Dynamic Enolate Recognition in Aqueous Solution by Zinc(II) in a Phenacyl-Pendant Cyclen Complex:  Implications for the Role of Zinc(II) in Class II Aldolases

Abstract

A zinc(II) complex of 1-(4-bromophenacyl)-1,4,7,10-tetraazacyclododecane, ZnL, has been synthesized to mimic the active center of class II aldolases. Its X-ray crystal structure showed that zinc(II) remains atop the four nitrogen atoms of cyclen (average Zn−N distance 2.170 Å) to bind with the carbonyl oxygen (Zn−O distance of 2.159(3) Å) and one H2O (Zn−O distance of 2.130(3) Å). Crystal data: monoclinic, space group P21/n (No. 14), with a = 12.221(8) Å, b = 11.052(7) Å, c = 18.194(9) Å, β = 97.12(3)°, V = 2438(5) Å3, Z = 4, R = 0.041, and R w = 0.046. The potentiometric pH titration of ZnL in aqueous solution disclosed dissociation of one proton with pK a = 8.41 at 25 °C and I = 0.1 (NaClO4), which yields a mixture of a hydroxide-bound complex (ZnL−OH-) and an enolate-bound complex (ZnH- 1L) in a 3:1 ratio, as determined by UV spectrophotometric and 13C and 1H NMR titrations. This is the first quantitative assessment of enolate formation promoted by a proximate zinc(II) ion near neutral pH in aqueous solution. The enolate-bound complex ZnH- 1L independently isolated by treatment of ZnL with an equivalent amount NaOMe in acetonitrile was fully characterized to compare with ZnL. The equilibrium between the ZnL−OH- and ZnH- 1L varied with temperature (15, 25, and 35 °C), from which thermodynamic parameters of Δ G = 3.0 kJ mol-1, Δ H = 8.7 kJ mol-1, and Δ S = 19 J mol-1 K-1 at 25 °C were determined. Because of the facile enolization by zinc(II), the methylene hydrogen atoms (adjacent to the carbonyl) of ZnL were readily exchanged by deuterium under physiological conditions. The half-life at 25 °C for this H−D exchange at pD 7 (20 mM MOPS buffer) was determined to be 25 min by 1H NMR measurements. Implications of the present results for the role of zinc(II) in the active center of class II aldolases are discussed.

Large pKa Shifts of α‐Carbon Acids Induced by Copper(II) Complexes

“…Table 2 are comparable with the 10 unit pK a shift found by Kimura et al with receptor 3, which similarly utilizes a metal cation to activate a carbonyl and subsequently reduce the pK a of the a methylene proton. [10] The above trends shown in Table 2 can be explained based on the thermodynamic cycle of receptor(R)-substrate(SH) binding illustrated in Figure 7 in which two routes to the bound substrate anion are shown. The first path, K 1 -K 2 , represents deprotonation of the substrate before binding to the host.…”

“…Kimura et al proposed a model system for class II aldolases to study how much the acidity of a hydrogen a to a carbonyl may be increased through coordination of the zinc(ii) center. [10] The model system, 4-bromophenacyl-pendant zinc cyclen (3), specifically sought to determine how the formation of the enediolate by a relatively weak base (glutamic carboxylate) at physiological pH is possible in the active site of class II aldolases. A reduction in the pK a of the methylene hydrogen of 10 pK a units was found.…”

Syntheses of Zinc Complexes with Multidentate Nitrogen Ligands: New Catalysts for Aldol Reactions

“…A model with four nitrogen atoms and a carbonyl group bound to the zinc ion has also been developed. [9] Proline has been used as an asymmetric catalyst, [10,11] and some early work has shown that the Zn II ion coordinated to pyridine and bi-and ter(pyridine)s can catalyze the reaction of aldehydes and ketones to give unsaturated ketones. [12] Chiral dinuclear Zn complexes with chiral binol as ligand as well as other oxygen-containing ligands have been recently reported to catalyze asymmetric aldol reactions.…”

Connectivity patterns and rotamer states of nucleobases determine acid–base properties of metalated purine quartets

“…The 1 H NMR spectra of 1a and 1b in [D 6 ]DMSO and [D 7 ]DMF likewise reveal the presence of two rotamers in ratios of ca. 3:1 and 4:1, respectively.…”

“…It took longer to recognize that additional factors and in particular the microenvironment around a potentially ionizable group and the medium (dielectric constant of solvent) markedly contribute to the overall effect. It was the undisputed achievement of model bioinorganic chemistry, among others, to provide a deeper understanding of this phenomenon [3][4][5][6][7][8][9]. When the field of metal-nucleic acid chemistry became popular during the second half of the last century, the topic of acidity/basicity alterations of nucleobases due to metal binding likewise started to receive attention, last but not least because of its potential impact on biorelevant features such as nucleobase tautomerism, base pairing and mispairing patterns, as well as acid-base catalysis involving nucleic acids .…”