Degradation of a VX Analogue: First Organometallic Reagent To Promote Phosphonothioate Hydrolysis Through Selective P−S Bond Scission

• Published in: Organometallics 2008-06, Vol.27 (11), p.2560-2564
• Main Authors: Kuo, Louis Y, Adint, Tyler T, Akagi, Allison E, Zakharov, Lev
• Format: Article
• Language: English
• ISSN: 0276-7333; 1520-6041
• DOI: 10.1021/om7012887

We report the first case of a metal complex that degrades a neurotoxin mimic under extremely mild conditions (pH 6.8, room temperature). The metallocene bis(η5-cyclopentadienyl)molybdenum(IV) dichloride (Cp2MoCl2; Cp = η5-C5H5) efficiently hydrolyzes the compound O,S-diethyl phenylphosphonothioate (DEPP), whose core functional group mimics the neurotoxin VX. Moreover, this is one of the few examples where phosphonothioate degradation yields exclusively the desired P−S bond scission under mild aqueous conditions (pH 7.2, 30 °C). Activation parameters for DEPP hydrolysis by Cp2MoCl2 in aqueous THF/acetone indicate (E a = 86 kJ/mol, ΔH ⧧= 83 kJ/mol, and ΔS ⧧ = −10 J/(mol K)) an intramolecular hydrolytic process that goes through an ordered transition state. Alteration of the cyclopentadienyl ligand showed that ansa-Cp2MoCl2 with enhanced Mo(IV) electrophilicity significantly decreased DEPP hydrolysis, while (CpMe)2MoCl2 with increased Mo(IV) electron density had the opposite effect. These structure–activity relationships as well as the activation parameters indicate DEPP hydrolysis is achieved by nucleophilic attack of a Cp2Mo-bound hydroxide on the phosphonothioate.