Sciencemadness Discussion Board

Synthesis of p-aminobenzoic acid from benzyl alcohol

wanderingalchemist - 20-10-2010 at 19:32

Hi Everyone! I'm new to this forum and this is my first post! :)

I am trying to synthesize p-aminobenzoic acid (PABA) with benzyl alcohol as my starting material.

Thus far I was able to find that I can dehydrate benzyl alcohol to benzoic acid, add a nitro and then reduce the nitro to an amine.

I haven't actually done the synthesis in lab yet, but I was wondering if anybody else has done the same type of synthesis before?

So far for my reagents I am using Potassium Permangenate then Sulfuric acid and Nitric acid for the dehydration. Then to add the anile, I am using sulfuric acid and nitric acid then Sn/HCl to reduce.

I am slightly apprehensive that my major product is going to be in the para position, since the carbonyl group on the benzene is slightly para activating.

Can someone direct me to some literature if possible?

:D

mnick12 - 20-10-2010 at 20:08

Well, Im not sure how you plan on making PABA from benzyl alcohol, care to list your steps? Also benzyl alcohol to is not a dehydration, it is an oxidation.
Quote:

I can dehydrate benzyl alcohol to benzoic acid, add a nitro and then reduce the nitro to an amine.


Nitration of benzoic acid does not give p-nitrobenzoic acid, it gives almost pure m-nitrobenzoic acid. The carboxyl group is pretty deactivating, and as a result it ends up directing electrophiles towards the m- position.

I would suggest you start from toluene nitrate then separate the isomers, either by fractional distillation under moderate vaccum (takes a while but gives a very pure prodcut). Or by freezing the mix, this does work but takes a few weeks for the solution to begin crystallizing. From there oxidize your nitrotoluene to nitrobenzoic acid then reduce. This does work but it is an awe-full lot work for something thats easy to get. I have seen PABA for sale online in 100gr quantities for a few bucks as a health supplement.

mr.crow - 20-10-2010 at 20:18

That seems like a waste of benzyl alcohol :( Better get some benzoic acid instead (food preservatives). You can use the alcohol to make benzyl chloride or benzaldehyde. Or you can try oxidizing toluene to benzoic acid with your KMnO4.

The meta position will yield anthranilic acid, which is still on the verboten list ;)

I think there was a procedure for nitrating benzoic acid in one of my textbooks...

mnick12 - 20-10-2010 at 20:33

Im afraid you are mistaken m-aminobenzoic acid is not anthranilic acid, o-aminobenzoic acid or 2-aminobenzoic acid is anthranilic acid.

wanderingalchemist - 20-10-2010 at 22:34

Hi mnick12! :)

I have the starting materials from my lab professor from my synthesis. It would be a luxury to start from toluene at this point, if it is going to take a few weeks for crystallization. He wants me use benzyl alcohol as my starting material to make a 0.5g yield of 4-aminobenzoic acid(PABA). I know that the -OH group would be para-directing, but I'm not sure if it would be a safe bet to add the nitro, reduce to an amine then oxidize the alcohol with potassium permangenate.

So far this is what I found in for the procedure:

Reduction of nitro(not quite exactly because this article is adding a nitro directly onto a benzene ring): http://www.erowid.org/archive/rhodium/chemistry/nitrobenzene...

From benzyl alcohol:
Benzyl alcohol is refluxed with potassium permanganate. The mixture hot filtered to remove manganese oxide and then allowed to cool to afford benzoic acid. From: http://www.newworldencyclopedia.org/entry/Benzoic_acid


Could it work?
Quote: Originally posted by mnick12  
Well, Im not sure how you plan on making PABA from benzyl alcohol, care to list your steps? Also benzyl alcohol to is not a dehydration, it is an oxidation.
Quote:

I can dehydrate benzyl alcohol to benzoic acid, add a nitro and then reduce the nitro to an amine.


Nitration of benzoic acid does not give p-nitrobenzoic acid, it gives almost pure m-nitrobenzoic acid. The carboxyl group is pretty deactivating, and as a result it ends up directing electrophiles towards the m- position.

I would suggest you start from toluene nitrate then separate the isomers, either by fractional distillation under moderate vaccum (takes a while but gives a very pure prodcut). Or by freezing the mix, this does work but takes a few weeks for the solution to begin crystallizing. From there oxidize your nitrotoluene to nitrobenzoic acid then reduce. This does work but it is an awe-full lot work for something thats easy to get. I have seen PABA for sale online in 100gr quantities for a few bucks as a health supplement.

wanderingalchemist - 20-10-2010 at 22:38


I had the unfortunate luck of picking benzyl alcohol as my starting material. :(

Was the book by Vogel? I probably already pilfered information from it. :P
Quote: Originally posted by mr.crow  
That seems like a waste of benzyl alcohol :( Better get some benzoic acid instead (food preservatives). You can use the alcohol to make benzyl chloride or benzaldehyde. Or you can try oxidizing toluene to benzoic acid with your KMnO4.

The meta position will yield anthranilic acid, which is still on the verboten list ;)

I think there was a procedure for nitrating benzoic acid in one of my textbooks...

mr.crow - 21-10-2010 at 06:17

Quote: Originally posted by mnick12  
Im afraid you are mistaken m-aminobenzoic acid is not anthranilic acid, o-aminobenzoic acid or 2-aminobenzoic acid is anthranilic acid.


Yeah sorry I messed it up

My textbook has a lab where they nitrate methyl benzoate to get the META product.

Nitrating toluene will give the ortho and para position.

EDIT: If this is a school project (and not something crazy for fun) you can try and change your target so the meta position is the final product. Then you can demonstrate oxidation, nitration and reduction reactions easily.

[Edited on 21-10-2010 by mr.crow]

not_important - 21-10-2010 at 10:58

Nitrating benzyl alcohol will give a mixture of all three isomers, plus some oxidation to benzoic acid and of the substituted alcohols to nitro benzoic acids. Thus you're left with separating isomers again, plus lower yields and additional side products.

The alcohol could be converted to an ester such as the acetate and that nitrated : http://www.sciencemadness.org/talk/viewthread.php?tid=8286&a...

You want to do the oxidation before the reduction of the nitro group, aromatic amines are easily oxidised; you can even convert the NH2 back to NO2 with permanganate. Alternatively you could reduce the nitro group, convert it to an amide (such as treating with acetic anhydride or acetyl chloride), then oxidise the alcohol, and finish off by hydrolising the amide. Note that the CH2OH will be esterfied again if the ester used during nitration was hydrolised, the ester is much easier to hydrolise than the amide to doing so selectivel is not much of a problem.



Note: If I were doing this for myself, I'd dissolve polystyrene in dichloromethane, nitrate that under conditions similar to nitrating toluene, then oxidise the polymer backbone with KMnO4 to get the nitrobenzoic acids. The backbone, and to al less extent the neighboring rings, make the ortho positions less accessible and thus increase the percentage of para nitration. The acids are fairly easy to separate, based on their relative pKa and steam volatility.


[Edited on 21-10-2010 by not_important]

wanderingalchemist - 21-10-2010 at 15:56

Esterfication of the benzyl alcohol into p-nitrobenzyl acetate would definitely solve my p-nitro problem. Once I have the p-nitrobenzyl acetate I can do a hydrolysis to get the carboxylic acid and then reduce my p-nitrobenzoic acid to p-aminobenzoic acid. Would this work?
Quote: Originally posted by not_important  
Nitrating benzyl alcohol will give a mixture of all three isomers, plus some oxidation to benzoic acid and of the substituted alcohols to nitro benzoic acids. Thus you're left with separating isomers again, plus lower yields and additional side products.

The alcohol could be converted to an ester such as the acetate and that nitrated : http://www.sciencemadness.org/talk/viewthread.php?tid=8286&a...

You want to do the oxidation before the reduction of the nitro group, aromatic amines are easily oxidised; you can even convert the NH2 back to NO2 with permanganate. Alternatively you could reduce the nitro group, convert it to an amide (such as treating with acetic anhydride or acetyl chloride), then oxidise the alcohol, and finish off by hydrolising the amide. Note that the CH2OH will be esterfied again if the ester used during nitration was hydrolised, the ester is much easier to hydrolise than the amide to doing so selectivel is not much of a problem.



Note: If I were doing this for myself, I'd dissolve polystyrene in dichloromethane, nitrate that under conditions similar to nitrating toluene, then oxidise the polymer backbone with KMnO4 to get the nitrobenzoic acids. The backbone, and to al less extent the neighboring rings, make the ortho positions less accessible and thus increase the percentage of para nitration. The acids are fairly easy to separate, based on their relative pKa and steam volatility.


[Edited on 21-10-2010 by not_important]

not_important - 22-10-2010 at 12:45

You could hydrolyse at get the nitro-benzyl alcohol, then oxidise that, yes. You still need to isolate the desired nitro isomer from the nitration mix first, or the desired isomer from the mixed benzoic acids after hydrolysis.





Nicodem - 23-10-2010 at 00:14

Quote: Originally posted by wanderingalchemist  
Esterfication of the benzyl alcohol into p-nitrobenzyl acetate would definitely solve my p-nitro problem. Once I have the p-nitrobenzyl acetate I can do a hydrolysis to get the carboxylic acid and then reduce my p-nitrobenzoic acid to p-aminobenzoic acid. Would this work?

I would suggest you to first learn some chemistry before attempting to do anything that might blow a mixture of nitric and sulfuric acid in your face. I'm not trying to discourage you from experimenting, but you should first understand what you do, much before you do it, particularly when what you are up to is something potentially dangerous. From your posts it is obvious you do not read scientific articles, don't have any experience or knowledge in practical chemistry, and know close to nothing about theory. You are not fit to design a potentially hazardous chemical experiment at this stage, especially not on a preparative scale which appears to be your goal. Try aproching the problem in the more conventional manner: searching the literature <-> reading <-> understanding <-> designing the experiment <-> evaluating the design -> performing it -> analysing the experimental data -> searching the literature ... and all over again.

wanderingalchemist - 25-10-2010 at 19:24

I appreciate your concern Nicoderm. :D And by no means am I quitting nor discouraged.

I admit that as I am preparing this synthesis, I am very hesitant about performing any experiments which is why I have my (PhD'd) professors ;). I am by no means an expert, and my chemistry is probably not up to par at this moment, however, I am searching the literature, reading, asking, more reading, more searching and trying to understand as much as I can. I would not attempt to do this alone, nor do I plan to. It would all be supervised by my instructor, and everything will have to go through an assessment before I even try anything.

It's daunting to jump into something like OChem when you have not done any for so many years.

I just want you to know that I will continue to ask questions. I just hope somebody out there can help me understand how I can do this synthesis safely and efficiently.
Quote: Originally posted by Nicodem  
Quote: Originally posted by wanderingalchemist  
Esterfication of the benzyl alcohol into p-nitrobenzyl acetate would definitely solve my p-nitro problem. Once I have the p-nitrobenzyl acetate I can do a hydrolysis to get the carboxylic acid and then reduce my p-nitrobenzoic acid to p-aminobenzoic acid. Would this work?

I would suggest you to first learn some chemistry before attempting to do anything that might blow a mixture of nitric and sulfuric acid in your face. I'm not trying to discourage you from experimenting, but you should first understand what you do, much before you do it, particularly when what you are up to is something potentially dangerous. From your posts it is obvious you do not read scientific articles, don't have any experience or knowledge in practical chemistry, and know close to nothing about theory. You are not fit to design a potentially hazardous chemical experiment at this stage, especially not on a preparative scale which appears to be your goal. Try aproching the problem in the more conventional manner: searching the literature <-> reading <-> understanding <-> designing the experiment <-> evaluating the design -> performing it -> analysing the experimental data -> searching the literature ... and all over again.

Nicodem - 26-10-2010 at 07:46

Then I suggest you to do experiments on no more than 10 mmol scale and pay attention to the exotherms so that upscaling to a preparative reaction will be less problematic. Forget about benzyl alcohol - that is a bad choice of a starting material. Rather follow the suggestion by not_important. That is a way more interesting route. Also, learn the basics first (stoichiometry, reactivity, how to read and understand experimental procedures, on how to do TLC, how to perform extractions, recrystallizations, distillations etc.).

RiP057 - 26-10-2010 at 17:08

IMO and I dont want to pay attention to details....

starting from Benzyl Alcohol I would react with I2 to get 4-Iodo-benzylalcohol from there displace with dimethylamine. I chose this way of making the dimethylamino group as trying to methylate a primary amine will give a cascade of all sorts, mono, di, and mainly trimethylamine. Finally oxidize to the benzoic acid, but seriously dont play with nitric acid unless you know what is up!!!!! Good luck finding Me2NH, and good luck coming up with an actual synth for all those steps... what I gave you was all theoretical

[Edited on 27-10-2010 by RiP057]

RiP057 - 26-10-2010 at 17:11

Quote: Originally posted by Nicodem  
Forget about benzyl alcohol - that is a bad choice of a starting material. Rather follow the suggestion by not_important.


I think the point of this was that it was a homework or lab assignment and the starting material was already pre determined by the student... hence he isnt going to change the SM

also I just gave a very plausable synth

[Edited on 27-10-2010 by RiP057]

not_important - 26-10-2010 at 17:41

Quote: Originally posted by RiP057  
IMO and I dont want to pay attention to details....

starting from Benzyl Alcohol I would react with I2 to get 4-Iodo-benzylalcohol from there displace with dimethylamine.... what I gave you was all theoretical


Truer words are rarely spoken. First off the target was given ass PABA, not the diMe analogue. Second is that benzyl alcohol isn't particularly activated, roughly the same as toluene, so the iodination will need to be pushed; it will also form o- and some m- isomeres, purification will be needed. Aromatic halogens are not that easy to displace when on fairly vanilla rings, even iodine; might require rather vigorous conditions and the -CH2OH group must survive those or be converted to some other radical not too difficult to take to the carboxyl.

I'd have to call it a not very plausible route, and to wrong product.

RiP057 - 26-10-2010 at 18:07

ok granted i made PDMABA, but my synth would work I dont know why i had it in my head that it was the dimethylamino.....

forgive me

however C6H5CH2OH--> IC6H4CH2OH --> NH2C6H4CH2OH --> NH2C6H4CO2H

is still very plausable, however now seeing that it is the amino and not the dimethylamino....

Benzyl Alcohol --> 4-NO2-Benzyl Alcohol --> 4-NH2-Benzyl Alcohol --> 4-NH2-Benzoic Acid

would be the way to go as far as synthesis goes

I would take solution of the benzyl alcohol in H2SO4 with magnetic stirring cooled in an ice bath and to that drip in a solution of NaNO2 in H2SO4 using a 1.1 mol equivalent to the OH... allow to come to room temperature and pour over ice then filter, recrystalize.....
Reduction of the nitroalcohol is easy as pie with Fe/HCl(aq) reflux until reaction is complete on TLC
If you are really worried about the amino group you can protect with Acetic Anyhdride, but it will just get hydrolyzed with the oxidation
take the aminealcohol and react with the stoichiometric amount of KMnO4 in KOH to allow for conversion to the benzoic acid....(im to lazy to do the calculation), acidify look at the cool colors created by the manganese and extract with toluene, strip solvent and recrystalize

humbly sorry for confusing and not paying attention

edit: added the reduction of the nitro group

[Edited on 27-10-2010 by RiP057]

[Edited on 27-10-2010 by RiP057]

RiP057 - 26-10-2010 at 18:13

Quote: Originally posted by not_important  

same as toluene, so the iodination will need to be pushed; it will also form o- and some m- isomeres, purification will be needed.

I'd have to call it a not very plausible route, and to wrong product.



first iodination is always a heated reaction I2/FeI3 or at least it goes faster, unless you have ICl or want to make ICl

benzyl alcohol will almost make no meta products of iodination...

yes the displacement reaction would be a harsh one as any displacement on a ring is not easy, however the hydroxyl group should be fine, and even if it isnt, it would only have Me2NH displace the OH as well, and that would be fine in the end because you are going to oxidize the benzylic position in more than likely refluxing KOH would would turn the then created amide into the acid

point taken pay attention, but I was only going that route because I thought it was the dimethylamino variant not the primary p-aminobenzoic acid

not_important - 27-10-2010 at 08:54

I2 does not iodinate less activated aromatics, oxidising agents are required. Even ICl does not do so, it will iodate m-xylene with its o,p- activating pair of alkyl substitutes and mesitylene with o,o,p triplet of alkyls; it also reacts with aromatic ethers - again fairly activated rings.

With ICl:

Ar-H + ICl => Ar-I + HCl

ArCH2OH + HCl => ArCH2Cl + H2O

which is a bit meta directing. The H2O can react with the ArCH2Cl giving the reverse reaction, and with ICl.

Chlorination and bromination of toluene produce a few percent of the meta isomer, unless unusual catalysts are used.

The ArCH2X group is fairly reactive, concentrated hydrochloric acid converts it to the chloride, many oxidising agents take it to the benzaldehyde or carboxylic acid; it will also react with activated aromatics (ie - phenols) to give a methylene bridge and water.