'Multicomponent crystal forms of biologically active hydrazone with

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‘Multicomponent crystal forms of biologically active hydrazone with some dicarboxylic acids: Salts or co-crystals?’ Liliana Mazur, Ilona Materek, Andrew D. Bond, and William Jones Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01795 • Publication Date (Web): 22 Feb 2019 Downloaded from http://pubs.acs.org on February 23, 2019

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Crystal Growth & Design

Multicomponent crystal forms of a biologically active hydrazone with some dicarboxylic acids: Salts or co-crystals? Liliana Mazur,a* Ilona Materek,a Andrew D. Bondb and William Jonesb a

Faculty of Chemistry, Maria Curie-Skłodowska University, Maria Curie-Skłodowska Square 2, 20-031 Lublin, Poland

b

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom

* Corresponding author: Liliana Mazur ([email protected]) Abstract A multifunctional, biologically active hydrazone compound (BZH) has been cocrystallized with four aliphatic dicarboxylic acids of different carbon linkage. Multiple hydrogen-bond donor and acceptor sites on both the ligand and the co-formers enlarge the spectrum of possible aggregation modes and facilitate the formation of different stoichiometric variations. The screening for multi-component molecular complexes was performed applying both crystallization from solution and mechanochemical neat grinding (NG) and liquid-assisted grinding (LAG) techniques. The outcomes were identified and characterized by powder X-ray diffraction as well as TG/DSC analyses. Single-crystal X-ray analysis, supported by dispersion-corrected DFT relative lattice energy calculations and CSD searches, has been performed to study the chemical nature (co-crystals vs. salts) of new forms as well as synthon preferences in the resulting solids. The study reveals that the crystals are based on neutral or ionic carboxyl-pyridyl and carboxyl-amide heterosynthons. The same products were obtained under all tested experimental conditions: salts for malonic and succinic acids and a co-crystal for the larger glutaric acid. For the asymmetric mesaconic acid, two concomitant crystal forms, a 1:1 co-crystal and a 2:3 disordered solid form, were found after solution crystallization. A methanol solvate of the 1:1 co-crystal was also obtained. The LAG and NG techniques resulted in non-solvated forms of the 1:1 and 2:3 co-crystals, respectively. The correlations between the protonation state of the components, intermolecular interactions, crystal packing features and thermal stability of the resulting solids are discussed. 1 ACS Paragon Plus Environment

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1. Introduction The synthesis of new solid-state forms is an important method towards modifying the physicochemical properties of organic functional materials.1-3 The crystalline form of a given compound confers important properties to the material, such as melting point,4,5 mechanical behaviour,6,7 aqueous solubility and dissolution rate,8,9 hydration stability,10 photostability11 and color.12 An improvement of undesirable physicochemical properties, witnessed in commercialization pipelines, is a major concern in the pharmaceutical industry. It is also an important issue in many other sectors of the chemical,13,14 agrochemical15 and food industries.16 Until recently, solid-form screening in drug development focused almost exclusively on the generation of polymorphs, salts, solvates/hydrates of the drug. Currently a viable alternative to polymorphs and salts are co-crystals.2,3,17-23 Co-crystals are multi-component solids in which the individual molecules are held together by non-covalent interactions, most often hydrogen bonds.2,3,20-22 Unlike salts, in which the components in the crystal lattice are in an ionized state, the components within a co-crystal are neutral and stabilized via non-ionic interactions.23 Multi-component crystals can be expected to form if the free-energy of the system is lower than that of the crystalline components themselves.24 Commonly, co-crystals are prepared by slow solvent evaporation from solution, the limitation being the solubility of the components in a given solvent or solvent mixture, but also the solubility of the cocrystal with respect to that of single components.25,26 Direct mixing, whether with the intermediacy of small, catalytic quantities of liquid (liquid-assisted grinding, LAG) or via direct mechanical grinding of the materials (neat grinding, NG), has proved to be a more direct and cost effective (lower cost, greater yield, time reduction, no residual solvents) way to prepare co-crystals.27-31 Interestingly, mechanochemical methods, in particular LAG, which appears to vary the kinetic vs. thermodynamic outcome for the system, renders access to co-crystal forms which are not readily obtainable either from solution or from the melt. In addition to polymorphism, grinding approaches provide a simple means to new solid forms through stoichiometric variation.32 It has been demonstrated that the LAG and NG approaches can provide a higher degree of control over stoichiometric variation, compared to crystallization from solution.33

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The rapidly growing popularity of co-crystal formation can be explained by the fact that such an approach provides an opportunity to synthesize new materials by design, based on the concept of supramolecular synthons.34 Thus, co-crystals can be engineered with the intention to improve or modify a particular solid-state property of a compound without affecting the intrinsic structure of the molecule.6,12,13 A key aspect of supramolecular chemistry is identifying and utilizing those synthons that occur repeatedly and predictably, regardless of the availability of other functional groups.35 Therefore when screening for co-crystals, it is necessary to consider the functional groups present in the molecule and to select co-formers that have complementary groups which might form strong hydrogen-bond interactions.36 Currently, apart from the use of statistical tools (e.g. hydrogen-bond propensity calculations37), co-crystal design can be assisted by some computational methods (e.g. ΔpKa calculations,38 prediction of molecular complementarity39 or molecular electrostatic potential surfaces40). Nonetheless, it is still difficult to predict the resulting molecular arrangement in a co-crystal composed of coformers containing a broad range of functional groups. Therefore in order to facilitate the design of co-crystals, salts or solvates based on such complex entities, it is necessary to extend our understanding of the self-assembly process by further crystallographic studies focused on synthon hierarchies in multi-component crystals.41 This work is a part of wider project devoted to new crystalline forms of biologically active 2-pyridinecarboxaldehyde N1-acylhydrazones.42,43 Acylhydrazones represent a special group of Schiff-base derivatives which exhibit a broad spectrum of biological activities. Some, for example, have been recognized as potent agents for the treatment of drug-resistant forms of tuberculosis,44-46 as a result of their lower toxicity compared to the closely related agent, isoniazid, which is an important first-line anti-tuberculosis drug.44-47 Others have been demonstrated to possess antibacterial,48 anti-inflammatory49 and anticancer properties.47,48,50 Given the breadth of applications, it is not surprising that the chemistry of N-acylhydrazones has been the subject of much interest in recent years. However, little attention has been given to date to their molecular complexes.4,51,52 For this reason we decided to investigate the propensity of 2pyridinecarboxaldehyde benzoylhydrazone42,53 (BZH), selected as a model system, to cocrystallize using some selected dicarboxylic acids (Scheme 1). As a co-crystal component, BZH possesses two distinct hydrogen-bonding sites: the amide group and 3 ACS Paragon Plus Environment


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the pyridine ring. In the presence of carboxylic acids, there are three possibilities of aggregation between the functional groups: (a) the amide-amide homodimer (when the amide group adopts a Z conformation),42 (b) the amide-carboxylic acid heterodimer and (c) the pyridine-carboxylic acid heterodimer (Scheme 2). Both (a) and (b) are based on the

(8) hydrogen-bonded ring motif,54 while (c) is based on the

(7) ring motif. The

presence of two distinct hydrogen-bonding sites may be expected to facilitate the formation of different stoichiometric variations, as previously reported for co-crystals of isonicotinamide.55

O1

N3

C2

N2

BZH

N1

OH malonic acid

O

OH

OH OH

HO

O

HO

H

O

succinic acid

O

C1

O

O

OH

HO O

O glutaric acid

mesaconic acid

Scheme 1. Molecular structures of 2-pyridinecarboxaldehyde benzoylhydrazone (BZH) and the co-formers used in this study. pKa1, pKa2 values: (a) malonic acid: 2.83, 5.69; (b) succinic acid: 4.16, 5.61; (c) glutaric acid: 4.34, 5.41; (d) mesaconic acid: 3.09, 4.75.

This paper reports the outcomes of screening for multi-component crystal forms of BZH with four pharmaceutically acceptable dicarboxylic acids, namely malonic, succinic, glutaric and mesaconic acid. The crystal structures and physicochemical properties of the resulting salts and co-crystals are discussed. A special emphasis is placed on the likely observation of a ‘salt-cocrystal continuum’, motivated by the study of the crystal structures formed from simple pyridines and dicarboxylic acids, as reported by Mohamed et al.,56 in which the authors demonstrated the limitations of empirical rules for predicting the stoichiometry and location of the acidic proton within the pyridinecarboxylic acid heterosynthons. In an effort to detect all possible multi-component phases, extensive solution-based screening, followed by mechanochemical (NG and LAG) synthesis has been performed. 4 ACS Paragon Plus Environment

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The resulting phases are characterized by single-crystal and powder X-ray diffraction (SC XRD, PXRD) as well as thermal techniques (TG/DSC & HSM). To establish the factors responsible for salt/co-crystal formation, the main intermolecular interaction patterns and supramolecular synthons are identified and analyzed. The analysis is supported by a survey of the Cambridge Structural Database (CSD) and dispersion-corrected DFT calculations applied to the O···H···N hydrogen bonds. Additionally, the melting points of the solid forms are correlated with the protonation state of BZH, changes in crystal density and packing arrangements. 2. Experimental section 2.1. Materials. All chemicals and solvents were purchased from commercial sources (Sigma-Aldrich Co., USA, or Polish Chemical Reagents, Poland) and used without further purification. The target hydrazone (BZH, Scheme 1) was obtained by reaction of 2pyridinecarboxaldehyde with benzhydrazide in methanolic solution following the general procedure described in the literature.42,53,57 2.2. Co-crystal Screening. All crystallization and grinding experiments were performed using the crystalline monohydrate phase of BZH (denoted BZHH2O). Solutioncrystallization experiments were carried out by dissolving BZHH2O and the acid coformers, mixed in 1:1 or 2:3 molar ratios in the minimum amount of the appropriate solvent. The full list of solvents used is given in Table 2. The solutions were allowed to evaporate slowly at room temperature. The resulting crystals were air dried before being subjected to further analysis. Mechanochemical screening was conducted by neat and liquid-assisted grinding in a ball mill (MM200, Retsch, Germany) at 30 Hz for 30 and/or 60 min. A 10 mL steel vessel with two steel balls (7 mm diameter) was used for a total quantity of 50 mg (1:1 or 2:3 molar ratio) of the reactants. For liquid-assisted grinding, 12.5 μL of liquid was added. In all experiments, the formation of a new form was confirmed by comparing the PXRD patterns and IR spectra of the starting materials and the products. In the case of BZH - glutaric acid (1:1), the powder sample obtained after liquid-assisted grinding was transferred to a 10 mL vial along with 2 mL of nitromethane. The suspension was stirred at 50–60 °C until a clear solution was obtained and the solution was then slowly cooled and stored in a tightly closed vial at 5 °C. Diffraction quality crystals of 3 appeared after 4 days. 5 ACS Paragon Plus Environment


2.2.1. Powder X-ray Diffraction. PXRD data were collected on a Phillips PW3710 diffractometer with Ni-filtered Cu K radiation (λ = 1.5418 Å) at 40 kV and 40 mA using an X’celerator RTMS detector. Prior to recording PXRD patterns, the samples were gently pressed onto a glass slide. The data were collected at room temperature over a 2 range of 3-50°. A step size of 0.0167° and a collection time of 5 min were used. PXRD overlays were generated using the X’Pert Highscore software. 2.2.2. IR Spectroscopy. IR spectra (600 − 4000 cm−1) were recorded at room temperature on a 6700FT-IR spectrophotometer in the ATR mode (Table 1S, Supporting Information). 2.3. X-ray Crystallography. Single crystal X-ray data for 1, 3 and 4a were collected on a Nonius KappaCCD diffractometer using graphite-monochromated MoKα radiation ( = 0.7107 Å). The standard data collection temperature was 180 K, maintained using an open flow nitrogen Oxford Cryostream device. Integration was carried out using HKL/ DENZO58 software, and a multi-scan absorption correction was applied using SORTAV.59 Single-crystal X-ray measurements for 2, 4a·CH3OH and 4b were carried out on an Agilent Technologies Xcalibur CCD diffractometer equipped with a molybdenum sealed X-ray tube, graphite monochromator and Oxford Cryosystems nitrogen gas-flow device (Cobra Plus). The CRYSALIS60 suite of programs was used for data collection, cell refinement and data reduction. A multi-scan absorption correction was applied. The structures were solved using direct methods implemented in SHELXS-9761 and refined with the SHELXL97 program61 (both operating under WinGX62). All non-H atoms were refined with anisotropic displacement parameters. The H atoms attached to C were positioned geometrically and refined using the riding model with Uiso(H) = 1.2–1.5 Ueq(C). The carboxyl and amide H atoms were found in difference Fourier maps and, where possible, refined with isotropic displacement parameters. The disordered carboxyl H6o/H3n proton in 4b was visible in the difference Fourier map and refined with equal (50/50) site occupancy factors (SOFs). The final data collection parameters and refinement statistics for all structures are summarized in Table 1. The CIF files for each refinement are available from the Supporting Information, or can be retrieved from the Cambridge Structural Database (CSD)63 (deposition numbers: CCDC 1874705–1874710).


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Table 1. Crystallographic data and structure refinement details. Crystal structure Chemical formula

1 C13H12N3O C3H3O4

Formula weight Crystal size / mm3 Crystal colour and form T/K Crystal system Space group a/Å b/Å c/Å /° β/° /° V / Å3 Z dcalc / g·cm−3 Θ range / ° µ / mm−1 Rint Refl. coll./unique Refl. with I>2σ(I) Param./restrains R1; wR2 [I>2σ(I)] R1; wR2 [all data] GOF on F2 min/max / e·Å−3

329.31 0.25×0.15× 0.12 colourless block 180(2) triclinic P-1 3.8470(1) 14.0710(6) 14.2247(7) 94.796(2) 95.599(2) 93.970(3) 761.31(5) 2 1.437 3.91−27.46 0.109 0.046 7008/3327 2472 229/0 0.049; 0.101 0.075; 0.115 1.06 −0.26/0.22

2 C13H12N3O 0.5(C4H4O4) 0.5(C4H6O4) 343.34 0.46×0.06× 0.04 colourless needle 100(2) monoclinic C2/c 32.836(5) 4.7966(9) 21.258(3) 90 107.25(2) 90 3197.5(9) 8 1.426 2.77−27.48 0.107 0.037 7768/3673 2673 238/0 0.065; 0.162 0.094; 0.180 1.16 −0.44/0.57

3 C13H11N3O C5H8O4

4a C13H11N3O C5H6O4

4b C13H11N3O 1.5(C5H6O4)

357.36 0.25×0.15× 0.1 colourless block 180(2) monoclinic P21/n 7.1194(1) 14.6490(3) 16.6603(5) 90 93.640(1) 90 1734.03(7) 4 1.369 3.65−27.41 0.102 0.065 19095/3880 2695 247/0 0.047; 0.102 0.079; 0.117 1.03 -0.35/0.24

355.35 0.12×0.12× 0.07 colourless block 180(2) triclinic P-1 6.8868(3) 10.6535(6) 13.0312(7) 69.066(3) 76.045(3) 72.687(3) 842.71(8) 2 1.400 3.78−25.38 0.104 0.039 6962/2981 2155 244/0 0.052; 0.126 0.082; 0.147 0.95 −0.24/0.23

420.40 0.58×0.27× 0.09 colourless needle 100(2) triclinic P-1 4.7780(3) 9.9290(8) 21.581(2) 79.777(6) 89.906(5) 84.191(6) 1002.3(1) 2 1.393 2.45−28.28 0.107 0.043 8980/4866 3040 305/0 0.064; 0.141 0.113; 0.188 1.05 −0.34/0.36

4a·CH3OH C13H11N3O C5H6O4 CH3OH 387.39 0.56×0.18× 0.04 colourless plate 295(2) triclinic P-1 6.673(1) 11.272(2) 13.945(2) 68.16(2) 84.18(1) 84.15(2) 966.3(3) 2 1.331 2.92−27.48 0.100 0.034 7715/4434 2573 271/0 0.057; 0.122 0.107; 0.153 1.02 −0.19/0.22

2.4. Survey of the Cambridge Structural Database. The CSD (ver. 5.39) was searched for structures containing at least two chemically different molecules bearing carboxyl or carboxylate group and 2-pyridine and/or N1-acylhydrazone units, respectively, using the following filters: (a) 3D coordinates determined; (b) R1 ≤ 7.5 %; (c) only organics. The searches were conducted using the program ConQuest 1.20.64 Crystal structures were analysed using the software Mercury 3.10.64 2.5. Thermal Analysis. The thermal stability of the products was examined using a Setsys 16/18 (Setaram) thermal analyser, recording the TG/DTG/DSC curves. The samples (4−7 mg) were heated in an open ceramic crucible at the temperature 30–650 °C in a flowing air atmosphere with a heating rate of 2 °C min−1. The mass loss was characterized by TG and was calculated based on the original sample mass. The temperatures of fusion were established from the DSC curves (see Table 1S, Supporting Information). TG/DSC analyses for 1–3, 4a and 4b (Figure 6S, Supporting Information) 7 ACS Paragon Plus Environment


in a nitrogen atmosphere were performed using a Mettler Toledo TGA/SDTA851e/SF/ 1100 instrument with a heating rate of 10 °C min-1. 5-8 mg of the sample was analyzed in a 0.1 mL aluminum pan. STARe software was used for data acquisition and analysis. 2.6. Hot-stage Microscopy (HSM). The Linkam LTS 350 hot-stage and polarizing microscope Nikon Eclipse 50iPOL were used for the analysis. The samples were studied over a temperature range of 25–180 °C at a constant heating rate of 2 °C min-1. 2.7. Computational modelling. The crystal structures were energy-minimized with dispersion-corrected density functional theory (DFT-D) using the CASTEP module65 in Materials Studio.66 The PBE functional67 was used with a plane-wave cut-off energy of 340 eV, in combination with the Grimme (2006) dispersion correction.68 All other parameters in Materials Studio were set to the ‘fine’ defaults. The unit-cell parameters were constrained to the experimental values and the determined space group symmetry was imposed except for 2 and 4b as described below. Each minimization was repeated with the proton of the O···H···Npyridyl unit starting on either the O or the N atom. In all cases, the proton migrated to the same minimized position (i.e. the minimized result is independent of the starting point). For 2 and 4b, the diacid molecules lie on symmetry elements. In 2, distinct succinic acid molecules lie on inversion centres and 2-fold rotation axes, with the latter forming interactions with the pyridyl group of BZH. Minimization of this structure was carried out in space group C2/c and also with the symmetry reduced to Cc, thereby placing all molecules on general positions. The results were identical. In the case of Cc, asymmetry was introduced by moving the proton from N onto O at only one end of the succinic acid molecule, but minimization reproduced the centrosymmetric dianion. This establishes the space group C2/c as appropriate for the minimized structure of 2. In 4b, one mesaconic acid molecule occupies a general position and one molecule is disordered across an inversion centre, with the latter involved in the interaction with the pyridyl group. For energy minimization, the space group of 4b was reduced to P1, retaining one orientation of the disordered molecule.


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The O···H···Npyridyl potential well was examined using an approach described by Mohamed et al.56 Starting from the minimized structures, the H atom was positioned along the N···H vector in steps over the range N–H = 0.95–1.65 Å. Each model was minimized in full in space group P1 with the unit-cell parameters and appropriate N–H distances constrained. For 2, the minimized C2/c structure was converted to a primitive equivalent (with half the unit-cell volume) before resetting to space group P1. The approach allows the other parts of the structure to respond to the constrained N–H distance, and as a result the energy changes are not necessarily solely due to the potential well in question. Rather, the method indicates the minimized energy of the whole structure under the assumption that the N–H distance is as specified. This is discussed further below when considering the results. 3. Results and discussion 3.1. Co-crystal screening. All the compounds under investigation (BZHH2O and coformers) are adequately soluble in water and most common organic solvents and solution-crystallization experiments were performed for the preliminary screening. Equimolar amounts of the two co-crystal formers were dissolved in the minimum amount of solvent with a set of 10 solvents with a range of polarities and functional groups selected. A summary of the screening results is given in Table 2. The outcomes of the solid-state and solution experiments are presented in Scheme 2. Single crystals of 1, 2, 4a, 4b and 4a·CH3OH suitable for X-ray diffraction studies were grown at room temperature using the standard solvent-evaporation technique. For the BZH – glutaric acid system, all solvents resulted only in amorphous products. Diffraction quality crystals of 3 were, however, obtained by recrystallization from a solution in nitromethane of the powder sample obtained by LAG (see details in the Experimental Section). Preliminary tests on the BZH – mesaconic acid (1:1) mixture revealed the existence together of the two multi-component crystal forms 4a, 4b (Figure 1S, Supplementary Information). Further studies on the 2:3 mixtures using various solvents exhibited preferential formation of 4b (Table 2). The solution-crystallization experiments on the BZH – mesaconic acid (1:1) mixture using pure methanol provided a new form 4a·CH3OH. This was the only solvate encountered. After mixing the co-crystal formers in a 2:3 ratio, concomitant crystallization of 4a·CH3OH and 4b was observed from 9 ACS Paragon Plus Environment


methanol. Thus, in the case of BZH – mesaconic acid mixtures the solution crystallization outcomes seem to be governed by the stoichiometric ratio of the co-crystal formers. However, the kind of the solvent used can also be decisive. To screen for further possible forms and to understand better the experimental conditions under which particular forms can arise, mechanical grinding was employed as a next step. As confirmed by the PXRD data, both neat and liquid-assisted grinding of equimolar amounts of BZHH2O and succinic acid gave the same crystalline form (2). As can be seen in Figure 1, the experimental powder patterns of the resulting solids are in good agreement with that simulated from the determined crystal structure of 2. Further attempts to obtain different solid forms (polymorphs or stoichiometric variations) for that system by varying the reaction time or a solvent were not successful. For both NG and LAG, increasing the grinding time from 30 to 60 min resulted solely in 2 (Figure 2S, Supporting Information). Hence, it seems likely that 2 is the thermodynamically stable form. Notably, the PXRD data revealed only partial conversion of the co-crystal formers after 30 min of milling using water as a solvent (Figure 1), which indicates that even a small (catalytic) amount of water added to the reaction mixture inhibits the reaction rate. Similar outcomes were observed after grinding experiments using 1:1 mixtures of BZH – malonic acid and BZH – glutaric acid; both NG and LAG led to the same multi-component solid forms (1 and 3 respectively), without any apparent additional forms. Comparison of the experimental PXRD patterns for the samples after NG and LAG (Figures 3S, 4S; Supporting Information) with those calculated from the crystallographic measurements showed good agreement. To identify suitable conditions for selective preparation of 4a and 4b, NG and LAG were performed for 1:1 and 2:3 BZH – mesaconic acid mixtures. Figure 5S (Supporting Information) presents the comparison of selected PXRD patterns of the samples after NG and those obtained in the LAG experiments with solvents of varying polarity (acetonitrile, ethanol, propan-1-ol). In the case of the LAG experiments, PXRD analysis of the ground materials confirmed the formation of the same solid form in all batches. Furthermore, the powder patterns of the resulting samples were quite similar to the simulated trace of the denser form 4a (Figure 2). Slight differences in the peak positions, 10 ACS Paragon Plus Environment

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particularly at higher 2θ, can be explained by contraction of the unit cell at low temperature in the single-crystal XRD data. In contrast, the PXRD pattern of the sample after NG is in good agreement with that calculated for structure 4b (Figure 2). However, in some NG experiments, when a larger amount of the sample was used (> 100 mg) a mixture of 4b and 4a was obtained. Thus, the LAG experiments with the 1:1 and 2:3 BZH – mesaconic acid mixtures led to form 4a, regardless of the solvent used, whereas NG mainly produced form 4b. It is also worth noting that co-crystal 4a, which is readily obtained by LAG, rarely appears after slow solvent evaporation from solution (an approach that tends to drive a system to thermodynamic products). A pure form 4a was obtained by rapid cooling of hot saturated solution of 1:1 BZH – mesaconic acid mixture in acetone. This may suggest that co-crystal 4a is a kinetic form, whereas 4b is a thermodynamic one. This seems to be consistent with the fact that recrystallization of the pure phase 4a from different solvents (e.g. propan-2-ol, acetone, acetonitrile) led to a mixture of forms 4a and 4b. There is no evidence of any phase transition or decomposition processes after further grinding of 4a and 4b, separately, with or without solvent.



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Scheme 2. An overview of the solid-state and solution reactions of BZH·H2O with malonic, succinic, glutaric and mesaconic acid. Table 2. Attempted co-crystal formation experiments and outcomes as determined by singlecrystal and powder XRD. Co-former/ BZH:acid ratio

Malonic acid (1:1)

Succinic acid (1:1)

1

2

Glutaric Acid (1:1)

Mesaconic acid (1:1) (2:3)

NG 3

4b

4b

3

4a

4a

4a·CH3OH 4b 4b 4b 4a+4b 4a+4b 4a+4b 4a+4b 4a+4b 4b

4a·CH3OH+4b 4b 4b 4b 4b 4b 4a+4b 4b 4a+4b 4b

LAG Solvent: nitromethane, acetonitrile

1

2

Solution crystallization Solvent: Methanol Ethanol Propan-1-ol Propan-2-ol Acetonitrile Nitromethane Acetone Chloroform Ethyl acetate Water

1 1 1 1 1

2 2 2 2 2 2 2 2

-

Figure 1. PXRD patterns for experiments involving succinic acid (succ): (a) pure BZHH2O after NG; (b) calculated BZH-succ (2); (c) BZH-succ prepared by NG; (d) BZH-succ prepared by LAG using nitromethane; (e) BZH-succ prepared by LAG using acetonitrile; (f) BZH-succ after LAG using water; (g) pure succinic acid.


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Figure 2. PXRD patterns for experiments involving mesaconic acid (mesac): (a) benzoylhydrazone monohydrate (BZHH2O) after NG; (b) calculated 4a; (c) calculated 4b; (d) 4b after NG; (e) 4a after LAG using nitromethane as a solvent; (f) pure mesaconic acid.

3.2. X-ray crystallography 3.2.1. Crystal structures. Crystallographic data for the structures are given in Table 1, whilst the plots of the molecular units with the atom-labelling schemes are shown in Figure 1S (Supporting Information). Selected molecular and hydrogen-bond geometrical parameters are given in Tables 2S and 3S, respectively. The crystallographic data indicate that 1 and 2 can be classified as salts, whereas 3, 4a and 4a·CH3OH are co-crystals. This was evidenced by proton location and analysis of the C–O bonds length in the acid molecules as well as the C–N–C angles in the pyridine ring (Table 2S). For example, the C–O and C=O bond distances of 1.308(2)–1.331(3) Å, 1.203(3)–1.206(2) Å, and C–N–C angles of 117.4(1)°–118.0(2)° observed in structures 3, 4a and 4a·CH3OH suggest neutral carboxyl-pyridyl synthons (A, B in Scheme 3), in contrast to the equivalent values of 1.269(2)–1.289(3) Å, 1.236(3)–1.243(2) Å and 121.6(2)°–122.5(2)° in crystals 1 and 2, corresponding to ionized pyridinium and carboxylate groups. More complex behaviour was observed for 4b where the bond lengths in the carboxylic group involved in the carboxyl···pyridyl interactions were 1.300(3) Å and 1.217(3) Å, and the bond angle at the pyridyl N atom was 118.9(2)°. Proton location both at the carboxyl O6 and pyridyl N3, supported by these geometrical values, suggest that 4b is disordered (at the measured temperature of 100 K). 13 ACS Paragon Plus Environment


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All the studied forms crystallize in centrosymmetric space groups. As expected from the ratio of hydrogen-bond donor and acceptor groups, there is one BZH molecule and one co-former in the asymmetric unit (ASU) of the resulting crystals, except for the (2:3) form 4b, where the ASU consists of one BZH molecule and one and a half molecules of mesaconic acid, and (1:1:1) 4a·CH3OH, where the ASU is completed by one solvent molecule. In all cases, BZH and co-formers are connected by N–H···O, O–H···N and/or O– H···O hydrogen bonds, supported by numerous C–H···O and C–H···N contacts. Noteworthy, excluding the solvate 4a·CH3OH, conventional hydrogen bonding is limited to BZH···coformer and co-former···co-former dimeric and multimeric units. Ph N1

O1

H

N1

O1 H

N2

H

N3

Ph

H O1

H

N2

R

O

N3

O H

H

N1

N1 N2

R

N3

B

O1 H

C Ph

N1 N2

H N3 + H

R

O

H

O1 H H N3 +

O

H

H

Ph H

O

O

H

N2

O

O

A

Ph O1

R

Ph

A’

R O

O

O

R

B’

H O

N1 N2

H H N3

D

Scheme 3. Hydrogen-bonding supramolecular heterosynthons encountered in the BZH – dicarboxylic acid systems. A, A’ and B, B’ refer to the neutral COOH···Narom and ionic COO-···Narom+ forms of ring and chain carboxylic acid-pyridine synthons, respectively.

BZH malonate (1:1) (1). The ASU in crystal 1 is composed of one BZH+ cation and one mono-anion of malonic acid; both are located at general positions. The BZH and coformer are connected by strong N3+–H3o···O4- (2.564(2) Å, 179(3)°) and weak C7– H7···O5 (3.240(2) Å, 125°) hydrogen bonds to form cyclic heterosynthon A’ (Scheme 3, Figures 3a, 3b). Another strong N1–H1n···O3 (2.878(2) Å, 165(2)°) hydrogen bond, supported by weak C2–H2···O3 (3.235(2) Å, 141°) interactions, which creates the amide14 ACS Paragon Plus Environment

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carboxylic acid

(6) heterosynthon C, connects neighbouring dimers into tetrameric

units across the inversion center. The malonate anion shows the anti conformation of the protonated carboxylic group and displays an O2–H2o···O5 (2.530(2) Å, 163(3)°) intramolecular hydrogen bond (Figure 3a). Intramolecular hydrogen bonding is a common feature in both ionized and non-ionized malonic acid molecules in the solid state.63 The 3D framework of 1 can be analyzed in terms of two two-dimensional substructures. The first utilizes weak Cpyr–H···Oamide and Cphenyl–H···Ocarb hydrogen bonds (Table 3S) which span the four-component units into supramolecular layers parallel to the (102) crystallographic planes (Figures 3b, 3c). The second is based on Caliph–H···Ocarb interactions between the malonate ions and π···π interactions between the planar BZH molecules, both formed due to the stacking of parallel (102) layers (Figure 3c).

b)

a)

Figure 3. Perspective view of 1 showing: a) four-component (BZH)+···(malac)- assemblies; b) (102) molecular layers, sustained by strong N−H···O and weak C−H···O/N hydrogen bonds, viewed along the a axis; c) 2D layers stacked in a “head-to-head” fashion viewed along the b axis. Dashed lines indicate the hydrogen bonds.

BZH succinate – succinic acid (2:1:1) (2). The salt form 2 crystallizes in space group C2/c with one BZH+ cation, one half of a succinate dianion and one half of a succinic acid molecule in the ASU. The succinic acid molecules are located on inversion centers whereas the succinate dianions lie on 2-fold axes. The molecules are arranged as alternating bilayers of BZH and single layers of the co-former, both parallel to the (100) planes (Figures 4b, 4d). Thus there are clear regions of succinate···succinic acid interactions and those where only BZH molecules interact. For the former, each succinic acid molecule is connected to two adjacent succinate ions via very short, linear O4– 15 ACS Paragon Plus Environment

c)


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H4o···O2- (2.594(3) Å, 177(2)°) hydrogen bonds supported by weak C15–H15···O4 (3.414(3) Å, 135°) interactions. The resulting chains are linked into the 2D succinate···succinic acid layers by additional C–H···O contacts (Table 3S, SI). The overall molecular arrangement in 2, however, appears to be governed by interactions at the ‘interface’ of those layers. The molecular conformation of the succinate ion is considerably twisted from planarity, with the angle between the least-squares planes of the carboxylate groups being ca 77.6°. As a result, each O2–C14–O3 unit can serve as a ‘bridge’ (Figure 4a) spanning two ‘face-to-face’ oriented BZH+ cations via two strong N3+–H3n···O2- (2.599(3) Å, 176(2)°) (synthon B’; Scheme 3) and N1–H1n···O3 (2.801(3) Å, 166(2)°) hydrogen bonds; the latter supported by a weak C2–H2···O3 (3.176(3) Å, 137°) contact (synthon C). This leads to the creation of (BZH)+···(succ)2- supramolecular stacks (columns) propagating along the b axis held together by succinic acid molecules (Figure 4b). Interactions between the BZH units are limited to weak C–H···O/N, C–H···π and π-stacking contacts (Figure 4c) involving aromatic rings and hydrazide units from adjacent, perpendicularly oriented molecules (Figure 4d).

c)

a)

b)

Figure 4. Part of the crystal structure of 2 showing: a) intermolecular interactions involving the BZH+ and succinate ions; b) crystal packing viewed along the b axis; c) intermolecular interactions between the adjacent BZH molecules; d) (100) double layers of BZH interconnected by (succ)···(succ)2- chains. Neutral succinic acid molecules and succinate ions are marked green and blue, respectively.


d)

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BZH – glutaric acid (1:1) (3). As confirmed by the crystallographic data the asymmetric unit of 3 contains one BZH and one glutaric acid molecule, both in their neutral forms (Table 2S, SI). The structure does not show any clear separation of the BZH and coformer molecules, as present in salt 2. The acid molecules adopt a bent conformation with torsion angles around the C15–C16 and C16–C17 bonds (Figure 1S) of -70.8(2)° and -73.2(2)°, respectively. The O2–C14–O3 carboxylic group is situated between two neighbouring BZH molecules, playing the role of the ‘supramolecular linkage’ (Figure 5b). The anti oriented hydroxyl group serves as a donor in the bifurcated O2–H2···O1,N2 hydrogen bonds (2.619(2) Å, 163(2)° and 3.194(2) Å, 122(2)°) creating the cyclic synthon D (Scheme 3, Figure 5a) and the dimer is additionally stabilized by weak C4– H4···O2 (3.598(2) Å, 161°) contacts. These bimolecular units are connected into molecular chains, propagating along the c axis (Figure 5b) via strong N1–H1n···O3 (2.926(2) Å, 167(2)°) hydrogen bonds accompanied by two weak C2–H2···O3 and C13– H13···O3 interactions (Table 3S; Figure 5a), creating two rings with and

(6) (synthon C)

(7) graph set notations. The second carboxylic group of the acid is involved in two

interactions with the pyridyl substituent from the next, inversion-related molecule (Figure 5a) leading to the cyclic synthon A. In this way, the antiparallel chains are held together into double supramolecular layers (Figure 5c). The interactions responsible for binding the 2D layers into the stable 3D architecture would appear to be π-stacking contacts between the overlapping aromatic rings and/or acylhydrazone units.

b)

a)

c)

Figure 5. Part of the crystal structure of 3 showing: a) hydrogen-bonded tetrameric motifs formed by BZH and malonic acid molecules; b) 2D molecular layer parallel to the (100) crystallographic planes; c) crystal packing viewed along the b axis.



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BZH – mesaconic acid (1:1) (4a). Form 4a crystallizes in space group P-1, with both co-crystal components located on general positions. As for co-crystal 3, the BZH and coformer molecules are not separated in the crystal and each acid molecule is involved in the creation of three out of the four main heterosynthons (Scheme 3), namely B, C and D (Figure 6a). The main supramolecular motif in crystal 4a is a double chain, propagating along the b axis (Figures 6b, 6c), constructed by alternately arranged BZH and mesaconic acid molecules. The mesaconic acid molecules adopt a planar conformation, apart from the O4–C17–O5 carboxylic group which is twisted by 20.8(2)° around the C17–C16 bond. The perpendicular orientation of the centrosymmetric BZH and mesaconic acid pairs promotes the formation of short, bifurcated O2–H2o···O1,N2 (2.600(3) Å, 158(2)° and 3.188(3) Å, 123(2)°) hydrogen bonds (heterosynthon D) and short, linear N1–H1n···O3 (2.897(3) Å, 162(2) °) interactions, supported by weak C2– H2···O3 (Table 3S, Supporting Information) contacts (heterosynthon C) between the carboxyl O2–C14–O3 group of the acid and hydrazine units of BZH. The second carboxylic group serves as a donor in a strong O4–H4o···N3 (2.699(3) Å, 169°) hydrogen bond to the pyridyl N atom (synthon B) thus creating a centrosymmetric hexameric motif (Figure 6a). It is noteworthy that this type of packing arrangement is not observed in any of the other structures reported in this work. The parallel, translation-related chains are linked by weak C–H···O interactions (Table 3S, Supporting Information), involving the pyridyl ring and carboxylic O5 atom (Figure 6b). The interactions between overlapping chains (Figure 6c) are limited to π-stacking contacts between aromatic rings.

a)

b)


c)

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Figure 6. Crystal structure of 4a: a) centrosymmetric BZH···mesaconic acid hexamers; b) hydrogen-bonded supramolecular chains propagated along the b axis; c) crystal packing in view along the c axis.

BZH mesaconate – mesaconic acid (2:1:2) (4b). The less dense form 4b, preferentially produced by NG as well as from solution, crystallizes in space group P-1, with one neutral and one half of the disordered mesaconic acid molecule in the ASU. The characteristic supramolecular motif in crystal 4b is a centrosymmetric tetramer (Figure 7a), created by two BZH and two mesaconic acid molecules, all being almost co-planar. At the inside of the motif, the components are packed in a ‘side-on’ manner so that the pyridyl ring and the hydrazide unit of BZH+ approach both carboxylic groups of the acid. As a result, the molecules can interact via strong, bifurcated O2–H2o···O1,N2 (2.684(3) Å, 179(2)° and 3.028(3) Å, 110(2)°) hydrogen bonds (synthon D), and the dimer is further stabilized by lateral C4–H4···O2 and C5–H5···O4 interactions (Table 3S, Supporting Information). The inversion-related dimers are linked by two O4–H4o···O5 (2.628(4) Å, 179(2)°) hydrogen bonds between the carboxylic group O4–C17–O5, giving the characteristic ring motif with the graph set notation

(8).

The principal intermolecular interactions in crystal 4b, however, seem to be the chargeassisted O6–H6o···N3 / N3+–H3o···O6- (2.601(5) Å, 179(3)°) hydrogen bonds (synthon B’) between the partly deprotonated carboxylic O6–C19–O7 group and the pyridyl N3 atom (Figure 7b). The second oxygen atom from the same carboxylate group serves as an acceptor in one strong N1–H1n···O7 (2.878(3) Å, 170(2)°) and two weak C2–H2o···O7 (synthon C), C13–H13···O7 hydrogen bonds (Table 3S, Supporting Information). Careful analysis of the resulting hexameric motif (Figure 7b) reveals its close similarity with that observed in salt 2 (Figure 4a). Likewise, the two parallel mesaconic ions serve as a ‘bridge’ between two pairs of ‘face-to-face’ oriented BZH molecules. The combination of tetrameric and hexameric motifs results in the creation of 2D supramolecular layers (Figure 7d), parallel to the (011) crystallographic planes. The adjacent layers, related by simple translation along the b axis (Figure 7c), are stabilized via weak intermolecular interactions involving pyridyl rings and mesaconic acid molecules (Table 3S, Supporting Information).



a)

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b)

d) c) Figure 7. Crystal structure of 4b: a) centrosymmetric tetramers formed by BZH and mesaconic acid; b) intermolecular interactions between BZH and partly deprotonated mesaconic acid molecules; c) crystal packing viewed along the a axis; d) crystal packing viewed along the [-110] direction.

BZH – mesaconic acid methanol solvate (1:1:1) (4a·CH3OH). The methanol solvate of BZH – mesaconic acid crystallizes in space group P-1, with one molecule of each cocrystal former and one molecule of the solvent in the ASU, all located on general positions. The crystal structure of 4a·CH3OH is stabilized primarily via strong hydrogen bonds. The imbalance in the total number of hydrogen-bond donor/acceptor atoms, observed in some other systems, is addressed by incorporation of the methanol molecules into the net, thereby satisfying the BZH acceptor capacity (Figure 8b) and enabling close packing of the molecules in the crystal. In contrast to the remaining structures, the primary supramolecular motifs in 4a·CH3OH are the ‘host-guest’ chains constructed by the translation-related BZH units ‘bridged’ by methanol molecules. It is worth noting that a similar supramolecular motif was observed in the crystal of 2pyridinecarboxaldehyde benzoylhydrazone monohydrate42 (BZHH2O), in which water molecules fill the voids between adjacent BZH units. Interestingly, repeated crystallization 20 ACS Paragon Plus Environment

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attempts at BZHH2O using diverse organic solvents, including methanol, led solely to its monohydrate.42 As in BZHH2O, the ‘host’ and ‘guest’ components are linked by short, almost linear N1–H1n···O1m (2.908(2) Å, 172(1)°) hydrogen bonds, enhanced by two weak C–H···O (Figure 8b, Table 3S) interactions. Moreover, the methanol molecule serves as a donor in bifurcated O1m–H1m···O1,N2 (2.817(3) Å, 154(1)° and 3.213(3) Å, 125(2)°) hydrogen bonds to the next, translation-related BZH, thus producing supramolecular chains extending along the a axis. Finally, the hydrogen-bonding potential of a single BZH molecule is met by strong O2–H2o···N3 (2.643(2) Å, 178(1)°) hydrogen bonds (Figure 8a), accompanied by weak C7–H7···O3 interactions (Table 3S, Supporting Information) involving the pyridine ring and the carboxylic acid group of the co-former (synthon A). As can be seen in Figure 8d, the ‘head-to-tail’ oriented mesaconic acid molecules, linked via short, linear O4–H4o···O5 (2.648(3) Å, 175(2)°) hydrogen bonds into centrosymmetric dimers, fill the voids between the adjacent, antiparallel oriented BZH – methanol chains. Thus there is a clear separation of BZH and mesaconic acid molecules in the crystal. The relative orientation of BZH and mesaconic acid molecules promote the formation of some other weak C–H···O interactions (Figure 8a), involving the aromatic rings of BZH as donors. As a result, each mesaconic acid is connected to three adjacent BZH molecules, giving multicomponent motifs, further transformed by inversion, creating (-123) sheets. Combination of the 1D chains and 2D sheet motifs creates the observed 3D architecture (Figure 8c).

a)


b)


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c) d) Figure 8. Part of the crystal structure of 4a·CH3OH showing: a) (-123) sheet motif involving strong O−H···O and weak C−H···O/N hydrogen bonds; b) ‘host-guest’ intermolecular interactions; c) molecular packing projection presenting antiparallel ’host-guest’ [100] supramolecular chains and (-123) sheet motifs; d) crystal packing viewed along the a axis.

3.2.2. Conformational analysis In the previous papers, attention was paid to the molecular conformation of BZH and some other closely related 2-pyridinecarboxaldehyde acylhydrazones in their unsolvated forms and hydrates.42,43 The molecular conformation of BZH in studied structures is found to be similar to that in BZH·H2O (CSD refcode: CIZRAE02)42 corresponding to a relatively lower-energy conformer. In most cases the molecule is almost flat as confirmed by the dihedral angle between the least-square planes of the aromatic rings (β; Table 3). No significant differences in the bond lengths and angles (Table 2S, Supporting Information) are observed within the central spacer unit between the two rings, which adopts the EZ’ conformation with the s-trans junction between the imine and amide functions (Scheme 1, Figure 1S). The single and double bonds are easily distinguished, which confirms that BZH exists in its keto-imino tautomeric form in all of the structures. A further common conformational feature is the anti orientation of the pyridyl N3 with respect to the imine N2 atom. A comprehensive conformational analysis for an isolated molecule of BZH using quantum-chemical calculations revealed the EE’ conformation to be energetically preferable in the gas phase by 5–9 kJ·mol-1, depending on the level of theory used.42 At the same time the torsion-angle-constrained energy scans around the C2–C3 and C1–C8 bonds indicated the anti conformation (with N2–C2–C3–N3 angle equal to 180° and O1–C1–C8–C9 being about 155°) to be energetically favourable. Interestingly, in the hydrate crystal structure BZHH2O and the structures reported 22 ACS Paragon Plus Environment

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herein the less stable EZ’ conformers are observed and both aromatic rings are slightly twisted from their ideal orientations. Such results can come from both specific intermolecular interactions (in particular those involving the amide and pyridyl groups) as well as steric effects in the crystals. Table 3. Selected torsion angles (1, 2, 3) and dihedral angles () between the best planes of aromatic rings in the molecular complexes and the BZH monohydrate.

1 (N2−C2−C3−N3) 2 (C1−N1−N2−C2) 3 (O1−C1−C8−C13) 

BZH·H2O (CIZRAE02)42 -175.1(1) -176.9(1) -158.2(1) 30.4(1)

1

2

3

4a

4b

174.1(1) 178.5(2) 168.1(1) 178.6(2) -171.8(2) -177.6(2) 177.9(2) -177.7(1) 179.0(2) -169.8(2) -153.0(2) -179.4(3) -166.6(2) -170.4(2) 175.4(2) 18.4(2) 24.9(2) 3.5(2) 8.4(1) 8.8(2)

4a·CH3OH 168.2(2) 177.9(2) -165.6(2) 2.8(2)

An overlay of the conformers found in the studied crystals is shown in Figure 9. As follows from this view and the corresponding torsion angles given in Table 3, the conformational differences between the BZH molecules are small and arise mainly due to rotation around the C2–C3 (1) and C1–C8 (3) bonds. The 2 torsion angle, which defines the conformation of the central spacer, deviates from 180° by no more than 3°, except for structure 4b where the rotation around the N1–N2 bond is about 10°. It is worth stressing, in spite of the presence of the higher-energy conformer, that form 4b has a higher melting point (Figure 12, Sect. 3.5) compared to 4a and 4a·CH3OH which suggests significant lattice energy gain owing to the inclusion of an additional co-former molecule and different intermolecular interaction patterns in the crystal. The main conformational variations in the molecule are described by the torsion angle 3, which in 2 and 4b deviates from the optimum value by more than 20° (Table 3). This can be explained by π-stacking interactions between the phenyl rings observed in both structures. The pyridyl ring is mostly coplanar to the imine group, but in 3 and 4a·CH3OH it is twisted from its plane by about 12°. In general, the BZH conformation in salt 1 was found to be closest to that in BZHH2O and the energy-minimized geometry for the isolated molecule. However, the minimumenergy conformer was not observed in the molecular complexes. Furthermore, there is



no straightforward relation between the protonation state of the molecule and its conformational behaviour.

Figure 9. Superposition of the BZH geometries extracted from the crystal structures of 1 (green), 2 (blue), 3 (orange), 4a (violet), 4b (brown) and 4a·CH3OH (red).

3.3. Synthon occurrences (CSD searches) CSD searches were performed to check the synthon preferences in two-component structures (salts and co-crystals) formed by carboxylic acids with molecules containing 2-pyridyl or both 2-pyridyl and N1-acylhydrazone moieties. The survey revealed 135 entries related to carboxylate/carboxylic acid: 2-pyridine combinations (excluding N1acylhydrazone co-formers). In this set there are 81 structures (60%) with carboxylic acid– pyridine heterosynthons, including 39 co-crystals and 42 salts. A total of 34 structures with the

(7) ring synthon (Scheme 3) were found, out of which 22 belong to subset A

and 12 to subset A’ with the neutral and ionic forms of the COOH···Narom motif, respectively. Simultaneously, 47 structures with the linear synthon B were found, of which 30 can be classified as salts (motif B’) and 17 as co-crystals (motif B). The dominance of linear heterosynthons B and B’ is not surprising when it is considered that many of the co-formers contain multiple hydrogen-bond donors and acceptors, e.g. hydroxyl, amide, amine units, which can interact with the carboxylic/carboxylate group to generate supramolecular tapes or sheets. On the other hand, the survey reveals that in the absence of competing HB groups heterosynthon A has a 50% occurrence rate in the set of 10 structures containing solely the carboxyl and 2-pyridyl moieties. Interestingly, the carboxylic acid homosynthon occurs in 57/135 (42.2%) of available structures.


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The literature survey and CSD data indicates that only a few N1-acylhydrazones have been explored for the production of co-crystals.4,51,52 The CSD search revealed 31 structures based on molecules containing both the pyridyl and N1-acylhydrazone group (Table 4S, Supporting Information). This includes 8 co-crystals of 2-pyridylcarboxaldehyde isonicotinoylhydrazone with either mono- or dicarboxylic acids. All of them exist as hydrates with water playing the role of supramolecular ‘linkage’ between the hydrazide group of the basic co-former. As in the case of BZH·H2O, the tendency to include water can be explained by the imbalance of the total number of hydrogen-bond donor and acceptor groups in the structure. The dominant supramolecular heterosynthon in all 8 co-crystals is the COOH···Narom motif involving the isonicotinoyl moiety. In most cases (6/8 structures) 2-pyridyl is excluded from strong hydrogenbonding. Alternatively, the pyridyl N atom serves as an acceptor via hydrogen bonding to water molecules (2/8 structures). However, due to the presence of the competitive 4pyridyl substituent, no general conclusion concerning the synthon preferences in the cocrystals of 2-pyridylcarboxaldehyde hydrazones can be drawn. Unfortunately, there is a lack of reported structural data for other 2-pyridylcarboxaldehyde hydrazones. Nonetheless, the study of the available data set (Table 4S, Supporting Information) shows some general trends. The small number of salts (4/31 structures; 12.9%) and the significant contribution of hydrates (18/31; 58.1%) are particularly worthy of note. When water molecules are present in the structure, they participate in the creation of water···amide···water hydrogen-bonding chains, which appear to contribute noticeably to the stabilization of the resulting crystal net. Otherwise, co-crystal formers are mostly stabilized via amide-carboxyl (8/13 structures) and/or carboxyl-amide (8/13 structures) heterosynthons C and D (Scheme 3). 3.4. DFT calculations In general, the DFT-D minimizations reproduced very well the crystallographic results. As expected, the non-H atom positions in the minimized structures deviate negligibly from the crystallographic positions. The principal interest is in the location of the H atoms in the O···H···Npyridyl hydrogen bonds. For most of the structures, the calculations confirmed the salt/co-crystal assignment from the X-ray analysis: 1 was shown clearly to be a salt, 2 was shown to be a salt at both ends of succinic acid, and 3, 4a and 4a·CH3OH were shown to be co-crystals. The disordered mesaconic structure 4b is the 25 ACS Paragon Plus Environment


most interesting in that the minimized structure in space group P1 showed a co-crystal at the C(H) end of the acid, but a salt at the C(Me) end. This is consistent with the H-atom disorder proposed from the X-ray crystallographic refinement in space group P–1. For the calculations examining the potential wells of the O···H···Npyridyl hydrogen bonds, (Figure 10) 1 and 2 show a well-defined minimum corresponding to a salt, as would be expected for the strongest acids amongst the co-formers, while 3, 4a and 4a·CH3OH show a minimum corresponding to a co-crystal. In 3, there is a relatively steep incline when moving towards a salt, while the profiles for 4a and 4a·CH3OH are flatter over the N–H range 1.2–1.6 Å. In the latter two structures, the O···H···Npyridyl unit under consideration is adjacent to CH in 4a, but adjacent to C(CH3) in 4a·CH3OH, showing that there is no difference in principle between the behaviour of the two ends of the mesaconic acid molecule. Common to both cases is that the carboxylic acid group at the other end of the molecule is protonated.

Figure 10. Relative lattice energy for minimised crystal structures as a function of constrained N–H distance for the O···H···Npyridyl interactions. 1 and 2 show clear minima corresponding to salts (N–H ≈ 1.10 Å), while 3, 4a and 4a·MeOH show shallow minima corresponding to cocrystals (N–H ≈ 1.55 Å). Calculations are not shown for 4b due to complex behaviour, described in the text.


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4b shows more complex behaviour. The sequence of calculations was carried out twice, examining the O···H···Npyridyl interaction at either the C(CH3) or the C(H) end of the mesaconic acid molecule, with the other end of the molecule free to relax during the minimization. Constraining the N–H distance at the C(CH3) end of the molecule, the C(H) end optimises to a co-crystal for N–H ≤1.40 Å, but optimises to a salt for N–H ≥ 1.50 Å. Hence, when the C(CH3) end is clearly a co-crystal, the C(H) end optimises to a salt. Constraining the N–H distance at the C(H) end of the molecule, the C(CH3) end optimises to a co-crystal for N–H ≤1.05 Å, but optimises to a salt for N–H ≥ 1.10 Å. Hence, when the C(H) end is clearly a salt, the C(CH3) end optimises to a co-crystal. This transition means that the calculated energy profiles do not reflect the individual O···H···Npyridyl interactions (so they are not shown in Figure 10). A final set of calculations with the H atoms constrained in positions defining the salt/salt, salt/co-crystal (x2) and cocrystal/co-crystal scenarios indicates the order of stability to be: salt/salt (least stable) < co-crystal/co-crystal < salt(C(H))/co-crystal(C(CH3)) < co-crystal(C(H))/salt(C(CH3)) (most stable). 3.5. Thermal stability studies The thermal stability of all the studied forms was evaluated by simultaneous TG/DSC analyses performed in open pans in both air (Figures 11, 12) and nitrogen atmospheres (Figure 6S, Supporting Information). For more comprehensive characterization of the transformations taking place during the desolvation of BZH·H2O and 4a·CH3OH, and detection of any possible phase-transitions in the case of the remaining forms, hot-stage microscopy (HSM) was employed (Figure 13 and Figure 7S). The thermal numerical data (Tm, Tfus) are collected in Table 1S (Supporting Information). Apart from solvate 4a·CH3OH, all of the forms are stable under ambient conditions and, as follows from the DSC curves, do not undergo any changes during heating up to the melting point. Furthermore, except for 4a·CH3OH (Figure 12) the TGA curves showed a negligible weight loss (

'Multicomponent crystal forms of biologically active hydrazone with

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