IChO 1973 · Theory problem 5

Shortest syntheses of ethyl benzoate and aminobenzoic acids

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Using your knowledge about the properties of benzene and its derivatives, write chemical equations for reactions by which ethyl ester of benzoic acid as well as o-, m-, and p-amino benzoic acids are prepared in the shortest way.

Official English text of the problem.

Answers

Taking benzene as the common starting material, the conventional short routes are:

  • Ethyl benzoate, CCOC(=O)c1ccccc1: benzene → toluene → benzoic acid → ethyl benzoate. Three reactions.
  • o-Aminobenzoic acid (2-aminobenzoic acid, anthranilic acid), Nc1ccccc1C(=O)O: benzene → toluene → 2-nitrotoluene → 2-nitrobenzoic acid → 2-aminobenzoic acid. Four reactions.
  • m-Aminobenzoic acid (3-aminobenzoic acid), Nc1cccc(C(=O)O)c1: benzene → toluene → benzoic acid → 3-nitrobenzoic acid → 3-aminobenzoic acid. Four reactions.
  • p-Aminobenzoic acid (4-aminobenzoic acid), Nc1ccc(C(=O)O)cc1: benzene → toluene → 4-nitrotoluene → 4-nitrobenzoic acid → 4-aminobenzoic acid. Four reactions.

Physical separation of isomers is not counted as a chemical reaction.

Solution

The essential choice is when to nitrate. A methyl group directs electrophilic substitution mainly to the ortho and para positions, whereas a carboxyl group directs it mainly to the meta position. In each aminobenzoic-acid synthesis, reduce the nitro group after oxidizing the methyl group, so that the amino group is not exposed to the strong oxidant.

The oxidation equations below are balanced net ionic equations for hot, acidified dichromate.

Ethyl ester of benzoic acid

First prepare toluene, Cc1ccccc1, by Friedel–Crafts methylation of benzene, c1ccccc1, with chloromethane, CCl, using anhydrous aluminium chloride:

\[ \ce{C6H6 + CH3Cl ->[AlCl3] C6H5CH3 + HCl} \]

Use excess benzene to limit further methylation.

Oxidize the methyl side chain to obtain benzoic acid, O=C(O)c1ccccc1:

\[ \ce{C6H5CH3 + Cr2O7^2- + 8H+ ->[heat] C6H5COOH + 2Cr^3+ + 5H2O} \]

Finally, esterify with ethanol, CCO, by heating with catalytic sulfuric acid:

\[ \ce{C6H5COOH + C2H5OH <=> C6H5COOC2H5 + H2O} \]

Excess ethanol or removal of water shifts the equilibrium toward ethyl benzoate.

o-Aminobenzoic acid

Prepare toluene by the methylation above, then nitrate it with concentrated nitric acid and sulfuric acid. Nitration gives mainly the ortho and para isomers, together with a small amount of the meta isomer. Separate the required ortho isomer, 2-nitrotoluene, Cc1ccccc1[N+](=O)[O-].

The equation for formation of the ortho product is:

\[ \ce{C6H5CH3 + HNO3 ->[H2SO4] o-NO2C6H4CH3 + H2O} \]

Oxidize its methyl group to give 2-nitrobenzoic acid, O=C(O)c1ccccc1[N+](=O)[O-]:

\[ \ce{o-NO2C6H4CH3 + Cr2O7^2- + 8H+ ->[heat] o-NO2C6H4COOH + 2Cr^3+ + 5H2O} \]

Then selectively hydrogenate the nitro group, for example using hydrogen over palladium on carbon:

\[ \ce{o-NO2C6H4COOH + 3H2 ->[Pd/C] o-NH2C6H4COOH + 2H2O} \]

The substituents retain their positions throughout oxidation and reduction, giving 2-aminobenzoic acid.

m-Aminobenzoic acid

Prepare benzoic acid by the first two reactions of the ethyl-benzoate route. Nitrate it with concentrated nitric acid and sulfuric acid, using heat because the carboxyl group deactivates the ring:

\[ \ce{C6H5COOH + HNO3 ->[H2SO4] m-NO2C6H4COOH + H2O} \]

The carboxyl group is meta-directing, so the principal product is 3-nitrobenzoic acid, O=C(O)c1cccc([N+](=O)[O-])c1. Isolate this product and reduce its nitro group:

\[ \ce{m-NO2C6H4COOH + 3H2 ->[Pd/C] m-NH2C6H4COOH + 2H2O} \]

This gives 3-aminobenzoic acid.

p-Aminobenzoic acid

Prepare toluene and nitrate it as above, isolating the para fraction, 4-nitrotoluene, Cc1ccc([N+](=O)[O-])cc1:

\[ \ce{C6H5CH3 + HNO3 ->[H2SO4] p-NO2C6H4CH3 + H2O} \]

Oxidize the methyl group to obtain 4-nitrobenzoic acid, O=C(O)c1ccc([N+](=O)[O-])cc1:

\[ \ce{p-NO2C6H4CH3 + Cr2O7^2- + 8H+ ->[heat] p-NO2C6H4COOH + 2Cr^3+ + 5H2O} \]

Finally, reduce the nitro group:

\[ \ce{p-NO2C6H4COOH + 3H2 ->[Pd/C] p-NH2C6H4COOH + 2H2O} \]

This gives 4-aminobenzoic acid without introducing an amino-protecting group.

For completeness, the additional molecular and ionic species used in these equations have the following SMILES:

Species SMILES
Hydrogen chloride, \(\ce{HCl}\) Cl
Nitric acid, \(\ce{HNO3}\) O=[N+]([O-])O
Sulfuric acid, \(\ce{H2SO4}\) OS(=O)(=O)O
Water, \(\ce{H2O}\) O
Hydrogen, \(\ce{H2}\) [H][H]
Hydrogen ion, \(\ce{H+}\) [H+]
Dichromate ion, \(\ce{Cr2O7^2-}\) [O-][Cr](=O)(=O)O[Cr](=O)(=O)[O-]
Chromium(III) ion, \(\ce{Cr^3+}\) [Cr+3]
Aluminium chloride, \(\ce{AlCl3}\), monomeric representation Cl[Al](Cl)Cl

These representations omit aqueous solvation; the aluminium chloride representation also omits its possible dimerization.

The solution was checked against the official solution.