A study of the reaction between sodium phenoxide and 2-chlorocyclohexanone-1,2-C14

Abstract

The formation of 2-phenoxycyclohexanone by the reaction of sodium phenoxide with 2-chlorocyclohexanone may occur by: (1) the Sn2 attack of phenoxide ion at the alpha-carbon; (2) the Sn2' attack of phenoxide ion at the 2-carbon in the enol, 6-chloro-1- cyclohexenol; or (3) the attack of phenoxide ion at either the alpha- or alpha'-carbon of a symmetrical cyclopropanone intermediate. A decision between the various possibilities is offered by the use of 2-chlorocyclohexanone-1,2-C14. Path 1 would lead only to 2-phenoxycyclohexanone with an equal distribution of radioactive label at C-1 and C-2. Path 2 alone would yield a product with the label equally distributed at C-1 and C-6. Path 3 would result in 50% of the initial activity at C-1 and 25% at C-2 and C-6 respectively. This procedure does not differentiate between a cyclopropanone or a zwitterionic intermediate since the radiochemical consequences of each are identical. An improved synthesis for 2-chlorocyclohexanone-1,2-C14 was found. The available literature synthesis consists of eleven steps in a yield of 5% (based on starting labeled sodium cyanide). The following sequence offers a synthesis in five steps with 15% overall yield. Tetramethylene dibromide was converted to adiponitrile which was then hydrolyzed to adipic acid. Esterification and cyclization afforded 2-hydroxycyclohexanone which was further reacted with equimolar amounts of thionyl chloride to yield 2-chlorocyclohexanone (1.55 +- 0.01 mc./mole). Overall yields were typically 35% of theoretical. Reaction of the alpha-chloroketone with sodium phenoxide gave 2-phenoxycyclohexanone (1.55 +- 0.01 mc./mole) in 76% yield. Degradation of the 2-phenoxycyclohexanone was accomplished by initial oxidation with potassium permanganate and the phenyl hydrogen adipate thus produced (1.55 mc./mole) was subjected to a Barbier-Wieland Reaction. The resulting benzophenone was isolated as the 2,4-dinitrophenylhydrazone (specific activity from duplicate experiment s 0.55 +- 0.01 and 0.57 +- 0.01 mc./mole). Given starting material, equally labeled at positions 1 and 2 of 1.55 mc. /mole, the calculated value for the benzophenone would be 0.58 +- 0.01 mc./mole assuming only path 3 was in operation. Since there is no significant difference from the duplicate experimental results, it was concluded that only a symmetrical intermediate (be it a cyclopropanone or zwitterion) is consistent with the results. Further support for the above contention was found in the observation that 2-chloro-6,6-dimethylcyclohexanone failed to react with sodium phenoxide after considerably longer reaction times than those used for the 2-chlorocyclohexanone.