Chemoselective Nucleophilic Fluorination Induced by Selective Solvation of the S N 2 Transition State Josefredo R. Pliego, Jr.* and Dorila Pilo ´ -Veloso* Departamento de Quı ´mica, UniVersidade Federal de Minas Gerais 31270-901, Belo Horizonte, MG, Brazil ReceiVed: October 6, 2006; In Final Form: December 1, 2006 Reaction of the fluoride ion with secondary alkyl halides leads to 90% of elimination reaction and only 10% of nucleophilic substitution in dipolar aprotic solvents. Adding water to the organic phase, the S N 2 yield increases in the cost of decreased reactivity. Using ab initio calculations, we have shown that it is possible to increase the reaction rate and the selectivity toward the S N 2 process through supramolecular organocatalysis. The catalytic concept is based on selective solvation of the transition state through two hydrogen bonds provided by the 1,4-benzenedimethanol. The two hydrogen bonds between the catalyst and the S N 2 transition state favor this pathway while just one strong hydrogen bond between the catalyst and the fluoride ion leads to a lower stabilization of the nucleophile, resulting in a higher reaction rate. Our calculations predict that the substitution product increases to 40% yield because of the selective catalysis provided by the 1,4- benzenedimethanol. Introduction Synthesis of organofluorine compounds has increased spec- tacularly in recent decades because of interesting and techno- logically useful properties obtained through introducing fluorine into organic molecules. 1-5 Demand for organofluorine species has induced a noticeable development in new reagents and catalysts aimed to perform efficient and selective fluorination, 6-19 and important advances have been achieved through both nucleophilic and electrophilic fluorination (Scheme 1). Never- theless, one of the most obvious and economically viable methods, nucleophilic fluorination of alkyl halides or sulfonate esters using alkaline fluorides salts, remains as a highly utilized procedure. Indeed, direct attachment of fluorine to organic molecules via nucleophilic displacement of halide ions utilizing KF requires inexpensive and readily available reagents. Nucleophilic fluorination is usually carried out in dipolar aprotic solvents or in apolar solvents using a phase-transfer catalyst such as tetraalkylamonium cations or crown ethers. Nevertheless, fluoride ion is not only a reactive nucleophile. Gas-phase studies show that it is a powerful base, 20-22 and a common side reaction of the interesting S N 2 pathway is the bimolecular elimination reaction. 8,14,23,24 In the liquid phase, this E2 process becomes the most important pathway when second- ary alkyl halides are used and makes the S N 2 process very inefficient. Thus, the search for new media, catalysts, or procedures aimed to induce chemoselective fluorination is highly desirable. In fact, emerging reaction media such as ionic liquids have also been recently studied for conducting nucleophilic fluorination but the same problem of low selectivity has also been reported. 25,26 Performing the reaction under high pressure is another investigated procedure and although improved S N 2 yields have been obtained, the process is not sufficiently selective. 27 A new approach for catalyzing organic reactions, where purely organic molecules are utilized as catalysts, 28-58 has emerged in recent years. Among these molecules, hydrogen bond based organocatalysts are specially attractive for control- ling ionic reactions in aprotic solvents. 59-61 In this way, considering the important role that selective nucleophilic fluorination could have in the efficient and environmental friendly preparation of organofluorine compounds, we have theoretically investigated the catalysis of S N 2 and E2 reactions through selective solvation of the transition state by two hydrogen bonds (Figure 1), a new concept proposed by Pliego in a recent report. 61 In this approach, two hydrogen bonds between the catalyst and the center of charge of the S N 2 transition state lead to rate acceleration and selectivity of the nucleophilic displacement process. The aim of the present paper is to show, via ab initio calculations, that this supramolecular organocatalytic concept can selectively induce nucleophilic fluorination. In fact, theoretical calculations are becoming powerful tools for understanding the reaction mechanism and designing new organocatalysts. 62-69 The Role of Hydrogen Bond in Nucleophilic Fluorination Fluoride ion is a very reactive species in the gas phase. Because it is a small ion with high charge/volume ratio, its solubilization in aprotic solvents is very difficult, and even in highly polar aprotic solvents like dimethyl sulfoxide (DMSO), the solubility of alkaline fluoride salts is limited. Phase-transfer catalysis is an usual procedure undertaken to solubilize fluoride salts. Liotta and Harris 18 have reported the use of crown ethers for solubilizing KF in acetonitrile and benzene solutions. The naked fluoride ion was utilized for nucleophilic displacement of alkyl halides. They observed that for 2-bromooctane, a high * E-mail: josef@netuno.qui.ufmg.br (J.P.), dorila@zeus.qui.ufmg.br (D.P-V.). SCHEME 1 1752 J. Phys. Chem. B 2007, 111, 1752-1758 10.1021/jp066580p CCC: $37.00 © 2007 American Chemical Society Published on Web 02/01/2007