How can you make p-aminobenzoic acid from benzene?

[chen]

I preferably want a practical way to do this not a way that would work on paper.

 

I tried to get a NH2 group on benzene first:

 

~Benzene + HNO3/H2SO4 ---> Benzene-NO2

 

~convert that to an amine by hydrogenation H2/Pd

 

But then I couldnt use a Friedel Craft Acylation to add an aldehyde to the ring because the aryl amine will react with the acyl chloride and make the reaction extremely slow:

 

Benzene-NH2 + CHOCl ---> Benzene-NHCHO

 

but on the other hand, that could be the protecting group to the amine. Is there any other way to add a carboxylic acid onto the benzene ring after that step?

<BR class=last-child>any thought is highly appreciated. Thank you.

[hypervalent_iodine]

A FC acylation to add an aldehyde to the ring? So you want to add a formaldehyde moiety to the ring? You couldn't do that with FC anyway. Formyl chloride is way too unstable. Did you maybe mean something else? Anyway, why do you need to add the amine first?

 

I had a think about what you needed to make. Starting from benzene I would follow with the initial nitration and hydrogenation to the amine. Amines are para activating, so you can then do another nitration to get para nitro aminobenzene. I would then convert the amine to a diazonium salt (using NaNO2 and HCl) so that you can convert it to a nitrile with Cu(CN)2 and KCN. The nitrile can then be changed to COOH with conc. H2SO4 in water. Then it's a case of hydrogenationg to get the nitro to an amine - though I'd be concerned of turning the acid into an alcohol. I just did a quick search around a science journal search engine and apparently there are ways around it. I'm not sure of the conditions though.

 

Also, is this a theoretical exercise or is this for something else? Seems like a mundane and pointless sort of thing to need synthesising on it's own when you can buy it.

[Horza2002]

Why are you trying to make this when its commercially avalible?

 

http://www.sigmaaldrich.com/catalog/Lookup.do?N5=CAS%20No.&N3=mode+matchpartialmax&N4=150-13-0&D7=0&D10=150-13-0&N1=S_ID&ST=RS&N25=0&F=PR

 

However if you want to make it, then another way to do it would be nitrate benzene and reduce to the amine. This would give you a para-directing group so that you can brominate para-to the amine. Convert this to the Grignard and finally react it with carbon dioxide will give you the product.

4aminobenzoic acid.pdf

[mississippichem]

You'll have to distill after the second nitration to separate 1-amino-4-nitrobenzene and the small amount of 1-amino-2-nitrobenzene that will also form if you take the "double-nitration" route. You should really just buy some though if this isn't a mental synthesis exercise. Nitration reactions of aromatics are nasty.

Edited January 15, 2011 by mississippichem

[John Cuthber]

Benzene

Toluene

4 nitro toluene

4 nitro benzoic acid

4 amino benzoic acid.

 

Of course, in reality you would start with toluene.

You would have to remove the 2 nitro and 3 nitro toluenes after the nitration but pretty much any nitration will run into that problem.

[Horza2002]

AS it evident so far, there are many ways to do this transformation. Was this just a theoretical excersise or was it something you actually wanted to do?

[hypervalent_iodine]

I like Horza's idea of using a Grignard, actually.

 

But yes, as mississippi pointed out, nitrations are kind of nasty. Grignards can be a touch difficult sometimes as well.

 

Horza, I think we can assume that it is. There's no reason you would actually need to go to the trouble of making something like this, unless it was maybe part of a larger molecule - in which case, the synthetic route would need changing.

[Horza2002]

Nitration reactions are not the safest reaction to perform seeing as you need such a strong combination of acids mixed together and heated. Coupled with the fact that an aryl amine is ortho para directing, you'll get a mixture of products. But that is a problem that is inherant to nitrations and can only really be sorted out by using sterially large groups to block the ortho site (not possible here without adding several more steps).

 

Grignards can also be a pian to make and use...the main practical problem would be making sure you keep oxygen and water out of the reaction (easy enough with practise). I've never tried making a carboxylic acid in this manor but I guess you would simply add a pellet of dry ice to the reaction.

[mississippichem]

Nitration reactions are not the safest reaction to perform seeing as you need such a strong combination of acids mixed together and heated. Coupled with the fact that an aryl amine is ortho para directing, you'll get a mixture of products. But that is a problem that is inherant to nitrations and can only really be sorted out by using sterially large groups to block the ortho site (not possible here without adding several more steps).

 

Grignards can also be a pian to make and use...the main practical problem would be making sure you keep oxygen and water out of the reaction (easy enough with practise). I've never tried making a carboxylic acid in this manor but I guess you would simply add a pellet of dry ice to the reaction.

 

The Grignard + carbon dioxide to give carb. acid reaction is a beautiful one; high yielding and clean. I've done it with dry ice pellets. One must be careful not to add too much dry ice though, a cold Grignard will conglomerate into a nasty divalent oranomagnesium species, and I'm not sure how reversible it is.

[hypervalent_iodine]

The Grignard + carbon dioxide to give carb. acid reaction is a beautiful one; high yielding and clean. I've done it with dry ice pellets. One must be careful not to add too much dry ice though, a cold Grignard will conglomerate into a nasty divalent oranomagnesium species, and I'm not sure how reversible it is.

 

If I remember correctly, it's not. I could be wrong on that though. It's been a little while since I've played with Grignard reactions.

[mississippichem]

If I remember correctly, it's not. I could be wrong on that though. It's been a little while since I've played with Grignard reactions.

 

 

Not reversible? Yeah I didn't think so. That's worth looking into.

[John Cuthber]

I like Grignard reagents.

When I was at college, as we had a good library, I even took the trouble to look up the original reference by M. Grignard (It is, of course, in French).

Even if you allow for the fact that they are relatively expensive they often offset this by producing good yields and easy work ups.

 

On the other hand, since you can't make one in the presence of an amine group they would be neither use nor ornament in the procedure indicated. It's not obvious to me what protecting group you might use.

[Horza2002]

Why can't you make them in the presence of an amine group? Does the forming grignard deprotonate the amine? If thats the case, then a simple double benzyl group should do the trick as you can remove it with a mild hydrogenation reaction (to leave the benzene ring alone). Mississippichem, are ou referring to the Schlenk equilibirium?

 

http://en.wikipedia.org/wiki/Schlenk_equilibrium

[hypervalent_iodine]

I like Grignard reagents.

When I was at college, as we had a good library, I even took the trouble to look up the original reference by M. Grignard (It is, of course, in French).

Even if you allow for the fact that they are relatively expensive they often offset this by producing good yields and easy work ups.

 

On the other hand, since you can't make one in the presence of an amine group they would be neither use nor ornament in the procedure indicated. It's not obvious to me what protecting group you might use.

 

Is there a problem with making a Grignard reagent with an intramolecular amine in it? I didn't think there was. Again, it's been a while since I've worked with Grignard.

 

 

 

[John Cuthber]

Grignard reagents are strong enough bases to deprotonate amines.

Benzyl might work. The usual suspects- conversion to amides or some such- wouldn't help because they, in turn, react with Grignard reagents.

[mississippichem]

Why can't you make them in the presence of an amine group? Does the forming grignard deprotonate the amine? If thats the case, then a simple double benzyl group should do the trick as you can remove it with a mild hydrogenation reaction (to leave the benzene ring alone). Mississippichem, are ou referring to the Schlenk equilibirium?

 

http://en.wikipedia.org/wiki/Schlenk_equilibrium

 

Yes, but when it gets cold enough or too concentrated, those "dimers, trimers...oligomers" go colloidal or even degrade to Mg clusters. It actually yields an extremely diverse mix of organomagnesium species.

[hypervalent_iodine]

Grignard reagents are strong enough bases to deprotonate amines.

Benzyl might work. The usual suspects- conversion to amides or some such- wouldn't help because they, in turn, react with Grignard reagents.

 

The Grignard reagent is being made with p amino-bromobenzene, so the amine is within the reagent.