K⁺ Ion Catalysis in Nucleophilic Displacement Reaction of Y-Substituted-Phenyl Picolinates with Potassium Ethoxide: Effect of Substituent Y on Reactivity and Transition State Structure

Abstract

Pseudo-first-order rate constants ($k_{obsd}$) have been measured spectrophotometrically for the nucleophilic substitution reaction of Y-substituted-phenyl picolinates (7a-f) with potassium ethoxide (EtOK) in anhydrous ethanol at $25.0{\pm}0.1^{\circ}C$. The plot of $k_{obsd}$ vs. [EtOK] curves upward while the plot of $k_{obsd}/[EtO^-]_{eq}$ vs. $[EtO^-]_{eq}$ is linear with a positive intercept in all cases. Dissection of $k_{obsd}$ into $k_{EtO^-}$ and $k_{EtOK}$ (i.e., the second-order rate constants for the reactions with the dissociated $EtO^-$ ion and ion-paired EtOK, respectively) has revealed that the ion-paired EtOK is more reactive than the dissociated $EtO^-$. The ${\sigma}^{\circ}$ constants result in a much better Hammett correlation than ${\sigma}^-$ constants, indicating that the reaction proceeds through a stepwise mechanism in which departure of the leaving group occurs after the rate-determining step (RDS). $K^+$ ion catalyzes the reaction by increasing the electrophilicity of the reaction center through formation of a cyclic transition state (TS). The catalytic effect decreases as the substituent Y becomes a stronger electron-withdrawing group (EWG). Development of a positive charge on the N atom of the picolinyl moiety through resonance interactions is responsible for the decreasing $K^+$ ion catalysis.

Introduction

Nucleophilic substitution reactions of esters with amines have intensively been investigated due to their importance in biological processes as well as in synthetic applications.1-4 The reactions have been reported to proceed through a concerted mechanism or via a stepwise pathway, in which the rate-determining step (RDS) is dependent on the basicity of the incoming amine and the leaving group.2-4 In general, the RDS changes from breakdown of a tetrahedral inter-mediate (T±) to its formation as the amine becomes more basic than the leaving group by 4 to 5 pKa units.2-4

Reactions of esters with anionic nucleophiles have also been carried out intensively to investigate the reaction mech-anism.5-7 Interestingly, alkali metal ions have been reported to behave as a Lewis acid catalyst or as an inhibitor in nucleophilic substitution reactions of esters with alkali-metal ethoxides (EtOM; M = K, Na, Li) depending on the nature of the electrophilic center (e.g., P=O, P=S, SO2, C=O).8-12 Buncel et al. have reported that the reaction of 4-nitrophenyl diphenylphosphinate (1) with EtOM is catalyzed by M+ ions and the catalytic effect increases as the size of M+ ions decreases (e.g., K+ < Na+ < Li+).8 In contrast, we have shown that the corresponding reaction of 4-nitrophenyl diphenyl-phosphonothioate (2) is inhibited by Li+ ion but is catalyzed by K+ ion and the K+ ion complexed by 18-crown-6-ether (18C6), indicating that the role of M+ ions is dependent on the electronic nature of the reaction centers (e.g., P=O vs. P=S).9

Alkali metal ions have also been reported to catalyze the reactions of 4-nitrophenyl benzoate (3) and 5-nitro-8-quinol-yl benzoate (4) with EtOM (M = K, Na, Li) in anhydrous ethanol.10 The catalytic effect decreases in the order K+ > Na+ > Li+ for the reaction of 3 but in the order Na+ > K+ > Li+ for the reaction of 4.10 Thus, M+ ions have been reported to catalyze the reactions of 3 and 4 by increasing either the electrophilicity of the reaction center through TSI or the nucleofugality of the leaving group via TSII on the basis of the contrasting M+ ion effects.10

In contrast, we have reported that the rate of reactions of 4-nitrophenyl salicylate (5) with EtOM decreases steeply as the concentration of EtOM increases.11 More interestingly, addition of inert salts such as LiSCN and KSCN to the reaction mixture causes a significant decrease in reactivity.11 Thus, M+ ions have been suggested to act as a strong inhibitor by forming a cyclic complex 5M, which inhibits the subsequent reaction to produce α-oxoketene 6.11

Scheme 1.

M+ ions has been reported to catalyze the reaction of 4-nitrophenyl picolinate (7a) with EtOM and the catalytic effect increases in the order Li+ > K+ > Na+.12 M+ ions would catalyze the reaction by increasing either the electrophilicity of the reaction center or the nucleofugality of the leaving group. However, the enhanced nucleofugality would be effective only for reactions in which leaving-group departure occurs in the RDS but would be ineffective for reactions in which departure of the leaving group occurs after the RDS. Thus, detailed information on the reaction mechanism is necessary to investigate the role of M+ ions. Our study has now been extended to the reaction of Y-substituted-phenyl picolinates (7b-f) with EtOK in anhydrous ethanol to investigate the reaction mechanism including the nature of RDS. We wish to report that the reaction proceed through a stepwise mechanism in which expulsion of the leaving group occurs after the RDS and that K+ ion catalyzes the reaction by increasing the electrophilicity of the reaction center as shown in Scheme 1

 

Results and Discussion

The kinetic study was performed spectrophotometrically under pseudo-first-order conditions in which the concent-ration of EtOK was in large excess over that of substrates 7b-f. All the reactions in this study obeyed pseudo-first-order kinetics and proceeded with quantitative liberation of Y-substituted-phenoxide ion. Pseudo-first-order rate con-stants (kobsd) were calculated from the equation, ln (A∞ – At) = –kobsdt + C. The correlation coefficient for the linear plots of ln (A∞ – At) vs. t was better than 0.9995 in all cases. It is estimated from replicate runs that the uncertainty in the kobsd values is less than ± 3%. The kinetic conditions and results are summarized in Table 1.

As shown in Figure 1, the plots of kobsd vs. [EtOK] curve upward for the reactions of 4-cyanophenyl picolinate (7b) and 4-acetylphenyl picolinate (7c) with EtOK. Similarly curved plots were obtained for the reactions of the other aryl picolinates 7d-f (Figures not shown). Such upward curvature is typical for nucleophilic substitution reactions of esters with alkali-metal ethoxide (EtOM), in which alkali-metal ion behaves as a Lewis acid catalyst and the ion-paired EtOM is more reactive than the dissociated EtO–. In fact, we have previously reported that M+ ions catalyze the reaction of 4-nitrophenyl picolinate (7a) with EtOM (M = K, Na, and Li).12

Table 1.Kinetic Data for the Reactions of Y-Substituted-Phenyl Picolinates (7b-f) with EtOK in Anhydrous Ethanol at 25.0 ± 0.1°C

Dissection of kobsd into kEtO− and kEtOK. To examine the above idea that K+ ion catalyzes the reaction, the kobsd values have been dissected into kEtO− and kEtOK (i.e., the second-order rate constants for the reactions with the dissociated EtO– ion and ion-paired EtOK, respectively). It was reported that EtOK exists as dimers or other aggregates in a high concentration (e.g., [EtOK] > 0.1 M).13 However, EtOK was suggested to exist mainly as the dissociated and ion-paired species in a low concentration (e.g., [EtOK] < 0.1 M).13 Since [EtOK] < < 0.1 M in this study, one might expect that both the dissociated EtO– and ion-paired EtOK would react with substrates 7a-f as shown in Scheme 2.

Figure 1.Plots of kobsd vs. [EtOK] for the reaction of 4-cyano-phenyl picolinate 7b (●) and 4-acetylphenyl picolinate 7c (○) with EtOK in anhydrous EtOH at 25.0 ± 0.1 °C.

Scheme 2.Reactions of 7 with the dissociated EtO–and ion-paired EtOK.

Thus, Eq. (1) can be derived on the basis of the kinetic results and the reactions proposed in Scheme 2. Under pseudo-first-order kinetic conditions (e.g., [EtOK] >> [7]), kobsd can be expressed as Eq. (2). It is noted that the dis-sociation constant Kd = [EtO–]eq[K+]eq/[EtOK]eq, and [EtO–]eq = [K+]eq at equilibrium. Accordingly, Eq. (2) can be con-verted to Eq. (3). The [EtO–]eq and [EtOK]eq values can be calculated from the reported Kd value of 11.1 × 10−3 M for EtOK14 and the initial concentration of EtOK using Eqs. (4) and (5).

One might expect that the plot of kobsd/[EtO–]eq vs. [EtO–]eq would be linear if the reaction proceeds as proposed in Scheme 2. In fact, the plots shown in Figure 2 exhibit ex-cellent linear correlations with positive intercepts, indicating that the derived equations based on the reactions proposed in Scheme 2 are correct. Accordingly, one can calculate the kEtO− and kEtOK /Kd values from the intercept and the slope of the linear plot, respectively. The kEtOK value can be cal-culated from the above kEtOK/Kd values and the reported Kd value for EtOK.14 In Table 2 are summarized the calculated kEtO− and kEtOK values for the reactions of 7a-f.

Figure 2.Plots of kobsd/[EtO–]eq vs. [EtO–]eq for the reactions of 4-cyanophenyl picolinate (7b, ● ) and 4-acetylphenyl picolinate (7c, ○ ) with EtOK in anhydrous EtOH at 25.0 ± 0.1 °C.

Table 2.aThe kinetic data for the reaction of 7a were taken from ref. 12.

As shown in Table 2, the kEtOK value is much larger than the kEtO− value in all cases. This supports the preceding idea that the ion-paired EtOK is more reactive than the dis-sociated EtO–. It is noted that both the kEtO− and kEtOK values decrease as the substituent Y becomes a weaker electron-withdrawing group (EWG), e.g., kEtO− decreases from 486 M–1s–1 to 61.5 and 1.43 M–1s–1 as the substituent Y changes from 4-NO2 to 4-COMe and H, in turn. In contrast, the kEtOK/kEtO− ratio (i.e., the catalytic effect exerted by K+ ion) increases as the substituent Y becomes a weaker EWG.

Deduction of Reaction Mechanism. K+ ion would cata-lyze the reaction of 7a-f by increasing the nucleofugality of the leaving Y-substituted-phenoxide or by increasing the electrophilicity of the reaction center. However, enhanced nucleofugality of the leaving group cannot be a cause of the K+ ion catalysis for reactions in which departure of the leaving group occurs after the rate-determining step (RDS).

If the current reaction proceeds through a concerted mech-anism, a partial negative charge would develop at the O atom of the leaving group. Since such negative charge could be delocalized to the subsituent Y through resonance inter-actions, Hammett correlation with σ– constants should result in a better correlation than σ° constants. In contrast, if the current reaction proceeds through a stepwise mechanism, departure of the leaving group would not be advanced in the transition state (TS). Because EtO– is much more basic and a poorer nucleofuge than Y-substituted-phenoxide. Accord-ingly, no negative charge would develop on the O atom of the leaving group if the reaction proceeds through a stepwise mechanism. In this case, σ° constants should give a better Hammett correlation than σ– constants.

To deduce the reaction mechanism, Hammett plots have been constructed using σ– and σ° constants. As shown in Figure 3(a), σ° constants result in a much better linear corre-lation than σ– constants (the inset) for the reaction with the dissociated EtO–. A similar result is demonstrated in Figure 3(b) for the reaction with the ion-paired EtOK. These results indicate that no negative charge develops on the O atom of the leaving group. This is contrary to the expectation if departure of the leaving group is involved in the RDS either for a concerted mechanism or for a stepwise pathway. Thus, one can conclude that the current reaction proceeds through a stepwise mechanism in which expulsion of the leaving group occurs after the RDS.

Figure 3.Hammett correlations of log kEtO− (a) and log kEtOK (b) with σY° and σY– (inset) for the reactions of Y-substituted-phenyl picolinates (7a-f) in anhydrous ethanol at 25.0 ± 0.1 °C.

TS Structures and Role of K+ Ion. Three different TS structures are plausible to explain the catalytic effect exerted by K+ ion. TSIII could increase the nucleofugality of the leaving group, while TSIV and TSV could enhance the electro-philicity of the reaction center. Since expulsion of the leav-ing group occurs after the RDS in this study, the reaction cannot be catalyzed by increasing the nucleofugality of the leaving group through TSIII One can also exclude a possibi-lity that K+ ion catalyzes the reaction through TSIV, in which the K+ and EtO– ions in TSIV are not ion-paired species. This is because the current reaction is catalyzed by the ion-paired EtOK but not by the dissociated K+. Thus, one can conclude that K+ ion catalyzes the reaction of 7a-f by increasing the electrophilicity of the reaction center through a TS structure similar to TSV.

The effect of the leaving-group substituent Y on the catalytic effect exerted by K+ ion (i.e., the kEtOK/kEtO− ratio) is illustrated in Figure 4. One can see that the kEtOK/kEtO− ratio decreases linearly as the substitutent Y in the leaving group becomes a stronger EWG, although the correlation coeffi-cient of the linear plot is not very good (R2 = 0.958). The kEtOK/kEtO− ratio should have resulted in a good correlation with the electronic nature of the substituent Y, if the reaction is catalyzed by increasing the nucleofugality of the leaving group through TSIII. In contrast, if the reaction is catalyzed by increasing the electrophilicity through TSV, the corre-lation of kEtOK/kEtO− ratio with the electronic nature of the substituent Y would not be excellent because of the long distance between the substituent Y and the N atom of the picolinyl moiety of TSV. Thus, the poor correlation shown in Figure 4 clearly supports the proposed TS structure (i.e., TSV) and reaction mechanism.

Figure 4.Plot showing K+ ion effect on the substituent Y for the reactions of Y-substituted-phenyl picolinates (7a-f) with EtOK in anhydrous ethanol at 25.0 ± 0.1 °C.

It is noted that the slope of the linear plot in Figure 4 is –1.30. Such a large slope indicates that the catalytic effect is strongly dependent on the electronic nature of the substituent Y. The dependence of the kEtOK/kEtO− ratio on the substituent Y can be explained by the resonance structures as modeled by I ↔ II and by III ↔ IV. It is evident that the contribution of the resonance structure II would decrease as the sub-stituent Y becomes a stronger EWG. In contrast, the re-sonance structure IV would become a major contributor with increasing electron-withdrawing ability of the substituent Y. In this case, the positively charged N atom of the resonance structure IV inhibits formation of TSV. This idea accounts nicely for the kinetic result that K+ ion catalysis decreases as the substituent Y becomes a stronger EWG.

 

Conclusions

The kinetic study on the reaction of 7a-f with EtOK has allowed us to conclude the following: (1) Dissection of kobsd into kEtO− and kEtOK has revealed that the ion-paired EtOK is more reactive than the dissociated EtO–. (2) The Hammett plots correlated with σ° constants result in much better linearity than those correlated with σ– constants, indicating that the reaction proceeds through a stepwise mechanism in which expulsion of the leaving group occurs after the RDS.(3) K+ ion catalyzes the reaction by increasing the electro-philicity of the reaction center through TSV. (4) The catalytic effect decreases as the substituent Y becomes a stronger EWG. (5) Development of a positive charge on the N atom through resonance interactions is responsible for the de-creasing K+ ion catalysis.

 

Experimental Section

Materials. Y-Substituted-phenyl picolinates (7a-f) were readily prepared by adding Y-substituted-phenol to the solu-tion of picolinyl chloride in the presence of triethylamine in anhydrous diethyl ether as reported previously.12 The crude products were purified by column chromatography (silica gel, methylene chloride/n-hexane 50/50). Their purity was checked by their melting points and 1H NMR spectra.

Kinetics.The kinetic study was carried out with a UV-vis spectrophotometer for slow reactions (e.g., t1/2 > 10 s) or a stopped-flow spectrophotometer for fast reactions (e.g., t1/2 ≤ 10 s) equipped with a constant temperature circulating bath to maintain the temperature in the reaction cell at 25.0 ± 0.1 °C. The reaction was followed by monitoring the appearance of Y-substituted-phenoxide ion. All reactions were carried out under pseudo-first-order conditions in which EtOK concentration was at least 20 times greater than the substrate concentration. The stock solution of EtOK was prepared by dissolving freshly cleaned potassium metal in anhydrous ethanol under nitrogen and stored in the refrigerator. The concentration of EtOK was determined by titration with potassium hydrogen phthalate. The anhydrous ethanol was further dried over magnesium and was distilled under N2 just before use.

All solutions were prepared freshly just before use under nitrogen and transferred by gas-tight syringes. Typically, the reaction was initiated by adding 5 μL of a 0.01 M solution of the substrate in CH3CN by a 10 μL syringe to a 10 mm quartz UV cell containing 2.50 mL of the thermostatted reaction mixture made up of anhydrous ethanol and aliquot of the EtOK solution.

Product Analysis. Y-Substituted-phenoxide ion was liberated quantitatively and identified as one of the products by comparison of the UV-vis spectrum at the end of reaction with the authentic sample under the experimental condition.