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Supramolecular of hydrogen-bonded rosette assemblies Mercedes Crego-Calama

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Mercedes Crego-Calama. Supramolecular chirality of hydrogen-bonded rosette assemblies. , Taylor & Francis: STM, Behavioural Science and Public Health Titles, 2007, 19 (01-02), pp.95-106. ￿10.1080/10610270600981716￿. ￿hal-00513491￿

HAL Id: hal-00513491 https://hal.archives-ouvertes.fr/hal-00513491 Submitted on 1 Sep 2010

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Supramolecular chirality of hydrogen-bonded rosette assemblies

Journal: Supramolecular Chemistry

Manuscript ID: GSCH-2006-0028

Manuscript Type: Review

Date Submitted by the 31-May-2006 Author:

Complete List of Authors: crego-calama, mercedes; University of Twente, SMCT

Supramolecular chirality, noncovalent synthesis, amplification of Keywords: chirality, diastereomeric synthesis, enantiomeric synthesis

Note: The following files were submitted by the author for peer review, but cannot be converted to PDF. You must view these files (e.g. movies) online. tif.sit

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1 2 3 4 5 Supramolecular chirality of hydrogen-bonded 6 7 rosette assemblies 8 9 10 Socorro Vázquez-Campos, Mercedes Crego-Calama*, and David N. Reinhoudt* 11 12 13 14 Laboratory of Supramolecular Chemistry and Technology, MESA+ Institute for 15 Nanotechnology and Faculty of Science and Technology, University of Twente, P.O. 16 ForB oPeerx 217, 7500 AReviewE Enschede, The Ne tOnlyherlands 17 18 19 20 Abstract 21 22 The control of chirality in synthetic self-assembled systems remains challenging 23 because of their lower stability and their higher susceptibility to racemization when 24 25 compared to covalent systems. In this review, we describe the supramolecular chirality 26 of noncovalent hydrogen-bonded assemblies formed by multiple cooperative hydrogen- 27 bonds between calix[4]arene dimelamines and cyanurates or barbiturates derivatives 28 (rosette assemblies). It is shown that the amplification of chirality (a high enantiomeric 29 or diastereomeric excess induced by a small initial amount of chiral bias) of double and 30 31 tetrarosette assemblies is influenced by bulky substitution on their components and 32 electronic properties of the substituents as well as their proximity to the rosette core. In 33 absence of chiral centers in their components, the assemblies form as a 34 of both (P and M). The synthesis of enantiomerically pure rosette 35 assemblies is conducted via induction of chirality using chiral barbiturates, followed by 36 substitution of the chiral components for achiral cyanurates (“chiral memory” concept). 37 38 The addition of an external auxiliary to a racemic mixture of P and M assemblies 39 leading to the formation of one of the two possible diastereomeric assemblies is also 40 described. Moreover, of self-assembled nanostructures on highly 41 oriented pyrolytic graphite (HOPG) surfaces is also discussed. 42 43 44 Graphical Abstract 45 46 A brief description of the supramolecular chirality of noncovalent hydrogen-bonded 47 rosette assemblies is presented. This overview includes diastereomeric and enantiomeric 48 noncovalent synthesis of rosette assemblies, chiral amplification and a brief discussion 49 on the chiral resolution of these aggregates on surfaces. 50 51 52 Keywords 53 54 Supramolecular chirality, noncovalent synthesis, amplification of chirality, 55 diastereomeric synthesis, enantiomeric synthesis, hydrogen-bonds 56 57 58 59 60

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1 2 3 4 5 1. Introduction 6 7 The three dimensional arrangement of atoms in defines the molecular 8 . In the case of supramolecular structures, the supramolecular 9 stereochemistry1 comes from the spatial arrangement of their molecular components 10 which are held together by weak interactions. Supramolecular chirality plays an 11 2 12 important role in life; nearly all biological polymers are optically pure meaning that all 13 their components have the same . All amino-acids in proteins are “left 14 handed” while all sugars in DNA, RNA and in the metabolic pathway are “right 15 handed”. Therefore, the control of supramolecular chirality has become an important 16 issue to undForerstand b ioPeerlogical proce ssReviewes such as protein foOnlylding or the expression and 17 18 transfer of genetic information. Supramolecular chirality results from both the 19 properties of the components and the way in which they associate. Therefore, the 20 chirality of the system at the supramolecular level can be formed by the association of 21 chiral components3, 4 as well as by a dissymmetric interaction of achiral components.5-17 22 Self-assembly of supramolecular structures occurs via non-covalent interactions such as 23 hydrogen bonding, coordination, aggregation, and electrostatic interactions. Especially 24 18, 19 25 hydrogen bonding interactions contribute in the selectivity of processes such as 26 molecular recognition, self-assembly, biomimicking as well as supramolecular 27 chirality.20-24 28 Clear examples of stereochemical selectivity in noncovalent synthesis can be observed 29 in the rosette assemblies. These are obtained by the combination of building blocks with 30 complementary hydrogen bonding motifs (three melamines and three isocyanuric acid 31 25-27 32 (CYA) or barbituric acid (BAR)) (Figure 1). This rosette motif forms large and 33 well-defined hydrogen-bonded structures. The formation of double rosette assemblies is 34 induced by mixing calix[4]arene derivatives, diametrically substituted with two 35 melamine units at the upper rim, with two equivalents of BAR or CYA (Figure 1).28 36 Extended tetra-, hexa- and octarosettes are obtained when calix[4]arene dimelamine 37 29-31 38 units are covalently linked. The rapid increase of number of hydrogen bonds 39 (double rosette = 36, tetrarosette = 72, hexarosette = 108 and octarosette = 142) in these 40 extended assemblies renders a high thermodynamic stability (Figure 1). 41 In this review, the control of the chirality of hydrogen-bonded assemblies based on 42 rosette motif at three different levels is described. Amplification of chirality (“Sergeant 43 44 and soldiers” principle), which takes place when the achiral building blocks of the 45 assemblies follow the helicity induced by the chiral components even when the chiral 46 molecules are present in very small amounts. Enantioselective noncovalent synthesis 47 (memory of supramolecular chirality) is also described where the use of a chiral 48 building block interacts stereoselectively to give preferentially one of the two possible 49 diastereomeric forms (P or M-). After the replacement of the chiral building block 50 51 by an achiral analog the induced chirality is preserved leading to the synthesis of 52 enantiomerically enriched double rosette assemblies. Furthermore, diastereomeric and 53 enantiomeric noncovalent synthesis of double rosettes can be achieved by the 54 introduction of a chiral guest; therefore inducing the formation of one specific helicity 55 of the rosette assemblies. The studies on enantioselectivity and amplification of chirality 56 57 in extended systems, tetrarosette assemblies, are also presented. Moreover, the induction 58 of chirality observed for these hydrogen-bonded rosette assemblies on highly oriented 59 pyrolytic graphite (HOPG) surfaces is also reviewed? 60

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1 2 3 4 5 2. Rosette assemblies: Formation and characterization 6 7 Double rosette assemblies 13•(DEB)/13•(CYA)6 are held together by a total of 36 8 hydrogen bonds. The assemblies are formed spontaneously by mixing calix[4]arene 9 dimelamines 1 with 2 equivalents of either barbituric acid (BAR) or cyanuric acid 10 (CYA) derivatives in apolar solvents such as chloroform, benzene or toluene (Figure 11 28, 32 12 1). Three conformational of double rosette assemblies can be formed D3-, 33, 34 13 C3h- and Cs-isomers (Figure 2). The assemblies with D3-symmetry, which is the 14 predominant , are chiral due to the staggered (antiparallel) of the two 15 melamine on each calix[4]arene unit, leading to a twist of the two different rosette 16 planes, whiForch can e ithPeerer adopt a cReviewlockwise ((P)-isome r)Only or counterclockwise ((M)- 17 18 isomer) conformation. In both C3h- and Cs-isomers, the two melamines on each 19 calix[4]arene unit adopt an eclipse (parallel) conformation and are therefore achiral. The 20 difference between the C3h- and Cs-isomers is the 180° of one of the 21 calix[4]arene dimelamines. 22 Double rosette assemblies can conveniently be characterized by 1H-NMR spectroscopy 23 in solution.32 Upon formation of the assembly the diagnostic signals for the BAR/CYA 24 25 hydrogen-bonded imide NH protons are present in the region between 13 and 16 ppm. 26 The number of signals that is observed indicates the symmetry type of rosette and the 27 symmetry of the assembly. For example, for the D3 and the C3h symmetry isomers of the 28 double rosette only two different hydrogen-bonded imide NH protons can be 29 distinguished and therefore showing two different signals in the 1H NMR spectrum. 30 However, for the Cs isomer six signals are observed due to the magnetic differences 31 35 32 between the six-hydrogen-bonded imide NH protons. For assemblies formed with 33 33 some bulky CYA derivatives all possible isomers were formed, while with BAR 34 derivatives preferentially the D3 isomers were obtained. 35 Hydrogen-bonded tetrarosette assemblies are extended rosettes formed by the 36 association of 3 calix[4]arene tetramelamines (two calix[4]arene dimelamines 37 38 covalently connected through two urea moieties) and 12 barbituric acid or cyanuric acid 39 derivatives (Scheme 1). The building blocks are held together via 72 cooperative 40 hydrogen bonds leading to the formation of a fully assembled tetrarosette structure 41 23.(DEB)12. 42 Rosette assemblies in general are formed as a racemic mixture of both (M)- and (P)- 43 9, 28, 32, 36 44 enantiomers when the components do not contain chiral centers. However, 45 complete induction of supramolecular chirality can be obtained for rosette assemblies 46 when one of the building blocks is chiral. The (M)- is formed when R,R 47 dimelamines assemble with BAR or CYA, while the assembly of S,S dimelamines with 48 BAR or CYA gives only the (P)-diastereomer ( 49 50 51 Scheme 2). This property makes it possible to study the rosette formation using circular 37 52 (CD) spectroscopy. It has been observed that, for example, double rosette -1 -1 53 assemblies exhibit a very strong induced CD signal (½Demax½ ~ 100 l·mol ·cm ), while 54 the individual chiral components are hardly CD active (½De ½ < 8.1 l·mol-1·cm-1). 55 max 56 Therefore, the observation of CD signal is a direct result of the assembly formation. The 57 CD curves of the (M)- and (P)-assemblies are perfect mirror images, reflecting their 58 enantiomeric relationship (Scheme 2). 59 Another characterization technique is the MALDI-TOF mass spectrometry using the 60 Ag+ labeling approach.34 This technique is extremely mild and provides a

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1 2 3 4 5 nondestructive method to generate positively charged assemblies by coordination of + 6 Ag to two cooperative p-donors, cyano or other functionalities. Finally, X-ray 7 crystallography provides unequivocal evidence that the assembly 13•(DEB)6 exists as 8 the D3-isomer (Figure 3). Furthermore, it shows that the calix[4]arene units are fixed in 9 a pinched cone conformation, which is the only conformation that allows simultaneous 10 11 participation of the calix[4]arene units in both the upper and the lower rosette motif. 12 The two rosette motifs are stacked on top of each other with an interatomic separation 32 13 of 3.5 Å at the edges to 3.2 Å in the centre of the rosette. The assembly dimensions are 14 1.2 nm height and ~3 nm width. 15 16 3. The conFortrol of tPeerhe supram olReviewecular chirality i n Onlyhydrogen-bonded rosette 17 18 assemblies 19 20 Supramolecular assemblies exhibit well-defined topologies, determined by the 21 arrangement and connectivity of their molecular components. Therefore, 22 supramolecular chirality involves the nonsymmetrical arrangement of molecular 23 24 components in noncovalent assemblies. The general method for controlling 25 supramolecular chirality is the introduction of chiral substituents into the components, 26 resulting in a mixture of two . On the other hand, the achiral components 27 can be assembled in such a way that the assembly has no elements of symmetry. 28 Therefore, supramolecular structures can be prepared in a diastereomeric or 29 enantiomeric form via noncovalent synthesis. 30 31 32 3.1 Diastereoselective noncovalent synthesis 33 34 The general method to control the supramolecular chirality is via the introduction of 35 chiral centers in the components of the assembly. The noncovalent diastereomeric 36 37 synthesis of double rosette assemblies was achieved in two different ways. First, by the 38 introduction of chiral centers in one of their components (calix[4]arene dimelamine or 39 barbituric/cyanuric acid derivatives) (Scheme 3). As a consequence six chiral centers 40 are obtained in close proximity to the core of the assembly.9 The presence of chiral 41 centers in the dimelamines of the calix[4]arene or in the cyanurate derivatives induces 42 quantitatively the formation of one handedness (P or M) of the hydrogen-bonded double 43 44 rosette assemblies. Chiral barbiturates were also studied obtaining a smaller inducing 45 effect in contrast to chiral dimelamines or cyanurates. From these studies it has been 46 concluded that the chiral induction is related to the distance between the chiral centers 47 and the core of the assembly. All diasteromerically pure assemblies presented very high 48 CD activities compare to the correspondent free components. This method gives 49 assemblies with a diastereomeric excess (d.e.) of 96 %. Important information about the 50 1 38 51 symmetry of the assembly is also obtained by H-NMR spectroscopy. 52 The second method to achieve the diastereoselective synthesis of the assemblies is via 53 complexation of chiral acids or diacids with a racemic mixture of amino-substituted 54 double rosette assemblies.39, 40 Amino functionalities positioned on a noncovalent 55 rosette platform stereospecifically recognize carboxylic acids with detailed structural 56 57 selectivities, both with respect to the substrate and the platform. The recognition takes 13, 41-43 58 place first by acid-base interactions. The double rosette hydrogen-bonded 59 assembly is used as a platform to organize the six amino functionalities at the periphery 60 acting as binding sites for guest complexation (Scheme 4). The interaction between host

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1 2 3 4 1 5 and guest becomes clear from the shifts of the signals in the H-NMR spectrum. The 6 chiral acids present a clear selectivity in binding towards one of the enantiomers (M or 7 P) of the double rosette assembly forming the corresponding diastereomeric complexes. 8 Therefore, the that is bound most strongly is amplified in the mixture 9 causing the CD spectrum of the assembly to show Cotton effects in the presence of 10 these chiral acids.40 With this methodology we obtained assemblies which have a d.e. of 11 12 ~90 %. 13 Moreover, supramolecular chirality can be observed with tetrarosette assemblies upon 14 saccharide complexation.44 Recognition of n-octyl b-D-glucopyranoside (b-D-Sugar, 15 Scheme 5) by the tetrarosette (P)-23.(DEB)12 is reflected by the shifts and splitting of 16 the proton sForignals on Peerthe second anReviewd third rosette floo rsOnly in the 1H-NMR spectrum, 17 18 whereas the corresponding signals of the first and fourth floor show no splitting. 19 Addition of the chiral saccharide leads to an increase in the intensities of the proton 20 signals indicating that only one of the two enantiomers of the racemic mixture 21 recognizes the chiral guest. The stereoselective recognition process results in the 22 formation of one diastereomeric system. Moreover, CD data gives also evidence that 23 24 there is a preferential formation of the enantiomer that binds more strongly to the chiral 25 saccharide guest, being CD active while the racemic mixture was CD silent. In 26 conclusion, the chirality of the guest determines the supramolecular chirality 27 of the tetrarosette assembly. 28 29 3.2 Enantioselective noncovalent synthesis 30 31 32 The synthesis of enantiopure self-assembled aggregates based on the “chiral memory” 33 concept implies the use of a , used as additive, which interact 34 stereoselectively and in a noncovalent manner with the achiral self-assembled rosette to 35 give preferentially one of the two possible diastereomeric forms of the assembly. When 36 this additive is replaced by an achiral additive, the resulting enantiomer is still optically 37 13, 41, 45, 46 38 active although none of its components are chiral. This strategy has been used 39 to synthesize enantiomerically pure self-assembled double rosette assemblies (Scheme 40 6).36 First, induction of supramolecular chirality was achieved with chiral barbiturates, 41 which are subsequently replaced by achiral cyanurates in a qualitative manner (Scheme 42 6a). The success of this approach relies primarily on the association between cyanurates 43 44 and melamines being much stronger than that between barbiturates and melamines, due 26, 38 45 to the higher acidity of the cyanurates. Therefore in these systems, the 46 enantiomerically pure assemblies are obtained from the corresponding diastereomers 47 and not by resolution of the enantiomeric racemic mixture. Following this method an 48 (e.e.) of 96 % was obtained.36 On the other hand, the complexation 49 50 of chiral diacids to amino substituted double rosettes and subsequent removal of the 51 acids leads to the generation of the enantiopure assembly. The removal of the diacids is 52 carried out via precipitation of the salt upon addition of amine, obtaining an 53 enantiomeric assembly with an e.e. of 90 % (Scheme 6b).39 54 55 3.3 Amplification of chirality: The “sergeant and soldiers” principle 56 57 58 Amplification of chirality is defined as the process in which a high enantiomeric or 59 diastereomeric excess is generated by the presence of small amounts of chiral 60 molecules.47 The sergeant and soldiers principle has been applied to dynamic hydrogen-

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1 2 3 4 bonded assemblies of well-defined molecular composition (double rosette assemblies) 5 48 6 (Figure 4). For example, chiral assemblies ((P)-1b3.((R)-MePheCYA)6) and racemic 7 assemblies (1b3.(BenCYA)6) were mixed in ratios ranging from 1:9 to 9:1 measuring 8 the CD intensity at 308 nm as a function of time at 70 °C (Figure 4). In all the studied 9 cases (Figure 4) the thermodynamic equilibrium is reached almost immediately after 10 mixing the assemblies. The CD-intensity of the mixtures will follow a linear behavior 11 12 when there is no amplification of the chirality in the system during the process of 13 increasing the ratio of the chiral assembly present. However, in these studies the typical 14 non-linear behavior of the “sergeants and soldiers” principle was observed (Figure 4). 15 The CD-intensities of the mixtures increase nonlinearly with the percentage of chiral 16 assembly prForovided. T hPeere 1H-NMR s pReviewectrum shows (figu reOnly not shown) the presence of 17 18 several signals in the region of 15-14 ppm due to the generation of heteromeric 19 assemblies (1b3.(BenCYA)n((R)-MePheCYA)6-n) (n = 1-5). These assemblies lead to the 20 formation of the (P)-diastereomer preferentially. 21 Moreover, a large variety of systems including chiral and racemic structurally related 22 assemblies have been studied in order to determine which parameters influences the 23 amplification of chirality for these types of hydrogen-bonded assemblies (Figure 4). The 24 25 introduction of different substituents in the calix[4]arene dimelamines or cyanurate 49 26 components of the double rosette assemblies was considered. The introduction of 27 bulky groups in the calix[4]arene dimelamine building blocks (R1, in Figure 4) 28 decreases the amplification of chirality. In addition, the amplification of chirality is 29 highly influenced by the presence of substituents directly attached to the calix[4]arene 30 31 skeleton (R2, Figure 4) obtaining different values depending on the substituents. For 32 example, the influence in the introduction of nitro groups in the calix[4]arene skeleton 33 (1b, Figure 4) leads to systems with a higher degree of chiral amplification. However, 34 the introduction of bromide substituents (1c, Figure 4) induces a decrease in 35 amplification of chirality. These differences can be due to steric or electronic factors 36 introduced by the substituents. On the other hand, the presence of bulky substituents in 37 38 the cyanurate components leads to an increase in the amplification of chirality. 50 39 The amplification of chirality can also be observed for tetrarosette assemblies. The 40 difference in free energy between the two enantiomers (P and M) of the tetrarosettes 41 introduced by a chiral center is higher than for double rosettes because it requires the 42 disruption of 24 hydrogen bonds for the dissociation of one tetramelamine building 43 44 block. Chiral amplification studies of these assemblies at different molar ratios of chiral 45 component showed the typical nonlinear behavior resulting from the “sergeants and 46 soldiers” principle. It has been observed that the control of amplification of chirality in 47 the rosette systems increases with the number of layers in the assemblies. The high 48 chiral amplification obtained can be compared with the chiral amplification obtained for 49 covalent polymeric structures. Moreover, the flexible spacer between the two layers in 50 51 the tetrarosette assembly has been substituted for a more rigid phenyl ring resulting in a 52 decreasing in the amplification of chirality, probably due to the introduction of 53 geometric constrains. 54 55 3.4 Chirality of rosette assemblies in 2-D 56 57 58 Highly ordered 2-D arrays of rosette nanostructures can be obtained by deposition of the 59 assemblies from an organic solvent, such as chloroform or toluene, on a freshly cleaved 60 highly oriented pyrolytic graphite (HOPG) surfaces as revealed by AFM studies.51-53

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1 2 3 4 5 Deposition of double rosette assemblies showed tightly packed rows with an interrow 6 distance of 3.8±0.2 nm attributed to the face-to-face stacking of the assemblies based on 7 cross-sectional analysis of assemblies with different substituents in the calix[4]arene 8 unit.55 In the case of tetrarosette assemblies the interrow spacing obtained of 4.6±0.1 nm 9 is comparable with the double rosettes. These data suggest that the arrangement of the 10 assemblies on the surface is the same as for double rosettes: face-to-face arrangement. 11 12 The orientations of the rods are related to the underlying substrate, therefore with 13 orientation differences of 60°. However, closer observations and analysis of the 14 domains showed the presence of deviating subdomains (Figure 5). The orientation of 15 the nanorod domains appears to be ±23° with respect to the orientation of the underlying 16 HOPG. TheForse observ aPeertions are mo rReviewe evident in the ca seOnly of tetrarosettes due to the 17 51 18 formation of higher-order hierarchical structures in 2-D. These orientations were 19 revealed by elucidating the nanometer-scale arrangement of the rosettes by high 20 resolution TM-AFM. As it has been shown in solution the rosette assemblies in absence 21 of elements of chirality they form racemic mixtures of P and M enantiomers. However, 22 after deposition on HOPG surfaces those structures are clearly chiral showing two types 23 of domains with different orientations respect to the nanorod direction. Therefore, 24 25 spontaneous resolution of the P and M rosettes into enantiopure domains took place on 54 26 HOPG surfaces after deposition of a racemic mixture. 27 28 4. Conclusions 29 30 31 Here, we have shown the control over many aspects of the supramolecular chirality of 32 hydrogen-bonded rosette assemblies resulting in the stereoselective synthesis of 33 diastereomeric and enantiomeric assemblies. Especially, the control over the processes 34 of chiral memory and chiral amplification could have promising applications in the 35 material science field. Furthermore, we have shown that racemic mixture of self- 36 assembled systems has been spontaneously resolved into enantiopure domains in 2D 37 38 supramolecular assemblies on HOPG. It is evident that control over supramolecular 39 chirality of synthetic increasingly complex assemblies will be of crucial importance to 40 their application in the field of molecular recognition, catalysis, material sciences, and 41 especially nanotechnology. Nevertheless, issues such as the understanding of the 42 relation between rosette structure and substitution pattern on one hand and the 43 44 orientation of the superstructures on surfaces in 2D on the other hand are challenges that 45 need to be addressed in the future. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 References 6 7 1. Lehn, J.-M., Supramolecular Chemistry, Concepts and Perspectives. VCH: New 8 York, 1995. 9 10 2. Clines, D., The Physical Origin of in Life. AIP Press: Woodbury, 11 NY, 1996. 12 3. Engelkamp, H.; Middelbeek, S.; Nolte, R. J. M., Self-assembly of disk-shaped 13 molecules to coiled-coil aggregates with tunable helicity. Science 1999, 284, (5415), 14 785-788. 15 16 4. NuckForolls, C.; PeerKatz, T. J.; VReviewerbiest, T.; Van EOnlylshocht, S.; Kuball, H. G.; 17 Kiesewalter, S.; Lovinger, A. J.; Persoons, A., and UV-visible 18 absorption spectra of the Langmuir-Blodgett films of an aggregating . J. Am. 19 Chem. Soc. 1998, 120, (34), 8656-8660. 20 5. DeRossi, U.; Dahne, S.; Meskers, S. C. J.; Dekkers, H., Spontaneous formation 21 of chirality in J-aggregates showing davydov splitting. Angew. Chem. Int. Ed. 1996, 35, 22 23 (7), 760-763. 24 6. Ezuhara, T.; Endo, K.; Aoyama, Y., Helical coordination polymers from achiral 25 components in crystals. Homochiral , homochiral helix winding in the 26 solid state, and chirality control by seeding. J. Am. Chem. Soc. 1999, 121, (14), 3279- 27 3283. 28 29 7. Huang, X.; Li, C.; Jiang, S. G.; Wang, X. S.; Zhang, B. W.; Liu, M. H., Self- 30 assembled spiral nanoarchitecture and supramolecular chirality in Langmuir-Blodgett 31 films of an achiral amphiphilic barbituric acid. J. Am. Chem. Soc. 2004, 126, (5), 1322- 32 1323. 33 8. Huang, X.; Liu, M. H., Chirality of photopolymerized organized supramolecular 34 35 polydiacetylene films. Chem. Commun. 2003, (1), 66-67. 36 9. Prins, L. J.; Huskens, J.; de Jong, F.; Timmerman, P.; Reinhoudt, D. N., 37 Complete of supramolecular chirality in a hydrogen-bonded 38 assembly. Nature 1999, 398, (6727), 498-502. 39 10. Ribo, J. M.; Crusats, J.; Sagues, F.; Claret, J.; Rubires, R., Chiral sign induction 40 by vortices during the formation of mesophases in stirred solutions. Science 2001, 292, 41 42 (5524), 2063-2066. 43 11. Viswanathan, R.; Zasadzinski, J. A.; Schwartz, D. K., Spontaneous Chiral- 44 Symmetry Breaking by Achiral Molecules in a Langmuir-Blodgett-Film. Nature 1994, 45 368, (6470), 440-443. 46 12. Yang, W. S.; Chai, X. D.; Chi, L. F.; Liu, X. D.; Cao, Y. W.; Lu, R.; Jiang, Y. 47 48 S.; Tang, X. Y.; Fuchs, H.; Li, T. J., From achiral molecular components to chiral 49 supermolecules and supercoil self-assembly. Chem. Eur. J. 1999, 5, (4), 1144-1149. 50 13. Yashima, E.; Maeda, K.; Okamoto, Y., Memory of macromolecular helicity 51 assisted by interaction with achiral small molecules. Nature 1999, 399, (6735), 449-451. 52 14. Yuan, J.; Liu, M. H., Chiral molecular assemblies from a novel achiral 53 amphiphilic 2-(heptadecyl) naphtha[2,3]imidazole through interfacial coordination. J. 54 55 Am. Chem. Soc. 2003, 125, (17), 5051-5056. 56 15. Zhai, X. D.; Zhang, L.; Liu, M. H., Supramolecular assemblies between a new 57 series of gemini-type amphiphiles and TPPS at the air/water interface: Aggregation, 58 chirality, and spacer effect. J. Phys. Chem. B 2004, 108, (22), 7180-7185. 59 60

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1 2 3 4 5 16. Zhang, L.; Lu, Q.; Liu, M. H., Fabrication of chiral Langmuir-Schaefer films 6 from achiral TPPS and amphiphiles through the adsorption at the air/water interface. J. 7 Phys. Chem. B 2003, 107, (11), 2565-2569. 8 17. Zhang, L.; Yuan, J.; Liu, M. H., Supramolecular chirality of achiral TPPS 9 complexed with chiral molecular films. J. Phys. Chem. 2003, 107, (46), 12768-12773. 10 18. Alberts, B.; Bray, D.; Lewis, J.; Raff, M.; Roberts, K.; Watson, J. D., Molecular 11 12 Biology of the Cell. second ed.; Garland: New York, 1989. 13 19. Macdonald, J. C.; Whitesides, G. M., Solid-State Structures of Hydrogen- 14 Bonded Tapes Based on Cyclic Diamides. Chem. Rev. 1994, 94, (8), 2383- 15 2420. 16 20. AjayForaghosh, A .Peer; George, S. JReview., First phenyleneviny Onlylene based organogels: Self- 17 18 assembled nanostructures via cooperative hydrogen bonding and pi-stacking. J. Am. 19 Chem. Soc. 2001, 123, (21), 5148-5149. 20 21. Ariga, K.; Kunitake, T., Molecular recognition at air-water and related 21 interfaces: Complementary hydrogen bonding and multisite interaction. Acc. Chem. Res. 22 1998, 31, (6), 371-378. 23 22. Fernandez-Lopez, S.; Kim, H. S.; Choi, E. C.; Delgado, M.; Granja, J. R.; 24 25 Khasanov, A.; Kraehenbuehl, K.; Long, G.; Weinberger, D. A.; Wilcoxen, K. M.; 26 Ghadiri, M. R., Antibacterial agents based on the cyclic D,L-alpha-peptide architecture. 27 Nature 2001, 412, (6845), 452-455. 28 23. Dapporto, P.; Paoli, P.; Roelens, S., Supramolecular structures by recognition 29 and self-assembly of complementary partners: An unprecedented ionic hydrogen- 30 31 bonded triple-stranded helicate. J. Org. Chem. 2001, 66, (14), 4930-4933. 32 24. Jonkheijm, P.; Hoeben, F. J. M.; Kleppinger, R.; van Herrikhuyzen, J.; 33 Schenning, A.; Meijer, E. W., Transfer of pi-conjugated columnar stacks from solution 34 to surfaces. J. Am. Chem. Soc. 2003, 125, (51), 15941-15949. 35 25. Seto, C. T.; Mathias, J. P.; Whitesides, G. M., Molecular Self-Assembly through 36 Hydrogen-Bonding - Aggregation of 5 Molecules to Form a Discrete Supramolecular 37 38 Structure. J. Am. Chem. Soc. 1993, 115, (4), 1321-1329. 39 26. Bielejewska, A. G.; Marjo, C. E.; Prins, L. J.; Timmerman, P.; de Jong, F.; 40 Reinhoudt, D. N., Thermodynamic stabilities of linear and crinkled tapes and cyclic 41 rosettes in melamine-cyanurate assemblies: A model description. J. Am. Chem. Soc. 42 2001, 123, (31), 7518-7533. 43 44 27. Whitesides, G. M.; Simanek, E. E.; Mathias, J. P.; Seto, C. T.; Chin, D. N.; 45 Mammen, M.; Gordon, D. M., Noncovalent Synthesis - Using Physical-Organic 46 Chemistry to Make Aggregates. Acc. Chem. Res. 1995, 28, (1), 37-44. 47 28. Vreekamp, R. H.; vanDuynhoven, J. P. M.; Hubert, M.; Verboom, W.; 48 Reinhoudt, D. N., Molecular boxes based on calix[4]arene double rosettes. Angew. 49 Chem. Int. Ed. 1996, 35, (11), 1215-1218. 50 51 29. Jolliffe, K. A.; Timmerman, P.; Reinhoudt, D. N., Noncovalent assembly of a 52 fifteen-component hydrogen-bonded nanostructure. Angew. Chem. Int. Ed. 1999, 38, 53 (7), 933-937. 54 30. Paraschiv, V.; Crego-Calama, M.; Fokkens, R. H.; Padberg, C. J.; Timmerman, 55 P.; Reinhoudt, D. N., Nanostructures via noncovalent synthesis: 144 hydrogen bonds 56 57 bring together 27 components. J. Org. Chem. 2001, 66, (25), 8297-8301. 58 31. Prins, L. J.; Neuteboom, E. E.; Paraschiv, V.; Crego-Calama, M.; Timmerman, 59 P.; Reinhoudt, D. N., Kinetic stabilities of double, tetra-, and hexarosette hydrogen- 60 bonded assemblies. J. Org. Chem. 2002, 67, (14), 4808-4820.

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1 2 3 4 5 32. Timmerman, P.; Vreekamp, R. H.; Hulst, R.; Verboom, W.; Reinhoudt, D. N.; 6 Rissanen, K.; Udachin, K. A.; Ripmeester, J., Noncovalent assembly of functional 7 groups on Calix[4]arene molecular boxes. Chem. Eur. J 1997, 3, (11), 1823-1832. 8 33. Prins, L. J.; Jolliffe, K. A.; Hulst, R.; Timmerman, P.; Reinhoudt, D. N., Control 9 of structural isomerism in noncovalent hydrogen-bonded assemblies using peripheral 10 chiral information. J. Am. Chem. Soc. 2000, 122, (15), 3617-3627. 11 12 34. Timmerman, P.; Jolliffe, K. A.; Calama, M. C.; Weidmann, J. L.; Prins, L. J.; 13 Cardullo, F.; Snellink-Ruel, B. H. M.; Fokkens, R. H.; Nibbering, N. M. M.; Shinkai, 14 S.; Reinhoudt, D. N., Ag+ labeling: A convenient new tool for the characterization of 15 hydrogen-bonded supramolecular assemblies by MALDI-TOF mass spectrometry. 16 Chem. Eur. ForJ 2000, 6 , (Peer22), 4104-4115 Review. Only 17 18 35. Timmerman, P.; Prins, L. J., Noncovalent synthesis of melamine- 19 cyanuric/barbituric acid derived nanostructures: Regio- and stereoselection. European J. 20 Org. Chem. 2001, (17), 3191-3205. 21 36. Prins, L. J.; De Jong, F.; Timmerman, P.; Reinhoudt, D. N., An enantiomerically 22 pure hydrogen-bonded assembly. Nature 2000, 408, (6809), 181-184. 23 37. Eliel, E. L.; Wilen, S. H., Stereochemistry of organic compounds. Wiley: New 24 25 York, 1994. 26 38. Prins, L. J.; Hulst, R.; Timmerman, P.; Reinhoudt, D. N., Diastereoselective 27 noncovalent synthesis of hydrogen-bonded double-rosette assemblies. Chem. Eur. J 28 2002, 8, (10), 2288-2301. 29 39. Ishi-i, T.; Crego-Calama, M.; Timmerman, P.; Reinhoudt, D. N.; Shinkai, S., 30 31 Enantioselective formation of a dynamic hydrogen-bonded assembly based on the chiral 32 memory concept. J. Am. Chem. Soc. 2002, 124, (49), 14631-14641. 33 40. Ishi-i, T.; Crego-Calama, M.; Timmerman, P.; Reinhoudt, D. N.; Shinkai, S., 34 Self-assembled receptors for enantioselective recognition of chiral carboxylic acids in a 35 highly cooperative manner. Angew. Chem. Int. Ed. 2002, 41, (11), 1924-1929. 36 41. Furusho, Y.; Kimura, T.; Mizuno, Y.; Aida, T., Chirality-memory molecule: A 37 38 D-2-symmetric fully substituted porphyrin as a conceptually new chirality sensor. J. 39 Am. Chem. Soc. 1997, 119, (22), 5267-5268. 40 42. Ikeda, M.; Takeuchi, M.; Sugasaki, A.; Robertson, A.; Imada, T.; Shinkai, S., 41 Strong positive allosterism which appears in molecular recognition with cerium(IV) 42 double decker porphyrins: Correlation between the number of binding sites and Hill 43 44 coefficients. Supramol. Chem. 2000, 12, (3), 321-+. 45 43. Inai, Y.; Tagawa, K.; Takasu, A.; Hirabayashi, T.; Oshikawa, T.; Yamashita, M., 46 Induction of one-handed helical screw sense in achiral peptide through the domino 47 effect based on interacting its N-terminal amino group with chiral carboxylic acid. J. 48 Am. Chem. Soc. 2000, 122, (47), 11731-11732. 49 44. Ishi-i, T.; Mateos-Timoneda, M. A.; Timmerman, P.; Crego-Calama, M.; 50 51 Reinhoudt, D. N.; Shinkai, S., Self-assembled receptors that stereoselectively recognize 52 a saccharide. Angew. Chem. Int. Ed. 2003, 42, (20), 2300-2305. 53 45. Kubo, Y.; Ohno, T.; Yamanaka, J.; Tokita, S.; Iida, T.; Ishimaru, Y., Chirality- 54 transfer control using a heterotopic zinc(II) porphyrin dimer. J. Am. Chem. Soc. 2001, 55 123, (50), 12700-12701. 56 57 46. Sugasaki, A.; Ikeda, M.; Takeuchi, M.; Robertson, A.; Shinkai, S., Efficient 58 chirality transcription utilizing a cerium(IV) double decker porphyrin: a prototype for 59 development of a molecular memory system. J. Chem. Soc. Perkin Trans. 1 1999, (22), 60 3259-3264.

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1 2 3 4 5 47. Feringa, B. L.; van Delden, R. A., Absolute asymmetric synthesis: The origin, 6 control, and amplification of chirality. Angew. Chem. Int. Ed. 1999, 38, (23), 3419- 7 3438. 8 48. Prins, L. J.; Timmerman, P.; Reinhoudt, D. N., Amplification of chirality: The 9 "sergeants and soldiers" principle applied to dynamic hydrogen-bonded assemblies. J. 10 Am. Chem. Soc 2001, 123, (42), 10153-10163. 11 12 49. Mateos-Timoneda, M. A.; Crego-Calama, M.; Reinhoudt, D. N., Controlling the 13 amplification of chirality in hydrogen-bonded assemblies. Supramol. Chem. 2005, 17, 14 (1-2), 67-79. 15 50. Mateos-Timoneda, M. A.; Crego-Calama, M.; Reinhoudt, D. N., Amplification 16 of chirality Forin hydrog ePeern-bonded tet raReviewrosette helices. Che mOnly. Eur. J 2006, 12, (9), 2630- 17 18 2638. 19 51. Schonherr, H.; Paraschiv, V.; Zapotoczny, S.; Crego-Calama, M.; Timmerman, 20 P.; Frank, C. W.; Vancso, G. J.; Reinhoudt, D. N., Unraveling the nanostructure of 21 supramolecular assemblies of hydrogen-bonded rosettes on graphite: An atomic force 22 microscopy study. PNAS 2002, 99, (8), 5024-5027. 23 52. van Manen, H. J.; Paraschiv, V.; Garcia-Lopez, J. J.; Schonherr, H.; Zapotoczny, 24 25 S.; Vancso, G. J.; Crego-Calama, M.; Reinhoudt, D. N., Hydrogen-bonded assemblies 26 as a scaffold for metal-containing nanostructures: From zero to two dimensions. Nano 27 Lett. 2004, 4, (3), 441-446. 28 53. Schonherr, H.; Crego-Calama, M.; Vancso, G. J.; Reinhoudt, D. N., 29 Spontaneous resolution of racemic hydrogen-bonded nanoassemblies on graphite 30 31 revealed by atomic force microscopy. Adv. Mater. 2004, 16, (16), 1416-1420. 32 54. Schonherr, H.; Calama, M. C.; Vansco, J. G.; Reinhoudt, D. N., Atomic Force 33 Microscopy Studies of Hydrogen-Bonded Nanostructures on Surfaces. In Dekker 34 Encyclopedia of Nanoscience and Nanotechnology, Marcel Dekker, Inc.: New York, 35 2004; pp 155-167. 36 55. Klok, H. A.; Jolliffe, K. A.; Schauer, C. L.; Prins, L. J.; Spatz, J. P.; Moller, M.; 37 38 Timmerman, P.; Reinhoudt, D. N., Self-assembly of rodlike hydrogen-bonded 39 nanostructures. J. Am. Chem. Soc. 1999, 121, (30), 7154-7155. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 Figure Captions 6 7 Figure 1: (a) Formation of double rosette assembly 13.(DEB)/ 13.(BuCYA)6 from three 8 calix[4]arene dimelamines 1 and six 5,5-diethylbarbiturate (DEB) or n-butyl cyanurate 9 10 (BuCYA) building blocks. (b) Schematic representation of double, tetra, hexa and 11 octarosettes. Each floor represents one rosette motif. 12 13 Figure 2: Schematic representation of the three isomeric forms for double rosette 14 assemblies: Staggered (D ), symmetrical eclipsed (C ), and unsymmetrical eclipsed 15 3 3h 16 (Cs). For Peer Review Only 17 18 Scheme 1: Formation of tetrarosette assembly 23.(DEB)12 / 23.(BuCYA)12 from three 19 tetramelamines 2 and twelve 5,5-dyethylbarbituric acid (DEB) or butyl cyanuric acid 20 (BuCYA) molecules. 21 22 23 Scheme 2: Representation of the process of induction of supramolecular chirality in 1 24 double rosette assemblies. Examples of their characterization by CD and by H-NMR 25 are also shown. 26 27 Figure 3: Top and side view of the X-ray structure of assembly 1 .(DEB) . 28 3 6 29 30 Scheme 3: Schematic representation of the diastereomeric noncovalent synthesis of 31 double rosette assemblies by introducing chirality in the dimelamines of the 32 calix[4]arene (bottom) and in the barbiturates or cyanurates (top). 33 34 35 Scheme 4: Illustration of induction of chirality by external chiral acids and diacids and 36 molecular structures of the different acids and diacids studied. 37 38 Scheme 5: Schematic representation of the process of induction of supramolecular 39 chirality in tetrarosette assemblies (P)/(M)-23.(DEB)12 by recognition of chiral 40 D L 41 saccharides (b- -Sugar and b- -Sugar). 42 43 Scheme 6: Enantioselective noncovalent synthesis of double rosettes exploiting the 44 memory effect. Memory effect (a) by exchanging a chiral barbiturate for an achiral 45 cyanurate and (b) by binding of a chiral guest and its subsequent precipitation. 46 47 48 Figure 4: (a) Molecular structures of calix[4]arene dimelamines 1a-j and BAR/CYA 49 derivatives; (b) Left: Plot of the relative CD intensity at 308 nm, versus the time for a 50 mixture of (P)-1b3.((R)-MePheCYA)6 and 1b3.(BenCYA)6 with different initial 51 fractions of 1b3.((R)-MePheCYA)6 (¨: 10%; *: 30%; ·: 50%; ■: 70%; D: 90%) (the 52 percentage of the graphic represents the relative CD-intensity reached at the 53 54 thermodynamic equilibrium); Right: Plot of the relative CD-intensities at the 55 thermodynamic equilibrium for different mole fractions of chiral component. The dotted 56 line represents the expected CD-intensities when ther is no amplification of chirality. 57 58 Figure 5: TM-AFM phase images of nanorod domains of tetrarosettes 23•(DEB)12 on 59 60 HOPG: (a) The orientation of several nanorod domains is related to the threefold symmetry of the HOPG substrate (scan size 600 nm ´ 600 nm). (b) Within the distinct

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1 2 3 4 5 defect region in the largest domain (inside square) a different orientation with an angle 6 of 46º can be recognized (scan size 200 nm ´ 200 nm). (c) The angle between different 7 domains on the same sample can be estimated as 46°, as shown by the arrows (scan size 8 100 nm ´ 100 nm). (d) TM-AFM phase image of nanorod domains of tetrarosettes 9 10 23•(DEB)12 on HOPG (insets: 2-D FFTs, left; Fourier-filtered sections, right). The unit 11 cell of the structure observed is indicated in the corresponding Fourier-filtered sections. 12 (e) Schematic of the mirror symmetry observed for the two different types of domains 13 shown in Figure 5d. (From Ref. 53, Copyright 2004 Wiley-VCH, Weinheim). 14 15 16 For Peer Review Only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For Peer Review Only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 Figure 1 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For Peer Review Only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Figure 2 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54

55 56 57 Scheme 1 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For Peer Review Only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Scheme 2 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 Figure 3 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For Peer Review Only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Scheme 3 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Scheme 4 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For Peer Review Only 17 Scheme 5 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 Scheme 6 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For Peer Review Only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 Figure 4 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For Peer Review Only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Figure 5 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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