Wolff rearrangement

The Wolff rearrangement is a reaction in organic chemistry in which an α diazocarbonyl compound is converted into a ketene by loss of dinitrogen with accompanying 1,2 rearrangement. The Wolff rearrangement yields a ketene as an intermediate product, which can undergo nucleophilic attack with weakly acidic nucleophiles such as water, alcohols, and amines, to generate carboxylic acid derivatives or undergo [2+2] cycloaddition reactions to form four membered rings. The mechanism of the Wolff rearrangement has been the subject of debate since its first use. No single mechanism sufficiently describes the reaction, and there are often competing concerted and carbene mediated pathways; for simplicity, only the textbook, concerted mechanism is shown below. The Wolff rearrangement has great synthetic utility due to the accessibility of α diazocarbonyl compounds, variety of reactions from the ketene intermediate, and stereochemical retention of the migrating group. However, the Wolff rearrangement has limitations due to the highly reactive nature of α diazocarbonyl compounds, which can undergo a variety of competing reactions. or transition metal catalysis. The reaction is occasionally called the Wolff Schröter rearrangement. Such a large barrier slows molecular rotations sufficiently to lead to an equilibrium between two conformers, an s trans and s cis conformer. s cis Conformers are electronically favored due to Coulombic attraction between the oxygen with a partial negative charge and the cationic nitrogen, as seen in the rightmost resonance structure. CIDNP studies show that photochemical rearrangement of diazoacetone, which largely exists in the s cis conformer, is concerted. Product ratios from direct and triplet sensitized photolysis have been used as evidence for proposals that claim that concerted products arise from the s cis conformer and stepwise products occur through the s trans conformer.

s trans α Diazo ketones do not have an antiperiplanar relationship between the leaving and migrating group, and thus are thought to generally rearrange stepwise. The stepwise mechanism begins with nitrogen extrusion, forming an α ketocarbene. The α ketocarbene can either undergo a 1,2 alkyl shift, to give the ketene product, or can undergo a 4π electrocyclic ring closure, to form an antiaromatic oxirene. This oxirene can reopen in two ways, to either α ketocarbene, which can then form the ketene product. There are two primary arguments for stepwise mechanisms. The first is that rate constants of Wolff rearrangements depend on the stability of the formed carbene, rather than the migratory aptitude of the migrating group. The most definitive evidence is isotopic scrambling of the ketene, as predicted by an oxirene intermediate, which can only occur in the stepwise path. In the scheme below, the red carbon is 13C labelled. The symmetric oxirene intermediate can open either way, scrambling the 13C label. If the substituents R1 and R2 are the same, one can quantify the ratio of products stemming from the concerted and stepwise mechanisms; if the substituents are different, the oxirene will have a preference in the direction it opens, and a ratio cannot be quantified, but any scrambling indicates some reactant is going through a stepwise mechanism. Under photolysis, the biphenyl (R1=R2=phenyl) substrate shows 20–30% label migration, implying 40–60% of product goes through the oxirene intermediate. α diazocyclohexanone shows no label scrambling under photolytic conditions, as it is entirely s cis, and thus all substrate goes through the concerted mechanism, avoiding the oxirene intermediate. These studies confirm that reactants that prefer s trans conformations tend to undergo stepwise reaction. The degree of scrambling is also affected by carbene stability, migratory abilities, and nucleophilicity of solvent. The observation that the migratory ability of a substituent is inversely proportional to amount of carbene formed, indicates that under photolysis, there are competing pathways for many Wolff reactions.

Under both thermolytic and photolytic conditions, there exist competing concerted and stepwise mechanisms. Many mechanistic studies have been carried out, including conformational, sensitization, kinetic, and isotopic scrambling studies. These all point to competing mechanisms, with general trends. α Diazo ketones that exist in the s cis conformation generally undergo a concerted mechanism, whereas those in the s trans conformation undergo a stepwise mechanism. Substituent effects on aryl groups are negligible, with the exception of NO2, which is a poor migrator. Heteroatoms, in general, are poor migratory groups, because their ability to donate electron density from their p orbitals into the π* C=O bond decreases migratory ability. involves the acylation of diazomethane with an acid chloride, to yield a primary α diazo ketone. The carbon terminus of diazomethane adds to the carbonyl, to create a tetrahedral intermediate, which eliminates chloride. The chloride then deprotonates the intermediate to give the α diazo ketone product. These α diazo ketones are unstable under acidic conditions, as the α carbon can be protonated by HCl and SN2 displacement of nitrogen can occur by chloride.

The Dakin–West reaction is a reaction of an amino acid with an acid anhydride in the presence of a base to form keto amides. The Franzen modification to the Dakin–West reaction is a more effective way to make secondary α diazo ketones. The Franzen modification nitrosates the keto amide with N2O3 in acetic acid, and the resulting product reacts with methoxide in methanol to give the secondary α diazo ketone.

Diazo transfer reactions are commonly used methods, in which an organic azide, usually tosylazide, and an activated methylene (i. e. a methylene with two withdrawing groups) react in the presence of a base to give an α diazo 1,3 diketone. The base deprotonates the methylene, yielding an enolate, which reacts with tosylazide and subsequently decomposes in the presence of a weak acid, to give the α diazo 1,3 diketone. The necessary requirement of two electron withdrawing groups makes this reaction one of limited scope. The scope can be broadened to substrates containing one electron withdrawing group by formylating a ketone via a Claisen condensation, followed by diazo transfer and deformylative group transfer. One of the greatest advantages of this method is its compatibility with unsaturated ketones. However, to achieve kinetic regioselectivity in enolate formation and greater compatibility with unsaturated carbonyls, one can induce enolate formation with lithium hexamethyldisilazide and subsequently trifluoroacylate rather than formylate.

If the reactant is a cyclic α diazo ketone, then Wolff rearrangement products will be the one carbon ring contracted product. These reactions are generally concerted due to the s cis conformation, and are photocatalyzed. The reaction below shows the concerted mechanism for the ring contraction of α diazocyclohexanone, followed by trapping of the ketene with a weakly acidic nucleophile. The first known example is the ring contracted Wolff rearrangement product of α diazocamphor, and subsequent kinetic hydration of the ketene from the more sterically accessible "endo" face, to give exo 1,5,5 trimethylbicyclo[2.1.1]hexane 6 carboxylic acid. Ring contractions have been used extensively to build strained ring systems, as ring size does not impede the Wolff rearrangement, but often impedes other reactions. There are many examples where the Wolff rearrangement is used to contract cyclopentanone to cyclobutane. The rearrangement is commonly used to form strained bicyclic and ring fused systems. There exist a handful of examples of ring contractions from cyclobutanones to cyclopropanes. The Wolff rearrangement is capable of contracting cyclohexanones to cyclopentanes, but is infrequently used to do so, because the Favorskii rearrangement accomplishes this transformation and the Wolff precursor is often more challenging to synthesize.

Ketene intermediates produced via the Wolff rearrangement are well known to undergo [2 + 2] thermal cycloadditions with olefins to form four membered rings in both intermolecular and intramolecular reactions, examples of both are shown below. Ketenes are able to undergo what is normally considered a forbidden [2 + 2] cycloaddition reaction because the ketene acts in an antarrafactial manner, leading to the Woodward Hoffmann allowed [πs2 + πa2] cycloaddition. The Danheiser benzannulation photolyses α diazo ketones and traps with an alkyne, which undergoes a pericyclic cascade, to ultimately form versatilely substituted phenols. The first step in the benzannulation is the photolysis of an α diazo ketone to form a vinylketene. The vinylketene then undergoes a [2 + 2] cycloaddition with an alkyne to form a 2 vinylcyclobutenone, which does a 4π electrocyclic ring opening to generate a dienylketene. The dienylketene subsequently undergoes a 6π electrocyclic ring closure followed by tautomerization, to form the phenolic benzannulated product.

The vinylogous Wolff rearrangement consists of a β,γ unsaturated diazo ketone undergoing a Wolff rearrangement, and a formal 1,3 shift of the CH2CO2R group. The vinylogous Wolff rearrangement yields a γ,δ unsaturated carboxylic acid derivative, which is the same retron as for the Claisen rearrangement. The variant was discovered when it was noticed that thermolysis of 1 diazo 3,3,3 triarylpropan 2 ones gave unexpected isomeric products. Copper (II) and rhodium (II) salts tend to give vinylogous Wolff rearranged products, and CuSO4 and Rh2(OAc)4 are the most commonly used catalysts. This is because they promote metal carbene formation, which can add to the olefin to form a cyclopropane, which can reopen via a retro [2 + 2] to form a formally 1,3 shifted ketene (vis à vis a normal Wolff rearranged ketene), which can be trapped by a nucleophile to give the vinylogous Wolff product.