Quantitative Determination of Active Species Transforming the R-NHC Coupling Process under Catalytic Conditions.

Palladium complexes with N-heterocyclic carbenes (Pd/NHC) serve as prominent precatalysts in numerous Pd-catalyzed organic reactions. While the evolution of Pd/NHC complexes, which involves the cleavage of the Pd-C(NHC) bond via reductive elimination and dissociation, is acknowledged to influence the catalysis mechanism and the performance of the catalytic systems, conventional analytic techniques [such as NMR, IR, UV-vis, gas chromatography-mass spectrometry (GC-MS), and high-performance liquid chromatography (HPLC)] frequently fail to quantitatively monitor the transformations of Pd/NHC complexes at catalyst concentrations typical of real-world conditions (below approximately 1 mol %). In this study, for the first time, we show the viability of using electrospray ionization mass spectrometry (ESI-MS). This approach was combined with the use of selectively deuterated H-NHC, Ph-NHC, and O-NHC coupling products as internal standards, allowing for an in-depth quantitative analysis of the evolution of Pd/NHC catalysts within actual catalytic systems. The reliability of this approach was affirmed by aligning the ESI-MS results with the NMR spectroscopy data obtained at greater Pd/NHC precatalyst concentrations (2-5 mol %) in the Mizoroki-Heck, Sonogashira, and alkyne transfer hydrogenation reactions. The efficacy of the ESI-MS methodology was further demonstrated through its application in the Mizoroki-Heck reaction at Pd/NHC loadings of 5, 0.5, 0.05, and 0.005 mol %. In this work, for the first time, we present a methodology for the quantitative characterization of pivotal catalyst transformation processes commonly observed in M/NHC systems.

Time-Resolved Formation and Operation Maps of Pd Catalysts Suggest a Key Role of Single Atom Centers in Cross-Coupling.

An approach to the spatially localized characterization of supported catalysts over a reaction course is proposed. It consists of a combination of scanning, transmission, and high-resolution scanning transmission electron microscopy to determine metal particles from arrays of surface nanoparticles to individual nanoparticles and individual atoms. The study of the evolution of specific metal catalyst particles at different scale levels over time, particularly before and after the cross-coupling catalytic reaction, made it possible to approach the concept of 4D catalysis-tracking the positions of catalytic centers in space (3D) over time (+1D). The dynamic behavior of individual palladium atoms and nanoparticles in cross-coupling reactions was recorded with nanometer accuracy via the precise localization of catalytic centers. Single atoms of palladium leach out into solution from the support under the action of the catalytic system, where they exhibit extremely high catalytic activity compared to surface metal nanoparticles. Monoatomic centers, which make up only approximately 1% of palladium in the Pd/C system, provide more than 99% of the catalytic activity. The remaining palladium nanoparticles changed their shape and could move over the surface of the support, which was recorded by processing images of the array of nanoparticles with a neural network and aligning them using automatically detected keypoints. The study reveals a novel opportunity for single-atom catalysis─easier detachment (capture) from (on) the carbon support surface is the origin of superior catalytic activity, rather than the operation of single atomic catalytic centers on the surface of the support, as is typically assumed.

Formation of a P162- Ink from Elemental Red Phosphorus in a Thiol-Amine Mixture.

A P162- polyphosphide dianion ink was produced by the reaction of red phosphorus with a binary thiol-amine mixture of ethanethiol (ET) and ethylenediamine (en). The polyphosphide was identified by solution 31P NMR spectroscopy and electrospray ionization mass spectrometry. This solute was compared to the reaction products of white phosphorus (P4) and other elemental pnictides in the same solvent system. The reaction of P4 with ET and en gives the same P162- polyphosphide; however, the easier handling and lower reactivity of red phosphorus highlights the novelty of that reaction. Elemental arsenic and antimony both give mononuclear pnictogen-sulfide-thiolate complexes upon reaction with ET and en under otherwise identical conditions, with this difference likely resulting from the greater covalency and tendency of phosphorus to form P-P bonds.

Toward Totally Defined Nanocatalysis: Deep Learning Reveals the Extraordinary Activity of Single Pd/C Particles.

Homogeneous catalysis is typically considered "well-defined" from the standpoint of catalyst structure unambiguity. In contrast, heterogeneous nanocatalysis often falls into the realm of "poorly defined" systems. Supported catalysts are difficult to characterize due to their heterogeneity, variety of morphologies, and large size at the nanoscale. Furthermore, an assortment of active metal nanoparticles examined on the support are negligible compared to those in the bulk catalyst used. To solve these challenges, we studied individual particles of the supported catalyst. We made a significant step forward to fully characterize individual catalyst particles. Combining a nanomanipulation technique inside a field-emission scanning electron microscope with neural network analysis of selected individual particles unexpectedly revealed important aspects of activity for widespread and commercially important Pd/C catalysts. The proposed approach unleashed an unprecedented turnover number of 109 attributed to individual palladium on a nanoglobular carbon particle. Offered in the present study is the Totally Defined Catalysis concept that has tremendous potential for the mechanistic research and development of high-performance catalysts.

On-Water Selectivity Switch in Microdroplets in the 1,2,3-Triazole Synthesis from Bromoethenesulfonyl Fluoride.

Water profoundly affects many organic reactions by accelerating them or changing their selectivity. Performing reactions "on-water" offers an intriguing opportunity to influence chemical reactivity. A nebulizer plume is an efficient way of generating microdroplets─the uniquely complex reaction environment which opens alternative possibilities that are not readily accessible in bulk emulsions. We describe the on-water switch of chemoselectivity in the formation of triazoles controlled by the on-water environment in dual spray. These conditions facilitate elimination of H-SO2F from the triazoline intermediate, whereas the reaction in organic solvents results in the exclusive HBr elimination. The influence of two-phase conditions was investigated to obtain the best reaction efficiency, and the crucial importance of the water/organic interface interactions was verified by pH variation and D2O use.

Reductive Aldol-type Reactions in the Synthesis of Pharmaceuticals.

The efficient chemo-, regio- and stereoselective formation of saturated carbon-carbon fragment is the critical challenge of organic synthesis; therefore, developing new methods for formation of these bonds is paramount. The rising interest for reductive aldol-type reactions is conditioned by its versatile applications, allowing the efficient formation of carbon-carbon bonds. The review aims to highlight the advantages and disadvantage of reductive aldol-type reactions to total synthesis of pharmaceutical substances in order to summarize knowledge and encourage further investigation of the field.

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

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 ß-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.

Cerebral Dopamine Neurotrophic Factor (CDNF): Structure, Functions, and Therapeutic Potential.

The cerebral dopamine neurotrophic factor (CDNF) together with the mesencephalic astrocyte-derived neurotrophic factor (MANF) form a unique family of neurotrophic factors (NTFs) structurally and functionally different from other proteins with neurotrophic activity. CDNF has no receptors on the cell membrane, is localized mainly in the cavity of endoplasmic reticulum (ER), and its primary function is to regulate ER stress. In addition, CDNF is able to suppress inflammation and apoptosis. Due to its functions, CDNF has demonstrated outstanding protective and restorative properties in various models of neuropathology associated with ER stress, including Parkinson's disease (PD). That is why CDNF already passed clinical trials in patients with PD. However, despite the name, CDNF functions extend far beyond the dopamine system in the brain. In particular, there are data on participation of CDNF in the maturation and maintenance of other neurotransmitter systems, regulation of the processes of neuroplasticity and non-motor behavior. In the present review, we discuss the features of CDNF structure and functions, its protective and regenerative properties.

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

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.

Effects of a Cc2d1a/Freud-1 Knockdown in the Hippocampus on Behavior, the Serotonin System, and BDNF.

The serotonin 5-HT1A receptor is one of the most abundant and widely distributed brain serotonin (5-HT) receptors that play a major role in the modulation of emotions and behavior. The 5-HT1A receptor gene (Htr1a) is under the control of transcription factor Freud-1 (also known as Cc2d1a/Freud-1). Here, using adeno-associated virus (AAV) constructs in vivo, we investigated effects of a Cc2d1a/Freud-1 knockdown in the hippocampus of C57BL/6J mice on behavior, the brain 5-HT system, and brain-derived neurotrophic factor (BDNF). AAV particles carrying the pAAV_H1-2_shRNA-Freud-1_Syn_EGFP plasmid encoding a short-hairpin RNA targeting mouse Cc2d1a/Freud-1 mRNA had an antidepressant effect in the forced swim test 5 weeks after virus injection. The knockdown impaired spatiotemporal memory as assessed in the Morris water maze. pAAV_H1-2_shRNA-Freud-1_Syn_EGFP decreased Cc2d1a/Freud-1 mRNA and protein levels. Furthermore, the Cc2d1a/Freud-1 knockdown upregulated 5-HT and its metabolite 5-hydroxyindoleacetic acid but not their ratio. The Cc2d1a/Freud-1 knockdown failed to increase mRNA and protein levels of Htr1a but diminished a 5-HT1A receptor functional response. Meanwhile, the Cc2d1a/Freud-1 knockdown reduced Creb mRNA expression and CREB phosphorylation and upregulated cFos mRNA. The knockdown enhanced the expression of a BDNF precursor (proBDNF protein), which is known to play a crucial part in neuroplasticity. Our data indicate that transcription factor Cc2d1a/Freud-1 is implicated in the pathogenesis of depressive disorders not only via the 5-HT1A receptor and transcription factor CREB but also through an influence on BDNF.

Mechanistic Study of Pd/NHC-Catalyzed Sonogashira Reaction: Discovery of NHC-Ethynyl Coupling Process.

The product of a revealed transformation-NHC-ethynyl coupling-was observed as a catalyst transformation pathway in the Sonogashira cross-coupling, catalyzed by Pd/NHC complexes. The 2-ethynylated azolium salt was isolated in individual form and fully characterized, including X-ray analysis. A number of possible intermediates of this transformation with common formulae (NHC)n Pd(C2 Ph) (n=1,2) were observed and subjected to collision-induced dissociation (CID) and infrared multiphoton dissociation (IRMPD) experiments to elucidate their structure. Measured bond dissociation energies (BDEs) and IRMPD spectra were in an excellent agreement with quantum calculations for coupling product π-complexes with Pd0 . Molecular dynamics simulations confirmed the observed multiple CID fragmentation pathways. An unconventional methodology to study catalyst evolution suggests the reported transformation to be considered in the development of new catalytic systems for alkyne functionalization reactions.

The Chronic Treatment With 5-HT2A Receptor Agonists Affects the Behavior and the BDNF System in Mice.

Serotonin 5-HT2A receptors and the brain-derived neurotrophic factor (BDNF) are involved in the pathophysiology and treatment of many psychiatric diseases. However, the interaction between 5-HT2A and BDNF is still poorly understood. In the present paper, the effects of chronic treatment with mixed 5-HT2A/2C receptor agonist DOI, highly selective 5-HT2A agonists TCB-2 and 25CN-NBOH on behavior and the BDNF system have been investigated. Chronic treatment of males of C57Bl/6 mice with DOI, TCB-2 and 25CN-NBOH (1 mg/kg, i.p., 14 days) resulted in desensitization of 5-HT2A receptors. Treatment with 25CN-NBOH significantly increased startle amplitude. At the same time all used drugs failed to affect anxiety, exploratory and stereotyped behavior as well as spatial memory and learning. TCB-2 and 25CN-NBOH increased the BDNF mRNA level. All 5-HT2A agonists increased the proBDNF level but failed to alter the mature BDNF protein level. TrkB and p75NTR mRNA levels were affected by all utilized agonists. All drugs decreased the total level as well as membrane TrkB protein one indicating downregulation of TrkB receptors. All agonists decreased the membrane p75NTR protein level. Thus, we have shown for the first time that the chronic activation of the 5-HT2A receptor with agonists has affected the BDNF system almost on all levels-transcription, proBDNF production, TrkB and p75NTR receptors' level. The obtained data suggested possible suppression in BDNF-TrkB signaling under chronic treatment with 5-HT2A agonists.

Genetic Background Underlying 5-HT1A Receptor Functioning Affects the Response to Fluoxetine.

The influence of genetic background on sensitivity to drugs represents a topical problem of personalized medicine. Here, we investigated the effect of chronic (20 mg/kg, 14 days, i.p.) antidepressant fluoxetine treatment on recombinant B6-M76C mice, differed from control B6-M76B mice by CBA-derived 102.73-110.56 Mbp fragment of chromosome 13 and characterized by altered sensitivity of 5-HT1A receptors to chronic 8-OH-DPAT administration and higher 5-HT1A receptor mRNA levels in the frontal cortex and hippocampus. Significant changes in the effects of fluoxetine treatment on behavior and brain 5-HT system in recombinant B6-M76C mice were revealed. In contrast to B6-M76B mice, in B6-M76C mice, fluoxetine produced pro-depressive effects, assessed in a forced swim test. Fluoxetine decreased 5-HT1A receptor mRNA levels in the cortex and hippocampus, reduced 5-HT1A receptor protein levels and increased receptor silencer Freud-1 protein levels in the hippocampus of B6-M76C mice. Fluoxetine increased mRNA levels of the gene encoding key enzyme for 5-HT synthesis in the brain, tryptophan hydroxylase-2, but decreased tryptophan hydroxylase-2 protein levels in the midbrain of B6-M76B mice. These changes were accompanied by increased expression of the 5-HT transporter gene. Fluoxetine reduced 5-HT and 5-HIAA levels in cortex, hippocampus and midbrain of B6-M76B and in cortex and midbrain of B6-M76C; mice. These data demonstrate that changes in genetic background may have a dramatic effect on sensitivity to classic antidepressants from the Selective Serotonin Reuptake Inhibitors family. Additionally, the results provide new evidence confirming our idea on the disrupted functioning of 5-HT1A autoreceptors in the brains of B6-M76C mice, suggesting these mice as a model of antidepressant resistance.

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

Invited for the cover of this issue are Valentine P. Ananikov and co-workers. The image depicts the dynamic behaviour of a Pd/NHC catalytic system with easy transition from molecular to ionic complex. Read the full text of the article at 10.1002/chem.201903221.

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.

Addressing Reversibility of R-NHC Coupling on Palladium: Is Nano-to-Molecular Transition Possible for the Pd/NHC System?

It has recently been shown that palladium-catalyzed reactions with N-heterocyclic carbene (NHC) ligands involve R-NHC coupling accompanied by transformation of the molecular catalytic system into the nanoscale catalytic system. An important question appeared in this regard is whether such a change in the catalytic system is irreversible. More specifically, is the reverse nano-to-molecular transformation possible? In view of the paramount significance of this question to the area of catalyst design, we studied the capability of 2-substituted azolium salts to undergo the breakage of C-C bond and exchange substituents on the carbene carbon with corresponding aryl halides in the presence of Pd nanoparticles. The study provides important experimental evidence of possibility of the reversible R-NHC coupling. The observed behavior indicates that the nanosized metal species are capable of reverse transition to molecular species. Such an option, known for phosphine ligands, was previously unexplored for NHC ligands. The present study for the first time demonstrates bidirectional dynamic transitions between the molecular and nanostructured states in Pd/NHC systems. As a unique feature, surprisingly small activation barriers (<18 kcal/mol) and noticeable thermodynamic driving force (-5 to -7 kcal/mol) were calculated for C-C bond oxidative addition to Pd(0) centers in the studied system. The first example of NHC-mediated Pd leaching from metal nanoparticles to solution was observed and formation of Pd/NHC complex in solution was detected by ESI-MS.

Henry Reaction Revisited. Crucial Role of Water in an Asymmetric Henry Reaction Catalyzed by Chiral NNO-Type Copper(II) Complexes.

Chiral copper(II) and cobalt(III) complexes (1-5 and 6, respectively) derived from Schiff bases of (S)-2-(aminomethyl)pyrrolidine and salicylaldehyde derivatives were employed in a mechanistic study of the Henry reaction-type condensation of nitromethane and o-nitrobenzaldehyde in CH2Cl2 (CD2Cl2), containing different amounts of water. The reaction kinetics was monitored by 1H and 13C NMR. The addition of water had a different influence on the activity of the two types of complexes, ranging from a crucial positive effect in the case of the copper(II) complex 2 to insignificant in the case of the stereochemically inert cobalt(III) complex 6. No experimental support was found by 1H NMR studies for the classical Lewis acid complexation of the carbonyl group of the aldehyde by the central copper(II) ion, and, moreover, density functional theory (DFT) calculations support the absence of such coordination. On the other hand, a very significant complexation was found for water, and it was supported by DFT calculations. In fact, we suggest that it is the Brønsted acidity of the water molecule coordinated to the metal ion that triggers the aldehyde activation. The rate-limiting step of the reaction was the removal of an α-proton from the nitromethane molecule, as supported by the observed kinetic isotope effect equaling 6.3 in the case of the copper complex 2. It was found by high-resolution mass spectrometry with electrospray ionization that the copper(II) complex 2 existed in CH2Cl2 in a dimeric form. The reaction had a second-order dependence on the catalyst concentration, which implicated two dimeric forms of the copper(II) complex 2 in the rate-limiting step. Furthermore, DFT calculations help to generate a plausible structure of the stereodetermining transition step of the condensation.

Investigation of Cytotoxic Activity of Mitoxantrone at the Individual Cell Level by Using Ionic-Liquid-Tag-Enhanced Mass Spectrometry.

A novel mitoxantrone conjugate was synthesized by coupling mitoxantrone with ionic liquid tags, and cytotoxic behavior of the designed conjugate was studied in normal and cancer cell lines. The synthesized mitoxantrone conjugate was oil at physiological temperatures and demonstrated high aqueous solubility. Sensitivity of electrospray ionization mass spectrometry (ESI-MS) to the mitoxantrone conjugate was improved by an order of magnitude, in comparison with original mitoxantrone dihydrochloride. The observed ESI-MS signals were shifted to a "clearer" lower-mass region of the spectrum, which allowed investigation of the drug at the level of individual cells. The ionic liquid tags proposed in the present work consist of an easily available imidazolium salt residue and show a number of key advantages from the points of view of drug conjugate synthesis, drug delivery and analytic detection.