Rapid, Scalable Buchwald-Hartwig Amination by Resonant Acoustic Mixing (RAM): Establishing Parameters for RAM Reaction Design

We outline the systematic development of Resonant Acoustic Mixing (RAM) for rapid, scalable Buchwald-Hartwig amination in the absence of bulk solvent. While RAM is rapidly emerging as a scalable methodology for media-free mechanochemical synthesis, the design parameters for reaction control, optimization, and scale-up remain poorly understood. This study establishes the filling ratio (φ), acceleration, and amount of liquid additive (η) as three critical parameters that can be used to design scalable Buchwald-Hartwig coupling reactions under RAM conditions. Systematic investigation of several model reactions reveals a relationship between reaction conversion and φ, providing a simple means to maximize conversion. The simultaneous real-time in situ monitoring of a model reaction through infrared thermography, fingerprint Raman, as well as low-frequency Raman (THz-Raman) spectroscopy enabled correlation of the reaction progress with the evolution of temperature during RAM, and established the RAM acceleration as a parameter that can be used to tune the reaction kinetic behavior. At high accelerations the reactions can proceed under sigmoidal kinetics, enabling multi-gram syntheses within 5 minutes, while lower accelerations can be used to switch the reactions to a more linear kinetic profile, associated with longer reaction times and milder temperature profiles. Following the reaction progress in the THz-Raman region is a reaction monitoring strategy that enables the detection of crystalline and non-crystalline phases in the reaction, permitting the observation of a non-crystalline intermediate whose evolution and replacement with the crystalline product could be tracked through non-negative least-squares fitting algorithm of the real-time spectroscopic data. This study establishes key parameters for manipulating the course and stoichiometric selectivity of a metal-catalyzed reaction in RAM and illustrates the scalability to at least 100 mmol without any protocol changes, except the volume of the vessel.