& Organocatalysis Triggering Activity of Catalytic Rod-Like Supramolecular Polymers Elisa Huerta, Bas van Genabeek , Brigitte A. G. Lamers, Marcel M. E. Koenigs, E. W. Meijer,* and Anja R. A. Palmans* [a] Abstract: Supramolecular polymers based on benzene-1,3,5- tricarboxamides (BTAs) functionalized with an l- or d-proline moiety display high catalytic activity towards aldol reactions in water. High turnover frequencies (TOF) of up to 27 10 4 s 1 and excellent stereoselectivities (up to 96 % de, up to 99% ee) were observed. In addition, the catalyst could be reused and remained active at catalyst loadings and sub- strate concentrations as low as 0.1 mol % and 50 mm, re- spectively. A temperature-induced conformational change in the supramolecular polymer triggers the high activity of the catalyst. The supramolecular polymer’s helical sense in com- bination with the configuration of the proline (l- or d-) is re- sponsible for the observed selectivity. Introduction The ability of Nature to create very specific structures—from protein folding to DNA double helices—is recognized as the key feature to obtain the high activity and selectivity that is needed to sustain life. In all cases, secondary interactions play crucial roles for folding proteins into active superstructures. Failure of an enzyme to fold correctly results in the loss of its activity. Based on these observations, an entire new field of chemistry that is inspired by the functioning of Nature has emerged. [1–3] In the field of organocatalysis, C C bond forming reactions in water have attracted considerable attention. [4–6] For example, proline-catalyzed aldol reactions can take place efficiently in water. [7–9] Interestingly, high activities and selectivi- ties are attained when the organocatalyst shows amphiphilic character and, consequently, the catalytic unit is sufficiently shielded from the aqueous medium during catalysis. [10–18] In these examples, hydrophobic effects are the dominant driving force for aggregate formation of the active organocatalytic species. Although directional supramolecular interactions, such as hydrogen bonding, have been investigated to control the catalytic properties of a variety of aggregates in both organic media [19–22] and in hydrolysis reactions in water, [23] the effect of directionality on the outcome of a chemical reaction is not triv- ial to predict. [24] In contrast, for organocatalysis in water, the impact of directional interactions in catalytically active aggre- gates has not yet been systematically explored, despite the fact that several reported hydrophobic l-Pro-based catalysts are, in principle, also capable of forming directional hydrogen bonds. [25–27] Benzene-1,3,5-tricarboxamides (BTAs) are well known mole- cules that self-assemble into helical, rod-like supramolecular polymers through the formation of a triple array of hydrogen bonds. [28, 29] When a stereogenic centre is introduced the helici- ty is biased and a Cotton effect is observed. [30] The remarkably strong amplification of chirality that is observed in these dy- namic supramolecular polymers has been used to study the ki- netics of racemizing supramolecular systems, [31] and to induce asymmetry in Rh-catalyzed hydrogenations in hexane. [22] BTAs can also be modified to self-assemble in water, in which hydro- phobic effects represent an additional driving force to promote self-assembly. [32] Amphiphilic BTAs behave as low molecular weight hydrogelators, [33] and when they are attached to a water soluble polymer they fold the polymer into well-de- fined single-chain polymeric nanoparticles. [34] The presence of hydrophobic compartments makes these polymers excellent candidates to mimic enzymes. [34–36] Herein, we report the catalytic activity and selectivity of l- and d-proline (Pro) that is covalently linked to a hydrophobic BTA for aldol reactions in water (Scheme 1). Directional hydro- gen bonding interactions are operative in this system, which make it possible to control the helicity and stability of the supramolecular polymers in water. We serendipitously found that the BTA-based l-Pro catalyst system 1a becomes highly active and stereoselective after a temperature treatment that triggers a conformational change in the supramolecular poly- mers. To study the relationship between the supramolecular polymer structure and the observed catalytic activity, we pre- pared a series of organocatalysts (compounds 1 and 2, Scheme 1) in which we varied the helical preference, the con- figuration of the proline, and the presence of directional hy- drogen-bonding interactions. We applied a combination of [a] Dr. E. Huerta , + M. Sc. B. van Genabeek , + B. A. G. Lamers, Dr. M. M. E. Koenigs, Prof. Dr. E. W. Meijer, Dr. Ir. A. R. A. Palmans Institute for Complex Molecular Systems Eindhoven University of Technology P.O. Box 513, 5600 MB Eindhoven (The Netherlands) E-mail: E.W.Meijer@tue.nl A.Palmans@tue.nl [ + ] These authors contributed equally to this work. Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/chem.201405410. Chem. Eur. J. 2015, 21, 1 – 10  2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 && These are not the final page numbers! ÞÞ Full Paper DOI: 10.1002/chem.201405410