Mass spectrometric kinetic method for molecular recognition: From *chiral analysis to isomeric quantification

Lianming Wu, Purdue University

Abstract

Mass spectrometric kinetic method for chiral analysis has many attractive features (it is fast, simple and accurate, there is no requirement for isotopic labeling, it is tolerant to impurities, and a commercial instrument can be used) and it allows rapid determination of very low enantiomeric excess, a challenging issue faced by the pharmaceutical industry. Recently, it has been successfully extended to rapid and accurate chiral and isomeric quantification, including ternary mixture analysis of optical and positional isomers as well as binary and ternary mixture analysis of different amino acids. The technique uses electrospray ionization or sonic spray ionization to generate the trimeric cluster ions followed by collision-induced dissociation (CID) in commercial ion trap and quadrupole/time-of-flight mass spectrometers. The dissociation kinetics is examined by the kinetic method, a sensitive linear free energy method of treating mass spectrometric results and converting them to thermochemical data. Chiral analysis of amino acids, α-hydroxy acids, antiviral nucleoside agent and some chiral drugs, as well as isomeric quantification of positional isomeric peptides, is demonstrated. The fixed-ligand kinetic method has been developed to improve accuracy in chiral and isomeric analysis by controlling and simplifying the dissociation kinetics. The key innovation is to replace one of the reference ligands with a fixed ligand (Lfixed) So that it is not lost during CID. By changing the properties (size, functionality, and chirality) of the fixed ligands, the metal-ligand and ligand-ligand interactions can be optimized to maximize chiral recognition. The generality of this approach is explored using antibiotics, peptides, and sugars. Further, multiple single-point calibration curves could be constructed using the fixed-ligand quotient ratio method by reversing the chirality of the fixed ligands and the reference ligands. This provides a solution when only one analyte has known optical purity. The fixed-ligand kinetic method allows one to accurately determine less than 2% enantiomeric excess.

Degree

Ph.D.

Advisors

Cooks, Purdue University.

Subject Area

Analytical chemistry

COinS