In this talk, I will describe our recent work on the design and preparation of novel supramolecular architectures based on a range of element-based non-covalent interactions such as halogen bonds, chalcogen bonds, and pnictogen bonds. In addition to standard wet chemistry and slow evaporation methods, the utility of mechanochemical and cosublimation techniques will be discussed. Considered together, these methods enable a broad exploration of the polymorphic cocrystalline landscape. For example, the cosublimation approach overcomes an anticooperative halogen-bonding effect to produce fully saturated cocrystals of the tritopic halogen bond donor 1,3,5-trifluoro-2,4,6-triiodobenzene with 1,4-diazabicyclo[2.2.2]octane.¹ I also report on dicyanoselenodiazole and dicyanotelluradiazole derivatives which work as promising supramolecular synthons with the ability to form double chalcogen bonds with a wide range of electron donors including halides and oxygen‐ and nitrogen‐containing heterocycles.² In addition to X-ray diffraction, solid-state multinuclear magnetic resonance (SSNMR) and nuclear quadrupolar resonance (NQR) spectroscopies are employed to characterize all products and to establish spectral signatures for the various classes of bonds. Given the elements involved in these bonds, we report on a wide range of nuclides including e.g., ¹⁷O, ³¹P, ^35/37Cl, ⁷⁷Se, ^79/81Br, ¹²⁵Te, ¹²⁷I, ^121/123Sb, etc. As most of these are quadrupolar nuclides, the utility of specialized NMR techniques and very high applied magnetic fields will be discussed. In favourable cases, in-situ solid-state NMR spectroscopy allows for real-time monitoring of cocrystallization reactions and for the determination of activation energies.³

1. Szell, P. M. J.; Gabriel, S. A.; Caron-Poulin, E.; Jeannin, O.; Fourmigué, M.; Bryce, D. L. Cryst. Growth Des. 2018, 18, 6227. https://doi.org/10.1021/acs.cgd.8b01089

2. Kumar, V.; Xu, Y.; Bryce, D. L. Chem. Eur. J., in press. https://doi.org/10.1002/chem.201904795

3. Xu, Y.; Champion, L.; Gabidullin, B.; Bryce, D. L. Chem. Commun. 2017, 53, 9930.
https://doi.org/10.1039/C7CC05051H

Different crystallization and screening techniques have been developed for the discovery of new multicomponent molecular crystals. Exploring the polymorphic space for a given organic molecule typically includes searches across well-defined conditions, among others solvents, additives, and temperature. In recent years, especially mechanochemistry has been used intensively for the screening for new solid forms and as a promising, alternative method for accessing new polymorphs of active pharmaceutical ingredients (APIs) and API-cocrystals.[1-2] The ever-increasing interest in this method is contrasted by a still limited mechanistic understanding of the mechanochemical reactivity and selectivity. Furthermore, the influence of liquids used during the grinding on the polymorphic outcome is still far from being understood. Time-resolved in situ investigations of milling reactions provide direct insights in the underlying mechanisms.[3-5] We recently introduced different setups enabling in situ investigation of mechanochemical reactions using synchrotron XRD combined with Raman spectroscopy and thermography allowing to detect crystalline, amorphous, eutectic, and liquid intermediates. In this contribution, we will discuss our recent results investigating the formation of (polymorphic) cocrystals and salts, thereby elucidating the influence of solvents and seeds on the polymorph formation.[6-8] Our results indicate that in situ investigation of milling reactions offer a new approach to tune and optimize mechanochemical processes.

A careful investigation of the packing in the nearly 1500 organic, well-refined (R£0.050), P1, Z>1 structures archived in the 2019 version of the Cambridge Structural Database [1] has revealed that the molecules (or ions) in ca. 85% of those structures are related by obvious approximate symmetry that is periodic in at least two dimensions. An example is shown in Fig. 1. The nearly 250 P1, Z=1 structures of molecules that could lie on special positions were also analyzed; ca. 70% were found to have approximate symmetry.

Figure 1. Views of LUSMAN, P1, Z=2 [2]; the second view, of a bilayer, is rotated by 90° around the horizontal from the first. The approximate c211 symmetry of a layer (001) with 0.5 < z < 1.5 (axes [110], [10]; angle 89.9°) is obvious. The angles of those axes with c are 77.8° and 81.8°.

In only 8% of the Z>1 structures does it seem likely that refinement in a higher symmetry space group or smaller unit cell would have been preferable. That percentage is, however, much higher (39%) for P1 crystals of achiral or racemic material, which account for 11% of all Z>1 structures considered. For P1, Z>1 crystals that are enantiomerically pure the frequency of overlooked symmetry is only 2%. For the Z=1 crystals the percentage is 10% overall and 17% for the crystals of achiral or racemic material.

In the abstract of R. E. Marsh’s (1999) paper titled “P1 or P? Or something else?” [3] he wrote
In approximately one-third of the structures in which chiral molecules crystallize in P1 with Z=2, the two molecules are related by
an approximate center of inversion.
The present study found that 32% of the P1, Z=2 structures of enantiomerically pure material are P mimics. Molecular features that promote P mimicry have been identified; they may have implications for the probability of formation of solid solutions.

The approximate symmetry is often subperiodic, as it is in the example shown in Fig. 1. The ratio of structures having 2-D to those having 3-D approximate periodic symmetry is about 2:3 but the ratio is imprecise because of the difficulty of deciding on the dimensionality. In some structures the approximate symmetry is clearly 3-D and in others it is clearly 2-D, but in many others the dimensionality is at the 3-D/2-D borderline. In only 22 structures, however, was the approximate symmetry identified as 1-D. The approximate subperiodic symmetry was described with the labels for layer and rod groups found in Vol. E of International Tables [4].

The surprisingly exact approximate symmetry found in many P1 crystals could result from a distortion during growth or cooling of a more symmetric nucleus, but in more than 3% of the Z>1 structures quite different layers alternate so that the P1 symmetry must have been established at the time of crystal nucleation.

[1] Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016), Acta Cryst. B72, 171-179. [2] Adam, W. & Zhang. A. (2003) Eur. J. Org. Chem. 2003, 587-591. [3] Marsh, R. E. (1999). Acta Cryst. B55, 931-936. [4] Kopský, V. & Litvin, D. B. (2002). Editors. International Tables for Crystallography, Vol. E, Subperiodic groups, Kluwer Academic Publishers, Dordrecht/Boston/London, 2002.

A 47-year-old polymorphic structure (Form δ) of the drug indomethacin (IDM) has been solved by 3D electron diffraction (3D ED). Since its discovery in 1974, the structure of δ-IDM had remained a mystery. By performing a unique crystallisation technique, we successfully cultivated its single crystal. The very thin, ribbon-like crystal was too small (~1 µm in width) to be studied by X-ray diffraction—including even the third generation of synchrotron radiation. With the aid of 3D ED, we finally elucidated the crystal structure of δ-IDM. The structure exhibits a very long b-axis with the slowest growth and shortest crystal dimension occurring along this direction. Consequently, reflections along 0k0 were missing in the 3D ED data and the structure could not be solved by direct methods. Instead, simulated annealing was employed to overcome this problem. This work highlights the powerfulness of 3D ED for structure determination of small crystals, which complements X-ray diffraction.

Non-Photochemical Laser-Induced nucleation (NPLIN) is a promising nucleation technique [1] for which more than eighty papers have been published. In an NPLIN experiment, a supersaturated solution of a molecule is irradiated by a laser (pulsed or continuous, focused or non-focused) that induces the molecule's nucleation. Even though glycine nucleation constitutes almost one-quarter of these research activities reported in the literature, the impact of different experimental conditions on its nucleation is still not fully understood [2]. NPLIN of glycine in water has been demonstrated at different molarities and different energy densities induced using a non-focalized pulsed laser (532 nm) at 290 K. A new index (Ind50), allowing easy comparison with the literature, was used to characterize the impact of molarities and energy densities on the nucleation efficiency. A threshold index (Ind_Thrs(β)) indicating the minimum energy density required to obtain in a given experimental condition one crystal per vials in average has been determined. The impact of the circular or linear polarization of the laser beam on the glycine polymorphism (α- or γ-glycine) has been studied and characterized using a third new index named NPLIN determinant. The experimental interface (glass-solution or air-solution) gives the opposite polymorphism behavior. The relationship between devices, solution, and experimental conditions and observable such as nucleation efficiency, nucleation site, induction time, crystal counting, and polymorphism have been modelized in a mind-map (Figure 1). Within this context, this work is a contribution towards a better understanding of the impact of experimental conditions on NPLIN nucleation that will permit a better design and control of NPLIN experimental setups.

[1] Garetz, B. A.; Aber, J. E.; Goddard, N. L.; Young, R. G.; Myerson, A. S. (1996) Phys. Rev. Lett. 77, 3475−3476.

[2] Clair, B.; Ikni, A.; Li, W.; Scouflaire, P.; Quemener, V.; Spasojević-de Biré, A. (2014) J. Appl. Crystallogr., 47, 1252−1260

Photo-induced electron transfer (PET) reactions are crucial for many biological and chemical reactions that occur in nature. Several studies are performed on many donor-bridge-acceptor (D-B-A) systems to have a better understanding of PET in terms of the rate of transfer and the overall geometry.[1] A mono-substituted pyrene derivative, pyrene-(CH₂)₂-N,N'-dimethylaniline, were designed where dimethylaniline (DMA) (electron donor) is connected to pyrene (electron acceptor) through alkane chain. Two polymorphic crystal forms, A and B, were crystallized in two separate crystallization batches in ethanol/ethyl acetate binary mixture. While, in the crystal structure A, pyrene and dimethylaniline are in axial orientation (P-1) with respect to each other, in B they are equatorial (P2₁/n). Studies on intramolecular PET has revealed the importance of conformational parameters of the molecules such as rotation around bonds that affects the distance and relative orientation of the donor and acceptor.[2] We have performed time-resolved (TR) pump-probe pink Laue X-ray diffraction experiments with the polymorphic crystals in ns time domain. TR pump-probe data was processed by RATIO[3] method by employing LaueUtil software[4]. The photodifference maps obtained from TR pump-probe diffraction measurements with polymorphic crystals, suggest electron transfer from DMA moiety. A thorough crystallographic and spectroscopic investigation with the polymorphic crystals, have allowed us to understand the important aspects of PET in this particular (D-B-A) system.