Using Equilibrium Isotope Effects To Detect Intramolecular OH/OH Hydrogen Bonds: Structural and Solvent Effects Thomas E. Vasquez, Jr., ² Jon M. Bergset, ² Matthew B. Fierman, ² Alshakim Nelson, ² Joshua Roth, ² Saeed I. Khan, ‡ and Daniel J. O’Leary* ,² Contribution from the Department of Chemistry, Pomona College, 645 North College AVenue, Claremont, California 91711, and Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, 405 Hilgard AVenue, Los Angeles, California 90024 Received August 17, 2001 Abstract: A comparative 1 H NMR study of partially deuterated 1,3- and 1,4-diols has demonstrated that intramolecular hydrogen bonds of different geometry can give rise to equilibrium isotope shifts of opposite sign in hydrogen-bond-accepting solvents such as DMSO-d6, acetone-d6, and THF-d8. The sign inversion is interpreted in terms of the ability of solvent molecules to form competitive intermolecular hydrogen bonds with the diol and in terms of the limiting chemical shifts for the interior and exterior hydroxyl groups. Deuterium is shown to prefer the intermolecular solvent hydrogen bond by 10.9 ( 0.5 cal/mol for 1,4-diol 3 dissolved in DMSO-d6 at room temperature. Pyridine-d5 is shown to be capable of amplifying positive (downfield) isotope shifts measured in DMSO-d6, in some cases by as much as a factor of 3. Its use is demonstrated for the assignment of the syn or anti relative configuration of 2,4-pentanediol and for the amplification of isotope shifts used to detect intramolecular hydrogen bonds in R- and -cyclodextrin. Studies in apolar solvents such as CD 2Cl2 and benzene-d6 reveal that the isotope shift is negative (upfield) for all hydrogen bond geometries studied. Larger isotope shifts are measured in benzene-d6, and a rationale for this amplification is presented. The use of apolar solvents is particularly useful for assigning the syn or anti configuration of 2,4-pentanediol. Introduction The use of hydroxyl groups in solution-phase NMR structural studies presents experimental challenges, largely a consequence of rapid chemical exchange among hydroxyl groups and, in some cases, protic solvents. Hydroxyl exchange rates can be slowed by dissolving in DMSO-d 6 or acetone-d 6 , 1-5 by super- cooling 6 aqueous solutions, or by using organic cosolvents. 7,8 Recent work from our laboratory has demonstrated the feasibility of using OH/OH scalar coupling as a method for detecting spatially proximal hydroxyl groups. 9 Intramolecular OH/OH hydrogen bonds in carbohydrates can also be detected with isotope effects 10 manifest in the 1 H or 13 C NMR spectra of partially deuterated compounds, 11 a method referred to as SIMPLE (secondary isotope multiplets of partially labeled entities) NMR. This technique has been applied as a qualitative test for spatially proximal OH groups. One of the first systems studied with the SIMPLE method was the cyclodextrins (Figure 1). Results obtained from the cyclodextrins are reviewed here for the purpose of introducing how SIMPLE is used for hydrogen bond detection. When R-cyclodextrin is dissolved in DMSO-d 6 , sharp hydroxyl resonances are observed for OH-2, OH-3, and OH-6. When the hydroxyl groups are partially deuterated, either by prior exchange or by addition of an exchangeable deuterium source, new resonances are observed for OH-2 and OH-3 but not OH- 6. The intensity of the new isotopically shifted resonances was found to increase as the deuterium content within the sample increased. Furthermore, the OH-2 and OH-3 isotope shifts were found to be of opposite sign. In R-cyclodextrin, for example, * To whom correspondence should be addressed. E-mail: doleary@ pomona.edu. ² Pomona College. ‡ University of California, Los Angeles. (1) Corio, P. L.; Rutledge, R. L.; Zimmerman, J. R. J. Am. Chem. Soc. 1958, 80, 3163-3164. (2) Kivelson, D.; Kivelson, M. G. J. Mol. Spectrosc. 1958, 2, 518-523. (3) McGreer, D. E.; Mocek, M. M. J. Chem. Educ. 1963, 40, 358-361. (4) Chapman, O. L.; King, R. W. J. Am. Chem. Soc. 1964, 86, 1256-1258. 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