Deuterated phenol derivatives

Isotope labeling by derivative formation with deuterated reagents is useful for the preparation of analogs such as dg-acetonides, da-acetates, da-methyl ethers, dg-methyl esters, etc. The required reagents are either commercially available or can be easily prepared. (The preparation of da-methyl iodide is described in section IX-F. Various procedures are reported in the literature for the preparation of dg-acetone, da-diazometh-ane57.i63.i73 and da-acetyl chloride. ) These reactions can be carried out under the usual conditions and they need no further discussion. A convenient procedure has been reported for the da-methylation of sterically hindered or hydrogen bonded phenolic hydroxyl functions by using da-methyl iodide and sodium hydroxide in dimethyl sulfoxide solution. This procedure should be equally applicable to the preparation of estradiol da-methyl ether derivatives. 

From the point of view of the synthetic organic chemist, the importance of aromatic thallation, and the remarkable degree of orientation control which can be exercised over this process, lies in the ease with which the resulting ArTlXj compounds can be converted into substituted aromatic derivatives in which the new substituent group has entered the ring at the position to which thallium was originally attached. Syntheses of phenols, nitroso compounds, biaryls, aromatic nitriles, thiophenols, and deuterated aromatic compounds have all been achieved these results are summarized briefly below. 

Specifically deuterated derivatives of phenols can be prepared conveniently by using appropriate combinations of acid- and base-catalyzed exchange reactions. Treating with NaOD (or NaOH) causes exclusive exchange in positions ortho and para to the phenolic group while D3P04 deuterates all available aromatic sites. As an example, the conversion of 4-hydroxy-3-methoxytoluene to 5-monodeutero- and 2,6-dideuteroderiva-tives is illustrated below. 

The direct deuteration, by deuterium chloride in deuterium oxide, of the upper rim of 25,27-dialkoxy derivatives of callx[4]arenes has been shown to occur at the unsubstituted para-position of phenolic rings. ... 

In method 2, each fuel sample and the standards in petroleum-derived JP-8 were spiked with 1 ppm deuter-ated d5-phenol as an internal standard. Then, 10 mL of each sample and standard were extracted three times with 3 mL of 0.5 N NaOH. The water phase containing phenolics was acidified to a pH of 3, and the phenolics were recovered by extracting three times with 3 mL of CH2CI2. The CH2CI2 extracts were analyzed by GC-MS in a scan range of 50-400 amu with 1-pL on-column injections. Quantitative analyses were based on the integrated areas divided by the area of the internal standard... 

Kinetic studies have shown a primary kinetic isotope effect upon deuteration of the phenolic proton. In some cases ligand exchange reactions restrict the stoichiometry that can be obtained. One of the most thoroughly studied reactions of this type is the attempted synthesis of the mono-aryloxide derivative by reaction of trimethyla-luminum [Al2Me6] with 2,6-di-tert-butyl-4-methylphenol (Eq. 6.52) which leads to the bis(aryloxide) owing to the two disproportionation reactions shown in Eq. 6.53. ... 

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