| Schmidt reaction | |
|---|---|
| Named after | Karl Friedrich Schmidt |
| Reaction type | Rearrangement reaction |
| Identifiers | |
| Organic Chemistry Portal | schmidt-reaction |
| RSC ontology ID | RXNO:0000170 |
Inorganic chemistry, theSchmidt reaction is anorganic reaction in which anazide reacts with acarbonyl derivative, usually analdehyde,ketone, orcarboxylic acid, under acidic conditions to give anamine oramide, with expulsion ofnitrogen.[1][2][3] It is named afterKarl Friedrich Schmidt (1887–1971), who first reported it in 1924 by successfully convertingbenzophenone andhydrazoic acid tobenzanilide.[4] Theintramolecular reaction was not reported until 1991[5] but has become important in the synthesis of natural products.[6]The reaction is effective withcarboxylic acids to give amines (above), and withketones to give amides (below).
The reaction is closely related to theCurtius rearrangement except that in this reaction the acyl azide is produced by reaction of the carboxylic acid with hydrazoic acid via the protonated carboxylic acid, in a process akin to aFischer esterification. An alternative, involving the formation of an acylium ion, becomes more important when the reaction takes place in concentrated acid (>90%sulfuric acid).[7] (In the Curtius rearrangement, sodium azide and an acyl chloride are combined to quantitatively generate the acyl azide intermediate, and the rest of the reaction takes place under neutral conditions.)
The carboxylic acid Schmidt reaction starts withacylium ion1 obtained fromprotonation and loss of water. Reaction withhydrazoic acid forms the protonated azido ketone2, which goes through arearrangement reaction with the alkyl group R, migrating over the C-N bond with expulsion of nitrogen. The protonatedisocyanate is attacked by water formingcarbamate4, which after deprotonation losescarbon dioxide to theamine.
In the reaction mechanism for the Schmidt reaction ofketones, the carbonyl group is activated by protonation fornucleophilic addition by the azide, forming azidohydrin3, which loses water in anelimination reaction to diazoiminium 5. One of the alkyl or aryl groups migrates from carbon to nitrogen with loss of nitrogen to give a nitrilium intermediate6, as in theBeckmann rearrangement. Attack by water converts6 to protonated imidic acid7, which undergoes loss of proton to arrive at the imidic acidtautomer of the finalamide. In an alternative mechanism, the migration occurs at9, directly after protonation of intermediate3, in a manner similar to theBaeyer–Villiger oxidation to give protonated amide10. Loss of a proton again furnishes the amide. It has been proposed that the dehydration to3 to give5 (and, hence, the Beckmann pathway) is favored by nonaqueous acids like conc. H2SO4, while aqueous acids like conc. HCl favor migration from9 (the Baeyer-Villiger pathway). These possibilities have been used to account for the fact that, for certain substrates likeα-tetralone, the group that migrates can sometimes change, depending on the conditions used, to deliver either of the two possible amides.[8]
The scope of this reaction has been extended to reactions of carbonyls with alkylazides R-N3. This extension was first reported by J.H. Boyer in 1955[9] (hence the nameBoyer reaction), for example, the reaction of3-nitrobenzaldehyde with β-azido ethanol:
Variations involving intramolecular Schmidt reactions have been known since 1991.[5] These areannulation reactions and have some utility in the synthesis of natural products;[6][10] such aslactams[11] andalkaloids.[12]
