Aminoalcohols incorporating a piperazine ring: Synthesis, complexation of a hexadentate ligand and DNA cleavage capability of copper(II) complexes

The facility of aminoalcohol ligand synthesis via ring opening of cyclohexene oxide with polyamines including a piperazine ring is illustrated here with the syntheses and characterization of (2′-hydroxycyclohexyl)piperazine (1), bis(2′-hydroxycyclohexyl)-piperazine (2), 4-{(2″-hydroxycyclohexyl)-2′-aminoethyl)}piperazine (3), 1-(2″-hydroxycyclohexyl)-4-{(2″-hydroxycyclohexyl)-2′-aminoethyl)}piperazine (4), and 1,4-bis[(2″-hydroxycyclohexyl)-3′-aminopropyl]piperazine (5) described, along with an analogue of 4 in which a single -CH₂-CH₂- alkyl chain replaces the piperazine ring, 1,5-bis[(2′-hydroxycyclohexyl)amine]-3-azapentane (6). The viability of 5 as a hexadentate ligand was established by preparation of its copper(II) complex and subsequent X-ray crystal structure analysis. The complex [Cu(5)](ClO₄)₂ cation lies in a distorted octahedral environment with the four nitrogen donors in an approximate plane also incorporating the copper (Cu-N_tert 2.058(4) A; Cu-N_sec 2.072(4) A) and the two alcohol groups occupying axial sites with elongated bonds (Cu-O 2.415(3) A). The piperazine ring adopts a ‘butterfly wing’ geometry, whereas the two cyclohexane rings are in chair conformations. Significant bond angle distortions occur around the copper, exacerbated by the axial Jahn-Teller bond length distortion. The ability of the copper(II) complexes of the aminoalcohols to promote DNA cleavage was examined. Complexes of 2, 3 and 5 are effectively inactive whereas 4 is an efficient single strand cleavage promoter; however, the more flexible close analogue of 4, 6, also proved ineffective. Such observations for a closely related series indicate the subtle influences of spectator ligand rigidity and steric congestion on DNA cleavage promotion.