[acarter5251]

I am interested in performing a Friedel Crafts acylation using a silyl protected hydroxy benzoic acid and benzene to form the benzophenone.  I have attempted this reaction with no success, and now I am wondering if the silyl protecting group is stable under the reaction conditions.  I know that silyl ethers can be removed under acidic conditions and that in the process of my reaction HCl is being produced, so I was wondering if it was possible that the protecting groups are being removed, resulting in a lack of my desired product?

Thanks in advance!

[kamiyu]

I think it is really quite likely that the silyl group won't survive. No matter you use Al salt or mineral acid as the catalyst, these stuff forms bond with the oxygen of the silyl ether, making the silicon positive and prone to nucleophilic attack.

I am wondering why HCl is formed, you used AlCl3? Indeed, my original thought for this Friedel Crafts reaction is to use mineral acid as the catalyst.

BTW, as mentioned above, the end product HCl is not the culprit, but the catalyst of this reaction, which are practically all acidic.

[acarter5251]

I think it is really quite likely that the silyl group won't survive. No matter you use Al salt or mineral acid as the catalyst, these stuff forms bond with the oxygen of the silyl ether, making the silicon positive and prone to nucleophilic attack.

I am wondering why HCl is formed, you used AlCl3? Indeed, my original thought for this Friedel Crafts reaction is to use mineral acid as the catalyst.

BTW, as mentioned above, the end product HCl is not the culprit, but the catalyst of this reaction, which are practically all acidic.

Yes I used AlCl3 as my Lewis acid.  Are there any alternative routes that you know of that could be taken to achieve this transformation?

[acarter5251]

Would it be possible to make the acid chloride then use phenyl magnesium bromide to form the benzophenone?

[kamiyu]

Agreed.

You may also consider cyano or ester group reacts with phenylmagnesium bromide to form the benzophenone, with the hydroxyl group protected.

[acarter5251]

Thank you very much!  I'll give the reaction of the acid chloride with phenyl magnesium bromide a try tomorrow

[kamiyu]

Just to remind you that it is worth going to SciFinder to check for the procedures/conditions for similar reaction.

Just a friendly reminder.

[rolnor]

Better use a cuprate or other softer nucleophile together with the acid chloride, othervise the initialy formed benzophenone can react further producing a alcohol. Benzonitrile though will react to form the ketone with a phenylmagnesiumbromide. March's Advanced Organic Chemistry cover this type of reaction well.

[acarter5251]

So, I made the nitrile from the aldehyde, followed by reaction with phenyl magnesium bromide and am not seeing the expected product. 

I added the Grignard slowly to the nitrile with lots of stirring and allowed it to go overnight.  I came back to a reaction mixture with a lot of white precipitate, added aqueous HCl and extracted, but my crude NMR is not showing anything that looks like my desired product. 

Are there any possible side products of adding phenyl magnesium bromide to a benzonitrile?  Would adding the nitrile into the Grignard make any difference?

[kamiyu]

So, I made the nitrile from the aldehyde, followed by reaction with phenyl magnesium bromide and am not seeing the expected product. 

I added the Grignard slowly to the nitrile with lots of stirring and allowed it to go overnight.  I came back to a reaction mixture with a lot of white precipitate, added aqueous HCl and extracted, but my crude NMR is not showing anything that looks like my desired product. 

Are there any possible side products of adding phenyl magnesium bromide to a benzonitrile?  Would adding the nitrile into the Grignard make any difference?

Sad to hear the reaction is not working. But there are a number of things worth noting:

1. What solvent did you use?

2. The white ppt may be the adduct of the PhMgBr on your nitrile or maybe just some inorganic Mg salt

3. Are you sure the PhMgBr you used is fresh? See: https://www.researchgate.net/post/How_to_measure_the_concentration_of_any_grignard_reagent_RMgX_in_situ

4. If the desired product is not present, then what is in the crude NMR? only the starting material? or wild mixture??

[acarter5251]

1.  I used DCM as my solvent.  The Grignard is a solution in ether though.

3.  I'm not positive how fresh the Grignard is.  The bottle was unopened, but it may have been a little old.

4.  The crude NMR contains peaks that correspond to the starting material, as well as additional peaks that are in the typical region for aromatic protons.  Not sure what they are, but they don't match up with the literature values for the proton NMR spectrum in the same solvent.

[kamiyu]

1. I used DCM as my solvent.  The Grignard is a solution in ether though.

3.  I'm not positive how fresh the Grignard is.  The bottle was unopened, but it may have been a little old.

4.  The crude NMR contains peaks that correspond to the starting material, as well as additional peaks that are in the typical region for aromatic protons.  Not sure what they are, but they don't match up with the literature values for the proton NMR spectrum in the same solvent.

Let me share with you some my own bench experiences.

When it comes to this sort of organometallic reagents, solvents can be important because of the level of aggregates. For example, in hexanes, n-BuLi is hexamer whose reactivity is weakened, while in THF, the aggregates are broken down so that the reactivity of n-BuLi increases.

As to DCM, I personally have the experience that a column chromatography which must use DCM and triethylamine (10% by volume) otherwise poor resolution. At the end of the day, my fraction will have some gel like things which is poorly soluble in DCM or acetone but water!! In the NMR, it shows a characteristic singlet peak at around 5.8 ppm (associated with a triplet and quartet in ratio of 6:9) . Indeed, this is the adduct between DCM and triethylamine.

Now, do you still think DCM and Grignard reagent are a good match with each other?

[acarter5251]

Very interesting!  Thanks for sharing your past experiences, and I will change the solvent to maybe THF and see what happens with my reaction.

Thank you so much!

[kamiyu]

1.  I used DCM as my solvent.  The Grignard is a solution in ether though.

3.  I'm not positive how fresh the Grignard is.  The bottle was unopened, but it may have been a little old.

4.  The crude NMR contains peaks that correspond to the starting material, as well as additional peaks that are in the typical region for aromatic protons.  Not sure what they are, but they don't match up with the literature values for the proton NMR spectrum in the same solvent.

This can be a source of uncertainty as well. Note that, Grignard reagent does not require storage in fridge (or the reagent will ppt in the solvent of storage)