• N&PD Moderators: Skorpio | thegreenhand

  • Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

Removal of primary Aryl Amine

C

clubcard

Bluelighter
Joined
Apr 12, 2013
Messages
1,483
Since this is a general reaction question, I am hoping that it;s OK.

For a long time I have been trying to find a convenient way to reduce an aryl-NH2 to a -H. I have noted that forming a diazonium chloride using NaNO2 + HCl and then reduction using H3PO2 is a general route. It isn't THAT onerous but a 1-step route wouldbe very much appreciated... or saving that, an alternative to the formation of a dizonium salt.
 
I don't know of any straight forward method that doesn't involve the formation of a diazonium...
It may be easier to use a different precursor.

There is an enzyme capable of converting arylamines into catechols but it's not very well known AFAIK, might be pretty difficult to acquire/produce. It's called aniline dioxygenase from Acinetobacter sp.

FEBS Press

febs.onlinelibrary.wiley.com febs.onlinelibrary.wiley.com
 
Last edited:
pretty sure those are both diazonium reactions
off the top of my head there is no obvcious way to remove an aryl-NH2
 
sekio said:
pretty sure those are both diazonium reactions
off the top of my head there is no obvcious way to remove an aryl-NH2
Click to expand...

Yep, just with slightly different reactants. But you always gotta lose N2 to make the reaction thermodynamically favorable. If someone finds another way they would surely publish it before sharing it here lol.

The enzyme I mentioned is able to do it by transforming it into glutamine (from glutamate), I think. So there might be another way to do it, but you'd probably need a special catalyst.
 
problems with the enzyme reaction:
1. unless your enzyme works in non aqueous media you are going to have severe problems with concentrations (or product precipitating out fouling the enzyme)
2. that's a dioxygenase, cachetols are not exactly any easier to reduce to the arene
3. needs gaseous O2... (good luck getting that soluble)
3b. and either stoichiometric NADH or some means of recycling NAD+ to NADH
4. just because the enzyme works on simple substrates does not mean it works on more complicated ones
 
Last edited:
God you guys are smart; maybe turning the amine into nitro could help out ? Creating NO2?
 
After an exhaustive search, the Sandmayer reaction looks like the only option. I'm well aware of the troubles of getting an -NH2 INTO an aromatic system so I suppose after all that, researchers would throw up their hands at a reduction (or replacement for a moiety that is easily removed).


There are quite a few papers that are titled 'alternative to Sandmayer reaction' and although I'm not certain, I'm pretty sure that an -F would work (they key is to get the LogP below but close to 5) although the metabolism would change.
 
sekio said:
problems with the enzyme reaction:
1. unless your enzyme works in non aqueous media you are going to have severe problems with concentrations (or product precipitating out fouling the enzyme)
2. that's a dioxygenase, cachetols are not exactly any easier to reduce to the arene
3. needs gaseous O2... (good luck getting that soluble)
3b. and either stoichiometric NADH or some means of recycling NAD+ to NADH
4. just because the enzyme works on simple substrates does not mean it works on more complicated ones
Click to expand...

Yeah that particular enzyme is certainly not a great option and it might not even work with Clubcard's substrate. I just shared it because I thought it was interesting that an enzyme can catalyze the deamination (or an aromatic molecule) via a completely different mechanism, mainly because we mostly don't know how to do it without converting NH2 it into N2.

It's true that there are many challenges regarding the use of enzymes as catalysts. Only a few enzymatic reactions can be readily used on an industrial scale, but that number is rapidly increasing.
There has been a lot of improvement in recent years, many of those points can be partly solved with things like protein engineering. You can also use flow chemistry to fix the dilution problem.
Cofactor recycling is definitely a big challenge specially with oxidoreductases, though NAD(P) it can be recycled through enzymatic cascades.
 
You can instead form the nitrosoacetanilide and reduce this by heating in methanol with sodium acetate:
This is actually three steps instead of two and requires N2O3 to form the nitrosoacetanilide so it may not offer any practical advantages.

Alternatively, you can exchange -NMe3+ for -F by pyrolysis of the trimethylanilinium fluorides:

I don't think any method is going to be easier than Sandmeyer because it's already one of the simplest reactions; if the problem is with the rxn conditions, there are mild variants out there.
 
You must log in or register to reply here.
Top