Regioselectivity of halogenation

When propane undergoes radical halogenation, regiochemistry becomes an issue. There are two 

Statistically, we should be able to predict what the product distribution should be (how much of each product to expect), based on the number of each type of hydrogen atom  

Based on this analysis, we should expect halogenation to occur at the primary position three times as often as it does at the secondary position. However, these expectations are not supported by observations. 

An energy diagram showing hydrogen abstraction producing either a primary or a secondary radical. 

When propane undergoes radical bromination (rather than chlorination), the following product distribution is observed  

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A nice example showing both the -regioselectivity of halogenation and also just how reactive pyrroles are (halogena-tion at all available positions) is shown in Scheme 27 <1999CC2195>. 

Fig. 5 Regioselectivity of halogen-metal exchange reactions with dihalogenated substrates...

The regioselectivity of the second step is consistent with MarkownikofF s rule because a halogen atom can stabilize a carbocation by resonance. 

Preparation of the substituted piperazine required for sul-falene (114) starts with bromination of 2-aminopiperazine to give the dihalide (150). Displacement of halogen by sodium methoxide proceeds regioselectively at the more reactive 3 position to give 151. Hydrogenolysis over palladium on charcoal gives the desired intermediate (152). 

When used with A-chloro-, A-bromo-, and A-iodosuccinimide, iron(III) chloride catalyzes the introduction of halogens into arenes. The reaction works well even with deactivated aromatic rings but in some cases the regioselective course is difficult to control (Scheme 39) [49]. 

There are also procedures in which the enolate is generated quantitatively and allowed to react with a halogenating agent. Regioselectivity can then be controlled by the direction of enolate formation. Among the sources of halogen that have been used under these conditions are bromine,125 (V-chlorosuccinimide,126 trifluoromethanesul-fonyl chloride,127 and hexachloroethane.128... 

Treating ally lie and homoallylic epoxy alcohols with an equivalent amount of halogen (Br2, I2) in the presence of a stoichiometric amount of Ti(OPr )4 provides halohydrins under mild conditions with a high degree of generality and with good regioselectivity (Scheme 4-12).26... 

The influence of substituents on the regioselectivity of fluorination of allylic alcohols with DAST has been studied and halogenation of the nitrogen of carbohydrate A-acetyl side-chains by HOCl has been monitored. ... 

The polymerization of halophenoxides by copper (II) mediated halide displacement is a mechanistically complicated reaction. Elucidation of the structure of the polymers is essential to an understanding of both the polymerization chemistry and the peculiar physical properties of the polymers. The physical tool which has yielded most information on the polymer structure is nmr. The first conclusion which derives from a study of the spectra of poly(dihalophenyleneoxides) is that regioselectivity in halogen displacement is more likely the source of the polymer properties than branching. A more rigorous confirmation of the polymer structures will depend on a detailed analysis of the spectra of model compounds for the chain segments. 

Halogenated quinolines very often nndergo nncleophilic addition with BuLi, so must be lithiated with LDA or LiTMP " The regioselectivity of their reactions parallels that of the pyridines, and similar halogen migrations are observed (Scheme 116) . ... 

Organoborane intermediates can also be used to synthesize alkyl halides. Replacement of boron by iodine is rapid in the presence of base.150 The best yields are obtained with sodium methoxide in methanol.151 If less basic conditions are desirable, the use of iodine monochloride and sodium acetate gives good yields.152 As is the case in hydroboration-oxidation, the regioselectivity of hydroboration-halogenation is opposite to that observed for direct ionic addition of hydrogen halides to alkenes. Terminal alkenes give primary halides. 

The stoichiometric equivalents of halogen fluorides, i.e. chlorine monofluoride, bromine monofluoride and iodine monofluoride, have found a wide application in addition reactions to double bonds. The equivalents are obtained by reacting A -haloamides or free halogens in combination with hydrogen fluoride or its salts as the source of fluoride ions. The reactions proceed under mild conditions at — 80 to 20 "C in anhydrous hydrofluoric acid or diethyl ether, tetrahydro-furan, dichloromethane or chloroform mainly by electrophilic addition with Markovnikov-type regioselectivity (anti addition).26-28... 

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