FOCUS REVIEW DOI: 10.1002/asia.201402682

Chirality in Ordered Porous Organosilica Hybrid Materials Michael W. A. MacLean,[a] Lacey M. Reid,[a] Xiaowei Wu,[a] and Cathleen M. Crudden*[a, b]

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Abstract: The ever-growing demand for chiral small molecules on a global scale has set a precedent for the proliferation of cost-effective and reliable methods for their synthesis and separation. Of these methods, those based on heterogeneous platforms present an unparalleled opportunity as they allow for the source of the chirality to be recycled. Chiral hybrid organosilica materials are one particularly interesting class of chiral heterogeneous platforms that creates a synergy between well-understood individual chiral molecules and the structural stability and inertness of the inorganic silicon scaffolds. This Focus Review summarizes the recent advances towards the incorporation of chirality into organosilica scaffolds, the synthesis of the chiral building blocks, and their promising applications towards facilitating asymmetric heterogeneous catalysis as well as chiral chromatography. Keywords: asymmetric catalysis · chirality · enantioselectivity · heterogeneous catalysis · mesoporous materials

Introduction

than the transition metal it modifies. As such, the drive to find effective recoverable chiral ligands is significant.[9a] In many instances, chiral chromatography is employed to quickly separate molecules to be tested, for example, for bioactivity rather than generating enantioenriched compounds by means of complex synthetic schemes. Thus the need for novel chiral separation systems is also paramount. There have been many reports and reviews that describe the immobilization of chiral sites onto pre-existing supports through adsorption or encapsulation to create a heterogeneous platform.[9b, 10] For example, Thomas, Johnson, and coworkers have shown that the ability of the chiral moiety to transfer chirality is enhanced when the catalytic site is constrained within a pore.[11] The proposed rationale for this effect is shown schematically in Figure 1a wherein the close proximity of the substrate, catalytic center, and chiral directing group create interactions that would enable only specific spatial interactions that result in higher selectivity.[11] This concept was realized with the allylic amination of cinnamyl acetate 1 (Figure 1b) with benzylamine 2 by a porous silicasupported 1,1’-bis(diphenylphosphino)ferrocene ligand to give 50 % yield of the branched isomer 3 with 99 % ee, whereas comparable homogeneous systems produce only the linear isomer.[12] A less frequently employed approach involves the creation of supports that are chiral in their own right, which allows the transformations to occur in a chiral environment. This includes the catalytic di-p-methane rearrangement of 11-formyl-12-methyldibenzobarrelene (4) to dibenzosemibullvalene (5; Figure 1c) that only occurs with selectivity when the reaction is performed inside the pores of a chiral host.[13] A large variety of chiral heterogeneous systems have been described, including polymers made with chiral monomers,[14] metal surfaces modified by chiral organic compounds,[15] metal–organic frameworks (MOFs) in which chiral groups have been incorporated into the struts of the framework,[16] and organosilica hybrid materials made from chiral siloxane precursors.[10c, 17] Organosilica hybrids benefit from the support and stability provided by purely inorganic materials along with the functionality (in this case chirality)

Since vant Hoffs first report of the relationship between chirality and structure,[1] and subsequent realizations of its importance to living organisms,[2] chemists have been developing methods to facilitate the desymmetrization of molecules and the separation of enantiomers.[3] The primary importance of such molecules is in the pharmaceutical industry,[4] as evidenced by the fact that all but two of the top 25 best-selling drugs of 2013 possess some form of chirality.[4, 5] Therefore the development of new ways to create molecules in an asymmetric fashion as well as new ways to facilitate their separation is of clear interest to the chemical community. The use of chiral auxiliaries to desymmetrize prochiral molecules has been both well understood and effective; however, it requires stoichiometric amounts of the chiral auxiliary.[6] This decreases the carbon efficiency of the synthesis while adding additional steps, which is ultimately undesirable.[6] A much more valuable approach is to employ transformations that generate one enantiomer from a prochiral or achiral starting material.[7] In the most successful of these methods, the chirality is conveyed by a chiral catalyst.[8] The large majority of enantioselective catalysts are homogeneous, despite the many advantages of heterogeneous systems, since rational design in heterogeneous systems is still very difficult.[9] Of critical importance are materials such as those described herein, which show chirality based on well-defined molecular species included in a recoverable support. Interestingly, in many enantioselective metal-catalyzed reactions, the chiral ligand is even more expensive [a] M. W. A. MacLean, L. M. Reid, Dr. X. Wu, Prof. C. M. Crudden Department of Chemistry, Queens University 90 Bader Lane, Kingston, Ontario, K7L3N6 (Canada) Fax: (+ 1) 613-533-6669 E-mail: [email protected] [b] Prof. C. M. Crudden Institute of Transformative Bio-Molecules (WPI-ITbM) Nagoya University, Chikusa, Nagoya, 464-8602 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201402682.

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that is introduced by means of the organic component. These unique materials are the subject of this review. Common methods for preparing organosilica hybrids for chiral applications are shown schematically in Figure 2.[10a, h, 17] The simplest method for preparing chiral orga-

Cathleen M. Crudden et al.

nosilica materials is grafting chiral functional groups that bear a condensable silane onto a preformed porous silica species (Figure 2a).[10a] This is an effective and quick way to generate functional materials; however, the amount of organic component that is incorporated is typically limited to

Michael MacLean completed his Honors BSc in Organic Chemistry at the University of New Brunswick in 2010, and shortly thereafter began his doctoral studies in the Crudden group at Queens University. His doctoral research focuses on the transmission of chirality through organosilica supports with the emphasis on the design and synthesis of the siloxane precursors.

Lacey Reid obtained her undergraduate degree in Chemistry and Biochemistry from Acadia University, Nova Scotia, Canada, in 2010. She started her masters research under the supervision of Prof. Cathleen Crudden at Queens University, and transferred into the chemistry PhD program in 2012. Her research focuses on the synthesis, characterization, and applications of chiral periodic mesoporous organosilica materials.

Xiaowei Wu completed her honors PhD in Materials Science at Shanghai Jiaotong University in 2008, and shortly thereafter began her postdoctoral fellowship in the Crudden group at Queens University. Her research focuses on the synthesis of chiral organosilica porous materials with an emphasis on chiral induction through introducing small amount of chiral siloxane precursors or chiral co-structure directing agents.

Cathleen Crudden obtained her BSc and MSc at the University of Toronto and her PhD at Ottawa University. After a brief stint in Japan in the labs of Shinji Murai and a postdoctoral fellowship with Scott Denmark at the University of Illinois, she began her independent career at the University of New Brunswick. In 2002 she moved to Queens University as a Queens National Scholar and currently maintains an active group at Queens in the areas of catalysis and materials. She is also cross-appointed at the Institute of Transformative Bio-Molecules associated with Nagoya University in Nagoya, Japan.

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Figure 1. a) Confinement effect in porous supports. b) Confinement principle applied to the allylic amination reaction between cinnamyl acetate and benzylamine. c) Di-p-methane rearrangement inside of a chiral support. Adapted with permission from Ref. [13]. Copyright 2005 American Chemical Society.

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Figure 2. Approaches to chiral organosilicas. a) Monofunctional chiral precursor grafted on preformed silica. b) Monofunctional chiral precursor incorporated during silica condensation. c) Bifunctional chiral precursor incorporated during silica condensation with a structure-directing agent leading to chiral periodic mesoporous organosilicas. d) Bifunctional chiral precursor incorporated during silica condensation but without structure-directing agents leading to xerogels.

smaller loadings, as pores become blocked at higher loadings. In addition, the chiral monomer is likely to be incorporated in a nonuniform manner, potentially with islands of high concentration and, similarly, areas of low concentration.[10h] More uniform incorporation is typically achieved when the siloxane precursor is added during the polycondensation process, in which an inorganic silica precursor is present along with a structure-directing agent (SDA), such as a surfactant or block copolymer. These agents combine to produce materials with chiral organosilica units spaced throughout the pores (Figure 2b).[10h] Unfortunately, the loading of the chiral component still remains limited to less than 25 %, since at higher loadings, the loss of bifunctional building blocks decreases the structural integrity of the material.[10h] The use of precursors with more than one condensable silane allows for the production of materials that can contain up to 100 % of the chiral organic species (Figure 2c, d).[10c, 17] More importantly, under these conditions, the chiral monomer can affect the structure of the bulk material. When SDAs are present during the polycondensation process, the resulting composites are porous and can be periodically ordered. These are often referred to as periodic mesoporous organosilicas (PMOs; Figure 2c).[10h] In instances in which the organosilicas are allowed to self-assemble without the assistance of a SDA, the resulting materials often show limited porosity and order; these are called xerogels (Figure 2d). Many interesting chiral xerogels have been prepared; however, owing to space limitations, these will not be explored further within this Focus Review.[17, 18]

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In principal, any precursor that bears two or more condensable silanes is able to undergo the templating process described above. In practice, however, siloxane precursors bridged by large flexible organic groups typically produce poor-quality materials on their own.[19] This has the important implication that many of the privileged chiral compounds used in homogeneous asymmetric systems will not be able to form “true” PMOs, that is, materials made solely of condensable organic silanes with good order and high porosity. As an alternative strategy, varying amounts of an additional condensable silane can be added as a structural component (Scheme 1) to improve the physical properties

Scheme 1. Structural supports used to enhance materials properties.

of the resulting organosilica material. When chosen properly, the added structural component should not have profound effects on the chirality or integrity of the materials, although this does diminish the chiral loading in the materials. Although this is not necessarily ideal, it is often unavoidable in the production of materials comprised of larger chiral

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atropisomers.[23, 24] This family of molecules is most well known for the 2,2’-diphosphane derivative (2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (BINAP), 9), used in asymmetric transition-metal catalysis, for which the Nobel Prize was awarded in 2001.[8, 24b] The alcohol analogue of BINAP (1,1’-bi-2-naphthol (BINOL), 6) is readily available in its enantiomerically pure form and has been effectively used both as an enantioselective catalyst[25] and a chiral dopant for the transfer of chirality to liquid crystals.[26] In one interesting example, BINOL was used to facilitate the production of helical conjugated polymers.[26a, c] Siloxane derivatives of this 1,1’-binaphthalene unit are represented by building blocks 13–19 in Scheme 3,[19, 27] and materials prepared from these monomers have been used in catalytic[27a–d, g, h] as well as chromatographic[19b] applications, which will be explored in further detail below. Garcia and co-workers reported the first of this family of surfactant-templated organosilicas in 2004 using siloxane precursor 13 with up to nine parts tetramethoxysilane (TMOS).[19a] The chirality in the resulting materials was observed by measuring the optical activity of their suspensions in solvent. The materials also showed different fluorescence enhancement effects for the enantiomers of 1,2-cyclohexyldiamine (7), thus indicating that some chiral recognition was observed.[19a] Crudden and co-workers reported the production of organosilicas with siloxane precursor 18, which featured the attachment of the siloxane source directly to the binaphthalene backbone in mixed-component materials to give organosilicas with ultra small mesopores when 1,4-bis(triethoxysilyl)benzene (BTEB) was used as the bulk silica source.[27e] In this case, the observation of twisted structures by scanning electron microscopy (Figure 3) that were correlated to the amount of chiral dopant provided evidence of

constituents. In this Focus Review we will focus on ordered, surfactant-templated porous materials in which a portion of the structural component can be considered to be made from chiral-bridged siloxane precursors, with particular emphasis on the creation of chirality in the support, the production of the chiral building blocks that form the support, as well as the use of chiral supports to facilitate asymmetric catalysis and enantioselective separations to help to meet the ever-growing demand for chiral molecules on a global scale.

1. Sources of Chirality in Ordered Materials To generate supports that are inherently chiral, the method of incorporating chirality is critical. In most instances this is achieved by the use of chiral siloxane precursors as building blocks in the construction of chiral materials (Figure 2c).[10c] It is also possible to create a chiral material through the chiral modification of an achiral chemical handle[10h, 20] or by chirality transfer in the solid state from a chiral dopant.[21] In all of these cases, some method must be used to assess the chirality of the resulting materials. As the solids are not transparent, and most methods for determination of chirality rely on selective absorption of light, new methods have been developed in many cases.[20b, 22] 1.1. Chiral Building Blocks As the field of asymmetric catalysis began to develop in the decades since the discovery of chirality, many different chiral structures have been used to transfer the chirality to the substrate. Although many of these are successful to some degree, there are families of molecules that perform much better than their counterparts; such molecules can be said to possess “privileged” structures in terms of chirality transfer. Selected examples of these are shown in Scheme 2. One such family of molecules is those based on derivatives of 1,1’-binaphthalene. These molecules are interesting in that chirality is centered about an axis rather than an atom. These so-called “axially chiral” molecules feature a high energy barrier for rotation about the central naphthyl–naphthyl bond that results in the existence of two resolvable

Figure 3. Dopant-dependent chiral organosilicas with helical morphology. Two left panels show the morphology obtained without the addition of chiral monomer (top = SEM, bottom = TEM) and the two right panels show increases in helical morphology when 21% of the chiral dopant is included (top = SEM, bottom = TEM).

Scheme 2. “Privileged” structures for chirality transfer in homogeneous systems.

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Scheme 3. Chiral siloxane precursors used to make chiral organosilicas.

chirality transfer. Subsequently, Crudden, Lemieux, and coworkers used 18 with BTEBp to make materials for which mixing small quantities of the organosilica with a prochiral nematic liquid crystal led to chirality transfer to the liquid crystals.[27f] Interestingly, the amount of the chiral material added to the liquid crystal had an effect on the twisting of the bulk liquid crystal.[27f] Another family of molecules that possesses a “privileged” structure with regards to chirality transfer are those based on trans-1,2-diaminocyclohexane 7. These structures have been incorporated into chiral ligands that have been employed in a host of enantioselective transformations, including asymmetric hydrogenation and C C bond-forming reactions.[28] As a result, diamino-bridged siloxane precursors are among the most commonly employed chiral building blocks for the formation of chiral organosilicas.[13, 29] The first reports by Corma and co-workers used a 2,2’-ethylenebis(nitrilomethylidene)diphenol (salen) derivative,[29a, b] whereas, more recently materials have been made from siloxane precursor 11.[29c, d] These materials will be revisited in regards to their catalytic behavior below. Cyclohexadiamine-bridged organosilicas have also been employed as chromatographic supports by using building block 12 to facilitate the enantioseparation of BINOL derivatives as will also be described below.[29e, f] Other noteworthy chiral siloxane precursors that have been reported for the formation of chiral organosilicas include 20,[22c] 21, and 24,[22b, 30] all of which are characterized by atom-centered chirality at a benzyl position. In one of the most thorough studies of chiral mesoporous materials to

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date, Inagaki, Shimada, and co-workers prepared PMOs with building block 20 under a variety of conditions.[22c] They then dissolved the silica polymers with fluoride to permit analysis of the chirality of the building blocks after incorporation into the materials. Interestingly, materials formed under acidic conditions resulted in microporous materials with high retention of chirality, whereas those formed under alkaline conditions gave well-ordered materials (with inclusion of 1.5 parts BTEB) but with complete racemization of chirality of the incorporated monomer units.[22c] Although the materials lost chirality, the method of examination of the chirality sets a high standard for the field. Frçba and co-workers also described a chiral PMO using organosilica monomers with benzylic stereocenters; however, their monomer (21) featured the siloxane attachment points on the aryl backbone, rather than directly on the chiral center as in the Ingaki/Shimada et al. materials.[22b] This approach led to a chiral ordered organosilica under acidic conditions that was porous without loss of chirality, as determined by measuring the specific optical activity of the chiral materials versus the monomer at varying concentrations.[22b] This is a very interesting approach that provides rigor to the analysis and is nondestructive. Polarz and coworkers reported materials made from the related 1,3,5,substituted benzyl alcohol-bridged siloxane precursor 24, for which the chirality was assessed by means of circular dichroism (CD) spectroscopy. The materials were tested in the catalytic enantioselective reduction of ketones, which will be discussed below.[30]

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Norbornane-bridged siloxane precursor 26 possesses a similar skeleton to the common chiral auxiliary camphor and contains four stereocenters.[31] Wang and co-workers created chiral organosilicas using this building block in 2010[31a] and again in 2012 with control of the mesostructure that gave rise to a chiral organosilicas with a variety of different morphologies. Dissolution of the silica framework and subsequent analysis of the organic component revealed that no racemization of the chiral component had occurred.[31b] Remarkably, given the amount of chirality in biological systems, biologically inspired siloxane precursors are relatively unusual; tartaric acid derivative 22,[32] and manitol derivative 23 are rare examples.[20a] Li, Yang, and co-workers created a tartardiamide-bridged organosilica from precursor 22, and the resulting materials were assessed for their catalytic performance in enantioselective oxidations.[32] The mannitol-bridged organosilica prepared from precursor 23 reported by Mehdi and co-workers was used as a host to stabilize gold nanoparticles that could be synthesized within the pores of materials.[20a] Other noteworthy biologically inspired materials based on amino acids have been prepared independently by Polarz et al.[20b] and Froba et al.,[33] albeit through a post-modification approach that will be discussed next. 1.2. Chiral Modification of Ordered Organosilicas An alternative approach to the generation of chiral organosilicas from chiral monomers involves the introduction of an achiral siloxane precursor with a chemical handle that can be functionalized to introduce chirality after the polycondensation has occurred. This method has clear advantages in that the (usually costly) chiral moiety does not need to be employed during the polycondensation process, which can be low yielding; and furthermore, by spacing the functionality over the materials, agglomeration of the chirality at the pore surface can be avoided.[10h, 20] In addition, since the materials synthesis conditions are typically harsh, this approach permits the incorporation of a wider variety of chiral subunits with more sensitive or complex functionality. Examples of this type of chiral material are shown in Scheme 4 and include OS2 and OS4.[20b, 33] The first report of this method was described in 2008 by Polarz and co-workers, who employed the carboxylic acid functionalized organosilica OS1, which was condensed with chiral amines to form OS2.[20b] This was applied to the methyl ester of the amino acid alanine as well as an alanine asparagine dipeptide. The resulting materials showed similar 13C magic-angle spinning (MAS) NMR spectra to those of materials produced through an analogous method in which alanine was attached and characterized prior to the polycondensation to form the organosilica. In an innovative assessment of chirality, measurement of the differential rates of adsorption of the two enantiomers of propylene oxide was employed. As shown in Figure 4, this represents the only example in which a chiral gas has been used to probe the chirality of an organosilica material.[20b]

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Scheme 4. Post-modification routes to chiral organosilicas.

Figure 4. Top: Adsorption of the two enantiomers of propylene oxide on the chiral surfaces of the OS2 material. Bottom: Adsorption data recorded at T = 313.15 K. R enantiomer: red; S enantiomer: blue. Reproduced with permission from Ref. [20b]. Copyright 2008 Wiley-VCH.

More recently, Frçba and co-workers prepared organosilica OS3 with amine functionality capable of forming peptides

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within the pores.[33] This concept was demonstrated using Nprotected alanine to facilitate the production of OS4 with a chiral amine in the pore walls following deprotection. Thus, it is possible to envisage the addition of subsequent amino acids by means of a deprotection–condensation approach, similar to that employed in solid-phase peptide synthesis.[33] Chiral organosilicas have also been produced that are functionalized in a subsequent step, as in OS6, which is formed from chiral boronic acid functionalized organosilica OS5, reported by Polarz and co-workers in 2006.[34] Although a quantitative assessment of the chiral precursor was not performed, the transformation of a boronic ester to an alcohol is known to proceed with retention of stereochemistry. However, the chirality transfer to the resulting organosilica was not determined.[34] The attachment of the chiral unit to the siloxane precursor can also be carried in a one-pot procedure. This was demonstrated with organosilica OS8 reported by Garcia and co-workers, who found that materials produced in this way had a more uniform distribution of chiral units throughout the material. A similar approach can also be used to incorporate BINOL-based precursor 15 in situ.[35]

unit to permit the introduction of an amine or halide (Scheme 7).[27a, d] In instances in which a flexible tether to the walls of the material is not problematic, reaction of an aminated substrate with 29 is a facile route to the desired siloxane precursor (Scheme 7, top).[27a] When a more rigid structure is desired, the silane can be attached through cross-cou-

1.3. Chiral Induction

Scheme 5. Chirality transfer from chiral dopant 27 to bulk-phase BTEBp.

All of the previously described approaches focus on molecular-scale chirality through the incorporation of building blocks in the walls of the materials. One fundamentally different approach involves the production of materials with a prochiral monomer, such as the molecule BTEBp, which is chiral; however, it cannot be resolved into its two enantiomers as the rotation about its central bond occurs too readily at ambient temperature. BTEBp, however, has been incorporated into organosilica materials that contain one enantiomer of a resolvable chiral dopant such as monomer 27.[21] This provides the possibility of chirality transfer from the resolvable chiral dopant to the prochiral biphenyl bulk to create chirality in the walls of the organosilica using only a small amount of the chiral component. Crudden and coworkers first reported this in 2008, in which the chirality transfer was assessed by circular dichroism (Scheme 5).[21]

Scheme 6. Direct functionalization of chiral molecules to produce siloxane precursors.

2. Synthesis of Chiral Building Blocks Although the aforementioned chiral building blocks can be quite complex, in many cases the initial source of chirality is commercially available, as in siloxane precursors 11–19, 22, and 23. The siloxane functional group is then attached directly through either an N-alkylation (Scheme 6, top)[29d] or the formation of a ureyl linkage by condensation with 3-isocyanatopropyl triethoxysilane (29; Scheme 6, bottom).[13] In some cases, the chiral source needs to be modified prior to introduction of the siloxane

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Scheme 7. Installation of a chemical handle prior to silicon attachment.

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Scheme 8. Silicon attachment to prochiral molecules.

pling strategies such as Heck[18a] or Masuda cross-couplings (16–18)[27d] (Scheme 7, bottom). An alternative route for the creation of chiral silane building blocks involves the introduction of chirality during attachment of the condensable silane. This can be seen in siloxane precursors 20 and 26, which are both derived from the asymmetric hydrosilylation of prochiral olefins.[22c, 31a] The key reaction is shown in Scheme 8 in which norbornene 34 is converted into chiral organosilane 35 by enantioselective hydrosilylation. Simple reaction with methanol gives rise to the siloxane precursor 26.[31a]

Scheme 9. Desymmetrization of prochiral siloxane precursors.

The desymmetrization of prochiral siloxane precursors can also give rise to building blocks for chiral organosilicas. One example is analogous to the hydrosilylation approach and involves the asymmetric hydroboration of 1,2-bis(trimethoxysilyl)ethylene (37) to give 38, the sol–gel precursor to organosilica OS5 (Scheme 9, top).[34] Siloxane precursor 24 was formed through asymmetric reduction of the prochiral ketone 40 (Scheme 9, bottom).[34]

Scheme 10. Materials used to catalyze asymmetric catalysis in ordered organosilica materials.

gands.[9b, 10c] The utility of these organosilicas for heterogeneous catalysis stems jointly from their high stability under a multitude of reaction conditions, as well as their recyclability (potentially conserving both the chiral source and the metal).[36] Ordered organosilica materials are particularly interesting for the heterogenization of catalytically active sites because the mesopores of the materials, in addition to allowing facile diffusion, have the potential to introduce size or shape selectivity to catalytic reactions[10e] while additionally providing the opportunity to tune the hydrophobicity within the pore.[36] A variety of organosilica materials (Scheme 10) have been employed in enantioselective transformations.[10c]

3. Asymmetric Catalysis with Ordered Organosilicas Unsurprisingly, the proliferation of methodologies for the manufacture of chiral hybrid organosilicas has resulted in their implementation as heterogeneous catalysts or li-

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Often several steps were needed to prepare the chiral site in the material prior to its use in catalysis. This is the case in organosilicas OS9 and OS11, which were prepared with protecting groups on the oxygen atoms that were cleaved to make the alcohols available for catalysis after condensation.[27b, 35a] Compounds OS17 and OS18 were prepared by a change in the oxidation state of the phosphorous post-condensation step.[27a, d] As mentioned previously, some of the more “privileged” structures in terms of chirality transfer are too large to form well-ordered materials on their own and thus require additional structural supports (Scheme 1). The materials shown in Figure 2 have been used in three classes of transformations: enantioselective oxidations, asymmetric additions to aldehydes and ketones, and the formation of carbon–carbon bonds in an enantioselective manner.

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ligand in the walls of the materials and comparable selectivity, yet lower yields were obtained for recycled materials.[27b] The diminution of enantioselectivity in the organosilica systems that employ alcohol-based ligands can likely be attributed to interactions between the active metal species and silanols present on the surface of the materials. In some cases, steps can be taken to minimize this effect by attaching TMS groups to the surface silanols; however, it is exceptionally difficult to remove all silanols by capping.[39] The epoxidation of olefins is another reaction that has been performed using chiral organosilicas.[10g, 32] Yang, Li, and co-workers used tartrate-based organosilica OS10 to catalyze the asymmetric epoxidation of allyl alcohol [Eq. (2)] albeit with moderate conversion and low enantioselectivity.[32] In this case, MCM-41 post-grafted materials showed comparable yield with much higher enantioselectivity [Eq. (2)].[10g]

3.1. Enantioselective Oxidation Reactions One of the classical methods for asymmetric oxidation employs TiIV and chiral bidentate diol ligands, including tartrate and BINOL-based systems.[37] These have been explored using organosilicas OS9–OS11, in the asymmetric oxidation of sulfides as well as the asymmetric epoxidation of allylic alcohols [Table 1, Eqs. (1) and (2), respectively].[27b, 32, 35a] Table 1. Enantioselective oxidation of sulfides.

Entry 1 2 3 4 5 6

3.2. Additions to Aldehydes and Ketones

Organosilica

Yield [%]

ee [%]

OS9 (in situ) OS9 OS9 (grafted) l-diisopropyltartrate OS11 (uniform) OS11

47 35 35 92 58 41

50[35a] 40[35a] 2[38] 94[35b] 42[27b] 15[27b]

The reactions of unsymmetrical ketones and aldehydes with nucleophiles and reducing agents have been studied extensively with heterogeneous chiral ligands. In one of the first examples, salen-based OS12 was employed in the vanadiumcatalyzed cyanosilylation of benzaldehyde [Eq. (3)].[29a] However, the organosilica fared worse relative to the grafted analogues.[29a]

Garcia and co-workers have described several examples of catalytically active chiral organosilicas such as OS9 that can be employed for the asymmetric oxidation of sulfides (Table 1, entries 1 and 2).[35, 38] Through optimization of the organosilica in terms of catalytic activity and selectivity, Garcia and co-workers found that organosilica materials performed better than their grafted counterparts (Table 1, entry 3),[38] ; however, they did not perform as well as homogeneous systems (Table 1, entry 4).[35b] Interestingly, organosilicas in which the tartrate component was incorporated during the polycondensation performed better than analogues prepared over multiple steps (Table 1, entries 1 and 2, respectively). This was attributed to a more uniform distribution of the catalytic sites. More recently, these systems have been expanded using an analogous BINOL-based organosilica OS11 (Table 1, entries 5 and 6).[27b] Once again the catalyst benefited from an even distribution of the

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The most well-studied reaction using silica-based heterogeneous ligands is the addition of diethyl zinc to benzaldehyde. Brunel and co-workers studied this extensively in grafted systems using aminoalcohols as the chiral ligands.[10f] Subsequently, Yang and co-workers examined the addition of diethylzinc to benzaldehyde in purely organosilica BINOL-based materials such as OS13 and OS14 [Table 2, entries 1–4; Eq. (4)]. They found that when a more rigid organosilica like OS13 was used, the reaction proceeded with only moderate enantioselectivity (Table 2, entry 1).[27c] The use of a more flexible organic bridge, as in OS14, resulted in a substantial increase in enantioselectivity (Table 2, entry 2).[27g] This might be due to the ability of OS14 to ach-

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the attachment of the silane directly to the backbone of the binaphthalene skeleton.[27d] Once complexed with ruthenium, these materials effected the reduction of b-keto esters with high yields and enantioselectivities [Eq. (5)] and could further be applied to the asymmetric transfer hydrogenation of ketones.[27d]

Table 2. Asymmetric additions of nucleophiles.

Conditions

Entry

Organosilica

Yield [%]

R=H Nuc = Et ACHTUNGRE(ZnEt2) TiACHTUNGRE(OiPr)4

1 2 3 4

OS13 OS14 OS14 (refined) OS14 (grafted)

99 99 99 99

39[27c] 92[27g] 94[27h] 94[27h]

R = CH3 Nuc = H ACHTUNGRE(iPrOH) [{RhACHTUNGRE(cod)Cl}2][a]

5 6 7 8

OS15 OS15 (xerogel) OS16 N,N’-bistolyldiaminocyclohexene

93 90 16 89

27[41] 39[42] 8[41] 47[42]

ee [%]

[a] Cyclooctadiene = cod.

3.3. Asymmetric Carbon–Carbon Bond Formation Carbon–carbon bond-forming reactions are some of the most important methods for the introduction of chirality into organic molecules.[43] As such, it is not surprising that heterogeneous organosilica ligands have also been tested in these types of reactions.[13, 29c, 30] The asymmetric Michael addition of malonates to nitroalkenes was reported by Liu, Li, and co-workers [Eq. (6)] using organosilica OS15, which gave the desired product in high yield and high enantioselectivity and could be recycled effectively up to nine times.[29c, d] This same catalyst was also highly effective for the alkylation of b-keto esters [Eq. (6)]. In both cases, the organosilica analogue was comparable to or better than homogeneous analogues. This was attributed to a positive effect of confinement of the chiral ligand within the hydrophobic pores, thereby enhancing the enantioselectivity (Figure 5).[29c]

ieve a more natural angle about the central naphthyl–naphthyl bond of BINOL, which more closely mimics the homogeneous analogue.[40] When particle morphology was controlled, it was found that spherical particles with well-ordered channels that radiate from the center of the particle prepared under basic conditions gave better enantioselectivities than those of materials made without morphology control (Table 2, entry 3), which were comparable to the results with grafted materials (Table 2, entry 4).[27h] Yang, Li, and co-workers examined chiral organosilicas for the rhodium-catalyzed asymmetric hydride-transfer reduction of acetophenone using organosilicas OS15 and OS16 (Table 2, entries 5–8).[41, 42] Unexpectedly, it was found that the reaction catalyzed by ordered organosilicas (Table 2, entry 5)[41] proceeded with lower enantioselectivities than low-surface-area xerogels reported by Moreau and co-workers (Table 2, entry 6).[42] Furthermore, and in contradiction to previous work, the more flexible ligand in material OS16 catalyzed the reaction with lower enantioselectivities (Table 2, entry 7). This decrease in selectivity was attributed to the burying of the diamine in the walls of the material that might be a result of the more hydrophobic linkage interacting more strongly with the structure-directing agent.[41] Overall, the use of these amine-based chiral organosilicas offers the possibility of recyclability at the expense of selectivity when compared to the homogeneous systems (Table 2, entry 8).[42] However, it is clear that the overriding principles that govern chirality transfer including flexibility of tether, methods of incorporation of chiral ligands, and overall structure of the material are not well understood and need to be optimized on a case-by-case basis. BINAP is the quintessential chiral bidentate phosphine ligand, often paired with late-transition metals for use in asymmetric catalysis.[8] Organosilicas OS17 and OS18 contain analogues of BINAP ligands and have been used in conjugation with ruthenium for asymmetric hydrogenations [Eq. (5)]. The first of these was reported by Yang and coworkers in 2009 using organosilica OS17 complexed with ruthenium to achieve high enantioselectivities for the hydrogenation of b-keto esters [Eq. (5)].[27a] More recently, Crudden and co-workers used organosilica OS18, which featured

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Garcia, Ihmels, and co-workers used organosilica OS16 to facilitate the room temperature radical-mediated di-p-methane rearrangement of dibenzobarralene [Eq. (7)].[13] Although the reaction proceeded in low yield and poor selectivity, the rearrangement of dibenzobarralene in solution does not proceed enantioselectively, even in the presence of chiral auxiliaries.[13]

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Figure 6. Aluminum-promoted ene reaction with various proposed binding states of the metal. Last entry (*) run at 55 8C whereas all other entries performed at 36 8C.

Figure 5. Nickel center in organosilica enhances catalytic activity.

Polarz and Kuschel employed alcohol-based organosilica OS19 to facilitate the Al-promoted ene reaction of b-methylstyrene and trichloroacetaldehyde [Eq. (8)].[30] It was necessary to cap the free silanols with trimethylsilyl chloride (TMSCl) to prevent the aluminum from coordinating to the silanol (as is typical with coordinated Lewis acid catalysis). Interestingly, when larger silicon capping groups were used (triethylsilyl (TES) or triisopropylsilyl (TIPS)) the enantioselectivity of the reaction increased [Eq. (8)] even though the diameter of the pores was decreased (Figure 6).[30]

adsorption. These interactions are thought to influence the active sites and thus the transition states of the catalytic reaction, thereby causing different energy barriers between the two enantiomers. In this way, the confinement effect can influence enantioselectivity and catalytic performance of organosilica materials, although as previously stated, these effects are far from well understood.

4. Chromatographic Separations Using Ordered Organosilicas as Chiral Supports Chiral ordered organosilica materials have also found uses in enantioselective separations as chiral stationary phases. In this case, uniform spherical particles of a defined size as well as uniform pores are important for effective separations in high-performance liquid chromatography (HPLC). Many examples of grafted analogues that separate enantiomers with varying degrees of effectiveness exist for chiral chromatography.[44] The first ordered organosilica example appeared in 2008 by Yang, Li, and co-workers using siloxane precursor 12 and BTEE to produce organosilica spheres with a diameter of 6–9 mm.[29e] The resulting silica spheres proved effective for the enantioseparation of BINOL. They exhibited higher separation capacity than commercial Kromasil silica grafted with 12. This result was attributed to the high chiral ligand loading and surface area of the organosilica spheres.[29e] More recently Di and co-workers observed a similar phenomenon when using chiral mesoporous organosilica spheres from BTEE with siloxane precursor 13.[19b] Once again, the organosilica spheres proved more effective at separating enantiomers than the grafted analogue. Given the fact that porous silicas are so frequently used for chromatographic applications, it is surprising that so few exam-

3.4. Factors That Affect Catalysis in Organosilica Species Ordered organosilica materials have the potential to be efficient nanoreactors with higher catalytic performance than homogeneous systems. Tuning the hydrophobic/hydrophilic balance of the surface can improve diffusion dynamics of the reagents into the pores and might serve to stabilize the catalytically active sites,[10b] and the presence of surface silanols can have a significant effect on catalytic selectivity. Furthermore, heterogeneous catalytic reactions that occur within the confined space of the mesopores have been proposed in some instances to be subject to confinement effects,[10b] which are attributed to a variety of forces, including van der Waals interactions, hydrogen bonding, and physical

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ples have been explored for chiral applications. This is clearly an area with the potential for significantly more study.

Conclusion To date, many interesting chiral organosilica materials have been produced. However, most of these are designed from a relatively small fraction of the chiral molecules that are prominent in the modern literature. By restricting research to this limited class of molecules, entire families of chiral molecules have been neglected. This has resulted in a relatively small applications base for catalytic transformations, with many similar organosilicas being designed to cover a small number of transformations, and very few examples of use in chiral chromatography. Most of these materials are made from large quantities of chiral building blocks, and relatively rare are examples that use small amounts of a chiral dopant to transfer chirality throughout the system. In the coming decades, as our understanding of the factors that govern the control of chirality in the solid state become more clear, we anticipate that the nature of the chiral organosilica materials produced will proliferate to set a standard for diverse, structurally stable supports. We also anticipate that the implementation of chiral organosilica materials towards asymmetric catalysis and chiral chromatography will continue to increase to meet the ever-growing global demand for chiral small molecules.

[11] [12]

[13] [14] [15]

[16] [17] [18]

[19]

Acknowledgements [20] C.M.C. thanks the Natural Sciences and Engineering Research Council (NSERC) for Discovery and Accelerator awards and the Canada Foundation for Innovation for infrastructure awards. M.W.A.M. and L.M.R. thank Queens University for QGS awards and CREATE graduate awards and scholarships as well as the WC Sumner Foundation for awards. M.W.A.M. also thanks the Province of Ontario for an OGS award, and L.M.R. thanks the NSERC for a PGSM award.

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FOCUS REVIEW Small wonders: As the global demand for chiral small molecules continues to grow, the need for chiral heterogeneous systems becomes ever more pronounced. Here we explore chiral surfactant-templated porous materials, with particular emphasis on the creation of chirality in the support, the production of the chiral building blocks, and their use in facilitating asymmetric catalysis and enantioselective separations (see figure).

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Mesoporous Materials Michael W. A. MacLean, Lacey M. Reid, Xiaowei Wu, &&&&—&&&& Cathleen M. Crudden* Chirality in Ordered Porous Organosilica Hybrid Materials

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