Substitution reactions in ionic liquids. A kinetic study Bradley Y. W. Man, James M. Hook and Jason B. Harper * School of Chemistry, University of New South Wales, Sydney NSW 2052, Australia Received 12 May 2005; revised 3 August 2005; accepted 12 August 2005 Available online 9 September 2005 Abstract—The rate of the substitution reaction of (R)-3-chloro-3,7-dimethyloctane (1) with either methanol or benzyl alcohol in mixtures containing the ionic liquid [Bmim][N(CF 3 SO 2 ) 2 ] was monitored using 35 Cl NMR spectroscopy. The enantiomeric excess of the product, (S)-3-methoxy-3,7-dimethyloctane (2a), was analyzed using chiral gas chromatography. This product showed a decreasing enantiomeric excess with increasing concentration of ionic liquid. The rate of reaction of substrate 1 in each case varied with the concentration of the ionic liquid. Polarity measurements of the solvent mixtures were undertaken by standard methods, which are compared both to each other and to the observed rates. Solvent reorganization and selective solvation are also each pro- posed as contributing to the difference in the observed rates of reaction. Ó 2005 Elsevier Ltd. All rights reserved. Ionic liquids have attracted considerable attention in recent years due to their unique properties, such as lack of measurable vapour pressure. 1 These properties have led to a variety of successful applications, ranging from industrial processes to green chemistry. 2,3 However, many processes carried out in ionic liquids proceed very differently when compared to those in traditional organ- ic solvents. Examples include changes in the rates and the selectivities of Diels–Alder reactions 4 and changes in the reactivity of organometallic catalysts. 3 While there are numerous reports of such differences, limited work has been done to explain these observations. 5,6 To understand the effects of ionic liquids on organic reactions, a simple nucleophilic substitution was tar- geted; the solvolysis of 3-chloro-3,7-dimethyloctane (1) is in either methanol or benzyl alcohol containing the ionic liquid [Bmim][N(CF 3 SO 2 ) 2 ](Fig. 1). While previous studies of this solvolysis reaction by Mu ¨ller et al. 7 and Takeuchi et al. 8 investigated the cause of the significant amounts of inversion seen for the process, our study focused on the effects of the ionic liquid on the rate of the solvolysis reaction and the enantiomeric excess of the product 2a. This is a particularly useful system, as it allows the study of the rate of the formation of the carbocation without the need to consider the nucleophilicity of the nucleo- phile. 5 Since ionic liquids are involatile, the reaction mixture cannot be directly analyzed using gas chroma- tography. Any attempts to remove the ionic liquid through flash chromatography would likely alter the mixture composition, leading to inaccurate results. Heteronuclear magnetic resonance spectroscopy inves- tigating a range of nuclei was examined and 35 Cl NMR spectroscopy proved to be a practical method based on the preliminary experiments. This method is consistent with the conductivity and titrimetric meth- ods developed by Takeuchi et al. 9 A drawback that may affect the use of 35 Cl NMR spec- troscopy, and is evident with the conductivity and the titrimetric methods, is that it cannot distinguish between events, which may release chloride. The two avenues for chloride release in this case are the formation of the carbocation and the elimination of hydrogen chloride to form alkenes. Given that the second possibility 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.08.064 Keywords: Ionic liquids; 35 Cl NMR spectroscopy; Substitution reac- tion; Kinetics. * Corresponding author. Tel.: +61 2 9385 4692; fax: +61 2 9385 6141; e-mail: j.harper@unsw.edu.au i) 1 2a R = CH 3 , ee = 61 -14% 2b R = CH 2 Ph OR Cl ee = 70% N N + S N S CF 3 F 3 C O O O O [Bmim][N(CF 3 SO 2 ) 2 ] Figure 1. Solvolysis of the linalool derivative 1 to give an ether: (i) ROH, NEt 3 , [Bmim][N(CF 3 SO 2 ) 2 ]. Tetrahedron Letters 46 (2005) 7641–7645 Tetrahedron Letters