Research on the Synthesis of p-Nitrobenzoic Acid

Chemical Properties：

Beige to yellow crystalline powder
4-Nitrophenylacetic acid is a member of the class of phenylacetic acids that is phenylacetic acid in which the phenyl grup is substituted at the para- position by a nitro group.

Uses: 

(4-Nitrophenyl)acetic Acid used in the synthesis of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones which may act as angiogenesis inhibitors. Also used in the one step construction of amino-substituted squaraine dye.

Definition: 

ChEBI: A monocarboxylic acid that is phenylacetic acid carrying a nitro substituent at position 4.

Safety Profile:

Moderately toxic intraperitoneal route. Mutation data reported. When heated to decomposition it emits toxic vapors of NOx.

Overview:

Ortho-nitrobenzoic acid is a highly demanded chemical raw material. It can be used in medicine and other organic synthesis processes, such as the synthesis of biphenylacetic acid and the highly effective antihypertensive drug amiloride. Moreover, further reactions of ortho-nitrobenzoic acid can produce para-aminobenzoic acid and para-hydroxybenzoic acid. These two products are both intermediates for medicine and pesticides, and have a large market demand.

Synthesis Research：
Currently, the main method for synthesizing p-nitrobenzene acetic acid in industry is the hydrolysis of p-nitrobenzene acetonitrile. Benzyl chloride cyanide is decomposed to obtain benzene acetonitrile, and benzene acetonitrile is then oxidized and hydrolyzed to obtain p-nitrobenzene acetic acid. The synthesis route is as follows:

In this synthesis method, highly toxic cyanide needs to be used. Additionally, benzyl acetonitrile is also highly toxic, and the reaction yield is not high. In developed countries, this process has basically been phased out. However, in China, this method is still the main method for producing benzene acetic acid series products. With the requirements of industrial upgrading and environmental protection, it is urgent to optimize the existing process.
The relevant research began with the readily available raw material 2-phenylethanol and used two routes – first nitration followed by oxidation, and first oxidation followed by nitration – to prepare p-nitrophenylacetic acid.
According to the literature, the route for preparing p-nitrophenylethanol using 2-phenylethanol has relatively high yield and purity. Therefore, an experiment was conducted to synthesize the target product by protecting the hydroxyl group of 2-phenylethanol first and then performing nitration and oxidation.

The hydroxyl group of 2-phenylethanol was protected and then nitroated. This process increased the proportion of ortho-products and reduced the occurrence of side reactions. In the step of oxidizing the alcohol to carboxylic acid, the current oxidants mostly use some measured inorganic oxidants, which is unfavorable for the environment. According to the literature, we adopted the NaClO2-NaClO-TEMPO system, achieving better yields and effects.
If the hydroxyl group is first oxidized to a carboxyl group, and then subjected to the nitration reaction, theoretically no protection is required and the product is mainly in the ortho and para positions. Therefore, the experiment also investigated the route of preparing p-nitrobenzyl acid by oxidizing 2-benzyl alcohol first and then nitrating it.

Conclusion:
2-Phenylethanol is a commonly used food flavoring agent. It has a wide range of sources and a low price. Using phenylethanol as the raw material, it can be synthesized into p-nitrophenylacetic acid through two routes. Regardless of which route is chosen, a good yield can be achieved. The route of first nitration and then oxidation can be adopted. Although the process is longer, the proportion of the ortho-product exceeds 90%, and p-nitrophenylethanol acid can be obtained with a relatively high yield. During the oxidation process of p-nitrophenylethanol, a high yield can be achieved using the TEMPO-NaClO2-NaClO system. However, due to the electron-withdrawing effect of the nitro group in nitrophenylethanol, the oxidation of nitrophenylethanol using the TEMPO-O2-Fe3(NO3)3 system has a low yield.
By adopting the route of oxidation followed by nitrification, the reaction steps are fewer, and using oxygen as the oxidant is both economical and environmentally friendly. However, the proportion of ortho-products in the products is relatively high. The separation and purification process is complex. Nevertheless, this route can produce intermediate products, and the conditions are mild, with high yields and low costs.

Contact Manager: Emma Song   Email Address: emma@coreychem.com