Showing papers in "Accounts of Chemical Research in 1998"

Foldamers: A Manifesto

Abstract: Nature relies on large molecules to carry out sophisticated chemical operations, such as catalysis, tight and specific binding, directed flow of electrons, or controlled crystallization of inorganic phases. The polymers entrusted with these crucial tasks, mostly proteins but sometimes RNA, are unique relative to other biological and synthetic polymers in that they adopt specific compact conformations that are thermodynamically and kinetically stable. These folding patterns generate “active sites” via precise three-dimensional arrangement of functional groups. In terms of covalent connectivity, the groups that comprise the active site are often widely spaced along the polymer backbone. The remarkable range of chemical capabilities that evolution has elicited from proteins suggests that it might be possible to design analogous capabilities into unnatural polymers that fold into compact and specific conformations. Since biological evolution has operated under many constraints, the functional properties of proteins and RNA should be viewed as merely exemplifying the potential of compactly folded polymers. The chemist’s domain includes all possible combinations of the elements, and the biological realm, vast and complex though it may be, is only a small part of that domain. Therefore, realization of the potential of folding polymers may be limited more by the human imagination than by physical barriers. I use the term “foldamer” to describe any polymer with a strong tendency to adopt a specific compact conformation. Among proteins, the term “compact” is associated with tertiary structure, and there is as yet no synthetic polymer that displays a specific tertiary structure. Protein tertiary structure arises from the assembly of elements of regular secondary structure (helices, sheets, and turns). The first step in foldamer design must therefore be to identify new backbones with well-defined secondary structural preferences. “Well-defined” in this case means that the conformational preference should be displayed in solution by oligomers of modest length, and I will designate as a foldamer any oligomer that meets this criterion. Within the past decade, a handful of research groups have described unnatural oligomers with interesting conformational propensities. The motivations behind such efforts are varied, but these studies suggest a collective, emerging realization that control over oligomer and polymer folding could lead to new types of molecules with useful properties. The purpose of this “manifesto” is to introduce a large audience to the broad research horizons offered by the concept of synthetic foldamers. The path to creating useful foldamers involves several daunting steps. (i) One must identify new polymeric backbones with suitable folding propensities. This goal includes developing a predictively useful understanding of the relationship between the repetitive features of monomer structure and conformational properties at the polymer level. (ii) One must endow the resulting foldamers with interesting chemical functions, by design, by randomization and screening (“evolution”), or by some combination of these two approaches. (iii) For technological utility, one must be able to produce a foldamer efficiently, which will generally include preparation of the constituent monomers in stereochemically pure form and optimization of heteropolymer synthesis. Each of these steps involves fascinating chemical challenges; the first step is the focus of this Account.

Synthetic Strategies, Structure Patterns, and Emerging Properties in the Chemistry of Modular Porous Solids†

Abstract: The designed construction of extended porous frameworks from soluble molecular building blocks represents one of the most challenging issues facing synthetic chemistry today. Recently, intense research activities directed toward the development of this field have included the assembly of inorganic metal clusters,1 coordination complexes,2 and organic molecules3 of great diversity into extended motifs that are held together either by strong metal-ligand bonding or by weaker bonding forces such as hydrogen-bonding and π-π interactions. Materials that have been produced in this way are referred to as modular since they are assembled from discrete molecules which can be modified to have well-defined function.4 The fact that the integrity of the building blocks is preserved during the synthesis and ultimately translated into the resulting assembled network offers numerous opportunities for designing frameworks with desirable topologies and architectures, thus paving the way for establishing connections between molecular and solid properties. At least three challenges have emerged in this area that must be reckoned with in order for the ideas of rational and designed synthesis of porous materials to become a reality with routine utility. First, it is difficult to control the orientation and stereochemistry of the building blocks in the solid state in order to achieve a given target molecular topology and architecture. Second, in most cases, the products of such assembly reactions are obtained as poorly crystalline or amorphous solids, thus prohibiting their full characterization by single-crystal X-ray diffraction techniques. Third, access to the pores within open structuressan aspect that is so critical to their utility as porous materialssis often prevented by either selfinterpenetration as observed for very open frameworks or strong host-guest interactions that lead to the destruction of the host framework when removal or exchange of guests is attempted. To define and investigate the parameters contributing to the assembly of materials from molecular building blocks, we have established a program aimed at constructing modular porous networks by linking inorganic metal sulfide clusters and organic molecules with transition metal ions. Our work has focused primarily on studying the issues outlined above, and this Account presents our progress toward finding viable and general solutions to these challenges. This is illustrated by some representative examples chosen from the chemistry developed in our research effort for the three building blocks shown in a-c. Their functionality, shape, size, and

The Molecular Wire Approach to Sensory Signal Amplification

Abstract: A chemosensor is a molecular device designed to detect a specific molecule or class of molecules.1a,b Research in this field is poised for considerable advances in the coming years with the advent of diverse methods for analyte detection and new developments in the field of molecular recognition. To date, the most common signal transduction schemes utilize optical or electrical methods.1c Fluorescence is a highly sensitive optical transduction method, and analyte binding events that produce an attenuation, enhancement, or wavelength shift in the emission can be used to produce a functional sensor.1d Changes in absorption spectra, while less sensitive, have also been extensively used.1e Redox processes are widely used in electrical-based transduction methods, and typical systems function in either potentiometric or amperometric modes.1f Conductometric detection schemes based on SnO2, conducting polymers,1h and phthalocyanines1i have also been investigated. As shown in Scheme 1, a chemosensor is composed of two functional elements, a receptor and a reporter group, which need not be separate in identity. When the equilibrium between the analyte and receptor is rapid, sensors can be produced that provide a real-time response, which continuously varies with the concentration of the analyte. The detection sensitivity is determined by both the ability to measure the transduction event and the association constant of the receptor-analyte complex. As a result, when pursuing higher sensitivity one may seek instrumentation improvements and/or endeavor to increase the magnitude of the association constant of the receptor-analyte complex. The standard approach to higher association constants is to design highly preorganized receptors that do not pay a high entropic penalty for complexation. The downside of this approach is that preorganization and high association constants generally result in slow dissociation kinetics. A molecular chemosensor with slow kinetics or an irreversible response cannot yield a reversible real-time response. Molecular systems displaying irreversible or slow behavior are nonetheless useful, but are properly called dosimeters or indicators. Methods may be developed to allow irreversible systems to function in a sensory device. For example, the device can be “reset” by chemical, electrochemical, photochemical, or physical events. These processes can cause the analyte to dissociate from the receptor or can result in the replacement of the indicator (chemosensor) molecules. Such approaches have the disadvantage of introducing additional complexity into the sensor devices. This Account describes an approach to enhancing the sensitivity of chemosensors in effect by “wiring chemosensory molecules in series” (Scheme 2). Recent work from my research laboratory has shown that this molecular wire approach provides a universal method by which to obtain signal amplification relative to single molecule systems. I will use the term molecular wire interchangeably with conducting polymer. For the sake of clarity, some representative conducting polymers are shown in Scheme 3. These materials are insulators in their neutral (undoped) Timothy M. Swager is a native of Montana and received a B.S. from Montana State University in 1983 and a Ph.D. from the California Institute of Technology in 1988. After a postdoctoral fellowship at the Massachusetts Institute of Technology (1988-1990), he began his independent academic career at The University of Pennsylvania and was promoted to Professor in 1996. He is currently a Professor of Chemistry at the Massachusetts Institute of Technology. His interests in supramolecular chemistry include the design of electronic polymers, sensors, and liquid crystals, molecular recognition, and catalysis. Scheme 1

Heterogeneous Catalysts for Liquid-Phase Oxidations: Philosophers' Stones or Trojan Horses?

Abstract: Introduction In the early seventies one of us1 was involved in the development of the heterogeneous Ti(IV)/SiO2 catalyst which forms the basis of the Shell process for the epoxidation of propylene with ethylbenzene hydroperoxide (reaction 1).2 Halcon3 and ARCO4,5 workers had previously found, independently, that soluble compounds of early transition metals, e.g., Mo, W, Ti, and V, catalyze reaction 1. The mechanism of catalysis involves withdrawal of electrons from a coordinated alkylperoxo moiety, thereby increasing the electrophilic character of the peroxidic oxygens, i.e., the metal ion acts as a Lewis acid. Hence, effective catalysts are both a strong Lewis acid and a weak oxidant in their highest oxidation state. The latter criterion is necessary in order to minimize competing one-electron oxidation of the ROO ligand leading to homolytic decomposition of ROOH (see Scheme 1). These criteria are best met by molybdenum(VI), and soluble molybdenum compounds exhibit the best combination of activity and selectivity.6,7 Soluble titanium(IV) compounds, on the other hand, are rather mediocre catalysts for reaction 1. In contrast, Ti(IV)/SiO2 exhibits selectivities comparable to homogeneous molybdenum and (for a heterogeneous catalyst) high activities.8 The superior catalytic activity of Ti(IV)/SiO2 was attributed to both an increase in Lewis acidity of the Ti(IV), owing to electron withdrawal by silanoxy ligands, and to site isolation of discrete Ti(IV) centers in the silica lattice preventing oligomerization to unreactive μ-oxo species (which readily occurs with soluble Ti(IV) compounds). Furthermore, it was demonstrated that only the combination of titanium(IV) with silica affords a stable heterogeneous catalyst; all other combinations, e.g., Mo(VI), W(VI), V(V), etc., on silica, gave rapid leaching of the metal ion. One property which soluble Ti(IV) compounds and Ti(IV)/SiO2 share is a marked sensitivity toward deactivation by strongly coordinating ligands, especially water.9 For this reason Ti(IV)/ SiO2 is an ineffective catalyst for epoxidations with aqueous hydrogen peroxide. Hence the appearance in the mid-eighties of Enichem patents10 describing the remarkable catalytic activity of titanium(IV) silicalite (generally known as TS-1) in, inter alia, the selective epoxidation of olefins under very mild conditions with 30% aqueous hydrogen peroxide (Figure 1) was greeted with some scepticism. Thus, two materials, Ti(IV)/SiO2 and TS-1, having roughly the same elemental composition, i.e., 2% Ti in SiO2, exhibited totally different catalytic properties. Initial attempts by various groups to reproduce the Enichem results were largely unsuccessful. However, once it became clear that certain parameters in the synthesis

Design by Directed Evolution

Abstract: The stunning array of features and functions exhibited by proteins in nature should convince most scientists of the power of evolutionary design processes. Natural selection acting on populations over long periods of time has generated a vast number of proteins ideally suited to their biological functions. When we try to recruit these remarkable molecular machines for new tasksfrom serving as industrial catalysts to being used as additives for laundry detergentswe find that they are often not so well suited. (The chemist is not terribly impressed with a synthesis requiring a reactor the size of a football field simply because the enzyme functions in water and the substrate does not dissolve, nor is she pleased with a catalyst shut down by the products of its own reaction.) Evolution is usually the culprit: proteins are optimized, and often highly specialized, for specific biological tasks. Most protein reengineering efforts have been by so-called rational design. The filtering effect of scientific publication (successes get published, failures mostly do not) might lead one to believe that we can, with reasonable probability of success, identify and modify the amino acids responsible for key properties such as an enzyme's substrate preference, stability, or activity in a nonnatural environment. In reality, we are far from being able to do this reliably. This is true even for the relatively small number of enzymes for which considerable structural and mechanistic data are available. Admitting ineptitude in rational design, however, frees us to consider other approaches which are hardly irrational. An alternative and highly effective design strategy can be found by looking to the processes by which all these proteins came about in the first place. My research has been devoted to recreating in the laboratory the key processes of evolution and doing it in such a way that we can design scientifically interesting and technologically useful molecules. The challenge is to collapse the time scale for evolution from millions of years to months or even weeks.

Oxygen Production in Nature: A Light-Driven Metalloradical Enzyme Process

Abstract: Dioxygen is thermodynamically hot but kinetically cool, which makes it an ideal reagent for maximizing biological free energy production and for carrying out difficult chemical transformations in enzyme active sites.1 The widespread use of dioxygen in biological catalysis has led to an enzyme classification scheme s monooxygenases, dioxygenases, oxidases s that is based on the specifics of the chemistry in which O2 participates. Examples of the remarkable utility of dioxygen in biology abound and include its use in maximizing ATP production in aerobic respiration, in C-H bond activation in the P450 enzymes and methane monoxygenases, and in the degradation of important biomaterials such as lignin. Although nature has devised a multitude of mechanisms by which to activate dioxygen for useful chemistry, only one system, Photosystem II (PSII) in plants and algae, has evolved that has the capacity to lift water out of its thermodynamic well to generate dioxygen. This singular development provided photosynthetic organisms with an abundant and ubiquitous substrate for growth and diversification. The molecular mechanism by which PSII is able to strip hydrogen atoms from water and release O2 as waste is coming into view. In this article, we review the physical structure and energetics of PSII. We then discuss and analyze a metalloradical enzyme mechanism for the water-oxidation process it catalyzes.

Enzyme Catalysis: Beyond Classical Paradigms†

Abstract: Despite many decades of intense study, a full description of enzyme catalysis at the molecular level remains to be achieved A number of aspects of biocatalysis are widely accepted, including (i) the conversion of a chemical reaction from an inter- to an intramolecular process with the concomitant decrease in the entropy of activation and (ii) the stabilization of the transition state (TS) by the precise orientation of multiple functional groups at the enzyme active site These functional groups perform the roles of general acid/base, electrophilic/nucleophilic catalysis and charge neutralization via electrostatic and H-bonding interactions The process of covalent bond breaking and forming in enzyme catalysis is accompanied by substrate binding, product release, and protein rearrangement steps, which are rate determining for many enzymes The resulting, multibarrier

Diaminoarylnickel(II) “Pincer” Complexes: Mechanistic Considerations in the Kharasch Addition Reaction, Controlled Polymerization, and Dendrimeric Transition Metal Catalysts

Abstract: It was in 1945 that researchers at the University of Chicago first reported that carbon tetrachloride could be added directly to olefinic double bonds (eq 1). This process was catalyzed by peroxides as radical initiators.1 This simple reaction is a classic example of anti-Markovnikov addition and has become known as the Kharasch addition reaction,2 in honor of its discoverer, M. S. Kharasch. In the late 1930s, Kharasch and independently Hey and Waters3 had presented a free-radical mechanism to explain this kind of addition reaction, and it is now generally accepted to occur in this manner.4 The use of the Kharasch addition is, however, often overlooked in synthetic organic chemistry although it has been employed in a number of specific syntheses. A few examples of these are shown in eqs 2-6.5-7 Both interand intramolecular Kharasch addition8 is possible.