C1-4 Alkylation of Aryl Bromides with Light Alkanes enabled by Metallaphotocatalysis in Flow

Abstract

The homologous series of gaseous C1-4 alkanes represents one of the most abundant sources of short alkyl fragments. However, their application in synthetic organic chemistry is exceedingly rare due to the challenging C-H bond cleavage, which typically demands high temperatures and pressures, thereby limiting their utility in the construction of complex organic molecules. In particular, the formation of C(sp²)-C(sp³) bonds is crucial for constructing biologically active molecules, including pharmaceuticals and agrochemicals. In this study, we present the previously elusive coupling between gaseous alkanes and (hetero)aryl bromides, achieved through a combination of Hydrogen Atom Transfer (HAT) photocatalysis and nickel-catalyzed cross coupling at room temperature. Utilizing flow technology allowed us to conduct this novel coupling reaction with reduced reaction times and in a scalable fashion, rendering it practical for widespread adoption in both academia and industry. Density Functional Theory (DFT) calculations unveiled that the oxidative addition constitutes the rate-determining step, with the activation energy barrier increasing with smaller alkyl radicals. Furthermore, radical isomerization observed in propane and butane analogues could be attributed to the electronic properties of the bromoarene coupling partner, highlighting the crucial role of oxidative addition in the observed selectivity of this transformation.

Keywords: DFT Calculations; Flow Chemistry; Light Alkanes; Nickel Catalysis; Photocatalysis.

Figure 1

A State of the art in gaseous alkane functionalization. B General strategies for light alkyl fragment incorporation C Ethylation, case study. D Design of an efficient arylation of light hydrocarbons.

Figure 2

Scope of the alkylation of (hetero)aryl bromides using gaseous alkanes as alkylating agents. Reaction conditions: (hetero)aryl bromide (0.3 mmol. 1.0 equiv.), TBADT (2×2.5 mol %), Ni Complex I (5 mol %), 2,6 Lutidine (1.1 equiv.) and LiBr (1.5 equiv.) in 3 mL of (CD₃CN: t‐BuOH=3 : 1), G : L=40 : 1, 144 W of 365‐nm LEDs. Selectivity reported in brackets. All yields are those of isolated products (Supporting Information for experimental details). [a] For the recirculation step TBADT (2.5 mol %) and Ni Complex I (5 mol %) were used. [b] For the recirculation step TBADT (3.5 mol %) and Ni Complex I (7 mol %) were used. [c] Yield determined by GC‐FID. See Supporting Information for experimental details.

Figure 3

A Parallel kinetic isotope effect. B Proposed reaction mechanism and the reactivity comparison between methyl, ethyl, and iso‐propyl radicals. C The activation strain analysis (ASA) and the energy decomposition analysis (EDA) of rate‐determining oxidative addition TS‐like structures. D Origin of the trend in electrostatic interaction energies. E Origin of the trend in orbital interactions.

Figure 4

A Influence of the electronic property of aryl bromides on the selectivity of alkylation using n‐butane. Selectivity determined with GC‐MS. [a] Yields determined by ¹H NMR using trichloroethylene as an external standard. [b] Volatile compounds. B Radical scrambling mechanism and the origin of regioselectivity. See Supporting Information for experimental details.