The current environmental concerns encourages the development of “greener” conditions, where possible, and the tight legislation on the maintenance of greenness in synthetic processes insists on preventing generation of waste, avoiding the use of auxiliary substances (e.g., organic solvents, additional reagents) and minimizing energy requirement [1]. The use of water as reaction medium [2] has received considerable attention in the context of green chemistry for several reasons: (i) it is cheap, safe, and environmentally benign, (ii) reactions in aq medium eliminate the additional efforts in making the substrates and reagents dry before use and thus reduce/eliminate the consumption of drying agents, energy, and time, (iii) and the unique physical and chemical properties of water can be utilized to realize reactivity or selectivity that can not be attained in organic solvents [3].

Results and Discussion: In pursuit of our recent efforts to develop environmentally friendly synthetic methodologies [4], we planned to develop an efficient and environmentally benign synthesis of benzothiazoles in water as the existing methodologies (Scheme 1) [5] do not fulfill the projected requirements of sustainable chemistry. Through a model reaction of 4-chlorobenzaldehyde with 2-aminothiophenol, we realized that the role of water may not be merely to serve as a reaction medium and propose a distinct role of water as ambiphilic dual activation catalyst (Scheme 2). The role of water may be explained by Scheme 2 [6]. Hydrogen bond formation between water and the carbonyl oxygen atom of the aldehyde causes ‘electrophilic activation’ making the carbonyl group more susceptible to nucleophilic attack. The oxygen atom of water in turn forms hydrogen bond with the SH hydrogen atom of 2aminothiophenol and increases the electron density at the sulfur atom (nucleophilic activation). Electrostatic attraction between the carbonyl group and the nitrogen lone pair atom forms the TS I [7]. Intramolecular nucleophilic attack by the nitrogen atom on the carbonyl carbon followed by elimination of H2O forms the thiazoline 1 which on dehydrogenation is converted to the thiazole. The faster reaction in water compared to that in other solvents justified its catalytic assistance through the TS - I. The alternate path involving imine formation followed by intramolecular nucleophilic attack of the SH group to the C = N of the imine is ruled out as no imine was detected after 6 h at 100 °C when 3,4-dimethoxybenzaldehyde was treated with 4-aminothiophenol in water. However, imine formation from aldehyde and 2aminothiophenol was reported under microwave heating in ionic liquid. This further suggested that the reaction in water is fundamentally different than that in other solvents or in the absence of solvent. To establish the mechanistic course of the reaction, we thought that the use of mass spectroscopic techniques would enable to identify the various possible transition state structures invovled in the course of thiazole formation as ESIMS is an emerging technology for the study of non-covalent complexes [8] and has been used for investigating organocatalytic reactions [9]. Thus, +pSIM ESI studies were performed (figure 1) and the following ions were detected (Table 1) that established the proposed mechanism (Scheme 2). Conclusion: The ESI-MS has been found to be an excellent tool for the investigation of water catalyzed reactions. It was possible to detect the important intermediates that provides substantial experimental proof to the proposed ‘ambiphilic dual activation’ role of water in catalyzing the reaction.