From Molecules to Silicon-Based Biohybrid Materials by Ball Milling

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From molecules to Silicon-based biohybrid materials by ball-milling Massimiliano Lupacchini, Andrea Mascitti, Lucia Tonucci, Nicola d'Alessandro, Evelina Colacino, and Clarence Charnay ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b02782 • Publication Date (Web): 15 Nov 2017 Downloaded from http://pubs.acs.org on November 15, 2017

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ACS Sustainable Chemistry & Engineering

From molecules to Silicon-based biohybrid materials by ball-milling Massimiliano Lupacchini,a,b,‡ Andrea Mascitti,a,b,‡ Lucia Tonucci,c Nicola d’Alessandro,b Evelina Colacino,a and Clarence Charnay,d,* a

Université de Montpellier, Institut des Biomolécules Max Mousseron (IBMM), UMR 5247

CNRS – UM – ENSCM, Place E. Bataillon, Campus Triolet, cc1703, 34095 Montpellier, Cedex, France. b

Department of Engineering and Geology (INGEO), “G. d’Annunzio” University of Chieti-

Pescara, Via dei Vestini, 31, 66100 Chieti Scalo, Italy c

Department of Philosophical, Educational and Economic Sciences, “G. d’Annunzio” University

of Chieti-Pescara, Via dei Vestini, 31, 66100 Chieti Scalo, Italy d

Institut Charles Gerhardt de Montpellier (ICGM), UMR-5253 CNRS-UM, Université

Montpellier Campus Triolet cc 1701, Place Eugène Bataillon, 34095, Montpellier cedex 05 (France). *e-mail: [email protected] KEYWORDS. Hybrid Materials, Bis-silylated organosilicon precursors, Amino Esters, Hydantoins, Ureas, Sol-Gel, 1,1’-Carbonyldiimidazole (CDI), Mechanochemistry, Liquid Assisted Grinding (LAG).

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ABSTRACT: Hybrid nanoparticles with a large bridging organic group were prepared by mechanochemical assisted sol-gel reaction. Planetary ball-mill (PBM) was used for the first time to access the bis-silylated precursors, containing complex functionalities (such as hydantoins or a symmetrical urea obtained from amino esters). The process is based on a sequential reaction pathway involving Liquid Assisted Grinding (LAG) and 1,1’-carbonyldimidazole (CDI)-mediated one-pot/two step reactions. Then, hydantoins and the symmetric urea were used for the one-pot preparation of the corresponding bis-silylated compounds in a vibrational ball-mill (VBM), followed by the mechanochemical sol-gel preparation of bio-hybrid bridged silsesquioxane nanospheres of uniform size.

INTRODUCTION The development of colloidal silsesquioxane particles have received considerable focus as a result of the large variety of chemical functionalities that can be introduced into the material framework.1-7 A wide range of organosilica particles have been designed for advanced applications such as composite nanomaterials,3 opto-electronics,6-8 catalysis,7,

9

separation,3,

6, 8

sensor

technologies1, 6 or nanomedecine.1-2 Among the huge variety of organosilica precursors, the bissilylated precursors with an organic linker lead to bridged silsesquioxane (BSQ) particles achieved with various bridges, morphologies and textures from nonporous BSQ to periodic mesoporous organosilicas (PMOs).2, 10-16 A considerable number of synthetic routes have been developed for the preparation of bis-silylated precursors with a variety of functionalized bridging groups8, 14, 1722

such as flexible alkylenes8, amines14, amino acids20, ureas17,19,21,22, carbamates8 and rigid

acetylenic14 or aromatic groups.8,14,18 More specifically, the functionalization of an


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organotrialkoxysilane is a common way to achieve a great number of complex bridged organosilicon precursors. One of the most useful approaches to prepare bridged monomers consists in the reaction of bifunctional organic molecules bearing electrophilic substituents with an organotrialkoxysilane containing a nucleophilic group such as amine function.7, 21 Hence, the synthesis of bis-silylated precursors remains of great interest for the synthesis23, 24 of advanced organosilica particles with complex organic bridging groups for targeted applications.23-24 In this way, we have developed an innovative method using a ball-milling technology to achieve bissilylated precursors containing complex functionalities obtained from –amino esters. In the recent years, there is a continuous research of different energy sources for chemical reactions: from microwaves synthesis25 to electrochemistry26 passing through high pressure systems,27 photochemistry,28 sonochemistry29 and ohmic heating.30 These enabling technologies are often used in connection with each other to offer very innovative, green and sustainable processes. A special place in the field is deserved to mechanochemistry, not only a valid alternative to chemistry in solution for the preparation of molecules,31-36 (pharmaceutical)37-38 materials,39-40 or to access active co-crystals41 and pharmaceutical ingredients (APIs),42-43 but also as a fully effective key strategy for new synthetic opportunities altering product selectivity44 or leading access to products elsewhere impossible to be obtained by other methods.36,

45

We recently

disclosed new mechanochemical pathways for the eco-friendly preparation of carbamates from amino acid derivatives.46-48 Useful building block for peptide synthesis, amino esters are also precursors of biologically relevant compounds containing the 2,4-imidazolidine scaffold (hydantoin family).49 We previously reported the use of mechanochemistry for the preparation of hydantoin-based APIs from amino esters,50-52 antibacterial agents for polymer textiles51 or enzyme inhibitors.53 However, mechanochemistry was not yet exploited to develop organosilicon


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precursors and never used in sol-gel process to achieve silsesquioxane particles. To the best of our knowledge, this technology was explored once for the sol-gel preparation of ‘nanohybrid supercapacitors’,54 based on centrifugation technology. Ball-milling was also scarcely exploited for the covalent immobilization of organic molecules on an inorganic support such as Al2O3,55 silica gel56 or graphene oxide.57-58 Moreover high-energy ball milling process was applied to provide nanocomposite materials with different oxide nanoparticles with a highly homogeneous crystalline structure and morphology such as iron oxide or TiO2 anatase nanoparticles.59-61 Mechanochemical reactions were recently reported for the preparation of dispersed nanoparticles of oxide materials from molecular or salts precursors.62-67 We disclose herein a new approach based on the use of mechanochemistry, to: i) access the silicon-derivatized hydantoin and urea scaffolds obtained from amino acid derivatives and ii) prepare functionalized biohydrid bridged silsesquioxane nanospheres via a mechanochemical assisted sol-gel procedure.

RESULTS AND DISCUSSIONS 1,1’-Carbonyldiimidazole (CDI) proved to be a safe, cheap and easy to handle, versatile acyl transfer agent to access 5-substituted-3-(alkoxycarbonyl)alkyl-hydantoin derivatives53 by mechanochemistry. In this paper the synthetic approach was further extended to explore the cascade reaction involving an amino ester hydrochloride salt (1.0 equiv) with CDI53 (0.5 equiv), leading to a symmetrical urea A, formed in situ via the 1H-imidazole-carboxamido-intermediate (Scheme 1).


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Scheme 1. CDI-mediated preparation of 5-substituted-3-(alkoxycarbonyl)alkyl-hydantoins 153 and 2, and symmetrical urea 3 in a planetary ball-mill (PBM) from amino esters hydrochloride salts. Hanusa’s formalism was used to represent mechanochemically activated reactions.68

Therefore, hydantoin 2 was obtained one-pot when cyclizing the symmetrical carbonyl diamino ester of aspartic acid [H-Asp(OtBu)-OMe, n=1, Scheme 1], while surprisingly HCl.H-Glu(OtBu)OMe (n=2, Scheme 1) led to the symmetrical urea 3, the intramolecular cyclization not occurring, even when extending the reaction time up to 6 hours. In both cases, orthogonal protection as tertbutyl ester was selected for the side chains, to avoid the reaction of carboxylic acid with CDI.69 It is worth mentioning that the final products could be recovered by precipitation in water, eliminating the water-soluble imidazole, the only by-product of the reaction. To date the use of CDI for the preparation of ureas by mechanochemistry was not reported yet. However, the preparation of ureas or thioureas respectively from substituted isocyanates70 62 or isothiocyanates7172 73,74

was already described by ball-milling. Thioureas were also accessed using activated


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reagents similar to CDI, such as bis(benzotriazolyl)methanethione73

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65

and thiocarbamoyl

benzotriazoles.73-74 65,66 CDI was also the key reagent for the unprecedented mechanochemical preparation of organosilicon substrates 4-6-Sil, presenting complex functionalities and structures potentially endowed with biological activity75-76

67,68

(Scheme 2) and to be used as substrates for the

preparation of hybrid nanomaterials. Usually, the preparation of organosilicon derivatives in solution77-80 69-72 requires excess of reagents and solvent, dry atmosphere and long reaction times (12 hours). Moreover, the reaction conditions are sometimes variable depending on the nature of the substrates (room temperature or heating at 70°C) and in the case of alcohols, the addition of extra strong base (NaOH or NaH) or activating agents to the reaction mixture can be necessary. On the contrary, under mechanochemical conditions, the stoichiometric reactions required no optimization, were general and performed in air atmosphere, the use of solvents was strongly reduced, and no extra activating agents were necessary in reactions involving CDI.48 73 Compounds 1-3 were deprotected in acidic medium using trifluoroacetic acid (TFA) and triisopropylsilane (TIPS), and directly used for the one-pot/two step preparation of the corresponding bis-silylated compounds 4-6-Sil in a vibrational ball-mill (Scheme 2). In the first step, carboxylic acid (and phenolic) functions reacted with CDI in a stainless steel jar, to afford the corresponding N-acyl-imidazole (and imidazole carboxylic ester) intermediate.69

61

Full

conversion of the substrates was observed, with the exception for hydantoin 4. Liquid-assisted grinding conditions (LAG)41 with EtOAc (40 μL) were used for a homogeneous mixing of the reactants. In the second step, 3-aminopropyltriethoxysilane (APTES) and diisopropylethylamine (DIPEA) were added into the jar and the reaction was mechanical shaked again for 2 hours


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(Scheme 2). Then, the bis-silylated precursors 4-6 Sil were reacted one pot by mechanochemical assisted sol-gel process. Scheme 2. Preparation of bis-silylated precursors 4-6-Sil and the corresponding bulk materials or the bridged nanosized polysisesquiloxanes 5-Sil NPs and 6-Sil NPs by mechanochemistry.

Bis-silylated 4-6 derivatives were polymerized in water and the corresponding bulk biohybrid materials 4-6-Sil were further characterized by solid state magnetic resonance (NMR) 29Si and 13C and CP-MAS NMR, FT-IR and SEM (Figure 1 and Figures S1 and S2 in the Supporting information) confirming the formation of bulk hybrid materials. The 29Si CP-MAS NMR spectra of bulk 4-6-Sil materials (Figure 2 and Figures S27, S30 and S33 in the supporting information) showed the presence of the siloxane network with a high condensation of the precursors [bis-


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(triethoxysilylpropyl) derivatives] with a T3 resonance at -68 ppm for all the 4-6-Sil materials, and a small amount of less condensed material with a T2 peak (-58 ppm) and a T1 peak at -45 ppm only in the case of 6-Sil. Moreover no signals Qn, n=1-4 due to SiO4 species were detected between 98 and -110 ppm on the 29Si spectra for the samples derived from 4-6 Sil, indicating no evidence for Si-C bond cleavage during the sol-gel process.

Figure 1. SEM micrographs for bulk hybrid material obtained from polymerization of 4-Sil


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The successful mechanochemical CDI-mediated incorporation of organic bridges into the silica framework of porous organosilica bulk materials was proven by FT-IR spectroscopy (Table 1, Figures 2B, 2D and S29 in the Supporting information and Table 1). The presence of the amide bond in the 4-6-Sil materials was confirmed by the presence of a characteristic absorption frequency due to the C=O stretching vibration, appearing at lower shift values compared to the C=O stretching vibration initially observed for the carboxylic acids in the substrates 4-6 (Table 1). Moreover, the high degree of condensation of siloxanes was confirmed by the presence of strong absorption bands typically associated to Si-O-Si bonds in the range of 1100 cm-1 (stretching) and 1020 cm-1 (flexing). The Si-(CH2)3 groups of the silsesquioxanes exhibit well-defined absorptions in the range of 1200 cm-1 (Table 1). Table 1. Comparison between the infrared (IR) characteristic group frequencies81 for COOH functional groups in 4-6, and CO-NH amide bonds and siloxane bonds in 4-Sil, 5-Sil and 6-Sil bulk polymers. Absorption frequency v (cm-1) Compound C=O(OH) vs. C=O(NH)

4 vs. 4-Sil

1682 / 1638

NH-C=O-NH

Si-(CH2)3

Si-O-Si

1198

1098 /

1714 1018 1199

5 vs. 5-Sil

1698 / 1652

1125 /

1713 1038 1197

6 vs. 6-Sil

1704 / 1640

1060 /

1711 1028


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(A)

(C)

(B)

(D)

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Figure 2. Solid State 29Si CP-MAS NMR (A, C) and FT-IT (B, D) spectra of bulk 5-Sil and 6-Sil materials respectively. The structure of functionalized bulk materials 4-6-Sil was further confirmed by 13C CP-MAS NMR spectra: a comparison between the 13C NMR spectra of the substrates 4-6 and bulk materials 4-6Sil showed the presence of additional peaks at 10, 18 and 48 ppm, confirming that the core of the bridging groups R (urea and hydantoin) were integrated into the organosilica framework through two triethoxysilyl with flexible propyl chains [(SiO)3Si-(CH2)3-R-(CH2)3-Si(OSi)3]. In order to prepare the Si-based biohybrid materials with uniform size and morphology, a freshly synthetized batch of bis-silylated 4-6-Sil was prepared and directly used for mechanochemical sol-


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gel process (Scheme 2). To the best of our knowledge, no study reported on the mechanochemical preparation of organosilicon based reagents, as well as on the preparation of biohybrid nanomaterials by sol-gel procedures in a ball-mill. The bis-silylated 4-6-Sil molecules were reacted in a vibrational ball-mill at 30 Hz, using a Teflon jar/ball combination for 2 hours in the presence of a surfactant micellar solution (5 mL), prepared by mixing at 323 K for 20 minutes 100 mg of cetyltrimethylammonium bromide (CTAB) surfactant with 50 mL of ultrapure water (18 MΩ cm-1) and sodium hydroxide (350 µL, 2M). At the end of the reaction, the milky suspension was recovered and treated as described in the supporting information. The reaction was repeated twice, confirming the reproducibility of the mechanochemical sol-gel process, and the biohybrid materials were fully characterized by Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS) (Figures 3 ). The TEM micrographs of the hybrid silsesquioxanes achieved from the two precursors 5-6 Sil reported in Figures 3A and 3C respectively, reveal the presence of nanosized particles having a spherical shape. The silsesquioxane nanospheres have an overall diameter of 150 ± 17 nm for 5-Sil NPs and 265± 50 nm for 6-Sil NPs as confirmed by dynamic light scattering (DLS). The surface properties have been also studied using a zeta potential (ZP) analyzer. The measurements revealed that the 5-Sil NPs exhibit a slightly negative ZP values around -3.8± 1.3 mV assimilated to a null value of the zeta potential in agreement with the uncharged molecular structure of the hydantoin group linker and the high proportion of the fully condensed T3 [C-Si(OSi)3] species observed for the bulk hybrid solid derived from 5-Sil (Figure 2A). The 6-Sil NPs exhibit a negatively charged surface with ZP values around -18.8 ± 1.30 mV due to the presence of deprotonated silanol groups (SiO-) taking into account the uncharged urea linker. The relatively high negative value observed for this sample is consistent with the 29Si CP-MAS


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NMR spectra previously displayed for the sample bulk derived from 6-Sil (Figure 2C) with a significant proportion of less condensed T2 [C-Si(OH)(OSi)2] and T1 [C-Si(OH)2(OSi)] species. Only in the case of 4-Sil the formation of dispersed nanoparticles was not observed, the bulk material being obtained. The presence of the aromatic cycle in the 4-Sil precursor may result in a more rigid bis-silylated precursor and the presence of some pi-stacking may disturb the sol-gel process and thus the size and shape of achieved particles.

Figure 3. (A, C) TEM Micrographs (scale bar: 500 nm) for silsesquioxane nanoparticles, exhibiting a spherical shape, prepared from hydantoin 5 and urea 6, (B, D) size average ca. 150 nm and 265 nm respectively determined by Dynamic Light Scattering (DLS). Moreover, the hydrolysis of the hydantoinic ring during mechanochemical sol-gel process was excluded on the base of literature reports. Ring opening usually occurs in harsh conditions such as


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in concentrated solution of NaOH 5N, at high temperatures (120-150°C) and for long reaction times (12 hours under reflux).82 For sake of comparison, attempts to prepare the same nanosized biohybrid materials also displaying controlled morphology and narrow-size distribution were carried out under stirring at 40°C overnight, as usually reported for similar “Stöber-like” sol-gel procedures.15, 83 In this case, the formation of nanoparticles was not observed as no any control of size and morphology was possible, validating our initial mechanochemical approach. Furthermore, for hybrid materials developed from solely an organic-bridged precursor, it was several times reported that the molecular design of the bridged linker group has a considerable impact on the structures of the resulting hybrid framework owing to the effect of the different interactions between the organic moieties on the self-assembly process.1, 6 As a result, the synthetic strategy to achieve one type of hybrid nanoparticles cannot be directly extended to synthesize different type of bridged silsesquioxane nanospheres and an optimization procedure is often needed to consider the different rates of hydrolysis or condensation significantly affected by the chemical structure of the bissilylated organosilica precursor. Moreover, the flexibility and the bulkiness of the organic bridge are known to remain challenging to synthesize bridged silsesquioxane materials.21 The biohybrid nanospheres easily achieved with the vibrational ball-mill assisted sol-gel process open new perspectives and developments for the synthesis of bridged silsesquioxane nanoparticles with desirable chemical functionalities to control the properties of the nanoparticles designed for various advanced applications such as chromatography, catalysis and biotechnologies.

CONCLUSION


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The synthesis of bis-silylated organosilica precursors with large organic bridging groups remains tricky due to the technical complexity of the separation and purifications steps for such nonvolatile compounds. The association between the mechanochemical reactivity of CDI, the intrinsically green sol-gel process, increased by the use of ball-milling herein described, presents many advantages such as: i) the straightforward preparation of a large variety of inedited silylated precursors, according to one-pot/two step reaction, displaying economy of solvent (only few microliters of AcOEt were used), surfactant (used to inhibit aggregation of achieved particles now realized also by mechanical disruption) and waste; ii) the possibility to access novel hybrid materials presenting covalently-bound organic molecules, including potentially bioactive compounds, and complex functionalities for eventual post-modifications; iii) to perform nonconventional mechanochemical sol-gel process, leading to uniform dispersed hybrid nanoparticles in short reaction times not easily accessible by conventional solution “Stöber-like” procedures and finally, to open up in the near future the way for greener synthesis of (bio)hybrid organosilica particles with controlled size and morphology.

ASSOCIATED CONTENT The following files are available free of charge. Experimental procedures (Materials and Methods), 1

H and

13

C NMR spectral data in solution of compounds 1-6, solid state

13

C and

29

Si CP-MAS

NMR, solid state FT-IR spectral data and SEM pictures for bulk polymers 5-6-Sil, (PDF )

AUTHOR INFORMATION


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Corresponding Author *e-mail: [email protected] Tel. +33 (0)4 67 14 38 64, Fax: +33 (0)4 67 14 38 04 ORCID ID (Clarence Charnay): 0000-0002-8796-3701 Author Contributions ‡These authors contributed equally. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Only persons having made significant scientific contributions to the work reported and who share responsibility and accountability for the results were associated to this article. Funding Sources The authors acknowledge the MIUR for the grants to A.M. and M.L. (Fondo Sostegno Giovani – FSG – 2012 and 2013). Notes The authors declare no competing financial interest.

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Table of Content


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Bis-silylated organosilicon reagents were prepared by Liquid Assisted Grinding procedures, followed by mechanochemical assisted sol-gel process to access biohybrid nanospheres.


21


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 OtBu 17 CDI (0.5 equiv) from Ref. 53 18 R1 O R1 K 2CO 3 (1.5 equiv) 19 R1 = -C6H 4-p-OtBu OMe OMe 20 N N HCl.H 2N N O H HN 21 PBM O O PBM 22 N 450 rpm, 2-4 h 23 O O 50 balls 1H-imidazole-carboxamido 24R1 = -(CH2)nCO2tBu tBuO intermediate 25 Zirconium oxide jar and balls 26 1, 88% 27 in situ 28 29 30 OtBu n =1 31 tBuO 32 O O OtBu O R1 O R1 33 n =1 * n =2 34 O MeO OMe HN O N N O 35 H H N MeO OMe O O 36 N N O X in situ OMe 37 H H O O 38 n = 2ACS Paragon Plus Environment OtBu 39 2, 66% 3, 76% O A d.r. 1:1 40 41

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(A)

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(B)

(C)


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From Molecules to Silicon-Based Biohybrid Materials by Ball Milling

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