Expanding the Solid Form Landscape of Bipyridines

Two bipyridine isomers (2,2′- and 4,4′-), used as coformers and ligands in coordination chemistry, were subjected to solid form screening and crystal structure prediction. One anhydrate and a formic acid disolvate were crystallized for 2,2′-bipyridine, whereas multiple solid-state forms, anhydrate, dihydrate, and eight solvates with carboxylic acids, including a polymorphic acetic acid disolvate, were found for the 4,4′-isomer. Seven of the solvates are reported for the first time, and structural information is provided for six of the new solvates. All twelve solid-state forms were investigated comprehensively using experimental [thermal analysis, isothermal calorimetry, X-ray diffraction, gravimetric moisture (de)sorption, and IR spectroscopy] and computational approaches. Lattice and interaction energy calculations confirmed the thermodynamic driving force for disolvate formation, mediated by the absence of H-bond donor groups of the host molecules. The exposed location of the N atoms in 4,4′-bipyridine facilitates the accommodation of bigger carboxylic acids and leads to higher conformational flexibility compared to 2,2′-bipyridine. For the 4,4′-bipyridine anhydrate ↔ hydrate interconversion hardly any hysteresis and a fast transformation kinetics are observed, with the critical relative humidity being at 35% at room temperature. The computed anhydrate crystal energy landscapes have the 2,2′-bipyridine as the lowest energy structure and the 4,4′-bipyridine among the low-energy structures and suggest a different crystallization behavior of the two compounds.

glass and covered with a filter paper. The crystallization product was characterized using polarized microscopy and powder X-ray diffractometry. Few of the crystallization products showed a transformation, as indicated in Table S1 (2,2'-BIPY) and Table S2 (4,4'-BIPY).
For 2,2'-BIPY only the in the literature described anhydrate (AH22) was obtained according to the PXRD data. However, in case of the formic acid evaporation experiment a microscopic observation of the particles confirmed that the initially formed solvate S-C122 desolvated already to the anhydrate AH22.

Slurry experiments in water and selected organic solvents
Slurry experiments in eleven organic solvents, chosen based on the watch-glass evaporation experiments, were performed in the temperature range between 10 and 30 °C (cycling).
Samples were withdrawn periodically and analysed "wet" using PXRD. All literature forms were confirmed and six new solvates found (one for 2,2'-BIPY and five for 4,4'-BIPY). The results are given in Table S3.

Cooling crystallization experiments
The cooling crystallization screen was designed from eleven solvents that were selected based   2. Potential energy surface scans (PES) of the carboxylic acids PES scans were performed at the B3LYP/6-31G(d,p) level of theory using GAUSSIAN09. 1 The dihedral angels marked in Figure S1 were scanned in 20° (1-dimensional scans) or 30° (2dimensional) scans. Dihedral angles not scanned were optimized (extended conformation of the acid). Figure S1. Carboxylic acids with the for the analyses selected dihedral angles marked in green and blue (C5 only).
2.1. Propionic acid (C3) Figure S2. Potential energy surface scan of propionic acid performed at the B3LYP/6-31G(d,p) level of theory and number of conformers found in the CSD (orange bars). Note that due to the symmetry of acid molecule most conformers are present twice in the 360° scan. Conformers were distributed uniformly, i.e. each CSD conformer is counted only once. Figure S3. Potential energy surface scan of butyric acid performed at the B3LYP/6-31G(d,p) level of theory and number of conformers found in the CSD (orange bars). Note that due to the symmetry of acid molecule most conformers are present twice in the 360° scan. Conformers were distributed uniformly, i.e. each CSD conformer is counted only once. Figure S4. Potential energy surface scan of valeric acid performed at the B3LYP/6-31G(d,p) level of theory and number of conformers found in the CSD (orange bars). Note that due to the symmetry of acid molecule most conformers are present twice in the 360° scan. Conformers were distributed uniformly, i.e. each CSD conformer is counted only once. Figure S5. 2D-Potential energy surface scan of valeric acid performed at the B3LYP/6-31G(d,p) level of theory, color coded according to intramolecular energy difference with respect to the global minimum conformation (in kJ mol −1 ). Figure S6. Potential energy surface scan of caproic acid performed at the B3LYP/6-31G(d,p) level of theory and number of conformers found in the CSD (orange bars). Note that due to the symmetry of acid molecule most conformers are present twice in the 360° scan. Conformers were distributed uniformly, i.e. each CSD conformer is counted only once. Figure S7. Potential energy surface scans of caprylic acid performed at the B3LYP/6-31G(d,p) level of theory and number of conformers found in the CSD (orange bars). Note that due to the symmetry of acid molecule most conformers are present twice in the 360° scan. Conformers were distributed uniformly, i.e. each CSD conformer is counted only once.

Representation of the experimental forms
The computational models were successful in reproducing the experimental structures (Table   S5). The structures were compared using the Molecular Similarity Module in Mercury to determine the root mean square deviation of the non-hydrogen atoms in a cluster of 15 molecules (rmsd15). 2   Table S5. Quality of the representation of the experimental structures of 2,2'-BIPY and 4,4'-BIPY.

Solid Form
Lattice parameters (cell vectors/Å, angles/ o )   Figure S8. Overlay of the 15-molecule cluster of the observed structure of AH22 (BIPYRL04 3 , colored by element) and calculated PBE-TS structure (green), rmsd15=0.12 Å.           Table S6 provides an overview over the number of structures and energy ranges of the structures selected to be generated/optimized at the different stages of the generation of the lattice energy landscapes. The lowest-energy PBE-TS structures of 2,2'-BIPY and 4,4'-BIPY are given in Tables S6 and S7, respectively.

Structure family similarity trees and Packing comparisons
The structure family similarity trees were calculated using the CCDC API packing similarity dendrogram script with clustering type settings "complete".

Substitution calculations
Substitution calculations were performed to investigate the potential of isostructural solvates.
The acetic acid molecule was pasted into the S-C144 structure (P21) and optimized with CASTEP as described in the manuscript in section 2.2. The obtained structure was calculated to be 0.71 kJ mol -1 less stable in lattice energy. An overlay of S-C144 and the hypothetical P21 structure is given in Figure S23.

Morphology of the solvates
The morphologies of the solvates were recoded using an Olympus SZX12 stereo-microscope equipped with an Olympus DP71 digital camera (Olympus, A).

Gravimetric moisture (de)sorption
The time vs. mass curve (water content) of 2,2'-BIPY shows a continuous mass loss, nearly independent of the relative humidity ( Figure S34). The mass loss can be related to sublimation of the compound.   Figure S38 shows exemplarily a contact preparation (melt film) of S-C244 and AH44. The "black line" at the contact zone of the two compounds relates to the eutectic temperature and forms at approx. 70 °C. Figure S38. Contact preparation of S-C244 and AH44 showing the eutectic temperature at 70 °C (encircled).

Stability at ambient conditions
All solvates were subjected to storage stability experiments at ambient conditions (RT, 30 -40% RH), and transformations monitored with PXRD. The diffractograms were recorded at first hourly and then daily. Only a selection of the recorded diffractograms is given. Figure S39. PXRD measurements monitoring the desolvation process of S-C144 at ambient conditions (t = x hours). Reference patterns are provided for the anhydrate (AH), hydrate (Hy2) and the solvate (SC and PBE-TS -simulated from the single crystal structure and optimized solvate structure, respectively). Figure S40. PXRD measurements monitoring the desolvation process of S-C244 at ambient conditions (t = x hours). Reference patterns are provided for the anhydrate (AH), hydrate (Hy2) and the solvate (SC and PBE-TS -simulated from the single crystal structure and optimized solvate structure, respectively). Figure S41. PXRD measurements monitoring the desolvation process of S-C344 at ambient conditions (t = x hours). Reference patterns are provided for the anhydrate (AH), hydrate (Hy2) and the solvate (SC and PBE-TS -simulated from the single crystal structure and optimized solvate structure, respectively). Figure S42. PXRD measurements monitoring the desolvation process of S-C444 at ambient conditions (t = x hours). Reference patterns are provided for the anhydrate (AH), hydrate (Hy2) and the solvate (SC and PBE-TS -simulated from the single crystal structure and optimized solvate structure, respectively). Figure S43. PXRD measurements monitoring the desolvation process of S-C544 at ambient conditions (t = x hours). Reference patterns are provided for the anhydrate (AH), hydrate (Hy2) and the solvate (SC and PBE-TS -simulated from the single crystal structure and optimized solvate structure, respectively). Figure S44. PXRD measurements monitoring the desolvation process of S-C644 and S-C844 at ambient conditions (t = x hours). Reference patterns are provided for the anhydrate (AH), hydrate (Hy2) and the solvate (SC -simulated from the single crystal structures).