Transition state imprinted polymer

In another example, partial hydrolysis of the EGDMA crosslinker led to an enhancement in the properties of a catalytically active MIP [27]. The MIP had been simultaneously covalently and noncovalently imprinted with ester hydrolysis transition state analogs of an ester hydrolysis reaction. Increases in both rate and selectivity were observed in the catalytic activity of transition state imprinted polymer upon treatment with NaOH/MeOH. These improvements were proposed to arise from greater accessibility to catalytic sites in the MIP. Hydrolysis of the crosslinker... 

The transition state analog (TSA) approach1651 which has proved so successful in the design of enzyme inhibitors and catalytic antibodies lends itself nicely, at least in principle, to the molecular imprinting of polymers. Polymerization carried out in the presence of the TSA, or with the TSA covalently but readily reversibly bound to a monomer, produces a polymer with a number of embedded TSA molecules. If these can be removed under rea-... 

Molecular imprinting is not limited to organic polymer matrices, but can also be applied to silica-based materials and even proteins. Proteins freeze-dried in the presence of a transition state analogue as template have been used successfully as catalysts, e.g., for the dehydrofluorination of a fluorobutanone. For instance, lyophilized 3-lactoglobulin imprinted in this manner with N-isopropyl-N-ni-trobenzyl-amine could accelerate the dehydrofluorination by a factor of 3.27 compared to the non-imprinted protein see Table 5 [62]. In a similar procedure, BSA was imprinted with N-methyl-N-(4-nitrobenzyl)-S-aminovaleric acid and showed an enhancement of the catalytic effect by a factor of 3.3 compared to the control protein for the same reaction see Table 5 [113]. 

This technique has also been employed for the preparation of a catalytic imprinted membrane by coating a cellulose membrane with a polymer incorporating particles imprinted with the transition-state analogue of a dehydrofluorination reaction [264]. The application of such an MIP composite membrane as the recognition element in an optical sensor has been reported for digitoxin analysis in serum samples by embedding digitoxin-MIP particles in polyvinyl chloride film in presence of plasticizer by the dry inversion process [265],... 

Scheme 5 The polymers were imprinted with the TSA (25) to mimic the tetrahedral transition state (24) generated during the hydrolysis of the 4-nitro-phenol-acetate (23)...

In 1997 the same group developed the first imprinted polymer able to catalyse a Diels-Alder reaction between tetrachlorothiophene dioxide (43) and maleic anhydride (44) to give the product (45). The imprinting strategy was inspired by previous work carried out by Hilvert et al. in 1989 for the development of catalytic antibodies with Diels-Alder capabilities [26]. The chlorendic anhydride (46) was used as a template because of its structural analogy with the transition state of the reaction (TSA). The resulting imprinted polymer showed a Michaelis-Menten behaviour and a ratio kcal/kunca equal to 270 (Scheme 8). 

Liu J, Wulff G (2008) Functional mimicry of carboxypeptidase A by a combination of transition state stabilization and a defined orientation of catalytic moieties in molecularly imprinted polymers. J Am Chem Soc 130 8044-8054... 

Another important research direction is the mimieking of enzymes and the construction of selective catalysts. For these purposes, the polymer is imprinted with the desired reaetion-product or better, a molecule which resembles the transition state of the reaction adducts. If the educts bind specifically to the recognition site, they become confined into these micro-reactors and are supposed to react faster and more defined than outside the cavities [445]. Examples for reactions in the presence of such synthetic enzymes can be found in [452,453,454,455,456,457] (cf Figure 40c). First positive results have been reported, e.g. an synthetic esterase , increasing the rate of alkaline hydrolysis of substituted phenyl-(2-(4-carboxy-phenyl)-acetic esters for 80 times [488] and Diels-Alder catalysis fiuic-tional holes containing titanium lewis-acids [489]... 

Mosbach prepared imprinted polymers with not only a more specific substrate binding but with a true catalytic turnover [148]. Certain N-protected amino acid derivatives formed pseudotetrahedral complexes in solution in the presence of Co and two molecules of 5-vinylimidazole. These were polymerised in the presence of divinylbenzene and the metal-ion and amino acids eluted together afterwards. Hydrolysis of the corresponding 4-nitrophenylester of the amino acid template showed an increase in catalytic activity (factor 2-4) compared with a blank prepared without the template. The polymer also exhibits a clear preference for the activated ester of the template, which suggests that hydrolysis indeed takes place inside the cavities. Two years later the scope was further broadened by the preparation of the first polymer imprinted with a transition state analogue. 

Very recently Mosbach et al. [156] have reported their latest results on p-elimination reactions catalysed by polymers molecularly imprinted with transition state analogues similar in structure to the haptens used in closely related work on catalytic antibodies [157]. There seems little doubt that this approach is likely to gather momentum, and run in parallel with the work on abzymes . 

It has already been reported that antibodies prepared against the transition state of a reaction show considerable catalytic activity [113]. For example, antibodies prepared against a phosphonic ester (as a transition state analogue for alkaline ester hydrolysis) enhanced the rate of ester hydrolysis by 10 -10" fold. Recently, similar systems based on imprinted polymers which display high catalytic activity have been successfully prepared. Initial attempts were performed by several groups [114-117] with imprinted polymers based on non-stoichiometric, non-covalent interactions, which, however, gave results far below those obtained with antibodies. Rate enhancements up to 6.7-fold were reached in one case. 

In a similar approach, very recently an imprinting procedure using labile covalent interactions was employed with quite some success [118]. Template monomer 17 was used to imprint a transition state analogue structure and to introduce at the same time a dicarboxylate moiety in the cavity. In this case a 120-fold rate enhancement compared to the solution and 55-fold compared to a control polymer containing statistically distributed dicarboxylates was observed. 

Slade and Vulfson have shown that the catalytic activity of native BSA in the dehydrofluorination reaction in aqueous media is greater than that reported for catalytic antibodies and molecularly imprinted polymers [30]. These authors therefore imprinted ]S-lactoglobulin and papain using A-isopropyl-4-nitrobenzyl amine as the transition state analogue. The catalytic activity of the imprinted proteins was evaluated in the dehydrofluorination reaction using acetonitrile as the reaction medium. A three fold rate enhancement in the A eat value vis-d-vis non-imprinted proteins was observed. 

A ligand of a metal complex is one of the most appropriate templates for a molecular-imprinted metal-complex catalyst. Several ligands have been reported as candidates because of their analogy to transition states or reaction intermediates for target reactions [51-64], Several metal complexes with single-site Co, Cu, Zn, Ti, Ru, Rh, and Pd species have been used as active metal sites coordinated with template ligands (Table 22.1). Acrylate polymers [54, 55, 60, 63, 64] or polystyrene-divinylbenzene (DVB) polymers [51, 53, 56] are common polymer supports for molecularly imprinted catalysts. 

Robinson DK, Mosbach K (1989) Molecular imprinting of a transition state analog leads to a polymer exhibiting esterolytic activity. J Chem Soc Chem Commun 14 969... 

Chiral imprints. The imprinting of organic [50] and inorganic materials [51] with transition state analog templates should, at least in principle, lead to what could be called artificial catalytic antibodies. Up to now, either the chiral recognition and/or the catalytic properties of such materials are still very poor. Some examples are a zeolite p, partially enriched in polymorph A [51], chiral footprints on silica surfaces [52], or several imprinted polymers [50]. 

The possibility to tailor-make MIPs towards a desired selectivity in combination with the high stability of the materials under a broad range of conditions has rendered MIPs attractive for the development of synthetic enzymes [243, 244]. A popular strategy has been to imprint a transition state analog to obtain a polymer that reduces the activation energy of the reaction. Catalytically active groups are often included in the polymer network. This approach has been applied towards ester and amide hydrolysis reactions [245, 246]. Examples of other reactions where MIPs have been utilized as enzyme mimics are isomerization [247], transamination [248], Diels-Alder reaction [249], 3-elimination [250] and regioselective cycloaddition [251]. 

Then the polymer was incubated with cobalt(II) ion again. When acetophenone and benzaldehyde were added, they were placed in the cavity appropriate for the reaction due to the imprinting effect (note that the template is similar to the transition state of the reaction). The cobalt(II)-catalyzed aldol reaction occurred smoothly [7]. 

One of the most attractive applications would be molecularly imprinted catalysts. In principle, such catalysts could be prepared if substrate, product or transition-state analogs could be used as template molecules, since to natural catalytic antibodies are produced in a similar way. Since molecularly imprinted polymers are considered to be analogous to antibodies in that binding sites are tailor-made, catalytic antibody-like activity in imprinted polymers could also be conceived, enabling an artifi-cial catalytic antibody with the advantageous features of synthetic molecules to be produced. 

Ester hydrolysis is most conveniently used because (1) its reaction mechanism is well established, and (2) both substrate and transition state analogs are easy to obtain. In Fig. 8.8b, phosphonic acid (2) is used as a transition state analog of the hydrolysis of substrate 3 [26]. A vinyl monomer of amidine 1 is chosen as a functional monomer because it readily forms stable complexes with the carboxylic acid ester and the phosphonic acid monoester. The imprinted polymers are synthesized in THF from 1 (the monomer), 2 (the template), and ethylene glycol dimethacrylate (the cross-linker) by using AIBN as the radical initiator. 

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