Stereoelectronic Effects on ¹H Nuclear Magnetic Resonance Chemical Shifts in Methoxybenzenes

Abstract

Investigation of all O-methyl ethers of 1,2,3-benzenetriol and 4-methyl-1,2,3-benzenetriol (3-16) by 1H NMR spectroscopy and density-functional calculations disclosed practically useful conformational effects on 1H NMR chemical shifts in the aromatic ring. While the conversion of phenol (2) to anisole (1) causes only small positive changes of 1H NMR chemical shifts (Delta delta < 0.08 ppm) that decrease in the order Hortho > Hmeta > Hpara, the experimental O-methylation induced shifts in ortho-disubstituted phenols are largest for Hpara, Delta delta equals; 0.19 +/- 0.02 ppm (n = 11). The differences are due to different conformational behavior of the OH and OCH3 groups; while the ortho-disubstituted OH group remains planar in polyphenols due to hydrogen bonding and conjugative stabilization, the steric congestion in ortho-disubstituted anisoles outweighs the conjugative effects and forces the Ar-OCH3 torsion out of the ring plane, resulting in large stereoelectronic effects on the chemical shift of Hpara. Conformational searches and geometry optimizations for 3-16 at the B3LYP/6-31G** level, followed by B3LYP/6-311++G(2d,2p) calculations for all low-energy conformers, gave excellent correlation between computed and observed 1H NMR chemical shifts, including agreement between computed and observed chemical shift changes caused by O-methylation. The observed regularities can aid structure elucidation of partly O-methylated polyphenols, including many natural products and drugs, and are useful in connection with chemical shift predictions by desktop computer programs.

Structural Features of Fréchet-Type Dendrons and Dendrimers in Single Crystals

“…The simplest model compound is methyl-phenyl-ether or anisole ( AN ), where the conformation, studied by various methods (NMR, , theoretical calculations microwave, TOFMS), was found to be planar, with the methoxy group in the plane of the phenyl ring. The energy barrier for OCH 3 group rotation about the Csp 2 −O bond in anisole in the gas phase is about 2.4 kcal·mol −1 . Two opposed effects are present here: (i) the p-π conjugation between oxygen lone pairs and the aromatic ring (that stabilize the planar conformation) and (ii) the steric repulsion between the methyl group and the ortho hydrogen atoms (that would lead to a syn perpendicular conformation).…”

Thioflavin T Hydroxylation at Basic pH and Its Effect on Amyloid Fibril Detection

“…All calculations were done in solvent using the CPCM approach, which is an implementation of the conductor-like screening solvation model (COSMO , ) in Gaussian 03. This approach has been shown to accurately determine the chemical shielding constants of a series of methoxybenzenes . Calculated chemical shielding constants were compared to chemical shifts by means of a linear regression referring to the experimental NMR data.…”

“…This approach has been shown to accurately determine the chemical shielding constants of a series of methoxybenzenes. 55 Calculated chemical shielding constants were compared to chemical shifts by means of a linear regression referring to the experimental NMR data.…”

Considerations for the Use of Polyphenols as Therapies in Neurodegenerative Diseases

“…For instance, acetylation of EGCG or resveratrol via esterification of their hydroxyl moieties yields stable pro-drugs in vivo whose acetyl groups can be hydrolyzed intracellularly by esterases to release the free polyphenol within the cell [194,195,196]. This strategy minimizes polyphenol auto-oxidation and allows better lipophilicity-dependent cellular uptake [197,198,199]. Production of conjugates with improved bioefficacy has also been a good approach to promote polyphenols absorption and activity.…”