Meta-Nitroacetophenone

Fig. 14.62. Polar hydrogenation/ hydrogenolysis of an aromatic ketone (meta-nitroacetophenone). CF3COOH causes a reversible protonation of the ketone to the carboxonium ion A. The reducing agent triethylsilane then transfers a hydride ion onto A to form a benzylic alcohol. This alcohol presumably is silylated, protonated, and converted into the benzyl cation B. A second hydride transfer yields the final product.

No reference was given to a detailed paper by R. Camps, Arch. d. Pharm. 240, 1 (1902). This author adds the acetophenone to ten times its weight of fuming nitric acid at temperatures of —10 to +20°. At the lower temperature a 96 per cent yield of nitroacetophenones was obtained, consisting of 45 per cent of the ortho derivative and 55 per cent of the meta. 

The acetyl group is attached to the ring by Friedel-Crafts acylation. It is a meta director, and its nitration gives the proper orientation of substituents. The order of the first two steps cannot be reversed, because Friedel-Crafts acylation of nitrobenzene is not possible (Section 12.16). Once prepared, m-nitroacetophenone can be reduced to m-nitroaniline by any of a number of reagents. Indeed, all three reducing combinations described in the text have been employed for this transformation. 

For acetophenone, only meta-nitration has preparative value. As for benz-aldehyde, this is favored by a large excess of concentrated or, better, fuming sulfuric acid and by reaction at as low a temperature as possible 209 yields of jw-nitroacetophenone exceeding 90% have been obtained in this way.210,211 Use of nitric acid alone or increase in the reaction temperature increases the amount of ortho-isomer formed,212 but this is nevertheless not a satisfactory method of synthesis. 

Both substituents of mefa-nitroacetophenone are meta directors. However, the Friedel-Crafts acylation reaction must be carried out first because the benzene ring of nitrobenzene is too deactivated to undergo a Friedel-Crafts reaction (Section 16.7). 

Positions ortho to the methoxy 4-Methoxy-3-nitroacetophenone group are meta to the carbonyl. 

A methoxy group is ortho, para-directing, and a carbonyl group is meta-directing. The open positions of the ring that are activated by the methoxy group in p-methoxyacetophenone are also those that are meta to the carbonyl, so the directing effects of the two substituents reinforce each other. Nitration of p-methoxyacetophenone yields 4-methoxy-3-nitroacetophenone. 

A less obvious example in which the success of a synthesis depends on the order of substituent placement on the ring is illustrated by the preparation of m-nitroacetophenone. Although both substituents are meta-directing, the only practical synthesis involves nitration of acetophenone (disconnection a). 

Let us examine possible syntheses of l-(3-nitrophenyl)ethanone (m-nitroacetophenone). Because both groups are meta directors, two possibilities appear available nitration of 1-phenylethanone or Friedel-Crafts acetylation of nitrobenzene. However, in practice, only the first route succeeds. 

We also have to beware of the limitations of each type of substitution process. We recall that Friedel— Crafts acylation does not occur when the ring contains a meta-directing group. For example, we can make w-nitroacetophenone by nitration of acetophenone, but not from Friedel—Crafts acylation of nitrobenzene. 

---