Hydrogen bonding-mediated oligobenzamide foldamer receptors that efficiently bind a triol and saccharides in chloroform

Article abstract of DOI:10.1039/b508773b

The self-assembly of two novel intramolecular hydrogen bonding-driven foldamers is described. Two linear symmetric aromatic amide oligomers, 1 and 2, which are incorporated with benzene subunits, have been prepared by continuous amide-coupling reactions. The existence of three-centred hydrogen bonds in the oligomers and consequently the folding conformation of the oligomers in solution have been characterized by ¹H NMR experiments and by comparing them with the reported solid state structure of the identical structural skeleton. Molecular modeling reveals a rigid crescent conformation for 1 with a cavity of ca. 0.9 nm in diameter and a helical conformation for 2 with a cavity of ca. 0.8 nm in diameter. Due to the existence of intramolecular hydrogen bonding, all the C=O groups in both oligomers are located inwardly. The binding of 1 and 2 towards a trihydroxyl guest and four saccharide derivatives have been investigated with ¹H NMR, fluorescence, and circular dichroism spectroscopy. The association constants of the corresponding 1:1 complexes have been determined by fluorescence titration experiments. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2005.

Full text of DOI:10.1039/b508773b

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P A P E R
Hydrogen bonding-mediated oligobenzamide foldamer receptors
that efficiently bind a triol and saccharides in chloroform
Hui-Ping Yi, Xue-Bin Shao, Jun-Li Hou, Chuang Li, Xi-Kui Jiang and Zhan-Ting Li*
State Key Laboratory of Bio-Organic & Natural Products Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China.
E-mail: ztli@mail.sioc.ac.cn; Fax: þ21 6416 6128; Tel: þ21 5492 5122
Received (in Montpellier, France) 20th June 2005, Accepted 12th July 2005
First published as an Advance Article on the web 2nd August 2005
The self-assembly of two novel intramolecular hydrogen bonding-driven foldamers is described. Two linear
symmetric aromatic amide oligomers, 1 and 2, which are incorporated with benzene subunits, have been
prepared by continuous amide-coupling reactions. The existence of three-centred hydrogen bonds in the
oligomers and consequently the folding conformation of the oligomers in solution have been characterized
1
by H NMR experiments and by comparing them with the reported solid state structure of the identical
structural skeleton. Molecular modeling reveals a rigid crescent conformation for 1 with a cavity of ca. 0.9
nm in diameter and a helical conformation for 2 with a cavity of ca. 0.8 nm in diameter. Due to the
existence of intramolecular hydrogen bonding, all the C O groups in both oligomers are located inwardly.
Q
The binding of 1 and 2 towards a trihydroxyl guest and four saccharide derivatives have been investigated
1
with H NMR, fluorescence, and circular dichroism spectroscopy. The association constants of the
corresponding 1 : 1 complexes have been determined by fluorescence titration experiments.
Introduction
Non-covalent forces-induced folding or self-coiling is
a
common feature of biological macromolecules. The DNA
double helices and protein folding represent the most typical
examples of biomolecules.1,2 In the past decade, there has
been increasing interest in developing foldamers, artificial
linear molecules that utilize non-covalent forces to modu-
late the folding or helical structures.3–11 Among other non-
covalent forces, hydrogen bonding has been widely utilized for
this purpose. To date, a number of structurally elaborate
aromatic amide folding and unfolding modes have been re-
ported.3,12–21
We previously reported that hydrogen bonding-induced
rigidified crescent and helical aromatic hydrazide oligomers
can strongly complex mono- or disaccharide derivatives in less
polar organic solvents like chloroform.22 Recently, Huc et al.
also found that hydrogen bonding-mediated oligopyridine-
dicarboxamides can promote the N-oxidation of the peripheral
pyridine units in oligopyridine-dicarboxamide-based folda-
mers23 or encapsulate small molecules like water in chloro-
form.24 Considering that the synthesis of unnatural folding
receptors is obviously of higher efficiency than the synthesis of
cyclophane or crown ether receptors of a comparable size, and
that the cavity of the folding receptors could be readily tuned
by modifying the structures of the assembling monomers,25
these results suggest that rigid, folding structures may become
a new generation of non-ring artificial receptors for molecular
recognition or sensing after the covalently-bonded molecular
tweezers.26,27 In the search for new folding receptors for
efficient molecular recognition, we had designed two new
oligoamides 1 and 2.28 We herein report their synthesis,
characterization and binding affinity towards triol and sacchar-
ide guests.29–35
T h i s j o u r n a l i s & T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 5
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 2 1 3 – 1 2 1 8
1213

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perature for 12 h and then concentrated under reduced pres-
sure. The resulting residue was triturated with ether (100 mL)
and the organic solution was washed with dilute hydrochloric
acid (1 N, 15 mL ꢀ 2), saturated sodium bicarbonate (20 mL),
water (30 mL) and brine (30 mL). After drying over sodium
sulfate, the solvent was removed under reduced pressure. The
resulting residue was subjected to column chromatography
(dichloromethane–methanol 25 : 1) to afford compound 1 as
a white powder (2.94 g, 75%). Mp 120–122 1C. 1H NMR (300
MHz, CDCl3): d 9.65 (s, 2 H), 1.59 (s, 2 H), 9.25 (s, 2 H), 9.15
(s, 1 H), 8.84 (s, 2 H), 6.44 (s, 2 H), 6.43 (s, 1 H), 6.40 (s, 1 H),
4.13 (t, J ¼ 8.7 Hz, 8 H), 4.00 (t, J ¼ 6.9 Hz, 4 H), 3.83 (s, 6 H),
3.81 (s, 3 H), 3.80 (s, 3 H), 3.78 (s, 6 H), 1.94–1.79 (m, 12 H),
1.46–1.18 (m, 60 H), 0.82–0.76 (m, 18 H). 13C NMR (300 MHz,
CDCl3): d 165.4, 162.8, 162.0, 161.8, 160.8, 160., 146.2, 146.5,
137.6, 121.1, 120.5, 117.0, 115.6, 114.6, 113.0, 96.9, 95.0, 69.9,
69.8, 69.3, 55.9, 55.8, 51.6, 31.8, 31.8, 29.7, 29.5, 29.4, 29.4,
29.3, 29.2, 29.2, 29.1, 29.1, 25.9, 25.9, 22.7, 22.7, 22.6, 14.1,
14.1. MS (ESI): m/z (%): 1583 [M þ Na]1. IR (film): n 3354,
Experimental
Melting points are uncorrected. All reactions were performed
1
under an atmosphere of dry nitrogen. The H NMR spectra
were recorded on 400 or 300 MHz spectrometers in the
indicated solvents. Chemical shifts are expressed in parts per
million (d) using residual solvent protons as internal standards.
Chloroform (d 7.26 ppm) was used as an internal standard for
chloroform-d as solvent. Elemental analysis was carried out at
the SIOC analytical center. Unless otherwise indicated, all
starting materials obtained were of the best quality from
commercial suppliers and used without further purification.
All solvents were dried before use following standard proce-
dures. Compound 15 was prepared according to the reported
method.36 The synthesis of compounds 16–19 has been re-
ported in a previous paper.22
Syntheses
2923, 2853, 1729, 1661, 1538, 1464, 1260, 1033, 804 cmꢁ1
.
Compound 4. To a solution of compound 322 (7.99 g, 17.7
mmol) in DMSO (50 mL), potassium hydroxide (0.99 g, 17.7
mmol) was added. The solution was stirred at 130 1C for 3 h
and then poured onto ice–water (150 mL). Dilute hydrochloric
acid (1 N) was added to adjust the pH of the solution to ca. 5.
The resulting precipitate was filtered off and washed thor-
oughly with water. After recrystallization from n-hexane,
compound 4 was obtained as a white solid (5.88 g, 76%).
Mp 101–102 1C. 1H NMR (300 MHz, CDCl3): d 8.71 (s, 1 H),
6.49 (s, 1 H), 4.27 (t, J ¼ 6.9 Hz, 2 H), 4.09 (t, J ¼ 6.3 Hz, 2 H),
3.86 (s, 3 H), 1.97–1.87 (m, 4 H), 1.70–1.45 (m, 4 H), 1.29 (m,
16 H), 0.89–0.87 (m, 6 H). MS (EI): m/z (%): 436 (18) [M]1,
194 (100), 212 (49), 163 (25), 195 (22), 162 (21), 43 (19).
Anal. Calcd. for C90H134N4O18: C, 69.29; H, 8.66; N, 3.59.
Found: C, 69.04; H, 8.71; N, 3.56.
Compound 9. A suspension of 1,4-dimethoxy-2-nitrobenzene
(6.18 g, 33.7 mmol) and Pd–C (5%, 0.30 g) in tetrahydrofuran
(50 mL) was stirred under 1 atmosphere of hydrogen gas at
room temperature for 8 h. The solid was removed over celite
and washed with dichloromethane. The combined filtrate was
then concentrated with a rotavapor. The resulting crude pro-
duct was subjected to flash chromatography (dichloromethane)
to afford the desired product as a white solid (5.07 g, 98%). Mp
80–81 1C [81 1C].37 1H NMR (300 MHz, CDCl3): d 6.71 (d, J ¼
8.7 Hz, 1 H), 6.34 (d, J ¼ 3.0 Hz, 1 H), 6.25 (q, J ¼ 9, 3.0 Hz,
1 H), 3.81 (s, 3 H), 3.74 (s, 3 H). MS (EI): m/z: 153 (52) [M]1,
154 (5), 139 (9), 138 (100), 111(5), 110 (28), 95 (20), 67 (6).
Compound 6. A solution of compound 4 (3.98 g, 9.10 mmol)
N-ethyl-N0-(3-dimethyl-aminopropyl)
and
carbodiimide
(EDCI, 1.51 g, 10.9 mmol) in dichloromethane was stirred at
room temperature for 30 min and then a solution of diamine 5
(2.61 g, 15.5 mmol) in dichloromethane (30 mL) was added
dropwise in 10 min. The solution was stirred at room tempera-
ture for 6 h and the solvent was removed under reduced
pressure. The resulting residue was triturated in ether (100
mL) and the organic phase washed with water (30 mL ꢀ 2),
dilute hydrochloric acid (1 N, 30 mL), saturated sodium
bicarbonate (20 mL ꢀ 2), and brine (30 mL). After drying
over sodium sulfate, the crude product was purified by column
chromatography (dichloromethane–methanol 50 : 1) to afford
6 as a white solid (3.96 g, 74%). Mp 118–120 1C. 1H NMR (300
MHz, CDCl3): d 9.92 (s, 1 H), 8.84 (s, 1 H), 8.14 (s, 1 H), 6.50
(s, 1 H), 6.48 (s, 1 H), 4.21 (t, J ¼ 6.9 Hz, 2 H), 4.08 (t, J ¼ 12
Hz, 2 H), 3.86 (s, 9 H), 3.60–3.59 (br, 2 H), 2.00 (m, 2 H), 1.89
(m, 2 H), 1.51–1.29 (m, 40 H), 0.82–0.81 (m, 6 H). 13C NMR
(300 MHz, CDCl3): d 165.3, 162.9, 161.8, 160.8, 143.4, 137.2,
122.0, 114.5, 113.2, 109.5, 97.0, 69.9, 69.4, 56.5, 56.1, 51.6, 49.1,
34.0, 31.8, 31.7, 29.4, 29.3, 29.2, 29.1, 29.0, 28.9, 25.9, 25.8,
25.6, 25.0, 22.7, 22.6, 14.1. MS (EI): m/z (%): 586 (50) [M]1,
195 (35), 163 (100), 153 (22), 57 (25), 43 (36), 41 (20). IR (film):
n 3347, 2923, 2851, 1720, 1650, 1545, 1284, 1255, 1102, 1036
cmꢁ1. Anal. calcd. for C33H50N2O7: C, 67.55; H, 8.59; N, 4.77.
Found: C, 67.39; H, 8.54; N, 4.71.
Compound 10. A solution of 4 (1.67 g, 3.83 mmol), oxalyl
chloride (0.50 g) and DMF (0.05 mL) in dichloromethane was
stirred at room temperature for 5 h and then concentrated
under reduced pressure to afford 8 as a yellow solid. This solid
was dissolved in chloroform (10 m) and the solution was added
to a stirred solution of 9 (0.76 g, 4.97 mmol) and triethylamine
(1.00 g, 10.0 mmol) in chloroform (30 mL). After stirring at
room temperature for 10 h, the solution was worked up as
described above for compound 1. The crude product was sub-
jected to column chromatography (petroleum ether–EtOAc
10 : 1) to produce 10 as a white solid (1.84 g, 84%). Mp 78–
80 1C. 1H NMR (300 MHz, CDCl3): d 10.14 (s, 1 H), 8.85 (m, 1
H), 8.42 (d, J ¼ 2.7 Hz, 1 H), 6.83 (d, J ¼ 8.7 Hz, 1 H), 6.60 (d,
d, J1 ¼ 8.7 Hz, J2 ¼ 2.4 Hz, 1 H), 6.49 (s, 1 H), 4.22 (t, J ¼ 7.2
Hz, 2 H), 4.09 (t, J ¼ 6.3 Hz, 2 H), 3.87 (s, 3 H), 3.83 (s, 3 H),
3.83 (s, 3 H), 2.01 (t, J ¼ 6.9 Hz, 2 H), 1.90 (t, J ¼ 6.9 Hz, 2 H),
1.52–1.29 (m, 20 H), 0.89–0.84 (m, 6 H). 13C NMR (300 MHz,
CDCl3): d 165.1, 163.0, 162.3, 160.8, 153.8, 142.5, 137.3, 128.9,
114.1, 113.0, 110.5, 108.8, 106.5, 96.8, 69.9, 69.3, 55.9, 55.8,
51.7, 31.8, 31.7, 29.4, 29.3, 29.2, 29.1, 29.0, 28.9, 25.9, 25.8,
22.7, 22.6, 14.1, 14.0. MS (EI): m/z (%): 571 (17) [M]1, 419
(51), 195 (38), 163 (100), 69 (22), 57 (47), 55 (30), 43 (78), 41
(43). Anal. calcd. for C33H49NO7: C, 69.32; H, 8.64; N, 2.45.
Found: C, 69.50; H, 8.72; N, 2.39.
Compound 1. To a stirred solution of 4,6-bis-n-octyloxy-
isophthalic acid22 (1.06 g, 2.51 mmol) in dichloromethane,
oxalyl chloride (0.2 mL, 2.33 mmol) and DMF (0.05 mL) were
added. The solution was stirred at room temperature for 4 h
and then concentrated in vacuo to afford crude compound 7 as
a yellow solid. This product was dissolved in chloroform (20
mL) and the solution was added to a solution of compound 6
(2.95 g, 5.01 mmol) and triethylamine (2.0 mL, 14.0 mmol) in
chloroform (50 mL). The solution was stirred at room tem-
Compound 11. A solution of compound 10 (1.65 g, 2.89
mmol) and potassium hydroxide (0.20 g, 3.46 mmol) in a
mixture of water (15 mL) and methanol (10 mL) was heated
under reflux for 3 h. After workup, the crude product was
recrystallized from ethanol to give 11 as a white solid (1.55 g,
96%). Mp 133–135 1C. 1H NMR (300 MHz, CDCl3): d 9.97 (s,
1 H), 9.10 (s, 1 H), 8.41 (d, J ¼ 2.7 Hz, 1 H), 6.83 (d, J ¼ 9.3
Hz, 1 H), 6.61 (d, J ¼ 9.3 Hz, 1 H), 6.54 (s, 1 H), 4.26 (t, J ¼
1214
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 2 1 3 – 1 2 1 8

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6.6 Hz, 2 H), 4.24 (t, J ¼ 6.6 Hz, 2 H), 3.86 (s, 3 H), 3.83 (s, 3
H), 2.02 (t, J ¼ 7.5 Hz, 2 H), 1.93 (t, J ¼ 6.6 Hz, 2 H), 1.45–1.26
(m, 20 H), 0.98–0.92 (m, 6 H). 13C NMR (300 MHz, CDCl3): d
213.0, 164.1, 161.6, 161.4, 160.9, 153.8, 142.6, 138.9, 128.8,
116.3, 110.8, 110.4, 108.5, 106.8, 96.5, 70.6, 70.4, 55.8, 31.8,
31.7, 29.3, 29.2, 29.1, 28.9, 28.8, 25.8, 22.6, 14.1. MS (EI): m/z
(%): 557 (17) [M]1, 163 (18), 153 (100), 138 (33), 57 (18), 44
(22), 43 (30), 41 (27). Anal. calcd. for C32H47NO7: C, 68.91; H,
8.49; N, 2.52. Found: C, 68.70; H, 8.53; N, 2.47.
Compound 12. By using the experimental procedure de-
scribed above for 6, this compound was prepared as a white
solid (67%) from the reaction of 11 and 5 (eluent for column
chromatography: dichloromethane–ethanol 60 : 1). Mp 150–
152 1C. 1H NMR (300 MHz, CDCl3): d 10.05 (s, 1 H), 9.83 (s, 1
H), 9.17 (d, J ¼ 1.5 Hz, 1 H), 8.44 (d, d, J2 ¼ 3.9 Hz, J2 ¼ 0.9
Hz, 1 H), 8.17 (d, J ¼ 0.6 Hz, 1 H), 6.81 (d, J ¼ 8.7 Hz, 1 H),
6.60 (d, d, J1 ¼ 9.0 Hz, J2 ¼ 3.6 Hz, 1 H), 6.50 (d, J ¼ 6.6 Hz, 2
H), 4.20 (t, J ¼ 6.9 Hz, 4 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.83
(s, 3 H), 3.79 (s, 3 H), 3.61 (br, 2 H), 1.99 (t, J ¼ 6.9 Hz, 4 H),
1.59–1.49 (m, 4 H), 1.39–1.26 (m, 20 H), 0.88–0.85 (m, 6 H).
13C NMR (300 MHz, CDCl3): d 162.4, 161.8, 160.1, 160.0,
153.9, 143.0, 142.6, 141.7, 137.6, 129.3, 122.2, 115.4, 110.4,
109.2, 108.3, 108.2, 106.8, 96.7, 96.4, 70.0, 70.0, 56.2, 56.1, 55.8,
55.8, 55.8, 55.6, 31.9, 31.8, 31.7, 29.7, 29.5, 29.4, 29.3, 29.3,
29.2, 29.1, 25.8, 22.7, 22.6, 14.1. IR (film): n 3359, 2925, 1660,
1536, 1281, 1223, 1198 cmꢁ1. MS (EI): m/z (%): 707 (46) [M]1,
275 (52), 163 (100), 153 (67), 69 (38), 57 (46), 55 (40), 43 (64).
Anal. calcd. for C41H57N3O8: C, 67.87; H, 8.12; N, 5.94.
Found: C, 67.68; H, 8.06; N, 5.82.
Scheme 1
emission, I, at a fixed wavelength were collected and Origin 6.0
software was used to fit a 1 : 1 binding isotherm to the data:
DI ¼ (DImax/[A]) ꢀ {0.5[G] þ 0.5([A] þ Kd) ꢁ 0.5([G]2
þ
{2[G](Kd ꢁ [A]) þ (Kd þ [A])2}1/2)}, where [A] is the concentra-
tion of 1 or 2, [G] is the concentration of the guest, Kd
¼
(Kassoc)
ꢁ1. Association constants reported are the average
values of two or three experiments.22
Results and discussion
The synthesis of 5-mer 1 is shown in Scheme 1. Compound 3
was first hydrolysed in DMSO, with potassium hydroxide as
base, to give acid 4 in 76% yield. The latter was treated with
diamine 5 in dichloromethane in the presence of N-ethyl-N0-(3-
dimethylaminopropyl)carbodiimide (EDCI) to afford com-
pound 6 in 74% yield. Finally, 6 was reacted with diacyl
chloride 7 in chloroform with triethylamine as base to produce
compound 1 in 75% yield.
Compound 2. By using the experimental procedure described
above for the preparation of 1, this compound was prepared as
a white solid (0.96 g, 60%) from the reaction of compounds 7
(0.37 g, 0.88 mmol) and 12 (1.25 g, 1.80 mmol) in chloroform
(eluent for column chromatography: dichloromethane–ethanol
1
25 : 1). Mp 186–188 1C. H NMR (300 MHz, CDCl3): d 9.98
(s, 2 H), 9.64 (s, 2 H), 9.59 (s, 2 H), 9.25 (s, 2 H), 9.21 (s, 1 H),
9.19 (s, 2 H), 8.48 (d, J ¼ 2.4 Hz, 2 H), 6.74 (d, J ¼ 9.0 Hz, 2
H), 6.53 (d, d, J1 ¼ 9.3 Hz, J2 ¼ 2.7 Hz, 2 H), 6.46 (s, 3 H), 6.44
(s, 2 H), 4.15 (m, 12 H), 3.82 (s, 6 H), 3.81 (s, 6 H), 3.80 (s, 6 H),
3.78 (s, 6 H), 1.92 (m, 12 H), 1.46–1.22 (m, 60 H), 0.88–0.81 (m,
18 H). 13C NMR (300 MHz, CDCl3): d 162.5, 161.9, 161.8,
160.3, 160.0, 159.9, 153.7, 146.4, 142.5, 137.7, 129.4, 128.5,
120.6, 120.3, 117.1, 115.4, 115.2, 115.1, 110.2, 108.2, 106.5,
96.5, 94.8, 55.8, 31.8, 29.5, 29.3, 29.2, 25.9, 25.8, 25.7, 14.1. IR
(film): n 3352, 2932, 2847, 1655, 1527, 1463, 1278, 1232, 1197,
710 cmꢁ1. MS (MALDI-TOF): m/z: 1825 [M þ Na]1. HRMS
For the synthesis of 7-mer 2 (Scheme 2), compound 4 was
first converted into acyl chloride 8 by oxalyl chloride in
dichloromethane. The latter was then reacted with aniline 9
to produce 10 in 84% yield (two steps). Compound 10 was
hydrolysed with potassium hydroxide in refluxing aqueous
methanol to afford intermediate 11 in 96% yield and the acid
was then coupled with 1 equivalent of diamine 5 to give aniline
12 in 67% yield. Finally, 12 was reacted with 7 in chloroform
and produced compound 2 in 60% yield. Compounds 1 and 2
are well soluble in common organic solvents like dichloro-
methane and chloroform and have been characterized by the
1H and 13C NMR and mass spectroscopy and microanalysis.
Previously, the localized three-centred intramolecular hydro-
gen bonding mode consisting of the S(6) and S(5) type38 has
been well-established and utilized to assemble a number of
folded and unfolded secondary structures.19–22,39,40 In addi-
tion, the three-centred hydrogen bonds in model compounds
1320,21 and 1414 have been established by X-ray analysis.
Because the backbones of longer oligomers 1 and 2 can be
regarded as
calcd.
C
for
C
104H148N6O20Na:
1825.3063.
Found:
104H148N6O20Na1 1825.3015.
Molecular mechanics calculation
The folding patterns of the oligomers were constructed by
using the Builder program within the package HyperChem.
Then they were optimized by the conjugate gradient with
AccuModel software 2.1 using the MM3 force field. To explore
lower energy conformation, molecular dynamics calculations
were performed without constraints for the oligomers.
Binding studies
For fluorescent titration experiments, typically a solution of
the receptor in chloroform was prepared at about 2.0–6.0 mM,
and a solution of the guest in chloroform was prepared at 5–50
mM. A mixture of the solutions with a fixed host concentration
and a changing guest concentration was placed in a cuvette and
the fluorescent spectra were sequentially recorded. Usually
15–20 spectra were recorded for one case. The values of the
a repeating combination of one or more 13 and 14, it is
reasonable to assume that, without additional important steric
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 2 1 3 – 1 2 1 8
1215

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1
Fig. 2 Partial H NMR spectra (400 MHz, 5 mM) of 15 þ 1 (1 : 1)
(a), 15 (b), and 15 þ 2 (1 : 1) (c) in chloroform-d at 298 K, highlighting
the downfield shifting of the OH signal of 15 upon complexation with
1 and 2.
Mixing 1 equiv. of 1 or 2 with 15 in chloroform-d caused the
OH signal of 15 to move downfield (Dd: 0.54 and 0.73 ppm,
respectively) substantially (Fig. 2), indicating that strong com-
plexation occurs between 1 or 2 and 15. Because intermolecular
hydrogen binding also exists between different molecules of 15,
a Job’s plot investigation could not be utilized to evaluate the
binding stoichiometry of the complex.41 To estimate the stoi-
chiometry between 15 and the hosts, 1H NMR spectra for [2] :
[15] ¼ 0 : 1–2.5 : 1 in chloroform-d were measured. The OH
signal of 15 moved downfield and the plot of the change versus
the concentration ratio gave rise to an inflexion at [2] : [15] ¼
1 : 1 (Fig. 3), supporting a 1 : 1 binding mode for the complex.
Scheme 2
hindrance, similar three-centred hydrogen bonds should also
exist in the longer oligomers, which would lead to a rigidified,
folded conformation for both oligomers.
The 1H NMR spectra of compounds 1, 2, and 10 in chloro-
form-d are presented in Fig. 1. As expected, all the amide
protons of the oligomers appeared in the downfield area (10.14
to 9.59 ppm), clearly indicating that three-centred hydrogen
bonding also exists in these molecules in solution. The resolu-
tion of the spectrum of 7-mer 2 (Fig. 1c) is not reduced
compared to that of 10 and 5-mer 1, implying that there is
1
A quantitative study of the complexing behaviour by the H
NMR titration method was found to be impossible due to lack
of a suitable probe (the HO signal of 15 was buried at high
concentrations of 1 or 2). It was also found that the fluores-
cence intensity of 1 and 2 in chloroform was increased sig-
nificantly upon addition of 15; the titration spectra of 2 with 15
in chloroform are presented in Fig. 4 as an example. The
titration results were utilized to derive the association
constants by fitting a 1 : 1 regression equation to the data
(Table 1).22,42 Both complexes display comparable stabilities,
which may be rationalized by considering that receptors 1 and
1
no important intermolecular p–p stacking in 2. The H NMR
dilution experiments in chloroform-d (from 15 mM to 0.5 mM)
revealed only very small shifting (o0.03 ppm) of the signals for
both 1 and 2 (Kself-assoc o 5 Mꢁ1), which is consistent with the
above observation.
A molecular modelling study revealed that 5-mer 1 possesses
a crescent conformation, whereas 7-mer 2 is long enough to
produce a helical conformation with the two peripheral ben-
zene subunits stacking with each other.14,22 In addition, all the
2 possess an identical number of C O groups.
Complexation driven by intermolecular hydrogen bonding is
a dynamic, reversible process. In order to obtain more insight
C
O oxygen atoms point into the cavity as a result of the
Q
Q
intramolecular hydrogen bonding, producing a polar cavity of
ca. 0.9 and 0.8 nm in diameter, respectively. Such a polar cavity
provides enough large space to complex multi-hydroxyl guests
through intermolecular hydrogen bonding.20,22 Therefore,
their binding affinity towards guest 15 was first investigated
in chloroform.
Fig. 1 Partial 1H NMR spectra (400 MHz, 5 mM) of 10 (a), 1 (b), and
2 (c) in chloroform-d at 298 K.
Fig. 3 Plot of the chemical shift change of the OH signal of 15 versus
[2] : [15] (in chloroform-d at 298 K).
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Fig. 5 Intermolecular NOE connection observed in complex 2 ꢂ 15 (6
mM) in chloroform-d (400 MHz) at 298 K (the mixing time is 0.5 s).
Fig. 4 The fluorescence spectra of 2 (3.0 ꢀ 10ꢁ5 M, excitation
wavelength ¼ 350 nm) in chloroform at 298 K, increasing with
incremental addition of 15 (0–500 times).
1
into the structure of the complexes, H NMR NOESY experi-
ments were performed for the 1 : 1 solutions of both systems in
chloroform-d, which revealed an intermolecular NOE connec-
tion between the H-a signal of 2 and the OH signal of 15 (Fig.
5). No other intermolecular NOEs were observed for both
complexes.
As a previous study had revealed that aromatic hydrazide-
based folding oligomers, which have a slightly larger cavity of
ca. 1.0 nm in diameter, are good non-cycle receptors for
saccharide guests in chloroform,22,43–46 the present foldamers
were also envisioned to be able to bind saccharides. To explore
this complexing possibility, saccharide derivatives 16–19 were
1
Related to the relatively strong binding feature of 1 and 2 to
the saccharide guests, chiral induction in chloroform through
complexation of the foldamer receptors for saccharides was
also investigated.22,31,47 For example, addition of saccharides
16 or 17 to a solution of 2 induces a negative Cotton effect of
moderate strength at ca. 269 nm, which is due to the foldamer’s
aromatic chromophore (Fig. 6). The induced CDs increased
with an increase of the concentration of the guest, and
decreased and eventually vanished with addition of polar
methanol in the solvent, indicating that the signals were
generated through intermolecular hydrogen bonding. In prin-
ciple, the helical 2 should give rise to two chiral conformational
isomers of the 1 : 1 ratio, upon complexation with chiral
saccharide guest, and the content of one isomer was increased
resulting in the formation of the new CD signal. Under similar
conditions, no induced CD signals were observed for 5-mer 1
chosen as guests. The H NMR investigation in chloroform-d
revealed significant changes of the chemical shift of the OH
signals of the guests. Due to overlapping of signals, a quanti-
1
tative study could not be carried out with H NMR spectro-
scopy. Addition of the guest to the solution of 1 or 2 in
chloroform also resulted in remarkable enhancement of the
fluorescent emission of the oligomers. Association constants in
chloroform were therefore determined from the fluorescence
titration data of the oligomers with the guests by assuming a
1 : 1 binding mode. The corresponding results are listed in
Table 1. It can be found thatthe complexes of saccharides with
more hydroxyl groups exhibit higher binding stabilities. As
expected, 7-mer receptor 2 did not display increased binding
affinity compared to 5-mer 1. This result is similar to the
observation for the complex of guest 15.
Table 1 Association constants and the associated free-energy change
of complexes between the novel aromatic amide receptors and multi-
hydroxyl guests in chloroform-d at 298 Ka
Complex
Kassoc/Mꢁ1
DG/kcal molꢁ1
1 ꢂ 15
2 ꢂ 15
1 ꢂ 16
1 ꢂ 17
1 ꢂ 18
1 ꢂ 19
2 ꢂ 16
2 ꢂ 17
2 ꢂ 18
2 ꢂ 19
a
1.8 (ꢃ 0.2) ꢀ 103
1.5 (ꢃ 0.2) ꢀ 103
5.5 (ꢃ 0.6) ꢀ 102
1.6 (ꢃ 0.2) ꢀ 103
1.7 (ꢃ 0.3) ꢀ 103
5.5 (ꢃ 0.7) ꢀ 103
7.8 (ꢃ 0.9) ꢀ 102
2.3 (ꢃ 0.3) ꢀ 103
2.4 (ꢃ 0.2) ꢀ 103
7.2 (ꢃ 0.8) ꢀ 103
4.4
4.3
3.8
4.4
4.4
5.2
4.0
4.6
4.7
5.3
Obtained based on emission at 455 nm (excitation wavelength ¼
Fig. 6 Induced CD spectrum of complexes of 2 (0.52 mM) with 16
(0.10 mM) (a) and 17 (0.10 mM) (b) in chloroform at 298 K.
350 nm).
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 2 1 3 – 1 2 1 8
1217

View Article Online
when the saccharide guest was added probably due to a smaller
conformational change of this shorter folding oligomer upon
complexation.
17 H. Jiang, J.-M. Le
´
ger and I. Huc, J. Am. Chem. Soc., 2003, 125,
3448.
18 D. Kanamori, T. Okamura, H. Yamamoto and N. Ueyama,
Angew. Chem., Int. Ed., 2005, 44, 969.
19 Z.-Q. Wu, X.-K. Jiang, S.-Z. Zhu and Z.-T. Li, Org. Lett., 2004, 6,
229.
Conclusion
20 Y.-Q. Chen, X.-Z. Wang, X.-B. Shao, J.-L. Hou, X.-Z. Chen,
X.-K. Jiang and Z.-T. Li, Tetrahedron, 2004, 60, 10253.
21 J. Zhu, X.-Z. Wang, Y.-Q. Chen, X.-K. Jiang, X.-Z. Chen and
Z.-T. Li, J. Org. Chem., 2004, 69, 6221.
22 J.-L. Hou, X.-B. Shao, G.-J. Chen, Y.-X. Zhou, X.-K. Jiang and
Z.-T. Li, J. Am. Chem. Soc., 2004, 126, 12386.
We have reported the synthesis and characterization of two
new hydrogen bonding-induced aromatic amide foldamers.
The new folding structures can efficiently complex multi-hy-
droxyl molecules and saccharide derivatives in chloroform
through intermolecular multiple hydrogen bonding. The com-
plexation for disaccharide guest is remarkably stronger, which
bodes well for the development of longer oligomers or poly-
mers of an identical skeleton for enhanced binding of sacchar-
ide molecules. Progress along this line might lead to the
development of unnatural systems of the nanoscale for macro-
molecular transportation or encapsulation.
23 C. Dolain, C. Zhan, J.-M. Le
Chem. Soc., 2005, 127, 2400.
24 J. Garric, J.-M. Leger and I. Huc, Angew. Chem., Int. Ed., 2005,
44, 1954.
´
ger, L. Daniels and I. Huc, J. Am.
´
25 A. R. Sanford, K. Yamato, X. Yang, L. Yuan, Y. Han and B.
Gong, Eur. J. Biochem., 2004, 271, 1416.
26 S. C. Zimmerman, Top. Curr. Chem., 1993, 165, 71.
27 M. Harmata, Acc. Chem. Res., 2004, 37, 862.
28 Rigid cyclophanes based on a similar backbone have been re-
ported recently, see: L. Yuan, W. Feng, K. Yamato, A. R.
Sanford, D. Xu, H. Guo and B. Gong, J. Am. Chem. Soc., 2004,
126, 11120.
29 For examples of other foldamer-based molecular recognition, see
ref. 30–35.
30 R. B. Prince, S. A. Barnes and J. S. Moore, J. Am. Chem. Soc.,
2000, 122, 2758.
31 A. Tanatani, M. J. Mio and J. S. Moore, J. Am. Chem. Soc., 2001,
123, 1792.
32 A. Tanatani, T. Hughes and J. S. Moore, Angew. Chem., Int. Ed.,
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33 H. Onouchi, K. Maeda and E. Yashima, J. Am. Chem. Soc., 2001,
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34 M. Inouye, M. Waki and H. Abe, J. Am. Chem. Soc., 2004, 126,
2022.
Acknowledgements
We are grateful to the Ministry of Science and Technology
(G2000078101), the National Natural Science Foundation of
China, and the Chinese Academy of Sciences for financial
support. We also thank the referees for rapid and helpful
comments on this work.
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