Question

Show how the tranquilizer valnoctamide can be synthesized using diethyl malonate as the source of the carboxamide group.

Short answer

Answer: The synthesis of valnoctamide from diethyl malonate involves the following steps: 1. Draw the structures of diethyl malonate and valnoctamide. 2. Introduce an amine functional group to diethyl malonate by reacting it with n-octylamine (nucleophilic acyl substitution). 3. Hydrolyze the remaining ester group to a carboxylic acid using aqueous acid, such as HCl. 4. Convert one carboxylic acid group to an amide using the Gabriel synthesis by first reacting with thionyl chloride (SOCl2) and then with ethylenediamine. 5. Hydrolyze one of the amide groups to convert it into a carboxylic acid using aqueous acid, such as H2SO4. 6. Remove one of the carboxylic acid groups by decarboxylation (heating under low-pressure) to form valnoctamide.

Step-by-step solution

Draw the structures of diethyl malonate and valnoctamide

First, visualize the structures of both diethyl malonate and the product valnoctamide. Diethyl malonate is a diester with the structure: O=C(CH_2COOEt)_2 Valnoctamide has the structure: CH_3(CH_2)_6CONHCH_2CH_2CH_3

Introduce amine functional group to diethyl malonate

Now, we need to introduce an amine functional group to diethyl malonate. Do this by performing nucleophilic acyl substitution with an eight-carbon amine, n-octylamine. The amine will attack one of the carbonyl groups, making it a leaving group and forming an amide bond: O=C(CH_2COOEt)_2 + HN(CH_2)_7CH_3 → O=C(NH(CH_2)_7CH_3)(CH_2COOEt)_2

Hydrolyze the remaining ester group

Next, hydrolyze the remaining ester group to a carboxylic acid. Use aqueous acid to accelerate the process. Typically, this involves heating the ester with an aqueous solution of a strong acid, such as hydrochloric acid (HCl): O=C(NH(CH_2)_7CH_3)(CH_2COOEt)_2 + 2H_2O + 2HCl → O=C(NH(CH_2)_7CH_3)(CH_2COOH)_2 + 2EtOH + 2Cl^-

Convert one carboxylic acid group to amide

Now we need to convert one of the two carboxylic acid groups on the molecule into an amide. To do this, we will use the Gabriel synthesis. First, react the compound with thionyl chloride (SOCl_2) to generate an acyl chloride: O=C(NH(CH_2)_7CH_3)(CH_2COOH)_2 + 2SOCl_2 → O=C(NH(CH_2)_7CH_3)(CH_2COCl)_2 + 2SO_2 + 2HCl Now, react the acyl chloride with ethylenediamine to introduce the required amine functionality: O=C(NH(CH_2)_7CH_3)(CH_2COCl)_2 + 2HNCH_2CH_2NH_2 → O=C(NH(CH_2)_7CH_3)(CH_2CONHCH_2CH_2NH_2)_2 + 2HCl

Hydrolysis of one amide group

Now, hydrolyze one of the amide groups to convert it into a carboxylic acid. Again, use aqueous acid for the hydrolysis: O=C(NH(CH_2)_7CH_3)(CH_2CONHCH_2CH_2NH_2)_2 + 2H_2O_2 + 2H_2SO_4 → O=C(NH(CH_2)_7CH_3)(CH_2COOH)_2 + N_2 + 2H_2O

Decarboxylation

Finally, remove one of the carboxylic acid groups by decarboxylation. Heat the compound under low-pressure to remove carbon dioxide (CO_2) and form valnoctamide: O=C(NH(CH_2)_7CH_3)(CH_2COOH)_2 → CH_3(CH_2)_6CONHCH_2CH_2CH_3 + CO_2 The resulting product is valnoctamide, successfully synthesized from diethyl malonate using the mentioned steps.