the Vilsmeier Haack reaction mechanism

Organic Chemistry

Remember, earlier, we discussed the Friedel–Crafts acylation which is used for preparing aryl ketones by reacting aromatic compounds with an acyl halide in the presence of a Lewis acid catalyst.

Now, here is a question: how can we prepare an aryl aldehyde instead of an aryl ketone?

 

 

The difference in trying to introduce a -CHO group vs -CRO is that we’d need either formyl chloride or formyl anhydride, and none of them is stable enough to be used in electrophilic aromatic substitution.  

In 1925, A. Vilsmeier and co-workers found that certain aromatic compounds are capable of undergoing formylation (adding a -CHO) group upon treatment with dimethylformamide (DMF) and POCl3:

 

 

Let’s see how this happens. The reaction consists of two parts: in the first part, DMF reacts with POCl3 forming the Vilsmeier reagent which is a chloromethyliminium salt, and being electrophilic, it reacts with the aromatic ring to form an aryl aldehyde in the second step:

 

 

So, what are the similarities and differences between the Vilsmeier reaction and the Friedel-Crafts acylation? Well, they are similar in that they both rely on preparing an electrophile which is then reacted with the aromatic ring to attach a carbonyl. The evident difference is that in the Friedel-Crafts acylation, we can easily see how the ROCl will end up on the ring as -RCO and thus make a ketone.

In the Vilsmeier reaction, on the other hand, the actual electrophile is the iminium salt, and it is structurally not nearly as close to the -COH species. And this is because once on the ring, it is then hydrolyzed to an aldehyde. You may not have covered this in your class yet, but here is a short summary of the hydrolysis, and you can read more details in this article:

 

 

Aside from the visual difference, the iminium ion (Vilsmeier reagent) is a weaker electrophile than, the oxonium ion of the Friedel–Crafts acylation, because of a greater +M effect of the NMe2 group compared to that of -O-AlCl3–.

 

 

This is the reason why Vilsmeier–Haack formylations generally work with aromatic compounds containing electron-donating groups such as aniline, phenol, and their derivatives.

Another important parameter here is the H atom because had it been an R, a ketone would have formed instead of the aldehyde. The problem which this, however, is that alkyl groups, being electron donors, suppress the electrophilicity of the carbon, and also make it more sterically hindered.

 

 

Because of this, acylation via Vilsmeier reaction is generally more difficult to achieve.

Vilsmeier reaction works for heterocyclic compounds as well. For example, pyrrole reacts on the more electron-rich 2-position because of the electron-donating nitrogen atom:

 

 

Other electrophiles such as enols can also be used to react with a Vilsmeier reagent, however, it falls off the scope of this discussion. You can read further about the Vilsmeier reaction, in March’s Advanced Organic Chemistry, Bruckner’s Advanced Organic Chemistry, in the Strategic Applications of Name Reactions by László Kürti and Barbara Czakó, and other relevant literature by searching, for example, in web of science.

In the next article, we will also discuss the Gattermann-Koch Reaction which relies on using CO and HCl for introducing the -CHO group to aromatic rings.

 

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