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Author: Subject: Help on Friedel Crafts alkylation and acylation of anisole and acetophenone
kuro96inlaila
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sad.gif posted on 8-8-2016 at 09:58
Help on Friedel Crafts alkylation and acylation of anisole and acetophenone


It's been a few years since I last went here, and god it's good to be back.

Guys I need help on this matter. I'm doing reading based research on the Friedel-Crafts alkylation and acylation of both anisole and acetophenone. The reference on acylation and alkylation of anisole is pretty much easy to find, as they has -OR group that activates the benzene ring to much more reactive species.

But on the matter of Friedel-Crafts acylation of acetophenone, I read here on page 296 that further acylation of acetophenone by acetyl chloride is not possible due to the moderate deactivating nature of -COR group:

https://books.google.com.my/books?id=0X4cQus2gz8C&pg=PA2...

and I still didn't find yet any reference on the alkylation of acetophenone.
Does -COR group make benzene ring unreactive enough for Friedel-Crafts alkylation impossible?

I'm planning to focus on alkylation by methyl chloride or ethyl chloride with AlCl3 catalyst, and acylation by acetyl chloride on both anisole and acetophenone. I'm also planning to write on the carbocation rearrangement and overalkylation but I think that gonna be clear once I know the restriction and limitation of Friedel-Crafts reaction on acetophenone.

Is there any restrictions on those Friedel-Crafts reaction? And how -OCH3 group (in anisole) and -COCH3 in acetophenone going to sterically hinder the substitution by said subtituents?




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kuro96inlaila
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[*] posted on 8-8-2016 at 18:19


okay I found one reference mention that Friedel crafts reaction would work on unreactive acetophenone given that it is catalysed by superacid with weakly nucleophilic solvent such as HF-SbF5, here:

https://www.jstage.jst.go.jp/article/cl1972/8/8/8_8_1003/_pd...

So under normal condition of Friedel-Crafts reaction with AlCl3 or FeCL3, acetophenone didn't undergo any reaction at all?




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clearly_not_atara
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[*] posted on 9-8-2016 at 10:11


FC acylation of acetophenone is slow at the boiling point of AcCl with only AlCl3 as a catalyst. Without high pressure, it's not feasible.

Substitution of acetophenone may be more profitably achieved with eg BrCl or ICl FC halogenation to the aryl halide followed by metal-catalyzed coupling reactions such as the Heck reaction. It is also possible to "reactivate" acetophenone by forming a ketal with ethylene glycol, or use exceptionally strong Lewis acids like SbF5.

Anisole undergoes FC reactions no problem, but may be degraded by AlCl3.
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[*] posted on 10-8-2016 at 04:40


the problem with FC alkylation of acetophenone is that the AlCl3 reacts with the ketone group rather than with alkyl halide to form the electrophile.The problem can be overcome by using an excess of AlCl3

baddeley, pg 229 - http://pubs.rsc.org/en/content/articlelanding/1949/jr/jr9490...
http://pubs.acs.org/doi/abs/10.1021/ja01531a023

there is a method to alkylate nitrobenzene using ethanol and H2SO4,maybe the same thing could be done with acetophenone ? http://pubs.acs.org/doi/abs/10.1021/jo00299a051?journalCode=...

like atara suggested,you could convert the ketone to a ketal and do the FC alkylation.During the work-up,the ketal will get hydrolysed to ketone and you will get your target compound

But the best thing to do IMHO,would be to avoid an FC reaction altogether and go via another route.
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kuro96inlaila
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[*] posted on 10-8-2016 at 13:59


Quote: Originally posted by clearly_not_atara  
FC acylation of acetophenone is slow at the boiling point of AcCl with only AlCl3 as a catalyst. Without high pressure, it's not feasible.

Substitution of acetophenone may be more profitably achieved with eg BrCl or ICl FC halogenation to the aryl halide followed by metal-catalyzed coupling reactions such as the Heck reaction. It is also possible to "reactivate" acetophenone by forming a ketal with ethylene glycol, or use exceptionally strong Lewis acids like SbF5.

Anisole undergoes FC reactions no problem, but may be degraded by AlCl3.


Thanks that cleared a lot if things!
So it seems the FC acylation directly to acetophenone isn't the ideal route to introduce new substitute to the aromatic acetophenone ring.




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[*] posted on 10-8-2016 at 14:54


Quote: Originally posted by CuReUS  
the problem with FC alkylation of acetophenone is that the AlCl3 reacts with the ketone group rather than with alkyl halide to form the electrophile.The problem can be overcome by using an excess of AlCl3

baddeley, pg 229 - http://pubs.rsc.org/en/content/articlelanding/1949/jr/jr9490...
http://pubs.acs.org/doi/abs/10.1021/ja01531a023

there is a method to alkylate nitrobenzene using ethanol and H2SO4,maybe the same thing could be done with acetophenone ? http://pubs.acs.org/doi/abs/10.1021/jo00299a051?journalCode=...

like atara suggested,you could convert the ketone to a ketal and do the FC alkylation.During the work-up,the ketal will get hydrolysed to ketone and you will get your target compound

But the best thing to do IMHO,would be to avoid an FC reaction altogether and go via another route.


Unfortunately I don't have access to said documents so I still kinda in the dark. How did the excess of AlCl3 prevent the formation of ketone electrophile?

alkylation by alcohol and H2SO4 probably can be done on acetophenone too consdering -NO2 is a strong deactivating group compared to ketone being moderate deactivating group. Not sure though if the mechanism is specific to -NO2 containing aromatics compounds.

Yeahh, conversion to ketal is probably the most desired pathway that involve FC reaction, next to option by other organic reaction.

Would FeCl3 be a more suitable catalyst than AlCl3? or would SbF5 sufficient for most FC reaction?
Well in this case I know every catalysts has it's own drawback and such referring to here:

http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.540...





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[*] posted on 11-8-2016 at 06:36


Quote: Originally posted by kuro96inlaila  
Quote: Originally posted by CuReUS  
the problem with FC alkylation of acetophenone is that the AlCl3 reacts with the ketone group rather than with alkyl halide to form the electrophile.The problem can be overcome by using an excess of AlCl3

How did the excess of AlCl3 prevent the formation of ketone electrophile?

I had a feeling my sentence about the electrophile would cause a confusion.I am sorry
what I meant was that the instead of reacting with the alkyl halide and forming an electrophile(like a normal FC reation) , the AlCl3 would form an adduct with the ketone group.
Now suppose you are using 1 mole of acetophenone and you put in 2 moles of AlCl3(which is an excess), I mole of AlCl3 gets wasted reacting with the ketone,but the remaining 1 mole reacts with the alkyl halide to form the eletrophile which attacks the benzene ring.

Quote:
alkylation by alcohol and H2SO4 probably can be done on acetophenone too consdering -NO2 is a strong deactivating group compared to ketone being moderate deactivating group.

I was thinking the same thing too.But my only worry is that there might be an acid catalysed aldol reaction.
Quote:
Would FeCl3 be a more suitable catalyst than AlCl3? or would SbF5 sufficient for most FC reaction?

the only difference I know between FeCl3 and AlCl3 is that since the former is less reactive, it forms the carbocation(from the alkyl halide) slowly because of which there is a lesser chance of rearrangement.For ex - suppose you react propyl bromide with benzene in the presence of AlCl3, you will get isopropylbenzene but if you use FeCl3,you will get n-propylbenzene

SbF5 is a very strong lewis acid,so it should be sufficient for most FC reactions.

[Edited on 11-8-2016 by CuReUS]
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kuro96inlaila
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[*] posted on 12-8-2016 at 01:23


Quote: Originally posted by CuReUS  
Quote: Originally posted by kuro96inlaila  
Quote: Originally posted by CuReUS  
the problem with FC alkylation of acetophenone is that the AlCl3 reacts with the ketone group rather than with alkyl halide to form the electrophile.The problem can be overcome by using an excess of AlCl3

How did the excess of AlCl3 prevent the formation of ketone electrophile?

I had a feeling my sentence about the electrophile would cause a confusion.I am sorry
what I meant was that the instead of reacting with the alkyl halide and forming an electrophile(like a normal FC reation) , the AlCl3 would form an adduct with the ketone group.
Now suppose you are using 1 mole of acetophenone and you put in 2 moles of AlCl3(which is an excess), I mole of AlCl3 gets wasted reacting with the ketone,but the remaining 1 mole reacts with the alkyl halide to form the eletrophile which attacks the benzene ring.

Quote:
alkylation by alcohol and H2SO4 probably can be done on acetophenone too consdering -NO2 is a strong deactivating group compared to ketone being moderate deactivating group.

I was thinking the same thing too.But my only worry is that there might be an acid catalysed aldol reaction.
Quote:
Would FeCl3 be a more suitable catalyst than AlCl3? or would SbF5 sufficient for most FC reaction?

the only difference I know between FeCl3 and AlCl3 is that since the former is less reactive, it forms the carbocation(from the alkyl halide) slowly because of which there is a lesser chance of rearrangement.For ex - suppose you react propyl bromide with benzene in the presence of AlCl3, you will get isopropylbenzene but if you use FeCl3,you will get n-propylbenzene

SbF5 is a very strong lewis acid,so it should be sufficient for most FC reactions.

[Edited on 11-8-2016 by CuReUS]


ohhh that's neat many useful information I can learn here.
On the subject of steric hindrance, I supposed there isn't much to talk about acetophenone since even if a new substitute is introduced it'll be at meta position, giving some room for the new substitute to attach.

But in case of anisole, let say I attach tert-butyl group at the ortho position, would the -OCH3 somehow hinder the attachment of tert-butyl group?
And if it is possible, on the matter of overalkylation, I'm thinking that the introduced alkyl groups would attach to para and both ortho carbon in the benzene ring, or is it going to be attached somewhere else?

as for the overalkylation of benzophenone (let say we are successful at attaching new -R at meta position) I'm thinking the overalkylation would attach 3 -R at meta, para and ortho group though I'm not sure which side of ortho it would be or should it be on both side.




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[*] posted on 12-8-2016 at 01:53


Quote: Originally posted by kuro96inlaila  

But in case of anisole, let say I attach tert-butyl group at the ortho position, would the -OCH3 somehow hinder the attachment of tert-butyl group?

no
https://en.wikipedia.org/wiki/Friedel%E2%80%93Crafts_reactio...
https://en.wikipedia.org/wiki/Butylated_hydroxyanisole
Quote:
And if it is possible, on the matter of overalkylation, I'm thinking that the introduced alkyl groups would attach to para and both ortho carbon in the benzene ring, or is it going to be attached somewhere else?

If you let it overalkylate,the whole ring might get alkylated;)

Quote:
as for the overalkylation of benzophenone (let say we are successful at attaching new -R at meta position) I'm thinking the overalkylation would attach 3 -R at meta, para and ortho group though I'm not sure which side of ortho it would be or should it be on both side.

As I said above,there is a possibility of the whole ring getting alkylated.But the ortho positions of the two rings between each other might escape substitution because there would be crowding,if long chain or bulky alkyl substituents are used.However,methyl groups might be able to slip in.
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Dennis A
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[*] posted on 13-4-2018 at 06:33


Does anybody have any personal experience particularly with "Aclyations" using p-toluenesulphonic acid and graphite as the catalyst ? I can only find one example of its kind and it states carboxylic acids can be used directly without the need of chlorination first which again assuming you dont have your acyl halide yet would save the whole process of using one in the first place eliminating reagents like thionyl chloride and the likes

here is the link

https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/fi...









[Edited on 13-4-2018 by Dennis A]
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[*] posted on 14-4-2018 at 17:53


Dennis A:

I followed up your posted reference on Google Scholar and found quite a bit of interesting related information. I suggest you give that a try and see what you can find.

AvB
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[*] posted on 16-4-2018 at 07:49


Still i am only able to find one reference detailing such so if you know something i don't please enlighten me ... Simply going on google scholar and searching the keywords " friedel crafts acylation p-TsOH toluenesulphonic acid graphite " all jumbled up and rearranged yields nothing related to what i am in search of so how you was able to achieve this still seams a mystery to me

If you have the links to related articles i would love to read them please post links and references

Regards

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