Chiral Discrimination of Acyclic Secondary Amines by 19F NMR.

Chiral aliphatic amine compounds exhibit a range of physiological activities, making them highly sought-after in the pharmaceutical industry and biological research. One notable obstacle in studying these compounds stems from the pronounced steric hindrance surrounding the nitrogen atom. This characteristic often leads to a weak affinity of acyclic secondary amines for molecular probes, making their chiral discrimination intricate. In response to this challenge, our research has unveiled a novel 19F-labeled probe adept at recognizing and distinguishing between enantiomers of these acyclic secondary amines. By strategically incorporating a single fluorine atom as the 19F label, we have managed to diminish the steric hindrance at the binding site. This alteration bolsters the probe's affinity toward bulkier analytes. As a testament to its effectiveness, we have successfully employed our probe in the chiral analysis of relevant pharmaceuticals, accurately determining their enantiocomposition.

Tailoring the Recognition Property of a 19F-Labeled Gallium-Based NMR Probe: The Influence of the Metal Center.

Chirality is a fundamental property of nature and an essential element of the life process. As the biological activities, metabolic pathways, and toxicity of individual enantiomers are often varied, methods to rapidly and accurately discriminate chiral analytes are in great demand. Here, we report a 19F-labeled gallium-based probe for the enantiodifferentiation of chiral monoamines, diamines, amino alcohols, amino acids, and N-heterocycles. A comparison between the new gallium-based probe and the previously developed aluminum aminotrisphenolate complex was performed. It was revealed that the gallium metal center displays a much stronger affinity toward the amino group compared to the hydroxy group, thereby producing simplified 19F NMR signals for analytes with multiple Lewis basic sites. For sterically bulky analyte, the replacement of the aluminum with gallium is envisioned to expand the binding pocket of the probe to allow different binding models to interconvert rapidly. This feature is important to the creation of easily interpretable 19F signals corresponding to each enantiomer. It is further demonstrated that the gallium-based probe is suitable for the assessment of the enantiomeric excess values of the crude products obtained in asymmetric reactions without the need for purification.

Improving the Sensitivity of Enantioanalysis with Densely Fluorinated NMR Probes.

Nuclear magnetic resonance (NMR) spectroscopy has long been utilized as a classic method for chiral discrimination of enantiomers. However, its sensitivity limitations have hindered the detection of analytes at low concentrations. In this study, we present our efforts to overcome this challenge by employing chiral NMR probes that are labeled with a significant number of chemically equivalent 19F atoms. Specifically, we have designed and synthesized three chiral palladium pincer complexes, all of which are labeled with nonafluoro-tert-butoxy groups to enhance detectability. The recognition of enantiomers with the probe induces distinct changes in microenvironments, resulting in differential perturbations on the chemical shift of the 19F atoms in proximity. This method is applicable to the enantiodifferentiation of various amines, amino alcohols, and amino acid esters. The abundance of 19F atoms enables the detection of chiral analytes at low concentrations, which is otherwise challenging to achieve through traditional 1H NMR-based analysis. Two of the probes are constructed with asymmetric pincer ligands with structurally varied sidearms, allowing for facile manipulation of the chiral binding pocket. The C2 symmetrical probe possesses 36 equivalent 19F atoms, enabling the determination of enantiocomposition of samples with concentrations in the low micromolar range.

19 F-Labeled Probes for Recognition-Enabled Chromatographic 19 F NMR.

The NMR technique is among the most powerful analytical methods for molecular structural elucidation, process monitoring, and mechanistic investigations; however, the direct analysis of complex real-world samples is often hampered by crowded NMR spectra that are difficult to interpret. The combination of fluorine chemistry and supramolecular interactions leads to a unique detection method named recognition-enabled chromatographic (REC) 19 F NMR, where interactions between analytes and 19 F-labeled probes are transduced into chromatogram-like 19 F NMR signals of discrete chemical shifts. In this account, we summarize our endeavor to develop novel 19 F-labeled probes tailored for separation-free multicomponent analysis. The strategies to achieve chiral discrimination, sensitivity enhancement, and automated analyte identification will be covered. The account will also provide a detailed discussion of the underlying principles for the design of molecular probes for REC 19 F NMR where appropriate.

Recognition-Enabled Automated Analyte Identification via 19F NMR.

Nuclear magnetic resonance (NMR) is an indispensable tool for structural elucidation and noninvasive analysis. Automated identification of analytes with NMR is highly pursued in metabolism research and disease diagnosis; however, this process is often complicated by the signal overlap and the sample matrix. We herein report a detection scheme based on 19F NMR spectroscopy and dynamic recognition, which effectively simplifies the detection signal and mitigates the influence of the matrix on the detection. It is demonstrated that this approach can not only detect and differentiate capsaicin and dihydrocapsaicin in complex real-world samples but also quantify the ibuprofen content in sustained-release capsules. Based on the 19F signals obtained in the detection using a set of three 19F probes, automated analyte identification is achieved, effectively reducing the odds of misrecognition caused by structural similarity.

Construction of Lewis Pairs for Optimal Enantioresolution via Recognition-Enabled "Chromatographic" 19F NMR Spectroscopy.

Chirality is a ubiquitous phenomenon in nature, serving as a foundation for a variety of life activities on earth. Separation-free methods that rapidly and accurately distinguish chiral analytes in complex systems are highly demanded in fields ranging from drug quality control to the screening of privileged chiral catalysts. However, in situ enantidifferentiation methods possessing resolution and tunability that are comparable to those achieved by chiral high-performance liquid chromatography are rare. Herein, we report a Lewis pair-based system for enantioanalysis via recognition-enabled "chromatographic" 19F NMR spectroscopy. The construction of Lewis pairs renders the detecting system not only enhanced affinity to chiral analytes but also superior and tunable resolving capability. Using this strategy, as many as 16 chiral analytes are simultaneously resolved without need for separation, thus opening new avenues for the development of precise and real-time detection methods that are robust enough for dealing with complex real-world samples.

Metal-Free C-H Functionalization via Diaryliodonium Salts with a Chemically Robust Dummy Ligand.

A two-step strategy for the transition-metal-free C-H functionalization of arenes using unsymmetrical iodonium salts as versatile synthetic linchpins is presented. The key to the success of this strategy is the identification of the 3,5-dimethyl-4-isoxazolyl (DMIX) group as a superior dummy ligand, which enables not only site-selective C-H functionalization to afford unsymmetrical iodonium salts, but also highly selective aryl transfer during the subsequent metal-free coupling reaction. Both electron-rich and moderately electron-deficient arenes can be converted into the iodonium salts through C-H functionalization, allowing for diverse structural elaboration by metal-free C-N, C-C, C-S, and C-O coupling.

Calix[4]trap: A Bioinspired Host Equipped with Dual Selection Mechanisms.

Regulation of recognition events evolving in time and space is vital for living organisms. During evolution, organisms have developed distinct and orthogonal mechanisms to achieve selective recognition, avoiding mutual interference. Although the merging of multiple selection mechanisms into a single artificial host may lead to a more adaptable recognition system with unparalleled selectivity, successful implementation of this strategy is rare. Inspired by the intriguing structures and recognition properties of two well-known biological ion binders-valinomycin and K+ channels-we herein report a series of hosts equipped with dual guest selection mechanisms. These hosts simultaneously possess a preorganized binding cavity and a confined ion translocation tunnel, which are crucial to the record-setting K+/Na+ selectivity and versatile capabilities to discriminate against a wide range of ion pairs, such as K+/Rb+, K+/Ba2+, and Rb+/Cs+. Mechanistic studies verify that the host's portal is capable of discriminating cations by their size, enabling varied ion uptake rates. The confined tunnel bearing consecutive binding sites promotes complete desolvation of ions during their inclusion into the buried cavity, mimicking the ion translocation within ion channels. Our results demonstrate that the capability to manipulate guest recognition both in equilibrium and out-of-equilibrium states allows the host to effectively discriminate diverse guests via distinct mechanisms. The strategy to merge orthogonal selection mechanisms paves a new avenue to creating more robust hosts that may function in complex biological environments where many recognition events occur concurrently.

Tailoring Sensors and Solvents for Optimal Analysis of Complex Mixtures Via Discriminative 19F NMR Chemosensing.

Separation-free analytic techniques capable of providing precise and real-time component information are in high demand. 19F NMR-based chemosensing, where the reversible binding between analytes and a 19F-labeled sensor produces chromatogram-like output, has emerged as a valuable tool for the rapid analysis of complex mixtures. However, the potential overlap of the 19F NMR signals still limits the number of analytes that can be effectively differentiated. In this study, we systematically investigated the influence of the sensor structure and NMR solvents on the resolution of structurally similar analytes. The substituents adjacent and distal to the 19F labels are both important to the resolving ability of the 19F-labeled sensors. More pronounced separation between 19F NMR peaks was observed in nonpolar and aromatic solvents. By using a proper sensor and solvent combination, more than 20 biologically relevant analytes can be simultaneously identified.

Molecular Sensors for NMR-Based Detection.

Reliable and precise methods capable of unambiguously identifying target analytes in real-world samples are indispensable in various fields, ranging from biological studies and diagnosis to quality control. Among various analytic techniques, nuclear magnetic resonance (NMR) is uniquely powerful as it provides multidimensional data useful for structural analysis at the atomic level. The rich information obtained from various NMR experiments allows one to access not only molecular structures and interactions but also the dynamics and diffusional properties. However, the interpretation of NMR data in the analysis of real-world mixtures can be challenging and is often complicated by the overlap of the NMR resonances of each component. Moreover, the inherently low sensitivity of the NMR technique hampers its implementation in many detections, where the analytes of interest are present at low concentrations. By a combination of heteronuclear NMR, dedicatedly designed sensors, ingenious transduction mechanisms, and powerful NMR pulse sequences, significant advancements were made to conquer these limitations. The present review summarizes the sensing systems that effectively facilitate NMR-based detection with an emphasis on the chemical perspective of sensor design and transduction mechanism. Advances in hyperpolarized sensors to boost the sensitivity of detection will also be included where appropriate.

Highly Enantioselective O-H Bond Insertion Reaction of α-Alkyl- and α-Alkenyl-α-diazoacetates with Water.

Catalytic asymmetric reactions in which water is a substrate are rare. Enantioselective transition-metal-catalyzed insertion of carbenes into the O-H bond of water can be used to incorporate water into the stereogenic center, but the reported chiral catalysts give good results only when α-aryl-α-diazoesters are used as the carbene precursors. Herein we report the first highly enantioselective O-H bond insertion reactions between water and α-alkyl- and α-alkenyl-α-diazoesters as carbene precursors, with catalysis by a combination of achiral dirhodium complexes and chiral phosphoric acids or chiral phosphoramides. Participation of the phosphoric acids or phosphoramides in the carbene transfer reaction markedly suppressed competing side reactions, such as ß-H migration, carbene dimerization, and olefin isomerization, and thus ensured good yields of the desired products. Fine-tuning of the ester moiety facilitated enantiocontrol of the proton transfer reactions of the enol intermediates and resulted in excellent enantioselectivity. This protocol represents an efficient new method for preparation of multifunctionalized chiral α-alkyl and α-alkenyl hydroxyl esters, which readily undergo various transformations and can thus be used for the synthesis of bioactive compounds. Mechanistic studies revealed that the phosphoric acids and phosphoramides promoted highly enantioselective [1,2]- and [1,3]-proton transfer reactions of the enol intermediates. Maximization of molecular orbital overlap in the transition states of the proton transfer reactions was the original driving force to involve the proton shuttle catalysts in this process.

Reactive Processing of Furan-Based Monomers via Frontal Ring-Opening Metathesis Polymerization for High Performance Materials.

Frontal ring-opening metathesis polymerization (FROMP) presents an energy-efficient approach to produce high-performance polymers, typically utilizing norbornene derivatives from Diels-Alder reactions. This study broadens the monomer repertoire for FROMP, incorporating the cycloaddition product of biosourced furan compounds and benzyne, namely 1,4-dihydro-1,4-epoxynaphthalene (HEN) derivatives. A computational screening of Diels-Alder products is conducted, selecting products with resistance to retro-Diels-Alder but also sufficient ring strain to facilitate FROMP. The experiments reveal that varying substituents both modulate the FROMP kinetics and enable the creation of thermoplastic materials characterized by different thermomechanical properties. Moreover, HEN-based crosslinkers are designed to enhance the resulting thermomechanical properties at high temperatures (>200 °C). The versatility of such materials is demonstrated through direct ink writing (DIW) to rapidly produce 3D structures without the need for printed supports. This research significantly extends the range of monomers suitable for FROMP, furthering efficient production of high-performance polymeric materials.

Chirality Sensing of N-Heterocycles via 19F NMR.

Methods to rapidly detect and differentiate chiral N-heterocyclic compounds become increasingly important owing to the widespread application of N-heterocycles in drug discovery and materials science. We herein report a 19F NMR-based chemosensing approach for the prompt enantioanalysis of various N-heterocycles, where the dynamic binding between the analytes and a chiral 19F-labeled palladium probe create characteristic 19F NMR signals assignable to each enantiomer. The open binding site of the probe allows the effective recognition of bulky analytes that are otherwise difficult to detect. The chirality center distal to the binding site is found sufficient for the probe to discriminate the stereoconfiguration of the analyte. The utility of the method in the screening of reaction conditions for the asymmetric synthesis of lansoprazole is demonstrated.

Dispersive 2D Triptycene-Based Crystalline Polymers: Influence of Regioisomerism on Crystallinity and Morphology.

The merging of good crystallinity and high dispersibility into two-dimensional (2D) layered crystalline polymers (CPs) still represents a challenge because a high crystallinity is often accompanied by intimate interlayer interactions that are detrimental to the material processibility. We herein report a strategy to address this dilemma using rationally designed three-dimensional (3D) monomers and regioisomerism-based morphology control. The as-synthesized CPs possess layered 2D structures, where the assembly of layers is stabilized by relatively weak van der Waals interactions between C-H bonds other than the usual π-π stackings. The morphology and dispersibility of the CPs are finely tuned via regioisomerism. These findings shed light on how to modulate the crystallinity, morphology, and ultimate function of crystalline polymers using the spatial arrangements of linking groups.

Difluorocarbene-Mediated Cascade Cyclization: The Multifunctional Role of Ruppert-Prakash Reagent.

A difluorocarbene-mediated cascade cyclization reaction for rapid access to gem-difluorinated 3-coumaranone derivatives was developed. The difluorocarbene acts as a bipolar CF2 building block, which enables a homologation cyclization process via sequentially reacting with the phenolate and the ester group on the same substrate. The potential application of this synthetic approach is demonstrated by a late-stage modification of diethylstilbestrol. Mechanistic studies revealed the multiple crucial roles played by the Ruppert-Prakash reagent.

Nonafluoro- tert-butoxylation of Diaryliodonium Salts.

A highly efficient method to incorporate the nonafluoro- tert-butoxy group into various arenes is developed. This C-O cross-coupling reaction proceeds smoothly in the absence of transition-metal catalyst with good functional group tolerance and scalability. In comparison with the conventional approach, this method avoids the use of nonafluoro- tert-butyl alcohol as the reaction solvent and does not require handling of hazardous diazonium salts. A series of OC(CF3)3-containing analogues of 19F NMR-based probes targeting various biologically relevant analytes are prepared.