46572-AC4
The Phenol - Amine Hydrogen Bond as a Director of Molecular Structure
I. Introduction
The goal of our research is to build on an initial discovery by our laboratory of a simple receptor able to undergo a pH-dependent conformation shift characterized by the formation of a network of phenol-amine hydrogen bonds. This network allows formation of a “closed”, or cup-like structure, which binds metal ions in a size-selective manner. In order to further understand and optimize this process, we are examining the structure and properties of a number of structural analogs. During the past year, we have focused on two primary areas of the research. First, we have begun the process of extending our initial quantum chemical (ab initio and density functional - DFT) calculations on amino acid side chains to several model receptors. This is important as a way to both understand the results of ion titration experiments, and predict the behavior of new receptors. Second, we have successfully synthesized four of the proposed pH-switchable ion receptors. During the coming months, we will study the ability of these compounds to bind ions, as measured by UV-vis titrations and isothermal titration calorimetry (ITC).
II. Progress in computational aspects
An initial requirement was to determine the feasibility of carrying out ab initio and DFT calculations on the full receptors, given our computing resources (primarily a single-CPU Linux-based PC). Preliminary efforts employed the RHF method and STO-3G basis set; while computationally inexpensive (minimized geometries were obtained in two CPU hours), this yielded phenol-amine hydrogen bond geometries that were not consistent with measured values in X-ray crystal structures. Moving to a higher level of theory (B3LYP density-functional method and STO3G basis set) substantially increased the time needed to optimize structures (5.3 CPU days on our system), but also provided geometries that made more sense. Therefore, we have decided to proceed using this protocol for optimizing geometries; energies for the optimized structures will be calculated via single-point calculations using a larger basis set (6-311G(d)) to improve accuracy. Thus far, we have completed modeling on five analogs of our initially synthesized receptor. While all show subtle differences in structure, perhaps most striking is the change in phenol-amine hydrogen bond length induced by the addition of an amino group at the 3-position on the aromatic ring, which increases this distance by 0.2 Angstroms.
III. Progress in synthesis and evaluation of new pH-switchable ion receptors
Four new analogs of our initial pH-switchable ion receptor (a tri-tyrosine ester of cyclohexane 1,3,5-trimethanol) have been synthesized, purified, and characterized. These are the 3-aminotyrosine derivative, the 3-chlorotyrosine derivative, the 3-nitrotyrosine derivative, and the 3-aminophenylalanine derivative. Both the 3-chloro and 3-nitrotyrosine derivatives are expected to have a lower pKa for the phenolic proton (8.51 and 7.23, respectively, vs. 9.99 for tyrosine), altering the range in which the closed (ion-binding) conformer is expected to exist. With these compounds in hand, we can now begin the process of analyzing their ability to bind ions, and their structural properties in solution.
