Question

Radiopaque imaging agents are substances administered either orally or intravenously that absorb X-rays more strongly than body material. One of the best known of these is barium sulfate, the key ingredient in the so-called barium cocktail for imaging of the gastrointestinal tract. Among other X-ray contrast media are the socalled triiodoaromatics. You can get some idea of the imaging for which they are used from the following selection of trade names: Angiografin, Gastrografin, Cardiografin, Cholegrafin, Renografin, and Urografin. Following is a synthesis for diatrizoic acid from benzoic acid.

Short answer

Question: Outline the synthesis of diatrizoic acid from benzoic acid. Answer: The synthesis of diatrizoic acid from benzoic acid involves the following steps: 1. Nitration of benzoic acid to form 3-nitrobenzoic acid 2. Reductive amination of 3-nitrobenzoic acid to form 3-aminobenzoic acid 3. Diazotization of 3-aminobenzoic acid to generate a diazonium group 4. Sandmeyer reaction to replace the diazonium group with an iodine atom, yielding iodo-benzoic acid 5. Converting benzoic acid to diatrizoic acid by forming a cyclic structure and oxidizing it to convert the carboxyl group to a diatrizoate ion; then converting the sodium salt into diatrizoic acid using a strong acid like HCl.

Step-by-step solution

Nitration of Benzoic Acid

In this step, nitric acid (HNO3) reacts with benzoic acid (C6H5COOH) to form 3-nitrobenzoic acid (C6H4(NO2)COOH). The nitration is the introduction of a nitro group (-NO2) into the benzene ring, which substitutes a hydrogen atom: C6H5COOH + HNO3 → C6H4(NO2)COOH + H2O

Reductive amination

In this step, zinc dust and hydrochloric acid are used to selectively reduce the nitro group to an amine group, yielding 3-aminobenzoic acid (C6H4(NH2)COOH): C6H4(NO2)COOH + 3Zn + 6HCl → C6H4(NH2)COOH + 3ZnCl2 + 2H2O

Diazotization

This step involves converting the amino group of 3-aminobenzoic acid into its corresponding diazonium group (N2+) by adding sodium nitrite (NaNO2) in the presence of hydrochloric acid (HCl): C6H4(NH2)COOH + HONO → C6H4(N2+)COOH + H2O

Sandmeyer reaction

In this step, we perform the Sandmeyer reaction to replace the diazonium group with an iodine atom by using potassium iodide (KI): C6H4(N2+)COOH + 3KI → C6H4I3COOH + 3K+

Converting Benzoic Acid to Diatrizoic Acid

Finally, to convert benzoic acid to diatrizoic acid, we need to transform the carboxyl group (COOH) into the corresponding diatrizoate ion (COO-). This can be done by adding hydroxylamine (NH2OH) to form a cyclic structure and then oxidizing it with certain oxidizing agents such as sodium hypochlorite (NaOCl): C6H4I3COOH + NH2OH → C6H4I3CONHOH C6H4I3CONHOH + NaOCl → C6H4I3COONa + H2O So, we now have the sodium salt of diatrizoic acid, which can be converted to diatrizoic acid by using a strong acid like HCl: C6H4I3COONa + HCl → C6H4I3COOH + NaCl With these steps, we have synthesized diatrizoic acid from benzoic acid.

Key concepts

Radiopaque Imaging Agents

Radiopaque imaging agents are crucial for medical diagnostics, particularly in radiology. They are chemicals introduced into the body to provide a clear contrast in X-ray images. Barium sulfate is a popular agent used for gastrointestinal imaging, but there is a diverse class of substances called triiodoaromatics—among them is diatrizoic acid—that enhance imaging of various organs. These agents have the unique ability to absorb X-rays significantly more than the surrounding body tissues, making it possible to visualize the internal structure of the body and diagnose conditions.

Diatrizoic acid, classified as a triiodoaromatic compound due to its three iodine atoms, is prominent in this category. Its high atomic number provides the density needed to stand out on X-ray films. Triiodoaromatics like diatrizoic acid allow for clearer imaging of blood vessels, the gastrointestinal tract, and other systems, all of which is essential for accurate diagnosis and treatment planning in healthcare.

Nitration Reaction

The nitration reaction marks the first step in the synthesis of diatrizoic acid. It's a fundamental process in organic chemistry that involves substituting a hydrogen atom on an aromatic ring with a nitro group. The typical nitrating agents are nitric acid and sulfuric acid.

This electrophilic aromatic substitution reaction increases the reactivity of benzoic acid's benzene ring, setting the stage for further modifications. Careful control of the reaction conditions determines the position of the nitro group on the ring and prevents the formation of undesired byproducts. Through this strategic introduction of the nitro group, which is later reduced to an amine in subsequent steps, chemists can begin transforming simple benzoic acid into sophisticated imaging agents like diatrizoic acid.

Reductive Amination

Following the nitration reaction, reductive amination takes center stage. This process converts a nitro group to an amine group, a pivotal transformation in synthesizing many bioactive compounds, including pharmaceuticals.

In the context of diatrizoic acid synthesis, reductive amination involves the use of zinc dust and hydrochloric acid to selectively reduce the nitro group of 3-nitrobenzoic acid to an amine group. The amine group is essential for the subsequent transformation of the compound, particularly allowing the diazotization process to occur. This multi-step chemical pathway showcases the complexity of synthesizing contrast media, where precision and accuracy are indispensable.

Sandmeyer Reaction

The Sandmeyer reaction is an essential synthetic tool in the chemist's repertoire, employed to introduce a variety of functional groups into aromatic compounds. In the synthesis of diatrizoic acid, it specifically allows the incorporation of iodine atoms into the compound via a diazonium intermediate.

In this classic reaction, diazonium salts react with copper salts or, as in this case, potassium iodide to substitute the diazonium group with another group like an iodine atom. Here, the result is a triiodinated compound, elevating the ability of the synthesized compound to absorb X-rays. This underlines the remarkable level of control chemists have over the complex molecules they create, which in this synthesis, results in an agent that is vital for medical imaging and diagnostics.