Short Synthesis of a Specifically Perdeuterated Hexaethylene Glycol Terminated Alkanethiol

Abstract

An oligo(ethylene glycol) terminated alkanethiol being an important building block for self-assembled monolayers was synthesized in three steps with high efficiency and without use of protective groups. The same sequence was utilized to prepare a specifically deuterated congener from an isotope-labeled starting material.

Keywords

oligo(ethylene glycol) - alkanethiol - self-assembled monolayer - mercaptane - thiourea

References and Notes

• 2a Singhvi R. Kumar A. Lopez GP. Stephanopoulos GN. Wang DI. Whitesides GM. Ingber DE. Science  1994,  264:  696 
• 2b Mrksich M. Chem. Soc. Rev.  2000,  29:  267 
• 2c Raghavan S. Chen CS. Adv. Mater.  2004,  16:  1303 
• 2d Li N. Tourovskaia A. Folch A. Crit. Rev. Biomed. Eng.  2003,  31:  423 
• 2e Girard PP. Cavalcanti-Adam EA. Kemkemer R. Spatz JP. Soft Matter  2007,  3:  307 
• 3 Chen CS. Mrksich M. Huang S. Whitesides GM. Ingber DE. Science  1997,  276:  1425 
• 4a Folch A. Toner M. Biotechnol. Prog.  1998,  14:  388 
• 4b Chiu DT. Jeon NL. Huang S. Kane RS. Wargo CJ. Choi IS. Ingber DE. Whitesides GM. Proc. Natl. Acad. Sci. U.S.A.  2000,  97:  2408 
• 5a Prime KL. Whitesides GM. Science  1991,  252:  1164 
• 5b Herrwerth S. Eck W. Reinhardt S. Grunze M. J. Am. Chem. Soc.  2003,  125:  9359 
• 6 Zhao C. Witte I. Wittstock G. Angew. Chem. Int. Ed.  2006,  45:  5469 ; Angew. Chem. 2006, 118, 5595
• 8a Buffeteau T. Desbat B. Turlet JM. Appl. Spectrosc.  1991,  45:  380 
• 8b Zawisza I. Wittstock G. Boukherroub R. Szunerits S. Langmuir  2007,  23:  9303 
• 9 Herrwerth S. Dissertation   Universität Heidelberg; Germany: 2002. 
• 10a Pale-Grosdemange C. Simon ES. Prime KL. Whitesides GM. J. Am. Chem. Soc.  1991,  113:  12 
• 10b Prime KL. Whitesides GM. J. Am. Chem. Soc.  1993,  115:  10714 
• 11a Saalmink M. van der Marel C. Stapert HR. Burdinski D. Langmuir  2006,  22:  1016 
• 11b Nagahori N. Nishimura S.-I. Chem. Eur. J.  2006,  12:  6478 
• 12a Boksanyi L. Liardon O. Kovats E. Helv. Chim. Acta  1976,  59:  717 
• 12b Flink S. Boukamp BA. van den Berg A. van Veggel FCJM. Reinhoudt DN. J. Am. Chem. Soc.  1998,  120:  4652 
• 13 Schwetlick K. Organikum   22 ed.:  Wiley-VCH; Weinheim: 2004. 
• 14 Canaria CA. Smith JO. Yu CJ. Fraser SE. Lansford R. Tetrahedron Lett.  2005,  46:  4813 

1

New address: Universite Louis Pasteur, Institut de Science et Ingenierie Supramoleculaires, Organic and Bioorganic Laboratory, ISIS-ULP-CNRS (UMR 7006), 8, Allee Gaspard Monge, 67083 Strasbourg Cedex, Fance

7

We actually presume a Br,O-acetal formation by a radical mechanism followed by hydrolysis.

15

Hexaethylene glycol (12-bromododecyl) ether (3a) NaH (145 mg, 3.63 mmol, 60% dispersion in mineral oil) was added portionwise to a solution of 1 (6.00 g, 21.3 mmol) in abs. DMF (60 mL) at 23 °C. After the reaction mixture was stirred for 1 h, 2a (1.20 g, 3.66 mmol) was added and the resulting mixture stirred for 17 h at the same temperature. Then it was diluted with Et₂O (100 mL) and washed with H₂O (50 mL). After the separation of the organic layer, the aqueous layer was extracted with Et₂O (2 × 25 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated. The crude product was purified by column chromatography [SiO₂, CH₂Cl₂-MeOH (15:1), R _f = 0.37] to obtain compound 3a (800 mg, 42%) as a colorless liquid. IR (ATR): 3440 (m), 2926 (s), 2856 (s), 1675 (vs), 1460 (m), 1387 (m), 1256 (m), 1094 (vs), 946 (w), 733 (w), 660 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.22-1.29 (m, 14 H), 1.36 (quint, J = 7.1 Hz, 2 H), 1.52 (quint, J = 6.8 Hz, 2 H), 1.80 (quint, J = 7.2 Hz, 2 H), 2.79 (s, 1 H), 3.35 (t, J = 6.9 Hz, 2 H), 3.39 (t, J = 6.8 Hz, 2 H), 3.51-3.56 (m, 4 H), 3.58-3.61 (m, 18 H), 3.66-3.68 (m, 2 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 25.93 (CH₂), 28.02 (CH₂), 28.60 (CH₂), 29.27 (CH₂), 29.32 (CH₂), 29.35 (CH₂), 29.38 (CH₂), 29.41 (CH₂), 29.48 (CH₂), 32.68 (CH₂), 38.86 (CH₂), 61.54 (CH₂), 69.90 (CH₂), 70.20 (CH₂), 70.40-70.47 (8 CH₂), 71.36 (CH₂), 72.40 (CH₂). HRMS (CI, isobutane): m/z calcd for C₂₄H₅₀BrO₇ [M⁺ + H]: 529.2740; found: 529.2740.
Hexaethylene glycol (12-bromododecyl- d ₂₄ ) ether (3b) IR (ATR): 3440 (m), 2926 (s), 2867 (s), 2197 (m), 2095 (m), 1456 (m), 1349 (m), 1256 (w), 1105 (vs), 946 (w), 731 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 2.96 (s, 1 H), 3.46-3.48 (m, 2 H), 3.49-3.51 (m, 2 H), 3.53-3.58 (m, 18 H), 3.61 (t, J = 4.6 Hz, 2 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 27.52-28.54 (m, 10 CD₂), 61.33 (CH₂), 69.68 (CH₂), 70.04 (CH₂), 70.25 (CH₂), 70.26-70.28 (5 CH₂), 70.32 (CH₂), 70.33 (CH₂), 72.32 (CH₂); signals for OCD₂ and CD₂Br are not observed. HRMS (CI, isobutane): m/z calcd for C₂₄H₂₆D₂₄BrO₇ [M⁺ + H]: 553.4246; found: 553.4245.

16

Hexaethylene glycol (12-bromododecyl) methyl ether (4a) A solution of MeI (2.60 g, 18.3 mmol) in abs. DMF (12 mL) was added to a cooled solution of NaH (55 mg, 1.38 mmol, 60% dispersion in mineral oil) in abs. DMF (12 mL) at -5 °C. After 15 min, a solution of alcohol 3a (487 mg, 0.920 mmol) in abs. DMF (12 mL) was added dropwise at -5 °C and the mixture was stirred for 3.5 h at the same temperature. Few drops of MeOH were added and the resulting mixture was poured into a mixture of ice-cold H₂O (5 mL) and Et₂O (10 mL). After layers were separated, the aqueous layer was extracted with Et₂O (2 × 10 mL) and the combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by column chroma-
tography [SiO₂, CH₂Cl₂-MeOH (24:1), R _f = 0.50] to obtain compound 4a (430 mg, 86%) as a colorless liquid. IR (ATR): 2925 (s), 2860 (s), 1659 (m), 1460 (m), 1352 (m), 1251 (m), 1106 (vs), 948 (w), 853 (w), 723 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.21-1.29 (m, 14 H), 1.31-1.39 (m, 2 H), 1.51 (quint, J = 6.9 Hz, 2 H), 1.79 (quint, J = 7.2 Hz, 2 H), 3.32 (s, 3 H), 3.34 (t, J = 6.9 Hz, 2 H), 3.38 (t, J = 6.8 Hz, 2 H), 3.48-3.52 (m, 4 H), 3.57-3.60 (m, 20 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 25.91 (CH₂), 27.99 (CH₂), 28.58 (CH₂), 29.24 (CH₂), 29.29 (CH₂), 29.32 (CH₂), 29.35 (CH₂), 29.38 (CH₂), 29.46 (CH₂), 32.65 (CH₂), 33.78 (CH₂), 58.83 (CH₃), 69.89 (CH₂), 70.34 (CH₂), 70.40-70.45 (9 CH₂), 71.32 (CH₂), 71.77 (CH₂). HRMS (CI, isobutane): m/z calcd for C₂₅H₅₂BrO₇ [M⁺ + H]: 543.2897; found: 543.2898.
Hexaethylene glycol (12-bromododecyl- d ₂₄ ) methyl ether (4b) IR (ATR): 2926 (s), 2866 (s), 2197 (m), 2095 (m), 1456 (m), 1350 (m), 1296 (w), 1106 (vs), 989 (m), 949 (w), 852 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 3.32 (s, 3 H), 3.48-3.51 (m, 4 H), 3.56-3.60 (m, 20 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 27.56-28.52 (m, 10 CD₂), 58.82 (CH₃), 69.81 (CH₂), 70.33 (CH₂), 70.40-70.42 (7 CH₂), 70.44 (CH₂), 70.47 (CH₂), 71.76 (CH₂); signals for OCD₂ and CD₂Br are not observed. HRMS (CI, isobutane): m/z calcd for C₂₅H₂₈D₂₄BrO₇ [M⁺ + H]: 567.4403; found: 567.4403.

17

Hexaethylene glycol (12-thiododecyl) methyl ether (5a) A solution of bromide 4a (418 mg, 0.768 mmol) and thiourea (65 mg, 0.853 mmol) in EtOH (0.2 mL) was degassed (freeze, pump, thaw) and refluxed under N₂ for 6 h. After cooling to 23 °C, NaOH (0.5 mL, c = 5 mol L^-1, aqueous solution) was added. The solution was again degassed (freeze, pump, thaw) and slowly heated to reflux. After refluxing for 2 h under N₂ atmosphere, it was cooled to 23 °C, acidified with HCl (1 mL, c = 2 mol L^-1) and diluted with CH₂Cl₂ (1 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 1 mL). The combined organic layers were washed with sat. aq NaHCO₃ solution (1 mL), dried over MgSO₄, filtered, and evaporated in vacuo. The crude product was purified by column chromatography [SiO₂, CH₂Cl₂-MeOH (24:1), R _f = 0.45] to obtain compound 5a (280 mg, 73%) as a colorless liquid. IR (ATR): 2923 (s), 2854 (s), 1458 (m), 1350 (m), 1248 (w), 1104 (vs), 1040 (w), 945 (m), 852 (m), 722 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.21-1.34 (m, 15 H), 1.47-1.60 (m, 4 H), 2.46 (q, J = 7.4 Hz, 2 H), 3.32 (s, 3 H), 3.40 (t, J = 6.8 Hz, 2 H), 3.48-3.53 (m, 4 H), 3.57-3.60 (m, 22 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 24.51 (CH₂), 25.97 (CH₂), 28.25 (CH₂), 28.94 (CH₂), 29.36-29.52 (7 CH₂), 33.92 (CH₂), 58.89 (CH₃), 69.93 (CH₂), 70.40-70.47 (9 CH₂), 71.39 (CH₂), 71.82 (CH₂). HRMS (CI, isobutane):
m/z calcd for C₂₅H₅₃O₇S [M⁺ + H]: 497.3512; found: 497.3512.
Hexaethylene glycol (12-thiododecyl- d ₂₄ ) methyl ether (5b)
IR (ATR): 2925 (s), 2866 (s), 2197 (m), 2095 (m), 1456 (m), 1350 (m), 1297 (w), 1246 (m), 1106 (vs), 947 (m), 852 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.23 (s, 1 H, SH), 3.32 (s, 3 H), 3.48-3.51 (m, 4 H), 3.56-3.60 (m, 20 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 27.55-28.56 (m, 10 CD₂), 58.83 (CH₃), 69.79 (CH₂), 70.33 (CH₂), 70.40-70.42 (7 CH₂), 70.46 (CH₂), 70.47 (CH₂), 71.75 (CH₂); signals for OCD₂ and CD₂SH are not observed. HRMS (CI, isobutane): m/z calcd for C₂₅H₂₉D₂₄O₇S [M⁺ + H]: 521.5018; found: 521.5018.