A Brief Introduction to Chemical Reaction Optimization.

From the start of a synthetic chemist's training, experiments are conducted based on recipes from textbooks and manuscripts that achieve clean reaction outcomes, allowing the scientist to develop practical skills and some chemical intuition. This procedure is often kept long into a researcher's career, as new recipes are developed based on similar reaction protocols, and intuition-guided deviations are conducted through learning from failed experiments. However, when attempting to understand chemical systems of interest, it has been shown that model-based, algorithm-based, and miniaturized high-throughput techniques outperform human chemical intuition and achieve reaction optimization in a much more time- and material-efficient manner; this is covered in detail in this paper. As many synthetic chemists are not exposed to these techniques in undergraduate teaching, this leads to a disproportionate number of scientists that wish to optimize their reactions but are unable to use these methodologies or are simply unaware of their existence. This review highlights the basics, and the cutting-edge, of modern chemical reaction optimization as well as its relation to process scale-up and can thereby serve as a reference for inspired scientists for each of these techniques, detailing several of their respective applications.

Impact of Surface Ligand on the Biocompatibility of InP/ZnS Quantum Dots with Platelets.

InP/ZnS quantum dots (QDs) have received a large focus in recent years as a safer alternative to heavy metal-based QDs. Given their intrinsic fluorescent imaging capabilities, these QDs can be potentially relevant for in vivo platelet imaging. The InP/ZnS QDs are synthesized and their biocompatibility investigated through the use of different phase transfer agents. Analysis of platelet function indicates that platelet-QD interaction can occur at all concentrations and for all QD permutations tested. However, as the QD concentration increases, platelet aggregation is induced by QDs alone independent of natural platelet agonists. This study helps to define a range of concentrations and coatings (thioglycolic acid and penicillamine) that are biocompatible with platelet function. With this information, the platelet-QD interaction can be identified using multiple methods. Fluorescent lifetime imaging microscopy (FLIM) and confocal studies have shown QDs localize on the surface of the platelet toward the center while showing evidence of energy transfer within the QD population. It is believed that these findings are an important stepping point for the development of fluorescent probes for platelet imaging.

The Influence of Defects on the Luminescence of Trivalent Terbium in Nanocrystalline Yttrium Orthovanadate.

Terbium-doped YVO4 has been considered a nonluminescent solid since the first classic studies on rare-earth-doped phosphors in the 1960s. However, we demonstrate that defect engineering of YVO4:Tb3+ nanoparticles overcomes the metal-metal charge transfer (MMCT) process which is responsible for the quenching of the Tb3+ luminescence. Tetragonal (Y1-xTbx)VO4 nanoparticles obtained by colloidal precipitation showed expanded unit cells, high defect densities, and intimately mixed carbonates and hydroxides, which contribute to a shift of the MMCT states to higher energies. Consequently, we demonstrate unambiguously for the first time that Tb3+ luminescence can be excited by VO43- → Tb3+ energy transfer and by direct population of the 5D4 state in YVO4. We also discuss how thermal treatment removes these effects and shifts the quenching MMCT state to lower energies, thus highlighting the major consequences of defect density and microstructure in nanosized phosphors. Therefore, our findings ultimately show nanostructured YVO4:Tb3+ can be reclassified as a UV-excitable luminescent material.

Bayesian Self-Optimization for Telescoped Continuous Flow Synthesis.

The optimization of multistep chemical syntheses is critical for the rapid development of new pharmaceuticals. However, concatenating individually optimized reactions can lead to inefficient multistep syntheses, owing to chemical interdependencies between the steps. Herein, we develop an automated continuous flow platform for the simultaneous optimization of telescoped reactions. Our approach is applied to a Heck cyclization-deprotection reaction sequence, used in the synthesis of a precursor for 1-methyltetrahydroisoquinoline C5 functionalization. A simple method for multipoint sampling with a single online HPLC instrument was designed, enabling accurate quantification of each reaction, and an in-depth understanding of the reaction pathways. Notably, integration of Bayesian optimization techniques identified an 81 % overall yield in just 14 h, and revealed a favorable competing pathway for formation of the desired product.

A Highly Stable Yttrium Organic Framework as a Host for Optical Thermometry and D2 O Detection.

The yttrium organic framework (Y0.89 Tb0.10 Eu0.01 )6 (BDC)7 (OH)4 (H2 O)4 (BDC=benzene-1,4-dicarboxylate) is hydrothermally stable up to at least 513 K and thermally stable in air in excess of 673 K. The relative intensities of luminescence of Tb3+ and Eu3+ are governed by Tb3+ -to-Eu3+ phonon-assisted energy transfer and Tb3+ -to-ligand back transfer and are responsible for the differing temperature-dependent luminescence of the two ions. This provides a ratiometric luminescent thermometer in the 288-573 K temperature range, not previously seen for MOF materials, with a high sensitivity, 1.69±0.04 % K-1 at 523 K. In aqueous conditions, loosely bound H2 O can be replaced by D2 O in the same material, which modifies decay lifetimes to yield a quantitative luminescent D2 O sensor with a useful sensitivity for practical application.

Nonredox CO2 Fixation in Solvent-Free Conditions Using a Lewis Acid Metal-Organic Framework Constructed from a Sustainably Sourced Ligand.

CO2 epoxidation to cyclic carbonates under mild, solvent-free conditions is a promising pathway toward sustainable CO2 utilization. Metal-organic frameworks (MOFs) explored for such applications so far are commonly composed of nonrenewable ligands such as benzene dicarboxylate (BDC) or synthetically complex linkers and therefore are not suitable for commercial utilization. Here, we report new yttrium 2,5-furandicarboxylate (FDC)-based MOFs: "UOW-1" and "UOW-2" synthesized via solvothermal assembly, with the former having a unique structural topology. The FDC linker can be derived from biomass and is a green and sustainable alternative to conventionally used BDC ligands, which are sourced exclusively from fossil fuels. UOW-1, owing to unique coordination unsaturation and a high density of Lewis active sites, promotes a high catalytic activity (∼100% conversion; ∼99% selectivity), a high turnover frequency (70 h-1), and favorable first-order kinetics for CO2 epoxidation reactions using an epichlorohydrin model substrate under solvent-free conditions within 6 h and a minimal cocatalyst amount. A systematic catalytic study was carried out by broadening the epoxide substrate scope to determine the influence of electronic and steric factors on CO2 epoxidation. Accordingly, higher conversion efficiencies were observed for substrates with high electrophilicity on the carbon center and minimal steric bulk. The work presents the first demonstration of sustainable FDC-based MOFs used for efficient CO2 utilization.

Zinc 1s Valence-to-Core X-ray Emission Spectroscopy of Halozincate Complexes.

The Zn 1s valence-to-core (VtC) X-ray emission spectra of seven ionic liquids have been measured experimentally and simulated on the basis of time-dependent density-functional theory (TDDFT) calculations. Six of the ionic liquids were made by mixing [C8C1Im]X and Zn(II)X2 at three different ZnX2 mole fractions (0.33, 0.50, or 0.67) for X = Cl or Br, and a further ionic liquid was made by mixing [P6,6,6,14]Cl and a mole fraction of ZnCl2 of 0.33. Calculations were performed for the [ZnX4]2-, [Zn2X6]2-, and [Zn4X10]2- ions to capture the expected metal complex speciation. The VtC emission spectra showed three bands arising from single-electron processes that can be assigned to emission from ligand p-type orbitals, zinc d-orbitals, and ligand s-type orbitals. For all seven ionic liquids, the highest occupied molecular orbital arises from the ligand p orbitals, and the spectra for the different size metal complexes for the same X were found to be very similar, in terms of both relative peak intensities and peak energies. For both experiments and TDDFT calculations, there was an energy difference of 0.5 eV between the Cl-based and Br-based metal complexes for the ligand s and p orbitals, while the Zn 3d orbital energies were relatively unaffected by the identity of the ligand. The TDDFT calculations find that for the ions with symmetrically equivalent zinc atoms ([Zn2X6]2- and [Zn4X10]2-), the most appropriate core-ionized reference state has a core-hole that is localized on a single zinc atom. In this framework, the spectra for the larger ions can be viewed as a sum of spectra for the tetrahedral complex with a single zinc atom with small variations in the structure of the coordinating ligands. Because the spectra are relatively insensitive to small changes in the geometry of the ligands, this is consistent with the small variation in the spectra measured in the experiment.

Direct Correlation of Carbon Nanotube Nucleation and Growth with the Atomic Structure of Rhenium Nanocatalysts Stimulated and Imaged by the Electron Beam.

Subnanometer Re clusters confined in a single-walled carbon nanotube are activated by the 80 keV electron beam to promote the catalytic growth of a new carbon nanotube. Transmission electron microscopy images the entire process step-by-step, with atomic resolution in real time, revealing details of the initial nucleation followed by a two-stage growth. The atomic dynamics of the Re cluster correlate strongly with the nanotube formation process, with the growth accelerating when the catalyst becomes more ordered. In addition to the nanotube growth catalyzed by Re nanoclusters, individual atoms of Re released from the nanocluster play a role in the nanotube formation.

A Hybridised Optimisation of an Automated Photochemical Continuous Flow Reactor.

A new hybridized algorithm that combines process optimisation with response surface mapping was developed and applied in an automated continuous flow reaction. Moreover, a photochemical cascade CSTR was developed and characterised by chemical actinometry, showing photon flux density of ten times greater than previously reported in batch. The success of the algorithm was then evaluated in the aerobic oxidation of sp³ C-H bonds using benzophenone as photosensitizer in the newly developed photo reactor.

Wall- and Hybridisation-Selective Synthesis of Nitrogen-Doped Double-Walled Carbon Nanotubes.

Controlled nitrogen-doping is a powerful methodology to modify the properties of carbon nanostructures and produce functional materials for electrocatalysis, energy conversion and storage, and sensing, among others. Herein, we report a wall- and hybridisation-selective synthetic methodology to produce double-walled carbon nanotubes with an inner tube doped exclusively with graphitic sp2 -nitrogen atoms. Our measurements shed light on the fundamental properties of nitrogen-doped nanocarbons opening the door for developing their potential applications.

Direct Synthesis of Multiplexed Metal-Nanowire-Based Devices by Using Carbon Nanotubes as Vector Templates.

We present the synthesis of metal nanowires in a multiplexed device configuration using single-walled carbon nanotubes (SWNTs) as nanoscale vector templates. The SWNT templates control the dimensionality of the wires, allowing precise control of their size, shape, and orientation; moreover, a solution-processable approach enables their linear deposition between specific electrode pairs in electronic devices. Electrical characterization demonstrated the successful fabrication of metal nanowire electronic devices, while multiscale characterization of the different fabrication steps revealed details of the structure and charge transfer between the material encapsulated and the carbon nanotube. Overall the strategy presented allows facile, low-cost, and direct synthesis of multiplexed metal nanowire devices for nanoelectronic applications.

All-Fullerene-Based Cells for Nonaqueous Redox Flow Batteries.

Redox flow batteries have the potential to revolutionize our use of intermittent sustainable energy sources such as solar and wind power by storing the energy in liquid electrolytes. Our concept study utilizes a novel electrolyte system, exploiting derivatized fullerenes as both anolyte and catholyte species in a series of battery cells, including a symmetric, single species system which alleviates the common problem of membrane crossover. The prototype multielectron system, utilizing molecular based charge carriers, made from inexpensive, abundant, and sustainable materials, principally, C and Fe, demonstrates remarkable current and energy densities and promising long-term cycling stability.

Chemical Reactions of Molecules Promoted and Simultaneously Imaged by the Electron Beam in Transmission Electron Microscopy.

The main objective of this Account is to assess the challenges of transmission electron microscopy (TEM) of molecules, based on over 15 years of our work in this field, and to outline the opportunities in studying chemical reactions under the electron beam (e-beam). During TEM imaging of an individual molecule adsorbed on an atomically thin substrate, such as graphene or a carbon nanotube, the e-beam transfers kinetic energy to atoms of the molecule, displacing them from equilibrium positions. Impact of the e-beam triggers bond dissociation and various chemical reactions which can be imaged concurrently with their activation by the e-beam and can be presented as stop-frame movies. This experimental approach, which we term ChemTEM, harnesses energy transferred from the e-beam to the molecule via direct interactions with the atomic nuclei, enabling accurate predictions of bond dissociation events and control of the type and rate of chemical reactions. Elemental composition and structure of the reactant molecules as well as the operating conditions of TEM (particularly the energy of the e-beam) determine the product formed in ChemTEM processes, while the e-beam dose rate controls the reaction rate. Because the e-beam of TEM acts simultaneously as a source of energy for the reaction and as an imaging tool monitoring the same reaction, ChemTEM reveals atomic-level chemical information, such as pathways of reactions imaged for individual molecules, step-by-step and in real time; structures of illusive reaction intermediates; and direct comparison of catalytic activity of different transition metals filmed with atomic resolution. Chemical transformations in ChemTEM often lead to previously unforeseen products, demonstrating the potential of this method to become not only an analytical tool for studying reactions, but also a powerful instrument for discovery of materials that can be synthesized on preparative scale.

Formation of Nickel Clusters Wrapped in Carbon Cages: Toward New Endohedral Metallofullerene Synthesis.

Despite the high potential of endohedral metallofullerenes (EMFs) for application in biology, medicine and molecular electronics, and recent efforts in EMF synthesis, the variety of EMFs accessible by conventional synthetic methods remains limited and does not include, for example, EMFs of late transition metals. We propose a method in which EMF formation is initiated by electron irradiation in aberration-corrected high-resolution transmission electron spectroscopy (AC-HRTEM) of a metal cluster surrounded by amorphous carbon inside a carbon nanotube serving as a nanoreactor and apply this method for synthesis of nickel EMFs. The use of AC-HRTEM makes it possible not only to synthesize new, previously unattainable nanoobjects but also to study in situ the mechanism of structural transformations. Molecular dynamics simulations using the state-of-the-art approach for modeling the effect of electron irradiation are performed to rationalize the experimental observations and to link the observed processes with conditions of bulk EMF synthesis.

Atomic charges of sulfur in ionic liquids: experiments and calculations.

Experimental near edge X-ray absorption fine structure (NEXAFS) spectra, X-ray photoelectron (XP) spectra and Auger electron spectra are reported for sulfur in ionic liquids (ILs) with a range of chemical structures. These values provide experimental measures of the atomic charge in each IL and enable the evaluation of the suitability of NEXAFS spectroscopy and XPS for probing the relative atomic charge of sulfur. In addition, we use Auger electron spectroscopy to show that when XPS binding energies differ by less than 0.5 eV, conclusions on atomic charge should be treated with caution. Our experimental data provides a benchmark for calculations of the atomic charge of sulfur obtained using different methods. Atomic charges were computed for lone ions and ion pairs, both in the gas phase (GP) and in a solvation model (SMD), with a wide range of ion pair conformers considered. Three methods were used to compute the atomic charges: charges from the electrostatic potential using a grid based method (ChelpG), natural bond orbital (NBO) population analysis and Bader's atoms in molecules (AIM) approach. By comparing the experimental and calculated measures of the atomic charge of sulfur, we provide an order for the sulfur atoms, ranging from the most negative to the most positive atomic charge. Furthermore, we show that both ChelpG and NBO are reasonable methods for calculating the atomic charge of sulfur in ILs, based on the agreement with both the XPS and NEXAFS spectroscopy results. However, the atomic charges of sulfur derived from ChelpG are found to display significant, non-physical conformational dependence. Only small differences in individual atomic charge of sulfur were observed between lone ion (GP) and ion pair IL(SMD) model systems, indicating that ion-ion interactions do not strongly influence individual atomic charges.

NEXAFS spectroscopy of ionic liquids: experiments versus calculations.

Experimental near edge X-ray absorption fine structure (NEXAFS) spectra are reported for 12 ionic liquids (ILs) encompassing a range of chemical structures for both the sulfur 1s and nitrogen 1s edges and compared with time-dependent density functional theory (TD-DFT) calculations. The energy scales for the experimental data were carefully calibrated against literature data. Gas phase calculations were performed on lone ions, ion pairs and ion pair dimers, with a wide range of ion pair conformers considered. For the first time, it is demonstrated that TD-DFT is a suitable method for simulating NEXAFS spectra of ILs, although the number of ions included in the calculations and their conformations are important considerations. For most of the ILs studied, calculations on lone ions in the gas phase were sufficient to successfully reproduce the experimental NEXAFS spectra. However, for certain ILs - for example, those containing a protic ammonium cation - calculations on ion pairs were required to obtain a good agreement with experimental spectra. Furthermore, significant conformational dependence was observed for the protic ammonium ILs, providing insight into the predominant liquid phase cation-anion interactions. Among the 12 investigated ILs, we find that four have an excited state that is delocalised across both the cation and the anion, which has implications for any process that depends on the excited state, for example, radiolysis. Considering the collective experimental and theoretical data, we recommend that ion pairs should be the minimum number of ions used for the calculation of NEXAFS spectra of ILs.

Carbon Nanotubes as Electrically Active Nanoreactors for Multi-Step Inorganic Synthesis: Sequential Transformations of Molecules to Nanoclusters and Nanoclusters to Nanoribbons.

In organic synthesis, the composition and structure of products are predetermined by the reaction conditions; however, the synthesis of well-defined inorganic nanostructures often presents a significant challenge yielding nonstoichiometric or polymorphic products. In this study, confinement in the nanoscale cavities of single-walled carbon nanotubes (SWNTs) provides a new approach for multistep inorganic synthesis where sequential chemical transformations take place within the same nanotube. In the first step, SWNTs donate electrons to reactant iodine molecules (I2), transforming them to iodide anions (I(-)). These then react with metal hexacarbonyls (M(CO)6, M = Mo or W) in the next step, yielding anionic nanoclusters [M6I14](2-), the size and composition of which are strictly dictated by the nanotube cavity, as demonstrated by aberration-corrected high resolution transmission electron microscopy, scanning transmission electron microscopy, and energy dispersive X-ray spectroscopy. Atoms in the nanoclusters [M6I14](2-) are arranged in a perfect octahedral geometry and can engage in further chemical reactions within the nanotube, either reacting with each other leading to a new polymeric phase of molybdenum iodide [Mo6I12]n or with hydrogen sulfide gas giving rise to nanoribbons of molybdenum/tungsten disulfide [MS2]n in the third step of the synthesis. Electron microscopy measurements demonstrate that the products of the multistep inorganic transformations are precisely controlled by the SWNT nanoreactor with complementary Raman spectroscopy revealing the remarkable property of SWNTs to act as a reservoir of electrons during the chemical transformation. The electron transfer from the host nanotube to the reacting guest molecules is essential for stabilizing the anionic metal iodide nanoclusters and for their further transformation to metal disulfide nanoribbons synthesized in the nanotubes in high yield.

Investigation of the Interactions and Bonding between Carbon and Group VIII Metals at the Atomic Scale.

The nature and dynamics of bonding between Fe, Ru, Os, and single-walled carbon nanotubes (SWNTs) is studied by aberration-corrected high-resolution transmission electron microscopy (AC-HRTEM). The metals catalyze a wide variety of different transformations ranging from ejection of carbon atoms from the nanotube sidewall to the formation of hollow carbon shells or metal carbide within the SWNT, depending on the nature of the metal. The electron beam of AC-HRTEM serves the dual purpose of providing energy to the specimen and simultaneously enabling imaging of chemical transformations. Careful control of the electron beam parameters, energy, flux, and dose allowed direct comparison between the metals, demonstrating that their chemical reactions with SWNTs are determined by a balance between the cohesive energy of the metal particles and the strength of the metal-carbon σ- or π-bonds. The pathways of transformations of a given metal can be drastically changed by applying different electron energies (80, 40, or 20 keV), thus demonstrating AC-HRTEM as a new tool to direct and study chemical reactions. The understanding of interactions and bonding between SWNT and metals revealed by AC-HRTEM at the atomic level has important implications for nanotube-based electronic devices and catalysis.

Direct Measurement of Electron Transfer in Nanoscale Host-Guest Systems: Metallocenes in Carbon Nanotubes.

Electron-transfer processes play a significant role in host-guest interactions and determine physicochemical phenomena emerging at the nanoscale that can be harnessed in electronic or optical devices, as well as biochemical and catalytic systems. A novel method for qualifying and quantifying the electronic doping of single walled carbon nanotubes (SWNTs) using electrochemistry has been developed that establishes a direct link between these experimental measurements and ab initio DFT calculations. Metallocenes such as cobaltocene and methylated ferrocene derivatives were encapsulated inside SWNTs (1.4 nm diameter) and cyclic voltammetry (CV) was performed on the resultant host-guest systems. The electron transfer between the guest molecules and the host SWNTs is measured as a function of shift in the redox potential (E1/2 ) of Co(II) /Co(I) , Co(III) /Co(II) and Fe(III) /Fe(II) . Furthermore, the shift in E1/2 is inversely proportional to the nanotube diameter. To quantify the amount of electron transfer from the guest molecules to the SWNTs, a novel method using coulometry was developed, allowing the mapping of the density of states and the Fermi level of the SWNTs. Correlated with theoretical calculations, coulometry provides an accurate indication of n/p-doping of the SWNTs.

Activation and deactivation of a robust immobilized Cp*Ir-transfer hydrogenation catalyst: a multielement in situ X-ray absorption spectroscopy study.

A highly robust immobilized [Cp*IrCl2]2 precatalyst on Wang resin for transfer hydrogenation, which can be recycled up to 30 times, was studied using a novel combination of X-ray absorption spectroscopy (XAS) at Ir L3-edge, Cl K-edge, and K K-edge. These culminate in in situ XAS experiments that link structural changes of the Ir complex with its catalytic activity and its deactivation. Mercury poisoning and "hot filtration" experiments ruled out leached Ir as the active catalyst. Spectroscopic evidence indicates the exchange of one chloride ligand with an alkoxide to generate the active precatalyst. The exchange of the second chloride ligand, however, leads to a potassium alkoxide-iridate species as the deactivated form of this immobilized catalyst. These findings could be widely applicable to the many homogeneous transfer hydrogenation catalysts with Cp*IrCl substructure.