An Assay for Aryl Radicals Using BHAS Coupling

Abstract

Aryl radicals are intermediates in many reactions, but determining their presence unambiguously is often challenging. As we recently reported, reaction of 2-iodo-1,3-dimethylbenzene 7 in benzene with KOtBu and a suitable organic additive, leads to a base-induced homolytic aromatic substitution (BHAS) coupling reaction giving 2,6-dimethylbiphenyl 12 and biphenyl 3 as coupled products, together with xylene. Biphenyl arises from a radical translocation and is the major coupling product. This paper now investigates that reaction, using deuterium isotope studies to provide detailed mechanistic support. The reaction gives very similar outcomes with two different radical generation sources, and in doing so, shows its ability to act as an assay for aryl radicals. An advantage of such a BHAS process is that it involves a chain reaction that can amplify radical activity.

A Hierarchy of Ligands Controls Formation and Reaction of Aryl Radicals in Pd-Catalyzed Ground-State Base-Promoted Coupling Reactions

“…In the known examples, the deprotonation step (here 13 → 14 versus 13- d 6 → 14- d 5 ) is not the rate-determining step in BHAS and does not lead to a primary kinetic isotope effect, i.e., k H / k D ∼ 1, and so BHAS reactions would have quite different profiles from the CMD route discussed above. , Although the rate of formation of 2,6-dimethylbiphenyl 8 is unaffected by the change of the solvent, the formation of biphenyl 9 by BHAS is retarded when the reaction is conducted in benzene- d 6 , with an isotope effect noted for the hydrogen (deuterium) atom transfer (HAT) step from benzene to the xylyl radical 11 (Scheme ). This was shown recently in studies that we conducted in C 6 D 6 and in C 6 H 6 , which were initiated by organic electron donors (see the SI).…”

“…Repeating the isotope experiments with the Pd(OAc) 2 /dppf system (Table ) using benzene versus benzene- d 6 as the solvent produced very similar results to those seen with our previously studied organic electron donor-initiated systems . The formation of the deuterated biphenyl (1.4%) was suppressed in benzene- d 6 (entry 2) relative to the biphenyl (12.4%) in benzene (entry 1), while the amount of deuterated 2,6-dimethylbiphenyl 8- d 10 was mostly unaffected in benzene- d 6 (3.9% entry 2) relative to 2,6-dimethylmethylbiphenyl 8 (3.1%) in benzene (entry 1), consistent with the reaction through a radical manifold.…”

“…Our assay for aryl radicals arises from the anomalous BHAS chemistry of the hindered substrate 2,6-dimethyliodobenzene 7 . Reaction of 2,6-dimethyliodobenzene 7 with benzene and KO t Bu in the presence of an initiator provides a characteristic ratio (ca.…”

“…Radical 11 can alternatively undertake hydrogen atom abstraction from benzene, forming the phenyl radical 12 together with m- xylene 10 . (The xylyl radicals can also abstract hydrogen from other sources, accounting for the much greater yields of xylene than of coupled products.) This phenyl radical 12 can then carry out BHAS coupling with benzene, producing biphenyl 9 (Scheme ).…”

“…In our development of the assay, the ratio of the yields of the two coupled products 8 and 9 was effectively the same (ca. 1:4) regardless of the initiation source, likely reflecting control by the ratio of the rate constants for the two possible reactions of radical 11 with benzene, i.e., k C–H for hydrogen atom abstraction from benzene and k C–C for addition to benzene …”