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21 March 2020

52 Pages

Flow Chemistry in Contemporary Chemical Sciences: A Real Variety of Its Applications

1
Laboratory of Nuclear Analytical Methods, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03–195 Warsaw, Poland
2
Department of Chemistry, University of Warsaw, Pasteura 1, 02–093 Warsaw, Poland
Molecules2020, 25(6), 1434;https://doi.org/10.3390/molecules25061434
This article belongs to the Special Issue Modern Flow Analysis
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Abstract

Flow chemistry is an area of contemporary chemistry exploiting the hydrodynamic conditions of flowing liquids to provide particular environments for chemical reactions. These particular conditions of enhanced and strictly regulated transport of reagents, improved interface contacts, intensification of heat transfer, and safe operation with hazardous chemicals can be utilized in chemical synthesis, both for mechanization and automation of analytical procedures, and for the investigation of the kinetics of ultrafast reactions. Such methods are developed for more than half a century. In the field of chemical synthesis, they are used mostly in pharmaceutical chemistry for efficient syntheses of small amounts of active substances. In analytical chemistry, flow measuring systems are designed for environmental applications and industrial monitoring, as well as medical and pharmaceutical analysis, providing essential enhancement of the yield of analyses and precision of analytical determinations. The main concept of this review is to show the overlapping of development trends in the design of instrumentation and various ways of the utilization of specificity of chemical operations under flow conditions, especially for synthetic and analytical purposes, with a simultaneous presentation of the still rather limited correspondence between these two main areas of flow chemistry.

1. Introduction

Monitoring and controlling the progress in the course of a given chemical reaction is a fundamental issue in various applications of chemical science. This concerns fundamental investigations into both the composition and the properties of various materials, as well as studies on various phenomena and processes occurring on micro- and macro-scales in the natural environment and in living organisms. It also concerns the optimization of various technological processes involving specific chemical reactions. As indicated by the progress in different areas of chemical science achieved over the past century (or more), one of the contributing factors in the yield of chemical reactions is the movement of reagents depending on various mechanisms. In both laboratory and industrial practices, the most commonly employed processes are those under conditions of the forced flow of reagents. Changes in the transport rate of reagents under flow conditions can be utilized in the physico-chemical examination of the kinetics of the reaction, as well as for the improvement of the efficiency of different steps in analytical procedures or for carrying out chemical synthesis with favorable yields.
In spite of the large number of various applications of carrying chemical reactions under flow conditions, the term “flow chemistry” can only recently be found in the chemical literature, and it is used almost exclusively for the description of chemical syntheses carried out under flow conditions. The search of literature databases indicated its first uses in the 1970s in various fields such as modeling of chemical laser operations [1], fabrication of materials for the nuclear industry [2], transport of pollutants associated with irrigation [3], or the aerothermodynamic analysis of a stardust sample return capsule in the National Aeronautics and Space Administration (NASA) mission [4]. First examples of the use of the term “flow chemistry” in chemical synthesis or analytical fields were found at the turn of 1990s and 2000s in work on the pulsed generation of concentration profiles in flow analysis [5] and in the description of continuous-flow microreactors with fluid propulsion achieved by magnetohydrodynamic actuation, which was employed for the amplification of DNA through the polymerase chain reaction [6]. This can be considered to be an analytical device; however, it simultaneously works via the synthesis of the desired product.
In the case of papers dealing with syntheses under flow conditions, so far generally considered in the present chemical literature as the only field of flow chemistry, the term “flow chemistry” started to be used from the middle of the 2000s onward [7]. The term “flow synthesis”, in turn, is commonly used in papers on organic synthesis since the 1970s [8].
The volume of published papers on widely recognized flow chemistry, including not only chemical synthesis but also flow analysis, fundamental physico-chemical investigations under flow conditions, or flow reactors in industrial applications, can be estimated to be 30 to 40 thousand papers in both scientific and technical journals. It should be taken into account that a very arbitrary selection of published works had to be made for the present review. Therefore, for instance, certain areas of measurements or studies under flow conditions are not included, for example, analytical process monitoring by dedicated industrial instrumentation or industrial processes carried out on a technological scale in flow reactors. This should be mentioned in order to not restrict the term “flow chemistry” in the context of modern chemical science and, simultaneously, to point out the importance of this field.
The intention of the author of this review is to present, for the first time in the literature, various fields of modern chemistry which should be considered within flow chemistry. A special emphasis is focused on the presentation of the development and chronology of inventions of numerous physico-chemical operations and appropriate instrumental devices, which are widely employed in both flow synthesis and flow analysis.

2. Milestones in the Development of Various Areas of Flow Chemistry

Although it is hard to underestimate the benefits of using numerous literature databases, tracing the evolution of various methodologies of conducting measurements or carrying out chemical syntheses under flow conditions is a very challenging task. The results of different applications of flow chemistry are distributed very broadly in hundreds of chemical journals and they are not always reported in the available databases. The general intention of preparing this section of the review is to present (at least roughly) the chronology of the development of the selected areas of flow chemistry.

2.1. Flow Analysis

It seems that the first chemical phenomenon to be observed under flow conditions and employed for analytical purposes was the separation of a mixture of chemical compounds on a flow-through column packed with a solid sorbent, which initiated the development of chromatographic methods. This is commonly attributed to Cwett’s works conducted at the University of Warsaw at the beginning of the 20th century [9,10], although a similar observation was published also earlier [11]. It is necessary, however, to admit that, regardless of the similarity of both operations, the commonly used term “flow analysis” is rather associated with the much later invention of continuous-flow analysis with the segmentation of flowing stream by Skeggs in the middle of the 1950s [12,13], where the segmentation of a flowing stream with air bubbles was essential for limiting the analyte dispersion along the tubing. The developed pioneering system consisted of several instrumental flow-through modules, which allowed performing different physico-chemical operations for the clinical determination of urea in blood with photometric detection in a mechanized manner. It means then that conventional flow analysis follows instrumental set-ups (schematically presented as manifolds), where determinations with different detection techniques can be carried out with various operations of on-line sample processing, with or without the segmentation of the flowing liquid. This understanding of flow analysis is confirmed by a large number of published books and review papers in various journals [14]. This also means that, despite involving flowing conditions, chromatographic methods, electrophoretic methods, mass spectrometry, or atomic spectrometry methods, where the flow of analytes from the sample introduction to the detector takes place, do not fall into the flow analysis category. The concept of constructing a flow analyzer with a segmented stream was used to develop many set-ups for numerous applications in various areas of analytical chemistry [15], as well as for commercial instruments by specialized manufacturers.
In further modification of that concept, the segmentation of a flowing liquid was eliminated from the measurement system [16], a very small sample volume (20–200 μL) was used [17], and a transient signal was used (as an analytical one) instead of steady signal values recorded in the segmented flow analyzers. An extraordinary impetus for the further development of that version of flow analysis called flow-injection analysis (FIA) was given by a series of papers published in the middle of the 1970s by Ruzicka and Hansen [18,19,20], as well as some parallel ones by Stewart et al. [21,22]. Fast development of that methodology resulted in the availability of numerous commercial instruments [23], as well as further development of the modified versions of FIA such as sequential injection analysis (SIA) [24] or lab-on-valve (LOV) systems, which integrated the injection modules with detection and some operations of sample treatment on a renewable bed of solid sorbents [25].
Already at the end of the 1970s pioneering microfluidic systems were designed and produced on silicon wafers, firstly employed as a capillary column in gas chromatography [26]. Then, since the beginning of the 1990s, their first applications in flow analysis were developed, e.g., in hyphenation with the surface plasmon resonance analyzer for the determination of immunoglobulins [27], or in a miniaturized system with detections by solid-state electrochemical sensors or small-volume optical detectors [28]. The currently observed development of measuring systems involves further miniaturization and instrumental integration of hydraulic, detecting, and sample processing operations. This is also associated with tapping into current achievements of nanotechnology and new technologies for the transmission and processing of measured signals.

2.2. Flow Synthesis

Organic chemistry is an exceptionally broad area of modern chemistry embracing fundamental investigations of mechanisms of reactions, identification of natural compounds, and optimization of laboratory syntheses, as well as their scaling up to a technological level. Utilizing flow conditions for carrying out chemical syntheses is a very important part of the development of flow chemistry. Although, as already mentioned, the term “flow chemistry” was used only recently, i.e., in the last two decades, the real beginnings of this methodology were much earlier. According to the Web of Science database, the first contribution to flow synthesis was a short report on the use of a flow reactor with a phosphoric acid catalyst on silica gel for dehydration of diethylcarbinol, published in 1932 [29]. An evident increased interest in the use of flow reactors, especially those with an immobilized catalyst, was noted no earlier than the 1960s [30,31]. Numerical methods were employed to evaluate the participation of diffusion, the convection of a reactant, and the kinetics of homogeneous and heterogeneous reactions in catalytic tubular reactors [30], while experimentally diffusional and chemical effects were examined for fast reactions of cyclopropane in flow reactors [32]. Flow synthesis in an open flow-system was reported for producing layers of gallium phosphide for some electronic applications [33]. A continuous-flow salt gradient was utilized in the preparation of polynucleotide–polypeptide complexes [34], while excellent yields in cryptate synthesis could be obtained via a cyclization reaction carried out with efficient mixing in a suitable flow cell [35]. The 1980s brought further development in designing automated systems where the progress in flow synthesis was monitored on-line and was increasingly controlled by the computer, which was reported, e.g., for solid-phase synthesis of peptides [36,37] and oligodeoxyribonucleotides [38]. In the latter case, more than 600 oligomers were produced in approximately 15 min. Alpha-gliadin peptides were synthesized in a continuous-flow set-up under ultrasonic field conditions, which accelerated the coupling reaction [39].
A substantial increase in the number of published papers on various innovations in flow synthesis was observed since the beginning of the 2000s. It seems that this can be essentially attributed to an increasing interest in this technology and its great potential for speeding up drug development by leading manufacturers of pharmaceutical industries [40], as well as by very active research groups from top academic institutions such as, e.g., the University of Cambridge in the United Kingdom (UK) [41], the California Institute of Technology [42], or the Massachusetts Institute of Technology (MIT) [43]. Numerous flow syntheses can be successfully enhanced with microwave activation [41,44], while conventional pumping in the flow systems with piston pumps can be replaced with a magnetohydrodynamic actuator [6] or by the use of electroosmotic flow [45]. Flow syntheses can be also carried out under supercritical conditions, which was first employed when producing narrow-size distribution quantum dots [46].
As of the middle of the 2000s, flow syntheses with the use of microfluidics were performed more and more commonly, allowing for the reduction of the amounts of reagents and solvents—a pioneering example of gas–liquid–solid hydrogenation [47] or the production of nano amounts of a 19F-labeled imaging probe for positron emission tomography (PET) [42]. Yet another direction in this trend was the use of droplet-based microfluidics, which was demonstrated, for instance, for the synthesis of anisotropic gold nanocrystal dispersions [48].
As it was shown, e.g., in the synthesis of the natural alkaloid called oxomartidine, complete synthesis of natural products can be carried out in a multistep procedure in the system with several packed columns containing immobilized reagents, catalysts, scavengers, or catch-and-release steps [7]. This work initiated intensive development of some other, similarly complex systems, also performed in microreactor networks, e.g., in the multistep synthesis of carbamate [49] or in the continuous-flow synthesis of carboxylic acids with the use of so-called tube-in-tube gas-permeable membrane reactors [50].
The most recent instrumental innovations in flow syntheses are, among others, the use of three-dimensional (3D) printed advanced reactors for Ag nanoparticles [51] or the creation of a robotic system for flow synthesis [52].

2.3. Fundamental Physico-Chemical Measurements under Flow Conditions

One of the areas where measurements under flow conditions were applied for decades is the investigation into the kinetics of chemical reactions, especially in the case of fast reactions taking place in solutions. Reports on such measurements can be found in the literature since the 1950s [53], while the stopped-flow methodology for this purpose was reported even earlier [54]. In the latter method, instead of the measurements of concentration changes in the monitored reaction along the length of the reaction tube, the detection system is located in the proximity of the mixing chamber into which the solutions of reagents are forced from the syringes. Kinetic measurements were also carried out in a typical flow analyzer with a segmented stream in studies on peptide bond hydrolysis [55]. Kinetic measurements in a stirred flow reactor for the alkaline bromination of acetone allowed evaluating both reaction orders, as well as determining the reaction-rate constants in a system of consecutive reactions [56].
Contemporary kinetic measurements are carried out with different detection techniques and in different configurations of flow systems. For instance, a successful application of this kind was reported for continuous-flow microfluidic devices with laser-based mid-infrared chemical imaging in studies on fast organometallic chemistry [57], while a microfluidic system—with in situ X-ray and fluorescence detection—was used in studies on hydrogelation kinetics [58]. In a microreactor set-up, kinetic data on exothermic synthesis by Michael addition was examined with fast in-line monitoring by Raman spectroscopy [59]. Then, two recently reported examples described kinetic studies devoted to free-radical chemistry under flow conditions with chemiluminescence detection. Infrared chemiluminescence detection was employed to monitor the kinetics of the reaction of •OH radicals with formamide and chemically activated carbamic acid [60]. The chemiluminescence of a methyl- cypridina luciferin analogue was employed to examine the kinetics of the reaction of superoxide radical ions with dissolved organic matter in a typical flow-injection analysis system [61].
In stopped-flow measurements, where the dead-time of a fraction of a millisecond can be reached in modern instrumentation, various spectral and electrochemical methods are used to investigate the kinetics of very fast reactions in solutions. Absorption or fluorescence spectroscopy are the two most commonly used detection techniques in dedicated commercial instruments. In a very early example of such works, the kinetics of unstable compounds in a biochemical reaction (e.g., the formation of catalase–hydrogen peroxide complex) was reported with spectrophotometric detection in a time span from milliseconds to several minutes [62]. Then, a very recent example was the examination of the kinetics of aroxyl-radical scavenging rates by important lipid-soluble antioxidant α-tocopherol and catechins [63]. An example of some recent stopped-flow kinetic investigations with the use of fluorimetric detection was a study on the binding of biotin and biocytin to avidin and streptavidin, which is broadly used in biotechnology and bioanalysis [64]. Creating a simple manifold that can be attached to a commercial stopped-flow apparatus, allowing kinetic studies to be performed from −12 °C to 45 °C, constitutes an instrumental improvement in such measurements reported in recent years [65]. The sensitivity of kinetic absorption measurements in ultraviolet (UV)–visible wavelengths can be enhanced by the use of optical cavity-based techniques. The reported low-cost experimental set-up providing broadband cavity enhancement of sensitivity by coupling to commercial stopped-flow instruments allows obtaining even 78-fold enhancement for the measurements at 434 nm, which was employed in the investigation of the kinetics of a potassium ferricyanide reaction with sodium ascorbate [66].
Among other spectroscopic detection techniques used under flow conditions, numerous applications in stopped-flow kinetic measurements were reported for circular dichroism (CD). This technique enables simultaneous monitoring of chiro-optical and absorbing transients, which was shown, for instance, in the binding of sulfonamide to bovine carbonic anhydrase [67]. Recently, CD detection is commonly employed to study protein folding kinetics [68], while ultraviolet CD was used to study the folding mechanism of the outer surface protein A. Kinetic measurements in a stopped-flow mode are also used with Fourier-transform infrared (FTIR) detection [69], whereas NMR spectroscopy was reported, for instance, in the examination of metallocene-catalyzed poly- merization of 1-hexene [70].
Electrochemical detections are used much less commonly in detection of stopped-flow measu- rements than in spectroscopy techniques. At the very early stage of the development of stop- ped-flow methodology, conductivity detection and potentiometric pH measurements were employed to study the following reaction: OH− + CO2 → HCO3− [71]. One recent example showed, e.g., the use of voltammetry in stopped-flow studies on the kinetics of reduction of cop- per-containing enzyme peptidylglycine monooxygenase [72]. The above-mentioned examples clearly show a crucial role of flow measurements in the evaluation of kinetic parameters for many different chemical processes.

2.4. Chemical Processing under Flow Conditions for Non-Analytical and Non-Synthetic Purposes

This section of the present review only very briefly highlights the importance of yet another field of investigations and processes which should also be considered as a substantial part of flow chemistry. It is based on research studies and processes oriented most commonly toward technological applications in flow reactors, but they are also commonly initiated in laboratory investigations under flow conditions. Moreover, they are usually investigated for final technological applications in environmental protection or the processing of various materials in different branches of industry, including food processing. The examples presented below were randomly and arbitrarily selected to roughly indicate the variety of areas and problems associated with this particular field of flow chemistry.
As already mentioned, these approaches do not follow the rules of the field of chemical engineering on a technological scale. A vast amount of literature on this subject can be found in technological journals, patents, and specialized books [73,74]; thus, in this section, only some examples from the current literature are provided.
Applications of a flow-through reactor with immobilized α-galactosidase, which was used in the reduction of raffinose concentration in beet sugar molasses [75], or in the application of a flow-through reactor for the photocatalytic decomposition of ethylene applied to control tomato ripening [76], are two examples of employing biotechnology in the food processing field. A dynamic flow approach was reported to examine the leaching of antioxidants from solid foods [77], while, for ore and mineral processing, a reflux flotation flow cell was designed to achieve fast flotation [78].
The processing of biomass of various origin, which can be carried out in flow-through reactors, is an important sector of modern biotechnology. For instance, the flash pyrolysis of microalgal or lignocellulose biomass in a flow reactor may lead to the production of bio-oils of a very different composition, depending on the type of an initial substrate and the conditions of pyrolysis [79]. The obtained products can be further employed as phenolic-rich bio-oils, liquid fuels, or fine chemicals. The hydrothermal conversion of a wet waste feedstock in a continuous-flow reactor may result in obtaining liquid or gas final products with acceptable residual organic contamination [80]. The production of bio-crude oil using hydrothermal liquefaction in a continuous-flow reactor was also reported from wastewater microalgae [81].
A particularly large number of research papers on both the investigation and the application of flow-through reactors were devoted to the development of different processes for environmental protection, involving various methods of chemical processing. The biological anaerobic removal of nitrate from wastes was developed with the use of a bioreactor packed with sludge carbonaceous material [82]. In yet another similar method for the biodegradation of 2-chlorophenol, adsorption and biodegradation processes were carried out in a flow-through reactor with suspended biomass on activated carbon [83]. The mechanism of removal included the sorption of a pollutant, its transport by diffusion in a biofilm, and biodegradation by suspended biomass. Just recently, the efficiency rates of bacterial aerobic granular sludge and algal–bacterial granular sludge packed in a 20-L continuous-flow reactor were compared for saline wastewater treatment [84]. Since high salinity enhances algae growth, the second material exhibited slightly higher total nitrogen and phosphorus removal efficiency.
Typical chemical processing methods were also widely investigated for water and wastewater treatment in flow-through reactors. These approaches include, first of all, various photochemical methods, involving (mainly) UV irradiation under different conditions with or without catalysts [85]. For instance, the photocatalytic degradation of bio-resistant dyes was demonstrated in a flow reactor with a TiO2 catalyst embedded into a cement matrix and deposited at the bottom [86]. Regarding other methods, the catalytic wet air oxidation of industrial wastewater was carried out in a flow reactor packed with copper nanoparticle-doped and graphitic carbon nanofiber-covered porous carbon beads [87]. A complete chemical oxygen demand (COD) reduction in industrial wastewater was observed under optimized conditions. A significant reduction (50% to 80%) of COD and the removal of numerous inorganic contaminants from drinking water could be obtained with the use of a flow reactor packed with a mixture of anionic and cationic ion-exchange resins [88].
The processes such as sonolysis, electrochemical oxidation, or irradiation with a beam of accelerated electrons can be employed in continuous-flow reactors for the efficient decomposition of organic pollutants in waters and wastewaters. For instance, separate or simultaneous sonolysis and ozonation were examined under flow conditions for the degradation of antibiotics in wastewater [89]. Electroactive pollutants such as residues of different pharmaceuticals can be efficiently removed by electrochemical oxidation, which was demonstrated, e.g., for the residues of the widely used anti-inflammatory drug called naproxen using different porous materials of anode [90]. A flow reactor with a boron-doped diamond anode enabled efficient degradation of azo dyes occurring in synthetic textile effluent [91], whereas an ultra-nanocrystalline, boron-doped diamond anode coated on a niobium substrate, also employed in a flow reactor, was successfully used for the minera- lization of a persistent pollutant perfluorooctanoic acid [92]. An aerosol flow reactor developed for the efficient decomposition of organic pollutants by electron beam irradiation can be mentioned as a final example of different flow reactors investigated for environmental purposes [93].
The above-mentioned examples are only a few randomly selected examples that can be found in thousands of papers published in scientific journals and patents on the use of flow reactors for this field of research activity. It is impossible to provide a more complete review of these applications or to discuss the evolution of their construction, the optimization of their operation, or the broad fields of applications. It is doubtless, however, whether these types of chemical processes should also be considered a part of flow chemistry. It is also impossible not to admit that the processes investigated and optimized in such flow reactors are often utilized in flow systems developed for both analytical and synthetic purposes, contributing to the final results of their functioning.

4. Toward the Automation of Chemical Flow Systems

The notions “to automate” or “automation” and their various derivatives are very loosely used when describing chemical instrumentation. The use of mechanical devices to replace, refine, extend, or supplement human effort in operating chemical instrumentation, including flow analytical and synthetic systems, does not mean automation of the instrument, which was clearly indicated already in 1994 in the International Union of Pure and Applied Chemistry (IUPAC) terminological recom- mendations [295]. Actually, the description covers only a different degree of the mechanization of instrumentation or experimental procedures. The word “automation” means introducing to such a procedure at least one operation which is entirely controlled and carried out by the feedback from the system (usually a computerized one) without any human intervention, which means self- monitoring or self-adjustment.
In the recent literature on flow synthesis, there were certain suggestions of how to diversify different flow synthesis systems, i.e., by differentiating between “automated” and “autonomous” flow synthesis systems [296]. As can be read, automated systems require human input to determine the boundaries of operating parameters, thresholds, and protocols, while autonomous flow synthesis systems can react to output parameters of the system such as, e.g., reaction yield or purity of the obtained products without human input. The employed control system should properly adjust the input parameters of the process. It seems that these two terms correspond exactly with the terms “mechanization” and “automation” in the above-mentioned IUPAC recommended terminology. This looks like another example of that invisible boundary between the decades of development of flow analysis and the re-discovery of both metrological and instrumental features for synthetic chemistry under flow conditions.

4.1. In-Line Analytical Monitoring in Flow Synthetic Systems

An application of real-time analytical monitoring of the progress of reactions carried out in flow synthesis systems is a crucial factor influencing the yield and the quality, i.e., the purity, of the fabricated product. Several decades of development of flow analysis and liquid chromatography methods resulted in the creation of a large number of flow-through spectrophotometric and electrochemical detectors, reported in the vast literature and commercially available from specialized manufacturers. Flow-through detectors for infrared spectroscopy are rarely used in flow analysis or LC, but they can be used in flow synthesis for the monitoring of selected compounds [297,298,299]. Raman spectroscopy analysis using a surface-enhanced Raman scatter (SERS) technique under flow conditions was also reported [300]. A number of examples were already presented in the literature on the application of NMR in flow analysis, e.g., in the determination of model drugs [301] or quantitative metabolome analysis of urine [302]. FIA systems can also be designed with mass spectrometry detection, for instance, for rapid determination of pesticides [303] or metabolome studies [304]. These randomly selected examples show the very broad experience gained in the use of the discussed sophisticated instrumental techniques in flow systems, which obviously can be adapted for real-time monitoring of the performance of flow synthesis systems.
One can find numerous examples of using analytical flow measurements for in-line monitoring among a large number of papers on flow synthesis. Most commonly used for this purpose are molecular spectroscopy techniques. For instance, in flow synthesis systems requiring minimal manual intervention, which were designed for the synthesis of a drug known as imatinib, a flow-through UV detector was used to determine when the reaction mixture exited the system in order to fractionate the reactor output for the off-line LC/MS analysis [201]. In the flow synthesis of fluorescent CdS nanoparticles in a microfluidic reactor, an in-line spectrometer to monitor the fluorescence spectra was employed [305], while, in a multi-stage flow synthesis of silica and two types of organic nanoparticles, in-line dynamic light scattering was used for real-time monitoring of the size of the obtained nanoparticles [306]. Numerous applications were reported for the use of infrared spectroscopy in real-time monitoring in flow synthesis systems, mostly using the so-called attenuated total reflection technique (ATR). Such a flow-through cell was attached, e.g., to the outlet of the electrochemical microflow reactor to monitor the on-line formation of the cationic intermediate [307]. An FTIR device with flow cells for ATR measurements using a gold-sealed diamond sensor (ReactIR) can be attached in-line at any part of the flow synthesis system to monitor the reagent consumption or product formation, as well as short-lived intermediates. It was employed, for instance, in the monitoring of fluorination and hydrogenation reactions, as well as the heterocycle saturation reaction for product monitoring; it was also used when screening reaction conditions, monitoring reactive intermediates in Curtius rearrangement, and monitoring hazardous wastes [308]. The last case was also separately presented showing the continuous monitoring of hazardous azide contaminants for the round-the-clock operation of a flow system in a fully automated fashion [309]. A multichannel Raman system equipped with ball-probe immersion optics was reported for monitoring each of the reagent lines and the product line in a flow system for the esterification of benzoic acid.
The hyphenation of flow synthesis with an appropriate analytical technique can be very helpful for quick optimization of the flow parameters and screening of the combinations of reagents. This was well illustrated by the so-called μSYNTAS system (microchip-based synthesis with total analysis system), which integrated the microreactor with a time-of-flight mass spectrometer via an electro-spray unit [310]. It was employed for the efficient continuous-flow generation of compound libraries on the microscale with real-time identification of the reaction components. In yet another example of applying such hyphenation, the microflow synthesis system was coupled to a miniaturized electrospray ionization (ESI) mass spectrometer to monitor reactive intermediates, screen starting materials, and optimize reaction parameters. This was employed for the generation of benzyne and its subsequent reaction with furan, showing the ability of such a hyphenated system to be adapted for safe operation due to the monitoring of hazardous intermediates and the generation of the desired target products [311].
An especially expanded flow synthesis platform, integrated in-line with a UPLC–MS set-up and made of commercially available components, was recently reported for both nanomole-scale reaction screening and micromole-scale synthesis [312]. It is characterized by enabling the preparation and analysis of up to 1500 reaction segments in a 24-h period. In a robotized synthesis–purification–sample-management platform, the preparative LC/MS system was integrated with the flow synthesis set-up for the generation of pharmaceutically active substances, where a 1000:1 split of a preparative system was directed toward another mass spectrometer for analysis [313]. Direct hyphenation of the HPLC set-up to a flow synthesis system can also be used for the same purpose, which was demonstrated, e.g., for a thermal isomerization reaction carried out in a flow reactor [314]. For the efficient generation of structure–activity relationship data, the flow synthesis system was implemented with a microfluidic biosensor chip employing fluorimetric detection [315]. It was developed for the preparation of the most active inhibitors of β-secretase (BACA1), considered as a key target in the research on Alzheimer’s disease.

4.2. Automated Flow Analytical and Synthetic Systems

In spite of the above-mentioned terminological recommendations [295], calling the flow analytical or flow synthesis systems automated is a misnomer. However, in the vast literature on flow chemistry in the fullest sense of the word, one can find several examples of really automated set-ups.
Titrations belong to the category of classic, yet still widely used, analytical quantitative procedures routinely employed in modern analytical chemistry, which are also adapted in flow systems. A very original concept which tells us how to carry out titrations is a so-called “binary search strategy”. It is based on a computer-controlled adjustment of the volumes of segments of a titrant and a titrand in order to reach stoichiometry, corresponding to the end point of titration. This is carried out in a computer-controlled system with automatic control and adjustment of the volume of segments using solenoid valves. Such systems were developed for acid–base titrations with photometric detection [316] and for the determination of copper complexation capacity, e.g., of milk, based on complexometric titration with chemiluminescence detection [317]. Two other examples of analytical automated flow systems concern the FIA set-ups with spectrophotometric detection developed for the speciation of Fe(III) and Fe(II) in water [318], as well as the simultaneous determination of thorium and uranium in environmental samples with the use of separation employing an extraction resin [319]. Different measuring procedures were programmed in these two both entirely computer-controlled measuring systems, and their selection for particular samples to be analyzed was made automatically based on a series of preliminary test measurements without human intervention. The main differences between the advanced programmed procedures are, e.g., the selection of an additional preconcentration step of analyte(s) or the dilution of the analyzed sample.
Although, in a very recent paper [296], one can learn that “future advances may include the hyphenation of online reactor analytics that would allow a read-out of the reaction progress to alter the reaction parameters using feedback algorithms”, and that it can be achieved in the upcoming years, some examples of this approach can already be found in the literature on flow synthesis. For instance, in the designed microfluidic platform for multidimensional screening, chemical reactions were evaluated employing multiple variables [320]. UV on-line monitoring was utilized in such a system in a feedback loop to control both the selection and the injection of a reagent, setting temperature, and sample collection, while the analysis of the reaction screen was carried out using UPLC/MS in the samples collected into 96-well plates. Then, an infrared flow-through detector was employed in another multistep segmented flow processing system for the synthesis of pyrazoles to control the pump for the accurate addition of reagents in combination with a LabVIEW software application [321]. It was also mentioned that the output from the infrared cell can also be potentially used, e.g., to control a fraction collector in a fully automated process.
The creation of a fully computerized autonomous flow chemistry platform for the studies of rhodium-catalyzed hydroformylation reactions was reported with the use of photodetectors, phase sensors, and mass flow controllers, but no information on the employed feedback loops was provided [322]. In some recently published papers, two extremely advanced and fully computerized systems for the flow synthesis of organic compounds were described for the synthesis of pharmaceuticals [52,312]. Both systems are reported as automated platforms, but no details on the use of the feedback loops for self-adjusting of any operations in their functioning are available.

4.3. Robotics, Digital Transmission, and Camera-Enabled Techniques in Flow Chemistry Instrumentation

A particular improvement in terms of the mechanization of complex, multi-modular instrumental systems, as well as their functioning in chemical laboratories, is the application of robots in their design. They offer significant technical enhancement in multistep procedures. Moreover, decision feedback loops can also be involved in their functioning, providing additional elements of automation to the operation of the whole instrumental set-up. A robot can be defined as a programmable, multifunctional machine which is capable of carrying out different operations using materials, parts, and specialized tools. In their second generation, they were equipped with numerous sensors, which make them automatic devices. As manipulators in the laboratory environment, they are designed in Cartesian, cylindrical, and spherical configurations. Their applications in chemical analytical laboratories for sample preparation were observed since the early 1980s [323]. In the same decade, their first applications for flow-injection analysis were reported for the preparation of oil samples prior to analysis using inductively coupled plasma (ICP) emission spectrometry [324]. A full description of a robotized sample preparation station was published in later works on the flow-injection photometric determinations of total polyphenols in olive oil [325] and starch determination in food products [326]. Figure 7a shows a scheme of a robotic station with a commercial, cylindrical-type robot called Zymate II Plus for sample preparation, involving sample weighting, microwave digesting, dissolving, and solvent extraction, as well as centrifugation [326]. The progress in the analytical applications of robots observed in next decades showed their essential advantages in the improvements achieved in small laboratories, in industrial research and development laboratories, and in the production of chemicals [327].
Figure 7. Examples of robotic systems developed for flow-injection analysis (a) [326] and flow synthesis (b) [52]: (a) FIA system developed for colorimetric determination of starch in food based on the determination of sugars using the neocuproine method; PEC—power and event controller; Ap—all-purpose hand; SH—syringe hand; P—peristaltic pump; FW—filter waste; DW—digester waste; CF—clean-up filter solution; SA—solution for assaying sugars; SV—switching valve; Rl—neocuproine channel; R2—NaOH channel; IV—injection valve; L—reactor; T—thermostat; W—waste; (b) robotic flow system for flow synthesis of organic compounds based on artificial intelligence planning; A—workflow for on-demand synthesis of a targeted organic compound; B—software modules combining cheminformatics and machine learning to design and validate synthetic pathways; C—photograph of the robotic flow chemistry platform, with a projected floorplan of the 6 × 4 ft working table.
It seems obvious that the application of laboratory robots may also improve multistep and multi-instrumental systems for conducting organic syntheses in flow systems, especially when a given procedure requires manipulation with numerous reagents and different modules of the system. The discussed works were published in the most recent decade and most of them reported developments with the contribution of widely known pharmaceutical companies (Pfizer, GlaxoSmithKline, Abbvie). A Kawasaki six-axis robot was used for liquid handling in a flow system for the monophasic synthesis of drug-like compounds via a plug-flow approach already mentioned in this paper [141]. Using a nucleophilic aromatic substitution reaction and diazo transfer, it was demonstrated that the developed system for performing chemical reactions on a microliter scale can be scaled up to provide a much larger quantity of the required product by working with larger plugs. In another example of a robotized flow synthesis system, a Mitsubishi six-axis robot was also employed to hand off samples between different instruments involved in the whole process [313]. These stations included a segmented flow-chemistry reactor, a preparative LC/MS purification set-up, pumps for dilution, a labeling station, and a centrifugal evaporator. The process ended with MS and NMR analysis; the multistep reaction-time was only about 30 min due to the possibility of carrying out various parallel operations, which significantly shortened the overall production time for the library. A combinatorial synthesis robot incorporating a continuous hydrothermal reactor was developed in the area of direct solid-state chemistry and employed in the flow synthesis of Zn–Ce oxides as crystalline nano powders [328] and iron-doped lanthanum nickelates, which are difficult to prepare in a single step [329].
The most advanced robotic platform for the above-mentioned flow synthesis [52] was recently reported. It employs artificial intelligence planning and generalizes millions of known reactions, via which the prediction of a particular route for execution in a modular continuous-flow platform can be made (Figure 7b).
The whole constructed robotic platform consists of two towers containing eight universal process bays, connecting fluidic, electrical, and pneumatic lines using the UR3 Universal Robot®. The selected process modules are moved from the storage location and configured into a given manifold. The workflow for retrosynthetic planning firstly identifies the reactor for a given target compound; then, the generation of precursors and a proposal of the reaction conditions take place. In the developed instrumentation, ATR–FTIR was only occasionally employed in-line; however, in further modifications of that set-up, in-line HPLC and frit will be implemented for the optimization of the robotic platform by designing an analytic tower in parallel with the process towers. The synthesis planning and its execution using this robotically reconfigurable flow chemistry platform was illustrated by the synthesis of 15 drug and drug-like molecules.
Although the applications of robots for sample processing in flow analysis were already presented in the early 1990s, this method of enhancement of flow analytical systems did not gain much support in subsequent decades. This can be ascribed to the quite common perception of the instrumentation for flow analysis as a cost-effective way to improve laboratory operations; hence, adding robots to such set-ups could be too costly. A completely different story is the case of flow synthesis systems which are most beneficial for the pharmaceutical chemistry. The robotization of the searching process for new active pharmaceutical ingredients and the optimization of their syntheses has to be considered as an exceptionally correct and valuable choice in the further development of instrumentation for such needs.
An increasing trend in the construction of new devices and measuring systems, as well as in chemical analysis, is the hyphenation of conventional devices with mobile consumer electronics (e.g., smartphones or web cameras), as well as their use for the transmission of measurement data of global teleinformatic networks [330,331]. Mobile phones and smartphones are more and more commonly used as signal transducers for optical sensors and biosensors, as well as for the same purpose in the development of microfluidic devices with spectrophotometric or luminescence detections in recent years. For instance, a microfluidic-based smartphone dongle with colorimetric detection was developed for simultaneous assays of hemoglobin and human immunodeficiency virus (HIV) antibodies [332], while a wearable, cotton–thread–paper-based microfluidic device was also designed for colorimetric enzymatic glucose sensing in sweat [333]. A fluorescence immunoassay of Escherichia coli was adapted to a microfluidic format with smartphone signal transducing for the determination of that pathogen in urine [334], and electrochemiluminescence detection was employed in a paper-based microfluidic system with wax screen-printing channels and carbon ink-based screen-printed electrodes for the determination of hydrogen peroxide, which can also be adapted for point-of-care detections of glucose [335].
Separate digital web cameras can also be employed for that purpose, replacing conventional spectrophotometers or luminescence detectors. This was illustrated, for instance, by the FIA lab-on-chip miniaturized system developed with the use of a photometric detector for acidity detection [336]. The fluorometric detection employing a web camera was reported in a conventional flow-batch system for the determination of a drug known as acetylcysteine with the use of Cd–Te quantum dots [337]. Smartphones or webcams can also be used in flow instrumentation to control the same functions, in addition to transducing a detection signal. This was reported, for instance, in a microfluidic set-up, where, in addition to the read-out biosensor, a smartphone was a part of the microfluidic liquid handling system combining elastomeric on-chip valves and compact pneumatic liquid pumping [338]. This can be applied in a bead-based fluoroimmunoassay, PCR-based analysis, flow cytometry, and nucleic acid sequencing. A similar concept was introduced into a smartphone electrochemical set-up developed for the determination of selected heavy metals in milk and fruit juices [339] (Figure 8a). In this case, the smartphone controls a programmable, prototype solid-state microwave flow digestion through a digital interface circuit, and it also performs fluidic operations (using a pump/valve) and differential pulse stripping voltammetry.
Figure 8. Examples of applications of webcam cameras in flow systems for analytical (a) [339] and synthetic (b) [340] applications: (a) manifold of measuring flow system involving programmable solid-state microwave flow digestion (a) and typical user interface (b) of the smart-phone-based electrochemical platform developed for determination of heavy metals in liquid foods; (b) seven-operation integrated flow platform for the synthesis of 2-aminoadamantane-2-carboxylic acid employing webcam cameras (P—pump; V—valve; M—mixer; R—reactor; C—column; S—reservoir). The output from the initial Grignard step is subjected to in-line quenching and then computer-controlled liquid–liquid phase separation. This solution undergoes a solvent switch, and the output is stored in a reservoir before being used for the Ritter reaction stage. The acidic output is quenched with a base, and the resulting salts are removed using a continuous filter. The filtrate is stored in a second reservoir before finally being heated to undergo cyclization.
The use of web cameras was also reported in controlling certain fluidic operations in flow systems for the synthesis of organic compounds [341]. They involve, among others, the monitoring of chemical events in microdroplets, observing the reaction within the microwave cavity, the formation of aggregate deposits in the glass chip, recording crystallization processes, and the visualization of the liquid/liquid extraction process with the use of a plastic float, e.g., to adjust the flow rate of pumped phases. An exemplary application of three webcams in a self-controlling, telescoped seven-step synthesis was shown in a process including Grignard, Ritter, and cyclization reactions, where extractions, solvent-switching, filtration, and quenching steps were involved [340] (Figure 8b). The functioning of such a complex system can be controlled by only one operator.
In scientific and technical literature since the 1960s, there can be found various attempts at using telecommunication for medical purposes in order to facilitate long-distance doctor–patient interactions, as well as for environmental purposes, such as the remote monitoring of instrumen- tation and collected data transmission. Based on the tremendous progress made over the recent decades in personal computing and mobile telephony, it is not surprising to also find some examples of the application of modern telemetry in flow chemistry instrumentation. For instance, employing a computer sound card and a transmission wireless microphone, wireless recording of outputs from a spectrophotometer used for detection in the FIA system was reported for a distance up to 30 m [342]. Obviously, all the systems developed with data acquisition using mobile phones can be easily adapted for the same purpose. One more pioneering development in this field to be mentioned here was the application of camera phones for signal acquisition from paper-based microfluidic devices for low-cost off-site diagnosis [343]. This was demonstrated for carrying out the colorimetric determination of glucose and protein in urine. Then, in another approach employing a dedicated circuit plugged into the Universal Serial Bus (USB) port of a mobile phone, amperometric detection could also be carried out in a microfluidic system. This was reported for the determination of a protein, which is a biomarker of the malaria parasite, using a poly(dimethylsiloxane) microfluidic chip [344].
One more important aspect of the current developments of flow chemistry is worth mentioning here. In the last two decades, there was an increase in the associations of flow chemistry with the fast development of nanotechnology. In the field of flow analysis, this can be seen as an increasing interest in the application of two- and three-dimensional nanostructures for the enhancement of detection techniques, in separation processes carried out under flow conditions and in the creation of nanofluidic and microfluidic analytical systems [345]. In the development of new methods for spectral detections, the use of quantum dots proved to be particularly fruitful [346], while, in the development of electrochemical detections and separation methods, other inorganic nanoparticles with different functionalization were used [347]. Then, the development of especially efficient and fast methods for the synthesis of various nanoparticles was the subject of numerous works in the field of flow synthesis. These initially involved inorganic nanoparticles [348,349,350], where metallic nanoparticles found numerous catalytic applications in microflow reactors for organic syntheses [348]. Various nanoparticles and microparticles were synthesized under flow conditions [351], and functionalized nanoparticles [352] were designated for biomedical applications. Using microfluidic systems for this purpose enables precise control of the processes, as well as their significant shortening via appropriate modulation of the most critical stages. This leads to an improvement in the reproducibility of synthetic processes and a better control of the morphology and the size distribution of nanoparticles [352].

5. Conclusions and Perspectives

Flow chemistry is doubtlessly a very significant field in modern chemistry, with respect to conducting scientific research and various kinds of applications, moving from traditional appro- aches into inorganic, organic, and physical chemistry and chemical technology. In addition to the specialized books listed below, there were tens if not hundreds of reviews published, so far, on the different areas of flow chemistry discussed above, of which many were cited. Very recent reviews in the field of flow synthesis include a general review on flow syntheses as green methods of chemical syntheses [353], a presentation of equipment and separation units [199], an outline of the use of flow methods for taming hazardous chemistry [128], a description of the applications of flow micro- reactors and electrolysis cells in electrosynthetic processes [228,229], and a review on the pharmaceutical applications of flow synthesis [154]. In the field of flow analysis, general reviews on its recent advances [14] and 60-year development, based on publications in the analytical journal Talanta [354], can be mentioned. Furthermore, there were also reviews on the spectroanalytical applications of multi-syringe flow-injection methods [355], as well as on the application of fluidized particles in flow analysis methods [356], microfluidic paper-based analytical devices [262], or the use of flow analysis for the determination of radionuclides in nuclear industry [357]. Among the recent reviews on the technological applications of flow methods, much attention was focused on photochemical methods [85] and solar photochemistry [224].
The invention of flow chemistry in the middle of the previous century has to be attributed to the creation of the concept of flow analysis, which, at that time, was a real breakthrough in the world of chemical analytical methods. It was employed, first of all, in medical diagnostics, very quickly expanding into the areas of environmental analysis, food chemistry, and industrial processes. The last years of the previous century brought a very essential transformation of its instrumental format to microfluidic systems, and a parallel phenomenon took place in the rapid increase in the interest in conducting chemical syntheses under flow conditions in organic chemistry.
The first apogee of the interest in flow analysis and its real routine applications was in the 1960s/1970s. Then, a certain renaissance took place between 1980 and 1990 along with the invention of injection methodologies. However, there were no spectacular commercial successes in this field, which is why chromatographic and atomic absorption techniques are more widely employed in routine analytical laboratories since then. Then, a new impetus was again provided in the last two decades with the creation of microsystems with wide prospects in medical applications, particularly for the design of devices for patient personal use. In the case of flow synthesis, the strongest impetus for its development came, without a doubt, from the pharmaceutical industry, where the search for new drugs is a top priority, and where microflow synthetic methodology trumps any other kind of instrumentation.
The main goal of this review article was to demonstrate how unjustified and far from reality it is to limit the term flow chemistry to flow synthesis, as can be found in thousands of published research papers. In fact, this notion concerns publications even in the most prestigious chemical scientific journals or books published by worldwide leading scientific publishers. Virtually all the metho- dologies of conducting chemical reactions or utilizing different unit operations are the same in flow analysis and flow synthesis, whereas their earlier applications are usually reported in flow analysis. The only difference between these two main fields of flow chemistry is the wide application of cryogenic conditions in conducting numerous reactions in organic syntheses, which are basically not used in flow analysis. It is truly bewildering how hermetic the progress is in the development of instrumental systems and methodologies in analytical and synthetic flow systems. Considering these two fields, twice as many books on flow analysis were published so far (Table 1), as compared to the books on flow synthesis (Table 2). However, in books on flow analysis published after 2000, one cannot find any remark on flow syntheses, although there is vast literature on carrying out different on-line reactions in flow analytical systems for sample treatment or the derivatization of analyte(s). On the other hand, none of the books on flow chemistry or flow synthesis mention the decades of development of flow analytical systems. One can find only some remarks on the use of analytical devices as additional accessories installed within flow synthetic systems for real-time monitoring of the progress of conducted reactions.
Table 2. Books published on flow synthesis.
With regard to the briefly overviewed developments of these methodologies and instrumen- tation, it seems to be fully justified to use the term flow chemistry to represent all other chemical processes carried out under flow conditions of the reacting mixture, a sample to be analyzed, and other media chemically transformed under flow conditions. Certain symptoms of a slight evolution toward such a situation can be noted in some recent papers on microfluidics. the outstanding dynamics of the development of these technologies is reflected by the long-standing publication of dedicated scientific journals and books (already about 50 to date), as well as the presence of numerous manufacturers of such systems on the market. In an increasing number of research papers reporting new achievements, one can find remarks on their potential applications, both for analytical and for synthetic purposes, which is now the reality.
There are several numbers worth mentioning at the end of this review. They are related to bibliographical or scientometric aspects of the discussed field of scientific research, based on the Institute for Scientific Information (ISI) Web of Science in all database modes, viewed on 25 January 2020. It shows 1505 publications when the key phrase “flow chemistry” is entered, with a rapid increase after 2007 and about 210 papers per year published in the last three years. Quite similar results can be found when searching for the “flow synthesis” phrase, with 1139 publications, and a fast increase in the number of publications since 2005, with about 160 papers per year published in the last three years. A search for the “flow analysis” phrase shows 21,804 publications, but this cannot be considered as adequate since it also includes papers on fluid mechanics, economy, or marketing issues. More appropriate seem to be the data obtained for the “flow-injection analysis” phrase, which, in fact, can be considered as the main stream of the development of flow analysis in recent decades. The search for this entry shows 13,649 published papers, with about 250 papers published per year in the last three years. Such statistics clearly show the large activity in all considered fields; however, it must be pointed out that the search for the “microfluidic” phrase gives 72,585 papers published since 1989, with about 7000 papers per year published in the last three years. This seems to express the most important trend in this field, showing an equal importance of the future development of both flow analysis and flow synthesis.

Conflicts of Interest

The authors declare no conflict of interest.

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