Evaluation of the interchangeability of C–H and C–F groups: insights from crystal packing in a series of isomeric fluorinated benzanilides{{ Deepak Chopra and T. N. Guru Row* Received 29th June 2007, Accepted 17th August 2007 First published as an Advance Article on the web 6th September 2007 DOI: 10.1039/b709938j A series of mono- and difluorinated benzanilides have been synthesized and characterized to unravel the importance of interactions involving organic fluorine. The effect of fluorine substitution on the molecular conformation and the solid-state organization of the molecules in the crystalline lattice have been discussed in terms of changes in molecular conformation and the supramolecular aggregation. It is noteworthy that the meta- and para-isomers (mono and difluorinated) are isostructural, with the ortho-isomers possessing minor conformational variations. Furthermore, the molecular conformation as obtained by theoretical DFT calculations is different from the solid-state conformation highlighting the importance of co-operative features brought by N–H … O and C–H … O hydrogen bonds, along with weak intermolecular interactions involving organic fluorine and aromatic C–H … p contacts in the solid state. Introduction Non-covalent forces play an important role in processes like folding and self-assembly. 1 In recent years, chemists have been engaged in the development of foldamers 2 and artificial molecules that utilize non-covalent forces to modulate folding or helical architectures. In this regard the strong directional characteristics associated with hydrogen bonds like O–H … O, 3 N–H … O 4,5 and N–H … N 6,7 are highly effective in the assembly of supramolecular structures. Recently there has been a lot of interest invoked in fluorine containing com- pounds in the field of medicine and agrochemicals. 8 Although it has been well established that the fluoride ion acts as a very strong proton acceptor 9,10 it has been reported that covalently bonded fluorine is a very weak intermolecular hydrogen-bond acceptor. 11,12 Intermolecular interactions in fluoro-aromatic molecules such as C–H … F, C–F … p and C–F … F–C contacts have been the focus of recent structural, photophysical, topochemical, polymorphism and DSC studies. 13–17 Amongst intermolecular interactions involving fluorine, C–H … F bonds have directional characteristics and are stabilized by electro- static forces, 13 C–F … p interaction 14 is considered as destabi- lizing and F … F interactions are ubiquitous 16 and recent studies in polymorphism 16b unravel the importance of these weak but important interactions. Most of the previously reported studies on such C–H … F–C hydrogen bonds have been limited to a selection of compounds where potential strong hydrogen bond donors and acceptors are absent. 18 However it has been reported that weak intermolecular inter- actions involving halogens are also observed in the presence of strong hydrogen bonds like O–H … O and N–H … O. 19 In addition to steric and electrostatic factors, two other effects could determine the changes involved depending on the type of fluorine substitution pattern. The first is its electron with- drawing effect, which increases the acidity of close hydrogen atoms thus enhancing their capacity to participate in hydrogen bonding, and the second is the ability of the fluorine atom to participate in weak interactions. The latter aspect may be of particular relevance, and although it is documented that weak fluorine based interactions are easily overridden by the stronger heteroatom based intermolecular interactions, cases have been reported in which the crystal structure is controlled by weak interactions of the type C–H … F–C. 20 Furthermore, comparison of the structures of several of the fluorinated cyclopropanes with those of the non-fluorinated counterparts revealed that close intermolecular contacts of fluorine sub- stituents with hydrogen are not solely due to crystal packing effects but are caused by weak X–H … F–C hydrogen bridges. 21 Recently it has been observed that intra-molecular N–H … F hydrogen bonding could be used to promote the stability of hydrazide-based quadruple hydrogen bonded hetero-dimers. 22 Recent studies highlight that rationally designed crescent and helical conformations of aromatic amides utilizing intra- molecular N–H … F hydrogen bonding might provide a novel approach to the formation of rigid and well-established conformations. 23 All these studies no doubt improve the understanding of crystal packing in fluorine containing molecules, but the fact that such studies have been carried out on diverse molecular skeletons makes a proper analysis of various intermolecular interactions somewhat tedious. Furthermore, fluorinated organic compounds are widely used in the synthesis of pharmaceuticals and agrochemicals. Due to their favourable chemical and biological properties such as solubility and bioavailability, they enhance the Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore-560012, India. E-mail: ssctng@sscu.iisc.ernet.in.; Fax: 91-080-23601310; Tel: 91-080-22932796 { CCDC reference numbers 285374–285381. For crystallographic data in CIF or other electronic format see DOI: 10.1039/b709938j { Electronic supplementary information (ESI) available: Synthetic procedure (Scheme S1); amounts of reactants taken for the synthesis of benzanilides (Table S1); description of various measuring techniques applied; important vibrational spectroscopic assignments (Table S2); melting point of the prepared compounds (Table S3). See DOI: 10.1039/b709938j PAPER www.rsc.org/crystengcomm | CrystEngComm 54 | CrystEngComm, 2008, 10, 54–67 This journal is ß The Royal Society of Chemistry 2008