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?'$ Review Article: Spectroscopic microreactors for heterogeneous catalysis Benjamin A. Rizkin,a) Filip G. Popovic,a) and Ryan L. Hartmanb) Department of Chemical and Biomolecular Engineering, New York University, 6 MetroTech Center, Brooklyn, New York 11201 (Received 3 May 2019; accepted 8 July 2019; published 5 August 2019) Microfluidic reactors with in situ spectroscopy have enabled many new directions of research over the last two decades. The miniature nature of these systems enables several key advantages in heterogeneous catalysis, which includes the reaction surface or interface accessible to spectroscopic equipment making the discovery of new catalytic materials possible. Devices fabricated with materials that are transparent to electromagnetic radiation enable in situ and in operando spectroscopy such as Raman, UV-Vis, and IR directly at the point of the reaction, and thus high fidelity, transient information on the reaction chemistry is available. Innovative designs with NMR, electrochemical impedance spectroscopy, x-ray techniques, or terahertz imaging have also advanced the field of heterogeneous catalysis. These methods have been successfully engineered to make major breakthroughs in the design of catalytic materials for important classes of chemical reactions. In this review, the authors provide an overview of recent advances in the design of microreactors with in situ spectroscopy for the study of heterogeneous catalysis to raise awareness among the vacuum science community on techniques, tools, existing challenges, and emerging trends and opportunities. © 2019 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/ licenses/by/4.0/). https://doi.org/10.1116/1.5108901

I. INTRODUCTION perspective1 and review2 succinctly details the state of the In the last two decades, microchemical systems have art of microreaction technology. These works explore proven indispensable to many fields of research ranging from opportunities for a move towards incorporating automation fl fl catalysis to cellular biology. There are many advantages to and self-optimization in continuous ow micro uidics for fi miniaturization of experiments such as the prevalence of enabling new reaction and separation technologies in ne surface forces over body forces, enabling researchers to chemical and pharmaceutical manufacturing. Related fl fl exploit physical phenomena to enhance heat and mass trans- reviews on the use of ow in chemistry and micro uidics can be found covering specific topics such as photochemi- port in their systems, along with having a highly controlled, 3,4 5 fi cal reactions, cascade reactions, functional material syn- reproducible, and quanti able environment. These microde- 6 7 vices also have the benefit of creating much less chemical thesis, and nanomaterials, as well as more general fl fl 8 waste or exposure to hazardous/toxic compounds at aggres- micro uidic ow chemistry related reviews. Inline spec- sive conditions, since reactions are performed with microliter troscopic integration schemes with microreactors and new developments implementing this approach are not specifi- instead of milliliter to liter volumes. This has the added 3–8 benefit of being able to sample a wider experimental range cally addressed in these works. However, other reviews regarding microfluidics and technique-specificinlineinte- given the same amount of time and resources. Perhaps most 9 critically, however, miniaturization allows for novel ways to gration approaches have been published. The trend toward miniaturization in analytical chemistry analyze chemical reactions and processes in situ and in oper- 10 ando, giving scientists and engineers a broader picture of is comprehensively reviewed by Ríos and Zougagh, and physics and chemistry. the more niche topic on miniaturized total chemical-analysis systems has been addressed in an extensive review by Guijt Perhaps one area that is uniquely well suited for the 11 application of microreactors is automation and high- and Manz. Reviews relating Raman spectroscopy to micro- fl 12–14 fl throughput screening. Due to the highly-quantifiable nature uidics have also been discussed. For a nonmicro uidic treatment on catalytic processes in aqueous environments of these reactors combined with precision sensors, low res- 15 idence volumes, and isothermal operation, it becomes pos- and their in situ monitoring, see Shi et al. There has also sible to control these systems with extreme precision and been a review published on heterogeneous electrocatalysis very quickly. This new area of research and application has by Kalz et al. who covered aspects of catalyst design ranging from critical length scales to different methods of catalyst shown promise in the research and discovery of new 16 physics and materials in broad fields such as macromolecu- and reaction characterization. fi lar science and electrochemistry. An outstanding recent A sizeable number of signi cant contributions cover the basic principles of the operando methodology.17–19 This methodology aims to uncover both structure and activity a)B. A. Rizkin and F. G. Popovic contributed equally to this work. information to better understand the relationship of the two by b)Electronic mail: [email protected] concurrently evaluating catalyst performance and surface

050801-1 J. Vac. Sci. Technol. A 37(5), Sep/Oct 2019 0734-2101/2019/37(5)/050801/22 © Author(s) 2019. 050801-1 050801-2 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-2 interactions during catalytic processes under technically rele- The scope of the present review is not intended to be an vant reaction conditions.20 For appropriate implementation of exhaustive examination of the literature but instead is meant the methodology, it is important to characterize multiple to be an update from 2013 onward of the major trends in the phases in a space- and time-resolved multitechnique fashion field of microreactors integrated with in situ spectroscopy for and understand the relations of phenomena at multiple the study of heterogeneous catalysis. For the state-of-the-art scales.21 There are reviews that cover the use of in situ or prior to 2013, you may find the excellent review by operando methodologies for specific reaction systems, such as Yue et al.32 instructive. Outstanding reviews on microfluidic the review by Rodriguez et al.22 on water-gas shift reaction synthesis of nanomaterials, including catalysts, can also be on metal oxide catalysts and Newton’s23 on time-resolved found by Marre and Jensen33 and by Song et al.34 Another operando x-ray techniques for the study of CO oxidation over primary objective of the present review is to raise awareness platinum. For a more general review of x-ray spectroscopy for amongst the vacuum science community on techniques, heterogeneous catalysis, see the work of Frenkel and van tools, emerging trends, and existing challenges within the Bokhoven.24 Unified multistep continuous flow platforms field of heterogeneous catalysis for the retrieval of high fidel- have found the use of different types of microfluidic and spec- ity transient catalytic information. Our review includes con- troscopic pairings as essential for their operation, whether it cepts on the design of microreactors and their integration be the utilization of in-line or in situ analysis techniques.25 with in situ spectroscopic techniques for those interested in A recent review by Al-Rifai et al.26 provides a perspective learning more about the field or applying the techniques in on how to use microreaction technology to help facilitate cat- their own investigations. alytic process development. From a kinetic-experimentation standpoint, the authors address how the expanded reaction space provided by microfluidic technology allows exploring II. DESIGN kinetics of novel processes windows, applications that suc- There are many design considerations to take into account cessfully extracted intrinsic kinetics and the challenges asso- when planning a new microchemical system for in situ ciated with this approach. Most importantly, for the purpose spectroscopic applications, including the flow regime, of this review, they provide what a microreactor requires for chemical compatibility, heat transfer, and transparency to appropriate integration with an analytical technique for in electromagnetic (EM) waves. By selecting the right material situ operation. Broadly speaking, the requirements are (i) suf- and tuning properties of the system, it becomes possible to ficient understanding of the flow behavior in the system that optimize the system for a given chemistry and spectroscopic allows for the accurate determination of the intrinsic reaction technique used. It is important to consider the critical kinetics, (ii) having the capability to dissipate the heat gener- length scales of the phenomena being analyzed, as well as ated by the electromagnetic beam of the chosen analytical the time scales and material transparency. These consider- technique and thus keep isothermal conditions, and (iii) dis- ations are shown in Fig. 1. An important fact to highlight in 27 allow any reaction fluid circumventing the catalysts. Fig. 1(a) is that reactor transport of species in traditional Another review paper which was published in recent years reactors is among the longest transport processes. This can emphasizes the potential of continuous multistep synthesis be a major hindrance, for example, when trying to extract and challenges of using integrated flow processing within the the inherent kinetics of a reaction. For this reason, it is 28 context of organic chemistry synthesis. The review paper favorable to make use of turbulent flow in the large-scale or highlights modularity as the most prominent virtue of these microfluidics in the laboratory, which reduces the character- systems and delineates novel concepts and challenges of the istic length scale (thus time scale) of transport processes by adoption of these systems within the organic chemists’ com- orders of magnitude. munity. A unique section on the importance of education on the capabilities of microfluidic flow systems is featured. fl The aforementioned reviews reflect the interdisciplinary A. Micro uidic phase behavior and multidisciplinary nature of research in heterogeneous The first main design consideration with a microfluidic catalysis. There exists a growing sense of the eclectic nature system is what phases will be present and what flow regimes of the field as marked by the high altitude conceptual review are desirable. There are a number of outstanding reviews on by Schlögl29 on heterogeneous catalysis. Another notable per- microfluidic mixing and multiphase flows.35–38 In the past, spective focuses on elucidating what criterion would help with microreactor systems have been fabricated to exploit laminar,39 unifying the principles of individual domains and subdomains tangential,40 multiphase,41 sheath,42 and many other types of of catalysis research.30 The connecting theme of these reviews flow. A summary of the conditions under which many of these is the acknowledgment that the goal of approaching catalysis flow types can be encountered is seen in Fig. 2. These dif- research is not to catalog individual relationships within the ferent flow regimes offer unique benefits with chemical reac- disciplines segregated due to practical necessity, but rather, tions at interfaces or mixing of different species, thereby delving into the nature of the active-site from an electronic enhancing mass transfer coefficients. Due to the small standpoint. However, this is not without its challenges and the dimensions and resulting influence of surface forces over perspective by Bligaard et al.31 offers, in addition to the previ- body forces, microfluidic systems also enable new para- ous reviews, an account on how the field can progress to more digms in mixing, allowing for quick and rapid mixing of standardized benchmarking. species. Different passive micromixer designs include T

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FIG. 1. (a) Typical length and time scales for physical and chemical phenomena present in a heterogeneous catalytic reactor, with the x-axis indicating the characteristic length scale and the y-axis indicating the characteristic time scale. Reprinted with permission from R. Schlögl, Angew. Chem. Int. Ed. 54, 3465 (2015). Copyright 2015, Wiley. It should be noted that reactor transport considerations are a major factor and microreactors can be used to mitigate this issue. (b) Left: spectroscopic techniques used in heterogeneous catalysis listed by their spatial resolution; Right: common spectroscopic FIG. 2. (a) Different multiphase flow regimes possible in microfluidics systems fi techniques listed by temporal resolution. Reprinted with permission from by varying the super cial liquid ( jL)andgas(jG) velocities. Adapted with per- Portela et al., Front. Chem. Sci. Eng. 12, 509 (2018). Copyright 2018, mission from Günther and Jensen, Lab Chip 6, 1487 (2006). Copyright 2006, Springer Nature. (c) Light spectrum transparency of various common The Royal Society of Chemistry. Datum from figure can be found at Refs. 41 materials used in microreactor fabrication. Reprinted with permission from and 43–45 outlining the different flow regimes. (b) A summary of governing Perro et al., React. Chem. Eng. 1, 577 (2016). Copyright 2016, The Royal forces with respect to the velocity and channel size. The area outlined with a Society of Chemistry. dashed line corresponds to conditions commonly encountered in microfluidics. Reproduced with permission from Günther and Jensen, Lab Chip 6, 1487 (2006). Copyright 2006, The Royal Society of Chemistry. (c) Select examples of multiphase flow in a microfluidic system with the top showing dispersed bubbly or Y shaped devices, sequential lamination, flow focusing, flow, the middle showing droplets or slug flow, and the bottom depicting an chaotic advection, or multiphase segmented flows, while elongated slug flow. Reproduced with permission from Pinho et al.,LabChip examples of active micromixers include pressure field dis- 14, 3843 (2014). Copyright 2014, The Royal Society of Chemistry (Ref. 46). turbance, electrokinetic, dielectrophoretic, electrowetting, and ultrasound devices.47 All these different geometries electrowetting device may not be suitable for a reactor offer unique benefits and challenges, for example, a using in situ electrochemical impedance spectroscopy (EIS). T-shaped micromixer may be a poor solution for mixing Overall, the selection of channel and micromixer geometry single-phase reagents with varying viscosities, while an relies heavily on the chemistry and analytical methods being

JVST A - Vacuum, Surfaces, and Films 050801-4 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-4 used, with numerous well-established solutions to choose C. Fabrication methods from Refs. 35–38. It should be noted that depending on Fabrication methods of microreactor systems for use in the system, other phenomena may affect the interplay of catalysis research is quite a broad topic. In one extreme, there constituents at the interface of heterogeneous systems. For exist steel and silicon microreactors capable of withstanding an account of such phenomena at solid-liquid interfaces, 1,59–61 refer to Sievers et al.48 Zhang et al.49 provide a more elevated temperatures and pressures. In the other, there detailed report on the hydrodynamics of g/l/s systems in are 3D printed or polymer cast microreactors which can be fi 62–64 micropacked-bed reactors. made quickly and ef ciently that are less resistant to aggressive conditions. Different techniques for the fabrication of microreactors can be seen in Fig. 3. Possible fabrication B. Theoretical considerations methods to choose from can include wet etching (isotropic and 66 67,68 An important design consideration for microreactors anisotropic), plasma etching, Computer Numerical with in situ spectroscopy involves the analysis and optimi- Control (CNC) machining, laser ablation machining, injection 69 zation of various physical properties of the microsystem. molding, soft lithography, fused deposition modeling, stereo- 70 The choice of these parameters is highly dependent on the lithography, and even paper-based methods. For a more system being studied and the physics at hand. Basic analy- broad review covering nanofabrication technologies, please sis could include calculation of the appropriate dimension- refer to Ref. 71. Common substrate materials include silicon, less quantities that govern the system. For the convenience glass, metals, various polymers (including ones transparent to of the reader, typical magnitudes of Reynolds (Re), Bond UV or IR wavelengths and highly chemical resistant fluoropol- (Bo), Weber (We), and Capillary (Ca) numbers in micro- ymers), resins, and even advanced composites. The main crite- reactors are given by ria for selecting a material and fabrication method are compatibility with the chemistry, transparency to the chosen inertial dUρ spectroscopic method, and availability of fabrication facili- Re ¼ ¼ 101 102, (1) viscous μ ties. Until recently, it has not been possible to fabricate compelling microdevices outside of a cleanroom, but recent gravity Δρd2g perfusion of CNC machines and 3D printers has made fabri- Bo ¼ ¼ 102, (2) interfacial σ cation more widely accessible, yet with challenges related to chemical compatibility and operation at elevated temperatures inertial ρU2d and pressures. Overall, there are many choices available for We ¼ ¼ 108, (3) interfacial σ microreactor materials and fabrication methods, with systems being developed for all major types of spectroscopy. viscous μU The next consideration in microreactor design for in situ Ca ¼ ¼ 104: (4) interfacial σ spectroscopy is designing a device, which has the right properties for the spectroscopic method being used. This could Individually, each of these numbers physically represents mean for optical methods that the reactor be transparent to the ratio between critical driving forces. For example, the the used wavelength, for x-ray systems that the reactor fit Reynolds number represents the ratio between inertial to into the space constraints of the instrument or that the viscous forces which dominate within the fluid and as such surface be modified to enhance the certain physical proper- can be used to predict flow turbulence. These numbers have ties. Traditional lab-on-a-chip platforms have been made by a significant impact on the phase behavior, as can be seen by using cleanroom fabrication techniques and bonding an Si the superficial velocities of Fig. 2(a). The fluid flow can be wafer to either Si or a glass (e.g., borosilicate), which offers manipulated just by controlling the magnitude of these good chemical compatibility and a wide range of possible parameters, which depends on the characteristic length, often temperatures and pressures. It has been shown that such the channel size or cross section [Fig. 2(b)]. Dimensionless microreactors are particularly well suited for the implementa- quantities for heat transfer and mass transfer are equally tion of spectroscopic techniques, e.g., as demonstrated by important, and a number of textbooks on chemical reaction Beuvier et al.72 Cheaper and faster fabrication methods of engineering are excellent references.50,51 such materials could broaden the participation of scientists in Computational fluid dynamics can help guide the design the field. As an example, sapphire is an excellent material for of any microreactor. Building the desired geometry one can the study of chemical reactions with in situ spectroscopy, yet study many parameters of interest such as the flow profile, it is difficult to process. Also, the use of polydimethylsilox- temperature gradients, frequency responses, or dimensionless ane (PDMS) and soft lithography has been a major trend, quantities using COMSOL, FEMLAB, FLUENT, FEMLAB, CFD-ACE+, especially in biological applications, due to its simplicity and or packages from Autodesk or other vendors. Additional sim- quick reproducibility, but is not ideal when it comes to ulations may be carried out as relevant to the system being chemical compatibility.73 Unique geometries are also studied, including physical modeling for the spectroscopic enabled by 3D printing, which can create structures not pos- technique chosen.52–58 Whatever the software package, per- sible with other methods and in much less time74 but with forming CFD calculations can save time during fabrication lower resolution compared to conventional micro- and nano- by identifying any limitations early on. fabrication methods. The use of 3D printing enables reactors

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surface-enhanced Raman spectroscopy (SERS) or resonance to enhance the signal from the chosen spectroscopic technique. The study of these metamaterials in a field of study in its own regard and a thorough discussion can be found from Salim and Lim.75 Overall, the selection of materials for a microreactor system is innately tied to the desired operating chemistry, pressure, temperature, and physical properties required by the spectroscopic technique. Despite the relative standardization of major fabrication techniques, there have been some interesting recent developments which show the potential of novel composite materials. One of these novel architectures is a photocatalytic reactor where the catalyst is imbedded directly in the walls of the reactor. Colmenares et al. used ultrasound to drive TiO2 nanoparticles (NPs) into the inner walls of a fluoropolymeric microtube. The resulting device was efficient at removing phenol from water and demonstrated the viability of hybrid polymer/nanoparticle reactors.76 Note, however, that fluoro- polymer capillaries can vary widely in their size due to current manufacturing methods, and many are permeable to certain gases.77 Several groups were also able to use fluori- nated polymers to 3D print or modify reactors, an exciting development for rapidly produced and chemically resistant microsystems.78–81 Another interesting study used a piezoelec- tric layer built onto a silicon/AlN chip. These in-line piezo- electrics enabled local heating, mixing, and viscosity sensing of individual droplets on a chip. The system was extensively ® modeled in COMSOL MULTIPHYSICS and was subsequently validated by performing a Diels–Alder reaction (see Fig. 4).82 Another example of a novel fabrication method includes the work of Pushpavanam et al. who used plasmonic nanoparticles with a biotemplating approach. Their work satu- rated the vascular structure of leaf with metal precursors, which enabled functionalization for catalytic activity as well as a range of spectroscopic techniques including absorption spectroscopy, SEM, TEM, electron diffraction, and FTIR.83 Another interesting novel contribution comes from Moschetta et al.,84 which incorporated a composite FIG. 3. Different techniques for the fabrication of microfluidic reactors. (a) General methodology for hot embossing, injection molding, and soft lithogra- polymer/oxide hollow fiber into their flow reactor as a con- phy of plastic materials. Reproduced with permission from Gale et al., tactor and was able to embed a catalyst structure into it. As Inventions 3, 60 (2018). Copyright 2018, Author(s), licensed under the such, this served a dual purpose of facilitating the chemical Creative Commons Attribution License (CC BY 4.0). (b) General process flow diagram for a cleanroom fabrication procedure featuring the operations of spin reaction as a catalyst/support material and as a membrane coating, photoresist exposure and development, etching metal deposition and to allow product separation. A final interesting example of bonding. Reproduced with permission from Cao et al., Processes 2, 141 a novel fabrication method was employed by Hoera et al. (2014). Copyright 2014, Author(s), licensed under the Creative Commons who used a luminescent temperature sensor combined with Attribution License (CC BY 3.0) (Ref. 65). (c) shows a precision microCNC machine made by Kugler precision. (d) is a rendering of the Fluidic Factory inkjet-printed microheating elements. The resultant device 3D microdevice printer made by Dolomite Microfluidics. (c) and (d) figures proved successful in the study of temperature-controlled reused under fair use from their respective manufacturer. continuous microfluidic reactions.85 Overall, the use of novel fabrication methods for microfluidic systems is an made of a variety of materials, including plastics, metals, and interesting development with promise of more highly inte- glass. Another consideration for the material choice relies on grated and capable platforms for understanding complex the surface chemistry of the material. For different applica- reactions under varying conditions. tions, it may be necessary to use either hydrophilic or hydrophobic materials. In many cases, these surfaces can be modified either chemically or physically (such as nanopillar D. Device packaging techniques arrays) to facilitate the desired fluidic contact angles. A final The final aspect of microreactor operation and integration consideration for material selection is if the material is into a system involves bonding the reactor and packaging it required to exhibit any kind of physical properties like into a platform which can be integrated with pumping and

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has been performed on using UV-activated compounds such as SU-8 (originally developed as a photoresist) both as a template for the device itself and as a high-strength bonding agent, enabling highly complex geometries to be con- structed.90 Overall, the choice of bonding method is highly dependent on the chosen construction of the reactor and is chosen based on the materials and chemistry involved. Finally, the device needs to be integrated with the fluidic handling aspect of the experiment. This is usually performed either through a compression chuck or through bonding fluid inlets to the reactor with epoxy. Figure 5 provides multiple perspectives on the packaging of the microfluidic device. For most high-pressure applications, a compression chuck is used where the reactor is sandwiched between two metal (or high-density plastic) plates and secured with bolts. By placing chemically compatible O-rings in properly-sized cav- ities under the reactor and compressing with a predicted force, a hermetic seal is created. Also, for lower pressure devices, a Luer Lock connection or tube can be epoxied directly to the reactor. There has also been work on soldering connections directly to microfluidic chips; however, this technique has not been widely adopted, reinforcing the prevalence of compression fittings for high-pressure systems.96 Overall, there are a plethora of bonding and packaging solutions which have been successfully implemented in a variety of microfluidic studies. An overview of packaging methodologies and consideration can be found from Lake et al.97 and Gale et al.98 with recent developments for high-throughput systems being highlighted by Refs. 87 and 99. For the packaging of high-pressure and high temperature systems, please refer to Ref. 61. The issue of interfacing the macro to the micro is addressed by Fredrickson and Fan.100

FIG. 4. (a) Schematic representation of the experimental setup showing the fluidic and electrical connections, thermal control system, and mounting III. SPECTROSCOPIC METHODS device. (b) Cartoon representation of the chip architecture showing different A. Optical spectroscopy deposited device layers. (c) SEM view of the MEMS resonator module. (d) Changes of motional resonance with time while performing a Diels–Alder 1. Raman spectroscopy reaction in a microfluidic system equipped with microelectrochemical resonators. All figures were reprinted with permission from Qu et al., Sens. Raman spectroscopy is one of the most versatile spectro- Actuators B 248, 280 (2017). Copyright 2017, APS Publishing. scopic techniques in the developing field of microreactors with in situ spectroscopy. The technique relies upon the phenomena of inelastic scattering of monochromatic light spectroscopic instruments. Numerous microreactor packaging [typically the source being lasers ranging from the near- methodologies are available and applied in research, with the infrared (NIR) to near ultraviolet range].101,102 It has found choice depending mostly on the materials of construction. a wide range of applications such as in the characterization With typical silicon and glass microreactors, usually anodic of materials in solid state physics103,104 (e.g., vibrational bonding is used to seal the glass to the silicon. This is modes of crystalline structures), identifying compounds in accomplished by placing the glass under a negative potential the forensic sciences105–107 and tissue imaging in the (cathode) and silicon under a positive potential (cathode) biology and medicine.108–110 under elevated temperatures. This causes the surfaces of The weak signal intensity is due to the low frequency of silicon and glass to become physically bonded to each other, Raman scattering events, modifications of the technique ideal for high-pressure use. Anodic bonding can also be used have been developed to compensate, such as SERS,111,112 between metals and glasses as long as the coefficient of surface-enhanced resonance Raman spectroscopy,105,113 thermal expansion is matched.86 Another common bonding coherent anti-stokes Raman spectroscopy,114,115 stimulated method involves creating a chemical bond between the top Raman scattering, and tip-enhanced Raman spectro- and bottom surfaces. This is accomplished through either the scopy.116,117 For a more detailed account of the evolution of use of chemical glues, epoxies, or activating surface groups Raman spectroscopy/microscopy, refer to Hazle et al.,118 and through a process such as plasma treatment.87–89 The work its integration with microfluidics, see Chrimes et al.14

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FIG. 5. (a) Schematic representation of a high-pressure microreactor system and chuck where (1) shows the bottom half of the chuck, (2) O-rings, (3) silicon microreactor, (4) top half of the chuck with fluidic connections, and (5) screws. (b) An example of a microfluidic chip with integrated HPLC column for integration with a mass spectrometer, (1) shows a macroview of the chip and (2) shows a zoomed in version. Reprinted with permission from Warias et al., ChemCatChem 10, 5382 (2018). Copyright 2018, Wiley (Ref. 91). (c) Photograph of a novel high-pressure OSTEMER microfluidic chip with embedded capillaries for fluid delivery. Reprinted with permission from Martin et al., Microfluid. Nanofluidics 20, 1 (2016). Copyright 2016, Springer Nature (Ref. 92). (d) Example of a laser welded fused silica capillary for fluid delivery. Adapted with permission from Lotter et al., Anal. Chem. 88, 7481 (2016). Copyright 2016, American Chemical Society (Ref. 93). (e) A compression chuck with an integrated heat exchanger for a packed-bed microreactor. Reprinted with permission from Hu et al., Lab Chip 14, 2014 (2014) (Ref. 94). Copyright 2014, The Royal Society of Chemistry. (f) Scheme of a high-pressure microsystem assembly similar that of (a) with an additional peltier module and heat sink for fine temperature control. Reprinted with permission from Chen et al., Lab Chip 17, 3051 (2017). Copyright 2017, The Royal Society of Chemistry (Ref. 95). (g) Photograph of microsystem assembly pictured in (f).

Surface-enhanced Raman spectroscopy has found wide- Coupling microfluidics with in situ Raman spectroscopy spread application across multiple fields, especially in the has proven to be advantageous, whether in its conventional biomedical field. This is partially due to the fact that the form or as SERS. The superior heat transfer characteristics signal enchantment has been reported to be as high as 108 compared to conventional systems reduces error in the for well optimized systems,119 by modifying the sample detection of Raman scattering which may arise due to the instead of the spectroscopic hardware. There are limita- generation of hot spots from the electromagnetic beam.124 tions, as the target analyte has to be in the vicinity of the Additionally, there are a variety of material options for the plasmonic surface and at the appropriate orientation.120 microfluidic devices that are transparent to the optical wave- Microfluidic devices may assist in this phenomenon by length of the Raman laser.125 being designed in ways that guide the flow of analytes to Since 2013, there have been a multitude of new studies inte- theplasmonicmetalsurface.121 There exist many excellent grating this analytical technique with microfluidic devices. For reviews regarding SERS, which cover its principles and the in situ analysis of heterogeneous catalysis systems, Raman application.122,123 spectroscopy offers its unique versatility to provide useful

JVST A - Vacuum, Surfaces, and Films 050801-8 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-8 information for multiple phases and resultant existing inter- prepared by sol-immobilization was Pd > AuPd > AuPdPt > faces. The following developments found in the literature high- (Au, Pt, and AuPt). The same catalysts prepared by a standard light this potential of Raman for a gas/solid and gas/liquid/ impregnation method displayed the same activity sequence solid system, respectively. The micro-view-cell developed by (albeit less active). With these results, the developed platform Reymond and Rudolf von Rohr126 provides an interesting proved suitable for interrogating catalyst reaction characteris- example of exploiting Raman techniques for examining the tics in a gas/liquid/solid system. An in situ/operando Raman interface of gas and solid phases for catalysis applications, as study was conducted by Engeldinger et al.128 on a gas/liquid/ well as the phases individually, for a heterogeneously catalyzed solid system involving mixed molybdate catalysts for an CO2 hydrogenation reaction. The data extracted by the Raman ammoxidation reaction. They were able to distinguish signal provided information about the surface state of the between various changes in the Raman band of the tested II working catalyst, but information was also provided on stream M MoO4 phase positions during ammoxidation cycles and composition and phase transitions of a commercial Cu/ZnO/ the creation and stabilization of definite FeII/FeIII redox states Al2O3 catalyst. Having a comprehensive overview of the in this complicated reaction mechanism. behavior of the phases in the system provided a substantive Other laboratories have attempted to take advantage of insight into its effect on reaction performance. the multifunctional nature that plasmonic metals offer when Another laboratory designed a micropacked-bed multireac- evaluating heterogeneous catalysis systems with Raman tor system with in situ Raman spectroscopy to evaluate the techniques. For example, Zhang et al.120 used immobilized stability and activity trends of catalysts, using benzyl alcohol gold nanoparticles on a “plug in” probe to simultaneously oxidation as a model gas/liquid/solid reaction (see Fig. 6).127 utilize their Raman signal enhancement properties as well as The catalysts examined comprised of 14 different combina- their catalytic properties. This resolves the problem gener- tions of Au, Pd, and Pt supported on TiO2. The group was ated by flowing a colloidal solution of nanoparticles (i.e., able to determine that the activity sequence for catalysts memory effect due to nanoparticle adsorption) when trying to reuse the microfluidic device and optimizing the amount of nanoparticles used.

2. Ultraviolet-visible spectroscopy Ultraviolet-visible (UV/Vis) spectroscopy is a type of absorptive or reflectance spectroscopy that involves the ultraviolet-visible part of the electromagnetic spectrum. Electrons undergo electronic transition when interacting with photons that correspond to this wavelength. Specifically, bonding and nonbonding electrons can absorb the energy of these photons to transition to higher antibonding orbitals. UV/Vis spectroscopy is routinely used in all types of laboratories for tasks as diverse as measuring protein activity to estimating the size of gold nanoparticles. UV/Vis spectroscopic techniques have recently been combined with microfluidic flow reactors for the extraction of Residence Time Distribution (RTD) information,129 analysis of continuous and discrete reaction parameters in organic flow synthesis,130 and monitoring segmented flow.131 Suarnaba et al.132 used in situ UV-Vis spectroscopy in a microreactor to study the dehydrogenation of 1-methyl-1,4-cyclohexadiene. The authors detected the onset of coke formation and confirmed the activity of the Pt catalyst. Ponce et al.133 designed and developed a Hollow Core Photonic Crystal Fiber (HC-PCF) microreactor to evaluate the relationship between bimetallic nanoparticles and its activity to the hydrogenation of azoben- zene. The laboratory was able to obtain sufficient light transmission and, furthermore, kinetic data for all particle sizes despite the transmission being a size-dependent. The same

FIG. 6. (a) Raman spectra taken at different points of the reaction indicating group previously used this reactor to evaluate to an Rh-NP dec- 134 phase changes of the mixed molybdate catalysts. Reprinted with permission orated HC-PCF catalyzed hydrogenation of Disperse Red 1. from Engeldinger et al., ChemCatChem 8, 976 (2016). Copyright 2016, AIP Heterogeneous photocatalytic reactors with in situ spec- Publishing LLC. (b) Micropacked-bed reactor for catalytic evaluation using troscopy have shown to be a prosperous area of research, as Raman spectroscopy. Reprinted with permission from Cao et al., Catal. Today 283, 195 (2017). Copyright 2017, Author(s), licensed under the they can be utilized as rapid, versatile platforms for the char- Creative Commons Attribution License (CC BY). acterization of photocatalysts. A unique advantage is that the

J. Vac. Sci. Technol. A, Vol. 37, No. 5, Sep/Oct 2019 050801-9 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-9 incident UV/Vis light can be exploited in a multifunctional optimize the weight/mixing ratio to 7:11 and a reaction rate manner for activating the reactants/substrate interaction and constant up to 0.067 min−1. The authors reported that the monitoring the reaction parameters.4 Utilizing UV/Vis radia- sampling interval time could be minimized to 10 s for achiev- tion in this way is highlighted by Li et al.135 The group ing real-time detection. Dionigi et al.138 developed a transpar- designed and integrated a photocatalytic microreactor with ent Pyrex microreactor in order to combine the optical absorption spectroscopy to monitor photocatalytic activity of characterization and reactivity measurements of photocata- a titanium oxide-decorated graphene oxide sheet, and a lysts. The proof of concept was demonstrated using photoca- summary of their experimental design can be seen in Fig. 7. talytic CO oxidation as a model reaction and provides a Using methylene blue photodegradation as a model reaction, means to evaluate a reaction with different illumination pat- they were able to use the photocatalytic microreactor to terns. Another laboratory monitored the catalytic activity of

FIG. 7. (a) Schematic diagram of a microreactor using real-time monitoring of photocatalytic activity using absorption spectroscopy. Reprinted with permission from Li et al., Sci. Rep. 6, 28803 (2016). Copyright 2016, Author(s), licensed under the Creative Commons Attribution License (CC BY). (Middle) Schematic drawings of the three different types [(b) shows ATR, (c) shows DRIFTS, and (d) shows transmission] of FTIR spectroscopic apparatuses used to study asymmetric hydrogenation of an alpha-amino ester. Reprinted with permission from Zhang et al., Org. Process Res. Dev. 20, 1668 (2016). Copyright 2016, American Chemical Society. (e) Phase domain Contour plot (left) and three different highlighted superimposed (right) spectra of in situ DRIFTS spectra of the dehydration of ethanol over γ-Al2O3. Reproduced with permission from Patil et al., React. Chem. Eng. 4, 675 (2018). Copyright 2018, The Royal Society of Chemistry.

JVST A - Vacuum, Surfaces, and Films 050801-10 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-10 the CO oxidation reaction using an interesting approach. powder characterization, which could benefit in situ monitor- Bu et al.139 used in situ UV-Vis to monitor the oxidation ing of heterogeneous catalysis in fixed micropacked-bed reac- states of Cu NPs via localized surface plasmon resonance, tors. The work by Paredes-Nunez et al. provide another and the products were measured in line with a mass spectrom- example of the successful application151 as well as the recent etry. Such an approach enabled the researchers to examine work by Patil et al.137 A more general overview of the inte- the catalysts dynamics under various reaction conditions, dis- gration of this specific technique for the study of catalytic covering that only under almost total oxygen conversion the reactions is provided by Meunier.152 Working within a Cu metallic phase is stable. similar conceptual framework, Zhang et al.136 incorporated both DR and ATR modes in addition to conventional FTIR to investigate asymmetric hydrogenation of α-amino ester in 3. Infrared spectroscopy a microflow system (see Fig. 7). Each of the different tech- Infrared/Fourier transform infrared spectroscopy is based on niques consistently provided the same information for identi- measurements of mid-IR radiation after passing through a cal analytes, but individually provided unique insights with sample. The difference lies in the fact that instead of sequen- characteristic spectral features. Sharma et al.153 used a tubular tially measuring absorbances of individual varying wavelengths microreactor coupled to an in situ DRIFTS spectroscopic from a monochromatic light source, FTIR spectrometers system to elucidate the mechanism of catalytic ethanol steam employ an ingenious combination of a broadband light source reforming over a supported rhodium. Ogrodowicz et al.154 and a Michelson interferometer and software, which converts developed an in situ FTIR method for the quantitative evalua- the raw data into a transmission spectrogram using Fourier tion of catalytic parameters of a solid heteropolyacids. The transform. Designed in such a way, the spectrometer can method garnered catalytic information by determining the achieve a higher signal-to-noise ratio for a given time-scan, conversion and yields which were a function of the acidity of higher throughput (resulting in a higher sensitivity), and accu- the catalysts. This revealed that the composition of the hetero- racy.140 NIR spectroscopy is a spectroscopic method that makes polyacids may play a more decisive role in their acidity than use of the near-infrared region of the electromagnetic spectrum. the structure. Loiland and Lobo155 were able to use in situ One peculiar advantage of NIR spectroscopy is that the sample FTIR to investigate the mechanism of NO oxidation over a penetration capability of the radiation is usually higher com- zeolite across a temperature range from ambient conditions to pared to its conventional IR. This penetrative quality of NIR 623 K. Investigating in such a manner, they were able to iden- radiation has been exploited in the biomedical field to monitor tify two different regimes of the reaction mechanism and microcirculation and the degree of oxygenation of hemoglo- NO+ as an intermediate species. Also, Li et al. used both bin.141,142 Some other fields of application are found in agricul- custom and commercial FTIR and DRIFTS cells to quantify ture (e.g., compositional analysis of foods),143 quality control of the thermal difference between a standard reactor and in situ pharmaceuticals,144 and astronomy. For reviews on IR spectro- measurements.156 Their work yielded insight into a tempera- scopy and its variations and for a more comprehensive over- ture correction coefficient which could be used to reconcile view of FTIR, refer to Perro et al. and Ozaki et al.145,146 measured difference between thermocouple data and the tem- Investigation of integrating traditional IR spectroscopic perature in an IR reactor. techniques as well as previously unincorporated or less developed spectroscopic techniques with microreactors is still B. Radio frequency spectroscopy ongoing. For example, the work by Anand et al.147 examined a l/s system involving the hydroprocessing of triglycerides 1. Nuclear magnetic resonance spectroscopy using various supports for the Pd catalyst and sulfided Nuclear magnetic resonance spectroscopy is a spectro- CoMoP/Alumina. Their work uncovered which intermediates scopic technique that relies on the phenomena of magnetic form under different catalytic conditions (reporting for the resonance of atomic nuclei to observe their corresponding first time anhydrides and cyclic ketones as intermediate local magnetic fields. Since these fields depend on intramo- species), and they were able to compare and determine the lecular magnetic interactions of atoms, information about the hydrogenation activity between the tested catalysts. Recent structure of molecules can be ascertained. This can further be work by Aguirre et al.148 was done to determine the limits of carried into other applications of this technique to isolate ATR-FTIR for investigating liquid-solid interfaces. Reactors solvent effects, reaction state information, and other informa- for heterogeneous catalysis involving condensed phases may tion regarding the state of the molecule, its environment, and engender nonideal catalytic reactor behavior, thus precluding the relationships between these various factors. For these them from in situ/operando studies. Work that develops tech- reasons, it is used in modern organic chemistry,157 cataly- niques that are compatible with microreactors which function sis,158 biology,159 medicine,157 and industry.160 as spectroscopic cells is of interest to further the field of het- In the realm of microfluidics and NMR, to provide a superfi- erogeneous catalysis.27,148 ATR-IR coupled with an electric cial overview, research has previously been done on monitoring field can be used to study electrochemistry, for example, reactions in real time,161 planar microcoils-based162 and sole- E-field acid-base chemistry.149 noidal microcoil163- based microflow probes, and optimizing Additionally, Perro et al.145 and Aguirre et al.150 NMR detectors specifically for planar microfludic devices.164 mention diffuse reflectance infrared Fourier transform NMR imaging in microfluidic chips was incepted as a tech- spectroscopy(DRIFTS),anFTIRmodemostlyusedfor nique at the start of the millennium.165 For a review that

J. Vac. Sci. Technol. A, Vol. 37, No. 5, Sep/Oct 2019 050801-11 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-11 focuses on the coupling of NMR spectroscopy with flow sensitivity made imaging of the reaction system possible. and microreactor systems for the rapid analysis and optimi- From this, reaction yield, reaction product distribution, and zation of reaction parameters and conditions, see Gomez mass transport phenomena information were extractable from andDeLaHoz.166 As for work in heterogeneous catalysis the data. Another work demonstrating the development of a and catalyst characterization, NMR spectroscopy was used novel NMR technique comes from Jarenwattananon et al.169 to spatially resolve visualizations of active regions of cata- The group devised a new NMR thermometry technique, lysts in a packed-bed microreactor.167 Motivation for some which evades traditional issues involving weak temperature of this work is to improve sensitivity, since NMR spectro- dependence of the phenomena and rapid attenuation by diffu- scopy is relatively insensitive compared to some other spec- sion, among others. The technique was used as a noninvasive troscopic methods, due to the weak intensity of probing tool to locate cold and hot spots in the heterogeneous radiation and the inherent nature of the principal effect. catalyzed hydrogenation of propylene. Arzumanov and As for current work in the field, one exceptional develop- Stepanov170 tackle the problem of distinguishing between ment is the use of remote detection NMR.168 The authors apparent and intrinsic activation barriers using a microreactor studied the heterogeneous hydrogenation of propene. Remote integrated with in situ 1H magic-angle spinning NMR. The detection allowed the authors to use highly sensitive micro- group investigated the kinetics of isotopically labeled propene coils that characterize the whole microfluidic channel network and the double-bond shift reaction over silicalite-1. (see Fig. 8) instantaneously. The advantage of using remote detection lies in the fact that time-of-flight information is available since encoding and detection are separated in 2. Electrochemical impedance spectroscopy space. Using this method, submillimeter spatial resolution EIS measures the properties of a sample as a function of was achieved and despite low concentration of gases, the the material’s opposition to current flow at varying frequen- cies. This frequency response is used to elucidate physical or kinetic information from a system by examining the relationship between current and applied potential in the frequency domain. The behavior of various systems can be modeled using a set of physical models which include considerations for the chemical structure and electronic properties and are analyzed as distributions of diffusion or relaxation times in a system.171 These systems have found broad applicability in a variety of fields due to their ability to take nondestructive in situ measurements, for example, the monitoring of small molecule electrosyntheses.172 EIS has found application in “soft” microchemical systems recently as a way to measure inherent properties of mild chemical or biological systems. There has been significant work done in biochemical engineering to develop immunosensors173 using this technology as it has shown very high sensitivity and selectivity for analytes. Liu et al. used EIS combined by cyclic vol- tammetry to detect trace amounts of therapeutic drugs. Using an Au-Ag alloy microwire (NPAMW) with a 3D nanoporous surface covered in molecularly imprinted polymer, they were able to detect species at concentrations as low as 8−12M. The resulting device was compact enough to monitor drug concentrations in vivo on a small animal.174 Finally, Shaw et al. were able to integrate in situ FT-EIS with a rapidly prototyped PDMS reactor. This allowed them to perform potentiometry on mercuric chloride, an environmental toxin, during breakdown in a system.175 Overall, EIS combinedwithsoftmicrofluidics allows for interesting developments in rapidly produced and reproducible micro total analysis system (μTAS) platforms. The systems are also incredibly sensitive to the electrical properties of quantum dots and can be exploited for both

FIG. 8. View of an integrated NMR/microreactor system for probing a propene physical understanding and detection purposes. EIS has been to propane catalytic conversion. (a) Schematic representation of experimental used to detect the electric dipole moment and charge of col- setup for remote detection NMR spectroscopy used for the study of gas phase loidal quantum dots.176 By coating analytes such as bacteria hydrogenation in a microﬂuidic reactor. (b) Sample spectrum measured by the setup of the reaction mixture. (c) A rendition of the imaging pulse sequence in nanoparticles, it becomes possible to detect very small used. Reprinted with permission from Zhivonitko et al., Lab Chip 13, 1554 quantities in solution and also providing unique challenges (2013). Copyright 2013, The Royal Society of Chemistry. in optimizing surface coverage and interactions.177 Both

JVST A - Vacuum, Surfaces, and Films 050801-12 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-12

FIG. 9. Setup for the EIS-based detection of bacteria in a microreactor using a Tesla-based mixer. (a) shows the reactor detail, (b) is an image of the electrodes, (c) is a micrograph of the tesla mixing channels, (d) is a microscope image of the electrodes, and (e) is a simulation of the electric field in the device. All figures reprinted with permission from Wang et al., Microchim. Acta 185 (2018). Copyright 2018, Springer Nature. schematic and actual images of the reactor used can be seen in Fig. 9. By using in situ EIS, it also becomes possible to visualize the time-dependent behavior of electronic or ionic charge transfer characteristics. By analyzing the deposition of gold FIG. 10. Modular EIS spectrometer fitted to a high-pressure microfluidic device for the study of fluid flow. Reprinted from Cobry et al., Flow Meas. nanoparticles to the surface of a polymer with EIS in a Instrum. 64, 194 (2018). Copyright (2018), Elsevier. microsystem, Wagner et al. were able to build a model, which help in the development of catalytic, optical, and electronic systems.178 constant. Synchrotrons are common in many types of experi- Finally, there has been recent work done to bring EIS ments ranging from fundamental physical studies at the large out of “soft” microreactor systems and into plate-and-frame hadron collider to smaller beam lines used for the study of type devices more common when working with high pres- heterogeneous catalysis in microsystems. See Fig. 11(a) for a sured or harsh chemistries. Cobry et al. were able to fabri- visual representation for a summary of its architecture. cate a novel EIS probe for use with a stainless steel Recent progress has been made to couple synchrotrons with – microreactor. The device was used to successfully gather microreactors for in situ spectroscopy.180,182 186 information of local processes like mass transport, resulting X-ray photoelectron spectroscopy (XPS), a common in a better understanding of phase distributions in the organic chemistry technique for the determination of chemi- microchannel (see Fig. 10).179 cal species and states in a sample, is just starting to see use in microfluidic tools. It has found application in determining the elemental composition of chemical samples with an atomic C. X-ray spectroscopic techniques number more than three at a depth of around 10–20 nm into a Synchrotron is a common light source for x-ray based surface by measuring the kinetic energy spectrum of photo- spectroscopic devices. It is a type of particle accelerator with electrons coming off of a surface under irradiation in vacuum a cyclic shape so that the accelerated particle beams may be conditions.187 Overall, XPS is an interesting new tool for the stored in a ring of electromagnets to keep the beams energy analysis of surface chemistry in microreactor platforms.

J. Vac. Sci. Technol. A, Vol. 37, No. 5, Sep/Oct 2019 050801-13 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-13

There have been several papers in the previous year’s using XPS as an in situ measurement technique in microsystems. One study involved examining all-carbon hierar- chical structures for use in multifunctional surface-active devices. The research group used microwave plasma and heating in alternate cycles to either make the surface of the nanotube carpet hydrophilic or hydrophobic, with a maximum aqueous contact angle of 165° achieved. This research has applications in environmental and biomedical sensors as well as microfluidic devices.188 XPS has also been used to better understand hollow composite fibers with an imbedded Pd (II) catalyst when combined with inductively coupled plasma. This study revealed that porous polyamide-imide (PAI) hollow fibers with catalytically active ions are a stable material for C-H functionalization.189 Overall, XPS has proven to be an interesting technique for analyzing surface chemistry in microsystems, but to the requirement of having an atmospherically-exposed sample it is impractical for many applications. X-ray absorption spectroscopy (XAS) is another technique which is common in traditional experimental chemistry but is just starting to find favor in microfluidics to study the chemical composition of surfaces. XAS works by using ion- izing radiation to eject a core electron from the atom. The x-ray energy is scanned and the absorbance is measured, giving information on the different core-electron binding energies in a sample.190 Overall, XAS suffers from the same types of drawbacks as XPS, in that the sample needs to be exposed directly to the radiation beam for measurements to take place and requires highly specialized equipment available in only a few locations worldwide. XAS has found relatively limited applications with microfluidic systems, but has proven extremely valuable at helping to understand the structure of solutes in an aqueous solution. Zheng et al. used XAS combined with a novel microfluidic device to measure the solvation structure of potassium ferricy- anide in water.183 This research demonstrates that the difficul- ties of XAS including vacuum compatibility, air-sensitivity, or high pressure/temperature operations can be successfully accommodated for. Recently, a group used an advanced version of XAS, extended x-ray absorption fine structure (EXAFS) spectroscopy to gain a finer understanding of the relationship of supported Pd nanoparticles and its catalytic ability to deoxygenate octanoic acid.184 Using the same method, Kanungo et al.185 used a bimetallic catalyst coated fl FIG. 11. (a) Representation of a synchrotron including the electron accelerator, micro ow channel to directly synthesize H2O2. This reaction the storage ring, the RF system and the hutches for suitable beamline exploi- system was compared to the corresponding monometallic tation. Reprinted with permission from T. Uruga, in XAFS Techniques for catalysts in order to cross-examine and distinguish the individ- Catalysts, Nanomaterials, and Surfaces, edited by Y. Iwasawa, K. Asakura, ual contributions of the metals to selectivity and activity. and M. Tada (Springer International, 2017), pp. 53–63. Copyright 2017, Springer Nature. (b) Photograph of a microreactor integrated with a synchro- XAS systems are also compatible with other spectroscopic tron showcasing various supporting components. Reprinted with permission techniques, such as infrared spectroscopy.191 For example, from Baier et al., Rev. Sci. Instrum. 86, 065101 (2015). Copyright 2015, AIP Gross et al.182 [Fig. 11(d)] integrated both in situ IR and high- Publishing LLC (Ref. 181). (c) Example of the variety of PtL3 XANES spec- fl tral data collected under different temperature cycles from the microsystem resolution x-ray microspectroscopy in a micro ow reactor to set up under (b). Reprinted with permission from Baier et al., Rev. Sci. study the supported gold nanocluster catalyzed cascade Instrum. 86, 065101 (2015). Copyright 2015, AIP Publishing LLC (Ref. dihydropyran formation. With such a system, the group 181). (d) Graphical representation of the positioning of the x-ray beam in managed to map the kinetic evolution of the organic phase comparison to another spectroscopic technique within a single system. Reprinted with permission from Gross et al., J. Am. Chem. Soc. 136, 3624 and the metallic catalyst in 1D with a spatial resolution of (2014). Copyright 2014, American Chemical Society. 15 μm. In 2018, Groppo et al. used small-angle x-ray scattering

JVST A - Vacuum, Surfaces, and Films 050801-14 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-14 small angle x-ray scattering, x-ray absorption spectroscopy, electrolyte composition.201 Overall, the manipulation and opti- mass spectroscopy [(SAXS)/XAS] with an in-line mass spec- mization of these engineered surfaces is critical for the practi- trometer (MS) to discover the dynamic behavior of a Pd/P4VP cable application of terahertz imaging to microsystems. catalyst used for the aerobic oxidation of 2-propanol.192 Their The direct application of terahertz imaging to microfluidic work gave insight into how the behavior of the Pd(OAc)2/P4VP systems has included works in chemical sensing and the catalyst is influenced by the support material and also how the investigation of innate physical properties of compounds. Pd2+ cationic species are dispersed in the system. This leads to Liu et al. used terahertz imaging to sense mixtures of IPA, the conclusion that the catalytic species exists at the “confluence ACN, and water in the 570–630 GHz domain. They also between its homogeneous and heterogeneous analogs.”192 used the technology to study molecular diffusion at the thin- Boubnov et al. used XAS combined with High Energy film interface between multistream flows.202 Terahertz has Resolution Fluorescence Detected X-ray Absorption Near Edge also been used to investigate hydration shell structures in situ Structure (HERFD-XANES) and X-ray Emission Spectroscopy by directly probing the hydrogen bonding network of the (XES) for the study of the catalytic reduction of NO over an hydration shell structure.203 Finally, terahertz imaging has Fe-ZSM-5 catalyst, leading to an increased understanding of the also been applying to measuring subwavelength sized objects reaction mechanism.186 Overall, XAS is an exciting new devel- in a flowing environment by using an embedded plasmonic opment for in situ measurements using microreactors. antenna, as can be seen in Ref. 204. Overall, terahertz X-ray diffraction (XRD) is a common laboratory technique imaging, a new and novel method, shows promise for gather- using radiation to gain insight into the crystal phase and struc- ing detailed information about mixtures, interfaces, and ture of particles that are within the same order of magnitude chemical properties in microfluidic devices. in size as the wavelength of x rays. Hoffman et al. recently used in situ/operando powder XRD to characterize a silica- E. Integrated spectroscopy supported cobalt catalyst used for Fischer–Tropsch reactions.193 The main contribution of this work was the design There are multiple new trends evolving for the study of and validation of a capillary XRD cell for the characterization catalysis in microfluidic systems with in situ spectroscopy of heterogeneous catalysts, which could then be applied to and the field is constantly changing. One brand of research other systems of interest. which is ever-evolving is the integration of multiple spectroscopic techniques in order to achieve a multifaced perspective of single process. An excellent example of such work is by D. Terahertz imaging Baier et al.181 Their work involves the design of a novel Since around 2013, there has been an increasing interest modular microreactor-interchangeable setup which allows the in applying terahertz imagining to microfluidic systems. use of synchrotron radiation techniques (XRD, XAS) as well Terahertz imaging allows for noninvasive and nonionizing as infrared thermography and Raman spectroscopy, all mean- imaging of aqueous systems with very high contrast.194 By while coupled on-line to MS. The system was validated by operating in the 0.1–10 THz domain (microwave-infrared), examining the catalytic partial oxidation of methane over a the detector is able to capture information about the vibra- Pt/Al2O3. Another example of such an approach comes from 205 tional and rotational modes of macromolecules which is ana- Zhao et al. Recently, there have been many developments lyzed in the frequency domain (THz-TDS).195 However, the to integrate sensing elements or plasmonic structures directly efficient use of terahertz imaging requires the application of onto chips. One interesting study mentioned earlier used materials with subwavelength scale elements to control the on-chip microelectrochemical resonators for local heating, EM waves and very precise excitation sources, creating diffi- mixing, and viscosity sensing of droplets directly in the 82 culties with system integration. experimental channel. Another study used biotemplating to 83 The study of metamaterials for use in these terahertz make a plasmonic structure directly out of a plant leaf, imaging systems has in itself comprised an entire field of which is just one example out of many of the successful inte- 206–209 research. Work has included the creation of tunable surfaces gration of plasmonics with microfluidic devices. for broadband absorption. This allows for the creation of smaller, more efficient sensors for point-of-use applications.196 There have also been studies on manipulation of the actual IV. SUMMARY AND CONCLUSIONS structure of the device to enhance the EM handling properties. Although many designs and integration schemes have This has included parallel-plate waveguides which create reso- been previously developed and researched for related micro- nant structures197 and microstructuring 3D surfaces for optimal fluidic fields, their transference to microreactor technology in optoelectronic properties.198 High aspect ratio metallic rod comparison has been slightly lagging. This can be attributed arrays have also been used to sense thin films on a polypropyl- to the imposed challenges by reaction processes which are ene substrate.199 There has also been work done on making usually carried out at elevated temperatures and pressures, devices with thin films total internal reflection geometries for function at high throughput, and deal with concentrated toxic sensitive characterization work, which has shown promise for and hazardous chemicals. However, as surveyed in this improving dielectric constant measurements of samples.200 review and shown in Table I, many research groups have con- Finally, work has been done on reducing the absorption of sol- tributed to overcoming these challenges. For a brief summary vents such as water, by optimizing the chip geometry and of the various advantages and disadvantages of the most

J. Vac. Sci. Technol. A, Vol. 37, No. 5, Sep/Oct 2019 050801-15 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-15

TABLE I. List of articles integrating in situ spectroscopic methods and microreactors for the study of heterogeneous catalysis since 2013.

Spectroscopic methods Reaction class Phases Authors Year investigated Catalyst composition present UV-ViS IR Raman NMR X ray

Zhivonitko et al. 2013 Hydrogenation Pt g/l ✓ (Ref. 168) Remote Detection NMR

Baier et al. (Ref. 181) 2015 Partial oxygenation Pt/γ-Al2O3 g/s ✓ ✓✓ IR thermography Zhang et al. (Ref. 136) 2016 Asymmetric Cinchonidine modified Pd g/l/s ✓ hydrogenation DR; Transmission; ATR;

Li et al. (Ref. 135) 2016 Photodegradation TiO2-decorated graphene l/s ✓ oxide Cao et al. (Ref. 127) 2017 Oxidation Different Au,Pd and Pt g/l/s ✓

combinations/TiO2

Reymond and Rudolf von 2017 Hydrogenation Cu/ZnO/Al2O3 g/s ✓ Rohr (Ref. 126) Zhang et al. (Ref. 120) 2018 Reduction, Au NPs g/s, l/s ✓ dimerization

Sun et al. (Ref. 184) 2015 Catalytic Pd NPs/SiO2 g/s ✓ deoxygenation EXAFS

Suarnaba et al. (Ref. 132) 2016 Dehydrogenation Pd/SiO2 l/s ✓ reaction

Sharma et al. (Ref. 153) 2016 Catalytic ethanol Rh/CeZrO2 g/s ✓ steam reforming DRIFTS Ponce et al. (Ref. 133) 2018 Hydrogenation PtNi NPs g/s ✓ Ogrodowicz et al. 2019 Alcohol dehydration Solid heteropolyacids g/s ✓ (Ref. 154) Loiland et al. (Ref. 155) 2015 NO oxidation H- and Na- exchanged g/s ✓ zeolites (BEA, MFI, and CHA)

Kanungo et al. (Ref. 185) 2019 Direct H2O2 AuPd NP coated g/l/s ✓ synthesis microchannel EXAFS Jarenwattananon et al. 2013 Hydrogenation Pt NP; Pd-MOF g/s ✓ (Ref. 169) NMR Thermo-graphy

Gross et al. (Ref. 182) 2014 Cascade Au@G4OH/SBA-15 l/s ✓✓ dihydropyran NEXAFS synthesis

Dionigi et al. (Ref. 138) 2013 Photocatalytic CO TiO2 g/s ✓ oxidation Cubillas et al. (Ref. 134) 2014 Hydrogenation Rh-NP ✓

Bu et al. (Ref. 139) 2016 CO oxidation Cu NPs, Cu2O, CuO g/s ✓ Arzumanov and Stepanov 2018 Double-bond shift Silicalite-1 g/s ✓ (Ref. 170) reaction

Zhao et al. (Ref. 205) 2015 Ethylene Pt-SiO2 NPs g/s ✓✓ ✓ hydrogenation EXAFS

Yao et al. (Ref. 191) 2014 CO oxidation CuO/CeO2 g/s ✓✓ Paredes-Nunez et al. 2015 Fischer–Tropsch 15% Co/Siralox® g/s ✓ (Ref. 151) synthesis DRIFTS Li et al. (Ref. 156) 2013 CO methanation Ni/alumina g/s ✓ Custom + DRIFTS

Hoffman et al. (Ref. 193) 2018 Fischer–Tropsch Co/SiO2 g/s ✓ process XRD

Groppo et al. (Ref. 192) 2018 Aerobic oxidation Pd/P4VP g/s ✓ SAXS/ XAS

JVST A - Vacuum, Surfaces, and Films 050801-16 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-16

TABLE I. (Continued.)

Spectroscopic methods Reaction class Phases Authors Year investigated Catalyst composition present UV-ViS IR Raman NMR X ray

Engeldinger et al. 2016 Ammoxidation Molybdate g/l/s ✓ (Ref. 128) Boubnov et al. (Ref. 186) 2014 Reduction of NO Fe-ZSM-5 g/s ✓ XANES + XES

Anand et al. (Ref. 147) 2018 Hydroprocessing of Pd/Al2O3, Pd/C, CoMo/ l/s ✓

triglycerides Al2O3

frequently used spectroscopic techniques for integrating with traditional metal and organometallic catalysis, the catalysts spectroscopic techniques, please refer to Table II. only have a single metal center which is responsible for the Overall studying heterogeneous catalysis using micro- catalytic activity. There has been significant progress in the reactors with in situ spectroscopy has proven to be a fruit- discovery of new catalyst molecules with two or more metal ful field for many areas of both fundamental and applied centers, as well as metal alloy catalysts with very high activity research. With discoveries ranging from a better fundamen- and selectivity. Through the use of in situ and operando tal understanding of solvent activity to the discovery of new methodologies, it may become possible to synthesize and test materials and processes, the contributions have been vast. many more of these novel catalysts much more quickly. In the coming years these systems, combined with even Processes like XAS and TEM could be used for the study of greater automation and enabled by more cost-effective and the catalyst surface, while techniques such as Raman could be quick fabrication techniques, will enable discoveries to be used to quantify the activity and selectivity. The application made even more quickly and efficiently in a variety of of in situ catalyst screening and optimization methodology fields. Additionally, with the application of standardization could also be applied to the study of cooperative catalysts across devices, equipment, fittings, and instruments, the dis- which work together to increase the selectivity of a chemical covery and sharing of science will even further be expe- reaction. Traditionally, these catalyst systems have been com- dited. We anticipate that the application of microsystems plicated to study due to overlapping reaction coordinate dia- and in situ spectroscopy will yield many new and exciting grams and the effects of different activators, co-catalysts, and discoveries in the coming years. solvents. Overall, the application of in situ methodology to next-generation mixed metal and alloy catalysts can result in the discovery of new materials for all sorts of academically, V. OUTLOOK AND FUTURE TRENDS medically, and industrially relevant reactions. A. Next-generation heterogeneous catalysis Considerable opportunity exists for the development of cata- A major limitation in the study of catalysis has been the lysts for application in green chemistry. Green chemistry is a inherent observation of “macro” phenomena—observations broadtermusedtodescribetheprocessofmakingchemical like exotherms and concentrations of species. The issue with production more environmentally friendly through reducing these measurements is the obfuscation of the innate behavior waste, changing to renewable feedstocks, and performing reac- of catalytic sites. This understanding becomes necessary for tions at more mild conditions. Through the development of the formulation of new nanostructured catalysts with a new heterogeneous catalysts using in situ spectroscopy, it “bottom up” technique. In such a process, the catalyst would becomes possible to target all of these areas by conducting be intelligently designed for the reaction necessary, and a rational experiments which provide a plethora of data on the synthesis pathway would be crafted for this very specificcat- process. Primarily, microfluidics allows for the fast screening alyst. By developing a better understanding of catalytic sites of multiple catalysts at varying conditions, thanks to the low and the microscopic phenomena taking place at them, it residence volume of the reactors. This also lowers the environ- would be possible to apply a more rational and intelligent mental footprint of conducting research by reducing the chemi- design to catalytic sites. This future approach of heteroge- cal waste generating and reducing Heating, Ventilation and Air neous catalysis is underscored in the conceptual review by Conditioning (HVAC) and electrical loads of research facilities. Schlögl, highlighting the need for novel methodologies to These microreactor systems can also be used to investigate a make way for a direction.29 This motivation created a need variety of new renewable feedstock options, which are often for new spectroscopic techniques with single-site resolution not a plug-and-play replacement for existing suppliers because to gain the fundamental understanding necessary to intelli- of trace impurities and differences in both composition and gently design catalysts from the “bottom up.” stereochemical makeup. Microsystems with in situ spectro- Another major application for the use of microfluidics with scopy may be able to screen these new feedstock materials and in situ spectroscopy for the study of heterogeneous catalysts is adapt processes for ideal performance, perhaps even in real with the relatively new field of mixed metal catalysts. In time to compensate for variability between batches.

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TABLE II. Summary of major spectroscopic methods with advantages and disadvantages of each.

Spectroscopic Expected developments to further Further method Advantages Disadvantages the field reading

UV-Vis (1) Simple use (1) Spectrum provides limited chemical (1) Increased detection ranges in Ref. 210 (2) Cheap information instruments Ref. 211 (3) Ubiquitous instrument in laboratories (2) Requires optically transparent (2) More robust noise canceling Ref. 212 (4) Miniaturizable material algorithms (5) Physically robust devices (3) Highly sensitive to RF and optical (6) Can be easily connected with fiber interference optics to provide remote detection IR (1) Fingerprint information for virtually all (1) Not suitable for aqueous solutions (1) Wider applicability of DRIFTS Ref. 145 organic compounds (2) Instruments can be expensive (2) Miniaturized interferometers Ref. 213 (2) Various detection modes possible (3) Requires transparent reactors Ref. 214 (3) FTIR used to fingerprint compounds (4) Many solvents absorb Ref. 215 (4) With ATR mode, a broader range of Ref. 152 systems can be analyzed (5) DRIFTS mode can provide information on surfaces and powders (6) Robust calibration stability and design Raman (1) Versatile; broad range of detectible (1) Weak signal intensity due to low (1) Easier deposition on Ref. 14 chemicals frequency of the Raman scattering SERS-active materials Ref. 123 (2) Highly compatible with aqueous effect (2) Automated analysis methods Ref. 122 systems due to water not exhibiting (2) Laser may heat up sample and and deconvolution strong Raman absorbance perturb analyzed area (3) Better time resolution (3) May be modified to SERS to improve (3) Surface must be uniform and planar (4) Pulsed stimulated Raman for sensitivity by orders of magnitude (4) Focal length may not be adequate enhanced resolution (4) Overlap of materials used for catalysis (5) Reliable SERS measurements highly and those used for SERS dependent of surface quality of (5) Applicable to all phases substrate NMR (1) Powerful technique for determining (1) Low sensitivity compared to other (1) Microcoils Ref. 166 structure spectroscopic analytical techniques (2) 2D NMR Ref. 32 (2) Excellent platform for analysis and (related to capillary tubing) (3) Improved sensitivity of characterization of product (2) Clogging if solid phase not totally benchtop NMR immobilized (3) Bubbles may distort NMR lineshape (4) Gas pressure may reduce NMR sensitivity (5) Uniform magnetic susceptibility of sample needed thus laminar flow is necessary X ray (1) Most useful technique for solid (1) Radiation hazards (1) More light sources Ref. 216 elemental analysis (2) Often expensive for in-house work, (2) Automated sample handling (2) Multiple variations available for requiring infrastructure for higher throughput on specialized (3) Sources of radiation are mostly existing sources (3) High sensitivity possible inaccessible (4) Relatively inapplicable to light element containing organic molecules (5) Mostly limited to g/s systems

Finally, microreactor systems with in situ spectroscopy heating and pumping operations. Overall, microsystems with in could be used for the development of catalysts which are situ process interrogation may lead to various breakthroughs active at more mild conditions. Many industrially relevant reac- and improvements in next-generation heterogeneous catalysis. tions like reforming and polymerization involve the use of very high temperature and pressure reactors, leading to obvious ﬂ energy use and safety issues. By developing catalysts which B. Design of analytical chemistry for continuous ow are active at more reasonable conditions, it may be possible to Science has outstanding analytical chemists just as engi- signiﬁcantly decrease the carbon emission related to these neering has chemical engineers. In the last century, the two

JVST A - Vacuum, Surfaces, and Films 050801-18 Rizkin, Popovic, and Hartman: Review Article: Spectroscopic microreactors for heterogeneous catalysis 050801-18 communities have grown independent to some degree of chemicals, investigating innate properties of a catalyst, or through the evolution of batch reactors and the analysis of building a highly modular and flexible synthesis unit. data offline. Notable innovations in analytical methods for Automation allows for collecting massive amounts of informa- production scale flow reactors have had broad applications, tion about the system, effectively creating data lakes for entire especially in quality assurance and process controls. An classes of chemical reactions. Overall, the prospect of micro- emergence of in situ spectroscopic techniques has material- reactor automation holds enormous promise in a variety of ized in the last decade as described in this review. Further applications in reaction and surface chemistry engineering. innovation of microreactors with in situ chemical methods In recent years, there have been some rather impressible will introduce new opportunities to rethink analytical chem- fully automated microfluidic systems built for various experi- istry in continuous flow. mental and commercial interests. Among these is a fully Surmountable challenges could be explored through inter- reconfigurable system for performing a variety of unit opera- disciplinary collaborations. For instance, the sample size, tions including heated and cooled well-mixed reactors, photo- representation, and the time scale of a reaction are common, reactors, packed-bed reactors, and liquid-liquid separators. yet they should not be, deciding factors in distinguishing a Such a system can be used to perform a multitude of reactions mechanistic insight. The concept of reactions in microfluidic including cross-couplings, olefination, reductive amination, droplets has tremendous merit, but how does one directly nucleophilic-aromatic substitution, and photoredox chemistry. measure the extent of the reaction for all practical purposes? Monitoring the reaction and separation zones by high- The classes of reactions performed in microreactors are very performance liquid chromatography (HPLC), MS, and vibra- broad, and analyses of microliter quantities amidst fluid tional spectroscopy is possible, in which system design soft- mechanics are not trivial. Electronics innovated for space ware such as LABVIEW enables advanced automation for the travel can also fail under a reactor’s aggressive operating creation of experimental methods.25 Highly automated micro- conditions. Spectroscopic techniques that are capable of fluidic systems with online LC/MS also allow single droplet operation in extreme environments are needed that can deci- homogeneous catalysis that can be used to optimize the turn- pher high fidelity, transient information. over number of organometallic cross-couplings.217 In princi- The fact that microreactors confine catalyst and fluids is ple, one could study heterogeneous catalysis in a similar way advantageous for noninvasive methods. The use of in situ using ultrafast in situ spectroscopic methods. Although there electromagnetic radiation to study reaction media mitigates have been over 900 papers published on the topic of automa- the need for sample collection, while it can introduce chal- tion of microfluidic systems in the last half decade, few have lenges in the reactor materials of construction and the focused on understanding heterogeneous catalysis. The ability design of analytical components, depending on the wave- to perform experiments and gather data autonomously opens length. In any case, however, design of a microreactor to up new doors in surface chemistry research by allowing for accommodate existing commercially available analytics experiments to be done both quicker and in much larger seems like a common storyline of a sobering motion picture volume than previously possible. film. “Fast” by its definition in the world of analytical chemistry is sometimes a turtle’s pace in reaction engineering, in fi large part due to the design of peripheral analytical compo- D. Arti cial intelligence and machine learning nents intended for batch samples. High-throughput screening Artificial intelligence (AI) and machine learning (ML) are applications of microreactors are in desperate need of new ana- two important tools which have come of age in the last lytical methods designed for flow. Ultrafast (approximately decade due to the increased computing abilities in laboratory femtosecond to microsecond), high-resolution (approximately environments. AI and ML in microfluidic systems have also nanometer), in situ measurements could enable the study of been used extensively in biomedicine, and comprehensive suspended catalyst particles, dynamic fluid-fluid and solid- reviews on the topic are available.218–220 These methods hold fluid interfaces, reacting intermediates, or help to answer significant promise for the field of heterogeneous catalysis, much deeper questions in reaction chemistry. In retrospect, because the ability to analyze and make decisions based on conventional wisdom would probably caution what one asks data quickly goes hand-in-hand with the rapid nature of mini- for. If analytical methods are designed for flow, then how will aturized experiments. we analyze so much data? Artificial intelligence allows for gaining a greater understanding of physical phenomena taking place in a reactor or reaction. Most artificial intelligence algorithms work by train- C. Integration with automation ing a series of bias and threshold value for layers of hidden One area where microreactor systems have very clear neurons, which work in a cascade fashion with an input and advantages over conventional methods is the amenability to output layer to get useable information from often convoluted automation and high-throughput experimentation. Due to inputs. While many AI algorithms are not directly based on the smaller footprint of the tubing and related mechanics, it first-principles models, the accuracy of well-trained algorithms becomes possible to create integrated systems with fully is in very good agreement with both model and experimental automated manifolds, pumps, and spectroscopic units on a data. Finally, AI comes in two main flavors—supervised, benchtop. This functionality allows for optimized operation where training output values are validated and given to the whether performing high-throughput synthesis of a library model and unsupervised where the AI trains itself based on

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