Vera M. Kolb

NEW SYNTHESES AND REACTIONS OF ORGANIC COMPOUNDS: REACTIONS WITH CARBON TETRACHLORIDE AND OTHER PERHALOMETHANES IN POWDERED POTASSIUM HYDROXIDE – t -BUTYL ALCOHOL

Ketones, sulfones, alcohols, and “acidic” hydrocarbons are readily halogenated with perhalomethanes—CCl 4 , CBr 4 , CBrCl 3 , CCl 2 Br 2 , etc,—in t-butyl alcohol-powdered potassium hydroxide. Depending upon the structure of the substrate, the halogenated derivative may be isolated or other, specific products formed from it in situ in this medium are obtained, generally in high yields. For the most part the halogenations with these reagents are selective and do not affect other sites of the substrate or other compounds that are usually sensitive to halogenating agents. Powdered potassium hydroxide suspended in t-butyl alcohol plays a special role in these halogenations as well as the subsequent reactions, which are all base-induced (“catalyzed”). The reactions occur rapidly apparently on the surface of the potassium hydroxide which is essentially insoluble in t-butyl alcohol. This phenomenon readily lends itself to commercial adaptation and high yields of products have been obtained merely by passing a solution of substrate in perhalomethane – t-butyl alcohol through a column packed with powdered potassium hydroxide on an inert support; the effluent is simply collected and evaporated, leaving the product. Evidence suggests that a finite concentration of potassium t-butoxide is maintained virtually on the surface of the potassium hydroxide (from commercial pellets, 15% H 2 O) in equilibrium with the KOH, H 2 O, and t-BuOH, and is responsible for the formation of substrate anion. In turn, these poorly solvated anions—in these studies mainly enolates or other varieties of carbanions —readily share an electron with perhalomethanes, and in the resulting caged radical/anion-radical pair (RARP) halogen-atom transfer is effected. Anions which cannot easily share an electron with the perhalomethanes are unreactive under these conditions; anions which actually transfer an electron to perhalomethanes are not halogenated either, but are responsible for the formation of free-radical related products. This chapter summarizes and categorizes the variety of new syntheses made available with these reactions. While the reaction pathways responsible for these syntheses are discussed in the respective sections, mechanistic details associated with the important halogenation step are described in the final section. The fact that CCl 4 , KOH, and t-BuOH are readily available, inexpensive, easily and safely handled and stored in any laboratory, and readily removed from the reaction products, contributes to the attractiveness of these new syntheses.

Study of the syn and anti isomerism of the long-lasting opiate antagonist naloxazone and related compounds

A 13C-NMR study of the long-acting opiate antagonists naloxazone (I) and naltrexazone (II) and the long-acting opiate agonist oxymorphazone (III) revealed that these compounds are formed as mixtures of their anti and syn isomers. The less crowded anti isomer was found to be the major product in all cases (ca. 80%). N,N-Dimethyl derivatives of naloxazone (IV), naltrexazone (V), and oxymorphazone (VI), which are sterically more crowded than the corresponding unsubstituted hydrazones I-III, were formed as almost exclusively anti isomers. Pure anti isomer of II was obtained as a 1:1 complex with ethanol. No syn-anti equilibration was observed during the 13C-NMR experiment in any of the cases studied. The relevance of our finding about the syn-anti isomerism of the opiate hydrazones to the understanding of their interactions with the opiate receptor is discussed.