Experimental, SOPPA(CCSD), and DFT analysis of substitutent effects on NMR 1 JCF coupling constants in fluorobenzene derivatives

Abstract

Interesting insight into the electronic molecular structure changes associated with substituent effects on the Fermi contact (FC) and paramagnetic spin-orbit (PSO) terms of 1JCF NMR coupling constants (SSCCs) in o-X-, m-X-, and p-X-fluorobenzenes (X = NH2; NO 2) is presented. The formulation of this approach is based on the influence of different conjugative and hyperconjugative interactions on a second-order property, which can be qualitatively predicted if it is known how they affect the main virtual excitations entering into that second-order property. A set of consistent approximations are introduced in order to analyze the behavior of occupied and virtual orbitals, which define some experimental trends for 1JCF spin-spin coupling constants. In addition, DFT hybrid functionals were used, and a similar degree of confidence to compute the 1JCF with those observed for the SOPPA(CCSD) method was obtained. The 1JCF SSCCs for ezetimibe, a commercially fluorinated drug used to reduce cholesterol levels, were measured and DFT-calculated, and the qualitative approach quoted above was applied. As a byproduct, a possible method to determine experimentally a significant PSO contribution to 1JCF SSCCs is discussed. © 2011 American Chemical Society.