Halogenation of cubane under phase-transfer conditions: single and double C-H-bond substitution with conservation of the cage structure.

The first highly selective C-H chlorination, bromination, and iodination of cubane (1) utilizing polyhalomethanes as halogen sources under phase-transfer (PT) conditions is described. Isomeric dihalocubanes with all possible combinations of chlorine, bromine, and iodine in ortho, meta, and para positions were also prepared by this method; m-dihalo products form preferentially. Ab initio and density functional theory (DFT) computations were used to rationalize the pronounced differences in the reactions of 1 with halogen (Hal(*)) vs carbon-centered trihalomethyl (Hal(3)C(*)) radicals (Hal = Cl, Br). For Hal(3)C radicals the C-H abstraction pathway is less unfavorable (DeltaG(double dagger)(298) = 21.6 kcal/mol for Cl(3)C(*) and 19.4 kcal/mol for Br(3)C(*) at B3LYP/6-311+G//B3LYP/6-31G) than the fragmentation of the cubane skeleton via S(H)2-attack on one of the carbon atoms of 1 (DeltaG(double dagger)(298) = 33.8 and 35.1 kcal/mol, respectively). In stark contrast, the reaction of 1 with halogen atoms preferentially follows the fragmentation pathway (DeltaG(double dagger)(298) = 2.1 and 7.5 kcal/mol) and C-H abstraction is more unfavorable (DeltaG(double dagger)(298) = 4.6 and 12.0 kcal/mol). Our computational results nicely agree with the behavior of 1 under PT halogenation conditions (where Hal(3)C(*) is involved in the activation step) and under free-radical photohalogenation with Hal(2) (Della, E. W., et al. J. Am. Chem. Soc. 1992, 114, 10730). The incorporation of a second halogen atom preferentially in the meta position of halocubanes demonstrates the control of the regioselectivity by molecular orbital symmetry.

Selective radical reactions in multiphase systems: phase-transfer halogenations of alkanes.

The present paper shows that selective radical reactions can be initiated and carried out in multiphase systems. This concept is applied to the selective functionalization of unactivated aliphatic hydrocarbons, which may be linear, branched, and (poly)cyclic, strained as well as unstrained. The phase-transfer system avoids overfunctionalization of the products and simplifies the workup; the selectivities are excellent and the yields are good. This is the only method for direct preparative iodination of alkanes applicable to large scale as well. We demonstrate that the reaction systems are indeed phase-transfer catalyzed through a systematic study of variations of the reactants, solvents, catalysts, and by measuring as well as computing the H/D kinetic isotope effects for the rate-limiting C-H abstraction step by *CHal3 radicals which are held responsible for the observed radical reactions. In the case of *CBr3, this key intermediate could also be trapped under otherwise very similar reaction conditions. To stimulate further work, the tolerance of some functional groups was tested as well.

Kinetic isotope effects for the C-H activation step in phase-transfer halogenations of alkanes

Within the scope of phase-transfer halogenations (Br and I) of alkanes, significant H/D kinetic isotope effects (KIE = 4-5) indicate that hydrogen abstraction is rate limiting. The excellent agreement of computed and experimentally determined H/D KIE as well as trapping experiments support the involvement of trihalomethyl radicals in the activation step.

The First Efficient Iodination of Unactivated Aliphatic Hydrocarbons.

No heavy metals, no enzymes, and a simple protocol: the direct iodination of aliphatic hydrocarbons, which has not been possible to date, can now be carried out in multiphase systems [see for example Eq. (1)]. In situ generated tetraiodomethane serves as a key intermediate in this selective radical chain reaction initiated by a single electron transfer. This room-temperature, efficient transformation is highly regioselective, easy to work-up, and hence widely applicable.