Kinetic Study on Nucleophilic Substitution Reactions of 4-Nitrophenyl X-Substituted-Benzoates with Potassium Ethoxide: Reaction Mechanism and Role of K⁺ Ion

Abstract

A kinetic study on nucleophilic substitution reactions of 4-nitrophenyl X-substituted-benzoates (7a-i) with EtOK in anhydrous ethanol at $25.0{\pm}0.1^{\circ}C$ is reported. The plots of pseudo-first-order rate constants ($k_{obsd}$) vs. [EtOK] curve upward. 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 $EtO^-$. Hammett plots for the reactions of 7a-i with the dissociated $EtO^-$ and ion-paired EtOK exhibit excellent linear correlations with ${\rho}_X$ = 3.00 and 2.47, respectively. The reactions have been suggested to proceed through a stepwise mechanism in which departure of the leaving-group occurs after the RDS. The correlation of the $k_{EtOK}/k_{EtO^-}$ ratio with the ${\sigma}_X$ constants exhibits excellent linearity with a slope of -0.53. It is concluded that the ion-paired EtOK catalyzes the reaction by increasing the electrophilicity of the reaction center rather than by enhancing the nucleofugality of the leaving group.

Introduction

Metal ions including alkali-metal ions have often been reported to behave as a Lewis acid catalyst or as an inhibitor in various acyl-group transfer reactions.1-10 Buncel and his coworkers have reported that alkali-metal ions catalyze the phosphinyl-transfer reaction of 4-nitrophenyl diphenylphosphinate (1a) with alkali-metal ethoxide (EtOM; M = Li, Na, K).8 They have found that the catalytic effect increases as the size of M+ ions decreases, e.g., K+ < Na+

Effects of alkali-metal ions on sulfonyl-transfer reactions of 4-nitrophenyl benzenesulfonate (3) with EtOM have also been investigated.11,12 Buncel et al. have reported that M+ ions catalyze the reaction and the catalytic effect increases as the size of M+ ions increases, i.e., Li+

One might expect that M+ ions catalyze the reaction of 4-nitrophenyl salicylate (4) with EtOM through the cyclic complex 4M, which could increase the electrophilicity of the reaction center. However, we have reported that M+ ions strongly inhibit the reaction.13 More interestingly, the reaction rate has been found to decrease as the concentration of EtOM increases.13 Thus, the cyclic complex 4M has been suggested to inhibit the reaction of 4 by retarding the subsequent E1cb reaction which yields an α-oxoketene.13

The reaction of 2-pyridyl benzoate (5) with EtOM has been performed to obtain further information on M+ ion effects.14 We have proposed that M+ ions catalyze the reaction by increasing either the electrophilicity of the reaction center or nucleofugality of the leaving group through a stable cyclic transition state (e.g., TSIII or TSIV).14

We have recently reported that benzoyl-transfer reaction of Y-substituted-phenyl benzoates (6a-j) with EtOK proceeds through a stepwise mechanism, in which departure of the leaving group occurs after the RDS, on the basis of the kinetic result that σo constants result in a much better linear correlation than σ- constants.15 K+ ion has been suggested to catalyze the reaction by increasing the electrophilicity of the reaction center rather than by enhancing the nucleofugality of the leaving group, on the basis of the kinetic results that (1) the reaction proceeds through a stepwise mechanism with formation of an intermediate being the RDS and (2) the catalytic effect is independent of the electronic nature of the substituent Y in the leaving group.15

Our study has been extended to the reactions of 4-nitrophenyl X-substituted-benzoates (7a-i) with EtOK in anhydrous ethanol to obtain further information on the reaction mechanism and the role of K+ ion (Scheme 1). We have also investigated the effects of the substituent X on the role of K+ ion as well as the reaction mechanism.

 

Results

The kinetic study was performed spectrophotometrically under pseudo-first-order conditions in which the concentration of EtOK was in large excess over that of 7a-i. The reaction obeyed pseudo-first-order kinetics and proceeded with quantitative liberation of 4-nitrophenoxide ion. Pseudofirst- order rate constants (kobsd) were calculated from the equation, ln (A∞– At) = –kobsdt + C. 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 7a-i with the dissociated EtO- and ion-paired EtOK (i.e., kEtO- and kEtOK, respectively) were calculated from the ionpairing treatment of the kinetic data and are summarized in Table 1 together with the kEtOK/kEtO- ratios.

Effect of K+ Ion on Reactivity. As shown in Figure 1, the plot of kobsd vs. [EtOK] curves upward for the reaction of 4-nitrophenyl 4-dimethylaminobenzoate (7a) with EtOK. Similarly curved plots were obtained for the reactions of substrates possessing an electron-donating or a weak electron- withdrawing substituent X in the benzoyl moiety (e.g., 7b-g). In contrast, the plots of kobsd vs. [EtOK] for the reactions of substrates bearing a strong electron-withdrawing substituent X (e.g., 7h and 7i) were almost linear (Figures not shown). The curved plot shown in Figure 1 is typical for alkaline ethanolysis of esters in which alkali-metal ions behave as a Lewis acid catalyst.8-12 Thus, one can suggest that K+ ion catalyzes the reactions of 7a-i with EtOK, although the catalytic effect becomes insignificant for the reactions of substrates possessing a strong electron-withdrawing substituent in the benzoyl moiety (e.g., 7h and 7i).

Figure 1.Plot of kobsd vs. [EtOK] for the reactions of 4-nitrophenyl 4-dimethylaminobenzoate (7a) with EtOK in anhydrous EtOH at 25.0 ± 0.1 ℃. [7a] = 2 𝗑 10-5 M.

Figure 2.Effect of added KSCN on reactivity for the reaction of 4-nitrophenyl 4-dimethylaminobenzoate (7a) with EtOK in EtOH at 25.0 ± 0.1 ℃.

Scheme 1

Scheme 2.Reactions of 7a-i with the dissociated EtO- and ionpaired EtOK.

To support the above idea that K+ ion behaves as a catalyst, reactions of 4-nitrophenyl 4-dimethylaminobenzoate (7a) with a given concentration of EtOK have been performed under various concentrations of KSCN as a K+ ion source. As shown in Figure 2, kobsd increases as the concentration of KSCN in the reaction medium increases up to [KSCN]/[EtOK] ≈ 1 and remains nearly constant thereafter. This supports the preceding idea that K+ ion catalyzes the reactions of 7a-i.

Dissection of kobsd into kEtO- and kEtOK. To quantify the catalytic effect exerted by K+ ion, the kobsd values have been dissected into the second-order rate constants for the reactions of 7a-i with the dissociated EtO- and ion-paired EtOK (i.e., kEtO- and kEtOK, respectively). It has previously been reported that EtOK exists as dissociated EtO- and ion-paired EtOK when [EtOK] < 0.1 M.16 Since the concentration of EtOK used in this study was lower than 0.1 M, substrates 7a-i would react with the dissociated EtO- and ion-paired EtOK as shown in Scheme 2.

One can derive Eq. (1) on the basis of the reactions proposed in Scheme 2. Under pseudo-first-order kinetic conditions (e.g., [EtOK] >> [7a-i]), kobsd can be expressed as Eq. (2). It is noted that the dissociation constant 𝐾d = [EtO-]eq[K+]eq/[EtOK]eq, and [EtO-]eq = [K+]eq at equilibrium. Thus, Eq. (2) can be converted to Eq. (3). The concentrations of [EtO-]eq and [EtOK]eq can be calculated from the reported 𝐾d value for EtOK (i.e., 𝐾d = 1.11 × 10-2 M)17 and the initial concentration [EtOK] using Eqs. (4) and (5).

Thus, one might expect that the plot of kobsd/[EtO-]eq vs. [EtO-]eq would be linear with a positive intercept if the reaction proceeds as proposed in Scheme 2. In fact, the plot shown in Figure 3 is linear with a positive intercept, indicating that the derived equations based on 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 calculated from the above kEtOK/𝐾d values and the reported 𝐾d value for EtOK. In Table 1 are summarized the calculated kEtO- and kEtOK values for the reactions of 7a-i.

Figure 3.Plot illustrating dissection of kobsd into the second-order rate constants kEtO-and kEtOK for the reaction of 4-nitrophenyl 4-dimethylamionobenzoate (7a) with EtOK in anhydrous EtOH at 25.0 ± 0.1 ℃.

As shown in Table 1, the second-order rate constant for the reactions of 7a-i with the ion-paired EtOK (i.e., kEtOK) increases as the substituent X in the benzoyl moiety changes from a strong electron-donating group (EDG) to a strong electron-withdrawing group (EWG), e.g., kEtOK increases from 0.269 M–1s–1 to 19.8 and 2090 M–1s–1 as the substituent X changes from 4-NMe2 to H and 4-NO2, in turn. A similar result is demonstrated for the corresponding reactions with the dissociated EtO-. However, kEtOK is larger than kEtO-, indicating that the ion-paired EtOK is more reactive than the dissociated EtO-. It is also noted that the catalytic effect exerted by K+ ion decreases as the substituent X changes from a strong EDG to a strong EWG, e.g., the kEtOK/kEtO- ratio decreases from 7.43 to 2.23 and 1.01 as the substituent changes from 4-Me2N to H and 4-NO2, in turn. This indicates that the catalytic effect of K+ ion is negligible for the reactions of substrates possessing a strong EWG (e.g., 7h and 7i), and is consistent with the result that the plots of kobsd vs. [EtOK] for the reactions of 7h and 7i are almost linear, as mentioned in the preceding section.

Table 1.Summary of Second-Order Rate Constants from Ion-Pairing Treatment of the Kinetic Data for Reactions of 4-Nitrophenyl X-Substituted-Benzoates (7a-i) with EtOK in Anhydrous EtOH at 25.0 ± 0.1 ℃

Deduction of Reaction Mechanism. Detailed information on the reaction mechanism is necessary to understand the role of K+ ion in current study. Nucleophilic substitution reactions of esters have been reported to proceed either through a concerted mechanism or via a stepwise pathway depending on the nature of the electrophilic center, e.g., a concerted mechanism for reactions of Y-substituted-phenyl diphenylphosphinates and diphenylphosphinothioates with EtO- (i.e., P=O and P=S centered electrophiles)9,18 while a stepwise mechanism for the corresponding reactions of Y-substituted-phenyl benzoates15 and benzenesulfonates12 (i.e., C=O and SO2 centered electrophiles).

To investigate the reaction mechanism, Hammett plots for the reactions of 7a-i with the dissociated EtO- and ion-paired EtOK have been constructed. As shown in Figure 4, the Hammett plots exhibit an excellent linear correlation with 𝜌X = 3.00 and 2.47 for the reactions with the dissociated EtO- and ion-paired EtOK, respectively.

One can get useful information on the reaction mechanism from the magnitude of 𝜌X values. It is expected that an EWG in the nonleaving group would increase the electrophilicity of the reaction center but decrease the nucleofugality of the leaving group, while an EDG would decrease the electrophilicity but increase the nucleofugality. Consequently, the 𝜌X value for a concerted reaction cannot be large due to the opposing substituent effects. In fact, a small 𝜌X value has often been reported for reactions which proceed through a concerted mechanism (e.g., 𝜌X = –0.3 for an SN2 reaction of benzyl bromides with OH-).19 In contrast, the 𝜌X value for a stepwise reaction has been reported to be strongly dependent on the RDS, i.e., a small 𝜌X value (𝜌X = 0.6 ± 0.1) for reactions in which the leaving group departs in the RDS,20 while a large 𝜌X value (𝜌X = 2.0 ± 0.3) for reactions in which the leaving group departs after the RDS.21

Figure 4.Hammett plots for the reactions of 7a-i with the ionpaired EtOK (●) and dissociated EtO- (○) in anhydrous EtOH at 25.0 ± 0.1 ℃. The identity of points is given in Table 1.

Thus, one can suggest that the reactions of 7a-i with the dissociated EtO- and ion-paired EtOK proceed through a stepwise mechanism in which departure of the leaving group occurs after the RDS on the basis of the large 𝜌X value obtained in the current reactions. This idea is further supported by our report that the reactions of Y-substituted-phenyl benzoates (6a-j) with the dissociated EtO- and ion-paired EtOK proceed through a stepwise mechanism with formation of an intermediate being the RDS.15

Role of K+ Ion. The kinetic result that the ion-paired EtOK is more reactive than the dissociated EtO- suggests that the ion-paired EtOK catalyzes the reactions of 7a-i by increasing either the electrophilicity of the reaction center through TSV or the nucleofugality of the leaving 4-nitrophenoxide through TSVI. However, one can exclude TSVII, in which K+ ion increases both the electrophilicity of the reaction center and the nucleofugality of the leaving group. This is because EtO- and K+ ions in TSVII are not ion-paired species.

It is apparent that catalysis through TSVI is effective only for reactions in which departure of the leaving group occurs in the RDS but is ineffective for reactions in which the leaving group departs after the RDS. Since the current reactions have been discussed to proceed through a stepwise mechanism in which departure of the leaving group occurs after the RDS, one can exclude a possibility that the reactions are catalyzed by increasing the nucleofugality of the leaving group through TSVI. Thus, one can conclude that the ion-paired EtOK catalyzes the reactions of 7a-i by increasing the electrophilicity of the reaction center through TSV. This is consistent with our previous report that the ion-paired EtOK catalyzes the reactions of Y-substituted-phenyl benzoates (6a-j) by increasing the electrophilicity of the reaction center through a TS structure similar to TSV.15

The catalytic effect through TSV would be more strongly dependent on the electronic nature of the substituent X in the benzoyl moiety of 7a-i than on that of the substituent Y in the nonleaving group of 6a-j. This is because the substituent X is one atom closer to the C=O bond than the substituent Y. Thus, one might expect that the kEtOK/kEtO- ratio would exhibit a better correlation with the electronic nature of the substituent X than with that of the substituent Y.

Figure 5.Plot showing the relationship between the catalyticeffect exerted by K+ ion (i.e., kEtOK/kEtO-) and σX constants for the reactions of 7a-i with EtOK. The identity of points is given in Table 1.

To examine the above idea, the kEtOK/kEtO- ratio for the reactions of 7a-i has been correlated with the σX constants in Figure 5. One can see an excellent linear correlation with a slope of –0.53. This is in contrast to our previous report that the kEtOK/kEtO- ratio for the reactions of Y-substituted-phenyl benzoates (6a-j) is independent of the electronic nature of the substituent Y.15 Thus, the contrasting results further support the conclusion that the reactions of 7a-i with EtOK are catalyzed by increasing the electrophilicity of the reaction center through TSV.

 

Conclusions

The current study has allowed us to conclude the following: (1) The plots of kobsd vs. [EtOK] curve upward. Dissection of kobsd into the second-order rate constants kEtOK and kEtO- has revealed that the ion-paired EtOK is more reactive than the dissociated EtO-. (2) Hammett plots for the reactions of 7a-i with the dissociated EtO- and ion-paired EtOK exhibit an excellent linear correlation with 𝜌X = 3.00 and 2.47, respectively. The large 𝜌X value has been taken as evidence for a stepwise mechanism, in which departure of the leaving-group occurs after the RDS. (3) The ion-paired EtOK catalyzes the reactions of 7a-i by increasing the electrophilicity of the reaction center through TSV rather than by enhancing the nucleofugality of the leaving group through TSVI.

 

Experimental Section

Materials. 4-Nitrophenyl X-substituted-benzoates (7a-i) were readily prepared by adding 4-nitrophenol to the solution solution of X-substituted-benzoyl chloride, N,N'-dicyclohexyl-carbodiimide and 4-dimethylaminopyridine in methylene chloride as reported previously.15 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.

Kinetics. The kinetic study was performed with a UV-vis spectrophotometer for slow reactions (e.g., 𝑡1/2 > 10 s) or with 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 ℃. The reaction was followed by monitoring the appearance of 4-nitrophenoxide ion at 400 nm. 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 potassium metal in anhydrous ethanol under nitrogen and stored in the refrigerator. The concentration of EtOK was determined by titration with mono potassium 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. 4-Nitrophenoxide 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.