Tomas Horsten

Well-dispersed Pt nanoparticles supported on hierarchically porous zeolite were identified as an efficient catalyst for fine chemicals production, in which biobased 2-furoic acid can be hydrogenated under mild conditions when coupled with H₂ generated in situ by NaBH₄ hydrolysis.

Abstract

Hydrogenation of biobased compounds can add value to platform molecules obtained from biomass refining. Herein, we explore the hydrogenation of 2-furoic acid (2-furancarboxylic acid, FCA), a derivative of furfural, with H₂ generated in situ by NaBH₄ hydrolysis at ambient conditions. Nearly complete conversion of FCA was obtained with tetrahydrofuroic acid (THFA) and 5-hydroxyvaleric acid (5-HVA) as the only two reaction products over Pt nanoparticles supported on hierarchical ZSM-5. Small Pt nanoparticles (2 to 3 nm) were stabilized by ZSM-5 nanosheets. At an optimized Pt loading, the Pt nanoparticles can catalyze the hydrolysis of NaBH₄ and the subsequent hydrogenation of FCA with the assistance of Brønsted acid sites. Nanostructuring ZSM-5 into nanosheets and its acidity contributes to the stability of the dispersed Pt nanoparticles. Deactivation due to NaBO₂ deposition on the Pt particles can be countered by a simple washing treatment. Overall, this approach shows the promise of mild hydrogenation of biobased feedstock coupled with NaBH₄ hydrolysis.

Nickel-electrocatalyzed homocoupling is applied to the preparation of bifuran-based monomers from methyl bromo-furancarboxylates that can be prepared from hemicellulose-based furfural. The protocol is run with graphite electrodes in an undivided cell, and the products are isolated by precipitation.

Abstract

Bifuran motifs can be accessed with nickel-bipyridine electrocatalyzed homocouplings of bromine-substituted methyl furancarboxylates, which, in turn, can be prepared from hemicellulose-derived furfural. The described protocol uses sustainable carbon-based graphite electrodes in the simplest setup – an undivided cell with constant current electrolysis. The reported method avoids using a sacrificial anode by employing triethanolamine as an electron donor.

A highly efficient electrocatalytic 1,2-dioxygenation of alkenes utilizing readily available materials in ambient conditions is developed. The protocol is widely applicable to aliphatic and aromatic alkenes with excellent faradaic efficiencies and yields of up to 96 %. The versatility of the method is expanded with alkenoic acids towards lactone derivatives and with other carboxylic acids like HCOOH.

Abstract

1,2-Dioxygenation of alkenes leads to a structural motif ubiquitous in organic synthons, natural products and active pharmaceutical ingredients. Straightforward and green synthesis protocols starting from abundant raw materials are required for facile and sustainable access to these crucial moieties. Especially industrially abundant aliphatic alkenes have proven to be arduous substrates in sustainable 1,2-dioxygenation methods. Here, we report a highly efficient electrocatalytic diacetoxylation of alkenes under ambient conditions using a simple iodobenzene mediator and acetic acid as both the solvent and an atom-efficient reactant. This transition metal-free method is applicable to a wide range of alkenes, even challenging feedstock alkenes such as ethylene and propylene, with a broad functional group tolerance and excellent faradaic efficiencies up to 87 %. In addition, this protocol can be extrapolated to alkenoic acids, resulting in cyclization of the starting materials to valuable lactone derivatives. With aromatic alkenes, a competing mechanism of direct anodic oxidation exists which enables reaction under catalyst-free conditions. The synthetic method is extensively investigated with cyclic voltammetry.

Versatile deuterated reagents, namely, d _n-alkyl sulfonium salts, d _n-alkyl halides, a d _n-alkyl azide, and a d _n-alkyl amine, were prepared and used to efficiently introduce d _n-alkyl groups into drug candidates and their analogues with complex skeletons. A liver microsomal metabolism study using 7-(d ₂-ethoxy)flavone as a model compound revealed a significant deuterium kinetic isotope effect due to the installed d ₂-ethoxy group.

Abstract

The pharmacokinetics of pharmaceutical drugs can be improved by replacing C−H bonds with the more stable C−D bonds at the α-position to heteroatoms, which is a typical metabolic site for cytochrome P450 enzymes. However, the application of deuterated synthons is limited. Herein, we established a novel concept for preparing deuterated reagents for the successful synthesis of complex drug skeletons with deuterium atoms at the α-position to heteroatoms. (d _n-Alkyl)diphenylsulfonium salts prepared from the corresponding nondeuterated forms using inexpensive and abundant D₂O as the deuterium source with a base, were used as electrophilic alkylating reagents. Additionally, these deuterated sulfonium salts were efficiently transformed into d _n-alkyl halides and a d _n-alkyl azide as coupling reagents and a d _n-alkyl amine as a nucleophile. Furthermore, liver microsomal metabolism studies revealed deuterium kinetic isotope effects (KIE) in 7-(d ₂-ethoxy)flavone. The present concept for the synthesis of deuterated reagents and the first demonstration of a KIE in a d ₂-ethoxy group will contribute to drug discovery research based on deuterium chemistry.

Nature Sustainability, Published online: 28 August 2023; doi:10.1038/s41893-023-01201-w

Manganese(I) complexes bearing simple, non-bifunctional bis(NHC) ligands were investigated as hydrogenation catalysts. Applying these complexes with KHBEt₃ as additive, various carboxylic acid esters and, additionally, ketones, nitriles, N-heteroarenes and alkenes were successfully hydrogenated. Mechanistic investigations by control experiments and DFT calculations indicate an inner-sphere mechanism and reveal the role of BEt₃ as cocatalyst.

Abstract

The use of bis(NHC) manganese(I) complexes 3 as catalysts for the hydrogenation of esters was investigated. For that purpose, a series of complexes has been synthesized via an improved two step procedure utilizing bis(NHC)-BEt₃ adducts. By applying complexes 3 with KHBEt₃ as additive, various aromatic and aliphatic esters were hydrogenated successfully at mild temperatures and low catalyst loadings, highlighting the efficiency of the novel catalytic system. The versatility of the developed catalytic system was further demonstrated by the hydrogenation of other substrate classes like ketones, nitriles, N-heteroarenes and alkenes. Mechanistic experiments and DFT calculations indicate an inner sphere mechanism with the loss of one CO ligand and reveal the role of BEt₃ as cocatalyst.

Halogen-atom-transfer (XAT) processes have revolutionized the use of ubiquitous halide reagents in organic chemistry. This mini-review focuses on recent C−C bond forming reactions that have exploited α-aminoalkyl radicals as metal-free XAT procedures.

Abstract

The merging of photocatalysis with halogen-atom transfer (XAT) processes has proven to be a versatile tool for the generation of carbon-centered radicals in organic synthesis. XAT processes are unique in that they generate radicals without requiring the use of strong reductants necessary for the traditional single electron transfer (SET) activation of halides. Pathways to achieve XAT in synthetic applications can be categorized into three major sections: i) heteroatom-based activators, ii) metal-based activators, and iii) carbon-based activators among which α-aminoalkyl radicals have taken the center stage. Access to these α-aminoalkyl radicals as XAT reagents has gained significant attention in the past few years due to the robustness of the reactions, the simplicity of the reagents required, and the broadness of their applications. Generation of these α-aminoalkyl radicals is simply achieved through the single electron oxidation of tertiary amines, which after deprotonation at the α-position generates the α-aminoalkyl radicals. Due to the wide scope of tertiary amines available and the tunable nucleophilicity of α-aminoalkyl radical formed, this strategy has become an attractive alternative to heteroatom/metal-based radicals for XAT. In this minireview, we focus our attention on recent (2020–2023) developments and uses of this robust technology to mediate XAT processes.

Hydrolysis of biorenewable muconic acids or their corresponding lactones in high temperature water allows the selective synthesis of levulinic acids. This enables direct access to novel substituted levulinic acids from biomass, creating novel opportunities for industrial applications. 3-Propyllevulinic acid was used to synthesize a novel plasticizer which performed equally well as a commercial, petrochemical phthalate-based benchmark.

Abstract

Levulinic acid is a key biorenewable platform molecule. Its current chemical production from sugars is plagued by limited yields, char formation and difficult separations. An alternative and selective route starting from muconic acid via simple heating in water at high temperature (180 °C) has been developed. Muconic acid can be obtained from sugars or catechol fermentation. Chemical oxidation of catechol is another possibility which advantageously can also be applied on substituted catechols, hereby providing substituted muconic acids. When applying the disclosed hydrothermal protocol on these substrates hitherto unknown substituted levulinic acids were accessed. In particular, 3-propyllevulinic acid has been synthesized from 4-propylcatechol, prepared from pine wood. This propylated derivative has been used for the synthesis of a 3-propyllevulinate diester, i.e. butane-1,4-diyl bis(4-oxo-3-propylpentanoate), via esterification with 1,4-butanediol. The diester showed superior performance as plasticizer in comparison to the corresponding levulinate diester in both PVC (polyvinyl chloride) and PLA (polylactic acid). It plasticizes equally effective as the notorious commercial phthalate-based benchmark DEHP (di-2-ethylhexyl phthalate) in PVC.

Imine-based covalent organic frameworks (COFs) were successfully formed and immobilized on an electrode surface promoted by electrogenerated acids, as demonstrated by Shinsuke Inagi et al. in their Research Article (e202307343).

Non-activated esters are prominently featured functional groups in polymer science, as ester functional monomers display great structural diversity and excellent compatibility with a wide range of polymerization mechanisms. Yet, their direct use as a reactive handle in post-polymerization modification has been typically avoided due to their low reactivity, which impairs the quantitative conversion typically desired in post-polymerization modification reactions. While activated ester approaches are a well-established alternative, the modification of non-activated esters remains a synthetic and economically valuable opportunity. In this review, we discuss past and recent efforts in the utilization of non-activated ester groups as a reactive handle to facilitate transesterification and aminolysis/amidation reactions, and the potential of the developed methodologies in the context of macromolecular engineering.

We present LABS (Laboratory Automation and Batch Scheduling), a python-based open source software that comes with a web-based user interface. Our goal is to provide an easy to adapt software for laboratory automation and lay the foundation for many future automation projects. Its reliability was showcased during a campaign of an electrochemical C−C coupling reaction.

Abstract

With LABS, an open source Python-based lab software is established that enables users to orchestrate automated synthesis setups. The software consists of a user-friendly interface for data input and system monitoring. A flexible backend architecture enables the integration of multiple lab devices. The software allows users to easily modify experimental parameters or routines and switch between different lab devices. Compared to previously published projects, we aim to provide a more widely applicable and easily customizable automation software for any experimental setup. The usefulness of this tool was demonstrated in the oxidative coupling of 2,4-dimethyl-phenol to the corresponding 2,2’-biphenol. In this context, the suitable electrolysis parameters for flow electrolysis were optimized by way of design of experiments.

Here we report a synthetic procedure for the efficient ex situ generation of thiazyl trifluoride gas (N≡SF₃) as a new Sulfur(VI)-Fluoride Exchange hub. In typical SuFEx fashion, this triple-bonded azasulfur(VI) fluoride reagent and its mono-substituted derivatives react highly effectively with various nucleophiles to deliver a library of unreported thiazynes.

Abstract

Sulfur(VI)-fluoride exchange (SuFEx) chemistry, an all-encompassing term for substitution events that replace fluoride at an electrophilic sulfur(VI), enables the rapid and flexible assembly of linkages around a S^VI core. Although a myriad of nucleophiles and applications works very well with the SuFEx concept, the electrophile design has remained largely SO₂-based. Here, we introduce S≡N-based fluorosulfur(VI) reagents to the realm of SuFEx chemistry. Thiazyl trifluoride (NSF₃) gas is shown to serve as an excellent parent compound and SuFEx hub to efficiently synthesize mono- and disubstituted fluorothiazynes in an ex situ generation workflow. Gaseous NSF₃ was evolved from commercial reagents in a nearly quantitative fashion at ambient conditions. Moreover, the mono-substituted thiazynes could be extended further as SuFEx handles and be engaged in the synthesis of unsymmetrically disubstituted thiazynes. These results provide valuable insights into the versatility of these understudied sulfur functionalities paving the way for future applications.

This work presents a flexible, straightforward methodology to synthesize phosphonamidates starting from commonly available phosphonates, and demonstrates the use of phosphonylaminium salts to mediate the harsh reactivity of phosphonochloridates. Our methodology is demonstrated on primary amines, secondary amines, ammonium acetate, aniline derivatives and different phosphonate diesters.

Abstract

Organophosphorus compounds such as phosphonamidates are gaining attention across different fields of chemistry, with interesting applications as pharmaceuticals, or pesticides. However, practical application of phosphonamidates is complicated by their difficult syntheses which often involve expensive or unstraightforward reagents and harsh conditions. To remedy these issues, we present a flexible, room temperature synthesis for novel P-alkylphosphonamidates without the need for intermediary purification. Commonly available phosphonates are first chlorinated by use of oxalyl chloride and phosphonylaminium salts are used to mediate the harsh reactivity of phosphonochloridates, giving rise to the desired products. We demonstrate the compatibility of our protocol with primary and secondary amines, as well as with different phosphonate esters. The proposed pathway also enables the synthesis of primary phosphonamidates using ammonium acetate as a cheap and safe alternative for ammonia. In future research, this protocol will also enable the synthesis of bioactive targets that are incompatible with current protocols.

C−F Insertion reactions represent a powerful approach to prepare complex fluorinated compounds, yet they are extremely scarce. Here we report a hydrogen bonding-mediated system that allows for activation of activated alkyl fluorides without sequestering the released fluoride in an unreactive by-product. This allows for formal insertion of fluorinated styrenes into the C−F bond affording gem-difluorinated products.

Abstract

C−F Insertion reactions represent an attractive approach to prepare valuable fluorinated compounds. The high strength of C−F bonds and the low reactivity of the fluoride released upon C−F bond cleavage, however, mean that examples of such processes are extremely scarce in the literature. Here we report a reaction system that overcomes these challenges using hydrogen bond donors that both activate C−F bonds and allow for downstream reactions with fluoride. In the presence of hexafluoroisopropanol, benzyl and propargyl fluorides undergo efficient formal C−F bond insertion across α-fluorinated styrenes. This process, which does not require any additional fluorinating reagent, occurs under mild conditions and delivers products featuring the gem-difluoro motif, which is attracting increasing interest in medicinal chemistry. Moreover, readily available organic bromides can be engaged directly in a one-pot process that avoids the isolation of organic fluorides.