December 14, 2019, 11:41:09 PM
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Topic: Basic: Aminolysis / hydrolysis of Acid halides  (Read 563 times)

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Offline Nozon

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Basic: Aminolysis / hydrolysis of Acid halides
« on: August 05, 2019, 11:50:32 AM »
Hello - I'm a college student and trying my best to understand organic chemistry.

But I keep feeling like my book oversimplifies things, so I just want to clear one thing out.
(Sorry if this is too basic for you)

According to my book, "John McMurry - Organic Chemistry with biological applications", it states that:

Reaction:
Acyl Halide  + disubstituted amine  (*2 if not NaOH is used) --> Amide + NaCl
Solvent:
NaOH + H2O.

But according to a former reaction - hydrolysis of acyl halide you'll have Carboxyl Acid in a reaction similar:
Acyl halide + NaOH + H2O --> Carboxyl acid.

Of my knowledge it requires you to modify the OH group from carboxyl acid with DCC to make it a better leaving group to make it react with amine and create amide.

So my question is - wouldn't the first stated reaction create both amide and carboxyl acid?

Best regards
Jacob

Offline OrganicDan96

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Re: Basic: Aminolysis / hydrolysis of Acid halides
« Reply #1 on: August 05, 2019, 12:02:46 PM »
you can make amides from acid chlorides without hydrolysis, think about solvent choice. these reactions normally are not conducted in water and sodium hydroxide is not used, what other bases could be used?

Offline wildfyr

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Re: Basic: Aminolysis / hydrolysis of Acid halides
« Reply #2 on: August 05, 2019, 12:21:32 PM »
It must to be referring to Schotten Baumann conditions. This is actually quite common (to my surprise).

But your point is taken, yes if you don't have a perfect setup, you can, and usually do, get some amount of hydrolysis when trying to make amines from acyl halides.

Its a matter of the setup and conditions. If there is no amine present those conditions will cause full hydrolysis. However with appropriate considerations, you can run an acid halide with an amine in the presence of water and NaOH, usually in the presence of an immiscible organic phase.

Offline Nozon

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Re: Basic: Aminolysis / hydrolysis of Acid halides
« Reply #3 on: August 05, 2019, 12:34:34 PM »
Thanks for a leading question.

I am wondering if you can avoid hydrolysis during aminolysis if you are making this reaction (example of the book)
3,4,5-Trimethoxy-benzoyl chloride + Morpholine in NaOH + H2O solvent.   - where it states the products solely are trimetozine + NaCl.

I might have used an ether as solvent to avoid the possibility of hydrolysis. Not sure which other base I would have used as equivalant to morpholine to avoid Cl- ions to react further.   

Sorry if I don't understand your hint.   



Offline Nozon

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Re: Basic: Aminolysis / hydrolysis of Acid halides
« Reply #4 on: August 05, 2019, 12:39:41 PM »
Wildfyr

Okay thank you so much - I have spent a few hours to look for an answer to this and seemed to be neglected where ever I read.


Thanks a lot for the help. 

Offline rolnor

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Re: Basic: Aminolysis / hydrolysis of Acid halides
« Reply #5 on: August 05, 2019, 12:58:42 PM »
You can just simply use 2eq. Of morpholine instead of NaOH but usually the acid chloride reacts a lot faster with amine then hydroxide. When aminoacids are protected with benzylchloroformate its possible to use NaHCO3 as base.

Offline wildfyr

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Re: Basic: Aminolysis / hydrolysis of Acid halides
« Reply #6 on: August 05, 2019, 01:35:37 PM »
It may say that the only product is trimetozine, but that's misleading fantasy book chemistry. In the real world there will be some amount of hydrolysis, meaning there will be carboxylic acid and some amine left over. The way such a material is isolated will make sure none of the starting materials remain in the final product, and also remove NaCl.

Offline OrganicDan96

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Re: Basic: Aminolysis / hydrolysis of Acid halides
« Reply #7 on: August 05, 2019, 03:11:56 PM »
you can use bases like pyridine, triethylamine or diisopropylethylamine

Offline Nozon

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Re: Basic: Aminolysis / hydrolysis of Acid halides
« Reply #8 on: August 05, 2019, 04:55:26 PM »
Rolnor - this may be one of the stupidest question you'll receive.

Is there any way to know which will react the fastest? I know about the transition gibbs tells you that, but if you don't know it, is there any way by just looking at a molecule to determine which reaction is faster?

Anyway - thanks for your input, I'll take that into consideration.

Offline Nozon

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Re: Basic: Aminolysis / hydrolysis of Acid halides
« Reply #9 on: August 05, 2019, 04:59:26 PM »
Wildfyr
Thanks for clarifying. Chemistry isn't my strongest suit. - I am very thankful that there's a forum like this.

OrganicDan96
Thanks - it does suggest pyridine but never showed any example with it in (So I thought that it might be less favorable).

Offline hypervalent_iodine

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Re: Basic: Aminolysis / hydrolysis of Acid halides
« Reply #10 on: August 05, 2019, 10:41:59 PM »
Wildfyr
Thanks for clarifying. Chemistry isn't my strongest suit. - I am very thankful that there's a forum like this.

OrganicDan96
Thanks - it does suggest pyridine but never showed any example with it in (So I thought that it might be less favorable).

Pyridine is good. TEA can cause issues with some substrates as it is capable of deprotonating alpha protons, but it is also a perfectly good choice. You can also use other inorganic bases like K3PO4 or carbonates. If you're interested, the following is a good paper related to the topic (although they don't mention the use of pyridine): https://www.sciencedirect.com/science/article/pii/S0040403909007898

Offline rolnor

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Re: Basic: Aminolysis / hydrolysis of Acid halides
« Reply #11 on: August 06, 2019, 04:14:10 AM »
Rolnor - this may be one of the stupidest question you'll receive.

Is there any way to know which will react the fastest? I know about the transition gibbs tells you that, but if you don't know it, is there any way by just looking at a molecule to determine which reaction is faster?

Anyway - thanks for your input, I'll take that into consideration.

Its actually not so easy to see wich is the best nucleophile in this case but the reason you can use hydroxide is that it will not go in to the organic phase where the acid chloride is. It is a bit strange to use hydroxide in your case, its better to use hydrogencarbonate, pyridine or a tertiary amine or simply 2eq. of morpholine. So I have to back here, if you have a homogenous system the hydroxide would also react fast with the acid chloride.

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