II: Transition-Metal-Generated Radicals

b. Cobaloxime Complexes

The discovery that carbon–cobalt bond homolysis in coenzyme B₁₂ (5) produced the carbon-cen­tered radical 6 (eq 1), led to investigation of simpler mole­cules that could model this behavior. Cobaloximes are one of several types of compounds found to be effective choices for this role.^13–16 Carbo­hydrate cobal­oximes 8 and 9 produce radicals 10 and 4, which recom­bine in the absence of radical traps (Scheme 6).¹³ In the presence of compounds that react with radicals, 10 and 4 undergo characteristic radical reactions; thus, the D-mannopyranos-1-yl radi­cal 10 adds to acrylonitrile (11) to give the adduct radical 12, which then combines with ·Co(dmgH)₂py (4) to form the addition pro­duct 13 (Scheme 7).¹³

A necessary condition for the reaction shown in Scheme 7 is that 4 [Co(dmgH)₂py] be stable enough to remain unchanged while the addition of 10 to 11 is taking place. The needed stability of 4 der­ives from protection of its radical center by the attached ligands; thus, 4 can be viewed as a persistent radical.

c. The Persistent-Radical Effect

Persistent radicals, such as ·Co(dmgH)₂py (4), are responsible for a type of reac­tivity known as the persistent-radical effect.^17–19 This effect causes a reaction that generates a persistent radical (R₁·) and a transient radical (R₂·) in equal amounts to give a higher yield of the cross-coupling product (R₁R₂) than would be expected from random radical coupling. The explanation for greater cross-coupling product formation begins with the recognition that although persistent and transient radicals are formed in equal amounts, this equality is short lived. Due to the reactive nature of transi­ent radicals their concentration decreases more rapidly in the early stages of a reaction than does the concentration of persistent radicals. (Transient radicals combine, disproportionate, and undergo other reactions much more rapidly than persistent radicals.) The rapidly developed, higher concentration of persistent radi­cals in the early stages of reaction means that any newly formed, transient radical is more likely to encounter and combine with a persistent radical than with another transient one; in other words, the cross-coupling product R₁R₂ becomes the major coupling product.

An example of the persistent radical effect is shown in the reaction given in Scheme 4, where carbon–cobalt bond homolysis in 1 or 2 produces the persistent radical 4 and the transient radical 3. Even with the extended heating or photolysis needed to reach equilibrium, there was no evidence of formation of a coupling product other than the cross-coupling products 1 and 2. The persistent radical effect also is operative in the addition reaction shown in Scheme 7. In this case the transient radical 12, produced by addition of 10 to acrylonitrile (11) , and the persistent radical 4 combine to form the only radical-coupling product isolated.

2. Carbon-Mercury Bond Homolysis

There are similarities in reactivity among compounds with C–Co and C–Hg bonds. Both bonds are strong enough to exist in stable structures at room temperature but both readily cleave upon photolysis. The result in each case is formation of a metal-centered and a carbon-centered radical. Carbon-centered radicals produced by carbon–mercury bond homol­ysis undergo typical radical reactions, such as the hydrogen-atom abstraction shown in Scheme 8.²⁰

3. Manganese(III) Acetate [Mn(OAc)₃] Reactions

Carbon-centered radicals can be generated by reaction of man­gan­ese(III) ace­tate with CH-acidic compounds such as the β-diketone shown in Scheme 9.^21–24 The first step in this process is formation of the enolate 15.²³ In the presence of an unsaturated compound two mechanisms for reaction of 15 are considered to be possible. In the first of these electron transfer forms man­gan­ese(II) acetate and the resonance-stabilized radical 16, which then adds to an unsat­urated compound. A second possible path­way for addition is a con­certed process in which the enolate 15 reacts directly with the unsaturated com­pound to produce the adduct radical 17 (Scheme 9).²³ Reac­tion by either of these pathways is believed to take place by inner-sphere electron transfer.

Since radical centers with two, attached carbonyl groups are electro­philic, radicals such as 16 (Scheme 9) add most easily to unsaturated com­pounds with electron-rich multiple bonds.²² This is the point at which carbohydrates typic­ally become involved in reactions begun by manganese(III) acetate because glycals have electron-rich π systems that are attractive targets for addition of elec­trophilic radicals; for example, the radical 19, formed by reac­tion of dimethyl­malonate (18) with man­gan­ese(III) acetate (eq 2), adds to the tri-O-acetyl-D-glucal 20 to produce the stereo­iso­meric radicals 21a and 21b (Scheme 10).^25,26 This addition, which occurs regioselectively at C-2, is followed by oxidation of the resulting radi­cals with a second molecule of manganese(III) acetate to give the corres­pond­ing cations 22a and 22b. These cations react with the solvent (acetic acid) to yield the final products (23a, 23b, 24a, and 24b). Manganese(III) acetate, therefore, is involved in both the formation and disappearance of the radicals in this reaction. (Electrophilic radicals and other aspects of radical philicity are discussed in Chapter 7.)

Manganese(III) acetate has a more complicated structure than the for­mula Mn(OAc)₃ indicates. It is an oxo-centered trimer of three manganese ions held together by six bridging acetates.^27–29 Three representations for this structure are shown in Figure 2. It is often convenient in dis­cussing reac­tions of this compound to use the abbreviated formula Mn(OAc)₃.

4. Ammonium Cerium(IV) Nitrate [(NH₄)₂Ce(NO₃)₆] Reactions

Reaction of CH-acidic compounds with ammonium cerium(IV) nitrate generates electrophi­lic, resonance-stabilized radicals in a manner similar to reaction with man­ganese(III) acetate.^30,31 As mentioned in the previous section, these radicals add readily to the electron-rich double bonds such those found in glycals (eq 3).³⁰ Oxidation of CH-acidic compounds with ammonium cerium(IV) nitrate to produce electrophilic radicals has the advantage, when compared to reactions with manganese(III) acetate, of being able to be conducted at or below room temperature. [The reactions of manganese(III) acetate and ammonium cerium(IV) nitrate are discussed further in Chapter 21 of Volume II.]