Bromination Wohl-Ziegler

Olefins react with bromine by addition of the latter to the carbon-carbon double bond. In contrast the Wohl-Ziegler bromination reaction using N-bromosuccinimide (NBS) permits the selective substitution of an allylic hydrogen of an olefinic substrate 1 by a bromine atom to yield an allylic bromide 2. 

The allylic bromination of an olefin with NBS proceeds by a free-radical chain mechanism. The chain reaction initiated by thermal decomposition of a free-radical initiator substance that is added to the reaction mixture in small amounts. The decomposing free-radical initiator generates reactive bromine radicals by reaction with the N-bromosuccinimide. A bromine radical abstracts an allylic hydrogen atom from the olefinic subsfrate to give hydrogen bromide and an allylic radical 3  

The chain propagation step consists of a reaction of allylic radical 3 with a bromine molecule to give the allylic bromide 2 and a bromine radical. The intermediate allylic radical 3 is stabilized by delocalization of the unpaired electron due to resonance (see below). A similar stabilizing effect due to resonance is also possible for benzylic radicals a benzylic bromination of appropriately substituted aromatic substrates is therefore possible, and proceeds in good yields. 

The low concentration of elemental bromine required for the chain propagation step is generated from NBS 4 by reaction with the hydrogen bromide that has been formed in the first step  

By this reaction a constantly low concentration of elemental bromine is supplied. With higher concentrations of free bromine, an addition to the carbon-carbon double bond is to be expected. 

R = alkyl R = H, alkyl, COR, CO2R R = H, alkyl, aryl, 0-alkyl, NR2 R = H, alkyl, aryl radical initiator ROOR, (Bz)202, AIBN Mechanism  

The mechanism of the Wohl-Ziegler bromination involves bromine radicals (and not imidoyl radicals). The radical initiator is homolytically cleaved upon irradiation with heat or light, and it reacts with Bra (which is always present in small quantities in NBS) to generate the Br- radical, which abstracts a hydrogen atom from the allylic (or benzylic) position. The key to the success of the reaction is to maintain a low concentration of Bra so that the addition across the C=C double bond is avoided. The Bra is regenerated by the ionic reaction of NBS with the HBr by-product. 

The research team of J. Tadanier prepared a series of C8-modified 3-deoxy-P-D-manno-2-octulosonic acid analogues as potential inhibitors of CMP-Kdo synthetase. One of the derivatives was prepared from a functionalized olefinic carbohydrate substrate by means of the Wohl-Ziegler bromination. The stereochemistry of the double bond was (Z), however, under the reaction conditions a cis-trans isomerization took place in addition to the bromination at the allylic position (no yield was reported for this step). It is worth noting that the authors did not use a radical initiator for this transformation, the reaction mixture was simply irradiated with a 150W flood lamp. Subsequently the allylic bromide was converted to an allylic azide, which was then subjected to the Staudinger reaction to obtain the corresponding allylic amine. 

Conformationally restricted analogues of lavendustin A were prepared by M. Cushman and co-wokers as cyctotoxic inhibitors of tubulin polymerization.  

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Bromination of olefines by NBS is also known as Wohl-Ziegler bromination and as already written, the reaction is specific at allylic position and good yields are obtained. 

Wohl-Ziegler bromination of cyclohexene 2a and treatment of the resulting 3-bromocyclohexene with tri(acetonitrile)tricarbonylmolybdenum, followed... 

In the first propagation step of the Wohl-Ziegler bromination, the bromine atom abstracts a hydrogen atom from the allylic position of the alkene and thereby initiates a substitution. This is not the only reaction mode conceivable under these conditions. As an alternative, the bromine atom could react with the C=C double bond and thereby start a radical addition to it (Figure 1.27). Such an addition is indeed observed when cyclohexene is reacted with a Br2/AIBN mixture. 

An allyl radical can be brominated at both termini of the radical. This is why two allyl bromides can result from the Wohl-Ziegler bromination of an alkene if the allyl radical intermediate is unsymmetrical (examples see Figures 1.29-1.31). Even more than two allyl bromides may form. This happens if the substrate possesses constitutionally different allylic H atoms, and if, as a result thereof, several constitutionally isomeric allyl radicals form and react with bromine without selectivity. 

Fig 1.29. With Wohl-Ziegler brominations unsymmetric allyl radicals can basically react with the bromine atom at any of their nonequivalent ends. The product in which the bromine is localized on the less alkylated C atom and in which the higher alkylated C=C bond is present will form preferentially. 

Fig. 1.30. In some cases the allyl radical intermediate of Wohl-Ziegler brominations is available from alkene double bond isomers, which can profitably be used when one of the substrates is more easily accessible or cheaper than its isomer.

Side Note 1.2. The Rate of the Wohl-Ziegler Bromination Is More Dependent on a Polar Effect than on Product Development Control... 

Fig. 1.31. The Wohl-Ziegler bromination of crotonic acid methyl ester D exclusively supplies the bromocrotonic ester G. However, vinyl acetic acid ester C and NBS exclusively yield the dibromo addition product B under Wohl-Ziegler conditions. Here, NBS acts as a Br2 source for addition rather than substitution. The fact that vinyl acetic acid ester and NBS do not react likewise to yield the bromocrotonic ester G is due to an electronic effect discussed in the text.

A further useful application of SC-CO2 as a reaction medium is the free-radical side-chain bromination of alkylaromatics, replacing conventional solvents such as tetra-chloromethane or chlorofluorohydrocarbons having no abstractable hydrogen atoms [920]. For example, bromination of ethylbenzene in SC-CO2 at 40 °C and 22.9 MPa yields 95 cmol/mol (1-bromoethyl)benzene, with practically the same regioselectivity as obtained in conventional tetrachloromethane as the solvent. Even the classical Wohl-Ziegler bromination of benzylic or allylic substrates using A-bromosuccinimide (NBS) can be conducted in SC-CO2 [920]. Irradiation of a solution of toluene, NBS, and AIBN (as initiator) in SC-CO2 at 40 °C and 17.0 MPa for 4 hours gave (bromomethyl)-... 

The mechanism of the allylic Wohl-Ziegler bromination involves free radicals, as shown in Scheme 2.36. 

When this reagent is used, the reaction is known as Wohl-Ziegler bromination. A nonpolar solvent is used, most often CCI4, but the reaction has been done in an ionic liquid. A variation in the reaction used NBS with 5% Yb(OTf>3 and 5%... 

Tetra-p-tolylsilane, prepared via Wurtz-coupling of 4-bromotoluene and SiCU, was brominated with NBS according to a procedure described by Drefahl [13] yielding a mixture of the three- and four-fold benzylic bromides la, lb which can be separated by repeated crystallization from acetone. A more convenient way is to convert the crude mixture in a Michaelis-Arbusow reaction to the phosphonates 2a, 2b and to separate these via chromatography (SiOa/ethyl acetate/ethanol). A second Wohl-Ziegler bromination/Michaelis-Arbusow sequence allows one to transform 2a into the tetrahedral 2b in moderate yield. 

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