substrate selective catalytic molecular hydrogels: the role of the hydrophobic effect
TRANSCRIPT
This journal is c The Royal Society of Chemistry 2013 Chem. Commun.
Cite this: DOI: 10.1039/c3cc45623d
Substrate selective catalytic molecular hydrogels:the role of the hydrophobic effect†
Cristina Berdugo, Juan F. Miravet* and Beatriu Escuder*
A catalytic hydrogel is reported for the substrate selective direct
aldol reaction of aliphatic ketones based on their hydrophobicity
and on the emergence of catalytic activity only after self-assembly
of the catalyst.
The emergence of new specific properties after the self-assemblyof simple molecular components is at the core of supramolecularchemistry and is gaining attention in the context of systemschemistry.1 In this approach, complex functional systemscan be constructed from simple building blocks provided withfunctional groups that self-organize into active supramolecularentities.2 Particularly interesting features may result in theemergence of chemical properties such as, for instance, changesin pKa values and multivalency, as a consequence of the creationof pre-organised arrays of binding groups.3
In molecular gels the gelator is a low-molecular-weightcompound that self-organizes into one-dimensional aggregatesby non-covalent interactions. In this way a self-assembledfibrillar network (SAFIN) is formed which percolates the solvent.4
Responsive gel materials can be obtained by self-assembly offunctional molecular components whose physical and chemicalproperties may be altered by the presence of one or multipleexternal stimuli.5 Moreover, molecular gels have also beenemployed for the confinement of proteins revealing interestingresults both on protein structure and function. Hydrophobicmicroenvironments created within the fibrillar network ofhydrogels have been described to minimize the denaturationof proteins.6 The fibrillar network of hydrogels has been alsoshown to mimic the cellular environment and it has been usedin biocatalysis. In this field, Xu and coworkers have reportedseveral examples of the use of molecular hydrogels for theincrease of activity and stability of enzymes in aqueous media.7
For instance, they have reported simple amino acid-basedmolecular hydrogels that mimic the cellular environment ofbioluminescence.8
In this context we have been recently involved in the study ofmolecular gels as media for molecular recognition as well as fororganic reactions.9 We have described systems in which the gelphase is reactive and can be transformed in the presence of otherreactive components.10 We have also reported other systemswhere the gel has a catalytic action that emerges after the self-assembly process.11 In particular, we reported as a proof ofconcept the use of a proline based hydrogel (1) (Scheme 1) as acatalyst for the direct aldol reaction between cyclohexanoneand 4-nitrobenzaldehyde.12 This reaction proceeded with highdiastereo- and enantioselectivities, and the hydrogels could bereused several times and easily recovered at the end of the process.It was foreseen that the hydrophobic effect was the main drivingforce for both self-assembly of the catalyst and the approach of thesubstrates to the catalytic centre.
Here we present evidence that the hydrophobic effect has akey role on the mechanism of this reaction and that it can beused to achieve substrate selectivity and moderate enantio-selectivity in the direct aldol reaction of linear alkyl ketones.
In order to monitor the effect of hydrophobicity on thecatalytic reaction, aliphatic ketones of different chain length wereused. Hydrogels were prepared at the minimum gel concen-tration (2 mM) and stabilized for 24 h prior to the addition ofthe reagents. In our previous work a small amount of toluene was
Scheme 1
Departament de Quımica Inorganica i Organica, Universitat Jaume I,
12071 Castello, Spain. E-mail: [email protected], [email protected];
Fax: +34 964728214; Tel: +34 964729155
† Electronic supplementary information (ESI) available: Experimental details oncharacterisation of products and additional X-ray information. CCDC 951964. ForESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc45623d
Received 24th July 2013,Accepted 10th September 2013
DOI: 10.1039/c3cc45623d
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used as a co-solvent.12 However, in the current study thealdehyde (water insoluble) is mixed with the ketone (liquid)and the mixture is directly added on top of the gel in order toexplore the effect of pure water. As can be seen in Table 1, after24 h of reaction, products were almost undetected for shortchain ketones. Yields were moderate for ketones with 5 and6 carbon atoms and increased considerably for the longer chainsof 2-nonanone and 2-dodecanone. It is also noticeable that theenantiomer ratios (e.r.) were maintained for the whole seriessuggesting that the steric demands of the reaction site are thesame in all cases. However, the kinetic profiles were differentas can be seen in Fig. 1 and clearly correlated with the alkylchain length. Reaction of ketones of 5 to 8 carbon atoms wassignificantly slower than for 2-nonanone and 2-dodecanone.These results have to be taken as semiquantitative due to theheterogeneity of the samples. However a clear trend is observedthat reveals an important role of the hydrophobicity of theketone. Indeed, a clear correlation of reactivity and log P valuescan be observed already at short reaction times (5 to 10 h), as canbe seen in Fig. 2. More polar ketones like 1,3-dihydroxyacetone(log P: �1.86), acetone (log P: 0.2) and 2-butanone (log P: 0.86)do not react, ketones of intermediate polarity (1 o log P o 2.5) havea low yield and less polar ketones 2-nonanone and 2-dodecanone(log P 4 3) show high yields already after 10 h.
The accepted mechanism for the direct aldol reaction involvesthe reaction of the proline catalyst and the ketone to form anenamine intermediate (Fig. 3) that adds later to the aldehyde
carbonyl group. In the current case, since the proline derivativeis not soluble in water and remains as a separated gel phase theketone must be placed within the gel aggregates in order toreact with compound 1. Therefore it seems reasonable thatthe more hydrophobic ketones will accumulate into the gelphase and react with the catalyst there. In fact, catalyst–ketoneenamine intermediates were not visible by NMR in solution,but could be detected by mass spectrometry (MS) for a sampleof hydrogel and 2-docecanone (0.2 : 10) stabilized for 6 h at r.t.(Fig. 3). Additionally, a water soluble analogue 2 was studiedin order to check if that reaction could happen with a similarcatalyst in solution. In that case the reaction did not work, neitherwith highly soluble ketones like acetone nor with 2-dodecanone.Remarkably, the reaction does not proceed in the absence of thehydrogel as catalytic phase.
Single crystals of 1�HCl�2H2O were obtained during thework-up of the reaction and, although the catalyst appears proto-nated, valuable information on the characteristics of the gel phasemay be extracted (Fig. 4 and ESI†). As can be seen, an intercalatedbilayer structure is formed in which the alkyl chains appearclosely packed by van der Waals and hydrophobic interactions.Besides, polar dipeptidic heads are forming a parallel b-sheet-like structure with intermolecular H-bonds between the alkylamide NH and valine carbonyl group (N–H� � �OQC, 2.837 Å,173.171) and between the valine amide NH and proline carbonylgroup (N–H� � �OQC, 2.910 Å, 164.681). The packing is com-pleted by chloride counterions and a layer of water moleculesthat interfaces with neighbouring bilayers. This layered structureresembles the one proposed previously from powder diffraction
Table 1 Direct aldol reaction of aliphatic ketones and 4-nitrobenzaldehydea
Ketone Yieldb (%) e.r.d
1,3-Dihydroxy-acetone o1 —Acetone 2c —2-Butanone o1 —2-Pentanone 22 65 : 352-Hexanone 42 70 : 302-Heptanone 68 70 : 302-Octanone 40 70 : 302-Nonanone 88 70 : 302-Dodecanone 98 65 : 35
a Hydrogel: 0.008 mmol of 1 (0.2 eq.) in water (4 mL); reagents:4-nitrobenzaldehyde (1 eq.), ketone (10 eq.), 25 1C, 24 h. b Determinedby NMR, average of 3 reaction samples. c 68% after 11 days. d Determinedby chiral-phase HPLC. Enantiomers not assigned.
Fig. 1 Yield of aldol product vs. reaction time.
Fig. 2 Yield of aldol product versus log P of ketone after 10 h of reaction.
Fig. 3 MS graph for a sample of hydrogel 1 and 2-dodecanone.
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data of xerogels of compound 1 and, although the conforma-tion of the head groups will be probably different, the hydro-phobic inner regions should be similar.12 In view of that, it canbe proposed that ketones bearing a long tail can be anchoredinto the bilayer by van der Waals and hydrophobic interactionsand then react in close proximity with the catalyst and formthe enamine intermediate. On the other hand, we have alreadyreported that hydrogel 1 reacts with aldehydes according totheir hydrophobicity which in the studied cases provoked thehydrogel disassembly.13 In the current case, it seems that 4-nitro-benzaldehyde, that is highly insoluble in water, could be forminginsoluble iminium intermediates that remain anchored to thehydrogel phase where they would react with enamine inter-mediates. A tentative scheme for the catalytic site is proposed inFig. 5 in which both reactants are positioned in close proximityby non-covalent interactions where they are then transformedby covalent catalysis.
In summary, we have shown that self-assembly of compound1 into hydrogels is driven by the hydrophobic effect and causesthe emergence of catalytic properties. Moreover, the hydrogelstructure builds up an active site which combines a recognitioncentre based on hydrophobic and van der Waals interactionsand a reaction centre for covalent catalysis. This is a clearexample of a simple although smart system where functionalityencoded at the molecular level is expressed only after self-assembly. Besides, the selectivity shown for hydrophobic sub-strates yields hydrophobic products that could accumulate inthe system and lead to new assemblies with interesting pro-perties such as the formation of new reaction compartments
(i.e. micelles, vesicles). This topic is of current interest as self-assembly and catalysis are thought to play a key role in prebioticchemistry.14 Currently we are exploring the potential of thesystem for the creation of compartments and the develop-ment of competitive behaviour towards the construction of cellmimetics.2d,15
This work was supported by the Ministry of Economy andCompetitiveness of Spain (Grants CTQ2009-13961, CTQ2012-37735 and an FPI fellowship for C.B.).
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2 For instance: (a) J. M. A. Carnall, C. A. Waudby, A. M. Belenguer,M. C. A. Stuart, J. J. P. Peyralans and S. Otto, Science, 2010, 327, 1502;(b) D. Jiao, F. Biedermann, F. Tian and O. A. Scherman, J. Am. Chem.Soc., 2010, 132, 15734; (c) J. Li, Y. Tang, Q. Wang, X. Li, L. Cun,X. Zhang, J. Zhu, L. Li and J. Deng, J. Am. Chem. Soc., 2012,134, 18522; (d) K. Adamala and J. W. Szostak, Nat. Chem., 2013,5, 495.
3 For instance: (a) A. Barnard and D. K. Smith, Angew. Chem., Int. Ed.,2012, 51, 6572; (b) V. Chechik, Annu. Rep. Prog. Chem., Sect. B, 2006,102, 357.
4 (a) P. Terech and R. G. Weiss, in Molecular Gels: Materials with Self-assembled Fibrillar Networks, ed. P. Terech and R. G. Weiss, Springer,Dordrecht, 2006; (b) F. Fages, Top. Curr. Chem., 2005, 256, 1.
5 (a) X. Yang, G. Zhang and D. Zhang, J. Mater. Chem., 2012, 22, 38;(b) M. D. Segarra-Maset, V. J. Nebot, J. F. Miravet and B. Escuder,Chem. Soc. Rev., 2013, 42, 7086.
6 S. Kiyonaka, K. Sada, I. Yoshimura, S. Shinkai, N. Kato and I. Hamachi,Nat. Mater., 2004, 3, 58.
7 Y. Gao, F. Zhao, Q. Wang, Y. Zhang and B. Xu, Chem. Soc. Rev., 2010,39, 3425.
8 Q. Wang, L. Li and B. Xu, Chem.–Eur. J., 2009, 15, 3168.9 B. Escuder, F. Rodrıguez-Llansola and J. F. Miravet, New J. Chem.,
2010, 34, 1044.10 J. F. Miravet and B. Escuder, Org. Lett., 2005, 7, 4791.11 (a) F. Rodrıguez-Llansola, B. Escuder and J. F. Miravet, Org. Biomol.
Chem., 2009, 7, 3091; (b) F. Rodrıguez-Llansola, B. Escuder andJ. F. Miravet, J. Am. Chem. Soc., 2009, 131, 11478.
12 F. Rodrıguez-Llansola, J. F. Miravet and B. Escuder, Chem. Commun.,2009, 7303.
13 F. Rodrıguez-Llansola, J. F. Miravet and B. Escuder, Chem. Commun.,2011, 47, 4706.
14 (a) H. Kuhn and C. Kuhn, Angew. Chem., Int. Ed., 2003, 42,262; (b) D. Deamer, S. Singaram, S. Rajamani, V. Kompanichenkoand S. Guggenheim, Philos. Trans. R. Soc. London, Ser. B, 2006,361, 1809; (c) M. Fishkis, Origins Life Evol. Biospheres, 2007,37, 537.
15 A. M. Brizard and J. H. van Esch, Soft Matter, 2009, 5, 1320.
Fig. 4 Single crystal X-ray structure of 1�HCl�2H2O.
Fig. 5 Proposed scheme of the hydrogel reaction site.
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