5
Isolating, Identifying, Imaging, and Measuring Substances and Structures

Some Challenges for Chemists and Chemical Engineers

  • Improve the tools for imaging and determining structure so that detailed chemical structures can be determined with tiny amounts of noncrystalline material.

  • Improve the ability of instruments to detect and quantify very low concentrations of important substances, even in very small volumes.

  • Develop effective methods for detecting dangerous materials, even when they are hidden.

  • Understand the chemistry that occurs in interplanetary and interstellar space, for which spectroscopy is the primary tool available.

  • Develop instruments for on-line process control that bring the power of modern analytical and structure-determination methods to chemical manufacturing technology

GOALS

Chemical scientists want to explore the natural world and identify all its chemical components. They also want and need to identify all of the new chemical substances produced directly and indirectly as a result of their synthetic and



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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering 5 Isolating, Identifying, Imaging, and Measuring Substances and Structures Some Challenges for Chemists and Chemical Engineers Improve the tools for imaging and determining structure so that detailed chemical structures can be determined with tiny amounts of noncrystalline material. Improve the ability of instruments to detect and quantify very low concentrations of important substances, even in very small volumes. Develop effective methods for detecting dangerous materials, even when they are hidden. Understand the chemistry that occurs in interplanetary and interstellar space, for which spectroscopy is the primary tool available. Develop instruments for on-line process control that bring the power of modern analytical and structure-determination methods to chemical manufacturing technology GOALS Chemical scientists want to explore the natural world and identify all its chemical components. They also want and need to identify all of the new chemical substances produced directly and indirectly as a result of their synthetic and

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering manufacturing endeavors. As described in Chapter 7, much of this has involved learning the nature of the substances that are part of, and produced by, living organisms. Generally it is necessary to learn how to separate complex mixtures into their pure components, and then determine the molecular structure of each component. This sequence is also necessary for the substances that are created in the laboratory or in manufacturing. If a mixture is produced, it must be separated into its components, and each new species must have its chemical structure determined. Detecting known substances, and determining their quantity, is also important. In synthetic research, it is essential to know the relative proportions of various reaction products. In manufacturing, it is important to detect any impurities in the product and to determine whether they are present in a significant amount. Analytical characterization is critical in pharmaceutical products, for instance. Products for practical uses—paint or adhesives, for example—will typically consist of several components. For proper and reliable performance it is important to measure the amounts of each of the components as part of a manufacturing quality control system. Manufacturers also commonly need to analyze the raw materials they receive, measuring the amounts of various substances in them to be sure that the material meets their requirements. Before it can be correctly processed into steel, iron ore must be analyzed to determine how much of other components need to be added to produce a metal alloy of the desired composition and properties. The determination of quantity in complex mixtures is also vital in health care and medicine. We are all familiar with the medical examinations in which a sample of blood or urine is sent to a laboratory for analysis. The procedures used have been developed by chemists, and are performed by trained chemical technicians. The high level of automation achieved by the chemists who designed these analytical procedures has greatly reduced the costs of such analyses. Clinical analysis continues to be driven by a need for better methods to detect and measure important proteins, for example, that while present in tiny amounts are relevant to our health and well-being. There is a constant need for better methods of chemical analysis, driven by our need to know “What’s in that, how much is present, and how long will it last?” The frontiers in this field lie in improving sensitivity to detect vanishingly small quantities, to separate extremely complex mixtures of chemical substances, and to assess the structures or compositions of components. Measurements using very small or very dilute samples can present a major challenge in clinical medicine or environmental analyses. Moreover, often we must deal with all of the above determinations in extremely small spaces, such as that of a living cell. Fundamentally new approaches may be needed to achieve these objectives. As an important example, there is currently a need for sensitive methods to detect—in a high-throughput environment—explosives in airplane baggage and in land mines in war-torn areas (see also Chapter 11). These problems are being approached by

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering developing very sensitive arrays of chemical detectors, sometimes called artificial noses, that can detect and identify volatile components of explosives in very small amounts. Other problems are learning to detect chemical and biological warfare agents, both on the battlefield and in civilian areas, and to detect trace components in our environment, either anthropogenic or of natural origin, that offer health risks to living organisms: human, beast, insect, fungus, and plant. PROGRESS TO DATE Structure Determination A vital activity of the chemical sciences is the determination of structure. Detailed molecular structure determinations require identifying the spatial locations of all of the atoms in molecules, that is, the atomic distances and bond angles of a species. It is important to realize that the three-dimensional architecture of molecules very much defines their reactivity and function. However, molecules are dynamic, a feature that is not reflected by static pictures. This last point requires further explanation. Because the atoms in all molecules move, even in the limit of the lowest temperatures obtainable, molecular structures really describe the average position about some equilibrium arrangement. In addition, rotations about certain bonds occur freely at common temperatures. Consequently, some molecules exist in more than one structure (conformation). Some molecules are so floppy that structural characterizations really refer to averages among several structures. Yet other molecules are sufficiently rigid that molecular structures can be quite precisely determined. The techniques available to achieve molecular structure determinations are limited. They include structural analysis with diffraction techniques—such as electron, neutron, and x-ray diffraction—and various absorption and emission techniques of electromagnetic radiation—such as microwave spectroscopy and nuclear magnetic resonance (NMR). For molecules with unpaired spins a companion technique of electron spin resonance spectroscopy (ESR) is highly informative. A number of other spectroscopies provide information that is related to molecular structure, such as coordination symmetry, electronic splitting, and/or the nature and number of chemical functional groups in the species. This information can be used to develop models for the molecular structure of the system under study, and ultimately to determine the forces acting on the atoms in a molecule for any arbitrary displacement of the nuclei. According to the energy of the particles used for excitation (photons, electrons, neutrons, etc.), different parts of a molecule will interact, and different structural information will be obtained. Depending on the relaxation process, each method has a characteristic time scale over which the structural information is averaged. Especially for NMR, the relaxation rate may often be slower than the rate constant of a reaction under study.

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering The application of theoretical tools for predicting molecular structure, such as ab initio calculations and density functional methods, are discussed in Chapter 6. These tools provide only a first approximation to the molecular structure. There is much room for further development of theoretical molecular structure calculations, but even so such methods have already become a standard part of molecular structure determinations. The following section presents a variety of instrumental spectroscopic techniques for the determination either of molecular structure or of parameters related to molecular structure. The applicability of each method, its particular advantages as well as its limitations, are presented. It is not an exhaustive list. The spectroscopic methods are discussed in order of increasing excitation energy. Nuclear Magnetic Resonance Spectroscopies NMR has proven to be invaluable as a tool for structure determination, particularly of new compounds isolated from nature. All synthetic chemists use NMR to see whether they have made the product they want, even if it is a previously unknown molecule. In fact, NMR has really revolutionized the practice of organic synthesis. NMR is typically applied to molecules in solution, so it can be used with noncrystalline materials, for which x-ray crystallography is not possible. It also can be used to learn whether the structure determined in the solid state by x-ray methods is maintained in solution. This is particularly important for proteins, which are flexible enough that they can change shape to some extent when they dissolve. A Nobel Prize in 1991 went to Richard Ernst for inventing new techniques in NMR that are important tools in the study of proteins. Kurt Wüthrich shared a Nobel Prize in 2002 for developing NMR methodology that enables determination of the three-dimensional structures of biological macromolecules in solution. NMR finds its main application in the analysis of solutions, using 1H as the most sensitive nucleus; 13C, 19F, and 31P nuclei are also used frequently. NMR yields information on chemical functional groups of organic ligands and has revolutionized work in synthesis. Multi-dimensional techniques can be used for finding spatial connections between nuclei and gaining information on molecular dynamics. An important recent advance is NMR on solids, not solutions, with which it is possible to study the structures of polymers, of proteins in membranes, and of chemicals immobilized on solid supports. The application of NMR to imaging the human body, or magnetic resonance imaging (MRI), has revolutionized the practice of medicine. The major current limitation of NMR is its sensitivity (ca. 10−4 M in 1H, 13C, 19F, 31P). It is expected that higher sensitivities will be reached in the future as more powerful magnets with improved instrumentation and software become available. The ultimate goal would be to perform NMR analyses of single molecules.

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering Rotational Spectroscopies Rotational spectra provide measurement of the moments of inertia of a chemical species. Bond angles and bond lengths can be derived by making isotopic substitutions and measuring the resulting changes in the moments of inertia. A major drawback of rotational spectroscopies is the limited information contained in a measurement of the moment of inertia. Consequently, while quite precise, it is generally limited to smaller molecules. It is the chief technique used to identify molecules in outer space, such as the components of interstellar gas clouds. Vibrational Spectroscopies Infrared and Raman spectroscopies provide complementary information concerning the type of functional groups present, as well as bond strengths in a molecule. Recent experiments using infrared pulse sequences offer the tantalizing possibility of bringing to infrared and Raman spectroscopies the same advantages that have been realized in pulsed NMR spectroscopies—greater sensitivity and higher information content. A major limitation of vibrational spectroscopies has been the congestion of overlapping features at lower frequencies. However this congestion makes an infrared spectrum a literal fingerprint of the structure of small molecules, so the identity of known molecules can be assessed from a library of their spectra. Some of the molecules in interstellar space have been identified by their infrared spectra. New resonant enhancement techniques can provide useful information about molecules on surfaces and at interfaces. Electronic Spectroscopies The interaction of species with shorter wavelengths of radiation causes electronic excitation (bound-bound electronic spectroscopy) or even ejection (bound-continuum photoionization). These events also show the fine structure of the motions of the nuclei. In addition, nuclear motions moderate the energies of the ejected electrons, and an analysis of the electron energy provides additional chemical information. Thus, x-ray photoelectron spectroscopy (XPS) is an excellent technique for determining an atom’s electron binding energies, at least for species on the surface of the material under study. Valuable information about surfaces can also be obtained from ultraviolet photoelectron spectroscopy (UPS), a technique that reveals ionization potentials and molecular orbital orderings for substances in general. By comparing the chemical shifts and peak heights of an unknown with standards or known reference materials, some predictions of the unknown structure can be made. In some exceptional but important cases, such as the photodetachment of negative ions, the wavelength of light causing photoionization is in the visible or even the near infrared, allowing extremely precise structure determinations.

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering Another noteworthy example is x-ray absorption fine structure (EXAFS). EXAFS data contain information on such parameters as coordination number, bond distances, and mean-square displacements for atoms that comprise the first few coordination spheres surrounding an absorbing element of interest. This information is extracted from the EXAFS oscillations, previously isolated from the background and atomic portion of the absorption, using nonlinear least-square fit procedures. It is important in such analyses to compare metrical parameters obtained from experiments on model or reference compounds to those for samples of unknown structure, in order to avoid ambiguity in the interpretation of results and to establish error limits. The absorption spectra in the x-ray absorption near edge structure (XANES) region contain information concerning coordination geometry and metal ion valence. EXAFS and XANES data can be obtained on samples in different physical states or in solution and can be made element selective by tuning the wavelength used for the study. A drawback of these absorption spectroscopies is the need to bring the sample to a large dedicated facility. Nuclear Structure Spectroscopies Nuclei also have bound energy levels that can be accessed with gamma-ray sources. Of great chemical interest is Mössbauer spectroscopy, which takes advantage of the recoil-free emission of gamma radiation from a solid radioactive material. Because the gamma emission is recoil-free, it can be resonantly absorbed by stationary nuclei in a solid. Typically, the gamma ray source is mechanically vibrated back and forth to Doppler shift the energy of the emitted gamma radiation. A detector records the frequencies of gamma radiation that are absorbed by the sample as the energy of the gamma radiation is scanned by Doppler shifting. The nuclear transitions are very sensitive to the local environment of the atom, and Mössbauer spectroscopy is a sensitive probe of the different environments an atom occupies in a solid material. By analyzing the chemical shifts and quadrupole splitting in Mössbauer spectra of samples containing Mössbauer-active nuclei, information on the state of oxidation and the local structure can be obtained. Only a few nuclei can be used for this purpose, so this method has limited but powerful applications. Diffraction Techniques X-ray, neutron, and electron diffraction techniques are used to determine crystal structures and can thus be used for molecular structure determinations. Because of its high resolution and applicability to small and often weakly diffracting samples, x-ray crystallography and powder diffraction are by far the methods of choice for most structure determinations on crystalline compounds,

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering either single crystals or crystalline powders. Diffraction techniques are not applicable to amorphous phases at present, but the exciting possibility looms on the horizon to use ultra-fast techniques to obtain diffraction patterns of possibly as little as one biological molecule (see below). The intensity and tunability of synchrotron radiation have revolutionized the application of x-rays for studying the structure of macromolecules, enabling much higher resolution information to be obtained on increasingly large and complex molecular systems. The average bulk crystalline structure determined from diffraction studies is expressed as simple, small, symmetric arrangements of atoms in a unit cell. However, local deviations from this average structure are often the driving force behind the collective behavior of a crystalline compound. Neutron crystallography has the unique advantage of high contrast for the location of hydrogen atoms, so it affords information complementary to that normally obtained from x-ray crystallography. As conventionally applied today, x-ray methods give rise to “time-averaged” structural information. Since many chemical processes, including the making and breaking of chemical bonds, occur in the subpicosecond time domain, time-resolved structural information has been limited and only indirectly available. Recent developments in electron diffraction and soon-to-be-available x-ray laser sources could dramatically improve the investigation of structural dynamics. Compressed electron pulses can be produced with reasonable intensities and widths of a few picoseconds; these are being used to study relatively simple molecular reactions. X-ray free-electron lasers, based on using high energy linear accelerators providing beams to long undulators, have the promise of easily reaching pulse lengths of only a few hundred femtoseconds and, with additional magnetic and optical compression schemes, likely the regime of only a few femtoseconds. Such x-ray free-electron lasers might have sufficient photons in a single pulse to record an entire diffraction pattern, hence bringing the most powerful tools used today for structural determination to bear on understanding chemical and biological reactions. A major limitation of diffraction techniques has been the need to obtain crystalline samples. If scientists could learn how to crystallize large molecules in a routine manner, a breakthrough would result. In the biological area, this limitation is keenly experienced for membrane-bound proteins, which are important in many biological functions. Scientists are now devising techniques and strategies to crystallize these proteins—if not in three-dimensional, then in two-dimensional lattices. Future development of spectroscopic structure-determination methods will depend on the availability of more powerful photon and particle sources as well as advances in photon and particle detectors. Impressive progress has been made in molecular structure determinations based on advances in computation power and in computational algorithms, such as fast Fourier-transform techniques, for nearly every form of spectroscopy and diffraction analysis. Hajdu and co-work-

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering ers1 have presented calculations estimating radiation damage of samples. They suggest that useful structural information might be obtained before radiation damage destroys the sample by using femtosecond x-ray pulses. Moreover, their calculations indicate that sufficiently bright light sources might be capable of imaging ultrasmall samples at sizes approaching that of a single biological molecule. Structure determination has greatly advanced with the invention of new ways to use x-ray crystallography, mainly new mathematical methods that permit the interpretation of the observed patterns of diffraction of x-rays by a crystal, translating it into the molecular structures in the crystal. A Nobel Prize in 1985 to Herbert Hauptmann and Jerome Karle recognized such an advance. Mass Spectrometry The “weighing” of a molecule of a chemical substance and of its fragments has great utility in both assessing molecular identity and determining molecular structure. The determination of molecular weight is after all one of the most elemental aspects of puzzling out the structure and identity of an unknown sample or a new substance. Furthermore, if the molecular mass can be determined with sufficient accuracy, the elemental formula of the substance can be estimated or at least the possible choices narrowed considerably. For materials such as those encountered in biologically derived samples, where the quantities available are very small, determining a molecular weight and elemental formula are extremely important steps. Ion cyclotron resonance mass spectrometry (ICR-MS) has been especially effective at exact mass determinations. Mass spectrometry requires that the material being studied be converted into a vapor. Great strides have been taken in recent years to address this problem, especially in enticing large, thermally fragile (bio)molecules into the vapor state. Matrix assisted laser ionization-desorption (MALDI) and electrospray ionization (ESI) are two current forefront methods that accomplish this task. Even components of bacteria and intact viruses are being examined with these approaches. John B. Fenn and Koichi Tanaka shared in the award of a Nobel Prize in 2002 for their respective contributions to development of electrospray ionization and soft laser desorption. A decade or so ago, mass spectrometry was regarded as a “mature” area of methodology. The invention of new ways to volatilize molecules, from solids and from surfaces, has revolutionized and re-invigorated this field. It is an excellent example of how new ideas can make even supposedly “dead” areas find new life. 1   Neutze, R.; Wouts, R.; Van der Spoel, D.; Weckert, E.; Hajdu, J. Nature, 406 (6797) p. 752, 2000.

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering Measurement Science, or Analytical Chemistry The scope of this branch of chemistry encompasses both the fundamental understanding of how to measure properties and amounts of chemicals, and the practical understanding of how to implement such measurements, including the design of the necessary instruments. The need for analytical measurements arises in all research disciplines, industrial sectors, and human activities that entail the need to know not only the identities and amounts of chemical components in a mixture, but also how they are distributed in space and time. These sectors of need include research in specific disciplines (such as chemistry, physics, materials science, geology, archeology, medicine, pharmacy, and dentistry) and in interdisciplinary areas (such as forensic, atmospheric, and environmental sciences), as well as the needs of government policy, space exploration, and commerce. Practical needs for analysis come from the activities of industrial enterprises and government functions that span manufacturing, shipping, communications, domestic power, water supplies, waste disposal, forensic analysis, environmental policies, international verification of quality and quantity (metrology), and far from least of all, national security. The need for measurements of chemicals is ubiquitous—measurements of the mass and dimensions of chemical substances and of their capacity to adsorb heat, to absorb or reflect light, and to respond to pressure and temperature. Many measurements also must be made under varying constraints of speed, cost, and location of the measurement. This enormous diversity of customers seeking analytical information places pressing and urgent demands on chemical scientists. In response, many great successes have been achieved but, at the same time, fast-moving advances in science, technology, and human activity continue to awaken sleeping giants that demand new, better, faster, cheaper, more sensitive, and more selective measurements. The following is an outline of some success stories in analytical measurements. They are categorized in terms of progress in improving sensitivity for measuring very small quantities, of dealing with sample complexity, of measuring large molecules, of making measurements in small dimensions, and of increasing the throughput of new analytical information. Sensitivity Nearly every area of measurement science can boast of progress in measuring ever-smaller quantities of chemicals, but several stand out in their stunning trace-analysis capabilities. Trace-metal analysis has come to be dominated by methods that volatilize the sample and then either measure its spectroscopic emission or absorption, or measure the masses of the gaseous metal ions using mass spectrometry. Volatilization is accomplished by various thermal means that include flames, furnaces, and inductively coupled or microwave plasmas. The com-

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering bination of the inductively coupled plasma with mass spectrometry allows high-sensitivity analysis of virtually every metallic element in the periodic table. These methods are used world-wide for trace-metal analysis. Lasers have innumerable uses in measurement science; in the excitation of molecular emission (fluorescence) they have become workhorses of analytical instruments and have produced remarkable levels of analytical sensitivity. Lasers are widespread as components of detectors in commercialized chromatographic instruments and clinical analyses. Laser-induced fluorescence has been carried to the ultimate sensitivity of detecting single molecules—there is no more sensitive measurement than this! The very idea of measuring ultralow concentrations loses its meaning when one detects a single molecule, but the fruit of this remarkable accomplishment is that one can contemplate measuring variations in properties of individual molecules, including enzymes and other proteins. In addition, by following the time behavior of a single molecule it would be possible to unmask many important aspects of structure, kinetics, and function of molecules that are hidden by measurements over averages of many molecules. This sensitivity advance revolutionizes how chemical scientists think about measuring molecular behavior, which in the past has always reflected averages of many molecules. Single-molecule spectroscopy thus offers valuable information that cannot be obtained by studying a bulk sample. In clinical analysis, one of the recent advances has been the use of antibodies to detect biologically important substances, including medicines. Chemists and chemical engineers devised ways to translate the binding of a molecule to an antibody into a detectable signal, sometimes amplifying the signal by an enzyme-catalyzed reaction that could be modulated by antibody binding. Such methods have largely replaced related methods using radioactive tracers. Sample Complexity Sample complexity refers to measurements of mixtures of chemicals and to their context. Complexity can mean large numbers of similar chemicals being simultaneously present (petroleum for example), mixtures of very large similar molecules (biomolecular systems), reactivity and thermal fragility of mixture components, and the context of the analysis (such as detection of explosives in airport luggage). The invention of various methods for separating the chemical components of complex mixtures has benefited enormously from the techniques generally known as chromatography and electrophoresis. These techniques and the instruments used in them are constantly being improved. The principal analytical methods for complex samples are those that separate the mixture by differential migration and then detect the separated components. The separation methods are chromatography, electrophoresis, and field flow fractionation; the detection methods—which need not be selective but must be sensitive—include absorption, laser-induced fluorescence, electrochemistry, and mass

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering spectrometry. Gas chromatography (GC), high-performance liquid chromatography (HPLC), and capillary electrophoresis (CE) have been extremely successful. HPLC has become the backbone of the pharmaceutical industry, providing essential information on purity (chemical and isomeric) of candidate and manufactured drug agents. GC is routinely the method of choice for gaseous or easily volatilized mixtures, and is commonly used with a mass spectrometer to identify the mixture components as well as to detect and measure their quantities. CE is the most powerful existing separations method (by orders of magnitude), and it is used for very difficult separations. As analytical chemistry has advanced into the world of molecules that biology creates, CE is the method of choice for the hugely complex mixtures of chemicals present in living organisms and their cellular subcomponents. CE has been employed for separation of the contents of individual cells and subcellular compartments (organelles), and it is the enabling analytical method for the Human Genome Project. An important frontier continues to be practical ways to combine the merits of different separation methods, such as HPLC-CE, to create hybrid separation techniques. Other analytical approaches to complex systems include methods that respond selectively to individual chemicals (or a selected class), the detection of which is of paramount importance. Examples are chemical and biological warfare agents, industrial pollutants and toxins, and carbon monoxide in the air in our homes. Attaining analytical selectivity outside a pristine laboratory setting is one of the most difficult and widely unsolved analytical needs. Ion mobility spectrometry (IMS) and gas chromatography/mass spectrometry (GC/MS) are on trial in airport security checkpoints. While one can point to many successes, including the CO detector in your home, analytical chemistry continues to struggle for sensitivity and selectivity in competition with nose-based odor detection by dogs! Macromolecules and Biomacromolecules The birth of polymer science provoked numerous new analytical challenges several decades ago; the existing thrust of chemical sciences into molecular biology is now provoking many more challenges at a rapid pace. Polymers, along with pharmaceuticals, are arguably the most important and beneficial substances that synthetic chemistry has brought to the human race. Synthetic polymers generally consist of individual molecules having different chain lengths and molecular weights. This complexity is an important factor in determining properties of the polymer. Understanding of relations between polymer structure and properties has been aided enormously by the development of gel permeation chromatography (which measures the dispersity of polymer chain length), of infrared spectroscopy (which measures functional groups), and of thermal methods like differential scanning calorimetry (which detects polymer crystallinity). There have likewise been early successes in addressing measurements of biopolymers, particularly their molecular weights, and to a more limited extent

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering their structure and folding. The most important techniques for structure determination, in addition to x-ray crystallography, include high-field nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). A host of computer-reliant nuclear relaxation protocols and high-field magnet technology have combined to cement an NMR foundation that has brought about a 30-fold advance in terms of chemical shift resolution from the first commercial introduction of NMR in the 1960s. In mass spectrometry, there is an ongoing evolution of ways to entice large, thermally fragile biomolecules into the gas phase; the methods of electrospray ionization (ESI) and matrix-induced laser desorption-ionization (MALDI) are presently the most widely adopted. Small Dimensions The measurement of a chemical on a surface or in a small volume has historically been quite challenging. The amounts of sample are small, so the measurement must be sensitive; the sample is spatially localized, so the measurement must be spatially selective; and the sample may exhibit ordering that the measurement must be able to detect. The advances in measurement capabilities in this arena have been truly remarkable and are ongoing. Most of the measurements are based on principles that were unknown 50 years ago. Surface analysis can now call on x-ray and Auger photoelectron spectroscopy (AES) to measure emitted photoelectrons, revealing the identity of atoms within several nanometers of a solid surface. Secondary ion mass spectrometry (SIMS) measures the emitted-ion consequences of crashing energetic or heavy ions onto the surface. Molecular ordering and quantities on surfaces can be delineated using vibrational spectroscopy, surface plasmon resonance spectroscopy, and Raman and surface enhanced Raman spectroscopy (SERS), all of which have been enabled by the laser. These advances in surface composition and structure analysis have been crucial in the development of the microelectronics industry, which lives or dies by the properties and composition of surfaces. Imaging of the lateral composition and topography of surfaces has long been an important area and includes topics like electron microscopy—which has made phenomenal advances in recent years—and scanning Auger electron spectroscopy. The measurement of ordering and arrangements of atoms and molecules in a small volume or on a surface was given a quantum leap by the invention of scanning tunneling microscopy (STM) and its progeny of various atomic force and surface force microscopies. The enabling tools in the new instruments were (again) the laser, piezoelectric materials, and computer instrument-control. It is presently possible to visualize the ordering of atoms on a surface, and even to arrange individual atoms, such as “quantum corrals,”2 with the contacting tip- 2   S. L. Silva and F. M. Leibsle, Surface Science, 441, L904, 1999.

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering probe. Much further understanding of the structures of semiconductor surfaces has been derived from STM measurements, with important technological dividends. DNA chains lying on a surface can be imaged, and even individual molecules can be stretched in order to understand the energy of their folding. Imaging of molecularly soft surfaces such as the surfaces of cells offers an enormous potential for understanding organization of molecules in natural life systems. The probe tips of surface probe microscopies can also be made chemically sensitive. This is an exciting development by giving us a new dimension of molecule-scale imaging of chemical properties, for instance by detecting interactions between a molecule on a probe tip with a receptor site on a surface. Emerging research on nanostructures will rely heavily on microscopy, including its STM and surface forces forms. There have also been major advances in measuring transfers of electrons within small sample dimensions. The science of attaching chemicals to electrodes (chemically modified electrodes) has enabled measurements of electron transfer kinetics associated with electrocatalysis and electroanalysis. Significant applications include attaching enzymes to the electrode coatings for use in, for example, the monitoring of blood glucose for diabetics. Another small-dimension analysis is enabled by using microscopically small electrodes, which are capable of detecting, in real time, the single-vesicle release of neurotransmitters from neuronal cells. These microelectrodes are having a substantial impact on the general science of neurochemistry. Overall analysis in small dimensions seems to be in an enormously promising infancy, and is far from having achieved its limits even with existing ideas. Throughput of Analytical Information The worlds of science and technology continually demand more information per unit time (and per unit cost); there is an ongoing revolution in response to this demand. The Human Genome Project, for example, provoked advances in capillary electrophoresis instrumentation that can now produce sequencing results on the order of one base pair per second. Combinatorial synthesis has precipitated orders-of-magnitude increases in the demand for the analysis of structural and reactivity information. In both DNA sequencing and combinatorial chemistry, the concept of “parallel” analysis has emerged, in which instrument design focuses on simultaneous analysis of many different samples. The scope of parallel analysis can be expected to grow for years to come. A significant concept in this emerging field is miniaturization of the entire measurement into a “Star Trek”-like microchip device that would allow instant analysis of a microsample with a microinstrument. The true capabilities of miniaturized instruments remain to be defined, but they are already impressive. Chip technologies hold the promise of allowing many parallel measurements to be done simultaneously at little cost.

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering Process Analysis Monitoring the course of chemical transformations during chemical processing and manufacturing is a crucial component of commercial activity. Desirably the analysis is in real time and with the required selectivity and sensitivity to adequately inform the process engineer. A possible future process analysis challenge is monitoring a chemical self-assembly process, where chemists and chemical engineers want to know about the “extent of reaction.” The chemical process may involve covalent chemical transformations, or be simply the adoption of the desired physical structure. The tools could be optical (UV-visible or IR absorption, for example) or measurements of density or heat evolution. When the evolution of structure effectively captures the “extent of reaction,” structural characterization tools should be sufficient. More difficult problems would be posed for process control in multicomponent materials with complex structural features where the measurements should be real-time (instantaneous) and provide information for feedback control of the process. The analytical time constants required for real-time measurements would be less than that inherent in the self-assembly, which may have widely varying inherent characteristic times, and are influenced by extensive molecular transport and organization. The close coupling of developments in new on-line measurements with process control theory and practice will be crucial to the fullest possible development of chemical manufacturing. This is only one example of many future challenges in process analysis. CHALLENGES AND OPPORTUNITIES FOR THE FUTURE Chemical measurements will continue to be challenged by the broad advances of the chemical sciences. It is not possible to overstate the future need for massively parallel, high-throughput, miniaturized, and widely distributed instrumental analyses, preferably with “smart instruments” that are self-calibrating and highly automated. Furthermore, a related need exists for massive automation in data reduction, storage, retrieval, and graphic presentation. The necessary devices will revolutionize the practice of medicine and the understanding of the life sciences, and they will provide chemists and chemical engineers with the tools for discovery and for process control. At the start of the 21st century, we are witnessing a discernible shift from hypothesis-driven science and technology to information-driven science and technology. In the 21st century, the interaction of measurement science with theory, modeling, and simulation will play a central role in the acquisition of information and its conversion into useful knowledge. New fundamental knowledge is essential for advancement in the measurement sciences, particularly in nanoscale science and technology, which are at the heart of future advances in automated storage and retrieval of information. The measurement sciences correspond to a

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering convergent need in both the Human Genome Project and the quest for new materials. Increasingly, precise and quantitative measurements are equally essential to advancing the acquisition of fundamental knowledge. The chemical world is often divided into “measurers” and “makers” of molecules. This division has deep historic roots, but it artificially impedes taking advantage of both aspects of the chemical sciences. Of key importance to all forms of chemistry are instruments and techniques that allow examination, in space and in time, of the composition and characterization of a chemical system under study. To achieve this end in a practical manner, these instruments will need to multiplex several analytical methods. They will need to meet one or more of the requirements for characterization of the products of combinatorial chemical synthesis, correlation of molecular structure with dynamic processes, high-resolution definition of three-dimensional structures and the dynamics of their formation, and remote detection and telemetry. The development of measurement tools of unprecedented specificity and sensitivity will be central to achieving a molecular-level understanding of complex systems that will allow molecular interactions and their time evolution to be fully understood. Moreover, the challenge of solving increasingly complex problems, with the accompanying paradigm shift from hypothesis-driven to information-driven science, places a premium on rapid, parallel, and inexpensive measurements. These trends are especially evident in the Human Genome Project, in combinatorial chemistry, and in the study of the chemical networks that control cell function. Additional instrumentation demands spring from the reduction in size of systems that must be studied to the microscale and nanoscale levels. This size reduction will require greatly increased instrumental sensitivity as well as new mathematical approaches to pattern recognition and graphics display. The need for new fundamental knowledge of interfacial and transport phenomena will be accentuated by the dramatic increase in the surface-to-volume ratio that will result from the corresponding reduction in sample size. New technologies that permit multiplexed measurement at higher spatial resolution and greater molecular specificity are emerging, and established technologies are being further developed to enhance speed, resolution, and sensitivity. Urgent expansion is needed for activities in the measurement sciences to achieve a variety of goals: Develop new concepts and associated instrumentation in five broad categories: High-performance instruments and measurements of unprecedented precision, sensitivity, spatial resolution, or specificity; Low-cost, robust instruments and measurements for monitoring and analyzing exceptionally small volumes, for real-time control of pro-

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Beyond the Molecular Frontier: Challenges for Chemistry and Chemical Engineering cesses, or for detection of chemicals and biotoxins without physical contact; High-throughput measurements, including informatics and mathematics for interpretation of large-volume data streams; Separation and analysis of chemical and biological mixtures of extreme complexity and heterogeneity; Determining the structural arrangements of atoms within noncrystalline chemical substances, and resolving how they change as a function of time, on any time scale. Integrate measurement science into the fundamental intellectual core of graduate education and training for scientists and engineers. WHY THIS IS IMPORTANT The most fundamental question that anyone can ask when looking at a new material is, “What are the molecules (or ions, etc.) in it, and how much of each is there?” For a chemical scientist, this means discovering the molecular composition of all the components in some substance, their quantitative amounts, and their arrangement with respect to each other. The context of this discovery can be our own bodies, the swamp next door, the air on the highway, the white powder in an envelope, and, in the broadest context, the planet next door or a galaxy away. When we want to know more about other planets in our solar system, we devise instruments that can go to those planets and examine their chemical components. The instruments need to be able to detect and measure the chemicals that are present, and determine if they might indicate present or past life on those planets. Such tools let chemists and chemical engineers isolate, detect, and measure—so they can explore the chemical universe. The instruments that allow them to determine chemical structures permit them to identify the novel components of that universe, including those parts of it that humans themselves create. In practical terms, detecting and measuring are critical to all aspects of human activity—to manufacturing, to our environment, to health and medicine, to agriculture, and to national security. Thus it is essential that chemical scientists continue to improve the tools and methods needed for this central scientific activity.