Schmidt Rearrangement

What Is Schmidt Rearrangement?

The Schmidt rearrangement (also known as the Schmidt reaction) is the acid-catalyzed reaction of hydrazoic acid (HN₃) with carbonyl compounds (ketones or aldehydes), carboxylic acids, tertiary alcohols, or alkenes to give amines, amides, or nitriles with the extrusion of nitrogen gas. The most synthetically useful variant of the reaction involves the conversion of ketones to amides via a 1,2-alkyl or aryl migration. The reaction was first reported in 1923 by Karl Friedrich Schmidt, a German chemist, after whom it is named.

The Schmidt rearrangement holds a prominent position in organic synthesis because it offers a direct, one-step method for the interconversion of carbonyl compounds and amines/amides. The reaction is mechanistically related to the Beckmann rearrangement, the Curtius rearrangement, and the Hofmann rearrangement; all involve nitrogen-to-carbon migration with loss of nitrogen or an equivalent leaving group. The Schmidt rearrangement is particularly valuable because it does not require the preparation of an oxime, acyl azide, or amide intermediate - the hydrazoic acid is added directly to the carbonyl substrate. However, the extreme toxicity and explosive nature of hydrazoic acid has limited its large-scale application. Safer alternatives, such as using NaN₃/acid or TMSN₃/acid, have been developed to generate HN₃ in situ.

• Reagents: HN₃ or azide sources: NaN₃ + strong acid (H₂SO₄, H₃PO₄, polyphosphoric acid, or methanesulfonic acid); TMSN₃ + acid. Strong Bronsted or Lewis acids are required to activate the carbonyl compound.
• Reactants: Carbonyl compounds: ketones, aldehydes; also carboxylic acids (giving amines via Curtius-type pathway) and tertiary alcohols or alkenes (via carbocation intermediates).
• Products: From ketones: amides (via N-insertion with 1,2-migration). From aldehydes: nitriles. From carboxylic acids: amines (via Curtius-type decarboxylation-rearrangement). From tertiary alcohols/alkenes: imines or amines (via Ritter-type pathway).
• Reaction Type: Acid-catalyzed 1,2-rearrangement with nitrogen insertion; nitrogen extrusion-migration cascade.
• Related Reactions: Beckmann rearrangement (oxime to amide via acid catalysis); Curtius rearrangement (acyl azide to isocyanate to amine); Hofmann rearrangement (amide to amine via isocyanate); Ritter reaction (nitrile + carbocation to amide).
• Experimental Tips:
  SAFETY WARNING: Hydrazoic acid is extremely toxic (comparable to hydrogen cyanide) and potentially explosive. All reactions should be conducted in a well-ventilated fume hood with appropriate personal protective equipment.
  a) In situ generation: NaN₃ is added portionwise to the carbonyl substrate in strong acid (e.g., H₂SO₄ or methanesulfonic acid) at 0-25 °C. This generates HN₃ in situ and minimizes handling of the free acid.
  b) Regioselectivity: For unsymmetrical ketones, the more electron-rich alkyl group migrates preferentially. The migratory aptitude generally follows the order: benzyl > phenyl > tertiary alkyl > secondary alkyl > primary alkyl > methyl.

Fig 1. Schmidt rearrangement reaction and its mechanism. [1]

Mechanism of Schmidt Rearrangement

Ketone-to-Amide Pathway

The Schmidt rearrangement of ketones begins with acid-catalyzed protonation of the carbonyl oxygen, generating an oxocarbenium ion. Hydrazoic acid adds to the activated carbonyl to form an alpha-azido alcohol intermediate. Protonation of the azide group followed by elimination of water generates an alpha-diazonium iminium intermediate. This highly energetic species undergoes a concerted 1,2-shift of one of the alkyl (or aryl) substituents from carbon to nitrogen, with concomitant loss of nitrogen gas (N₂). The resulting nitrilium ion is hydrolyzed during aqueous workup to give the corresponding amide. The overall transformation results in formal insertion of an NH group between the carbonyl carbon and one of its alpha-substituents.

Aldehyde-to-Nitrile Pathway

When the substrate is an aldehyde, the 1,2-shift involves migration of the hydrogen atom. The resulting intermediate is directly a nitrile, which is stable and does not require hydrolysis. This pathway provides a convenient synthesis of nitriles from aldehydes under acidic conditions.

Carboxylic Acid and Tertiary Alcohol Pathways

When carboxylic acids are used as substrates, the reaction follows a Curtius-type mechanism: the acyl azide intermediate undergoes Curtius rearrangement (loss of N₂ and migration to form an isocyanate), which then hydrolyzes to give the amine with one fewer carbon atom (decarboxylation). With tertiary alcohols or alkenes, acid-catalyzed formation of a carbocation is followed by Ritter-type capture by HN₃ (or its equivalent) and subsequent rearrangement to amines or imines.

Application Examples of Schmidt Rearrangement

• Lactam Synthesis: The Schmidt rearrangement of cyclic ketones is one of the most efficient methods for the preparation of lactams. For example, cyclohexanone is converted to epsilon-caprolactam, the monomer for Nylon-6, on an industrial scale. The reaction of substituted cyclohexanones provides regioselective access to substituted caprolactams, which are valuable building blocks for pharmaceutical synthesis.
• Synthesis of Isoquinolone and Related Heterocycles: The intramolecular Schmidt reaction of delta-azido ketones or related precursors has been developed as a powerful method for the construction of nitrogen heterocycles. Under acidic conditions, the tethered azide reacts with the ketone to generate a fused bicyclic lactam system. This approach has been applied to the synthesis of isoquinolones, benzazepinones, and related pharmacologically relevant scaffolds.
• Natural Product Synthesis: The Schmidt rearrangement has been employed as a strategic transformation in the total synthesis of various alkaloid natural products. The ability to install a nitrogen atom directly into a carbocyclic framework makes it an attractive disconnection for the synthesis of complex amines and amides. Cheoljae Kim et al. synthesized the tricyclic core structure of stemonamine alkaloids via a one-pot gold (I) catalytic cyclization and Schmidt rearrangement reaction. [2]
• Formation of Amides and Nitriles: Liu et al. reported a new synthetic route in which trifluoromethanesulfonic anhydride, formic acid and acetic acid can activate the bulk chemical nitromethane, making it a nitrogen donor in a Schmidt-like reaction, replacing the azide. This method can be used for the synthesis of amides and nitriles of alkynes and simple alkylbenzenes. [3]

Fig 2. Synthetic examples via Schmidt rearrangement reaction.

Related Products

CAS No.	Structure	Product
159610-89-6		Fmoc-azidolysine
100-83-4		3-Hydroxybenzaldehyde
1000340-35-1		4-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde
1000341-64-9		6-Chloro-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde
1001020-14-9		3-(Trifluoromethyl)-1H-pyrazole-4-carbaldehyde
104-09-6		p-tolylacetaldehyde
104-53-0		3-Phenylpropionaldehyde
109346-94-3		2-(3,5-Difluorophenyl)acetaldehyde
109347-40-2		(3-BROMOPHENYL)ACETALDEHYDE
109347-45-7		2-(4-tert-Butylphenyl)acetaldehyde
122-57-6		Benzalacetone
122-84-9		4-Methoxyphenylacetone
131-55-5		2,2',4,4'-Tetrehydroxybenzophenone
131-56-6		2,4-Dihydroxybenzophenone
131-57-7		Oxybenzone
131-58-8		2-Methylbenzophenone
13103-80-5		1- (3- Hydroxyphenyl) - 1- propanone

References

1. Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 483-485.
2. Kim, Cheoljae, et al. The Journal of Organic Chemistry 79.22 (2014): 11119-11124.
3. Liu, Jianzhong, et al. Science 367.6475 (2020): 281-285.

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