Wohl-Ziegler reaction

The Wohl-Ziegler reaction is the reaction of an allylic or benzylic substrate with 7V-bromosuccinimide (NBS) under radical initiating conditions to provide the eor-responding allylie or benzylie bromide. Conditions used to promote the radieal reaction are typieally radical initiators, light and/or heat earbon tetrachloride (CCI4) is typieally utilized as the solvent. 

WBromosuccinimide (NBS) contains a small amount of HBr from the reaction between NBS and moisture. The minute amount of HBr, in turn, reacts with NBS to provide a low, constant concentration of Br2. Moreover, NBS reacts with the HBr by-product to produce Br2 and to prevent HBr addition across the double bond. 

The bromine radieal is now available for the next cyele of the radical chain reaction. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 291, Springer International Publishing Switzerland 2014 

Alfred Wohl (1863-1939), born in Graudenz, Germany, received his Ph.D. from A. W. Hofmann. In 1904, he was appointed Professor of Chemistry at the Technische Hochsehule in Danzig. 

Afawe Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 272, Springer-Verlag Berlin Heidelberg 2009 

Ziegler, K. Spath, A. Schaaf, E. Schumann, W. Winkehnann, E. Am. 1942, SSI, 80-119. Karl Ziegler (1898-1973), bom in Helsa, Germany, received Ph.D. in 1920 from von Auwers at the University of Marhurg. He became the director of the Max-Planck-Institut fur Kohlenforschung at Miilheim/Ruhr in 1943 and stayed there until 1969. He shared the Nohel Prize in Chemistry in 1963 with Giulio Natta (1903-1979) for their work in polymer chemistry. The Ziegler-Natta catalyst is widely used in polymerization. 

Although the transformation is typically non-stereoselective, the reaction results in the selective functionalization of the allylic or benzylic position due to the nature of the reaction conditions which results in primarily attack of weak C-H bonds with insertion of a halide. 

In a subsequent report, Ziegler and co-workers systematically studied the halogenation of several allylic substrates using a variety of reagents including A -bromo and A -chloro pthalimide, chloramine-T, N-bromo and A -chlorosaccharin, A -chloro-A -benzoyl-p-toluenesulfonamide, N-chloro-di-/ -toluylsulfonamide, and most notably, iV-bromo and N-chlorosuccinimide. Successful allylic bromination was reported for several substrates, among which were the conversion of cyclohexene (7) into bromocyclohexene (8) and the conversion of phenyl propene 9 into cinnamyl bromide (10). 

The initiation step provides a radical source by thermal or photochemical dissociation of initiators, which then provides bromine radicals by reaction with Br2. Initiators are sometimes present in the alkene as allyl hydroperoxides which may be present due to inadvertent, prior autooxidation. Bromine or HBr may be present in trace amounts in NBS. Reaction of the bromine radical 20 with the substrate 1 proves selective for allylic or benzylic hydrogens due to the near thermoneutral nature of the reaction which breaks the C-H bond and forms the H-Br bond. Reaction of the formed carbon-centered radical 21 with Br2 provides the desired bromide 3 and Br 20. Hydrogen bromide 17 reacts with NBS to form succinimide 4 and resupplies the required low concentration of Br2. Alternatively, reaction of substrate radical 21 with NBS 2 provides product 3 and succinimidyl radical 22 (S ). Due to energy and kinetics considerations, abstraction of the allylic hydrogen by the S should be slower than abstraction of bromine from NBS by an allyl radical. In using solvents in which NBS, succinimide 4 or it s radical 22 are not very soluble, S is not the key chain-carrier. Byproducts and side-reactions can occur with S.  

Additives may also impact the mechanism. Accelerators to the reaction were found to be 1) radical initiators, 2) bromine generators and 3) /-amines. The importance of initiation and the fact that bromine plays a crucial role in the reaction mechanism makes it easy to understand the impact of such additives. However, one must realize that the Br2 concentration must be kept relatively low or alkene addition products may be observed. The impact of /-amines as accelerators is somewhat less obvious, but most likely arises from amine-induced, homolytic decomposition of NBS or hydroperoxide. Retarders of the reaction are common inhibitors of radical formation or substances that will intercept the chain-carriers like tetrabromo-/ -benzoquinone, 5-trinitrobenzene, m-dinitrobenzene, or hydroquinone. 

Curran, T. T. Wohl-Ziegler reaction. In Name Reactions for Homologations-Part 1 Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 661-674. (Review). 

Radical-initiated allylic bromination using NBS, and catalytic AIBN as initiator or NBS under photolysis. 

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The direct introduction of a halogen atom (usually bromine) by means of V-haloamine (generally iV-bromosuccinimide) in the allyl position is known as the Wohl-Ziegler reaction ... 

Williamson synthesis Wohl-Ziegler reaction Wolff rearrangement Wolff Kishner reduction Wurtz reaction Wurtz-Fittig reaction... 

The synthesis of anastrozole (Scheme 3.3) began with an 8 2 displacement of commercially available 3,5-fc (bromomethyl)toluene (19) using potassium nitrile and a phase-transfer catalyst, tetrabutylammonium bromide (Edwards and Large, 1990). The resulting fcw-nitrile 20 in DMF was then deprotonated with sodium hydride in the presence of excess methyl iodide to give the fc -dimethylated product 21. Subsequently, a Wohl-Ziegler reaction on 21 was carried out using A-bromosuccinamide (NBS), and a catalytic amount of benzoyl peroxide (BPO) as the radical initiator. Finally, an Sn2 displacement of benzyl bromide 22 with sodium triazole in DMF afforded anastrozole (2) as a white solid. 

Wohl in 1919 reported that A -bromoacetamide (CH CONHBr) induced allylic bromination. " Then iV-bromosuccinimide (30) was described in 1942 by Ziegler and co-workers to be useful in such free radical bromination reactions (equation 41), " and this widely utilized procedure is known as the Wohl-Ziegler reaction. In 1963 the mechanism of the reaction was proposed to involve halogen atoms in the hydrogen abstraction step " " " instead of succinimidyl radicals as had been commonly supposed. The halogen atom mechanism had previously been proposed by Gosselain et al. for reactions of yV-chlorosuccinimide. " ... 

Wohl Ziegler reaction, 926, 927 Wolff-Kishner reduction, 510, 511J, 516 Huang-Minlon modification of, 510, 516... 

A second general method involves the bromination of alkenes with jY-bromosuccinimide (the Wohl-Ziegler reaction). A radical-chain reaction takes place between A-bromosuccinimide (NBS) and alkenes, which com-... 

The direct introduction of bromine into the allylic position of an alkene using ZV-bromosuccinimide is known as the Wohl-Ziegler reaction. Bromination is carried out in anhydrous reagents (to avoid hydrolysis of the bromoimide), usually boiling carbon tetrachloride or chloroform solution. The progress of the reaction can be followed by the fact that at first the dense N-bromosuccinimide is at the bottom of the flask and is gradually replaced by succinimide, which rises... 

The formation of oxygen- and carbon-centered radicals by the thermolysis of peroxides or azo compounds is well known. Today, these compounds have been also used as radical initiators. For example, treatment of a CC14 solution of toluene and Af-bromosuccinimide (NBS) in the presence of a catalytic amount of benzoyl peroxide in refluxing conditions gives benzyl bromide in good yield as shown in Scheme 1.5. This is called the Wohl-Ziegler reaction. 

Djerassi, C. Brominations with N-bromosuccinimide and related compounds. The Wohl-Ziegler reaction. Chem. Rev. 1948,43, 271-317. Horner, L., Winkelmann, E. H. Course of substitution. XV. N-Bromosuccinimide-properties and reactions. Angew. Chem. 1959, 71, 349-365. 

Brominations are, in most cases, carried out by methods similar to those for the preparation of chlorine derivatives. Sampey (127) gives a history of the photobromination of benzene and toluene. Davis (123) made a thorough examination of the relative rates of bromination of the olefins, concentrating particularly on ethylene. An unusual method for producing bromine compounds is by the use of bromosuccinimide or related compounds. This method is called the Wohl-Ziegler reaction and causes allylic bromination. It has been the subject of a couple of reviews (124,1 0). 

A more convenient method for halogenation of allylic and benzylic C-H moieties uses the readily available A-bromosuccinimide (NBS, 170) or NCS (173) with heat and/or light, in what is called the Wohl-Ziegler reaction. Reaction of NBS with cyclohexene in refluxing carbon tetrachloride gives bromocyclo-... 

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