Efficient palladium-catalyzed electrocarboxylation enables late-stage carbon isotope labelling.

Carbon isotope labelling of bioactive molecules is essential for accessing the pharmacokinetic and pharmacodynamic properties of new drug entities. Aryl carboxylic acids represent an important class of structural motifs ubiquitous in pharmaceutically active molecules and are ideal targets for the installation of a radioactive tag employing isotopically labelled CO2. However, direct isotope incorporation via the reported catalytic reductive carboxylation (CRC) of aryl electrophiles relies on excess CO2, which is incompatible with carbon-14 isotope incorporation. Furthermore, the application of some CRC reactions for late-stage carboxylation is limited because of the low tolerance of molecular complexity by the catalysts. Herein, we report the development of a practical and affordable Pd-catalysed electrocarboxylation setup. This approach enables the use of near-stoichiometric 14CO2 generated from the primary carbon-14 source Ba14CO3, facilitating late-stage and single-step carbon-14 labelling of pharmaceuticals and representative precursors. The proposed isotope-labelling protocol holds significant promise for immediate impact on drug development programmes.

Low Pressure Carbonylation of Benzyl Carbonates and Carbamates for Applications in 13 C Isotope Labeling and Catalytic CO2 Reduction.

Herein, we report a methodology to access isotopically labeled esters and amides from carbonates and carbamates employing an oxygen deletion strategy. This methodology utilizes a decarboxylative carbonylation approach for isotope labeling with near stoichiometric, ex situ generated 12 C, or 13 C carbon monoxide. This reaction is characterized by its broad scope, functional group tolerance, and high yields, which is showcased with the synthesis of structurally complex molecules. A complementary method that operates by the catalytic in situ generation of CO via the reduction of CO2 liberated during decarboxylation has also been developed as a proof-of-concept approach that CO2 -derived compounds can be converted to CO-containing frameworks. Mechanistic studies provide insight into the catalytic steps which highlight the impact of ligand choice to overcome challenges associated with low-pressure carbonylation methodologies, along with rational for the development of future methodologies.

Lignocellulose Conversion via Catalytic Transformations Yields Methoxyterephthalic Acid Directly from Sawdust.

Poly(ethylene terephthalate) polyester represents the most common class of thermoplastic polymers widely used in the textile, bottling, and packaging industries. Terephthalic acid and ethylene glycol, both of petrochemical origin, are polymerized to yield the polyester. However, an earlier report suggests that polymerization of methoxyterephthalic acid with ethylene glycol provides a methoxy-polyester with similar properties. Currently, there are no established biobased synthetic routes toward the methoxyterephthalic acid monomer. Here, we show a viable route to the dicarboxylic acid from various tree species involving three catalytic steps. We demonstrate that sawdust can be converted to valuable aryl nitrile intermediates through hydrogenolysis, followed by an efficient fluorosulfation-catalytic cyanation sequence (>90%) and then converted to methoxyterephthalic acid by hydrolysis and oxidation. A preliminary polymerization result indicates a methoxy-polyester with acceptable thermal properties.

Rapid Access to Carbon-Isotope-Labeled Alkyl and Aryl Carboxylates Applying Palladacarboxylates.

Herein, we report a strategy for the formation of isotopically labeled carboxylic esters from boronic esters/acids using a readily accessible palladium carboxylate complex as an organometallic source of isotopically labeled functional groups. The reaction allows access to either unlabeled or full 13C- or 14C-isotopically labeled carboxylic esters, and the method is characterized by its operational simplicity, mild conditions, and general substrate scope. Our protocol is further extended to a carbon isotope replacement strategy, involving an initial decarbonylative borylation procedure. Such an approach allows access to isotopically labeled compounds directly from the unlabeled pharmaceutical, which can have implications for drug discovery programs.

Catalytic disconnection of C-O bonds in epoxy resins and composites.

Fibre-reinforced epoxy composites are well established in regard to load-bearing applications in the aerospace, automotive and wind power industries, owing to their light weight and high durability. These composites are based on thermoset resins embedding glass or carbon fibres1. In lieu of viable recycling strategies, end-of-use composite-based structures such as wind turbine blades are commonly landfilled1-4. Because of the negative environmental impact of plastic waste5,6, the need for circular economies of plastics has become more pressing7,8. However, recycling thermoset plastics is no trivial matter1-4. Here we report a transition-metal-catalysed protocol for recovery of the polymer building block bisphenol A and intact fibres from epoxy composites. A Ru-catalysed, dehydrogenation/bond, cleavage/reduction cascade disconnects the C(alkyl)-O bonds of the most common linkages of the polymer. We showcase the application of this methodology to relevant unmodified amine-cured epoxy resins as well as commercial composites, including the shell of a wind turbine blade. Our results demonstrate that chemical recycling approaches for thermoset epoxy resins and composites are achievable.

Exploring the Parameters Controlling Product Selectivity in Electrochemical CO2 Reduction in Competition with Hydrogen Evolution Employing Manganese Bipyridine Complexes.

Selective reduction of CO2 is an efficient solution for producing nonfossil-based chemical feedstocks and simultaneously alleviating the increasing atmospheric concentration of this greenhouse gas. With this aim, molecular electrocatalysts are being extensively studied, although selectivity remains an issue. In this work, a combined experimental-computational study explores how the molecular structure of Mn-based complexes determines the dominant product in the reduction of CO2 to HCOOH, CO, and H2. In contrast to previous Mn(bpy-R)(CO)3Br catalysts containing alkyl amines in the vicinity of the Br ligand, here, we report that bpy-based macrocycles locking these amines at the side opposite to the Br ligand change the product selectivity from HCOOH to H2. Ab initio molecular dynamics simulations of the active species showed that free rotation of the Mn(CO)3 moiety allows for the approach of the protonated amine to the reactive center yielding a Mn-hydride intermediate, which is the key in the formation of H2 and HCOOH. Additional studies with DFT methods showed that the macrocyclic moiety hinders the insertion of CO2 to the metal hydride favoring the formation of H2 over HCOOH. Further, our results suggest that the minor CO product observed experimentally is formed when CO2 adds to Mn on the side opposite to the amine ligand before protonation. These results show how product selectivity can be modulated by ligand design in Mn-based catalysts, providing atomistic details that can be leveraged in the development of a fully selective system.

Pd-Catalyzed Difluoromethylations of Aryl Boronic Acids, Halides, and Pseudohalides with ICF2 H Generated ex Situ.

An expedient ex-situ generation of difluoroiodomethane (DFIM) and its immediate use in a Pd-catalyzed difluoromethylation of aryl boronic acids and ester derivatives in a two-chamber reactor is reported. Heating a solution of bromodifluoroacetic acid with sodium iodide in sulfolane proved to be effective for the generation of near stoichiometric amounts of DFIM for the ensuing catalytic coupling step. A two-step difluoromethylation of aryl (pseudo)halides with tetrahydroxydiboron as a low-cost reducing agent, both promoted by Pd catalysis, proved effective to install this fluorine-containing C1 group onto several pharmaceutically relevant molecules. Finally, the method proved adaptable to deuterium incorporation by simply adding D2 O to the DFIM-generating chamber.

Selective N-Terminal Acylation of Peptides and Proteins with Tunable Phenol Esters.

Selective modification of peptides and proteins is of foremost importance for the development of biopharmaceuticals and exploring biochemical pathways, as well as other applications. Here, we present a study on the development of a general and easily applicable selective method for N-terminal acylation of biomolecules, applying a new type of phenol esters. Key to the success was the development of highly tunable phenol activators bearing in the ortho-position, sulfonic acid or sulfonamide, acting as a steric shield for hydrolysis, and electron-withdrawing groups in the other ortho- and para-position for controlling the reactivity of the activated phenol esters. A library of heptapeptides, testing all 20 natural amino acids positioned at the N-terminal, were acylated in a selective manner at the N-terminus. The majority showed high conversion and excellent Nα-selectivity. Several biologically relevant biomolecules, including DesB30 insulin and human growth hormone, could also be modified at the N-terminal in a highly selective way, exemplified by either a fluorophore or a fatty acid sidechain. Finally, taking advantage of the possibility to accurately adjust the reactivity of the phenol esters, we present a potential strategy for the construction of dual active biopharmaceuticals through the employment of a bifunctional acylation linker and demonstrate its use in the creation of a GLP-1 insulin analogue, coupled through the lysine residue of GLP-1 and the N-terminal PheB1 amine of DesB30 insulin.

New Phenol Esters for Efficient pH-Controlled Amine Acylation of Peptides, Proteins, and Sepharose Beads in Aqueous Media.

This paper describes the discovery, synthesis, and use of novel water-soluble acylation reagents for efficient and selective modification, cross-linking, and labeling of proteins and peptides, as well as for their use in the effective modification of sepharose beads under pH control in aqueous media. The reagents are based on a 2,4-dichloro-6-sulfonic acid phenol ester core combined with a variety of linker structures. The combination of these motifs leads to an ideal balance between hydrolytic stability and reactivity. At high pH, good to excellent conversions (up to 95%) and regioselectivity (up to 99:1 Nε/Nα amine ratio) in the acylation were realized, exemplified by the chemical modification of incretin peptides and insulin. At neutral pH, an unusually high preference toward the N-terminal phenylalanine in an insulin derivative was observed (>99:1 Nα/Nε), which is up until now unprecedented in the literature for more elaborate reagents. In addition, the unusually high hydrolytic stability of these reagents and their ability to efficiently react at low concentrations (28 µM or 0.1 mg/mL) are exemplified with a hydroxy linker-based reagent and are a unique feature of this work.

Evaluation of Manganese Catalysts for the Hydrogenative Deconstruction of Commercial and End-of-Life Polyurethane Samples.

Polyurethane (PU) is a thermoset plastic that is found in everyday objects, such as mattresses and shoes, but also in more sophisticated materials, including windmills and airplanes, and as insulation materials in refrigerators and buildings. Because of extensive inter-cross linkages in PU, current recycling methods are somewhat lacking. In this work, the effective catalytic hydrogenation of PU materials is carried out by applying a catalyst based on the earth-abundant metal manganese, to give amine and polyol fractions, which represent the original monomeric composition. In particular, Mn-Ph MACHO is found to catalytically deconstruct flexible foam, molded foams, insulation, and end-of-life materials at 1 wt.% catalyst loading by applying a reaction temperature of 180 °C, 50 bar of H2 , and 0.9 wt.% of KOH in isopropyl alcohol. The protocol is showcased in the catalytic deconstruction of 2 g of mattress foam using only 0.13 wt.% catalyst, resulting in 90 % weight recovery and a turnover number of 905.

Regioselective Hydroalkylation of Vinylarenes by Cooperative Cu and Ni Catalysis.

Disclosed here is a dual copper and nickel catalytic system with a silyl hydride source for promoting the linear selective hydroalkylation of vinylarenes. This carbon-carbon bond-forming protocol is applied to couple a variety of functionalized vinylarenes with alkyl halides applying a nickel(II) NNN pincer complex in the presence of an NHC-ligated copper catalyst. This combination allows for a 1 mol % loading of the nickel catalyst leading to turnover numbers of up to 72. Over 40 examples are presented, including applications for pharmaceutical diversification. Labeling experiments demonstrated the regioselectivity of the reaction and revealed that the copper catalyst plays a crucial role in enhancing the rate for formation of the reactive linear alkyl nickel complex. Overall, the presented work provides a complimentary approach for hydroalkylation reactions, whilst providing a preliminary mechanistic understanding of the cooperativity between the copper and nickel complexes.

Promoting Selective Generation of Formic Acid from CO2 Using Mn(bpy)(CO)3Br as Electrocatalyst and Triethylamine/Isopropanol as Additives.

Urgent solutions are needed to efficiently convert the greenhouse gas CO2 into higher-value products. In this work, fac-Mn(bpy)(CO)3Br (bpy = 2,2'-bipyridine) is employed as electrocatalyst in reductive CO2 conversion. It is shown that product selectivity can be shifted from CO toward HCOOH using appropriate additives, i.e., Et3N along with iPrOH. A crucial aspect of the strategy is to outrun the dimer-generating parent-child reaction involving fac-Mn(bpy)(CO)3Br and [Mn(bpy)(CO)3]- and instead produce the Mn hydride intermediate. Preferentially, this is done at the first reduction wave to enable formation of HCOOH at an overpotential as low as 260 mV and with faradaic efficiency of 59 ± 1%. The latter may be increased to 71 ± 3% at an overpotential of 560 mV, using 2 M concentrations of both Et3N and iPrOH. The nature of the amine additive is crucial for product selectivity, as the faradaic efficiency for HCOOH formation decreases to 13 ± 4% if Et3N is replaced with Et2NH. The origin of this difference lies in the ability of Et3N/iPrOH to establish an equilibrium solution of isopropyl carbonate and CO2, while with Et2NH/iPrOH, formation of the diethylcarbamic acid is favored. According to density-functional theory calculations, CO2 in the former case can take part favorably in the catalytic cycle, while this is less opportune in the latter case because of the CO2-to-carbamic acid conversion. This work presents a straightforward procedure for electrochemical reduction of CO2 to HCOOH by combining an easily synthesized manganese catalyst with commercially available additives.

Nickel-Mediated Alkoxycarbonylation for Complete Carbon Isotope Replacement.

Many commercial drugs, as well as upcoming pharmaceutically active compounds in the pipeline, display aliphatic carboxylic acids or derivatives thereof as key structural entities. Synthetic methods for rapidly accessing isotopologues of such compounds are highly relevant for undertaking critical pharmacological studies. In this paper, we disclose a direct synthetic route allowing for full carbon isotope replacement via a nickel-mediated alkoxycarbonylation. Employing a nickelII pincer complex ([(N2N)Ni-Cl]) in combination with carbon-13 labeled CO, alkyl iodide, sodium methoxide, photocatalyst, and blue LED light, it was possible to generate the corresponding isotopically labeled aliphatic carboxylates in good yields. Furthermore, the developed methodology was applied to the carbon isotope substitution of several pharmaceutically active compounds, whereby complete carbon-13 labeling was successfully accomplished. It was initially proposed that the carboxylation step would proceed via the in situ formation of a nickellacarboxylate, generated by CO insertion into the Ni-alkoxide bond. However, preliminary mechanistic investigations suggest an alternative pathway involving attack of an open shell species generated from the alkyl halide to a metal ligated CO to generate an acyl NiIII species. Subsequent reductive elimination involving the alkoxide eventually leads to carboxylate formation. An excess of the alkoxide was essential for obtaining a high yield of the product. In general, the presented methodology provides a simple and convenient setup for the synthesis and carbon isotope labeling of aliphatic carboxylates, while providing new insights about the reactivity of the N2N nickel pincer complex applied.

Catalytic Hydrogenation of Polyurethanes to Base Chemicals: From Model Systems to Commercial and End-of-Life Polyurethane Materials.

Polyurethane (PU) is a highly valued polymer prepared from diisocyanates and polyols, and it is used in everyday products, such as shoe soles, mattresses, and insulation materials, but also for the construction of sophisticated parts of medical devices, wind turbine blades, aircrafts, and spacecrafts, to name a few. As PU is most commonly used as a thermoset polymer composed of cross-linked structures, its recycling is complicated and inefficient, leading to increasing PU waste accumulating every year. Catalytic hydrogenation represents an atom-efficient means for the deconstruction of polyurethanes, but so far the identification of an efficient catalyst for the disassembly of real-life and end-of-life PU samples has not been demonstrated. In this work, we reveal that a commercially available catalyst, Ir- iPrMACHO, under 30 bar H2 and 150-180 °C, is a general catalyst for the effective hydrogenation of the four cornerstones of PU: flexible solid, flexible foamed, rigid solid, and rigid foamed, leading to the isolation of aromatic amines and a polyol fraction. For the first time, a variety of commercial PU materials, including examples of foams, inline skating wheels, shoe soles, and insulation materials, has been deconstructed into the two fractions. Most desirable, our reaction conditions include the use of isopropyl alcohol as a representative of a green solvent. It is speculated that a partial glycolysis at the surface of the PU particles is taking place in this solvent and reaction temperatures in the presence of catalytic amounts of base. As such a more efficient hydrogenation of the solubilized PU fragments in isopropyl alcohol becomes possible. As the isolated anilines are precursors to the original isocyanate building blocks, and methods for their conversion are well-known, the work reported in this paper provides a realistic indication of a potential circular plastic economy solution for PU. Preliminary experiments were also undertaken applying Mn- iPrMACHO for the deconstruction of a commercial flexible PU foam. Although successful, more forcing conditions were required than those when applying Ir- iPrMACHO.

Low-Valence Znδ+ (0<δ<2) Single-Atom Material as Highly Efficient Electrocatalyst for CO2 Reduction.

A nitrogen-stabilized single-atom catalyst containing low-valence zinc atoms (Znδ+ -NC) is reported. It contains saturated four-coordinate (Zn-N4 ) and unsaturated three-coordinate (Zn-N3 ) sites. The latter makes Zn a low-valence state, as deduced from X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, electron paramagnetic resonance, and density functional theory. Znδ+ -NC catalyzes electrochemical reduction of CO2 to CO with near-unity selectivity in water at an overpotential as low as 310 mV. A current density up to 1 A cm-2 can be achieved together with high CO selectivity of >95 % using Znδ+ -NC in a flow cell. Calculations suggest that the unsaturated Zn-N3 could dramatically reduce the energy barrier by stabilizing the COOH* intermediate owing to the electron-rich environment of Zn. This work sheds light on the relationship among coordination number, valence state, and catalytic performance and achieves high current densities relevant for industrial applications.

On-demand synthesis of phosphoramidites.

Automated chemical synthesis of oligonucleotides is of fundamental importance for the production of primers for the polymerase chain reaction (PCR), for oligonucleotide-based drugs, and for numerous other medical and biotechnological applications. The highly optimised automised chemical oligonucleotide synthesis relies upon phosphoramidites as the phosphate precursors and one of the drawbacks of this technology is the poor bench stability of phosphoramidites. Here, we report on the development of an on-demand flow synthesis of phosphoramidites from their corresponding alcohols, which is accomplished with short reaction times, near-quantitative yields and without the need of purification before being submitted directly to automated oligonucleotide synthesis. Sterically hindered as well as redox unstable phosphoramidites are synthesised using this methodology and the subsequent couplings are near-quantitative for all substrates. The vision for this technology is direct integration into DNA synthesisers thereby omitting manual synthesis and storage of phosphoramidites.

Are Amines the Holy Grail for Facilitating CO2 Reduction?

The selective and efficient reduction of carbon dioxide represents a key solution to producing non-fossil-fuel-based feedstocks for the chemical industry, while alleviating the increasing atmospheric concentration of this greenhouse gas. A variety of catalytic methods for the CO2 reduction reaction (CO2 RR) have been developed, including hydrogenations and electrochemical or photochemical reductions. For many of the most significant breakthroughs reported in the last decade, we realized that amines or closely related functional groups play a critical role for such transformations, and in several cases, are directly associated with the catalyst as a pendant group. Amines play multiple roles, such as CO2 trapping agents, proton shuttles, electron donors, or facilitators of CO2 reductions through formamide derivatives. In this Viewpoint, we compile some of these recent findings, and discuss their significance in a broader context in an attempt to provide guidelines for the design of new catalysts with enhanced activity and selectivity.

A Nickel(II)-Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides.

A series of pharmaceutically relevant small molecules and biopharmaceuticals bearing aliphatic carboxamides have been successfully labeled with carbon-13. Key to the success of this novel carbon isotope labeling technique is the observation that 13 C-labeled NiII -acyl complexes, formed from a 13 CO insertion step with NiII -alkyl intermediates, rapidly react in less than one minute with 2,2'-dipyridyl disulfide to quantitatively form the corresponding 2-pyridyl thioesters. Either the use of 13 C-SilaCOgen or 13 C-COgen allows for the stoichiometric addition of isotopically labeled carbon monoxide. Subsequent one-pot acylation of a series of structurally diverse amines provides the desired 13 C-labeled carboxamides in good yields. A single electron transfer pathway is proposed between the NiII -acyl complexes and the disulfide providing a reactive NiIII -acyl sulfide intermediate, which rapidly undergoes reductive elimination to the desired thioester. By further optimization of the reaction parameters, reaction times down to only 11 min were identified, opening up the possibility of exploring this chemistry for carbon-11 isotope labeling. Finally, this isotope labeling strategy could be adapted to the synthesis of 13 C-labeled liraglutide and insulin degludec, representing two antidiabetic drugs.

Design and Applications of a SO2 Surrogate in Palladium-Catalyzed Direct Aminosulfonylation between Aryl Iodides and Amines.

A new SO2 surrogate is reported that is cheap, bench-stable, and can be accessed in just two steps from bulk chemicals. Essentially complete SO2 release is achieved in 5 minutes. Eight established sulfonylation reactions proceeded smoothly by ex situ formation of SO2 by utilizing a two-chamber system in combination with the SO2 surrogate. Furthermore, we report the first direct aminosulfonylation between aryl iodides and amines. Broad functional group tolerance is demonstrated, and the method is applicable to pharmaceutically relevant substrates, including heterocyclic substrates.