Nitration of methyl benzoate

The nitration of methyl benzoate to prepare methyl m-nitrobenzoate is an example of an electrophilic aromatic substitution reaction, in which a proton of the aromatic ring is replaced by a nitro group  

Many such aromatic substitution reactions are known to occur when an aromatic substrate is allowed to react with a suitable electrophilic reagent, and many other groups besides nitro may be introduced into the ring. 

You may recall that alkenes (which are electron-rich due to an excess of electrons in the tt system) can react with an electrophilic reagent. The intermediate formed is electron-deficient. It reacts with the nucleophile to complete the reaction. The overall sequence is called electrophilic addition. Addition of HX to cyclohexene is an example. 

Aromatic compounds are not fundamentally different from cyclohexene. They can also react with electrophiles. However, because of resonance in the ring, the electrons of the tt system are generally less available for addition reactions because an addition would mean the loss of the stabilization that resonance provides. In practice, this means that aromatic compounds react only with powerfully electrophilic reagents, usually at somewhat elevated temperatures. 

Benzene, for example, can be nitrated at 50°C with a mixture of concentrated nitric and sulfuric acids the electrophile is N02 (nitronium ion), whose formation is promoted by action of the concentrated sulfuric acid on nitric acid ) 

Prelab Exercise Draw the complete mechanism for the nitration of methyl benzoate. Show the resonance forms that make the methyl ester group a meta director and deactivator of the aromatic ring. 

Benzene and somewhat less reactive aromatic compounds such as methyl benzoate can be nitrated with a mixture of nitric and sulfuric acids, which ionizes completely to generate the nitronium and hydronium ions  

Hot concentrated nitric acid is also a good oxidizing agent. For example, benzoin is oxidized easily to benzil (Chapter 50). Activated aromatic compounds such as amines and phenols can be nitrated using just concentrated nitric acid  

5-Trinitrobenzene cannot be prepared by nitration of m-dinitro-benzene, even with the use of heat, concentrated sulfuric acid, and fuming nitric acid because the two nitro groups strongly deactivate the benzene ring. 

In the present experiment sulfuric acid serves as the solvent  

---

The nitration of methyl benzoate runs unusually smoothly, but it is essential to keep the temperature within the specified limits, otherwise the yield falls at 50°, 193 g. of solid product is obtained, while at 70° the yield falls to 130 g. 

Methyl m-nitrobenzoate has been prepared by the esterification of m-nitrobenzoic acid 1 this method is, however, obviously much less satisfactory than nitration of methyl benzoate. Nitration by means of fuming nitric acid has also been applied to methyl benzoate,2 but the use of the ordinary nitration mixture of concentrated sulfuric add and concentrated nitric acid is more satisfactory. 

Remove the ether by simple distillation or by evaporation on the steam bath under an aspirator tube. See Fig. 5 in Chapter 5 or Fig. 9 in Chapter 3 or use a rotary evaporator (Fig. 7 in Chapter 10). When evaporation ceases, add 2-3 g of anhydrous sodium sulfate to the residual oil and heat for about 5 min longer. Then decant the methyl benzoate into a 50-mL round-bottomed flask, attach a stillhead, dry out the ordinary condenser and use it without water circulating in the jacket, and distill. The boiling point of the ester is so high (199°C) that a water-cooled condenser is liable to crack. Use a tared 25-mL Erlenmeyer as the receiver and collect material boiling above 190°C. A typical student yield is about 7 g. See Chapter 36 for the nitration of methyl benzoate. 

With C, things have become more transparent, as the amino group may derive from reduction of the nitro group in D, the product of nitration of methyl benzoate, E, our ultimate starting material. 

The preparation of a number of miscellaneous acids is described. m-Nitrobenzoic acid. Although m-nitrobenzoic acid is the main product of the direct nitration of benzoic acid with potassium nitrate and concentrated sulphuric acid, the complete separation of the small quantity of the attendant para isomer is a laborious process. It is preferable to nitrate methyl benzoate and hydrolyse the resulting methyl w-nitrobenzoate, which is easily obtained in a pure condition ... 

Methyl m-nitrobenzoate. In a 1 htre round-bottomed or bolt-head flask, fitted with a mechanical stirrer, place 102 g. (94 ml.) of pure methyl benzoate (Section IV,176) support a separatory funnel containing a mixture of 62 -5 ml, of concentrated sulphuric acid and 62 -5 ml. of concentrated nitric acid over the mouth of the flask. Cool the flask in an ice bath to 0-10°, and then run in the nitrating mixture, with stirring. 

Into a 2-1. round-bottom flask fitted with a mechanical stirrer, are placed 400 cc. of concentrated sulfuric acid cooled to o°, and 204 g. (1.5 mols.) of pure methyl benzoate (Note 1). The mixture is cooled by means of an ice bath to o-io° and then, with stirring, there is added gradually by means of a dropping funnel a mixture of 125 cc. concentrated nitric acid (sp. gr. 1.42) and 125 cc. concentrated sulfuric acid. During the addition of the nitrating acid, which requires about one hour, the temperature of the reaction mixture should be kept within the range 5-15° (Note 2). 

On diluting the methyl alcoholic filtrate with water, 10-20 cc. of oil separates more of this oil is formed by nitrating at higher temperatures, amounting to 57 cc. at 50° and 100 cc. at 70°. The oil consists not merely of methyl o-nitrobenzoate with some of the meta compound but contains also traces of dinitrobenzoic ester and nitrophenolic compounds. Unchanged methyl benzoate does not appear to be present. 

Nitration of hydroxypropiophenone (7-1) followed by conversion of the phenol to its methyl ether by means of methyl iodide provides the intermediate (7-2) the nitro group is then reduced to the corresponding amine (7-3) by catalytic reduction. The newly introduced amine is then replaced by a nitrile group by successive conversion to the diazonium salt by means of nitrous acid followed by treatment with cuprous cyanide (7-4). Reaction with aluminum chloride removes the methyl ether to afford the ortho acylphenol (7-5). This is converted to the chromone (7-6) as above by reaction with benzoyl chloride and sodium benzoate. The nitrile is next hydrolyzed to the carboxylic acid (7-7) by means of sulfuric acid. The acid is then converted to its acid chloride by means of thionyl chloride and that treated with 2-(A -piperidyl)ethanol (7-8). There is thus obtained flavoxate (7-9) [8], a muscle relaxant whose name reflects its flavone nucleus. 

---