Controlling (E/Z)-Stereoselectivity of -NHC=O Chlorination: Mechanism Principles for Wide Scope Applications

Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo-ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl₅ served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl₅ reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl₅; the key regioselectivity-limiting nitrilimine intermediate (8-Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo-electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity-limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl₃. DFT calculations, synthetic methodology optimization, X-ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism-inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)-bis-hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)-stereoisomers especially in medicinal chemistry and protein modification.