Publications
2025
Pflaum, Niklas; Pauls, Mike; Kumar, Ajeet; Kutta, Jan Roger; Nuernberger, Patrick; Hauer, Patrick; Bannwarth, Christopher; Bach, Thorsten: Oxetane Cleavage Pathways in the Excited State: Photochemical Kinetic Resolution as an Approach to Enantiopure Oxetanes. J. Am. Chem. Soc. 147, 2025, 13893-13904.
Chiral spirocyclic oxetanes [2-oxo-spiro(3H-indole-3,2′-oxetanes)] were subjected to irradiation in the presence of a chiral thioxanthone catalyst (5 mol %) at λ = 398 nm. An efficient kinetic resolution was observed, which led to an enrichment of one oxetane enantiomer as the major enantiomer (15 examples, 37−50% yield, 93−99% ee). The minor enantiomer underwent decomposition, and the decomposition products were carefully analyzed. They arise from a photocycloreversion (retro-Paternò–Büchi reaction) into a carbonyl component and an olefin. The cycloreversion offers two cleavage pathways depending on whether a C−O bond scission or a C−C bond scission occurs at the spirocyclic carbon atom. The course of this reaction was elucidated by a suite of mechanistic, spectroscopic, and quantum chemical methods. In the absence of a catalyst, cleavage occurs exclusively by initial C−O bond scission, leading to formaldehyde and a tetrasubstituted olefin as cleavage products. Time-resolved spectroscopy on the femtosecond/picosecond time scale, synthetic experiments, and calculations suggest the reaction to occur from the first excited singlet state (S1). In the presence of a sensitizer, triplet states are populated, and the first excited triplet state (T1) is responsible for cleavage into an isatin and a 1,1-diarylethene by an initial C−C bond scission. The kinetic resolution is explained by the chiral catalyst recruiting predominantly one enantiomer of the spirocyclic oxindole. A two-point hydrogen-bonding interaction is responsible for the recognition of this enantiomer, as corroborated by NMR titration studies and quantum chemical calculations. Transient absorption studies on the nanosecond/microsecond time scale allowed for observing the quenching of the catalyst triplet by either one of the two oxetane enantiomers with a slight preference for the minor enantiomer. In a competing situation with both enantiomers present, energy transfer to the major enantiomer is suppressed initially by the better-binding minor enantiomer and─as the reaction progresses─by oxindole fragmentation products blocking the binding site of the catalyst.
Project Area B
Huber, Matthias; Kumar Ajeet; Hauer, Jürgen; Thyrhaug, Erling; Hess, Corinna R.: Photoredox capacity expanded by the Cu site of CuFe-Mabiq. Chem. Commun. 61, 2025, 5731-5734.
The monometallic Fe-Mabiq and bimetallic CuFe-Mabiq photoredox catalysts feature similar optical spectra and short excited-state lifetimes. Nevertheless, they exhibit markedly different photochemistry. Photoreduction proceeds significantly faster for the bimetallic complex, and uniquely generates the three-electron reduced form. These characteristics underpin the self-sensitized photocatalytic behaviour of the bimetallic complex.
Project area B
Rodríguez-Camargo, Andrés; Terban, Maxwell W.; Paetsch, Martina; Rico, Elio A.; Graf, Daniel; Hirpara, Radhika; Duppel, Viola; Moudrakovski, Igor; Etter, Martin; Guijarro, Néstor; Ochsenfeld, Christian; Dinnebier, Robert E.; Yao, Liang; Lotsch, Bettina V.: Cyclopalladation of a covalent organic framework for near-infrared-light-driven photocatalytic hydrogen peroxide production. Nat. Synth, 2025. doi.org/10.1038/s44160-024-00731-1
Covalent organic frameworks (COFs) have been developed as photosensitizers for photocatalytic energy conversion over the past decade; however, COF photocatalysts have yet to demonstrate the ability to harvest near-infrared light (above 760 nm, approximately 53% of the solar spectrum) for fuel or chemical conversion. In this work we introduce a post-synthetic functionalization strategy for COFs by incorporating a palladacycle directly into the COF backbone, extending the light absorption of an azobenzene-based COF into the near-infrared region. This approach enables homogeneous, atomically distributed palladium functionalization with a high loading of 12 wt% and without noticeable formation of palladium nanoparticles. The cyclopalladated COF, TpAzo-CPd, was used as a catalyst for photocatalytic hydrogen peroxide production under 810 nm illumination. This study demonstrates the use of COFs for near-infrared photocatalysis and opens the door to palladium-single-site COF catalysts for a wide range of chemical transformations.
Project Area C
Iglhaut, Maximilian; Freund, Philip; Bach, Thorsten: Photochemical Deracemization of N-Carboxyanhydrides En Route to Chiral α-Amino Acid Derivatives. Angew. Chem. Int. Ed. 64, 2025, e202418873
N-Carboxyanhydrides 1 (NCAs) are activated α-amino acid derivatives that can be modified in a minimum-waste process to give a variety of products. Photochemical deracemization using chiral catalyst 2 for stereochemical editing of the α-stereogenic center provided access to intermediates (R)-1 that can be immediately subjected to further transformations.
Project Area B
Lemke, Yannick; Ochsenfeld, Christian: Top-Down versus Bottom-Up Approaches for σ-Functionals Based on the Approximate Exchange Kernel. J. Phys. Chem. A 129, 2025, 774-787.
Recently, we investigated a number of so-called σ- and τ-functionals based on the adiabatic-connection fluctuation–dissipation theorem (ACFDT); particularly, extensions of the random phase approximation (RPA) with inclusion of an exchange kernel in the form of an antisymmetrized Hartree kernel. One of these functionals, based upon the approximate exchange kernel (AXK) of Bates and Furche, leads to a nonlinear contribution of the spline function used within σ-functionals, which we previously avoided through the introduction of a simplified “top-down” approach in which the σ-functional modification is inserted a posteriori following the analytic coupling strength integration within the framework of the ACFDT and which was shown to provide excellent performance for the GMTKN55 database when using hybrid PBE0 reference orbitals. In this work, we examine the analytic “bottom-up” approach in which the spline function is inserted a priori, i.e., before evaluation of the analytic coupling strength integral. The new bottom-up functionals, denoted σ↑AXK, considerably improve upon their top-down counterparts for problems dominated by self-interaction and delocalization errors. Despite a small loss of accuracy for noncovalent interactions, the σ↑AXK@PBE0 functionals comprehensively outperform regular σ-functionals, scaled σ-functionals, and the previously derived σ+SOSEX- and τ-functionals in the WTMAD-1 and WTMAD-2 metrics of the GMTKN55 database.
Project Area C
2024
Frank, Eduard; Park, Sooyoung; Harrer, Elias; Flügel, Jana L.; Fischer, Marcel; Nuernberger, Patrick; Rehbein, Julia; Breder, Alexander: Asymmetric Migratory Tsuji–Wacker Oxidation Enables the Enantioselective Synthesis of Hetero- and Isosteric Diarylmethanes, J. Am. Chem. Soc. 632, 2024, 34383-34393.
Diarylmethanes play, in part, a pivotal role in the design of highly potent, chiral, nonracemic drugs whose bioactivity is typically affected by the substitution pattern of their arene units. In this context, certain arenes such as para-substituted benzenes or unsubstituted heteroarenes cause particular synthetic challenges, since such isosteric residues at the central methane carbon atom are typically indistinguishable for a chiral catalyst. Hence, the stereoselective incorporation of isosteric (hetero)arenes into chiral methane scaffolds requires the use of stoichiometrically differentiated building blocks, which is typically realized through preceding redox-modifying operations such as metalation or halogenation and thus associated with disadvantageous step- and redox-economic traits. As a counter-design, we report herein a generalized enantioselective synthesis of chiral diarylmethanes by means of an asymmetric migratory Tsuji−Wacker oxidation of simple stilbenes. The title protocol relies on the well-adjusted interplay of aerobic photoredox and selenium-π-acid catalysis to allow for the installation of a broad variety of arenes, including isosteric ones, into the methane core. Facial differentiation and regioselectivity are solely controlled by the selenium catalyst, which (a) renders the E/Z-configuration of the stilbene substrates inconsequential and (b) permits the stereodivergent synthesis of both product enantiomers from a single catalyst enantiomer, simply by employing constitutionally isomeric starting materials. Altogether, this multicatalytic platform offers the target structures with high levels of enantioselectivity in up to 97% ee, which has also been successfully exploited in expedited syntheses of antihistaminic (R)- and (S)-neobenodine.
Project Area B
Lemke, Yannick; Kussmann, Jörg; Ochsenfeld, Christian: Highly Accurate and Robust Constraint-Based Orbital-Optimized Core Excitations, J. Phys. Chem. A 128, 2024, 9804-9818.
We adapt our recently developed constraint-based orbital-optimized excited-state method (COOX) for the computation of core excitations. COOX is a constrained density functional theory (cDFT) approach based on excitation amplitudes from linear-response time-dependent DFT (LR-TDDFT), and has been shown to provide accurate excitation energies and excited-state properties for valence excitations within a spin-restricted formalism. To extend COOX to core-excited states, we introduce a spin-
unrestricted variant which allows us to obtain orbital-optimized core excitations with a single constraint. Using a triplet purification scheme in combination with the constrained unrestricted Hartree−Fock formalism, scalar-relativistic zero-order regular approximation corrections, and a semiempirical treatment of spin−orbit coupling, COOX is shown to produce highly accurate results for K- and L-edge excitations of second- and third-period atoms with subelectronvolt errors despite being based on LR-TDDFT, for which core excitations pose a well-known challenge. L- and M-edge excitations of heavier atoms up to uranium are also computationally feasible and numerically stable, but may require more advanced treatment of relativistic effects. Furthermore, COOX is shown to perform on par with or better than the popular ΔSCF approach while exhibiting more robust convergence, highlighting it as a promising tool for inexpensive and accurate simulations of X-ray absorption spectra.
Dauth, Bastian; Giusto, Paolo; König, Burkhard; Gschwind, Ruth M.: In-situ Monitoring of Photocatalysis on Polymeric Carbon Nitride Thin Films, Angew. Chem. Int. Ed. 63, 2024, e202412972.
Polymeric carbon nitride has attracted significant interest in heterogeneous photocatalysis due to its activity under visible-light irradiation. Herein, we report on using carbon nitride-coated NMR tubes for in-situ studies of photocatalytic reaction mechanisms. In a first step, we exploited carbon nitride-coated crimp vials as batch photoreactors for visible photocatalytic fluorinations of unactivated C(sp3)-H bonds, with moderate to excellent yields and reusability over multiple cycles. Eventually, carbon nitride-coated NMR tubes were used as a photoreactor by coupling them with optical fiber irradiation directly inside the spectrometer. This enabled us to follow the reaction with in-situ NMR spectroscopy identifying reactive intermediates otherwise elusive in conventional analyses. The method provides advantages for the study of photocatalytic mechanisms of complex reactions and substantially reduces the need of comparative tests for depicting reaction intermediates and conversion pathways.
Kussmann, Jörg, Lemke, Yannick; Weinbrenner, Anthea; Ochsenfeld, Christian: A Constraint-Based Orbital-Optimized Excited State Method (COOX), J. Chem. Theory Comput. 20, 2024, 8461-8473.
In this work, we present a novel method to directly calculate targeted electronic excited states within a self-consistent field calculation based on constrained density functional theory (cDFT). The constraint is constructed from the static occupied-occupied and virtual-virtual parts of the excited state difference density from (simplified) linear-response time-dependent density functional theory calculations (LR-TDDFT). Our new method shows a stable convergence behavior, provides an accurate excited state density adhering to the Aufbau principle, and can be solved within a restricted SCF for singlet excitations to avoid spin contamination. This also allows the straightforward application of post-SCF electron-correlation methods like MP2 or direct RPA methods. We present the details of our constraint-based orbital-optimized excited state method (COOX) and compare it to similar schemes. The accuracy of excitation energies will be analyzed for a benchmark of systems, while the quality of the resulting excited state densities is investigated by evaluating excited state nuclear forces and excited state structure optimizations. We also investigate the performance of the proposed COOX method for long-range charge transfer excitations and conical intersections with the ground-state.
Drontschenko, Viktoria; Ochsenfeld, Christian: Low-Scaling, Efficient and Memory Optimized Computation of Nuclear Magnetic Resonance Shieldings within the Random Phase Approximation Using Cholesky-Decomposed Densities and an Attenuated Coulomb Metric. J. Phys. Chem. A 128, 2024, 7950-7965.
An efficient method for the computation of nuclear magnetic resonance (NMR) shielding tensors within the random phase approximation (RPA) is presented based on our recently introduced resolution-of-the-identity (RI) atomic orbital RPA NMR method [Drontschenko, V. J. Chem. Theory Comput. 2023, 19, 7542–7554] utilizing Cholesky decomposed density type matrices and employing an attenuated Coulomb RI metric. The introduced sparsity is efficiently exploited using sparse matrix algebra. This allows for an efficient and low-scaling computation of RPA NMR shielding tensors. Furthermore, we introduce a batching method for the computation of memory demanding intermediates that accounts for their sparsity. This extends the applicability of our method to even larger systems that would have been out of reach before, such as, e.g., a DNA strand with 260 atoms and 3408 atomic orbital basis functions.
Peschel, Martin; Kussmann, Joerg; Ochsenfeld, Christian; de Vivie-Riedle, Regina: Simulation of the non-adiabatic dynamics of an enone-Lewis acid complex in an explicit solvent, Phys. Chem. Chem Phys. 26, 2024, 23256-23263.
Unlocking the full potential of Lewis acid catalysis for photochemical transformations requires a comprehensive understanding of the ultrafast dynamics of substrate-Lewis acid complexes. In a previous article [Peschel et al., Angew. Chem. Int. Ed., 2021, 60, 10155], time-resolved spectroscopy supported by static calculations revealed that the Lewis acid remains attached during the relaxation of the model complex cyclohexenone-BF3. In contrast to the experimental observation, surface-hopping dynamics in the gas phase predicted ultrafast heterolytic dissociation. We attributed the discrepancy to missing solvent interactions. Thus, in this work, we present an interface between the SHARC and FermiONs++ program packages, which enables us to investigate the ultrafast dynamics of cyclohexenone-BF3 in an explicit solvent environment. Our simulations demonstrate that the solvent prevents the dissociation of the complex, leading to an intriguing dissociation–reassociation mechanism. Comparing the dynamics with and without triplet states highlights their role in the relaxation process and shows that the Lewis acid inhibits intersystem crossing. These findings provide a clear picture of the relaxation process, which may aid in designing future Lewis acid catalysts for photochemical applications. They underscore that an explicit solvent model is required to describe relaxation processes in weakly bound states, as energy transfer to the solvent is crucial for the system to reach its minimum geometries.
Ghosh, Mangish; Mandal, Tirtha; Leprii, Mattia, Barham, Joshua P.; Rehbein, Julia; Reiser, Oliver: Electrochemical Homo- and Crossannulation of Alkynes and Nitriles for the Regio- and Chemoselective Synthesis of 3,6-Diarylpyridines, Angew. Chem. Int. Ed. 63, 2024, e202411930.
We disclose a mediated electrochemical [2 + 2+ 2] annulation of alkynes with nitriles, forming substituted pyridines in a single step from low-cost, readily available starting materials. The combination of electrochemistry and a triarylamine redox mediator obviates the requirements of transition metals and additional oxidants. Besides the formation of diarylpyridine moieties via the homocoupling of two identical alkynes, the heterocoupling of two different alkynes depending on their electronic nature is possible, highlighting theunprecedented control of chemoselectivity in this cata-lytic [2 + 2 + 2] process. Mechanistic investigations likecyclic voltammetry and crossover experiments combinedwith DFT calculations indicate the initial oxidation of an alkyne as the key step leading to the formation of a vinyl radical cation intermediate. The utilization of continuous flow technology proved instrumental for an efficient process scale-up. The utility of the products is exemplified by the synthesis of π-extended molecules, being relevant for material or drug synthesis.
Grotjahn, Sascha; Müller, Lea; Pattanaik, Aryaman; Falk, Alexander; Barison, Giorgia; Bauer, Jonathan O.; Rehbein, Julia; Gschwind, Ruth M.; König, Burkhard: Regio-, diastereo- and enantioselectivity in the photocatalytic generation of carbanions via hydrogen atom transfer and reductive radicalpolar crossover, Org. Chem. Front. 11, 2024, 5890-5900.
A sequence involving photocatalytic hydrogen atom transfer (HAT), reductive radical-polar crossover (RRPCO), and protonation/deuteration for stereochemical editing at benzylic positions is described. A sys-tematic screening of substrates with benzylic C-H bonds provides trends in reactivity for C–H activation by silane thiols. A cis/trans isomerization of dihydrobenzofurans proceeding under kinetic control in the HAT step is presented, and the concept is transferred to a deracemization by chiral silane thiols as HAT reagents in a proof of concept study.
Tiefel, Anna; Grenda, Daniel J.; Allacher, Carina; Harrer, Elias; Nagel, Carolin H.; Kutta, J. Roger; Hernández-Castillo, David; Narasimhamurthy, Poorva R.; Zeitler, Kirsten; González, Leticia; Rehbein, Julia; Nuernberger, Patrick; Breder, Alexander: Unimolecular net heterolysis of symmetric and homopolar σ-bonds, Nature 632, 2024, 550-556.
Bishi, Sangita; Lenka, Bhabani Sankar; Kreitmeier, Peter; Reiser, Oliver; Sarkar, Debayan: g-C3N4 Photocatalyzed Decarboxylative Oxidation of Carboxylic Acids and the Oxidation of Alkenes and Alkanes, Adv. Synth. Catal. 366, 2024, 3397-3403.
The decarboxylative oxygenation of readily available carboxylic acids as well as the oxidation of alkenes and alkanes has been accomplished through visible light using g-C3N4 as a robust and recyclable catalyst. The scalable protocol furnishes an array of aldehydes and ketones under mild reaction conditions, requiring only molecular oxygen as an oxidant. Notably, no addition of stochiometric amounts of base is required, and furthermore, the reaction proceeds efficiently open to the air.
Tian, Yaming; Pu, Xiang; Sánchez, Alejandro Heredero; Meneszes-da-Silva, Wagner; Gschwind, R. M.; König, Burkhard: Photoinduced Radical Borylation of Robust Carbon–Heteroatom Bonds, Adv. Synth. Catal., 366, 2024, 1-11.
Photoinduced borylation has emerged as a valuable strategy for synthesizing arylboronic esters. However, photochemical transformations involving inert bonds such as C(sp2)−F bonds are still challenging. Herein, we report a straightforward and operationally simple method for the activation of various inert carbon–heteroatom bonds, enabling the synthesis of diverse arylboronic esters without the need for transition metals or catalysts. Mechanistic investigations reveal that the deprotonation of DMSO plays a pivotal role in the reaction, and the excited DMSO anion can undergo electron transfer to the aryl substrates activated by anionic sp2–sp3 diboron compounds, i. e., [FB2pin2]−, thereby facilitating the cleavage of carbon–heteroatom bonds. The reaction allows the conversion of diverse Caryl–hetero bonds in batch and flow reactors into the corresponding arylboronic esters. The products can be used in a subsequent Suzuki-Miyaura cross-coupling without isolation.
Roy, Susmita; Hauer, Jürgen; Maiti, Sankar Kiran: Development of non-invasive diagnosis based on FTIR spectroscopy, Vibrational Spectroscopy 134, 2024, 103724.
Numerous illnesses progress silently, often reaching a critical stage by the time symptoms appear, making medical intervention difficult. While there exist sophisticated clinical techniques for precise disease detection, they are often invasive procedure and as a rule of thumb is used only with definite symptomatic cases. In addition, the extreme clinical costs prevent a large population from taking advantage of contemporary medical facilities. A non-invasive, economically feasible screening method that detects diseases even in their pre-symptomatic stages may overcome many critical challenges in health and medicine. Utilizing vibrational spectroscopy to identify volatile metabolites offers promise as such a non-invasive, cost-effective diagnostic tool. The article outlines the potential of vibrational spectroscopy for non-invasive diagnostics and proposes a method for its clinical implementation.
Fauser, Steffen; Drontschenko, Viktoria; Ochsenfeld, Christian; Görling, Andreas: Accurate NMR Shieldings with σ‑Functionals, J. Chem. Theory comput. 20, 2024, 6028-6036.
In recent years, density-functional methods relying on a new type of fifth-rung correlation functionals called σ-functionals have been introduced. σ-Functionals are technically closely related to the random phase approximation and require the same computational effort but yield distinctively higher accuracies for reaction and transition state energies of main group chemistry and even outperform double-hybrid functionals for these energies. In this work, we systematically investigate how accurate σ-functionals can describe nuclear magnetic resonance (NMR) shieldings. It turns out that σ-functionals yield very accurate NMR shieldings, even though in their optimization, exclusively, energies are employed as reference data and response properties such as NMR shieldings are not involved at all. This shows that σ-functionals combine universal applicability with accuracy. Indeed, the NMR shieldings from a σ-functional using input orbitals and eigenvalues from Kohn–Sham calculations with the exchange-correlation functional of Perdew, Burke and Ernzerhof (PBE) turned out to be the most accurate ones among the NMR shieldings calculated with various density-functional methods including methods using double-hybrid functionals. That σ-functionals can be used for calculating both reliable energies and response properties like NMR shieldings characterizes them as all-purpose functionals, which is appealing from an application point of view.
Yakubov, Shahboz; Dauth, Bastian, Stockerl, Willibald J.; da Silva, Wagner; Gschwind, Ruth M.; Barham, Joshua Philip: Protodefluorinated Selectfluor® Aggregatively Activates Selectfluor® for Efficient Radical C(sp3)−H Fluorination Reactions, ChemSusChem. 17, 2024, e202401057.
Efficient fluorination reactions are key in the late-stage functionalization of complex molecules in medicinal chemistry, in upgrading chemical feedstocks, and in materials science. Radical C(sp3)−H fluorinations using Selectfluor® - one of the most popular fluorination agents - allow to directly engage unactivated precursors under mild photochemical or thermal catalytic conditions. However, H−TEDA(BF4)2 to date is overlooked and discarded as waste, despite comprising 95% of the molecular weight of Selectfluor®. We demonstrate that the addition of H−TEDA(BF4)2 at the start of fluorination reactions markedly promotes their rates and accesses higher overall yields of fluorinated products (~3.3x higher on average across the cases studied) than unpromoted reactions. Several case studies showcase generality of the promotor, for photochemical, photocatalytic and thermal radical fluorination reactions. Detailed mechanistic investigations reveal the key importance of aggregation changes in Selectfluor® and H−TEDA(BF4)2 to fill gaps of understanding in how radical C(sp3)−H fluorination reactions work. This study exemplifies an overlooked reaction waste product being upcycled for a useful application.
Klöpfer, Viktor; Chinchole, Anurag; Reiser, Oliver: Dual iron- and organophotocatalyzed hydroformylation, hydroacylation and hydrocarboxylation of Michael-acceptors utilizing 1,3,5-trioxanes as C1-Synthone, Tetrahedron Chem 10, 2024, 100073.
A protocol based on photocatalytic cycles of both iron(III)chloride and 9,10-dicyanoanthracene (DCA) is developed for the masked hydroformylation, hydroacylation, and hydrocarboxylation of Michael-Acceptors utilizing readily available 1,3,5-trioxanes. Initiated by the LMCT of [FeCl4]– to generate chlorine radicals that promote hydrogen atom transfer (HAT) from the trioxanes, 9,10-dicyanoanthracene is used as co-photocatalyst to accelerate the formation of the desired products by facilitating the reoxidation of iron(II) to iron(III). The methodology is robust, allowing the generation of aldehydes, ketones, and carboxylic acids either by altering the trioxane and deprotection strategy or by subsequent photocatalyzed conversion of the initially obtained aldehydes.
Tian, Yaming; Silva, Wagner; Gschwind, R. M.; König, Burkhard: Accelerated photochemical reactions at oil-water-interface exploiting melting point depression, Science 383, 2024, 750-756.
Water can accelerate a variety of organic reactions far beyond the rates observed in classical organic solvents. However, using pure water as a solvent introduces solubility constraints that have limited the applicability of efficient photochemistry in particular. We report here the formation of aggregates between pairs of arenes, heteroarenes, enamines, or esters with different electron affinities in an aqueous medium, leading to an oil-water phase boundary through substrate melting point depression. The active hydrogen atoms in the reactants engage in hydrogen bonds with water, thereby accelerating photochemical reactions. This methodology realizes appealingly simple conditions for aqueous coupling reactions of complex solid molecules, including complex drug molecules that are poorly soluble in water.
Kolb, Daniel; Friedmann, Kai; König, Burkhard: Tandem Synthesis of Benzylidenemalononitrile Derivatives in/on Water under Visible Light, ChemCatChem 16, 2024, e202400936.
Tandem processes are valuable tools that allow to build molecular complexity while reducing waste production and the number of steps of synthetic routes. In this work, the in situ photooxidation of benzyl alcohols to the corresponding benzaldehydes is coupled with a Knoevenagel condensation for the preparation of benzylidenemalononitrile derivatives. In this rapid one-pot tandem process, sodium anthraquinone-1,5-disulfonate (SAS) and β-alanine are employed as safe and inexpensive catalysts, while air is used as a terminal oxidant. Moreover, using water as reaction medium results in most cases in the precipitation of the target products, thus facilitating their isolation.
Xu, Yi; Peschel, Martin; Jänchen, Miriam; Foja, Richard; Storch, Golo; Thyrhaug, Erling; de Vivie-Riedle, Regina; Hauer, Jürgen: Determining Excited-State Absorption Properties of a Quinoid Flavin by Polarization-Resolved Transient Spectroscopy, J. Phys. Chem A. 128, 2024, 3830-3839.
As important naturally occurring chromophores, photophysical/chemical properties of quinoid flavins have been extensively studied both experimentally and theoretically. However, little is known about the transition dipole moment (TDM) orientation of excited-state absorption transitions of these important compounds. This aspect is of high interest in the fields of photocatalysis and quantum control studies. In this work, we employ polarization-associated spectra (PAS) to study the excited-state absorption transitions and the underlying TDM directions of a standard quinoid flavin compound. As compared to transient absorption anisotropy (TAA), an analysis based on PAS not only avoids diverging signals but also retrieves the relative angle for ESA transitions with respect to known TDM directions. Quantum chemical calculations of excited-state properties lead to good agreement with TA signals measured in magic angle configuration. Only when comparing experiment and theory for TAA spectra and PAS, do we find deviations when and only when the S0 → S1 of flavin is used as a reference. We attribute this to the vibronic coupling of this transition to a dark state. This effect is only observed in the employed polarization-controlled spectroscopy and would have gone unnoticed in conventional TA.
Märsch, Julia; Reiter, Sebastian; Rittner, Thomas; Rodriguez-Lugo, Rafael E.; Whitfield, Maximilian; Scott, Daniel J.; Jan Kutta, Roger; Nuernberger, Patrick; de Vivie-Riedle, Regina; Wolf, Robert: Cobalt-Mediated Photochemical C−H Arylation of Pyrroles, Angew. Chem. Int. Ed. 63, 2024, e202405780.
Precious metal complexes remain ubiquitous in photoredox
catalysis (PRC) despite concerted efforts to find more earth-abundant
catalysts and replacements based on 3d metals in particular. Most
otherwise plausible 3d metal complexes are assumed to be unsuitable
due to short-lived excited states, which has led researchers to
prioritize the pursuit of longer excited-state lifetimes through careful
molecular design. However, we report herein that the C−H arylation
of pyrroles and related substrates (which are benchmark reactions for
assessing the efficacy of photoredox catalysts) can be achieved using
a simple and readily accessible octahedral bis(diiminopyridine) cobalt
complex, [1-Co](PF6)2. Notably, [1-Co]2+ efficiently functionalizes
both chloro- and bromoarene substrates despite the short excitedstate
lifetime of the key photoexcited intermediate *[1-Co]2+ (8 ps).
We present herein the scope of this C−H arylation protocol and
provide mechanistic insights derived from detailed spectroscopic and
computational studies. These indicate that, despite its transient
existence, reduction of *[1-Co]2+ is facilitated via pre-assembly with
the NEt3 reductant, highlighting an alternative strategy for the future
development of 3d metal-catalyzed PRC.
Bergwinkl, Sebastian; Nuernberger, Patrick; Dick, Bernhard; Kutta, Roger Jan: Enhanced intersystem crossing in a thiohelicene, ChemPhotoChem 8, 2024, e202300343.
The photophysics of a helicene derivative in which two benzene units are replaced by thiophene units (thiohelicene, 6H) was studied by steady state and transient absorption and emission spectroscopies covering time ranges from femtoseconds to minutes. Efficient intersystem crossing (ISC) to the triplet state was observed, by far exceeding that of the parent helicene and the corresponding oxo-helicene. Quantum chemical calculations indicate that the helical distortion and the heavy atom effect of sulfur cooperate in promoting spin-orbit coupling, and that the most efficient decay channel involved the T2 or even the T3 state. These insights can help in the design of more efficient triplet sensitizes for may applications.
Hierlmeier, Gabriele; Kutta, Roger Jan; Coburger, Peter; Stammler, Hans-Georg; Schwabedissen, Jan; Mitzel, Norbert W.; Dimitrova, Maria; Berger, Raphael J.F.; Nuernberger, Patrick; Wolf, Robert: Structure and photochemistry of di-tert-butyldiphosphatetrahedrane, Chem. Sci. 15, 2024, 5596-5603.
Di-tert-butyldiphosphatetrahedrane (tBuCP)2 (1) is a mixed carbon- and phosphorus-based tetrahedral molecule, isolobal to white phosphorus (P4). However, despite the fundamental significance and well-explored reactivity of the latter molecule, the precise structure of the free (tBuCP)2 molecule (1) and a detailed analysis of its electronic properties have remained elusive. Here, single-crystal X-ray structure determination of 1 at low temperature confirms the tetrahedral structure. Furthermore, quantum chemical calculations confirm that 1 is isolobal to P4 and shows a strong largely isotropic diamagnetic response in the magnetic field and thus pronounced spherical aromaticity. A spectroscopic and computational study on the photochemical reactivity reveals that diphosphatetrahedrane 1 readily dimerises to the ladderane-type phosphaalkyne tetramer (tBuCP)4 (2) under irradiation with UV light. With sufficient thermal activation energy, the dimerisation proceeds also in the dark. In both cases, an isomerisation to a 1,2-diphosphacyclobutadiene 1′ is the first step. This intermediate subsequently undergoes a [2 + 2] cycloaddition with a second 1,2-diphosphacyclobutadiene molecule to form 2. The 1,2-diphosphacyclobutadiene intermediate 1′ can be trapped chemically by N-methylmaleimide as an alternative [2 + 2] cycloaddition partner.
Grotjahn, Sascha; Graf, Christina; Zelenka, Jan; Pattanaik, Aryaman; Müller, Lea; Jan Kutta, Roger; Rehbein, Julia, Roithová, Jana, Gschwind Ruth M.; Nuernberger, Patrick; König, Burkhard: Reactivity of superbasic carbanions generated via reductive radical-polar crossover in the context of photoredox catalysis, Angew. Chem. Int. Ed. 63, 2024, e202400815.
Photocatalytic reactions with a reductive radical-polar crossover (RRPCO) involve intermediates with carbanionic reactivity. These are best described as free carbanions. Reactions with such carbanions depend on the balance between their nucleophilicity and basicity. Deprotonation of reaction partners and common organic solvents such as acetonitrile, dimethylformamide, and dimethylsulfoxide is the main competing reaction to nucleophilic addition.
Nikitin, Maksim; Babawale, Florence; Tastekin, Sena; Antonietti, Markus; Ghosh, Indrajit; König, Burkhard: C(sp2)–S cross-coupling reactions with nickel, visible light, and mesoporous graphitic carbon nitride, Green Chem. 26, 2024, 5845-5851.
Cross-coupling reactions play a vital role in modern organic synthesis, enabling the construction of necessary C–C or C–(het)atom bonds for synthetic transformations. Although C(sp2)–C and C(sp2)–N cross-coupling reactions have received significant attention, recent advancements have also highlighted the significance of C(sp2)–S cross-coupling reactions. These reactions lead to the synthesis of valuable compounds, including pharmaceuticals and materials. In a recent report, we introduced Adaptive Dynamic Homogeneous Catalysis (AD-HoC) as an efficient method for C(sp2)–S cross-coupling reactions. This method operates without the need for any ligands, base, or additional additives, relying solely on essential parameters. In this report, we discuss the use of mesoporous graphitic carbon nitride (mpg-CN) as an all-organic heterogeneous photocatalyst in such transformations. The versatility and robustness of the reaction are showcased with fifty synthetic examples, achieving up to a 98% yield. The use of mpg-CN as a catalyst additionally enables the easy recovery of the photocatalyst from the reaction mixture and facilitates the sequential execution of multiple cross-coupling reactions with consistent yields of the desired products using a simple setup. This approach is a significant advancement in the field, both in terms of operational simplicity and environmental impact, traits that we all envision for sustainability.
Yan, Peng; Stegbauer, Simone; Wu, Qinqin; Kolodzeiski, Elena; Stein, Christopher; Lu, Ping; Bach, Thorsten: Enantioselective Intramolecular ortho Photocycloaddition Reactions of 2-Acetonaphthones, Angew. Chem. Int. Ed. 63, 2024, e202318126.
2-Acetonaphthones, which bear an alkenyl group tethered to its C1 carbon atom via an oxygen atom, were found to undergo an enantioselective, intramolecular ortho photocycloaddition reaction. A chiral oxazaborolidine Lewis acid leads to a bathochromic absorption shift of the substrate and enables an efficient enantioface differentiation. Visible light irradiation (λ = 450 nm) triggers the reaction which is tolerant of various groups at almost any position except carbon atom C8 (16 examples, 53-99% yield, 80-97% ee). Consecutive reactions were explored including a sensitized rearrangement to tetrahydrobiphenylenes, which occurred with full retention of configuration. Evidence was collected that the catalytic photocycloaddition occurs via triplet intermediates, and the binding mode of the acetonaphthone to the chiral Lewis acid was elucidated by DFT calculations.
Kiprova, Natalia; Desnoyers, Marine; Narobe, Rok; Klufts-Edel, Arthur; Chaud, Juliane; König, Burkhard; Compain; Philippe; Kern, Nicolas: Towards a General Access to 1-Azaspirocyclic Systems via Photoinduced, Reductive Decarboxylative Radical Cyclizationse. Chem. Eur. J. 30, 2024, e202303841.
A convenient and versatile approach to important 1-azaspirocy-clic systems relevant to medicinal chemistry and natural products is reported herein. The main strategy relies on a reductive decarboxylative cyclization of redox-active esters which can be rapidly assembled from abundant cyclic azaacids and tailored acceptor sidechains, with a focus on alkyne acceptors enabling the generation of useful exo-alkene moieties. Diastereoconvergent variants were studied and could be achieved either through remote stereocontrol or conformational restriction in bicyclic carbamate substrates. Two sets of metal-free photocatalytic conditions employing inexpensive
eosin Y were disclosed and studied experimentally to highlight key mechanistic divergences.
2023
Publications
Kolb, Daniel; Almasalma, Ahmad A.; Morgenstern, Martin; Ganser, Leon; Weidacher, Isabel; Burkhard, König: Photocatalytic Dehydroformylation of Benzyl Alcohols to Arenes, ChemPhotoChem, 7, 2023, e20230016.
The combination of photoinduced hydrogen atom transfer (HAT) and cobalt catalysis gives access to a mild dehydroformylation sequence for the defunctionalization of benzyl alcohols to arenes. The transformation proceeds through a stepwise radical pathway, wherein benzylic and acyl radicals are generated as key intermediates. As a result, stable C−C bonds can be cleaved while generating concomitant syngas (CO+H2).
Žurauskas, Jonas; Boháčová, Soňa; Wu, Shangze; Butera, Valeria; Schmid, Simon; Domański, Michal, Slanina, Tomáš; Barham, Joshua P.: Electron-Poor Acridones and Acridiniums as Super Photooxidants in Molecular Photoelectrochemistry by Unusual Mechanisms, Angew. Chem. Int. Ed. 62, 2023, e202307550.
Under photoelectrochemical conditions, dicyanated acridones are precatalysts for acridinium ions as closed-shell, highly potent arene photooxidants. Despite the lifetime permitting diffusion-controlled quenching, a preassembly with substrate nonetheless operates. Highlighting the profound influence of preassembly on photocatalysis, quenching diverts from single to double electron transfer reduction of the excited state to an acridinide anion.
Schwinger, Daniel P., Pickl, Thomas; Bach, Thorsten: Photochemical Isomerization of Cyclohept-1-ene-1-carbaldehyde: Strain-Release Cycloadditions and Ene Reactions, J. Org. Chem. 88, 2023, 12844-12852.
Cyclohept-1-ene-1-carbaldehyde undergoes photoinduced E → Z isomerization at λ = 350 nm. The ring strain facilitates Diels–Alder cycloaddiions with 1,3-dienes, [3 + 2] cycloadditions with 1,3-dipoles, and ene reactions with olefins. Products are trans-fused at the cycloheptane core and were obtained in yields of up to 82%. Single crystal X-ray analyses corroborated the constitution and relative configuration of key products. With BF3 as a Lewis acid and 2,3-dimethylbuta-1,3-diene, cyclohept-1-ene-1-carbaldehyde reacted in the dark and rearranged stereoselectively to a tricyclic ketone (87%).
Delgado, José A. C.; Tian, Ya-Ming; Marcon, Michela; König, Burkhard: Side-Selective Solid-Phase Metallaphotoredox N(in)-Arylation of Peptides, J. Am. Chem. Soc. 145, 2023, 26452-26462.
Postsynthetic diversification of peptides through selective modification of endogenous amino acid side chains has enabled significant advances in peptide drug discovery while expanding the biological and medical chemistry space. However, current tools have been focused on the modification of reactive polar and ionizable side chains, whereas the decoration of aromatic systems (e.g., the N(in) of the tryptophan) has been a long-standing challenge. Here, we introduce metallaphotocatalysis in solid-phase peptide synthesis for the on-resin orthogonal N-arylation of relevant tryptophan-containing peptides. The protocol allows the chemoselective introduction of a new C(sp2)−N bond at the N(in) of tryptophan in biologically active protected peptide sequences in the presence of native redox-sensitive side chains. The fusion of metallaphotocatalysis with solid-phase peptide synthesis opens new perspectives in diversifying native amino acid side chains.
Wylie, Luke; Barham, Joshua P., Kirchner, Barbara: Solvent Dependency of Catalyst-Substrate Aggregation Through π-π Stacking in Photoredox Catalysis, ChemPhysChem, 24, 2023, e202300470.
The formation of photoredox catalyst assemblies on substrates is investigated using molecular dynamics via the angle, distance and longevity of the interactions. In addition, the solvent effect on these complex formations is also examined.
Ghosh, Indrajit; Shlapakov, Nikita; Karl, Tobias A.; Düker, Jonas; Nikitin, Maksim; Burykina, Julia V.; Ananikov, Valentine P.; König, Burkhard: General cross-coupling reactions with adaptive dynamic homogeneous catalysis chloroiodane-HFIP assemblies, Nature 619, 2023, 87-93.
Cross-coupling reactions are among the most important transformations in modern organic synthesis1,2,3. Although the range of reported (het)aryl halides and nucleophile coupling partners is very large considering various protocols, the reaction conditions vary considerably between compound classes, necessitating renewed case-by-case optimization of the reaction conditions4. Here we introduce adaptive dynamic homogeneous catalysis (AD-HoC) with nickel under visible-light-driven redox reaction conditions for general C(sp2)–(hetero)atom coupling reactions. The self-adjustive nature of the catalytic system allowed the simple classification of dozens of various classes of nucleophiles in cross-coupling reactions. This is synthetically demonstrated in nine different bond-forming reactions (in this case, C(sp2)–S, Se, N, P, B, O, C(sp3, sp2, sp), Si, Cl) with hundreds of synthetic examples under predictable reaction conditions. The catalytic reaction centre(s) and conditions differ from one another by the added nucleophile, or if required, a commercially available inexpensive amine base.
Kolb, Daniel; Morgenstern, Martin; König, Burkhard: Decarbonylation of Benzaldehydes by Dual Photoorgano-Cobalt Catalysis, Chem. Commun. 59, 2023, 8592.
We report a mild alternative to thermally-driven noble-metal catalyzed decarbonylation protocols for the defunctionalization of benzaldehydes in short reaction times. Our cooperative photocatalytic system involves thioxanthone as an inexpensive HAT-agent and a cobalt complex required for selective C(sp2)–C(sp2) bond cleavage. The generated acyl and phenyl intermediates are postulated to be stabilized as cobalt complexes.
Xu, Yi; Mewes, Lars; Thyrhaug, Erling; Sláma, Vladislav; Šanda, František; Langhans, Heinz; Hauer, Jürgen: Isolating Pure Donor and Acceptor Signals by Polarization-
Controlled Transient Absorption Spectroscopy, J. Chem. Phys. Lett. 14, 2023, 5390-5396.
The optical spectra of molecules are often highly congested, inhibiting definite assignment of features and dynamics. In this work, we demonstrate and apply a polarization-based strategy for the decomposition of time-resolved optical spectra to analyze the electronic structure and energy transfer in a molecular donor−acceptor (D−A) dyad. We choose a dyad with orthogonal transition dipole moments for D and A and high fluorescence quantum yield to show that polarization-controlled ultrafast transient absorption spectra can isolate the pure D and A parts of the total signal. This provides a strategy to greatly reduce spectral congestion in complex systems and thus allows for detailed studies of electronic structure and electronic energy transfer.
Großkopf, Johannes; Heidecker, Alexandra H.; Bach, Thorsten: Photochemical Deracemization of 3-Substituted Oxindoles, Angew. Chem. Int. Ed. 62, 2023, e202305274.
Racemic 3-substituted oxindoles were successfully converted into enantiomerically pure or enriched material (up to 99 % ee) upon irradiation at λ=366 nm in the presence of a chiral benzophenone catalyst (10 mol %). The photochemical deracemization process allows predictable editing of the stereogenic center at carbon atom C3. Light energy compensates for the associated loss of entropy and enables the decoupling of potentially reversible reactions, i.e. a hydrogen atom transfer to (photochemical) and from (thermal) the carbonyl group of the catalyst. The major enantiomer is continuously enriched in several catalytic cycles. The obtained oxindoles were shown to be valuable intermediates for further transformations, which proceeded with complete retention at the stereogenic center.
Drontschenko, Viktoria; Bangerter, Felix H.; Ochsenfeld, Christian: Analytical Second-Order Properties for the Random Phase Approximation: Nuclear Magnetic Resonance Shieldings, J. Chem. Theory Comput. 19, 2023, 7542-7554.
A method for the analytical computation of nuclear magnetic resonance (NMR) shieldings within the direct random phase approximation (RPA) is presented. As a starting point, we use the RPA ground-state energy expression within the resolution-of-the-identity approximation in the atomic-orbital formalism. As has been shown in a recent benchmark study using numerical second derivatives [Glasbrenner, M. J. Chem. Theory Comput. 2022, 18, 192], RPA based on a Hartree–Fock reference shows accuracies comparable to coupled cluster singles and doubles (CCSD) for NMR chemical shieldings. Together with the much lower computational cost of RPA, it has emerged as an accurate method for the computation of NMR shieldings. Therefore, we aim to extend the applicability of RPA NMR to larger systems by introducing analytical second-order derivatives, making it a viable method for the accurate and efficient computation of NMR chemical shieldings.
Chaibuth, Pawittra; Engl, Sebastian; Reichle, Alexander; Chainok, Kittipong; Sukwattanasinitt, Mongkol; Reiser, Oliver: In Situ Generated, Tetracoordinated Copper(II)-Quinoline Complexes as Photocatalysts for the Chlorosulfonylation of Alkenes and Alkynes, Adv. Synth.Catal., 365, 2023, 4701-4747.
A series of copper complexes was synthesized and studied as photocatalysts for the chlorosulfonylation of olefins. Featuring a tetradentate ligand consisting of one amino quinoline and two methyl pyridine moieties, the resulting Cu(II)-complex is effective under visible light irradiation to add sulfonyl chlorides to alkenes and alkynes, including unactivated aliphatic olefins. A weak base additive such as Na2CO3 prevents catalyst poisoning, resulting in an improvement of reaction yields and catalyst lifetime. A broad scope of sulfonyl chlorides and alkenes/alkynes as coupling partners are amenable for the title process, including examples previously reported unsuccessful with established copper-based photocatalysts.
Harvey, Freya M.; Heidecker, Alexandra H.; Merten, Christian; Bach, Thorsten: Diastereoselective, Lewis acid-mediated Diels–Alder reactions of allenoic acid derivatives and 1,3-cyclopentadienes, Org. Biomol. Chem. 21, 2023, 4422-4428.
Allenes with different substituents at their terminal carbon atom display axial chirality and can be obtained in enantiopure form by a photochemical deracemization protocol. It has now been studied under which conditions allenoic acid derivatives undergo a Diels–Alder reaction with 1,3-cyclopentadienes and which products result. Cyclic derivatives (lactams, lactones) underwent an exo-selective reaction catalyzed by the Lewis acid Eu(fod)3, while acyclic derivatives yielded with high preference the endo-products (EtAlCl2 as the preferred Lewis acid). The exocyclic double bond forms with exquisite diastereoselectivity and the chirality transfer is close to perfect. The method was applied to the synthesis of the sesquiterpenes β-santalol (1) and 10(E)-β-santalic acid (13).
Mandal, Tirtha; Katta, Narenderreddy; Paps, Hendrik; Reiser, Oliver: Merging Cu(I) and Cu(II) Photocatalysis: Development of a Versatile Oxohalogenation Protocol for the Sequential Cu(II)/Cu(I)-Catalyzed Oxoallylation of Vinylarenes, ACS Org. Inorg. Au 3, 2023, 171176.-
A sequential photocatalytic strategy is developed via the merger of Cu(II)/Cu(I)-catalytic cycles for the oxoallylation of vinyl arenes via α-haloketones. The initial Cu(II)-photocatalyzed oxohalogenation exploits ligand-to-metal charge transfer (LMCT) to generate halide radicals from acyl halides utilizing air as a terminal oxidant and can be employed for the late-stage modification of pharmaceuticals and agrochemicals. α-Bromoketones obtained this way can be subsequently subjected to a one-pot Cu(I)-photocatalyzed allylation. This sequential photocatalysis proceeds in a highly regio- and chemoselective fashion and is inconsequential to the electronic nature of styrenes.
Leverenz, Malte; Brockmann, Hendrik; Dreuw, Andreas; Bach, Thorsten; Storch, Golo: Enantiodivergent Photochemical Rearrangements Due to Different Coordination Modes at an Oxazaborolidine Lewis Acid Catalyst, ACS Catal. 13, 2023, 5896-5905.
A strong enantiodivergence ranging from +92% ee to −45% ee was observed in the oxadi-π-methane rearrangement of 2,4-cyclohexadienones. Oxazaborolidine-based Lewis acid catalysts of the same absolute configuration were applied in all cases, and the stereochemical outcome is solely a function of the oxazaborolidine substituents. Based on the results of an extended catalyst library screening (27 examples) and by interrogating plausible catalyst–substrate complexes in the ground state with density functional theory (DFT) methods, we could link the switch in enantioselectivity to a change in substrate binding. If the typical substrate binding at the convex catalyst side is inhibited by bulky substituents, our results indicate that substrates instead bind to the concave side, and enantiomeric products result. Studies by TDDFT in the S1 excited state further clarified the mechanistic picture by connecting efficient product formation with trajectories that reach a conical intersection with more excess energy. Our analysis was validated by the stereochemical outcome achieved with five structurally different catalysts.
Wallach, Christoph; Selic, Yasmin; Geitner, Felix S.; Kumar, Ajeet; Thyrhaug, Erling; Hauer, Jürgen; Karttunen, Antti J.; Fässler, Thomas F.: Probing Charge-Transfer Processes in a Covalently Linked [Ge9]-Cluster Imine Dyad, Angew. Chem. Int. Ed. 62, 2023, e202304088.
C60 donor dyads in which the carbon cage is covalently linked to an electron-donating unit have been discussed as one possibility for an electron-transfer system, and it has been shown that spherical [Ge9] cluster anions show a close relation to fullerenes with respect to their electronic structure. However, the optical properties of these clusters and of functionalized cluster derivatives are almost unknown. We now report on the synthesis of the intensely red [Ge9] cluster linked to an extended π-electron system. [Ge9{Si(TMS)3}2{CH3C=N}-DAB(II)Dipp]− (1−) is formed upon the reaction of [Ge9{Si(TMS)3}2]2− with bromo-diazaborole DAB(II)Dipp-Br in CH3CN (TMS=trimethylsilyl; DAB(II)=1,3,2-diazaborole with an unsaturated backbone; Dipp=2,6-di-iso-propylphenyl). Reversible protonation of the imine entity in 1− yields the deep green, zwitterionic cluster [Ge9{Si(TMS)3}2{CH3C=N(H)}-DAB(II)Dipp] (1-H) and vice versa. Optical spectroscopy combined with time- ependent density functional theory suggests a charge-transfer excitation between the cluster and the antibonding π* orbital of the imine moiety as the cause of the intense coloration. An absorption maximum of 1-H in the red region of the electromagnetic spectrum and the corresponding lowest-energy excited state at λ=669 nm make the compound an interesting starting point for further investigations targeting the design of photo-active cluster compounds.
Kumar, Ajeet; Malevich, Pavel; Mewes, Lars; Wu, Shangze; Barham, Joshua P.; Hauer, Jürgen: Transient absorption spectroscopy based on uncompressed hollow core fiber white light proves pre-association between a radical ion photocatalyst and substrate, J. Chem. Phys. 158, 2023, 144201.
We present a hollow-core fiber (HCF) based transient absorption experiment, with capabilities beyond common titanium:sapphire based setups. By spectral filtering of the HCF spectrum, we provide pump pulses centered at 425 nm with several hundred nJ of pulse energy at the sample position. By employing the red edge of the HCF output for seeding CaF2, we obtain smooth probing spectra in the range between 320 and 900 nm. We demonstrate the capabilities of our experiment by following the ultrafast relaxation dynamics of a radical cationic photocatalyst to prove its pre-association with an arene substrate, a phenomenon that was not detectable previously by steady-state spectroscopic techniques. The detected preassembly rationalizes the successful participation of radical ionic photocatalysts in single electron transfer reactions, a notion that has been subject to controversy in recent years.
Binder, Julia; Biswas, Aniruddha; Gulder, Tanja: Biomimetic chlorine-induced polyene cyclizations harnessing hypervalent chloroiodane-HFIP assemblies, Chem. Sci. 14, 2023, 3907-3912.
While bromo- and iodocyclizations have recently been successfully implemented, the challenging chlorocyclizations have been scantly investigated. We present a selective and generally applicable concept of chlorination-induced polyene cyclization by utilizing HFIP–chloroiodane networks mimicking terpene cyclases. A manifold of different alkenes was converted with excellent selectivities (up to d.r. >95 : 5). The cyclization platform was even extended to several structurally challenging terpenes and terpenoid carbon frameworks.
Mandigma, Mark John P., Mattia; Stockerl; Kaur, Jaspreet; Barham, Joshua P.:Organophotocatalytic Mechanisms: Simplicity or Naïvety? Diverting Reactive Pathways by Modifications of Catalyst Structure, Redox States and Substrate Preassemblies, ChemCatChem 15, 2023, e202201542.
Photocatalysis is a powerful tool to assemble diverse chemical scaffolds, yet a bottleneck on its further development is the understanding of the multitude of possible pathways when practitioners rely only on oversimplified thermodynamic and optical factors. Recently, there is a growing number of studies in the field that exploit, inter alia, kinetic parameters and organophotocatalysts that are synthetically more programmable in terms of their redox states and opportunities for aggregation with a target substrate. Non-covalent interactions play a key role that enables access to a new generation of reactivities such as those of open-shell organophotocatalysts. In this review, we discuss how targeted structural and redox modifications influence the organophotocatalytic mechanisms together with their underlying principles. We also highlight the benefits of strategies such as preassembly and static quenching that overcome common reactivity issues (e. g., diffusion rate limits and energetic limits).
Ritu, Ritu; Kolb, Daniel; Jain, Nidhi; König, Burkhard: Synthesis of Linear Enamides and Enecarbamates via Photoredox Acceptorless Dehydrogenation, Adv. Synth. Catal. 365, 2023, 605-611.
In recent years, several methods for the direct desaturation of aliphatic compounds have been developed, facilitated by the unique combination of photoredox and transition-metalcatalysis. Hereby, alkenes with high functionalizationpotential can be prepared in a straight forward fashion. We adapted a previously reported system involving tetrabutylammoniumdecatungstate (TBADT) as hydrogen atom transfer (HAT) agent and a cobaloxime co-catalyst for dihydrogen evolution for the dehydrogenative preparation of linear enamides and enecarbamates from saturated precursors. The substrate scope includes severa lnatural products and drug derivatives. The reaction does not require noble metal catalysts, exhibits short reaction times compared to previous methods and is suitable for the late stage functionalization of drug derivatives.
Arnold, Andreas M.; Dullinger, Philipp; Biswas, Aniruddha; Jandl, Christian; Horinek, Dominik; Gulder, Tanja: Enzyme-like polyene cyclizations catalyzed by dynamic, self-assembled, supramolecular fluoro alcohol-amine clusters, Nat Commun. 14, 2023, 813.
Terpene cyclases catalyze one of the most powerful transformations with respect to efficiency and selectivity in natural product (bio)synthesis. In such polyene cyclizations, structurally highly complex carbon scaffolds are built by the controlled ring closure of linear polyenes. Thereby, multiple C,C bonds and stereocenters are simultaneously created with high precision. Structural preorganization of the substrate carbon chain inside the active center of the enzyme is responsible for the product- and stereoselectivity of this cyclization. Here, we show that in-situ formed fluorinated-alcohol-amine supramolecular clusters serve as artificial cyclases by triggering enzyme-like reactivity and selectivity by controlling substrate conformation in solution. Because of the dynamic nature of these supramolecular assemblies, a broad range of terpenes can be produced diastereoselectively. Mechanistic studies reveal a finely balanced interplay of fluorinated solvent, catalyst, and substrate as key to establishing nature’s concept of a shape-selective polyene cyclization in organic synthesis.
Reichle, Alexander; Reiser, Oliver: Light-induced homolysis of copper(II)-complexes – a perspective for photocatalysis, Chem. Sci. 14, 2023, 4449.
Over the past decade, photocatalysis has developed into a powerful strategy for the selective functionalization of molecules through radical intermediates. Besides the well-established iridium- or ruthenium-based photocatalysts, which ideally fulfill the requirements for a photocatalyst, such as long excited-state lifetimes and photostability, the shift towards earth-abundant metal-based photocatalysts has so far been less explored. The concept of light-induced homolysis (LIH) for generating radicals has recently gained significant interest as a new platform for inducing photoreactions with earth-abundant 3d-metal complexes despite only having excited-state lifetimes in the low nanosecond range or even below. Cu(II)-complexes play a prominent role in exploiting this concept, which will be discussed by showcasing recent developments in organic synthesis with a view to identifying the future prospects of this growing field.
Tian, Ya-Ming; Hofmann, Evamaria; Silva, Wagner; Pu, Xiang; Touraud, Didier; Gschwind, Ruth M.; Kunz, Werner; König, Burkhard: Enforced Electronic-Donor-Acceptor Complex Formation in Water for Photochemical Cross-Coupling, Angew. Chem. Int. Ed. 62, 2023, e202218775.
The amino alcohol meglumine solubilizes organic compounds in water and enforces the formation of electron donor acceptor (EDA) complexes of haloarenes with indoles, anilines, anisoles or thiols, which are not observed in organic solvents. UV-A photoinduced electron transfer within the EDA complexes induces the mesolytic cleavage of the halide ion and radical recombination of the arenes leading, after rearomatization and proton loss to C−C or C−S coupling products. Depending on the substitution pattern selective and unique cross-couplings are observed. UV and NMR measurements reveal the importance of the assembly for the photoinduced reaction. Enforced EDA aggregate formation in water allows new activation modes for organic photochemical synthesis.
Reichle, Alexander; Koch, Magdalena; Sterzel, Hannes; Großkopf, Lea-Joy; Floss, Johannes; Rehbein, Julia; Reiser, Oliver: Copper(I) Photocatalyzed Bromonitroalkylation of Olefins: Evidence for Highly Efficient Inner-Sphere Pathways, Angew. Chem. Int. Ed. 62, 2023, e202219086.
We report the visible light-mediated coppercatalyzed vicinal difunctionalization of olefins utilizing bromonitroalkanes as ATRA reagents. This protocol is characterized by high yields and fast reaction times under environmentally benign reaction conditions with exceptional scope, allowing the rapid functionalization of both activated and unactivated olefins. Moreover, late-stage functionnalization of biologically active molecules and upscaling to gram quantities is demonstrated, which offers manifold possibilities for further transformations, e.g. access to nitro- and aminocyclopropanes. Besides the synthetic utility of the title transformation, this study undergirds the exclusive role of copper in photoredox catalysis showing its ability to stabilize and interact with radical intermediates in its coordination sphere. EPR studies suggest that such interactions can even outperform a highly favorable cyclization of transient to persistent radicals contrasting iridium-based photocatalysts.
Kutta, Roger J.; Großkopf, Johannes; van Staalduinen, Nils; Seitz, Antonia; Pracht, Philipp; Breitenlechner, Stefan; Bannwarth, Christoph; Nuernberger, Patrick; Bach, Thorsten: Multifaceted View on the Mechanism of a Photochemical Deracemization Reaction, J. Am. Chem. Soc. 145, 2023, 2354-2363.
Upon irradiation in the presence of a chiral benzophenone catalyst (5 mol %), a racemic mixture of a given chiral imidazolidine-2,4-dione (hydantoin) can be converted almost quantitatively into the same compound with high enantiomeric excess (80–99% ee). The mechanism of this photochemical deracemization reaction was elucidated by a suite of mechanistic experiments. It was corroborated by nuclear magnetic resonance titration that the catalyst binds the two enantiomers by two-point hydrogen bonding. In one of the diastereomeric complexes, the hydrogen atom at the stereogenic carbon atom is ideally positioned for hydrogen atom transfer (HAT) to the photoexcited benzophenone. Detection of the protonated ketyl radical by transient absorption revealed hydrogen abstraction to occur from only one but not from the other hydantoin enantiomer. Quantum chemical calculations allowed us to visualize the HAT within this complex and, more importantly, showed that the back HAT does not occur to the carbon atom of the hydantoin radical but to its oxygen atom. The achiral enol formed in this process could be directly monitored by its characteristic transient absorption signal at λ ≅ 330 nm. Subsequent tautomerization leads to both hydantoin enantiomers, but only one of them returns to the catalytic cycle, thus leading to an enrichment of the other enantiomer. The data are fully consistent with deuterium labeling experiments and deliver a detailed picture of a synthetically useful photochemical deracemization reaction.
Birnthaler, Dominik; Narobe, Rok; Lopez-Berguno, Eliseo; Haag, Christoph; König, Burkhard: Synthetic Application of Bismuth LMCT Photocatalysis in Radical Coupling Reactions, ACS Catal. 13, 2023, 1125-1132.
Ligand-to-metal charge transfer (LMCT) photocatalysis allows the activation and synthetic utilization of halides and other heteroatoms in metal complexes. Many metals are known to undergo LMCT but so far remain underutilized in the field of catalysis. A screening assay identifying LMCT activity helped us to expand this catalysis concept to the application of bismuth LMCT in organic radical coupling reactions. We demonstrate its application for the generation of two different radicals (chlorine and carboxyl) in net-oxidative as well as redox-neutral photochemical reactions. Detailed investigation of the model Giese-type coupling revealed BiCl4– and BiCl52– as catalytically active bismuth species under 385 nm irradiation. Combined cyclic voltammetry and UV–vis studies gave insight into the reactivity of the highly reactive bismuth(II) catalyst fragment.
Petek, Nejc; Brodnik, Helena; Reiser, Oliver; Štefane, Bogdan: Copper- and Photoredox-Catalyzed Cascade to Trifluoromethylated Divinyl Sulfones, J. Org. Chem. 88, 2023, 6538-6547.
A Cu(I)-photoredox-catalyzed trifluoromethylchlorosulfonylation reaction of terminal alkynes under visible light conditions was developed, giving rise to trifluoromethyl-substituted vinylsulfonyl chlorides, which can subsequently be coupled to a second alkyne under photocatalytic conditions. The transformation proceeds with high regio- and stereoselectivity and can be applied to aliphatic and aromatic alkynes with various functional groups. Trifluoromethyl-substituted divinyl sulfones prepared by this protocol can be readily used as synthetically valuable intermediates as demonstrated with various postmodification examples.
More Publications
Tian, Xianhai; Liu, Yuliang; Yakubov, Shahboz; Schütte, Jonathan; Chiba, Shunsuke; Barham, Joshua P.: Photo- and electro-chemical strategies for the activations of strong chemical bonds, Chem. Soc. Rev.b53, 2024, 263.
The employment of light and/or electricity – alternatively to conventional thermal energy – unlocks new reactivity paradigms as tools for chemical substrate activations. This leads to the development of new synthetic reactions and a vast expansion of chemical spaces. This review summarizes recent developments in photo- and/or electrochemical activation strategies for the functionalization of strong bonds...
Großkopf, Johannes; Bach, Thorsten: Catalytic Photochemical Deracemization via Short‐Lived Intermediates. Angew. Chem. Int. Ed. 62, 2023, e202308241.
Photochemical deracemization offers a unique opportunity to directly obtain enantiopure compounds from their racemates. Short-lived intermediates play a key role in the enantioselectivity-determining step. The review covers comprehensively the research performed in the area and discusses current developments.
Lepori, Mattia; Stockerl; Schmid, Simon; Barham, Joshua P.: Photoredox catalysis harvesting multiple photon or electrochemical energies, Beilstein J. Org. Chem. 19, 2023, 1055-1145.
Photoredox catalysis (PRC) is a cutting-edge frontier for single electron-transfer (SET) reactions, enabling the generation of reactive intermediates for both oxidative and reductive processes via photon activation of a catalyst. Although this represents a significant step towards chemoselective and, more generally, sustainable chemistry, its efficacy is limited by the energy of visible light photons. Nowadays, excellent alternative conditions are available to overcome these limitations, harvesting two different but correlated concepts: the use of multi-photon processes such as consecutive photoinduced electron transfer (conPET) and the combination of photo- and electrochemistry in synthetic photoelectrochemistry (PEC). Herein, we review the most recent contributions to these fields in both oxidative and reductive activations of organic functional groups. New opportunities for organic chemists are captured, such as selective reactions employing super-oxidants and super-reductants to engage unactivated chemical feedstocks, and scalability up to gram scales in continuous flow. This review provides comparisons between the two techniques (multi-photon photoredox catalysis and PEC) to help the reader to fully understand their similarities, differences and potential applications and to therefore choose which method is the most appropriate for a given reaction, scale and purpose of a project.
Lemke, Yannick; Ochsenfeld, Christian: Highly accurate σ- and τ-functionals for beyond-RPA methods with approximate exchange kernels, J. Chem. Phys. 159, 2023, 194104.
σ-Functionals are promising new developments for the Kohn–Sham correlation energy based upon the direct Random Phase Approximation (dRPA) within the adiabatic connection formalism, providing impressive improvements over dRPA for a broad range of benchmarks. However, σ-functionals exhibit a high amount of self-interaction inherited from the approximations made within dRPA. Inclusion of an exchange kernel in deriving the coupling-strength-dependent density–density response function leads to so-called τ-functionals, which – apart from a fourth-order Taylor series expansion – have only been realized in an approximate fashion so far to the best of our knowledge, most notably in the form of scaled σ-functionals. In this work, we derive, optimize, and benchmark three types of σ- and τ-functionals including approximate exchange effects in the form of an antisymmetrized Hartree kernel. These functionals, based on a second-order screened exchange type contribution in the adiabatic connection formalism, the electron–hole time-dependent Hartree–Fock kernel (eh-TDHF) otherwise known as RPA with exchange (RPAx), and an approximation thereof known as approximate exchange kernel (AXK), are optimized on the ASCDB database using two new parametrizations named A1 and A2. In addition, we report a first full evaluation of σ- and τ-functionals on the GMTKN55 database, revealing our exchange-including functionals to considerably outperform existing σ-functionals while being highly competitive with some of the best double-hybrid functionals of the original GMTKN55 publication. In particular, the σ-functionals based on AXK and τ-functionals based on RPAx with PBE0 reference stand out as highly accurate approaches for a wide variety of chemically relevant problems.
Großkopf, Johannes; Plaza, Manuel; Kutta, Roger Jan; Nuernberger, Patrick; Bach, Thorsten: Creating a Defined Chirality in Amino Acids and Cyclic Dipeptides by Photochemical Deracemization. Angew. Chem. Int. Ed. 62, 2023, e202313606.
2,5-Diketopiperazines are cyclic dipeptides displaying a wide range of applications. Their enantioselective preparation has now been found possible from the respective racemates by a photochemical deracemization (53 examples, 74 % to quantitative yield, 71–99 % ee). A chiral benzophenone catalyst in concert with irradiation at λ = 366 nm enables to establish the configuration at the stereogenic carbon atom C6 at will. If other stereogenic centers are present in the diketopiperazines they remain unaffected and a stereochemical editing is possible at a single position. Consecutive reactions, including the conversion into N-aryl or N-alkyl amino acids or the reduction to piperazines, occur without compromising the newly created stereogenic center. Transient absorption spectroscopy revealed that the benzophenone catalyst processes one enantiomer of the 2,5-diketopiperazines preferentially and enables a reversible hydrogen atom transfer that is responsible for the deracemization process. The remarkably long lifetime of the protonated ketyl radical implies a yet unprecedented mode of action.
2022
Publications
Artmann, Kevin; Pollok, Corina H.; Merten, Christian; Nuernberger, Patrick: Wavelength-dependent photochemistry of a salicylimine derivative studied with cryogenic and ultrafast spectroscopy approaches, Phys. Chem. Chem. Phys. 24, 2022, 30017-30026.
Salicylimines are versatile compounds in which an excited-state intramolecular proton transfer and torsional motions may set in upon photoexcitation. Here, we study N-(α-phenylethyl)salicylimine (PESA) to elucidate how the photochemical reaction pathways depend on the excitation wavelength and to what extent the relative photoproduct distribution can be steered towards a desired species. DFT structure and potential energy calculations disclose that the most stable ground-state conformer is an enol species and that the photodynamics may proceed differently depending on the excited state that is reached. With matrix isolation infrared spectroscopy, the predominance of the enol conformer of PESA is confirmed. Illumination of the cryogenic sample with different wavelengths shifts the ratio of enol and keto products, and by sequential irradiation a selective re- and depopulation is possible. Femtosecond transient absorption spectroscopy further reveals that also at room temperature, the outcome of the photoreaction depends on excitation wavelength, and in combination with the calculations, it can be rationalized that the decisive step occurs within the first hundred femtoseconds. Since the ultrafast dynamics mostly match those of similar salicylimines, our findings might also apply to those systems and provide additional insight into their reported sensitivity on excitation energy.
Rigotti, Thomas; Bach, Thorsten: Bicyclo[2.1.1]hexanes by Visible Light-Driven Intramolecular Crossed [2 + 2] Photocycloadditions, Org. Lett. 24, 2022, 8821-8825.
Bicyclo[2.1.1]hexanes have become increasingly popular building blocks in medicinal chemistry as bridged scaffolds that provide unexplored chemical space. We herein report a visible light-driven approach to these compounds that relies on an intramolecular crossed [2 + 2] photocycloaddition of styrene derivatives enabled by triplet energy transfer. Bicyclo[2.1.1]hexanes were obtained in good to high yields (19 examples, 61%-quantitative yield) and allowed for further functionalizations by consecutive reactions, thereby opening different pathways to decorate the aliphatic core structure.
Yakubov, Shahboz; Stockerl, Willibald J.; Tian, Xianhai; Shahin, Ahmed; Mandigma, Mark John P.; Gschwind, Ruth M.; Barham, Joshua P.: Benzoates as photosensitization catalysts and auxiliaries in efficient, practical, light-powered direct C(sp3)—H fluorinations, Chem. Sci. 13, 2022, 14041-14051.
Of the methods for direct fluorination of unactivated C(sp3)–H bonds, photosensitization of SelectFluor is a promising approach. Although many substrates can be activated with photosensitizing catalysts, issues remain that hamper fluorination of complex molecules. Alcohol- or amine-containing functional groups are not tolerated, fluorination regioselectivity follows factors endogenous to the substrate and cannot be influenced by the catalyst, and reactions are highly air-sensitive. We report that benzoyl groups serve as highly efficient photosensitizers which, in combination with SelectFluor, enable visible light-powered direct fluorination of unactivated C(sp3)–H bonds. Compared to previous photosensitizer architectures, the benzoyls have versatility to function both (i) as a photosensitizing catalyst for simple substrate fluorinations and (ii) as photosensitizing auxiliaries for complex molecule fluorinations that are easily installed and removed without compromising yield. Our auxiliary approach (i) substantially decreases the reaction's induction period, (ii) enables C(sp3)–H fluorination of many substrates that fail under catalytic conditions, (iii) increases kinetic reproducibility, and (iv) promotes reactions to higher yields, in shorter times, on multigram scales, and even under air. Observations and mechanistic studies suggest an intimate ‘assembly’ of auxiliary and SelectFluor prior/after photoexcitation. The auxiliary allows other EnT photochemistry under air. Examples show how auxiliary placement proximally directs regioselectivity, where previous methods are substrate-directed.
Jurberg, Igor D.; Nome, Rene A.; Crespi, Stefano; Atvars, Teresa D. Z.; König, Burkhard: Visible Light-Enhanced C—H Amination of Cyclic Ethers with Iminoiodinanes, Adv.Synth. Catal. 364, 2022, 4061-4068.
A two-step protocol allowing the C−H amination of cyclic ethers with iminoiodinanes, followed by the reduction of the resulting intermediate has been developed for the preparation of amino alcohols. The initial C−H functionalization is accelerated by visible light, improving the reactivity compared to the thermal process performed in the dark. The effect of different substituents on the photochemical reactivity of iminoiodinanes has been studied both experimentally and computationally. Photophysical measurements and DFT calculations were performed to better understand the observed reactivities and corroborate the proposed mechanistic proposal.
Wang, Hua; Wang, Shun; George, Vincent; Llorente, Galder; König, Burkhard: Photo-Induced Homologation of Carbonyl Compounds for Iterative Syntheses, Angew. Chem. Int. Ed. 61, 2022, e202211578.
A photo-induced Büchner-Curtius-Schlotterbeck type reaction for carbonyl homologation is described. The protocol allows the use of carbonyl compounds as safe and readily available diazo precursors through direct photoexcitation of corresponding N-tosylhydrazone anions. Functionalized aliphatic aldehydes and ketones are prepared in a practical and iterative manner.
Schwinger, Daniel P.; Peschel, Martin T.; Rigotti, Thomas; Kabaciński, Piotr; Knoll, Thomas; Thyrhaug, Erling; Cerullo, Giulio; Hauer, Jürgen; de Vivie-Riedle, Regina; Bach, Thorsten: Photoinduced B–Cl Bond Fission in Aldehyde-BCl3 Complexes as a Mechanistic Scenario for C–H Bond Activation, J. Am. Chem. Soc. 144, 2022, 18927-18937.
In concert with carbonyl compounds, Lewis acids have been identified as a versatile class of photocatalysts. Thus far, research has focused on activation of the substrate, either by changing its photophysical properties or by modifying its photochemistry. In this work, we expand the established mode of action by demonstrating that UV photoexcitation of a Lewis acid–base complex can lead to homolytic cleavage of a covalent bond in the Lewis acid. In a study on the complex of benzaldehyde and the Lewis acid BCl3, we found evidence for homolytic B–Cl bond cleavage leading to formation of a borylated ketyl radical and a free chlorine atom only hundreds of femtoseconds after excitation. Both time-dependent density functional theory and transient absorption experiments identify a benzaldehyde-BCl2 cation as the dominant species formed on the nanosecond time scale. The experimentally validated B–Cl bond homolysis was synthetically exploited for a BCl3-mediated hydroalkylation reaction of aromatic aldehydes (19 examples, 42–76% yield). It was found that hydrocarbons undergo addition to the C═O double bond via a radical pathway. The photogenerated chlorine radical abstracts a hydrogen atom from the alkane, and the resulting carbon-centered radical either recombines with the borylated ketyl radical or adds to the ground-state aldehyde-BCl3 complex, releasing a chlorine atom. The existence of a radical chain was corroborated by quantum yield measurements and by theory. The photolytic mechanism described here is based on electron transfer between a bound chlorine and an aromatic π-system on the substrate. Thereby, it avoids the use of redox-active transition metals.
Chinchole, Anurag; Henriquez, Marco A.; Cortes-Arriagada, Diego; Cabrera, Alan R.; Reiser, Oliver: Iron(III)-Light-Induced Homolysis: A Dual Photocatalytic Approach for the Hydroacylation of Alkenes Using Acyl Radicals via Direct HAT from Aldehydes, ACS Catal. 12, 2022, 13549-13554.
A dual photocatalytic protocol was developed to generate acyl radicals from readily available aldehydes via hydrogen atom transfer (HAT). Synergistic cooperation, being supported by DFT studies, between earth-abundant iron(III)chloride and 9,10-diphenylanthracene (DPA) to activate the aldehyde for a HAT step proved to be an efficient, economic, and green route for the hydroacylation of electron-deficient alkenes under UV-light irradiation with broad functional group compatibility. This methodology can be conveniently scaled up and applied to produce valuable materials from renewable feedstock chemicals.
Katta, Narenderreddy; Zhao, Quan-Qing; Mandal, Tirtha; Reiser, Oliver: Divergent and Synergistic Photocatalysis: Hydro- and Oxoalkylation of Vinyl Arenes for the Stereoselective Synthesis of Cyclopentanols via a Formal [4+1]-Annulation of 1,3-Dicarbonyls, ACS Catal. 12, 2022, 14398-14407.
The controllable divergent reactivity of 1,3-dicarbonyls is described, which enables the efficient hydro- and oxoalkylation of vinyl arenes. Both reaction pathways are initiated through the formation of polarity-reversed C-centered-radical intermediates at the active methylene center of 1,3-dicarbonyls via direct photocatalytic C–H bond transformations. The oxoalkylation of alkenes is achieved under aerobic conditions via a Cu(II)-photomediated rebound mechanism, while the corresponding hydroalkylation becomes possible under a nitrogen atmosphere by the combination of 4CzIPN and a Brønsted base. The breadth of these divergent protocols is demonstrated in the late-stage modification of drugs and natural products and by the transformation of the products to a variety of heterocycles such as pyridines, pyrroles, or furans. Moreover, the two catalytic modes can be combined synergistically for the stereoselective construction of cyclopentanol derivatives in a formal [4+1]-annulation process.
Park, Sooyoung; Dutta, Amit K.; Allacher, Carina; Abramov, Anton; Dullinger, Philipp; Kuzmanoska, Katerina; Fritsch, Daniela; Hitzfeld, Patrick; Horinek, Dominik; Rehbein, Julia; Nuernberger, Patrick; Gschwind, Ruth M.; Breder, Alexander: Hydrogen-Bond-Modulated Nucleofugality of SeIII Species to Enable Photoredox-Catalytic Semipinacol Manifolds, Angew. Chem. Int. Ed. 61, 2022, e202208611.
Chemical bond activations mediated by H-bond interactions involving highly electronegative elements such as nitrogen and oxygen are powerful tactics in modern catalysis research. On the contrary, kindred catalytic regimes in which heavier, less electronegative elements such as selenium engage in H-bond interactions to co-activate C−Se σ-bonds under oxidative conditions are elusive. Traditional strategies to enhance the nucleofugality of selenium residues predicate on the oxidative addition of electrophiles onto SeII-centers, which entails the elimination of the resulting SeIV moieties. Catalytic procedures in which SeIV nucleofuges are substituted rather than eliminated are very rare and, so far, not applicable to carbon-carbon bond formations. In this study, we introduce an unprecedented combination of O−H⋅⋅⋅Se H-bond interactions and single electron oxidation to catalytically generate SeIII nucleofuges that allow for the formation of new C−C σ-bonds by means of a type I semipinacol process in high yields and excellent selectivity.
Stegbauer, Simone; Jandl, Christian; Bach, Thorsten: Chiral Lewis acid catalysis in a visible light-triggered cycloaddition/rearrangement cascade, Chem. Sci. 13, 2022, 11856-11862.
Cascade (domino) reactions facilitate the formation of complex molecules from simple starting materials in a single operation. It was found that 1-naphthaldehyde derivatives can be converted to enantioenriched (82–96% ee) polycyclic benzoisochromenes via a cascade of ortho photocycloaddition and ensuing acid-catalysed rearrangement reactions. The cascade was initiated by irradiation with visible light (λ = 457 nm) and catalysed by a chiral AlBr3-activated 1,3,2-oxazaborolidine (14 examples, 65–93% yield). The absolute configuration of the products was elucidated by single crystal X-ray crystallography. Mechanistic experiments suggest that the ortho photocycloaddition occurs on the triplet hypersurface and that the chiral catalyst induces in this step the observed enantioselectivity.
Wang, Huaiju; Tian, Ya-Ming; König, Burkhard: Energy- and atom-efficient chemical synthesis with endergonic photocatalysis, Nat. Rev. Chem. 6, 2022, 745-755.
Endergonic photocatalysis is the use of light to perform catalytic reactions that are thermodynamically unfavourable. While photocatalysis has become a powerful tool in facilitating chemical transformations, the light-energy efficiency of these processes has not gathered much attention. Exergonic photocatalysis does not take full advantage of the light energy input, producing low-energy products and heat, whereas endergonic photocatalysis incorporates a portion of the photon energy into the reaction, yielding products that are higher in free energy than the reactants. Such processes can enable catalytic, atom-economic syntheses of reactive compounds from bench-stable materials. With respect to environmental friendliness and carbon neutrality, endergonic photocatalysis is also of interest to large-scale industrial manufacturing, where better energy efficiency, less waste and value addition are highly sought. We therefore assess here the thermochemistry of several classes of reported photocatalytic transformations to showcase current advances in endergonic photocatalysis and point to their industrial potential.
Ritu; Das, Saikat; Tian, Ya-Ming; Karl, Tobias; Jain, Nidhi; König, Burkhard: Photocatalyzed Dehydrogenation of Aliphatic N‑Heterocycles Releasing Dihydrogen, ACS Catal. 12, 2022, 10326-10332.
We report the iridium–nickel dual photocatalytic acceptorless and redox neutral dehydrogenation of aliphatic heterocycles yielding cyclic alkenes without overoxidation at room temperature. Excitation of the iridium photocatalyst initiates the formation of a nickel hydride intermediate that yields alkenes and H2 via β-hydride elimination. The reaction proceeds regioselectively and the scope was demonstrated by the synthesis of 12 biologically relevant molecules and drugs. In addition, commercially and easily available N-heterocyclic alkane starting materials were converted into functionalized alkenes of high synthetic and commercial value using the method.
Lemke, Yannick; Graf, Daniel; Kussmann, Jörg; Ochsenfeld, Christian: An assessment of orbital energy corrections for the direct random phase approximation and explicit σ-functionals, Mol. Phys. 121, 2022, e2098862.
The σ-functionals developed in the Görling group [J. Chem. Phys. 154, 014104 (2021); ibid. 155, 134111 (2021)] facilitate impressive improvements over the direct random phase approximation (dRPA) and provide chemical accuracy for a broad spectrum of benchmarks concerning reaction energies and barrier heights, but struggle considerably with problems related to self-interaction. We herein assess two possible corrections to the orbital energies in the construction of the noninteracting response function for the dRPA and σ-functionals: (i) The scaling corrections of Yang and co-workers, which have been successfully applied within DFT, and (ii) the admixture of exact exchange in a post-SCF fashion similar to some double-hybrid functionals. An analysis of static shifts to the virtual orbital energies reveals the choice of corrections to be a difficult balancing act, as the effect of the corrections vastly differs between benchmark sets. Scaling corrections are found to provide substantial improvements to self-interaction problems, but seem adversarial for thermochemistry in combination with RPA. The post-SCF inclusion of exact exchange in combination with a semicanonical projection is shown to retain the accuracy of σ-functionals over a wide range of exact exchange admixtures and reduces the computational cost of the SCF calculation compared to hybrid functionals, but provides smaller improvements to self-interaction problems than scaling corrections for the most challenging cases.
Kristinaityte, Kristina; Mames, Adam; Pietrzak, Mariusz; Westermair, Franz F.; Silva,Wagner; Gschwind, Ruth M.; Ratajczyk, Tomasz; Urbańczyk, Mateusz: Deeper Insight into Photopolymerization: The Synergy of Time-Resolved Nonuniform Sampling and Diffusion NMR, J. Am. Chem. Soc. 144, 2022, 13938-13945.
The comprehensive real-time in situ monitoring of chemical processes is a crucial requirement for the in-depth understanding of these processes. This monitoring facilitates an efficient design of chemicals and materials with the precise properties that are desired. This work presents the simultaneous utilization and synergy of two novel time-resolved NMR methods, i.e., time-resolved diffusion NMR and time-resolved nonuniform sampling. The first method allows the average diffusion coefficient of the products to be followed, while the second method enables the particular products to be monitored. Additionally, the average mass of the system is calculated with excellent resolution using both techniques. Employing both methods at the same time and comparing their results leads to the unequivocal validation of the assignment in the second method. Importantly, such validation is possible only via the simultaneous combination of both approaches. While the presented methodology was utilized for photopolymerization, it can also be employed for any other polymerization process, complexation, or, in general, chemical reactions in which the evolution of mass in time is of importance.
Narobe, Rok; Murugesan, Kathiravan; Haag, Christoph; Schirmer, Tobias Emanuel; König, Burkhard: C(sp3)-H Ritter amination by excitation of in situ generated iodine(III)-BF3 complexes, Chem. Commun. 58, 2022, 8778-8781.
Visible light excitation of a hypervalent iodine (III)-BF3 complex enables the formation of carbocations from C(sp3)–H bonds. The complex is generated catalytically from a iodoarene, a carboxylate ligand, an oxidizing agent (Selectfluor) and the Lewis acid BF3. This modular catalytic system allowed us to conveniently screen performance of different in situ formed complexes. Their excitation leads to hydrogen abstraction from the C(sp3)–H precursor which is followed by a rapid oxidation of the formed carbon radical to give carbocationic intermediates. These were reacted in a Ritter-type amination to give access to synthetically valuable amine derivatives. Moreover, the method is practically simple and based on readily available chemicals.
Jeremias, Noah; Peschel, Martin T.; Jaschke, Constantin; de Vivie-Riedle, Regina; Bach, Thorsten: Photochemical Ring Contraction of 5,5-Dialkylcyclopent-2-enones and in situ Trapping by Primary Amines, J. Org. Chem. 88, 2023, 6294-6303.
If substituted in the 5,5-position, cyclopent-2-enones undergo a smooth photochemical rearrangement to ketenes. A concomitant cyclopropane formation occurs due to a 1,3-shift of the C5 carbon atom from the carbonyl carbon atom (C1) to carbon atom C3. In this study, the cyclopropyl-substituted ketene intermediates were trapped in situ by primary amines providing an efficient entry into 2,2-disubstituted cyclopropaneacetic amides (24 examples, 49–95% yield). A remarkable feature of the reaction is the fact that the photochemical rearrangement can occur from either the first excited singlet (S1) or the respective triplet state (T1). In line with experimental results (triplet quenching, sensitization), XMS-CASPT2 calculations support the existence of efficient reaction pathways to the intermediate ketene both on the singlet and on the triplet hypersurface.
Lemke, Yannick; Kussmann, Jörg; Ochsenfeld, Christian: Efficient Integral-Direct Methods for Self-Consistent Reduced Density Matrix Functional Theory Calculations on Central and Graphics Processing Units, J. Chem. Theory Comput. 18, 2022, 4229-4244.
Reduced density matrix functional theory (RDMFT), a promising direction in the problem of describing strongly correlated systems, is currently limited by its explicit dependence on natural orbitals and, by extension, the costly need to construct two-electron integrals in the molecular orbital basis. While a resolution-of-the-identity approach can reduce the asymptotic scaling behavior from O(N5) to O(N4), this is still prohibitively expensive for large systems, especially considering the usually slow convergence and the resulting high number of orbital optimization steps. In this work, efficient integral-direct methods are derived and benchmarked for various approximate functionals. Furthermore, we show how these integral-direct methods can be integrated into existing self-consistent energy minimization frameworks in an efficient manner, including improved methods for calculating diagonal elements of the two-electron integral tensor as required in self-interaction-corrected functionals and second derivatives of the energy with respect to the occupation numbers. In combination, these methods provide speedups of up to several orders of magnitude while greatly diminishing memory requirements, enabling the application of RDMFT to large molecular systems of general chemical interest, such as the challenging triplet–quintet gap of the iron(II) porphyrin complex.
Tian, Xianhai; Kaur, Jaspreet; Yakubov, Shahboz; Barham, Joshua P.: α-Amino Radical Halogen Atom Transfer Agents for Metallaphotoredox-Catalyzed Cross-Electrophile Couplings of Distinct Organic Halides, ChemSusChem 15, 2022, e202200906.
Cross coupling: A practical dual Ni/photoredox catalyzed cross-electrophile coupling of organic halides by employing readily available α-amino radicals as halogen atom transfer agents is reported. Both coupling partners can be flexibly chosen as limiting reactant to forge 6 different types of C−C bond for a broad scope of applications (>70 examples) including late-stage functionalizations of pharmaceutical compounds. The reaction is scalable in batch and continuous flow.
Schwinger, Daniel P.; Peschel, Martin T.; Jaschke, Constantin; Jandl, Christian; de Vivie-Riedle, Regina; Bach, Thorsten: Diels–Alder Reaction of Photochemically Generated (E)-Cyclohept-2-enones: Diene Scope, Reaction Pathway, and Synthetic Application. J. Org. Chem. 87, 2022, 4838-4851.
Cyclohept-2-enone undergoes isomerization upon irradiation with UV light to its (E)-isomer, which exhibits significant ring strain. XMS-CASPT2 calculations revealed that this process can proceed on both the singlet and triplet hypersurface. (E)-Cyclohept-2-enone can undergo a Diels-Alder reaction with different dienes at room temperature, yielding trans-fused six-membered rings (up to 98% yield). In case of cyclic dienes, the exo-product was the major isomer in most cases. The Diels-Alder reaction with furan was studied in greater detail. Experimental and theoretical outcome via DLPNO-CCSD(T) calculations matched and the relative configuration of the diastereomers was corroborated via X-ray analysis. Other cyclic enones were also successfully employed. In the end, the method was applied to the total synthesis of racemic trans-α-himachalene.
Foja, Richard; Walter, Alexandra; Jandl, Christian; Thyrhaug, Erling; Hauer, Jürgen; Storch, Golo: Reduced Molecular Flavins as Single-Electron Reductants after Photoexcitation. J. Am. Chem. Soc. 144 (11), 2022, 4721-4726.
Flavoenzymes are involved in a multitude of chemical reactions and the cofactor can act as the catalytically active species in different oxidation states. While (photo)oxidation reactions with molecular flavins are established, no report of reduced, molecular flavins in the conversion of organic substrates are available. We report a catalytic method using reduced, molecular flavins as photoreductants and γ-terpinene as sacrificial reductant. A design for air-stable, reduced flavins using a conformational bias strategy is presented and circumvents rapid reduction of O2 from air. Using our catalytic strategy, we were able to perform a 5-exo-trig cyclization of barbituric acid derivatives, effectively replacing SmI2 as a reductant for this reaction. Such flavin catalyzed reductions are anticipated to be beneficial for other transformations and other reactivities are highlighted in this publication.
Kumar, Manoj; Verma, Shalini, Verma; Mishra, Vivek; Reiser, Oliver; Verma, Akhilesh K.: Visible-Light-Accelerated Copper-Catalyzed [3 + 2] Cycloaddition of N-Tosylcyclopropylamines with Alkynes/Alkenes, J. Org. Chem. 87, 2022, 6263-6272.
Copper-catalyzed [3+2] cycloadditions of N-tosylcyclopropylamine with alkynes and alkenes have been accomplished under visible light irradiation. The developed approach is compatible with a range of functionalities and allows the synthesis of diversified aminated cyclopentene and cyclopentane derivatives being relevant for drug synthesis. The protocol is operationally simple and economically affordable as it does not require any ligand, base, or additives. As the key step, the one-electron oxidation of the N-tosyl moiety by visible light-induced homolysis of a transient Cu(II)-tosylamide complex is proposed, providing a facile entry for N-centered radicals.
Reichle, Alexander; Sterzel, Hannes; Kreitmeier, Peter; Fayad, Remi; Castellano, Felix N.; Rehbein, Julia; Reiser, Oliver: Copper(II)-photocatalyzed decarboxylative oxygenation of carboxylic acids, Chem. Commun. 58, 2022, 4456-4459.
Showcasing the concept of light-induced homolysis for the generation of radicals, the CuII-photocatalyzed decarboxylative oxygenation of carboxylic acids with molecular oxygen as the terminal oxidant is described. Two CuII-carboxylate complexes with different coordination geometries were synthesized and characterized by X-ray analysis, correlating their structure with their ability to initiate light-induced decarboxylations.
Zhao, QuanQing; Rehbein, Julia; Reiser, Oliver: Thermoneutral synthesis of spiro-1,4- cyclohexadienes by visible-light-driven dearomatization of benzylmalonates. Green Chem. 24, 2022, 2772-2776.
The inherent aromaticity of aromatic compounds, especially unactivated aromatic compounds, render them challengeable to undergo dearomatization process. We report here the dearomatizative coupling of benzylmalonates and alkynes to spiroanellated 1,4-cyclohexadienes, which proceeds via activation with visible light with perfect atom economy in high yields (up to 98%). In this protocol, no preactivation of the substrates or employment of stoichiometric high energy reagents, being the traditional approach to drive thermoneutral transformations, is necessary. Calculations suggest that the overall process is approximately thermoneutral, showcasing the special opportunities of light-driven processes to develop sustainable transformations that defy thermodynamic requirements.
Rigotti, Thomas; Schwinger, Daniel P.; Graßl, Raphaela; Jandl, Christian; Bach, Thorsten: Enantioselective Crossed Intramolecular [2+2] Photocycloaddition Reactions Mediated by a Chiral Chelating Lewis Acid. Chem. Sci. 13, 2022, 2378-2384.
Despite the fact that intramolecular crossed [2+2] photocycloaddition reactions lead to intriguing, otherwise inaccessible bridged skeletons, there has so far not been any enantioselective variants thereof. This study concerned the enantioselective crossed [2+2]-photocycloaddition of 2-(alkenyl¬oxy)cyclohex-2-enones to bridged cyclobutanes. It was found that the reaction could be performed with high enantioselectivity (80-94% ee) when employing a chiral-at-rhodium Lewis acid catalyst (2 mol%) under visible light irradiation. The oxygen atom contained in the tether allowed a bidentate binding of the substrate by a chiral Lewis acid which enabled a stereocontrolled intramolecular [2+2] photocycloaddition to tricyclic bridged products that contain up to four stereogenic centres and a tertiary oxygen substituted carbon atom in α-position to the carbonyl group. The synthetic utility of the method was demonstrated by different consecutive reactions that allowed the manipulation of the crossed cyclobutane scaffold preserving the enantiopurity of the compounds.
Till, Marion; Streitferdt, Verena; Scott, Daniel J.; Mende, Michael; Gschwind, Ruth M.; Wolf, Robert: Photochemical transformation of chlorobenzenes and white phosphorus into arylphospines and phosphounium salts. Chem. Commun. 58, 2022, 1100-1103.
Chlorobenzenes are important starting materials for the preparation of commercially valuable triarylphosphines and tetraarylphosphonium salts, but their use for the direct arylation of elemental phosphorus has been elusive. Here we describe a simple photochemical route toward such products. UV-LED irradiation (365 nm) of chlorobenzenes, white phosphorus (P4) and the organic superphotoreductant tetrakis(dimethylamino)ethylene (TDAE) affords the desired arylphosphorus compounds in a single reaction step.
More Publications
Gilbert, Audrey; Bach, Thorsten: The Awakening of a Sleeping Beauty: The ortho Photocycloaddition in the Total Synthesis of Protoilludane- and Prezizaene-Type - Sesquiterpenes. Synlett, 34, 2023, 1343-1355.
Photochemical cascade (domino) reactions provide a unique opportunity for the construction of complex molecular architectures. Specifically, an intramolecular ortho photocycloaddition of 7-(alkenyloxy)-indanones triggers a sequence of consecutive reactions that can lead in a single operation to the complete skeleton of two important classes of sesquiterpenes: protoilludanes and prezizaenes. In the former case, two transformations follow the initial photocycloaddition, while in the latter case, there are three consecutive transformations, two of which are initiated by a photon. Remarkably, the reaction cascades proceed with exquisite diastereoselectivity, generating three (protoilludane) or five (prezizaene) stereogenic centers with defined relative configurations.
Sempere, Yeshua; Morgenstern, Martin; Bach, Thorsten; Plaza, Manuel: Reactivity and Selectivity Modulation Within a Molecular Assembly: Recent Examples from Photochemistry. Photochem. Photobiol. Sci. 21, 2022, 719-737.
In recent years, photochemical reactions have emerged as powerful transformations which significantly expand the repertoire of organic synthesis. Nevertheless, a certain lack of selectivity can sometimes limit their application and scope. In this context, nowadays a major research effort continues to focus on an improved control over stereo- and chemoselectivity that can be achieved in molecular assemblies between photosubstrates and an appropriate host molecule. In this tutorial review, some recent and representative examples of photochemical transformations were collected whose unique outcome is dictated by the formation of a molecular assembly driven by non-covalent weak interactions.
Review
Engl, Sebastian; Reiser, Oliver: Copper-photocatalyzed ATRA reactions: concepts, applications, and opportunities, Chem. Soc. Rev. 51, 2022, 5287-5299.
Atom transfer radical addition (ATRA) reactions are linchpin transformations in synthetic chemistry enabling the atom-economic difunctionalization of alkenes. Thereby a rich chemical space can be accessed through smart combinations of simple starting materials. Originally, these reactions required toxic and hazardous radical initiators or harsh thermal activation and thus, the recent resurgence and dramatic evolution of photocatalysis appeared as an attractive complement to catalyze such transformations in a mild and energy-efficient manner. Initially, this technique relied primarily on complexes of precious metals, such as ruthenium or iridium, to absorb the visible light. Hence, copper photocatalysis rapidly developed into a powerful alternative, not just from an economic point of view. Originally considered to be disadvantageous as a pathway for deactivation by quenching their excited state, the dynamic nature of Cu-complexes enables them to undergo facile ligand exchange and thus opens up special opportunities for transformations utilizing their inner-coordination sphere. Moreover, the ability of Cu(II), representing a persistent radical, to capture incipient radicals offers the possibility to access heretofore elusive two-component, but also three-component, ATRA reactions, not feasible with ruthenium or iridium catalysts. In this regard, the idea of using Cu(I)-substrate assemblies as active photocatalysts is an emerging field to achieve such 3-component coupling reactions even under enantioselective control, which is reflected by an increasing number of reports being covered in this review.
2021
Publications
Großkopf, Johannes; Plaza, Manuel; Seitz, Antonia; Breitenlechner, Stefan; Storch, Golo, Bach, Thorsten: Photochemical Deracemization at sp3-hybridized Carbon Centers via a Reversible Hydrogen Atom Transfer. J. Am Chem. Soc. 143 (50), 2021, 21241-21245.
The selective synthesis of enantiopure compounds has received great attention and became a flourishing research area within recent decades. Despite a tremendous progress in this field, it remains challenging to convert a racemic mixture directly into one of its enantiomers. In this work a conceptually new method for a photochemical deracemization, apart from triplet sensitization or photoredox processes, was established which relies on a selective hydrogen atom transfer (HAT) to a chiral benzophenone photocatalyst. It enables the conversion of racemic hydantoins into a single enantiomer (ee’s of up to 99%) by reverting the configuration at a sp3-hybridized carbon center.
Keil, Erika; Malevich, Pavel; Hauer, Jürgen: Achromatic frequency doubling of supercontinuum pulses for transient absorption spectroscopy. Optics Express 29, 2021, 39042-39054.
In this article, a technique for obtaining tunable ultrashort pulses in the near UV and blue spectral range is described. The resulting pulses are broadband and tunable, have stable pulse energies and can be compressed down to 12 fs by conventional optics. The suitability of the pulses for spectroscopic applications is tested by employing them as a pump in a transient absorption experiment on β-carotene in solution.
Rothfelder, Robin; Streitferdt, Verena; Lennert, Ulrich; Cammarata, Jose; Scott, Daniel J.; Zeitler, Kirsten; Gschwind, Ruth M.; Wolf, Robert: Photocatalytic Arylation of P4 and PH3: Reaction Development Through Mechanistic Insight. Angew. Chem. Int. Ed. 60, 2021, 24650-24658.
Detailed 31P{1H} NMR spectroscopic investigations provide deeper insight into the complex, multi-step mechanisms involved in the recently reported photocatalytic arylation of white phosphorus (P4). Specifically, these studies have identified a number of previously unrecognized side products, which arise from an unexpected non-innocent behavior of the commonly employed terminal reductant Et3N. The different rate of formation of these products explains discrepancies in the performance of the two most effective catalysts, [Ir(dtbbpy)(ppy)2][PF6] (dtbbpy=4,4′-di-tert-butyl-2,2′-bipyridine) and 3DPAFIPN. Inspired by the observation of PH3 as a minor intermediate, we have developed the first catalytic procedure for the arylation of this key industrial compound. Similar to P4 arylation, this method affords valuable triarylphosphines or tetraarylphosphonium salts depending on the steric profile of the aryl substituents.
Krolo, Tomislav; Bhattacharyya, Aditya; Reiser, Oliver: Accessing HIV-1 Protease Inhibitors through Visible-Light-Mediated Sequential Photocatalytic Decarboxylative Radical Conjugate Addition–Elimination–Oxa-Michael Reactions. Org. Lett. 23, 2021, 6283-6287.
A photocatalytic decarboxylative radical conjugate addition–elimination–oxa-Michael reaction of hydroxyalkylated carboxylic acids with cyclopentenones is developed to construct diverse cyclopentanonyl-fused functionalized 5–7 membered cyclic ethers. The stereoselective synthetic strategy is amenable to substructural variation, establishing a direct total synthetic route to two diastereomers of C3-amino cyclopentyltetrahydrofuranyl-derived potent HIV-1 protease inhibitors with low nanomolar IC50 values.
