Gabriel synthesis

[chiddler]

of primary amines

this is TBR

i don't understand how the mechanism for this reaction would work. After the first hydrolysis, why would the amine be removed in favor of a hydroxyl? Amines are much much less acidic.

Bonus question is why does wikipedia list a slightly different reaction? I like this reaction better because it makes a lot more sense, for what it's worth.

thanks!

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[SaintJude]

http://science.uvu.edu/ochem/index.php/alphabetical/g-h/gabriel-synthesis/

So, I take it you are referring to Stage 1 of the Gabriel Synthesis shown in the webpage. Where a hydroxyl group deprotonates the phthalimide?

 

[chiddler]

Step 3 when the OH- attacks the amide and removes the nitrogen compound from the main molecule so it becomes an amine.

How can the OH- do that?

 

[lkthlttr]

Step 3 when the OH- attacks the amide and removes the nitrogen compound from the main molecule so it becomes an amine.

How can the OH- do that?

That is just base catalyzed amide hydrolysis. The carbonyl carbon is a good electrophile and the hydroxide ion is an excellent nucleophile.

 

[chiddler]

That is just base catalyzed amide hydrolysis. The carbonyl carbon is a good electrophile and the hydroxide ion is an excellent nucleophile.

but you don't see this reaction with acetamide + base. this is because the amine is a horrible leaving group compared to hydroxide.

 

[prolixity29]

Trying to understand this now, too. Welcoming other opinions here.

I thought that amides can be hydrolyzed - base-catalyzed hydrolysis is one of the few ways to convert an amide into a COOH that can then be "re-used" to make the more unstable COOH derivatives (the more reactive ones).

Also, the pKb of ammonia is 4.76, the pKb of primary amines is 4, and the pKb of hydroxide is -1.7 So hydroxide is in fact the stronger base and therefore has a stronger affinity for the carbonyl electrophile.

 

[chiddler]

what i didn't realize when i originally posed this question is that acid catalyzed hydrolysis is a good way to break up amides.

Trying to understand this now, too. Welcoming other opinions here.

I thought that amides can be hydrolyzed - base-catalyzed hydrolysis is one of the few ways to convert an amide into a COOH that can then be "re-used" to make the more unstable COOH derivatives (the more reactive ones).

Also, the pKb of ammonia is 4.76, the pKb of primary amines is 4, and the pKb of hydroxide is -1.7 So hydroxide is in fact the stronger base and therefore has a stronger affinity for the carbonyl electrophile.

don't think base catalysis works with amides because the ammonia is just too poor a leaving group. acid catalysis, on the other hand, works well because it grants the N a cationic state making it into a decent enough leaving group for water to replace.

also you are not comparing properly. the reason you should not look at NH3's basicity is because this tells us how badly NH3 wants a proton. what does this say about how strongly it binds the carbonyl carbon? not very much.

a more proper comparison is how acidic is NH3? this asks the question: how easily can -NH2 break its bond with the carbonyl carbon so that hydroxyl can be replaced?

if doesn't make sense i can draw it a little more nicely to illustrate what i mean.

 

[milski]

Amides can go through hydrolysis, either in a strong base or strong acid. It takes heat and time but it can be done. The mechanism is in my textbook, but there is nothing too fancy about it - you make a tetrahedral intermediate, then NH2/NH3 leaves.

There are three ways to "disconnect" the synthesized amine from the cyclic part of the molecule:
- hydrolysis in acid or base - it's really just a hydrolysis of an amide - this is what TPR has.
- the reaction with H2N2H2 (hydrazine?) - that's what wikipedia has, we did not go over the mechanism, just got the products.

 

[chiddler]

amide and base works, you say?

do you know what kind of conditions are required?

 

[milski]

amide and base works, you say?

do you know what kind of conditions are required?

So says the book.

Heat, time and strong base. The book says that amides are fairly stable and I do have a vague recollection of my professor saying something in the lines of "It will take time but if you heat it up and leave it overnight, it will eventually hydrolyze." How strong of a base? NaOH/KOH are good enough.

 

[chiddler]

thanks. sorry for the redundancy, you repeated yourself lol

 

[milski]

thanks. sorry for the redundancy, you repeated yourself lol

No worries. I think I'm not selling any of my textbooks until I'm done with MCAT. Seems that having a good reference can be rather handy when studying.

 

[chiddler]

I realized an error I made. I was thinking of formation of an amide from a carboxylic acid. What i should of been thinking of is the opposite: formation of a carboxylic from an amide.

So to be clear: From a carboxylic acid to an amide, you absolutely must have an acid. Basic conditions no matter how harsh will not help.

The reverse can swing both ways, however.

THIS is right. Right?

 

[SaintJude]

I realized an error I made. I was thinking of formation of an amide from a carboxylic acid. What i should of been thinking of is the opposite: formation of a carboxylic from an amide.

So to be clear: From a carboxylic acid to an amide, you absolutely must have an acid. Basic conditions no matter how harsh will not help.

The reverse can swing both ways, however.

THIS is right. Right?

Did you mean to write from amide to carboxylic acid? I assume you did b/c to form an amide you just need
1.acid chloride + ammonia or
2. acid anhydride + ammonia or
3. (less common) COOH + ammonium carbonate --> ammonium carboxylate w/ heat --> amide

Anyway, assuming you were taking about amide--> carboxylic acid

Kaplan says this:

Extreme condition (e.g strong acid) are necessary to hydrolyze an amide. The peptide bond is an amide linkage that has double-bond character from resonance, which helps it to make it the most stable carboxylic acid derivative. Hydrolysis can also occur if conditions are basic enough. The reaction is similar, except that the nucleophile is a hydroxide ion. The product of this rx will be the carboxylate ion.

 

[chiddler]

No i meant carboxylic acid to an amide lol

 

[SaintJude]

Why would you need strong acid conditions if carboxylic acid are more reactive than amides?

You just need to turn the carboxylic acid into a ammonium carboxylate---and that will just require an ammonium...

 

[chiddler]

because putting ammonia into a carboxylic acid will convert it into a salt so it will not react.

you need acid to keep the carboxylic acid protonated so that it reacts with the ammonia.

 

[prolixity29]

So says the book.

Heat, time and strong base. The book says that amides are fairly stable and I do have a vague recollection of my professor saying something in the lines of "It will take time but if you heat it up and leave it overnight, it will eventually hydrolyze." How strong of a base? NaOH/KOH are good enough.

See this was my original confusion with the basic mechanism. The bases used for the deprotonation of the pthalimide and then later to displace the primary amine (after the SN2 attack on the alkyl halide) are essentially the same (some strong hydroxide base). So for the deprotonation -OH is a weaker nucleophile but then after the alkylation it becomes a comparatively better nucleophile?

By the discussion of the pKbs I gave before the deprotonation should definitely occur. The only thing I can think of to rationalize the SN2 reaction is the relative concentration of -OH compared to the amide. With so much more hydroxide floating around, the probability of releasing the primary amine suddenly becomes so much higher. Hence the "strong basic conditions" requirement.