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Utilizing Chemical Imaging to Address Scientific and Technical Challenges: Case Studies

This chapter provides a series of real-life “case studies” to help illustrate a grand challenge for chemical imaging. Before presenting the case studies, the grand challenge and a brief introduction to imaging techniques are discussed. More technical information about specific imaging techniques is provided in greater detail in Chapter 3.

A GRAND CHALLENGE FOR CHEMICAL IMAGING

Chemical imaging helps us to answer difficult questions, especially when these questions occur in complex chemical environments. At present, imaging lies at the heart of our high-technology industry in terms of process development and quality control. The ability to image the interior of the human body with techniques such as ultrasound and magnetic resonance imaging (MRI) has revolutionized medical diagnosis and treatment. Satellite imaging is now an indispensable tool in climate prediction and modeling. Use of remote imaging is crucial to our national security. Our capability to image will in many ways define our scientific, technological, economic, and national security future.

Clearly, advances in chemical imaging capabilities will result in more fundamental understanding of chemical processes. In this chapter, chemical imaging is addressed in the context of an overarching goal to understand and control complex chemical processes.



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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging 2 Utilizing Chemical Imaging to Address Scientific and Technical Challenges: Case Studies This chapter provides a series of real-life “case studies” to help illustrate a grand challenge for chemical imaging. Before presenting the case studies, the grand challenge and a brief introduction to imaging techniques are discussed. More technical information about specific imaging techniques is provided in greater detail in Chapter 3. A GRAND CHALLENGE FOR CHEMICAL IMAGING Chemical imaging helps us to answer difficult questions, especially when these questions occur in complex chemical environments. At present, imaging lies at the heart of our high-technology industry in terms of process development and quality control. The ability to image the interior of the human body with techniques such as ultrasound and magnetic resonance imaging (MRI) has revolutionized medical diagnosis and treatment. Satellite imaging is now an indispensable tool in climate prediction and modeling. Use of remote imaging is crucial to our national security. Our capability to image will in many ways define our scientific, technological, economic, and national security future. Clearly, advances in chemical imaging capabilities will result in more fundamental understanding of chemical processes. In this chapter, chemical imaging is addressed in the context of an overarching goal to understand and control complex chemical processes.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging UNDERSTANDING AND CONTROLLING COMPLEX CHEMICAL PROCESSES Understanding and controlling complex chemical processes requires the ability to perform multimodal imaging across all length and time scales. That is, researchers would like the capability to image a material or a process using multiple techniques, including those that can “focus” on a particular aspect of the material or process (through varying length scales), as well as capture images at appropriate time dimensions to acquire necessary information. An overarching objective for future breakthroughs using chemical imaging techniques is to gain a fundamental understanding and control of these complex chemical structures and processes. While this is the grand challenge for chemical imaging, more specific requirements need to be addressed in order to meet this comprehensive challenge. These include: understanding and controlling self-assembly, complex biological processes, and complex materials. Each of the challenges is amplified further below. Understanding and Controlling Self-Assembly The self-assembly of small molecular units into larger structures is a common and important occurrence in nature. In the biological realm, proteins and RNA fold into specific functional conformations. Cells divide and communicate with each other by rearranging subcellular units. Some theorists hypothesize that the spontaneous formation of lipid vesicles is responsible for the beginning of life. Outside biology, we marvel at the growth of snowflakes. We find numerous uses for soap and liquid-crystal displays. We make materials with varying properties by tuning the degree and the nature of aggregation. Indeed, many proposed methods for creating nanomaterials are based on self-assembly. Molecular assemblies are formed through strong and weak chemical forces. Understanding the types, magnitudes, directions, and distances associated with these interactions is thus of fundamental and practical importance. Chemical imaging can elucidate many of these processes by providing spatial and temporal relationships among the interacting units. We would like, at one extreme, to follow the rotation, formation, and breakage of individual bonds and, at the other, to investigate cooperative effects and sequences of events over extended domains. The same or different small assemblies can be tracked as they grow into larger assemblies. In addition, chemical transformations within these structures can be monitored to elucidate environmental effects on reactivity and ultimately can be controlled by the patterned exposure to electromagnetic radiation and other fields. To gain better understanding of and to control molecular assembly processes, one needs chemical imaging techniques that can follow interactions at a broad range of length and time scales. During assembly, it would be advantageous to record inter- and intramolecular orientations and distances at picosecond to second

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging time scales, measure the forces between selected pairs of atoms or between selected molecular domains, and detect proximal versus long-range ordering of complexes. Once the self-assembly process is complete, imaging could be employed to follow single-molecule reactions within these structures. There are a few published examples of the monitoring of DNA synthesis and hybridization. However, major advances in imaging tools will be required to tackle the whole spectrum of molecular self-assembly processes. Understanding and Controlling Complex Biological Processes In the postgenomic era, there is a pressing need to functionally annotate the products of the many sequenced genes whose functions are unknown. Exploring the proteome represents a mammoth task. Although the number of genes encoded in the genomes of higher organisms has turned out to be fewer than originally thought (tens of thousands for mammals), the complexity introduced during cell development and gene expression is enormous. Combinatorial reorganization of gene fragments during immune cell development, alternate splicing pathways after transcription, and posttranslational modification of proteins and the resulting chemical heterogeneity result in millions of functionally distinct protein species. Add to this the extensive interplay of the many metabolic intermediates and connected pathways and the complexity increases even farther. This inherent complexity and heterogeneity, which is in many respects the hallmark of a living system, puts very serious limits on the utility of traditional biochemical methodologies that are based on the separation and isolation of components. A cell is much more than a list of gene products and small molecules. Just as important as the chemical formula of each component is a detailed understanding of where it is, at what time, and with what partners. Although generating a complete four-dimensional map of cellular (and ultimately organismal) complexity at the molecular level is currently beyond our capability, this is the long-range goal of chemical imaging in the realm of biology. Clearly, much has to be done to achieve this goal, but many of the fundamental concepts and tools have been or are being developed now. From low-energy radio waves that tickle the states of nuclei, to infrared light that captures the nature and energies of chemical bonds, to visible light that probes electronic structure, to high-energy X-rays and electrons that report on electron density, spectroscopy provides detailed information and generally does so in a spatially and temporally patterned way. Scanning probe microscopy, while still largely an in vitro approach, adds an additional dimension in which mechanical and electrical probes can be applied directly. Everything from whole organisms to individual biomolecules has been imaged with these kinds of techniques. The challenge now is to come to grips with the chemical, spatial, and temporal heterogeneity involved—monitoring many molecules, molecular species, or whole cells simultaneously and thereby determining in detail the complex interactions and

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging networks that are the chemical essence of life. Thus, there are issues of scale and a dramatic need for multiscale approaches that allow one to place the chemistry within the context of the overarching biological system. As our ability to probe with high resolution has improved, a number of researchers have begun to consider reversing the direction of information transfer, using the same concepts and tools inherent in chemical imaging to project information into biological systems, thereby controlling their function. A somewhat crude example of this approach is laser surgery in which specific cells, or even small parts of cells, are ablated with a focused laser beam. A more sophisticated approach that has recently become possible is to specifically turn genes on or off with light, giving complete control of gene expression within a population of cells as a function of both space and time. In general, the concept of refitting our molecular imaging probes to become “full-duplex” molecules, functioning both to report on the environment that surrounds them and to manipulate that environment in an externally controlled way, is an idea that is just taking form and provides new vistas both for fundamental research in biology and for environmental, medical, and synthetic applications. Understanding and Controlling Complex Materials In a high-tech society, the quality of life, economic potential, and security often rest on its ability to predict and control the properties of materials. These properties can range from the common (porous, dielectric, high-strength, magnetic, chemically reactive) to the exotic (superconductivity, superlattice, superfluidity, giant magnetoresistance). In complex materials, these properties, both exotic and common, are generally determined and controlled by the degree of coupling between the components that make up the material and their resulting level of complexity (e.g., chemical and physical heterogeneity, composition, phase, morphology). Often, the degree to which we can successfully harness a particular property or phenomenon into new technologies is based largely on our knowledge and understanding of material systems at or below the size scale of the constituents and components that constitute them. For example, the discovery of new physical phenomena such as superconductivity is only the first step in what can be a long process to bring a discovery to technological relevance or commercialization. While the properties of superconductivity hold the promise of revolutionizing everything from transportation to medicine, the technological and economic impacts will go unrealized without advances in our understanding of and improvements in superconducting materials. However, progress in understanding these systems has been hampered by the absence of chemical imaging and dynamics tools that can provide nondestructive, real-time, three-dimensional imaging with relevant resolution. In all types of materials, phenomena such as fracture, creep, segregation, roughening, and delamination ultimately determine the utility of a material for a

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging given application. For example, by controlling the onset of fracture, a potato chip bag can be an effective, high-strength, low-porosity container that keeps chips from going stale, while at the same time allowing a child to rip open (fracture) the package with ease. Phenomena such as fracture mechanics are useful but not always well understood; as a consequence, these and other materials advances come by way of much trial and error. This is due in large part to the lack of suitable analytical instrumentation that can image over several length scales such things as the formation of stress (morphology contrast) and the resulting phenomena (fracture). While improved performance (e.g., high directional strength) is often an important driver in technology development, materials advances that make the technology affordable and more durable offer value and motivation as well. In addition, complex materials can comprise several unique components (metals and nonmetals, liquids and solids, magnetic and nonmagnetic materials) that, when combined, generate a material whose properties are altered or totally distinct from those of the original. An example of this is the thin-film material systems that exhibit giant magnetoresistivity (GMR). Any of the thin films acting alone would exhibit no unique or exotic properties. However, when several materials are combined in a precise manner, the phenomenon of GMR is observed, and high-density data storage is realized. Through advances in chemical imaging capability, we will increase both our basic understanding of the phenomena that determine the utility of complex materials and our ability to control or “tune” a material’s properties. In this way, we will go from using the inherent properties of traditional material, (e.g., the strength of steel) to programming particular properties, such as low weight and high strength, into engineered materials that are tailored for a given application. IMAGING TECHNIQUES The development of multiple imaging techniques provides researchers with powerful tools to probe multiple aspects of chemical problems. A more detailed discussion of these techniques is provided in Chapter 3; however, the techniques are introduced briefly here. Optical Techniques and Magnetic Resonance Techniques employing the ultraviolet (UV), visible, and near-infrared parts of the spectrum have the advantage of high sensitivity (single photon), high time resolution (femtoseconds), and moderate spatial resolution (on the order of 100 nm). Structural information is obtainable by infrared to radio-frequency techniques (e.g., magnetic resonance). Together, these techniques have enabled the visualization of individual molecules and the measurement of excited state dynamics from such molecules on the picosecond time scale. It is also possible to follow the time course of chemical reactions on the femtosecond time scale when

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging whole populations can be synchronized by light. Confocal detection and nonlinear excitation have made it possible to follow the dynamics of complex chemical systems (such as cells and tissues) using multiple probes and in three dimensions. As a whole, these technologies have also made it possible to optically pattern chemical reactivity with very high spatial resolution in three dimensions. Imaging well below the surface of an object (e.g., deep tissue imaging) remains a challenge in optical spectroscopy, but could be substantially improved with the production of labels absorbing and/or emitting farther to the red. Vibrational imaging using Raman scattering and infrared (IR) absorption provides something like a structural “fingerprint” of matter as it is determined by the kinds of atoms, their bond strengths, and their arrangements in a specific molecule. Recent developments based on a combination of modern laser spectroscopy, scanning probe techniques, and nanotechnology provide capabilities for sensitive vibrational imaging at the single-molecule level. These developments also provide capabilities at nanoscale lateral resolution, where linear and nonlinear Raman scattering is exploited in enhanced and strongly confined local optical fields of tailored nanostructures. Electron Microscopy, X-rays, Ions, and Neutrons With wavelengths that are about 1,000 times smaller than that of visible light, electrons provide a high-resolution probe of chemical and structural information below surfaces of materials. Images of atomic arrangements over a large range of length scales can be obtained using electron microscopy (EM) techniques. Although significant limitations to their use exist (e.g., the need for a vacuum to produce and transmit electrons, electron beam damage to samples), EM techniques have had a tremendous impact on fields ranging from condensed matter physics to structural biology. X-rays are able to penetrate materials more deeply than visible light or electrons and make it possible to determine the identity and local configuration of all the atoms present in a sample. Using X-rays, it is possible to image almost every conceivable sample type and gain unique insights into the deep internal molecular and atomic structure of most materials from objects as large as a shipping container to those significantly smaller than the nucleus of a single cell. Proximal Probes (Force Microscopy, Near Field, Field Enhancement) Proximal probe microscopes employ a variety of materials such as tungsten wire (scanning tunneling microscopy), silicon nitride pyramid and cantilever (atomic force microscopy), or optical fiber (near-field optical microscopy) in close proximity to the sample of interest for the purposes of recording an image of the sample, performing spectroscopic experiments, or manipulating the sample. All such methods were originally developed primarily for the purpose of obtaining

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging the highest possible spatial resolution in imaging experiments. Since then, many other unique advantages of these techniques have been realized. These methods are especially useful for understanding the chemistry of surfaces—for example, the electrophilicity of individual surface atoms, the organization of atoms or molecules at or near the surface, and the electronic properties of atomic or molecular assemblies. Processing, Analysis, and Computation Processing, analysis, and computation are not imaging techniques per se but, rather, play a fundamental role in enhancing their capabilities. In addition, computational methods, particularly when applied to computer modeling and simulation, extend imaging capabilities to address problems that have not or cannot be addressed using standing imaging techniques. CASE STUDIES A series of real-life “case studies” is presented to illustrate the importance of the technical issues that have been introduced in this chapter and show how chemical imaging can contribute to understanding them. The examples are not meant to serve as an exhaustive list of all problems that can be addressed with advances in chemical imaging. Instead, they have been included to focus on current capabilities and limitations and offer insights into where breakthroughs are needed to increase the capabilities and potential for chemical imaging. More technical information about specific imaging techniques is provided in greater detail in Chapter 3. Case Study 1: Mobile Crystalline Material-41 (MCM-41) MCM-41 is an interesting self-assembled material1 that has a wide range of applications. The starting material is a monomeric surfactant, cetyltrimethyl-ammonium bromide (CTAB), similar to those used as detergents. With a long hydrophobic end and a hydrophilic head, the monomers form spherical micelles that have a hydrophobic core and a hydrophilic surface when the concentration of the monomer surpasses the critical micellar concentration. At higher concentrations, the micelles rearrange into cylindrical rods. At still higher concentrations, the rods self-assemble into hexagonal arrays. After the introduction of silicate molecules, the arrays form silica particles that possess well-defined shapes. By adding agents that alter the hydrophobicity or hydrophilicity of various parts of the structures, one can control each step of the self-assembly process. The result is a mesoporous structure with tunable pore size, variable channel length, and predictable shape (Figure 2.1 and Figure 2.2).2 MCM-41 has been employed as an industrial catalyst for many years. The assembled structure is pyrolized to become a permanent inorganic matrix.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging FIGURE 2.1 MCM-41 units are formed from self-assembly to create honeycomb structures that can be functionalized on the inside (light blue) to create confined catalytic sites. SOURCE: Courtesy of Victor S. Lin, Iowa State University. FIGURE 2.2 These honeycomb units further assemble into larger structures that can include worms, spheres, ovals, and so on, depending on preparative conditions. SOURCE: Courtesy of Victor S. Lin, Iowa State University. Functionalization of the matrix allows incorporation of a variety of catalytic activities into the material. Recently, procedures were developed to add functional groups that are electrostatically or hydrophobically attractive to the ammonium surfactant head groups and are able to compete with silicate anions during self-assembly. This has led to a class of mesoporous materials that are functionalized only on the inside of the pores. Highly selective polymerization and cooperative catalytic systems have been developed from these materials.3 Furthermore, by incorporating caps onto the pores, chemical reagents can be stored in the channels,

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging to be released simply by detaching the caps at the desired time and location.4 This scheme holds promise as a controlled drug and gene delivery protocol. Chemical Imaging Technique(s) Involved Current methods used to image MCM-41 include (1) analytical transmission electron microscopy (TEM) to determine structure, size, morphology, and local chemical composition; (2) energy-dispersive X-ray spectroscopy (EDXS) in a scanning electron microscope (SEM) to determine chemical composition;5 and (3) electron energy loss spectroscopy (EELS) for elemental analysis.6 Insights Obtained Using Chemical Imaging The spatial and temporal progression of individual events involved in the formation of each type of structure can be monitored directly. A combination of imaging modes can be applied, each elucidating the process at a different length scale. Millimeter-scale variations can then be explained by nanometer-scale fluctuations. After the structures are built, single-molecule imaging can be employed to study catalytic reactions inside the nanopores. Imaging Limitations Limitations include the following: The imaging rate of current technologies is not fast enough for continuous monitoring of microsecond transformations. Single-molecule imaging techniques are not yet capable of monitoring several different chemical species simultaneously. There is a lack of technologies for imaging the length scale between optical microscopy (diffraction limit) and proximal probes. The need for chemical derivatization for fluorescence imaging often limits accessibility. Opportunities for Imaging Development Opportunities to develop imaging techniques for this application would include the following: Optical imaging at microsecond to nanosecond time scales per consecutive image One instrument for imaging the entire length scale from nanometers to millimeters Single-molecule imaging without fluorescence labeling

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging Case Study 2: Organic Electronics Organic materials are now being employed as the active components in electronic circuitry. Perhaps the best examples of such materials are the semiconducting polymers used in polymer-based light-emitting diodes (polymer-LEDs). As a result of the successful development of extremely pure polymeric materials, polymer-LEDs are now being incorporated into commercially available display devices. Emerging applications of small-molecule, oligomeric, and polymeric organic semiconductors include their use in photovoltaics (solar cells) and organic field effect transistors. The primary benefits of such materials include the ability to manufacture moldable, flexible materials for use in large-area devices. Importantly, such materials can easily be cast as thin films, offering the potential for significant cost reductions in comparison to traditional inorganic devices. Microscopic imaging experiments have played a key role in the development of these organic material devices and have provided detailed information on the local chemical and physical properties. They have helped researchers better understand intermolecular interactions, molecular organization within nanometer scale (and larger) domains, electronic coupling between individual molecules in the aggregate, and the mechanisms of electrical charge generation, injection, transport, and recombination. Microscopic methods will continue to provide vital information on molecular- to micrometer-length scales for both existing and emerging materials. Examples are shown below (Figures 2.3-2.5, respectively): a FIGURE 2.3 Left: urea-substituted thiophenes on a graphite surface. Right: a model. SOURCE: Reprinted with permission from Gesquiere, A., M.M.S. Abdel-Mottaleb, S. De Feyter, F.C. De Schryver, F. Schoonbeek, J. van Esch, R.M. Kellogg, B.L. Feringa, A. Calderone, R. Lazzaroni, and J.L. Bredas. 2000. Molecular organization of bis-urea substituted thiophene derivatives at the liquid/solid interface studied by scanning tunneling microscopy. Langmuir 16:10385-10391. Copyright 2000 American Chemical Society.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging FIGURE 2.4 Honeycomb structure formed from block copolymer films. SOURCE: Reprinted from de Boer, B., U. Stalmach, P. F. van Hutten, C. Melzer, V.V. Krasnikov, and G. Hadziioannou. 2001. Supramolecular self-assembly and opto-electronic properties of semiconducting block copolymers. Polymer 42: 9097-9109. Copyright 2001 with permission from Elsevier. FIGURE 2.5 NSOM topography and polarized luminescence from poly(dihexylfluorene) (an organic semiconductor) film. SOURCE: Reprinted with permission from Teetsov, J.A. and D.A. Vanden Bout. 2001. Imaging molecular and nanoscale order in conjugated polymer thin films with near-field scanning optical microscopy. J. Am. Chem. Soc. 123:3605-3606. Copyright 2001 American Chemical Society. scanning tunneling microscopy (STM) image of and model for organized thiophene monolayers deposited on a graphite surface; an image of organized honeycomb structures formed in a film prepared from block copolymers of poly(phenylene vinylene)-poly(styrene) showing micrometer-scale phase separation of the component polymers as seen by fluorescence microscopy and SEM (inset); and near-

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging Case Study 8: Molecular Motors Although biology abounds with amazingly complex molecular systems, perhaps the most astounding of these are the variety of molecular motors that perform the nanoscale mechanical work of living systems. Converting the chemical energy of adenosine 51-triphosphate (ATP) to mechanical work, these motors turn, or step, or induce enzymatic reactions. A variety of imaging techniques have been applied to the investigation of molecular motors. The most revealing have been performed at the single-molecule level. Indeed, the study of molecular motors is one of the most cited successes of single-molecule imaging. Single-molecule fluorescence has been used to visualize molecules moving or being moved by molecular motors in a field. Scanning probe spectroscopies have been adapted to measure the forces and mechanical parameters of motor function. Piconewton forces and nanometer movements have been measured using these techniques, opening a world of nanomechanics that previously was entirely unknown. Chemical Imaging Technique(s) Involved The techniques involved are single-molecule spectroscopy including optical (fluorescence) methods and single-molecule mechanical manipulation including scanning probe techniques (e.g., force measurements). Insights Obtained Using Chemical Imaging Chemical imaging at the single-molecule level has led to new understanding of mechanisms of molecular motors (force, torque, etc.). Imaging Limitations Imaging methods used at the single-molecule level can be applied only to selected molecules or molecular machines, primarily outside a living cell. It is important to study how individual molecules work together, ultimately in living cells. Opportunities for Imaging Development Single-molecule imaging techniques with improved temporal and spatial resolution have to be developed. Of particular importance is the ability to follow the dynamic activities of a single molecule, such as movements, structural changes, and catalytic functions. Future single-molecule studies both in vitro and in vivo will generate new knowledge of the working of molecular motors and other macro-molecule machines and uncover mysteries in living systems (Figures 2.16 and 2.17).

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging FIGURE 2.16 A stylized cartoon of myosin V “walking” along an actin filament. Myosin V has the function of carrying cargo while walking along an actin tightrope and progressing in 37 nm steps. This movement has been observed using total internal reflection fluorescence (TIRF) spectroscopy of individual myosin molecules. SOURCE: Reprinted with permission from 2003. Science (cover), 300(5628), based on Yildiz, A., J.N. Forkey, S.A. McKinney, T. Ha, Y.E. Goldman, and P.R. Selvin. 2003. Myosin V walks hand-over-hand: Single fluorophore imaging with 1.5-nm localization. Science 300:2061-2065. Copyright 2003 AAAS.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging FIGURE 2.17 Results of total internal reflection fluorescence (TIRF) measurements in which the discrete and processive stepping action of myosin can be seen clearly. SOURCE: Reprinted with permission from Yildiz, A., J.N. Forkey, S.A. McKinney, T. Ha, Y.E. Goldman, and P.R. Selvin..2003. Myosin V walks hand-over-hand: Single fluorophore imaging with 1.5-nm localization. Science 300:2061-2065. Copyright 2003 AAAS. Case Study 9: Reverse Imaging In addition to using imaging as a technique to obtain spatially and temporally patterned chemical data from a sample, one can also pattern chemical reactions in space and time using similar methods. Figure 2.18 demonstrates an example in which multiphoton scanning with ultrafast laser pulses was used to polymerize a photoresist resin with about 120 nm spatial resolution in three dimensions. Photopolymerization is only one way in which the pattern and time course of chemical reactions can be controlled using imaging instruments. Atoms can be moved around on surfaces, specific genes can be turned on in one cell and not in a neighboring cell, and large arrays of heteropolymers (DNA, protein, etc.) can be synthesized on surfaces in which the chemical identity of each molecule at each position is distinct and known. (See Chapter 3 for further details.)

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging FIGURE 2.18 Example of reverse imaging in which multiphoton scanning with ultrafast laser pulses was used to polymerize a photoresist resin with about 120 nm spatial resolution. In panels a-f and h, the white bar is 2 microns. SOURCE: Kawata, S., H.-B. Sun, T. Tanaka, and K. Takada. 2001. Finer features for microdevices. Nature 412:697-698. Chemical Imaging Technique(s) Involved Multiphoton microscopy has been used to initiate photopolymerization of a photoresist material in three dimensions with resolution in the hundred-nanometer range. Insights Obtained Using Chemical Imaging It is clearly possible to use chemical imaging not only to observe the structure and dynamics of chemical systems, but also to manipulate them at high resolution. This example presents a paradigm for the use of imaging to create much more complex chemical systems, patterned in three dimensions with extraordinary resolution.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging Imaging Limitations The wavelength of the light source employed dictates the fabrication resolution. In addition, in this case only a single chemical species, a photopolymer, is being manipulated. The potential exists for much more complex patterned chemical fabrications. Opportunities for Imaging Development There is no reason that chemical imaging in general cannot be turned on its head and used to manipulate chemical systems rather than just observe them. Because identifying features of chemistry can be observed in the imaging process shows that the probes used perturb this chemistry and that this perturbation can be patterned and controlled in both time and space. Considerably more could be done with high-throughput photopatterning of complex chemical systems. In addition, other techniques, such as control of individual magnetic particles in three dimensions with applied magnetic fields, should provide new vistas for fabrication and analysis as well as new opportunities for drug delivery in clinical settings. Case Study 10: Terahertz Imaging for Electromagnetic Materials Research One area of imaging spectroscopy that has attracted considerable attention recently is terahertz (THz)24 radiation research. THz imaging is currently being touted in security- and defense-related applications, such as airport passenger and mailroom package screening. However, this case study focuses on the potential of time-resolved THz spectroscopy (TRTS). The THz frequency range spans the region between about 3 cm–1 (0.1 THz) to about 300 cm–1 (10 THz).25 The radiation source may be generated from either continuous wave or short-pulsed lasers; the latter source of radiation allows TRTS studies to take place with subpicosecond temporal resolution. THz spectroscopy was born from research efforts to produce and detect ultra-short electrical currents as they traveled down a transmission line.26 In 1988-1989, it was discovered that electromagnetic radiation pulses produced by time-varying current could be propagated through free space and picked up by a detector.27 By placing a sample between a THz source and detector, one could measure the differences in radiation pulses due to scattering or absorption by the sample to understand its chemical properties. TRTS has numerous applications in materials science, chemistry, and biological research. One such application is in the study of charge transport in titanium dioxide (TiO2), a material that is used in photovoltaic and photocatalytic systems. Scientists are currently studying electron transport in TiO2 in order to better understand its photosensitive properties and engineer a more efficient surface for harnessing solar energy. Figure 2.19 shows a Grätzel solar cell, which

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging FIGURE 2.19 A schematic of the Grätzel solar cell. SOURCE: Smestad, G.P.; M. Grätzel. 1998. Demonstrating electron transfer and nanotechnology: A natural dye-sensitized nanocrystalline energy converter. J. Chem. Educ. 75: 752-756. utilizes dye-sensitized TiO2. Figure 2.20 shows the general scheme of dye sensitization of TiO2. The photon energy of sunlight is not strong enough to excite an electron from the TiO2 valence band to the conduction band in bulk; as a result, the surface of the TiO2 film on a photovoltaic device is coated with a monolayer of a charge-transfer dye in order to photoexcite dye molecules that then inject

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging FIGURE 2.20 A schematic of the dye sensitization of TiO2. SOURCE: Beard, M.C., G.M. Turner, and C.A. Schmuttenmaer. 2002. Terahertz spectroscopy. J. Phys. Chem. B 106:7146-7159. electrons into the TiO2 semiconductor.28 TRTS can be used to dynamically measure the mobilized electrons on a picosecond time scale within the conduction band without being affected by the dye molecules.29 In studies of TiO2 conduction, TRTS has several advantages over fluorescence and other optical methods of spectroscopy. For example, one such advantage is that assumptions about electron behavior need not be made to analyze spectra obtained through THz spectroscopy. Characterization of photoinjected electron dynamics in dye-sensitized TiO2 (Figure 2.20) has previously been performed using the mid-infrared region of the spectrum.30 However, in these studies, it must be assumed that electron behavior follows the Drude model31 to account for transient infrared absorption of electrons. THz spectroscopy allows

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging complex conductivity responses to be obtained without assuming any prior model for electron behavior. In fact, TRTS revealed that the charge carriers significantly deviated from Drude behavior in colloidal, sintered TiO2.32 Furthermore, scattering responses have the greatest variation within the terahertz spectrum; thus a great deal of information regarding the dynamics of electron mobility may be obtained in this region. Finally, TRTS may be carried out at subpicosecond time resolution in order to follow the ultrafast dynamics of electron transfer within this system. Ultimately, the advantages of using TRTS to examine semiconductor materials may also be applied to spectroscopic methods for biological and medical imaging purposes. Chemical Imaging Technique(s) Involved Terahertz spectroscopy uses continuous wave (CW) and short pulsed laser excitation in the spectrum region between infrared and microwave frequencies. Pulsed laser excitation using pulse widths in the range of 10-100 femtoseconds has enabled the use of time-resolved terahertz spectroscopy, which is capable of capturing dynamic information at subpicosecond time scales. Insights Obtained Using Chemical Imaging Time-resolved terahertz imaging is capable of providing information about the dynamics of chemical reactions in materials science, chemistry, and biology. Imaging Limitations There exists a need for high-power pulsed CW radiation sources to enable fast switching times and high repetition rates for electromagnetic resonance experiments. In addition, commercial development of THz sources is needed so that this technology can be made more widely available to the research community. Furthermore, current detectors for THz spectroscopy have high cooling requirements to minimize noise in spectral data; further developments are needed to provide inexpensive and user-friendly detector options. Opportunities for Imaging Development Terahertz imaging offers the possibility of understanding complex reactions in which the chemical state of the sample under study changes with time. An extension of this ability is the control of chemical reactions in a highly specific manner; this will require the manipulation and channeling of the energy in a system such that the possible outcomes (degrees of freedom) are narrowed to those that one desires.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging CONCLUSION As demonstrated by the case studies presented in this chapter, chemical imaging has a wide variety of applications that have relevance to almost every facet of our daily lives. These applications range from medical diagnosis and treatment to the study and design of material properties in novel products. To continue receiving benefits from these technologies, sustained efforts are needed to facilitate understanding and manipulation of complex chemical structures and processes. Chemical imaging offers a means by which this can be accomplished by allowing the acquisition of direct, observable information about the nature of these chemistries. NOTES AND REFERENCES    1. Kresge, C.T., M.E. Leonowicz, W.J.Roth, J.C. Vartuli, and J.S. Beck. 1992. Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism. Nature, 359:710-712.    2. (a) Huh, S., J.W. Wiench, B.G. Trewyn, M. Pruski, and V.S.-Y. Lin. 2003. Tuning of particle morphology and pore properties in mesoporous silicas with multiple organic functional groups. Chem. Comm. 2364-2365.    (b) Huh, S., J.W. Wiench, J.-C. Yoo, M. Pruski, and V. S.-Y. Lin. 2003. Organic functionalization and morphology control of mesoporous silicas via a co-condensation synthesis method. Chem. Mater. 15:4247-4256.    3. (a) Lin, V. S.-Y., D.R. Radu, M.-K. Han, W. Deng, S. Kuroki, B.H. Shanks, and M. Pruski. 2002. Oxidative polymerization of 1,4-diethynylbenzene into highly conjugated poly(phenylene butadiynylene) within the channels of surface-functionalized mesoporous silica and alumina materials. J. Am. Chem. Soc. 124:9040-9041.    (b) Huh, S., H.-T. Chen, J.W. Wiench, M. Pruski, and V.S.-Y. Lin. 2005. Cooperative catalysis by general acid and base bifunctionalized mesoporous silica nanospheres. Angew. Chem. Int. Ed. 44:1826-1830.    4. (a) Lai, C.-Y., B.G. Trewyn, D.M. Jeftinija, K. Jeftinija, S. Xu, S. Jeftinija, and V.S.-Y. Lin. 2003. A mesoporous silica nanosphere-based carrier system with chemically removable CdS nanoparticle caps for stimuli-responsive controlled release of neurotransmitters and drug molecules. J. Am. Chem. Soc. 125:4451-4459.    (b) Radu, D.R., C.-Y. Lai, K. Jeftinija, E.W. Rowe, S. Jeftinija, and V.S.-Y. Lin, 2004. A polyamidoamine dendrimer-capped mesoporous silica nanosphere-based gene transfection reagent. J. Am. Chem. Soc. 126:13216-13217.    5. Chang, H.- L., C. -M. Chun, I.A. Aksay, and W. -H. Shih. 1999. Conversion of fly ash into mesoporous aluminosilicate. Ind. Eng. Chem. Res. 38:973-977.    6. Ciuparu, D., R. F. Klie, Y. Zhu, and L. Pfefferle. 2004. Synthesis of pure boron single-wall nanotubes. J. Phys. Chem. B 108:3967-3969.    7. Barbara, P.F., A.J. Gesquiere, S.-J.Park, Y.J. Lee. 2005. Single-molecule spectroscopy of conjugated polymers. Acc. Chem. Res. 38:602-610.    8. de Boer, B., U. Stalmach, P.F. van Hutten, C. Melzer, V.V. Krasnikov, G. Hadziioannou. 2001. Supramolecular self-assembly and opto-electronic properties of semiconducting block copolymers. Polymer 42:9097-9109.    9. Gesquiere, A., M.M.S. Abdel-Mottaleb, S. De Feyter, F.C. De Schryver, F. Schoonbeek, J. van Esch, R.M. Kellogg, B.L. Feringa, A. Calderone, R. Lazzaroni, and J.L. Bredas. 2000. Molecular organization of bis-urea substituted thiophene derivatives at the liquid/solid interface studied by scanning tunneling microscopy. Langmuir 16:10385-10391.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging       10. Teetsov, J.A., and D.A. Vanden Bout. 2001. Imaging molecular and nanoscale order in conjugated polymer thin films with near-field scanning optical microscopy. J. Am. Chem. Soc. 123:3605-3606.    11. Wong, K.F., M.S. Skaf, C.-Y. Yang, P.J. Rossky, B. Bagchi, D. Hu, J. Yu, and P.F. Barbara. 2001. Structural and electronic characterization of chemical and conformational defects in conjugated polymers. J. Phys. Chem. B 105:6103-6107.    12. Schaller, R.D., L.F. Lee, J.C. Johnson, L.H. Haber, R.J. Saykally, J. Vieceli, I. Benjamin, T.-O. Nguyen, and B.J. Schwartz. 2002. The nature of interchain excitations in conjugated polymers: Spatially varying interfacial solvatochromism of annealed MEH-PPV films studied by near-field scanning optical microscopy (NSOM). J. Phys. Chem. B 106:9496-9506.    13. Barbara, P.F., A.J. Gesquiere, S.-J. Park, and Y.J. Lee. 2005. Single-molecule spectroscopy of conjugated polymers. Acc. Chem. Res. 38:602-610.    14. McNeill, J.D., D.Y. Kim, Z. Yu, D.B. O’Connor, and P.F. Barbara. 2004. Near field spectroscopic investigation of fluorescence quenching by charge carriers in pentacene-doped tetracene. J. Phys. Chem. B 108:11368-11374.    15. Muller, E.M., and J.A. Marohn. 2005. Microscopic evidence for spatially inhomogeneous charge trapping in pentacene. Advanced Materials 17:1410-1414.    16. Barbara, P.F., A.J. Gesquiere, S.-J. Park, and Y.J. Lee. 2005. Single-molecule spectroscopy of conjugated polymers. Acc. Chem. Res. 38:602-610.    17. Nonsense suppressors are produced by tethering a nonnatural amino acid to a stop (or “non-sense”) anticodon in tRNA. As a result, the stop codon in an mRNA sequence is converted from a protein synthesis termination site to a site at which the nonnatural amino acid may specifically be inserted. DNA base substitutions that correspond to the stop anticodon of tRNA may thus be made in order to specifically incorporate nonnatural amino acids into proteins.    18. Wang, L., and P.G. Schultz. 2005. Expanding the genetic code. Angew. Chem. Int. Ed. 44:34-66.    19. Monahan, S.L., H.A. Lester, and D.A. Dougherty. 2003. Site-specific incorporation of unnatural amino acids into receptors expressed in mammalian cells. Chem. Biol. 10:573-580.    20. Information and images for this case study are provided courtesy of the Cancer Research Microscopy Facility, University of New Mexico Hospital; the W.M. Keck foundation; and the following individuals: Anthony L. Garcia, Linnea K. Ista, Dimiter N. Petsev, Michael J. O’Brien, Paul Bisong, Andrea A. Mammoli, Steven R.J. Brueck, and Gabriel P. Lopez.    21. Jeong, J.-H., N. Goldenfeld, and J. Dantzig. 2001. Phase field model for three dimensional dendritic growth with fluid flow. Phys. Rev. E 64:041602.    22. Vetsigian, K., and N. Goldenfeld. 2003. Computationally efficient phase-field models with interface kinetics. Phys. Rev. E 68:60601.    23. Goldenfeld, N., B.P. Athreya, and J.A. Dantzig. 2005. Renormalization group approach to multiscale simulation of polycrystalline materials using the phase field crystal model. Phys. Rev. E 72:1-4.    24. THz spectroscopy is also known as far-infrared (FIR) spectroscopy.    25. 1 THz is equivalent to 33.33 cm-1 (wavenumbers), 0.004 eV photon energy, or 300 µm wavelength.    26. (a) Schmuttenmaer, C.A. 2004. Exploring dynamics in the far-infrared with terahertz spectroscopy. Chem. Rev. 104:1759-1779.    (b) Beard, M.C., G.M. Turner, and C.A. Schmuttenmaer. 2002. Terahertz spectroscopy. J. Phys. Chem. B 106:7146-7159.    27. (a) Smith, P.R., D.H. Auston, and M.C. Nuss. 1988. Subpicosecond photoconducting dipole antennas. IEEE J. Quantum Electron. 24:255-260.    (b) Fattinger, C., and D. Grischkowsky. 1989. Terahertz beams. Appl. Phys. Lett. 54:490-492.    28. (a) O’Regan, B., and M. Grätzel. 1991. A low-cost, high-efficiency solar cell based on dyesensitized colloidal TiO2 films. Nature 353:737-740.    (b) Beard, M.C., G.M. Turner, and C.A. Schmuttenmaer. 2002. Terahertz spectroscopy. J. Phys. Chem. B 106:7146-7159.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging       29. Turner, G.M., M.C. Beard, and C.A. Schmuttenmaer. 2002. Carrier localization and cooling in dye-sensitized nanocrystalline titanium dioxide. J. Phys. Chem. B 106:11716-11719.    30. (a) Heimer, T.A., and E.J. Heilweil. 1997. Direct time-resolved infrared measurement of electron injection in dye-sensitized titanium dioxide films. J. Phys. Chem. B 101:10990-10993.    (b) Gosh, H.N., J.B. Asbury, and T. Lian. 1998. Direct observation of ultrafast electron injection from coumarin 343 in TiO2 nanoparticles by femtosecond infrared spectroscopy. J. Phys. Chem. B 102:6482-6486.    31. The Drude model applies the kinetic theory of gases to metal conduction. It describes valence electrons as charged spheres that move through a “soup” of stationary metallic ions with finite chance for scattering.    32. Beard, M.C., G.M. Turner, and C.A. Schmuttenmaer. 2002. Terahertz spectroscopy. J. Phys. Chem. B 106:7146-7159.