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Proceedings of 12th ISMAS Symposium cum Workshop on Mass Spectrometry

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Investigation of the Ambiphilic Dual Activation Role of Water in Catalysing Organic Reactions: Electro Spray Ion Mass Spectrometry
Sunay V. Chankeshwara, Santosh Rudrawar and Asit K. Chakraborti* Department of Medicinal Chemistry National Institute of Pharmaceutical Education and Research (NIPER) Sector 67, S. A. S. Nagar, Punjab 160062 Email: akchakraborti@niper.ac.in Introduction: 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. Scheme 1. Strategies for the synthesis of benzothiazoles.
X N H S R B S R N C S NH2 A SH Y Z R

H(Cl/Br/SMe) N X = H, Cl, Br, I, SMe; Y = O, Se; Z = H, OH, OR, NH2 R = Aryl, Heteroaryl, Aryl alkyl, Alkyl, NHMe

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

12th ISMAS-WS-2007, March 25-30, 2007, Cidade de Goa, Dona Paula, Goa

Proceedings of 12th ISMAS Symposium cum Workshop on Mass Spectrometry

IRP-2

carbonyl carbon followed by elimination of H2O forms the thiazoline 1 which on dehydrogenation is converted to the thiazole. Scheme 2. The role of water during the reaction of an aldehyde with 2-aminothiophenol for benzothiazole synthesis.
SH H NH2 H2 O N H H Ar(R) TS - I SAr(R) Ar(R) N H N H OH2 + S O H H2O H

O (R)Ar H

H O

SAr(R) + N H OH

S Ar(R) N 1

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). Table 1. Potential transition state/intermediate in the formation of benzothiazoles. Entry Structure
H H H S N H H O O H

Mol. Formula

Exact Mass

Cl

C13H14ClNO2S
Cl

283.04

SN OH H H
+

C13H12ClNOS

265.03

12th ISMAS-WS-2007, March 25-30, 2007, Cidade de Goa, Dona Paula, Goa

Proceedings of 12th ISMAS Symposium cum Workshop on Mass Spectrometry


SH Cl

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N
S N H Cl

C13H10ClNS

247.02

C13H11ClNSCl

248.03

S N H S Cl

C13H10ClNS

247.02

C13H8ClNS

245.01

Figure 1. (a) TIC and (b) +pSIM spectrum of the reaction mixture after 10 min.

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.

12th ISMAS-WS-2007, March 25-30, 2007, Cidade de Goa, Dona Paula, Goa

Proceedings of 12th ISMAS Symposium cum Workshop on Mass Spectrometry

IRP-2

Reference 1. (a) J. H. Clark, Green Chem. (1999) 1. (b) P. Tundo, P. Anastas, D. S. Black, J. Breen, T. Collins, S. Memoli, J. Miyamoto, M. Polyakoff, W. Tumas, Pure Appl. Chem. 72 (2000) 1207. 2. (a) Organic Synthesis in Water: P. A. Grieco, Ed.; Blackie Academic and Professional: London (1998). C. J. Li, T. H. Chang, In Organic Reactions in Aqueous Media; Wiley: New York (1997). (b) N. Azizi, Saidi, M. R. Org. Lett. 7 (2005) 3649. (c) C.-J. Li, Chem. Rev. 105 (2005) 3095. 3. K. Manabe, S. Limura, X.-M. Sun, S. Kobyashi, J. Am. Chem. Soc. 124 (2002) 11971 and references therein. 4. (a) S. V. Chankeshwara, A. K. Chakraborti, Org. Lett. 8 (2006) 3259 (b) G. L. Khatik, R. Kumar, A. K. Chakraborti, Org. Lett. 8 (2006) 2433. 5. (a) A. K. Chakraborti, C. Selvam, G. Kaur, S. Bhagat, Synlett (2004) 851. (b) A. K. Chakraborti, Rudrawar, S.; Sharma, L; Kaur, G. Synlett (2004) 1533. (c) Rudrawar, S.; Kondaskar, A.; A. K. Chakraborti, Synthesis (2005) 2521 and the referentes therein. 6. (a) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. Int. Ed. Engl. 10 (1971) 496. (b) C. Larpent, H. Patin, Tetrahedron 44 (1988) 6107. (c) C. Larpent, G. Meignan, H. Patin, Tetrahedron 46 (1990) 6381. (d) G. Jenner, Tetrahedron 52 (1996) 13557. (e) X. Zhang, K. N. Houk, Tetrahedron Lett. 41 (2000) 3107. 7. X.; Zhang, K. N. Houk, J. Org. Chem. 70 (2005) 9712. 8. B. N. Pramanik, P. L. Bartner, U. A. Mirza, Y.-H. Liu, A. K. Ganguly, J. Mass. Spectrom. 33 (1998) 911. 9. W. Schrader, P. P. Handayani, C. Burstein, F. Glorius, Chem Commun. (2007) 716.

12th ISMAS-WS-2007, March 25-30, 2007, Cidade de Goa, Dona Paula, Goa