Dr John F Gallagher
email: john.gallagher@dcu.ie

Mark Farrell

Niall Hehir

Pavle Mocilac

Emmanuel Aubert

Enrique Espinosa

Benoît Guillot

Christian Jelsch

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

Keywords: Chlorine, Crystal structure, Conformational analysis, Contact Enrichments, Correlation, Electrostatic energy, Halogen, Melting Points, Pyridine

établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction:

In the natural world, bromine and chlorine derivatives are pre-eminent amongst the >5000 known and naturally produced organo-halogen (RX) compounds (where R = alkyl/aryl; X = halogen). [START_REF] Gribble | Naturally Occuring Organohalogen Compounds -A Comprehensive Survey[END_REF][START_REF] Gribble | Naturally occurring organohalogen compounds[END_REF][3][START_REF] Gribble | The diversity of naturally produced organohalogens[END_REF][START_REF] Gribble | Recently Discovered Naturally Occurring Heterocyclic Organohalogen Compounds[END_REF][START_REF] Gribble | A recent survey of naturally occurring organohalogen compounds[END_REF] As such, naturally occurring fluorine and iodine compounds are much less common (at ca. 5% of the total). However, the recent and substantial rise in the use of fluorine in pharmaceuticals [START_REF] Müller | Fluorine in pharmaceuticals: Looking beyond intuition[END_REF][START_REF] Wang | Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001-2011[END_REF] and agrochemicals has been well documented. [START_REF] Banks | Organofluorine chemistry: Principles and Commercial Applications[END_REF][START_REF] Jeschke | The unique role of halogen substituents in the design of modern agrochemicals[END_REF][START_REF] Jeschke | Progress of modern agricultural chemistry and future prospects[END_REF][START_REF] Jeschke | Latest generation of halogen-containing pesticides[END_REF] The role and application of halogen atoms (and especially fluorine) in organic materials and pharmaceuticals has attracted widespread scientific interest. [START_REF] Yoder | Fluorinated amino acids in protein design and engineering[END_REF][START_REF] Luthe | Influence of fluoro-substitution on the planarity of 4-chlorobiphenyl (PCB 3)[END_REF][START_REF] Klösener | Effects of fluoro substitution on 4-bromodiphenylether (PBDE 3)[END_REF][START_REF] Babudri | Fluorinated organic materials for electronic and optoelectronic applications: the role of the fluorine atom[END_REF][START_REF] Berger | Organic fluorine compounds: a great opportunity for enhanced materials properties[END_REF][START_REF] Marsh | Fluorinated Proteins: From Design and Synthesis to Structure and Stability[END_REF][START_REF] Gillis | Applications of Fluorine in Medicinal Chemistry[END_REF] The net effect of halogens on the chemical and physical properties of molecules and ultimately on research applications is an on-going scientific focus. [START_REF] Gribble | Naturally Occuring Organohalogen Compounds -A Comprehensive Survey[END_REF][START_REF] Gribble | Naturally occurring organohalogen compounds[END_REF][3][START_REF] Gribble | The diversity of naturally produced organohalogens[END_REF][START_REF] Gribble | Recently Discovered Naturally Occurring Heterocyclic Organohalogen Compounds[END_REF][START_REF] Gribble | A recent survey of naturally occurring organohalogen compounds[END_REF][START_REF] Müller | Fluorine in pharmaceuticals: Looking beyond intuition[END_REF][START_REF] Wang | Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001-2011[END_REF][START_REF] Banks | Organofluorine chemistry: Principles and Commercial Applications[END_REF][START_REF] Jeschke | The unique role of halogen substituents in the design of modern agrochemicals[END_REF][START_REF] Jeschke | Progress of modern agricultural chemistry and future prospects[END_REF][START_REF] Jeschke | Latest generation of halogen-containing pesticides[END_REF][START_REF] Yoder | Fluorinated amino acids in protein design and engineering[END_REF][START_REF] Luthe | Influence of fluoro-substitution on the planarity of 4-chlorobiphenyl (PCB 3)[END_REF][START_REF] Klösener | Effects of fluoro substitution on 4-bromodiphenylether (PBDE 3)[END_REF][START_REF] Babudri | Fluorinated organic materials for electronic and optoelectronic applications: the role of the fluorine atom[END_REF][START_REF] Berger | Organic fluorine compounds: a great opportunity for enhanced materials properties[END_REF][START_REF] Marsh | Fluorinated Proteins: From Design and Synthesis to Structure and Stability[END_REF][START_REF] Gillis | Applications of Fluorine in Medicinal Chemistry[END_REF] The key differences between the F, Cl, Br and I halogens are best exemplified in their respective steric and electronic properties. How these impact on and modify steric properties and electronic molecular environments is important. While fluorine is usually classified separately to chlorine, the heavier halogens bromine and iodine are often classified together in terms of their general chemical behaviour. [START_REF] Gribble | Naturally Occuring Organohalogen Compounds -A Comprehensive Survey[END_REF][START_REF] Gribble | Naturally occurring organohalogen compounds[END_REF][3][START_REF] Gribble | The diversity of naturally produced organohalogens[END_REF][START_REF] Gribble | Recently Discovered Naturally Occurring Heterocyclic Organohalogen Compounds[END_REF][START_REF] Gribble | A recent survey of naturally occurring organohalogen compounds[END_REF][START_REF] Yoder | Fluorinated amino acids in protein design and engineering[END_REF][START_REF] Luthe | Influence of fluoro-substitution on the planarity of 4-chlorobiphenyl (PCB 3)[END_REF][START_REF] Klösener | Effects of fluoro substitution on 4-bromodiphenylether (PBDE 3)[END_REF][START_REF] Babudri | Fluorinated organic materials for electronic and optoelectronic applications: the role of the fluorine atom[END_REF][START_REF] Berger | Organic fluorine compounds: a great opportunity for enhanced materials properties[END_REF][START_REF] Marsh | Fluorinated Proteins: From Design and Synthesis to Structure and Stability[END_REF][START_REF] Gillis | Applications of Fluorine in Medicinal Chemistry[END_REF] As such, organochlorine derivatives are generally studied as a distinct class and their behaviour and applications are readily contrasted with related organohalogens. [START_REF] Gribble | Naturally Occuring Organohalogen Compounds -A Comprehensive Survey[END_REF][START_REF] Gribble | Naturally occurring organohalogen compounds[END_REF][3][START_REF] Gribble | The diversity of naturally produced organohalogens[END_REF][START_REF] Gribble | Recently Discovered Naturally Occurring Heterocyclic Organohalogen Compounds[END_REF][START_REF] Gribble | A recent survey of naturally occurring organohalogen compounds[END_REF][START_REF] Müller | Fluorine in pharmaceuticals: Looking beyond intuition[END_REF][START_REF] Wang | Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001-2011[END_REF][START_REF] Banks | Organofluorine chemistry: Principles and Commercial Applications[END_REF][START_REF] Jeschke | The unique role of halogen substituents in the design of modern agrochemicals[END_REF][START_REF] Jeschke | Progress of modern agricultural chemistry and future prospects[END_REF][START_REF] Jeschke | Latest generation of halogen-containing pesticides[END_REF][START_REF] Yoder | Fluorinated amino acids in protein design and engineering[END_REF][START_REF] Luthe | Influence of fluoro-substitution on the planarity of 4-chlorobiphenyl (PCB 3)[END_REF][START_REF] Klösener | Effects of fluoro substitution on 4-bromodiphenylether (PBDE 3)[END_REF][START_REF] Babudri | Fluorinated organic materials for electronic and optoelectronic applications: the role of the fluorine atom[END_REF][START_REF] Berger | Organic fluorine compounds: a great opportunity for enhanced materials properties[END_REF][START_REF] Marsh | Fluorinated Proteins: From Design and Synthesis to Structure and Stability[END_REF][START_REF] Gillis | Applications of Fluorine in Medicinal Chemistry[END_REF] The control and manipulation of intermolecular interactions lies at the heart of understanding molecular aggregation and therefore plays a central role in design and applications across supramolecular chemistry, crystal engineering and structural sciences. 20- 24 Intra-and intermolecular interactions can play a role in influencing molecules towards the most favoured conformation(s) that are mostly retained in the crystal structure, [START_REF] Desiraju | The weak hydrogen bond in structural chemistry and biology[END_REF][START_REF] Domenicano | Strength from Weakness: Structural Consequences of Weak Interactions in Molecules, Supermolecules and Crystals[END_REF][START_REF] Nishio | CH/ hydrogen bonds in crystals[END_REF][START_REF] Dance | Molecules embracing in Crystals[END_REF][START_REF] Alvarez | A cartography of the van der Waals territories[END_REF][START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] but unusual geometries can be stabilised in the crystal state. The whole range of interactions typically observed in organic molecules ranges from strong hydrogen bonding e.g. N/O-H…O/N, through moderate hydrogen/halogen bonding [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] through to C-H…, aromatic donor-acceptor interactions to weaker contacts and van der Waals contacts. [START_REF] Desiraju | The weak hydrogen bond in structural chemistry and biology[END_REF][START_REF] Domenicano | Strength from Weakness: Structural Consequences of Weak Interactions in Molecules, Supermolecules and Crystals[END_REF][START_REF] Nishio | CH/ hydrogen bonds in crystals[END_REF][START_REF] Dance | Molecules embracing in Crystals[END_REF][START_REF] Alvarez | A cartography of the van der Waals territories[END_REF][START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] Halogen bonding, although recognised several decades ago has undergone an incredible surge in recent research activity. [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] While fluorine is often treated as a distinct entity, it is usually convenient to evaluate all of the halogens (F, Cl, Br I) to determine their steric and electronic influences on molecular structure and aggregation. [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF] From a structural chemistry viewpoint, the role of chlorine in organic structures has not attracted the same attention as fluorine (fluoro-containing drugs) or the bromine/iodine pair (from a fundamental research perspective). [START_REF] Müller | Fluorine in pharmaceuticals: Looking beyond intuition[END_REF][START_REF] Wang | Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001-2011[END_REF][START_REF] Yoder | Fluorinated amino acids in protein design and engineering[END_REF][START_REF] Luthe | Influence of fluoro-substitution on the planarity of 4-chlorobiphenyl (PCB 3)[END_REF][START_REF] Klösener | Effects of fluoro substitution on 4-bromodiphenylether (PBDE 3)[END_REF][START_REF] Babudri | Fluorinated organic materials for electronic and optoelectronic applications: the role of the fluorine atom[END_REF][START_REF] Berger | Organic fluorine compounds: a great opportunity for enhanced materials properties[END_REF][START_REF] Marsh | Fluorinated Proteins: From Design and Synthesis to Structure and Stability[END_REF][START_REF] Gillis | Applications of Fluorine in Medicinal Chemistry[END_REF][START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF][START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF] Despite this and given the major role of chlorinated compounds in the agricultural industry as insecticides and herbicides, [START_REF] Banks | Organofluorine chemistry: Principles and Commercial Applications[END_REF][START_REF] Jeschke | The unique role of halogen substituents in the design of modern agrochemicals[END_REF][START_REF] Jeschke | Progress of modern agricultural chemistry and future prospects[END_REF][START_REF] Jeschke | Latest generation of halogen-containing pesticides[END_REF] the present study serves as a template to examine the role of chlorine in a 33 chlorobenzamide isomer grid for direct comparisons with halogenated analogues. [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF][START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF] In previous work, the effects of methyl or fluorine were analysed for comparisons in series of benzamides and pyridinecarboxamides using extensive physicochemical measurements. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF] Macrocycles derived from benzamides and devoid of strong hydrogen bond donors have been reported and the effect of halogen bonding on their 1D and 2D structures noted. [START_REF] Mocilac | Trezimides and Tennimides: New Imide-Based Macrocycles[END_REF][START_REF] Mocilac | Halogen bonding directed supramolecular assembly in bromo-substituted trezimides and tennimides[END_REF][START_REF] Mocilac | Halogenated tennimides and trezimides: impact of halogen bonding and solvent role on porous network formation and inclusion[END_REF] Herein, a series of nine chlorobenzamide (Clxx) isomers as ClC 6 H 4 CONHC 5 H 4 N (Scheme 1) is presented. The nine compound Clxx series is synthesised from three p-/m-/o-chlorobenzoyl chlorides and three p-/m-/o-aminopyridine isomers using standard synthetic procedures: these are analogues of the fluorobenzamide (Fxx) isomer grid. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] We present the structures, conformational analyses and physicochemical properties of Clxx, together with highlighting correlations with crystal properties and molecular charge densities.

Materials, Methods and equipment

All chemicals, materials, vendors, spectroscopic and crystallographic methods together with computational programs and equipment are as noted previously. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF] Chemicals and silica (Davisil) were used as purchased from Sigma Aldrich, TLC alumina, silica plates from Fluka. Melting points were measured using a Stuart Scientific SMP40 automated melting point apparatus. IR spectroscopy was recorded using a Perkin Elmer Spectrum GX FTIR spectrometer by the ATR method: bands are quoted in cm -1 . NMR spectroscopy was performed on a Bruker BioSpin UltraShield NMR spectrometer (293±1 K), at 400 or 600 MHz for 1 H and 100.62 MHz for the [START_REF] Yoder | Fluorinated amino acids in protein design and engineering[END_REF] C resonance. The 1 H spectra were recorded in CDCl 3 with the [START_REF] Yoder | Fluorinated amino acids in protein design and engineering[END_REF] C spectra in CDCl 3 . The NMR chemical shift values () are in ppm, referenced to TMS and coupling constants (J) are quoted in Hz.

The single crystal X-ray data collections for all nine Clxx isomers as ten crystal structures (Clpp, Clmp, Clop, Clpm, Clmm, Clom, Clpo_O, Clpo_N, Clmo, Cloo; Scheme 1) together with data reduction, structure solution and refinements are typically routine. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF][START_REF]Oxford Diffraction Ltd ABSFAC and CrysAlisPro CCD/RED Version 1.171[END_REF][START_REF] Sheldrick | A short history of SHELX[END_REF][START_REF] Mcardle | SORTX -a program for on-screen stick-model editing and autosorting of SHELX files for use on a PC[END_REF] Selected crystallographic and structural information are as detailed in the ESI (Tables S1, S2a-c, pgs 5-10) [START_REF] Sheldrick | A short history of SHELX[END_REF][START_REF] Spek | Single-crystal structure validation with the program PLATON[END_REF] with pertinent structural details provided in the main manuscript in Tables 1,2. Molecular and hydrogen bonding diagrams (Figures 123456789) are depicted with displacement ellipsoids drawn at the 30% probability level. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Spek | Single-crystal structure validation with the program PLATON[END_REF][START_REF] Macrae | Mercury: visualization and analysis of crystal structures[END_REF] The computational calculations [START_REF] Frisch | Gaussian 09 Revision B.01[END_REF][START_REF] Becke | Density-Functional Thermochemistry. 3. The Role of Exact Exchange[END_REF][START_REF] Krishnan | Self-Consistent Molecular-Orbital Methods. 20. Basis Set For Correlated Wave-Functions[END_REF] are routine, [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF] with optimisations and conformational analyses in gas phase as performed using the DFT method [B3LYP/6-311++G(d,p)]. [START_REF] Becke | Density-Functional Thermochemistry. 3. The Role of Exact Exchange[END_REF][START_REF] Krishnan | Self-Consistent Molecular-Orbital Methods. 20. Basis Set For Correlated Wave-Functions[END_REF] All calculations were performed using Gaussian09 [START_REF] Frisch | Gaussian 09 Revision B.01[END_REF] for Linux/Unix operating on a SGI Altix ICE 8200EX high performance computing system at the ICHEC (Galway, Ireland). R-factor definitions as R[F 2 > 2(F 2 )], wR(F 2 ). 51

Methods [START_REF] Jelsch | Advances in protein and smallmolecule charge-density refinement methods using MoPro[END_REF][START_REF] Domagała | An improved experimental databank of transferable multipolar atom models-ELMAM2. Construction details and applications[END_REF][START_REF] Allen | Bond lengths in organic and metal-organic compounds revisited: X-H bond lengths from neutron diffraction data[END_REF][START_REF] Guillot | MoProViewer: a tool to study proteins from a charge density science perspective[END_REF][START_REF] Jelsch | Atom interaction propensities of oxygenated chemical functions in crystal packings[END_REF] Electrostatic energy calculations were performed with the MoProSuite software. [START_REF] Jelsch | Advances in protein and smallmolecule charge-density refinement methods using MoPro[END_REF] The multipolar electron density of the molecules was modelled by transfer of the ELMAM2 charge density database without further refinement. [START_REF] Domagała | An improved experimental databank of transferable multipolar atom models-ELMAM2. Construction details and applications[END_REF] The asymmetric unit content was rendered electrically neutral after charge density transfer by applying a uniform valence population shift to all atoms. The N-H and C-H bonds were elongated to standard distances obtained from neutron diffraction. [START_REF] Allen | Bond lengths in organic and metal-organic compounds revisited: X-H bond lengths from neutron diffraction data[END_REF] The electrostatic energy is computed over pairs of atoms using the Hansen and Coppens multipolar atom model. The lattice electrostatic energy was computed with the VMoPro module in real space. The software can compute the energy in successive parallelepiped shells around the unit cell. Convergence was achieved over the [-9a,9a]  [-9b,9b]  [-9c,9c] space around the molecule containing 19 3 unit cells.

The Hirshfeld surface and decomposition of intermolecular contacts in pairs of chemical species were computed around the different moieties of the asymmetric unit with the program MoProViewer. [START_REF] Guillot | MoProViewer: a tool to study proteins from a charge density science perspective[END_REF] The polar H N and hydrophobic H C atoms were distinguished. Crystal contact enrichment ratios were averaged, as noted by Jelsch and Bisseyou: S4-S7). Dimers Footnotes: C 6 is the (C11,...,C16) benzene ring and C 5 N is the (C21,...,C26) pyridine ring defined for the least squares (LS) planes in Scheme 2; the bridging amide plane is defined as the 5 atom C ipso -C(O)NC ipso (or C11, C1, O1, N1, C21) LS plane, with reference to Figures 123456789 2 and3.

Results and Discussion

Crystal structure results:

Nine Clxx benzamide isomers are reported (as ten crystal structures), presenting a wide variety of molecular geometries and structures, with Clpo or para-Chloro-N'-(orthopyridyl)benzamide crystallizing as the Clpo_N and Clpo_O polymorphs (N pyridine or O amide suffixes denote the primary intermolecular hydrogen bonding acceptor). There is isomorphous overlap between some Clxx structures with their Fxx, [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] NxxF, [START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF] Mxx [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] or NxxM [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF] isomer grid relatives (ESI, Figures S1,S2) and there is also structural similarity with the CxxM and CxxOMe carbamates. [START_REF] Mocilac | The First Phenyl-N-pyridinylcarbamate Structures: Structural and Conformational Analysis of Nine Methoxyphenyl-Npyridinylcarbamates[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of an isomer grid of nine tolyl-N-pyridinylcarbamates[END_REF] Computational studies in gas phase are analysed for comparisons directly with the crystal structure results. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF][START_REF] Frisch | Gaussian 09 Revision B.01[END_REF][START_REF] Becke | Density-Functional Thermochemistry. 3. The Role of Exact Exchange[END_REF][START_REF] Krishnan | Self-Consistent Molecular-Orbital Methods. 20. Basis Set For Correlated Wave-Functions[END_REF] Only salient features of each Clxx structure are presented, with further information in the ESI (Tables S1, S2a-c).

The Clpp, Clmp, Clop series: Isomorphism Clpp (Figure 1) crystallises in the monoclinic system (space group P2 1 /c, with Z=4) and augments a series of seven isomorphous compounds that includes the parent Hpp, [START_REF] Noveron | Engineering the structure and magnetic properties of crystalline solids via the metaldirected self-assembly of a versatile molecular building unit[END_REF] the Fpp, Fmp, Fop triad (Figure S2, ESI), [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Donnelly | Assembling an isomer grid: the isomorphous 4-, 3-and 2-fluoro-N'-(4-pyridyl)benzamides[END_REF] 25p, 67 Clpp and Brpp. [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] These molecules display varied peripheral H/F/Cl/Br atom-site positions and the resultant isomorphous series is unusual in that the structures have similar unit-cell parameters, packing and alignment but different interaction/contact geometries at the secondary level. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF][START_REF] Bombicz | The way from isostructurality to polymorphism. Where are the borders? The role of supramolecular interactions and crystal symmetries[END_REF][START_REF] Palma | Ni(II), Cu(II) and Zn(II) complexes of tetraphenylazadipyrromethene[END_REF][START_REF] Gelbrich | Structural systematics of 4,4'disubstituted benzenesulfonamidobenzenes. 1. Overview and dimer based isostructures[END_REF][START_REF] Gelbrich | The crystal structure of methyl paraben at 118 K does not represent a new polymorph[END_REF] Disparities are primarily due to the 0.30.7 Å differences between typical organic C-H/F/Cl/Br bond lengths (Å) and resulting directional influence of the peripheral X atoms on weaker interactions and contacts in their respective crystal structures. With increasing numbers of structures available on the CSD, [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF] it is expected that progress will be made towards forming a continuum where isomorphous series of molecules overlap with series of isostructural compounds. In fact, Mpp (para-Methyl-N'-(para-pyridyl)benzamide) bears a resemblance to Clpp and is considered as an isostructural relative. [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] In the literature there is considerable on-going interest on groups of isomorphous structures that exhibit structural diversity. [START_REF] Bombicz | The way from isostructurality to polymorphism. Where are the borders? The role of supramolecular interactions and crystal symmetries[END_REF][START_REF] Palma | Ni(II), Cu(II) and Zn(II) complexes of tetraphenylazadipyrromethene[END_REF][START_REF] Gelbrich | Structural systematics of 4,4'disubstituted benzenesulfonamidobenzenes. 1. Overview and dimer based isostructures[END_REF][START_REF] Gelbrich | The crystal structure of methyl paraben at 118 K does not represent a new polymorph[END_REF] The Clpp structure contains an intramolecular C26-H26…O1 contact (C26…O1 = 2.891(2) Å, C-H…O = 117). The classic N-H…N intermolecular interaction [N1…N24 i = 3.114(2) Å, 139.2(17); symmetry code i = 1-x, y+½, ½-z, ESI, Table S2a] with C(6) motif is the principal hydrogen bond and the remaining intermolecular interactions comprise C-H…O [3.3482(2) Å, 130] and Cl14…C() halogen bonding contacts [3.3269(18) Å, C14-Cl14…C21 xix = 150.10(7); symmetry code xix = x,½-y,½+z], [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] linking the non-planar molecules into a 3D structure (Figure 1), together with C-H… and aromatic stacking. [START_REF] Desiraju | The weak hydrogen bond in structural chemistry and biology[END_REF][START_REF] Nishio | CH/ hydrogen bonds in crystals[END_REF][START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] Clpp forms part of an isomorphous series that widens the structural scope of a group of similar structures. 40 [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] Clmp crystallises in the triclinic system (space group P , with Z=8), containing four independent molecules in the asymmetric unit (Z'=4) [START_REF] Brock | High-Z' structures of organic molecules: their diversity and organizing principles[END_REF][START_REF] Das | Two carbamate derivatives with Z'=2 and 3: An interplay of strong and weak hydrogen bonds[END_REF][START_REF] Steed | Packing Problems: High Z′ Crystal Structures and Their Relationship to Cocrystals, Inclusion Compounds, and Polymorphism[END_REF] (Figure 2). Trials in a subunit cell (with c-axis halved) in P2 1 /n gives a result with R = 0.11 having at least four non-H atoms with unusual displacement ellipsoids; this result was discarded. In Clmp the major differences between all four molecules (A, B, C, D) are exemplified by different O=CCC torsion angles [with a range >30, from 144.06( 14) to 177.91( 13)] and distinct N1-H1…N24 distances [0.25 Å, from 2.9431(16) Å to 3.1913( 16) Å]. However, the (A, B) and (C, D) molecules form distinct pairs that are broadly similar in conformation (Table 2). The aromatic rings in Clmp twist by between 5 and 11 relative to each other (i.e. by 5.19(4) in C; 10.98(9) in A), whereas the amide group is twisted away from both aromatic rings in molecules A and B only, as molecules C and D are essentially planar. The chlorine atom is located as Cl-syn relative to the amide N-H (as for Fmp). [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] An intramolecular contact is present as C22-H22…O1 in all four molecules in a d(C,O) range from 2.8073(17) to 2.8709( 16) Å, with angles 115 to 121. Molecules aggregate by N-H…N intermolecular interactions as ADAD… and BCBC… alternating pairs. The N1…N24 distances are 2.9431( 16), 3.1913(16) iii Å (for A, D) and 3.0120( 16), 3.1576 (16) ii Å (for B, C) with the C(6) motif forming zigzag chains parallel with (001). In addition parallel offset amide…arene stacking contributes to structural stability and packing, especially involving centrosymmetric related C molecules with short C…C contact distances of 3.32, 3.36 Å. [START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] Weaker intermolecular C-H…N/O hydrogen bonds also influence with C-H…N playing an auxiliary role to the N-H…N, in addition to weak C-H…Cl contacts. [START_REF] Desiraju | The weak hydrogen bond in structural chemistry and biology[END_REF][START_REF] Domenicano | Strength from Weakness: Structural Consequences of Weak Interactions in Molecules, Supermolecules and Crystals[END_REF][START_REF] Nishio | CH/ hydrogen bonds in crystals[END_REF][START_REF] Dance | Molecules embracing in Crystals[END_REF][START_REF] Alvarez | A cartography of the van der Waals territories[END_REF][START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] Molecules stack with the relatively planar (C green, D yellow) molecular pairs along the c-axis direction as (C…C…D…D…) and forming a herringbone arrangement with the A (red) and B (blue) pairs (packing diagram). The Clmp crystal structure contains two slightly different molecular geometries and stacking sequences in the (A, B) and (C, D) pairs with packing influences from the N-H...N hydrogen bonded chains and parallel offset … stacking effects. [START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] This may be a contributing factor in the isolation of the Clmp crystal structure with Z'=4. [START_REF] Brock | High-Z' structures of organic molecules: their diversity and organizing principles[END_REF][START_REF] Das | Two carbamate derivatives with Z'=2 and 3: An interplay of strong and weak hydrogen bonds[END_REF][START_REF] Steed | Packing Problems: High Z′ Crystal Structures and Their Relationship to Cocrystals, Inclusion Compounds, and Polymorphism[END_REF] Clop is isomorphous with the Brop crystal structure. [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] Molecules of Clop twist from nonplanar geometry (Figure 3) due to the influence of the ortho-Cl12 atom (Cl-syn) but the amido-pyridine group remains essentially planar due to the C26-H26…O1 intramolecular contact. Clop aggregates by intermolecular N1-H1…N24 hydrogen bonds into 1D chains [as C (6)] that are further linked into 2D sheets parallel with (001) by Cl12…O1 xxi halogen bonding interactions [Cl12…O1 xxi = 3.1104(18) Å; N c = 0.95], [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] with C12-Cl12…O1 = 161.09(8), Cl12…O1=C1 = 111.27 (12). The N-H…N interaction geometry is regular with N1…N24 vi = 3.010(3) Å (N1-H1…N24 vi = 175.9(18)), but the orientation is skewed towards 120 with N1…N24 vi …C21 vi (= 137). A C15-H15…O1 vii interaction is also noted. The Clpm, Clmm, Clom series: twinning and isomorphous behaviour. Clpm is a twinned structure with four molecules (A to D; Z'=4) [START_REF] Brock | High-Z' structures of organic molecules: their diversity and organizing principles[END_REF][START_REF] Steed | Packing Problems: High Z′ Crystal Structures and Their Relationship to Cocrystals, Inclusion Compounds, and Polymorphism[END_REF] 2). The N…N range is 3.150(4) to 3.203(4) Å and assisted by flanking C16 A/B/C/D /C26 A/B/C/D …N23 B/C/D/A interactions and contacts (with P-anti). Additionally C-H…Cl/O/ weak hydrogen bonds augment the intermolecular contacts. [START_REF] Desiraju | The weak hydrogen bond in structural chemistry and biology[END_REF][START_REF] Domenicano | Strength from Weakness: Structural Consequences of Weak Interactions in Molecules, Supermolecules and Crystals[END_REF][START_REF] Nishio | CH/ hydrogen bonds in crystals[END_REF][START_REF] Dance | Molecules embracing in Crystals[END_REF][START_REF] Alvarez | A cartography of the van der Waals territories[END_REF][START_REF] Martinez | Rethinking the term "pi-stacking[END_REF][START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF] Crystal structures with Z'=4 are uncommon though not unusual and have been encountered in related series; [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF][START_REF] Brock | High-Z' structures of organic molecules: their diversity and organizing principles[END_REF][START_REF] Das | Two carbamate derivatives with Z'=2 and 3: An interplay of strong and weak hydrogen bonds[END_REF][START_REF] Steed | Packing Problems: High Z′ Crystal Structures and Their Relationship to Cocrystals, Inclusion Compounds, and Polymorphism[END_REF] Mpm crystallises in the triclinic system (space group P1, with Z=Z'=4), [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] NmpF [START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF] and Clmp likewise (space group P , with Z=8 and Z'=4). One can surmise that two independent molecules (Z'=2) can be accommodated by N-H…N interactions in a 1-D chain. Statistically, structures with Z'=4 are considerably less likely to arise. [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF][START_REF] Brock | High-Z' structures of organic molecules: their diversity and organizing principles[END_REF][START_REF] Das | Two carbamate derivatives with Z'=2 and 3: An interplay of strong and weak hydrogen bonds[END_REF][START_REF] Steed | Packing Problems: High Z′ Crystal Structures and Their Relationship to Cocrystals, Inclusion Compounds, and Polymorphism[END_REF] The cumulative effects and strengths of aromatic stacking [START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] together with intermolecular contacts e.g. C16 A/B/C/D …N23 B/C/D/A may have a subtle but important impact on intermolecular organisation and packing. [START_REF] Desiraju | The weak hydrogen bond in structural chemistry and biology[END_REF][START_REF] Domenicano | Strength from Weakness: Structural Consequences of Weak Interactions in Molecules, Supermolecules and Crystals[END_REF][START_REF] Nishio | CH/ hydrogen bonds in crystals[END_REF][START_REF] Dance | Molecules embracing in Crystals[END_REF][START_REF] Alvarez | A cartography of the van der Waals territories[END_REF][START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] The Clmm(H 2 O) monohydrate is isomorphous with Brmm(H 2 O). [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] The Clmm(H 2 O) structure crystallises with three main hydrogen bonds driving aggregation using N1-H1…O1W ix , O1W-H2W…O=C i and O1W-H1W…N23. [START_REF] Desiraju | The weak hydrogen bond in structural chemistry and biology[END_REF][START_REF] Domenicano | Strength from Weakness: Structural Consequences of Weak Interactions in Molecules, Supermolecules and Crystals[END_REF][START_REF] Nishio | CH/ hydrogen bonds in crystals[END_REF][START_REF] Dance | Molecules embracing in Crystals[END_REF][START_REF] Alvarez | A cartography of the van der Waals territories[END_REF][START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] The former two interactions combine to form a R 4 4 (12) assembly with two H 2 O molecules sandwiched between two Clmm (as Cl-syn; P-syn) (Figure 5). The remaining O1W-H1W…N23 interaction links tetrameric [Clmm(H 2 O)] 2 assemblies via the pyridine N23 atom; each tetramer has two O1W-H1W donors and N23 acceptors for a total of four hydrogen bonds per assembly. Hydrogen bonding is maximised whereby three donor groups (N-H, 2  O-H) and three acceptors (O=C, O, N) participate with water playing a critical role in aggregation. In our isomer grids, benzamide hydrates are usually obtained from recrystallization in halogenated solvents or ethyl acetate. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF] They tend to have a meta-N pyridine atom favouring hydrogen bonded ring formation with water molecules incorporated (adventitiously) between benzamides. Clom adopts a (Cl-anti; P-anti) conformation with an intramolecular C22-H22…O1 interaction [2.8845(19) Å, 120)] and Cl12…O1 contact [Cl12…O1 = 3.1811(13) Å] (Figure 6). [START_REF] Desiraju | The weak hydrogen bond in structural chemistry and biology[END_REF][START_REF] Domenicano | Strength from Weakness: Structural Consequences of Weak Interactions in Molecules, Supermolecules and Crystals[END_REF][START_REF] Nishio | CH/ hydrogen bonds in crystals[END_REF][START_REF] Dance | Molecules embracing in Crystals[END_REF][START_REF] Alvarez | A cartography of the van der Waals territories[END_REF][START_REF] Martinez | Rethinking the term "pi-stacking[END_REF][START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] Clom is isomorphous with Brom, [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] and is similar in structure to Mom (M-anti; P-anti) aggregating with N-H…N chain formation. [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] This arrangement contrasts with Fom (F-syn; Panti) [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] having two intramolecular C-H…O contacts, an intramolecular N-H…F interaction and weak N-H…O=C chain association. As such, Clom molecules do not exhibit intramolecular N-H…Cl interactions but assemble by N-H…N interactions as 1-D chains along the c-axis direction. These are weakly linked into 2D sheets by C-H…O interactions and with type I halogen…halogen C arom -Cl…(Cl-C arom ) xxiv interactions of 3.3699(10) Å (Figure 6); though considerably longer than the aromatic C-Cl…Cl-C contact of 3.165(3) Å noted in (ClIO) 3 . [START_REF] Mocilac | Halogenated tennimides and trezimides: impact of halogen bonding and solvent role on porous network formation and inclusion[END_REF] The trade-off in interactions works for Clom and one can postulate that differences between Mom, [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] Fom, [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] and Clom derive from an intricate balance between intramolecular (mainly N-H…F interactions for F in Fom) and intermolecular (mainly N-H…N formation for Me (Mom) and Cl (Clom)) forces. It also suggests that that in terms of aggregation, the Fom polymorphs are rather unexpected and influenced by intramolecular forces. 43 The Clpo, Clmo, Cloo series: polymorphism in Clpo (Clpo_O and Clpo_N) [START_REF] Brittain | Polymorphism in Pharmaceutical Solids[END_REF][START_REF] Bernstein | Polymorphism in Molecular Crystals[END_REF][START_REF] Yu | Polymorphism in Molecular Solids: An Extraordinary System of Red, Orange, and Yellow Crystals[END_REF][START_REF] Brittain | Polymorphism and solvatomorphism[END_REF][START_REF] Steed | Understanding exceptional polymorphs[END_REF] Clpo crystallises as two polymorphs, both P-syn, (Figures 7,8; monoclinic system, space group C2/c, with Z=8: Z'=1). Thus Clpo_O (from ethyl acetate) forms intermolecular interactions as (i) N-H…O=C interactions in C( 4) chains along the b-axis direction with N1…O1 xi = 3.1296(14) Å, (ii) parallel offset ring stacking interactions with C1…C16 xxv = 3.3488 (19) Å and (iii) C15-H15…N22 xii interactions forming dimers [3.5199(19) Å] as R 2 2 (16) rings. [START_REF] Desiraju | The weak hydrogen bond in structural chemistry and biology[END_REF][START_REF] Domenicano | Strength from Weakness: Structural Consequences of Weak Interactions in Molecules, Supermolecules and Crystals[END_REF][START_REF] Nishio | CH/ hydrogen bonds in crystals[END_REF][START_REF] Dance | Molecules embracing in Crystals[END_REF][START_REF] Alvarez | A cartography of the van der Waals territories[END_REF][START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] Clpo_O with amide…amide interactions is distinctly different to the related orthopyridine (Yxo) structures (Y = Me, 45 F, [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] Cl (see below), Br), e.g. Mxo, Fxo (x = para-, meta-, ortho-) which aggregate as cyclic N-H…N hydrogen bonded dimers. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] The pyridine ortho-N atom facilitates the formation of compact R 2 2 (8) rings in the six Mxo and Fxo structures (as P-syn) with secondary interactions, e.g. interdimer interactions completing the structural interactions. The driving force towards Yxo hydrogen bonded dimer formation remains, and with a range of geometries available, despite both intramolecular (C-H…O) and intermolecular interactions competing (as above) to potentially disrupt dimer formation. Clpo_O though forms weakly held dimers that are comparable with the related Fpm_O [R 2 2 (18)], [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] nevertheless with a smaller hydrogen bonded ring size (16 atoms vs 18 atoms). Unexpectedly, and from crystallisation experiments attempts to obtain a series of benzamide hydrates, the Clpo_N polymorph was isolated from a mixture of acetonitrile and water. Clpo_N aggregates as hydrogen bonded N-H…N dimers (and similar to the six Fxo, Mxo), [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] linked together into a 1-D chain by weak C-H…O contacts, further linked by C-H…O contacts aligning along the c-axis direction. The anticipated Clpo_N structure has a lower than expected KPI (packing index) of 67.1 compared to 70.0 for (Clpo_O) and this is due to the presence of voids in Clpo_N (Table 3). [START_REF] Spek | Single-crystal structure validation with the program PLATON[END_REF] Analysis of the Clpo_N molecular packing shows channel formation but these voids are barely large enough to accommodate a hydrogen atom or H 2 molecule (Figure 8). In summary, there is a trade-off in crystallising Clpo as (a) Clpo_O with an increased number of moderate strength interactions (N-H…O=C, C-H…, N and C…C stacking) and optimum packing (70.0) at the expense of (b) the stronger expected N-H…N cyclic dimer formation in Clpo_N with looser packing (67.1). Of note is compound ROY which is an extraordinary example of a molecular compound having ten polymorphs isolated to date. [START_REF] Yu | Polymorphism in Molecular Solids: An Extraordinary System of Red, Orange, and Yellow Crystals[END_REF] In ROY there are four polymorphs crystallising in the monoclinic system (space group P2 1 /c) making it rather unusual to have a high number of polymorphs as a subset in one space group. 78 Clmo aggregates as cyclic N-H…N hydrogen bonded dimers and N-H… contacts (with slipped/stepped aromatic rings; Figure 9), contrasting with Clpo, though similar in molecular structure (dihedral angles) to Mpo. [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] The N1…N22 xv distance of 3.1990(17) Å is the longest in the nine Yxo hydrogen bonded dimers reported to date (for Y = Me, F, Cl). [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] The Mxo triad [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] forms symmetrical, planar dimers about inversion centres, whereas the Fxo series 43 aggregate as twisted hydrogen bonded dimers in Fpo (about a 2-fold axis) and with two independent molecules in the asymmetric units of Fmo, Foo (both crystallising in the triclinic system, space group P ). Of further note in Clmo is the lack of halogen bonding interactions of any consequence involving the chlorine atom Cl13, which is exclusively surrounded by several C-H atoms (ESI: Tables S4-S5).

Cloo is isomorphous with Broo, [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] and forms N-H…N hydrogen bonded dimers about 2-fold axes and is similar in conformation to Foo. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] Compact parallel offset heterocycle stacking interactions involving the ortho-pyridine rings dominate with short C24…C26 xxvii distances of 3.3049(18) Å about inversion centres (Figure 9). In tandem, C-H…(arene) contacts arise involving the aromatic C16-H16 and C23-H23 moieties with symmetry related benzene rings.

The aggregation can also be viewed as Cloo dimers that stack in columns in the b-axis direction with tight pyridine...pyridine stacking interactions contributing to form tightly interwoven 2-D sheets. For comparisons, although both Clmo and Cloo exhibit regular behaviour in their respective aggregation, for all three Clxo isomers the carbonyl atom O1 has barely any influence on molecular aggregation.

Figure 9:

The Clmo dimer and pyridine…pyridine ring parallel stacking interactions in Cloo.

Summary of the Clxx solid-state structural results

The notable structural results for the Clxx series are: (i) the Clpo_O, Clpo_N polymorphic pair [START_REF] Brittain | Polymorphism in Pharmaceutical Solids[END_REF][START_REF] Bernstein | Polymorphism in Molecular Crystals[END_REF][START_REF] Yu | Polymorphism in Molecular Solids: An Extraordinary System of Red, Orange, and Yellow Crystals[END_REF][START_REF] Brittain | Polymorphism and solvatomorphism[END_REF][START_REF] Steed | Understanding exceptional polymorphs[END_REF] (both as Z'=1 in space group C2/c) and with voids present in the Clpo_N polymorph, (ii) the Clmp and Clpm structures having a relatively high Z'=4 in the asymmetric unit, [START_REF] Brock | High-Z' structures of organic molecules: their diversity and organizing principles[END_REF][START_REF] Das | Two carbamate derivatives with Z'=2 and 3: An interplay of strong and weak hydrogen bonds[END_REF][START_REF] Steed | Packing Problems: High Z′ Crystal Structures and Their Relationship to Cocrystals, Inclusion Compounds, and Polymorphism[END_REF] which is rather uncommon in benzamide structures reported to date, [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] and (iii) the distinct lack of intermolecular Cl…O and Cl…N halogen bonding, apart from clear-cut cases such as Clop (as aromatic C-Cl…O=C interactions) and Clom (with aromatic C-Cl…Cl-C contacts). There is, however, a C-Cl… intermolecular contact where the Cl -hole faces the pyridine ring in Clpp at an angle (C-Cl,  ring centroid) = 163.34(7). [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] The Clxx isomer grid places in context the structural relationships that exist between isomer grids, e.g. Mxx, [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] Fxx [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] and Brxx. [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] Overall, the structural landscape is broad, but overlaps include (a) five Clxx isomers that are isomorphous with their Brxx 68 analogues as the Clpp/Brpp, Clop/Brop, Clmm/Brmm monohydrates, Clom/Brom and Cloo/Broo pairs, and (b) the Clpp isomer being isomorphous with several related structures, including the parent Hpp, [START_REF] Noveron | Engineering the structure and magnetic properties of crystalline solids via the metaldirected self-assembly of a versatile molecular building unit[END_REF] Fpp, Fmp, Fop triad, [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Donnelly | Assembling an isomer grid: the isomorphous 4-, 3-and 2-fluoro-N'-(4-pyridyl)benzamides[END_REF] 25p, 67 Clpp and Brpp. [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] Our results show the considerable overlap between the Clxx and Brxx 68 structures and greater differences with their Fxx and Mxx isomer grid analogues. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] The only molecular series where there is continuity between the structures is for the Xpp series, which is extensive at the isomorphous and isostructural level, especially so as it overlaps with Fpp/Fmp/Fop triad. Subtle differences at the molecular level do not impact on the overall molecular aggregation (isomorphous series) and differences between the crystal structures are noted at the secondary level. [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF][START_REF] Noveron | Engineering the structure and magnetic properties of crystalline solids via the metaldirected self-assembly of a versatile molecular building unit[END_REF][START_REF] Donnelly | Assembling an isomer grid: the isomorphous 4-, 3-and 2-fluoro-N'-(4-pyridyl)benzamides[END_REF][START_REF] Mcmahon | A structural systematic study of three isomers of difluoro-N-(4-pyridyl)-benzamide[END_REF][START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF][START_REF] Bombicz | The way from isostructurality to polymorphism. Where are the borders? The role of supramolecular interactions and crystal symmetries[END_REF][START_REF] Palma | Ni(II), Cu(II) and Zn(II) complexes of tetraphenylazadipyrromethene[END_REF][START_REF] Gelbrich | Structural systematics of 4,4'disubstituted benzenesulfonamidobenzenes. 1. Overview and dimer based isostructures[END_REF][START_REF] Gelbrich | The crystal structure of methyl paraben at 118 K does not represent a new polymorph[END_REF] Why is there such a considerable overlap between Clxx, Brxx but not with Fxx or Mxx?

In order to quantify the isomorphous relationships in the isomer grids studied to date, Table 4 is presented and highlights the isomorphous behaviour and relationships between various Yxx benzamide structures (Y = Me, 45 F, [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] Cl, this work Br 68 ; x = para-, meta-, ortho-). [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF][START_REF] Donnelly | Assembling an isomer grid: the isomorphous 4-, 3-and 2-fluoro-N'-(4-pyridyl)benzamides[END_REF][START_REF] Mcmahon | A structural systematic study of three isomers of difluoro-N-(4-pyridyl)-benzamide[END_REF][START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF][START_REF] Bombicz | The way from isostructurality to polymorphism. Where are the borders? The role of supramolecular interactions and crystal symmetries[END_REF][START_REF] Palma | Ni(II), Cu(II) and Zn(II) complexes of tetraphenylazadipyrromethene[END_REF][START_REF] Gelbrich | Structural systematics of 4,4'disubstituted benzenesulfonamidobenzenes. 1. Overview and dimer based isostructures[END_REF][START_REF] Gelbrich | The crystal structure of methyl paraben at 118 K does not represent a new polymorph[END_REF] Another set of relationships is to be expanded upon in the Clxx/NxxCl isomer series in future papers in addition to the Brxx and NxxBr series (NxxCl and NxxBr are the amide bridged reversed isomers of Clxx and Brxx, respectively). 68 4 highlights the significant overlap in isomorphous behaviour between 5 of the 9 pairs of structures (55%) in the Clxx and Brxx isomer grids. [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] This is not altogether unexpected and the isomer series as presented demonstrates mutual similarities and differences with their Fxx and Mxx analogues. Another group is the para-para series (Ypp) spanning at least seven benzamides from the parent Hpp to Brxx, with differences only obvious at the secondary interaction level. [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF][START_REF] Noveron | Engineering the structure and magnetic properties of crystalline solids via the metaldirected self-assembly of a versatile molecular building unit[END_REF][START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF][START_REF] Bombicz | The way from isostructurality to polymorphism. Where are the borders? The role of supramolecular interactions and crystal symmetries[END_REF][START_REF] Palma | Ni(II), Cu(II) and Zn(II) complexes of tetraphenylazadipyrromethene[END_REF][START_REF] Gelbrich | Structural systematics of 4,4'disubstituted benzenesulfonamidobenzenes. 1. Overview and dimer based isostructures[END_REF][START_REF] Gelbrich | The crystal structure of methyl paraben at 118 K does not represent a new polymorph[END_REF] A question arises as to why is there so much structural overlap between the Clxx and Brxx analogues? This can be addressed by comparing our results with a CSD [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF] study by Mukherjee and Desiraju in 2014, [START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF] in which they analysed a series of Cl/Br-containing structures where the pairs differ by replacement of a C-X (X = Cl or Br). [START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF] In providing an insight into the behaviour of analogous pairs their statistical analysis highlights a high degree of similarity between both sets and with 57% of the C-Cl/Br pairs sharing the same space group, Z and reduced cell parameters (within 1 Å). In their comprehensive study, [START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF] the relative absence of Cl…Cl (or Br…Br) contacts was further noted and only observed in <8% of structures (including disorder, classification ambiguities and Cl…Br interactions). Our present results and statistics (55%) therefore correlate well with those reported from Mukherjee and Desiraju. [START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF] The interchange of Cl/Br in the majority of structural pairs from the Mukherjee and Desiraju CSD study, [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF] does not result in major structural changes or diversity and hence the high degree of structural overlap. [START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF]

Ab initio modelling and conformational analyses

In order to investigate the modelled, optimised structures of the nine Clxx molecules and differences with their solid-state molecular structures, optimisation of the modelled Clxx molecules was performed using the ab initio software Gaussian09 55 based on the DFT method (hybrid density functional B3LYP with 6-311G++(d,p) basis set, gas phase). [START_REF] Becke | Density-Functional Thermochemistry. 3. The Role of Exact Exchange[END_REF][START_REF] Krishnan | Self-Consistent Molecular-Orbital Methods. 20. Basis Set For Correlated Wave-Functions[END_REF] Models with optimised geometries (Table 5) were then used in the conformational analysis procedure. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF] Each of the Clxx structures was subject to full Potential Energy Surface (PES) scans (±180, increment of 5) of the two key C12-C11-C1=O1 (, Cl-ring) and C1-N1-C21-C26 (, P-ring) dihedral angles. Each of the asymmetric (meta-or ortho-) chlorophenyl (Clring) or pyridine (P-ring) groups, can adopt, relative to the amide linker, two conformations (syn or anti) (Scheme 3), as denoted by syn (Cl-syn, P-syn) or anti (Cl-anti, P-anti). Aromatic rings with a para-pyridine N and/or para-phenyl Cl atoms are not subject to this convention.

The results provide nine diagrams with two PES curves highlighting the conformational preferences (syn/anti) and with the rotational barriers for both dihedral angles in kJ.mol -1 . [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] The Potential Energy Surface conformational analysis for nine Clxx optimized in the gas phase: the equivalent solid-state angle is shown by () with, if applicable, an assigned identifier. Enlarged versions are available in the ESI (Figure S3).

The geometry optimization and conformational analysis of the nine Clxx structures reveals several interesting observations. Firstly, the optimized Clxx geometries more closely resembles the methylbenzamide (Mxx) [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] isomer grid than the related fluorine analogues (Fxx). [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] The Clox triad is not planar like the equivalent Fox triad. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] This is mainly due to the absence of intramolecular N-H…Cl hydrogen bonding in the former and to the presence of intramolecular N-H…F interactions in the latter. However, the P-ring is still co-planar with the amide linker plane. In addition, the Cl-ring in the Clox triad exhibits a greater deviation from planarity, as already noted in the Mox triad, [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] since the Cl atoms in the Clox triad do not form intramolecular hydrogen bonds with the amide N-H as the latter moiety prefers to interact with strong hydrogen bond acceptors such as amide C=O and pyridine N atom. It is interesting also to note that the Clmo calculations suggest that the Cl-anti conformation is more stable than the Cl-syn conformation as would be expected.

The height of rotational barriers (energy differences) is comparable with the equivalent PES diagrams in the Fxx isomer series as well as for P-rings in Mxx. [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] The profiles of the Clo-rings are asymmetric, though similar in shape to the Fo-rings (which are symmetric due to planarity/hydrogen bonding) and with slightly lower energy barriers. The Clp and Clm PES diagrams are very similar both in shape and barrier height to the Fp and Fm rings in Fxx. [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] In each PES curve in Figure 10 the position of the solid-state dihedral angles of the Cl-and Prings are marked by a dot (either  or ) and if there is more than one molecule/polymorph these are marked with a corresponding letter. These marks illustrate the deviation of the solid-state angles from the optimized ones (at  = 0) and from the closest global minimum.

In most of the nine Clxx isomers there are small deviations (+/-30) from the optimized starting points or closest minima, and up to ca. 3-4 kJ.mol -1 of energy difference. Although for Clmm and Clop, energy differences from the most stable conformer are noticeable, in general, there are no significant deviations between the global minima except for Clom.

In Clmm the most stable conformer in vacuo is Cl-syn but the Cl-anti conformation is observed in the solid-state. This conformational change from Cl-syn to Cl-anti is necessary to allow the formation of N1-H1…O1W hydrogen bonding that is essential for molecular aggregation in the crystal structure. If the Clmm molecule retained the Cl-syn conformation, then formation of this hydrogen bonding arrangement would be hampered. In the Clop crystal structure the Clo-ring deviates by 90 from its gas phase optimized minimum and is positioned between the Cl-syn and Cl-anti conformation. However, the energy expense of this deviation is just 3 kJ.mol -1 and the angle change (deviation) is preferred as it facilitates the C12-Cl12…(O1=C1) xxi halogen bonding and C15-H15…O1 vii hydrogen bonding formation.

In the Clom crystal structure the meta-pyridine ring adopts the unfavorable P-anti conformation which is 5 kJ.mol -1 higher in energy than the alternative P-syn conformation. This conformational change is also seen in Brom [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] and Mom [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] and allows the formation of regular hydrogen bonded N-H…N zig-zag chains. There is a chlorine…chlorine contact which is almost in a head-to-head geometry as C12-Cl12…Cl12 = 167.66(6); see ESI (Figure S10). This configuration seems unfavourable at first glance as the two -holes are almost oriented towards each other. Moreover, the electrostatic energy from the deformation electron density part is indeed positive E elec-Def (Cl…Cl) = +0.8kJ.mol -1 ). However, as the neutral spherical atom contribution (E elec-Neu = -4.5kJ.mol -1 ) is very negative and the penetration energy (cross term describing the interaction between deformation and neutral spherical components) is very small, the interaction is globally stabilized from an electrostatic viewpoint (E elec = -3.5kJ.mol -1 ).

In general terms, conformational analysis of the nine Clxx isomers exhibits agreement between the conformations of the solid-state and modeled molecular structures, apart from the Clop, Clmm and Clom isomers (as noted above in the PES diagrams, Figure 10). These findings are consistent with our previous results in similar, related isomer grids though the optimized Clxx geometries more closely resemble the methylbenzamide (Mxx) [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] isomers than the related fluorine analogues (Fxx). [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] Melting point analysis: [81][START_REF] Brown | Melting point and molecular symmetry[END_REF][START_REF] Vishweshwar | Molecular complexes of homologous alkanedicarboxylic acids with isonicotinamide: X-ray crystal structures, hydrogen bond synthons, and melting point alternation[END_REF][START_REF] Slovokhotov | Symmetry of van der Waals molecular shape and melting points of organic compounds[END_REF][START_REF] Podsiadło | Chemistry of density: extension and structural origin of Carnelley's rule in chloroethanes[END_REF][START_REF] Yalkowsky | Carnelley's Rule and the Prediction of Melting Point[END_REF][START_REF] Gamidi | Estimation of Melting Temperature of Molecular Cocrystals Using Artificial Neural Network Model[END_REF][START_REF] Bujak | Melting point, molecular symmetry and aggregation of tetrachlorobenzene isomers: the role at halogen bonding[END_REF][START_REF] Mishra | Can Melting Point Trends Help Us Develop New Tools To Control the Crystal Packing of Weakly Interacting Ions?[END_REF] comparisons with related series

For the Clxx series, it is noted that Carnelley's rule 81 is adhered to on symmetry grounds with the most symmetrical Clpp (para-Chloro-N'-(para-pyridyl)benzamide) having the highest melting point (mp = 207C) and the unsymmetrical Clmo (meta-Chloro-N'-(orthopyridyl)benzamide having the lowest mp (100C). The trends in Table 6 generally correspond with the average mps of the Fxx [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] and Mxx [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] series as well as the Brxx series [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] where five isomorphous pairs of Clxx/Brxx 68 are noted to have similar melting points (and within a range of 10-15C). The highest mp usually corresponds to a para-para (pp) isomer and the lowest typically from one of the ortho-meta/meta-ortho (om/mo) pairs. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] The Clxp triad has, on average, higher mps than Clxm or Clxo. For the corresponding analysis, the Clpx triad has the highest average compared to Clmx and Clox. Differences can be attributed to subtle and distinct secondary interactions that arise in the Clxx/Brxx pairs and their effect on melting points. The Clxx melting point ranges (Table 6) exhibit distinct differences when compared with their fluorine (Fxx) [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] and methylbenzamide analogues (Mxx), (ESI, Table S3). [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] The Clxx melting point ranges are on average 20C higher than the equivalent fluorinated Fxx systems (ESI; Figure S2, Table S3), with an average( standard deviation) mp for the nine Clxx isomers of 14834C compared with 131C for Fxx. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] Moreover, the average mp for the Brxx series (147C) [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] is similar to Clxx. This is not surprising given that five of the Clxx and Brxx [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] structures are isomorphous pairs with melting points within 10-15C of each other. These values differ considerably from the average mps for the Mxx, [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] NxxF [START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF] and NxxM 46 series (ESI, Table S3) with average values of 116C, 117C and 113C, respectively. The distinct differences stem from the chloro, fluoro and methyl substitution in Clxx, Fxx, Mxx and the reversed amide bridge for their NxxF and NxxM analogues. The question arises as to why differences arise between related series of isomer grids? All other things being equal, the effect of chlorine substitution in Clxx compared to fluorine or methyl is to bestow an average higher mp of 17C compared to Fxx, which is 15C greater than Mxx (as BrCl>F>Me). The Clxx, Fxx, Mxx series have higher average melting points than their corresponding amide bridge reversed NxxCl (134C), NxxF (117C) and NxxM (113C) isomer grids. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF] In analysis of series of isomers and related congeners, it is important to be able to examine related structures and their physicochemical properties. [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF][START_REF] Bombicz | The way from isostructurality to polymorphism. Where are the borders? The role of supramolecular interactions and crystal symmetries[END_REF][START_REF] Palma | Ni(II), Cu(II) and Zn(II) complexes of tetraphenylazadipyrromethene[END_REF][START_REF] Gelbrich | Structural systematics of 4,4'disubstituted benzenesulfonamidobenzenes. 1. Overview and dimer based isostructures[END_REF][START_REF] Gelbrich | The crystal structure of methyl paraben at 118 K does not represent a new polymorph[END_REF][START_REF] Abad | X-ray structure of fluorinated N-(2-chloropyridin-4-yl)-N'-phenylureas. Role of F substitution in the crystal packing[END_REF][START_REF] Tuchalski | X-ray investigations of nebivolol and its isomers[END_REF][START_REF] Capacci-Daniel | Halogen/methyl exchange in a series of isostructural 1,3-bis(mdihalophenyl) ureas[END_REF][START_REF] Dumitru | Weak intermolecular hydrogen and halogen interactions in an isomorphous halogen series of pseudoterpyridine Zn-II complexes[END_REF][START_REF] Gomes | The crystal structures of four N-(4halophenyl)-4-oxo-4H-chromene-3-carboxamides[END_REF] The CSD as a repository for structural information is important for ancillary information such as melting points. 40- 42,90-94 In designing series of compounds, the drive to obtain a high melting point isomer should be influenced by the choice of Cl or Br-derivatives over F or Me and with parasubstitutions where possible. Conversely, methyl-substituted and meta-or orthosubstituted are preferred for lower melting point compounds. [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF][81][START_REF] Brown | Melting point and molecular symmetry[END_REF][START_REF] Vishweshwar | Molecular complexes of homologous alkanedicarboxylic acids with isonicotinamide: X-ray crystal structures, hydrogen bond synthons, and melting point alternation[END_REF][START_REF] Slovokhotov | Symmetry of van der Waals molecular shape and melting points of organic compounds[END_REF][START_REF] Podsiadło | Chemistry of density: extension and structural origin of Carnelley's rule in chloroethanes[END_REF][START_REF] Yalkowsky | Carnelley's Rule and the Prediction of Melting Point[END_REF][START_REF] Gamidi | Estimation of Melting Temperature of Molecular Cocrystals Using Artificial Neural Network Model[END_REF][START_REF] Bujak | Melting point, molecular symmetry and aggregation of tetrachlorobenzene isomers: the role at halogen bonding[END_REF][START_REF] Mishra | Can Melting Point Trends Help Us Develop New Tools To Control the Crystal Packing of Weakly Interacting Ions?[END_REF]

Physicochemical and melting point relations

In order to try to relate the melting point temperatures to energies, additional analyses were conducted to identify correlations and trends. [START_REF] Jelsch | Advances in protein and smallmolecule charge-density refinement methods using MoPro[END_REF][START_REF] Domagała | An improved experimental databank of transferable multipolar atom models-ELMAM2. Construction details and applications[END_REF][START_REF] Allen | Bond lengths in organic and metal-organic compounds revisited: X-H bond lengths from neutron diffraction data[END_REF][START_REF] Guillot | MoProViewer: a tool to study proteins from a charge density science perspective[END_REF][START_REF] Jelsch | Atom interaction propensities of oxygenated chemical functions in crystal packings[END_REF] The variation in the Gibbs free energy involves changes in enthalpy (H) and entropy (S): G = H-TS. At the melting point T m , the system is in equilibrium so that the free energy of the melting equals zero (G f = 0), [START_REF] Yalkowsky | Carnelley's Rule and the Prediction of Melting Point[END_REF] and the following equation holds:

T m = H m /S m (equation 1)
Consequently, enthalpy and entropy changes are both determining in the melting point temperatures. A larger enthalpy of melting leads to a higher temperature value. Here, the melting point temperatures T m are shown together with the estimated lattice electrostatic energy (E lat ) of the compounds in the ESI (Figure S4). The Clmm monohydrate crystal structure is not included as it has a different chemical content; it has the largest electrostatic cohesive energy but a small T m value.

Globally, it appears that the two quantities T m and E lat are only moderately correlated (correlation factor = 47%). The isomers with highest T m tend however to have the largest negative E lat values, as shown by the positive sign of the correlation between -E lat and T m for the Clxx isomer grids. Assuming electrostatics play a significant role in the stabilization of the crystal structure, it can indeed be expected that the electrostatic lattice energy E lat of the Clxx isomers relates to their melting enthalpy, and therefore to T m from equation 1, as discussed hereafter.

The entropy change S m also contributes to the melting point temperature. This quantity is largely dependent on the arrangement of the constituent groups in the molecule and therefore to the increase in the number of different available states (S m > 0) upon the phase transition from an organized crystal structure to a liquid state. [START_REF] Yalkowsky | Carnelley's Rule and the Prediction of Melting Point[END_REF] Hence, one can expect a molecule with a high degree of rotational symmetry to show a smaller increase in entropy and, as a result, an increased T m temperature (equation 1). For para-substituted compounds, the rotational symmetry of the molecule is higher with respect to the more unsymmetrical ortho-and meta-substituted Clxx isomers.

In an attempt to model Carnelley's rule, the ortho-/meta-/para-position descriptor f is introduced (Figure 11a). [81][START_REF] Brown | Melting point and molecular symmetry[END_REF][START_REF] Vishweshwar | Molecular complexes of homologous alkanedicarboxylic acids with isonicotinamide: X-ray crystal structures, hydrogen bond synthons, and melting point alternation[END_REF][START_REF] Slovokhotov | Symmetry of van der Waals molecular shape and melting points of organic compounds[END_REF][START_REF] Podsiadło | Chemistry of density: extension and structural origin of Carnelley's rule in chloroethanes[END_REF][START_REF] Yalkowsky | Carnelley's Rule and the Prediction of Melting Point[END_REF][START_REF] Gamidi | Estimation of Melting Temperature of Molecular Cocrystals Using Artificial Neural Network Model[END_REF][START_REF] Bujak | Melting point, molecular symmetry and aggregation of tetrachlorobenzene isomers: the role at halogen bonding[END_REF][START_REF] Mishra | Can Melting Point Trends Help Us Develop New Tools To Control the Crystal Packing of Weakly Interacting Ions?[END_REF] The f(Clxx) function, defined as:

f(Clxy) = g(x) + g(y) (equation 2)
with g(m) = g(o) = 0 and g(p)=1, takes values 0, 1 or 2 as resulting from addition of ortho = meta = 0, para = 1 contributions. This descriptor yields, alone, a correlation value of 0.82 with the melting temperature values (Figure 11a). It represents, in a rudimentary way, the differences in entropy changes due to the variations in the substituent moiety positions. The variable f(Clxx), defined to model Carnelley's rule is therefore anti-correlated with the entropy variation upon melting. A double linear regression to fit T m against the Carnelley f function values and E lat set of variables leads to a correlation of 0.957 (ESI, Figure S5). This model has the advantage to account simultaneously for the enthalpic (through E lat ) and the entropic (through f) contributions to the melting temperature T m .

The energetic contributions of strong N-H…N/O hydrogen bonds (E HB ) and the rest of interactions (E lat -E HB ) were also evaluated. While the electrostatic energy between H N and N/O atoms is on average -44 kJ.mol -1 , weaker C-H…O and C-H…N contacts have an energy lower than -20 kJ.mol -1 . The single fitting of T m against E lat -E HB (correlation = -0.63 in Table 7, Figure 11b) is stronger than against E lat (correlation factor = -0.47 in Table 7 and Figure S4; ESI), suggesting that contributions to H m enthalpy are rather due to the weaker interactions. Moreover, the non-existent dependence between T m and E HB (correlation factor = 0.09 in Table 7) also accounts for the same trend.

Comparison of the double linear regressions in Figure S5 (ESI) and Figure 11c further supports the evidence. Indeed, the 0.957 correlation found in Figure S5 (involving all electrostatic interactions) is only slightly lower than that described by the contributions of weaker interactions only (those excluding stronger HB's) in Figure 11c. The E HB contribution in the former is compensated by the variation of the other fitting parameter f in the corresponding T fit function. Accordingly, one can think that, at the melting point, weaker interactions will firstly dissociate because their intermolecular forces will not be able to restore their equilibrium solid-state geometries, while stronger interactions maintain their restoring forces. Overall, a high correlation such as presented herein (Figure 11c) might suggest a possible predictive behavior of the model, which will be further tested in studies of related series of Yxx substituted benzamides. [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] The mean disagreement (as defined from the |T fit -T m |/T m value calculated over the eight data points) is respectively, <5.2% and <5.5% in the double linear regression fittings in Figure 11c and Figure S5 (ESI). The most important deviation (10%) is observed for Cloo in both fittings.

The lattice electrostatic energy E lat was compared with E Syms , the electrostatic interaction energy of the molecule with its immediate neighbouring molecules in the crystal packing (Figure 12). For all Clxx isomers, the E Syms and E lat values are very similar (Figure 12a), which shows that most of the lattice electrostatic energy originates from interactions with molecules directly in contact with the original molecule under study (i.e. the nearest neighbours). The energy values were computed for the four independent molecules (labelled as A=1, B=2, C=3, D=4) in the Clmp and Clpm crystal structures and averaged. The Clpm crystal structure is rather peculiar with molecules related by translation along the short unit cell axis a = 4.0095(4) Å which interact and result in an unfavourable electrostatic energy as electropositive/negative complementarity is not achieved. The E elec values are all positive between dimers related by translation vector a in the Clpm crystal structure, +1.5, +1.8, +12.4 and +11.7 kJ.mol -1 for dimers 1 (A), 2 (B), 3 (C) and 4 (D), respectively.

For the 10 Clxx structures (including both Clpo_O and Clpo_N polymorphs, the hydrated Clmm and the averaged values for the four independent molecules in Clmp and Clpm), the plotted E Syms vs E lat data (Figure 12b) are highly and linearly correlated. Indeed, the linear fitting between the two sets of values is E Syms = 1.028( 57) and E lat + 0(6) (with a correlation factor R = 0.9877). The external disagreement (as defined by the fitting parameter of the slope) is lower than 3%, while the internal disagreement (as defined by the mean |E Syms -E lat |/E lat ) value calculated for the data) is 5%. The most important deviation in the internal disagreement is found for Clmo (14%).

The hydrogen bond contribution E HB to the electrostatic energies were also computed as E elec between H N and N/O atoms) (ESI, Figure S9). Other properties have also been analysed in the search for correlations that could be related to the melting temperature variations amongst the Clxx benzamides studied (Table 7). For instance, there is no correlation established between the mp temperature and the crystal density.

Contacts analysis

The intermolecular interactions of the isomer grid have been quantified using Hirshfeld surface analysis. The definition of enrichment ratios of contact has been detailed. [START_REF] Jelsch | The enrichment ratio of atomic contacts in crystals, an indicator derived from the Hirshfeld surface analysis[END_REF][START_REF] Jelsch | Likelihood of atom-atom contacts in crystal structures of halogenated organic compounds[END_REF] The enrichment ratio  XY for a pair of elements (X,Y) is defined as the ratio between the proportion of actual contacts in the crystal and the theoretical proportion of equidistributed random contacts. An enrichment ratio larger than unity reveals that the contacts between a pair of elements are over-represented. The average statistics on crystal contacts are listed in Table 8, while data on each individual crystal structure are presented (Figure 13 and ESI, Table S4). The Clxx benzamide molecules are reasonably hydrophobic as the surface comprises just 14% of hydrophilic atoms (O, H N , N). The contacts between hydrophobic atoms (C, H C , Cl) account for 78% of the interaction surface while polar contacts involving only (H N , O, N) atoms represent just 5% in the nine Clxx crystal structures. The cross contacts between hydrophobic and polar atoms constitute 17% of the surface and are mainly weak hydrogen bonds of C-H…O type (5.5%) and C-H…N (4.4%). All polar…non-polar cross interactions between atoms are, on average, underrepresented, except the weak C-H…O hydrogen bonds. The partition between hydrophobic contacts (781)%, hydrophilic (51)% and cross contacts (172)% is quite stable in the nine non-hydrated Clxx isomers (ESI, Table S6).

Amongst all contacts in the nine Clxx non-hydrated crystals, the H N …N strong hydrogen bond is on average the most enriched at  = 11(4). The Clpo_O structure is the only one where the hydrogen bond donor N-H interacts strongly with the amide oxygen atom (as amide…amide interactions). The Clpp crystal structure is also peculiar, as both H N …N and H N …O are enriched ( = 4.0 and 2.0) due to the presence of a bifurcated hydrogen bond (contact), with d(N…H N ) = 2.441 (19) Å and d(O…H N ) = 2.837(17) Å. In the Clmo crystal structure, a secondary long distance electrostatic interaction d(H N …O) = 3.266(18) Å also forms, in addition, to the primary d(H N …N)= 2.45(2) Å hydrogen bond. [START_REF] Desiraju | The weak hydrogen bond in structural chemistry and biology[END_REF][START_REF] Domenicano | Strength from Weakness: Structural Consequences of Weak Interactions in Molecules, Supermolecules and Crystals[END_REF][START_REF] Nishio | CH/ hydrogen bonds in crystals[END_REF][START_REF] Dance | Molecules embracing in Crystals[END_REF][START_REF] Alvarez | A cartography of the van der Waals territories[END_REF][START_REF] Martinez | Rethinking the term "pi-stacking[END_REF][START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF] All self contacts between charged atoms (O, N, H N ) are generally avoided as they are not favourable from an electrostatic viewpoint. [START_REF] Jelsch | The enrichment ratio of atomic contacts in crystals, an indicator derived from the Hirshfeld surface analysis[END_REF][START_REF] Jelsch | Likelihood of atom-atom contacts in crystal structures of halogenated organic compounds[END_REF] However, in the Cloo and Clmo crystal structures, the N-H and N acceptor atoms are in close proximity resulting in the formation of a double N-H…N hydrogen bond with graph set R 2 2 (8) (around a two-fold axis and inversion centre, respectively) leading to secondary H N …H N contacts. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF] The vast majority of intermolecular interactions are hydrophobic in nature, they constitute the five most represented contacts and four of them have C xy proportions larger than 11%. The Cl -…H C + contact is the most enriched between the hydrophobic atom types and is considered as a weak hydrogen bond. [START_REF] Desiraju | The weak hydrogen bond in structural chemistry and biology[END_REF][START_REF] Domenicano | Strength from Weakness: Structural Consequences of Weak Interactions in Molecules, Supermolecules and Crystals[END_REF][START_REF] Nishio | CH/ hydrogen bonds in crystals[END_REF][START_REF] Dance | Molecules embracing in Crystals[END_REF][START_REF] Alvarez | A cartography of the van der Waals territories[END_REF][START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] It is slightly attractive from an electrostatic point of view; for example the Cl3…H13 contact in Clmp (x-1,y,z+1, d = 3.00 Å) yields an energy between the two multipolar atoms of -2.4 kJ.mol -1 . The H C …Cl contact is, on average, the only enriched contact formed by chlorine in the Clxx series. H C has been noted to be a favoured partner for organic halogen atoms in several families of molecules. [START_REF] Jelsch | Likelihood of atom-atom contacts in crystal structures of halogenated organic compounds[END_REF] The O…Cl and N…Cl contacts are, on average, quite disfavoured (with <> = 0.3) with halogen bonding absent in all but one structure. [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] Clop exhibits a typical Cl…O halogen bond with d(O,Cl) = 3.1104(18) Å and a C-Cl…O angle of 161.08(8) which is not far from linearity (180). The electrostatic energy between Cl and O atoms is however, slightly positive (unfavourable) at 1.5 kJ.mol -1 . In two other crystal structures, these contacts do occur and leading to enrichment values larger than unity. The Cloo structure has three long range Cl…N contacts, while ClmmH 2 O has several long Cl…O and Cl…N contacts. [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] The Cl…Cl contacts have on average an enrichment equal to unity but they only occur in half of the Clxx crystal structures. A significantly enriched and short Cl…Cl contact occurs only in the Clom structure (ESI, Figure S10). [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] In the Clxx benzamides the C…C contacts are slightly enriched due to the occurrence of aromatic donor…acceptor interactions between aromatic rings. [START_REF] Martinez | Rethinking the term "pi-stacking[END_REF] Two aromatic rings with the Cl -and N -atoms have the ability to form favorable stacking interactions. Heterocycles have a good propensity to form ring stacking as the electropositive and electronegative atoms can be interacting partners. [START_REF] Salonen | Aromatic Rings in Chemical and Biological Recognition: Energetics and Structure[END_REF] For example in the Cloo and Clom structures, the N-C 5 NH 4 group is in a parallel displaced interaction with symmetry related rings through an inversion center and the N atoms are located in opposite directions. In Clpo_N, the entire O=C-(NH)C 5 H 4 N moiety is in a parallel stacking mode with itself through an inversion center.

In Clop, the same self-interaction occurs and in addition the pyridine ring forms a cross interaction with the chlorobenzene ring of a symmetry related Clop molecule. The ClmmH 2 O crystal structure has the highest  CC = 2.0 ratio and shows extensive aromatic ring stacking in the a-axis direction of the whole (nearly planar) benzamide molecule with symmetry-related rings through an inversion center. This occurs in the Clmp crystal (Z'=4) as well, where stacking along the c-axis occurs through an alternation of crystallographic inversion and non-crystallographic pseudo-inversion symmetry operations. The Clpm crystal is unusual as the four independent molecules (A-D) show parallel displaced stacking through a translation (and not an inversion) along the short axes (a = 4.01 Å). Consequently, this Clpm crystal structure exhibits unusually enriched O…O and Cl…Cl contacts. [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] The linear correlation coefficient R between the enrichment ratios found in the nine Clxx non-hydrate crystals is displayed in Table S7 (ESI). As a reference, a set of 9 random variables taking values in the [0,1] interval, yields a root mean square rms(R) value of 0.35. For further reference, rms(R) is 0.40 and the average is <R> = -0.05 for the enrichment ratios in Clxx. However, a few correlations take significant values up to 0.96, in terms of absolute value. Very large correlations should have a chemical meaning while moderate values may be explained or may be incidental due to limited sample size. The analysis highlights some clear trends but also shows some absence of correlations.

The two strong hydrogen bonds O…H N and N…H N are inversely-correlated, as could be expected (with r = -0.45). The strong and weak hydrogen bonds N…H N and N…H C turn out to be the most anti-correlated contacts (with R = -0.96), as all Clxx crystals, except for Clpo_O, have a N-H…N hydrogen bond. Conversely, the O…H N and O…H C which are both mildly enriched, on average, occur in an unrelated way in the crystal packings (with R = 0.07).

Among the hydrophobic contacts, the  CC and  CHc values are 56% correlated while the  CC and  HcHc values display an R value of -50%. The correlation R = 0.79 between  CC and  NN may be explained by the concomitant occurrence of stacking between the pyridine heterocycles.

Conclusions

A series of nine Clxx benzamide isomers have been analysed for comparisons and show a degree of correlation with the related Fxx, Mxx benzamides, [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] and especially with Brxx 68 in terms of isomorphous behaviour. [START_REF] Abad | X-ray structure of fluorinated N-(2-chloropyridin-4-yl)-N'-phenylureas. Role of F substitution in the crystal packing[END_REF][START_REF] Tuchalski | X-ray investigations of nebivolol and its isomers[END_REF][START_REF] Capacci-Daniel | Halogen/methyl exchange in a series of isostructural 1,3-bis(mdihalophenyl) ureas[END_REF][START_REF] Dumitru | Weak intermolecular hydrogen and halogen interactions in an isomorphous halogen series of pseudoterpyridine Zn-II complexes[END_REF][START_REF] Gomes | The crystal structures of four N-(4halophenyl)-4-oxo-4H-chromene-3-carboxamides[END_REF] In terms of their physicochemical behaviour, the series builds on our knowledge of isomeric relationships and shows that Clxx and Brxx behave largely in a similar fashion and differing substantially from the Fxx and Mxx isomer grids. The Clxx series provides examples such as the Clpp isomorphous/isostructural relationship with several Xpp relatives [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF] and considerable overlap between Clxx and Brxx (with five isomorphous pairs), though much less so with Fxx and Mxx. Both can be rationalised as being influenced by strong hydrogen bonding dominating the interactions in solution and at the crystallization event, with the halogens having similar (Br, Cl) and different (Cl, F) steric and electronic influences on intermolecular interactions. [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] Our results indicate the dominance of N-H…N over N-H…O=C interactions in Yxx work [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF][START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] The transition from Me to F to Cl to Br shows the differences between the role of switching F/H position (steric/electronic) to structures where replacement by Cl or Br shows increasing crystal structure overlap, [START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF] and where the effect of the halogen on structure and interactions is more noteable.

Within the Clxx grid, examples include the two Clpo polymorphs which crystallise in the same space group (Z'=1) which is relatively rare though not unusual. [START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF][START_REF] Yu | Polymorphism in Molecular Solids: An Extraordinary System of Red, Orange, and Yellow Crystals[END_REF] The Clpo_N crystal structure crystallises with lattice voids of dimensions similar in size to H 2 molecules. Of interest is the preponderance of para-meta substituted (pm) crystal structures observed with Z'=4 in the Cl, F, Me series of compounds studied to date, including Clpm and Clmp from this study. However, the Brxx and NxxBr series [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] do not contain any crystal structures with Z'>2. [START_REF] Brock | High-Z' structures of organic molecules: their diversity and organizing principles[END_REF][START_REF] Steed | Packing Problems: High Z′ Crystal Structures and Their Relationship to Cocrystals, Inclusion Compounds, and Polymorphism[END_REF] Of note is that there is a lack of Cl…O and Cl…N halogen bonding interactions in Clxx apart from the Clpp, Clop and Clom structures. [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] This can be attributed to the fact that there is only one halogen atom (Cl) per molecule and there is considerable competition with other interactions. The pyridine N atom is rather involved in the formation of strong hydrogen bonds with H-N, while the amide O atom generally forms weaker C-H…O hydrogen bonds. On the other hand, the C-H…Cl weak hydrogen bonds have a more favourable electrostatic energy than the Cl…O/N halogen bonding. [START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF] The Clxx isomer grid provides an illustration of Carnelley's rule, which relates the crystal melting temperature to the symmetry of the crystallized molecule. [81][START_REF] Brown | Melting point and molecular symmetry[END_REF][START_REF] Vishweshwar | Molecular complexes of homologous alkanedicarboxylic acids with isonicotinamide: X-ray crystal structures, hydrogen bond synthons, and melting point alternation[END_REF][START_REF] Slovokhotov | Symmetry of van der Waals molecular shape and melting points of organic compounds[END_REF][START_REF] Podsiadło | Chemistry of density: extension and structural origin of Carnelley's rule in chloroethanes[END_REF][START_REF] Yalkowsky | Carnelley's Rule and the Prediction of Melting Point[END_REF][START_REF] Gamidi | Estimation of Melting Temperature of Molecular Cocrystals Using Artificial Neural Network Model[END_REF][START_REF] Bujak | Melting point, molecular symmetry and aggregation of tetrachlorobenzene isomers: the role at halogen bonding[END_REF][START_REF] Mishra | Can Melting Point Trends Help Us Develop New Tools To Control the Crystal Packing of Weakly Interacting Ions?[END_REF] An empirical function based on the substituent positions and the lattice electrostatic energy is introduced, allowing us to obtain the fitted melting temperatures which are more than 95% correlated with the experimental values. Given the high correlation, this model will be further refined in series of related benzamides and its possible predictive behaviour will be evaluated.

The entropic component of T m has been related to molecular symmetry using the fdescriptor, which accounts for the ortho-/meta-/para-positions differentiating the local symmetry of the Clxx molecular structures. On the other hand, from an investigation of simple fittings of the melting point T m , it demonstrates that the one based on E lat -E HB accounts for a better correlation than from the total lattice electrostatic energy E lat . This trend suggests that the enthalpic component of T m is better described by weaker solid-state interactions. When a double linear regression of T m against either (E lat -E HB , f) or (E lat , f) is carried out, a similar good correlation is however, obtained in both cases, because the fitting parameters absorb the electrostatic contribution of stronger HB's that are included in E lat . Hence, any of the T fit models could be used in the prediction of melting points for related series of Yxx substituted benzamides. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF][START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] Similar melting points were found for the Clxx and Brxx series, [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] which exhibit five isomorphous pairs with T m values within 10-15C of each other. This suggests that the H m component of T m could be strongly dependent on the relative orientations of molecules found in the molecular assembly that forms the solid-state. Indeed as related Clxx and Brxx [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] pairs exhibit the same molecular symmetry, the S m entropic component is expected to be comparable. Similar T m values are thus pointing towards similar H m values in the isomorphous structures. The related pairs in the Clxx and Brxx series are built by equivalent molecular packing and molecular orientations in their assemblies. This trend could be brought close to the previous indications on the enthalpic contributions to T m , is mainly driven by the weaker interactions rather than by the intensity difference of stronger interactions.

The Hirshfeld surface analysis shows that the strong hydrogen bond O…H N (or O…H N in Clpo_O) is the most enriched contact type followed by the weak hydrogen bonds Cl…H C and O…H C . Hydrophobic atoms (C, H C , Cl) generally prefer to interact within their subgroup with the exception of the over-represented O…H C contacts.

In conclusion, the N-H…N intermolecular interaction type dominates in Clxx, and largely in the absence of solvates and the Cl atoms only engage in weak C-H…Cl hydrogen bonds. Five of the Clxx form isomorphous pairs with their Brxx analogues and with Clpp isomorphous with several close benzamide relatives. Analysis of the melting point temperatures T m reveals correlations involving both molecular symmetry and electrostatic energies. In future work, the structural and physicochemical aspects of the amide bridge reversed NxxCl series and bromo-containing derivatives (Brxx, NxxBr) will be reported as well as an overview of the halogenated benzamide research. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF][START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] This Yxx research will be placed in context in light of on-going developments in related areas. [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF][START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF][START_REF] Kofoed | X-ray diffraction data as a source of the vibrational free-energy contribution in polymorphic systems[END_REF] Expanding the domain of X-ray crystallography in combination with theoretical calculations will enhance our knowledge and understanding of the physicochemical properties of molecular systems. 98

Graphical Abstract

Physicochemical In the manuscript the symmetry codes quoted correspond to those in the Table 2a (above) although given the crystal structure discussion and its discussion then they may not actually be in order in the text.

TABLE S2C: SELECTED INTERMOLECULAR INTERACTIONS FOR THE MAIN PAPER.

Clxx

D-H•••A D-H (Å) H•••A (Å) D•••A (Å) D-H•••A (°)

Clpp N1-H1 In the manuscript the symmetry codes quoted correspond to those for the most important intermolecular interactions in the Table (above) although given the crystal structure discussion and its development they may not actually seem in order.

FIGURE S3. : ENLARGED FORMAT FOR EASE OF VIEWING/COMPARISONS

The Potential Energy Surface conformational analysis for Clxx molecules optimized in the gas phase: the equivalent solid-state angle is shown by () with, if applicable, an assigned identifier.

Clpp

Figure S5

Scatterplot of the experimental T m and fitted T fit fusion temperatures. The double linear regression was performed on the ortho-/meta-/para-positions descriptor f(Clxy) and E lat .

Figure S6.

Scatterplot of lattice E lat and density

Scatterplot of H N …N distance vs. lattice electrostatic energy in the Clxx crystal structures with one molecule per asymmetric unit. Clpo_O was excluded due to absence of any H N …N hydrogen bonding interaction.

Scheme 1 :

 1 Scheme 1: The Clxx molecular structures with Clx representing the p-/m-/o-ClC 6 H 4 C=O and x the p-/m-/o-HNC 5 H 4 N moieties (x = para-/meta-/ortho-substitution).

  .The Clmp and Clpm structures have Z'=4. * = Clmm is a hydrate (hydrogen bonding distances all involve O1W).

Scheme 2 :

 2 Scheme 2: A diagram of the three planes (with only non-hydrogen atoms used in the interplanar calculations of Tables2 and 3.

Figure 1 :

 1 Figure 1: ORTEP of Clpp and CPK view of the N1-H1…N24 and C14-Cl14…C() contacts.[START_REF] Metrangolo | Halogen Bonding: Fundamentals and Applications; Structure and Bonding[END_REF][START_REF] Raatikainen | Breathing molecular crystals: halogen-and hydrogenbonded porous molecular crystals with solvent induced adaptation of the nanosized channels[END_REF][START_REF] Desiraju | Definition of the halogen bond (IUPAC Recommendations[END_REF][START_REF] Mukherjee | Halogen bonds in some dihalogenated phenols: applications to crystal engineering[END_REF][START_REF] Makhothkina | Cocrystal or Salt: Solid State-Controlled Iodine Shift in Crystalline Halogen-Bonded Systems[END_REF][START_REF] Bauza | The Bright Future of Unconventional /-Hole Interactions[END_REF][37][START_REF] Kolar | Computer Modeling of Halogen Bonds and Other sigma-Hole Interactions[END_REF][START_REF] Tepper | Halogen Bonding in Solution: Anion Recognition, Templated Self-Assembly, and Organocatalysis Angew[END_REF]

Figure 2 :

 2 Figure 2: ORTEPs of Clmp (molecules A and D, top) and a CPK packing view (A, B, C, D).

Figure 3 :

 3 Figure 3: ORTEP of Clop; CPK view of the N1-H1…N24 vi interaction, Cl12…O1=C1 xxi contact.

Figure 4 :

 4 Figure 4: ORTEP of Clpm (molecule C) and a CPK view of the N1-H1…N23 chain.

(Figure 4 )

 4 , assigned as (A, B) and (C, D) pairs in the asymmetric unit and differing slightly in their inter-planar C 6 /C 5 N angles of 11.93(15), 11.78(14), 35.29(10) and 33.18(9). Geometrical differences are noted by intermolecular C16 A/B/C/D …C24 B/C/D/A contacts of 3.743(5) Å, 3.709(5) Å, 3.774(5) Å, 3.834(5) Å along the (ABCD) n hydrogen bonded chains as linked by modest N1-H1…N23 interactions (Table

Figure 5 :

 5 Figure 5: ORTEP view of Clmm(H 2 O) and R 4 4 (12) assembly of Clmm with H 2 O molecules.

Figure 6 :

 6 Figure 6: ORTEP of Clom and a CPK view of the Cl12…Cl12 xxiv and C-H…O contacts.

Figure 7 :

 7 Figure 7: Views of Clpo_O with N-H…O=C and aromatic stacking interactions (left) and intramolecular C-H…O interactions and intermolecular C-H…N contacts (right).

Table 3 :

 3 Differences between the Clpo_O and Clpo_N polymorphs (in Å,). a Polymorph KPI 53 C 6 /C 5 N () N-H…N/O (Å,) C -H … N/O (Å,) b C-H…O (Å,) b,c Clpo_O 70.0 3.44(8) 3.1296(14) xi , 157.7(15) 3.5199(18), 168 2.8954(17), 116 Clpo_N 67.1 36.75(7) 3.0715(19) xiii , 162.4(17) 3.329(2), 129 2.840(2), 121 a = Packing index KPI from PLATON 53 ; aromatic interplanar angles C 6 is the C 6 benzene ring, C 5 N is the 6 non-H atom of the pyridine ring in Scheme 2 (); primary hydrogen bonding distances in (Å), angles in (). b = Aromatic C-H hydrogen atoms as riding atoms in refinement and without esd's. c = Intramolecular C26-H26…O1 contact (distances in Å; angles in ).

Figure 8 :

 8 Figure 8: The cyclic dimer in Clpo_N with CPK views of the voids along the c-axis.

a 57 Scheme 3 :Figure 10 :

 57310 Scheme 3: The four possible Clxx conformations for the ClC 6 H 4 and C 5 NH 4 pyridyl rings.

Figure 11 .

 11 (a) Scatterplot of the experimental melting point T m and and f(Clxx) symmetry descriptor. The ortho-/meta-/para-positions descriptor f(Clxy) is defined as f(Clxy) = g(x) + g(y), where g(m)=g(o)=0 and g(p)=1). The line shows the linear fit of the two variables T m and f. (b) Scatterplot of T m and (E lat -E HB ), where E lat is the lattice electrostatic energy and E HB is the electrostatic energy between the two atoms involved in the strong hydrogen bond (N…H N or O…H N ) atoms using the transferred multipolar atom model. (c) Double linear fit of melting point using the f and E lat -E HB parameters.

Figure 12 .

 12 The E HB values are inversely correlated with the d(H N …N/O) distances. The Clom structure has the strongest E lat value, which is due to having both the strongest H N …N hydrogen bond energy (shortest H N …N of 1.894 Å, 2.073(17) Å and E lat -E HB complement. The longest N-H…N bond is noted in Clmo, with d(N,H N )=2.302, 2.45(2) Å; it has the weakest E HB ; Clmo has two molecules related by an inversion centre to form a hydrogen bonded dimer as a cyclic R 2 2 (8) ring with two N-H…N interactions in close proximity. (a) A plot of E lat (electrostatic lattice energy) and E Syms (electrostatic interaction energy between a central molecule and its nearest neighbours) for the ten Clxx crystal structures. (b) Linear fitting of E syms vs. E lat . Energies are in kJ.mol -1 .

Figure 13 .

 13 Figure 13. The % of contacts in the 9 non-hydrated Clxx crystal structures. The contacts of all four independent molecules in Clmp and Clpm crystal structures are depicted.

  properties of a 33 isomer grid of mono-chlorobenzamides (Clxx) (x = p-/m-/o-) are reported. Clpo forms two polymorphs as Clpo_N (N-H…N interactions with void formation as depicted in the graphic) and Clpo_O (O-H…O interactions). Weak C-H…Cl hydrogen bonds are the only favoured interaction partner of Cl with halogen bonding mostly absent. The melting temperatures T m have been correlated to both molecular symmetry and electrostatic energies.

Figure S2 .

 S2 Figure S2. DIAGRAMS OF FIGURES REFERENCED IN THE TEXT. 43-46Representative examples of Fxx (with Fpp depicted below),[START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] Mxx (Mpp depicted below),[START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] NxxF (NppF depicted below)[START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF] and NxxM (NppM depicted below).[START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF]

  xxii) 1-x, 1-y, 1-z; (xxiii) -x, -y, -1-z; (xxiv) -x, -y, 2-z; (xxv) = 1/2-x, 1/2-y, -z; (xxvii) 1-x, 1-y, -z; (xxvii) -x, 2-y, -z.

  Figure S4Scatterplot of the melting point temperature and computed lattice electrostatic energy.

Table 1 :

 1 Selected crystallographic data for Clxx (full details available; TableS1in ESI)[START_REF]Oxford Diffraction Ltd ABSFAC and CrysAlisPro CCD/RED Version 1.171[END_REF][START_REF] Sheldrick | A short history of SHELX[END_REF][START_REF] Mcardle | SORTX -a program for on-screen stick-model editing and autosorting of SHELX files for use on a PC[END_REF][START_REF] Spek | Single-crystal structure validation with the program PLATON[END_REF][START_REF] Macrae | Mercury: visualization and analysis of crystal structures[END_REF] Structure

Crystal system; Space group Z' Unit cell volume (Å 3 ) R, wR 2 factors

	Clpp	Monoclinic; P2 1 /c	1 1070.40(14)	0.038, 0.098
	Clmp	Triclinic; P	4 2145.05(8)	0.039, 0.113
	Clop	Orthorhombic; Pbca	1 2192.4(7)	0.041, 0.089
	Clpm	Triclinic; P	4 2156.6(4)	0.043, 0.084
	Clmm	Monoclinic; P2 1 /c	1 1142.99(13)	0.050, 0.097
	Clom	Monoclinic; C2/c	1 2256.16(9)	0.034, 0.089
	Clpo_O	Monoclinic; C2/c	1 2134.8(3)	0.031, 0.089

Clpo_N Monoclinic; C2/c 1 2222.78(5) 0.032, 0.093 Clmo Triclinic; P 1 530.27(6) 0.034, 0.100 Cloo Monoclinic; C2/c 1 2166.51(16) 0.036, 0.110 Footnote:

Table 2 :

 2 Salient

	Packing

structural features (inter-planar angles, distances, packing; Å,) of Clxx. 51 Structure C 6 /C 5 N () C 6 /amide () C 5 N/amide () N…N/O (Å)

Table 4 :

 4 Isomorphous relationships in several series of benzamides[START_REF] Allen | The Cambridge Structural Database: a quarter of a million crystal structures and rising[END_REF][START_REF] Thomas | WebCSD: the online portal to the Cambridge Structural Database[END_REF][START_REF] Groom | The Cambridge Structural Database[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF][START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF][START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF][START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF][START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] Other Fxx[START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] Clxx Brxx 68 Mxx[START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF]

	Hpp 65 Fpp	Clpp	Brpp	Mpp
	25p 67 Fmp Clmp	Brmp Mmp
	Fop	Clop	Brop	Mop
	Fpm Clpm	Brpm Mpm
	Fmm Clmm* Brmm* Mmm
	Fom Clom	Brom Mom
	Fpo	Clpo	Brpo	Mpo
	Fmo Clmo	Brmo Mmo
	Foo	Cloo	Broo	Moo

Isomorphous pairs highlighted in colour. * crystallises as a monohydrate

Table

Table 5 :

 5 Torsion angles () of optimised Clxx isomers a Clxx

		/	/	/
	Clpp	-24.41	-5.29	-2.90
	Clmp	26.57	5.26	2.89
	Clop	32.98	-1.52	3.19
	Clpm	-24.17	-5.65	-2.31
	Clmm	26.50	6.05	2.19
	Clom	-32.75	0.94	-3.10
	Clpo	-21.57	-3.63	-2.34
	Clmo	22.16	2.96	2.56
	Cloo	37.22	0.07	3.06

Table 6 :

 6 Melting point averages for Clxx isomer grid.

	Clxx isomers Clpx Clmx Clox
	para (Clxp)	207  187 169
	meta (Clxm) 151 113 # 136
	ortho (Clxo) 133 100 * 136

Footnote: Clpp has the highest mp  ; Clom the lowest mp * , Clmm is a hydrate, Clpo is Clpo_O

Table 7 .

 7 Linear correlation coefficients (%) (R) between several properties and variables.

	Correlation	T m	E lat	f (Carnelley)	density	E HB
	E lat	-47
	f (Carnelley)	83	45
	Crystal density	1	54	25
	E HB	89	72	42	79
	E lat -E HB	-63	94	-14	30	44
	Dipole  #	26	-75	-2	79	-60

#

The Clxx single molecule dipole moment

Table 8 .

 8 Average % of intermolecular contacts C xy and their enrichment  xy in the 9 nonhydrated Clxx structures. The standard deviations (sd) are in parentheses. The hydrophobic and hydrophilic groups are separated by lines. The  XY >>1 ratios are in bold and correspond to the significantly enriched contacts. H N …H N and O…H N contacts have three large  values and six small or zero values, therefore their standard deviations (sd's) are large. The last row shows the average chemical content on the Hirshfeld surface.

	C xy	C	H C	C l	N	O	H N
	C	13(3)
	H C	29(6)	11(4)			% contacts
	Cl	7(3)	16(4)	1(1)
	N	2.3(12)	4.4(18)	0.5(11)	0.1(1)
	O	3.1(13)	5.5(23)	0.5(12)	0.2(3)	0(0)
	H N	0.6(6)	0.6(4)	0.2(4)	3.6(16)	1.1(17)	0.0(3)
	C	1 . 2 ( 3 )
	H C	1.0(3)	0.8(3)			enrichment

TABLE S1 . CRYSTAL STRUCTURE DATA: EXPERIMENTAL DETAILS Experiments

 S1 were carried out at 294 K using a Xcalibur, Sapphire3, Gemini Ultra. H atoms were treated by a mixture of independent and constrained refinement as CSD codes 1878555 to 1878564.

	C22-H22•••O1		0.93		2.31		2.8844 (18)	120
	Clxx isomers Clpo_O polymorph	Clom		Clpo_O		Clpo_N		Clmo	Cloo
	N1-H1•••O1 xi		(polymorph) 0.807 (17) 2.368 (17) (polymorph) 3.1296 (14)	157.7 (15)
	Clxx isomers Crystal data C15-H15•••N22 xii	Clpp	0.93	Clmp	2.60	Clop	Clpm 3.5199 (18)	Clmm_H 2 O 168
	Crystal data Chemical formula C26-H26•••O1	C 12 H 9 ClN 2 O 0.93	C 12 H 9 ClN 2 O 2.37	C 12 H 9 ClN 2 O 2.8954 (17) C 12 H 9 ClN 2 O	C 12 H 9 ClN 2 O 116
	Chemical formula M r Clpo_N polymorph	C 12 H 9 ClN 2 O 232.66	C 12 H 9 ClN 2 O 232.66	C 12 H 9 ClN 2 O 232.66	C 12 H 9 ClN 2 O 232.66	C 12 H 9 ClN 2 O•H 2 O 232.66
	M r Crystal system, space group a, b, c (Å) Crystal system, space group N1-H1•••N22 xiii a, b, c (Å) C15-H15•••O1 xiv C26-H26•••O1 Clmo , ,  (°) N1-H1•••N22 xv , ,  (°) C26-H26•••O1 V (Å 3 ) Cloo V (Å 3 ) Z N1-H1•••N22 xvi Z Radiation type C26-H26•••O1 Radiation type  (mm -1 ) C16-H16•••Cg1 xvii  (mm -1 ) Crystal shape Crystal size (mm) Data collection Crystal shape C23-H23•••Cg1 xvi Crystal size (mm) Cg1 is the ring centroid of the benzene ring {C11,...,C16}. 232.66 232.66 Monoclinic, P2 1 /c Triclinic, Pˉ1 5.6453(5), 11.7673(8), 16.2271(12) 11.4395(2), 12.9293(2), 14.8943(4) Monoclinic, C2/c Monoclinic, C2/c 0.762 (18) 2.337 (18) 232.66 Orthorhombic, Pbca 9.3966(18), 12.0918(19), 19.295(4) Monoclinic, C2/c 3.0715 (19) 232.66 Triclinic, Pˉ1 4.0095(4), 21.385(2), 27.378(3) Triclinic, Pˉ1 0.93 2.66 3.329 (2) 18.1011(4), 10.8717(2), 26.611(2), 5.2075(4), 27.0371(3), 8.2490(1), 5.8841(3), 7.3302(5), 0.93 2.24 2.840 (2) 11.4678(3) 15.4341(13) 10.7506(1) 12.6907(8) 90, 91.302(2), 90, 93.485(7), 90, 112.0204 77.717(6), 0.84(2) 2.45(2) 3.1990 (17) 90, 96.791(7), 90 89.979(2), 76.924(2), 88.507(1) 90, 90, 90 112.717(9), 93.377(8), 90 90 (14), 90 82.504(5), 0.93 2.31 2.8906 (17) 88.442(5) 2256.16(9) 2134.8(3) 2222.78(5) 530.27(6) 92.305(8) 1070.40(14) 2145.05(8) 2192.4(7) 2156.6(4) 8 8 8 2 0.835 (16) 2.219 (16) 3.0485 (14) 4 8 8 8 Mo K M o K C u K M o K 0.93 2.28 2.8700 (16) Mo K M o K M o K M o K 0.32 0.34 2.87 0.34 0.93 2.73 3.5414(15) 0.33 0.33 0.33 0.33 Block Block Block Needle 0.48 × 0.24 × 0.18 0.46 × 0.28 × 0.22 0.56 × 0.08 × 0.04 0.55 × 0.10 × 0.06 0.15 0.14 0.11 0.11 Block Block Block Block 0.93 2.70 3.4233(15) 0.22 × 0.20 × 0.35 × 0.23 × 0.36 × 0.18 × 0.37 × 0.29 ×	250.68 Monoclinic, P2 1 /c Monoclinic, 162.4 (17) C2/c 129 21.8178(9), 121 6.6955(3), 7.4273(5), 14.8776(6) 18.0819(10), 90, 94.541(4), 148.9(17) 8.9461(6) 90, 107.948(7), 90 120 90 2166.51(16) 8 171.9 (14) 1142.99(13) M o K 121 4 0.33 146 M o K 0.32 0.05 0.17 × 0.10 × 0.29 Block 135 Block 0.52 × 0.35 ×
	Absorption correction Data collection Absorption correction T min , T max	Analytical Multi-scan (Empirical SCALE3 ABSPACK) (ABSFAC, Clark & Reid, 1998) 0.957, 0.976	Multi-scan Multi-scan (Empirical SCALE3 ABSPACK) (Empirical SCALE3 ABSPACK) 0.98, 1.00	Analytical Multi-scan (Empirical SCALE3 ABSPACK) (ABSFAC, Clark & Reid, 1998) 0.481, 0.747	Multi-scan Analytical (ABSFAC, Clark & Reid, 1998) (Empirical SCALE3 ABSPACK) 0.90, 1.00	Analytical (ABSFAC, Clark Analytical & Reid, 1998) (ABSFAC, Clark & Reid, 1998) 0.877, 0.920
	T min , T max Measured, independent Measured, independent, and observed [I > 2(I)] reflections observed [I > 2(I)] reflections R int	0.859, 1.000 8589, 2476, 7681, 2325, 1594 1702 0.025	0.922, 1.000 7164, 2280, 21867, 11150, 7857 1841 0.018	0.85, 1.00 5698, 1751, 16862, 2412, 1308 1658 0.013	0.919, 0.983 4063, 2303, 15313, 8956, 4067 1890 0.014	9415, 2816, 0.947, 0.984 2212 8847, 2480, 917 0.015
	R int (sin /) max (Å -1 )	0.027 0.650		0.015 0.642		0.066 0.575		0.035 0.655	0.097 0.686
	(sin /) max (Å -1 ) Refinement	0.648		0.693		0.647		0.640	0.651
	R[F 2 > 2(F 2 )], wR(F 2 ), S Refinement R[F 2 >2(F 2 )], wR(F 2 ), S No. of reflections	0.034, 0.089, 0.038, 0.098, 1.03 1.00 2476	0.031, 0.089, 0.039, 0.113, 1.07 1.08 2280	0.032, 0.093, 0.041, 0.089, 0.86 1.06 1751	0.034, 0.100, 0.043, 0.084, 0.76 1.09 2303	0.036, 0.110, 1.09 0.050, 0.097, 0.76 2816
	No. of reflections No. of parameters	2325 149		11150 150		2412 150		8956 150	2480 149
	No. of parameters No. of restraints	150 0		593 0		149 0		594 0	166 0
	No. of restraints  max ,  min (e.Å -3 )	0 0.22, -0.28	0 0.17, -0.18	0 0.16, -0.25	0 0.18, -0.20	3 0.25, -0.26
	 max ,  min (e.Å -3 )	0.36, -0.40	0.41, -0.56	0.18, -0.15	0.16, -0.20	0.29, -0.19

Computer programs: CrysAlis PRO, Oxford Diffraction Ltd., Version 1.171.33.55 (release 05-01-2010 CrysAlis171 .NET), Version 1.171.34.40 (release 27-08-2010 CrysAlis171 .NET), SHELXS14/7 (Sheldrick, 2014), SHELXL14/7 (Sheldrick, 2014), PLATON (Spek, 2009), SHELXL14/7.

Symmetry code(s):

(i) -x+1, y+1/2, -z+1/2; (ii) x-1, y, z; (iii) x+1, y, z; (iv) x, y-1, z; (v) -x, -

y+3, -z+1; (vi) -x+1/2, y+1/2, z; (vii) -x-1/2, y+1/2, z; (viii) x-1, y+1, z; (ix) x, -y+1/2, z-1/2; (x) x, -y+1, z-1/2; (xi) x, y+1, z; (xii) -x+1/2, -y+3/2, -z; (xiii) -x, y, -z-1/2; (xiv) x, -y, z+1/2; (xv) -x+2, -y+1, -z; (xvi) -x, y, -z+1/2; (xvii) 1/2-x, 1/2+y, 1/2-z and additional interactions in Table 2b (xviii) 2-x, -y, 1-z; (xix) x, 1/2-y, 1/2+z; (xx) 1-x, 2-y, -z; (xxi) 1/2+x, y, 1/2-z;

Table S9 .

 S9 Proportion of contact types (%) in the 10 Clxx crystal structures.

		C xy	C	H C	Cl	N	O	H N
		atom C	C 18.2	H C	Cl	N	O	H N
		C H C	12.1 17.4	13.5			Clmp
		H C Cl	32.6 9.5	6.5 16.2	2.2			Clmo
		Cl N	4.8 3.8	23.6 2.8	0.1 0.2	0.1
		N O	1.9 1.7	3.5 8.2	0.0 0.3	0.0 0.1	0.0
		O H N	4.6 1.3	3.3 0.3	0.0 0.0	0.9 4.2	0.0 0.1	0.0
		H N C	0.2 20.2	0.2	0.0	3.8	1.4	0.6
		C H C	11.7 16.6	12.6			Clpm
		H C Cl	32.2 7.8	11.9 17.3	2.1			Clom
		Cl N	5.0 4.0	13.0 4.3	3.6 0.0	0.0
		N O	3.8 1.7	2.6 6.8	0.0 0.4	0.0 0.0	0.4
		O H N	1.9 1.4	8.0 1.1	0.0 0.0	0.0 3.3	0.0 0.0	0.0
		H N	1.3	0.7	0.0	4.5	0.0	0.0
	and	C	15.3
		H C Cl C xy N C O H C H N Cl C N H C O Cl H N/O	26.3 4.4 C 0.8 18.6 4.7 12.5 0.1 3.8 3.3 15.9 19.9 1.2 10.1 2.6	13.6 17.7 H C 1.5 6.3 9.9 0.1 14.0 1.0 18.7 8.9 11.7 6.8	Cl 0.2 2.8 0.0 1.1 0.3 1.3 2.6 0.0 1.8	N 0.0 0.0 4.6 0.0 0.0 4.5	O Clmm_HOH 0.0 0.0 0.0 6.6	Cloo H N/O 0.7 Clop 0.3
		N	2.4	3.9	0.0	0.0
		O	1.7	5.9	3.3	0.0	0.0
		H N	1.4	1.0	0.0	4.1	0.0	0.0
		C	18.2
		H C	20.9	13.3				Clpo_N
		Cl	7.3	17.3	1.4
		N	2.7	2.9	0.0	0.1
		O	1.8	8.1	0.1	0.0	0.0
		H N	0.4	0.7	0.0	4.3	0.0	0.7
		C	11.6
		H C	30.9	8.1				Clpo_O
		Cl	7.7	17.8	1.0
		N	3.8	7.2	0.0	0.0
		O	3.4	1.9	0.0	0.2	0.0
		H N	0.7	1.3	0.0	0.0	4.5	0.0
		C	8.2
		H C	37.2	7.1				Clpp
		Cl	12.6	13.9	0.0
		N	1.1	4.5	0.9	0.3
		O	3.2	5.0	0.0	0.1	0.0
		H N	0.0	0.3	0.0	3.8	2.0	0.0

Table S10 .

 S10 Contact enrichment ratios in the Clxx crystals.

		C	0.7
		Exy H C	C 1.4	H C 0.5	C l	N	O Clpp	H N
		C Cl	1.0 1.3	1.4	0
		H C N	1.3 0.3	0.5 1.1	0.6	1.1	Clmo
		Cl O N H N C	0.5 0.9 0.6 0 1.5	2.2 1.3 0.9 0.1	0 0 0 0	0.2 11.4 0	0 6.4	0
		O H N H C C Cl	1.3 0.1 0.7 1.0 0.9	0.9 0.1 1.1 1.5	0 0 0.9	1.7 11.2	0 4 Clmp	5.2
		H C N	1.2 1	0.7 0.7	0.1	0.3	Clom
		Cl O N H N C	0.6 0.5 1 0.6 1.6	1.3 2.2 0.6 0.1	0.2 2.3 0 0	0.2 12.7 0	0 0.4	0
		O H N H C C Cl	0.6 0.6 0.7 1.4 0.7	2 0.3 1 1.6	0 0 1	0 12.8	0 0 Clpm	0
		H C N	1.0 1	0.9 1	0	0	Cloo
		Cl O N H N	0.5 0.5 0.2 0.7	1.7 2 0.4 0.5	0.3 0.1 2.2 0	0 0 9.6	1.7 0	0.3
	and	O	1.3	1.4	0	0	0
		H N	0	0.1	1.2	13.1	0	5.2
		C Exy	1.4 C	H C	C l	N	O	H N/O
		H C C	0.7 2.0	1.2			Clop
		Cl Hc	1.2 0.7	1.2 1.0	0		ClmmH 2 O
		N Cl	0.7 0.5	0.9 1.8	0 0.2	0
		O H N N C O	0.5 0.6 1.1 1.5 0.2	1.4 0.4 0.3 1.5	2.4 0 1.1 1.1	0 12.2 0.0 0.0	0 0 0.0	0
		H C H N/O	0.8 0.4	0.9 0.9	0.7	3.9	Clpo_N 3.0	0.2
		Cl	0.8	1.7	0.7
		N	0.8	0.8	0	0.4
		O	0.5	2.1	0.1	0	0
		H N	0.2	0.3	0	12.8	0	6
		C	1.0
		H C	1.2	0.6			Clpo_O
		Cl	0.8	1.7	0.6
		N	1.0	1.7	0	0
		O	1.0	0.5	0	0.4	0
		H N	0.3	0.5	0	0	13.9	0

Table S12 .

 S12 Correlation coefficient c between the different enrichment ratios of the nine non-hydrated Clxx crystal structures. The c values with the largest magnitude are in bold characters. Numbers highlighted in yellow are discussed in the manuscript. -0.56 0.38 -0.30 -0.31 -0.47 0.02 -0.42 -0.02 0.66 -0.15 C:H N 0.46 -0.56 0.38 -0.30 -0.31 -0.47 0.02 -0.42 -0.02 0.66

	Contact C:H N	C:C	N:H N	N:C	N:N	O:H N	O:C	O:N	O:O	Cl:H N
	H N :H N	-0.65 0.23	0.31 -0.45 -0.14 -0.24 0.51	0.35 -0.23 0.46
	C:H N		-0.65 0.23	0.31 -0.45 -0.14 -0.24 0.51	0.35 -0.23
	C:C			0.49	0.01	0.79 -0.39 -0.34 -0.79 -0.40 0.44
	N:H N				0.32	0.31 -0.45 -0.66 -0.46 -0.36 0.41
	N:C					-0.34 0.19 -0.89 -0.19 -0.14 -0.09
	N:N						-0.41 0.02 -0.63 -0.18 0.30
	O:H N							0.14 -0.10 -0.13 -0.18
	O:C								0.41	0.32 -0.22
	O:N									0.62 -0.32
	O:O										-0.19
	H C:C	-0.42 0.11 -0.53 0.46	0.56	0.56 -0.64 0.02	0.46 -0.50
	N:H N	0.18 -0.24 0.00	0.31	0.10	0.21 -0.96 -0.40 0.59 -0.01
	N:C	0.22 -0.02 0.24	0.15	0.07 -0.63 -0.23 -0.90 0.67 -0.24
	N:N	-0.59 -0.14 -0.73 0.03	0.72	0.64 -0.41 0.28	0.31 -0.15
	O:H N	-0.21 0.67	0.04 -0.22 -0.24 -0.35 0.33	0.07	0.13 -0.28
	O:C	-0.22 0.17 -0.14 -0.27 -0.25 0.28	0.58	0.86 -0.80 0.26
	O:N	0.55 -0.43 0.56 -0.41 -0.49 -0.47 0.64	0.03 -0.70 0.68
	O:O	-0.19 -0.32 -0.20 -0.22 -0.34 -0.32 0.45	0.20 -0.56 0.77
	Cl:H N	-0.13 -0.10 -0.17 -0.02 0.17	0.56 -0.46 0.14	0.28	0.07
	Cl:C		-0.41 0.96 -0.16 -0.26 -0.43 0.01 -0.52 -0.05 0.16
	Cl:N			-0.22 0.51 -0.34 0.15 -0.01 0.35 -0.03 -0.65
	Cl:O				-0.19 -0.35 -0.51 0.15 -0.47 -0.09 0.07
	Cl:Cl					-0.29 0.29 -0.43 0.04 -0.04 -0.52
	H C :H N						0.23 -0.10 -0.21 0.57 -0.29
	H C :C							-0.34 0.65 -0.09 -0.19
	H C :N								0.24 -0.59 0.19
	H C :O									-0.64 0.12
	H C :Cl										-0.40
	c(E,E')	Cl:C	Cl:N	Cl:O	Cl:Cl H

N :H N C :H N H C :C H C :N H C :O H C :Cl H C :H C

Acknowledgements

This research was part-funded by the Programme for Research in Third Level Institutions (PRTLI) Cycle 4 (Ireland) and co-funded through the European Regional Development Fund (ERDF), part of the European Union Structural Funds Programme (ESF). The Irish Centre for High End Computing (ICHEC) is thanked for computer resource allocation, support and assistance with the computational calculations (http://www.ichec.ie). The authors warmly thank the Region Lorraine for a FEDER Chercheur d'Avenir grant (2015-2018).

Supplementary Information

Crystallographic data for the ten Clxx crystal structures have been deposited with the Cambridge Crystallographic Data Centre, CCDC no. 1878555 to 1878564. CIF data may be downloaded from the CCDC website https://summary.ccdc.cam.ac.uk/structure-summaryform or obtained free of charge from The Director, CCDC, 12 Union road, Cambridge, CB2 1EZ, U.K. (fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk). The structural data are available as CIF files from the corresponding author Professor John F. Gallagher (DCU).

ELECTRONIC SUPPLEMENTARY INFORMATION

At the interface of isomorphous behaviour in a 33 isomer grid of mono-chlorobenzamides: Analyses of the interaction landscapes via contact enrichment studies.

3.

Scheme S1: Clxx with the four general Clxx ring conformations; nomenclature.

4.

Diagrams of Figures referenced in the text (as Fpp, Mpp, NppF, NppM and 25p).

5.

Table S1.

Crystal Structure Data: Experimental details.

7.

Table S2a.

Selected hydrogen-bond parameters (Å,).

9.

Table S2b: Interactions and contacts (plus halogen bonding) (Å,).

Table S2c:

Selected Intermolecular interactions for the main paper.

Figures:

Enlarged format for ease of comparisons (from Figure 10 in paper).

Ab Initio calculations [Enlarged PES diagrams from main paper]. The Fxx, [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] NxxF, [START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF] Mxx [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] or NxxM [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF] analogues of Clxx present study and Brxx [START_REF] Hehir | Structural systematics of halogenated benzamides[END_REF] The Fxx series is just a simple replacement of chlorine by fluorine and the Mxx series is likewise a replacement of chlorine by the methyl group. The NxxF [START_REF] Mocilac | Structures and conformational analysis of a 33 isomer grid of nine N-(fluorophenyl)pyridinecarboxamides[END_REF] and NxxM [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of nine N-(tolyl)pyridinecarboxamides and three chlorinated relatives[END_REF] series are the amide bridged reversed isomers of Fxx [START_REF] Mocilac | Structural systematics and conformational analyses of a 33 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships[END_REF] and Mxx [START_REF] Mocilac | Synthesis, structural and conformational analysis of a 33 isomer grid based on nine methyl-N-(pyridyl)benzamides[END_REF] (although synthesised from different acyl chloride and amine starting materials).

Melting point

Hpp 65 can be regarded as similar to Fxx and Clxx and as the parent compound for reference (and without any halide atom attached)

Clxx

Interaction type D-H or D-X H•••A D•••A or X•••A D-H•••A or C-X•••A

Clpp * C26-H26

Repulsive -type I Cl...Cl / 3.3699 (10) 167.66( 6)

The value quoted in

Contribution of the N-H…N and N-H…O strong hydrogen bonds to the lattice electrostatic energy.

Table S11

The