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Maui3
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How to selectively alkylate an aromatic ring?
I am looking to alkylate a benzene-deriative selectively multiple times. Are there any good ways to do this? I know a FC-alkylation will result in
byproducts. I thought about maybe brominating, then doing a Wurtz-Fittig reaction, but I am not sure about how selective the bromination will be.
Note: I am running on very low sleep. I probably said some very confusing stuff in this post. I apologize.
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DraconicAcid
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It depends on what alkyl groups you want to put on, and where (and what else is on the ring). FC may result in rearrangement of the alkyl groups and
multiple alkylations- one can get around that by acyalting the ring, and then reducing the acyl group to an alkyl one (at least, on paper).
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Maui3
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I am planning on adding 2 isoamyl and 2 ethyl groups to catechol diacetate. I already have the bromides of them, so I would like if there was a way I
could use them for this. Thanks for the response too :-)
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Keras
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I would try to add the ethyl groups first. You can use acetic anhydride for FC-acylation, then use Wolff-Kieshner reduction to turn your carbonyl
group into alkane*. You do that twice, then you use FC-alkylation to attach your isoamyl groups at the remaining positions.
* You can’t acylate more than one position at a time because of the de-activating effect of the carbonyl group.
Esters, as far as I know, are weakly activating, so it should work.
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Niklas
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Attempting any type of FC reaction on catechol diacetate would likely cause a Fries rearrangement to occur as the primary reaction. You can use that
to install the acetyl groups tho, and just wait with remaking the diacetate until having reduced and alkylated things.
Wurtz-Fittig wouldn’t really be an option on a catechol I believe, the diacetate would most definitely quickly be reduced via a Bouvault-Blanc
resulting in the phenolate, which would then form an ether via a Williamson as a side reaction.
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Maui3
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Thanks! This helps a lot. Considering both of your concerns and suggestions, would something like this be possible?
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Keras
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That’s the spirit, however I don’t see why you esterify the -OH groups if you plan to get the phenol at the end.
Also, I don’t know if acylation would happen in the ortho positions or para. Because para, ortho and meta mix up, I don’t think there’s any
privileged position. Steric hindrance would probably lead the acyl groups to attach elsewhere (in 4 or 5, para to the hydroxy groups).
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Maui3
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Thanks for the encouragement!
The reason for esterifying the -OH groups is that I am worried, that the acetic anhydride and isoamyl bromide will attach to the -OH groups (instead
of on the ring) if the -OH groups are left un-protected.
Do you have any suggestions to increase the acylation on the desired positions? If acyl groups attach to the para position (and there isn't anything I
can do about it), I would need to get some obscure reagent, that after the Wolff-Kieschner reduction would give the isoamyl group, right? Otherwise, I
could possibly first attach the isoamyl with FC-alkylation, then the FC-acylation, assuming that the isoamyl group (in alkylation) will also attach to
para position relative to the hydroxy groups.
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Maui3
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Thanks for the encouragement!
The reason for esterifying the -OH groups is that I am worried, that the acetic anhydride and isoamyl bromide will attach to the -OH groups (instead
of on the ring) if the -OH groups are left un-protected.
Do you have any suggestions to increase the acylation on the desired positions? If acyl groups attach to the para position (and there isn't anything I
can do about it), I would need to get some obscure reagent, that after the Wolff-Kieschner reduction would give the isoamyl group, right? Otherwise, I
could possibly first attach the isoamyl with FC-alkylation, then the FC-acylation, assuming that the isoamyl group (in alkylation) will also attach to
para position relative to the hydroxy groups.
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DraconicAcid
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The isoamyl groups will certainly rearrange if you try doing FC with isoamyl bromide.
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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Maui3
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How (or could) I prevent that? What about doing an acylation of the catechol with isovaleryl chloride, followed by the Wolff-Kieschner reduction - to
get the isoamyl groups? I do really want to prevent using isovaleryl chloride. I haven't checked the price, but I am already sure it's very expensive,
lol
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DraconicAcid
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The only alternative I can see is to halogenate the ring, and convert the isoamyl bromide to a Gilman reagent. But I only have experience with that
reaction on paper.
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Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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Maui3
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Yes, that does not sound particularly fun, lol. Why wouldn't it work with isovaleryl chloride/bromide followed by the Wolff-Kieschner?
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DraconicAcid
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It would, but you said you wanted to avoid that.
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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Maui3
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Sorry, I see that I should have phrased it better now. I meant that I'd probably rather go through the hassle of making isovaleryl chloride than
Gilman reagents.
If I decide to do the isovaleryl chloride-method, I should attach the isovaleryl chloride first, right? .. since it'll attach in the para positions
relative to the OH groups.
[Edited on 20-1-2025 by Maui3]
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Niklas
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Quote: Originally posted by Maui3 | Thanks! This helps a lot. Considering both of your concerns and suggestions, would something like this be possible? |
There are two problems that come to my mind, most notably the fact that you most definitely won’t have ortho selectivity for the acetylation but
rather para. So it‘d be best to go around this by installing the isovaleryl groups first using isovaleryl chloride, in which case you wouldn’t
have to protect the phenol anymore, as you can purposely acylate the oxygen and then rearrange using AlCl3 (Fries rearrangement as stated before).
Other than that it’s just what’s already been said, you won‘t be able to do double acetylation, so you‘ll painfully have to install and reduce
every ketone separately, and I can’t really think of a better method when starting from catechol.
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DraconicAcid
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Once word of note- I have smelled isovaleric acid, and would not want to work with the halide.
Our students roll dice to find out what acid they are going use for esterification in a particular lab- if they roll for isovaleric acid, they are
permitted to roll again. If they dare use it, they are provided with a disposable lab coat for that experiment (which will be burned immediately
afterwards), and are advised to bring a ziploc bag and a change of clothes. It's like a sockful of parmesan cheese that's been worn during a marathon
and left behind the radiator for a month.
Please remember: "Filtrate" is not a verb.
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Maui3
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Niklas, that sounds very much fine to me. As long as it works (in theory), I won't complain, lol.
DraconicAcid, Haha, thank you for the story. It really does sound horrible. I do have these "coverall"s - if it smells that horribly, I could probably
use them. I am quite sensitive to smells like "A sockful of parmesan cheese that's been worn during a marathon and left behind the radiator for a
month.", so it's going to be really fun. I will update you all soon, as I'll probably do the experiment (isovaleric acid) tommorow - though not with
the halide, as I do not have thionyl chloride on hand.
Last question (for now): I could probably research this myself, and I do feel I should research better first before asking, but I still feel you all
might have some advice: are there other chlorinating agents that can be used to chlorinate carboxylic acids, that aren't thionyl/oxalyl/phosphorous
chloride(s)? I don't imagine I could use TCCA or hypochlorites, but I am a bit unsure.
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Niklas
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Quote: Originally posted by Maui3 | Last question (for now): I could probably research this myself, and I do feel I should research better first before asking, but I still feel you all
might have some advice: are there other chlorinating agents that can be used to chlorinate carboxylic acids, that aren't thionyl/oxalyl/phosphorous
chloride(s)? I don't imagine I could use TCCA or hypochlorites, but I am a bit unsure. |
I think using TCCA actually is an option, even if works somewhat badly probably, but if I remember correctly it forms a type of Vilsmeier reagent with
DMF (only required catalytically) which can be used to chlorinate carboxylic acids (and even be used in the formylation of aromatic compounds).
Alternatively I guess there is the otc approach via sulfur chlorides, could safe a little bit of effort at least by going via James Cambell‘s
approach of directly mixing TCCA and sulfur, but either way that method is rancid tho..
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Maui3
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Interesting Niklas! Thanks, I'll definitely look that up.
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Maui3
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I am done with the isovaleric acid now. I should have bought scented candles before beginning the synthesis, lol. It smells quite bad.. and it lingers
around. When I added the isoamyl alcohol to the nitric acid, and the NO2 was released, even just the small amount of particles of the isovaleric acid
clinged to my fingers. I am writing this with a glove on my one hand, because it smells that horrible.
Anyway, I am quite happy with how it went.. though somehow it must've decomposed, since it had a camphorous-like smell once I was done. I was also a
bit sceptical about the amounts of 80% nitric acid per isoamyl alcohol (85 g : 18 g) used, and since it started to fume HNO3/NO2-vapors when I was
concentrating the solution, something was probably off with the nitric acid.
I am not sure if the nitric acid could decompose it? .. Anyway, it was as nightmare to make that big an amount of nitric acid, so next time it's KMnO4
for the oxidation.
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DraconicAcid
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Quote: Originally posted by Maui3 | I am done with the isovaleric acid now. I should have bought scented candles before beginning the synthesis, lol. It smells quite bad.. and it lingers
around. When I added the isoamyl alcohol to the nitric acid, and the NO2 was released, even just the small amount of particles of the isovaleric acid
clinged to my fingers. I am writing this with a glove on my one hand, because it smells that horrible. |
I waaaaarnnnned you!!!!!
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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Texium
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Permanganate or dichromate is the way to go for sure. Nitric acid oxidations of alcohols are unreliable and may produce nitrate esters and other
nasties.
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Maui3
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DraconicAcid, You're right!! And thank you for that! At least that made my buy the "coverall"s, and I really appreciate I wore one of those now.
Texium, Thank you. I'll buy some permanganate or make some dichromate from forks now lol. If I use potassium dichromate for this oxidation, it has to
be in a dilute sulfuric acid solution, right?
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Maui3
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Since this is quite a long process (where a lot could go wrong), I just want to be sure I am doing the correct thing - even though I might be
triple-checking.
Is this the idea (for now)?
I assume aaa lotttt of loss of product in all of these steps, so I think in some of the steps I won't isolate the compound, and just do the next
reaction (if there are no biproducts).
Also, I had a hard time finding a procedure for the oxidation of isoamyl alcohol to isovaleric acid with potassium permanganate (though I did find one
with dichromate). I finally found someone oxidizing the isoamyl alcohol with permanganate on youtube, but they only got a 5% yield (if I remember
correctly). I would like to get more than a 5% yield, since the reagents are expensive lol. Is that low of a yield expected?
[Edited on 23-1-2025 by Maui3]
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