Structural Analysis of Glycosyl Cations and Other Intermediates Using Cryogenic Infrared Spectroscopy

Knowing the structure of reactive intermediates can yield unprecedented insight into organic reaction mechanisms. In particular for glycosyl cations – the reactive intermediates in glycosylations – the stereoselectivity of the reaction could be predicted by knowing the structure of the intermediate. The structure reveals whether an acyl protecting group of the monosaccharide unit interacts with the positively charged anomeric carbon so that it would shield one side from nucleophilic attack and thus steer the stereoselectivity of the reaction. These postulated approaches have been termed neighboring-group and remote participation. However, the short lifetime of reactive intermediates impedes their structural characterization in solution. Hence, for glycosyl cations, the structure remained elusive until very recently. These intermediates are not intrinsically unstable, but well-defined minima on the potential energy surface. Therefore, the ionic intermediates can be generated inside the vacuum of a mass spectrometer, free from nucleophiles or solvent molecules. In this environment, the isolated intermediates are stable and can subsequently be characterized using spectrometric or spectroscopic techniques. Recent advances in instrumentation allow coupling mass spectrometers with infrared lasers for infrared ion spectroscopy. Thus, highly-resolved infrared spectra of the analyte ions can be obtained by using cryogenic infrared spectroscopy in helium nanodroplets. To assign the obtained spectrum to a structure, it can be compared to harmonic frequencies of promising candidate structures calculated using density functional theory. This workflow was successfully used to determine the structure of several glycosyl cations, based on which, a new selective building block for 1,2-cis galactosylations was developed and its stereoselectivity was rationalized. Furthermore, it was determined that c-fragments of RNA dinucleotides are identical to the intermediate of RNA autohydrolysis. Finally, potentially antiaromatic carbocations were investigated.

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