Vilsmeier-Haack Reaction-百灵威

The Vilsmeier-Haack reaction or Vilsmeier-Haack formylation uses DMF, phosphoryl chloride (POCl₃), and water to convert an electron-rich arene to a substituted benzaldehyde. First, DMF and phosphoryl chloride form an iminium salt called the “Vilsmeier reagent”. Then the aromatic compound attacks the Vilsmeier reagent, disturbing its aromaticity. Deprotonation by DMF restores aromaticity, and a chloride ion is released to form an aryl iminium intermediate. Exposure to water affords the final aryl aldehyde.

Lab Tips:

Electron-rich alkenes and 1,3-dienes are also suitable substrates for this reaction. ^[1]
The relative reactivity of five-membered heterocycles is pyrrole > furan > thiopene. ^[2]
The reaction temperature, dependent on the reactivity of the substrate, ranges from below 0°C to up to 80°C. ^[2]
Formylation at the less sterically hindered (para) position on a substituted benzene ring is favored. ^[2] Electronic effects however may also influence product distribution.

_{1. Jones, G., Stanforth, S. P. The Vilsmeier reaction of non-aromatic compounds. Org. React. 2000, 56, 355-659.
2. Kürti, L., Czakó, B. (2005). Strategic Applications of Named Reactions in Organic Synthesis; Background and Detailed Mechanisms. Burlington, MA: Elsevier Academic Press.}

Reagents: DMF, Acid Chloride (POCl₃, SOCl₂, Oxalyl Chloride, etc.), Solvent (Halogenated Hydrocarbon, DMF, or POCl₃), Water
Reactant: Electron-Rich Aromatic or Heteroaromatic Compound
Product: Substituted Benzaldehyde or Heteroaromatic Aldehyde
Type of Reaction: Nucleophilic Addition (Vilsmeier Reagent Formation), Electrophilic Aromatic Substitution
Bond Formation: Ar-C=O

Mechanism

Original Paper

Vilsmeier, A.; Haack, A. Über Die Einwirkung von Halogenphosphor Auf Alkyl-Formanilide. Eine Neue Methode Zur Darstellung Sekundärer Und Tertiärer p-Alkylamino-Benzaldehyde Berichte der deutschen chemischen Gesellschaft (A and B Series) 1927, 60 (1), 119–122.

Top Citations

Efficient One-Pot Synthesis of Highly Substituted Pyridin-2(1H)-Ones via the Vilsmeier−Haack Reaction of 1-Acetyl,1-Carbamoyl Cyclopropanes. Org. Lett. 2007, 9 (12), 2421–2423.

Synthesis of α-Carbolines via Pd-Catalyzed Amidation and Vilsmeier−Haack Reaction of 3-Acetyl-2-Chloroindoles. Org. Lett. 2011, 13 (6), 1398–1401.

β-Formyl-BODIPYs from the Vilsmeier−Haack Reaction. J. Org. Chem. 2009, 74 (19), 7525–7528.

Related Compounds

DMF (CAS 68-12-2)

Phosphorous Oxychloride (CAS 10025-87-3)