Toward a Small Molecule, Biomimetic Carbonic Anhydrase Model: Theoretical and Experimental Investigations of a Panel of Zinc(II) Aza-Macrocyclic Catalysts

Abstract

A panel of five zinc-chelated aza-macrocycle ligands and their ability to catalyze the hydration of carbon dioxide to bicarbonate, H(2)O + CO(2) → H(+) + HCO(3)(–), was investigated using quantum-mechanical methods and stopped-flow experiments. The key intermediates in the reaction coordinate were optimized using the M06-2X density functional with aug-cc-pVTZ basis set. Activation energies for the first step in the catalytic cycle, nucleophilic CO(2) addition, were calculated from gas-phase optimized transition-state geometries. The computationally derived trend in activation energies was found to not correspond with the experimentally observed rates. However, activation energies for the second, bicarbonate release step, which were estimated using calculated bond dissociation energies, provided good agreement with the observed trend in rate constants. Thus, the joint theoretical and experimental results provide evidence that bicarbonate release, not CO(2) addition, may be the rate-limiting step in CO(2) hydration by zinc complexes of aza-macrocyclic ligands. pH-independent rate constants were found to increase with decreasing Lewis acidity of the ligand-Zn complex, and the trend in rate constants was correlated with molecular properties of the ligands. It is suggested that tuning catalytic efficiency through the first coordination shell of Zn(2+) ligands is predominantly a balance between increasing charge-donating character of the ligand and maintaining the catalytically relevant pK(a) below the operating pH.

Insights into the Relationship of Catalytic Activity and Structure: A Comparison Study of Three Carbonic Anhydrase Mimics

“…the active site of CA. For zinc-cyclam, there are two isomers depending on how the hydrogen atoms connected to the nitrogen atoms are positioned: "two up and two down" and "all up" [19]. "Two up and two down", as shown in Fig.…”

“…Since only the Zn-OH − form catalyzes the hydrolysis reaction, Zhang et al proposed a simplified three-step reaction mechanism to calculate the intrinsic Figure 7 Reaction rate constant of CO 2 hydrolysis using zinc-tri as the catalyst versus pH based on the rate from the microkinetic model at t = 2 ms (-) compared to experimental results: from Zhang et al [16] and from Koziol et al [19].…”

“…Reaction rate constant of CO 2 hydrolysis by zinc-cyclam versus pH based on the rate from the microkinetic model at t = 2 ms (-) compared to experimental results ( ) from Koziol et al [19]. reaction rate constant, which is independent of pH.…”

Synthesis and crystal structure of a polymeric zinc(II) complex derived from 4-nitro- phenylacetic acid and propane-1,3-diamine

“…Zinc is a very important element in biological systems, functions as the active site of hydrolytic enzymes, such as carboxypeptidase and carbonic anhydrase [5,6]. Zinc complexes with carboxylate ligands have been widely reported for their versatile structures and applications [7][8][9][10].…”

Crystallographic Snapshot of an Arrested Intermediate in the Biomimetic Activation of CO2

“…[10] The success of such a biomimetic approach is reflected in the growing number of zinc-based systems reported to activate CO 2 rapidly and reversibly under mild conditions. [11][12][13][14] In contrast, structural analogues that replicate the substrate binding sites of these metalloenzymes are comparatively rare. This prompted us to investigate the activation of CO 2 using tetrabutylammonium hydroxide [(n-C 4 H 9 ) 4 …”