Question

Propose a synthesis for diphenhydramine starting from benzophenone, benzoic acid, and \(2-(N, N\)-dimethylamino) ethanol. The hydrochloride salt of diphenhydramine, best known by its trade name of Benadryl, is an antihistamine.

Short answer

Question: Propose a synthesis of diphenhydramine from benzophenone, benzoic acid, and 2-(N,N-dimethylamino)ethanol. Answer: The synthesis of diphenhydramine involves three main steps. First, react benzophenone with benzoic acid in the presence of a dehydrating agent, such as thionyl chloride, to form benzophenone imine. Second, react benzophenone imine with 2-(N,N-dimethylamino)ethanol, forming the aminoalkyl ether linkage and yielding diphenhydramine. Finally, an optional step is to react the diphenhydramine with hydrochloric acid to obtain diphenhydramine hydrochloride, commonly known as Benadryl.

Step-by-step solution

React benzophenone with benzoic acid

First, we need to create a linkage between benzophenone and benzoic acid. The benzophenone doesn't have any active site for this reaction, so we first need to prepare benzophenone imine by reacting benzophenone with benzoic acid in the presence of a dehydrating agent (like thionyl chloride, SOCl2). The benzophenone imine will be formed by the elimination of water. Benzophenone: \(\ce{C6H5C(=O)C6H5}\) Benzoic acid: \(\ce{C6H5COOH}\) Intermediate product (Benzophenone imine): \(\ce{C6H5C(=NH)C6H5}\)

React benzophenone imine with 2-(N,N-dimethylamino)ethanol

In this step, we will react benzophenone imine with 2-(N,N-dimethylamino)ethanol. The lone pair of electrons on the nitrogen atom of 2-(N,N-dimethylamino)ethanol can attack the imine carbon of benzophenone imine, forming the aminoalkyl ether linkage. 2-(N,N-dimethylamino)ethanol: \(\ce{H3C-N(CH3)-CH2CH2OH}\) The reaction will be: \(\ce{C6H5C(=NH)C6H5 + H3C-N(CH3)-CH2CH2OH -> C6H5C(NH-CH2CH2-N(CH3)2)C6H5}\) The obtained product is diphenhydramine.

Formation of the hydrochloride salt (optional)

If we want to obtain diphenhydramine hydrochloride, we can react the diphenhydramine with hydrochloric acid (HCl): \(\ce{C6H5C(NH-CH2CH2-N(CH3)2)C6H5 + HCl -> C6H5C(NH-CH2CH2-N(CH3)2)C6H5.HCl}\) So, the final product obtained is diphenhydramine hydrochloride, which is commonly known as Benadryl.

Key concepts

Organic Synthesis

Organic synthesis is like a complex dance of atoms and molecules coming together to produce a new, useful compound. It involves the step-by-step construction of complex chemical compounds from simpler ones. In the educational domain, it's akin to putting together a puzzle where each piece represents a different reaction or process. It is in this manner that we prepare pharmaceuticals like diphenhydramine, a well-known antihistamine.

Benzophenone

Benzophenone acts as a keystone in our synthesis puzzle. This compound is akin to a building block in a Lego set, waiting to be transformed into something greater. It's a common starting material in organic synthesis because of its stability and the reactivity of the carbonyl group. Benzophenone itself doesn't directly engage with other compounds; we need to activate it, like waking it up from a deep slumber, by converting it into an imine to make it react with benzoic acid.

Benzoic Acid

Benzoic acid is like the second parent molecule in the synthesis of diphenhydramine. In the kitchen of organic chemistry, it's like a spice that's added to a dish to bring out a new flavor. When we combine benzoic acid with benzophenone imine, it's like creating a new recipe that will eventually lead us to our desired medicinal compound.

2-(N,N-dimethylamino)ethanol

Imagine 2-(N,N-dimethylamino)ethanol as a connector piece in our molecular construction set. This molecule has a nitrogen atom with a lone pair of electrons that is just waiting to latch onto the benzophenone imine. It's this small but mighty molecule that will introduce the necessary amine functionality into our growing organic structure. The reaction where it attaches to the benzophenone imine is key to completing our synthesis puzzle.

Schotten-Baumann Reaction

The Schotten-Baumann reaction is an essential tool in an organic chemist's arsenal. It's a technique used to transform our sleepy benzophenone into a more reactive imine, which is necessary for the next step of our synthesis. Guised in the simple formality of mixing and heating, this reaction is the gateway to creating the connections needed for larger, more complex structures like diphenhydramine.

Amine Alkylation

Amine alkylation is a process like greeting a friend with a hearty handshake. The lone pair of electrons on the nitrogen atom of 2-(N,N-dimethylamino)ethanol reaches out to the benzophenone imine’s carbon, forming a firm bond. This step is vital as it extends the molecule to include the necessary amine group, a fundamental feature of the diphenhydramine structure.

Hydrochloride Salt Formation

The formation of the hydrochloride salt is the final flourish, the bow on a present. It involves introducing hydrochloric acid to our synthesized diphenhydramine, transforming it into a salt form—diphenhydramine hydrochloride. This not only helps in stabilizing the compound but also enhances its water solubility, making it an effective medication for use as an antihistamine.