Oligo-m-aniline foldamers

Article abstract of DOI:10.1016/j.tetlet.2012.09.050

Nitrogen atoms showed intriguing properties such as, they can adopt sp ² or sp³ electronic configurations and form various degrees of conjugations with the adjacent aromatic rings depending on the electric nature of aromatic rings. T

Full text of DOI:10.1016/j.tetlet.2012.09.050

Tetrahedron Letters 53 (2012) 6426–6429
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oligo-m-aniline Foldamers
Sen Li a, De-Xian Wang a, , Mei-Xiang Wang b,
⇑
⇑
a Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
b The Key Laboratory of Bioorganic Phosphorous Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
a r t i c l e i n f o
a b s t r a c t
Nitrogen atoms showed intriguing properties such as, they can adopt sp2 or sp3 electronic configurations
and form various degrees of conjugations with the adjacent aromatic rings depending on the electric nat-
ure of aromatic rings. Through deliberate combination of nitrogen atoms with aromatics of different elec-
tric nature, oligo-m-aniline foldamers were synthesized with a two-directional synthetic protocol. The
synthesized hexamer and heptamer gave a snake-shape folding structure in the crystalline state. By
means of 2D NOESY NMR experiments, both the hexamer and heptamer were found to adopt similar fold-
ing structures in solution as those in the solid state.
Article history:
Received 6 August 2012
Revised 3 September 2012
Accepted 13 September 2012
Available online 21 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Folding is the central process of biological macromolecules such
as proteins and DNA to carry out their biological functions. Inspired
by the sophisticated structures and functions of the macromole-
cules, synthetic foldamers have attracted much attention since
the end of last century.1 In addition to the initial attempts to mimic
the biological helical structure by designing unnatural peptide ana-
structures. Herein, we report an efficient two-directional synthetic
method for the preparation of desired compounds. We also show
that the resulting oligo-m-anilines adopt folding structure both
in solid state and solution.
We initiated our synthesis by applying a two-directional frag-
ment coupling approach. As illustrated in Scheme 1, nucleophilic
aromatic substitution reaction of 2-n-butoxy-5-tert-butylben-
zene-1,3-diamine 1 with 1,5-difluoro-2,4-dinitrobenzene 2 in the
presence of DIPEA in THF at room temperature gave trimer 3 in a
high yield of 83%. Further treatment of 3 with 2 under similar con-
ditions afforded a pentamer 5 in a moderate yield. In addition to 5,
the reaction also gave a heptamer 7 in 8% yield. Similar reaction of
5 and 1 gave the desired hexamer 6 in 25% yield.
The structures of all the synthesized compounds were estab-
lished on the basis of their spectroscopic data and microanalysis
(see Supplementary data, Figs. S9–S20). To put the structure be-
yond any doubt, and also to understand the structure at the molec-
ular level, single crystals of compound 5–7 were cultivated. To our
delight, single crystals of 6 and 7 were obtained and their struc-
tures were determined unambiguously. As illustrated in Figures 1
and 2, both compounds 6 and 7 formed a folding structure and
some interesting structural features are worth addressing. First of
all, in both cases the bridging nitrogen atoms adopted sp2 elec-
tronic configuration and tended to conjugate with the electron
deficient 2,4-dinitro-substituted benzene rings rather than elec-
tron rich 2-alkoxy-5-butyl-substituted benzene rings. In addition
to conjugation effect, hydrogens attached on the bridging nitrogen
atoms formed N–H. . .O hydrogen bondings with the neighbouring
nitro groups, which enhanced the rigidity of dinitro-substituted m-
phenylenediamine rings. Foldamers are therefore composed of lar-
ger and conjugated dinitro-substituted 1,3-phenylenediamine seg-
ments, and smaller n-butoxylated benzene units. It is noticeable
logues, such as b,
c
and d-peptides,1a,k,n,2 recent years have wit-
nessed a growing interest in foldamers comprising aromatic
building units.1b–f,m,h Among various artificial foldamers, oligoa-
mides are the most extensively studied ones since moieties of
amide units constitute effective hydrogen bond donors.1b,d–f,h,3
In the past decade, we have focused on the study of hetero-
atom-bridged calixaromatics, a new generation of macrocyclic host
molecules in supramolecular chemistry.4 It has been found that the
bridging heteroatoms, such as nitrogen atoms, can adopt sp2 or sp3
electronic configurations and form various degrees of conjugations
with the adjacent aromatic rings depending on the electronic nat-
ure of the aromatic rings, which results in the formation of differ-
ent conformations and cavities.3a,d,5
Heteroatom-bridged calixaromatics are synthesized by the frag-
ment coupling approach (FCA) and the one-pot reaction from read-
ily available and simple aromatic dinucleophiles such as m-
phenylenediamines and resorcinol derivatives, and aromatic
dielectrophiles including 2,6-dibromopyridines, 4,6-dichloropyri-
mides and cyanuric chloride. Both methods are effective in the for-
mation of macrocyclic compounds. This has led us to rationalize
that the linear oligomeric precursors may adopt or fold to correct
conformations prior to macrocyclization. To test our hypothesis,
we synthesized several oligo-m-anilines and investigated their
⇑
Corresponding authors. Tel.: +86 10 62565610; fax: +86 10 62564723 (D.-X.W.).
E-mail address: dxwang@iccas.ac.cn (D.-X. Wang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.050

S. Li et al. / Tetrahedron Letters 53 (2012) 6426–6429
6427
O2N
NO2
DIPEA (3 eq)
THF, rt
O2N
F
NO2
F
+
H2N
NH2
N
H
N
H
NH2
H2N
O
O
O
83%
2
1
2
3
DIPEA (2.5 eq)
THF, rt
9
1
7
C
8
O2N
NO2
NO2
E
O2N
NO2
O2N
4
5
A
D
O
B
N
H
N
H
F
N
H
3
N
H
6
F
2
O
10
11
12
13
5
(46%)
12
11
+
1
7
O2N
F
NO2
O2N
5
NO2
10
NO2
F
O2N
NO2
O2N
4
A
B
C
8
E
F
D
O
G
N
H
N
H
N
H
N
H
N
H
N
H
1
2
O
6
3
9
O
DIPEA (1.0 eq)
CH3CN, rt
17
25%
13
14
18
15
16
19
20
7 (8%)
21
20
19
1
7
13
NO2
16
O2N
F
NO2
O2N
NO2
10
O2N
11
5
4
17
A
2
B
C
8
E
D
O
F
N
H
6
N
H
3
N
H
9
N
H
N
H
NH2
18
14
O
O
15
12
22
26
30
23
27
31
24
25
32
33
28
29
6
Scheme 1. Synthesis of oligomers 5, 6 and 7.
that the two fragments twist each other affording the dihedral an-
gles in the range of 45–70°, which lead to the folding of the whole
molecules (Figs. 1 and 2). It is also worth noting that the alkoxy and
t-butyl substituents oriented to the same direction, acting as the
side chains to further stabilize the folding structure. The t-butyl
Similar to compound 6, intermolecular multiple
tween 2,4-dinitro-substituted benzene rings are also observed in
oligomer 7 (Fig. S2, B and C).
p
–
p
stackings be-
To study the structures of oligo-m-aniline compounds 5, 6 and 7
in solution, we carried out two-dimensional (2D) NOESY NMR
experiments. Compounds 5–7 gave well-resolved proton signals
in their 1H NMR spectra, and all signals were assigned based on
peak intensity (integration) coupling patterns, deuteration experi-
ments and NOE (see Supplementary data). We first examined the
structure of 6 in solution, which was illustrated in Figure S3. Five
N–1H signals of 6 showed very different chemical shift values.
Whereas protons H6, H9 and H15 gave similar chemical shifts at
9.94, 9.87 and 9.90, respectively, H3 and H12 moved to downfield
and upfield, respectively, giving the chemical shift value of 10.23
and 9.61. The changes of chemical shift of H3 and H12 suggested
that they are located in a local environment different from H6, H9
and H15. Moreover, cross-peaks between protons of H2 and H4,
H3 and H12, H5 and H8, H8 and H10, H11 and H14, H14 and H16 were
observed, which were in good agreement with the environment of
protons in solid state, indicating the folding structure of 6 in solu-
tion (Fig. S3). In the case of 7, cross-peaks between 1H signals H2
groups formed C–H. . .p interaction with the neighbouring benzene
rings. The alkoxy substituents, on the other hand, tended to form
Van der Waals interactions in the solid state (Fig. S1, A and
Fig. S2, A). Moreover, the presence of bulky groups inhibited the
mobility of the conformation because of the steric effect.
A few other interesting features of the intermolecular interac-
tions of the folding oligomers are worth addressing. In the case
of 6, for example, the folding oligomers were linked with a dichlo-
romethane molecule through C–H. . .p interaction between dichlo-
romethane and 2-butoxy-5-tert-butylaniline moiety (Fig. S1, B),
giving one dimensional infinite chain structure. In the two dimen-
sional direction, two folding oligomers aligned head to tail, forming
multiple
p–p stackings between 2,4-dinitro-substituted benzene
rings (Fig. S1, C). In the case of 7, chloroform acted as the linker be-
tween the folding oligomers, forming Cl. . .O interaction with one
molecule and C–H. . .O hydrogen bonding with another molecule.

6428
S. Li et al. / Tetrahedron Letters 53 (2012) 6426–6429
Figure 1. Crystal structure of 6. Selected bond length [Å]: C1-N3 1.354, N3-C7
1.424, C9-N4 1.432, N4-C21 1.356, C25-N7 1.365, N7-C27 1.408, C31-N8 1.417, N8-
C41 1.362, C43-N11 1.361, N11-C47 1.420; selected angle: <C1-N3-C7 125.46°, <C9-
N4-C21 123.09°, <C25-N7-C27 124.42°, <C31-N8-C41 126.25°, C43-N11-C47
126.67°; hydrogen bond distances [Å]: O1. . .H3A 2.004, O6. . .H4A 1.979,
O9. . .H7A 2.013, O12. . .H8A 2.001, O14. . .H11A 1.979; hydrogen bond angles: N3-
H3A. . .O1 130.57°, N4-H4A. . .O6 130.59°, N7-H7A. . .O9 129.89°, N8-H8A. . .O12
129.32°, N11-H11A. . .O14 131.18°. The probability is 25%. t-Butyl, alkoxy substit-
utents, a aryl and alkyl hydrogens are omitted for clarity.
Figure 2. Crystal structure of 7. Selected bond length [Å]: C61-N12 1.355, N12-C51
1.423, C47-N11 1.426, N11-C45 1.356, C41-N8 1.362, N8-C29 1.427, C27-N7 1.431,
N7-C23 1.358, C21-N4 1.355, N4-C11 1.427, C7-N3 1.432, N3-C5 1.355; selected
angle: <C61-N12-C51 127.96°, <C47-N11-C45 126.95°, <C41-N8-C29 125.43°,
<C27-N7-C23 123.69°, C21-N4-C11 124.60°, C7-N3-C5 125.75°; hydrogen bond
distances [Å]: O19. . .H12A 1.941, O14. . .H11A 1.965, O11. . .H8A 1.969, O9. . .H7A
2.011, O6. . .H4A 1.982, O4. . .H3A 1.993; hydrogen bond angles: N12-H12A. . .O19
133.83°, N11-H11A. . .O14 132.60°, N8-H8A. . .O11 131.53°, N7-H7A. . .O9 129.49°,
N4-H4A. . .O6 131.04°, N3-H3A. . .O4 130.08°. The probability is 25%. t-Butyl, alkoxy
substitutents, aryl and alkyl hydrogens are omitted for clarity.
and H4, H5 and H6, H3 and H8, H8 and H13, H2 and H13, H5 and H11
,
H3 and H9, H3 and H10, H4 and H14 were found in Figure 3 and Fig-
ure S4, also agreeing well with the folding structure in the solid
state. Noticeably, the long distance NOE between H5 and H11, H3
Figure 3. 2D NOESY NMR spectrum of 7. The 2D NOESY NMR experiment was carried out at 223 K with the concentration of 7 being 0.025 M and mixing time 800 ms,
respectively.

S. Li et al. / Tetrahedron Letters 53 (2012) 6426–6429
6429
and H9, H3 and H10 further evinced the folding structure in solution
References and notes
(Fig. 3 and Fig. S4). It is worth addressing that the intensity of the
cross-peak between N–1H signals H3 and H9 in 7 is stronger than
that of H3 and H12 in 6, indicating the result of two set of N–H con-
tacts. The structure of 5 in solution was also examined by means of
NOESY NMR spectrum. From Figure S5, several cross-peaks were
1. (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173; (b) Huc, I. Eur. J. Org. Chem. 2004,
17; (c) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev.
2001, 101, 3893; (d) Gong, B. Acc. Chem. Res. 2008, 41, 1376; (e) Li, Z.-T.; Hou, J.-
L.; Li, C. Acc. Chem. Res. 2008, 41, 1343; (f) Saraogi, I.; Hamilton, D. Chem. Soc. Rev.
2009, 38, 1726; (g) Nakano, T.; Okamoto, Y. Chem. Rev. 2001, 101, 4013;
(h)Foldamers: Structure, Properties and Applications; Heeht, S., Huc, I., Eds.; Viley-
VCH: Weinheim, 2007; (i) Bautista, A. D.; Craig, C. J.; Harker, E. A.; Schepartz, A.
Curr. Opin. Chem. Biol. 2007, 11, 685; (j) Cheng, R. P.; Gellman, S. H.; DeGrado, W.
F. Chem. Rev. 2001, 101, 3219; (k) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008,
41, 1366; (l) Juwarker, H.; Jeong, K.-S. Chem. Soc. Rev. 2010, 39, 3664; (m) Ni, B.-
B.; Yan, Q.; Ma, Y.; Zhao, D. Coord. Chem. Rev. 2010, 254, 954; (n) Martinek, T. A.;
Fülöp, F. Chem. Soc. Rev. 2012, 41, 687; (o) Schafmeister, C. E.; Brown, Z. Z.;
Gupta, S. Acc. Chem. Res. 2008, 41, 1387.
2. (a) Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1994, 116, 1054; (b) Appella, D.
H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.; Huang, X.; Barchi, J. J., Jr;
Gellman, S. H. Nature 1997, 387, 381; (c) Seebach, D.; Matthews, J. L. Chem.
Commun. 1997, 21, 2015; (d) Seebach, D.; Abele, S.; Gademann, K.; Jaun, B.
Angew. Chem., Int. Ed. 1999, 38, 1595; (e) Zhao, X.; Jia, M.-X.; Jiang, X.-K.; Wu, L.-
Z.; Li, Z.-T.; Chen, G.-J. J. Org. Chem. 2004, 69, 270.
3. (a) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. Angew. Chem., Int. Ed. Engl. 1994, 33,
446; (b) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1996, 118, 7529;
(c) Berl, V.; Huc, I.; Khoury, R.; Krische, M.; Lehn, J.-M. Nature 2000, 407, 720; (d)
Zhu, J.; Parra, R. D.; Zeng, H.; Skrzypczak-Jankun, E.; Zeng, X. C.; Gong, B. J. Am.
Chem. Soc. 2000, 122, 4219; (e) Jiang, H.; Léger, J.-M.; Huc, I. J. Am. Chem. Soc.
2003, 125, 3448; (f) Gan, Q.; Bao, C.; Kauffmann, B.; Grélard, A.; Xiang, J.; Liu, S.;
Huc, I.; Jiang, H. Angew. Chem., Int. Ed. 2008, 47, 1715; (g) Hu, H.-Y.; Xiang, J.-F.;
Yang, Y.; Chen, C.-F. Org. Lett. 2008, 10, 69.
4. For reviews on heteracalixaromatics see: (a) Wang, M.-X. Chem. Commun. 2008,
4541; (b) Maes, W.; Dehaen, W. Chem. Soc. Rev. 2008, 37, 2393; (c) Tsue, H.;
Ishibashi, K.; Tamura, R. Top. Heterocycl. Chem. 2008, 17, 73; (d) Wang, M.-X. Acc.
Chem. Res. 2012, 45, 182; (e) Thomas, J.; Rossom, W. V.; Hecke, K. V.; Meervelt, L.
V.; Smet, M.; Maes, W.; Dehaen, W. Chem. Commun. 2012, 48, 43; (f) König, B.;
Fonseca, M. H. Eur. J. Inorg. Chem. 2000, 2303.
observed, such as H2 and H4, H3 and H4, H5 and H6, H3 and H10
,
H6 and H10, H2 and H9, H4 and H9, H5 and H6. Though the NOE be-
tween H2 and H9, H8 and H9 indicated they are closely neighboured
in the structure, it is hard to conclude that 5 existed in a folding
form in solution.
In summary, we have synthesized the first examples of oligo-m-
aniline foldamers through a fragment coupling protocol. As re-
vealed by X-ray crystallography, the hexamer and heptamer give
a snake-shape folding structure in the crystalline state. On the ba-
sis of 2D NOESY NMR experiments, both hexamer and heptamer
adopt similar folding structures as those in the solid state.
Acknowledgments
We thank the NNSFC (20875094, 21072197, 91127008,
20820102034), MOST (2011CB932501), CAS and the Tsinghua Uni-
versity for financial support.
Supplementary data
Supplementary data (experimental details, full characterization of
products, crystal structures, 2D 1H NMR NOESY spectra, 1H and 13C
NMR of the products) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.050.
5. Wang, M.-X.; Zhang, X.-H.; Zheng, Q.-Y. Angew. Chem., Int. Ed. 2004, 43, 838.