Heterofunctionalized Carbosilane Dendritic Systems: Bifunctionalized

Jul 22, 2014 - Taking into account the chemical diversity at the focal point for both neutral- and anionic-terminated dendrons, such as azide, alcohol...
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Heterofunctionalized Carbosilane Dendritic Systems: Bifunctionalized Dendrons as Building Blocks versus Statistically Decorated Dendrimers Marta Galán, Elena Fuentes-Paniagua, F. Javier de la Mata,* and Rafael Gómez* Departamento de Quı ́mica Orgánica y Quı ́mica Inorgánica and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Universidad de Alcalá, Campus Universitario, E-28871 Alcalá de Henares, Spain S Supporting Information *

ABSTRACT: “Click” chemistry based on thiol−ene synthetic protocols has been used to successfully bifunctionalize anionic carbosilane dendritic structures in two effective ways. The first consists of the formation of statistically heterofunctionalized dendrimers, the second being the synthesis of heterofunctionalized dendrons. Regarding the latter approach, a versatile and simple procedure has been developed for the synthesis of a library of anionic carbosilane dendrons. Taking into account the chemical diversity at the focal point for both neutral- and anionic-terminated dendrons, such as azide, alcohol, amine, bromine, carboxylic acid, and alkyne, these dendritic systems may act as building blocks to give more original dendritic architectures. Other examples have been reported by Cheung and Chow24,25 by selective protection of alcohol groups in the hydroquinone monomer or Newkome26 or Simanek27 using heterofunctional monomers that after their coupling in the last synthetic step allow decoration of the surface with different functional groups in a very precise way. Nevertheless, no examples for carbosilane structures have been described so far using this approach. Regarding the statistical bifunctionalization of dendrimers, it has mainly been accomplished for PAMAM dendrimers. As an example, Xi et al.28 prepared rhodium metallodendrimers by complexation with partially substituted phosphine-terminated dendrimers along with the presence of solubilizer groups such as sulfonic acids for hydroformylation reactions. Crooks et al.29 have also used this approach for the generation of Pt and Pd nanoparticles through the presence of hydroxylic groups that generate nanoparticles of low size along with quaternized amine to avoid metal complexation. A final example is the modification of PAMAM dendrimers of high generations containing altogether fluorescein, folic acid, and ammonium groups responsible for the targeted delivery of nucleic acids against cancer.30 In addition, the statistical bifunctionalization of PPI has also been accomplished.31 However, for carbosilane dendrimers, very few examples have been recorded in the literature. Muzafarov et al. achieved the partial silanolysis of Si− Cl terminated dendrimers and the posterior hydrolysis of the remaining Si−Cl bonds for the formation of fluorinated derivatives of carbosilane dendrimers.32 Meanwhile, in our group, partial dansyl-terminated dendrimers were prepared by selective reaction of primary amine-terminated dendrimers with dansyl chloride.33 An interesting example related to this first

1. INTRODUCTION Since dendrimers were first described in the 1980s,1−5 these new types of macromolecules have been widely and successfully synthesized and applied to different fields, such as material sciences and engineering, biology, and biomedicine.6−10 Their multivalency and nanoscale size make them especially appropriate for biomedical applications in their interaction with different cellular components or in the delivery of bioactive molecules.11−13 In addition to dendrimers, other perfect dendritic architectures are the so-called dendritic wedges or dendrons, which are cone-shaped molecules with two different types of functional groups, one at the periphery and another at the focal point. Dendrons have usually been synthesized for dendrimer synthesis14−18 through convergent methods, but they can also be regarded as new bifunctionalized systems or building blocks to prepare heterofunctionalized molecules, such as Janus-type dendrimers,19,20 or hybrid nanocompounds (dendronization of nanoparticles, carbon nanotubes, or quantum dots among others).21,22 In order to prepare hetero- or bifunctional dendritic systems, two main strategies can be used: (i) the direct insertion of different functional groups at the periphery of a dendrimer in either a statistical or a precise form and (ii) the binding of two or more dendrons with different peripheral groups, topologies, and sometimes generations. Regarding the first approach, focused on specific bi- or multifunctionalization of the dendritic surface, one of the simplest examples has been presented by Frechet et al. using a biodegradable dendrimer based on bis(hydroxymethyl) propanoic acid (bis-HMPA) where the treatment with cyclic carbonate and the subsequent workup gave rise to two different functional groups, amide and alcohol groups, at the surface.23 © 2014 American Chemical Society

Received: May 1, 2014 Published: July 22, 2014 3977

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approach is the synthesis of carbosilane homodendrimers containing two orthogonal functions or properties introduced by the reagent in the capping reaction that in fact could be considered as a third possible approach.34 Considering the second approach, suitable and orthogonal focal points at the dendrons are needed in order to form the socalled Janus dendrimers. Although it requires more synthetic efforts than homofunctional dendrimers, there are outstanding examples in the literature based on scaffolds of different nature. In recent years, synthetic approaches based on “click” chemistry have emerged, to simplify the process of formation and to obtain dendritic families with a great variety of functional groups.20,22,35 However, few examples of heterofunctionalized carbosilane dendrimers have been published so far using this approach. Janus carbosilane/phosphorhydrazone dendrimers36 have been synthesized by the “click” Staudinger reaction to afford oily products or, for instance, amphiphilic poly(ethylene oxide)−carbosilane dendrimers designed to form micelles in aqueous solution.37 Our research group has recently prepared the first water-soluble cationic Janus dendrimers containing both polyethylene glycol and carbosilane moieties, via an azide−alkyne coupling “click” reaction with the aim to reduce the toxicity associated with the cationic carbosilane framework and improve the liberation time of short nucleic acids for gene therapy.38 Therefore, there is a need to find synthetic protocols for dendrons with suitable focal points which could act as building blocks in the formation of new dendritic architectures. We have recently adopted “click” thiol−ene chemistry as a powerful functionalization strategy not only for allyl- or vinylterminated carbosilane scaffolds in the preparation of homodendrimers39,40 but also for carbosilane dendrons bearing amine or ammonium groups at the periphery.41 In order to combine different functionalities into one dendritic structure, we have explored “click” thiol−ene chemistry as the main tool to obtain anionic heterofunctionalized spherical carbosilane dendrimers and transferred this knowledge toward the synthesis of a new library of anionic dendrons with different chemical groups at their focal point. The latter strategy provides interesting building blocks with a wide variety of possibilities regarding further coupling with biological systems or the preparation of new Janus-type dendrimers.

Figure 1. Skeletons of G2 dendrimers and G1−G3 dendrons used in this work.

a colorless oil, although it contains small amounts of photoinitiator that were later removed in subsequent reaction steps. The 1H NMR spectrum of compound 1 confirms statistical functionalization with one amine group per molecule by means of integration of the signals of the new chain arising from thiol−ene addition. Two different groups of signals can be observed. The first group consists of one chain with three methylenic groups between the terminal silicon atom and the sulfur atom of the cysteamine fragment, with resonances at δ 0.57 (a), 1.54 (b), and 2.57 (c) near the sulfur atom. The second group is that with the two methylenic groups coming from the introduced cysteamine, which appeared at δ 2.92 (d) and 3.22 (e) for the methylene groups bonded β and α to the ammonium group, respectively. A signal for the hydrogens on the nitrogen atom can also be observed, as a broad singlet around δ 8.28 (f). In the 13C NMR spectrum, the same chains can be observed, with resonances at δ 13.2 (a), 22.5 (b), and 23.9 (c) for the first chain and δ 29.0 (d) and 39.0 (e) for the second (see Figure 2). As these signals refer to only 1 equiv in a second-generation dendrimer, which contains 15 allyl groups, their intensities are very low, especially in 13C NMR, and some of them will be hidden by other signals after further functionalization of the periphery. Functionalization with sulfonate or carboxylate groups was performed using a thiol−ene chemistry protocol, as previously reported elsewhere for the preparation of homofunctionalized dendrimers.40 The desired compound with both an amine and sulfonate groups G2Si(NH2)[(CH2)3SO3Na]15 (2) was obtained after addition of HS(CH2)3SO3Na over the remaining allyl fragments and subsequent treatment with NaOH for the neutralization of the ammonium group. The analogous system containing carboxylate groups G2Si(NH2)(CH2CO2Na)15 (4) was formed by addition of HSCH2COOMe to the allyl precursor, affording G2Si(NH3Cl)(CH2COOMe)15 (3) as a colorless oil, and subsequent reaction with NaOH. Products 2 and 4 were both isolated as white solids in moderate yields (60−70%) (see Scheme 1). The 1H and 13C NMR spectra reveal the expected signals for functionalization with these fragments, as previously reported.40

2. RESULTS AND DISCUSSION In order to simplify the dendrimer and dendron nomenclature, a number of abbreviations will be used in this work. In general, the employed nomenclature is of type GnSiYm for dendrimers and XGn(Y)m for dendrons, where Gn stands for the dendritic generation and (Y)m for the peripheral function and its number. Si denotes the silicon atom core, for dendrimers, and X refers to the nature of the focal point, in the case of dendrons (Figure 1). Statistically Heterofunctionalized Anionic Carbosilane Dendrimers. With the allyl-terminated carbosilane dendrimer G2SiA16, described elsewhere,42 as the starting material, where A denotes allyl groups, “click” thiol−ene addition 43 has been used to introduce two different functionalities. Treatment with 1 equiv of cysteamine hydrochloride over a solution of dendrimer G2SiA16 in a THF/ MeOH mixture (1/3), in the presence of 0.1 molar % of DMPA as photoinitiator, and stirring under a UV lamp with λmax 365 nm for 30 min afforded G2Si(NH3Cl)A15 (1) (see Scheme 1) containing, statistically, one ammonium group per molecule. This product is formed in almost quantitative yield as 3978

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Scheme 1. Synthesis of Statistically Heterofunctionalized Dendrimers 1−4 via Thiol−Ene Addition

Figure 2. 1H (A) and 13C (B) NMR spectra of the statistically heterofunctionalized dendrimer G2Si(NH3Cl)A15 (1).

NMR signals of cysteamine fragment are hidden in the 1H NMR spectrum but can be observed as low-intensity resonances in the 13C NMR spectrum (see Figures S3−S5 in the Supporting Information).

Afterward, compound 2 or 4 was dissolved in DMF and treated with an excess of fluorescein isothiocyanate (FITC) for 18 h inside a dark flask (Scheme 2). DMF was removed under reduced pressure, and excess fluorescein was extracted in EtOH 3979

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Scheme 2. Synthesis of Fluorescein-Labeled Anionic Carbosilane Dendrimers 5 and 6

Figure 3. NMR spectra for statistically bifunctionalized dendrimers containing FITC, 5 (1H (A), 13C (B) and 2D-DOSY (C) NMR) and 6 (1H (D) NMR) in D2O.

A 2D-DOSY experiment confirmed the fluorescein bonding to the dendrimers. In Figure 3C, it can be observed how the different fragments (fluorescein and dendrimer) move in a single front, suggesting the same diffusion coefficient. Therefore, the synthesized products confirm the “click” thiol−ene chemistry approach as an easy, fast, and versatile tool to prepare statistically heterofunctionalized carbosilane dendrimers (see the Supporting Information, Figure S1, for examples of structural representations). Finally, it is worth noting that all the statistically heterofunctionalized anionic carbosilane dendrimers prepared in this section are air- and water-stable.

to afford the compound G2Si[NH(FITC)][(CH2)3SO3Na)]15 (5) or G2Si[NH(FITC)](CH2CO2Na)15 (6) with anionic groups and a molecule of fluorescein covalently attached through a thiourea linker as yellow to orange solids in good yields (80−90%). Due to the covalent attachment of fluorescein, new signals arise in 1H and 13C NMR spectra in the aromatic region, confirming the presence of this fragment (Figure 3). Small changes are observed in the 1H NMR for the methylenic groups directly bonded to the amine group involved in the newly formed bond, being more evident in 13C NMR with the shifting of this signal to ca. δ 50 (b). 3980

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Heterofunctionalized Anionic Carbosilane Dendrons. Regarding the second approach, a family of anionic carbosilane dendrons has been prepared which displays anionic (sulfonate or carboxylate) groups in its periphery with variable focal points. Allyl-terminated dendrons with a bromine atom at the focal point BrGnAm (n = 1, m = 2; n = 2, m = 4; n = 3, m = 8) were used as precursors and synthesized from 1-bromobutene in a sequence of hydrosilylation and Grignard addition reactions, as previously described.17 In this way, the bromine-based focal point and its subsequent functionalization (see below) are separated from the first silicon atom by four methylene groups. Very briefly, the main NMR data of these compounds are the resonances of the CH2Br focal point, consisting of one triplet at ca. δ 3.40 in the 1H NMR spectra and one signal at ca. δ 33.5 in the 13C NMR spectra, and the resonances of peripheral allyl groups, consisting of one doublet at ca. δ 1.54 and two multiplets at ca. δ 4.84 and 5.74 in the 1H NMR spectra and three resonances at ca. δ 21.2, 113.0, and 135.0 in the 13C NMR spectra. From these dendrons, substitution at the focal point of the bromine atoms with different functional groups such as azide, alcohol, alkyne, amine, and carboxylic acid was achieved with the aim of obtaining building blocks able to form stable links such as triazole ring, urea, thiourea, and ether functions or unstable bonds such as ester and amide groups. For the introduction of the azide moiety, a direct method can be employed, as this group does not interfere in the subsequent thiol−ene reaction. Precursors reacted with NaN3 upon heating in DMF to afford the dendrons N3GnAm (n = 1, m = 2 (7); n = 2, m = 4 (8); n = 3, m = 8 (9)) as colorless oils in high yields (see Scheme 3). NMR spectroscopy clearly confirmed

compounds HOGnAm (n = 1, m = 2 (10); n = 2, m = 4 (11); n = 3, m = 8 (12)) were obtained as colorless oils in high yields (Scheme 3). NMR spectroscopy confirmed the change at the focal point (Figure 4) by means of the resonances in the 1H NMR spectra for the new HOCH2CH2O chain at ca. δ 3.68 as a multiplet due to coupling with the OH group and δ 3.48 as one triplet for the other methylene group. A broad signal arising from the HO group can be also observed at ca. δ 2.00. In the 13C NMR spectra, the appearance of signals at ca. δ 71.7 and 70.9 for the methylenic carbons linked to the oxygen atom that generate the ether bond and at ca. δ 61.7 for the CH2 group bound to the hydroxyl confirms the introduction of this group. The propargyl group was also introduced directly by the addition of an excess of propargyl alcohol previously treated with NaH to produce the sodium salt under inert conditions. The compounds PrgGnAm (n = 1, m = 2 (13); n = 2, m = 4 (14); n = 2, m = 8 (15)) were obtained as colorless oils in moderate yields (Scheme 3). NMR spectroscopy confirmed again the change at the focal point (Figure 4) by means of the resonances in the 1H NMR spectra for the new CH2O group at ca. δ 4.12 and for the hydrogen in the alkyne group at ca. δ 2.40, both as singlets. In the 13C NMR spectra the CH2O group appeared at ca. δ 58.0 and the two signals for the unsaturated bond appeared at ca. δ 80.0 and 74.0. However, for the inclusion of −NH2 and −COOH at the focal point, it was not possible to accomplish a direct reaction, as it required the formation of intermediates such as the phthalimide (Pht) fragment for primary amines −NH2 or azide groups for carboxylic acids −COOH. In this way, addition of KPht to solutions of dendrons BrG n A m led to the corresponding modified dendrons PhtGnAm (n = 1, m = 2 (16); n = 2, m = 4 (17); n = 3, m = 8 (18)) upon heating in DMF in high yields (Scheme 3). Again, NMR spectroscopy confirmed introduction of the phtalimide group at the focal point (Figure 4), appearing in the 1H NMR spectra as one triplet at ca. δ 3.61 for the CH2N group and one resonance at ca. δ 37.4 for the carbon atom of this group in the 13C NMR spectra. The phtalimide-modified dendrons 16−18 were further reacted with H2NNH2 in EtOH at 80 °C to give the corresponding modified dendrons NH2GnAm (n = 1, m = 2 (19); n = 2, m = 4 (20); n = 3, m = 8 (21)). The reaction can be followed by 1H NMR spectroscopy by shifting of the triplet for the CH2N group to ca. δ 2.63. Also, one resonance at ca. δ 41.7 for the carbon atom of this group in the 13C NMR spectra confirms this modification (see Figure 4 and Scheme 3). The carboxylic acid group was introduced by reaction of dendrons N3GnAm (7−9) with 5-hexynoic acid through a Huisgen 1,3-dipolar cycloaddition, using 5% CuSO4 and 10% sodium ascorbate in a THF/water mixture, isolating the new dendrons HOOCGnAm (n = 1, m = 2 (22); n = 2, m = 4 (23); n = 3, m = 8 (24)) as yellow oils in moderate yields (Scheme 3). NMR spectroscopy showed the formation of the triazolic ring (Figure 4) by means of the resonances in the 1H NMR spectra at ca. δ 7.30 coupled with its signal in the 13C NMR at ca. δ 134.4. In 13C NMR, one more signal indicates formation of the triazolic ring at ca. δ 146.9 and the presence of a carboxylic acid is observed by a resonance of the carbonyl group at ca. δ 177.7. Once allyl-terminated dendrons with adequate focal points were obtained, we proceeded to modify their periphery via thiol−ene addition. Dendrons of the type PrgGnAm were not used to obtain anionic functionalized systems, as alkyne groups can also suffer thiol−yne addition and therefore are not

Scheme 3. Synthesis of Allyl-Terminated Dendrons with Different Focal Points (7−24)

modification of the focal point (see Figure 4), as the resonance of the initial BrCH2− group was not observed. The presence of the new N3CH2− fragment was identified in the 1H NMR spectra as one triplet at ca. δ 3.20 and in the 13C NMR spectra at ca. δ 51.0. Regarding the hydroxyl group, it can be introduced at the focal point directly by heating mixtures of dendritic starting materials with excess ethylene glycol and NaH. Thus, the 3981

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Figure 4. 1H NMR spectra of first-generation allyl-terminated dendrons with different focal points.

Scheme 4. Thiol−Ene Functionalization with Sulfonate Peripheral Groups (25−34)

orthogonal to the thiol−ene protocol. Therefore, coupling reactions of this group with, for instance, azide groups need to be accomplished prior to surface modification. In the case of dendrons of type NH2GnAm a modification of the direct use of the thiol−ene protocol through the use of a phtalimide intermediate was needed because of the same reason mentioned above. Thus, solutions of dendrons XGnAm (X = N3 (8, 9), HO (11, 12), Pht (17, 18), HOOC (23, 24)) and sodium 3-mercapto-1propanesulfonate in THF/MeOH/H2O were stirred under UV irradiation to afford the new wedges XGn(S(CH2)3SO3Na)m (X = N3, n = 2 and m = 4 (25), n = 3 and m = 8 (26); X = OH, n = 2 and m = 4 (27), n = 3 and m = 8 (28); X = Pht, n = 2 and m = 4 (29), n = 3 and m = 8 (30); X = HOOC, n = 2 and m = 4 (31), n = 3 and m = 8 (32)) (Scheme 4), which were obtained as white solids in high yields. For these reactions the presence of 2,2′-dimethoxy-2-phenylacetophenone (DMPA) as a photoinitiator was necessary. The addition of the thiol to the allyl groups was regioselective at the β-position (vide infra). These compounds were now soluble in water and slightly soluble in other polar solvents as alcohols and DMSO. The NMR spectroscopic and analytical data for derivatives 25−32 were consistent with their proposed structures (see

Figure 5 for an example). The presence of the new chain Si(CH2)3S was confirmed by 1H NMR, which showed two multiplets at ca. δ 1.64 and 2.61 for the protons of the SiCH2CH2CH2S and the CH2S groups, respectively, whereas the resonance of the methylene group bonding the silicon atom is hidden in the multiplet of the other CH2Si in the skeleton. The outer chain S(CH2)3SO3Na was observed as two multiplets at ca. δ 2.68 and 3.00 for the protons of the SCH2 and the CH2SO3 groups, respectively, and also a multiplet about δ 2.03 for the inner methylene of the chain. The carbon atoms of the CH2 groups of the chain Si(CH2)3S were observed in the 13C NMR spectra at ca. δ 13.1 for the SiCH2 group, 24.0 for the −CH2− group, and ca. δ 35.2 for the CH2S group, whereas those belonging to the chain S(CH2)3SO3 appeared at ca. δ 30.3 for the SCH2 group and ca. δ 50.1 for the CH2SO3 group while the methylene group at the β position with respect to both S atoms appeared at ca. δ 24.5. α-addition could not be observed for any generation of the dendrons, because the associated doublet at 1.20 ppm in the 1H NMR spectra is overlapped with the resonances of the intermediate alkyl chains. In other similar compounds, the integration of this resonance indicated less than 3% formation of this function.43 However, as thiol−ene modification of the periphery is performed in order 3982

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NH2Gn(S(CH2)3SO3Na)m (n = 2, m = 4 (33); n = 3, m = 8 (34)) in good yields. The presence of the new focal point NH2CH2− in dendrons 33 and 34 was clearly identified by NMR spectroscopy by means of the new triplet at ca. δ 2.65 in the 1H NMR for the CH2N of the focal point and by the resonance at ca. δ 41.9 in the 13C NMR spectra for the carbon atom of this group (see Figure S9 in the Supporting Information). In a similar way, solutions of dendrons XGnAm (X = N3 (8, 9), HO (11, 12), HOOC (23, 24)) and methyl thioglycolate in THF/MeOH were stirred under UV irradiation to afford the new wedges XGn(SCH2CO2CH3)m (X = N3, n = 2 and m = 4 (35), n = 3 and m = 8 (36); X = OH, n = 2 and m = 4 (37), n = 3 and m = 8 (38); X = HOOC, n = 2 and m = 4 (39), n = 3 and m = 8 (40)) (Scheme 5), which were obtained as colorless oils in high yields. For these reactions the presence of a photoinitiator was not necessary. To obtain the analogous derivatives with NH2 at the focal point, direct thiol−ene addition of methyl thioglycolate proved to be unsuccessful. The presence of a free amine group at the focal point of the dendron can interfere in the stabilization of the formed radicals; therefore, treatment of dendrons (NH2)GnAm (17, 18) with HCl was necessary prior to thiol−ene addition, forming the ammonium salts. The presence of DMPA as photoinitiator was also needed for these compounds, affording after neutralization of the focal point with K2CO3 dendrons of the type NH2Gn(SCH2CO2CH3)m (n = 2, m = 4 (41); n = 3, m = 8 (42)) as colorless oils in high yields. Compounds 35−42 were all soluble in organic polar solvents such as alcohols, THF, and Et2O. The NMR spectroscopic and analytical data for derivatives 35−42 were consistent with their proposed structures (see Figure 5 for an example). The presence of the new chain Si(CH2)3S was confirmed by 1H NMR, which showed two multiplets at ca. δ 1.48 and 2.54 for the protons of the SiCH2CH2CH2S and the CH2S groups, respectively, whereas the resonance of the methylene group bonding the silicon atom is again hidden within the multiplet of the other CH2Si groups in the skeleton. The outer chain SCH2CO2CH3 was observed as two singlets at ca. δ 3.12 and 3.64 for the protons of the

Figure 5. 1H NMR spectra of sulfonate (25, top), methyl ester (35, middle), and carboxylate (43, bottom) terminated second-generation dendrons with an azide group at the focal point. Asterisks (*) denote the carbosilane scaffold.

to obtain anionic decorated compounds, the presence of αaddition products does not interfere in the subsequent properties of the dendrons. Removal of the protecting Pht group of dendrons to generate others with an −NH2 function at the focal point was achieved by addition of hydrazine to dendrons 29 and 30, giving

Scheme 5. Thiol−Ene Functionalization with Methyl Ester (35−42) and Carboxylate (43−50) Peripheral Groups

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Scheme 6. Synthesis of Fluorescein-Labeled Anionic Carbosilane Dendrons 51 and 52

of the biodistribution when a fluorescent probe or a contrast agent is attached in both types of arquitectures. Regarding the synthetically controlled approach, a versatile and simple procedure has been developed for the synthesis of a library of anionic carbosilane dendrons. Taking into account the chemical diversity at the focal point for both neutral and anionic terminated dendrons, such as −N3, −OH, −NH2, −Br, −COOH, or −alkyne, these dendritic systems may act as building blocks for obtaining more original dendritic architectures. In this way, different strategies can be accomplished through formation of stable links such as a triazole ring, urea, thiourea, and ether functions or unstable bonds such as ester and amide groups, allowing their combination with both small molecules (such as drugs, peptides, and organometallic and coordination complexes, among others) and nanoscale building blocks (such as antibodies, DNA, nanoparticles, and nanotubes, in addition to hybrid systems as Janus-type dendrimers).

SCH2 and the OCH3 groups, respectively. The carbon atoms of the CH2 groups of the chain Si(CH2)3S were observed in the 13 C NMR spectra at resonances similar to those of the sulfonate-modified dendrons, at ca. δ 13.1 for the SiCH2 group, at δ 24.4 for the inner methylene group, and at ca. δ 36.1 for the CH2S group, whereas those belonging to the acrylate moiety appeared at ca. δ 33.1 for the SCH2 group, δ 52.0 for the OCH3 group, and δ 170.0 for the carboxylic carbon. The anionic derivatives were easily obtained by treatment of XGn(SCH2CO2CH3)m dendrons with an excess of NaOH in MeOH. Thus, the compounds XGn(SCH2CO2Na)m (X = N3, n = 2 and m = 4 (43), n = 3 and m = 8 (44); X = OH, n = 2 and m = 4 (45), n = 3 and m = 8 (46); X = HOOC, n = 2 and m = 4 (47), n = 3 and m = 8 (48); X = NH2, n = 2 and m = 4 (49), n = 3 and m = 8 (50)) were obtained as white solids in moderate yields and all were soluble in water. The peripheral modification was followed by means of the disappearance of the resonance of the OCH3 group in both 1H and 13C NMR and the shift of the SCH2CO and CH2S signals in 13C to ca. δ 36.8 and 35.8, respectively, along with that the carboxylate group to ca. δ 178.0 as a result of the delocalization of the negative charge. Finally, as an example of bifunctionalization using this approach, anionic carbosilane dendrons containing FITC at the focal point have been synthesized. By a procedure analogous to that used for statistically heterofunctionalized anionic carbosilane dendrimers, fluorescein isothiocyanate (FITC) was reacted with NH2Gn(S(CH2)3SO3Na)m (n = 2, m = 4 (33); n = 3, m = 8 (34)) to afford (FITC)Gn(S(CH2)3SO3Na)m (n = 2, m = 4 (51); n = 3, m = 8 (52)) (see Scheme 6). 1H and 13C NMR spectroscopy of these compounds confirms the coupling with FITC by means of the occurrence of new signals in the aromatic region arising from the FITC scaffold, between δ 7.60 and 6.95 in 1H and between δ 132 and 128 in 13C, and the shifting of the methylene group bound directly to the N atom of the carbosilane dendron, which can be followed in 13C NMR to ca. δ 54 (see Figure S6 in the Supporting Information). Again, all of the heterofunctionalized anionic carbosilane dendrimers prepared in this section are air- and water-stable.

4. EXPERIMENTAL SECTION 4.1. General Methods. Unless otherwise stated, reagents were obtained from commercial sources and used as received. The compounds GnXYm (X = Si, Y = allyl) were synthesized as reported.17,39,44−48 Thiol−ene reactions were carried out employing a HPK 125 W mercury lamp from Heraeus Noblelight with maximum energy at 365 nm, in normal glassware under an inert atmosphere. NMR spectra were recorded on a Varian Unity VXR-300 spectrometer (300.13 (1H), 75.47 (13C) MHz) or on a Bruker AV400 spectrometer (400.13 (1H), 100.60 (13C), 79.49 (29Si) MHz). Chemical shifts (δ) are given in ppm. 1H and 13C resonances were measured relative to solvent peaks considering TMS 0 ppm; meanwhile, 29Si resonances were measured relative to external TMS. When necessary, assignment of resonances was done from HSQC, TOCSY, and DOSY NMR experiments. Elemental analyses were performed on a PerkinElmer 240C instrument. Mass spectra were obtained from an Agilent 6210 spectrometer (ESI). Only second -generation systems are described in this section. Descriptions for the rest of the prepared compounds can be found in the Supporting Information along with other data of interest. 4.2. Statistically Heterofunctionalized Dendrimers. 4.2.1. G2Si((CH2)3SCH2CH2NH3Cl)A15 (1). A solution in a THF/ MeOH mixture (1/2) of the dendrimer G2SiA16 (0.506 g, 0.29 mmol) was prepared, and 1 equiv of cysteamine hydrochloride (HSCH2CH2NH3Cl, 0.034 g, 0.29 mmol) and 0.007 g of DMPA as photoinitiator were added. The solution was deoxygenized with an argon current for 3 min, and the reaction was carried out under an UV light for 30 min. After evaporation of the solvents, compound 1 was obtained as a yellow oil (0.62 g, 100%). 1H NMR (CDCl3): δ 8.28 (3 H, s, NH3), 5.78 (15 H, m, SiCH2CHCH2), 4.82 (30 H, dd, SiCH2CHCH2), 3.22 (2 H, t, CH2NH3), 2.92 (2 H, t, SCH2CH2NH3), 2.57 (2 H, t, SiCH2CH2CH2S), 1.56 (30 H, d, SiCH2CHCH2), 1.54 (2 H, m, SiCH2CH2CH2S), 1.33 (24 H, m, SiCH2CH2CH2Si), 0.57 (50 H, t, SiCH2), 0.02 (24 H, s, SiMeCH2CH2CH2S), −0.07 (12 H, s, SiMe). 13C{1H} NMR (CDCl3): δ 134.7 (SiCH2CHCH2), 113.1 (SiCH2CHCH2), 39.0 (CH2NH3), 29.0 (SCH2CH2NH3), 23.9 (SiCH2CH2CH2S), 22.5 (SiCH2CH2CH2S), 21.5 (SiCH2CHCH2), 19.1−17.7 (SiCH2, SiCH2CH2CH2Si), 13.2 (SiCH2CH2CH2S), −4.9 (SiMe), −5.6 (SiMeCH2CHCH2).

3. CONCLUSIONS “Click” chemistry based on thiol−ene synthetic protocols has been used to successfully bifunctionalize anionic carbosilane dendritic structures in two effective ways. The first consists of the formation of a statistically heterofunctionalized dendrimer, while the second consists of the synthesis of heterofunctionalized dendrons. Without taking into account the distinct polydispersity shown by these systems, which can be an important parameter to be considered depending on the type of application they are used in, two different topologies have been prepared with the possibility of including the same two functionalities into the dendritic scaffold. This property could lead to the achievement of different degrees of activities or stabilities when a catalyst or drug is included or a modification 3984

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Organometallics

Article

4.2.2. G2Si((CH2)3SCH2CH2NH2)((CH2)3SCH2CH2CH2SO3Na)15 (2). Compound 1 (0.32 g, 0.14 mmol) was dissolved in a THF/MeOH mixture (3/1), and an aqueous solution of the sodium salt of 3mercapto-1-propanesulfonate (HSCH2CH2CH2SO3Na, 0.43 g, 2.18 mmol) and DMPA (0.06 g, 0.22 mmol) was added in four steps each 1 h. After UV light irradiation over 4 h, 1 equiv of Na2CO3 (0.01 g, 0.14 mmol) was added in order to neutralize the ammonium group. Finally, solvents were removed under vacuum and compound 2 was dissolved in distilled water and purified with a nanofiltration device with cellulose membranes with a cutoff limit MWCO = 1000 Da. After water evaporation compound 2 was obtained as a white solid (0.41 g, 63%). 1H NMR (D2O): δ 3.23 (2 H, t, CH2NH2), 2.99 (32 H, m, CH2SO3Na, SCH2CH2NH2), 2.67 (30 H, m, SCH2CH2CH2SO3Na), 2.64 (32 H, m, SiCH2CH2CH2S, SiCH2CH2CH2S), 2.02 (30 H, m, SCH2CH2CH2SO3Na), 1.62 (30 H, m, SiCH2CH2CH2S), 1.58 (24 H, d, SiCH2CH2CH2Si), 0.66 (80 H, m, SiCH2), 0.01 (36 H, s, SiMe). 13 C{1H} NMR (D2O): δ 49.1 (CH2SO3Na), 38.2 (CH2NH2), 34.4 (SiCH2CH2CH2S), 29.4 (SCH2CH2CH2SO3Na), 28.4 (SCH2CH2NH2), 23.6 (SCH2CH2CH2SO3Na), 23.1 (SiCH2CH2CH2S), 17.7 (SiCH2CH2CH2Si, SiCH2CH2CH2Si), 12.2 (SiCH2CH2CH2S), −5.2 (SiMe), −5.8 (SiMeCH2CH2CH2S). 4.2.3. G2Si((CH2)3SCH2CH2NH3Cl)((CH2)3SCH2CO2CH3)15 (3). Compound 1 (0.31 g, 0.14 mmol) was dissolved in a THF/MeOH mixture (3/1), and the needed amount of methyl thioglycolate was added (HSCH2COOCH3, 0.21 mL, 2.1 mmol). The reaction mixture was stirred under an UV light for 4 h at room temperature. After evaporation of the solvent, compound 3 was purified by means of size exclusion chromatography to afford a yellow oil (0.37 g, 78%). 1H NMR (CDCl3): δ 3.72 (45 H, s, OCH3), 3.20 (30 H, s, SCH2CO), 2.61 (32 H, t, SiCH2CH2CH2S), 1.55 (30 H, m, SiCH2CH2CH2S), 1.26 (24 H, m, SiCH2CH2CH2Si), 0.55 (80 H, m, SiCH2), −0.06 (24 H, s, SiMeCH2CH2CH2S), −0.09 (12 H, s, SiMe). 13C{1H} NMR (CDCl3): δ 170.9 (CO), 52.3 (OCH3), 36.3 (SiCH2CH2CH2S), 33.3 (SCH2CO), 23.6 (SiCH2CH2CH2S), 19.2−17.6 (SiCH2CH2CH2Si, SiCH2CH2CH2Si), 13.3 (SiCH2CH2CH2S), −5.1 (SiMe), −5.2 (SiMeCH2CH2CH2S). 4.2.4. G2Si((CH2)3SCH2CH2NH2)((CH2)3SCH2CO2Na)15 (4). Compound 3 (0.37 g, 0.108 mmol) was dissolved in a THF/MeOH mixture (1/3), and an excess (3 equiv per methyl ester group) of NaOH (0.19 g, 0.013 mol) was added. The solution was stirred overnight. Solvents were removed under vacuum pressure, and compound 4 was obtained and dissolved in water and purified by nanofiltration with cellulose membranes with a cutoff limit of MWCO = 1000. Water was removed under vacuum, and compound 4 was isolated as a white solid (0.32 g, 85%). 1H NMR (D2O): δ 3.22 (30 H, s, SCH2CO), 2.61 (32 H, t, SiCH2CH2CH2S), 1.63 (32 H, m, SiCH2CH2CH2S), 1.41 (24 H, m, SiCH2CH2CH2Si), 0.65 (80 H, m, SiCH2CH2CH2Si(Me)CH2CH2CH2S), 0.04 (36 H, s, SiMe). 13C{1H} NMR (D2O): δ 177.0 (CO), 37.7 (CH2NH2), 36.1 (SCH2CO), 35.0 (SiCH2CH2CH2S), 29.5 (SCH2CH2NH2), 22.5 (SiCH2CH2CH2S), 17.7 (SiCH2CH2CH2S, SiCH2CH2CH2Si, SiCH2CH2CH2Si), 12.3 (SiCH2CH2CH2S), −5.9 (SiMe). 4.2.5. G2Si((CH2)3SCH2CH2NHFITC)((CH2)3SCH2CH2CH2SO3Na)15 (5). Compound 2 (0.20 g, 0.04 mmol) was dissolved in DMF in a dark flask, and 1.2 equiv of fluorescein isothiocyanate (FITC, 0.019 g, 0.05 mmol) was added in the presence of NEt3 (0.1 mL). The reaction mixture was protected from light and stirred overnight at room temperature. The next day, the solvent was removed under reduced pressure and the excess FITC was extracted with EtOH. Compound 5 was dried under vacuum and obtained as a yellow-orange solid (0.18 g, 93%). 1H NMR (D2O): δ 7.92−7.63−7.23−6.68 (9 H, m, FITC), 3.84 (1 H, s, NH), 3.73 (2 H, m, SCH2CH2NH), 2.99 (30 H, m, CH2SO3Na), 2.85 (2 H, m, SCH2CH2NH), 2.66 (30 H, m, SCH2CH2CH2SO3Na), 2.59 (32 H, m, SiCH2CH2CH2S), 2.02 (30 H, m, SCH2CH2CH2SO3Na), 1.59 (30 H, m, SiCH2CH2CH2S), 1.37 (24 H, d, SiCH2CH2CH2Si), 0.64 (80 H, m, SiCH2), 0.00 (36 H, s, SiMe). 13C{1H} NMR (D2O): δ 224.3 (CS), 171.0 (CO), 130.1− 114.8 (CAr-FITC), 50.1 (CH2SO3Na), 49.3 (CH2NH), 36.0 (SCH2CH2NH), 35.3 (SiCH2CH2CH2S), 30.3 (SCH 2 CH 2 CH 2 SO 3 Na), 24.5 (SCH 2 CH 2 CH 2 SO 3 Na), 24.0

(SiCH2CH2CH2S), 19.3−17.6 (SiCH2CH2CH2Si, SiCH2CH2CH2Si), 13.2 (SiCH2CH2CH2S), −4.2 (SiMe), −4.9 (SiMeCH2CH2CH2S). Anal. Calcd for C164H311N2Na15O50S32Si13 (4847.25 g/mol): C, 40.64; H, 6.47; N, 0.58; S, 21.17. Found: C, 42.23; H, 6.54; N, 1.02; S, 14.97. 4.2.6. G2Si((CH 2 )3SCH 2CH 2NHFITC)((CH2 )3SCH 2CO 2Na)15 (6). Compound 4 (0.20 g, 0.04 mmol) was dissolved in DMF in a dark flask, and 1.2 equiv of fluorescein isothiocyanate (FITC, 0.019 g, 0.05 mmol) was added in the presence of NEt3 (0.1 mL). The reaction mixture was protected from light and stirred overnight at room temperature. The next day, the solvent was removed under reduced pressure and the excess FITC was extracted with EtOH. Compound 5 was dried under vacuum and obtained as a yellow-orange solid (0.15 g, 90%). 1H NMR (D2O): δ 8.02−7.62−7.17−6.60 (9 H, m, FITC), 3.63 (2 H, m, SCH2CH2NH), 3.19 (30 H, s, SCH2CO), 2.57 (30 H, t, SiCH2CH2CH2S), 1.59 (28 H, m, SiCH2CH2CH2S), 1.37 (24 H, m, SiCH2CH2CH2Si), 0.62 (80 H, m, SiCH2), 0.01 (24 H, s, SiMe). 13 C{1H} NMR (D2O): δ 178.0 (CO), 171.7 (CO-FITC), 131.3−112.3 (CAr-FITC), 53.1 (CH2NH), 36.9 (SCH2CO), 35.9 (SCH2CH2NH), 32.5 (SiCH 2 CH 2 CH 2 S), 23.6 (SiCH 2 CH 2 CH 2 S), 18.6−17.7 (SiCH2CH2CH2Si, SiCH2CH2CH2Si), 13.1 (SiCH2CH2CH2S), −4.3 (SiMe), −5.0 (SiMeCH2CH2CH2S). Anal. Calcd for C149H251N2Na15O35S17Si13 (3885.64 g/mol): C, 50.32, H, 8.45, N, 0.41, S, 15.03. Found: C, 49.36, H, 8.25, N, 2.39, S, 12.94. 4.3. Heterofunctionalized Dendrons. In order to simplify the description of the preparations, the thiol−ene addition protocols are described as a general protocol for the functionalization of allylterminated dendrons bearing different focal points with sulfonate and carboxylate groups. Whenever a deviation from these protocols was needed, this is described in the preparation of the selected compound. The amounts of reagents and the obtained yields are specified below. 4.3.1. General Procedure for Thiol−Ene Functionalization with Sulfonate Groups. The starting dendron with allyl groups at the periphery was dissolved in a THF/MeOH mixture (1.5:0.5 mL), and a 0.5 mL aqueous solution containing 1.2 equiv of HSCH2CH2CH2SO3Na per each allyl group was prepared. Over the dendron solution, a fourth of the aqueous solution was added along with 0.025%molar % of photoinitiator (2,2-dimethoxy-2-phenylactenophenone, DMPA). The mixture was deoxygenized and stirred under UV light for 1 h. The aqueous solution was added stepwise each 1 h with the photoinitiator. The total irradiation time was 4 h. Afterward, solvents were removed under vacuum and the products were dissolved in distilled water and purified by nanofiltration with cellulose membranes with a cutoff limit MWCO = 500−1000 Da. Finally, water was removed and the desired products were obtained as white solids with moderate yields (60−70%). 4.3.2. General Procedure for Thiol−Ene Functionalization with Methyl Ester Groups. The starting dendron with allyl groups at the periphery was dissolved in a THF/MeOH mixture (1.5/0.5 mL), and the stoichiometric amount of HSCH2COOCH3 (methyl thioglycolate) was added. The mixture was stirred under UV light for 4 h. Afterward, solvents were removed under reduced pressure and the products were purified by size exclusion chromatography in THF. The desired compounds were obtained as yellow oils in high yields (>90%). 4.3.3. General Procedure for Conversion of Methyl Ester to Carboxylate Groups. Dendrons with methyl ester groups at their periphery were dissolved in a THF/MeOH mixture (1/3), and an excess of NaOH was added (3 equiv per methyl ester group). The mixtures were stirred overnight at room temperature. Afterward, solvents were removed and the products were dissolved in distilled water and purified by nanofiltration with cellulose membranes with a cutoff limit MWCO = 500−1000 Da. Finally, water was evaporated and the desired compounds were dried under vacuum to give the products as white solids with moderate yields (60−70%). 4.3.4. Dendrons with an Azide Group at the Focal Point. 4.3.4.1. N3GnAm. BrGnAm was treated with a 3-fold excess of NaN3 in DMF in the presence of 0.1% of NaI for 18 h at 90 °C. The desired products were extracted in Et2O. Organic phase was dried over anhydrous MgSO4 and solvent was removed under reduced pressure to obtain the dendrons as colorless oils in high yields (80−90%). 3985

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(83%). 1H NMR (CDCl3): δ 5.72 (4 H, m, SiCH2CHCH2), 4.78 (8 H, m, SiCH2CHCH2), 3.66 (2 H, m, HOCH2CH2O), 3.49 (2 H, q, HOCH2CH2O), 3.44 (2 H, t, OCH2CH2CH2CH2Si), 1.55 (2 H, m, OCH2CH2CH2CH2Si), 1.55 (8 H, d, SiCH2CHCH2), 1.30 (6 H, m, OCH 2 CH 2 CH 2 CH 2 Si, SiCH 2 CH 2 CH 2 Si), 0.56 (10 H, m, OCH2CH2CH2CH2Si, SiCH2), −0.05 (6 H, s, SiMeCH2CHCH2), −0.09 (3 H, s, SiMeCH2CH2CH2Si). 13C{1H} NMR (CDCl3): δ 134.7 (SiCH2CHCH2), 113.0 (SiCH2CHCH2), 71.8 (HOCH2CH2O), 71.0 (OCH2CH2CH2CH2Si), 61.7 (HOCH2CH2O), 33.6 (OCH2CH2CH2CH2Si), 21.4 (SiCH2CHCH2), 20.5 (OCH 2 CH 2 CH 2 CH 2 Si), 18.6−17.5 (SiCH 2 CH 2 CH 2 Si), 13.8 (OCH2CH2CH2CH2Si), −5.1 (SiMeCH2CH2CH2Si), −6.0 (SiMeCH2CHCH2). Anal. Calcd for C27H54O2Si3 (494.97 g/mol): C, 65.52, H, 11.00. Found: C, 65.52; H, 10.78. ESI-MS: [M + H]+ = 495.35, [M + NH4]+ = 512.37, [M + Na]+= 517.33. 4.3.5.2. HOG2[(CH2)3SCH2CH2CH2SO3Na]4 (27). Reagents: 11 (0.31 g, 0.63 mmol), sodium 3-mercapto-1-propanesulfonate (0.55 g, 2.52 mmol), DMPA (0.06 g, 0.02 mmol). Yield: 0.54 g (72%). 1H NMR (D 2 O): δ 3.72 (2 H, m, HOCH 2 CH 2 O), 3.59 (2 H, m, HOCH2CH2O), 3.55 (2 H, m, OCH2CH2CH2CH2), 2.99 (8 H, m, SCH2CH2CH2SO3Na), 2.68 (8 H, m, SCH2CH2CH2SO3Na), 2.61 (8 H, m, SiCH2CH2CH2S), 2.03 (8 H, m, SiCH2CH2CH2SO3Na), 1.63 (10 H, m, OCH2CH2CH2CH2Si, SiCH2CH2CH2S), 1.42 (6 H, m, OCH2CH2CH2CH2Si, SiCH2CH2CH2Si), 0.66 (18 H, m, CH2Si), 0.04 (9 H, s, SiCH3). 13C{1H} NMR (D2O): δ 71.6 (HOCH2CH2O), 70.9 (OCH 2 CH 2 CH 2 CH 2 Si), 60.5 (HOCH 2 CH 2 O), 50.1 (SCH2CH2CH2SO3Na), 35.2 (SiCH2CH2CH2S), 33.0 (OCH 2 CH 2 CH 2 CH 2 Si), 30.3 (SCH 2 CH 2 CH 2 SO 3 Na), 24.5 (SCH2CH2CH2SO3Na), 24.0 (SiCH2CH2CH2S), 18.5 (SiCH2CH2CH2Si), 13.1 (SiCH2), −4.4 (SiMeCH2CH2CH2Si), −4.9 (SiMeCH2CH2CH2S). Anal. Calcd for C39H82Na4O14S8Si3 (1207.80 g/ mol): C, 38.78; H, 6.84; S, 21.24. Found: C, 39.24; H, 5.72; S, 16.45. 4.3.5.3. HOG2[(CH2)3SCH2CO2CH3]4 (37). Reagents: 11 (0.31 g, 0.63 mmol), methyl thioglycolate (0.25 mL, 2.53 mmol). Yield: 0.55 g (95%). 1H NMR (CDCl3): δ 3.67 (14 H, s, OCH3, HOCH2CH2O), 3.47 (2 H, t, HOCH2CH2O), 3.41 (2 H, t, OCH2CH2CH2CH2Si), 3.16 (8 H, s, SCH2CO), 2.57 (8 H, t, SiCH2CH2CH2S), 1.79 (2 H, q, OCH2CH2CH2CH2Si), 1.51 (8 H, m, SiCH2CH2CH2S), 1.22 (6 H, SiCH2CH2CH2Si, OCH2CH2CH2CH2Si), 0.51 (18 H, s, SiCH2), −0.10 (6 H, s, SiMeCH 2 CH 2 CH 2 S), −0.13 (3 H, s, SiMeCH2CH2CH2Si). 13C{1H} NMR (CDCl3): δ 170.9 (CO), 71.6 (HOCH2CH2O), 71.0 (OCH2CH2CH2CH2Si), 61.7 (HOCH2CH2O), 52.3 (OCH3), 36.3 (SiCH2CH2CH2S), 33.3 (SCH2CO), 32.2 (OCH2CH2CH2CH2Si), 23.6 (SiCH2CH2CH2S), 20.5 (OCH 2 CH 2 CH 2 CH 2 Si), 18.6−18.3 (SiCH 2 CH 2 CH 2 Si), 13.3 (OCH2CH2CH2CH2Si, SiCH2CH2CH2S), −5.2 (SiMeCH2CH2CH2Si), −5.3 (SiMeCH2CH2CH2S). 4.3.5.4. HOG2[(CH2)3SCH2CO2Na]4 (45). Reagents: 37 (0.55 g, 0.60 mmol), NaOH (0.30 g, 2.54 mmol). Yield: 0.39 g (68%). 1H NMR (D2O): δ 3.70 (2 H, t, HOCH2CH2O), 3.57 (2 H, t, HOCH2CH2O), 3.53 (2 H, t, OCH2CH2CH2CH2Si), 3.45 (1 H, s, HO), 3.18 (8 H, s, SCH2CO), 2.57 (8 H, t, SiCH2CH2CH2S), 1.60 (10 H, m, OCH2CH2CH2CH2Si, SiCH2CH2CH2S), 1.39 (6 H, SiCH2CH2CH2Si, OCH2CH2CH2CH2Si), 0.62 (18 H, m, SiCH2), −0.01 (9 H, s, SiMe). 13C{1H} NMR (D2O): δ 178.1 (CO), 71.4 (HOCH2CH2O), 70.8 (OCH2CH2CH2CH2Si), 60.4 (HOCH2CH2O), 36.8 (SiCH2CH2CH2S), 35.7 (SCH2CO), 31.7 (OCH2CH2CH2CH2Si), 23.5 (SiCH2CH2CH2S), 20.1 (OCH 2 CH 2 CH 2 CH 2 Si), 18.4−18.0 (SiCH 2 CH 2 CH 2 Si), 13.5 (OCH 2 CH 2 CH 2 CH 2 Si), 13.0 (SiCH 2 CH 2 CH 2 S), −5.3 (SiMeCH2CH2CH2Si), −5.4 (SiMeCH2CH2CH2S). Anal. Calcd for C35H66Na4O10S4Si3 (951.37 g/mol): C, 44.19; H, 6.99; S, 13.48. Found: C, 43.89; H, 6.46; S, 11.21. 4.3.6. Dendrons with a Propargyl Group at the Focal Point. 4.3.6.1. PrgGnAm. An excess of propargyl alcohol was treated with NaH in dried THF at 0 °C for 1 h. Afterward, BrGnAm was added dropwise in dried THF under an argon atmosphere and the mixture was stirred for 18 h at 80 °C. Solvents were removed, and the crude product was extracted in Et2O to provide the desired products in high

Data for N3G2A4 (8) are as follows. Reagents: BrG2A4 (4.00 g, 7.78 mmol), NaN3 (1.52 g, 23.0 mmol), NaI. Yield: 3.16 g (85%). 1H NMR (CDCl3): δ 5.76 (4 H, m, SiCH2CHCH2), 4.82 (8 H, m, SiCH2CHCH2), 3.26 (2 H, t, N3CH2CH2CH2CH2Si), 1.61 (2 H, q, N3CH2CH2CH2CH2Si), 1.53 (8 H, d, SiCH2CHCH2), 1.33 (6 H, m, N 3 CH 2 CH 2 CH 2 CH 2 Si, SiCH 2 CH 2 CH 2 Si), 0.59 (10 H, t, NCH2 CH2CH2CH 2Si, SiCH 2CH2 CH 2Si), −0.01 (6 H, s, SiMeCH2CHCH2), −0.06 (3 H, s, SiMeCH2CH2CH2Si). 13C{1H} NMR (CDCl3): δ 134.8 (SiCH2CHCH2), 113.0 (SiCH2CHCH2), 51.0 (N 3 CH 2 CH 2 CH 2 CH 2 Si), 32.6 (N 3 CH 2 CH 2 CH 2 CH 2 Si), 21.4 (SiCH 2 CHCH 2 ), 21.1 (N 3 CH 2 CH 2 CH 2 CH 2 Si), 18.5−18.2 (SiCH2CH2CH2Si), 17.9 (SiCH2CH2CH2Si), 13.5 (NCH2CH2CH2CH2Si), −5.2 (SiMeCH2CH2CH2Si), −5.8 (SiMeCH2CHCH2). Anal. Calcd for C25H49N3Si3 (475.93 g/mol): C, 63.09, H, 10.38, N, 8.83. Found: C, 63.21, H, 9.82, N, 6.97. ESI-MS: [M + H]+ = 476.33. 4.3.4.2. N3G2[(CH2)3SCH2CH2CH2SO3Na]4 (25). Reagents: 8 (0.30 g, 0.63 mmol), sodium 3-mercapto-1-propanesulfonate (0.55 g, 2.52 mmol), DMPA (0.08 g, 0.25 mmol). Yield: 0.46 g (62%). 1H NMR (D2O): δ 3.36 (2 H, m, N3CH2CH2CH2CH2Si), 3.01 (8 H, m, SCH2CH2CH2SO3Na), 2.69 (8 H, m, SCH2CH2CH2SO3Na), 2.62 (8 H, m, SiCH2CH2CH2S), 2.05 (8 H, m, SCH2CH2CH2SO3Na), 1.63 (10 H, m, SiCH2CH2CH2S, N3CH2CH2CH2CH2Si), 1.38 (6 H, SiCH2CH2CH2Si, N3CH2CH2CH2CH2Si), 0.68 (18 H, m, SiCH2), 0.05 (9 H, m, SiCH 3 ). 1 3 C{ 1 H} NMR (D 2 O): δ 50.8 (N 3 CH 2 CH 2 CH 2 CH 2 Si), 50.1 (SCH 2 CH 2 CH 2 SO 3 Na), 35.2 (SiCH2CH2CH2S), 32.4 (N3CH2CH2CH2CH2Si), 30.3 (SCH 2 CH 2 CH 2 SO 3 Na), 24.5 (SCH 2 CH 2 CH 2 SO 3 Na), 24.0 (SiCH2CH2CH2S), 21.1 (N3CH2CH2CH2CH2Si), 18.5 (SiCH2CH2CH2Si), 13.1 (N3CH2CH2CH2CH2Si, SiCH2CH2CH2S), −5.0 (SiMe). Anal. Calcd for C37H77N3Na4O12S8Si3 (1188.76 g/mol): C, 37.38; H, 6.53; N, 3.53; S, 21.58, Found: C, 36.88; H, 6.93; N, 5.22; S, 17.44. 4.3.4.3. N3G2[(CH2)3SCH2CO2CH3]4 (35). Reagents: 8 (0.32 g, 0.67 mmol), methyl thioglycolate (0.29 mL, 2.69 mmol). Yield: 0.56 g (98%). 1 H NMR (CDCl 3 ): δ 3.61 (14 H, s, OCH 3 , N3CH2CH2CH2CH2Si), 3.09 (8 H, s, SCH2CO), 2.51 (8 H, t, SiCH2CH2CH2S), 1.45 (10 H, m, SiCH2CH2CH2S, N 3 CH 2 CH 2 CH 2 CH 2 Si), 1.15 (6 H, m, SiCH 2 CH 2 CH 2 Si, N3CH2CH2CH2CH2Si), 0.45 (18 H, m, SiCH2), −0.16 (6 H, s, SiMeCH2CH2CH2S), −0.20 (3 H, s, SiMeCH2CH2CH2Si). 13C{1H} NMR (CDCl3): δ 170.1 (CO), 52.0 (OCH3), 50.7 (N3CH2CH2CH2CH2Si), 36.1 (SiCH2CH2CH2S), 33.1 (SCH2CO), 32.4 (N 3 CH 2 CH 2 CH 2 CH 2 Si), 23.4 (SiCH 2 CH 2 CH 2 S), 20.9 (N 3 CH 2 CH 2 CH 2 CH 2 Si), 18.6−18.1 (SiCH 2 CH 2 CH 2 Si), 13.1 (N3CH2CH2CH2CH2Si, SiCH2CH2CH2S), −5.3 (SiMeCH2CH2CH2Si), −5.5 (SiMeCH2CH2CH2S). 4.3.4.4. N3G2[(CH2)3SCH2CO2Na]4 (43). Reagents: 35 (0.56 g, 0.62 mmol), NaOH (0.40 g, 8.07 mmol). Yield: 0.53 (91%). 1H NMR (D2O): δ 3.35 (2 H, t, N3CH2CH2CH2CH2Si), 3.20 (8 H, s, SCH2CO), 2.90 (2 H, m, N3CH2CH2CH2CH2Si), 2.60 (8 H, t, SiCH2CH2CH2S), 1.62 (10 H, m, SiCH2CH2CH2S, N 3 CH 2 CH 2 CH 2 CH 2 Si), 1.35 (6 H, m, SiCH 2 CH 2 CH 2 Si, N3CH2CH2CH2CH2Si), 0.65 (18 H, m, SiCH2), 0.03 (9 H, m, SiCH 3 ). 1 3 C{ 1 H} NMR (CDCl 3 ): δ 177.0 (CO), 49.9 (N3CH2CH2CH2CH2Si), 35.9 (SCH2CO), 34.9 (SiCH2CH2CH2S), 31.2 (N 3 CH 2 CH 2 CH 2 CH 2 Si), 22.6 (SiCH 2 CH 2 CH 2 S), 20.0 (N 3 CH 2 CH 2 CH 2 C H 2 Si), 17.5 (SiCH 2 CH 2 CH 2 Si), 12.1 (SiCH2CH2CH2S, N3CH2CH2CH2CH2Si), −6.3 (SiMe). Anal. Calcd for C33H61N3Na4O8S4Si3 (932.33 g/mol): C, 42.51; H, 6.59; N, 4.51; S, 13.76. Found: C, 40.97; H, 6.74; N, 6.53; S, 15.87. 4.3.5. Dendrons with an Alcohol Group at the Focal Point. 4.3.5.1. HOGnAm. An excess of ethylene glycol was treated with NaH in dried THF at 0 °C for 1 h. Afterward, BrGnAm was added dropwise in dried THF under argon atmosphere and stirred for 18 h at 80 °C. Solvents were removed and the crude product was extracted in Et2O to provide the desired products in moderate yields (70−80%) as oils. Data for HOG2A4 (11) are as follows. Reagents: BrG2A4 (2.00 g, 3.89 mmol), HOCH2CH2OH (0.65 mL, 11.6 mmol), NaH (0.62 g, 15.5 mmol), crown ether 18C6 (0.20 g, 0.76 mmol), NaI. Yield: 1.60 g 3986

dx.doi.org/10.1021/om500464k | Organometallics 2014, 33, 3977−3989

Organometallics

Article

66.74, H, 11.42, N, 3.11. Found: C, 67.19, H, 11.06, N, 3.18. ESI-MS: [M + H]+ = 450.34. 4.3.8.2. NH2G2[(CH2)3SCH2CH2CH2SO3Na]4 (33). Reagents: 29 (0.51 g, 0.89 mmol), sodium 3-mercapto-1-propanesulfonate (0.84 g, 4.25 mmol), DMPA (0.13 g, 0.42 mmol), hydrazine (0.45 mL, 14.0 mmol). Yield: 0.60 g (60%). 1H NMR (D2O): δ 3.00 (8 H, t, SCH2CH2CH2SO3Na), 2.70 (8 H, t, SCH2CH2CH2SO3Na), 2.62 (10 H, t, SiCH2CH2CH2S, NH2CH2CH2CH2CH2Si), 2.04 (8 H, q, SCH2CH2CH2SO3Na), 1.74 (2 H, m, NH2CH2CH2CH2CH2Si), 1.64 (8 H, m, SiCH2CH2CH2S), 1.44 (6 H, m, SiCH2CH2CH2Si, NH2CH2CH2CH2CH2Si), 0.67 (18 H, m, SiCH2), 0.04 (9 H, m, SiCH3). 13C{1H} NMR (D2O): δ 50.1 (SCH2CH2CH2SO3Na), 39.4 (NH 2 CH 2 CH 2 CH 2 CH 2 Si), 35.3 (SiCH 2 CH 2 CH 2 S), 31.2 (NH 2 CH 2 CH 2 CH 2 CH 2 Si), 30.3 (SCH 2 CH 2 CH 2 SO 3 Na), 24.5 (SCH2CH2CH2SO3Na), 24.0 (SiCH2CH2CH2S), 21.4 (NH 2 CH 2 CH 2 CH 2 CH 2 Si), 18.7 (SiCH 2 CH 2 CH 2 Si), 13.2 (SiCH2CH2CH2S, NH2CH2CH2CH2CH2Si), −4.2 (SiMeCH2CH2CH2Si), −4.9 (SiMeCH2CH2CH2S). Anal. Calcd for C37H79NNa4O12S8Si3 (1162.76 g/mol): C, 38.22; H, 6.85; N, 1.20; S, 22.06, Found: C, 39.00; H, 6.48; N, 3.04; S, 19.15. 4.3.8.3. NH2Gn[(CH2)3SCH2CO2CH3]m. NH2GnAm was disolved in a THF/MeOH mixture (3/1), and 1 equiv of 4 M HCl in dioxane was added. The mixture was stirred for 30 min, and after that methyl thioglycolate was added along with 10 molar % of the photoinitiator DMPA. After 4 h of stirring under UV light, the solvents were removed and the compounds were purified by size exclusion chromatography in THF. Neutralization of the focal point with Na2CO3 was performed in order to give the amine-functionalized products. Data for NH2G2[(CH2)3SCH2CO2CH3]4 (41) are as follows. Reagents: 20 (0.81 g, 1.18 mmol), methyl tioglycolate (0.72 mL, 7.21 mmol), DMPA (0.15 g, 0.61 mmol), HCl (0.45 mL, 4 M in dioxane). Yield: 0.64 g (87%). 1H NMR (CDCl3): δ 3.56 (12 H, s, OCH3), 3.05 (8 H, s, SCH 2 CO), 2.46 (10 H, t, SiCH 2 CH 2 CH 2 S, NH2CH2CH2CH2CH2Si), 1.68 (2 H, m, NH2CH2CH2CH2CH2Si), 1.40 (8 H, m, SiCH2CH2CH2S), 1.10 (6 H, SiCH2CH2CH2Si, NH2CH2CH2CH2CH2Si), 0.41 (18 H, m, SiCH2), −0.20 (6 H, s, SiMeCH2CH2CH2S), −0.24 (3 H, s, SiMeCH2CH2CH2Si). 13C{1H} NMR (CDCl3): δ 170.9 (CO), 52.2 (OCH3), 36.2 (SiCH2CH2CH2S), 3 6 . 0 (N H 2 C H 2 C H 2 C H 2 C H 2 Si), 33.2 (S CH 2 CO), 31.4 (NH 2 CH 2 CH 2 CH 2 CH 2 Si), 23.5 (SiCH 2 CH 2 CH 2 S), 22.9 (NH2 CH2CH2CH2CH2Si), 18.4−18.2 (SiCH2 CH2 CH2Si), 13.2 (SiCH2CH2CH2S, NH2CH2CH2CH2CH2Si), −5.4 (SiCH3). 4.3.8.4. NH2G2[(CH2)3SCH2CO2Na]4 (49). Reagents: 41 (1.03 g, 1.18 mmol), NaOH (0.56 g, 14.2 mmol). Yield: 0.65 g (61%). 1H NMR (D2O): δ 3.17 (8 H, s, SCH2CO), 2.58 (10 H, t, SiCH2CH2CH2S, NH 2 CH 2 CH 2 CH 2 CH 2 Si), 1.61 (10 H, m, SiCH 2 CH 2 CH 2 S, NH 2 CH 2 CH 2 CH 2 CH 2 Si), 1.38 (6 H, m, SiCH 2 CH 2 CH 2 Si, NH2CH2CH2CH2CH2Si), 0.62 (18 H, m, SiCH2), −0.02 (9 H, m, SiCH 3 ). 1 3 C{ 1 H} NMR (CDCl 3 ): δ 178.0 (CO), 38.6 (NH2CH2CH2CH2CH2Si), 36.0 (SCH2CO), 35.0 (SiCH2CH2CH2S), 30.3 (NH2 CH2 CH2 CH 2 CH 2 Si), 22.7 (SiCH 2 CH2 CH2 S), 20.3 (NH 2 CH 2 CH 2 CH 2 CH 2 Si), 17.6 (SiCH 2 CH 2 CH 2 Si), 12.2 (SiCH2CH2CH2S, NH2CH2CH2CH2CH2Si), −5.5 (SiMeCH2CH2CH2Si), −5.9 (SiMeCH2CH2CH2S). Anal. Calcd for C33H63NNa4O8S4Si3 (906.33 g/mol): C, 43.73; H, 7.01; N, 1.55; S, 14.15. Found: 45.36; H, 7.36; N, 3.74; S, 10.25. 4.3.9. Dendrons with a Carboxylic Acid Group at the Focal Point. 4.3.9.1. HOOCGnAm. Allyl-terminated dendrons with an azide group at the focal point were treated with a small excess of 5-hexynoic acid in the presence of sodium ascorbate (40 molar %) and CuSO4 (10 molar %) in a deoxygenated mixture of THF and water over 2 days at 60 °C. The crude products were treated with a 30% aqueous solution of NH4Cl for 30 min, and afterward solvents were removed and the modified dendrons were extracted with AcEt and purified by size exclusion chromatography in THF to provide the desired products in moderate yields (60%) as yellow oils. Products were denoted as HOOCGnAm from first to third generation. Data for HOOCG2A4 (24) are as follows. Reagents: 8 (0.39 g, 1.76 mmol), 5-hexynoic acid (0.24 mL, 2.11 mmol), sodium ascorbate

yields (80−90%) as yellowish oils. Products were named as PrgGnAm from first to third generation. Data for PrgG2A4 (14) are as follows. Reagents: BrG2A4 (3.00 g, 5.84 mmol), HCCCH2OH (0.7 mL, 12.0 mmol), NaH (0.52 g, 13.0 mmol), crown ether 18C6 (0.30 g, 1.16 mmol), NaI. Yield: 2.61 g (91%). 1H NMR (CDCl3): δ 5.69 (4 H, m, SiCH2CHCH2), 4.79 (8 H, m, SiCH2CHCH2), 4.09 (2 H, d, OCH2CCH), 3.48 (2 H, t, OCH2CH2CH2CH2Si), 2.37 (1 H, s, OCH2CCH), 1.58 (2 H, q, OCH2CH2CH2CH2Si), 1.50 (8 H, d, SiCH2CHCH2), 1.30 (6 H, m, OCH 2 CH 2 CH 2 CH 2 Si, SiCH 2 CH 2 CH 2 Si), 0.56 (10 H, m, OCH2CH2 CH2CH2 Si, SiCH 2CH2 CH2 Si), −0.50 (6 H, s, SiMeCH2CHCH2), −0.10 (3 H, s, SiMeCH2CH2CH2Si). 13C{1H} NMR (CDCl3): δ 134.8 (SiCH2CHCH2), 113.0 (SiCH2CHCH2), 80.0 (OCH2CCH), 74.0 (OCH2CCH), 69.8 (OCH2CH2CH2CH2Si), 58.0 (OCH 2 CCH), 33.4 (OCH 2 CH 2 CH 2 CH 2 Si), 21.4 (SiCH 2 CHCH 2 ), 20.5 (OCH 2 CH 2 CH 2 CH 2 Si), 18.6−18.2 (SiCH2CH2CH2Si), 17.8 (SiCH2CH2CH2Si), 13.7 (OCH2CH2CH2CH2Si), −5.1 (SiMeCH2CH2CH2Si), −5.8 (SiMeCH2CHCH2). Anal. Calcd for C28H52OSi3 (488.97 g/mol): C, 68.78, H, 10.72. Found: C, 69.89, H, 11.52. ESI-MS: [M + H]+= 489.34. 4.3.7. Dendrons with a Phthalimide Group at the Focal Point. 4.3.7.1. PhtGnAm. Allyl-terminated dendrons with a bromide group in the focal point were treated with a 3-fold excess of phthalimide potassium salt in DMF and 0.1% of NaI for 18 h at 80 °C. Afterward, DMF was evaporated from the crude mixture and the phthalimidemodified dendrons were extracted in Et2O from distilled water. The organic fractions were washed once with NaCl-saturated water and dried over anhydrous MgSO4. They were filtered, and the solvent was removed under vacuum to provide dendrons as colorless oils in high yields (70−80%). Data for PhtG2A4 (17) are as follows. Reagents: BrG2A4 (0.39 g, 0.76 mmol), potassium phthalimide (0.58 g, 3.06 mmol), NaI. Yield: 0.35 g (78%). 1H NMR (CDCl3): δ 7.83−7.70 (4 H, m, ArH), 5.75 (4 H, m, SiCH2CHCH2), 4.80 (8 H, m, SiCH2CHCH2), 3.66 (2 H, t, NCH2CH2CH2CH2Si), 1.68 (2 H, q, NCH2CH2CH2CH2Si), 1.54 (8 H, d, SiCH 2CHCH2 ), 1.32 (6 H, m, NCH 2CH2CH2 CH2 Si, SiCH 2 CH 2 CH 2 Si), 0.56 (10 H, t, NCH 2 CH 2 CH 2 CH 2 Si, SiCH2CH2CH2Si), 0.03 (6 H, s, SiMeCH2CHCH2), −0.09 (3 H, s, SiMeCH2CH2CH2Si). 13C{1H} NMR (CDCl3): δ 168.3 (CO), 134.8 (SiCH2CHCH2), 133.7 (CH−Ar), 132.1 (Cipso), 123.1 (CH−Ar), 113.0 (SiCH 2 CHCH 2 ), 37.6 (NCH 2 CH 2 CH 2 CH 2 Si), 32.4 (NCH2CH2CH2CH2Si), 21.4 (SiCH2CHCH2), 21.3 (NCH 2 CH 2 CH 2 CH 2 Si), 18.5−18.1 (SiCH 2 CH 2 CH 2 Si), 17.8 (SiCH 2 CH 2 CH 2 Si), 13.5 (NCH 2 CH 2 CH 2 CH 2 Si), −5.2 (SiMeCH2CH2CH2Si), −5.8 (SiMeCH2CHCH2). Anal. Calcd for C33H53NO2Si3 (580.04 g/mol): C, 68.33, H, 9.21, N, 2.41. Found: C, 69.61, H, 8.91, N, 2.40. ESI-MS: [M + H]+ = 580.34. 4.3.8. Dendons with an Amine Group at the Focal Point. 4.3.8.1. NH2GnAm. PhtGnAm dendrons were treated with a 10-fold excess of hydrazine in EtOH at 90 °C for 18 h. When the reaction was complete, excess hydrazine was evaporated under vacuum and the desired product was extracted in hexane. The organic phase was dried over anhydrous MgSO4 and the solvent evaporated to give the modified dendrons as colorless oils in high yields (80−90%). Data for NH2G2A4 (20) are as follows. Reagents: 17 (4.00 g, 6.88 mmol), hydrazine (3.4 mL, 0.19 mol). Yield: 3.01 g (97%). 1H NMR (CDCl3): δ 5.73 (4 H, m, SiCH2CHCH2), 4.79 (8 H, m, SiCH2CHCH2), 2.65 (2 H, t, NCH2CH2CH2CH2Si), 1.53 (8 H, d, SiCH2CHCH2), 1.44 (2 H, q, NCH2CH2CH2CH2Si), 1.31 (6 H, m, NCH 2 CH 2 CH 2 CH 2 Si, SiCH 2 CH 2 CH 2 Si), 0.56 (10 H, m, NCH2 CH2CH2CH 2Si, SiCH 2CH2 CH 2Si), −0.04 (6 H, s, SiMeCH2CHCH2), −0.10 (3 H, s, SiMeCH2CH2CH2Si). 13C{1H} NMR (CDCl3): δ 134.7 (SiCH2CHCH2), 112.9 (SiCH2CHCH2), 41.8 (NCH 2 CH 2 CH 2 CH 2 Si), 37.8 (NCH 2 CH 2 CH 2 CH 2 Si), 21.4 (SiCH 2 CHCH 2 ), 21.2 (NCH 2 CH 2 CH 2 CH 2 Si), 18.6−18.1 (SiCH2CH2CH2Si), 17.8 (SiCH2CH2CH2Si), 13.7 (NCH2CH2CH2CH2Si), −5.2 (SiMeCH2CH2CH2Si), −5.8 (SiMeCH2CHCH2). Anal. Calcd for C25H51NSi3 (449.94 g/mol): C, 3987

dx.doi.org/10.1021/om500464k | Organometallics 2014, 33, 3977−3989

Organometallics

Article

C39H69N3Na4O10S4Si3 (1044.45 g/mol): C, 44.85; H, 6.66; N, 4.02; S, 12.28. Found: C, 43.15; H, 6.72; N, 5.12; S, 9.35. 4.3.10. Dendrons with a Fluorescein Group at the Focal Point. 4.3.10.1. (FITC)G2[(CH2)3SCH2CH2CH2SO3Na]4 (51). A solution in DMF of dendron 33 (0.15 g, 0.13 mmol) was prepared inside a dark flask. A 0.1 mL portion of NEt3 was added, and the solution was stirred for 30 min before the addition of FITC (1.2 equiv, 0.06 g, 0.15 mmol). The mixture was stirred overnight at room temperature. Afterward, the solvent was removed under reduced pressure and FITC in excess was extracted with EtOH. The resulting solid was dried under vacuum to give compound 51 as a yellow-orange solid (0.18 g, 92%). 1H NMR (D2O): δ 7.78, 7.70, 7.05, 6.68 (9 H, m, FITC), 3.42 (2H, m, NHCH2CH2CH2CH2Si), 3.00 (8 H, t, SCH2CH2CH2SO3Na), 2.70 (8 H, t, SCH2CH2CH2SO3Na), 2.62 (10 H, t, SiCH2CH2CH2S), 2.04 (6 H, q, SCH2CH2CH2SO3Na), 1.74 (2 H, m, NHCH2CH2CH2CH2Si), 1.64 (8 H, m, SiCH2CH2CH2S), 1.44 (6 H, m, SiCH2CH2CH2Si, NHCH2CH2CH2CH2Si), 0.67 (18 H, m, SiCH2), 0.04 (9 H, m, SiCH3). 13C{1H} NMR {1H} (D2O): δ 132.1−115.4 (CAr-FITC), 53.8 (NHCH 2 CH 2 CH 2 CH 2 Si), 49.1 (CH 2 SO 3 Na), 35.9 (SiCH2CH2CH2S), 29.5 (SCH2CH2CH2SO3Na), 23.7 (SCH2CH2CH2SO3Na), 23.1 (SiCH2CH2CH2S), 17.6 (SiCH2CH2CH2Si, SiCH2CH2CH2Si), 12.6 (SiCH2CH2CH2S), −5.5 (SiMe).

(0.14 g, 0.70 mmol), copper(II) sulfate (0.03 g, 0.18 mmol). Yield: 0.33 g (56%). 1H NMR (CDCl3): δ 9.53 (1 H, s, HO), 7.29 (1 H, s, C2HN3), 5.75 (4 H, m, SiCH2CHCH2), 4.81 (8 H, m, SiCH2CHCH2), 4.29 (2 H, t, NCH2CH2CH2CH2Si), 2.78 (2 H, t, COCH2CH2CH2), 2.40 (2 H, t, COCH2CH2CH2), 1.99 (2 H, q, COCH2CH2CH2), 1.89 (2 H, q, NCH2CH2CH2CH2Si), 1.52 (8 H, d, SiCH2CHCH2), 1.27 (6 H, m, NCH2CH2CH2CH2Si, SiCH2CH2CH2Si), 0.60−0.53 (10 H, t+t, NCH2 CH2CH2CH 2Si, SiCH 2CH2 CH 2Si), −0.03 (6 H, s, SiMeCH2CHCH2), −0.09 (3 H, s, SiMeCH2CH2CH2Si). 13C{1H} NMR (CDCl 3 ): δ 177.9 (CO), 146.9 (CH 2 CCHN), 134.8 (SiCH2CHCH2), 120.7 (CH2CCHN), 113.0 (SiCH2CHCH2), 49.9 (NCH2CH2CH2CH2Si), 34.1 (NCH2CH2CH2CH2Si, COCH2CH2CH2), 24.6 (COCH2CH2CH2), 24.5 (COCH2CH2CH2), 21.4 (SiCH2CHCH2), 21.0 (NCH2CH2CH2CH2Si), 18.6−17.8 (SiCH 2 CH 2 CH 2 Si), 13.4 (NCH 2 CH 2 CH 2 CH 2 Si), −5.2 (SiMeCH2CH2CH2Si), −5.8 (SiMeCH2CHCH2). Anal. Calcd for C31H57N3O2Si3 (588.06 g/mol): C, 63.32, H, 9.77, N, 7.15. Found: C, 63.91, H, 10.08, N, 4.14. ESI-MS: [M + H]+= 588.38. 4.3.9.2. HOOCG2[(CH2)3SCH2CH2CH2SO3Na]4 (31). Reagents: 24 (0.20 g, 0.33 mmol), sodium 3-mercapto-1-propanesulfonate (0.29 g, 1.34 mmol), DMPA (0.34 g, 1.32 mmol). Yield: 0.23 g (54%). 1H NMR (D 2 O): δ 7.72 (1 H, s, C 2 HN 3 ), 4.40 (2 H, t, NCH2CH2CH2CH2Si), 3.06 (2 H, t, COCH2CH2CH2), 2.97 (8 H, t, SCH2CH2CH2SO3Na), 2.75 (2 H, t, COCH2CH2CH2), 2.64 (8 H, m, SCH2CH2CH2SO3Na), 2.57 (8 H, m, SiCH2CH2CH2S), 2.40 (2 H, q, COCH2CH2CH2), 2.19 (2 H, q, NCH2CH2CH2CH2Si), 2.00 (8 H, m, SCH2CH2CH2SO3Na), 1.58 (8 H, m, SiCH2CH2CH2S), 1.31 (6 H, m, NCH2CH2CH2CH2Si, SiCH2CH2CH2Si), 0.59 (18 H, m, NCH2CH2CH2CH2Si, SiCH2CH2CH2Si), −0.03 (9 H, s, SiMe). 13 C{ 1 H} NMR (D 2 O): δ 50.0 (SCH2 CH 2 CH 2 SO 3 Na), 49.5 (NCH2CH2CH2CH2Si), 35.1 (SiCH2CH2CH2S), 33.2 (NCH2CH2CH2CH2Si, COCH2CH2CH2), 30.2 (SCH2CH2CH2SO3Na), 24.6 (COCH2CH2CH2), 24.4 (SCH2CH2CH2SO3Na), 24.1 (COCH2CH2CH2), 23.9 (SiCH2CH2CH2S), 20.6 (NCH2CH2CH2CH2Si), 18.3 (SiCH2CH2CH2Si), 13.0 (CH2Si), −5.3 (SiMe). Anal. Calcd for C43H85N3Na4O14S8Si3 (1300.88 g/mol): C, 39.70; H, 6.59; N, 3.23; S, 10.72. Found: C, 39.70; H, 6.59; N, 3.23; S, 10.72. 4.3.9.3. HOOCG2[(CH2)3SCH2CO2CH3]4 (39). Reagents: 24 (0.24 g, 0.40 mmol), methyl thioglycolate (0.16 mL, 1.63 mmol). Yield: 0.36 g (89%). 1H NMR (CDCl3): δ 7.71 (1 H, s, CH triazolic ring), 4.42 (2 H, t, NCH2CH2CH2CH2Si), 3.15 (8 H, s, SCH2CO), 3.06 (2 H, t, COCH2CH2CH2), 2.75 (2 H, t, COCH2CH2CH2), 2.58 (8 H, t, SiCH2CH2CH2S), 2.39 (2 H, q, COCH2CH2CH2), 2.19 (2 H, q, NCH2CH2CH2CH2Si), 1.79 (2 H, q, NCH2CH2CH2CH2Si), 1.52 (8 H, m, SiCH 2 CH 2 CH 2 S), 1.24 (6 H, SiCH 2 CH 2 CH 2 Si, NCH2CH2CH2CH2Si), 0.51 (18 H, m, SiCH2), −0.09 (6 H, s, SiMeCH2CH2CH2S), −0.13 (3 H, s, SiMeCH2CH2CH2Si). 13C{1H} NMR (CDCl3): δ 177.9 (CO), 170.9 (CO), 146.9 (CH2CCHN), 120.7 (CH2CCHN), 52.3 (OCH3), 49.9 (NCH2CH2CH2CH2Si), 36.3 (SiCH2CH2CH2S), 34.0 (NCH2CH2CH2CH2Si, COCH2CH2CH2), 33.3 (SCH2CO), 23.6 (SiCH2CH2CH2S), 20.9 (NCH 2 CH 2 CH 2 CH 2 Si), 18.6−17.8 (SiCH 2 CH 2 CH 2 Si), 13.4 (NCH2CH2CH2CH2Si). −5.2 (SiMeCH2CH2CH2Si), −5.3 (SiMeCH2CH2CH2S). 4.3.9.4. HOOCG2[(CH2)3SCH2CO2Na]4 (47). Reagents: 39 (0.36 g, 0.36 mmol), NaOH (0.17 g, 4.27 mmol). Yield: 0.23 g (63%). 1H NMR (D 2 O): δ 7.73 (1 H, s, C 2 HN 3 ), 4.39 (2 H, m, NCH2CH2CH2CH2Si), 3.23 (8 H, s, SCH2CO), 2.63 (10 H, m, SiCH2CH2CH2S, COCH2CH2CH2), 2.22 (2 H, m, COCH2CH2CH2), 1.91 (2 H, q, COCH2CH2CH2), 1.65 (10 H, m, SiCH2CH2CH2S, NCH 2 CH 2 CH 2 CH 2 Si), 1.44 (8 H, m, SiCH 2 CH 2 CH 2 Si, NCH2CH2CH2CH2Si, SiCH2CHCH2), 0.64 (18 H, m, SiCH2), 0.05 (9 H, s, SiCH3). 13C{1H} NMR (D2O): δ 176.9 (CO), 172.2 (COOH), 146.3 (CH 2 CCHN), 120.9 (CH 2 CCHN), 49.1 (NCH2CH2CH2CH2Si), 36.0 (SiCH2CH2CH2S), 34.8 (SCH2CO), 25.0 ( COCH 2 CH 2 CH 2 ) , 23.9 ( COCH 2 CH 2 CH 2 ), 22.9 (SiCH2CH2CH2S), 17.8 (SiCH2CH2CH2Si), 12.3 (SiCH2CH2CH2S), −5.3 (SiCH3CH2CH2CH2Si), −5.8 (SiCH3). Anal. Calcd for

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ASSOCIATED CONTENT

S Supporting Information *

Text and figures giving selected molecular structures, NMR spectra of all compounds, and synthetic protocols of dendrimers and dendrons of generations 1 and 3. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*F.J.d.l.M.: e-mail, [email protected]. *R.G.: fax, (+34) 91 885 4683; e-mail, [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work has been supported by grants from CTQ2011-23245 (MINECO), Consortium NANODENDMED ref S2011/ BMD-2351 (CAM) awarded to R.G. This work was also supported by CIBER-BBN as an initiative funded by VI National R & D & i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions, and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. This work was also supported by the Ministerio de Educación (FPU grants) for M.G. and E.F.

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REFERENCES

(1) Buhleier, E.; Wehner, W.; Vogtle, F. Synthesis 1978, 2, 155. (2) Newkome, G. R.; Yao, Z. Q.; Baker, G. R.; Gupta, V. K. Abstr. Pap., Am. Chem. Soc. 1985, 189, 166. (3) Newkome, G. R.; Yao, Z. Q.; Baker, G. R.; Gupta, V. K. J. Org. Chem. 1985, 50, 2003. (4) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin, S.; Roeck, J.; Ryder, J.; Smith, P. Polym. J. 1985, 17, 117. (5) Denkewalter R. G.; Kolc J.; Lukasavage W. J. U.S. Patent No 4,289,872, 1981. (6) Svenson, S. Eur. J. Pharm. Biopharm. 2009, 71, 445. (7) Astruc, D.; Boisselier, E.; Ornelas, C. Chem. Rev. 2010, 110, 1857. (8) Konkolewicz, D.; Monteiro, M. J.; Perrier, S. b. Macromolecules 2011, 44, 7067. (9) Mintzer, M. A.; Grinstaff, M. W. Chem. Soc. Rev. 2011, 40, 173. (10) Walter, M. V.; Malkoch, M. Chem. Soc. Rev. 2012, 41, 4593. (11) Svenson, S.; Tomalia, D. Adv. Drug Delivery Rev. 2005, 57, 2106. 3988

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Organometallics

Article

(12) Menjoge, A. R.; Kannan, R. M.; Tomalia, D. A. Drug Discovery Today 2010, 15, 171. (13) Medina, S. H.; El-Sayed, M. E. H. Chem. Rev. 2009, 109, 3141. (14) Aljamal, K.; Ramaswamy, C.; Florence, A. Adv. Drug Deliver. Rev. 2005, 57, 2238. (15) Wong, S.; Appelhans, D.; Voit, B.; Scheler, U. Macromolecules 2001, 34, 678. (16) van Heerbeek, R.; Reek, J. N. H.; Paul, C. J. K.; van Leeuwen, P. W. N. M. Tetrahedron 1999, 40, 7127. (17) Sánchez-Nieves, J.; Ortega, P.; Muñoz-Fernández, M. Á .; Gómez, R.; de la Mata, F. J. Tetrahedron 2010, 66, 9203. (18) Andrés, R.; de Jesús, E.; de la Mata, F. J.; Flores, J. C.; Gómez, R. Eur. J. Inorg. Chem. 2005, 3742. (19) Caminade, A. M.; Laurent, R.; Delavaux-Nicot, B.; Majoral, J. P. New J. Chem. 2012, 36, 217. (20) Wu, P.; Malkoch, M.; Hunt, J. N.; Vestberg, R.; Kaltgrad, E.; Finn, M. G.; Fokin, V. V.; Sharpless, K. B.; Hawker, C. J. Chem. Commun. 2005, 5775. (21) Paez, J. I.; Martinelli, M.; Brunetti, V.; Strumia, M. C. Polymers 2012, 4, 355. (22) Walter, M. V.; Lundberg, P.; Hult, A.; Malkoch, M. J. Polym. Sci., Polym. Chem. 2011, 49, 2990. (23) Goodwin, A. P.; Lam, S. S.; Frechet, J. M. J. J. Am. Chem. Soc. 2007, 129, 6994. (24) Cheung, S.-Y.; Chow, H.-F. Chem. Eur. J. 2009, 15, 8874. (25) Chow, H. F.; Leung, C. F. Macromolecules 2004, 37, 3595. (26) Newkome, G. R.; Kim, H. J.; Moorefield, C. N.; Maddi, H.; Yoo, K. S. Macromolecules 2003, 36, 4345. (27) Steffensen, M. B.; Simanek, E. E. Angew. Chem., Int. Ed. 2004, 43, 5178. (28) Gong, A. J.; Fan, Q. H.; Chen, Y. M.; Liu, H. W.; Chen, C. F.; Xi, F. J. Mol. Catal. A: Chem. 2000, 159, 225. (29) Oh, S. K.; Kim, Y. G.; Ye, H. C.; Crooks, R. M. Langmuir 2003, 19, 10420. (30) Baker, J. R.; Quintana, A.; Piehler, L.; Banazak-Holl, M.; Tomalia, D.; Raczka, E. Biomed. Microdevices 2001, 3, 61. (31) Fischer, M.; Appelhans, D.; Klajnert, B.; Bryszewska, M.; Voit, B.; Rogers, M. Biomacromolecules 2010, 11, 1314. (32) Shumilkina, N. A.; Myakushev, V. D.; Tatarinova, E. A.; Buzin, M. I.; Voronina, N. V.; Laptinskaya, T. V.; Gallyamov, M. O.; Khokhlov, A. R.; Muzafarov, A. M. Polym. Sci., Ser. A 2006, 48, 1240. (33) Ortega, P.; Serramía, M. J.; Samaniego, R.; de la Mata, F. J.; Gomez, R.; Muñoz-Fernandez, M. A. Org. Biomol. Chem. 2009, 7, 3079. (34) Krupkova, A.; Cermák, J. J. Inorg. Organomet. Polym. 2012, 22, 470. (35) Ledin, P. A.; Friscourt, F.; Guo, J.; Boons, G. J. Chem. Eur. J. 2011, 17, 839. (36) Gottis, S.; Rodriguez, L.-I.; Laurent, R.; Angurell, I.; Seco, M.; Rossell, O.; Majoral, J.-P.; Caminade, A.-M. Tetrahedron Lett. 2013, 54, 6864. (37) Chang, Y.; Kwon, Y. C.; Lee, S. C.; Kim, C. Macromolecules 2000, 33, 4496. (38) Sánchez-Nieves, J.; Fransen, P.; Pulido, D.; Lorente, R.; MuñozFernández, M. Á .; Albericio, F.; Royo, M.; Gómez, R.; de la Mata, F. J. Eur. J. Med. Chem. 2014, 76, 43. (39) Fuentes-Paniagua, E.; Hernandez-Ros, J. M.; Sanchez-Milla, M.; Camero, M. A.; Maly, M.; Perez-Serrano, J.; Copa-Patino, J. L.; Sanchez-Nieves, J.; Soliveri, J.; Gomez, R.; de la Mata, F. J. RSC Adv. 2014, 4, 1256. (40) Galán, M.; Sánchez Rodríguez, J.; Jimenez, J. L.; Relloso, M.; Maly, M.; De la Mata, F. J.; Muñoz-Fernández, M. A.; Gómez, R. Org. Biomol. Chem. 2014, 12, 3222. (41) Fuentes-Paniagua, E.; Pena-Gonzalez, C. E.; Galan, M.; Gomez, R.; de la Mata, F. J.; Sanchez-Nieves, J. Organometallics 2013, 32, 1789. (42) Schlenk, C.; Frey, H. Chem. Monthly 1999, 130, 3. (43) Rissing, C.; Son, D. Y. Organometallics 2008, 27, 5394. (44) van der Made, A. W.; van Leeuwen, P. W. N. M. J. Chem. Soc., Chem. Commun. 1992, 1400.

(45) van der Made, A. W.; van Leeuwen, P. W. N. M.; De Wilde, J. C.; Brandes, R. A. C. Adv. Mater. 1993, 5, 466. (46) Knapen, J. W. J.; van der Made, A. W.; de Wilde, J. C.; van Leeuwen, P. N. M. W.; Wijkens, P.; Grove, D. M.; van Koten, G. Nature 1994, 372, 659. (47) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. Rev. 1999, 99, 1665. (48) Newkome, G. R.; Shreiner, C. Chem. Rev. 2010, 110, 6338.

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