Fred L. Tobiason

Conformation and Complexation of Tannins: NMR Spectra and Molecular Search Modeling of Flavan-3-ols

Studies of flavan‐3‐ols in their biologically significant phenolic form show that both H‐6 and C‐6 resonances are downfield from H‐8 and C‐8. Therefore, assignments for the H atoms of the A‐ring are inverse to those commonly reported. By contrast, in the methyl ether and methyl ether acetate derivatives, both H‐8 and C‐8 are downfield from H‐6 and C‐6 and assignments commonly reported for C‐6 and C‐8 are incorrect. The assignments commonly reported for the peracetate derivatives are correct. In contrast to results observed for dimeric flavans, solvent effects on chemical shifts and coupling constants are small in monomeric flavan derivatives. The small heterocyclic ring J2,3 coupling constants of 2,3‐cis‐flavans can be defined by lineshape analysis of H‐3. These results provide the first evidence for the conformations of the common 2,3‐cis‐flavans in solution. With the exception of compounds carrying a bulky acetate at C‐3, a GMMX global search protocol provides reasonable predictions of heterocyclic ring coupling constants.

Dipole moment, solution, and solid state structure of (–)-epicatechin, a monomer unit of procyanidin polymers

The structure of (–)-epicatechin has been determined in the crystalline state. Crystals are orthorhombic, P212121, a= 670.8(1), b 1 329.1 (3), c= 1 426.2(4) pm, Z= 4, Dc= 1.516 g cm–3, R= 0.041 for 1 624 observations. Intramolecular hydrogen bonds are absent. The aliphatic hydroxy group and three of the four phenolic hydroxy groups participate in intermolecular hydrogen bond formation. The aromatic ring bonded to C(2) is in an equatorial position, but the hydroxy group bonded to C(3) adopts an axial position. Comparison with the published structure for 8-bromotetra-O-methyl-(+)-catechin reveals that epimerization at C(3) alters the fused ring system primarily at C(2) and C(3). The heterocyclic ring is more closely described as a half-chair in (–)-epicatechin than in 8-bromotetra-O-methyl-(+)-catechin. Dipole moments have been measured for (–)-epicatechin in solution. At 300 K the root-mean-square dipole moment is 3.91 ± 0.04 D, and the temperature coefficient is small and negative. The behaviour of the dipole moment is easily rationalized via a theoretical rotational isomeric state analysis based on the structure found in the crystalline state.

Predicting heterocyclic ring coupling constants through a conformational search of tetra-O-methyl-(+)-catechin

Abstract A GMMXc conformational search routine gives a family of conformations that reflects the Boltzmann-averaged heterocyclic ring conformation as evidenced by accurate prediction of all three coupling constants observed for tetra-O-methyl-(+)-catechin.

Temperature Dependence of (+)-Catechin Pyran Ring Proton Coupling Constants as Measured by NMR and Modeled Using GMMX Search Methodology

Abstract The pyran ring proton coupling constants for (+)-catechin have been experimentally determined in deuterated methanol over a temperature range of 213 K to 313 K. The experimental coupling constants were simulated to 0.04 Hz on the average at a 90% confidence limit using a LAOCOON method. The temperature dependence of the coupling constants was reproduced from the Boltzmann distribution of the conformational ensemble generated by the GMMX searching program.

Crystal structure, conformational analyses, and charge density distributions for ent-epifisetinidol : an explanation for regiospecific electrophilic aromatic substitution of 5-deoxyflavans

Abstract Molecular modeling and molecular orbital analyses of ent-epifisetinidol gave good predictions of the approximate “reverse half-chair” conformation found for the crystal structure. MNDO 2 and AM1 analyses of HOMO electron densities provided an explanation for the stereospecific electrophilic aromatic substitution at C(6) in 5-deoxy-flavans.

Predicting carbohydrate chain and heterocyclic ring coupling constants in monosaccharides using gmmx conformational searching 1

Abstract The gmmx global searching program was applied to D -glucitol and α- and β- D -glucopyranose to predict the 3 J HH nuclear magnetic resonance (NMR) coupling constants, which were then compared with the experimental NMR values determined in aqueous solution. The conformational search was conducted using the technique of mixed combination Monte Carlo movements of atom coordinates and bond rotations, with the best coupling constants determined with the hydrogen bonding function turned off and the dielectric constant set between 4.0 and 5.0. The gmmx Boltzmann averaged coupling constants for D -glucitol were found to fit with a root-mean-square (rms) deviation of 1.3 Hz compared with a molecular dynamics rms value of 1.9 Hz. For α- and β- D -glucopyranose, the coupling constants were found to fit the experimental NMR values with an rms of 0.7 Hz including the values for the hydroxymethyl group. The conformations of the lowest energy structures were found and compared with X-ray crystal structures. The lowest energy 4 C 1 and 1 C 4 conformers for both α- and β- D -glucopyranose were studied, with the 1 C 4 reverse-chair conformations for α- and β- D -glucopyranose found to be 5.0 and 5.9 kcal mol −1 higher respectively than the 4 C 1 structures. The relative energy of the α- D -glucopyranose 1 C 4 conformer agreed with that found by MM3, but the β- D -glucopyranose 1 C 4 conformer had a lower relative energy and a different hydroxyl group configuration than that found by a number of other computational methods.

Phenolic Resin Adhesives

Phenolic resins have played an important role in industrial advancement for over 80 years. The term phenolic is applied to those materials formed during the condensation reaction between phenol or substituted phenols and formaldehyde. Although Adolph Baeyer1 first reacted phenol and an aldehyde in 1872 to produce a resinous material, and Arthur Smith was issued the first phenolic resin patent in 1899,2 it is Leo H. Baekeland who is considered the creator of the phenolic resin industry. He published a series of papers3, 4 beginning in 1905, and established the Bakelite Company in the U.S. in 1910. This eventually became a division of the Union Carbide Company in 1939.2 Over the years many scientists have helped make phenolic resin products an integral part of modern life.

Bridged calix[4]arenes; X-ray crystal and molecular structures and spectroscopic studies

Single crystals of two macrocyclic compounds of the calix[4] arene type, in which two opposite para-positions are connected by an additional aliphatic chain where n= 5 (1a) or n= 7 (1c) respectively, were obtained from acetone without incorporation of solvent. Crystals of compound (1a) are monoclinic, space group P21/n, a= 8.879(1), b= 17.216(4), c= 18.167(3)A, β= 98.16(1)°, V= 2 748.2 A3, Z= 4, Dx= 1.258 g cm–3, final R-value 0.046 (2 476 unique reflections); crystals of compound (1c) are monoclinic, space group P21/c, a= 18.105(3), b= 9.117(2), c= 19.123(2)A, β= 97.84(1)°, V= 3127.0 A–3, Z= 4, Dx= 1.166 g cm–13, final R-value 0.043 (4 470 unique reflections). In both cases the arrangement of the four phenolic residues corresponds to the cone conformation. This cone is strongly distorted in the case of compound(1a), where two aromatic rings are nearly parallel. For the whole series of bridged calix[4]arenes (n= 5–14) FTIR spectra were measured in CCl4. A decreasing OH-stretching frequency with increasing chain length n shows an increasing strength of the intramolecular hydrogen bonds. These results, which are also supported by the 1H NMR data, are discussed in connection with the molecular conformations found in the crystalline state.

MNDO Molecular Orbital Analyses of Models for Proanthocyanidin-Methylolphenol Reactions

The MNDO molecular orbital method has been applied to molecular structures that model or react with proanthocyanidins. Atom net charge distribution, structural parameters, heats of formation, and ionization potentials are evaluated for: (+)-catechin, (−)-epicatechin, catechol, resorcinol, phloroglucinol, o- and p-methylolphenol, and o-and p-benzoquinone methide in an investigation of chemical reactivity under different pH conditions. Other MO calculations are reviewed, and the optimized MNDO MO parameters are compared with existing literature data. The total net and HOMO electronic charge distribution is evaluated in terms of nucleophilicity and chemical reactivity. The HOMO frontier orbitals in polyhydroxybenzene and the LUMO orbitals in the benzoquinone methides play an important role in chemical reactivity.

Modeling the conformation of polyphenols and their complexation with polypeptides: self-association of catechin and its complexation with L-proline glycine oligomers.

Over the past 10 years, several scientific thrusts have come together in the study of flavanoids that make it possible to move forward into the study of complexation between polyphenols and polypeptides. Enhanced understanding of the conformational properties of flavanoid monomers and polyflavanoids through molecular modeling, combined with the detailed NMR experimental data now in the literature, provide the foundation.1–13 Recent work using conformational searching techniques with the GMMX6–8 protocol has shown additional detail about the distribution of pseudo equatorial and pseudo low-energy axial conformers in the ensemble, as shown in figure 1. This leads to information about the relationship between the conformer ensemble and the Boltzmann averaged NMR proton coupling constants that one would expect to observe in a solution. Figure 1 also illustrates the pseudo equatorial to axial transformation that takes place in all catechin or (+)-catechin-(4α→8)-(+)-catechin (B3) dimer complexes during the conformer searches and which would also be expected to occur in solution. Interest continues to further understand the details about this conformer distribution as well as in the prediction of complexation of tannins with metal ions and proteins. Although the GMMX software has given many interesting results, it is limited in handling cases that require systematic conformational searching of molecules combined in a complex. In addition, there are no solvent model options.