Activated hydrogens in saturated carbonyl compounds

Complete exchange of protons in a sterically unhindered position a to a carbonyl group can be achieved by heating a solution of the ketone in O-deuterated solvents in the presence of an acid or base catalyst, the latter being the more effective. The most commonly used solvents are methanol-OD, ethanol-OD, and the aprotic solvent anhydrous tetrahydrofuran or dioxane mixed with deuterium oxide. Under alkaline conditions the exchange rate in 153 2 14,164 stcroids, for example, is usually 

With some ketones there is a sufficient difference in the rate of loss of various a-hydrogens at the enolization step and a steric preference for the incoming deuterium during ketonization to facilitate selective exchange of certain a-hydrogens. Typical examples are the steroids. 

There is no generally reliable rule of thumb to predict whether an axial or equatorial proton will exchange faster. For instance, in the examples discussed above, the slowest rate of exchange is found for the S -axial proton in 5a-androstan-7-one (1) [see(2)-(4)] and the 2fi-equatorial proton in 5a-androstan-l 1-one (5) [see (6)-(9)]. Furthermore, the results of base-catalyzed exchange cannot necessarily be predicted from the corresponding 

Interestingly enough, both protons at C-11 are exchanged quite readily in 12-keto steroids. In these compounds C-11 is the only possible enolization site where the axial (/3) proton is probably expelled first. During ketonization, the deuteron attack is more likely to occur from the less hindered a-side. By this sequence the proton which was originally at the lla-equato-rial position becomes axial and readily available for expulsion in the next enolization step. Thus, isomerization of the C-11 hydrogens may be an important reason for the facile exchange at this position. (For a more detailed discussion of the mechanism of enolization and ketonization reactions, see ref 114.) 

If the ketone function is adjacent to a hydrogen-bearing asymmetric center, the compound can undergo epimerization. In steroids with a normal skeletal configuration (8/3, 9a, 14a) there is no detectable epimerization at C-8 or C-9 during the exchange of and 11- ketones. 

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