Reaction Partners Research Articles

Mesoionische N‐Heterocyclische Olefine verschieben die obere Grenze der Nucleophilie‐Skala

AbstractMesoionische, 1,2,3‐Triazol‐abgeleitete N‐heterocyclische Olefine (mNHOs) mit außerordentlich elektronenreicher, exocyclischer CC–Doppelbindung wurden synthetisiert und spektroskopisch charakterisiert, z. T. durch Röntgenstrukturanalyse. Die Kinetik der mNHO‐Reaktionen mit Arylidenmalonaten (ArCH=C(CO2Et)2) zu zwitterionischen Addukten wurde photometrisch in THF bei 20 °C verfolgt. Die resultierenden Geschwindigkeitskonstanten 2. Ordnung k2(20 °C) korrelieren linear mit zuvor bestimmten Elektrophilieparametern E der Arylidenmalonate (Referenzelektrophile) und liefern gemäß der Beziehung lg k2(20 °C)=sN(N+E) die nucleophilspezifischen N‐ und sN‐Parameter der mNHOs. Die mNHOs sind mit 21<N<32 viel stärkere Nucleophile als herkömmliche NHOs. Einige mNHOs übertreffen sogar die Reaktivität von mono‐ und diakzeptor‐substituierten Carbanionen. Es wird an Beispielen gezeigt, dass es die so bestimmten Reaktivitätsparameter ermöglichen, die Geschwindigkeitskonstanten für mNHO‐Reaktionen mit weiteren Michael‐Akzeptoren zu berechnen. Auch die Reaktionen mit anderen elektrophilen Reaktionspartnern, inklusive Kohlenstoffdioxid, das zwitterionische mNHO‐Carboxylate bildet, lassen sich vorhersagen. Die Nucleophilie‐Parameter N korrelieren linear mit einer Linearkombination der quantenchemisch berechneten Methylkation‐Affinitäten und %Vbur („buried volumes“) der mNHOs, was ein wertvolles Werkzeug liefert, um Reaktivitäten starker Kohlenstoff‐Nucleophile maßzuschneidern.

Acetaldehyde in the Enders triple cascade reaction via acetaldehyde dimethyl acetal.

Asymmetric organocatalyzed multicomponent reactions represent an important toolbox in the field of organic synthesis to build complex scaffolds starting from simple starting materials. The Enders three-component cascade reaction was a cornerstone in the field and a plethora of organocatalyzed cascade reactions followed. However, acetaldehyde was not shown as a successful reaction partner, probably because of its high reactivity. Herein, we report the Enders-type cascade reaction using acetaldehyde dimethyl acetal, as a masked form of acetaldehyde. This strategy directly converts acetaldehyde, nitroalkenes and enals into stereochemically dense cyclohexenals in good yield and excellent enantioselectivity.

Palladium-Catalyzed Asymmetric (3 + 2) Cycloaddition of 5-Allenyloxazolidine-2,4-Diones with Barbiturate-Derived Alkenes: Synthesis of Spirobarbiturate-γ-Lactams.

The 5-allenyloxazolidine-2,4-diones had been synthesized as novel precursors of π-allyl palladium zwitterion and were applied in a palladium-catalyzed enantioselective (3 + 2) annulation by using barbiturate-derived alkenes as the reaction partner in the presence of an axially chiral phosphoramidite ligand. This reaction proceeded smoothly under mild reaction conditions, affording highly functionalized spirobarbiturate-γ-lactam derivatives in excellent yields along with high diastereo- and enantioselectivities. The scale-up reaction and further transformation of the product were also successful.

Base-Catalyzed Phenol-Mannich Condensation of Preformed Cesium Iminodiacetate. The Direct Synthesis of Calcein Blue AM and Related Acyloxymethyl Esters.

A rapid and highly practical one-flask procedure for the positionally selective preparation of (acyloxy)methyl N-(2-hydroxybenzyl)iminodiacetate and related diesters from iminodiacetic acid and phenols is described. The key to this multicomponent phenol-Mannich condensation resides in the use of cesium iminodiacetate as the reaction partner. This protocol has been applied in an unusually direct synthesis of the intracellular fluorescent dye Calcein blue AM, for which scant experimental and spectroscopic data are presently available.

Diastereo- and atroposelective synthesis of N-arylpyrroles enabled by light-induced phosphoric acid catalysis

The C−N axially chiral N-arylpyrrole motifs are privileged scaffolds in numerous biologically active molecules and natural products, as well as in chiral ligands/catalysts. Asymmetric synthesis of N-arylpyrroles, however, is still challenging, and the simultaneous creation of contiguous C−N axial and central chirality remains unknown. Herein, a diastereo- and atroposelective synthesis of N-arylpyrroles enabled by light-induced phosphoric acid catalysis has been developed. The key transformation is a one-pot, three-component oxo-diarylation reaction, which simultaneously creates a C−N axial chirality and a central quaternary stereogenic center. A broad range of unactivated alkynes were readily employed as a reaction partner in this transformation, and the N-arylpyrrole products are obtained in good yields, with excellent enantioselectivities and very good diastereoselectivities. Notably, the N-arylpyrrole skeletons represent interesting structural motifs that could be used as chiral ligands and catalysts in asymmetric catalysis.

Palladium-Catalyzed Trans-Selective Synthesis of Spirocyclic Cyclobutanes Using α,α-Dialkylcrotyl- and Allylhydrazones.

Herein, we demonstrate the use of E/Z mixtures of α,α-disubstituted crotylhydrazones to obtain spirocyclic vinylcyclobutanes in a diastereoselective fashion. We show 24 examples of a 1,1-insertion/4-exo-trig tandem process to produce these motifs. Additionally, spirocyclic alkylidene cyclobutanes can be obtained by using α,α-disubstituted allylated hydrazones (11 examples). In this study, we show that the aryl migrating group has a dramatic impact on the course of the reaction. Specifically, allylic C-H insertion products can be obtained in good yields using bromoenones as reaction partners. When Pd(0) is used with no aryl or alkenyl bromide, an intramolecular cyclopropanation reaction takes place to afford [2.1.0]-bicycles.

The membrane surface as a platform that organizes cellular and biochemical processes.

Membranes are essential for life. They act as semi-permeable boundaries that define cells and organelles. In addition, their surfaces actively participate in biochemical reaction networks, where they confine proteins, align reaction partners, and directly control enzymatic activities. Membrane-localized reactions shape cellular membranes, define the identity of organelles, compartmentalize biochemical processes, and can even be the source of signaling gradients that originate at the plasma membrane and reach into the cytoplasm and nucleus. The membrane surface is, therefore, an essential platform upon which myriad cellular processes are scaffolded. In this review, we summarize our current understanding of the biophysics and biochemistry of membrane-localized reactions with particular focus on insights derived from reconstituted and cellular systems. We discuss how the interplay of cellular factors results in their self-organization, condensation, assembly, and activity, and the emergent properties derived from them.

Peptide Diversification through Addition Reaction of Free Carboxylic Acids to Ynamides

Peptide modification has emerged as an important topic in the academic community and pharmaceutical industry. However, they are primarily focused on the diversification of amines, thiols, and alcohols. Direct and chemoselective modification of acid residues in peptides is relatively underdeveloped. In this context, we report a novel and efficient method for the direct functionalization of acid residues in peptides. By using ynamides as reaction partners, the adducts are rapidly obtained in moderate to excellent yields at room temperature in water. This approach shows excellent chemoselectivity and a broad scope including dipeptides bearing unprotected Trp or Tyr residue and free Ser or Gln residue.

Electrochemical Nickel-Catalyzed C(sp3)-C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates.

Formation of new C(sp3)-C(sp3) bonds is a powerful synthetic tool to increase molecular diversity, which is highly sought after in medicinal chemistry. Traditional generation of carbon nucleophiles and more modern cross-electrophile-coupling methods typically lack sufficient selectivity when cross-coupling of analogous C(sp3)-containing reactants is attempted. Herein, we present a nickel-catalyzed, electrochemically driven method for the coupling of alkyl bromides with alkyl tosylates. Selective cross-coupling transformations were achieved even between C(sp3)-secondary bromides and tosylates. Key to achieve high selectivity was the combination of the tosylates with sodium bromide as the supporting electrolyte, gradually generating small amounts of the more reactive bromide by substitution and ensuring that one of the reaction partners in the nickel-catalyzed electroreductive process is maintained in excess during a large part of the process. The method has been demonstrated for a wide range of substrates (>30 compounds) in moderate to good yields. Further expanding the scope of electroorganic synthesis to C(sp3)-C(sp3) cross-coupling reactions is anticipated to facilitate the switch to green organic synthesis and encourage future innovative electrochemical transformations.

Borane-Catalyzed C-F Bond Functionalization of gem-Difluorocyclopropenes Enables the Synthesis of Orphaned Cyclopropanes.

Herein, we disclose an approach to synthesize tert-alkyl cyclopropanes by leveraging C-F bond functionalization of gem-difluorocyclopropenes using tris(pentafluorophenyl)borane catalysis. The reaction proceeds through the intermediacy of a fluorocyclopropenium ion, which was confirmed by the isolation of [Ph2(C6D5)C3]+[(C6F5)3BF]-. We found that silylketene acetal nucleophiles were optimal reaction partners with fluorocyclopropenium ion intermediates yielding fully substituted cyclopropenes functionalized with two α-tert-alkyl centers (63-93% yield). The regioselectivity of the addition to cyclopropenium ions is controlled by their steric and electronic properties and enables access to 3,3-bis(difluoromethyl)cyclopropenes in short order. The resulting cyclopropene products are readily reduced to the corresponding orphaned cyclopropanes under hydrogenation conditions. Quantum chemical calculations reveal the nature of the C-F bond cleavage steps and provide evidence for catalysis by boron and not silylated oxonium ions, though Si-F bond formation is the enthalpic driving force for the reaction.

Cooperative Network Formation via Two Colour Light Activated λ-Orthogonal Chromophores.

Independently addressing photoreactive sites within one molecule with two colours of light is a formidable challenge. Here, we combine two sequence independent λ-orthogonal chromophores in one heterotelechelic dilinker molecule, to exploit their disparate reactivity utilizing the same reaction partner, a maleimide-containing polymer. We demonstrate that polymer network formation only proceeds if two colours of light are employed. Upon single colour irradiation, linker-decorated post-functionalized polymers are generated at either wavelength and in either sequence. Network formation, however, is only achieved by sequential or simultaneous two colour irradiation. The herein introduced photoreactive system demonstrates the power of wavelength orthogonal chemistry in macromolecular synthesis.

Diverse mechanisms in proton knockout reactions from the Borromean nucleus ^{17}text {Ne}

Nucleon knockout experiments using beryllium or carbon targets reveal a strong dependence of the quenching factors, i.e., the ratio (hbox {R}_{textrm{s}}) of theoretical to the experimental spectroscopic factors (hbox {C}^2{textrm{S}}), on the proton-neutron asymmetry in the nucleus under study. However, this dependence is greatly reduced when a hydrogen target is used. To understand this phenomenon, exclusive ^{1}text {H}(^{17}text {Ne},2hbox {p}~^{16}text {F}) and inclusive ^{12}text {C}(^{17}text {Ne},2hbox {p}~^{16}text {F})hbox {X}, ^{12}text {C}(^{17}text {Ne},^{16}text {F})hbox {X} as well as ^{1}text {H}(^{17}text {Ne},^{16}text {F})hbox {X} (X-denotes undetected reaction products) reactions with ^{16}text {F} in the ground and excited states were analysed. The longitudinal momentum distribution of ^{16}{textrm{F}} and the correlations between the detached protons were studied. In the case of the carbon target, there is a significant deviation from the predictions of the eikonal model. The eikonal approximation was used to extract spectroscopic factor values hbox {C}^2{textrm{S}}. The experimental hbox {C}^2hbox {S} value obtained with C target is markedly lower than that for H target. This is interpreted as rescattering due to simultaneous nucleon knockout from both reaction partners, ^{17}text {Ne} and ^{12}text {C}.

Trivalent Phosphine‐Catalyzed Reactions Using Fluorinated Building Blocks

AbstractThe development of novel synthetic methodologies to incorporate fluorine/s or fluoroalkyl group/s into the frameworks of organic molecules has become a highly prioritized research area because such modifications can tune their physiochemical and biological properties. In recent years, nucleophilic phosphine catalysis has been extensively explored to achieve this goal, and significant progress has been made. This review summarizes the methodological advancements of cycloaddition, addition and coupling reactions employing fluorinated building blocks as electrophilic and/or nucleophilic reaction partners under phosphine catalysis to construct structurally and synthetically valuable organofluorine compounds, with special emphasis on the synthetic strategies, proposed reaction mechanisms and synthetic utilities.

Asymmetric (4+n) Cycloadditions of Indolyldimethanols for the Synthesis of Enantioenriched Indole‐Fused Rings

AbstractCatalytic asymmetric construction of chiral indole‐fused rings has become an important issue in the chemical community because of the significance of such scaffolds. In this work, we have accomplished the first catalytic asymmetric (4+2) and (4+3) cycloadditions of 2,3‐indolyldimethanols by using indoles and 2‐naphthols as suitable reaction partners under the catalysis of chiral phosphoric acids, constructing enantioenriched indole‐fused six‐membered and seven‐membered rings in high yields with excellent enantioselectivities. In addition, this approach is used to realize the first enantioselective construction of challenging tetrahydroindolocarbazole scaffolds, which are found to show promising anticancer activity. More importantly, theoretical calculations of the reaction pathways and activation mode offer an in‐depth understanding of this class of indolylmethanols. This work not only settles the challenges in realizing catalytic asymmetric cycloadditions of indolyldimethanols but also provides a powerful strategy for the construction of enantioenriched indole‐fused rings.

Asymmetric (4+n) Cycloadditions of Indolyldimethanols for the Synthesis of Enantioenriched Indole-Fused Rings.

Catalytic asymmetric construction of chiral indole-fused rings has become an important issue in the chemical community because of the significance of such scaffolds. In this work, we have accomplished the first catalytic asymmetric (4+2) and (4+3) cycloadditions of 2,3-indolyldimethanols by using indoles and 2-naphthols as suitable reaction partners under the catalysis of chiral phosphoric acids, constructing enantioenriched indole-fused six-membered and seven-membered rings in high yields with excellent enantioselectivities. In addition, this approach is used to realize the first enantioselective construction of challenging tetrahydroindolocarbazole scaffolds, which are found to show promising anticancer activity. More importantly, theoretical calculations of the reaction pathways and activation mode offer an in-depth understanding of this class of indolylmethanols. This work not only settles the challenges in realizing catalytic asymmetric cycloadditions of indolyldimethanols but also provides a powerful strategy for the construction of enantioenriched indole-fused rings.

A Click Chemistry‐Based Artificial Metallo‐Nuclease

AbstractArtificial metallo‐nucleases (AMNs) are promising DNA damaging drug candidates. Here, we demonstrate how the 1,2,3‐triazole linker produced by the Cu‐catalysed azide‐alkyne cycloaddition (CuAAC) reaction can be directed to build Cu‐binding AMN scaffolds. We selected biologically inert reaction partners tris(azidomethyl)mesitylene and ethynyl‐thiophene to develop TC‐Thio, a bioactive C3‐symmetric ligand in which three thiophene‐triazole moieties are positioned around a central mesitylene core. The ligand was characterised by X‐ray crystallography and forms multinuclear CuII and CuI complexes identified by mass spectrometry and rationalised by density functional theory (DFT). Upon Cu coordination, CuII‐TC‐Thio becomes a potent DNA binding and cleaving agent. Mechanistic studies reveal DNA recognition occurs exclusively at the minor groove with subsequent oxidative damage promoted through a superoxide‐ and peroxide‐dependent pathway. Single molecule imaging of DNA isolated from peripheral blood mononuclear cells shows that the complex has comparable activity to the clinical drug temozolomide, causing DNA damage that is recognised by a combination of base excision repair (BER) enzymes.

A Click Chemistry-Based Artificial Metallo-Nuclease.

Artificial metallo-nucleases (AMNs) are promising DNA damaging drug candidates. Here, we demonstrate how the 1,2,3-triazole linker produced by the Cu-catalysed azide-alkyne cycloaddition (CuAAC) reaction can be directed to build Cu-binding AMN scaffolds. We selected biologically inert reaction partners tris(azidomethyl)mesitylene and ethynyl-thiophene to develop TC-Thio, a bioactive C3 -symmetric ligand in which three thiophene-triazole moieties are positioned around a central mesitylene core. The ligand was characterised by X-ray crystallography and forms multinuclear CuII and CuI complexes identified by mass spectrometry and rationalised by density functional theory (DFT). Upon Cu coordination, CuII -TC-Thio becomes a potent DNA binding and cleaving agent. Mechanistic studies reveal DNA recognition occurs exclusively at the minor groove with subsequent oxidative damage promoted through a superoxide- and peroxide-dependent pathway. Single molecule imaging of DNA isolated from peripheral blood mononuclear cells shows that the complex has comparable activity to the clinical drug temozolomide, causing DNA damage that is recognised by a combination of base excision repair (BER) enzymes.

Reactivity Differences of Trigonal Pyramidal Nonheme Iron(IV)-Oxo and Iron(III)-Oxo Complexes: Experiment and Theory.

High-valent metal-oxo species play critical roles in enzymatic catalysis yet their properties are still poorly understood. In this work we report a combined experimental and computational study into biomimetic iron(IV)-oxo and iron(III)-oxo complexes with tight second-coordination sphere environments that restrict substrate access. The work shows that the second-coordination sphere slows the hydrogen atom abstraction step from toluene dramatically and the kinetics is zeroth order in substrate. However, the iron(II)-hydroxo that is formed has a low reduction potential and hence cannot do OH rebound favorably. The tolyl radical in solution then reacts further with alternative reaction partners. By contrast, the iron(IV)-oxo species reacts predominantly through OH rebound to form alcohol products. Our studies show that the oxidation state of the metal influences reactivities and selectivities with substrate dramatically and that enzymes will likely need an iron(IV) center to catalyze C-H hydroxylation reactions.

Synthesis of Heterocycles from Donor-Acceptor Cyclopropanes: A Five-Year Recap

AbstractThis review discusses the utility of donor-acceptor cyclopropanes (DACs) for the construction of heterocycles. In addition to (3+2), (3+3), and (4+3) cycloaddition pathways, nucleophilic ring-opening reactions, intramolecular transformations, and cycloisomerizations in the presence of suitable catalysts pave the way for the generation of heterocycles from DACs. The mild reactions conditions employed and the variety of starting materials that can be used as reaction partners make the DAC route for heterocycle synthesis attractive. The literature covered in this review is from the period 2018 to 2023.1 Introduction2 Synthesis of Nitrogen Heterocycles2.1 By Annulations with Anthranils and Azadienes2.2 By Nucleophilic Attack of Anilines and Hydrazones2.3 By Reaction with Ureas and Thioureas2.4 By Annulation Reactions Using an Azomethine Imine2.5 By Reaction with Other Nitrogen Heterocycles2.6 By Other Transformations3 Synthesis of Oxygen Heterocycles3.1 By Intramolecular Transformations3.2 By Intermolecular Reactions4 Synthesis of Sulfur and Selenium Heterocycles4.1 By Reaction with Thiocarbonyl Substrates4.2 By Reaction with Thio- and Selenocyanates and Thiosulfonate Salts5 Synthesis of N–S and N–O Heterocycles6 Conclusions

The Fate of Water in Hydrogen-Based Iron Oxide Reduction.

Gas-solid reactions are important for many redox processes that underpin the energy and sustainability transition. The specific case of hydrogen-based iron oxide reduction is the foundation to render the global steel industry fossil-free, an essential target as iron production is the largest single industrial emitter of carbon dioxide. This perception of gas-solid reactions has not only been limited by the availability of state-of-the-art techniques which can delve into the structure and chemistry of reacted solids, but one continues to miss an important reaction partner that defines the thermodynamics and kinetics of gas phase reactions: the gas molecules. In this investigation, cryogenic-atom probe tomography is used to study the quasi in situ evolution of iron oxide in the solid and gas phases of the direct reduction of iron oxide by deuterium gas at 700°C. So far several unknown atomic-scale characteristics are observed, including, D2 accumulation at the reaction interface; formation of a core (wüstite)-shell (iron) structure; inbound diffusion of D through the iron layer and partitioning of D among phases and defects; outbound diffusion of oxygen through the wüstite and/or through the iron to the next free available inner/outer surface; and the internal formation of heavy nano-water droplets at nano-pores.