A structural systematic study of three families of salicyclic acid derivatives

Abstract

Crystal structure assembly is a subtle compromise between geometrical features, a natural tendency to minimize the free, empty, volume, linked to the involvement of classical van der Waals forces, and the ability of particular complementary functional groups to form additional cohesive directional interactions. Depending on the system considered, each of these factors can have a more pronounced influence in determining the crystal packing. In order to develop a successful strategy to design new solid forms by a crystal engineering approach a complete understanding of crystal structure is required. It involves the so called “retrosynthetic” approach which allows the identification of robust assemblies. However, this procedure is worthless without a systematic approach able to define the structural consequences deriving from small changes in the molecular skeleton of a given target molecule.
In this thesis three families of substituted salicylic acid derivatives have been prepared and separately studied in order to compare the crystal structures and determine whether the substitution and the associated changes in shape and electrostatic of the parent molecule introduce alternative intermolecular interactions or molecular patterns. The first family is based on acetylsalicylic acid derivatives (aspirins) and contains 15 novel structures together with some substituted derivatives already present on the CSD. The second family contains 13 new structures of substituted salicylic acid and, as for aspirin derivatives, some already reported in CSD. The last family contains 13 new crystal structures of molecular salts based on the pair 4-aminopyridine-salicylic acid derivatives. The families of compounds are those in which the parent molecules are substituted with small groups (Cl, Br, I, Me, NO2, MeO etc.) and in different positions. The only exception is given by the acetylamino derivatives, which were included in the analysis in order to verify if they can compete with the carboxylic group in forming particular intermolecular interactions and consequently different supramolecular synthons.
The results in this work clearly showed that the substituent groups have an important role in generating similarities but, also, differences within the family under study. Furthermore the analysis has shown the significant involvement of both weak intermolecular interactions and shape-related packing features in the crystal structure assembly. In the other hand, the analysis showed the importance of particular functional group in defining robust supramolecular synthons.
The three families studied showed, apart from a small number of exceptions, predictable synthons (carboxylic dimers for the aspirins and the salicylic acids and the well known pyridine-carboxylate synthon for the salts) observed in the majority of the structures

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