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Robust calorimetric data for highly exothermic organolithium reactions are obtained within a modular 3D printed continuous flow calorimeter.

To automate and democratize model-based experimental design for flow chemistry applications, we report the development of open-source software, Optipus. Reaction models are built in an iterative and automated fashion, for rapid reaction development.

We develop a continuous flow protocol for the synthesis of sulfonyl chlorides from disulfides and thiols, using 1,3-dichloro-5,5-dimethylhydantoin (DCH) as a dual-function reagent for oxidative chlorination.

An automated continuous flow and real-time analytics platform facilitates the generation of quantitative data to understand the sensitivity of the reaction performance in the presence of different functional groups and heterocycles.

Artificial neural networks (ANNs) facilitate rapid quantification of process spectra from inline process analytical technologies. Data fusion also enables combination of multiple data sources, resulting in better quality concentration measurements.

N-Chloroamines have recently seen interest as substrates for atom-transfer radical addition (ATRA) reactions with olefins, to form β-chloroamine products, with complete atom incorporation. We report the development of a fully continuous method for N-chloroamine formation and photochemical reaction, utilizing membrane separation to purify the reactive intermediate species. Through detailed reaction optimization, supported by computational studies, we have determined that this type of reaction can be activated by direct substrate irradiation or via a range of triplet sensitizers at different wavelengths (up to 540 nm), allowing access to more favorable and sustainable reaction conditions. A number of substrates were reacted under sensitized or unsensitized conditions and the longer-term stability of the process was demonstrated in a 4.5 h experiment, achieving 94% yield and a throughput of 21.2 g h−1. This study serves to bring N-chloroamines to the fore as ATRA substrates, for implementation in efficient and sustainable synthetic routes.

Ozonolysis reactions are generally high-yielding, highly selective, and sustainable processes, especially when performed in green solvents. However, ozonolysis is underutilized in organic synthesis and chemical manufacture due to the safety concerns associated with handling ozone (O3) gas and the highly reactive ozonide intermediate. In this article, the development of ozonolysis reactions within a dedicated microreactor platform suitable for gas–liquid transformations is described. The optimization of the reaction conditions for the ozonolysis of cyclohexene to hexanedial, and thioanisole to methyl phenyl sulfoxide is presented. Cyclohexene is transformed to hexanedial in 94% yield at 0 °C within 1.7 seconds. In a similar fashion, the ozonolysis of thioanisole was achieved in 99% yield at 0 °C within

Metal oxides represent an abundant and non-toxic class of photocatalysts for organic transformations. However, their use in larger scale processes is complicated by incompatibilities with continuous flow processing – a proven scale-up route for photochemistry. We detail the development of an efficient atom transfer radical addition protocol using a sustainable solvent system (acetone : PEG 400) and a low loading (2 mol%) of Bi2O3, which can be handled in an oscillatory flow reactor. Optimization of the reaction and oscillatory parameters led to high throughput (36 g in 4 h, 89% yield, 599 g L−1 h−1), with a process mass intensity (PMI) of just 8.5. The process also facilitates high recyclability (3 cycles with no loss of yield), and was demonstrated to be applicable to a range of other substrates on multigram scale, in moderate to excellent yields.

Despite the fact that continuous flow processing exhibits well-established technical advances, aqueous micellar chemistry, a field that has proven extremely useful in shifting organic synthesis to sustainable water-based media, has mostly been explored under conventional batch-based conditions. This is particularly because of the fact that the reliable handling of slurries and suspensions in flow has been considered as a significant technical challenge. Herein, we demonstrate that the strategic application of an oscillatory plug flow reactor enables heterogeneous catalytic reductive aminations in aqueous micellar media enhancing mass transport and facilitating process simplicity, stability and scalability. The micellar flow process enabled a broad range of substrates, including amino acid derivatives, to be successfully transformed under reasonably mild conditions utilizing only very low amounts of Pd/C as a readily available heterogeneous catalyst. The preparative capabilities of the process along with the recyclability of the heterogenous catalyst and the aqueous reaction media were also demonstrated.

Catalytic enantioselective transformations provide well-established and direct access to stereogenic synthons that are broadly distributed among active pharmaceutical ingredients (APIs). These reactions have been demonstrated to benefit considerably from the merits of continuous processing and microreactor technology. Over the past few years, continuous flow enantioselective catalysis has grown into a mature field and has found diverse applications in asymmetric synthesis of pharmaceutically active substances. The present review therefore surveys flow chemistry-based approaches for the synthesis of chiral APIs and their advanced stereogenic intermediates, covering the utilization of biocatalysis, organometallic catalysis and metal-free organocatalysis to introduce asymmetry in continuously operated systems. Single-step processes, interrupted multistep flow syntheses, combined batch/flow processes and uninterrupted one-flow syntheses are discussed herein., This review surveys continuous flow approaches for the synthesis of chiral APIs and their advanced stereogenic intermediates, covering the utilization of biocatalysis, organometallic catalysis and metal-free organocatalysis to introduce asymmetry.

The development of a ruthenium-catalyzed continuous flow ester hydrogenation using hydrogen (H2) gas is reported. The reaction was utilized for the reduction of an important precursor in the synthesis of abediterol, a β2-adrenoceptor agonist that has undergone phase IIa clinical trials for the treatment of asthma and chronic obstructive pulmonary disorder. The reaction was investigated within a batch autoclave by using a design of experiments (DoE) approach to identify important parameter effects. The optimized flow process was successfully operated over 6 h with inline benchtop 19F NMR spectroscopy for reaction monitoring. The protocol is shown to be high yielding (98% yield, 3.7 g h−1) with very low catalyst loading (0.065 mol%). The environmental impact of the Ru-catalyzed hydrogenation was assessed and compared to an existing stoichiometric lithium aluminum hydride (LAH) reduction and sodium borohydride (NaBH4) reduction. The process mass intensity (PMI) for the Ru-catalyzed hydrogenation (14) compared favorably to a LAH reduction (52) and NaBH4 reduction (133).

Utilization of highly reactive compounds in novel flow syntheses requires new tools for process development. This work presents such a tool in the form of a modular calorimeter designed for direct heat flux measurements in continuous flow applications. The calorimeter consists mainly of 3D printed parts, which can be adapted and reassembled easily to meet user-defined applications. By utilizing selective laser melting (SLM) of stainless steel and digital light processing (DLP) of a UV curable resin, a device is produced to meet the requirements of handling highly reactive organic compounds. Calorimeter segments are temperature-regulated independently of each other by a microcontroller, allowing isothermal operation conditions. Direct heat flux measurements are possible in the device through Seebeck elements which are calibrated internally at prevailing process conditions with the aid of heating foils. Functionality of the designed calorimeter is shown by good agreement of conducted heat flux measurements with literature.

Nickel/photoredox catalyzed C–N couplings of hydrazine-derived nucleophiles provide a powerful alternative to Pd-catalyzed methods. This continuous-flow photochemical protocol, optimized using design of experiments, achieves these couplings in short residence times, with high selectivity. A range of (hetero)aryl bromides and chlorides are compatible and understanding of process stability/reactor fouling has been discerned.

The development of new protocols for peptide bond formation which avoid side reactions, including epimerization, are very important. The acyl azide method for the preparation of peptides is very good at maintaining chiral integrity, however; acyl azides are considered to be highly unstable and potentially explosive intermediates. Thus, the acyl azide method is underutilized by the synthetic community. Acyl azides were safely generated and reacted in situ within a continuous-flow system. The acyl azide was generated by using nitrous acid in water, and efficiently extracted into the organic phase containing the amine nucleophile for peptide coupling. The protocol has been used to prepare a number of dipeptides (5 examples) without epimerization (

Inline benchtop NMR analysis is established as a powerful tool for reaction monitoring, but its capabilities are somewhat limited by low spectral resolution, often leading to overlapping peaks and difficulties in quantification. Using a multivariate analysis (MVA) statistical approach to data processing these hurdles can be overcome, enabling accurate quantification of complex product mixtures. By employing rapid data acquisition (2.0 s recording time per spectrum), we demonstrate the use of inline benchtop NMR to guide the optimization of a complex nitration reaction in flow. Accurate quantification of four overlapping species was possible, enabling generation of a robust DoE model along with accurate evaluation of dynamic experiments.

Flash vacuum pyrolysis of methyl N-methyl-N-nitrosoanthranilate leads to elimination of nitric oxide and disproportionation of the formed N-radical to 7-(methylamino)phthalide and methyl N-methylanthranilate. This transformation was found to be a convenient, solvent-free method for the preparation of 7-(methylamino)phthalides. An alternative route through pyrolysis of N-benzyl-N-methyl anthranilates was also investigated.

The catalytic enantioselective synthesis of the chiral key intermediate of the antidepressant (−)-paroxetine is demonstrated as a continuous flow process on multi-gram scale. The critical step is a solvent-free organocatalytic conjugate addition followed by a telescoped reductive amination–lactamization–amide/ester reduction sequence. Due to the efficient heterogeneous catalysts and the solvent-free or highly concentrated conditions applied, the flow method offers key advances in terms of productivity and sustainability compared to earlier batch approaches.

In an effort to push the boundaries of optical oxygen sensors, this contribution shows the development of a measurement system for high O2 content in organic solvents specifically designed for flow reactors. Presented sensors were prepared by directly melting an oxygen indicator dye into a highly resistant polymer matrix, leading to the ability to measure oxygen contents up to 59 mmol L−1 in tetrahydrofuran, toluene, acetone, dimethylformamide, cyclohexane and methyl tert-butyl ether. Long-term effects to the solvent were investigated by exposing the sensors for 22 hours to the respective solvent at 25 °C. Linearity according to Stern–Volmer was obtained for every single sensor in order to provide a system that can be easily initialized by two-point calibration into continuous flow reactors. To demonstrate the applicability of the sensor under reaction conditions, an oxidation of a Grignard reagent with molecular oxygen was performed in a flow reactor. The sensors were able to show the oxygen decrease during reaction and allowed online reactant quantification.

Currently, the monitoring of multistep continuous flow processes by multiple analytical sources is still seen as a resource intensive and specialized activity. In this article, the coupling of a modular microreactor platform with real-time monitoring by inline IR and NMR, in addition to online UPLC, is described. Using this platform, we rapidly generated experimental data (17 iterations in under 2 hours) to access information on the different chemical species at multiple points within the reactor and to generate process understanding. We highlight the application of the platform in the optimization of a multistep organolithium transformation. The optimized continuous flow conditions were demonstrated in a scale-out experiment with in-process monitoring to afford the desired product in 70% isolated yield and provided a throughput of 4.2 g h−1.

Additive manufacturing has gained a lot of interest in recent years to create customized reactors and equipment for milli- and micro flow applications. This work presents the development of 3D printed stainless steel reactors for the oxidation of Grignard reagents in flow. In our first approach a 3D printed micro CSTR-cascade was designed as a tool to get more insight in the reaction kinetics. Novel optical sensors were integrated inline in the cascade to monitor the oxygen consumption in real time. Based on the obtained experimental data and CFD simulations, a customized 3D printed split and recombine reactor was designed especially for the needs of the reaction.

Continuous-flow production of chiral intermediates plays an important role in the development of building blocks for Active Pharmaceutical Ingredients (APIs), being α-amino acids and their derivatives widely applied as building blocks. In this work we developed two different strategies for the synthesis of intermediates used on the synthesis of levetiracetam/brivaracetam and ethambutol. The results obtained show that methionine methyl ester can be continuously converted to the desired ethambutol intermediate by RANEY® Nickel dessulfurization/reduction strategy whereas levetiracetam/brivaracetam intermediates could be synthesized by both RANEY® Nickel (without H2) and Pd/C-H2 approach or by photochemical desulfurization.

Herein, we describe a continuous flow protocol for the generation, purification and quantification of nitrosyl chloride (NOCl). The generation of this useful but hazardous reagent is based on the reaction of aqueous NaNO2 with HCl as readily available starting materials. The reagent, which is formed immediately upon mixing of the reactants, is rapidly extracted into a suitable organic phase, such as CHCl3 or CH2Cl2, and separated using a continuous flow liquid–liquid membrane separator. A convenient method for the in-line monitoring of reagent concentration, based on flow UV/vis analysis, has also been developed and implemented. The synthetic utility of the nitrosyl chloride generator was demonstrated by integrating a continuous flow photochemical reactor downstream to perform the synthesis of cyclohexanone oxime from cyclohexane, an important industrial process.

BrCCl3 represents a rarely used benzylic brominating reagent with complementary reactivity to other reagents. Its reactivity has been revisited in continuous flow, revealing compatibility with electron-rich aromatic substrates. This has brought about the development of a p-methoxybenzyl bromide generator for PMB protection, which was successfully demonstrated on a pharmaceutically relevant intermediate on 11 g scale, giving 91% yield and a PMB-Br space–time-yield of 1.27 kg L−1 h−1.

The design and construction of a low-cost and compact USB photometer based on open source hardware and software is described. The device, featuring a 1 ms sample acquisition time, utilizes a single interchangeable light emitting diode (LED) as a light source in combination with photodiode detectors and a Texas Instruments LaunchPad as the main control unit. An appropriately constructed flow cell can be connected to a flow reactor made out of transparent polymeric material such as perfluoroalkoxy (PFA) tubing. The flow cell can be moved to different positions of the tube in order to take measurements at different residence times without having to disassemble the photometer or the flow reactor system. The bespoke photometer was used to determine the residence time distribution (RTD) of various microreactors/micromixers, as well as for measuring the reaction rate constant for the base-induced hydrolysis of p-nitrophenol acetate in a biphasic segmented flow system. Owing to the 1 ms sample acquisition time of the novel device the lengths of individual segments can be measured in real time.

Fluoroform (CHF3) can be considered as an ideal reagent for difluoromethylation reactions. However, due to the low reactivity of fluoroform, only very few applications have been reported so far. Herein we report a continuous flow difluoromethylation protocol on sp3 carbons employing fluoroform as a reagent. The protocol is applicable for the direct Cα-difluoromethylation of protected α-amino acids, and enables a highly atom efficient synthesis of the active pharmaceutical ingredient eflornithine.

The halogenation of organic substrates is one the most important transformations in organic synthesis. The most straightforward, inexpensive and atom economic halogenations involve the use of elemental halogens (X2) or hydrogen halides (HX). However, X2 and HX reagents are highly reactive, toxic and corrosive materials. Halogenations using these reagents are usually very fast and exothermic reactions, in which selectivity issues occur. Using continuous flow chemistry halogenations involving X2 and HX can be performed in a safe and controllable manner. Reagents can be accurately dosed even for gas/liquid reactions, and exotherms are easily controlled. Hazardous chemicals can be readily quenched in line avoiding any undesired exposures and significantly enhancing the process safety.

A novel macromolecular photoredox catalyst based on [Ru(bpy)3]2+ anchored to a 2nd-generation PAMAM dendrimer has been developed. Its catalytic activity under visible light irradiation and recyclability using organic solvent nanofiltration with a size-exclusion membrane have been explored under continuous flow conditions.

A simple continuous flow setup for the generation and use of elemental chlorine for organic synthesis has been developed. The chlorine generator is based on the reaction of HCl with NaOCl, generating NaCl and H2O as the only side products. As a proof-of-concept, the reactor has been applied for a variety of chlorinations and oxidations of organic compounds.

Bromine azide (BrN3), a useful but extremely toxic and explosive reagent for the preparation of vicinal 1,2-bromine azide compounds, was safely generated and reacted in situ with alkenes in a continuous flow photoreactor. BrN3 was generated by a novel procedure from NaBr and NaN3 in water, and efficiently extracted into an organic phase containing the alkene thus avoiding decomposition. The resulting addition products have been used for the preparation of several useful building blocks.

A fully continuous four step process for the preparation of β-amino acids from their corresponding α-amino acids utilizing the Arndt–Eistert homologation approach is described.

Non-fluorinated vinyldiazo compounds with trans-configuration irrespective of the nature of 3-R(1)-substituent (R(1) = H, Me, TBSO) even under ambient conditions easily cyclize to produce pyrazoles, while cis-stereoisomers undergo similar ring closure only at elevated temperatures or decompose to produce vinyloxocarbene reaction products. The 3-CF3-substituted analogues with cis- or trans-configuration do not produce pyrazoles at all, but on heating furnish only vinylcarbene derived products. DFT calculations of theoretical energy barriers adequately explain the different experimental reactivity found for stereoisomeric vinyldiazocarbonyl compounds, and a new model for their interconversion through the corresponding pyrazoles has been suggested.

The development of multistep continuous flow reactions for the synthesis of important intermediates for the pharmaceutical industry is still a significant challenge. In the present contribution the biaryl-hydrazine unit of Atazanavir, an important HIV protease inhibitor, was prepared in a three-step continuous flow sequence in 74% overall yield. The synthesis involved Pd-catalyzed Suzuki–Miyaura cross-coupling, followed by hydrazone formation and a subsequent hydrogenation step, and additionally incorporates a liquid–liquid extraction step.

A detailed investigation on the microwave-assisted preparation of iron oxide nanoparticles on mesoporous Si-SBA-15 support is described, employing a dedicated single-mode microwave reactor with internal reaction temperature control. Using iron(II) chloride as iron precursor and ethanol as solvent, extensive optimization studies demonstrate that after 3–5 min at 150–200 °C well-defined 3–5 nm iron oxide nanoparticles (Fe2O3, hematite phase) are obtained. In contrast to the chosen reaction temperature, reaction time and stirring efficiency are of critical importance in the preparation of these supported nanoparticles. Extended reaction times (>10 min) lead to a significant proportion of larger aggregates while inefficient stirring also produces low quality nanoparticles as a result of poor dispersion and delivery of the iron precursor to the mesoporous support. Carefully executed control studies between microwave and conventionally heated experiments applying otherwise identical reaction conditions demonstrate that the quality of the obtained supported iron oxide nanoparticles is largely independent on the heating mode, as long as a the exact same temperature profile can be maintained.

The temperature profiles obtained from both an external infrared and internal fiber-optic sensor were compared for heating and synthesizing the ionic liquid 1-butyl-3-methylimidazolium bromide (bmimBr) under microwave conditions. Utilizing a single-mode microwave reactor that allows simultaneous infrared/fiber-optic temperature measurements, significant differences between the two methods of temperature monitoring were revealed. Due to the strong microwave absorptivity of ionic liquids and the delay experienced in monitoring temperature on the outer surface of a heavy-walled glass vial, external infrared temperature sensors can not be used to accurately control the temperature in the heating of ionic liquids under microwave conditions. The use of internal fiber-optic probes allows the monitoring and control of the heating behavior in a much better way. In order to prevent the strong exotherm in the synthesis of bmimBr under microwave conditions the use of a reaction vessel made out of silicon carbide is the method of choice. Because of the high thermal conductivity and effusivity of silicon carbide, the heat generated during the ionic liquid formation is efficiently exchanged with the comparatively cool air in the microwave cavity via the silicon carbide ceramic.

First described almost a decade ago, "click" reactions such as the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) are widely used today in organic and medicinal chemistry, in the polymer and material science field, and in chemical biology. While most click reactions can be performed at room temperature there are instances where some form of process intensification is required. In this tutorial review, aimed at the synthetic chemistry community, examples of click chemistry carried out under non-classical reaction conditions, such as for example applying microwave heating or continuous flow processing will be highlighted.

Flash vacuum pyrolysis of an equimolar mixture of 4-pivaloyl- and 4-methoxycarbonyl-5-tert-butylfuran-2,3-dione affords the new and remarkably stable α-oxoketene 6 as the result of an unusual dimerization of the primarily formed monomeric α-oxoketenes 1 and 3, respectively. [2 + 2] Cycloaddition reactions of 6 and dialkylcarbodiimides furnish functionalized imino-β-lactams 7, while reaction with nucleophiles results in complete degradation of 6 into smaller fragments. Structural confirmation of 6 and 7 is mainly based upon single crystal X-ray analyses.

Enantiomerically pure dihydropyrimidones (DHPMs) were prepared by lipase-catalyzed enzymatic resolution of two types of activated DHPM esters. In the first model series, pivaloyloxymethyl-activated DHPM C5-esters 10a–c were resolved on an analytical scale by various lipases in two different solvent systems with selectivities E 200) to furnish, after deprotection, DHPMs (R)- and (S)-13 on a semi-preparative scale. Treatment of (R)-13 with trichloroacetyl isocyanate produced the antihypertensive agent (R)-SQ 32926.

Conformationally rigid polyheterocycles 14a,b which mimic the putative receptor-bound conformation of dihydropyridine type calcium channel modulators are prepared in a six-step reaction sequence starting from urea, ethyl acetoacetate and 2-alkenylbenzaldehydes. The key step in the synthesis involves the regio- and diastereoselective intramolecular 1,3-dipolar cycloaddition reaction of a dihydropyrimidine-fused isomunchnone dipole. Deprotection of the CBZ-protected intermediates 13a,b leads to the desired target molecules 14a,b. Prolonged exposure of these cyclic enamines in solution to the atmosphere results in oxidation to the corresponding α-hydroxy imines 16a,b. Catalytic hydrogenation of the related N-benzyl-protected polycycle 19 furnishes the fully saturated hexahydropyrimidine derivative 20. The relative stereochemistry in 20 was established by an X-ray crystallographic analysis.

Methylthio- and methoxy-substituted carboxy(vinyl)ketenes 10 and 16a have been identified by Ar matrix isolation FTIR spectroscopy following flash vacuum thermolysis (FVT) of Meldrum’s acid derivatives 7 and 13a. Methylthio(methyl)methyleneketene 9 and alkoxy(methyl)methyleneketene 15 are formed concurrently at high FVT temperatures. The alkoxy(methyl)methyleneketenes 15 do not isomerise to alkoxy(vinyl)ketenes 18, which have been generated and identified in other reactions. Ethoxy(methyl)methyleneketene 15b readily eliminates ethene in a retro-ene type reaction to produce acetylketene 22. Ketenes 15 react with alcohols and amines to produce 3-alkoxybutenoic acid derivatives 21.

Phenyliminopropadienone, PhNCCCO, is prepared and characterized, and initial chemical reactions are described.

N-Adamantylimidoylketene 2 produced from pyrroledione 1 is in thermal equilibrium with azetin-2-one 4; 2 also thermally rearranges to oxoketenimine 3; azetin-2-one 4 is photolytically converted into imidoylketene 2, and thermally cleaved to adamantyl isocyanate 5 and 1-phenylpropyne 6.

The thermal decomposition of geminal diazides 1a, b leading to pyrazolo[4,3-d]pyrimidines 4ab and the photochemical decomposition of 1a yielding uracil-5-carboxylate 6 is described; the single crystal X-ray analysis of 4a is also reported.

The use of high-temperature/pressure gas–liquid continuous flow conditions dramatically enhances the iron-catalyzed aerobic oxidation of 2-benzylpyridines to their corresponding ketones. Pressurized air serves as a readily available oxygen source and propylene carbonate as a green solvent in this radically intensified preparation of synthetically valuable 2-aroylpyridines.

Investigations on heterogeneous iron catalysis in the selective aerobic oxidation of a primary alcohol are presented. Continuous flow technology was used in combination with an iron oxide nanoparticle catalyst stabilized in a mesoporous aluminosilicate support (“flow nanocatalysis”) as a process intensification tool to maximize catalyst efficiency. Using 5 mol% 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as a co-catalyst, up to 42% benzyl alcohol as a simple model substrate was selectively converted to benzaldehyde in a single pass of the reactor. Full conversion was achieved by continuous recirculation, simulating an extension of the catalyst bed. ICPMS analysis indicated that the catalyst is highly stable and does not leach under the investigated conditions, providing solid evidence for the participation of a heterogeneous iron species in the catalytic cycle.

High-speed microwave chemistry has attracted considerable attention in the past two decades with new and innovative applications in organic and peptide synthesis, polymer chemistry, material sciences, nanotechnology and biochemical processes continuously being reported in the literature. In particular the introduction of benchtop single-mode microwave reactors just over ten years ago has revolutionized the way many scientists today perform reactions in the laboratory. Unfortunately, the accurate measurement of reaction temperature in these devices is far from being trivial and requires both a basic understanding of microwave dielectric heating effects and use of appropriate temperature monitoring devices. In this tutorial review frequently occurring problems in the determination of accurate reaction temperatures in single-mode microwave reactors are discussed.

A novel and highly versatile mechanochemically synthesized low-loaded (0.25 wt.%) supported iron oxide nanocatalyst has been demonstrated to be highly active and selective for the production of o- and p-benzylmethylbenzene (preferentially) C–C alkylated products in the continuous flow alkylation of toluene with benzyl chloride as compared to the etherification product (dibenzyl ether) observed in the alkylation of toluene with benzyl alcohol. The low quantities of highly accessible iron oxide nanoparticles on the external surface of an aluminosilicate support provided versatile acidic sites that were able to promote both the alkylation of toluene with benzyl alcohol and benzyl chloride. ICP-MS analysis revealed that the catalyst is highly stable and does not significantly leach under the investigated conditions, providing solid evidence of an iron-catalysed heterogeneous protocol.

The ionic liquid, tributylmethylammonium methylcarbonate, has been employed as a catalytic base for clean N-methylation of indole with dimethylcarbonate. The reaction conditions were optimised under microwave heating to give 100% conversion and 100% selectivity to N-methylindole, and subsequently transferred to a high temperature/high pressure (285 °C/150 bar) continuous flow process using a short (3 min) residence time and 2 mol% of the catalyst to efficiently methylate a variety of different amines, phenols, thiophenols and carboxylic acid substrates. The extremely short residence times, versatility, and high selectivity have significant implications for the synthesis of a wide range of pharmaceutical intermediates, as high product throughputs can be obtained via this scalable continuous flow protocol. It has also been shown that the ionic liquid can be generated in situ from tributylamine, which has the net effect of transforming an ineffective stoichiometric base into a highly efficient catalyst for this broad class of reactions.

Microwave-assisted syntheses of colloidal nanocrystals (NCs), in particular CdSe quantum dots (QDs), have gained considerable attention due to unique opportunities provided by microwave dielectric heating. The extensive use of microwave heating and the frequently suggested specific microwave effects, however, pose questions about the role of the electromagnetic field in both the formation and quality of the produced QDs. In this work a one-pot protocol for the tunable synthesis of monodisperse colloidal CdSe NCs using microwave dielectric heating under carefully controlled conditions is introduced. CdSe QDs are fabricated using selenium dioxide as a selenium precursor, 1-octadecene as a solvent and reducing agent, cadmium alkyl carboxylates or alkyl phosphonates as cadmium sources, 1,2-hexadecanediol to stabilize the cadmium complex and oleic acid to stabilize the resulting CdSe QDs. Utilizing the possibilities of microwave heating technology in combination with accurate online temperature control the influence of different reaction parameters such as reaction temperature, ramp and hold times, and the timing and duration of oleic acid addition have been carefully investigated. Optimum results were obtained by performing the reaction at 240 °C applying a 5 min ramp time, 2 min hold time before oleic acid addition, 90 s for oleic acid addition, and a 5 min hold time after oleic acid addition (8.5 min overall holding at 240 °C). By using different cadmium complexes in the microwave protocol CdSe QDs with a narrow size distribution can be obtained in different sizes ranging from 0.5-4 nm by simply changing the cadmium source. The QDs were characterized by TEM, HRTEM, UV-Vis, and photoluminescence methods and the size distribution was monitored by SAXS. Control experiments involving conventional conductive heating under otherwise identical conditions ensuring the same heating and cooling profiles, stirring rates, and reactor geometries demonstrate that the electromagnetic field has no influence on the generated CdSe QDs. The resulting CdSe NCs prepared using either conductive or microwave dielectric heating exhibited the same primary crystallite size, shape, quantum yield and size distribution regardless of the heating mode.

The mechanism of the Dakin-West reaction has been thoroughly investigated by monitoring the reaction using ESI-MS/MS techniques in combination with M06-2X/6-311++G(d,p) calculations. Several of the key intermediates in the previously proposed "azlactone" mechanism have been experimentally detected and characterized. In particular, interception of the mixed anhydrides involved in the early and late stages of the mechanistic scheme, as well as of the cyclic acyl-oxazolone intermediate, supports the original pathway suggested by Dakin and West. All intermediates and transition structures involved in several competing mechanisms have been calculated. The theoretical calculations support the experimental results and corroborate the proposed "azlactone" mechanism. The pathway involving the cyclic oxazolone ("azlactone") intermediate represents an energy barrier more than 3 kcal mol(-1) lower than for the competing aldol-type mechanism, thus ruling out this alternative mechanism. The DFT calculations explain the observed ESI-MS data and assess those intermediates which the experiments cannot fully elucidate.

The question “why should microwave chemistry be green?” is evaluated in the context of the twelve principles of green chemistry, with a focus on the 6th principle: design for energy efficiency. A significant number of publications on microwave-assisted organic transformations during the past 25 years describe this non-classical heating technology as being “green”, assuming that microwave dielectric heating is more energy efficient than classical conductive heat transfer methods. In this Perspective article, we critically assess the energy efficiency of microwave-assisted transformations in the context of scaling-up this technology to production quantities.