Kinetics and Mechanism of Anilinolyses of Aryl Methyl and Aryl Propyl Chlorothiophosphates in Acetonitrile

Abstract

Nucleophilic substitution reactions of Y-aryl methyl (8) and Y-aryl propyl (10) chlorothiophosphates with substituted anilines and deuterated anilines are investigated kinetically in acetonitrile at $55.0^{\circ}C$. A concerted mechanism is proposed for 8 based on the negative ${\rho}_{XY}$ (= -0.23) value, while a stepwise mechanism with a rate-limiting leaving group departure from the intermediate is proposed for 10 based on the positive ${\rho}_{XY}$ (= +0.68) value. The deuterium kinetic isotope effects (DKIEs; $k_H/k_D$) are 0.89-1.28 and 0.62-1.20 with 8 and 10, respectively. Primary normal and secondary inverse DKIEs are rationalized by a frontside attack involving hydrogen bonded, four-center-type transition state and backside attack involving in-line-type transition state, respectively.

Introduction

As final part on going kinetic studies on the anilinolyses of the chlorothiophophates [(R1O)(R2O)P(=S)Cl-type where R1 = R2 = alkyl and/or aryl], the reactions of Y-aryl methyl (8) and Y-aryl propyl (10) chlorothiophosphates with substituted anilines (XC6H4NH2) and deuterated anilines (XC6H4ND2) have been kinetically investigated in acetonitrile (MeCN) at 55.0 ± 0.1 ℃ (Scheme 1). The aim of this work is to obtain further information on the thiophosphoryl transfer reactions by comparing the anilinolyses of the following chlorothiophosphates in terms of the selectivity parameters, steric effects of the two ligands on the rate, reaction mechanism, deuterium kinetic isotope effects (DKIEs) and activation parameters: dimethyl [1: (MeO)2P(=S)Cl],1a ethyl methyl [2: (MeO)(EtO)P(=S)Cl],1b diethyl [3: (EtO)2-P(=S)Cl],1a ethyl propyl [4: (EtO)(PrO)P(=S)Cl],1b dipropyl [5: (PrO)2P(=S)Cl],1c dibutyl [6: (BuO)2P(=S)Cl],1d diisopropyl (7: (i-PrO)2P(=S)Cl],1b Y-aryl ethyl [9: (EtO)(YC6H4O)-P(=S)Cl],1e Y-aryl phenyl [11: (PhO)(YC6H4O)P(=S)Cl]1f and Y-aryl 4-chlorophenyl [12: (4-Cl-C6H4O)(YC6H4O)- P(=S)Cl]1f chlorothiophosphates. 1-12 are numbered according to the sequence of the summation of the Taft steric constants of the two ligands (R1 and R2).2,3

Scheme 1.Reactions of Y-aryl methyl (8) and Y-aryl propyl (10) chlorothiophosphates with XC6H4NH2(D2) in MeCN at 55.0 ℃.

 

Results and Discussion

Tables 1-3 list the second-order rate constants (kH/M−1 s−1), ρX(H) and βX(H) with X, and ρY(H) with Y, respectively, of the reactions of 8 and 10 with X-anilines. The substituent effects of X and Y on the reaction rates are compatible with a typical nucleophilic substitution reaction and the rate increases with more basic aniline and with more electronwithdrawing substituent Y. The rates of 8 are 2-7 times faster than those of 10 depending on X and/or Y. The free energy relationships with X and Y are all linear. The Hammett (Figs. S1 and S2 with 8 and 10, respectively) and Brönsted (Figs. S3 and S4 with 8 and 10, respectively) plots for substituent X variations in the nucleophiles, and Hammett plots (Figs. S5 and S6 with 8 and 10, respectively) for substituent Y variations in the substrates are shown in the supporting information. The magnitudes of the ρX(H) (= –2.60 to –2.51) and βX(H) (= 0.89-0.93) values with 8 are somewhat smaller than those (ρX(H) = –3.30 to –2.97 and βX(H) = 1.05- 1.17) with 10. The ρY(H) (= 0.60-0.78) values with 8 are more or less smaller than those (ρY(H) = 0.62-1.04) with 10. This may suggest that the degrees of both bond formation and cleavage with 10 are greater than those with 8 in the transition state (TS). The ρX(H) values invariably decrease (i.e., more negative value; ∂ρX(H) < 0) with 8, whereas those invariably increase (i.e., less negative value; ∂ρX(H) > 0) with 10 as substituent Y becomes more electron-withdrawing (∂σY > 0). Meanwhile, the ρY(H) values consistently decrease (i.e., less positive value; ∂ρY(H) < 0) with 8, whereas those consistently increase with 10 (i.e., more positive value; ∂ρY(H) > 0) as the pyridine becomes less basic (∂σX > 0). Note that the variation trends of the ρX(H) values for substituent X variations in the nucleophiles and ρY(H) values for substituent Y variations in the substrates with 8 is opposite to those with 10, resulting in ∂ρX(H)/∂σY = (–)/(+) < 0 and ∂ρY(H)/∂σX = (–)/ (+) < 0 with 8, while ∂ρX(H)/∂σY = (+)/(+) > 0 and ∂ρY(H)/∂σX = (+)/(+) > 0 with 10 (vide infra).

Table 1.Second-Order Rate Constants (kH × 104/M–1 s–1) of the Reactions of 8 and 10 with XC6H4NH2 in MeCN at 55.0 ℃

Table 2.aCorrelation coefficients (r) of the ρX(H) and βX(H) values are better than 0.986.

Table 3.aCorrelation coefficients (r) of ρY(H) values are better than 0.983.

Table 4 summarizes the second-order rate constants (kH) with unsubstituted aniline, natural bond order (NBO) charges at the reaction center P atom in the gas phase [B3LYP/6-311+G(d,p) level of theory], summations of the Taft steric constants of R1 and R2 [],2,3 Brönsted coefficients (βX(H)), cross-interaction constants (CICs; ρXY(H)),4 DKIEs (kH/kD) and variation trends of the kH/kD values with X in the nucleophiles and with Y in the substrates for the reactions of 1-12 with XC6H4NH2(D2) in MeCN at 55.0 ℃. The variation trends of the kH/kD values with X and Y are represented by an vertical and horizontal arrows, respectively. The vertical (↑ or ↓) and horizontal arrows (→ or ←) indicate the direction of the consistent increase in the kH/kD value with X and Y, respectively. For example, ↑ indicates an increase of the kH/kD value with a more electron-donating X, and → indicates an increase of the kH/kD value with a more electron-withdrawing Y.

Table 4.aY = H.

The sequence of the anilinolysis rates of 1-11 is not consistent with expectations for the positive NBO charge at the reaction center P atom, indicating that the inductive effects of the two ligands are not major factor to decide the anilinolysis rates of the chlorothiophosphates. According to Taft Eq. of ‘log kH = δΣES + C’, Figure 1 shows the Taft plot of log kH (with C6H5NH2) against the summation of the Taft steric constants of the two ligands for the anilinolyses of 1- 11 in MeCN at 55.0 ℃, giving the sensitivity coefficients of δ = 0.65 ± 0.09 (r = 0.948) and δ = 0.25 ± 0.27 (r = 0.803) with seven substrates of 1-7 (a group containing two alkoxy ligands) and four substrates of 8-11 [b group containing phenoxy ligand(s)], respectively.5 It is worthy of note that: (i) the sequence of the anilinolysis rates is inversely proportional (roughly) to the size of the two ligands; (ii) but divided into two groups; a group of 1-7 and b group of 8-11; and (iii) the correlation coefficient with b group is not good. The steric effects of the two ligands on the anilinolysis rates of the P=O counterparts, chlorophosphates [(R1O)(R2O)-P(=O)Cl-type], show the same trends as those of the chlorothiophosphates. 1a,e,6 These indicate that the steric effects of the two ligands on the anilinolysis rates of chloro(thio)phosphates play an important role and that a group is ‘very different’ from b group regarding the steric effects of the two ligands on the rate.7

Figure 1.Taft plot of log kH vs ΣES for the reactions of 1-11 with C6H5NH2 in MeCN at 55.0 ℃. The number of the substrate and two ligands of R1O and R2O are displayed next to the corresponding point.

Figure 2 shows the ρXY(H) values for the reactions of 8 and 10 with X-anilines in MeCN at 55.0 ℃, based on the definition of the CIC: log (kXY/kHH) = ρXσX + ρYσY + ρXYσXσY, hence, ρXY = ∂2log (kXY/kHH)/(∂σX∂σY) = ∂ρX/∂σY = ∂ρY/ ∂σX.4 The signs of the ρXY(H) are negative (ρXY(H) = –0.23) and positive (ρXY(H) = +0.68) for 8 and 10, respectively (vide supra). Thus, a concerted mechanism is proposed for 8 while a stepwise mechanism with a rate-limiting leaving group departure from the intermediate for 10, because the ρXY has a negative value in a concerted SN2 (or a stepwise mechanism with a rate-limiting bond formation) and a positive value for a stepwise mechanism with a rate-limiting leaving group expulsion from the intermediate.4 The degree of tightness of the TS structure with 10 is greater than that with 8 because the magnitude of ρXY is inversely proportional to the distance between X and Y through the reaction center.4,8

Figure 2.Plots of ρX(H)  vs σY and ρY(H) vs σX of the reactions of 8 and 10 with XC6H4NH2 in MeCN at 55.0 °C. The obtained ρXY(H) values by multiple regression are: (a) ρXY(H) = –0.23 ± 0.10 (r = 0.976) with 8; (b) ρXY(H) = +0.68 ± 0.11 (r = 0.980) with 10.

Tables 5 and 6 list the second-order rate constants (kD/M–1 s–1) with the deuterated anilines (XC6H4ND2) and DKIEs (kH/kD) with 8 and 10 in MeCN at 55.0 ℃, respectively. The DKIEs show primary normal (kH/kD > 1) and secondary inverse (kH/kD <1) depending on the substituents X and/or Y for both 8 (kH/kD = 0.89-1.28) and 10 (kH/kD = 0.62-1.20). The variation trends of the kH/kD values with Y are the same for both 8 and 10, and the kH/kD values become larger with a more electron-withdrawing Y, noted as horizontal arrow of → in Table 4. In contrast, the variation trends of the kH/kD values with X for 8 are opposite to those for 10: the kH/kD values become larger with a more electron-withdrawing X for 8 (↓), whereas those become larger with a more electrondonating X for 10 (↑), noted as vertical arrows in Table 4. At a glance, the variation trends of the kH/kD values with X and/ or Y could be one of the strong tools to clarify the reaction mechanism: (i) 8, 9, 11 and 12, via a SN2 mechanism, show the variation trends of ↓→; (ii) while 10, via a stepwise mechanism with a rate-limiting bond cleavage, shows ↑←. However, the variation trends of the kH/kD values with X and/ or Y cannot be the supporting evidence to substantiate the mechanism based on: (i) the anilinolysis of Y-aryl phenyl chlrophosphates, via a SN2 mechanism (ρXY(H) = –1.31), showing ↑←;6a (ii) Y-aryl ethyl chlorophosphates, via a SN2 mechanism (ρXY(H) = –0.60), showing ↓→;1e (iii) Y-aryl 4- chlorophenyl chlrophosphates, via a SN2 mechanism (ρXY(H) = –0.31), showing ↑←;6b (iv) O-aryl methyl phosphonochloridothioates, via a SN2 and stepwise mechanism with a rate-limiting bond cleavage (ρXY(H) = –0.95 and 0.77 with strongly and weakly basic anilines, respectively), showing ↑→;9a (v) Y-aryl phenyl isothiocyanophsphates, via a stepwise mechanism with a rate-limiting bond cleavage and SN2 (ρXY(H) = 1.41 and –0.18 with the strongly and weakly basic anilines, respectively), showing ↑→;9b (vi) Y-aryl ethyl isothiocyanophsphates, via a SN2 and stepwise mechanism with a rate-limiting bond cleavage (ρXY(H) = –0.14 and 3.89 with the strongly and weakly basic anilines, respectively), showing ↑→.9c The βX(H) values of 1-12 are relatively large in the range of 0.8-1.5, and this indicates that it could be sometimes dangerous to suggest the reaction mechanism based on the βX(H) values.

Table 5.Second-Order Rate Constants (kD × 104/M−1s−1) of the Reactions of 8 and 10 with XC6H4ND2 in MeCN at 55.0 ℃

Table 6.aStandard error {= 1/kD[(ΔkH)2 + (kH/kD)2 × (ΔkD)2]1/2}.

When partial deprotonation of the aniline occurs in a ratelimiting step by hydrogen bonding (e.g. TSf in Scheme 2), the kH/kD values are greater than unity, primary normal (kH/kD > 1.0).10 In contrast, the DKIEs can only be secondary inverse (kH/kD <1.0) when an increase in the steric congestion occurs in the bond-making process (e.g. TSb in Scheme 2), because the N–H(D) vibrational frequencies invariably increase upon going to the TS.11 In this respect, primary normal and secondary inverse DKIEs are rationalized by a frontside equatorial attack involving hydrogen bonded four-center-type TSf and backside apical attack involving in-line-type TSb, respectively. In the case of 10, the min value of kH/kD = 0.62 with X = 3-Cl and Y = 4-MeO indicates severe steric congestion in the TS. Table R1 lists six substrates, showing (kH/kD)min < 0.62, studied in this lab.12 As seen in Table R1, there are no consistent relationships between: (kH/kD)min and (i) X; (ii) Y; (iii) anilinolysis mechanism as mentioned earlier.

Scheme 2.Backside attack involving in-line-type TSb and frontside attack involving a hydrogen bonded, four-center-type TSf.

Tables 7 and 8 list the activation parameters, enthalpies and entropies of activation, for the anilinolyses of 8 and 10, respectively.13 The enthalpies of activation are relatively low (5-11 kcal mol–1) and the entropies of activation are relatively large negative values (–39 to –59 cal mol–1 K–1) for the anilinolyses of 1-11 as seen in Table R2.14 The relatively low activation enthalpy and large negative activation entropy are typical for the aminolyses of the P=S (and P=S) systems.

Table 7.aCalculated by Eyring equation.

Table 8.aCalculated by Eyring equation.

 

Experimental Section

Materials. Substrates of 8 and 10 were prepared as reported earlier.15

Kinetic Procedure. The second-order rate constants and selectivity parameters were obtained as previously described.1 Initial concentrations were as follows; [substrate] = 5 × 10−3 M and [X-Aniline] = (0.10-0.30) M for both substrates.

Product Analysis. Phenyl methyl and 3-methoxyphenyl propyl chlorothiophosphate were reacted with excess aniline for more than 15 half-lives at 55.0 ℃ in MeCN. Acetonitrile was evaporated under reduced pressure. The product mixture was treated with ether by a work-up process with dilute HCl and dried over anhydrous MgSO4. The product was isolated through column chromatography (25-30% ethyl acetate/n-hexane) and then dried under reduced pressure. The analytical and spectroscopic data of the product gave the following results (supporting information):

(C6H5O)(CH3O)P(=S)NHC6H5. Brown gummy solid; 1H-NMR (400 MHz, MeCN-d3) δ 3.79-3.83 (d, 3H), 6.67 (d, br, 1H, J = 8.8 Hz), 6.79-6.90 (d, 1H), 7.02-7.09 (t, 1H), 7.15-7.25 (m, 4H) 7.26-7.45 (m, 4H); 13C-NMR (100 MHz, MeCN-d3) δ 54.26, 115.97, 118.17, 119.56, 121.89, 123.4, 126.2, 130.19, 130.9; 31P-NMR (162 MHz, MeCN-d3) δ 74.36 (P=S, 1P, d, J = 13.9 Hz); GC-MS (EI, m/z) 279 (M+).

(3-CH3O-C6H4O)(C3H7O)P(=S)NHC6H5. Brown liquid; 1H-NMR (400 MHz, CDCl3 and TMS) δ 1.19-1.26 (m, 3H), 1.74-1.76 (q, 2H), 3.71 (s, 3H), 4.04-4.24 (m, 2H), 5.56 (br. d, J = 3.8 Hz, 1H), 6.70-6.77 (m, 2H), 7.02 (t, 4H), 7.08 (d, 4H), 7.18 (t, 1H), 7.27-7.29 (m, 2H); 13C-NMR (100 MHz, CDCl3 and TMS) δ 10.2, 23.3, 55.3, 69.4, 107.3, 111.3, 113.5, 118.0, 122.5, 129.4, 129.8, 139.2, 151.4, 160.4; 31P-NMR (162 MHz, CDCl3 and TMS) δ 66.9 (1P, P=S); GC-MS (EI, m/z) 337 (M+).