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Author: Subject: Getting Discouraged With Organic Chemistry As A Hobby. Failed Steglich Esterification
Cou
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[*] posted on 16-7-2020 at 22:20
Getting Discouraged With Organic Chemistry As A Hobby. Failed Steglich Esterification


as far as i know, this is the first attempt of an SM user to do the steglich esterification at home.

https://www.organic-chemistry.org/abstracts/literature/931.s...

http://orgsyn.org/demo.aspx?prep=CV7P0093

i tried to make tert-butyl butyrate

to a flask cooled to 0 C, I added 50 mL dichloromethane, 0.05 mol butyric acid, 0.003 mol DMAP (6 mol %), 0.15 mol tert-butyl alcohol, and after making sure the mixture was at 0 C, I slowly added about 0.06 mol n,n-dicyclohexylcarbodiimide over 5 minutes. After allowing to warm to room temp, the mixture was already opaque with white precipitate.

After 3 hours I gravity filtered to remove dicyclohexylurea precipitate, then washed the filtrate with 25 mL of 0.5 N HCl (might not be enough to neutralize all the bases) and 25 mL of saturated sodium bicarbonate solution. I dried with MgSO4 and filtered once more into a distilling flask. I started distilling and the result here was saddening. tert-butyl butyrate should boil between 135-137 C. After all the DCM distilled over, a small amount of liquid was distilling around 70-100 C, which I collected just in case. i didn't get a new liquid distilling until some random burnt-smelling crap come over between 150 C and 180 C and made my eyes burn if I got too close. It separated into two layers in the beaker. I stopped distilling when the crap coming over was 180 C, and the boiling flask was left with some dark yellow viscous liquid. Whatever all this crap is, maybe an N-acylurea side product, it definitely isn't just the ester, but I definitely smell something fruity that smells like an ester. It has a pleasant grape kind of smell that overpowers everything else

I suspect maybe I didn't wash with enough HCl, so there was still a lot of excess DCC AND DMAP remaining. Perhaps i will try this again with a larger acid wash. But this is the volume of dilute acid wash that was used in the orgsyn procedure. I don't know why they used such a small volume for washing.

another possible mistake is distilling at high temperature instead of reduced pressure, which would cause all sorts of side reactions. from now on I would evap the DCM with a fan , then filter any solids, before proceeding to vacuum distillation.

When adding the DCC in a salt water bath, monitor the reaction temperature closely to make sure it doesn't get too far hot from 0 C. Allow to cool before adding more. I'm not sure why this is necessary, maybe it avoids formation of side products

I was trying to make my next video about the steglich esterification. I got some footage of every step if you want to see it.

The chemicals for this reaction are a little pricey, so it's sad to mess up. But I still have a good amount of each chemical left, and lots of money saved up if I need to re-up on DCM and DCC

Do you guys have any input? I hope I can get this right when I try it again.

[Edited on 7-17-2020 by Cou]




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B(a)P
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[*] posted on 16-7-2020 at 23:26


Nice write up, thanks for sharing. Unfortunately this is way outside my area of knowledge, but i am sure others will assist this being the forum that it is.
Don't be discouraged. You will always learn way more from your failures than your successes.
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[*] posted on 17-7-2020 at 08:49


I agree with B(a)P, think of all the failures of yesteryear how many Chemists tried and tried before something succeeded. Just because it in a paper doesn't mean it is fail safe, many chemists will do a documented procedure and have it fail. There are many factors that lead to a failed procedure.

I am still a fairly new chemist so I do not have any insight to your reaction but I can make a suggestion that helps me when I get frustrated with a reaction. Often I move to another reaction, usually a fun one with a rewarding outcome, it takes my mind off the failure and makes me happy about the success.

Don't let a failure ruin your hobby and your career, failure and the want of success is what propels chemistry forward.

Syn
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[*] posted on 17-7-2020 at 09:11


Quote: Originally posted by Cou  

to a flask cooled to 0 C, I added 50 mL dichloromethane, 0.05 mol butyric acid, 0.003 mol DMAP (6 mol %), 0.15 mol tert-butyl alcohol, and after making sure the mixture was at 0 C, I slowly added about 0.06 mol n,n-dicyclohexylcarbodiimide over 5 minutes. After allowing to warm to room temp, the mixture was already opaque with white precipitate.

The procedure mentions monoethyl fumarate, stirring for three hours and a dark-brown mixture




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[*] posted on 17-7-2020 at 09:42


You may have decomposed your product by heating it up too much. T-butyl esters can easily undergo elimination reactions when heated, which in your case would form isobutylene and butyric acid. You should consider distilling under vacuum instead.



As below, so above.
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[*] posted on 17-7-2020 at 11:16


get a vacuum pump Cou....



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[*] posted on 17-7-2020 at 12:16


I have a vacuum pump, ready to try this reaction again after stocking up on a few pounds of dry ice for vacuum trap and 0 C reaction flask bath (salt water bath did not cool effectively enough)

Also you should submerge the receiving flask in a cold bath in order to prevent distilllate from boiling again at reduced pressure.

[Edited on 7-17-2020 by Cou]




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[*] posted on 17-7-2020 at 16:23


Are you monitoring your reaction at all? I did this reaction extensively in undergrad making NHP-esters using DIC instead of DCC (just easier to measure since DCC melts and is PITA) and it takes a while... I would usually leave it overnight (per a Baran publication), which could be beneficial since your alcohol is so bulky. Also, make sure your DCM is dry (I used to just dry over mol. sieves.).

I had quick look on reaxys for the synthesis of this ester and couldn't find anything using the Steglich esterification (doesn't mean it won't work but could be telling)... I did find an interesting method from the Baran lab (picture attached). I also found an even simpler procedure (SYNTHETIC COMMUNICATIONS,26(14), 2715-2721 (1996)) but it looks too good to be true. They claim 70% yield for your desired product.

By the way, I believe there is a reagent that is used to make t-Bu esters called 2-Tert-Butyl-1,3-dicyclohexylisourea which I think is an intermediate in the Steglich esterification. I've never used it but I have seen it a lot in the literature. I may have a review article on it if you're interested (you could make it w/ you current inventory but it could be a bit overkill, but definitely good for learning more chemistry).

It might be worth exploring simpler, cheaper methods before you use more expensive reagents.



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[*] posted on 17-7-2020 at 18:18


I prefer methods that work for all tertiary alcohols (i.e. can be extended to tert-amyl alcohol) and not just t-BuOH, since I'm building an assortment of esters


What strikes me difficult about the steglich esterification is that DCC is difficult to remove from solution in DCM. Theres no easy way to quench it. I think washing with a good amount of aqueous acid might protonate DCC so that it migrates into aqueous layer as an imide salt, but not sure. A scientist is supposed to try to answer questions themselves. I would test it out by dissolving some DCC in DCM, washing with acid, chilling w/ dry ice to precipitate all dicyclohexylurea, and evaporating the DCM to check if anything is remaining.

If the boiling point of the ester is a good amount lower or higher than DCC, then I dont think it matters, the ester will separate during vacuum distillation anyway. But the BP of tert-butyl butyrate is close to DCC .

Another option would be to use DCC as the limiting reagent so it's all consumed. E.g. 1 molar equivalent butyric acid and 0.9 equiv DCC. The acid is easily removed with a sodium carbonate wqsh.

If i give up on the steglich esterification, I will look into another method of carboxylic acid activation I saw in "azolides in biochemistry and organic chemistry" when I get home soon.




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[*] posted on 17-7-2020 at 18:25


Quote:
After allowing to warm to room temp, the mixture was already opaque with white precipitate.

This makes it sound like your DCM wasn't completely dry. Even a little water will destroy DCC.

Also, you did stir it the whole time, correct? Orgsyn doesn't mention a warming period; "stirred at room temp for 3 hr" probably means "stirred under thermal inertia for 3 hr after removing from the ice bath" not "warmed to room temp and then stirred for 3 hr".

[Edited on 18-7-2020 by clearly_not_atara]




[Edited on 04-20-1969 by clearly_not_atara]
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[*] posted on 17-7-2020 at 18:52


It's Methylene Chloride (Dichloromethane), ACS, 99.5+%



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[*] posted on 17-7-2020 at 18:55


Quote: Originally posted by Cou  
I prefer methods that work for all tertiary alcohols (i.e. can be extended to tert-amyl alcohol) and not just t-BuOH, since I'm building an assortment of esters


What strikes me difficult about the steglich esterification is that DCC is difficult to remove from solution in DCM. Theres no easy way to quench it. I think washing with a good amount of aqueous acid might protonate DCC so that it migrates into aqueous layer as an imide salt, but not sure. A scientist is supposed to try to answer questions themselves. I would test it out by dissolving some DCC in DCM, washing with acid, chilling w/ dry ice to precipitate all dicyclohexylurea, and evaporating the DCM to check if anything is remaining.

If the boiling point of the ester is a good amount lower or higher than DCC, then I dont think it matters, the ester will separate during vacuum distillation anyway. But the BP of tert-butyl butyrate is close to DCC .

Another option would be to use DCC as the limiting reagent so it's all consumed. E.g. 1 molar equivalent butyric acid and 0.9 equiv DCC. The acid is easily removed with a sodium carbonate wqsh.

If i give up on the steglich esterification, I will look into another method of carboxylic acid activation I saw in "azolides in biochemistry and organic chemistry" when I get home soon.


Cool, maybe you can answer some of our questions? people probably haven't tried this method at home cause you normally need column chromatography to separate the product from the urea by-products.

If you have access to DCC why don't you buy some oxalyl chloride and DMF to make acid chlorides? these will typically be way more effective (provided you keep everything relatively dry). Don't waste reagents re-inventing a work up procedure btw, just look at the supp-info of the method to see what others did...
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[*] posted on 17-7-2020 at 19:08


Quote: Originally posted by HeYBrO  
Quote: Originally posted by Cou  
I prefer methods that work for all tertiary alcohols (i.e. can be extended to tert-amyl alcohol) and not just t-BuOH, since I'm building an assortment of esters


What strikes me difficult about the steglich esterification is that DCC is difficult to remove from solution in DCM. Theres no easy way to quench it. I think washing with a good amount of aqueous acid might protonate DCC so that it migrates into aqueous layer as an imide salt, but not sure. A scientist is supposed to try to answer questions themselves. I would test it out by dissolving some DCC in DCM, washing with acid, chilling w/ dry ice to precipitate all dicyclohexylurea, and evaporating the DCM to check if anything is remaining.

If the boiling point of the ester is a good amount lower or higher than DCC, then I dont think it matters, the ester will separate during vacuum distillation anyway. But the BP of tert-butyl butyrate is close to DCC .

Another option would be to use DCC as the limiting reagent so it's all consumed. E.g. 1 molar equivalent butyric acid and 0.9 equiv DCC. The acid is easily removed with a sodium carbonate wqsh.

If i give up on the steglich esterification, I will look into another method of carboxylic acid activation I saw in "azolides in biochemistry and organic chemistry" when I get home soon.


If you have access to DCC why don't you buy some oxalyl chloride and DMF to make acid chlorides?


considering this option.




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[*] posted on 17-7-2020 at 21:08


I have run many Steglich esterifications using both DCC and carbonyldiimidazole (CDI) mostly to make t-butyl esters. Your problem is probably in the work-up. The wash with HCl likely cleaved your ester to a large extent if the wash was not done cold. Some t-butyl esters are very sensitive to acid and enough HCl may have been extracted into your DCM layer to do the deed. The cleavage can only take a few minutes of contact time. I always used ice cold citric acid (preferred) or dilute sodium bisulfate to work up these reactions involving t-butyl esters. The only base you are trying to remove is DMAP which is not present in any significant amount so not much acid is required.

The esterification reaction needs to be run chilled to avoid rearrangement of the O-acylurea intermediate to the N-acylurea which is unreactive. It is good to let the reaction go for an hour or two in the cold just to make sure it goes to completion. There is no harm in letting it go as long as it is kept chilled.

By the way, even though I have DCC in my home lab, I rarely use it. DCC is a wicked skin sensitizer and once you have been sensitized you cannot get close to the stuff again without breaking out in a rash. It should only be used with protective equipment and in a well ventilated area. I prefer the use of CDI/DMAP to make esters as CDI is easy to weigh out and the by-product (imidazole) is water soluble. See Staab's book on azolides for details.

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[*] posted on 18-7-2020 at 20:38


U guys have given good advice. I won't use EDC because it costs a fortune. I'm considering either using PCl5 or (COCl)2/DMF to convert carboxylic acids to acid chlorides, or using CDI.

I'm leaning towards the first option b/c it's commonly shown in undergrad organic chemistry textbooks. Occam's razor.

[Edited on 7-19-2020 by Cou]




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[*] posted on 18-7-2020 at 23:32


Come on dude, I failed so many syntheses at the first try, in special when done at home, at work not so much.
At home, you're your own supervisor, so it is understandable to expect it to turn out well since this is how we like to think of us, as being more capable than we are.
But take this, and use it well: be glad that you had a bad experience, those are the greatest learning opportunities of them all.
Now you know details you would have never even thought of to consider.
This is much more valuable than your desired ester is, actually I would even say, this is an invaluable outcome to learn of.

Good luck for the experiment!

I have to say, I read your endeaveours with so much joy, most threads here don't reach that level of excitement for me.
You slowly but steadily are becoming a real capable chemist and it just warms my heart to watch this, with every time you post something of your practice I am astonished and satisfied.
You are one of the sole reasons I am absolutely certain home chemistry is not dead at all, but also will never die either!
Thank you for that Cou, you turned out more than pretty great over time :)
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[*] posted on 19-7-2020 at 01:08


I'm usually quite surprised when a synthesis works the first time or I don't see any points which I could have done differently to get a higher yield. It happens, bu not often.
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[*] posted on 19-7-2020 at 06:52


Quote:
I have to say, I read your endeaveours with so much joy, most threads here don't reach that level of excitement for me.
You slowly but steadily are becoming a real capable chemist and it just warms my heart to watch this, with every time you post something of your practice I am astonished and satisfied.
You are one of the sole reasons I am absolutely certain home chemistry is not dead at all, but also will never die either!
Thank you for that Cou, you turned out more than pretty great over time


Indeed.

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[*] posted on 20-7-2020 at 19:13


Cou,

Attached is a paper which may be quite useful to you. It uses only easily available and relatively benign reagents to prepare t-butyl esters. The article has been cited numerous times and it appears that the method is quite general. Many examples exist in the citations beyond the type exemplified in the paper.

By the way I found this article and its citations with a relatively simple google/google scholar search.

There are also acid catalyzed reactions of t-butyl methyl ether to obtain t-butyl esters of carboxylic acids. If you are interested you can find these with a google search.

Don't get discouraged - after all it is an experimental science.

AvB

Attachment: t-Butyl Esters and Ethers using MgSO4 + H2SO4 wright1997.pdf (219kB)
This file has been downloaded 40 times

[Edited on 21-7-2020 by AvBaeyer]
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[*] posted on 9-8-2020 at 19:39


Most experiments fail. It's humbling.
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