Preparation, characterisation and structural analysis of salts and co-crystals of organic compounds

Abstract

In this thesis the factors influencing the formation of a binary compound and the proton transfer within the binary compound have been investigated. The formation of a binary compound, or heteromeric system, over a homomeric system requires the heteromeric system to be more energetically favourable than the homomeric system. In some circumstances, however, no solid crystallises at all. Proton transfer within the binary compound can lead to the formation of a salt, whereas a binary compound containing neutral components is called a co-crystal. The ‘rule of three’ which predicts that proton transfer requires a difference of at least three units between the pKa of the acid and the pKa of the conjugate acid has also been investigated. In particular the relevance of this rule to diprotic acids and bases, and amide groups has been examined. The expression of starting material properties in the binary compounds was also explored.
To achieve this an array of diacids and bases have been chosen that consist of ?,?-alkanedicarboxylic acids, ?,?-alkenedicarboxylic acids and tartaric acids with a selection of aliphatic amines, nitrogen-containing heterocycles and imidazole derivatives. The nitrogen-containing heterocycles include some amide functionalities. These compounds have been systematically crystallised together using a liquid-handling robot in a high-throughput manner commonly used in the pharmaceutical industry.
The novel structures of 42 salts, 11 co-crystals and 6 mixed co-crystal/salt systems have been prepared and characterised using single crystal X-ray diffraction. Together with the binary compounds already present on the CSD, this has provided the opportunity to assess the impact of various factors on the crystal structures and properties of a total of 61 salts, 11 co-crystals and 8 mixed salt/co-crystal systems. Across the series of ?,?-alkanedicarboxylic acids it has been found that members with an even number of carbons in their alkyl chain (even diacids) form binary compounds more often than those with an odd number of carbons (odd diacids). The diacids with four carbons in their alkyl chains are most likely to form binary compounds. The melting point alternation seen in the ?,?-alkanedicarboxylic acids is also expressed in the binary products. This is particularly prominent with the 2-imidazoldinone-alkanedicarboxylic acid co-crystals, where the supramolecular structure formed by the even diacids is different to that formed by the odd diacids. This has been attributed to the different orientation of the carboxyl groups in the odd diacids.
Although the ‘rule of three’ has been found to be applicable to the first ionisation of the diacids, it does not account for the ubiquitous formation of diprotonated bases where the pKa difference is often less than 2 units. Indeed the stoichiometry of the binary compounds was found to often be unpredictable and difficult to rationalise simply. The deprotonation of the diacids appeared to be determined by the optimal hydrogen bonding motifs rather than the pKa. There were also found to be similarities in supramolecular structures within the groups of compounds which could be used to predict the structures of other similar compounds.

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