Gas-Phase Chemistry DOI: 10.1002/ange.200800072 Organic Reactions of Ionic Intermediates Promoted by Atmospheric- Pressure Thermal Activation** Hao Chen, Livia S. Eberlin, Marcela Nefliu, Rodinei Augusti, and R. Graham Cooks* 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 [1,2] and supercritical carbon dioxide, [3] as well as the replacement of acid catalysts by supercritical water (400 8C, 200 bar) and near-critical water (275 8C, 60 bar), [4–6] has already been demonstrated in organic synthesis. These developments, and accompanying studies of reaction mech- anisms 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 reac- tions to generate the ions of interest. [7–15] Mass spectrometry can be employed to study the reac- tivity of organic reactants by using electrospray ionization (ESI) [16,17] to generate ionic reagents under ambient pres- sure. [18–22] ESI has been widely used to ionize organic and biological samples, thus allowing compounds to be protonat- ed 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 dissoci- ation equilibrium H 2 OQH + + OH À and the electrochemical reaction 2 H 2 OQ4H + + O 2 + 4e À [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, [24] which can be used, among other things, for protein/peptide ion dissociation and hence as an aid in sequencing. Herein we have employed this atmospheric- pressure activation method to promote reactions of organic ions generated by electrosonic spray ionization (ESSI), [25] 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 1 a). The Fischer indole synthesis, which involves formation of the ubiquitous indole ring system by reaction of an aryl hydrazine and a ketone or aldehyde, has remained a useful synthetic method for over 100 years. [26] Various catalysts have been used to effect the cyclization of aryl hydrazones derived from ketones, including Brønsted acids (H 2 SO 4 , HCl, PPA, AcOH, Brønsted acidic ionic liquids), [27, 28] Lewis acids (ZnCl 2 , TiCl 4 , PCl 3 ), [29] and solid acids (zeolite, montmoril- lonite clay). [30] The Borsche–Drechsel cyclization [31] is similar to the Fischer indole synthesis in that the reactant ketone is a cyclohexanone, although the product is a tetrahydrocarba- zole. A solution of the two reactants, phenylhydrazine (PhNHNH 2 ;2 mL) and cyclohexanone (2 mL), in methanol (1 mL) was analyzed by using ESSI. As directly observed by ESSI mass spectrometry (Figure 1 b), the protonated form of the condensation product, cyclohexanone phenylhydrazone, at m/z 189, is generated. However, the protonated tetrahy- drocarazole product ion (m/z 172) was not detected, thus indicating no observable cyclization had occurred. To facilitate Borsche–Drechsel cyclization, atmospheric- pressure thermal activation [24] was used to activate the protonated cyclohexanone phenylhydrazone (m/z 189). When the sprayed droplets from ESSI were directed into a stainless-steel coiled tube heated at 200 8C, the ion corre- sponding to protonated tetrahydrocarbazole (m/z 172) was generated (Figure 1c). The details of the activation process of protonated cyclohexanone phenylhydrazone have not been elucidated. As generated by ESSI, this ion is initially solvated and present in the electrosprayed microdroplets. As the ion is Scheme 1. Borsche–Drechsel cyclization promoted by thermal activa- tion and using ESSI to form the ionic intermediate (protonated hydrazone). [*] Prof. H. Chen, [+] L. S. Eberlin, M. Nefliu, Prof. R. G. Cooks Department of Chemistry Purdue University West Lafayette, IN 47907 (USA) Fax: (+ 1)765-494-9421 E-mail: cooks@purdue.edu Prof. R. Augusti Department of Chemistry Federal University of Minas Gerais Belo Horizonte, MG 31270-901 (Brazil) [ + ] Current address: Center for Intelligent Chemical Instrumentation Department of Chemistry and Biochemistry, Ohio University Athens, OH 45701 (USA) [**] This work was supported by the US National Science Foundation (CHE04-12782). Zuschriften 3470 # 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2008, 120, 3470 –3473