A New Insight into Using Chlorine Leaving Group and Nucleophile Carbon Kinetic Isotope Effects To Determine Substituent Effects on the Structure of S N 2 Transition States Kenneth C. Westaway,* ,² Yao-ren Fang, ² Susanna MacMillar, ‡ Olle Matsson,* ,‡ Raymond A. Poirier,* ,§ and Shahidul M. Islam § Department of Chemistry and Biochemistry, Laurentian UniVersity, Sudbury, Ontario P3E 2C6, Canada, Department of Biochemistry and Organic Chemistry, Uppsala UniVersity, P.O. Box 576, SE-751 23 Uppsala, Sweden, and Department of Chemistry, Memorial UniVersity, St. John’s, Newfoundland and Labrador A1B 3X7, Canada ReceiVed: April 17, 2007 Chlorine leaving group k 35 /k 37 , nucleophile carbon k 11 /k 14 , and secondary R-deuterium [(k H /k D ) R ] kinetic isotope effects (KIEs) have been measured for the S N 2 reactions between para-substituted benzyl chlorides and tetrabutylammonium cyanide in tetrahydrofuran at 20 °C to determine whether these isotope effects can be used to determine the substituent effect on the structure of the transition state. The secondary R-deuterium KIEs indicate that the transition states for these reactions are unsymmetric. The theoretical calculations at the B3LYP/aug-cc-pVDZ level of theory support this conclusion; i.e., they suggest that the transition states for these reactions are unsymmetric with a long NC-C R and reasonably short C R -Cl bonds. The chlorine isotope effects suggest that these KIEs can be used to determine the substituent effects on transition state structure with the KIE decreasing when a more electron-withdrawing para-substituent is present. This conclusion is supported by theoretical calculations. The nucleophile carbon k 11 /k 14 KIEs for these reactions, however, do not change significantly with substituent and, therefore, do not appear to be useful for determining how the NC-C R transition-state bond changes with substituent. The theoretical calculations indicate that the NC-C R bond also shortens as a more electron-withdrawing substituent is placed on the benzene ring of the substrate but that the changes in the NC-C R transition-state bond with substituent are very small and may not be measurable. The results also show that using leaving group and nucleophile carbon KIEs to determine the substituent effect on transition-state structure is more complicated than previously thought. The implication of using both chlorine leaving group and nucleophile carbon KIEs to determine the substituent effect on transition-state structure is discussed. Introduction The effect of substituents on the structure of the S N 2 transition state has been of major interest for several decades. 1-12 The major experimental tool used to determine the substituent effect on transition-state structure has been a kinetic isotope effect (KIE). Although many different types of KIEs have been used to probe the transition states of S N 2 reactions, 4,6-9,13-17 most of the studies have used leaving group KIEs to determine the relative lengths of C R -LG transition-state bonds. 1,4,9,15,18 Until recently, the interpretation of these KIEs was thought to be straightforward; i.e., it was believed that a larger leaving group KIE was indicative of greater C R -LG bond rupture in the transition state. However, a recent theoretical investigation of chlorine leaving group KIEs 19 indicated that the interpretation of these KIEs was not as straightforward as had been previously thought. In fact, this study showed that all of the chlorine leaving group KIEs for 26 S N 2 reactions with methyl chloride fell in a very narrow range of values and that there was no relationship between the magnitude of the KIE and the C R -Cl bond length in the transition state! The total KIE (k 35 /k 37 ) is the product of the tunneling KIE (KIE T ), the imaginary frequency ratio or temperature-independent factor (TIF), and the temperature- dependent factor (TDF) that represents the isotope effect on the vibrational contribution to the KIE, 20,21 eq 1 where R represents the isotopically substituted reactant, q indicates the transition state, µ i ) hν i /k B T, and the ν i ’s are the vibrational frequencies. The relationship between the magnitude of the KIE and the C R -Cl bond length in the transition state failed because the product of KIE T and TIF accounted for a significant portion of the total KIE and was not related to transition-state structure in any discernible way. This meant that one could not use the magnitude of the total KIE to estimate the C R -Cl transition-state bond length even though the TDF term of the KIE was related to the length of the C R -Cl bond in the transition state. 19 A subsequent study by Matsson, Paneth, Westaway and co-workers 22 has demonstrated that one can still use a leaving group chlorine KIE to determine the length of the C R -Cl bond in a reaction where the solvent has been varied, i.e., to determine the solvent effect on the length of the C R -Cl bond in an S N 2 transition state. The next question was whether one could use chlorine leaving group KIEs to determine the * Authors to whom correspondence should be addressed. E-mail: kwestaway@laurentian.ca; olle.matsson@biorg.uu.se; rpoirier@mun.ca. ² Laurentian University. ‡ Uppsala University. § Memorial University. 8110 J. Phys. Chem. A 2007, 111, 8110-8120 10.1021/jp0729765 CCC: $37.00 © 2007 American Chemical Society Published on Web 07/31/2007 Downloaded by CKRN CNSLP MASTER on July 28, 2009 Published on July 31, 2007 on http://pubs.acs.org | doi: 10.1021/jp0729765