Chiral stationary phases and applications in gas chromatography.

Chiral compounds are ubiquitous in nature and play a pivotal role in biochemical processes, in chiroptical materials and applications, and as chiral drugs. The analysis and determination of the enantiomeric ratio (er) of chiral compounds is of enormous scientific, industrial, and economic importance. Chiral separation techniques and methods have become indispensable tools to separate chiral compounds into their enantiomers on an analytical as well on a preparative level to obtain enantiopure compounds. Chiral gas chromatography and high-performance liquid chromatography have paved the way and fostered several research areas, that is, asymmetric synthesis and catalysis in organic, medicinal, pharmaceutical, and supramolecular chemistry. The development of highly enantioselective chiral stationary phases was essential. In particular, the elucidation and understanding of the underlying enantioselective supramolecular separation mechanisms led to the design of new chiral stationary phases. This review article focuses on the development of chiral stationary phases for gas chromatography. The fundamental mechanisms of the recognition and separation of enantiomers and the selectors and chiral stationary phases used in chiral gas chromatography are presented. An overview over syntheses and applications of these chiral stationary phases is presented as a practical guidance for enantioselective separation of chiral compound classes and substances by gas chromatography.

Phosphorylation in liquid sulfur dioxide under prebiotically plausible conditions.

In nature, organophosphates provide key functions such as information storage and transport, structural tasks, and energy transfer. Since condensations are unfavourable in water and nucleophilic attack at phosphate is kinetically inhibited, various abiogenesis hypotheses for the formation of organophosphate are discussed. Recently, the application of phosphites as phosphorylation agent showed promising results. However, elevated temperatures and additional reaction steps are required to obtain organophosphates. Here we show that in liquid sulfur dioxide, which acts as solvent and oxidant, efficient organophosphate formation is enabled. Phosphorous acid yields up to 32.6% 5' nucleoside monophosphate, 3.6% 5' nucleoside diphosphate, and the formation of nucleoside triphosphates and dinucleotides in a single reaction step at room temperature. In addition to the phosphorylation of organic compounds, we observed diserine formation. Thus, we suggest volcanic environments as reaction sites for biopolymer formation on Early Earth. Because of the simple recyclability of sulfur dioxide, the reaction is also interesting for synthesis chemistry.

From amino acid mixtures to peptides in liquid sulphur dioxide on early Earth.

The formation of peptide bonds is one of the most important biochemical reaction steps. Without the development of structurally and catalytically active polymers, there would be no life on our planet. However, the formation of large, complex oligomer systems is prevented by the high thermodynamic barrier of peptide condensation in aqueous solution. Liquid sulphur dioxide proves to be a superior alternative for copper-catalyzed peptide condensations. Compared to water, amino acids are activated in sulphur dioxide, leading to the incorporation of all 20 proteinogenic amino acids into proteins. Strikingly, even extremely low initial reactant concentrations of only 50 mM are sufficient for extensive peptide formation, yielding up to 2.9% of dialanine in 7 days. The reactions carried out at room temperature and the successful use of the Hadean mineral covellite (CuS) as a catalyst, suggest a volcanic environment for the formation of the peptide world on early Earth.

In Situ Mass Spectrometric and Kinetic Investigations of Soai's Asymmetric Autocatalysis.

Invited for the cover of this issue is Oliver Trapp and his co-workers at Ludwig-Maximilians-Universität München, the Max-Planck-Institute for Astronomy and Ruprecht-Karls-Universität Heidelberg. The image depicts a magic trick representing the autocatalytic process reported in the manuscript. Read the full text of the article at 10.1002/chem.202003260.

In Situ Mass Spectrometric and Kinetic Investigations of Soai's Asymmetric Autocatalysis.

Chemical reactions that lead to a spontaneous symmetry breaking or amplification of the enantiomeric excess are of fundamental interest in explaining the formation of a homochiral world. An outstanding example is Soai's asymmetric autocatalysis, in which small enantiomeric excesses of the added product alcohol are amplified in the reaction of diisopropylzinc and pyrimidine-5-carbaldehydes. The exact mechanism is still in dispute due to complex reaction equilibria and elusive intermediates. In situ high-resolution mass spectrometric measurements, detailed kinetic analyses and doping with in situ reacting reaction mixtures show the transient formation of hemiacetal complexes, which can establish an autocatalytic cycle. We propose a mechanism that explains the autocatalytic amplification involving these hemiacetal complexes. Comprehensive kinetic experiments and modelling of the hemiacetal formation and the Soai reaction allow the precise prediction of the reaction progress, the enantiomeric excess as well as the enantiomeric excess dependent time shift in the induction period. Experimental structural data give insights into the privileged properties of the pyrimidyl units and the formation of diastereomeric structures leading to an efficient amplification of even minimal enantiomeric excesses, respectively.

Thiete Dioxides as Templates Towards Twisted Scaffolds and Macrocyclic Structures.

Thiete dioxide units have been employed as a template for further functionalization through C-H activation strategies. Using simple thiete dioxide building blocks, a new library of axially chiral molecules has been synthesized that owe their stability to electrostatic interactions in the solid state. Similar starting materials were further engaged in the formation of cyclic trimeric structures, opening the pathway to unprecedented macrocyclic ring systems.

Selective Ruthenium-Catalyzed Transformation of Carbon Dioxide: An Alternative Approach toward Formaldehyde.

Formaldehyde is an important precursor to numerous industrial processes and is produced in multimillion ton scale every year by catalytic oxidation of methanol in an energetically unfavorable and atom-inefficient industrial process. In this work, we present a highly selective one-step synthesis of a formaldehyde derivative starting from carbon dioxide and hydrogen gas utilizing a homogeneous ruthenium catalyst. Here, formaldehyde is obtained as dimethoxymethane, its dimethyl acetal, by selective reduction of carbon dioxide at moderate temperatures (90 °C) and partial pressures (90 bar H2/20 bar CO2) in the presence of methanol. Besides the desired product, only methyl formate is formed, which can be transformed to dimethoxymethane in a consecutive catalytic step. By comprehensive screening of the catalytic system, maximum turnover numbers of 786 for dimethoxymethane and 1290 for methyl formate were achieved with remarkable selectivities of over 90% for dimethoxymethane.

Identifying high-performance catalytic conditions for carbon dioxide reduction to dimethoxymethane by multivariate modelling.

In times of a warming climate due to excessive carbon dioxide production, catalytic conversion of carbon dioxide to formaldehyde is not only a process of great industrial interest, but it could also serve as a means for meeting our climate goals. Currently, formaldehyde is produced in an energetically unfavourable and atom-inefficient process. A much needed solution remains academically challenging. Here we present an algorithmic workflow to improve the ruthenium-catalysed transformation of carbon dioxide to the formaldehyde derivative dimethoxymethane. Catalytic processes are typically optimised by comprehensive screening of catalysts, substrates, reaction parameters and additives to enhance activity and selectivity. The common problem of the multidimensionality of the parameter space, leading to only incremental improvement in laborious physical investigations, was overcome by combining elements from machine learning, optimisation and experimental design, tripling the turnover number of 786 to 2761. The optimised conditions were then used in a new reaction setup tailored to the process parameters leading to a turnover number of 3874, exceeding by far those of known processes.

Significant sensitivity enhancement in Hadamard transform high-performance liquid chromatography by application of long modulation sequences constructed from lower order sequences.

Hadamard encoding, utilizing pseudo-random injection sequences with n-bit (2n-1) elements, is applied in analytical sciences to enhance the signal-to-noise ratio (S/N) of weak analyte signals. We have developed a software approach that allows using Hadamard encoding on standard HPLC systems. This strategy is only limited by the number of instructions that can be transmitted to the autosampler and its performance degrades if an accumulation of chromatographic irregularities occurs while applying long modulation sequences. Here we demonstrate that such sequences (>4000 elements) can be subdivided into suitable subsequences, which can be independently executed. The measured subchromatograms are subsequently realigned and deconvoluted yielding a chromatogram with increased S/N. This opens an avenue to achieve unprecedented sensitivity gains. In the analysis of highly diluted nucleoside samples an S/N enhancement of up to 30-fold was observed. Furthermore, we applied the method to a sample containing the antibiotic drug fidaxomicin and found a significant sensitivity improvement that strongly depends on the applied elution conditions.

Direct Hadamard Transform Capillary Zone Electrophoresis without Instrumental Modifications.

We report the first successful implementation of a multiplexing method on a standard capillary electrophoresis system with UV detection that is independent of additional hardware. This was achieved using the Hadamard transform approach and employing vial exchange and voltage suspensions for translation of pseudorandom binary sequence elements into sample and background electrolyte injections of a capillary zone electrophoresis separation. Sequences exceeding peak capacity of the capillary were subdivided into shorter subsequences measured successively and realigned afterward based on EOF marker or analyte peaks. This way, we realized and deconvoluted modulation sequences as long as 8-bit (255 injections) for two systems containing either AMP or a mixture of the nucleotides (A,C,G,U)MP resulting in electropherograms of considerably improved signal-to-noise ratio. We achieved factors of intensity enhancement of around 6.9 and 5.2, respectively (theoretical maximum 8.0). This contribution, further, presents experimental and simulation studies on the effects on zones during injection and separation when experiencing voltage suspensions. Besides analysis of EOF behavior and influence of diffusion dispersion, we also provide data on the significance of specific electrophoretic errors such as peak position shift, inconsistent sample injection, and peak broadening on the quality of the inverse Hadamard transform. Moreover, the application of our approach to the practical analysis of a milk sample is described. The results demonstrate the applicability of multiplexing on unmodified standard CE instrumentation and establish a new suitable methodology to enhance the low sensitivity of on-column UV detection in capillary electrophoresis.

Improving the signal-to-noise ratio in gel permeation chromatography by Hadamard encoding.

Increasing sensitivity without further preconcentration steps is a major challenge in separation sciences. In this study a macro control approach that allows the implementation of Hadamard encoding on standard HPLC instrumentation was applied to the analysis of polysiloxane and polystyrene polymers by gel permeation chromatography. Here, the use of pseudo-random modulation sequences with 1023 elements (512 sample injections) improved the signal-to-noise ratio (S/N) by up to an order of magnitude. Comparison with conventional single injection confirmed the linearity and accuracy of the deconvolution process for the whole mass range of the column.

Synthesis of Naphthylpyridines from Unsymmetrical Naphthylheptadiynes and the Configurational Stability of the Biaryl Axis.

A series of different unsymmetrically substituted naphthyl-based diynes were synthesized. These substrates formed the foundation for the assembly of novel biaryls containing pyridine moieties with differently substituted five-membered rings in the backbone of the newly formed heterobiaryl system. The key step for their efficient construction was the photo- and cobalt-catalyzed [2 + 2 + 2] cycloaddition reaction between the corresponding naphthyldiyne and aceto- or benzonitrile. The heterobiaryl products have been isolated and investigated with respect to the configurational stability of their biaryl axis using dynamic chiral HPLC; subtle effects of the substitution pattern on the stability of the axis were observed. For several compounds the activation barriers (ΔG(‡)) of racemization were determined. Suitable substitution of the five-membered ring backbone exemplarily allowed the Co-catalyzed enantioselective cyclization to yield the enantiomerically enriched heterobiaryl.

Hyphenation of Hadamard Encoded Multiplexing Liquid Chromatography and Circular Dichroism Detection to Improve the Signal-to-Noise Ratio in Chiral Analysis.

The hyphenation of HPLC and circular dichroism (CD) detection is a useful analytical tool that can significantly facilitate the analysis (e.g., the assignment of the configuration) and quantitation of chiral compounds. HPLC-CD chromatograms often exhibit a low signal-to-noise ratio compared to chromatograms obtained by conventional UV detection. In this study we demonstrate for the first time the hyphenation of Hadamard encoded multiplexing HPLC with circular dichroism detection where positive and negative signals overlap. Here, a macro control of the HPLC instrument that was developed for conventional HPLC was implemented in HPLC-CD. In the chiral analysis of racemic samples, exemplified for warfarin, the signal-to-noise ratio could be enhanced by an order of magnitude. The presented results highlight the great modularity of the software controlled implementation of multiplexing and its facile transfer to other detection techniques.

Implementation of Hadamard encoding for rapid multisample analysis in liquid chromatography.

Multiplexing based on pseudo-binary modulation sequences is known to increase the signal-to-noise ratio. In this work, Hadamard transform multiplexing is used in high-performance liquid chromatography to increase the sample throughput. Using structured modulation sequences to encode and control sample injections in combination with a fitting algorithm to deconvolute the complex data allowed us to evaluate convoluted chromatograms of up to 128 samples containing three and five analytes, respectively, with good accuracy (<2% deviation). In comparison to conventional high-performance liquid chromatography the analysis time could be reduced by 30 and 55%, respectively.

Development of a straightforward and robust technique to implement hadamard encoded multiplexing to high-performance liquid chromatography.

High-performance liquid chromatography (HPLC) is an indispensable technique to separate, quantify, and identify a broad range of compounds. Recent advances in HPLC technology led to the development of ultrahigh-performance instruments that allow rapid sample analysis with high efficiency. Nevertheless, there is still the opportunity to increase the sample throughput and to improve the signal-to-noise ratio by the application of multiplexing, where the injected samples are encoded with defined sequences. The obtained signal is then deconvoluted to give conventional chromatograms. In this work we present a method and technique which can be easily implemented in commercially available HPLC instruments to perform multiplexing analysis. Using our approach, multiplexing can be performed on standard laboratory equipment by software control and offers an inherent advantage in sensitivity and minimization of analysis time, demonstrated for the analysis of highly diluted polynuclear aromatic hydrocarbon (PAH) samples in water.