Thomas J. Wenzel

Assignment of absolute configuration using chiral reagents and NMR spectroscopy

An overview of chiral reagents that are used to assign the absolute configuration of particular classes of compounds using NMR spectroscopy is presented. The use of chiral derivatizing agents, chiral solvating agents, metal complexes, and liquid crystals is described.

Utility of crown ethers derived from methyl β-d-galactopyranoside and their lanthanide couples as chiral NMR discriminating agents

Abstract Two chiral crown ethers derived from methyl β- d -galactopyranoside are examined as chiral NMR discriminating agents for protonated primary amines, amino alcohols, and amino acids. In combination, the solubility and use of the two crown ethers span a range of common NMR solvents including chloroform, acetonitrile, and methanol, which are compatible with the solubilities of various protonated amines. Enantiomeric discrimination is observed in the spectra of most substrates in the presence of the crown ethers. In several cases, the enantiomeric discrimination is larger than observed with previously reported chiral crown ethers. The crown ether V contains a β-diol unit capable of forming a chelate bond with lanthanide(III) ions. Adding ytterbium(III)nitrate to NMR samples in acetonitrile containing V causes substantial enhancements in the enantiodiscrimination in the spectra of several substrates.

Water-Soluble Calix[4]resorcinarenes with Hydroxyproline Groups as Chiral NMR Solvating Agents

Water-soluble calix[4]resorcinarenes containing 3- and 4-hydroxyproline, d-nipecotic acid, (S)-2-(methoxymethyl)pyrrolidine, (S)-2-pyrrolidine methanol, and (S,S)-(+)-2,4-bis(methoxymethyl)pyrrolidine substituents are synthesized and evaluated as chiral NMR solvating agents. The derivatives with the hydroxyproline groups are especially effective at causing enantiomeric discrimination in the spectra of water-soluble cationic and anionic compounds with pyridyl, phenyl, and bicyclic aromatic rings. Binding studies show that mono- and ortho-substituted phenyl rings associate within the cavity of the calix[4]resorcinarenes, as do naphthyl rings with mono-, 2,3-, and 1,8-substitution patterns. Anthracene derivatives with an amino or sulfonyl group at the 1-position bind within the cavity, as well. Aromatic resonances of the substrates exhibit substantial upfield shifts because of shielding from the aromatic rings of the calix[4]resorcinarene. The effectiveness of the reagents at producing chiral recognition in 1H NMR spectra is demonstrated with sodium mandelate, the sodium salt of tryptophan, and doxylamine succinate. While no one reagent is consistently the most effective, the calix[4]resorcinarenes with trans-4-hydroxyproline and trans-3-hydroxyproline moieties generally produce the largest nonequivalence in the 1H NMR spectra of the substrates.

Studies of metal chelates with the novel ligand 2,2,7-trimethyl-3,5-octanedione

Abstract The synthesis of the novel ligand 2,2,7-trimethyl-3,5-octanedione, H(tod), is described, as well as the preparation of some of the transition metal and lanthanide complexes containing the anion of this unsymmetrical beta-diketone ligand. The structure of Cu(tod)2 has been determined by X-ray crystallography to be square-planar with the isobutyl groups cis to each other. Thermogravimetric analyses indicate that several of these metal complexes are volatile and thermally stable compounds. Metal complexes containing this ligand also show unusually high solubilities in non-polar solvents such as n-hexane. The properties of these compounds indicate that they may be useful for vapour-plating of metals, as fuel additives, and in other applications.

Enantiomeric discrimination in the NMR spectra of underivatized amino acids and α-methyl amino acids using (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid

Abstract The compound (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid ( I ) is a useful chiral NMR discriminating agent for underivatized amino acids and α-methyl amino acids. The α-methyl amino acids, when mixed with I in methanol, are protonated through a reaction with a carboxylic moiety of I and associate with the crown ether. Amino acids such as tryptophan, valine, alanine, and phenylglycine can be solubilized at suitable concentrations in methanol through the addition of deuterium chloride. The NMR spectra of mixtures of these amino acids with I show enantiomeric discrimination. Addition of ytterbium(III)nitrate to crown-substrate mixtures causes only small shifts and no discernible enhancements in enantiomeric discrimination in the NMR spectra of the substrates.

A Water-Soluble Calix[4]resorcinarene with α-Methyl-l-prolinylmethyl Groups as a Chiral NMR Solvating Agent

A water-soluble calix[4]resorcinarene containing α-methyl-L-prolinylmethyl groups is synthesized and evaluated as a chiral NMR solvating agent. Aryl-containing substrates with substituted amines are studied.

Lanthanide ions as luminescent chromophores for liquid chromatographic detection

Abstract The chloride and nitrate salts of Tb(III) and Eu(III) can be employed as luminescent chromophores for reversed-phase liquid chromatographic detection. The method is applicable to specific compounds that are capable of either transferring energy to, or quenching the background luminescence of, a lanthanide ion. Addition of the lanthanide ion is achieved through a post-column reaction device. Mobile phases containing methanol and acetonitrile can be employed. Significant quenching of the lanthanide luminescence is observed in mobile phases containing water. This quenching can be reduced by the addition of potassium acetate. Higher temperatures increase the intermolecular energy transfer resulting in an increase in the sensitivity. Oxygen quenches the lanthanide luminescence and measures to remove oxygen from the mobile phase must be taken. The selectivity of the energy transfer can be used to both simplify chromatograms and aid in the identification of compounds.

Lanthanide ions as luminescent chromophores for the liquid chromatographic detection of polynucleotides and nucleic acids.

Europium(III) and terbium(III) can be used as luminescent chromophores for the liquid chromatographic detection of certain nucleotides and nucleic acids. The method is dependent upon an energy transfer from the nucleic acid to the lanthanide ion. Of the base moieties, only xanthine, guanine, and thiouridine have appropriate excited state energy levels for efficient energy transfer. The lanthanide ion can be added in a pre- or post-column mode. The applicability of the method was demonstrated for the detection of homologous polynucleotides such as poly X and poly G. The method was also used to detect transfer RNA from Escherichia coli.

Lanthanide–Crown Ether Mixtures as Chiral NMR Shift Reagents for Amino Acid Esters, Amines and Amino Alcohols

Two chiral crown ethers, 2,3:4,5‐bis[1,2‐(3‐phenylnaphtho)‐1,6,9,12,15,18‐hexaoxacycloeicosa‐2,4‐diene and 1,2:5,6‐di‐O‐isopropylidene‐3,4‐[(tert‐butylbenzenediyl)bis(oxyethoxy)ethyl‐D‐mannitol, were evaluated as organic‐soluble chiral NMR resolving agents. The crown ethers are useful resolving agents for protonated amino acid esters, amines and amino alcohols. Enantiodiscrimination with the crown ethers is better in methanol than in acetonitrile or chloroform. Organic‐soluble lanthanide tetrakis(β‐diketonate) anions, which are formed in solution by mixing a lanthanide tris(β‐diketonate) and silver β‐diketonate, can be added to crown–substrate mixtures to enhance the enantiomeric resolution. The lanthanide‐induced enhancement occurs because the enantiomers of the substrate have different association constants with the crown ethers. The enantiomer that associates less favorably with the crown ether is more available to complex with the lanthanide.

Carboxymethylated cyclodextrins and their complexes with Pr(III) and Yb(III) as water-soluble chiral NMR solvating agents for cationic compounds

Cyclodextrins that are indiscriminately carboxymethylated at the 2-, 3-, and 6-positions are used as chiral NMR solvating agents for cationic substrates with phenyl, naphthyl, pyridyl, indoline, and indole rings. Enantiodifferentiation with the alpha-, beta-, and gamma-cyclodextrin derivatives is compared. The carboxymethylated derivatives are almost always more effective as chiral NMR solvating agents for cationic substrates than native cyclodextrins. The most effective carboxymethylated cyclodextrin varies for different substrates, and at times even different resonances of the substrate. Addition of paramagnetic praseodymium(III) or ytterbium(III) to mixtures of the carboxymethylated cyclodextrin and substrate often causes enhancements in enantiomeric discrimination and facilitates measurements of enantiomeric purity. The lanthanide ion bonds to the carboxymethyl groups and causes perturbations in the chemical shifts in the NMR spectra of substrate molecules in the cyclodextrin cavity.