Structural systematics and conformational analyses of a 3×3 isomer grid and three chlorinated relatives

The focus of our research is to bridge solid state structural studies with computational (ab initio) modelling methods by exploring the influence of different functional groups and their position in semi-rigid small drug-like molecules.1-3 A 3×3 isomer grid of nine N-(tolyl)pyridinecarboxamides (C13H12N2O) as NxxM (x = para-/meta-/ortho-) (Scheme 1A) has been synthesised and characterised to evaluate and correlate structural relationships from both solid-state (Table 1, Figs. 1,2,4) and ab initio calculations (Fig. 3). The effect of pyridinoyl group (Nx) and methyl group (xM) substitution patterns on molecular structure and conformations (syn/anti, Scheme 1B) from calculations (gas phase and solvated forms), as well as on crystal packing and conformations in solid state is explored, allowing evaluation and rationalisation of disorder and unexpected conformations in the solid state structures

Entry point into new trimeric and tetrameric imide-based macrocyclic esters derived from isophthaloyl dichloride and methyl 6-aminonicotinate

The one-step reaction of isophthaloyl dichloride with the 2-aminopyridine derivative (methyl 6-aminonicotinate) yields (i) a trimer-based macrocycle (EsIO)3 and (ii) a tetramer-based macrocycle (EsIO)4 in modest isolated synthetic yields (total of 25%), together with (iii) longer open-chain oligomers. The macrocyclisation relies on the semi-flexible imide hinge formed by reaction of the 2-amino(pyridine) functional group with two acyl chloride functional groups. The determining factors in macrocycle synthesis are (a) imide formation using the heteroaromatic ortho-N functionality; (b) the inherent ability of the imide to twist by 85-115 degrees from planarity (as measured by the CO...CO imide torsion angles and from computational calculations), thereby providing a hinge for macrocyclic ring closure or potentially (non)helical assembly in oligomer/polymer formation and (c) the conformational flexibility of the isophthaloyl group with meta-related carbonyl groups to twist and adopt either syn- or anti-conformations, although the syn-conformation is observed structurally for all isophthaloyl groups in both (EsIO)3 and (EsIO)4 macrocycles

Structural systematic studies and conformational analyses of a 3x3 isomer grid of fluoro-N-(pyridyl)benzamides; physicochemical correlations, polymorphism and isomorphous relationships

The effect of fluorine and pyridine N atom substitution patterns on molecular structure and conformation is probed in a 3 3 isomer grid (Scheme 1) of fluoro-N-(pyridyl)benzamides (Fxx) (C12H9N2OF, x = para-/meta-/ortho-) to evaluate and correlate structural relationships between the solid-state and ab initio calculations. Physicochemical comparisons are analysed with an extended series of three related 3 x 3 isomer grids. Our analysis integrates crystal structure analyses, computational chemistry and conformational analyses together with NMR data and physicochemical trends such as melting point analysis. This study concludes structural systematics survey of four fluoro/methyl substituted benzamide/pyridinecarboxamide isomer grids

Structural systematics of drug-like molecules: from benzamides to tennimides

A structural systematic study was undertaken on benzamides, carbamates and substituted benzamide derivatives as 3×3 isomer grids comprising N-(pyridyl)benzamide (Fxx and Mxx) (x = para-/meta-/ortho-) and N-(phenyl)pyridinecarboxamide (NxxF and NxxM) grids. These were synthesised and characterised, with their crystal structures determined by single crystal X-ray diffraction. Five series of CxxR (R = CH3, OCH3, F, Cl, Br) carbamate isomer grids have been synthesised and characterised, with some pertinent structures determined by X-ray diffraction. Ab initio modelling, conformational analysis and comparisons of experimental solid state with optimised molecular geometries have facilitated an examination of the relationships between conformations and inter/intramolecular interactions, rationalisation of differences between the solid state and calculated structures, as well as the presence of molecular disorder and polymorphism. New classes of macrocycles have been developed including tetramers and trimers, based on our earlier research on benzamides and carbamates. These systems include various para-substituted derivatives (F, Cl, Br, CH3 CO2CH3) and have been fully characterized by 1H, 13C, 19F NMR and IR spectroscopy, while their crystal and molecular structures have been determined by single crystal X-ray diffraction. The development of tennimides and trezimides as new macrocycles based on an imide backbone, presents an important entry point into a potentially fruitful area. Furthermore, discovery of trezimides is especially important since no analogous macrocycle has been reported. Synthesis of tennimides and trezimides has been accomplished using a one-step synthetic strategy over a range of derivatives and presents a basis for synthesis of analogous macrocycles. Tennimides and trezimides proved to be rigid and stable compounds. The determining factors in the cyclisation are (i) the presence of the imide ortho-pyridine/pyrimidine rings and (ii) the inherent ability of the imide group to twist by 80-120°, as measured by the 'CO···CO' torsion angle, providing a 'hinge' for ring closure or helical assembly. The trezimides can adopt two distinct conformations in the solid state, (though one is preferred), whereas the tennimides adopt discrete conformational states as oc, cc and oo that highlight subtle macrocyclic geometric changes on cavity opening (o) and closing (c) (though these interconvert in solution)

Imide-based trezimide and tennimide macrocycles.

Reaction of isophthaloyl dichloride (I) with 2-aminopyridine or 2-aminopyrimidine (O, 26O) provides a facile entry into a new class of imide-based ‘3+3’ macrocyclic trimer (IO)3, (26IO)3 (as trezimides), together with the known tetramer (IO)4, (26IO)4 (tennimide) scaffold.1-5 Trezimides can adopt two asymmetric conformations, isolated as (P) in (IO)3 and (R) in (26IO)3.2,4 The tennimide (26IO)4 structure exhibits three discrete conformations as cc/oc/oo, highlighting subtle geometric changes with the tennimide channel (pore) open (o) and/or closed (c). Macrocycle formation (competing with oligomer/polymer formation) relies on the ortho-pyr(im)idine N functionality and imide hinge ('COCO' twist) with the inherent flexibility of the isophthaloyl groups (Figures 1-5)

Aggregation in isomeric imides: analysis of the weak interactions in six N-(benzoyl)-N-(2-pyridyl)benzamides

International audienceCrystal structures of 4-chloro-N-(4-chlorobenzoyl)-N-(2-pyridyl)benzamide (I) Clpod, 3-chloro-N-(3-chlorobenzoyl)-N-(2-pyridyl)benzamide (II) Clmod and 2-chloro-N-(2-chlorobenzoyl)-N-(2-pyridyl)benzamide (III) Clood together with three methylated analogues, Mpod, Mmod and Mood, are presented herein. The Clxod acyclic imides are produced from reacting the 4-/3-/2-chlorobenzoyl chlorides (Clx) with 2-aminopyridine (o), respectively, together with their benzamide analogues Clxo; the Mxod/Mxo triad are produced similarly and in good yield. The five Clxod, Mpod and Mmod structures adopt the open transoid conformations as expected, but Mood crystallises with cisoid oriented benzoyl groups, and this conformation was unexpected, though not unknown. Halogen bonding contacts and weak hydrogen bonding C-H···N/O/π contacts are noted in the structures lacking strong hydrogen bonding donor atoms/groups but possessing a variety of strong and weaker acceptor atoms/groups. For Clxod, contact studies show that both hydrogen and carbon account for a high percentage of elements (70–75%) on the molecular surface and being the most abundant have C···H forming 26–30% of the contacts. Contact enrichment ratios are an indicator of the likelihood of chemical species to form intermolecular interactions with themselves and other species. The C-H···N and C-H···O are the most enriched (with EHN > 2.15), indicating that these weak hydrogen bonds are the driving force in the Clxod crystal packing formation. For Mxod, the C···H contact type at 40–52% is the most abundant contact type and C-H···O and C-H···N weak hydrogen bonds dominate with enrichment values in the 1.48–1.78 range. In Mxod, N/O···N/O contacts are effectively absent, except for Mpod (0.2%, N···N contacts) and both H···H and C···C non-polar contacts are moderately impoverished while the C···H interactions are slightly enriched (E = 1.1–1.21)

Aggregation in Three Benzamide or Pyridylcarboxamide Hydrates: Formation of 1D Chains Comprising Water Molecules in a Chloro(pyridyl)benzamide Dihydrate

Three benzamide hydrated derivatives as para-methyl-N-(3-pyridyl)benzamide monohydrate (I) or Mpm ∙ H2O; N-(3-fluorophenyl)-4-pyridylcarboxamide monohydrate (II) or NpmF ∙ H2O and para-chloro-N-(3-pyridyl)benzamide dihydrate (III) or Clpm ∙ 2H2O are obtained from a series of crystallization experiments using a range of solvents to obtain polymorphs and solvates (hydrates). Most of the crystallization experiment attempts did not provide hydrates and yielded the starting parent crystalline materials. However, from the experiments, two benzamides, Mpm as a monohydrate and Clpm as a dihydrate were isolated and together with a carboxamide monohydrate as NpmF ∙ H2O are reported herein. The water molecules play a key role in crystal structure formation using classical hydrogen bonding via amide N–H···OH2, O–H···Npyridine and O–H···O=C interactions. They compensate for the excess of strong hydrogen bonding acceptors over donors in the benzamide/pyridinecarboxamide molecules, by participating as O-H hydrogen bond donors twice and usually as an O acceptor once. In the Clpm dihydrate, both water molecules form hydrogen bonded chains along the a-axis direction. The lack of hydrate formation in the majority of related benzamides is presumably related to the relative hydrophobicity of these compounds. This work is licensed under a Creative Commons Attribution 4.0 International License

Structure property relationships in halogenated aromatic amides and imides

The effect of halogens (X) and pyridine N atom substitution patterns on molecular structure and conformation is analyzed and discussed herein. Several series of 3 x 3 isomer grids (Scheme 1; Figs 1-3) of halo-N-(pyridyl)benzamides (Xxx) (C12H9N2OX, x = para-/meta-/ortho-) and their corresponding imides (Fig. 4) have been evaluated and correlated in terms of their structural relationships