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Due to their intrinsic physical properties, which includes being able to perform as volatile liquids at room and biological temperatures, fragrance ingredients/intermediates make ideal candidates for continuous-flow manufacturing. This review highlights the potential crossover between a multibillion dollar industry and the flourishing sub-field of flow chemistry evolving within the discipline of organic synthesis. This is illustrated through selected examples of industrially important transformations specific to the fragrances and flavours industry and by highlighting the advantages of conducting these transformations by using a flow approach. This review is designed to be a compendium of techniques and apparatus already published in the chemical and engineering literature which would constitute a known solution or inspiration for commonly encountered procedures in the manufacture of fragrance and flavour chemicals.

With the emergence of stretchable/wearable devices, functions, such as sensing, energy storage/harvesting, and electrical conduction, should ideally be carried out by a single material, while retaining its ability to withstand large elastic deformations, to create compact, functionally-integrated and autonomous systems. A new class of trimodal, stretchable yarn-based transducer formed by coating commercially available Lycra® yarns with PEDOT:PSS is presented. The material developed can sense strain (first mode), and temperature (second mode) and can power itself thermoelectrically (third mode), eliminating the need for an external power-supply. The yarns were extensively characterized and obtained an ultrahigh (gauge factor ∼3.6 × 105, at 10–20% strain) and tunable (up to about 2 orders of magnitude) strain sensitivity together with a very high strain-at-break point (up to ∼1000%). These PEDOT:PSS-Lycra yarns also exhibited stable thermoelectric behavior (Seebeck coefficient of 15 μV K−1), which was exploited both for temperature sensing and self-powering (∼0.5 μW, for a 10-couple module at ΔT ∼ 95 K). The produced material has potential to be interfaced with microcontroller-based systems to create internet-enabled, internet-of-things type devices in a variety of form factors.

Soil organic matter (SOM) in tropical forests is an important store of carbon (C) and nutrients. Although SOM storage could be affected by global changes via altered plant productivity, we know relatively little about SOM stabilisation and turnover in tropical forests compared to temperate systems. Here, we investigated changes in soil C and N within particle size fractions representing particulate organic matter (POM) and mineral-associated organic matter (MAOM) after 13 years of experimental litter removal (L−) and litter addition (L+) treatments in a lowland tropical forest. We hypothesized that reduced nitrogen (N) availability in L− plots would result in N-mining of MAOM, whereas long-term litter addition would increase POM, without altering the C:N ratio of SOM fractions. Overall, SOM-N declined more than SOM-C with litter removal, providing evidence of N-mining in the L− plots, which increased the soil C:N ratio. However, contrary to expectations, the C:N ratio increased most in the largest POM fraction, whereas the C:N ratio of MAOM remained unchanged. We did not observe the expected increases in POM with litter addition, which we attribute to rapid turnover of unprotected SOM. Measurements of ion exchange rates to assess changes in N availability and soil chemistry revealed that litter removal increased the mobility of ammonium-N and aluminium, whereas litter addition increased the mobility of nitrate-N and iron, which could indicate SOM priming in both treatments. Our study suggests that altered litter inputs affect multiple processes contributing to SOM storage and we propose potential mechanisms to inform future work.

For a single nano-optical material, it is difficult to possess high transmittance and adequately filter ultraviolet (UV) and infrared radiation (IR) simultaneously. Consequently, hybrid nano-optical materials comprising components of appropriate proportions for superimposing serviceable optical property are required. The design, optimization and processing of new composite blends with an aim to creating defect free thin films is far from a trivial endeavor. In this report, optimum composition and optical properties of hybrid nano-optical material has been determined and improved by crossover matching experiments and ball milling, respectively. Film preparation has been optimized to reduce defects expressed as cracks, tiny bubbles, strips, groove points, corrugation, and formation of acicular fibers by regulating proportion of polyvinyl butyral colloid and dry film processes. Two ameliorative processing conditions are exemplified where the resultant composite films possessed 86% maximum transmittance in the visible range and 90% and 50% blocking rate with respect to the IR and UV bands.

The synthesis of the naturally occurring toxin pyocyanin has been realized in a short 4 step sequence. The key photochemical reaction and isolation of the final product has been facilitated by the use of flow chemistry techniques and immobilised reagents. Using these procedures gram quantities of pyocyanin were easily prepared in high yield and purity.

The prefusion Spike protein of SARS-CoV2 binds advanced glycation end product (AGE) glycated human serum albumin (HSA) and a higher mass, hyperglycosylated/glycated, IgG3, as determined by matrix assisted laser desorption mass spectrometry (MALDI-ToF MS). We set out to investigate if the total blood plasma of patients who had recovered from acute respiratory distress as a result of COVID-19, contained more glycated HSA and higher mass (glycosylated/glycated) IgG3 than those with only clinically mild or asymptomatic infections. A direct dilution and disulphide bond reduction method was development and applied to plasma samples from SARS-CoV2 seronegative (N = 30) and seropositive (N = 31) healthcare workers and 38 convalescent plasma samples from patients who had been admitted with acute respiratory distress syndrome (ARDS) associated with COVID-19.Patients recovering from COVID-19 ARDS had significantly higher mass, AGE-glycated HSA and higher mass IgG3 levels. This would indicate that increased levels and/or ratios of hyper-glycosylation (probably terminal sialic acid) IgG3 and AGE glycated HSA may be predisposition markers for development of ARDS as a result of COVID-19 infection. Furthermore, rapid direct analysis of plasma samples by MALDI-ToF MS for such humoral immune correlates of COVID-19 presents a feasible screening technology for the most at risk; regardless of age or known health conditions.Abstract Figure

The involvement of IgG3 in the humoral immune response to SARS-CoV2 infection has been implicated in the pathogenesis of ARDS in COVID-19. The exact molecular mechanism is unknown but may be due to the differential ability of IgG3 Fc region to fix complement and stimulate cytokine release. We examined convalescent patients antibodies binding to immobilised nucleocapsid and spike protein by MALDI-ToF mass spectrometry. IgG3 was a major immunoglobulin found in all samples. Differential analysis of the spectral signatures found for nucleocapsid versus spike protein demonstrated that the predominant humoral immune response to nucleocapsid was IgG3, whilst against spike it was IgG1. However, the spike protein displayed a strong affinity for IgG3 itself which it would bind from control plasma samples as well as from those previously infected with SARS-CoV2, much in the way Protein-G binds IgG1. Furthermore, detailed spectral analysis indicated a mass shift consistent with hyper-glycosylation or glycation was a characteristic of the IgG3 captured by the spike protein. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/21259077v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@181773eorg.highwire.dtl.DTLVardef@bb8d58org.highwire.dtl.DTLVardef@13cbe05org.highwire.dtl.DTLVardef@df579e_HPS_FORMAT_FIGEXP M_FIG C_FIG

This review presents a comprehensive overview on selected synthetic routes towards commercial drug compounds as published in both journal and patent literature. Owing to the vast number of potential structures, we have concentrated only on those drugs containing five-membered heterocycles and focused principally on the assembly of the heterocyclic core. In order to target the most representative chemical entities the examples discussed have been selected from the top 200 best selling drugs of recent years.

To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics we screened 10,240 compounds, selecting those that protected against neomycin and gentamicin in zebrafish lateral-line hair cells and, when retested in mouse cochlear cultures, prevented gentamicin-induced death of outer hair cells (OHCs). Of 64 compounds that protected zebrafish hair cells, 8 protect OHCs from gentamicin in vitro. These hits share structural features and all block, to varying degrees, the OHC’s mechano-electrical transducer (MET) channel, a known route of aminoglycoside entry into hair cells. Further characterisation of one of the strongest MET-channel blockers, UoS-7692, revealed it additionally protects against kanamycin and tobramycin, and does not abrogate the bactericidal activity of gentamicin. UoS-7692 behaves, like the aminoglycosides, as a permeant blocker of the MET channel, significantly reduces gentamicin-Texas Red loading into OHCs, and preserves lateral-line function in neomycin-treated zebrafish. Trans-tympanic injection of UoS-7692 protects mouse OHCs from furosemide-kanamycin exposure in vivo and partially preserves hearing. The results confirm the hair-cell MET channel as a viable target for the identification of compounds that protect the cochlea from aminoglycosides, and provide a series of hit compounds that will inform the design of future otoprotectants.

We have prepared a library of functionalized quinolines through the magnesiation of 7-chloroquinolines under mild conditions, employing both batch and continuous flow conditions. The preparation involved the generation of mixed lithium-magnesium intermediates, which were reacted with different electrophiles. Mixed lithium-zinc reagents allowed the synthesis of halogenated and arylated derivatives. Some of the synthesized 4-carbinol quinolines have shown interesting antiproliferative properties, their hydroxyl group being a suitable amino group bioisostere. We also report a two-step approach for optically active derivatives.

Hybrid organic–inorganic perovskites have generated considerable research interest in the field of optoelectronic devices. However, there have been significantly fewer reports of their thermoelectric properties despite some promising early results. In this article, we investigate the thermoelectric properties of bismuth-doped CH3NH3PbBr3 (MAPbBr3) single crystals. The high-quality Bi-doped crystals were synthesized by inverse temperature crystallization and it was found that Bi substitutes onto the B-site of the ABX3 perovskite lattice of MAPbBr3 crystals with very little distortion of the crystal structure. Bi doping does not significantly alter the thermal conductivity but dramatically enhances the electrical conductivity of MAPbBr3, increasing the charge carrier density by more than three orders of magnitude. We obtained a negative Seebeck coefficient of −378 μV K−1 for 15% (x = 0.15) Bi-doped MAPb(1−x)BixBr3 confirming n-type doping and also measured the figure of merit, ZT. This work highlights routes towards controlled substitutional doping of halide perovskites to optimise them for thermoelectric applications.

A novel rearrangement sequence of 3-hydroxyazetidines via a Ritter initiated cascade provides highly substituted 2-oxazolines in high yields. The reaction conditions and substrate scope of the transformation have been studied demonstrating the generality of the process. The derived products can also be functionalized in order to undergo further intramolecular cyclization leading to a new class of macrocycle. The final cyclization step was shown to be a transformation amenable to continuous flow processing allowing for a dramatic reduction in the reaction time and simple scale-up.

The hydroxy-pyrazole and 3-hydroxy-oxindole motifs have been utilised in several pharma and agrochemical leads but are distinctly underrepresented in the scientific literature due to the limited routes of preparation. We have developed a one-pot procedure for their synthesis starting from simple isatins. The method employs cheap and easy-to-handle building blocks and allows easy isolation.

It is well established that the abundances of nitrogen (N) transforming microbes are strongly influenced by land-use intensity in lowland grasslands. However, their responses to management change in less productive and less fertilized mountain grasslands are largely unknown. We studied eight mountain grasslands, positioned along gradients of management intensity in Austria, the UK, and France, which differed in their historical management trajectories. We measured the abundance of ammonia-oxidizing bacteria (AOB) and archaea (AOA) as well as nitrite-reducing bacteria using specific marker genes. We found that management affected the abundance of these microbial groups along each transect, though the specific responses differed between sites, due to different management histories and resulting variations in environmental parameters. In Austria, cessation of management caused an increase in nirK and nirS gene abundances. In the UK, intensification of grassland management led to 10-fold increases in the abundances of AOA and AOB and doubling of nirK gene abundance. In France, ploughing of previously mown grassland caused a 20-fold increase in AOA abundance. Across sites the abundance of AOB was most strongly related to soil NO3--N availability, and AOA were favored by higher soil pH. Among the nitrite reducers, nirS abundance correlatedwas most strongly with N parameters, such as soil NO3--N, microbial N. leachate NH4+-N, while the abundance of nirK-denitrifiers was affected by soil total N, organic matter (SOM) and water content. We conclude that alteration of soil environmental conditions is the dominant mechanism by which land management practices influence the abundance of each group of ammonia oxidizers and nitrite reducers. (C) 2018 Elsevier B.V. All rights reserved.

A detailed account on the outcome of the thermal reaction between benzylidene phthalides and various amino acid derivatives is reported. It was discovered that the tricyclic pyrroles as previously described are not the products formed in these reactions. Instead under high-temperature conditions decarboxylated phthalamide adducts are formed within 5-10 minutes. Additionally, an unprecedented alkene transposition mechanism has been identified leading to the final products of these reactions. Royal Society School of Chemistry, University College Dublin 2020-10-06 JG: PDF replaced with correct version

A continuous flow procedure for the synthesis of methyl glycosides (Fischer glycosylation) of various monosaccharides using a heterogenous catalyst has been developed. In-depth analysis of the isomeric composition was undertaken and high consistency with corresponding results observed under microwave heating was obtained. Even in cases where addition of water was needed to achieve homogeneity—a prerequisite for the flow experiments—no detrimental effect on the conversion was found. The scalability was demonstrated on a model case (mannose) and as part of the target-oriented synthesis of d-glycero-d-manno heptose, both performed on multigram scale. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00706-018-2306-8) contains supplementary material, which is available to authorized users.

This communication describes an unprecedented substitution cascade, in which 4-methylpyridine, following deprotonation with LDA, twice acts as a carbon nucleophile in an unusual SNAr process, to form a novel triarylmethane structure. A proposed mechanism for this sequence is presented that is supported by single crystal X-ray analysis of the resulting product. We believe this unique transformation is of note as it highlights a neat and efficient entry as a single step to complex triarylmethane architectures containing both substituted phenyl and pyridyl aromatics.

A flow based multistep processing sequence to reliably provide the delivery of a highly functional cyclopentenone is described. The exemplification of employing solid dosing of reagents and in-line aqueous extraction has enabled an integrated workflow in a highly automated reactor setup.

We report a series of multi-step flow operations to deliver an advanced hydrazine intermediate used in the assembly of the neurotensin modulator SR 142948A. Several new reactor configurations have enabled chemical transformations that would be otherwise difficult or dangerous to perform at scale. Overall the flow approach has allowed the preparation of kilogram quantities of the required hydrazine through a short and efficient route.

A simple yet robust flow set-up for the efficient desulfurization of a series of thioimidazoles is presented, which generates the corresponding imidazole derivatives in high yields. The strategic choice of peristaltic over piston pumps allowed reliable delivery of the heterogeneous stream of the thioimidazole substrate into a T-piece where it reacted with NaNO2 in the presence of acetic acid. This approach enabled the controlled and safe formation of the reactive nitrosonium species without uncontrolled exposure to hazardous nitrous oxide by-products as observed in related batch protocols. The value of the resulting imidazole products was further demonstrated by their conversion into various esters representing new derivatives of the known analgesic etomidate through an efficient one-pot Corey–Gilman–Ganem oxidation procedure.

The Centiloid (CL) method enables quantitative values from Aβ-amyloid (Aβ) imaging to be expressed in a universal unit providing pathological, diagnostic and prognostic thresholds in clinical practice and research and allowing integration of multiple tracers and methods. The method was developed for 11C-PiB scans with zero CL set as the average in young normal subjects and 100 CL the average in subjects with mild Alzheimer’s disease (AD). The method allows derivation of equations to convert the uptake value of any tracer into the same standard CL units but first requires head-to-head comparison with 11C-PiB results. We derived the equation to express 18F-florbetaben (FBB) binding in CL units. Paired PiB and FBB PET scans were obtained in 35 subjects. including ten young normal subjects aged under 45 years (33 ± 8 years). FBB images were acquired from 90 to 110 min after injection. Spatially normalized images were analysed using the standard CL method (SPM8 coregistration of PET data to MRI data and the MNI-152 atlas) and standard CL regions (cortex and whole cerebellum downloaded from http://www.gaain.org ). FBB binding was strongly correlated with PiB binding (R 2 = 0.96, SUVRFBB = 0.61 × SUVRPiB + 0.39). The equation to derive CL values from FBB SUVR was CL units = 153.4 × SUVRFBB − 154.9. The CL value in the young normal subjects was −1.08 ± 6.81 for FBB scans compared to −0.32 ± 3.48 for PiB scans, giving a variance ratio of 1.96 (SDFBB CL/SDPiB CL). 18F-FBB binding is strongly correlated with PiB binding and FBB results can now be expressed in CL units.

Antimony-tin-doped indium oxide (IATO) as transparent conducting oxide (TCO) exhibits significant optical property on blocking UV and Infrared(IR) for wavelengths less ∼400 nm and over ∼1400 nm as well as appropriate transmissivity on visible wavelength in our work that can be as an optional idea optical material applying in shielding film or nanocomposite to achieve desired optical application. We have successfully developed an optimal synthesis system which allows for a single hydrothermal oxidation directly synthesizing IATO nanoparticles without high-temperature calcination. These nanoparticles show superior size, crystallinity, agglomeration and are free of intermediates In(OH) 3 and InOOH. We also have demonstrated they give scope to desired optical property as a result of an altered IATO band gap energy. We highlight this approach due to the shortened preparation time, the reduced energy consumption and the decreased chemical usage which dramatically save on production costs and protect environment.

Contains fulltext : 225159.pdf (Publisher’s version ) (Open Access) USH2A variants are the most common cause of Usher syndrome type 2, characterized by congenital sensorineural hearing loss and retinitis pigmentosa (RP), and also contribute to autosomal recessive non-syndromic RP. Several treatment strategies are under development; however, sensitive clinical trial endpoint metrics to determine therapeutic efficacy have not been identified. In the present study, we have performed longitudinal retrospective examination of the retinal and auditory symptoms in (i) 56 biallelic molecularly confirmed USH2A patients and (ii) ush2a mutant zebrafish to identify metrics for the evaluation of future clinical trials and rapid preclinical screening studies. The patient cohort showed a statistically significant correlation between age and both rate of constriction for the ellipsoid zone length and hyperautofluorescent outer retinal ring area. Visual acuity and pure tone audiograms are not suitable outcome measures. Retinal examination of the novel ush2au507 zebrafish mutant revealed a slowly progressive degeneration of predominantly rods, accompanied by rhodopsin and blue cone opsin mislocalization from 6 to 12 months of age with lysosome-like structures observed in the photoreceptors. This was further evaluated in the ush2armc zebrafish model, which revealed similar changes in photopigment mislocalization with elevated autophagy levels at 6 days post fertilization, indicating a more severe genotype-phenotype correlation and providing evidence of new insights into the pathophysiology underlying USH2A-retinal disease.

The nitrosation of several alkanes using tert-butyl nitrite has been performed in flow showing a remarkable reduction in the reaction time compared with batch processing. Due to the necessity for large excesses of the alkane component a continuous recycling process was devised for the preparation of larger quantities of material.

A simple protocol yielding ortho-substituted nitrosophenols from phenols is demonstrated, in the form of copper(II) bis(nitrosophenolato) complexes. The developed methodology was applied to a range of substrates, confirming the role of the copper in both the formation and protection of the challenging 1, 2-substitution pattern. Using polymer supported thiourea, the Cu could be stripped from the complexes and thus enabled the isolation or identification of the uncoordinated ligands and their decomposition products, in yields generally low in line with the intrinsic high reactivity of 2-nitrosophenols. The product complexes are useful intermediates as demonstrated in revisiting a formal [4 + 2] cycloaddition with dimethylacetylene dicarboxylate to synthesise bicyclic products in variable yields, revealing the product has a novel structure different from those previously reported in the literature.

The syntheses of the title compounds demonstrate a privileged introduction of a nitroso (and a hydroxyl via the Baudisch reaction) group to an aromatic ring. These complexes first appeared in the literature as early as 1939, and a range of applications has subsequently been published. However, optimisations of the preparative sequences were not considered, and as such, the reactions have seldom been utilised in recent years; indeed, there remains confusion in the literature as to how such complexes form. In this review, we aim to demystify the misunderstanding surrounding these remarkable complexes and consider their renewed application in the 21st century.

The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our synthetic capabilities. As a result many new preparative routes have been designed towards commercially relevant drug compounds achieving more efficient and reproducible manufacture. This review article aims to illustrate the holistic systems approach and diverse applications of flow chemistry to the preparation of pharmaceutically active molecules, demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line analysis and purification to final formulation and tableting. Although this review will primarily concentrate on large scale continuous processing, additional selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technology and transformational nature that flow chemistry can leverage to an overall process.

The synthesis of thiazoles and thiophenes starting from nitriles, via a modified Gewald reaction has been studied for a number of different substrates. 1,4-Dithiane-2,5-diol was used as the aldehyde precursor to give either 2-substituted thiazoles or 2-substituted aminothiophenes depending on the substitution of the α-carbon to the cyano group.

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs ∗ 63), c.1996C>T (p.Arg666 ∗ ), c.2632G>T (p.Glu878 ∗ ), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.

The free radical polymerisation of aqueous solutions of acrylic acid (1) has been studied using a continuous flow reactor to quickly screen reaction parameters such as temperature, residence time, monomer- and initiator concentration. The experimental data sets produced established a theoretical basis for conducting scale up processes to efficiently produce larger quantities of poly(acrylic acid) delivered with good control over the molecular weight and dispersity.

A robust approach allowing for the efficient trifluoroacetylation of a series of highly substituted pyrrolidines in a diastereoselective manner is reported. The transformation is based on a Dakin–West reaction of advanced pyrrolidine 2-carboxylic acid derivatives that can be assembled stereoselectively in four synthetic steps. Importantly, this work demonstrates how the introduction of lateral substituents on the pyrrolidine scaffold enables the generation of the desired trifluoroacetylation products, which was not possible previously due to the exclusive formation of trifluoromethylated oxazoles (vide infra). In the course of this work we succeeded for the first time in isolating and characterizing (HRMS, IR, 1H, 13C and 19F NMR, X-ray) different intermediates of the Dakin–West reaction allowing us to probe its mechanism.

A flow system to perform Chan–Lam coupling reactions of various amines and arylboronic acids has been realised employing molecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has been used to simplify the delivery of the oxygen accelerating the optimisation phase and allowing easy access to elevated pressures. A small exemplification library of heteroaromatic products has been prepared and the process has been shown to be robust over extended reaction times.

Two series of boehmeriasin A analogs have been synthesized in short and high yielding processes providing derivatives differing either in the alkaloid's pentacyclic scaffold or its peripheral substitution pattern. These series have enabled, for the first time, comparative studies into key biological properties revealing a new lead compound with exceptionally high activity against liver cancer cell lines in the picomolar range for both well (Huh7, Hep3B and HepG2) and poorly (Mahlavu, FOCUS and SNU475) differentiated cells. The cell death was characterized as apoptosis by cytochrome-C release, PARP protein cleavage and SubG1 cell cycle arrest. Subsequent testing associated apoptosis via oxidative stress with in situ formation of reactive oxygen species (ROS) and altered phospho-protein levels. Compound 19 decreased Akt protein phosphorylation which is crucially involved in liver cancer tumorigenesis. Given its simple synthetic accessibility and intriguing biological properties this new lead compound could address unmet challenges within liver cancer therapy.

An efficient heterogeneous amidation catalyst has been prepared by co-polymerisation of styrene, DVB with 4-styreneboronic acid, which shows wide substrate applicability and higher reactivity than the equivalent homogeneous phenylboronic acid, suggesting potential cooperative catalytic effects. The catalyst can be easily recovered and reused; suitable for use in packed bed flow reactors.

Soil organic carbon (SOC) dynamics represent a persisting uncertainty in our understanding of the global carbon cycle. SOC storage is strongly linked to plant inputs via the formation of soil organic matter, but soil geochemistry also plays a critical role. In tropical soils with rapid SOC turnover, the association of organic matter with soil minerals is particularly important for stabilising SOC but projected increases in tropical forest productivity could trigger feedbacks that stimulate the release of stored SOC. Here, we demonstrate limited additional SOC storage after 13–15 years of experimentally doubled aboveground litter inputs in a lowland tropical forest. We combined biological, physical, and chemical methods to characterise SOC along a gradient of bioavailability. After 13 years of monthly litter addition treatments, most of the additional SOC was readily bioavailable and we observed no increase in mineral-associated SOC. Importantly, SOC with weak association to soil minerals declined in response to long-term litter addition, suggesting that increased plant inputs could modify the formation of organo-mineral complexes in tropical soils. Hence, we demonstrate the limited capacity of tropical soils to sequester additional C inputs and provide insights into potential underlying mechanisms.

Although ionic polymerisations are a valuable methodology historically they are less widely used because they are considered capricious, requiring significantly more optimisation due to their sensitivity to the specific reaction and processing conditions. Increasingly though flow processing regimes are being successfully implemented to allow better control over reaction parameters and facilitate a more consistent processing environment; this has also shown promising results for challenging reactions such as ionic polymerisation. Furthermore, as flow chemistry is becoming more widely implemented additional and complementary processing tools such as photochemical, supported reagents and enzymatic based plug-in reactors are being evaluated for their ability to expand the range of polymers on offer. Supplementing this era of advanced and accelerated synthesis is an explosion in direct integrated analysis routines and the development of smart self-optimising platforms capable of self-sustained assembly of new polymers. Whilst the machines have been taking over the physical synthesis, chemists have been starting to think beyond simply the isolated stage of polymer synthesis, considering options to create more encompassing work-flows. The next generations of polymer synthesis will encompass all aspects of synthesis, purification and final analysis as a single unified sequence. These new polymer products will ultimately be used for new applications such as light-emitting diodes and in photovoltaics.

Polymers are an important class of compounds used in many commercial products; for example, in the aerospace and automotive industries functioning as low weight construction parts and seals, through into the packaging of food and drink and even as aqueous soluble polymers, which are found in numerous detergents and other cleaning products. Significant research has, therefore, been invested towards the design and synthesis of new polymers using a variety of polymerisation techniques to deliver specifically tailored structures with refined macromolecular structures including tailoring parameters such as molecular weight, polydispersity and tacticity. One interesting approach, which has started to demonstrate value in the synthesis of polymers, is the conducting of polymerisation processes in a dynamic continuous flow scenario. Flow polymerisation has been shown to facilitate access to new polymers which cannot be synthesised or would be difficult to prepare under conventional batch conditions through improved control over the various reaction parameters. In this chapter, a brief selective overview is given of the various syntheses of polymers and polymeric particles that have been reported in the literature via flow processes to date.

Coumalic acid is a valuable platform compound which can be prepared from malic acid, a biorenewable feedstock readily derived from the fermentation of glucose. Current batch procedures to synthesise coumalic acid have several drawbacks, which we address with the aid of tubular flow systems and a simple heated rotating flow reactor. The prepared coumalate derivatives can be further used in inverse electron demand Diels–Alder reactions to synthesise compounds with many applications including molecular electronics, with the added advantage of providing metal-free preparations.

© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim With glycerol being a bulk waste product, the interest in converting it to other value-added products is steadily increasing. A scalable continuous flow process was developed for the synthesis of glycerol carbonate (2-GLC) from glycerol and dimethyl carbonate on a hydroxide functional resin. High conversion and selectivity were obtained while the residence times were typically shorter than 10 min. Continuous production of 2-GLC was achieved in high throughput and with improved processing metrics, creating the foundations for a production level process. ispartof: CHEMICAL ENGINEERING & TECHNOLOGY vol:41 issue:10 pages:2014-2023 status: published

Global change is affecting primary productivity in forests worldwide, and this, in turn, will alter long‐term carbon (C) sequestration in wooded ecosystems. On one hand, increased primary productivity, for example, in response to elevated atmospheric carbon dioxide (CO2), can result in greater inputs of organic matter to the soil, which could increase C sequestration belowground. On other hand, many of the interactions between plants and microorganisms that determine soil C dynamics are poorly characterized, and additional inputs of plant material, such as leaf litter, can result in the mineralization of soil organic matter, and the release of soil C as CO2 during so‐called “priming effects”. Until now, very few studies made direct comparison of changes in soil C dynamics in response to altered plant inputs in different wooded ecosystems. We addressed this with a cross‐continental study with litter removal and addition treatments in a temperate woodland (Wytham Woods) and lowland tropical forest (Gigante forest) to compare the consequences of increased litterfall on soil respiration in two distinct wooded ecosystems. Mean soil respiration was almost twice as high at Gigante (5.0 μmol CO2 m−2 s−1) than at Wytham (2.7 μmol CO2 m−2 s−1) but surprisingly, litter manipulation treatments had a greater and more immediate effect on soil respiration at Wytham. We measured a 30% increase in soil respiration in response to litter addition treatments at Wytham, compared to a 10% increase at Gigante. Importantly, despite higher soil respiration rates at Gigante, priming effects were stronger and more consistent at Wytham. Our results suggest that in situ priming effects in wooded ecosystems track seasonality in litterfall and soil respiration but the amount of soil C released by priming is not proportional to rates of soil respiration. Instead, priming effects may be promoted by larger inputs of organic matter combined with slower turnover rates.

The advances made in chemistry during the last 70 years are excellently illustrated by the development of the industrial synthesis of vitamin A, a diterpene crucial in preventing premature death and visual problems. Arens and van Dorp published the first route in 1946, and critical contributions have been made by a number of scientists since, benefitting from fruitful collaborations between industry and academia. However, these improvements have been mostly incremental, and the work has been performed by a limited number of companies; as yet, there is still no ‘ideal’ synthesis of vitamin A.

An automated continuous reactor for the synthesis of organic compounds, which uses online mass spectrometry (MS) for reaction monitoring and product quantification, is presented. Quantitative and rapid MS monitoring was developed and calibrated using HPLC. The amidation of methyl nicotinate with aqueous MeNH2 was optimised using design of experiments and a self-optimisation algorithm approach to produce >93% yield.

A new enabling technology for performing photochemical reactions in a continuous fashion is presented. This photo-reactor is compatible with existing flow systems and can be furthermore linked to a photo-spectrometer in order to allow for real time analysis of photochemical reactions. In this communication we wish to report the profiling of this system and its application to the continuous synthesis of ibuprofen based on a photo-Favorskii rearrangement reaction of a readily available α-chloropropiophenone precursor.

This review which is the second in this series summarises the most common synthetic routes as applied to the preparation of many modern pharmaceutical compounds categorised as containing a six-membered heterocyclic ring. The reported examples are based on the top retailing drug molecules combining synthetic information from both scientific journals and the wider patent literature. It is hoped that this compilation, in combination with the previously published review on five-membered rings, will form a comprehensive foundation and reference source for individuals interested in medicinal, synthetic and preparative chemistry.

An efficient reaction cascade delivering a series of pyrrolo[1,2-a]quinolines bearing phosphonate or phosphine oxide moieties is presented. This sequence exploits the in situ transformation of propargylic alcohols into transient allenes by means of a strategic [2,3]-sigmatropic rearrangement followed by trapping of the resulting allenes by an adjacent pyrrole ring. Furthermore, the initial small scale batch process was successfully translated into a continuous flow process allowing efficient preparation of selected pyrrolo[1,2-a]quinolines on multigram scale without any safety concerns due to the reaction’s inherent exothermic profile.