Thioamides: Versatile bonds to induce directional and cooperative hydrogen bonding in supramolecular polymers

Article abstract of DOI:10.1002/chem.201204273

The amide bond is a versatile functional group and its directional hydrogen-bonding capabilities are widely applied in, for example, supramolecular chemistry. The potential of the thioamide bond, in contrast, is virtually unexplored as a structuring moiety in hydrogen-bonding-based self-assembling systems. We report herein the synthesis and characterisation of a new self-assembling motif comprising thioamides to induce directional hydrogen bonding. N,N′,N′′-Trialkylbenzene-1,3,5-tris(carbothioamide)s (thioBTAs) with either achiral or chiral side-chains have been readily obtained by treating their amide-based precursors with P₂S₅. The thioBTAs showed thermotropic liquid crystalline behaviour and a columnar mesophase was assigned. IR spectroscopy revealed that strong, three-fold, intermolecular hydrogen-bonding interactions stabilise the columnar structures. In apolar alkane solutions, thioBTAs self-assemble into one-dimensional, helical supramolecular polymers stabilised by three-fold hydrogen bonding. Concentration- and temperature-dependent self-assembly studies performed by using a combination of UV and CD spectroscopy demonstrated a cooperative supramolecular polymerisation mechanism and a strong amplification of supramolecular chirality. The high dipole moment of the thioamide bond in combination with the anisotropic shape of the resulting cylindrical aggregate gives rise to sufficiently strong depolarised light scattering to enable depolarised dynamic light scattering (DDLS) experiments in dilute alkane solution. The rotational and translational diffusion coefficients, D _trans and D_rot, were obtained from the DDLS measurements, and the average length, L, and diameter, d, of the thioBTA aggregates were derived (L=490 nm and d=3.6 nm). These measured values are in good agreement with the value L_w=755 nm obtained from fitting the temperature-dependent CD data by using a recently developed equilibrium model. This experimental verification validates our common practice for determining the length of BTA-based supramolecular polymers from model fits to experimental CD data. The ability of thioamides to induce cooperative supramolecular polymerisation makes them effective and broadly applicable in supramolecular chemistry. Thioamide bonds: The polymerisation of a thioamide-based supramolecular motif is elucidated by combining depolarised dynamic light scattering and temperature-dependent spectroscopic measurements (see figure). A cooperative polymerisation mechanism and strong amplification of chirality makes this a highly versatile structuring motif. Copyright

Full text of DOI:10.1002/chem.201204273

FULL PAPER
DOI: 10.1002/chem.201204273
Thioamides: Versatile Bonds To Induce Directional and Cooperative
Hydrogen Bonding in Supramolecular Polymers
Tristan Mes, Seda Cantekin, Dirk W. R. Balkenende, Martijn M. M. Frissen,
Martijn A. J. Gillissen, Bas F. M. De Waal, Ilja K. Voets, E. W. Meijer,* and
Anja R. A. Palmans*[a]
Abstract: The amide bond is a versatile
functional group and its directional hy-
drogen-bonding capabilities are widely
applied in, for example, supramolecular
chemistry. The potential of the thioa-
mide bond, in contrast, is virtually un-
explored as a structuring moiety in hy-
drogen-bonding-based self-assembling
systems. We report herein the synthesis
and characterisation of a new self-as-
sembling motif comprising thioamides
to induce directional hydrogen bond-
ing. N,N’,N’’-Trialkylbenzene-1,3,5-tris-
(carbothioamide)s (thioBTAs) with
either achiral or chiral side-chains have
been readily obtained by treating their
amide-based precursors with P2S5. The
thioBTAs showed thermotropic liquid
crystalline behaviour and a columnar
mesophase was assigned. IR spectro-
scopy revealed that strong, three-fold,
intermolecular hydrogen-bonding inter-
actions stabilise the columnar struc-
tures. In apolar alkane solutions, thio-
BTAs self-assemble into one-dimen-
sional, helical supramolecular polymers
stabilised by three-fold hydrogen bond-
ing. Concentration- and temperature-
dependent self-assembly studies per-
formed by using a combination of UV
and CD spectroscopy demonstrated a
cooperative supramolecular polymeri-
sation mechanism and a strong amplifi-
cation of supramolecular chirality. The
high dipole moment of the thioamide
bond in combination with the aniso-
tropic shape of the resulting cylindrical
aggregate gives rise to sufficiently
strong depolarised light scattering to
enable depolarised dynamic light scat-
tering (DDLS) experiments in dilute
alkane solution. The rotational and
translational diffusion coefficients,
Dtrans and Drot, were obtained from the
DDLS measurements, and the average
length, L, and diameter, d, of the thio-
BTA aggregates were derived (L=
490 nm and d=3.6 nm). These meas-
ured values are in good agreement
with the value Lw =755 nm obtained
from fitting the temperature-dependent
CD data by using a recently developed
equilibrium model. This experimental
verification validates our common
practice for determining the length of
BTA-based supramolecular polymers
from model fits to experimental CD
data. The ability of thioamides to
induce cooperative supramolecular pol-
ymerisation makes them effective and
broadly applicable in supramolecular
chemistry.
Keywords: dynamic light scatter-
ing · polymers · self-assembly ·
supramolecular
thioamides
chemistry
·
Introduction
good proteolytic stability, strong hydrogen-bond-donating
capacity and easy synthetic accessibility.[3] The introduction
of thioamide bonds into peptides at specific positions allows
tuning of the stability of a-helical structures and investiga-
tion of the folding dynamics of b-sheet formation.[4] Also,
the thioamide group is an effective fluorescence quencher
and useful for investigating conformational changes in oligo-
peptides and proteins.[5] The thioamide group normally re-
sides in a trans conformation; however, under UV light, the
trans conformer readily isomerises to the cis conformer.[6]
This characteristic has been successfully applied to generate
a photoswitchable element within a peptide backbone and
allows the on/off switching of catalytic activity in enzymes.[7]
Apart from the potential of the thioamide in elucidating
protein dynamics and folding, the replacement of proteolyti-
cally sensitive amides by thioamides has been a successful
strategy in the design of new inhibitors; closthioamide was
recently described as a very potent antibiotic for several re-
sistant bacteria strains.[8] Despite all these attractive proper-
ties, the thioamide bond has received remarkably little at-
The importance of amide groups for directional hydrogen-
bonding interactions is well recognised in proteins, polya-
mides and in supramolecular chemistry.[1,2] In contrast, the
thioamide group is much less explored, although it possesses
many beneficial properties such as a high dipole moment,
[a] Dr. T. Mes, Dr. S. Cantekin, D. W. R. Balkenende, M. M. M. Frissen,
M. A. J. Gillissen, B. F. M. De Waal, Dr. I. K. Voets,
Prof. Dr. E. W. Meijer, Dr. A. R. A. Palmans
Institute for Complex Molecular Systems
Laboratory of Macromolecular and Organic Chemistry
Eindhoven University of Technology
PO Box 513, 5600 MB Eindhoven (The Netherlands)
Fax : (+31)402-451-036
E-mail: E.W.Meijer@tue.nl
A.Palmans@tue.nl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204273.
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tention in the field of supramolecular chemistry. Although
thioamide-containing macrocycles and polymers are effec-
tive metal chelators[9] and anion binders,[10] the ability of the
thioamide bond as a structuring moiety in hydrogen-bond-
ing-based self-assembling systems is virtually unexplored.
In recent years, we and others have explored in detail the
properties of N,N’,N’’-trialkylbenzene-1,3,5-tricarboxamides
(BTAs), discotic molecules consisting of a central benzene
and three alkyl chains coupled to the core through amide
bonds.[11] These simple compounds show considerable appli-
cation potential as thermotropic liquid crystals,[12] organo-
gels,[13] nucleating agents for isotactic polypropylene[14] and
multivalent scaffolds for biomedical applications.[15] In addi-
tion, the effect of subtle changes in the molecular structures
of BTAs on their self-assembling properties has been stud-
ied by our group. For example, the effect of variations in
amide connectivity[16] and the number of stereogenic cen-
tres,[17] and the introduction of isotope chirality[18] and hy-
drophilic[19] or fluorophilic[20] side-chains into the BTA struc-
tures have been analysed. In all cases, the self-assembly is
highly cooperative and governed by the formation of three
hydrogen bonds between consecutive discs.[21]
In general, hydrogen bonds between thioamides are re-
ported to be weaker than in secondary amides.[22] In addi-
tion, thioamides show UV/CD absorption at higher wave-
lengths than amides.[23] This latter feature facilitates the
probing of their self-assembly in systems with additional
chromophores. Herein, we show that the replacement of the
amide bond by a thioamide in BTAs results in a supramo-
lecular motif with self-assembling properties similar to those
of amide-based BTAs. The supramolecular polymers formed
show a comparable stability to their amide counterparts and
a strong amplification of the supramolecular chirality. Re-
markably, the high dipole moment of thioamides in combi-
nation with the highly anisotropic shape of the formed ag-
gregates allows an in-depth depolarised dynamic light scat-
tering analysis from which the length of the supramolecular
polymers can be derived. Although theoretical models that
describe cooperative self-assembly allow prediction of the
average number of monomer units per polymer chain,[24] the
experimental validation of these predictions for BTA-based
supramolecular polymers proved to be a challenging task.
The depolarised dynamic light scattering experiments have
enabled us, for the first time, to relate the theoretically pre-
dicted lengths of thioBTA-based supramolecular polymers
to measured quantities.
Scheme 1. Synthesis of the thioBTAs 2a–c from the corresponding BTAs
1a–c.
either an achiral n-dodecyl (2a), a chiral (S)-3,7-dimethyloc-
tyl ((S)-2b) or an (R)-3,7-dimethyloctyl side-chain ((R)-2c).
All compounds were purified by column chromatography
and isolated in reasonable yields (48, 66 and 25%, respec-
tively). IR spectroscopy showed the complete disappearance
of the C=O stretch at 1640 cmꢀ1, indicative of the full con-
version of the amides 1 into thioamides 2 (see Figure S1 in
1
the Supporting Information). H and 13C NMR analysis in
combination with MALDI-TOF MS further confirmed the
proposed structures and high purity of compounds 2a–c.
Behaviour of thioBTAs 2a–c in the solid state: With the
help of polarised optical microscopy (POM) and differential
scanning calorimetry (DSC), the thermal behaviour of thio-
BTAs 2a,b was investigated. Under crossed polarisers, com-
pound 2a is mobile and birefringent at room temperature
indicating the presence of a mesophase. In contrast, com-
pound 2b is an amorphous solid at room temperature with
birefringent textures starting to appear above 1008C. The
clearing temperatures into the isotropic liquid are around
263 and 2888C for 2a and 2b, respectively.[26] The phase-
transition temperatures and corresponding enthalpies were
then accurately determined by DSC. The results are dis-
cussed for the second heating (heating/cooling rates of
10 Kminꢀ1, see Figure S2 in the Supporting Information for
full traces). Compound 2a shows two thermal transitions at
ꢀ4.5 (DH=3.30 kJmolꢀ1) and 2548C (DH=6.05 kJmolꢀ1)
whereas compound 2b shows two transitions at 95 (DH=
3.65 kJmolꢀ1) and 2608C (DH=11.30 kJmolꢀ1). The first
transition is attributed to the transition into the mesophase
and the second one to the clearing temperature. Interesting-
ly, the clearing temperatures are about 30 K higher than
those reported for the corresponding amide derivatives (see
Table S1), which indicates a more stable mesophase for thio-
BTAs.[12a,c,27]
Results and Discussion
Synthesis and characterisation: A number of synthetic meth-
ods are available for converting amides into thioamides.[25]
We selected P2S5 because of its ease of reaction and accessi-
bility.[25d] After optimisation of the reaction conditions, thio-
BTAs 2a–c were prepared by treating their amide counter-
parts 1a–c with an excess of P2S5 at reflux in toluene
(Scheme 1). Three derivatives were prepared, comprising
The textures grown by the slow cooling of compounds
2a,b are typical of the presence of a columnar mesophase
(see Figure S3 in the Supporting Information for representa-
tive examples). The nature of the mesophase was deter-
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Thioamides in Supramolecular Polymers
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mined on the basis of the X-ray diffraction (XRD) measure-
ments performed on compound 2a. The diffraction pattern
of compound 2a at 1008C is presented in Figure S4 and the
data are summarised in Table S2 in the Supporting Informa-
tion. In the small-angle area, three reflections at 1.82, 1.05
yet offers good solubility for the thioBTAs. The IR spectra
of compound 2b in MCH (c=2 mm, T=208C) shows identi-
cal NH and CN stretches to the solid-state sample (see Fig-
ure S4 in the Supporting Information). These similar values
indicate that the columnar structures stabilised by hydrogen
bonds in the solid state are retained in MCH solution.
The UV spectra of the thioBTAs in MCH are significantly
redshifted compared with those of the amide-based BTAs.[30]
The UV spectrum of 2c (Figure 2A), for example, shows a
and 0.92 nm are found. The spacings show a reciprocal ratio
p
of 1: 3:2, which is consistent with hexagonal packing of the
columnar structures. In addition, two reflections are found
in the wide-angle area, a diffuse reflection at 0.45 nm and a
sharper reflection at 0.35 nm. The first corresponds to the
disordered aliphatic side-chains and the second is represen-
tative of the interdisc distance. The sharpness of the reflec-
tion at 0.35 nm indicates an ordered packing of the discs
within the columnar structures. The intercolumnar distance
is approximately 2.10 nm. The mesophase of compound 2a
could thus be assigned as Colho.
IR spectroscopy is a sensitive tool for assessing the pres-
ence of hydrogen-bonding interactions in the solid state.
Previous research from our group unambiguously showed
that three-fold intermolecular hydrogen bonding is present
in the mesophase and in the crystalline state of the amide-
BTAs, characterised by peaks at around 3240 (NH stretch),
1640 (amide I) and 1564 cmꢀ1 (amide II).[11,12c] The IR spec-
trum of compound 2a in the mesophase (Figure 1) shows an
Figure 2. a) Overlay of the UV and CD spectra of compound 2c;
b) mirror-image CD spectra of 2b,c in MCH (c=2.2ꢁ10ꢀ5 m); c) UV
spectra and d) CD spectra of 2b between 20 and 808C (the arrows show
the shifts upon increasing the temperature; c=1.7ꢁ10ꢀ5 molLꢀ1 in
MCH).
lmax at 228 nm with a pronounced shoulder at 305 nm,
whereas the lmax of 1c is located at 195 nm in MCH. In addi-
tion, the CD spectrum of 2c is more complicated than that
of 1c. The CD spectrum of 2c shows several positive and
negative extrema (De=ꢀ53.3 Lmolꢀ1 cmꢀ1 at 216 nm, De=
20.7 Lmolꢀ1 cmꢀ1 at 228 nm, De=ꢀ48.2 Lmolꢀ1 cmꢀ1 at
Figure 1. IR spectrum of compound 2a (bulk, mesophase) at room tem-
perature.
238 nm,
De=55.9 Lmolꢀ1 cmꢀ1
at
316 nm,
De=
11.6 Lmolꢀ1 cmꢀ1 at 377 nm), whereas that of 1b shows one
positive extremum at 195 nm and one negative extremum at
223 nm. The enantiomers 2b,c display perfect mirror-image
CD spectra (Figure 2B). These observations indicate that
thioBTAs self-assemble in MCH in helical supramolecular
polymers, similarly to amide-based BTAs, and that the pres-
ence of stereogenic centres biases the helicity. Increasing the
temperature to 808C results in a redshift of the UV maxi-
mum of 2b to 237 nm whereas the shoulder is blueshifted to
295 nm (Figure 2C). Increasing the temperature also results
in the disappearance of the Cotton effect (Figure 2D). The
shifts in the lmax in the UV spectra and the reduction of the
Cotton effect upon increasing the temperature are consis-
tent with reaching the molecularly dissolved state of thio-
NH stretch at 3180 cmꢀ1, a CN vibration at 1539 cmꢀ1 and a
C=S vibration at 693 cmꢀ1.[28] The low value for the NH
stretch in the thioBTAs is indicative of the presence of
ꢀ
strong hydrogen bonding; the N H stretch in non-hydro-
gen-bonded systems is at around 3400 cmꢀ1.[29] Although 2b
is crystalline at room temperature, its IR spectrum is very
similar to that of 2a (see Figure S1 in the Supporting Infor-
mation), which indicates that the helical columnar packing
of the thioamides is retained in the crystalline state.
Self-assembly of thioBTAs in dilute alkane solution: We se-
lected methylcyclohexane (MCH) as the solvent of choice to
evaluate the self-assembly of thioBTAs because it is apolar
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E. W. Meijer, A. R. A. Palmans et al.
Table 1. Thermodynamic parameters for the self-assembly of 1b and 2b
in MCH as obtained from the equilibrium model.
BTAs at higher temperatures. In fact, the UV spectrum at
808C is similar to the UV spectrum of molecularly dissolved
thioamide BTAs in THF in which the shoulder is also locat-
ed at 293 nm (see Figure S5 in the Supporting Information).
The mechanism of self-assembly was further investigated
by performing temperature-dependent CD spectroscopy on
compound 2b at concentrations between 2ꢁ10ꢀ5 and 5ꢁ
10ꢀ5 molLꢀ1 in MCH (Figure 3). The temperature-depend-
[a]
[b]
BTA DHELO
[kJmolꢀ1
DS
DHNP
K[b]
[105 mꢀ1
K2
[mꢀ1
]
s[b]
]
[Jmolꢀ1 Kꢀ1
]
[kJmolꢀ1
]
]
1b[c] ꢀ72
ꢀ128
ꢀ71
ꢀ30
ꢀ19
8.7
4.9
5
185
5.4ꢁ10ꢀ6
3.7ꢁ10ꢀ4
2b
ꢀ54
[a] The nucleation penalty, DHNP, has a negative value, which implies that
the enthalpy associated with the nucleation process is positive and hence
unfavourable. [b] The equilibrium constant for elongation, K, the equili-
brium constant for dimerisation, K2, and the cooperativity factor, s, were
calculated at 298 K. [c] Data obtained from ref. [31].
previously determined for the amide BTA 1b are included
in Table 1.[31]
The thermodynamic values derived for thioBTA self-as-
sembly show notable differences compared with amide-
based BTA self-assembly. First, both the enthalpy and entro-
py of elongation are less negative for thioBTA 2b (DHELO
=
ꢀ54.0 kJmolꢀ1, DS=ꢀ71 Jmolꢀ1 Kꢀ1) than for the amide
BTA 1b (DHELO =ꢀ72.0 kJmolꢀ1, DS=ꢀ128 Jmolꢀ1 Kꢀ1).
To ensure that this difference is not related to a fitting
error, we also derived a van’t Hoff plot for both compounds
(see Figure S7 and Table S3 in the Supporting Informa-
tion).[17] Also, the enthalpy and entropy associated with thio-
Figure 3. Temperature-dependent CD effect for 2b probed at l=317 nm
and c=5ꢁ10ꢀ5 (&), 4ꢁ10ꢀ5 (&), 3ꢁ10ꢀ5 (*) and 2ꢁ10ꢀ5 molLꢀ1 (*) in
MCH.
BTA
self-assembly
(DH=ꢀ54.2 kJmolꢀ1,
DS=
ent cooling curves are typical for a cooperative aggregation
process in which a nucleation and elongation phase can be
distinguished. The two phases are separated by the (concen-
tration-dependent) temperature of elongation, Te. To quanti-
fy the thermodynamic parameters of the self-assembly of
2b, the CD cooling curves were analysed by applying a re-
cently developed mathematical model for supramolecular
polymerisation reactions (see Figure S6A in the Supporting
Information).[31] In this model, which is based on equilibria
between monomers, oligomers and polymers, the aggrega-
tion process is divided into a nucleation and elongation
regime. In the nucleation regime, the formation of a dimer,
described by the equilibrium constant K2, for dimerisation is
assumed to result in a stable nucleus. In the elongation
regime, in which additional monomers add to the growing
polymer chain, all equilibrium constants K (K2 ¼K) are as-
sumed to be equal. Because the nucleation step is highly un-
favourable, the equilibrium constant for nucleation is much
smaller than that for elongation (K2 !K).
The thermodynamic parameters describing the nucleation
and elongation processes are derived by performing non-
linear least-squares analyses on the experimental melting
curves. The simultaneous fit of the different concentrations
gives values to the enthalpy of elongation, DHELO, the asso-
ciated entropy, DS, and the nucleation penalty, DHNP. From
these values, the equilibrium constants for the nucleation,
K2, and elongation phase, K, can be calculated. Importantly,
the cooperativity factor s, defined as K2/K and a direct
measure of the cooperativity of the system, can be calculat-
ed from the obtained results. The results are summarised in
Table 1. Increasingly small numbers for s indicate an in-
creasingly cooperative system. As a reference, the values
ꢀ56.0 Jmolꢀ1 Kꢀ1) are less negative than those for the
amide-based
BTA
1b
(DH=ꢀ73.0 kJmolꢀ1,
DS=
ꢀ113.0 Jmolꢀ1 Kꢀ1). The elongation of the thioBTA 2b and
the amide BTA 1b starts at similar temperatures under
identical concentrations, although the solubility of 2b in
MCH is much better than that of 1b. Importantly, the re-
sults show that the cooperativity factor, s, is around 100
times larger for the thioBTAs, which indicates a less cooper-
ative self-assembly behaviour. The self-assembly of the achi-
ral thioBTA (see Figure S6B in the Supporting Information)
is similar to that of chiral 2b, albeit the cooperativity is
slightly lower (s=7ꢁ10ꢀ4) and the enthalpy release is slight-
ly more negative (DHELO =ꢀ64.1 kJmolꢀ1).
Amplification of chirality: Amplification of supramolecular
chirality, that is, a small enantiomeric excess or a small
amount of chiral compound biases the supramolecular helic-
ity in a non-linear fashion, is typically investigated by per-
forming majority rules (MR) and sergeants-and-soldiers
(SaS) experiments.[32] The MR experiment is performed by
mixing the two enantiomers and the MR effect is operative
when the intensity of the CD effect at a certain wavelength
changes non-linearly as a function of the enantiomeric
excess (ee).[33] In this case, the enantiomer present in the
majority dictates the helical sense to which the minority
enantiomer adjusts. Alternatively, the SaS experiment in-
volves mixing of a few chiral units (sergeants) with large
number of achiral units (soldiers) consisting of equal
amounts of P (right-handed)- and M (left-handed)-type su-
pramolecular polymers.[34] When the SaS effect is operative,
a strong non-proportional increase in the CD effect is ob-
served. Previous results from our group showed a pro-
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Thioamides in Supramolecular Polymers
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nounced amplification of supramolecular chirality in C=O-
and N-centred BTAs.
A majority rules experiment was performed by mixing the
enantiomer pair 2b and 2c in different ratios and probing
the magnitude of the CD effect at 317 nm (Figure 4). The
CD effect is non-linear with respect to the ee. For 100%> j
Dtrans and Drot, of the supramolecular thioBTAs. Because of
the nature of the hydrogen-bonding array in aggregated thi-
oamides, the thioamides are rotated out-of-the-plane in a
parallel fashion giving rise to a strong dipole moment. An
increase in the size of the aggregate results in an anisotropy
of the polarisability. Thus, the high dipole moment of a thio-
amide bond in combination with the highly anisotropic
shape of the resulting cylindrical aggregate gives rise to suf-
ficiently strong depolarised scattering to enable DDLS
measurements of the rotational and translational diffusion
coefficients, Dtrans and Drot.
We performed all the DDLS measurements at 258C in
MCH with c=9ꢁ10ꢀ4 molLꢀ1. The initial decay rate, G, can
be extracted from the intensity autocorrelation functions.
Then the rotational and translational diffusion coefficients,
Dtrans and Drot, can be extracted from G=6Drot +Dtransq2 in
which q is the scattering wave vector (Figure 5). We used a
hydrodynamic model for the diffusion of spherical end-
capped cylinders to compute the length L and diameter d of
the thioBTA aggregates from the measured diffusion coeffi-
cients.[38] Values of L=490 nm and d=3.6 nm were obtained
(Table 2). In addition, the degree of polymerisation, DP, of
1439 was extracted.[39]
Figure 4. Majority rules experiment performed on 2b and 2c in MCH
(c=2.2ꢁ10ꢀ5 molL ꢀ1, CD effect probed at 317 nm).
eej >15%, the CD effect is constant, which indicates the
presence of only one type of helical column. For 15%>
jeej >0%, the ee linearly decreases, which is indicative of
the formation of columnar structures with the opposite hel-
icity. An ee of 15% is needed to fully bias one helicity,
which indicates that a ratio of enantiomers of 57.5:42.5 is
sufficient for there to be only one helical sense. This also
implies that helical columns tolerate up to 42.5% of the un-
preferred enantiomer. In addition, an SaS experiment was
performed that showed that chiral compound 2c biases the
helical sense of achiral thioBTAs (see Figure S8 in the Sup-
porting Information). The MR and SaS effects found for thi-
oBTAs are similar in magnitude to those observed in the
previously studied C=O- and N-centred BTAs.[16,17]
Table 2. Measured translational diffusion coefficient, Dtrans, rotational dif-
fusion coefficient, Drot, length, L, diameter, d, and average degree of pol-
ymerisation, DP, and calculated values weight average degree of poly-
merisation, DPw, number average degree of polymerisation, DPn, aggre-
gate length based on DPw, Lw, and aggregate length based on DPn, Ln for
2b.[a]
Measured
Drot [sꢀ1
]
196ꢁ5
Dtrans [m2 sꢀ1
h [Pas]
]
(6.24ꢁ0.15)ꢁ10ꢀ12
7.36ꢁ10ꢀ4
490
L [nmꢀ1
d [nm]
DP
]
3.6
1439
Calculated
2157
1080
755
348
Dimensions of thioBTA-based supramolecular polymers: To
date, the experimental determination of the length of rigid
cylindrical supramolecular polymers by scattering techni-
ques has proved a challenge. Although several systems
forming rigid one-dimensional supramolecular polymers
have been analysed by scattering techniques, the exact de-
termination of the length and diameter of the supramolecu-
lar polymer is not trivial and often only lower limits can be
obtained.[35] Depolarised dynamic light scattering (DDLS)
measurements, in contrast, have been successfully applied to
quantify the mean length and diameter of rigid nanorods in
solution.[36] Because the rotational and translational diffu-
sion display different functional dependencies on rod length
and diameter, the length and diameter of the nanorods can
be determined from these two measurements. Remarkably,
the DDLS measurements of (rigid) supramolecular poly-
mers have not been reported, presumably because they re-
quire a large anisotropy in the polarisability of the parti-
cle.[37]
DPw
DPn
Lw [nm]
Ln [nm]
[a] Determined at c=9ꢁ10ꢀ4 molLꢀ1 and 258C.
From the thermodynamic parameters discussed in Table 1,
we can calculate the number-average degree of polymeriza-
tion, DPn, and the weight-average degree of polymerisation,
DPw, of the supramolecular polymers at a selected tempera-
ture and concentration (Table 2).[24a] At c=9ꢁ10ꢀ4 m and
258C, the DPn and DPw are approximately 1080 and 2157,
respectively.[40] This corresponds to a chain length of around
755 nm (based on the DPw and an interdisc distance of
0.35 nm). The calculated chain length of 755 nm is in good
agreement with the experimentally obtained value of
490 nm. In addition, XRD measurements revealed an inter-
columnar distance of 2.1 nm for the LC phase of 2a at
1008C, conditions under which the aliphatic chains are
molten and highly disordered. Taking into account the inter-
In this work we conducted DDLS measurements to deter-
mine the rotational and translational diffusion coefficients,
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E. W. Meijer, A. R. A. Palmans et al.
genic centres biases one helicity. In addition, strong amplifi-
cation of the supramolecular chirality was observed. Depo-
larised DLS experiments showed that the average length, L,
and diameter, d, of the thioBTA stacks are 490 and 3.6 nm,
respectively. These measured values are in good agreement
with the value of Lw =755 nm obtained from fitting the tem-
perature-dependent CD data and the intercolumnar distance
of 2.1 nm in the columnar mesophase. This is the first exper-
imental verification in which we have validated our common
practice for determining the length of the supramolecular
BTA-based polymers from model fits to experimental CD
data.
The ability of a thioamide to induce cooperative, direc-
tional hydrogen bonding in supramolecular polymerisations
makes it versatile and broadly applicable. Compared with
the amide bond, thioamides offer a number of additional ad-
vantages when designing new supramolecular motifs. First,
the absorption wavelength is shifted to higher values, which
facilitates the performance of spectroscopic experiments in
the presence of other chromophores. Secondly, the high
dipole moment of the thioamide bond enables DDLS meas-
urements, which allows the lengths and diameters of rod-
like aggregates to be determined. Thirdly, thioamides can be
switched to a cis conformation with UV light. We are cur-
rently exploring the possibility of such a photochemical trig-
ger to turn “off” or “on” the self-assembly behaviour of this
new class of self-assembling discotics by switching between
the trans and cis conformations of the thioamide bonds.
Experimental Section
Materials: Compounds 1a–c were synthesised according to a published
procedure.[12c] Toluene was dried on an activated alumina column and
used immediately. All other chemicals were used as received.
Methods: CD and UV spectra were recorded on a Jasco J-815 CD spec-
trometer equipped with a Jasco PTC-348 WI temperature controller. Ex-
periments were conducted by using spectroscopic-grade methylcyclohex-
ane as the solvent. Cells with an optical path length of 1 cm were em-
ployed. The concentration-independent value of the Cotton effect, the
Figure 5. a) Field autocorrelation functions at different angles with corre-
sponding cumulant fit (full line) and b) angular dependence of extracted
decay rates (G) and linear fit (—) to determine the values of Drot and
Dtrans (full line) for 2b (c=9ꢁ10ꢀ4 in MCH, T=258C).
molar circular dichroism (De), was calculated as De=CD effect/ACHTUNGTRENNUNG(32980cl)
in which c is the concentration in molLꢀ1 and l is the optical path length
in cm. 1H and 13C NMR spectra were recorded on a Varian Gemini
400 MHz NMR spectrometer (400 MHz for 1H NMR and 100 MHz for
13C NMR). 1H chemical shifts are reported in ppm downfield from tetra-
methylsilane (TMS) and 13C chemical shifts are reported downfield from
TMS with the resonance of the deuteriated solvent as the internal stand-
ard. IR spectra were recorded on a Perkin–Elmer 1600 FT-IR spectrome-
ter. Polarised optical microscopy (POM) measurements were performed
with a Jenaval polarisation microscope equipped with a Linkam THMS
600 heating device with crossed polarisers. The thermal transitions were
determined by DSC from the second heating run by using a Perkin–
Elmer DSC-7 instrument under nitrogen with heating and cooling rates
of 20 Kminꢀ1. MALDI-TOF mass spectrometry was performed with a
PerSeptive Biosystems Voyager DE-PRO spectrometer or a Bruker auto-
flex speed spectrometer with a-cyano-4-hydroxycinnamic acid (CHCA)
as the matrix system.
calation of solvent molecules within the aggregates,[18d,41] the
experimentally determined diameter of the aggregates of
3.6 nm is in good agreement with the expected value.
Conclusion
We have reported a facile synthesis and molecular character-
isation of chiral and achiral N,N’,N’’-trialkylbenzene-1,3,5-
tris(carbothioamide)s (thioBTAs). The thioBTAs show ther-
motropic liquid crystalline behaviour. IR spectroscopy re-
vealed that three-fold intermolecular hydrogen bonding sta-
bilises the columnar structures in the mesophase and in
methylcyclohexane. In analogy to their amide counterparts,
thioBTAs self-assemble cooperatively into one-dimensional,
helical supramolecular polymers and the presence of stereo-
Wide- and small-angle X-ray diffraction measurements: The samples for
wide-angle X-ray diffraction (WAXD) and small-angle X-ray diffraction
(SAXD) were prepared in 0.7 mm Lindemann glass capillaries. The sam-
ples were analysed on a Bruker–Nonius D8-Discover X-ray diffractome-
ter with a 0.154 nm copper radiation source equipped with a home-built
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Thioamides in Supramolecular Polymers
FULL PAPER
sample oven (TU Delft, Prof. Dr. S. J. Picken and co-workers). The scat-
tering data were recorded with a 2D detector (1024ꢁ1024) and the
sample-to-detector distance was 8.4 (WAXD) or 34 cm (SAXD). The ca-
pillary was placed inside a vertically aligned graphite tube with a trans-
versal hole, which allows the incident X-ray beam to cross freely. The
temperature of the graphite tube was controlled by a system formed by a
thermocouple connected to a proportional integral-derivative (PID) con-
troller and power supply, which acts as a fast-response online oven rang-
ing from room temperature to 3508C.
Acknowledgements
This work was supported by the Dutch National Research School Combi-
nation Catalysis Controlled by Chemical Design (NRSC-Catalysis) and
the Netherlands Organization for Scientific Research (Spinoza-NWO)
foundations. I.K.V. gratefully acknowledges support from VENI-NWO
and the European Union (FP7-PEOPLE-2011-CIG). The authors would
like to thank Michel van Houtem and Carel Fitiꢂ for help with the X-ray
diffraction measurements, Charley Schaefer and Peter Korevaar for pro-
viding assistance with fitting of the data and the ICMS animation studio
for the artwork.
Depolarised dynamic light scattering: DDLS measurements were con-
ducted on an ALV/CGS-3 MD-4 compact goniometer system equipped
with a multiple tau digital real time correlator (ALV-7004; solid-state
laser: l=532 nm, 40 mW). In a typical experiment, the scattering angle q
was varied between 20 and 1508 in steps of 10 (first step) and 158 (subse-
quent steps) performing 3ꢁ30 s experiments at each angle. The liquid
samples were held in 5 mm borosilicate cells. The translational and rota-
tional diffusion coefficients (Dtrans and Drot) were obtained from the ini-
tial decay rate G extracted from the intensity autocorrelation functions
by third-order cumulant analysis according to G=6Drot +Dtransq2.[40]
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Synthesis of thioBTAs 2a–c: N,N’,N’’-TrisACTHUNTGRNEUNG(dodecyl)benzene-1,3,5-trithio-
amide (2a): Compound 1a (2.0 g, 2.81 mmol) was dissolved in toluene
(100 mL) and P2S5 (2.10 g, 9.4 mmol) was added. The solution was heated
at reflux for 4 h and then an additional amount of P2S5 (1.5 g, 6.7 mmol)
was added and the heating was continued for another 16 h. The solution
was then cooled to 908C and MeOH (200 mL) was added. The clear solu-
tion was cooled to room temperature and evaporated to dryness. Di-
chloromethane (200 mL) was added and the solution extracted with
water (200 mL), satd. NaHCO3 (3ꢁ200 mL) and brine (200 mL). After
drying over MgSO4 the organic layer was evaporated to dryness and a
viscous oil was obtained. Then MeOH (50 mL) was added and the mix-
ture stirred for 5 min. MeOH was decanted and the procedure repeated
with additional MeOH (50 mL). The combined MeOH layers were
evaporated to dryness and the crude product was purified by column
chromatography (SiO2, gradient CHCl3 to CHCl3/EtOAc, 98:2) to afford
a yellowish solid (1.03 g, 48%). 1H NMR (400 MHz, CDCl3): d=9.20 (s,
3H; Ar-H), 7.20 (t, 3H; NH), 3.68 (m, 6H; NHCH2), 2.0–0.9 ppm (m,
63H; NHCH2ACHTUNGTRENNUNG
(CH2)9CH3); 13C NMR (100 MHz, CDCl3): d=194.9, 138.8,
47.2, 32.0, 29.9, 29.8, 29.7, 29.6, 29.5, 27.9, 27.5, 22.7, 14.1 ppm; IR (208C,
film): n˜ =3180 (NH), 1539 (amide II), 691 cmꢀ1 (C=S); MS (MALDI-
TOF): m/z calcd for C45H81N3S3: 759.56; found: 760.57 [M+H]+, 782.55
[M+Na]+; DSC: Tm1 =ꢀ4.568C (DH=3.29 kJmolꢀ1), Tm2 =2548C (DH=
6.0 kJmolꢀ1).
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Compound 1b (1.2 g, 1.9 mmol) was dissolved in toluene (35 mL) and
P2S5 (1.25 g, 5.6 mmol) was added. The solution was heated at reflux for
3 h, the solution was cooled to 908C and MeOH (75 mL) was added. The
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(CH3)2); 13C NMR
1.9–0.9 ppm (m, 51H; NHCH2CHCH3ACHTNUTRGENNUG(CH2)3CHACHTUNGTRENNGUN
(100 MHz, CDCl3): d=194.9, 138.9, 45.3, 39.3, 37.0, 34.9, 31.3, 28.0, 24.9,
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A
procedure identical to that used for 2b was applied. Compound 2c was
obtained as a yellowish solid (0.18 g, 25%). 1H NMR (400 MHz, CDCl3):
d=8.85 (s, 3H; Ar-H), 7.60 (t, 3H; NH), 3.68 (m, 6H; CH2NH), 1.9–
0.9 ppm (m, 51H; NHCH2CHCH3ACHTUNGTRENNU(G CH2)3CHCAHUTNGTRENN(UGN CH3)2); IR (208C, film): n˜ =
3180 (NH), 1540 (amide II), 695 cmꢀ1 (S=C); MS (MALDI-TOF): m/z
calcd for C39H69N3S3: 675.45; found: 676.35 [M+H]+, 698.33 [M+Na]+.
Chem. Eur. J. 2013, 00, 0 – 0
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Received: November 30, 2012
Revised: March 20, 2013
Published online: && &&, 0000
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www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Thioamides in Supramolecular Polymers
FULL PAPER
Thioamide bonds: The polymerisation
of a thioamide-based supramolecular
motif is elucidated by combining depo-
larised dynamic light scattering and
temperature-dependent spectroscopic
measurements (see figure). A coopera-
tive polymerisation mechanism and
strong amplification of chirality makes
this a highly versatile structuring motif.
Supramolecular Polymers
T. Mes, S. Cantekin,
D. W. R. Balkenende, M. M. M. Frissen,
M. A. J. Gillissen, B. F. M. De Waal,
I. K. Voets, E. W. Meijer,*
A. R. A. Palmans* ........... &&&& — &&&&
Thioamides: Versatile Bonds To
Induce Directional and Cooperative
Hydrogen Bonding in Supramolecular
Polymers
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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9
&
ÞÞ
These are not the final page numbers!