Catalysis Science & Technology

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Design strategies for engineering selectivity in bio-inspired heterogeneous catalysts
David J. Xuereb and Robert Raja*
Downloaded on 30 March 2011 Published on 11 March 2011 on | doi:10.1039/C0CY00088D

Received 16th December 2010, Accepted 12th February 2011 DOI: 10.1039/c0cy00088d In an era where the requirement for greener chemical processes is so exigent, the growing need for developing novel routes to environmentally benign and sustainable catalytic procedures is highly desirable. Heterogenising bio-inspired transition-metal complexes on a diverse range of porous supports provides a viable alternative for achieving some of these goals, particularly in terms of reducing waste and by increasing efficiency and selectivity in industrially significant catalytic processes. Choosing an appropriate spatial-restricting support is vital for facilitating enhancements in rate and stereoselectivity, as this plays a pivotal role in optimising the orientation of desired transition-states through varying confinement effects, by utilising a myriad of pore-window apertures for regulating diffusion of organic molecules. The nature of the active site can also be further attuned by adopting an appropriate encapsulation strategy, which could eventually assist in maximising the hydrophilic/hydrophobic character of the support. The nature of the active site and its involvement in the catalytic process can be characterised by using a wide-range of physico-chemcial spectroscopic techniques, which provide valuable insights for drawing mechanistic relationships, which in turn facilitates structure–property correlations.

Incentive for biocatalysts in industry: drawbacks and solutions
Department of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK. E-mail:; Fax: +44 (0)2380 593781; Tel: +44 (0)2380 592144

Enzymes have been found to catalyse a wide-range of organic transformations with a high-degree of activity and selectivity.

David Xuereb graduated from Cardiff University in 2008. He is studying towards a PhD at the University of Southampton with Dr Robert Raja. His research is primarily focused on the heterogenization of organocatalysts for fine chemical applications, including C–C bond formation and oxidation reactions. Other areas of interest include the utilization of solid oxidants for chemical processes and the catalytic function of metal David J. Xuereb coordinated amino acidderivatized frameworks and porous inorganic–organic hybrid materials.

Robert Raja completed his PhD in 1997 and was awarded a Royal Commission for the Exhibition of 1851 Fellowship at the Royal Institution of Great Britain. He worked with Bayer Chemicals, Leverkusen, Germany (2000–2003) as a Research Chemist developing one of the first series of heterogeneous, organometallic chiral catalysts for fine-chemical and pharmaceutical applications. He returned to Cambridge University in 2004 as a Senior Robert Raja Research Associate concentrating on the discovery and design of novel single-site heterogeneous catalysts. In 2006, he was appointed as Reader/Associate Professor in Chemistry at the University of Southampton where he focuses on engineering active sites for industrially significant catalytic transformations, using environmentally benign reagents, energyrenewable feedstocks and sustainable processes. He has won several awards and prizes, the most notable being the Erskine Fellowship (2008) awarded by the University of Canterbury (New Zealand) and the Barrer Award (2005) by the Royal Society of Chemistry.
Catal. Sci. Technol.

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The Royal Society of Chemistry 2011

Table 2 Advantages and disadvantages of enzymes for industrial transformations4 Advantages High stereoselectivity High chemo-selectivity Compatible with water as solvent Mild operating conditions Disadvantages Stability Availability Low specific substrate activity Long development times Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs. Compared with other types of alternatives. to a great degree. Zeolites and mesoporous silicas are suitable hosts for anchoring and encapsulating single-site bio-derived catalysts because of their large surface areas and robust composition. biocatalysts are combined or used in conjunction with chemical catalysts for a network of reactions. the main advantage of enzymes as catalysts is their unsurpassed selectivity. in situ characterisation as well as proprietary precincts. Given the above. Already an increasing number of bio-transformations are carried out on an industrial scale. by their lack of stability (Table 2). Enzymes are also highly active under mild conditions such as temperature. Progressively. at a compound annual growth rate (CAGR) of 9. harsher temperatures. even though in principle a large breadth of chemical reactions can be catalysed. A further advantage of enzymes is their wide-diversity in terms of the reactions that they are able to catalyse. Enzymes are used to increase chemo.and regio-selectivity. Sci. utilising biocatalytic processes2. many reservations have been raised Table 1 Summary of chemicals produced on a scale of 41000 metric tons per year (tpy) as a result of biocatalysis4 Product High fructose corn syrup (HFCS) Lactose-free milk Acrylamide Cocoa butter Nicotinamide D-Pantothenic acid (S)-chloropropionic acid 6-Aminopenillianic acid 7-Aminocephalosporanic acid Aspartames L-Aspartate D-Phenylglycine D-p-OH-phenylglycine Enzyme Glucose isomerase Lactase Nitrilase Lipase Nitrilase Aldonolactonase Lipase Penicillin amidase Glutaryl amidase Thermolysin Aspatase Hydantoinase/carbamoylase Hydantoinase/carbamoylase Production scale (tpy) 41 000 000 41 00 000 410 000 41000 focusing on their drawbacks. Immobilising an entire enzyme can be thought of as an arduous task. homogeneous and heterogeneous catalysts. Developing strategies for anchoring these active entities on stable inorganic frameworks leads to the creation of highly active and selective catalysts that can facilitate highly stereoselective transformations for the production of fine-chemicals.4 Over the past few decades. for example. pressure and pH. which means they can be applied to an increasing number of applications on an industrial scale.1039/C0CY00088D Catal. This journal is c The Royal Society of Chemistry 2011 . irrespective of the advantages of using biocatalysts. It is this unsurpassed | doi:10. but their best asset is enabling enantiomeric control. but of greater significance is the enzymes lack of stability in varying conditions and desired media. The biggest advantage of enzymes is their supreme selectivity. via bimolecular pathways. Enzymes also require co-substrates and co-factors which lead to cost considerations. A main reason for this is a deficient knowledge base of biotechnology and. The different routes used for immobilisation such as in situ encapsulation or post-synthetic modification of the framework can alter the nature of the active catalyst.3 using primarily fixed-bed immobilised enzyme reactors or batch reactors (Table 1). Using water as a solvent meets industrial processing goals such as attaining sustainable development and carrying out manufacturing by more environmentally-benign methods. such durations can easily be deemed too long for many industrial applications. compared to patent lifetimes around the same length.and stereoselectivity that has caught the eye of the pharmaceutical industrial giants of the present day. This restricted substrate specificity is a huge shortcoming because. Technol.3% between 1999 and 2009. the stability of the enzyme is rather limited and often leads to their deactivation. Furthermore. stable catalysts that are amenable for industrial processing can be developed. only certain substrates could be directly employed due to the size-selection preferences of the enzyme. through the immobilisation of a functional mimic of the active site in an enzyme.View Online The most fundamental transformations from simple oxidations of straight chain alkanes to intricate rearrangements are catalysed with exceptional selectivity. In many cases enzymes can achieve enantioselectivies of 499% enantiomeric excess (ee) in an undemanding fashion. which is offset. which is a major cause for concern in downstream processing.1 The market is forecast to grow to over $1000 billion in 2014 demonstrating the requirement for highly efficient and selective catalysts to meet the growing demand. Another drawback is development cycles are too long for new industrial biocatalysts. Another benefit is that reactions are preferentially carried out in aqueous media therefore providing a ‘greener’ route. In most cases. problems associated with substrate specificity may also be overcome. which leads to a shortfall of desired reactions from specific substrates to targeted products. chemo. Metalloenzyme mimics have long held the fascination of synthetic chemists and both structural and functional enzyme mimics have been rationally developed through the interaction of transition-metal complexes containing suitable amino acid residues. which reiterates the importance of using enzymes in industry and their notable characteristic for effecting highly stereoselective organic and bio-organic catalytic transformations.rsc. pressures and pH are required for maximising efficiencies and yields leading to narrow operation windows within specific reactions. The importance of enantiomerically pure drug syntheses is evident from the growth of the global pharmaceutical market to $808 billion in 2009.5 The availability of enzymes for commercial exploitation has been limited due to a lack of in-depth. which makes them easier to work with on a small scale. This would also aid the recovery and reusability of the catalyst and make it amenable for continuous processing. Many of the products formed are isolated as a particular enantiomer. but are also more appealing on an industrial scale on a cost and efficiency basis. but by mimicking the catalytic function of its active site.

amidato. within the chain itself (except amino and carboxylate) and in side-chains. Amino. 3). we wish to highlight some of the methodologies and strategies for heterogenising bio-inspired catalysts on different solid supports. a basic amino group (–NH2). oxidation of aromatics and dealkylations. FeII sites directly bind O2 for substrate | doi:10. Side-chains can also coordinate to the metal centre. Iron and copper ions frequently occur as metal centres in biological oxidation systems and act as proficient catalysts.12 Fig. Fig. O-donor. Metalloenzymes containing iron active sites. for example. which can be very diverse due to electronic and geometric differences arising from ligand environments. The amino acids stabilise and isolate the metal active-centre providing a specific binding pocket for particular substrates to attach (Fig.1039/C0CY00088D A metalloenzyme is a lengthy protein that contains a small metal complex in the active site that is coordinated by amino acids from the protein scaffold. consequently providing a measure of how successful each framework type is for catalysis and what applications can be envisaged in the future from these materials. due to dissociation of the acidic proton to form a bidentate N. However. 2 (A) Typical coordination sphere of an amino acid containing transition-metal complex. Binuclear iron enzymes are also useful O2 activation compounds. Rieske dioxygenases and extradiol dioxygenases) (Fig. Sci. Fig. Amino acids are good metal-complexing agents because of the electron donating effect of the substituents. This journal is c The Royal Society of Chemistry 2011 Catal. 3 Mono-nuclear enzyme active sites. Devising active sites analogous to metalloenzymes Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs.View Online In this article.8 Heme-enzymes play critical roles in the biological hydroxylation of saturated carbon–hydrogen bonds. amido.9 Mononuclear non-heme enzymes catalyse oxidative transformations either by FeIII-sites activating substrates for reactions with dioxygen (e. epoxidation of olefins. while high spin FeIII sites activate the substrate for direct reaction with O2. which are composed of an acidic carboxyl group (–COOH). Proteins coordinate to metal ions by dative bonds formed through nitrogen.g. soluble methane monooxygenase (sMMO). . (C) Possible coordination sphere of a bis-complex of histidine coordinated through the imidazole group. heteroatom oxidation. e. 1 Schematic of an active site within a metalloenzyme. carbonyl and carboxylate ligands can be located at the C. a hydrogen atom and a characteristic side chain (–R). amino group of lysine and arginine. Technol.6 The peptide chain is made up of small building blocks of amino acids. intradiol dioxygenases and lipoxygenases) or through FeII-sites activating oxygen by direct binding to O2. (B) Examples of amino acids that can also coordinate through the side chains. Forming chelate rings through the amino and carboxylate groups is a common feature of amino acid coordination spheres. resulting in iron–oxygen intermediates that react with the substrate10 (e. in order to devise a suitable strategy for encapsulation or immobilisation of the active site. 2). has a carboxylate-bridged dinuclear iron centre11 that is capable of oxidizing aromatics and methane (the most inert hydrocarbon with a C–H bond energy of 104 kcal molÀ1). a di-iron containing enzyme. oxygen and sulfur atoms that make up the enzyme backbone. consist of a substantial group of dioxygen activating enzymes that show significant promise for functionalising a wide range of organic substrates with high efficiency and selectivity.g. it is important to understand the function and composition of the metalloenzyme. imidazole group of histidine.g. mercapto group of methionine or carboxylato groups of aspartate and glutamate7 (see Fig.or N-termini of the peptide chain. the activity and selectivity of which can be attributed to their inherent electronic properties and accessible redox capabilities. 1).

both as mimics of natural enzymes and for processes of industrial interest.15 Dicopper species that contain a binuclear copper centre as the active site (e. Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs. 4 Mono-nuclear and bi-nuclear examples of different copper sites in enzymes.rsc. particulate methane monooxygenases (pMMO)} are effective in highly demanding hydroxylation reactions and oxidations of inert hydrocarbons such as methane. chemically robust and easy to separate from reaction mixtures by filtration or centrifugation. with each methodology of heterogenisation having explicit benefits most notably in selectivity. more specifically metal-complexes. and apply them to the rational design of zeolite-based catalysts.24 The ionic interactions between the support and the metal-ion are strong enough to hold the guest metal in place. careful combinations of metal complexes immobilised as active sites throughout an inorganic matrix can result in catalysts that can mimic the functional aspects of enzymes. exhibit better thermal stability and display superior solvent and substrate versatility compared to biological metalloenzymes. Each T atom is tetrahedrally bonded to four oxygen atoms forming a bridge to neighbouring T atoms. The primary building units are single TO4 tetrahedra. 4).g. which in turn can serve as substrates to yield carboxylic acids. A metal cation can be readily exchanged into the zeolite to balance the overall net negative charge on the framework.20 Amino acid–transition-metal complexes can perform as isolated active sites when encapsulated in inorganic host materials such as aluminosilicates or covalently bonded to mesoporous silica frameworks and polymers.29.23 have shown that the hydrophobic–hydrophilic properties of a heterogeneous catalyst plays a determinant role in enhancing both the activity and selectivity of a reaction.14 Mononuclear copper enzymes {e. which can impede or assist diffusion on a size selective basis. for mimicking the catalytic function of cytochrome P450 enzymes. Somorjai and Park21 have recently highlighted the seven molecular components that influence the selectivity of heterogeneously-catalysed reactions and have elegantly demonstrated how it would be possible to correlate these molecular factors for the development of hybrid systems. Sci. The catalyst may also be recovered and recycled numerous times due to the heterogeneous nature. Romanovsky and co-workers31–33 first reported the synthesis of metallophthalocyanines inside the supercages on the zeolite Na–Y in 1977. Using this rationale. These supports act as substitutes to the protein scaffold and create a spatial environment similar to that of the natural enzymes. tyrosinase and catechol oxidase) can selectively oxidize phenols to catechols and further to quinone. copper metal centres play a major role in biological dioxygen activation systems13 (Fig.17 the support is the degree of the hydrophilicity or hydrophobicity. activity and selectivity may be enhanced through chemical modifications of the active site by altering immobilisation procedures or by changing the support type. Single copper-ion-containing enzymes {e. facilitate separation of products from reactants and aid catalyst recyclability. Due to similarities in the structure and chemical properties between metallophthalocyanines and metalloporphyrins. galactose oxidase (GO)} also play an important role in the two-electron reduction of O2 to peroxide coupled with oxidation of organic molecules.19 or by the use of artificial proteins. Encapsulation strategies encompassing channels and cages in microporous solids Zeolites are porous crystalline aluminosilicates with threedimensionally connected channels. stable at high temperatures. where T is an aluminium or silicon atom.g. zeolites serve as a substitute for the protein scaffold of natural enzymes and provide a controlled steric environment.30 These heterogeneous catalysts are resistant to harsh reaction conditions.35 have often been used as substitutes. One of the most important properties of Catal. In these architectures. Zeolites have the ability to act as catalysts for chemical reactions which take place within their internal cavities. due to different polarities and transitionstates that the reactant can adopt.18 designed organic ligands.27. which is desirable from an industrial perspective. therefore presenting an alternative to conventional biological and chemical processes. In an attempt to prepare heterogeneous analogues of This journal is c Rationale for heterogenised bio-inspired catalysts Understanding the nature and the coordination sphere of the active metal centre in a metalloenzyme provides valuable insights for developing design strategies for heterogenising bio-inspired catalysts for chemical transformations. which can play an important role in determining the catalytic outcome.1039/C0CY00088D Furthermore. Catalyst stability. Structural and functional enzyme mimics have been developed through the assembly of transition-metal complexes with natural amino acids. which provide a stereochemicaly demanding void space for catalysis to occur. novel single-site heterogeneous catalysts can be created. such as the organized pores and channels. within their structure.View Online Fig. such as oxidation of primary alcohols to aldehydes. Zeolites can incorporate guest molecules. which take advantage of and facilitate enzyme selectivity in a heterogeneous medium. The Royal Society of Chemistry 2011 .28 Zeolite encapsulated active centres offer many advantages.g. the latter34.25. Researchers from DuPont36–39 were among the early pioneers to exploit the chemistry of natural enzymes. The replica heterogeneous catalysts are more versatile to pH changes.26 Aluminosilicates are ideal supports and by astute choice of the metal complex. Each framework type has its own inherent degree of water attraction but can also be altered by post-treatments. Technol. Choice of support is based upon consideration of experimental conditions of intended reaction. They are thermally stable. where the catalysis proceeds. adopt strategies for the encapsulation of transition-metal complexes within porous | doi:10. Corma and co-workers22.16. due to the availability of empty channels and cages.

42 Although these systems enabled selectivity control and inhibition of auto-oxidation.38. ligand adsorption (C). .57 ligand adsorption58 and ship-in-bottle methods. Jacobs et al. These workers had established earlier44–46 that a range of metal complexes could be successfully immobilised within the internal cavities of a zeolitic framework and demonstrated the viability of a supramolecular system. ‘ship in a bottle’ (D) and zeolite synthesis methods (E). embedded in a polydimethyl siloxane membrane.49 and extensive studies have been reported for the selective oxidation of organic compounds using a range of oxygen sources.rsc. for example.36 The isolation of the active centres within the zeolitic cavities suppresses dimerisation reactions that lead to the formation of the inactive m-oxo and peroxo-complexes of cobalt. flexible ligand (B).59 The ship-in-bottle method involves assembling the final active metal complex inside the pores of the host by reacting smaller precursors to afford the larger complex that becomes sterically entrapped inside the cages. 5): ion exchange. 5 Methods for encapsulating metal complexes within zeolites: Ion exchange (A).43 reported a composite catalytic system that achieves realistic mimicry of cytochrome P-450. This method has been used for encapsulating metal–amino acid complexes inside a zeolite structure—an example of this is Fig.55 flexible ligand approach. Fe(II)–Pd(0) particles were encapsulated in zeolite A and these exhibited remarkable substrate and regioselectivity in the oxidation of unactivated alkanes with molecular oxygen. which were more stable than those formed by the same complexes in free | doi:10. with the actual enzymatic process. The polymer acts as a mimic of the phospholipid membrane where the active centre of cyctochrome P-450 is located and this system oxidises cyclohexane at room temperature with rates comparable to that of the natural enzyme.1039/C0CY00088D haemoglobin and myoglobin. This journal is c The Royal Society of Chemistry 2011 Catal. involves the exposure of a sodium-ion charge balanced zeolite to a solution containing other cations.47 Since the early work of the DuPont scientists. where complexes of manganese(II) with bipyridine. which were in turn. This route was employed for encapsulating metal–phthalocyanine or metal–porphyrin complexes within the zeolite.50–53 A number of routes54 are known for preparation of metal complexes inside zeolites (Fig.48. have the potential to oxidise alkanes and alkenes under mild conditions.37 Such encapsulated complexes formed adducts with dioxygen. facilitating an exchange of the sodium ions. cobalt(II) salen complexes were encapsulated within the supercages of zeolite-Y. by incorporating iron phthalocyanine complexes in crystals of zeolite Y. Sci. when encapsulated in the supercages of zeolites X and Y.59 The ion-exchange strategy.41 which reversibly bind to dioxygen. they displayed very little.38.56 zeolite synthesis.36–39 there have been numerous efforts aimed at the activation of molecular oxygen by metal complexes.40.View Online Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs.39 In a similar attempt to prepare analogues of cyctochrome P-450. in terms of mechanistic analogy. Technol.36.

This journal is c The Royal Society of Chemistry 2011 .66 The general coordination for a Cu complex with two a-amino acids is the binding of both the amino acid by an amino nitrogen and a carboxyl oxygen.60. Bedioui and their colleagues devised a method61 for synthesising zeolite Na–X around cobalt(II) and copper(II) hexadecafluorophthalocyanines using the zeolite synthesis method shown in Fig. Fig..57 Metal phthalocyanines. and thereby encapsulating it. which in turn. Cu2+ forms mono-histidine complexes and within a pH range 6–10. 8 Charged 1 : 1 Cu-complex which can coordinate to the zeolite framework oxygen atoms (left) and the neutral homogeneous 1 : 2 complex coordinated through two NNO-ligands (right).65 Weckhuysen et al.55 The type of bonding though. using the zeoliteencapsulation strategy that has been described earlier. a NNOO coordination or a glycine-like bonding.1039/C0CY00088D Fig. EXAFS and XANES. as contamination by uncomplexed or partially-complexed metal ions as well as the presence of free ligands cannot be ruled out. two histidine ligands coordinate to the Cu2+ ion in a square-planar geometry. in a confined space in the cages of the zeolite. such intrazeolite complexes are physically-trapped (size-inclusion) inside the zeolitic pores and are not necessarily.60 Based on one form of a proposed structure by Baute et al. this method poses the added complications of not having a well-defined active centre. dramatically improved the catalytic potential of the encapsulated catalyst. The strategy initially involves ion-exchanging a sodium-enriched zeolite Y (Na–Y) with a solution of Cu–histidine at pH 7.64. In solution. 6). The flexible-ligand method involves the synthesis of metal complexes in the zeolite cavity by coordination of the ligand with the exchanged metal cations. Furthermore.68 the isolation and stabilisation of a mononuclear copper(II) complex with a 3. the authors observe a neutral bis-ligand species (Fig. Preformed transition-metal complexes are included in the zeolite synthesis mixture and the zeolite is formed around the metal complex. Recently.64 pioneered the immobilisation of Cu(histidine) complexes within the cages of zeolite Y using an ion-exchange strategy. with a view to enhancing the oxidative stability of the metal complex. i. anchored to the surface. 7 Visual representation of amino acid coordinated transition metal complex (Fe3+–proline) encapsulated within zeolite X (left) and copper-phthalocyanine entrapped within a zeolite supercage (right). On immobilisation.59. entrapped Cu–histidine complex60 (Fig. UV/Vis/NIR. They introduced electron-withdrawing halogen substituents in the phthalocyanine ligand. However. right).68 Catal. encapsulated by the ion-exchange method. Complexes with previously exchanged metal ions are able to diffuse freely through the zeolite pores. in the case of [Cu(His)2]+. Sci. 7).55. Bis complexes are formed by coordination of four nitrogen atoms from the imidazole and the amine group of each molecule. between an amino acid and Cu2+ is similar for all a-amino acids with the exception of histidine. bis complexes are formed.3-bis(1-methylimidazol-2-yl)propionate (abbreviated: MIm2Pr) ligand (see Fig.3. which are both influenced by the pH of the reaction. but can easily be washed out from the zeolite Fig.56 However. while the carboxylate group coordinates in an apical plane. as well as the carboxylate oxygens that can also coordinate to the metal.64 for the room temperature oxidation of benzyl alcohol to benzaldehyde.154 (A) a refined complex is determined as one histidine ligand coordinating in a tridentate facial-like manner and the fourth position occupied by a framework oxygen atom from a Brønsted acid site (in red) (B). which is identical to the homogeneous analogue. porphyrins and amino acids provide examples of such entrapped catalysts (Fig. Using a combination of spectroscopic tools. The capability of the copper complex to undergo ion-exchange is dependant on its charge and stability. an equilibrium exists between the NNNN (histamine-like coordination) and NNNO (one histidine is bound histamine-like and the other glycine-like) bonding in the coordination plane of the bis(histidine) complexes.61–63 Transition-metal complexes containing amino acids immobilized within zeolitic supports generate isolated active centres that function as effective selective oxidation catalysts using benign oxidants such as air and display high turnovers and selectivity in oxidation reactions. 5. less than 1% of the Cu2+ is coordinated to the histidine ligand. The zeolite synthesis method follows a kind of templated synthesis approach. 8. 6). 6 A combination of XRF. This approach is well suited for the encapsulation of metal–salen complexes. At low pH values of around 2.rsc. as the carboxylate oxygen of one of the histidine ligands can partially replace one of the imidazole nitrogens. using it as a sort of template. 8). Weckhuysen’s group have elegantly demonstrated67. as the salen ligand offers the flexibility to move throughout the channels. the two histidine ligands are coordinated to the Cu2+ in the coordination plane by the amido N and the imidazole N. However. Technol. On increasing the pH to 3. Balkus Jr. a framework oxygen atom replaces one of the histidine ligands60 ( | doi:10.e. IR and Raman spectroscopy is used to elucidate the composition of Cu–histidine complex encapsulated within zeolite Y. they demonstrated that.View Online Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs. ESR.

6). which displays a higher catalytic potential than its homogeneous analogue. hypoxanthine. Interesting changes in activity and selectivity were observed by simply changing the oxidant (Fig. adenine.72 Spectroscopy and computational modelling have helped elucidate the nature of the active site. Although in this instance. mononuclear. Sci.83 In particular.85.79 Chiral copper(II) coordination polymers have proved effective in the enantioselective oxidative coupling of 2-naphthols.80. Technol. the use of in situ vibrational spectroscopic techniques showed that amino acid complexes that were covalently anchored to polymeric supports displayed a greater stability. in the oxidation p-chlorotoluene and epoxidation of olefins. The encapsulated Fe3+–proline selectivity oxidises the hydrocarbon to cyclohexanone (99.65 Spectroscopic data of the encapsulated catalysts offer more information about the nature of the active site such as the coordination sphere. This is not limited to just zeolite models. left).87. and benzyl alcohol (Scheme 1). whilst using tert-butylhydroperoxide (TBHP) as the oxidant produced preferentially cyclohexanol.73–76 Oxovanadium(IV) and copper(II) complexes of amino acid derived tridentate ligands (L-alanine and L-isoleucine) when anchored to polymer matrices (e. when bonding to a range of bio-monomers (purine. including the epoxidation of olefins (styrene. 8.g. The Royal Society of Chemistry 2011 Catal. monoligand [Cu(MIm2Pr)] charged species (Fig. because cyclohexanone is a vital precursor in the manufacture of e-caprolactam (for nylon-6) and adipic acid (for nylon 6. In both cases far more conversion was achieved with the heterogeneous analogues due to the generation of isolated active sites in the encapsulation procedure. conformations and configurations between the active complexes and their hosts. complex structure and metal oxidation state. gas adsorption studies and surface area measurements65 were carried out ( | doi:10. This approach has been rationally extended to the adsorption and intercalation of metal-substituted amino acid complexes in clays69–78 and further to the immobilisation amino-acid-derived ligands and related complexes in polymer matrices.5 mol%) with O2.rsc. guanine.81 Anchoring Cu(II)– and Mn(II)–valine onto cross-linked styrene–divinylbenzene results in stable. chloromethylated polystyrene) display higher activities and turnovers.57 In order to ascertain whether the Fe3+–proline complex was encapsulated within the supercages of the zeolite.86 The merits of immobilising single-site homogeneous catalysts has paved the way for exploring the interface. prepared by the zeolite-synthesis and flexible ligand methods (described earlier) have shown65 promising potential in the oxidation of cyclohexane This journal is c Scheme 1 Cyclohexane oxidation to cyclohexanol and cyclohexanone (top). 9). recyclable catalysts that are highly active for a range of industrially-significant reactions. etc. cis-cyclooctene. this can be taken in general terms whereby these techniques are used in characterizing the active site on other systems too. which have helped gain a deeper insight into the interplay of bonds. Cu(MIm2Pr)2.71 The clay structure and composition influence the activation of the reactant and its suspension stability provides ease of access of the substrate to the imbedded catalytic-active sites. 10). . with retention of higher activities. as well as combining the advantages of homogeneous as well as heterogeneous catalysts. the spectroscopic information can provide detailed information on the catalytic sites that in future can be used to elucidate a plausible mechanistic Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs. The oxidation of cyclohexane to cyclohexanone is an important chemical reaction. Benzyl alcohol oxidation to benzaldehyde (bottom). 9 Catalytic results for the cyclohexane oxidation with zeolite encapsulated Fe3+–proline complex. norbornylene and cyclohexene) and oxidation of alcohols (cyclohexanol and benzyl alcohol). compared to the non-polymer-bound analogues. This further facilities access of the substrate molecule (benzyl alcohol) to the immobilised.View Online structure.77–84 Cu(II)–lysine and Cu–(histidine) complexes intercalated between layers of saponite clays by cation exchange display promising catalytic potential in several oxidation reactions using tert-butylhydroperoxide as the oxidant. The distinct decrease in the BET surface area and micropore volume shows the complex resides within the cages of the aluminosilicate. The catalytic efficiency of these materials has been attributed to the peptide bond formation which derives from the above structure-composition effect.82. Powder XRD studies revealed the structural integrity of the zeolite was intact after the encapsulation process and further confirmed that there are no phase impurities or defect structures in the framework and that no additional peaks due to neat complex on the outer surface were detected. Kharasch–Sosnovsky reactions and in the kinetic resolution of secondary alcohols by asymmetric acylation with ee’s reaching up to 90%. for potential industrial exploitation.88.1039/C0CY00088D Fig.69 Hydrotalcite-functionalised bio-inspired Mo(II) complexes have been proven to be more stable than their homogeneous counterparts in olefin epoxidation70 whilst intercalation of chiral catalytic centres (such as L-proline) in anionic clays has resulted high enantiomeric excess (94%) in the asymmetric aldol reaction of benzaldehyde and acetone. for electron transfer reactions. as opposed to being adsorbed on the external surface.89–91 Heterogeneous Fe3+–proline complexes. Baeyer–Villiger oxidations. using the example of an iron–proline complex entrapped within zeolite X.) and its coordination geometry.

The Royal Society of Chemistry 2011 . and product molecules from.94 The silanol groups at the surface of the channels can be organofunctionalised and then used to host organometallic and transition-metalcontaining catalysts by coordinating to metal centres.57. In fact.97 which can be facilely used to functional the surface of the mesoporous silica. which regulates the diffusion of reactant molecules to. because the pore diameters can be in excess ˚ .View Online Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs. The nN–H bands of neutral N–H groups are observed at 3285 cmÀ1 for zeolite entrapped Fe3+–proline and at 3210 cmÀ1 for neat Fe3+– proline.93 so as to accommodate a broader scope of substrates.96 RSi(OEt)3 and RSiCl3 are the most popular silylating agents. which is a feature of strongly interacting Fe3+ ions. A notable example is MCM-41 (M41S) which has ordered pores of hexagonally packed one-dimensional channels comprising of a very large surface area. well-separated from others by the cavities and channels of the zeolitic host.65 The impressive selectivities.26 which is indicative of isolated iron(III) ions and further validates the notion of the complexes being well-dispersed throughout the material. Sci. DR UV-Vis spectroscopy reveals the nature of Fe species confined within zeolite-X. in order This journal is c pathway. giving rise to isolated single-site heterogeneous catalysts. although in Fe3+–proline–X. This is not the case with mesoporous silica frameworks. The absence of the dNH2+ vibration at 1550 cmÀ1 is evident. activity and reusability achieved through this encapsulation method augur well for future sustainable applications. A major drawback of zeolites as supports is the microporous nature of the pore architecture. the active site that is contained within a small pore or channel. with mesoporous silicas. around 1650 and 1400 cmÀ1. Technol. The hydrophilicity of the silica may also be altered by decreasing the amount of silanol groups on the surface by grafting less polar organic compounds therefore enhancing surface hydrophobicity. This strategy can be specifically adopted for larger channel architectures. The zeolite encapsulated complex also reveals this signal. The band at 45 400 cmÀ1 can be assigned to highly distributed and segregated Fe3+ sites92 therefore providing evidence for the complex occupying isolated single-sites throughout the inorganic motif. which in turn can influence catalytic activity. that can be utilized in industrially significant reactions.95 Introduction of functional groups via silylation is the most reliable method to prepare inorganic–organic hybrid materials.1039/C0CY00088D which are due to ligand to metal charge transitions (LMCT) involving iron in tetrahedral or octahedral | doi:10. 10 N2 physisorption isotherms and pXRD patterns for zeolite with and without encapsulated complex. The above characterisation evidence further substantiates that the complexes are present in the mononuclear form. the bands are readily superimposed into a broad signal between 3700 and 2800 cmÀ1.rsc.65 The heterogeneous Fe3+–prolinebased catalyst produces bands at 37 600 cmÀ1 and 45 400 cmÀ1 Catal. Fig. respectively. As with most solid supports. such as hydrophilic mesoporous silicas. Table 3 IR adsorption (cmÀ1) frequencies of the neat Fe3+–proline complex and the corresponding zeolite encapsulated analogue IR assignment n O–H (Si–OH) n N–H n C–H n C–H n C–H nas COOÀ ns COOÀ Fe(L-pro)2 neat complex 3210 2970 2945 2870 1662 1416 Fe(L-pro)2–zeolite entrapped 3740 3285 2945 1662 Covalent anchoring strategies using mesoporous silica Porous inorganic solids can be used for anchoring wellseparated catalytic centres in order to replicate the behaviour of homogeneous and enzymatic catalysts. a range of pore of 500 A ˚ ). which can correspond to hydrogen bonding between proline and the zeolite inner surface. hence diameters are potentially available (from 25–250 A judicious choice of pore aperture imparts desired spatial constraints or freedom with respect to the mechanistic pathway. In this case the FTIR spectra (Table 3) of neat and encapsulated Fe3+–proline confirm that the carboxyl group of the ligand is deprotonated due to the strong band at 1662 cmÀ1 resulting in an antisymmetric (nas COOÀ) and a symmetric stretching mode (ns COOÀ). practical advantages include high mechanical and thermal stability and straightforward separation of the catalyst from the reaction mixture. which substantiates that the amino group is not protonated and most likely coordinates to the iron centre. The absence of a signal around 1750 cmÀ1 (which is typical of the COOH species) further confirms that the carboxyl group is involved in binding to the metal ion. which is highly likely due to interacting Fe3+–proline centres located near the extremities of the cages of zeolite X. More importantly this spectrum produces another signal at g = 4.54. Electron Paramagnetic Resonance (EPR) spectrum65 of the neat iron complex consists of a broad resonance at g = 2.

rsc. therefore with the additional interaction on the pore wall potentially affecting the stereoselective outcome. Greater enantioselectivities can be attained using the restricted conditions in the concave pores of a mesoporous silica because the limiting dimensions hinder the possible orientations of bulky reactants so that interactions with the inner walls dictate Catal. 12 Depiction of the dppf–diamine palladium dichloride catalyst attached to nonporous silica (A). particularly in the vicinity of a tethered active site.98. (%) 76 98 99+ 1 (%) 99+ 98 50 2 (%) — 2 50 ee (%) — 43 95 Scheme 2 Allylic amination of cinnamyl acetate with benzylamine (Trost-Tsuji reaction). 30 A Results show (Table 4) that the homogeneous catalyst forms the straight chain product almost exclusively and this is mirrored by a very similar outcome in the case of the unconfined heterogeneous catalyst. the catalyst tethered in the mesopore gives an equal amount of the regioisomers. no spatial restrictions in the uninhibited catalysts that would preferentially produce branched isomers and consequently give impressive ee’s. mesoporous silica with pores diameters in the range of ca. silica frameworks also do not swell on exposure to solvent or reactants and are readily available in a range of pore diameters. The soluble catalyst attached to the silsesquioxane produced a racemate. thereby proving the chiral advantage of creating a hindered active site that is immobilised within the channels of the framework. Fig.2 0 bis(diphenylphosphino)ferrocenyl] | doi:10.99 The homogeneous catalyst comprised of the active metal complex attached to a soluble silsesquioxane100 moiety. One heterogeneous analogue was covalently attached to nonporous silica. 11). containing the same (S)-1-[(R)-1.95 Table 4 Allylic amination of cinnamyl acetate with benzylamine catalysed by dppf–diamine palladium dichloride catalyst in a homogeneous form. tethered to nonporous silica and confined within mesoporous silica98. and the other to ˚.N 0 -dimethylethylenediamine palladium dichloride active centre. This rationale can promote the cost effectiveness of using anchored inexpensive chiral ligands rather than more extravagant auxiliaries as in homogeneous catalysts. On the other hand.1039/C0CY00088D Fig. This has been suitably demonstrated in the allylic amination of the Trost-Tsuji reaction (Scheme 2) by making a direct comparison with 3 different catalysts (1 homogeneous and 2 heterogeneous. The approaching prochiral compound would experience interactions with the chiral ligands and the metal centre but also more significantly with the inner wall. spatially confined mesoporous silica. but more significantly exhibits an ee of 95% of the branched product.101 Once again the confined form gave conversions far superior to that of the non-confined analogue with an order of magnitude improvement in ee. Technol. In addition.View Online Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs. to be re-used without degrading. Further proof of this concept was observed in the one step conversion of ethyl nicotinate to ethyl nipecotinate using the same catalysts. This journal is c The Royal Society of Chemistry 2011 . would induce chirality in a target molecule (Fig. 12). which is far superior to the ee of 43% of the diminutive yield of the same product from the unconfined solid catalyst. 11 Substrate interactions that govern selectivity when a transition-metal complex is covalently anchored within a mesopore. MCM-41 (B) and to a soluble silsesquioxane moiety (C). It was originally hoped that deliberate restrictions of space inside the pore.99 Form of Pd catalyst Homogeneous Tethered-non-porous Tethered-mesoporous Conv. Sci. These results indicate that there are Fig. The sum of these interactions would be approximately the same order of the two transitionstates that determine enantiomeric excess.

13 Rhodium diamine complexes covalently anchored to mesoporous silica (A) and results of asymmetric hydrogenations. less enantioselectivity was observed (Fig.107. The same Rh catalyst can be anchored via ionic interactions with the pore wall (B) and employed in the hydrogenation of methyl benzoylformate. non-covalently anchored catalyst gives the same correlation in results to that of the covalently anchored series.5-cyclooctadiene) are covalently tethered to porous silica with inexpensive ligands. This methodology can be further applied to the immobilisation of bio-inspired complexes for selective catalytic | doi:10. through dipole charges in the ligands and anchoring the compound through hydrogen bonding with the surface silanol functionalities (Fig. Technol. Sci. A differing methodology for immobilising metal complexes to mesoporous silica is through ionic attachment—an approach that was adopted by de Rege et al. methyl groups111 and this also influences the stability of the amino groups. the silica surface must be derivatized with an amino group and this is most commonly achieved by the co-condensation of 3-aminopropyl-trimethoxysilane. proving that chiral restriction does indeed boost enantioselectivity. It reflects that as the declining influence of the spatial constraints from the inner wall decreases.View Online Scheme 3 Asymmetric hydrogenation of E-a-phenyl cinnamic acid and methyl benzoylformate. 15).95 attached to concave surfaces produces better ee’s than that of the convex or homogeneous catalysts (Fig.rsc. This journal is c The Royal Society of Chemistry 2011 . Using covalent methods similar to those applied in previous immobilisation approaches.104 Through this approach. Non-covalently tethered rhodium catalysts were immobilised in the same way onto mesoporous silica supports that contained a range of different pore apertures.108 solitary amino acids or peptides can be grafted onto amino-functionalised mesoporous silica by solid phase peptide synthesis (SPPS) methodology109 (Fig. the confined. The Rh1(COD)AEP catalyst was immobilized in this way and used again in the industrially-significant hydrogenation of methylbenzoylformate to methyl mandelate. 13).g. Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs. Catal.103 (Scheme 3). 13). 14). with more room available inside the nanospace around the active site.1039/C0CY00088D stereospecificity. Grafting a mixture of 3-aminopropyl and methyl groups to the surface Fig. so does the preference for a particular stereoisomer. First.106 As expected. This theory is established further in the asymmetric hydrogenation of E-a-phenylcinnimic acid and methylbenzoylformate102. Results show95 that.105. 14 Effect of surface curvature on the enantioselectivity of the reaction with a range of pore apertures (left) and a graphical representation (right) to show how the constrained environment imposed by the pore walls facilitates stereoselectivity. a negatively charged counter-ion could be used to attract a metal-cation-containing complex. The material with just the 3-aminopropyl moieties shows a poor hydrothermal stability because the basicity of the functional groups gives rise to the fast hydrolysis of the silica. RhI(COD) metal centres (where COD: 1. The chiral complex Fig.110 The hydrophobic character inside the pores can be adjusted by co-functionalization with other species e. such as (S)-(À)-2aminomethyl-1-ethylpyrrolidine (AEP).

The free N-terminal amine of an already attached peptide chain is coupled to a single N-protected amino acid. for example trifluoroacetic acid. was covalently anchored and coordinated to transition-metal centres via an auto-assembly route. Technol. DIC) (Fig. 17 Synthesis of the HisGlyGlyGlu peptide chain on functionalised silica by SPPS113 (A) and how the peptide link may coordinate to a copper centre to form a metal complex (B). improves hydrothermal stability due to a decreasing basic character inside the pores. in a coupling reaction through the formation of a peptide bond. 15 SPPS method of covalently attaching amino acids to silica. a short peptide motif. mesoporous silica via SPPS and these have shown promising trends in the oxidation of hydrocarbons. with surface bound amide | doi:10. 16). To remove a t-Boc protecting group acidic conditions are used.112 This elegant method was implemented by Pirngruber et al.1039/C0CY00088D Fig.109 This solid phase method is beneficial because the material can be easily recovered by filtration and any unreacted reagents left at the end of the synthetic coupling step can be removed facilely by a washing procedure. basic conditions are used such as piperidine in DMF. SPPS comprises of repeated cycles of coupling and deprotection of successive amino acids. providing a new N-terminal amine to which a further amino acid can be attached. This unit is then deprotected.112 in order to mimic the active core of the enzyme methane mono-oxygenase (MMO). Fig.View Online Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs. Immobilising a short peptide chain rather Catal. To remove Fmoc from a peptide chain.rsc. The main difficulty is preventing the formation of incomplete peptide chains but this can be overcome by capping unreacted surface amino groups and maximising the yield of the coupling steps. There are two main types of activating groups: triazolols (HOBt. HOAt) and carbodiimides (DCC. Activating agents are used when coupling a carboxyl group of an amino acid to make the reaction proceed at a much faster rate. 17) and short peptide complexes with iron and copper have been immobilised on This journal is c Fig. This technique was a major breakthrough allowing the synthesis of peptides and small proteins. It is a common conception that Fmoc chemistry has many advantages over t-Boc chemistry. Fmoc and t-Boc protecting groups. Instead of immobilising single amino acids on porous silica. found in the active site of the enzyme of His-x-x-Glu. in order to mimic the structure of the metalloprotein more closely.111 Amino acids (such as Fe3+–proline that were previously encapsulated within the cages of zeolites using the ‘‘zeolite synthesis method’’ described earlier) can be covalently anchored onto a mesoporous support by the formation of very stable bonds. Each method involves different protection. The Royal Society of Chemistry 2011 . 16 Common activating and protecting groups used in SPPS. A number of amino acids (Fig. deprotection and cleavage steps. Sci. which could be attached to an insoluble support. as it generates peptides of higher quality and in better yield. Two major termini are used in solid phase peptide synthesis.

provides crucial information in identifying the merits of the respective immobilisation strategies. Technol. therefore significantly increasing the metal loading.View Online than single amino acids made it possible to incorporate more coordination sites. First the silica is derivatized. More recently chiral copper proline-derived complexes have been immobilised on mesoporous silica and employed as heterogeneous catalysts in the asymmetric epoxidation of a-b-unsaturated ketones. However. usually with amino functionalities.115 This procedure gives good yield and.113 Studies proved no metal leaching from the bio-derivatized support. In this instance the tether is generated quickly and reliably by joining smaller units together. which makes spectroscopic characterisation difficult. has been used to immobilize proline on hydrophobic supports.118 The covalently anchored copper complex produces conversions in Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs. (%) 88 89 92 89 ee (%) 83 82 83 82 Fig. in fact. 19).1039/C0CY00088D Fig. This journal is c The Royal Society of Chemistry 2011 . because the metal content stayed constant before and after reaction. Making a direct comparison between the catalytic results of the same transition-metal complex (Fe3+–proline) encapsulated within a zeolite framework (using the zeolite synthesis approach that has been outlined earlier) to the one that has been and covalently anchored to the silica in the preceding section.113 The complexes of iron and copper with the covalently anchored HisGlyGlyGlu peptide sequence gave superior activities when compared to iron and copper immobilized on a non-peptide-modified support or one single amino acid derivatized silica. the use of EXAFS along with geometrical constraints allowed for credible structural models of the complexes to be developed. Using the iron– proline complex as a case study in the selective oxidation of benzyl alcohol to benzaldehyde. 18). excess of 85% with greater than 82% ee for a range of substrates (see Table 5) and is also recycled effectively for up to 5 times with marginal loss in yield and no drop in enantioselectivity. | doi:10. 19 Epoxidation of unsaturated ketones using a heterogenised prolinamide copper complex. giving rise to highly effective heterogeneous catalysts.112 The immobilised complexes have also been tested in the oxidation of cyclohexane using hydrogen peroxide as the oxidant to produce cyclohexanol and cyclohexanone. A similar route to immobilization of organic moieties to silica is by using ‘click’ chemistry114 protocols.116 This route for immobilisation on hydrophilic silica provides amino acid derivatised frameworks that can coordinate to transition metal centres (Fig. using H2O2 and triethyl amine as an additive117 (Fig. One problem associated with self-assembly is that mixtures of complexes with varying coordination modes arise. Catal. 18 Immobilisation of amino acids on silica by the ‘click chemistry’ method. Triethyl amine was added to the mixture because a-b-unsaturated ketones require basic conditions in order to achieve impressive conversion and selectivity. This example further illustrates the proof of concept of covalently attaching bio-inspired metal complexes and highlights the impressive selectivities that can be achieved with this novel approach. as can be detected through ICP analysis. tethered by the most popular reaction within click chemistry.4-dione Conv. Additional benefits of improvement in catalytic properties were observed by complexation of the metal-ions to the peptide chain when compared to that of the grafted single amino acids. followed by coordination to transition-metal centres. both methods of immobilisation (zeolite encapsulation versus covalent anchoring to Table 5 Conversion and enantioselectivity of different substrates under optimized conditions using covalently immobilized copper complex117 Substrate Chalcone 4-phenyl-3-buten-2-one Cyclohex-2-enone Naphthalene-1. azide alkyne Huisgen cycloaddition using a Cu catalyst.rsc.

Oxidation reactions. furnishing a less well-defined active site which in turn would produce a lower activity.130 Through spatial constraints. The range of substrates and scope of reactions that can be catalysed by heterogenised amino acids and their derivatives (Fig. This can be accredited to the more robust and stable immobilization procedure that the covalent attachment strategy to the silica surface imparts. can also individually act as organocatalysts. cysteine or amino acid derived organocatalysts could be covalently anchored to the inner walls of mesoporous silica. by as much as 80% when TBHP is used as the oxidant. Diffusion rates of substrate molecules to the active centre and products on entering and leaving the porous support also play a decisive role in determining the activity of the catalyst.123 Michael Reactions124 and a-functionalisation of carbonyl compounds. These materials have shown promise as heterogeneous organocatalysts for industrial significant reactions. The pore apertures of the microporous zeolite encapsulated iron–proline complex are far smaller than the mesopores of silica. because of the chemical bonds that restrain the immobilized complex to a definite space. 21) by building on current methodologies that are reported in the literature. between the support and the amino acid at a molecular level.129 Tethering is carried out through the side-chain or a functionalized side-chain of a derivatised amino acid and not through a SPPS technique (described earlier). Judiciously controlling the orientation of the channels and the pore-diameter of the mesoporous support could facilitate enhancements in the desired stereochemical outcome. Sci. selective single-site heterogeneous catalysts. Within the zeolite architecture.View Online New directions and scope in heterogeneous organocatalysis Among the many applications and varying substrates that can be oxidised or transformed by these bio-derived catalysts immobilised on silica.1039/C0CY00088D Fig. dimerise and therefore deactivate. Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs. mesoporous silica) increase the activity of the catalyst as observed by the improvement of turnover numbers (TON’s) in comparison to the corresponding homogeneous analogue (Fig. because the mechanism of catalysis relies on the amino and carboxylate groups to be free for substrate binding. as the degree of hydrophilicity and hydrophobicity is significantly altered. The potential for expanding the scope and industrial applicability of heterogenised organocatalysts demands a greater understanding of the synergistic effects. the heterogenised amino acids (on their own). similar to that described earlier for the immobilisation of transition-metal amino acid complexes. In recent years amino acids. Organocatalysis has become a prominent facet in some of the most indispensable fundamental transformations in organic chemistry.125 Using a rationale. such as the direct asymmetric aldol reaction. amino acids with functional side chains that can react with tethering silanes such as lysine. A potential hurdle associated with acquiring this knowledge-base is the lack of spectroscopic handles an organic moiety has Catal. use far less mol% of catalyst and potentially give rise to significant improvements in activity and selectivity. Organocatalysts can be covalently anchored to mesoporous silica (Fig. via the pendant silanol groups of the mesoporous silica. such as the Hajos–Parrish–Eder–Sauer–Wiechert reaction126. glutamic | doi:10. displaying high activities and selectivities in some of the most demanding and fundamental organic transformations.127 and intramolecular [4+2] cycloadditions. which could provide valuable insights on structure– property relationships and its mechanistic significance.rsc. as TON’s are significantly enhanced compared to the zeolite-encapsulated analogue.128 This approach has the potential to improve recoverability and recyclability. as observed earlier with anchored transition-metal amino acid complexes. therefore reactants and products will be impeded to a greater extent on gaining access to and departing from the active site. which rely on the use of aqueous oxidants such as hydrogen peroxide or acetyl peroxyborate (APB). which can be attributable to the exceptional stereoselectivity that can be achieved.121. arginine. The structure–property differences of the supports additionally affect the catalytic turnover. 20 Improvements in TON’s for benzyl alcohol oxidation on immobilisation of Fe3+–proline complex in zeolite X and further enhancements on covalent attachment to mesoporous silica. 22) is ever expanding131 and immobilisation of these organic moieties could result in the design and development of more stable. highly active. Technol. the active centres are less likely to aggregate. The catalyst anchored on mesoporous silica also exists as a more isolated single-site entity.122 Mannich reactions. more than one complex could be potentially be encapsulated in each cage. This journal is c The Royal Society of Chemistry 2011 . have been used to catalyse essential transformations used in the fine chemical and pharmaceutical industries.120 depend upon a fine balance of hydrophilic/ hydrophobic interactions. which are not coordinated to the transition-metal centres. 20).119. especially that of L-proline. The improvement is far more apparent in the case of the covalent anchoring of the metal complex to mesoporous silica. With the catalyst chemically bound to the mesoporous silica surface via covalent bonds. nature of the active site and a precise balance of substrate–catalyst–pore wall interactions. the stereoselectivity of the catalytic reaction could also be suitably enhanced.

with only a small minority of them being subject to the stringent tests that are required for development at an industrial scale. Fig. as well as revealing of the breadth and scope of what can be achieved in the near future. But. in situ characterisation techniques and a more detailed and fundamental understanding of the nature of the active centre and its mechanistic significance in the catalytic process are less well-understood that impede the implementation of bio-inspired heterogeneous catalysts in industry. 21 Rationale (A) and generalised strategy (B) for derivatizing (tethering) an amino acid through the side chain or functionalised side chain. there are evidentially a number of limitations associated with such catalysts and immobilisation procedures. Nevertheless. 22 Examples of applications with immobilised amino acids such as lysine that act as enamine catalysts.1039/C0CY00088D Fig. Sci. benefits of the synthesis methodologies. several techniques are surface sensitive and are therefore ineffective if the organocatalyst is encapsulated within the host. In addition. solid-state methods of characterisation such as MAS NMR and FT-IR are able to provide some meaningful insights into the nature of the active-site. in reality. in order to highlight the pioneering routes to heterogenisation. this reduces the number of spectroscopic techniques that are available at one’s disposal for in-depth characterisation with a view to elucidating the nature of the active site. yet questions still linger on their stability. in-depth. Specific approach employing L-lysine (C) as an exemplar amino acid. It must be noted that immobilisation of a homogeneous catalyst on to a support has a number of This journal is c The Royal Society of Chemistry 2011 . We have emphasised earlier the importance and Catal. Since there is no metal present and the bulk of material is the support. Technol.View Online Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs.125 when attached on to an inorganic support. In light of the numerous advantages highlighted over the course of this | doi:10.rsc. These catalysts have shown promising results in laboratory-based environments.

high-throughput experimentation and molecular modelling. in intricately designed reaction cells. in Catal. but it would be sensible to assume that some of these factors are due to unfavourable effects of the support. the nature of active-sites and the coordination geometry in their immediate vicinity can be quantified to elucidate the catalytic significance of the results.139 Being able to establish structures at interfaces with atomic scale resolution may one day be applied and advanced to more complex structures. Downloaded on 30 March 2011 Published on 11 March 2011 on http://pubs. which provides valuable insights for a better understanding of the rate and energetic interactions associated with these catalytic processes. substrate selection.22.View Online constraints at present. With a greater understanding of the thermodynamic parameters. which ironically are the very same factors that are responsible for boosting catalytic properties. preliminary investigations into structure–activity correlations have been acquired by recent advances in spectroscopy. This also facilitates the calculation of binding energies and transition states. By building on results obtained with IR. which in the near future could elucidate reaction mechanisms on catalytic surfaces. There is a lacuna in the field with respect to modelling kinetic and thermodynamic data for predicting diffusion limitations and reaction pathways. Through spatially-resolved methods of detection of the chemical structure and temperature133 and using a combination of complementary techniques such as UV-Vis/Raman and FT-IR/ED-EXAFS. further improves the quality of information obtained and affords a greater knowledge about the investigated system. The activity of an anchored catalyst in a porous host often depends on diffusion of solvent and substrate molecules. spatially resolved fashion. will play an important role. for studying changes in oxidation states. Technol. This can be achieved by performing a range of kinetic studies. activity and selectivity were | doi:10. from a more fundamental perspective.145–150 By using the above advances concurrently. it should be possible to develop structure–activity correlations relating to bio-inspired systems.135 which provides detailed insights into the working principles of the heterogeneous catalytic system. in single-site heterogeneous catalysts. Sci. encapsulated or bio-inspired catalysts need to explicitly identify the individual steps in a catalytic process at a molecular level.142. UV-Vis. by establishing the exact nature of different types of active sites and in what ways the geometry of the metal or ligand affects the ensuing catalysis. By combining recent advances in spectroscopy and operando techniques along with theoretical calculations and computational modelling. by providing a particular catalyst environment and controlling the hydrophilicity of the support. conformational flexibility of the ligands. hydrophilicity/hydrophobicity. from a spectroscopic and computational viewpoint. with a view to understanding the overall mechanism of the reaction. Being able to recognize the relationship between the support and the active site can lead to optimisation strategies for catalytic processes.138. for building a complete reaction profile. presence of surface modifiers.143 thereby presenting information that can be rationally applied to the development of new strategies for designing new catalysts or optimising existing ones. an explicit understanding of why heterogenisation improves catalysis in some cases and not in others has still not fully been explored.144 Theoretical ab initio calculations could also be performed to model the active site.151 All of these techniques outlined above can provide valuable insights for correlating experimental observations with theoretical predictions. but currently the extent of each factor has not been quantified and. such as to observe catalyst environments and conformations on analogous surfaces.132 Through in-depth characterisation. NMR and X-ray absorption spectroscopy (EXAFS and XANES). DFT orientated approaches that are tailored to the design of new immobilised. providing further insights into the interactions between the transition-metal and other substituents that make up the framework. BET. how it can be altered and what repercussions this would have if suitably modified. The key to understanding the influence of the support on catalysis. SEM/TEM. EPR. in situ measurements using appropriate probe molecules need to be suitably deployed. the nature of the active site.134 Multiple technique operando set-ups render the measurement of spectra in a time-resolved. Zewail140 has described 4D electron microscopy as having the potential to decipher the fundamental forces of complex structures. framework topology. is 4D electron microscopy. the possibility of being able to design better catalysts with a view to predicting structure–property relationships may be a distant realisation.137 The powerful focusing capabilities of electrons allow structures to be resolved down to the atomic scale and the technique has been used to This journal is c directly determine the structure and dynamics of substrates on hydrophilic supports. dispersion and measure of active-sites. under in situ conditions. The influence of support type.1039/C0CY00088D The Royal Society of Chemistry 2011 . which could potentially reveal the key steps that may require improvement from a design perspective.141 which further demonstrates the valuable role theoretical chemical tools offer in the studies of inorganic frameworks such as zeolites. Ultimately.23 Characterising the nature of the active site is imperative in being able to optimise catalysis as well as predict catalytic outcomes. Using these connections made it viable to maximise the activity of the Ti-catalyst. kinetic modelling studies can be undertaken with a view to studying the effects of bifunctional and multifunctional active sites. information on the roles of different catalyst variables were uncovered. space-resolved profiling and combining high-throughout experimentation with data modelling. diffusion and adsorption all play important roles. with a view to identifying the rate-determining step and the overall limitations within a reaction.136. However. Density Functional Theory (DFT) can elucidate the properties of a support and therefore postulate the potential implications it can have on a catalytic reaction.rsc. An example of this is the epoxidation of bulky olefins and methyl oleate by porous titanosilicates. as long as this remains the case. such as the catalytic properties of heterogeneous nanoparticles or in phase transitions. Associations of the properties of the support silicate. local coordination environment and emergence of transition-states. Another technique currently being pioneered. The reasons for inhibiting catalysis are unclear. by calculating energy barriers and the stability of the intermediates. There is scope for quantifying the support characteristics such as acidity and reactivity. Moreover. its interactions with the support or framework and its ability to facilitate synergistic enhancements in catalytic potential can be more quantitatively rationalised.

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