FULL PAPER Synthesis and Conformational Analysis of Dicationic N,N'-Bridged Bis(benzimidazolium) and Bis(imidazolium) Macrocycles Istva ´n Bitter,* [a] Zsolt Török, [a] Viktor Csokai, [a] Alajos Grün, [a] Barbara Bala ´zs, [b] Ga ´bor To ´th, [b] György M. Keseru ˝, [a] Zolta ´n Kova ´ri, [c] and Ma ´tya ´ s Czugler [e] Keywords: Nitrogen heterocycles / Alkylations / Cyclizations / Conformational analysis Two-step alkylations of benzimidazole, 2-methylbenzimida- zole, and imidazole at their nitrogen atoms with various bi- functional alkylating agents have afforded a series of 16- membered quaternary azacyclophanes. Of these macro- cycles, those bearing methyl or methoxy groups on the azole Introduction Recently, azaaromatic onium macrocycles (cyclophanes) have attracted much attention due to their supramolecular structures coupled with their positively charged character. In biochemical host-guest processes such as enzyme-substrate interactions, onium compounds play an important role in the electrostatic binding of the substrate to the enzyme. [1] The fast rates and high specificities of en- zymatic reactions partly originate from the electrostatic sta- bilization of charged transition states by onium moieties. [2] Therefore, onium cyclophanes possessing a relatively hydro- phobic cavity (binding site) and onium residues at defined positions on the macrocycle (catalytic site) can be used as artificial enzymes or as receptors to study inclusion electro- static catalysis. [1] Although a great number of macrocyclic and linear aza- aromatic compounds, in which quaternary ammonium units constitute essential parts of the structure, have been known for a long time, [1] imidazolium cyclophanes (I) (Figure 1) have only been reported in the last few years, [3-8] despite the fact that imidazole compounds are frequently encoun- tered in biological systems (quite recently, benztriazolium cyclophanes have also been described [9] ). Another aspect that has aroused interest in bridged bis- (imidazolium) and dibenzimidazolium salts (Ia and IIb) has been the recent preparation of N,N'-dialkylimidazol-2-ylid- [a] Department of Organic Chemical Technology, Budapest University of Technology and Economics, P. O. Box 91, 1521 Budapest, Hungary Fax: (internat.) + 36-1/463-3648 E-mail: bitter.oct@chem.bme.hu [b] Technical Analytical Research Group of the Hungarian Academy of Sciences, Institute for General and Analytical Chemistry, Budapest Universityof Technology and Economics, Szent Gelle ´rt te ´r 4, 1111 Budapest, Hungary [c] Gedeon Richter Ltd., Computer Assisted Drug Discovery, P. O. Box 27, 1475 Budapest 10, Hungary [d] Department of Chemical Information Technologies, Budapest University of Technology and Economics, Szent Gelle ´rt te ´r 4, 1111 Budapest, Hungary [e] Chemical Research Centre, Hungarian Academy of Sciences, P. O. Box 17, 1525 Budapest, Hungary Eur. J. Org. Chem. 2001, 2861-2868  WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001 1434-193X/01/0815-2861 $ 17.50+.50/0 2861 or at the aromatic bridges have been found to exist as mix- tures of conformers. In some cases, the structures of the con- formers have been determined by NMR methods and X-ray crystallography, and have been correlated with the results of a computer-aided conformational search. Figure 1. General formula of N,N'-bridged imidazolium and bridged 2,2'-biimidazolium salts enes [10] as isolable nucleophilic carbenes derived from imid- azolium salts by simple deprotonation. By analogy, both I and II were expected to be potential precursors of macro- cyclic carbenes or their tetraazafulvalene-type dimers. [11,12] Generally, bis(azolium) salts (I) have been synthesized by two-step procedures. [3-5,7,8,11] A bifunctional alkylating agent (α,ω-dihaloalkanes, xylenyl bromides) is first con- densed on the N(1) atom of imidazole or benzimidazole in the presence of base (NaH, NaOH, KOH/PTC). In the next step, the linear precursor thus formed is cyclized at the N(2) atoms with the same or a different alkylating reagent to afford quaternary salts I (Scheme 1). A similar approach can be used for the preparation of dibenzimidazolium salts II, although one-pot cycloalkylations of 2,2'-bibenzimid- azole have also been described. [11] Scheme 1. Synthetic approach to bis(imidazolium) salts I Some interesting reactions of the bridged dications I and II have been reported. [11,12] Treatment of the bis(imidazol- ium) dication Ia [A,B = (CH 2 ) 3 ] with either KH in DMSO or with NaNH 2 in NH 3 afforded tetraazafulvalene IIIa (n =