Mechanism of an Elusive Solvent Effect in Organozinc Reagent Synthesis

Abstract

Solvent effects are often difficult to understand in cases where reaction intermediates, and thus their differential behavior in different solvents, are not directly observable by traditional ensemble analytical techniques. Herein, the sensitivity of single-particle fluorescence microscopy uniquely enables direct observation of organozinc intermediates and solvent effects on their build-up and persistence. When combined with NMR spectroscopy, these imaging data pinpoint the previously elusive mechanistic origin of solvent effects in the synthesis of widely used organozinc reagents. These findings characterize the acceleration of oxidative addition of the starting organoiodide to the surface of zinc metal in DMSO relative to THF, but once formed, surface intermediates display similar persistence in either solvent. The current studies are the first demonstration of a highly sensitive, single-particle fluorescence microscopy technique to pinpoint otherwise elusive solvent effects in synthetic chemistry.

Keywords: mechanism; organozinc; oxidative addition; single-particle fluorescence microscopy; solvent Effect.

Scheme 1.

(a) Schematic of the broader mechanistic problem with traditional ensemble analytical techniques. (b) Two mechanistic hypotheses for solvent effects in organozinc synthesis.

Scheme 2.

(a) Bench-scale chemical reaction monitored by NMR spectroscopy. (b) NMR spectroscopy yield relative to internal standard vs time, in DMSO-d₆ (red) and THF-d₈ (blue). (c) Chemical reaction for fluorescence microscopy experiments. (d) Representative zinc particle in DMSO after 30 min, fluorescence microscopy image. (e) Representative zinc particle in THF after 30 min, fluorescence microscopy image. Green “hot spots” of observable intermediate 4, and the full chemical structure of imaging agent 3. Images d and e are displayed at the same brightness/contrast settings for direct comparison.

Scheme 3.

Fluorescence microscopy: (a) Relative persistence of oxidative addition intermediate 4 in DMSO at ambient temperature. (b) Activation of Zn surface (shown as Zn*) by stirring in THF, consistent with removal of a surface oxide layer being the source of the induction period observed in THF in Scheme 2b. (c) No activation of Zn surface with DMSO upon presoaking.