Online monitoring of small volume reactions using compact liquid chromatography instrumentation

A wide variety of analytical techniques have been employed for monitoring chemical reactions, with online instrumentation providing additional benefits compared to offline analysis. A challenge in the past for online monitoring has been placement of the monitoring instrumentation as close as possible to the reaction vessel to maximize sampling temporal resolution and preserve sample composition integrity. Furthermore, the ability to sample very small volumes from bench‐scale reactions allows the use of small reaction vessels and conservation of expensive reagents. In this study, a compact capillary liquid chromatography instrument was used for online monitoring of as small as 1 mL total volume of a chemical reaction mixture, with automated sampling of nanoliter‐scale volumes directly from the reaction vessel used for analysis. Analyses to demonstrate short‐term (∼2 h) and long‐term (∼ 50 h) reactions were conducted using tandem on‐capillary ultraviolet absorbance followed by in‐line mass spectrometry detection or ultraviolet absorbance detection alone, respectively. For both short‐ and long‐term reactions (10 and 250 injections, respectively), sampling approaches using syringe pumps minimized the overall sample loss to approximately 0.2% of the total reaction volume.