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POLYMER-SUPPORTED REAGENTS Introduction Since the original reports by Merrifield, published some 40 years ago (1), solid supports have been widely used as a synthetic device to avoid expensive and long winded purification processes, principally due to the simplicity of isolating the support and its bound material by direct filtration. There are a number of other advantages when using solid supports; most notably reactions can be driven to completion using high concentrations and mass action of reagents and synthesis can be easily automated (2). With the introduction of a range of high throughput synthesis methods (3–5), solid supports have become even more indispensable (6), for example, with the use of polymer-supported reagents and catalysts (7), which maintains the target molecules in solution but immobilizes the other component, and renders possible the parallel monitoring of supported reactions but in a solution sense. The most utilized polymer support in solid-phase chemistry is still a copolymer of styrene and divinyl benzene [DVB (2%)], known as a gel-type resin, because of its “gelatinous” and nonmacroporous behavior, originally used by Merrifield for the synthesis of the first tetrapeptide made by solid-phase synthesis (see POLYPEPTIDE SYNTHESIS, SOLID-PHASE METHOD). Nevertheless, there are some problems correlated with the use of this support, such as its voluminous nature when swollen, its lack of physical stability under harsh handling conditions, and its incompatibility with a number of solvents (8). For this reason, several groups of researchers have investigated a number of alternative solid supports, for solid-phase chemistry, in order to improve resin properties, such as physical robustness, ease of handling, enhancement in loading, Encyclopedia of Polymer Science and Technology. Copyright John Wiley & Sons, Inc. All rights reserved.

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improvement of reaction kinetics, and so forth. This article presents an overview of the materials commonly used in solid-supported chemistry and their evolution.

Styrene–DVB-Based Resins Polystyrene resins (25–300 µm) are the most commonly used supports in solidphase chemistry and, in a variety of formats, are extensively used in a wide range of industrial processes (see STYRENE POLYMERS). These basic materials can be easily obtained by radical polymerization of a suspension of an organic phase (the styrene and divinylbenzene monomers in varying proportions) in water, in the presence of a stabilizer (in order to reduce the surface tension of the droplets and to prevent their aggregation) (9). A minimum level (usually at least 0.5%) of DVB is required in order to ensure that the polymer obtained is insoluble in organic solvents. The percentage of DVB (cross-linker), influences the physical and chemical properties of the support. High levels of cross-linking produce more rigid supports; therefore, drastic conditions of reaction such as mechanical stirring and high temperatures are permissible, but on the other hand slower reactions are often observed because of the fact that the reagents cannot easily diffuse within the polymer network (10). On the other hand, low levels of cross-linking produce highly swellable but more fragile beads, which, however, exhibit better reaction kinetics. In most chemical reactions, the solvent plays a fundamental role and this effect is enhanced in solid-supported chemistry. When in contact with so-called “good” or “poor” solvents, the beads can swell or shrink (this effect depends principally on the level of cross-linking and can be considered akin to the polymer tending to dissolve in the solvent). This phenomenon can increase the ability of reagents to diffuse into the beads, and therefore dramatically influences reaction rates. Reactivity within beads is also highly dependent on resin loading. Loading variations can for example vary, allowing concentrations within beads to range between 50 µM and 0.5 M. As in solution chemistry, such concentration effects can cause huge effects on reaction rates, depending upon the reaction under investigation as a result of electrostatics and/or steric effects of the reagents. To avoid some of these type of issues, spacers are often placed between the polymer and the reactive functionality of the resin (11), but the high concentration of material on a bead is often ignored in solid-phase synthesis. The reactive functionality (the site of chemistry) on a resin can be added during or after polymerization as shown in Figure 1 (12). Direct functionalization can be performed by including a third monomer into the original monomer mixture, which already bears the desired functional group. Chloromethylstyrene is often used in this regard because it can be easily transformed into a wide range of alternatives (Fig. 2) and is a monomer that incorporates well into styrene/divinyl benzene mixtures (Fig. 1). Post-functionalization is usually carried out by electrophilic aromatic substitution in the presence of a Lewis acid (27) or by metallation of a brominated resin (Fig. 1) (28). Good quality polymers are obtained by direct functionalization with the resulting functionality uniformly distributed throughout the bead. However, there are other factors that influence the quality of the polymer. As mentioned by

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Fig. 1. Functionalization of polystyrene resins.

Czarnik (29), resins from different batches often show different chemical behaviour, as the process of suspension polymerization depends upon many factors such as reactor geometry, agitator design, and agitation rate (30). Uniform, spherical beads are preferred for reproducible chemistry, irregular particles being much more sensitive to mechanical destruction and often falling apart during the reaction. Both 6- and 8-multiparallel polymerization systems have been designed, and these systems show very good reproducibility when used for the synthesis of polymer libraries (Fig. 3) (31), attesting to the parallel advantages of synthesis and maintaining a consistent reaction geometry. A second-generation system allowed 8-multiple polymerizations with the possibility of changing the stirring rate of each reaction vessel. The level of functional groups or “loading,” expressed in mmol/g, can cover a wide range of values (from 0 to virtually 7 mmol/g), but this level varies greatly depending on the application of the support. Generally, the loading and application of polystyrene resins can be grouped as follows: (1) 2 mmol/g, preferred for scavenger and reagents based resins, as these types of reagents are added in excess

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Fig. 2. Preparation of solid-supported reagents and catalysts by derivatization of chloromethyl polystyrene. (1: Ref. 13, 2: Ref. 14, 3: Ref. 13, 4: Ref. 15, 5: Ref. 16, 6: Ref. 17, 7: Ref. 18, 8:NR3 –DMF 110◦ C, 9: Ref. 19, 10: Ref. 20, 11: Ref. 13, 12: Ref. 21, 13: Ref. 22, 14: Ref. 23, 15: Ref. 24, 16: Ref. 25, 17: Ref. 12, 18: Ref. 26).

Resin Types Gel-Type Polystyrenes. Gel-type polystyrenes can be synthesized by radical suspension polymerization of styrene and DVB as reported in 1946 by Hohenstein and Mark (9,32). When suspended in a solvent with good swelling properties, these “white soft beads” assume a gelatinous state; their volume may increase by 6–8 times and they become optically transparent. This process of swelling, as well as the shrinking, occurs from the outside to the inside of the polymer network and the increment of volume is in correlation with its solvation. This plays an important role in chemistry, because it is through such processes that the reactants diffuse into the polymer network where 99% of the functional sites reside (33).

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Fig. 3. (a) Multiparallel suspension polymerization system; (b) close-up of reaction vessel.

As a consequence, the solvent has to be chosen to allow swelling of the resin (34). However, swelling is not the only “solvent dependency”, as the type of functionality also affects solvent compatibility. Thus, while Merrifield resins (chloromethyl polystyrene) shrink in highly polar solvents such as water, ion exchange resins show the opposite behavior and do not swell in “good swelling solvents” such as dimethylformamide (DMF). Merrifield observed that the volume of the beads and their behavior with the solvent changed continuously as the supported peptide was grown, attesting to the importance of the resin and the attached molecules, a factor which obviously is influenced by resin loading (35). There are thus a number of other factors which need to be considered when handling and evaluating gel-based supports. If the beads are fully swollen in a “good solvent” and then shrunk rapidly in a bad solvent (eg washing step), “mechanical shock” can take place and the beads may disintegrate, especially with large beads (osmotic shock) (36). To avoid this issue, beads should be washed gradually, starting from a good solvent to a poor solvent, while in the fully swollen state beads should not be agitated with rigid materials, or they may become damaged. Although a number of issues are correlated with the use of this material, gel-type polystyrene resins are the most used supports in solid-phase chemistry, because of their acceptable loading capacity and relative good kinetics when fully swollen in good solvents. Macroporous-Type Resins. Macroporous resins were prepared as long ago as 1962 by Millar (37). Macroporous resins have been used for many years

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Fig. 4. Synthesis of macroporous polystyrene chloromethyl resin.

as ion-exchange materials, polymeric adsorbents (38), and preparative reverse phases for purification of biomolecules (39), but there are also several examples of this type of support in organic synthesis as carriers for reagents and catalysts (40,41). Even although the IUPAC definition for macroporous refers to materials that have pores with a diameter greater or equal to 50 nm, the term has been generalized in the resin area to include resins that present a porous structure in the dry state (36). The formation of the pores occurs when an inert solvent, or porogen, is added to a polymerization mixture containing relatively high levels of cross-linker (Fig. 4). After polymerization, removal of the solvent from the beads leaves intact pores that do not collapse because of the high level of cross-linker used (>20%). The morphology of the pores (surface area, total pore volume, and average pore diameters) can be adjusted and controlled by an appropriate choice of the type and amount of porogen and the level of cross-linker used (42). Several porogens (also called diluents) have been used to prepare macroporous resins (43), and they can be divided in three main classes: (1) Solvating (SOL), such as toluene or dichloroethane (small pore) (2) Nonsolvating (NONSOL), such as n-heptane or alcohols (large pores) (3) Polymeric (POLY), such as linear polystyrene (very large pores) (44) Pore formation and their different morphologies have been explained in a recent review (Fig. 5) (36). When polymerization begins, droplets are formed by the suspension process. The monomer droplets start forming small spherical, so-called microgel, particles.

Fig. 5. Pore formation in macroporous resins. (1) Highly solvated swollen microgels, (2) aggregation of swollen microgels, (3) phase separation, (4) solvent removal.

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Fig. 6. SEM micrograph of macroporous resins synthesized using (a) toluene (solvating) and (b) heptane (nonsolvating) porogen.

If these contain a good solvent for the monomers, such as toluene, these particles are fully solvated until there is a high conversion to polymer. Thus, when phase separation takes place (ie, the polymer is no longer soluble in the solvent), the environment within the particle contains only a small amount of unreacted monomer. These particles, therefore, retain their identity and the network of small pores already generated between them is essentially retained. When a nonsolvating porogen, such as heptane, is used, the microgel particles are poorly swollen and phase separation takes place early (low conversion to polymer). In this case the droplet contains a high level of unreacted monomers and these have the effect not only of fusing the microgel particles together, but also of causing significant filling of small pores between the microgel particles. The results of two extreme cases are shown in the Figure 6. Smooth beads polymerized with 200% vol/vol of toluene showed a rough surface only when magnified, whereas beads obtained from heptane (150% vol/vol) gave an irregular morphology. To improve the benefits of solid-supported reagents and scavengers, macroporous beads need to have a large surface area and large pores. While a high surface area provides more sites for functionalization, large pores provide efficient transport of reagents through the beads. However, as suggested by Sherrington, these two parameters are obviously related (12). If a resin bead has a large surface area and a large number of pores, then each pore is likely to have a small diameter and vice versa. Experimentally, these parameters are measured by nitrogen adsorption/desorption (BET) (45), mercury intrusion porosimetry (46), and electron microscope techniques. Another consequence of the fixed pores and the rigid structure (high DVB levels) is that macroporous resins have limited swelling. Thus a wide range of solvents commonly used in organic synthesis can be used in solid-phase “macroporous resin assisted chemistry” (even water), without modification of the reaction conditions as required for the use of gel-type resins. Moreover, the rigid structure makes these supports very resistant to mechanical agitation and easy to handle (macroporous resins do not stick like gel type resins).

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A comparison between macroporous and 2% gel-based Merrifield resins was performed by Janda (47) who demonstrated the efficiency of washing a dye from pretreated resins was better with a macroporous resin than a gel-type resin. Comparison of a palladium catalyst, for Wacker olefin oxidation, supported on gel-type and macroporous resins gave better results on the macroporous support. Contributions in this area have also been made by Labadie who demonstrated good results using tailored macroporous resins, commonly known as ArgoPore (these resins had surface area, pore volume, and loading well defined for optimal performance in solid-phase chemistry), for example, reactions in water such as the TiCl3 mediated reduction of nitro compounds, periodate-mediated olefin oxidations (48), Suzuki reactions on polymer-supported iodides and bromides (49), and alkylation of supported acids via enolate formation at low temperature (50). Nowadays, it is possible to find a wide range of macroporous polymer-supported reagents and catalysts commercially available. In conclusion, well-designed macroporous resins exhibit better efficiency and kinetics than gel-type resins in highly polar solvents and have become a valid alternative for solid-phase chemistry, without significant swelling and washing issues, although maximum available loadings cannot be as high as the gel-type counterpart (commercially available macroporous resins for solid-phase chemistry have a loading that depends on the manufacturer (ie, Argonaut Technologies: 0.2–1.8 mmol/g; Polymer Labs: 3.0 mmol/g). Microgel Polystyrenes. Microgels are soluble polymers with a certain degree of cross-linking, but can be precipitated using an appropriate solvent (51). Beads with a diameter of 5–25 µm can be prepared by radical dispersion polymerization in the presence of a surfactant. It is imperative to use low levels of monomers during preparation to avoid macrogelation due to the aggregation of the microgels to form large-size particles. One of the main characteristics reported for microgels are their ease of handling when solubilized. A consequence of their solubility is that reactions can be easily monitored by classical solution-phase techniques (eg NMR) but that materials can then be readily recovered in a solid-phase manner. Janda reported a detailed investigation of polymerization parameters such as the type of solvent, percentage of monomer, and level and different type of cross-linker and showed that polymers with good characteristics could be obtained using 5 wt% monomer solution in tetrahydrofuran (THF) (52). Good polymers were achieved using 10% of DVB or 5% of alternative cross-linkers (Fig. 7). Precipitation of the soluble polymers was achieved by addition of cold methanol and filtration through a glass frit. Becuse of their recent deployment there are only a few examples in literature on the use of this material in solid-phase chemistry. Wulff (53) used microgel

Fig. 7. Cross-linker used in the preparation of microgels.

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Fig. 8. Microgel-supported oxazaborolidines catalysts.

polymers for the preparation of supported oxazaborolidines as catalysts for asymmetric reduction of ketones (Fig. 8). This type of catalyst, supported on polystyrene gel type resins, gave results comparable to the homogeneous counterpart. However, because of the poor mechanical properties of the resin under the reaction conditions, a more suitable polymer support was needed. Unfortunately, highly cross-linked resins, with their poor kinetics, decreased the overall selectivity of the catalyst. Although linear polymers were used (54), microgels offered advantages because of their ease of handling. Janda used these supports to perform the solid-phase synthesis of oxazoles (55) and later produced a combinatorial library of phthalimides in good purities and yields using these supports. In addition, microgels were used for the preparation of supported tris(2-aminomethyl)amine and borohydrides to remove isocyanates and to reduce aldehydes respectively. Polystyrene Nanoparticles. Polymer-based nanoparticles are used in several areas of life science, for example drug delivery (56), and one such polymer matrix commonly used is poly(L-lactic acid) (57). However, nanoparticles with a polystyrene–DVB matrix have been also synthetized (58,59) and used as novel solid supports for organic synthesis (60). The method commonly used to generate these monodisperse particles is Microemulsion Polymerization (qv) (58). However, nanoparticles have also been prepared by precipitation polymerization (61). A microemulsion of styrene and DVB, with an amphiphilic comonomer, in water (three component oil-in-water) (62) allows the preparation of nanobeads with a hard core of polystyrene and the amphiphilic comonomer dispersed on the surface with diameters around 50 and 300 nm that can be precipitated by the addition of methanol. Functionalization of the nanoparticles surface, can be easily achieved using the functionalized amphiphilic comonomer (Fig. 9) (60).

Fig. 9. Synthesis of functionalized polystyrene nanobeads.

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These types of beads were used by Cammidge (60) to perform a solid-phase synthesis of porphyrin derivatives following the method described by Leznoff and co-workers (63). Although the final yield of the product was not brilliant (4 and 8% for both the isomers), they were higher than that achieved using “conventional polystyrene resin.”

PEG-Grafted Resins Although gel-type resins are the most widely used supports in solid-phase chemistry, it has been found that such supports are not always the most suitable for peptide synthesis. This is due to two main factors: polystyrene chains are hydrophobic and are not completely compatible with peptides and, furthermore, bulky peptides can adopt unfavorable conformations within the polystyrene cross-linked matrix. These issues can be avoided by performing the synthesis on linear polymers such as poly(ethylene glycol) (PEG) (64,65), as PEG is soluble in a wide range of organic solvents and, when linked to polypeptides, enhances solubilization. Furthermore, Bayer demonstrated that during coupling reactions, PEG-linked amino acids had the same kinetic properties as amino acid esters (66). However, the main problem in liquid-phase peptide synthesis is the separation of linear PEG from the final polypeptide after cleavage. Because of its compatibility with peptide chemistry, several authors began to solve the issue of PEG isolation by grafting it onto polystyrene–DVB resin. As reported by Bayer, polymer grafting by simple reaction with oligomeric PEG and Merrifield resin did not give good results (68), because of the fact that the hydroxylic PEG functionalities could react with two adjacent chloromethyl PS groups, giving an additional degree of cross-linking and reducing the final loading of the resin. However, Barany demonstrated that the grafting of PEG could be achieved by the use of a bifunctional amino-PEG acid (Table 1, entry 2) (69,70). Unfortunately, this support has not found wide use, probably because of its amide linkage. Bayer described grafting of PEG onto PS resin, by direct anionic polymerization of ethylene oxide onto poly(styryl-methyltetraethylene glycol ether) (68). The “tentacle polymer” so obtained is commercialized by Rapp Polymere under the name of TentaGel and it is the second most used support for solid-phase organic synthesis after polystyrene resin (Table 1, entry 1) (67). The main characteristic of these resins is their greater swelling in polar solvents such as water, methanol, ethanol, etc, compared to PS resins. As shown in Table 2, entry 2, the swelling of TentaGel is uniform in high to medium polarity solvents. This behavior allows the packing of resins into columns for continuous flow peptide syntheses (68). Moreover, because of the fact that molecules bound to the highly solvated PEG chains are in a “solution-like” environment and the interactions with the hydrophobic polystyrene backbone are reduced, reaction rates in solid-phase peptide synthesis on TentaGel are greater than on the equivalent Merrifield resins (74,75). Because of the high mobility of PEG chains, gel-phase and MAS NMR result in narrow lines (76). Kinetic comparisons between TentaGel and other supports have been carried out (77,78), and there are several examples of “nonpeptide”

Table 1. PEG Branched Resins Entry

Resin

Structure

Linkage a

Author

References

Bayer Rapp

67,68

TentaGel

Benzylether

2

PS–PEG

Amide

Barany

69,70

3

ArgoGel

Diol

Gooding

71

4

NovaGel

Uretane

Hudson

72

5

PS–MPEG

Phenylether

Bradley

73

144

1

a Original

version of TentaGel.

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Table 2. Resin Swelling (mL/g of Resin) Entry 1 2 3 4 5 6

Resin a

TentaGel PS–PEGb ArgoGelc NovaGeld PS–MPEGe Gel-typef

H2 O

CH3 OH

CH3 CN

DMF

CH2 Cl2

THF

3.6 2.8 3.9 — 2.4 —

3.6 4.2 4.7 4.0 2.8 1.6

4.2 3.7 — 5.0 — 3.2

4.7 5.1 6.0 7.0 5.8 5.6

6.3 5.6 7.5 10.0 8.2 8.3

5.0 3.9 5.8 7.5 8.4 8.8

a Obtained

from Rapp Polymere. low loading. c Obtained from Argonaut Technologies. d Obtained from Novabiochem. e 7% PEG derivative included. f PS-DVB (1%). b PS–PEG

chemistry where the rates are faster on TentaGel than PS resins (ie, Suzuki reactions using supported boronic acids (79), or Sm(II) mediated radical cyclizations (80), or Sharpless asymmetric dihydroxylations) (81). Yan, however, demonstrated that this rule was not always true (82), and found that some reactions, for example terminal modification of aspartic acid or the synthesis of dansyl hydrazones, were faster on PS resins. There are several drawbacks that limit the use of TentaGel resin as a universal support for solid-phase chemistry. The substitutions of TentaGel resins are lower than PS resins although loading can be increased by decreasing the grafting level. However, Lee has demonstrated recently that the swelling of these types of resins depends on the level of grafted PEG (83). When the solvent used was water, there was a direct relationship between PEG level and swelling, but in other solvent systems such as THF or DMF there was a discontinuous trend until the level of PEG was greater than 72% by weight. A method to increase loading was demonstrated by Bradley by dendrimerization. In this way, TentaGel bead loading was amplified about 10 times (Fig. 10) (84,85).

Fig. 10. Dendrimeris for loading improvement.

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Fig. 11. Preparation of ruthenium-supported catalysts.

There is at least one other main issue that has to be cited. It has been observed that traces of linear PEG are found in final products after cleavage because of the weak benzyl ether bond that links the PEG to the polystyrene backbone. For this reason, Gooding prepared a PEG-grafted polystyrene resin using a polystyrene diol as a scaffold for the PEG grafting (Table 1, entry 3) (71) [Rapp also used hydroxyethyl PS in the new generation of TentaGel resins (TentaGel S)]. In this way, the chemical stability as well as the loading (0.4–0.5 mmol/g) of such resins was improved. The higher stability of this support was proved by repeated amide cleavages under acidic conditions, where no impurities of linear PEG were found even after long treatments (86). This resin is commercially available from Argonaut Technologies under the name of ArgoGel, and it has been used as a support in the preparation of substituted imidazoles, N-alkyl sulfonamides, acylamines, benzofurans, etc (71). De Miguel demonstrated the use of such flexible supports for the immobilization of a highly selective ruthenium cluster catalyst for hydrogenation of olefins and ketones (Fig. 11) (87). Recently, the same group reported the use of such supported catalysts in applications such as gas sensors for H2 S, CO, and SO2 by color changing of the resin (88). During his research to improve PEG-grafted resins, Hudson, following the example of Barany, by linking oligomeric PEG chains to aminomethylated resins by a urethane linkage (Table 1, entry 4) (72). These “NovaGel” resins have been commercialized by Novabiochem. The main difference between these supports and the others previously described is that the reactive functionality is still bound to the polystyrene backbone and not to the PEG chains. The effect of the PEG grafting in this case improves swelling as shown in Table 2, entry 4. However, even if the urethane linkage is more stable than the benzyl ether linkage, leaching of linear PEG can contaminate the final product. Recently, Bradley reported the preparation of novel supports using a principle similar to NovaGel resin, where short PEG chains were linked in the polymer by a phenyl ether and the functionality copolymerized into the beads backbone (Table 1, entry 5). Polystyrene–MPEG nongrafted resins were prepared by adding a new PEG derivative comonomer during polymerization as shown in Table 1, entry 5 (73). Such resins exhibit higher loading capacities (0.63–0.77 mmol/g) compared to PEG-grafted resins and at the same time showed broad solvent compatibility (Table 2, entry 5) and improved resistance to acidic and basic conditions. In addition, during their synthetic evaluations, such supports showed similar, if not better, results compared to grafted polymers without detection of PEG impurities in the final products.

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Alternative Cross-Linkers for Polystyrene-Based Resins To overcome the incompatibility of the hydrophobic polystryrene–DVB matrix with highly polar solvents (aqueous), alternative types of cross-linkers have been utilized over the last few years. Polyethers have been extensively used for this purpose and properties such as swelling and mechanical stability have been improved compared to gel-type resins. The cross-linking agents described herein are (1) PEG and (2) (poly)tetrahydrofuran based. Copoly(styrene–PEG). As explained above, PEG grafted onto polystyrene improves its swelling properties in polar solvents (89). One of the major drawbacks of this type of supports is their inherent low loading (0.2–0.6 mmol/g) because a large part of the polymer mass is PEG (∼70%) (48). An alternative to this method is to include PEG in the polymer matrix during polymerization as a cross-linker. Vinyl PEG derivatives have been used to replace DVB as a cross-linker in the synthesis of a polymer matrix (TTEDA–PS: tetraethyleneglycol diacrylate cross-linker–polystyrene) (90). Although this resin showed comparable mechanical properties to gel-type resins, it showed much more effective swelling and solvatation than PS–DVB in polar and nonpolar solvents. The synthesis of an 18-residue peptide on such a chloromethylated resin afforded better yield and purity than PS–DVB. Later bis-styrene–PEG monomers were synthesized, copolymerized with styrene, and used in supporting catalyst in Diels–Alder reactions (91). Oligo(ethylene glycol) styrene derivatives have also been synthesized and copolymerized with styrene by Meldal to prepare polymers used for peptide synthesis (92). Kurth reported an interesting evaluation of the swelling and diffusion properties for these polymers compared to 2% DVB polystyrene (93). In this study several PEG-based cross-linkers, linking two styrene monomers (with different polyether chain lengths, n = 1, 2, 4, 6; see Fig. 12), were prepared and used to prepare a library of PEG-based resins using different proportions of PEG cross-linking (2%, 10%, 20%). As expected, the swelling of these beads in all solvents was much better than their 2% PS–DVB counterpart. At low levels of PEG cross-linking (2%) the swelling was independent of the PEG tether length, but at high levels (20%) better swelling was observed when n = 6. In conclusion, the swelling and at the same time the physical stability of the beads were improved. The diffusion of the reagents within these resins was measured by the inclusion of a vinyl dye derivative (dansyl derivative) in the monomer mixture, and the fluorescence quenching of the resulting polymer bound dye was measured by adding triethyloxonium tetrafluoroborate

Fig. 12. Synthesis of PEG cross-linked PS resin.

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Fig. 13. Synthesis of POEPS-3.

in accordance with the method of Shea (94). These studies showed only a slight difference between conventional PS resins and that modified with PEG cross-linker when the reactions were performed in a good swelling solvent (toluene); however, in poor solvents the PEG-based cross-linked resins showed the best kinetics. However, one of the drawbacks of using this type of cross-linker is that PEG is connected to the polystyrene backbone by a benzyl ether bond that could be cleaved by the use of Lewis or protic acids. Meldal reported the synthesis and the use of an alternative cross-linker containing a three-carbon spacer between the PEG chain and the polystyrene backbone (85) (Fig. 13). Properties such as swelling, loading, diffusion, and ability to furnish high quality MAS-NMR have been investigated and compared to commercial counterparts such as TentaGel, ArgoGel, 2% PS-DVB, and macroporous PS (96). The results of this study showed that POEPS-3 was comparable to TentaGel and ArgoPore, in terms of swelling, NMR quality, and diffusion. Moreover, these supports showed better swelling in the range of solvents tested. Copoly(styrene-butylene glycol). Because of the favorable properties shown by the PEG-based cross-linkers, Janda investigated other types of crosslinkers (97). Because of the tendency of PEG to complex organometallic compounds and its high hydrophilicity, new types of polystyrene resin containing “polytetrahydrofuran”–styrene derivatives as cross-linkers were prepared to allow

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Fig. 14. Cross-linker used in the synthesis of copoly(styrene-tetrahydrofuran) resins.

better solvation of the resin and its functionality that might show reactivity close to homogeneous-phase conditions. Resins with 1–2% of cross-linker (Fig. 14, A) degraded in the presence of strong Lewis acids (TMSOTf) or strong bases (BuLi). However, increasing the cross-linking level (5–10%) gave resins that were unaffected by these conditions. Resins with 1–2% of cross-linker (Fig. 14, B) showed good stability under the conditions reported above. The resin synthesized with 2% of cross-linker (Fig. 14, B) is commercialized under the name of JandaJel. The main characteristic of these resins was their incredible swelling in organic solvents, almost doubled compared to conventional gel-type 1% polystyrene resin with 1% DVB (Table 3). JandaJel was used to prepare a small library of phthalides where the key step of the synthesis was the ortho-lithiation of the supported benzamide (98). The same research group investigated several applications of these resins: Jacobson asymmetric epoxidation with a supported catalyst (99); synthesis of tertiary amines using the REM linker (100); solid-phase synthesis of oligoesters (101); solid-phase peptide synthesis using a routine Boc Protocol (102). Other benefits were reported by Shibasaki during the development of new supported catalysts for Reisser- and Strecker-type reactions (103,104). In a recent publication (105), atom transfer radical polymerization ligands on JandaJel were used to remove a copper catalyst, because of its better solvent compatibility compared to PS–DVB. However, although JandaJel showed less efficiency compared to low molecoular polyethylene capped with appropriate ligands previously developed (106), the reaction times were shorter. In conclusion, JandaJel is more “organic solvent-like” than PS–DVB. However, although its excessive swelling might improve reaction kinetics and yields, it can be a drawback because of the difficulty of handling the support during library synthesis. Table 3. Swelling Comparison Between Gel-Type and JandaJel Resinsa Volume of swollen resins, mL/g Resins (cross-linking) Merrifield (1) Merrifield (2) JandaJel (1) JandaJel (2) a Ref.

97.

Dioxane

THF

DMF

Benzene

DCM

6.0 5.4 14.8 7.8

6.4 5.4 14.0 7.4

4.8 4.2 10.4 6.0

6.6 6.6 14.6 8.2

6.0 5.8 15.0 7.4

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Table 4. Scavenging Efficiencies Using Different Amines Amine Benzylamine Butylamine Phenylethylamine Diethylamine 3,5-dimethylamine

Solvent

Amount scavenged %

THF THF DCM DCM THF

75 77 78 90 48

Alternative Formats for Polystyrene Supports The synthesis of combinatorial libraries by the split and mix method allows thousands of compounds to be obtained in just a few synthetic steps. In accordance with the original concept, each resin bead bears one single compound, and identification of biologically active compounds can be achieved directly on the beads. The drawback of this process is that the amount of compound that each bead can carry is limited (a few hundreds of picomoles), which is not enough for chemical identifications. To resolve this issue several approaches have been developed. The original method by Bradley was the enhancement of loading by “dendrimerization” (107). Bigger beads can be used, but such supports suffer from poor reaction kinetics and a propensity to disintegrate. Several authors have proposed different formats for solid-supported chemistry for split and mix as well as parallel synthesis applications to improve the issues described above and to improve the ease of handling. Monoliths and Discs. Fr´echet and co-workers introduced the monolith format in the 1990s for applications in chromatography (108) and solid-supported catalysts (109). In 1999, Sherrington described the preparation of polymer discs, cut from monoliths, for synthetic purposes (110). Among the cross-linkers used, PEG1000 diacrylates showed better resistance to mechanical stirring and osmotic shock than PS–DVB. After chloromethylations, the discs were coupled with 5-bromosalicylic acid and treated with phenylboronic acid in the presence of Pd(PPh3 )4 . Unfortunately, the Suzuki products were not obtained in good yields. In the same year, Fr´echet demonstrated the use of their porous-grafted macroporous polystyrene–DVB monolith-disc in so-called “reactive filtration” with good results (111). For the preparation of the monoliths, the monomer mixtures and the porogen were placed into a shrinkable polyethylene tube that acted as a mould inside a glass tube. After polymerization, the glass tube was broken, leaving the monolith tightly trapped in the polyethylene tube which could be cut into 5-mm disc shapes (Fig. 15) (112). The resulting PE-encircled discs showed good mechanical stability and also ease of handling. To increase the accessibility of the inner reactive groups and also the number of functionalities, the monolith surface was grafted as showed in Figure 16. The chloromethyl polystyrene discs (Fig. 16, A) reacted with azobis(4-cyanovaleric acid) (ACVA), a symmetrical azo initiator, to give the polymer-supported acid (Fig. 16, B and C). The pores were then filled with an appropriate monomer and polymerized to afford the final products (Fig. 16, D). The initiator could also react with two chloromethyl groups (Fig. 16, C) and this was indeed preferred to obtain

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Fig. 15. Preparation of monolithic discs using the method of Fr´echet (112).

better grafting as propagation could occur from both the sides of the initiator and, therefore, maximize grafting efficiencies. Supported disc-reagents were prepared for acylation of several amines in a flow system (113), affording very good conversions into the corresponding amides (114). The major advantage of this format is that the polymer could be fitted into a cartridge, allowing easy interchangeability during automatic synthesis. Moreover, they could be used to perform synthesis and purification in a flow system (114). One other application of such monoliths, for the synthesis of a split and mix library, was presented by Janda (115). The preparation of “euclidean-shape” monoliths was performed using a monomer mixture of styrene, chlroromethylstyrene, and 1,4- bis(vinylphenoxy)butane as cross-linker. Dodecanol was used as inert diluent and benzoyl peroxide as initiator. Films. PS-based films were introduced by Sherrington to be used as an easy device for FTIR in situ monitoring (116). Thin films (76mm × 14mm × 60–120µm) were obtained by polymerization of monomers in presence of porogen (for macroporous films), and a UV-sensitive initiatior, inserted between two microsocpe slides (Fig. 17). The microscope slides were filled by capillarity, and polymerization initiated by UV irradiation. Gel-type films were produced using different cross-linkers coupled with styrene and chloromethylstyrene (CMS). The best films were obtained using a

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Fig. 16. Grafting of polymer discs.

PEG1000/1500 -DVB cross-linker, but the PS–DVB films resulting were fragile. The chemistry of these gel-type films was evaluated by nucleophilic displacement of the chlorine with 5-bromosalicylic ester. Macroporous films were also produced using styrene, DVB, and 4-vinylpyridine. Flexible and resistant films were obtained using long-chain alcohols as porogens. To evaluate diffusion through the macroporous films, the pyridine functionality was methylated with methyliodide

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Fig. 17. Preparation of polymeric films (116).

in acetone and the yellow color of the film examined due to the pyridinium iodide charge transfer absorption band. Treatment of the supported pyridinium salt with KMnO4 allowed the film to change color to purple because of the exchange of the iodide with the permanganate. Treating the supported pyridinium salt with CuSO4 caused the film to turn blue because of coordination of the pyridine with Cu(II). The supported-pyridinium salts were also used for the preparation of immobilized rhodium complexes and for mechanistic studies on the carbonylation of olefins by FTIR (117). Plugs and Tablets. In 2001, Bradley introduced resin plugs as a method to handle polymer supports (118). Plugs were achieved by sintering resin beads with an inert polymer matrix (ultrahigh molecular weight PE). The plugs were obtained in cylindrical forms (9.9-mm length × 7.5-mm diameter) and had loadings between 50 and 150 µmol). Although both PS- and PEG- grafted resins were used for the preparation of the plugs, they are now prepared using StratoSphere resins and commercialized by Polymer Laboratories with the name of StratoSphere Plugs (Fig. 18). During their evaluations, plugs were used as supports for solid-phase synthesis of small libraries of biaryl compounds, sulfonamides, tertiary amines, ureas, and amides. Although yields and purities were similar to the loose beads counterpart, the reaction times were slightly increased. Because of their mechanical stability and limited swelling, plugs are much easier to handle than the corresponding

Fig. 18. (a) Cross-section of a resin plug (100 × magnification); (b) single bead within the matrix of the resin plugs (270 × magnification); (c) illustration of the dimension of the resins plugs.

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Fig. 19. Preparation and use of palladium plug-supported catalyst.

loose beads. In solution-phase synthesis, plugs have been employed as supports for immobilized palladium catalysts to prepare libraries of biaryl compounds (Fig. 19) with yields comparable to Pd(PPh3 )4 (119). In conclusion, plug-supported palladium maintained comparable catalytic activities, but were much easier to handle than the homogeneous analogue Pd(PPh3 )4 . An alternative to improve resin handling was introduced by Ruhland, who described the preparation of tablets obtained from the compression of a blend of resin with solid reagents or catalysts (120). The preparation of such tablets involved three steps: swelling of the beads (and the solid reagent or catalyst) in a good solvent; sieving; and compression. The first step was essential for the preparation of mechanically stable tablets. The effect of swelling and drying resulted in agglomerations caused by bead–bead interactions as observed by SEM. Observation of the tablet structure showed that the beads were distorted after compression but not destroyed. The disintegration time of the tablets, measured by gentle shaking, was very solvent-depending and implicated that the swelling of the beads caused disintegration. As a consequence, good solvents such as THF or DCM gave shorter times of disruption (7–16 min) than DMSO or ethanol (>30 min). Functionalized tablets were employed to carry out Mitsunobu reactions and amine acylations, giving results comparable to the corresponding loose resins. During syntheses, tablets were loaded in 48-well plates in only 3 min, whereas the same procedure applied to resin beads took much longer. Moreover, preparation of tablets allowed the protection of sensitive functional groups from moisture or oxygen, and also a drastic reduction in the time of exposure to toxic hazardous and dusty materials in the working environment.

Nonpolystyrene Polymer Matrices All the polymer supports described so far for solid-phase chemistry have a common factor: the main presence of a polystyrene backbone. Although this polymer matrix has good characteristics, such as chemical and mechanical stability (depending on the type and amount of cross-linker) and favorable loadings in solvent, its compatibility with polar solvents and large biomolecules, such as enzymes and receptors, is quite poor (121). In order to resolve these problems, several authors have replaced hydrophobic polystyrene with a more amphiphilic backbone. In the

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Fig. 20. Preparation of polyamide resins (Pepsin)

early 1970s, Sheppard introduced polyacrylamide supports, prepared by emulsion polymerization (Fig. 20), as an alternative to polystyrene gel-type resin for polypeptide synthesis (122). Such resins showed good swelling in highly polar solvents (see ACRYLAMIDE POLYMERS). Moreover, polypeptides were obtained in higher yields and purities and their syntheses were faster than with traditional polystyrene gel-type resin. These commercialized resins are still in use for largescale preparation (33). However, such supports, being very soft and fragile, are difficult to work with (123). Pepsin K was prepared by polymerization of pepsin monomers within rigid macroporous particles to help solve this problem (124). In the 1990s, Meldal, following the work of Sheppard, developed an improved support which was named PEGA (PEG–polyacrylamide) (125), obtained by inverse suspension polymerization (126) of N,N-dimethylacrylamide cross-linked with different bis-acrylic-PEG derivatives (Fig. 21, A). Functionalization was introduced by inclusion of acryloyl-PEG-NH2 monomers (Fig. 21, C; loading = 0.08–0.13 mmol/g) or acryloyl-sarcosine

Fig. 21. Monomers used for the preparation of PEGA.

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Fig. 22. PEGA supported ruthenium catalyst.

methylester monomer (Fig. 21, D; loading = 0.22–1.0 mmol/g) (127). The first version of such resins (PEG1900 ) allowed the diffusion of biomolecules with a mass of ∼32 kDa into the beads. Although monomer A (Fig. 21), prepared using PEG4000,6000,8000 , improved the limit (>120 kDa), handling and loadings were poor. Recently, Gardossi observed that the introduction of a positive charge by trialkylammonium species in PEGA1900 allowed better swelling than neutral PEGA and consequent inclusion of large proteins (128) although favorable charge–charge interactions are perhaps a more reasonable explanation (but also see Section 3.1). Although the main area of use of PEGA remains for biological based chemistry, because of size accetability (129–131), it has also been used with water-insoluble ruthenium catalysts for metathesis reactions in aqueous and protic solvents (in such conditions the nonsupported catalyst does not work) (Fig. 22) (132). This catalyst not only showed good activity in metathesis reactions but also did not need to be used in degassed solution, as required by conventional Grubbs catalysts (133). However, the main problem of PEGA is its difficulty of handling: having to be handled in a solvated state as it may disintegrate when dry. A more robust cross-linked ethoxylate acrylate resin (CLEAR) was presented in 1996 by Kempe and Barrany (134). The main component of such supports is a branched PEG-acrylate derivative used in ∼50 mol% (Fig. 23), which gave good swelling in a range of solvents.

Fig. 23. Trimethylopropane ethoxylate (14/3 EO/OH) triacrylate.

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Fig. 24. Preparation of PEG-MA.

Unfortunately, CLEAR is vulnerable to strong bases (such as NaOH or NH3 ), although complete polymer dissolution occurs only after long reaction times. In 2001, Fr´echet introduced PEG-MA (PEG methacrylate) (135). The monomers are PEG methacrylate derivatives (Fig. 24, A) and ethylene dimethacrylate is used at 2 mol% as a cross-linker (Fig. 24, B). Although such monomers are soluble in aqueous media, the preparation of PEG-MA was conducted by a “modified suspension polymerization.” As expected for resins that contained poly(ethylene glycol), PEG-MA was compatible with a broad range of polar and nonpolar solvents. Swelling depended on the chain length of the PEG incorporated in the monomer (Fig. 24, A), longer chains giving better swelling. Although loadings calculated were much lower (51–67%) than the ones expected, such values were still much higher than commercial PEG-grafted resins (1.2–1.8 mmol/g). The PEG-MAs were used for the preparation of a small library of hydantoins. The advantages of using PEG clearly reside in the improved property of the tailored polymer matrix. Loading, solvent compatibility (and so, swelling), and mechanical resistance depend on the level of this polymeric monomer. In 2002, Meldal prepared a new class of polymers named SPOCC (superpermeable organic combinatorial chemistry) resins (136). The main characteristic of these polymers was that the backbones and cross-linker both contained PEG. The second generation of such polymers (SPOCC194 ) was prepared by cationic polymerization of the two monomers shown in Figure 25. Novel SPOCCs exhibit great chemical resistance under various reaction conditions, because there are no benzyl ether, ester, and amide linkages. The use of shorter PEG chains in SPOCC194 allowed higher loading compared to the previous generation resins (longer PEG chains), although swelling decreased. Although mainly used in peptide chemistry, SPOCC resins have seen successfully tested in a variety of different organic transformations (136,137). Direct comparison of this support, PS resin, and TentaGel showed comparable if not better kinetics in peptide synthesis. Cellulose: From Paper to Beads. The first use of cellulose (qv) as a solid support for peptide chemistry can be attributed to Merrifield. Unfortunately, at

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Fig. 25. Preparation of SPOCC194 .

that time, only a dipeptide was obtained in unsatisfactory yield. Moreover, cellulose was not chemically stable to the conditions used in the synthesis. Merrifield decided to abandon this support and to search for others with better properties (138). Peptides and oligonucleotides have been synthesized on paper and cotton (139,140), and Frank demonstrated, in 1992, the flexibility of cellulose for the preparations of large arrays of peptides on membranes by Spot synthesis (141). At the end of the synthesis, biological assays could be performed directly on each spot on the filter disk, as cellulose is compatible with many binding, enzymatic, and cellular essays (142). However, paper membranes are not suitable for scavenger or supported reagents, because of difficulties in their handling and their limited loading. In 1977, Stamberg found a method to prepare spherical cellulose particles with a certain degree of porosity by heating a viscose suspension (an aqueous solution of sodium cellulose xanthate) in a water-immiscible solvent under stirring (143). Such beads became commercially available under the name of Perloza. Because of the availability of three hydroxyl groups for each glucopyranose monomer, such supports provided very high loadings. Functionalized cellulose beads (0.37–0.65 mmol/g) were used for the synthesis of peptides (5–34 amino acids). The analysis of crude peptides (20 amino acids length) showed better purity when assembled on Perloza than polystyrene (144). The application of cellulose beads in solution-phase chemistry was demonstrated by Chesney and Steel (145). In their procedure, the pendant hydroxyl groups first reacted with allyl bromide; addition of bromine in water was followed by treatment with excess of tris(2-aminoethyl)amine and led to supported branched amino resins (2.2 mmol/g, 4 mmol/g). Such amino resins exhibited good and uniform swelling properties in polar and nonpolar solvents (between 8 and 10 mL/g in all solvents). Moreover, they allowed the synthesis of small libraries of amides and ureas in quite good purities and yields by the scavenging of excess acid chloride and isocyanate derivatives (Fig. 26, B). Treatment of Perloza with the enzyme cellulase allowed the complete biodegradation of the beads to glucose that, after treatment with brewers’ yeast, led to ethanol, CO2 , and H2 O. The supported allyl beads were also reactive enough to permit their application as a scavenger of bromine (Fig. 26, A) (146). Recently, Perloza aniline

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Fig. 26. Scavenger uses of biodegradable cellulose beads.

functionalized beads were used for a synthesis of a library of pyrazoles. Once the reaction conditions were established, the “catch and release” method was adopted and allowed the continuous recycling of the beads without decreasing yields and purities (147). In conclusion, cellulose beads have interesting properties, such as relatively high loading, cheapness, chemical and mechanical stability, and recycling and easy disposal, factors that could be of use in large-scale industrial processes. As can be seen, over the years there has been huge development in supports for synthetic applications, with variation of improvement in loading, morphologies, and polymer type. Gel-type polystyrene resins are still the most widespread supports in solidphase organic chemistry, exhibiting good characteristics of loading, swelling, and handling. However, they are not universal. Although an ideal support should be inert to reactions conditions, it does not mean that it does not have to interact with the reagents. “Resin beads are like solvents,” suggested Czarnic (29), and this concept could be expanded by saying that “different polymer supports are like different solvents.” As the choice of a particular solvent can change the course of a reaction, a polymer support has to be considered in the same way. For this reason, research groups continue the early work of Merrifield (139) in order to screen

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and synthesize new and enhanced polymer supports for a range of chemical and biological applications.

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71. O. W. Gooding, S. Baudart, T. L. Deegan, K. Heisler, J. W. Labadie, W. S. Newcomb, J. A. Porco, and P. van Eikeren, J. Comb. Chem. 1, 113–122 (1999). 72. J. H. Adams, R. M. Cook, D. Hudson, V. Jammalamadaka, M. H. Lyttle, and M. F. Songster, J. Org. Chem. 63, 3706–3716 (1998). 73. S. Alesso, Z. Yu, D. Pears, A. P. Worthington, R. W. A. Luke, and M. Bradley, Tetrahedron 59, 7163–7169 (2003). 74. E. Bayer and W. Rapp, in M. E. Harris, ed., Poly(Ethylene Glycol) Chemistry: Biotechnical and Biomedica Applications, Plenum Press, New York, 1992, p. 325. 75. S. A. Kates, N. A. Sol´e, M. Beyermann, G. Barany, and F. Albericio, Peptide Res. 9, 106–113 (1996). 76. E. Bayer, A. Klaus, H. Willisch, W. Rapp, and B. Haemmasi, Macromolecules 23, 1937–1940 (1990). 77. D. P. Walsh, C. Pang, P. B. Parikh, Y.-S. Kim, and Y.-T Chang, J. Comb. Chem. 4, 204–208 (2002). 78. D. Walsh, D. Wu, and Y.-T. Chang, Curr. Opin. Chem. Biol. 7, 353–361 (2003). 79. B. Ruhland, A. Bombrun, and M. A. Gallop, J. Org. Chem. 62, 7820–7826 (1997). 80. X. Du and R. W. Armstrong, J. Org. Chem. 62, 5678–5679 (1997). 81. H. Han and K. Janda, Angew. Chem., Int. Ed. Engl. 36, 1731–1733 (1997). 82. W. Li and B. Yan, J. Org. Chem. 63, 4092–4097 (1998). 83. Y.-S. Lee and B.-D. Park, React. Fun. Polym. 44, 41–46 (2000). 84. V. Swali, N. K. Wells, J. Langley, and M. Bradley, J. Org. Chem. 62, 4902–4903 (1997). 85. S. Lebreton, B. Newcomb, and M. Bradley, Tetrahedron Lett. 43, 2475–2478 (2002). 86. E. Swayze, Tetrahedron Lett. 38, 8465–8468 (1997). 87. C. M. G. Judkins, K. A. Knights, B. F. G. Johnson, Y. R. de Miguel, R. Raja, and J. M. Thomas, Chem. Commun. 2624–2625 (2001). 88. C. M. G. Judkins, K. A. Knights, B. F. G. Johnson, and Y. R. de Miguel, Polyhedron 22, 3–7 (2003). 89. Y. Kohno, N. Ogawa, K. B. Chung, and W. Fakuda, Makromol. Chem. 193, 3009–3021 (1992). 90. M. Renil, R. Nagaraj, and V. N. Rajasekharan, Tetrahedron 50, 6681 (1994). 91. K. Kamahori, K. Ito, and S. Itsuno, J. Org. Chem. 61, 8321 (1996). 92. M. Renil and M. Meldal, Tetrahedron Lett. 37, 6185 (1996). 93. M. E. Wilson, K. Paech, W.-J. Zhou, and J. Kurth, J. Org. Chem. 63, 5094–5099 (1998). 94. K. J. Shea, Y. Okahata, and T. K. Dougherty, Macromolecules 17, 296–300 (1984). 95. J. Buchardt and M. Meldal, Tetrahedron Lett. 39, 8695–8698 (1998). 96. M. Grøtli, C. H. Gotfredsen, J. Rademann, J. Buchardt, A. J. Clark, J. Ø. Duus, and M. Meldal, J. Comb. Chem. 2, 108–119 (2000). 97. P. H. Toy and K. Janda, Tetrahedron Lett. 40, 6329–6332 (1999). 98. P. H. Toy, T. S. Reger, P. Garibay, J. C. Garno, J. A. Malikayil, G. Liu, and K. Janda, J. Comb. Chem. 3, 117–124 (2001). 99. T. S. Reger and K. Janda, J. Am. Chem. Soc. 122, 6929–6934 (2000). 100. P. H. Toy, T. S. Reger, and K. Janda, Org. Lett. 2, 2205–2207 (2000). ¨ 101. O. Brummer, B. Clapham, and K. Janda, Tetrahedron lett. 42, 2257–2259 (2001). 102. J. A. Moss, T. J. Dickerson, and K. D. Janda, Tetrahedron Lett. 43, 37–40 (2002). 103. H. Nogami, S. Matsanaga, M. Kanai, and M. Shibasaki, Tetrahedron Lett. 42, 279–283 (2001). 104. M. Takamura, K. Funabashi, M. Kanai, and M. Shibasaki, J. Am. Chem. Soc. 123, 6801–6808 (2001). 105. M. E. Honigfort and W. J. Brittain, Macromolecules 36, 3111–3114 (2003). 106. S. Liou, J. T. Rademarcher, D. Malaba, M. E. Pallack, and W. J. Brittain, Macromolecules 33, 4295–4296 (2000). 107. C. Fromont and M. Bradley, Chem. Commun. 283–284 (2000).

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108. F. Svec and J. M. J. Fr´echet, J. Anal. Chem. 64, 820–822 (1992). 109. F. Svec and J. M. J. Fr´echet, J. Science 273, 205–211 (1996). 110. N. Hird, I. Huges, D. Hunter, M. G. J. T. Morrison, D. C. Sherrington, and L. Stevenson, Tetrahedron 55, 9575–9584 (1999). 111. J. A. Tripp, J. A. Stein, F. Svec, and J. M. J. Fr´echet, Org. Lett. 2, 195–198 (1999). 112. J. A. Tripp, F. Svec, and J. M. J. Fr´echet, J. Comb. Chem. 3, 216–223 (2001). 113. P. Hodge, Curr. Opin. Chem. Biol. 7, 362–373 (2003). 114. J. A. Tripp, F. Svec, and J. M. J. Fr´echet, J. Comb. Chem. 3, 604–611 (2001). 115. A. R. Vaino, and K. Janda, Proc. Natl. Acad. Sci. U.S.A. 97, 7692–7696 (2000). 116. P. H. Findlay, S.-M. Leinonen, T., M. G. J., E. E. A. Shepherd, and D. C. Sherrington, J. Mater. Chem. 10, 2031–2034 (2000). 117. BP Chemicals Ltd, Purolite International, Johnson Matthey plc, University of Sheffield, and University of Straclyde, ACCP News Applied Catalysis and Catalytic Processes, No. 3, 2000, pp. 6–7. 118. B. Atrash, M. Bradley, R. Kobylecki, D. Cowell, and J. Reader, Angew. Chem., Int. Ed. Engl. 40, 938–941 (2001). 119. B. Atrash and M. Bradley, Tetrahedron Lett. 44, 4779–4782 (2003). 120. T. Ruhland, P. Holm, and K. Andersen, J. Comb. Chem. 5, 842–850 (2003). ´ N. F. Sepetov, J. A. Ostrem, P. Strop, 121. J. Vagner, G. Barany, K. S. Lam, V. Krchnak, and M. Lebl, Proc. Natl. Acad. Sci. U.S.A. 93, 8194–8199 (1996). 122. E. Atherton, D. L. J. Clive, and R. C. Sheppard, J. Am. Chem. Soc. 97, 6584–6585 (1975). 123. E. Atherton, E. Brown, R. C. Sheppard, and A. A. Rosevear, Chem. Commun. 1151 (1981). 124. R. Arshady, E. Atherton, D. L. J. Clive, and R. C. Sheppard, J. Chem. Soc., Perkin Trans. 1 529–537. (1981). 125. M. Meldal, Tetrahedron Lett. 33, 3077–3080 (1992). 126. R. Arshady, Colloid. Polym. Sci. 268, 948–958 (1990). 127. M. Renil, M. Ferreras, J. M. Delaisse, N. T. Foged, and M. Meldal, J. Pept. Sci. 4, 195–210 (1998). 128. A. Basso, L. De Martin, L. Gardossi, G. Margetts, I. Brazendale, A. Y. Bosma, R. Ulijn, and S. Flitsch, Chem. Commun. 1296–1297. (2003). 129. S. Leon, R. Quarrel, and G. Lowe, Bioorg. Med. Chem. Lett. 8, 2997–3002 (1998). 130. H. K. Smith and M. Bradley, J. Comb. Chem. 1, 326–332 (1999). 131. M. Conza and H. Wennemers, Chem. Commun. 866–867. (2003). 132. S. J. Connon and S. Blechert, Bioorg. Med. Chem. Lett. 12, 1873–1876 (2002). 133. D. M. Lynn, B. Mohr, L. M. Henling, M. W. Day, and R. H. Grubbs, J. Am. Chem. Soc. 122, 6601 (2000). 134. M. Kempe and G. Barrany, J. Am. Chem. Soc. 118, 7083–7093 (1996). 135. R. Kita, F. Svec, and J. M. J. Fr´echet, J. Comb. Chem. 3, 564–571 (2001). 136. J. Rademann, M. Grøtli, M. Meldal, and K. Bock, J. Am. Chem. Soc. 121, 5459–5466 (1999). 137. L. P. Miranda, W. D. Lubell, K. M. Halkes, T. Groth, M. Grøtli, J. Rademann, C. H. Gotfredsen, and M. Meldal, J. Comb. Chem. 4, 523–529 (2002). 138. R. B. Merrifield, in J. I. Seeman, ed., Profiles, Pathways and Dreams: Autobiographies of Eminents Chemists, American Chemical Society, Washington, D.C., 1993. 139. R. Frank, W. Heikens, G. Heistberg-Moutsis, and H. Bl¨ocker, Nucleic Acids Res. 11, 4365–4377 (1983). 140. R. Frank and R. Doring, Tetrahedron 44, 6031–6040 (1983). 141. R. Frank, Tetrahedron 48, 9217–9232 (1992). 142. U. Reineke, R. Volkmer-Engert, and J. S. Mergener, Curr. Opin. Biotechnol. 12, 59–64 (2001).

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143. U.S. Pat. 4,055,510 (Oct. 25, 1977), J. Peska, J. Stamberg, and Z. Blace. (Ceskoslovenska Akademie Ved). 144. D. R. Englebretsen and D. R. K. Harding, Int. J. Peptide Protein Res. 43, 546–554 (1994). 145. A. Chesney, P. Barnwell, D. F. Stonehouse, and P. G. Steel, Green Chem. 2, 57–62 (2000). 146. A. Chesney, P. G. Steel, and D. F. Stonehouse, J. Comb. Chem. 2, 434–437 (2000). 147. L. De Luca, G. Giacomelli, A. Porcheddu, M. Salaris, and M. Taddei, J. Comb. Chem. 5, 465–471 (2003).

GENERAL REFERENCES For nice, historical review of solid-supported reagents catalysts, and sorbents, see D. C. Sherrington, J. Polym. Sci. A 39, 2364–2377 (2001), and also D. Hudson, J. Comb. Chem. 1, 336–360 (1999); J. Comb Chem. 1, 403–457 (1999).

MARK BRADLEY NICOLA GALAFFU University of Southampton

POLYMETHACRYLATES.

See METHACRYLIC ESTER POLYMERS.

POLY(METHACRYLIC ACID).

See ACRYLIC (AND METHACRYLIC) ACID

POLYMERS.

POLYNUCLEOTIDES.

See Volume 3.

POLYOXYMETHYLENE.

See ACETAL RESINS.