Organic reactions of ionic intermediates promoted by atmospheric-pressure thermal activation.

Interest in “green chemistry” has made the development of environmentally benign alternatives to organic solvents and conventional acid catalysts an active area of investigation. The replacement of organic solvents with recyclable ionic liquids and supercritical carbon dioxide, as well as the replacement of acid catalysts by supercritical water (400 8C, 200 bar) and near-critical water (275 8C, 60 bar), has already been demonstrated in organic synthesis. These developments, and accompanying studies of reaction mechanisms under unusual conditions, have increased the interest in nontraditional ways of carrying out reactions and exploring their mechanisms. Several such approaches are based on mass spectrometry, the best established of which is the use of chemical ionization and gas-phase Brønsted acid/base reactions to generate the ions of interest. Mass spectrometry can be employed to study the reactivity of organic reactants by using electrospray ionization (ESI) to generate ionic reagents under ambient pressure. ESI has been widely used to ionize organic and biological samples, thus allowing compounds to be protonated at their basic sites or deprotonated at their acidic sites. The protonation process with ESI is known to occur even when the analyte is dissolved in pure protic solvents, such as water or methanol, without any added acids or bases. The dissociation equilibrium H2OQH + + OH and the electrochemical reaction 2H2OQ4H + + O2 + 4e [23] are proton sources. This phenomenon prompted us to use ESI as a mild alternative to acid catalysis for generating ionic intermediates in organic reactions. As the protonated analyte ions (potential reaction intermediates in solution-phase reactions) generated by ESI are thermalized by numerous collisions with third body gaseous molecules at atmospheric pressure, they must be activated to undergo reaction. We recently developed an atmospheric-pressure thermal activation method based on a heated coiled tube, which can be used, among other things, for protein/peptide ion dissociation and hence as an aid in sequencing. Herein we have employed this atmosphericpressure activation method to promote reactions of organic ions generated by electrosonic spray ionization (ESSI), a variant form of ESI. By using this strategy, several organic reactions, including the Fischer indole synthesis, the Borsche– Drechsel cyclization, and the pinacol rearrangement, have been successfully performed under mild conditions (Scheme 1 and Figure 1a).