Seeking Advice on Optimizing Synthesis of p-Nitroaniline

[Arslan1995]

Hello ACS Community,

I hope you are all doing well. I am currently working on the synthesis of p-Nitroaniline via the nitration of aniline, followed by selective reduction, and I have encountered some difficulties that I hope to get advice on.

Background:

• The goal of my project is to synthesize p-Nitroaniline efficiently while minimizing side reactions and impurities.
• I am using a nitration step (aniline to p-nitroaniline) followed by acetylation to protect the amino group and subsequent selective reduction of the nitro group.
• I have been following a standard protocol from [reference paper/standard method], but my yields and selectivity are lower than expected.

Details:

• Reagents: Aniline, nitric acid, sulfuric acid, acetic anhydride, and reducing agents like iron/HCl.
• Conditions: Nitration at 0-5°C to favor para-selectivity, acetylation at room temperature, reduction under controlled acidic conditions.
• Observations: The crude reaction mixture contains significant amounts of byproducts, and my TLC analysis shows multiple spots, suggesting incomplete or unwanted reactions.

Challenges:

1. Selectivity: I am getting a mixture of ortho- and para-nitroaniline, with para being the desired product. The ratio is not as high as expected (~60:40 instead of the ideal ~80:20).
2. Yield: The overall yield is consistently below 55%, whereas literature reports yields around 75-85%.
3. Purity: My NMR and HPLC spectra indicate impurities, possibly unreacted aniline or side products.

Questions:

• Has anyone faced similar challenges in the selective nitration of aniline? Any recommendations for improving para-selectivity?
• Would a different protection strategy for the amino group help improve selectivity?
• Are there alternative reduction methods (besides iron/HCl) that might offer better yields with fewer side reactions?
• Could the low yield be due to incomplete acetylation, and how can I confirm this?

Any insights, protocol modifications, or references to relevant literature would be greatly appreciated! I would love to hear your thoughts and experiences.

Thank you in advance for your help!