Approximating the Strength of the Intramolecular Hydrogen Bond in 2-Fluorophenol and Related Compounds: A New Application of a Classic Technique.

Abstract

Fluorinated organic compounds are ubiquitous in the pharmaceutical and agricultural industries. To better discern the mode of action of these compounds, it is critical to understand the strengths of hydrogen bonds involving fluorine. While established techniques can determine these strengths for intermolecular complexes, there is no analogous scheme for intramolecular hydrogen bonds. This work uses 1H nuclear magnetic resonance spectroscopy to measure the strength of intramolecular hydrogen bonds in ortho-substituted phenols. Titration of each phenol with DMSO in CCl4 yields a free energy of binding (ΔG). Subtraction of this value from the ΔG of binding of the standard, 4-fluorophenol, is shown to give the difference in ΔG for the cis and trans isomers of the ortho-substituted phenols. This difference is conventionally taken to be approximately equal to the ΔG of the intramolecular hydrogen bond. These data complement theoretical methods, which yield slightly larger ΔGs. Both theory and experiment point to a weak intramolecular hydrogen bond in 2-fluorophenol. The other 2-X-phenols have stronger hydrogen bonds, following the order F < Cl ≈ Br < OCH3. The methodology developed here can be readily applied to other systems with intramolecular hydrogen bonds.