Phenanthroline dicarboxamide-based helical foldamers: Stable helical structures in methanol

Article abstract of DOI:10.1021/jo052222r

A series of new aromatic oligoamides 2-5 based on 1,10-phenanthroline diacid and o-phenylenediamine have been synthesized through a convergent segment coupling strategy. These oligomers can fold into well-defined helical structures in solution through int

Full text of DOI:10.1021/jo052222r

Supporting Information
Phenanthroline Dicarboxamide-based Helical Foldamers: Stable
Helical Structures in Methanol
Zhi-Qiang Hu, Hai-Yu Hu and Chuan-Feng Chen*
Laboratory of Chemical Biology, Center for Molecular Science, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China
E-mail: cchen@iccas.ac.cn
Table of contents
1. Experimental section--------------------------------------------------------------------------S2
2. Comparison of partial 1H NMR spectra for 1, 2 and 3 in CDCl3 -----------------------S7
3. Comparison of partial 1H NMR spectra for 1 in CDCl3 and CD3OD-------------------S8
4. Comparison of partial 1H NMR spectra for 2 in CDCl3 and CDCl3/D2O--------------S9
5. 1H NMR spectra of 4 in CDCl3 at various concentrations ------------------------------S10
6. Representative UV spectra for 2-5 in CH2Cl2 at various concentrations--------------S11
7. ε versus oligomer length n for oligomers 1 to 5 in CH2Cl2 and CH2Cl2/CH3CN----S13
8. Table S1. Crystallographic parameters for the compounds 2, 4, 5 and 21------------ S14
9. Crystal structures -----------------------------------------------------------------------------S16
S1

1. Experimental section
General methods. Melting points, taken on an electrothermal melting point apparatus, are
uncorrected. 1H and 13C NMR spectra were obtained in CDCl3 solution (chemical shifts in
ppm relative to internal TMS, J in Hertz). Mass spectra were obtained by EI and
MALDI-TOF techniques. Materials obtained commercially were used without further
purification.
Compound 7: To the solution of the methyl ester 6 (304 mg, 1 mmol) in THF (15 mL)
and MeOH (8 mL) was added KOH (168 mg, 3 mmol). The mixture was stirred at ambient
temperature for 5h, then neutralized with excess AcOH and extracted with chloroform.
The organic phase was washed with water, dried over anhydrous MgSO4 and then
concentrated to give the acid as a white solid in quantitative yield, which was used without
further purification. A solution of the acid (290 mg, 1 mmol) in SOCl2 (10 mL) was
refluxed for 2h, the excess SOCl2 was then removed by reduced pressure to give acid
chloride. The acid chloride was dissolved in anhydrous CH2Cl2 (10 mL), and dropwise
added over a period of 10 min to a solution of aniline (280 mg, 3 equiv) in CH2Cl2 (10 mL)
at 0°C. The mixture was stirred at room temperature for 4 h. The organic phase was
washed with 2N HCl twice and dried over anhydrous Na2SO4. The solvent was removed
and the residue was purified by recrystallization from methanol to give product 7 as a
white solid (0.34 g, 93 % based on the acid). Mp: 190-191 °C; 1H NMR (CDCl3): δ 10.14
(s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), 7.82 (s, 1H), 7.78 (d, J = 7.5 Hz,
2H), 7.61 (t, J = 8.4 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 4.12 (d, J =
13
6.5 Hz, 2H), 2.36-2.24 (m, 1H), 1.14 (d, J = 6.7 Hz, 6H); C NMR (CDCl3): δ 163.6,
161.1, 153.1, 147.4, 138.7, 137.4, 129.1, 127.0, 125.7, 125.4, 124.6, 123.3, 119.7, 99.7,
75.8, 28.1, 19.2; EI-MS: m/z 365 [M]+; Anal. calcd for C20H19N3O4: C 65.74, H 5.24, N
11.50; found: C 65.95, H 5.28, N 11.50.
Compound 8: A mixture of compound 7 (365 mg, 1 mmol) dissolved in CH2Cl2 (15 mL)
and 10 % Pd/C (20 mg) was stirred at ambient temperature under an atmosphere of
S2

hydrogen for 10 h. The solution was filtered and the CH2Cl2 was evaporated to afford 8 as
1
a yellow solid in quantitative yield. Mp: 176-177 °C; H NMR (CDCl3): δ 9.99 (s, 1H),
7.80 (d, J = 7.7 Hz, 2H), 7.70 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.41-7.34 (m, 3H), 7.15 (t,
J = 7.4 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 5.01 (broad, 2H), 4.00 (d, J = 6.4 Hz, 2H),
13
2.32-2.12 (m, 1H), 1.10 (d, J = 6.7 Hz, 6H); C NMR (CDCl3): δ 163.4, 162.7, 148.5,
143.6, 137.74, 137.3, 129.1, 127.9, 124.3, 123.0, 119.9, 111.7, 110.7, 98.6, 75.1, 28.2,
19.2; EI-MS: m/z 335 [M]+; Anal. calcd for C20H21N3O2: C 71.62, H 6.31, N 12.53; found:
C 71.62, H 6.43, N 12.46.
Compound 9: To a solution of 8 (335 mg, 1 mmol) in methanol (40 mL) was added
dimethyl acetylenedicarboxylate (156 mg, 1.1 mmol). After the reaction mixture was
stirred for 8 h at room temperature, the resulting yellow prisms were collected to give 9
1
(0.339 g, 71 %). Mp: 168-170°C; H NMR (CDCl3): δ 11.76 (s, 1H), 10.49 (s, 1H), 8.09
(d, J = 7.7 Hz, 2H), 7.89 (d, J = 8.4Hz, 1H), 7.80 (s, 1H), 7.48-7.38 (m, 3H), 7.17 (t, J =
7.4 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H,), 5.53 (s, 1H), 4.10 (d, J = 6.5 Hz, 2H,), 3.86 (s, 3H),
13
3.83 (s, 3H), 2.35-2.22 (m, 1H), 1.14 (d, J = 6.7 Hz, 6H); C NMR (CDCl3): δ 170.1,
164.9, 163.7, 162.1, 149.8, 146.6, 138.7, 138.3, 135.9, 128.8, 126.9, 124.2, 122.8, 120.0,
115.7, 114.6, 99.1, 93.6, 75.4, 53.0, 51.6, 28.2, 19.2; EI-MS: m/z 477 [M]+; Anal. calcd for
C26H27N3O6: C 65.40, H 5.70, N 8.80; found: C 65.41, H 5.76, N 8.83.
Compound 10: After the mixture solution of 9 (477 mg, 1 mmol) in diphenylether (20
mL) was refluxed for 30 min, the solution was cooled to room temperature and diluted
with petroleum ether (40 mL). The resulting yellow solid was collected and recrystallized
from methanol to afford 10 (0.24 g, 54 %). Mp 238-240 °C; 1H NMR (CDCl3): δ 10.58 (s,
1H), 9.85 (s, 1H), 8.27 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.85 (s, 1H), 7.84 (d, J
= 7.7 Hz, 2H), 7.46 (t, J = 8.1 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H),
13
4.10 (s, 3H), 4.06 (d, J = 6.6 Hz, 2H), 2.31-2.18 (m, 1H), 1.15 (d, J = 6.7 Hz, 6H); C
NMR (CDCl3): δ 178.6, 163.6, 162.9, 161.0, 150.5, 137.8, 137.3, 135.7, 135.2, 129.3,
125.6, 124.7, 123.2, 123.0, 119.5, 116.9, 114.3, 101.8, 75.8, 53.9, 28.1, 19.2; EI-MS: m/z
S3

445 [M]+; Anal. calcd for C25H23N3O5: C 67.41, H 5.20, N 9.43; found: C 67.48, H 5.47, N
9.04.
Compound 11: To a mixture of 10 (445 mg, 1 mmol), triphenylphosphine (225 mg, 1.1
mmol) and 2-methyl-1-propanol (82 mg, 1.1 mmol) in anhydrous THF (35 mL) at 0°C
under N2 was added diisopropyl azodicarboxylate (183 mg, 1.05 mmol). After being
stirred at 0 °C for 30 min and then at room temperature for 8 h, the reaction mixture was
concentrated and methanol was added. The resulting solid was collected and washed with
cold methanol for three times to afford 11 as a white solid (0.35 g, 71.8 %). Mp: 194-195
°C; 1H NMR (CDCl3): δ 10.82 (s, 1H), 8.32 (q, J = 9.2 Hz, 2H), 8.08 (s, 1H), 7.98 (d, J =
7.9 Hz, 2H), 7.83 (s, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H), 4.21-4.12 (m,
13
7H), 2.41-2.28 (m, 2H), 1.20 (d, J = 6.7 Hz, 6H), 1.18 (d, J = 6.7 Hz, 6H); C NMR
(CDCl3): δ 166.0, 163.3, 162.9, 162.4, 151.5, 148.8, 145.7, 138.1, 128.9, 124.2, 122.9,
122.6, 121.2, 120.2, 120.2, 104.0, 102.0, 75.5, 75.4, 53.2, 28.3, 28.2, 19.3; EI-MS: m/z
501 [M]+; Anal. calcd for C29H31N3O5·½H2O: C 68.22, H 6.32, N 8.23; found: C 68.47, H
6.35, N 8.24.
Compound 12: To the mixture solution of the methyl ester 11 (501 mg, 1 mmol) in THF
(15 mL) and methanol (8 mL) was added KOH (168 mg, 3 mmol). After being stirred at
ambient temperature for 5h, the reaction mixture was neutralized with excess AcOH and
then extracted with chloroform. The organic phase was washed with water, dried over
anhydrous MgSO4 and concentrated to give 12 as a white solid in quantitative yield, which
was used without further purification. Mp: 209-211 °C; 1H NMR (CDCl3): δ 10.77 (s, 1H),
8.46 (broad, 1H), 8.20 (q, J = 9.2 Hz, 2H), 7.86 (s, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.71 (s,
1H), 7.21 (t, J = 7.6 Hz, 2H), 7.00 (t, J = 7.2 Hz, 1H), 4.13-4.04 (m, 4H), 2.35-2.27 (m,
2H), 1.18-1.16 (m, 12H); 13C NMR (CDCl3): δ 165.4, 164.1, 163.0, 161.6, 151.8, 150.3,
141.7, 140.8, 137.8, 128.7, 124.0, 122.7, 122.0, 121.4, 120.3, 119.6, 103.7, 102.5, 76.4,
75.6, 28.2, 28.1, 19.2, 19.1; EI-MS: m/z 487 [M]+; Anal. calcd for C28H29N3O5·½H2O: C
67.73, H 6.09, N 8.46; found: C 67.55, H 6.04, N 8.45.
S4

Compound 15: To a solution of 14 (275 mg, 1 mmol) in methanol (25 mL) was added
dimethyl acetylenedicarboxylate (156 mg, 1.1 mmol). After the reaction mixture was
stirred for 8 h at room temperature, the resulting yellow prisms were collected to give 15
(312 mg, 75 %). Mp: 149-150 °C; 1H NMR (CDCl3): δ 11.16 (s, 1H), 7.83 (d, J = 8.4 Hz,
1H), 7.56 (s, 1H), 7.43 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 5.57 (s, 1H), 4.08 (s,
3H), 4.04 (d, J = 6.3 Hz, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 2.35-2.22 (m, 1H), 1.13 (d, J = 6.7
13
Hz, 6H); C NMR (CDCl3): δ 169.0, 166.1, 165.1, 162.9, 147.4, 145.4, 139.8, 137.4,
127.4, 122.9, 115.0, 114.6, 101.3, 96.6, 75.2, 53.1, 52.8, 51.4, 28.2, 19.2; EI-MS: m/z 416
[M]+; Anal. calcd for C21H24N2O7: C 60.57, H 5.81, N 6.73; found: C 60.66, H 5.82, N
6.67.
Compound 16: After diphenylether (20 mL) was heated to about 200 ºC, 15 (416 mg, 1
mmol) was added. The mixture was refluxed for 30 min, and the solution was cooled to
room temperature and diluted with petroleum ether (40 mL). The resulting yellowish solid
was collected by filter and purified by column chromatography (284 mg, 74 %). Mp
182-183 °C; 1H NMR (CDCl3): δ 10.91 (broad, 1H), 8.25 (d, J = 9.1 Hz, 1H), 7.93 (d, J =
9.1 Hz, 1H), 7.63(s, 1H), 7.15 (s, 1H), 4.11 (s, 3H), 4.09 (s, 3H), 4.05 (d, J = 6.5 Hz, 2H),
13
2.39-2.26 (m, 1H), 1.17 (d, J = 6.7 Hz, 6H); C NMR (CDCl3): δ 178.8, 165.5, 163.0,
162.8, 148.3, 139.4, 136.9, 135.7, 125.6, 123.5, 123.3, 116.8, 114.8, 104.2, 75.6, 53.8,
53.2, 28.2, 19.2; EI-MS: m/z 384 [M]+; Anal. calcd for C20H20N2O6: C 62.49, H 5.24, N
7.29; found: C 62.12, H 5.25, N 7.15.
Compound 17: To a solution of 16 (384 mg, 1 mmol ) in dry DMF (25 mL), K2CO3 (828
mg, 6 mmol ) and 1-bromo-2-methyl propane (408 mg, 3 mmol ) were added. The mixture
was stirred at 100 ºC for 10h. After DMF was removed under reduced pressure, CH2Cl2
was added and washed with water twice. The solvent was removed to leave a yellow solid.
The crude product was purified by recrystalization from methanol to provide 16 as white
1
solid (361 mg, 82 %). Mp 179-181 °C; H NMR (CDCl3): δ 9.34 (s, 2H), 7.86 (s, 2H),
4.12 (d, J = 6.5 Hz, 4H), 4.10 (s, 6H), 2.33 (m, 2H), 1.17 (d, J = 6.7 Hz, 12H); 13C NMR
S5

(CDCl3): δ 166.6, 162.8, 149.3, 146.2, 122.8, 120.9, 104.1, 75.4, 53.0, 28.2, 19.2; EI-MS:
m/z 440 [M]+; Anal. calcd for C24H28N2O6·1/2 H2O: C 64.78, H 6.46, N 6.30; found: C
64.81, H 6.58, N 6.24.
S6

2. Comparison of 1H NMR for 1, 2 and 3 in CDCl3.
Hg
Hg
R
R
R
R
R
R
Hd
NH
Ha
N
N
Hd
N
N
H
Ha
HN
NH
N
N
N
Hb
Hc
H
O
O
O
N
NH
O
Hb
Hc
O
O
He
Hf
1 R=OBu-i
2 R=OBu-i
Hg
R
Hm
R
R
R
R
R
Hd
Hi
N
N
Ha
N
N
N
N
H
HN
NH
HN
NH
NH
O
N
Hb
Hc
O
O
O
O
O
He
Hf
3 R=OBu-i
Figure S1. Comparison of partial 1H NMR spectra for 1, 2 and 3 in CDCl3.
S7

3. Comparison of partial 1H NMR spectra for 1 in CDCl3 and CD3OD.
(b)
*
*
(a)
ppm (t1)
1
Figure S2. Comparison of partial H NMR spectra for 1 in (a) CDCl3 and (b)
CD3OD/CDCl3 (4:1).
S8

4. Comparison of partial 1H NMR spectra for 2 in CDCl3 and D2O/CDCl3.
Figure S3. Comparison of partial 1H NMR spectra for 2 in (a) CDCl3 and (b) D2O/CDCl3.
S9

5. 1H NMR spectra of 4 in CDCl3 at various concentrations
Figure S4. 1H NMR spectra (300 MHz, CDCl3) of 4 at various concentrations. a, 0.6 mM;
b, 1 mM; c, 5 mM.
S10

6. Representative UV spectra for 2-5 in CH2Cl2 at various concentrations.
0.40
2*10-5
0.35
8*10-6
6*10-6
0.30
4*10-6
2*10-6
0.25
0.20
0.15
0.10
0.05
0.00
300
320
340
360
380
400
Wavelength (nm)
Figure S5. Representative UV spectra for 2 in CH2Cl2 at various concentrations.
2*10-5
8*10-6
0.5
6*10-6
4*10-6
0.4
2*10-6
0.3
0.2
0.1
0.0
300
320
340
360
380
400
Wavelength (nm)
Figure S6. Representative UV spectra for 3 in CH2Cl2 at various concentrations.
S11

2*10-5
8*10-6
6*10-6
4*10-6
2*10-6
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
300
320
340
360
380
400
Wavelength (nm)
Figure S7. Representative UV spectra for 4 in CH2Cl2 at various concentrations.
0.9
2*10-5
0.8
8*10-6
6*10-6
0.7
0.6
4*10-6
2*10-6
0.5
0.4
0.3
0.2
0.1
0.0
300
320
340
360
380
400
Wavelength (nm)
Figure S8. Representative UV spectra for 5 in CH2Cl2 at various concentrations.
S12

7. ε versus oligomer length n for oligomers 1 to 5 in CH2Cl2 and CH2Cl2/CH3CN
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
Oligomer length (n)
Figure S9. The molar extinction coefficient ε (324 nm) versus oligomer length n for
oligomers 1 to 5 in CH2Cl2 (green) and CH2Cl2:/CH3CN=7:3 (red).
S13

8. Table S1. Crystallographic parameters for the compounds 2, 4, 5 and 21a.
Compound
2
4
5
21
Empirical
formula
C
64.5H72N8O10.5 C118H118N16O20 C154H166N2O28 C63H68 N9 O9.25
Formula weight
Temperature [K]
Crystal system
Space group
a [Å]
1127.30
293(2)
2080.28
293(2)
2745.07
293(2)
1099.26
293(2)
triclinic
P-1
triclinic
P-1
monoclinic
P2/c
triclinic
P-1
14.020(5)
15.153(5)
16.128(6)
110.655(6)
92.140(6)
104.819(6)
3068.5(19)
2
15.446 (3)
18.167 (4)
21.565 (4)
81.08(3)
82.77(3)
82.46 (3)
5892(2)
2
19.598(4)
15.696 (3)
24.508(5)
90.00
14.224(3)
15.299(4)
17.295(4)
97.973(4)
104.545(4)
117.658(4)
3080.1(12)
2
b[Å]
c[Å]
α [°]
100.17(3)
90.00
β [°]
γ [°]
V [Å3]
7421(3)
2
Z
ρ [Mgm-3]
GooF
1.220
1.173
1.229
1.185
0.994
1.092
1.095
1.022
0.0742
0.1259
0.3320
0.1869
0.4918
0.0949
R1 (I = 2σ (I))
wR (all data)
0.2777
0.3150
a
These crystals were easy to effloresce, so they were all measured in sealed tubes. The
S14

poor qualities of the structures may be due to weak diffraction intensity, strong
disorganization of isobutyl side chains and included solvent molecules. However, all C
and N atoms belonging to the backbone of the helix except those for the end benzene rings
were accurately located (equivalent isotropic displacement parameters of 0.10 Å2 or less).
For the C atoms belonging to the end benzene rings in the crystal structures for 2, 4, 5 and
21, equivalent isotropic displacement parameters are less than 0.12 Å2, 0.23 Å2, 0.14 Å2
and 0.11 Å2, respectively. Overall, the X-ray data should be considered correct and
meaningful.
S15

9. Crystal structures.
Figure S10. Side views of crystal structure of 2 with methanol molecules presented at the
ends of the helix. Hydrogen atoms are omitted for clarity.
Figure S11. Side views of crystal structure of 5 with methanol molecules presented at the
ends of the helix. Hydrogen atoms are omitted for clarity.
Figure S12. The approximate crystallographic distances for specific proton pairs observed
in oligomers 4 (a) and 5 (b) that correspond to the proton pairs for which “long-range”
NOEs are observed for 3.
S16