| Beckmann rearrangement | |
|---|---|
| Named after | Ernst Otto Beckmann |
| Reaction type | Rearrangement reaction |
| Identifiers | |
| Organic Chemistry Portal | beckmann-rearrangement |
| RSC ontology ID | RXNO:0000026 |
TheBeckmann rearrangement, named after the German chemistErnst Otto Beckmann (1853–1923), is arearrangement of anoximefunctional group to anamide functional group.[1][2] The rearrangement has also been successfully performed on haloimines andnitrones. Cyclic oximes and haloimines yieldlactams.
The Beckmann rearrangement is often catalyzed by acid; however, other reagents have been known to promote the rearrangement. These includetosyl chloride,thionyl chloride,phosphorus pentachloride,phosphorus pentoxide,triethylamine,sodium hydroxide,trimethylsilyl iodide among others.[3] TheBeckmann fragmentation is another reaction that often competes with the rearrangement, though careful selection of promoting reagent and solvent conditions can favor the formation of one over the other, sometimes giving almost exclusively one product. The rearrangement occursstereospecifically forketoximes and N-chloro/N-fluoro imines, with the migrating group beinganti-periplanar to the leaving group on the nitrogen. Certain conditions have been known toracemize the oxime geometry, leading to the formation of bothregioisomers. The rearrangement ofaldoximes occurs with stereospecificity in thegas phase and without stereospecificity in the solution phase. A few methodologies allow for the rearrangement of aldoximes to primary amides, but fragmentation commonly competes in these systems. Nitrone rearrangement also occurs without stereospecificity; the regioisomer formed has the amide nitrogen substituted with the group possessing the greatestmigratory aptitude.
The archetypal Beckmann rearrangement[4] is the conversion ofcyclohexanone tocaprolactam via the oxime. Caprolactam is the feedstock in the production ofNylon 6.[5]
TheBeckmann solution consists ofacetic acid,hydrochloric acid andacetic anhydride, and was widely used to catalyze the rearrangement. Other acids, such assulfuric acid,polyphosphoric acid, andhydrogen fluoride have all been used.Sulfuric acid is the most commonly used acid for commercial lactam production due to its formation of an ammonium sulfate by-product when neutralized withammonia.Ammonium sulfate is a common agriculturalfertilizer providing nitrogen and sulfur.
The most commonreaction mechanism of the Beckmann rearrangement consists generally of analkyl migration anti-periplanar to the expulsion of a leaving group to form anitrilium ion. This is followed bysolvolysis to animidate and thentautomerization to the amide:[6]
This nitrilium ion has been known to be intercepted by other nucleophiles, including the leaving group from the oxime.[3]
Presumably after the phenyl group migrates and expels thecyanate, the latter then attacks the nitrilium ion formed. Incarbon tetrachloride theisocyanate can be isolated, whereas inethanol, theurethane is formed after solvolysis of the isocyanate.
One computational study has established the mechanism accounting for solvent molecules and substituents.[7] The rearrangement of acetone oxime in the Beckmann solution involved three acetic acid molecules and one proton (present as anoxonium ion). In thetransition state leading to the iminium ion (σ-complex), the methyl group migrates to the nitrogen atom in aconcerted reaction as the hydroxyl group is expelled. The oxygen atom in the hydroxyl group is stabilized by three acetic acid molecules. In the next step the electrophilic carbon atom in the nitrilium ion is attacked by water and a proton is donated back to acetic acid. In the transition state leading to the imidate, the water oxygen atom is coordinated to 4 other atoms. In the third step, an isomerization step protonates the nitrogen atom leading to theamide.
The same computation with ahydroxonium ion and 6 molecules of water has the same result, but when the migrating substituent is a phenyl group, the mechanism favors the formation of an intermediate three-membered π-complex. This π-complex is not found in the H3O+(H2O)6.
With the cyclohexanone-oxime, the relief ofring strain results in a third reaction mechanism, leading directly to the protonated caprolactam in a single concerted step without the intermediate formation of a π-complex or σ-complex.
Beckmann rearrangement can be renderedcatalytic usingcyanuric chloride andzinc chloride as aco-catalyst. For example,cyclododecanone can be converted to the correspondinglactam, themonomer used in the production ofNylon 12.[8][9]
Thereaction mechanism for this reaction is based on acatalytic cycle with cyanuric chloride activating thehydroxyl group via anucleophilic aromatic substitution. The reaction product is dislodged and replaced by new reactant via an intermediateMeisenheimer complex.
The Beckmann fragmentation is a reaction that frequently competes with the Beckmann rearrangement.[3] When the group α to the oxime is capable of stabilizingcarbocation formation, the fragmentation becomes a viable reaction pathway. The reaction generates anitrile and a carbocation, which is quickly intercepted to form a variety of products. The nitrile can also be hydrolyzed under reaction conditions to givecarboxylic acids. Different reaction conditions can favor the fragmentation over the rearrangement.
Quaternary carbon centers promote fragmentation by stabilizing carbocation formation throughhyperconjugation. As shown in the above picture, the "stable" carbocation is formed, which then loses a hydrogen to give a site ofunsaturation. Oxygen and nitrogen atoms also promote fragmentation through the formation ofketones andimines respectively.
Sulfur is also capable of promoting fragmentation, albeit at a longer range than oxygen or nitrogen.
Silicon is capable of directing the fragmentation through thebeta-silicon effect.
The carbocation intermediate in this reaction is intercepted by nucleophilicfluoride from diethylaminosulfur trifluoride (DAST):[10]
The oxime ofcyclohexenone with acid formsaniline in a dehydration –aromatization reaction called theSemmler–Wolff reaction orWolff aromatization[11][12][13][14]
The mechanism can be shown as below:
The reaction is intrinsically a special case of the Beckmann rearrangement combined withneighbouring group participation.
Anindustrial synthesis of paracetamol developed byHoechst–Celanese involves the acid-catalyzed Beckmann rearrangement ofpiceoloxime:[15]
