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Kinetics and Mechanism of Pyridinolyses of Ethyl Methyl and Ethyl Propyl Chlorothiophosphates in Acetonitrile
Kinetics and Mechanism of Pyridinolyses of Ethyl Methyl and Ethyl Propyl Chlorothiophosphates in Acetonitrile
Bulletin of the Korean Chemical Society. 2013. Nov, 34(11): 3372-3376
Copyright © 2013, Korea Chemical Society
  • Received : August 08, 2013
  • Accepted : August 28, 2013
  • Published : November 20, 2013
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Hasi Rani Barai
Hai Whang Lee

Abstract
The kinetic studies on the reactions of ethyl methyl ( 2 ) and ethyl propyl ( 4 ) chlorothiophosphates with Xpyridines have been carried out in acetonitrile at 35.0 ℃. The free energy correlations with X show biphasic concave upwards with a break point at X = H ( 2 ) and 3-Ph ( 4 ), respectively. A stepwise mechanism with a ratelimiting leaving group expulsion from the intermediate is proposed based on the magnitudes of selectivity parameters for both substrates. The considerably large values of β X = 1.50( 2 ) and 1.44( 4 ) with strongly basic pyridines and relatively small values of β X = 0.43( 2 ) and 0.36( 4 ) with weakly basic pyridines are interpreted as a change of the attacking direction of the X-pyridines from a frontside to a backside attack toward the chloride leaving group.
Keywords
Introduction
To extend the kinetic studies on the pyridinolyses of the chlorothiophosphates [(R 1 O)(R 2 O)P(=S)Cl-type], 1 the nucleophilic substitution reactions of ethyl methyl (2) and ethyl propyl (4) chlorothiophosphates with X-pyridines are kinetically investigated in acetonitrile (MeCN) at 35.0 ± 0.1 ℃ ( Scheme 1 ). The kinetic results of the present work are compared with those of dimethyl (1: R 1 = R 2 = Me), 1a diethyl (3: R 1 = R 2 = Et), 1a dipropyl (5: R 1 = R 2 = Pr), 1d dibutyl (6: R 1 = R 2 = Bu), 1e diisopropyl (7: R 1 = R 2 = i -Pr), 1f Y-aryl ethyl (8: R 1 = Et, R 2 = YC 6 H 4 ) 1c and Y-aryl phenyl (9: R 1 = Ph, R 2 = YC 6 H 4 ) 1b chlorothiophosphates. The purpose of this work is to gain further information on the reactivity, steric effects and mechanism depending upon the variation of the two ligands (R 1 O and R 2 O) for the thiophosphoryl transfer reactions. 1-9 are numbered according to the sequence of the summation of the Taft steric constants of R 1 and R 2 . 2
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Pyridinolyses of ethyl methyl (2) and ethyl propyl (4) chlorothiophosphates in MeCN at 35.0 ℃.
Results and Discussion
Table 1 summarizes the second-order rate constants [ k 2 (M −1 s −1 )] and selectivity parameters, ρ X and 𝛽 X . The substituent effects of the nucleophiles upon the pyridinolysis rates correlate with those for a typical nucleophilic substitution reaction where the stronger nucleophile leads to a faster rate with a positive charge development at the nucleophilic N atom in the transition state (TS). However, both the Hammett (log k 2 vs 𝜎 X ; Figs. S1 and S2 in supporting information) and Brönsted [log k 2 vs p K a (X); Figs. 1 and 2 ] plots are biphasic concave upwards with a break point at X = H (2) and 3-Ph (4), respectively. The rate of 2 is slightly faster than that of 4. The magnitudes of ρ X [= −7.27(2), −6.96(4)] and 𝛽 X [= 1.50(2), 1.44(4)] with strongly basic pyridines are 3-4 times larger than those [ ρ X = −2.54(2), −2.16(4); 𝛽 X = 0.43(2), 0.36(4)] with weakly basic pyridines.
Table 2 summarizes the second-order rate constants ( k 2 ) with unsubstituted pyridine at 35.0 ℃, natural bond order (NBO) charges at the reaction center P atom in the substrate in the gas phase [B3LYP/6-311 + G(d,p) level of theory], summations of the Taft steric constants [Σ E S = E S (R 1 ) + E S (R 2 )] of the two ligands, 2 Brönsted coefficients (𝛽 X ) and crossinteraction constants (CICs; ρ XY ) 3 for the pyridinolyses of nine chlorothiophosphates ( 1-9 ) in MeCN. The dependence of the two ligands on the rate is relatively weak, e .g., k 2 (1.54 × 10 −3 with 1; fastest)/ k 2 (0.137 × 10 −3 with 8; slowest) ≈ 11, whereas the rate is strongly dependent upon the substituent X in the pyridines, e . g ., k 2 (600 + 10 −3 with X = 4-MeO)/ k 2 (0.128 × 10 −3 with X = 4-CN) ≈ 4,700 for 2 as seen in Table 1 .
Second-Order Rate Constants (k2× 104/M−1s−1) and Selectivity Parameters (ρXand 𝛽X) of the Reactions of Ethyl Methyl (2) and Ethyl Propyl (4) Chlorothiophosphates with X-Pyridines in MeCN at 35.0 ℃
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aX = (4-MeO, 4-Me, 3-Me, H). bX = (H, 3-Ph, 3-Cl, 3-Ac, 4-Ac, 3-CN, 4-CN). cr = 0.999. dr = 0.999. er = 0.998. fr = 0.982. gX = (4-MeO, 4-Me, 3-Me, H, 3-Ph). hX = (3-Ph, 3-Cl, 3-Ac, 4-Ac, 3-CN, 4-CN). ir = 0.999. jr = 0.998. kr = 0.999. lr = 0.963.
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Brönsted plot of the reactions of ethyl methyl chlorothiophosphate (2) with X-pyridines in MeCN at 35.0 ℃.
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Brönsted plot of the reactions of ethyl propyl chlorothiophosphate (4) with X-pyridines in MeCN at 35.0 ℃.
There is no linear correlation between the rates and NBO charges at the reaction center P atom in the substrates. These suggest that that the inductive effects of the two ligands are not a major factor determining the pyridinolysis rates of the chlorothiophosphates. 4 The Taft eq., ‘log k 2 = 𝛿Σ E S + C’, is introduced to understand the steric effect of the two ligands on the rate. Herein, ‘Σ E S = E S (R 1 ) + E S (R 2 )’ is employed instead of ‘Σ E S = E S (R 1 O) + E S(R 2 O)’ because the data of E S (R i O) is not available [ E S (R) = 0(Me); −0.07(Et); −0.36(Pr);−0.39(Bu); −0.47( i -Pr); −2.48(Ph)]. 2 Figure 3 shows the Taft plot of log k 2 with unsubstituted pyridine (C 5 H 5 N) against the summation of the Taft steric constants of the two ligands for the pyridinolyses of nine chlorothiophosphates ( 1-9 ) in MeCN at 35.0 ℃. The plot gives the sensitivity coefficient of 𝛿 = 0.14 ± 0.06 (r = 0.668; poor linearity) with nine substrates of 1-9 . This indicates that the steric effects of the two ligands are not major factor but minor one determining the pyridinolysis rates of the chlorothiophosphates.
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Taft plot of log k2 vs ΣES for the reactions of 1-9 with C5H5N in MeCN at 35.0 ℃. The number of the substrate and two ligands are displayed next to the corresponding point.
Summary of the Second-Order Rate Constants (k2× 103/M−1s−1), NBO Charges at the Reaction Center P Atom, Summations of the Taft Steric Constants (ΣES), Brönsted Coefficients (𝛽X) and CICs (ρXY) for the Pyridinolyses of1-9in MeCN
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aValue with C5H5N at 35.0 ℃. bValue with Y = H. cΣES = ES(R1) + ES(R2). dStrongly/weakly basic pyridines. eα-block(strong nucleophiles and weak electrophiles)/b-block(weak nucleophiles and weak electrophiles)/c-block(strong nucleophiles and strong electrophiles)/d-block(weak nucleophiles and strong electrophiles)
In contrast to the pyridinolyses of the chlorothiophosphates, the anilinolysis rates of the chlorothiophosphates 5 and aminolysis (anilinolysis 5b c 6 and pyridinolysis) 1a 7 rates of the chlorophosphates exhibit consistent dependence upon the steric effects of the two ligands, but divided into two groups; 𝑎 group containing two alkoxy ligands and b group containing phenoxy ligand(s). This suggests that the steric effects of the two ligands on the rate in the 𝑎 group are essentially ‘different’ from those in the b group, and that the steric effects of the two ligands play an important role in determining the anilinolysis rates of the P=S systems and aminolysis (anilinolysis and pyridinolysis) rates of the P=O systems.
The free energy relationships with X of 1-9 are all biphasic concave upwards. The 𝛽 X values of 1 , 3 and 5-7 are similar: 𝛽 X = 1.0-1.3 with strongly basic pyridines and 𝛽 X = 0.2-0.3 with weakly basic pyridines, strongly suggesting the same pyridinolysis mechanisms. 1a d - f A concerted mechanism was proposed for the pyridinolyses of 1 , 3 and 5-7 . 1a d - f The 𝛽 X (= 2.31-2.33) values of 8 with strongly basic pyridines are the greatest among all the pyridinolyses of the P=O and P=S systems involving chloride leaving group, studied in this lab. 1e The 𝛽 X (= 1.4-1.5) values of 9 with strongly basic pyridines are relatively large. 1b The 𝛽 X values of 8 and 9 with weakly basic pyridines are somewhat greater than those of 1, 3 and 5-7 . In the present work of 2 and 4 , the 𝛽 X values of 1.50( 2 ) and 1.44( 4 ) with strongly basic pyridines and 0.43( 2 ) and 0.36( 4 ) with weakly basic pyridines are close to those of 9 .
The Hammett plots of 8 for the substituent Y variations in the substrates are biphasic concave upwards with a break (minimum) point at Y=H while those of 9 are concave downwards with a break point at Y=H. Thus, the four values of CICs, ρ XY , were obtained for both 8 and 9 . In the case of 8, the CICs ( ρ XY ) are all null in spite of the biphasic free energy correlations for both substituent X and Y variations, because the ρ X values with both strongly and weakly basic pyridines are almost constant. This reaction is the only one, having all ρ XY = 0 with four blocks until now: a -block (strong nucleophiles and weak electrophiles), b -block (weak nucleophiles and weak electrophiles), c -block (strong nucleophiles and strong electrophiles) and d -block (weak nucleophiles and strong electrophiles). Herein, the null of ρ XY value implies that the distance between X and Y does not vary from the intermediate to the second TS, in which the reaction proceeds through a stepwise mechanism with a ratelimiting leaving group departure from the intermediate. 8 In the case of 9 , a stepwise process was proposed involving a rate-limiting step change from bond breaking with a - and b -blocks based on the large positive ρ XY value to bond formation with c - and d -blocks based on the negative ρ XY value. 9
The biphasic concave upward free energy relationships with X were interpreted as a change of the nucleophilic attacking direction from a frontside attack TSf with strongly basic pyridines based on the large magnitudes of 𝛽 X values to a backside attack involving in-line-type TSb with weakly basic pyridines based on the relatively small magnitudes of 𝛽 X values. It is worthy of note that a frontside attack TSf yields greater magnitudes of ρ X and 𝛽 X values compared to a backside attack. 10
In the present work of 2 and 4 , the 𝛽 X values [1.50( 2 ) and 1.44( 4 ) with strongly basic pyridines and 0.43( 2 ) and 0.36( 4 ) with weakly basic pyridines] are quite similar to those of 9 with Y = electron-donating ( a , b -blocks), 1b in which the proposed mechanism is a stepwise process with a ratelimiting leaving group expulsion from the intermediate. Thus, the authors accordingly propose the pyridinolysis mechanism of 2 as a stepwise process with a rate-limiting leaving group departure from the intermediate, and a change of the nucleophilic attacking direction from a frontside attack TSf with strongly basic pyridines based on the large 𝛽 X value to a backside attack involving in-line-type TSb ( Scheme 2 ) with weakly basic pyridines based on the relatively small 𝛽 X value. Table 3 summarizes the proposed mechanism and the attacking direction of the pyridine toward the chloride leaving group.
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Backside attack TSb and frontside attack TSf.
Proposed Mechanism and Attacking Direction for the Pyridinolyses of1-9in MeCN
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aStrongly/weakly basic pyridines.
Activation Parameters for the Reactions of1-9with C5H5N in MeCN
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aSee Tables S1 and S2 in supporting information. bValue with Y=H.
Activation parameters, enthalpies and entropies of activation, for the pyridinolyses (with C 5 H 5 N) of 1-9 are summarized in Table 4 . The enthalpies of activation are relatively small (5-9 kcal mol −1 ) and entropies of activation are relatively large negative values (−42 to −57 cal mol −1 K −1 ), except 4 where the enthalpy of activation is relatively large (Δ H = 15.2 kcal mol −1 ) and entropy of activation is relatively small negative value (Δ S = −25 cal mol −1 K −1 ). 11 The small value of activation enthalpy and large negative value of activation entropy are typical for the aminolyses (pyridinolyses or anilinolyses) of P=S (and P=O) systems regardless of the mechanism, concerted, stepwise with a rate-limiting bond making or stepwise with a rate-limiting bond breaking. In other words, it is sometimes dangerous to clarify the mechanism by means of the activation parameters.
Experimental Section
Materials . HPLC grade MeCN (water content 0.005%) and GR grade X-pyridines were used without further purification. Ethyl methyl ( 2 ) and ethyl propyl ( 4 ) chlorothiophosphates were prepared via one step synthetic route. Ethyl dichlorothiophosphate was reacted with methanol and propanol for 2 and 4 , respectively, at −10.0 ℃ with constant stirring. The product mixture was dried under reduced pressure and isolated by column chromatography [ethyl acetate (10% and 1% for 2 and 4 , respectively) + n -hexane]. 12 The analytical and spectroscopic data of the substrates gave the following results (see supporting information):
(MeO)(EtO)P(=S)Cl : Colorless liquid; 1 H-NMR (400 MHz, CDCl 3 & TMS) 𝛿 1.39-1.43 (aliphatic, 3H, t), 3.85- 3.93 (aliphatic, 3H, br), 4.27-4.32 (aliphatic, 2H, q); 13 CNMR (100 MHz, CDCl 3 & TMS) 𝛿 15.61, 55.39, 66.34; 31 PNMR (162 MHz, CDCl 3 & TMS) 𝛿 81.72 (1P, s, P=S); GCMS (EI, m / z ) 174 (M + ).
(EtO)(PrO)P(=S)Cl : Colorless liquid; 1 H-NMR (400 MHz, CDCl 3 & TMS) 𝛿 0.98-1.02 (aliphatic, 3H, t), 1.40-1.44 (aliphatic, 3H, t), 1.75-1.81 (aliphatic, 2H, m), 4.16-4.27 (aliphatic, 2H, q), 4.29-4.32 (aliphatic, 2H, t); 13 C-NMR (100 MHz, CDCl 3 & TMS) 𝛿 9.97, 15.62, 23.16, 66.09, 71.47; 31 P-NMR (162 MHz, CDCl 3 & TMS) 𝛿 74.42 (1P, s, P=S); GC-MS (EI, m / z ) 202 (M + ).
Kinetic Procedure . Rates were measured conductometrically at 35.0 ℃ as reported earlier. 1 Initial concentrations of substrates and nucleophiles were as follows; [substrate] = 5 × 10 −3 M and [XC 5 H 4 N] = (0.10-0.30) M.
Product Analysis . Ethyl methyl ( 2 ) and ethyl propyl ( 4 ) chlorothiophosphates were reacted with excess pyridine, for more than 15 half-lives at 35.0 ℃ in MeCN, respectively. 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. Analytical and spectroscopic data of the product gave the following results (see supporting information):
[(MeO)(EtO)P(=S)NC5H5]+Cl : Light brown gummy solid; 1 H-NMR (400 MHz, MeCN- d 3 ) 𝛿 1.10-1.13 (aliphatic, 3H, t), 3.39-3.44 (aliphatic, 2H, q), 4.38 (aliphatic, 3H, s), 7.80-7.84 (aromatic, 2H, t), 8.31 (aromatic, 1H, t), 8.72-8.74 (aromatic, 2H, d); 13 C-NMR (100 MHz, MeCN- d 3 ) 𝛿 17.0, 64.1, 66.9, 128.1, 129.6, 130.9, 144.8, 145.4, 146.9; 31 PNMR (162 MHz, MeCN- d 3 ) 𝛿 43.9 (1P, s, P=S); LC-MS for C 8 H 13 ClNO 2 PS (EI, m / z ), 254 (M + ).
[(EtO)(PrO)P(=S)NC5H5]+Cl : Colorless liquid; 1 HNMR (400 MHz, CDCl 3 & TMS) 𝛿 0.99-1.04 (aliphatic, 3H, t), 1.74-1.77 (aliphatic, 3H, t), 2.10-2.14 (aliphatic, 2H, m), 4.99-5.01 (aliphatic, 2H, t), 5.10-5.12 (aliphatic, 2H, q), 8.08-8.11 (aromatic, 2H, t), 8.21 (aromatic, 1H, br), 8.53- 8.59 (aromatic, 2H, t); 13 C-NMR (100 MHz, CDCl 3 & TMS) 𝛿 10.4, 17.2, 25.1, 57.4, 63.2, 127.3, 128.4, 141.0, 145.0, 145.8; 31 P-NMR (162 MHz, CDCl 3 & TMS) 𝛿 54.0 (1P, s, P=O); LC-MS for C 10 H 17 ClNO 2 PS (EI, m / z ), 281(M + ).
Acknowledgements
This work was supported by Inha University Research Grant.
References
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