A Family of Amphiphilic Cyclodextrin Liquid Crystals Governed by Dipole–Dipole Interactions

Article abstract of DOI:10.1002/cplu.201600556

A novel family of amphiphilic cyclodextrin(CD)-based liquid crystals that bear O-acetylated oligoethylene glycol chains at the secondary face is reported. Unlike most of the previously reported liquid crystals (LC) based on chemically modified CDs, which depend on H-bonding as the primary intermolecular forces, the present CD derivatives self-assemble into highly ordered smectic liquid crystal phases via the weaker dipole–dipole intermolecular interactions. The obtained materials are found to display much improved properties such as improved thermostability, reduced clearing temperatures, and better fluidity. The present work opens up new possibilities to design CD-based LC materials.

Full text of DOI:10.1002/cplu.201600556

Accepted Article
Title: First Family of Amphiphilic Cyclodextrin Liquid Crystals Driven by Dipole-
Dipole Interactions
Authors: Chang-Chun Ling; Pier-Luc Champagne; David Ester; Sandra M Ward;
Vance E Williams
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First Family of Amphiphilic Cyclodextrin Liquid Crystals Driven
by Dipole-Dipole Interactions
Pier-Luc Champagne,[a] David Ester,[b] Sandra Ward,[c] Vance E. Williams[b] and Chang-Chun Ling*[a]
Abstract: A novel family of amphiphilic cyclodextrin(CD)-based
liquid crystals that bear O-acetylated oligoethylene glycol chains at
the secondary face has been reported. Unlike most of the previously
reported liquid crystals based on chemically modified CDs, which
depend on H-bonding as the primary intermolecular forces, the
present CD derivatives self-assemble into highly ordered smectic
liquid crystal phases via the weaker dipole-dipole intermolecular
interactions. The obtained materials are found to possess much
improved properties such as improved thermostability, reduced
clearing temperatures and better fluidity. The present work opens up
new possibilities to design CD-based LC materials thus should
stimulate future development of LC materials based on CDs.
This H-bond network was believed to be crucial for driving the
amphiphilic CDs to self-assemble into thermotropic LCs;10 it is
also the primary intermolecular force used in literature to design
amphiphilic CD-based LC mesophases so far.7-8
Introduction
Amphiphilic cyclodextrin (CD) derivatives1-3 have the ability to
self-assemble4-6 to form ordered superstructures in a solution
because of nanosegregation of their polar and apolar groups. In
the absence of solvents, amphiphilic CD derivatives can also
self-organize through molecular reorganization; new materials
such as thermotropic liquid crystals (LCs)7-10 can be obtained
upon changing temperatures. CD-based materials are of
particular interest for LC research, because of their relatively
rigid, truncated-cone-shaped geometry, making them a unique
class of scaffolds. The presence of a hydrophobic cavity in CDs
can be further exploited for generating LC materials based on
host-guest chemistry.11 The three common members, , 
andCDs, are all polar polyhydroxylated carbohydrates that
can be easily turned into amphiphilic materials via installation of
aliphatic groups to one of the two ends of the cone.12-17 The first
class of amphiphilic CD derivatives known to form LC
mesophases had all primary hydroxyl groups of CD replaced
with a n-octadecylthio group7 (1, Figure 1), which permits the
remaining secondary hydroxyl groups to interact in solid phase,
forming a complex network of inter-/intra-molecular H-bonds.18-19
Figure 1. Previously synthesized -CD derivatives and new targets.
Through a systematic study, previously, we synthesized a
series of per-6-n-octadecylthio-β-CD derivatives10 (Figure 1) that
are substituted either at all O-2 positions with an alkyl group of
small sizes (such as methyl (2), ethyl (3) and other lager groups
such as allyl and benzyl groups (not shown); it was found only
amphiphilic derivatives with smaller alkyl groups (2-3) formed LC
mesophases while the other derivatives with larger substituents
did not. We rationalized that the alkyl groups at O-2 positions
served the role of delimitating groups that control the distance
between secondary face of CD molecules in the bilayers of the
solid states, thus they effectively modulate the H-bond strength.
Only amphiphilic CD derivatives with smaller groups could form
LC mesophases because the molecules of the adjacent layer
could get closer, thus interact with each other via a network of
intermolecular H-bonds of sufficient strength. On the other hand,
when all the secondary hydroxyl groups were substituted with
alkyl groups such as methyl (4) or benzyl (5) groups, they all lost
their ability to form H-bond network, thus were unable to form LC
mesophases.10 Although in theory, compound (5) could engage
a network of - interactions between adjacent layers, but
clearly, this type of intermolecular force was too weak to induce
molecular self-assembling in solid state. In the present work, we
report a novel strategy to design CD-based LC materials by
[a]
Pier-Luc Champagne, Prof. Dr. Chang-Chun Ling
Alberta Glycomics Centre, Department of Chemistry
University of Calgary
2500 University Drive NW, Calgary Alberta T2N 1N4, Canada
E-mail: ccling@ucalgary.ca
[b]
[c]
David Ester, Prof. Dr. Vance E. Williams
Department of Chemistry
Simon Fraser University
8888 University Dr, Burnaby, B.C. V5a 1S6 Canada
Prof. Dr. Sandra Ward
Department of Chemistry & Biochemistry
California Polytechnic State University
San Luis Obispo, CA 93407 USA
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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invoking dipole-dipole as the primary intermolecular force to
promote self-assembling. We designed a series of O-acetylated
oligoethylene glycol (OEG) functionalized amphiphilic CD
derivatives (6-8, Figure 1) which were synthesized efficiently,
and our results revealed that they all possess excellent abilities
to form LC mesophases with improved properties. This
constitutes the first examples of CD-based LC materials
reported in the literatures using dipole-dipole as the principal
intermolecular force.
3.09 ppm which was assigned to be the mesylates, and another
two deshielded proton signals at 4.64 and 4.51 ppm, assigned to
be the H-6a’s and H-6b’s of -CD scaffold, which are
significantly deshielded due to the electron-withdrawing effect of
the mesylate group. Moreover, another two sets of alkynic
protons were observed at 2.55 and 2.53 ppm, respectively,
corresponding to the terminal protons of the two types of
propargyl groups at the O2- and O3-positions of the CD.
Results and Discussion
Designs and Synthesis
OEGs are polar compounds fully miscible with water because of
their multiple polar C-O bonds; the oxygen atoms of OEGs can
act as H-bond acceptors and the terminal hydroxyl groups can
also act as H-bond donors. This is in contrast with the
hydrocarbons which contain only nonpolar C-C and C-H bonds.
The difference in polarity prompted us to investigate the
possibility of combining both polar OEGs and nonpolar alkyl
groups within the CD scaffold; this would create a new class of
amphiphilic CD derivatives. Furthermore, if the remaining
terminal hydroxyl group of the OEG group is protected, such as
with an acetate group, we can prevent the synthesized CD
derivatives from interacting with each other via H-bonding in
solid phase. Consequently, the strongest intermolecular forces
that the targeted CD derivatives could have would be dipole-
dipole interactions. Compared to above mentioned CD
derivatives, these new CD amphiphiles could have significantly
different thermotropic properties in solid states.
Scheme 1. Preparation of per-6-O-mesyl-2,3-O-propargylated -CD
intermediate (11).
We next undertook the synthesis of three O-acetylated
OEG reactants 13, 15 and 19, containing respectively a di-, tri-
and tetra-ethylene glycol unit (Scheme 2). Each compound also
contained a terminal azido group that can react with the
propargyl groups of compound 11.
As shown in Scheme 2, compounds 1325 and 15 were
prepared respectively from their mono-chlorinated alcohols 12
and 14 in two steps.
Figure 1 shows the design of our synthetic targets 6-8
based on -CD, which have fourteen OEG groups incorporated
to the secondary face and seven n-octadecyl groups to the
primary face. The length of the OEG groups were chosen
among those containing 2-4 repeating units of the ethylene
glycol, and the involved linking chemistry was the highly efficient
copper (I) catalyzed Huisgen 1,3-dipolar cycloaddition.20-21 We
chose to incorporate n-octadecylthio groups to the primary face,
because previous results showed that this group provided the
best LC properties.
Scheme 1 illustrates the synthesis of the key β-CD
intermediate 11 that bears fourteen propargyl groups at all O2
and O3 positions and seven mesylates at all the O6 positions.
Compound 11 was prepared from the previously reported per-6-
O-tert-butyldimethylsilyl-2,3-di-O-propargylated compound 922
which was desilylated with tetra-n-butylammonium fluoride in
THF as a solvent;22 we now found the acid (HCl)-catalyzed
condition to remove all the tert-butyldimethylsilyl groups in a
mixture of 2:1 methanol-chloroform23-24 is more convenient; the
Scheme 2. Preparation of O-acetylated di-, tri- and tetra-ethylene glycol
azides 15, 18 and 22 for incorporation to the secondary face of -CD.
desired heptol (10) was obtained in 92% yield after
a
chromatography on silica gel using 15% methanol in
dichloromethane as a eluent. The subsequent per-6-mesylation
of compound 10 was carried out in anhydrous dichloromethane
using methanesulfonyl chloride as a reagent and pyridine as a
base to afford the heptamesylate 11 in excellent yield (91%).
In the case of compound 12, the terminal hydroxyl group
was acetylated first using the conventional acetylation conditions
(acetic anhydride/pyridine), and O-acetylated intermediates were
then subjected to a direct substitution with sodium azide in N,N-
dimethylformamide at 70° C overnight, to afford the desired
1
The 1D H NMR spectra of compound 11 showed a singlet at
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compound 13 in 55% combined yield. The preparation of
compound 15 was carried out in a similar two-step procedure as
13, but in reversed order. The combined yield for compound 15
was excellent (91%, two steps).
The completeness of the substitution was confirmed by the
presence of a C7 axial symmetry in the 1H NMR spectra of
isolated compound 20. For instance, two sets of triazole protons
were observed at 8.06 and 7.94 ppm, each integrated as 7
protons; they correspond to the two groups of triazole fragments
attached to the O2 and O3-positions; in addition, the seven
mesylates also appeared as a singlet at 3.10 ppm, and the two
sets of methylene protons directly attached to O2 and O3 of
glucopyranosyl units were observed at 5.19/4.84 ppm and
4.82/4.78 ppm, more deshielded than before, as a result of the
formed aromatic 1,2,3-triazole rings. The anomeric protons of all
glucopyranosyl units also appeared as a doublet at 5.17 ppm (J
= 2.9 Hz), while each of the other proton types of the
glucopyranosyl units was also observed as a single set of signal
with the expected coupling pattern. These are further confirmed
by the 13C NMR spectrum (see experimental). Additionally, the
identity of compound 20 was also confirmed by the electrospray
high-resolution mass spectrometry: expected m/z: 2318.7834 for
(C175H266N42O91S7 + H+), found m/z 2318.7709.
To synthesize the O-acetylated tetraethylene glycol
monoazide 19, we utilized the commercially available alcohol 16
as a starting material. First, a regioselective monoacetylation
was carried out using controlled amount of acetic anhydride (1
equiv.) in anhydrous pyridine, this afforded the intermediate
mono-ol 17 in 45% yield after a purification by chromatography
on silica gel, using a gradient of acetone-toluene as an eluent
(1025%). Compound 17 was then subjected to a mesylation
(18, 85% yield) and subsequent azide substitution of the
mesylate, affording the desired compound 19 in 86% yield.
With the O2,O3-polypropargylated β-CD scaffold 11 and the
three O-acetylated OEG monoazides 13, 15 and 19 in hand, we
continued our synthesis by preparing the three final targets 6-8
(Scheme 3). Compound 11 was first coupled with an excess of
diethylene glycol azide 13 (1.35 equiv. per C≡CH) via the
efficient copper(I)-mediated Huisgen 1,3-dipolar cycloaddition.
The two other OEGs conjugates 21 and 22 were also
prepared in a similar manner as 20 and the two desired
compounds were obtained in pure form in 85% and 76% yields,
respectively.
The synthesis of final targets 6-8 required a persubstitution
of all 6-mesylates in each of the compounds 20-22 with n-
octadecylthio group. This was carried out in DMF under argon at
75° C using 1-octadecanethiol (5 equiv. per mesylate) as a
reagent and cesium carbonate as a base. After stirring overnight,
some de-O-acetylations were observed, as evidenced by the
observation of several closely spaced spots on TLC as well as
high resolution mass spectrometry; this was probably due to a
nucleophilic attack of O-acetates by the octadecylthiolate.
Nevertheless, the intermediate products were reacetylated at
65° C using acetic anhydride/pyridine conditions to afford a
single spot; after purification by chromatography on silica gel,
the target compounds 6, 7 and 8 were isolated in pure form in
63% 97% and 82% yield, respectively.
The structures of all final products were confirmed by 1H
1
and 13C NMR spectra. For example, Figure 2 shows the H-13C
HSQC correlation NMR spectrum of compound 6. As can be
seen, the mesylate signals attached to the C-6 were no longer
observed (around 3.1 ppm); instead, the two protons (H-6a and
H-6b) were then observed at a more shielded region (3.15 ppm
and 3.05 ppm), supporting the successful replacement of all
mesylates with the less electron withdrawing thiolate, and the
two -methylene protons (adjacent to the sulfur atom) of the
octadecylthio groups were observed at 2.58 ppm as a triplet.
Finally, a singlet appeared at 2.05 ppm, which corresponded to
the two types of acetate groups linked to the end of both O2/O3-
OEG chains.
Scheme 3. Cu(I)-mediated Huisgen 1,3-dipolar cycloaddition of ω-O-
acetylated di- to tetra-ethylene glycol polar residues to the secondary face of
-CD and subsequent n-octadecanethiolation to the primary face.
The reaction was carried out in acetone at 65°C and in the
presence of diisopropylethylamine as a base; after stirring for
~20 hours, the desired product 20 that contain seven primary
mesylate was isolated in 84% yield by chromatography on silica
gel, using a gradient of methanol in dichloromethane (1.5  5%)
as an eluent.
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materials of amphiphilic CDs, where the formed mesophases
were observed to be much less fluid. Upon further cooling, more
organized domains formed and their movement were observed
to be gradually reduced and eventually the entire slides were
covered with fan-shaped textures as seen in Figure 3d-e.
Compounds 7 and 8 were observed to exhibit similar changes in
textures upon cooling as compound 6, but with phase changes
taking place at lower temperature ranges (Figure 3b-e). Based
on the characteristic bâtonnets and fan-shaped textures,
compounds 6-8 were identified to form smectic A mesophases.
Figure 2. 1H-13C HSQC correlation NMR spectra of compound 6, recorded in
CHCl3 at 400 MHz
The structures of compounds 6-8 were further confirmed
by high-resolution electrospray ionization mass spectrometry.
For example, for compound 6, a peak at m/z 2984.7654 was
observed, which corresponds to the double charged species
[C294H504N42O70S7 + 2H]2+ (calc. m/z: 2984.7680). On the other
hand, for both compounds 7 and 8, a peak at m/z 2195.6204 or
2401.0805 was observed in each case, which corresponds
respectively to the triple charged species of compound 7
(calculated [C322H560N42O84S7 + 3H]3+: 2195.6368 or compound 8
(calculated [C350H616N42O98S7 + 3H]3+: 2401.0924).
Figure 3. Textures of compounds 6-8 observed under POM during cooling
from their clearing temperatures. Compound 6 forms a LC phase from ~56 –
230.6 ˚C. Compound 7 forms a LC phase from ~53 – 195. Compound 8 forms
a LC phase from ~38 – 159.4.
Mesomorphic Properties
All final compounds 6-8 were characterized with thermogravi-
metric analysis (TGA), Cross-polarized optical microscopy
(POM) and differential scanning calorimetry (DSC). TGA
revealed both compounds 6 to be stable up to 283 °C (~95%)
while compound 7 has similar thermostability - up to 260 °C; the
least stable of the three is compound 8 which was found to be
stable up to 190 °C (~95%). (See supporting info).
Under POM, the compound with the shortest OEG chains
(6) cleared at the highest temperature (234.3 °C, Figure 3a),
while increasing the length of the OEG chains had a decreasing
effect on their clearing temperature (compound 7: 194.8 °C;
compound 8: 157.7 °C). This is in sharp contrast with H-bond-
mediated LC materials based on CD such as 1, which was
observed to slowly decompose before entering into the isotropic
liquid phase.
Figure 4. DSC thermograms of compounds 6-8. The first heating cycle for all
compounds was omitted because of thermal history.
Upon cooling from their isotropic phases, all three
compounds were observed to form LC mesophases. For
example, compound 6, small bâtonnet domains form from the
isotropic phase (Figure 3b); upon further cooling, these domains
were observed to grow, and fuse to form larger bâtonnets
(Figure 3c). These bâtonnets are commonly observed at the
transition from the isotropic phase to fluid smectic mesophases.
This is in contrast with our previously reported H-bond based LC
Figure 4 shows the DSC thermograms obtained for
compounds 6-8. As can be seen, all three compounds showed a
large endothermic phase transition at the low temperature on
heating (54.8 °C for 6, 45.9 °C for 7 and 39.3 °C for 8), which
was associated with a large enthalpic change (23.8 J/g for 6,
18.6 J/g for 7 and 39.3 J/g for 8); these corresponded to the
melting of compound 6-8 from solid to LC phase in each case.
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Each of these transitions was mirrored with a matching large
exothermic phase transition (51.1 °C (24.3 J/g) for 6, 38.4 °C
peak. At higher angles, a broad peak is observed at 4.6 Å
representative of a disordered array of molecules in each layer.
This XRD data clearly agrees with the formation of a smectic A
LC phase. The room temperature X-ray of this compound was
also obtained. Much like compound 6, the layered structure is
maintained; sharp (001), (002), and (003) peaks of 64 Å, 31 Å,
and 20 Å respectively are found in the low angle region. Once
again, the wide angle peak was observed to grow much sharper
at a distance of 4.1 Å indicative of a more ordered array of
molecules within the layers.
Similarly, for compound 8, XRD was measured at 20 ˚C
below the clearing temperature (~130 ˚C). In the low angle
region, two sharp peaks corresponding to distances 55 Å and 27
Å respectively were observed, which were indexed to the (001)
and (002) peaks of a smectic phase. However, no peaks were
observed at the high angle region. The absence of peaks at
higher angles is not uncommon for the low order smectic phases.
The room temperature X-ray of this compound showed that the
layered structure was maintained; sharp (001) and (002) peaks
associated with a layer spacing of 60 Å are found in the low
angle region. Again, no higher angle are peaks observed.
(19.9 J/g) for
7 and 35.6 °C (23.3 J/g) for 8), which
corresponded to the transition of compound 6-8 from LC phase
to solid phase. However, for all compounds, only small enthalpic
changes (< 2.5 J/g) were observed before clearing from LC
mesophases into the isotropic phases during the heating cycle,
as well as from isotropic phases to LC mesophases during the
cooling cycle. Due to a combination of broadening and small
enthalpies, some transitions were too broad to be detected by
DSC. All these were consistent with Sm A to isotropic phase
transitions which are associated with very little change in
ordering.
Powder X-Ray Diffraction
Powder X-ray diffraction (XRD) of compound 6 was performed at
variable temperatures to confirm the formation of a smectic A LC
phases indicated by POM. The diffraction patterns at 20 ˚C and
50 ˚C below the clearing temperature, i.e. ~210 and 180 ˚C
respectively, are very consistent. At low angles, we observe
sharp (001) and (002) peaks of 48 Å and 24 Å, respectively
corresponding to the layered structure of a smectic phase. At
higher angles, there is a broad peak at 4.7 Å, indicating a
relative lack of order of the molecules within a layer. This XRD
data strongly supports the formation of a smectic A LC phase. At
room temperature, the X-ray diffraction of this compound shows
a similar pattern in the low angle region; with sharp (001), (002),
and (003) peaks of 55 Å, 27 Å, and 18 Å, respectively indicating
that the lamellar structure is maintained, albeit with an increased
layer spacing. In the higher angle region we find that the peak
corresponding to a distance of 4.2 Å has grown significantly
sharper, consistent with the molecules being much more
ordered within the layers. This XRD pattern is consistent with the
formation of a higher order smectic phase such as crystal B
phase.
Molecular Packing in Solid State
Molecular modeling showed all compounds 6-8 have a conical
structure, due to the presence of twice the number of OEG
chains at the secondary face than octadecylthio chains on the
primary face. In their most extended conformations, the
calculated length of compounds 6, 7 and 8 was about 43.6, 47.7
and 51.4 Å respectively (Figure 6). Since in all three cases, the
X-ray determined periodicity of less than twice the molecular
length, this suggests significant intercalation between molecules
of adjacent layers. The longest periodicity determined by XRD
for compound 8 (55 Å) is unexpectedly shorter than the other
two compounds, suggesting slightly increased degrees of
intercalation in the LC phase and solid state of this compounds.
The wedge shaped geometry of each molecule could be used to
explain their smectic packing patterns (Figure 6). As can be
seen, the hydrophobic region is the narrower end of the wedge
which is constant for all three compounds, while the hydrophilic
OEG chains occupy the wider end of the wedge which increases
in length from 6 to 8. This geometry may lead to a steep
increase in curvature of the cone from 6 to 8. To compensate for
this, the hydrophobic tails of compound 8 may intercalate to a
greater extent than the others. Additionally, the increasing chain
lengths could result in more disorder of the OEG region, leading
to them taking up less space vertically and more spaced laterally.
Figure 5. Variable temperature XRD plots of compounds 6, 7 and 8, recorded
at Tc-20 and room temperature.
Conclusions
This is the first report of CD-based amphiphilic materials that
form LC mesophases via dipole-dipole interactions as the
primary intermolecular force. Comparing to the previously
reported LC materials based on H-bonding as the primary
driving force, the new materials have improved properties, such
as lower clearing points, improved molecular stability and
improved fluidity. Since the first report of CD-based LC
For compound 7, the XRD data obtained was very similar
to that of compound 6, confirming the formation of a smectic A
LC phase. The diffraction patterns of the LC phase were also
measured at 20 ˚C and 50 ˚C below the clearing temperature. In
the low angle region we see a sharp (001) peak corresponding
to a layer spacing of 60 Å, as well as a less pronounced (002)
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thermotropic LC more than twenty years ago, there have been
only very few examples of CD-based LC materials, the results
obtained from current study should stimulate the design and
development of future CD-based supramolecular materials by
involving other fundamental intermolecular forces.
Figure 6. Left: molecular models show compounds 6, 7 and 8 have respectively a dimension of 43.6, 47.7 and 51.4 Å in the most extended conformation. Right:
Proposed bilayer packing of molecules in LC phase and solid state.
mmol, 28 equiv.) was added. The reaction was then cooled to 0˚C, and a
solution of 80% propargyl bromide in toluene (14.18 mL, 127 mmol, 56
equiv.) and tetrabutylammonium iodide (TBAI, 260 mg; 0.7 mmol, 0.31
equiv.) was added. After 20 min, MeOH (~ 5 mL) was added to quench
Experimental Section
the reaction. The solvent was removed under reduced pressure, and the
residue was dissolved in ethyl acetate (~ 150 mL). This solution was
General methods
subsequently washed with water (~ 25 ml), saturated brine solution (2 x
Analytical TLC was performed on Silica Gel 60-F254 (Merck, Darmstadt)
with detection by quenching of fluorescence and/or by charring with 5%
sulfuric acid in water or with a ceric ammonium molybdate dip. All
commercial reagents were used as supplied unless otherwise stated.
Column chromatography was performed on Silica Gel 60 (Silicycle,
Ontario). Organic solutions from extractions were concentrated under
vacuum at < 40 C (bath). 1H NMR spectra were recorded at 400 MHz on
Bruker spectrometers. The first order proton chemical shifts H and C are
reported in  (ppm) and referenced to either residual CHCl3 (H 7.24, C
77.0, CDCl3), residual CD2HOD (H 3.30, C 49.5, CD3OD), residual
CD3SOCD2H (H 2.50, C 39.51, CD3SOCD3) or residual C5D4HN (H
7.22, C 123.87, C5D5N). 1H and 13C NMR spectra were assigned with
the assistance of GCOSY, GHSQC spectra. High resolution ESI-QTOF
mass spectra were recorded on an Agilent 6520 Accurate Mass
Quadrupole Time-of-Flight LC/MS spectrometer. Polarized optical
microscopy was performed on OLYMPUS BX-41 equipped with a Linkam
hot stage. Thermal analyses were performed using TA-Q200 differential
scanning calorimetry instrument. Thermogravimetric Analysis was
performed using TGA Q50 instrument.
25 mL), and the organic layer was dried over anhydrous Na2SO4 and
evaporated. The mixture was purified by column chromatography using a
mixture of 3% ethyl acetate in hexanes as eluent to afford compound 9
as a colorless foam (3.93 g, 70% yield). Rf = 0.32 (EtOAc: Hexane, 1: 9).
1H NMR (400 MHz, CDCl3) δ 5.23 (d, J = 3.5 Hz, 7H, 7 × H-1,), 4.68 (dd,
J = 15.3, 2.4 Hz, 7H, 7 × H-OCHaHb-C≡CH), 4.53 – 4.49 (dd, J = 15.3,
2.4 Hz, 7H, 7 × H-OCHaHb-C≡CH), 4.52-4.48 (dd, J = 16.0, 2.4 Hz, 7H,
7 × H-OCHaHb-C≡CH), 4.46-4.42 (dd, J = 16.0, 2.4 Hz, 7H, 7 × H-
OCHaHb-C≡CH), 4.20 – 4.09 (m, 7H, 7 × H-5), 3.90 (dd, J = 9.0, 9.0 Hz,
7H, 7 × H-3), 3.84 (dd, J = 9.0, 9.0 Hz, 7H, 7 × H-4), 3.66 (dd, J = 10.7,
~1 Hz, 7H, 7 × H-6a), 3.59 (dd, J = 10.5, ~1 Hz, 7H, 7 × H-6b), 3.50 (dd,
J = 9.5, 3.5 Hz, 7H, 7 × H-2), 2.53 (dd, J = 2.3, 2.3 Hz, 7H, 7 × C≡CH),
2.42 (dd, J = 2.3, 2.3 Hz, 7H, 7 × C≡CH), 0.90 (s, 63H, 7 × TBDMS), 0.04
(d, 42H, 7 × TBDMS). m/z (HRMS MALDI-TOF) calcd for [C1175H336O28S7
+ Na]+ 3133.2805; found: 3133.2754.
Per-2,3-di-O-propargyl–-cyclodextrin (10)
Compound 9 (120 mg, 0.049 mmol) was dissolved in a mixture of CH2Cl2
– MeOH (2 : 1, 3 mL). After stirring for 5 min, a solution of HCl in MeOH
(prepared as previously reported, by adding concentrated HCl to MeOH
to obtain pH ~1) was added to the reaction until pH = 1-2, and the
progress of the reaction was monitored by TLC using a mixture of 25%
ethyl acetate in hexanes and a mixture of 17% MeOH in CH2Cl2. Once
Per-6-O-tert-butyldimethylsilyl-2,3-di-O-propargyl–-cyclodextrin (9)
To a solution of per-6-O-tert-butyldimethylsily--CD26-27 (4.4 g, 2.27
mmol) in anhydrous DMF (40 mL), NaH (60% in mineral oil, 2.55 g, 63.7
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the reaction was completed (~2.5 hr), the reaction mixture was
concentrated under reduced pressure. The solid residue was purified by
column chromatography on silica gel using a 1015% gradient of MeOH
CH2Cl2 as eluent to afford the desired compound 10 (74.2 mg, 92%). Rf
EtOAc : hexane to afford the monoazide intermediate (~ 4.212 g), which
was acetylated using a mixture of pyridine (8 mL) and acetic anhydride
(4.55 mL, 48 mmol) at 70 ˚C. After stirring for 7 hrs, the mixture was
evaporated to dryness under reduced pressure. The mixture was purified
by column chromatography on silica gel using a 5  10% gradient of
EtOAc - hexane) as the eluent to afford the desired compound 15 (5.01 g,
91% over 2 steps). Rf 0.20 (EtOAc : Hexane, 20:80). 1H NMR (400 MHz,
CDCl3) δ 4.18-4.13 (m, 2H, CH2-OAc), 3.68-3.64 (m, 2H, OCH2-c), 3.64-
1
0.38 (MeOH : CH2Cl2, 20 : 80). H NMR (400 MHz, CD3OD) δ 5.27 (d, J
= 3.6 Hz, 7H, 7 × H-1), 4.66 (dd, J = 15.3, 2.4 Hz, 7H, 7 × OCHa-C≡CH),
4.53 (dd, J = 15.3, 2.4 Hz, 7H, 7 × OCHb-C≡CH), 4.48 (d, J =2.4 Hz, 14H,
14 × OCHaHb-C≡CH), 3.96 (dd, J = 12.4, 3.6 Hz, 7H, 7 × H-6a), 3.92 –
3.70 (m, 28H, 7 × H-3, 7 × H-4, 7 × H-6b, 7 x H-5 ), 3.57 (dd, J = 9.4, 3.6
Hz, 7H, 7 x H-2), 2.89 (t, J = 2.4 Hz, 7H, 7 × C≡CH), 2.83 (t, J = 2.4 Hz,
7H, 7 × C≡CH).
3.61 (m, 2H, OCH2-d), 3.61-3.58 (m, 4H, 1 X OCH2-b, 1 X OCH -e), 3.32
2
(t, J = 5.2 Hz, 2H, N-CH2), 2.01 (s, 3H, Ac). 13C NMR (101 MHz, CDCl3) δ
170.86 C=O (OAc), 71.32 (CH2-OAc), 70.59 (OCH2), 70.54 (OCH2),
70.01 (OCH2), 63.47 (N3-CH2-CH2), 50.60 (N3-CH2), 20.81 (Ac).
Per-6-O-methanesulfonyl-2,3-di-O-propargyl--cyclodextrin (11)
2-(2-(2-(2-Hydroxyethoxy)ethoxy)ethoxy)ethyl acetate (17)
Compound 10 (78 mg, 0.047 mmol) was dissolved in a mixture of
anhydrous CH2Cl2 (2 mL) and anhydrous pyridine (0.1 mL). The solution
was then cooled to 0˚C, and MsCl (0.06 mL, 0.8 mmol, 17.5 equiv.) was
then added dropwise. The temperature of the reaction was then allowed
to rise gradually to room temperature. After stirring overnight, the mixture
was concentrated under reduced pressure. The crude mixture was
dissolved in CH2Cl2 (~100 mL), and the organic solution was washed
with a saturated solution of NaHCO3 (1 x 60mL) and brine (2 x 60 mL),
dried over anhydrous Na2SO4, evaporated under reduced pressure. The
crude product was purified by column chromatography on silica gel using
a 10  30% gradient of acetone – toluene as the eluent to afford the
desired compound 11 (94 mg, 91%). Rf 0.29 (EtOAc : Toluene, 20 : 80).
1H NMR (400 MHz, CDCl3) δH 5.28 (d, J = 3.7 Hz, 7H, 7 × H-1), 4.64 (dd,
J = 15.5, 2.4 Hz, 7H, 7 × Ha_Propargyl), 4.62 – 4.55 (m, 14H, 7 × H-6a, 7
× H-6b), 4.52 (dd, J = 15.5, 2.4 Hz, 7H, 7 × Hb_Propargyl), 4.48
(overlapped, 7H, 7 × Ha_Propargyl), 4.44 (dd, J = 16.4, 2.4 Hz, 7H, 7 ×
Hb_Propargyl), 3.97 (ddd, J = 9.8, 2.9, 2.9 Hz, 7H, 7 × H-5), 3.90 (dd, J =
8.8, 9.4 Hz, 7H, 7 × H-4), 3.75 (dd, J = 8.9, 9.7 Hz, 7H, 7 × H-3), 3.58 (dd,
J = 9.7, 3.6 Hz, 7H, 7 × H-2), 3.09 (s, 21H, 7 × OMs), 2.55 (t, J = 2.4 Hz,
7H, 7 × C≡CH), 2.53 (dd, J = 2.4 Hz, 7H, 7 × C≡CH).
A solution of tetraethyleneglycol (16, 2.25 g; 12 mmol) in anhydrous
pyridine (6 mL) and acetic anhydride (1.1 mL, 11.6 mmol) was stirred at
room temperature overnight. The mixture was concentrated under
reduced pressure and co-evaporated with toluene. The crude mixture
was purified by column chromatography on silica gel using a 10  25%
gradient of acetone – toluene as the eluent to afford the desired product
1
17 as a colorless oil (1.84 g, 67%). Rf 0.57 (acetone : toluene, 60:40). H
NMR (400 MHz, CDCl3) δ 4.20 (t, J = 4.8 Hz, 2H, CH2-OAc), 3.70 – 3.63
(m, 12H, 6 x CH2), 3.60 – 3.57 (m, 2H, CH2-OH), 2.71 (s, 1H, OH), 2.05
(s, 3H, OAc).
2-(2-(2-(2-Azidoethoxy)ethoxy)ethoxy)ethyl acetate (19)
Compound 17 (1.84 g, 0.008 mol) was dissolved in anhydrous CH2Cl2 (4
mL) and pyridine (0.02 mol, 1.89 mL); the reaction mixture was cooled to
0˚C, and MsCl (1.21 mL, 0.016 mol, 2 equiv.) was added dropwise. After
stirring overnight, the reaction mixture was concentrated under reduced
pressure, and the residue was purified by column chromatography on
silica gel using 3% MeOH – CH2Cl2 as the eluent to afford the desired
product (18) as a colorless oil (1.98 g, 81%), which was used directly for
the next step.
2-(2-Azidoethoxy)ethyl acetate (13)
To a solution of 2-(2-Chloroethoxyl)ethanol 12 (2.36 g, 18.9 mmol) in
anhydrous pyridine (12 mL), was added acetic anhydride (5.37 mL, 57
mmol, 3 equiv.), and the reaction was stirred overnight. The reaction
mixture was concentrated to dryness, and co-evaporated with toluene for
several times. The crude intermediate (~2.85 g) was dissolved in DMF
(20 mL), and NaN3 (4.93 g, 75.8 mmol, 4 equiv.) was added. After stirring
at 70 ˚C overnight, the mixture was diluted with CH2Cl2 (~ 250 mL),
washed with saturated brine (3 x 100 mL), the organic solution was
subsequently dried over anhydrous Na2SO4, and evaporated. The crude
mixture was purified by column chromatography on silica gel using a
mixture of 10% EtOAc – hexane as eluent to afford the desired
compound 13 as a colorless oil (1.82 g, 55% yield). Rf = 0.23 (EtOAc :
Hexane, 10 : 90). 1H NMR (400 MHz, CDCl3) 4.24-4.20 (m, 2H, CH2-
OAc), 3.75 (t, J = 6.1 Hz, 2H, OCH2), 3.73-3.69 (m, 2H, OCH2), 3.62 (t, J
= 6.1 Hz, 2H, N-CH2), 2.07 (s, 3H, Ac). 13C NMR (101 MHz, CDCl3) δ
170.86 C=O (OAc), 72.30 (CH2-OAc), 69.93 (OCH2), 63.03 (OCH2),
50.52 N-CH2, 20.77 (Ac).
To a solution of compound 18 (2.98 g, 9.5 mmol) in DMF (5 mL), was
added NaN3 (1.23 g, 18.9 mmol, 2.0 equiv.), and the reaction was stirred
at 70˚C overnight. The reaction mixture was concentrated under reduced
pressure. The crude mixture was worked up as above and purified by
column chromatography on silica gel using a 10  15% gradient of
acetone – hexane as the eluent. The desired product 19 (2.13 g) was
isolated as a colorless oil in 86% yield. Rf 0.49 (Acetone : Hexane, 30:70).
1H NMR (400 MHz, CDCl3) δH 4.14 (t, J = 4.8 Hz, 2H, CH2-OAc), 3.64-
3.57 (m, 12H, 6 × OCH2), 3.31 (t, J = 5.1 Hz, 2H, N-CH2), 2.00 (s, 3H,
Ac). 13C NMR (101 MHz, CDCl3) δ 170.74 C=O (OAc), 70.89-70.27
(OCH2), 69.82 (OCH2), 68.88 (OCH2), 63.39 (N3-CH2-CH2), 50.48 (N3-
CH2), 20.62 (Ac).
Compound (20)
To a solution of heptamesylate 11 (120 mg; 0.05 mmol) in acetone (2.5
mL), was added monoazide 13 (0.197 g, 1.1 mmol, 21 equiv.) DIPEA (20
µL, 0.015 mmol; 0.3 equiv.) and CuI (20 mg, 0.11mmol, 0.14 eq); the
reaction was heated to 65 C under argon overnight. More monoazide 13
(0.09 g, 0.5 mmol, 9.8 equiv.), DIPEA (20 µL, 0.015 mmol, 0.3 eq) and
CuI (20 mg, 0.1 mmol, 0.002eq) were added, and the reaction was
continued for another 6 hrs under at the same temperature. The reaction
mixture was concentrated under reduced pressure. The solid residue
was partitioned between ethyl acetate (125 mL) and 10% aqueous EDTA
(2 x 50 mL) solution for 30 min. The organic layer was separated, dried
over anhydrous Na2SO4 and evaporated. The crude mixture was purified
2-(2-(2-Azidoethoxy)ethoxy)ethyl acetate (15)
To a solution of 2-(2-(2-chloroethoxy)ethoxy)ethanol (14, 4.64 g; 27.6
mmol) in anhydrous DMF (20 mL), was added NaN3 (3.58 g, 55.2 mmol,
2 equiv.), and the mixture was heated to 70 ˚C overnight. The crude
mixture was diluted with CH2Cl2 (~ 125 mL), washed with saturated brine
(2 x 100 mL), dried over anhydrous Na2SO4, and evaporated. The crude
mixture was purified by column chromatography using a mixture of 15%
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by column chromatography on silica gel using a 1.5  5% gradient of
MeOH – CH2Cl2 as the eluent. The desired product 20 was isolated as a
white foam (211 mg, 84% yield). Rf 0.35 (MeOH : CH2Cl2, 5 : 95). [α]D=
NMR (100 MHz, CDCl3) δc 171.0 (x 14, C=O), 145.1 (x 7, triazole),
144.2 (x 7, triazole), 124.8 (x 7, triazole), 124.4 (x 7, triazole), 98.7 (x 7,
C-1), 80.6 (x 7, C-3), 78.9 (x 7, C-4), 78.2 (x 7, C-2), 70.5-70.3 (x 28,
OCH2), 69.6 (x 7, C-5), 69.1-69.4 (x 49, OCH2, N-CH2-b, C-6), 67.2 (x 7,
CH2-triazole), 64.3 (x 7, CH2-triazole), 63.5 (x 14, CH2-OAc), 49.9 (x 7, N-
CH2), 49.8 (x 7, N-CH2), 37.1 (x 7, Ms), 21.0 (x 14, OAc). m/z (HRMS
MALDI-TOF) calcd for [C231H378N42O119S7 + 2H]2+: 2935.1504, found:
2935.1303.
1
14.23 (c 5.2, CH2Cl2). H NMR (400 MHz, CDCl3) δH 8.06 (s, 7H, 7 × H
triazole), 7.94 (s, 7H, 7 × H triazole), 5.22-5.13 (m, 14H, 7 × OCHaHb-
triazole, 7 × H-1), 4.91-4.73 (m, 21H, 21 × OCHaHb-triazole), 4.64 – 4.57
(m, 14H, 7 × H-6a, 7 × H-6b), 4.54 (t, J = 5.0 Hz, 14H, 7 × N-CH2), 4.48 (t,
J = 5.4 Hz, 14H, 7 × N-CH2), 4.19-4.11 (m, 28H, 14 × CH2-OAc), 4.06 –
3.94 (m, 14H, 7 × H-5, 7 × H-3), 3.91 (t, J = 5.2 Hz, 14H, 7 × CH2-b), 3.85
(t, J = 5.1 Hz, 14H, 7 × CH2-b), 3.71 – 3.56 (m, 35H, 7 × H-4, 28 × OCH2),
3.54 (dd, J = 9.5, 2.5 Hz, 7H, 7 × H-2), 3.10 (s, 21H, 7 × Ms), 2.04 (s,
42H, 14 × OAc). 13C NMR (100 MHz, CDCl3) δc 170.93 (x 14, C=O),
145.10 (x 7, triazole), 144.21 (x 7, triazole), 124.81 (x 7, triazole), 124.43
(x 7, triazole), 98.65 (x 7, C-1), 80.58 (x 7, C-3), 78.91 (x 7, C-4), 78.27 (x
7, C-2), 70.37 (x 21, OCH2), 69.52 (x 7, C-5), 69.23 (x 7, CH2-b1), 69.16
(x 7, CH2-b2), 68.95 (x 35, OCH2, N-CH2-b, C-6), 67.73 (x 7, CH2-
triazole), 64.39 (x 7, CH2-triazole), 63.23 (x 14, CH2-OAc), 49.89 (x 7, N-
CH2), 49.78 (x 7, N-CH2), 37.21 (x 7, Mes), 20.82 (x 14, OAc). m/z
(HRMS MALDI-TOF) calcd for [C175H266N42O91S7 + 2H]2+: 2318.7834,
found: 2318.7709.
Compound (6)
Compound 20 (12 mg, 0.003 mmol) was dissolved DMF (0.5 mL) under
argon. To this solution, was added Cs2CO3 (24 mg, 0.073 mmol), n-
C18H37SH (26 mg, 0.091 mmol); the mixture was then heated overnight at
75 ˚C. The reaction mixture was then evaporated to dryness under
reduced pressure. The residue was dissolved in CH2Cl2, and filtered off
by column chromatography on silica gel using 5% MeOH - CH2Cl2 as the
eluent. The fractions containing partially de-O-acetylated products
(charred with 5% H2SO4 on TLC) were pooled and evaporated to
dryness. The mixture was reacetylated using a mixture of pyridine (0.6
mL) and acetic anhydride (0.5 mL) at 60˚C for 1 hour. The reaction
mixture was evaporated to dryness under reduced pressure again. The
residue was purified by column chromatography on silica gel using a 3 
5% gradient of MeOH – CH2Cl2 as the eluent to afford the pure product 6
(12 mg, 77% yield) as a clear wax. Rf 0.37 (MeOH : CH2Cl2, 6 : 94). [α]D
18 (c 8.0, CH2Cl2). 1H NMR (400 MHz, CDCl3) δH 8.02 (s, 7H, 7 ×
H_triazole), 7.98 (s, 7H, 7 × H_triazole), 5.24 (d, J = 2.9 Hz, 7H, 7 × H-1),
5.20 (d, J = 11.0 Hz, 7H, 7 × OCHaHb-triazole), 4.87 (d, J = 12.4 Hz, 7H,
7 × OCHaHb-triazole) 4.80 (d, J = 10.7 Hz, 7H, 7 × OCHaHb-triazole),
4.77 (d, J =12.0 Hz, 7H, 7 × OCHaHb-triazole) 4.56 – 4.47 (m, 14H, 7 ×
N-CH2), 4.45 (t, J = 5.4 Hz, 14H, 7 × N-CH2), 4.21-4.10 (m, 28H, 14 ×
CH2-OAc), 4.06 – 4.00 (m, 7H, 7 × H-5), 3.97 - 3.75 (m, 42H, 14 × OCH2,
7 × H-3, 7 × H-4), 3.69 – 3.56 (m, 28H, 14 × OCH2), 3.52 (m, 7H, 7 × H-
2), 3.23-3.00 (m, 14H, 7 × H-6a, 7 × H-6b), 2.58 (t, J = 7.4 Hz, 14H, 7 ×
S-CH2_octadecyl), 2.04 (s, 42H, 14 × OAc), 1.58 (m, 14H, 7 ×
SCH2CH2_octadecyl), 1.32-1.25 (m, 210H, 105 × CH2_octadecyl), 0.90 (t,
J = 6.9 Hz, 21H, 7 × CH3_octadecyl). 13C NMR (100 MHz, CDCl3) δC
170.79 (C=O), 145.10 (triazole), 145.32 (triazole), 144.75 (triazole),
124.86 (triazole), 124.42 (triazole), 98.25 (C-1), 81.46 (C-4), 80.92 (C-3),
78.27 (C-2), 71.76 (C-5), 69.18 (OCH2), 69.14 (OCH2), 68.92 (O-CH2),
67.32 (OCH2-triazole), 64.35 (OCH2-triazole), 63.23 (CH2-OAc), 49.75
(N-CH2), 49.65 (N-CH2), 34.33 (C-6), 34.07 (S-CH2), 29.32-31.98
(CH2_octadecyl), 22.29 (CH2_octadecyl), 20.85 (OAc), 14.10
(CH3_octadecyl). m/z (HRMS MALDI-TOF) calcd for [C294H504N42O70S7 +
2H]2+: 2984.7680, found: 2984.7654.
Compound (21)
Compound 21 was obtained similarly as 20 using heptamesylate 11 (120
mg; 0.05 mmol), monoazide 15 (0.27 g 1.26 mmol), DIPEA (20 µL, 1.9
mmol), CuI (20 mg) at 65 C. The pure product 21 (265 mg, 0.050 mmol)
was isolated in 93% yield by column chromatography on silica gel using
a 3  6% gradient of MeOH – CH2Cl2 as the eluent. Rf 0.35 (MeOH :
CH2Cl2, 10 : 90). [α]D = 17.95 (c 3.9, CH2Cl2). 1H NMR (400 MHz, CDCl3)
δ 8.05 (s, 7H, 7 × H triazole), 7.93 (s, 7H, 7 × H triazole), 5.19 (d, J =
11.4 Hz, 7H, 7 × OCHaHb-triazole), 5.15 (d, J = 3.4 Hz, 7H, 7 × H-1),
4.88-4.74 (m, 21H, 21 × OCHaHb-triazole), 4.62 – 4.56 (m, 14H, 7 × H-
6a, 7 x H-6b), 4.54 (t, J = 5.6 Hz, 14H, 7 × N-CH2), 4.48 (t, J = 5.4 Hz,
14H, 7 × N-CH2), 4.23-4.16 (m, 28H, 14 × CH2-OAc), 4.04 – 3.98 (m, 7H,
7 × H-5), 3.98 – 3.94 (m, 7H, 7 × H-3), 3.91 (t, J = 5.7 Hz, 14H, 7 × CH2-
b), 3.86 (t, J = 5.4 Hz, 14H, 7 × CH2-b), 3.71 – 3.56 (m, 91H, 7 x H-4, 14
x CH2-c, 14 × CH2-d, 14 × CH2-e), 3.54 (dd, J = 9.7, 3.4 Hz, 7H, 7 × H-2),
3.09 (s, 21H, 7 × Ms), 2.07 (s, 42H, 14 × OAc). 13C NMR (100 MHz,
CDCl3) δc 170.93 (14 x C=O), 145.11 (7 x C-quaternary-triazol), 144.22
(7 x C-quaternary-triazole), 124.79 (7 x CH-triazol), 124.44 (7 x CH-
triazol), 98.65 ( 7 x C-1), 80.58 ( 7 x C-3), 78.91 (7 x C-4), 78.27 (7 x C-2),
70.37 (21 x OCH2), 69.58 (7 x C-5), 69.05 (21 x OCH2, 14 x N-CH2-b, 7
x C-6), 67.30 (7 x CH2-beside-triazole), 64.30 (7 x CH2-beside-triazole),
63.49 (14 x CH2-OAc), 49,96 (7 x N-CH2), 49.83(7 x N-CH2), 37.13(7 x
Mes), 20.63(14
x CH3(OAc)). m/z (HRMS MALDI-TOF) calcd for
[C203H322N42O105S7 + 3H]3+: 1751.6470, found: 1751.6397.
Compound (7)
Compound (22)
Compound 21 (47 mg; 0.009 mmol) was reacted with Cs2CO3 (61 mg,
0.19 mmol), n-C18H37SH (17 mg, 0.058 mmol) in a mixture of DMF (0.25
mL) and THF (0.25 mL) as compound 6. The partially O-deacetylated
intermediates were isolated and reacetylated as above using pyridine
(0.6 mL) and Ac2O (0.5 mL) at 60˚C for 1 hr and after evaporation, the
reaction mixture was purified by column chromatography on silica gel
using a 3  5% gradient of MeOH – CH2Cl2 as the eluent. The pure
product 7 (57.2 mg) was isolated as a clear wax in 97% yield. Rf 0.42
Compound 22 was obtained similarly as 20 using heptamesylate 11 (96
mg; 0.04 mmol), monoazide 19 (0.32 g 1.9 mmol), DIPEA (20 µL, 1.9
mmol), CuI (20 mg, 0.11 mmol, 0.17 equiv.) at 55 C. The pure product
22 (194 mg, 0.033 mmol) was isolated in 76% yield by column
chromatography on silica gel using a 2  5% gradient of MeOH – CH2Cl2
as the eluent. Rf 0.3 (MeOH: CH2Cl2, 5: 95). [α]D = 12.0 (c 9, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δH 8.05 (s, 7H, 7 × H_triazole), 7.91 (s, 7H, 7 ×
H_triazole), 5.18 (d, J = 11.0 Hz, 7H, 7 × OCHaHb-triazole), 5.13 (d, J =
2.9 Hz, 7H, 7 × H-1), 4.83 (m, 14H, 14 × OCHaHb-triazole), 4.76 (d, J =
12.7 Hz, 7H, 7 × OCHaHb-triazole) 4.62 – 4.55 (m, 14H, 7 × H-6a, 7 × H-
6b), 4.53 (t, J = 5.4 Hz, 14H, 7 × N-CH2), 4.47 (t, J = 5.3 Hz, 14H, 7 × N-
CH2), 4.24 - 4.19 (m, 28H, 14 × CH2-OAc), 4.06 – 3.95 (m, 7 × H-5, 7H),
3.96 – 3.89 (m, 21H, 7 × H-3, 7 × OCH2), 3.86 (t, J = 5.4 Hz, 21H, 7 ×
OCH2), 3.71 – 3.56 (m, 147H, 7 × H-4, 70 x OCH2), 3.53 (dd, J = 9.7, 2.9
Hz, 7H, 7 × H-2), 3.09 (s, 21H, 7 × Ms), 2.07 (s, 42H, 14 × OAc). 13C
1
(MeOH : CH2Cl2, 8 : 92). [α]D = 13.6 (c 2.4, CH2Cl2). H NMR (400 MHz,
CDCl3): δ 8.02 (s, 7H, 7 × H_triazole), 7.99 (s, 7H, 7 × H_triazole), 5.31-
5.10 (m, 14H, 7 × H-1, 7 × OCHaHb-triazole), 4.87 (d, J = 12.4 Hz, 7H, 7
× OCHaHb-triazole) 4.80 (d, J = 10.7 Hz, 7H, 7 × OCHaHb-triazole), 4.92
- 4.73 (m, 21H, 21 × OCHaHb-triazole) 4.57– 4.48 (m, 14H, 7 × N-CH2),
4.45 (t, J = 5.3 Hz, 14H, 7 × N-CH2), 4.22 - 4.16 (m, 28H, 14 × CH2-OAc),
4.06 – 4.00 (m, 7H, 7 × H-5), 3.96 - 3.91 (m, 7H, 7 × H-3), 3.91 - 3.83 (m,
28H, 14 × OCH2), 3.78 (dd, J = 8.8, 8.8 Hz, 7H, 7 × H-4), 3.69 – 3.62 (m,
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28H, 14 × OCH2), 3.62 - 3.54 (m, 28H, 28 × OCH2), 3.52 (dd, J = 9.6,
3.1 Hz, 7H, 7 × H-2), 3.22 - 2.97 (m, 14H, 7 × H-6a, 7 × H-6b), 2.58 (t, J
= 7.3 Hz, 14H, 7 × S-CH2_octadecyl), 2.07 (s, 42H, 14 × OAc), 1.62 -
1.52 (m, 14H, 7 × SCH2CH2_octadecyl), 1.32 - 1.25 (m, 210H, 105 ×
CH2_octadecyl), 0.94 (t, J = 6.7 Hz, 21H, 7 × CH3_octadecyl). 13C NMR
(100 MHz, CDCl3): δC 170.9 (C=O), 145.3 (triazole), 144.7 (triazole),
124.8 (triazole), 124.4 (triazole), 98.3 (C-1), 81.5 (C-4), 81.0 (C-3), 79.0
(C-2), 71.7 (C-5), 70.3 - 70.5 (OCH2), 69.4 (OCH2), 69.3 (OCH2), 69.1
(OCH2), 69.1 (N-CH2), 67.2 (OCH2-triazole), 64.3 (OCH2-triazole), 63.2
(CH2-OAc), 49.9 (N-CH2), 49.8 (N-CH2), 34.3 (C-6), 34.1 (S-CH2), 29.3 -
31.9 (CH2_octadecyl), 22.7 (CH2_octadecyl), 20.9 (OAc), 14.1
(CH3_octadecyl). m/z (HRMS MALDI-TOF) calcd for [C322H560N42O84S7 +
3H]3+ calc.: 2195.6368, found: 2195.6204.
intensity peak, unless otherwise noted. Only peaks with greater than 1%
intensity in the low angle region were analysed.
Molecular Modelling
The three dimensional coordinates of the β-CD scaffold were taken from
its crystal structure29 and modified using Insight II/Builder module to
obtain the molecular model of compounds 6-8. The atomic potentials and
partial charges of the three molecules were assigned using the CVFF
forcefield and their geometries were subsequently minimized within
Insight II/Discover module using the Steepest Descent algorithm
(maximum RMS derivative = 0.1 kcal/Å; ε=1).
Compound (8)
Acknowledgements
Compound 8 was prepared from compound 22 (16 mg; 0.0027 mmol)
Cs2CO3 (12.4 mg, 0.04 mmol;), n-C18H37SH (11 mg, 0.040 mmol) in DMF
(1.5 mL) at 60 ˚C as compound 6. The partially O-deacetylated
intermediates were isolated by column chromatography (1  5% MeOH
– CH2Cl2) and reacetylated at 60 ˚C for 1 hr using a mixture of pyridine
(0.6 mL) and acetic anhydride (0.5 mL) as above. The pure product 8
(15.8 mg) was isolated as a clear wax in 82% yield by column
chromatography using a 1  5% gradient. Rf 0.42 (MeOH : CH2Cl2, 8 :
92). [α]D +26.4 (c 2.4, CH2Cl2). 1H NMR (400 MHz, CDCl3): δH 8.01 (s, 7H,
7 × H_triazole), 8.00 (s, 7H, 7 × H_triazole), 5.23 (d, J = 9.6 Hz, 7H, 7 ×
OCHaHb-triazole), 5.13 (d, J = 2.6 Hz, 7H, 7 × H-1), 4.89 - 4.73 (m, 21H,
7 × OCHaHb-triazole, 14 × OCHaHb-triazole), 4.51 (t, J = 5.5 Hz, 14H, 7
× N-CH2), 4.45 (t, J = 5.5 Hz, 14H, 7 × N-CH2), 4.24 - 4.20 (m, 28H, 14 ×
CH2-OAc), 4.05 – 3.99 (m, 7H, 7 × H-5), 3.94 – 3.84 (m, 35H, 7 × H-3, 14
× OCH2), 3.77 (dd, J = 8.6, 8.6 Hz, 7H, 7 × H-4), 3.71 – 3.67 (m, 28H, 14
× OCH2), 3.66 - 3.54 (m, 112H, 56 × OCH2), 3.52 (dd, J = 9.7, 3.0 Hz, 7H,
7 × H-2), 3.14 (dd, J = 12.4, <1 Hz, 7H, 7 × H-6a), 3.07 (dd, J = 12.5, <1
Hz, 7H, 7 × H-6b), 3.09 (s, 21H, 7 × OMs), 2.57 (t, J = 7.4 Hz, 14H, 7 ×
S-CH2_octadecyl), 2.08 (s, 42H, 14 × OAc), 1.58 (m, 14H, 7 ×
SCH2CH2_octadecyl), 1.33 - 1.24 (m, 210H, 105 × CH2_octadecyl), 0.90
(t, J = 6.7 Hz, 21H, 7 × CH3_octadecyl). 13C NMR (100 MHz, CDCl3): δC
170.9 (C=O), 145.2 (triazole), 144.6 (triazole), 124.8 (triazole), 124.4
(triazole), 98.3 (C-1), 81.5 (C-4), 80.9 (C-3), 79.0 (C-2), 71.7 (C-5), 70.5
(OCH2), 70.4 (OCH2), 70.4 (OCH2), 69.4 (OCH2), 69.3 (OCH2), 69.1 (N-
CH2), 67.2 (OCH2-triazole), 64.2 (OCH2-triazole), 63.6 (CH2OAc), 49.9
(N-CH2), 49.8 (N-CH2), 34.3 (C-6), 34.1 (S-CH2_octadecyl), 29.19 - 31.93
We are grateful to Dr. Ping Zhang for recording all the HRMS of
compounds reported in this work and for her insightful advice, to
Dr. Thomas Baumgartner for the use of the TGA Q50
thermogravimetric analysis instrument. The financial support
from Alberta Innovates – Technology Futures, the Natural
Sciences and Engineering Research Council of Canada, and the
University of Calgary are greatly acknowledged.
Keywords: Cyclodextrin • Liquid Crystal • Dipole-dipole
interactions • Supramolecular self-assembly • Oligoethylene
glycol
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A novel concept to design amphiphilic
cyclodextrin (CD)-based liquid crystals
is reported. The new CD derivatives
bear O-acetylated oligoethylene glycol
chains at the secondary face and
thioalkyl groups at the primary face
and self-assemble into highly ordered
smectic liquid crystal phases with
much improved properties via the
weaker dipole-dipole interactions.
Pier-Luc Champagne,[a] David Ester,[b]
Sandra Ward,[c] Vance E. Williams[b] and
Chang-Chun Ling[a]*
First Family of Amphiphilic
Cyclodextrin Liquid Crystals Drived
By Dipole-Dipole Interactions
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