Cytotoxic Activity of Salicylic Acid-Containing Drug Models with Ionic and Covalent Binding

Three different types of drug delivery platforms based on imidazolium ionic liquids (ILs) were synthesized in high preparative yields, namely, the models involving (i) ionic binding of drug and IL; (ii) covalent binding of drug and IL; and (iii) dual binding using both ionic and covalent approaches. Seven ionic liquids containing salicylic acid (SA-ILs) in the cation or/and in the anion were prepared, and their cytotoxicity toward the human cell lines CaCo-2 (colorectal adenocarcinoma) and 3215 LS (normal fibroblasts) was evaluated. Cytotoxicity of SA-ILs was significantly higher than that of conventional imidazolium-based ILs and was comparable to the pure salicylic acid. It is important to note that the obtained SA-ILs dissolved in water more readily than salicylic acid, suggesting benefits of possible usage of traditional nonsoluble active pharmaceutical ingredients in an ionic liquid form. © 2015 American Chemical Society

Cytotoxic Activity of Salicylic Acid-Containing Drug Models with Ionic and Covalent Binding

Three different types of drug delivery platforms based on imidazolium ionic liquids (ILs) were synthesized in high preparative yields, namely, the models involving (i) ionic binding of drug and IL; (ii) covalent binding of drug and IL; and (iii) dual binding using both ionic and covalent approaches. Seven ionic liquids containing salicylic acid (SA-ILs) in the cation or/and in the anion were prepared, and their cytotoxicity toward the human cell lines CaCo-2 (colorectal adenocarcinoma) and 3215 LS (normal fibroblasts) was evaluated. Cytotoxicity of SA-ILs was significantly higher than that of conventional imidazolium-based ILs and was comparable to the pure salicylic acid. It is important to note that the obtained SA-ILs dissolved in water more readily than salicylic acid, suggesting benefits of possible usage of traditional nonsoluble active pharmaceutical ingredients in an ionic liquid form. © 2015 American Chemical Society

Ten-fold boost of catalytic performance in thiol-yne click reaction enabled by a palladium diketonate complex with a hexafluoroacetylacetonate ligand

Palladium complexes with fluorinated acetylacetonate chelating ligands were studied as catalysts for alkyne hydrothiolation. A ten-fold increase in the catalytic efficiency was achieved by using 0.1 mol% of Pd(hfpd)2 complex (hfpd = hexafluoroacetylacetonate) with a variety of thiol-yne coupling partners. The principal possibility of a hundred-fold increase in the efficiency of Pd-catalyzed Markovnikov-type RSH addition with 0.01 mol% of the catalyst was successfully achieved with the hfpd ligand for the first time. The hexafluoroacetylacetonate chelating ligand not only enhanced the affinity of palladium centers to the triple bond of acetylene, but also stabilized the catalytic system against formation of insoluble polymeric [Pd(SPh)2]n species, thus ensuring that the reaction operates homogeneously. Utilizing other diketonate ligands resulted in cocktail-type catalysis with variable and poorly predictable contributions of homogeneous and heterogeneous pathways. © 2018 The Royal Society of Chemistry

Ten-fold boost of catalytic performance in thiol-yne click reaction enabled by a palladium diketonate complex with a hexafluoroacetylacetonate ligand

Palladium complexes with fluorinated acetylacetonate chelating ligands were studied as catalysts for alkyne hydrothiolation. A ten-fold increase in the catalytic efficiency was achieved by using 0.1 mol% of Pd(hfpd)2 complex (hfpd = hexafluoroacetylacetonate) with a variety of thiol-yne coupling partners. The principal possibility of a hundred-fold increase in the efficiency of Pd-catalyzed Markovnikov-type RSH addition with 0.01 mol% of the catalyst was successfully achieved with the hfpd ligand for the first time. The hexafluoroacetylacetonate chelating ligand not only enhanced the affinity of palladium centers to the triple bond of acetylene, but also stabilized the catalytic system against formation of insoluble polymeric [Pd(SPh)2]n species, thus ensuring that the reaction operates homogeneously. Utilizing other diketonate ligands resulted in cocktail-type catalysis with variable and poorly predictable contributions of homogeneous and heterogeneous pathways. © 2018 The Royal Society of Chemistry

A New Mode of Operation of Pd-NHC Systems Studied in a Catalytic Mizoroki-Heck Reaction

Metal complexes bearing N-heterocyclic carbene (NHC) ligands are typically considered the system of choice for homogeneous catalysis with well-defined molecular active species due to their stable metal-ligand framework. A detailed study involving 19 different Pd-NHC complexes with imidazolium, benzimidazolium, and triazolium ligands has been carried out in the present work and revealed a new mode of operation of metal-NHC systems. The catalytic activity of the studied Pd-NHC systems is predominantly determined by the cleavage of the metal-NHC bond, while the catalyst performance is strongly affected by the stabilization of in situ formed metal clusters. In the present study, the formation of Pd nanoparticles was observed from a broad range of metal complexes with NHC ligands under standard Mizoroki-Heck reaction conditions. A mechanistic analysis revealed two different pathways to connect Pd-NHC complexes to "cocktail"-type catalysis: (i) reductive elimination from a Pd(II) intermediate and the release of NHC-containing byproducts and (ii) dissociation of NHC ligands from Pd intermediates. Metal-NHC systems are ubiquitously applied in modern organic synthesis and catalysis, while the new mode of operation revealed in the present study guides catalyst design and opens a variety of novel opportunities. As shown by experimental studies and theoretical calculations, metal clusters and nanoparticles can be readily formed from M-NHC complexes after formation of new M-C or M-H bonds followed by C-NHC or H-NHC coupling. Thus, a combination of a classical molecular mode of operation and a novel cocktail-type mode of operation, described in the present study, may be anticipated as an intrinsic feature of M-NHC catalytic systems. © 2017 American Chemical Society

Pd and Pt Catalyst Poisoning in the Study of Reaction Mechanisms: What Does the Mercury Test Mean for Catalysis?

The mercury test is a rapid and widely used method for distinguishing truly homogeneous molecular catalysis from nanoparticle metal catalysis. In the current work, using various M0 and MII complexes of palladium and platinum that are often used in homogeneous catalysis as examples, we demonstrated that the mercury test is generally inadequate as a method for distinguishing between homogeneous and cluster/nanoparticle catalysis mechanisms for the following reasons: (i) the general and facile reactivity of both molecular M0 and MII complexes toward metallic mercury and (ii) the very high and often unpredictable dependence of the test results on the operational conditions and the inability to develop universal quantitatively defined operational parameters. Two main types or mercury-induced transformations, the cleavage of M0 complexes and the oxidative-reductive transmetalation of MII complexes, including a reaction of highly popular MII/NHC complexes, were elucidated using NMR, ESI-MS, and EDXRF techniques. A mechanistic picture of the reactions involving metal complexes was revealed with mercury, and representative metal species were isolated and characterized. Even in an attempt to not overstate the results, one must note that the use of the mercury tests often leads to inaccurate conclusions and complicates the mechanistic studies of these catalytic systems. As a general concept, distinguishing reaction mechanisms (homogeneous vs cluster/nanoparticle) by using catalyst poisoning requires careful rethinking in the case of dynamic catalytic systems. © 2019 American Chemical Society

Fast and Slow Release of Catalytically Active Species in Metal/NHC Systems Induced by Aliphatic Amines

The behavior of ubiquitously used nickel, palladium, and platinum complexes containing N-heterocyclic carbene ligands was studied in solution in the presence of aliphatic amines. Transformation of M(NHC)X2L complexes readily occurred according to the following reactions: (i) release of the NHC ligand in the form of azolium salt and formation of metal clusters or nanoparticles and (ii) isomerization of mono-NHC complexes M(NHC)X2L to bis-NHC derivatives M(NHC)2X2. Facile cleavage of the M-NHC bond was observed and provided the possibility for fast release of catalytically active NHC-free metal species. Bis-NHC metal complexes M(NHC)2X2 were found to be significantly more stable and represented a molecular reservoir of catalytically active species. Slow decomposition of the bis-NHC complexes by removal of the NHC ligands (also in the form of azolium salts) occurred, generating metal clusters or nanoparticles. The observed combination of dual fast- and slow-release channels is an intrinsic latent opportunity of M/NHC complexes, which balances the activity and durability of a catalytic system. The fast release of catalytically active species from M(NHC)X2L complexes can rapidly initiate catalytic transformation, while the slow release of catalytically active species from M(NHC)2X2 complexes can compensate for degradation of catalytically active species and help to maintain a reliable amount of catalyst. The study clearly shows an outstanding potential of dynamic catalytic systems, where the key roles are played by the lability of the M-NHC framework rather than its stability. © 2018 American Chemical Society

Ionic Pd/NHC Catalytic System Enables Recoverable Homogeneous Catalysis: Mechanistic Study and Application in the Mizoroki-Heck Reaction

N-Heterocyclic carbene (NHC) ligands are ubiquitously utilized in catalysis. A common catalyst design model assumes strong M-NHC binding in this metal-ligand framework. In contrast to this common assumption, we demonstrate here that lability and controlled cleavage of the M-NHC bond (rather than its stabilization) could be more important for high-performance catalysis at low catalyst concentrations. The present study reveals a dynamic stabilization mechanism with labile metal-NHC binding and [PdX3](-)[NHC-R](+) ion pair formation. Access to reactive anionic palladium intermediates formed by dissociation of the NHC ligands and plausible stabilization of the molecular catalyst in solution by interaction with the [NHC-R](+) azolium ion is of particular importance for an efficient and recyclable catalyst. These ionic Pd/NHC complexes allowed for the first time the recycling of the complex in a well-defined form with isolation at each cycle. Computational investigation of the reaction mechanism confirms a facile formation of NHC-free anionic Pd in polar media through either Ph-NHC coupling or reversible H-NHC coupling. The present study formulates novel ideas for M/NHC catalyst design

A New Mode of Operation of Pd-NHC Systems Studied in a Catalytic Mizoroki-Heck Reaction

Metal complexes bearing N-heterocyclic carbene (NHC) ligands are typically considered the system of choice for homogeneous catalysis with well-defined molecular active species due to their stable metal-ligand framework. A detailed study involving 19 different Pd-NHC complexes with imidazolium, benzimidazolium, and triazolium ligands has been carried out in the present work and revealed a new mode of operation of metal-NHC systems. The catalytic activity of the studied Pd-NHC systems is predominantly determined by the cleavage of the metal-NHC bond, while the catalyst performance is strongly affected by the stabilization of in situ formed metal clusters. In the present study, the formation of Pd nanoparticles was observed from a broad range of metal complexes with NHC ligands under standard Mizoroki-Heck reaction conditions. A mechanistic analysis revealed two different pathways to connect Pd-NHC complexes to "cocktail"-type catalysis: (i) reductive elimination from a Pd(II) intermediate and the release of NHC-containing byproducts and (ii) dissociation of NHC ligands from Pd intermediates. Metal-NHC systems are ubiquitously applied in modern organic synthesis and catalysis, while the new mode of operation revealed in the present study guides catalyst design and opens a variety of novel opportunities. As shown by experimental studies and theoretical calculations, metal clusters and nanoparticles can be readily formed from M-NHC complexes after formation of new M-C or M-H bonds followed by C-NHC or H-NHC coupling. Thus, a combination of a classical molecular mode of operation and a novel cocktail-type mode of operation, described in the present study, may be anticipated as an intrinsic feature of M-NHC catalytic systems. © 2017 American Chemical Society