Kinetics and Mechanism of the Aminolyses of Bis(2-oxo-3-oxazolidinyl) Phosphinic Chloride in Acetonitrile

Abstract

The aminolyses, anilinolysis and pyridinolysis, of bis(2-oxo-3-oxazolidinyl) phosphinic chloride (1) have been kinetically investigated in acetonitrile at 55.0 and $35.0^{\circ}C$, respectively. For the reactions of 1 with substituted anilines and deuterated anilines, a concerted SN2 mechanism is proposed based on the selectivity parameters and activation parameters. The deuterium kinetic isotope effects ($k_H/k_D$) invariably increase from secondary inverse to primary normal as the aniline becomes more basic, rationalized by the transition state variation from a backside to a frontside attack. For the pyridinolysis of 1, the authors propose a stepwise mechanism with a rate-limiting step change from bond breaking for more basic pyridines to bond formation for less basic pyridines based on the selectivity parameters and activation parameters. Biphasic concave upward free energy relationship with X is ascribed to a change in the attacking direction of the nucleophile from a frontside attack with more basic pyridines to a backside attack with less basic pyridines.

Introduction

Continuing the kinetic studies on the aminolyses of (Lig1)(Lig2)P(=O or =S)Cl-type substrates, the reactions of bis(2-oxo-3-oxazolidinyl) phosphinic chloride (1) with anilines [XC6H4NH2(D2)] and pyridines (XC5H4N) are examined in acetonitrile (MeCN) at 55.0 ± 0.1 and 35.0 ± 0.1 ℃ (Schemes 1 and 2), respectively. The purpose of this work is to gain further information on the phosphoryl transfer reactions regarding the selectivity parameters, deuterium kinetic isotope effects (DKIEs), activation parameter and steric effects of the two ligands.

Scheme 1.Anilinolysis of bis(2-oxo-3-oxazolidinyl) phosphinic chloride (1) in MeCN at 55.0 ℃.

Scheme 2.Pyridinolysis of bis(2-oxo-3-oxazolidinyl) phosphinic chloride (1) in MeCN at 35.0 ℃.

 

Results and Discussion

The second-order rate constants (kH and kD) of the anilinolysis in MeCN at 55.0 ℃ are summarized in Table 1, together with the Hammett ρX (Fig. S1) and Brönsted βX (Fig. 1) selectivity parameters and DKIEs (kH/kD). The stronger nucleophile leads to the faster rate as observed in a typical nucleophilic substitution reaction with positive charge development at the nucleophilic N atom in the transition state (TS). The magnitudes of the ρX(H) (= –3.23) and βX(H) (= 1.14) values with anilines are somewhat larger than those (ρX(D) = –2.61 and βX(D) = 0.92) with deuterated aniline, suggesting more sensitive to substituent effects of the anilines compared to those of deuterated anilines. The magnitudes of kH/kD values invariably decrease from the primary normal DKIEs (kH/kD = 1.57-1.16 ＞ 1) with X = (4- MeO, 4-Me) to the secondary inverse DKIEs (kH/kD = 0.97- 0.61 < 1) with X = (3-Me, H, 4-F, 3-MeO, 4-Cl, 3-Cl) as the aniline becomes less basic. Table 2 summarizes the secondorder rate constants (kPyr) of the pyridinolysis in MeCN at 35.0 ℃. The substituent effects of the nucleophiles upon the pyridinolysis rates also correlate with those for a typical nucleophilic substitution reaction. Both the Hammett (Fig. S2) and Brönsted (Fig. 2) plots, however, are biphasic concave upwards with a break point at X = H. The magnitudes of the ρX (= –9.05 ± 0.01; r = 0.999) and βX (= 1.98 ± 0.04; r = 0.999) values with more basic pyridines (X = 4-MeO, 4- Me, 3-Me, H) are much greater than those [ρX = –1.33 ± 0.04 (r = 0.999) and βX = 0.22 ± 0.06 (r = 0.985)] with less basic pyridines (X = H, 3-Ph, 3-MeO, 3-Cl, 3-Ac, 4-Ac, 3-CN, 4-CN).

Table 1.Second-Order Rate Constants (kH(D) × 104/M-1 s-1), Selectivity Parameters (ρX and βX) and DKIEs (kH/kD) of the Reactions of Bis(2-oxo-3-oxazolidinyl) Phosphinic Chloride (1) with XC6H4NH2(D2) in MeCN at 55.0 ℃

Table 2.Second-Order Rate Constants (kPyr × 104/M−1 s−1) of the Reactions of Bis(2-oxo-3-oxazolidinyl) Phosphinic chloride (1) with XC5H4N in MeCN at 35.0 ℃

Figure 1.Brönsted plot of the reactions of bis(2-oxo-3-oxazolidinyl) phosphinic chloride (1) with XC6H4NH2(D2) in MeCN at 55.0 ℃.

Figure 2.Brönsted plot of the reactions of bis(2-oxo-3-oxazolidinyl) phosphinic chloride (1) with X-pyridines in MeCN at 35.0 ℃.

Table 3 summarizes the second-order rate constants (kH) with unsubstituted aniline (C6H5NH2), Brönsted coefficients (βX(H)), cross-interaction constant (CIC, ρXY(H)),1 enthalpies (ΔH‡/kcal mol-1) and entropies (ΔS‡/cal mol-1K-1) of activation with unsubstituted aniline, and DKIEs (kH/kD) of the reactions of 1 and 2 (Y-aryl phenyl chlorophosphate)2 with XheC6H4NH2(D2) in MeCN at 55.0 ℃. T authors reported that the steric effects (over the inductive effects) of the two ligands are the major factor to determine the anilinolysis rates: the larger the two ligands, the steric effects become greater in the TS, and the rate becomes slower.3 The size of 2-oxo-3-oxazolidinyl in 1 is smaller than that of PhO in 2. The anilinolysis rate (C6H5NH2) of 1 is more or less slower than that of 2 with Y = H [(PhO)2P(=O)Cl]; the ratio of kH(2 with Y = H)/kD(1) = 1.26. At a glance, the kinetic results are not in line with expectation for the steric effects of the two ligands. Taking into account the structure difference between 1 and 2, the presence of the oxygen atom between phenyl ring and reaction center phosphorus in 2 would render more available space to aniline nucleophile compared to 1 where the five-membered ring is directly bonded to reaction center P. Thus, the rate of 2 is somewhat faster than that of 1 in in spite of the larger size of the phenoxy ligand compared to that of the 2-oxo-3-oxazolidinyl ligand. In other words, the steric congestion due to the two 2-oxo-3-oxazolidinyl ligands in 1 is somewhat greater than that due to the two phenoxy ligands in 2 in the TS. The value of βX(H) (= 1.14) of 1 is slightly smaller than that of 2 (βX(H) = 1.36 with Y = H).2 The activation parameters, determined for the anilinolysis (with C6H5NH2) of 1 and 2, are quite similar. The enthalpies of activation are relatively low (ΔH‡ = 9.7 kcal mol–1 with both 1 and 2) and entropies of activation are relatively large negative values (ΔS‡ = –44 and –43 cal mol–1 K–1 with 1 and 2, respectively). In general, the relatively low activation enthalpy and large negative activation entropy are typical for the aminolyses of phosphoryl transfer reactions.

Table 3.aValue with unsubstituted aniline (X = H). bValue with Y = H. cSee Table S1 in Supporting Information.

The DKIEs can be only secondary inverse (kH/kD < 1) in a normal SN2 reaction, because the N−H(D) vibrational frequencies invariably increase upon going to the TS (e.g., inline- type TSb in Scheme 3; backside attack), given the increase in steric hindrance in the bond formation step.4 In inline- type TSb in Scheme 3; backside attack), given the increase in steric hindrance in the bond formation step.4 In contrast, when partial deprotonation of the aniline occurs in a rate-limiting step by hydrogen bonding (e.g., hydrogenbonded, four-center-type TSf in Scheme 2; frontside attack), the DKIEs are primary normal (kH/kD ＞1).5 The variation trends of kH/kD values with X of 1 and 2 are the same; the stronger the aniline, the kH/kD values becomes larger. A backside attack TSb was proposed for the anilinolysis of 2 based on the secondary inverse DKIEs, kH/kD = 0.61—0.87.2 In the present work, the authors propose that the attacking direction of aniline toward the reaction center P atom changes from predominant frontside attack involving hydrogen bonded, four-center-type TSf with stronger anilines (X = 4- MeO, 4-Me) based on the primary normal DKIEs (kH/kD = 1.16-1.57) to dominant backside attack involving in-linetype TSb with weaker anilines (X = 3-Me- H, 4-F, 3-MeO, 4-Cl, 3-Cl) based on the secondary inverse DKIEs (kH/kD = 0.61-0.97). These can be rationalized by the gradual TS variation from a frontside to a backside attack as the aniline becomes less basic. The considerably small value of kH/kD = 0.61 with X = 3-Cl suggests severe steric hindrance, whereas the relatively large value of kH/kD = 1.57 with X = 4-MeO suggests the extensive hydrogen bonding in the TS.

A concerted mechanism was proposed based on the negative ρXY (= –1.31) value for the anilinolysis of 2.2 In the present work of 1, a concerted mechanism is proposed based on: (i) the Brönsted coefficient of βX(H)(1) = 1.14 is comparable with βX(H)(2) = 1.24-1.68; (ii) the activation parameters of 1 (ΔH‡ = 9.7 kcal mol-1 and ΔS‡ = –44 cal mol–1 K–1) are quite similar to those of 2 (ΔH‡ = 9.7 kcal mol–1 and ΔS‡ = –43 cal mol–1 K–1); and (iii) the same variation trends of the DKIEs with X of 1 and 2, where the magnitude of kH/kD increases with a stronger aniline.

Table 4.aValue with unsubstituted pyridine (X = H) at 35.0 oC. bValue with Y = H. cValue of kPyr = 2660 × 10−4 M−1 s−1 at 35.0 oC is an extrapolated value in the Arrhenius plot with kinetic data: kPyr = 371, 940, and 1350 × 10–4 M–1 s–1 at 5.0, 15.0 and 25.0 oC, respectively. dMore/less basic pyridines at 35.0 oC. eValue at 25.0 oC. fa-block(stronger nucleophiles and weaker electrophiles)/b-block(weaker nucleophiles and weaker electrophiles)/c-block(stronger nucleophiles and stronger electrophiles)/d-block(weaker nucleophiles and stronger electrophiles). gSee Table S2 in Supporting Information.

The second-order rate constants (kPyr) with unsubstituted pyridine at 35.0 ℃, Br önsted coefficients (βX), CICs (ρXY),enthalpies (ΔH‡/kcal mol–1) and entropies (ΔS‡/cal mol–1 K–1) of activation with C5H5N for the pyridinolyses of 1, 26 and 2S (Y-aryl phenyl chlorothiophosphate)7 in MeCN are summarized in Table 4. The pyridinolysis rate of 2 is much faster than that of 1; kPyr(2)/kPyr(1) = 707 at 35.0 ℃.8 This strongly suggests that the pyridinolysis mechanism of 2 is different from that of 1. A concerted mechanism with very early TS was proposed for the pyridinolysis of 2, in which the extent of both bond formation and leaving group departure is small, based on the small βX (= 0.16-0.18) and small negative CIC (ρXY = –0.15).16 The pyridinolysis rate of 2S is relatively slow due to the so-called “thio effect”,which is mainly the electronegativity difference between O and S and favors P=O over P=S.9 In the pyridinolysis of 2S,four different values of ρXY are available because both Hammett plots for substituent X and Y variations are biphasic with a break point. A stepwise mechanism with a ratelimiting leaving group departure from the intermediate was proposed for a-block (stronger nucleophiles and weaker electrophiles) and b-block (weaker nucleophiles and weaker electrophiles) based on the positive sign of ρXY, while a stepwise process with a rate-limiting bond formation was proposed for c-block (stronger nucleophiles and stronger electrophiles) and d-block (weaker nucleophiles and stronger electrophiles) based on the negative sign of ρXY.710 The nonlinear free energy correlations of biphasic concave upward plots with X were rationalized by a change in the attacking direction of the nucleophile from a backside (TSb in Scheme 4) with less basic pyridines to a frontside attack (TSf in Scheme 4) with more basic pyridines.7

Scheme 3.Backside attack involving in-line-type TSb and frontside attack involving hydrogen-bonded, four-center-type TSf (L = H or D). Lig1 and Lig2 represent the two ligands.

Scheme 4.Backside attack TSb and frontside attack TSf (A = O or S).

In the present work of the pyridinolysis of 1, the authors propose a stepwise mechanism with a rate-limiting step change from bond breaking with more basic pyridines to bond formation with less basic pyridines based on: (i) the considerably large βX = 1.98 with the stronger nucleophiles and small βX = 0.22 with the weaker nucleophiles, as observed in 2S where βX(2S) = 1.36-1.50 and 0.23-0.48 with the stronger and weaker nucleophiles, respectively; (ii) the relatively small enthalpy of activation and large negative entropy of activation (ΔH‡ = 3.5 kcal mol–1 and ΔS‡ = –63 cal mol–1 K–1), as observed in 2S (ΔH‡ = 6.4 kcal mol–1 and ΔS‡ =–53 cal mol–1 K–1); and (iii) biphasic concave upward free energy relationship with X, as observed in 2S. Biphasic concave upward free energy relationship for substituent X variations in the nucleophiles are ascribed to a change in the attacking direction of the nucleophile from a frontside (TSf) with more basic pyridines to a backside (TSb) with less basic pyridines.

The attacking direction of the nucleophile changes from a frontside to a backside as the nucleophile becomes less basic for both the anilinolysis and pyridinolysis. However, there is the difference between the anilinolysis and pyridinolysis regarding the mechanism: (i) in the anilinolysis, a concerted mechanism regardless of the attacking direction; (ii) in the pyridinolysis, a stepwise process with a rate-limiting bond breaking involving a frontside attack whereas with a ratelimiting bond formation involving a backside nucleophilic attack.11

 

Experimental Section

Materials. Bis(2-oxo-3-oxazolidinyl) phosphinic chloride and 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.23 Pyridines were used without further purification.

Kinetic Procedure. Rates and selectivity parameters were obtained as previously described for the anilinolysis23 and pyridinolysis.67 Initial concentrations for both the anilinolysis and pyridinolysis were as follows; [substrate] = 5 × 10−3 M and [nucleophile] = (0.10-0.30) M.

Product Analysis. In the case of the anilinolysis, bis(2- oxo-3-oxazolidinyl) phosphinic chloride was reacted with excess aniline for more than 15 half-lives at 55.0 ℃ in MeCN. The aniline hydrochloride salt was separated by filtration. Solvent was removed under reduced pressure. The product was isolated through treatment with ether and dilute HCl by a work up process and then dried over MgSO4. After filtration the product was isolated by evaporating the solvent under reduced pressure. In the case of the pyridinolysis, bis(2-oxo-3-oxazolidinyl) phosphinic chloride was reacted with excess pyridine, for more than 15 half-lives at 35.0 ℃ in MeCN. Solvent was removed under reduced pressure. The product was isolated by adding ether and insoluble fraction was collected. The product was purified to remove excess pyridine by washing several times with ether and MeCN. The analytical and spectroscopic data of the products gave the following results (see Supporting Information):

[C6H8N2O4P(=O)NHC6H5]: White solid crystal; mp 204- 205 ℃; 1H-NMR (400 MHz, MeCN-d3) δ 3.92-3.97 (m, 4H), 4.32-4.40 (m, 4H), 6.88-6.90 (m, 1H), 7.05-7.32 (m, 5H); 13C-NMR (100 MHz, MeCN-d3) δ 45.43, 65.04, 118.39, 120.08, 123.87, 130.51, 174.11; 31P-NMR (162 MHz, MeCN-d3) δ 3.57 (1P, s, P=O); GC-MS (EI, m/z) 311 (M+).

[(C6H8N2O4)P(=O)NC5H5]+Cl–: White solid crystal; mp 131-132.0 ℃; 1H-NMR (400 MHz, D2O) δ 3.98-4.02 (m, 4H), 4.41-4.50 (m, 4H), 8.12-8.83 (m, 5H); 13C-NMR (100 MHz, D2O) δ 45.7, 64.8, 126.2, 127.6, 156.9, 160.0, 173.4, 180.0; 31P-NMR (162 MHz, D2O) δ 3.77 (1P, s, P=O) ; LCMS for C11H13N3O5PCl (EI, m/z), 333 (M+).