Topochemical click reaction: Spontaneous self-stitching of a monosaccharide to linear oligomers through lattice-controlled azide-alkyne cycloaddition

Article abstract of DOI:10.1002/anie.201201023

No activation needed: A topochemical click reaction that dispenses with catalyst, solvent, or other modes of activation takes place in crystals of a sugar derivative. The spontaneous, regiospecific azide-alkyne cycloaddition gives linear polymers that are difficult to synthesize by conventional solution-state chemistry (see picture). Copyright

Full text of DOI:10.1002/anie.201201023

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DOI: 10.1002/anie.201201023
Click Polymerization
Topochemical Click Reaction: Spontaneous Self-Stitching of
a Monosaccharide to Linear Oligomers through Lattice-Controlled
Azide–Alkyne Cycloaddition**
Atchutarao Pathigoolla, Rajesh G. Gonnade, and Kana M. Sureshan*
Dedicated to Professor Yutaka Watanabe
The
copper(I)-catalyzed
azide–alkyne
cycloaddition
tion of a terminal alkyne and an azide to give the 1,4-
substituted triazole in high yield[5] is recognized as “the cream
of the crop” among click reactions. Ru-catalyzed azide–
alkyne cycloaddition (RuAAC) is an important complemen-
tary method to CuAAC for regiospecific synthesis of 1,5-
substituted triazoles.[6] Though azide and alkyne are spring-
loaded, high-energy compounds and their cycloaddition is
thermodynamically favorable with relatively large driving
force (DG8 ꢀ À61 kcalmolÀ1), they do not react spontane-
ously simply by mixing due to the high energy barrier
(activation energy DG ꢀ+ 26 kcalmolÀ1).[7] Catalysts essen-
tially facilitate the formation of a transition state either by
reducing the activation energy through electronic reorganiza-
tion and/or by bringing the reactants into close proximity.
Encapsulation in a constrained space[8] or cavity can also
facilitate proximity and transition-state-like arrangement.
Entrapping azide and alkyne partners in a host cavity is
known to turn an otherwise nonspecific uncatalyzed cyclo-
addition into a regiospecific one.[9] Similarly, co-localization
of pharmacophore fragments with azide and alkyne function-
alities in enzyme cavities has been exploited for target-guided
synthesis of high affinity inhibitors of these enzymes.[10]
In our attempt to synthesize d-galactose-based triazole-
linked cyclodextrin analogues, freshly prepared monomer
1 (Figure 1A, see Supporting Information Scheme S1) under
standard CuAAC conditions gave a mixture of cyclodimer,
cyclotrimer, cyclotetramer, and higher cyclic oligomers.
However an aged crystalline sample of 1 did not give any of
these products and was also found to be insoluble in the
reaction solvent (THF) and other common organic solvents
(chloroform, ethyl acetate, acetonitrile, toluene). Interest-
ingly, a freshly prepared and crystallized sample and aged
crystals were morphologically indistinguishable (Figure 1B
and C). Comparison of a freshly made sample with an aged
sample by TLC revealed that the aged sample is chemically
inhomogeneous, containing several polar compounds (Fig-
ure 1D). Identical morphology but chemical inhomogeneity
is suggestive of some spontaneous topochemical reaction, that
is, chemical transformation controlled by the crystal lattice.[11]
Chromatographic separation of the aged sample (15 d at
room temperature) gave dimer 2 ( ꢀ 30%), trimer 3 ( ꢀ 7%),
and an inseparable mixture of higher oligomers ( ꢀ 60%).
HRMS and IR spectral analyses of major product 2 (see
Supporting Information Figure S1 and Figure 1F) suggested
that it is a linear dimer of 1 with at least one free alkyne and
one free azide group. A detailed structural analysis by
(CuAAC) click reaction is unarguably the most simple,
efficient, and general technique for linking two molecules
with the highest regiospecificity and atom economy.[1] The
power of CuAAC to make tailor-made functional materials or
conjugates has not only revolutionized chemistry and other
branches of science, such as life sciences and materials
science, but also continues to offer practicable solutions to
exciting problems in various disciplines of science.[2] Concerns
regarding the toxicity of copper in biological systems moti-
vated researchers to develop elegant catalyst-free azide–
alkyne click reactions.[3] However, a perfectly green click
system would be one which reacts regiospecifically without
catalyst, solvent, or other modes of activation. We now report
lattice-controlled spontaneous topochemical azide–alkyne
click oligomerization of a sugar derivative with azide and
alkyne functionalities to give linear polymers (pseudos-
tarches) in a regiospecific manner in the crystal, which are
otherwise difficult to synthesize by conventional solution-
state chemistry. This report on a “perfectly green” click
reaction in the crystal will pave the way for research towards
other topochemical click reactions.
“Click chemistry” refers to high-yielding modular chem-
ical reactions of wide scope and high regiospecificity, giving
inoffensive byproducts under simple reaction conditions.[4]
The copper(I)-catalyzed regiospecific 1,3-dipolar cycloaddi-
[*] A. Pathigoolla, Prof. Dr. K. M. Sureshan
School of Chemistry, Indian Institute of Science Education and
Research, Thiruvananthapuram
CET campus, Trivandrum-695016 (India)
E-mail: kms@iisertvm.ac.in
Homepage: http://iisertvm.ac.in/scientists/kana-m-sureshan/per-
sonal-information.html
Dr. R. G. Gonnade
Center for Material Characterization, National Chemical Laboratory
Pune, Pashan road, Pune-411008 (India)
[**] The authors thank Dr. Vinesh Vijayan for useful discussions
regarding NMR. National Institute for Interdisciplinary Science and
Technology, Trivandrum is thanked for their help in PXRD experi-
ments. A.P. thanks Council of Scientific and Industrial Research
(CSIR) for a Junior Research Fellowship assistance. K.M.S. thanks
Department of Science and Technology (DST, India) for a Ramanu-
jan 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.201201023.
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oligomers (both cyclic and
linear oligomers) with nonuni-
form (both 1,4- and 1,5-) tri-
azole linkages.
Interestingly solutions of
1 in common organic solvents
(DMF, THF, DCM, CHCl3,
ethyl acetate) were stable for
months, and chemically homo-
geneous 1 could be obtained by
evaporation. Usually the crys-
talline state is considered to be
more stable, and crystallization
is
a method of purification.
However, crystalline 1 is unsta-
ble and hence reacts spontane-
ously in a topochemical manner
to give products in the crystal.
This suggests that the reacting
alkyne and azide groups are
probably trapped in
a local
“transition-state-like” arrange-
ment in the crystal, which facil-
itates regiospecific cycloaddi-
tion.
Interestingly, the Cu-cata-
lyzed solution-phase reaction
of 1 gives cyclic products with
1,4-triazolyl linkage, while the
uncatalyzed spontaneous reac-
tion in the crystal gives linear
oligomers with 1,5-triazolyl
linkage in a highly regiospecific
manner (Figure 2). Though sev-
eral triazole-linked cyclodextrin
analogues have been synthe-
Figure 1. A) Structure of 1. B) Photograph of a freshly made and crystallized sample of 1. C) Photograph
of crystals of 1 aged for 40 d. D) TLC comparison of freshly made and aged samples of 1. E) MALDI-TOF
spectrum of an aged crystalline sample of 1 showing m/z peaks due to dimer to pentadecamer. F) IR
spectral comparison of freshly made 1 (I), linear dimer (II), and aged sample of 1 (III).
1H NMR, 13C NMR, DEPT, COSY, NOESY, HMQC, and
HMBC spectroscopy revealed that 2 has a 1,5-triazolyl
linkage, as shown in Figure 2A (see Supporting Information
Section 7 for details).
sized by CuAAC reaction of monomers in solution, formation
of linear polymer was not reported in any of these cases.[12]
Formation of linear oligomers in the crystals of 1 suggests that
the monomers are arranged in head-to-tail fashion in the
crystal and, since the molecular motion is restricted in the
crystal, they polymerize linearly in a topochemical manner to
give linear polymers (Figure 2B).
Differential scanning calorimetric (DSC) analysis of
a freshly crystallized sample of 1 showed a melting point of
85.48C, in accordance with that determined with a melting
point apparatus. Continued heating of this molten sample up
to 2508C resulted in a broad exothermic peak between 100
and 2208C, suggestive of the uncontrolled thermal cyclo-
addition reaction in the melt (Figure 3A). This explains the
very broad and unresolved signals in the 1H NMR spectrum of
a sample kept at a temperature above its melting point (vide
supra). The DSC analyses of crystalline samples of 1 kept at
room temperature for different time periods revealed gradual
reaction in the crystals. As time progressed the melting point
shifted to lower temperatures, presumably due to depression
of the melting point by the presence of increasing amounts of
oligomers. FTIR monitoring of this topochemical reaction
The MALDI-TOF MS of an aged crystalline sample
(Figure 1E) showed a mixture of oligomers ranging from
dimer to pentadecamer, suggestive of click polymerization in
the crystalline state. Despite the presence of many oligomers
in an aged crystalline sample, its 1H NMR spectrum was
surprisingly simple, clear, and well resolved (see Supporting
Information Figure S7). This suggests that the triazole linkage
is isomerically uniform (only 1,5 isomer) in all oligomers and
at each triazolyl unit in a given oligomer. This is due to highly
regiospecific cycloaddition controlled by the crystal lattice. A
similar uniform pattern was observed when a fresh sample of
1 was heated at 708C (below its melting point) for 24 h (see
Supporting Information Figure S8). However, sudden melting
of a pure sample of 1 followed by continued heating of the
melt resulted in formation of heterogeneous oligomers
showing very broad and unresolved peaks (see Supporting
1
Information Figure S9) in the H NMR spectrum. This could
be due to the uncontrolled and nonspecific thermal cyclo-
addition in the molten state giving rise to heterogeneous
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showed gradual disappearance of alkynic
hydrogen and azide signals with time, as
expected.
To establish the topochemical nature of
this reaction, it was followed by powder (P)
XRD at regular intervals (Figure 3B and
Supporting Information Section 10).
A
ground crystalline sample of 1 was made
and kept at room temperature, and its
PXRD pattern recorded at regular inter-
vals for four weeks, by which time most of
the starting material was converted to
oligomers. Well-resolved sharp peaks were
seen throughout this time period with
gradual appearance of new peaks and
disappearance/shift of some of the peaks
of the starting material. This confirms
preservation of the crystalline state even
after the reaction, an important criterion
for topochemical reaction.
To correlate the solid-state reactivity
with the molecular arrangement, crystal
structure analysis of monomer 1 was car-
ried out (Figure 4). Molecules in crystals of
1 assemble in a head-to-tail fashion to form
a helix around the crystallographic two-
fold screw axis (b axis) through
Figure 2. A) Spontaneous regiospecific oligomerization of 1 in the crystal. B) Schematic
representation of the reactions in solution and in the crystal.
À
À
À
weak C H···O, C H···N, and C
H···p hydrogen bonds. This
assembly brings the reactive
alkyne and azide groups of adja-
cent molecules in a helix into
close proximity with a preorgan-
ized transition-state-like geom-
etry in a cavity in the crystal
matrix (Figure 4A), as antici-
pated. Interestingly, both of
these motifs are held in this
parallel orientation by two
weak hydrogen bonds (one
CH···N and one CH···O) from
another neighboring molecule
of an adjacent helix (Fig-
ure 4B). While C6H6A···N3A
holds the azide, C9H9···O6
holds the alkyne group. These
weak hydrogen bonds connect
helices together to provide
a well-guided “reaction chan-
nel” throughout the crystal lat-
tice. The involvement of these
two weak hydrogen bonds in
driving the reaction by preor-
ganizing the two reacting groups
tightly in a transition-state-like
orientation is very interesting.
The approach of the terminal
alkyne carbon atom to the ter-
minal azide nitrogen atom in the
Figure 3. A) DSC plot of 1 at 30 min (I), 24 h (II), 48 h (III), and 78 h (IV). B) PXRD monitoring of the
topochemical reaction at room temperature, showing sharp peaks even after the reaction. C) 1H NMR
monitoring of topochemical click reaction at 508C.
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Though the philosophy of click chemistry overlaps with green
chemistry principles, a perfectly green click reaction will be
the one that avoids the use of catalysts, solvents, or other
means of activation. In this context, a topochemical click
reaction is even more attractive as it is also simple and
proceeds spontaneously. We hope this report will allure
researchers to explore design of topochemical click reactions.
Experimental Section
Crystal data of 1: CCDC 860868 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif. C30H31N3O5, M = 513.58, colorless
needle, 0.19 ꢀ 0.04 ꢀ 0.02 mm, monoclinic, space group P21, a =
10.514(5), b = 8.482(4), c = 15.238(7) ꢁ, b = 101.595(8)8, V=
1331.1(10) ꢁ3,
Z = 2,
T= 100(2) K,
2qmax = 50.008,
1calcd =
1.281 gcmÀ3, F(000) = 544, m = 0.088 mmÀ1, 9356 reflections collected,
4580 unique reflections (Rint = 0.0356), multiscan absorption correc-
tion, Tmin = 0.983, Tmax = 0.998, 394 parameters, 184 restraints, GoF =
1.147, R1 = 0.0938, wR2 = 0.2102, R indices based on 3851 reflections
with I > 2s(I) (refinement on F2), D1max = 0.48, D1min = À0.27 eꢁÀ3
.
Figure 4. A) Crystal packing of 1 showing alkyne and azide motifs
located in a cavity. B) Stabilization of the transition-state-like arrange-
ment in the crystal by weak hydrogen bonds. C) Crystal packing
showing infinite head-to-tail assembly of monomers along the screw
axis with properly oriented azide and alkyne motifs for spontaneous
reaction.
Received: February 7, 2012
Published online: March 16, 2012
Keywords: click chemistry · green chemistry · polymerization ·
.
pseudosugars · topochemistry
crystal explains the regiospecific formation of the 1,5 isomer.
As the monomers are arranged in head-to-tail fashion along
the helical axis (Figure 4C), the reaction proceeds along this
axis and leads to formation of linear oligomers.
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We monitored the kinetics of this topochemical reaction
1
using H NMR spectroscopy. A bulk sample of crystals was
kept at room temperature, and small fractions were with-
1
drawn at regular intervals and analyzed by H NMR spec-
troscopy after dissolving in CDCl3 (Figure 3C). From the first
day onwards, oligomerization was observed, as judged from
a gradual increase in intensity of triazole-connected anomeric
protons and a concomitant decrease in intensity of alkynyl
protons. The reaction followed sigmoidal kinetics at room
temperature, as expected of a topochemical reaction. Similar
reaction pattern and kinetics were observed when the
reaction was carried out at higher or lower temperature.
Interestingly, this topochemical click reaction is even facile at
À108C, albeit with a reduced rate.
In conclusion, we have reported a spontaneous regiospe-
cific topochemical azide–alkyne cycloaddition of a monosac-
charide analogue to provide 1,5-triazolyl-linked linear oligo-
saccharide analogues, which are otherwise difficult to synthe-
size by conventional solution-state chemistry due to prefer-
ential formation of cyclic oligomers. The crystal lattice forms
a reaction nanovessel, wherein the reactant motifs (alkyne
and azide) are entrapped; their transition-state-like arrange-
ment facilitates the reaction, their relative orientation in the
nanovessel dictates the regiospecificity, and the crystal
packing dictates the linearity. Unarguably, click chemistry
has received enormous attention from chemistry and other
fields of science ranging from material science to biology due
to its simple and practical utility for various applications.
´
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