Chiral Nitrogen Research Articles

Nitrogen-Oxidized Tröger's Base Macrocyclic Arenes: Unprecedented Enantioselective Recognition in Water.

Achieving high enantioselectivity with synthetic receptors, particularly in water, remains a significant challenge despite the success seen in natural biological systems. In this study, we introduce a facile synthesis of Tröger's base (TB)-containing macrocyclic arenes (TBn), where TB units are linked via methylene bridges, providing the macrocycles with a rigid framework. Oxidation of enantiopure TBn yields corresponding chiral nitrogen oxides (TBnNO) with excellent water solubility, attributed to the high polarity of the N-O bond, surpassing the pH limitations of traditional ion-functionalized approaches. Remarkably, TBnNO exhibits exceptional enantioselective recognition toward a wide range of chiral guests in aqueous solution, achieving enantioselectivities as high as 41.0. The underlying mechanism involves a combination of hydrophobic interactions and steric effects caused by rigid chiral cavities. These findings highlight the potential of nitrogen-oxidized macrocycles as a transformative tool for supramolecular application in water.

Nitrogen‐Oxidized Tröger's Base Macrocyclic Arenes: Unprecedented Enantioselective Recognition in Water

AbstractAchieving high enantioselectivity with synthetic receptors, particularly in water, remains a significant challenge despite the success seen in natural biological systems. In this study, we introduce a facile synthesis of Tröger's base (TB)‐containing macrocyclic arenes (TBn), where TB units are linked via methylene bridges, providing the macrocycles with a rigid framework. Oxidation of enantiopure TBn yields corresponding chiral nitrogen oxides (TBnNO) with excellent water solubility, attributed to the high polarity of the N−O bond, surpassing the pH limitations of traditional ion‐functionalized approaches. Remarkably, TBnNO exhibits exceptional enantioselective recognition toward a wide range of chiral guests in aqueous solution, achieving enantioselectivities as high as 41.0. The underlying mechanism involves a combination of hydrophobic interactions and steric effects caused by rigid chiral cavities. These findings highlight the potential of nitrogen‐oxidized macrocycles as a transformative tool for supramolecular application in water.

Counterintuitive Isomerization of TFSI- and TFSI--Cation Correlated Isomerization: Insights into the Low Melting Points of TFSI--Based Ionic Liquids.

Ionic liquids (ILs), particularly bis(trifluoromethane)sulfonamide (TFSI-)-based ILs, have attracted substantial attention in electrochemical energy storage, ionic gating for superconductivity, and iontronic sensing. However, underestimating TFSI- isomerization and overlooking TFSI--cation correlation make the origin of their most characteristic property, low melting points (Tm), ambiguous. Traditional static electronic structure calculations assume that C2-symmetric trans enantiomers of TFSI- easily isomerize into cis enantiomers through four symmetrically equivalent pathways over a barrier of 7.1 kJ mol-1. Herein, ab initio molecular dynamics (AIMD) simulations combined with metadynamics reveal that the unusual oscillation of the central nitrogen atom promotes TFSI- to undergo complex isomerization. Specifically, asymmetric trans-to-cis diastereomers of TFSI- experience restricted interconversion (20-52 kJ mol-1) through four distinct asymmetric pathways. The adaptive oscillation and hybridization of chiral nitrogen boost nN → σ*S-C negative hyperconjugation for stabilizing conformational structures and enlarging energy barriers. The orientational distortion of oxygen atoms' lone pairs enhances conjugation but breaks the C2-symmetry. The coexistence of both helicity and chiral nitrogen breaks the enantiomeric relationship. Furthermore, Raman characterization and AIMD simulations confirm the positive correlation between the relative stability of cis-TFSI- and its countercation's polarity. TFSI- and countercations make a mutual conformational selection instead of free isomerization. Surprisingly, Tm increases with the cation-dependent conformational rigidity of TFSI-, offering new fundamental insights into the low Tm of ILs. This descriptor encoding the dependence of thermal property on cation-anion correlated isomerization provides material design guidelines and property prediction capability.

Direct flipping dynamics and quantized enrichment of chirality at single-molecule resolution.

Chirality is an important aspect of nature, and numerous macroscopic methods have been developed to understand and control chirality. For the chiral tertiary amines, their flexible flipping process makes it possible to achieve high chiral controllability without bond formation and breaking. Here, we present a type of stable chiral single-molecule devices formed by tertiary amines, using graphene-molecule-graphene single-molecule junctions. These single-molecule devices allow real-time, in situ, and long-time measurements of the flipping process of an individual chiral nitrogen center with high temporal resolution. Temperature- and bias voltage-dependent experiments, along with theoretical investigations, revealed diverse chiral intermediates, indicating the regulation of the flipping dynamics by energy-related factors. Angle-dependent measurements further demonstrated efficient enrichment of chiral states using linearly polarized light by a symmetry-related factor. This approach offers a reliable means for understanding the chirality's origin, elucidating microscopic chirality regulation mechanisms, and aiding in the design of effective drugs.

A computational investigation on the photochemistry of the popular spin‐trap agent N‐tert‐butyl‐α‐phenylnitrone (PBN) and thermal isomerization pathways of its photoproduct oxaziridine

AbstractComputational investigation on the low‐lying photo‐excited states of N‐tert‐butyl‐α‐phenylnitrone (PBN), a well‐known spin‐trap agent, has revealed its photo‐product (oxaziridine) formation channel. The S0‐S2 vertical excitation in PBN is subsequently followed by a non‐radiative decay pathway through S2/S1 and S0/S1 conical intersections (CIs) with CNO‐kinked structures, situated around 23 kcal/mol and 45 kcal/mol below the vertically excited S2 state, respectively. The reverse photo‐process of PBN formation involves photo‐excitation of oxaziridine to its S2 and S3 photo‐excited states. The forward photo‐isomerization leads to the trans‐oxaziridine with a backside CNO kink (trans‐OXB) while the reverse path studied by us, connects its front‐side CNO‐kinked analogue (trans‐OXF) with the PBN. Our search for the reverse thermal reaction paths from these two oxazirdines has led to their corresponding transition states, one at 35 kcal/mol and the other at 27 kcal/mol above trans‐OXF and trans‐OXB geometries, respectively. They lead to two different isomers (E and Z) of PBN which supports the reported nature of products from the trans‐oxaziridine in this thermal reaction. The inversion path of the chiral nitrogen atom of this N‐tert‐butyl‐oxaziridine (barrier 21 kcal/mol) has also been tracked. This reaction path has been compared with that of the N‐methyl (barrier 30 kcal/mol) and N‐acyl (barrier 10.5 kcal/mol) oxaziridine analogues.

Asymmetric electrophilic functionalization of amino-substituted heteroaromatic compounds: a convenient tool for the enantioselective synthesis of nitrogen heterocycles.

The catalytic asymmetric electrophilic functionalization of the less reactive N-heteroaromatic compounds has been reported using the approach of the introduction of an exocyclic amino substituent. This strategy has allowed enantioselective Friedel-Crafts alkylation in pyrazoles, isoxazoles and isothiazoles, as well as in aminoindoles, aminobenzofurans and aminobenzothiophenes. Several stereoselective methods have been used for the 1,4-addition or 1,2-addition of these heteroaromatic compounds to different electrophiles employing organocatalysts or chiral metal complexes. The activating exocyclic amino substituent has also been used as a nucleophile in tandem reactions, including formal cycloadditions ([3+2] and [3+3]), for the synthesis of highly functionalized chiral nitrogen heterocycles.

Copper-Catalyzed Enantioselective Aerobic Alkene Aminooxygenation and Dioxygenation: Access to 2-Formyl Saturated Heterocycles and Unnatural Proline Derivatives.

Alkene aminooxygenation and dioxygenation reactions that result in carbonyl products are uncommon, and protocols that control absolute stereochemistry are rare. We report herein catalytic enantioselective alkene aminooxygenation and dioxygenation that directly provide enantioenriched 2-formyl saturated heterocycles under aerobic conditions. Cyclization of substituted 4-pentenylsulfonamides, catalyzed by readily available chiral copper complexes and employing molecular oxygen as both oxygen source and stoichiometric oxidant, directly provides chiral 2-formyl pyrrolidines efficiently. Reductive or oxidative workup of these aldehydes provides their respective amino alcohols or amino acids (unnatural prolines). Enantioselective synthesis of an indoline and isoquinolines is also demonstrated. Concurrently, cyclization of various alkenols under similar conditions provides 2-formyl tetrahydrofurans, phthalans, isochromans, and morpholines. The nature of the copper ligands, the concentration of molecular oxygen, and the reaction temperature all impact the product distribution. Chiral nitrogen and oxygen heterocycles are common components of bioactive small molecules, and these enabling technologies provide access to saturated heterocycles functionalized with ready-to-use carbonyl electrophiles.

Cinchona-Alkaloid-Derived NN Ligands and Achiral Phosphines for Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatic and α-Chloroheteroaryl Ketones.

A concise synthesis of cinchona-alkaloid-derived NN ligands bearing alkyl substituents on chiral nitrogen atoms was described. Iridium catalysts containing new chiral NN ligands and achiral phosphines were effective for the asymmetric hydrogenation of heteroaromatic ketones, which afforded corresponding alcohols in up to 99.9% ee. The same protocol was applicable to the asymmetric hydrogenation of α-chloroheteroaryl ketones. Most importantly, the gram-scale asymmetric hydrogenation of 2-acetylthiophene and 2-acetylfuran proceeded smoothly even under 1 MPa of H2.

Advances in Asymmetric N Construction of Metal and Organic Small Molecules

Lot of natural products, pharmaceuticals and functional materials with chiral amines do many useful job, and this group also a valuable constituents of versatile building blocks and important chiral catalysts as well as chiral auxiliaries in organic synthesis. Therefore, to develop efficient methods for the synthesis of structurally diverse chiral amines and chiral amine scaffolds has great importance and huge application vaule. symmetric catalysis is the most efficient method to synthesize chiral organic molecules. Cooperatively catalyzed by transition metal and small organic molecules can be used to simultaneously or continuously activates the bonds and rebuild, it can help some reaction which can not happen with only one catalyst to move on. This article reviews some cases of chiral nitrogen formation through metal catalysis, organic small molecule catalysis and their synergistic catalysis, and briefly discusses the challenges and future development directions in this area.

Compounds of amine-substituted cyclic amines: synthesis and structures

Cyclic tetra-amines with amine substituents on the central carbon atom of C3 ring segments are readily prepared by reduction of nitro-substituted aza-macrocycles, formed by reactions of metal-ion amine compounds with formaldehyde and a nitro-alkane. Reactions of bis-(ethane-1,2-diamine)-copper(ii) or -nickel(ii) cations with formaldehyde and nitroethane form the trans (anti) and cis (syn) isomers of (6,13-dimethyl-6,13-di-nitro-1,4,8,11-tetra-azacyclotetradecane)-copper(ii) or -nickel(ii)) cations, which are readily reduced to form the trans and cis-6,13-diamino cations, from which the trans- and cis-amine substituted cyclic tetra-amines can be isolated. Similar reactions for the (3,7-diaza-nonane-1,9-diamine)-copper(ii) or -nickel(ii) cations lead to 6-methyl-1,4,8,11-tetra-azacyclotetradecane-6-amine. Amine-substituted cyclic tetra-amines with different ring sizes or alkyl substituents can similarly be prepared by using different diamines or alkyl-nitro compounds. This review is primarily about compounds formed by trans-6,13-diamino and 6-amino-1,4,8,11-tetraazacyclotetradecanes with d-transition-metal ions. The amines react with transition-metal ions in much the same manner as 1,4,8,11-tetraazacyclotetradecane (cyclam), forming compounds with isomeric configurations arising from the four chiral nitrogen centres of coordinated cyclam, the cis- or trans-configurations of the amine substituents and a form of geometrical isomerism arising from the relationship between the chiral coordinated cyclam configuration and the orientation of the substituents. The amine-substituted cyclams coordinate by the four cyclam nitrogen atoms, in planar or folded arrangements, and also by one or both of the amine substituents. Non-coordinated amine substituents can be protonated. The amine substituents can be modified by methylation, amide formation and reaction with aldehydes to form imines. The imines formed with functionalised aldehydes can be reduced to form variously functionalised secondary amine substituents. This all leads to complex coordination chemistry and X-ray crystallographic structure determinations have been critical in understanding the configurations present. Structures in the Cambridge Crystallographic Data Base of all relevant compounds are listed.

Catching the elusive chiral nitrogen compound

The world of chirality, or the handedness of a molecule, is dominated by controlling how atoms and functional groups are arranged around a central carbon. Until now, there hasn’t been a straightforward way for chemists to make compounds with chiral nitrogen centers, which are important in drugs and biologically active molecules. Matthew Kitching and colleagues at Durham University have found that adding a carbon fragment to an amine and binding the resulting ammonium to a common chiral compound gives chiral N compounds in high specificity, in a single-pot reaction ( Nature 2021, DOI: 10.1038/s41586-021-03735-5 ). “Most people don’t think about an amine being chiral because it rapidly interconverts,” Kitching says. The lone electron pair that gives amines their typical trigonal pyramidal shape can tunnel through the N center, flipping the molecule inside out like an umbrella in a windstorm. By treating an amine with an alkyl bromide compound, Kitching’s team

Catching the elusive chiral nitrogen compound

Catching the elusive chiral nitrogen compound

Organocatalytic Enantioselective Construction of Chiral Azepine Skeleton Bearing Multiple-Stereogenic Elements.

Enantioselective construction of molecules bearing multiple stereogenic elements is increasingly related to the synthesis of enantiopure natural products, pharmaceuticals, and functional materials. However, atom-economical and enantioselective approaches to install multiple stereogenic elements in a small molecular template by limited chemical transformation remain challenging. We describe an organocatalytic enantioselective method for the preparation of polychiral molecules bearing four types of stereogenic elements in fused azepines via vinylidene ortho-quinone methide (VQM)-mediated intramolecular electrophilic aromatic substitution. This method was proved robust with a wide range of substrate scope (46-92 % yield), with excellent diastereoselectivity (>20:1 dr) and enantioselectivity achieved (up to 97 % ee). Optical properties and Ru3+ -induced fluorescence responses of these compounds suggest their potential applications in optoelectronic materials and heavy metal ion detection.

Nickel-Catalyzed C(sp3)-H Functionalization of Benzyl Nitriles: Direct Michael Addition to Terminal Vinyl Ketones.

An efficient nickel(0)-catalyzed addition of benzyl nitriles to terminal vinyl ketones via C(sp3)-H functionalization has been developed. The reaction provides a novel and efficient protocol for the synthesis of α-functionalized benzyl nitriles with a wide range of structural diversity under mild reaction conditions while obviating the use of a strong base. The work might be potentially useful toward the development of an enantioselective variant using chiral nitrogen ligands.

Cyclic Diplatinum Complex with a Tröger's Base Ligand and Reductive Elimination of a Highly Strained Ring Molecule

The cover picture shows the structures of Tröger's base derivatives in this study. Tröger's base has a compact molecular structure with two chiral nitrogen atoms (upper left). A cyclic diplatinum complex with C-bonded Tröger's base ligand is synthesized and characterized (lower left). This complex undergoes reductive elimination of the cyclic dimer of Tröger's base (bottom right). Due to the conjugated biphenylene groups, the molecule contains the angle between the aromatic planes of Tröger's base, 65–66°, which is much smaller than those previously reported for Tröger's base derivatives (88–114°) (https://doi.org/10.1002/zaac.202100085).

Liverpool Chirochem raises $2.8 million

Liverpool Chirochem, a provider of building-block chemicals for pharma R&D, has raised $2.8 million from investors to hire additional staff and expand output at its headquarters and R&D center in Liverpool, England, and its analytical center and production lab in Taizhou, China. A 2014 spin-off from Liverpool University, the firm specializes in chiral nitrogen heterocycles.

A chiral ligand accessible in one step: Synthesis of bis-((R)-(+)-bornyl)acenaphthenequinonediimine and of its zinc and nickel complexes

A new neutral chiral nitrogen ligand was obtained in one step from commercially available acenaphthenequinone and (R)-(+)-bornylamine. Use of titanium tetraisopropoxide is the key to obtain good yields of the condensed product. Ring strain in the bicyclic system helps in stabilizing the otherwise unstable Alkyl-BIAN type derivative, but is not enough to render the free ligand indefinitely stable. However, complexes of the ligand with the ZnCl2 and NiBr2 fragment were prepared and are stable. The single crystal X-ray structure of ((R)-(+)-Bornyl-BIAN)NiBr2 has been determined.

Resolution of chiral nitrogen atoms in 1D helical coordination polymers

A unique stereochemically labile secondary amine with a chiral nitrogen atom assemble cobalt and zinc ions in the aid of chelating ancillary ligands to give rise to three helical 1D coordination polymers, [Co(p‑cpdba)(2,2′‑bpy)]n (1), {[Zn(p‑cpdba)(2,2′‑bpy)]}n (2) and [Zn(p‑cpdba)(1,10‑phen)]n (3) (cpdba2− = 4‑(4‑carboxyphenylamino)‑3,5‑dinitrobenzolate, 2,2′‑bpy = 2,2′‑bipyridine, 1,10‑phen = 1,10‑phenanthroline). Compound 1 exhibits a racemic double-stranded chained structure with chelating 1,10‑phen occupying two sites of the octahedral cobalt(II). By changing to five-coordinated square pyramidal zinc(II) and employing 2,2′‑bpy and 1,10‑phen, two triple-stranded chained compounds 2 and 3 are synthesized. As expected, all chiral nitrogen atoms within each chiral chain of every triple-stranded helix in 2 and 3 have the same absolute configuration due to the confining growth along one dimension. Therefore, the resolution of chiral nitrogen atom is achieved though only at a one-dimensional scale.

A “Mitsubishi emblem” tetrauclear aluminum complex containing two unsymmetric N2O2‐ligands and a symmetric NO3‐ligand as initiator for polymerization of rac‐lactide

ABSTRACTA novel hydroxy‐, methoxy‐, and phenoxy‐bridge “Mitsubishi emblem” tetranuclear aluminum complex (1) is synthesized from an unsymmetric amine‐pyridine‐bis(phenol) N2O2‐ligand (H2L1) and a symmetric amine‐tris(phenol) NO3‐ligand (H2L2). Two same configuration chiral nitrogen atoms are formed in the tetranuclear Al complex upon coordination of the unsymmetric tertiary amine ligand to central Al. Complex 1 initiates controlled ring‐opening polymerization (ROP) of rac‐lactide and afford polylactide (PLA) with narrow molecular weight distributions (Mw/Mn = 1.05–1.19). The analysis of 1H NMR spectra of the oligomer indicates that the methoxy group is the initiating group and the ring‐opening polymerization of lactide follows a coordination‐insertion mechanism. The Homonuclear decoupled 1H NMR spectroscopy suggests the isotactic‐rich chains is preferentially formed in PLA. The study on kinetics of the ROP of lactide reveals the homopropagation rate is higher than the cross‐propagation rate, which is in agreement with the observed isotactic selectivity in the ROP of rac‐lactide. The stereochemistry of the polymerization was also supported by activation parameters. The introduction of unsymmetric ligand H2L1 has an effect on stereoslectivity of polymerization. This result may be of interest for the design of multinuclear metal complex catalysts containing functionalized ligands. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 2084–2091

Synthesis of chiral and achiral cobalt complexes for hydrogenation studies.

Catalytic hydrogenation reactions have diverse applications in the petrochemical, food, pharmaceutical, and agricultural industries for the efficient synthesis of useful molecules. Specifically, asymmetric hydrogenation of olefins is a key method in the synthesis of single-enantiomer products necessary for the pharmaceutical industry, in particular. However, precious metals such as ruthenium, rhodium, and iridium are the basis for many of the current catalysts. It would be advantageous to replace these more expensive and toxic metals with first-row transition metals that are abundant and environmentally compatible. In addition, most catalytic systems for asymmetric hydrogenation are supported by phosphine ligands. Thus, chiral nitrogen-based ligands provide an opportunity to investigate a relatively underexplored area of hydrogenation chemistry. To this end, we are pursuing cobalt complexes supported by chiral nitrogen-based ligands. The synthesis of a previously reported chiral nitrogen ligand, (R,R)-2,6-bis[1-(N-piperidinyl)ethyl]pyridine, is underway with characterization by NMR spectroscopy. Upon successful synthesis of the ligand, cobalt complexes will be targeted in order to investigate asymmetric hydrogenation reactivity. In addition, synthesis of cobalt complexes bearing the achiral congener ligand, pip2NNN [pip2NNN = 2,6-bis(piperidylmethyl)pyridine], is underway in order to compare reactivity of chiral versus achiral complexes.