Joshua Britton

A dehydrative cross-coupling of 1-phenylethanol catalysed by sugar derived, in situ formed palladium(0) nanoparticles under acidic conditions is realised. The acidic conditions allow for use of alcohols as a feedstock in metal-mediated coupling reactions via their in situ dehydration and subsequent cross-coupling. Extensive analysis of the size and morphology of the palladium nanoparticles formed in situ showed that the zero-valent metal was surrounded by hydrophilic hydroxyl groups. EDX-TEM… Show more

A dehydrative cross-coupling of 1-phenylethanol catalysed by sugar derived, in situ formed palladium(0) nanoparticles under acidic conditions is realised. The acidic conditions allow for use of alcohols as a feedstock in metal-mediated coupling reactions via their in situ dehydration and subsequent cross-coupling. Extensive analysis of the size and morphology of the palladium nanoparticles formed in situ showed that the zero-valent metal was surrounded by hydrophilic hydroxyl groups. EDX-TEM imaging studies using a prototype silicon drift detector provided insight into the problematic role of molecular oxygen in the system. This increased understanding of the catalyst deactivation allowed for the development of the cross-coupling methodology. A 250-12,000 fold increase in molar efficiency was observed when compared to related two-step protocols that use alternative feedstocks for the palladium-mediated synthesis of stilbenes. This work opens up a new research area in which the active catalyst is formed, stabilised and regenerated by a renewable sugar. Show less

The continuous flow synthesis of active pharmaceutical ingredients, value-added chemicals, and materials has grown tremendously over the past ten years. This revolution in chemical manufacturing has resulted from innovations in both new methodology and technology. This field, however, has been predominantly focused on synthetic organic chemistry, and the use of biocatalysts in continuous flow systems is only now becoming popular. Although immobilized enzymes and whole cells in batch systems are… Show more

The continuous flow synthesis of active pharmaceutical ingredients, value-added chemicals, and materials has grown tremendously over the past ten years. This revolution in chemical manufacturing has resulted from innovations in both new methodology and technology. This field, however, has been predominantly focused on synthetic organic chemistry, and the use of biocatalysts in continuous flow systems is only now becoming popular. Although immobilized enzymes and whole cells in batch systems are common, their continuous flow counterparts have grown rapidly over the past two years. With continuous flow systems offering improved mixing, mass transfer, thermal control, pressurized processing, decreased variation, automation, process analytical technology, and in-line purification, the combination of biocatalysis and flow chemistry opens powerful new process windows. This Review explores continuous flow biocatalysts with emphasis on new technology, enzymes, whole cells, co-factor recycling, and immobilization methods for the synthesis of pharmaceuticals, value-added chemicals, and materials. Show less

The adoption of and opportunities in continuous flow synthesis ('flow chemistry') have increased significantly over the past several years. Continuous flow systems provide improved reaction safety and accelerated reaction kinetics, and have synthesised several active pharmaceutical ingredients in automated reconfigurable systems. Although continuous flow platforms are commercially available, systems constructed 'in-lab' provide researchers with a flexible, versatile, and cost-effective… Show more

The adoption of and opportunities in continuous flow synthesis ('flow chemistry') have increased significantly over the past several years. Continuous flow systems provide improved reaction safety and accelerated reaction kinetics, and have synthesised several active pharmaceutical ingredients in automated reconfigurable systems. Although continuous flow platforms are commercially available, systems constructed 'in-lab' provide researchers with a flexible, versatile, and cost-effective alternative. Herein, we describe the assembly and use of a modular continuous flow apparatus from readily available and affordable parts in as little as 30 min. Once assembled, the synthesis of a sulfonamide by reacting 4-chlorobenzenesulfonyl chloride with dibenzylamine in a single reactor coil with an in-line quench is presented. This example reaction offers the opportunity to learn several important skills including reactor construction, charging of a back-pressure regulator, assembly of stainless-steel syringes, assembly of a continuous flow system with multiple junctions, and yield determination. From our extensive experience of single-step and multistep continuous flow synthesis, we also describe solutions to commonly encountered technical problems such as precipitation of solids ('clogging') and reactor failure. Following this protocol, a nonspecialist can assemble a continuous flow system from reactor coils, syringes, pumps, in-line liquid–liquid separators, drying columns, back-pressure regulators, static mixers, and packed-bed reactors. Show less

Multi-step continuous flow synthesis enables a parallel approach to obtain agrochemicals and pharmaceuticals containing 3-fluoroalkyl pyrazole cores. In this system, fluorinated amines are transformed into pyrazole cores through a telescoped in situ generation and consumption of diazoalkanes. Once synthesized, additional continuous flow and batch reactions add complexity to the pyrazole core via C–N arylation and methylation, TMS cleavage, and amidation. Using this modular assembly line… Show more

Multi-step continuous flow synthesis enables a parallel approach to obtain agrochemicals and pharmaceuticals containing 3-fluoroalkyl pyrazole cores. In this system, fluorinated amines are transformed into pyrazole cores through a telescoped in situ generation and consumption of diazoalkanes. Once synthesized, additional continuous flow and batch reactions add complexity to the pyrazole core via C–N arylation and methylation, TMS cleavage, and amidation. Using this modular assembly line approach, Bixafen and Fluxapyroxad were synthesized in 38 % yield over four continuous flow steps in an overall reaction time of 56 min. Finally, coupling selected continuous flow processes with an offline (batch) Ullmann coupling afforded Celecoxib, Mavacoxib, and SC-560 in 33–54 % yield over two to three steps. Show less

Driving chemical transformations in dynamic thin films represents a rapidly thriving and diversifying research area. Dynamic thin films provide a number of benefits including large surface areas, high shearing rates, rapid heat and mass transfer, micromixing and fluidic pressure waves. Combinations of these effects provide an avant-garde style of conducting chemical reactions with surprising and unusual outcomes. The vortex fluidic device (VFD) has proved its capabilities in accelerating and… Show more

Driving chemical transformations in dynamic thin films represents a rapidly thriving and diversifying research area. Dynamic thin films provide a number of benefits including large surface areas, high shearing rates, rapid heat and mass transfer, micromixing and fluidic pressure waves. Combinations of these effects provide an avant-garde style of conducting chemical reactions with surprising and unusual outcomes. The vortex fluidic device (VFD) has proved its capabilities in accelerating and increasing the efficiencies of numerous organic, materials and biochemical reactions. This Review surveys transformations that have benefited from VFD-mediated processing, and identifies concepts driving the effectiveness of vortex-based dynamic thin films. Show less

A rapid and modular continuous flow synthesis of highly functionalized fluorinated pyrazoles and pyrazolines has been developed. Flowing fluorinated amines through sequential reactor coils mediates diazoalkane formation and [3+2] cycloaddition to generate more than 30 azoles in a telescoped fashion. Pyrazole cores are then sequentially modified through additional reactor modules performing N-alkylation and arylation, deprotection, and amidation to install broad molecular diversity in short… Show more

A rapid and modular continuous flow synthesis of highly functionalized fluorinated pyrazoles and pyrazolines has been developed. Flowing fluorinated amines through sequential reactor coils mediates diazoalkane formation and [3+2] cycloaddition to generate more than 30 azoles in a telescoped fashion. Pyrazole cores are then sequentially modified through additional reactor modules performing N-alkylation and arylation, deprotection, and amidation to install broad molecular diversity in short order. Continuous flow synthesis enables the safe handling of diazoalkanes at elevated temperatures, and the use of aryl alkyne dipolarphiles under catalyst free conditions. This assembly line synthesis provides a flexible approach for the synthesis of agrochemicals and pharmaceuticals, as demonstrated by a four-step, telescoped synthesis of measles therapeutic, AS-136A, in a total residence time of 31.7 min (1.76 g h-1). Show less

Essentially all biochemistry and most molecular biology experiments require recombinant proteins. However, large, hydrophobic proteins typically aggregate into insoluble and misfolded species, and are directed into inclusion bodies. Current techniques to fold proteins recovered from inclusion bodies rely on denaturation followed by dialysis or rapid dilution. Such approaches can be time consuming, wasteful, and inefficient. Here, we describe rapid protein folding using a vortex fluidic device… Show more

Essentially all biochemistry and most molecular biology experiments require recombinant proteins. However, large, hydrophobic proteins typically aggregate into insoluble and misfolded species, and are directed into inclusion bodies. Current techniques to fold proteins recovered from inclusion bodies rely on denaturation followed by dialysis or rapid dilution. Such approaches can be time consuming, wasteful, and inefficient. Here, we describe rapid protein folding using a vortex fluidic device (VFD). This process uses mechanical energy introduced into thin films to rapidly and efficiently fold proteins. With the VFD in continuous flow mode, large volumes of protein solution can be processed per day with 100-fold reductions in both folding times and buffer volumes. Show less

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches… Show more

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9. Show less

Nature applies enzymatic assembly lines to synthesize bioactive compounds. Inspired by such capabilities, we have developed a facile method for spatially segregating attached enzymes in a continuous-flow, vortex fluidic device (VFD). Fused Hisn-tags at the protein termini allow rapid bioconjugation and consequent purification through complexation with immobilized metal affinity chromatography (IMAC) resin. Six proteins were purified from complex cell lysates to average homogeneities of 76 %… Show more

Nature applies enzymatic assembly lines to synthesize bioactive compounds. Inspired by such capabilities, we have developed a facile method for spatially segregating attached enzymes in a continuous-flow, vortex fluidic device (VFD). Fused Hisn-tags at the protein termini allow rapid bioconjugation and consequent purification through complexation with immobilized metal affinity chromatography (IMAC) resin. Six proteins were purified from complex cell lysates to average homogeneities of 76 %. The most challenging to purify, tobacco epi-aristolochene synthase, was purified in only ten minutes from cell lysate to near homogeneity (>90 %). Furthermore, this “reaction-ready” system demonstrated excellent stability during five days of continuous-flow processing. Towards multi-step transformations in continuous flow, proteins were arrayed as ordered zones on the reactor surface allowing segregation of catalysts. Ordering enzymes into zones opens up new opportunities for continuous-flow biosynthesis. Show less

Organic chemistry is continually evolving to improve the syntheses of value added and bioactive compounds. Through this progression, a concomitant advancement in laboratory technology has occurred. Many researchers now choose to mediate transformations in continuous-flow systems given the many benefits over round bottom flasks. Furthermore, reaction scale up is often less problematic as this is addressed at the inception of the science. Although single-step transformations in continuous-flow… Show more

Organic chemistry is continually evolving to improve the syntheses of value added and bioactive compounds. Through this progression, a concomitant advancement in laboratory technology has occurred. Many researchers now choose to mediate transformations in continuous-flow systems given the many benefits over round bottom flasks. Furthermore, reaction scale up is often less problematic as this is addressed at the inception of the science. Although single-step transformations in continuous-flow systems are common, multi-step transformations are more valuable. In these systems, molecular complexity is accrued through sequential transformations to a mobile scaffold, much like an in vitro version of Nature's polyketide synthases. Utilizing this methodology, multi-step continuous-flow systems have improved the syntheses of active pharmaceutical ingredients (APIs), natural products, and commodity chemicals. This Review details these advancements while highlighting the rapid progress, benefits, and diversification of this expanding field.

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Enzymes catalyze chemical transformations with outstanding stereo- and regio-specificities, but many enzymes are limited by their long reaction times. A general method to accelerate enzymes using pressure waves contained within thin films is described. Each enzyme responds best to specific frequencies of pressure waves, and an acceleration landscape for each protein is reported. A vortex fluidic device introduces pressure waves that drive increased rate constants (kcat) and enzymatic efficiency… Show more

Enzymes catalyze chemical transformations with outstanding stereo- and regio-specificities, but many enzymes are limited by their long reaction times. A general method to accelerate enzymes using pressure waves contained within thin films is described. Each enzyme responds best to specific frequencies of pressure waves, and an acceleration landscape for each protein is reported. A vortex fluidic device introduces pressure waves that drive increased rate constants (kcat) and enzymatic efficiency (kcat/Km). Four enzymes displayed an average seven-fold acceleration, with deoxyribose-5-phosphate aldolase (DERA) achieving an average 15-fold enhancement using this approach. In solving a common problem in enzyme catalysis, a powerful, generalizable tool for enzyme acceleration has been uncovered. This research provides new insights into previously uncontrolled factors affecting enzyme function. Show less

A versatile enzyme immobilization strategy for thin film continuous flow processing is reported. Here, non-covalent and glutaraldehyde bioconjugation are used to immobilize enzymes on the surfaces of borosilicate reactors. This approach requires only ng of protein per reactor tube, with the stock protein solution readily recycled to sequentially coat >10 reactors. Confining reagents to thin films during immobilization reduced the amount of protein, piranha-cleaning solution, and other… Show more

A versatile enzyme immobilization strategy for thin film continuous flow processing is reported. Here, non-covalent and glutaraldehyde bioconjugation are used to immobilize enzymes on the surfaces of borosilicate reactors. This approach requires only ng of protein per reactor tube, with the stock protein solution readily recycled to sequentially coat >10 reactors. Confining reagents to thin films during immobilization reduced the amount of protein, piranha-cleaning solution, and other reagents by ∼96%. Through this technique, there was no loss of catalytic activity over 10 h processing. The results reported here combines the benefits of thin film flow processing with the mild conditions of biocatalysis Show less

Inspired by nature's ability to construct complex molecules through sequential synthetic transformations, we have developed an assembly line synthesis of α-aminophosphonates.In this approach, simple starting materials are continuously fed through a thin-film reactor where the intermediates accrue molecular complexity as they progress through the flow system.Flow chemistry allows rapid multi-step transformations to occur via reaction compartmentalization, an approach not amenable to using… Show more

Inspired by nature's ability to construct complex molecules through sequential synthetic transformations, we have developed an assembly line synthesis of α-aminophosphonates.In this approach, simple starting materials are continuously fed through a thin-film reactor where the intermediates accrue molecular complexity as they progress through the flow system.Flow chemistry allows rapid multi-step transformations to occur via reaction compartmentalization, an approach not amenable to using conventional flasks.Thin film processing can also access facile in situ solvent exchange to drive reaction efficiency, and through this method,α-aminophosphonate synthesis requires only 443 s residence time to produce 3.22 g h-1.Assembly line synthesis allows unprecedented reaction flexibility and processing efficiency. Show less

At the “Prospects for Flow Chemistry” symposium during Pacifichem 2015, in Honolulu,
Hawaii, an exciting portrait of a diverse and dynamic field was painted. A group of
multidisciplinary chemists presented their research, views, and critical insight into this
rapidly expanding area of organic chemistry. Fifty-one lectures were presented,
accompanied by a poster presentation

In situ-generated, glucose-derived palladium(0) nanoparticles were shown to be convenient and effective catalysts for aqueous Mizoroki–Heck, Sonogashira and Suzuki–Miyaura cross-coupling reactions. The addition of only 4–10 mol% glucose to the reaction mixture lead to a significant increase in yield of the desired products in comparison to processes that omitted the renewable sugar. Interestingly, the Mizoroki–Heck reaction was observed to proceed in good yield even as the reaction reached… Show more

In situ-generated, glucose-derived palladium(0) nanoparticles were shown to be convenient and effective catalysts for aqueous Mizoroki–Heck, Sonogashira and Suzuki–Miyaura cross-coupling reactions. The addition of only 4–10 mol% glucose to the reaction mixture lead to a significant increase in yield of the desired products in comparison to processes that omitted the renewable sugar. Interestingly, the Mizoroki–Heck reaction was observed to proceed in good yield even as the reaction reached acidic pH levels. Extensive analysis of the size and morphology of the in situ-formed palladium nanoparticles using advanced analytical techniques showed that the zero valent metal was surrounded by hydrophilic hydroxyl groups. The increased aqueous phase affinity afforded by these groups allowed for facile recycling of the catalyst. Show less

A vortex fluidic device (VFD) is effective in mediating the synthesis of di-esters at room temperature. Processing under ambient conditions allows for a simple and efficient synthesis, whilst operating under continuous flow addresses scalability. The rotational speed of the sample tube and the flow rate were critical variables during reaction optimization, and this relates to the behaviour of the fluid flow at a molecular level. Whilst at specific rotational speeds the tube imparts a… Show more

A vortex fluidic device (VFD) is effective in mediating the synthesis of di-esters at room temperature. Processing under ambient conditions allows for a simple and efficient synthesis, whilst operating under continuous flow addresses scalability. The rotational speed of the sample tube and the flow rate were critical variables during reaction optimization, and this relates to the behaviour of the fluid flow at a molecular level. Whilst at specific rotational speeds the tube imparts a vibrational response into the fluid flow, the flow rate dictates residence time and the ability to maintain high levels of shear stress. The combination of mechanically induced vibrations, rapid micromixing and high levels of shear stress generate yields up to 90% for 3.25 minutes or less residence time. These results are key for devising greener and more efficient processes both mediated by the VFD and other continuous flow platforms. Show less

Thin film flow chemistry using a vortex fluidic device (VFD) is effective in the scalable acylation of amines under shear, with the yields of the amides dramatically enhanced relative to traditional batch techniques. The optimized monophasic flow conditions are effective in ≤80 seconds at room temperature, enabling access to structurally diverse amides, functionalized amino acids and substituted ureas on multigram scales. Amide synthesis under flow was also extended to a total synthesis of… Show more

Thin film flow chemistry using a vortex fluidic device (VFD) is effective in the scalable acylation of amines under shear, with the yields of the amides dramatically enhanced relative to traditional batch techniques. The optimized monophasic flow conditions are effective in ≤80 seconds at room temperature, enabling access to structurally diverse amides, functionalized amino acids and substituted ureas on multigram scales. Amide synthesis under flow was also extended to a total synthesis of local anesthetic lidocaine, with sequential reactions carried out in two serially linked VFD units. The synthesis could also be executed in a single VFD, in which the tandem reactions involve reagent delivery at different positions along the rapidly rotating tube with in situ solvent replacement, as a molecular assembly line process. This further highlights the versatility of the VFD in organic synthesis, as does the finding of a remarkably efficient debenzylation of p-methoxybenzyl amines. Show less

The effect on the solid-state packing of six dipicolinic acid-based esters as a function of ester group has been investigated. For each 4-bromo dipicolinic acid ester, a pairwise O···H interaction is the main structure-directing feature. However, changing the ester shifts this interaction, while extension of the ethyl ester results in a loss of this pairwise O···H interaction. Introduction of a benzyl group reinstates this interaction.

A facile approach has been developed for non-covalently stabilising pristine C60 and multi-walled carbon nanotubes (MWCNTs) in water in the presence of p-phosphonic acid calix[8]arene, along with the formation of a ‘pea-pod’ encapsulation of the fullerene inside the MWCNTs. Aqueous dispersions of the different carbon nano-materials are readily decorated with palladium nanoparticles

Conversion of high free fatty acid (FFA) feedstock (94.4 %) to biodiesel with undetectable FFA content is effective using room temperature vortex fluidic flow chemistry, with the conversion taking < 1 minute residence time, using dramatically less methanol and acid catalyst compared to other processes. Optimum conditions are 1:6 volumetric ratio of oil feedstock to methanol and 0.2 molar equivalents of H2SO4 catalyst loading, for a combined flow rate of 3.50 mL/min in a 17.7 mm internal… Show more

Conversion of high free fatty acid (FFA) feedstock (94.4 %) to biodiesel with undetectable FFA content is effective using room temperature vortex fluidic flow chemistry, with the conversion taking < 1 minute residence time, using dramatically less methanol and acid catalyst compared to other processes. Optimum conditions are 1:6 volumetric ratio of oil feedstock to methanol and 0.2 molar equivalents of H2SO4 catalyst loading, for a combined flow rate of 3.50 mL/min in a 17.7 mm internal diameter tube rotating at 7500 rpm. This work furthers the viability of using high FFA content feedstocks for biodiesel production. Show less

The Vortex Fluidic Device (VFD) provides a new ``green'' alternative for many industrially important organic chemistry processes including the generation of biodiesel. Improved chemical kinetics have also been demonstrated for a number of reactions. This relatively simple device, comprising essentially of a rapidly rotating tube, provides advantages ranging from reduced energy requirements and waste streams to high flow rates and the avoidance of clogging. The VFD is effective due to the… Show more

The Vortex Fluidic Device (VFD) provides a new ``green'' alternative for many industrially important organic chemistry processes including the generation of biodiesel. Improved chemical kinetics have also been demonstrated for a number of reactions. This relatively simple device, comprising essentially of a rapidly rotating tube, provides advantages ranging from reduced energy requirements and waste streams to high flow rates and the avoidance of clogging. The VFD is effective due to the interplay between fluid mechanics and chemistry providing near optimal conditions for the required reactions. This contribution provides an insight into the rich fluid mechanics of the device. Show less

Rapid Fischer esterification reactions occur under solventless, continuous flow conditions in dynamic thin films. These esterifications use limited catalyst, require no additional heat input and occur within the confinements of an inexpensive vortex fluidic device (VFD). The associated mechanoenergy is primarily delivered from two types of vibration, which are manifested in sharp increases in yield. These vibrations promote the existence of Faraday waves, adding a new tool to chemical synthesis.

A thin film vortex fluid device (VFD) is effective in the room temperature continuous flow conversion of sunflower oil to biodiesel. Optimised VFD operating parameters affords high purity biodiesel, with no saponification, without the need for the otherwise conventional use of a co-solvent or the use of complex catalysts. The biodiesel, glycerol biproduct and catalyst also spontaneously separate post-VFD processing, and the catalyst can then be readily recycled three times without the need for… Show more

A thin film vortex fluid device (VFD) is effective in the room temperature continuous flow conversion of sunflower oil to biodiesel. Optimised VFD operating parameters affords high purity biodiesel, with no saponification, without the need for the otherwise conventional use of a co-solvent or the use of complex catalysts. The biodiesel, glycerol biproduct and catalyst also spontaneously separate post-VFD processing, and the catalyst can then be readily recycled three times without the need for further complex down-streaming processing. Show less

J.Britton and J. Camp, Catalysis Application, Chemistry Today, 30, June 2012

There is currently considerable interest in the use of CO2 as a chemical feedstock. In this article, the requirements for the effective use of CO2 as part of a carbon capture and utilization process to enhance the financial viability of carbon capture and storage are discussed. These are then illustrated with work done on the development of catalysts for the synthesis of cyclic carbonates from epoxides and CO2 in flue-gas at one bar pressure and 20-100oC in both batch and gas-phase flow… Show more

There is currently considerable interest in the use of CO2 as a chemical feedstock. In this article, the requirements for the effective use of CO2 as part of a carbon capture and utilization process to enhance the financial viability of carbon capture and storage are discussed. These are then illustrated with work done on the development of catalysts for the synthesis of cyclic carbonates from epoxides and CO2 in flue-gas at one bar pressure and 20-100oC in both batch and gas-phase flow reactors. Show less

Essentially all biochemistry and most molecular biology experiments require recombinant proteins. However, large, hydrophobic proteins typically aggregate into insoluble and misfolded species, and are directed into inclusion bodies. Current techniques to fold proteins recovered from inclusion bodies rely on denaturation followed by dialysis or rapid dilution. Such approaches can be time consuming, wasteful, and inefficient. Here, we describe rapid protein folding using a vortex fluidic… Show more

Essentially all biochemistry and most molecular biology experiments require recombinant proteins. However, large, hydrophobic proteins typically aggregate into insoluble and misfolded species, and are directed into inclusion bodies. Current techniques to fold proteins recovered from inclusion bodies rely on denaturation followed by dialysis or rapid dilution. Such approaches can be time consuming, wasteful, and inefficient. Here, we describe rapid protein folding using a vortex fluidic device. This process uses mechanical energy introduced into thin films to rapidly and efficiently fold proteins. With the VFD in continuous flow mode, liters of protein solution can be processed per day with 100-fold reductions in both folding times and buffer volumes. Show less