Negative ion laser desorption/ionization time‐of‐flight mass spectrometric analysis of small molecules by using nanostructured substrate as matrices

Matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) is an excellent analytical technique for rapid and sensitive analysis of macromolecules such as polymers and proteins. However, the main drawback of MALDI‐TOF MS is its difficulty to detect small molecules with mass below 700 Da because of the intensive interference from MALDI matrix in the low mass region. In recent years there has been considerable interest in developing matrix‐free laser desorption/ionization by using nanostructured substrates to substitute the conventional organic matrices, which is often referred as surface‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (SALDI‐TOF MS). Despite these attractive features, most of the current SALDI‐TOF MS for the analysis of small molecules employ positive ion mode, which is subjected to produce multiple alkali metal adducts, and thus increases the complexity of the analysis. Different from the complicated adducts produced in positive ion mode, mass spectra obtained in negative ion mode are featured by deprotonated ion peaks without matrix interference, which simplifies the interpretation of mass spectra and detection of unknown. In this review, we critically survey recent advances in nanostructured substrates for negative ion LDI‐TOF MS analysis of small molecules in the last 5 years. Special emphasis is placed on the preparation of the nanostructured substrates and the results achieved in negative ion SALDI‐MS. In addition, a variety of promising applications including environmental, biological, and clinical analysis are introduced. The ionization mechanism of negative ionization is briefly discussed.