Radicals, anti-Markovnikov initiation

The mechanism of the addition reaction under these conditions is not an ionic sequence rather, it is a much faster radical chain sequence. The reason is that the activation energies of the component steps of radical reactions are very small, as we observed earlier during the discussion of the radical halogenation of alkanes (Section 3-4). Consequently, in the presence of radicals, anti-Markovnikov hydrobromination simply outpaces the regular addition pathway. The initiation steps are... 

We have now seen two pathways for adding HBr across a donble bond the ionic pathway (which gives Markovnikov addition) and the radical pathway (which gives anti-Markovnikov addition). Both pathways are actnally in competition with each other. However, the radical reaction is a mnch faster reaction. Therefore, we can control the regiochemistry of addition by carefully choosing the conditions. If we use a radical initiator, like ROOR, then the radical pathway will predominate, and we will see an anti-Markovnikov addition. If we do not use a radical initiator, then the ionic pathway will predominate, and we will see a Markovnikov addition ... 

Similar to the addition of secondary phosphine-borane complexes to alkynes described in Scheme 6.137, the same hydrophosphination agents can also be added to alkenes under broadly similar reaction conditions, leading to alkylarylphosphines (Scheme 6.138) [274], Again, the expected anti-Markovnikov addition products were obtained exclusively. In some cases, the additions also proceeded at room temperature, but required much longer reaction times (2 days). Treatment of the phosphine-borane complexes with a chiral alkene such as (-)-/ -pinene led to chiral cyclohexene derivatives through a radical-initiated ring-opening mechanism. In related work, Ackerman and coworkers described microwave-assisted Lewis acid-mediated inter-molecular hydroamination reactions of norbornene [275]. 

Taylor in 1925 demonstrated that hydrogen atoms generated by the mercury sensitized photodecomposition of hydrogen gas add to ethylene to form ethyl radicals, which were proposed to react with H2 to give the observed ethane and another hydrogen atom. Evidence that polymerization could occur by free radical reactions was found by Taylor and Jones in 1930, by the observation that ethyl radicals formed by the gas phase pyrolysis of diethylmercury or tetraethyllead initiated the polymerization of ethylene, and this process was extended to the solution phase by Cramer. The mechanism of equation (37) (with participation by a third body) was presented for the reaction, - which is in accord with current views, and the mechanism of equation (38) was shown for disproportionation. Staudinger in 1932 wrote a mechanism for free radical polymerization of styrene,but just as did Rice and Rice (equation 32), showed the radical attack on the most substituted carbon (anti-Markovnikov attack). The correct orientation was shown by Flory in 1937. In 1935, O.K. Rice and Sickman reported that ethylene polymerization was also induced by methyl radicals generated from thermolysis of azomethane. 

It is possible to obtain anti-Markovnikov products when HBr is added to alkenes in the presence of free radical initiators, e.g. hydrogen peroxide (HOOH) or alkyl peroxide (ROOR). The free radical initiators change the mechanism of addition from an electrophilic addition to a free radical addition. This change of mechanism gives rise to the anh-Markovnikov regiochemistry. For example, 2-methyl propene reacts with HBr in the presence of peroxide (ROOR) to form 1-bromo-2-methyl propane, which is an anh-Markovnikov product. Radical additions do not proceed with HCl or HI. 

The addition of thiols to C—C multiple bonds may proceed via an electrophilic pathway involving ionic processes or a free radical chain pathway. The main emphasis in the literature has been on the free radical pathway, and little work exists on electrophilic processes.534-537 The normal mode of addition of the relatively weakly acidic thiols is by the electrophilic pathway in accordance with Markovnikov s rule (equation 299). However, it is established that even the smallest traces of peroxide impurities, oxygen or the presence of light will initiate the free radical mode of addition leading to anti-Markovnikov products. Fortunately, the electrophilic addition of thiols is catalyzed by protic acids, such as sulfuric acid538 and p-toluenesulfonic acid,539 and Lewis acids, such as aluminum chloride,540 boron trifluoride,536 titanium tetrachloride,540 tin(IV) chloride,536 540 zinc chloride536 and sulfur dioxide.541... 

Azido-phenylselenenylations of olefinic compounds can be effected with BAIB/PhSeSePh/NaN3 in CH2C12 (Scheme 14) [37]. Such additions proceed in anti-Markovnikov fashion and appear to be initiated by addition of the azido radical to the C,C-double bond. While cyclohexene and ds-4-octene gave 3 1 and 2 1 mixtures of diastereomeric adducts under these conditions, dihydropy-ran was converted cleanly to the trans-addition product. Regioselective azido-phenylselenenylations of dihydropyran derivatives and O-protected glycals with this reagent have also been documented [21,38,39]. 

The composition of the reaction products (1 1 adducts) needs further clarification. In the case of terminal olefins the anti-Markovnikov 1 1 addition product is almost the only 1 1 adduct, whereas the isomeric amide is formed in minute amounts only. Markovnikov-additions of free radicals to olefins have been observed in other cases too as side products (28). The point of initial attack in the free radical addition to an olefin of the type RCH=CH2 is at the terminal carbon. The intermediate radical (I) produced by this process (anti-Markovnikov) has a higher degree of resonance stabilization than the alternative radical (II) (4, 78). This means that in the present reaction,... 

When a similar reaction occurs under conditions favoring the formation of radicals— that is, in the presence of light or a peroxide that can initiate the reaction—the addition still occurs, but with the opposite regiochemistry. The bromine adds to the less highly substituted carbon, and the addition is said to occur in an anti-Markovnikov manner. Examples are provided by the following equations ... 

In 1933, M. S. Kharasch and F. W. Mayo found that some additions of HBr (but not HC1 or HI) to alkenes gave products that were opposite to those expected from Markovnikov s rule. These anti-Markovnikov reactions were most likely when the reagents or solvents came from old supplies that had accumulated peroxides from exposure to the air. Peroxides give rise to free radicals that initiate the addition, causing it to occur by a radical mechanism. The oxygen-oxygen bond in peroxides is rather weak, so it can break to give two alkoxy radicals. 

Alkoxy radicals (R—O -) initiate the anti-Markovnikov addition of HBr. The mechanism of this free-radical chain reaction is shown in Mechanism 8-3. 

Secondary phosphines reacted readily with N-vinylpyrroles under radical initiation to give regiospecifically anti-Markovnikov adducts, diorganylethyl-2-(pyrrol-l-yl)phosphines 169 in 88-91% yields (Equation (53)) (03TL2629). 

Radical chloroaminations are known, using radical, transition metal ion or photochemical initiation. They also occur without overt initiation, thus anti-Markovnikov additions to terminal alkenes occur with N,N-dichlorourethane in benzene at 5-40 C (yields <= 60%)P Similar reactions occur with N,N-dichlo-roarenesulfonamides in CH2CI2 at or below room temperature (yields mostly 53-91% 10% with isobu-tylene). ° The remaining N—Cl bond is reaiUly reduced if desired with sodium sulflte. N-Halosulfoximines also add to alkenes thermally or photolytically. ... 

The best experimental conditions to introduce a phenylseleno and an azido group to the alkene double bond are those which employ diphenyl diselenide, sodium azide and iodobenzene diacetate in methylene chloride. Under these conditions, however, the addition reaction occurs through the radical mechanism illustrated in Scheme 12 [581. The addition therefore occurs with an anti Markovnikov orientation and it is not stereospecific. The reaction is initiated by the oxidation of the azido anion to the azido radical, which adds to the alkene to afford a carbon radical. This is trapped by the PhSeSePh to afford the final product and a PhSe radical, which dimerizes to give the diselenide. 

To account for this peroxide effect, Kharasch and Mayo proposed that addition can take place by two entirely different mechanisms Markovnikov addition by the ionic mechanism that we have just discussed, and anti-Markovnikov addition by a free-radical mechanism. Peroxides initiate the free-radical reaction in their absence (or if an inhibitor, p. 189, is addedX addition follows the usual ionic path. 

Anti-Markovnikov The addition to a double bond of a molecule in which the negative part joins to the carbon that initially had the most hydrogens, usually the result of a radical mechanism. Antiperiplanar See anticlinal. 

Enantiodifferentiating anti-Markovnikov polar photoadditions of alcohols to 1,1-diphenyl-l-alkenes 107 and 108 sensitized by optically active naphthalene(di)car-boxylates 41-43, 71, 72, and 91 were investigated in detail (Scheme 19) [70], Since this photoaddition involves the attack of alcohol to a radical cationic species of the substrate alkene [71], the use of polar solvents is desirable for obtaining the adduct in a high yield. However, in polar solvents, the radical ionic sensitizer-substrate pair produced upon photoexcitation is immediately dissociated by solvation, and no chirality transfer is expected to occur. Thus the optical and chemical yields are often conflicting issues, and therefore the critical control of solvent polarity is essential for obtaining the optically active product with an appreciable ee in reasonable chemical yield. In fact, the initial attempts on 107, employing naphthalenecarboxylate sensitizers with chiral terpenoid auxiliaries (a-c and f) and a pentane solvent afforded a best ee of 27% for adduct 110 (R = Me), but in < 2% yield [70a]. 

In the presence of a radical initiator, alkenes react with reactive molecules such as hydrogen bromide to give simple 1 1 adducts rather than a polymer. The initiator radical reacts rapidly with an HBr molecule to give a bromine atom (6.49), which starts the chain reaction. In the first propagation step, the bromine atom adds to the alkene 61 to give the adduct radical 62 (reaction 6.50). Since 62 abstracts a hydrogen atom from HBr by reaction (6.51) more rapidly than it would add to the alkene to form a polymer radical as in (6.43), the chain continues with reactions (6.50) and (6.51) as the propagating steps, and the product is the primary bromo compound 63. This anti-Markovniko addition is in the reverse direction to the polar addition discussed in Chapter 5. Since the radical chain reaction is faster than the polar reaction, the anti-Markovnikov product dominates if radicals are present. If the Markovnikov product is required, the reaction must be carried out in the dark, in the absence of free radical initiators, and preferably with a radical inhibitor present. 

The regioselectivity of addition of hydrogen bromide to alkenes can be complicated if a free-radical chain addition occurs in competition with the ionic addition. The free-radical chain reaction is readily initiated by peroxidic impurities or by light and leads to the anti Markovnikov addition product. The mechanism of this reaction is considered more fully in Chapter 11. Conditions that minimize the competing radical addition include use of high-purity alkene and solvent, exclusion of light, and addition of a radical inhibitor. ... 

The reaction with HBr is also significant in terms of regiochemistry. The reaction results in the anti-Markovnikov orientation, with the bromine adding to the less-substituted carbon of the double bond. The anti-Markovnikov addition of HBr to alkenes was one of the earliest free radical reactions to be put on a firm mechanistic basis. In the presence of a suitable initiator, such as a peroxide, a radical chain mechanism becomes competitive with the ionic mechanism for addition of HBr. 

Scheme 11.5 gives some examples of these radical addition reactions. Entries 1 to 3 show anti-Markovnikov addition of HBr. The reaction in Entry 1 was carried out by passing HBr gas into the alkene, using benzoyl peroxide as the initiator, apparently near room temperature. Entry 2 is an example of anti-Markovnikov addition to... 

When heteroatom containing substrates react with peroxides, or other radical initiators, hydrogen atom transfer can occur, as in the transfer of hydrogen from an acetal to the radical, generating the alkane and the a-alkoxy radical, 133. The presence of the heteroatom a to the carbon bearing the radical center leads to enhanced stability. Such radicals add to alkenes, usually with anti-Markovnikov orientation, as in the radical... 

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