Crystal structures ofN6-modified-amino acid nucleobase analogs(iii): adenine-valeric acid, adenine-hexanoic acid and adenine-gabapentine

In this manuscript we report the synthesis and structural characterization of three amino acid adenine derivatives:N-(7H-purin-6-yl)-5-aminovaleric (N-6-5AValAde) (1),N-(7H-purin-6-yl)-6-aminohexanoic (N-6-6AHexAde) (2) andN-(7H-purin-6-yl)gabapentine (N-6-GabapenAde) (4); and the hydrochloride form of2, (3). In compound (1) with a neutral adenine ring and the chain arranged almost in an orthogonal position, the carboxylic groups interact with the N(7) and N(6)-H(6) of the neighbour molecule forming 1D supramolecular polymers. It also establishes strong N(9)-HMIDLINE HORIZONTAL ELLIPSISN(3) interactions between the adenine rings leading to self-assembled dimers. In the layered compound (2), the adenine also forms self-assembled dimersviadouble N(9)-HMIDLINE HORIZONTAL ELLIPSISN(3) interactions. However, conversely to (1), the chain is arranged in the same plane of the ring facilitating the formation of coplanar self-assembled dimersviathe Hoogsteen face. In the hydrochloride form ofN(6)-6AHexAde (compound3) the adenine ring is protonated in N(1) which is hydrogen bonded to the chloride anion [N(1)-HMIDLINE HORIZONTAL ELLIPSISCl = 2.198 angstrom]. As with the neutral compound (1), the carboxylic group is bound to N(7) and the H-N(6) of a neighbour molecule and the double and strong [N(9)-HMIDLINE HORIZONTAL ELLIPSISN(3) = 2.069 angstrom] interaction between coplanar adenine rings is present. A common feature of compounds (1)-(3) (linear amino acid), is the formation of adenineMIDLINE HORIZONTAL ELLIPSIScarboxylic group interactionsviathe de Hoogsteen site of adenine, and also adenineMIDLINE HORIZONTAL ELLIPSISadenine self-association via N(9)-HMIDLINE HORIZONTAL ELLIPSISN(3) interactions. In compound (4), that incorporates a gabapentine chain attached to the adenine ring, 3D packing is organized again with protonated carboxylate and N(7)/H-N(6) contacts: [O(19)-HMIDLINE HORIZONTAL ELLIPSISN(7) and O(18)MIDLINE HORIZONTAL ELLIPSISHN(6)] and a water molecule that holds 3 different molecules together by forming three O/NMIDLINE HORIZONTAL ELLIPSISH hydrogen bonds. Again stacking interactions between the eclipsed pyrimidine rings in anti disposition [C(5)MIDLINE HORIZONTAL ELLIPSISC(2)/C(2)MIDLINE HORIZONTAL ELLIPSISC(5) of 3.387 angstrom] are observed. Finally, we studied the noncovalent interactions observed in the solid state architecture using DFT calculations, and rationalized the interactions using molecular electrostatic potential surfaces and the quantum theory of "atoms-in-molecules". The aim of this study is to investigate the competition between homodimer formation by the Hoogsteen face of the adenine/adeninium, self-association of the carboxylic group, or the interaction of the carboxylic group with the adenine/adeninium cation.