemithioacetal and K w is the ion product of water. Based on the estimated pK, for the hemithioacetal of 12.9 (Table I), the value of kh is approximately 8 X lo8 s-l. T h e rate constant for expulsion of the thiol anion from t h e anionic addition intermediate, T-, is given by
8.3 x 10-5
k-1 = k l K R S H / ( K h e m i K T H )
a
Reference 3. pH maintained with 0.01 M acetic acid buffer. dication of a break a t high buffer concentrations nor of buffer catalysis of the addition of the free thiol, RSH. Typical data a r e shown in Figure 5 and t h e rate constants for general acid catalysis of the addition of a series of aromatic thiol anions are summarized in Tables IV-VII.
(18)
in which K R ~ isHthe acid dissociation constant of the thiol, and is equal to 5.8 X lo6 s-l. Thus, the intermediate T- will abstract a proton from the solvent and go on to give the stable hemithioacetal product some 100 times for each time it expels ethanethiol anion and reverts to starting materials. Since proton transfer from the solvent is fast and the attack step is rate determining ( k h > k-1) there is no requirement or advantage for catalysis of the proton transfer step by buffer acids
Table VII. Acid-Catalyzed Addition of Pentafluorobenzenethiol Anion to Acetaldehyde at 25 OC, Ionic Strength 1 .O M (KCI)
Acid H@+ (H2O)
(D20) Cyanoacetic (HzO) W20) (Dz0) Phosphoricb Chloroacetic Methoxyacetic Acetic
Hexafluoroacetone hydrate Pentafluoroacetone hydrate Boric (HzO)
(D20)
Hexafluoro-2-propanol (H20)
(Dz0)
Trifluoroacetone hydrate Trifluoroethanol Water
Total buffer, M
0-0.2 0-0.2 0-0.2 0-0.3 0-0.2 0-0.2 0-0.4 0.005-0.2 0.01-0.05 0.01-0.05 0.01-0.05 0.005-0.015 0.005-0.015 0.0025-0.0125 0-0.5 0-0.05 0-0.2 0-0.2 0-0.1 0-0.2 0-0.4 0-0.8
PH (PD)
1.97" 2.65" 3.15" 1.38 2.28" 3.02' 2.27 3.03 2.99 3.73 3.65 4.22 4.76 4.96 3.02d 4.28e 4.2of 4.711 4.231 4.751 4.181 4.221
No. of points
1 O-3kcat, M-2 s - I
20 2
150 165
5
11
5 5
6 5
6.7 24
5
5
8.7 f 0.5
5
5
5.6 f 0.3
5 5
2.2 f 0.2
5 5 5
6 5 5 5 5
5 5 5
4
1.1 0.58 f 0.07 0.037 0.028 0.29 0.20 0.047 50.0026 3 f 1 x 10-5
a pH maintained with dilute hydrochloric acid. k,,, for phosphate monoanion is 5 1 X lo3 M-*s-'. ' pH maintained with 0.01 M methoxyacetic acid buffer, 70% acid. pH maintained with 0.01 M chloroacetic acid buffer, 30% acid. e pH maintained with 0.005 M acetic acid buffer, 70% acid. f pH maintained with 0.01 M acetic acid buffer, 70% acid.
Journal of the American Chemical Society
1 99:24 /
November 23, 1977
7939 Table VIII. Estimated Microscopic Rate Constants for Hemithioacetal Formation Thiol k l , M-I s-’ k-1, s-’ kh, S-’
Ethanethiol Methoxyethanethiol Methyl mercaptoacetate p-Methoxybenzenethiol 3,4-Dichlorobenzenethiol p-Nitrobenzenethiol Pentafluorobenzenethiol
4.7 x 1 0 5 b 4.7 x 1 0 5 b 2.3 x 105 8 X IO4’ 7.7 x 103’ 3.2 X IO2
’
5.8 X 2.3 x 3.6 x 4.8 x 1.4 x
7.9 x lO8d 107c 107c 107h
109c
6.3 x 109c 1
x
IOIOC
5.0 X IO8
3.8 x 107d
k-h, M-l
k,, M-I
S-’
e e 6 f 4.6 X 109f*g
3 x 109
5.7 x 107h
3.4 x 108d 5 x 107d 3.8 x 107d 4.3 x 107d
s-l0
2 x 10s
6.7 & 0.8 X IO9 gJ 5.6 f 2 x 109g 9.6 x 109 k , / 1.1 k 0.4 X l o l o ’
6.2 X lo8 1.3 x 109 5.1 X lo8
For boric acid; calculated from eq 20, using estimated values Of ~ K T (method H I, Table I). Reference 3. Calculated from eq 18, using average value of KTHfrom methods I1 and 111 (Table I), except for ethanethiol and methoxyethanethiol, where method I was used. Calculated from the observed value of k-h and the average ~ K T from H methods I1 and 111 (Table I) or PKTHfrom method I and a value of k-h = 1 X 1OIo M-I s-l for ethanethiol and methoxyethanethiol using eq 17. e Assumed to be 1 X 1 O l o M-I s-l by analogy with other hemithioacetals for which k-h is rate determining in the hydroxide ion catalyzed breakdown. f The large uncertainty results from the correction for partially rate-determining breakdown of T- in the reverse direction, which depends critically on the error in ko and k 1. g Calculated from the observed rate constant for approach to equilibrium from the forward direction and the experimental equilibrium constants. Average value calculated from the concentration of H + or HA required to reach half of the maximum increase in kobsd, according to eq 6. Estimated from intersection of Brfnsted plots for catalysis by hydrogen bonding at PKHA= 16.0 times 55.5 M and the statistical factor of 2. j The ratio of k-l/kh = 4 suggests that the k-l step is partially rate determining. A correction for partially rate determining k-h from k-h(corr) = k-h(obs) (1 -k k-I/ kh)/(k-]/kh), gives k-hfcorr) = 8 X IO9 M-I s-1, Calculations show that no significant curvature (> (kh f k,[HA])), so that there is no change in rate-determining step as the catalyst concentration is increased. This behavior is observed for the reactions with p-methoxybenzenethiol anion
Journal of the American Chemical Society
and all other thiol anions that are less basic than methyl mercaptoacetate anion (Figure 5 ) ) The Brfnsted plot for the reaction with p-methoxybenzenethiol (Figure 7) is similar to the Eigen curve for a trapping mechanism in that there is a break a t pK 12.6, close to the estimated pK of the addition intermediate of 12.1, and the catalytic constants of four weak acids show no dependence on acidity, as expected for diffusioncontrolled trapping. However, the catalytic constants for stronger acids are larger and the shape of the Brfnsted curve is significantly different from that for methyl mercaptoacetate. This suggests that for moderately strong acids some mechanism of catalysis other than the simple trapping mechanism becomes significant for this thiol. The same conclusion is required to explain the continued rate increases at high concentrations of relatively strong acids that are observed with methyl mercaptoacetate (Figure 1).
Catalysis by Hydrogen Bonding and Preassociation Mechanisms. The Brfnsted plot for general acid catalysis of the addition of the weakly basic pentafluorobenzenethiol anion to acetaldehyde (Figure 8) has a slope of a = 0.26 and is clearly different from the Eigen curve with a limiting slope of zero for diffusion-controlled trapping and from the Brfnsted plot for the addition of p-methoxybenzenethiol anion (Figures 6 and 7 ) . This slope means that there is significant stretching of the A-H bond and is of the magnitude that is expected if there is hydrogen bonding2* of the catalyzing acid to the developing negative charge on oxygen in the transition state for the formation of the anionic intermediate T- (1). =(-'. .\ . c-O(-). . . H-A
/ 1
Similar, but slightly smaller values of a are found for catalysis of the addition of the more basic anion of 3,4-dichlorobenzenethiol and values of a = 0.2 have been reported previously for the anions of benzenethiol, p-nitrobenzenethiol, and thioacetic acid.3 Catalysis of the addition of methyl mercaptoacetate anion a t high concentrations of relatively strong acids, under conditions in which catalysis by trapping is insignificant, also increases with increasing acidity of the catalyst and follows a
/ 99:24 / November 23, 1977
7941
RS-+ $ = O +HA
I 0
I 0
I 4
pK,
f
I
I
12
16
P/4
Figure 8. Brfnsted plot for general acid catalysis of the addition of pentafluorobenzenethiol anion to acetaldehyde at 25 “ C and ionic strength 1.0 M. The Eigen curve for diffusion-controlled proton transfer (dotted line) was calculated from eq 12 with ~ K T =H1 1.8 (arrow) and HA = 60 M-2 s-l. The solid line was calculated from eq 13 and k-1 = 6.1 X lo9 s-’, ~ K T = H 11.8, HA = 60 M-* s-l, and a = 0.26.
~
REAC~ION COORDINATE Figure 9. Free energy-reaction coordinate diagrams for a trapping mechanism (upper curve) and a preassociation mechanism (lower curve)
with a thermodynamically favorable proton transfer. The perturbations introduced by hydrogen bonding in the transition state for the preassociation mechanism (k’l, V-1) and in the T-.HA complex are shown as dashed lines.
Brfnsted line with a slope of a = 0.13 f 0.03, as shown in the lower line of Figure 6. Comparison of Figures 6,7, and 8 shows that the catalysis by hydrogen bonding ( a > 0) becomes progressively more important relative to catalysis by trapping ( a = 0) as the basicity of the thiol anion decreases, and represents the predominant mechanism of catalysis of the addition of pentafluorobenzenethiol anion. In Figure 7 the calculated Eigen curve for catalysis by trapping (dotted line) intersects the dashed line of slope a = 0.16 for catalysis by hydrogen bonding a t a pK of 7 for the catalyzing acid. T h e observed rate constants for catalysis of the addition of pentafluorobenzenethiol anion by carboxylic acids a r e faster than the rate constants for diffusion-controlled trapping of the intermediate T-, shown by the dotted line in Figure 8, by factors of up to 100. This means that free T- cannot be a n intermediate in the reaction and that the reaction must proceed r through a pathway in which T- is formed in the presence of the catalyzing acid through a preassociation m e c h a n i ~ m . ~ , ~ ~ . ~ ~ l I I ! l I I / l A preassociation mechanism could occur without stabilization of the transition state for S-C bond formation, with stabiliPKHA zation of the transition state by hydrogen bonding ( V IScheme , Figure 10. (A) Schematic Brqnsted plots for general acid catalysis by a II), or by a concerted mechanism ( k c ,Scheme 11). Hydrogen preassociation mechanism with hydrogen bonding ( a > 0) and trapping bonding catalysis through a preassociation mechanism involves (a = 0) for strong acids. The k’, point is the catalytic constant expected a n initial association of reactants and catalyst in a n encounter for hydrogen bonding to solvent (k1/55.5)and the k , point is the catalytic complex (K,,,, Scheme 11),S-C bond formation with stabiliconstant for water through a trapping mechanism. (B) Brqnsted plot for the same reaction in the reverse direction expressed as general base cazation of the transition state by hydrogen bonding to H A (k’l), talysis. The OH- point is the catalytic constant expected for hydrogen rapid proton transfer within the T-sHA complex (k,), and bonding to hydroxide ion through a preassociation mechanism and k o ~ separation of A- from TH. This mechanism follows the lower is the catalytic constant for diffusion-controlled proton abstraction from pathway with the dashed line in Figure 9. A preassociation the product. The rate constant for rate-determining proton transfer (kp. mechanism without hydrogen bonding is shown by the lower k-p) in the region near ApK = 0 is shown as the dotted line. solid line. In the reverse direction the addition intermediate breaks down within the T-sHA complex (P-1) faster than the for a trapping mechanism, the upper line is the observed catalyst diffuses away ( k - a ) ,so that the addition intermediate Brpnsted curve for a preassociation mechanism with hydrogen is not a t equilibrium with respect to proton transfer. T h e same proton transfer must ultimately occur in a bonding, and the dashed line is the Brfnsted slope that would preassociation mechanism as in a trapping mechanism in order be observed if the k’l step were rate determining for all acids. The dotted line represents the rate constant if the proton to give the neutral hemithioacetal product, and for weak acids this proton transfer, k,, will become rate determining. For still transfer step, k,, is rate limiting, which can be represented approximately5 by a Brfnsted slope of 0.5 for a short distance weaker acids the separation of the complex TH-A-, with the on either side of ApK = 0, and the right-hand part of the curve rate constant kb, becomes rate determining and the Brfnsted plot will approach a slope of - 1.O. This is illustrated schemarepresents the region in which the separation of A- and TH is rate determining. In the reverse direction (Figure 10B) this tically in Figure 10A, in which the lower line is the Eigen curve
r/
Gilbert, Jencks
/ Addition of Thiol Anions to Acetaldehyde
1942 Table IX.Summarya of Solvent Deuterium Isotope Effects for the Acid-Catalyzed Addition of Thiol Anions to Acetaldehyde
*------7
t
I 6
Yi
General Thiol acid catalyst p-Methoxybenzenethiol Cyanoacetic Boric Hexafluoro-2-propan-
kcat(~)/kcat(~)
1.34 f 0.1 0.9 f 0.1 1.1 f 0.1
01
Water Pentafluorobenzenethiol Cyanoacetic Boric Hexafluoro-2-propan-
2
1.8 f 0.2b 1.7 f 0.2 1.3 f 0.3 1.5 f 0.3
01
H2O+
0
-2
2
4
6
8
Figure 11. Dependence of the catalytic constants for the general-acidcatalyzed addition of thiol anions to acetaldehyde on the PKRSHof the nucleophile at 25 OC and ionic strength 1.O M; ( 0 )cyanoacetic acid; (0) hexafluoro-2-propanol; (A)boric acid; (0)water/55.5 M. The water point for methyl mercaptoacetate is k , = k h k I / k - l . The dashed lines are drawn with a slope of p,, = 0.24. The value of Pnucfor catalysis by water and boric acid is 1.O f 0.2.
region represents rate-determining diffusion-controlled encounter of strong bases with T H , for which P = 0. With weaker bases the proton transfer step, k - p , and then the breakdown of T- within the T-aHA complex become rate determining; the latter step is faster than the stepwise reaction pathway that requires dissociation of the T-sHA complex, shown by the lower solid line. T h e rate constant for catalysis by hydroxide ion, koH-, shows a characteristic positive deviation from the Brfnsted line in Figure 10B because of its rapid rate of facilitated diffusion;22the same positive deviation is seen for k , = khkl/k-l in the forward direction (Figure IOA). T h e rate constants k', and k'OH- for catalysis by hydrogen bonding to water and hydroxide ion a r e not observed because the slower, diffusion-controlled proton transfer step is rate determining. T h e ratio k,/k', is equal to khlk-1 and defines the extent to which proton transfer is rate determining. T h e change in the mechanism of catalysis for strong and weak acids with changing pK of the thiol nucleophile is also manifested in structure-reactivity correlations, as shown in Figure 1 I . Reactions in which trapping is rate determining follow lines of slope PnUc= 1.0 f 0.2. Reactions in which the rate-determining step is nucleophile attack assisted by hydrogen bonding to carboxylic acids and the proton involve only partial formation of the C-S bond in the transition state and show a smaller dependence on the basicity of the nucleophile, with a slope of Pnuc 0.2. T h e trapping mechanism involves formation of the addition intermediate T- in a rapid equilibrium step in which the negative charge on the attacking thiol anion is lost, followed by proton transfer and diffusion away of the conjugate base of the catalyst. T h e effects of polar substituents on the equilibrium addition step a r e similar to those for protonation of the thiol anion because both reactions involve loss of the negative charge and formation of a covalent bond to the sulfur atom. This accounts for t h e slope of pnUc= 1.O for the reactions involving proton transfer from water and from boric acid in the Brqnsted-type correlation of Figure 11. T h e slope of pnUc 0.2 for the reactions catalyzed by stronger acids is consistent with catalysis by hydrogen bonding, with a transition state that involves only a partial loss of negative charge on the thiol anion as it attacks the carbonyl group in the
-
-
Journal of the American Chemical Society
/
0.91 f 0.15
a Data from Tables IV and VII. This isotope effect calculated for the reaction in the reverse direction for the reaction of hydroxide ion with the hemithioacetal using ( k ~ / k ~ =) ~( k~H /"k D ) f w d KHRSHKDwKDhemi/(KDRSHKHwKHhemi) is 1.1, consistent with a diffusion-controlled reaction.'
rate-determining step (1). For methyl mercaptoacetate, the rate constants for cyanoacetic acid catalysis are known for both the hydrogen bonding and trapping mechanisms. These rate constants fall on the lines of slope 0.2 and 1.O, respectively. Figure 11 also demonstrates that the importance of catalysis by hydrogen bonding depends on the pK of the acid catalyst. Catalysis by the strong acid cyanoacetic acid proceeds predominantly by the hydrogen bonding mechanism for all thiols of p K < 7 (Pnuc = 0.2). Catalysis by the weaker acids hexafluoro-2-propanol (pK = 9.2) and borate (pK = 9.0) occurs by trapping (Pnuc= 1 .O) for all thiols of pK > 2.7. T h e positive deviation of the rate constant for hexafluoro-2-propanol catalysis of the addition of pentafluorobenzenethiol anion suggests that for this weakly basic thiol, there is catalysis by hydrogen bonding even with weakly acidic catalysts. For the addition of p-methoxybenzenethiol anion, the rate constants for catalysis by trapping and by hydrogen bonding a r e similar. Thus, the hydrogen bonding and trapping mechanisms are energetically comparable and both mechanisms of catalysis should be observed depending on the pK of the acid catalyst. This is consistent with the positive deviation of the catalytic constants for strong acids above the Brqnsted line of slope zero defined by the catalytic constants for weaker acids (Figure 7). T h e solvent deuterium isotope effects for the catalyzed reactions a r e small, in the range expected for catalysis by trapping or hydrogen bonding (Table IX). The small isotope effects for hexafluoro-2-propanol catalysis of methoxybenzenethiolate addition and for boric acid catalysis of both reactions a r e consistent with diffusion-controlled trapping and the larger isotope effects for hexafluoro-2-propanol catalysis of pentafluorobenzenethiolate addition and for cyanoacetic acid catalysis a r e consistent with catalysis by hydrogen bonding, but experimental errors and the small rate differences preclude definitive conclusions. T h e activity of boric acid as a catalyst is of special interest because boric acid is a pseudoacid that ionizes by extracting hydroxide ion from the solvent rather than by donation of a proton to a base.*' Boric acid falls on the Brpnsted line for catalysis of the addition of the anions of p-methoxybenzenethiol and methyl mercaptoacetate. This is consistent with a mechanism of catalysis involving rate-determining proton transfer through a n intermediate water molecule. T h e rate
T-
+ HO + B ( O H ) 3 + TH + OB(OH)3H
H
(21)
constants for thermodynamically favorable proton transfer to
T- from boric acid ( k a ,Table VIII) a r e close to the rate con-
99:24 / November 23, 1977
1943 the strength of the hydrogen bond between H A and the transtant of 9.1 X lo8 M-I s-l that has been reported for a thersition state. The different mechanisms for the addition reaction modynamically favorable proton transfer mediated by borate a r e defined in Scheme 11. (ApK = 3.8).26 Boric acid is a poor catalyst for protonation of Enforced general acid catalysis by trapping must appear carbon in a vinyl ether and a ketene acetal3] and borate anion whenever the rate constant for breakdown of T- to reactants, is a poor catalyst for e n ~ l i z a t i o nThis . ~ ~ is consistent with the k-1, becomes larger than the rate constant for conversion of conclusion that proton transfer to and from carbon ordinarily T- to TH by proton abstraction from water, kh. Thus, the does not involve a n intermediate water molecule.33 appearance of catalysis by trapping depends directly on On the other hand, boric acid shows a negative 6zi;ation of k-llkh. When kh kHA, k’HA > k l k , / k - l , and k’-l > k-,) it occurs by a preassociation mechanism in which the T-mHA complex breaks down faster than it separates and the intermediates are not at equilibrium with the bulk solvent with respect to transport processes. In the absence of hydrogen bond stabilization a preassociation mechanism occurs only when the intermediate breaks down with a rate constant faster than the rate constant for diffusional separation of the T-.HA c ~ m p l e x usually , ~ ~ ~ ~ ~ ~ ~ about 101o-lOll s-l, but if there is significant stabilization of the complex and transition state by hydrogen bonding, the value of k - , will be reduced and a preassociation mechanism can occur with values of k’-1 and k-l of lo9 s - ] or less (Table VIII). When the reaction is forced to proceed through a preassociation mechanism with an initial association of nucleophile, aldehyde, and acid in an encounter complex, any stabilization of the transition state by H A relative to water will result in an increase in the observed rate and catalysis by hydrogen bonding with a > 0. If a preassociation mechanism is not enforced, kl rather than kh will be rate determining for the “water” reaction, catalysis by H A must compete with catalysis by 55 M water, and a larger catalytic constant and a value are required in order for catalysis by hydrogen bonding to be significant. The preassociation mechanism causes a rate increase not only by hydrogen bonding to the transition state but also by placing a proton donor in position to rapidly protonate Tas soon as it is formed and thereby auoiding the higher energy proton transfer step that involves rate-determining diffusion of relatively strong acids to the unstable intermediate T-. In the reverse reaction it avoids the rate-determining diffusion away of H A from T- with the rate constant k - , and, as a consequence of this, the observed reaction rates with weak bases are larger than the rates of the overall process of proton abstraction from T H by weak bases through the Eigen mechanism. In the special case in which catalysis at low acid concentration is by trapping and at high concentrations by hydrogen bonding, as in the methyl mercaptoacetate reaction, HA is larger than k’HA (Figure 6), but catalysis by hydrogen bonding can be observed because of the change in rate-determining step at high acid concentrations. In this case there is significant catalysis by hydrogen bonding even when proton transfer is fast and the catalysis is not enforced through a preassociation mechanism. Thus, there is a small but significant stabilization of the transition state by hydrogen bonding (through k’l) relative to the transition state for the uncatalyzed reaction ( k l ) so that catalysis can be detected without the advantage described by eq 25. Such nonenforced catalysis has also been
Journal of the American Chemical Society / 99:24 / November 23, 1977
1945
observed for the addition of weakly basic carbanions7 and of sulfite dianion3’ to the carbonyl group. The rate constant of k - l = 5 X lo6s-’ for the expulsion of methylamine from 236is essentially the same as the rate con-
0.3/r A
0-
I +
H-C-NHBCHS
I
GHi
Q
O.;_ 0.1
2
stant of k-1 = 5.8 X l o 6 s-l for the breakdown of T- with expulsion of ethanethiol anion (Table VIII). This suggests that general acid catalysis of the addition of less basic amines should proceed through the same spectrum of mechanisms as with less basic thiol anions. Evidence for several of these mechanisms has already been reported by Sayer et al. for the addition of “a-effect” amines to substituted benzaldehyde^.^,^ The results reported here establish that there is stabilization of the transition state by hydrogen bonding in the attack of certain thiol anions on carbonyl compounds, but do not rigorously establish whether or not the overall catalyzed reaction is stepwise or concerted: Le., whether the reaction path proceeds through the intermediate species T-.HA in a stepwise mechanism or proceeds directly on to TH.A- through a concerted mechanism without passing through discrete steps or intermediates. The following evidence provides support for the stepwise reaction mechanism. (1) The fact that T- exists in water with a significant lifetime (>>10-13 s) means that a concerted mechanism of catalysis is not enforced by a rate of expulsion of RS- from Tthat is so fast that T- does not exist and the reaction could not be stepwise. (2) The water-catalyzed addition reaction certainly proceeds in a stepwise mechanism through T- followed by a slow, thermodynamically unfavorable proton transfer and, since water falls on the Brfnsted plot for general acid catalysis by hydrogen bonding, the same must be true for catalysis by other weak acids. (3) Strong acids fall on the same Brfnsted line as weaker acids and there is no evidence for an upward curvature of the Brfnsted slope for strong acids, showing that there is no additional, lower energy reaction pathway that is different from the pathway followed by weak acids. A concerted mechanism would be required if there were no barrier for proton transfer within the hydrogen bond so that the species T-aHA cannot exist as an intermediate in a stepwise reaction mechanism. It is necessary that the basicity of the transition state be greater than that of water in order to obtain significant stabilization by hydrogen bonding to an acid H A and it is probable that the transition states have pK values in the range of roughly 2-9, as described in the following section. If there were a single potential well hydrogen bond with no barrier for proton transfer in these transition states, a thermodynamically favorable transfer of the proton would be expected to take place from strong catalyzing acids to the carbonyl oxygen atom in the transition state and the Bronsted coefficient a would approach 1.0 for the proton and other strong acids. Therefore, the fact that the observed values of a are all small means that there must be a barrier that prevents motion of the proton toward oxygen in the transition state. This would be expected if the proton is in one potential well of a double potential well hydrogen bond; the barrier could be caused by the presence of a water molecule between A H and the carbonyl oxygen atom. However, the possibility cannot be rigorously excluded that the barrier disappears for the more basic species T- so that T--HA would not exist as a discrete intermediate when H A is a strong acid.
O‘
2
1 4
1 6
! B
O
1
1
a
10
T
2 O
4
0
12
16
p K#A Figure 12. (A) Variation in a with the P K R ~ of H the nucleophile. (B) Variation in Snucwith the P K H Aof the acid catalyst. The solid lines have been drawn with a slope of 1/ c 2 = 0.026.
Structure-Reactivity Interactions. We consider here changes in the structure of the transition state for general-acid-catalyzed attack of thiol anions on acetaldehyde, as measured by changes in the Brfnsted coefficient a and in Pnuc, with changing structure of the reactants and catalyst. It is firmly established by the experimental data that the Brfnsted coefficient a increases with decreasing basicity of the attacking thiol anion. No general acid catalysis is detectable for the attack of methoxyethanethiol anion. The absence of a rate increase in the presence of 1 M formate buffer,* 50% anion, sets an upper limit of IO5 MF2 s-l on the rate constant for catalysis by formic acid and a 6 0.09 for the Brfnsted coefficient for this reaction. General acid catalysis of the attack step is detectable with relatively strong acids for the less basic methyl mercaptoacetate anion (Figure 6, a = 0.1 3 f 0.03) and exhibits increasing values of a as the basicity of the thiol anion decreases, with a value of a = 0.26 for catalysis of the attack of pentafluorobenzenethiol anion (Table X). This increase in a with decreasing pK,,, of the attacking nucleophile can be described according to
dcu 1 -- W n u c = --
(28)
-dpKnuc c2 ~ P K H A with a Cordes coefficient3* 1/c2 = 0.026 that is the slope of a plot of a against pK,,, (Figure 12A). It is required by eq 28 that there be a corresponding increase in the sensitivity of the rate to the basicity of the attacking nucleophile, Pnuc,as the strength of the catalyzing acid decreases (PKHAincreases). The dependence of the rate constants for catalysis by the proton, cyanoacetic and acetic acids, and water on the basicity of the nucleophile is shown in Figure 13. The observed rate constants have been corrected for catalysis by trapping and the
Gilbert, Jencks
/ Addition of Thiol Anions to Acetaldehyde
7946 RS-+-O-+~A
2
1 4
I
I
6
8
0 RS$C=O.HA 10
R s-
Figure 13. Dependence of the catalytic constants for the hydrogen bonding H the thiol. Catalytic constants for carboxylic mechanism on the P K R ~of
points for water ( k , , Table VIII) are based on a n extrapolation of the Brfnsted plots obtained with stronger acids. Although there may be some curvature within the individual lines, it is clear that there is a n increase in the slope, Pnuc,with increasing pK of the catalyst. T h e increase in Pnucis consistent with the slope of 1/c2 = 0.026 (Figure 12B) and the d a t a for thiols of pK = 2.6-7.8 are consistent with lines of slope 0.14,0.24,0.29, and 0.58 (Figure 13, solid lines) as required by eq 28 and the value of 1/c2 = 0.026. Figure 1 3 illustrates how the reciprocal relationships required by eq 28 follow directly from t h e experimental data with no assumptions about mechanism or transition state structure. T h e increasing slopes, Pnuc,with decreasing acid strength that a r e shown in the figure require that for a given series of catalyzing acids the range of rate constants, and hence the value of a, be smaller for a thiol of pK = 7.8 than for a thiol of pK = 2.6. These results may be described in terms of the reaction coordinate diagrams of Figure 14 in which the horizontal and vertical axes a r e defined by the observed values of a and Pnuc and presumably represent some measure of the amount of proton transfer and of C-S bond formation, respectively. The energy contour lines a r e omitted from Figure 14 for clarity. Changes in the pK of the catalyst and nucleophile correspond to changes in the energy of the right edge and top edge of the diagrams, respectively, and such changes will shift the position of the transition state in a direction that is determined by the orientation and geometry of the saddle point and reaction ~ o o r d i n a t eT. ~h e~ observed decrease in a with increasing basicity of the nucleophile corresponds to a shift in the position of the transition state to the left along the x axis. This shift can be accounted for if the reaction coordinate on the diagram has a significant horizontal component so that it is rotated clockwise from the vertical. Such a reaction coordinate, for the attack of a weak nucleophile catalyzed by a weak acid, is shown in Figure 14A. An increase in the basicity of the nucleophile lowers the energy of the top relative to the bottom of the diagram and shifts the position of the transition state in directions parallel and perpendicular to the reaction coordinate, as shown by the single-headed arrows. T h e resultant of these arrows, shown by t h e dashed arrow, requires a horizontal shift of the
/ 99:24 /
1-
O HA
RS-+-OH.A-
t
R s+= OH.A-
a-
RS-+-OH.A-
' B
I
r t
acids have been corrected for catalysis due to trapping by subtracting the observed catalytic constant for boric acid and the catalytic constants for the proton have been corrected by subtracting ten times this catalytic constant. The catalytic constants HA, for water were estimated from the intersection of the Brfnsted plots at PKHA= 16.0,except for ethanethiol and methoxyethanethiol anions for which k'HA = k1/55.5 M. The data are for catalysis by the proton (e);cyanoacetic acid (0);acetic acid (A); and water (A).The solid lines are drawn with slopes given by the Cordes coefficient l/cz = 0.026. The dashed line is drawn as described in the text.
J o u r n a l of the American Chemical Society
a-
R s:>~ = 0 ,HA
R SC;=
+
OH .A-
Figure 14. Reaction coordinate diagrams illustrating (A) the effect of increasing basicity of the nucleophile for the reaction of a weak nucleophile catalyzed by a weak acid and (B) the effect of decreasing acidity of the acid catalyst for the reaction of a strong nucleophile catalyzed by a strong acid.
transition state to the left, corresponding to the observed decrease in a, and is consistent with a downward shift, corresponding to a decrease in fin,,. T h e corresponding diagram for the attack of a strong nucleophile catalyzed by a strong acid, shown in Figure 14B, serves to illustrate the effect of changing pK of the catalyst. A decrease in t h e acidity of the catalyzing acid raises the energy of the right relative to the left side of the diagram and shifts the position of the transition state in directions parallel and perpendicular to the reaction coordinate, as shown by the vectors. The resultant shift in the position of the transition state corresponds to a n upward motion, leading to the observed increase in finUc,and does not require any horizontal shift that would correspond to a change in a. The Brfnsted line in Figure 8 for acids of pK = - 1.7 to 9 and the lower line in Figure 6, for catalysis by hydrogen bonding, give no evidence for a change in a with changing pK of the acid and are inconsistent with any large change. These shifts in the position of the transition state a r e consistent with a direction of t h e reaction coordinate that is rotated by only a moderate amount from the vertical, with a relatively small downward curvature along the reaction coordinate and a steeper upward curvature perpendicular to the reaction coordinate. This is what might be expected for a hydrogen-bonded transition state in which the proton is in a potential well that moves to the right as t h e transition state becomes more basic and approaches the structure of the anionic addition intermediate T-. T h e d a t a also suggest that the value of P,,, increases with decreasing basicity of the attacking thiol anion; this may be described as a "Hammond-Marcus" effect.39 The value of fin", is 0.1 f 0.1 for the attack of basic, aliphatic thiol anions on acetaldehyde2 and is -0.6 for the attack of weakly basic, aromatic anions in a "water" reaction (Figure 13). The data are not adequate to determine whether there is curvature within the series of aromatic thiol anions. T h e slower attack of thiol
November 23, I977
7947 anions on esters and thiol esters exhibits a value of Pnuc= 0.3 with no indication of any difference between aliphatic and aromatic thiols;23 however, the data do not completely exclude the possibility that Pnuc is larger for the aromatic thiol anions. A decrease in Pnuc with increasing basicity of the nucleophile corresponds to a downward movement of the transition state in Figure 14. Such a shift is consistent with a large vertical component to the reaction coordinate and a smaller curvature in the parallel than in the perpendicular direction to the reaction coordinate, as suggested above, so that a decrease in the energy of the top relative to the bottom edge of the diagram shifts the transition state downward in a direction that is predominantly parallel to the reaction coordinate. The change in Pnuc with increasing basicity of the nucleophile is described, within experimental error, by a coefficient p y = dPnuc/ -bpKnuc = 0.089, as shown by the dashed line in Figure 13. This dashed line, for hydrogen bonding catalysis by water, is drawn according to
description of the reaction, but they d o serve to illustrate that the changes in CY and Pnucwith changing structure of the reactants a r e not unreasonable and may be described in terms of the behavior that might be expected for a hydrogen-bonding mechanism.
References and Notes
+
log k'HA = 2.75 0 . 6 4 p K ~ s ~0 . 3 p K ~ ~ -k 0 . 0 2 6 p K ~ ~ p K 0~ .s0~8 9 p K 2 ~ s ~ / 2(29) in which the coefficient of the last term is b&,c/-bPKRSH. T h e coefficient of the fourth term represents the Cordes coefficient, 1/c2, and the coefficients of the other terms a r e defined by the intercepts of the Cordes plots in Figure 12. Equation 29 also predicts curvature of the lines for catalysis by other acids in Figure 13, but the d a t a a r e not of sufficient accuracy to determine the presence or absence of such curvature. These structure-reactivity relationships a r e utilized to define a n energy surface for the reaction in the accompanying pa per .39 A transition state with increased S-C bond formation will have a n increased negative charge and basicity on the carbonyl oxygen atom that will give a correspondingly stronger hydrogen bond to the catalyzing acid. The increase in hydrogen bond strength is expected to follow some relationship such as that proposed by Hine40 (eq 30 and 3 1) log K A B= ~ P K H A P K H ~ o ) ( P K H ~ o-+PKBH) - 1.74 (30)
in which K A Bcorresponds to the ratio of the rate constants for catalysis by a n acid of PKHAand by water ( k l ) ,PKBH is the pK of the conjugate acid of the transition state, and 7 is a constant taken as equal to 0.024. Substitution of the observed values of CY into eq 3 I gives PKBHvalues for the transition state that increase from
