Haters gona hate this How Molecular Recognition Developed into Molecular Recognition Technology
Posted on September 12, 2015 by Reed M. Izatt, PhD
Pedersen’s Ground-Breaking Discovery
How one molecule recognizes another has long intrigued scientists. The ability to explore this recognition property in a systematic way was accelerated by Pedersen’s discovery at duPont in the 1960s that cyclic polyether hosts selectively complexed alkali metal ion guests [1]. This discovery laid the foundation for achievement of an elusive goal: creation of reagents of high specificity for a single chemical species with minimal interference from competing species.
UcorePhoto1My research partner, James J. Christensen, and I were among the first scientists, beginning in 1969, to quantitate the selectivity noted by Pedersen by measuring and compiling log K values for macrocycle-metal ion interactions [2]. An important result of Pedersen’s work was that it became immediately evident to the scientific community that well known organic chemistry synthetic procedures could be used to prepare an essentially unlimited variety of new ligands that could be used to investigate host-guest selectivity in a well-designed and selective manner for a wide range of species. I was young in 1969 and Pedersen was near retirement from duPont. We became good friends (Figure 1). Jim Christensen and I were the first non-duPont scientists to visit Pedersen after publication of his cyclic polyether investigations and our early studies involved compounds provided by him. He and his work had a great influence on me and my future research direction in host-guest molecular recognition processes, which I appreciate. My vision of where this work might lead is given in our first publication describing our results [2a]: “there exist unusual opportunities for the synthesis of macrocyclic molecules that exhibit a high degree of selectivity in metal binding.” My associates and I capitalized on these opportunities as will become evident in the material which follows. I have had the opportunity to prepare several publications honoring Pedersen, which describe his life and work that led to his receipt of the 1987 Nobel Prize in Chemistry [3]. His early contributions to the field of molecular recognition were truly monumental.
Remarkable Growth of Macrocyclic Chemistry Leading to the 1987 Nobel Prize in Chemistry
The message was out and, world-wide, scientists responded quickly and with fervor. A new field of science was born which early on was termed macrocyclic chemistry. A new term, ‘crown ether,’ became part of the chemistry vocabulary. This term reflected the similarity between a ‘crown’ on a monarch’s head and the fit of the cyclic polyether host to the metal guest.
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UcorePhoto2An illustration of this fit is shown in Figure 2 for the ligand 18-crown-6 containing K+ in its cavity. Ionic radii match for this host-guest pair, Na+ would be too small and ‘rattle around’ while Cs+ would be too large and lie above the cavity. The fit of the guest metal ions in the host cavity is consistent with log K values valid in methanol at 25 °C for 18-crown-6 interactions with these metal ions, i.e., Na+ = 4.36 , K+ = 6.10, and Cs+ = 0.99 [4]. Our research specialties included the determination and interpretation of thermodynamic quantities (log K, ΔH, ΔS) for host-guest interactions. These quantities, especially log K, provide a quantitative basis for measuring and understanding molecular recognition processes. Over the years, I have been involved in preparation of numerous Chemical Reviews articles on thermodynamic quantities associated with macrocycle host-metal ion (and other) guest interactions [5]. The thermodynamic values in these compilations have been valuable because they provide a measure of molecular recognition and a basis for intelligent design of guest-selective hosts.
A decade after Pedersen’s landmark publication, the macrocyclic chemistry field had shown remarkable growth. Roeland Nolte remembers [6] that during a stay as visiting scientist in Donald Cram’s laboratory at UCLA in 1981, Cram told him that “after reading Pedersen’s paper he had become so excited that he had made the decision to completely change his research program.” This attitude was catching. Nolte goes on to say, “After having seen the potential of host-guest chemistry and the way it was approached by Cram, i.e., by designing compounds with the help of space-filling (CPK) models, we became fascinated and concluded that we should start a line of research in The Netherlands in which this new type of chemistry was incorporated.” Another early worker, Jean-Marie Lehn, had coined the term, ‘supramolecular chemistry,’ to describe the broadening of the scope of host-guest chemistry which he and his research group spearheaded [7]. To quote Prof Lehn, “Beyond molecular chemistry, supramolecular chemistry aims at constructing highly complex, functional chemical systems from components held together by intermolecular forces.” These components can be visualized as host-guest systems bonded by intermolecular forces, which are much weaker than covalent chemical bonds. The guest systems may include organic guests as well as metal ions and the number and variety of hosts synthesized expanded far beyond macrocyclic compounds.
UcorePhoto3Lehn’s article [7a], particularly the early part, describes the development of supramolecular chemistry, which, in his case, resulted in his receipt of the 1987 Nobel Prize together with Donald Cram and Charles Pedersen. The 1987 Nobel Prize in Chemistry was awarded for the “development and use of molecules with structure-specific interactions of high selectivity.” [8] The three Nobel Laureates were not alone in the pursuit of molecular recognition processes. Journals were initiated with molecular recognition prominently portrayed in their titles to meet the demand for publication of research results in this rapidly expanding field [3b,9]. I was on the Editorial Board of one of these journals [3b] for several decades. I am also editing a book to be published by Wiley in early 2016 which will feature chapters authored by some of the prominent workers in the fields of macrocyclic and supramolecular chemistry, see [6].
From Molecular Recognition to Industrial Selective Separations: The Birth of Molecular Recognition Technology
During the 1970s and 1980s, our research effort was aimed at identifying the principles underlying molecular recognition processes in metal ion-organic ligand interactions. As these principles were learned, our interests turned to studies of selective transport of metal ions in liquid membrane systems. Our goal was to study the ability of pre-designed hydrophobic macrocycles to selectively transport metal ions from one aqueous phase to a second aqueous phase separated by an organic liquid phase [10]. The hydrophobic metal-selective carrier macrocycle was located in the organic phase.
As our knowledge base grew, it occurred to us that a practical application of our metal selectivity studies might be achieved by attaching the macrocycle by a chemical bond to a solid substrate, such as silica gel, making regeneration and reuse of the valuable macrocycle possible. We reported achievement of this goal in 1988 [11] and the same year IBC Advanced Technologies, Inc. (IBC) was formed as a spin-off company from our academic research program at Brigham Young University (BYU). The vision we had of the potential value of this new technology in metal separations and in metal recovery is seen in the opening remarks in the paper announcing our achievement [11]:
“Sir: The recent permanent attachment of macrocycles such as the crown ethers to silica gel via a hydrocarbon-type linkage has made possible the design of systems capable of the selective and quantitative removal of cations from aqueous solutions. These systems can be operated indefinitely without loss of the expensive macrocycle and maintain the selectivity shown toward metal ions in aqueous solution by the particular macrocycle in the free state. These systems are of potential value in concentrating cations present at the nanogram-per-milliliter level, making their analysis by conventional procedures possible, and in selectively removing either wanted or unwanted metal cations from solutions in which they are present in the milligram-per-milliliter to nanogram-per-milliliter range. The latter application is treated in this correspondence using the alkaline-earth cations, Ag+, Hg2+, Tl+, and Pb2+.”
UcorePhoto4The term ‘Molecular Recognition Technology’ or ‘MRT’ was coined in 1989 by Steven R. Izatt, President and CEO of IBC to describe the innovative technology and products of the Company [12], which were based on the pioneering work of my associates and me at Brigham Young University [13]. Adding the word technology to molecular recognition signifies the accomplishment of practical applications (i.e., products or systems for which a customer will pay money). MRT systems are engineered to perform selective separations in industry. Ligands are developed that not only have pre-determined selectivities, but can be incorporated into commercial applications efficiently and cost-effectively. In selective metals extraction, this typically means (1) attachment of the ligand to a solid support in a way such that it retains its selectivity, as well as other thermodynamic and kinetic properties; (2) incorporation of the solid-supported ligand (trade named SuperLig®) into a column resulting in a system that can not only effectuate a selective separation but can be used for repeated cycles of efficient loading and elution; (3) production of a pure concentrated end-product by proper elution of the column; and (4) compatibility of all of the chemistry associated with the MRT system (washes, elutions and final product production) with the existing plant chemistry up-stream and downstream of the MRT system. MRT is well known today in extractive metallurgy [4,13,14], radionuclide separations [15], and chemical analysis [16]. Early successes of MRT were its adoption by Impala to process the palladium produced at its Springs Refinery in South Africa and by Tanaka Kikinzoku, Kogyo K.K. in Japan to recover rhodium from spent precious metal wastes [13,14]. A hallmark of these processes is that they are based on green chemistry principles [4,13,14] resulting in significant economic and environmental advantages to the customer.
MRT1MRT has been recognized for its innovative features in commercial metal separations and recovery. Four of these recognitions are now listed. (1) Professor Jerald S. Bradshaw and I in 1996 jointly received the prestigious American Chemical Society National Award in Separations Science and Technology [17]. Inscribed on the award plaque were the words: For advancing the separations science of metals and for new technology to forward industrial-scale recovery of metals from aqueous solutions. (2) IBC’s separations technology is used to analyze radionuclides. The environmental and health consequences of radionuclides can be grave. They can enter the food chain and contaminate water, milk or other nutrients. Empore Rad Disks, developed jointly by IBC, 3M and Argonne National Laboratory, have dramatically reduced the time required to analyze radionuclides, such as strontium and radium (i.e., day(s) to less than 20 minutes), in experimental samples. Winner of both the R&D 100 Award in 1996 (this award was subsequently selected, in 1999, as being in the top one percentile of all awards ever given by R&D magazine), and the Federal Laboratory Consortium Award for Excellence in Technology Transfer, Rad Disks are marketed and used worldwide [15]. (3) Steven R. Izatt received the 2008 International Precious Metals Institute (IPMI) Jun-ichiro Tanaka Distinguished Achievement Award [18]. This Award, sponsored by Tanaka Kikinzoku Kogyo K.K. is the Institute’s highest award and recognizes an individual for his or her significant contributions to the advancement of the precious metals industry, technical, economic, or managerial. (4) IBC was awarded the Council for Chemical Research’s 2011 Collaboration Research Award, as part of a team of U.S. Department of Energy (DOE) national labs, DOE contractors and a university [19]. IBC was recognized by Savannah River National Laboratory in 2013 as a commercial partner in the team that successfully developed and implemented a cesium extractant that serves as the baseline technology for alkaline liquid waste treatment in the Salt Waste Processing Facility at the Savannah River Site, South Carolina [20]. This team received a United States Department of Energy 2013 Secretary’s Honor Award [21].
I have shown the progression over the past half-century of our research program from early concepts of molecular recognition to intensive studies of carrier-induced selective transport of metals across liquid membranes to the creation of novel, versatile, and highly metal-selective solid supported systems that have been used world-wide for over two decades for commercial green chemistry metal separations and analyses. The latest achievement made using MRT has been the demonstrated green chemistry separation in early 2015 of individual rare earth metals at the laboratory scale [22]. Scale-up of the REE separations is underway and a pilot plant is expected to be operational in early 2016 [23] that will be capable of producing individual rare earth metals at >99% recovery and >99% purity, with minimal waste generation.
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