Porous Silica-Based Organic-Inorganic Hybrid Catalysts: a Review

catalysts

Review Porous Silica-Based Organic-Inorganic Hybrid Catalysts: A Review

Andrea Erigoni * and Urbano Diaz *

Instituto de Tecnología Química, Universitat Politècnica de València-Consejo Superior de Investigaciones Cientíﬁcas, Avenida de los Naranjos s/n, E-46022 Valencia, Spain * Correspondence: [email protected] (A.E.); [email protected] (U.D.)

Abstract: Hybrid organic-inorganic catalysts have been extensively investigated by several research groups in the last decades, as they allow combining the structural robust-ness of inorganic solids with the versatility of organic chemistry. Within the field of hybrid catalysts, synthetic strategies based on silica are among the most exploitable, due to the convenience of sol-gel chemistry, to the array of silyl- derivative precursors that can be synthesized and to the number of post-synthetic functionalization strategies available, amongst others. This review proposes to highlight these advantages, firstly describing the most common synthetic tools and the chemistry behind sol-gel syntheses of hybrid catalysts, then presenting exemplificative studies involving mono- and multi-functional silica-based hybrid catalysts featuring different types of active sites (acid, base, redox). Materials obtained through different approaches are described and their properties, as well as their catalytic performances, are compared. The general scope of this review is to gather useful information for those approaching the synthesis of organic-inorganic hybrid materials, while providing an overview on the state-of-the art in the synthesis of such materials and highlighting their capacities.

Keywords: organic–inorganic hybrid composites; porous-materials; catalysis; silica-based materials; sol-gel synthesis; post-synthetic functionalization

Citation: Erigoni, A.; Diaz, U. Porous 1. Introduction to Hybrid Organic-Inorganic Materials Silica-Based Organic-Inorganic Catalysis plays a crucial role in the chemical industry since many decades. Approxi- Hybrid Catalysts: A Review. Catalysts 2021, 11, 79. https://doi.org/10.33 mately, 85–90% of the products of chemical industry are made in catalytic processes. They 90/catal11010079 are indispensable in the production of transportation fuels, with about 440 oil refineries heavily relying on them (data of the year 2007) and in the production of bulk and fine Received: 16 December 2020 chemicals in all branches of the chemical industry. They are key players in the prevention Accepted: 7 January 2021 of pollution, in the abatement of automotive or industrial exhaust and they provide en- Published: 8 January 2021 vironmental and economic advantages by enhancing the selectivity toward the desired product, in turn avoiding or limiting the production of unwanted byproducts. Catalysts Publisher’s Note: MDPI stays neu- offer alternative, energetically favorable mechanisms to non-catalyzed reaction, therefore tral with regard to jurisdictional clai- enabling processes to be carried out under industrially feasible conditions of temperature ms in published maps and institutio- and pressure. Catalysts come in many forms, from atoms and small molecules to macro- nal affiliations. molecules such as enzymes and crystalline structures such as zeolites and metal oxides. Moreover, they can be employed in different conditions: liquid, gaseous or at the surface of solids [1]. In heterogeneous catalysis, solid materials catalyze reactions of molecules in the gas Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. or liquid phase. They provide several advantages over homogeneous catalysts, such as the This article is an open access article ease of separation from the reaction mixture and consequent better recyclability and reuse. distributed under the terms and con- In addition, solid frameworks and macromolecules bring about additional properties, ditions of the Creative Commons At- compared to homogeneous catalysts, which have been exploited by scientists for several tribution (CC BY) license (https:// decades. Examples involve the shape selectivity of microporous zeolites that, due to the creativecommons.org/licenses/by/ shape of the cavity in which the active site is located, allows for the catalytic activation of a 4.0/). specific reactant or promote the formation of a specific product by stabilizing the transition

Catalysts 2021, 11, 79. https://doi.org/10.3390/catal11010079 https://www.mdpi.com/journal/catalysts Catalysts 2021, 11, x FOR PEER REVIEW 2 of 41

Catalysts 2021, 11, 79 2 of 39 the shape of the cavity in which the active site is located, allows for the catalytic activation of a specific reactant or promote the formation of a specific product by stabilizing the statetransition that precedes state that the precedes desired product. the desired Nature product. pioneered Nature this pioneered strategy with this much strategy greater with success,much greater speciﬁcally success, with specifically enzymes, with in which enzymes, the way in which they arethe foldedway they onto are themselves folded onto allowsthemselves for exceptional allows for speciﬁcity exceptional toward specificity certain toward reactants certain and reactants selectivity and toward selectivity certain to- productsward certain (Figure products1)[ 2– 5(Figure]. Another 1) [2– instance5]. Another is the instance synthesis is the of synthesis supported of supported noble metal no- nanoparticles.ble metal nanoparticles. Due to their Due small to size, their nanoparticles small size, nanoparticles expose a relatively expose large a relatively surface arealarge that,surface when area they that, are when used inthey homogeneous are used in phase,homogeneous cause them phase, to aggregatecause them and to sinter,aggregate in turnand lowering sinter, in the turn surface lowering area the exposed surface and area lowering exposed their and free lowering energy. their By depositingfree energy. the By nanoparticlesdepositing the onto nanoparticles solid supports onto (often solid porous), supports chemists (often porous), have been chemists able to limithave sintering, been able allowingto limit sintering, the use of allowing these catalysts the use over of these multiple catalysts cycles over and multiple easing theircycles separation and easing from their theseparation reaction from mixture the [reaction6–8]. Even mixture further, [6–8 in]. Even the last further, decades in the scientists last decades have scientists been able have to coordinatebeen able singleto coordinate atoms of single various atoms metals of various within a metals solid support, within a with solid major support, advantages with major in termsadvantages of catalytic in terms activity of catalytic and atom activity economy and [atom9,10]. economy [9,10].

Figure 1. (A): Stereoview of the active site of glucose oxidase with the modelled substrate β-d- glucoseFigure [1.4]. (A Reproduced): Stereoview with of the permission active site of of the glucose International oxidase w Unionith the of modelled Crystallography. substrate ( Bβ-):d The- glucose [4]. Reproduced with permission of the International Union of Crystallography. (B): The structure of γ-valerolactone within zeolite pores as obtained using in situ X-ray diffraction data [5]. structure of γ-valerolactone within zeolite pores as obtained using in situ X-ray diffraction data Reprinted with permission from [5]. Copyright 2020, Nature Springer. (C): Single Pt atoms bounded [5]. Reprinted with permission from [5]. Copyright 2020, Nature Springer. (C): Single Pt atoms tobounded N- rich orto N S-- rich or regions S- rich in regions doped in carbonaceous doped carbonaceous supports supports [10]. Reprinted [10]. Reprinted with permissionwith per- frommission [10]. from Copyright [10]. Copyright 2018, Nature 2018, Springer. Nature Springer. Among the different types of heterogeneous catalysis, hybrid organic-inorganic catalysts provide some unique properties, compared to purely inorganic catalysts (e.g., zeo-

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Catalysts 2021, 11, 79 Among the different types of heterogeneous catalysis, hybrid organic-inorganic3 ofcat- 39 alysts provide some unique properties, compared to purely inorganic catalysts (e.g., zeo- types) and purely organic ones (e.g., resins). In fact, they combine the advantages of inorganic solids (high mechanical, thermal, and structural stability) and organic molecules or types)macromolecules and purely (flexibility organic onesand functionality). (e.g., resins). In fact, they combine the advantages of inorganicIn general, solids (highthe concept mechanical, of hybrid thermal, material and structuralrefers to a stability)solid composed and organic of two molecules types of orbuilding macromolecules blocks, an (flexibilityinorganic one and and functionality). an organic one, mixed with each other at the nano- metricIn sca general,le. By thecleverly concept combining of hybrid different material organic refers and to ainorganic solid composed precursors, of two many types au- ofthors building have beenblocks, able an to inorganic guide their one andself-assembly, an organic achieving one, mixed hybrids with each featuring other unique at the nanometric scale. By cleverly combining different organic and inorganic precursors, many properties for applications as advanced materials in several fields. In the last few decades, authors have been able to guide their self-assembly, achieving hybrids featuring unique these types of materials underwent tremendous development, thanks to soft sol–gel and properties for applications as advanced materials in several fields. In the last few decades, self-assembling micellar processes (Figure 2) [11]. Hybrid materials can be classified ac- these types of materials underwent tremendous development, thanks to soft sol–gel and cording to the interactions between organic and inorganic building blocks. Quite logically, self-assembling micellar processes (Figure2)[ 11]. Hybrid materials can be classified the strength and the directionality of chemical bonds holding them together are crucial according to the interactions between organic and inorganic building blocks. Quite logically, aspects to consider in the pursuit of designing a hybrid material with specific properties. the strength and the directionality of chemical bonds holding them together are crucial aspects to consider in the pursuit of designing a hybrid material with specific properties.

FigureFigure 2.2. Scheme of of the the main main chemical chemical routes routes for for the the synthesis synthesis of of organic organic-inorganic-inorganic hy hybridsbrids [11 [11]. ]. ReprintedReprinted withwith permissionpermission fromfrom [[1111].]. CopyrightCopyright 2005,2005, RoyalRoyal SocietySociety ofof Chemistry.Chemistry.

SanchezSanchez andand RibotRibot classifiedclassified asas ClassClass I hybrids those inin which weakweak bondsbonds (hydrogen(hydrogen oror vanvan derder WaalsWaals bonding)bonding) givegive cohesioncohesion toto thethe wholewhole structurestructure (Figure(Figure3 ).3). Organic Organic dies dies havehave beenbeen imbedded imbedded in in amorphous amorphous sol-gel sol-gel matrixes, matrixes, in orderin order to improve to improve their their stability stability and avoidand avoid the formation the formation of dimers of dimers or oligomers or oligomers [12,13 [].12,13 Antibacterial]. Antibacterial agents agents also have also beenhave depositedbeen deposited onto silicaonto supportssilica supports through through H-bond H- interactionsbond interactions [14]. Inorganic[14]. Inorganic fillers fillers have longhave beenlong imbeddedbeen imbedded into organic into organic polymeric polymeric matrixes matrixes in order in to order improve to improve their mechanical their me- properties.chanical properties. However, However, traditional traditional filler blending filler blending occurs underoccurs high unde viscosityr high viscosity conditions, con- whichditions, lead which to partial lead to agglomeration partial agglomeration of the inorganic of the inorganic particles, particles, lowering lowering the matrix-filler the ma- interactions.trix-filler interactions. By generating By generating the inorganic the inorganic particles particles in-situ byin- sol-gelsitu by chemistry,sol-gel chemistry, a much a bettermuch dispersionbetter dispersion can be achievedcan be achieved [15,16]. Wet[15,16 or]. dry Wet impregnation or dry impregnation have been have implemented been im- toplemented obtain Class to obtain I hybrids, Class as I wellhybrids, [17]. as well [17].

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Catalysts 2021, 11, 79 In Class II materials, the two phases are linked together through strong chemical4 of 39 bonds (covalent, coordination or ionic bonding) [11,17,18]. This types of hybrids are of special interest for catalytic applications.

Figure 3. (A): Schematic representation of the porous structure of a phenyl modiﬁed silica matrix Figure 3. (A): Schematic representation of the porous structure of a phenyl modified silica matrix doped with Rhodamine 6G molecules [13]. Reprinted with permission from [13]. Copyright 2015, doped with Rhodamine 6G molecules [13]. Reprinted with permission from [13]. Copyright 2015, NatureNature Springer. Springer. (B) (:B Structure): Structure of PVP of PVP-silica-silica hybrid hybrid material material [15]. [Reprinted15]. Reprinted with permission with permission from [15from]. Copyright [15]. Copyright 1992, Nature 1992, Nature Springer. Springer.

InIn fact, Class while II materials, weak bonds the between two phases organic are linkedand inorganic together building through blocks strong would chemical be susceptiblebonds (covalent, to breakage coordination in the reaction or ionic media, bonding) with [ 11consequent,17,18]. This loss types of structural of hybrids proper- are of tiesspecial and interestcatalytic for activity, catalytic strong applications. bonds would favor the preservation of the hybrid catalysts, allowingIn fact, while for using weak the bonds catalyst between over organicmultiple and cycles. inorganic There buildingare two main blocks families would of be susceptible to breakage in the reaction media, with consequent loss of structural properties hybrid materials belonging to class II that are commonly implemented as heterogeneous and catalytic activity, strong bonds would favor the preservation of the hybrid catalysts, catalysts: metal-organic frameworks and mesoporous silica-based hybrids. Other types of allowing for using the catalyst over multiple cycles. There are two main families of hybrid materials have also been described, e.g., organozeolites [19], silica-graphene com- hybrid materials belonging to class II that are commonly implemented as heterogeneous posites [20] and laminar metal oxides featuring organocatalysts in the interlaminar space catalysts: metal-organic frameworks and mesoporous silica-based hybrids. Other types [21]. of hybrid materials have also been described, e.g., organozeolites [19], silica-graphene composites [20] and laminar metal oxides featuring organocatalysts in the interlaminar 2. Mesoporous Silica-Based Hybrid Materials space [21]. Since the development of M41S materials by the Mobil Oil Company in 1992, porous Catalysts 2021, 11, x FOR PEER REVIEWmaterials2. Mesoporous with large Silica-Based specific surface Hybrid areas Materials has been a field of extensive research, particu-5 of 41

larly withSince regard the development to potential ofapplications M41S materials in areas by thesuch Mobil as catalysis, Oil Company adsorption, in 1992, gas porous storage,materials chromatography, with large specific controlled surface drug areas-delivery has been and a sensor field of technology. extensive research, Like microporous particularly crystalline zeolites, this class of materials feature very large specific surface areas, ordered organicwith regard moieties to potential to a porous applications solid silica in support. areas such As it as will catalysis, be shown adsorption, below, these gas organic storage, pore systems and well-defined pore size distributions. However, unlike zeolites, M41S moietieschromatography, (featuring controlled acidic, basic, drug-delivery redox sites) and can sensor be catalytically technology. active Like for microporous a specific reac- crys- materials exhibit amorphous pore walls and their pore diameters is comprised between 2 titallineon and zeolites, being selective this class toward of materials the formation feature very of one large product, specific instead surface of areas, another. ordered Bound- pore andsystems 10 nm. and The well-defined most representative pore size distributions. materials belonging However, to unlikethis class zeolites, include M41S silica materials solids ing catalytically active organic moieties to solid supports, opens up to the possibility of MCMexhibit-41 amorphous (with a hexagonal pore walls arrangement and their pore of diametersthe mesopores), is comprised MCM- between48 (with 2a andcubic 10 ar- nm. carrying out reactions under heterogeneous regime, allowing for recovery and reuse of rangementThe most representativeof the mesopores), materials and MCM belonging-50 (with to thisa laminar class includestructure) silica (Figure solids 4) MCM-41[22]. these valuable catalyst over multiple cycles, easing product separation and purification (withNot a hexagonallong after arrangementtheir discovery, of theresearchers mesopores), began MCM-48 attempting (with to a cubicincorporate arrangement organic of [1,22]. componentsthe mesopores), within and an MCM-50 inorganic (with silica a laminarframework structure) to achieve (Figure symbiosis4)[22]. of the properties of both components. The combination of the properties of organic and inorganic building blocks within a single material is highly attractive. In fact, this allows for the possibility of combining the enormous variety of functional groups, typical of organic chemistry, with the advantages of a thermally stable and robust inorganic substrate. This is particularly appealing for applications in heterogeneous catalysis. The symbiosis of organic and inorganic components can lead to materials with considerably different properties from those of their individual, isolated components. Several synthetic methodologies allow to functionalize silica matrixes with specific organic functionalities such as C=C multiple bonds, alcohols, thiols, sulfonic and carboxylic acids, amines, as sol-gel chemistry provides versatile and effective ways of anchoring Figure 4. Structures of mesoporous M41S materials: MCM-41 (A), MCM-48 (B) and MCM-50 (C)[22]. Figure 4. Structures of mesoporous M41S materials: MCM-41 (A), MCM-48 (B) and MCM-50 (C) [Reprinted22]. Reprinted with with permission permission from from [22]. [ Copyright22]. Copyright 2006, 2006, John John Wiley Wiley and Sons.and Sons.

Silica-based hybrids can be achieved by (i) post-synthetic modification of the pore surface of a purely inorganic silica material (grafting), (ii) co-condensation of a silica precursor and a silyl derivative bearing the functional group of interest (“one-pot” approach), (iii) condensation of bisilylated precursors featuring the functional group of interest in the linker between the two alkoxysilyl groups (alone or together with a minimal amount of tetra-alkoxysilyl precursor), leading to a material in which the organic functionalities are imbedded within the pore walls.

2.1. Post-Synthetic Modification (Grafting) Grafting refers to the post-synthesis modification of the surfaces of mesostructured silica phases with organic groups. This process is mainly carried out by reaction of orga- nosilanes of the type RSi(OR’)3 with the free silanol groups on the pore surfaces. Less frequently chlorosilanes ClSiR3 or silazanes HN(SiR3)2 are used (Figure 5). In principle, by varying of the organic residue R, functionalization with different organic groups can be achieved. By implementing this approach, the mesostructure of the starting silica phase is usually retained. On the other hand, a reduction in the porosity of the hybrid, compared to the parent mesoporous silica, is usually observed, proportionally to the size of the grafted organic moieties. Furthermore, the organic silyl-derivatives might preferentially react with the surface silanol groups that they will encounter first, i.e., those located at the pore mouth or at the initial part of the mesoporous channels. This effect is modulated by several factor. Firstly, the reactivity of the alkoxy groups bounded to the silicon atom determines the ease with which hydrolysis/condensation reactions can occur.

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Not long after their discovery, researchers began attempting to incorporate organic components within an inorganic silica framework to achieve symbiosis of the properties of both components. The combination of the properties of organic and inorganic building blocks within a single material is highly attractive. In fact, this allows for the possibility of combining the enormous variety of functional groups, typical of organic chemistry, with the advantages of a thermally stable and robust inorganic substrate. This is particularly appealing for applications in heterogeneous catalysis. The symbiosis of organic and inorganic components can lead to materials with considerably different properties from those of their individual, isolated components. Several synthetic methodologies allow to functionalize silica matrixes with specific organic functionalities such as C=C multiple bonds, alcohols, thiols, sulfonic and carboxylic acids, amines, as sol-gel chemistry provides versatile and effective ways of anchoring organic moieties to a porous solid silica support. As it will be shown below, these organic moieties (featuring acidic, basic, redox sites) can be catalytically active for a specific reaction and being selective toward the formation of one product, instead of another. Bounding catalytically active organic moieties to solid supports, opens up to the possibility of carrying out reactions under heterogeneous regime, allowing for recovery and reuse of these valuable catalyst over multiple cycles, easing product separation and purification [1,22]. Silica-based hybrids can be achieved by (i) post-synthetic modification of the pore surface of a purely inorganic silica material (grafting), (ii) co-condensation of a silica precursor and a silyl derivative bearing the functional group of interest (“one-pot” approach), (iii) condensation of bisilylated precursors featuring the functional group of interest in the linker between the two alkoxysilyl groups (alone or together with a minimal amount of tetra-alkoxysilyl precursor), leading to a material in which the organic functionalities are imbedded within the pore walls.

2.1. Post-Synthetic Modiﬁcation (Grafting)

Catalysts 2021, 11, x FOR PEER REVIEW Grafting refers to the post-synthesis modiﬁcation of the surfaces of mesostructured6 of 41 silica phases with organic groups. This process is mainly carried out by reaction of organosi- lanes of the type RSi(OR’)3 with the free silanol groups on the pore surfaces. Less frequently chlorosilanes ClSiR3 or silazanes HN(SiR3)2 are used (Figure5).

Figure 5. Grafting of a generic silyl-derivative RSi(OR’)3 onto a mesoporous silica pore walls [22]. Figure 5. Grafting of a generic silyl-derivative RSi(OR’)3 onto a mesoporous silica pore walls [22]. ReprintedReprinted with with permission permission from from [22 [22].] Copyright. Copyright 2006, 2006, John John Wiley Wiley and and Sons. Sons. In principle, by varying of the organic residue R, functionalization with different The diffusion of the silyl-derivative compounds through the mesopores also play a organic groups can be achieved. By implementing this approach, the mesostructure of the startingcrucial silicarole and phase is primarily is usually determined retained. On by the its othersize, relative hand, a to reduction the pores in diameter, the porosity and of by thethe hybrid, chemical compared affinity to between the parent the mesoporous organic moieties silica, isand usually surface observed, silanol proportionally groups. Lastly, towhile the size in an of initial the grafted stage organicof the grafting, moieties. silyl Furthermore,-derivatives the are organic allowed silyl-derivatives to diffuse through might the pore channels before the catalyst (acid or base) is added into the mixture, molecules baring acidic or base functionalities can catalyze their own hydrolysis and condensation before reaching optimal diffusion, leading to a worse distribution of organic moieties throughout the porous framework. A key advantage, unique to this method, is the fact that the templating agent used for generating the mesopores is entirely removed by calcination, prior to the grafting procedure. The grafting approach allows for introducing organic functionalities onto a pre-existing mesoporous silica framework and for that, in these hybrids, the organic moieties are expected to be pending from the pore walls, partially occupying the mesoporous channels. Grafting procedures are also employed to modify the polarity of the support’s surface. In fact, silanol-capping hydrophobic moieties, e.g., trimethyl-silyl species, can make the pore walls more hydrophobic, with beneficial effect on the properties of the hybrid materials, for certain applications.

2.2. Co-Condensation Method (“One-Pot”) An alternative method to synthesize ordered hybrid organic-inorganic mesoporous silica phases is the co-condensation method. It is possible to prepare mesostructured silica phases by the co-condensation of tetra-alkoxysilanes, typically tetraethyl ortosilicate (TEOS) or tetramethyl ortosilicate (TMOS), together with trialkoxyorganosilanes of the type RSi(OR’)3 in the presence of structure-directing agents, obtaining materials with organic residues pending covalently from the pore walls (Figure 6). By using structure-directing agents that are typically implemented in the synthesis of pure mesoporous silica phases (e.g., MCM or SBA silica phases), organo-functionalized silica hybrids can be prepared in such a way that the organic linkers, connecting the functional group of interest to the inorganic support, are pending directly from the pore walls, with the silicon atoms deriving from hydrolysis/condensation of the alkoxy-silyl groups being imbedded into the silica pore walls. Since the organic functionalities are direct components of the silica matrix, pore blocking is not a problem in the co-condensation method, although a slight decrease in the pore diameter can be detected. Moreover, the organic units are generally more homogeneously distributed than in hybrid mesoporous materials obtained by grafting process.

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preferentially react with the surface silanol groups that they will encounter first, i.e., those located at the pore mouth or at the initial part of the mesoporous channels. This effect is modulated by several factor. Firstly, the reactivity of the alkoxy groups bounded to the silicon atom determines the ease with which hydrolysis/condensation reactions can occur. The diffusion of the silyl-derivative compounds through the mesopores also play a crucial role and is primarily determined by its size, relative to the pores diameter, and Catalysts 2021, 11, x FOR PEER REVIEW 7 of 41 by the chemical affinity between the organic moieties and surface silanol groups. Lastly, while in an initial stage of the grafting, silyl-derivatives are allowed to diffuse through the pore channels before the catalyst (acid or base) is added into the mixture, molecules baring acidicNevertheless, or base functionalitiesthe co-condensation can catalyze method their presents own also hydrolysis a number and of condensation disadvantages: beforethe degree reaching of mesoscopic optimal diffusion, order of leadingthe resulting to a materials worse distribution tend to decreases of organic with moieties increasing throughoutconcentration the porous of RSi(OR’) framework.3 in the A synthesis key advantage, mixture. unique Consequently, to this method, the relative is the factamount that of theorganic templating moieties agent in used the modified for generating silica phases the mesopores does not is normally entirely removed exceed 40 by mol%. calcination, Further- priormore, to thethe yield grafting with procedure. which the organic The grafting groups approach can be incorporated allows for introducing into the pore organic-wall net- functionalitieswork is generally onto not a pre-existing 100% and it mesoporousdecreases proportionally silica framework to the and amount for that,of organic in these silyl- hybrids,derivative the organicin the synthesis moieties mixture. are expected These to observations be pending can from be the explained pore walls, by the partially fact that occupyingan increasing the mesoporous proportion channels.of RSi(OR’) Grafting3 in the proceduresreaction mixture are also promotes employed homocondensa- to modify theti polarityon reactions, of the favoring support’s the surface. formation In fact,of oligomers. silanol-capping These phenomena hydrophobic are moieties, caused e.g.,by the trimethyl-silyldifferent hydrolysis species, and can makecondensation the pore rates walls of more the hydrophobic,different silyl- withtype beneficialprecursors. effect It is a onpotential the properties problem of the whenever hybrid materials,this synthetic for certainstrategy applications. is implemented, as the homogeneous distribution of the organic functionalities in the framework cannot be guaranteed. More- 2.2. Co-Condensation Method (“One-Pot”) over, exceeding in the loading of organic groups can lead to a reduction in the pore diameter,An pore alternative volume, method and specific to synthesize surface areas. ordered From hybrid a purely organic-inorganic methodological mesoporous point of view, silicaa higher phases degree is the of co-condensation care needs to be taken method. in the It removal is possible of the to surfactant, prepare mesostructured used to generate silicathe phasesmesopores. by the Calcination co-condensation cannot of be tetra-alkoxysilanes, implemented as it typicallywould compromise tetraethyl ortosilicate the integrity (TEOS)of the or organic tetramethyl groups ortosilicate Si-R. Consequently, (TMOS), together template with removal trialkoxyorganosilanes is commonly done of theby typecontin- RSi(OR’)uous extraction,3 in the presence carried of out structure-directing using a soxhlet apparatus. agents, obtaining Although materials fairly effective, with organic an in- residuescomplete pending removal covalently of the template from the is pore usually walls observed. (Figure6 ).

Figure 6. Co-condensation between tetraethyl ortosilicate (TEOS) and a generic silyl-derivative Figure 6. Co-condensation between tetraethyl ortosilicate (TEOS) and a generic silyl-derivative compound, RSi(OR’)3, followed by calcination/extraction to achieve hybrid organic-inorganic meso- porouscompound, silica [22 RSi(OR’)]. Reprinted3, followed with permission by calcination/extraction from [22]. Copyright to achieve 2006, hybrid John Wileyorganic and-inorganic Sons. mesoporous silica [22]. Reprinted with permission from [22]. Copyright 2006, John Wiley and Sons.

An additional tool to incorporate specific organic functionalities within silica-based materials are tethering procedures. For that, firstly, mono-silanes RSi(OR’)3 are incorporated into a silica support (either by co-condensation or grafting). Afterwards, in a post- synthetic step, an organocatalyst featuring the active site of interest and a specific functional group R* is reacted with the hybrid material. R and R* need to be chosen properly, so that they can react and form a covalent bond that can guarantee the anchoring of the organocatalyst. Example of such R/R* pairs include primary amine and isocyanate, reacting to form urea group; thiol and terminal alkene, reacting in presence of a radical initiator

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By using structure-directing agents that are typically implemented in the synthesis of pure mesoporous silica phases (e.g., MCM or SBA silica phases), organo-functionalized silica hybrids can be prepared in such a way that the organic linkers, connecting the functional group of interest to the inorganic support, are pending directly from the pore walls, with the silicon atoms deriving from hydrolysis/condensation of the alkoxy-silyl groups being imbedded into the silica pore walls. Since the organic functionalities are direct components of the silica matrix, pore blocking is not a problem in the co-condensation method, although a slight decrease in the pore diameter can be detected. Moreover, the organic units are generally more homogeneously distributed than in hybrid mesoporous materials obtained by grafting process. Nevertheless, the co-condensation method presents also a number of disadvantages: the degree of mesoscopic order of the resulting materials tend to decreases with increasing concentration of RSi(OR’)3 in the synthesis mixture. Consequently, the relative amount of organic moieties in the modified silica phases does not normally exceed 40 mol%. Furthermore, the yield with which the organic groups can be incorporated into the pore- wall network is generally not 100% and it decreases proportionally to the amount of organic silyl-derivative in the synthesis mixture. These observations can be explained by the fact that an increasing proportion of RSi(OR’)3 in the reaction mixture promotes homocondensation reactions, favoring the formation of oligomers. These phenomena are caused by the different hydrolysis and condensation rates of the different silyl-type precursors. It is a potential problem whenever this synthetic strategy is implemented, as the homogeneous distribution of the organic functionalities in the framework cannot be guaranteed. Moreover, exceeding in the loading of organic groups can lead to a reduction in the pore diameter, pore volume, and specific surface areas. From a purely methodological point of view, a higher degree of care needs to be taken in the removal of the surfactant, used to generate the mesopores. Calcination cannot be implemented as it would compromise the integrity of the organic groups Si-R. Consequently, template removal is commonly done by continuous extraction, carried out using a soxhlet apparatus. Although fairly effective, an incomplete removal of the template is usually observed. An additional tool to incorporate specific organic functionalities within silica-based materials are tethering procedures. For that, firstly, mono-silanes RSi(OR’)3 are incorporated into a silica support (either by co-condensation or grafting). Afterwards, in a post-synthetic step, an organocatalyst featuring the active site of interest and a specific functional group R* is reacted with the hybrid material. R and R* need to be chosen properly, so that they can react and form a covalent bond that can guarantee the anchoring of the organocatalyst. Example of such R/R* pairs include primary amine and isocyanate, reacting to form urea group; thiol and terminal alkene, reacting in presence of a radical initiator to form a thioether; a halide (Br or I) functioning as good leaving group in a SN2 reaction and a strong nucleophile.

2.3. Periodic Mesoporous Organosilicas (PMOs) PMOs are a class of silica-based organic–inorganic hybrid materials obtained by hydrolysis and condensation reactions of bridged silsesquioxane precursors of general formula (R’O)3Si-R-Si(OR’)3, used as the only silicon source [23,24]. In contrast with the two methods previously reported (grafting and direct synthesis), in this case, the organic building blocks bear two alkoxy-silyl groups that can largely improve their incorporation in the three-dimensional network as well as their homogeneous distribution throughout the solid (Figure7A). Moreover, a major difference between PMOs and silica-based hybrids obtained by co-condensation and grafting is that in the former, active sites are imbedded into the pore walls, rather than pending from the surface of the support. As in the case of the synthesis of pure silica mesophases, the use of a surfactant in the presence of bi-silylated organosilica precursors allows obtaining materials featuring ordered mesopores, narrow pore size distribution and in which the organic bridges are integral components of the silica network [22]. Catalysts 2021, 11, 79 8 of 39

Catalysts 2020, 10, x FOR PEER REVIEW 8 of 43

239 240 FigureFigure 7 A: General 7. (A synthetic): General pathway synthetic to PMOs pathway [22]. Reprinted to PMOs with [22 permissi]. Reprintedon of ref with 22. Copyright permission from [22]. 241 2006, JohnCopyright Wiley and 2006, Sons. John B: Representative Wiley and Sons. bridged (B): silsesquioxanes Representative [25 bridged]. Reprinted silsesquioxanes with permission [25 ]. Reprinted 242 of ref 25.with Copyright permission 2008, from American [25]. Chemical Copyright Society. 2008, American Chemical Society.

243 Nevertheless,Although bridged presentingpolysilsesquioxanes several featurin advantagesg a wide over range grafting of bridging and co-condensation, groups have been the syn- 244 prepared. thesisIn 1999, of PMOsthree research also bring groups about independently challenging aspects, reported the on most mesoporous notable being organosilica the synthesis of 245 hybrids fromthe bi-silylated suitable bi-silylated precursors precursors.baring methyl In fact,or ethyl alkoxy-silyl groups as groups organic are bridges highly [23,24,26 reactive]. species 246 After that, andseveral synthesizing PMOs were complexprepared featuring molecules ethylene, baring ethenylene, two of such phenylene groups and and thiophene a specific as organic 247 R groups. Rigidbridged unsaturated group R, precursors is often a able challenging to form weak task. interaction, such as π−π can self-assemble 248 in the synthesis Nevertheless,mixture. When bridgedhydrolysis/condensati polysilsesquioxaneson take place, featuring this order a wide can range be preserved of bridging and groups 249 layered “crystal-like”have been structural prepared. sub-domains In 1999, three can be research included groupsin the final independently PMO-type materials. reported The on meso- 250 first materialsporous featuring organosilica 1,4-phenylene hybrids bridges from was bisilylated prepared in precursors 2002. Upon baring varying methyl the size orof ethylthe R groups 251 bridged unit,as organicmaterials bridges featuring [23 layers,24,26 of]. different After that, width several were obtained PMOs were (5.6 - prepared 11.9 Å) [27 featuring]. Building ethylene, 252 upon theseethenylene, early studies, phenylene a variety and thiopheneof organic asgroups, R groups. ranging Rigid from unsaturated hydrocarbons precursors and able to 253 heteroaromaticsform to weak metal interaction, complexes, have such been as π successfully−π can self-assemble incorporated in into the PMO synthesis hybrids mixture. (Figure When 254 7 B) [22,25,28hydrolysis/condensation]. take place, this order can be preserved and layered “crystal-like” structural sub-domains can be included in the final PMO-type materials. The first materials 255 3. Sol-Gel Chemistry and Hybrid Materials featuring 1,4-phenylene bridges was prepared in 2002. Upon varying the size of the R bridged unit, materials featuring layers of different width were obtained (5.6–11.9 Å) [27]. Building upon these early studies, a variety of organic groups, ranging from hydrocarbons

and heteroaromatics to metal complexes, have been successfully incorporated into PMO hybrids (Figure7B) [22,25,28]. Catalysts 2021, 11, x FOR PEER REVIEW 9 of 41

Figure 7. (A): General synthetic pathway to PMOs [22]. Reprinted with permission from [22]. Cop- yright 2006, John Wiley and Sons. (B): Representative bridged silsesquioxanes [25]. Reprinted with permission from [25]. Copyright 2008, American Chemical Society.

Nevertheless, bridged polysilsesquioxanes featuring a wide range of bridging groups have been prepared. In 1999, three research groups independently reported on mesoporous organosilica hybrids from bisilylated precursors baring methyl or ethyl groups as organic bridges [23,24,26]. After that, several PMOs were prepared featuring ethylene, ethenylene, phenylene and thiophene as R groups. Rigid unsaturated precursors able to form weak interaction, such as can self-assemble in the synthesis mixture. When hydrolysis/condensation take place, this order can be preserved and layered “crystal-like” structural sub-domains can be included in the final PMO-type materials. The first materials featuring 1,4-phenylene bridges was prepared in 2002. Upon varying the size of the R bridged unit, materials featuring layers of different width were obtained (5.6–11.9 Å ) [27]. Building upon these early studies, a variety of organic groups, ranging from hydrocarbons and heteroaromatics to metal complexes, have been successfully incorporated into PMO hybrids (Figure 7B) [22,25,28].

3. Sol-Gel Chemistry and Hybrid Materials In this Section, a description of the sol-gel chemistry of silica is reported, with a spe- Catalysts 2021, 11, 79 cific focus on aspects that need to be considered when designing and preparing9 silica of 39 - based hybrid materials. In a general definition, a sol is defined as a colloidal dispersion of particles in a liquid, while a gel consists of a continuous solid skeleton enclosing a continuous liquid phase. The formal definition of sol-gel processing is therefore the growth of 3.colloidal Sol-Gel particles Chemistry and and their Hybrid linking Materials together to form a gel. In this section, a description of the sol-gel chemistry of silica is reported, with a specific focus3.1. Hydrolysis on aspects Reactions that need to be considered when designing and preparing silica-based hybrid materials. In a general definition, a sol is defined as a colloidal dispersion of particles Hydrolyzed silica in aqueous solution is constituted by orthosilicic acid, Si(OH)4. Pro- in a liquid, while a gel consists of a continuous solid skeleton enclosing a continuous liquid tonation of silanols to form cationic species ≡Si(OH2)+ can occur below pH 2, while further phase.hydrolysis The formal involves definition the deprotonation of sol-gel processing of a silanol is thereforegroup to the form growth an anionic of colloidal species particles and their linking together to form a gel. Si(OH)3O− above pH 7, and Si(OH)2O22− above pH 12 (Figure 8). Silicate gels are most often 3.1.synthesized Hydrolysis by Reactions acid/base-catalyzed hydrolysis of alkoxides dissolved in water and/or their parent alcohols [29,30]. Reaction 1 in Figure 8 describes the hydrolysis of an alkoxide Hydrolyzed silica in aqueous solution is constituted by orthosilicic acid, Si(OH) precursor molecule. 4. Protonation of silanols to form cationic species ≡Si(OH )+ can occur below pH 2, while The hydrolysis reaction of alkoxy-silyl precursors can2 be acid or base catalyzed. Acid further hydrolysis involves the deprotonation of a silanol group to form an anionic species catalysts protonate the alkoxide group, making a better leaving group (ROH) that does Si(OH) O− above pH 7, and Si(OH) O 2− above pH 12 (Figure8). Silicate gels are most not require3 a proton transfer in the 2transition2 state. Base catalysts contributes to the reac- often synthesized by acid/base-catalyzed hydrolysis of alkoxides dissolved in water and/or tion rate by increasing the concentration of strongly nucleophilic OH− species, which at- their parent alcohols [29,30]. Reaction 1 in Figure8 describes the hydrolysis of an alkoxide tack the electrophilic silicon atom, with release of a −OR species. precursor molecule.

Figure 8. Protonation/deprotonation of orthosilicic acid. Hydrolysis and condensation reactions of Figure 8. Protonation/deprotonation of orthosilicic acid. Hydrolysis and condensation reactions of silica precursors. silica precursors. The hydrolysis reaction of alkoxy-silyl precursors can be acid or base catalyzed. Acid catalysts protonate the alkoxide group, making a better leaving group (ROH) that does not require a proton transfer in the transition state. Base catalysts contributes to the reaction

rate by increasing the concentration of strongly nucleophilic OH− species, which attack the electrophilic silicon atom, with release of a −OR species.

3.2. Condensation Reactions Concerning the condensation of silicic units, Iler [31] divides the polymerization process into three approximate pH domains: pH < 2, 2–7, and >7. At pH 2, a boundary is present, due the point of zero charge, i.e., surface charge is zero, and the isoelectric point, i.e., electrical mobility of the silica particles, is also zero. A pH of 7, represents another boundary, because both the solubility and dissolution rates are maximized at or above pH 7, and because above pH 7 the silica particles are appreciably ionized. Consequently, particle growth occurs without aggregation or gelation. Below pH 2, condensation involves the protonation of a silanol (or an alkoxide), followed by nucleophilic attack on the silicon atom by a ≡SiOH species (reactions (2) and (3) in Figure8). In this case, the reaction rate is favored by the presence of a better leaving group (H2O or ROH). Moreover, like for acid-catalyzed hydrolysis, the reaction does not require a proton transfer in the transition state. Above pH 2, condensation involves a bi-molecular nucleophilic condensation mech- − anism (SN2-Si), featuring the attack of hydrolyzed, anionic species (≡SiO ) on neutral species. Due to inductive effects, the most acidic silanols, which are the most likely to be deprotonated, are the most highly condensed species. Consequently, condensation occurs preferentially between more condensed species and less condensed, neutral, species. In Catalysts 2021, 11, 79 10 of 39

other words, monomers and oligomers feed the growth of bigger particles. More speciﬁ- cally, once tetramers are formed, they tend to cyclize due to the proximity of chain ends and further growth occurs by addition of monomer and other low-molecular-weight species to cyclic species to form particles, and by aggregation of particles to form bigger networks.

3.3. Particle Growth and Si-O-Si Hydrolysis The hydrolysis rate of siloxane bond (Si-O-Si) increases above pH 4 and at very low pH. In general, siloxane networks are formed under those conditions in which depolymerization is less likely to occur, i.e., when the condensation is irreversible and siloxane bonds cannot be hydrolyzed once they are formed. Particle growth above pH 7 differs from that below pH 7 by at least two factors. Firstly, while near the isoelectric point no electrostatic repulsion is present, so that growth and aggregation processes occur altogether, at pH above 7 particles are appreciably charged, which makes particle aggregation unlikely. Secondly, above pH 7, the size dependence of the solubility of silica increases. Consequentially, particle growth is mediated by Ostwald ripening, a process in which smaller, more soluble particles dissolve and feed the growth on larger, less soluble particles. The growth ceases when the difference in solubility between Catalysts 2021, 11, x FOR PEER REVIEWthe largest and smallest particles becomes negligible [32]. 11 of 41

In Figure9, a schematic representation of hydrolysis and condensation reaction of silica, under acid or base catalysis, is reported.

Figure 9. Schematic representation of hydrolysis/condensation reactions of tetramethyl ortosilicate Figure 9. Schematic representation of hydrolysis/condensation reactions of tetramethyl ortosilicate (TMOS) under acid and base catalysis. (TMOS) under acid and base catalysis.

Overall, it has been observed that acid catalyzed sol-gel processes lead to the formation of bigger particles with less defects, while base catalyzed syntheses lead to the formation of smaller particles featuring more defects. The solubility of silica can be influenced also by changing the reaction medium. For example, by replacing water with a 90% methanol 10% water mixture, the solubility of silica is reduced by a factor of 28 and hydrolysis of siloxane bond is less likely.

3.4. Fluoride-Catalyzed Hydrolysis and Condensation Besides acid and base catalysis, there is a less common way to catalyze sol-gel reactions. F− ions have been reported to efficiently catalyze hydrolysis/condensation of alkoxy silanes decades ago [33]. Hydrolysis/condensation reactions follow the pathways reported in Figure 10. In the hydrolysis reaction, a nucleophilic fluorine ion approaches a molecule of alkoxy silane in solution. A SN2 reaction occurs, forming a partially fluorinated silicon

Catalysts 2021, 11, 79 11 of 39

Overall, it has been observed that acid catalyzed sol-gel processes lead to the formation of bigger particles with less defects, while base catalyzed syntheses lead to the formation of smaller particles featuring more defects. The solubility of silica can be inﬂuenced also by changing the reaction medium. For example, by replacing water with a 90% methanol 10% Catalysts 2021, 11, x FOR PEER REVIEWwater mixture, the solubility of silica is reduced by a factor of 28 and hydrolysis of siloxane12 of 41 bond is less likely.

3.4. Fluoride-Catalyzed Hydrolysis and Condensation alkoxide that in presence of H3O+, yields water and alcohol as by-products. Due to strong Besides acid and base catalysis, there is a less common way to catalyze sol-gel reactions. inductive effect, fluorine withdraws electron density from the silicon atom, making it F− ions have been reported to efficiently catalyze hydrolysis/condensation of alkoxy silanes more susceptible to nucleophilic attack from H2O. Consequentially, a pentacovalent com- decades ago [33]. Hydrolysis/condensation reactions follow the pathways reported in plex is formed in the presence of water. The complex reacts to form a partially hydrated Figure 10. In the hydrolysis reaction, a nucleophilic fluorine ion approaches a molecule silicon alkoxide and hydrofluoric acid. The condensation process occurs by formation of of alkoxy silane in solution. A SN2 reaction occurs, forming a partially fluorinated silicon a hexacovalent intermediate. + alkoxide that in presence of H3O , yields water and alcohol as by-products. Due to strong inductiveIler postulated effect, fluorine that withdraws the effectiveness electron of density fluorine from in the the polymerization silicon atom, making reaction it moreis due to the smaller ionic radius of the fluorine anion, compared to that of the hydroxyl. Other susceptible to nucleophilic attack from H2O. Consequentially, a pentacovalent complex − − − − − isanions, formed such in theas Cl presence, Br , I , NO of water.3 , SO4 Theare all complex bulkier reactsthan hydroxyl to form and a partially for that, hydrated are much siliconless effective alkoxide than and hydroxyl hydrofluoric in catalyzing acid. The these condensation reactions process by nucleophilic occurs by attack formation [34]. of a hexacovalent intermediate.

Figure 10. Fluoride-catalyzed hydrolysis (A) and condensation (B) of tetramethyl ortosilicate [34]. ReprintedFigure 10. with Fluoride permission-catalyzed from hydrolysis [34]. Copyright (A) and 1986, condensation Elsevier. (B) of tetramethyl ortosilicate [34]. Reprinted with permission from [34]. Copyright 1986, Elsevier. Iler postulated that the effectiveness of fluorine in the polymerization reaction is due to theUnder smaller optimal ionic radius conditions, of the fluorinefluoride anion,catalyzed compared sol-gel tosynthesis that of thecan hydroxyl. lead to mesopo- Other rous materials featuring− − high− surface− area− and relatively narrow pore size distribution. anions, such as Cl , Br ,I , NO3 , SO4 are all bulkier than hydroxyl and for that, are muchReale lesset al. effective studied than the influence hydroxyl of in Si/F catalyzing− ratio on these the reactionstextural properties by nucleophilic of pure attack silica [ 34ma-]. terials.Under For optimalthat, they conditions, used NH4F fluoride as fluoride catalyzed source, sol-gel as NH synthesis4+/NH3 equilibrium can lead to in meso- water porousensured materials the presence featuring of protons high surface in the areareaction and relativelymedium, needed narrow for pore the size mechanism distribution. de- Realescribed et al.in Figure studied 10. the Varying influence the ofSi/F Si/F− ratio− ratio between on the 15 texturaland 320, properties they were ofable pure to obtain silica + 2 materials.materials featuring For that, specific they used surface NH4 Farea as fluoridevalues (BET) source, rangi asng NH from4 /NH 5003 toequilibrium 1000 m /g and in watermean ensured pore size the (BJH) presence ranging of protonsbetween in 75 the and reaction 30 Å . The medium, authors needed explained for thethese mechanism variations describedby considering in Figure that 10the. Varyinglarger the the mesoporous Si/F− ratio diameter, between the 15 larger and 320, the theyaverage were silica able par- to obtainticle radius. materials This featuring could denote specific that surface the nucleati area valueson of (BET)silica particles ranging from is highly 500 to disfavored 1000 m2/g at andhigh mean fluoride pore concentration, size (BJH) ranging which betweenwould result 75 and in a 30 low Å. Theconcentration authors explained of viable thesenuclei variationsthat can grow by considering at the expenses that the of the larger silica the precursor, mesoporous in solution. diameter, Accordingly, the larger the high average fluo- silicaride concentration particle radius. would This promot could denotee the formation that the nucleationsilica particles of silicafeaturing particles large is diameter highly and large inter-particle void. The authors also studied the effect of the alcohol used as co- solvent by preparing materials using a 1:1 mixture of water and one among methanol, ethanol and 2-propanol. Upon increase of the alcohol size, surface area decreased and mean pore size increased. Nucleophilic attack of water to the fluorinated silicon intermediate, which is the rate determining step in the TMOS hydrolysis, is less favored by more polar solvents. Consequentially, a lower amount of nuclei is formed as consequence of the slower hydrolysis kinetics. Coherently, the silica material prepared in 2-butanol resembles that prepared using the highest fluoride concentration [35].

Catalysts 2021, 11, 79 12 of 39

disfavored at high fluoride concentration, which would result in a low concentration of viable nuclei that can grow at the expenses of the silica precursor, in solution. Accord- ingly, high fluoride concentration would promote the formation silica particles featuring large diameter and large inter-particle void. The authors also studied the effect of the alcohol used as co-solvent by preparing materials using a 1:1 mixture of water and one among methanol, ethanol and 2-propanol. Upon increase of the alcohol size, surface area decreased and mean pore size increased. Nucleophilic attack of water to the fluorinated silicon intermediate, which is the rate determining step in the TMOS hydrolysis, is less favored by more polar solvents. Consequentially, a lower amount of nuclei is formed as consequence of the slower hydrolysis kinetics. Coherently, the silica material prepared in 2-butanol resembles that prepared using the highest fluoride concentration [35]. It is important to highlight that these syntheses are carried out at neutral pH, 36 ◦C, using low amount of solvent and in the absence of templating agents. By tuning the composition of the synthesis mixture, it is possible to achieve highly porous materials, with textural properties that are tuned for a specific application. Moreover, F− sol-gel syntheses allow to incorporate Al and Ti within the network as well as organic building blocks, by substituting a fraction of TMOS with an equimolar amount of either an Al (or Ti) precursor or a silyl-derivative of the type RSi(OR‘)3, baring a functional group R of interest.

3.5. Surfactant-Mediated Sol-Gel Synthesis As mentioned before, surfactants are widely implemented in sol-gel synthesis to achieve mesoporous silica materials, for applications in several ﬁelds. Supramolecular aggregates of ionic surfactants (long-chain alkyltrimethylammonium halides) and non- ionic triblock copolymers have been used as structure-directing agents (SDAs) in many synthetic procedures. In solution, under certain conditions, they form of a lyotropic liquid- crystalline phase, which can guide the assembly of ordered mesostructured materials through hydrolysis and condensation of the silica precursors under basic conditions. The mesoporous materials are obtained by removal of the surfactant by extraction or calcination. Typically, a lyotropic liquid-crystalline phase is formed above a certain concentration of surfactant. However, a cooperative self-assembly between the SDA and the silica precursors can lead to a liquid-crystal phase with hexagonal, cubic, or laminar arrangement, even at lower concentration of surfactant. An essential condition to ensure this cooperative self-assembly and avoid phase separation is the presence of attractive interactions between the template and the silica precursor. Such interactions vary, depending on the type of surfactant and on the pH of the solution. If the reaction takes place under basic conditions, silica species will be present in the form of anions. If a cationic quaternary ammonium surfactant is used as the SDA, electrostatic interactions such as those depicted in Figure 11A will be produced. However, if the preparation takes place below pH 2, silica species will be positively charged and to produce an interaction with the cationic surfactant, it is necessary to add a counter ion X− (usually a halide, Figure 11B). Although less commonly, negatively charged surfactants (e.g., long-chain alkyl phosphates) can also be used as the SDA. Compared to positively charged surfactant, a reverse situation is expected, with protonated silicon species interacting with the negatively charged functional groups of the surfactant molecules, at pH below 2 (Figure 11C), and a mediating positive ion M+ needed under basic conditions (Figure 11D). Lastly, when non-ionic surfactants are used (e.g., long chain amines), attractive interaction between SDA molecules and silica precursors are provided by hydrogen bonds. Such interactions can be promoted by adding to the mixture either polar molecules (e.g., polyethylene oxide, depicted as triangles in Figure 11E) or ion pairs (Figure 11F) [22]. CatalystsCatalysts 20212021,, 1111,, x 79 FOR PEER REVIEW 1413 of of 41 39

Figure 11. Schematic representation of the possible interactions between silica precursors and Figure 11. Schematic representation of the possible interactions between silica precursors and sur- factantsurfactant molecules molecules [22]. [Reprinted22]. Reprinted with withpermission permission from from[22]. Copyright [22]. Copyright 2006, John 2006, Wiley John Wileyand Sons. and Sons.

3.6.3.6. Silyl Silyl-Derivatives-Derivatives Precursors Precursors TheThe most implemented implemented precursors precursors for for sol-gel sol- synthesisgel synthesis of silica of are silica tetraethylortholisi- are tetraethy- lortcateholisicate (TEOS) and (TEOS) tetremethylorthosilicate and tetremethylorth (TMOS).osilicate Bernards (TMOS). etBernards al. studied et al. the studied hydrolizability the hy- drolizabilityof siloxane featuringof siloxane alkoxy featuring residues alkoxy of residues different of length. different They length. found They that found the hydrolyz- that the hydrolyzabilityability of the silanes of the insilanes an acidic in an environment acidic environment was inversely was inversely proportional proportional to the sizeto the of sizethe of alkoxy the alkoxy terminal terminal groups groups (TMOS (TMOS > TEOS > TEOS > TPOS, > TPOS, Figure Figure 12 1).2). TheyThey explained that that Catalysts 2021, 11, x FOR PEER REVIEWthethe effect effect of of the the alcohols alcohols on on the the hydrolysis hydrolysis rate rate of each of each of the of silanes the silanes was due was to due differences to differ-15 of 41 inences degree in degreeof dissociation of dissociation of HCl in of each HCl one in each of the one alcohols of the (methanol alcohols (methanol > ethanol, > 1- ethanol,propa- nol1-propanol > 2-propanol) > 2-propanol) [36]. [36]. Alkoxy groups are highly reactive species. They can easily undergo partial hydrolysis and condensation leading to oligomers. This is particularly problematic considering that, in many cases, they are used as precursors of materials in which the functional groups R need to be homogeneously dispersed throughout the material (heterogeneous catalysts, adsorbents, sensors etc.). Silyl derivatives are very moisture-sensitive. For that, the design of synthetic routes usually aims to incorporate the alkoxysilyl group in the last step of the preparation of the building block. Whenever this is not possible, silyl derivatives need to be protected from humidity, by storing them under inert atmosphere and by always carrying out reactions that involve them under anhydrous conditions, especially if acid or bases are also present in the reaction mixture. Additional care needs to be taken in the work-up procedure, as distillation at high temperature can cause spontaneous condensation of alkoxy groups. The size of the alkoxy group also affects the kinetic of hydrol- Figure 12. Ball and stick representation of tetramethyl ortosilicate (TMOS), tetraethyl orthosilicate ysisFigure with 12. TMOS Ball and containing stick representation synthesis of mixture, tetramethyl reaching ortosilicate the sol (TMOS),-gel transition tetraethyl after orth shorterosilicate time,(TEOS)(TEOS) compared and and tetrapropyl tetrapropyl to TEOS orthosilicate ort-basedhosilicate mixtures. (TPOS). (TPOS). This is in line with what can be deduced by observing the mechanism depicted in Figure 9 and the ball and stick structures depicted in Alkoxy groups are highly reactive species. They can easily undergo partial hydrolysis Figure4. Silica 12.- BasedEthoxy Hybrids substituent in Heterogeneouss are bulkier than Catalysis methoxy ones and therefore they partially hinderand condensation the approach leading of the tonucleophile oligomers. to This the issilicon particularly [29]. Consequentially, problematic considering methoxysilyl that, With the aim of highlighting the broad scope of application of silica-based hybrid groupsin many are cases, expected they to are be used less asstable precursors and more of materialsreactive than in which ethoxysilyl the functional groups. groups R needcatalysts, to be a homogeneously general overview dispersed of different throughout type of active the material sites bounded (heterogeneous onto silica catalysts, supports adsorbents,is described sensors in this etc.).Section Silyl (summarized derivatives in are Table very moisture-sensitive.1), together with few For representative that, the design ex- ofamples synthetic of their routes synthesis usually and aims applications. to incorporate the alkoxysilyl group in the last step of the preparation of the building block. Whenever this is not possible, silyl derivatives need to be protectedTable 1. Families from humidity, of hybrid bycatalysts storing described them under in this inert review atmosphere article. and by always carrying out reactions that involve themCatalyst under anhydrous conditions, especiallyActive if acid Site or bases Heteropolyacids (HPAs) Acid Sulfonic acids Acid Amines Base N-cycles Base Organometallic complexes Redox Metal nanoparticles Redox Multi-functional catalysts Multiple

4.1. Acid Catalysts Many reactions in the chemical industry are carried out under acid catalysis conditions. Purely inorganic microporous zeolites are perhaps the most notable example of heterogeneous catalysts, being them implemented in several chemical processes [37]. Never- theless, the small pore size limits their application to certain reactions, while others require catalysts in which the active sites are accessible to bulkier molecules. To overcome the pore size limitations, inorganic acids such as polyphosphoric acid [38], perchloric acid [39], fluoroboric acid [40] and sulfuric acid [41] have been supported onto silica. Although effective in overcoming some of the limitations of microporous acid catalysts, these purely inorganic materials present little margin for modifications and fine tuning of their properties for a specific catalyzed reaction. Another solution to this problem is functionalizing mesoporous silica supports with organic molecules baring Brönsted acid groups [42]. Considering the different possibilities, the two main classes of materials developed through this approach are silica-supported heteropolyacids and silica-supported sulfonic acids. Heteropolyacids (HPAs) are polyoxometalates constituted by MOx polyhedra (usually distorted octahedra) which surround one or more heteroatoms (Figure 13) [43]. Sev- eral authors reported on silica-supported HPAs for applications in heterogeneous catalysis [44–48]. Sato et al. supported three types of HPA over differently porous silica by wet impregnation: phosphotungstic acid (H3PW12O40‧nH2O), silicotungstic acid (H4SiW12O40‧24H2O), and phosphomolybdic acid (H3PMo12O40‧nH2O). The catalysts were used in the vapor-phase dehydration of glycerol to acrolein. It was found that silico-tungstic acid, supported on silica materials featuring mesopores of 10 nm, showed the best

Catalysts 2021, 11, 79 14 of 39

are also present in the reaction mixture. Additional care needs to be taken in the work-up procedure, as distillation at high temperature can cause spontaneous condensation of alkoxy groups. The size of the alkoxy group also affects the kinetic of hydrolysis with TMOS containing synthesis mixture, reaching the sol-gel transition after shorter time, compared to TEOS-based mixtures. This is in line with what can be deduced by observing the mechanism depicted in Figure9 and the ball and stick structures depicted in Figure 12. Ethoxy substituents are bulkier than methoxy ones and therefore they partially hinder the approach of the nucleophile to the silicon [29]. Consequentially, methoxysilyl groups are expected to be less stable and more reactive than ethoxysilyl groups.

4. Silica-Based Hybrids in Heterogeneous Catalysis With the aim of highlighting the broad scope of application of silica-based hybrid catalysts, a general overview of different type of active sites bounded onto silica supports is described in this section (summarized in Table1), together with few representative examples of their synthesis and applications.

Table 1. Families of hybrid catalysts described in this review article.

Catalyst Active Site Heteropolyacids (HPAs) Acid Sulfonic acids Acid Amines Base N-cycles Base Organometallic complexes Redox Metal nanoparticles Redox Multi-functional catalysts Multiple

4.1. Acid Catalysts Many reactions in the chemical industry are carried out under acid catalysis conditions. Purely inorganic microporous zeolites are perhaps the most notable example of heterogeneous catalysts, being them implemented in several chemical processes [37]. Nevertheless, the small pore size limits their application to certain reactions, while others require catalysts in which the active sites are accessible to bulkier molecules. To overcome the pore size limitations, inorganic acids such as polyphosphoric acid [38], perchloric acid [39], fluoroboric acid [40] and sulfuric acid [41] have been supported onto silica. Although effective in overcoming some of the limitations of microporous acid catalysts, these purely inorganic materials present little margin for modifications and fine tuning of their properties for a specific catalyzed reaction. Another solution to this problem is functionalizing mesoporous silica supports with organic molecules baring Brönsted acid groups [42]. Considering the different possibilities, the two main classes of materials developed through this approach are silica-supported heteropolyacids and silica-supported sulfonic acids. Heteropolyacids (HPAs) are polyoxometalates constituted by MOx polyhedra (usually distorted octahedra) which surround one or more heteroatoms (Figure 13)[43]. Several authors reported on silica-supported HPAs for applications in heterogeneous catalysis [44–48]. Sato et al. supported three types of HPA over differently porous silica by wet impregnation: phosphotungstic acid (H3PW12O40·nH2O), silicotungstic acid (H4SiW12O40·24H2O), and phosphomolybdic acid (H3PMo12O40·nH2O). The catalysts were used in the vapor-phase dehydration of glycerol to acrolein. It was found that silico-tungstic acid, supported on silica materials featuring mesopores of 10 nm, showed the best catalytic activity, with 98 mol% conversion and an acrolein selectivity higher than 85 mol%. Moreover, they observed an influence of the meropores size on the catalytic activity, with a very steep deactivation of the catalysts when the HPA were supported onto a silica material having mesopores of 3 nm [49]. In another study, Blanco et al. used silica supported H3PMo12O40·nH2O and H3PW12O40·nH2O for dehydration reactions of different alcohols. Specifically, the Catalysts 2021, 11, x FOR PEER REVIEW 16 of 41

catalytic activity, with 98 mol% conversion and an acrolein selectivity higher than 85 mol%. Moreover, they observed an influence of the meropores size on the catalytic activity, with a very steep deactivation of the catalysts when the HPA were supported onto a Catalysts 2021, 11, 79 silica material having mesopores of 3 nm [49]. In another study, Blanco et al. used silica15 of 39 supported H3PMo12O40‧nH2O and H3PW12O40‧nH2O for dehydration reactions of different alcohols. Specifically, the dehydration of 1,2-diphenylethanol, 1-3,4-dimethoxyphenyl-2- phenylethanol and cholesterol was investigated. The authors found both catalysts to be dehydration of 1,2-diphenylethanol, 1-3,4-dimethoxyphenyl-2-phenylethanol and choles- highly active and selective with no appreciable loss of the catalytic activity over multiple terol was investigated. The authors found both catalysts to be highly active and selective cycles [50]. Laurenti et al. prepared silica supported H4SiW12O40‧nH2O and with no appreciable loss of the catalytic activity over multiple cycles [50]. Laurenti et al. H3PW12O40‧nH2O by wet impregnation and tested them for the alkylation of 3-methylthi- prepared silica supported H SiW O ·nH O and H PW O ·nH O by wet impregnation ophene with 2-methyl-2-butene,4 12 used40 as 2 model reaction3 12 for40 gasoline2 desulfurization. and tested them for the alkylation of 3-methylthiophene with 2-methyl-2-butene, used as Their performances were shown to be superior to those of zeolites USY, Beta and MCM- model reaction for gasoline desulfurization. Their performances were shown to be superior 22. Supported H3PW12O40‧nH2O was also tested in a real feed of FCC gasoline with prom- to those of zeolites USY, Beta and MCM-22. Supported H PW O ·nH O was also tested ising results [51]. Although highly active for some specific3 activation,12 40 2 polyoxometales in a real feed of FCC gasoline with promising results [51]. Although highly active for suchsome as speciﬁcHPAs provide activation, little polyoxometales room for fine tuning such as of HPAsthe chemical provide structure little room and for consequen- ﬁne tuning tialof optimization the chemical of structure the catalytic and consequentialactivity of the optimizationheterogeneous of catalysts. the catalytic activity of the heterogeneous catalysts.

FigureFigure 13. 13. BallBall and and stick stick representations representations of oftwo two of ofthe the most most common common HPA HPA variants. variants. P (black), P (black), Mo Mo (dark(dark grey), grey), O O (light (light grey) grey) [43 [43].]. Reprinted Reprinted with with permission permission from from [43 [43].]. Copyright Copyright 2014, 2014, Elsevier. Elsevier. Perhaps, the most versatile way to incorporate strong Brönsted acid sites into meso- Perhaps, the most versatile way to incorporate strong Brönsted acid sites into mesoporous silica matrixes is the synthesis of supported sulfonic acid groups. The acidity of porous silica matrixes is the synthesis of supported sulfonic acid groups. The acidity of the sulfonic acid proton is strongly influenced by its chemical make-up, which allows for the sulfonic acid proton is strongly influenced by its chemical make-up, which allows for a fine tuning of the acidity of the sulfonic proton by exploiting the versatility of organic a fine tuning of the acidity of the sulfonic proton by exploiting the versatility of organic synthesis [52]. synthesis [52]. Since 1998, sulfonic acid groups have been supported onto mesoporous silicas [53,54]. Since 1998, sulfonic acid groups have been supported onto mesoporous silicas In the first studies on these hybrid acid catalysts, two approaches were typically im- [53,54]. In the first studies on these hybrid acid catalysts, two approaches were typically plemented: (i) post synthetic grafting of 3-mercaptopropyltrimethoxysilane (MPTMS) implemented:followed by oxidation (i) post synthetic of the thiol graft groupsing of to 3 sulfonic-mercaptopropyltrimethoxysilane acid moieties and (ii) co-condensation (MPTMS) followedof MPTMS by oxidation with TEOS of the or TMOS,thiol groups also to followed sulfonic by acid oxidation. moieties and Since (ii) their co-condensation introduction, ofmany MPTMS advances with have TEOS been or TMOS, made, such also as followed increasing by the oxidation. MPTMS Since loading their through introduction, a coating manymethod advances [52], replacing have been calcination made, suc withh as extractionincreasing methods the MPTMS [55], loading and co-functionalization through a coating of methodMPTMS [52 and], replacing octyl substituents calcination to enhancewith extraction the catalytic methods activity [55], by and increasing co-functionalization the hydropho- ofbicity MPTM ofS the and hybrid octyl catalyst substituents [56]. Supportedto enhance sulfonic the catalytic acid catalysts activity areby primarilyincreasing employed the hy- drophobicityin biomass conversion of the hybrid [52]. catalyst However, [56]. their Supported versatility sulfonic allowed acid their catalysts successful are primarily implemen- employedtation in otherin biomass catalytic conversion processes [52 such]. However, as synthesis their ofversatility 2,2-bis(5-methylfuryl)propane allowed their successful by implementationcondensation of in acetone other with catalytic 2-methylfuran processes [ such53], esterification as synthesis of of D-sorbitol 2,2-bis(5- withmethylfu- lauric ryl)propaneacid [57], synthesis by condensation of monolaurin of acetone by direct with esterification2-methylfuran of [53 glycerol], esterification with lauric of D acid-sorbi- [58], tolFries with and lauric Beckmann acid [57], rearrangements synthesis of monolaurin [59,60], syntheses by direct ofesterification polyhydroquinoline of glycerol deriva- with tives [61], synthesis of β-aminocarbonyls through Mannich reactions [62], and others [52]. Several substrates featuring sulfonic acid groups have been implemented as precursors for the sulfonation of mesoporous materials. From the point of view of the inclusion of sulfonic acid groups into the final hybrid materials, different approaches can be followed: (i) implementation of commercial sulfur-containing organosiloxanes and eventual conversion of the sulfur-based functional groups to sulfonic acid moieties, usually carried out after incorporation into the solid material (e.g., MPTMS); (ii) synthesis of new silyl-derivatives containing sulfonic acid groups; (iii) functionalization of supported organic moieties with Catalysts 2021, 11, x FOR PEER REVIEW 17 of 41

lauric acid [58], Fries and Beckmann rearrangements [59,60], syntheses of polyhydroquinoline derivatives [61], synthesis of β-aminocarbonyls through Mannich reactions [62], and others [52]. Several substrates featuring sulfonic acid groups have been implemented as precursors for the sulfonation of mesoporous materials. From the point of view of the inclusion of sulfonic acid groups into the final hybrid materials, different approaches can be followed: (i) implementation of commercial sulfur-containing organosiloxanes and eventual Catalysts 2021, 11, 79 conversion of the sulfur-based functional groups to sulfonic acid moieties, usually16 carried of 39 out after incorporation into the solid material (e.g., MPTMS); (ii) synthesis of new silyl- derivatives containing sulfonic acid groups; (iii) functionalization of supported organic moieties with sulfuric acid [52,63,64]. In Figure 14, some organic moieties that have been sulfuricsuccessfully acid [52used,63 ,64to ].synthesize In Figure silica14, some-supported organic sulfonic moieties acid that catalysts have been are successfully reported, in- usedcluding to synthesize alkyl-sulfonic silica-supported acids (precursors sulfonic 1, 2), acid aryl catalysts-sulfonic areacids reported, (precursors including 3, 4, 8, alkyl-10, 11), sulfonicS-containing acids (precursorsheterocycles 1, (precursors 2), aryl-sulfonic 5–7 and acids 12) (precursors and bridged 3, species 4, 8, 10, (precursor 11), S-containing 13). Un- heterocyclessurprisingly, (precursors using different 5–7 and siloxane 12) and precursors bridged speciesinfluences (precursor the properties 13). Unsurprisingly, of the final cat- usingalyst, different across the siloxane board. precursors A few examples inﬂuences are reported the properties below. of the ﬁnal catalyst, across the board. A few examples are reported below.

Figure 14. List of some of the precursors implemented in the synthesis of silica supported sulfonic Figure 14. List of some of the precursors implemented in the synthesis of silica supported sulfonic acids [52]. acids [52]. An increase in hydrophobicity, and consequently hindered catalyst deactivation by wa- An increase in hydrophobicity, and consequently hindered catalyst deactivation by ter, and an increase in the mass transfer of hydrophobic compounds have been achieved by water, and an increase in the mass transfer of hydrophobic compounds have been using phenylsulfonic acid derivatives instead of propylsulfonic acid moieties [52]. Phenyl- achieved by using phenylsulfonic acid derivatives instead of propylsulfonic acid moieties sulfonic acid siloxane-based precursors have been used by several authors to synthesize supported[52]. Phenylsulfonic sulfonic acid acid materials siloxane- thatbased have precursors shown have superior been catalytic used by propertiesseveral authors when to comparedsynthesize both supported with others sulfonic non-commerial/non-aromatic acid materials that have shown catalysts superior and with catalytic commercial proper- resinsties when such as compared Amberlyst-15 both (Figure with others 14, precursors non-commerial/non 8, 10, 11) [65-–aromatic69]. Lindlar catalysts et al. reported and with commercial resins such as Amberlyst-15 (Figure 14, precursors 8, 10, 11) [65–69]. Lindlar the synthesis of MCM-41-Ph-SO3H (Figure 14, precursor 11) [52] with pore diameters of up toet 6 al. nm reported by implementing the synthesis swelling of MCM agents.-41-Ph Firstly,-SO3H (Figure the phenyl 14, precursor groups were 11) grafted[52] with onto pore thediameters silica surface; of up to subsequently, 6 nm by implementing chlorosulfonic swelling acid agents. was used Firstly, for sulfonation.the phenyl groups However, were chlorosulfonicgrafted onto the acid silica could surface; also reactsubsequently, with free chlorosulfonic silanols. To avoid acid was this used phenomenon, for sulfonation. cap- pingHowever, agents, chlorosulfonic such as trimethoxymethylsilane, acid could also react were with graftedfree silanols. after functionalizationTo avoid this phenome- with thenon, phenyl capping precursor. agents, such For the as trimethoxymethylsilane, sulfonation of mesoporous were silica grafted materials, after functionaliz grafting isation the mostwith widely the phenyl used precursor. method, due For to the the sulfonation advantages of it mesoporous has over co-condensation silica materials, method, grafting the is main one being SDA removal by calcination rather than by extraction, which is usually not completely effective and would imply the use of a solvent. Nevertheless, Gedeona et al. found that after extraction, further calcination with slow heating ramp up to 200 ◦C could completely remove P123 from the extracted sample [70]. The functionalization of fluorinated sulfonic acid precursors inside the mesopores was first reported by Harmer et al. in 1997 [71]. In these hybrid mesoporous materials, the acidity of the sulfonic acid groups is strongly enhanced by the presence of electroneg- ative fluorine atoms in its proximity. However, the preparation and stability of these hybrids are major drawbacks as they would often undergo leaching and consequent deactivation [65]. 1,2,2-Trifluoro-2-hydroxy-1-trifluoromethylethane sulfonic acid sultones Catalysts 2021, 11, 79 17 of 39

(Figure 14, precursor 6) have been directly anchored onto silica surfaces through a direct synthetic strategy [72]. The same authors reported another strategy for the preparation of fluorinated supported sulfonic acids through a platinum-catalyzed hydrosilylation procedure. The resulting silyl-derivative could then be anchored onto the silica surface through a co-condensation reaction or grafting [73]. In our group, we recently prepared two silica-supported aryl-sulfonic acid catalysts, one of them featuring a fluorinated aromatic ring (starting from precursors 3 and 4, Figure 14). After an in-depth characterization, the hybrids were tested in the acetal formation reaction between benzaldehyde and ethylene glycol. Although, both catalysts showed excellent performances, the fluorinated hybrid was able to retain its catalytic activity over three catalytic cycles, while the non-fluorinated one showed a minimal but progressive loss of catalytic activity. A hydrophobic version of the catalysts, in which surface-silanols were capped with hexamethyl disilazane, was prepared and tested in the same catalytic process. The hydrophobic catalysts showed a drop in their catalytic activity, compared to the hydrophilic hybrids, indicating a beneficial role of the polar surface of the silica support on the overall catalytic activity [74]. Recently, supported N-propylsulfamic acid groups have drawn significant interest. Sulfamic acid-based catalysts can be described as strong acids that are zwitterionic in the absence of water (Figure 14; precursor 9) [75,76]. These catalysts are easily separable from reaction mixtures and can be recycled different times if supported on the surface of mesopores. Under alkaline or neutral pH, sulfamic acid derivatives can be boiled without appreciable hydrolysis. However, they slowly hydrolyze under acid conditions, giving a supported primary amine and releasing a molecule of sulfuric acid [77]. Supporting complex sulfonic-functionalized moieties is not a trivial task, especially when green chemistry standards need to be met. Phenyl-sulfonic acid catalysts often require using either corrosive agents for sulfonation of aromatic precursors or expensive pre-sulfonated reactants, to begin with. Even less trivial is the synthesis of fluorinated compounds, with the few silyl-derivatives reported being synthesized through low-yielding steps, starting from expensive reactants. There is room for improvement also in the synthetic strategies implemented to obtain the silica-supported hybrid catalysts. The use of expensive surfactants and of acid/base reactants in the sol-gel processes, as well as the high calcination temperatures, are also aspects that need to be kept into account when designing a hybrid catalyst with potential scaling-up perspectives.

Sulfonated Periodic Mesoporous Organosilicas (PMOs) As mentioned before, many studies have been carried out with the scope of tuning the hydrophilic/hydrophobic nature of supported sulfonic acid materials, due to the influence that this parameter has on their catalytic activity. This is particularly important, because one of the main catalytic applications of supported sulfonic acid moieties involves the use of hydrophobic fatty acids as reactants [78,79]. Silanol-capping with hydrophobic groups and implementation of hydrophobic sulfonated silyl-derivatives are viable alternatives, which nevertheless present disadvantages such as decreasing the pore size and consequent mass transfer limitations in the case of bulky compounds [80]. Periodic mesoporous organosilicas (PMOs) are often regarded as the next generation of these catalysts, with sufficient hydrophobicity and crystal-like pore walls. The first sulfonated benzene-bridged PMO (Ph- PMO-SO3H) was synthesized through the condensation of 1,4-bis(triethoxysilyl)benzene (BTEB) in presence of specific SDAs. The solid obtained was then sulfonated with a 25% solution of SO3/H2SO4. The same authors also carried out a co-condensation of BTEB and MPTMS under basic conditions, in the presence of a SDA, achieving a Ph-PMO with pendant thiol groups, subsequently converted to sulfonic acid by treatment with HNO3 at room temperature for 24 h [81]. The use of acidic SBA-15-like PMOs, in which the location of the acid sites could be controlled has been proposed and tested in acid-catalyzed reactions in hot water [82]. The hybrids were prepared either by the condensation of BTEB, followed by sulfonation using Catalysts 2021, 11, 79 18 of 39

chlorosulfonic acid (catalyst 1) or by MPTMS condensation and further oxidation with H2O2 (catalyst 2). The acidity of the materials was studied by calorimetric measurements of the adsorption of ammonia. The catalytic activity of the materials was tested in the gas-phase dehydration of isopropanol, used as a model reaction, and compared with the reference acid sulfonated resin, i.e., Amberlyst-15. While the oxidation step of MPTMS thiol groups to sulfonic acid groups in H2O2 did not affect the mesoscopic structure, the treatment with chlorosulfonic acid, to incorporate sulfonic acid moieties in the structural aromatic units, did affect it. In spite of the partially compromised structure, catalyst 1 (obtained by treatment with chlorosulfonic acid) showed catalytic activity in the gas-phase dehydration of isopropanol equivalent to that of Amberlyst-15, although with progressive partial loss of the activity due to the leaching of sulfur species. On the other hand, SBA-15-like PMOs obtained by H2O2 oxidation of the thiol groups (catalyst 2) showed lower catalytic activity in the gas-phase dehydration of isopropanol. However, catalyst 2 did not show any significant leaching of sulfur species was observed. The catalytic performances of these materials were also evaluated in biomass val- orization, such as cellobiose hydrolysis in hot water. At 150 ◦C the catalysts showed significant leaching of sulfur species with the catalytic activity observed mainly due to species performing in homogeneous phase. Extensive washing of the catalysts prior to the treatment somehow improved their stability and recyclability. The washing step probably acted by removing the labile species that leached in the catalytic tests. Consequently and unsurprisingly, this led to lower catalytic activity in the first cycle [82]. In another example, Jerome et al. also studied different types of silica supported sulfonic acid materials and monitored the catalytic activities for the aqueous synthesis of bis(indolyl)methanes [83]. They extensively studied the effect of hydrophobicity on the catalytic activities and found that an increase in hydrophobicity led to better catalytic performances for this reaction. By comparing Ph-PMO-Pr-SO3H and SBA-15-PrSO3 catalysts, the former, in which phenyl groups are present within the pore walls, showed higher catalytic activity [84]. The versatility of silica-based synthesis, allows for the incorporation of multiple functionalities, either to improve the catalytic efficiency of a specific active site or to carry out multi-step cascade reactions. As an example of the former, in some catalytic processes, the activity of sulfonic acid catalysts benefits from the presence of amine-type functionalities. Thiel et al. introduced amine groups via post-synthesis functionalization of a BTEB- based PMO-SO3H obtaining a bi-functional PMO (Figure 15)[85]. Firstly, BTEB was reacted with tert-butyloxycarbonyl(Boc)-protected APTS in the presence of SDA molecules. The resulting PMO structure was then sulfonated with chlorosulfonic acid. Finally, the protecting group was removed from the catalyst. The catalyst was tested in nitroaldol condensation reactions, with excellent yields. The authors also tested the catalytic activity of N-protected PMO-SO3H/-NHBoc in nitroaldol condensation reaction, recording no conversion. Interestingly, the protected system exhibited remarkable activity in the conversion of dimethoxyphenyl-methane to benzaldehyde. This catalyst was also compared with monofunctionalized mesoporous materials (SBA-NH2 and PMO-SO3H) with both catalysts performing worse than the bi-functional catalyst PMO-SO3H/-NH2. In another relevant study Alauzun et al. reported the synthesis a bi-functional mesoporous material containing two antagonist functions, i.e., an acidic group in the framework and a basic one in the channel pores. The material was synthesized by co-condensation of a mixture of a bridged disilane featuring a disulfur group–(MeO)3Si-(CH2)3-S-S-(CH2)3- Si(OMe)3 (S2); tetraethyl orthosilicate (TEOS); a silyl-derivative featuring a protected amine group–(MeO)3Si-(CH2)3-NHBoc. The synthesis was carried out in the presence of non-ionic surfactant P123. The final bi-functional hybrid catalyst was obtained by post-synthetic reduction of disulfide units followed by their oxidation to SO3H groups and deprotection of amino groups [86]. Overall, relatively few reports on sulfonic acid-functionalized PMOs Catalysts 2021, 11, 79 19 of 39

are reported in the scientiﬁc literature; synthesis and puriﬁcation of molecules featuring a sulfonic acid group and two alkoxy-silyl functionalities, to work as bridged precursor, are demanding tasks that pose severe limitations, related to the strong tendency of bisilylated Catalysts 2021, 11, x FOR PEER REVIEWmoieties to undergo spontaneous hydrolysis/condensation (higher than that of monosily-20 of 41

lated ones), together with the harsh conditions that are usually required for the preparation of platform molecules featuring sulfonic acids.

Figure 15. Synthesis of a bi-functionalized PMO for nitroaldol catalytic reactions [52,84]. Reprinted withFigure permission 15. Synthesis from [of52 a]. bi Copyright-functionalized 2018, JohnPMO Wiley for nitroaldol and Sons. catalytic reactions [52,84]. Reprinted with permission from [52]. Copyright 2018, John Wiley and Sons. 4.2. Base Catalysts AnotherIn another important relevant classstudy of Alauzun catalysts et areal. reported those carrying the synthes baseis functionalities, a bi-functional meso- able toporous activate material certain containing functional two groups antagonist by electron-donation. functions, i.e., an Within acidic thegroup realm in the of silica-frame- supportedwork and hybrids,a basic one the in majority the channel of these pores. catalysts The material consist ofwas N-based synthesized compounds by co-condensa- (amines andtion N-cycles of a mixture of various of a nature)bridged and disilane consequentially featuring a this disulfur class ofgroup hybrids–(MeO) have3Si been-(CH vastly2)3-S-S- studied.(CH2)3-Si(OMe) Bigi et al.3 (S2); indicated tetraethyl a strong orthosilicate correlation (TEOS); between a silyl the activity-derivative scale featuring of supported a pro- aminestected andamine that group of the–(MeO) corresponding3Si-(CH2)3- homogeneousNHBoc. The synthesis counterparts, was carried the order out ofin activitythe pres- beingence primaryof non-ionic > secondary surfactant > P123. tertiary The in final nitroaldol bi-functiona condensationl hybrid catalyst reactions was at obtained 90 ◦C[87 ].by However,post-synthetic this general reduction trend of has disulfide not always units been followed conﬁrmed. by their For oxidation example, to Kitayama SO3H groups et al. reportedand deprotection on mesoporous of amino silica groups FSM-16 [86 functionalized]. Overall, relatively with secondary few reports amines on sulfonic being more acid- activefunctionalized for the aldol PMOs reaction are reported than FSM-16 in the scientific functionalized literature; with synthesis primary and amines purification [88]. In of anothermolecules study, featuring Katz eta sulfonic al. found acid that group acid–base and two synergy alkoxy between-silyl functionalities, surface silanols to work and as primarybridged amines precursor, could are also demanding affect the catalytictasks that activity pose severe and that limitations, such cooperativity related to enhanced the strong thetendency selectivity of bisilylated to unsaturated moieties products to undergo in base-catalyzed spontaneous hydrolysis/condensation reactions, such as the Michael, (higher Henrythan that and of Knoevenagel monosilylated reactions ones), [ 89together]. with the harsh conditions that are usually re- quiredShantz for etthe al. preparation prepared a of series platform of surface-anchored molecules featuring amines sulfonic by either acids. grafting or tethering reactions and compared their activity in the Henry reaction between nitrobenzaldehyde and4.2. nitromethane Base Catalysts (Figure 16A). The authors found the primary amine (catalyst 1) to be the less active than secondary and tertiary amine. They also observed differences in selec- Another important class of catalysts are those carrying base functionalities, able to tivity. The primary amine appeared to follow the imine formation mechanism, favoring activate certain functional groups by electron-donation. Within the realm of silica-sup- the formation of the nitrostyrene product. On the other hand, the samples containing ported hybrids, the majority of these catalysts consist of N-based compounds (amines and secondary amines resulted to be highly selective to the nitroalcohol product. Interestingly, N-cycles of various nature) and consequentially this class of hybrids have been vastly the selectivity to the nitroalcohol product increased proportional to the amine loading. studied. Bigi et al. indicated a strong correlation between the activity scale of supported Among the secondary amines, the less sterically hindered one (catalyst 2) appeared to be amines and that of the corresponding homogeneous counterparts, the order of activity the most active. Clearly, the activity of supported amines cannot be rationalized only upon being primary > secondary > tertiary in nitroaldol condensation reactions at 90 °C [87]. their basic strength, in terms of pKa, but other aspects such as nucleophilicity and the However, this general trend has not always been confirmed. For example, Kitayama et al. reaction mechanisms need to be considered [90–92]. reported on mesoporous silica FSM-16 functionalized with secondary amines being more Silica-supported guanidine moieties have also been synthesized by several authors andactive implemented for the aldol in areaction number than of catalytic FSM-16 reactions. functionalized Dupont with et al. primary synthetized amines a guanidine- [88]. In another study, Katz et al. found that acid–base synergy between surface silanols and primary amines could also affect the catalytic activity and that such cooperativity enhanced the selectivity to unsaturated products in base-catalyzed reactions, such as the Michael, Henry and Knoevenagel reactions [89]. Shantz et al. prepared a series of surface-anchored amines by either grafting or tethering reactions and compared their activity in the Henry reaction between nitrobenzaldehyde and nitromethane (Figure 16A). The authors found the primary amine (catalyst 1) to

Catalysts 2021, 11, x FOR PEER REVIEW 21 of 41

be the less active than secondary and tertiary amine. They also observed differences in selectivity. The primary amine appeared to follow the imine formation mechanism, favoring the formation of the nitrostyrene product. On the other hand, the samples containing secondary amines resulted to be highly selective to the nitroalcohol product. Interestingly, the selectivity to the nitroalcohol product increased proportional to the amine loading. Among the secondary amines, the less sterically hindered one (catalyst 2) appeared to be the most active. Clearly, the activity of supported amines cannot be rationalized only upon their basic strength, in terms of pKa, but other aspects such as nucleophilicity and the reaction mechanisms need to be considered [90–92]. Silica-supported guanidine moieties have also been synthesized by several authors and implemented in a number of catalytic reactions. Dupont et al. synthetized a guanidine-based silyl-derivative by reacting 3-aminopropyltrimethoxysilane and dicyclohexyl- carbodiimide (Figure 16B). The silyl-derivative was grafted onto silica and the hybrid was tested for the production of biodiesel. Conversions up to 98% were obtained for soybean oil methanolysis at 353 K for 3 h. The catalytic system was transposed to a semi-pilot scale in a continuous flow reactor [93]. In another study, Sartori et al. used a guanidine-based Catalysts 2021, 11, 79 hybrid catalyst in the cycloaddition of epoxides, to produce cyclic carbonates at20 140 of 39°C. Different epoxides were used, with yield at 70 h ranging between 55 and 95 %. The catalyst was less active than the homogeneous counterpart, although it could be reused over three catalytic cycles [94]. based silyl-derivativeAnother relevant by class reacting of base 3-aminopropyltrimethoxysilane hybrid catalysts are supported and imidazolium dicyclohexylcar- based bodiimidemoieties. (FigureIn an exemplificative 16B). The silyl-derivative study, Hesemann was grafted et al. developed onto silica a and mesoporous the hybrid SBA was-15 testedtype forsilica, the bearing production ionic of imidazoliu biodiesel.m Conversions substructures, up via to 98% post were-synthesis obtained grafting for soybean reactions oilusing methanolysis bisilylated at imidazolium 353 K for 3 h. precursors The catalytic (Figure system 16C was). Passivated transposed versions to a semi-pilot of the hybrids scale inwere a continuous prepared ﬂow and reactorthe four [93 catalysts]. In another were study,tested Sartoriin Henry et al.reactions used a and guanidine-based cycloadditions ◦ hybridof carbon catalyst dioxide in the to cycloadditionepichlorohydrin. of epoxides, In both types to produce of reaction, cyclic the carbonates passivated at 140versionsC. Differentshowed epoxides higher catalytic were used, activity, with yieldalthough at 70 to h ranginga lesser betweenextent in 55 the and case 95 %.of Thecycloaddition catalyst wasreactions. less active than the homogeneous counterpart, although it could be reused over three catalytic cycles [94].

FigureFigure 16. 16.( A(A):): Schematic Schematic representationrepresentation ofof thethe grafted amines amines [ [8787].]. Reprinted Reprinted with with permission permission fromfrom [87 [87].]. Copyright Copyright 2010, 2010, Elsevier. Elsevier. (B): (B Synthesis): Synthesis of guanidine-basedof guanidine-based silyl-derivative silyl-derivative [93]. [93 Reprinted]. Re- withprinted permission with permission from [93]. from Copyright [93]. Copyright 2011, Royal 2011, Society Royal ofSociety Chemistry. of Chemistry. (C): Imidazolium-based (C): Imidazolium- silyl-derivativesbased silyl-derivatives [95]. Reprinted [95]. Reprinted with permission with permission from [95 from]. Copyright [95]. Copyright 2013, John 2013, Wiley John andWiley Sons. and (DSons.): 1,8-bis(dimethylamino)naphthalene (D): 1,8-bis(dimethylamino)naphthalene (DMAN)-based (DMAN) silyl-derivative.-based silyl-derivative. Reprinted Reprinted with permission with from [96]. Copyright 2011, Royal Society of Chemistry. (E): Silica-supported pyrrolidine-based chiral ionic liquid [97]. Reprinted with permission from [97]. Copyright 2008, Elsevier. (F): Silica- functionalized pyrrolidine-based chiral hybrid catalyst. Reprinted with permission from [98]. Copy- right 2018, Royal Society of Chemistry.

Another relevant class of base hybrid catalysts are supported imidazolium based moieties. In an exemplificative study, Hesemann et al. developed a mesoporous SBA-15 type silica, bearing ionic imidazolium substructures, via post-synthesis grafting reactions using bisilylated imidazolium precursors (Figure 16C). Passivated versions of the hybrids were prepared and the four catalysts were tested in Henry reactions and cycloadditions of carbon dioxide to epichlorohydrin. In both types of reaction, the passivated versions showed higher catalytic activity, although to a lesser extent in the case of cycloaddition reactions. The authors speculated a beneficial synergistic effect involving the imidazolium cation, its counter-ion and the hydrophobic groups introduced during the passivation of the material [95]. Gianotti et al. prepared a hybrid catalyst using proton sponges as organic building blocks. The proton sponges, i.e., diamines that exhibit very high basicity, were reacted to obtain bi-silylated building blocks (Figure 16D). The resulting precursors were co-condensed with TMOS under fluoride catalyzed conditions. The hybrid was tested in the Knoevenagel condensation between benzaldehyde and ethyl cyanoacetate, showing high activity and recyclability over four catalytic cycles [96]. Catalysts 2021, 11, 79 21 of 39

The capacity for electron rich atoms, such as N, to coordinate electrophilic atoms, together with the versatility of organic syntheses, allows for the possibility of functionalizing silica supports with chiral amines to carry out asymmetric catalytic reactions. Wang et al. developed a silica supported pyrrolidine-based chiral ionic liquid capable of catalyzing Michael addition reaction of ketones with nitrostyrenes in good yields, excellent enantioselectivities and high diastereoselectivities. The catalyst could be reused up to six times (Figure 16E) [97]. In another study, Llopis et al. reported on a new chiral mesoporous hybrid material based on pyrrolidine units integrated into an organic–inorganic structure, obtained from a bi-silylated precursor. The mesoporous hybrid was prepared by ﬂuoride sol-gel methodology under soft synthesis conditions and in the absence of structural directing agents. The chiral solid was tested as asymmetric catalyst in the Michael addition reaction between a wide range of linear aldehydes to nitroalkenes with excellent yields as well as high enantioselectivities. The hybrid catalyst was stable, easily separable and could be reused several times (Figure 16F) [98]. From this very broad overview, the potential of hybrid organic-inorganic catalysts in heterogeneous catalysis is very clear. Organic species featuring base active sites of different nature, strength (pKa), reactivity (nucleophilicity) and stereo-selectivity can be supported onto silica supports for applications as heterogeneous catalysts in industrially relevant reactions. To highlight the multi-disciplinary character of this ﬁeld, it should be pointed out that the synthesis and reactivity of many amines have been extensively studied by organic chemists throughout the decades and, as a welcomed consequence, the body of literature that resulted provide many key tools that have been implemented in the synthesis of silyl-derivatives, featuring the optimal active site for a given catalytic process.

Base–H-Bond Donor Cooperative Catalysis Silica-based materials functionalized with amine groups are known to efficiently catalyze C-C coupling reactions, especially when weak acid sites are present in close proximity to amine function. Cooperative effect of multiple active sites is well known. Undoubtedly, the most notable example are enzymes, in which multiple active sites (e.g., acid, base, H-bond donor) co-catalyze a given reaction. The complex enzyme architecture allows the catalytic sites and substrates to adopt a favorable conformation to promote the cooperative interaction, as functional groups placement and overall flexibility of the structure are optimal for such synergy to occur. Slight modifications of these parameters can have a major impact on mechanistic pathways and catalytic rates [99]. Accounting for all variables contributing to this synergy and properly understanding the cooperative action occurring between the two sites are crucial aspects in the rational design of a catalyst [100]. Moreover, such insights can improve the rational design of hybrid catalysts featuring additional functional groups, such as metal nanoparticles or clusters. Many studies have been conducted by several authors, focused on understanding the effect of several variables on the activity of such catalysts in C-C bond formation reactions, such as aldol and nitro-aldol additions. Key feature that influence this cooperativity have been highlighted by the studies below described. Firstly, silanol groups appeared to be the ideal partner for cooperative catalysis carried out by amines. Brunelli et al. prepared a series of materials containing low loadings (0.36 mmol/g) of primary amine, to ensure the presence of enough silanol groups to act cooperatively with the base sites. The materials were prepared by grafting the silyl-derivatives onto the surface of the silica in a sequential fashion, firstly reacting the 3-aminopropyl triethoxysilane and then the protected carboxylic acid organosilane derivative. A fraction of the amino-functionalized silica was not functionalized with carboxylic acid groups and was used for comparison. By following the procedure, the authors ensured to have the same amount of amine grafted onto the catalysts. The catalysts were tested in the reaction between 4-nitrobenzaldehyde and acetone. The amine–silanol cooperative catalyst (Figure 17, cat. 1) showed an initial TOF of 3.0 h−1, which the authors reported as high catalytic activity for primary amines, confirming the efficient acid–base synergy. By Catalysts 2021, 11, x FOR PEER REVIEW 23 of 41

such as aldol and nitro-aldol additions. Key feature that influence this cooperativity have been highlighted by the studies below described. Firstly, silanol groups appeared to be the ideal partner for cooperative catalysis carried out by amines. Brunelli et al. prepared a series of materials containing low loadings (0.36 mmol/g) of primary amine, to ensure the presence of enough silanol groups to act cooperatively with the base sites. The materials were prepared by grafting the silyl-derivatives onto the surface of the silica in a sequential fashion, firstly reacting the 3-aminopropyl triethoxysilane and then the protected carboxylic acid organosilane derivative. A fraction of the amino-functionalized silica was not functionalized with carboxylic acid groups and was used for comparison. By following the procedure, the authors ensured to have the same amount of amine grafted onto the catalysts. The catalysts were tested in the re-

Catalysts 2021, 11, 79 action between 4-nitrobenzaldehyde and acetone. The amine–silanol cooperative catalyst22 of 39 (Figure 17, cat. 1) showed an initial TOF of 3.0 h−1, which the authors reported as high catalytic activity for primary amines, confirming the efficient acid–base synergy. By introducing the protected carboxylic acid, the catalytic activity dropped, compared to the amineintroducing-silanol material, the protected with carboxylican initial TOF acid, of the 1.5 catalytich−1 (Figure activity 17, cat. dropped, 2). Finally, compared unprotect- to the − ingamine-silanol the carboxylic material, acid provided with an an initial amine TOF–carboxylic of 1.5 h acid1 (Figure organosiliceous 17, cat. 2). Finally,material unprotect- which showeding the the carboxylic lowest catalytic acid provided activity an of amine–carboxylic the three catalysts acid with organosiliceous an initial TOF material of 1.2 which h−1 −1 (Figureshowed 17, cat. the 3). lowest Surface catalytic silanols activity proved of to the be threebetter catalysts cooperative with partners an initial than TOF carboxylic of 1.2 h acids.(Figure Such 17 ,trend cat. 3). was Surface ascribed silanols to differences proved to bein betterpKa values cooperative for silanols partners and than carboxylic carboxylic acids,acids. with Such the trendformer was being ascribed optimal to for differences cooperative in pKa catalysis. values HMDS for silanols-capping and of carboxylic surface silanolsacids, induced with the a former drop of being the initial optimal TOF for to cooperative 0.8 h−1 (Figure catalysis. 17, cat. HMDS-capping 4) [101]. of surface silanols induced a drop of the initial TOF to 0.8 h−1 (Figure 17, cat. 4) [101].

FigureFigure 17. 17.HybridHybrid bi-functional bi-functional catalysts catalysts tested tested in the in reaction the reaction of 4-nitrobenzaldehyde of 4-nitrobenzaldehyde with ace- with ace- tonetone [101 [101]. Reprinted]. Reprinted with with permission permission from from [101 [101]. Copyright]. Copyright 2012, 2012, American American Chemical Chemical Society. Society.

TheThe length length of the of thealkyl alkyl linker linker bounding bounding the amine the amine to the to silica the silicasupport support is also is an also im- an portantimportant parameter. parameter. Brunelli Brunelli et al. etstudied al. studied the effect the effectof the oflength the lengthof such of linker such linkeron the on performancesthe performances of the hybrid of the porous hybrid organosiliceous porous organosiliceous materials. materials. They prepared They an prepared array of an silicaarray-supported of silica-supported amines, bounded amines, to bounded the surface to the through surface linkers through of different linkers of size different (Figure size 18A(Figure). Silanol 18A-capped). Silanol-capped versions of versionsthe catalysts of the were catalysts also prepared. were also Firstly, prepared. the materials Firstly, the materials were tested for CO2 capture (Figure 18B), showing a much lower adsorption were tested for CO2 capture (Figure 18B), showing a much lower adsorption capacity for capacity for linkers shorter than C3. Additionally, no further increase in the adsorption linkers shorter than C3. Additionally, no further increase in the adsorption was observed was observed for materials featuring butyl or pentyl linkers. For HMDS-capped mate-rials, for materials featuring butyl or pentyl linkers. For HMDS-capped mate-rials, the CO2 ad- the CO adsorption capacity was significantly lower for solids featuring C3 or longer sorption capacity2 was significantly lower for solids featuring C3 or longer linkers, as the linkers, as the capping molecule blocked the cooperative interaction needed for efficient capping molecule blocked the cooperative interaction needed for efficient CO2 adsorption. CO adsorption. Non-passivated and passivated hybrids were also tested for their catalytic Non-passivated2 and passivated hybrids were also tested for their catalytic activity in the activity in the aldol condensation of 4-nitrobenzaldehyde with acetone (Figure 18C–E). aldol condensation of 4-nitrobenzaldehyde with acetone (Figure 18C–E). Upon increasing Upon increasing the length of the carbon chain, up to C3, a surge in the reaction rate the length of the carbon chain, up to C3, a surge in the reaction rate was observed. Further was observed. Further increase in the linker length beyond propyl resulted in identical increase in the linker length beyond propyl resulted in identical catalytic rates. Lastly, as catalytic rates. Lastly, as for CO2 adsorption, silanol-capping proved to be detrimental for for CO2 adsorption, silanol-capping proved to be detrimental for the performances of the the performances of the hybrids, once again confirming the beneficial cooperative effect of hybrids,base sites once and again surface confirming silanols. the The beneficial importance cooperative of the linker effect length of base lies sites in theand factsurface that it silanols.affects The the distanceimportance between of the surface linker length silanols lies and in amine the fact groups, that it ultimatelyaffects the influencingdistance be- the tweensimultaneous surface silanols interaction and amine of the twogroups, sites ultimately can havewith influencing the substrate the simultaneous molecules. interaction ofThe the distance two sites between can have amine with functionalthe substrate groups molecules. and surface silanol groups can also be modulated by varying the pore size. In fact, larger pores will feature a lower surface curvature, which will locate surface silanols farther from the amines than they would be, were they anchored on a support featuring smaller pores. Accordingly, supporting amines on support with larger pores will require anchoring the base sites through longer alkyl

linkers [102]. At a mechanistic level, the beneﬁcial effect of silanol groups lies in their ability to activate the carbonyl bond of the substrate through hydrogen-bridge interactions which promote the nucleophilic attack by the base. Moreover, they favor diffusion of polar molecules throughout the pore system and promote their adsorption, which in turn increase their local concentration, with beneﬁcial effects on the reaction rate [103–105]. Catalysts 2021, 11, x FOR PEER REVIEW 24 of 41

The distance between amine functional groups and surface silanol groups can also be modulated by varying the pore size. In fact, larger pores will feature a lower surface curvature, which will locate surface silanols farther from the amines than they would be, were they anchored on a support featuring smaller pores. Accordingly, supporting amines on support with larger pores will require anchoring the base sites through longer alkyl linkers [102]. At a mechanistic level, the beneficial effect of silanol groups lies in their ability to activate the carbonyl bond of the substrate through hydrogen-bridge interactions which

Catalysts 2021, 11, 79 promote the nucleophilic attack by the base. Moreover, they favor diffusion of polar23 mol- of 39 ecules throughout the pore system and promote their adsorption, which in turn increase their local concentration, with beneficial effects on the reaction rate [103–105].

FigureFigure 18. 18. (A(A): ):Silica Silica-supported-supported alkylamines alkylamines used used as adsorbent as adsorbent and andas heterogeneous as heterogeneous catalysts. catalysts. ((BB)):: Amine Amine efficiencies efﬁciencies for for CO CO2 adsorption2 adsorption (400 (400 ppm ppm in inHe). He). (C) (:C Schematic): Schematic representation representation of the of the aldolaldol condensation condensation between between 4 4-nitrobenzaldehyde-nitrobenzaldehyde and and acetone. acetone. Performances Performances of of the the non non-passivated-passivated(D) and(D) and passivated passivated (E) hybrids(E) hybrids in thein the reaction reaction between between of of 4-nitrobenzaldehyde 4-nitrobenzaldehyde and and acetone acetone [ 99]. [Reprinted99]. Reprinted with with permission permission from from [99]. [ Copyright99]. Copyright 2012, 2012, American American Chemical Chemical Society. Society.

4.3.4.3. Organometallic Organometallic Catalysts Catalysts TheThe possibility possibility of of covalently covalently incorporate incorporate organic organic moieties moieties within within inorganic inorganic insoluble insoluble structures,structures, allowed severalseveral research research groups groups to to heterogenize heterogenize organometallic organometallic complexes. complexes. This Thisis perhaps is perhaps one ofone the of mostthe most promising promising area area of research of research within within the fieldthe field of hybrid of hybrid catalysts cat- alystspreparation, preparation, as transition as transition metal metal complexes complexes can catalyze can catalyze a number a number of reactions of reactions including in- cludingC-C, C-N, C-C, C-O C-N, bonding C-O bonding formations, formations, oxidations, oxidations, reductions, reductions, as well as as well different as different kind of kindasymmetric of asymmetric reactions. reactions. Considering Considering the vast the amount vast amount of literature of literature on this on topicthis topic [106 [–106109–], rather than thoroughly describing the state-of-the-art on silica-supported metal complexes, 109], rather than thoroughly describing the state-of-the-art on silica-supported metal com- in this section, relevant examples involving silica-supported complexes of different metals plexes, in this section, relevant examples involving silica-supported complexes of differ- are shown, with the scope of describing common synthetic approaches implemented to ent metals are shown, with the scope of describing common synthetic approaches imple- obtain them. mented to obtain them. Suzuki-Miyaura, Heck and Sonogashira coupling reactions are among the most efficient routes for the formation of C-C bonds. Palladium catalysts have been long known to be highly active in these coupling reactions and several types of ligands have been used to support palladium onto silica matrixes [110]. Luo et al. synthesized a mesoporous silica-supported palladium imino-pyridine complex by implementing a multi-step strategy. Firstly, they carried out a nucleophilic substitution reaction between imino-pyridine ligand and 3-chloropropyl triethoxysilane, achieving a silyl-derivative with coordination capacity. Secondly, they grafted the silyl-derivative onto MCM-41. Lastly, after quantifying the amount of ligand in the solid, they obtained the supported complex by suspending the solid in a palladium acetate solution in acetone, at room temperature (Figure 19). The catalyst was found to be an efficient for Suzuki-Miyaura coupling reactions in aqueous medium. The reactions of various aryl bromides with arylboronic acids were carried out, Catalysts 2021, 11, x FOR PEER REVIEW 25 of 41

Suzuki-Miyaura, Heck and Sonogashira coupling reactions are among the most efficient routes for the formation of C-C bonds. Palladium catalysts have been long known to be highly active in these coupling reactions and several types of ligands have been used to support palladium onto silica matrixes [110]. Luo et al. synthesized a mesoporous silica- supported palladium imino-pyridine complex by implementing a multi-step strategy. Firstly, they carried out a nucleophilic substitution reaction between imino-pyridine lig- and and 3-chloropropyl triethoxysilane, achieving a silyl-derivative with coordination capacity. Secondly, they grafted the silyl-derivative onto MCM-41. Lastly, after quantifying the amount of ligand in the solid, they obtained the supported complex by suspending Catalysts 2021, 11, 79 24 of 39 the solid in a palladium acetate solution in acetone, at room temperature (Figure 19). The catalyst was found to be an efficient for Suzuki-Miyaura coupling reactions in aqueous medium. The reactions of various aryl bromides with arylboronic acids were carried out, usingusing low low Pd Pd loading loading in in the the reaction reaction mixture mixture (0.1 (0.1 mol mol %), with%), with good good to excellent to excellent yields yields and veryand lowvery Pd low leaching Pd leaching (<0.2 (<0.2 ppm) ppm) [111]. [111].

Figure 19. Schematic representation of the preparation of MCM-41 supported Pd complex [111]. Figure 19. Schematic representation of the preparation of MCM-41 supported Pd complex [111]. Reprinted with permission from [111]. Copyright 2013, Elsevier. Reprinted with permission from [111]. Copyright 2013, Elsevier. Varma et al. prepared a Pd-NHC-based organosilica, synthesizing firstly the silyl- derivativeVarma of theet al. carbene, prepared then a promotingPd-NHC-based the coordination organosilica, of synthesizing the metal and firstly then carryingthe silyl- derivative of the carbene, then promoting the coordination of the metal and then carrying out a sol-gel process catalyzed by NH4F (Figure 20). The integrity of the organic building blockout a wassol-gel confirmed process by ca13talyzedC CP/MAS by NH NMR.4F (Figure However, 20). The the integrity catalyst exhibited of the organic a BET building surface areablock of was only confirmed 5 m2/g. As by mentioned 13C CP/MAS above, NMR. bridged However, silsesquioxane the catalyst are exhibited prone to a assembleBET surface in anarea ordered of only fashion 5 m2/g. whenever As mentioned they canabove, act asbridged rigidbuilding silsesquioxane blocks, are i.e., prone whenever to assemble they are in constitutedan ordered by fash unsaturatedion whenever bonds they that can block act as the rigid rotation building of the blocks, atoms i.e. around, whenever the bond they axes. are Catalysts 2021, 11, x FOR PEER REVIEWItconstituted appears that by in unsaturated the case of thebonds silyl-derivatives that block the reported rotation in of this the study, atoms the around flexible the propyl26 bondof 41 linkersaxes. It allowed appears conformational that in the case rearrangements of the silyl-derivatives of such building reported blocks, in this which study, favored the flexible the formationpropyl linkers of non-porous allowed conformational solids. rearrangements of such building blocks, which favored the formation of non-porous solids. The hybrid catalyst was tested in Heck and Suzuki coupling using different substrates, showing good catalytic activity. However, it should be pointed out that considering the non-porous nature of the solid, the majority of the active sites was most likely inaccessible by the substrate molecules [112].

Figure 20. Preparation of Pd-NHC organosilica [112]. Reprinted with permission from [112]. Copy- Figure 20. Preparation of Pd-NHC organosilica [112]. Reprinted with permission from [112]. Cop- right 2008, Elsevier. yright 2008, Elsevier. The hybrid catalyst was tested in Heck and Suzuki coupling using different substrates, showingSanchez good et catalytical. prepared activity. mesoporous However, silica it should-supported be pointed chiral out ruthenium that considering NHC-based the catalystsnon-porous for natureasymmetric of the solid,reactions. the majorityNeutral ofunsymmetrical the active sites pyridine was most pincer likely-type inaccessible ligands withby the lateral substrate (S)-prolinamide molecules [112 donor]. function and a N-heterocyclic carbene (NHC) moiety were Sanchezprepared. et The al. preparedprolinamide mesoporous substituents silica-supported of the CNN-pincer chiral backbone ruthenium were NHC-based function- alizedcatalysts with for a asymmetrictriethoxysilyl reactions. group. The Neutral incorporation unsymmetrical of ruthenium pyridine was pincer-type achieved by ligands Lin’s methodwith lateral of transmetalation (S)-prolinamide from donor intermediate function and silver a N-heterocyclic (I) complexes. carbene Lastly, the (NHC) silyl moiety-deriv- ativewere Ru prepared. complexes The were prolinamide grafted by substituents heating at reflux of the in CNN-pincer toluene for backbone24 h (Figure were 21). func- The heterogenizedtionalized with catalysts a triethoxysilyl were observed group. to The be incorporation highly active, ofselective, ruthenium and wasrecyclable achieved in the by asymmetricLin’s method hydrogenation of transmetalation of alkenes from intermediateand showed promising silver (I) complexes. results in the Lastly, cyclopropa- the silyl- nation of styrenes [113].

Catalysts 2021, 11, x FOR PEER REVIEW 26 of 41

Figure 20. Preparation of Pd-NHC organosilica [112]. Reprinted with permission from [112]. Cop- yright 2008, Elsevier.

Sanchez et al. prepared mesoporous silica-supported chiral ruthenium NHC-based catalysts for asymmetric reactions. Neutral unsymmetrical pyridine pincer-type ligands with lateral (S)-prolinamide donor function and a N-heterocyclic carbene (NHC) moiety were prepared. The prolinamide substituents of the CNN-pincer backbone were function- Catalysts 2021, 11, 79 alized with a triethoxysilyl group. The incorporation of ruthenium was25 of 39achieved by Lin’s method of transmetalation from intermediate silver (I) complexes. Lastly, the silyl-derivative Ru complexes were grafted by heating at reflux in toluene for 24 h (Figure 21). The derivative Ru complexes were grafted by heating at reﬂux in toluene for 24 h (Figure 21). Theheterogenized heterogenized catalystscatalysts were were observed observed to be highlyto be highly active, selective, active, selective, and recyclable and in recyclable in the theasymmetric asymmetric hydrogenationhydrogenation of alkenes of alkenes and showed and showed promising promising results in the results cyclopropa- in the cyclopropa- nationnation of styrenesof styrenes [113]. [113].

FigureFigure 21. 21.Schematic Schematic representation representation of the synthesis of the synthesis of silica-supported of silica chiral-supported Ru complexes chiral [113 Ru]. complexes [113]. ReprintedReprinted with with permission permission from [113 from]. Copyright [113]. Copyright 2011, Royal 2011, Society Royal of Chemistry. Society of Chemistry. Corma et al. reported on the synthesis of periodic mesoporous organosilicas prepared using a bisilylated vanadyl Schiff base complexes as building block. The synthesis of the catalysts was carried out following the scheme reported in Figure 22. Firstly, a Suzuki coupling between p-vinylphenylboronic acid and 4-bromosalicylaldehyde derivatives was carried out (step b), followed by the diimine formation using ethylenediamine or (1R,2R)- (−)-l,2-diaminocyclohexane (step c). Subsequently, the formation of the vanadyl complex was performed (step d). The authors reported that an alternative strategy in which vanadyl complexation was carried out after the introduction of the trimethoxysilane groups on the ligand led to extensive hydrolysis and the formation of untreatable mixtures. Then, radical coupling between 3-mercaptopropyltrimethoxysilane and the p-styryl residues was performed, to achieve the bisilylated vanadyl complex. Lastly, the organic building blocks were co-condensed with TEOS, in different proportions, to obtain the hybrid PMOs. The templating agent was removed by extraction. The catalysts were tested in the room-temperature cyanosilylation of aldehydes in chloroform, using trimethylsilyl cyanide as reagent, showing high conversions and com- plete selectivities to the desired silylated cyanohydrins. Although ee of 30% was observed for the cyanosilylation of benzaldehydes, the result was much lower than that observed for the same reaction performed using the vanadyl complex in homogeneous phase [114,115]. Catalysts 2021, 11, x FOR PEER REVIEW 27 of 41

Corma et al. reported on the synthesis of periodic mesoporous organosilicas prepared using a bisilylated vanadyl Schiff base complexes as building block. The synthesis of the catalysts was carried out following the scheme reported in Figure 22. Firstly, a Su- zuki coupling between p-vinylphenylboronic acid and 4-bromosalicylaldehyde derivatives was carried out (step b), followed by the diimine formation using ethylenediamine or (1R,2R)-(−)-l,2-diaminocyclohexane (step c). Subsequently, the formation of the vanadyl complex was performed (step d). The authors reported that an alternative strategy in which vanadyl complexation was carried out after the introduction of the trimethoxysilane groups on the ligand led to extensive hydrolysis and the formation of untreatable mixtures. Then, radical coupling between 3-mercaptopropyltrimethoxysilane and the p- styryl residues was performed, to achieve the bisilylated vanadyl complex. Lastly, the organic building blocks were co-condensed with TEOS, in different proportions, to obtain the hybrid PMOs. The templating agent was removed by extraction. The catalysts were tested in the room-temperature cyanosilylation of aldehydes in chloroform, using trimethylsilyl cyanide as reagent, showing high conversions and com- plete selectivities to the desired silylated cyanohydrins. Although ee of 30% was observed for the cyanosilylation of benzaldehydes, the result was much lower than that observed for the same reaction performed using the vanadyl complex in homogeneous phase [114,115]. The incorporation of delicate organic molecules within inorganic structures often requires custom-made synthetic strategies that allow preserving their integrity. This is particularly true for supported organometallic complexes. For example, while in some cases the best strategy is the incorporation of the ligand within the support and subsequent coordination with the metal, in other cases this approach will lead to the formation of supported nanoparticles, as some metals tend to aggregate more than others. In other cases, the alkoxy-silyl groups could be susceptible to reactants that are needed to synthesize some organometallic complexes (e.g., strong hydrated bases) and a strategy that Catalysts 2021, 11, 79 would consider this aspect would be in need. Overall, knowledge about sol-gel synthesis 26 of 39 and organometallic chemistry are both crucial to successfully prepare silica-supported organometallic complexes.

Figure 22. 22. SchematicSchematic representation representation of the of synthesis the synthesis of PMOs of PMOscontaining containing vanadyl Schiff vanadyl base Schiff com- base complexes [115 [115].]. Reprinted Reprinted with with permission permission from from [115]. [ 115Copyright]. Copyright 2004, Elsevier. 2004, Elsevier.

The incorporation of delicate organic molecules within inorganic structures often requires custom-made synthetic strategies that allow preserving their integrity. This is particularly true for supported organometallic complexes. For example, while in some cases the best strategy is the incorporation of the ligand within the support and subsequent coordination with the metal, in other cases this approach will lead to the formation of supported nanoparticles, as some metals tend to aggregate more than others. In other cases, the alkoxy-silyl groups could be susceptible to reactants that are needed to synthesize some organometallic complexes (e.g., strong hydrated bases) and a strategy that would consider this aspect would be in need. Overall, knowledge about sol-gel synthesis and organometallic chemistry are both crucial to successfully prepare silica-supported organometallic complexes. Organic-inorganic solids have also been cleverly implemented to incorporate metal nanoparticles within silica structures [116,117]. In a representative example, Budroni et al. prepared Au nanoparticles embedded in silica. Firstly, ionic gold was reduced with hydrazine, in the presence of a mixture of 1-dodecanethiol and 3-mercaptopropyltrimethoxysilane (MPMS). Alkanethiols lowers the surface energy of the Au particles and consequently their tendency to aggregate. Alkanethiol-stabilized gold nanoparticles were then dispersed into an ethanol solution, together with TEOS. Hydrolysis and condensation of the alkoxysilyl groups was carried out using NH4F as catalysts. 1-dodecanethiol molecules act as physical spacers between the particles and the silica shell. The method proposes to include the nanoparticles into a shell of silica that will prevent them from aggregation at high temperature, at the same time without limiting the accessibility of the reactant to the catalytic sites [118]. In another study, the same authors prepared a material composed of palladium nanoparticles embedded into amorphous silica. Firstly, they prepared Pd nanoparticles in an inverse microemulsion system, reducing PdCl2 with hydrazine and stabilizing the metal particles with a mixture of two thiols, 1-dodecanethiol (DT) and 3- mercaptopropyltrimethoxysilane (MPMS). Subsequent co-condensation of TEOS in presence of the stabilized nanoparticles allowed to incorporate the Pd NPs into a silica matrix. The alkoxy silyl groups of the MPMS molecules promoted the intimate mixture of palladium nanoparticles and the silica precursor. Lastly, calcination in air and reduction in H2/N2 mixture led to the ﬁnal material (Figure 23A) [117]. Barau et al. reported on the synthesis of silica-supported palladium nanoparticles, achieved through different approaches. Firstly, they prepared a catalyst by adding the palladium precursor in the synthetic mixture during the preparation of the mesoporous Catalysts 2021, 11, 79 27 of 39

support (co-gelation); then, they prepared two more catalysts by wet impregnation using a Pd-containing solution and either a pure silica support or a mesoporous silica previously functionalized with aminopropyl groups. The catalyst prepared by wet impregnation using an aminopropyl-functionalized support showed superior catalytic activity in the Heck reaction between iodobenzene and methylacrylate. The authors reported that by preparing the catalyst in such manner, a homogeneously distributed nanoparticle system, stabilized by the pending organic moieties, should be achieved [119]. Johnston et al. immobilized Pd nanoparticles onto silica-based mesocellular foams (MCFs). MCF feature a three-dimensional structure with high surface area (500–800 m2/g) and interconnected pores of size tunable between 25 and 42 nm, interconnected by 9–22 nm windows [120]. The authors used a support featuring 29 nm pores and 15 nm windows; moreover, the silica support was functionalized with aminopropyl groups, in order to promote the interactions between palladium nanoparticles and the support. TEM microscopy on the resulting material showed a narrow particle size distribution (1–2 nm, Figure 23B). The hybrid was found to be a highly efﬁcient heterogeneous catalyst for the oxidation of alcohols. Primary and secondary benzylic alcohols were oxidized to the corresponding carbonyl compounds in high yields, using air as the source of molecular oxygen. The catalyst was found to be highly stable and was recycled several times without any leaching of the metal [121]. A rather interesting approach to the incorporation of Pd nanoparticles was reported by Ma and co-workers. They used an amino-functionalized SBA-16 as support and reduced Pd(OAc)2 precursor by chemical reduction with NaBH4 (Figure 23C). SBA-16 is an ordered mesoporous material with cage-like structures [122]. This mesoporous silica has a tunable cage size (4–10 nm) and pore entrance size generally smaller than 4 nm. Each nanocage is interconnected by eight neighboring pore entrances in three special dimensions. Besides hosting metal complexes, isolated nanocages of SBA-16 can limit the growth of metal nanoparticles by the spatial restrictions [123,124]. Based on the literature on the topic, it appears that -NH2 groups play a crucial role in stabilizing small Pd nanoparticles. Their Catalysts 2021, 11, x FOR PEER REVIEW 29 of 41 ability to coordinate palladium through the N lone electron pair and the steric blockage, provided by the aminopropyl pendant fragments as a whole, limits particle migration onon the the surface surface of the of support, the support, ultimately ultimately hindering particle hindering aggregation particle and aggregation leaching. and leaching. Moreover,Moreover, the thebase base character character of the amine of the groups amine opens groups up to the opens use of up these to thehybrids use as of these hybrids as multimulti-functional-functional catalysts catalysts for cascade for cascadereactions. reactions.

FigureFigure 23. 23. (A): (SchematicA): Schematic representation representation of the synthesis of theof silica synthesis-supported of Pd silica-supported NPs. Reprinted Pd NPs. Reprinted with permission from [117]. Copyright 2007, Elsevier. (B): TEM images of MCF-supported Pd NPs [with121]. Reprinted permission with permission from [117 from]. Copyright [121]. Copyright 2007, 2012, Elsevier. John Wiley ( andB): Sons. TEM (C images): Schematic of MCF-supported Pd representationNPs [121]. of Reprinted the synthesis with of Pd/SBA permission-16. Reprinted from with [121 permission]. Copyright from [124 2012,]. Copyright John Wiley and Sons. (C): 2010, Elsevier. Schematic representation of the synthesis of Pd/SBA-16. Reprinted with permission from [124]. 5.Copyright Silica-Based 2010, Multi Elsevier.-Functional Hybrid Catalysts The possibility of incorporating active sites within solid structures, fixing them in specific regions of the material opens up to the possibility of designing heterogeneous catalysts featuring multiple active sites, to carry out cascade or tandem reactions, using only one recoverable catalytic system. This is no trivial task, considering that catalytically active sites are, by definition, reactive functional groups and that different active sites can interact with each other (or annihilate) in the synthesis mixture preventing their homogeneous distribution or causing their mutual inactivation. To avoid this, clever synthetic strategies are in need. Approaches based on silica are particularly advantageous for this purpose, for various reasons. The versatility of sol-gel chemistry and the reactivity of the surface of silica materials make it possible to introduce different functionalities in subsequent steps (e.g., co-condensation and grafting). Silica supports are also generally cheap and easy to synthetize. Moreover, their thermal and mechanical stability, their high surface area, tunable pore size diameter and the ease with which their surface can be modified in a post-synthesis step (introducing additional functional groups or varying their hydrophilic/hydrophobic properties) are welcomed features for inorganic supports. In this section, representative examples describing some synthetic strategies used for preparing multi-functional silica-based heterogeneous catalysts are reported. Gianotti et al. prepared bi-functional mesoporous hybrid materials, containing both acid groups and proton sponges. Co-condensation of TMOS, 3-mercaptopropyltriethoxysilane (MPTES) and bisilylated 1,8-bis(dimethylamino)naphthalene (DMAN-2Sil), was carried out under NH4F catalysis, at low temperature and neutral pH (Figure 24A). After the synthesis, in order to oxidize thiol groups to sulfonic acids, the hybrid was stirred in 30% H2O2 solution. The authors also prepared ordered mesoporous organosilica featuring the same functional groups. They achieved that by implementing a surfactant-mediated

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5. Silica-Based Multi-Functional Hybrid Catalysts The possibility of incorporating active sites within solid structures, fixing them in specific regions of the material opens up to the possibility of designing heterogeneous catalysts featuring multiple active sites, to carry out cascade or tandem reactions, using only one recoverable catalytic system. This is no trivial task, considering that catalytically active sites are, by definition, reactive functional groups and that different active sites can interact with each other (or annihilate) in the synthesis mixture preventing their homogeneous distribution or causing their mutual inactivation. To avoid this, clever synthetic strategies are in need. Approaches based on silica are particularly advantageous for this purpose, for various reasons. The versatility of sol-gel chemistry and the reactivity of the surface of silica materials make it possible to introduce different functionalities in subsequent steps (e.g., co- condensation and grafting). Silica supports are also generally cheap and easy to synthetize. Moreover, their thermal and mechanical stability, their high surface area, tunable pore size diameter and the ease with which their surface can be modified in a post-synthesis step (introducing additional functional groups or varying their hydrophilic/hydrophobic properties) are welcomed features for inorganic supports. In this section, representative examples describing some synthetic strategies used for preparing multi-functional silica- based heterogeneous catalysts are reported. Gianotti et al. prepared bi-functional mesoporous hybrid materials, containing both acid groups and proton sponges. Co-condensation of TMOS, 3-mercaptopropyltriethoxysilane (MPTES) and bisilylated 1,8-bis(dimethylamino)naphthalene (DMAN-2Sil), was carried out under NH4F catalysis, at low temperature and neutral pH (Figure 24A). After the synthesis, in order to oxidize thiol groups to sulfonic acids, the hybrid was stirred in 30% H2O2 solution. The authors also prepared ordered mesoporous organosilica featuring the same functional groups. They achieved that by implementing a surfactant-mediated one-pot co-condensation of MPTES, disilylated-DMAN and TEOS, in presence of hexadecylamine (HDA). Template removal was performed by ethanol extraction using a Soxhlet apparatus and the thiol groups were oxidized to sulfonic acid groups with a H2O2 solution. Lastly, the bifunctional hybrids were also prepared by multi-step synthesis (Figure 24B). In this case, firstly, both ordered and non-ordered containing MPTES silicas were synthesized following a template route and a NH4F co-condensation route at room temperature. Secondly, after extraction of the template and oxidation of the thiol groups to sulfonic acids, monosilylated DMAN (DMAN-1Sil) was grafted both on ordered and non-ordered materials. The hybrid catalysts were tested in the one-pot cascade reaction involving an acid-catalyzed acetal hydrolysis followed by a base-catalyzed Knoevenagel or nitroaldol (Henry) reaction. Interestingly, non-ordered hybrids, prepared by NH4F catalyzed route, showed superior catalytic activity, compared to the other hybrids. This was particularly true when a more demanding methylene compound (such as diethylmalonate or nitromethane) was used as substrate. The authors tentatively ascribed the enhanced activity to the higher structural flexibility of the non-ordered silica network and to the higher amount of silanol groups that can perform a cooperative electrophilic activation [63]. In another study, Asefa et al. prepared bi-functional mesoporous organosilicas baring Pd-diamino and propylamino residues. The synthesis was carried out following the scheme reported in Figure 25, using MCM-41 and SBA-15 as supports. For both hybrids, firstly, 3-aminopropyltrimethoxysilane was grafted onto the silica support. Then, a silyl- functionalized Pd complex was prepared by mixing at room temperature PdII acetate and N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (1:1 mol ratio). The silyl-derivative was then grafted onto the amino-functionalized mesoporous silica, in toluene, to achieve the bi-functional hybrid catalyst. The authors attributed great importance to using the appropriate solvent in each of the grafting procedures carried out. Specifically, by using isopropanol, they were able to achieve a more homogenous dispersion of the active sites throughout the surface of the support, at the same time leaving enough free silanol groups to perform a second grafting. For that, they used toluene, which is reportedly a good Catalysts 2020, 10, x FOR PEER REVIEW 29 of 43

Catalysts950 2021and, 11 ,a 79 NH4F co-condensation route at room temperature. Secondly, after extraction of the template 29 of 39 951 and oxidation of the thiol groups to sulfonic acids, mono-silylated DMAN (DMAN-1Sil) was grafted 952 both on ordered and non-ordered materials. The hybrid catalysts were tested in the one-pot cascade 953 reaction involving an acid-catalyzed acetal hydrolysis followed by a base-catalyzed Knoevenagel or solvent for grafting processes. The hybrid catalysts were tested in the one-pot tandem 954 nitroaldol (Henry) reaction. Interestingly, non-ordered hybrids, prepared by NH4F catalyzed route, Sonogashira-Henry reactions (Figure 25, inset). The catalysts showed to be active in the 955 showed superior catalytictandem activity, reaction compared with a 60% to the yield other of thehybrids. Sonogashira-Henry product, after 5 h [125].

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throughout the surface of the support, at the same time leaving enough free silanol groups to perform a second grafting. For that, they used toluene, which is reportedly a good solvent for grafting processes. The hybrid catalysts were tested in the one-pot tandem So- 956 nogashira-Henry reactions (Figure 25, inset). The catalysts showed to be active in the tan- Figure 24. (A): One-pot synthesisdem reaction of bi-functional with a 60% mesoporous yield of the hybrids. Sonogashira (B): DMAN-Henry grafting product, on after mesoporous 5 h [125 silicas]. 957containing Figure sulfonic 24 acids. A: One-pot Reprinted synthesis with permission of bi-func fromtional [63 ].mesoporous Copyright 2013, hybrids. Royal B Society: DMAN of Chemistry. grafting on 958 mesoporous silicas containing sulfonic acids [63]. Reprinted with permission of ref 63. Copyright 959 2013, Royal Society of Chemistry.

960 This was particularly true when a more demanding methylene compound (such as 961 diethylmalonate or nitromethane) was used as substrate. The authors tentatively ascribed the 962 enhanced activity to the higher structural flexibility of the non-ordered silica network and to the 963 higher amount of silanol groups that can perform a cooperative electrophilic activation [63]. 964 In another study, Asefa et al. prepared bi-functional mesoporous organosilicas baring Pd- 965 diamino and propylamino residues. The synthesis was carried out following the scheme reported in 966 Figure 25, using MCM-41 and SBA-15 as supports. For both hybrids, firstly, 3- 967 aminopropyltrimethoxysilane was grafted onto the silica support. Then, a silyl-functionalized Pd 968 complex was prepared by mixing at room temperature PdII acetate and N-(2-aminoethyl)-3- 969 aminopropyltrimethoxysilane (1:1 mol ratio). The silyl-derivative was then grafted onto the amino- 970 functionalized mesoporous silica, in toluene, to achieve the bi-functional hybrid catalyst. The authors 971 attributed great importance to using the appropriate solvent in each of the grafting procedures 972 carried out. Specifically, by using isopropanol, they were able to achieve a more homogenous

973 dispersion of the activeFigure sites 25. throughoutSchematic representationthe surface of of the the support, synthesis at of the bi-functional same time hybrid leaving catalyst enough baring amino Figure 25. Schematic representation of the synthesis of bi-functional hybrid catalyst baring amino 974 free silanol groups tofunctionalities perform a second and Pd-diamino grafting. For complexes. that, they Inset: used Sonogashira-Henry toluene, which is tandem reportedly reaction a used for functionalities and Pd-diamino complexes. Inset: Sonogashira-Henry tandem reaction used for 975 good solvent for grafting processes. The hybrid catalysts were tested in the one-pot tandem testingtesting the the activity activity of of the the hybrid hybrid catalyst. catalyst. Reprinted Reprinted with with permission permission from from [125 [125]. Copyright]. Copyright 2011, 2011, 976 Sonogashira-Henry JohnreactionsJohn Wiley Wiley (Figureand and Sons. Sons. 25, inset). The catalysts showed to be active in the tandem 977 reaction with a 60% yield of the Sonogashira-Henry product, after 5 h [125]. Another interesting possibility is the coexistence of acid/base functionalities together Another interesting possibility is the coexistence of acid/base functionalities together with metal nanoparticles, to perform tandem or cascade reactions. In an interesting study, with metal nanoparticles, to perform tandem or cascade reactions. In an interesting study, Bäckvall et al. prepared an artiﬁcial metalloenzyme with two different modes of reactivity: Bäckvall et al. prepared an artificial metalloenzyme with two different modes of reactivity: one exhibited by a nanometallic component and one by an enzyme. The presence of the one exhibited by a nanometallic component and one by an enzyme. The presence of the two functionalities in the same cavity of a mesoporous heterogeneous support created an environment in which these active sites could work in close proximity to one another in a cooperative fashion, to perform tandem catalysis. In this work, siliceous mesocellular foams (MCFs) were used as inorganic supports. MCFs are a class of porous siliceous materials featuring high pore volume and cavities, which make them the ideal platform for supporting macromolecules such as enzymes. The approach used for the multi-step synthesis was based on leaving the incorporation of the enzyme as the last one, as by doing otherwise the macromolecule would have risked to be affected by the strongly basic condition in which the metal nanoparticles could be obtained. An amino-functionalized MCF was used as support for Pd nanoparticles deposition (1–2 nm in diameter) [121]. The material was then suspended in aqueous glutaraldehyde in phosphate buffer, to react the remaining amine groups, not interacting with the Pd. The enzyme Candida antarctica lipase B (CALB) was then reacted with the pendant aldehyde groups, to achieve the bi-functional catalyst (Figure 26). The catalyst was tested in the dynamic kinetic resolution (DKR) of a primary amine. In this reaction a lipase enzyme selectively transforms only one enantiomer of the starting amine into the corresponding amide. The racemization reaction allows interconversion of the amine enantiomers and continuously feeds the enzyme catalyzed reaction with more reactive enantiomer (Figure 26B,C). The hybrid catalyst proved to be exceptionally active for the DKR of 1-phenylethylamine and ethyl methoxy acetate with quantitative yield and ee of 99%.

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two functionalities in the same cavity of a mesoporous heterogeneous support created an environment in which these active sites could work in close proximity to one another in a cooperative fashion, to perform tandem catalysis. In this work, siliceous mesocellular foams (MCFs) were used as inorganic supports. MCFs are a class of porous siliceous materials featuring high pore volume and cavities, which make them the ideal platform for supporting macromolecules such as enzymes. The approach used for the multi-step synthesis was based on leaving the incorporation of the enzyme as the last one, as by doing otherwise the macromolecule would have risked to be affected by the strongly basic condition in which the metal nanoparticles could be obtained. An amino-functionalized MCF was used as support for Pd nanoparticles deposition (1–2 nm in diameter) [121]. The material was then suspended in aqueous glutaraldehyde in phosphate buffer, to react the remaining amine groups, not interacting with the Pd. The enzyme Candida antarctica lipase B (CALB) was then reacted with the pendant aldehyde groups, to achieve the bi-functional catalyst (Figure 26). The catalyst was tested in the dynamic kinetic resolution (DKR) of a primary amine. In this reaction a lipase enzyme selectively transforms only one enantiomer of the starting amine into the corresponding amide. The racemization reaction allows interconversion of the amine enantiomers and continuously feeds the enzyme catalyzed reaction with more reactive enantiomer (Figure 26B,C). The hybrid catalyst proved to be exceptionally active for the DKR of 1-phenylethylamine and ethyl methoxy acetate with Catalysts 2020quantitative, 10, x FOR PEER yield REVIEW and ee of 99%. 31 of 43

1005 1006 FigureFigure 26 A 26.: Synthesis(A): Synthesis of the ofbi-func the bi-functionaltional hybrid hybrid catalyst. catalyst. B: Schematic (B): Schematic representation representation of a general of a 1007 dynamicgeneral kinetic dynamic resolution kinetic (DKR) resolution of a (DKR) primary of aamine. primary C: amine.DKR of (Can): amine DKR of with an aminea bi-functional with a bi- 1008 biomimeticfunctional catalyst biomimetic in which catalyst Pd nanoparticles in which Pd nanoparticles and a lipase and(CALB) a lipase are (CALB)co-immobilized are co-immobilized in the same in 1009 porethe of same MCF pore [121 of]. Reprinted MCF. Reprinted with permission with permission of ref 121. from Copyright [121]. Copyright 2012, John 2012, Wiley John and Wiley Sons. and Sons.

1010 LayeredLayered structures structures also provide also provide interesting interesting synthetic synthetic alternatives alternatives for preparing for preparing multifunctional multi- functional catalysts. Corma et al. prepared a bifunctional acid-base hybrid catalyst starting 1011 catalysts. Corma et al. prepared a bi-functional acid-base hybrid catalyst starting from laminar MWW from laminar MWW zeolite (Figure 27). For that, ﬁrstly, they proceeded with swelling of 1012 zeolite (Figure 27). For that, firstly, they proceeded with swelling of the layered zeolitic precursors, the layered zeolitic precursors, in presence of cetyltrimethylammonium hydroxide (CTMA). 1013 in presence of cetyltrimethylammonium hydroxide (CTMA). The positively charged The positively charged alkylammonium groups in the surfactant molecules facilitated the 1014 alkylammoniuminteraction groups with thein negativethe surfactant charges molecule of thes zeolitic facilitated framework. the interaction Secondly, with the the swollen negative 1015 chargesmaterial of the zeolitic was suspended framework. in a Secondly, dioxane solution the swollen of 1,4-bis(triethoxysilyl) material was suspended benzene in (BTEB).a dioxane 1016 solutionThis of 1,4-bis(triethoxysilyl) aryl-bridged silsesquioxane benzene molecules (BTEB). This were aryl-bridged able to diffuse silsesquioxane in the interlayer molecules space were 1017 able to diffusebetween in thethe zeolitesinterlayer layers space and between to covalently the zeolites bind layers them throughand to covalently the alkoxide bind groups. them through The 1018 the alkoxideswelling groups. agents The were swelling removed agents by were acid remo extraction.ved by acid X-ray extraction. diffraction X-ray allowed diffraction to observe allowed 1019 to observe the presence of dimeric pillaring moieties constituted by two condensed BTEB molecules 1020 located in the interlayer space. Lastly, the aromatic bridging moieties were functionalized with amine 1021 groups, to obtain the bi-functional catalyst. Specifically, the pillared hybrid MWW-BTEB material 1022 was reacted in a HNO3/H2SO4 mixture to incorporate -NO2 groups, which were then reduced to -NH2 1023 through reaction with SnCl2. The final material featured a hierarchical system of pores and the 1024 presence of the two active sites in different pore frameworks. Specifically, the acid sites were located 1025 within the micropores of the zeolitic layers and the basic amino groups were located in the mesopores 1026 formed by intercalation of the organic pillaring agents. 1027 The catalyst was tested in a cascade reaction, involving an acetal hydrolysis followed by a 1028 Knoevenagel condensation. Specifically, benzaldehyde dimethylacetal was hydrolyzed to produce 1029 benzaldehyde, which was reacted with malononitrile to give benzylidene malononitrile. The results 1030 showed high activity of the catalyst in the tandem reaction, with a product yield of 96% after 7.2 h of 1031 reaction and a selectivity of 99% [126].

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the presence of dimeric pillaring moieties constituted by two condensed BTEB molecules located in the interlayer space. Lastly, the aromatic bridging moieties were functionalized with amine groups, to obtain the bi-functional catalyst. Specifically, the pillared hybrid MWW-BTEB material was reacted in a HNO3/H2SO4 mixture to incorporate -NO2 groups, which were then reduced to -NH2 through reaction with SnCl2. The final material featured a hierarchical system of pores and the presence of the two active sites in different pore Catalysts 2021, 11, x FOR PEER REVIEW 33 of 41 frameworks. Specifically, the acid sites were located within the micropores of the zeolitic layers and the basic amino groups were located in the mesopores formed by intercalation of the organic pillaring agents.

FigureFigure 27.27. (A)):: Synthetic Synthetic procedure procedure implemented implemented for for the the synthesis synthesis of of the the pillared pillared hybrid hybrid zeolitic zeolitic materialsmaterials from MWW precursors. ( (BB):): Layered Layered hybrid hybrid material material obtained obtained by by pillaring pillaring with with BTEB BTEB silsesquioxanesilsesquioxane molecules (MWW (MWW-BTEB).-BTEB). Reprinted Reprinted with with permission permission from from [126 [126]. ].Copyright Copyright 2010, 2010, AmericanAmerican ChemicalChemical Society.Society.

TheIn another catalyst study, was tested Gaona in et a cascadeal. prepared reaction, functional involving acid an-base acetal hybrid hydrolysis materials followed based byon a(organo)aluminosilicate Knoevenagel condensation. layers Speciﬁcally, prepared benzaldehyde through direct dimethylacetal hydrothermal was synthesis hydrolyzed pro- tocesses produce in the benzaldehyde, presence of aluminum which was-rich reacted alkaline with media malononitrile and two combined to give types benzylidene of orga- malononitrile.nosiloxane precursors. The results They showed were high able activity to achieve of the isolated catalyst in aluminosilicate the tandem reaction, sheets with with aamino product and/or yield sulfonic of 96% groups after 7.2 homogeneously h of reaction and distributed a selectivity along of 99% their [126 external]. surface, lo- catedIn between another study,the layers. Gaona The et al.NH prepared2-functionalized functional hybrid acid-base material hybrid was materials prepared based by hy- on (organo)aluminosilicatedrothermal synthesis in layers which prepared triethoxymethylsilane through direct hydrothermal (TEMS) and synthesis 3-aminopropyl processes tri- inmethoxysilane the presence of(APTMS) aluminum-rich were implemented alkaline media as and silicon two combinedprecursors types together of organosiloxane with sodium precursors.aluminate (NaAlO They were2) and able NaOH. to achieve The slurry isolated was aluminosilicate stirred at room sheetstemperature with amino until gelation and/or sulfonicoccurred groups and it homogeneouslywas then transferred distributed into a stainless along their steel external autoclave surface, and locatedheated at between 135 °C thefor layers.9 days under The NH autogenous2-functionalized pressure hybrid and materialstatic conditions. was prepared Finally, by hydrothermalthe solid was washed synthesis in which triethoxymethylsilane (TEMS) and 3-aminopropyl trimethoxysilane (APTMS) with distilled water and dried. A catalyst featuring HSO3 moieties was prepared, as well, wereby using implemented as silicon precursors as silicon precursors a mixture of together TEMS and with 3 sodium-mercaptopropyltrimethoxysilane aluminate (NaAlO2) and NaOH.(MPTMS). The The slurry thiol was groups stirred resulting at room temperaturefrom the use until of the gelation MPTMS occurred were oxidized and it was to then sul- transferred into a stainless steel autoclave and heated at 135 ◦C for 9 days under autoge- fonic acids by stirring the material in an acid ethanolic solution (0.02 M H2SO4) at room noustemperature pressure for and 24 statich. Finally, conditions. by using Finally, TEMS, theAPTMS solid and was MPTMS washed as with silicon distilled sources, water the and dried. A catalyst featuring HSO3 moieties was prepared, as well, by using as silicon authors were able to prepare laminar materials featuring both NH2 and HSO3 groups. In- precursors a mixture of TEMS and 3-mercaptopropyltrimethoxysilane (MPTMS). The thiol dividual nanolayers were able to interact with each other through multiple types of inter- groups resulting from the use of the MPTMS were oxidized to sulfonic acids by stirring the actions, such as Van der Waals, hydrogen or ionic interactions, allowing to obtain layered material in an acid ethanolic solution (0.02 M H SO ) at room temperature for 24 h. Finally, crystalline materials without using a structure2 di4recting agent. Different catalytic reac- by using TEMS, APTMS and MPTMS as silicon sources, the authors were able to prepare tions were implemented to test the activity of the different hybrids. The condensation of laminar materials featuring both NH and HSO groups. Individual nanolayers were able carbonyl compounds with active methylenic2 substrates,3 in reactions such as Knoevenagel to interact with each other through multiple types of interactions, such as Van der Waals, and Henry was used to probe the activity of NH2-functionalized catalyst, whereas acetal- hydrogen or ionic interactions, allowing to obtain layered crystalline materials without ization of benzaldehyde with methanol to 1,1-dimethoxytoluene was used to test the ac- using a structure directing agent. Different catalytic reactions were implemented to test tivity of the HSO3-functionalized material. The performances of the bi-functional acid- the activity of the different hybrids. The condensation of carbonyl compounds with active base catalysts were evaluated in one-pot two-step process involving an acid-catalyzed ac- methylenic substrates, in reactions such as Knoevenagel and Henry was used to probe etal hydrolysis followed by a base-catalyzed Knoevenagel reaction, with a product yield the activity of NH2-functionalized catalyst, whereas acetalization of benzaldehyde with of 92%. This study provided a valid alternative to the typical mesoporous silica for appli- methanol to 1,1-dimethoxytoluene was used to test the activity of the HSO3-functionalized material.cations as Theinorganic performances supports of for the the bi-functional synthesis of acid-base multi-functional catalysts hybrid were evaluatedorganic-inor- in ganic catalysts [127]. Li et al. prepared a series of catalysts by immobilizing Pd nanoparticles onto amino- functionalized SBA-15. Firstly, the hybrid support was prepared by one-pot co-condensation of TEOS and aminopropyltrimethoxysilane (APTMS) in presence of block copolymer P123; then, palladium nanoparticles were supported by adsorption/reduction procedure. The amino groups present on the silica support were designed for playing two roles: stabilizing the Pd NPs against aggregation and leaching, both by weak interaction between the N lone pair and the empty orbitals of the Pd atoms and by partial occlusion of the pore

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one-pot two-step process involving an acid-catalyzed acetal hydrolysis followed by a base-catalyzed Knoevenagel reaction, with a product yield of 92%. This study provided a valid alternative to the typical mesoporous silica for applications as inorganic supports for the synthesis of multi-functional hybrid organic-inorganic catalysts [127]. Li et al. prepared a series of catalysts by immobilizing Pd nanoparticles onto amino- functionalized SBA-15. Firstly, the hybrid support was prepared by one-pot co-condensation of TEOS and aminopropyltrimethoxysilane (APTMS) in presence of block copolymer P123; Catalysts 2021, 11, x FOR PEER REVIEW 34 of 41 then, palladium nanoparticles were supported by adsorption/reduction procedure. The amino groups present on the silica support were designed for playing two roles: stabilizing the Pd NPs against aggregation and leaching, both by weak interaction between the N lone pairchannels, and the and empty acting orbitals as Brønsted of the Pdbase atoms sites andin a bycascade partial reaction occlusion (Figure of the 28). pore The channels, bi-func- andtional acting catalyst as Brønsted provided base full sites yield in a of cascade the hydrogenated reaction (Figure product. 28). The To bi-functional access the key catalyst role providedplayed by full each yield of the of two the hydrogenatedactive sites, mono product.-functional To access catalysts the keyfeaturing role played only one by of each the oftwo the sites two were active prepared. sites, mono-functional As expected, NH catalysts2-functionalized featuring only SBA one-15 led of the to a two 100% sites yield were of prepared.product B1 As (Figure expected, 28B) NHand2 -functionalizedno conversion was SBA-15 observed led to using a 100% Pd yieldNPs supported of product onto B1 (Figurepure silica 28B) SBA and-15. no conversion was observed using Pd NPs supported onto pure silica SBA-15.

FigureFigure 28.28.( (AA):): SynthesisSynthesis procedureprocedure forfor thethe SBA-15-NHSBA-15-NH22/Pd/Pd-p-p catalyst. catalyst. (B (B):): One One-pot-pot Knoevenagel Knoevenagel condensation/hydrogenationcondensation/hydrogenation multi-stepmulti-step cascade cascade reaction reaction sequence sequence between between benzaldehyde benzaldehyde and and ethyl

cyanoacetate.ethyl cyanoacetate. (C): TEM (C): image TEM image of the SBA-15-NHof the SBA-215/Pd-p-NH2 catalyst/Pd-p catalyst after ﬁve after catalytic five catalytic cycles. cycles. Reprinted withReprinted permission with permission from [128]. from Copyright [128]. 2010,Copyright John Wiley2010, John and Sons. Wiley and Sons.

Interestingly,Interestingly, aa physical mix mixtureture of of the the two two mono mono-functional-functional catalysts catalysts also also gave gave a 100 a 100%% yield yield of ofthe the desired desired product product C1. C1. However, However, while while the the bi- bi-functionalfunctional catalyst catalyst was was able able to toretain retain its its catalytic catalytic activity, activity, with with 88 88% % yield ofof productproduct C1C1 inin thethe 5th 5th catalyticcatalytic cycle,cycle, thethe physicalphysical mixture mixture of of the the two two mono-functional mono-functional catalysts catalysts suffered suffered from from fast deactivation, fast deactivation, with onlywith aonly 26% a yield26% yield of product of product C1 obtainedC1 obtained in thein the third third catalytic catalytic cycles. cycles. Presumably, Presumably, the the interactionsinteractions between between the the Pd Pd NPs NPs and and the the surface surface of of the the silicasilica support,support, without without any any organic organic groups,groups, are are relatively relatively weak weak and and cannot cannot prevent prevent aggregation aggregation and and leaching leaching of of the the Pd Pd species species duringduring thethe catalysis.catalysis. OnOn thethe otherother hand,hand, thethe presencepresence ofof pendantpendant aminopropylaminopropyl moietiesmoieties stabilizedstabilized Pd Pd nanoparticlesnanoparticles within within the the mesoporousmesoporous channels, channels, allowing allowing the the hybrid hybrid to to retain retain itsits performancesperformances over more more catalytic catalytic cycles. cycles. TEM TEM images images recorded recorded on on the the bifunctional bifunctional hy- hybridbrid after after five five catalytic catalytic cycles cycles enforce enforce this this hypothesis hypothesis (Figure (Figure 28C 28):C): the the nanoparticles nanoparticles ap- appearpear to to be be well well dispersed dispersed throughout throughout the the porous porous channels channels of of the the suppor supportt and nono macro-macro- aggregatesaggregates areare visiblevisible [ 128[128].]. BesidesBesides these these representative representative examples, examples, many many other other articles articles and and reviews reviews have have been pub-been lishedpublished dealing dealing with with silica-based silica-based multi-functional multi-functional catalysts catalysts featuring featuring various various combinations combina- oftions active of active sites [ 18sites,64 ,[12918,64–133,129]. –133]. TheThe fieldfield ofof multi-functionalmulti-functional organic-inorganicorganic-inorganic hybridhybrid catalystscatalysts isis stillstill inin aarelatively relatively earlyearly stagestage ofof development.development. However,However, thethe reportedreported literatureliterature suggestssuggests that,that, likely,likely, the the full full potentialpotential of of this this field field is is still still largely largely unexplored. unexplored. Coexistence Coexistence of acidof acid and and base base functionalities functionali- inties the in reactionthe reaction mixture mixture was was not not possible possible before before the the development development of of organic-inorganic organic-inorganic hybrids. Nowadays, catalytic processes involving subsequent acid + base catalyzed steps carried out in homogeneous phase require neutralization and purification of the intermediates, which contemplate the use corrosive reactants and great energy consumption. Moreover, acid/base catalytic steps followed by a redox step are present in the majority of production processes in the fine chemicals and pharmaceuticals industries. Proof-of-concept studies such as those reported in this review opens up the development or more and more multi-functional catalysts to be implemented in the chemical industry. Lastly, as the field of artificial enzymes develops [134], the versatility of silica-based approaches to supporting organic molecules, opens up to the possibility of supporting a higher number of these macro-biomolecules to achieve higher stability and reusability [135].

Catalysts 2021, 11, 79 33 of 39

hybrids. Nowadays, catalytic processes involving subsequent acid + base catalyzed steps carried out in homogeneous phase require neutralization and purification of the intermediates, which contemplate the use corrosive reactants and great energy consumption. Moreover, acid/base catalytic steps followed by a redox step are present in the majority of production processes in the fine chemicals and pharmaceuticals industries. Proof-of- concept studies such as those reported in this review opens up the development or more and more multi-functional catalysts to be implemented in the chemical industry. Lastly, as the field of artificial enzymes develops [134], the versatility of silica-based approaches to supporting organic molecules, opens up to the possibility of supporting a higher number of these macro-biomolecules to achieve higher stability and reusability [135].

6. Conclusions and Perspectives In the last decades, silica-based hybrid organic-inorganic materials have been proposed by ever more researchers as viable alternative to traditional heterogeneous catalysts. In the first part of this review article, after a briefly introducing the concept of hybrid catalyst, the focus was put on silica-based organocatalysts. Different synthetic strategies commonly implemented to obtain them were described, such as co-condensation, grafting and PMOs synthesis. Then, an in-depth description of the chemistry behind sol-gel processes was presented. Specific focus was put on the effect of the pH and on the catalyst used (acid, base, fluoride ions). The interactions between silica precursors and templating agents of different nature were also described, as well as the most commonly implemented alkoxysilyl precursors. In the second part of this review, the main classes of organic-inorganic hybrid catalysts were introduced. Relevant exemplificative studies, drawn from the scientific literature, were presented, with specific focus on the synthetic strategies implemented to obtain them and on the effect they turned out to have on the properties of the hybrid catalyst. Acid catalysts were firstly described, specifically heteropolyacids (HPAs) and supported-sulfonic acids. These hybrids offer to overcome size and diffusion limitation that microporous zeolites (by far the most widely implemented class of heterogeneous acid catalysts) encounter when the catalytic process involves bulky substrates. Although HPA-based catalysts showed promising results for a number of catalytic applications, supported-sulfonic acid groups seem to offer better perspectives in term of their versatility. In fact, the acidity of the sulfonic acid proton can be tuned by changing the nature of the substituent onto which the sulfonic acid group is attached. However promising, silica-supported sulfonic acid catalysts offer room for improvements, as they are typically obtained from costly substrates and, in many cases, from multi-step, low-yielding syntheses. Then, silica-supported base catalysts were described. Specifically, representative studies involving the use of silica-supported amines of different type were described, e.g., alkyl-amines, guanidines, proton sponges. After this overview, the cooperative effect occurring between supported amines and the polar silanol groups present on the surface of the porous supports was accessed in details. Supported amines are usually employed as heterogeneous catalysts in processes involving C-C bond formation reactions starting from substrates carrying a carbonyl group (e.g., Knoevenagel condensation, Henry reaction, Michael addition). For these reactions, surface silanol groups play a key role by favoring the adsorption of substrate molecules and activating the carbonyl group by H-bond interaction with the oxygen atom. Different strategies to prepare, silica-supported organometallic catalysts were then described. The incorporation of such delicate functional groups have been achieved by methodologies involving, amongst others, (i) the anchoring of the ligand and subsequent metal coordination; (ii) the synthesis of the organometallic complex starting from a silylated pincer-type ligand and subsequent grafting onto the silica support; (iii) the synthesis of the organometallic complex through coordination by multiple silylated ligand molecules and subsequent grafting. The possibility of using hybrid organic-inorganic catalysts as scaffold for stabilizing metal nanoparticles was also described. In the last section, reports on the synthesis of silica-based multi-functional hybrid catalysts are reported. By means of Catalysts 2021, 11, 79 34 of 39

custom-designed synthetic strategies, several authors were able to incorporate multiple functional groups, sometimes incompatible with each other, within a single solid porous catalyst. As this review hopefully demonstrated, the versatility of sol-gel chemistry of silica, thermal and mechanical and textural properties of silica-based materials and the reactivity of their surface are all features that can be taken advantage of, in the rational design of a functional material. The chemistry of silyl-derivatives allows preparing precursors carrying the functional group of interest, e.g., catalytic sites, ligands, hydrophobic moieties. Finally, post-synthetic modiﬁcation of the hybrid materials opens up to the possibility of anchoring precursors that can be then converted to the functional groups of interest (e.g., nitro to amine; thiol to sulfonic acid), which can make the incorporation of reactive functional groups that would be otherwise impossible. However, for this ﬁeld to develop further within industries, some drawbacks should be overcome. Firstly, to achieve sustainability on an industrial scale, cheaper and greener way to synthesize silyl-derivatives precursors are in need (e.g., sulfonic acid catalysts precursors); Secondly, a better understanding of deactivation mechanisms would allow designing heterogeneous catalysts and catalytic processes that could work over more cycles. Lastly, as it was shown in Section 4.2, understanding the interaction between the silica support and the pendant organic molecules can provide key information to maximize the catalytic activity of a given catalyst. Although this has been extensively studied for Base–H-bond donor catalysts, the interaction between other type of organic functionalities and silica supports is still relatively unexplored.

Author Contributions: Conceptualization, A.E. and U.D.; original draft preparation, A.E.; editing and review, A.E. and U.D.; supervision, U.D. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Spanish Government (MAT2017-82288-C2-1-P and Severo Ochoa Excellence Program SEV-2016-0683) and MULTY2HYCAT (EU-Horizon 2020 funded project under grant agreement no. 720783). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Acknowledgments: A.E. acknowledge “la Caixa” foundation for the PhD scholarship. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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