Inclusion of the Niflumic Acid Anion in β-cyclodextrin: A Solution NMR and X-ray Structural Investigation

Abstract

We report parallel solution and solid state studies of the inclusion of the anionic form of the non-steroidal anti-inflammatory drug niflumic acid (2-[[3-(trifluoromethyl)phenyl]-amino]-3-pyridinecarboxylic acid) in the host g -cyclodextrin ( g -CD). 1 H NMR data for the interaction between host and guest in aqueous solution recorded at 300 MHz indicated a strong preference for insertion of the trifluoromethylphenyl residue, rather than the pyridinecarboxylate moiety, in the host cavity. A 1:1 complex stoichiometry was determined by the continuous variation method utilising chemical shifts of both host and guest protons. Analysis of the data using a new flexible program developed for this purpose yielded an overall association constant K of 336 M m 1 at 298 K. The NMR data indicate a dynamic equilibrium between complexed and uncomplexed species but do not distinguish guest entry from the primary and secondary sides of the host. Reaction between the Cs + salt of niflumic acid and g -CD yielded the crystalline complex ( g -CD) 2 ·(Cs + niflumate m ) 4 ·22H 2 O whose single crystal X-ray structure was determined. A novel inclusion mode for this host, namely entry of guest trifluoromethylphenyl residues from both the primary and secondary sides, was revealed by the X-ray analysis.