Kinetics and Mechanism of the Anilinolysis of Aryl N,N-Dimethyl Phosphoroamidochloridates in Acetonitrile

Abstract

The nucleophilic substitution reactions of Y-aryl N,N-dimethyl phosphoroamidochloridates with substituted anilines and deuterated anilines are kinetically investigated in acetonitrile at $65.0^{\circ}C$. A stepwise mechanism with a rate-limiting leaving group departure from the intermediate is proposed based on the positive ${\rho}_{XY}$ value. The deuterium kinetic isotope effects involving deuterated anilines show secondary inverse with all the nucleophiles, rationalized by a dominant backside nucleophilic attack.

Introduction

The nucleophilic substitution reactions of tetracoordinate phosphorus involving a leaving group of chloride have been extensively studied, experimentally1,2 and theoretically,3 in this lab. Two main types of displacement processes are well known in neutral phosphoryl and thiophosphoryl group transfer reactions: a stepwise mechanism involving a trigonal bipyramidal pentacoordinate (TBP-5C) intermediate and a concerted displacement at phosphorus through a single pentacoordinate transition state (TS). Continuing the kinetic studies on the phosphoryl transfer reactions, the reactions of Y-aryl N,N-dimethyl phosphoroamidochloridates with substituted anilines (XC6H4NH2) and deuterated anilines (XC6H4ND2) have been kinetically investigated in acetonitrile (MeCN) at 65.0 ± 0.1 ℃ (Scheme 1). The kinetic results of the present work are discussed based on the selectivity parameters and deuterium kinetic isotope effects (DKIEs). The aim of this work is to gain further information on the substituent effects, DKIEs and mechanism of the phosphoryl transfer reactions.

Scheme 1.Studied reactions of Y-aryl N,N-dimethyl phosphoroamidochloridates with XC6H4NH2(D)2 in MeCN at 65.0℃.

 

Results and Discussion

Tables 1-4 summarize the second-order rate constants, kH with anilines, kD with deuterated anilines, Hammett (ρX(H) and ρX(D)) and Brönsted (βX(H) and βX(D)) coefficients for substituent X variation in the nucleophiles, and Hammett coefficients (ρY(H)) for substituent Y variation in the substrates, respectively. The Hammett (Fig. 1: log kH vs σX and Fig. S1: log kD vs σX) and Brönsted [Fig. 2: log kH vs pKa(X) and Fig. S2: log kD vs pKa(X)] plots with X and Hammett plots (Fig. 3: log kH vs σY and Fig. S3: log kD vs σY) with Y are shown in Figures 1-3 and Figures S1-S3 (see supporting information). All the free energy correlations with X and Y are linear without breaking point or region. The rate increases with a more electron-donating substituent X and a more electron-withdrawing substituent Y, which is compatible with a typical nucleophilic substitution reaction with positive charge development at the nucleophilic N atom (ρX < 0) and negative charge development at the reaction center P atom (ρY > 0) in the transition state (TS). The rates with anilines are faster than those with deuterated anilines. The magnitudes of the selectivity parameters of ρX(H), βX(H) and ρY(H) with anilines are somewhat larger than those (ρX(D), βX(D) and ρY(D)) with deuterated aniline, suggesting more sensitive to substituent effects of the anilines compared to those of deuterated anilines.

The cross-interaction constant (CIC) is one of the strong tools to clarify the mechanism based on the substituent effects of the nucleophiles, substrates, and/or leaving groups on the reaction rates.4 The sign and magnitude of the CIC have made it possible to correctly interpret the reaction mechanism and the degree of tightness of the TS, respectively. The sign of the CIC [ρXY, Eqs. (1)] is negative in a stepwise reaction with a rate-limiting bond formation (or in a normal SN2 reaction), and positive in a stepwise reaction with a rate-limiting leaving group expulsion from the intermediate. The magnitude of the CIC is inversely proportional to the distance (or interaction) between X and Y through the reaction center; the tighter the TS, the greater the magnitude of the CIC.

Table 1.Second-Order Rate Constants (kH × 104/M‒;1 s‒1) of the Reactions of Y-Aryl N,N-Dimethyl Phosphoroamidochloridates with XC6H4NH2 in MeCN at 65.0℃

Table 2.Second-Order Rate Constants (kD × 104/M‒1 s‒1) of the Reactions of Y-Aryl N,N-Dimethyl Phosphoroamidochloridates with XC6H4ND2 in MeCN at 65.0℃

Table 3.Hammett (ρX(H) and ρX(D)) and Brönsted (βX(H) and βX(D)) Coefficients with X for the Reactions of Y-Aryl N,N-Dimethyl Phosphoroamidochloridates with XC6H4NH2(D2) in MeCN at 65.0 ℃

Table 4.Hammett Coefficients (ρY(H) and ρY(D)) with Y for the Reactions of Y-Aryl N,N-Dimethyl Phosphoroamidochloridates with XC6H4NH2(D2) in MeCN at 65.0 ℃

Figure 4 shows the plots of ρX(H or D) vs σY and ρY(H or D) vs σX to determine the ρXY(H or D) values according to Eq. (1b). The ρXY(H) and ρXY(D) values are calculated with thirty five and twenty five second-order rate constants, respectively, giving acceptable correlation coefficients.5 The sign of both ρXY(H) and ρXY(D) is positive, and the magnitude of ρXY(H) (= 1.22) with anilines is nearly two times greater than that (ρXY(D) = 0.64) with deuterated anilines. Thus, the authors propose a stepwise mechanism with a rate-limiting leaving group departure from the intermediate based on the positive sign of ρXY(H) and ρXY(D). The greater magnitude of ρXY(H) with anilines compared to that of ρXY(D) with deuterated anilines indicates that the interaction between X and Y with anilines is greater than that with deuterated anilines in the TS. This suggests that the TS with anilines is more tight compared to that with deuterated anilins. The suggestion is in line with the greater magnitudes of ρX(H), βX(H) and ρY(H) with anilines than those (ρX(D), βX(D) and ρY(D)) with deuterated aniline.

In addition to the CICs, the DKIEs (kH/kD) are also one of the strong tools to clarify the reaction mechanism. When partial deprotonation of the aniline occurs in a rate-limiting step by hydrogen bonding (e.g. TSf in Scheme 2), the kH/kD values are greater than unity, primary normal (kH/kD > 1.0).6 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.7 In this respect, DKIEs have provided a useful means to determine the TS structures in the nucleophilic substitution reactions, and how the reactants, especially through changes in substituents, alter the TS structures. Incorporation of deuterium in the nucleophile has an advant-age in that the α-DKIEs reflect only the degree of bond formation, especially for the secondary inverse DKIEs. Thus, the greater the extent of bond formation, the greater the steric congestion, and the smaller the kH/kD value becomes.

Figure 1.Hammett plots (log kH vs σX) with X of the reactions of Y-aryl N,N-dimethyl phosphoroamidochloridates with XC6H4NH2 in MeCN at 65.0 ℃.

Figure 2.Brönsted plots [log kH vs pKa(X)] with X of the reactions of Y-aryl N,N-dimethyl phosphoroamidochloridates with XC6H4NH2 in MeCN at 65.0 ℃.

Figure 3.Hammett plots (log kH vs σY) with Y of the reactions of Y-aryl N,N-dimethyl phosphoroamidochloridates with XC6H4NH2 in MeCN at 65.0 ℃.

Figure 4.Plots of ρY(H or D) vs σX and ρX(H or D) vs σY of the reactions of Y-aryl N,N-dimethyl phosphoroamidochloridates with XC6H4NH2(D2) in MeCN at 65.0 ℃. The obtained values by multiple regression are (a) ρXY(H) = 1.22 ± 0.05 (r = 0.995) with anilines and (b) ρXY(D) = 0.64 ± 0.05 (r = 0.993) with deuterated anilines.

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

Table 5.aStandard error {= 1/kD[(ΔkH)2 + (kH/kD)2 × (ΔkD)2]1/2} from ref. 9.

Table 6.Activation Parameters for the Reactions of Y-Aryl N,N-Dimethyl Phosphoroamidochloridates with Aniline (C6H5NH2) in MeCN

In the present work, the DKIEs are secondary inverse with all the anilines as seen in Table 5. The secondary inverse DKIEs are substantiated by a backside nucleophilic attack involving in-line-type TSb (Scheme 2). The magnitudes of the kH/kD values invariably decrease with a more electronwithdrawing substituent X (4-Me → 3-Cl) and a more electron- donating substituent Y (4-Cl → 4-MeO). This means that the steric congestion in the TS invariably increases as the aniline becomes less basic and the substrate becomes less acidic. In other words, the lower reactivity of the nucleophile results in a greater degree of bond formation, and at the same time, the lower reactivity of the substrate results in a greater degree of bond formation. Accordingly, the minimum value of kH/kD = 0.42 with X = 3-Cl and Y = 4- MeO indicates very severe steric congestion in the TS,8 suggesting great extent of bond formation.

Activation parameters, enthalpies and entropies of activation, are determined as shown in Table 6. The enthalpies of activation are relatively low and entropies of activation are relatively large negative value. The relatively low value of activation enthalpy and large negative value of activation entropy are typical for the aminolyses of P=O systems.10

 

Experimental Section

Materials. HPLC grade acetonitrile (water content 0.005%) were used without further purification. Anilines were redistilled or recrystallized before use. Deuterated anilines were synthesized as reported earlier.1 Y-Aryl N,N-dimethyl phosphoroamidochloridates were prepared by reacting N,NDimethyl phosphorodichloridate (1 mol) with substituted phenol (1 mol) for 3 h in the presence of triethylamine in methylene chloride on cooling bath at ‒10.0℃ with constant stirring. Triethylamine hydrochloride was separated by filtration. The filtrate was treated with water-NaHCO3 and ether for work up after removal of solvent under reduced pressure. Ether extracted organic part was dried over anhydrous MgSO4 for 2-3 h. The product mixture was isolated by filtration and finally separated through column chromatography (silica gel, ethyl acetate/n-hexanehexane) and dried under reduced pressure using oil diffusion pump and were identified by TLC, 1H-NMR, 13C-NMR, 31P-NMR and GC-MS. The analytical and spectroscopic data of the substrates gave the following results (see supporting information).

4-Methoxyphenyl N,N-Dimethyl phosphoroamidochloridate, [(4-CH3O-C6H4O)(NMe2)P(=O)Cl]: Colorless liquid; 1H-NMR (400 MHz, CDCl3 and TMS) δ 2.81-2.85 (m, 6H), 3.79 (s, 3H), 6.85-6.88 (m, 2H), 7.16-7.17 (m, 2H); 13CNMR (100 MHz, CDCl3 and TMS) δ 36.78, 55.62, 114.7, 121.4, 143.4, 157.3; 31P-NMR (162 MHz, CDCl3 and TMS) δ 19.32 (1P, PO); GC-MS (EI, m/z) 249 (M+).

4-Methylphenyl N,N-Dimethyl Phosphoroamidochloridate, [(4-CH3-C6H4O)(NMe2)P(=O)Cl]: Colorless liquid; 1H-NMR (400 MHz, CDCl3 and TMS) δ 2.33 (s, 3H), 2.81- 2.90 (m, 6H), 6.12-7.17 (m, 4H); 13C-NMR (100 MHz, CDCl3 and TMS) δ 20.77, 36.79, 115.1, 120.2, 130.3, 135.5, 159.7; 31P-NMR (162 MHz, CDCl3 and TMS) δ 18.92 (1P, PO); GC-MS (EI, m/z) 233 (M+).

Phenyl N,N-Dimethyl Phosphoroamidochloridate, [(C6H5O)(NMe2)P(=O)Cl]: Colorless liquid; 1H-NMR (400 MHz, CDCl3 and TMS) δ 2.83-2.89 (m, 6H), 7.23-7.28 (m, 3H), 7.35-7.39 (m, 2H); 13C-NMR (100 MHz, CDCl3 and TMS) δ 36.77, 120.4, 125.8, 129.9, 149.9; 31P-NMR (162 MHz, CDCl3 and TMS) δ 18.64 (1P, PO); GC-MS (EI, m/z) 219 (M+).

3-Methoxyphenyl N,N-Dimethyl Phosphoroamidochloridate, [(3-CH3O-C6H4O)(NMe2)P(=O)Cl]: Colorless liquid; 1H-NMR (400 MHz, CDCl3 and TMS) δ 2.82-2.86 (m, 6H), 3.80 (s, 3H), 6.79-6.81 (m, 2H), 6.84-6.86 (m, 1H), 7.23- 7.26 (m, 1H); 13C-NMR (100 MHz, CDCl3 and TMS) δ 36.77, 55.50, 106.5, 111.7, 112.5, 130.2, 150.8, 160.7; 31PNMR (162 MHz, CDCl3 and TMS) δ 18.48 (1P, PO); GCMS (EI, m/z) 249 (M+).

4-Chlorophenyl N,N-Dimethyl Phosphoroamidochloridate, [(4-Cl-C6H4O)(NMe2)P(=O)Cl]: Colorless liquid; 1H-NMR (400 MHz, CDCl3 and TMS) δ 2.81-2.89 (m, 6H), 7.21-7.25 (m, 2H), 7.32-7.34 (m, 2H); 13C-NMR (100 MHz, CDCl3 and TMS) δ 36.76, 121.8, 129.9, 131.3, 148.4; 31PNMR (162 MHz, CDCl3 and TMS) δ 18.70 (1P, PO); GCMS (EI, m/z) 354 (M+).

Kinetics Measurement. Rates and selectivity parameters were obtained as previously described.1 Initial concentrations: [Substrate] = 5 × 10−3 M and [X-Aniline] = (0.10-0.30) M.

Product Analysis. Phenyl N,N-dimethyl phosphoroamidochloridate was reacted with excess aniline for more than 15 half-lives at 65.0℃ in MeCN. Solvent 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. Then the product was isolated through column chromatography (30% ethyl acetate/n-hexane) and then dried under reduced pressure. The analytical and spectroscopic data of the product gave the following results (see supporting information).

[(C6H5O)(NMe2)P(=O)NHC6H5]. White solid crystal; mp 117-118.0 ℃ 1H-NMR (400 MHz, CDCl3 and TMS) δ 2.76-2.79 (m, 6H), 5.26 (s, br., 1H), 6.98-7.33 (m, 10H); 13CNMR (100 MHz, CDCl3 and TMS) δ 36.54, 117.5, 120.3, 121.8, 124.7, 129.3, 129.7, 139.5, 150.5; 31P-NMR (162 MHz, CDCl3 and TMS) δ 11.56 (1P, P=O); GC-MS (EI, m/z) 276 (M+).