Crystal-to-Crystal Synthesis of Helically Ordered Polymers of Trehalose by Topochemical Polymerization

Article abstract of DOI:10.1002/anie.201914164

The synthesis of crystalline helical polymers of trehalose via topochemical azide–alkyne cycloaddition (TAAC) of a trehalose-based monomer is presented. An unsymmetrical trehalose derivative having azide and alkyne crystallizes in two different forms havi

Full text of DOI:10.1002/anie.201914164

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Accepted Article
Title: Crystal-to-crystal synthesis of helically ordered polymers of
trehalose via topochemical polymerization
Authors: Kana M Sureshan, Kuntrapakam Hema, and Rajesh G
Gonnade
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914164
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10.1002/anie.201914164
Angewandte Chemie International Edition
RESEARCH ARTICLE
Crystal-to-crystal synthesis of helically ordered polymers of
trehalose via topochemical polymerization
Kuntrapakam Hema,[a] Rajesh G. Gonnade,[b] and Kana M. Sureshan*[a]
Abstract: We describe the synthesis of crystalline helical polymers
of trehalose via topochemical azide-alkyne cycloaddition (TAAC) of a
trehalose-based monomer. An unsymmetrical trehalose derivative
having azide and alkyne crystallizes in two different forms having
almost similar packing; Form I, from ethyl acetate/n-hexane and form
II, from chloroform/n-hexane. In form I, the alkyne group is
disordered over two distant positions; A and B. When the alkyne is
at position B, molecules form a head-to-tail arrangement with an
orientation suitable for their TAAC reaction to yield the polymer.
However, in form II the chloroform molecules occupy the position B
and thus block the reactive orientation. Upon heating, both the
crystals undergo TAAC reaction to form crystalline polymers.
Various studies revealed that form II releases the chloroform
molecules upon heating, which makes the position B accessible for
the alkyne and thus to react. Powder X-ray diffraction (PXRD)
studies revealed that the monomers in both the crystals polymerize
in a crystal-to-crystal fashion and Circular Dichroism (CD) studies of
the product crystals revealed that the formed polymer is helically
ordered. This solvent-free, catalyst-free polymerization method that
eliminates the tedious purification of the polymeric product
exemplifies the advantage of topochemical polymerization reaction
over traditional solution-phase polymerization.
polymers having pendant trehalose units have been synthesized
(Figure 1a) and these trehalosylated polymers have been shown
to stabilize proteins against various stresses4 and prevent
aggregation of amyloid beta.5 Co-polymers containing trehalose
Introduction
Monosaccharides are structurally unique molecules possessing
a pro-electrophilic hemiacetal group and several nucleophilic
hydroxyl groups. Due to the presence of these mutually
complimentary functionalities, monosaccharides can undergo
enzymatic homopolymerization via iterative glycosylation to form
specific polysaccharides possessing wide-ranging biological
functions and interesting material properties.1 The glycosylation
connects two monosaccharides through a glycosidic bond
between the anomeric carbon and another carbon and the
disaccharide thus formed undergoes further sequential
glycosylation to form the polysaccharide. However, when the
monosaccharides are connected through two anomeric carbons,
there is no possibility of chain growth beyond dimer. α,α-
Trehalose is such a symmetrical disaccharide found in nature
and is known to possess remarkable properties.2 For instance,
α,α-trehalose is known to prevent aggregation, fusion, and lysis
of lipid membranes and proteins.3 Hence there is much interest
in the synthesis of trehalose-based polymers.4-9 Several
Figure 1. Different categories of trehalose-containing polymers. a) Polymers
having pendant trehalose units. b) Co-polymers of trehalose and another co-
monomer. c) Trehalose-main chain polymer from an unsymmetrical monomer.
units in the backbone have also been synthesized (Figure 1b) by
the copolymerization of a symmetrically functionalized trehalose-
based monomer with a co-monomer having complimentary
reacting group and these trehalose copolymers have been used
for nucleic acid delivery.6-8 However, there is no report on
[a]
[b]
K. Hema, K. M. Sureshan
School of Chemistry
Indian Institute of Science Education and Research
Thiruvananthapuram
Kerala 695551, India
polymerization of
a
single trehalose-derived monomer
unsymmetrically substituted with two complimentary reactive
groups to give trehalose-backbone polymers. Here we report a
crystal-to-crystal synthesis of a trehalose-based polymer via the
topochemical polymerization of a trehalose-derived monomer
unsymmetrically substituted with two complementary reacting
motifs (Figure 1c).
E-mail: kms@iisertvm.ac.in
R. G. Gonnade
Physics and Materials Chemistry Division
National Chemical Laboratory
Pune 411008, India
RGG contributed to this paper by refining the crystal structures
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The main issues associated with the chemical synthesis of
glycopolymers are (i) the difficult purification of the product from
byproducts and other impurities, (ii) tedious removal of metal-
based catalysts due to their complexation or entrapment in the
polymer matrix, (iii) premature cessation of polymerization due
to precipitation (iv) requirement of large amount of solvents for
reaction and purification.10 Topochemical reactions, the crystal-
state reaction between two proximally-placed reacting groups,
have received much attention due to their high yield,
regiospecificity, ability to yield products that are not attainable by
solution-phase synthesis and non-requirement of catalysts,
solvents, purification etc.11 There are several examples of
topochemical polymerization, wherein a monomer has been
converted to the polymer in the crystal state.12 We have
developed topochemical azide-alkyne cycloaddition (TAAC)
polymerization for the synthesis of various biopolymer mimics.13
When monomers substituted with azide and alkyne motifs are
aligned, in their crystals, in head-to-tail fashion and with proximal
placement of the azide and alkyne groups, they undergo 1,3-
dipolar cycloaddition reaction to form triazole-linked polymers.
We planned to use this strategy for the synthesis of trehalose-
based polymers (Figure 1c).
crystallization from a solution of mixture of ethyl acetate and n-
hexane (2:1; v/v) yielded long rod-shaped crystals (form I),
crystallization from a mixture of chloroform and n-hexane (2:1;
v/v) gave rectangular blocks (form II). As their morphologies
were different, we made a comparative analysis by recording
their melting points, differential scanning calorimetry (DSC)
profiles, powder X-ray diffraction (PXRD) and thermogravimetric
analysis (TGA). While form I showed a m.p. of 119-120 oC, form
o
II melted in the range 123-125 C. The DSC profiles of each of
these two crystals showed an endothermic peak ascribable to
the heat of melting followed by broad exothermic peak
presumably due to the heat liberated in the azide-alkyne
cycloaddition reaction in the molten state (Figure 2c). The
o
o
endothermic peaks at 119 C and 125 C in the case of form I
and form II respectively matched with their melting points
determined using a melting point apparatus. PXRD patterns of
both the crystals were found to be different, confirming that
these two crystals are two different crystal forms (Figure 2d).
Results and Discussion
We have synthesized an unsymmetrically substituted trehalose-
derivative (1; Scheme 1) from trehalose,14 wherein the primary
hydroxyl positions were modified with alkyne and azide
functionalities, for TAAC polymerization (Scheme S1, SI).
Compound 1 gave crystals of different morphologies when
crystallized from different solvent systems (Figure 2b). While
Scheme 1. Synthesis of the monomer 1. a) MsCl, pyr, 0 oC, 67%; b) NaN3,
DMF, 80 oC, 87%; c) Propargyl bromide, NaH, DMF, 0 oC, 85%; d) i. CAN,
acetonitrile: H2O (4:1); ii. Ac2O, pyr, 82%.
Figure 2. a) Chemical structure of the unsymmetrically substituted trehalose-
derivative 1. b) Photographs of the crystals obtained from ethyl acetate/n-
hexane (form I) and chloroform/n-hexane (form II). Comparison of: c) DSC; d)
PXRD and e) TGA profiles of form I (black) and form II (red).
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10.1002/anie.201914164
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Interestingly, the TGA of form II exhibited a weight loss of 12%
in the temperature of window 100-125 oC while that of form I did
We have determined the melting points of the crystals kept at 90
oC for different durations. The melting points of both the crystal
forms gradually reduced with time for the first 36 h (Figure 4c)
and crystals heated for more than 36h did not melt but charred
at very
o
1
not show any weight loss until 300 C (Figure 2e). The H NMR
spectrum of crystals of form II (obtained from chloroform and n-
hexane) taken in DMSO-d6 displayed the peak corresponding to
chloroform at 8.32 ppm implying the presence of chloroform in
these crystals (Figure S1, SI).
To get further structural insights, single crystal X-ray analyses
were carried out for these crystals. Both the crystals adopted
orthorhombic P212121 space group (Table S1, SI). While the
asymmetric unit of form I showed a single molecule of 1, the
asymmetric unit of form II contained one molecule of chloroform
along with a molecule of 1. Careful analysis of these crystal
structures revealed that the molecular packing is similar except
for the presence of chloroform in one of the crystals (Figure 3).
Thus form II is a solvate of form I. Several non-covalent
interactions such as C-H…O, C-H…N and C-H…π hydrogen
bondings were found to stabilize the molecular packing in both
the forms (Table S2, SI).
In both the forms, both the azide and alkyne groups exhibited
positional disorders (Figure S3, SI). However, in form I, the
propargyl group switched between two distant positions; position
A and position B with an occupancy ratio of 0.65:0.35 (Figure
3a). Interestingly, when the propargyl group is in position A,
there is no probability for the TAAC reaction to happen. When it
is in position B, the reactive alkyne and azide groups are
proximal (showed in dashed lines, Figure 3a) and are parallel to
each other for the TAAC reaction to proceed along a-direction
connecting the disaccharide molecules in zig-zag fashion (along
the pink arrow, Figure 3a). In form II, a molecule of chloroform
occupies the position B (Figure 3b) and this prevents the
attainment of proximal arrangement of azide and alkyne groups
for the TAAC reaction to proceed. We have previously observed
that many crystals having azide and alkyne groups at proximity
and in reactive orientation can undergo spontaneous TAAC
reaction even at room temperature.15,13e In this context, the
temporary prevention of attaining the reactive arrangement by
the guest (chloroform) molecules is beneficial for long-time
storage of the crystals in the unreactive state.
Figure 3. Crystal packing shows similar molecular arrangements in form I and
form II. The azide and alkyne groups are represented in ball and stick model.
a) Crystal packing of form I showing the partial occupancy of alkyne at
positions A and B; when alkyne is at position B, the crystal is in a reactive
configuration. Plausible TAAC polymerization path, along a-direction, is shown
in pink arrow. b) Molecular packing in form II showing chloroform trapped in
position B.
The crystals of both the forms were stable at room temperature
o
(35 C) for several months. In order to investigate the thermal
reactivity of these crystals at higher temperatures, we have
o
heated them at 90 C, far below their melting points. To monitor
the progress of the reactions, small fractions of these crystals
1
were withdrawn at different intervals and analyzed by H NMR
spectroscopy after dissolving in CDCl3 (Figure 4a and Figure 4b).
From 24 h onwards, we observed the gradual appearance of
new peaks corresponding to the triazole-linked products in the
1H NMR spectra of both the forms. This time-dependent 1H NMR
spectroscopy analyses revealed the gradual disappearance of
the alkyne C-H signal (2.34 ppm) and concomitant amplification
of triazole C-H signals (7.50-7.69 ppm) suggesting gradual
azide-alkyne cycloaddition in the crystals.
high temperatures. This gradual decrease in the melting point is
due to the gradual formation of oligomeric products in the parent
monomer crystal. Small amounts of products initially formed act
as impurity in the parent crystal and hence shows this colligative
property (depression in melting point). As the time progresses,
larger and larger polymers are formed and this is the reason for
the non-melting of crystals kept at 90 oC for more than 36h.
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Figure 4. (a, b) Time-dependent 1H NMR (CDCl3) showing TAAC reaction in the crystals of form I (a) and form II (b). c) Decrease in the melting points of crystals
of form I (black) and form II (red). (d, e) Time-dependent DSC during TAAC reaction of form I (d) and form II (e). f) Comparison of PXRD profiles of form I, form II
and crystals of form II after heating at 75 oC.
Solid-state FTIR spectra of both form I and form II showed the
azide stretching signal at 2108 cm-1. Time-dependent FTIR
spectroscopy revealed the gradual reduction in the intensity of
this signal with time suggesting the gradual consumption of
azide groups due to its participation in the cycloaddition reaction
(Figure S4, SI). Furthermore, time-dependent DSC analyses of
both form I and form II, showed gradual decrease in the intensity
of exothermic peak due to the azide-alkyne cycloaddition
reaction in the melt (Figure 4d and Figure 4e). This indicates the
gradual depletion of free azide and alkyne groups with progress
of time, which in turn implies the progress of azide-alkyne
cycloaddition reaction in the crystals with time.
kinetics as expected of a topochemical reaction (Figure S5, SI).
The topochemical reaction of form II implies that, upon heating,
chloroform escapes from the crystals providing free space for
the propargyl group to reach position B. Accordingly, the TGA
o
analysis of the form II crystals heated for 36 h at 90 C showed
no weight loss confirming the escape of chloroform (Figure S6,
SI). Additionally, we have heated the crystals of form II at 75 oC
for 24 h, by which time the chloroform molecules escaped
completely as was evident from its 1H NMR spectrum. The
heated single crystal undergoes cracking along with the
desolvation, which makes it unsuitable for SCXRD analysis.
However, unit cell determination of a small piece of this cracked
crystal revealed cell parameters identical to that of form-I (SI,
section 19). In addition, the PXRD profile of these heated
The complete conversion of both forms of the monomer 1 to the
corresponding polymers took place within 96 h of heating
(Figure 4). These solid-state reactions clearly followed sigmoidal
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crystals matched with that of form I implying the conversion of
form II to form I upon loss of chloroform (Figure 4f).
Figure 5. (a, b) Time-dependent PXRD profiles of form I (a) and form II (b). (c, d) Photographs of crystals before and after TAAC reaction of form I (c) and form II
(d). (e, f) MALDI-TOF mass spectra of the polymers obtained from form I (e) and form II (f).
Furthermore, we probed the crystallinity of form I and form II
during the course of the solid-state reaction by using time-
dependent PXRD. The gradual conversion of monomer crystal
to product crystal was evident from the gradual disappearance
of peaks due to monomers (especially the major peak) and the
concomittant appearance and growth of new peaks. We
observed that at every stage of the reaction, the crystallinity was
maintained in both the forms proving that the reactions
happened under topochemical control (Figure 5a and Figure 5b)
and are crystal-to-crystal reactions. However, crystals of both
form I and form II developed cracks during the TAAC reaction
and were unsuitable for the SCXRD analysis (Figure 5c and
Figure 5d). However, the transparency of the crystals was
unaffected. The excessive movement of the reactive groups to
undergo TAAC reaction could be the reason for the cracking of
crystals.
The polymers obtained were found to be soluble in several
organic solvents such as chloroform, ethylacetate, acetone,
DMF, DMSO and acetonitrile. MALDI-TOF analyses of the
products obtained from form I and form II revealed the presence
of large oligomers upto 25-mers (Figure 5e and Figure 5f). Gel
permeation chromatography (GPC) analysis showed average
molecular weights of 7,327 g/mol and 6,870 g/mol for polymers
formed from form I and form II respectively (Figure S11, SI).
The solid state CD spectrum of TAAC products (in KBr, Figure
6) obtained from both form I and form II showed the signatures
for the presence of helicity. Solid-state CD spectra of polymers,
obtained from form I and form II, showed negative cotton effect
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at around 220 nm with shoulder at 215 nm. This implies that
both the TAAC products adopt helical orientation in the solid-
states. However, the random polymer made by dissolving the
TAAC product in dichloromethane followed by evaporation
showed no regular shape (Figure S13, SI). This clearly shows
the importance of topochemical reaction in dictating the packing
of the polymers. The polymers have been found to have helical
nature in solution (Figure S14, SI).
Keywords: Click reaction • Helical polymer • Polysaccharide •
Topochemical reaction • Trehalose
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Acknowledgements
KMS thank the Department of Science and Technology (DST)
for a SwarnaJayanti Fellowship.
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10.1002/anie.201914164
Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
Crystal-to-crystal synthesis of
helical polymers of trehalose
via topochemical azide-alkyne
cycloaddition (TAAC) reaction
of a monomer is discussed.
This solvent-free, catalyst-free
polymerization method that
Kutrapakam Hema, Rajesh G.
Gonnade, Kana M. Sureshan*
Crystal-to-crystal
synthesis
of helically ordered polymers
of trehalose via topochemical
polymerization
eliminates
the
tedious
purification steps exemplifies
the elegance of topochemical
polymerization reaction over
traditional
solution-phase
polymerization.
This article is protected by copyright. All rights reserved.