Imprinted Polymers with Memory for Small Molecules, Proteins, Or Crystals**

HIGHLIGHTS Imprinted Polymers with Memory for Small Molecules, Proteins, or Crystals** Börje Sellergren* Introduction template to the monomer or growing polymer during synthesis and, after template removal, provide the subsequent binding interactions (Table 1). Removal of the template from Molecular recognition is associated with biological proc- the formed polymer thus generates a structure complemen- esses such as the immuno response, ligand ± receptor inter- tary to the template structure or to an analogous structure. actions, and enzyme catalysis. The ability of biological hosts to This simple and appealing concept has for more than 50 strongly and specifically bind to a particular molecular years[8] attracted chemists from several disciplines in their structure is a key factor in the biological machinery. Well- search for solutions to their particular problems. Nevertheless known examples are the sensitivity of the immuno response,[1] advances in the field have been slow and real applications that where antibodies are generated in response to minute can be commercially exploited are still lacking. However, in amounts of a foreign antigen, or the energy saved by enzymes view of some recent promising developments this may be due to their ability to stabilize the transition state of the about to change. Combinatorial techniques for rapid, parallel reaction to be catalyzed.[2] With biological examples as synthesis and testing of large groups of materials promise, for models, chemists hope to be able to mimic these properties instance, to accelerate the development of new recognition for various applications.[3±5] For instance stable recognition elements significantly.[9, 10] Furthermore clever design of link- elements capable of strongly and selectively binding mole- ers to position the binding-site functional groups at distances cules could be used in robust, sensitive analytical methods for allowing subsequent rebinding by electrostatic interactions the analysis of trace levels of compounds in complex matrices. has resulted in materials that exhibit excellent recognition Alternatively such recognition elements could be used to properties for highly interesting targets such as peptides[11] separate undesirable compounds from foods or biological and steroids.[12] Also larger molecules such as proteins can fluids, for targeted delivery of drugs, or for demanding now be recognized by surface imprinting techniques.[13] Thus, separations at a preparative level in the fine-chemical template imprinting is not restricted to low molecular weight industry. targets. Recent contributions have shown that even imprinting Robust molecular recognition elements with antibody-like of whole cells[14] and inorganic crystals[15] generates structures ability to bind and discriminate between molecules or other capable of efficient recognition of the corresponding template structures can today be synthesized using molecular imprint- structure. Finally, imprinting of metal ions for sequestration or ing techniques.[6, 7] This includes the synthesis of cross-linked sensing[7] and molecularly imprinted enzyme mimics[4] are polymers in the presence of templates which may be small burgeoning areas, but outside the scope of this contribution. molecules, biological macromolecules, microorganisms, or This highlight will summarize some of the most promising whole crystals (Scheme 1). Functional monomers that can recent developments for the generation of templated binding be linked covalently or noncovalently to the template bind the sites and then provide connections to potential applications. Noncovalent Imprinting for the Recognition of Small Molecules The most successful noncovalent imprinting systems are based on commodity acrylic or methacrylic monomers, cross- linked with ethyleneglycol dimethacrylate (EDMA). Meth- acrylic acid (MAA) is, to date, the most widely used functional monomer, as can be seen from the numerous examples in the literature.[7, 16] The most common procedure applied to imprinting with l-phenylalanine anilide (l-PA) is outlined in Scheme 2.[17, 18] The broad applicability of MAA as a functional monomer is related to the fact that the carboxylic acid group serves well as Scheme 1. Imprinting of network polymers with various templates. The a hydrogen-bond and proton donor and as a hydrogen-bond template can be a small molecule, protein, cell, or crystal. acceptor.[19] In aprotic solvents such as acetonitrile, carboxylic [*] Dr. B. Sellergren acids and amine bases form contact hydrogen-bonded assem- Institut für Anorganische Chemie und Analytische Chemie Johannes blies, where the association strength for a given acid increases Gutenberg Universität Mainz with the basicity of the base.[20] Thus templates containing Duesbergweg 10 ± 14, 55099 Mainz (Germany) Brùnsted basic or hydrogen-bonding functional groups are Fax : ( 49) 6131-392-2710 E-mail: [email protected] potentially suitable templates for the MAA/EDMA sys- [10, 17, 18] [**] The author is grateful to Dr. Andrew Hall and Dr. Gunter Büchel for tem. Furthermore, hydrogen bonds can form with linguistic advice. templates containing acid,[21] amide,[22] or functionalized Angew. Chem. Int. Ed. 2000, 39, No. 6 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 0570-0833/00/3906-1031 $ 17.50+.50/0 1031 HIGHLIGHTS Table 1. Approaches for imprinting small molecules.[a] Synthesis Rebinding Attachments Ref. covalent covalent [40] [41] covalent noncovalent [12] [31] covalent ± noncovalent noncovalent [42] [11] metal ion mediated metal ion mediated [43] noncovalent noncovalent [23] [a] T template, M polarizable group. Scheme 2. Imprinting protocol for the recognition of l-phenylalanine anilide (l-PA). AIBN azobisisobutyronitrile, EDMA ethyleneglycol dimethacrylate, MAA methacrylic acid. 1032 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 0570-0833/00/3906-1032 $ 17.50+.50/0 Angew. Chem. Int. Ed. 2000, 39, No. 6 HIGHLIGHTS nitrogen heterocycles,[23, 24] the latter two being particularly stable. However, other criteria are that the template is soluble in the most common solvents or monomers used in the imprinting step, that it is available in preparative amounts, and that it is stable under the conditions of the polymerization and does not undergo reactions with free radicals. Provided that these criteria are fulfilled the resulting molecularly imprinted polymers (MIPs) usually exhibit a significant and selective rebinding of the template when compared to non- imprinted control polymers. The potential for a given monomer template pair to produce templated sites can be predicted by measuring the stability constants, for example by spectroscopic techniques, in a homogeneous solution mimicking the monomer mixture prior to polymerization.[17, 25] This can ultimately be used as a preliminary screening procedure to search for suitable functional monomers. With 9-ethyladenine (8, see Table 1) as template a comparison can be made between the solution stability of the complex and the binding constant and site density obtained in experiments for batch rebinding to the imprinted material. 9-Ethyladenine associates with butyric acid in chloroform at three sites with estimated association constants of 114, 41, and 5m1 respectively.[26] Assuming similar association constants between MAA and this template prior to polymerization the major part of the template would be present in the complexed form. The corresponding imprinted polymer prepared in chloroform exhibited an adsorption isotherm that could be fitted to a bi-Langmuir adsorption model, resulting in a class of high-energy binding sites with a binding constant (K ) in chloroform of 76000m1, a efficient recognition also in aqueous media. Furthermore, similar to the binding energies observed for designed syn- since the functional monomer is quantitatively associated with thetic receptors of the same molecule.[23] Also of interest is the the template prior to polymerization, the nonspecific binding fact that more than 30% of the added template resulted in is minimized. Functional-group complementarity is thus one high-affinity binding sites (site density n 20 mmolg1). basis for the choice of functional monomer. In the case of Usually, however, the yield is considerably lower, often in templates with low polarity and with few functional groups the range of only a few percent. Subtracting the binding to a that can interact with functional monomers, it may be reference polymer imprinted with benzylamine from the beneficial to use amphiphilic monomers stabilizing the binding to a polymer imprinted with 9-ethyladenine gave a monomer template assemblies by hydrophobic and van der mono-Langmuir isotherm (K 79000m1), thus indicating that a Waals forces. Thus cyclodextrins have been used to template the sites probed in this experiment are isolated and relatively binding sites for cholesterol (10, b-CD b-cyclodextrin)[28] or uniform. The remaining sites interact nonselectively with to enhance the selectivity in the imprinting of amino acids.[29] solutes binding to carboxylic acids and limit the degree of Monomers based on bile acids or cholesterol (11a) have also separation that can be achieved. been used to generate binding sites for cholesterol (11b).[30] In In spite of the pronounced recognition observed for a a comparison of a number of common adsorbents, the number of important targets with the use of MAA as adsorbents imprinted with cholesterol exhibited the largest functional monomer, recognition of any given target molecule

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