Surface Modification Using Phosphonic Acids and Esters - Chemical

Review pubs.acs.org/CR

Surface Modification Using Phosphonic Acids and Esters Clémence Queffélec,† Marc Petit,†,‡ Pascal Janvier,† D. Andrew Knight,§ and Bruno Bujoli*,† †

LUNAM Université, CNRS, UMR 6230, Chimie Et Interdisciplinarité: Synthèse Analyse Modélisation (CEISAM), UFR Sciences et Techniques, 2, rue de la Houssinière, BP 92208, 44322 NANTES Cedex 3, France ‡ Université Pierre et Marie Curie (UPMC), CNRS, UMR7201, Institut Parisien De Chimie Moléculaire (IPCM), 4 place Jussieu, 75252 Paris Cedex 05, France § Chemistry Department, Florida Institute of Technology, 150 West University Boulevard, Melbourne, Florida 32901, United States 4.6. Discussion about Advantages and Limitations of Phosphonic Acids 5. Applications of Phosphonate-Coated Materials 5.1. Bonding of Bioactive Molecules for the Development of New Biotechnologies 5.1.1. Biological Microarrays 5.1.2. Phosphonate-Based Surfaces for the Purification of Complex Biological Media 5.1.3. Surface-Modified Nanoparticles and Their Bioconjugation 5.1.4. Drug Immobilization for the Design of Local Drug Delivery Devices 5.1.5. Derivatization of Implants to Favor or Inhibit Interactions with Cells 5.1.6. Supported Artificial Biological Membranes 5.2. Supported Catalysis 5.2.1. Immobilized Phosphonic Acid Functionalized Nitrogen Ligands 5.2.2. Phosphonic Acid Functionalized Phosphine Ligands 5.2.3. Phosphonic Acid Functionalized Arene Complexes 5.3. Grafting of Photoactive and Electroactive Molecules 5.3.1. Dye-Sensitized Solar Cells 5.3.2. Photocatalysis and Electrocatalysis 5.3.3. Electrochromism 5.3.4. Electro-optical and Organic Electronics Devices 5.4. Surface Modification for the Detection or Complexation of Soluble Chemical Species 6. Concluding remarks Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Coordination Properties of Phosphonic Acids/ Esters, A Short Summary 3. Common Routes to Functional Phosphonic Acid/ Esters for Surface Modification 3.1. Direct Introduction of Phosphonic Acid or Ester Functional Groups (Route A) 3.1.1. Michaelis−Arbuzov and Michaelis− Becker Reactions 3.1.2. Hirao Cross-Coupling 3.1.3. Hydrophosphonylation 3.1.4. Phospha-Michael Addition 3.1.5. Synthesis of α-Hydroxyphosphonates from Aldehydes 3.1.6. Introduction of gem-Bisphosphonate Groups 3.1.7. Conversion of Phosphonate Esters to Phosphonic Acids 3.2. Indirect Introduction of Phosphonic Acid/ Ester Functional Groups (Route B) 3.2.1. α,ω-Aminophosphonates 3.2.2. α,ω-Hydroxyphosphonates 3.2.3. α,ω-Carboxaldehydephosphonates 3.3. Concluding Remarks 4. Types of Surface Modifications and Related Mechanisms 4.1. Protective Layers 4.2. Characterization of Phosphonate Binding onto Metal/Metal Oxide Surfaces 4.3. Modification of Metal Nanoparticles 4.4. Modification of γ-Zirconium Phosphate 4.5. Coatings Based on Metal PhosphonateBased Multilayer Films © 2012 American Chemical Society

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3784 3785 3786 Received: November 7, 2011 Published: April 24, 2012

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dx.doi.org/10.1021/cr2004212 | Chem. Rev. 2012, 112, 3777−3807

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to that found in α-zirconium phosphate (α-Zr(O 3 P− OH)2.H2O), in which the hydroxyl group pointing into the interlayer space was replaced by a phenyl ring (Figure 1).11,12

1. INTRODUCTION The design of organically modified surfaces is a rapidly expanding field of research in materials science in which the central purpose is access to materials possessing tunable properties in diverse areas (derivatization of substrates with reactive end groups for further modification, protective layers, analytical or biological sensors, catalysis, biomedical devices, solar batteries, etc.). This modification can be performed using traditional polymer coatings or layer by layer deposition of ionic species,1 but the next-generation technologies increasingly involve grafting onto the surface using appropriate functional molecules, thus providing a better control of the density and orientation of the organic component at the surface. For this purpose, the organic backbone to be bound onto the surface requires the presence of anchoring groups compatible with the chemical nature of the substrate to be modified, some of the most usual including reactive silicon-based groups [SiH3, Si(OR)3, or SiCl3] for silica and glass,2 or thiol groups for gold.3−5 Since the late 1970s, it has been demonstrated that phosphonic acids (PAs), RPO3H2 [R is an organic component] readily react with a wide range of metal salts and oxides, leading to a rich variety of 1D to 3D metal organic frameworks (MOFs), also called metal phosphonates.6−8 The cohesion of these networks results from the formation of PO-metal ionocovalent bonds, which usually provide highly stable architectures, especially for metal cations of high oxidation states, as compared to those obtained with the carboxylic acid functionality. Since the 1990s, this unique property has quite naturally led to a global interest from industry and academia, for using phosphonic acids to functionalize the surface of metals and oxides, as well as any type of solid having surface exposed metal centers. With the exception of the case of glass and silica, for which the family of silane groups is particularly efficient for the preparation of functional coatings, the phosphonic acid functionality was often found to be superior for other inorganic substrates, because of the higher robustness and stability of metal−OP over metal−OSi bonds.9,10 Moreover phosphonic acids show a high compatibility with other organic functional groups and both their ester [RPO3R2] and acid [RPO3H2] forms can generally be used for surface modifications, which can thus be performed in many solvents including water. This review highlights selected examples of this diverse and interdisciplinary field, in which a variety of scientific areas support the development of groundbreaking technologies. In this context, the review first discusses, in a general way, usual routes for the synthesis of phosphonic acid/esters and their compatibility with other functional groups or molecules. Then the types of inorganic surfaces which can be modified using phosphonic acid chemistry is summarized, as well as the related mechanisms involved when attaching phosphonate groups onto these surfaces. The review finally goes on to outline the richness of applications which can be developed from the resulting functional materials.

Figure 1. Idealized crystal structure of layered zirconium phenylphosphonate. Reprinted with permission from reference 11. Copyright 1978 Elsevier.

Ten years later, results from Mallouk et al.,13,14 Clearfield et al.,15 and Bujoli et al.16−18 began to appear, reporting layered parent structures combining divalent or trivalent metals, and alkyl or phenylphosphonic acids. From this point, a tremendous amount of research has been done to move away from these prototypical systems, providing evidence for the richness of phosphonic acid coordination chemistry. Landmark advances which attracted attention include: (i) The large variety of metal ions which were shown to be suitable for the design of phosphonate MOFs.6−8 (ii) The use of PAs carrying end-reactive functional groups capable of binding to metal centers, thus allowing the tuning of the dimensionality and architecture of the resulting MOFs. In the first reports, relatively simple phosphonic acids were used (i.e., X-(CH2)n-PO3H2, where X = NH2,19−21 CO2H,22−33 or PO3H234−42), while more and more complex precursors have now been investigated in the literature, showing the richness of metal phosphonate chemistry.43−48 (iii) The design of 3D open-frameworks consisting of organically lined inorganic architectures,49−53 pillared layered structures,7,50,54−58 molecular phosphonate cages,59−62 or metal phosphonates synthesized using amine templates.40,63−68 (iv) Physical properties in relation to some specific metal-PO3 arrangements in layered compounds, in particular interesting magnetic behaviors resulting from the 2D confinement of the metal atoms, with the case of Fe(II),69 Mn(II),70,71 Ni(II) ,72 and V(IV)34,73,74 phosphonates addressed in the earliest examples. (v) A wide choice of routes available for the preparation of metal phosphonates. Hydrothermal synthesis is the method of choice to improve the crystallinity of the prepared materials,45 but non aqueous solvents (i.e., CH2Cl2, THF, CH3CN, DMSO, and alcohols) can be also of interest when phosphonate esters,75 alkylmetals,62 or metal alkoxides precursors76 are used to access metal

2. COORDINATION PROPERTIES OF PHOSPHONIC ACIDS/ESTERS, A SHORT SUMMARY Metal phosphonate chemistry has emerged over the last three decades. One of the very first examples was the layered zirconium phenylphosphonate (Zr(O3 P−C 6 H5 ) 2 ) which showed an in-plane zirconium−PO3 arrangement very close 3778


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phosphonates with high specific surface area or for film processing. The different binding modes of phosphonic acids to metals have now been extensively illustrated in the literature, on the basis of numerous X-ray structure determinations. In this context, the connectivity of the PO3 groups (i.e., the number of metal atoms bonded to each of the three oxygen atoms; Figure 2) can significantly vary according to the nature and oxidation

3.1. Direct Introduction of Phosphonic Acid or Ester Functional Groups (Route A)

In a very recent review in this journal, Bunch et al.79 have reported an extensive description of modern chemical methods for the introduction of phosphonic acid groups on organic substrates. In the present paper, we have selected the most convenient and accessible routes among these methods, in order to guide materials chemists in the design of suitable strategies for phosphonate-mediated surface modifications. 3.1.1. Michaelis−Arbuzov and Michaelis−Becker Reactions. The Michaelis−Arbuzov reaction, also known as the Arbuzov reaction, is one of the most versatile reactions for the formation of P−C bonds. Discovered by Michaelis in 1898,80 this reaction was widely studied by Arbuzov81 and consists of the reaction of a triester phosphite with an alkyl halide, resulting in the conversion of P(III) to a pentavalent phosphorus species (Scheme 2).82 While elevated temperatures Scheme 2. Michaelis−Arbuzov Reaction and Subsequent Phosphonate Ester Hydrolysis

are required for activation of this transformation, very recent data have shown that for some specific substrates this reaction can be advantageously operated at room temperature in the presence of a suitable Lewis acid.83 Barney et al.84 recently proposed a straightforward synthesis of benzyl or allyl phosphonates from the corresponding alcohols using triethylphosphite and zinc iodide. Benzyl phosphonates esters are usually prepared from benzyl halides and trialkylphosphite via an Arbuzov reaction and this procedure is a convenient alternative, although benzylic compounds bearing an electron-withdrawing group are much less reactive (Scheme 3).

Figure 2. Typical examples of connectivities present in metal phosphonates: (111) connectivity in the layered (R)-Zn(O3PCH2P(O)(CH3)(C6H5)) structure77 (left). Reprinted with permission from reference 77. Copyright 2001 Royal Society of Chemistry; (112) connectivity in the Zn(O3PCH3) layered structure78 (right). Reprinted with permission from reference 78. Copyright 2000 Elsevier. Note that higher connectivities result in closer packing within the layers.

state of the metal atom, as well as reaction conditions (temperature, pH, etc.) and bulkiness of the organic component bound to phosphorus. This explains the versatility found in metal phosphonate architectures, ranging from molecular species to highly packed three-dimensional networks.

Scheme 3. Synthesis of Benzyl or Allyl Phosphonates from Alcohols84

3. COMMON ROUTES TO FUNCTIONAL PHOSPHONIC ACID/ESTERS FOR SURFACE MODIFICATION While researchers from various disciplines are potentially interested in surface modification, a selection of the most convenient strategies for the introduction of phosphonic acid or ester groups on organic backbones is described hereafter. For that purpose, two main approaches can be considered, either direct introduction of these groups [route A] or coupling reactions using suitably functionalized phosphonate reagents [route B] (Scheme 1). Scheme 1. Two Main Routes Towards Functional Phosphonates

On the other hand, the Michaelis−Becker reaction has also become the reaction of choice for the synthesis of dialkyl esters of alkylphosphonic acids, using in this case secondary phosphite reagents (Scheme 4).80 This synthetic protocol can be for example attractive in the case of heat-sensitive substrates, since this reaction can most often be performed at room temperature.85−88 3779


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that the reaction can be performed under milder conditions than the Hirao reaction (Scheme 7).

Scheme 4. Michaelis−Becker Reaction

Scheme 7. Synthesis of Arylphosphonates by Cross-Coupling Reaction with Arylboronic Acids In an interesting review, Iorga et al.89 described the preparation of various alkynylphosphonates by Michaelis− Arbuzov and Michaelis−Becker reactions. 3.1.2. Hirao Cross-Coupling. While the two methods described above proceed well starting from alkyl halides, some specific conditions are often needed in the case of aryl and vinyl halides. In this context, in the early 80s, Hirao et al. reported the first palladium catalyzed cross-coupling of such halides with dialkyl phosphites (Scheme 5).90−92

3.1.3. Hydrophosphonylation. Another attractive route to organophosphonates reported by Tanaka et al. consists of the addition of HPO 3 R 2 to alkenes, 106 and terminal alkynes107,108 using either palladium or rhodium-based catalysts (Scheme 8). This atom-economic process was found to be versatile, efficient, and clean.

Scheme 5. Hirao Cross-Coupling (X = I or Br)90,91

Scheme 8. Tanaka’s Hydrophosphonylation106−108

Since then, this approach has largely been explored to prepare various functional phosphonates. Interestingly, Montchamp et al.93 have reinvestigated the Hirao cross-coupling by expanding the reaction to aryl chlorides, which do not react under usual Hirao conditions, while reducing at the same time the amount of palladium catalyst to 1 mol %. Because of the cost of palladium, researchers have also investigated possible replacement of palladium with other transition metals. For instance Buchwald et al.,94 Fu et al.95,96 and Ogawa et al.97 have replaced palladium with copper with good success. On the other hand, the use of nickel has also been considered98−101 but in that case relatively harsh conditions are required for this reaction (high temperature over 150 °C). Kabalka and Guchhait102−104 have shown the applicability of vinylboronic acids as cross-coupling partners (Scheme 6). The

In the case of alkenes, the reaction only works when using five-membered cyclic hydrogen phosphonates (i.e., 4,4,5,5tetramethyl-1,3,2-dioxaphospholane 2-oxide). On the other hand, the palladium-catalyzed hydrophosphonylation of alkynes and allenes109 affords various Markovnikov alkenylphosphonates with high regioselectivity and good yields. Beletskaya and Genêt110,111 modified Tanaka’s procedure by changing the catalyst to commercially available Pd2(dba)3·CHCl3 in the presence of triphenylphosphine (Scheme 9). A variety of diethyl alkyl-, aryl-, and heteroScheme 9. Beletskaya’s Hydrophosphonylation111

Scheme 6. Synthesis of Vinylphosphonates by CrossCoupling Reaction with Vinylboronic Acids103

arylvinylphosphonates were thus synthesized as a result of the Markovnikov addition, which upon hydrogenation (including asymmetric hydrogenation) gave a series of biologically active compounds. Recently, Han and co-workers attempted to replace palladium with other transition metals and reported an efficient nickel-catalyzed addition of dialkyl phosphites to terminal alkynes, which resulted in alkenylphosphonate compounds with high yield, stereo- and regioselectivity.112 In addition, the same reaction catalyzed by copper under air113 led to aerobic

reaction proceeds well, in a stereospecific manner, with triethyl phosphite and 4 mol % of Pd(OAc)2, thus making this reaction attractive due to the availability of boronic acid derivatives. Finally, Zhuang et al.105 have recently published an efficient method to prepare arylphosphonates from arylboronic acids using a copper-based catalyst. The advantage of that coupling is 3780


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oxidative coupling yielding to alkynylphosphonates (Scheme 10).

Scheme 12. Ishii’s and Parson’s Hydrophosphonylation121,122

Scheme 10. Nickel or Copper-Catalyzed Addition of Dialkyl Phosphites to Terminal Alkynes112,113

Scheme 13. Some Examples of Phospha-Michael Additions.124−126 Another straightforward route to phosphonic acids was recently developed by Montchamp et al.114 based on the palladium-catalyzed hydrophosphinylation of alkenes and alkynes with hypophosphorous acid,115−117 and subsequent oxidation of the resulting H-phosphinic acids (Scheme 11). Finally in 1958, the first radical addition of phosphonates to alkenes was described by Stiles118 in the presence of di-tertbutyl peroxide. Yields were however moderate and some improvements in the reaction were first reported by Nifantev and co-workers,119,120 until Ishii et al.121 developed an efficient methodology for the hydrophosphonylation of various alkenes and alkynes with dialkyl phosphites, according to a manganese and air mediated radical process. The authors suggested that MnII is oxidized by air into MnIII which catalyzed the reaction (Scheme 12). At the same time, Parsons and co-workers reported similar reactions using benzodioxaboroles (PBD) on different alkenes (Scheme 12).122 Hydrophosphonylation of alkenes or nitriles by radical transfer mediated by titanocene/propylene oxide has also been recently reported by Virieux et al..123 3.1.4. Phospha-Michael Addition. Similar to the Michaelis−Arbuzov and Michaelis−Becker reactions, the phospha-Michael reaction124 is one important method for P− C bond formation which consists in the 1,4-addition of nucleophiles derived from the HPO3R2 general structure, to unsaturated alkenes (Scheme 13). Most often, this reaction is carried out using a base, such as tetramethylguanidine (TMG) but microwave-activation can be an alternative.125 The Fe2O3-mediated conjugate addition of a chiral phosphite to alkylidene malonates was also reported (Scheme 13, last equation), and the easy cleavage of the chiral auxiliary from the addition products led to optically active β-substituted βphosphonomalonates in good yields and high enantiomeric excesses.126 3.1.5. Synthesis of α-Hydroxyphosphonates from Aldehydes. Addition of H-phosphonates to carbonyl com-

pounds in basic media, in particular aldehydes, is a very convenient method for the synthesis of α-hydroxyphosphonates and is known as the Pudovik reaction (Scheme 14).127 Scheme 14. Pudovik Reaction

Very recently, various catalysts have been developed for this C−P bond formation, including MoO2Cl2 (5 mol %, 80 °C) in a smooth and solvent-free procedure128 or lanthanide amides (i.e., [(Me3Si)2N]3Ln-(μ-Cl)Li(THF)3 (0.1 mol. %, 25 °C)), for which the reaction proceeded in very good yields at room temperature within 5 min.129

Scheme 11. Tandem Hydrophosphinylation−Oxidation of Alkenes Towards Phosphonic Acids114

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It is worth mentioning that asymmetric versions of this reaction showing high enantioselectivities were also documented in the literature, using different chiral catalysts.130−133 3.1.6. Introduction of gem-Bisphosphonate Groups. As mentioned in section 4, gem-bisphosphonates (Figure 3) often show a higher binding stability toward inorganic surfaces than their monophosphonic analogues.

approaches required soft conditions and allowed easy purification of the products by simple filtration.143 Finally, in situ generation of the carboxylic acid by hydrolysis of the corresponding nitrile in aqueous methanesulfonic acid, and subsequent treatment with phosphorus trichloride was also found to be a powerful method to prepare various hydroxylbisphosphonic acids in good yields.144 Moreover, the introduction of gem-bisphosphonate moieties has also been reported by Kaboudin et al.145 by treatment of primary amines with triethyl orthoformate and diethyl phosphite under microwave irradiation (Scheme 17), reaction

Figure 3. General structure of gem-bisphosphonates.

Scheme 17. Synthesis of gem-Bisphosphonates from Primary Amines145

Given that many gem-bisphosphonates have found widespread applications as drugs for the treatment of bone disease, such as osteoporosis,134−136 as well as ligands for 99mTc-based bone imaging agents,137 a large number of methods have been developed for their synthesis, principally starting from terminal alkyne, primary amine, nitrile, or carboxylic acid groups. A selection of the most representative examples is detailed hereafter. In this context, several groups have investigated the synthesis of hydroxy-1,1-bisphosphonic acids. Many of these compounds were obtained from carboxylic acids reacted with phosphorus trichloride and phosphoric acid in high-boiling solvents (Scheme 15).138,139 The same reaction, when performed under microwave irradiation led to the expected products within 20 min.140

known as the Kabachnik−Fields reaction. The same endproducts were also obtained upon treatment of primary amines with tetraethyl diphosphonodiazomethane [Et2O3P−(C N2)−PO3Et2] in the presence of rhodium catalysts,146 while this reaction works similarly with alcohols.147 On the other hand, Montchamp and co-workers148 have reported the room temperature radical addition of sodium hypophosphite (NaH2PO2.H2O) to terminal alkynes to produce 1-alkyl-1,1-bis-H-phosphinates, which are directly converted into the corresponding phosphonates upon ozonolysis (Scheme 18). It is also noteworthy that the OH group in hydroxy-1,1bisphosphonates can be easily replaced by a third phosphonate ester group, thus leading to alkyl-1,1,1-trisphosphonate esters.149 3.1.7. Conversion of Phosphonate Esters to Phosphonic Acids. As evidenced in this section, most often the available approaches to functionalizing organic substrates with PO3H2 groups consist in the preliminary preparation of their phosphonate ester intermediates which are in addition usually far much easier to purify. For the subsequent conversion of phosphonate esters into their acid analogues, different methods have been reported. Refluxing in concentrated hydrochloric acid is an easy route for this transformation, but for sensitive products requiring milder reaction conditions, the McKenna’s method150 using bromotrimethylsilane is an efficient and more

Scheme 15. Synthesis of Hydroxy-1,1-bisphosphonic Acids from Carboxylic Acids or Their Acyl Chloride Analogues138,139,141

More recently, a direct access to hydroxy-1,1-bisphosphonic acids from carboxylic acids when activated as acyl chlorides, has been described by Lecouvey et al., using tris(trimethylsilyl)phosphite (Scheme 15),141 while Frangioni et al.142 have reported a one-pot treatment with trimethylphosphite and dimethylphosphite at 0 °C to room temperature. As an alternative, the same reaction was proposed by Lebreton et al., in which activation of the carboxylic acid was performed using a borane (Scheme 16). Interestingly, these two

Scheme 16. Synthesis of Hydroxy-1,1-bisphosphonic acids by Lebreton et al.143

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Scheme 18. Synthesis of gem-Bisphosphonates from Terminal Alkynes by Montchamp et al.148

Scheme 19. General Synthesis of α,ω-Aminophosphonates, via Reduction of Azido Groups154

onitrile (n = 3) or 5-bromovaleronitrile (n = 4), which are converted into the corresponding diethyl phosphonate via an Arbuzov reaction.159 3.2.2. α,ω-Hydroxyphosphonates. To obtain α,ωhydroxyphosphonates, a common way begins with a monobromination of the parent α,ω-diol. From our observation, this reaction was found to be more selective for long carbon chains (n > 8). Then, after protection of the residual alcohol (for example via a THP ether), the phosphonic ester group can be introduced via a Michaelis−Becker reaction, and final cleavage of the protecting group leads to the expected compound (Scheme 21).160,161 3.2.3. α,ω-Carboxaldehydephosphonates. One rapid route to alkylphosphonates bearing a terminal aldehyde function consists in the transformation of commercially available α,ω-halogenoalkenes into the corresponding phosphonates using Arbuzov162 or Michaelis−Becker reactions,163 followed by ozonolysis of the terminal double bond to form the expected aldehyde (Scheme 22).164

appropriate method, leading to trimethylsilyl phosphonate esters, which are readily hydrolyzed in protic medium (water or alcohol) in a clean manner. In the particular case of benzyl ester groups, the use of hydrogen with palladium on charcoal was required and the resulting phosphonic acids were obtained in very good yields.151 3.2. Indirect Introduction of Phosphonic Acid/Ester Functional Groups (Route B)

Unlike direct functionalization, coupling reactions using simple suitably functionalized phosphonate reagents (i.e., Z−(CH2)n− PO3R2) offer potential control of the distance of the immobilized species from the surface by varying the length of the (CH2)n spacer. Among functional phosphonates of practical use for this purpose, those bearing terminal primary amine, alcohol or aldehyde functions are probably the most relevant, since they should allow easy coupling on carboxylic acid or amine residues present on the organic backbone which is to be immobilized. Although some of them are commercially available, especially those with short spacer (n = 1−4), a selection of some convenient routes to these coupling agents is described below. 3.2.1. α,ω-Aminophosphonates. Many methods have been reported for the preparation of α,ω-aminophosphonates and two main examples will be presented. From commercially available α,ω-dihalogenoalkanes one phosphonate end group is first introduced by an Arbuzov reaction,152,153 followed by nucleophilic substitution of the last bromine atom by an azido group, which is reduced to yield the corresponding amine upon treatment with hydrogen and Pd/C in alcoholic medium (Scheme 19).154 It is noteworthy that in our hands higher yields were obtained for the first step of the synthesis when the carbon chain was long (n > 8), otherwise a significant amount of the α,ω-bisphosphonate was formed.155 Alternatively, α,ω-aminophosphonates could be obtained by reduction of the α,ω-cyano phosphonate analogues using sodium borohydride and cobalt chloride,156,157 or hydrochloric acid, platinum oxide and hydrogen (Scheme 20).158 While diethyl cyanomethylphosphonate (n = 1) and diethyl 2cyanoethylphosphonate (n = 2) are commercially available, longer tethers require for example the use of 4-bromobutyr-

3.3. Concluding Remarks

Introducing the phosphonate groups following route A (i.e., in the very last steps of the synthesis of the molecule to be immobilized) can in some cases be an advantage, since chromatography purification of phosphonate-containing intermediates throughout the whole multistep synthesis is expected to be more time-consuming. However, in the case of highly functionalized sophisticated substrates, phosphonylation can be a problem, especially in the case of palladium-mediated catalytic couplings onto aromatic rings. In our opinion, route B is often preferable, since introduction of Z−(CH2)n−PO3R2 functional phosphonic esters on complex organic backbones is usually simpler, and in addition offers a higher modularity. Indeed, the length and rigidity of the tether can be easily varied and this can be used as a tool for tuning the orientation of the immobilized species on the surface. From a general viewpoint, the Michaelis−Arbuzov reaction is the most popular method when quite simple phosphonic acids have to be prepared for a surface modification purpose, since it works generally well. The Michaelis−Becker and the Hirao reactions are the two other methods of choice which are also widely used. It should also be noted that given the higher chemical stability of the attachment via gem-bisphosphonic versus monophosphonic anchors, we believe that the chemistry of bisphosphonates will develop significantly in the near future.

Scheme 20. Synthesis of α,ω-Aminophosphonates via Reduction of Cyano Groups157−159

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Scheme 21. General Synthesis of α,ω-Hydroxyphosphonates (DHP = 3,4-Dihydropyran; PTSA = para-Toluenesulfonic Acid)160,161

systems based on PA monolayers deposited on flat metal or metal oxide samples, on which the stability, density and thickness of the coatings were probed using surface characterization techniques. These include: (i) Water contact angle measurements and atomic force microscopy (AFM), which are commonly used to characterize the quality of the deposited monolayer.174−178 For example, the wetting properties of the modified substrate are markedly changed when longchain phosphonic acids are used (highly hydrophobic coatings), while AFM allows providing evidence of the uniformity, roughness and thickness of the PA overlayer, which is expected to reproduce the substrate topography. (ii) X-ray photoelectron spectroscopy (XPS) and time of flight secondary ion mass spectrometry (TOF-SIMS), proved to be useful to probe the formation of P−O− metal bonds on the surface. Indeed, the grafting of the PA could be evidenced by the presence of characteristic fragments (i.e., TiOPO2−, TiOPO3−, TiO2PO3−) in the negative secondary ion TOF-SIMS spectra and typical binding energies in the O 1s and P 2p XPS spectra.179−181 (iii) Solid-state NMR, which can provide insight into the binding mode of the phosphonate anchor group, via 31P and 17O MAS experiments, and also high resolution fast MAS 1H NMR in the event that P−OH groups are still present after monolayer formation.182,183 (iv) Diffuse reflectance IR Fourier transform (DRIFT) allows investigating the coordination of the PAs to the metal oxide surface, on the basis of the absorption band pattern in the “P−O” region (1300−800 cm−1).75,184−186 (v) Other optical methods were also used. Caruso et al. have recently reported that the surface functionalization of porous titanium/zirconium mixed oxides can be monitored in situ by simple UV−visible spectroscopy, when employing a bisphosphonic acid coupled to a UV active benzamide moiety. 187 In another example, Blanchard et al. have shown that surface second harmonic generation (SHG) intensity measurements allowed to characterize the surface coverage of monolayers comprised of two phosphonic acid constituents, a rigid chromophore and an aliphatic diluent. The coexistence of ordered and disordered domains could thus be evidenced.188 In many of these reports,9,10 properties of siloxane versus phosphonate monolayers were compared, in terms of quality of the formed films and hydrolytic stability. Apart from oxides based on silicon, phosphonic acids were in most cases found to be at least similar to organosilicon compounds in efficiency of coverage of metal oxides, with grafting densities far superior in the particular case of titania and zirconia.165 As an alternative, the use of phosphonate esters (alkyl and silyl) has also been

Scheme 22. Synthesis of Phosphonates Bearing a Carboxaldehyde End-Group162−164

4. TYPES OF SURFACE MODIFICATIONS AND RELATED MECHANISMS 4.1. Protective Layers

Significant benefits in using PAs to access surface-modified materials have first been evidenced in the case of metals and metal oxides (silica and mica, alumina, titania, zirconia, iron oxide, etc.),165 with an abundant patent literature since the 1960s in the field of anticorrosion coatings. Phosphonatemediated corrosion inhibition is commonly achieved via the formation of a thin, uniform and dense metal phosphonate protective layer on the material to be protected (i.e., carbon steel, aluminum, zinc), which prevents oxygen diffusion toward the metal surface.166−169 Corrosion inhibitor formulations often include 1-hydroxy-1,1-diphosphonic acid (HEDP, H2PO3− CH(OH)−PO3H2), amino-tris(methylenephosphonic acid) (AMP, N−(CH2−PO3H2)3), hexamethylenediaminetetrakis(methylenephosphonic acid) (HDTMP, (H2O3P−CH2)2−N− (CH2)6−N−(CH2−PO3H2)2), and hydroxyphosphonoacetic acid (HPA, H2O3P−CH(OH)−CO2H), which generate, in the presence of metal cations present in solution in the treatment process (i.e., Ca, Mg, Zn, Ba, etc.), stable complexes of low solubility on the substrate surface. In this context, the complex formation constant of the system is critical to ensure a controlled and regular deposition of the protective layer. Another approach is found in the anodization of a metal surface which creates a nonporous oxide layer. Introduction of PAs (usually an alkylphosphonic acid) into the anodizing bath or immersion of the anodized substrate in a PA aqueous solution results in the formation of a protective self-assembled monolayer chemically bonded to the oxide surface via the formation of stable M−O−P bonds, which significantly decreases the anodic dissolution of the metal.170,171 It is noteworthy that such oxide-covered materials modified with alkyl and perfluoroalkylphosphonate show reduced coefficient of friction values of the resulting surface.172,173 4.2. Characterization of Phosphonate Binding onto Metal/Metal Oxide Surfaces

Although the structural characterization of bulk metal phosphonates can be usually performed using X-ray diffraction from single crystals or powders, there are true challenges in designing methods to investigate the arrangement of surface bound phosphonic acids. Indeed, the surface modified materials exhibit a heterogeneous composition, where the area of interest, namely, the metal/phosphonic acid interface represents a minor part. For this reason, many studies have focused on model 3784


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geometry. In the particular case of PA-modified anatase, the binding mode of the anchoring groups was found to be predominantly tridentate from 17O MAS NMR studies. For that purpose 17O-enriched phenylphosphonic acid and water were used, thus allowing determining on model systems (i.e., phosphonate-oxo-alkoxo titanium clusters) characteristic isotropic chemical shifts and quadrupolar constants for the different types of oxygen sites (PO, P−O−H, P−O−Ti, Ti−O−Ti).182 In addition, high-resolution 1H solid-state NMR techniques can easily probe the presence or absence of P−OH groups and help to discriminate isolated residual P−OH groups versus dipolar coupled P−OH groups, giving evidence of the extent of phosphonic acid functions condensed with surface hydroxyl groups.183 In the case of Sn(IV)-doped In2O3 (indium tin oxide or ITO), a theoretical characterization was performed, based on density functional theory (DFT). Bredas et al. have developed an atomistic model describing the ITO surface and studied the PA adsorption at the quantum mechanical level. The results thus obtained were consistent with experimental XPS studies, confirming the formation of P−O−In bonds with a predominantly bidentate/tridentate PA binding mode.199

reported for the surface modification of metal oxides in non aqueous media.75,186,189,190 Potential benefits in using phosphonate esters include for example cases where the phosphonic acid analogues are sparingly soluble. On the other hand, this can be a method for limiting the formation of bulk metal phosphonate side products via a dissolution/precipitation process, when using oxides easily soluble in PA aqueous solutions. In addition, phosphonate self-assembled monolayer (SAM) formation on SiO2 or Si is difficult to achieve by comparison with other metal oxides. Therefore, authors recommend either solid-state annealing of the phosphonic acid film at 120−140 °C for a couple of hours to convert the PO3H2 groups physisorbed through H-bonding to surface bound phosphonate,191,192 or to activate the glass/silicon substrate by generating a nanometer scale metal oxide layer (i.e., aluminum oxide) which results in a higher surface reactivity for phosphonic acid binding.193 For example, a large variety of porphyrinic derivatives bearing mono or tripodal arylphosphonic acid tethers of different lengths has been successfully attached to a SiO2 surface to form robust monolayers.194,195 The purpose was to investigate the electron-transfer and charge retention characteristics of the immobilized porphyrins in the perspective of applications in molecular information storage. While PAs contain three potential binding sites, various coordination modes have been proposed which vary according to the exposed crystallographic planes and type of metal of the oxide surface, and most importantly which strongly depend on the reaction conditions. These include mono, bi-, or tridentate coordination in a bridging or chelating mode (Figure 4). PA

4.3. Modification of Metal Nanoparticles

Research on inorganic nanoparticles (NPs) is rapidly expanding with a large variety of applications, as well as strategies for their synthesis.200,201 Most often, surface modification of the NPs is critical, in particular to avoid their aggregation, make them dispersible in liquid media or derivatize them with functional end groups for further modification. For the two former purposes, the use of surfactants is a very convenient approach, while the latter can be achieved either via deposition of protective polymer (i.e., dextran, polyethylene glycol) or inorganic (i.e., SiO2) coatings resulting in core−shell structures, or via self-assembled monolayers grafted on the NPs’ surface. Here again, the exceptional binding properties of phosphonic acids to oxide surfaces have attracted much attention and many examples of decorated inorganic NPs using phosphonateterminated molecules have recently appeared in the literature (see for example the case of SnO2,202,203 TiO2,189,204 Y2O3,205 Fe3O4 [magnetite],206,207 and Fe2O3 [maghemite]208,209). This includes metallic NPs, which are usually surrounded by an oxidized layer. Among inorganic NPs, those based on superparamagnetic iron oxide are intensively studied because of their wide range of applications210 including their important use as contrast agents in magnetic resonance imaging (MRI). In this context, it has been shown that derivatization of the surface using phosphonate anchors allowed preservation of the magnetic properties of the NPs, in sharp contrast to the case of carboxylate, for which a decrease of the net magnetization of the NPs was observed.211 Thus the nanoparticles could be described as a core of magnetite surrounded by a maghemite layer. Interestingly, by decreasing the size of the NPs the relative abundance of the external shell is significant enough to make possible its characterization using XPS, FTIR, and Mössbauer techniques. It was thus suggested that the binding of phosphate groups occurred with Fe3+ ions in octahedral sites, as phosphate-bridged binuclear species,212 and the same behavior can be very likely extrapolated to the PO3 moiety. Moreover, binding of the phosphonate groups led to an increase of the magnetization in the surface layer, which partly compensated the contribution of the organic layer to decrease

Figure 4. Schematic view of some possible binding modes of PAs upon adsorption on metal oxide surfaces, ranging from simple hydrogen bonding interactions to tridentate coordination.

binding results from the ability of the phosphonate groups to displace hydroxide ions that coordinate to the metal exposed on the surface, with the concomitant release of a water or an alcohol molecule186,196 depending on whether PAs or phosphonate esters are used as the anchoring functionality. This condensation reaction is thus pH and temperature dependent. It should be noted that some authors183,185,197 recommend subsequent heat treatment to increase the deprotonation rate of the P−OH groups, which results in the formation of metal−O−P bonds and enhances the stability of the monolayer. In this respect, a simple and qualitative test198 can be carried out to investigate the adhesion and resistance of the monolayers which consists in pressing a Scotch tape onto the surface and quickly peeling the tape off.185 Afterward, spectroscopic methods, such as DRIFT, can indicate whether the coating is still present, as a function of the adhesive strength of the tape. While evidence of PA binding onto a metal oxide surface can be easily achieved using the characterization techniques mentioned above, discerning accurately the PA adsorption mode is more challenging due to the lack of precise spectroscopic data specific to each type of coordination 3785


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the free phosphonic acids produces stable films exposing active metal ions on the surface which can bind easily phosphonic acids. Thus, self-assembled multilayer coatings can then be deposited by repeating sequential exposure to α,ω-bisphosphonic acids222 (or even poly phosphorylated polymers223) and metal ions solutions (Scheme 24). While this process was developed with various types of metal ions,224−228 higher stability was provided to the films when using tetravalent zirconium ions. It was shown that the structural arrangement of the inorganic continuous lattice within these multilayered architectures resembled very closely to the in-plane structure of the solid-state analogues. Rubinstein et al.229,230 have also reported the step-by-step self-assembly of hybrid multilayers, in which the film integrity is preserved, when using alternately diphosphonic acid building blocks and tetrahydroxamate linkers [2(HO-NH−C(O))−R−(C(O)− NH−OH)2], which both can bind Zr(IV) ions strongly. Similar films can be alternatively adsorbed on a zirconium phosphonate surface engineered by the Langmuir−Blodgett (LB) method. First the substrate is made hydrophobic using long-chain thiols (gold) or trichlorosilanes (glass). An octadecyl phosphonic acid monolayer is then transferred onto the substrate and adsorption of Zr4+ ions finally cross-links the monolayer interface.160,231−234 The advantage of the method is to result in a very smooth, uniform and well-defined zirconium phosphonate monolayer, which is ideal for its use as a model surface. However the monolayer can be easily scratched and the LB process is quite slow and requires specific equipments, making unlikely the large scale industrial production of such substrates. For this reason, other strategies have been reported for the preparation of the Zr4+ underlying layer, and many of them consist in the treatment of the substrate with phosphorus oxychloride (POCl3) which then allow binding of zirconium ions by reaction with aqueous zirconium oxychloride (ZrOCl2). This process was for example applied to glass slides coated with aminopropylsilane235−237 or metal oxide thin layers such as ITO,238 and gold slides covered with α,ω-hydroxyalkylthiols.239 As described in section 5, mono- or multilayer phosphonate films have been used for various applications, with two routes for obtaining the expected property: (i) adsorption of a functional phosphonic acid capping layer on the Zr terminated surface in the last step of the film deposition process (ii) use of functional bisphosphonic acid building blocks for assembling the multilayer structure.

magnetization.213 Particular application of phosphonate-decorated NPs in the health sciences area will be presented in section 5.1.3. 4.4. Modification of γ-Zirconium Phosphate

In another field, much interest has also been focused around the use of PAs for the functionalization of layered structures, in particular γ-zirconium phosphate (γ-ZrPO4[O2P(OH)2]·2H2O, hereafter γ-ZrP) and layered hydroxides. In the former case, following the pioneering work of Alberti et al.,214,215 many reports have shown that γ-ZrP can undergo transformation into phosphonate/phosphate hybrids. Most often the reaction proceeds by direct intercalation of the PA and subsequent binding of the PA to the layers driven by topotactic exchange in which surface O2P(OH)2 groups are displaced by bidentate phosphonate groups (Scheme 23). Scheme 23. Schematic Representation of the Phosphonate/ Phosphate Exchange Reaction Occurring in the γ-ZrP Structure

The interlayer distance of the resulting hybrid compounds is directly related to the size of the PA’s organic component. In some cases, preliminary exfoliation of the lamellae is necessary to facilitate access of the PA to the exchangeable sites, using water/acetone mixtures54,216 or via amine preintercalation.217 According to this strategy, various functional layered products (e.g., PA = H2O3P−R−Y with Y = SO3H, CO2H, crown ether) and porous pillared structures (e.g., PA = benzene- or biphenyldiphosphonic acid) were thus obtained.7,55,56 4.5. Coatings Based on Metal Phosphonate-Based Multilayer Films

Deposition of metal phosphonate multilayer films on inorganic substrates is an intensively studied field.7 The first step for building up such multilayered systems consists in priming the surface using a long-chain molecule bound by one end to the surface, while the other end-group is a phosphonic acid, directed away from the support.197,218−221 When dipped in an aqueous metal salt solution, coordination of the metal ions to

Scheme 24. Step-by-Step Procedure for the Formation Metal Phosphonate Multilayer Films

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Figure 5. Some examples of modified glass surfaces for the covalent immobilization of amino-terminated oligonucleotides.

4.6. Discussion about Advantages and Limitations of Phosphonic Acids

(iv) The nature of the PO-metal bond can vary from an ionic to covalent character as a function of the nature and oxidation state of the metal ion and therefore influences the stability of the phosphonic acid attachment to the surface. In fact, very strong metal/phosphonate interaction are observed in the case of metal ions of high oxidation state (tetravalent and higher), thus explaining the increasing use of phosphonic acids as modifiers of titanium dioxide, zirconium dioxide, ITO or fluorinedoped SnO2 (FTO). For such substrates, the anchoring stability to pH is very significant and phosphonate chemistry likely represents the better option, taking account of the decreased chemical stability of the silane bond from Si−O−Si ≫ Zr−O−Si > Ti−O−Si.10

The use of phosphonic acids for surface modification is quite recent compared to the use of silicon-based coatings, despite the fact that solid state chemists have investigated the coordination chemistry of phosphonic acids for some time. This could be explained by the lack of commercially available precursors, a fact that has only recently been addressed. Although convenient and general routes for their preparation have been reported, and are summarized in section 3, they require expertise in organic chemistry and appropriate synthesis facilities especially if route A (Scheme 1) is selected. It should be noted that SMEs (small and medium-sized enterprises) have recently appeared which propose the customized synthesis of functional phosphonic acids. Other limitations in the use of phosphonic acids to functionalize inorganic surfaces have also to be considered, including the following main aspects: (i) Low packing densities are to be expected when the organic group attached to the phosphonic acid is bulky. Nevertheless, this drawback can be minimized by introducing several PO3H2 groups on the molecule to be immobilized, while resulting in addition in a more stable multipoint attachment of the latter on the surface, (ii) Depending on the solubility of the inorganic substrate to be modified, two competing chemical processes may occur: the desired grafting reaction and/or a dissolution/ precipitation process resulting from the release of metal ions from the substrate which are trapped by phosphonic acids to form metal phosphonate compounds. In order to get a pure monolayer grafting, this problem can be solved in some cases either by varying the pH of the phosphonic acid aqueous coating solution, or by using organic solvents or the ester form of the phosphonic acid functions. On the contrary, this dissolution/precipitation process is sometimes desired, for example in the case of anticorrosion coatings, (iii) Depending on the hydrophilic/hydrophobic nature of the organic backbone decorated with PO3H2 groups, the corresponding compounds can be hardly soluble in aqueous or non aqueous media. In such cases, some authors in the literature75 recommend the use of PO3R2 phosphonate ester analogues, for which solubility is usually not a problem,

5. APPLICATIONS OF PHOSPHONATE-COATED MATERIALS 5.1. Bonding of Bioactive Molecules for the Development of New Biotechnologies

Research which bridges materials chemistry and the life sciences has shown increasing impact in the context of the rapidly developing biotechnology area. Indeed, materials chemists have a key role to play in addressing major challenges related to the design of new concepts in biomaterials engineering. 5.1.1. Biological Microarrays. When using presynthesized biological probes, the usual strategy for microarray preparation most often involves robotic printing of the probes onto a reactive surface coated on glass slides. This results in the patterning of the surface with a high density of nanosized spots, each individual spot containing a different probe capable of capturing a specific target. This makes this tool well adapted to high throughput experiments, usable for example for DNA sequencing, protein expression analysis or protein−protein interaction studies.240−246 For limiting inaccuracy in target capture, covalent attachment of the probes on the microarray surface is commonly carried out, while another challenge is controlling orientation of the immobilized interaction partner to optimize binding site exposure and accordingly the detection sensitivity. In the case of DNA microarrays, covalent attachment of probes is commonly performed via their modification with terminal primary amine tethers247,248 that can bind active groups (i.e., activated acids, epoxide, aldehyde, etc.) present on the functionalized glass surface. A convenient method for the preparation of these glass substrates consists in the deposition 3787


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anchoring groups is hardly possible. To preserve the highaffinity binding of protein probes, such as antibodies, once immobilized, one appealing approach consists in the preparation of a functional surface capable of chelating a short peptide sequence fused at the N- or C-terminal end of the proteins. In this context, since nickel nitrilotriacetic acid (NTA) chelates bound to resins were commonly used for chromatographic purification (i.e., Immobilized Metal ion Affinity Chromatography [IMAC]255−257) of oligohistidine-tagged recombinant proteins, surfaces covered with Ni:NTA pendant groups have thus been prepared in the literature, providing stable multipoint attachment of the protein via the oligohistidine moiety.258 Such Ni:NTA reactive groups were for example tethered to gold, quartz, silicon, or magnetic Fe/Pt nanoparticles, and in most cases to glass slides spread with a thin layer of functionalized polymer matrix.259−264 In the latter case, the coating is usually inhomogeneous with an uncontrolled density of NTA head groups. A similar strategy was applied by Cinier et al.265 with a zirconium octadecylphosphonate monolayer for which a bifunctional adaptor was designed, which contained a bisphosphonic acid anchor at one extremity to bind the surface and a nickel NTA chelate at the other end. This allowed preparation of a smooth surface having a high and controlled density of Ni:NTA groups capable of oriented immobilization of oligohistidine-tagged nanofitins, a new family of small and stable capture proteins (Scheme 25, left). The ability of nanofitins immobilized in this way to capture protein targets was found to be retained. The Ni:NTA-modified zirconium phosphonate surface evaluated relative to commercially available protein microarray substrates competed very favorably, showing high detection sensitivity.265 More interestingly, while affitins binds very poorly to the bare zirconium phosphonate surface, by analogy with studies performed with phosphate-terminated ss and ds-DNAs, direct binding of phosphorylated affitins on this substrate was very recently successfully investigated. For this purpose, a peptide tag was genetically fused at the C-terminus end of selected nanofitins. The peptide sequence was carefully designed to make possible its in vitro phosphorylation by casein kinase II, which resulted in a nanocluster made of four phosphate serine moieties that proved efficient for the specific and direct immobilization of the corresponding nanofitins on the zirconium phosphonate surface in a microarray format (Scheme 25, right). In addition, the affitins orientation was thus controlled, and the microarray obtained according to this strategy was shown to be highly efficient in terms of both specificity, sensitivity and signal-to-noise ratio.266 Finally, glycan arrays have been developed for investigating carbohydrate−protein multivalent interactions. In this context, Wong et al.267 have prepared aluminum oxide-coated glass slides, the surface of which was spotted with a robot using oligosaccharides derivatized with a pentylphosphonic acid tail group [(CH2)5PO3H2] to attach the probe covalently. The resulting array could be used for binding analysis of antibody targets to the immobilized glycan probes with very good sensitivity. 5.1.2. Phosphonate-Based Surfaces for the Purification of Complex Biological Media. Characterization of phosphate transfer or removal on proteins is of major importance to understand regulation pathways of many cellular functions. This is usually done very easily by analysis of phosphorylated proteins using mass spectrometry, provided

of a surface bound monolayer of functional groups using organosilane-coating protocols (Figure 5). As discussed in section 4.5, metal phosphonate mono- or multilayer films can be deposited on various substrates according to different strategies. While metal ions exposed at the surface of such films were known to bind phosphonic acids, a novel concept emerged in the field of biological microarrays, based on the covalent attachment of phosphate-terminated probes on these active surfaces. In the case of zirconium phosphonate films, this approach is very attractive since free phosphate groups are expected to bind strongly and phosphorylation can be achieved using enzymes without affecting the probes functionality. The first evidence of this was reported by Nonglaton et al. in the case of 5′-phosphate terminated oligonucleotides for which specific binding to a zirconium octadecylphosphonate (ODPA-Zr) monolayer was found to occur (Figure 6a).249−251

Figure 6. Immobilization of phosphate-terminated ss-DNA (a) and dsDNA (b) on a zirconium octadecylphosphonate monolayer, for the specific capture of complementary oligonucleotide sequences (a) or DNA-binding proteins (b). Adapted with permission from reference 6. Copyright 2011 Royal Society of Chemistry.

It is worth noting that Mallouk and co-workers227,252 have shown that unmodified single stranded (ss) and double stranded (ds) DNAs bind on aluminum phosphonate thin films deposited on a gold electrode, thus allowing detection of the probes by electrogenerated chemiluminescence. Binding of the probes was likely driven by interaction of Al(III) surface sites with lateral phosphodiester groups, but this trend was not observed in the Nonglaton study since oligonucleotides were found to interact very poorly with the ODPA−Zr surface in the absence of terminal phosphate groups on the probes.253 Then successful extension of this concept to the immobilization of phosphate terminated ds-DNA was reported by Monot et al.254 for the characterization of protein−DNA interactions. For a model ds-DNA sequence, the ability of the immobilized probe to capture its protein target was improved when placing a polyguanine segment between the protein interaction domain and terminal phosphate groups. In addition the location and number of phosphate linkers in the duplex probes was found to influence the sensitivity and specificity of the arrays, and best results were obtained for bisfunctionalization on the two ends of one of the two strands of the ds-DNA probes (Figure 6b). By contrast, for the design of microarrays suitable for proteome research, stable surface attachment of proteins while controlling their orientation is highly challenging, since specific organic conjugation of these multifunctional structures with 3788


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Scheme 25. Oriented and Stable Immobilization of Nanofitins (Capture Proteins) onto a Zirconium Octadecylphosphonate Monolayera

a

Left View: The ODPA surface is functionalized with Ni:NTA groups for binding proteins fused with a hexahistidine tag. Right view: Immobilization occurs directly on the ODPA surface for proteins fused with a peptide tag containing phosphorylated serine blocks.265,266.

of the Lewis acidity of the zirconium dioxide surface, making it compatible with protein chromatography. Among surface

that phosphopeptide enrichment of the samples is performed in a preliminary step. Not surprisingly, by analogy with results described in the previous section, phosphopeptide capture by surface exposed zirconium phosphonate sites was recently investigated (Figure 7) and compared to traditional IMAC stationary phases, based on iron(III) complexed to aminopolycarboxylates, usually NTA or IDA [-N(CH2CO2Na)2]. It was thus found that zirconium phosphonate-coated adsorbents, including polymer beads,268 porous silicon wafers,269 magnetic nanoparticles270 and polymer-based capillary column stationary phases271 bind phosphopeptides in complex biological mixtures far more specifically than do conventional Fe3+-IMAC materials. On the other hand, phosphonate-mediated zirconia surface modification has been reported for designing a biocompatible ion-exchange chromatography stationary phase suitable for the separation and purification of various biomolecules.272−275 Indeed, covalent binding of phosphonic acid groups to coordinatively unsaturated zirconium species allows fine-tuning

Figure 7. Immobilization of phosphopeptides on zirconium phosphonate-coated adsorbents. In the given example, attachment to the surface occurs via a phosphorylated serine moiety. 3789


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Scheme 26. Some Examples of Derivatization of NPs Surfaces Using Phosphonic Acid Anchors. Adapted with permission from reference 6. Copyright 2011 Royal Society of Chemistry

were designed upon derivatization of the NPs surface with terminal functional groups, such as primary amine (from 2aminoethyl phosphonic acid (Scheme 26b)282) or carboxylic acid groups (from N-phosphonomethyl iminodiacetic acid (PMIDA)283,284 or 5-hydroxy-5,5′-bis(phosphono)pentanoic acid (Scheme 26c)).285 Bioconjugation could then be performed using pendant primary amine groups (CO2H platform) or carboxylic acid or isocyanate groups (NH2 platform) present on the biomolecule [drug, protein, peptide, etc.] to be immobilized.286 For example, the resulting phosphonate-based functional shell could thus be coupled with folic acid, making possible the selective detection of cancer cells overexpressing the folate receptor by magnetic resonance imaging.283 Interestingly, Das and co-workers have recently reported that phosphonate-coated SPIO NPs for the design of multimodal imaging probes can be generated in a single step, via the alkalimediated coprecipitation of Fe2+ and Fe3+ in the presence of the selected phosphonic acid (i.e., PMIDA).284 On the other hand, de Rosales et al. have investigated the labeling of the inorganic surface of SPIO NPs using bifunctional bisphosphonate molecules suitably derivatized with chelating ligands for positron emission tomography (PET) isotopes (99mTc or 64 Cu),287,288 in order to design dual PET-MRI agents. Moreover, Lukes et al.289 have recently described the use of TiO2 NPs for the development of multimodal diagnostic, therapeutic nanoprobes. For this purpose, a gadolinium complex of DOTA and a fluorescent dye (rhodamine B) were both derivatized with phosphonic acid functions, and coadsorbed in a single step on the NPs, in aqueous medium. After penetration of the resulting nanoprobes in various cell lines, in vitro cell tracking was successfully performed by means of dual MRI and optical imaging. 5.1.4. Drug Immobilization for the Design of Local Drug Delivery Devices. In the case of approved drugs bearing phosphonic acid functions, advantage can be taken of the coordinating abilities of these functional groups to immobilize drugs within inorganic materials for the design of drug delivery systems. Among drugs featuring such characteristics, gem-bisphosphonates (BPs) are widely used in medicine (Figure 8), in particular for the treatment of osteoporosis and bone metastasis.134,135

modifiers investigated for zirconia, EDTPA (ethylene diamineN,N,N′,N′-tetra(methylene phosphonic) acid − [(H2O3PCH2)2NCH2CH2N(CH2PO3H2)2]) proved efficient to produce commercially available chromatographic supports (Zirchrom) suitable for the purification of biologically active species such as monoclonal antibodies, even at large scale. Furthermore, adjustable separation selectivities can be obtained upon quaternarization of the nitrogen center of EDTPA. Similar strategies were also developed for tuning the Lewis acidity of magnesia-zirconia stationary phases.276 5.1.3. Surface-Modified Nanoparticles and Their Bioconjugation. Many groups in industry and academia worldwide are actively developing superparamagnetic iron oxide nanoparticles (SPIO) with the emergence of a vast number of applications in health sciences, including for example combined in vivo magnetic resonance imaging (MRI) and optical imaging (i.e., for determination of tumor margins) via multimodal NPs based on fluorescent optical probes conjugated to SPIO NPs, hyperthermic heating of tumors, drug delivery. In this context, biofunctionalization of the NPs is most often required to avoid aggregation or rapid clearance by the Mononuclear Phagocyte System.277 For this purpose, appropriate coatings are being developed, some of which consisting in the NP surface modification using molecules derivatized with phosphonic acid groups. For example, β-glucosidase was successfully attached onto maghemite nanoparticles, via preliminary functionalization of the surface using 4-aminomethylbenzyl phosphonic acid, which then allowed covalent binding of the enzyme through a reductive amination approach. However, immobilization of the enzyme resulted in a decrease of its activity although its stability overtime was found to be enhanced.278 In another example, Basly et al. reported SPIO NPs covered by a monolayer of grafted trispegylated-benzylphosphonic acid (Scheme 26a). When compared to commercially available polymer-decorated (Dextran T10) SPIO-based contrast agents, the resulting phosphonate-coated NPs showed higher contrast ratio enhancements.279 It is also worth noting that bisphosphonates anchors were found to bind more strongly to iron oxide NPs than monophosphonic acid, thus conferring higher stability in water at physiologic pH.280,281 Recently, potential nanomagnetic platforms toward diagnosis and therapy 3790


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A similar mechanism was also evidenced in human bones on the basis of NMR spectroscopy investigations.299,300 Moreover, while the BP release from the CaP is driven by the phosphate concentration in the medium, sustained, and controlled delivery of the drug can thus be obtained. Therefore, hydroxyapatite coatings covering metal implants (i.e., titanium, tantalum) were used to graft bisphosphonate drugs. After implantation in animal healthy and osteoporotic models, the local elution of BPs from the CaP coatings invariably promoted substantial bone formation around the implantation site, resulting in an increase of the implant mechanical fixation.301−306 It is also worth noting that the drug release did not inhibit bone remodelling nor the healing process. Quite logically, this approach was extended to injectable Zoledronate-loaded CDA granules leading to similar in vivo results, that is, bone restoration and reinforcement of trabecular microarchitecture in osteoporotic sites.307 Also of potential high interest, incorporation of BPs in injectable calcium phosphate cements (CPC) was recently investigated since the unique self-hardening properties of these materials open a new range of applications due to their increased mechanical strength. However, blending BPs within a CPC composition is expected to be a challenge. Indeed, the apatitic CPC setting reaction is usually based on the dissolution of a CaP component with the concomitant precipitation of less soluble CDA crystals, and entanglement of these crystals provide the final mechanical properties of the hardened cement. Therefore, when adding BPs in a cement composition, a significant part of the Ca2+ ions released during the course of the setting reaction is trapped by the BP, thus resulting in slowing down or even fully inhibiting the hardening process. As a consequence only very low doses of BP (∼0.004−0.01 wt %, with respect to the solid phase) can be directly incorporated in apatitic CPCs.308 To increase the amount of BP loaded in such CPCs, different successful strategies have been investigated to minimize inhibition of the setting. This includes (i) reduction of the liquid/powder ratio and addition of gelatin,309 which behaves as an accelerator of the setting reaction,310 and (ii) grafting of the BP onto the surface of one of the solid component of the CPC (i.e., CDA).311 In the latter case, strong immobilization of the drug on CDA limits the amount of BP present in the liquid fraction of the paste, leading to low impact of the BP content on the setting time while keeping a liquid/ powder ratio high enough to ensure good injectability of the CPC. According to a similar concept, chemical probes which can be activated by pH, and functionalized with a hydroxy-1,1bisphosphonic acid end-group to target bone tissues (Figure 9) were used by Kikuchi et al.312 for the selective imaging of bone-resorption osteoclasts. Indeed, the BODIPY probe does not fluoresce at physiological pH but leads to intense fluorescence signals at the low-pH values (∼ 4.5) specifically present in bone areas undergoing resorption. 5.1.5. Derivatization of Implants to Favor or Inhibit Interactions with Cells. Orthopedic metal implants, based mainly on stainless steel or titanium and its alloys, are of widespread use for fracture repair and joint replacement surgery. While these mechanically resistant metal alloys are biocompatible, many efforts are now focused on the modification of their surfaces to induce specific or enhanced interactions with the biological media in the close environment of the implantation site. Grafting of antiosteoporotic drugs has already been mentioned in the previous section, but two other

Figure 8. Selected examples of gem-bisphosphonates used as antiosteoporotic drugs.

These drugs are most often administered orally but suffer from many drawbacks, principally a low patient compliance partly due to side effects when taking the medication.290 Accordingly, a tremendous interest has recently focused on the design of implantable devices that would allow minimizing BP adverse effects via the local and controlled delivery of the drug in selected implantation sites. Among potential drug carriers, polymers have been investigated, in which the BP is either bonded to the polymer backbone291 or immobilized by ionic interactions within ammonium-based cationic polymers.292 On the other hand, mesoporous silica frameworks are now largely considered, but in the specific case of BPs, the interaction of the silica walls (via silanols) with the phosphonic acid functions of the drug are too weak to provide high drug loadings.293 Interestingly Si−Zr based mesoporous binary oxides were recently investigated as a BP delivery vector. In addition to higher stability of these materials in aqueous media compared with pure mesoporous silica, the complexation of the phosphonate groups from the drug to the zirconia surface sites strongly modify the BP release profile, which can be modulated upon varying the Zr/Si ratio in the host matrix.294 More importantly, many synthetic calcium phosphates which are widely used as bone substitutes or metal implant coatings for orthopedic and dental surgery, have received considerable interest as BP carriers, in relation with the high affinity of BPs for the mineral component of bone tissue. However, some calcium phosphates (CaPs) of biological interest including for example BCP (biphasic calcium phosphate, a mixture of hydroxyapatite (HA, Ca10(PO4)6(OH)2) and β-tricalcium phosphate (β-TCP, Ca3(PO4)2)) or pure β-TCP have been found to be unsuitable for this purpose. Indeed, due to partial dissolution of these materials in the presence of BP aqueous solutions, precipitation of crystalline bisphosphonate calcium complexes occurred onto the surface of the CaP.295,296 Unlike other CaPs, calcium deficient apatites (CDA) were shown to behave differently under the same conditions, since reversible chemical binding of the bisphosphonate to the CDA takes place through a chemical exchange between phosphate groups from the CaP with phosphonate groups from the BP (Scheme 27).295,297,298 Scheme 27. Schematic Representation of the Binding Mechanism of gem-Bisphosphonates on Calcium Deficient Apatites. Reprinted with Permission from Reference 296. Copyright 2008 American Chemical Society

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alternative consisted in the direct binding of peptides derivatized with terminal polyphosphonic acids.318−320 Indeed, polyphosphonic acid anchors, especially gem-bisphosphonate groups, were found to lead to coatings of higher chemical stability by comparison with monophosphonic analogues.321 Finally, α,ω-diphosphonic acid SAMs were also formed on titanium, and the surface exposed PO3 tail groups could adsorb positively charged collagen I via electrostatic interactions.322 Another option was to bind zirconium ions to the functional phosphonic acid surface and then bind cell attractive peptides to the Zr complex species.323 5.1.5.2. Derivatization with Terminal Functions Capable of Inhibiting Bacterial Adhesion. Nosocomial or hospitalacquired infections represent a huge burden on the health system. For example, implant-associated infection is one of the most important complications in orthopedic surgery, in particular in the case of the treatment of open fractures by external fixation or revision surgery. Treatment of the infection is often made difficult due to bacterial adhesion and biofilm formation on the biomaterial surface which results in decreased sensitivity to antibiotics.314 Therefore, many approaches have been developed for the surface derivatization of implants to make them capable of resisting bacterial colonization. Strategies investigated to prevent implant infection include (i) passive nonfouling coatings which inhibit bacterial adhesion by tuning the hydrophobic/hydrophilic balance of the implant surface, in particular using hydrophilic polyethylene glycol (PEG) chains or zwitterionic end-groups tethered to the surface324 and (ii) active coatings having either the ability to kill bacteria (via surface bound quaternary ammonium salts or antibiotics)325 or delivering antibacterial agents (silver ions, nitrogen monoxide).326 As mentioned in the previous section, the use of phosphonate anchors for the surface derivatization of metal and metal alloys implants is an attractive route, leading to stable SAM coatings. For instance, coatings based on silver thiolate terminal groups have been prepared according to this strategy, showing significant inhibition of biofilm formation by comparison with the bare metal surface (Scheme 28a).327,328

Figure 9. In vivo fluorescence imaging of bone-resorbing osteoclasts according to Kikuchi et al.. At low-pH, protonation of the dialkylamino function results in fluorescence of the BODIPY probe. Adapted with permission from reference 312. Copyright 2011 American Chemical Society.

fields have also attracted attention: (i) implant coatings to improve adhesion of bone to the metal313 for enhancement of the implant long-term stability and (ii) surface modification of implants for the prevention of nosocomial infections.314 For this purpose various strategies are currently being developed, including the use of phosphonic acid-containing modifiers. 5.1.5.1. Derivatization of Implants to Promote Cell Adhesion. Grafting bioactive molecules onto the native oxide surface of implants by means of silanization may result in unsatisfactory binding stability under physiological conditions. Hence, the use of phosphonic acid anchors has been considered and were found to offer higher chemical robustness than siloxane analogues.315 Self-assembled α,ω-hydroxy- and carboxyalkyl phosphonate monolayers were easily produced on both smooth and rough titanium and titanium oxide surfaces.177,179 Subsequent coupling of bioactive molecules (cell attachment peptides [RGD], bone morphogenic proteins [BMP-2]) to the surface exposed hydroxyl or carboxy end-groups resulted in bioactive surfaces capable of promoting cell proliferation or local bone growth.179,316,317 A simpler and more practical

Scheme 28. Some Example of Biofouling Coatings on Metal Oxide Substrates, Using Functional Phosphonic Acids. Adapted with Permission from Reference 6. Copyright 2011 Royal Society of Chemistry

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5.2.1. Immobilized Phosphonic Acid Functionalized Nitrogen Ligands. Phosphonic acid functionalized 2,2′bipyridine ligands334 were coordinated to rhodium and iridium and the resulting complexes grafted to 20−100 nm titanium oxide particles.76 The catalytic activity of the hybrid materials toward hydrogenation of aromatic ketones using 40 bar of H2 and alkaline methanol was studied. It was shown that catalytic activity of the supported rhodium and iridium complexes was similar to that found in the analogous homogeneous systems. In addition, catalytic activity was retained after separation of the material and subsequent recycle, and metal leaching from the catalyst was negligible. The catalysts were prepared as shown in Scheme 29, via condensation of the metal bipyridine complexes

Surface immobilization of PEG on titanium substrates was successfully performed using phosphonic acid having a terminal thioester function, which can subsequently be converted into an amide bond using a PEGylated cysteine group (Scheme 28c).329 In addition, antibacterial phosphonate monolayers based on terminal quaternary ammonium species were prepared using far milder conditions when using gembisphosphonate versus monophosphonate anchors (Scheme 28b).330 In a different context, Fishbein et al.331 have reported the modification of the metal alloy surfaces of stents with a monomolecular bisphosphonate layer, which then enables covalent attachment of specific vector-binding agents. The resulting modified metallic implants were shown to allow therapeutic gene delivery to the arterial wall and offer promising solutions to prevent arterial reobstruction after stenting. 5.1.6. Supported Artificial Biological Membranes. In a different area, solid supported bilayer lipid membranes are of particular interest since they can be used as models to investigate many features of cell membranes, including their interaction with proteins. In this context, among different other routes, phosphonate chemistry has also been used to prepare stable lipid bilayers, partially anchored to a solid support, taking advantage of strong binding of the phosphate and phosphonate groups present in the bilayer to surface metal ions, such as zirconium (zirconium phosphonate monolayer transferred on glass)332 and aluminum (aluminum oxide sputtered on gold).333 This results in an inner layer which shows low fluidity in contrast to the outer layer, and it was shown that such supported lipid bilayers can be considered as viable membrane mimics (Figure 10).

Scheme 29. Immobilization of Water-Soluble Phosphonic Acid Derivatives of Rhodium 2,2′-Bipyridine Complexes, for the Heterogeneous Reduction of Aromatic Ketones under Hydrogen Pressure76,335

with in situ generated titanium oxide/hydroxide particles from Ti(OiPr)4 under aqueous conditions. After optimization of the immobilization process, a >99% conversion of acetophenone to alcohol was achieved, rhodium being more efficient than iridium. For the competitive reduction of mixtures of alkenes and ketones, olefinic bonds were reduced to the corresponding alkanes in preference to ketone reduction with the supported catalyst.335 The opposite trend is observed under homogeneous conditions. Porphyrins and metalloporphyrins are ideal molecules for functionalization with the phosphonic acid group, and were first screened as supported homogeneous catalysts when selfassembled as a pure metal phosphonate polymer. This approach consists in the condensation of the phosphonic acid functionalized catalytic species with a suitable metal precursor (commonly a soluble metal salt) in aqueous or organic solution. This general method is outlined in Scheme 30. For example, Bujoli et al. prepared a series of zinc phosphonate-supported manganese porphyrin complexes, which were active for alkane hydroxylation and olefin epoxidation using iodosylbenzene as the oxidant.156,336 X-ray powder diffraction revealed the absence of layering within these structures, although selectivity for competitive hydroxylation of an alkane mixture of cyclododecane and cyclohexane to the corresponding alcohols was distinctly different from homogeneous counterparts (cyclododecanol:cyclohexanol ∼5:1), because of the inherent shape selectivity effects of the phosphonate support. Examples of phosphonate-supported manganese porphyrins are shown in Figure 11. A similar approach was successfully used by Ma et al. (metal phosphonate network, titanium; catalyst, amino-alcohol palladium complex;337 metal phosphonate network, zirconium;

Figure 10. Schematic representation of a phospholipid bilayer immobilized on a zirconium phosphonate-modified surface.332.

5.2. Supported Catalysis

Phosphonate-based materials are ideally suited for catalytic applications. Some of the advantages include: (i) straightforward preparation of phosphonate functionalized ligands for stabilizing catalytically active metals; (ii) variation in supporting substrate, for example metal oxides or self-assembled polymeric phosphonate networks; and (iii) the robust phosphonate linkage which allows for variations in catalytic conditions such as temperature, pressure and solvents used. Other practical advantages of heterogenized catalysts include ease of separation of the catalyst from the reaction mixture and possible shape selectivity for organic transformations resulting from microenvironmental control within the phosphonate material. 3793


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zirconium octadecylphosphonic acid film, similar to that described in Figure 6 (section 5.1.1), using zirconium phosphonate linkages for surface binding. Catalytic oxidation activity of the film was compared to the homogeneous counterpart using the iodosylbenzene-mediated epoxidation of cyclooctene as the model reaction. Interestingly, the catalytic activity of the metalloporphyrin film was greater than that of the complex under homogeneous conditions.339 The increased activity of the film is explained by prevention of noncatalytically active manganese porphyrin oxo-dimer formation which occurs in solution. Similarly, manganese porphyrins functionalized with phosphonic acid functions were assembled as zirconium phosphonate multilayer films on ITO electrodes to obtain supported oxidation catalysts.340 On the other hand, Fu and co-workers have reported a series of polystyrene-based scaffolds used for the design of supported catalysts. Condensation of polystyrene oligomers having phosphonic acid end-groups with zirconium oxychloride and sodium dihydrogen phosphate result in the self-assembly of a zirconium phosphate/phosphonate hybrid containing polystyryl units in which the aromatic moieties can be then functionalized to anchor chiral salen catalysts.341−345 After grafting diamines onto the polymer surface, chiral manganese(II) salen complexes were coordinated via an axial interaction. These supported complexes catalyze the asymmetric epoxidation of olefins using either m-CPBA/NMO or NaClO/ PPNO as the oxidant system. In most cases, improvements in catalytic activity and enantioselectivity over the homogeneous counterparts were observed. Simple separation of the active catalysts by precipitation was achieved by addition of hexane to the reaction mixtures. More recently, use of this polymeric material has been extended to olefin epoxidation with a molybdenum(VI) complex.346 Finally, the proline ligand immobilized onto the surface of magnetite nanoparticles has been reported to catalyze the CuI mediated N-arylation of various nitrogen heterocycles in good to excellent yields (Scheme 31).206 For that purpose, the NPs were first decorated using a phosphonate-terminated azide, thus allowing subsequent coupling by click chemistry of a proline functionalized with terminal alkyne group. The magnetic nanoparticle-supported proline ligand was readily recovered upon magnetic decantation and reused with no significant loss of activity. 5.2.2. Phosphonic Acid Functionalized Phosphine Ligands. A number of examples of phosphonic acid and phosphonate functionalized phosphine ligands have appeared

Scheme 30. Schematic Representation of the Preparation of Catalysts Incorporated As Part of the Pure Metal Phosphonate Networks. Reprinted with Permission from Reference 76. Copyright 2001 American Chemical Society

Figure 11. Immobilized manganese porphyrins within zinc phosphonate networks.156,336.

catalyst, amino-alcohol/bisphosphine ruthenium complex338) for the preparation of supported hydrogenation catalysts. Moreover, a monolayer film of a phosphonic acid functionalized manganese porphyrin has also been used as a model for supported oxidation catalysis. Using Langmuir− Blodgett and self-assembled monolayer techniques, manganese 5,10,15,20-tetrakis(tetrafluorophenyl-4′-octadecyloxyphosphonic acid) porphyrin (Figure 12) was immobilized onto a

Figure 12. Epoxidation of cyclooctene by PhIO, catalyzed by manganese porphyrins in monolayers films (R2 = C6F4−O−C18H36−PO3H2) and in solution (R2 = C6F5), according to Benitez et al.339 3794


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Scheme 31. Preparation of Magnetite Nanoparticle-Supported Proline for the CuI-Catalyzed Arylation of Nitrogen Heterocycles, According to Chouhan et al.206

in the literature. For example, triphenylphosphine trisphosphonic acid (TPPTP), originally reported as a ligand for aqueous phase and biphasic homogeneous catalysis, was also used for anchoring palladium(II) complexes to SiO2.347 Pd(TPPTP)4 was prepared via the reaction of Na2PdCl4 with p-TPPTP and NaBH4 and subsequently grafted onto silica gel. This supported catalyst was found to be active for the phosphonylation of phenyl triflate. In addition, the molybdenum carbonyl complex [Mo(CO)5(m-TPPTP)] was described, however the catalytic activity for this complex was not investigated. Later, TPPTP was also reported as a stabilizing phosphine ligand for cobalt in the hydroformylation of alkenes. Reaction of p-TPPTP with the cobalt carbonyl Co2(CO)8 under biphasic conditions gave either Co6(CO)3(p-TPPTP)2(H2O)24 with six crystallographically distinct cobalt ions or Co4(CO)3(pTPPTP)2(H2O)24 with four crystallographically distinct cobalt ions, depending on the pH of the reaction mixture. The cation [Co(CO)3(p-TPPTP)2]+ was subsequently reacted with Ti(OiPr)4 via a sol−gel method similar to that described above to give an amorphous TiO2-supported Co(I) alkene hydroformylation catalyst as shown in Figure 13.348 Tests on the

Figure 14. Ruthenium phosphine-phosphonic acid complexes immobilized as heterogeneous asymmetric hydrogenation catalysts.349,350

complexes (Ru-L1-DPEN and Ru-L2-DPEN; Figure 14) developed by Noyori (DPEN is 1,2-diphenylethylenediamine) and the resulting catalysts showed an exceptionally high activity and selectivity (up to 99.2% ee) for the asymmetric hydrogenation of prochiral aromatic ketones.350 Catalyst recycle was possible without any loss of enantioselectivity. It is notable that the supported catalyst showed superior enantioselectivities when compared to the homogeneous counterparts reported by Noyori. In addition a monophosphonic acid version of this RuBINAP/DPEN system was also immobilized on magnetite nanoparticles, and it was found that the heterogenized catalytic system can be readily recycled by magnetic decantation up to 14 times without altering activity nor enantioselectivity of the catalyst for the asymmetric hydrogenation of aromatic ketones.207 Finally, the same group has also reported similar immobilization of BINOL-derived bisphosphonic acids. After drying the resulting solids, treatment with excess titanium isopropoxide generate active catalysts for the addition of diethyl zinc to aromatic aldehydes, leading to chiral secondary alcohols in high yields and ee values up to 72%.351 5.2.3. Phosphonic Acid Functionalized Arene Complexes. Examples of catalytic organometallic complexes without stabilizing nitrogen-containing or phosphine ligands are much rarer. One example of a chromium arene tricarbonyl bisphosphonic acid when reacted with zinc nitrate gave an amorphous inorganic-organometallic hybrid material which

Figure 13. Cobalt-TPPTP complex used for TiO2 supported hydroformylation catalyst.348

activity of this supported complex in the hydroformylation of 1octene showed that the material has similar activity to other supported cobalt-based hydroformylation systems, but with a different selectivity. In one catalytic run a 26% conversion to aldehydes with a normal/branched ratio of 0.57 was observed, with only a trace of alcohol byproduct. Unmodified cobalt catalysts give much higher normal/branched ratios (1.4−4.4), and phosphine-cobalt complexes usually show even higher normal/branched ratios. Chiral phosphonic acid functionalized phosphine ruthenium complexes based on the 1,1′-binaphthyl framework (Ru-L1 and Ru-L2; Figure 14) have been successfully incorporated into amorphous porous zirconium phosphonate networks, according to the self-assembly method described in section 5.2.1 upon reaction with an alcoholic solution of zirconium alkoxide. These immobilized chiral catalysts have been used for heterogeneous asymmetric hydrogenation of β-ketoesters with ee values up to 95%.349 Following a similar strategy, these phosphine ligands were also immobilized as the mixed ruthenium BINAP/DPEN 3795


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bipyridine complexes having phosphonic acid groups directly bound to the aromatic backbone, the 4,4′ positions (Figure 15b) was preferable since the 5,5′ positions, as well as the presence of spacers (i.e., methylene or proline-based spacers), was found to decrease the photon-to-current conversion efficiency.358,359,363 Interestingly, Grätzel et al. showed that introduction of two hydrophobic nonyl chains at the 4,4′ positions of the second bipyridine block (Figure 15c) very significantly improved the power conversion efficiency of the resulting DSC (≥8%), under illumination with simulated air mass 1.5 sunlight.365 For the first time, this amphiphilic sensitizer gave evidence that phosphonate-anchored ruthenium polypyridyl complexes can match the performances of carboxylate analogues. Finally, to limit aggregation phenomena, coadsorption of a dye with amphiphilic molecules (i.e., bisneohexylphosphinic acid), which play the role of insulator, was found to retard interfacial recombination of photogenerated charge carriers and promote long-term stability of the device.366 TiO2 sensitization using phosphonic acid-functionalized porphyrins have also been studied, leading generally to very low performances,367 by comparison with polypyridyl ruthenium complexes. In contrast to n-type SCs, the development of DSCs based on p-type SCs has appeared only very recently to investigate tandem devices, in particular using nickel oxide.368 In that case, novel sensitizers have to be developed to provide efficient hole injection from the photoexcited dye in the valence band of the p-SC. In this context, attachment of ruthenium trisbipyridine complexes was investigated while varying the anchoring group (i.e., carboxylate, methylenephosphonate, carbodithioate or catechol; Figure 16), showing that the observed photo-

catalyzed the oligomerization of phenylacteylene (Scheme 32).

352

Scheme 32. Chromium Arene Bisphosphonic Acid Used As a Catalyst for Phenylacetylene Oligomerization352

5.3. Grafting of Photoactive and Electroactive Molecules

Surface modification of semiconductors using stimulable molecular species is under intense investigation for the design of various novel technologies, including for example dye solar cells (DSCs), photocatalytic systems or optical data storage systems. For this purpose, the choice of the anchoring function is of critical importance because of its high influence on the chemical stability of the assembly and the interfacial electronic communication efficiency. In particular, many reports have focused on the potential of phosphonic acids versus carboxylic acids as grafting functions, including theoretical studies aiming at comparing the binding energies, vertical excitations, time scales, and mechanism of interfacial electron transfer of various sensitizers bound to titanium dioxide by using those two types of linkers.353 5.3.1. Dye-Sensitized Solar Cells. As an alternative to conventional inorganic p−n junction solar cells, the DSC technology is based on the attachment of sensitizers on the surface of n-type wide band gap semiconductor (SC) oxides to provide electronic coupling between the inorganic support and the light-harvesting immobilized species. In particular, TiO2 nanocrystalline films have been largely used since they are transparent with unique electronic properties, while their high surface area allows binding of high amounts of redox-active dyes. While the most efficient devices reported in the literature were based on ruthenium complexes grafted on TiO2 via carboxylate anchors (i.e., Ru(4,4′-(CO2H)2bpy)2(NCS)2; Figure 15a),354,355 the alternative use of phosphonate anchors for

Figure 16. Example of ruthenium trisbipyridine complexes used as photosensitizers for DSCs.368,369

conversion efficiency compared well with the well-known standard p-SC sensitizer (coumarin C343), especially for the species derivatized with methylenephosphonic acid binders which exhibit high stability of the surface bound Ru(III) complex and therefore significant light harvesting efficiency (LHE).369 5.3.2. Photocatalysis and Electrocatalysis. Converting solar to chemical energy for the production of fuels (water splitting) or useful organic chemicals (CO2 reduction) is a highly challenging research area, which can be addressed upon immobilization of suitable photoexcitable molecular systems onto conducting or semiconducting oxide surfaces. Visible light induced water splitting is one of the most difficult problems in photochemistry and a recent report by Mallouk et al.370 gave an update on current approaches based on dye-sensitized semiconductors, in which attachment of the

Figure 15. Some examples of polypyridyl ruthenium photosensitizers (a) R1 = CO2H, R2 = H; (b) R1 = PO3H2, R2 = H; (c) R1 = PO3H2, R2 = (CH2)8−CH3.

immobilization of the sensitizers was first explored by Grätzel et al.356,357 with phosphonate-derivatized terpyridine, and later by other groups.358−364 One significant advantage of PO3mediated bound sensitizers over carboxylate analogues was the higher chemical stability in water even at low pH or in the presence of solvent-free ionic liquid electrolytes, but unfortunately the overall efficiency was about 30% smaller due to a lower absorbance in the red part of the visible spectrum and weaker electronic coupling.363 In the case of ruthenium 2,2′3796


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dye to the surface is in many cases performed using phosphonate moieties, because of its stability toward water induced desorption. Photocatalytic water reduction was thus performed using niobate nanoparticles (H4Nb6O17), sensitized by a trisbipyridine ruthenium derivative (Figure 16, R1 = R2 = PO3H2) and mediating the electron transfer between the dye and platinum particles that catalyze hydrogen evolution from EDTA solutions (ethylenediamine tetraacetic acid) acting as sacrificial electron donor, with observed 20−25% external quantum yields.371 In another study by Armstrong et al.,372 the same sensitizer was grafted on TiO2 nanoparticles onto which a [Ni−Fe−Se]hydrogenase enzyme was coadsorbed. Using triethanolamine as a sacrificial electron donor, the resulting system was found to be very promising and produced H2 at a turnover frequency of ∼50 mol(H2) s−1 (mol total hydrogenase)−1 at pH 7 and 25 °C, under the typical solar irradiation of northern European sky. A step beyond this was recently achieved by Mallouk et al.373 with a photoelectrochemical cell which allowed photoassisted overall water splitting (oxidation + reduction), in the absence of sacrificial redox agent. In the anodic compartment water reduction is performed at a platinum electrode, while a trisbipyridine ruthenium sensitizer is again involved for water oxidation (Figure 17).

Figure 18. [Ru(Mebimpy)(bpy)(OH2)]2+ water oxidation catalysts developed by Meyer et al..374.

1.2 × 10−10 mol/cm2 on FTO and ITO, and 5.3 × 10−8 mol/ cm2 on FTO/TiO2 were achieved after soaking the electrodes in a methanol solution of the complex for ∼4 h. It was then found that the surface-bound complex retains its ability for sustained electrocatalytic water oxidation (applied potential: 1.85 V at pH 5). Concerning the photoreduction of CO2 to CO, Armstrong et al.375 have recently developed a prototype hybrid system, where a trisbipyridine ruthenium complex ([Ru(4,4′-(PO3H2)2bpy)(bpy)2]Br2) is attached to the surface of TiO2 nanoparticles via phosphonate anchors along with the CO2-reducing enzyme CODH1 which is coadsorbed onto the semiconductor. It was found that clean CO2 to CO conversion occurred via a twoelectron reduction pathway with this system by using visible light, and that the TiO2 NPs were acting as an electron relay between the ruthenium dye and the enzyme. At pH 6 and 20 °C, an average production of 250 μmol (g of TiO2)−1 h−1 was obtained which was clearly superior to that obtained with other sensitized TiO2 systems. In another example, Suzuki et al.376 reported efficient photoconversion of CO2 to formic acid under visible light irradiation. This was achieved by using a hybrid system consisting in a ruthenium complex ([RuII(4,4′-(R1)2bpy)(bpy)(CO)2]) anchored on a p-type photoactive N-doped Ta2O5 semiconductor, via carboxylate (R1 = CO2H) or phosphonate (R1 = PO3H2) binders, where the bisfunctionalized bipyridine was first bound to the surface prior to assembling the final ruthenium complex. Photoexcited electrons of the conduction band of N−Ta2O5 were transferred to the ruthenium dye LUMO which promotes the two-electron reduction of CO2 to HCO2H. Compared to the use of the unbound complex (R1 = H), the immobilized ruthenium dye was found to exhibit higher photocatalytic activity, and interestingly the phosphonateanchored photocatalyst showed a turnover number of HCO2H formed per metal complex 4.9 times higher than that of the carboxylate analogue. 5.3.3. Electrochromism. Grafting viologen chromophores (i.e., 4,4′-bipyridinium derivatives) containing phosphonic acid moieties onto nanostructured TiO2 films on conducting glass have been investigated for the design of electrochromic devices.377−379 Large color changes from transparent to either deep blue or deep green could be achieved with fast switching times (1−2 s).380 The performances of the resulting electrochromic windows are largely determined by the electron withdrawing or donating properties of the substituent present on the viologen compounds. Will et al. have also reported the immobilization of phosphonate-functionalized trisbipyridyl ruthenium complexes on metal oxide particles, where a viologen moiety was linked to one of the bipyridine unit (RV; Figure 19).

Figure 17. Examples of polypyridyl ruthenium sensitizers used for photoassisted overall water splitting by Mallouk et al.373

The ruthenium complex acts as a stabilizer for 2 nm-large IrO2·nH2O nanoparticles via its malonate moiety, while its selective attachment to a porous nanocrystalline TiO2 anode film is provided by the phosphonate groups. In this system, under visible light illumination and assistance by a small applied voltage, hydrated iridium oxide NPs catalyze water oxidation. However, the quantum efficiency is low (∼1%), since the electron transfer from the IrO2·nH2O nanoparticles to the oxidized dye is much slower than back electron transfer from titanium dioxide to the Ru(III) complex. Nevertheless, this example gives a proof-of-concept of overall water splitting in a sensitizer-based photosystem. In the same area, approaches based on electrocatalysis have also been developed. For instance, phosphonate-mediated surface binding of the water oxidation catalyst [Ru(Mebimpy)(bpy)(OH2)]2+ (Figure 18, R1 = H)) was successfully performed by Meyer et al.374 on FTO or ITO electrodes as well as transparent films of TiO2 nanoparticles on FTO (FTO/ TiO2), when replacing the bpy unit by its bisphosphonate analogue (Figure 18, R1 = CH2PO3H2). Saturation coverages of 3797


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Figure 20. Structure of quaterthiophenediphosphonic acid.

films with second-order nonlinear optical properties, by assembling alternate layers of α,ω-bisphosphonate azo derivatives and zirconium ions.385,390 Surprisingly, and to the best of our knowledge, this attractive concept that appeared in the early 90s did not lead to the design of applicable devices yet, and no significant use of this layer-by-layer approach in other areas has been reported. This is probably related to the fact that this technique requires high skills to obtain reproducible and well ordered multilayer metal phosphonate films, with good uniformity and controlled thickness. In addition their mechanical stability, although not documented, is expected to be poor, and there is a lack of data on the stability of such assemblies over time. In addition, other tools have been reported for growing similar multilayers having optical properties, including the recent use of copper(I)catalyzed azide−alkyne cycloaddition, also known as “click” chemistry.391 Significant barriers to charge injection at interfaces of organic semiconductors and conducting oxides are often observed in organic electronic devices (for example, organic light emitting diodes (OLED)). One way to enhance charge transport across interfaces between so dissimilar materials is to graft organics to the electrode surface to increase compatibility with the organic component. In this context, phosphonic acids have often been used as surface modifiers of conducting oxides and improvement of the device performances were found to vary depending on the phosphonic acid used. Examples of surface modifiers recently reported include n-alkyl phosphonic acids, benzyl phosphonic acids with different degrees of fluorination or quaterthiophene phosphonic acid.392−395 Thus, recent reports from the literature shows the increasing use of functional phosphonic acids as a tool for interface engineering for organic electronics,396,397 including for example deposition of SAMs containing hole-transporting molecules on ITO to increase polymer LEDs (PLEDs) performances398 or binding of an efficient electron-injection layer based on polyfluorene containing phosphonate groups to an aluminum anode for the design of high-performance all-polymer white-light-emitting diodes (PWLEDs).399 In the area of photoactive materials, recent research has focused on the immobilization of lanthanide emitters. For example, luminescent lanthanide complexes derivatized with four phosphonate silyl ester groups (Figure 21) were successfully immobilized on in situ generated amorphous titania or zirconia matrices from their respective alkoxides under aqueous conditions.400 In these complexes, the naphthyl groups act as antenna chromophores sensitizing the metal-

Figure 19. Structure of the RV viologen chromophore used by Will et al. for the design of rewritable devices.381

This RV complex (n = 4) was assembled on a nanostructured TiO2 film supported on conducting glass and then incorporated in a sealed two-electrodes system, containing triethanolamine as a sacrificial donor dissolved in the electrolyte. Under open circuit conditions, irradiation of the TiO2-RV electrode (applied potential: 0.45 V) using the blue-green light from an Ar-ion laser beam allows to write well-defined patterns, as a consequence of the formation of a significant amount of the reduced form of the viologen component, after electron transfer from the Ru-complex. The resulting pattern could be optically read by using a nonadsorbed red output of a He−Ne laser source. This experimental setup gives the proof-of-principle of a rewritable device, since the radical cation of the viologen component which is stable for hours, can be then reoxidized by applying a voltage of +1.0 V for 15 s, leading to the reset of the system.381 In addition the long-lived formation of the viologen radical cation is not observed in a similar system where TiO2 is replaced by Sb-doped SnO2.382 Finally, transparent nanostructured anatase membranes onto which the same RV (n = 1 or 4) complexes were anchored were found to turn blue upon exposure to visible light, and a lifetime of the blue color state on the time scale of hours was observed upon application of an appropriate negative potential.383 Ruthenium(II) trisbipyridyl complexes in which one or three of the bipyridine ligands are functionalized by phosphonic acid functions have also been adsorbed to mesoporous TiO2/ITO electrodes to exhibit electrogenerated chemiluminescence when potentiostated at positive voltages in the presence of oxalate in buffered aqueous solution.384 The stability of the modified surfaces increased, as the number of phosphonic acid substituents per chromophore was increased. 5.3.4. Electro-optical and Organic Electronics Devices. As outlined in section 4.5, metal bisphosphonate multilayer thin films have received considerable interest (see Scheme 24). Those are most often based on long chain aliphatic α,ωbisphosphonates, but the use of electron donor or acceptor bisphosphonate building blocks has also been investigated for the design of potentially electroactive or photoactive multilayered materials. One of the first examples by Katz et al.237 reported the use of a quaterthiophenediphosphonic acid (Figure 20). Layer-by-layer growth of such films enabled to incorporate electron donors and electron acceptors in separated alternating layers, leading to efficient photoinduced charge separation and directional electron transport. Following the concept of Katz et al.,385 some examples include systems based on porphyrin/viologen,386 viologen/pphenylenediamine387,388 or porphyrin/perylenediimide.389 This layer-by-layer method was also applied to produce acentric thin

Figure 21. Phosphonate-derivatized europium DOTA complex immobilized on titania and zirconia supports.400 3798


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based luminescence of the complexed Eu3+ ion. The sensitized emission of Eu3+ ions was preserved in all the resulting hybrid materials and was higher in the case of the zirconia support.

adsorption of uranyl species was an order of magnitude higher when compared to analogues having only a monomodal porosity.

5.4. Surface Modification for the Detection or Complexation of Soluble Chemical Species

6. CONCLUDING REMARKS

In another application, phosphonic acids have been grafted onto inorganic substrates to develop devices for the detection and measurement (sensors) or trapping (extractant) of molecular species in solution. In this context, binding of the targets can be achieved (i) via the phosphonate coating by itself or (ii) via the presence of suitable dangling functions available on the surface. For example, in the first category, well-ordered and oriented copper bisphosphonate multilayer thin films of general formula Cu2(O3P−R−PO3)2 have been assembled on the gold electrodes of quartz crystal microbalance. The film structure is related to that of the bulk layered divalent Cu(O3PR)·H2O phosphonate, which upon dehydration shows an unsaturated copper site capable of binding Lewis bases of suitable dimension. Detection of ammonia at gas-phase concentrations of 0.01−25% was thus reported with such ultrathin films (

Surface Modification Using Phosphonic Acids and Esters - Chemical

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