Chromatography Forum

I am not so clear why small molecules are not suitable for analyzing by LC/MS. Could you explain?
Thanks

I do not agree with your broad statement. Small is a relative term. There are many small molecules that can be analyzed by LC-MS such as TEA, pyridine, benzoic acid.... These all ionize well under LC-ESI-MS conditions. For analysis by LC-MS the molecule must have an ionizable group such as an amino nitrogen or carboxylic acid group. However, even some molecules without an N or acid group will ionize if they can form a stable carbocation or an odd radical ion. Many small molecules such as benzene cannot be analyzed by GC-MS since it does not have any functionality that will allow it to ionize under the soft LC-MS source condtions. Small molecules like ethanol would not ionize under ESI-MS conditions and is probably too volatile and its mass may be outside the range of some MS detectors. So mass range may also be a factor in whether LC-MS would be appropriate. Many small molecules can form clusters which can be hard to avoid under ESI mode. Whether LC-MS is used depends entirely on the compound and requirements of the method. A small molecule may ionize under LC-MS conditions but may not give the detection limit your method requires therefore you may have to use GC-MS, or consider other types of detectors (e.g. ELSD).

Absolutely! Nothing wrong with small molecules at all!

LC-MS generally doesn't work on volatile molecules, because it has to remove the solvent used in LC, and anything that removes volatile solvents also removes volatile analytes!

Electrospray relies on a molecule having a reasonably polar group, but small things can be polar too.

Most LC-MS systems have some sort of lower-limit on mass, but it's often really quite low. There are plenty of "small" molecules bigger than 50Da.

Even salt gives quite nice electrospray results. Yes, NaCl forms clusters, but the 3*3*3-ion cluster is always one of the strongest (this is 13NaCl+Na, or in negative mode, 13NaCl+Cl). This is actually a useful observation, and evidence that NaCl forms a cubic lattice even when very small numbers of ions are involved; many other ionic compounds form different lattices at vanishingly small abundance to the lattice they form at higher abundance (irrelevant but fun physical chemistry fact!).