Function of Acetic Acid in Aspirin

[nymbler_064]

I was just wondering if anyone would be able to tell me why acetic acid is reacted with salicylic acid to form aspirin. I am aware that the latter is toxic and that the addition of acetic acid lessens its effects, but what specific properties does acetic acid have that enable it to do so. I have tried to research this, but have found no relevant information.

Many thanks.

 

[Borek]

You couldn't find any information, because the question is flawed and has no answer. What you get is a completely different compound, which doesn't inherit any of the acetic acid characteristic.

 

[nymbler_064]

I'm so sorry - I'm only just starting to learn about organic chemistry. Many thanks for your reply.

 

[chemisttree]

The acidic OH on the phenyl group of salicylic acid tears up your gut. Reacting away that acidic proton by converting it to an ester (acetate ester) makes the compound more tolerable as acetylsalicylic acid.

Salicylic acid, isolated as a tea or decoction from the bark of the willow tree, was used once to treat fever. [http://en.wikipedia.org/wiki/Salicylic_acid] It's interesting that removing that acidic proton and replacing it with bismuth produces the acitive ingredient in Pepto Bismol... an-over-the-counter medication for stomach and digestive ailments!

 

[Ygggdrasil]

The acidic OH on the phenyl group of salicylic acid tears up your gut. Reacting away that acidic proton by converting it to an ester (acetate ester) makes the compound more tolerable as acetylsalicylic acid.

Wait, that doesn't make sense. Wouldn't the carboxylic acid group of salicylic acid be more of a concern than the phenol as the carboxylic acid has a lower pKa?

Rather, acetylsalicylic acid and other non-steroidal anti-inflamatory drugs act by inhibiting the cyclooxygenase (COX) enzymes. The COX enzymes are involved in the synthesis of protaglandins, molecules that mediate a variety of cellular responses like inflamation. Aspirin, in particular, binds to the COX enzymes and transfer its acetyl group from the drug to a serine in the active site of COX, irreversibly inhibiting the enzyme.

http://www.chups.jussieu.fr/polys/certifopt/saule_coxib/theme/1vane2003.pdf

 

[alxm]

Wait, that doesn't make sense. Wouldn't the carboxylic acid group of salicylic acid be more of a concern than the phenol as the carboxylic acid has a lower pKa?

It's true that Aspirin is less damaging to your gut than straight salicylic acid, and it's acid-related but as you point out, not that simple. IIRC, it has something to do with different acid solubilities and different rates of penetration into the intestinal membranes, which is what causes the problems.

 

[chemisttree]

Wait, that doesn't make sense. Wouldn't the carboxylic acid group of salicylic acid be more of a concern than the phenol as the carboxylic acid has a lower pKa?

It makes perfect sense. The ortho effect for substituted benzoic acids is well known, especially for the ortho hydroxy group. That acidic proton at the ortho position makes the carboxylic acid about 15 times stronger. pKa of salicylic acid is 2.97 and that of benzoic acid is about 4.2.

Rather, acetylsalicylic acid and other non-steroidal anti-inflamatory drugs act by inhibiting the cyclooxygenase (COX) enzymes. The COX enzymes are involved in the synthesis of protaglandins, molecules that mediate a variety of cellular responses like inflamation. Aspirin, in particular, binds to the COX enzymes and transfer its acetyl group from the drug to a serine in the active site of COX, irreversibly inhibiting the enzyme.

http://www.chups.jussieu.fr/polys/certifopt/saule_coxib/theme/1vane2003.pdf

The question was about the side effect not the mechanism of action. You can read about the history of the development of the acetyl derivitave of salicylic acid http://qfalcon.wordpress.com/2009/02/17/history-and-uses-of-aspirin/"

 

[Ygggdrasil]

Ah, I didn't realize that the phenol group would stabilize the carboxylate and increase its acidity. Thanks for pointing that out.

Since aspirin is probably a much better COX inhibitor than salicylic acid, it may also be the case that lower doses of aspirin are needed to achieve the same effect compared to salicylic acid. Thus, the combination of the decreased acidity as well as the lower doses required could contribute to why aspirin is more tolerable to the gut.

 

[DrDu]

As alxm already pointed out, I also don't think that it is primary a problem of the acidity of salicylic acid. The hydrochloric acid in the stomach is certainly much more acidic than salicylic acid can ever be.

 

[chemisttree]

Ah, I didn't realize that the phenol group would stabilize the carboxylate and increase its acidity. Thanks for pointing that out.

Since aspirin is probably a much better COX inhibitor than salicylic acid, it may also be the case that lower doses of aspirin are needed to achieve the same effect compared to salicylic acid. Thus, the combination of the decreased acidity as well as the lower doses required could contribute to why aspirin is more tolerable to the gut.

Absolutely. Imagine consuming several tens of mL of something at a pH of 2.4 or even less. It is like drinking a few mouthfuls of phosphoric acid. Hoo boy!

Replace that with a pinch of powder no more acidic than orange juice and more effective to boot!