Solid-Phase Synthesis and Combinatorial Technologies

ion current. The whole process of measuring the activity of L8 on a specific CO oxidation lasted only 2 h, representing a significant improvement in terms of throughput when compared to classical materials sciences procedures.

Screening results for L8 in the O2-promoted oxidation showed the expected Rh > Pd > Pt activity plus a temperature dependence for the most active alloy catalysts. Eighty percent to 85% of Rh was preferred in the alloys below 350 °C, while at higher temperatures the most active library individuals contained just 70–80% Rh. The NO-promoted oxidation could also lead to production of N2O via an undesired secondary process that should preferably be minimized. The screening results (measured as N2 and N2O production) were often comparable in terms of metal reactivity, but N2O formation at different temperatures was indeed observed and could be minimized, selecting Rh-rich alloys at 600 °C as the best catalysts from L8.

The same group reported the use of MS-based screening techniques for the dehydrogentation of ethane to ethylene, using also an optical detection scheme in combination with MS (62). A higher throughput was reported by Senkan et al. (63) using array microreactors (52) and capillary microprobe sampling with on-line Quadrupole Mass Spectrometry for the dehydrogenation of cyclohexane to benzene. More sensitive conditions to better discriminate catalyst selectivity were used by Orschel et al. (64), who employed spatially resolved MS for the oxidation of propene using air at normal pressure; the use of other spatially resolved techniques (GC, IR thermography, UV/VIS, and so on) was also hypothesized by authors. Hoffmann et al. (65) reported a system easily reconducible to conventional catalytic experiments for the oxidation of CO with Au-based catalysts at rt; MS, GC and non dispersive IR were used as screening methods.

The reported examples clearly show how accurate qualitative and/or quantitative screening protocols, based on more or less complex analytical techniques, allow the selection of heterogeneous catalysts and the establishment of SARs from hundreds of library individuals in an acceptable time. An increase in throughput via new technological developments, allowing materials libraries to reach the sizes obtained with synthetic organic libraries, will significantly increase the usefulness and the utilization of heterogeneous catalyst libraries and of materials libraries in general.

11.2.3 Screening Libraries for Electrochemical Catalysts

Reddington et al. (66) reported the synthesis and screening of a 645-member discrete materials library L9 as a source of catalysts for the anode catalysis of direct methanol fuel cells (DMFCs), with the relevant goal of improving their properties as fuel cells for vehicles and other applications. The anode oxidation in DMFCs is reported in equation 1 (Fig. 11.12). At the time of the publication, state-of-the-art anode catalysts were either binary Pt–Ru alloys (67) or ternary Pt–Ru–Os alloys (68). A systematic exploration of ternary or higher order alloys as anode catalysts for DMFCs was not available, and predictive models to orient the efforts were also lacking.

594 MATERIALS AND POLYMERIC COMBINATORIAL LIBRARIES

4 vertex positions

L9

645-member discrete library

made of Rh, Ru, Ir, Os and Pt

Figure 11.12 Structure of the Pt-Rh-Os-Ir-Ru discrete catalyst libraryL9 for the oxidation of methanol.

L9 was built from the combination of five elements (Pt, Ru, Os, Ir, and Rh) in a quaternary phase diagram (combinations of up to four elements from the five possible; 57). The quaternary phase diagram can be represented by a 10 × 10 × 10 × 10 tetrahedron (Fig. 11.12), where the 4 vertices represent the pure elements, the 48 positions on the edges (6 × 8) represent the binary alloys, the 112 positions on the faces (4 × 28) represent the ternary alloys, and the 56 inner positions represent the quaternary alloys to give a total of 220 different compositions. The addition of a fifth element increased the library composition by 1 (element) + 32 (4 × 8, binary alloys) + 168 (6 × 28, ternary alloys) + 224 (4 × 56, quaternary alloys) = 425 different compositions, giving a total number of 645 library individuals for L9 (Fig. 11.12).

The library was prepared by automated inkjet deposition of aqueous/glycerol solutions of metal salts with appropriate viscosity (step a, Fig. 11.13). The deposition surface was composed of carbon paper to ensure electric conduction and the desired chemical inertness. The deposited salts were reduced to metallic elements (step b);

a:inkjet deposition of water/glycerol solutions of H2PtCl6, RuCl3, OsCl3, K2IrCl6 and RhCl3; b: reduction with aqueous NaBH4; c: washings and drying procedures; d: electric connection; e: fluorescence-

Figure 11.13 Synthetic route to the Pt-Rh-O-Ir-Ru discrete catalyst library L9 and fluores- cence-based screening strategy based on 11.8 to discover the novel catalysts 11.9 and 11.10.

then the substrate was washed and dried to give the final library L9 (step c). The library was screened by measurement of the H+ ions released in the anodic reaction, according to equation 1. First, L9 was connected electrically to create an anode compartment (step d); then each library individual was tested (step e) using a moving electrode and an electrolyte solution containing methanol, water, and the fluorescent indicator 11.8 (Fig. 11.13). The Ni2+ complex 11.8 is not luminescent at neutral pH, but the release of protons makes it fluorescent at acidic pH and gives an optically readable, semiquantifiable signal.

Several active compositions were detected from screening. Among them, the quaternary alloy 11.9 (Fig. 11.13) was selected as the best candidate, reprepared in bulk quantity, and compared with the best commercially available binary alloy catalyst 11.10. The performance of 11.9 was significantly superior to 11.10 in suitable DMFC conditions, even using a nonoptimized preparation of the quaternary alloy while 11.10 was tested as a high-surface-area catalyst. The structure of 11.9 could not easily have been predicted by rational means, especially with regard to the relative composition of the alloy, once more proving the usefulness of combinatorial technologies in this area.

11.2.4 Screening Libraries for Photoluminescent Materials

Wang et al. (69) reported the synthesis and the visible-light-imaging screening of a 1024-member discrete photoluminescent library L10 (Fig. 11.14). The library was prepared on a Si surface (2.5 cm2) containing 650- m2 individual sites spaced by 100- m empty portions. Thin-film deposition was performed using five rotating masks M1–M5 (Fig. 11.15) with the following scheme:

1.M1,1: Ga2O3 (355 nm);

2.M1,2: Ga2O3 (426 nm);

3.M1,3: SiO2 (200 nm);

4.M1,4: SiO2 (400 nm);

5.M4,1: CeO2 (3.5 nm);

6.M4,2: EuF3 (11.3 nm);

7.M4,3: Tb4O7 (9.2 nm);

8.M5,1: Ag (3.8 nm);

9.M5,2: TiO2 (6.9 nm);

10.M5,3: Mn3O4 (5.8 nm);

11.M2,1: Gd2O3 (577 nm);

12.M2,2: ZnO (105 nm);

13.M2,3: ZnO (210 nm);

14.M3,1: Gd2O3 (359 nm);

15.M3,2: Y2O3 (330 nm); and

16.M3,3: Y2O3 (82.5 nm).

The plates were rotated counterclockwise with 90° increments, considering their position in Fig. 11.15 as Mx,1 and the positions Mx,2, Mx,3, and Mx,4 respectively, as 90°, 180°, and 270° rotations (see M1,2 in Fig. 11.15). The sequential deposition scheme allowed the combination of the library components (Ga2O3, SiO2, Gd2O3, ZnO, Y2O3) and the dopants (EuF3, CeO2, Tb4O7, Ag, TiO2, and Mn3O4) as 1024 different composites in a 32 × 32 grid. Extensive studies were performed to optimize the library processing to obtain high-quality, uniform materials in each position, and the adopted procedure afforded satisfactory overall results.

The library was screened under ultraviolet irradiation at 254 nm to excite the library individuals using several filters to determine the emission nature (green, red, or blue) of the library individuals. An image of the plate was taken using a charge-coupled detector (CCD) camera with high spatial resolution, and this was used to rapidly discriminate among the photoluminescent library composites. Quantitative determination of their properties was subsequently obtained via spectrophotometric acquisition of the emission and excitation spectra of the ≈100 luminescent samples. A standard phosphor (11.11, Zn2SiO4–Mn, Fig. 11.14) was included in the library and was used to measure the relative photon output Q for each sample. The most promising samples demonstrated a Q of 60–75% when compared to the standard 11.11. They all contained Gd and Ga, with or without the addition of Ag as dopant. Resynthesis of pure individuals did not confirm the optical screening results, and the release of some Si from the surface was postulated. Additional studies and the synthesis of a focused library identified the promising Si-doped, blue photoluminescent material 11.12 (Fig. 11.14).

Similar studies (70, 71) were reported by the same authors on different composites using the same screening strategy. The ease and speed of this visual imaging screening, which has been used in many of the previously mentioned photoluminescent libraries,

luminescent properties of ion-implanted samples on a SiO2 film. A recent review has specifically covered the examples of combinatorial libraries aimed to the discovery of novel luminescence materials (75).

11.2.5 Screening Libraries for Ferroelectric/Dielectric Materials

Chang et al. (76) reported the synthesis and screening of a 256-member discrete ferroelectric materials library L12 to be used for microwave-related applications. The library was built on a LaAlO3 single-crystal substrate using radiofrequency sputtering of known base elements (Ba, Sr, and Ti oxides) in different combinations, with additional dopants selected as a maximum of three out of nine metallic elements. The adopted synthetic sequence used moving masks M1–M4 and 90° degree rotation increments as seen for L10 (Fig. 11.15) in the following sequence:

1.no mask: TiO2 (87 nm);

2.M2,1: Fe2O3 (0.7 nm);

3.M2,2: W (0.5 nm);

4.M2,3: CaF2 (1.2 nm);

5.M3,1: Cr (0.4 nm);

6.M3,2: Mn3O4 (0.7 nm);

7.M3,3: CeO2 (1.2 nm);

8.M4,1: MgO (0.7 nm);

9.M4,2: Y2O3 (1.0 nm);

10.M4,3: La2O3 (1.2 nm);

11.M1,1: BaF2 (164 nm);

12.M1,2: SrF2 (27 nm) + BaF2 (132 nm);

13.M1,3: SrF2 (41 nm) + BaF2 (94 nm); and

14.M1,4: SrF2 (68 nm) + BaF2 (83 nm).

The library synthesis was completed by progressive heating under an oxygen atmosphere to thoroughly mix the library constituents and the dopants. Screening for ferroelectric/dielectric materials was performed using the previously reported scan- ning-tip microwave near-field microscope (STMNM) (77). This device allowed a low-micrometer resolution on the library substrate and a high-throughput characterization of the 256 individual composites. A microwave impedance image of the library was obtained, and the most active library composites were identified together with a reasonable SAR related to the dopants and the percentages of main library elements.

A recent report presented Continuous Composition Spread (CCS) approaches (37) to identify thin film dielectrics with varying composition among the system Zr-Sn-Ti- O (78). A structural-driven approach was applied to the discovery of a high dielectric perovskite polymorphic material (79).

Many other combinatorial technologies applications will appear in this emerging field, and their usefulness will also become more apparent for nonimmediate uses. A larger number of scientists working in this field should also be attracted by the potential

600 MATERIALS AND POLYMERIC COMBINATORIAL LIBRARIES

benefits of a combinatorial approach, with obvious positive effects on the output of relevant materials science libraries.

11.3 POLYMERIC COMBINATORIAL LIBRARIES

11.3.1 General Considerations

Polymer science is a very popular subject in combinatorial technologies, as solid-phase chemistry is based on availability and flexibility of various solid supports made from different polymeric structures. This subject has been extensively covered in Section 1.1, and it remains the main interest of many groups that work to constantly improve the quality and the flexibility of available supports using classical polymer chemistry methods, and hence it will not be covered further here.

Polymer libraries have recently been the focus of several publications with the aim either to discover novel polymeric materials for a specific application (primary libraries) or to rapidly optimize the properties of known polymers (focused libraries). All the major areas where successful combinatorial approaches to polymer libraries have been reported are covered in the following sections with the help of a specific, recent example and up-to-date referencing. Several other papers dealing with polymer combinatorial libraries can be consulted by the interested reader (80–89).

11.3.2 Polymer Libraries as Sources of Soluble Copolymers

Soluble supports for solution-phase combinatorial synthesis were extensively covered in Section 8.5. A recent survey of available soluble supports, with respect to their use in the soluble supported synthesis of various classes of chemicals (90), highlights the wide range of physicochemical properties (especially regarding solubility, tendency to crystallize, and solubilization power) that are embedded in different polymers and copolymers. The assessment of a sort of SAR for the composition of copolymers versus their physicochemical properties would require the preparation of a large number of examples. Combinatorial approaches to soluble support libraries could be highly beneficial in this perspective.

An intriguing paper by Gravert et al. (91) reported the combinatorial synthesis of an array of copolymers L13 using radical polymerization by means of the free-radical initiator 11.12 (92) and the vinylic monomers M1 and M2 (Fig. 11.17). The initiator contained a diazene moiety, known to initiate and propagate free-radical polymerization at 70 °C, and the TEMPO group, which requires 130 °C for initiation of the same process. The first monomer set (five representatives) was used as solvent for 11.12 and polymerization was conducted at 70 °C to give intermediates 11.13 (step a, 5 reactions, Fig. 11.17). Compounds 11.13 were then dissolved in the second monomer set (four from the five representatives excluding the five homopolymeric combinations) and polymerized at 130 °C (step b, 20 reactions, Fig. 11.17) to give the final array L13. The array was characterized for its composition using typical polymer chemistry methods, such as size exclusion chromatography (SEC) and transmission electron

11.12NC

a M1

CN

N O

11.13

b M2

L13

20 discrete copolymers

Figure 11.17 Synthesis of the solution-phase, discrete copolymer library of soluble supports L13 and structures of monomers used for its synthesis.

microscopy (TEM). The excellent quality of each polymeric library component was verified.

Each L13 individual was evaluated as a potential soluble support in liquid-phase combinatorial synthesis. A great variation in the solubility profiles was observed for the 20 copolymers, the most relevant of which are reported in Table 11.2. The copolymer M1,2–M2,3 was selected, being very soluble in apolar solvents such as THF and diethyl ether, insoluble in polar solvents such as water and alcohol, and nonswelling in any solvent. It thus resulted complementary to PEG-based supports and

602 MATERIALS AND POLYMERIC COMBINATORIAL LIBRARIES

TABLE 11.2 Solubility Properties of L13 Individualsa

Solubility Toluene Et2O THF Acetone MeCN OCM DMF DMSO MeOH Water

aS = soluble; SW = swelling, I = insoluble.

was considered a promising candidate for the transfer of PEG-incompatible synthetic routes onto soluble supports.

The combinatorial assembly of isocyanate-decorated dendrimers was reported by Newkome et al. (93) as a method to modulate the solubility, reactivity and viscosity properties of such popular materials. This modulation has an obvious impact for the discovery of high loading, soluble and flexible supports for high throughput organic synthesis.

The structures of five protected functionalized isocyanate building blocks AP3– EP3 (94, 95) are reported in Fig. 11.18, top. The protected side chains for each building block allowed further increase of ramification and loading (n → 3n sites after an isocyanate coupling), but above all allowed a combinatorial deprotection/decoration strategy reported for a specific example in Fig. 11.18, bottom. The starting polyamine dendrimer 11.14 (32-PPI, schematically represented as in Fig. 11.18) (96) was treated with a stoichiometeric mixture of isocyanates DP3 and EP3 (0.5 eqs. each, step a, Fig. 11.18) to give the mixed, fully protected ureido dendrimer 11.15. Treatment with formic acid (step b) selectively deprotected the amine functions of DP3 to give 11.16 which was treated with a stoichiometric mixture of AP3, BP3 and DP3 (step c, Fig. 11.18). The resulting, hyperbranched 11.17 is an example of the obtainable multi-func-