Chapter I

1.1 Motivation Since its inception in the mid-1980’s, matrix assisted laser desorption/ionization (MALDI) has revolutionized analytical and biological chemistry by making possible the detection of large, intact biological molecules in the gas phase. This technique also motivated improvements in mass spectrometry, resulting in significant improvements in resolution and mass accuracy for biological analysis. These accomplishments were recognized with the partial award of the 2002 Nobel Prize in Chemistry. While the contributions of MALDI to the study of biological molecules clearly represent the technique’s most significant advances, MALDI is a generic analytical technique that has also been applied to a wide range of materials and disciplines. Improvements of the technique with regard to applications, equipment and new classes of compounds, continue to be developed. However, the analytical successes of MALDI have proceeded at a faster rate than the understanding of the fundamental processes, and there is every reason to expect that improved understanding of these processes, in addition to satisfying scientific curiosity, will motivate further advances. The fact that MALDI is a general process, accommodating a wide range of materials and experimental conditions, while making it particularly useful, complicates efforts to define the underlying mechanisms. In fact, it is generally acknowledged that a standard model of MALDI is not likely to exist. Historically, laser mass spectrometry of biological molecules was limited those having molecular weights less than ~10,000 amu. Larger molecules could not be desorbed with laser energies beneath values that induced fragmentation. The key breakthrough realized in MALDI was the use of a matrix material to absorb laser energy and lead to the dissolution of the sample and liberation of the larger biomolecules into the gas-phase. The matrix was originally chosen to match an available laser wavelength that was also not strongly absorbed by the biomolecule, limiting the coupling of energy into the molecule that might result in undesirable photochemistry and fragmentation. The matrix also serves to assist in the ion formation of the analyte through