H-bond pattern in arylpiperazine structures. Structures of cis and trans 2-{4-[4-(2-methoxyphenyl)piperazin-1-yl]but-2-enyl}isoindoline- 1,3-diones and their hydrochloride salts Janina Karolak-Wojciechowska a, * , Agnieszka Mrozek a , Andrzej Fruzin ´ ski a , Małgorzata Szczesio a , Piotr Kowalski b , Teresa Kowalska b a Institute of General and Ecological Chemistry, Technical University of Lódz ´, _ Zeromskiego 116, 90-924 Lódz ´, Poland b Institute of Organic Chemistry and Technology, Cracow University of Technology, Warszawska 24, 31-155 Kraków, Poland article info Article history: Received 11 March 2010 Accepted 10 June 2010 Available online 16 June 2010 Keywords: Structure of bases and salts Salt bridges in arylpiperazines Hydrogen bonds pattern abstract The crystal structures of cis and trans-isomers of 2-{4-[4-(2-methoxyphenyl)piperazin-1-yl]but- 2-enyl}isoindoline-1,3-diones have been solved in two different forms – as free bases and as hydrochlo- rides. It was concluded that the conformations of arylpiperazine derivatives with an aliphatic spacer in their neutral and protonated forms are similar and usually extended. The molecule bending found for the free cis-isomer is reflected in variation of the supramolecular synthons formation. The hydrogen bonds pattern in studied structure was analyzed. In the crystals of both free bases head-to-head dimers are predominant, while in hydrochlorides inter-ionic salt bridges form the main structure motifs. The most important difference in hydrogen bonds patterns of both forms lies in the fact that piperazine car- bon atoms contribute to weak C@OH–C interactions as proton donors only in the structures of hydro- chlorides. This article will also review selected arylpiperazine structures deposited in CSD from the point of view of their hydrogen bonds pattern. Ó 2010 Elsevier B.V. All rights reserved. 1. Introduction Arylpiperazine represents an important structural moiety in many compounds of pharmacological interest [1,2]. Among them, the most essential classes of 5-HT 1A serotonin receptor ligands [3] contain the arylpiperazine fragment with different N1 substit- uents varying in shape, size and rigidity (Scheme 1). In molecules under discussion the arylpiperazine, tail of the molecule, and the heterocyclic head are separated with a spacer (or linker). In the aryl position substituted phenyl is typically located while the heterocy- clic head is an amide or imide. There has been a controversy con- cerning the role of the spacer, whether it participates actively in binding to the receptor or it acts simply as a distance arm in the form of a chain of 2–5 atoms [4]. Despite that, there are two vari- ants of the spacer arrangement: either as a fully flexible chain (e.g., methylene groups –(CH 2 ) n – and/or heteroaliphatic chains with Y-heteroatom) or with a conformation restricted by incorporation of constrained elements such as rings or double bonds [4–6]. The active form of arylpiperazine ligands with respect to 5- HT 1A receptor is the one with protonated N1 nitrogen which guardants binding to Asp carboxylic group [7]. The general meth- od for prediction of the receptor–ligand supramolecular assem- blies is to use non-covalent interactions, such as hydrogen bonds, to guide the organization of small molecules into larger clusters [8–10]. Therefore, from structural viewpoint, it would be of especially attractive to compare the crystal and molecular structures of the same arylpiperazine in form of free base with those of the corresponding salt, the most convenient hydrochlo- ride. Until now, among the arylpiperazines deposited in CSD [11], the structures of the same chemical specie in both forms were not reported. In the present work, the crystal and molecular structures of cis (1 and 1a) and trans (2 and 2a) 2-{4-[4-(2- methoxyphenyl)piperazin-1-yl]but-2-enyl}isoindoline-1,3-diones, in the form of free bases (1 and 2) and their hydrochlorides (1a and 2a, respectively), have been investigated (Scheme 2). The incorporation of the C@C double bond into the spacer, hindering the spacer flexibility, was found to be the crucial for trans-isomer (2a) to be more active with respect to 5-HT 1A receptor than the corresponding cis-isomer (1a) [6]. Beside evaluation of main mol- ecules conformation, crystallographic studies make it possible to identify and compare the hydrogen-bonding networks for two variants of the same species. This article will also review selected arylpiperazine structures deposited in CSD [11] from the point of view of their crystals architecture. 0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.molstruc.2010.06.017 * Corresponding author. Tel.: +48 426313122; fax: +48 426313128. E-mail address: Janina.Karolak-Wojciechowska@p.lodz.pl (J. Karolak-Wojcie- chowska). Journal of Molecular Structure 979 (2010) 144–151 Contents lists available at ScienceDirect Journal of Molecular Structure journal homepage: www.elsevier.com/locate/molstruc