α‐Amino nitriles are versatile structural motifs in a variety of biologically active compounds and pharmaceuticals and they serve as valuable building blocks in synthesis. The preparation of α‐ and β‐functionalized α‐amino nitriles from readily available scaffolds, however, remains challenging. Herein is reported a novel dual catalytic photoredox/copper‐catalyzed chemo‐ and regioselective radical carbocyanation of 2‐azadienes to access functionalized α‐amino nitriles by using redox‐active esters (RAEs) and trimethylsilyl cyanide. This cascade process employs a broad scope of RAEs and provides the corresponding α‐amino nitrile building blocks in 50–95 % yields (51 examples, regioselectivity >95 : 5). The products were transformed into prized α‐amino nitriles and α‐amino acids. Mechanistic studies suggest a radical cascade coupling process.
- Award ID(s):
- 1902509
- NSF-PAR ID:
- 10348035
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 13
- Issue:
- 13
- ISSN:
- 2041-6520
- Page Range / eLocation ID:
- 3740 to 3747
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract α‐Amino nitriles are versatile structural motifs in a variety of biologically active compounds and pharmaceuticals and they serve as valuable building blocks in synthesis. The preparation of α‐ and β‐functionalized α‐amino nitriles from readily available scaffolds, however, remains challenging. Herein is reported a novel dual catalytic photoredox/copper‐catalyzed chemo‐ and regioselective radical carbocyanation of 2‐azadienes to access functionalized α‐amino nitriles by using redox‐active esters (RAEs) and trimethylsilyl cyanide. This cascade process employs a broad scope of RAEs and provides the corresponding α‐amino nitrile building blocks in 50–95 % yields (51 examples, regioselectivity >95 : 5). The products were transformed into prized α‐amino nitriles and α‐amino acids. Mechanistic studies suggest a radical cascade coupling process.
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Biomass is abundant, inexpensive and renewable, therefore, it is highly expected to play a significant role in our future energy and chemical landscapes. The US DOE has identified furanic compounds (furfural and 5-(hydroxymethyl)furfural (HMF)) as the top platform building-block chemicals that can be readily derived from biomass sources [1]. Electrocatalytic conversion of these furanic compounds is an emerging route for the sustainable production of valuable chemicals [2, 3]. In my presentation, I will first present our recent mechanistic study of electrocatlytic hydrogenation (ECH) of furfural through a combination of voltammetry, preparative electrolysis, thiol-electrode modifications, and kinetic isotope studies [4]. It is demonstrated that two distinct mechanisms are operable on metallic Cu electrodes in acidic electrolytes: (i) electrocatalytic hydrogenation (ECH) and (ii) direct electroreduction. The contributions of each mechanism to the observed product distribution are clarified by evaluating the requirement for direct chemical interactions with the electrode surface and the role of adsorbed hydrogen. Further analysis reveals that hydrogenation and hydrogenolysis products are generated by parallel ECH pathways. Understanding the underlying mechanisms enables the manipulation of furfural reduction by rationally tuning the electrode potential, electrolyte pH, and furfural concentration to promote selective formation of important bio-based polymer precursors and fuels We further studied the mechanisms on the Pb electrode, based on the potential regulated ECH and ER products. Isotopic incorporation studies and electrokinetics have confirmed ECH process to alcohol and alkyl product followed different pathways: alcohol was generated from Langmuir Hinshelwood step through surface-bound furfural and hydrogen, which is sensitive to surface structures. In contrast, alkyl product was formed through an Eley–Rideal step via surface-bound furfural and the inner-sphere protons. By modifying the electrode/electrolyte interface, we have elucidated H2O and H3O+ matters in forming alcohol and alkyl products, respectively. Dynamic oscillation studies and electron paramagnetic resonance (EPR) finally confirmed that the alcohol and dimer products shared the same intermediate. The dimer was formed through the intermediate desorption from the surface to form radicals and the self-coupling of two radicals at the bulk electrolyte. Next, I will present electrocatalytic conversion of HMF to two biobased monomers in an H-type electrochemical cell [5]. HMF reduction (hydrogenation) to 2,5-bis(hydroxymethyl)furan (BHMF) was achieved under mild electrolyte conditions and ambient temperature using a Ag/C cathode. Meanwhile, HMF oxidation to 2,5-furandicarboxylic acid (FDCA) with ~100% efficiency was facilitated under the same conditions by a homogeneous nitroxyl radical redox mediator. We recently developed a three-electrode flow cell with an oxide-derived Ag (OD-Ag) cathode and catbon felt anode for paring elecatalytic oxidation and reduction of HMF [6]. The flow cell has a remarkably low cell voltage: from ~7.5 V to ~2.0 V by transferring the electrolysis from the H-type cell to the flow cell. This represents a more than fourfold increase in the energy efficiency at the 10 mA operation. A combined faradaic efficiency of 163% was obtained to BHMF and FDCA. Alternatively, the anodic hydrogen oxidation reaction on platinum further reduced the cell voltage to only ~0.85 V at 10 mA operation. These paired processes have shown potential for integrating renewable electricity and carbon for distributed chemical manufacturing in the future.more » « less
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Abstract Multifunctional organoboron compounds increasingly enable the simple generation of complex, Csp3‐rich small molecules. The ability of boron‐containing functional groups to modify the reactivity of α‐radicals has also enabled a myriad of chemical reactions. Boronic esters with vacant p‐orbitals have a significant stabilizing effect on α‐radicals due to delocalization of spin density into the empty orbital. The effect of coordinatively saturated derivatives, such as N‐methyliminodiacetic acid (MIDA) boronates and counterparts, remains less clear. Herein, we demonstrate that coordinatively saturated MIDA and TIDA boronates stabilize secondary alkyl α‐radicals via σB‐Nhyperconjugation in a manner that allows site‐selective C−H bromination. DFT calculated radical stabilization energies and spin density maps as well as LED NMR kinetic analysis of photochemical bromination rates of different boronic esters further these findings. This work clarifies that the α‐radical stabilizing effect of boronic esters does not only proceed via delocalization of radical character into vacant boron p‐orbitals, but that hyperconjugation of tetrahedral boron‐containing functional groups and their ligand electron delocalizing ability also play a critical role. These findings establish boron ligands as a useful dial for tuning reactivity at the α‐carbon.
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Abstract Multifunctional organoboron compounds increasingly enable the simple generation of complex, Csp3‐rich small molecules. The ability of boron‐containing functional groups to modify the reactivity of α‐radicals has also enabled a myriad of chemical reactions. Boronic esters with vacant p‐orbitals have a significant stabilizing effect on α‐radicals due to delocalization of spin density into the empty orbital. The effect of coordinatively saturated derivatives, such as N‐methyliminodiacetic acid (MIDA) boronates and counterparts, remains less clear. Herein, we demonstrate that coordinatively saturated MIDA and TIDA boronates stabilize secondary alkyl α‐radicals via σB‐Nhyperconjugation in a manner that allows site‐selective C−H bromination. DFT calculated radical stabilization energies and spin density maps as well as LED NMR kinetic analysis of photochemical bromination rates of different boronic esters further these findings. This work clarifies that the α‐radical stabilizing effect of boronic esters does not only proceed via delocalization of radical character into vacant boron p‐orbitals, but that hyperconjugation of tetrahedral boron‐containing functional groups and their ligand electron delocalizing ability also play a critical role. These findings establish boron ligands as a useful dial for tuning reactivity at the α‐carbon.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D2SC00500J
