Sciencemadness Discussion Board
Not logged in [Login ]
Go To Bottom

Printable Version  
 Pages:  1  
Author: Subject: How to selectively alkylate an aromatic ring?
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 19-1-2025 at 13:46
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.
View user's profile View All Posts By User
DraconicAcid
International Hazard
*****




Posts: 4388
Registered: 1-2-2013
Location: The tiniest college campus ever....
Member Is Offline

Mood: Semi-victorious.

[*] posted on 19-1-2025 at 18:48


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).



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.
View user's profile View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 20-1-2025 at 00:38


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 :-)
View user's profile View All Posts By User
Keras
National Hazard
****




Posts: 972
Registered: 20-8-2018
Location: (48, 2)
Member Is Offline


[*] posted on 20-1-2025 at 01:11


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.
View user's profile View All Posts By User
Niklas
Hazard to Self
**




Posts: 61
Registered: 1-12-2023
Location: Germany
Member Is Offline

Mood: Polymerized

[*] posted on 20-1-2025 at 02:13


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.
View user's profile View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 20-1-2025 at 03:29


Thanks! This helps a lot. Considering both of your concerns and suggestions, would something like this be possible?

View user's profile View All Posts By User
Keras
National Hazard
****




Posts: 972
Registered: 20-8-2018
Location: (48, 2)
Member Is Offline


[*] posted on 20-1-2025 at 05:55


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).
View user's profile View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 20-1-2025 at 06:10


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.
View user's profile View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 20-1-2025 at 06:10


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.
View user's profile View All Posts By User
DraconicAcid
International Hazard
*****




Posts: 4388
Registered: 1-2-2013
Location: The tiniest college campus ever....
Member Is Offline

Mood: Semi-victorious.

[*] posted on 20-1-2025 at 07:16


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.
View user's profile View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 20-1-2025 at 07:37


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 :P
View user's profile View All Posts By User
DraconicAcid
International Hazard
*****




Posts: 4388
Registered: 1-2-2013
Location: The tiniest college campus ever....
Member Is Offline

Mood: Semi-victorious.

[*] posted on 20-1-2025 at 07:40


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.



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.
View user's profile View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 20-1-2025 at 07:49


Yes, that does not sound particularly fun, lol. Why wouldn't it work with isovaleryl chloride/bromide followed by the Wolff-Kieschner?
View user's profile View All Posts By User
DraconicAcid
International Hazard
*****




Posts: 4388
Registered: 1-2-2013
Location: The tiniest college campus ever....
Member Is Offline

Mood: Semi-victorious.

[*] posted on 20-1-2025 at 08:05


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.
View user's profile View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 20-1-2025 at 08:15


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]
View user's profile View All Posts By User
Niklas
Hazard to Self
**




Posts: 61
Registered: 1-12-2023
Location: Germany
Member Is Offline

Mood: Polymerized

[*] posted on 20-1-2025 at 09:43


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.
View user's profile View All Posts By User
DraconicAcid
International Hazard
*****




Posts: 4388
Registered: 1-2-2013
Location: The tiniest college campus ever....
Member Is Offline

Mood: Semi-victorious.

[*] posted on 20-1-2025 at 10:22


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.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
View user's profile View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 20-1-2025 at 10:35


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.
View user's profile View All Posts By User
Niklas
Hazard to Self
**




Posts: 61
Registered: 1-12-2023
Location: Germany
Member Is Offline

Mood: Polymerized

[*] posted on 20-1-2025 at 11:19


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..
View user's profile View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 20-1-2025 at 11:21


Interesting Niklas! Thanks, I'll definitely look that up.
View user's profile View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 21-1-2025 at 07:34


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.
View user's profile View All Posts By User
DraconicAcid
International Hazard
*****




Posts: 4388
Registered: 1-2-2013
Location: The tiniest college campus ever....
Member Is Offline

Mood: Semi-victorious.

[*] posted on 21-1-2025 at 10:11


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.
View user's profile View All Posts By User
Texium
Administrator
********




Posts: 4637
Registered: 11-1-2014
Location: Salt Lake City
Member Is Offline

Mood: Preparing to defend myself (academically)

[*] posted on 21-1-2025 at 10:56


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.



Come check out the Official Sciencemadness Wiki
They're not really active right now, but here's my YouTube channel and my blog.
View user's profile Visit user's homepage View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 21-1-2025 at 12:19


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?
View user's profile View All Posts By User
Maui3
Hazard to Others
***




Posts: 109
Registered: 9-9-2024
Member Is Offline


[*] posted on 23-1-2025 at 01:55


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]
View user's profile View All Posts By User
 Pages:  1  

  Go To Top