Modern Flow Analysis Printed Edition of the Special Issue Published in Molecules www.mdpi.com/journal/molecules Paweł Kościelniak Edited by Modern Flow Analysis Modern Flow Analysis Editor Paweł Ko ́ scielniak MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade • Manchester • Tokyo • Cluj • Tianjin Editor Paweł Ko ́ scielniak Jagiellonian University, Faculty of Chemistry Poland Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Molecules (ISSN 1420-3049) (available at: https://www.mdpi.com/journal/molecules/special issues/Flow Analysis). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year , Article Number , Page Range. ISBN 978-3-03936-738-2 ( H bk) ISBN 978-3-03936-739-9 (PDF) c © 2020 by the authors. 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Contents About the Editor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Paweł Ko ́ scielniak Modern Flow Analysis Reprinted from: Molecules 2020 , 25 , 2897, doi:10.3390/molecules25122897 . . . . . . . . . . . . . . 1 Marek Trojanowicz Flow Chemistry in Contemporary Chemical Sciences: A Real Variety of Its Applications Reprinted from: Molecules 2020 , 25 , 1434, doi:10.3390/molecules25061434 . . . . . . . . . . . . . . 7 Apichai Intanin, Prawpan Inpota, Threeraphat Chutimasakul, Jonggol Tantirungrotechai, Prapin Wilairat and Rattikan Chantiwas Development of a Simple Reversible-Flow Method for Preparation of Micron-Size Chitosan- Cu(II) Catalyst Particles and Their Testing of Activity Reprinted from: Molecules 2020 , 25 , 1798, doi:10.3390/molecules25081798 . . . . . . . . . . . . . . 59 Bruno J. R. Greg ́ orio, Ana Margarida Pereira, Sara R. Fernandes, Elisabete Matos, Francisco Castanheira, Agostinho A. Almeida, Ant ́ onio J. M. Fonseca, Ana Rita J. Cabrita and Marcela A. Segundo Flow-Based Dynamic Approach to Assess Bioaccessible Zinc in Dry Dog Food Samples Reprinted from: Molecules 2020 , 25 , 1333, doi:10.3390/molecules25061333 . . . . . . . . . . . . . . 73 Jixin Qiao Dynamic Flow Approaches for Automated Radiochemical Analysis in Environmental, Nuclear and Medical Applications Reprinted from: Molecules 2020 , 25 , 1462, doi:10.3390/molecules25061462 . . . . . . . . . . . . . . 85 V ́ ıctor Vicente Vilas, Sylvain Millet, Miguel Sandow, Luis Iglesias P ́ erez, Daniel Serrano-Purroy, Stefaan Van Winckel and Laura Aldave de las Heras An Automated SeaFAST ICP-DRC-MS Method for the Determination of 90 Sr in Spent Nuclear Fuel Leachates Reprinted from: Molecules 2020 , 25 , 1429, doi:10.3390/molecules25061429 . . . . . . . . . . . . . . 113 Burkhard Horstkotte and Petr Solich The Automation Technique Lab-In-Syringe: A Practical Guide Reprinted from: Molecules 2020 , 25 , 1612, doi:10.3390/molecules25071612 . . . . . . . . . . . . . . 127 Antonios Alevridis, Apostolia Tsiasioti, Constantinos K. Zacharis and Paraskevas D. Tzanavaras Fluorimetric Method for the Determination of Histidine in Random Human Urine Based on Zone Fluidics Reprinted from: Molecules 2020 , 25 , 1665, doi:10.3390/molecules25071665 . . . . . . . . . . . . . . 149 Jucineide S. Barbosa, Marieta L.C. Passos, M. das Gra ̧ cas A. Korn and M. L ́ ucia M. F. S. Saraiva Enzymatic Reactions in a Lab-on-Valve System: Cholesterol Evaluations Reprinted from: Molecules 2019 , 24 , 2890, doi:10.3390/molecules24162890 . . . . . . . . . . . . . 161 Kanokwan Kiwfo, Wasin Wongwilai, Tadao Sakai, Norio Teshima and Kate Grudpan Determination of Albumin, Glucose, and Creatinine Employing a Single Sequential Injection Lab-at-Valve with Mono-Segmented Flow System Enabling In-Line Dilution, In-Line Single- Standard Calibration, and In-Line Standard Addition Reprinted from: Molecules 2020 , 25 , 1666, doi:10.3390/molecules25071666 . . . . . . . . . . . . . . 173 v Joanna Kozak, Justyna Paluch, Marek Kozak, Marta Duracz, Marcin Wieczorek and Paweł Ko ́ scielniak Novel Approach to Automated Flow Titration for the Determination of Fe(III) Reprinted from: Molecules 2020 , 25 , 1533, doi:10.3390/molecules25071533 . . . . . . . . . . . . . . 185 Justyna Paluch, Joanna Kozak, Marcin Wieczorek, Michał Wo ́ zniakiewicz, Małgorzata Goł ą b, Ewelina P ́ ołtorak, Sławomir Kalinowski and Paweł Ko ́ scielniak Novel Approach to Sample Preconcentration by Solvent Evaporation in Flow Analysis Reprinted from: Molecules 2020 , 25 , 1886, doi:10.3390/molecules25081886 . . . . . . . . . . . . . . 197 J. Jim ́ enez-L ́ opez, E.J. Llorent-Mart ́ ınez, S. Mart ́ ınez-Soli ̃ no and A. Ruiz-Medina Automated Photochemically Induced Method for the Quantitation of the Neonicotinoid Thiacloprid in Lettuce Reprinted from: Molecules 2019 , 24 , 4089, doi:10.3390/molecules24224089 . . . . . . . . . . . . . . 211 Thitirat Mantim, Korbua Chaisiwamongkhol, Kanchana Uraisin, Peter C. Hauser, Prapin Wilairat and Duangjai Nacapricha Dual-Purpose Photometric-Conductivity Detector for Simultaneous and Sequential Measurements in Flow Analysis Reprinted from: Molecules 2020 , 25 , 2284, doi:10.3390/molecules25102284 . . . . . . . . . . . . . . 221 vi About the Editor Paweł Ko ́ scielniak was born in Krakow, Poland, in 1952. He received his Ph.D. in 1981 from the Faculty of Chemistry, Jagiellonian University in Krakow. He is a full professor (since 2000) and head of the Department of Analytical Chemistry at Jagiellonian University (since 1997). In 1993–2020, he managed the research group Team of Analytical Flow Techniques. In 2013, he received the scientific award of the Japanese Association for Flow Injection Analysis. He is a member of the Committee of Analytical Chemistry of the Polish Academy of Sciences. Prof. Ko ́ scielniak is an author, co-author and editor of more than 300 scientific articles, books and book chapters. His main areas of scientific interest are flow analysis, forensic chemistry and environmental analysis, with special attention paid to such issues as analytical calibration, the examination and elimination of interference effects, and the optimization and validation of analytical procedures. vii molecules Editorial Modern Flow Analysis Paweł Ko ́ scielniak Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland; pawel.koscielniak@uj.edu.pl; Tel.: + 48-1268-62411 Received: 22 June 2020; Accepted: 23 June 2020; Published: 24 June 2020 Abstract: A brief overview of articles published in this Special Issue of Molecules titled “Modern Flow Analysis” is provided. In addition to cross-sectional and methodological works, there are some reports on new technical and instrumental achievements. It has been shown that all these papers create a good picture of contemporary flow analysis, revealing the most current trends and problems in this branch of flow chemistry. Keywords: flow analysis; flow chemistry The idea to process an analytical sample through its flow to a measuring apparatus was one of the milestones in the development of the chemical analysis. The creator of this idea is considered Leonard T. Skeggs, Jr., who was the first to construct an analytical flow system and in 1957 presented its application in clinical analysis [ 1 ]. The motive for his action, as he wrote himself, was quite simple: “The sta ff s of laboratories of clinical chemistry are confronted with an ever-increasing number and variety of determinations”, and it is also current, maybe even more so nowadays. Therefore, it is no wonder then that flow analysis has grown over the years and has found more and more followers. Since "Skeggs times", many di ff erent flow techniques, systems and modules have been proposed, providing the possibility of analyzing many samples in a short time with increased safety of analytical work and with results of very good sensitivity and precision. These fully mechanized, automated and often miniaturized systems are increasingly using new methodologies and materials to improve the quality and speed of sample processing. The flow mode has been shown to favor various ways of manipulating sample and reagents, facilitating analytical operations such as calibration, titration or multi-component analysis. It also turned out that the hydrodynamic conditions of the flowing solutions create new possibilities for conducting and controlling chemical reactions. The latter feature of flow systems has been noticed and exploited in other chemical fields, particularly in organic chemistry. Constructed slightly later than analytical systems, the first flow systems dedicated to the synthesis of organic compounds proved to be so useful and e ff ective that, over the years, flow synthesis has acquired the established general name "flow chemistry", bypassing flow analysis. This situation makes it di ffi cult to objectively assess the current state of flow analysis and its proper role and place in the development of chemistry as applied science. Unfortunately, the aforementioned problem usually escapes the attention of flow analysts. More important and valuable is the review article written by Trojanowicz entitled “Flow Chemistry in Contemporary Chemical Sciences: A Real Variety of Its Applications” [ 2 ]. In this article, the author presents the in-depth comparative characteristics of flow analysis and flow synthesis, paying special attention to the chronology of inventions of physico-chemical operations and appropriate instrumental devices, which are widely employed in both areas of flow chemistry. It reveals many of their mutual, sometimes surprising similarities in terms of both the construction and operation of flow systems and their stages of development, primarily in the spheres of mechanization, automation and miniaturization. He proves his thesis with many literature examples (357 references!), including selected items from recent years, giving an excellent picture of contemporary, modern flow analysis and flow synthesis. Molecules 2020 , 25 , 2897; doi:10.3390 / molecules25122897 www.mdpi.com / journal / molecules 1 Molecules 2020 , 25 , 2897 He finishes his work with a very important statement: “...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”. In my opinion, the article should be a must-read for analysts interested in flow chemistry, and above all for those who are starting their scientific and didactic work in this field. A very good example of how to take advantage and practice the common features of flow chemistry is presented in [ 3 ]. The flow-based system working on the principle of segmented injection analysis (SIA), very popular and currently widely used in flow analysis, was used for synthesis of uniform micron-size CS-Cu(II) catalyst particles. It was also exploited to fast and e ff ective monitoring of the catalytic activity of the synthesized particles for the reduction of p-nitrophenol with excess borohydride. The flow-based method provided advantages over the manual method in terms of throughput for preparation of the particles (100 drops min − 1 ), size distribution of the particles (150–210 μ m) and their uniformity. Another example justifying the concept of flow chemistry are the flow-based studies of bioaccessibility of bioactive compounds from food. The bioaccessibility test provides valuable information to choose the right dose and source of food matrices and thus to ensure the nutritional e ffi ciency of food products. A valuable advantage of flow systems is the ability to quickly and precisely test the rate of absorption of compounds. Such a system was used for the implementation of dynamic extractions, aiming at the evaluation of bioaccessible zinc and the characterization of leaching kinetics in dry dog food samples [ 4 ]. This dynamic procedure was proved to be more flexible than the static traditional batch methods, allowing, in addition, the natural non-equilibrium processes to be much better imitated. Dynamic flow procedures are also the main subject of the review paper written by Qiao [ 5 ]. In this case, the author focused on the implementation of various flow techniques for the determination of radionuclides. Typical analytical challenges involved in this area include, for instance, very low radioactivity of a sample, matrix e ff ects and need to separate exactly the radioisotopes from the sample matrix. Based on the literature study author proved that the flow analysis meets all these requirements. He showed that the versatile flow approaches can be utilized in di ff erent steps for radiochemical analysis, including sample pretreatment, chemical separation and purification, as well as source preparation and detection. The flow mode makes the analysis fast, low laborious and-what is perhaps most important in this case-safe for operators because of less exposure to radioactivity. In conclusion, the author stated that “...continuous development of more advanced flow approaches is necessary to cope with the growing demands for radiochemical analysis in di ff erent fields...”. As if in response to this expectation, in [ 6 ], a commercially available fully automated flow-based device (SeaFAST) is presented that is dedicated to the determination of 90 Sr at trace levels in nuclear spent fuel leachate samples. Isotope 90 Sr is a fast released and hard to measure fission product and is of great interest due to its toxicity and high energy emission. The system, composed of an autosampler, series of syringes and a valve module, is coupled to ICP-MS combines the use of a Sr-specific resin and the reaction with oxygen as reaction gas in a dynamic reaction cell (DRC). As experimentally proved, strontium was possible to be determined in a single operational sequence of separation, pre-concentration and elution avoiding sophisticated and time-consuming procedures. In addition, the developed method was revealed to be safe, rapid, selective, and sensitive, showing a good agreement in terms of measurement uncertainties when compared with the classical radiochemical method. Syringe-based flow systems are one of the examples of very useful and e ffi cient flow devices that provides the possibility to establish di ff erent sample pathways and to assure a very stable and reproducible flow rate. Multisyringe Flow Injection Analysis (MSFIA) has been introduced in 1999 [ 7 ] and was intensively developed in the following years. In 2012 it was shown that the syringe can be used not only as a kind of pump, but also as a chamber in which the sample is fully processed before measurements [ 8 ]. From now on, this technique, called Lab-in-Syringe (LIS), is gaining more and more interest, constantly undergoing new modifications, modes of operation and technical improvements. 2 Molecules 2020 , 25 , 2897 In this context, a very needed and helpful article is work [ 9 ], aimed to bring the LIS technique closer to newcomers and users of other flow techniques. The article reviews the di ff erent options for instrumental configurations and operations possible to be performed using LIS, including syringe orientation, in-syringe stirring modes, in-syringe detection, additional inlets, and addable features. Great attention is paid to LIS applications in the field of automation of the sample pretreatment procedures, especially of extraction processes in the liquid phase. The possible contributions of 3D printing techniques to LIS are also mentioned. In addition to the unmistakable advantages of this technique, some of its limitations are discussed that arise mainly from the large dead volume of a syringe. The article as a whole is not only a very good guide to LIS, but also gives a more general picture of new conceptual, technical and instrumental tools contributing to the development of flow analysis. A common feature of di ff erent flow techniques developed in the last years is the minimization of sample volume, reagent consumption and waste production. These features are consistent with the requirements of the recently fashionable and very needed policy named “green analytical chemistry” (GAC). Its purpose is obviously to reduce the risk from analytical laboratories to the environment and human health. Flow analysis naturally favors these aspirations, although di ff erent e ff orts are still underway to improve flow techniques in this direction. An example of a GAC-oriented flow technique is the Sequential Injection Analysis (SIA) [ 10 ]. It consists of gradually introducing small segments of the sample and reagents into a separate conduit, mixing them and delivering to the detector after bringing the reaction to a certain stage. Such a technique, named zone fluidics by authors, was used for the spectrofluorimetric determination of histidine in the urine samples [ 11 ]. Before reaching the detector, the reacting sample was stopped for a time selected as a compromise between sensitivity and sampling throughput. The method allowed histidine to be determined directly with minimum sample preparation and with very good precision and accuracy. The method ensured also minimal consumption of reagents and generation of waste compared to continuous flow techniques. The “green” idea can be also implemented by completely processing a sample with a very small volume using the selection valve (Lab-on-Valve), which is an integral part of the SIA system. Such a technique ( μ SIA-LOV) was applied to the determination of cholesterol in serum samples [ 12 ], which is a widely relevant in clinical diagnosis, since higher values of cholesterol in human blood are an important risk factor for cardiovascular problems. The analytical method was based on the implementation of enzymatic reactions performed in the μ SIA-LOV system by cholesterol esterase, cholesterol oxidase and peroxidase. The results obtained were shown to be reliable and accurate, confirming the usefulness of this methodology for the routine determinations of cholesterol and for other clinical determinations. The automation and the miniaturization of the analytical procedure leads to the reproducibility improvement and the reduction of reagents. As the authors emphasize, the revealed advantages are relevant when the methodology developed is compared with other automatic methodologies used in the flow analysis. The modification of the segmented injection analysis (SIA) towards GAC may also consist of merging the sample and reagents in the form of liquid segments limited by air segments of very small volume (on the order of several or several dozen microliters}. After some time, a single segment of reaction products is formed that is of limited dispersion and undiluted by the carrier stream. An example of the successful application of this mono-segmented technique is the simultaneous determination of albumin, glucose, and creatinine (the key biomarkers for diabetes mellitus) in the urine samples [ 13 ]. Due to the flow methodology, the fast reaction (for albumin) and slow reactions (for glucose and creatinine) were appropriately synchronized. From the analytical reliability point of view, what was important was the possibility of calibrating carefully the determinations by both external and standard addition methods without the change of the system configuration. In work [ 14 ], the mono-segments were created for the titration purpose with use of three syringe pumps equipped with nine-position selection valves. During the titration process, two syringe pumps dispensed well-known decreasing and increasing volumes of the sample and titrant, respectively, 3 Molecules 2020 , 25 , 2897 which were then introduced simultaneously into the system, joined at the confluence point, and merged in the mixing coil to complete the reaction. Before and after introducing the defined volumes of sample and titrant, a segment of air was inserted using the third pump to form a monosegment. This simple and fully automated procedure, imitating traditional titration way, was used for the determination of iron(III) in the presence of iron(II), allowing one analysis to be performed for 6 min with very good precision and accuracy, and consuming as little as 2.4 mL of both sample and titrant solution. Yet another approach to GAC requirements is to develop methods of sample processing that do not require a large number or amount of reagents. One of the ways used very often for the sample preparation is the sample preconcentration coupled with the analyte isolation from the sample matrix. It has been shown that a sample can be e ff ectively preconcentrated in the mechanized sequential injection system on the basis of the membraneless evaporation [ 15 ]. The main element of the system was the preconcentration module working under high temperature and diminished pressure. Using di ff erent evaporation conditions, various values of the signal enhancement factor (from several to 20) could be achieved. The applicability of the method was positively verified on the example of the determination of Zn in certified reference materials of drinking water and wastewater using the capillary electrophoresis method. The purpose of sample preconcentration is to enhancement the analytical signal, which consequently gives the opportunity to determine the analyte with increased precision and diminished limit of quantification. The signal enhancement can be performed by various ways. A very interesting way has been displayed with the use of the simple flow manifold equipped with multicommutated solenoid valves and a spectrofluorimetric detector [ 16 ]. The analyte was online irradiated with UV light to produce a highly fluorescent photoproduct that was then retained on a solid support placed in the detector flow cell. By doing so, the pre-concentration e ff ect of the photoproduct was achieved in the detection area, increasing the sensitivity. The method was demonstrated on the example of the determination of insecticide thiacloprid, one of the main neonicotinoids, in lettuce samples. The analytical results were characterized with very good precision and accuracy, and a low detection limit of 0.24 mg kg − 1 One more modification of the flow manifold that aimed to improve the detection capability is shown in [ 17 ]. This work presents a dual detector that consisted of a paired emitter–detector diode (PEDD) and a capacitively coupled contactless conductivity detector (C4D) for flow-based photometric and conductivity measurements, respectively. They have been incorporated in a single flow cell of an original design. In di ff erent flow configurations, the system was able to be adapted to either sequential or simultaneous determination of two analytes in a sample. In particular, the urine samples were analyzed in regard to the conductivity and creatinine concentration for monitoring the health problems in the human body. It is seen that the articles included in this Special Issue of Molecules titled ”Modern Flow Analysis” very well reflect the current state of flow analysis, which to a large extent is also a picture of modern flow chemistry. At the same time, these works give a picture of extraordinary ingenuity and creativity in solving problems and creating new, more and more perfect analytical approaches. Once again, it turns out that flow analysis is the area of analytical chemistry, in which imagination and scientific courage play a great role. One should hope that this is a guarantee of its further development in the future. Funding: This research received no external funding. Conflicts of Interest: The author declare no conflict of interest. References 1. Skeggs, L.T., Jr. An automatic method for colorimetric analysis. Am. J. Clin. Path. 1957 , 28 , 311–322. [CrossRef] [PubMed] 2. Trojanowicz, M. Flow chemistry in contemporary chemical sciences: A real variety of its applications. Molecules 2020 , 25 , 1434. [CrossRef] [PubMed] 4 Molecules 2020 , 25 , 2897 3. Intanin, A.; Inpota, P.; Chutimasakul, T.; Tantirungrotechai, J.; Wilairat, P.; Chantiwas, R. Development of a simple reversible-flow method for preparation of micron-size chitosan-Cu(II) catalyst particles and their testing of activity. Molecules 2020 , 25 , 1798. [CrossRef] [PubMed] 4. Greg ó rio, B.J.R.; Pereira, A.M.; Fernandes, S.R.; Matos, E.; Castanheira, F.; Almeida, A.A.; Fonseca, A.J.M.; Cabrita, A.R.J.; Segundo, M.A. Flow-based dynamic approach to assess bioaccessible zinc in dry dog food samples. Molecules 2020 , 25 , 1333. [CrossRef] [PubMed] 5. Qiao, J. Dynamic flow approaches for automated radiochemical analysis in environmental, nuclear and medical applications. Molecules 2020 , 25 , 1462. [CrossRef] [PubMed] 6. Vilas, V.V.; Millet, S.; Sandow, M.; P é rez, L.I.; Serrano-Purroy, D.; Van Winckel, S.; Aldave de las Heras, L. An automated SeaFAST ICP-DRC-MS method for the determination of 90 Sr in spent nuclear fuel leachates. Molecules 2020 , 25 , 1429. [CrossRef] [PubMed] 7. Cerd à , V.; Estela, J.M.; Forteza, R.; Cladera, A.; Becerra, E.; Altimira, P.; Sitjar, P. Flow techniques in water analysis. Talanta 1999 , 50 , 695–705. [CrossRef] 8. Maya, F.; Estela, J.M.; Cerd à , V. Completely automated in-syringe dispersive liquid-liquid microextraction using solvents lighter than water. Anal. Bioanal. Chem. 2012 , 402 , 1383–1388. [CrossRef] [PubMed] 9. Horstkotte, B.; Solich, P. The automation technique Lab-in-Syringe: A practical guide. Molecules 2020 , 25 , 1612. [CrossRef] [PubMed] 10. R ̊ užiˇ cka, J.; Marshall, G. Sequential injection: A new concept for chemical sensors, process analysis and laboratory assays. Anal. Chim. Acta 1990 , 237 , 329–343. [CrossRef] 11. Alevridis, A.; Tsiasioti, A.; Zacharis, C.K.; Tzanavaras, P.D. Fluorimetric method for the determination of histidine in random human urine based on zone fluidics. Molecules 2020 , 25 , 1665. [CrossRef] [PubMed] 12. Barbosa, J.S.; Passos, M.L.C.; Korn, M.A.; Saraiva, M. Enzymatic reactions in a Lab-on-Valve system: Cholesterol evaluations. Molecules 2020 , 25 , 2890. [CrossRef] [PubMed] 13. Kiwfo, K.; Wongwilai, W.; Sakai, T.; Teshima, N.; Grudpan, K. Determination of albumin, glucose, and creatinine employing a single sequential injection Lab-at-Valve with mono-segmented flow system enabling in-line dilution, in-line single-standard calibration, and in-line standard addition. Molecules 2020 , 25 , 1666. [CrossRef] [PubMed] 14. Kozak, J.; Paluch, J.; Kozak, M.; Duracz, M.; Wieczorek, M.; Ko ́ scielniak, P. Novel approach to automated flow titration for the determination of Fe(III). Molecules 2020 , 25 , 1533. [CrossRef] [PubMed] 15. Paluch, J.; Kozak, J.; Wieczorek, M.; Wo ́ zniakiewicz, M.; Goł ̨ ab, M.; P ó łtorak, E.; Kalinowski, S.; Ko ́ scielniak, P. Novel approach to sample preconcentration by solvent evaporation in flow analysis. Molecules 2020 , 25 , 1886. [CrossRef] [PubMed] 16. Jim é nez-L ó pez, J.; Llorent-Mart í nez, E.J.; Mart í nez-Soliño, S.; Ruiz-Medina, A. Automated photochemically induced method for the quantitation of the neonicotinoid thiacloprid in lettuce. Molecules 2020 , 25 , 4089. [CrossRef] [PubMed] 17. Mantim, T.; Chaisiwamongkhol, K.; Uraisin, K.; Hauser, P.C.; Wilairat, P.; Nacapricha, D. Dual-purpose photometric-conductivity detector for simultaneous and sequential measurements in flow analysis. Molecules 2020 , 25 , 2284. [CrossRef] [PubMed] © 2020 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http: // creativecommons.org / licenses / by / 4.0 / ). 5 molecules Review Flow Chemistry in Contemporary Chemical Sciences: A Real Variety of Its Applications Marek Trojanowicz 1,2 1 Laboratory of Nuclear Analytical Methods, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03–195 Warsaw, Poland; trojan@chem.uw.edu.pl 2 Department of Chemistry, University of Warsaw, Pasteura 1, 02–093 Warsaw, Poland Academic Editor: Pawel Ko ́ scielniak Received: 17 February 2020; Accepted: 16 March 2020; Published: 21 March 2020 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 e ffi cient 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. Keywords: flow analysis; flow synthesis; flow reactors; flow-injection analysis 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 di ff erent 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 e ffi ciency of di ff erent 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 Molecules 2020 , 25 , 1434; doi:10.3390 / molecules25061434 www.mdpi.com / journal / molecules 7 Molecules 2020 , 25 , 1434 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 di ff erent 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 di ff erent 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 di ff erent detection techniques can be carried out with various operations of on-line sample 8 Molecules 2020 , 25 , 1434 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 μ L) 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 – 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