Kinetic Study on Nucleophilic Substitution Reactions of 4-Nitrophenyl X-Substituted-2-Methylbenzoates with Cyclic Secondary Amines in Acetonitrile: Reaction Mechanism and Failure of Reactivity-Selectivity Principle

Abstract

A kinetic study is reported on nucleophilic substitution reactions of 4-nitrophenyl X-substituted-2-methylbenzoates (5a-e) with a series of cyclic secondary amines in MeCN at $25.0{\pm}0.1^{\circ}C$. The Hammett plots for the aminolysis of 5a-e are nonlinear, e.g., substrates possessing an electron-donating group (EDG) in the benzoyl moiety deviate negatively from the linear line composed of substrates bearing no EDG. In contrast, the Yukawa-Tsuno plots for the same reactions exhibit excellent linear correlations with ${\rho}_X$ = 0.30-0.59 and r = 0.90-1.15, indicating that the nonlinear Hammett plots are caused by stabilization of the substrates possessing an EDG through resonance interactions but are not due to a change in the rate-determining step (RDS). The Br${\phi}$nsted-type plots are linear with ${\beta}_{nuc}$ = 0.66-0.82. Thus, the aminolysis of 5a-e has been suggested to proceed through a stepwise mechanism in which departure of the leaving group occurs at the RDS. The ${\rho}_X$ and ${\beta}_{nuc}$ values for the aminolysis of 5a-e increase as the reactivity of the substrates and amines increases, indicating that the reactivity-selectivity principle is not applicable to the current reactions.

Introduction

Nucleophilic substitution reactions of esters with amines are an important class of reactions in biological processes as well as synthetic applications.1 Thus, numerous studies have been carried out to investigate the reaction mechanism. Aminolysis of esters has been reported to proceed through a stepwise mechanism with one or two intermediates (e.g., a zwitterionic tetrahedral intermediate T± and its deprotonated form T-), or via a concerted pathway depending on the reaction conditions (e.g., the nature of electrophilic center, reaction medium, electronic nature of the substituent in the nonleaving group, basicity of the leaving group, etc.).2-12

Reactions of 4-nitrophenyl benzoate (1a) with a series of cyclic secondary amines have been suggested to proceed through a stepwise mechanism on the basis of a linear Brønsted-type plot with βnuc = 0.81,7 while the corresponding reactions of O-4-nitrophenyl thionobenzoate (1b) have been reported to proceed through two intermediates (i.e., T± and T-) since the plots of kobsd vs. [amine] exhibit upward curvature.8 In contrast, aminolyses of 4-nitrophenyl diphenylphosphinate (2a)9 and diphenylphosphinothioate (2b)10 have been proposed to proceed through a concerted mechanism on the basis of a linear Brønsted-type plot with βnuc = 0.38-0.53. This demonstrates convincingly that the nature of the electrophilic center (e.g., C=O, C=S, P=O, P=S) is an important factor which governs the reaction mechanism.

The nature of reaction medium has also been reported to influence the reaction mechanism.11a We have reported that the Brønsted-type plot for the reactions of 2,4-dinitrophenyl benzoate, a derivative of 1a, with a series of cyclic secondary amines curves downward (i.e., βnuc decreases from 0.74 to 0.34 as the amine basicity increases) in 80 mol % H2O/20 mol % DMSO11a but is linear with βnuc = 0.40 in MeCN.11b Thus, the reactions have been suggested to proceed through a stepwise mechanism with a change in the RDS in the aqueous medium but via a concerted pathway in the aprotic solvent.11

The electronic nature of the substituent X in the nonleaving group has been reported to control the reaction mechanism in aminolysis of 4-pyridyl X-substituted-benzoates (3) in MeCN.12 We have shown that the plots of kobsd vs. [amine] curve upward for the reactions of substrates possessing a strong electron-withdrawing group (EWG) in the benzoyl moiety of 3 but are linear for the reactions of those bearing a weak EWG or an EDG.12 Thus, the reactions have been concluded to proceed through a stepwise mechanism with two intermediates (i.e., T± and T-) when the substrate possesses a strong EWG in the benzoyl moiety.12 However, the deprotonation process from T± to yield T- is absent when the substrate bears a weakly EWG or an electron-donating group (EDG).12

In our recent report, nucleophilic substitution reactions of Y-substituted-phenyl 2-methylbenzoates (4) with piperidine in MeCN proceed through a stepwise mechanism with a change in the RDS on the basis of the kinetic result that the Brønsted-type plot exhibits downward curvature (e.g., βlg decreases from -1.05 to -0.41 as the leaving-group basicity decreases).13 Our study has now been extended to the reactions of 4-nitrophenyl X-substituted-2-methylbenzoates (5a-e) with a series of cyclic secondary amines in MeCN (Scheme 1) to investigate the effect of substituent X in the nonleaving group on the reaction mechanism.

Scheme 1

 

Results and Discussion

The kinetic study was performed under pseudo-first-order conditions in which the amine concentration was kept at least 20 times in excess of the substrate concentration. The reactions obeyed first-order kinetics in all cases and the pseudo-first-order rate constants (kobsd) were calculated from the equation, ln (A∞ – At) = –kobsdt + C. The plots of kobsd vs. amine concentrations are linear and pass through the origin, indicating that general-base catalysis by a second amine molecule is absent. Accordingly, the second-order rate constants (kN) were calculated from the slope of the linear plots. The kN values calculated in this way are summarized in Table 1. The uncertainty in the kN values is estimated to be less than ± 3% based on the replicate runs.

Effect of Substituent X on Reactivity and Reaction Mechanism. As shown in Table 1, the kN values increase as the substituent X in the benzoyl moiety changes from an EDG to an EWG, e.g., the kNvalue for the reactions with piperidine increases from 2.88 × 10-2 M-1s-1 to 7.79 × 10-2 and 2.07 × 10-1 M-1s-1 as the substituent X changes from 4-MeO to H and 3-NO2,, in turn. Similar results are demonstrated for the corresponding reactions with the other amines. However, the dependence of the kN value on the electronic nature of the substituent X is not significant for the reactions with weakly basic amine, e.g., the kN for the reaction with morpholine increases from 1.02 × 10-3 M-1s-1 to 2.08 × 10-3 and 3.06 × 10-3 M-1s-1, in turn.

The effect of the substituent X on the kN value is illustrated in Figure 1. The Hammett plots are not linear for the reactions of 5a-e with all the amines studied. It is seen that substrates possessing an EDG in the benzoyl moiety (i.e., 5a and 5b) deviate negatively from the linear line composed of the substrates bearing no EDG. It is also noted that such deviation is more significant for the substrate possessing a stronger EDG (i.e., 5a) than that bearing a weaker EDG (i.e., 5b).

Nonlinear Hammett plots have been interpreted as a change in the reaction mechanism or RDS depending on the type of curvature.15 Concave upward curvature has often been reported for nucleophilic substitution reactions of benzylic systems which proceed through an SN1 mechanism for substrates possessing an EDG (i.e., a negative ρX) but via an SN2 mechanism for substrates bearing an EWG (i.e., a positive ρX).15 In contrast, convex downward curvature has been interpreted as a change in the RDS on changing the substituents from EDGs to EWGs.15 Thus, one might suggest that the nonlinear Hammett plots obtained from the reactions of 5a-e indicate a change in the RDS of a stepwise mechanism, i.e., from formation of T± (i.e., the k1 step) to its breakdown (i.e., the k2 step) as the substituent X changes from EDGs to EWGs. This idea appears to be reasonable since an EDG in the benzoyl moiety of the substrate would retard the rate of nucleophilic attack (i.e., a decrease in k1) but accelerate departure of the leaving 4-nitrophenoxide (i.e., an increase in k2) while an EWG would increase k1 but decrease k2.

Figure 1.Hammett plots for the reactions of 4-nitrophenyl X-substituted-2-methylbenzoates (5a-e) with cyclic secondary amines in MeCN at 25.0 ± 0.1. The identity of points is given in Table 1.

Table 1.aThe pKa data for the conjugate acids of amines in MeCN were taken from ref. 14. X = 4-MeO (5a), 4-Me (5b), H (5c), 3-Cl (5d), 3-NO2 (5e).

However, we propose that the nonlinear Hammett plots are not due to a change in the RDS. Because the RDS is not governed by the magnitude of k1 and k2 values but should be determined by the k2/k-1 ratio (e.g., RDS = the k1 step when k2/k-1 ＞ 1, while RDS = the k2 step when k2/k-1 ＜ 1). We propose that the nonlinear Hammett plots shown in Figure 1 are caused by stabilization of substrates possessing an EDG (e.g. 5a and 5b) through resonance interactions between the electron-donating substituent X and the C=O bond as illustrated by the resonance structures I ↔ II. This is because such resonance interactions could stabilize the GS of the substrate and cause a decrease in the reactivity (i.e., negative deviation from the Hammett plots).

To examine the validity of the above argument, the Yukawa-Tsuno Eq. (1) has been employed. Eq. (1) was originally derived to account for the kinetic results obtained from solvolysis of benzylic systems in which a positive charge develops partially at the reaction center.16 The r value in eq. (1) represents the resonance demand of the reaction center or the extent of resonance contribution, while the term (σX + - σXo) is the resonance substituent constant that measures the capacity for π-delocalization of the π-electron donor substituent.16,17

As shown in Figure 2, Yukawa-Tsuno plots for the reactions of 5a-e exhibit excellent linear correlations with the ρX = 0.31-0.60 and r = 0.90-1.15. The linear Yukawa-Tsuno plots clearly indicate that the reactions proceed without changing the RDS (or reaction mechanism) on changing the substituent X in the benzoyl moiety. Furthermore, the large r values suggest that the resonance contribution is significant in the current reactions. Thus, one can conclude that the nonlinear Hammett plots shown in Figure 1 are caused by stabilization of substrates possessing an EDG through resonance interactions.

Figure 2.Yukawa-Tsuno plots for the reactions of 4-nitrophenyl X-substituted-2-methylbenzoates (5a-e) with cyclic secondary amines in MeCN at 25.0 ± 0.1. The identity of points is given in Table 1.

Effect of Amine Basicity on Reactivity and Reaction Mechanism. As shown in Table 1, the kN values for the reactions of 5a-e decrease as the amine basicity decreases, e.g., the kN value for the reactions of 5a decreases from 2.88 × 10-2 M-1s-1 to 3.46 × 10-3 and 1.02 × 10-3 M-1s-1 as the pKa of the conjugate acid of the amine decreases from 18.8 to 17.6 and 16.6, in turn. Similar results are shown for the reactions of 5b-e although the kNvalue for a given substrate increases less significantly as the substituent X changes from an EWG to a stronger EDG as mentioned in the preceding section.

Figure 3.Brønsted-type plots for reactions of 4-nitrophenyl X-substituted-2-methylbenzoates (5a, 5c and 5e) with a series of cyclic secondary amines in MeCN at 25.0 ± 0.1 ºC. The identity of points is given in Table 1.

The effect of amine basicity on reactivity is illustrated in Figure 3. The statistically corrected Brønsted-type plots using p and q (e.g., p = 2 and q = 1 except q = 2 for piperazine)18 are linear with a βnuc value of 0.66, 0.71 and 0.82 for the reactions of 5a, 5c and 5e, in turn. Similarly linear plots are obtained for the reactions of 5b and 5d with a βnuc value of 0.71 and 0.78, respectively (Figures not shown). It is noted that the βnuc value becomes smaller for the reactions of substrates possessing a stronger EDG in the benzoyl moiety (or the reactivity of the substrate decreases).

The βnuc value of 0.71-0.82 obtained for the reactions of 5b-e is typical of reactions reported previously to proceed through a stepwise mechanism in which departure of the leaving group occurs in the RDS.2,7-12 In contrast, the βnuc value of 0.66 obtained for the reactions of 5a appears to be slightly smaller than the lower limit for reactions reported to proceed through a stepwise mechanism.2,7-12 Nevertheless, we propose that the reactions of 5a proceed also through a stepwise mechanism in which departure of the leaving group (i.e., 4-nitrophenoxide) occurs at the RDS. Because, as discussed in the preceding section, the electronic nature of the substituent X in the benzoyl moiety of 5a-e does not affect the reaction mechanism including the RDS. Thus, one can suggest that the magnitude of βnuc value cannot be an absolute measure to deducing the reaction mechanism.

Evidence for Failure of Reactivity-Selectivity Principle. It is well known that the magnitude of ρX and βnuc values represents a sensitivity (or selectivity) parameter for a series of reactions. The ρX and βnuc values have generally been reported to be larger for the less reactive reactions than for the more reactive ones, which is in accord with the reactivity- selectivity principle (RSP).19,20 However, the ρX value shown in Figure 4 (a) increases linearly with increasing the basicity (or reactivity) of the incoming amine. Similarly, the βnuc value illustrated in Figure 4 (b) also increases linearly with increasing the σX constant of the substituent X (or with increasing reactivity of the substrate). This is quiet an unexpected result from the RSP.

Figure 4.Correlations of ρX with pKa of the conjugate acid of amines (a) and βnuc with σX of the substituent X (b) for the aminolysis of 4-nitrophenyl X-substituted-2-methylbenzoates (5a-e) in MeCN at 25.0 ± 0.1 ℃.

The magnitude of ρX values represents a relative degree of the rehybridization of the C=O bond at the TS (or the charge transfer from the N atom of the attacking amine to the carbonyl carbon of substrates 5a-e). It is apparent that the charge transfer from the amine to the substrates would increase with increasing the amine basicity. Thus, one might expect that the ρX value increases as the basicity of the attacking amine increases. In fact, Figure 4(a) shows a good linear correlation between the ρX value and the pKa of the conjugate acid of the amine with a slope of 0.13. This is clearly against the RSP.

It is also known that the magnitude of the βnuc value represents a relative degree of bond formation between the incoming amine and the substrate (or a formal charge of the N atom of the attacking amine at the TS). Accordingly, one might expect that the degree of bond formation would increase with increasing the electrophilicity of the C=O bond of the substrates 5a-e. It is clear that the electrophilicity of the reaction center would increase on changing the substituent X from an EDG to an EWG. Thus, one might expect that the βnuc value, representing a degree of bond formation or a formal charge, is dependent on the electronic nature of the substituent X. In fact, Figure 4(a) shows a good linear correlation between the βnuc value and the σX constant of the substituent X. This is also against the RSP.

 

Conclusions

The current study has allowed us to conclude the following: (1) The Hammett plots for the aminolysis of 5a-e are nonlinear, while the Yukawa-Tsuno plots exhibit excellent linear correlations with ρX = 0.30-0.59 and r= 0.90-1.15, indicating that the nonlinear Hammett plots are caused by stabilization of the substrates possessing an EDG and that the electronic nature of the substiuent X does not affect the RDS. (2) The Brønsted-type plots for the reactions of 5a-e are linear with βnuc = 0.66-0.82. The reactions are suggested to proceed through a stepwise mechanism in which departure of the leaving group occurs at the RDS. (3) The ρX and βnuc values for the aminolysis of 5a-e increase as the reactivity of the reactants (i.e., the substrates and amines) increases, indicating that the RSP is not applicable to the current reactions.

 

Experimental Section

Materials. Compounds 5a-e were readily prepared from the reaction of the respective X-substituted-2-metylbenzoyl chloride with 4-nitrophenol in anhydrous ether in the presence of triethylamine as reported previously.21 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 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 °C. All of the reactions in this study were carried out under pseudo-first-order 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 4-nitrophenoxide up to 9 halflives.

Product Analysis. 4-Nitrophenoxide (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.