Question

Sulfanilamide Multi-step Synthesis

Discuss the chemistry behind the chemical reactions and experimental techniques (region/stereoselectivity of the reactions, use of LeChatelier’s principle to maximize yields, why some reactions are moisture sensitive, the importance of protecting groups, etc.

Include each of the reactions using structures and the complete mechanisms. The mechanism must be NEATLY hand drawn by you and will be graded for completeness and accuracy.

Specific details to include:

Formation of the arylsulfonyl chloride from acetanilide by reaction with chlorosulfonic acid (2 parts)

Why was it so important to be sure that the acetanilide created in week 1 had a chance to dry completely before taking it on in week 2?

Discuss why it was so important to control the temperature carefully in the first step (EAS reaction). What was the potential consequence of allowing the reaction mixture to heat up too much during the beginning part of the reaction?

Formation of the sulfonamide from the arylsulfonyl chloride by reaction with ammonium hydroxide.

Describe why ammonia is the best nucleophile present in aqueous ammonium hydroxide.

Hydrolysis of the Amide to give Sulfanilamide

Describe roles of HCl in this reaction?

Why is it necessary to heat this reaction? In other words, how reactive are amides to nucleophilic acyl substitution reactions?

Include a short description about the purpose of the use of amide protecting groups in this two week experiment. Why did you make the acetanilide vs. using the aniline as the starting material for the EAS reaction?   Why not just use the nitrobenzene as the starting material for the EAS reaction, then reduce at a later stage?

General Procedure

You may choose to include a general outline of the techniques you are using including a summarized description of the reaction procedure.   Do NOT include specific procedural details.

i.e. for the synthesis of Triphenylmethanol via a Grignard reagent, the summarized description would be something like: “The synthesis of triphenylmethanol follows a three step sequence. First, a Grignard reagent is synthesized from the reaction of bromobenzene and magnesium in a dry vessel under reflux. Benzophenone was then added to form triphenylmethoxide, which was hydrolyzed to form triphenylmethanol.”

Answer 1

Mechanism you can check from below link

http://www.organicchem.org/oc2web/lab/exp/sulfa/sulfamechanism.html

Chlorosulfonic acid reacts exothermically and violently with water producing sulfuric acid, hydrochloric acid, and large quantities of dense white acid fumes. To avoid this reaction acetanilide should be dry.

In beginning of step, there is release of HCl gas. To control this evolution of HCl gas, reaction is proceed and low temperature.

Sulfonyl chlorides contain a good leaving group (Cl). That is what makes them highly reactive towards water and other nucleophiles such as ammonia (NH3).

In hydrolysis of amide, H+ attach at carbonyl carbon to activate toward nucleophilic substitute. Subsequent water attacks on activated carbon and generate tetrahedron intermediate and followed by release of acetic acid and sulfanilamide.