What Is Wolff Rearrangement?
The Wolff rearrangement is the conversion of an alpha-diazoketone into a ketene via a 1,2-rearrangement with concomitant extrusion of nitrogen gas (N2). The reaction can be initiated thermally, photochemically, or by transition-metal catalysis (typically silver(I) oxide or silver(I) salts). The resulting ketene is highly reactive and is usually trapped in situ by a nucleophile (water, alcohol, or amine) to give the corresponding carboxylic acid, ester, or amide with one additional carbon atom. When combined with the preparation of the alpha-diazoketone from an acyl chloride and diazomethane, the overall sequence constitutes the Arndt-Eistert homologation, which is the most important application of the Wolff rearrangement. The reaction was first reported in 1902 by Ludwig Wolff, a German chemist, after whom it is named.
The Wolff rearrangement occupies a unique position in organic synthesis as the key step in the Arndt-Eistert reaction, one of the most reliable methods for the one-carbon homologation of carboxylic acids. The reaction proceeds through a ketocarbene (or carbenoid) intermediate that undergoes a 1,2-shift of the group adjacent to the carbonyl to form the ketene. The migratory aptitude in the Wolff rearrangement follows the order: H > aryl > alkyl, which is the reverse of the migratory aptitude in the related Curtius, Schmidt, and Beckmann rearrangements. This unusual selectivity arises from the different electronic nature of the migrating terminus in the ketocarbene intermediate. The reaction has also been employed in the construction of strained ring systems, where the ketene intermediate can undergo intramolecular cycloaddition reactions, and in photochemical transformations of diazoketones for the synthesis of complex polycyclic frameworks.
- Reagents: Thermal or photochemical initiation; transition-metal catalysts: silver(I) oxide (Ag2O), silver benzoate (AgOCOPh), or other Ag(I) salts; nucleophiles for in situ ketene trapping: H2O to carboxylic acid, ROH to ester, RNH2 to amide.
- Reactants: Alpha-diazoketones (R-CO-CHN2), typically prepared from the corresponding acyl chloride and diazomethane. The R group can be alkyl, aryl, alkenyl, or heteroaryl.
- Products: Ketenes (R-CH=C=O), usually trapped in situ to give carboxylic acids, esters, or amides with one additional carbon atom (Arndt-Eistert homologation). The ketene can also undergo [2+2] cycloaddition or other pericyclic reactions if not trapped by a nucleophile.
- Reaction Type: 1,2-Rearrangement via ketocarbene intermediate.
- Related Reactions: Arndt-Eistert reaction (acid to acid chloride to alpha-diazoketone to Wolff rearrangement to homologated acid); Curtius rearrangement; Lossen rearrangement; Beckmann rearrangement.
- Experimental Tips:
a) Alpha-diazoketone preparation: The acyl chloride is treated with 2-3 equiv of diazomethane in ether at 0 °C. The resulting alpha-diazoketone is usually not isolated but used directly.
b) Wolff rearrangement conditions: Ag2O catalysis in the presence of the trapping nucleophile is the most common protocol. The reaction is typically conducted at room temperature or with gentle warming.
c) Photochemical variant: Irradiation of the alpha-diazoketone with UV light in the presence of the trapping agent provides an alternative to metal catalysis, and can lead to different selectivity in some cases.
Fig 1. Wolff rearrangement reaction and its mechanism. [1]
Mechanism of Wolff Rearrangement
Step 1: Generation of the Ketocarbene
The reaction is initiated by the decomposition of the alpha-diazoketone, which can be effected thermally, photochemically, or by transition-metal catalysis. Under thermal or photochemical conditions, N2 is extruded directly to generate a free ketocarbene (R-CO-CH:). In the presence of silver(I) catalysts, the decomposition proceeds through a silver carbenoid intermediate (R-CO-C(Ag)-H), which can be considered a stabilized, metal-associated form of the carbene. The silver carbenoid is generally more selective and less prone to side reactions than the free carbene.
Step 2: 1,2-Migration to Form the Ketene
The key step is a 1,2-shift of the R group (or hydrogen) from the carbonyl carbon to the carbene carbon. This migration occurs with its bonding electron pair and is, in many respects, analogous to a 1,2-alkyl shift in carbocation chemistry, but the migrating terminus is an electron-deficient carbene center rather than a carbocation. The product of the migration is a ketene (R-CH=C=O).
Step 3: Ketene Trapping
The ketene is highly electrophilic and is trapped in situ by the nucleophile present in the reaction medium. In the context of the Arndt-Eistert reaction, water gives the homologated carboxylic acid, alcohols give esters, and amines give amides. If no trapping agent is present, the ketene can dimerize or undergo [2+2] cycloaddition with itself or other unsaturated components in the reaction mixture.
Application Examples of Wolff Rearrangement
- Beta-Amino Acid Synthesis: The Arndt-Eistert protocol has been extensively applied to the synthesis of beta-amino acids from alpha-amino acid precursors. The reaction proceeds with complete retention of the alpha-stereocenter, making it a reliable method for accessing enantiopure beta-amino acids, which are important building blocks for beta-peptides and peptidomimetics.
- Ring Contraction: Erin N. Hancock et al. reported a total synthetic route for (+)-[5]-ladderanoic acid, in which a [2+2] cycloaddition reaction of cyclopentenone was followed by cyclocondensation via Wolf rearrangement to obtain the [4]-ladderene intermediate. [2] Moreover, the photochemical Wolff rearrangement of cyclic alpha-diazoketones leads to ring contraction with formation of a strained cyclic ketene. This has been exploited in the synthesis of highly strained ring systems, including cyclobutanones and cyclopropanones. The photochemical variant has also been used to construct complex polycyclic frameworks that are difficult to access by other methods, including in the total synthesis of several natural products.
- Synthesis of Indole and Pyrrole Derivatives: Xinwei Hu et al. reported a highly regioselective method for the carbonyl acetylation of indole and pyrrole using α-diazoketones. This reaction combines Wolf rearrangement and cross-coupling reactions to achieve the efficient synthesis of various 3-carbonylacetylindole and 2-carbonylacetylpyrrole derivatives. [3]
Fig 2. Synthetic examples via Wolff rearrangement reaction.
Related Products
References
- Jie Jack Li. Name Reactions - A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 580-582.
- Hancock, Erin N., et al. Angewandte Chemie International Edition 59.1 (2020): 436-441.
- Hu, Xinwei, et al. Organic Letters 20.19 (2018): 6140-6143.
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