Beckmann rearrangement
The Beckmann rearrangement, named after the German chemist Ernst Beckmann rearrangement
Otto Beckmann (1853–1923), is a rearrangement of an oxime functional
Named after Ernst Otto
group to substituted amides.[1][2] The rearrangement has also been successful
Beckmann
performed on haloimines and nitrones. Cyclic oximes and haloimines yield
lactams. Reaction type Rearrangement
reaction
The Beckmann rearrangement is often catalyzed by acid, however other
Identifiers
reagents have been known to promote the rearrangement. These include
tosyl chloride, thionyl chloride, phosphorus pentachloride, phosphorus Organic beckmann-
pentoxide, triethylamine, sodium hydroxide, trimethylsilyl iodide among Chemistry rearrangement
others.[3] The Beckmann fragmentation is another reaction that often Portal
competes with the rearrangement, though careful selection of promoting
RSC ontology RXNO:0000026
reagent and solvent conditions can favor the formation of one over the other,
sometimes giving almost exclusively one product. The rearrangement occurs ID
stereospecifically for ketoximes and N-chloro/N-fluoro imines, with the
migrating group being anti-periplanar to the leaving group on the nitrogen. Certain conditions have been known to
racemize the oxime geometry, leading to the formation of both regioisomers. The rearrangement of aldoximes occurs
with stereospecificity in the gas 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 greatest migratory aptitude.
The archetypal Beckmann rearrangement[4] is the conversion of cyclohexanone to caprolactam via the oxime.
Caprolactam is the feedstock in the production of Nylon 6.[5]
The Beckmann solution consists of acetic acid, hydrochloric acid and acetic anhydride, and was widely used to
catalyze the rearrangement. Other acids, such as sulfuric acid, polyphosphoric acid, and hydrogen 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 with ammonia. Ammonium sulfate is a common agricultural fertilizer
providing nitrogen and sulfur.
Contents
Reaction mechanism
Cyanuric chloride assisted Beckmann reaction
Beckmann fragmentation
Semmler–Wolff reaction
Applications in drug synthesis
See also
References
External links
Reaction mechanism
The most common reaction mechanism of the Beckmann rearrangement consists generally of an alkyl migration anti-
periplanar to the expulsion of a leaving group to form a nitrilium ion. This is followed by solvolysis to an imidate and
then tautomerization 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 the cyanate, it then attacks the nitrillium ion formed. In carbon
tetrachloride the isocyanate can be isolated, whereas in ethanol the urethane 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 an oxonium ion). In the transition state leading to the iminium ion (σ-complex), the methyl group migrates
to the nitrogen atom in a concerted 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 the amide.
The same computation with a hydroxonium 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 H3 O+(H2 O)6 .
With the cyclohexanone-oxime, the relief of ring 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.
Cyanuric chloride assisted Beckmann reaction
Beckmann rearrangement can be rendered catalytic using cyanuric chloride and zinc chloride as a co-catalyst. For
example, cyclododecanone can be converted to the corresponding lactam, the monomer used in the production of
Nylon 12.[8][9]
The reaction mechanism for this reaction is based on a catalytic cycle with cyanuric chloride activating the hydroxyl
group via a nucleophilic aromatic substitution. The reaction product is dislodged and replaced by new reactant via an
intermediate Meisenheimer complex.
Beckmann fragmentation
The Beckmann fragmentation is a reaction that frequently competes with the Beckmann rearrangement.[3] When the
group α to the oxime is capable of stabilizing carbocation formation, the fragmentation becomes a viable reaction
pathway. The reaction generates a nitrile and a carbocation, which is quickly intercepted to form a variety of
products. The nitrile can also be hydrolyzed under reaction conditions to give carboxylic acids. Different reaction
conditions can favor the fragmentation over the rearrangement.
Quaternary carbon centers promote fragmentation by stabilizing carbocation formation through hyperconjugation. As
shown in the above picture, the "stable" carbocation is formed, which then loses a hydrogen to give a site of
unsaturation. Oxygen and nitrogen atoms also promote fragmentation through the formation of ketones and imines
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 the beta-silicon effect.
The carbocation intermediate in this reaction is intercepted by nucleophilic fluoride from diethylaminosulfur
trifluoride (DAST):[10]
Semmler–Wolff reaction
The oxime of cyclohexenone with acid forms aniline in a dehydration – aromatization reaction called the Semmler–
Wolff reaction or Wolff aromatization [11][12][13][14]
The mechanism can be shown as below:
The reaction is intrinsically a special case of Beckmann rearrangement combined with neighbouring group
participation.
Applications in drug synthesis
An industrial synthesis of paracetamol developed by Hoechst–
Celanese involves the conversion of a methyl ketone to an
acetanilide via a Beckmann rearrangement.[15]
The Beckmann rearrangement is also used in the synthesis of
DHEA, benazepril, ceforanide, elanzepine, 17-azaprogesterone,
elantrine, prazepine, enprazepine, and etazepine.
See also
Curtius rearrangement
This route also involves the Beckmann
Dakin reaction rearrangement
Schmidt reaction
Stieglitz rearrangement
Lossen rearrangement
References
1. Beckmann, E. (1886). "Zur Kenntniss der Isonitrosoverbindungen" ([Link]
k90705g/[Link]) [On [our] knowledge of isonitroso compounds]. Berichte der Deutschen
Chemischen Gesellschaft. 19: 988–993. doi:10.1002/cber.188601901222 ([Link]
Fcber.188601901222).
2. Donaruma, L. G.; Heldt, W. Z. (1960). "The Beckmann rearrangement. (Review)". Org. React. 11: 1–
156.
3. Gawley, R. E. (1988). "The Beckmann reactions: rearrangement, elimination-additions,
fragmentations, and rearrangement-cyclizations. (Review)". Org. React. 35: 14–24.
4. Eck, J. C.; Marvel, C. S. (1939). "Ε-Benzoylaminocaproic Acid" ([Link]
8185016/[Link] Organic Syntheses. 19: 20.
doi:10.15227/orgsyn.019.0020 ([Link] Archived from the
original ([Link] on 2012-09-28. Retrieved
2005-08-18. Eck, J. C.; Marvel, C. S. (1943). "Ε-Benzoylaminocaproic Acid" ([Link]
web/20120928185016/[Link] Organic Syntheses.
2: 76. Archived from the original ([Link] on 2012-
09-28. Retrieved 2005-08-18.
5. Josef Ritz; Hugo Fuchs; Heinz Kieczka; William C. Moran. "Caprolactam". Ullmann's Encyclopedia of
Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a05_031.pub2 ([Link]
1002%2F14356007.a05_031.pub2).
6. Lezcano-González, Inés; Boronat, Mercedes; Blasco, Teresa (April 2009). "Investigation on the
Beckmann rearrangement reaction catalyzed by porous solids: MAS NMR and theoretical
calculations". Solid State Nuclear Magnetic Resonance. 35 (2): 120–129.
doi:10.1016/[Link].2009.02.001 ([Link] PMID 19286355
([Link]
7. Yamabe, S.; Tsuchida, N.; Yamazaki, S. (2005). "Is the Beckmann Rearrangement a Concerted or
Stepwise Reaction? A Computational Study" ([Link]
26/abs/[Link]). Journal of Organic Chemistry. 70 (26): 10638–10644.
doi:10.1021/jo0508346 ([Link] PMID 16355980 ([Link]
[Link]/16355980).
8. Furuya, Y.; Ishihara, K.; Yamamoto, H. (2005). "Cyanuric Chloride as a Mild and Active Beckmann
Rearrangement Catalyst" ([Link]
html). Journal of the American Chemical Society. 127 (32): 11240–11241. doi:10.1021/ja053441x (htt
ps://[Link]/10.1021%2Fja053441x). PMID 16089442 ([Link]
9. Taber, Douglass F.; Straney, Patrick J. (2010). "The Synthesis of Laurolactam from Cyclododecanone
via a Beckmann Rearrangement". J. Chem. Educ. 87 (12): 1392. Bibcode:2010JChEd..87.1392T (htt
ps://[Link]/abs/2010JChEd..87.1392T). doi:10.1021/ed100599q ([Link]
21%2Fed100599q). S2CID 96699202 ([Link]
10. Kirihara, Masayuki; Niimi, Kanako; Momose, Takefumi (1997). "Fluorinative -cleavage of cyclic
ketoximes with diethylaminosulfur trifluoride: an efficient synthesis of fluorinated carbonitriles".
Chemical Communications. 6 (6): 599–600. doi:10.1039/a607749h ([Link]
749h).
11. W. Semmler, Ber. 25, 3352 (1892)
12. L. Wolff, Amp. 322, 351 (1902)
13. Name reactions and reagents in organic synthesis, Bradford P. Mundy,Michael G. Ellerd,Frank G.
Favaloro
14. Beckmann Rearrangements. An Investigation of Special Cases E. C. Horning, V. L. Stromberg, H. A.
Lloyd J. Am. Chem. Soc., 1952, 74 (20), pp 5153–5155 doi:10.1021/ja01140a048 ([Link]
021%2Fja01140a048)
15. US patent 5155273 ([Link]
Fritch, John R. (Corpus Christi, TX); Fruchey, Stanley O. (Bad Soden/T.S., DE); Horlenko, Theodore
(Corpus Christi, TX); Aguilar, Daniel A. (Corpus Christi, TX); Hilton, Charles B. (Corpus Christi, TX);
Snyder, Phillip S. (Rock Hill, SC); Seeliger, William J. (Corpus Christi, TX), "Production of
acetaminophen", published 13 October 1992, assigned to Hoechst Celanese Corporation
(Somerville, NJ)
External links
Animation of the Beckmann rearrangement ([Link]
[Link])
Animation of the Beckmann rearrangement (caprolactam) ([Link]
_U_2_startAnimGif.gif)
Retrieved from "[Link]
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