DOI: 10.1002/asia.201402682

Chirality in Ordered Porous Organosilica Hybrid Materials

Michael W. A. MacLean,[a] Lacey M. Reid,[a] Xiaowei Wu,[a] andCathleen M. Crudden*[a, b]

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FOCUS REVIEW

Abstract: The ever-growing demand for chiral small molecules on a global scale has set a precedentfor the proliferation of cost-effective and reliable methods for their synthesis and separation. Ofthese methods, those based on heterogeneous platforms present an unparalleled opportunity asthey allow for the source of the chirality to be recycled. Chiral hybrid organosilica materials areone particularly interesting class of chiral heterogeneous platforms that creates a synergy betweenwell-understood individual chiral molecules and the structural stability and inertness of the inorgan-ic silicon scaffolds. This Focus Review summarizes the recent advances towards the incorporationof chirality into organosilica scaffolds, the synthesis of the chiral building blocks, and their promis-ing applications towards facilitating asymmetric heterogeneous catalysis as well as chiral chroma-tography.

Keywords: asymmetric catalysis · chirality · enantioselectivity · heterogeneous catalysis · mesopo-rous materials

Introduction

Since van�t Hoff�s first report of the relationship betweenchirality and structure,[1] and subsequent realizations of itsimportance to living organisms,[2] chemists have been devel-oping methods to facilitate the desymmetrization of mole-cules and the separation of enantiomers.[3] The primary im-portance of such molecules is in the pharmaceutical indus-try,[4] as evidenced by the fact that all but two of the top 25best-selling drugs of 2013 possess some form of chirality.[4,5]

Therefore the development of new ways to create moleculesin an asymmetric fashion as well as new ways to facilitatetheir separation is of clear interest to the chemical commun-ity.

The use of chiral auxiliaries to desymmetrize prochiralmolecules has been both well understood and effective;however, it requires stoichiometric amounts of the chiralauxiliary.[6] This decreases the carbon efficiency of the syn-thesis while adding additional steps, which is ultimately un-desirable.[6] A much more valuable approach is to employtransformations that generate one enantiomer from a prochi-ral or achiral starting material.[7] In the most successful ofthese methods, the chirality is conveyed by a chiral cata-lyst.[8] The large majority of enantioselective catalysts arehomogeneous, despite the many advantages of heterogene-ous systems, since rational design in heterogeneous systemsis still very difficult.[9] Of critical importance are materialssuch as those described herein, which show chirality basedon well-defined molecular species included in a recoverablesupport. Interestingly, in many enantioselective metal-cata-lyzed reactions, the chiral ligand is even more expensive

than the transition metal it modifies. As such, the drive tofind effective recoverable chiral ligands is significant.[9a] Inmany instances, chiral chromatography is employed toquickly separate molecules to be tested, for example, forbioactivity rather than generating enantioenriched com-pounds by means of complex synthetic schemes. Thus theneed for novel chiral separation systems is also paramount.

There have been many reports and reviews that describethe immobilization of chiral sites onto pre-existing supportsthrough adsorption or encapsulation to create a heterogene-ous platform.[9b,10] For example, Thomas, Johnson, and co-workers have shown that the ability of the chiral moiety totransfer chirality is enhanced when the catalytic site is con-strained within a pore.[11] The proposed rationale for thiseffect is shown schematically in Figure 1a wherein the closeproximity of the substrate, catalytic center, and chiral direct-ing group create interactions that would enable only specificspatial interactions that result in higher selectivity.[11] Thisconcept was realized with the allylic amination of cinnamylacetate 1 (Figure 1b) with benzylamine 2 by a porous silica-supported 1,1’-bis(diphenylphosphino)ferrocene ligand togive 50 % yield of the branched isomer 3 with 99 % ee,whereas comparable homogeneous systems produce onlythe linear isomer.[12] A less frequently employed approachinvolves the creation of supports that are chiral in their ownright, which allows the transformations to occur in a chiralenvironment. This includes the catalytic di-p-methane rear-rangement of 11-formyl-12-methyldibenzobarrelene (4) todibenzosemibullvalene (5 ; Figure 1c) that only occurs withselectivity when the reaction is performed inside the poresof a chiral host.[13]

A large variety of chiral heterogeneous systems havebeen described, including polymers made with chiral mono-mers,[14] metal surfaces modified by chiral organic com-pounds,[15] metal–organic frameworks (MOFs) in whichchiral groups have been incorporated into the struts of theframework,[16] and organosilica hybrid materials made fromchiral siloxane precursors.[10c,17] Organosilica hybrids benefitfrom the support and stability provided by purely inorganicmaterials along with the functionality (in this case chirality)

[a] M. W. A. MacLean, L. M. Reid, Dr. X. Wu, Prof. C. M. CruddenDepartment of Chemistry, Queen�s University90 Bader Lane, Kingston, Ontario, K7L3N6 (Canada)Fax: (+1) 613-533-6669E-mail : cathleen.crudden@chem.queensu.ca

[b] Prof. C. M. CruddenInstitute of Transformative Bio-Molecules (WPI-ITbM)Nagoya University, Chikusa, Nagoya, 464-8602 (Japan)

Supporting information for this article is available on the WWWunder 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 forchiral applications are shown schematically in Fig-ure 2.[10a, h,17] The simplest method for preparing chiral orga-

nosilica materials is grafting chiral functional groups thatbear a condensable silane onto a preformed porous silicaspecies (Figure 2a).[10a] This is an effective and quick way togenerate functional materials; however, the amount of or-ganic component that is incorporated is typically limited to

Michael MacLean completed his HonorsBSc in Organic Chemistry at the Universi-ty of New Brunswick in 2010, and shortlythereafter began his doctoral studies in theCrudden group at Queen�s University. Hisdoctoral research focuses on the transmis-sion of chirality through organosilica sup-ports with the emphasis on the design andsynthesis of the siloxane precursors.

Lacey Reid obtained her undergraduatedegree in Chemistry and Biochemistryfrom Acadia University, Nova Scotia,Canada, in 2010. She started her master�sresearch under the supervision of Prof.Cathleen Crudden at Queen�s University,and transferred into the chemistry PhDprogram in 2012. Her research focuses onthe synthesis, characterization, and appli-cations of chiral periodic mesoporous or-ganosilica materials.

Xiaowei Wu completed her honors PhDin Materials Science at Shanghai JiaotongUniversity in 2008, and shortly thereafterbegan her postdoctoral fellowship in theCrudden group at Queen�s University.Her research focuses on the synthesis ofchiral organosilica porous materials withan emphasis on chiral induction throughintroducing small amount of chiral silox-ane precursors or chiral co-structure di-recting agents.

Cathleen Crudden obtained her BSc andMSc at the University of Toronto and herPhD at Ottawa University. After a briefstint in Japan in the labs of Shinji Muraiand a postdoctoral fellowship with ScottDenmark at the University of Illinois, shebegan her independent career at the Uni-versity of New Brunswick. In 2002 shemoved to Queen�s University asa Queen�s National Scholar and currentlymaintains an active group at Queen�s inthe areas of catalysis and materials. She isalso cross-appointed at the Institute ofTransformative Bio-Molecules associatedwith Nagoya University in Nagoya,Japan.

Figure 1. a) Confinement effect in porous supports. b) Confinement prin-ciple applied to the allylic amination reaction between cinnamyl acetateand benzylamine. c) Di-p-methane rearrangement inside of a chiral sup-port. Adapted with permission from Ref. [13]. Copyright 2005 AmericanChemical Society.

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smaller loadings, as pores become blocked at higher load-ings. In addition, the chiral monomer is likely to be incorpo-rated in a nonuniform manner, potentially with islands ofhigh concentration and, similarly, areas of low concentra-tion.[10h] More uniform incorporation is typically achievedwhen the siloxane precursor is added during the polycon-densation process, in which an inorganic silica precursor ispresent along with a structure-directing agent (SDA), suchas a surfactant or block copolymer. These agents combine toproduce materials with chiral organosilica units spacedthroughout the pores (Figure 2b).[10h] Unfortunately, theloading of the chiral component still remains limited to lessthan 25 %, since at higher loadings, the loss of bifunctionalbuilding blocks decreases the structural integrity of the ma-terial.[10h]

The use of precursors with more than one condensablesilane allows for the production of materials that can con-tain up to 100 % of the chiral organic species (Fig-ure 2c,d).[10c,17] More importantly, under these conditions,the chiral monomer can affect the structure of the bulk ma-terial. When SDAs are present during the polycondensationprocess, the resulting composites are porous and can be pe-riodically ordered. These are often referred to as periodicmesoporous organosilicas (PMOs; Figure 2c).[10h] In instan-ces in which the organosilicas are allowed to self-assemblewithout the assistance of a SDA, the resulting materialsoften show limited porosity and order; these are called xero-gels (Figure 2d). Many interesting chiral xerogels have beenprepared; however, owing to space limitations, these willnot be explored further within this Focus Review.[17, 18]

In principal, any precursor that bears two or more con-densable silanes is able to undergo the templating processdescribed above. In practice, however, siloxane precursorsbridged by large flexible organic groups typically producepoor-quality materials on their own.[19] This has the impor-tant implication that many of the privileged chiral com-pounds used in homogeneous asymmetric systems will notbe able to form “true” PMOs, that is, materials made solelyof condensable organic silanes with good order and high po-rosity. As an alternative strategy, varying amounts of an ad-ditional condensable silane can be added as a structuralcomponent (Scheme 1) to improve the physical properties

of the resulting organosilica material. When chosen proper-ly, the added structural component should not have pro-found effects on the chirality or integrity of the materials, al-though this does diminish the chiral loading in the materials.Although this is not necessarily ideal, it is often unavoidablein the production of materials comprised of larger chiral

Scheme 1. Structural supports used to enhance materials properties.

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

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constituents. In this Focus Review we will focus on ordered,surfactant-templated porous materials in which a portion ofthe structural component can be considered to be madefrom chiral-bridged siloxane precursors, with particular em-phasis on the creation of chirality in the support, the pro-duction of the chiral building blocks that form the support,as well as the use of chiral supports to facilitate asymmetriccatalysis and enantioselective separations to help to meetthe ever-growing demand for chiral molecules on a globalscale.

1. Sources of Chirality in Ordered Materials

To generate supports that are inherently chiral, the methodof incorporating chirality is critical. In most instances this isachieved by the use of chiral siloxane precursors as buildingblocks in the construction of chiral materials (Figure 2c).[10c]

It is also possible to create a chiral material through thechiral modification of an achiral chemical handle[10h, 20] or bychirality transfer in the solid state from a chiral dopant.[21]

In all of these cases, some method must be used to assessthe chirality of the resulting materials. As the solids are nottransparent, and most methods for determination of chiralityrely on selective absorption of light, new methods havebeen developed in many cases.[20b, 22]

1.1. Chiral Building Blocks

As the field of asymmetric catalysis began to develop in thedecades since the discovery of chirality, many differentchiral structures have been used to transfer the chirality tothe substrate. Although many of these are successful tosome degree, there are families of molecules that performmuch better than their counterparts; such molecules can besaid to possess “privileged” structures in terms of chiralitytransfer. Selected examples of these are shown in Scheme 2.One such family of molecules is those based on derivativesof 1,1’-binaphthalene. These molecules are interesting inthat chirality is centered about an axis rather than an atom.These so-called “axially chiral” molecules feature a highenergy barrier for rotation about the central naphthyl–naph-thyl bond that results in the existence of two resolvable

atropisomers.[23, 24] This family of molecules is most wellknown for the 2,2’-diphosphane derivative (2,2’-bis(diphe-nylphosphino)-1,1’-binaphthyl (BINAP), 9), used in asym-metric transition-metal catalysis, for which the Nobel Prizewas awarded in 2001.[8,24b] The alcohol analogue of BINAP(1,1’-bi-2-naphthol (BINOL), 6) is readily available in itsenantiomerically pure form and has been effectively usedboth as an enantioselective catalyst[25] and a chiral dopantfor the transfer of chirality to liquid crystals.[26] In one inter-esting example, BINOL was used to facilitate the produc-tion of helical conjugated polymers.[26a, c] Siloxane derivativesof this 1,1’-binaphthalene unit are represented by buildingblocks 13–19 in Scheme 3,[19,27] and materials prepared fromthese monomers have been used in catalytic[27a–d,g,h] as wellas chromatographic[19b] applications, which will be exploredin further detail below.

Garcia and co-workers reported the first of this family ofsurfactant-templated organosilicas in 2004 using siloxaneprecursor 13 with up to nine parts tetramethoxysilane(TMOS).[19a] The chirality in the resulting materials was ob-served by measuring the optical activity of their suspensionsin solvent. The materials also showed different fluorescenceenhancement effects for the enantiomers of 1,2-cyclohexyl-diamine (7), thus indicating that some chiral recognition wasobserved.[19a] Crudden and co-workers reported the produc-tion of organosilicas with siloxane precursor 18, which fea-tured the attachment of the siloxane source directly to thebinaphthalene backbone in mixed-component materials togive organosilicas with ultra small mesopores when 1,4-bis(-triethoxysilyl)benzene (BTEB) was used as the bulk silicasource.[27e] In this case, the observation of twisted structuresby scanning electron microscopy (Figure 3) that were corre-lated to the amount of chiral dopant provided evidence of

Scheme 2. “Privileged” structures for chirality transfer in homogeneoussystems.

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

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chirality transfer. Subsequently, Crudden, Lemieux, and co-workers used 18 with BTEBp to make materials for whichmixing small quantities of the organosilica with a prochiralnematic liquid crystal led to chirality transfer to the liquidcrystals.[27f] Interestingly, the amount of the chiral materialadded to the liquid crystal had an effect on the twisting ofthe bulk liquid crystal.[27f]

Another family of molecules that possesses a “privileged”structure with regards to chirality transfer are those basedon trans-1,2-diaminocyclohexane 7. These structures havebeen incorporated into chiral ligands that have been em-ployed in a host of enantioselective transformations, includ-ing asymmetric hydrogenation and C�C bond-forming reac-tions.[28] As a result, diamino-bridged siloxane precursors areamong the most commonly employed chiral building blocksfor the formation of chiral organosilicas.[13,29] The first re-ports by Corma and co-workers used a 2,2’-ethylenebis(nitri-lomethylidene)diphenol (salen) derivative,[29a,b] whereas,more recently materials have been made from siloxane pre-cursor 11.[29c,d] These materials will be revisited in regards totheir catalytic behavior below. Cyclohexadiamine-bridgedorganosilicas have also been employed as chromatographicsupports by using building block 12 to facilitate the enantio-separation of BINOL derivatives as will also be describedbelow.[29e, f]

Other noteworthy chiral siloxane precursors that havebeen reported for the formation of chiral organosilicas in-clude 20,[22c] 21, and 24,[22b, 30] all of which are characterizedby atom-centered chirality at a benzyl position. In one ofthe most thorough studies of chiral mesoporous materials to

date, Inagaki, Shimada, and co-workers prepared PMOswith building block 20 under a variety of conditions.[22c]

They then dissolved the silica polymers with fluoride topermit analysis of the chirality of the building blocks afterincorporation into the materials. Interestingly, materialsformed under acidic conditions resulted in microporous ma-terials with high retention of chirality, whereas those formedunder alkaline conditions gave well-ordered materials (withinclusion of 1.5 parts BTEB) but with complete racemiza-tion of chirality of the incorporated monomer units.[22c] Al-though the materials lost chirality, the method of examina-tion of the chirality sets a high standard for the field.

Frçba and co-workers also described a chiral PMO usingorganosilica monomers with benzylic stereocenters; howev-er, their monomer (21) featured the siloxane attachmentpoints on the aryl backbone, rather than directly on thechiral center as in the Ingaki/Shimada et al. materials.[22b]

This approach led to a chiral ordered organosilica underacidic conditions that was porous without loss of chirality, asdetermined by measuring the specific optical activity of thechiral materials versus the monomer at varying concentra-tions.[22b] This is a very interesting approach that providesrigor to the analysis and is nondestructive. Polarz and co-workers reported materials made from the related 1,3,5,-substituted benzyl alcohol-bridged siloxane precursor 24, forwhich the chirality was assessed by means of circular dichro-ism (CD) spectroscopy. The materials were tested in the cat-alytic enantioselective reduction of ketones, which will bediscussed below.[30]

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

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Norbornane-bridged siloxane precursor 26 possesses a sim-ilar skeleton to the common chiral auxiliary camphor andcontains four stereocenters.[31] Wang and co-workers createdchiral organosilicas using this building block in 2010[31a] andagain in 2012 with control of the mesostructure that gaverise to a chiral organosilicas with a variety of different mor-phologies. Dissolution of the silica framework and subse-quent analysis of the organic component revealed that noracemization of the chiral component had occurred.[31b]

Remarkably, given the amount of chirality in biologicalsystems, biologically inspired siloxane precursors are rela-tively unusual; tartaric acid derivative 22,[32] and manitol de-rivative 23 are rare examples.[20a] Li, Yang, and co-workerscreated a tartardiamide-bridged organosilica from precursor22, and the resulting materials were assessed for their cata-lytic performance in enantioselective oxidations.[32] Themannitol-bridged organosilica prepared from precursor 23reported by Mehdi and co-workers was used as a host to sta-bilize gold nanoparticles that could be synthesized withinthe pores of materials.[20a] Other noteworthy biologically in-spired materials based on amino acids have been preparedindependently by Polarz et al.[20b] and Froba et al.,[33] albeitthrough a post-modification approach that will be discussednext.

1.2. Chiral Modification of Ordered Organosilicas

An alternative approach to the generation of chiral organo-silicas from chiral monomers involves the introduction of anachiral siloxane precursor with a chemical handle that canbe functionalized to introduce chirality after the polycon-densation has occurred. This method has clear advantages inthat the (usually costly) chiral moiety does not need to beemployed during the polycondensation process, which canbe low yielding; and furthermore, by spacing the functionali-ty over the materials, agglomeration of the chirality at thepore surface can be avoided.[10h, 20] In addition, since the ma-terials synthesis conditions are typically harsh, this approachpermits the incorporation of a wider variety of chiral subu-nits with more sensitive or complex functionality. Examplesof this type of chiral material are shown in Scheme 4 and in-clude OS2 and OS4.[20b, 33] The first report of this methodwas described in 2008 by Polarz and co-workers, who em-ployed 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 ala-nine as well as an alanine asparagine dipeptide. The result-ing materials showed similar 13C magic-angle spinning(MAS) NMR spectra to those of materials producedthrough an analogous method in which alanine was attachedand characterized prior to the polycondensation to form theorganosilica. In an innovative assessment of chirality, mea-surement of the differential rates of adsorption of the twoenantiomers of propylene oxide was employed. As shown inFigure 4, this represents the only example in which a chiralgas has been used to probe the chirality of an organosilicamaterial.[20b]

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

Scheme 4. Post-modification routes to chiral organosilicas.

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

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within the pores.[33] This concept was demonstrated using N-protected alanine to facilitate the production of OS4 witha chiral amine in the pore walls following deprotection.Thus, it is possible to envisage the addition of subsequentamino acids by means of a deprotection–condensation ap-proach, similar to that employed in solid-phase peptide syn-thesis.[33]

Chiral organosilicas have also been produced that arefunctionalized in a subsequent step, as in OS6, which isformed from chiral boronic acid functionalized organosilicaOS5, reported by Polarz and co-workers in 2006.[34] Al-though a quantitative assessment of the chiral precursor wasnot performed, the transformation of a boronic ester to analcohol is known to proceed with retention of stereochemis-try. However, the chirality transfer to the resulting organo-silica was not determined.[34]

The attachment of the chiral unit to the siloxane precur-sor can also be carried in a one-pot procedure. This wasdemonstrated with organosilica OS8 reported by Garcia andco-workers, who found that materials produced in this wayhad a more uniform distribution of chiral units throughoutthe material. A similar approach can also be used to incor-porate BINOL-based precursor 15 in situ.[35]

1.3. Chiral Induction

All of the previously described approaches focus on molecu-lar-scale chirality through the incorporation of buildingblocks in the walls of the materials. One fundamentally dif-ferent approach involves the production of materials witha prochiral monomer, such as the molecule BTEBp, which ischiral; however, it cannot be resolved into its two enantio-mers as the rotation about its central bond occurs too readi-ly at ambient temperature. BTEBp, however, has been in-corporated into organosilica materials that contain oneenantiomer of a resolvable chiral dopant such as monomer27.[21] This provides the possibility of chirality transfer fromthe resolvable chiral dopant to the prochiral biphenyl bulkto create chirality in the walls of the organosilica using onlya small amount of the chiral component. Crudden and co-workers first reported this in 2008, in which the chiralitytransfer was assessed by circular dichroism(Scheme 5).[21]

2. Synthesis of Chiral Building Blocks

Although the aforementioned chiral building blockscan be quite complex, in many cases the initialsource of chirality is commercially available, as insiloxane precursors 11–19, 22, and 23. The siloxanefunctional group is then attached directly througheither an N-alkylation (Scheme 6, top)[29d] or theformation of a ureyl linkage by condensation with3-isocyanatopropyl triethoxysilane (29 ; Scheme 6,bottom).[13] In some cases, the chiral source needsto be modified prior to introduction of the siloxane

unit to permit the introduction of an amine or halide (Sche-me 7).[27a, d] In instances in which a flexible tether to thewalls of the material is not problematic, reaction of an ami-nated substrate with 29 is a facile route to the desired silox-ane precursor (Scheme 7, top).[27a] When a more rigid struc-ture is desired, the silane can be attached through cross-cou-

Scheme 6. Direct functionalization of chiral molecules to produce silox-ane precursors.

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

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

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pling strategies such as Heck[18a] or Masuda cross-couplings(16–18)[27d] (Scheme 7, bottom).

An alternative route for the creation of chiral silanebuilding blocks involves the introduction of chirality duringattachment of the condensable silane. This can be seen in si-loxane precursors 20 and 26, which are both derived fromthe asymmetric hydrosilylation of prochiral olefins.[22c,31a]

The key reaction is shown in Scheme 8 in which norbornene34 is converted into chiral organosilane 35 by enantioselec-tive hydrosilylation. Simple reaction with methanol givesrise to the siloxane precursor 26.[31a]

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

3. Asymmetric Catalysis with OrderedOrganosilicas

Unsurprisingly, the proliferation of methodologies for themanufacture of chiral hybrid organosilicas has resulted intheir implementation as heterogeneous catalysts or li-

gands.[9b,10c] The utility of these organosilicas for heterogene-ous catalysis stems jointly from their high stability undera multitude of reaction conditions, as well as their recycla-bility (potentially conserving both the chiral source and themetal).[36] Ordered organosilica materials are particularly in-teresting for the heterogenization of catalytically active sitesbecause the mesopores of the materials, in addition to allow-ing facile diffusion, have the potential to introduce size orshape selectivity to catalytic reactions[10e] while additionallyproviding the opportunity to tune the hydrophobicity withinthe pore.[36] A variety of organosilica materials (Scheme 10)have been employed in enantioselective transformations.[10c]

Scheme 8. Silicon attachment to prochiral molecules.

Scheme 9. Desymmetrization of prochiral siloxane precursors.

Scheme 10. Materials used to catalyze asymmetric catalysis in ordered or-ganosilica materials.

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Often several steps were needed to prepare the chiral site inthe material prior to its use in catalysis. This is the case inorganosilicas OS9 and OS11, which were prepared with pro-tecting groups on the oxygen atoms that were cleaved tomake the alcohols available for catalysis after condensa-tion.[27b, 35a] Compounds OS17 and OS18 were prepared bya change in the oxidation state of the phosphorous post-con-densation step.[27a, d] As mentioned previously, some of themore “privileged” structures in terms of chirality transferare too large to form well-ordered materials on their ownand thus require additional structural supports (Scheme 1).The materials shown in Figure 2 have been used in threeclasses of transformations: enantioselective oxidations,asymmetric additions to aldehydes and ketones, and the for-mation of carbon–carbon bonds in an enantioselectivemanner.

3.1. Enantioselective Oxidation Reactions

One of the classical methods for asymmetric oxidation em-ploys TiIV and chiral bidentate diol ligands, including tartrateand BINOL-based systems.[37] These have been exploredusing organosilicas OS9–OS11, in the asymmetric oxidationof sulfides as well as the asymmetric epoxidation of allylicalcohols [Table 1, Eqs. (1) and (2), respectively].[27b,32, 35a]

Garcia and co-workers have described several examplesof catalytically active chiral organosilicas such as OS9 thatcan be employed for the asymmetric oxidation of sulfides(Table 1, entries 1 and 2).[35,38] Through optimization of theorganosilica in terms of catalytic activity and selectivity,Garcia and co-workers found that organosilica materialsperformed better than their grafted counterparts (Table 1,entry 3),[38] ; however, they did not perform as well as homo-geneous systems (Table 1, entry 4).[35b] Interestingly, organo-silicas in which the tartrate component was incorporatedduring the polycondensation performed better than ana-logues prepared over multiple steps (Table 1, entries 1 and2, respectively). This was attributed to a more uniform dis-tribution of the catalytic sites. More recently, these systemshave been expanded using an analogous BINOL-based or-ganosilica OS11 (Table 1, entries 5 and 6).[27b] Once againthe catalyst benefited from an even distribution of the

ligand in the walls of the materials and comparable selectivi-ty, yet lower yields were obtained for recycled materials.[27b]

The diminution of enantioselectivity in the organosilica sys-tems that employ alcohol-based ligands can likely be attrib-uted to interactions between the active metal species and si-lanols present on the surface of the materials. In some cases,steps can be taken to minimize this effect by attaching TMSgroups to the surface silanols; however, it is exceptionallydifficult to remove all silanols by capping.[39]

The epoxidation of olefins is another reaction that hasbeen performed using chiral organosilicas.[10g,32] Yang, Li,and co-workers used tartrate-based organosilica OS10 tocatalyze the asymmetric epoxidation of allyl alcohol[Eq. (2)] albeit with moderate conversion and low enantio-selectivity.[32] In this case, MCM-41 post-grafted materialsshowed comparable yield with much higher enantioselectivi-ty [Eq. (2)].[10g]

3.2. Additions to Aldehydes and Ketones

The reactions of unsymmetrical ketones and aldehydes withnucleophiles and reducing agents have been studied exten-sively with heterogeneous chiral ligands. In one of the firstexamples, salen-based OS12 was employed in the vanadium-catalyzed cyanosilylation of benzaldehyde [Eq. (3)].[29a]

However, the organosilica fared worse relative to the graft-ed analogues.[29a]

The most well-studied reaction using silica-based heteroge-neous ligands is the addition of diethyl zinc to benzalde-hyde. Brunel and co-workers studied this extensively ingrafted systems using aminoalcohols as the chiral ligands.[10f]

Subsequently, Yang and co-workers examined the additionof diethylzinc to benzaldehyde in purely organosilicaBINOL-based materials such as OS13 and OS14 [Table 2,entries 1–4; Eq. (4)]. They found that when a more rigid or-ganosilica like OS13 was used, the reaction proceeded withonly moderate enantioselectivity (Table 2, entry 1).[27c] Theuse of a more flexible organic bridge, as in OS14, resulted ina substantial increase in enantioselectivity (Table 2,entry 2).[27g] This might be due to the ability of OS14 to ach-

Table 1. Enantioselective oxidation of sulfides.

Entry Organosilica Yield [%] ee [%]

1 OS9 (in situ) 47 50[35a]

2 OS9 35 40[35a]

3 OS9 (grafted) 35 2[38]

4 l-diisopropyltartrate 92 94[35b]

5 OS11 (uniform) 58 42[27b]

6 OS11 41 15[27b]

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ieve a more natural angle about the central naphthyl–naph-thyl bond of BINOL, which more closely mimics the homo-geneous analogue.[40] When particle morphology was con-trolled, it was found that spherical particles with well-or-dered channels that radiate from the center of the particleprepared under basic conditions gave better enantioselectiv-ities than those of materials made without morphology con-trol (Table 2, entry 3), which were comparable to the resultswith grafted materials (Table 2, entry 4).[27h]

Yang, Li, and co-workers examined chiral organosilicasfor the rhodium-catalyzed asymmetric hydride-transfer re-duction of acetophenone using organosilicas OS15 andOS16 (Table 2, entries 5–8).[41,42] Unexpectedly, it was foundthat the reaction catalyzed by ordered organosilicas(Table 2, entry 5)[41] proceeded with lower enantioselectivi-ties than low-surface-area xerogels reported by Moreau andco-workers (Table 2, entry 6).[42] Furthermore, and in contra-diction to previous work, the more flexible ligand in materi-al OS16 catalyzed the reaction with lower enantioselectivi-ties (Table 2, entry 7). This decrease in selectivity was attrib-uted to the burying of the diamine in the walls of the mate-rial that might be a result of the more hydrophobic linkageinteracting more strongly with the structure-directingagent.[41] Overall, the use of these amine-based chiral orga-nosilicas offers the possibility of recyclability at the expenseof selectivity when compared to the homogeneous systems(Table 2, entry 8).[42] However, it is clear that the overridingprinciples that govern chirality transfer including flexibilityof tether, methods of incorporation of chiral ligands, andoverall structure of the material are not well understoodand need to be optimized on a case-by-case basis.

BINAP is the quintessential chiral bidentate phosphineligand, often paired with late-transition metals for use inasymmetric catalysis.[8] Organosilicas OS17 and OS18 con-tain analogues of BINAP ligands and have been used inconjugation with ruthenium for asymmetric hydrogenations[Eq. (5)]. The first of these was reported by Yang and co-workers in 2009 using organosilica OS17 complexed withruthenium to achieve high enantioselectivities for the hydro-genation of b-keto esters [Eq. (5)].[27a] More recently, Crud-den and co-workers used organosilica OS18, which featured

the attachment of the silane directly to the backbone of thebinaphthalene skeleton.[27d] Once complexed with rutheni-um, these materials effected the reduction of b-keto esterswith high yields and enantioselectivities [Eq. (5)] and couldfurther be applied to the asymmetric transfer hydrogenationof ketones.[27d]

3.3. Asymmetric Carbon–Carbon Bond Formation

Carbon–carbon bond-forming reactions are some of themost important methods for the introduction of chiralityinto organic molecules.[43] As such, it is not surprising thatheterogeneous organosilica ligands have also been tested inthese types of reactions.[13,29c,30]

The asymmetric Michael addition of malonates to nitroal-kenes was reported by Liu, Li, and co-workers [Eq. (6)]using organosilica OS15, which gave the desired product inhigh yield and high enantioselectivity and could be recycledeffectively up to nine times.[29c,d] This same catalyst was alsohighly effective for the alkylation of b-keto esters [Eq. (6)].In both cases, the organosilica analogue was comparable toor better than homogeneous analogues. This was attributedto a positive effect of confinement of the chiral ligandwithin the hydrophobic pores, thereby enhancing the enan-tioselectivity (Figure 5).[29c]

Garcia, Ihmels, and co-workers used organosilica OS16 tofacilitate the room temperature radical-mediated di-p-meth-ane rearrangement of dibenzobarralene [Eq. (7)].[13] Al-though the reaction proceeded in low yield and poor selec-tivity, the rearrangement of dibenzobarralene in solutiondoes not proceed enantioselectively, even in the presence ofchiral auxiliaries.[13]

Table 2. Asymmetric additions of nucleophiles.

Conditions Entry Organosilica Yield[%]

ee[%]

R =H 1 OS13 99 39[27c]

Nuc= Et 2 OS14 99 92[27g]ACHTUNGTRENNUNG(ZnEt2) 3 OS14 (refined) 99 94[27h]

Ti ACHTUNGTRENNUNG(OiPr)4 4 OS14 (grafted) 99 94[27h]

R =CH3 5 OS15 93 27[41]

Nuc= H 6 OS15 (xerogel) 90 39[42]ACHTUNGTRENNUNG(iPrOH) 7 OS16 16 8[41]

[{Rh ACHTUNGTRENNUNG(cod)Cl}2][a] 8 N,N’-bistolyldiaminocyclo-

hexene89 47[42]

[a] Cyclooctadiene =cod.

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Polarz and Kuschel employed alcohol-based organosilicaOS19 to facilitate the Al-promoted ene reaction of b-meth-ylstyrene and trichloroacetaldehyde [Eq. (8)].[30] It was nec-essary to cap the free silanols with trimethylsilyl chloride(TMSCl) to prevent the aluminum from coordinating to thesilanol (as is typical with coordinated Lewis acid catalysis).Interestingly, when larger silicon capping groups were used(triethylsilyl (TES) or triisopropylsilyl (TIPS)) the enantio-selectivity of the reaction increased [Eq. (8)] even thoughthe diameter of the pores was decreased (Figure 6).[30]

3.4. Factors That Affect Catalysis in Organosilica Species

Ordered organosilica materials have the potential to be effi-cient nanoreactors with higher catalytic performance thanhomogeneous systems. Tuning the hydrophobic/hydrophilicbalance of the surface can improve diffusion dynamics ofthe reagents into the pores and might serve to stabilize thecatalytically active sites,[10b] and the presence of surface sila-nols can have a significant effect on catalytic selectivity. Fur-thermore, heterogeneous catalytic reactions that occurwithin the confined space of the mesopores have been pro-posed in some instances to be subject to confinement ef-fects,[10b] which are attributed to a variety of forces, includingvan der Waals interactions, hydrogen bonding, and physical

adsorption. These interactions are thought to influence theactive sites and thus the transition states of the catalytic re-action, thereby causing different energy barriers betweenthe two enantiomers. In this way, the confinement effect caninfluence enantioselectivity and catalytic performance of or-ganosilica materials, although as previously stated, these ef-fects are far from well understood.

4. Chromatographic Separations Using OrderedOrganosilicas as Chiral Supports

Chiral ordered organosilica materials have also found usesin enantioselective separations as chiral stationary phases. Inthis case, uniform spherical particles of a defined size aswell as uniform pores are important for effective separationsin high-performance liquid chromatography (HPLC). Manyexamples of grafted analogues that separate enantiomerswith varying degrees of effectiveness exist for chiral chroma-tography.[44] The first ordered organosilica example ap-peared in 2008 by Yang, Li, and co-workers using siloxaneprecursor 12 and BTEE to produce organosilica sphereswith a diameter of 6–9 mm.[29e] The resulting silica spheresproved effective for the enantioseparation of BINOL. Theyexhibited higher separation capacity than commercial Kro-masil silica grafted with 12. This result was attributed to thehigh chiral ligand loading and surface area of the organosili-ca spheres.[29e] More recently Di and co-workers observeda similar phenomenon when using chiral mesoporous orga-nosilica spheres from BTEE with siloxane precursor 13.[19b]

Once again, the organosilica spheres proved more effectiveat separating enantiomers than the grafted analogue. Giventhe fact that porous silicas are so frequently used for chro-matographic applications, it is surprising that so few exam-

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

Figure 5. Nickel center in organosilica enhances catalytic activity.

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

Conclusion

To date, many interesting chiral organosilica materials havebeen produced. However, most of these are designed froma relatively small fraction of the chiral molecules that areprominent in the modern literature. By restricting researchto this limited class of molecules, entire families of chiralmolecules have been neglected. This has resulted in a rela-tively small applications base for catalytic transformations,with many similar organosilicas being designed to covera small number of transformations, and very few examplesof use in chiral chromatography. Most of these materials aremade from large quantities of chiral building blocks, and rel-atively rare are examples that use small amounts of a chiraldopant to transfer chirality throughout the system. In thecoming decades, as our understanding of the factors thatgovern the control of chirality in the solid state becomemore clear, we anticipate that the nature of the chiral orga-nosilica materials produced will proliferate to set a standardfor diverse, structurally stable supports. We also anticipatethat the implementation of chiral organosilica materials to-wards asymmetric catalysis and chiral chromatography willcontinue to increase to meet the ever-growing globaldemand for chiral small molecules.

Acknowledgements

C.M.C. thanks the Natural Sciences and Engineering Research Council(NSERC) for Discovery and Accelerator awards and the Canada Foun-dation for Innovation for infrastructure awards. M.W.A.M. and L.M.R.thank Queen�s University for QGS awards and CREATE graduateawards and scholarships as well as the WC Sumner Foundation forawards. M.W.A.M. also thanks the Province of Ontario for an OGSaward, and L.M.R. thanks the NSERC for a PGSM award.

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Received: June 18, 2014Published online: && &&, 0000

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FOCUS REVIEW

Mesoporous Materials

Michael W. A. MacLean,Lacey M. Reid, Xiaowei Wu,Cathleen M. Crudden* &&&&—&&&&

Chirality in Ordered Porous Organo-silica Hybrid Materials

Small wonders : As the global demandfor chiral small molecules continues togrow, the need for chiral heterogene-ous systems becomes ever more pro-nounced. Here we explore chiral sur-factant-templated porous materials,with particular emphasis on the crea-tion of chirality in the support, theproduction of the chiral buildingblocks, and their use in facilitatingasymmetric catalysis and enantioselec-tive separations (see figure).

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