This Review summarizes the advances in fluorination via C(sp 2)-H and C(sp 3)-H activation. Transition metal catalyzed approaches championed by palladium have allowed the installation of a fluorine substituent at C(sp 2) and C(sp 3) sites exploiting the reactivity of high oxidation transition metal fluoride complexes combined with the use of directing group (some transient) to control regio-and stereoselectivity. The large majority of known methods employ electrophilic fluorination reagents, but methods combining a nucleophilic fluoride source with an oxidant have appeared. A number of ligands have proven to be effective for C(sp 3)-H fluorination directed by weakly coordinating auxiliaries, thereby enabling control over reactivity and selectivity. Methods relying on the formation of radical intermediates are complementary to transition metal catalyzed processes as they allow for undirected C(sp 3)-H fluorination. To date, radical C-H fluorinations mainly employ electrophilic N-F fluorination reagents but a unique bio-inspired Mn(III)-catalyzed oxidative C-H fluorination has been developed. Overall, the field of late stage nucleophilic C-H fluorination has progressed much more slowly, a state of play explaining why C-H 18 F-fluorination is still in its infancy. C-F reductive elimination C(sp 2)-H C(sp 3)-H C(sp 3)-H

Cyclo[18]carbon (C 18 , a molecular carbon allotrope) can be synthesized by dehalogenation of a bromocyclocarbon precursor, C 18 Br 6 , in 64% yield, by atomic manipulation on a sodium chloride bilayer on Cu(111) at 5 K, and imaged by high-resolution atomic force microscopy. This method of generating C 18 gives a higher yield than that reported previously from the cyclocarbon oxide C 24 O 6 . The experimental images of C 18 were compared with simulated images for four theoretical model geometries, including possible bond-angle alternation: D 18 h cumulene, D 9 h polyyne, D 9 h cumulene, and C 9 h polyyne. Cumulenic structures, with ( D 9 h ) and without ( D 18 h ) bond-angle alternation, can be excluded. Polyynic structures, with ( C 9 h ) and without ( D 9 h ) bond-angle alternation, both show a good agreement with the experiment and are challenging to differentiate.

Small-ring cage hydrocarbons are common bioisosteres for para-substituted benzene rings in drug design 1 . The popularity of these structures derives from the superior pharmacokinetic properties they exhibit compared to the parent aromatics, including improved solubility and reduced susceptibility to metabolism 2,3 . A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesised by ring-opening of the inter-bridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions 4 . In contrast, scaffolds mimicking metasubstituted arenes are lacking due to the challenge of synthesising saturated isosteres that accurately reproduce substituent vectors 5 . Here we show that bicyclo[3.1.1]heptanes (BCHeps), hydrocarbons whose bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally-relevant carbon-and heteroatom-substituted BCHeps, including pharmaceutical

Photoredox catalysis has transformed the landscape of radical-based synthetic chemistry. Additions of radicals generated through photoredox catalysis to carbon−carbon πbonds are well-established; however, this approach has yet to be applied to the functionalization of carbon−carbon σ-bonds. Here, we report the first such use of photoredox catalysis to promote the addition of organic halides to the carbocycle [1.1.1]propellane; the product bicyclo[1.1.1]pentanes (BCPs) are motifs of high importance in the pharmaceutical industry and in materials chemistry. Showing broad substrate scope and functional group tolerance, this methodology results in the first examples of bicyclopentylation of sp 2 carbon−halogen bonds to access (hetero)arylated BCPs, as well as the functionalization of nonstabilized sp 3 radicals. Substrates containing alkene acceptors allow the single-step construction of polycyclic bicyclopentane products through unprecedented atom transfer radical cyclization cascades, while the potential to accelerate drug discovery is demonstrated through late-stage bicyclopentylations of natural productlike and druglike molecules. Mechanistic investigations demonstrate the importance of the photocatalyst in this chemistry and provide insight into the balance of radical stability and strain relief in the reaction cycle.