Schmidt reaction

The Schmidt reaction is an organic reaction involving alkyl migration over the carbon to nitrogen chemical bond in an azide with expulsion of nitrogen. [cite book |author=Plagens, Andreas; Laue, Thomas M. |title=Named organic reactions | edition = 2nd Ed. |publisher=John Wiley & Sons |location=Chichester |year=2005 |pages= |isbn=0-470-01041-X |oclc= |doi= |accessdate=] 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:

and ketones form amides:

A catalyst is required which can be a protic acid usually sulfuric acid or a lewis acid. The reaction was discovered in 1924 by Karl Friedrich Schmidt (1887-1971) [cite journal | title = Über den Imin-Rest | author = Karl Friedrich Schmidt | journal = Ber. | year = 1924 | volume = 57 | pages = 704 | doi = 10.1002/cber.19240570423] 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

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.

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 a 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.

Reactions involving alkyl azides

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 [cite journal | title = The Acid-catalyzed Reaction of Alkyl Azides upon Carbonyl Compounds | author = J. H. Boyer and J. Hamer | journal = J. Am. Chem. Soc. | volume = 77 | issue = 4 | pages = 951–954 | doi = 10.1021/ja01609a045 | year = 1955] (hence the name Boyer reaction) for example the reaction of m-nitrobenzaldehyde with β-azido-ethanol:

Variations involving intramolecular Schmidt reactions have been known since 1991. [cite journal | title = Intramolecular Schmidt reaction of alkyl azides | author = Jeffrey Aube and Gregory L. Milligan | journal = J. Am. Chem. Soc. | year = 1991 | volume = 113 | issue = 23 | pages = 8965–8966 | doi = 10.1021/ja00023a065] An intramolecular reaction has been applied to the synthesis of novel bicyclic lactams: [cite journal | title = Cation-pi Control of Regiochemistry of Intramolecular Schmidt Reactions en Route to Bridged Bicyclic Lactams | author = Lei Yao and Jeffrey Aubé | journal = J. Am. Chem. Soc. | year = 2007 | volume = 129 | issue = 10 | pages = 2766–2767 | format = Communication | doi = 10.1021/ja068919r]

ee also

*Curtius rearrangement
*Hofmann rearrangement

References

Further reading

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