Nitrogen-to-functionalized carbon atom transmutation of pyridine.

The targeted and selective replacement of a single atom in an aromatic system represents a powerful strategy for the rapid interconversion of molecular scaffolds. Herein, we report a pyridine-to-benzene transformation via nitrogen-to-carbon skeletal editing. This approach proceeds via a sequence of pyridine ring-opening, imine hydrolysis, olefination, electrocyclization, and aromatization to achieve the desired transmutation. The most notable features of this transformation are the ability to directly install a wide variety of versatile functional groups in the benzene scaffolding, including ester, ketone, amide, nitrile, and phosphate ester fragments, as well as the inclusion of meta-substituted pyridines which have thus far been elusive for related strategies.

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis.

Organocatalysis has established itself as a third pillar of homogeneous catalysis, besides transition metal catalysis and biocatalysis, as its use for enantioselective reactions has gathered significant interest over the last decades. Concurrent to this development, machine learning (ML) has been increasingly applied in the chemical domain to efficiently uncover hidden patterns in data and accelerate scientific discovery. While the uptake of ML in organocatalysis has been comparably slow, the last two decades have showed an increased interest from the community. This review gives an overview of the work in the field of ML in organocatalysis. The review starts by giving a short primer on ML for experimental chemists, before discussing its application for predicting the selectivity of organocatalytic transformations. Subsequently, we review ML employed for privileged catalysts, before focusing on its application for catalyst and reaction design. Concluding, we give our view on current challenges and future directions for this field, drawing inspiration from the application of ML to other scientific domains.

Improving reproducibility through condition-based sensitivity assessments: application, advancement and prospect.

The fluctuating reproducibility of scientific reports presents a well-recognised issue, frequently stemming from insufficient standardisation, transparency and a lack of information in scientific publications. Consequently, the incorporation of newly developed synthetic methods into practical applications often occurs at a slow rate. In recent years, various efforts have been made to analyse the sensitivity of chemical methodologies and the variation in quantitative outcome observed across different laboratory environments. For today's chemists, determining the key factors that really matter for a reaction's outcome from all the different aspects of chemical methodology can be a challenging task. In response, we provide a detailed examination and customised recommendations surrounding the sensitivity screen, offering a comprehensive assessment of various strategies and exploring their diverse applications by research groups to improve the practicality of their methodologies.

Surface Tension Manipulation with Visible Light through Sensitized Disequilibration of Photoswitchable Amphiphiles.

Azoarene isomerization lies at the heart of numerous applications from catalysis or energy storage to photopharmacology. While efficient switching between their E and Z isomers predominantly relies on UV light, a recent study by Klajn and co-workers introduced visible light sensitization of E azoarenes and subsequent isomerization as a tool coined disequilibration by sensitization under confinement (DESC) to obtain high yields of the Z isomer. This host-guest approach is, however, still constrained to minimally substituted azoarenes with limited applicability in advanced molecular systems. Herein, we expand DESC for the assembly of surfactants at the air-water interface. Leveraging our expertise with photoswitchable amphiphiles, we induce substantial alterations of water's surface tension through reversible arylazopyrazole isomerization. After studying the binding of charged surfactants to the host, we find that the surface activity differences upon visible light irradiation for both isomers are comparable to those obtained by UV light excitation. The method is demonstrated on a large concentration range and can be activated using green or red light, depending on the sensitizer chosen. The straightforward implementation of photoswitch sensitization in a complex molecular network showcases how DESC enables the improvement of existing systems and the development of novel applications driven by visible light.

Alkyne-tagged imidazolium-based membrane cholesterol analogs for Raman imaging applications.

Cholesterol is an important lipid playing a crucial role in mediating essential cellular processes as well as maintaining the basic structural integrity of biological membranes. Given its vast biological importance, there is an unabated need for sophisticated strategies to investigate cholesterol-mediated biological processes. Raman-tagged sterol analogs offer the advantage of being visualizable without the need for a bulky dye that potentially affects natural membrane integration and cellular interactions as it is the case for many conventionally used fluorescent analogs. Herein, we report a series of alkyne-tagged imidazolium-based cholesterol analogs (CHIMs) with large Raman scattering cross-sections that readily integrate into HEK cells and primary monocyte-derived macrophages and allow (multiplexed) cellular Raman imaging. We envision Raman-tagged CHIM analogs to be a powerful platform for the investigation of cholesterol-mediated cellular processes complementary to other established methods, such as the use of fluorescent analogs.

Switchable and Chemoselective Arene Hydrogenation for Efficient Late Stage Applications.

The incorporation of three-dimensional structures into drug molecules has demonstrated significant improvements in clinical success. Late-stage saturation of drug molecules provides a direct pathway for this transformation. However, achieving selective and controllable reduction of aromatic rings remains challenging, particularly when multiple aromatic rings coexist. Herein, we present the switchable and chemoselective hydrogenation of benzene and pyridine rings. The utility of the protocol has been comprehensively investigated in diversified substrates with the assistance of a fragment-screening technique. This approach provides convenient access to a diverse array of cyclohexane and piperidine compounds, prevalent in various bioactive molecules and drugs. Furthermore, it discloses promising avenues for applications in the late-stage switchable saturation of drugs, facilitating an increase in the fraction of sp3-carbons which holds the potential to enhance the medicinal properties of drugs.

EnTdecker - A Machine Learning-Based Platform for Guiding Substrate Discovery in Energy Transfer Catalysis.

Due to the magnitude of chemical space, the discovery of novel substrates in energy transfer (EnT) catalysis remains a daunting task. Experimental and computational strategies to identify compounds that successfully undergo EnT-mediated reactions are limited by their time and cost efficiency. To accelerate the discovery process in EnT catalysis, we herein present the EnTdecker platform, which facilitates the large-scale virtual screening of potential substrates using machine-learning (ML) based predictions of their excited state properties. To achieve this, a data set is created containing more than 34,000 molecules aiming to cover a vast fraction of synthetically relevant compound space for EnT catalysis. Using this data predictive models are trained, and their aptitude for an in-lab application is demonstrated by rediscovering successful substrates from literature as well as experimental validation through luminescence-based screening. By reducing the computational effort needed to obtain excited state properties, the EnTdecker platform represents a tool to efficiently guide substrate selection and increase the experimental success rate for EnT catalysis. Moreover, through an easy-to-use web application, EnTdecker is made publicly accessible under entdecker.uni-muenster.de.

Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π + 2σ] Cycloaddition Reactions.

As the chemistry that surrounds the field of strained hydrocarbons, such as bicyclo[1.1.0]butane, continues to expand, it becomes increasingly advantageous to develop alternative reactivity modes that harness their unique properties to access new regions of chemical space. Herein, we report the use of photoredox catalysis to promote the single-electron oxidation of bicyclo[1.1.0]butanes. The synthetic utility of the resulting radical cations is highlighted by their ability to undergo highly regio- and diastereoselective [2π + 2σ] cycloaddition reactions. The most notable feature of this transformation is the breadth of alkene classes that can be employed, including nonactivated alkenes, which have so far been elusive for previous strategies. A rigorous mechanistic investigation, in conjunction with DFT computation, was undertaken in order to better understand the physical nature of bicyclo[1.1.0]butyl radical cations and thus provides a platform from which further studies into the synthetic applications of these intermediates can be built upon.

Standardizing Substrate Selection: A Strategy toward Unbiased Evaluation of Reaction Generality.

With over 10,000 new reaction protocols arising every year, only a handful of these procedures transition from academia to application. A major reason for this gap stems from the lack of comprehensive knowledge about a reaction's scope, i.e., to which substrates the protocol can or cannot be applied. Even though chemists invest substantial effort to assess the scope of new protocols, the resulting scope tables involve significant biases, reducing their expressiveness. Herein we report a standardized substrate selection strategy designed to mitigate these biases and evaluate the applicability, as well as the limits, of any chemical reaction. Unsupervised learning is utilized to map the chemical space of industrially relevant molecules. Subsequently, potential substrate candidates are projected onto this universal map, enabling the selection of a structurally diverse set of substrates with optimal relevance and coverage. By testing our methodology on different chemical reactions, we were able to demonstrate its effectiveness in finding general reactivity trends by using a few highly representative examples. The developed methodology empowers chemists to showcase the unbiased applicability of novel methodologies, facilitating their practical applications. We hope that this work will trigger interdisciplinary discussions about biases in synthetic chemistry, leading to improved data quality.

γ-Amino Alcohols via Energy Transfer Enabled Brook Rearrangement.

In the long-standing quest to synthesize fundamental building blocks with key functional group motifs, photochemistry in the recent past has comprehensively established its attractiveness. Amino alcohols are not only functionally diverse but are ubiquitous in the biologically active realm of compounds. We developed bench-stable bifunctional reagents that could then access the sparsely reported γ-amino alcohols directly from feedstock alkenes through energy transfer (EnT) photocatalysis. A designed 1,3-linkage across alkenes is made possible by the intervention of a radical Brook rearrangement that takes place downstream to the EnT-mediated homolysis of our reagent(s). A combination of experimental mechanistic investigations and detailed computational studies (DFT) indicates a radical chain propagated reaction pathway.

Late-Stage Saturation of Drug Molecules.

The available methods of chemical synthesis have arguably contributed to the prevalence of aromatic rings, such as benzene, toluene, xylene, or pyridine, in modern pharmaceuticals. Many such sp2-carbon-rich fragments are now easy to synthesize using high-quality cross-coupling reactions that click together an ever-expanding menu of commercially available building blocks, but the products are flat and lipophilic, decreasing their odds of becoming marketed drugs. Converting flat aromatic molecules into saturated analogues with a higher fraction of sp3 carbons could improve their medicinal properties and facilitate the invention of safe, efficacious, metabolically stable, and soluble medicines. In this study, we show that aromatic and heteroaromatic drugs can be readily saturated under exceptionally mild rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed-hydrogenation conditions, converting sp2 carbon atoms into sp3 carbon atoms and leading to saturated molecules with improved medicinal properties. These methods are productive in diverse pockets of chemical space, producing complex saturated pharmaceuticals bearing a variety of functional groups and three-dimensional architectures. The rhodium-catalyzed method tolerates traces of dimethyl sulfoxide (DMSO) or water, meaning that pharmaceutical compound collections, which are typically stored in wet DMSO, can finally be reformatted for use as substrates for chemical synthesis. This latter application is demonstrated through the late-stage saturation (LSS) of 768 complex and densely functionalized small-molecule drugs.

Artificial Intelligence for Retrosynthetic Planning Needs Both Data and Expert Knowledge.

Rapid advancements in artificial intelligence (AI) have enabled breakthroughs across many scientific disciplines. In organic chemistry, the challenge of planning complex multistep chemical syntheses should conceptually be well-suited for AI. Yet, the development of AI synthesis planners trained solely on reaction-example-data has stagnated and is not on par with the performance of "hybrid" algorithms combining AI with expert knowledge. This Perspective examines possible causes of these shortcomings, extending beyond the established reasoning of insufficient quantities of reaction data. Drawing attention to the intricacies and data biases that are specific to the domain of synthetic chemistry, we advocate augmenting the unique capabilities of AI with the knowledge base and the reasoning strategies of domain experts. By actively involving synthetic chemists, who are the end users of any synthesis planning software, into the development process, we envision to bridge the gap between computer algorithms and the intricate nature of chemical synthesis.

Bridging the information gap in organic chemical reactions.

The varying quality of scientific reports is a well-recognized problem and often results from a lack of standardization and transparency in scientific publications. This situation ultimately leads to prominent complications such as reproducibility issues and the slow uptake of newly developed synthetic methods for pharmaceutical and agrochemical applications. In recent years, various impactful approaches have been advocated to bridge information gaps and to improve the quality of experimental protocols in synthetic organic publications. Here we provide a critical overview of these strategies and present the reader with a versatile set of tools to augment their standard procedures. We formulate eight principles to improve data management in scientific publications relating to data standardization, reproducibility and evaluation, and encourage scientists to go beyond current publication standards. We are aware that this is a substantial effort, but we are convinced that the resulting improved data situation will greatly benefit the progress of chemistry.

Silver-Enabled Cycloaddition of Bicyclobutanes with Isocyanides for the Synthesis of Polysubstituted 3-Azabicyclo[3.1.1]heptanes.

Synthesis of bicyclic scaffolds has emerged as an important research topic in modern drug development because they can serve as saturated bioisosters to enhance the physicochemical properties and metabolic profiles of drug candidates. Here we report a remarkably simple silver-enabled strategy to access polysubstituted 3-azabicyclo[3.1.1]heptanes in a single operation from readily accessible bicyclobutanes (BCBs) and isocyanides. The process is proposed to involve a formal (3+3)/(3+2)/retro-(3+2) cycloaddition sequence. This novel protocol allows for rapid generation of molecular complexity from simple starting materials, and the products can be easily derivatized, further enriching the BCB cycloaddition chemistry and the growing set of valuable sp3-rich bicyclic building blocks.

The Electron-Rich and Nucleophilic N-Heterocyclic Imines on Metal Surfaces: Binding Modes and Interfacial Charge Transfer.

The strongly electron-donating N-heterocyclic imines (NHIs) have been employed as excellent surface anchors for the thermodynamic stabilization of electron-deficient species due to their enhanced nucleophilicity. However, the binding mode and interfacial property of these new ligands are still unclear, representing a bottleneck for advanced applications in surface functionalization and catalysis. Here, NHIs with different side groups have been rationally designed, synthesized, and analyzed on various metal surfaces (Cu, Ag). Our results reveal different binding modes depending on the molecular structure and metal surface. The molecular design enables us to achieve a flat-lying or upright configuration and even a transition between these two binding modes depending on the coverage and time. Importantly, the two binding modes exhibit different degrees of interfacial charge transfer between the molecule and the surface. This study provides essential microscopic insight into the NHI adsorption geometry and interfacial charge transfer for the optimization of heterogeneous catalysts in coordination chemistry.

Chemoselective Heterogeneous Hydrogenation of Sulfur Containing Quinolines under Mild Conditions.

Sulfur, alongside oxygen and nitrogen, holds a prominent position as one of the key heteroatoms in nature and medicinal chemistry. Its significance stems from its ability to adopt different oxidation states, rendering it valuable as both a polarity handle and a hydrogen bond donor/acceptor. Nevertheless, the poisonous nature of its free electron pairs makes sulfur containing substrates inaccessible for many catalytic protocols. Strong and (at low temperatures) irreversible chemisorption to the catalyst's surface is in particular detrimental for heterogeneous catalysts, possessing only few catalytically active sites. Herein, we present a novel heterogeneous Ru-S catalyst that tolerates multiple sulfur functionalities, including thioethers, thiophenes, sulfoxides, sulfones, sulfonamides, and sulfoximines, in the hydrogenation of quinolines. The utility of the products was further demonstrated by subsequent diversifications of the sulfur functionalities.

Double Strain-Release [2π+2σ]-Photocycloaddition.

In pursuit of potent pharmaceutical candidates and to further improve their chemical traits, small ring systems can serve as a potential starting point. Small ring units have the additional merit of loaded strain at their core, making them suitable reactants as they can capitalize on this intrinsic driving force. With the introduction of cyclobutenone as a strained precursor to ketene, the photocycloaddition with another strained unit, bicyclo[1.1.0]butane (BCB), enables the reactivity of both π-units in the transient ketene. This double strain-release driven [2π+2σ]-photocycloaddition promotes the synthesis of diverse heterobicyclo[2.1.1]hexane units, a pharmaceutically relevant bioisostere. The effective reactivity under catalyst-free conditions with a high functional group tolerance defines its synthetic utility. Experimental mechanistic studies and density functional theory (DFT) calculations suggest that the [2π+2σ]-photocycloaddition takes place via a triplet mechanism.

Photoredox-Enabled Dearomative [2π + 2σ] Cycloaddition of Phenols.

Dearomative photocycloaddition of monocyclic arenes is an appealing strategy for comprehending the concept of "escape from flatland". This brings the replacement of readily available planar aromatic hydrocarbon units with a 3D fused bicyclic core with sp3-enriched carbon units. Herein, we outline an intermolecular approach for the dearomative photocycloaddition of phenols. In order to circumvent the ground-state aromaticity and to construct conformationally restrained building blocks, bicyclo[1.1.0]butanes were chosen as coupling partners. This dearomative approach renders straightforward access to a bicyclo[2.1.1]hexane unit fused to a cyclic enone moiety, which further contributed as a synthetic linchpin for postmodifications. Mechanistic experiment advocates for a plausible onset from both the reactants, depending on the redox potential.

Tailored Monolayers of N-Heterocyclic Carbenes by Kinetic Control.

Despite the substantial success of N-heterocyclic carbenes (NHCs) as stable and versatile surface modification ligands, their use in nanoscale applications beyond chemistry is still hampered by the failure to control the carbene binding mode, which complicates the fabrication of monolayers with the desired physicochemical properties. Here, we applied vibrational sum-frequency generation spectroscopy to conduct a pseudokinetic surface analysis of NHC monolayers on Au thin films under ambient conditions. We observe for two frequently used carbene structures that their binding mode is highly dynamic and changes with the adsorption time. In addition, we demonstrate that this transition can be accelerated or decelerated to adjust the binding mode of NHCs, which allows fabrication of tailored monolayers of NHCs simply by kinetic control.

Energy transfer photocatalysis: exciting modes of reactivity.

Excited (triplet) states offer a myriad of attractive synthetic pathways, including cycloadditions, selective homolytic bond cleavages and strain-release chemistry, isomerizations, deracemizations, or the fusion with metal catalysis. Recent years have seen enormous advantages in enabling these reactivity modes through visible-light-mediated triplet-triplet energy transfer catalysis (TTEnT). This tutorial review provides an overview of this emerging strategy for synthesizing sought-after organic motifs in a mild, selective, and sustainable manner. Building on the photophysical foundations of energy transfer, this review also discusses catalyst design, as well as the challenges and opportunities of energy transfer catalysis.