Evaluation of fluorine-mediated intermolecular interactions in tetrafluorinated tetrahydroisoquinoline derivatives: synthesis and computational studies

Abstract

Intermolecular interactions involving the aromatic C—F group in the absence of other strong hydrogen bond acceptors is the theme of this article. Weak interactions involving fluorine are known to generate various supramolecular synthons, thereby altering the crystal structures of small organic molecules. It is demonstrated that the weak interactions involving organic fluorine play a major role in directing crystal packing of highly flexible organic molecules like diphenyl tetrahydroisoquinolines reported herein. The intramolecular C—H...F hydrogen bonds are found to be significant in controlling the molecular conformation in specific cases wheras the intermolecular interactions involving the C—F groups result in a wide range of supramolecular synthons involving C—H...F and C—F...F—C interactions. The interactions are studied computationally to provide insight into their energies and the topology of the interactions is studied using Atoms in Molecules. C—H...F—C interactions are found to be quite stabilizing in nature with the stabilization energy of −13.9 kcal mol−1.

Structural and Computational Analysis of Organic Fluorine-Mediated Interactions in Controlling the Crystal Packing of Tetrafluorinated Secondary Amides in the Presence of Weak C–H···O═C Hydrogen Bonds

“…The mono- and difluorinated amides ( 2 ) enabled us to evaluate the intermolecular interactions involving fluorine in the presence of a strong hydrogen bond . The third library of molecules ( 6 ) offered a platform to understand fluorine-mediated interactions in the absence of other intermolecular interactions involving oxygen, which has been discussed elsewhere . Herein, we intend to report synthesis, spectroscopic and structural characterization, and computational analysis of various weak intermolecular interactions and their importance in altering the crystal structures of isomeric tetrafluorinated secondary amides ( 4 ) shown in Scheme in the absence of strong hydrogen bonds but in the presence of weak hydrogen bonds.…”

“…64 The third library of molecules ( 6) offered a platform to understand fluorinemediated interactions in the absence of other intermolecular interactions involving oxygen, which has been discussed elsewhere. 65 Herein, we intend to report synthesis, spectroscopic and structural characterization, and computational analysis of various weak intermolecular interactions and their importance in altering the crystal structures of isomeric tetrafluorinated secondary amides (4) shown in Scheme 1 in the absence of strong hydrogen bonds but in the presence of weak hydrogen bonds. The following scheme (Scheme 2) represents the naming of the molecules synthesized and used in the manuscript.…”

Investigation of C–F···F–C Interactions Using Experimental and Theoretical Charge Density Analyses

“…In the earlier studies on fluorinated compounds by some of us, we encountered that several of them crystallize via weak C–F···F–C and C–H···F–C interactions. , Further, we selected a few of those compounds for a detailed understanding of C–F···F–C interactions. In the current manuscript, we report the charge density studies of weak interactions mediated by organic fluorine in N -(2,5-difluorophenyl)-3,5-difluoro- N -(3-methoxyphenethyl)­benzamide ( 1 , Scheme ) using experimental X-ray diffraction data and theoretical structure factors generated from periodic calculations.…”

“…Among the halogens, fluorine is regularly found in drugs and pharmaceuticals, and its presence makes that molecule biologically active. In contrast, the corresponding nonfluorinated analogue is observed to be biologically inactive. − Recently, some of us have performed thorough geometrical analysis to understand the role of organic fluorine in various systems like substituted methanol, monosubstituted isoquinolines derivatives, disubstituted isoquinolines derivatives, tetrasubstituted isoquinolines derivatives, azobenzenes, N -benzylideneanilines, etc. These studies revealed that the interactions offered by organic fluorine could be utilized in building various robust supramolecular architectures.…”