Vilsmeier-Haack Reaction

Description: The Vilsmeier-Haack reaction is a way of installing an aldehyde on an electron-rich aromatic ring, using an electron-poor reagent (the Vilsmeier reagent) generated from DMF (N,N-dimethylformamide) and phosphorus oxychloride (POCl₃).

Notes:  The reaction does not work on benzene itself; the aromatic ring has to be quite electron-rich and have strong pi donors such as OCH3 and NR2. It also works well for electron-rich heterocycles such as pyrrole, furan, thiophene and indole.

See Also:  Friedel-Crafts acylation, Reimer-Tiemann reaction,

Examples:

Notes:

Note that the aromatic rings are all quite electron-rich, such as N,N-dimethylaniline (Example 1) and anisole (Example 2). Pyrrole and N-methylpyrrole (Example 3) are selective for the 2- position, as is benzofuran (Example 4).

The usual source of the aldehyde (-CHO) is N,N-dimethylformamide (DMF) but other formamides can be used, such as N-methylanilinamide (example 5) which works with anthracene.

Thiophene (Example 6) tends to be selective for the 2-position, but indole (Example 7) is selective for the 3-position.

Mechanism: 

The first step here is just thinking about the resonance structure of N,N-dimethylformamide (Step 1, arrows A and B).

In this reaction it’s the oxygen of DMF that is the nucleophile for the next step.

Part 1: Resonance Structure of DMF

OK. Now that we have our nucleophile identified, the first step is addition of that nucleophile to the electrophile POCl3 (Step 2, arrows C and D) to give the addition product.

Next, chloride ion is eliminated to re-form the P=O bond (Step 3, arrows E and F). Then the chloride ion acts as a nucleophile to attack the electrophilic carbon atom (Step 4, arrows G and H) to give the addition product, which then eliminates chloride (Step 5, arrows I and J) to give the Vilsmeier reagent . In this case Cl₂P(O)O(-) is the counter-ion.

Part 2: Formation of Vilsmeier Reagent

OK, now that we have our Vilsmeier reagent, it can now act as an electrophile in the presence of an electron-rich aromatic ring. The first step is attack of the ring on the Vilsmeier reagent (Step 1, arrows K and L) to form the new C-C bond, which then undergoes elimination to restore aromaticity (Step 2, arrows M and N).

Next, chloride ion is eliminated to form the new iminium ion (Step 3, arrows O and P).

At this step the iminium undergoes hydrolysis by water. These steps haven’t been drawn out but it’s covered here [Hydrolysis of imines].

The final product is a “formylated” aromatic ring with a new -CHO bond (an aldehyde).

This sequence is the “Vilsmeier-Haack” reaction.

Part 3: Vilsmeier-Haack Reaction

Notes:  We showed POCl₃ here, but there are many other electrophiles that can be used in the formation of the Vilsmeier reagent. A common one is oxalyl chloride (COCl)₂ , which is commonly used for formation of acid halides from carboxylic acids.

For many more examples, definitely check out the two reviews of the Vilsmeier-Haack reaction in Organic Reactions.

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(Advanced) References and Further Reading

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