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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on February 02, 2021, 08:14:06 PM
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We need to remove two acetyl groups from aromatic oxygen atoms and replace them with hydrogens. We found a paper that performed a similar deacetylation in the presence of our other functional group; and these workers used three different methods, including hydrazine hydrate. They used HPLC on the milligram scale to purify their product. We plan to work on the hundreds of milligrams scale, and preparative HPLC is not realistic for us right now. Therefore, I was planning to use silica gel chromatography. What I was wondering about is the work-up prior to chromatography. We could try extraction (ethyl acetate vs. water, then brine). I might be inclined to use two or three portions of ethyl acetate. Another possibility is to remove the volatiles and strip with toluene. However, acethydrazide is not volatile: 129 °C/18 mmHg (lit.); therefore, I am doubtful that rotary evaporation would do anything.
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There will also be unreacted hydrazine, as well as acethydrazide, at the end of the reaction. One thing that I just noticed. The paper that I am following used their NMR sample (the diacetylated aromatic compound) in DMSO as their reactant in the hydrazine step. I am not sure that I need to use DMSO; maybe THF or DMF would be fine.
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I contacted one of the coauthors, and he suggested using an aqueous acid in the extraction, to pull hydrazine into the water phase. Our other functional group is inert to ammonium chloride or TFA, and I cannot see why it would be acid-labile. I found a pKa of acetylhydrazide of 3.24, which I presume refers to the ammonium form. The pKa of hydrazine itself is 8.10.
https://chem.nlm.nih.gov/chemidplus/rn/1068-57-1
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DOI: 10.1002/ejoc.200800232 (M. Lang et al., European Journal of Organic Chemistry, (20), 3544-3551; 2008. Wolfgang Steglich is a coauthor)
I did a quick SciFinder search and I found a synthesis of benzene-1,2,4-triol from its tris-acetylated precursor. They worked under argon, and they used a slight excess of hydrazine, with methanol as their solvent. They used 2 M HCl in their extraction (probably to remove hydrazine and its by-product, as I noted above) and dried the combined ethyl acetate layers with sodium sulfate.
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https://www.sigmaaldrich.com/catalog/product/aldrich/751855?lang=en®ion=US
Is there any tendency for hydrazine to add into acetonitrile? Given that one can buy hydrazine in acetonitrile, I would suspect not, but I get paid to worry about such things. We need to dissolve our reactant in something, and alcohols (which were my first choice) were not terribly successful.
Regarding the HCl extraction in the Steglich reference, a second function of HCl is presumably to protonate the aromatic hydroxyl groups.
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Regarding hydrazine adding to MeCN I highly doubt it would, and the fact that it can be bought in MeCN means it must be stable in MeCN. The only way I can see it reacting is if you had a strong enough base to deprotonate on the methyl group. I doubt though, that that "enolate" would readily form.
Are you able to use other bases to remove the acetyl group such as NaOMe or Methylamine in methanol?
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I have removed one acetyl group from a ohenolic OH with just NH3 in methanol, I dont think you need hydrazine. The acetamide product can be removed with vacuum.
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Rolnor, I have seen ammonia used to remove two acetyl groups in the same paper from which we originally took the hydrazine method (not the Steglich reference). Right now that procedure is looking more attractive than it had before. On the other hand, perhaps we have thought through most of the bugs of the hydrazine method. Ammonia and its by-product are more volatile. Hydrazine can be added in only slight excess, but I have not checked the mole to mole ratio in regards to ammonia.
Guitarmaniac, the third method in the paper we are following (which has the same functional group as our molecule) was catalytic methoxide in methanol, but they did not specify exactly how much methoxide. In effect we flipped a three-sided coin to pick one method. Methylamine crossed my mind but I did not look into it much. Does it have anything to recommend it or any drawbacks, in your opinion?
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Hi Babcock_Hall, sorry for the very delayed reply! I have been very busy at work.
When I use catalytic methoxide I use about 10 mol% and it is a good solid methodology for ester deprotections but methylamine in ethanol or methanol is better because of the nucleophilicity of the amine.
The benefits of methylamine are that the reaction is quick but you do need several equivalents to get full deprotection. For one of my molecules I had two benzoyl ester protecting groups on a di-phenolic compound and I used methylamine in ethanol at 4 equiv. The reaction proceeded well and by LCMS I got full conversion and a yield of 89%.
The main drawback of methylamine is that if the reaction is sluggish, you cant heat the reaction beyond 40 odd degrees (from experience) as the methylamine boils off.
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I have used 5% NH3 in ammonia, its fast att ambient temperature.
I think if you use methoxide you get a minus-charge on the phenol when the first acetyl is hydrolyzed, this will repell the methoxide anion and hinder the second acetyl to be hydrolyzed.
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rolnor,
Good point about repulsion. Do you mean in water?
Guitarmaniac86,
I wonder if hydrazine is more nucleophilic than ammonia in this reaction, owing to the α-effect. If so, it might be advantageous in some circumstances. However, a quick skim of the topic leads me to believe that whether or not one observes enhanced nucleophilicity depends upon the reaction.
https://pubs.acs.org/doi/10.1021/jo301497g
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You will get phenoxide anion in any solvent if you hydrolyze with methoxide. The phenoxide anion will repell methoxide from attacing the second acetylester because its so close. Hydrazine is a more powerfull nucleophile but its probably not neccesary.
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333
I have used 5% NH3 in ammonia, its fast att ambient temperature.
Hi rolnor,
Do you mean 5% NH3 in water or in some other solvent?
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No, you dissolve ammonia gas in MeOH. You can use a very large excess. You can buy 2M NH3 in MeOH I think.
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rolnor,
Thank you; your comments are always helpful and thought-provoking. I re-read the paper in question, and they used 2 M ammonia in methanol as one of their three methods. In my case, the two oxygen atoms are in a 1,4 (para) relationship; therefore, repulsion may not be as bad as when they are in an ortho relationship.
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Thats true, para will not be a problem if not the phenylring itself is charged in some way.
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Just a quick update, our first attempt had some glitches which reduced yield, and we repeated the deacetylation. This week we will purify the combined products and see what we have.
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How does it look on TLC?
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The product ran more slowly than the starting material on TLC, with the solvent being 3% acetone in DCM. For a column 3% acetone is not polar enough to move the product much, but 6% is looking roughly right (the Rf was about 0.32).
EDT
Removal using hydrazine is probably a fine method, but if I had to start from scratch, I might use ammonia in methanol.
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That sound good. If you dipp the plate in 0.5%KMnO4 it should give strong staining compared to the diacetylcompound.
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Do I understand correctly that the phenol-type groups gives more reaction with KMnO4 than the acetylated phenols? I was unaware of that.
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Possibly due to oxidation to quinone(s) which is blocked when acetylated? Also, FeCl3 is selective stain for phenols giving gray ish spots on yellow/orange background IIRC.
Do you need to run the collumn? Dont know the structure but phenoxide could be water soluble so you can get rid of the remaining organics just by dissolving it in basic water and extract with organics, then acidify and maybe it precipitates or get extracted again.
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Yes, phenols stain KMnO4 very much, esters does not.
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We used d6-acetone as our NMR solvent for the silica-purified material. In retrospect my choice of solvent was not ideal; residual water is in the vicinity of the acetyl methyl groups, and the phenolic-OH signals were not strong. There was a huge roll with an integral of less than one that may or may not have been a phenolic -OH. The carbon NMR was a cleaner experiment; I have only glanced at it, but there is no sign of either carbon of an acetyl group. Tentatively, I would say that the method was successful. We may make up a sample in a different NMR solvent, such as DMSO. Chloroform would be a challenge, but we might be able to get enough material into solution for 1H NMR only. Obtaining MS data is not trivial for us right now, but it may become much more routine in a few months.
EDT
Thanks to all. Chemical Forums is a great resource for us!
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Great!
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One more follow-up: I was able to get enough material into CDCl3 for 1H NMR, but the signal-to-noise ratio was low. I see two candidates for the two Ar-OH hydrogens, and there is little to nothing where the acetyl methyl groups would be. Again, thanks to everyone here.
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A very preliminary result suggests that our product has the desired biological effect (we have a long way to go). I am very grateful for the advice received in these threads.
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Great!