Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on October 15, 2020, 05:09:33 PM
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doi:10.1016/j.bmc.2007.06.016
http://dx.doi.org/10.1016/j.ejmech.2014.05.014
We are attempting to acetylate a quinol bearing an aldehyde. The acetylation conditions that we are using come from two nearly identical procedures. Both use potassium carbonate, acetic anhydride, and are in diethyl ether. We are not see any reaction by TLC after about 90 minutes, whereas the papers we are following suggest that the reaction is finished in 2-3 hours. I was thinking of letting it run overnight. If that does not lead to a complete reaction, the only other thing that I can think of is to add a small amount of DMAP. I have not seen DMAP used as a catalyst in this sort of reaction in my searches so far, although I have seen it used in esterifications involving DCC, and I have seen it used stoichiometrically in one acetylation. Any ideas or thoughts about a good way to proceed?
EDT
We took one more time point, and there is still little evidence of a reaction. One supposes that the product will have a larger value of Rf than the reactant.
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All of the reagents except the potassium carbonate come from unopened containers. The solid settled less quickly this morning when I briefly discontinued stirring the reaction. Yet the TLC this morning gave only a hint of a product and mostly starting material. I wonder whether or not the K2CO3 should have been ground to make a finer powder. I am also thinking about checking the starting material by NMR. One other problem may be in discriminating between mono- and di-acetylation.
EDT
The only not-fresh reagent was potassium carbonate, and it is possible that water in this reagent was the problem.
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If the compound is identical with the one in the paper then maybe ground K2CO3 might be important. If not I wonder why this strange conditions are used, ether seems like a unusual solvent? Why not use 2eq. Ac2O+pyridine in DCM?
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Our substrate is strictly identical to the one in the two papers. I like the idea of grinding dry potassium carbonate, and I am concerned that the potassium carbonate we used might not have been dry. I have also heard that people sometimes substitute in cesium carbonate, but I am unsure whether or not this would be a good idea.
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I wonder if maybe one of the OH-groups is hydrogenbonded to the aldehyde carbonyl? This would explain why K2CO3 is used?
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I'd try the reaction in dry THF and warm it up and see if anything happens.
If not, I would try DMAP, triethylamine and THF.
On the note of cesium carbonate, I have found it to be a much better base and use it in place of pot carb now.
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We had a tricky acetylation and we used neat Ac2O and DMAP to make it work. The workup was painful though.
Also, the procedure described in the paper seems weird to me. First of all, the deprotonated quinone will be hardly soluble in ether so maybe that is the issue?
I would try Ac2O+DMAP in DCM or acetonitrile/THF..
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Thank you. Would you use a catalytic amount of DMAP? Would you use a base?
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Whats wrong with neat acetic anhydride? Its pretty common. BP is 140, or you can stir it with a bunch of water (keep it cold!) to remove the Ac2O after the reaction.
Some DMAP wouldn't hurt either to hedge your bets. I guess 1.1 eq since it would be acting as a base and catalyst.
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I agree with wilfyr, just reflux with Ac2O, I have done that, then just evaporate with aspirator vacuum.
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Thank you. Would you use a catalytic amount of DMAP? Would you use a base?
We used over 2 eq because it acted as a base as well and we needed to do bis-acetylation otherwise we got a mixture of compounds
Whats wrong with neat acetic anhydride? Its pretty common. BP is 140, or you can stir it with a bunch of water (keep it cold!) to remove the Ac2O after the reaction.
Some DMAP wouldn't hurt either to hedge your bets. I guess 1.1 eq since it would be acting as a base and catalyst.
Nothing wrong with it but required excessive amount of water/base in workup. We did like 500 mg reaction but ended up using almost 500 mL of water/base to quench the acid which worked but was bit too much for me based on the amount of product we were getting in the end.
Also, adding water to Ac2O takes time, I just perfomed acetylation with it in aq. NaHCO3 as a solvent so it probably takes quite some time to decompose.
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We tried one suggestion (Reddit/Chempros), which was to use cesium carbonate (sealed bottle). We are still not seeing anything by TLC. It was suggested to me that the product might have the same Rf as the starting material in EtOAc/hexanes and that I might try DCM with a small percentage of EtOAc or acetone. Thoughts?
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You can evaporate the excess A2O on rotavapor, just turn up the heat in the water-bath.
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Funny you should mention that. We hoped to recover the unreacted aldehyde from the first reaction. After acidifying, we removed the solvent from the first reaction, the one performed with potassium (not cesium) carbonate. I noticed that I could still smell acetic acid or possibly the anhydride, even being at 40 °C bath temperature with a moderate vacuum. I can go a bit higher in vacuum and in temperature.
I have not yet had the chance to try a different TLC solvent, but possibly tomorrow.
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Is it possible for one if the hydroxyl groups being hydrogen-bonded to the aldehyde carbonyl? If so the acetylation is much more difficult.
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It's interesting that you should mention that, as well. We obtained a H-1 NMR spectrum of the starting material. One of the phenol-type hydrogens was just under 5 ppm, which is within 0.5 ppm of others that I have observed. The other one was at greater than 10 ppm, not that far from the aldehyde hydrogen. I have to wonder about hydrogen bonding myself. However, the protocols that I have been following are for this exact molecule, which suggests that whatever the problem is, it is not insurmountable.
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Yes, if its this shift its hydrogen bonded. That explaines why standard acetylation conditions are not used. I have acylated this type of phenol, if you use DMAP you can do it.
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I was thinking of setting up a small test reaction with 2.1 moles of DMAP per mole of diol. I was thinking about trying 2.1 moles of acetic anhydride per mole of diol as well. That way there will not be much left over anhydride. I was also thinking about refluxing.
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I think it should work, if not AcCl can be used. You can se that the mono-acetylated derivative will have about the same Rf on TLC because the hydrogen-bonded OH is verylipophilic. The di-acetylated will actually have lower Rf.
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Both of the protocols that we consulted (they are nearly identical, except for the workup) use about a twofold excess of acetic anhydride over quinol, even accounting for the fact that there are two acetylations. It is unclear to me how the excess anhydride was removed by these two sets of workers.
One of the two protocols (Salome 2014) used sodium carbonate and concentration under a vacuum. I am not sure how quickly acetic anhydride hydrolyzes, but that is one possibility. Another is that they used something other than typical rotary evaporation procedures. By this I mean they might have gone to higher temperature in their rotary evaporation step, or they might have removed the remaining anhydride under high vacuum. Their last step was trituration with pentane, and I am not sure what they were trying to remove.
The other protocol (Klein 2007) used bicarbonate in the wash. They also said that they used a vacuum. They did not triturate.
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Acetic anhydride and acetic acid can be easily removed by vacuum, If you aren't using house vac, but instead a rotary vein pump directly attached to your rotovap, I doubt you'd have to go over 70°C.
Pentane trituration would also remove these I think.
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A quick update: We ran a TLC of the cesium ion reaction mixture using 2% acetone as the solvent, and the reaction product has a higher Rf than the starting aldehyde. This suggests that either mono-acetylation or di-acetylation took place. We plan to work this up. We will also try to run a TLC on the original, potassium crude product.
EDT
We have a Welch pump on our rotary evaporator. But we are now checking the TLC of the first reaction as well, just in case we obtained product without realizing it.
EDT2
The first reaction (with potassium carbonate) also has a higher Rf than the starting aldehyde in the new TLC solvent system.
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I may have a mixture of mono- and di-acetylated material as my product, as judged by NMR. I do not presently have conditions to separate the mono-acetylated and di-acetylated forms. My next step is a Horner Wadsworth Emmons reaction. I am tempted to try it, but to increase slightly the amount of DBU, which is the base. Thoughts?
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Can't you base wash the mono out?
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Base is used to hydrolyze the ester in some protocols. I am not sure how fast this reaction is.
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Just a weak bicarb solution to deprotonate the phenol and transfer to water layer. Ester hydrolysis typically requires some combination of time, heat, or strong base on all but the most sensitive esters.
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Now that I think about it again, there was a Na2CO3 wash in the workup. One might think that this would remove all of the molecules with a phenolic -OH group, but that did not happen. The phenolic -OH is probably H-bonding with the carbonyl group; maybe this changed its behavior somehow.
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We performed two acetylation reactions, and they looked similar by NMR. We decided to go on to the next step of the overall synthesis. When we performed TLC on the starting material for this second step (the starting material being the acetylated aldehyde), we observed two spots, with Rf values that were very close to each other. These are likely to be the mono-acetylated and di-acetylated aldehydes, with the top spot more likely to be the mono-acetylated product on the basis of relative intensities. Two different solvent systems gave similar results. It would be quite challenging to separate them by silica gel chromatography, and for whatever reason, the sodium carbonate wash step did not completely remove the monoacetylated compound. The presumed product of the second reaction has a very different Rf, fortunately for us.
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There is also using weak NaOH solution. Should bust any H-bonding.