Stereoelectronic effects on 1H nuclear magnetic resonance chemical shifts in methoxybenzenes

Investigation of all O-methyl ethers of 1,2,3-benzenetriol and 4-methyl-1,2,3-benzenetriol (3-16) by H-1 NMR spectroscopy and density-functional calculations disclosed practically useful conformational effects on H-1 NMR chemical shifts in the aromatic ring. While the conversion of phenol (2) to anisole (1) causes only small positive changes of H-1 NMR chemical shifts (Delta delta < 0.08 ppm) that decrease in the order H-ortho > H-meta > H-para, the experimental O-methylation induced shifts in ortho-disubstituted phenols are largest for H-para, Delta delta = 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 H-para. 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 H-1 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.