At the Interface of Isomorphous Behavior in a 3 × 3 Isomer Grid of Monochlorobenzamides: Analyses of the Interaction Landscapes via Contact Enrichment Studies

Abstract

The physicochemical properties of a 33 isomer grid of mono-chlorobenzamides (Clxx) are reported with comprehensive studies of their crystal structures and interaction environments (Clx = para-/meta-/ortho-chlorobenzoyl and x = para-/meta-/orthoaminopyridine substitutions). The nine compound Clxx series was synthesised from the three p-/m-/o-chlorobenzoyl chlorides and three p-/m-/o-aminopyridine isomers using standard synthetic procedures. Clxx exhibits some similarities to the related Fxx and Brxx congeners e.g. the isomorphous behaviour of Clpp (para-Chloro-N'-(parapyridyl)benzamide) with several close relatives, and there are five isomorphous pairs of Clxx and Brxx crystal structures. Notably Clmp and Clpm both crystallise with Z'=4 in space group P but show important differences. The overall lack of isomers crystallising with solvate molecules is noteworthy, except for Clmm(H 2 O). In all Clxx crystal structures, strong N-H…N hydrogen bonds form, however, Clpo also crystallises as the unexpected Clpo_O polymorph with N-H…O=C intermolecular hydrogen bonding. The Clxo triad (with orthopyridines) exhibits the expected cyclic N-H…N dimer formation with R 2 2 (8) hydrogen bonded rings. The H C atom type, forming weak C-H…Cl hydrogen bonds, is the only favoured interaction partner of chlorine in Clxx. Conformational analyses (gas phase) together with crystal contact enrichment studies place Clxx in context and at the interface of hydrogen and halogen bonding interactions, though strong hydrogen bonding dominates. In Clxx the interaction energies with nearest neighbours are shown to contribute to most of the lattice electrostatic energies. The melting temperatures T m show correlation with both molecular symmetry (Carnelley's rule) and total electrostatic energy of the weak interactions; in addition, these T m values can be well predicted from a linear fit combining both descriptors. In Clxx, N-H…N hydrogen bonds dominate, largely in the absence of solvates, and with five Clxx forming isomorphous pairs with Brxx analogues; Clpp being isomorphous with several close benzamide relatives. Analysis of T m reveals correlations involving both symmetry and electrostatic energies.

Probing the Electronic Properties and Interaction Landscapes in a Series of N-(Chlorophenyl)pyridinecarboxamides

“…The nine N -(chlorophenyl)pyridinecarboxamide crystal structures ( NxxCl ) are grouped in triads for structural comparisons with pertinent structural data presented in Tables 1 and 2 . Comparisons are made with the Clxx series 56 (as their amide-bridge reversed isomers) together with the related NxxF , 50 (methyl) NxxM , 51 and NxxBr analogues. 54 …”

“…Overall, 2D sheets interlock into a 3D structure by using 2 × (C13–H13···O1=C1) and 2 × (C1=O1···H13–C13) weak H-bonds per aggregate. This hydrate aggregation is similar to related benzamide hydrates with all strong hydrogen bonding donors and acceptors used ( e.g ., in Clpm· 2 H 2 O 75 and Clmm·H 2 O ( 56 )). The closest contacts with the para -chlorine Cl14 atom involve three H atoms (H23, H25, and H26) on symmetry related molecules but with all of the H···Cl14 distances larger than 3.0 Å.…”

“… 18 Such pairs are observed to adopt the same space group, number of molecules in the unit cell, and reduced unit cell parameters (within 1 Å). Using this, our study aimed to compare the Clxx grid 56 with the NxxCl series and make structural comparisons with the Brxx and NxxBr analogues. 54 …”

“… 63 , 64 The computational calculations 65 − 67 were performed as described previously. 56 Optimizations and conformational analyses in the gas phase were performed using the DFT method [B3LYP/6-311++G(d,p)]. 66 , 67 All calculations were performed using Gaussian09 65 for Linux/Unix operating on an SGI Altix ICE 8200EX high-performance computing system at the ICHEC (Galway, Ireland).…”

Properties and interactions – melting point of tribromobenzene isomers

“…Numerous studies have been dedicated to the rules and factors affecting the melting point that could be calculated as the quotient of enthalpy and entropy of melting (Carnelley, 1882;Beacall, 1928;Holler, 1948;Gavezzotti, 1995;Brown & Brown, 2000;Boese et al, 1999;Thalladi & Boese, 2000;Thalladi et al, 2000a,b,c;Katritzky et al, 2001;Bujak et al, 2008;Joseph et al, 2011;Podsiadło et al, 2012Podsiadło et al, , 2013Yalkowsky & Alantary, 2018;Gallagher et al, 2019). The studies showed that the location of substituents in molecules and their ability to form intermolecular interactions cannot be neglected when explaining the melting-point differences of isomers.…”