Rod-coil copolymers from oligo(p-benzamide) foldamers

Article abstract of DOI:10.1039/b617598h

Self assembling rod-coil copolymers were synthesized in which oligo(p-benzamide) rods up to the octamer were prepared via iterative solution synthesis employing the acid labile 2,4-dimethoxybenzyl amide protective group. The Royal Society of Chemistry 200

Full text of DOI:10.1039/b617598h

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www.rsc.org/materials | Journal of Materials Chemistry
Rod–coil copolymers from oligo(p-benzamide) foldamers{{
Helga Seyler, Elena Berger-Nicoletti and Andreas F. M. Kilbinger*
Received 4th December 2006, Accepted 26th January 2007
First published as an Advance Article on the web 15th February 2007
DOI: 10.1039/b617598h
Self assembling rod–coil copolymers were synthesized in which oligo(p-benzamide) rods up to the
octamer were prepared via iterative solution synthesis employing the acid labile
2,4-dimethoxybenzyl amide protective group.
Rod-like molecules with nanometre dimensions have recently
attracted increased attention.1 Most of these shape persistent
molecules gain rigidity from either helix formation2 or
p-conjugation.3 Molecular rods offer the possibility to position
reactive centres at known distances from each other which is,
for example, important for the study of electron and energy
transfer. On the other hand they are useful nano-scaffolds used
in the construction of larger shape persistent molecules as well
as in supramolecular chemistry.4 Oligo(p-benzamide)s
(OPBAs) are particularly interesting molecular rods as they
combine chain stiffness with the ability to form multiple
hydrogen bonds. This combination of shape persistence and
directionality in non-covalent bond formation makes them
interesting building blocks for the construction of supramole-
cular objects such as rod–coil copolymers. Rod–coil copoly-
mers are an important class of supramolecular polymer. They
offer the possibility of creating defined nano-structures in
solution or the solid state on length scales much smaller than
typically accessible using coil–coil block copolymers.5 We
recently described the synthesis and aggregation behaviour of
rod–coil copolymers in which the rod-segments are based on
shape persistent OPBA.6,7
The greatest challenge in synthesizing OPBA for use in
supramolecular chemistry is their strong aggregation and
hence low solubility in most organic solvents.8 We previously
reported a precursor route9 as well as a solid supported
synthesis protocol10,11 that overcomes these limitations. Here
we describe a new synthetic route to OPBA up to the octamer
using N-2,4-dimethoxybenzyl (N-DMB) protection on every
second amide group.
As shown in Scheme 1, p-aminobenzoic acid (1) was reduc-
Scheme 1 Synthesis of OPBA dimers (5, 7) and the tetramer (8).
tively alkylated using 2,4-dimethoxy benzaldehyde (2) and
sodium borohydride to give the secondary amine 4 (50% over
two steps). Acylation of 4 with p-nitrobenzoyl chloride gave the
N-DMB protected dimer 5 (82%). The nitro group of 5 could be
reduced to the amine using Pd/C and ammonium formate to give
amino acid 7 (90%). The nitro reduction at rt was found to be
slow and completion of reaction was monitored by RP-HPLC
(reversed phase-HPLC, see ESI{). Using an activation protocol
described by Zollinger and co-workers12 and more recently by
Ueda and co-workers,13 5 could be transformed into the acid
chloride 6 using thionyl chloride in NMP without any detectable
loss of the DMB-protective group. Acylation of 7 with 6 gave the
tetramer 8 (68%).
We were fortunate to grow single crystals of 8 from an
ethanol–water (20 : 1 v/v) mixture which allowed X-ray
crystallographic analysis (see crystal data§14). Of particular
interest was the conformation of the three amide bonds in 8.
Johannes Gutenberg-Universita¨t Mainz, Institut fu¨r Organische Chemie,
Duesbergweg 10-14, 55099 Mainz, Germany.
E-mail: akilbing@uni-mainz.de
{ This paper is part of a Journal of Materials Chemistry issue
highlighting the work of emerging investigators in materials chemistry.
{ Electronic supplementary information (ESI) available:
Experimental; X-ray structure of 8; HPLC elugrams; mass and
NMR spectra. See DOI: 10.1039/b617598h
§ CCDC reference number 629491. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b617598h
1954 | J. Mater. Chem., 2007, 17, 1954–1957
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It has been well established that secondary aromatic amides
(Ar–CONH–Ar) exist predominantly in the trans conforma-
tion while the tertiary aromatic amides of the type Ar–CONR–
Ar (R = alkyl) prefer the cis conformation (with respect to the
phenyl rings).15 In a previous report we could show that this
was also true for OPBA dimers in solution as well as in the
solid state.10
propargylamine to install a terminal alkyne in 13 (95%).
Poly(ethylene glycol) mono-methyl ether mono-azide16 could
be reacted with 13 in a [2 + 3]-cycloaddition under Cu(I)-
catalysis17 to give the block copolymer 14 (40%) in which both
blocks are 1,4-linked via a 1,2,3-triazole unit.
Block copolymer 14 which most likely adopts a coil–coil-like
conformation showed no aggregation in chloroform. The
presence of DMB-N-protective groups on every second amide
effectively disrupted the aggregation process. It is important to
note that a virtually identical synthetic strategy using a dimer
analogous to 7 carrying a p-methoxybenzyl group was
unsuccessful when carried out on a solid support. We
attributed this to backbone aggregation of the oligomers on
the solid phase. For this reason we previously reported that
complete N-protection is necessary for successful solid
supported synthesis of such oligomers.10 In the case described
here, the bulky polymer chain of 14 possibly helps in reducing
the aggregation strength via steric shielding. 14 could be
analyzed by MALDI-TOF mass spectroscopy (Fig. 1, left).
The mass spectrum shows only the fully protected block
copolymer as the sodium, potassium and lithium adduct.
The DMB-protective group was removed by dissolving 14 in
a mixture of trifluoroacetic acid (TFA), chloroform and
Of the three amide bonds present in 8 only the centre one
exists in the trans conformation while the outer ones are in the
cis conformation. This confirms the previous assumption that
this conformational preference persists in longer OPBAs.
COSY and NOESY-NMR spectroscopy of solutions of 8
allowed the complete peak assignment of the 1H-NMR
spectroscopic data and showed that at least one tertiary amide
existed exclusively in the cis conformation (the conformation
of the other amide group could not be assigned due to
overlapping peaks; see ESI{).
Continuing with the iterative strategy, 8 could be reduced to
the amine 9 using Pd/C and ammonium formate (90%,
Scheme 2). In situ activation of 8 with thionyl chloride in
NMP gave the acid chloride 10, which was coupled with 9 to
give the octamer 11 (52%). 11 could be converted into an
acid chloride in situ (SOCl2–NMP) and coupled with
Scheme 2 Synthesis of an OPBA octamer (11) and conjugation with poly(ethylene glycol) to yield a coil–coil copolymer (14) or rod–coil
copolymer (15) after DMB-deprotection.
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Fig. 1 MALDI-TOF mass spectrum of protected 14 (left) and unprotected 15 (right).
anisole at rt for 15 h. The ease of protective group removal
could be demonstrated by addition of polymer 14 to neat TFA.
This immediately gave a purple coloured solution, indicative
of the successfully cleaved DMB cation. Polymer 15, in
which all aromatic amides are assumed to exist exclusively in
the all-trans conformation was further purified by silica gel
chromatography in THF and DMF. Fig. 1 (right) shows the
MALDI-TOF mass spectrum of 15. Two mass distributions,
one for the potassium and one for the sodium adduct of 15 can
be observed.
high molecular weight (.2 6 106 g mol21) outside the
calibration limit of the GPC setup. Similar behaviour has
previously been observed by us for other rod–coil copolymers
in chloroform solution.9
The GPC elugram of the same sample of 15 in DMF (Fig. 2,
bottom) also showed the presence of aggregates as well as
molecularly dissolved polymer. The aggregates of 15 in DMF
appear as a multi modal mass distribution, which was
unexpected and had not been observed by us previously.
However, the previously reported rod–coil copolymers differed
from the ones shown here.6,7,9 Detailed investigations had
previously been carried out on a hepta(p-benzamide) carrying
six amide groups. The octamer shown here carries eight amide
groups and it is likely that this causes the increased
aggregation strength. By comparing the very different aggre-
gate masses and mass distributions in the elugrams of 15 in
CHCl3 and DMF it could safely be concluded that all
aggregation phenomena were due to non-covalent interactions
rather than covalent cross-linking.
Fig. 2 (top, middle) shows the chloroform GPC traces for
14, 15 as well as for the parent PEG–azide. A shift to higher
mass is clearly visible going from PEG–N3 to the N-DMB-
protected block copolymer 14. The elugram of 14 showed the
molecularly dissolved polymer eluting at the poly(styrene)
equivalent hydrodynamic radius (Mn = 3500 g mol21, Mw
3800 g mol21; PDI = 1.07).
=
The GPC trace of 15 in chloroform showed the presence of
molecularly dissolved polymer as well as high molecular
weight aggregates. The non-covalent aggregates elute at very
The non-aggregating N-DMB-protected copolymer 14 could
be analysed by 1H-NMR spectroscopy in DMSO-d6 and all
peaks of the spectrum could be assigned. A 1H-NMR spectrum
of 15 was recorded in DMSO-d6. The polymer appeared to
aggregate in this solvent, as the aromatic signals of the OPBA
block integrated to only 15% of the expected value when
compared to the integral of the PEG methylene protons. This
can be explained, considering the observed aggregation of 15
in DMF (see GPC results above). The solvent (DMSO-d6) was
then removed under vacuum and the residue dissolved in
deuterated sulfuric acid, which is known to be a strong
1
hydrogen bond disrupting solvent.18 The H-NMR spectrum
of 15 in D2SO4 shows a significant increase in intensity of the
aromatic protons in the range d = 7.0–8.5 compared to the
spectrum recorded in DMSO-d6. This marked difference in
intensity is further evidence for the strong aggregation of 15 in
DMSO (NMR data is available in the ESI{).
In order to further study the aggregation phenomena,
chloroform solutions of 15 were investigated by transmission
electron microscopy (TEM). Fig. 3 shows a representative
TEM image of aggregates of 15. Elongated, rod-like micelles
can be observed similar to those reported previously.7 The
Fig. 2 GPC traces. Top: PEG–N3 (dashed line) and 14 (full line) in
CHCl3; middle: 15 in CHCl3; bottom: 15 in DMF.
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Foundation (DFG) and the Fonds der Chemischen Industrie
(FCI) for financial support and BASF Ludwigshafen for a
generous donation of NMP.
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In conclusion, we have successfully employed the 2,4-
dimethoxybenzyl protective group for the protection of
oligo(p-benzamide)s up to the octamer. Protection of every
second amide group was sufficient to suppress aggregation
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AFMK thanks Dr. Dieter Schollmeyer for X-ray crystal-
lographic analysis, Sonngard Hartmann for help with the
TEM measurements and Andreas Scherrmann for NMR
measurements in D2SO4. AFMK thanks the German Science
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J. Mater. Chem., 2007, 17, 1954–1957 | 1957