Chiral Ion Research Articles

Asymmetric Bromination/Semipinacol Rearrangement Enabled by Brønsted Acids of Stereogenic-at-Cobalt(III) Complexes.

On the basis of the chiral ion pair between catalytic anionic stereogenic-at-cobalt(III) complexes and halonium ion intermediates, an asymmetric halogenation/semipinacol rearrangement reaction has been established using N-bromosuccinimide as the halogen source. This protocol provides an alternative approach for accessing a diverse set of chiral β-bromocycloketones in good yields with high enantioselectivities (≤96% yield, 95.5:4.5 er).

Chirality in Singlet Fission: Controlling Singlet Fission in Aqueous Nanoparticles of Tetracenedicarboxylic Acid Ion Pairs.

The singlet fission characteristics of aqueous nanoparticles, self-assembled from ion pairs of tetracene dicarboxylic acid and various amines with or without chirality, are thoroughly investigated. The structure of the ammonium molecule, the counterion, is found to play a decisive role in determining the molecular orientation of the ion pairs and its regularity, spectroscopic properties, the strength of the intermolecular coupling between the tetracene chromophores, and the consequent singlet fission process. Using chiral amines has led to the formation of crystalline nanosheets and efficient singlet fission with a triplet quantum yield as high as 133% ±20% and a rate constant of 6.99×109s-1. The chiral ion pairs also provide a separation channel to free triplets with yields as high as 33% ±10%. In contrast, nanoparticles with achiral counterions do not show singlet fission, which gave low or high fluorescence quantum yields depending on the size of the counterions. The racemic ion pair produces a correlated triplet pair intermediate by singlet fission, but no decorrelation into two free triplets is observed, as triplet-triplet annihilation dominates. The introduction of chirality enables higher control over orientation and singlet fission in self-assembled chromophores. It provides new design guidelines for singlet fission materials.

Shape Shifting and Locking in Mechanically Responsive Organic‐Inorganic Hybrid Materials for Thermoelastic Actuators

AbstractThe construction of mechanically responsive materials with reversible shape‐shifting, shape‐locking, and stretchability holds promise for a wide range of applications in fields such as soft robotics and flexible electronics. Here, we report novel thermoelastic one‐dimensional organic–inorganic hybrids (R/S‐Hmpy)PbI3 (Hmpy=2‐hydroxymethyl‐pyrrolidinium) to show mechanical responses. The single crystals undergo two phase transitions at 310 K and 380 K. When heated to 380 K, they show shape‐shifting and expansion along the b‐axis by about 13.4 %, corresponding to a larger deformation than that of thermally activated shape memory alloys (8.5 %), and exhibit a strong actuation force. During the cooling process, the stretched crystal shape maintains and a shape‐locking phenomenon occurs, which is lifted when the temperature decreases to 305 K. Meanwhile, due to the introduction of chiral ions, the thermal switching shows a 10‐fold second‐order nonlinear switching contrast (common values typically below 3‐fold). This study presents a thermoelastic actuator based on shape‐shifting and ‐locking of organic–inorganic hybrids for the first time. The dielectric and nonlinear optical switching properties of organic–inorganic hybrids broaden the range of applications of mechanically responsive crystals.

Shape Shifting and Locking in Mechanically Responsive Organic-Inorganic Hybrid Materials for Thermoelastic Actuators.

The construction of mechanically responsive materials with reversible shape-shifting, shape-locking, and stretchability holds promise for a wide range of applications in fields such as soft robotics and flexible electronics. Here, we report novel thermoelastic one-dimensional organic-inorganic hybrids (R/S-Hmpy)PbI3 (Hmpy=2-hydroxymethyl-pyrrolidinium) to show mechanical responses. The single crystals undergo two phase transitions at 310 K and 380 K. When heated to 380 K, they show shape-shifting and expansion along the b-axis by about 13.4 %, corresponding to a larger deformation than that of thermally activated shape memory alloys (8.5 %), and exhibit a strong actuation force. During the cooling process, the stretched crystal shape maintains and a shape-locking phenomenon occurs, which is lifted when the temperature decreases to 305 K. Meanwhile, due to the introduction of chiral ions, the thermal switching shows a 10-fold second-order nonlinear switching contrast (common values typically below 3-fold). This study presents a thermoelastic actuator based on shape-shifting and -locking of organic-inorganic hybrids for the first time. The dielectric and nonlinear optical switching properties of organic-inorganic hybrids broaden the range of applications of mechanically responsive crystals.

Chiral recognition without π−π-interactions: Highly efficient chiral strong cation exchangers lacking an aromatic unit in the molecular structure

Current state-of-the-art chiral stationary phases (CSPs) enable chiral resolution of almost any racemic mixture of choice. The exceptions represent ionizable and ionized substances that fail at any attempts to resolve on commercially available CSPs. These compounds, however, can be efficiently separated on chiral ion exchangers. Commercially available Cinchona alkaloids-based chiral weak ion-exchangers are typically used for chiral resolution of organic acids, while zwitterion ion-exchangers are efficient in the resolution of acids, bases, and zwitterions. The latter possess in their structure a cation exchange unit, which alone can serve as a cornerstone of chiral strong cation exchangers facilitating chiral separation of various basic racemic mixtures.Although chiral strong cation exchangers (cSCX) are efficient CSPs, their structural variations have not been thoroughly studied so far. It was assumed that the mechanism of chiral recognition of basic compounds by cSCX is based predominantly on π-π-interactions, hydrogen bonding and steric interactions (CSP I). To verify this assumption, we aimed in our study on the design and synthesis of cSCX first lacking lateral polar substituents on the aromatic unit in the selector's structure (CSP II), and second, to replace the aromatic unit by a cyclohexane ring (CSP III and IV), thereby to omit completely the π-π-interactions. We hypothesized that this structural change should lead to a partial or complete loss of enantiorecognition power of the selectors. Surprisingly, the non-aromatic cSCXs have shown chiral recognition capability comparable to that of previously described chiral cation exchange-type CSPs: from 16 analytes screened, 11 analytes were baseline resolved and 5 partially resolved on CSP I, while non-aromatic CSP III resolved 10 analytes baseline and 6 partially.We discuss the structural motifs of the known cSCX and the novel non-aromatic selectors in a relationship with their chromatographic performance using a set of basic analytes. Moreover, we present a theory of an effective chiral recognition mechanism by two novel non-aromatic cSCXs based on the chromatographic results and quantum mechanical calculations.

Enantioselective Sulfonation of Enones with Sulfinates by Thiourea/Tertiary-Amine Catalysis

AbstractChiral γ-keto sulfones are significant structures in both organic synthesis and pharmaceutical chemistry. Although there are many choices for obtaining racemic forms, only a few enantioselective methods have been reported. We have developed a simple way for obtaining chiral γ-keto sulfones in moderate yields and moderate enantiomeric ratios. Readily available sulfinates were directly used as substrates that could be converted into sulfinic acids by treatment with boric acid. The bifunctional catalyst forms a chiral ion pair with the sulfinic acid and controls the enantioselectivity of the sulfonation through hydrogen bonding.

Stereodivergent Construction of Csp3 -Csp3 Bonds Bearing Vicinal Stereocenters by Synergistic Palladium and Phase-Transfer Catalysis.

Synergistic catalysis has emerged as one of the most powerful tools for stereodivergent formation of Csp3 -Csp3 bonds bearing vicinal stereocenters. Despite the many successes that have been achieved in this field, stereodivergent Csp3 -Csp3 coupling reactions involving stabilized nucleophiles remain challenging because of the competing single-catalysis pathway. Herein, we report a synergistic palladium/phase-transfer catalyst system that enables diastereodivergent Csp3 -Csp3 coupling reactions of 1,3-dienes with stabilized nucleophile oxindoles. Both the syn and anti coupling products, bearing quaternary and tertiary vicinal stereocenters, could be selectively produced in good yields with high enantio- and diastereoselectivities. Non-covalent activation of the stabilized nucleophile via chiral ion pair in a biphasic system is a crucial success factor in achieving diastereodivergence.

Stereodivergent Construction of Csp3−Csp3Bonds Bearing Vicinal Stereocenters by Synergistic Palladium and Phase‐Transfer Catalysis

AbstractSynergistic catalysis has emerged as one of the most powerful tools for stereodivergent formation of Csp3−Csp3bonds bearing vicinal stereocenters. Despite the many successes that have been achieved in this field, stereodivergent Csp3−Csp3coupling reactions involving stabilized nucleophiles remain challenging because of the competing single‐catalysis pathway. Herein, we report a synergistic palladium/phase‐transfer catalyst system that enables diastereodivergent Csp3−Csp3coupling reactions of 1,3‐dienes with stabilized nucleophile oxindoles. Both thesynandanticoupling products, bearing quaternary and tertiary vicinal stereocenters, could be selectively produced in good yields with high enantio‐ and diastereoselectivities. Non‐covalent activation of the stabilized nucleophile via chiral ion pair in a biphasic system is a crucial success factor in achieving diastereodivergence.

Chiral separation of dipeptides on Cinchona-based zwitterionic chiral stationary phases under buffer-free reversed-phase conditions.

Chiral zwitterion ion exchangers represent efficient chiral stationary phases for stereoselective resolution of various analytes including chiral acids, bases, and zwitterions. In this contribution, we have focused on utilization of chiral zwitterionic sorbents, denoted as ZWIX (+A) and ZWIX (-A). These are analogical chiral systems to commercially available columns, Chiralpak ZWIX (+) and Chiralpak ZWIX (-), which are usually operated with buffered mobile phases. In this contribution, we have studied the enantiorecognition power of the ZWIX (+A) and ZWIX (-A) columns on a series of dipeptides operated under buffer-free reversed-phase conditions. Retention characteristics of zwitterionic dipeptides are discussed using an electrostatically driven adsorption model, which provides a good fit with both monotonous and U-shaped curves.

Stereoselective Synthesis of Sulfinate Esters via a Chiral Ion Pair

Key words cation catalysis - sulfinate esters - asymmetric catalysis - stereoselectivity - ion pair

Asymmetric Azidation under Hydrogen Bonding Phase-Transfer Catalysis: A Combined Experimental and Computational Study.

Asymmetric catalytic azidation has increased in importance to access enantioenriched nitrogen containing molecules, but methods that employ inexpensive sodium azide remain scarce. This encouraged us to undertake a detailed study on the application of hydrogen bonding phase-transfer catalysis (HB-PTC) to enantioselective azidation with sodium azide. So far, this phase-transfer manifold has been applied exclusively to insoluble metal alkali fluorides for carbon–fluorine bond formation. Herein, we disclose the asymmetric ring opening of meso aziridinium electrophiles derived from β-chloroamines with sodium azide in the presence of a chiral bisurea catalyst. The structure of novel hydrogen bonded azide complexes was analyzed computationally, in the solid state by X-ray diffraction, and in solution phase by 1H and 14N/15N NMR spectroscopy. With N-isopropylated BINAM-derived bisurea, end-on binding of azide in a tripodal fashion to all three NH bonds is energetically favorable, an arrangement reminiscent of the corresponding dynamically more rigid trifurcated hydrogen-bonded fluoride complex. Computational analysis informs that the most stable transition state leading to the major enantiomer displays attack from the hydrogen-bonded end of the azide anion. All three H-bonds are retained in the transition state; however, as seen in asymmetric HB-PTC fluorination, the H-bond between the nucleophile and the monodentate urea lengthens most noticeably along the reaction coordinate. Kinetic studies corroborate with the turnover rate limiting event resulting in a chiral ion pair containing an aziridinium cation and a catalyst-bound azide anion, along with catalyst inhibition incurred by accumulation of NaCl. This study demonstrates that HB-PTC can serve as an activation mode for inorganic salts other than metal alkali fluorides for applications in asymmetric synthesis.

Total Synthesis of (+)-Kingianin A by Enantioselective Cycloaddition of Strained Cyclobutenone

AbstractWe report here the first asymmetric total synthesis of (+)-kingianin A via dimerization of an enantioenriched bicyclo[4.2.0]octadiene. The synthesis features a chiral oxazaborolidinium ion catalyzed Diels–Alder reaction of strained cyclobutenone and stereoselective functionalization of the cyclobutane ring. A preliminary biological study indicated that (+)-kingianin A exhibits potent anticancer activities.

Enantioselective metabolomics by liquid chromatography-mass spectrometry

Metabolomics strives to capture the entirety of the metabolites in a biological system by comprehensive analysis, often by liquid chromatography hyphenated to mass spectrometry. A particular challenge thereby is the differentiation of structural isomers. Common achiral targeted and untargeted assays do not distinguish between enantiomers. This may lead to information loss. An increasing number of publications demonstrate that the enantiomeric ratio of certain metabolites can be meaningful biomarkers of certain diseases emphasizing the importance of introducing enantioselective analytical procedures in metabolomics. In this work, the state-of-the-art in the field of LC-MS based metabolomics is summarized with focus on developments in the recent decade. Methodologies, tagging strategies, workflows and general concepts are outlined. Selected biological applications in which enantioselective metabolomics has documented its usefulness are briefly discussed. In general, targeted enantioselective metabolomics assays are often based on a direct approach using chiral stationary phases (CSP) with polysaccharide derivatives, macrocyclic antibiotics, chiral crown ethers, chiral ion exchangers, donor-acceptor phases as chiral selectors. Rarely, these targeted assays focus on more than 20 analytes and usually are restricted to a certain metabolite class. In a variety of cases, pre-column derivatization of metabolites has been performed, especially for amino acids, to improve separation and detection sensitivity. Triple quadrupole instruments are the detection methods of first choice in targeted assays. Here, issues like matrix effect, absence of blank matrix impair accuracy of results. In selected applications, multiple heart cutting 2D-LC (RP followed by chiral separation) has been pursued to overcome this problem and alleviate bias due to interferences. Non-targeted assays, on the other hand, are based on indirect approach involving tagging with a chiral derivatizing agent (CDA). Besides classical CDAs numerous innovative reagents and workflows have been proposed and are discussed. Thereby, a critical issue for the accuracy is often neglected, viz. the validation of the enantiomeric impurity in the CDA. The majority of applications focus on amino acids, hydroxy acids, oxidized fatty acids and oxylipins. Some potential clinical applications are highlighted.

Studies of intermolecular proton transfer, its influence on the liquid crystal properties and electrically-driven transport of chiral ions in mixtures of chiral liquid crystalline 4-phenylpyridine derivative and organic acids of various strength

Series of organic acids with various strength were mixed with chiral liquid crystalline 4-phenylpyridine derivative and tendency of these acid-base mixtures to form either intermolecular hydrogen-bonded associates or ionic systems was characterized basing on mid-infrared absorption spectroscopy. For this purpose several liquid crystalline 4-carboxybiphenyl acids were synthesized, including two new fluorinated chiral compounds, with enhanced strength of the acid. The stoichiometric acid-base mixtures were investigated in terms of their phase types and phase transition temperatures. The acid-base mixtures were doped into nematic liquid crystal host with negative dielectric anisotropy and characterized in terms of their miscibility in twisted nematic phase at room and elevated temperature and in terms of their helical twisting power. Selected mixtures exhibiting intermolecular proton transfer, good solubility in the liquid crystal host forming twisted nematic phase and sufficient helical twisting power to observe reflection band below 2500 nm were investigated in liquid crystal cells with respect to the change of the transmission in the near-infrared range upon high amplitude AC and DC electric fields, searching for broadening of the reflection band.

Unexpected effects of mobile phase solvents and additives on retention and resolution of N-acyl-D,L-leucine applying Cinchonane-based chiral ion exchangers

Chiral ion exchangers based on quinine (QN) and quinidine (QD), namely Chiralpak QN-AX and QD-AX as anionic and ZWIX(+) and ZWIX(-) as zwitterionic ion exchanger chiral stationary phases (CSPs) have been investigated with respect to their retention and chiral resolution characteristics. For the evaluation of the effects of the composition of the polar organic bulk solvents of the mobile phase (MP) and those of the organic acid and base additives acting as displacers necessary for a liquid chromatographic ion-exchange process, racemic N-(3,5-dinitrobenzoyl)leucine and other related analytes were applied. The main aim was to evaluate the impact of the MP variations on the observed, and thus the apparent enantioselectivity (αapp), and the retention factor. Significant differences were found using either polar protic methanol (MeOH) or polar non-protic acetonitrile (MeCN) solvents in combination with the acid and base additives as counter- and co-ions. It became clear, that the charged sites of both the chiral selectors of the CSPs and the analytes get specifically solvated, accompanied by the adsorption of all MP components on the CSP, thereby building a stagnant “stationary phase layer” with a composition different from the bulk MP. Via a systematic change of the MP composition, trends of resulting αapp and retention factors have been identified and discussed.In a detailed set of experiments, the effect of the concentration of the acid component in the MP containing MeOH or MeCN was specifically investigated, with the acid considered to be a displacer in anion-exchange type chromatographic systems.Surprisingly, all four chiral columns retained and resolved the tested N-acyl-Leu analytes with αapp values up to 21 within a retention factor window of 0.03 and 10 with pure MeOH as eluent. However, using pure MeCN as eluent, an almost infinite-long retention of the acidic analyte was noticed in all cases. We suggest that the rather different thickness of the solvation shells generated by MeOH or MeCN around the charged/chargeable sites of the chiral selector determines eventually the strength of the electrostatic selector–selectand interactions.As a control experiment we included the non-chiral N-acylglycine derivatives as analyte in all cases to support the interpretations with respect to the contribution of the enantioselective and non-enantioselective retention factor increments as a part of the observed αapp.

Three-phase electrodes: simple and efficient tool for analysis of ion transfer processes across liquid-liquid interface—twenty years on

In this review, we focus on major achievements of the three-phase electrode methodology applied for studying ion transfers across an interface between two immiscible liquids. Exactly 20 years ago, the group of electrochemists led by Fritz Scholz, invented an elegant and simple set up suitable to get access to the thermodynamics of ion transfers across liquid/liquid interface. Within the last two decades, besides determination of thermodynamics of the transfer of many important ionic substances, three-phase electrodes have been applied for many other purposes. Thermodynamics of interfacial chemical reactions, kinetics of ion and electron transfer, interfacial catalysis, recognition of chiral ions, synthesis of nano-particles, and biosensor development are some of the milestones achieved by application of three-phase electrodes. While elaborating briefly major achievements, future perspectives of this simple, but powerful electrochemical tool, have been also envisaged.

Asymmetry on the plus side

Organic Chemistry Numerous positively charged metal catalysts have been paired with chiral negative ions to select for just one of two mirror-image products. Genov et al. now report a potentially general strategy to invert the charges in this paradigm. Because intrinsically negative metal catalysts are comparatively rare, the authors appended a sulfonate group to the common bipyridyl ligand. Iridium complexes of this ligand paired with chiral positive ions could borylate just one of two aryl rings appended to carbon or phosphorus centers with high enantioselectivity. Science , this issue p. [1246][1] [1]: /lookup/doi/10.1126/science.aba1120

Enantioselective α-Amination of Acyclic 1,3-Dicarbonyls Catalyzed by N-Heterocyclic Carbene.

Herein, we describe a method for the catalytic enantioselective α-amination of α-substituted acyclic 1,3-ketoamides and 1,3-amidoesters that affords the products possessing N-substituted quaternary stereocenters with a chiral N-heterocyclic carbene (NHC). The reaction is based on the utilization of an intrinsic Brønsted base characteristic of NHC that enables the catalytic formation of a chiral ion pair comprising the enolate and the azolium ion. A series of challenging open-chain α-substituted 1,3-dicarbonyls are aminated via this method with ee's of ≤99%.

Recovery of High-Energy Photoelectron Circular Dichroism through Fano Interference.

It is commonly accepted that the magnitude of a photoelectron circular dichroism (PECD) is governed by the ability of an outgoing photoelectron wave packet to probe the chiral asymmetry of a molecule. To be able to accumulate this characteristic asymmetry while escaping the chiral ion, photoelectrons need to have relatively small kinetic energies of up to a few tens of electron volts. Here, we demonstrate a substantial PECD for very fast photoelectrons above 500eV kinetic energy released from methyloxirane by a participator resonant Auger decay of its lowermost O 1s excitation. This effect emerges as a result of the Fano interference between the direct and resonant photoionization pathways, notwithstanding that their individual effects are negligibly small. The resulting dichroic parameter has an anomalous dispersion: It changes its sign across the resonance, which can be considered as an analogue of the Cotton effect in the x-ray regime.

Evaluation of superficially porous particle based zwitterionic chiral ion exchangers against fully porous particle benchmarks for enantioselective ultra-high performance liquid chromatography

Zwitterionic chiral ion-exchange selectors (ZWIX) obtained by conjugation of quinine and 2-aminocyclohexanesulfonic acid via a carbamate bond were immobilized on three different silica particle types, viz. 120 Å 3 μm fully porous particles (FPP), 200 Å 3 μm FPP and 160 Å 2.7 μm superficially porous particles (SPP). Selector densities were determined by elemental analysis and the porosities of packed columns measured by inverse size exclusion chromatography with polystyrene standards. Liquid chromatographic tests with a set of chiral zwitterionic, acidic and basic analytes showed that the surface chemistry was successfully transferred to the distinct particle morphologies. The chromatographic performance of the three columns was evaluated by acquiring van Deemter curves. The results showed that the column packed with the SPP particles gives the best performance and kinetic plots further demonstrated that they represent the most favorable compromise in terms of speed, efficiency and pressure drop. Sub-minute separations could be accomplished at much lower pressure drop on the core-shell column, e.g. 2-amino-2-phenylbutyric acid was baseline separated in less than 15 s on a 5 cm long column. The Maxwell effective medium theory with second order approximation was applied to calculate effective diffusion in the mesoporous zones of SPP and FPP, which allowed eventually to deconvolute the individual peak dispersion contributions (ha, hb, hc,m, hc,s, hc,ads). The efficiency gain of the 160 Å SPP column compared to the 120 Å FPP (benchmark) column was mainly due to lower eddies (ha), smaller c-term accounting for slow adsorption-desorption kinetics in enantioselective chromatography (hc,ads), and also due to lower stationary mass transfer resistance (hc,s). Enhanced effective diffusion (Deff) in the SPP column contributed to a lower longitudinal diffusion (hb). In contrast, the mobile phase mass transfer coefficient was similar in the two columns leading to comparable hc,m contributions. This study discloses some options for improvement of the efficiency of ZWIX-type chiral columns such as replacing narrow pore (120 Å) by wide pore (200 Å) particles, substituting FPP by SPP and reducing the selector density on the surface.