[Fireredburn1]

In one of the steps in the synthesis of the drug loperamide, reacting the lactone with hydrogen bromide in acetic acid opens the lactone ring. Is my proposed mechanism correct? Also, why does the bromide nucleophile does not attack the carbonyl carbon but instead on the alkyl carbon? Does this have to do with the concept of hard/soft nucleophiles? Lastly, what is the purpose of acetic acid?



Another step of the synthesis involves adding aqueous dimethylamine to the acyl chloride which results in a cyclisation. Is my proposed mechanism correct? It looks like an unusual reaction, why does O-alkylation happen?



Thank you !

[orthoformate]

Hi Fireredburn1,

In your first mechanism, you don't show the protonated lactone before bringing in the bromide. Where is the proton sitting? Also, your ending structure is a carboxylate. Wouldn't that be a carboxylic acid in this reaction?

The acetic acid works as a solvent, it's a very good solvent for this reaction.

you glossed over some arrow pushing in the second mechanism, but it looks right to me.

Have a great holiday!

[Dan]

Also, why does the bromide nucleophile does not attack the carbonyl carbon but instead on the alkyl carbon?

Both are probably attacked, but consider the steric environment of each site, and also what would happen if the acyl C was attacked - will it lead to a stable product or react further? Think about reversibility.

Another step of the synthesis involves adding aqueous dimethylamine to the acyl chloride which results in a cyclisation. Is my proposed mechanism correct? It looks like an unusual reaction

This is a well established method for oxazoline formation, check wikipedia etc.