Structural and Computational Studies of Small Organic and Biological Molecules
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Over the last three decades high-pressure X-ray diffraction techniques have been widely utilised to perform structural studies in many areas of research. For example, physicists make use of these experimental techniques to investigate metals, conductor and semi-conductor compounds among others, whereas geochemists apply them to study the conditions deep within the Earth’s interior. Furthermore, pressure studies have reached an important status in chemistry, biology and planetary science, and have proved to be a new notable tool to study the structure of a variety of small molecule compounds, from inorganic (e.g. rock salt) to organic (e.g. urea) and biological molecules (e.g. amino acids). The main reason for this is the necessity to obtain a better understanding of different processes which take place at extreme conditions of pressure, such as the existence of life in the deep ocean (e.g. extremophiles) or the finding of amino acids, such as cysteine, in space. Small molecules, such as glycine and glutathione, may play important roles in these biological processes and therefore a good knowledge of their structural features could be essential to explain how they happen. The work described here focuses on one of the principal features of intermolecular bonding in small organic and biological molecules, namely the hydrogen bond. Although the hydrogen bond has been studied for almost a century, this important directional intermolecular interaction is still one of the most highly investigated topics in chemistry and biology due to the many aspects of its nature which are still unknown or not well understood. The hydrogen bond is directly involved with the crucial biochemical processes of amino acids, peptides, proteins and even DNA and RNA and therefore, in short, it is essential for life. Its importance goes beyond biomolecules and organic molecules, since the hydrogen bond is also present in inorganic compounds, such as clusters containing different types of ligands and metals, e.g. manganese and iron, and consequently it is implicated in many catalytic pathways. In this work, we have combined experimental and computational techniques to investigate the effect of pressure on the crystal structures of amino acids and small organic molecules, and in particular on the crystal packing of cyclopropylamine, α-glycine, L-α-aspartic acid and L-α-glutamine. The experimental study of these structures was aimed to determine the principal structural changes as a function of pressure. The computational study was carried out to investigate the energetics of the crystal structures: i.e., the sublimation, lattice and proton transfer energies, as well as the energies of the individual hydrogen bonds, in order to relate the structural changes observed by experiment. A new computational method was initially tested on the simplest naturally occurring amino acid, α-glycine, which had been previously studied experimentally at high pressure by our research group. Experimental results support the existence of a new polymorph of cyclopropylamine (Phase II), which was found at 1.2 GPa. This new molecular structure crystallises in the orthorhombic space group Pbca, with 8 molecules in the unit cell and one in the asymmetric unit. The molecular packing is formed by zig-zag chains of molecules linked via a short N-H…N hydrogen bond, with unusually only one of the hydrogen atoms of the NH2 group of the cyclopropylamine molecule involved in the hydrogen bonding network. A computational study was applied to the two polymorphs of cyclopropylamine (Phase I and Phase II), in order to investigate the energetics of these systems. It was found that the energies of the hydrogen bonds present in the Phase I and Phase II crystal structures of cyclopropylamine have very similar energies, falling in the range of 1 to 4 kcal mol-1 (6 to 16 kJ mol-1). Experimental results on amino acids showed that the effect of pressure (from 0 to approximately 6 GPa) did not cause significant changes in the crystal structures of L-α-aspartic acid and L-α-glutamine, other than a decrease in the lengths of the various hydrogen bonds and intermolecular contacts. Additionally, ab initio calculations carried out on α-glycine, L-α-aspartic acid and L-α-glutamine indicated that the hydrogen bonds present in the crystal structure of amino acids exhibit very different energies, falling over a much wider range of 1 to 30 kcal mol-1 (∼4 to 120 kJ mol-1), compared to that found for small organic molecules. This finding does not agree with what was expected according to previous hydrogen bonding classifications, and we attribute this to the zwitterionic nature of the amino acid molecules which is present in the solid state. Finally, it was found that the energies of the hydrogen bonds found in the amino acids investigated correlates with the experimental compressibility studies, so that the hydrogen bond exhibiting the lowest energy is also the weakest, and most easily compressed.