Theoretical Study of Phosphoryl Transfer Reactions

A detailed molecular understanding of the mechanisms of the dephosphorylation of phosphate triesters due to nucleophilic attack can be very useful for the design of nucleophiles that are more efficient. In this work, we report a combined experimental and theoretical study of the reaction of hydroxylamine with paraoxon. The profile of the reaction rate according to pH was determined, and it was found that protonated hydroxylamine was unreactive, while the neutral form reacted via the zwitterion tautomer, with an overall free energy barrier of 23.0 kcal mol‐1. The anionic form was the most reactive, with a free energy barrier of 18.1 kcal mol‐1. Computational calculations revealed 2 mechanisms for the nucleophilic attack of the zwitterion form: the usual backside attack and a new frontside attack mechanism. The former proceeded according to a 2‐step associative mechanism, while the latter was a concerted single‐step mechanism involving attack of the hydroxylamine oxygen on the phosphorus center and interaction of the NH3+ group with the oxygen of the P═O group. The calculations indicated that the free energy barrier for the frontside attack was more favorable than the backside attack by 3 kcal mol‐1, supporting the notion that the observed reaction occurs by frontside attack. The reaction with the anionic hydroxylamine form occurred according to a single‐step concerted ANDN mechanism.

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Cleaving paraoxon with hydroxylamine: Ammonium oxide isomer favors a Frontside attack mechanism

Lima

Cruz

Fernandes

et al. 2018

J of Physical Organic Chem

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Kinetics and Mechanism of the Benzylaminolysis of O,O-Diethyl S-Aryl Phosphorothioates in Dimethyl Sulfoxide

Adhikary¹,

Lee²

2011

Bulletin of the Korean Chemical Society

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The reactions of O,O-diethyl Z-S-aryl phosphorothioates with X-benzylamines are kinetically investigated in dimethyl sulfoxide at 85.0 °C. The Hammett (log k 2 vs σ X ) and Brönsted [log k 2 vs pK a (X)] plots are biphasic concave downwards for substituent X variations in the nucleophiles with a break point at X = H. The signs of the cross-interaction constants (ρ XZ ) are positive for both the strongly and weakly basic nucleophiles. Considerably great magnitude of ρ XZ (= 6.56) value is observed with the weakly basic nucleophiles, while ρ XZ = 0.91 with the strongly basic nucleophiles. Proposed reaction mechanism is a stepwise process with a ratelimiting leaving group expulsion from the intermediate involving a backside nucleophilic attack with the strongly basic nucleophiles and a frontside attack with the weakly basic nucleophiles. The kinetic results are compared with those of the benzylaminolysis of O,O-diphenyl Z-S-aryl phosphorothioates.

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Kinetics and Mechanism of the Pyridinolysis of S-Aryl Phenyl Phosphonochloridothioates in Acetonitrile

Adhikary¹,

Lumbiny²,

Lee³

2011

Bulletin of the Korean Chemical Society

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Kinetic studies on the reactions of Y-S-aryl phenyl phosphonochloridothioates with X-pyridines have been carried out in MeCN at 55.0 ºC. The Hammett and Brönsted plots for substituent X variations in the nucleophiles are biphasic concave upwards with a break point at X = H. The Hammett plots for substituent Y variations in the substrates are biphasic concave upwards with a break point at Y = H, and the sign of ρ Y is changed from unusual negative (ρ Y < 0) with the weaker electrophiles to positive (ρ Y > 0) with the stronger electrophiles. The stepwise mechanism is proposed on the basis of the ρ X , β X , and ρ XY values as follows: a ratelimiting leaving group departure from the intermediate involving a frontside attack and product-like TS for the stronger nucleophiles and weaker electrophiles; a rate-limiting leaving group departure from the intermediate involving a backside attack and product-like TS for the weaker nucleophiles and electrophiles; a rate-limiting bond formation involving a frontside attack for the stronger nucleophiles and electrophiles; a rate-limiting bond formation involving a backside attack for the weaker nucleophiles and stronger electrophiles. The substituent effects of X and Y on the pyridinolysis mechanisms of R 1 R 2 P(=S)Cl-type substrates are discussed.

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Theoretical Study of Phosphoryl Transfer Reactions

Cited by 27 publications

References 36 publications

Cleaving paraoxon with hydroxylamine: Ammonium oxide isomer favors a Frontside attack mechanism

Cleaving paraoxon with hydroxylamine: Ammonium oxide isomer favors a Frontside attack mechanism

Kinetics and Mechanism of the Benzylaminolysis of O,O-Diethyl S-Aryl Phosphorothioates in Dimethyl Sulfoxide

Kinetics and Mechanism of the Pyridinolysis of S-Aryl Phenyl Phosphonochloridothioates in Acetonitrile

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