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

Abstract

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.

Modular Synthesis of Dipyrroloquinolines: A Combined Synthetic and Mechanistic Study

“…Accordingly, we conducted liquid-beam IR-laser desorption mass spectrometry − on the Brønsted acid-triggered reaction of silyl enol ether 3a as this constitutes a very sensitive tool for the online detection of reaction intermediates (Figure ). , …”

In situ monitoring of photocatalyzed isomerization reactions on a microchip flow reactor by IR-MALDI ion mobility spectrometry

“…IR-MALDI is a very soft ionization method that allows detection of short-lived and sensitive intermediates. In the MS configuration applied in [3], the microbeam was situated in the high vacuum region of the MS, enabling the direct transfer of the intermediates into that region after IR-MALDI and thus their immediate detection. IR-MALDI-MS, at atmospheric pressure (AP), has been used to investigate a vinylogous Mannich reaction performed in continuous flow on a microchip [6].…”

“…Moreover, there is a controlled mixing of fluids, an enhanced reactivity due to the increased photon flux in photochemical reactions, and continuous multistep syntheses are possible [ 1 ]. Additionally, the product is constantly spatially separated from the irradiated reaction zone, which reduces the degree of photodegradation of products and increases the productivity of photochemical processes [ 2 , 3 ]. An overview of the photoreactions in capillary flow reactors can be found in [ 1 , 2 , 4 , 5 ].…”

“…Alternative to ESI, infrared microbeam matrix-assisted laser desorption and ionization (IR-MALDI in high vacuum) MS can be employed. This methodology was used to investigate the kinetics of the synthesis of pyrrolo[2,1-b]benzoxazoles [ 3 ]. IR-MALDI is a very soft ionization method that allows detection of short-lived and sensitive intermediates.…”

On-chip mass spectrometric analysis in non-polar solvents by liquid beam infrared matrix-assisted laser dispersion/ionization

“…IR-MALDI is mainly applied to analyze compounds in aqueous media, as the method utilizes water or alcoholic solvents as an absorbing matrix. The absorption of infrared light due to the OH stretch vibration of the aqueous or alcoholic medium is a prerequisite to promote the crucial generation of gas-phase ions of dissolved analytes [59][60][61][62][63][64]. While this works well for polar compounds, e.g., for biochemical applications, it severely restricts the application scope in synthetic organic chemistry where non-polar solvents are widely used.…”