A crystal-to-crystal synthesis of triazolyl-linked polysaccharide

Article abstract of DOI:10.1002/anie.201303372

Crystal sweets: Polysaccharide synthesis is hampered by many factors. These problems can be circumvented by the crystal-to-crystal azide-alkyne cycloaddition polymerization of an unprotected monosaccharide, which gives a crystalline glycopolymer regiospecifically in quantitative yield. Copyright

Full text of DOI:10.1002/anie.201303372

Angewandte
Chemie
Communications
Non-Natural Polysaccharides
A. Pathigoolla,
K. M. Sureshan*
&&&& — &&&&
A Crystal-to-Crystal Synthesis of Triazolyl-
Linked Polysaccharide
Crystal sweets: Polysaccharide synthesis
is hampered by many factors. These
problems can be circumvented by the
crystal-to-crystal azide–alkyne cycloaddi-
tion polymerization of an unprotected
monosaccharide, which give a crystalline
glycopolymer regiospecifically in quanti-
tative yield.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
DOI: 10.1002/anie.201303372
Non-Natural Polysaccharides
A Crystal-to-Crystal Synthesis of Triazolyl-Linked Polysaccharide**
Atchutarao Pathigoolla and Kana M. Sureshan*
Dedicated to Professor K. N. Ganesh on his 60th Birthday
Polysaccharides find application in many fields, such as foods,
cosmetics, medicine, materials, chromatography, and tissue
engineering.[1] As natural polysaccharides are prone to
enzymatic degradation by microorganisms,[2] glycopolymers
with non-natural linkages[3] are also of tremendous interest
because of their enzymatic and chemical stability and
improved properties. Hence there is considerable interest in
the synthesis of both natural polysaccharides and non-natural
glycopolymers. Both chemical synthesis[4] and in vitro enzy-
matic synthesis[5] have been adopted for such glycopolymer
Figure 1. A) 1D hydrogen-bonded zigzag arrangement in crystal structures of pyranose derivatives with 2,3-diequatorial diol. B) Viewed along the
chain axis. C) Proposed arrangement of sugar derivatives with CRMs and their topochemical reaction.
synthesis. The lack of enzymes for polymerization of wide
range of natural and non-natural sugars, the high substrate
specificity and poor stability of enzymes, low yield, slow rate
of the reaction, and precipitation of the oligomers before
complete polymerization are major limitations of in vitro
enzymatic polymerization. Concerns regarding conventional
chemical synthesis arise from low yield, poor control over the
stereo- and regioselectivity, polydispersity, the requirement of
toxic catalysts, necessity of laborious protecting-group manip-
ulations,[6] and difficult purification of the polymer. A high
yielding method for the synthesis of stereoregular polymers
which avoids catalyst, solvents, protecting groups, and purifi-
cation is desirable.
[*] A. Pathigoolla, Prof. Dr. K. M. Sureshan
School of Chemistry, Indian Institute of Science Education and
Research Thiruvananthapuram, CET-Campus
Thiruvananthapuram-695016 (India)
E-mail: kms@iisertvm.ac.in
Homepage: http://iisertvm.ac.in/scientists/kana-m-sureshan/per-
sonal-information.html
[**] A.P. thanks CSIR-India for Senior Research Fellowship assistance.
K.M.S. thanks the Department of Science and Technology (DST,
India) for a Ramanujan Fellowship. This work was made possible by
financial support from DST and CSIR.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303372.
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
Topochemical polymerization, proximity driven polymer-
ization in a crystal lattice,[7] offers a solvent-free and catalyst-
free method for making crystalline polymers[8] of high order,
stereocontrol, and homogeneity. However, there are only
a limited class of compounds, such as diynes,[7b,8a,9] triynes,[10]
dienes,[11] trienes,[12] dienoic acid derivatives[13] and quinodi-
methane derivatives,[8d,14] known to undergo topochemical
polymerization. This limit is due to the difficulty in designing
a crystal satisfying the stringent geometrical requirements for
the reacting partners in the crystal lattice. We have reported
a serendipitous observation of a lattice controlled azide–
alkyne cycloaddition in a fully protected sugar derivative
giving a heterogeneous mixture of 1,5-triazolyl connected
oligosaccharides.[15] This discovery has prompted us to
design a topochemical polymerization of an unpro-
tected monosaccharide based on crystal engineering
principles. We envisioned that a monosaccharide suit-
ably substituted with azide and alkyne motifs, two
complimentary reactive motifs (CRMs), if crystallized
in such a way that the CRMs of adjacent molecules
orient proximally, would react topochemically to yield
a polysaccharide analogue in a highly selective and
efficient manner. Herein we report the first design and
synthesis of a 1,4-triazolyl-linked polysaccharide (pol-
ytriazolyl saccharide; PTS) through a crystal-to-crystal
topochemical azide–alkyne dipolar cycloaddition.
The crystals of 1 (m.p. 1318C) were very stable under
ambient conditions for several months. However, a sample
kept at 708C for 24 h underwent azide–alkyne cycloaddition
to produce traces of triazole product as evidenced from its
1H NMR spectrum (see Supporting Information). At higher
temperatures, the reaction was very facile and complete in
a few hours. The solubility, in DMSO, of the product formed
decreased with increased heating temperature for the same
time. For instance, while the crystals kept at 908C for 4 h were
completely soluble in DMSO, the crystals kept at 1008C for
4 h were completely insoluble. Also, at a particular temper-
ature, the sample heated for longer time was less soluble than
the sample heated for a shorter time. These behaviors suggest
Pyranosides with 2,3-diequatorial diol motifs show
1D hydrogen-bonded zigzag arrangement in their
crystals (Figure 1A, also see Supporting Informa-
tion).[16] Such an arrangement places C1 and C4
perpendicular to the hydrogen-bonded chain axis. We
reasoned that if azide and alkyne are introduced at C1
and C4, then they might assemble and orient prox-
imally, forming a chain in a direction perpendicular to
the H-bonded chain (Figure 1C) as they can have
À
attractive interactions, such as p–p stacking or C
H···N hydrogen bonding,[15,17] which might facilitate
1,3-dipolar cycloaddition between them.
We have synthesized compound 1 (Figure 2A,B) in
nine steps from d-(+)-galactose (see Supporting
Information). In the crystal structure, compound
1 adopted the usual 4C1 conformation for the pyranose
ring with gt conformation for the hydroxymethyl
group. The intermolecular hydrogen bonding by 2-
OH and 3-OH result in the formation of hydrogen
bonded zigzag assembly along the “a” direction as
anticipated (Figure 2C). The 6-OH also forms a hydro-
gen bond with O5 of a neighboring molecule, resulting
in the formation of helical assembly in the “a”
direction. This hydrogen bond connects the zigzag
assemblies along the “b” direction. As anticipated,
p···p interactions between azide and alkyne motifs
connect the molecules along the “c” direction in
a wave-like topology (Figure 2D). The alkyne and
Figure 2. A) Structural formula and B) ORTEP diagram of monomer 1. C) Pack-
ing along the “ab” plane. The green dotted zigzag lines represent the hydrogen
azide functional groups are arranged proximally with
an average separation of 3.29 ꢀ in a parallel orienta-
tion similar to the transition-state arrangement for
their 1,3-dipolar cycloaddition to form 1,4-disubsti-
tuted triazole (Figure 2E).
À
À
bonds, O2 H2’···O3 and O3 H3’···O2, along the “a” direction. Pink dotted
À
lines represent the O6 H6’···O5 hydrogen-bonded helical assembly. D) The
p···p interaction between azide and alkyne along the “c” direction. E) Close-up
view of the interaction between the azide and alkyne.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
we have solved the structure of the
polymer 2 by single-crystal XRD. The
X-ray diffraction pattern of the polymer
2 was very sharp and clear, similar to
that of monomer 1. It is noteworthy that
the crystal structure could be refined to
a very good R-Factor (2.98) suggestive
of the highly homogeneous nature of
the polymer in the crystal. Interestingly,
the space group of the polymer was
same (P212121) as that of the monomer
1. The polymerization resulted in slight
change of unit cell parameters. While
“a” (4.718 ꢀ in 1 and 4.954 ꢀ in 2) and
“b” (12.423 ꢀ in 1 and 12.899 ꢀ in 2)
increased slightly, “c” (19.626 ꢀ in
1 and 16.128 ꢀ in 2) decreased consid-
erably leading to a reduction in cell
volume and
a concomitant 11.7%
increase in density. A comparison of
the crystal structures of the monomer
1 and the polymer 2 revealed that major
positional changes, after polymeri-
zation, are in the “c” direction (see
Supporting Information). This change
could be due to the formation of
covalent linkages at the expense of
Figure 3. Comparison of the 1H NMR and 13C NMR spectra of monomer 1 with polymer 2.
that the crystals of 1 undergo topochemical polymerization
and the degree of polymerization increases with time and
temperature.
noncovalent interactions along this direction.
4
Sugar units in their normal C1 conformation are con-
nected through the 1,4-triazolyl moiety along the “c”
direction forming polymeric chains. The polymer chain
adopts a right-handed helical conformation in the crystals in
which each sugar unit is cork-screwed 1808 relative to its
neighbor. Though the crystal structure of galactan, the natural
polymer of d-galactose, has not been reported to date,
modeling studies predicted a right-handed helical structure
for b(1,4)-d-galactan.[20] The one dimensional zigzag hydro-
gen-bonded arrangement along “a” direction, as observed in
monomer 1, is also conserved in the polymer 2. While in the
monomer 1, two hydroxy groups are involved in forming two
The progress of the reaction was monitored by IR and
1H NMR spectroscopy. While the IR spectrum of the
monomer 1 showed a sharp signal at 2130 cmÀ1 from the
azide stretching, the azide signal has almost disappeared in
the IR spectrum of a sample kept at 908C for 12 h or 1008C
for 1 h (see Supporting Information). The 1H NMR spectra of
the heated sample also showed the absence of the signals
arising from monomer 1 (e.g. H-1 at d = 4.41 ppm) and the
presence of the triazolyl proton signal (d = 8.22 ppm). The
1H NMR and 13C NMR spectra of the polymer were very
clear, with distinct signals for each proton and carbon atom of
the repeating unit, suggestive of the formation of higher
polymers of uniform size (Figure 3). Structural assignment
using various NMR techniques revealed the presence of only
1,4-triazolyl linkages between the sugar units (see Supporting
Information). This regiospecificity is due to the topochemical
control of the polymerization. Note that uncatalyzed thermal
reactions in solution lead to non-selective cycloaddition
forming a heterogeneous mixture of products, but CuI
catalyzed reactions in solution lead to the formation of
a mixture of 1,4-triazolyl-linked cyclic oligomers (see Sup-
porting Information).
À
À
parallel extended hydrogen bonded (O2 H2’···O3 and O3
À
H3’···O2) zigzag chains, only a single hydrogen bond (O3
H3’···O3) between neighboring sugar units of adjacent
polymer chains is involved in the zigzag arrangement in the
polymer 2 (Figure 4). Also, it is interesting to note that both
O2–H2’ and O3–H3’ change their H-bond acceptor partners
after the polymerization. While the O3–H3’ changes its
partner from O2 to O3, the O2–H2’ changes its acceptor
partner from O3 to N3 in the polymer (Figure 5). The gt
conformation of the hydroxymethyl group is maintained in
the polymer too, which allows interchain hydrogen bonds
between O6–H6’ and O5 of a sugar unit in the adjacent chain.
To correlate structure and properties and to aid the design
of better properties, it is necessary to have high-quality solid-
state structures of polymers. However, the structural charac-
terization of both natural and synthetic polysaccharides is
a formidable challenge because of their amorphous nature
and difficulty in their crystallization from a heterogeneous
mixture. Only very few crystal structures of polysaccharides
The products of many topochemical polymerizations are
either amorphous or microcrystalline which does not allow
structural determination through single-crystal X-ray diffrac-
tion (XRD).[18] There are very few examples for which the
structure of polymer could be solved by single-crystal
XRD.[8a,9c,12,19] As the crystal morphology was preserved in
our case, even after polymerization (kept for 5 h at 1008C),
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
(cellulose and chitin) are known and they are not well
resolved structures (R factor over 18).[21] Our crystal
structure is the only high quality (more reliable)
structure of a glycopolymer available to date with an R
factor of 2.98. In the crystal structure of natural
polysaccharides such as cellulose and chitin there are
intramolecular hydrogen bonds between adjacent
sugar units across the glycosidic linkages.[1e,21] How-
ever, the large spatial separation arising from the long
triazolylmethyloxy linker between sugar units in our
case prevents any such intramolecular noncovalent
interaction between sugar units. But all the hydroxy
groups are involved in interchain hydrogen bonds,
which are absent in natural polysaccharides.[1e] Each
polymeric chain is in noncovalent interaction with six
other chains leading to a close-packed arrangement.
Thermogravimetric analysis revealed that the polymer
2 has high thermal stability, similar to that of natural
polysaccharides (see Supporting Information).
In conclusion, exploiting the unique mode of
arrangement of a class of pyranose derivatives and
by applying crystal-engineering principles, we could
topochemically prepare
a
highly homogeneous,
enzyme stable, crystalline glycopolymer regiospecifi-
cally in its crystal in quantitative yield without using
solvents, catalysts, or protecting groups. This is an
important development as conventional solution-
phase synthesis leads to a heterogeneous mixture of
polymers as a result of uncontrolled, non-selective,
irregular, and incomplete polymerization. This is the
first successful synthesis of a stereoregular polysac-
charide analogue (poly1,4-triazolyl b-galactose) by
topochemical polymerization of an unprotected mon-
osaccharide,
b-1-azido-4-O-propargyl-d-galactose.
This is also the first crystal-to-crystal transformation
involving azide–alkyne 1,3-dipolar cycloaddition.
While the head-to-tail arrangement of the monomer
in the crystal lattice facilitated polymer formation,
orientation of the alkyne and azide motifs in the
crystal dictated the regiochemistry. The availability of
three hydroxy groups per monomer and the presence
of an alkyne and an azide motif at either of the termini
of each polymer chain might allow chemical modifi-
Figure 4. A) Structural formula and B) ORTEP diagram of the polymer 2.
C) Packing in the “ab” plane. The green zigzag dotted line represents the
hydrogen bonding along the “a” direction. Pink dotted lines represent the O6
H6’···O5 hydrogen-bonded helical assembly. D) The triazole-linked polymer
aligned along the “c” direction. The triazole motifs are highlighted as a ball and
stick model.
À
cation of this polymer to make several functional polymers.
Received: April 21, 2013
Revised: May 14, 2013
Published online: && &&, &&&&
Keywords: azide–alkyne cycloaddition · polymerization ·
.
polysaccharides · topochemical reactions
[1] a) S. Dumitriu, Polysaccharides: Structural Diversity and Func-
tional Versatility, 2nd ed., Marcel Dekker, New York, 2005;
b) “Polysaccharides I: Structure, Characterization and Use”: T.
Heinze, Advances in Polymer Science, Vol. 186, Springer, Berlin,
2005; c) D. Klemm, B. Philipp, T. Heinze, U. Heinze, W.
Wagenknecht, Comprehensive Cellulose Chemistry, Vol. 1 and
2, 1st ed., Wiley-VCH, Weinheim, 1998; d) Y. Habibi, L. A.
Figure 5. Prominent noncovalent lattice interactions before (A) and
after (B) the topochemical reaction.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Lucia, O. J. Rojas, Chem. Rev. 2010, 110, 3479; e) D. Klemm, B.
Heublein, H.-P. Fink, A. Bohn, Angew. Chem. 2005, 117, 3422;
Angew. Chem. Int. Ed. 2005, 44, 3358.
[10] a) J. Xiao, M. Yamg, J. W. Lauher, F. W. Fowler, Angew. Chem.
2000, 112, 2216; Angew. Chem. Int. Ed. 2000, 39, 2132; b) R. Xu,
W. B. Schweizer, H. Frauenrath, Chem. Eur. J. 2009, 15, 9105.
[11] a) M. Hasegawa, Chem. Rev. 1983, 83, 507; b) S. Nagahama, T.
Tanaka, A. Matsumoto, Angew. Chem. 2004, 116, 3899; Angew.
Chem. Int. Ed. 2004, 43, 3811.
[2] S. B. Leschine, Annu. Rev. Microbiol. 1995, 49, 399.
[3] E. L. Dane, M. W. Grinstaff, J. Am. Chem. Soc. 2012, 134, 16255.
[4] M. Metzke, J. Z. Bai, Z. Guan, J. Am. Chem. Soc. 2003, 125,
7760.
[5] S. Kobayashi, J. Sakamoto, S. Kimura, Prog. Polym. Sci. 2001, 26,
1525.
[12] T. Hoang, J. W. Lauher, F. W. Fowler, J. Am. Chem. Soc. 2002,
124, 10656.
[13] a) A. Matsumoto, K. Sada, K. Tashiro, M. Miyata, T. Tsubouchi,
T. Tanaka, T. Odani, S. Nagahama, T. Tanaka, K. Inoue, S.
Saragai, S. Nakamoto, Angew. Chem. 2002, 114, 2612; Angew.
Chem. Int. Ed. 2002, 41, 2502; b) S. Oshita, A. Matsumoto,
Chem. Eur. J. 2006, 12, 2139.
[14] a) T. Itoh, T. Suzuki, T. Uno, M. Kubo, N. Tohnai, M. Miyata,
Angew. Chem. 2011, 123, 2301; Angew. Chem. Int. Ed. 2011, 50,
2253; b) T. Itoh, S. Nomura, T. Uno, M. Kubo, K. Sada, M,
Miyata, Angew. Chem. 2002, 114, 4482; Angew. Chem. Int. Ed.
2002, 41, 4306.
[6] J. Kadokawa, Chem. Rev. 2011, 111, 4308.
[7] a) G. J. M. Schmidt, Pure Appl. Chem. 1971, 27, 647; b) J. W.
Lauher, F. W. Fowler, N. S. Goroff, Acc. Chem. Res. 2008, 41,
1215; c) M. A. Garcia-Garibay, Acc. Chem. Res. 2003, 36, 491;
d) V. Ramamurthy, K. Venkatesan, Chem. Rev. 1987, 87, 433;
e) K. Tanaka, F. Toda, Chem. Rev. 2000, 100, 1025; f) J. N.
Gamlin, R. Jones, M. Leibovitch, B. Patrick, J. R. Scheffer, J.
Trotter, Acc. Chem. Res. 1996, 29, 203; g) K. Biradha, R. Santra,
Chem. Soc. Rev. 2013, 42, 950.
[8] a) T.-J. Hsu, F. W. Fowler, J. W. Lauher, J. Am. Chem. Soc. 2012,
134, 142; b) H. Zepik, E. Shavit, M. Tang, T. R. Jenesen, K.
Kjaer, G. Bolbach, L. Leiserowitz, I. Weissbuch, M. Lahav,
Science 2002, 295, 1266; c) J. G. Nery, G. Bolbach, I. Weissbuch,
M. Lahav, Angew. Chem. 2003, 115, 2207; Angew. Chem. Int. Ed.
2003, 42, 2157; d) S. Nomura, T. Itoh, M. Ohtake, T. Uno, M.
Kubo, A. Kajiwara, K. Sada, M. Miyata, Angew. Chem. 2003,
115, 5626; Angew. Chem. Int. Ed. 2003, 42, 5468.
[15] A. Pathigoolla, R. G. Gonnade, K. M. Sureshan, Angew. Chem.
2012, 124, 4438; Angew. Chem. Int. Ed. 2012, 51, 4362.
[16] a) H. Wehlan, M. Dauber, M.-T. M. Fernaud, J. Schuppan, R.
Mahrwald, B. Ziemer, M.-E. J. Garcia, U. Koert, Angew. Chem.
2004, 116, 4698; Angew. Chem. Int. Ed. 2004, 43, 4597; b) R.
Luboradzki, O. Gronwald, M. Ikeda, S. Shinkai, D. N. Rein-
houdt, Tetrahedron 2000, 56, 9595; c) L. Jessen, E. T. K. Haupt, J.
Heck, Chem. Eur. J. 2001, 7, 3791.
[9] a) G. Wegner, Makromol. Chem. 1972, 154, 35; b) G. Wegner,
Pure Appl. Chem. 1977, 49, 443; c) A. Sun, J. W. Lauher, N. S.
Goroff, Science 2006, 312, 1030; d) R. Xu, W. B. Schweizer, H.
Frauenrath, J. Am. Chem. Soc. 2008, 130, 11437; e) R. Xu, V.
Gramlich, H. Frauenrath, J. Am. Chem. Soc. 2006, 128, 5541;
f) E. Jahnke, I. Lieberwirth, N. Severin, J. P. Rabe, H. Frauen-
rath, Angew. Chem. 2006, 118, 5510; Angew. Chem. Int. Ed. 2006,
45, 5383; g) Z. Li, F. W. Fowler, J. W. Lauher, J. Am. Chem. Soc.
2009, 131, 634; h) Y. Xu, M. D. Smith, M. F. Geer, P. J. Pellechia,
J. C. Brown, A. C. Wibowo, L. S. Shimizu, J. Am. Chem. Soc.
2010, 132, 5334; i) T. N. Hoheisel, S. Schrettl, R. Marty, T. K.
Todorova, C. Corminboeu, A. Sienkiewicz, R. Scopelliti, W. B.
Schweizer, H. Frauenrath, Nat. Chem. 2013, 5, 327.
[17] B. P. Krishnan, S. Ramakrishnan, K. M. Sureshan, Chem.
Commun. 2013, 49, 1494.
[18] F. Guo, J. Martꢁ-Rujas, Z. Pan, C. E. Hughes, K. D. M. Harris, J.
Phys. Chem. C 2008, 112, 19793.
[19] X. Ouyang, F. W. Fowler, J. W. Lauher, J. Am. Chem. Soc. 2003,
125, 12400.
[20] C. Ryttersgaard, L. L. Leggio, P. M. Countinho, B. Henrissat, S.
Larsen, Biochemistry 2002, 41, 15135.
[21] a) Y. Nishiyama, J. Sugiyama, H. Chanzy, P. Langan, J. Am.
Chem. Soc. 2003, 125, 14300; b) Y. Nishiyama, P. Langan, H.
Chanzy, J. Am. Chem. Soc. 2002, 124, 9074; c) M. N. V.
Ravikumar, R. A. A. Muzzarelli, C. Muzzarelli, H. Sashiwa,
A. J. Domb, Chem. Rev. 2004, 104, 6017.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!