Chemistry
Schmidt Reaction
The Schmidt reaction is a chemical reaction that involves the conversion of a carboxylic acid to an amide by reaction with hydrazoic acid (HN3) in the presence of a catalyst such as silver nitrate. The reaction proceeds through an intermediate isocyanate, which is then hydrolyzed to form the amide. This reaction is widely used in organic synthesis for the preparation of amides.
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4 Key excerpts on "Schmidt Reaction"
eBook - PDF- Jie Jack Li(Author)
- 2009(Publication Date)
- Wiley(Publisher)
This process is somewhat related to the Beckmann rearrangement of oximes; however, the Schmidt Reaction is more succinct, allowing the conversion of ketones to amides in a single operation. Considering its widespread 354 Name Reactions for Homologations-2 application in synthesis, the Schmidt Reaction with ketones is the focus of this chapter. 1.2.6.2 Historical Perspecthe The Schmidt Reaction was discovered in 1924 by Karl Friedrich Schmidt (1887-1971) who successfully converted benzophenone to benzanilide using hydrazoic acid.’-6 Schmidt collaborated with Curtius at the University of Heidelberg, where Schmidt became a Professor of Chemistry in 1923. 1.2.6.3 Mechanism The Schmidt Reaction of carboxylic acids proceeds via acylium ion, which undergoes addition with hydrazoic acid to generate acyl azide. This azide rearranges with loss of nitrogen to give isocyanate, which leads to an amine upon hydr~lysis.~ Reaction of ketones with hydrazoic acid gives azidohydrin intermediates, which undergo rearrangement to form arnide~.~ The iminocarbonium ions can further react with hydrazoic acid, thus resulting in tetrazoles as the common by-products. Tetrazole formation is favoured when a large excess of hydrazoic acid is empl~yed.~ Chapter 1. Rearrangements 355 Addition of hydrogen azide to olefins results in alkyl azides, which rearranges to form imines.* R R R -H @ R R R - H* \ - H - ) + NH R N-R Tertiary alcohols are converted to azides via carbenium ions, and these azides rearrange to generate imines.' "Fi " d 1.2.6.4 Variations and Improvements The Schmidt Reaction of ketones with hydrazoic acid requires the presence of an acid catalyst. Sulfuric acid is the most common catalyst, but Lewis acids have also been utilized. Hydrazoic acid is usually made in situ by treatment of sodium azide with sulphuric acid. The strongly acidic conditions can bring about decomposition of acid-sensitive substrates and result in undesired by-products.
eBook - PDF- Thomas Laue, Andreas Plagens(Authors)
- 2005(Publication Date)
- Wiley-Interscience(Publisher)
An important side-reaction however is the formation of nitriles 13, resulting in a significant lower yield of amides, as compared to the reaction of ketones. Sometimes the nitrile 13 even is the major product formed: R C O H C H O NHR RCN 11 12 13 Schmidt Reaction 253 When applied to a cycloketone, the Schmidt Reaction leads to formation of a ring-expanded lactam—e.g. 14 ! 15: 5 O R N R H O 14 15 In recent years the applicability of the Schmidt Reaction for the synthesis of more complex molecules—especially the variant employing alkyl azides—has been further investigated. Cycloketones bearing an azidoalkyl side-chain at the ˛-carbon center have been shown to undergo, upon treatment with trifluoroacetic acid or titanium tetrachloride, an intramolecular Schmidt Reaction to yield bicyclic lactams. e.g. 16 ! 17. 6 Intermolecular Schmidt Reactions of alkyl azides and hydroxyalkyl azides with cycloketones in the presence of a Lewis acid, lead to formation of N-alkyl lactams and N-hydroxyalkyl lactams respectively in good yield. 7 The synthesis of chiral lactams by an asymmetric Schmidt Reaction has also been reported. 8 By application of the Schmidt Reaction, the conversion of a carboxylic acid into an amine that has one carbon atom less than the carboxylic acid, can be achieved in one step. This may be of advantage when compared to the Curtius reaction or the Hofmann rearrangement ; however the reaction conditions are more drastic. With long-chain, aliphatic carboxylic acids yields are generally good, while with aryl derivatives yields are often low. The Schmidt Reaction of ketones works best with aliphatic and alicyclic ketones; alkyl aryl ketones and diaryl ketones are considerably less reactive. The reaction is only seldom applied to aldehydes as starting materials. The hydrazoic acid used as reagent is usually prepared in situ by treatment of sodium azide with sulfuric acid. Hydrazoic acid is highly toxic, and can detonate upon contact with hot laboratory equipment.
eBook - PDFScience of Synthesis: Houben-Weyl Methods of Molecular Transformations Vol. 21
Three Carbon-Heteroatom Bonds: Amides and Derivatives; Peptides; Lactams
- Steven M. Weinreb(Author)
- 2014(Publication Date)
- Thieme Chemistry(Publisher)
The Schmidt Reaction is related in many ways to the Beckmann rearrangement of ketone-derived oximes (see Section 21.1.5.4); however, the former process is more succinct, allowing the direct conversion of the ketone into an amide. The ketone-to-amide conversion with hydrazoic acid requires the presence of an acid catalyst. Concentrated sulfuric acid is most commonly employed for this purpose, al- though Lewis acids can also be used. Hydrazoic acid is usually prepared in situ by treat- ment of sodium azide with concentrated sulfuric acid. An alternative method of generat- ing hydrazoic acid involves the reaction of polyphosphoric acid with sodium azide. [39] SAFETY: Hydrazoic acid is violently explosive and of variable sensitivity in concen- trated or pure states. It is a severe irritant with effects on the central nervous system. 146 Science of Synthesis 21.1 Amides Scheme 17 The Schmidt Reaction of Ketones with Hydrazoic Acid [36–38] R 1 R 2 O + HN 3 H + R 1 NHR 2 O Two pathways have been proposed for the acid-catalyzed conversion of ketones into amides with hydrazoic acid (Scheme 18). [36] Each begins with the addition of the azide to the activated ketone, affording the common intermediate 42. In path a, synchronous al- kyl or aryl group migration occurs with loss of nitrogen, giving the corresponding amide directly. In this route, the relative migratory aptitudes should determine the course of the transformation. In path b, initial dehydration affords iminodiazonium ion 43, which un- dergoes rearrangement with concomitant loss of nitrogen through migration of the sub- stituent oriented anti to the diazonium leaving group to form an iminocarbonium ion 44. Finally, rehydration and tautomerization lead to the amide products.
eBook - PDFOrganic Azides
Syntheses and Applications
- Stefan Bräse, Klaus Banert, Stefan Bräse, Klaus Banert(Authors)
- 2011(Publication Date)
- Wiley(Publisher)
The resulting aziridine is then cleaved, restoring aromaticity. Finally, migration of the methylene group occurred and upon workup, ketone 39 was obtained. 7.7 Combined Schmidt Rearrangement Cascade Reactions Domino reactions, which combine sequential transformations in a single pot, can allow the rapid development of complex products from simple starting materials. 56–58 One design feature required for successful domino process involves control over the order of reaction events. Since Bronsted acids or Lewis acids are required for the initiation of nearly all azido-Schmidt Reactions, combining such reactions with other acid-accelerated processes presents a logical starting point for assembling Schmidt-centric tandem reactions. Initial attempts to utilize the Schmidt Reactions of azides and ketones focused on combining that process with the ubiquitous Diels–Alder cycloaddition reaction. The first example of a combined Diels–Alder/Schmidt Reaction was made in the context of a formal total synthesis of ( ±)-stenine, 59 which led to a detailed examination of the scope and the development of the overall sequence. 60 Since intermolecular Schmidt Reactions of ketones are much less facile than their intramolecular counterparts, the prior unifica- tion of ketone and azide through a Diels–Alder cycloaddition can facilitate an intramo- lecular Schmidt Reaction. Thus, when an azide-containing diene 40 was combined with 2-cyclopentenone in the presence of MeAlCl 2 , tricyclic lactam 41 was obtained in modest yield (Scheme 7.34). Another strategy employed was to inhibit the intramolecular reaction of an azido and keto group within the same molecule through the incorporation of enone separating the two groups. When 42 was treated with butadiene in the pres- ence of MeAlCl 2 , bicyclic amide 43 was formed in moderate yield.
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