Kinetic Study on Nucleophilic Displacement Reactions of Y-Substituted-Phenyl 2-Methylbenzoates with Cyclic Secondary Amines in Acetonitrile: Effects of Modification of 2-MeO in Benzoyl Moiety by 2-Me on Reactivity and Reaction Mechanism

Abstract

The second-order rate constants ($k_N$) have been measured spectrophotometrically for nucleophilic substitution reactions of Y-substituted-phenyl 2-methylbenzoates (6a-e) with a series of cyclic secondary amines in MeCN at $25.0{\pm}0.1^{\circ}C$. Comparison of the $k_N$ values for the reactions of 4-nitrophenyl 2-methylbenzoate (6d) with those reported previously for the corresponding reactions of 4-nitrophenyl 2-methoxybenzoate (5) reveals that 6d is significantly less reactive than 5, indicating that modification of 2-MeO in the benzoyl moiety of 5 by 2-Me (i.e., $5{\rightarrow}6d$) causes a significant decrease in reactivity. This supports our previous report that aminolysis of 5 proceeds through a six-membered cyclic intermediate, which is highly stabilized through intramolecular H-bonding interactions. The Br${\o}$nsted-type plot for the reactions of 6d with a series of cyclic secondary amines is linear with ${\beta}_{nuc}=0.71$, which appears to be a lower limit of ${\beta}_{nuc}$ for a stepwise mechanism with breakdown of an intermediate ($T^{\pm}$) being rate-determining step (RDS). The Br${\o}$nsted-type plot for the reactions of 6a-e with piperidine is curved, i.e., the slope of Br${\o}$nsted-type plot (${\beta}_{lg}$) decreases from -1.05 to -0.41 as the leaving-group basicity decreases. The nonlinear Br${\o}$nsted-type plot has been taken as evidence for a stepwise mechanism with a change in RDS (e.g., from the $k_2$ step to the $k_1$ process as the leaving-group basicity decreases). Dissection of $k_N$ into the microscopic rate constants associated with the reactions of 6a-e with piperidine (e.g., $k_1$ and $k_2/k_{-1}$ ratio) also supports the proposed mechanism.

Introduction

Aminolysis of esters has been reported to proceed through a concerted mechanism or via a stepwise pathway with a zwitterionic tetrahedral intermediate (T±) depending on reaction conditions (e.g., the nature of electrophilic center, reaction medium, basicity of leaving group, etc.).1-10 Reactions of 2,4-dinitrophenyl diphenylphosphinate (1a) with primary and secondary amines have been concluded to proceed through a concerted mechanism on the basis of linear Brønsted-type plots with βnuc = 0.38 and 0.53 for the reactions with primary and secondary amines, respectively.6a,c A similar conclusion has been drawn for the corresponding reactions of 2,4-dinitrophenyl diphenylphosphinothioate (1b).6b The concerted mechanism has been further supported by an excellent linear Yukawa-Tsuno plot with βY = 2.24 and r = 0.22 for the reactions of Y-substituted-phenyl diphenylphosphinates (including 1a) with ethylamine.6a On the contrary, aminolysis of 2,4-dinitrophenyl benzenesulfonate (2) has been suggested to proceed through a stepwise mechanism with a change in rate-determining step (RDS) based on a curved Brønsted-type plot, i.e., the slope of the plot (βnuc) decreases from 0.88 to 0.41 as the basicity of the incoming amine increases.7 Thus, the nature of the electrophilic center (P=O, P=S and SO2) has been suggested to affect the reaction mechanism.67

The nature of the reaction medium has been suggested to be also an important factor to determine the reaction mechanism. We have reported that the Brønsted-type plot for the reactions of 2,4-dinitrophenyl benzoate (3) with a series of secondary amines is curved in H2O (i.e., βnuc decreases from 0.74 to 0.34 as the basicity of the incoming amine increases)8a but is linear with βnuc = 0.40 in MeCN.8b Thus, the reactions have been proposed to proceed through a stepwise mechanism with a change in RDS in the aqueous medium8a but via a concerted pathway in the aprotic solvent.8b

However, we have recently reported that aminolysis of esters possessing a highly basic leaving group (e.g., 4-pyridyl benzoate, 4) or bearing 2-methoxy group in the nonleaving benzoyl moiety (e.g., 4-nitrophenyl 2-methoxybenzoate, 5) proceeds through a stepwise mechanism even in MeCN.910 A decreased nucleofugality of the highly basic 4-pyridyloxide in 4 and the stability gained from the H-bonding interactions in the cyclic intermediate (i.e., 5NH) have been suggested to lead the reactions to proceed through a stepwise mechanism.910

Scheme 1

Our study has now been extended to reactions of Ysubstituted- phenyl 2-methylbenzoates (6a-e) with a series of cyclic secondary amines in MeCN to get further information on the reaction mechanism (Scheme 1). The kinetic results in this study have been compared with those reported previously for the corresponding reactions of 510 to investigate the effect of changing the 2-MeO in the benzoyl moiety of 5 by 2-Me on reactivity and reaction mechanism.

 

Results and Discussion

All the reactions in this study were carried out under pseudo-first-order conditions in which the amine concentration was kept in excess of the substrate concentration, and obeyed first-order kinetics. Pseudo-first-order rate constants (kobsd) were calculated from the equation, ln (A∞ – At) = –kobsdt + C. The plots of kobsd vs. [amine] were linear and passed through the origin, indicating that general-base catalysis by a second amine molecule is absent. The secondorder rate constants (kN) were calculated from the slope of the linear plots of kobsd vs. [amine]. It is estimated that the uncertainty in the kN value is less than ± 3% based on the replicate runs. The kN values are summarized in Table 1 for the reactions of 4-nitrophenyl 2-methylbenzoate (6d) with a series of cyclic secondary amines and in Table 2 for those of Y-substituted-phenyl 2-methylbenzoates (6a-e) with piperidine.

Effect of Amine Basicity on Reactivity and Reaction Mechanism. Table 1 shows that the kN value for the reaction of 6d decreases as the amine basicity decreases, e.g., it decreases from 77.9 × 10−3 M−1s−1 to 7.05 × 10−3 and 2.08 × 10−3 M−1s−1 as the pKa of the conjugate acid of the incoming amine decreases from 18.8 to 17.6 and 16.6, in turn. The kN values for the corresponding reactions of 5 exhibit a similar trend. However, Table 1 shows that the kN values are significantly larger for the reactions of 5 than for those of 6d, indicating that replacing 2-MeO in the benzoyl moiety of 5 by 2-Me causes a significant decrease in reactivity. One can suggest that the large difference in the reactivities of 5 and 6d is not due to the difference in the inductive or steric effects exerted by the MeO and Me groups in the o-position of the benzoyl moiety. This is because their inductive and steric effects would not be so different.11 The significantly higher reactivity shown by 5 appears to be consistent with our previous proposal that the reactions of 5 proceed through the cyclic intermediate 5NH, which gains a high stability through the intramolecular H-bonding interaction.10

Table 1.Summary of Second-Order Rate Constants for the Reactions of 4-Nitrophenyl 2-Methoxybenzoate (5) and 4-Nitrophenyl 2-Methylbenzoates (6d) with Cyclic Secondary Amines in MeCN at 25.0 ± 0.1 ℃

In Figure 1(a) is demonstrated the effect of amine basicity on reactivity of 6d toward the cyclic secondary amines. The Brønsted-type plot exhibits an excellent linear correlation with βnuc = 0.71 when the kN and pKa values are corrected statistically using p and q (i.e., p = 2 and q = 1 except q = 2 for piperazine).13 This is almost identical to the Brønstedtype plot for the aminolysis of 5 as shown in Figure 1(b), which has been reported to proceed through a stepwise mechanism with the leaving-group departure being the RDS on the basis of a linear Brønsted-type plot with βnuc = 0.70.10 Thus, it is proposed that the aminolysis of 6d proceeds also through a stepwise mechanism with breakdown of the intermediate being RDS. One can also suggest that the modification of 2-MeO by 2-Me does not influence the reaction mechanism and that a βnuc value of 0.70 or 0.71 is a lower limit of βnuc for reactions proceeding through a stepwise mechanism in which departure of the leaving-group occurs in the RDS.

Figure 1.Brønsted-type plots for the reactions of 4-nitrophenyl 2- methylbenzoate (a) and 2-methoxybenzoate (b) with cyclic secondary amines in MeCN at 25.0 ± 0.1 ℃. The identity of the points is given in Table 1.

Effect of Leaving-Group Basicity on Reactivity and Reaction Mechanism. One might argue that a linear Brønsted-type plot with βnuc = 0.71 is not sufficient to deduce the reaction mechanism. To get more conclusive information on the reaction mechanism, reactions of Ysubstituted- phenyl 2-methylbenzoates (6a-e) with piperidine have been carried out. Piperidine was chosen as a nucleophile since it is the most basic secondary amines available. Thus, one might expect a curved Brønsted-type plot if the reactions of 6a-e with piperidine proceed through a stepwise mechanism with a change in RDS.

As shown in Table 2, the kN value for the reactions of 6a-e with piperidine increases as the leaving-group basicity decreases, e.g., it increases from 3.21 × 10−6 M−1s−1 to 3.74 × 10−3 and 8.86 M−1s−1 as the pKa of the conjugate acid of the leaving group decreases from 25.0 to 22.1 and 17.9, in turn.

The effect of leaving-group basicity on reactivity is illustrated in Figure 2. The Brønsted-type plot for the reactions of 6a-e with piperidine is curved. Such a curved Brønsted-type plot is typical of reactions reported previously to proceed through a stepwise mechanism with a change in the RDS, e.g., quinuclidinolysis of diaryl carbonates,15 piperidinolysis of aryl benzoates16 and aryl 2-methoxybenzoates. 10 Thus, the nonlinear Brønsted-type plot observed for the current reactions can be taken as evidence for a change in RDS of a stepwise reaction, e.g., the RDS changes from the breakdown of T± to its formation as the leavinggroup basicity decreases. This is consistent with the preceding proposal that the reaction of 6d with the cyclic secondary amines proceeds through a stepwise mechanism on the basis of the linear Brønsted-type plot with βnuc = 0.71.

Thus, the nonlinear Brønsted-type plot has been analyzed using a semiempirical equation, Eq. (1), in which βlg1 and βlg2 represent the slope of the Brønsted-type plot shown in Figure 2 for the reactions substrates possessing a weakly basic leaving group and a strongly basic leaving group, respectively, while kNo refers to the kN value at pKao (defined as the pKa at the center of the Brønsted curvature, where k2 = k−1).15 The βlg1, βlg2, and pKa o values determined are −0.41, −1.05, and 19.4, in turn.

Table 2.Summary of Second-Order Rate Constants for the Reactions of Y-Substituted-Phenyl 2-Methylbenzoates (6a-e) with Piperidine in MeCN at 25.0 ± 0.1 ℃a

Figure 2.Brønsted-type plot for the reactions of Y-substitutedphenyl 2-methylbenzoates (6a-e) with piperidine in MeCN at 25.0 ± 0.1 ℃. The identity of the points is given in Table 2.

Dissection of kN into k1 and k2/k−1. The microscopic rate constants associated with the reactions of 6a-e with piperidine (e.g., the k1 and k2/k−1 ratios) have been calculated as follows. Eq. (2) can be simplified to Eqs. (3) and (4). Then, βlg1 and βlg2 can be expressed as Eqs. (5) and (6), respectively.

Eq. (6) can be rearranged as Eq. (7). Integral of Eq. (7) from pKao results in Eq. (8). Since k2 = k−1 at pKao, the term (log k2/k−1)pKao is zero. Therefore, one can calculate the k2/k−1 ratio for the reactions of 6a-e with piperidine from Eq. (8) using βlg1 = −0.41, βlg2 = −1.05 and pKao = 19.4. The k1 values have been determined from eq (2) using the kN values in Table 2 and the k2/k−1 ratios calculated above. The results are summarized in Table 3.

Table 3.Summary of the Microscopic Rate Constants Associated with the Reactions of Y-Substituted-Phenyl 2-Methylbenzoates (6a-e) with Piperidine in MeCN at 25.0 ± 0.1 ºC

The effects of leaving-group basicity on k1 and the k2/k−1 ratios for the reactions of 6a-e with piperidine are illustrated in Figure 3. The Brønsted-type plots exhibit excellent linear correlations with a slope −0.38 for k1 (a) and −0.64 for k2/k−1 (b). A similar result has been reported for reactions which proceed through a stepwise mechanism with formation of an intermediate being the RDS (e.g., for piperidinolysis of 6a-e in aqueous medium16 and for reactions of O-aryl thionobenzoates with anionic nucleophiles such as OH−, CN−, and N3− ions).17

Figure 3.Brønsted-type plots for the reactions of Y-substitutedphenyl 2-methylbenzoates (6a-e) with piperidine in MeCN at 25.0 ± 0.1 ℃. (a) for k1 and (b) for k2/k−1. The identity of points is given in Table 3.

Figure 3(b) shows that the k2/k−1 ratio increases as the leaving-group basicity decreases, i.e., k2/k−1 > 1 when pKa < 19.4, while k2/k−1 < 1 when pKa > 19.4. This is consistent with the preceding argument that the reaction of 6a-e with piperidine proceeds through a stepwise mechanism with a change in RDS upon changing the leaving-group basicity, e.g., breakdown of T± is RDS when pKa > 19.4 but formation of T± is RDS when pKa < 19.4.

 

Conclusions

The current study has allowed us to conclude the following: (1) 4-Nitrophenyl 2-methoxybenzoate (5) is significantly more reactive than 4-nitrophenyl 2-methylbenzoate (6d), indicating that replacing the 2-MeO in the benzoyl moiety of 5 by 2-Me causes a significant decrease in reactivity. This supports our previous proposal that the aminolysis of 5 proceeds through a six-membered cyclic intermediate (i.e., 5NH), which is highly stabilized through intramolecular Hbonding interactions. (2) The Brønsted-type plots for the reactions of 5 and 6d are linear with βnuc = 0.70 or 0.71, indicating that modification of the 2-MeO by 2-Me does not affect the reaction mechanism. A βnuc value of 0.70 or 0.71 appears to be a lower limit for reactions which proceed through a stepwise mechanism with leaving-group departure being RDS. (3) The curved Brønsted-type plot observed for the reactions of 6a-e with piperidine supports a stepwise mechanism with a change in RDS (e.g., from the k2 step to the k1 process as the leaving-group basicity decreases).

 

Experimental Section

Materials. Compounds 6a-e were readily prepared from the reaction of 2-methylbenzoyl chloride with Y-substituted phenol in anhydrous ether in the presence of triethylamine as reported previously.16 Their purity was confirmed from melting points and 1H NMR characteristics. MeCN was distilled over P2O5 and stored under nitrogen. The amines and other chemicals used in this study were of the highest quality available.

Kinetics. The kinetic study was performed using a UV-vis spectrophotometer equipped with a constant temperature circulating bath to keep the reaction temperature at 25.0 ± 0.1 ℃. All the reactions were carried out under pseudo-firstorder conditions in which the amine concentration was at least 20 times greater than the substrate concentration. Typically, the reaction was initiated by adding 5 μL of a 0.02 M of substrate stock solution in MeCN by a 10 μL syringe to a 10 mm UV cell containing 2.50 mL of the reaction medium and amine. The reactions were followed by monitoring the appearance of Y-substituted-phenoxide ion up to 9 to 10 half-lives.

Product Analysis. Y-Substituted-phenoxide (and/or its conjugate acid) was liberated quantitatively and identified as one of the reaction products by comparison of the UV-vis spectra obtained after completing the reactions with those of authentic samples under the same kinetic conditions.