A Zinc(II) Complex of 1,5,9-Triazacyclododecane ([12]aneN3) as a Model for Carbonic Anhydrase

Article abstract of DOI:10.1021/ja00171a020

Among macrocyclic tri- and tetraamines tested, a 12-membered triamine, [12]aneN₃, is the most appropriate ligand that mimics the ligand field surrounding Zn^II in carbonic anhydrases. In its 1:1 Zn^IIL complex, the H₂O bound at the fourth coordination site deprotonates with the pK_a value of 7.30 at 25°C, I = 0.1 (NaClO₄), almost the same value being reported for the Zn^II-enzymes. The resulting hydroxo complex is precipitated as a trimer from pH 8 aqueous solution, which with a formula of [Zn^IIL(OH)]₃(ClO₄)₃·HClO ₄ has been analyzed by X-ray crystal study. The crystals of (11)₃·(ClO₄)·HClO₄, C₂₇H₆₇N₉O₁₉CLZn₃, are trigonal, space group R3c with six molecules of 11 in the unit cell of dimensions a = 22.103 (1) A?, c = 16.514 (2) A?. Anion binding affinity to the Zn^IIL complex is determined by pH titration to have an order of OH^- (log K = 6.4) ? CH₃COO^- (2.6) > SCN^- (2.4) > I^- (1.6) > Br^- (1.5) > F^- (0.8), which is almost comparable with the anion inhibition order and magnitude reported for carbonic anhydrase activities. Moreover, like the Zn^II-enzymes, the [Zn^IIL(OH)]⁺ species catalyzes methyl acetate hydrolysis and acetaldehyde hydration, where the Zn^II-bound OH^- commonly acts as a nucleophile to the carbonyl carbons. The plots of these rate constants vs pH in either case show the kinetic pK_a values of Zn^IIL(OH₂) to be nearly the same as the thermodynamically obtained values of 7.3 at 25°C and 7.9 at 0°C. Various outstanding properties of Zn^II in enzymes (over other metal ions such as Co^III), which contribute to its biological significance, have been well demonstrated by the present macrocyclic triamine complex behaviors.