Advances in click chemistry for silica-based material construction

Abstract

Click chemistry is undoubtedly the most powerful 1,3-dipolar cycloaddition reaction in organic synthesis. Because the click reaction can be used to straightforwardly attach two different molecules, this type of synthesis has attracted much attention from scientists. If the desired molecule is functionalized with azide or alkyne group(s), it can be readily attached to the target molecule or substrate through the click reaction. The potential of this reaction is very great; moreover, alkyne and azide groups can be incorporated into a widespread range of substituents. In addition, the resulting 1,2,3-triazoles have desirable features in electronic devices, solar cells and medicinal chemistry. In this study, different types of silica based surfaces were investigated for the click reaction, including flat silica materials, silica nanoparticles and porous silica compounds. Moreover, the advantages and applications of various triazole modified silica surfaces were compared.

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Ghodsi Mohammadi Ziarani

Ghodsi Mohammadi Ziarani was born in Iran, in 1964. She received her B.Sc degree in Chemistry from Teacher Training University, Tehran, Iran, in 1987, her M.Sc degree in Organic Chemistry from the Teacher Training University, Tehran, Iran, under the supervision of Professor Jafar Asgarin and Professor Mohammad Ali Bigdeli in 1991 and her Ph.D degree in asymmetric synthesis (Biotransformation) from Laval University, Quebec, Canada under the supervision of Professor Chenevert, in 2000. She is currently a full Professor in the Science faculty of Alzahra University. Her research interests include organic synthesis, heterocyclic synthesis, asymmetric synthesis, natural products synthesis, synthetic methodology and applications of nano-heterogeneous catalysts in multicomponent reactions.

Zahra Hassanzadeh

Zahra Hassanzadeh was born in 1988 in Shiraz, Iran. She received her B.Sc degree in Chemistry from Pierre et Marie curie University, Paris, France in 2011. She continued her studies in Iran and received her M.Sc degree in Organic Chemistry from Alzahra University in 2014 under the supervision of Prof. Ghodsi Mohammadi Ziarani. Her research field study was microwave assisted synthesis of organic compounds.

Parisa Gholamzadeh

Parisa Gholamzadeh was born in 1986 in Tehran, Iran. She received her B.Sc and M.Sc degrees from Alzahra University (2010 and 2012, respectively). Presently she is working towards her Ph.D Degree in Organic Chemistry at Alzahra University under the supervision of Prof. Ghodsi Mohammadi Ziarani. Her research field is the synthesis of oxindole based heterocyclic compounds and surface modification of silica based compounds and their applications.

Shima Asadi

Shima Asadi was born in 1984 in Garmsar, Iran. She received her B.Sc degree from Alzahra University (2006) and her M.Sc degree in Organic Chemistry at Shahid Beheshti University, Tehran, Iran (2010) under the supervision of Dr Mohammad Reza Nabid. She completed her Ph.D degree under supervision of Prof. Ghodsi Mohammadi Ziarani at Alzahra University (2014). She is currently working towards her postdoctoral fellow with Professor Majid Heravi. Her research projects concern the development of new heterogeneous catalysts based on metal nanoparticles and their application in organic transformations.

Alireza Badiei

Alireza Badiei was born in Iran, in 1965. He received B.Sc and M.Sc degrees in Chemistry and Inorganic Chemistry from the Teacher Training University (Kharazmi), Tehran, Iran, in 1988 and 1991, respectively, and his Ph.D degree in Synthesis and Modification of Nanoporous Materials from Laval University, Quebec, Canada, in 2000. He is currently Full Professor in the Chemistry Faculty of Tehran University. His research interests include nanoporous materials synthesis, modification of nanoporous materials and application of organic–inorganic hybrid materials in various fields such as catalysis, adsorption, separation and sensors.

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1. Introduction

1.1. Click chemistry

The “click chemistry” concept has recently had an enormous impact on chemical philosophy and the design of diverse supramolecular, biomaterial and highly functionalized compounds. There are four types of click chemistry; these are shown in Scheme 1. Among these, the Huisgen 1,3-dipolar cycloaddition catalyzed by Cu(I) (copper-catalyzed azide-alkyne cycloaddition, or CuAAC) is the most common; therefore, it is now often referred to as the “click chemistry reaction”.¹

Scheme 1 Different types of Huisgen click chemistry.

1.2. Advantages of CuAAC in click chemistry

To date, a large variety of copper catalysts have been developed and used for the CuAAC reaction. Among the tested catalysts, Cu(I) in the form of either CuI or CuBr is the best, especially CuI, because it can be prepared easily in the laboratory. Moreover, Cu²⁺ is also extensively used in the presence of a reducing agent such as sodium ascorbate, which converts it from Cu(II) to Cu(I).² Therefore, the availability of the catalyst is one of the most important advantages of this method. Furthermore, separation of the catalyst from the reaction mixture is simple; it can be removed via washing with water and diluted HCl solution.

In most cases, alkyl azides and alkyne groups do not tend to react with other functional groups; however, in click reactions, they participate in a highly chemoselective manner.³ The other significant advantage of click chemistry relates to the monitoring of the reaction, which does not require complex techniques. The completion of the reaction can be monitored by FT-IR spectroscopy, because both alkyne and azide groups have characteristic peaks in the ranges of 2260–2100 cm⁻¹ and 2160–2120 cm⁻¹, respectively. Thus, when these peaks have disappeared, the reaction is complete.⁴

1.3. Importance of click synthesis and 1,2,3-triazoles

Because the click reaction can be used to straightforwardly attach two different molecules, this type of synthesis has attracted much attention from scientists. If the desired molecule is functionalized with azide or alkyne group(s), a target molecule or substrate can be attached to it through the click reaction. For instance, triazoles are stable compounds in acidic and basic media as well as under reductive and oxidative conditions, due to their high aromatic stabilization.^5,6 Various drugs contain 1,2,3-triazole moiety such as Tazobactam. Moreover, to obtain more efficient drugs or improve their activities, scientists are continually attempting to modify the molecular structure of medicines. In this regard, a new derivative of cephalosporins with good oral availability was obtained by linking the triazole moiety to its core.⁷ Another significant application of the click reaction is the insertion of triazole moieties into the structure of nucleosides, especially the pyrimidine ring; this is reported to have antiviral and cytotoxic properties.⁸ The click reaction is one of the best ways to generate dimers, chimeras and multivalent drugs such as daunorubicin dimers⁹ and vitamin D₃.¹⁰ The CuAAC reaction has also been confirmed to be a valuable method for the immobilization of ligands on DNA. Such a ligand inhibited the production of DNA damaging oxygen radicals by the redox chemistry of copper(I).¹¹ A few studies have been published on the application of the click reaction in different fields of science.^12–14

1.4. Click reaction on solid surfaces

Initially, the surface of gold was modified with triazole moieties. The surface was functionalized with DNA, sugar, nanoparticle receptors and porphyrin redox catalysts.^15–17 The advantages of this method for the click reaction include high quality and molecularly well-defined monolayers on gold surfaces, as well as simple characterization using analytical methods. However, modification of the gold surface with self-assembled multilayers (SAMs) is difficult because the gold–sulfur bond is readily photooxidized and consequently, SAMs are damaged in the presence of highly reducing or oxidizing organic solvents.^18,19

Furthermore, the first application of CuAAC on silica surfaces was established.²⁰ The low cost and high availability of silicas are advantages of this method. In addition, the silica surface is not electroactive in comparison to gold particles. The gold surface is modified using thiol groups, whereas silanes are applied for the silica surface modification; therefore, the monolayer and self-assembled multilayers (SAMs) are grafted on the silica surface through a covalent bond, and they are more stable in comparison with those on the gold surface. The production of fluorescent transparent glasses and also tailor-made silica base triazoles using this technique has attracted the attention of researchers.^21–23

Silicon compounds are excellent technological materials because they can be easily obtained and doped to obtain an electroactive surface. Therefore, the modification of silicon surfaces, like that of silica surfaces, is more promising than gold surface modification.³ There are several reports that confirm the applications of this feasible and wide-scope chemical approach because of its many advantages, such as stereospecific and mild reaction conditions, low temperature, high yield, and the use of green solvents such as water.^24–26 In a continuation of our previous studies,^27–29 in this study, applications of click chemistry are investigated as a powerful tool for the triazole functionalization of silicon based materials, including flat silicon materials, glass silica surfaces, silica nanoparticles and porous silicon (PSi).

2. Click chemistry on the surface of flat silicas

2.1. Click chemistry on the surface of wafer silicon materials

The single crystal of Si is the most common semiconductor; it can be prepared as wafers up to 300 mm in diameter. A wafer silicon is a thin circular slice (the thickness depends on the wafer diameter, but is typically less than 1 mm) of crystalline silicon.³⁰ When crystalline silicon is cut into wafers, its surface is aligned in one of the several relative directions recognized as crystal orientations. The orientation is determined by the Miller index, in which (100), one-zero-zero, or (111), one-one-one, faces are the most common for silicon. The orientation is significant because many structural and electronic properties of a single crystal are highly anisotropic.³¹ Wafer silicon materials are widely applied in the production of solar cells and integrated circuits.³² Later, some examples of click reactions on the surface of wafer silicon will be described.

2.1.1. Click chemistry on the surface of Si (100). The click reaction could also be used to couple two alkynes without any protection or activation steps. In this regard, to immobilize the alkyne onto an acetylenyl surface, a simultaneous azide-alkyne cycloaddition is required. The effectiveness of this method was examined by coupling an alkyne-labeled ferrocene (2) onto an alkyne terminated Si (100) surface (5). The characterizations indicated that the coupling of two alkynes via a click reaction is chemically and electronically well established and gave powerful functionalized monolayers of alkyne-ferrocene (6) or alkyne-ODN (7) on the silicon surface (Scheme 2). The redox properties of the film were investigated and were close to ideal; therefore, the surfaces obtained using these procedures provides potential applications in the field of label-free DNA sensing. Because this procedure uses commercially available alkyne-tagged ODNs with low cost and a well-behaved semiconductor/organic layer interface, it will be valuable.³³

Scheme 2 Tandem “click” reactions on electrodes of acetylenyl Si (100).

Australian researchers compared the reactivity of alkynes to alkenes on hydrogen-terminated Si (100) surfaces. These reactions occurred under conditions wherein a monolayer is formed via hydrosilylation. In the first approach, monolayers (8) were formed from different solutions, including various mole fractions of an alkyne (9) in the presence of a trifluorothioacetate distal moiety and an alkene (10) with a terminal carboxylic acid functional group. The XPS and electrochemical results showed that on Si (100) surfaces, alkynes are more reactive than alkenes (Scheme 3). Then, a molecule containing an alkyne at one end and an alkene at the other end (non-1-yne-8-ene) (11) was used as a hydrosilylation reagent. Once the molecule was grafted on the silica surface to obtain 12, azidoferrocene was coupled to the free alkyne moieties via a CuAAC reaction. Electrochemical studies were then used to detect the number of ferrocene moieties, which were attached to the SAM surface on compound 13. The result shows that the alkyne end reacted preferentially with the silicon surface compared with the alkene end. The XPS and electrochemical results demonstrated that on Si (100) surfaces, alkynes are more reactive than alkenes. The reactivity ratio of alkynes to alkenes changed when the temperature decreased, with a significant decrease from 95 to 65 °C. Surfaces containing ferrocene could have applications in electronics, biochemistry, and biosensor technologies (Scheme 4).³⁴

Scheme 3 Preparation of monolayers from different solutions of an alkyne in the presence of trifluorothioacetate and an alkene with a terminal carboxylic acid group.

Scheme 4 Preparation of monolayers from a molecule containing both an alkyne and alkene moiety (non-1-yne-8-ene).

An efficient approach was introduced to transmit the beneficial chemical functionalities of ferrocenyl groups (15) to an acetylene-passivated silicon surface (16) via acetylenylation followed by a click reaction to obtain surface 17. The fabricated interface presents robust redox properties and spectroscopically proposes a superior passivation of the underlying silicon surface. Cyclic voltammetry (CV) demonstrated the presence of electronic communication between the ferrocene centre and the underlying semiconductor surface. These modified silicon electrodes could find application in biosensing and memory devices. This method was also used on gold electrodes using alkanethiol self-assembled monolayers (Scheme 5).³⁵

Scheme 5 Functionalization of a silicon surface by ferrocenyl groups via acetylenylation followed by a click reaction.

Alkyne-terminated alkyl monolayers (19) were functionalized on Si (100) using the click reaction to fix the ferrocene derivatives (18) onto the Si (100) surface. Monitoring of the reaction by X-ray photoelectron spectroscopy, X-ray reflectometry and CV shows that the surface acetylenes (19) successfully reacted to obtain surfaces containing ferrocene moieties (20). This process enabled the production of organic monolayers grafted onto silicon surfaces; these have the advantages of being stable, powerful, and practically an ideal electrochemistry surface in aqueous conditions. A Si (100) surface grafted with a dialkyne, 1,8-nonadiyne (14), coupled with an azidomethylferrocene (15) via the click reaction, resulted in an electrochemically active surface linked with triazole species. The XPS experiment presented no sign of silicon oxide, even between −100 and 800 mV, versus Ag/AgCl in aqueous electrolytes. It could be deduced that the formation of π bonds between the distal alkynes grafted onto the surface prevented the silicon oxidation. Silicon (100) electrodes could find applications, in a variety of solvents, in bioapplications, and photovoltaics; oxide-free silicon has received considerable attention for molecular electronics and non-electrochemical areas (Scheme 6).³⁶

Scheme 6 Grafting of ferrocene derivatives onto a Si (100) surface via the click reaction.

This indirect grafting procedure is a combination of silanization and click chemistry reactions. The ethynyl-ferrocene (2) was grafted onto the Si surface via a mixed organic/inorganic linker composed of a thin dielectric SiO₂ layer linked to a C₃ linker terminated by a triazole ring and thus the desired ferrocene was prepared on surface 21. This linker was tested for the first time and has the advantages of thin dielectric layers and the versatility of the two step procedure. AFM images and CV of a ferrocene linked on Si (C₂ linker) and a C₃ linker were compared; the results showed that the organic/inorganic linker resulted in better layer uniformity, and the redox charge retention properties could be controlled. The result also showed that the organic moieties have an important role in charge retention, and the mixed linker could be used in memory applications due to its tunnel barrier tuning (Scheme 7).³⁷

Scheme 7 Indirect grafting protocol on SiO₂ with n = 3.

A three-step procedure for the preparation of a ferrocene-modified silicon surface was applied. In the first step, 11-bromo-1-undecene was grafted onto the Si (100) surface (22); treatment with NaN₃ led to 23, followed by coupling of ethynylferrocene (2) via azide-alkyne 1,3-dipolar cycloaddition. This method could ensure good coverage and resistance towards additional synthetic stages, and the surface had good contact due to the position of the redox centers at the external surface. The existence and chemical properties of the redox species grafted onto the Si surface were characterized by the XPS method; the electrochemical method showed that the functionalization of Si (100) by the click reaction guaranteed a good assembly of organic monolayers and a well-established charge transfer reaction to the ethynyl-ferrocene (Scheme 8).³⁸

Scheme 8 Chemical derivatizations of hydrogenated silicon surfaces via click reactions.

The Si (100) surface was also functionalized with alkyne-terminated alkyl monolayers (28) using the copper(I)-catalyzed 1,3-dipolar cycloaddition reaction of the azide ends with the terminal alkynes, which were grafted onto the Si surface. The surface functionalization began with hydrosilylation, followed by grafting of alkyne-terminated alkyl moieties (25) in aqueous conditions. Further derivatization obtained a hydrolytically resistant 1,4-disubstituted surface triazole via a click reaction, which did not require any activation, protection or deprotection procedures. The monitoring of the reaction by X-ray photoelectron spectroscopy and X-ray reflectometry showed that the acetylene groups on the surface efficiently reacted with the alkyl azides. A variety of azides (26) with different functionalities were reacted without any modification of the reaction conditions; any disorder in the layers led to surfaces 28–30. The external surface of these modified silicons showed cell-adhesion properties, which could be applied in biosensing (Scheme 9).^39,40

Scheme 9 Functionalization of a Si (100) surface by hydrosilylation followed by grafting of alkyne-terminated alkyl moieties in aqueous conditions via a copper(I)-catalyzed 1,3-dipolar cycloaddition reaction.

A method of preparing electrochemically switchable surfaces on Si (100) was reported by Ciampi and coworkers. The switching property of these surfaces prevents resistance against cell adsorption and enables cell adhesion. Monolayers were grafted onto the non-oxidized silicon surface through hydrosilylation of 1,8-nonadiyne (14) (to confirm the silicon passivation and aqueous conditions).^36,39 A coumarin molecule (31) functionalized with an azide was coupled with 1,8 nonadiyne via azide-alkyne 1,5-dipolar cycloaddition. SAM-3, which contains a quinone moiety, could be electrochemically converted back to multilayer 31 via a “trimethyl lock” lactonization process. In the 1970s, the trimethyl lock scheme⁴¹ was introduced to simplify cyclization reactions.⁴² It is also used in redox-sensitive resins for solid-phase peptide synthesis⁴³ and in the liberation of small peptides engaged in adhesion of cells on gold surfaces.⁴⁴ OEG is a cell-adhesion-resistant molecule, which was attached to SAM-2 to create a surface that prevents cell adhesion. To produce a surface susceptible to cell adhesion, molecule 31 was cleaved by decreasing the potential. The reaction was monitored by XPS, X-ray reflectometry, and contact angle, and cell adhesion investigations to control the electrochemical modifications of the electrode surface. To verify the efficiency of the switchable structure, the Si (100) electrode was surrounded by OEG antifouling molecule 32. Assembly protocols and chemical modules were used on the silicon surface due to its stable surface chemistry;⁴⁵ this material has been adapted for use in the microelectronics industry,⁴⁶ due to the facility of microfabrication and nanostructuring of the material^47,48 and the adjustable electrical⁴⁹ and optical features of silicon (Scheme 10).^50,51

Scheme 10 Passivation of Si surface through hydrosilylation of 1,8-nonadiyne (16) (SAM-1) followed by a click reaction between coumarin (25) functionalized with an azide coupled with 1,8 nonadiyne (SAM-2), pursued by different steps, such as oxidation and activation, leading to (SAM-3), which is converted back to multilayer 25 via a “trimethyl lock” lactonization process.

The direct electron transfer between cytochrome c and a pyridinyl group was studied on SAM Si (100) electrodes. The self-monolayer-modified Si (100) (36) was prepared using a click reaction between acetylene-terminated alkyl groups and isonicotinic acid (35) functionalized with different azides (33 and 34). The presence of a para-ester linkage inhibited the capacity of the isonicotinic acid terminated layers to bind the redox site of cytochrome c. A difference in the ability to ligate to cytochrome c was displayed by the amide and ester, due to hydrogen bonding, which contributes to an electronic coupling between two redox couples; to study cytochrome c, the hydrogen bonding character of a functionalized gold electrode was adopted to control the rate of electron transfer (Scheme 11).⁵²

Scheme 11 Depiction of the formation of pyridinyl Si (100) electrodes.

Antifouling surfaces can resist the nonspecific adsorption of cells and proteins; these surfaces have found different applications in many fields such as biomedical devices,⁵³ prototypes for cell adhesion⁵⁴ and biosensors.⁵⁵ Australian researchers functionalized a Si surface with oligoethylene glycol (OEG) molecules via a click reaction between an azide group at one side and an ionisable group at the other side. The modification of the surface was verified using water angle goniometry and XPS. Moreover, the antifouling role of these surfaces was verified, and it was found that the antifouling behavior was preserved after modification of the surface by charged molecules (37–40). However, the protein adsorption at various pH levels showed that the electrostatics had a greater influence on the antifouling properties than ethylene glycol. Therefore, the functional groups on the surfaces, including amine, alcohol, and carboxylic acid, may also be utilized for further surface modification. For instance, the surface can be modified with proteins, peptides and enzymes using carbodiimide coupling chemistry. Moreover, these charged molecules may be utilized in smart surfaces (Scheme 12).⁵⁶

Scheme 12 Surface modification process: (a) HF-etching, producing a hydrogen-terminated Si (100) surface; (b) hydrosilylation, producing an alkyne-terminated surface; (c) ‘click’-modification, attaching various ethylene glycol derivatives to the surface via triazole rings. For simplicity, all head groups are shown in their non-ionized forms.

Haensch and coworkers functionalized silicon surfaces, p-type Si (100), with bromine-terminated SAMs (41). This functionalization was due to the chemical stability of bromine-terminated SAMs (41) towards many modification sequences. Bromine functionalities allowed the formation of regular monolayers and could be used in organic reactions. Chemical modifications, such as substitution, cycloaddition, supramolecular chemistry and ionic interactions, which can occur simultaneously, were studied on alkyl bromides. Different alkyl amines were used for the nucleophilic substitution reaction. The acetylene end groups (42) were created by the substitution reaction of bromine by propargylamine. Then, a click reaction was performed between the azide and alkyne terminated ends to obtain 1,4-disubstituted triazole (43) (Scheme 13). To introduce supramolecular building blocks into SAMs (41), bromine was substituted by an amino-functionalized terpyridine to obtain 44. Steric effects led to mixed monolayers of terpyridine and bromine functions. Additional surface modification reactions, such as complexation with a Ru(III)-modified poly(ethylene glycol) (PEG) terpyridine monocomplex, azide substitution, and subsequent 1,3-dipolar cycloaddition, are demonstrated in Scheme 14. In addition, the surface composition can be changed by the construction of a monocomplex (Scheme 14). These surfaces can be used as catalysts or are applicable for the fabrication of smart surfaces (45).⁵⁷

Scheme 13 Modification of a bromine-terminated monolayer.

Scheme 14 Surface modification of SAMs with terpyridine, complexation with a Ru(III)-modified PEG terpyridine monocomplex, and the click reaction.

Clickable monolayers were formed on powdered silica and on silicon (100). 11-Bromo-undecylsiloxane (46) was replaced by 11-azido-undecylsiloxane (47) and then coupled with three acetylene derivatives, R–CHCH–R′ (R,R′ = C₆H₁₃, H (a); COOCH₃, H (b); COOC₂H₅, COOC₂H₅ (c)) to form 48 using azide-alkyne copper-catalyzed cycloaddition. Acetylenes b and c reacted with powdered silica (47) on the wafer surface at 70 °C in the absence of catalyst, and no reaction was reported with acetylene a. The exceptional properties of this reaction in solution, such as high selectivity, quantitative yields, no byproducts, and straightforward reaction conditions, will likely enable the expansion of this method in chemically functionalized surfaces (Scheme 15).⁵⁸

Scheme 15 Modification of 11-bromo-undecylsiloxane (46) into 11-azido-undecylsiloxane (47) followed by coupling of the azide side with three acetylene derivatives (a–c) via click reactions.

In another publication, a macrocycle of nickel(II) β-azido-meso-tetraphenylporphyrin was grafted on a silicon (100) surface through a linker possessing two terminal alkyne groups. In the first step, the C≡C triple bond of the alkynes was hydrosilylated, followed by a CuAAC reaction between the alkyne-terminated silicon surface (16) and the azidoporphyrin derivative (49). This study had the advantage of aiding electron transfer through the para-phenyl position of TPP, which made it faster than through a meso-phenyl substituent (Scheme 16).⁵⁹

Scheme 16 Schematic of the grafting sequence. Reaction conditions: (i) nonadiyne, 140 °C, 12 h and (ii) nickel(II) β-azido-meso-tetraphenylporphyrin, CuSO₄·5H₂O, ascorbic acid, dry DMF, 50 °C, 17 h.

Ostaci's research team grafted polymer brushes onto passivated silicon (100) surfaces via an alkyne-azide copper catalyzed cycloaddition between azido polymers (51) and alkynyl functionalized silicon surfaces (50). First, an alkyne functionalized SAM (50) was deposited onto the silicon substrates to passivate the silicon surfaces; then, linear brush precursors containing azide groups, such as PEG-N₃, PMMA-N₃, and PS-N₃ (M_n = 20 000 g mol⁻¹) (51), were linked into functionalized SAMs by a click reaction in THF, leading to 52. The SAM, PMMA, PEG and PS layers were characterized by ellipsometry, scanning probe microscopy, and water contact angle measurements. The click reaction was not influenced by the chemical properties of the polymer brushes. These experiments could be expanded by grafting a variety of polymers onto passivated silicon surfaces (Scheme 17).⁶⁰

Scheme 17 Grafting of polymer brushes on passivated silicon surfaces.

A functional method for grafting azide-terminated polymers onto alkyne-functionalized brushes (55) by the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition has been studied. After preparation of polymer 53, alkyne-functionalized brushes were fixed in melt by thermal ring-opening of the glycidyl groups by the silanols from the silicon (100) substrate to obtain 54. Finally, the grafting of α-methoxy-ω-azido-poly(ethylene glycol)s (M_w = 5000, 20 000, and 50 000 g mol⁻¹) by the click reaction was performed in sealed reactors at 60 °C for 72 h using a polymer weight fraction of 10% in THF and Cu(PPh₃)₃Br/DIPEA as the catalytic system. The alkyne-functionalized brushes and PEG brushes were monitored by ellipsometry, scanning probe microscopy, and water contact angle measurements. This “grafting-to” brushes technique represents a fast and versatile method to provide thick homogeneous brushes (55) with high surface coverage (Scheme 18).⁶¹

Scheme 18 Grafting alkyne-functionalized brushes on a silica surface followed by the click reaction.

PEG has been grafted to silicon (100) substrates by Cu(I)-catalyzed cycloaddition reactions. Initially, the silicon surface was functionalized with ethynyldimethylchlorosilane (EDMS) (56),⁶² which allows passivation of the surface against brushes and adsorption of the linear precursors; thus, surface 57 was generated. This procedure occurred in the vapor phase or in toluene solution and was monitored by water contact angle. Then, α-methoxy-ω azido-PEGs were grafted to the alkyne functionalized SAMs (57) in THF using Cu(PPh₃)₃Br/DIPEA as the catalyst to give surface 58. Ellipsometry, scanning probe microscopy and water contact angle measurements were used to verify the effect of the polymer concentration in the grafting solution as well as the reaction time on the thickness, morphology and wetting properties of the PEG (Scheme 19).⁶³

Scheme 19 Grafting of polymer brushes on “passivated” silicon substrates via click chemistry.

Treated monolayers based on silicon (100) surfaces could be chemically reworked using MW irradiation. To adopt a heating process to functionalize SAM, chemical and thermal tests were performed to verify the stability of these layers under MW irradiation conditions. FT-IR, AFM and contact angle measurements were used to compare the quality and morphology of the monolayers (59) before and after MW irradiation. The chemical modification was analyzed through a click reaction between the azide end and the acetylene end. The FT-IR technique verified the coupling of acetylene groups with different molar masses through click reactions onto the silicon surfaces and the generation of compounds 60 and 61. The reaction occurred in 5 min, and the heating technique shows that increasing the temperature results in a rapid reaction (Scheme 20).⁶⁴

Scheme 20 Coupling of different masses of acetylene groups via click reactions.

A unique peptide with the ability to bond to a SiO₂ surface possessing biomimetic properties was synthesized from silicon (100) wafers by Hassert and coworkers.⁶⁵ This peptide was functionalized with a bioactive integrin binding c[RGDfK]-ligand† and a fluorescent probe (TAMRA) through the combination of a Diels–Alder reaction with inverse electron demand (DAR_inv) and Huisgen copper(I) catalyzed reactions (CuAAC). An α_Vβ₃-integrin binding c[RGDfK] peptide was inserted into a high affinity silicon oxide binding peptide (highSP)-Pra by DAR_inv. Therefore, the TAMRA-azide was coupled with the c[RGDfK]-highSP peptide via a CuAAC reaction. Further studies showed the important role of c[RGDfK]-highSP-TAMRA coated silicon oxide in the cell spreading and viability of osteosarcoma cells. This biological surface with silicon oxide could find applications in microarrays,⁶⁶ microchip–neuron interfaces,⁶⁷ medical devices,⁶⁸ biologically modified field-effect transistors (BioFET),⁶⁹ and silicon nanoparticles as drug delivery systems (Scheme 21).^65,70

Scheme 21 Illustration of the stepwise DARinv and CuAAC reaction, showing the cell attractive c[RGDfK]-dienophile ligand linked to the diene-highSP-Pra peptide by DARinv. The fluorescence probe TAMRA-azide was subsequently introduced by CuAAC.

Currently, PEG is widely utilized in antifouling coatings by virtue of its capability to diminish protein adsorption and ameliorate biocompatibility. To improve the stability and density of the PEG layers, a stepwise strategy of grafting PEG layers onto silicon surfaces was engaged. The stepwise strategy began with a hydrosilylation procedure using a 1,8-nonadiyne, and then the alkyne-terminated surface (62) was coupled with an azide containing an amine group via azide-alkyne Huisgen cycloaddition to obtain compound 63. The amine group was then conjugated with the PEG layer to create an antifouling surface (64). To demonstrate the antifouling surface properties, an adsorption test of human serum albumin (HAS) and lysozyme (Lys) on the PEG layers in phosphate buffer solution was performed. The results showed no fouling of HAS onto the PEG layers; however, lysozyme protein was adsorbed in a very small quantity (Scheme 22).⁷¹

Scheme 22 Stepwise strategy of grafting PEG layers onto silicon surfaces.

The aminophenyl groups grafted onto silica surface 65 were converted into azidophenyl 66, and then the acetylene-functionalized reagents were coupled with the azidophenyl groups by a click reaction to obtain compound 67. Fluorescence spectroscopy verified the presence of fluorescein-tagged DNA single strands, and SFG spectroscopy studies verified the label free DNA hybridization, showing the appearance of duplex formation. Triazole functionalization depended on the acetylene reagent; it was reduced when the alkynyl derivatives become too rigid such as phenylacetylene, or when the alkynyl derivatives were too large such as alkynylated DNA (Scheme 23).⁷²

Scheme 23 Conversion of aminophenyl groups onto azidophenyl groups, followed by the click reaction.

2.1.2. Click chemistry on the surface of Si (111). Surface functionalization of silicon has an important role in the development of silicon-based sensors. Hydrolytic cleavage can be prevented using organic monolayers directly bonded to hydrogen-terminated silicon substrates via Si–C bonds (68). Gouget-Laemmel and coworkers first prepared homemade hydrogen-terminated Si (111) by cleaning the surface of silicon platelets using H₂SO₄ and H₂O₂ followed by etching in a 50% HF solution for 5 s. The terminal azide groups on the monolayer surface (69) were subjected to bio-conjugation with propargylated derivatives of glycans via a copper-catalyzed “click” reaction. The prerequisite azide-functionalized silicon surface was formed by hydrosilylation of undecylenic acid with hydrogen-terminated silicon substrate followed by the reaction of carboxylic acid groups with short and bifunctional OEG chains possessing an azide group at one end and an amine function at the other. Functionalizing azido-surfaces with propargyl mannose via a click reaction obtained structure 70 (Scheme 24). Modification of the silica surface was monitored by FT-IR spectroscopy, XPS, and colorimetric UV-Vis spectroscopy to establish the amount of clicked mannose on the surface of the silicon; this was determined to be about 70%. The resulting mannose terminated surface (70) is selective to lectins and provides a new carbohydrate sensor to detect glycan binding protein (GBP) (71) events.⁷³

Scheme 24 (a) Modified crystalline (111) silicon featuring decyl chains with terminal carboxyl groups. (b) Introduction of OEG spacers bearing terminal azido moieties via conjugation with a biorthogonal spacer, H₂N–C₂H₄–EG₈–N₃. (c) Click reaction with a propargylated derivative of mannose analog. (d) Interaction with a specific GBP (e) and with a nonspecific GBP.⁷³

Wang and Cai prepared H-terminated silicon (111) surfaces by a procedure similar to that previously described; then, they modified the silicon (111) surface with alkynyl groups and grafted azido OEG on the modified surface via CuAAC using microwave (MW) irradiation to obtain structure 74. The monolayers on the surface of hydrogen-terminated Si (111) (72) were prepared by photografting of α,ω-alkynene, which was inhibited by a trimethylgermanyl (TMG) group. Performing MW instead of the usual heating technique causes a significant amelioration in the reaction. MW irradiation notably improved the elimination of germanium and also the click coupling. Cu(I) was used in the click coupling and led to the elimination of the TMG groups. XPS experiments and contact angle measurement proved the high quality of the monolayers, which presented alkynyl ends protected by TMG (Scheme 25).⁷⁴ They proved that the direct CuAAC coupling of OEG-azides onto a TMG alkynyl modified silica surface can generally obtain higher yields (∼70%) compared to other methodologies.¹³ It was also demonstrated that a monolayer surface functionalized with mannose could be useful in tracking living targets (Scheme 26).⁷⁵

Scheme 25 Formation of TMG-terminated monolayer on Si (111) and the subsequent attachment of OEG derivatives using a MW-assisted click reaction.⁷⁴

Scheme 26 Preparation of TMG-terminated film (A) from an alkenyne, its deprotection to obtain ethynyl-containing film B, and direct CuAAC reactions with the azides promoted by Cu¹⁺ to form films containing CF₃ (C), OEG (D), mannose (E), glucose (F), and biotin (G).⁷⁵

In the present study, a Si (111) surface was functionalized through a chlorination procedure to obtain 75; alkylation led to 76, followed by the grafting of benzoquinone via copper-catalyzed azide-alkyne cycloaddition to produce compound 77. Electrochemical studies were performed on the triazole silica surface in addition to intramolecular cyclization and reaction of ferrocene carboxylic acid with the amine terminus. In the next step, this technique could be employed in preparing modified surfaces, combining organic and biological molecules on Si (111), and in nanomechanical and nanoelectronic sensors because of its selective biopassivation (Scheme 27).⁷⁶

Scheme 27 Functionalization of Si (111) through chlorination and alkylation followed by copper-catalyzed azide-alkyne cycloaddition.

Antimicrobial peptides (AMPs) were fixed onto a bio-inert surface via Huisgen 1,3-dipolar cycloaddition. The bio-inert surface (78) was formed via a hydrosilylation reaction and then coated with OEG-alkenes and OEG-alkenes with a terminal alkyne, which was protected by a TMG group. In the next stage, AMPs functionalized with an azide group were grafted onto the silicon surface via a click reaction and deprotected with a catalytic amount of Cu(I) to obtain surface 79. The preparation of mixed monolayers was surveyed by XPS, ellipsometry and contact angle measurement. Different azido-labeled biomolecules could be grafted onto the bio-inert surface to use in sensing and identifying cells. The immobilized peptides exhibited remarkable bactericidal activity when their density was above ∼1.6 molecule per cm², whereas remaining cyto-compatible with mammalian cells (Scheme 28).⁷⁷

Scheme 28 Surface hydrosilylation using a mixture of the TMG-protected alkenyne TMG-EG10 and the alkene EG7 on H-terminated Si (111) surfaces, followed by attachment of IG-25 with an azido tag (N3-IG-25). The corresponding peptide-presenting surfaces 79a–e are formed upon CuAAC reaction of N₃-IG-25 with the TMG-alkyne surfaces 78a–e.

2.2. Click reaction on glass silica surfaces

Multilayer assemblies (83) have been fabricated via layer-by-layer (LbL) thin films using click chemistry. The multilayer films (81) were created by the interaction of the silica glass surface, including azide-terminated SAMs (83) with multiacetylene molecule (84) via CuAAC. In the following step, the multilayer film (83) was created by the interaction of the multilayer surface (81) with multiazide molecule (85) by a click reaction. These two steps can be repeated infinitely to achieve any bilayer assembly. Even in the presence of several layers, the resulting thin films are electrochemically active. To exploit the functionality of this method, multilayers containing synthetic porphyrins, perylene diimides and also their mixture have been constructed. These thin films were characterized by UV-Vis absorption, water contact angle and electrochemical techniques, which indicated that multilayer growth is consistent over tens of layers (Scheme 29).⁷⁸ CV is an important electroanalytical technique, which determines the product stability, the existence of intermediates in the redox reactions, the kinetics of electron transfer, and the reversibility of a reaction.⁷⁹ Palomaki and Dinolfo, after preparing multilayers containing synthetic porphyrins and perylene diimides, applied CV to determine the electrochemical activities of the products (Fig. 1). Accordingly, they found that the surface charge increases with increasing number of porphyrin layers on the multilayer structures, which demonstrates the potency of multilayers of porphyrin compounds in electrochemical applications.⁷⁸

Scheme 29 Synthesis and construction of multilayer films.

Fig. 1 Cyclic voltammetric current response vs. potential for 1–4 bilayers of 1 on indium tin oxide (ITO) electrode.⁷⁸

In the publication of Oberhansl et al., functionalization of a glass silicon oxide surface via different steps led to a CuAAC reaction. First, the surface was functionalized with alkoxysilanes via GPTMS (86), then the epoxy ring was opened with propargylamine to obtain an amino alcohol (87). In the next step, the reaction between the alkyne-terminated silicon surface and the azide substrate led to a triazole group (89) (Scheme 30).⁸⁰

Scheme 30 Functionalization strategy for silicon oxide-based substrates to enable surface click chemistry.

To summarize this section, wafer silicon is a thin circular slice of crystalline silicon. According to the orientation of cutting, different wafer silicones are obtained such as Si (100) and Si (111). Some examples of click reactions on the surface of wafer silicones showed that the click reaction is a good method for grafting various functional groups, polymers, biopolymers, and complexes. The modified silicon wafers showed a wide variety of applications, as follows. It was mentioned that the grafting of ferrocene compounds to a silicon surface can be feasible through the click reaction. Surfaces containing ferrocene could have applications in electronics, biochemistry, and biosensor technologies due to their electrochemical properties. In addition, the presence of π bonds between the distal alkynes grafted onto the surface prevents silicon oxidation. Furthermore, a carboxylic acid modified surface is a good choice for coupling with proteins, peptides and enzymes using carbodiimide.

3. Click reactions on the surface of silica nanoparticles

Degradable capsules have been fabricated using polyrotaxanes (PRXs) by the click reaction. The PRXs contained α-cyclodextrin (α-CD) (90) and PEG (9). These compounds are biologically harmless and increase the degradability of capsules. The PRXs possessed three terminal alkyne groups and could be coupled to azide-functionalized silica (91) via azide-alkyne click chemistry. In the next step, the PRXs were cross-linked with a degradable linker to obtain compound 92. Even after the dissolution of the silica template, the structure formed by cross-linking was well-established. TEM images (Fig. 2a) showed the size of the capsules to be around 2 μm. It was possible for the PRXs to assemble parallel to the silica surface via the treatment of both alkyne groups of one PRX on the surface. According to the AFM image (Fig. 2b and c), the minimum thickness of the capsules was approximately 9 nm, and it is also clear that side reactions did not occur, because this would lead to a smaller wall thickness than that observed (thickness of PRX ∼ 2 nm). Then, doxorubicin (DOX), a chemotherapy drug, was loaded onto the capsules and conjugated to RCDs through their OH groups. At the surface of the PRXs, the alkyne fractions were accessible for supplementary functionalization of the capsules. The degradation of the capsules occurred over 90 min at 37 °C in a solution of glutathione in water. This study could be a useful protocol for the formation and application of degradable capsules that maintain their composition, structure and functionality (Scheme 31).⁸¹

Fig. 2 (a) TEM image, (b and c) AFM images of air-died capsules.⁸¹

Scheme 31 (A) Formation of PRX 4 by PEG 1 threading with RCDs, followed by capping of polypseudorotaxane (B) modular assembly of a degradable PRX capsule via click chemistry. (a) Clicking the alkyne-modified PRX 4 onto the azide-modified silica surface. (b) Crosslinking the assembled PRXs with cystamine (H₂NCH₂CH₂–SSCH₂CH₂NH₂). (c) Capsules are formed by dissolution of the core using buffered HF. (d) PEG (M_w 2000)-functionalized capsules can be formed by clicking on PEG-N₃ (e) followed by removal of the core using buffered HF.

To formulate organosoluble silica-polypeptide particles, Balamurugan et al. attempted to synthesize silica nanoparticles. The silica nanoparticles were prepared using the Stöber process⁸² in which concentrated ammonium hydroxide in ethanol reacts with tetraethoxysilane. Subsequently, the surface of the mono-dispersed silica was functionalized with azide groups. The grafting of α-helical, alkyne-terminated hydrophobic polypeptides onto azido-silica nanoparticles was based on ring opening polymerization and click reactions. The ring-opening polymerization of the N-carboxyanhydride of γ-stearyl-α-L-glutamate⁸³ in the presence of propargylamine as initiator allows the preparation of the alkyne end-terminated poly(γ-stearyl-α-L-glutamate) (alkyne-PSLG) (94). The azide-end was added to the reaction with 3-bromopropyltrichlorosilane,⁸⁴ followed by substitution with sodium azide. The functionalization was verified by FTIR and XPS techniques. The click reaction coupled the alkyne-PSLG (94) to azido-silica (93) in THF or toluene in the presence of pentamethyldiethylenetriamine (PMDETA) and Cu(I) bromide. The hybrid particles (95) can be applied in drug delivery systems, colloidal crystals, and photonic materials (Scheme 32).^85,86

Scheme 32 Click reaction between azido-silica and alkyne-polypeptide.

6-Azidohexyl methacrylate (AHMA) monomer containing a clickable 2-azidoethyl group was polymerized via reversible addition–fragmentation chain transfer (RAFT) on the surface of silica nanoparticles (96). A kinetics comparison of AHMA polymerization by 4-cyanopentanoic acid dithiobenzoate (CPDB) attached to nanoparticle silica and AHMA polymerization by free CPDB was performed. The kinetic studies of PAHMA grafted nanoparticle functionalization via the click reaction indicated that the rate of PAHMA grafted on the surface (97) was much higher than the AHMA polymerization by free CPDB under similar conditions, which was caused by a localized concentration effect. High molecular weight alkynes surface-grafted under PAHMA conditions showed lower reaction rates compared to free PAHMA, which was caused by steric effects. After the polymerization processes, a click reaction was performed between surface 30 and various alkyne-terminated materials to obtain compound 98. The approach of coupling RAFT polymerization with click chemistry suggested a new strategy of reworking nanoparticle surfaces with functional polymers (Scheme 33).⁸⁷

Scheme 33 Click reaction on PAHMA/SiO₂.

The combination of reversible addition fragmentation technique chain transfer agent (RAFT CTA) and click chemistry is a strategy that can be used to modify the surface of silica nanoparticles without any protection groups. Two step synthetic routes were used to modify the surface of silica nanoparticles. First, the surface was reworked with polystyrene and polyacrylamide brushes via RAFT CTA. Then, azide-modified silica nanoparticles (101) were synthesized by substitution of the bromide in 3-bromopropyltrichlorosilane (100) with an azide. The carboxyl-terminated trithiocarbonate RAFT CTA was converted to an alkyne group via esterification with propargyl alcohol in the presence of EDC coupling agent and DMAP base. This procedure was followed via coupling reaction of the azide-terminated end (101) with the alkyne-terminated end polymer by a click reaction, which led to 102. Polymers fixed onto the surface by a click reaction provided high grafting density. This approach has been used to fabricate homopolymer (PAAm, PS, PMA) (102) and di-block copolymer (PS-b-PMA) modified silica nanoparticles (Scheme 34).⁸⁴

Scheme 34 Click reaction of azide-modified silica with alkyne-terminated end polymers.

A novel approach to produce bio-conjugated Janus silica particles based on two-step click reactions was studied by Zhang and coworkers. Janus silica particles were coated with two different molecules: biotin molecule on one hemisphere and PEG on the other. The template was formed from polystyrene coated with azide modified silica particles. Herein, the azide modified silica particles were frozen on PS particles via a Pickering emulsion. To functionalize these hemispheres with biotin and PEG, one hemisphere was first inhibited with PS, then the unoccupied side was functionalized with biotin, and in the next step, PS was replaced by PEG chains. Both functionalizations were performed via Huisgen CuI-catalyzed azide-alkyne cycloaddition (CuAAC). The functionalization of the Janus particles was monitored by FT-IR, TGA and TEM techniques. The bioavailability of the Janus particles to avidin was verified by avidin/4′-hydroxyazobenzene-2-carboxylic acid (HABA); these particles could find applications in drug delivery and bio-detection. This approach could be extended to bio-molecules and polymer chains (Scheme 35).⁸⁸

Scheme 35 Functionalization of Janus silica particles with biotin molecule on one hemisphere and PEG molecules on the other.

The preparation of smart hybrid SiO₂ nanoparticles based on RAFT polymerization and 1,3-Huisgen cycloaddition was demonstrated by Chen and coworkers. First, alkyne terminated thermo responsive poly(N-isopropylacrylamide) (PNIPAM) was polymerized by RAFT of NIPAM monomer; then, azide-modified SiO₂ (103) was coupled with alkyne terminated PNIPAM (104) by a click reaction. This approach permits control of the molecular weight, molecular weight distribution, and structure of polymers grafted onto solid surfaces. The hybrid nanoparticles were found to have thermoresponsive character and were monitored by FTIR, XPS, TGA, DLS, and TEM. The smart nanoshell was affected by the solution temperature and switched between a solvated, incompact open nanoshell and a compact closed nanoshell. This core–shell structure (105) has potential applications in the controlled release of drugs, DNA, protein, smart catalysts, smart separation systems, and the preparation of smart nanoreactors (Scheme 36).⁸⁹

Scheme 36 Schematic of the synthesis of hybrid silica nanoparticles coated with thermoresponsive PNIPAM brushes via RAFT polymerization and click chemistry.⁸⁹

Two approaches of grafting cobalt(II) Schiff base complexes to silica supports via click reactions were successfully reported. The first approach consisted of the step-wise production of silica bounding Schiff base ligand followed by its eventual complexation with cobalt ions. In the second approach, the prepared Co(II) Schiff base complex was directly fixed to the silica support via copper catalyzed azide-alkyne cycloaddition. The synthesized complexes showed catalytic applications in the oxidation of alcohols to carbonyl compounds. The catalytic complex was recycled and reused for several runs without any significant loss of activity (Scheme 37).⁵⁵

Scheme 37 Two approaches of grafting cobalt(II) Schiff base complexes to silica supports via the azide-alkyne Huisgen cycloaddition reaction.

To summarize this section, owing to the nano-sized dimensions of silica nanoparticles, these compounds are fabricated as degradable capsules and/or core–shell compounds and may be used in the controlled release of drugs, DNA, and proteins, as well as in smart catalysts, in smart separation systems, and in the preparation of smart nanoreactors.

4. Click chemistry on the surface of porous silicon (PSi)

Mesoporous silicon (PSi) has the advantages of being considered as a photonic crystal sensor in a rugate filter and also as a high surface area porous electrode. The prefabricated PSi is chemically characterized to supply it with stability in aqueous conditions and enable chemical coupling via the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction. The applicability of this PSi sensor for controlling the coupling process at the surface was demonstrated by the covalent coupling of ferrocene and by a ligand-exchange reaction. Both classes of reactions were controlled by virtue of optical reflectivity and electrochemical measurements via the oxidation/reduction of the surface binded redox species (Scheme 38).⁹⁰

Scheme 38 Coordination of Os(bpy)₂Cl₂ onto isonicotinic acid modified PSi electrodes via ligand exchange.

The surface of mesoporous silica could also be functionalized by covalent bonds through a Huisgen cycloaddition reaction. The functionalization was monitored by TGA, gas adsorption, SAXS, and FT-IR. First, SBA-15 silica (15 nm in diameter) was synthesized using triisopropylbenzene as a micelle expander. Then, the surface was modified with aminopropyl groups (108), which were transformed to propargyl-bearing groups (109) through a reaction with 4-pentynoyl chloride. The prefabricated pores were reacted with azide-functionalized poly(methyl methacrylate) (PMMA) and oligo(ethylene glycol) and were also protected and deprotected with D-galactose to obtain 110. The grafting procedure allowed the introduction of homogeneous polymer films of thicknesses up to about 2 nm without any appreciable pore blocking. Homogeneous layers of monosaccharides were also obtained with notable grafting efficiency. The results showed that the click reaction is a robust method to prepare mesoporous silicas with available pores, which could be functionalized with different macromolecules and biomolecules (Scheme 39).⁹¹

Scheme 39 “Click” grafting on the surface of ordered mesoporous silica.

A porous silicon (Psi) surface was PEGylated using the Cu(I)-catalyzed alkyne-azide cycloaddition reaction. The reaction was performed in two steps. In the first step, passivation of porous layers via hydrosilylation occurred and the alkyne ended surface (111) was synthesized using 1,6-hepdadiyne followed by the protection of captured protein molecules from denaturation in the presence of the PEG layer by a click reaction to obtain 112. The PEGylation reaction was regularly tracked by photoacoustic FT-IR, XPS, contact angle and model protein adsorption measurements (Scheme 40).⁹²

Scheme 40 PEGylation of PSi using click chemistry.

The combination of the optical properties of PSi photonic crystals and the chemical adaptability of acetylene-terminated SAMs was studied by Ciampi's research team. Two procedures were engaged to change the internal surface of the pores: hydrosilylation followed by azide-alkyne Huisgen cycloaddition. The FT-IR spectroscopy and optical reflectivity measurements showed that the surface of the acetylenes had reacted efficiently to produce the desired functions (118a–d). The click reaction led to a versatile and efficient functionalization of PSi for a variety of applications using silicon based sensing devices and implantable biomaterials (Scheme 41).⁹³

Scheme 41 Click chemistry on acetylenyl PSi photonic crystals.

An ionic liquid, methylimidazolium, was fixed onto a SBA-15 support using 1,3-dipolar Huisgen cycloaddition. This reaction was performed in three steps; first, surface functionalization was achieved with Cl-terminated molecules (118); then, the –OH groups were protected (119), followed by substitution of Cl by azide groups (120). Then, 3-ethynyl-1-methylimidazole was added to the reaction to obtain a triazole via a click reaction (121). The surface characterization methods confirmed that the ionic liquid was immobilized inside the pores and the ordered porous structure remained unchanged. SBA-15 functionalized by the click reaction could be used in anion removal from wastewater (Scheme 42).⁹⁴

Scheme 42 Preparation of clickable SBA-15.

Ethynylferrocene (Fc), 1-ethynylpyrene (pyrene), and (5-ethynyl-2 pyridylmethyl)bis(pyridylmethyl) amine (TPA) were also loaded onto SBA-15 via 1,3-dipolar Huisgen cycloaddition. The alkyne end was clicked onto the azide surface (122), which was loaded onto SBA-15 through direct synthesis,⁹⁵ wherein different molar quantities of Si–N₃ were co-condensed with tetraethoxy-orthosilicate (TEOS). The preparation process of 123 was performed by removing the P₁₂₃ organic polymer under mild Soxhlet extraction conditions, which left the organoazide covalently fixed in the templated pores (123). The pore dimensions and the surface area of SBA-15-N₃-x were monitored by powder X-ray diffraction and N₂ absorption isotherm measurements, which showed that the ordered structure was compatible with the original SBA-15. Modified surfaces of mesoporous silica with organosilane groups could find application in the heterogenization of discrete metal catalysts and enzymes.^96–98 Aside from recycling and separation advantages, the site isolation of catalysts in hybrid materials supplies potential activity improvement such as a decrease in harmful bimolecular catalyst interactions (Scheme 43).^99–102

Scheme 43 Preparation of SBA-15-R via the click reaction.

Mesoporous silica SBA-15 was functionalized with azidopropyl groups. This functionalized Psi was prepared with a variety of azides of 0.03–0.7 mmol g⁻¹ via a direct synthesis and a co-condensation approach. The ethylene group was then grafted onto the Psi surface through Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (“click” chemistry) to obtain 124. Ferrocene, tris(pyridylmethyl)amine (TPA), iron porphyrin (FeTPP), and pyrene were loaded onto the surface, which shows the efficiency of this method. Restraining the azide loading and the concentration of the alkyne group during the click reaction could control the grafting of these four species. The influence of surface loading has been observed in metal complex speciation and catalytic epoxidation reactions. This technique has the advantage of performing site-isolation in an environment that promotes the metal reactivity and ligand stability. The SBA-15-[Mn(TPA)]-catalyzed epoxidation showed the reliance on surface loading. The comparison of site-isolated, site-dense and homogeneous complexes supplies insight into the catalytic speciation and ligand activity (Scheme 44).¹⁰³

Scheme 44 A comparison of homogeneous, site-isolated and site-dense complexes provides insight into the catalytic speciation and ligand activity.¹⁰³

An innovative method for developing mesoporous silica-based multifunctional microdot arrays was performed by coupling inkjet printing (IJP), evaporation-induced self-assembly (EISA), and click chemistry. In the first step, the microdots were functionalized with (3-azidopropyl)triethoxysilane (AzPTES) (125); then, an IJP procedure was performed, due to the selectivity, resolution and flexibility of this technique. In the next step, the silica precursor tetraethyl orthosilicate (TEOS) was co-condensed during the evaporation-induced self-assembly (EISA) of micelles on the substrate. After extracting the surfactant, alkynes, such as propargyl alcohol, methyl pent-4-ynoate, ethynylferrocene, and N-propargyl-4-amino-1,8-naphthalimide, were coupled with the azide 126 via Huisgen 1,3-dipolar cycloaddition to generate 127. This approach has the advantage of functionalizing each microdot in a one-pot procedure via a multi head printer and enables grafting of a variety of molecules by the click reaction. The click reaction with these four species has applications in detection procedures; in particular, N-propargyl-4-amino-1,8-naphthalimide and ethynylferrocene in mesoporous silica microdots could find applications in fluorescence or electrochemical detection (Scheme 45).¹⁰⁴

Scheme 45 Click functionalization of mesoporous silica.¹⁰⁴

A new method was introduced to prepare bifunctional acid/base mesoporous silica nanoparticles by co-condensation of tetraethoxysilane with two orthogonally functionalized triethoxyalkylsilanes. A very efficient click reaction was performed between the azide silica surface (128) and compound 129. The final product (130) can be applied as a catalyst in the Henry reaction (Scheme 46).⁷³

Scheme 46 Preparation of bifunctional acid/base mesoporous silica nanoparticles.

Kar and co-workers reported the preparation of grafted mesoporous compound by poly-L-lysine (PLL) via a NCA polymerization followed by click chemistry. Azdiopropyl groups were grafted onto the surface of SBA-15 (131) and then reacted with the alkyne end of poly-L-lysine (132), which was synthesized by NCA polymerization with the intermediate of N-TMS as initiator. This grafting method led to the generation of 133 and could be applied to high molecular weights and also high grafting densities of polypeptides and polyethylene (134) to produce 135 (Scheme 47).⁷⁴

Scheme 47 Preparation of grafted mesoporous compound by poly-L-lysine (PLL) via NCA polymerization followed by click chemistry.

The modification of a mesoporous silica surface via enzymes was demonstrated in a novel method. The protease trypsin was grafted to the surface of SBA-15 pores via copper(I)-catalyzed alkyne-azide cycloaddition to obtain (137). The efficiency of this technique was demonstrated by the absence of protein leaching and the powerful covalent immobilization of functional enzyme density with the simultaneous conservation of enzyme activity (Scheme 48).¹⁰⁵

Scheme 48 Covalent attachment of trypsin to SBA-15 by click chemistry.¹⁰⁵

To summarize this section, porous silicon and/or silica compounds are useful materials as photonic crystal sensors in rugate filters and also as high surface area porous electrodes. They could be also used in ion removal of wastewater because of their porous structure, which can trap the ions. Heterogenizations of discrete metal catalysts and enzymes, as well as fluorescence or electrochemical detection, are other applications of these materials.

5. Conclusion

Copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition, known as “click chemistry”, is a powerful method of generating triazoles in organic synthesis. This strategy is also well-established and is frequently used as a versatile transformation for the connection of alkyne ended materials with azide compounds to produce triazole groups. The applications of click chemistry for the construction of diverse silica based compounds were covered in this review. Different types of silica based surfaces were investigated for this reaction, including flat silica materials, silica nanoparticles and porous silica compounds. Because wafer silicon materials are useful in the fields of solar cells and electronics, modification of their surfaces with electron-rich molecules such as ferrocene compounds through click reactions is the best option, due to the resulting electrochemical properties. Moreover, triazole modified silica nanoparticles are more applicable in medicinal chemistry as protein and/or drug delivery compounds or in catalysis systems, owing to their dimensions. Porous silica and silicon compounds with internal surfaces modified by click reactions are more applicable in photonic crystal sensors, fluorescence or electrochemical detection, porous electrodes and catalysis. Accordingly, it was found that each of these components has its own strengths and weaknesses, and research continues on the path of growth and development of the click reaction on silica surfaces. We believe that it is necessary to study triazole modified silica-based surfaces in academic research, and also for application in industrial fields.

Abbreviations

GPTMS	(3-Glycidoxypropyl) methyldiethoxysilane
EDC	1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
DMAP	4-Dimethylaminopyridine
AFM	Atomic-force microscopy
CuAAC	Copper-catalyzed azide-alkyne cycloaddition
CV	Cyclic voltammetry
EDMS	Ethynyldimethylchlorosilane
FT-IR	Fourier transform infrared spectroscopy
GBP	Glycan binding protein
HAS	Human serum albumin
MW	Microwave
OEG	Oligo(ethylene glycol)
ODNs	Oligodeoxynucleotides
PEG	Poly(ethylene glycol)
PMA	Polyacrylamide
PMMA	Polymethyl methacrylate
PRXs	Polyrotaxanes
RAFT	Reversible addition–fragmentation chain transfer
SBA	Santa Barbara amorphous
SEM	Scanning electron microscope
SPM	Scanning probe microscopy
SFM	Scanning-force microscopy
SAMs	Self-assembled multilayers
SFG	Sum frequency generation spectroscopy
THF	Tetrahydrofuran
TEM	Transmission electron microscopy
TMG	Trimethylgermanyl
XPS	X-ray photoelectron spectroscopy
XRD	X-ray powder diffraction
α-CD	α-Cyclodextrin

Acknowledgements

We gratefully acknowledge the financial support from the Research Council of Alzahra University and the University of Tehran.

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Footnote

† Cyclic RGD peptides like.

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