Taming the Chlorine Radical: Enforcing Steric Control over Chlorine-Radical-Mediated C–H Activation

Abstract

Chlorine radicals readily activate C–H bonds, but the high reactivity of these intermediates precludes their use in regioselective C–H functionalization reactions. We demonstrate that the secondary coordination sphere of a metal complex can confine photoeliminated chlorine radicals and afford steric control over their reactivity. Specifically, a series of iron­(III) chloride pyridinediimine complexes exhibit activity for photochemical C­(sp3)–H chlorination and bromination with selectivity for primary and secondary C–H bonds, overriding thermodynamic preference for weaker tertiary C–H bonds. Transient absorption spectroscopy reveals that Cl· remains confined through formation of a Cl·|arene complex with aromatic groups on the pyridinediimine ligand. Furthermore, photocrystallography confirms that this selectivity arises from the generation of Cl· within the steric environment defined by the iron secondary coordination sphere.

Synthetic Applications of Photocatalyzed Halogen‐Radical Mediated Hydrogen Atom Transfer for C−H Bond Functionalization

“…As a matter of fact, while bromine atoms somehow allow for discrete levels of site-selectivity due to the lower BDE of the HÀ Br bond (see Table 1), a HÀ Cl bond is much stronger, providing a considerably higher thermodynamic force for hydrogen abstraction. [114] Furthermore, the greater selectivity of brominemediated HAT can be explained based on the fact that this is an endergonic process. Thus, according to the Hammond postulate, the reaction features a "late" transition state with a marked radical character on the carbon atom.…”

“…More recently, Nocera and colleagues managed to go towards the opposite direction and shift the selectivity away from more thermodynamically accessible tertiary positions by capitalizing on steric hindrance (Scheme 27D). [114] In detail, they demonstrated that Cl * , photoeliminated from an Fe III chloride pyridinediimine (PDI) complex via LMCT, can be confined by the secondary coordination sphere of the metal complex itself. This interaction creates a bulky Cl * j arene complex that possesses a considerable steric hindrance compared to the free chlorine atom.…”

Visible-Light-Induced Iron Group Metal Catalysis: Recent Developments in Organic Synthesis

“…The chlorine radical-induced charge-transfer complexes were known to alter the selectivity in alkane activation. 21 Based on this strategy, Nocera and co-workers designed an iron(III) pyridinediimine (PDI) complex, 22 of which the ligand could form a charge-transfer complex with a chlorine radical. The arene−Cl• interaction could be leveraged to confine a photoeliminated chlorine radical within the secondary coordination sphere of the synthesized metal complexes, affording steric-controlled products over the reactivity of chlorine radical.…”

Regioselective control of biocatalytic C–H activation and halogenation

“…Although C-H activation reactions have found high utility in synthetic chemistry, site selectivity can be challenging to achieve as the weakest or most sterically-accessible C-H bond is typically activated by the catalyst, it can be difficult to prevent undesired activation of C-H bonds of similar strength, and functional group compatibility can be low. To address these challenges, chemical catalysts have been designed to use ligand architecture or spatial orientation to achieve selectivity [15][16][17][18][19][20][21][22][23] . In contrast, enzymes routinely achieve both stereo-and regioselectivity when presented with similar sites of equivalent reactivity since their three-dimensional chiral architecture naturally creates asymmetry.…”