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Author: Subject: Attempted synthesis of propyl 4 aminobenzoate
diggafromdover
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[*] posted on 17-4-2017 at 12:45
Attempted synthesis of propyl 4 aminobenzoate


Have not finished this one yet, but I thought I would give you all my lab notes and await your speculations.
The objective of the procedure was to synthesize propyl 4-aminobenzoate, which is an old-timey local anesthetic aka "Risocaine", via Fisher esterification from PABA and n-propanol using concentrated sulfuric acid as a catalyst.

I combined 13.7 g of PABA with 35 ml of n-propanol in a 250 ml round bottomed flask. I added a few grains of activated charcoal as boiling chips.

I then added 10 ml concentrated sulfuric acid in approximately 1 ml increments over several minutes. The flask warmed noticeably to the touch.

I swirled the flask gently to mix, but the contents remained heterogeneous.
After adding a 300 mm Liebig condenser in reflux position, I applied a small flame and noticed almost immediately a bark brown streak in the reaction mixture.

I paused the flame and ran in another 40 ml of n-propanol, swirling the mixture to better mix it. The mixture was then observed to be a light shade of purple.

I then resumed heating with a slightly higher flame and brought the mixture to reflux at the rate of several droplets per second. This continued for a hour with occasional swirling to clear unreacted PABA from the sidewalls of the flask.

The mixture was then allowed to cool somewhat and was added slowly to 250 ml of tap water with 35 g of sodium bicarbonate in a 500 ml round bottomed flask.

When the evolution of carbon dioxide ceased, then the PH was tested and found to be in the range of 8 to 9.

The product separated as follows. At the stop was an oily brown scummy layer, below was a cloudy light brown emulsified later and a denser brown emulsified layer. I placed this in a 1 liter seperatory funnel and left it overnight.

The next morning, I observed that the mixture had further separated. The middle layer now sat atop a heap of globules, which themselves sat on the denser lower layer.

The lower level was so dense as to clog the outlet of the seperatory funnel.

I added 50 ml of Kleen-Strip toluene to the seperatory funnel with the objective of breaking the emulsion, which then occurred.

I drained off and reserved the aqueous lower layer and stopped work with 3 cm or so of yellowish oily material dissolved in toluene. The look and smell of this material was similar to a 50 year old memory of nitrobenzene.

The question here is what happened? The intended product is a white powdery substance barely soluble in water with no perceptible aroma.
This is not what I have right now.




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Praxichys
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[*] posted on 18-4-2017 at 09:35


The brown goop suggests primarily that perhaps there was an impurity in your starting material that was affected by the sulfuric acid.

What is the source of your PABA? The stuff found in health food stores and inside gel caps have anticaking agents to keep the filling machines running smoothly. Did you recrystallize it before use?

I'm a little skeptical of your activated carbon boiling chips. They might also be the culprit for adding color to the solution. Substances adsorbed into activated carbon have their electron densities altered and can be susceptible to a variety of reactions. Try it with a couple of pieces of broken glass instead; it will eliminate catalytic side reactions as a variable, however improbable.

The emulsion is probably caused by a huge excess of n-propanol. Use as little as possible next time and be gentle with the heat until it all melts together. I suspect local overheating has also caused something of a problem, perhaps decarboxylating the PABA to aniline, leading to strange colors as tars form. Melting will happen more quickly and overheating mitigated somewhat if you charge the flask with the liquid ingredients first. However, I highly recommend using a boiling salt water bath, oil bath, mantle, or sand bath rather than a direct flame. Your reaction temp at reflux is only around 100C.

You can avoid the emulsion problem by switching from reflux to simple distillation at the end of the esterification and distilling off some of the extra propanol. The sulfuric acid will hang on to the water and keep the equilibrium from swinging back to the reactant side, and the elimination of propanol will save you headaches later.

You can save bicarbonate and further avoid an emulsion problem if you extract the acidic solution directly and then wash the extract in bicarbonate solution to remove residual p-aminobenzoic and sulfuric acid. I doubt bicarb is strong enough to break the ester, but try to minimize letting it sit with the product. Use a small amount of saturated bicarb solution to help push the nonpolar-ish compounds into the toluene layer. If it starts to look emulsion-like, chuck in a bunch of NaCl and shake like hell before you use the sep funnel, and do it the second you see two clean layers.

After that, if you're still getting a colored product, add some decolorizing charcoal and stir for about 15 minutes, then filter. Pull off the solvent and recrystallize the product, see what happens.

As for what you have right now, go ahead and pull the toluene off and try to recrystallize it to take out the color. It may be salvageable. Out of curiosity, why did you choose toluene and not something like diethyl ether? The lower the BP, the better off you will be when you go to remove the solvent at the final step. High-BP solvents can cause fogging and loss of product to decomp during solvent removal.

[Edited on 18-4-2017 by Praxichys]




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Metacelsus
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[*] posted on 18-4-2017 at 10:16


Also, that seems like a lot of sulfuric acid. Why did you use so much?



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Praxichys
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[*] posted on 18-4-2017 at 10:43


Typically these "one-pot" Fischers use a ton of sulfuric acid to compensate for the lack of a mechanism to remove water continuously. The yield is always much lower than a dean-stark setup but the reaction can be performed and satisfactory product obtained with a minimum of glass.



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diggafromdover
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[*] posted on 19-4-2017 at 04:57


Thanks a bunch everyone for the comments.

I bought a couple of pounds of PABA from a bulk supplement dealer.

Yeah, I overheated things. Next run will be much more gentle.

I used toluene because I had it. DCM or Ether would have been better.

I still have both extracts sitting in bottles. The aqueous is growing fine needle-like crystals. The toluene extract is awaiting distillation.

My next try is going to be a more gentle one pot extravaganza using less propanol and H2SO4. I am going to experiment with tapioca pearls or silica gel as an onboard dessicant.

If it works, I will have pain-killer and a pudding.





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[*] posted on 19-4-2017 at 07:34


@diggafromdover, working with flames and ether is a really bad idea considering the extreme flammability of ether. If you're heating too strong, a gas layer may form between your liquid and the glass with overheating as a result. Maybe indirect heating in a steam bath is what works. Working with a portable heating plate is safer than flame. Additionally, not sure if a cosolvent is really neccessary, but if reflux is the only condition you can achieve, maybe a low boiling solvent is indeed the best option.
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[*] posted on 19-4-2017 at 10:04


Wouldn't use a flame with ether, a warm thought can set it off. I was using it to reflux a propanol solution under a tall condenser.



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[*] posted on 27-6-2017 at 08:37
More data


What I thought was activated charcoal was actually Ferric Oxide (Sorb OO). The side reaction now makes sense, and looks more interesting than what I was originally attempting.

So the task has forked. Fork 1, the original synthesis. Fork2, what goes on between 4-Aminobenzoic acid and Ferric Oxide in a strongly acidic medium? What was that purple/brown coloration?

I am going to try a few permutations on a near micro scale - just looking to replicate the color change.

Filmatleven.







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[*] posted on 28-6-2017 at 06:20


my idea:
you should notice PABA has two function groups, amino and carboxylic acid groups .under your reaction condition, by-product, the amide from one PABA with another PABA would be formed. In fact, the chain could be longer, you will get polymer if reaction time long enough.

If you want to make the ester from PABA and propanol, better try thionyl chloride method.
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