The integration of LC-MS and NMR for the analysis of low molecular weight trace analytes in complex matrices

This review discusses the integration of liquid chromatography (LC), mass spectrometry (MS), and nuclear magnetic resonance (NMR) in the comprehensive analysis of small molecules from complex matrices. We first discuss the steps taken toward making the three technologies compatible, so as to create an efficient analytical platform. The development of online LC-MS-NMR, highlighted by successful applications in the profiling of highly concentrated analytes (LODs 10 mu g) is discussed next. This is followed by a detailed overview of the alternative approaches that have been developed to overcome the challenges associated with online LC-MS-NMR that primarily stem from the inherently low sensitivity of NMR. These alternative approaches include the use of stop-flow LC-MS-NMR, loop collection of LC peaks, LC-MS-SPE-NMR, and offline NMR. The potential and limitations of all these approaches is discussed in the context of applications in various fields, including metabolomics and natural product discovery.