Mass Spectrometry-Based Identification of Ortho-, Meta- and Paraisomers Using Infrared Ion Spectroscopy

Distinguishing positional isomers, such as compounds having different substitution patterns on an aromatic ring, presents a significant challenge for mass spectrometric analyses and is a frequently encountered difficulty in, for example, drug metabolism research. Here, we demonstrate infrared ion spectroscopy (IRIS) as a promising new mass spectrometry-based technique that easily differentiates between positional isomers of disubstituted phenyl-containing compounds. By analyzing different substitution patterns over several sets of isomeric compounds, we show that IRIS produces a highly consistent and distinct pattern of IR bands, especially in the range between 650 and 900 cm^-1, that are mostly independent of the specific chemical functionality contained in the substituent group. These patterns are accurately predicted by quantum-chemically computed IR spectra and correspond well with tabulated IR group-frequencies known from conventional absorption spectroscopy. Therefore, we foresee that this method will be generally applicable to disubstituted phenyl-containing compounds and that direct interpretation of experimental IRIS spectra in terms of ortho-, meta- or para-substitution is possible, even without comparison to experimental or computationally predicted reference spectra. Strategies for the analysis of larger compounds having more congested IR spectra as well as of compounds having low (electrospray) ionization efficiencies are presented in order to demonstrate the broad applicability of this methodology.