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DOI: 10.1002/ejoc.201201540

Comparison of the Electrophilic Reactivities of N-Acylpyridinium Ions and Other Acylating Agents
Tobias A. Nigst[a] and Herbert Mayr*[a]
Dedicated to Professor Ernst-Ulrich Wrthwein on the occasion of his 65th birthday
Keywords: Kinetics / Linear free energy relationships / Acylation / Amines / Organocatalysis
The kinetics of the reactions of carbanions, carboxylate anions, and primary and secondary amines with acylating agents were studied in acetonitrile and dimethyl sulfoxide (DMSO) under first-order conditions by UV/Vis spectrophotometry and conductimetry. Whereas reactions of a large variety of nucleophiles with ordinary carbanions and Michael acceptors generally follow the linear free energy relationship lg k2 (20 C) = sN(N + E), separate correlation lines for different types of nucleophiles were found when (lg k2)/ sN was plotted against N for the reactions with acyl derivatives 25. Even when nucleophilic attack is rate determining, the reactivities of acylating agents towards nucleophiles cannot be described by a single set of nucleophile-independent electrophilicity parameters.

Introduction
Nucleophilic substitution reactions at acyl derivatives are of eminent importance in chemistry and biology, and many investigations have dealt with the corresponding reaction mechanisms, which are summarized in Scheme 1.[1] Usually acylations are multistep reactions, certain steps of which may be catalyzed by acids or bases. Several mechanistic scenarios have been discovered, and their occurrence was found to depend on the substrates and the reaction conditions. As shown in Scheme 1 (top), acylium ions can be formed in different ways before they undergo fast subsequent reactions with nucleophiles. When the substrates possess -acidic protons, ketenes may be generated in the presence of bases. There has been much debate concerning whether attack of the nucleophiles at the carbonyl group displaces X in a concerted manner or whether tetrahedral intermediates are involved.[1,2] In 1972, Ritchie discovered that the relative reactivities of various anionic nucleophiles towards triarylmethyl cations, aryl tropylium ions and aryldiazonium ions do not depend on the electrophile and can be described by Equation (1), where lg k0 is an electrophile-specific parameter and N+ is a nucleophile-specific parameter.[3]
[a] Department Chemie, Ludwig-Maximilians-Universitt Mnchen, Butenandtstrasse 513 (Haus F), 81377 Mnchen, Germany Fax: +49-89-218077717 E-mail: [email protected] Homepage: http://www.cup.uni-muenchen.de/oc/mayr/ Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201201540.
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Scheme 1. Mechanisms for acylation reactions.

lg k = lg k0 + N+

(1)

As the rate constants for the reactions of aryl acetates showed a different reactivity pattern, Ritchie concluded that the reactivities of esters cannot be described by Equation (1).[4] We have previously reported that the reactions of carbocations and quinone methides with different classes of -, -, and n-nucleophiles follow the linear free energy relation1

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ship Equation (2), where electrophiles are characterized by one parameter (E) and nucleophiles are characterized by two solvent-dependent parameters (N and sN).[5]
lg k2(20 C) = sN(N + E) (2)

T. A. Nigst, H. Mayr

Recently, we studied the rates of the addition reactions of carbon nucleophiles to nonactivated carbonyl groups in aprotic solvents.[6] For these investigations, acceptor stabilized carbanions, such as malonate or the highly nucleo-

philic phenylacetonitrile anions, could not be used as reference nucleophiles because of the high reversibility of these reactions. On the other hand, the reactions of sulfur ylides with aldehydes, imines, and enones yielded the corresponding epoxides, aziridines, and cyclopropanes quantitatively. Because in many of these reactions the initial CC bond formation, which leads to betains, was found to be rate determining, it became possible to quantify the electrophilicities of aldehydes, imines, and enones by Equation (2). We now report on the electrophilic reactivities of acyl compounds 15 (Figure 1), which undergo substitution reactions with carbanions 612, amines and hydrazines 13 28, and carboxylate anions 2930 (Figure 2). These data are used to examine the applicability of the linear free energy relationship (2) for the quantitative characterization of acyl electrophiles.

Results and Discussion

The products obtained by reactions of amines and hydrazines with carboxylic acid chlorides, anhydrides and esters have previously been reported.[2b,79] Methylhydrazine (28) reacts smoothly at its methyl-substituted nucleophilic center with most electrophiles,[10] including benzhydrylium ions and quinone methides.[11] However, the situation is more complicated in acylation reactions. Whereas several anhydrides, including benzoic anhydride (2) and acetic anhydride (3), were found to react with methylhydrazine (28) selectively at the NHMe group, the corresponding reactions with ethyl acetate occurred at the NH2 group predominantly (Scheme 2).[8,9] Nucleophilic displacement of the BAc2 type with rate-determining addition was claimed for the reaction of 28 with acetic anhydride, whereas the corresponding reaction with ethyl acetate was claimed to proceed through addition-elimination with rate-limiting proton transfer.[8] Hinman and Fulton further observed that the selectivity for NH2 attack of methylhydrazine (28) in reactions with esters increased with increasing size of the acyl group, that is, the percentage of 1-acyl-1-methylhydrazine decreased in the order: methyl acetate methyl propionate methyl isobutyrate.[9]

Scheme 2. Relative ratios of NH2 and NHMe acylation of methylhydrazine (28) with different acylating agents.[8]

Figure 2. Nucleophiles used in this study. Counterion of the carbanions: K+.[b] Counterion of the carboxylates: nBu4N+. 2
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[a]

The combination of 4-nitrophenyl benzoate (1) with two equivalents of potassium diethyl malonate (7) in dimethyl sulfoxide (DMSO) at 20 C yielded 31 after workup with
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4-toluenesulfonic acid, that is, 1 reacted with nucleophilic replacement of 4-nitrophenolate by the carbanion (Scheme 3). Treatment of 31 with one equivalent of KOtBu in DMSO yielded the corresponding enolate K+31 quantitatively. Similar substitutions by carbon nucleophiles have previously been reported for the reactions of benzoic anhydride (2) with the anion of malononitrile (9),[12] benzoyl chloride (4) with the anions of acetylacetone (6),[13] ethyl cyanoacetate (8),[14] and malononitrile (9),[15] as well as for the reaction of phenyl benzoate with the anion of nitromethane (11).[16]

linear for all reactions, and the second-order rate constants k2 (Table 1) were obtained as the slopes of these plots according to Equation (3).
kobs = k2[Nu] + k0 (3)

Figure 3. Exponential increase of the absorbance at = 435 nm during the reaction of 4-nitrophenyl benzoate ([1] = 6.79 105 m) with potassium ethyl cyanoacetate ([8] = 4.08 103 m; kobs = 8.51 104 s1) in DMSO at 20 C. Inset: A plot of kobs vs. [8] yields the second-order rate constant k2 = 1.96 101 m1 s1.

Scheme 3. Reaction of potassium diethyl malonate (7) with 4-nitrophenyl benzoate (1) and subsequent deprotonation of 31 with KOtBu.

Kinetic Investigations 4-Nitrophenyl benzoate (1) is the least reactive acylating agent in the series 15. The rates of its reaction with carbanions and amines were determined spectrophotometrically in DMSO solution at 20 C by monitoring the appearance of the 4-nitrophenolate anion with conventional or stopped-flow UV/Vis spectrophotometry. Stock solutions of the carbanions were prepared by partial deprotonation of the CH acids (612-H) with 0.5 equiv. of KOtBu in DMSO. Ethyl cyanoacetate (8) was used as the isolated potassium salt. The kinetics were performed under first-order conditions by using a large excess of the nucleophiles (10 equiv. compared to the electrophile). The first-order rate constants kobs were obtained by leastsquares fitting of the monoexponential function A = A0 (1 ek(obs)t) + C to the increases of the UV/Vis absorbance of the 4-nitrophenolate; a typical example is shown in Figure 3. Plots of kobs versus nucleophile concentrations were
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It was not possible to employ ester 1 in excess for these kinetic investigations, because the resulting products contain CH groups that are more acidic than the original CH acids, and protonate the carbanions 612. Because the reactions of the highly reactive acylating agents 25 with carbanions were too rapid even for the stopped-flow method, and reactions with other carbon nucleophiles such as enamines gave complex kinetics, we limited our investigations to the kinetics of the reactions of 25 with amines and carboxylate anions in acetonitrile at 20 C. As benzoic anhydride (2) and 1-benzoyl-4-(dimethylamino)pyridinium chloride (5) have absorption maxima at higher wavelengths than the reaction products, their reactions with amines and carboxylates were monitored spectrophotometrically under first-order conditions with the nucleophiles in excess. The N-acyl-pyridinium chloride 5 was synthesized by treatment of benzoyl chloride (4) with an equimolar amount of 4-(dimethylamino)pyridine (DMAP) in acetonitrile followed by precipitation (Et2O) and isolation of the product.[27] Alternatively, stock solutions of 5 were generated by mixing solutions of equal amounts of DMAP and benzoyl chloride (4). As demonstrated for the reaction of 5 with benzylamine (15), both methods gave rate constants that differed by less than 3 %. For all reactions of 2 and 5 with amines and carboxylates, monoexponential decays of the absorbances at = 280 or 317 nm, respectively, were observed. Again, correlations of the first-order rate constants kobs with the concentrations of the nucleophiles were linear, and the second-order rate constants k2 were derived from the slopes of these correlations (Table 2).
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Nu Solvent N, sN 17.64, 20.22, 19.62, 19.36, 25.11, 20.71, 21.54, 15.28, 14.29, 16.07, 15.70, 17.19, 17.35, 0.73[a] 0.65[a] 0.67[a] 0.67[a] 0.54[b] 0.60[c] 0.62[d] 0.65[e] 0.67[f] 0.61[e] 0.64[h] 0.71[h] 0.68[f] k2exp [m1 s1] 1.93 102 6.10 102 1.96 101 9.22 101 3.06 101 8.37 101 1.14 101 7.70 101 2.49 103 [g] 2.59 4.45 1.32 101 5.39 101[i] 1.05 101 4.20[l] 1.48 103
[k] [l]

T. A. Nigst, H. Mayr

Table 1. Second-order rate constants k2 for the reactions of 4-nitrophenyl benzoate (1) with carbanions, amines, and alkoxide anions at 20 C; for an explanation of k2calc see the section on correlation analysis. k2calc [m1 s1] 6.46 103 5.33 101 2.07 101 1.39 101 2.59 102 1.10 3.61 3.28 104 5.57 105 1.63 103 6.89 104 3.55 103 5.79 103 6.93 104 6.26 107 1.31 103 k2exp/k2calc 2.99 1.14 101 9.45 101 6.64 1.18 101 7.60 101 3.15 2.35 103 4.47 101 1.59 103 6.46 103 3.72 103 9.31 101 1.51 104 6.71 106 1.13 106 Carbanions 6 DMSO 7 DMSO 8 DMSO 9 DMSO 10 DMSO 11 DMSO 12 DMSO Amines 15 DMSO 15 CH3CN 17 DMSO 18 DMSO 25 DMSO 25 CH3CN Alkoxide anions EtO EtOH HO H2O HOO H2O

15.78, 0.65[j] 10.47, 0.61[h] 15.40, 0.55[h]

[a] From ref.[5c] [b] From ref.[17] [c] From ref.[18] [d] From ref.[19] [e] From ref.[20] [f] From ref.[21] [g] Second-order rate constant extrapolated from the Eyring plot from ref.[7c] [h] From ref.[22] [i] Second-order rate constant at 25 C from ref.[23] [j] From ref.[24] [k] Second-order rate constants at 25 C from ref.[25] [l] Second-order rate constants at 25 C from ref.[26] Table 2. Second-order rate constants k2 [m1 s1] for the reactions of 25 with amines, hydrazines and carboxylates in acetonitrile at 20 C.
Nu N, sN Amines 13 12.35, 0.72[a] 14 13.77, 0.70[a] 15 14.29, 0.67[a] 16 14.37, 0.66[a] 17 14.11, 0.71[a] 18 15.11, 0.63[a] 19 15.27, 0.63[a] 20 16.45, 0.56[c] 21 13.24, 0.93[a] 22 14.51, 0.80[a] 23 15.10, 0.73[a] 24 15.65, 0.74[a] 25 17.35, 0.68[a] 26 18.64, 0.60[a] 27 16.15, 0.68[d] 28 17.73, 0.58[d] Carboxylates 29 16.82, 0.70[e] 30 15.30, 0.76[e] 2 5.43 101 7.45 101 7.55 101 1.80 102 3.82 102 4.54 102 2.01 103 4.05 101 2.23 101 8.30 101 3.16 103 2.07 104 5.81 101 1.36 103 3 1.06 102 1.43 102 1.76 102 4.49 102 5.77 102 7.35 102 7.88 6.54 101 9.15 101 5.57 102 4 6.28 102 1.00 104 1.14 104 1.63 104 4.16 104 4.14 103 2.86 104 2.96 104 3.45 105 5 1.64 2.78 102 4.78 102 [b] 6.56 102 1.53 103 3.52 103 4.27 103 1.81 104 2.13 2.68 101 6.14 101 5.70 102 1.43 104 1.80 105 2.87 102 6.10 103 1.19 106 4.93 104

to obtain absolute values of . For all reactions of 3 and 4, monoexponential increases of the conductivity were observed due to the formed ammonium ions. The secondorder rate constants k2 were obtained from the linear correlations of the first-order rate constants with the concentrations of the nucleophiles (Table 2).

Correlation Analysis Figure 4 shows a plot of the second-order rate constants for the reactions of primary (closed circles) and secondary amines (open circles) with 1-benzoyl-4-(dimethylamino)pyridinium chloride (5) versus the corresponding rate constants for the reactions of these nucleophiles with benzoic anhydride (2). A linear correlation comprising both primary and secondary amines is found. However, when the second-order rate constants for the reactions of primary (closed symbols) and secondary amines (open symbols) with acetic anhydride (3; diamonds in Figure 5), benzoyl chloride (4; triangles in Figure 5) and 4-nitrophenyl benzoate (1; squares in Figure 5) were plotted versus the corresponding rate constants for the reactions of these nucleophiles with benzoic anhydride (2), primary and secondary amines do not follow the same correlation. Whereas the correlation lines for secondary amines are above those of the primary amines for benzoyl chloride (4) and acetic anhydride (3), the only secondary amine studied with 4-nitrophenyl benzoate (1) is located below the correlation line for the primary amines. It is therefore concluded that the relative reactivities of primary and secondary amines depend on the nature of the acylating agents. Vice versa, the relative reactivities of the acyl compounds also depend on the nature of the nucleophilic reaction partner (Figure 6). For primary amines, the
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[a] From ref.[21] [b] The average of the second-order rate constants from the reaction of 15 with the isolated 1-benzoyl-(4-dimethylamino)pyridinium chloride 5 (k2 = 473 m1 s1) and by mixing solutions of 4 with equimolar amounts of DMAP (k2 = 484 m1 s1). [c] From ref.[28] [d] From ref.[11] [e] Nucleophilicity parameters at 25 C from ref.[29]

The kinetics of the reactions of acetic anhydride (3) and benzoyl chloride (4) with primary and secondary amines were evaluated from measurements of the relative conductivities (rel) under first-order conditions. Because we have previously demonstrated the proportionality between concentration and conductivity of the ammonium salts under these conditions, we did not calibrate the conductivity cell
4
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oline (24). A comparison of the reactivities of the acylating agents 15 towards n-propylamine (18; left side of Figure 6) and diethylamine (23; right side of Figure 6) shows that the reactivities of these electrophiles are comparable to those of quinone methides and amino-substituted benzhydrylium ions.

Figure 4. Correlation of the second-order rate constants k2 for the reactions of 1-benzoyl-4-(dimethylamino)pyridinium chloride (5) with primary (filled circles) and secondary amines (open circles) versus the second-order rate constants for the corresponding reactions with benzoic anhydride (2).

Figure 6. Comparison of the second-order rate constants k2 for reactions of acylating agents 15, benzhydrylium ions, and quinone methides[21] with n-propylamine (18, left side) and diethylamine (23, right side).

Figure 5. Correlation of the second-order rate constants k2 for the reactions of the acylating agents 1 (squares), 3 (diamonds), and 4 (triangles) with primary (filled symbols) and secondary amines (open symbols) versus the second-order rate constants for the corresponding reactions with benzoic anhydride (2).

relative reactivities of the acylating agents 15 decrease in the order: benzoyl chloride (4) 1-benzoyl-4-(dimethylamino)pyridinium chloride (5) acetic anhydride (3) benzoic anhydride (2) 4-nitrophenyl benzoate (1). In contrast, the acyclic secondary amines 2123 react 1.5 to 3.7 times faster with acetic anhydride (3) than with 1benzoyl-4-(dimethylamino)pyridinium chloride (5), whereas the reactivity order is reversed for the more reactive morphEur. J. Org. Chem. 0000, 00

To test the applicability of Equation (2) for predicting the rate constants for the aminations of 25, we plotted (lg k2)/sN versus the nucleophilicity parameters N of the amines (Figure 7). For all of these highly reactive acyl compounds, where a concerted mechanism can be assumed or where the initial attack of the nucleophile is rate limiting,[1,2b] separate linear correlation lines are found for primary (circles) and secondary amines (squares), showing that primary amines react up to 50 times faster than secondary amines of comparable nucleophilicity N towards benzhydrylium ions. In general, the gap between the reactivities of primary and secondary amines is smaller for better leaving groups and electrophiles with lower steric demand, that is, the gap decreases in the order: 1-benzoyl-4-(dimethylamino)pyridinium chloride (5) benzoic anhydride (2) acetic anhydride (3) benzoyl chloride (4). Furthermore, it can be noted that the slopes of the correlation lines are significantly greater than unity, which implies that the acylation reactions are more sensitive towards changes of the nucleophiles than the corresponding reactions with benzhydrylium ions. The parent hydrazine (20) has a similar reactivity to that of ordinary primary amines in reactions with benzoic anhydride (2; Figure 7, a) and the 1-benzoyl-4-(dimethylamino)pyridinium chloride (5; Figure 7, c), whereas methylhydrazwww.eurjoc.org

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T. A. Nigst, H. Mayr

ine (28) and 1,2-dimethylhydrazine (27) lie on or slightly below the correlation lines for secondary amines. Figure 7 (c) also shows that the carboxylate anions 29 and 30 (triangles) exhibit similar reactivities towards 1-benzoyl-4-(dimethylamino)pyridinium chloride (5) as primary amines of the same nucleophilicity N. Bruice et al.[30] reported that methylhydrazine (28) reacted more slowly with phenyl acetate than the parent hydrazine (20), in contrast to their relative reactivities towards benzhydrylium ions for which 28 reacted eight times faster than 20.[11] In line with the results presented by Bruice et al., we now find methylhydrazine (28) to react 1.5 to 3 times more slowly than hydrazine (20) with benzoic anhydride (2) and 1-benzoyl-4-(dimethylamino)pyridinium chloride (5). Even when we consider the statistical correction of the reactivity of hydrazine (20) due to the presence of two nucleophilic centers, its reactivity towards 5 still exceeds that of the HNMe terminus of methylhydrazine (28). This behavior is in line with the 2 to 50 times higher reactivity of primary amines compared with secondary amines of the same nucleophilicity N, which overcompensates the 8 times higher reactivity of 28 compared with 20 in reactions with benzhydrylium ions (Figure 7, c). Depending on the size of the gap between the correlations for primary and secondary amines, the reactivity of the NHMe terminus of methylhydrazine (28) can be below or above that of 20, and 28 may alternatively react with the methylated or nonmethylated terminus (Scheme 2). The statistically corrected Brnsted correlation for the reactions of amines with 5 shows that primary amines have similar reactivities to those of isobasic, cyclic secondary amines (Figure 8; the Brnsted correlation for the corre-

Figure 7. Plot of (lg k2)/sN vs. N for the reactions of (a) benzoic anhydride (2), (b) benzoyl chloride (4), and (c) 1-benzoyl-4-(dimethylamino)pyridinium chloride (5) with carboxylates (triangles), primary (circles) and secondary amines (squares) in acetonitrile at 20 C. The analogous correlation for acetic anhydride (3) is shown in Figure S1 of the Supporting Information. The second-order rate constants for the acylation reactions of hydrazines (open symbols) were not used for the calculation of the linear regressions for primary or secondary amines. 6
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Figure 8. Brnsted plot of the statistically corrected second-order rate constants versus the statistically corrected basicities[31] for the reactions of 5 with amines at 20 C in acetonitrile (p = number of equivalent protons of the conjugated acids;[32] q = number of equivalent nucleophilic centers;[32] filled circles: primary amines, open circles: secondary amines, open symbol: hydrazine).
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sponding reactions of 2 is shown in Figure S2 of the Supporting Information). This observation is in contrast to the relative reactivities towards benzhydrylium ions, for which the secondary amines were found to be considerably more nucleophilic than isobasic primary amines.[11,21] Clearly, the influence of steric effects is more pronounced for the acylation reaction; the large negative deviation of tert-butylamine (13) in Figure 8 is in line with this interpretation. In our recent investigations of the reactivities of hydrazines towards benzhydrylium ions, we did not find enhanced nucleophilicities of hydrazines compared with isobasic primary amines, that is, we did not find evidence for the effect.[11] Because of the poor quality of the Brnsted plot shown in Figure 8 it was again not possible to derive clear evidence for the operation of an -effect in the reaction of hydrazine 20 with the N-benzoylpyridinium ion 5. However, the fact that 20 reacts 1.5 orders of magnitude faster with 5 than isobasic amines [morpholine (24), benzylamine (15)] is in line with the previous statement that the magnitude of the -effect increases with the slope of the Brnsted correlation.[33] Ritchie reported that the rate constants for the reactions of esters with a variety of nucleophiles could not be described by the N+ parameters defined by Equation (1).[4] If both nucleophilic attack and subsequent expulsion of the leaving group contribute to the second-order rate constants, as in the reactions of less reactive acylating agents (for example esters), good correlations of the second-order rate constants for the reactions with the nucleophilicity parameters N according to Equation (2) cannot be expected. A linear correlation of moderate quality is obtained when (lg k2)/sN for the reactions of carbanions with 4-nitrophenyl benzoate (1) is plotted versus the nucleophilicity parameters N of the carbanions (diamonds in Figure 9). According to Equation (2), the electrophilicity parameter E of 1 (E = 20.6) was determined by a least-squares fit, that

is, by minimization of 2 = {lg k2 sN(N + E)}2 using fixed values of N and sN as published previously.[34] The last column of Table 1 shows that the experimentally determined rate constants for the carbanions with 1, for which the CC bond-forming step is rate determining, agree within a factor of 9 with those calculated by Equation (2), which is within the error limit of the equation. The reactivity of 1 is one order of magnitude lower than that of benzaldehyde (E = 19.52),[6] which can be rationalized by ground-state stabilization due to the mesomeric interaction of the oxygen lone pair with the carbonyl group. A remarkable deviation from the correlation line for the carbanions is found for the reactions of 1 with primary and secondary amines, which are 1.5 to 4 orders of magnitude faster than predicted by their benzhydrylium-based nucleophilicity parameters (circles and squares in Figure 9). An even greater deviation of 4 to 7 orders of magnitude is observed for alkoxide anions (triangles in Figure 9), showing that in reactions with O- and N-nucleophiles the anomeric stabilization[35] of the tetrahedral intermediates already affects the transition states.

Conclusions
We have shown that the rate constants for the reactions of ester 1 with carbanions can be described by the linear free energy relationship Equation (2), using the benzhydrylium-derived nucleophilicity parameters N and sN for carbanions. Amines and alkoxide anions react considerably faster than expected from their reactivity parameters N and sN, which can be explained by the anomeric stabilization of the tetrahedral intermediate. The second-order rate constants for the reactions of primary amines with the highly electrophilic acylating agents 25 correlate well with the benzhydrylium-derived nucleophile-specific parameters N and sN of the amines. The same is true for the corresponding reactions of secondary amines. However, both series of amines follow separate correlations, which implies that a single set of reactivity parameters for nucleophiles and electrophiles is not sufficient to describe the rates of acylation reactions, even in cases in which the nucleophilic attack at the carbonyl group is rate determining.

Experimental Section
General: Acetylacetone (6-H), diethyl malonate (7-H), ethyl cyanoacetate (8-H), malononitrile (9-H), nitromethane (11-H), nitroethane (12-H), tert-butylamine (13), isopropylamine (14), benzylamine (15), allylamine (16), ethanolamine (17), n-propylamine (18), n-butylamine (19), N,N-bis(2-methoxyethyl)amine (21), di-n-propylamine (22), diethylamine (23), morpholine (24), piperidine (25), pyrrolidine (26), and methylhydrazine (28) were purchased and purified by distillation prior to use. 4-Nitrophenyl benzoate (1), benzoic anhydride (2), acetic anhydride (3), benzoyl chloride (4), 4cyanophenylacetonitrile (10-H), hydrazine monohydrate (20H2O), tetra-n-butylammonium benzoate (29), tetra-n-butylammonium 4nitrobenzoate (30), potassium tert-butoxide, p-toluenesulfonic acid
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Figure 9. Plot of (lg k2)/sN versus the corresponding nucleophilicity parameters N for the reactions of 4-nitrophenyl benzoate (1) with carbanions (filled diamonds). When the slope is set to unity as required by Equation (2), E = 20.64 is obtained. For comparison, the data for anions (open triangle), primary (open circles) and secondary amines (open squares) are also shown, which were not used for the correlation.
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monohydrate, and 4-(dimethylamino)pyridine were purchased and used without further purification. Acetonitrile ( 99.9 %, extra dry) and DMSO ( 99.9 %, extra dry) were purchased and used without further purification. 1-Benzoyl 4-(dimethylamino)pyridinium chloride (5),[27] potassium diethyl malonate (7),[36] potassium ethyl cyanoacetate (8)[36] and 1,2-dimethylhydrazine (27)[11] were synthesized as described previously.
1 H (400 or 600 MHz) and 13C NMR (100 or 150 MHz) spectra were measured with a Varian Inova 400 or Varian 600 instrument. The chemical shifts refer to the solvent residual signals as internal standard: CDCl3 (H = 7.26 ppm, C = 77.2 ppm), or [D6]DMSO (H = 2.50 ppm, C = 39.5 ppm). The following abbreviations were used for signal multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. NMR signal assignments were based on additional 2D-NMR experiments (COSY, HSQC, and HMBC). Mass spectra were recorded with a MAT 95 Q instrument.

T. A. Nigst, H. Mayr probe (5 mm light path) by fiber optic cables with standard SMA connectors. All kinetic measurements were carried out in Schlenk glassware under exclusion of moisture. The temperature of the solutions during the kinetic studies was maintained at 20 C 0.1 C by circulating bath thermostats and monitored with thermocouple probes that were inserted into the reaction mixture. Stopped-flow spectrophotometer systems (Applied Photophysics SX.18MV-R or Hi-Tech SF-61DX2) were used for the investigation of fast reactions (10 ms 1/2 10 s). The kinetic runs were initiated by mixing equal volumes of solutions of the nucleophiles and the electrophiles. A stopped-flow system (Hi-Tech SF-61DX2, Pt electrodes) was used for the conductometric investigation. The kinetic runs were initiated by mixing equal volumes of the solutions of the nucleophiles and the electrophiles. Supporting Information (see footnote on the first page of this article): Additional figures, details of the individual runs of the kinetic experiments, and copies of the NMR spectra.

Diethyl 2-Benzoylmalonate (31): A solution of 4-nitrophenyl benzoate (1; 827 mg, 3.40 mmol) in DMSO (20 mL) was added to a stirred solution of potassium diethyl malonate (7; 1.35 g, 6.81 mmol) in DMSO (40 mL) at 20 C and stirred for 2 h. After addition of 4-toluenesulfonic acid monohydrate (1.29 g, 6.78 mmol), water (40 mL) was added and the solution was extracted with Et2O (3 100 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (ether/pentane) to give 31 (571 mg, 2.16 mmol, 64 %) as a colorless oil in a 9:1 ratio of the keto and enol (marked with *) form in CDCl3.[37] 1H NMR (600 MHz, CDCl3): = 13.40 (br s, 1 H, OH*), 7.887.90 (m, 2 H, 2 HAr), 7.577.60 (m, 1 H, HAr), 7.547.56 (m, 2 H, 2 HAr*), 7.437.78 (m, 2 H and 1 H, 2 HAr, HAr* superimposed), 7.377.39 (m, 2 H, 2 HAr*), 5.28 (s, 1 H, CH), 4.32 (q, J = 7.2 Hz, 2 H, CH2*), 4.214.29 (m, J = 4 Hz, 2 CH2), 4.05 (q, J = 7.2 Hz, 2 H, CH2*), 1.33 (t, J = 7.1 Hz, 3 H, CH3*), 1.23 (t, J = 7.1 Hz, 6 H, 2 CH3), 1.01 (t, J = 7.2 Hz, 3 H, CH3*) ppm. 13C NMR (150 MHz, CDCl3): = 189.1 (s), 175.4 (s*), 171.1 (s*), 166.3 (s*), 165.0 (s), 135.5 (s), 134.1 (d), 131.3 (d*), 130.2 (s*), 129.0 (d), 128.6 (d), 128.4 (d*), 127.7 (d*), 100.4 (s*), 62.5 (t), 62.0 (d), 61.8 (t*), 61.4 (t*), 14.2 (q*), 14.0 (q), 13.7 (q*) ppm. HRMS (EI): m/z calcd. for C14H16O5+ [M+] 264.0992; found 264.0992. Potassium Diethyl 2-Benzoylmalonate (K+31): Diethyl 2-benzoylmalonate (31; 50 mg, 0.19 mmol) was added to a solution of KOtBu (21 mg, 0.19 mmol) in [D6]DMSO (1 mL). The product (K+31) was immediately analyzed by NMR spectroscopy. 1H NMR (400 MHz, [D6]DMSO): = 7.187.28 (m, 5 H, HAr), 3.73 (q, J = 7.1 Hz, 4 H, 2 CH2), 0.87 (t, J = 7.1 Hz, 6 H, 2 CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): = 188.8 (s), 169.6 (s), 146.9 (s), 127.3 (d), 126.9 (d), 126.7 (d), 90.7 (s), 56.9 (t), 14.3 (q) ppm. Kinetics: The kinetics of the reactions of 4-nitrophenyl benzoate (1), benzoic anhydride (2), and 1-benzoyl-4-(dimethylamino)pyridinium chloride (5) with carbanions 612, amines 1328, and carboxylates 29 and 30 were followed by UV/Vis spectroscopy in acetonitrile or DMSO at 20 C. The kinetics of the reactions of acetic anhydride (3) and benzoyl chloride (4) with amines 1328 were followed by conductimetry in acetonitrile at 20 C. For slow reactions (1/2 10 s), the spectra were collected at specified times with a J&M TIDAS diode array spectrophotometer that was connected to a Hellma 661.502-QX quartz Suprasil immersion 8
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Acknowledgments
We acknowledge financial support by the Deutsche Forschungsgemeinschaft (DFG) (SFB 749) and the Fonds der Chemischen Industrie. [1] a) J. P. Guthrie, Reviews of Reactive Intermediate Chemistry (Eds.: M. S. Platz, R. A. Moss, M. Jones Jr.), Wiley-Interscience, Hoboken, 2007, pp. 345; b) D. P. N. Satchell, R. S. Satchell, in: Supplement B: The Chemisty of Acid Derivatives, vol. 2 (Ed.: S. Patai), John Wiley & Sons, New York, 1992, pp. 748802. [2] For selected examples, see: a) T. W. Bentley, G. Llewellyn, J. A. McAlister, J. Org. Chem. 1996, 61, 79277932; b) A. Williams, Acc. Chem. Res. 1989, 22, 387392; c) B. C. Lee, J. H. Yoon, C. G. Lee, I. Lee, J. Phys. Org. Chem. 1994, 7, 273279. [3] For reviews, see: a) C. D. Ritchie, Can. J. Chem. 1986, 64, 22392250; b) C. D. Ritchie, Pure Appl. Chem. 1978, 50, 1281 1290; c) C. D. Ritchie, Acc. Chem. Res. 1972, 5, 348354. [4] C. D. Ritchie, J. Am. Chem. Soc. 1975, 97, 11701179. [5] a) H. Mayr, A. R. Ofial, Pure Appl. Chem. 2005, 77, 1807 1821; b) H. Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 6677; c) R. Lucius, R. Loos, H. Mayr, Angew. Chem. 2002, 114, 97102; Angew. Chem. Int. Ed. 2002, 41, 9195; d) H. Mayr, T. Bug, M. F. Gotta, N. Hering, B. Irrgang, B. Janker, B. Kempf, R. Loos, A. R. Ofial, G. Remennikov, H. Schimmel, J. Am. Chem. Soc. 2001, 123, 95009512; e) H. Mayr, M. Patz, Angew. Chem. 1994, 106, 9901010; Angew. Chem. Int. Ed. Engl. 1994, 33, 938957; f) For a comprehensive listing of nucleophilicity parameters (N, sN) and electrophilicity parameters (E) see: http://www.cup.uni-muenchen.de/oc/mayr/ DBintro.html. [6] R. Appel, H. Mayr, J. Am. Chem. Soc. 2011, 133, 82408251. [7] For selected examples, see: a) J. Isaad, A. Perwuelz, Tetrahedron Lett. 2010, 51, 53285332; b) I.-H. Um, K.-H. Kim, H.R. Park, M. Fujio, Y. Tsuno, J. Org. Chem. 2004, 69, 3937 3942; c) H. J. Koh, H. C. Lee, H. W. Lee, I. Lee, Bull. Korean Chem. Soc. 1995, 16, 839844; d) M. Jedrzejczak, R. E. Motie, D. P. N. Satchell, R. S. Satchell, W. N. Wassef, J. Chem. Soc. Perkin Trans. 2 1994, 14711479; e) D. J. Palling, W. P. Jencks, J. Am. Chem. Soc. 1984, 106, 48694876. [8] a) F. E. Condon, J. Org. Chem. 1972, 37, 36083615; b) W. J. Theuer, J. A. Moore, J. Org. Chem. 1964, 29, 37343735. [9] R. L. Hinman, D. Fulton, J. Am. Chem. Soc. 1958, 80, 1895 1900. [10] a) K. Too, D. M. Brown, E. Bongard, V. Yarley, L. Vivas, D. Loakes, Bioorg. Med. Chem. 2007, 15, 55515562; b) K.
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Electrophilic Reactivities of Acylating Agents Banert, M. Hagedorn, J. Schlott, Chem. Lett. 2003, 32, 360 361; c) C. Gibson, S. L. Goodman, D. Hahn, G. Hlzermann, H. Kessler, J. Org. Chem. 1999, 64, 73887394; d) T. Ryckmans, H.-G. Viehe, J. Feneau-Dupont, B. Tinant, J.-P. Declercq, Tetrahedron 1997, 53, 17291734; e) C. L. Branch, A. W. Guest, S. C. Finch, Beecham Group p. l. c., US5275816, 1994; f) A. W. Guest, R. G. Adams, M. J. Basker, E. G. Brain, C. L. Branch, F. P. Harrington, J. E. Neale, M. J. Pearson, I. I. Zomaya, J. Antibiot. 1993, 46, 12791288; g) H. Hilpert, A. S. Dreiding, Helv. Chim. Acta 1984, 67, 15471561; h) D. L. Trepanier, K. L. Shriver, J. N. Eble, J. Med. Chem. 1969, 12, 257260; i) M. Busch, E. Opfermann, H. H. Walther, Ber. Dtsch. Chem. Ges. 1904, 37, 23182333. [11] T. A. Nigst, A. Antipova, H. Mayr, J. Org. Chem. 2012, 77, 81428155. [12] N. E. Kayaleh, R. C. Gupta, F. Johnson, J. Org. Chem. 2000, 65, 45154522. [13] a) L. Claisen, Justus Liebigs Ann. Chem. 1896, 291, 25137; b) L. Claisen, Justus Liebigs Ann. Chem. 1893, 277, 162206; c) J. U. Nef, Justus Liebigs Ann. Chem. 1893, 277, 5978. [14] a) J.-C. Jung, E. B. Watkins, M. A. Avery, Heterocycles 2005, 65, 7794; b) A. Michael, O. Eckstein, Ber. Dtsch. Chem. Ges. 1905, 38, 5053. [15] a) B. C. Kraybill, L. L. Elkin, J. D. Blethrow, D. O. Morgan, K. M. Shokat, J. Am. Chem. Soc. 2002, 124, 1211812128; b) H. Graboyes, G. E. Jaffe, I. J. Pachter, J. P. Rosenbloom, A. J. Villani, J. W. Wilson, J. Weinstock, J. Med. Chem. 1968, 11, 568573. [16] a) A. Riahi, M. Shkoor, O. Fatunsin, M. A. Yawer, I. Hussain, C. Fischer, P. Langer, Tetrahedron 2009, 65, 93009315; b) A. Riahi, M. Shkoor, R. A. Khera, H. Reinke, P. Langer, Tetrahedron Lett. 2009, 50, 30173019. [17] O. Kaumanns, R. Appel, T. Lemek, F. Seeliger, H. Mayr, J. Org. Chem. 2009, 74, 7581. [18] T. Bug, T. Lemek, H. Mayr, J. Org. Chem. 2004, 69, 75657576. [19] T. Lemek, H. Mayr, J. Org. Chem. 2003, 68, 68806886. [20] T. B. Phan, C. Nolte, S. Kobayashi, A. R. Ofial, H. Mayr, J. Am. Chem. Soc. 2009, 131, 1139211401. [21] T. Kanzian, T. A. Nigst, A. Maier, S. Pichl, H. Mayr, Eur. J. Org. Chem. 2009, 63796385; the rate constant for the reaction of 23 with (dma)2CH+ BF4 was calculated by using Equation (2). [22] S. Minegishi, H. Mayr, J. Am. Chem. Soc. 2003, 125, 286295. [23] I.-H. Um, S.-E. Jeon, J.-A. Seok, Chem. Eur. J. 2006, 12, 1237 1243. [24] T. B. Phan, H. Mayr, Can. J. Chem. 2005, 83, 15541560. [25] J.-A. Seo, S.-I. Kim, Y. J. Hong, I.-H. Um, Bull. Korean Chem. Soc. 2010, 31, 303308. [26] I.-H. Um, J.-Y. Lee, S.-Y. Bae, E. Buncel, Can. J. Chem. 2005, 83, 13651371. [27] M. S. Wolfe, Synth. Commun. 1997, 27, 29752984. [28] T. A. Nigst, J. Ammer, H. Mayr, Angew. Chem. 2012, 124, 13811385; Angew. Chem. Int. Ed. 2012, 51, 13531356. [29] H. F. Schaller, A. A. Tishkov, X. Feng, H. Mayr, J. Am. Chem. Soc. 2008, 130, 30123022. [30] T. C. Bruice, A. Donzel, R. W. Huffman, A. R. Butler, J. Am. Chem. Soc. 1967, 89, 21062121. [31] J. F. Coetzee, G. R. Padmanabhan, J. Am. Chem. Soc. 1965, 87, 50055010. [32] a) J. W. Bunting, J. M. Mason, C. K. M. Heo, J. Chem. Soc. Perkin Trans. 2 1994, 22912300; b) C. K. M. Heo, J. W. Bunting, J. Chem. Soc. Perkin Trans. 2 1994, 22792290; c) Bell, R. P. The Proton in Chemistry, Methuen, London, 1959, p. 159. [33] a) E. Buncel, I.-H. Um, Tetrahedron 2004, 60, 78017825; b) A. P. Grekov, V. Y. Veselov, Russ. Chem. Rev. 1978, 47, 631 648; c) N. J. Fina, J. O. Edwards, Int. J. Chem. Kinet. 1973, 5, 126. [34] A similar value of E (20.74 1.04) can be obtained by averaging the values E = {(lg k2)/sN} N, which are calculated for each of the reactions of 1 with the nucleophile 612. [35] a) I. Cumpstey, Org. Biomol. Chem. 2012, 10, 25032508; b) C. L. Perrin, Tetrahedron 1995, 51, 1190111935; c) P. P. Graczyk, M. Mikoajczyk, in: Topics in Stereochemistry, vol. 21 (Eds.: E. L. Eliel, S. H. Wilen), John Wiley & Sons, New York, 1994, pp. 159349; d) E. Juaristi, G. Cuevas, Tetrahedron 1992, 48, 50195087. [36] I. Zenz, H. Mayr, J. Org. Chem. 2011, 76, 93709378. [37] Analytic data have been published previously, see: Q. Shen, W. Huang, J. Wang, X. Zhou, Org. Lett. 2007, 9, 44914494. Received: November 16, 2012 Published Online:

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FULL PAPER
The kinetics of the reactions of amines and carbanions with acylating agents were studied in acetonitrile and DMSO solution at 20 C. Separate correlation lines for different types of nucleophiles were found when (lg k2)/sN was plotted against the nucleophilicity parameters N for these reactions, indicating the limitation of the depicted correlation.

T. A. Nigst, H. Mayr

Kinetics
T. A. Nigst, H. Mayr* .................... 110 Comparison of the Electrophilic Reactivities of N-Acylpyridinium Ions and Other Acylating Agents Keywords: Kinetics / Linear free energy relationships / Acylation / Amines / Organocatalysis

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