Supporting Information Molecular
patterning
at
a
liquid/solid
interface:
the
foldamer approach Min Li, Cristian Gobbo, Inge De Cat, Rienk Eelkema, Bernard Vanaverbeke, Roberto Lazzaroni, Steven De Feyter and Jan van Esch.
1. Experimental Section of synthesis Methods and materials: Starting materials and reagents were purchased from Aldrich or Acros. 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride is indicated as DMTMM.1 All solvents were dried according to standard procedures. Tetrahydrofuran
and
dimethylformamide
are
indicated
as
THF
and
DMF,
respectively. Solvent removal (bulk amount), unless differently specified in the procedure, was worked out at 45 ºC, applying different vacuum with regard to the solvent. 1H-NMR and
13
C-NMR spectra were recorded at 25 ºC in CDCl3 on a ‘Varian
Inova-300’ (at 300MHz for 1H-NMR and at 75.42 MHz for
13
C-NMR) and on a ‘Bruker
Advance-400’ (at 400 MHz for 1H-NMR and at 100.57 MHz for
13
C-NMR). Chemical
shift were given relative to TMS using the residual solvent peak of CHCl3 at 7.27 ppm (for 1H-NMR) and CDCl3 at 77.2 ppm (for splitting patterns in
1
13
C-NMR) as internal standards. The
H-NMR spectra are designated as follows: s (singlet), d
(doublet), t (triplet), m (multiplet), br (broad). MS (EI ionization) were acquired on a ‘Shimadzu GCMS-QP2010S’ system in EI+ ionization mode. MS (ESI ionization) were performed on a ‘Shimadzu LCMS-2010A’. The most intensive peak was abbreviated as (100%). Melting points (m.p.) were measured on ‘Electrothermal IA9300’ apparatus. IR spectra were recorded on ‘Perkin Elmer Spectrum One’ FT-IR spectrometer.
1
Synthesis
2-(Tetrahydro-2H-pyran-2-yloxy)phenol (5): Catechol (35.5 g, 0.32 mol) was dissolved in CH2Cl2 (180 ml). Pyridinium p-toluenesulfonate (PPTS, 1.11 g, 4.25 mmol) and dihydropyran (29.3 ml, 0.32 mol) were added in sequence and the solution was stirred 3h. The solution was extracted with NaOH(aq) (300ml) at pH=13. The aqueous layer was adjusted to pH=7.5 with HCl(aq) and extracted with CH2Cl2 (200ml, 2x). The organic layer was separated, dried over anhydrous Na2SO4 and, after filtration of the solution, the solvent was removed under vacuum. The obtained solid was dissolved in petroleum ether:CH2Cl2 = 50:50 and filtered over silica gel. After removal of solvent, the product was obtained as colorless oil. Yield: 41.2 g (0.21 mol, 66%). Rf (CH2Cl2) = 0.59. 1H-NMR (CDCl3): δ 7.08 (d, 3J = 8.0 Hz, 1H), 6.98 6.95 (m, 2H), 6.83 - 6.79 (m, 1H), 6.56 (s, 1H), 5.18 (d, 3J = 4.4 Hz, 1H), 4.03 - 3.98 (m, 1H), 3.66 - 3.61 (m, 1H), 2.05 - 1.80 (m, 3H), 1.75 - 1.55 (m, 3H).
13
C-NMR
(CDCl3): δ 147.4, 144.6, 123.8, 120.2, 118.0, 115.9, 100.3, 63.8, 30.8, 24.9, 19.75. MS (EI+): m/z 194, 121, 110, 85 (100%), 67, 57.
2-(2-(3-Chloropropoxy)phenoxy)tetrahydro-2H-pyran (6): Compound 5 (40.6 g, 0.21 mol) was dissolved in acetone (500ml). Pre-dried (105 ºC) K2CO3 (87.0 g, 0.63 mol) was added to the stirred solution. The mixture was stirred at reflux for 10 min. and 1-bromo-3-chloropropane (42.0 ml, 0.42 mol) was added dropwise. The resulting mixture was stirred at reflux for 20 h. The mixture was cooled down at r.t. and filtered. The solvent was removed from the filtered solution. The crude product was dissolved in CH2Cl2 (500ml) and the solution was washed with NaOH(aq) at pH=13 (500ml, 2x). The organic layer was dried over anhydrous Na2SO4. The solution was filtrated and the solvent was removed to obtain an oil that was further purified by column chromatography (silica gel, petroleum ether: ethyl acetate). Applying eluent with gradient, product was collected at petroleum ether: ethyl acetate = 75:25. The eluent was removed to obtain a colorless oil. Yield: 46.9 g (0.17 mol, 83%). Rf (CH2Cl2) = 2
0.68. 1H-NMR (CDCl3): δ 7.16 (d, 3J = 8.0 Hz, 1H), 7.00 - 6.87 (m, 3H), 5.40 (s, 1H), 4.17 (t, 3J = 9.0 Hz, 2H), 4.01 (t, 3J = 12.0 Hz, 1H), 3.89 (t, 3J = 9.0 Hz, 2H), 3.67 3.55 (m, 1H), 2.30 - 2.21 (m, 2H), 2.12 - 1.81 (m, 3H), 1.78 -1.40 (m, 3H).
13
C-NMR
(CDCl3): δ 149.7, 147.2, 122.9, 122.0, 118.7, 115.3, 97.8, 66.1, 62.3, 41.8, 32.8, 30.6, 25.5, 19.0. MS (EI+): m/z 207, 186, 148, 110 (100%), 92, 81, 64.
2-(2-(3-Azidopropoxy)phenoxy)tetrahydro-2H-pyran (7): Compound 6 (46.9 g, 0.17 mol) was dissolved in DMF (240 ml). The solution was stirred and NaN3 (15,0 g, 0.20 mol) was added. The mixture was stirred at 60 °C for 22 h. The mixture was filtrated and the solvent was removed from the filtrated solution. The obtained residue was poured into water (400ml), and extracted with CH2Cl2 (400ml, 2x). The combined organic layers were washed with NaHCO3(sat.) (400ml) and dried over anhydrous Na2SO4. The solution was filtrated and the solvent removed to obtain a brownish oil. High vacuum was applied to remove last traces of solvent. Yield: 47.9 g (0.17 mol, 100%). Rf (CH2Cl2) = 0.61. 1H-NMR (CDCl3): δ 7.13 (d, 3J = 7.6 Hz, 1H), 6.98 - 6.90 (m, 3H), 5.40 (s, 1H), 4.10 (t, 3J = 5.6 Hz, 2H), 4.00 (t, 3J = 10.8 Hz, 1H), 3.62 – 3.54 (m, 3H), 2.11 - 1.84 (m, 5H), 1.74 - 1.56 (m, 3H).
13
C-NMR (CDCl3): δ 149.6, 147.2,
122.8, 122.0, 118.6, 115.1, 97.7, 66.2, 62.2, 48.5, 30.6, 29.2, 25.5, 19.0. MS (EI+): m/z 193, 151, 136, 121, 110, 92, 81, 56(100%).
Tert-butyl 3-(2-(tetrahydro-2H-pyran-2-yloxy)phenoxy) propyl carbamate (9): Compound 7 (46.6 g, 0.17 mol) was dissolved in THF (330 ml). Triphenylphosphine (43.9 g, 0.17 mol) was added and the solution was stirred 90 min under N2 atmosphere at room temperature. Water (15.2 ml, 0.84 mol) was added and the solution was stirred 3.5 h at room temperature under normal atmosphere. The solvent was removed and the residue was dried under high vacuum to remove water traces. The obtained mixture was dissolved in CH2Cl2 (330 ml) and, in sequence, triethylamine (TEA, 24 ml, 0.17 mol) and di-tert-butyl dicarbonate (55 ml, 0.26 mol) were added. The solution was stirred for 1h and solvent and triethylamine were 3
removed under vacuum at 60 °C. The obtained mixture was purified by column chromatography (silica gel, petroleum ether: ethyl acetate). Applying eluent with gradient, product was collected at petroleum ether: ethyl acetate = 75:25. The eluent was removed to obtain a colorless oil. Yield: 55.1 g (0.16 mol, 94%). Rf (heptane : ethyl acetate : TEA = 50 : 50 : 1 ) = 0.62. 1H-NMR (CDCl3): δ 7.13 (d, 3J = 7.5 Hz, 1H), 6.97 - 6.91 (m, 3H), 5.38 (s, 1H), 5.18 (br, 1H), 4.10 - 3.95 (m, 3H), 3.63 - 3.58 (m, 1H), 3.38 (d, 3J = 5.0 Hz, 2H), 2.09 - 1.74 (m, 5H), 1.81 - 1.56 (m, 3H), 1.44 (s, 9H).
13
C-NMR (CDCl3): δ 156.1, 149.4, 146.9, 122.5, 121.6, 117.9, 114.4, 97.7, 79.1,
68.0, 62.3, 38.6, 30.4, 29.5, 28.4, 25.2, 19.1. MS (EI+): m/z 193, 110 (100%), 84, 81, 56.
Tert-butyl 3-(2-hydroxyphenoxy)propylcarbamate (10): Compound 9 (55.0 g, 0,16 mol) was dissolved in ethanol (240 ml). Pyridinium p-toluenesulfonate (PPTS, 3.97 g, 15.7 mmol) was added and the solution was heated at 55 °C for 4h. The solvent was removed and the obtained crude was dissolved in CH2Cl2 (250 ml). The solution was extracted with 1M NaOH(aq) (200 ml, 2x). After extraction the aqueous layers were combined and set to pH = 7.0 with HCl(aq) and extracted with CH2Cl2 (400 ml, 2x). The organic layers were combined and dried over anhydrous Na2SO4. The solution was filtrated and the solvent was removed to obtain the desired product as white solid. Yield: 40.1 g (0.15 mol, 96%). Rf (heptane : ethyl acetate : TEA = 50 : 50 : 1) = 0.54. m.p. = 58.9 – 60.5 °C. 1H-NMR (CDCl3): δ 6.95 (d, 3J = 8.5 Hz, 1H), 6.90 - 6.80 (m, 3H), 6.25 (s, 1H), 4.69 (br, 1H), 4.11 (t, 3J = 5.9 Hz, 2H), 3.37 (d, 3J = 6.0 Hz, 2H), 2.00 (m, 2H), 1.45 (s, 9H).
13
C-NMR (CDCl3): δ 156.4, 146.5, 145.9, 122.0,
120.1, 115.4, 113.0, 79.8, 66.5, 37.5, 29.9, 28.5. MS (EI+): m/z 193, 167, 151, 136, 121, 110(100%), 84, 81, 59, 56.
4
Methyl
2-(2-(3-(tert-butoxycarbonylamino)propoxy)phenoxy)acetate
(11a):
Compound 10 (11.5 g, 43.0 mmol) was dissolved in acetone (140 ml). K2CO3 (7.1 g, 51.6 mmol) was added and the solution was stirred at reflux for 30 min. Methyl bromoacetate (4.9 ml, 51.6 mmol) was added and the solution was stirred at reflux for 39 h. The mixture was brought to room temperature and the solid was filtered off. The solvent was removed from the filtered solution and the resulting residue was dissolved in CH2Cl2 (150 ml). The organic layer was washed with 1M NaOH(aq) (100 ml, 2x) and NaHCO3(sat.) (100 ml). The solvent was removed from the organic layer and the obtained residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate). Applying eluent with gradient, product was collected at petroleum ether: ethyl acetate = 75:25. The eluent was removed to obtain the product as yellow oil. Yield: 12.6 g (37.0 mmol, 86%). Rf (heptane : ethyl acetate = 50 : 50) = 0.52. 1H-NMR (CDCl3): δ 7.11 – 6.82 (m, 4H), 5.44 (br, 1H), 4.71 (s, 2H), 4.10 (t, 3J = 5.6 Hz, 2H), 3.79 (s, 3H), 3.37 (d, 3J = 5.6 Hz, 2H), 2.01 (t, 3J = 5.6 Hz, H), 1.44 (s, 9H). 13C-NMR (CDCl3): δ 169.6, 156.1, 148.9, 147.9, 122.6, 121.3, 114.5, 114.2, 78.9, 68.1, 66.4, 52.1, 38.7, 29.3, 28.4. MS (EI+): m/z 182, 150, 122, 102(100%), 74, 57.
Methyl
4-(2-(3-(tert-butoxycarbonylamino)propoxy)phenoxy)butanoate
(11b):
Compound 10 (9.7 g, 36.3 mmol) was dissolved in acetone (120 ml). K2CO3 (6.0 g, 43.4 mmol) was added and the solution was stirred at reflux for 30 min. Methyl 4bromobutyrate (5.5 ml, 43.4 mmol) was added and the solution was stirred at reflux for 39 h. The mixture was brought to room temperature and the solid was filtered off. The solvent was removed from the filtered solution and the resulting residue was dissolved in CH2Cl2 (150 ml). The organic layer was washed with1M NaOH(aq) (100 ml, 2x) and NaHCO3(sat.) (100 ml). The solvent was removed from the organic layer and the obtained residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate). Applying eluent with gradient, product was collected at petroleum ether: ethyl acetate = 75:25. The eluent was removed to obtain the 5
product as white solid. Yield: 10.2 g (27.9 mmol, 77%). Rf (heptane : ethyl acetate : TEA = 50 : 50 : 1) = 0.63. m.p. = 53.7 - 54.0 °C. 1H-NMR (CDCl3): δ 7.00 - 6.82 (m, 4H), 5.31 (br, 1H), 4.10 - 4.05 (m, 4H), 3.69 (s, 3H), 3.38 (d, 3J = 5.4 Hz, 2H), 2.55 (t, 3
J = 7.2 Hz, 2H), 2.21 - 2.12 (m, 2H), 2.01 (t, 3J = 5.8 Hz, 2H), 1.45 (s, 9H).
13
C-NMR
(CDCl3): δ 173.8, 156.3, 149.0, 121.7, 121.6, 114.2, 114.0, 79.2, 68.1, 51.8, 39.0, 30.7, 29.7, 28.7, 24.8. MS (EI+): m/z 207, 136, 121, 110, 101(100%), 84, 81, 69, 59, 56.
Methyl
6-(2-(3-(tert-butoxycarbonylamino)propoxy)phenoxy)hexanoate
(11c):
Compound 10 (10.1 g, 37.8 mmol) was dissolved in acetone (125 ml). K2CO3 (6.3 g, 45.3 mmol) was added and the solution was stirred at reflux for 30 min. Methyl 6bromohexanoate (7.2 ml, 45.3 mmol) was added and the solution was stirred at reflux for 39 h. The mixture was brought to room temperature and the solid was filtered off. The solvent was removed from the filtered solution and the resulting residue was dissolved in CH2Cl2 (150 ml). The organic layer was washed with 1M NaOH(aq) (100 ml, 2x) and NaHCO3(sat.) (100 ml). The solvent was removed from the organic layer and the obtained residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate). Applying eluent with gradient, product was collected at petroleum ether: ethyl acetate = 75:25. The eluent was removed to obtain the product as colorless oil. Yield: 11.5 g (29.1 mmol, 77%). Rf (ethyl acetate) = 0.86. 1HNMR (CDCl3): δ 6.95 - 6.83 (m, 4H), 5.33 (br, 1H), 4.12 - 3.97 (m, 4H), 3.67 (s, 3H), 3.37 (d, 3J = 5.6 Hz, 2H), 2.35 (t, 3J = 7.6 Hz, 2H), 2.02 - 1.97 (m, 2H), 1.91 - 1.81 (m, 2H), 1.76 - 1.65 (m, 2H), 1.56 - 1.43 (m, 11H).
13
C-NMR (CDCl3): δ 174.2, 156.2,
149.1, 148.7, 121.6, 121.1, 114.1, 113.5, 79.1, 68.7, 68.1, 51.6, 38.8, 34.1, 29.6, 28.9, 28.6, 25.8, 24.8. MS (EI+): m/z 207, 193, 129, 121, 110, 97, 87, 84, 81, 69(100%), 59, 58, 56.
6
2-(2-(3-(Tert-butoxycarbonylamino)propoxy)phenoxy)acetic
acid
(Boc.4a):
Compound 11a (11.3 g, 33.1 mmol) was dissolved in methanol (90 ml) and LiOH (1.19 g, 49.7 mmol) was added. The solution was stirred at room temperature for 48 h. The solvent was removed and the residue was poured into water (100 ml) adjusted to pH=1 with HCl(aq) and extracted with CH2Cl2 (100 ml, 2x). The combined organic layers were dried over anhydrous Na2SO4 and the solid was filtered off. The solvent was removed to obtain a white solid. The solid was recrystallized from CH2Cl2/heptane and, after filtration, white crystals of product were collected. The crystals were rinsed with heptane and dried at 45 °C under vacuum. Yield: 10.1 g (31.1 mmol, 94%). Rf (heptane : ethyl acetate = 1:1) = 0.13. m.p. = 111.2 - 111.7 °C. 1
H-NMR (CDCl3): δ 7.06 - 6.89 (m, 4H), 4.96 (br, 1H), 4.66 (s, 2H), 4.10 (s, 2H), 3.41
- 3.37 (m, 2H), 2.05 - 1.97 (m, 2H), 1.43 (s, 9H).
13
C-NMR (CDCl3): δ 171.2, 156.6,
149.4, 147.9, 124.0, 121.8, 117.5, 113.8, 79.8, 68.7, 67.3, 38.4, 29.9, 28.6. MS (EI+): m/z 251, 168, 163, 150, 124, 122, 121, 109, 102(100%).
4-(2-(3-(Tert-butoxycarbonylamino)propoxy)phenoxy)butanoic
acid
(Boc.4b):
Compound 11b (8.3 g, 22.6 mmol) was dissolved in methanol (63 ml) and LiOH (0.81 g, 33.8 mmol) was added. The solution was stirred at room temperature for 48 h. The solvent was removed and the residue was poured into water (100 ml) adjusted to pH=1 with HCl(aq) and extracted with CH2Cl2 (100 ml, 2x). The combined organic layers were dried over anhydrous Na2SO4 and the solid was filtered off. The solvent was removed to obtain a white solid. The solid was recrystallized from CH2Cl2/heptane and, after filtration, white crystals of product were collected. The crystals were rinsed with heptane and dried at 45 °C under vacuum. Yield: 7.6 g (21.4 mmol, 95%). Rf (ethyl acetate) = 0.67. m.p. = 81.0 - 81.5 °C. 1H-NMR (CDCl3): 7
δ 6.95 - 6.82 (m, 4H), 5.19 (br, 1H), 4.12 - 4.02 (m, 4H), 3.45 - 3.35 (m, 2H), 2.60 (t, 3
J = 6.8 Hz, 2H), 2.23 - 2.12 (m, 2H), 2.07 - 1.98 (m, 2H), 1.44 (s, 9H).
13
C-NMR
(CDCl3): δ 177.3, 156.6, 148.9, 121.4, 113.7, 113.4, 79.8, 68.1, 67.3, 38.7, 31.1, 29.8, 28.6, 24.5. MS (EI+): m/z 193, 158, 121, 110(100%), 102.
6-(2-(3-(Tert-butoxycarbonylamino)propoxy)phenoxy)hexanoic
acid
(Boc.4c):
Compound 11c (10.3 g, 26.0 mmol) was dissolved in methanol (83 ml) and LiOH (0.94 g, 39.2 mmol) was added. The solution was stirred at room temperature for 48 h. The solvent was removed and the residue was poured into water (100 ml) adjusted to pH=1 with HCl(aq) and extracted with CH2Cl2 (100 ml, 2x). The combined organic layers were dried over anhydrous Na2SO4 and the solid was filtered off. The solvent was removed to obtain a white solid. The solid was recrystallized from CH2Cl2/heptane and, after filtration, white crystals of product were collected. The crystals were rinsed with heptane and dried at 45 °C under vacuum. Yield: 8.6 g (22.5 mmol, 86%). Rf (ethyl acetate) = 0.72. m.p. = 63.9 - 64.9 °C. 1H-NMR (CDCl3): δ 6.95 - 6.82 (m, 4H), 5.24 (br, 1H), 4.10 - 3.98 (m, 4H), 3.42 - 3.31 (m, 2H), 2.39 (t, 3
J = 6.8 Hz, 2H), 2.04 - 1.94 (m, 2H), 1.91 - 1.80 (m, 2H), 1.78 - 1.67 (m, 2H), 1.60 -
1.53 (m, 2H), 1.45 (s, 9H).
13
C-NMR (CDCl3): δ 178.2, 156.4, 148.6, 121.6, 120.9,
114.2, 113.2, 79.4, 68.4, 67.9, 38.7, 29.6, 28.9, 28.5, 25.7, 24.6. MS (EI+): m/z 206, 193, 158, 121, 115, 110, 102(100%).
Tert-butyl 3-(2-(2-(dodecylamino)-2-oxoethoxy)phenoxy)propylcarbamate (12a): Compound 4a (0.96 g, 2.94 mmol) was dissolved in THF and dodecylamine (0.60 g, 3.23 mmol) was added. After the mixture had been stirred for 10 min, and the solution had become clear, DMTMM (0.90 g, 3.23 mmol) was added and the solution 8
was stirred for 21 h. The solution was filtered and the solvent was removed to obtain the crude mixture. The crude was dissolved in the minimum amount of CH2Cl2 and purified by column chromatography (silica gel, petroleum ether: ethyl acetate). Applying eluent with gradient, product was collected at petroleum ether: ethyl acetate = 65:35. The eluent was removed to obtain the product as white solid. Yield: 1.33 g (2.67 mmol, 91%). Rf (ethyl acetate) = 0.81. m.p. = 78.6 - 79.0 °C. 1H-NMR (CDCl3): δ 7.02 - 6.87 (m, 5H), 5.11 (br, 1H), 4.53 (s, 2H), 4.10 (t, 3J = 5.6 Hz, 2H), 3.39 - 3.27 (m, 4H), 2.05 - 1.97 (m, 2H), 1.60 - 1.39 (m, 11H), 1.35 - 1.15 (m, 18H), 0.88 (t, 3J = 6.8 Hz, 3H) .
13
C-NMR (CDCl3): δ 168.7, 156.2, 148.9, 147.6, 123.0, 121.6, 115.1,
113.4, 79.4, 69.4, 67.4, 39.3, 38.6, 32.1, 29.9, 29.8, 29.6, 29.5, 28.6, 27.1, 22.9, 14.3.
Tert-butyl 3-(2-(4-(dodecylamino)-4-oxobutoxy)phenoxy)propylcarbamate (12b): Compound 4b (0.61 g, 1.73 mmol) was dissolved in THF and dodecylamine (0.35 g, 1.91 mmol) was added. After the mixture had been stirred for 10 min, and the solution had become clear, DMTMM (0.53 g, 1.91 mmol) was added and the solution was stirred for 21 h. The solution was filtered and the solvent was removed to obtain the crude mixture. The crude was dissolved in the minimum amount of CH2Cl2 and purified by column chromatography (silica gel, petroleum ether: ethyl acetate). Applying eluent with gradient, product was collected at petroleum ether: ethyl acetate = 65:35. The eluent was removed to obtain the product as white solid. Yield: 0.77 g (1.47 mmol, 85%). Rf (ethyl acetate) = 0.65. m.p. = 86.0 - 86.6 °C. 1H-NMR (CDCl3): δ 6.97 - 6.80 (m, 4H), 6.24 (br, 1H), 5.06 (br, 1H), 4.16 - 4.00 (m, 4H), 3.44 - 3.30 (m, 2H), 3.24 - 3.16 (m, 2H), 2.54 - 2.40 (m, 2H), 2.25 - 2.12 (m, 2H), 2.05 - 1.94 (m, 2H), 1.50 - 1.36 (m, 11H), 1.36 - 1.16 (m, 18H), 0.88 (t, 3J = 6.8 Hz, 3H) .
13
C-NMR
(CDCl3): δ 172.7, 156.4, 148.8, 147.5, 121.8, 121.3, 114.0, 113.7, 79.5, 68.1, 67.5, 39.8, 38.8, 33.1, 32.2, 30.0, 29.9, 29.8, 29.6, 28.7, 27.3, 25.5, 23.0, 14.4.
9
Tert-butyl
3-(2-(6-(dodecylamino)-6-oxohexyloxy)phenoxy)propylcarbamate
(12c): Compound 4c (0.87 g, 2.27 mmol) was dissolved in THF and dodecylamine (0.46 g, 2.50 mmol) was added. After the mixture had been stirred for 10 min, and the solution had become clear, DMTMM (0.69 g, 2.50 mmol) was added and the solution was stirred for 21 h. The solution was filtered and the solvent was removed to obtain the crude mixture. The crude was dissolved in the minimum amount of CH2Cl2 and purified by column chromatography (silica gel, petroleum ether: ethyl acetate). Applying eluent with gradient, product was collected at petroleum ether: ethyl acetate = 65:35. The eluent was removed to obtain the product as white solid. Yield: 1.18 g (2.16 mmol, 95%). Rf (ethyl acetate) = 0.62. m.p. = 82.5 - 82.9 °C. 1H-NMR (CDCl3): δ 6.97 - 6.82 (m, 4H), 5.77 (br, 1H), 5.29 (br, 1H), 4.09 - 3.96 (m, 4H), 3.42 - 3.30 (m, 2H), 3.25 - 3.16 (m, 2H), 2.19 (t, 3J = 7.2 Hz, 2H), 2.06 - 1.93 (m, 2H), 1.92 - 1.77 (m, 2H), 1.77 - 1.66 (m, 2H), 1.56 - 1.36 (m, 13H), 1.36 - 1.17 (m, 18H), 0.88 (t, 3J = 6.8 Hz, 3H) . 13C-NMR (CDCl3): δ 173.2, 156.4, 149.4, 148.9, 121.9, 121.2, 114.4, 113.6, 79.3, 68.8, 68.2, 39.8, 39.0, 37.0, 32.2, 30.0, 29.9, 29.8, 29.6, 29.1, 28.8, 27.3, 26.2, 25.8, 23.0, 14.4.
2-(2-(3-Aminopropoxy)phenoxy)-N-dodecylacetamide (13a): Compound 12a (1,30 g, 2.63 mmol) was dissolved in the minimum amount of ether. After complete dissolution, ethereal-HCl (13.2 ml, 1.0 M) was added and the solution was stirred for 17 h, noticing the formation of a white solid while the reaction was taking place. Ether (50 ml) was added and the solution was extracted with slightly warm water (150ml, 2x) adjusted to pH=1 with HCl(aq). The combined aqueous layers were adjusted to pH=13 with NaOH(aq) and extracted with CH2Cl2 (200ml, 2x). The combined organic layers were dried over anhydrous Na2SO4, the solid was filtered off and the solvent 10
was removed to obtain the product as white solid. Yield: 0.94 g (2.38 mmol, 90%). m.p. = 73.5 - 74.0 °C. 1H-NMR (CDCl3): δ 7.08 (br, 1H), 7.02 - 6.87 (m, 4H), 4.50 (s, 2H), 4.11 (t, 3J = 6.4 Hz, 2H), 3.35 - 3.27 (m, 2H), 2.94 (br, 2H), 2.01 - 1.92 (m, 2H), 1.55 - 1.49 (m, 2H), 1.40 - 1.20 (m, 20H), 0.87 (t, 3J = 6.8 Hz, 3H) . 13C-NMR (CDCl3): δ 168.5, 149.1, 147.4, 123.0, 121.3, 115.5, 113.5, 69.4, 67.0, 39.3, 39.0, 33.0, 31.9, 29.7, 29.6, 29.4, 29.3, 26.9, 22.7, 14.3. MS (EI+): m/z 358, 336, 212, 180, 166, 150, 135, 123(100%), 107, 100.
4-(2-(3-Aminopropoxy)phenoxy)-N-dodecylbutanamide (13b): Compound 12b (0.77 g, 1.48 mmol) was dissolved in the minimum amount of ether. After complete dissolution, ethereal-HCl (13.0 ml, 1.0 M) was added and the solution was stirred for 17 h, noticing the formation of a white solid while the reaction was taking place. Ether (50 ml) was added and the solution was extracted with slightly warm water (150ml, 2x) adjusted to pH=1 with HCl(aq). The combined aqueous layers were adjusted to pH=13 with NaOH(aq) and extracted with CH2Cl2 (200ml, 2x). The combined organic layers were dried over anhydrous Na2SO4, the solid was filtered off and the solvent was removed to obtain the product as white solid. Yield: 0.52 g (1.24 mmol, 84%). m.p. = 61.6 - 62.2 °C. 1H-NMR (CDCl3): δ 7.02 (br, 1H), 6.95 - 6.86 (m, 4H), 4.12 (t, 3
J = 5.6 Hz, 2H), 4.02 (t, 3J = 5.6 Hz, 2H), 3.22 - 3.12 (m, 2H), 2.97 (br, 2H), 2.40 (t,
3
J = 7.2 Hz, 2H), 2.17 - 2.09 (m, 2H), 2.09 - 1.93 (m, 2H), 1.48 - 1.36 (m, 2H), 1.36 -
1.18 (m, 18H), 0.89 (t, 3J = 6.8 Hz, 3H) .
13
C-NMR (CDCl3): δ 172.7, 149.1, 148.7,
121.8, 121.3, 114.2, 113.7, 68.7, 67.9, 40.4, 39.6, 33.3, 32.8, 32.0, 29.8, 29.7, 29.5, 27.1, 26.0, 22.8, 14.3. MS (EI+): m/z 254(100%).
6-(2-(3-Aminopropoxy)phenoxy)-N-dodecylhexanamide (13c): Compound 12c (1.15 g, 2.10 mmol) was dissolved in the minimum amount of CH2Cl2. After complete 11
dissolution, ethereal-HCl (19.0 ml, 1.0 M) was added and the solution was stirred for 36 h noticing the formation of a white solid while the reaction was taking place. Ether (50 ml) was added and the solution was extracted with slightly warm water (150ml, 2x) adjusted to pH=1 with HCl(aq). The combined aqueous layers were adjusted to pH=13 with NaOH(aq) and extracted with CH2Cl2 (200ml, 2x). The combined organic layers were dried over anhydrous Na2SO4, the solid was filtered off and the solvent was removed to obtain the product as white solid. Yield: 0.83 g (1.85 mmol, 88%). m.p. = 65.0 - 65.4 °C. 1H-NMR (CDCl3): δ 6.93 - 6.84 (m, 4H), 6.15 (br, 1H), 4.08 (t, 3
J = 6.0 Hz, 4H), 3.98 (t, 3J = 5.6 Hz, 2H), 3.25 - 3.16 (m, 2H), 2.94 (br, 1H), 2.18 (t,
3
J = 7.2 Hz, 2H), 1.98 - 1.91 (m, 2H), 1.87 - 1.77 (m, 2H), 1.76 - 1.66 (m, 2H), 1.56 -
1.40 (m, 6H), 1.36 - 1.17 (m, 18H), 0.88 (t, 3J = 6.8 Hz, 3H) .
13
C-NMR (CDCl3): δ
173.1, 149.2, 149.0, 121.5, 121.2, 113.9, 113.8, 68.9, 67.9, 39.7, 37.0, 32.1, 29.9, 29.8, 29.5, 29.1, 27.2, 26.1, 25.7, 22.9, 14.3. MS (EI+): m/z 282(100%), 222, 180, 167, 142, 114, 100.
N-(3-(2-(2-(Dodecylamino)-2-oxoethoxy)phenoxy)propyl)tetradecanamide
(1):
Compound 13a (915 mg, 2.32 mmol) was dissolved in THF (20 ml) and myristic acid (481 mg, 2.11 mmol) was added. After the mixture had been stirred at r.t. for 10 min noticing the formation of a precipitate, DMTMM (0.82 g, 2.95 mmol) was added and the mixture was stirred at reflux for 21 h. The mixture was filtrated at hot conditions to remove the insoluble material and the mother liquors were slowly cooled down to r.t. noticing the formation of the product as precipitate. The filtrated solid was dissolved in boiling ethyl acetate (140 ml); the hot solution was filtrated and slowly cooled down to r.t in order to obtain crystallization of the product. The mixture was filtered and the product was collected as white crystals that were, first, dried at 45 °C under vacuum and, then, freeze dried to get the pure product 1. Yield: 0.78 g (1.29 mmol, 55%). Rf (ethyl acetate) = 0.64. m.p. = 110.3 - 111.0 °C. 1H-NMR (CDCl3): δ 7.10 - 6.84 (m, 5H), 5.98 (br, 1H), 4.53 (s, 2H), 4.09 (t, 3J = 5.8 Hz, 2H), 3.53 - 3.45 (m, 2H), 3.36 3.27 (m, 2H), 2.14 (t, 3J = 7.4 Hz, 2H), 2.02 (t, 3J = 5.8 Hz, 2H), 1.70 - 1.45 (m, 4H), 12
1.36 - 1.18 (m, 38H), 0.88 (t, 3J = 6.9 Hz, 6H) .
13
C-NMR (CDCl3): δ 173.4, 168.7,
148.8, 147.6, 123.3, 121.7, 115.6, 113.6, 69.6, 67.4, 39.3, 37.4, 37.1, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 27.1, 26.0, 22.9, 14.3. ATR-IR: 3346, 3290, 2918, 2849 1679, 1657, 1641, 1538, 1506. MS (EI+): m/z 268(100%), 112, 100. Elemental analysis calc.: C, 73.71; H, 11.03; N, 4.65; O, 10.61. Found: C, 73.50; H, 11.10; N, 4.70; O, 10.70.
N-(3-(2-(4-(Dodecylamino)-4-oxobutoxy)phenoxy)propyl)tetradecanamide
(2):
Compound 13b (416 mg, 0.95 mmol) was dissolved in THF (8 ml) and myristic acid (197 mg, 0.86 mmol) was added. After the mixture had been stirred at r.t. for 10 min noticing the formation of a precipitate, DMTMM (0.33 g, 1.20 mmol) was added and the mixture was stirred at reflux for 21 h. The mixture was filtrated at hot conditions to remove the insoluble material and the mother liquors were slowly cooled down to r.t. noticing the formation of the product as precipitate. The filtrated solid was dissolved in boiling ethyl acetate (140 ml); the hot solution was filtrated and slowly cooled down to r.t in order to obtain crystallization of the product. The mixture was filtered and the product was collected as white crystals that were, first, dried at 45 °C under vacuum and, then, freeze dried to get the pure product 2. Yield: 0.43 g (0.67 mmol, 71%). Rf (ethyl acetate) = 0.58. m.p. = 124.0 - 124.4 °C. 1H-NMR (CDCl3): δ 6.96 - 6.85 (m, 4H), 6.57 (br, 1H), 6.04 (br, 1H), 4.15 - 4.02 (m, 4H), 3.56 - 3.47 (m, 2H), 3.24 - 3.16 (m, 2H), 2.44 (t, 3J = 6.8 Hz, 2H), 2.19 - 2.11 (m, 2H), 2.03 - 1.96 (m, 2H), 1.65 - 1.55 (m, 2H), 1.55 - 1.18 (m, 40H), 0.87 (t, 3J = 6.9 Hz, 4H).
13
C-NMR (CDCl3): δ 173.5,
172.7, 149.2, 148.7, 121.9, 121.3, 114.2, 113.8, 68.2, 67.5, 39.8, 37.1, 33.1, 32.1, 29.8, 29.7, 29.6, 27.2, 26.0, 25.6, 22.9, 14.3. ATR-IR: 3300, 2917, 2849, 1639, 1594, 1557, 1507. MS (EI+): m/z 268, 254(100%), 112, 100. Elemental analysis calc.: C, 74.24; H, 11.18; N, 4.44; O, 10.14. Found: C, 73.81; H, 11.20; N, 4.48; O, 10.51.
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N-(3-(2-(6-(Dodecylamino)-6-oxohexyloxy)phenoxy)propyl)tetradecanamide (3): Compound 13c (759 mg, 1.69 mmol) was dissolved in THF (15 ml) and myristic acid (351 mg, 1,54 mmol) was added. After the mixture had been stirred at r.t. for 10 min noticing the formation of a precipitate, DMTMM (0.69 g, 2.50 mmol) was added and the mixture was stirred at reflux for 21 h. The mixture was filtrated at hot conditions to remove the insoluble material and the mother liquors were slowly cooled down to r.t. noticing the formation of the product as precipitate. The filtrated solid was dissolved in boiling ethyl acetate (140 ml); the hot solution was filtrated and slowly cooled down to r.t in order to obtain crystallization of the product. The mixture was filtered and the product was collected as white crystals that were, first, dried at 45 °C under vacuum and, then, freeze dried to get the pure product 3. Yield: 0.51 g (0.77 mmol, 50%). Rf (ethyl acetate) = 0.55. m.p. = 133.8 - 134.4 °C. 1H-NMR (CDCl3): δ 6.96 - 6.85 (m, 4H), 6.47 (br, 1H), 5.89 (br, 1H), 4.07 (t, 3J = 5.5 Hz, 2H), 4.01 (t, 3J = 6.2 Hz, 2H), 3.53 - 3.45 (m, 2H), 3.26 - 3.17 (m, 2H), 2.23 - 2.13 (m, 4H), 2.04 - 1.10 (m, 50H), 0.88 (t, 3J = 6.4 Hz, 4H).
13
C-NMR (CDCl3): δ 173.5, 173.2, 149.3, 148.7, 121.9,
121.3, 114.5, 113.8, 68.9, 68.5, 39.8, 38.1, 37.1, 36.9, 32.1, 29.9, 29.8, 29.7, 29.6, 29.2, 27.2, 26.2, 26.1, 25.8, 22.9, 14.3. ATR-IR: 3295, 2918, 2850, 1632, 1543, 1507. MS (EI+): m/z 282, 254(100%), 112, 100. Elemental analysis calc.: C, 74.72; H, 11.32; N, 4.25; O, 9.71. Found: C, 74.61; H, 11.40; N, 4.29; O, 9.70.
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2. Molecular modeling The calculations were carried out using Accelrys Materials Studio 4.4, with the Forcite module. The atomic charges were assigned using the pcff force field and then the geometry was optimized and the energy calculated with the Dreiding force field, which better accounts for H-bonding interactions. The graphite layer was maintained frozen during the calculations, since molecular physisorption is not expected to affect the substrate structure.
Energy calculations for monomers in vacuum (kcal/mol)
1
2
3
Total
Valence
energy
energy
Folded
42.0
21.2
Unfolded
56.9
Folded
Non-
Hydroge
Van der
Electro-
n bond
Waals
static
20.8
-3.4
48.7
-24.5
18.7
38.2
0
54.7
-16.5
46.4
23.3
23.1
-1.8
51.9
-27.0
Unfolded
56.3
19.7
36.6
0
57.8
-21.2
Folded
47.2
24.7
22.5
-3.4
54.4
-28.6
Unfolded
59.8
20.4
39.4
0
60.8
-21.4
Hydroge
Van der
Electro-
n bond
Waals
static
bond energy
Energy calculations for monomers on graphite (kcal/mol)
1
2
3
Non-
Total
Valence
energy
energy
Folded
-35.6
31.8
-67.4
-3.2
-39.9
-24.3
Unfolded
-24.6
28.3
-52.9
0
-36.4
-16.5
Folded
-36.2
35.5
-71.7
-2.9
-40.4
-28.4
Unfolded
-28.4
28.8
-57.2
0
-36.0
-21.2
Folded
-42.1
34.6
-76.7
-3.4
-44.8
-28.5
Unfolded
-30.0
29.3
-59.3
0
-38.0
-21.3
bond energy
15
3. STM measurements Compounds 1, 2 and 3 (2 mg) were completely dissolved in 1-phenyloctane (1 ml) at 60 °C and the solution was let to stand at r.t. overnight. The formed precipitate was filtered off and a droplet of the saturated solution was introduced directly onto a freshly cleaved graphite (HOPG, grade ZYB, Advanced Ceramics Inc., Cleveland, USA) surface. STM experiments were carried out with a Molecular Imaging PicoSPM (Agilent) at 1-phenyloctane/graphite interfaces. Tips were mechanically formed from Pt/Ir wires (80/20). All STM images were recorded in the constant-current mode. The images were processed by scanning probe image processor (SPIP) software (Image Metrology ApS). The imaging parameters (setpoint of the tunneling current and bias voltage) are indicated in the figure captions.
16
4. IR measurements in solution IR spectra in solution were recorded on ‘Perkin Elmer Spectrum One’ FT-IR spectrometer using a 3 mm thick cell and a 4 cm-1 resolution was applied. Measurements were performed at 25 ºC. Number of scans varied from 256 to 1024 based on the concentration of the sample. Solvent subtraction, baseline correction and normalization of absorbance value to 1 were applied. Saturated solutions in phenyloctane were obtained by the same procedure as for STM measurements. 1 mM Dichloromethane solutions were prepared by dissolution of the analyte in the solvent. Less concentrated solutions were prepared by subsequent dilutions.
17
Overlapped spectra of compound 1, 2 and 3:
Minimal foldamers 1, 2 and 3 in the wavenumber range 3500 – 3200 cm-1. Line: saturated solution in 1-phenyloctane. Dash: 5 times dilution for compound 1 and 2, and 1.25 times dilution for compound 3 from the saturated solution (‘monomeric state’ concentration) in 1-phenyloctane. Dash dot: 12.5 μM for compound 1 and 3, and 6.25 μM for compound 2 (‘monomeric state’ concentration) in dichloromethane. 18
Dilution series of minimal foldamers in phenyloctane: Saturated solutions are set as 100%.
Dilution series of minimal foldamers in dichloromethane:
References 1. Kunishima, M.; Kawachi, C.; Morita, J.; Terao, K.; Iwasaki, F.; Tani, S., 4-(4,6dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride: An efficient condensing agent leading to the formation of amides and esters. Tetrahedron 1999, 55, (46), 1315913170.
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