Organische Chemie

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Imidazo[1,5-a]pyridines – a versatile platform for structurally distinct N-heterocyclic olefins and π-extended heterocycles
(2025-04-17) Esken, Robin; Antoni, Patrick W.; Lorenz, Yannick; Burdenski, Chris; Kirchhoff, Jan-Lukas; Strohmann, Carsten; Hansmann, Max M.
The synthesis of polarized N-heterocyclic olefins (NHOs) based on an imidazo[1,5-a]pyridine scaffold is presented. In contrast to regular NHOs the unique bicyclic heterocyclic core allows the incorporation of various substituents in close proximity to the highly polarized exocyclic C─C bond. The donor properties of the new carbon-based ligand class were quantified and the coordination chemistry explored. Alkenyl or alkynyl groups at the C5-position lead to spontaneous cyclization to yield imidazo[2,1,5-de]quinolizines. The unique cyclization strategy was compatible with a wide range of substitution patterns and yields highly electron-rich π-delocalized heterocycles. The electronic structure of the novel partially antiaromatic heterocycle was thoroughly investigated. One-electron oxidation occurs at low potentials and lead to a stable monomeric radical-cation confirmed by XRD, which showed solution phase fluorescence expanding into the field of open-shell organic materials.
Ph3PC – a monosubstituted C(0) atom in its triplet state
(2025-01-27) Kutin, Yury; Koike, Taichi; Drosou, Maria; Schnegg, Alexander; Pantazis, Dimitrios A.; Kasanmascheff, Müge; Hansmann, Max M.
This study introduces a novel class of carbon-centered diradicals: a monosubstituted C atom stabilized by a phosphine. The diradical Ph3P→C was photochemically generated from a diazophosphorus ylide precursor (Ph3PCN2) and characterized by EPR and isotope-sensitive ENDOR spectroscopy at low temperatures. Ph3P→C features an axial zero-field splitting parameter D=0.543 cm−1 with a vanishingly small rhombicity |E|/D=0.002. Time- and temperature-dependent measurements confirm a triplet ground state with a lifetime of approximately 10 min at 127 K in toluene-d8. Multireference electronic structure calculations predict a clear triplet ground state with a singlet-triplet gap greater than 20 kcal/mol. In contrast to divalent C(0) compounds, such as Ph3P→C←PPh3, in which carbon needs excitation into a highly-excited closed-shell 2s02p4 configuration, Ph3P→C can be explained by direct involvement of carbon in its natural 3P state arising from the 2s22p2 configuration.
Cycloadditions of diazoalkenes with P4 and tBuCP: access to diazaphospholes
(2024-07-01) Hauer, Sebastian; Reitz, Justus; Koike, Taichi; Hansmann, Max M.; Wolf, Robert
Diazoalkenes readily react with tert-butylphosphaalkyne (tBuCP) and white phosphorus (P4) to afford novel phosphorus heterocycles, 3H-1,2,4-diazamonophospholes and 1,2,3,4-diazadiphospholes. Both species represent rare examples of neutral heterophospholes. The mechanism of formation and the electronic structures of these formal (3+2) cycloaddition products were analyzed computationally. The new phospholes form structurally diverse coordination compounds with transition metal and main group elements. Given the growing number of stable diazoalkenes, this work offers a straightforward route to neutral aza(di-)phospholes as a new ligand class.
Cleavage of carbodicarbenes with N2O for accessing stable diazoalkenes: two-fold ligand exchange at a C(0)-atom
(2024-09-06) He, Yijie; Lyu, Yichong; Tymann, David; Antoni, Patrick W.; Hansmann, Max M.
The cleavage of carbophosphinocarbenes and carbodicarbenes with nitrous oxide (N2O) leads to the formation of room-temperature stable diazoalkenes. The utility of Ph3P/N2 and NHC/N2 ligand exchange reactions were demonstrated by accessing novel benzimidazole- and benzothiazole derived diazoalkenes, which are not accessible by the current state-of-the-art methods. The stable diazoalkenes subsequently allow further ligand exchange reactions at C(0) with carbon monoxide, isocyanide, or a diamidocarbene (DAC). Overall, the combination of hitherto unknown NHC/N2 and N2/L (L = DAC, CO, R−NC) ligand exchange reactions at a C(0) center allow the selective functionalization of the carbodicarbene ligand structure which represents a new methodology to rapidly assemble novel carbodicarbenes or cumulenic compounds.
2-Methylene-1,2-dihydropyridines (2-pyNHOs): highly nucleophilic enamines
(2024-04-30) Behnke, Annika; Eitzinger, Andreas; He, Yijie; Antoni, Patrick W.; Ofial, Armin R.; Hansmann, Max M.
The high reactivity of 2-methylene-1,2-dihydropyridines also known as 2-methylpyridinium derived N-heterocyclic olefins (2-pyNHOs) has been recognized in organic synthesis, yet a quantification of their nucleophilicity is lacking. Herein we used stopped-flow photometry to determine the nucleophilicity of a series of 2-pyNHOs from the kinetics of their reactions with quinone methides and benzhydrylium ions as reference electrophiles in four organic solvents at 20 °C. The kinetic data was evaluated by using the Mayr-Patz equation, lg k(20 °C)=sN(N+E), which gave nucleophilicity parameters N (and sN). With N in the range of 19.4–21.2 (in DMSO), 2-pyNHOs exceed the reactivity of classical enamines, such as pyrrolidino-cyclopent-1-ene. The addition of 2-pyNHOs to quinone methides resulted in the formation of zwitterionic adducts with pyridinium and phenolate moieties. Subsequent tautomerization yielded entirely neutral pyridine-2(1H)-ylidene-phenol species in several cases. Formation of the zwitterionic adducts from 2-pyNHOs and neutral electrophiles was almost equally fast in the polar solvents acetonitrile and DMSO, but proceeded one to two orders of magnitude slower in the less polar solvents dichloromethane or THF.
Mesoionic N-heterocyclic olefins as initiators for the Lewis pair polymerization of epoxides
(2024-03-24) Haug, Iris; Reitz, Justus; Ziane, Célia; Buchmeiser, Michael R.; Hansmann, Max M.; Naumann, Stefan
Mesoionic N-heterocyclic olefins (mNHOs) have recently emerged as a novel class of highly nucleophilic and super-basic σ-donor compounds. Making use of these properties in synthetic polymer chemistry, it is shown that a combination of a specific mNHO and a Mg-based Lewis acid (magnesium bis(hexamethyldisilazide), Mg(HMDS)2) delivers poly(propylene oxide) in quantitative yields from the polymerization of the corresponding epoxide (0.1 mol% mNHO loading). The initiation mechanism involves monomer activation by the Lewis acid and direct ring-opening of the monomer by nucleophilic attack of the mNHO, forming a zwitterionic propagating species. Modulation of the mNHO properties is thereby a direct tool to impact initiation efficiency, revealing a sterically unencumbered triazole-derivative as particularly useful. The joint application of mNHOs together with borane-type Lewis acids is also outlined, resulting in high conversions and fast polymerization kinetics. Importantly, while molar mass distributions remain relatively broad, indicating faster propagation than initiation, the overall molar masses are significantly lower than found in the case of regular NHOs, underlining the increased nucleophilicity and ensuing improved initiation efficiency of mNHOs.
Self-assembled monolayers of N-heterocyclic olefins on Au(111)
(2023-09-24) Berg, Iris; Schio, Luca; Reitz, Justus; Molteni, Elena; Lahav, Linoy; Bolaños, Carolina Gutiérrez; Goldoni, Andrea; Grazioli, Cesare; Fratesi, Guido; Hansmann, Max M.; Floreano, Luca; Gross, Elad
Self-assembled monolayers (SAMs) of N-heterocyclic olefins (NHOs) have been prepared on Au(111) and their thermal stability, adsorption geometry, and molecular order were characterized by X-ray photoelectron spectroscopy, polarized X-ray absorption spectroscopy, scanning tunneling microscopy (STM), and density functional theory (DFT) calculations. The strong σ-bond character of NHO anchoring to Au induced high geometrical flexibility that enabled a flat-lying adsorption geometry via coordination to a gold adatom. The flat-lying adsorption geometry was utilized to further increase the surface interaction of the NHO monolayer by backbone functionalization with methyl groups that induced high thermal stability and a large impact on work-function values, which outperformed that of N-heterocyclic carbenes. STM measurements, supported by DFT modeling, identified that the NHOs were self-assembled in dimers, trimers, and tetramers constructed of two, three, and four complexes of NHO−Au-adatom. This self-assembly pattern was correlated to strong NHO−Au interactions and steric hindrance between adsorbates, demonstrating the crucial influence of the carbon-metal σ-bond on monolayer properties.
Pyridinium‐derived mesoionic N‐heterocyclic olefins (py‑mNHOs)
(2023-12-28) Sun, Qiu; Eitzinger, Andreas; Esken, Robin; Antoni, Patrick W.; Mayer, Robert J.; Ofial, Armin R.; Hansmann, Max M.
Mesoionic polarization allows access to electron-rich olefins that have found application as organocatalysts, ligands, or nucleophiles. Herein, we report the synthesis and characterization of a series of 3-methylpyridinium-derived mesoionic olefins (py-mNHOs). We used a DFT-supported design concept, which showed that the introduction of aryl groups in the 1-, 2-, 4-, and 6-positions of the heterocyclic core allowed the kinetic stabilization of the novel mesoionic compounds. Tolman electronic parameters indicate that py-mNHOs are remarkably strong σ-donor ligands toward transition metals and main group Lewis acids. Additionally, they are among the strongest nucleophiles on the Mayr reactivity scale. In reactions of py-mNHOs with electron-poor π-systems, a gradual transition from the formation of zwitterionic adducts via stepwise to concerted 1,3-dipolar cycloadditions was observed experimentally and analyzed by quantum-chemical calculations.
Spiro-C(sp3)-atom transfer: Creating rigid 3D structures with Ph2SCN2
(2025-02-21) Sun, Qiu; Belting, Jan-Niklas; Hauda, Julian; Tymann, David; Antoni, Patrick W.; Goddard, Richard; Hansmann, Max M.
The introduction of a single C-atom into organic substrates typically results in the formation of flat molecules containing unsaturated C(sp)-centers. Adding a single C(sp3)-atom surrounded by four σ-C–C bonds, which opens up the three-dimensional space, is an unresolved problem in synthetic chemistry. We report the synthesis and application of the diazosulfur ylide Ph2S=C=N2 reagent that combines the reactivity of both sulfur ylides and diazo compounds to create carbon spiro-centers in a general fashion by the sequential or single-step installation of a C(sp3)-atom. New C–C and C–X (where X is O or N) bonds can be created around the C(sp3)-atom, which can ultimately be extended to four C–C σ-bonds in one step without resorting to transition metal catalysis. Ph2SCN2 can also be used to access highly strained frameworks containing (oxa)spiro[2.2]pentanes as well as tricyclic spiro-compounds.
Room‐temperature‐stable diazoalkenes by diazo transfer from azides: pyridine‐derived diazoalkenes
(2023-03-03) Reitz, Justus; Antoni, Patrick W.; Holstein, Julian J.; Hansmann, Max M.
Recently, stable diazoalkenes have received significant attention as a new substance class in organic chemistry. While their previous synthetic access was exclusively limited to the activation of nitrous oxide, we here establish a much more general synthetic approach utilizing a Regitz-type diazo transfer with azides. Importantly, this approach is also applicable to weakly polarized olefins such as 2-pyridine olefins. The new pyridine diazoalkenes are not accessible by the activation of nitrous oxide, allowing for a considerable extension of the scope of this only recently accessed functional group. The new diazoalkene class has properties distinct from the previously reported classes, such as photochemically triggered loss of dinitrogen affording cumulenes and not C−H insertion products. Pyridine-derived diazoalkenes represent the so far least polarized stable diazoalkene class reported.
Diazoalkenes: from an elusive intermediate to a stable substance class in organic chemistry
(2023-04-24) Hansmann, Max M.
Over decades diazoalkenes (R2C=C=N2) were postulated as reactive intermediates in organic chemistry even though their direct spectroscopic detection proved very challenging. In the 1970/80ies several groups probed their existence mainly indirectly by trapping experiments or directly by matrix-isolation studies. In 2021, our group and the Severin group reported independently the synthesis and characterization of the first room-temperature stable diazoalkenes, which initiated a rapidly expanding research field. Up to now four different classes of N-heterocyclic substituted room-temperature stable diazoalkenes have been reported. Their properties and unique reactivity, such as N2/CO exchange or utilization as vinylidene precursors in organic and transition metal chemistry are presented. This review summarizes the early discoveries of diazoalkenes from their initial postulation as transient, elusive species up to the recent findings of the room-temperature stable derivatives.
Asymmetrische Synthese und Diversifikation stannylierter Cyclopropane und deren Anwendung in der Totalsynthese von Naturstoffen
(2024) Zimmer , Anne; Fürstner, Alois; Krause, Norbert
Mithilfe eines neuen heteroleptischen Dirhodium Katalysators für die enantioselektive Cyclopropanierung von Olefinen mit einem α stannyliertem Diazo Ester konnten zahlreiche optisch aktive, stannylierte Cyclopropane diastereoselektiv synthetisiert werden. Die erhaltenen stannylierten Cyclopropane wurden anschließend mittels stereoretentiver (carbonylativer) Stille Kupplung sowie durch Zinn-Lithium Austausch diversifiziert. Auf diese Weise konnten vielzählige, divers dekorierte und auf anderem Wege zum Teil schwer zugängliche, chirale Cyclopropane in optisch aktiver Form hergestellt werden. Die entwickelte Methodik wurde anschließend in der Totalsynthese mehrerer Naturstoffe angewandt. Eine Zielstruktur umfasste die Familie der Salinilactone, welche aus S. arenicola isoliert wurde, eine Spezies von marinen Bakterien der Gattung Salinispora. Ihre Mitglieder verfügen über ein bizyklisches [3.1.0]-Lactongerüst mit variierender Acylseitenkette. Zwei der Mitglieder, Salinilacton B und C, konnten so synthetisiert werden. Eine weitere Zielstruktur beinhaltete Integrifolian-1,5-dion, ein Naturstoff welcher aus Lippia integrifolia isoliert wurde, einem holzigen, in Agentinien beheimateten Busch. Die Struktur von Integrifolian-1,5-dion umfasst einen Cyclopropanring, welcher mit einem zehngliedrigen Kohlenstoffring verbunden ist, woraus sich ein Bicyclo[8.10]undecansystem ergibt. Die Synthese konnte über insgesamt 16 Schritte (14 Schritte in der längsten linearen Sequenz) erzielt werden. Schließlich wurde das erhaltene Integrifolian-1,5-dion mittels drei weiterer Schritte in das nah verwandte Lippifolian-1(6)-en-5-dion überführt.
Pushing the upper limit of nucleophilicity scales by mesoionic N‐heterocyclic olefins
(2023-08-04) Eitzinger, Andreas; Reitz, Justus; Antoni, Patrick W.; Mayr, Herbert; Ofial, Armin R.; Hansmann, Max M.
A series of mesoionic, 1,2,3-triazole-derived N-heterocyclic olefins (mNHOs), which have an extraordinarily electron-rich exocyclic CC-double bond, was synthesized and spectroscopically characterized, in selected cases by X-ray crystallography. The kinetics of their reactions with arylidene malonates, ArCH=C(CO2Et)2, which gave zwitterionic adducts, were investigated photometrically in THF at 20 °C. The resulting second-order rate constants k2(20 °C) correlate linearly with the reported electrophilicity parameters E of the arylidene malonates (reference electrophiles), thus providing the nucleophile-specific N and sN parameters of the mNHOs according to the correlation lg k2(20 °C)=sN(N+E). With 21
Ph3PCN2: a stable reagent for carbon atom transfer
(2024-07-18) Koike, Taichi; Yu, Jhen-Kuei; Hansmann, Max M.
Precise modification of a chemical site in a molecule at the single-atom level is one of the most elegant yet difficult transformations in chemistry. A reagent specifically designed for chemoselective introduction of monoatomic carbon is a particularly formidable challenge. Here we report a straightforward, azide-free synthesis of a crystalline and isolable diazophosphorus ylide Ph3PCN2, a stable compound with a carbon atom bonded to two chemically labile groups, triphenylphosphine (PPh3) and dinitrogen (N2). Without any additives, the diazophosphorus ylide serves as a highly selective transfer reagent for fragments including Ph3PC to deliver phosphorus ylide-terminated heterocumulenes and CN2 to produce multi-substituted pyrazoles. Ultimately, even exclusive C-atom transfer is possible: In reactions with aldehydes, acyclic and cyclic ketones (R2C=O), the C-atom substitution forms a vinylidene (R2C=C:) en route to alkynes or butatrienes.
Synthesis of redox-responsive core–shell nanoparticles: insights into core-crosslinking efficiency
(2023-07-25) Olszowy, Yannik; Wesselmann, Janick; Over, Shenja Fabienne; Pätzold, Florian; Weberskirch, Ralf
Core-crosslinked micelles have become an important class of materials for biomedical applications. However, there has been little work attempting to quantify the efficiency of the core crosslinking reaction, instead residual polymers are usually removed by dialysis. In this work we have prepared core crosslinked micelles based on poly(2-ethyl-2-oxazoline)-block-poly(n-butyl acrylate-co-D,L-homocysteine thiolactone acrylamide). Core crosslinking was examined by the addition of six different di- and triamines and nucleophilic ring-opening of the thiolactone ring. By using size exclusion chromatography (SEC) we were able to quantify the amount of crosslinked micelle and free block copolymer and were able to optimize the crosslinking conditions in terms of temperature, reaction time and crosslinker equivalents to obtain up to 80% core-crosslinked micelles. Subsequently, micelles that were crosslinked with cystamine were degraded in the presence of dithiothreitol (DTT) and resulted in degradation times of 1.5 h to 5 h and depended strongly on the composition of the hydrophobic core as shown by dynamic light scattering (DLS) and size exclusion chromatography (SEC). Cytotoxicity assays of the core-crosslinked micelles and block copolymer precursors were performed with COS7 cells and revealed high cell viabilities up to 0.1 mg mL−1.
Polymerbasierte Nanopartikel zur Anwendung in tandemkatalytischen Reaktionen
(2023) Dieter, Marvin; Weberskirch, Ralf; Krause, Norbert
Die nicht-orthogonale Tandemkatalyse ermöglicht es mehrstufige Synthesen chemischer Produkte auf einen Schritt zu reduzieren. Dadurch ist es möglich auf eine intermediäre Aufarbeitung der Zwischenprodukte zu verzichten, was zu einer starken Reduktion der in mehrstufigen Synthesen benötigten Mengen an Lösungsmitteln und Energie führt und den Prozess stark vereinfacht. Eine Schlüsselrolle bei der Realisierung eines solchen Ansatzes ist die Kompartimentierung der beteiligten Katalysatoren, da diese sich möglicherweise gegenseitig inhibieren oder deren spezifische Reaktionsbedingungen nicht kompatibel miteinander sind. Es sind mehrere Prinzipien zur räumlichen Separation von Katalysatoren auf verschiedenen Trägermaterialien bekannt, jedoch sind dabei insbesondere polymerbasierte Systeme aufgrund ihrer einfachen und vielfältigen Funktionalisierungsmöglichkeiten besonders geeignet. In dieser Arbeit wurde das auf einem Mikropartikel immobilisierte Enzym Candida Antarctica Lipase B in Kombination mit maßgeschneiderten, amphiphilen Polymeren eingesetzt. Die amphiphilen Polymere wurden dabei jeweils im Kern mit einem Kupfer- und L-Prolin-Katalysator funktionalisiert und bildeten in Wasser Mizellen aus. Um eine gegenseitige Inhibierung der beteiligten Katalysatoren durch Vermischung der Mizellen zu verhindern, wurden diese im Kern vernetzt. Die so erhaltenen kernvernetzten Nanopartikel wurden im Rahmen einer dreistufigen tandemkatalytischen Eintopf-Reaktion, bestehend aus einer Esterhydrolyse, einer aeroben Alkoholoxidation und einer asymmetrischen Aldolreaktion in Wasser eingesetzt.
Organische Hybrid-Verbindungen auf Basis elektronenreicher Olefine
(2023) Antoni, Patrick Wolf; Hansmann, Max; Strohmann, Carsten
Synthesis and characterization of cationic hydrogels from thiolated copolymers for independent manipulation of mechanical and chemical properties of cell substrates
(2022-02-20) Pätzold, Florian; Stamm, Nils; Kamps, Dominic; Specht, Maria; Bolduan, Patrick; Dehmelt, Leif; Weberskirch, Ralf
Cells sense both mechanical and chemical properties in their environment and respond to these inputs with altered phenotypes. Precise and selective experimental manipulations of these environmental cues require biocompatible synthetic materials, for which multiple properties can be fine-tuned independently from each other. For example, cells typically show critical thresholds for cell adhesion as a function of substrate parameters such as stiffness and the degree of functionalization. However, the choice of tailor-made, defined materials to produce such cell adhesion substrates is still very limited. Here, a platform of synthetic hydrogels based on well-defined thiolated copolymers is presented. Therefore, four disulfide crosslinked hydrogels of different composition by free radical polymerization are prepared. After cleavage with dithiothreitol, four soluble copolymers P1–P4 with 0–96% cationic monomer content are obtained. P1 and P4 are then combined with PEGDA3500 as a crosslinker, to fabricate 12 hydrogels with variable elasticity, ranging from 8.1 to 26.3 kPa and cationic group concentrations of up to 350 µmol cm−3. Systematic analysis using COS7 cells shows that all of these hydrogels are nontoxic. However, successful cell adhesion requires both a minimal elasticity and a minimal cationic group concentration.
Organic four‐electron redox systems based on bipyridine and phenanthroline carbene architectures
(2022-03-17) Antoni, Patrick W.; Golz, Christopher; Hansmann, Max M.
Novel organic redox systems that display multistage redox behaviour are highly sought-after for a series of applications such as organic batteries or electrochromic materials. Here we describe a simple strategy to transfer well-known two-electron redox active bipyridine and phenanthroline architectures into novel strongly reducing four-electron redox systems featuring fully reversible redox events with up to five stable oxidation states. We give spectroscopic and structural insight into the changes involved in the redox-events and present characterization data on all isolated oxidation states. The redox-systems feature strong UV/Vis/NIR polyelectrochromic properties such as distinct strong NIR absorptions in the mixed valence states. Two-electron charge–discharge cycling studies indicate high electrochemical stability at strongly negative potentials, rendering the new redox architectures promising lead structures for multi-electron anolyte materials.
Gold(I) NHC catalysts immobilized to amphiphilic block copolymers: a versatile approach to micellar gold catalysis in water
(2022-06-23) Petersen, Hanne; Ballmann, Monika; Krause, Norbert; Weberskirch, Ralf
Fifteen gold(I)-NHC-functionalized amphiphilic block copolymers that differ in the type of linker (ethyl, pentyl, octyl and benzyl) that attaches the gold(I) NHC catalyst to the block copolymer backbone, as well as, the substitution pattern of the NHC ligand (i. e. mesityl, methyl, 2,6-diisopropylphenyl and n-hexyl) were synthesized by a reversible addition and fragmentation transfer (RAFT) polymerization process. Micelle formation of the gold(I) NHC polymers was analyzed by electron microscopy and dynamic light scattering and revealed spherical and rod-like particles from 12 to 96 nm. In the micellar, gold(I) catalyzed cycloisomerization of an allene to the corresponding dihydrofuran, linker flexibility and substitution pattern of the NHC-ligand showed a strong effect on the catalytic activity. Best results were obtained were obtained for gold(I) NHC catalysts bound to the polymer backbone by pentyl linker whereas the rather stiff benzyl linker gave lowest catalyst conversion. Moreover, the polymer catalyst could be recycled in four consecutive runs and gave activities from 35 to 84 % in the fourth run and underscores the importance of fine tuning structural parameters to achieve high conversion under micellar reaction conditions.

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