Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: asdfTT123 on April 18, 2013, 06:30:33 PM
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Hi all,
I'm doing some synthesis in my laboratory for a research project but I'm the only one here with experience and I don't have much - only a bachelors of chemistry. I wish to convert this compound (5-Aminonicotinic acid) to the methyl or ethyl ester form (either will do). The compound is as follows:
(https://www.chemicalforums.com/proxy.php?request=http%3A%2F%2Fwww.chemicalbook.com%2FCAS%2FGIF%2F24242-19-1.gif&hash=1fd0fa52896ef0eca9d8ddbfd047d18f9b3ff6bf)
I have two methods of going about this reaction. The first one was suggested by a chemist in another lab:
1. Add 1:3 equivalence ratio of 5-aminonicotinic acid to thionyl chloride (SOCl2) in an excess of methanol (to form methyl ester). First, add SOCl2 dropwise to chilled 5-aminonicotinic acid in methanol in an ice water bath with drying tube (anhydrous). Allow reaction to stir for 30 minutes on ice and then gradually bring up to room temperature. Then, reflux overnight for about 16 hours under anhydrous conditions. Rotovap away methanol and then dissolve remaining in water and 1 N NaOH (about 50 mL) and verify the pH to be between 7-8. Next, extract with 3x 50 mL ethyl acetate. Wash EtOAc with brine, dry with sodium sulfate, filter, and then concentrate again to obtain final product.
I did this the other day and found that I ended up with no product in my final ethyl acetate. I find that the starting material (5-aminonicotinic acid) has a very difficult time dissolving in methanol. It's not until I add the thionyl chloride that the compound dissolves slightly. After refluxing for about an hour, the compound should fully dissolve. I try to run a TLC plate with both methanol/dichloromethane or ethyl acetate/hexanes but I always get a blotched TLC for some reason (streaks). Because of my solubility issues I'm unable to run a TLC of the starting material either because I have a hard time getting it to dissolve in anything (tried water, dichloromethane, methanol, ethanol, ethyl acetate, etc). I'm surely left with a compound after I concentrate the initial methanol away but it will not extract into ethyl acetate even if the pH is neutral. Any ideas?
The following method is listed in a protocol in a publication:
2. Add 5.0 g of 5-aminonicotinic acid into 200 mL of ethanol and 40 mL of concentrated HCl. Reflux for 36 hours while monitoring reaction with TLC. Concentrate under reduced pressure upon completion and then dissolve remaining residue with distilled water and neutralize with 1 N NaOH. Extract the aqueous layer with 5x EtOAc (3x 50 mL), try with sodium sulfate, filter, and concentrate to obtain a white crystalline solid.
I'm currently following this protocol but I find that the TLC is very difficult to run under any solvent system and the reaction is proceeding very slowly (due to this reaction being in equilibrium).
Does anyone have any suggestions about how I can form the ester of the above compound? I'm open to suggestions in regards to troubleshooting. Thanks!
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Forum rules no duplicate posts
so I deleted the other
you can PM me if you have questions about rules
hope you get some help here
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My apologies! Sorry I overlooked them
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Why not suspend your compound in thionyl chloride and heat it to reflux. As the acid chloride forms it should dissolve.
If this is the case keep heating until it has all dissolved. Evaproate the remaining thionyl chloride and dissolve the residue in methanol or ethanol. Stir it overnight, then add some solid bicarbonate and stir, filter wash the solid with methanol then evaporate the combined filtrates. Don't extract it, if you have to use dichloromethane.
Run an H-NMR of your product.
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Thanks for the reply. So to clarify, just use thionyl chloride as the solvent in large excess? How would I evaporate the thionyl chloride away after formation of the acyl chloride? Do I simply rotovap it away? After the excess thionyl chloride is gone, will the acyl chloride precipitate out as a solid?
What is the purpose of the bicarbonate? Just to neutralize the acid? Also, why is using dichloromethane an issue?
Also, how safe is it to use thionyl chloride in great excess and is working directly with the acyl chloride an issue?
Thanks for explaining...been awhile since I did any organic synthesis.
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Also for the second protocol I listed, is it better to use sulfuric acid (concentrated) instead of concentrated HCl? Anybody have any idea why the group published their protocol using HCl instead of sulfuric acid catalyst?
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Just use the thionyl chloride as a solvent.
Remove the excess on the rota. vap. I have no ides if your acid chloride is a solid or not.
The bicarbonate is to remove and residual acid which may be present.
Thionyl chloride should be used in a fume hood, destroy any excesses with propanol or similar.
No issues with the acid chloride, just keep it away from water.
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Also for the second protocol I listed, is it better to use sulfuric acid (concentrated) instead of concentrated HCl? Anybody have any idea why the group published their protocol using HCl instead of sulfuric acid catalyst?
Well you can't reflux conc. (96%) sulphuric acid. But this may be the better reaction, you can do it at lower temperatures.
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Is the aqueous HCl procedure the only lit method? I would have expected that using gaseous HCl plus methanol would have been better. Did the authors indicate why aqueous HCl was used?
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We have some experience with turning nicotinic acid derivatives into amides in my lab, but the amino group would probably mess up our typical procedure, which is to make the 4-nitrophenylester and displace it with the nucleophile of choice.
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Also for the second protocol I listed, is it better to use sulfuric acid (concentrated) instead of concentrated HCl? Anybody have any idea why the group published their protocol using HCl instead of sulfuric acid catalyst?
Well you can't reflux conc. (96%) sulphuric acid. But this may be the better reaction, you can do it at lower temperatures.
I'm wondering why you cannot reflux sulfuric acid? I remember doing a synthesis of isopentyl alcohol via fischer esterification many years ago and we refluxed a mixture of isopentyl alcohol/acetic acid and a small catalytic amount of sulfuric acid (~ 1 mL) just fine.
I was thinking of taking my current reaction with the HCl catalyst, rotovaping away all of the EtOH and water and then adding back fresh EtOH + catalytic sulfuric acid and refluxing a few more hours to improve yield.
Bad idea?
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Is the aqueous HCl procedure the only lit method? I would have expected that using gaseous HCl plus methanol would have been better. Did the authors indicate why aqueous HCl was used?
Yep, it was the only one listed in lit and there was no explanation why aqueous HCl was used. Nevertheless, I only have aqueous (12.1 N) HCl in my lab. :P
Also, I'm unsure why the lit had us use EtOH instead of MeOH. Because later in the synthesis of my desired compound, the esterification is simply used as a protecting group. I would have thought that methoxide is a better protecing group than ethoxide. Am I correct in this assumption?
Anyways, they reported an ~85% yield. I don't have any issues going about it this way as long as the purification of the ester from the carboxylic acid is straightforward.
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Just use the thionyl chloride as a solvent.
Remove the excess on the rota. vap. I have no ides if your acid chloride is a solid or not.
The bicarbonate is to remove and residual acid which may be present.
Thionyl chloride should be used in a fume hood, destroy any excesses with propanol or similar.
No issues with the acid chloride, just keep it away from water.
Alright, I will give this a try if the acid catalyzed fischer esterification fails. Do you mean to destroy the excess SOCl2 collected via rotovap with propanol? I can't simply discard it through my halogenated waste jug?
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We have some experience with turning nicotinic acid derivatives into amides in my lab, but the amino group would probably mess up our typical procedure, which is to make the 4-nitrophenylester and displace it with the nucleophile of choice.
Our ultimate goal is to simply convert the amino group into an azide group for use as a crosslinking reagent. But in order to do this, we need to protect the acid group with an ester and then regenerate the acid after the azido has been added.
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Alright, I will give this a try if the acid catalyzed fischer esterification fails. Do you mean to destroy the excess SOCl2 collected via rotovap with propanol? I can't simply discard it through my halogenated waste jug?
There are several good responses on here - some active-ester routes, some Fischer esterification. I just wanted to say, FOR THE LOVE OF GOD DO NOT DO THIS. You will cause a lab disaster.
To dispose of excess SOCl2, slowly drip it into aqueous base in a FUME HOOD from a dropping funnel or similar.
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Well you can't reflux conc. (96%) sulphuric acid. But this may be the better reaction, you can do it at lower temperatures.
[/quote]
I'm wondering why you cannot reflux sulfuric acid? I remember doing a synthesis of isopentyl alcohol via fischer esterification many years ago and we refluxed a mixture of isopentyl alcohol/acetic acid and a small catalytic amount of sulfuric acid (~ 1 mL) just fine.
Bad idea?
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Well 1 mL of conc. sulphuric acid is hardly refluxing sulphuric acid!
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Alright, I will give this a try if the acid catalyzed fischer esterification fails. Do you mean to destroy the excess SOCl2 collected via rotovap with propanol? I can't simply discard it through my halogenated waste jug?
There are several good responses on here - some active-ester routes, some Fischer esterification. I just wanted to say, FOR THE LOVE OF GOD DO NOT DO THIS. You will cause a lab disaster.
To dispose of excess SOCl2, slowly drip it into aqueous base in a FUME HOOD from a dropping funnel or similar.
Can you reiterate what I should not do and why that is? Sorry, im a bit confused as I stated two things in the quote that you posted.
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Sorry for the barrage of posts guys, but I'm really trying to figure this out before I leave lab this weekend.
I checked the TLC of the HCl catalyzed fischer esterification I have going on. Dipped a little straight out of the reaction and ran it on 4:1 EtOAC:Hexanes. The TLC streaked really badly but I saw basically two spots. The higher one, which I presume is the ester product is still lighter than the bottom spot. The bottom spot is at the starting point of the TLC and streaks upwards about 1/4th of the plate. Why is the plate streaking? I'm spotting a very minimal amount.
Anyways, the TLC only looks slightly better than the one I ran yesterday before I left lab (i.e. the top spot is a little darker) and I doubt refluxing over the weekend will do much to improve my yield. So I was thinking of just rotovapping away the solvent and replacing with fresh anhydrous 200 proof EtOH and adding a catalytic (4 mL) of sulfuric acid and then refluxing.
Thoughts?
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Perhaps you should change your TLC solvent to a DCM/Methanol mixture, say 5% MeOH.
If the reaction is working, albeit slowly, just leave it refluxing over the weekend, if you are allowed to to that.
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Sorry, I meant that under no circumstances should you place UNREACTED thionyl chloride in the waste. It will break down to SO2 and HCl, probably bursting or geysering the container, and you will have the worst mess ever on your hands even if no one is injured.
I agree with your idea to rotovap it down, then refill with H2SO4 (a good dehydrating acid) and more absolute alcohol. Make sure your absolute is fresh and/or stored over sieves. You are basically describing a crude replacement for the Dean-Stark trap. (You don't have one of those handy, do you?)
The use of an alcohol to quench the excess thionyl chloride is okay too. I don't recall the precise procedure we used for this, so I refrained from mentioning it.
I agree with switching to a chloroform/MeOH or DCM/MeOH TLC solvent. You are thoroughly drying the TLC plates before running them, right?
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Perhaps you should change your TLC solvent to a DCM/Methanol mixture, say 5% MeOH.
If the reaction is working, alhttp://www.chemicalforums.com/Smileys/classic/huh.gifbeit slowly, just leave it refluxing over the weekend, if you are allowed to to that.
Yes, it does appear to be slowly working but my impatient self is wondering if it's worth it to rotovap away the liquid and replace with anhydrous EtOH + catalytic sulfuric acid. I suppose just check the progress on monday?
Also, I just tried running the TLC with DCM and methanol and although it still streaks, it streaks much less, thanks. From the TLC, the reaction is still less than 50% to completion.
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Sorry, I meant that under no circumstances should you place UNREACTED thionyl chloride in the waste. It will break down to SO2 and HCl, probably bursting or geysering the container, and you will have the worst mess ever on your hands even if no one is injured.
I agree with your idea to rotovap it down, then refill with H2SO4 (a good dehydrating acid) and more absolute alcohol. Make sure your absolute is fresh and/or stored over sieves. You are basically describing a crude replacement for the Dean-Stark trap. (You don't have one of those handy, do you?)
The use of an alcohol to quench the excess thionyl chloride is okay too. I don't recall the precise procedure we used for this, so I refrained from mentioning it.
I agree with switching to a chloroform/MeOH or DCM/MeOH TLC solvent. You are thoroughly drying the TLC plates before running them, right?
Thanks again your your help and the tip with the thionyl chloride - I'll def keep in mind if I need to use it again.
Yeah, our lab is very basic...I'm the only one here with any organic synthesis experience (but not much) so we don't have a Dean-Stark setup. I bought the very basic equipment to do some simple synthesis.
Yep, I'm trying to thoroughly dry the TLC plate before running it. I will try using a heat gun to dry more thoroughly if needed.
I'm thinking if I don't see much more progress this afternoon I'll rotovap and replace with anhydrous/absolute EtOH + sulfuric acid. About how much sulfuric acid do you think I may need if the reaction volume is ~100 mL of EtOH?
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Although I like the idea of using conc sulfuric, unless the literature is is really old or from some obscure laboratory, the 85% yield may reflect some special requirement (or the slowness consistent with the unfavorable equilibrium created by the excess water).
Given the lit yield is 85%, I might add more anhydrous alcohol just to sway the equilibrium. I'd add a lot more.