Vilsmeier-Haack reaction

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The Vilsmeier-Haack reaction , more often just called the Vilsmeier reaction , is a name reaction in organic chemistry . It was named after the German chemists Anton Vilsmeier and Albrecht Haack . The reaction originally referred to the formylation of activated aromatics with N , N -disubstituted formamides using phosphorus oxychloride (POCl 3 ). The scope of this reaction has continuously expanded.

It is sometimes also named after Zdenek Arnold (1922–1996), a Prague chemist, who extended it to a large number of aliphatic substrates in a long series of works from 1958 to 1978 (all with the title Synthetic reactions of Dimethylformamide ) (Vilsmaier-Haack -Arnold Formylations, VHA).

scope of application

The enormous scope of the reaction is described in several review articles. In addition to formylation, it also extends to benzoylation . Besides electron-rich aromatics, alkenes, easily dehydrating alcohols, enolizable ketones and carboxylic acid derivatives , acetals, enol ethers, enamines and other compounds can also be acylated. The amide components used are N , N - dimethylformamide , the more reactive N -methylformanilide , and in individual cases primary and unsubstituted carboxamides and thiocarboxamides . In the order of decreasing reactivity, the oxyhalides used are phosphoryl chloride , phosgene and thionyl chloride . Oxalyl chloride can serve as a phosgene substitute.

Overview reaction

The reaction of N , N -dimethylaniline with a formamide is shown as an example in the following reaction . The radicals R 1 and R 2 can be aryl or alkyl radicals .

Overview reaction of the Vilsmeier reaction

Be in the Vilsmeier reaction preferably para - products formed. It is limited to electron-rich aromatics, such as. B. phenols , amines or furans . Other acid halides can also be used for the reaction . In addition, numerous alkenes can be made to extend the chain. This reaction belongs to B. the Gattermann synthesis , the Gattermann-Koch synthesis or the Kreutzberger formylation to a group of reactions. These use derivatives of formyl chloride , which are not freely stable, in the sense of Friedel-Crafts acylation for the formylation of activated aromatics. In contrast to the Gattermann synthesis, secondary and tertiary amines can also be reacted in the Vilsmeiers reaction . In addition, it is one of the most important formylations on aromatics, since the use of excess dimethylformamide means that further solvents can be dispensed with.

Reaction mechanism

A possible reaction mechanism is presented below. The mechanism is shown using the example of N , N -dimethylaniline with dimethylformamide . First, the so-called Vilsmeier reagent, a chloriminium ion, is formed from the formamide and the phosphorus oxychloride :

Formation of the Vilsmeier reagent

For this purpose, the oxygen atom of the dimethylformamide ( 1 ) attacks the phosphorus atom of the phosphorus oxychloride ( 2 ). Then a chlorine atom is attached to the α - carbon atom of 3 . Finally, the oxygen is split off and the chloriminium ion 4 is formed . The chloriminium ion reacts in an electrophilic aromatic substitution reaction with the activated aromatic:

Mechanism of the Vilsmeier reaction

The Vilsmeier reagent 4 electrophilically attacks the aniline derivative 5 and then forms the reactive intermediate 6 through rearomatization . After a chloride ion has been split off, hydrolysis takes place with the formation of intermediate stage 7 . The ammonium ion 8 is formed by a 1.3 proton shift . Finally, the secondary amine (here dimethylamine ) and a proton are split off with formation of 4- (dimethylamino) benzaldehyde ( 9 ).

Individual evidence

  1. ↑ Anton Vilsmeier , A. Haack: On the action of halophosphorus on alkylformanilides. A new method for the representation of secondary and tertiary p -alkylaminobenzaldehydes in: Chemischeberichte 60, 1927, p. 119, doi : 10.1002 / cber.19270600118 .
  2. ^ E. Campaigne, WL Archer: p-Dimethylaminobenzaldehyde In: Organic Syntheses . 33, 1953, p. 27, doi : 10.15227 / orgsyn.033.0027 ; Coll. Vol. 4, 1963, p. 331 ( PDF ).
  3. ^ Andraos, Named organic reactions, section Albrecht Haack .
  4. ↑ Christian Reichardt: Vilsmeier – Haack – Arnold Formylations of Aliphatic Substrates with N-Chloromethylene-N, N-dimethylammonium Salts. J. Pract. Chem. 341 (1999) No. 7, pp. 609-615.
  5. ^ Dürr H. in Houben-Weyl, Methods of Organic Chemistry , Chapter 1.4.1.2, Page 149, Volume E3, Fourth Edition, Thieme Verlag.
  6. ↑ Sasikala, KA (2010): Vilsmeier-Haack reactions in synthesis of Heterocycles: An Overview , Chapter 2 of the doctoral thesis.
  7. ^ O. Meth-Cohn, SP Stanforth: The Vilsmeier-Haack Reaction in: Comp. Org. Syn. 2, 1991, pp. 777-794, doi : 10.1016 / B978-0-08-052349-1.00049-4 .
  8. ↑ Rajanna KC et al. (2013): Kinetics and mechanism of certain benzoylation reactions under Vilsmeier-Haack conditions using benzamide and oxychloride in acetonitrile medium , International Journal of Chemical Kinetics , pages 69-80, Volume 45, Issue 2, doi : 10.1002 / kin.20740 .
  9. ↑ a b W. Uhl, A. Kyritsoulis: Name and keyword reactions in organic chemistry . Friedr. Vieweg & Sohn Verlag, Braunschweig 1984, ISBN 3-528-03581-1 , p. 155-156 .
  10. ↑ a b T. Laue, A. Plagens: Name and catchword reactions of organic chemistry . 5th, through. Edition. Teunner Verlag, Wiesbaden 2006, ISBN 3-8351-0091-2 , p. 330-332 .