Cyclohexyl radical selectivity

High Peroxide Process. An alternative to maximizing selectivity to KA in the cyclohexane oxidation step is a process which seeks to maximize cyclohexyUiydroperoxide, also called P or CHHP. This peroxide is one of the first intermediates produced in the oxidation of cyclohexane. It is produced when a cyclohexyl radical reacts with an oxygen molecule (78) to form the cyclohexyUiydroperoxy radical. This radical can extract a hydrogen atom from a cyclohexane molecule, to produce CHHP and another cyclohexyl radical, which extends the free-radical reaction chain. 

With the radical 29, even though loss of an equatorial hydrogen should be sterically less hindered and is favored thermodynamically (by relief of 1,3 interactions of the axial methyl), there is an 8-fold preference for loss of the axial hydrogen (at 100 ( i. The selectivity observed in the disproportionation of this and other substituted cyclohexyl radicals led Beckwith18 to propose that disproportionation is subject to stereoelectronic control which results in preferential breaking of the C-H bond which has best overlap with the orbital bearing the unpaired spin. 

Radical addition to conjugated systems is an important part of chain propagation reactions. The rate constants for addition of cyclohexyl radical to conjugated amides have been measured, and shown to be faster than addition to styrene. In additions to RCH=C(CN)2 systems, where the R group has a chiral center, the Felkin-Ahn rule (p. 148) is followed and the reaction proceeds with high selectivity. Addition of some radicals, such as (McsSijaSi-, is reversible and this can lead to poor selectivity or isomerization. ... 

A large number of accurate rate constants are known for addition of simple alkyl radicals to alkenes.33-33 Table 2 summarizes some substituent effects in the addition of the cyclohexyl radical to a series of monosubstituted alkenes.36 The resonance stabilization of the adduct radical is relatively unimportant (because of the early transition state) and the rate constants for additions roughly parallel the LUMO energy of the alkene. Styrene is selected as a convenient reference because it is experimentally difficult to conduct additions of nucleophilic radicals to alkenes that are much poorer acceptors than styrene. Thus, high yield additions of alkyl radicals to acceptors, such as vinyl chloride and vinyl acetate, are difficult to accomplish and it is not possible to add alkyl radicals to simple alkyl-substituted alkenes. Alkynes are slightly poorer acceptors than similarly activated alkenes but are still useful.37... 

The results demonstrate the value of being able to select the matrix independently of the radical precursor. The e.s.r. spectra of alkyl radicals trapped in their parent hydrocarbon or halohydrocarbon are often poorly resolved, and only the major hyperfine splitting constants can be determined. By using a bulky hydrocarbon such as camphane or adamantane as a matrix a marked increase in resolution has been observed for the spectra of many alkyl radicals up to Ce and all of the cyclo-alkyl radicals up to Cy. As an example, the spectra of the cyclohexyl radical trapped in matrices of cyclohexane and camphane are shown in Fig. 7. In cyclohexane the a and major )3-proton hyperfine splittings are not well resolved, and the small )3 splitting is not observed at all, whereas in camphane all three hyperfine splittings are readily observed. 

With an alkene having an X-substituent at one end and a Z-substituent at the other, radicals can show different regioselectivity depending upon their SOMO energy, since both possible products are stabilised. Thus nucleophilic radicals like the cyclohexyl radical react with methyl crotonate 7.40 selectively (92 8) at C-3, responding to the large coefficient at that site in the LUMO. The electrophilic benzoyloxy radical, however, is less selective and actually attacks a little more rapidly (55 45) at C-2, which has the larger coefficient in the HOMO.992... 

Similarly, the cyclohexene 7.107 selectively loses the axial hydrogen from the allylic position with the C—H bond best aligned with the % bond, and the intermediate radical 7.108 selectively picks up the chlorine atom from the axial direction to give the less stable of the two possible diastereoisomers 7.109.1037 The cyclohexyl radical 7.111 derived from pyrolysis of the oxalate 7.110 again loses the axial hydrogen selectively to give the alkene 7.112, although the alternative 7.113 is the more stable isomer.1038... 

Two equatorial /i-substituents are present in cyclic carbohydrate radicals, in which the pyranose ring forms a heterocyclic cyclohexyl radical37. The glucosyl radicals A, B, and C below all show preferred equatorial attack in addition reactions to alkenes the actual selectivity depends on the radical and alkene substituents. In reactions of cyclohexyl radicals with only one equatorial /1-substituent, addition of 1,2-disubstituted alkenes yields only the equatorial addition product. 

Similar lo the effect of ring oxygen atoms is the influence of a carbonyl group adjacent to the radical center 6. In allylation reactions of 2-oxocyclohexyl radicals, the formation of an axial product is slightly enhanced compared to the corresponding cyclohexyl radicals. This is in contrast lo the situation in cyclopentyl radicals, where the introduction of adjacent carbonyl groups leads to a lowering of cisjtrans selectivity in allylation reactions (see this section Cyclopentyl Radicals),... 

Annulated ring systems have as /1,7-substituents, when compared to annulated cyclopentyl radical systems, a stronger effect on the stereoselectivity than the corresponding combination of acyclic substituents. In all cases, attack tram to the /J.y-m-annulated ring is preferred. The stereoselectivity depends, furthermore, on additional substituents at the radical and the alkene, but it appears that the reactions of cyclohexyl radicals proceed less selectively than their cyclopentyl analogs. One frequently used route to these systems is sequential cyclization/ addi-tion reactions, in which the primary radical cyclizes to form the bicyclic ring system, followed by intermolecular addition to an alkene45,47 74. 

Similar to the selectivities observed in five-ring annulations of carbocyclic systems (see previous section), cyclic 3-oxa-5-hexenyl radicals exhibit a distinct preference for the formation of l,5-c( s-configurated products. This is illustrated by the reaction of five- and six-membered /i-phenylselenocrotonates with triphenyltin hydride59. The intermediate cyclopentyl or cyclohexyl radicals cyclize exclusively in the 5-exo mode to yield the corresponding c -fused "/-lactones. 

The influence of the alkene substituent R2 has been investigated in addition reactions of cyclohexyl radicals to maleic anhydride17 l9. The final hydrogen abstraction step again occurs with high selectivity anti to the /(-substituent R1. The a-substituent R2 further enhances the stereoselectivity and the highest values are found for R2 = t-Bu19. 

TBA-I catalyzed the oxidation of cyclohexane with 1 atm molecular oxygen at 365 K. The main products wa e cyclohexanol and cyclohexanone and an induction period was observed. The selectivities changed little with time. A small amount of dicyclohexyl, which is formed by the reaction of two cyclohexyl radicals, was observed. Neither acids nor oxoesters were observed. The induction period and the formation of dicyclohexyl suggest that the reaction involves a radical-chain autoxidation mechanism. The... 

Houk and coworkers investigated the diastereofacial selectivity in radical additions of substituted cyclohexyl radicals to alkenes [13]. In this work, the force field developed by Spellmeyer and Houk was applied to intermolecular homolytic addition with success and demonstrated the added versatility of the HS model over the BS procedure which is limited to intramolecular systems. Extraordinarily accurate predictions of diastereoselectivity were made. For example, acrylonitrile is predicted to react with the 4-ter -butyl-2-methylcyclohexyl radical 28 to alford the products... 

The most interesting studies included the evaluation of the reactivity of the same radicals for two different reaction paths, 16 and 17. The computational studies correctly selected path 16 as the most reactive one. However, the question remains is there sufficient selectivity to accomplish only transformation 16. The computed selectivity index was 0.0336 (0.1216-0.0980). These values assured the formation of products only through a five-memebered ring formation. This was in full agreement with experimenal results [128]. It is well known that a secondary radical is more stable than a primary radical. The calculations supported this by favoring the cyclohexyl radical by 7.7 kcal/mol over the cyclopentylmethyl radical. Therefore, formation of the six-membered ring product was thermodynamically controlled. 

The most important process (which accounts for most of the uses of radical cychzations in synthesis) is the selective 5-exo-cyclization of the 5-hexenyl radical to give the cyclopentyl methyl radical. This occurs even though the alternative - a 6-endo cyclization to give a more stable, cyclohexyl radical - is thermodynamically more favorable. Thus, the 5-ex o-cycHzation proceeds under kinetic control. The preference for 5-ex o-cyclization is explained by an early transition state with little product character. The transition state is a strain-free chair-like arrangement, which nicely accommodates the stereoelectronically required attack angle on the alkene. This model also nicely explains the stereochemical outcome of the cycHzation reaction. Assuming that substituents prefer to adopt pseudo-equatorial positions in the chair-Uke transition state, we see why ... 

Fortunately, in recent times, considerable knowledge has been gained about both termination modes. Beckwith [29] reviewed the topic of regio-selectivity and stereo-selectivity in several types of radical reactions. He suggested that the disproportionation reaction (of cyclohexyl radicals) is under stereo-electronic control and is not based that much on thermochemical factors. Relatively simple rules may be applied to predict the outcome of such radical reactions. Reviews on this topic have been published by Gibian and Corely [21], Alfassi [24] and Moad and Solomon [22, 30]. In general, the relative... 

An investigation concerning the /p5o-substitution of a nitro group in 2-nitrothiophenes demonstrated that 1-adamantyl radical (Ad) and cyclohexyl radical (Cyclohex ) selectively attack the /p5o-positions of thiophenes bearing... 

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