Microscopy Reveals: Impact of Lithium Salts on Elementary Steps Predicts Organozinc Reagent Synthesis and Structure.

Abstract

Lithium chloride is known to promote the direct insertion of metallic zinc powder into organohalides in the practical synthesis of organozinc reagents, but the reason for its special ability is poorly understood. Pioneering a combined approach of single-metal-particle fluorescence microscopy with 1H NMR spectroscopy, we herein show that the effectiveness of different lithium salts toward solubilizing intermediates on the surface of zinc metal establishes a previously unknown reactivity correlation that predicts the propensity of that salt to promote macroscale reagent synthesis and also predicts the solution structure of the ultimate organozinc reagent. A salt-free pathway is also identified. These observations of an organometallic surface intermediate, its elementary-step reactivity, and the impact of various synthetic conditions (salt, salt-free, temperature, stirring, and time) on its persistence, are uniquely available from the sensitivity and spatial localization ability of the microscopy technique. These studies unify previously disparate observations under a single unified mechanistic framework. This framework enables the rational prediction of salt effects on multiple steps in organozinc reagent synthesis and reactivity. This is an early example of single-particle microscopy characterization of elementary steps providing predictive power in reaction development by gaining a sensitive and selective spectral handle on an important intermediate, highlighting the role of this next generation of analytical tools in the development of synthetic chemistry.