Investigation of Structural Trends in Mono-, Di-, and Pentafluorobenzonitriles Using Fourier Transform Microwave Spectroscopy.

The ground state rotational spectra of a series of fluorinated benzonitriles (BN), namely, 2-fluorobenzonitrile (2FBN), 3-fluorobenzonitrile (3FBN), 2,3-difluorobenzonitrile (23DFBN), 2,4-difluorobenzonitrile (24DFBN), and pentafluorobenzonitrile (PFBN), have been investigated between 4 and 24 GHz using Fourier transform microwave (FTMW) spectroscopy. The assigned transitions include those due to the parent as well as the (13)C and (15)N singly substituted isotopologues which were observed in natural abundance. The spectroscopic analysis allowed the derivation of substitution (rs) and effective ground state structures (r0) to investigate the effect of mono-, di-, and pentafluoro substitution on the geometry of the BN backbone and are compared here with ab initio values of the equilibrium parameters (re) obtained from MP2/6-311++G(2d,2p) calculations. Analysis of the (14)N hyperfine structure provides additional information about the electronic structure surrounding the nitrogen atom. The observed geometry changes relative to the reference BN compound are interpreted using natural bond orbital (NBO) analysis to describe differences in the hybridization at various sites and contributions from plausible resonance structures.

Planar-bilayer activities of linear oligoester bolaamphiphiles.

Voltage-clamp experiments of eight oligoester bolaamphiphiles in two subclasses are described. Syntheses of three new terephthalate-based compounds were achieved in three linear steps. Together with five previously described, related compounds, the ion transport activity was assessed by means of the voltage-clamp technique. All of the compounds show multiple types of conductance behavior in planar bilayers, a subset of which was exponentially voltage-dependent. The varied and irregular activities were summarized with the aid of a recently developed "activity-grid" method.

Solid-phase synthesis of a library of linear oligoester ion-channels.

A solid-phase synthesis protocol was used to prepare fifteen new linear tetra-, and penta-esters structurally related to an active lead compound. The structures were assembled from three types of hydroxyl protected building blocks: monoalkyl esters of hydroxyglutaric acid, omega-hydroxyacids, and alpha-hydroxymethylalkanoic acids. The standard methodology gave acceptable quantities of material free of small molecule impurities. Mass spectrometric analysis revealed the presence of deletions due to incomplete coupling, as well as additions and macrolactones due to partial acidic rearrangement on release from the solid-support. The amount of these impurities could be estimated from the (1)H NMR spectra, and their implications for subsequent activity analysis are discussed.

Structure-activity relationships in linear oligoester ion-channels.

The ion transport activity of eighteen linear oligoesters was assessed using a quantitative fluorescence assay to monitor the collapse of a pH gradient across a vesicle bilayer membrane. Significant activity was associated with compounds that have extended lengths comparable to the thickness of the bilayer membrane, and with the most hydrophilic members of the compounds surveyed. Substantial differences in activity between constitutional isomers were also observed. The aggregation of active compounds in aqueous solution was detected by a pyrene fluorescence probe, and subsequently detected as a rate-limiting step in a sequential vesicle experiment.

Solid-phase synthesis of oligoester ion channels.

A simple synthesis of oligoesters from TBDMS-protected-beta- and THP-protected-omega-hydroxycarboxylic acids using a solid-phase synthesis protocol is reported. Procedures were optimized for the efficient production of ion channel candidates in high purity with minimal purification. The product oligoesters were evaluated for ion transport activity using a fluorescent dye/vesicle assay. Oligoesters produced by this strategy show structure-dependent activity; the most active compounds are closely comparable to previously known oligoesters, but are available at a fraction of the synthetic effort.