Alkenes, radical addition reversibility

The reversal of the regiochemistry of addition is the result of the reversal of the order in which the two components add to the alkene. Radical addition leads to the formation of the more stable... 

There have also been relatively few mechanistic studies of the addition of iodine. One significant feature of iodination is that it is easily reversible, even in the presence of excess alkene. The addition is stereospecifically anti, but it is not entirely clear whether a polar or a radical mechanism is involved. ... 

This comparison suggests that of these two similar reactions, only alkene additions are likely to be a part of an efficient radical chain sequence. Radical additions to carbon-carbon double bonds can be further enhanced by radical stabilizing groups. Addition to a carbonyl group, in contrast, is endothermic. In fact, the reverse fragmentation reaction is commonly observed (see Section 10.3.6) A comparison can also be made between abstraction of hydrogen from carbon as opposed to oxygen. 

The regiochemistry of nucleophilic addition to alkene radical cations is a function of the nucleophile and of the reaction conditions. Thus, water adds to the methoxyethene radical cation predominantly at the unsubstituted carbon (Scheme 3) to give the ff-hydroxy-a-methoxyethyl radical. This kinetic adduct is rearranged to the thermodynamic regioisomer under conditions of reversible addition [33]. The addition of alcohols, like that of water, is complicated by the reversible nature of the addition, unless the product dis-tonic radical cation is rapidly deprotonated. This feature of the addition of protic nucleophiles has been studied and discussed by Arnold [5] and Newcomb [84,86] and their coworkers. 

A majority of radical addition occurs with electron-poor alkenes using alkyl halides in the presence of BusSnH. These reactions are feasible due to a proper matching between the radical acceptor and the donor. However, when the alkene is electron-rich and since simple alkyl radicals are considered as nucleophilic, the reaction is not a practical method for carbon-carbon bond formation. By applying the concept of polarity-reversal catalysis, an additional reagent is introduced which alleviates the mismatch between the partners and makes the reaction feasible. A few examples illustrating this concept have been described in this review. 

A range of addition reactions of (TMS)3GeH with alkynes, alkenes, ketones, azines, and quinones has been studied using EPR. In addition, synthetic studies of hydrogermylation of alkynes have shown that the reaction proceeds regio- and stereo-selectively, whereas reactions with alkenes do not take place (presumably owing to the reversibility of the germyl radical addition) (Scheme 29). 

Unlike alkenes, which react reversibly with h, alkynes react in solution irreversibly with I2, forming ( )-l,2-diiodoalkenes.89 The reaction may involve radicals rather than ionic species.90 Ordinary alumina appears to promote the addition, forming electrophilic species.866 The addition of iodine to 1,4-dichloro-but-2-yne is analogous to the addition found with bromine cited above (Scheme 19).28... 

Each of the syntheses of seychellene summarized in Scheme 20 illustrates one of the two important methods for generating vinyl radicals. In the more common method, the cyclization of vinyl bromide (34) provides tricycle (35).93 Because of the strength of sjp- bonds to carbon, the only generally useful precursors of vinyl radicals in this standard tin hydride approach are bromides and iodides. Most vinyl radicals invert rapidly, and therefore the stereochemistry of the radical precursor is not important. The second method, illustrated by the conversion of (36) to (37),94 generates vinyl radicals by the addition of the tin radical to an alkyne.95-98 The overall transformation is a hydrostannylation, but a radical cyclization occurs between the addition of the stannyl radical and the hydrogen transfer. Concentration may be important in these reactions because direct hydrostannylation of die alkyne can compete with cyclization. Stork has demonstrated that the reversibility of the stannyl radical addition step confers great power on this method.93 For example, in the conversion of (38) to (39), the stannyl radical probably adds reversibly to all of the multiple bond sites. However, the radicals that are produced by additions to the alkene, or to the internal carbon of the alkyne, have no favorable cyclization pathways. Thus, all the product (39) derives from addition to the terminal alkyne carbon. Even when cyclic products might be derived from addition to the alkene, followed by cyclization to the alkyne, they often are not found because 0-stannyl alkyl radicals revert to alkenes so rapidly that they do not close. 

A second example for a sulfur-directed cyclization, in which even two thio-phenyl groups were present as substituents on the target alkene 36, is shown in Scheme 14 [85]. This substitution pattern is capable of reversing the usual regios-electivity observed for aryl radical additions to enamides. In the presence of a fivefold excess of tributyltin hydride, one sulfur group is removed immediately after the cyclization step. The resulting tricyclic thioether 37 was further converted to mappicine ketone 38. 

Reversed regioselectivity in aryl radical additions to enamides and enamines can also be observed with aryl substituents on the alkene [86]. This cyclization type has been successfully applied in the synthesis of protoberberines and the pavine alkaloids. Argemonine (39) was obtained from a 6-exo cyclization of 40 passing through a well-stabilized benzylic radical (Scheme 15). 

The apparent chemoselectivity for the addition of the electrophilic S-centered radicals to the less electron-rich alkyne moiety in enyne 138 can be rationalized by the fact that addition of S radicals to both aUcenes and alkynes proceeds smoothly (the rate constants for addition of S radicals to alkenes are about three orders of magnitude larger than those for the addition to alkynes), but is also reversible. However, the reversibility is less pronounced for the radical addition to alkynes, due to the high reactivity of the vinyl radicals formed (compared to alkyl radicals), which undergo subsequent reactions at faster rates than undergoing fragmentation back to the S... 

Under a nitrogen atmosphere, even iodine azide undergoes addition to alkenes with a reversal of the regiochemistry, consistent with a radical pathway24,38 41. Furthermore, the solvent and the source of iodine azide affect the nature of the reagent and consequently the regio- and stereoselectivity of the addition14 16 42,43. 

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... 

The stannylformylation of ordinary alkenes seems difficult to achieve, because of the reversibility of the stannyl radical addition step. That is to say, intermolecu-lar CO trapping of the -stannyl radical cannot compete well with the rapid reverse reaction which regenerates the tin radical and an alkene (Scheme 4-6). 

In some cases the addition of bromide to alkene radical cations is reversible. For example, the addition of bromide to the p-methyl-4-methoxystyrene radical cation occurs reversibly, as demonstrated by the formation of the radical cation when the P-bromo radical is generated independently by photolysis of l-(4-methoxyphenyl)-l,2-dibtomopropane (Eq. 18). An equilibrium constant of 2 x 10 M has been measured for the loss of bromide from this radical in acetonitrile. The apparent lack of reactivity of 1,3-dioxole radical cations with bromide ion in water has also been explained on the basis of reversible addition with rapid loss of bromide from the product radical. However, on the basis of the solvent effects noted above, it is also possible that the lack of reactivity in water is a solvent effect since decreases in reactivity of 4 to 5 orders of magnitude have been observed for reactions of bromide ion with styrene radical cations in largely aqueous solvent mixtures. - ... 

Atom radical transfer polymerisation (ATRP) has its roots in atom transfer radical addition (ATRA), which involves the formation of 1 1 adducts of alkyl halides and alkenes, and is also catalysed by transition metal complexes. ATRP is a modification of the Kharasch addition reaction (Kharasch et al. 1945) although there may be some differences (Minisci 1975). A general mechanism for ATRP is shown in Scheme 10.5. In ATRP the radicals or the active species are generated through a reversible redox process catalysed by a transition metal complex (Mtn-L/... 

It has long been known that thiyl radicals add reversibly to double bonds (cf. Scheme 1) [17]. The (Z)-( ) interconversion of olefins by the addition-elimination sequence of thiyl radicals [18] is now an established methodology in chemical synthesis [19] and has been applied successfully as the key step in the synthesis of elaborate molecules such as the antifungal macrocyclic lactone (-)-gloeosporone [20a] and the antibiotic-antitumor agent (+)-hitachimycin [20b]. The E/Z ratio after equilibration generally reflects the thermodynamic stability of (Z)- and ( )-alkenes. It has recently been shown that equilibrium Z/E-18/82) for ( )- and (Z)-hexen-l-ol is reached with PhS radical in 1 h at 80°C [21]. Comparatively, the same isomeric composition is reached in 4h and lOh with Bu3Sn and (TMS)3Si respectively under similar conditions. 

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