Nitration of Salicylic Acid

Why synthesize 5-nitrosalicylic acid?

* Basic intermediate in the synthesis of mesalazine starting from salicylic acid.
* Mesalazine is one of the most important active species used in the pharmaceutical field for the treatment of various pathologies such as ulcerative colitis and Crohn’s disease.
* Irritable bowel disorder (IBD) has long been treated with aminosalicylates such as sulfasalazine and mesalazine.

General mechanism (step 1)

General mechanism (step 2)

Overall reaction mechanism

General procedure overview

* Organic reaction: stirring at low temperatures.
* Separation: filtration.
* Purification: recrystallization.
* Analysis: melting point, IR, and 1H NMR.

Nitration of salicylic acid is an example of:

electrophilic aromatic substitution.

* Makes the arenium ion as an intermediate.

In this experiment…

you will be preparing 5-nitrosalicylic acid by the reaction of salicylic acid with a nitrating mixture of sulfuric and nitric acids.

* Makes the nitronium ion.
* The carboxylic acid substituent is meta directing and the hydroxyl group is ortho-para directing. Both groups direct the nitro to the 5-position. Although the 3-position is also electronically favored, steric hindrance from the –OH group discourages nitration at the 3-position. Nitration will occur primarily at the 5-position as long as a low reaction temperature is maintained.

Procedure

* Make apparatus with salicylic acid.
* Cool it.
* Add nitric acid.
* Begin stirring.
* Add 900 microliters of sulfuric acid dropwise over 15 minutes. Once done, let it stir in the ice-bath for 20 minutes.
* Add ice cold water dropwise.
* Break up the product formed.
* Vacuum filter.
* Recrystallize.
* Dissolve crude product in distilled water and then add ethanol.
* Heat and then cool.
* Vacuum filter.
* Melting point, IR, and 1H NMR.