Regioselectivity of radical attack

S. S. Shaik, E. Canadell, J. Am. Chem. Soc. 112, 1446 (1990). Regioselectivity of Radical Attacks on Substituted Olefins. Application of the State-Correlation-Diagram (SCD) Model. 

The regioselectivity of radical attack may be summarized in the rule of thumb in STATEMENT 3. 

The most vexed subject in this field is the site of radical attack on substituted aromatic rings. Some react cleanly where we should expect them to. Phenyl radicals add to naphthalene 7.36, to anthracene 7.37 and to thiophene 7.38, with the regioselectivity shown on the diagrams. In all three cases, the frontier orbitals are clearly in favour of this order of reactivity (because of the symmetry in these systems, both HOMO and LUMO have the same absolute values for the coefficients). 

The intervention of a SET path in (hetero)aromatic nitration has been the subject of an extended debate [65]. The evidence is usually based either on the detection of intermediates or on the regioselectivity of the attack in relation to the spin and charge density on the radical cation. Limiting the attention to heteroaromatic substrates, it should be noted that the radical cations were detected spectroscopically [66] or even isolated as a salt [67] during nitration of, e.g., phenothiazine, phenox-... 

The observed non-Markovnikov regioselectivity of radical addition of HBr to an alkene is a combination of a sferic factor and an elecfronic factor. First, a bromine radical attacks the less hindered carbon of fhe double bond (the steric factor). Second, as mentioned in Section 8.5D, the relative stabilities of radicals parallel those of carbocations (Section 6.3A). 

From a synthetic point of view, the regioselectivity and stereoselectivity of the cyclization are of paramount importance. As discussed in Section 11.2.3.3 of Part A, the order of preference for cyclization of alkyl radicals is 5-exo > 6-endo 6-exo > 7-endo S-endo > 1-exo because of stereoelectronic preferences. For relatively rigid cyclic structures, proximity and alignment factors determined by the specific geometry of the ring system are of major importance. Theoretical analysis of radical addition indicates that the major interaction of the attacking radical is with the alkene LUMO.321 The preferred direction of attack is not perpendicular to the it system, but rather at an angle of about 110°. 

Most of the dienes investigated experimentally show high regioselectivity in radical addition reactions. The preferred position of attack is shown in Scheme 2. 

Based on the orbital approximations, it is clear that/(r) is the DFT analog of the frontier orbital regioselectivity for nucleophilic (f (r)) and electrophilic (/ (r)) attack. It is then reasonable to define a reactivity indicator for radical attack by analogy to the corresponding orbital indicator,... 

Methyl tricyclo[4.1.0.0 ]heptane-l-carboxylate gives a cation-radical in which the spin density is almost completely localized on C-1 while the positive charge is on C-7. The revealed structural feature of the intermediate cation-radical fairly explains the regioselectivity of N,N-dichlorobenzenesulfonamide addition to the molecular precursor of this cation-radical. In the reaction mentioned, the nucleophilic nitrogen atom of the reactant adds to electrophilic C-7, and the chlorine radical attacks C-1 whose spin population is maximal (Zverev and Vasin 1998, 2000). 

Because the addition steps are generally fast and consequently exothermic chain steps, their transition states should occur early on the reaction coordinate and therefore resemble the starting alkene. This was recently confirmed by ab initio calculations for the attack at ethylene by methyl radicals and fluorene atoms. The relative stability of the adduct radicals therefore should have little influence on reacti-vity 2 ). The analysis of reactivity and regioselectivity for radical addition reactions, however, is even more complex, because polar effects seem to have an important influence. It has been known for some time that electronegative radicals X-prefer to react with ordinary alkenes while nucleophilic alkyl or acyl radicals rather attack electron deficient olefins e.g., cyano or carbonyl substituted olefins The best known example for this behavior is copolymerization This view was supported by different MO-calculation procedures and in particular by the successful FMO-treatment of the regioselectivity and relative reactivity of additions of radicals to a series of alkenes An excellent review of most of the more recent experimental data and their interpretation was published recently by Tedder and... 

Despite that the regioselective cyclization of 5-hexenyllithiums could be synthetically useful, in those years there was no real development of this methodology9, probably due to the lack of a convenient and efficient procedure for the preparation of unsaturated alkyllithiums and to the conventional belief that simple alkenes are not thought of as sites of nucleophilic attack. Moreover, this was a period when radical cyclizations and radical cascade reactions came to the fore10, and 5-hexenyl substrates were used as probes for radical intermediates in reactions suspected of proceeding via single-electron transfer (SET). 

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