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Author: Subject: Using N-bromosuccinimide to synthesize acyl bromides or carboxamides
Rich_Insane
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[*] posted on 27-9-2013 at 08:34
Using N-bromosuccinimide to synthesize acyl bromides or carboxamides


I found a reference "Volume 31, Issue 49, 1990, Pages 7237–7240" that describes a radical-mediated synthesis of acid bromides from aldehydes. The paper also describes synthesis of carboxamides (N-substituted and primary) through this route.

There are three problems that make this procedure not feasible for me:

1) They use CCl4 as a solvent, which I do not want to work with (it's hard for me to get as well). My thought was to use DCM or methanol as a solvent instead.
2) They use AIBN (Azobisisobutyronitrile) as a radical initiator... I don't know where I would get this, even though it is used as an initiator for plastic synthesis.
3) If I wanted to prepare a primary carboxamide, I would need to get NH3 gas into the reaction after the acid bromide is formed. I don't think I can use aq. ammonia for this, as that would promote formation of the carboxylic acid. Would ammonia gas generated from ammonium chloride and sodium hydroxide work in this case?

These people performed the reaction under an inert atmosphere, but I feel like the only reason that was necessary was to prevent moisture from entering the system... So perhaps a strictly controlled atmosphere is not necessary?

Attachment: 1990&_sk=999689950&view=c&wchp=dGLbVzb-zSkWW&_acct=C000008658&_version=1&_userid=1001915&md5=98b3.pdf (219kB)
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sonogashira
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[*] posted on 27-9-2013 at 08:38


If you have PPh3 you can make the acid bromide in DCM from the acid and NBS.
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Rich_Insane
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[*] posted on 27-9-2013 at 08:40


I've seen that reference somewhere, but I'm interested in a route that gives direct access to an amide or an acyl halide from the aldehyde.
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Nicodem
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[*] posted on 27-9-2013 at 09:29


This oxidation of aldehydes to acyl halides was mentioned in another post and briefly reviewed in the acetic anhydride thread.
Quote: Originally posted by Rich_Insane  
I found a reference "Volume 31, Issue 49, 1990, Pages 7237–7240" that describes a radical-mediated synthesis of acid bromides from aldehydes.

Volume of what? When you cite, make sure you really do.
Quote:
1) They use CCl4 as a solvent, which I do not want to work with (it's hard for me to get as well). My thought was to use DCM or methanol as a solvent instead.

Methanol? Think again.
Dichloromethane and some other chlorinated solvents can be used in radical halogenations with NBS or 1,3-dibromo-5,5-dimethylhydantoin. So can acetonitrile, methyl acetate, t-butyl acetate, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene or benzotrifluoride, with varying efficiency. In some cases, one can use also ethyl acetate, t-butanol, benzene or acetone, though some of these tend to react more than acetonitrile or methyl acetate, so you need to compensate with an excess of the reagent. The point is to use solvents that have no easily abstractable hydrogens.
Quote:
2) They use AIBN (Azobisisobutyronitrile) as a radical initiator... I don't know where I would get this, even though it is used as an initiator for plastic synthesis.

You don't need AIBN. You can use other radical initiators like dibenzoyl peroxide, sunlight or a light bulb directed into the reaction flask. AIBN is used just out of convenience, not because of efficiency or lack of alternatives.
Quote:
3) If I wanted to prepare a primary carboxamide, I would need to get NH3 gas into the reaction after the acid bromide is formed. I don't think I can use aq. ammonia for this, as that would promote formation of the carboxylic acid. Would ammonia gas generated from ammonium chloride and sodium hydroxide work in this case?

Why would aq. ammonia not work? Aqueous 25% ammonia is commonly used to make amides from acyl halides or acid anhydrides.
Quote:
These people performed the reaction under an inert atmosphere, but I feel like the only reason that was necessary was to prevent moisture from entering the system...

In principle, oxygen is known to quench the radical chain reactions, hence the radical halogenations perform better under inert atmosphere and degassed solvents. Therefore, air inhibits them, but it does not stop them.

It appears to me that you are unaware that the substrate must be resistant to electrophilic bromination under the reaction conditions.




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Rich_Insane
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[*] posted on 27-9-2013 at 18:13



Quote:

Volume of what? When you cite, make sure you really do.



Oops, my bad, it's from Tetrahedron Letters. I have also attached the PDF to my first post.


Quote:

Dichloromethane and some other chlorinated solvents can be used in radical halogenations with NBS or 1,3-dibromo-5,5-dimethylhydantoin. So can acetonitrile, methyl acetate, t-butyl acetate, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene or benzotrifluoride, with varying efficiency. In some cases, one can use also ethyl acetate, t-butanol, benzene or acetone, though some of these tend to react more than acetonitrile or methyl acetate, so you need to compensate with an excess of the reagent. The point is to use solvents that have no easily abstractable hydrogens.


I realized that methanol would not be compatible here. At first I thought the problem would be the NBS, but this is a radical-mediated reaction.

So before I proceed, is my understanding of the reaction correct?:

The initiator forms a bromine radical from NBS. The radical is highly electrophilic and pulls an electron off of the terminal hydrogen. The substrate forms a radical that will react readily with NBS. From there, the acid halide reacts with the nucleophilic amine to yield the carboxamide.


Quote:

Why would aq. ammonia not work? Aqueous 25% ammonia is commonly used to make amides from acyl halides or acid anhydrides


I always thought acid halides were quite reactive towards water. Does the acid halide react more readily with NH3 than with water?


Quote:

It appears to me that you are unaware that the substrate must be resistant to electrophilic bromination under the reaction conditions.



I was unaware of this. Sadly, I think that the substrate will undergo electrophilic aromatic bromination. A second opinion would be great though. Below is the substrate I intend to use to form the acid bromide (which will then be treated with an amine to the amide):



The 3,4-methylenedioxy group, if I am correct, acts as an ortho/para directing substituent. Bromination of 1,2-methylenedioxybenzene gives 4-bromo-1,2-methylenedioxybenzene. Bromination could occur at any of the open sites on the aromatic ring (if I am right). :(

Apologies for the crude picture, by the way. I included both potential reactions that could occur.






[Edited on 28-9-2013 by Rich_Insane]
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Nicodem
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[*] posted on 28-9-2013 at 09:47


For the mechanism, see the school textbooks or tutorials. Its just everywhere. Surely you know how to use the internet search engines.
Quote: Originally posted by Rich_Insane  
I always thought acid halides were quite reactive towards water. Does the acid halide react more readily with NH3 than with water?

Yes, they react with water, but ammonia is much more nucleophilic than water. Some acyl chloride does gets hydrolyzed, but most of it reacts with ammonia to give the amide. The yields of ammonolysis of acid halides in conc. aq. ammonia are generally excellent, though sometimes a biphasic reaction media needs to be used due to solubility issues or yields optimization. See the examples in the literature.
Quote:
Sadly, I think that the substrate will undergo electrophilic aromatic bromination. A second opinion would be great though. Below is the substrate I intend to use to form the acid bromide (which will then be treated with an amine to the amide):

I ain't stupid, you know. There is a methyl group missing there.
Anyway, the electrophilicity of NBS is modulated by the polarity and acidity of the media. In CCl4, it is quite possible the rate of the electrophilic substitution is negligible, provided the radical initiator or light is plentiful/intense. On the other extreme, in acetonitrile, I would expect the electrophilic substitution to go comparably fast.





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Rich_Insane
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[*] posted on 28-9-2013 at 10:17



Quote:

Anyway, the electrophilicity of NBS is modulated by the polarity and acidity of the media. In CCl4, it is quite possible the rate of the electrophilic substitution is negligible, provided the radical initiator or light is plentiful/intense. On the other extreme, in acetonitrile, I would expect the electrophilic substitution to go comparably fast.


Ah, interesting. I wonder if chloroform could be used in place of CCl4. The electrophilic bromination reaction is more favored as the acidity and polarity of the solvent increases, right?
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