A Complex Catalytic Reaction Caught in the Act: Intermediates and Products Sampling Online by Liquid μ‐Beam Mass Spectrometry and Theoretical Modeling

Liquid‐beam IR–laser desorption mass spectrometry has been used to monitor the reactants, intermediates, and products of a complex organic signature reaction in real time on multiple timescales directly from the liquid phase. The reaction was chosen because it has advantages in medicinal chemistry applications, and the three‐component, modular construction provides a means to generate molecular diversity rapidly. Under Lewis acid catalysis, a vinylogous Mannich reaction was monitored as it generated a δ‐amino‐α‐silyloxy‐α,β‐unsaturated ester, which upon hydrolysis to the corresponding α‐keto ester spontaneously reacted in a [3+2] cycloannulation to the final pyrrolo[2,1‐b]benzoxazole. The kinetic data were compared with predictions of quantum chemical calculations to elucidate and verify or exclude reaction pathways and mechanisms for a possible rational optimization of the reaction. The simplicity and rapid response of this approach make it a very powerful technique for online characterization of chemical reactions on timescales spanning several orders of magnitude. This enables full control over chemical reactions, thereby maximizing the product yield. This combined experimental and theoretical approach opens up a new route for the study of novel chemistry in liquid‐phase reactions. Caught in the act: Infrared‐free liquid MALDI mass spectrometry enabled the quantitative tracing of the reactant, product, and intermediate concentrations during a complex chemical reaction. A complex, catalytically initiated vinylogous Mannich reaction on its way to form the final benzoxazole was investigated in detail. Through combination of the experimental MS analysis with theoretical DFT calculations and kinetic modeling the complete reaction mechanism was resolved.