Combinatorial Libraries of Polymeric Catalysts as Enzyme Mimetics

Enzymes have found widespread use in industry in a multitude of chemical reactions because of their often perfect selectivities and high activities under relatively mild reaction conditions [47, 48]. For a multitude of the most different reasons, chemists are obviously stimulated to rationally design and synthesize numerous classes of low- and high-molecular-weight synthetic enzyme catalysts (''synzymes'') that mimic, improve, substitute, or exceed a natural enzymatic function or structure. However, most of them have fallen short of the goal of efficiently reproducing enzymatic catalysis, but, nonetheless, these studies have brought more insights into enzymatic reactions [49].

Immobilized (polymer supported) catalysts are of increasing importance in synthetic organic chemistry and library synthesis. In this scenario, established (metal) organic catalysts are anchored to a solid support to facilitate product work-up, separation, isolation, and catalyst recycling. However, the scope and limitations of these catalysts are reviewed elsewhere [50].

A novel approach to identify enzyme-like new organic catalysts is by searching through a multitude of''randomly'' generated polymeric systems [51]. Random

Fig. 32.9. Examples of a combinatorially functionalized polymeric catalysts based on poly(allylamine) (PAA) or poly(ethyleneimine)(PEI) facilitating the hydrolysis of phosphate esters or the reduction of a-keto carboxylates.

compounds are meant to be combinatorially functionalized polymers. Assuming a proper juxtaposition of multiple functional, catalytically active groups within the polymer, the groups of Menger and Ford developed synthetic methodology for combinatorially functionalized polymers hoping to effect catalysis of several target reactions.

One of the first applications of this concept in combinatorial catalysis was the development of phosphatase-like catalysts [52], or a combinatorially developed polymeric reducing agent (Fig. 32.9) [53]. In these studies, commercially available poly(allylamine) (PAA) or poly(ethyleneimine) (PEI) was functionalized with various combinations and proportions of small diverse sets (three, four, and eight) of carboxylic acids to afford randomly functionalized polymers bearing variably substituted amide groups ranging in concentration from 5% to up to 60% and leaving some amino functions unreacted. Automation facilitated the synthesis of up to 8198 combinatorial variations of the polymeric reducing agents. To introduce redox-active capabilities into the reducing polymer catalysts, 1,4-dihydropyridine (DHP), known from NADH models to reduce activated ketones to alcohols, was incorporated. Depending on the kind of reaction to be catalyzed, metal ions such as Mg(II), Zn(II), and Fe(III) [52], or Cu(II), Mg(II), and Zn(II) ions were added [53]. In each case, the polymeric mixtures were then screened spectrophotometrically either in a one-at-a-time fashion [52], or in a parallel 96-at-a-time microtiter plate format [53].

Analysis of initial hydrolysis rates of the bis-(p-nitrophenyl)phosphate test substrate concluded some composition-activity relationships (degree and nature of carboxylic acid content with respect to catalytic activity). Significant rate accelerations (kcat/kuncat) of up to 3 x 104 (exceeding that of a catalytic antibody for the same reaction) [54] were observed for a specific polymer composition in the presence of Fe(III) ions [52].

About 92% of the polymeric reducing agents were found to be catalytically inactive in the reduction of benzoylformate (a-keto carboxylate) to the mandelate (a-hydroxy carboxylate) as the test reaction. Among others, two of the most active polymer compositions could be identified, and, for example, an active PEI-based polymer had a functional composition of 5% dihydropyridine, 2.5% 2-imidazol-acetic acid, 15% 2-naphthyl carboxylic acid, 2.5% 3-mercaptopropionic acid, and 5% Zn(II) [53].

A library of 1344 polymeric variations with an amide bond functionalization ranging up to 20% was obtained by aminolysis of poly(acrylic anhydride) and sets of mixtures of three to four amines taken from a library of 11 amines and using an instrumentational set-up for library synthesis similar to that described above (Fig. 32.10) [55].

Assuming that these polymeric catalysts possessing both acid and basic functional groups in proper spatial orientation would likely catalyze the dehydration of

Fig. 32.10. Example of a combinatorially functionalized polymeric catalyst based on poly(acrylic anhydride) facilitating the dehydration ofb-hydroxyketones.

Fig. 32.11. Representative structural element of a hydrolytically active trimethylammonium (TMA) functionalized polymer.

Fig. 32.11. Representative structural element of a hydrolytically active trimethylammonium (TMA) functionalized polymer.

b-hydroxy ketones, the researchers spectrometrically monitored the appearance of the b-aryl-a,b-unsaturated carbonyl chromophore of the product. About 1% of the polymeric catalysts revealed a significant rate enhancement (kcat/kuncat = 920). For comparison, an antibody-catalyzed dehydration of the test substrate afforded a catalytic rate enhancement of 1200 above background [56]. Several other interesting features could be assessed rapidly such as the observation of a ''nonbiological induced fit,'' i.e. a substrate-induced transformation into a catalytically active conformation upon variation of the reaction parameters such as temperature and pH.

Ion exchange latexes, especially those bearing quaternary ammonium anion exchange sites, significantly increase the hydrolysis rate of activated esters such as the ever-popular p-nitrophenyl diphenyl phosphate [57]. In this context, Miller and Ford reported the parallel synthesis of a small library of 32 anion exchange alkyl methacrylate latexes via radical polymerization which contained @ 20% of quaternary ammonium units (Fig. 32.11) [58]. The latexes comprised monomers such as vinylbenzyl chloride, sets of aliphatic methacrylates, divinylbenzene (crosslinker), and (m-/p-vinylbenzyl) trimethylammonium chloride (stabilizer). The number and combination of the aliphatic monomers were combinatorially varied and additional anion exchange sites were introduced by quaternization of the benzylchloride residues with either trimethylamine or tributylamine. Pseudo-first-order reaction rate coefficients were spectrophotometrically determined. Relative rate enhancements ranged from 2.3 for a polystyrene-trimethyl ammonium (TMA) latex to 16.5 for a 2-ethylhexyl methacrylate-tributyl ammonium (TBA) latex. In addition, several other composition-activity relationships and performance trends could be rationalized from the molecular structure.

The random nature of the synthesis of polymeric catalysts leads to a lack of structural information about catalytically active sites. However, a polymeric system that serves a useful function, even devoid of detailed structural information, may be generally of great interest. The obvious ease and practicability of this approach may allow for a rapid evolution and optimization of polymeric catalysts and may be useful, especially if reproducibility issues are carefully addressed, to identify active polymeric catalysts for many other important chemical reactions.

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