Electrophilic aromatic substitution
Vilsmeier-Haack formylation
How the Vilsmeier-Haack formylation works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: DMF, POCl₃; then H₂O (NaOAc). Conditions: 0 °C → 25–80 °C; aqueous work-up. Bonds formed: C–C (Ar–CHO after hydrolysis); bonds broken: P–Cl; C=O (DMF); C–Cl. Stereochemistry: Para (or most electron-rich position) selective. Rate and selectivity: EAS step rate-limiting; arene must be electron-rich.
At a glance
Step 1: Vilsmeier reagent forms
POCl₃ activates DMF's carbonyl oxygen, and loss of a phosphate leaving group generates a highly electrophilic chloroiminium ion (the 'Vilsmeier reagent') — an iminium analog of an acylium ion, just built from formamide instead of an acid chloride.
Step 2: EAS on the electron-rich arene
An electron-rich arene (like an activated phenol ether or a pyrrole) attacks this chloroiminium ion — ordinary electrophilic aromatic substitution, forming the familiar resonance-stabilized arenium intermediate before losing a proton to restore aromaticity.
Step 3: Hydrolysis to the aldehyde
Aqueous hydrolysis of the resulting iminium salt reveals the aldehyde — this reagent combination formylates electron-rich arenes far too unreactive for the harsher Gattermann-Koch conditions covered earlier in this library.
Abbreviations and terms
- Ar
- Aryl group. Any aromatic ring substituent such as phenyl.
- OMe
- Methoxy. –OCH₃.
- DMF
- N,N-Dimethylformamide. Polar aprotic solvent – dissolves ionic nucleophiles but does not H-bond to them, speeding SN2 and SNAr.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- POCl3
- Phosphoryl chloride. Dehydrating/chlorinating agent (Vilsmeier, Bischler–Napieralski).
- EAS
- Electrophilic aromatic substitution. An electrophile replaces H on an arene via a Wheland intermediate.
- Wheland
- Wheland intermediate (arenium ion). The cyclohexadienyl cation formed when an electrophile adds to a benzene ring.
How it compares with related reactions
| Vilsmeier-Haack formylation | Bromination of benzene (FeBr₃-catalyzed) | Duff reaction | |
|---|---|---|---|
| Reagents | DMF, POCl₃; then H₂O (NaOAc) | Br₂ with FeBr₃ (Lewis-acid catalyst) | Hexamethylenetetramine (HMTA), acid (AcOH/glycerol or TFA); then H₃O⁺ |
| Conditions | 0 °C → 25–80 °C; aqueous work-up | Anhydrous, 25 °C, dark | Heat, 100–150 °C; aqueous hydrolysis |
| Stereochemistry | Para (or most electron-rich position) selective | None (planar, achiral) | Ortho-selective (OH directs; H-bonded iminium) |
| Rate / selectivity | EAS step rate-limiting; arene must be electron-rich | Slow step = arenium formation; deactivated rings react poorly | Moderate; electron-rich phenols only |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Vilsmeier-Haack formylation?
DMF, POCl₃; then H₂O (NaOAc). Conditions: 0 °C → 25–80 °C; aqueous work-up.
Which bonds are formed and which are broken?
Formed: C–C (Ar–CHO after hydrolysis). Broken: P–Cl; C=O (DMF); C–Cl.
What is the stereochemical outcome?
Para (or most electron-rich position) selective
What controls the rate or the selectivity?
EAS step rate-limiting; arene must be electron-rich
Study guides that help with this reaction
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go
- How to answer mechanism questions in an exam