Schmidt reaction

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The Schmidt reaction is an organic reaction involving alkyl migration over the carbonnitrogen chemical bond in an azide with expulsion of nitrogen.[1][2] A key reagent introducing this azide group is hydrazoic acid and the reaction product depends on the type of reactant: Carboxylic acids form amines through an isocyanate intermediate (1) and ketones form amides (2):

Schmidt reaction

A catalyst that can be a protic acid – usually sulfuric acid or a Lewis acid – is required. The reaction was discovered in 1924 by Karl Friedrich Schmidt (1887–1971),[3] who successfully converted benzophenone and hydrazoic acid to benzanilide. It is a tool regularly used in organic chemistry for the synthesis of new organic compounds, for example, in that of the unusual 2-quinuclidone.

Reaction mechanism[edit]

The carboxylic acid Schmidt reaction starts with acylium ion 1 obtained from protonation and loss of water. Reaction with hydrazoic acid forms the protonated azido ketone 2, which goes through a rearrangement reaction with the alkyl group R, migrating over the C-N bond with expulsion of nitrogen. The protonated isocyanate is attacked by water forming carbamate 4, which after deprotonation loses carbon dioxide to the amine.

Schmidt reaction mechanism amine formation

The reaction is related to the Curtius rearrangement except that in this reaction the azide is protonated and hence with different intermediates.

In the reaction mechanism for the ketone Schmidt reaction, the carbonyl group is activated by protonation for nucleophilic addition by the azide, forming intermediate 3, which loses water in an elimination reaction to temporary imine 4, over which one of the alkyl groups migrates from carbon to nitrogen with loss of nitrogen. A similar migration is found in the Beckmann rearrangement. Attack by water and proton loss converts 5 to 7, which is a tautomer of the final amide.

Schmidt reaction mechanism amide formation

Reactions involving alkyl azides[edit]

The scope of this reaction has been extended to reactions of carbonyls with alkyl azides R-N3. This extension was first reported by J.H. Boyer in 1955 [4] (hence the name Boyer reaction), for example, the reaction of m-nitrobenzaldehyde with β-azido-ethanol:

The Boyer reaction

Variations involving intramolecular Schmidt reactions have been known since 1991.[5] An intramolecular reaction has been applied to the synthesis of novel bicyclic lactams:[6]

Intramolecular Schmidt Reaction

See also[edit]

References[edit]

  1. ^ Plagens, Andreas; Laue, Thomas M. (2005). Named organic reactions (2nd ed.). Chichester: John Wiley & Sons. ISBN 0-470-01041-X. 
  2. ^ Wolff, H. Org. React. 1946, 3.
  3. ^ Schmidt, K. F. (1924). "Über den Imin-Rest". Berichte der deutschen chemischen Gesellschaft (A and B Series) 57 (4): 704–723. doi:10.1002/cber.19240570423.  edit
  4. ^ J. H. Boyer and J. Hamer (1955). "The Acid-catalyzed Reaction of Alkyl Azides upon Carbonyl Compounds". J. Am. Chem. Soc. 77 (4): 951–954. doi:10.1021/ja01609a045. 
  5. ^ Jeffrey Aube and Gregory L. Milligan (1991). "Intramolecular Schmidt reaction of alkyl azides". J. Am. Chem. Soc. 113 (23): 8965–8966. doi:10.1021/ja00023a065. 
  6. ^ Lei Yao and Jeffrey Aubé (2007). "Cation–π Control of Regiochemistry of Intramolecular Schmidt Reactions en Route to Bridged Bicyclic Lactams" (Communication). J. Am. Chem. Soc. 129 (10): 2766–2767. doi:10.1021/ja068919r. PMC 2596723. PMID 17302421. 

Further reading[edit]