Synthesis of New Pyridinoazacrown Ethers Containing Aromatic and Heteroaromatic Proton Ionizable Substituents

Methods for the synthesis of pyridinocrowns functionalized with various proton ionizable groups have been elaborated. Sixteen new ligands containing pyridine rings as part of the macrocycle or as a side arm have been prepared. Different interactive abilities of the OH and NH functions of 3,9-dioxa-6-azaundecane-1,11-diol (3) in strong base allowed the synthesis of pyridinoazacrowns 1 and 2 by cyclization with 2,6-bis((tosyloxy)methyl)pyridine (4) and THP- protected 4-hydroxy-2,6-bis((tosyloxy)methyl)pyridine (5). Pyridinoazacrown 1 was functionalized with different proton ionizable side arms by treatment first with formaldehyde in methanol to form the N-methoxymethyl derivative 6 and then treating 6 with 5-chloro-8-hydroxyquinoline or the appropriate substituted phenol. Pyridinoaza-18-crown-6 ligands containing p-methylphenol (7), p-methoxphenol (8), p-chlorophenol (9), p-fluorophenol (10), p-cyanophenol (11), 2-formyl-4-bromophenol (12), or 5-chloro-8-hydroxyquinoline (13) groups were prepared by this process. Pyridinoazacrowns 1 and 2 were alkylated with 2-hydroxy-5-nitrobenzyl chloride or 5-chloro-8-methoxy-2-(bromomethyl)quinoline followed by removal of the protecting groups to form p-nitrophenol- and 5-chloro-8-hydroxy-2-quinolinyl-substituted ligands (16, 18, and 21). Macrocycles 22 and 23 containing proton ionizable triazole and phenol functions inside the macrocyclic cavity and a pyridine side arm were prepared by cyclization of the appropriate dihalide with 6-(2{prime}-pyridylmethyl)-3,9-dioxa-6-azaundecane-1,11-diol followed by cleavage of the THP or methoxy protecting groups. Preliminary complexation data show that the phenol-substituted pyridinoaza-18-crown-6 ligands form strong complexes with various metal cations and exhibit high selectivity toward Ag{sup +}. Macrocycle 16 containing a p-nitrophenol substituent formed a complex with benzylamine. The crystal structures for 16 and its benzylamine complex are also given here.