Sciencemadness Discussion Board - Reduction of 4-nitrobenzoic acid

Reduction of 4-nitrobenzoic acid

Dullemarc - 22-6-2018 at 05:41

Hey all, new user but old lurker

Have relly enyoyed this site, found alot of great help and inspiration lurking around for years now

Now to my "problem" or more like a dilemma.

Final goal is Benzocaine. The 4-NitroBenzoic Acid is made from scratch. Starting out with paint thinner to get toluene.

So now I need to convert my 4-NitroBenzoic Acid to 4-Aminobenzoic acid

There are now 2 ways (I can think of) to get there:
Esterification to ethyl 4-nitrobenzoate and the reduce it to Benzocaine with tin and HCL

Or Reduce the p-nitrobenzoic acid with tin and hydrochloric acid to p-amino benzoic acid, and then esterfied with ethanol and sulfuric acid.

I got 5grams of 4-nitrobenzoic acid, and around 10 grams of Tin(II) chloride crystals (SnCl2·2H2O) I made some time ago in case I needed to test for gold at some point.
I Got plenty of tin granules and HCL in case I need more .

What produces the better results, and in what order would you do it.

The best word in a laboratory is not eureka, but weird.

[Edited on 22-6-2018 by Dullemarc]

[Edited on 22-6-2018 by Dullemarc]

CuReUS - 22-6-2018 at 06:42

do the esterification first,then reduce -https://pubs.acs.org/doi/10.1021/ja01691a031

Dullemarc - 22-6-2018 at 06:49

Sadly don't have access to https://pubs.acs.org

But what are the paper reason for doing the esterification first?

And thank you for replying

Chemi Pharma - 22-6-2018 at 07:40

Quote: Originally posted by CuReUS

do the esterification first,then reduce -https://pubs.acs.org/doi/10.1021/ja01691a031

I'd rather do exactly the opposite. Reduce first, than esterificate.

My reasons are I did this reaction a few times, starting from p-nitrobenzoic acid, that's here in Brazil is cheap and easy to get. The p-amino benzoic acid produced is very soluble in ethyl alcohol (1g/08 ml alcohol), while p-nitrobenzoic acid don't (1g/110ml alcohol). This way you can effetively separate the amino species from the nitro species that remains unreduced.

At the end this procedure will afford a much more pure benzocaine than you first esterificate and reduce it later, affording a mixture of ethyl p-nitrobenzoate and ethyl p-aminobenzoate, which is hard to separate.

And another thing: Nitroarenes with alkyl, halo, phenoxy, carboxilic or carbinol groups attached can be reduced easily not only with tin/SnCl2/HCl, but with a role of reducing agents like:

a) NiCl2/NaBH4,
b) Fe/HCl,
c) Tin/NH4Br,
d)Fe/acetic acid,
e)(NH4)2SO4/Mg or Al,
f)Fe/CaCl2,
g)Fe/NH4OH,
h)Na2S,
i)Zn/Acetic acid.

Look at the related papers below:

Attachment: nitrocompounds reductions to amines with Na2S.doc (82kB)
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Attachment: nitrocompounds reductions to amines with Zn and acetic acid.doc (109kB)
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Attachment: sodium borohydride-nicl2-reduction of nitro compounds.pdf (399kB)
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Attachment: nitrocompounds reductions to amines with Fe and HCl.doc (78kB)
This file has been downloaded 528 times

Attachment: nitrocompounds reductions to amines with FeSO4 and NH4OH.pdf (361kB)
This file has been downloaded 482 times

Attachment: reduction of nitrocompounds with Fe + CaCl2.pdf (99kB)
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Attachment: reduction of nitroarenes to anilines with tin and NH4Br.pdf (449kB)
This file has been downloaded 441 times

Attachment: nitrocompounds reductions to amines with Fe and acetic acid.doc (85kB)
This file has been downloaded 459 times

Attachment: reduction of nitrocompounds with Ammonium sulfate and Mg or Al.pdf (115kB)
This file has been downloaded 451 times

EDIT: Chemplayer did exactly the opposite I preach here, in his video on You Tube, and reduced the ethyl p-nitrobenzoate with sodium dithionite which, I think, it's the worst reducing agent you can use to reduce nitro-arenes, talking in therms of yield. I'm sure his product was highly contaminated with residual ethyl p-nitrobenzoate unreduced and I don't recommend anyway his method to sinthesize a reazonable pure benzocaine. You can see his video preparing benzocaine from p-nitrobenzoic acid at his channel at "BitChute Channel", cause now he was banished from you tube.

[Edited on 22-6-2018 by Chemi Pharma]

Metacelsus - 22-6-2018 at 10:46

I've done the reduction with Sn/HCl. It works reasonably well. I would recommend to reduce before esterification, so that you don't have to worry about ester hydrolysis.

DraconicAcid - 22-6-2018 at 10:56

Not sure if this is helpful, but Merck says that benzocaine is synthesized industrially by the reduction of ethyl nitrobenzoate with water and iron, and a small amount of acid.

Dullemarc - 22-6-2018 at 13:03

Quote: Originally posted by Chemi Pharma

Quote: Originally posted by CuReUS

do the esterification first,then reduce -https://pubs.acs.org/doi/10.1021/ja01691a031

First of all thank you, been reading and will do so tormorrow aswell.
Really interesting reading so far.

Have decided I will go with the reduce first, then esterificate.

And I did not know chemplayer have had to move sites. Thought the channel just died, but happy to see them still going strong. But ye their method seems a bit messy.

How should I reduce it, should I just add plenty of tin and HCL and reflux it for a long time since its granules and not powder.
Or will 10grams of Tin(II) chloride crystals (SnCl2·2H2O) in water do the trick?

[Edited on 22-6-2018 by Dullemarc]

Chemi Pharma - 22-6-2018 at 13:44

Quote: Originally posted by Dullemarc

How should I reduce it, should I just add plenty of tin and HCL and reflux it for a long time since its granules and not powder. Or will 10grams of Tin(II) chloride crystals (SnCl2·2H2O) in water do the trick?

@Dullemarc, you'd better follow the directions given by "Nile Red" in his You tube channel in the video where he reduces nitrobenzene to aniline with tin/HCl.

"Nile Red" ever have a nice work up and theoretical support for the reactions he gives away. I'm sure that after saw the video you'll be able to adaptate the procedure to p-nitrobenzoic acid. He covered in another video the esterification of PABA to it's ethyl ester as well.

Take a look on these videos and reply later:

https://www.youtube.com/watch?v=nKWOZajmAQo

https://www.youtube.com/watch?v=RiTN1EYB-rs

zed - 22-6-2018 at 14:08

Me, I'm lazy.

I like my chemistry, but Para Amino Benzoic Acid, is available as an OTC supplement.

https://purebulk.com/paba-powder-para-aminobenzoic-acid/

Inexpensive too.

UC235 - 22-6-2018 at 15:12

I'd just buy the PABA if it were me. Consider Thiourea dioxide as a reducing agent. It's most active in alkaline solutions and your acid will be soluble as the sodium salt, making for an easy homogenous reduction.

Ammonia is also a suitable base and was used successfully when I prepared luminol.

Attachment: thiox reduction nitroaromatics.pdf (140kB)
This file has been downloaded 442 times

CuReUS - 22-6-2018 at 23:26

Quote: Originally posted by Dullemarc

But what are the paper reason for doing the esterification first?

the nitro group being electron withdrawing would activate the COOH to undergo esterification faster,whereas the amino would do the exact opposite and might also end up getting alkylated

Quote: Originally posted by Chemi Pharma

first esterificate and reduce it later, affording a mixture of ethyl p-nitrobenzoate and ethyl p-aminobenzoate, which is hard to separate.

the paper I linked gives an yield of 98%.Also,the esterification and reduction happen in one pot

Quote: Originally posted by Metacelsus

so that you don't have to worry about ester hydrolysis.

that's why the jacs paper uses alcoholic HCl

[Edited on 23-6-2018 by CuReUS]

wildfyr - 23-6-2018 at 13:02

The Bechamp reduction (iron filings and HCl) is a very mild and less toxic nitro reduction technique than the tin based one. You also can't conceive of anything with easier to obtain starting materials. You can also get a lot of the metallic garbage out using a magnet.

Make sure you push it all the way or else there will be diazo compound impurities (highly colored). This is true for most nitro reductions.

I also agree, reduce then esterify. All but the most mild nitro reductions will probably hydrolyze the ester. I've played this game before trying to get selectivity for reducing nitro (over an aldehyde), and found myself using some pretty obscure mild nitro reduction procedures (to poor effect).

Its dead easy to esterify this with absolute alcohol and a drop of sulfuric acid stirring over night.

Tsjerk - 23-6-2018 at 23:57

How do you workup the ester? Distill of the ethanol and dilute the ester in any non-polar and wash with carbonate?

CuReUS - 24-6-2018 at 00:32

the bechamp reaction is not as easy as it seems-http://www.sciencemadness.org/talk/viewthread.php?tid=63564#...
http://www.sciencemadness.org/talk/viewthread.php?tid=462&am...

Quote:

All but the most mild nitro reductions will probably hydrolyze the ester.

how does it matter if the reducing agent is strong or weak ?what matters is whether there is water or not.
NO water=NO "hydro"lysis

Quote:

I've played this game before trying to get selectivity for reducing nitro (over an aldehyde), and found myself using some pretty obscure mild nitro reduction procedures (to poor effect).

which reducing agent did you use? and on what substrate? because good ol dithionite can do the job-https://www.sciencedirect.com/science/article/pii/S004040390...
another way using a little obscure reagent-http://pubs.rsc.org/-/content/articlelanding/2014/gc/c3gc420...
using bechamp-pubs.acs.org/doi/abs/10.1021/jm020235g

Quote: Originally posted by Tsjerk

How do you workup the ester? Distill of the ethanol and dilute the ester in any non-polar and wash with carbonate?

you don't need to,according to the paper I linked above,because the esterification followed by reduction happens in one pot

[Edited on 24-6-2018 by CuReUS]