Reactive Intermediate Chemistry

Figure 4.16. First-order rate constants for ring openings of substituted cyclopropylcarbinyl radicals at ambient temperature. [Data from (71, 113, 115–121).]

In many cases, rate constants for the fragmentation reactions are not available, but the reactions can be deduced to be quite fast because intermediate radicals are not trapped efficiently by reactive hydrogen atom donors.

Homolytic cleavage reactions of alkoxyl radicals are quite common, and the reactions have good synthetic utility.52,124 Cleavage of the tert-butoxyl radical (10) gives methyl radical and acetone with a rate constant of 2 104 s 1 at ambient temperature in benzene.125 This fragmentation represents the low end of the kinetic range for alkoxyl radical cleavages that give alkyl radicals because other alkyl radicals are more stable than methyl. The rate of homolysis is also strongly influenced by the stability of the carbonyl product formed in the elimination. For example, when the same alkyl radical was expelled from a series of alkoxyl radicals, the rate constants for elimination were a function of the carbonyl compound formed with the following relative values:126 0.013 (formaldehyde), 0.19 (acetaldehyde), 1 (acetone), 8.8 (benzaldehyde), and 22 (benzophenone).

O O

CH3

10

Some homolytic fragmentation reactions are driven by formation of small, stable molecules. Alkyl acyloxyl radicals (RCO2) decarboxylate rapidly (k > 1 109 s 1) to give alkyl radicals, and even aryl acyloxyl radicals (ArCO2) decarboxylate to aryl radicals with rate constants in the 106 s 1 range.46 Azo radicals produced in the homolysis of azo initiators eliminate nitrogen rapidly. Elimination

of carbon monoxide from acyl radicals occurs but is slow enough (k 104– 105 s 1)7,33 such that the acyl radical can be trapped in a bimolecular process,

and addition of a radical to carbon monoxide followed by acyl radical trapping is a useful synthetic carbonylation sequence.7

4.2.3. Heterolytic Radical Addition and Fragmentation Reactions

4.2.3.1. Additions. Radicals can react with anionic species to give radical anion adducts as shown for radical 11. Such addition reactions are steps in chain reaction

processes described as SRN1 (unimolecular radical nucleophilic substitution) reactions.127,128 The SRN1 reactions typically involve aryl radicals that are produced by

reduction of an aryl halide to give the corresponding radical anion that expels halide. Therefore, these reactions provide an important method for aromatic substitution.129 In a typical reaction sequence, the radical anion adduct 12 would transfer an electron to a molecule of reactant (ArX) in a chain propagation step to give the neutral product of an overall substitution reaction sequence.

Whether the addition step in an SRN1 sequence is labeled as heterolytic or homolytic is a semantic question that depends on the MO energy levels of the initially formed adduct. Alkyl radicals also can react in SRN1 sequences. If a simple alkyl radical reacted with an anion, the partially occupied MO in the radical anion adduct would reside on the original anion moiety, and the reaction would have the appearance of a homolytic addition. In many SRN1 examples involving alkyl radical reactions, however, the radical is stabilized by strong electron-withdrawing groups such as nitro, and charge in the radical anion would be carried largely on the original radical part of the adduct.

Aryl radical additions to anions are generally very fast, with many reactions occurring at or near the diffusion limit. For example, competition studies involving mixtures of nucleophiles competing for the phenyl radical showed that the relative reactivities were within a factor of 10, suggesting encounter control,130 and absolute rate constants for additions of cyanophenyl and 1-naphthyl radicals to thiophenoxide, diethyl phosphite anion, and the enolate of acetone are within an order of magnitude of the diffusional rate constant.131

4.2.3.2. Fragmentations. Heterolytic fragmentation reactions of radicals with leaving groups b to the radical center produce a radical cation and an anion. Such reactions might seem rare, but in actuality they are likely to be relatively common. The reaction sequence is described in the same context as heterolysis of a closed-shell species (Fig. 4.17). Dissociation of the radical gives an intimate or contact pair comprised of the radical cation and anion. The pair can recombine to give the original radical or a rearranged radical, or it can react in, for example, a proton transfer reaction. The contact ion pair can become solvated, and the solvent-separated ion

pair can diffuse apart to give free ions. In highly polar media, the heterolysis reaction might be observed directly by the formation of free radical cations and anions. In low-polarity solvents, the ions can react with one another without diffusing apart, and the mechanism might be inferred.

Examples of radical heterolysis reactions are shown in Figure 4.18. Heterolysis of C40 deoxyribonucleic acid (DNA) radicals is thought to be the anaerobic pathway for strand cleavage induced by DNA-damaging drugs such as iron-bleomycin. The pathway was supported in an important early study that showed that various alkyl radicals with b-leaving groups (halide, phosphate, sulfonate) reacted in water to give acid, presumably by heterolysis followed by nucleophilic capture or deprotonation of the radical cation by water.132 Heterolysis of phosphate groups and the

mesylate group in b-substituted a-methoxy radicals gives diffusively free radical cations in moderately polar solvents such as acetonitrile.133,134 1,2-Migrations of

carboxylate and phosphate groups observed when b-ester radicals react in low polarity solvents are well-known reactions135 that might proceed via ion pairs produced in the dissociative pathway.136 The radical heterolysis reaction provides a nonoxidative entry to radical cations and could become an important synthetic method.137

4.2.4. Composite Group-Transfer Reactions. Intermolecular group transfers of large organic moieties are composite reactions involving formation of an intermediate by homolytic addition followed by homolytic fragmentation. In organic synthetic conversions, this type of reaction provides a means for maintaining functionality at a radical position as opposed to completing a chain sequence with a hydrogen atom transfer reaction. The sequence is employed often in radical polymerizations to control the growth of polymer chains without terminating radical chain reactions and to add functional groups into polymer chains.122

Some examples of addition–elimination reactions are shown in Figure 4.19. The allylation reaction shown138,139 is typical of a sequence often employed in organic

Figure 4.19. Examples of group transfers by addition–elimination.

156 RADICALS

Figure 4.20. Migrations involving addition–elimination.

synthesis. Vinylation of a radical center is possible when the radicophile is a b- substituted styrene140 or acrylate. The third example in Figure 4.19 is a propagation step when Barton’s PTOC esters are used as radical precursors.50 Addition to the

thione moiety occurs at sulfur to give an intermediate that fragments. Xanthate esters and other thiones react in a similar manner as PTOC esters,108,141 and

the thione addition–fragmentation sequence is the basis of the Barton–McCombie deoxygenation reaction.142,143

Intramolecular homolytic addition– elimination reactions result in group migrations (Fig. 4.20). Most commonly, 1,2-migrations are involved because formation of a small ring has only a slight entropy penalty even if the enthalpy is unfavorable due to ring strain in the intermediate. The migration of the vinyl group in the 2,2- dimethyl-3-butenyl radical is representative; a small amount of cyclic product is obtained when the reaction is conducted in the presence of thiophenol.144 Other

groups that migrate in a similar manner include carbonyls and their derivatives, acetylenes, aryl groups, and the cyano group.103,145–147 The second example in

the figure is the migration of the phenyl group in the neophyl rearrangement, a well-calibrated125 reaction that has been known for many years. The cyclization onto a carbonyl group in the third example is the heart of an important ringexpansion sequence for synthesis.148 As one would expect, migration reactions with heteroatom-centered radicals also occur; for example, phenyl migration in 1-phenylalkoxyl radicals149 is analogous to the neophyl rearrangement.

4.3. Radical Termination Reactions

Termination reactions convert radicals to closed-shell compounds. Radical–radical coupling reactions are the reverse of homolytic cleavage reactions and are common, but radicals with b-hydrogen atoms also react in disproportionation reactions as shown for 13. The selectivity of radical–radical terminations is low because the

reactions are highly exothermic, and activation barriers for radical–radical reactions are typically smaller than the apparent activation barriers for diffusion.

H H

13

The termination rate constant kT appeared in the rate law for a radical chain reaction in Section 3.2. It is typically a diffusional rate constant, on the order of 1010 M 1 s 1 at ambient temperature. Diffusional rate constants can be predicted from diffusion theory or determined experimentally using, for example, the hydrocarbon analogue of a radical as a model. The rate constant for termination is often less than the rate constant for diffusion, however, due to a phenomenon known as spin statistical selection.150 When two mono-radicals form an encounter complex, the ensemble has a 25% probability of being in a singlet state and a 75% probability of being in a triplet state. If intersystem crossing (or spin flip) is slow on the scale of the lifetime of the encounter complex, which is common for a pair of organic radicals, then the triplet ensemble cannot react because it would give a high-energy excited state product. Thus, the termination rate constant in this case would be 25% of the diffusional rate constant. When heavy atoms are present in the radicals, intersystem crossing rates can increase, and the termination rate constants can approach the diffusional limit.

Knowledge of diffusional rate constants might seem arcane, but the diffusional values were critically important for establishing absolute rate constants for radical reactions. Before lasers were available, kinetic ESR studies were typically performed at low temperatures with continuous irradiation from a UV source.32 In this experimental design, a reaction is followed that is in competition with radical–radical termination reactions, and one obtains a ratio of the rate constant for the reaction of interest to the (diffusional) rate constant for termination. Increasing understanding of diffusion resulted in adjustments in diffusional rate constants to larger numbers and, accordingly, larger derived rate constants for the radical reactions. In reading the literature on radical chemistry, one should be aware of the possibility that currently accepted values for radical reaction rate constants can be a factor of 2– 4 larger than values appearing in articles that are 30– 40 years old.

5. CONCLUSION AND OUTLOOK

Organic radical chemistry in synthesis has truly blossomed in the past two decades, and more dramatic advances are expected given the vast scope of synthesis. Radical methodology is attractive because typical conditions for carbon-radical generation and functionalization do not require protection of alcohol and carbonyl functionality

158 RADICALS

and because cyclic compounds can be produced and further functionalized in cascade sequences. Significant progress in, for example, stereocontrol,10,151,152 asymmetric induction,153,154 and kinetic information changed somewhat mysterious

reactions into powerful synthetic methods. Another driving force for further developing radical-based synthetic methodology is ‘‘green chemistry.’’ Virtually all radicals are stable in water, and radical-based functionalization reactions can, in principle, allow one to avoid organic solvents.

Computational methods93 have advanced to the point that quite accurate bond energies in general and activation barriers for reactions of ‘‘apolar’’ radicals can be computed with good accuracy. This finding in part reflects the fact that homolytic reactions do not create charge, and computations in the gas phase provide good approximations for neutral ground and transition states in condensed phase. Further advances in computational methods are expected in reactions of polarized radicals and reactions that involve heterolytic pathways, and this should follow general advances in handling solvent interactions and charge effects in polar reactions.

Radicals in biological reactions have only become well-appreciated recently. Although alluded to in this chapter, biological radical reactions have not been a focus, which is not a reflection of a lack of examples, however. In addition to destructive reactions, such as the DNA fragmentation in Figure 4.18, a wide range of constructive biological radical reactions are known. Perhaps the most impressive is the reduction of ribonucleotides to 20-deoxyribonucelotides by ribonucleotide reductase, a radical reaction involved in the production of all DNA.155 Many radical reactions in biology are known to be effected by coenzyme B12-dependent and S-adenosylmethionine-dependent enzymes, both of which give the 50-deoxyadeno- sin-50-yl radical that abstracts a hydrogen atom from substrate.155 The mechanisms of many of the biological radical reactions are poorly understood, however, in part because organic radical analogies are not known. It is possible that much new radical chemistry remains to be uncovered by studying biological radical reactions and that this will involve ‘‘polar radical’’ reaction pathways where enzymes catalyze reactions of radicals with polar groups and regions, much like they catalyze polar reactions of closed-shell molecules.

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