[22], Epoxides are a useful class of cation equivalents that react rapidly with alkyl azides in the presence of a Lewis acid to afford hydroxymethyl iminium ions. [1], Azides are nucleophilic at their terminal nitrogen atoms, and may add to suitably activated electrophiles in the presence of a Brønsted or Lewis acid. We also acknowledge previous National Science Foundation support under grant numbers 1246120, 1525057, and 1413739. This reaction has considerable utility for the synthesis of hindered or cyclic amides and amines. Lett., You can call them Electrophile and Nucleophile if you like. Don’t Forget Acid-Base Reactions; Did you know that more than half of organic chemistry is based on acid-base reaction? The formation of extremely explosive diazidomethane under these conditions has been observed. 1). In fact, this reaction is one of a select few that result in the selective insertion of nitrogen into the less hindered of two carbon-carbon bonds (Eq. Found: C, 62.76; H, 7.21; N, 9.11. In this reaction azide (conjugate base of hydrazoic acid) reacts with a carbonyl derivative (such as carboxylic acid, aldehyde, ketone) under acidic conditions to give amine or amides with release of nitrogen. [10], The mechanism of the reaction of carboxylic acids with hydrazoic acid is well understood. ... With MyLab and Mastering, you can connect with students meaningfully, even from a distance. The less substituted carbon rarely migrates (Eq. 17). 8). An important caution concerns the use of sodium azide in methylene chloride solutions for the synthesis of alkyl azides. [8] Stereogenic centers migrate with retention of configuration. 2627-2630. At this stage, one can envision two mechanistic pathways that lead to amides. Schmidt Reaction. 3). This is the product if an aldol addition reaction is heated for prolonged periods. Legal. [28] In addition, the initial isocyanate products can easily be converted to urethanes and ureas through treatment with alcohols or amines, an impossible transformation under the conditions of the Schmidt reaction. [19], One useful intermolecular method involves the use of hydroxyalkyl azides, whose pendant hydroxy groups may attack the intermediate oxocarbenium ion present after migration to form iminium ethers. Unless otherwise noted, LibreTexts content is licensed by CC BY-NC-SA 3.0. D. Caturvedi, A. K. Chaturvedi, N. Mishra, V. Mishra, Synlett, 2012, 23, The Schmidt reaction is the reaction of hydrazoic acid or an alkyl azide with a carbonyl compound, alkene, or alcohol, often in the presence of a Brønsted or Lewis acid. Reach every student. G. Fang, Z. Liu, S. Cao, H. Yuan, J. Zhang, L. Pan, Org. Master Organic Chemistry Reaction Guide. ↑ Ito, M.; Koyakumaru, K.-i. For these applications, the Schmidt reaction exhibits advantageous site selectivity and atom economy. For these reactions, the azide and carbonyl carbon must be separated by four or five atoms to facilitate cyclization, with four preferred (Eq. Click to Learn More! Although Schmidt reactions of carboxylic acids are certainly possible and have been studied in detail, the Curtius rearrangement of carboxylic acids to isocyanates is a much more mild and practical method for the synthesis of amines from carboxylic acids (Eq. Interruption of Formal Schmidt Rearrangement/Hosomi-Sakurai Reaction of [16] The behavior of heteroaromatic ketones is more difficult to predict. Although the family of Schmidt reactions includes a number of variants, they all result in the migration of a substituent from carbon to nitrogen with loss of a molecule of dinitrogen. [6] The observation of tetrazole side products at high concentrations of hydrazoic acid[7] and similar product ratios in conceptually related Beckmann and Schmidt reactions[8] provide evidence of the Beckmann-type mechanism in reactions of hydrazoic acid. Employing a chiral hydroxyalkyl azide resulted in highly diastereoselective migration, and subsequent removal of the nitrogen substituent produced the lactam as a single enantiomer. Like the Schmidt reaction, the site selectivity of the Beckmann rearrangement is generally controlled by stereoelectronic factors and the relative prevalence or reactivity of geometric isomers. Substrates containing five-carbon tethers react only in the presence of relatively strong Lewis acids. It is a rearrangement reaction. The Schmidt reaction of carboxylic acids, which produces amines, is in direct competition with the milder Curtius rearrangement,[4] and is rarely used in practice. 2, blue pathway), the azidohydrin may rearrange to afford amides directly after loss of a proton. The mechanisms of reactions of ketones with hydrazoic acid begin with addition of HN3 to the carbonyl group to form adizohydrin intermediate I. The acid-catalysed reaction of hydrogen azide with electrophiles, such as carbonyl compounds, tertiary alcohols or alkenes. Intermolecular reactions of benzylic and tertiary cations with alkyl azides are also known. After a rearrangement and extrusion of N 2, amines, nitriles, amides or imines are produced. Make a chart of reactions of a specific class of compounds to master organic chemistry. [20], Many Schmidt reactions of cationic electrophiles are subject to carbocationic rearrangements. 14; however, an appropriately positioned alkyl azide was smoothly converted to the lactam in the presence of TFA. Organic Chemistry Quizzes, Practice Exams, Study Guides, Reaction Guides and More! The Diels-Alder Reaction. The range of ketones that engage in the intramolecular Schmidt reactions is exceptionally broad.