Nucleophilic Substitution Reactions of Y-Substituted-Phenyl Benzoates with Potassium Ethoxide in Anhydrous Ethanol: Reaction Mechanism and Role of K⁺ Ion

Abstract

Pseudo-first-order rate constants ($k_{obsd}$) have been measured spectrophotometrically for the reactions of Y-substituted-phenyl benzoates (5a-j) with potassium ethoxide (EtOK) in anhydrous ethanol at $25.0{\pm}0.1^{\circ}C$. The plots of $k_{obsd}$ vs. [EtOK] curve upward regardless of the electronic nature of the substituent Y in the leaving group. Dissection of $k_{obsd}$ into the second-order rate constants for the reactions with the dissociated $EtO^-$ and ion-paired EtOK (i.e., $k_{EtO^-}$ and $k_{EtOK}$, respectively) has revealed that the ion-paired EtOK is more reactive than the dissociated $EtO^-$. The Br${\phi}$nsted-type plots for the reactions with the dissociated $EtO^-$ and ion-paired EtOK exhibit highly scattered points with ${\beta}_{lg}$ = -$0.5{\pm}0.1$. The Hammett plots correlated with ${\sigma}^o$ constants result in excellent linear correlations, indicating that no negative charge develops on the O atom of the leaving Y-substituted-phenoxide ion in transition state. Thus, it has been concluded that the reactions with the dissociated $EtO^-$ and ion-paired EtOK proceed through a stepwise mechanism, in which departure of the leaving group occurs after the RDS, and that $K^+$ ion catalyzes the reactions by increasing the electrophilicity of the reaction center through a four-membered cyclic TS structure.

Introduction

Metal ions have often been reported to behave as a Lewis acid catalyst in nucleophilic substitution reactions of esters.1,11 Since Lewis acidity increases as the charge density increases, most studies have focused on reactions involving multivalent metal ions (e.g., Mg2+, Co2+, Zn2+, La3+, Eu3+, etc.).2-4 Effects of alkali-metal ions on nucleophilic substitution reactions have been investigated much less intensively.5-11 Buncel and his coworkers have initiated the first systematic study on alkaline ethanolysis of 4-nitrophenyl diphenylphosphinate (1a) in anhydrous ethanol to investigate alkali-metal ion effect.5a They have found that alkali-metal ions catalyze the reaction in the order K+ ＜ Na+ ＜ Li+ and that the catalytic effect disappears in the presence of complexing agents (e.g., crown ethers or cryptands).5a In contrast, we have shown that Li+ ion inhibits the corresponding reaction of 4-nitrophenyl diphenylphosphinothioate (1b) while K+ and 18C6-complexed K+ ions catalyze the reaction.8 A similar result has been reported for the reactions of 4-nitrophenyl diethyl phosphate (2a, paraoxon) and 4-nitrophenyl diethyl phosphorothioate (2b, parathion) with EtOM (M = Li, Na, K), e.g., M+ ions catalyze the reactions of 2a in the order K+ ＜ Na+ ＜ Li+ while the reaction of 2b is strongly inhibited by Li+ ion but is catalyzed by K+ and 18C6- complexed K+ ions.9 These demonstrate convincingly that the effect of M+ ions is dependent on the nature of the electrophilic centers (e.g., P=O vs. P=S).

Effects of alkali-metal ions have also been investigated for the reactions of Y-substituted-phenyl phenyl carbonates (3) with EtOM.10c The reactions of 3 with the dissociated EtO- and ion-paired EtOK have been concluded to proceed through a concerted mechanism on the basis of excellent linear Yukawa-Tsuno plots with ρY = 2.11 and r = 0.21 for the reaction with EtO- and ρY = 1.62 and r = 0.26 for the reaction with EtOK. We have also shown that M+ ions catalyze the reaction in the order Li+ ＜ Na+ ＜ K+.10c

On the contrary, we have reported that M+ ions strongly inhibit the reaction of 4-nitrophenyl salicylate (4) with EtOM in anhydrous ethanol, e.g., the k obsd value decreases as the concentration of M+ ions increases up to a certain concentration and then levels off thereafter. The inhibitory effect of M+ ions has been found to be in the order K+ < Na+ < Li+.11a Formation of a stable 6-membered cyclic complex (4M) has been suggested to be responsible for the inhibitory effect since 4M would prevent the subsequent reaction (i.e., formation of 𝛼-oxoketene through an E1cb mechanism).11a

Our study has been extended to reactions of Y-substituted-phenyl benzoates (5a-j) with EtOK in anhydrous ethanol to investigate the role of K+ ion as well as the reaction mechanism (Scheme 1). We wish to report that the reactions proceed through a stepwise mechanism, in which departure of the leaving group occurs after the rate-determining step (RDS), and that K+ ion catalyzes the reaction by increasing the electrophilicity of the reaction center rather than by increasing the nucleofugality of the leaving group.

Scheme 1

 

Results and Discussion

The kinetic study was performed spectrophotometrically under pseudo-first-order conditions in which the concentration of EtOK was in large excess over that of 5a-j. 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 constants (kobsd) were calculated from the slope of linear plots of ln (A∞ - At) vs. time. It is estimated from replicate runs that the uncertainty in the kobsd values is less than ± 3%. The second-order rate constants for the reactions of 5a-j with the dissociated EtO- and ion-paired EtOK (i.e., kEtO- and kEtOK, respectively) were calculated from the ion-pairing treatment of the kinetic data as shown in the following section and are summarized in Table 1.

Dissection of kobsd into kEtO- and kEtOK. As shown in Figure 1, the plot of kobsd vs. [EtOK] for the reaction of 4-methylphenyl benzoate (5a) curves upward. A similar result is obtained for the corresponding reactions of the other aryl benzoates 5b-j (Figures not shown). Such upward curvature has often been reported for alkaline ethanolysis of esters in which alkali-metal ions behave as a Lewis acid catalysis.5-11 Thus, one can suggest that K+ ion catalyzes the current reactions.

Alkali-metal ethoxides (EtOM, M = Li, Na, K) have been reported to exist as the dissociated EtO- and ion-paired EtOM when [EtOM] ＜ 0.1 M.12 Since the concentration of EtOK used in the present study was lower than 0.1 M, one can suggest that substrates 5a-j would react with the dissociated EtO- and ion-paired EtOK as shown in Scheme 2.

A rate equation can be derived as Eq. (1) on the basis of the reactions proposed in Scheme 2. Under pseudo-first-order kinetic conditions (e.g., [EtOK] >> [5a-j]), kobsd can be expressed as Eq. (2). Since the dissociation constant Kd = [EtO-]eq[K+]eq/[EtOK]eq, and [EtO-]eq= [K+]eq at equilibrium, Eq. (2) becomes Eq. (3). The concentrations of [EtO-]eq and [EtOK]eq can be calculated from the reported Kd value of 1.11 × 10-2 M for EtOK13 and the initial concentration [EtOK] using Eqs. (4) and (5).

Figure 1.Plots of kobsd vs. [EtOK] for the reactions of 4-methylphenyl benzoate (5a) with EtOK in anhydrous EtOH at 25.0 ± 0.1 ℃.

Scheme 2.Reactions of 5a-j with the dissociated EtO– and ion-paired EtOK.

Thus, the plot of kobsd/[EtO-]eq vs. [EtO-]eq would be linear with a positive intercept, if the reaction proceed as proposed in Scheme 2 and the derived equations are correct. In fact, the plot shown in Figure 2 is linear with a positive intercept for the reaction of 5a with EtOK. A similar result was obtained for the corresponding reactions of the other aryl benzoates (i.e., 5b-j). Accordingly, the kEtO- and kEtOK/Kd values have been calculated from the intercept and the slope of the linear plots, respectively. The kEtOK values have been calculated from the above kEtOK/Kd values and the reported Kd value for EtOK. The calculated kEtO- and kEtOK values in this way are summarized in Table 1 together with the pKa values of Y-substituted phenols in EtOH and the kEtOK/kEtO- ratios.

Figure 2.Plot illustrating dissection of kobsd into second-order rate constants kEtO- and kEtOK for the reaction of 4-methylphenyl benzoate (5a) with EtOK in anhydrous EtOH at 25.0 ± 0.1 ℃.

Table 1.aThe pKa data for Y-substituted-phenols in anhydrous EtOH were taken from ref 14

Deduction of Reaction Mechanism. As shown in Table 1, the second-order rate constant for the reaction with the ion-paired EtOK (i.e., kEtOK) is larger than that for the reaction with the dissociated EtO- (i.e., kEtO-) in all cases. This implies that the ion-paired EtOK is more reactive than the dissociated EtO- and is consistent with the idea that K+ ion catalyzes the current reactions.

K+ ion could catalyze the current reactions either by increasing the electrophilicity of the electrophilic center through TSI or by enhancing the nucleofugality of the leaving group via TSII. One might exclude TSIII, which would increase both the electrophilicity of the reaction center and the nucleofugality of the leaving group. This is because the EtO- and K+ ions in TSIII are not ion-paired species. It is apparent that the enhanced nucleofugality through TSII is effective only for reactions in which departure of the leaving group occurs in the rate-determining step (RDS) but is ineffective for reactions in which the leaving group departs after the RDS. Thus, information on the reaction mechanism including the RDS is necessary to investigate the role of K+ ion in the current reactions.

Nucleophilic substitution reactions of esters 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 nucleophile and the leaving group (Scheme 1).15-20 To investigate the reaction mechanism, Brønsted-type plots have been constructed for the reactions of 5a-j with the dissociated EtO- and ion-paired EtOK. As shown in Figure 3, the Brønsted-type plots are linear but exhibit highly scattered points with a β1g value of -0.64 or -0.42. A β1g value of -0.5 ± 0.1 is typical for reactions reported previously to proceed through a concerted mechanism.15-20 However, one cannot conclude whether the reactions in this study proceed through a concerted mechanism or via a stepwise pathway from the poorly correlated Brønsted-type plots. More conclusive information is required to deduce the reaction mechanism.

Figure 3.Brønsted-type plots for the reactions of 5a-j with dissociated EtO- (a) and ion-paired EtOK (b) in anhydrous EtOH at 25.0 ± 0.1 ℃. The identity of points is given in Table 1.

One might expect that a partial negative charge develops on the O atom of the leaving aryloxide, if departure of the leaving group occurs in the RDS. Since such negative charge could be delocalized to the substituent Y in the leaving group through the resonance interaction, σ- constants should result in a much better Hammett correlation than σo constants. In contrast, if the reaction proceeds through a stepwise mechanism, departure of the leaving group would occur after the RDS, because EtO- is more basic and a poorer nucleofuge than Y-substituted-phenoxide. Accordingly, if the current reaction proceeds through a stepwise mechanism, no negative charge would develop on the O atom of the leaving group in the rate-determining TS. In this case, σo constants should result in a much better Hammett correlation than σ- constants.

Figure 4.Hammett correlations with σ- (a) and σo (b) constants for the reactions of 5a-j with the ion-paired EtOK in anhydrous EtOH at 25.0 ± 0.1 ℃. The identity of points is given in Table 1.

Figure 5.Hammett correlations with σ- (a) and σo (b) constants for the reactions of 5a-j with the dissociated EtO- in anhydrous EtOH at 25.0 ± 0.1 ℃. The identity of points is given in Table 1.

To deduce the reaction mechanism, Hammett plots have been constructed using σ- and σo constants for the reactions with the ion-paired EtOK. As shown in Figure 4, the Hammett plot correlated with σ- constants (a) exhibits highly scattered points (R2 = 0.975). In contrast, the corresponding plot correlated with σo constants (b) results in an excellent linear correlation (R2 = 0.997) with ρY = 1.86. This is only possible for a stepwise mechanism in which departure of the leaving-group occurs after RDS.

A similar result is demonstrated in Figure 5, although the slope of the Hammett plot is larger for the reactions with the dissociated EtO- (ρY = 2.81) than for those with the ionpaired EtOK (ρY = 1.86). Thus, one can conclude that the reactions of 5a-j with the dissociated EtO- and ion-paired EtOK proceed through a stepwise mechanism with formation of an intermediate being the RDS.

Role of K+ Ion. As mentioned in the preceding section, K+ ion could catalyze the reaction by increasing either the electrophilicity of the reaction center through TSI or the nucleofugality of the leaving group via TSII. However, TSII is not effective for reactions in which departure of the leaving group occurs after the RDS. It is noted that the current reactions proceed through a stepwise mechanism in which departure of the leaving group occurs after RDS. Thus, one can conclude that the current reactions are catalyzed by increasing the electrophilicity through TSI rather than by enhancing the nucleofugality of the leaving group via TSII.

The above argument can be further supported by the kEtOK/kEtO- ratio (Table 1), which represents the magnitude of the catalytic effect shown by K+ ion. One might expect that the kEtOK/kEtO- ratio would be strongly dependent on the electronic nature of the substituent Y in the leaving group, if the reactions are catalyzed through TSII. This is because the substituent Y is close to the O atom of the leaving group (proximal). On the contrary, the kEtOK/kEtO- ratio would be independent of the electronic nature of the substituent Y, if the reactions are catalyzed through TSI. This is because the substituent Y is located too far from the O atom of the C=O bond to influence the electron density of the O atom (distal). In fact, Table 1 shows that the kEtOK/kEtO- ratio is almost independent of the electronic nature of the substituent Y. This supports the preceding idea that the current reactions are catalyzed by increasing the electrophilicity of the reaction center through TSI.

 

Conclusions

The current study has allowed us to conclude the following: (1) The ion-paired EtOK is more reactive than the dissociated EtO- toward the substrates 5a-j. (2) The Brønsted-type plots for the reactions with the dissociated EtO- and ion-paired EtOK exhibit highly scattered points with β1g = -0.5 ± 0.1. (3) The Hammett plots correlated with σo constants result in excellent linear correlations, indicating that no negative charge develops on the O atom of the leaving aryloxides. (4) The reactions with the dissociated EtO- and ion-paired EtOK proceed through a stepwise mechanism in which departure of the leaving group occurs after the RDS. (5) K+ ion catalyzes the reactions by increasing the electrophilicity of the reaction center through TSI.

 

Experimental Section

Materials. Y-Substituted-phenyl benzoates (5a-j) were prepared by modification of literature procedures by adding the respective phenol to the solution of benzoyl chloride in methylene chloride as reported previously.21 The crude product was purified by column chromatography (silica gel, methylene chloride/n-hexane 50/50). The purity was checked by their melting points and 1H NMR spectra. 18-Crown-6-ether was recrystallized from MeCN and dried under vacuum. The anhydrous ethanol used was further dried over magnesium and distilled under N2 just before use.

Kinetics. The kinetic study was performed with a UV-vis spectrophotometer equipped with a constant temperature circulating bath to maintain the temperature in the reaction cell at 25.0 ± 0.1 ℃. The reaction was followed by monitoring the appearance of the leaving Y-substituted phenoxide ion. All reactions were carried out under pseudo-first-order conditions in which EtOK concentrations were at least 20 times greater than the substrate concentration. The EtOK stock solution was prepared by dissolving potassium metal in anhydrous ethanol under nitrogen and stored in the refrigerator. The concentration of EtOK was determined by titration with mono potassium phthalate.

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 0.02 M solution of the substrate in CH3CN by a 10μL 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.