The dawn of cross-coupling

Ananikov V. P., Nature Catalysis, 2021, 9, 3011-3042.
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Methods for the direct one-step replacement of a hydrogen atom in a C–H bond by an organic functional group can create enormous possibilities for synthetic applications. On the way to solve this challenge, the discovery of the reaction of organopalladium complexes with olefins opened a new era in catalysis and organic chemistry.

Visualization of the Mechanical Wave Effect on Liquid Microphases and Its Application for the Tuning of Dissipative Soft Microreactors

Kashin A. S., Degtyareva E. S., Ananikov V. P., J. Am. Chem. Soc. Au, 2021, ASAP.
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The development of approaches for creation of adaptive and stimuli-responsive chemical systems is particularly important for chemistry, materials science, and biotechnology. The understanding of response mechanisms for various external forces is highly demanded for the rational design of task-specific systems. Here, we report direct liquid-phase scanning electron microscopy (SEM) observations of the high frequency sound-wave-driven restructuring of liquid media on the microlevel, leading to switching of its chemical behavior. We show that under the action of ultrasound, the microstructured ionic liquid/water mixture undergoes rearrangement resulting in formation of separated phases with specific compositions and reactivities. The observed effect was successfully utilized for creation of dissipative soft microreactors formed in ionic liquid/water media during the sonication-driven water transfer. The performance of the microreactors was demonstrated using the example of controlled synthesis of small and uniform gold and palladium nanoparticles. The microsonication stage, designed and used in the present study, opened unique opportunities for direct sonochemical studies with the use of electron microscopy.

Nanoscale Advancement Continues—From Catalysts and Reagents to Restructuring of Reaction Media

Kashin A.S., Ananikov V. P., Angew. Chem. Int. Ed., 2021, ASAP.
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Comprehensive studies dedicated to the search for specific properties of matter at the micro- and nanoscales have greatly enriched the fields of chemistry and materials science. From the point of view of synthetic chemistry, discoveries in the field of nanoscale catalysis, in which the size effects of active centers are used to accelerate the reactions, are of particular importance. However, another approach for the promotion of chemical transformations based on the micro- or nanoconfinement of reacting molecules or even on the structuring of the reaction media as a whole is gaining interest as a highly valuable tool. Herein, we highlight the example of an increase in the efficiency of phenol alkylation and tert-butylation of benzyl alcohol in reaction media based on ionic liquids by the creation of acidic microdomains in the presence of small molecule additives.

Metal nanoparticles in ionic liquids: Synthesis and catalytic applications

Seitkalieva M.M., Samoylenko D.E., Lotsman K.A., Rodygin K.S., Ananikov V.P., Coord. Chem. Rev., 2021, 445, 213982.
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The development of metal nanoparticle chemistry in ionic liquids (ILs) media has had a paramount impact on various fields, including catalysis, energy research, nanotechnology and materials science, among many other directions. This review highlights various methods for producing metal nanoparticles in ILs, with particular focus on palladium, platinum, ruthenium, copper, nickel, cobalt, gold, silver, iron and alloys. The scope of methods includes chemical syntheses as well as electrochemical and physical approaches. Due to strong practical demand, a particular emphasis is placed on the catalytic activity of the obtained nanoparticles in a variety of reactions.

Formation and stabilization of nanosized Pd particles in catalytic systems: Ionic nitrogen compounds as catalytic promoters and stabilizers of nanoparticles

Chernyshev V.M., Khazipov O.V., Eremin D.B., Denisova E.A., Ananikov V.P., Coord. Chem. Rev., 2021, 437, 213860.
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Actual palladium catalysts in synthetic transformations in reaction mixtures are usually represented by dynamic catalytic systems that contain various interconvertible forms of metal particles, including molecular complexes, metal clusters, and nanoparticles. The low thermodynamic stability of Pd nanoparticles can lead to their aggregation and, as a consequence, to the deactivation of the catalytic systems. Therefore, stabilization of nanosized Pd particles is of key importance to ensure efficient catalysis. This review discusses the main pathways for the formation of Pd nanoparticles and clusters from various precatalysts in catalytic systems, as well as current views on the mechanisms of stabilization of these nanosized Pd particles using various types of ionic nitrogen compounds, such as ammonium, amidinium, azolium, and pyridinium salts. The use of ionic nitrogen compounds as specially added or in situ formed stabilizers, ligands, catalytic promoters, heterogenized catalysts (supported ionic liquid phase, SILP) and reaction media (ionic liquids) is exemplified by several important catalytic reactions. The main effects of ionic nitrogen compounds on catalytic processes are also discussed, including possible involvement in catalytic cycles and unwanted side reactions.

Ionic liquids: prospects for nucleic acid handling and delivery

Egorova K.S., Posvyatenko A.V., Larin S.S., Ananikov V.P., Nucleic Acids Res., 2021, 49, 1201–1234.
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Operations with nucleic acids are among the main means of studying the mechanisms of gene function and developing novel methods of molecular medicine and gene therapy. These endeavours usually imply the necessity of nucleic acid storage and delivery into eukaryotic cells. In spite of diversity of the existing dedicated techniques, all of them have their limitations. Thus, a recent notion of using ionic liquids in manipulations of nucleic acids has been attracting significant attention lately. Due to their unique physicochemical properties, in particular, their micro-structuring impact and tunability, ionic liquids are currently applied as solvents and stabilizing media in chemical synthesis, electrochemistry, biotechnology, and other areas. Here, we review the current knowledge on interactions between nucleic acids and ionic liquids and discuss potential advantages of applying the latter in delivery of the former into eukaryotic cells.

Neural Network Analysis of Electron Microscopy Video Data Reveals the Temperature‐Driven Microphase Dynamics in the Ions/Water System

Kashin A.S., Boiko D.A., Ananikov V.P., Small, 2021, 2007726.
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Real‐time field‐emission scanning electron microscopy (FE‐SEM) measurements and neural network analysis were successfully merged to observe the temperature‐induced behavior of soft liquid microdomains in mixtures of different ionic liquids with water. The combination of liquid FE‐SEM and in situ heating techniques revealed temperature‐driven solution restructuring for ions/water systems with different water states and their critical point behavior expressed in a rapid switch between thermal expansion and shrinkage of liquid microphases at temperatures of ≈100–130 °C, which was directly recorded on electron microscopy videos. Automation of FE‐SEM video analysis by a neural network approach allowed quantification of the morphological changes in ions/water systems during heating on the basis of thousands of images processed with a speed almost equal to the frame rate of original electron microscopy videos. Tracking and evolution of the micro‐heterogeneous domains, hypothesized in the Ioliomics concept, was mapped and quantified for the first time. The present study describes the concept for quick acquisition of big data in electron microscopy, develops rapid neural network analysis and shows how to link microscopic data to fundamental molecular properties.

Development of 3D+G Printing for the Design of Customizable Flow Reactors

Kucherov F.A., Romashov L.V., Ananikov V.P., Chem. Engin. J., 2021, 132670.
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An in-depth study of chemical processes at plastic-metal interfaces led to the development of a novel approach to the creation of lab-on-a-chip microflow reactors. The developed method combines 3D printing of the reactor core by fused deposition modeling using conventional plastic material (ABS), followed by chemical (electroless copper) and galvanic plating (nickel) of the resulting piece (in overall, 3D+G printing process). Detailed analysis of the pieces along all 3D+G stages by electron microscopy revealed step-by-step processes on the plastic-metal interface, which finally allowed innovative reactor design. Despite being made from low-cost materials in a simple procedure, flow reactors are characterized by chemical resistance, versatile geometry, modular design and excellent operating performance. Complete reactor assembly was formulated and successfully tested in a variety of chemical processes targeted on biologically active molecules, including homogeneous, heterogeneous and photochemical reactions. Reactor modules can be combined into cascades to perform sequential reactions. Metallized reactors can be used multiple times in a variety of chemical processes.

Deep neural network analysis of nanoparticle ordering to identify defects in layered carbon materials

Boiko D.A., Pentsak E.O., Cherepanova V.A, Gordeev E.G., Ananikov V.P., Chem. Sci., 2021, Advance Article.
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Smoothness/defectiveness of the carbon material surface is a key issue for many applications, spanning from electronics to reinforced materials, adsorbents and catalysis. Several surface defects cannot be observed with conventional analytic techniques, thus requiring the development of a new imaging approach. Here, we evaluate a convenient method for mapping such "hidden" defects on the surface of carbon materials using 1–5 nm metal nanoparticles as markers. A direct relationship between the presence of defects and the ordering of nanoparticles was studied experimentally and modeled using quantum chemistry calculations and Monte Carlo simulations. An automated pipeline for analyzing microscopic images is described: the degree of smoothness of experimental images was determined by a classification neural network, and then the images were searched for specific types of defects using a segmentation neural network. An informative set of features was generated from both networks: high-dimensional embeddings of image patches and statics of defect distribution.

Building bio-Profiles for common catalytic reactions

Egorova K.S., Galushko A.S., Dzhemileva L.U., D'yakonov V.A., Ananikov V.P., Green Chem., 2021, 23, 6373-6391.
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In this work, we present a powerful approach for fast assessment of the potential biological impact of chemical processes on living organisms. This approach includes building bio-Profiles based on cytotoxicity data and calculating bio-Factors for chemical reactions. Bio-Profiles allow visual determination of substances with the highest and the lowest contributions to the "overall cytotoxicity" of a given chemical process, whereas bio-Factors indicate the quantitative change in the "overall cytotoxicity" during the process. This information provides the necessary initial description of the plausible biological impact of a given chemical reaction and can be used for subsequent optimization of the process from the viewpoint of toxicity of its components. To illustrate the proposed concept, measurements of biological activity were carried out for ca. thirty compounds in two cell lines and bio-Profiles were constructed for four practically relevant catalytic reactions (Suzuki cross-coupling, oxidative C–C coupling, the Friedel–Crafts reaction, and the Heck reaction). In addition, practical application of bio-Profiles was illustrated by the example of the Suzuki reaction and it showed the largest influence of aryl halides (X = Cl, Br, I), a modest influence of solvents and a small contribution of the catalyst to the overall toxicity profile.

Biomass- and calcium carbide-based recyclable polymers

Metlyaeva S.A., Rodygin K.S., Lotsman K. A., Samoylenko D.E., Ananikov V.P., Green Chem., 2021, 23, 2487.
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Biomass is a renewable source of valuable feedstock for the chemical industry of the future. A promising approach to the utilization of valuable components of biomass is the synthesis of monomers and polymers, if the overall technology is designed for a clean cycle without pollution of the environment with newly created polymers. In this work, we have developed a methodology for the recycling of polymers based on biomass and calcium carbide. First, we modified a series of biomass-derived terpene alcohols with calcium carbide followed by polymerization of the isolated vinyl ethers. Then, to study the recycling potential, the obtained polymers were subjected to pyrolysis at moderate temperatures (200–450 °C). The pyrolysis products were analyzed using TGA-MS, GC-MS, and NMR, and it was found that the polymers can be transformed quite easily. The products of the pyrolysis consisted of the starting terpenols, as well as the corresponding non-toxic ketones or aldehydes: up to 87% of the starting alcohol or up to 100% of the total sum of alcohol + aldehyde or alcohol + ketone (GC-yields). Then, the reaction mixture was hydrogenated and resulted in the formation of starting alcohol only. According to the studied pathway of polymers re-building, a terpene fragment attached to the main polyethylene chain through an oxygen atom promotes the transformation of the obtained polymers. Thus, the products of pyrolysis are environmentally friendly and can be reused in the further synthesis of monomers. The developed system has shown a unique assembling/disassembling ability and advances the concept of reusable bio-derived high value-added materials.

A large-scale study of ionic liquids employed in chemistry and energy research to reveal cytotoxicity mechanisms and to develop safe design guide

Dzhemileva L.U., D'yakonov V.A., Seitkalieva M.M., Kulikovskaya N.S., Egorova K.S., Ananikov V.P., Green Chem., 2021, ASAP.
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Device-level applications of organic electrolytes unavoidably imply extensive contacts with the environment. Despite their excellent scientific potential, ionic liquids (ILs) cannot be approved for practical usage until their life cycle and impact on the environment are assessed. In this work, we carried out the first large-scale study on the mechanisms of the cytotoxic action of various classes of ionic liquids, including imidazolium, pyridinium, pyrrolidinium, ammonium, and cholinium ILs (25 in total). We determined the biological effect of these ILs in seven cell lines of various origins (HEK293 (human embryonic kidney), U937 (human myeloid leukemia), Jurkat (human T-cell leukemia), HL60 (human acute promyelocytic leukemia), K562 (human chronic myelogenous leukemia), A549 (human alveolar adenocarcinoma), A2780 (human ovarian carcinoma)). The induction of apoptosis in cells upon treatment with the majority of the ILs tested was subsequently demonstrated. The new data suggest that ILs trigger the mitochondrial pathway of apoptosis due to the dissipation of the mitochondrial membrane potential and release of cytochrome c from mitochondria into the cytoplasm. The obtained results corroborate the earlier reported data on the cytotoxic effects of ILs, providing new insight into the detailed mechanisms of IL cytotoxicity. In addition, the first illustrative guide to be employed for designing ILs with targeted biological activity is compiled. As a possible link between the electrochemical behavior of ILs and their biological activity, the relation between IL cytotoxicity and the electrophoretic mobility of IL cations is assessed.

Systematic study of aromatic-ring-targeted cycloadditions of HMF platform chemicals

Averochkin G.M., Gordeev E.G., Skorobogatko M.K., Kucherov F.A., Ananikov V.P., ACS Sustainable Chem. Eng., 2021, ASAP.
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The reaction space of the furanics-to-aromatics (F2A) conversion process for HMF-based platform chemicals has been explored both experimentally and by quantum chemistry methods. For the first time, a structure-activity relationship was established in furan-yne cycloaddition for a number of different HMF derivatives. Correlations between the activation energy of the cycloaddition stage and the structure of the substrates were established by molecular modeling methods. Analysis of the concerted and stepwise mechanisms of cycloaddition in the singlet and triplet electronic states of the molecular system was carried out. A series of biobased 7-oxanorbornadienes was obtained in the reaction with dimethyl acetylenedicarboxilate. Various methods of aromatization of the obtained [4+2] adducts have been examined. Rearrangement catalyzed by a Lewis acid leads to the formation of a phenol derivative, while reduction by diironnonacarbonyl leads to the formation of functionalized benzene. Systematic study of the cycloaddition process has revealed a simple way to analyze and predict the relative reactivity of furanic substrates.

Catalytic C‐H Functionalization of Unreactive Furan Cores in the Bio‐derived Platform Chemicals

Karlinskii B.Ya., Ananikov V.P., Chem. Sus. Chem, 2021, ASAP.
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C‐H functionalization is one of the most convenient and powerful tools in the arsenal of modern chemistry, deservedly nominated as the "Holy Grail" of organic synthesis. A frequent disadvantage of this method is the need for harsh reaction conditions to carry out transformations of inert C‐H bonds, which limits the possibility of its use for modifying less stable substrates. Biomass‐derived furan platform chemicals, which have a relatively unstable aromatic furan core and highly reactive side chain substituents, are extremely promising and valuable organic molecules that are currently widely used in a variety of research and industrial fields. The high sensitivity of furan derivatives to acids, strong oxidants, and high temperatures significantly limits the use of classical methods of C‐H functionalization for their modification. New methods of catalytic functionalization of non‐reactive furan cores are urgently required to obtain a new generation of materials with controlled properties and potentially bioactive substances.

Biomass-Derived Ionic Liquids Based on a 5-HMF Platform Chemical: Synthesis, Characterization, Biological Activity, and Tunable Interactions at the Molecular Level

Seitkalieva M.M., Vavina A.V., Posvyatenko A.V., Egorova K.S., Kashin A.S., Gordeev E.G., Strukova E.N., Romashov L.V., Ananikov V.P., ACS Sustainable Chem. Eng., 2021, 9, 3552–3570.
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A new family of protic ammonium ionic liquids (ILs) with various inorganic anions was synthesized from bio-derived 5-HMF. Starting with cellulose biomass, a complete preservation of the C6 unit was achieved throughout the synthetic sequence (no carbon loss). Evaluation of green metrics showed a significant advantage of the developed bio-derived pathway to access ILs from a natural renewable source, depending on feasible routes to 5-HMF manufacturing. The reduced number of synthetic steps and availability of the starting materials were the key advantages. Experimental physicochemical and biological studies, as well as computational modeling revealed a unique multifunctional intrinsic organization of these bio-derived ILs. The nature of interactions between the cations and anions of the novel ILs was mapped at the molecular level. The substituents in the cationic core and the nature of the original building blocks had a prominent impact on cytotoxicity of the novel ILs. The obtained results suggest possible sustainable applications of the least toxic ILs, while the regulation of biological activity of the ILs via the corresponding structural adjustments can find biological and medicinal applications. The 5-HMF-derived IL with a sulfate anion demonstrated potentially useful properties in dissolution of microcrystalline cellulose.

Biobased C6-Furans in Organic Synthesis and Industry: Cycloaddition Chemistry as a Key Approach to Aromatic Building Blocks

Kucherov F.A., Romashov L.V., Averochkin G.M., Ananikov V.P., ACS Sustainable Chem. Eng., 2021, 9, 3011.
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Rapid development in the area of cellulose biomass conversion to furanic platform chemicals has led to expectations of their valuable practical use. Impressive research progress in this direction has resulted in several achievements but at the same time identified a key challenge—the necessity to produce aromatic compounds. In this perspective, we analyze the current stage of development of the furanics-to-benzene conversion process (F2B process) in connection with a bioderived route to aromatic compounds. Cycloaddition reactions between bioderived C 6-furans as diene components and alkene/alkyne units are discussed in detail, followed by considering the subsequent aromatization reaction. Progress in the development of the F2B process and future challenges are outlined in this perspective. The key role of the F2B process in the overall biomass to aromatics transformation is discussed in view of the implementation of carbon neutral sustainable technologies in practice.

Stabilization of the Pd–NHC framework with 1,2,4-triazol-5-ylidene ligands toward decomposition in alkaline media

Chernenko A.Yu., Astakhov A.V., Kutyrev V.V., Gordeev E.G., Burykina J.V., Minyaev M.E., Khrustalev V.N., Chernyshev V.M., Ananikov V.P., Inorg. Chem. Front., 2021, Advance Article.
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Complexes of Pd(II) with NHC ligands can suffer facile decomposition in the presence of alkali metal hydroxides, alkoxydes and other strong oxygen-containing bases via the reductive elimination of the NHC and Pd-coordinated base anion, the so-called O–NHC coupling. O–NHC coupling can represent a serious problem for the stability of Pd/NHC catalytic systems in numerous practically important reactions conducted in the presence of bases. In the present study, a new approach to stabilizing the Pd–NHC bond against cleavage by strong bases was developed. The approach relies on the installation of an NH–acidic RNH substituent at position 3 of the triazole ring of the 1,2,4-triazol-5-ylidene ligand. A series of new Pd/NHCs containing RNH substituents (R = Ac, Ph, alkyl) in triazole NHC ligands were synthesized. These complexes undergo reversible deprotonation of the RNH group in strong alkaline media and demonstrate superior stability of the Pd–NHC bond, significantly higher than complexes of similar structure without the RNH group. DFT calculations revealed that the anionic Pd/NHC complex containing an N-deprotonated acetamido group (R = Ac) is more kinetically stable against O–NHC coupling and less prone to lose NHC via heterolytic dissociation of the Pd–NHC bond than the neutral complex. The new complexes with RNH-functionalized NHC ligands were tested as precatalysts in the Suzuki–Miyaura coupling of p-tolyl bromide with phenylboronic acid in the presence of KOH and revealed more than 2 times higher TONs than similar complexes without the RNH group or ligandless Pd system.

Different Effects of Metal-NHC Bond Cleavage on the Pd/NHC and Ni/NHC Catalyzed α-Arylation of Ketones with Aryl Halides

Shepelenko K.E., Soliev S.B., Galushko A.S., Chernyshev V. M., Ananikov V. P., Inorg. Chem. Front., 2021, 8, 1511-1527.
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Recently, the dynamic nature of the metal-NHC bond has been proposed and the key role of chemical evolution in changing the nature of catalytically active sites is now an emerging topic. A comparative analysis of the ketone α-arylation reaction with aryl halides, catalyzed by M/NHC complexes, was carried out in the present study and showed a fundamental difference in the behavior of the catalytic system for M = Ni and Pd. In situ evolution of Ni/NHC complexes with cleavage of the Ni-NHC bond leads to complete deactivation of catalytic systems, regardless of the nature of the aryl halide ArX (X = Cl, Br, I). However, upon Pd/NHC catalysis, the cleavage of the Pd-NHC bond causes deactivation only in the case of aryl chlorides. In the reactions of more active aryl iodides and aryl bromides, NHC-disconnected Pd species, formed as a result of the chemical transformation of Pd/NHC complexes, can provide effective catalysis in the arylation reaction under study. New catalytic systems based on Pd/NHC and Ni/NHC complexes generated in situ from stable imidazolium salts, IPrHCl and IPr*OMeHCl, and Pd(OAc)2 (0.1 mol%) or NiCl2Py2 (5 mol%) were developed for the selective α-arylation of methylaryl ketones (Pd-catalysis) and other ketones less prone to aldol-crotonic condensation (Ni-catalysis). The present study has shown that the different effects of the metal-NHC bond cleavage should be taken into account for the efficient choice and optimization of catalytic systems to carry out arylation reaction with various aryl halides.

Comparative Study of Aryl Halides in Pd-Mediated Reactions: Key Factors Beyond the Oxidative Addition Step

Galushko A.S., Prima D.O., Burykina J.V., Ananikov V.P., Inorg. Chem. Front., 2021, 8, 620-635.
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Although practical catalytic transformations involving aryl chlorides are difficult to implement, they are highly desirable since the starting compounds are inexpensive and readily available. Retarded oxidative addition of aryl chlorides to palladium catalyst as compared to aryl bromides and aryl iodides is typically taken for granted as an explanation for the overall inefficiency of the process. The comparative experimental study and analysis reported herein suggest that oxidative addition cannot be considered the sole reason of the observed low reactivity of aryl chlorides. Other factors were found to play an important role in influencing the reactivity of aryl halides. The present findings suggest that a substantial revision of catalyst design principles is necessary for successful transformations of aryl chlorides.

Evidence for “cocktail”-type catalysis in Buchwald–Hartwig reaction. A mechanistic study

Prima D.O., Madieva M., Burykina Ju.V., Minyaev M.V., Boiko D.A., Ananikov V. P., Catal. Sci. Technol., 2021, ASAP.
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The mechanism of the C–N cross-coupling reaction, catalyzed by palladium complexes with N-heterocyclic carbene ligands (Pd/NHC), was evaluated in detail at the molecular and nanoscale levels. For the first time, the formation of a "cocktail"-type catalytic system was proven for the Buchwald–Hartwig reaction. The unique ability of the Pd/NHC system to generate several types of catalytic centers (Pd complexes, clusters and nanoparticles) and the involvement of complementary pathways (homogeneous and heterogeneous) were discovered to take place in a "one pot" manner directly in the reaction vessel. Access to various catalytic centers from a single and readily available Pd/NHC complex is the key to designing a universal catalytic system with adaptive tuning capability.

Organocatalytic Deuteration Induced by the Dynamic Covalent Interaction of Imidazolium Cations with Ketones

Galkin K.I., Gordeev E.G., Ananikov V.P., Adv. Synth. Catal., 2021, ASAP.
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In this article, we suggest a new organocatalytic approach based on the dynamic covalent interaction of imidazolium cations with ketones. A reaction of N‐alkyl imidazolium salts with acetone‐d6 in the presence of oxygenated bases generates a dynamic organocatalytic system with a mixture of protonated carbene/ketone adducts acting as H/D exchange catalysts. The developed methodology of the pH‐dependent deuteration showed high selectivity of labeling and good chiral functional group tolerance. Here we report a unique methodology for efficient metal‐free deuteration, which enables labeling of various types of α‐acidic compounds without trace metal contamination.

Transition metal “cocktail”-type catalysis

Prima D.O., Kulikovskaya N.S., Galushko A.S., Mironenko R.M., Ananikov V.P., Curr. Opin. Green Sustain. Chem., 2021, ASAP.
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An introduction to the concept of a "cocktail" of catalysts is provided together with a brief description of experimental methods and approaches to study "cocktail"-type catalytic systems. The evolution of catalytically active centers and dynamic phenomena in heterogeneous and homogeneous catalysis are summarized. The key role of processes such as leaching, ligand transformations, aggregation and redeposition is highlighted. Two principal pathways to afford "cocktail"-type catalytic systems (bottom-up and top-down) are discussed in view of the participation of metal complexes, clusters and nanoparticles in catalysis.

Ni/NHC catalysis in C–H functionalization using air-tolerant nickelocene and sodium formate for in situ catalyst generation

Khazipov O.V., Shepelenko K.E., Pasyukov D.V., Chesnokov V.V., Soliev S.B., Chernyshev V.M., Ananikov V.P., Org. Chem. Front., 2021, ASAP.
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C–H functionalization in the area of fine organic synthesis is dominated by noble metal catalysts, which represent the most expensive and least sustainable options. Sustainable C–H functionalization may involve Ni catalysts. However, Ni(0) complexes are unstable under regular conditions and are more difficult to obtain as compared to Pd(0) or Rh( I). In the present study, a facile method for Ni0/NHC-catalyzed C–H alkylation and alkenylation of heteroarenes with alkenes and internal alkynes is presented. This method relies on the in situ generation of Ni0/NHC complexes from air-tolerant bench-stable precursors, Ni(Cp)2, NHCHCl salts and sodium formate. The optimized catalytic system demonstrates broad substrate scope and high selectivity (>60 products were obtained in up to 99% isolated yield). The approach represents a user-friendly alternative for air-sensitive and labile (NHC)Ni0 and Ni(COD)2 precatalysts or complexes. The intermediates involved in the catalytic system were investigated and possible decomposition routes were mapped with NMR and ESI-MS. Rational control over the catalyst decomposition pathways further strengthens the sustainability of the procedure.

Synergistic/antagonistic cytotoxic effects in mixtures of ionic liquids with doxorubicin or mitoxantrone

Egorova K.S., Posvyatenko A.V., Fakhrutdinov A.N., Galushko A.S., Seitkalieva M.M., Ananikov V.P., J. Mol. Liq., 2021, 323, 114870.
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An NMR spectroscopy study of ionic liquid/drug systems at a molecular level and a scanning electron microscopy study in the liquid phase at a nano-scale level were applied for the first time to study ionic preparations of well-known anticancer drugs. Cytotoxicity of binary mixtures of imidazolium ionic liquids with doxorubicin or mitoxantrone was studied in human colorectal adenocarcinoma CaCo-2 cells, and the evidence of synergism/antagonism was assessed. Of the ten drug-containing mixtures tested, four demonstrated significant synergistic or antagonistic cytotoxic effects. These mixtures revealed distinct micro-structured patterns, as shown by scanning electron microscopy, whereas nuclear magnetic resonance evidenced the formation of strong interactions between the drug and the ionic liquid in some of the mixtures. Notably, all the test substances induced the cell death via necrosis in the CaCo-2 cell line, thus revealing the dependence of the observed cytotoxic effects on the cell type. The observed synergistic effects suggested possible benefits of applying ionic liquids in drug formulations.

New Bio‐Based Furanic Materials Effectively Absorb Metals from Water and Exert Antimicrobial Activity

Klushin V.A., Kashparova V.P., Chizhikova A.A., Andreeva V.E., Chernysheva D.V., Ulyankina A.A., Kutsevalova O.Yu., Smirnova N.V., Kravchenko O.A., Ananikov V.P., Chem. Eur. J., 2021, ASAP.
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Development of sustainable bio‐based materials for removal of toxic contaminants from water is a high priority goal. Novel bio‐based binary and ternary copolymers with enhanced ion‐exchange, adsorption and antibacterial properties were obtained using plant biomass‐derived diallyl esters of furandicarboxylic acid (FDCA) as crosslinking agents and easily available vinyl monomers. The synthesized copolymer materials showed higher sorption capacities for Ni(II), Co(II) and Cu(II) compared to the commercial ion‐exchange resins and maintained their high metal adsorption capacities for over 10 cycles of regeneration. The synthesized copolymer gels containing 1–5 wt% of the crosslinker showed excellent water absorption capacities. The synthesized copolymers with 1% crosslinker content showed swelling ratios high enough to also act as moisture absorbents. The synthesized copolymers with crosslinker content of 10 wt% performed as contact‐active antibacterials by inhibiting the growth of Gram‐positive ( S. aureus) and Gram‐negative bacteria (E. coli, K. pneumonia) in suspension tests.

Comparing Separation vs. Fresh Start to Assess Reusability of Pd/C Catalyst in Liquid-Phase Hydrogenation

Mironenko R., Saybulina E., Trenikhin M., Izmailov R., Lotsman K., Rodygin K., Ananikov V.P., ChemCatChem, 2021, ASAP.
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The reusability of metal catalysts is a key issue for the potential application of new catalysts in research and industrial practice. The most common procedure for testing catalyst reusability in liquid-phase heterogeneous reactions is based on separating a catalyst from a reaction mixture followed by the next run. An alternative procedure called "fresh start" consists of the addition of a new portion of reagents to the reaction mixture without any isolation operation. In this work, we compare both procedures in a model Pd/C-catalyzed hydrogenation with different heteroatoms, e.g., O-, S-, and N-vinyl derivatives. It was shown that regardless of whether the catalyst is stable or potentially poisoned during the reaction, both procedures lead to comparable results. It appears that a much easier implementation of a fresh start procedure may be an option of choice. The possibilities of using both procedures to rationalize the experimental protocol for assessing Pd/C catalyst reusability in liquid-phase hydrogenations are discussed.

Detection and Structural Investigation of Elusive Palladium Hydride Intermediates Formed from Simple Metal Salts

Kostyukovich A.Yu., Burykina Ju.V., Eremin D.B., Ananikov V.P., Inorg. Chem., 2021, 60, 7128–7142.
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The Mizoroki–Heck reaction is one of the most known and best studied catalytic transformations and has provided an outstanding driving force for the development of catalysis and synthetic applications. Three out of four classical Mizoroki–Heck catalytic cycle intermediates contain Pd–C bonds and are well known and studied in detail. However, a simple palladium hydride (which is formed after the product-releasing beta-H-elimination step) is a kind of elusive intermediate in the Mizoroki–Heck reaction. In the present study, we performed a combined theoretical and mass spectrometry (MS) study of palladium hydride complexes [PdX2H]− (X = Cl, Br, and I), which are reactive intermediates in the Mizoroki–Heck reaction. Static and molecular dynamic calculations revealed that these species have a T-shaped structure with a trans-arrangement of halogen atoms. Other isomers of [PdX2H]− are unstable and easily rearrange into the T-shaped form or decompose. These palladium hydride intermediates were detected by MS in precatalyst activation using NaBH4, Et3N, and a solvent molecule as reducing agents. Online MS monitoring allowed the detection of [PdX2H]− species in the course of the Mizoroki–Heck reaction.

3D Printing to Increase the Flexibility of the Chemical Synthesis of Biologically Active Molecules: Design of On-Demand Gas Generation Reactors

Erokhin K.S., Gordeev E.G., Samoylenko D.E., Rodygin K.S., Ananikov V.P., Int. J. Mol. Sci., 2021, 22, 9919.
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The development of new drugs is accelerated by rapid access to functionalized and D-labeled molecules with improved activity and pharmacokinetic profiles. Diverse synthetic procedures often involve the usage of gaseous reagents, which can be a difficult task due to the requirement of a dedicated laboratory setup. Here, we developed a special reactor for the on-demand production of gases actively utilized in organic synthesis (C2H2, H2, C2D2, D2, and CO2) that completely eliminates the need for high-pressure equipment and allows for integrating gas generation into advanced laboratory practice. The reactor was developed by computer-aided design and manufactured using a conventional 3D printer with polypropylene and nylon filled with carbon fibers as materials. The implementation of the reactor was demonstrated in representative reactions with acetylene, such as atom-economic nucleophilic addition (conversions of 19–99%) and nickel-catalyzed S-functionalization (yields 74–99%). One of the most important advantages of the reactor is the ability to generate deuterated acetylene (C2D2) and deuterium gas (D2), which was used for highly significant, atom-economic and cost-efficient deuterium labeling of S,O-vinyl derivatives (yield 68–94%). Successful examples of their use in organic synthesis are provided to synthesize building blocks of heteroatom-functionalized and D-labeled biologically active organic molecules.

Computational Design of Radical Recognition Assay with the Possible Application of Cyclopropyl Vinyl Sulfides as Tunable Sensors

Sahharova L.T., Gordeev E.G., Eremin D.B., Ananikov V.P., Int. J. Mol. Sci., 2021, 22, 7637.
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The processes involving the capture of free radicals were explored by performing DFT molecular dynamics simulations and modeling of reaction energy profiles. We describe the idea of a radical recognition assay, where not only the presence of a radical but also the nature/reactivity of a radical may be assessed. The idea is to utilize a set of radical-sensitive molecules as tunable sensors, followed by insight into the studied radical species based on the observed reactivity/selectivity. We utilize this approach for selective recognition of common radicals—alkyl, phenyl, and iodine. By matching quantum chemical calculations with experimental data, we show that components of a system react differently with the studied radicals. Possible radical generation processes were studied involving model reactions under UV light and metal-catalyzed conditions.

Quaternary Ammonium Compounds (QACs) and Ionic Liquids (ILs) as Biocides: From Simple Antiseptics to Tunable Antimicrobials

Vereshchagin A.N., Frolov N.A., Egorova K.S., Seitkalieva M.M., Ananikov V.P., Int. J. Mol. Sci., 2021, 22(13), 6793.
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Quaternary ammonium compounds (QACs) belong to a well-known class of cationic biocides with a broad spectrum of antimicrobial activity. They are used as essential components in surfactants, personal hygiene products, cosmetics, softeners, dyes, biological dyes, antiseptics, and disinfectants. Simple but varied in their structure, QACs are divided into several subclasses: Mono-, bis-, multi-, and poly-derivatives. Since the beginning of the 20th century, a significant amount of work has been dedicated to the advancement of this class of biocides. Thus, more than 700 articles on QACs were published only in 2020, according to the modern literature. The structural variability and diverse biological activity of ionic liquids (ILs) make them highly prospective for developing new types of biocides. QACs and ILs bear a common key element in the molecular structure–quaternary positively charged nitrogen atoms within a cyclic or acyclic structural framework. The state-of-the-art research level and paramount demand in modern society recall the rapid development of a new generation of tunable antimicrobials. This review focuses on the main QACs exhibiting antimicrobial and antifungal properties, commercial products based on QACs, and the latest discoveries in QACs and ILs connected with biocide development.

One-Pot and Two-Chamber Methodologies for Using Acetylene Surrogates in the Synthesis of Pyridazines and Their D-Labeled Derivatives

Ledovskaya M., Polynski M., Ananikov V.P., Chem. Asian J., 2021, ASAP.
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Acetylene surrogates are efficient tools in modern organic chemistry with largely unexplored potential in the construction of heterocyclic cores. Two novel synthetic paths to 3,6-disubstituted pyridazines were proposed using readily available acetylene surrogates through flexible C2 unit installation procedures in a common reaction space mode (one-pot) and distributed reaction space mode (two-chamber): (1) an interaction of 1,2,4,5-tetrazine and its acceptor-functionalized derivatives with a CaC2-H2O mixture performed in a two-chamber reactor led to corresponding pyridazines in quantitative yields; (2) [4+2] cycloaddition of 1,2,4,5-tetrazines to benzyl vinyl ether can be considered a universal synthetic path to a wide range of pyridazines. Replacing water with D2O and vinyl ether with its trideuterated analog in the developed procedures, a range of 4,5-dideuteropyridazines of 95-99% deuteration degree was synthesized for the first time. Quantum chemical modeling allowed to quantify the substituent effect in both synthetic pathways.

Unusual Effect of Impurities on the Spectral Characterization of 1,2,3-Triazoles Synthesized by the Cu-Catalyzed Azide–Alkyne Click Reaction

Fakhrutdinov A.N., Karlinskii B.Ya., Minyaev M.E., Ananikov V.P., J. Org. Chem., 2021, ASAP.
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The analysis of products synthesized by Cu-catalyzed click reactions can be complicated due to the presence of metal impurities in isolated substances, which may "selectively" distort some signals in NMR spectra. Such a pronounced impurity effect was found in both 1H and 13C NMR spectra for a number of 1,4-substituted 1,2,3-triazoles. Recording of the full undistorted spectra is possible with additional product treatment, with more thorough purification, or by recording the spectra at low temperatures. The reasons for the distortion and disappearance of signals have been thoroughly studied; it was shown that impurities of paramagnetic metal ions in small amounts lead to this effect. Here, we want to deliver a warning message to the community: when all NMR signals in a spectrum are distorted, this situation is easy to detect. However, if only a few signals are "selectively" removed by impurities and the rest of the spectrum appears normal, this situation is much harder to notice. Therefore, incorrect conclusions about chemical structure may be obtained. Here, we demonstrated the example of Cu2+ ions, but one may anticipate a similar effect for other paramagnetic metal contaminants if the organic molecule has a functional group capable of coordination (heteroatom or a multiple bond).

Visualization of Catalyst Dynamics and Development of a Practical Procedure to Study Complex “Cocktail”-Type Catalytic Systems

Galushko A.S., Gordeev E.G., Kashin A.S., Zubavichus Y.V., Ananikov V.P., Faraday Discuss., 2021, ASAP.
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The ability to distinguish molecular catalysis from nanoscale catalysis provides a key to success in the field of catalyst development, particularly for the transition to sustainable economies. Complex evolution of catalyst precursors, facilitated by dynamic interconversions and leaching, makes the identification of catalytically active forms an independent task, sometimes very difficult. We propose a simple method for in situ capturing of nanoparticles with carbon-coated grids directly from reaction mixtures. Application of this method to Mizoroki-Heck reaction allowed visualization of dynamic changes of the dominant form of palladium particles in reaction mixtures with homogeneous and heterogeneous catalyst precursors. Changes in the size and shape of palladium particles reflecting the progress of the catalytic chemical reaction were demonstrated. Detailed computational modeling was carried out to confirm the generality of this approach and its feasibility for different catalytic systems. The computational models revealed strong binding of metal particles to the carbon coating comprising efficient binding sites. The approach was tested for trapping Cr, Co, Ag, Ni, Cu, Pd, Cd, Ir, Ru and Rh nanoparticles from solutions containing micromolar starting concentrations of the metal precursors. The developed approach provides a unique tool for studying intrinsic properties of catalytic systems.

Sustainable Hydrogenation of Vinyl Derivatives Using Pd/C Catalysts

Mironenko R.M., Saybulina E.R., Stepanova L.N., Gulyaeva T.I., Trenikhin M.V., Rodygin K.S., Ananikov V.P., Catalysts, 2021, 11, 179.
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The hydrogenation of unsaturated double bonds with molecular hydrogen is an efficient atom-economic approach to the production of a wide range of fine chemicals. In contrast to a number of reducing reagents typically involved in organic synthesis, hydrogenation with H2 is much more sustainable since it does not produce wastes (i.e., reducing reagent residues). However, its full sustainable potential may be achieved only in the case of easily separable catalysts and high reaction selectivity. In this work, various Pd/C catalysts were used for the liquid-phase hydrogenation of O-, S-, and N-vinyl derivatives with molecular hydrogen under mild reaction conditions (room temperature, pressure of 1 MPa). Complete conversion and high hydrogenation selectivity (>99%) were achieved by adjusting the type of Pd/C catalyst. Thus, the proposed procedure can be used as a sustainable method for vinyl group transformation by hydrogenation reactions. The discovery of the stability of active vinyl functional groups conjugated with heteroatoms (O, S, and N) under hydrogenation conditions over Pd/C catalysts opens the way for many useful transformations.

ESI-MS Analysis of Thiol-yne Click Reaction in Petroleum Medium

Degtyareva E.S., Burykina J.V., Ananikov V.P., Molecules, 2021, 26, 2896.
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Petroleum contains a large number of heteroatomic compounds, but today, most of them are not efficiently utilized. The constant development of the sustainability concept recalls for rethinking the usage of fossil resources with improved chemical utility. In order to initiate research aimed at involving active petroleum compounds in chemical transformations, a new analytical method for product detection is needed. Here, we study the click reaction of thiols with alkynes, leading to the formation of α-vinyl sulfides directly in the petroleum environment. The reaction was carried out using an (IMes)Pd(acac)Cl catalyst, which demonstrated tolerance to petroleum components. In this study, the concentration of thiols ranged from 1 M to 0.01 M (from 8% to 0.1%). To detect products at low concentrations, a special alkyne labeled with an imidazole moiety was used. This approach made it possible to observe the formation of vinyl sulfides by electrospray ionization mass spectrometry (ESI-MS), which provides an opportunity for further optimization of the reaction conditions and future developments for the direct involvement of oil components in chemical reactions.

Tri-tert-butyl(n-alkyl)phosphonium Ionic Liquids: Structure, Properties and Application as Hybrid Catalyst Nanomaterials

Arkhipova D.M., Ermolaev V.V., Miluykov V.A., Valeeva F.G., Gaynanova G.A., Zakharova L.Ya., Minyaev M.E., Ananikov V.P., Sustainability, 2021, 13(17), 9862.
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A series of sterically hindered tri- tert-butyl(n-alkyl)phosphonium salts (n-CnH2n+1 with n = 1, 3, 5, 7, 9, 11, 13, 15, 17) was synthesized and systematically studied by 1H, 13C, 31P NMR spectroscopy, ESI-MS, single-crystal X-ray diffraction analysis and melting point measurement. Formation and stabilization palladium nanoparticles (PdNPs) were used to characterize the phosphonium ionic liquid (PIL) nanoscale interaction ability. The colloidal Pd in the PIL systems was described with TEM and DLS analyses and applied in the Suzuki cross-coupling reaction. The PILs were proven to be suitable stabilizers of PdNPs possessing high catalytic activity. The tri-tert-butyl(n-alkyl)phosphonium salts showed a complex nonlinear correlation of the structure–property relationship. The synthesized family of PILs has a broad variety of structural features, including hydrophobic and hydrophilic structures that are entirely expressed in the diversity of their properties.

Acetylene and ethylene – universal C2 molecular units in cycloaddition reactions

Ledovskaya M.S., Voronin V.V., Rodygin K.S., Ananikov V.P., Synthesis, 2021, ASAP.
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Acetylene and ethylene are the smallest molecules that contain an unsaturated carbon-carbon bond and can be efficiently utilized in a large variety of cycloaddition reactions. In the present review, we summarize the application of these C2 molecular units in cycloaddition chemistry and highlight their amazing synthetic opportunities.

Calcium Carbide: Versatile Synthetic Applications, Green Methodology and Sustainability

Rodygin K.S., Ledovskaya M.S., Voronin V.V., Lotsman K.A., Ananikov V. P., Eur. J. Org. Chem., 2021, 2021, 43-52.
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Acetylene is a key building block for organic chemistry and potentially can be involved in a diverse range of synthetic transformations. However, critical analysis of practical considerations showed that application of gaseous acetylene in regular synthetic labs encounters a number of difficulties. Safety limitations due to flammable and explosive nature of gaseous acetylene and requirements for specialized high‐pressure equipment impose serious drawbacks. Typical reaction conditions involve excess of gaseous reactant, which is simply released to the atmosphere at the end of the reaction, thus generating waste and causing contamination. Calcium carbide brings a new green and sustainable wave into powerful alkyne transformations and significantly expands the repertoire of traditional acetylene chemistry. The novel trend of using calcium carbide instead of gaseous acetylene is synthetically beneficial and opens a novel reactivity for the C≡C unit. This review highlights recent advances in carbide chemistry, demonstrates its advantages and prospects in term of green synthetic approach.

Cycloaddition Reactions of In Situ Generated C2D2 in Dioxane: Efficient Synthetic Approach to D2-Labeled Nitrogen Heterocycles

Voronin V., Ledovskaya M., Rodygin K., Ananikov V. P., Eur. J. Org. Chem., 2021, ASAP.
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In this work, a universal synthetic approach to the synthesis of D2-labeled nitrogen heterocycles based on cycloaddition reactions of in situ generated dideuteroacetylene is reported. A key feature of the developed method is the use of dioxane as a deuterium-exchange-proof solvent, which allowed dideuterosubstituted heterocycles to be obtained in up to 99% deuteration. The developed method was demonstrated to be suitable for the synthesis of D2-labeled triazoles, isoxazoles, pyrazoles and pyridazines.

NMR Parameters of Imidazolium Ionic Liquids as Indicators of Their State and Properties in Aqueous Solutions

Shahkhatuni A.A., Shahkhatuni A.G., Mamyan S.S., Ananikov V.P. & Harutyunyan A.S. , J. Sol. Chem., 2021, 50, 90.
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Seven 1-methylimidazolium-based ionic liquids (ILs) and their aqueous solutions were systematically investigated in order to explore how the NMR spectroscopic properties (chemical shifts, spin–spin coupling constants) are connected or correlated with several physical and chemical properties (density, viscosity, water content, etc.) of ILs and their aqueous mixtures. 1H and 13C NMR chemical shifts of ILs vary markedly depending on different anions, alkyl chain length, and water content. Addition of water affected the NMR parameters in various manners, altering several of them significantly, while others did not change distinctly. Dissimilar behavior of NMR parameters in various solvents at various concentrations allows one to conclude that they reflect several contributions from different properties of ILs and can be used for deep structural investigations.