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Author: Subject: Synthesis of Benzocaine
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[*] posted on 14-10-2014 at 20:57
Synthesis of Benzocaine


Purpose: To prepare benzocaine (a local anesthetic) from p-aminobenzoic acid and ethanol, via a Fischer esterification reaction.

Note: The ethanol used was denatured, and contained about 90% ethanol by weight.

Experimental:

1)10.02 g PABA (0.7306 moles) were placed into a 500 mL round-bottom flask.

2) About 75 mL of denatured ethanol were added, and the flask was swirled to dissolve the PABA. As with most Fischer esterifications, the alcohol is the excess reagent, and also serves as the solvent for the reaction.

3) Roughly 8 mL of ~92% sulfuric acid were added, which caused localized boiling and caused the formation of a white precipitate, which turned the contents of the flask into slurry.

4) A few more mL of denatured ethanol was used to remove sulfuric acid from the glass joint.

5) The solution was heated to reflux, but the precipitate did not dissolve. It remained thick and milky.

6)More ethanol was added through the condenser, which raised the volume of solution to ~1/3 of the flask. This caused the precipitate do dissolve.

7) Reflux was stopped after ~2 hours.

8) Saturated sodium carbonate solution was added, which raised the pH above 7. This caused the benzocaine to precipitate from the solution, and 2 layers formed, with the bottom one being aqueous.*

9) The benzocaine was isolated from the lower aqueous layer via vacuum filtration over porous glass, and was allowed to dry for about 24 hours.

10) The organic layer was crashed out into water, precipitating more benzocaine than the aqueous layer.

Conclusions:

The theoretical yield for this reaction was 12.04 grams of benzocaine, and 6.05 grams were obtained. This corresponds to a 50.1% yield. Verdict: Not that great...

*The product was isolated from the aqueous and the organic layers separately. The organic layer was found to contain about 5 times more product than the aqueous layer. This was caused by the “salting out” effect that the sodium carbonate had on the ethanol, and because the benzocaine was more soluble in the ethanol, most of it remained there.

Corrections to Procedure:

1) In the future, the sulfuric acid used will be concentrated to ~98% in order to exclude water from the reaction.

2) A pressure-equalizing addition funnel will be filled with dry magnesium sulfate, and will be placed between the condenser and the reaction vessel. This will serve to trap water produced during the reaction.

Sorry for lack of pictures.


[Edited on 15-10-2014 by Awesomeness]




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[*] posted on 14-10-2014 at 21:17


Excellent example of a classic lab, and good notes! I would love to see how the yields compare with your changes for next time.
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[*] posted on 14-10-2014 at 21:41


Notes:



Note: The ethanol used was denatured, and contained about 90% ethanol by weight. <-- what is the denaturant? methanol?

10.02 g PABA (0.7306 moles) <-- check your m.w. there. Also, what was the source of the material?

3) Roughly 8 mL of ~92% sulfuric acid were added, which caused localized boiling and caused the formation of a white precipitate, which turned the contents of the flask into slurry. <-- how many equivalents of acid is this? I would have used about 1.1 if I was just making the procedure up on the fly.

8) Saturated sodium carbonate solution was added, which raised the pH above 7. This caused the benzocaine to precipitate from the solution, and 2 layers formed, with the bottom one being aqueous.* <-- I would just have added enough water after this to form a single phase.

9) The benzocaine was isolated from the lower aqueous layer via vacuum filtration over porous glass, and was allowed to dry for about 24 hours. <-- was it rinsed with some distilled water or anything or allowed to dry out with sodium sulfate/carbonate/bicarbonate contamination?

2) A pressure-equalizing addition funnel will be filled with dry magnesium sulfate, and will be placed between the condenser and the reaction vessel. This will serve to trap water produced during the reaction. <-- worthless. If you got the idea from that video (that I somewhat regret putting up) about methyl benzoate, that won't do much to improve yield and will probably reduce it through physical entrainment. You're already using a large excess of alcohol to drive the equilibrium in favor of product.


Personal thoughts:

Most of your missing yield is probably unconverted PABA, rinsed away with the alkaline water at the end of the reaction as sodium p-aminobenzoate. By dropping the pH down to about ~4 with acetic/citric acid, you could recover the unconverted material.

Did you do any product characterization? even a m.p. would be appreciated.







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[*] posted on 14-10-2014 at 23:04


Did you not check for consumption of starting material by TLC (or other means)? How do you know that the reaction was "done" after 2 hr reflux (clearly it wasn't but you know what I'm getting at)?

UnintentionalChaos's comments are all valid, particularly the first two. You're not using enough acid as "catalyst": you're forming substoichiometric amine bisulfate (that white solid in suspension...), with no free sulfuric acid present to do the catalysis. This is probably the biggest reason for the low conversion.

One further comment: 10g is a pretty big first run. I would prefer to see a 1 g scale use test to work out the problems, then scale up when everything is satisfactory, otherwise you're burning materials. But I'm a PRD chemist, so I'll be biased on this one.
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[*] posted on 15-10-2014 at 01:12


On second look, there is definitely something interesting with your math as others have noted. While TLC may be optimal for determining reaction completeness, if you have a Dean Stark trap, a possible alternative may be using a hydrometer.
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[*] posted on 15-10-2014 at 03:47


Thanks for the input. To address some questions:

-0.7306 moles is incorrect. I meant to write 0.07306 moles.
-The denaturants in the ethanol were methanol and isopropanol. This would've caused some product loss, as not all of the PABA was converted to benzocaine specifically.
-The PABA was BulkSupplements brand, which claims to be 100% PABA.
-The point regarding the amine bisulfate is one I clearly didn't think of. The quantity of acid used was basically arbitrary.
-The product was washed with distilled water, and air was pulled through for several minutes to dry it slightly.
-UC, I'll be sure to watch that methyl benzoate video.

-Capillary tubes are in the mail. A melting point will be taken as soon as they arrive. I'll keep you posted.

Thanks again for the advice.


[Edited on 15-10-2014 by Awesomeness]




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[*] posted on 26-10-2014 at 08:50


This is a very popular prep on YouTube. I guess there may be some recreational usage avenues there somewhere (theoretically, I was told, but wouldn't, of course know anything).

A couple of things. Why doesn't anyone ever talk about continuing on and making benzocaine HCL?
Benzocaine as precipitated here by the carbonate will be almost completely insoluble in water, can be washed thoroughly with cold water and is mildly alkaline. Dissolved in ethanol, could a water-soluble salt be made by gassing with HCL or other procedure?

I believe some product may be lost by localized heating during the acid addition. I failed to exercise proper care opening the stopcock on my dropping funnel when I did this once. My yield was really crappy and there were some oxidation byproducts hanging around, darkening the color of some of the reactants which persisted through to the end product. It actually looked like pinkish smoke rising from the little stream of concentrated sulfuric acid. I was able to re-crystallize the product later which demonstrated the remarkable nature of our often overlooked and underappreciated most excellent solvent of all time: dihydrogen oxide! The fisherman's friend.
[IMG]http://i175.photobucket.com/albums/w128/Captain_Pike_photos/chemistry%20photos/benzocainerecrystallizationresizedtolessthanoneM.jpg [/IMG]

I WILL FIX THIS IMAGE BUSINESS (blush)

benzocaine recrystallization resized to less than one M.jpg - 115kB
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[*] posted on 4-11-2014 at 14:24


Gassing the product or a suspension of it would work. You could also had hydrochloric acid and evaporate it, but this may not be as time efficient.

Sorry for not reporting the MP of the product yet. I'm pretty busy right now, but that is on the way.




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[*] posted on 13-11-2014 at 15:40
local anesthetic


anesthetic is not analgesic, like menthol
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[*] posted on 15-11-2014 at 08:13


Quote: Originally posted by orville redenbacher  
anesthetic is not analgesic, like menthol

I'm not sure the relevance. Local anesthetics (an important specification) and analgesics do often have different mechanisms of action (sodium channel blockade versus typically mu opioid agonism).
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[*] posted on 22-11-2014 at 21:54


Finally, I got around to taking the melting point of the sample.

Melting range was 79-81 C, compared to 90 C literature value.

A recrystallization has not been done yet, so I will post the MP after recrystallization.




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[*] posted on 13-12-2014 at 13:08


Impure ethanol is so annoying. I've learned to just make my own with a package of turboyeast and a few potatoes.
Then a simple distillation along with anhydrous magnesium sulphate should solve the problem.
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[*] posted on 13-12-2014 at 13:33
Drying the alcohol


Did you dry your ethanol before this reaction was performed? It doesn't go well with water in the pot.
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[*] posted on 13-12-2014 at 13:48
Baby steps!


Quote: Originally posted by tshirtdr1  
Did you dry your ethanol before this reaction was performed? It doesn't go well with water in the pot.

Shan't make a difference when he's using denatured alcohol.
I believe conventional denatured alchol has it at around 95% pure with methanol and isopropanol impurities.

Remember - Before you clean your beer glass, remember to take the dead rat out first! ;)

[Edited on 13-12-2014 by dermolotov]
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[*] posted on 13-12-2014 at 15:23


The ethanol was not dried beforehand. Here in the US, the "denatured alcohol" that I can best find is about 50/50 methanol/ethanol.

So, you like a little ethanol with your denaturant, eh?




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[*] posted on 13-12-2014 at 15:31


Try looking for "Green Denatured Alcohol". The brand that I buy is Klean Strip and the MSDS claims to be at least 90% ethanol. It's generally sitting right next to the denatured alcohol.
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[*] posted on 13-12-2014 at 15:37


Quote: Originally posted by Awesomeness  
The ethanol was not dried beforehand. Here in the US, the "denatured alcohol" that I can best find is about 50/50 methanol/ethanol.

Again... It doesn't matter if it's dried when it's THAT contaminated. Remember: Don't clean the beer glass until you remove the dead rat!
90% is still pretty contaminated when you could just get everclear. Everclear just has some other sugars but mainly consists of ethanol and water (NO methanol due to the FDA's limits).

Perform a simple distillation of the ethanol?
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[*] posted on 13-12-2014 at 17:22


If it was Kleanstrip SLX denatured alcohol, there is also several percent of methyl isobutyl ketone present in the denatured alcohol.



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[*] posted on 14-12-2014 at 05:34


It DOES matter if it is dried. This is an esterification reaction. If if is not dried, you will revert to starting materials. If it IS dried, and the denaturant is another alcohol, then you will simply get impurities with esters of the other alcohols. Since you cannot test your product to see what you got, I suspect it was mostly PABA. Dry it over DRIED magnesium sulfate, distill onto sieves, or decant, then try again. I have actually done this reaction intentionally with different alcohols, which turned out not to be properly dried, and got nothing except for the absolute ethanol.

[Edited on 14-12-2014 by tshirtdr1]
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[*] posted on 14-12-2014 at 12:50


Quote: Originally posted by tshirtdr1  
If it IS dried, and the denaturant is another alcohol, then you will simply get impurities with esters of the other alcohols.

My problem is that you will get other impure esters which may affect the results moreso than the ambient humidity.
He quoted saying denatured ethanol is 50:50 with methanol. That is ludicrously impure.

Perhaps I should explain my regional metaphor: "Don't clean the cup before you remove the dead rat"
It'd be silly to remove a smaller impurity before the larger impurity. In this case, I am comparing the dead rat to other alcohols present besides ethanol and the small little scuff marks on the cup I am comparing to the water. Sure... you should clean the whole cup before serving again. But do what needs to be done first - remove other non-ethanol alcohol impurities first.
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[*] posted on 14-12-2014 at 13:10


Right. He should get a better alcohol source, then distill from magnesium sulfate to molecular sieves with a good fractionating column. You can even buy mouthwash at the dollar store that contains about 25% ethanol. Distill. Dry. Distill again.
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biggrin.gif posted on 14-12-2014 at 13:29
Agreement!


Quote: Originally posted by tshirtdr1  
Right. He should get a better alcohol source, then distill from magnesium sulfate to molecular sieves with a good fractionating column. You can even buy mouthwash at the dollar store that contains about 25% ethanol. Distill. Dry. Distill again.

Everclear works as well:
http://en.wikipedia.org/wiki/Everclear_(alcohol)

90-95% in most formats I've seen. Distill with Magnesium Sulphate or Calcium Chloride. Once should be enough. I feel like the molecular sieve would be overkill
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[*] posted on 14-12-2014 at 13:52


This may be of interest:
<iframe sandbox width="560" height="315" src="//www.youtube.com/embed/ZMxT8ra1hwk" frameborder="0" allowfullscreen></iframe>
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[*] posted on 21-12-2014 at 18:23


Look in some organic lab manuals. It seems benzocaine was a not uncommon 1st year organic lab exercise. It's always made by esterification of PABA with ethanol catalyzed by H2SO4. The more water in the alcohol the more H2SO4 you need. It's best to start with absolute ethanol and if you can't get it try to get specially denatured ethanol that doesn't have another alcohol in it. Dehydrating 95% EtOH is IMHO trickier by far than making benzocaine.

[Edited on 22-12-2014 by chemrox]




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[*] posted on 22-12-2014 at 05:00


Quote: Originally posted by CaptainPike  
This is a very popular prep on YouTube. I guess there may be some recreational usage avenues there somewhere (theoretically, I was told, but wouldn't, of course know anything).
It is used to cut cocaine. One can better mimic the nasal effects of cocaine using benzocaine as an adulterant instead of something like baking soda, to increase profits. At one of my early jobs, I had the unfortunate experience of being solicited for benzocaine manufacture by a co-worker who liked to involve himself in such activities. I was young, but luckily had the sense to refuse. Some friends of mine say that he was recently incarcerated.



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