KEYWORDS: hydrogen/deuterium exchange, isotope effect, isotopic polymorphism, influence on crystallization behavior ABSTRACT:Hydrogen/deuterium (H/D)-exchange, is generally seen as a negligible criterion in the formation of crystal structures of chemical compounds. On the other hand, it could already be shown that the aggregation of molecules in the solid state of selected organic and inorganic compounds can be very sensitive to the small H/D-change in the isotopic substitution pattern of the considered molecules or the use of deuterated solvents during the crystallisation process. This perspective highlights the extraordinary aggregation behavior in certain cases of deuterated versus the non-deuterated small inorganic and organic compounds.

The influence of pure solvents (p.a.) and impure solvents (techn. quality) on the crystallization of polymorphic forms of non-, partial-, and per-deuterated acridine from solution was investigated. Remarkably different crystallization behavior of acridine and deuterated acridine related to the used solvents was observed, especially shown in the case of acetone.

The crystal packing motifs of acenes are usually built up by heringbone C−H•••π interactions; on the contrary, N-heteroacenes form C−H•••N contacts. In the case of dihydroazaacenes the molecular structure of a rigid aromatic system is interrupted by a flexible part. The influence of heterocyclic CH 2 /NH substitution on the crystallization behavior and crystal packing of 9,10-dihydroacridine (DHAC) and 9,10-dihydroanthracene (DHAN) as well as a 1:1 mixture of both compounds was investigated by differential scanning calorimetry (DSC) measurements, hot stage microscopy methods, and crystal structure determination.

2(1H)-Pyrazinones are attractive scaffolds, both as templates and as starting materials for heterocycles' construction.[1] Some of the fomer show very promising activity as í-opioid receptor agonists, and NNRTI's (non-nucleoside reverse transcriptase inhibitors). Besides this intrinsic value, they can also be transformed into a useful tool for the synthesis of 'modified' peptides. [2] In continuation of our studies on 2(1H)-pyrazinones, [3] solid-state characterisation allowed to separate two conformational polymorphs of 5-chloro-3-phenyl-2(1H)-pyrazinone, the crystal growth of which was influenced by temperature. Form I crystallises from a methanol solution at room temperature in the monoclinic space group P21/c, whereas form II crystallises at low temperature in the centrosymmetric triclinic space group with two independent molecules in the asymmetric unit. Single-crystal XRD revealed that two aromatic rings are coplanar in I but show a twist around the C-C bond in II. The results of PXRD studies as well as an analysis of the intermolecular interactions in the packing will be presented. How well do we currently understand the aggregation of small molecules in the solid state? Most of intermolecular interactions are not very strong and their formation is related to and affected by small changes in the molecular structure and the crystallisation conditions. Continuing our investigations on aggregation of substituted aromatic molecules in the solid state, we studied the influence and boundaries of weak directing substituents like deuterium on the aggregation of small molecules. Hydrogen/deuterium (H/D)-exchange, the smallest possible modification of a molecule, is generally seen as a non dominating parameter in the formation of crystal structures of chemical compounds.On the other hand, we can show that the aggregation of molecules in the solid state of polymorphic N-heterocycle systems like pyridine-N-oxide or acridine or even benzidine can be very sensitive on small changes of the isotopic substitution pattern of the well selected molecules. One amazing example is pyridine. An isotopic substitution leads to the formation of a new polymorph. Re-crystallisation from pentane allows the formation of a new stable polmorph of pentadeuteropyridine [1]. Our own recent investigations of partially deutero-substituted pyridine-N-oxides yield two different polymorphs for a partial deuterated compound. Both the low-temperature and the high-temperature phases are stable and reversible [2,3] [1]

The famous Miller experiment to model the primordial soup demonstrated that amino acids can form spontaneously as the essential building blocks of life in solutions. It is, however, still an open question how self-recognition processes influence the transformation of these spontaneously formed amino acids in solvents into higher ordered structures in the solid state, thereby creating chiral materials and catalytically competent structures. The understanding of the first steps of molecular self-assembly processes in such environments will thus give important clues towards the understanding of biological evolution. Most of intermolecular interactions are not very strong and their formation is related to and affected by small changes in the molecular structure and the crystallisation conditions. Continuing our investigations on aggregation of substituted aromatic molecules in the solid state, we studied the influence and boundaries of weak directing substituents like deuterium on the aggregation of small molecules. Hydrogen/deuterium (H/D)-exchange, the smallest possible modification of a molecule, is generally seen as a non dominating parameter in the formation of crystal structures of chemical compounds. On the other hand, it could already be shown that the aggregation of molecules in the solid state of polymorphic N-heterocycle systems like pyridine-N-oxide or acridine can be very sensitive to small changes of the isotopic substitution pattern of the selected molecules. Within our project, the molecular aggregation of amino acids in solution with the formation of molecular aggregates and pre-nucleation clusters in deuterated and non-deuterated systems, and in particular the role of the solvent in these processes, will be studied in both experiment and theory.