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E-mail: hwlee@inha.ac.krReceived March 24, 2014, Accepted March 31, 2014Key Words : Biphasic free energy correlation, Phosphoryl transfer reaction, Pyridinolysis, Aryl N,N-Dimethylphosphoroamidochloridate The kinetic studies on the reactions of Y-aryl N,N-di-methyl phosphoroamidochloridates (1) with X-anilines anddeuterated anilines in acetonitrile (MeCN) were reported bythis lab.

concave upwards with a break point at X = 3-Ph and Y = H, respectively. The sign of cross-interaction constants (CICs; ρXY) is positive with all X and Y. Proposed mechanism is a stepwise process with a rate-limiting leaving group departure from the intermediate with all X and Y. The kinetic results of 1 are compared with those of Yaryl phenyl chlorothiophosphates (2). In the case of Y = electron-withdrawing groups, the cross-interaction between Y and Y, due to additional substituent Y, is significant enough to change the sign of ρXY from negative with 2 to positive with 1, indicative of the change of mechanism from a rate-limiting bond formation to bond breaking.

E-mail: hwlee@inha.ac.krReceived December 16, 2013, Accepted January 6, 2014The kinetic studies on the reactions of O,O-diethyl Z-S-aryl phosphorothioates with X-pyridines have beencarried out in dimethyl sulfoxide. The free energy correlations with X in the nucleophiles are biphasic concaveupwards with a break point at X = H, while those for substituent Z variations in the leaving groups are linear.The negative sign of ρ

E-mail: hwlee@inha.ac.krReceived November 22, 2013, Accepted December 5, 2013The kinetic studies on the reactions of O-methyl N,N-diisopropylamino phosphonochloridothioate with X-anilines and X-pyridines have been carried out in acetonitrile. The free energy relationship with X in theanilines exhibits biphasic concave upwards with a break region between X = (H and 4-F), giving unusualnegative β

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 C. A stepwise mechanism with a rate-limiting leaving group departure from the intermediate is proposed based on the positive ρXY value. The deuterium kinetic isotope effects involving deuterated anilines show secondary inverse with all the nucleophiles, rationalized by a dominant backside nucleophilic attack.

Summary of the Second-Order Rate Constants ( k 2 × 10 3 /M –1 s –1 ) at 35.0 o C, NBO Charges at the Reaction Center P Atom,Summations of the Steric Constants and Selectivity Parameters ( X and  XY ) for the Reactions of 1 - 11 with X-Pyridines in MeCNno R 1 OR 2 O k 2 × 10 3 a charge at P – E S  X e  XY 1 MeO MeO 1.54 c 1.687 0 1.09/0.20 – 2 MeO EtO 0.620 1.693 0.07 1.50/0.43 – 3 EtO EtO 1.19 c 1.701 0.14 1.02/0.29 – 4 EtO PrO 0.609 1.700 0.43 1.44/0.36 – 5 PrO PrO 1.16 1.702 0.72 1.08/0.31 – 6 BuO BuO 1.01 1.703 0.78 1.26/0.31 – 7 i -PrO i -PrO 0.460 1.723 0.94 0.99/0.15 – 8 MeO YC 6 H 4 O 0.835 b 1.686 2.48 0.89-0.98/0.29-0.32 –0.71/–0.36 e 9 EtO YC 6 H 4 O0.137 b,d 1.687 2.55 2.31-2.33/0.45-0.47 0/0/0/0 f 10 PrO YC 6 H 4 O 0.781 b 1.687 2.84 0.74-0.93/0.30-0.39 1.59/0.94 e 11 PhO YC 6 H 4 O 0.333 b 1.661 4.96 1.36-1.50/ 0.23-0.48 2.42/5.14/–1.02/–0.04 fa Value with X = H at 35.0 o C. b Value with Y = H. c Extrapolated value. d Empirical kinetic data. e Strongly/weakly basic pyridines.

Nucleophilic substitution reactions of ethyl methyl (2), ethyl propyl (4) and diisopropyl (7) chlorothiophosphates with substituted anilines and deuterated anilines are investigated kinetically in acetonitrile at . A concerted mechanism is proposed based on the selectivity parameters. The deuterium kinetic isotope effects (DKIEs; ) are secondary inverse () with 2, primary normal and secondary inverse () with 4, and primary normal () with 7. The primary normal and secondary inverse DKIEs are rationalized by frontside attack involving hydrogen bonded, four-center-type transition state, and backside attack involving in-line-type transition state, respectively. The anilinolyses of ten chlorothiophosphates are examined based on the reactivity, steric effect of the two ligands, thio effect, reaction mechanism, DKIE and activation parameter.

)are positive for both electron-donating and electron-withdrawing Y substituents. The kinetic results of 1 arecompared with those of Y-aryl phenyl chlorothiophosphates (2). The cross-interaction between Y and Y, dueto additional substituent Y, is significant enough to result in the change of the sign of ρ

) invariably increase from secondaryinverse to primary normal as the aniline becomes more basic, rationalized by the transition state variation froma backside to a frontside attack. For the pyridinolysis of 1, the authors propose a stepwise mechanism with arate-limiting step change from bond breaking for more basic pyridines to bond formation for less basicpyridines based on the selectivity parameters and activation parameters. Biphasic concave upward free energyrelationship with X is ascribed to a change in the attacking direction of the nucleophile from a frontside attackwith more basic pyridines to a backside attack with less basic pyridines.Key Words : Phosphoryl transfer reaction, Anilinolysis, Pyridinolysis, Bis(2-oxo-3-oxazolidinyl) phosphinicchloride, Deuterium kinetic isotope effectIntroductionContinuing the kinetic studies on the aminolyses of(Lig

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 βX = 1.50(2) and 1.44(4) with strongly basic pyridines and relatively small values of βX = 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.

E-mail: hwlee@inha.ac.krReceived June 5, 2013, Accepted June 14, 2013Key Words : Thiophosphoryl transfer reaction, Biphasic free energy correlation, Pyridinolysis, O-Propyl andO-isopropyl phenyl phosphonochloridothioatesContinuing the kinetic studies on the pyridinolyses of thephosphonochloridothioates, the nucleophilic substitutionreactions of O-propyl (4) and O-isopropyl (5) phenylphosphonochloridothioates with X-pyridines have beencarried out kinetically in acetonitrile (MeCN) at 35.0 ± 0.1oC (Scheme 1). The kinetic results of the present work arecompared with those of the pydidinolyses of Y-O-arylmethyl [1; Me(YC

N2 mechanism is proposed for the anilinolyses of 1, 3 and 4. The anilinolysis rates of the phosphonochloridothioates are predominantly dependent upon the steric effects over the inductive effects of the two ligands. The deuterium kinetic isotope effects (DKIEs; kH/kD) are primary normal with 1 and 3, while secondary inverse with 4. Primary normal and secondary inverse DKIEs are rationalized by frontside and backside nucleophilic attack transition state, respectively. The DKIEs of the phosphonochloridothioates do not have any consistent correlations with the two ligands.

< 1. Key Words : Phosphoryl transfer reaction, Anilinolysis, (2R,4R,5S)-(+)-2-Chloro-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine 2-sulfide, Deuterium kinetic isotope effect IntroductionThe anilinolysis rates of cyclic five-membered ring phos-phate esters are much faster than their acyclic counterparts inacetonitrile (MeCN).

The kH and kD values with X-anilines and deuterated Xanilines, respectively, are summarized in Table 1, together with the DKIEs (kH/kD) and Hammett ρX(H and D) and Bronsted βX(H and D) coefficients. The pKa(X) values of the X-anilines in water were used to obtain the Bronsted βX values in MeCN, and this procedure was justified experimentally and theoretically. 3 The values of pKa(X) and σX of the deuterated X-anilines are assumed to be identical to those of the Xanilines. Perrin and coworkers reported that the basicities of β-deuterated analogs of benzylamine, N,N-dimethylaniline and methylamine increase roughly by 0.02 pKa units per deuterium, and that these effects are additive. 4 Thus, the pKa(X) values of deuterated X-anilines may be slightly greater than those of X-anilines, however, the difference is too small to be taken into account. The anilinolysis rate increases with a more electrondonating substituent X in the nucleophile which is consistent with a typical nucleophilic substitution reaction with positive charge development at the nucleophilic reaction center N atom in the transition state (TS). The Hammett (Fig. 1; log kH(D) vs σX) and Bronsted [Fig. 2; log kH(D) vs pKa(X)] plots for substituent X variations in the nucleophiles give considerably large magnitudes of ρX(H) = –4.83 (ρX(D) = –5.24) and βX(H) = 1.71 (βX(D) = 1.85). The magnitudes of selectivity parameters with the deuterated anilines are slightly greater than those with the anilines. The DKIEs are primary normal (kH/kD > 1) and the values of DKIEs invariably increase as the nucleophile becomes weaker. The remarkably large value of kH/kD = 2.19 with X = 3-Cl is the largest one, observed for the phosphoryl transfer reactions in this lab. 8

E-mail: hwlee@inha.ac.krReceived October 27, 2011, Accepted November 7, 2011Key Words : Phosphoryl transfer reaction, Pyridinolysis, Bis(N,N-dimethylamino) phosphinic chloride, Bi-phasic concave upward free energy relationshipThe kinetic studies of the pyridinolyses of tetracoordi-nated phosphorus have been studied extensively by this lab.

correlations for substituent X variations in the nucleophiles exhibit biphasic concave upwards with a breakpoint at a X = 3-Cl. Unusual positive ρX (= +5.40) and negative βX (= –0.83) values are obtained with the weakly basic pyridines. The pyridinolysis rate of 5 is hundreds times slower compared to that of bis(phenyl) chlorophosphate because of the steric hindrance of the four ortho-methyl substituents in the two phenyl rings. Ion-pair mechanism is proposed and positive ρX and negative βX values are substantiated by an imbalance of the transition state.

The nucleophilic substitution reactions of ethylene phosphorochloridate (1c) with substituted anilines () and deuterated anilines () are investigated kinetically in acetonitrile at . The anilinolysis rate of 1c involving a cyclic five-membered ring is four thousand times faster than its acyclic counterpart (1a: diethyl chlorophosphate) because of great positive value of the entropy of activation of 1c ( compared to negative value of 1a () over considerably unfavorable enthalpy of activation of 1c () compared to 1a (). Great enthalpy and positive entropy of activation are ascribed to sterically congested transition state (TS) and solvent structure breaking in the TS. The free energy correlations exhibit biphasic concave upwards for substituent X variations in the X-anilines with a break point at X = 3-Me. The deuterium kinetic isotope effects are secondary inverse ( > 1) with the weakly basic anilines and rationalized by the TS variation from a dominant backside attack to a dominant frontside attack, respectively. A concerted mechanism is proposed and the primary normal deuterium kinetic isotope effects are substantiated by a hydrogen bonded, four-center-type TS.

= 0.91 with the strongly basic nucleophiles. Proposed reaction mechanism is a stepwise process with a rate-limiting leaving group expulsion from the intermediate involving a backside nucleophilic attack with thestrongly basic nucleophiles and a frontside attack with the weakly basic nucleophiles. The kinetic results arecompared with those of the benzylaminolysis of O,O-diphenyl Z-S-aryl phosphorothioates.Key Words : Phosphoryl transfer reaction, Benzylaminolysis, O,O-Diethyl Z- S-aryl phosphorothioate, Cross-interaction constant, Concave downward free energy correlationIntroductionThe various phosphoryl and thiophosphoryl transfer reac-tions have been studied kinetically by this lab: anilinolysis

The nucleophilic substitution reactions of bis(N,N-dimethylamino) phosphinic chloride (3) with substituted anilines () and deuterated anilines () are investigated kinetically in acetonitrile at . The anilinolysis rate of 3 is rather slow to be rationalized by the conventional stereoelectronic effects. The magnitudes of (= -6.42) and (= 2.27) values are exceptionally great. The deuterium kinetic isotope effects (DKIEs; ) are secondary inverse ( = 0.69-0.96). A concerted mechanism involving a backside attack is proposed on the basis of secondary inverse DKIEs and the variation trend of the values with X. The anilinolyses of six phosphinic chlorides in MeCN are briefly reviewed by means of DKIEs, steric effects of the two ligands, positive charge of the reaction center phosphorus atom, and selectivity parameters to obtain systematic information on phosphoryl transfer reaction mechanism.

pKa values for the anilinium ions determined in DMSO, an approximate straight line is obtained when they are plotted against those determined in water. 4 Spillane and coworkers reported that the βX value for the reactions of N-phenyl sulfamoyl chloride (PhNHSO2Cl) with X-anilines in DMSO is similar when determined using the pKa values of anilines measured in water (βX = 0.69) and DMSO (βX = 0.62). 5 Accordingly, it may be inferred that the βX values in Table 1 are reasonably positive. The pKa and σ values of deuterated anilines are assumed to be the same as those of anilines. The pKa(X) values of deuterated X-anilines may be slightly greater than those of X-anilines, however, the difference is too small to be taken into account. 6 Figures 1 and 2 show the Hammett (log kH(D) vs σX) and Bronsted [log kH(D) vs pKa(X)] plots, respectively, for substituent X variations in the nucleophiles. The rate consistently increases with a more electrondonating substituent X in the nucleophile, which is consistent with a typical nucleophilic substitution reaction with positive charge development at the nucleophilic N atom in the transition state (TS). The magnitudes of the ρX and βX values with the deuterated anilines are slightly greater than those with the anilines, suggesting more sensitive to substituent effects of the deuterated anilines compared to the

studied substrate of 1,2-phenylene phosphorochloridate is cyclic five-membered ring of phosphorus ester, and the anilinolysis rate of 1 is much faster than its acyclic analogue (4: ethyl phenyl chlorophosphate) because of extremely small magnitude of the entropy of activation of 1 compared to 4. The Hammett and Bronsted plots exhibit biphasic concave upwards for substituent X variations in the nucleophiles with a break point at X = 3Me. The values of deuterium kinetic isotope effects (DKIEs; kH/kD) change from secondary inverse (kH/kD 1) with the weakly basic anilines. The secondary inverse with the strongly basic anilines and primary normal DKIEs with the weakly basic anilines are rationalized by the transition state (TS) variation from a predominant backside attack to a predominant frontside attack, in which the reaction mechanism is a concerted SN2 pathway. The primary normal DKIEs are substantiated by a hydrogen bonded, four-center-type TS.

C. The kinetic results of 1 are comparedwith those of Y-aryl phenyl chlorophosphates (2). The substrate 1 has one more identical substituent Ycompared to substrate 2. The cross-interaction between Y and Y, due to additional substituent Y, is significantenough to result in the change of the sign of cross-interaction constant (CIC) from negative ρ