The Fascinating History of the Development of LC-MS; a Personal Perspective

Today LC-MS is considered as a commonplace analytical tool that has been around for years. Most users do not give a second thought to the history of the development of this fascinating technique. It is twenty years since the first commercial instrument dedicated to atmospheric pressure ionisation (API) was produced by a small and then unknown company called Sciex, and so now is probably a good time to review some of the significant
challenges that were faced to develop the technique.

I would like to take you through some of the pioneering work that was carried out in this area, and discuss some of the exotic approaches that were taken by the pioneers of LC-MS prior to the API breakthrough. I have been working in mass spectrometry for nearly 40 years, and I consider myself fortunate to have grown up during the various stages in the development of LC-MS. What I have attempted to do in this article is give you a personal view of what I consider some of the landmarks on the road to achieving the perfect interface between LC and MS and how that technique plays a major part in the analytical chemists daily life.

Let me take you back to 1968 when the first ever attempt to interface these two apparently incompatible techniques together was published in the Russian Journal of Physical Chemistry by Victor Tal’rose [1]. This was a landmark publication for its time, because it was the first attempt connect LC to MS. They managed to spray a very small amount of liquid into a conventional high voltage electron impact mass spectrometer. This was no mean feat, as the ionisation source in the mass spectrometer needed to be at high vacuum (10-7 torr). Liquid produces a lot of gas as the pressure is reduced, and so this was seen by the mass spectrometry community as an incredible feat, and lots of excitement was generated around this direct liquid introduction (DLI) approach. However, it was soon realised that electron impact, due to its inability to deal pressures in excess of 10-6 Torr, was not going to be a practical approach and interest waned. In 1973 Baldwin and McLafferty recognised that this approach could be viable if the liquid was sprayed into a chemical ionisation source as the amount of liquid entering the mass spectrometer could be increased [2]. They developed a DLI LC-MS interface (Figure 1), which was more robust and was capable of generating a stable ion beam in the mass spectrometer; but the liquid flow rate was still very low.