Étienne Rochette

Metal-free catalytic C-H bond activation and borylation of heteroarenes

A metal-free catalyst born of frustration Boron (a Lewis acid) and nitrogen or phosphorus fragments (both Lewis bases) tend to pair up. Keeping them separated on opposite ends of the same molecule creates a “frustrated” Lewis pair. Such molecules can manifest powerful reactivity, such as scission of the hydrogen-hydrogen bond in H2. Légaré et al. now extend this reactivity to the cleavage of carbon-hydrogen bonds in heteroaromatic compounds such as furans and pyrroles (see the Perspective by Bose and Marder). Their frustrated Lewis pair complex catalyzed borylation of these compounds. The selectivity pattern of the reaction complemented that seen with the metal catalysts conventionally used. Science, this issue p. 513; see also p. 473 Boron and nitrogen centers cooperatively catalyze a reaction that has previously relied on transition metal catalysts. [Also see Perspective by Bose and Marder] Transition metal complexes are efficient catalysts for the C-H bond functionalization of heteroarenes to generate useful products for the pharmaceutical and agricultural industries. However, the costly need to remove potentially toxic trace metals from the end products has prompted great interest in developing metal-free catalysts that can mimic metallic systems. We demonstrated that the borane (1-TMP-2-BH2-C6H4)2 (TMP, 2,2,6,6-tetramethylpiperidine) can activate the C-H bonds of heteroarenes and catalyze the borylation of furans, pyrroles, and electron-rich thiophenes. The selectivities complement those observed with most transition metal catalysts reported for this transformation.

Spontaneous Reduction of a Hydroborane To Generate a B−B Single Bond by the Use of a Lewis Pair

The ansa-aminohydroborane 1-NMe2 -2-(BH2 )C6 H4 crystallizes in an unprecedented type of dimer containing a B-H bond activated by one FLP moiety. Upon mild heating and without the use of any catalyst, this molecule liberates one equivalent of hydrogen to generate a diborane molecule. The synthesis and structural characterization of these new compounds, as well as the kinetic monitoring of the reaction and the DFT investigation of its mechanism, are reported.

Ambiphilic Frustrated Lewis Pair Exhibiting High Robustness and Reversible Water Activation: Towards the Metal-Free Hydrogenation of Carbon Dioxide.

The synthesis and structural characterization of a phenylene-bridged Frustrated Lewis Pair (FLP) having a 2,2,6,6-tetramethylpiperidine (TMP) as the Lewis base and a 9-borabicyclo[3.3.1]nonane (BBN) as the Lewis acid is reported. This FLP exhibits unique robustness towards the products of carbon dioxide hydrogenation. The compound shows reversible splitting of water, formic acid and methanol while no reaction is observed in the presence of excess formaldehyde. The molecule is incredibly robust, showing little sign of degradation after heating at 80 °C in benzene with 10 equiv. of formic acid for 24 h. The robustness of the system could be exploited in the design of metal-free catalysts for the hydrogenation of carbon dioxide.

Ambiphilic Molecules: From Organometallic Curiosity to Metal-Free Catalysts

Ambiphilic molecules were first used as functional ligands for transition elements, which could enable intriguing organometallic transformations. In the past decade, these intramolecular Lewis pairs, first considered organometallic curiosities, have become staples in organometallic chemistry and catalysis, acting as Z ligands, activating inert molecules using the concept of frustrated Lewis pair (FLP) chemistry, and acting as metal-free catalysts. In this Account, we detail our contribution to this blossoming field of research, focusing on the use of ambiphilic molecules as metal-free catalysts for CO2 reduction and C-H borylation reactions. A major emphasis is put on the mechanistic investigations we carried out using reactivity studies and theoretical tools, which helped us steer our research from stoichiometric transformations to highly active catalytic processes. We first report the interaction of aluminum-phosphine ambiphilic molecules with carbon dioxide. Although these Lewis pairs can bind CO2, a study of the deactivation process in the presence of CO2 and hydroboranes led us to discover that simple phosphinoborane molecules could act as active precatalysts for the hydroboration of carbon dioxide into methanol precursors. In these systems, the Lewis basic sites interact with the reducing agents rather than with the electrophilic carbon of CO2, increasing the nucleophilicity of hydroboranes. Simultaneously, the weak Lewis acids stabilize the oxygen of the gas molecule in the transition state, leading to high reaction rates. Replacing the phosphine by an amine leads to a system enabling CO2 hydrogenation, albeit only in stoichiometric transformations. Investigation of the protodeborylation deactivation of aminoboranes led us to develop metal-free catalysts for the C-H borylation of heteroarenes. By protecting the Lewis acid sites of these catalysts using fluoride, we were able to synthesize practical, air-stable precatalysts allowing the convenient synthesis of heteroarylboronic esters on a multigram scale. Contrary to general perception of FLP chemistry, we also demonstrated that a significant increase in activity could be obtained by reducing the steric bulk around the active site. These smaller systems exist as stable dimers and are more energetically costly to dissociate into active FLPs, but the approach of the substrate and the C-H activation step are significantly favored compared to the bulkier analogues. An in-depth study of the stability and reactivity of these aminoborane molecules also allowed us to develop a metal-free catalytic S-H bond borylation system, and to report stoichiometric and spontaneous B-B bond formation and Csp3-H bond activation processes, highlighting the importance of H2 release as a thermodynamic driving force in these FLP transformations.

Metal-Free Borylation of Heteroarenes using Ambiphilic Aminoboranes: On the Importance of Sterics in Frustrated Lewis Pair C-H Bond Activation

Two novel frustrated Lewis pair (FLP) aminoboranes, (1-Pip-2-BH2-C6H4)2 (2; Pip = piperidyl) and (1-NEt2-2-BH2-C6H4)2 (3; NEt2 = diethylamino), were synthesized, and their structural features were elucidated both in solution and in the solid state. The reactivity of these species for the borylation of heteroarenes was investigated and compared to previously reported (1-TMP-2-BH2-C6H4)2 (1; TMP = tetramethylpiperidyl) and (1-NMe2-2-BH2-C6H4)2 (4; NMe2 = dimethylamino). It was shown that 2 and 3 are more active catalysts for the borylation of heteroarenes than the bulkier analogue 1. Kinetic studies and density functional theory calculations were performed with 1 and 2 to ascertain the influence of the amino group of this FLP-catalyzed transformation. The C-H activation step was found to be more facile with smaller amines at the expense of a more difficult dissociation of the dimeric species. The bench-stable fluoroborate salts of all catalysts (1F-4F) have been synthesized and tested for the borylation reaction. The new precatalysts 2F and 3F are showing higher reaction rates and yields for multigram-scale syntheses.

Frustrated Lewis pair mediated Csp3-H activation

The cleavage of a Csp3 -H bond by an N/B frustrated Lewis pair (FLP) is reported. Upon mild heating, the ambiphilic molecule (2-NMe2 -C6 H4 )2 BH activates the C-H bond of a methyl group in α position of a nitrogen atom to generate an unprecedented N-B heterocycle. Upon further heating, the novel species rearranges through a hydride abstraction/1,2-aryl shift sequence. The mechanistic details of these transformations are investigated by quantum mechanical calculations.