Sciencemadness Discussion Board - Synthesis of Benzocaine

Synthesis of Benzocaine

subsecret - 14-10-2014 at 20:57

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]

Chemosynthesis - 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.

UnintentionalChaos - 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.

DJF90 - 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.

Chemosynthesis - 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.

subsecret - 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]

CaptainPike - 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

subsecret - 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.

local anesthetic

orville redenbacher - 13-11-2014 at 15:40

anesthetic is not analgesic, like menthol

Chemosynthesis - 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).

subsecret - 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.

dermolotov - 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.

Drying the alcohol

tshirtdr1 - 13-12-2014 at 13:33

Did you dry your ethanol before this reaction was performed? It doesn't go well with water in the pot.

Baby steps!

dermolotov - 13-12-2014 at 13:48

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]

subsecret - 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?

gdflp - 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.

dermolotov - 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?

UnintentionalChaos - 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.

tshirtdr1 - 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]

dermolotov - 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.

tshirtdr1 - 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.

Agreement!

dermolotov - 14-12-2014 at 13:29

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

forgotpassword - 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>

chemrox - 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]

Praxichys - 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.

dermolotov - 26-12-2014 at 22:23

Quote: Originally posted by Praxichys

That would be quite the moral quarrel... My logic behind that would be that it's not illegal by any means and I could get it purer than any person they would get in contact with. I would probably do it just because I enjoy the concept of being paid for manufacturing common chemicals.

Un-irregardless, it is indeed used to cut cocaine. It's sold only as a topical gel (because nothing ever is just pure powder) and so it's not as easy to get it in powder form.
I remember that corn starch was another tell that your dealer is good. It protects some nasal mucus membranes that cocaine seeks to destroy.

subsecret - 26-12-2014 at 23:41

The amount of benzocaine needed to get high is lethal, so it cannot be used on its own for that sort of recreation. Being able to poke pins into your hand is fun though, but only when you can't feel the pain.

IIRC, it's illegal (in many parts) to claim to sell drugs. For instance, selling powdered sugar as if it's cocaine.

But heck, you could sell as much benzocaine as you wanted, as it's not illegal.

[Edited on 27-12-2014 by Awesomeness]

Praxichys - 27-12-2014 at 09:13

@ Awesomeness -

That would constitute aiding and abetting the manufacture and distribution of an illegal substance, and is punishable just as harshly as the crime itself.

subsecret - 27-12-2014 at 09:54

Wait, selling benzocaine, or selling materials as if they were illegal substances?

dermolotov - 27-12-2014 at 10:06

Quote: Originally posted by Praxichys

@ Awesomeness -

That would constitute aiding and abetting the manufacture and distribution of an illegal substance, and is punishable just as harshly as the crime itself.

Huh? If I were to synthesise and distribute benzocaine on craigslist by the kilo, surely there's no law against that?

Isn't that the essence of debate right now?

Little_Ghost_again - 27-12-2014 at 10:08

People use it or teething powders to cut cocaine so they can get more money for less coke.
How do I know?
We have the police come and give drug lectures at school, I didnt know anything about drugs until they started doing this. Now I even have a pretty good idea how to grow a herbal plant that soothes the mind

subsecret - 27-12-2014 at 11:05

Sure, if you cut cocaine with it, but if it was benzocaine on its own, I don't see a problem.

It's an OTC product.

CaptainPike - 12-1-2015 at 04:49

… but seriously folks

No actual coke dealer would cut his product with benzocaine. Especially if it were powder he was dealing (water-soluble cocaine HCl) the benzocaine wouldn't even dissolve in water if the customer cooked it, and it would stay in one's nose like sawdust if one was a snorter of the drug.

I don't know how benzocaine might smoke (vaporize). I suppose if a dealer of crack or rock (freebase) figured out a way to mix his freebase with benzocaine, it might physically work. Interesting…

[Edited on 12-1-2015 by CaptainPike]

Haber - 14-1-2015 at 10:29

As a rule of thumb, never believe in drug information provided by the school.

OnT: Is PABA available in any otc product of some sort?
Would like to try this preparation, without going via the para-nitrotoluene route.

gdflp - 14-1-2015 at 10:33

PABA is used as a nutritional supplement, try looking for it in health food or vitamin stores. If not, look online, nearly every nutritional supplement retailer sells PABA reasonably cheaply.