Toward large tubular helices based on the polymerization of tri(benzamide)s

Article abstract of DOI:10.1002/pola.28029

Herein we present the synthesis and polycondensation of mono- and di-N-protected, bis-substituted tri(benzamide)s with the aim to create large, tubular helices. We synthesized 2,4-dimethoxy and 2,5-bis-TEGylated aminobenzoic acid derivatives as bent and linear monomers and introduced p-methoxybenzyl (PMB) amide protecting groups to the oligobenzamide backbone. An iterative coupling strategy allowed for sequence control, giving rise to oligomers consisting of one bent and two linear monomers. The resulting meta-para-para-linked aromatic trimers carried either one or two PMB-protecting groups. With high organosolubility and flexibility, this synthetic strategy generated suitable precursors for subsequent polycondensation reactions. After polymerization, treatment with acid triggered the cleavage of the N-protecting groups. We hypothesize that the hydrogen bonding pattern generated along the polyaramide backbone could lead to the formation of a helical polymer. A drastic change in hydrodynamic volume was observed by gel permeation chromatography and dissolution in a chiral solvent lead to the observation of a circular dichroism signal for this polymer. The results of the polycondensations of N-protected oligobenzamides are reported herein. The formation of macrocycles as well as polymers could also be observed, giving a highly interesting insight into the underlying mechanism of the polycondensation of flexible, oligobenzamide-based oligomers.

Full text of DOI:10.1002/pola.28029

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Toward Large Tubular Helices Based on the Polymerization of
Tri(benzamide)s
Maren Schulze, Andreas F. M. Kilbinger
Department of Chemistry, University of Fribourg, Fribourg, Switzerland
Correspondence to: A. F. M. Kilbinger (E-mail: andreas.kilbinger@unifr.ch)
Received 16 October 2015; accepted 21 November 2015; published online 8 January 2016
DOI: 10.1002/pola.28029
ABSTRACT: Herein we present the synthesis and polycondensa-
tion of mono- and di-N-protected, bis-substituted tri(benza-
mide)s with the aim to create large, tubular helices. We
synthesized 2,4-dimethoxy and 2,5-bis-TEGylated aminobenzoic
acid derivatives as bent and linear monomers and introduced
p-methoxybenzyl (PMB) amide protecting groups to the oligo-
benzamide backbone. An iterative coupling strategy allowed
for sequence control, giving rise to oligomers consisting of
one bent and two linear monomers. The resulting meta-para-
para-linked aromatic trimers carried either one or two PMB-
protecting groups. With high organosolubility and flexibility,
this synthetic strategy generated suitable precursors for subse-
quent polycondensation reactions. After polymerization, treat-
ment with acid triggered the cleavage of the N-protecting
groups. We hypothesize that the hydrogen bonding pattern
generated along the polyaramide backbone could lead to the
formation of a helical polymer. A drastic change in hydrody-
namic volume was observed by gel permeation chromatogra-
phy and dissolution in a chiral solvent lead to the observation
of a circular dichroism signal for this polymer. The results of
the polycondensations of N-protected oligobenzamides are
reported herein. The formation of macrocycles as well as poly-
mers could also be observed, giving
a highly interesting
insight into the underlying mechanism of the polycondensation
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of flexible, oligobenzamide-based oligomers.
2016 Wiley
Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54,
1731–1741
KEYWORDS: polyaramides; polycondensation; helices; fol-
damers; sequence control
of the nonbiological foldamers and helical polymers reported
to date do not exhibit an inner cavity.11(d),12 Hence, the inter-
est in the construction of synthetic, helical supramolecules
containing interior spaces has greatly increased during the
past decade.
INTRODUCTION Complex folding processes of supramole-
cules are plentiful in nature, ensuring the correct function of
millions of organisms. They can be found, for example, in the
folding of proteins, the DNA double helix or ion channels.1 In
proteins, the information for the self-assembly of the final
structure is already encoded in the smallest unit—the amino
acid sequence—and their folding is then based on the inter-
play of multiple noncovalent interactions. Hence, a careful
design of the monomer structure is necessary to store infor-
mation on a molecular level, which is later on transformed
into a well-defined structure.2 In recent years, various
research groups dedicated their work to the synthesis of
nature-imitating supramolecules by mimicking the underly-
ing forces: A combination of hydrogen bonds,3 electrostatic,4
hydrophobic and solvophobic5 interactions, aromatic–aro-
matic interactions,3(i),6 the introduction of sterically demand-
ing side groups,4(e),7 and/or metal-coordination8 results in
the generation of predictable conformations and stabilizes
Bis-Substituted aromatic oligoamide foldamers are especially
suitable to approach this task. They exhibit tremendous
shape-persistence caused by their aromatic backbone, the
double bond character of the amide bonds and the formation
of an intramolecular, three-center hydrogen bonding pattern
along the aramide backbone.3(c,i),13 Even though they can
theoretically exhibit various conformations, the preference at
every rotationally flexible bond forces the supramolecule
into one favored conformation. Other factors such as entropy,
the influence of functional side chains or solvent effects can
thereby be neglected.3(d),11(b),14 The first example of a hollow
structure constructed from aromatic oligoamides comprised
the molecular apple peel described by Huc and his group.15
The inclusion of small molecules in helical capsules via host-
guest interactions has been reported multiple times since
then.16 The group of Gong invented a concept for the
the supramolecule. This allowed for the creation of synthetic
(d,e),5(e),6(a),9
single-, double-, or triple-stranded helices,4
ion
channels,10 and foldamers.3(c),(d,i),9(d),11 However, the majority
Additional Supporting Information may be found in the online version of this article.
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construction of foldamers and helices with even larger cav-
ities and tunable sizes.3(g),13(c),17 The underlying idea is to
incorporate meta- as well as para-linked, bis-substituted
amino acids in a sequence-controlled manner into the back-
bone.13(c) The inner diameter thereby increases with an
increasing number of para-linked amino acids. The largest
diameter constructed by alternating bis-methoxylated meta-
and para-amino acids reported to date measures 30 Å. The
low yields of the coupling steps however limited the number
of coupled amino acids to 21, making the creation of a helix
with more than one helical turn impossible.17 To obtain
higher molecular weights, an approach via polycondensation
of meta-diamines and meta-diacid chlorides was recently
described by the Gong group.18 The formation of macro-
cycles could be observed because of the preorganizational
effect of the rigid, shape-persistent backbone. However, the
polymerization of a bis-substituted diacid chloride and a
flexibility-inducing mono-substituted diamine resulted in
high molecular weight polymers. Their solvophobically
driven folding then led to a racemic mixture of helical (P
and M) polyamides with an inner cavity of 8.2 Å and multi-
ple turns. In contrast to conventional organic synthesis, poly-
merization techniques have the advantage to deliver high
molecular weights, however, the monomer sequence within
the polymer chain cannot be controlled. Furthermore, the
above-described helical polymers exhibit smaller inner diam-
eters than the aromatic oligoamide foldamers prepared by
organic synthesis. In conclusion, either high molecular
weights or large inner diameters can be generated by the
methods described to date.
thereby be triggered through the cleavage of the protecting
groups upon treatment with acid.3(g),20 In that way, the ara-
mide backbone undergoes a conformational change from cis
(E) to trans (Z) (cis/trans with respect to the phenyl rings)
through the formation of the intramolecular hydrogen bond-
ing pattern.
The results of this new route including the synthesis and
characterization of mono- and di-N-protected, bis-substituted
tri(benzamide)s and thorough investigations concerning the
polycondensation technique are presented herein.
EXPERIMENTAL
Materials
Solvents of analytical grade were purchased from Honeywell,
Acros Organics, Sigma Aldrich, Fisher Scientific, and Fluka
and were used without further purification. Solvents of tech-
nical grade were purified by distillation, if necessary. Tetra-
hydrofuran for use in polymerizations was purchased as a
sealed bottle from Acros Organics (extra dry, AcroSeal) and
transferred into a glove box. Deuterated chloroform (CDCl3)
was purchased from Cambridge Isotope Laboratories. All fur-
ther chemicals were purchased from Sigma Aldrich, Acros
Organics, Alfa Aesar, and Merck and used as received.
Techniques
Standard 1H and 13C nuclear magnetic resonance spectra
were recorded on a Bruker Avance III 300 at a frequency of
300 and 75 MHz, respectively, or at 500 MHz (1H) and 125
MHz (13C) on a Bruker Avance III 500 spectrometer. All
NMR-signals were referenced internally to residual solvent
signals. Electron spray ionization (ESI) mass spectra were
recorded on a Bruker-Ion Trap MS esquire HCT mass spec-
trometer. Matrix assisted laser desorption and ionization
time-of-flight (MALDI-ToF) measurements were performed
on a Bruker ultrafleXtremeTM MALDI-ToF mass spectrometer.
DCTB was used as matrix and sodium trifluoroacetate used
as salt. RP-HPLC analysis was performed on a HP 1090 Liq-
uid Chromatograph (Hewlett Packard) using a PerfectSil col-
umn (MZ Analysentechnik, Mainz, Germany, 250 3 4.0 mm;
120 ODS-2.5 lm). Samples were dissolved in acetonitrile and
eluted with an acetonitrile/water gradient buffered with
0.1% TFA starting from 10% acetonitrile rising to 100%
over a period of 40 min. UV signals were detected at
254 nm. For recycling HPLC a Japan Analytical Industry Next
System equipped with a preparative MZ Kromasil C18 Col-
umn and a UV detector at 254 nm was used. 10 wt-% solu-
tions of the sample in acetonitrile were prepared and eluted
in acetonitrile/water (75/25). For gel permeation chroma-
tography in chloroform an instrument consisting of a Dura-
tec vacuum degasser, a JASCO PU-2087plus pump and a set
of two MZ-Gel SDplus linear columns (300 3 8 mm, 5 mm
particle size) was used. Signal detection occurred by use of
an Applied Biosystems 759A UV detector (set to 254 nm
Based on the studies by our group on substituted oligo- and
poly(p-benzamide)s from aminosalicylic acid derivatives,19
we developed a concept for the construction of large, tubular
helices combining conventional organic chemistry (sequence
control) and polymer science (higher molecular weights).
We established a synthetic strategy including iterative cou-
pling steps toward a bent tri(benzamide) monomer, which is
subsequently polymerized to a coil-like polymer by polycon-
densation. Acidic cleavage of amide N-protecting groups (PG)
leads to the formation of the final helical structure. Depend-
ing on the size of the precursor, that is, the number of linear
monomers within the oligomer (here two), helices with inner
cavities of varying diameters can in principle be synthesized.
To address the synthetic challenges involved in the formation
of helices, the bent oligomeric precursor carries various fea-
tures. The triethylene glycol monomethyl ether (TEG) side
chains ensure excellent organosolubility at all stages of the
synthesis. The substitution pattern (2,5-substitution for the
para-linked (“linear”) monomer, 2,4-substitution for the
meta-linked (“bent”) monomer) results in three-center
hydrogen bond formation, stabilizing the folded, helical con-
formation. To avoid macrocyclization during polymerization,
one or two amide bonds were chosen to carry a p-methoxy-
benzyl (PMB) N-protecting group, leading to an E-conforma-
tion of the resulting tertiary amide bond and suppression of
the hydrogen bond formation. The folding of the helix could
wavelength) and
a Knauer Smartline 2300 RI-Detektor
(refractive index). Calibration was done using Malvern Poly-
calTM UCS-PS polystyrene standards. UV/Vis spectroscopy
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was performed on a JASCO V-630 UV-VIS spectrophotometer,
circular dichroism spectra were recorded on a JASCO J-715
spectropolarimeter.
70.65 (1), 70.80 (1), 70.88 (1), 71.74 (1), 71.76 (1),
71.82 (1), 108.70 (2), 113.54 (2) 114.38 (2), 115.27 (2),
116.95 (2), 119.47 (1), 128.71 (1), 130.47 (2), 132.91
(1), 134.72 (1), 139.35 (1), 146.77 (1), 147.27 (1),
149.05 (1), 150.55 (1), 158.94 (1), 164.66 (1), 166.24
(1); HR-MS (ESI1): m/z calculated for [C50H74N2O22Na]15
1077.46310, found 1077.46256; RP-HPLC: 19.38 min.
4-((4-Methoxybenzyl)amino)22,5-bis(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)benzoic Acid L-2
4-Amino-2,5-bis(2-(2-(2-methoxyethoxy)-ethoxy)ethoxy)ben-
zoic acid L-1 (0.95 g, 2.0 mmol) and p-anisaldehyde (0.31 g,
2.2 mmol) were dissolved in dry dichloromethane (65 mL)
and glacial acetic acid (0.57 mL, 0.01 mol) was added. After
stirring at room temperature for 30 min, sodium triacetoxy-
borohydride (1.27 g, 6.0 mmol) was added and the mixture
stirred at room temperature overnight. Water was added
and the aqueous phase extracted with dichloromethane four
times. The combined organic layers were dried over magne-
sium sulfate. The solvent was removed under reduced pres-
sure to yield a crude oil. Purification by recycling HPLC
[acetonitrile/water (75/25)] yielded monomer L-2 (0.46 g,
PMB-Protected Trimer 3
Bent monomer B-1 and protected dimer 2 were dried at the
Schlenk line overnight. The protected dimer (420 mg, 0.4
mmol) was dissolved in NMP (3 mL) and thionyl chloride
(0.4 mL, 0.6 mmol) was added dropwise at 0 8C. The ice
bath was removed and the reaction was run for 2 h at room
temperature after which excess thionyl chloride was
removed at the Schlenk line for 1 h. The bent monomer
(157 mg, 0.4 mmol) was dissolved in NMP (3 mL) and added
dropwise to the activated acid chloride. The mixture was
stirred at room temperature overnight. Ethyl acetate was
added, the organic phase washed with water five times,
dried over magnesium sulfate and evaporated under reduced
pressure to yield trimer 3 (560 mg, 0.39 mmol, 98%) as a
1
0.8 mol) as light brown oil in 40% yield. H NMR (300 MHz,
CDCl3): d (ppm) 5 3.34 (s, 3 H), 3.35 (s, 3 H), 3.47–3.56 (m,
4 H) 3.57–3.71 (m, 13 H) 3.77–3.83 (m, 7 H), 4.16 (t,
3J 5 4.40 Hz, 4 H), 4.34 (d, 3J 5 5.46 Hz, 2 H), 5.61 (t,
3J 5 5.36 Hz, 1 H), 6.06 (s, 1 H), 6.84–6.90 (d, 3J 5 8.75 Hz,
3
2 H), 7.22–7.27 (d, J 5 8.75 Hz, 2 H), 7.47 (s, 1 H); 13C NMR
brown
oil.
HR-MS
(ESI1):
m/z
calculated
for
[C73H95N3O26Na]1 5 1452.61016, found 1452.60989; RP-
and APT (75 MHz, CDCl3): d (ppm) 5 46.50 (1), 55.20 (2),
58.93 (2), 68.64 (1), 68.84 (1), 69.22 (1), 69.51 (1),
70.43 (1), 70.46 (1), 70.49 (1), 70.61 (1), 71.73 (1),
71.77 (1), 94.69 (2), 104.18 (1), 114.04 (2), 114.64 (2),
128.26 (2), 129.83 (1), 140.36 (1), 144.53 (1), 154.41
(1), 158.84 (1), 166.25 (1); HR-MS (ESI1): m/z calculated
for [C29H44NO11]1 5 582.29144, found 582.29005; RP-HPLC:
17.87 min.
HPLC: 24.74 min.
PMB-Protected Trimer T-1
Protected trimer 3 (560 mg, 0.39 mmol) was dissolved in
DMF (28 mL) and tin(II) chloride (370 mg, 1.95 mmol) was
added. The mixture was stirred at 60 8C overnight, after
which 5 eq. were added additionally. The reaction was car-
ried out for two more nights. Ethyl acetate and water were
added to the mixture and the aqueous phase was extracted
with ethyl acetate four times. The combined organic layers
were washed with brine, dried over magnesium sulfate and
the solvent removed under reduced pressure. The trimer
was purified by recycling HPLC in acetonitrile/water (85/
15) at 40 8C to obtain pure T-1 (105 mg, 0.075 mmol, 19%)
as an orange oil. 1H NMR (500 MHz, 52 8C, CDCl3): d
(ppm) 5 3.34–3.36 (m, 12 H), 3.49–3.75 (m, 50 H), 3.88–
3.96 (m, 8 H), 4.27–4.45 (m, 2 H), 5.28–5.31 (m, 1 H), 6.63
PMB-Protected Dimer 2
Both monomers were dried at the Schlenk line overnight.
Linear monomer 1 (363 mg, 0.74 mmol) was dissolved in
NMP (2 mL) and thionyl chloride (0.08 mL, 1.1 mmol) was
added dropwise at 0 8C. The ice bath was removed and the
reaction was run for 2 h at room temperature after which
excess thionyl chloride was removed at the Schlenk line for
1 h. PMB-protected linear monomer L-2 (430 mg, 0.74
mmol) was dissolved in NMP (2 mL) and added dropwise to
the activated acid chloride. The mixture was stirred at room
temperature overnight. Ethyl acetate was added, the organic
phase washed with water five times, dried over magnesium
sulfate and evaporated under reduced pressure. The brown
oil was purified via recycling HPLC in acetonitrile/water
(85/15) at 40 8C to yield 2 (290 mg, 0.27 mmol, 37%) as an
orange oil. 1H NMR (300 MHz, CDCl3): d (ppm) 5 3.31 (s,
3 H), 3.32 (s, 3 H), 3.34 (s, 3 H), 3.35 (s, 3 H), 3.45–3.86 (m,
51 H), 3.91–4.08 (m, 6 H), 4.08–4.20 (m, 2 H), 4.44 (d,
2J 5 14.35 Hz, 1 H), 5.38 (d, 2J 5 14.35 Hz, 1 H), 6.77 (d,
3J 5 8.80 Hz, 2 H), 6.84 (s, 1 H), 7.12 (s, 1 H), 7.17–7.19 (d,
3J 5 8.80 Hz, 2 H), 7.19 (s, 1 H), 7.43 (s, 1 H); 13C NMR and
APT (75 MHz, CDCl3): d (ppm) 5 50.41 (1), 55.11 (2),
58.86 (2), 58.90 (2), 68.26 (1), 68.77 (1), 69.16 (1),
69.37 (1), 69.46 (1), 70.05 (1), 70.26 (1), 70.31 (1),
70.39 (1), 70.42 (1), 70.45 (1), 70.52 (1), 70.57 (1),
3
(s, 1 H), 6.70–6.76 (m, 2 H), 6.79 (d, J 5 8.33 Hz, 2 H), 6.88
3
(s, 1 H), 7.05 (d, J 5 7.77 Hz, 2 H), 7.14–7.23 (m, 4 H) 7.38
3
(t, J 5 7.39 Hz, 2 H) 7.50–7.55 (m, 1 H); 13C NMR and DEPT
(125 MHz, 52 8C, CDCl3): d (ppm) 5 51.28 (2), 55.18 (1),
55.56 (1), 58.83 (1), 58.86 (1), 67.95 (2), 68.14 (2),
69.27 (2), 69.66 (2), 69.85 (2), 70.45 (2), 70.49 (2),
70.53 (2), 70.57 (2), 70.66 (2), 70.69 (2), 70.73 (2),
70.95 (2), 72.00 (2), 77.19 (1), 95.68, 101.47, 110.26,
111.10, 113.59 (1), 113.66 (1), 114.77, 119.45, 121.73 (1),
121.89, 123.19, 125.55 (1), 126.59, 129.28 (1), 129.54,
130.42 (1), 132.30, 133.92, 134.16, 140.06, 147.18, 149.78,
150.98, 158.85, 159.09, 159.84, 161.58, 161.85, 162.68,
168.90, 169.15; HR-MS (ESI1): m/z calculated for
[C73H97N3O24Na]1 5 1422.63598, found 1422.63645; RP-
HPLC: 20.39 min.
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Polymerization of Trimer T-1
evaporated under reduced pressure to give trimer 5
Trimer T-1 (105 mg, 0.075 mmol) was dried at the Schlenk
line overnight and transferred into a glove box. To start the
polymerization, 2.2 eq. LiHMDS (0.17 mL, 1M in THF) were
added in one portion under vigorous stirring. After stirring
at room temperature overnight, the mixture was quenched
by addition of saturated aqueous ammonium chloride solu-
tion and extracted with dichloromethane four times. The
combined organic layers were washed with water, dried over
magnesium sulfate and the solvent removed under reduced
pressure to yield the cyclic trimer P-1 (100 mg, 95%).
(790 mg, 0.60 mmol, 86%) as a brown oil. 1H NMR (300
MHz, CDCl3): d (ppm) 5 3.33 (s, 3 H), 3.34 (s, 3 H), 3.36 (s,
3
3 H), 3.37 (s, 3 H), 3.42–4.01 (m, 48 H), 4.29 (t, J 5 4.72 Hz,
2 H), 4.39 (d, 2J 5 14.35 Hz, 1 H), 4.46 (m, 2 H), 5.38 (d,
2J 5 14.16 Hz, 1 H), 6.21 (s, 1 H), 6.81–6.87 (m, 3 H), 7.06
(d, 3J 5 7.37 Hz, 2 H), 7.24 (d, 3J 5 8.50 Hz, 2 H), 7.38 (t,
3J 5 7.56 Hz and 8.05 Hz, 2 H), 7.63 (s, 1 H), 7.72 (s, 1 H),
7.94 (s, 1 H), 8.14 (s, 1 H), 10.44 (s, 1 H); HR-MS (ESI1):
m/z calculated for [C65H88N3O25]1 5 1310.57070, found
1310.57074; RP-HPLC: 23.09 min.
MALDI-ToF
(DCTB,
NaTFA):
m/z
calculated
for
[C67H91N3O23Na]1 5 1328.5941, found 1328.5903; GPC
(CHCl3): Mn 840 g/mol, Mw 860 g/mol, ÐM 1.02.
PMB-Protected Trimer T-2
Protected trimer 5 (400 mg, 0.3 mmol) was dissolved in
DMF (20 mL) and tin(II) chloride dihydrate (690 mg, 3.0
mmol) was added. The mixture was stirred at 40 8C for
72 h. Ethyl acetate was added and the mixture extracted
between ethyl acetate and water four times. The combined
organic layers were washed with saturated aqueous sodium
hydrogencarbonate and brine, dried over magnesium sulfate
and the solvent removed under reduced pressure. The prod-
uct was purified by recycling HPLC in acetonitrile/water
(85/15) at 35 8C to give the pure trimer T-2 (86 mg, 0.067
mmol) as a yellow oil in 22% yield. 1H NMR (300 MHz,
CDCl3): d (ppm) 5 3.33 (s, 6 H), 3.35 (s, 3 H), 3.37 (s, 3 H),
3.45–3.72 (m, 45 H), 3.75 (s, 4 H), 3.77–3.89 (m, 10 H),
Linear Dimer 4
Both monomers were dried at the Schlenk line overnight.
Linear monomer 1 (468 mg, 0.95 mmol) was dissolved in
NMP (1 mL) and thionyl chloride (0.1 mL, 1.43 mmol) was
added dropwise at 0 8C. The ice bath was removed and the
reaction was run for 2 h at room temperature, after which
excess thionyl chloride was removed at the Schlenk line for
1 h. L-1 (440 mg, 0.95 mmol) was dissolved in NMP
(1.5 mL) and added dropwise to the activated acid chloride.
The mixture was stirred at room temperature overnight.
Ethyl acetate was added, the organic phase was washed with
water five times, dried over magnesium sulfate and evapo-
rated under reduced pressure to give dimer 4 (700 mg, 0.75
mmol) as a brown oil in 79% yield. 1H NMR (300 MHz,
CDCl3): d (ppm) 5 3.32 (s, 3 H), 3.34 (s, 3H), 3.37 (s, 7 H),
3.43–3.78 (m, 41 H), 3.83–3.87 (m, 3 H), 3.90 (m, 7 H), 4.31
(m, 5 H), 4.42 (m, 3 H), 4.54 (m, 3 H), 7.70 (s, 1 H), 7.77 (s,
1 H), 7.98 (s, 1 H), 8.56 (s, 1 H), 10.80 (s, 1 H); 13C NMR
and APT (75 MHz, CDCl3): d (ppm) 5 58.92 (2), 58.94 (2),
58.96 (2), 68.59 (1), 69.05 (1), 69.23 (1), 69.59 (1),
69.70 (1), 70.17 (1), 70.50 (1), 70.55 (1), 70.62 (1),
70.69 (1), 70.80 (1), 71.04 (1), 71.10 (1), 71.78 (1),
71.83 (1), 71.88 (1), 106.14 (2), 112.51 (2), 112.78 (1),
115.17 (2), 118.48 (2), 126.72, 134.06 (1), 141.75, 142.48
(1), 146.46 (1), 150.34 (1), 152.49 (1), 161.79 (1),
165.32 (1); HR-MS (ESI1): m/z calculated for
[C42H66N2O21Na]1 5 957.40558, found 957.40493; RP-HPLC:
18.83 min.
3
4.04–4.10 (m, 3 H), 4.13–4.16 (m, 3 H), 4.30 (t, J 5 5.10 Hz,
2 H), 4.39 (d, 2J 5 14.15 Hz, 1 H), 4.51 (br. s., 2 H), 5.36 (d,
2J 5 14.15 Hz, 1 H), 6.19 (s, 1 H), 6.41 (s, 1 H), 6.79 (s, 1 H),
4
3
4
6.82 (d, J 5 2.18 Hz, 2 H), 7.05 (d, J 5 7.39 Hz, J 5 1.26 Hz,
2
2 H), 7.20 (s, 1 H), 7.23 (d, J 5 8.65 Hz, 2 H), 7.34–7.39 (m,
2 H), 7.59 (s, 1 H), 7.62 (s, 1 H), 8.18 (s, 1 H), 10.33 (s,
1 H); 13C NMR and DEPT (75 MHz, CDCl3): d (ppm) 5 51.05
(1), 55.08 (2), 55.47 (2), 55.95 (2), 58.81 (2), 58.87 (2),
67.70 (1), 67.87 (1), 69.08 (1), 69.19 (1), 69.29 (1),
69.32 (1), 69.57 (1), 69.83 (1), 70.39 (1), 70.50 (1),
70.56 (1), 70.65 (1), 71.75 (1), 71.77 (1), 71.83 (1),
71.86 (1), 77.20, 95.28 (2), 100.47 (2), 104.30 (2),
109.53, 111.17, 112.37, 113.45 (2), 115.86 (2), 120.30,
121.77 (2), 122.77, 125.44 (2), 129.19 (2), 129.55, 130.42
(2), 131.31 (2), 134.09, 140.31, 140.49, 142.73, 148.91,
150.76, 153.15, 158.82, 159.79, 161.44, 162.61, 163.63,
169.48;
HR-MS
(ESI1):
m/z
calculated
for
[C65H89N3O23Na]1 5 1302.57846, found 1302.57777; RP-
PMB-Protected Trimer 5
HPLC: 21.27 min.
Both monomers were dried at the Schlenk line overnight.
Linear dimer 4 (650 mg, 0.70 mmol) was dissolved in NMP
(2 mL) and thionyl chloride (0.08 mL, 1.04 mmol) was
added dropwise at 0 8C. The ice bath was removed and the
reaction was run for 2 h at room temperature after which
excess thionyl chloride was removed at the Schlenk line for
1 h. Bent phenyl ester B-1 (275 mg, 0.70 mmol) was dis-
solved in NMP (1.5 mL) and added dropwise to the activated
acid chloride. The mixture was stirred at room temperature
overnight. Ethyl acetate was added, the organic phase
washed with water five times and twice with saturated aque-
ous sodium hydrogencarbonate solution. The combined
organic layers were dried over magnesium sulfate and
Polymerization of Trimer T-2
Trimer T-2 (86 mg, 0.067 mmol) was dried at the Schlenk
line overnight and cooled to 210 8C by using a cryostat. To
start the polymerization, 3.2 eq. LiHMDS (0.21 mL, 1 M in
THF) were added in one portion. Due to the high viscosity,
stirring was not possible, and the solution was warmed up
to room temperature after 10 min upon which the solution
formed a gel. After stirring at room temperature for 1 h, the
mixture was quenched by addition of saturated aqueous
ammonium chloride solution and extracted with dichlorome-
thane four times. The combined organic layers were washed
with water, dried over magnesium sulfate and the solvent
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SCHEME 1 Iterative coupling strategy toward the di-PMB-protected trimer T-1. PMB, p-methoxybenzyl; TEG, triethylene glycol.
removed under reduced pressure to yield a mixture of macro-
cycles and polymers (80 mg). The higher molecular weight frac-
tion was separated by preparative GPC in chloroform to yield
Schlenk line and the solid washed with dichloromethane three
times to yield the deprotected polymer H-1 as brown solid in
quantitative yield (35 mg). MALDI-ToF (DCTB): m/z calculated
for [C204H302N12O85Li]1 5 4285.982, found 4285.622; GPC
(THF): Mn 5500 g/mol, Mw 6300 g/mol, ÐM 1.1.
1
the protected polymer P-2 (40 mg, 47%). H NMR (300 MHz,
CDCl3): d (ppm) 5 3.24–3.39 (m, 13 H), 3.40–4.03 (m, 49 H),
4.10 (br. s, 3 H), 4.24 (br. s, 2 H), 4.45 (br. s, 2 H), 4.92 (br. s,
1 H), 6.17 (br. s, 1 H), 6.80 (d, 3J 5 6.05 Hz, 2 H), 6.89 (m, 1 H),
7.24 (d, 3J 5 6.79 Hz, 2 H), 7.67 (br. s, 1 H), 8.10 (d, 3J 5 9.17 Hz,
2 H), 8.53 (br. s, 1 H), 10.53 (m, 2 H); MALDI-ToF (DCTB): m/z
calculated for [C413H583N21O155Li]1 5 8323.854, found
8323.305[C472H666N24O177Li]1 5 9509.401, found 9509.791;
GPC (CHCl3): Mn 6900 g/mol, Mw 11,100 g/mol, ÐM 1.6.
RESULTS AND DISCUSSION
The syntheses of the oligomers presented here were based
on two different monomers: the linear monomer (L), which
originated from p-aminobenzoic acid, and the bent monomer
(B), which derived from m-aminobenzoic acid. The synthetic
route toward the linear monomer L-1 (Scheme 1) has been
described previously.21 The preparation of methyl-2,4-
dimethoxy-5-nitrobenzoate, a key intermediate in the synthe-
sis of the bent monomer, has been reported elsewhere.14
The following steps toward the final structure of B-1
(Scheme 1) can be found in the Supporting Information.
Deprotected Polymer H-1
Polymer P-2 (40 mg) was dissolved in a 1:1-mixture of
dichloromethane and trifluoroacetic acid (3 mL). The solu-
tion was stirred at room temperature for three days. Tri-
fluoroacetic acid and dichloromethane were removed at the
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and high-resolution ESI-mass spectrometry, which can be
found in the Supporting Information.
The polycondensation of trimer T-1 followed the protocol we
reported previously.21 In a first attempt, we polymerized T-1
in dry THF by addition of 2.2 eq. LiHMDS (1M in THF) with
a final monomer concentration of 0.25 mol/L (Scheme 2).
The polycondensation was carried out at room temperature
overnight and the obtained product subsequently characterized
by GPC (chloroform). The comparison with the elugram of the
starting material (Fig. 1, top, red) revealed a higher molecular
weight shoulder after polymerization (Fig. 1, top, blue). The
major fraction, however, did not show an increase in molecular
weight. MALDI-ToF mass spectroscopic analysis revealed the
formation of a cyclic trimer (Fig. 1, bottom and Scheme 2).
SCHEME 2 Polycondensation of the di-PMB-protected trimer T-
1 resulted in the unexpected formation of the cyclic trimer P-1.
The inner triethylene glycol ether side chains are omitted for
clarity. PMB, p-methoxybenzyl; TEG, triethylene glycol.
We previously investigated the Yokozawa-like polycondensa-
tion22 of phenyl ester derivatives of L-1. In doing so, we
could already draw important conclusions with regard to the
polycondensation of bis-substituted tri(benzamide)s and
their required constitution: the polymerization of monomers
carrying a primary amine resulted in the in situ formation of
a polyanion, which showed only modest solubility in THF.
The introduction of an N-amide protecting group to increase
the organosolubility during polymerization however led to a
sterical hindrance of the reactive center and a deactivation
of the monomer. A polycondensation reaction could not take
place.
All our efforts to polymerize trimer T-1 gave only the cyclic
trimer as the majority compound (see detailed discussion in
Based on these two facts, we designed the di-PMB-protected
oligomer T-1 (Scheme 1), comprised of two N-protected
amides to avoid polyanion formation upon exposure to
strong base during polymerization. Moreover, T-1 carried a
primary amino group at the N-terminus to prevent sterical
hindrance.
Synthesis and Polymerization of the di-PMB-Protected
Trimer T-1
In the synthesis of the di-PMB-protected trimer T-1 (Scheme
1) we started from one bent monomer B-1, one linear mono-
mer 1 (nitro form of L-1) and one linear monomer L-2. The
iterative coupling strategy is presented in Scheme 1.
The linear monomer L-1 could be converted to L-2 with p-
anisaldehyde in a direct reductive amination by the use of
sodium triacetoxy borohydride and glacial acetic acid. Purifi-
cation via recycling HPLC gave the pure monomer L-2 in
40% yield. The subsequent reaction between monomers 1
and L-2 followed the standard coupling protocol, which our
group has optimized for the synthesis of oligo(p-benza-
mide)s.23 The reaction showed a high conversion, the purifi-
cation of the PMB-protected dimer 2 by recycling HPLC
however limited the yield to 37%. Dimer 2 could then be
coupled with the bent monomer B-1 to the trimer 3 in 98%
yield. The reduction of the nitro group succeeded using
tin(II)chloride in DMF and stirring the reaction mixture at
60 8C for three days. The final compound was purified by
recycling HPLC to yield the pure di-PMB-protected trimer T-
1 in 19% yield. The formation of all compounds was vali-
dated by 1H and 13C NMR spectroscopy, analytical RP-HPLC
FIGURE 1 Top: GPC elugram in CHCl3 of the trimer T-1 (red)
and the raw product mixture after polycondensation (blue).
Bottom: MALDI-ToF spectrum of the cyclic trimer P-1 (Na1-
adduct). Inset: Comparison of the isotope pattern of the cyclic
trimer (green) with the calculated one (stars). [Color figure can
be viewed in the online issue, which is available at wileyonline-
library.com.]
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SCHEME 4 Polycondensation of the mono-PMB-protected
trimer T-2, resulting in the formation of macrocycles and poly-
mer P-2. PMB, p-methoxybenzyl; TEG, triethylene glycol.
the enhancement of the molecular weight, based on the
choice of the trimer. The low molecular weight part of the
GPC elugram of P-2 clearly resolves the formed cyclic
oligomers (Fig. 2 red, 19.5–22 min.).
In an attempt to prevent the formation of cycles, a second
polymerization of trimer T-2 was carried out at 210 8C.
Unfortunately, efficient stirring of the solution was not possi-
ble due to the very high viscosity of T-2. After 10 min, we
therefore warmed the mixture to room temperature and
received a similar result as for the first polymerization. The
GPC (chloroform) analysis indicated the formation of both
low molecular weight cycles and polymers, the polymer frac-
tion however increased compared to the result of the first
polymerization (Fig. S29 in the Supporting Information).
SCHEME 3 Iterative coupling strategy to the mono-PMB-
protected trimer T-2. PMB, p-methoxybenzyl; TEG, triethylene
glycol.
the Supporting Information). To avoid cycle formation we
synthesized mono-PMB-protected trimer, T-2 (Scheme 3) in
order to create a longer distance between the reactive cen-
ters rendering a macrocyclization geometrically unfavorable.
The results of the polycondensation of the mono-PMB-
protected oligomer T-2 are presented in the next section.
The formation of cycles was confirmed by MALDI-ToF MS
analysis (Figs. S30 and S31 in the Supporting Information).
Contrary to the polymerization of the di-PMB-protected
trimer T-1, in which only cyclic trimers were formed, several
larger cycles, namely the cyclic hexamer, nonamer, and
dodecamer could also be observed.
Synthesis and Polymerization of the Mono-PMB-
Protected Trimer T-2
The synthetic route toward the mono-N-protected trimer T-2
(Scheme 3) followed the same iterative coupling strategy as
T-1 (Scheme 1), using two unprotected, linear monomers
and one bent monomer. The reaction between 1 and L-1
yielded the unprotected, linear dimer 4 (79%), which could
be coupled with B-1 to the trimer 5 (86%). 5 was reduced
by the use of tin(II)chloride dihydrate in DMF at 40 8C for
three days. Purification via recycling HPLC gave the mono-
PMB-protected trimer T-2 in 22% yield. The final product
was thoroughly investigated by 1D and 2D NMR spectros-
copy and the results can be found in the Supporting
Information.
The polycondensation of trimer T-2 was carried out at a
very high monomer concentration: 3.2 eq. of LiHMDS (1M in
THF) were added to T-2 in one portion under vigorous stir-
ring (Scheme 4).
After 18 h of reaction time at r.t., the reaction mixture was
analyzed by GPC (chloroform) which revealed the formation
of low molecular weight cycles and a higher molecular
weight fraction (Fig. 2, red). The comparison with the GPC-
elugram of the cyclic trimer P-1 (Fig. 2, black) emphasizes
FIGURE 2 Mass distribution of the polymer P-2 determined by
GPC (chloroform) before (red) and after (blue) recycling GPC in
comparison with the mass distribution of the cyclic trimer P-1
(black). [Color figure can be viewed in the online issue, which
is available at wileyonlinelibrary.com.]
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condensation, might exist in an E/Z-equilibrium (Scheme S2
in the Supporting Information) facilitating the macrocycliza-
tion. This phenomenon is currently investigated in our
group.
To isolate the higher molecular weight fraction correspond-
ing to the polymer P-2, preparative GPC in chloroform was
carried out. Analysis of the separated polymer fraction (Fig.
2, blue) via analytical GPC (chloroform), gave a molecular
weight of Mn 5 7000 g/mol and Mw 5 11,100 g/mol. The
MALDI-ToF mass spectrum of the higher molecular weight
fraction is shown in Figure 3 (top) and verifies the formation
of P-2 by displaying the exact repeat unit of the trimer T-2
of 1185.50 g/mol (see also Fig. S32 in the Supporting
Information).
The major peaks could be assigned to the Li-salt of the poly-
mer carrying a carboxylic acid and an amine as end groups.
The polymer with the isotopic (all 12C) mass of 8327.34 g/
mol consists of exactly seven repeat units, the one with the
isotopic (all 12C) mass of 9512.84 g/mol exactly of eight
repeat units. The longest polymer chain detected by MALDI-
ToF MS analysis therefore consists of 24 aromatic amino
acids. Further NMR-characterization of the polymer P-2 is
reported in the Supporting Information.
Deprotection of the Polymer
The cleavage of the protecting groups of polymer P-2 was
achieved by treatment with trifluoroacetic acid in dichloro-
methane [1:1 (vol:vol) mixture] for three days at room tem-
perature (Scheme 5).
After deprotection, the polymer H-1 showed a drastically
modified solubility in organic solvents compared to polymer
P-2. It was insoluble and swelled in chlorinated solvents
such as chloroform and dichloromethane, but it was soluble
in THF, DMSO, acetone, and (2R,3R)-butane-2,3-diol. There-
fore, a direct comparison of the GPC elugrams in chloroform
was not possible. The GPC (THF) elugram of polymer H-1
shows a significant shift toward higher molecular weights
(Fig. 5) compared to the elugram of polymer P-2. This shift
could be an indication for the proposed structural change
from coil-like to helical, which the polymer is expected to
undergo upon amide N-deprotection. The coil-like structure
of polymer P-2 is expected to convert into a helix through
the formation of the intramolecular hydrogen bonding pat-
tern along the backbone of polymer H-1. The proposed
FIGURE 3 Top: MALDI-ToF mass spectrum (section) of the
higher molecular weight polymers built in polymerization P-2
(Li1-adducts) The 7-mer and 8-mer of the trimeric monomer
are shown. Bottom: MALDI-ToF mass spectrum (section) of the
deprotected, helical polymer H-1 (Li1-adducts). The 4-mer and
5-mer of the trimeric monomer are shown. [Color figure can be
viewed in the online issue, which is available at wileyonlineli-
brary.com.]
Two cis-amide conformations (with respect to the phenyl
rings) are essential for the ring closure of a tribenzamide to
occur. We therefore hypothesize that the amide anion, which
is formed by deprotonation with LiHMDS during the poly-
SCHEME 5 Cleavage of the amide N-PMB-protecting groups by treatment with trifluoroacetic acid. PMB, p-methoxybenzyl; TEG,
triethylene glycol.
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FIGURE 6 Normalized UV absorption (blue) and circular
dichroism spectra (black) of polymer H-1 dissolved in (2R,3R)-
Butane-2,3-diol (1.9 mg/mL, solid lines) and acetone (0.75 mg/
mL, dotted lines). [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
FIGURE 4 GPC (THF) elugrams of polymer P-2 (red) before and
polymer H-1 (blue) after amide N-deprotection. [Color figure
can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
(rigid) helical polymer even of low molecular weight would
exhibit a large excluded inner volume and could thereby
elute at an earlier retention time in the GPC run.
ized), as can be seen in Figure 6. While the acetone solution
did not give any significant CD signal, the (2R,3R)-butane-
2,3-diol solution showed a clear, albeit small circular dichro-
ism signal. We believe that the chiral solvent interacts with
the polymer H-1 thereby slightly favoring the formation of
either a plus or minus helix. We believe that this slight enan-
tiomeric excess gives rise to the observed CD-spectrum in
Figure 6.
In order to obtain further data points that could support the
helix hypothesis, we dissolved the polymer H-1 in acetone
(1.7 mg in 1.8
g solvent) and (2R,3R)-butane-2,3-diol
(2.4 mg in 1.22 g solvent). The solutions were sonicated for
5 min, filtrated through syringe filters (pore size 0.45 lm)
and the clear solutions investigated by circular dichroism
(CD) and ultraviolet (UV) absorption spectroscopy (normal-
Both, the shift in the gpc elugram (Fig. 5) as well as the CD
signal in a chiral solvent (Fig. 5) support the hypothesis of a
helical shape of H-1 but do not provide unambiguous evi-
dence. We are currently investigating the improvement in
polymerization conditions to obtain larger sample amounts
in the future for more detailed and thorough analytical
investigations.
Furthermore, MALDI-ToF MS analysis verified the successful
cleavage of the amide N-PMB-protecting groups by display-
ing a repeat unit of 1065.99 g/mol, which corresponds to
the N-deprotected trimer (Fig. 3, bottom). The polymer was
predominantly detected as the Li-ion-adduct.
Figure 5 shows one helical turn of a hypothetical helical
polymer H-1, for which we calculated an inner diameter of
around 4 nm (based on a molecular mechanics model), in
accordance with data on helical structures or macrocycles
built from meta-para-linked oligoamides known from the
literature.3(g),17
CONCLUSIONS
A new synthetic strategy toward segmented polyaramides
that might adopt a helical shape has been described. We
have developed a synthetic route, in which we combined the
sequence-controlled synthesis of bent, shape-persistent tri-
benzamides with their polycondensation. This combination
FIGURE 5 Model structure of one helical turn of a hypothetical
helical polymer H-1 with a calculated inner diameter of around
4 nm. In this representation six repeat units are necessary to
create one full turn, the presence of eight repeat units was con-
firmed by MALDI ToF MS (Fig. 3, top). TEG, triethylene glycol.
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has the advantage of being able to reach higher molecular
weights than organic synthesis alone. Furthermore, it would
in principle be possible to determine the inner diameter of
such an assumed helix by the number of linear monomers
incorporated into the oligomeric precursor. In this publica-
tion we report the synthesis and characterization of two bis-
substituted tribenzamides consisting of one bent and two
linear monomers. Triethylene glycol side chains and N-amide
protecting groups were attached to the oligoaramides to
enhance their organo solubility. Moreover, the protecting
groups could selectively be cleaved by addition of acid after
polymerization of the trimers. The two trimers, namely the
mono- and di-PMB-protected bis-substituted tri(benz-amide)s
showed significantly different results in their polycondensa-
tion reactions. The fully protected trimer predominantly
formed cyclic trimers upon addition of LiHMDS. The preorga-
nizational effect of the rigid aromatic backbone caused by
the preference for the E-conformation of the tertiary, pro-
tected amide bonds facilitated the macrocyclization reaction.
As expected, the polycondensation of the more rigid, mono-
protected trimer generated polymers in addition to cycles.
Separation of the coil-like polymers by means of preparative
GPC and subsequent cleavage of the PMB-protecting groups
by treatment with trifluoroacetic acid yielded a polymer for
which we hypothesize a helical geometry. The molecular
composition of the final compound was validated by MALDI-
ToF analysis. A dramatic change in hydrodynamic radius
could be observed by gpc analysis upon PMB-deprotection of
the obtained polymer. Circular dichroism spectroscopy of the
PMB-deprotected polymer in a chiral solvent showed a small
but significant CD-signal indicating the formation of an enan-
tiomeric excess of a chiral superstructure in a chiral solvent.
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