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III. Generation of Carbon-Centered Radicals

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    23943
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    A. Atom-Transfer Reactions

    Carbon-centered radicals often are generated by atom-transfer reac­tions. The transfer usually is of a halogen atom, but hydrogen-atom transfer also can take place. Absolute rate constants for producing carbon-centered radicals by reaction of halogenated compounds with Bu3Sn· are found in Table 1. Table 2 contains a similar set of rate constants that includes those for atom-transfer reac­tions involving (Me3Si)3Si· and Et3Si·. (Tables 1 and 2 also contain some group-trans­fer reac­tions.) To produce a radical selectively by atom transfer, one atom in the substrate must be more reactive than any other atom or group. A typical pair of propagation steps that selectively form a carbo­hydrate radical is shown in Scheme 1, where an iodine atom is trans­ferred from a car­bo­hydrate to a tin-centered radical.8

    t1.png

    t2.png

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    Examining the rate constants in Tables 1 and 2 offers insight into why iodides and bromides are so frequently used in carbon-centered radical gener­ation. Reactions of compounds containing these atoms are so rapid that rarely is there com­petition in radical formation from replacement of other groups or atoms commonly pre­sent in a reacting molecule. Chlorides are substan­tially less reactive than iodides and bromides; con­se­quently, chlorine atom abstraction is a less effective way for selectively gen­er­ating carbon-centered radicals. (Fluorides are effectively unreac­tive.) Another factor favoring the use of iodides and bromides is a synthetic one. Sulfonate esters, which are easily prepared from carbohydrates, are converted readily into the corres­ponding iodides and bro­mides by nucleo­philic displacement reaction.

    Because the rate constants listed in Tables 1 and 2 are for reactions of organic com­pounds that are structurally simpler than carbo­hydrates, in using these rate constants for carbohydrate reactions the assumption is that the same reactive substituent will have a similar rate constant for reaction in a more complex compound. Although such an assumption is reason­able, often neces­sary, and usually valid, extrapolation of rate constants from simple com­pounds to carbohydrates needs to be treated with caution because some of the struct­ural features that affect the reactivity of carbohydrates and carbo­hydrate radi­cals cannot be adequately accounted for in simpler systems. (Such a situation involving pyranos-1-yl radicals was discussed in Sections VI.B. and VI.C. of Chapter 7.)

    B. Group-Transfer Reactions

    Group transfer can be a more complicated process than atom transfer because atom transfer consists of a single elementary reaction, but group transfer often requires two such reactions. Since the halogen-atom-transfer reac­tions shown in Tables 1 and 2 are irreversible, for each of these reactions the rate constant for halogen-atom transfer is the same as that for carbon-centered radical forma­tion. The situation is different for group-transfer reactions because the first step in group transfer often is rever­sible. In such a situation the absolute rate constant for reaction of a substrate with Bu3Sn·(Table 1) or (Me3Si)3Si· (Table 2) is larger than the rate constant for carbon-centered radical formation.

    The effect on radical reactivity of a reversible reaction during group transfer can be seen by com­paring three pairs of competing reactions.2 The common reaction in each of these three is between 1-bromooctane and (Me3Si)3Si· (Scheme 2). Since this reaction gives the octyl radical R· in a single, irreversible step, the rate constant for reaction of the bromide with (Me3Si)3Si· is the same as the rate constant for formation of R·. Also, since R· then abstracts a hydrogen atom from (Me3Si)3SiH, the amount of octane formed is directly related to the number of octyl radicals pro­duced.

    s2.png

    The first comparison experiment involves reaction of molar-equivalent amounts of 1-bro­mo­octane, cyclohexyl isonitrile, and tris(trimethylsilyl)­si­lane.2 A proposed mechanism for the reac­tion between the isonitrile and (Me3Si)3Si· is give in Scheme 3. If the addition of (Me3Si)3Si· to the isonitrile is irreversible, then the ratio of cyclohexane to octane in the product mixture would be the same as the ratio of the rate constants given the Table 2 for reactions of the isonitrile and the bromide, respectively. ­The information in Scheme 3 shows that these ratios are similar but not the same. One conclu­sion that can be drawn from this information is that the addition of (Me3Si)3Si· to cyclohexyl isoni­trile is reversible. Whenever the reverse reac­tion takes place, it effectively reduces the rate of cyclohexane formation and causes the ratio of cyclohexane to octane to be smaller than that expected from the ratio of the rate constants kNC and kBr (Scheme 3).

    s3.png

    The addition of the (Me3Si)3Si· to cyclohexyl phenyl selenide (Scheme 4) and cyclohexyl xan­thate (Scheme 5) presents a picture with more dramatic differences.2 Competi­tion experiments with 1-bromooctane show that the rate constants for group transfer from the selenide and the xan­thate are substant­i­ally less than the rate constants shown in Table 2. This reduced reactivity can be explained by assuming that the addition of (Me3Si)3Si· to these compounds is a frequently reversed process.

    s4.png

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    C. Fragmentation Reactions

    The basic structure of carbohydrates makes possible the formation of both carbon-centered and oxygen-centered (alkoxy) radicals. The reactions that characterize oxygen-centered radicals are hydrogen-atom abstraction and radical frag­mentation. When an oxygen-centered radical fragments, the result is usually a radical centered on a carbon atom; thus, the alkoxy radical 4 frag­ments to give the ring-open, carbon-centered radical 5 (Scheme 6).9 The lack of an effective hydrogen donor in the reaction mixture allows fragmen­tation to take place without competition from hydrogen-atom abstraction.

    s6.png

    In the reaction shown in Scheme 7 the oxygen-centered radical 6 and the carbon-centered radi­cal 7 exist in a pseudoequilibrium. Both radicals abstract hydrogen atoms from Bu3SnH.10 Due to the differences in the rate constants for ring opening (kfra = 1.1 x 107 s–1M–1 at 80 oC) and ring closure (kcyc = 1.0 x 106 s–1M–1 at 80 oC), the ring-open radical 7 dominates the pseudoequi­librium, but because the rate constant for hydrogen-atom abstraction by 6 (kH = 4.7 x 108 s–1M–1 at 80 oC) is so much larger than that for hydrogen-atom abstraction by 7 (kH = 6.4 x 106 s–1M–1 at 80 oC), the major reaction product arises from hydrogen-atom abstraction by the oxygen-centered radical 6. A related reaction that also is controlled by the large rate constant for hydrogen-atom abstraction by an oxy­gen-cen­tered radical is pictured in Scheme 8, where abstrac­tion by the alkoxy radical 9 is respon­sible for the only product formed.11 There is no evidence for competing fragmen­ta­tion of 9 leading to ring opening; in partic­ular, no ring-open product is formed and no epimerization takes place at the hydroxyl-bearing carbon atom. (Epimerization would be expected if a ring opening took place that was followed by rapid ring closure.)

    s7.png

    s8.png

    D. Electron-Transfer Reactions

    Dissociative electron transfer takes place when a compound containing a reactive atom or group accepts an electron and undergoes fragmentation (Scheme 9). Electron capture can be extremely rapid if an electron is free in solution; thus, the rate constant for capture of a solvated elec­tron by the nucleoside 10 is 1.6 x 1010 M–1s–1 at 22 oC.12,13

    s9.png

    Radical formation by electron transfer also can take place by reaction between trans­i­tion-metal complexes such as (NH4)2Ce(NO3)6, Mn(OAc)3, SmI2, and Cp2TiCl and carbo­hydrate der­ivatives that include iodides, bro­mides, and sulfones; for example, complexes involving samar­ium(II) iodide frequently are elec­tron donors in reactions of carbohydrates (Scheme 10). A com­mon reaction for SmI2 is a second electron transfer to the initially formed radical R· to produce an organo­sa­marium compound (Scheme 10). This second electron transfer is fast enough that it can limit the ability of R· to undergo radical transforming reactions such as cyclization and group migra­tion.

    s10.png

    Reactions involving SmI2 typically are conducted in the presence of hexa­methyl­phos­phor­amide (HMPA), a compound that complexes with SmI2 and increases its ability to donate an elec­tron. Greater electron-donating ability not only increases the rate constant for formation of the radical R· but it also increases the rate at which this radical reacts with a second molecule of SmI2. The data in Table 3 show that when the 5-hexenyl radical reacts with SmI2, the rate constants for reaction increase from 5 x 105 M–1s–1 to 6.8 x 106 M–1 s–1 at 25 oC as the amount of added HMPA increases.14 The magnitude of these rate constants is such that if a radical is to do anything other than simple combination with a molecule of SmI2, this “other reaction” must be rapid. An example of a reaction of a radical that does take place more rapidly than combination with SmI2 is the cyclization shown in Scheme 11.15,16 (Chapter 20 in Volume II contains further information about and discussion of the reactions of carbohydrate derivatives with SmI2.)

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    s11.png


    This page titled III. Generation of Carbon-Centered Radicals is shared under a All Rights Reserved (used with permission) license and was authored, remixed, and/or curated by Roger W. Binkley and Edith R. Binkley.