Experimental, SOPPA(CCSD), and DFT Analysis of Substitutent Effects on NMR ¹J_CF 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 (1)J(CF) NMR coupling constants (SSCCs) in o-X-, m-X-, and p-X-fluorobenzenes (X = NH(2); 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 (1)J(CF) spin-spin coupling constants. In addition, DFT hybrid functionals were used, and a similar degree of confidence to compute the (1)J(CF) with those observed for the SOPPA(CCSD) method was obtained. The (1)J(CF) 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 (1)J(CF) SSCCs is discussed.

Computational NMR coupling constants: Shifting and scaling factors for evaluating 1JCH

“…The fact that fitted couplings present a similar quality notwithstanding the used functional/basis set is not surprising. Previous DFT studies show that the substituent effects on coupling constants and chemical shifts are predicted correctly; that is, the qualitative trends of these effects are well reproduced although the calculated values vary more with experiments.…”

Computational 19F NMR. 1. General features

“…Some early computational work (aimed at benchmarking and validation) included F 2 as test molecule, which proved to be challenging [26][27][28]. Interest in modeling 19 F shifts has steadily continued, and several papers have appeared in the last decade aimed at general structural issues, solution chemistry and physical organic chemistry, [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] solid-state issues (especially the prediction of chemical shift tensors), [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] J-couplings [65][66][67][68][69][70][71][72]…”

F···HO intramolecular hydrogen bond as the main transmission mechanism for 1hJF,H(O) coupling constant in 2′‐fluoroflavonol

“…matches reasonably well with the corresponding values for 3 in Table , which were obtained using the PBE1PBE, B3LYP and BHandH functionals. The latter has been found to be accurate in estimating 19 F‐based couplings; therefore, the curve obtained at the B3LYP/6‐31g(d,p) is expected to be well reproduced.…”