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Dual Substituent Effects on Anilinolysis of Bis(aryl) Chlorothiophosphates
Dual Substituent Effects on Anilinolysis of Bis(aryl) Chlorothiophosphates
Bulletin of the Korean Chemical Society. 2013. Dec, 34(12): 3597-3601
Copyright © 2013, Korea Chemical Society
  • Received : August 29, 2013
  • Accepted : September 09, 2013
  • Published : December 20, 2013
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Hasi Rani Barai
Hai Whang Lee

Abstract
The reactions of bis(Y-aryl) chlorothiophosphates ( 1 ) with substituted anilines and deuterated anilines are investigated kinetically in acetonitrile at 55.0 o C. The Hammett plots for substituent Y variations in the substrates show biphasic concave upwards with a break point at Y = H. The cross-interaction constants ( ρ XY ) are positive for both electron-donating and electron-withdrawing Y substituents. The kinetic results of 1 are compared with those of Y-aryl phenyl chlorothiophosphates ( 2 ). The cross-interaction between Y and Y, due to additional substituent Y, is significant enough to result in the change of the sign of ρ XY from negative with 2 to positive with 1 . The effect of the cross-interaction between Y and Y on the rate changes from negative role with electron-donating Y substituents to positive role with electron-withdrawing Y substituents, resulting in biphasic concave upward free energy correlation with Y. A stepwise mechanism with a rate-limiting leaving group departure from the intermediate involving a predominant frontside attack hydrogen bonded, four-centertype transition state is proposed based on the positive sign of ρ XY and primary normal deuterium kinetic isotope effects.
Keywords
Introduction
A concerted mechanism involving a frontside nucleophilic attack was proposed for the anilinolysis of Y-aryl phenyl chlorothiophosphates [ 2 ; (YC 6 H 4 O)(PhO)P(=S)Cl] in acetonitrile (MeCN) 1 based on the negative cross-interaction constant (CIC; ρ XY = –0.22) 2 and primary normal deuterium kinetic isotope effects (DKIEs; k H / k D = 1.11-1.33). The kinetic studies on the reactions of bis(Y-aryl) chlorothiophosphates [ 1 ; (YC 6 H 4 O) 2 P(=S)Cl] with substituted anilines and deuterated anilines are investigated kinetically in MeCN at 55.0 ± 0.1 ℃ ( Scheme 1 ). The aim of this work is to study the dual substituent effects on the reaction mechanism where the substrate has the same substituent Y in each phenyl ring.
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Reactions of bis(Y-aryl) chlorothiophosphates (1) with XC6H4NH2(D2) in MeCN.
Results and Discussion
Table 1 lists the second-order rate constants of k H and k D with XC 6 H 4 NH 2 and XC 6 H 4 ND 2 , respectively. The substituent effects on the rates are compatible with a typical nucleophilic substitution reaction. The stronger nucleophile leads to the faster rate with positive charge development at the nucleophilic nitrogen atom and a more electron-withdrawing substituent Y in the substrate leads to the faster rate with negative charge development at the reaction center phosphorus atom in the transition state (TS). However, the Hammett (log k H vs σ Y ) plots for substituent Y variations in the substrates show biphasic concave upwards with a break point at Y = H ( Fig. 1 ). The rate with aniline is always faster than its corresponding deuterated aniline, resulting in primary normal DKIEs ( k H / k D > 1). The Hammett ( ρ X(H and D) ) and Brönsted ( β X(H and D) ) coefficients for substituent X variations in the nucleophiles are summarized in Table 2 , and the Hammett coefficients ( ρ Y(H and D) ) with Y are summarized in Table 3 . The ρ Y(H and D) values are calculated from the plots of log k (H and D) against σ Y although all the studied substrates contain the two Y-substituted phenyl rings. The Hammett (log k H vs σ X ), Hammett (log k D vs σ X ), Brönsted [log k H vs pK a (X)] and Brönsted [log k D vs p K a (X)] plots with X, and Hammett (log k D vs σ Y ) plots with Y are shown in Figures S1-S5, respectively (supporting information). The magnitudes of ρ X , ρ Y and β X with anilines are larger than those with deuterated anilines. The magnitudes of ρ X(H) (= –3.70 to –3.94) and β X(H) (= 1.30-1.39) values of 1 are comparable with those of 2 ( ρ X(H) = –3.81 to –4.01 and β X(H) = 1.34-1.41). The magnitudes of ρ Y(H and D) values with electron-withdrawing Y (= H, 3-MeO, 4-Cl) are much greater than those with electron-donating Y (= 4-MeO, 4-Me, H). From now on, for convenience, electron-donating Y (= 4-MeO, 4-Me, H) and electron-withdrawing Y (= H, 3-MeO, 4-Cl) substituents are described as e-d and e-w block, respectively.
Second-Order Rate Constants (kH(D)× 105/M–1s–1) of the Reactions of Bis(Y-aryl) Chlorothiophosphates (1) with XC6H4NH2(D2) in MeCN at 55.0 ℃
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Second-Order Rate Constants (kH(D) × 105/M–1 s–1) of the Reactions of Bis(Y-aryl) Chlorothiophosphates (1) with XC6H4NH2(D2) in MeCN at 55.0 ℃
Hammett (ρX(H and D)) and Brönsted (βX(H and D)) Coefficients with X for the Reactions of Bis(Y-aryl) Chlorothiophosphates (1) with XC6H4NH2(D2) in MeCN at 55.0 ℃a
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aCorrelation coefficients (r) of ρX and βX values are better than 0.997
Hammett Coefficients (ρY(H and D)) with Y for the Reactions of Bis(Y-aryl) Chlorothiophosphates (1) with XC6H4NH2(D2) in MeCN at 55.0 ℃
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aY = (4-MeO, 4-Me, H; e-d block). bY = (H, 3-MeO, 4-Cl; e-w block). a,bCorrelation coefficients (r) of ρY values are better than 0.982.
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Hammett plots with Y of the reactions of bis(Y-aryl) chlorothiophosphates (1) with XC6H4NH2 in MeCN at 55.0 ℃.
When both the nucleophile and substrate have only one substituent X and Y, respectively, a Taylor series expansion of log k XY around σ X = σ Y = 0 leads to Eq. (1). 3 Herein, pure second- ( e.g. , ρXXσX 2 or ρYYσY 2 ), third- ( e.g. , ρXXYσX 2 σY or ρXYYσXσY 2 ), and higher-derivative terms ( e.g. , ρXXXYσX 3 σY or ρXXYYσX 2 σY 2 , etc ) are neglected because they are normally too small to be taken into account. Figure 2 shows the positive values of ρ XY(H) = 0.22 and 0.81 with e-d and e-w block, respectively. Figure S6 also shows the positive values of ρ XY(D) = 0.28 and 0.59 with e-d and e-w block, respectively (supporting information). Both anilines and deuterated anilines, the magnitude of ρ XY value with e-w block is larger than that with e-d block. 4 This suggests that the distance between X and Y with e-w block is closer than that with e-d block in the TS ( vide infra ). 5
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In the present work, the modified Eq. (3) is introduced in which the cross-interaction between Y (in one phenyl ring) and Y (in the other phenyl ring) is included because all the studied substrates have identical substituent Y in each phenyl ring. The third and fourth terms on the right-side of Eq. (3) indicate the cross-interaction between X and two Y, and Y (in one phenyl ring) and Y (in the other phenyl ring), respectively. The value of ρ YY(H) reflects the cross-interaction between the two substituents, Y and Y, in the TS. In Eq. (3), pure second-, third-, and higher-derivative terms are not considered as in Eq. (1). The values of ρ X(H) , ρ Y(H) , ρ XY(H) and ρ YY(H) obtained by multiple regression are described in Eqs. (4) and (5) with e-d and e-w block, respectively. As a matter of course, the values of ρ XY(H) = 0.22 [Eq. (4)] and 0.81 [Eq. (5)] with e-d and e-w block, respectively, have the same values calculated from Eq. (2) because ρ XY is defined as ∂ρX/∂σY = ∂ρY/∂σX .
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Plots of ρY(H) vs σX and ρX(H) vs σY of the reactions of bis(Y-aryl) chlorothiophosphates with XC6H4NH2 in MeCN at 55.0 ℃ to determine ρXY(H) according to Eq. (2). The values of ρXY(H) = 0.22 ± 0.10 (r = 0.992) and 0.81 ± 0.12 (r = 0.988) with (a) e-d and (b) e-w block, respectively, are obtained by multiple regression.
Note the sign and magnitudes of ρ YY(H) values of –1.11 (negative and five times greater than ρ XY(H) ) and +11.1 (positive and fourteen times greater than ρ XY(H) ) with e-d and e-w block, respectively. The ρ YY(D) values with deuterated anilines, –1.01 with e-d and 10.9 with e-w block, are quite similar to those with anilines. 6 These results suggest that: (i) the values of ρ YY(H) = –1.11 and 11.1 with e-d and e-w block, respectively, are attributed to the cross-interaction between Y and Y in each phenyl ring in the TS; (ii) the cross-interaction between the two substituents, Y and Y, is significant in the TS; (iii) the cross interaction between Y and Y with ew block is much greater than that with e-d block in the TS; (iv) the negative sign of ρ YY(H) with e-d block indicates that the cross-interaction between Y and Y reduces the rate, i.e. , negative role in the rate, whereas the positive sign of ρ YY(H) with e-w block implies that the cross-interaction between Y and Y induces remarkable enhancement of the rate i.e. , positive role in the rate; and finally (v) the opposite effect of the cross-interaction between Y and Y on the rate with e-d and e-w block leads to biphasic concave upward free energy relationship for substituent Y variations with a break point at Y = H.
The variation tendencies of the ρ X and ρ Y values with Y and X, respectively, of 1 are opposite to those of 2 . As a result, the sign of ρ XY(H) with 1 is opposite to that of ρ XY(H) with 2 . This implies that an additional substituent Y to the other phenyl ring in the substrate changes the reaction mechanism from a concerted S N 2 in 2 (based on ρ XY(H) = –1.31) to a stepwise process with a rate-limiting leaving group departure from the intermediate in 1 (based on ρ XY(H) = +0.22 and +0.81 with e-d and e-w block, respectively). 5
The nonlinear free energy correlation of a concave upward plot is generally diagnostic of a change in the reaction mechanism, while nonlinear free energy correlation of the concave downward plot is generally interpreted as a rate-limiting step change from bond breaking with less basic nucleophiles to bond formation with more basic nucleophiles. 7 In the present work, however, the concave upward free energy correlation with Y is interpreted as a change in the effect of the cross-interaction between Y and Y on the rate from negative with e-d block to positive role with e-w block.
The DKIEs can only be secondary inverse ( k H / k D < 1.0) when an increase in the steric congestion occurs in the bondmaking process ( e.g. TSb in Scheme 2 ) because the N–H(D) vibrational frequencies invariably increase upon going to the TS. 8 In contrast, when partial deprotonation of the aniline occurs in a rate-limiting step by hydrogen bonding ( e.g. TSf in Scheme 2 ), the k H / k D values are greater than unity, primary normal ( k H / k D > 1.0). 9 In the present work, the DKIEs are all primary normal ( k H / k D 1.0; Table 4 ), indicating that partial deprotonation of the aniline occurs in a rate-limiting step by hydrogen bonding. The DKIEs invariably decrease as substituent X changes from electron-donating to electron-withdrawing, and invariably increase as substituent Y changes from electron-donating to electron-withdrawing. Accordingly, the max value of DKIE ( k H / k D = 1.31) is observed with X = 4-MeO and Y = 4-Cl, indicating that the extent of the hydrogen bonding is the largest in the TS. The larger values of primary normal DKIEs with e-w block than those with e-d block indicate that the extent of hydrogen bond with e-w block is greater than that with e-d block in the TS. This is consistent with larger magnitude of the ρ XY value with e-w block than that with e-d block ( vide supra ).
In summary, the authors propose a stepwise mechanism with a rate-limiting leaving group expulsion from the inter-mediate based on the positive ρ XY values for both e-d and e-w blocks despite the biphasic concave upward free energy relationship, and dominant frontside nucleophilic attack involving a hydrogen bonded, four-center-type TSf based on the primary normal DKIEs. Concave upward free energy correlation with Y is ascribed to the opposite effect of the cross-interaction between Y and Y in the same substrate with e-d and e-w block.
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Backside attack in-line-type TSb and frontside attack hydrogen bonded, four-center-type TSf (L = H or D).
The DKIEs (kH/kD) for the Reactions of Bis(Y-aryl) Chlorothiophosphates (1) with XC6H4NH2(D2) in MeCN at 55.0 ℃
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aStandard error {= 1/kD[(ΔkH)2 + (kH/kD)2 × (ΔkD)2]1/2} from ref 10.
Activation Parameters for the Reactions of Bis(Y-aryl) Chlorothiophosphates (1) with C6H5NH2in MeCN
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Activation Parameters for the Reactions of Bis(Y-aryl) Chlorothiophosphates (1) with C6H5NH2 in MeCN
Activation parameters, enthalpies and entropies of activation, are determined as shown in Table 5 . The enthalpies of activation are relatively low and entropies of activation are relatively large negative value. The relatively low values of activation enthalpies (7-9 kcal mol –1 ) and relatively large negative values of activation entropies (–49 to –57 cal mol –1 K –1 ) are typical for the aminolyses of P=S(O) systems.
Experimental Section
Materials. Bis(Y-aryl) chlorothiophosphates were prepared by reacting thiophosphoryl chloride with substituted phenol 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-NaHCO 3 and ether for work up after removal of solvent under reduced pressure. Ether extracted organic part was dried over anhydrous MgSO 4 for 6-8 h. The product mixture was isolated by filtration and finally separated through column chromatography (silica gel, ethyl acetate/ n -hexane) and dried under reduced pressure using oil diffusion pump and were identified by TLC, 1 H-NMR, 13 C-NMR, 31 P-NMR and GC-MS. The physical constants after column chromatography (silicagel/ethylacetate + n -hexane) were as follows 11 (supporting information);
Bis(4-methoxyphenyl) Chlorothiophophate: White solid crystal; mp 64.0-65.0 ℃; 1 H-NMR (400 MHz, CDCl 3 and TMS) δ 3.81 (s, 6H), 6.89-6.91 (d, 4H), 7.21-7.26 (d, 4H); 13 C-NMR (100 MHz, CDCl 3 and TMS) δ 55.6, 114.7, 122.2, 129.4, 140.1, 154.4; 31 P-NMR (162 MHz, CDCl 3 and TMS) d 66.6 (1P, P=S); GC-MS (EI, m/z ) 344 (M + ).
Bis(4-methylphenyl) Chlorothiophophate: White solid crystal; mp 54.0-55.0 ℃; 1 H-NMR (400 MHz, CDCl 3 and TMS) δ 2.36 (s, 6H), 7.19-7.21 (s, 8H); 13 C-NMR (100 MHz, CDCl 3 and TMS) δ 20.8, 121.0, 130.3, 136.1, 148.1; 31 P-NMR (162 MHz, CDCl 3 and TMS) δ 65.2 (1P, P=S); GC-MS (EI, m/z ) 312 (M + ).
Bis(3-methoxyphenyl) Chlorothiophophate: Liquid; 1 HNMR (400 MHz, CDCl 3 and TMS) δ 3.82 (s, 6H), 6.85-6.87 (t, 4H), 6.91-6.93 (d, 2H), 7.26-7.31 (m, 2H); 13 C-NMR (100 MHz, CDCl 3 and TMS) δ 55.53, 107.4, 112.2, 113.3, 130.1, 151.0, 160.7; 31 P-NMR (162 MHz, CDCl 3 and TMS) δ 63.6 (1P, P=S); GC-MS (EI, m/z ) 344 (M + ).
Bis(4-chlorophenyl) Chlorothiophophate: Liquid; 1 HNMR (400 MHz, CDCl 3 and TMS) δ 7.23 (d, 2H), 7.25 (d, 2H), 7.37 (d, 2H), 7.39 (d, 2H); 13 C-NMR (100 MHz, CDCl 3 and TMS) δ 122.6, 130.0, 132.2, 148.5; 31 P-NMR (162 MHz, CDCl 3 and TMS) δ 64.1 (1P, P=S); GC-MS (EI, m/z ) 353 (M + ).
Kinetics Measurement. 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 [nucleophile] = (0.10-0.30) M.
Product Analysis. Diphenyl chlorothiophosphate was reacted with excess aniline for more than 15 half-lives at 55.0 ℃ 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 MgSO 4 . 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 (supporting information):
[(C6H5O)2P(=S)NHC6H5]: Brown liquid; 1 H-NMR (400MHz, CDCl 3 and TMS) δ 3.39 (s, br., 1H), 6.68-6.70 (m, 5H), 6.74-6.78 (m, 3H), 7.13-7.22 (m, 6H), 7.27-7.38 (m, 1H); 13 C-NMR (100 MHz, CDCl 3 and TMS) δ 118.3, 118.4, 121.3, 121.4, 122.9, 125.6, 129.6, 138.9, 150.3; 31 P-NMR (162 MHz, CDCl 3 and TMS) δ 62.6 (1P, P=S); GC-MS (EI, m/z ) 341 (M + ).
Acknowledgements
This work was supported by Inha University Research Grant.
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