Optimizing side chains for crystal growth from water: A case study of aromatic amide foldamers

Abstract

The growth of crystals of aromatic compounds from water much depends on the nature of the water solubilizing functions that they carry. Rationalizing crystallization from water, and structure elucidation, of aromatic molecular and supramolecular systems is of general value across various fields of chemistry. Taking helical aromatic foldamers as a test case, we have validated several short polar side chains as efficient substituents to provide both solubility in, and crystal growth ability from, water. New 8-amino-2-quinolinecarboxylic acids bearing charged or neutral aminomethyl, carboxymethyl, sulfonic acid, or bis(hydroxymethyl)-methoxy side chains in position 4 or 5, were prepared on a multi gram scale. Fmoc protection of the main chain amine and suitable protections of the side chains ensured compatibility with solid phase synthesis. One tetrameric and five octameric oligoamides displaying these side chains were synthesized and shown to be soluble in water. In all cases but one, crystals were obtained using the hanging drop method, thus validating the initial design principle to combine polarity and rigidity. The only case that resisted crystallization appeared to be due to exceedingly high water solubility endowed by eight sulfonic acid functions. The neutral side chain did provide crystal growth ability from water but contributed poorly to solubility.