Formation and Stability of N-Heterocyclic Carbenes in Water: The Carbon Acid pK a of Imidazolium Cations in Aqueous Solution Tina L. Amyes,* Steven T. Diver,* John P. Richard, Felix M. Rivas, and Krisztina Toth Contribution from the Department of Chemistry, UniVersity at Buffalo, SUNY, Buffalo, New York 14260 Received December 1, 2003; E-mail:tamyes@chem.buffalo.edu Abstract: We report second-order rate constants kDO (M -1 s -1 ) for exchange for deuterium of the C(2)- proton of a series of simple imidazolium cations to give the corresponding singlet imidazol-2-yl carbenes in D 2O at 25 °C and I ) 1.0 (KCl). Evidence is presented that the reverse protonation of imidazol-2-yl carbenes by solvent water is limited by solvent reorganization and occurs with a rate constant of kHOH ) kreorg ) 10 11 s -1 . The data were used to calculate reliable carbon acid pKas for ionization of imidazolium cations at C(2) to give the corresponding singlet imidazol-2-yl carbenes in water: pKa ) 23.8 for the imidazolium cation, pKa ) 23.0 for the 1,3-dimethylimidazolium cation, pKa ) 21.6 for the 1,3- dimethylbenzimidazolium cation, and pKa ) 21.2 for the 1,3-bis-((S)-1-phenylethyl)benzimidazolium cation. The data also provide the thermodynamic driving force for a 1,2-hydrogen shift at a singlet carbene: K12 ) 5 × 10 16 for rearrangement of the parent imidazol-2-yl carbene to give neutral imidazole in water at 298 K, which corresponds to a favorable Gibbs free energy change of 23 kcal/mol. We present a simple rationale for the observed substituent effects on the thermodynamic stability of N-heterocyclic carbenes relative to a variety of neutral and cationic derivatives that emphasizes the importance of the choice of reference reaction when assessing the stability of N-heterocyclic carbenes. It is 40 years since the striking report of Olofson and co- workers of facile deuterium exchange of the C(2)-proton of the 1,3-dimethylimidazolium cation (DMI) in D 2 O (Scheme 1). 1 The deprotonation of imidazolium cations at C(2) results in the formation of formally neutral carbon bases which are examples of nucleophilic singlet carbenes that are strongly stabilized by the presence of two heteroatoms at the carbenic center (Scheme 1). 2-6 The electron-rich nature of N-heterocyclic carbenes has led to their wide-ranging application in organometallic cataly- sis, 3,6,7 and they also serve as nucleophilic catalysts in several important reactions such as benzoin condensation 8-12 and acyl transfer. 13,14 Despite the isolation and characterization of a vast array of stable N-heterocyclic and other diamino carbenes, 2-4 there are no systematic data for the formation and stability of imidazol- 2-yl carbenes in aqueous solution at room temperature. More- over, the kinetic and thermodynamic acidity of the C(2)-proton of simple imidazolium cations has not been examined in the light of modern theories of proton transfer at carbon. We report here a study of the deuterium exchange reactions of the C(2)-proton for a series of simple imidazolium cations (Chart 1) in D 2 O at 25 °C and I ) 1.0 (KCl). The data are used to obtain reliable carbon acid pK a s for ionization of these imidazolium cations at C(2) to give the corresponding singlet imidazol-2-yl carbenes in water. We also report the first deter- mination of the thermodynamic driving force for a 1,2-hydrogen shift at a singlet carbene: K 12 ) 5 × 10 16 for rearrangement of (1) Olofson, R. A.; Thompson, W. R.; Michelman, J. S. J. Am. Chem. Soc. 1964, 86, 1865-1866. (2) Alder, R. W. In Carbene Chemistry; Bertrand, G., Ed.; FontisMedia S. A.; Marcel Dekker Inc.: New York, 2002; pp 153-176. (3) Bourissou, D.; Guerret, O.; Gabbaie, F. P.; Bertrand, G. Chem. ReV. 2000, 100, 39-91. (4) Arduengo, A. J., III Acc. Chem. Res. 1999, 32, 913-921. (5) Warkentin, J. In AdVances in Carbene Chemistry; Brinker, U. H., Ed.; JAI Press Inc.: Stamford, CT, 1998; Vol. 2, pp 245-295. (6) Herrmann, W. A.; Ko ¨cher, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2162- 2187. (7) Herrmann, W. A. Angew. Chem., Int. Ed. Engl. 2002, 41, 1290-1309. (8) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726. (9) Wanzlick, H. W.; Kleiner, H. J. Chem. Ber. 1963, 96, 3024-3027. (10) Lappert, M. F.; Maskell, R. K. J. Chem. Soc., Chem. Commun. 1982, 580- 581. (11) Teles, J. H.; Melder, J.-P.; Ebel, K.; Schneider, R.; Gehrer, E.; Harder, W.; Brode, S.; Enders, D.; Breuer, K.; Raabe, G. HelV. Chim. Acta 1996, 79, 61-83. (12) Miyashita, A.; Suzuki, Y.; Kobayashi, M.; Kuriyama, N.; Higashino, T. Heterocycles 1996, 43, 509-512. (13) Grasa, G. A.; Kissling, R. M.; Nolan, S. P. Org. Lett. 2002, 4, 3583- 3586. (14) Nyce, G. W.; Lamboy, J. A.; Connor, E. F.; Waymouth, R. M.; Hedrick, J. L. Org. Lett. 2002, 4, 3587-3590. Scheme 1 Published on Web 03/12/2004 4366 9 J. AM. CHEM. SOC. 2004, 126, 4366-4374 10.1021/ja039890j CCC: $27.50 © 2004 American Chemical Society