Scope Carbon–hydrogen bond activation

1 scope

1.1 overview
1.2 selectivity of c-h activation
1.3 innate selectivity
1.4 guided selectivity

scope
overview

two pathways achieve c-h activation: innate c-h activation or guided c-h activation. figure depicts 2 oxidation products possible, depending on reagents used functionalize specific c-h bond.

selectivity of c-h activation

among various factors affect selectivity in c-h activation, more sterically accessible c-h bond have more selectivity @ position.

in figure above, axial c-h bond in cis-1,2-dimethylcyclohexane selectively oxidized on equatorial c-h bond. during oxidation, axial methyl group becomes planar, decreasing 1,3-diaxial interactions in transition state, stabilizes transition state.

an alkene c–h bond activation rhodium catalyst demonstrated in synthesis of strained bicyclic enamine:

innate selectivity

innate selectivity observed reactions functionalize c-h bonds lack influence of directing forces, relying on natural reactivity of molecule. inductive (through-bond) effects can explain innate selectivity of c-h bond in molecule through examination of electronic nature of bonds. presence , proximity of electron-withdrawing groups (ewgs) or electron-donating groups (edgs) can heavily influence electron density of c-h bond. reactivity trend nonmetal insertion tertiary>secondary>primary. steric effects can influence selectivity of c-h bond activation: bulky groups can decrease rate of functionalizing adjacent c-h bond.

for oxaziridine (left), 1st site oxidized preferably due not distance electron-withdrawing obz group because of substitution—the carbon tertiary—and more electron rich. similarly, secondary methylene position in trifluoromethyldioxirane (tfdo, right) farthest away electron-withdrawing group selectively oxidized. note here, oxaziridine, substitution @ carbon affects selectivity; secondary methylene position preferred on terminal methylene position because former has secondary carbon while latter has primary one.

in oxidation of cyclohexane compound, tertiary site on ring preferential on tertiary site of isopropyl substituent. 2 methyl groups hinder oxidation on isopropyl group, making less hindered cyclohexyl site more favorable.

guided selectivity

in contrast innate selectivity, guided selectivity results external reagents or directing groups affecting nature of specific c-h bonds.

the figure above demonstrates use of pyridine directing group activate selectively c-h bond form c-halogen bond. pyridine derivatives commonly used ortho-selective c-h functionalization. such reactions use metals palladium catalyze sp c-h activation. similar system uses pyridine acetoxylate c-h bond, forming c-oac bond, instead of c-x halogen bond.

the mechanism pyridine based pd-catalyzed c-h activation reactions involves catalytic cycle in ligand directs molecule interact pd form metallacycle intermediate. intermediate oxidized form pd species, followed reductive elimination form c-o bond , release product.

see meta-selective c-h functionalization more examples of directed c-h activation.