Sciencemadness Discussion Board

Fluorinating the benzene ring

Chemi Pharma - 4-10-2017 at 05:40

Hi everybody.

Does anyone here knows about an OTC procedure to exchange the Halogen like Cl, BR or I attached to a benzene ring for fluorine?

This reaction is called HALEX REACTION, but searching at Sciencemadness, other foruns and the Web I can't find any OTC way to do this. Just complex procedures.

Any help? preferably with support papers. Thanks.

[Edited on 4-10-2017 by Chemi Pharma]

woelen - 4-10-2017 at 06:08

Then apparently this is a complex procedure. Fluorinating organics differs a lot of chlorinating or brominating things. You need completely different reagents and conditions.

Show us what you've found so far, give concise descriptions of the procedures. Maybe others then will jump in. Just asking such a question without showing any results or any effort does not invite people to help you. It may be considered a spoonfeeding request.

Chemi Pharma - 4-10-2017 at 06:39

Quote: Originally posted by woelen  
Show us what you've found so far, give concise descriptions of the procedures. Maybe others then will jump in. Just asking such a question without showing any results or any effort does not invite people to help you. It may be considered a spoonfeeding request.


Ok. Let's go!

I have a paper that claims nitrohalobenzenes undergoes fluorination with alkali fluorides like sodium, potassium and cesium fluorides with a reasonable yield (attached below-FLUONITROBENZENES.Pdf). But the reaction tube must be sealed under vacuum at 290ºC for 24 hours. This procedure doesn't work with unactivated aryl halides. This is my case.

Other paper brings the need of use antimony trifluorodichloride to do the HALEX reaction, made in situ by reacting antimony trifluoride with chlorine, the first it's not exactly an OTC reagent (attached below-fluorination of aromatic halogenated - SbF3.pdf).

The last paper I have claims that HALEX reactions can be done with aryl halogenate and alkaline or ammonium fluoride, but demand the use of a catalyst made by the reaction of PCL5 with dialkylamines, what is not exactly true OTC (attached below-fluorination of aromatic halogenated - Halex Reaction.pdf).

I don't believe there's no way to do this exchange with alkaline or ammonium fluorides with no catalyser or, at least, something more OTC.

I'm sure I had a paper telling this, but i lost it in the last ramsonware attack I suffered.

Anyone can give any help?







Attachment: FLUORONITROBENZENES.pdf (229kB)
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Attachment: fluorination of aromatic halogenated - Halex Reaction.pdf (1.2MB)
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Attachment: fluorination of aromatic halogenated - SbF3.pdf (203kB)
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Texium - 4-10-2017 at 07:12

If you could make the corresponding aniline of the compound you're trying to make, you could potentially use the Balz-Schiemann reaction, which is essentially a variant of the Sandmeyer reaction. It uses tetrafluoroboric acid as the fluorinating agent, which can be prepared in situ from boric acid and aqueous HF.

https://en.wikipedia.org/wiki/Balz%E2%80%93Schiemann_reactio...

https://en.wikipedia.org/wiki/Fluoroboric_acid

Chemi Pharma - 4-10-2017 at 07:31

Great help zts16.

It's just the paper I had missed. Now I remember (Fluorobenzene):

http://orgsyn.org/demo.aspx?prep=cv2p0295

Sure, sandmeyer reaction with fluoboric acid, which is an OTC reagent.

Very grateful!

Heavy Walter - 4-10-2017 at 09:06

Hi Chemi

Do you know this reference?



Attachment: Sintesis de Organo_F_Review-main.pdf (5.8MB)
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Chemi Pharma - 4-10-2017 at 09:36

Thanks Heavy for the reference.

However the study tells more about polyfluorinated aromatics, which is not my case, it brings interesting knowledge about substitution reactions involving fluorinated compounds.

Boffis - 4-10-2017 at 12:35

@Chemi Pharma There is a paper in the JACS that describes the use of KF and various polar organic solvents such as nitrobenzene, Dimethylsulphoxide DMSO, Dimethylformamide DMF, etc without the phosphinium salts as catalyst (ref 1).

Interestingly the very next paper (ref 2) is about the formation of aromatic fluoro compounds from amine via diazonium fluoroborates or fluorophosphate but without isolation of the solid diazonium salt (as per the procedure in Vogel. Ref 3 and Org Synth. Ref 4) using aqueous acetone as the medium with cuprous chloride as the catalyst.

Ref 1: JACS; 1956, v78, iss23, p6034 ja01604a022
Ref 2: JACS; 1956, v78, iss23, p6038 ja01604a023
Ref 3: Vogel, Practical Organic Chemistry 5th ed, 939 (fluorobenzene)
Ref 4: Org Synth., Col Vol 5 p133



Attachment: CV5P0133.pdf (322kB)
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CuReUS - 4-10-2017 at 20:30

Quote: Originally posted by zts16  
If you could make the corresponding aniline of the compound..

https://en.wikipedia.org/wiki/Aryne
from chlorobenzene -http://www.freepatentsonline.com/y2005/0096489.html

[Edited on 5-10-2017 by CuReUS]

Boffis - 9-10-2017 at 04:23

While looking through the references above I see that 2,4-dinitro-fluorobenzene is prepared by halogen exchange but could it also be prepared by nitration fluorobenzene or is there a good reason why this doesn't work?

On a slightly different issue; what is the purpose of trifluoromethyl groups on aromatic compounds? I have seen many reported syntheses where one or more of the substrates ha this functional group in it but it doesn't seem to play any part in the reaction. Are the fluorine atoms on this functional group reactive or inert? For instance is this functional group easily hydrolysable to a carboxylic acid group?

[Edited on 9-10-2017 by Boffis]

Crowfjord - 9-10-2017 at 06:45

I believe trifluoromethyl groups are used where one wants a small, hydrophobic electronegative group. The fluorines are pretty inert, as I understand it. Much less labile than the rest of the halogens. In medicinal chemistry, the trifluoromethyl is used when a group is needed that is more hydrophobic than methyl, but about the same size.

Texium - 9-10-2017 at 07:36

Another property that is appealing in medicinal chemistry is that trifluoromethyl groups are not easily oxidized like methyl groups.

clearly_not_atara - 9-10-2017 at 14:04

If you can make an N-heterocyclic carbene you can use this to prepare a phenol deoxyfluorinating reagent as follows:

NHC + Cl2 (maybe Br2?) >> NHC-Dichloride

NHC-dichloride + 2 F- >> NHC-difluoride + 2 Cl-

The rxns must be performed under anhydrous conditions. I think any fluoride salt wil work as long as it's soluble in the rxn medium. Then:

NHC-difluoride + phenol >> NHC-derived urea + fluoroarene + HF

http://www.organic-chemistry.org/abstracts/lit3/345.shtm

Boffis - 10-10-2017 at 07:18

Thanks for the replies re the trifluoromethyl group guys.

I have found that there is a lot of information about the mononitration of fluorobenzene to give mainly the p-isomer which occurs more rapidly under most conditions that the nitration of chloro or bromobenzene but I can't find anything on the dinitration.

Dr.Bob - 11-10-2017 at 05:59

A stated, the CF3- group is like a really large, but electron withdrawing alternate to a methyl group. It increases the lipohilicity of a compound, generally increasing the half life in vivo, often reducing metabolism at and near the CF3, and it has about the steric bulk of a bromo group, with less reactivity and molecular weight. In size R groups might be ranked as H < F < Me <=Cl < CF3 <= Br < I In an aromatic ring, they are strongly electron withdrawing, maybe more than Cl or Br, don't have my handy Hammett value table here, but that can change the properties of other groups on the ring, for instance removing charge from a carbonyl group (eg acyl group), or modifying the acidity of a benzoic acid. Since methyl groups donate electrons, this is one of the best ways to test the effects of electronics, although a chlorine also works well for that swap. A methyl and chloro group are very close in size, depending on which set of assumptions you use in modelling.

CF3 groups are inert towards most conditions, but can be hydrolyzed by strong base in some cases to a COOH group. This has been used as a way to install a COOH group on some heterocycles, although I don't have a reference handy. But it takes pretty harsh conditions.