Question

Novocaine, a local anesthetic, is a compound of formula \(\mathrm{C}_{13} \mathrm{H}_{20} \mathrm{O}_{2} \mathrm{~N}_{2}\). It is insoluble in water and dilute \(\mathrm{NaOH}\), but soluble in dilute HC1. Upon treatment with \(\mathrm{NaNO}_{2}\) and \(\mathrm{HCl}\) and then with \(\beta\) -naphthol, a highly colored solid is formed. When Novocaine is boiled with aqueous \(\mathrm{NaOH}\), it slowly dissolves. The alkaline solution is shaken with ether and the layers are separated. Acidification of the aqueous layer causes the precipitation of a white solid A; continued addition of acid causes \(A\) to redissolve. Upon isolation \(A\) is found to have a melting point of \(185-6^{\circ}\) and the formula \(\mathrm{C}_{7} \mathrm{H}_{7} \mathrm{O}_{2} \mathrm{~N}\). Evaporation of the ether layer leaves a liquid \(\mathrm{B}\) of formula \(\mathrm{C}_{6} \mathrm{H}_{15} \mathrm{ON}\). B dissolves in water to give a solution that turns litmus blue. Treatment of \(B\) with acetic anhydride gives C, \(\mathrm{C}_{8} \mathrm{H}_{17} \mathrm{O}_{2} \mathrm{~N}\), which is insoluble in water and dilute base, but soluble in dilute HCl. \(\mathrm{B}\) is found to be identical with the compound formed by the action of diethylamine on ethylene oxide. (a) What is the structure of Novocaine? (b) Outline all steps in a complete synthesis of Novocaine from toluene and readily available aliphatic and inorganic reagents. $$ \begin{array}{|l|l|l|} \hline {\text { CARBOXYLIC ACIDS }} \\ \hline \text { Name } & \text { Formula } & \begin{array}{c} \text { M.p. } \\ { }^{\circ} \mathrm{C} \end{array} \\ \hline \text { o-Nitrobenzoic } & \circ-\mathrm{O}_{2} \mathrm{NC}_{6} \mathrm{H}_{4} \mathrm{COOH} & 147 \\ \hline \text { m-Nitrobenzoic } & \mathrm{m}-\mathrm{O}_{2} \mathrm{NC}_{6} \mathrm{H}_{4} \mathrm{COOH} & 141 \\ \hline \text { p-Nitrobenzoic } & \mathrm{p}-\mathrm{O}_{2} \mathrm{NC}_{6} \mathrm{H}_{4} \mathrm{COOH} & 242 \\ \hline \text { Phthalic } & \mathrm{o}-\mathrm{C}_{6} \mathrm{H}_{4}(\mathrm{COOH})_{2} & 231 \\ \hline \text { Isophthalic } & \mathrm{m}-\mathrm{C}_{6} \mathrm{H}_{4}(\mathrm{COOH})_{2} & 348 \\ \hline \text { Terephthalic } & \mathrm{p}-\mathrm{C}_{6} \mathrm{H}_{4}(\mathrm{COOH})_{2} & 300 \text { sub1. } \\ \hline \text { Salicylic } & \mathrm{o}-\mathrm{HOC}_{6} \mathrm{H}_{4} \mathrm{COOH} & 159 \\ \hline \text { p-Hydroxybenzoic } & \mathrm{p}-\mathrm{HOC}_{6} \mathrm{H}_{4} \mathrm{COOH} & 213 \\ \hline \text { Anthranilic } & \mathrm{o}-\mathrm{H}_{2} \mathrm{NC}_{6} \mathrm{H}_{4} \mathrm{COOH} & 146 \\ \hline \text { m-Aminobenzoic } & \mathrm{m}-\mathrm{H}_{2} \mathrm{NC}_{6} \mathrm{H}_{4} \mathrm{COOH} & 179 \\ \hline \text { p-Aminobenzoic } & \mathrm{p}-\mathrm{H}_{2} \mathrm{NC}_{6} \mathrm{H}_{4} \mathrm{COOH} & 187 \\ \hline \text { o-Methoxybenzoic } & \mathrm{o}-\mathrm{CH}_{3} \mathrm{OC}_{6} \mathrm{H}_{4} \mathrm{COOH} & 101 \\ \hline \text { m-Methoxybenzoic } & \mathrm{m}-\mathrm{CH}_{3} \mathrm{OC}_{6} \mathrm{H}_{4} \mathrm{COOH} & 110 \\ \hline \text { p-Methoxybenzoic(Anisic) } & \mathrm{p}-\mathrm{CH}_{3} \mathrm{OC}_{6} \mathrm{H}_{4} \mathrm{COOH} & 184 \\ \hline \end{array} $$

Short answer

The structure of Novocaine is $$ \mathrm{O}=\mathrm{C}(\mathrm{O}[\mathrm{CH}_{2}\mathrm{CH}_{2}\mathrm{N}(\mathrm{CH}_{2}\mathrm{CH}_{3})_{2}])\mathrm{C}_{6}\mathrm{H}_{4}\mathrm{NH}_{2}$$ and can be synthesized from toluene in the following steps: (1) Nitration of toluene to form para-nitrotoluene (2) Reduction of para-nitrotoluene to form para-aminotoluene (3) Carboxylation of para-aminotoluene to form para-aminobenzoic acid (PABA) (4) Reaction of ethylene oxide with diethylamine to get diethylethanolamine (5) Esterification of PABA with diethylethanolamine to obtain Novocaine.

Step-by-step solution

Analyze the reactions of Novocaine

The problem states several reactions: 1. Novocaine is insoluble in water and dilute NaOH but soluble in dilute HCl. 2. Novocaine + NaNO2 + HCl leads to formation of a highly colored solid with β-naphthol. 3. Novocaine + hot NaOH causes Novocaine to dissolve. 4. Aqueous and ether layers are separated, and Aqueous layer + HCl gives A (white solid, \(\mathrm{C}_{7} \mathrm{H}_{7} \mathrm{O}_{2} \mathrm{~N}\), mp \(185-6^{\circ}\)). 5. Ether layer evaporation leaves B (liquid, \(\mathrm{C}_{6} \mathrm{H}_{15} \mathrm{ON}\)), which turns litmus blue when dissolved in water. 6. B + Ac2O gives C (\(\mathrm{C}_{8} \mathrm{H}_{17} \mathrm{O}_{2} \mathrm{~N}\)). 7. B = compound formed by diethylamine with ethylene oxide. We can use these reactions to help identify the structure of Novocaine.

Identify A and B structures based on the reactions

Given that B forms from diethylamine and ethylene oxide, we can deduce its structure to be Diethylethanolamine \((\mathrm{C}_{6} \mathrm{H}_{15} \mathrm{ON})\). From the reactions, we can deduce that Novocaine contains a carboxylic acid group since it is soluble in aqueous HCl and forms solid A en precipitating on acidification. A is a carboxylic acid with the carboxylic group attached to \(\mathrm{C}_{7} \mathrm{H}_{7} \mathrm{O}_{2} \mathrm{~N}\). The melting point mentioned suggests A is para-aminobenzoic acid since it has a melting point of \(187^{\circ}\) from the given table.

Deduce Novocaine's structure

Now, we have structures of A and B, and we have that Novocaine has the molecular formula \(\mathrm{C}_{13} \mathrm{H}_{20} \mathrm{O}_{2} \mathrm{~N}_{2}\). When adding the formulas of A and B (\(\mathrm{C}_{7} \mathrm{H}_{7} \mathrm{O}_{2} \mathrm{~N}\) and \(\mathrm{C}_{6} \mathrm{H}_{15} \mathrm{ON}\), respectively), we get the exact same molecular formula as Novocaine. Also, Novocaine reacts with NaNO2 and HCl to give A and B. Therefore, we can conclude that Novocaine is an ester formed by A and B. So, the structure of Novocaine is para-aminobenzoic acid (A) esterified with Diethylethanolamine (B).

(a) Novocaine's Structure

Using the information from the above steps, we can conclude that Novocaine has the structure: $$ \mathrm{O}=\mathrm{C}(\mathrm{O}[\mathrm{CH}_{2}\mathrm{CH}_{2}\mathrm{N}(\mathrm{CH}_{2}\mathrm{CH}_{3})_{2}])\mathrm{C}_{6}\mathrm{H}_{4}\mathrm{NH}_{2}$$

(b) Develop the synthesis of Novocaine from toluene

To synthesize Novocaine from toluene, we can follow these steps: 1. Nitration of toluene: Toluene + HNO3 + H2SO4 -> para-nitrotoluene (p-NT) 2. Reduction of p-NT: para-nitrotoluene + H2 + Pd/C -> para-aminotoluene (p-AT) 3. Carboxylation of p-AT: para-aminotoluene + CO2 + NaOH -> para-aminobenzoic acid (PABA) + NaCl 4. Reaction of Ethylene oxide with diethylamine to get Diethylethanolamine: Ethylene oxide + diethylamine -> Diethylethanolamine 5. Esterification of PABA with Diethylethanolamine to get Novocaine: para-aminobenzoic acid + Diethylethanolamine -> Novocaine This synthesis involves converting toluene to para-aminobenzoic acid, then reacting with diethylamine to form diethylethanolamine, and finally, esterifying para-aminobenzoic acid with diethylethanolamine to get Novocaine.

Key concepts

Organic Chemistry

Organic chemistry plays a crucial role in understanding the structure and synthesis of complex molecules like Novocaine. Novocaine, as an organic compound, boasts a precise arrangement of carbon atoms accompanied by hydrogen, oxygen, and nitrogen. This aligns with the core principles of organic chemistry, which study the myriad ways in which these elements combine, interact, and react.

Central to this discipline are the concepts of functional groups, which are specific groupings of atoms within molecules that have characteristic reactivity patterns. In the synthesis of Novocaine from toluene, we observe various key transformations - nitration, reduction, carboxylation, and esterification - which are staple processes in organic synthesis. These processes alter the electron configuration and reactivity, effectively sculpting the desired compound's architecture step-by-step.

Local Anesthetic Chemistry

The chemistry of local anesthetics such as Novocaine centers on their ability to block nerve impulses, which is pivotal for their numbing effect. This function relies on the compound's structure, particularly the presence and arrangement of an aromatic ring, an ester linkage, and an amine group.

Local anesthetics are traditionally categorized as esters or amides based on their linkage. Novocaine falls into the ester group, where the ester linkage is a focal point for metabolic breakdown, leading to lesser duration of action compared to amide anesthetics. In the proposed synthesis, understanding these structural necessities guides the choice of reactions to create the local anesthetic's defining features, demonstrating the deep relationship between a molecule's structure and its medicinal properties.

Carboxylic Acids and Esters

Carboxylic acids and esters are fundamental functional groups in organic chemistry and contribute significantly to Novocaine's structure. The solubility properties and the white solid formed upon treatment with HCl hint at the presence of a carboxylic acid in Novocaine.

Para-aminobenzoic acid (PABA), identified in the exercises, exemplifies a carboxylic acid, which has an acidic hydrogen atom that reacts with bases and can form esters. Conversion to esters, like in the case of Novocaine’s synthesis, is achieved through esterification. This reaction's vital role is evidenced in creating the ester linkage connecting the aromatic ring to the diethylethanolamine side chain, distinguishing Novocaine's structurally active form.

Amine Reactions

Amines are a class of organic compounds characterized by the presence of a nitrogen atom with a lone pair, making them nucleophilic and basic. Within the context of Novocaine, the amine group becomes integral when reacting with ethylene oxide to generate diethylethanolamine – a process demonstrating the typical reaction of amines with epoxides.

This reaction increases the chain length and introduces an alcohol functional group, contributing to the final structure's complexity. Amines also display basicity by turning litmus blue, an observation confirming the structure of compound B. Such reactions are essential in the step-by-step assembly and confirmation of Novocaine's structure and illustrate the amine's multi-faceted role in synthesis and characterization of organic compounds.