Radicals, anti-Markovnikov chain reaction

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... 

A typical example of a nonpolymeric chain-propagating radical reaction is the anti-Markovnikov addition of hydrogen sulfide to a terminal olefin. The mechanism involves alternating abstraction and addition reactions in the propagating steps ... 

Free radical additions to mono-olefins are quite common and can frequently be employed to advantage on a synthetic scale. Formamide, for example, on exposure to sunlight or UV radiation adds to olefins in an anti-Markovnikov sense giving 1 1 adducts that are readily isolated and crystallized. Moreover, since alkyl formamides may be conveniently converted to carboxylic acids by conventional means, the reaction represents a general method of chain extension. 

Kharasch and Mayo in 1933," in the first of many papers on the subject, showed that the addition of HBr to allyl bromide in the presence of light and air occurs rapidly to yield 1,3-dibromopropane, whereas in the absence of air and with purified reagents, the reaction is slow and 1,2-dibromopropane is formed. The latter reaction is the normal addition occurring by an ionic pathway giving the Markovnikov orientation. In 1933 the mechanism of the abnormal process ( anti-Markovnikov addition) was not discussed, and it was only in 1937 that the free radical chain mechanism for this process was proposed by Kharasch and his co-workers. "" The mechanism was extended to propene, for which the role of peroxides in promoting the reaction was demonstrated (equations 30, 31). This mechanism was also proposed... 

The addition of hydrogen halides to simple olefins, in the absence of peroxides, takes place by an electrophilic mechanism, and the orientation is in accord with Markovnikov s rule.116 When peroxides are added, the addition of HBr occurs by a free-radical mechanism and the orientation is anti-Markovnikov (p. 751).137 It must be emphasized that this is true only for HBr. Free-radical addition of HF and HI has never been observed, even in the presence of peroxides, and of HCI only rarely. In the rare cases where free-radical addition of HCI was noted, the orientation was still Markovnikov, presumably because the more stable product was formed.,3B Free-radical addition of HF, HI, and HCI is energetically unfavorable (see the discussions on pp. 683, 693). It has often been found that anti-Markovnikov addition of HBr takes place even when peroxides have not been added. This happens because the substrate alkenes absorb oxygen from the air, forming small amounts of peroxides (4-9). Markovnikov addition can be ensured by rigorous purification of the substrate, but in practice this is not easy to achieve, and it is more common to add inhibitors, e.g., phenols or quinones, which suppress the free-radical pathway. The presence of free-radical precursors such as peroxides does not inhibit the ionic mechanism, but the radical reaction, being a chain process, is much more rapid than the electrophilic reaction. In most cases it is possible to control the mechanism (and hence the orientation) by adding peroxides... 

Reaction 1 has been postulated both in oxidations of alkanes in the vapor phase (29) and in the anti-Markovnikov addition of hydrogen bromide to olefins in the liquid phase (14). Reaction 2 involves the established mechanism for free-radical bromination of aromatic side chains (2). Reaction 4 as part of the propagation step, established in earlier work without bromine radicals (26), was not invoked by Ravens, because of the absence of [RCH3] in the rate equation. Equations 4 to 6, in which Reaction 6 was rate-determining, were replaced by Ravens by the reaction of peroxy radical with Co2+ ... 

The change in regiochemistry is a result of a change in the mechanism of the reaction, from an ionic mechanism in the Markovnikov reaction to a radical chain mechanism in the anti-Markovnikov reaction. The radical chain mechanism for the addition of hydrogen bromide to 1-butene is outlined in the following equations ... 

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. 

Many students wonder why the reaction with Markovnikov orientation does not take place in the presence of peroxides, together with the free-radical chain reaction. It actually does take place, but the peroxide-catalyzed reaction is faster. If just a tiny bit of peroxide is present, a mixture of Markovnikov and anti-Markovnikov products results. If an appreciable amount of peroxide is present, the radical chain reaction is so much faster than the uncatalyzed ionic reaction that only the anti-Markovnikov product is observed. 

In Section 8-3B, we saw the effect of peroxides on the addition of HBr to alkenes. Peroxides catalyze a free-radical chain reaction that adds HBr across the double bond of an alkene in the anti-Markovnikov sense. A similar reaction occurs with alkynes, with HBr adding with anti-Markovnikov orientation. 

The group VB hydrides show trends in reactivity similar to those of group IVB. The N-H bond can be reacted with alkenes only under the influence of catalysts or under forcing conditions. The P-H bond can be added to alkenes (hydrophosphination) in a free radical chain process, or under photolytic conditions. Such reactions proceed in good yield and in an anti-Markovnikov manner. Some typical free radical P-H additions are listed in Table 1 . The addition of phosphinyl radicals is reversible and can lead to... 

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. 

The addition of S-H compounds to alkenes by a radical chain mechanism is a quite general and efficient reaction.The mechanism is analogous to that for hydrogen bromide addition. The energetics of both the hydrogen abstraction and addition steps are favorable. The reaction exhibits anti-Markovnikov regioselectivity. 

Anti-Markovnikov addition of HBr,18e induced by radical-formers or photo-chemically, is preparatively important.152 An olefin and atomic bromine can, by reactions (a) and (b) form the radials (3) and (4) respectively, of which (3) is usually the more stable. (3) reacts with HBr to give the anti-Markovnikov adduct, together with a new bromine atom (radical chain reaction). Thus in the presence of small amounts of oxygen or peroxide (added specifically or already present in old preparations), allyl bromide affords the abnormal (anti-Markovnikov) 1,3-dibromopropane within 30 minutes and Mayo and Waling153 have collected numerous other examples. 

Another famous appHcation of mechanistic chemistry was contributed by Morris Kharasch (1895-1957) at the University of Chicago. It was well known since the mid-19th century that addition reactions of HX (HCl, H-OH, etc) to unsymmetrical alkenes occur in a manner that places hydrogen on the olefinic carbon attached to more hydrogen atoms than the other olefinic carbon (Markovnikov s rule). However, when HX is hydrogen bromide (HBr), addition is typically anti-Markovnikov. Kharasch found that traces of peroxides (commonly present on glassware surfaces) initiate a free radical chain reaction for HBr (not for other HX). Careful removal of peroxides Ifom glassware prior to reaction removes the potential free radical mechanism and HBr adds in a normal Markovnikov mode (intermediacy of carbocation, rather than Ifee radical, intermediates). 

Scheme 30.2 The free radical chain reaction mechanism between a thiol and an unactivated carbon-carbon double bond to form the anti-Markovnikov thiol-ene addition product. Adapted from Ref [22].

The mechanism proposed for the peroxide effect involves a radical chain reaction. The initiation step (equation 9.31) produces a bromine atom, which then attaches to the less alkyl-substituted carbon atom of a carbon-carbon double bond (equation 9.32). The resulting alkyl radical then abstracts a hydrogen atom from HBr to produce the anti-Markovnikov product and regenerate a bromine atom in the second propagation step (equation 9.33). Termination steps, not shown, interrupt the chain reaction. 

The mechanism for anti-Markovnikov addition of hydrogen bromide is a radical chain reaction initiated by peroxides. 

Radiolysis of mixtures of thiols and olefins in the absence of oxygen leads to anti-Markovnikov addition across the double bond in a long chain reaction involving free radicals. The propagation steps for a terminal... 

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