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Profiling the heterogeneous landscape of cell types and biomolecules is rapidly being adopted to address current imperative research questions. Precision medicine seeks advancements in molecular spatial profiling techniques with highly multiplexed imaging capabilities and subcellular resolution, which remains an extremely complex task. Surface-enhanced Raman spectroscopy (SERS) imaging offers promise through the utilization of nanoparticle-based contrast agents that exhibit narrow spectral features and molecular specificity. The current renaissance of gold nanoparticle technology makes Raman scattering intensities competitive with traditional fluorescence methods while offering the added benefit of unsurpassed multiplexing capabilities. Here, we present an expanded library of individually distinct SERS nanoparticles to arm researchers and clinicians. Our nanoparticles consist of a ∼60 nm gold core, a Raman reporter molecule, and a final inert silica coating. Using density functional theory, we have selected Raman reporters that meet the key criterion of high spectral uniqueness to facilitate unmixing of up to 26 components in a single imaging pixel

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 10

SERS with molecular immobilization and resonant Raman amplification by complex-loaded enhancer (MIRRACLE) enables detection of hazardous phenolic pollutants down to nM concentrations in gasoline fuel and freshwater samples.

Supercharging reagents assist protein ionization by producing higher charge states and increasing signal intensities, thus improving sensitivity. Described here is an approach to employ a dual-spray ionization source with DMSO as a supercharging reagent to expand in-source supercharging. Under denaturing conditions, dual-source supercharging enhances ionization up to an order of magnitude for proteins of various properties and sizes, but the effect is not uniform. Efficient mixing of solutions from two nebulizing plumes was observed, which allowed sufficient transfer of supercharging molecules to a protein. The described method and proposed mechanism require at least 2.5% of DMSO to produce visible enhancement.

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.

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 β-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.

The 2021 Faraday Discussion on reaction mechanisms in catalysis attracted over a hundred delegates from around the world. Notwithstanding the challenges we faced in 2020, the online platform brought together leading scientists passionate about understanding the mechanisms of catalysed reactions. The meeting showed the great shape of the field and proved the ability of the community to face global challenges, and to be adaptive, flexible, and responsive.

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.

Catalytic atom-economic hydrothiolation of cyclopropyl acetylenes was developed. Using Pd/NHC complex as a precatalyst, regioselective addition of thiols to cyclopropyl acetylenes was successfully ...

The influence of the accuracy of mass measurements on the number of possible structural compositions and the computation time of computer-aided interpretation of mass spectrometric data has been evaluated. Experimental measurements have been performed for two model objects in the range of small and medium masses using high, ultrahigh, and extreme high resolution electrospray ionization mass spectrometers. The number of possible solutions have been examined and prospects of using machine learning in combination with mass spectrometry for predicting new data on reaction mechanisms and searching for hidden relationships in the chemical space have been demonstrated. It has been shown that there are two types of relationships between the molecular formula and the mass determination error depending on the ion mass: a nonlinear curve is observed for small molecules and a linear relationship is observed for large molecules.

Main types of the M–NHC bond transformations and their impact on activity and stability of M/NHC catalytic systems are considered., Complexes of metals with N-heterocyclic carbene ligands (M/NHC) are typically considered the systems of choice in homogeneous catalysis due to their stable metal–ligand framework. However, it becomes obvious that even metal species with a strong M–NHC bond can undergo evolution in catalytic systems, and processes of M–NHC bond cleavage are common for different metals and NHC ligands. This review is focused on the main types of the M–NHC bond cleavage reactions and their impact on activity and stability of M/NHC catalytic systems. For the first time, we consider these processes in terms of NHC-connected and NHC-disconnected active species derived from M/NHC precatalysts and classify them as fundamentally different types of catalysts. Problems of rational catalyst design and sustainability issues are discussed in the context of the two different types of M/NHC catalysis mechanisms.

Multiplexing capabilities and sensitivity of surface-enhanced Raman spectroscopy (SERS) nanoparticles (NPs) are strongly dependent on the selected Raman reporter. These Raman-active molecules are responsible for giving each batch of SERS NPs its unique spectral fingerprint. Herein, we studied four types of SERS NPs, namely, AuNPs labeled with trans-1,2-bis(4-pyridyl)ethylene (BPE), 4,4'-bis(mercaptomethyl)biphenyl (BMMBP), 5-(4-pyridyl)-1,3,4-oxadiazole-2-thiol (PODT), and 5-(4-pyridyl)-1H-1,2,4-triazole-3-thiol (PTT), and demonstrated that the best level of theory could be chosen based on inner products of DFT-calculated and experimental Raman spectra. We also calculated the theoretical spectra of these Raman reporters bound to Au20 clusters to interrogate how SERS enhancement would affect their spectral fingerprint. Importantly, we found a correlation between B3LYP-D3 calculated and experimental enhancement factors, which opens up an avenue toward predicting which Raman reporters could offer improved sensitivity. We observed 0.5 and 3 fM limits of detection for BMMBP- and PTT-labeled 60 nm AuNPs, respectively.

The 2021 Faraday Discussion on reaction mechanisms in catalysis attracted over a hundred delegates from around the world. Notwithstanding the challenges we faced in 2020, the online platform brought together leading scientists passionate about understanding the mechanisms of catalysed reactions. The meeting showed the great shape of the field and proved the ability of the community to face global challenges, and to be adaptive, flexible, and responsive.

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.

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.

Until recently, chemical derivatives of platinum group metals have not been in a systematic direct contact with living organisms. The situation has changed dramatically due to anthropogenic activity, which has led to significant redistribution of these metals in the biosphere. Millions of modern cars are equipped with automotive catalytic converters, which contain rhodium, palladium and platinum as active elements. Everyday usage of catalytic technologies promotes the propagation of catalyst components in the environment. Nevertheless, we still have not accumulated profound information on possible ecotoxic effects of these metal pollutants. In this study, we report a case of an extraordinarily rapid development of lethal toxicity of a rhodium (III) salt in the terrestrial plants Pisum sativum, Lupinus angustifolius and Cucumis sativus. The growth stage, at which the exposure occurred, had a crucial impact on the toxicity manifestation: at earlier stages, RhCl3 killed the plants within 24 h. In contrast, the salt was relatively low-toxic in human fibroblasts. We also address phytotoxicity of other common metal pollutants, such as palladium, iron, nickel and copper, together with their cytotoxicity. None of the tested compounds exhibited phytotoxic effects comparable with that of RhCl3. These results evidence the crucial deficiency in our knowledge on environmental dangers of newly widespread metal pollutants.

Magnetic stir bars are routinely used by every chemist doing synthetic or catalytic transformations in solution. Each bar lasts for months or years, as the regular PTFE (polytetrafluoroethylene) co...

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 complexe...

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.

Trichomonas vaginalis causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against T. vaginalis and other protozoa but has significant human toxicity. In a systematic structure-activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1-C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against T. vaginalis and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live T. vaginalis than the enzyme, suggesting that alternative targets exist. Furthermore, all tested gold(I) complexes acted independently of Mz and were able to overcome Mz resistance, making them candidates for the treatment of Mz-refractory trichomoniasis.

Solar energy is one of the main renewable energy sources currently being researched, with commercial thin film solar cells currently made of CdTe or CuIn(1-x)GaxSe2 (CIGS) absorbers. However, whilst these materials make up the majority of the thin film commercial market, these solar cells have various problems relating to materials cost, and toxicity of constituent elements. Kesterite (Cu2ZnSn(S,Se)4) solar cells are becoming increasingly popular due to their tuneable band gap, relative affordability of the constituent elements, and the ability to produce high efficiency devices from solution processes. However, often expensive and toxic materials are used in production. In this paper we report on a newly developed amine-thiol solvent system based on 10% cysteamine in ethanolamine, which has low toxicity, is user-friendly and is able to readily dissolve all kesterite constituent elements, including metals and their oxides. The dissolution process and the structures of the prevalent metal complexes formed were investigated with the aid of spectroscopic methods, such as electrospray ionization mass spectrometry (ESI-MS) and infrared multiple photon dissociation (IRMPD). In most cases, two molecules of cysteamine were bound to the metals as bidentate ligands. By employing spin coating of the resulting inks, devices of up to 8.1% power conversion efficiency were fabricated.

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...

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.

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.

Organic systems still dominate several traditional areas of chemical science and well-known applications, such as the synthesis of pharmaceutical compounds and drugs. However, a fascinating trend has appeared recently to combine pure organic systems into advanced molecular architectures and to create hybrid molecular systems. These interdisciplinary areas, where possible connections between organic and hybrid systems may be developed, are the focus of the present review to develop valuable practical applications.

In the present review, we consider the transformations of molecular catalysts, leaching, aggregation and various interconversions of metal complexes, clusters and nanoparticles that occur during catalytic processes. The role of catalyst evolution and the mechanistic picture of “Cocktail”-type systems are considered from the perspective of the development of a new generation of efficient, selective and re-usable catalysts for synthetic applications. Rational catalyst development and the improvement of catalyst performance cannot be achieved without an understanding of the dynamic nature of catalytic systems.

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.

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 stud...

A catalytic system based on OX-1 metal–organic framework nanosheets is reported, incorporating catalytically active palladium (Pd) species. The Pd@OX-1 guest@host system is rapidly synthesized via a one-step single-pot supramolecular assembly, with the possibility of controlling the Pd loading. The structures of the resulting framework and of the active Pd species before and after catalytic reactions are studied in detail using a wide variety of techniques including synchrotron radiation infrared spectroscopy, inelastic neutron scattering, and X-ray absorption spectroscopy. Crystals of the resulting Pd@OX-1 composite material contain predominantly atomic and small cluster Pd species, which selectively reside on benzene rings of the benzenedicarboxylate (BDC) linkers. The composites are shown to efficiently catalyze the Suzuki coupling and Heck arylation reactions under a variety of conditions. Pd@OX-1 further shows potential to be recycled for at least five cycles of each reaction as well as an ability to recapture active Pd species during both catalytic reactions.

Fragmentation of fluorinated 18,19-dihydrothevinols and thevinols under electrospray ionization with collisionally activated dissociation accompanied by the elimination of an amine fragment from the cycle and the subsequent loss of H2O and CH3OH have been studied. For thevinol derivatives with a double bond at C18=C19, the [M + H]+ ions undergo the retro-Diels–Alder fragmentation, the abundance of which depends on substituents at the nitrogen and C20 atoms. The retro-Diels–Alder fragmentation of the [M + H]+ ions of thevinols bearing–CH3,–CH2CH=CH2, and $$ - C{H_2} - \triangleleft $$ groups at the nitrogen atom occurs due to the formation of a protonated diene molecule, whereas the elimination of a neutral diene in thevinols with hydrogen at the nitrogen atom has been observed.

Usual oxygen bases decompose M/NHC complexes to give “NHC-free” metal species and azolones., Numerous reactions are catalyzed by complexes of metals (M) with N-heterocyclic carbene (NHC) ligands, typically in the presence of oxygen bases, which significantly shape the performance. It is generally accepted that bases are required for either substrate activation (exemplified by transmetallation in the Suzuki cross-coupling), or HX capture (e.g. in a variety of C–C and C-heteroatom couplings, the Heck reaction, C–H functionalization, heterocyclizations, etc.). This study gives insights into the behavior of M(ii)/NHC (M = Pd, Pt, Ni) complexes in solution under the action of bases conventionally engaged in catalysis (KOH, NaOH, t-BuOK, Cs2CO3, K2CO3, etc.). A previously unaddressed transformation of M(ii)/NHC complexes under conditions of typical base-mediated M/NHC catalyzed reactions is disclosed. Pd(ii) and Pt(ii) complexes widely used in catalysis react with the bases to give M(0) species and 2(5)-oxo-substituted azoles via an O–NHC coupling mechanism. Ni(NHC)2X2 complexes hydrolyze in the presence of aqueous potassium hydroxide, and undergo the same O–NHC coupling to give azolones and metallic nickel under the action of t-BuOK under anhydrous conditions. The study reveals a new role of NHC ligands as intramolecular reducing agents for the transformation of M(ii) into “ligandless” M(0) species. This demonstrates that the disclosed base-mediated O–NHC coupling reaction is integrated into the catalytic M/NHC systems and can define the mechanism of catalysis (molecular M/NHC vs. “NHC-free” cocktail-type catalysis). A proposed mechanism of the revealed transformation includes NHC-OR reductive elimination, as implied by a series of mechanistic studies including 18O labeling experiments.

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.

Acetonitrile solutions of nickel(II) acetylacetonate, which is ubiquitously used in different fields of organometallic chemistry and catalysis, were investigated by means of electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (MS/MS). The detected Ni2(acac)3+ ion with the binuclear Ni2O2 core underwent a wide range of reactions after collision-induced dissociation, leading to a variety of products. Activation of C–H, C–C, and C–O bonds was observed involving the binuclear nickel complex. In sharp contrast, similar ions involving mononuclear and trinuclear nickel species did not show such exceptional behavior. The findings may open a fascinating direction in the field of superatoms to develop new chemical transformations for organometallic chemistry and catalysis. The higher relative stability of binuclear species was also observed in ESI mass spectra of copper and vanadyl complexes with acetylacetonate ligands, Cu2(acac)3+ and (VO)2(acac)3+. An important point concerns the puri...

The necessary prerequisites to carry out efficient NMR/MS studies and the important points required to avoid inconsistent measurements are discussed. A comparative assessment of the sensitivity and accuracy of NMR, EI-MS and ESI-MS measurements was carried out to evaluate typical laboratory research performance. Accurate NMR measurements are possible in the 10–1–10–3 M concentration range, with spectral studies still being possible at concentrations of approximately 10–4–10–5 M. EI-MS is more sensitive and can operate at concentrations of 10–6 M, while commonly available ESI-MS can be efficient up to a concentration of 10–18 M.

The great impact of the nanoscale organization of reactive species on their performance in chemical transformations creates the possibility of fine-tuning of reaction parameters by modulating the nano-level properties. This methodology is extensively applied for the catalysts development whereas nanostructured reactants represent the practically unexplored area. Here we report the palladium- and copper-catalyzed cross-coupling reaction involving nano-structured nickel thiolate particles as reagents. On the basis of experimental findings we propose the cooperative effect of nano-level and molecular-level properties on their reactivity. The high degree of ordering, small particles size, and electron donating properties of the substituents favor the product formation. Reactant particles evolution in the reaction is visualized directly by dynamic liquid-phase electron microscopy including recording of video movies. Mechanism of the reaction in liquid phase is established using on-line mass spectrometry measurements. Together the findings provide new opportunities for organic chemical transformations design and for mechanistic studies., Direct visualization and characterization of the influence of nanoscale organization on the reactivity of organic functional groups in solution remain a challenge. Here, the authors report the real-time observation of the involvement of a nanostructured reagent in a cross-coupling reaction using advanced liquid-phase electron microscopy.