Methyl group isotopic substitution

An example is the preparation of 18-trideuterio 5a-steroids bearing a side chain at C-17. Labeling of this position with three deuteriums was accomplished by utilizing the Johnson procedure for steroid total synthesis. This synthesis involves, in part, introduction of the 18-angular methyl group by methylation of the D-homo-17a-keto-17-furfurylidene intermediate (243). By substituting d3-methyl iodide in this step, the C/D cis- and ra/J5-18,18,18-d3 labeled ketones [(244) and (245)] are obtained. Conversion of the C/D tra 5-methylation product (245) into 18,18,18-d3-d /-3)8-hydroxy-5a-androstan-17-one (246) provides an intermediate which can be converted into a wide variety of C-18 labeled compounds of high (98%) isotopic... 

The molecules most profitably studied in connection with purely steric isotope effects have been isotopically substituted biphenyl derivatives. Mislow et al. (1964) reported the first more or less clearcut example of this kind in the isotope effect in the configurational inversion of optically active 9,10-dihydro-4,5-dimethylphenanthrene (7), for which an isotopic rate ratio ( d/ h) of 1-17 at 295-2°K in benzene solution was determined. The detailed conformation of the transition state is not certain in this case, as it involves the mutual passage of two methyl groups, and thus it is difficult to compare the experimental results with... 

In order to assess the validity of such an approach, within the assumptions of the model outlined, we have recently undertaken an examination of deuterium isotope effects on both the radiative and unimolecular dissociation rates. One such case is that of the protonated dimer of acetone in which either the methyl groups, the protonated oxygen, or both, are deuterium substituted. Results for these four systems are shown in Figure 14 and the rate data derived are summarized in Table 1. 

Chiral Methyl or Methylene Groups. Upon following a specific set of reactions, utilizing isotopically labeled reagents, chiral methylene groups (e.g., R-CHD—RO ) or chiral methyl groups (e.g., R—CHDT) can be substituted or incorporated into substrates. With such labeled compounds, stereochemical issues not apparent with the unlabeled substrate can be readily addressed. ... 

The o-substituted benzoic acid methyl ester of formula (CH3)2NC6H4C02CH3 has been found to lose both the ester methyl and the amine methyl in metastable ion decompositions. It has been proposed that the bond cleavage to eliminate the ester methyl is accompanied by a hydrogen transfer from one of the other methyl groups to the carbonyl oxygen in a 7-membered cyclic transition state [83]. The mechanistic proposal rests upon isotope effects observed on substituting deuterium in methyl groups. 

The obvious problem now is to question why a dissociative 7 -complex substitution mechanism is required in addition to the associative mechanism to interpret these isotope exchange reactions. Inspection of the dissociative mechanism shows that if a substituent such as a methyl group is present in the molecule (i.e., toluene from benzene, or the pico-lines from pyridine), then it would appear difficult to form a a bond at the adjacent carbon positions in the picolines (18) owing to steric... 

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