Syntheses of phosphorylcholine-substituted silsesquioxanes via thiol-ene ‘click’ reaction

Tetrahedron Letters 56 (2015) 1562–1565

Contents lists available at ScienceDirect

Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Syntheses of phosphorylcholine-substituted silsesquioxanes via thiol-ene ‘click’ reaction Lei Liu a, Su Jung Lee a, Myong Euy Lee a,⇑, Philjae Kang b, Moon-Gun Choi b a Department of Chemistry & Medical Chemistry, College of Science and Technology, Research & Education Center for Advanced Silicon Materials, Yonsei University, Wonju, Gangwondo 220-710, Republic of Korea b Department of Chemistry and Molecular Structure Laboratory, Yonsei University, Seoul 120-749, Republic of Korea

a r t i c l e

i n f o

Article history: Received 18 December 2014 Revised 29 January 2015 Accepted 6 February 2015 Available online 13 February 2015

a b s t r a c t Phosphorylcholine-substituted silsesquioxanes were synthesized via the UV-initiated thiol-ene ‘click’ reaction of octakis(3-mercaptopropyl)octasilsesquioxane (POSS-SH) with 2-methacryloyloxyethylphos phorylcholine or allylphosphorylcholine in mixed (DMF/MeOH) solvents, respectively. In addition, the crystal structures of POSS-SH and MPC were first determined. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Phosphorylcholine Silsesquioxane Thiol-ene ‘click’ chemistry

With the increasing demand for biomedical materials, phosphorylcholine (PC)-containing materials have been very attractive to many researchers due to their excellent blood compatibility, biocompatibility, and hydrophilicity. The PC moiety has an ideal structure as predicted by the ‘fluid-mosaic model’, a model of the bio-membrane structure proposed by Singer and Nicolson.1 Furthermore, phospholipids containing PC as a head group are major components of all eukaryotic cell membranes and are present in all bacteria.2 Accordingly, PC derivatives show a high affinity for living organs and tissues, and are widely used in the construction of bio-membranes3 and super-hydrophilicity materials,4 and serve as excellent anti-fouling surface modifiers.5 Over the past decade, efforts have been made to synthesize PC-containing silicon biomaterials. For instance, copolymers of 2-methacryloyloxyethyl phosphorylcholine (MPC) and 3-trimethoxysilylpropylmethacrylate (MPS) were synthesized by radical polymerization to modify contact lenses.6 3-Mercaptopropyltrimethoxy silane was used to initiate the thiol-ene radical photo-polymerization of MPC, in which the trimethoxysilyl group acts as an end-blocker and coupling agent to enable poly (MPC) to coat biodegradable Mg–Al–Zn alloys.7 In addition to these polymers, several micro-molecules have been also studied. For instance, chloro-dimethylsilanated PC was synthesized and implanted on a glass surface to construct biomembranes.8 A hydrosilylation reaction was used to synthesize trimethoxysilanated MPC to modify biomedical Ti–Al–V alloys.9 ⇑ Corresponding author. Tel.: +82 033 760 2237; fax: +82 033 760 2182. E-mail address: [email protected] (M.E. Lee). http://dx.doi.org/10.1016/j.tetlet.2015.02.021 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

Recently, our group synthesized methallylsilanated PCs via copper-catalyzed ‘click’ reactions to modify silica beads.10 Thus, PC-containing silicon chemicals have been widely used in biomedical and surface science fields. On the other hand, polyhedral oligomeric silsesquioxane (POSS) is ‘a next generation material for biomedical applications.’11 POSS has been demonstrated to be a promising nanomaterial for hybrid preparation,12 and its cytocompatibility makes it suitable for drug release and tissue engineering applications.13 Usually, POSS derivatives possess the general formula (RSiO1.5)n with well-defined nanometer structures and appended organic groups at the vertexes of the cage. These organic groups can be further functionalized to yield POSS hybrids. In this study, octakis(3-mercaptopropyl)octasilsesquioxane (POSS-SH) was chosen to be further functionalized using alkenyl-PCs in order to provide new biomedical POSS-PC hybrids. Herein, we report syntheses of PC-substituted silsesquioxanes (2 and 3) via the UV-initiated thiol-ene ‘click’ reaction of POSSSH with MPC and allyl phosphorylcholine (APC) in mixed dimethyl formamide (DMF)/methanol solvents, respectively. POSS-SH (1) was obtained through the hydrolysis of (3-mercaptopropyl)trimethoxysilane (MPTMOS) in the presence of di-n-butyltin dilaurate catalyst. The crystal structures of 1 and MPC were determined for the first time by single-crystal X-ray crystallographic analysis. The condensation of MPTMOS to obtain 1, usually is conducted by the method described by Marsmann and co-workers,14 which is a standard acid hydrolysis [HCl(aq)/alcohol] at room temperature,

1563

L. Liu et al. / Tetrahedron Letters 56 (2015) 1562–1565 SH HS

OMe HS

Si

OMe

OMe

HCl(aq) methanol 3 days

OH HS

Si OH

OH

di-n-butyltin dilaurate 7 days HS

condensation

hydrolysis

O Si Si O O

Si HS

O Si

O O Si O

O Si SH

SH

O O O Si Si O

SH

SH

1 (37%)

Scheme 1. Synthesis of 1.

and it takes a very long reaction time, ca. 5 weeks to give low yield (16.9%). Ni and co-workers reported an improved synthetic route which was acid hydrolysis at high temperature (60 °C) for 3 days.11 This method afforded 1 as a viscous liquid in more than 60% yield. In this work, as shown in Scheme 1, the hydrolysis of MPTMOS was performed in methanol with concentrated hydrochloric acid (37 wt %). The condensation step was carried out in the presence of di-n-butyltin dilaurate catalyst, which is a well-known catalyst for condensation reactions of silanols and has been used in the synthesis of octakis(3-chloropropyl)octasilsesquioxane.15 The first hydrolysis step was carried out at room temperature for three days. The hydrolysis time shorter than three days gave low yields of 1 (<37%; 19% for 1 day, 28% for 2 days), indicating that the reaction time must be at least three days. In the second step, 1 h after the addition of di-n-butyltin dilaurate catalyst to the reaction mixture, the solution became turbid. After two days, crystalline 1 (single T8-caged, Fig. 1) started to form, and within seven days, 1 was obtained in 37% yield. If the second step was carried out for longer than seven days, higher yields were expected to be obtained, although mostly as larger amounts of amorphous oligomer and polysilsesquioxanes.15 Thus, longer condensation reaction times are not recommended. To get crystals suitable for X-ray analysis,16 the obtained 1 (0.1 g) was recrystallized from the mixed solvent of DMF (1 mL) and diethyl ether (14 mL) through slow evaporation at room temperature. In addition, we recently reported an improved synthetic route and succeeded in obtaining crystalline APC,17 which has a structure similar to MPC. In this work, we were fortunate to obtain a single crystal of MPC using the diffusion vapor method in saturated acetonitrile solution and diethyl ether,18 which had not previously been reported.

Crystal structures for 1 and MPC are shown in Figures 1 and 2, respectively. As shown in Figure 1, the Si–O bond lengths of 1 are in the range of 1.616(15)–1.627(15) Å and the S–C bond lengths are in the range of 1.815(2)–1.818(2) Å. The Si–O–Si bond angles are varied considerably [142.2(10)°–154.9(10)°] due to the steric effect of the mercaptopropyl groups. The Si–C–C–C torsion angles in 1 are 166–176° which is distinct from that in the 3-propyl ethanethioate substituted POSS (170–174°) reported by Ervithayasuporn et al. in 2011.19 Regarding the C–C–C–S torsion angles in 1, they are 174– 178° distinct from 3-propyl ethanethioate analogs (nearly 180°). These distinctions might be due to the effect of intermolecular hydrogen bonding. For MPC structures shown in Figure 2a a C4– C5 double bond length of 1.333(2) Å and a C3–O6 double bond length of 1.206(18) Å are seen. In the tetrahedral PO4 unit, there are different P–O lengths that vary from 1.479(10) to 1.629(10) Å. The P1–O1 and P1–O2 lengths have similar values of 1.479(10) and 1.483(10) Å, which are significantly shorter than the P–O single bond length [1.630(1) Å] and longer than the P–O double bond length [1.380(1) Å]. The bond lengths for P1–O3 of 1.629(10) Å and P1–O4 of 1.611(10) Å are in accordance with the P–O single bond length. These bond lengths indicate that the O1– P–O2 of MPC has a canonical resonance structure, which explains why the bond lengths for P1–O1 and P1–O2 are longer than a typical P–O double bond. Anion delocalization over the two oxygen atoms weakens the anionic character of each oxygen atom. The (CH3)3N+CH2 unit in MPC exhibits a tetrahedral structure. The cationic character of the ammonium unit would be decreased because of the inductive effect in addition to the steric effect of the three methyl groups. Moreover, Figure 2b shows that the shortest distance from N to O is 3.63 Å, which is longer than the sum of the Van der Waals radii, RRvdW N–O = 3.07 Å. These results suggest there was no inter- or intra-molecular interaction. It is well known

Figure 1. Crystal structure of 1. Gray: carbon; yellow: silicon; red: oxygen; brown: sulfur; white: hydrogen. Thermal ellipsoids are shown at the 50% probability.

1564

L. Liu et al. / Tetrahedron Letters 56 (2015) 1562–1565

Figure 2. (a) Crystal structure of MPC. Gray: carbon; red: oxygen; purple: phosphorus; blue: nitrogen; white: hydrogen. Thermal ellipsoids are shown at the 50% probability. (b) Intra- and inter-molecular distances from N to O.

O

O

O

O

P

O O

SR1

N R1S

MPC

O Si Si O O

MPC, 2 mol % Ph2CO, DMF/methanol

SH HS

O

HS

Si HS

O Si Si O O O Si

O Si

R1S

SH

O Si SH O

O O Si Si O

O

O

R.T. 20 min, 300 nm UV

Si R1S

O Si O

O Si

SR1 O Si SR1

O O Si Si O

O

SR2

O P

SH

N

R2S

O APC

SH

APC, 2 mol % Ph2CO, DMF/methanol

1

O R.T. 25 min, 300 nm UV

R2S

Si R2S

O Si Si O O O Si O

O Si

O Si SR2 O

O O Si Si O

O H2C

P O

O

O O

N (R ) 1

H2C

SR2

O P

O

SR2

3(93 %)

SR2 O

SR1

2(92 %)

R1S O

O

N O

(R2)

O

Scheme 2. Synthesis of 2 and 3.

that the UV-initiated thiol-ene ‘click’ reaction has been widely used to functionalize biomolecules and biomacromolecules, because it proceeds under mild conditions in the presence of oxygen, is regioselective, tolerates many functional groups, can be performed neat or in benign solvents, and provides quantitative or near-quantitative yield with simple or no chromatographic separation required.4,20,21 Thus, this reaction could provide an optimal method to combine POSS and PC moieties. Generally, PC-containing chemicals are only soluble in alcohols and water, while POSSs are insoluble in alcohols and water but soluble in THF and DMF. To synthesize 2 and 3 (Scheme 2), a mixed (methanol/THF) solvent was initially used. As the reaction began, the mixture turned turbid, and partially PC-substituted POSSs precipitated because of their insolubility in THF. Next, the solvent mixture was changed to a methanol/DMF system, in which the reaction proceeded smoothly to afford 2 or 3 as yellow powders in 92% or 93% yield, respectively.22,23 Shorter reaction time (20 min) to synthesize 2 proves that the acryloyl group on MPC is more reactive than the simple vinyl group on APC. Then, to confirm 1 was fully substituted, the products were thoroughly characterized by NMR, IR, and HR-MS. The 1H NMR spectra showed chemical shifts representing the complete disappearances of –SH at 1.36 ppm, CH@C at 5.60 and 6.20 ppm (MPC) or at around 6.0 ppm (APC), and formation of the mercaptomethyl-

ene (CH2S) at 2.51–2.56 (2) or 2.50–2.53 (3) ppm. FT-IR spectra showed complete disappearances of C@C at around 1640 cm 1 and S–H at 2551 cm 1. 29Si NMR spectra exhibited a single peak at –66.63 (2) or –66.65 (3) ppm, respectively. HR-MS (ESI) gave the expected molecular weights for 2 and 3. From these results, 1 was demonstrated to be fully substituted by a-addition thiol-ene reactions. In addition, the PC substitutions improved the solubility of POSS-SH in protic solvents such as water, methanol, and ethanol. But POSS-PC is insoluble in THF and ether, while soluble in DMF. In conclusion, 2 and 3, pure a-addition products, were efficiently synthesized via thiol-ene ‘click’ reactions in mixed (methanol/DMF) solvents in the presence of benzophenone (2 mol %) under UV irradiation (300 nm). Structures of MPC and 1 were determined by crystallographic analysis. In addition, the PC moiety improved the solubility of POSS-SH in protic solvents. PC-POSS hybrids may have potential biomedical applications like drug carriers, etc. Acknowledgments This research was supported by the Research and Education Center for Advanced Silicon Materials (RECASM) financially supported by the KCC Corporation. The authors also thank the KCI for providing chemicals.

L. Liu et al. / Tetrahedron Letters 56 (2015) 1562–1565

Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.02. 021.

17. 18.

References and notes 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

13.

14. 15.

16.

Singer, S. J.; Nicolson, G. L. Science 1975, 175, 720. Doherty, G. J.; McMahon, H. T. Annu. Rev. Biophys. 2008, 37, 65. Ishihara, K.; Ueda, T.; Nakabayashi, N. Polym. J. 1990, 22, 355. Goda, T.; Tabata, M.; Sanjoh, M.; Uchimura, M.; Iwasaki, Y. N.; Miyahara, Y. Chem. Commun. 2013, 8683. Fukazawa, K.; Ishihara, K. ACS Appl. Mater. Interfaces 2013, 5, 6832. Xu, L. N.; Ma, P. P.; Chen, X.; Shen, J. RSC Adv. 2014, 4, 15030. Ye, S. H.; Jang, Y. S.; Yun, Y. H.; Venkat, S.; Joshua, R. W.; Yi, H.; Lara, J. G.; Ishihara, K.; William, R. W. Langmuir 2013, 29, 8320. Durrani, A. A.; Hayward, J. A.; Chapman, D. Biomaterials 1986, 7, 121. Ye, S. H.; Johnson, J. C. A.; Woolley, J. R.; Murata, H.; Gamble, L. J.; Ishihara, K.; Wager, W. R. Colloids Surf. B 2010, 79, 357. Liu, L.; Song, J. H.; Lee, M. E.; Han, Y. R.; Jun, C.-H. Tetrahedron Lett. 2014, 55, 6245. Xu, Z. Q.; Ni, C. H.; Yao, B. L.; Tao, L.; Zhu, C. P.; Han, Q. B.; Mi, J. Q. Colloid Polym. Sci. 2011, 289, 1777. (a) Ervithayasuporn, V.; Wang, X.; Kawakami, Y. Chem. Commun. 2009, 5130; (b) Aziz, Y. E.; Bassindale, A. R.; Taylor, P. G.; Horton, P. N.; Stephenson, R. A.; Hursthouse, M. B. Organometallics 2012, 31, 6032; (c) Endo, H.; Takeda, N.; Unno, M. Organometallics 2014, 33, 4148. (a) Li, J. Z.; Zhou, Z.; Ma, L.; Chen, G. X.; Li, Q. F. Macromolecules 2014, 47, 5739; (b) Nair, B. P.; Vaikkath, D.; Nair, P. D. Langmuir 2014, 30, 340; (c) Wang, D. K.; Varanasi, S.; Strounina, E.; Hill, D. J. T.; Symons, A. L.; Whittaker, A. K.; Rasoul, F. Biomacromolecule 2014, 15, 666. Dittmar, U.; Hendan, B. J.; Florke, U.; Marsmann, H. C. J. Organomet. Chem. 1995, 489, 185. (a) Fierens, P.; Vandendunghen, G.; Segers, W.; van Elsuwe, R. React. Kinet. Catal. Lett. 1978, 8, 179; (b) Marciniec, B.; Dutkiewicz, M.; Maciejewski, H.; Kubicki, M. Organometallics 2008, 27, 793.  (no. 2), Crystal data: C24H56O12S8Si8, M = 1017.88, triclinic, space group P 1) a = 9.5597(5) Å, b = 9.5897(6) Å, c = 13.8133(9) Å, a = 74.275(2)°,

19. 20.

21.

22.

23.

1565

b = 78.917(2)°, c = 79.132(2)°, V = 1183.66(12) Å3, Z = 2, T = 100.0 K, l(Mo Ka) = 0.628 mm 1, Dcalc = 1.428 g/cm3, 21463 reflections measured (4.388° 6 2H 6 52.178°), 4681 unique (Rint = 0.0422, Rsigma = 0.0325) which were used in all calculations. The final R1 was 0.0332 (I > 2r(I)) and wR2 was 0.0854 (all data). CCDC: 1035682. Liu, L.; Lee, M. E.; Kang, P. J.; Choi, M.-G. Phosphorus, Sulfur Silicon Relat. Elem. 2014. ID: GPSS-2014-0175. Crystal data: C11H22NO6P, M = 295.26, monoclinic, space group P21/n (no. 14), a = 8.1293(6) Å, b = 8.6531(6) Å, c = 20.0849(16) Å, b = 90.345(3)°, V = 1412.82(18) Å3, Z = 4, T = 100.0 K, l(Mo Ka) = 0.217 mm 1, Dcalc = 1.388 g/ 3 cm , 32766 reflections measured (4.05° 6 2H 6 52.12°), 2798 unique (Rint = 0.0376, Rsigma = 0.0158) which were used in all calculations. The final R1 was 0.0297 (I > 2r(I)) and wR2 was 0.0811 (all data). CCDC: 1035681. Ervithayasuporn, V.; Tomeechai, T.; Takeda, N.; Unno, M.; Chaiyanurakkul, A.; Hamkool, R.; Osotchan, T. Organometallics 2011, 30, 4475. (a) Alexander, K.; Tucker, S.; Richard, A. F.; Robin, L. G. J. Am. Chem. Soc. 2011, 133, 11026; (b) Hoyle, C. E.; Bowman, C. N. Angew. Chem., Int. Ed. 2010, 49, 1540. (a) Dondoni, A.; Massi, A.; Nanni, P.; Roda, A. Chem. Eur. J. 2009, 15, 11444; (b) Zuo, Y. J.; Lu, H. F.; Xue, L.; Wang, X. M.; Ning, L.; Feng, S. Y. J. Mater. Chem. C 2014, 2, 2724. Compound 2 was obtained as yellow powder in 92%. Mp 156–158 °C. 1H NMR (CD3OD, 400 MHz): d = 4.23 (br s, 32H, OCOCH2CH2), 4.02–4.06 (t, 16H, CH2CH2N), 3.61 (s, 16H, CH2N), 3.17 (s, 72H, NCH3), 2.77 (m, 8H, COCH), 2.51–2.56 (t, 16H, CH2S), 2.56–2.62 (t, 16H, SCH2), 1.63 (m, 16H, SiCH2CH2), 1.19 (d, 24H, CHCH3), 0.72–0.74 (t, 16H, SiCH2). 13C NMR (CD3OD, 100 MHz) 175.91, 66.97, 64.80, 64.27, 60.09, 54.32, 41.16, 35.66, 25.64, 23.87, 17.14, 11.42. 29Si NMR (CD3OD, 79 MHz) 66.63. 31P NMR (CD3OD, 161 MHz) 0.58. HRMS (ESI) m/z 942.5903 ([M+Na]+, z = 3, 100%), 1694.9547 ([M+Na]+, z = 2, 71%). IR (KBr, cm 1) 2943(CH2), 1734(CO), 1648(SCH2), 1235, 1094(POCH2), 968(NCH3). Compound 3 was obtained as yellow powder in 93%. Mp 152–154 °C. 1H NMR (CD3OD, 400 MHz): d = 4.21 (s, 16H, PO4CH2), 3.90–3.94 (t, 16H, CH2CH2N), 3.60 (s, 16H, CH2N), 3.18 (s, 72H, NCH3), 2.50–2.53 (t, 16H, CH2S), 2.57–2.60 (t, 16H, SCH2), 1.84–1.87 (t, 16H, SCH2CH2), 1.63–1.67 (t, 16H, SiCH2CH2), 0.72– 0.75 (t, 16H, SiCH2). 13C NMR (CD3OD, 100 MHz) 67.01, 64.85, 59.92, 54.29, 34.88, 31.37, 28.49, 23.84, 11.50. 29Si NMR (CD3OD, 79 MHz) 66.65. 31P NMR (CD3OD, 161 MHz) 0.29. HR-MS (ESI) m/z 942.2552 ([M+Na]+, z = 3, 100%), 1413.3829 ([M+Na]+, z = 2, 72%). IR (KBr, cm 1) 2937(CH2), 1652(SCH2), 1236, 1091(POCH2), 973(NCH3).