[acarter5251]

Hello,

I am currently trying to synthesize a benzophenone from either vanillin or vanillonitrile using phenyl magnesium bromide as a reactant.  I have tried many different protocols that I have found in the literature, but every time I do the reaction, I seem to get many different side products and it turns into a total mess.  I have been using THF as my solvent, adding the Grignard to the substrate and vice versa.  I have tried doing the reaction with the flask in an ice bath; I have tried adding reagents very slowly, all with no success.  Are there any suggestions someone with more experience could share to help with performing a reaction such as this?

Thanks in advance!

[AWK]

Vanilin has a phenol group free and decomposes Grignard reagent.

[acarter5251]

If I were using an excess of Grignard, would this still present the problem?  Or is it better to protect the phenol prior to reacting with the Grignard?

[AWK]

Usually phenol group is protected by TMSCl.

[wildfyr]

Use a bulkier silyl chloride (TBDMS or TIPS) for increased water stability during silyl ether synthesis and the grignard reaction workup. But AWK is totally right. Also, you should still do it cold and slow.

[acarter5251]

If you don't mind my asking, why does the presence of the phenol interfere so much with the reaction?  My thought was that I would have an equivalent of PhMgBr reacting with the phenol to deprotonate and form benzene, while any additional equivalents would then add to the nitrile or aldehyde to form the benzophenone/alcohol (respectively).  Then, acidic workup would give the phenol again and the benzene could be evaporated from the mixture when drying.  Is there anything that I am missing that presents problems?

Not calling your suggestions into question, just want to learn where I went wrong!

[AWK]

Benzene change solubility of PhMgBr in THF (solid). Vanilin derivative with -OMgBr group is solid. May be PhMgBr on prolonged time (since reaction between solids is slow) gives Ph₂Mg. Grignard reagent easily reacts with H2O, CO₂ and O₂. Choose the best explanation(s) or give another one(s).
There is no easy explanation. Many scientists for above 100 years have studied this complex reaction and experimentally found optimized conditions.