Supramolecular flow chemistry: Construction of multiscale supramolecular assemblies by micro/nanofluidic techniques

The rapid and precise fabrication of multiscale supramolecular assemblies using micro/nanofluidic techniques has emerged as a dynamic area of research in supramolecular chemistry, materials chemistry, and organic chemistry. This review summarizes the application of micro/nanofluidic techniques in constructing supramolecular assemblies, including nanoscale supramolecular assemblies such as macrocycles and cages, microscale supramolecular assemblies such as metal organic frameworks (MOFs) and covalent organic frameworks (COFs), and macroscale supramolecular assemblies such as supramolecular hydrogels. Compared to conventional synthesis methods, micro/nanofluidic techniques for the production of supramolecular assemblies have significant advantages, including enhanced safety, high reaction rates, improved selectivity/yield, and scalability. Additionally, micro/nanofluidic systems facilitate the creation of precisely controllable micro/nanoconfined environments, allowing for a unique flow behavior that improves our understanding of the supramolecular self-assembly process. Such systems may also lead to the development of novel supramolecular assemblies that differ from those generated via traditional methods.

Micro/nano flow chemistry by Beyond Limits Manufacturing

In September 2018,we proposed the cutting-edge concept of“Beyond Limits Manufacturing”(BLM).BLM technology is based on the three-dimensional inner engraving or precise outer engraving of ultra-fast laser,to invent micro/nano scale flow chips or devices,which makes it possible for the microform,integration,economy,safety,high efficiency,green and intelligence of research,development and manufacturing process,so as to realize transformational manufacturing in the era of Industry 4.0.In this paper,we reviewed the representative results we made in the field of micro/nano flow chemistry during the implementation of the BLM major project(December 2019 to August 2023),and discussed its application prospects in micro/nano flow chemistry.

Recent advances in chemical fixation of CO_(2)based on flow chemistry

Carbon dioxide(CO_(2))is an attractive C1 building block in chemical synthesis due to its abundance,availability and sustainability.However,the low reactivity and high stability generally limits its transformations under mild conditions to value added chemicals.Recent advances in flow chemistry provide effective means for the chemical transformation of CO_(2),and many new methods and techniques that fully utilized the advantages of continuous flow platforms for the chemical fixation of CO_(2)have been realized.In view of the rapid development and the urgent need for continuous transformation of CO_(2),herein we wish to present an update of the recent advances in this research area.

Continuous synthesis of ultrasmall core-shell upconversion nanoparticles via a flow chemistry method

A continuous synthesis method for the less than 10 nm core-shell upconversion nanoparticles was developed via coiled tube embedded flask reactors and a flow solvothermal co-participation reaction up to 300℃.Fast nucleation of hexagonal nanocrystals in less than 9 min residence time was achieved owing to the excellent heating ability of the reactors,and a two-step reaction strategy was created for the synthesis of β-NaYF4:Gd,Yb,Er/Ho/Tm@NaYF_(4) particles without intermediate purification.

Flow chemistry in the multi-step synthesis of natural products

The total synthesis of natural products is constantly facing many challenges derived from the complexed chemical structures,the lengthy synthetic routes,the time-consuming workup procedures and the large environmental footprint.In the past two decades,performing chemical transformations in continuous flow using various types of microreactors and in-line auxiliary technologies have been demonstrated effectively in respects of enhanced re-action yield and selectivity,excellent reproducibility and easy scale-up,safe proceeding hazardous reaction.And the rapid synthesis of natural products,which has been enabled in continuous flow based upon the significant improvement of overall yield within a short residence time via processing intensification and systematic auto-mation,is essential to furnish sufficient quantity for the bioactivity investigation of structural diversity modifi-cation,structure-activity relationship during drug discovery and the increasing consumption of medical treatment.In this review,the multi-step continuous flow synthesis of natural products is highlighted to provide a comprehensive recognization on the intrinsic merits of flow chemistry for organic chemists to purposefully develop the flow synthetic approaches of natural products in the future.

Methanolysis of amides under high-temperature and high-pressure conditions with a continuous tubular reactor

The methanolysis of amides,which is widely employed in the synthetic organic chemistry,hardly occurs under mild conditions.To safely and controllably intensify the methanolysis reaction with hightemperature and high-pressure environment,a continuous tubular reaction technology is developed,whose space-time yield is over twice of that of the conventional batch reaction.The methanolysis of acetanilide is selected as the representative reaction,and the influences of temperature,pressure,reactant and catalyst concentration,and residence time on the reaction performances are systematically investigated.Taking the advantages of precise temperature and reaction time control by the tubular reactor,the kinetics of acetanilide methanolysis are determined and compared to the kinetics of acetanilide hydrolysis reaction.The tubular reaction method is also employed to test a variety of other amides to show the effects of substituents,steric hindrance,and alkalinity on the reaction rate of methanolysis.

Continuous-flow enzymatic synthesis of chiral lactones in a three-dimensional microfluidic reactor

A new continuous-flow process for the enzymatic synthesis of optically pureγ-lactones,which are used as flavors and fragrances in the food and cosmetic industries,was developed in a three-dimensional microfluidic reactor.The microchannels(175 mm in length,0.9 mm in depth,and 1.72 mL in volume)were carved precisely inside a single borosilicate glass(90 mm×75 mm×12 mm)with ultrafast femtosecond laser micromachining.The flow field analysis and reaction simulation showed that the mixing of substrates and enzymes was enhanced,allowing the adjustment of residence time in a wide window.SmCR_(V4),a carbonyl reductase with excellent catalytic activity and enantioselectivity towardγ/δ-keto acids,was employed for the asymmetric synthesis of various chiral lactones.30 mmol/L(R)-γ-decalactone(3g)can be obtained in 26 s with a space-time yield(STY)up to 16,877 g L^(-1)d^(-1),which is 14.4 times higher than the highest STY of batch reaction reported previously.This continuous-flow process was applied to the synthesis of 6 chiral lactones.In addition,the scaled-up synthesis of 3g was carried out in 6 cascade microreactors continuously for 6 h,demonstrating the feasibility and stability of the 3D continuous-flow process in enzymatic synthesis of optically pure compounds.

Photo-induced 1,2-aryl migration of 2-chloro-1-arylpropanone under batch and flow conditions:Rapid,scalable and sustainable approach to 2-arylpropionic acids

We report the photo-mediated 1,2-aryl migration of 2‑chloro-1-arylpropanones to 2-arylpropionic acids using HCOONa as an acid scavenger.This pragmatically focused study obviates the multiple-step sequence in the industrially employed,ZnO-promoted rearrangement strategy,and offers rapid access to various 2-arylpropionic acids under environmentally friendly conditions.Furthermore,the successful transfer of this batch photochemistry to a continuous flow platform led to improved scalability and enabled the gram-scale synthesis of loxoprofen.

A sequential continuous flow synthesis and purification process of calcium dibutyryladenosine cyclophosphate

Calcium dibutyryladenosine cyclophosphate is a widely used cardiovascular drug.The traditional batch synthesis process suffers from long reaction times,tedious operations,and unstable yields.Herein,a sequential continuous flow synthesis combined with a multistage in-line purification process of calcium dibutyryladenosine cyclophosphate was developed.The acylation reaction was completed in a continuous coil reactor at 160℃ in 20 min.And the high toxic solvent pyridine was replaced by acetonitrile.Furthermore,the multistage in-line purification process was integrated into the homemade 3D circular cyclone-type micromixer chip.Combining with the membrane phase separators,the residence time of the purification step was 30 s.The isolated yield of this sequential continuous process was 92%with 99%purity.

Waste-minimized continuous flow copper-catalyzed azide-alkyne cycloaddition with low metal contamination

Metal contamination is a waste-generating and serious issue in the synthesis of chemicals,in particular in the case of products with biological activity.The appropriate selection of operating conditions plays a crucial role in the abatement of metal leaching in solution and associated wastes.Herein we report a waste-minimized continuous flow process for the synthesis of 1,4-disubstitutedβ-keto 1,2,3-triazoles exploiting the use of a copper tube flow reactor(CTFR).The selection of the proper azeotropic mixture allowed an almost quantitative recovery of the reaction medium greatly influencing the E-factor of the protocol.A thorough understanding of the main parameters affecting the waste generation was given by calculation of the E-factor distribution for different work-up tested under batch and flow conditions.Furthermore,the measurement of different green metrics(AE:Atom Economy,SF:Stoichiometric Factor,RME:Reaction Mass Efficiency,and MRP:Mass Recover Parameter)clearly demonstrated the benefits of the flow scale-up that allowed to perform a low environmental footprint CuAAC reaction.

Efficient synthesis of lithium rare-earth tetrafluoride nanocrystals via a continuous flow method

As an important upconversion illuminant material, LiREF4 nanocrystals were efficiently synthesized in a continuous reactor with the assistant of a new precursor solution. The employed trioctylamine solvent in the solution had a strong interaction with HF, and helped to avoid the generation of unnecessary solid components as LiF and NH4REF4 during the reaction. A silicon carbide reactor was developed to carry out the synthesis reaction, where LiYF4:Yb,Er/Ho/Tm quickly nucleated in 5 min at 300℃. The reaction time to successfully prepare 15 nm sized nanocrystals was less than 30 min, and the space-time yield of the flow synthesis method was 14.8 times that of a control group batch reaction. The prepared nanocrystals had a strong illuminant ability, which could find its use in the area of security mark printing.

Challenges and Recent Developments of Photoflow-Reversible Deactivation Radical Polymerization(RDRP)

Photo-controlled reversible-deactivation radical polymerizati on(photo-RDRP)has been investigated as a"green"and spatiotem-porally controlling pathway for polymer synthesis.While the combination of photo-RDRP and flow chemistry has offered opportunities to increase light intensity and enable uniform light irradiation,problems associated with flow approaches still remain for photoflow-RDRP,which has hindered merging flow polymerization with other cutting-edge techniques.Herein,we summarize challenges and recent achievements in photoflow-RDRP including the development of(a)droplet/slug-flow to regulate reside nee time distribution,(b)mixing techniques to tailor polymer,(c)polymerization in duced self-assembly,and(d)computer-aided synthesis.We hope this work will provide in formative knowledge to people in related fields and stimulate novel ideas to promote polymer synthesis in both academia and industry.

Facile synthesis of gradient copolymers enabled by droplet-flow photo-controlled reversible deactivation radical polymerization

Monomer sequence influences the properties and applications of polymers.Consequently,massive efforts have been made to implement sequence control of polymers.In this work,we developed a computer-aided droplet-flow polymerization based on photo-controlled reversible-deactivation radical polymerization(photo-RDRP),enabling synthesis of gradient copolymers of tunable sequential arrangements,low dispersity and good structural fidelity from various monomers without following their intrinsic reactivities,which is a key limitation in sequence control.The obtained gradient copolymers exhibit unique thermal properties and stimulus responsiveness comparing with the random and block counterparts,and their glass transition behaviour could be regulated by the gradient tendency.We believe that the unprecedented gradient photo-RDRP based on flow synthesis opens a robust and versatile avenue to streamline the synthesis of well-defined gradient polymers,and is compatible with other polymerization mechanisms.

Facile Control of Molecular Weight Distribution via Droplet-Flow Light-Driven Reversible-Deactivation Radical Polymerization

Molecular weight distribution(MWD)is fundamental for polymer analysis,which influences many important properties of polymeric materials.In this work,we demonstrate the development of a computer-aided droplet-flow system that combines photo-mediated reversible-deactivation radical polymerization(RDRP)and chain transfer agent(CTA)diffusion strategy to enable facile MWD control for the first time.Synthetic advantages of this photo-flow polymerization allow controlled chain-growth to yield a variety of polymers of tunable MWDs in a broad range(Ð≈1.1—1.9)with predetermined molecular weights(Mn≈4—30 kDa)and good chain-end fidelity.Notably,the computer-aided platform has streamlined an automatic and high-throughput pathway to prepare polymer libraries of tunable MWDs.For copolymers,chemical compositions could be readily regulated besides MWDs with the droplet-flow platform.We believe that this work should be attractive for polymer engineering,and informative to create more flow polymerization techniques toward on-demand control of diverse polymer characters.

Computer-Aided Living Polymerization Conducted under Continuous-Flow Conditions

Continuous-flow techniques have promoted the development of synthetic chemistry due to advantages such as outstanding mass/heat transfer,on-demand scalability,improved safety,precise regulation on reaction parameters,etc.Recently,the combination of flow polymerization with computer scienee has gained considerable interests,leading to a variety of cutting-edge synthetic techniques.This review summarizes emerging achievements realized via the integration of computer science and living flow polymerizations,including 1)high-throughput living polymerizations in flow,2)programmable regulations of dispersity profile,se-que nee and topology for polymers,3)modular desig n with on line mon itori ng,as well as 4)self-optimized living polymerizati ons in flow.We expect that this summary will furnish informative kno wledge to scie ntists in related directions and in spire new ideas to further empower on-demand polymer engineering with modern techniques.

A green access to supported cinchona alkaloid amide catalysts for heterogeneous enantioselective allylsilylation of aldehydes and process intensity evaluation in batch and flow

We report herein a new class of polystyrene-supported cinchona alkaloid amide catalysts for enantioselective allylation of various aldehydes using allyltrichlorosilane under both batch and continuous flow conditions.The supported catalyst was synthesized using an environmentally benign coupling agent with a surfactant in aqueous media.Under batch conditions,consistently high yields and enantioselectivity were obtained for the allylation of aliphatic aldehydes with recycling and reuse of the catalyst for more than 10 runs.Subsequently,this catalytic system was successfully implemented into a packed bed flow reactor with similar efficiency and enantiose-lectivity.While flow is a viable option,the batch methodology has better potential for application at a larger-scale setting upon the comparison of space-time yield and catalyst loadings.With the sustainable synthesis and great recyclability of our polymeric catalyst,this methodology holds great potential for the large-scale delivery of valuable enantiopure homoallylic alcohols.

Synthetic Automations:A Revolution from"Stone Age"to Modern Era

Traditional synthesis made outstanding achievements but still suffers various drawbacks,such as manual operation,poor efficiency,and lack of reproducibility.Thanks to the development of laboratory automation,synthetic chemistry is now chasing a pavement from a labor-intensive process to intelligent automation.Herein,we highlight some of the most recent representative breakthroughs in automated synthesis and present an outlook for this field.We hope this Topic can arouse chemists'interest in automated synthe-sis and drive synthetic automation to a better intelligent and automatic way.

Synthesis of Acridinium Photocatalysts via Site-Selective C–H Alkylation

Acridinium dyes have been broadly used as photocatalysts,but it remains synthetically challenging to fine-tune their catalytic performance by functionalization of their structural cores.Acridinium photocatalysts are usually prepared through de novo synthesis,which involves difficult steps and requires sensitive organometallic reagents.

Recent advances in autonomous synthesis of materials

The synthesis of materials has been an important task throughout human history,and the ability to perform successful and efficient syntheses has been a factor in industrial revolutions and societal development.Recently,the rapid development of sophisticated techniques such as flow synthesis methods,artificial intelligence,infor-mation technology,and robotics,has facilitated the autonomous synthesis of chemicals with minimal effort and at little cost to the economy.This trend has influenced recent materials research and could potentially reduce the time from discovery of materials to their commercialization.In this short review,we focus on the autonomous synthesis of materials.We first discuss how autonomous synthesis could change materials research.Then,we provide some examples of autonomous syntheses in flow reactors.Finally,we present examples of autonomous syntheses using non-flow methods.

Automated and remote synthesis of poly(ethylene glycol)-mineralized ZIF-8 composite particles via a synthesizer assisted by femtosecond laser micromachining

Mineralization of the ZIF-8 in the presence of biomacromolecules has been demonstrated to be a general way for making bioentities@ZIFs composites.The ZIF-8 crystals permit controlled storage and utilization of the bioentities,thus can benefit drug delivery,cold-chain breaking etc.With the increasing needs on personal care and distributed manufacturing,automated synthesis controlled by a computer becomes the next challenge.In this work,we designed an automatic synthesis system to prepare PEG mineralized ZIF-8 composite particles.This system is based on flow chemistry with the microfluidic chips fabricated by femtosecond laser micromachining.The particles were synthesized and monitored automatically.Furthermore,this synthesizer could be extended for fabrication of vaccine particles under remote control through internet.