Phosphodiester Cleavage Properties of Copper(II) Complexes of 1,4,7-Triazacyclononane Ligands Bearing Single Alkyl Guanidine Pendants

Three new metal-coordinating ligands, L1·4HCl [1-(2-guanidinoethyl)-1,4,7-triazacyclononane tetrahydrochloride], L2·4HCl [1-(3-guanidinopropyl)-1,4,7-triazacyclononane tetrahydrochloride], and L3·4HCl [1-(4-guanidinobutyl)-1,4,7-triazacyclononane tetrahydrochloride], have been prepared via the selective N-functionalization of 1,4,7-triazacyclononane (tacn) with ethylguanidine, propylguanidine, and butylguanidine pendants, respectively. Reaction of L1·4HCl with Cu­(ClO4)2·6H2O in basic aqueous solution led to the crystallization of a monohydroxo-bridged binuclear copper­(II) complex, [Cu2L12(μ-OH)]­(ClO4)3·H2O (C1), while for L2 and L3, mononuclear complexes of composition [Cu­(L2H)­Cl2]­Cl·(MeOH)0.5·(H2O)0.5 (C2) and [Cu­(L3H)­Cl2]­Cl·(DMF)0.5·(H2O)0.5 (C3) were crystallized from methanol and DMF solutions, respectively. X-ray crystallography revealed that in addition to a tacn ring from L1 ligand, each copper­(II) center in C1 is coordinated to a neutral guanidine pendant. In contrast, the guanidinium pendants in C2 and C3 are protonated and extend away from the Cu­(II)–tacn units. Complex C1 features a single μ-hydroxo bridge between the two copper­(II) centers, which mediates strong antiferromagnetic coupling between the metal centers. Complexes C2 and C3 cleave two model phosphodiesters, bis(p-nitrophenyl)­phosphate (BNPP) and 2-hydroxypropyl-p-nitrophenylphosphate (HPNPP), more rapidly than C1, which displays similar reactivity to [Cu­(tacn)­(OH2)2]2+. All three complexes cleave supercoiled plasmid DNA (pBR 322) at significantly faster rates than the corresponding bis(alkylguanidine) complexes and [Cu­(tacn)­(OH2)2]2+. The high DNA cleavage rate for C1 {kobs = 1.30 (±0.01) × 10–4 s–1 vs 1.23 (±0.37) × 10–5 s–1 for [Cu­(tacn)­(OH2)2]2+ and 1.58 (±0.05) × 10–5 s–1 for the corresponding bis(ethylguanidine) analogue} indicates that the coordinated guanidine group in C1 may be displaced to allow for substrate binding/activation. Comparison of the phosphate ester cleavage properties of complexes C1–C3 with those of related complexes suggests some degree of cooperativity between the Cu­(II) centers and the guanidinium groups.