F...H-N hydrogen bonding driven foldamers: Efficient receptors for dialkylammonium ions

Article abstract of DOI:10.1002/anie.200500982

(Graph Presented) Intramolecular F...H-N hydrogen bonds have been utilized for the first time to construct a new series of foldamers from aromatic amides (see picture; R¹ = H, Me; R² = CON(n-C ₈H₁₇)₂)

Full text of DOI:10.1002/anie.200500982

Angewandte
Chemie
Molecular Recognition
DOI: 10.1002/anie.200500982
À
F···H N Hydrogen Bonding Driven Foldamers:
Efficient Receptors for Dialkylammonium Ions**
Chuang Li, Shi-Fang Ren, Jun-Li Hou, Hui-Ping Yi,
Shi-Zheng Zhu, Xi-Kui Jiang, and Zhan-Ting Li*
An essential attribute of biomacromolecules such as proteins
and nucleic acids is their accurate control over the non-
covalent forces that govern folding and self-assembly pro-
cesses.[1] In recent years, chemists have been engaged in the
development of foldamers,[2] artificial molecules that utilize
noncovalent forces to modulate folding or helical structures.
À
Among other noncovalent forces, the O···H N hydrogen
bonding motif has been widely utilized for this purpose,[3,4]
a
À
number of pyridine-N···H N hydrogen-bonded folding archi-
tectures have also been developed.[5] Although it has been
well established that the fluoride ion acts as a very strong
proton acceptor,[6,7] it has been reported that covalently
bound fluorine is a very weak intermolecular hydrogen-
bonding acceptor.[8,9] We recently found that intramolecular
À
F···H N hydrogen bonding could be used to promote the
stability of hydrazide-based quadruply hydrogen-bonded
heterodimers.[10] We envisioned that rationally designed,
À
intramolecular F···H N hydrogen bonding might provide a
novel approach for the formation of new rigid, well-estab-
lished conformations. Herein, we demonstrate how intra-
À
molecular F···H N hydrogen bonding controls the crescent
and helical conformations of aromatic amides to such an
[*] C. Li, S.-F. Ren, J.-L. Hou, H.-P. Yi, Prof. Dr. S.-Z. Zhu,
Prof. Dr. X.-K. Jiang, Prof. Dr. Z.-T. Li
State Key Laboratory of Bio-Organic and
Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
Fax: (+86)21-6416-6128
E-mail: ztli@mail.sioc.ac.cn
[**] We thank the Ministry of Science and Technology (G2000078101),
the National Natural Science Foundation of China, and the Chinese
Academy of Sciences for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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extent that the new foldamers can strongly bind dialkylam-
monium ions.
The molecular design was based on the recently estab-
evaporation of a dichloromethane/ethyl acetate solution of 7–
9. All three compounds adopt a well-defined planar con-
À
formation, which is rigidified by intramolecular F···H N
[11,12]
À
lished three-centered O···H N hydrogen-bond motif.
hydrogen bonds (Figure 1). For 7, the F···H (amide) distance
Compounds 1–6 were prepared and a comparison of the
Figure 1. The crystal structures of a) 7, b) 8, and c) 9.
À
is 2.227 Š, and the F···H N angle is 106.378. The fluorine
atoms of both 8 and 9 are located in the proximity of the
amide hydrogen atom due to the formation of the three-
centered hydrogen bonds. The F···H (amide) distance in the
six- and five-membered hydrogen bonds is 1.935 and 2.184 Š
for 8, and 1.968 and 2.183 Š for 9, respectively, and the
À
corresponding F···H N angles are 135.72 and 107.598 for 8
and 135.98 and 111.218 for 9. All these values fall in the range
À
chemical shift of the amide proton in 2–6 with that in 1, which
cannot form intramolecular hydrogen bonds (Table 1),
reveals a significant downfield shift of their NH signals,
suggesting the formation of an intramolecular hydrogen bond
in 2–6. Larger changes with respect to 1 are exhibited for 4–6
than for 2 and 3, indicating that the NH protons in 4–6 are
involved in two hydrogen bonds simultaneously, as observed
in the RO-related systems.[11–13]
Numerous attempts to crystallize 2–6 were unsuccessful.
Given the well-known crystallinity of triphenylmethyl and
nitro compounds,[14,15] compounds 7–9 were prepared. Crys-
tals of 7–9 suitable for X-ray analysis were grown by slow
considered acceptable for F···H N hydrogen bonds, namely,
À
the F···HN distance is less than 2.3 Š and the F···H N angle is
greater than 908.[9a] In contrast, the F···HN distance for the
amine group in 7 is 2.385 Š, which is outside the acceptable
range given above. In addition, the skeleton of 3-mer 9 adopts
a folding conformation.
À
The three-centered F···H N hydrogen-bonding motif,
which is present both in solution and in the solid state, is an
ideal candidate for the construction of foldamers. To explore
this possibility, 5-mer 10 and 7-mers 11a and 11b (Scheme 1)
were synthesized, as shown in Scheme 2 and Scheme 3. Thus,
acid 12 was first transformed to amide 13, which was then
reduced to diamine 14. Treatment of 14 with 2-fluoroiso-
phthaloyl chloride afforded 15. Finally, reaction of 15 with 2-
fluorobenzoyl chloride yielded 10. For the preparation of 11a,
16 was first reduced to amine 17, which was acylated to yield
18. The latter was then hydrolyzed to acid 19, followed by a
coupling reaction to give 20. Treatment of 20 with 2-
fluoroisophthaloyl chloride afforded 11a (Scheme 3). Com-
pound 11b was prepared according to the similar route.
The peaks in the 1H NMR spectrum of 10, 11a, and 11b in
CDCl3 are sharp. Their signals have been assigned based on
2D-NOESY and COSY experiments. As expected, their NH
signals are also shifted downfield substantially (Table 1) and
Table 1: Chemical shifts (ppm) of the NH signals of 1–8, 10, and 11a in
CDCl3 (1.0 mm) at 258C.[a]
Compound
Chemical
shift
Compound
Chemical
shift
1
2
3
4
5
7.78
6
7
8
10
11a
8.57 (0.79)
8.43 (0.65)
8.88 (1.10)
8.91 (1.13)
9.04 (1.26)
8.00 (0.22)
8.47 (0.69)
8.83 (1.05)
8.92 (1.14)
[a] The value in parentheses is the downfield change of the chemical shift
relative to that of 1.
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the values are comparable to those of
the shorter oligomers 4, 5, and 8. The
results indicate that three-centered
À
F···H N hydrogen bonding also
occurs in these oligomers. Moderate
NOE values between Ha and Hb of
the terminal benzene rings was
observed for 11b (Scheme 1).
Because similar NOE values were
not revealed for 10 even at the higher
concentration
of
10 mm,
the
observed NOE between Ha and Hb
in 11b can only be ascribed to that
produced by an end-to-end arrange-
ment, as shown in Scheme 1. This
cross-ring NOE strongly supports a
rigidified helical conformation of
11b in chloroform.[4a,b] In contrast,
5-mer 10 is not long enough for its
Scheme 1. The structure of crescent 10 and helical 11a and 11b. Compound 11b displayed intra-
molecular end-to-end NOE values (500 MHz, 2.5 mm in CDCl3 at 258C), which support a helical
conformation for 11.
two end benzene units to stack or even to be in close
proximity. In principle, a similar NOE might also be displayed
in 11a, but this could not be assigned due to signal overlap for
the terminal benzene groups.
Molecular modeling revealed a crescent planar confor-
mation for 10 and a helical conformation for 11a and 11b, in
which the fluorine atoms converge towards the center of their
skeletons creating a polar internal cavity of 6.5 and 6.6 Š
diameter, respectively. Such a cavity appears well suited to
complex secondary R2NH2+ ions in a manner similar to that of
dibenzo[24]crown-8.[16] The interactions of 10 and 11a with
symmetrical 21·HCl were first investigated by means of ESI-
MS analysis of their 1:1 solutions (1.0 mm) in chloroform.
Scheme 2. The synthesis of 10: a) oxalyl chloride, DMF (cat.), THF, RT,
0.5 h; b) NH(n-C8H17)2, NEt3, THF, À108C, 1 h, 59%; c) H2, Pd/C,
MeOH/THF, RT, 48 h, 92%; d) 2-fluoroisophthaloyl chloride, NEt3,
CH2Cl2, RT, 0.5 h, 33%; e) 2-fluorobenzoyl chloride, NEt3, CH2Cl2, RT,
1 h, 47%.
Strong peaks for the complexes 10·21·HCl and 11a·21·HCl
1
were observed (Figure 2). The H NMR NOESY spectrum
also revealed intermolecular a NOE of modest strength for
the 1:1 solution of 10 and 21·HCl as well as 11a and 21·HCl in
CDCl3 (Scheme 4). These results clearly indicate that strong
intermolecular F···H electrostatic interactions or hydrogen
À
bonding also exist between the new F···H N hydrogen-
bonded foldamers and 21·HCl.[17]
Addition of 21·HCl to the solution of 10 and 11a in
chloroform remarkably decreased the intensity of the emis-
sion for the folding oligomers in the fluorescent spectrum.
Similar quenching was not observed when 21·HCl was
replaced with nBu4N+ClÀ under identical conditions. This
result rules out the possibility of a salt effect at a higher
concentration of ammonium and indicates that the reduction
of the emission intensity was caused by the complexation of
the folding molecules around the ammonium ion. As an
example, the titration spectra of 11a with 21·HCl are provided
in Figure 3. By fitting the data to a 1:1 binding mode, the
association constant Kassoc of complexes 10·21·HCl and
Scheme 3. The synthesis of 11a: a) H2, Pd/C, MeOH/THF, RT, 24 h,
98%; b) 2-fluoro-3-(methoxycarbonyl)benzoyl chloride, NEt3, CH2Cl2,
0.5 h, 91%; c) LiOH, THF/H2O, RT, 5 h, 98%; d) 2-fluoro-5-methylben-
zene-1,3-diamine, EDCI, DMAP (cat.), CH2Cl2, RT, 12 h, 45%; e) 2-fluo-
roisophthaloyl chloride, NEt3, CH2Cl2, RT, 1 h, 55%.
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11a·21·HCl was determined to be 4.9(Æ0.6) ” 106 and 8.1-
(Æ0.9) ” 106 mÀ1, respectively.[4b] The 1:1 stoichiometry of the
complexes was estimated based on Job plots. The binding
constants are considerably larger than that of the complex
between dibenzo[24]crown-8 and dialkylammonium ions (ca.
2.7 ” 104 mÀ1 in chloroform),[18] suggesting that highly efficient
electrostatic interactions or hydrogen bonding could occur
intermolecularly between fluorine and ammonium protons
due to the rigidified conformation of the oligomers. By using
the same method, the Kassoc values for the complexes of 10
with chiral 22·HCl as well as 11a with chiral 22·HCl were
determined to be 2.4(Æ0.2) ” 105 and 7.3(Æ0.8) ” 105 mÀ1
,
respectively. The values are notably lower than those of the
respective complexes with 21·HCl, but still larger than that of
the complex between dibenzo[24]crown-8 and dialkylammo-
nium ions.
Given the above strong binding features, chirality induc-
tion through complexation of 10 and 11a with chiral l-
tyrosine-derived ammonium 22·HCl was investigated.[4b,19]
The guest molecule itself (22·HCl) exhibits a CD signal at
about 277 nm. Therefore, induced CD spectra generated from
the interaction of 22·HCl with 10 and 11a were obtained by
subtracting the spectrum of 22·HCl from that of the complex.
Figure 4 shows the typical CD curves of the complexes. Both
Figure 2. ESI mass spectrum obtained from the 1:1 solution (1.0 mm)
of a) 10 and 21·HCl and b) 11a and 21·HCl in chloroform.
Figure 4. Induced CD spectra of complexes of 22·HCl (1.0 mm) with
a) 10 (1.0 mM), b) 11a (0.01 mm), c) 11a (0.05 mm), and 11a
(0.2 mm) in chloroform at 258C.
Scheme 4. Intermolecular NOE connections revealed by the NOESYspectrum
(500 MHz) of the 1:1 solution of a) 10 and 21·HCl and b) 11a and 21·HCl in
CDCl3 (4.0 mm) at 238C (mixing time: 0.5 s).
complexes gave rise to negative CD signals, which increased
with the increase of the concentration of the foldamers. The
intensity of the CD signals decreased on addition of polar
methanol in the solvent and vanished in a mixture of
methanol and chloroform (1:3 (v/v)), indicating that the
signals were generated through intermolecular electrostatic
interactions or hydrogen bonding. The different shape of the
signals of the two complexes presumably reflects the different
binding environments for both complexes.
In conclusion, we have demonstrated that intramolecular
À
F···H N hydrogen bonds can be utilized to construct a new
generation of folding architectures. The new foldamers
strongly bind dialkylammonium ions by means of intermo-
À
lecular electrostatic interactions or F···H N hydrogen bond-
ing, which can give rise to chiral induction or amplification
through complexation with chiral l-tyrosine-derived ammo-
nium ions. It has been proposed that organic fluorine hardly
ever accepts hydrogen bonds, the present work reveals that
Figure 3. Fluorescent spectra of 11a (1.5ꢀ10À5 m, excitation wave-
length=330 nm) in CHCl3 at 258C, decreased gradually on addition of
21·HCl (0 to 4.0ꢀ10À5 m).
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À
[13] The proximity of the Fand HN groups in 2 and other compounds
relatively stable F···H N hydrogen bonds can be formed, at
=
may be partially caused by the repulsion of the F and C O
least, in elaborately designed aromatic amides. This opens
new possibilities in supramolecular chemistry. Future work
will be aimed at the construction of helical and tubular
systems with deeper and larger cavities. It also remains to be
groups. Nevertheless, the coplanarity of the benzene units in 7–9
in the solid state supports the formation of intramolecular
hydrogen bonds. We thank the referees for the stimulating
comments on this issue.
À
shown whether intra- or intermolecular F···H O hydrogen
bonds can be formed in organofluorine molecules.
[14] P. S. Corbin, L. J. Lawless, Z.-T. Li, Y. Ma, M. J. Witmer, S. C.
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Received: March 17, 2005
Published online: August 3, 2005
[17] Complexes between fluorine-containing cyclophanes and am-
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[18] This is the largest value for the dialkylammonium ions inves-
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Keywords: fluorine · foldamers · hydrogen bonds ·
molecular recognition
.
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