Combinatorial Aspects of Materials Science

Bill Archibald, Oliver Brummer, Martin Devenney,

Daniel M. Giaquinta, BerndJandeleit, W. Henry Weinberg, and

Thomas Weskamp

Abstract

Combinatorial chemistry, coupled with high-throughput screening and integrated data management systems, has forever changed the drug discovery process, promising to bring to the marketplace more drug entities per unit time than ever before. With rising economic demands to increase efficiency in other areas of research and development, it is not surprising that a similar paradigm is taking hold in the chemical industry as a whole. In particular, combinatorial synthesis and sophisticated screening technologies are now being applied to the discovery of more efficient materials, and with these new technologies come the promise of faster commercialization rates and reduced research and development costs.

The combinatorial process aims at efficiently exploring the large parameter space that controls the properties of a material through the application of rapid parallel or combinatorial synthesis and subsequent high-throughput characterization for a given application. Certain synthesis and screening protocols developed in the pharmaceutical industry can be adapted to the new areas of research, whereas, in other areas, a completely new set of techniques must be developed. Unlike in the pharmaceutical industry where aspects such as solvent, temperature, and additives are held constant to eliminate assay variability, the examination of processing conditions in the search for new materials is a critical component of the combinatorial search. The variation of process and reaction conditions, combined with parallel synthesis, results in an exponential increase in the total number of experiments, dramatically increasing the chances of identifying a new material.

Over the past 6 years, since the initial application of combinatorial methods to materials science discovery research, tremendous advances in this rapidly growing field have been made in the academic, private, and public sectors. The goal of this review is to examine the contributions made during this time period and to provide insight as to what the future may hold for combinatorial materials research.

Handbook of Combinatorial Chemistry. Drugs, Catalysts, Materials. Vol. 2. Edited by K. C. Nicolaou, R. Hanko, and W. Hartwig Copyright Ā© 2002 WILEY-VCH Verlag GmbH, Weinheim ISBN: 3-527-30509-2

1018 | 34 Combinatorial Aspects of Materials Science 34.1

Introduction

With increasing competition in the chemical industry, new products must be brought to the market place rapidly. Global market pressures are driving the chemicals and advanced materials industries to improve research and development (R & D) productivity as measured by return on investment. Principal drivers include reduced cycle times and higher quality at lower cost, with reduced environmental impact.

This dilemma was first encountered in the pharmaceutical industry, where long development times and high research costs necessitated the introduction of new research approaches to accelerate the drug discovery process. Virtually every major drug manufacturer now applies this "new" research technology, "combinatorial chemistry,'' as the cornerstone of its research and development program; routinely, libraries of up to 1,000,000 distinct compounds are synthesized and screened for biological activity. This approach is feasible both because of the fact that technology challenges have been addressed, as well as because of the broad availability of low-cost computers, reliable robotics, molecular modeling, experimental design strategies, and database software tools [1-10]. The advent of combinatorial chemistry thus created novel research areas such as chemoinformatics to manage the huge amount of structural and functional information obtained from library-based research [11].

This new paradigm is now taking hold in the R&D centers of American, European, and Japanese advanced materials industries where combinatorial methodologies are being increasingly applied. Among others, advanced materials comprise optical and electronic materials, polymers, and catalysts for commodity, specialty, and fine chemical application. Combinatorial techniques represent a powerful research strategy when applied to problems where complex interactions within an extensive parameter space dictate the properties of a material, and these techniques will unquestionably influence the way materials research is carried out in these fields in the future.

For example, in the case of heterogeneous catalysis, where active sites exist on the exterior and/or interior surface of a porous solid-state inorganic material, library synthesis can be carried out by a variety of deposition methods. In the case of homogeneous catalysis, where the active site is most often a metal ion stabilized by organic ligands, library synthesis may be carried out using combinatorial ligand synthesis. This process allows combinatorial homogeneous catalysis to rapidly take advantage of the numerous solid- and solution-phase synthetic combinatorial methodologies, including polymer-supported reagents [12-17].

Three different approaches to the task of preparing and testing libraries of compounds exist (Fig. 34.1). Conventional research provides thorough quality control at the expense of throughput in a "one-at-a-time" or serial manner of synthesis and characterization. Truly combinatorial methods involving ''split-and-pool'' syntheses are much faster and allow for the preparation of large numbers of compounds, but often lack control over the purity of the compounds entering the assay

library design

synthetic methods

screening methods

traditional 1

slow,

slow, assays

synthesis | *

low throughput

very accurate

spatially addressable format, medium to

parallel [ | synthesis | c

fast, assays accurate

high throughput

pooled 1 synthesis |__ /

split-pool, very high throughput

extremely fast, assays require deconvolution strategies

Fig. 34.1. Conventional, parallel, and pooled approaches to synthesis and screening

Fig. 34.1. Conventional, parallel, and pooled approaches to synthesis and screening screen. Methods intermediate between these two extremes are based on parallel or array syntheses, in a spatially addressable format with usually one compound per well or region, coupled to automated screens.

A SciFinderĀ® reference search performed in February 2001 using the key word ''combinatorial'' resulted in more than 9000 ''hits.'' An analysis of the literature search demonstrates the tremendous growth of scientific publications and patent applications in the combinatorial field. Although most contributions deal with combinatorial applications within pharmaceutical, biological, and medical disciplines, recent years have witnessed significant advances in the development of combinatorial approaches to the discovery and optimization of new materials and catalysts, as is clearly shown by the increasing number of scientific publications and patent applications during the last few years within these areas. Additionally, an increasing number of review articles on the application of combinatorial methods to catalyst discovery and optimization, a process dubbed ''combinatorial catalysis,'' has appeared in the recent literature [18]. Furthermore, recent advances of combinatorial chemistry and high-throughput screening for chemical process development have been reviewed [19, 20]. Consequently, several recent reviews address combinatorial high-throughput methodologies and experimental strategies in further detail [21-32].

This chapter, covering the years 1995 to 2001, summarizes the latest developments in the application of combinatorial methodologies to the discovery of new solid-state and organic polymeric materials. Patents, patent applications, and conference proceedings have generally not been included but are well appreciated and acknowledged. Combinatorial approaches to catalyst discovery and process optimization will be treated in a subsequent chapter.

After this introductory section, the following section, Section 34.2, summarizes the efforts in combinatorial materials science beginning with a general overview of combinatorial materials synthesis techniques. Section 34.3 describes examples of novel high-throughput screening technologies, while Section 34.4 summarizes some applications of combinatorial methods in the search for novel or improved electronic, magnetic, and optical properties. Section 34.5 describes case studies showing the application of combinatorial techniques to the discovery of a new phosphor and an example of the application of combinatorial methodologies applied to the optimization of thin-film layers in an organic light-emitting device (LED) device. Combinatorial methods in polymers are described in Section 34.6. Section 34.7 includes a summary and an outlook concerning the future of combinatorial materials science.

34.2

Combinatorial Solid-state Materials Science

The properties of solid-state materials often arise from complex interactions involving the host structure, dopants, defects, and interfaces. Therefore, they depend sensitively on both composition and processing conditions. Few general principles have emerged that allow the prediction of structure beyond binary systems and the resulting properties of such solid-state compounds. Conventional ''one-at-a-time'' synthesis and characterization can be a long and expensive process, and combinatorial materials science holds great promise in facilitating the materials discovery and optimization enterprises.

Conventional materials research typically begins with a decision on a generalphase space which targets a property of interest and which is based on a set of physical or chemical constraints, many of which may be empirically or intuitively grounded. This parameter space is then divided into discrete compositions that must be synthesized and screened for properties of interest. Chemical additions, substitutions, and modifications of synthesis and processing conditions allow the researcher to optimize the properties of a given system. This process is typically long and laborious, and may or may not lead to a promising material. The integrated application of rapid synthesis, high-throughput screening, and sophisticated data analysis allows for a promising alternative to the time-consuming classical methodology. However, a well thought-through experimental design of the experiments (DOE) is required to reduce the number of samples that will be necessary to define sample spaces within the experimental universe or to direct screening to other spaces (feedback loop).

The combinatorial process relies on the implementation and coupling of highspeed synthesis and high-throughput screening techniques. These methods facilitate more efficient explorations of a given composition space and offer a valuable tool for the investigation of ternary and higher order systems. However, it is often impossible to rapidly synthesize materials the physical characteristics of which (e.g. composition, microstructure, grain size, and density) are exactly the same as materials made using the final production process. Similarly, screening of desired properties is often very slow. Thus, combinatorial studies are based on the predictive capabilities of synthesis and screening tools, and the challenge of the combinatorial process is to implement appropriate synthesis and screening techniques. Rather than comparing the properties of a few specific compositions within a phase space, entire phase spaces can now be examined in a single experiment. The first library of compounds is often a broad compositional search covering an entire phase space,

Discovery Library

(100-1,000 elements)

Secondary Library

(10-100 elements)

Fig. 34.2. Schematic process of the combinatorial materials discovery and optimization paradigm. Large numbers of diverse compounds are rapidly synthesized and screened for desired properties.

Follow-up Library

(optimization)

Scaleup

(developmental candidates)

Fig. 34.2. Schematic process of the combinatorial materials discovery and optimization paradigm. Large numbers of diverse compounds are rapidly synthesized and screened for desired properties.

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