New Cyclophanes as Initiator Cores for the Construction of Dendritic Receptors: Host‐guest complexation in aqueous solutions and structures of solid‐state inclusion compounds

Cyclophanes 3 and 4 were prepared as initiator cores for the construction of dendrophanes ( dendritic cydophanes ) 1 and 2 , respectively, which mimic recognition sites buried in globular proteins. The tetra‐oxy[6.1.6.1]paracyclophane 3 was prepared by a short three‐step route ( Scheme 1 ) and possesses a cavity binding site shaped by two diphenylmethane units suitable for the inclusion of flat aromatic substrates such as benzene and naphthalene derivatives as was shown by 1 H‐NMR binding titrations in basic D 2 O phosphate buffer ( Table 1 ). The larger cyclophane 4 , shaped by two wider naphthyl(phenyl)methane spacers, was prepared in a longer, ten‐step synthesis ( Scheme 2 ) which included as a key intermediate the tetrabromocyclophane 5 . 1 H‐NMR Binding studies in basic borate buffer in D 2 O/CD 3 OD demonstrated that 4 is an efficient steroid receptor. In a series of steroids ( Table 1 ), complexation strength decreased with increasing substrate polarity and increasing number of polar substituents; in addition, electrostatic repulsion between carboxylate residues of host and guest also affected the binding affinity strongly. The conformationally flexible tetrabromocyclophane 5 displayed a pronounced tendency to form solid‐state inclusion compounds of defined stoichiometry, which were analyzed by X‐ray crystallography ( Fig. 2 ). 1,2‐Dichloroethane formed a cavity inclusion complex 5a with 1:1 stoichiometry, while in the 1:3 inclusion compound 5b with benzene, one guest is fully buried in the macrocyclic cavity and two others are positioned in channels between the Cyclophanes in the crystal lattice. In the 1:2 inclusion compound 5c , two toluene molecules penetrate with their aromatic rings the macrocyclic cavity from opposite sides in an antiparallel fashion. On the other hand, p ‐xylene (= 1,4‐dimethylbenzene) in the 1:1 compound 5d is sandwiched between the cyclophane molecules with its two Me groups penetrating the cavities of the two macrocycles. In the 1:2 inclusion compound 5e with tetralin (= 1,2,3,4‐tetrahydronaphthalene), both host and guest are statically disordered. The shape of the macrocycle in 5a – e depends strongly on the nature of the guest ( Fig. 4 ). Characteristic for these compounds is the pronounced tendency of 5 to undergo regular stacking and to form channels for guest inclusion; these channels can infinitely extend across the macrocyclic cavities ( Fig. 6 ) or in the crystal lattice between neighboring cyclophane stacks ( Fig. 5 ). Also, the crystal lattice of 5c displays a remarkable zig‐zag pattern of short Br…O contacts between neighboring macrocycles ( Fig. 7 ).