Reactive Intermediate Chemistry

142 RADICALS

and carbon dioxide, respectively. The decarboxylation reaction of an alkyl acyloxyl radical is comparable to or faster than diffusional processes, but aryl acyloxyl radicals decarboxylate less rapidly46 due to the instability of an aryl radical. The 2-cyano-2-methylethyl radical from AIBN is a relatively stable radical; it will react with tin hydride or (Me3Si)3SiH in an initiation sequence such as that shown in Figure 4.6, but it is not reactive enough for many radical reactions, such as addition to an acrylate ester, and it adds reversibly to the thione group of a xanthate. When a highly reactive radical from the initiator is necessary, diacyl peroxides are preferred over AIBN.

A relatively new method for thermal radical initiation has gained popularity in synthetic applications. A small amount of Et3B is added to the reaction mixture that has not been rigorously deoxygenated.47,48 The borane reacts with oxygen, apparently generating ethyl radicals. A major advantage for this mode of radical initiation is the low reaction temperatures (as low as 78 C) that can be achieved when stereoselective reactions are desired.49

Radical initiation in synthetic applications can be achieved without a special initiator when one employs members of the PTOC family of radical precursors

or related thione compounds (see Fig. 4.9). The PTOC precursors were developed mainly by Barton’s group50,51 in the 1980s and comprise mixed anhydrides of a

thiohydroxamic acid and a carboxylic acid or other acid. The commonly used thiohydroxamic acid is N-hydroxypyridine-2-thione. The PTOC derivatives are typically generated in situ, and the reaction mixture is heated or photolyzed with visible light to initiate radical reactions. Rate constants for thermal decomposition of PTOC derivatives have not been determined, but PTOC esters appear to be unstable >50–60 C, and radical initiation can be accomplished in refluxing benzene or toluene. Related oxygen-centered radical precursors react thermally and in chain reactions to give alkoxyl radicals.52 A family of nitrogen-centered radical

precursors is known for aminyl and amidyl radicals and aminium radical cations.53,54

4.1.2. Photolysis. One method of photochemical initiation involves photochemically activated homolysis reactions. The common thermal initiators can be cleaved photochemically, but the molar extinction coefficients of some of these species are small leading to poor efficiency. For example, laser generation of the tertbutoxyl radical in laser flash photolysis studies involves irradiation of a solution containing 50% di-tert-butyl peroxide with a high-energy eximer laser.55 Photolysis of AIBN with light from a mercury lamp is relatively efficient. The PTOC derivatives are yellow-colored compounds with a strong long wavelength absorbance centered at lmax ¼ 360 nm. These species are cleaved readily with visible light irradiation from a conventional tungsten-filament bulb. Many thermally stable compounds with relatively weak bonds can be cleaved photochemically; thus, an alkyl iodide, an alkyl phenylselenide, or a ditin compound such as hexabutyldistannane can be irradiated to initiate radical reactions.

Another method of photochemical initiation involves electron-transfer reactions of electronically excited states that are produced photochemically. The process is

known as photoinduced electron transfer (PET).56,57 The excited states are strong oxidants or reductants, and they oxidize or reduce substrates to give radical ions. Much of the chemistry of PET involves reactions of the radical ions and is discussed in Chapter 6, but cleavage reactions of the radical ions will produce radicals.

4.1.3. Electron Transfer. Both oxidative and reductive electron-transfer reactions will initiate radical chemistry. Chemical redox is discussed here, but the principles also apply to electrochemical reactions.58 When an alkyl halide is reduced, the radical ions lose halide in a concomitant or subsequent heterolytic reaction that gives a radical. In reactions of halides with metals such as lithium or magnesium, the organic radical is further reduced to give an organometal species. With mild reducing agents such as samarium diiodide (SmI2),59 reduction of an organic halide gives a radical that is subsequently reduced with a half-life in the microsecond range,60 and some radical reactions compete favorably with the second reduction step. A simple example is shown in Figure 4.11; the radical cyclization step competes effectively with the reduction of the initial radical, and the product radical is ultimately reduced to an organosamarium reagent that is protonated by alcohol.60

Radicals also can be produced by oxidation with the same constraints as in reductive entries to radicals. That is, the oxidizing agent must react relatively slowly with the radical. Manganese(III) acetate61 has been widely used for entries to enol radicals that react by radical addition reactions to give products that are further oxidized. An example is shown in Figure 4.11.62 Cerium(IV) reagents can be used in similar oxidation-initiated radical reactions.63 Hypervalent iodine species oxidize a number of compounds including alcohols to alkoxyl radicals,64 and anilides to N-arylamidyl radicals (Fig. 4.11).65

Reversible redox reactions can initiate radical chemistry without a follow-up reduction or oxidation reaction. In successful reactions of this type, the redox step that produces the radical is thermodynamically disfavored. For example, Cu(I) complexes react reversibly with alkyl halides to give Cu(II) halide complexes and an alkyl radical. The alkyl radical can react in, for example, an addition reaction, and the product radical will react with the Cu(II) halide to give a new alkyl halide. This type of reaction sequence, which has been applied in living radical

polymerizations, is in the general family of nonchain radical reactions discussed earlier.66,67

CuðIÞ complex þ R X Ð CuðIIÞX complex þ R

4.2. Elementary Propagation Reactions

Radicals undergo both homolytic and heterolytic versions of many reactions, whereas heterolytic processes predominate in reactions of closed-shell species. A major difference between radical and closed-shell molecule reactions is the rates of reactions. In general, rate constants for radical reactions are much larger than the rate constants for equivalent reactions in closed-shell molecules, in part due

RCO2Me

N N

Figure 4.11. Examples of redox-initiated radical reactions. Samarium diiodide reduction of the bromide gives a radical that cyclizes faster than the second reduction reaction. Manganese triacetate oxidation of the b-keto ester gives an enol radical that is not further oxidized by the manganese reagent. The IBX oxidizes anilides to the corresponding radicals. Hexamethylphosphoramide ¼ HMPA and Tetrahydrofuran ¼ THF.

to the absence of one electron that would occupy a high energy orbital in the transition state in a radical reaction.

4.2.1. Homolytic Atomand Group-Transfer Reactions. Atomand grouptransfer reactions are among the most important radical propagation reactions in fine chemical synthesis, but they usually are undesired side reactions in radical polymerizations because they terminate polymer chain growth even though they are not chain-termination reactions per se. Atom-transfer reactions include hydrogen and halogen transfers. Group transfers involve the exchange of pseudohalogens, such as a phenylselenyl group transfer. Relatively large multiatom groups, such as the allyl group, transfer by a composite addition–elimination sequence discussed in Section 4.2.4.

4.2.1.1. Hydrogen Atom Transfers. Hydrogen atom transfers occur in a single-step process that can be termed SH2 (substitution, homolytic, bimolecular) in analogy to the well-known SN2 substitution reaction, and many of these reactions are kinetically well characterized. The reaction of Bu3SnH with the propyl radical shown in Figure 4.6 is an example. In chain reactions for synthesis, group 14 (IV A) metal hydrides (mainly stannanes and silanes) are commonly employed because the metal-centered radical thus formed will react with an organic halide, pseudo-halide, thione, or other radical precursor to propagate the chain reaction, and extensive

tables of rate constants for hydrogen atom transfer reactions of group 14 (IV A) hydrides are available.15,68 Commonly employed group 14 (IV A) hydrides are tri-

butyltin hydride, triphenyltin hydride, and tris(trimethylsilyl)silane, (TMS)3SiH. Tributylgermanium hydride can be used, but it seldom has been, and triethylsilane reacts too slowly with carbon radicals to be useful in chain reactions. Thiols and selenols react rapidly with carbon radials and can be employed in some chain reactions, but the thiyl and selenyl radicals will not react rapidly with an organic halide. Other hydrogen atom donors that have been employed in synthetic applications are phosphines and reactive hydrocarbons such as 1,4-cyclohexadiene. Hydrogen atom transfer reactions from organic solvents are possible, and oxygen-centered radicals and aryl radicals abstract hydrogen from ethers rapidly, but alkyl radicals react slowly enough with ethers such as THF that the reactions are not of consequence.

Figure 4.12 shows rate constants at ambient temperature for reactions of group

14 (IV A) and group (VI A) 16 metal hydrides with several types of organic radi- cals.15,69–72 Within each group, the rate constants increase with decreasing M H

bond strength, reflecting the thermodynamics of the hydrogen atom transfer reaction. In addition, the kinetics reflect a polar contribution. As the nucleophilicity of the radical increases, the rate constants for reactions with electron-rich hydrogen atom donors from Group 14 (IV A) decrease. The group 16 (VI A) hydrides are electron-poor hydrogen atom donors, and increasing nucleophilicity in the radical results in faster hydrogen atom transfer reactions in this group. Note that, whereas the S H BDE for a thiol is greater than the Sn H BDE for a stannane, an alkyl radical reacts faster with t-BuSH than with Bu3SnH.

146 RADICALS

Figure 4.12. Second-order rate constants for reactions of hydrogen atom donors with various radical types at ambient temperature. Data sources: group 14 (IV A) hydrides (15); aminyl radicals (69); amidyl radicals (70); alkyl radials with group 16 (VI A) hydrides (71); acyl radical with PhSeH (72).

The polar effect on the kinetics of atom-transfer reactions permits the use of combinations of a group 14 (IV A) and a group 16 (VI A) metal hydride when neither reagent can be used independently. The compound Et3SiH reacts too slowly with alkyl radicals to support a chain reaction, and a thiol cannot support a radical chain reduction of an alkyl halide because the thiyl radical will not abstract the halogen atom from the alkyl halide. However, the two reagents can be used in combination for the alkyl halide reduction chain reaction.73 An alkyl radical reacts rapidly with t-BuSH, the thiyl radical thus formed reacts rapidly with Et3SiH, and the silyl radical abstracts a halogen atom efficiently from an alkyl halide.74 In a similar manner, a combination of Bu3SnH and a catalytic amount of PhSeH, conveniently generated by reaction of PhSeSePh with the tin hydride in situ, can be employed when one wishes to take advantage of the very fast trapping of alkyl radicals by PhSeH.71,75

4.2.1.2. Halogenand ChalcogenTransfers. Halogen and chalcogen transfers to carbon radicals76 are synthetically important for radical functionalization reactions, and organic halides and, less commonly, alkyl phenyl chalcogenides are useful radical precursors. Halogen atom transfer reactions and pseudo-halogen group transfers most likely occur by SH2 mechanisms. It is possible that intermediates are formed with the larger atoms such as iodine and tellurium, but a large leaving-group effect was found in reactions of arene-substituted arylselenides with alkyl radicals,

suggesting that an intermediate adduct was not formed in these reactions.77 Group 14 (IV A) radicals react rapidly with alkyl halides and pseudo-halides to generate alkyl radicals, but group 16 (VI A) radicals (oxyl, thiyl, selenyl) do not abstract halogen atoms.

The rate constants for reactions of alkyl radicals with various organic halides demonstrate a clear dependence on the thermodynamics of the reactions. Iodides react faster than bromides, which react faster than chlorides, and the rate constants for reactions for a series of bromides or iodides correlate with the stability of the radical product.78,79 The reactions of a primary alkyl radical with an iodomalonate

106 M 1 s , respectively, at 50 C). To a good approximation, the rate constants for reactions of RSePh are the same as those for reactions of RBr, and the rate constants for reactions of RTePh are about the same as those for reactions of RI.77 Dichalcogenides are useful for radical functionalization reactions; they react with

primary alkyl radicals at ambient temperature with the following rate constants: MeSSMe, 6 104 M 1 s 1; PhSSPh, 2 105 M 1 s 1; PhSeSePh, 2:6 107 M 1 s 1; PhTeTePh, 1:1 108 M 1 s 1.22

Abstractions of halogen atoms from alkyl halides by silyl, germanyl, and stannyl

radicals are among the most important reactions for producing an organic radical in chain-reaction sequences. These reactions are very fast as shown in Figure 4.13.74,80

Both the tris(trimethylsilyl)silyl radical81 and the tributylgermanyl radical80 react with alkyl halides with rate constants similar to those of the tributylstannyl radical. Reactions of the group 14 (IV A) metal-centered radicals with alkyl phenyl selenides have rate constants comparable to those for the analogous bromides.

Intramolecular group-transfer reactions82,83 can involve either direct displacements or addition–fragmentation reactions that are discussed in Section 4.2.4. A direct displacement is shown in the reaction of aryl radical 1, produced from the corresponding bromide. Cyclization of 1 is fast enough to compete efficiently

Figure 4.13. Second-order rate constants for reactions of tributylstannyl and triethylsilyl radicals with various alkyl halides at ambient temperature. [Data from (74) and (80).]

this radical to an electron-rich enol ether and slower than addition to styrene. On the other hand, the nucleophilic 1-hydroxy-1-methylethyl radical adds to methyl acrylate >4 orders of magnitude faster than it reacts with an enol ether and faster than it adds to styrene.

Intramolecular homolytic additions of radicals to alkenes, or radical cyclizations, are among the historically important reactions that led organic synthetic chemists to radical methodology. Cyclizations of carbon-centered radicals onto unactivated alkene moieties in five-membered ring-forming reactions are fast enough to be accomplished with no special techniques due to the acceleration afforded by the intramolecular nature of the reaction. Thus, five-membered carbocycles, which have limited entries from other synthetic approaches, are readily available by radical methods. In unsubstituted systems, cyclization of the 5-hexenyl radical (k ¼ 2 105 s 1) and the 6-heptenyl radical (k ¼ 6000 s 1) are fast enough to be used in synthetic sequences. When an accelerating group such as an ester in an acrylate is present, macrocycles with 10–18-membered rings can be prepared in radical cyclizations.89

The regioselectivity of radical cyclization reactions will be biased by a radical stabilizing group on an unsaturated moiety as in intermolecular additions, but there is a strong preference for exo cyclizations over endo cyclizations in small ringforming reactions when no stabilizing group is present. Thus, the 5-exo cyclization of the 5-hexenyl radical (4) is 50 times faster than 6-endo cyclization even though cyclizations onto the terminal carbon gives the thermodynamically favored radical.90 The explanation of this kinetic preference with force field calculations was an early success of computational methods applied to study radical reac- tions.91–93 Stereoselectivity in 5-exo cyclizations that give disubstituted cyclopentyl products is modest, but, again, the product ratios are well modeled in the force field studies.93

50 : 1

4

Rate constants for several 5-exo radical cyclizations are shown in Figure 4.15.71,90,94 –96 The general trends in the kinetics are similar to those found

in intermolecular additions. It is tempting to assume that the large rate enhancements found when a radical stabilizing group is bonded to the incipient radical center will be paralleled by large rate retardations when the same group is present on the original radical center. That is not the general case, however, because the kinetic

radicals to activated alkenes at ambient temperature have rate constants in the 106– 108 M 1 s 1 range.80 Highly reactive alkoxyl radicals add rapidly to the alkene moiety to give thermodynamically favored carbon radical products.110 For example, cyclization of the 4-pentenyl-1-oxyl radical (6) is 3 orders of magnitude faster than cyclization of the 5-hexenyl radical and has the same 50:1 preference for 5-exo cyclization over 6-endo cyclization as observed with the carbon radical analogue.111 Cyclization of the dialkylaminyl radical 7 is slower than cyclization of 5-hexenyl and approximately theromoneutral,112 whereas cyclization of amidyl radical (8) is very fast and strongly favored thermodynamically.70

4.2.2.2. Fragmentations. Homolytic fragmentations of carbon radicals to give carbon radical products mainly involve ring openings of strained threeand four-mem- bered rings. The simplest representative, the cyclopropylcarbinyl radical (9) ring opening to the 3-butenyl radical, is one of the most well-studied radical reactions and is the archetypal fast radical reaction with a rate constant for ring opening at ambient temperature of 7 107 s 1.71,113 Cyclopropylcarbinyl compounds have been used as probes to test for radical intermediates in a wide range of reactions. The cyclobutylcarbinyl radical opens to the 4-pentenyl radical with a rate constant that is smaller by >4 orders of magnitude.114

9

Rate constants for ring openings of substituted cyclopropylcarbinyl radicals show the same types of kinetic effects as seen in radical additions to substituted

alkenes with an obvious relationship to the thermodynamics of the reaction (Fig. 4.16).71,113,115–121 Minor steric effects influence the kinetics, however, and

these are apparent in computational results that accurately reproduce the barriers for reaction.115 When the substituent is at the radical center, the kinetics of ring openings are only slightly affected unless a conjugating group such as phenyl is the substituent. As with 5-hexenyl radical cyclizations, this might appear counterintuitive, but the only group that is clearly out of line with the thermochemistry is the ester group, and ring openings of cyclopropylcarbinyl radicals with an ester at the radical center are accelerated by polarized transition states.121

A large number of homolytic fragmentation reactions of carbon radicals with b-leaving groups are known from studies in the gas and condensed phase.122,123