Novel foldamer structural architecture from cofacial aromatic building blocks

Article abstract of DOI:10.1039/b822113h

This communication demonstrates the utility of peri-substituted 1,8-diphenylnaphthalene as an effective building block for the construction of novel conformationally ordered synthetic oligomers displaying cofacial structural features.

Full text of DOI:10.1039/b822113h

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COMMUNICATION
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Novel foldamer structural architecture from cofacial aromatic
building blockswz
Panchami Prabhakaran,a Vedavati. G. Puranik,b Jima N. Chandran,c
¨
Pattuparampil R. Rajamohanan,* Hans-Jorg Hofmann* and Gangadhar J. Sanjayan*
c
d
a
Received (in Cambridge, UK) 9th December 2008, Accepted 26th March 2009
First published as an Advance Article on the web 6th May 2009
DOI: 10.1039/b822113h
This communication demonstrates the utility of peri-substituted
1,8-diphenylnaphthalene as an effective building block for the
construction of novel conformationally ordered synthetic
oligomers displaying cofacial structural features.
makes the 1,8-diarylnaphthyl unit an excellent template for
building cofacial structures.11
Thus, it was anticipated that positioning of hydrogen-bond
directing12 conformationally restricted aryl units on the 1,8-
peri-positions of naphthalene building blocks would pave the
way for the creation of conformationally ordered structural
units with cofacial arrangements of the aryl rings. For this
purpose, we selected 2,6-diaminopyridine as a co-building
block, anticipating that the resulting oligomer would have
suitable intramolecular hydrogen bonding arrangements
which would help the molecule to adopt symmetrical cofacial
structural architecture. In addition to this, use of pyridine
rings on the backbone can aid the molecule to participate in
processes such as molecular recognition and self-assembly,
which are known for these classes of systems.13
The significance of non-covalent interactions in structural
pre-organization and functioning of various bio-machineries
has been explored with non-natural synthetic molecular
frameworks which led to the expanding field of foldamers,
promising new horizons to various interdisciplinary areas.1
These de novo designed molecules with diverse backbones find
potential applications in molecular recognition,2 drug design,3
and material sciences.4 The design of novel backbones might
be a daunting task because, similar to the natural analogs, the
overall conformation is based on the nature and arrangement
(sequence) of the monomer building blocks.5 Owing to the
predictable and stable conformation, abiotic backbones have
been proved to be attractive targets in foldamer research.6
Although the majority of them display helical conformations,7
a common feature observed in biomolecules, sheet8 and rod9
conformations, can also be attained with a proper tuning of
the backbone. In this context, development of structural
architectures different from those classically observed would
be of considerable interest.10
The cofacial 1,8-diphenylnapthalene unit 2a was accessed
by Suzuki coupling14 by reacting the diboronic acid 115
with methyl-5-bromo-2-methoxy benzoic acid methyl ester
Herein we describe the synthesis and conformational studies
of a novel class of abiotic hybrid oligoamides with cofacial
structural architecture. The peri-positioning of phenyl rings at
the 1- and 8-positions of the naphthyl ring leads to an almost
parallel orientation of the aryl rings to each other and to their
nearly perpendicular orientation to the naphthyl ring. This
a Division of Organic Chemistry, National Chemical Laboratory,
Dr Homi Bhabha Road, 411 008, Pune, India.
E-mail: gj.sanjayan@ncl.res.in; Fax: (+91) 020-25893153;
Tel: (+91) 020-25902082
b Central Material Characterization Division, National Chemical
Laboratory,
Dr Homi Bhabha Road, 411 008, Pune, India
c Central NMR Facility, National Chemical Laboratory,
Dr Homi Bhabha Road, 411 008, Pune, India.
E-mail: pr.rajamohanan@ncl.res.in; Fax: (+91) 020-25893153;
Tel: (+91) 020-25902075
d Universitat Leipzig, Fakultat fur Biowissenschaften, Pharmazie und
¨
Psychologie, Institut fur Biochemie, Bruderstraße 34, D-04103,
¨
¨
¨
Leipzig, Germany. E-mail: hofmann@rz.uni-leipzig.de
¨
w Dedicated to Prof. P. Balaram on the occasion of his 60th birthday.
z Electronic supplementary information (ESI) available: Full experi-
mental and theoretical procedures, 1H, 13C, 2D NMR data, ESI mass
spectra, and crystal data of 2a and 3. CCDC 707751 (2a) and CCDC
662712 (3). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b822113h
Scheme 1 Reagents and conditions: (i) methyl-5-bromo-2-methoxy-
benzoic acid methyl ester, DABCO, Pd(OAc)2, K2CO3, TBAB,
PEG-400, 110 1C 15 h; (ii) LiOH, dioxane, H2O; (iii) (COCl)2, DMF
(cat.), DCM, rt, 3 h; (iv) mono-boc-2,6-diaminopyridine, Et3N, rt,
12 h; (v) TFA, DCM, rt, 30 min; (vi) 2e, Et3N, DCM, rt, 12 h.
ꢀc
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(Scheme 1, for experimental details, see ESIz). Although
1,8-diarylnapthalenes can in principle exist in syn and anti
conformations, the syn isomer of 2a was preferentially
obtained during the palladium-catalyzed Suzuki coupling, as
evidenced from its crystal structurey (see also ESIz). This is
presumably caused by chelation effects.16
bond-mediated duplex formation through intermolecular inter-
actions (Fig. 1(c) and (d)). The hydrogen-bonded duplex
features an eight-membered ring network, formed via inter-
molecular H-bonding involving NH and N of the amino-
pyridines as the H-bond donors and acceptors, respectively. It is
noteworthy, that this is a feature usually observed in N-acetylated
2-aminopyridines, wherein the donor and acceptor groups are
clearly projected for self-assembly.13 The duplex also features an
oval cavity in which a water molecule was encapsulated.
Support for S(6)-type intramolecular hydrogen bonding in
solution comes from NMR studies. The strong NOE between
the centrally positioned NH (d 10.14 ppm) and its adjacent
methoxy group (d 3.73 ppm, see ESIz) indicates their close
proximity and suggests the existence of S(6)-type intra-
molecular H-bonding, as observed in the solid state. The
negligible shift of this NH (Dd o 0.01 ppm) with the addition
of a polar solvent such as DMSO-d6 in a titration experiment
(see ESIz) further suggests its intramolecular nature. On the
contrary, the terminal pyridyl amide NH (d 8.48 ppm)
underwent extensive broadening in CDCl3, suggesting its
involvement in intermolecular H-bonding.
The diacid chloride 2c gave the oligomer 3 in 75% yieldz on
reaction with mono-boc-2,6-diaminopyridine.17 The key step
for the synthesis of the higher oligomer 5 was the partial
hydrolysis of the bis-ester 2a to afford the mono-acid 2d using
LiOH (1 equiv.) in MeOH–H2O (9 : 1). The bis-amine 4 was
obtained by the TFA-mediated Boc-deprotection of 3.
Oligomer 5 was accessed by reacting the monoacid chloride
2e, obtained by reacting the monoacid 2d with oxalyl chloride
in DCM containing a catalytic amount of DMF, with the
diamine 4 in DCM containing triethylamine. Further purifica-
tion of the oligomer 5 was difficult due to its poor solubility in
most organic solvents. However, the mass spectral character-
istics clearly confirmed its formation [MALDI-TOF: calc. for
C90H70N6O14, 1459.50 (M + H)+; found: 1459.89 (M + H)+;
1481.84 (M + Na)+; 1497.75 (M + K)+, see ESIz].
Extensive efforts to crystallize the oligomers resulted in the
formation of crystals of 3.y Analysis of the crystal data
revealed that both peri aryl rings have syn orientation and
are cofacial along with the hydrogen-bonded pyridyl rings and
almost perpendicular to the naphthalene ring.
The structural investigation of the higher oligomer 5 in the
solution state could not be undertaken owing to its poor
solubility in the majority of the organic solvents. This is
presumably due to extensive aggregation in solution, a known
problem with polyaromatic compounds.21
The S(6)-type18 six-membered intramolecular hydrogen bond
between the amide NH and methoxy group ortho to the
carbonyl group (Fig. 1(a) and (b)) facilitates the molecule to
grow further co-facially, as evident from the solid-state
structure, although the pyridyl rings at the termini are splayed
out presumably to minimize steric interactions and through-
space Coulomb repulsion.19 Interestingly, 3 undergoes hydrogen
The difficulty in getting crystals of the higher oligomer 5
suitable for X-ray diffraction studies prompted us to
investigate its conformation by means of theoretical studies
(Fig. 2). Computational studies employing ab initio MO
theory have successfully contributed to predict the conforma-
tion of numerous foldamer classes.20 Consideration of
correlation energy at the MP2/6-31G* level confirms the
experimentally found preference of the syn orientation of the
peri aryl rings over the anti orientation (DE = 9.0 kJ molꢁ1).
This comes from the influence of dispersion forces between the
parallel aromatic side chains. At the HF/6-31G* level, the anti
orientation is preferred by 10.0 kJ molꢁ1 (see ESIz). Thus, the
syn structure was considered for the calculations on compound 5.
As seen in the crystal structure of the oligomer 3, the
calculated structure of oligomer 5 retains the cofacial arrange-
ment of the aryl rings appended on the peri positions of the
naphthyl moiety (Fig. 2). The cofacial structural architecture
Fig. 1 Solid-state structure of oligomer 3 (a, b: various views of the
Fig. 2 Two views of the structural architecture of oligomer 5
obtained at the HF/6-31G* level of ab initio MO theory.
crystal structure; c, d: various views of the H-bonded duplex).
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also features the S(6)-type intramolecular hydrogen bonds, as
observed in the shorter oligomer 3.
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In summary, this work demonstrates the utility of peri-
substituted 1,8-diphenylnaphthalene as an effective building
block for the construction of novel conformationally ordered
synthetic oligomers. The striking feature of these oligomers is
their unusual conformation featuring cofacial structural
architectures, which are different from those classically
observed.7–9 The self-assembly of the oligomer 3 forming
hydrogen-bonded molecular duplexes by intermolecular
hydrogen bonding is remarkable. Studies to modulate the
solubility profile of the higher-order oligomers, which
may facilitate investigation of their trans-annular p–p
interactions,22 are under work.
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P. P. is thankful to CSIR, New Delhi, for a Senior Research
fellowship. G. J. S. thanks International Foundation for
Science (IFS, Sweden) for financial support. H. J. H. thanks
Deutsche Forschungsgemeinschaft (HO2346/1-3 and SFB
610) for continuous financial support.
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Notes and references
y Crystal data for 2a (C46.50H47.50ClN6O8.50): M = 861.86. Single
crystals of 2a were grown by slow evaporation of a mixture of
methanol and DCM. Crystal dimensions 0.33 ꢂ 0.23 ꢂ 0.07 mm.
Quadrant data acquisition. Total scans = 4, total frames = 2424,
y range = 1.87–25.001, completeness to y of 25.01 is 99.8%. Triclinic,
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ꢀ
space group P1, a = 12.0667(8), b = 14.506(1), c = 15.091(1) A, a =
92.767(7), b = 109.028(1), g = 105.108(6)1, V = 2385.0(3) A3, Z = 2,
Dc = 1.200 g cmꢁ3, m(Mo-Ka) = 0.137 mmꢁ1, 23 258 reflections
measured, 8380 unique [I 4 2s(I)], R = 0.0935, Rw = 0.2298.
Crystal data for 3 (C28H24O6): M = 456.47. Single crystals of the
compound were grown by slow evaporation of a mixture of ethyl
acetate and pet. ether. Crystal dimensions 0.38 ꢂ 0.11 ꢂ 0.08 mm.
Quadrant data acquisition. Total scans = 4, total frames = 2424,
y range = 2.17–25.001, completeness to y of 25.001 is 99.8%. Triclinic,
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ꢀ
P1, a = 8.0132(5), b = 10.2043(6), c = 15.3713(9) A, a = 86.8620(10),
b = 75.9320(10), g = 67.0470(10)1, V = 1121.54(12) A3, Z = 2,
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measured, 3953 unique [I 4 2s(I)], R value 0.0572, wR2 = 0.1396.
z Synthesis of oligomer 3: To a stirred solution of the diacid 6 (1 g,
2.3 mmol, 1 equiv.) in dry DCM (15 ml), 2 drops of DMF were added
followed by the dropwise addition of oxalyl chloride (1.2 ml, 9.2,
4 equiv.). After 3 h at room temperature, solvent and excess oxalyl
chloride were removed from the reaction mixture under reduced
pressure to obtain the crude bis-acid chloride which was directly
reacted with a reaction mixture containing mono-boc-2,6-diamino-
pyridine (9.2 mmol, 4 equiv.) and triethylamine (9.2 mmol, 4 equiv.) in
DCM (10 ml). The reaction mixture was allowed to stir overnight at rt.
Work-up followed by column chromatographic purification afforded 3
(eluent: 80% dichloromethane–petroleum ether, Rf = 0.4) as a white
solid (1.41 g, 75%) which could be crystallized from a solution of
dichloromethane and MeOH; mp 172 1C (decomp.). Found: C, 68.26;
H, 5.84; N, 10.44. Calc. for C46H46N6O8: C, 68.13; H, 5.72; N, 10.36;
nmax (CHCl3)/cmꢁ1: 3421, 3356, 3018, 1730, 167, 1587, 1506, 1497,
1456, 1369, 1305, 1217, 1153, 1053, 1028; 1H NMR (CDCl3, 400 MHz):
d 10.12, (s, 2H), 8.48 (br s, 2H), 8.08–8.06 (m, 2H), 7.98–7.96,
J = 8.28 Hz, 2H), 7.77–7.73 (m, 6H), 7.58–7.54 (t, J = 7.54 Hz,
2H), 7.40–7.38 (d, J = 7.04 Hz, 2H), 7.18–7.16 (dd, J = 2.26 Hz,
J = 6.29 Hz, 2H), 6.69–6.67 (d, J = 8.80 Hz, 2H), 3.73 (s, 6H), 1.38
(s, 18H); 13C NMR (CDCl3, 100 MHz): d 163.1, 155.4, 152.5, 150.8,
150.1, 140.9, 138.7, 136.7, 135.6, 135.3, 133.2, 130.6, 130.0, 128.8,
125.2, 119.4, 110.6, 108.9, 107.7, 81.1, 56.1, 28.1; ESI MS: 810.96
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