Pressure-accelerated copper-free cycloaddition of azide and alkyne groups pre-organized in the crystalline state at room temperature

Article abstract of DOI:10.1039/c2gc36069a

We have designed a supramolecular system to pre-organize the azide and alkyne functional groups via electrostatic and arene-perfluoroarene interactions. After pre-organization, high pressure was applied to accelerate the copper-free cycloaddition of the azide and alkyne groups in the crystalline state.

Full text of DOI:10.1039/c2gc36069a

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Green Chemistry
Cite this: Green Chem., 2012, 14, 2703
www.rsc.org/greenchem
COMMUNICATION
Pressure-accelerated copper-free cycloaddition of azide and alkyne groups
pre-organized in the crystalline state at room temperature†
Hao Chen, Ben-Bo Ni, Fan Gao and Yuguo Ma*
Received 11th July 2012, Accepted 16th August 2012
DOI: 10.1039/c2gc36069a
Moreover, a hydraulic press is more convenient and easier to
handle, compared to expensive diamond anvil cells (DACs).
Electrostatic interaction is an important non-covalent inter-
action in supramolecular chemistry.7–10 Recently, arene–perfluo-
roarene interaction has been gradually utilized in crystal
engineering. Its binding energy is 3.7–4.7 kcal mol−1 in crystal-
line state,11,12 which induces the alternating face-to-face stacking
of phenyl and perfluorophenyl units.13–16 Here we took advan-
tage of these two non-covalent interactions to construct a supra-
molecular system in solid state with 4-ethynylaniline (1) and
4-azido-2,3,5,6-tetrafluorobenzoic acid (2). As shown in Fig. 1,
electrostatic interactions link the amine and carboxylic acid in
the horizontal direction, while arene–perfluoroarene interactions
induced the face-to-face stacking in the vertical direction. The
alkyne and azide functional groups were arranged in a favourable
position for 1,3-dipolar cycloaddition which was then accelerated
by pressure to afford a regioselective product in high yield.
1 and 2 were dissolved in common organic solvents, such as
THF, acetone and methanol. Then solvents were removed under
vacuum at room temperature to obtain the corresponding salt 1·2
We have designed a supramolecular system to pre-organize
the azide and alkyne functional groups via electrostatic and
arene–perfluoroarene interactions. After pre-organization,
high pressure was applied to accelerate the copper-free cyclo-
addition of the azide and alkyne groups in the crystalline
state.
Recently, pressure-accelerated/induced reactions have been
gradually applied in syntheses, especially in organic syntheses in
the solid state.1 Advantages of such reactions include high
yields, convenient work up and the “green” process. In these
reactions, the cell volume shrinks under pressure, which leads to
a decrease of the activation energy and acceleration of the reac-
tion rate.1e Moreover, products of pressure-accelerated/induced
reactions may be different to products resulting from thermal
activation.1b This phenomenon has been found in various reac-
tions, e.g., [4 + 2] Diels–Alder cycloadditions,2 List–Barbas–
Mannich reactions,3 and polymerizations.1a
The copper-catalyzed azide–alkyne cycloaddition (CuAAC)
reaction has become the most important reaction in click chem-
istry due to its mild reaction conditions, high yields and regio-
selectivity.4 To avoid the toxicity of the copper ions, great effort
has been made towards developing copper-free AACs.5 Many
findings are striking in terms of further advancing the application
of CuAAC click chemistry under aqueous condition.6 Herein, we
report an environmentally friendly and efficient pressure-acceler-
ated copper-free AAC at room temperature. In this system, the
azide and alkyne functionality were pre-organized in the crystal-
line state via electrostatic and arene–perfluoroarene interactions
before high pressure was applied to accelerate the cycloaddition
reaction to regioselectively afford 1,4-disubstituted triazole. The
high pressure equipment used in this research was a hydraulic
press and evacuable pellet die which were usually used to
prepare standard IR samples. It actually produces over 1 GPa of
pressure and is available for reactions up to the gram level.
1
as a yellow solid. The H NMR spectra in CDCl3 indicated that
no reaction occurred during this process (see Fig. S7 in ESI†). In
the powder X-ray diffraction (PXRD) pattern (Fig. 2a), the
complex 1·2 showed completely different diffraction patterns in
comparison to that from the simple mixing of 1 and 2,
suggesting that complex 1·2 was a co-crystal or an assembly of 1
and 2. Fig. 2b shows the IR spectra of 1, 2 and complex 1·2. In
the case of 2, the 1709 cm−1 peak could be assigned to the
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Lab
of Polymer Chemistry & Physics of Ministry of Education, College of
Chemistry, Peking University, Beijing, 100871, China.
E-mail: ygma@pku.edu.cn; Fax: (+86) 10-6275-1708;
Tel: (+86) 10-6275-6660
†Electronic supplementary information (ESI) available: Experimental
details, 1H NMR, 13C NMR and 19F NMR spectra, single crystal data
and structure refinement of complexes 1′·2 and 2·3. CCDC reference
numbers 874309 and 874310. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c2gc36069a
Fig. 1 Schematic representation of the pressure-accelerated 1,3-dipolar
cycloaddition of the azide and alkyne groups pre-organized via electro-
static and arene–perfluoroarene interactions.
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 2703–2705 | 2703

View Article Online
Fig. 2 (a) Powder X-ray diffraction: red, black, and blue lines corres-
pond to complex 1·2, 1 and 2, respectively. (b) FT-IR in the solid state:
red, black, and blue lines correspond to complex 1·2, 1 and 2,
respectively.
Fig. 3 (a) Reaction conditions. 1,3-dipolar cycloaddition: r.t., 1 GPa,
overnight or r.t., CuI, THF, Et3N. Hydration: air, 24 h. Partial H NMR
spectra of product in DMSO-d6 (b) crude (c) after wash with CHCl3 and
acetone.
1
CvO group. In salt 1·2, that peak shifted to 1582 cm−1, which
indicated the deprotonation of the carboxylic acid to the carbox-
ylate anion.10 We considered that the carboxylate group and the
ammonium group were strongly associated with electrostatic
interactions.
As a control molecule, 4-azidobenzoic acid (2′) was also
studied. In the IR spectra of a mixture of 1 and 2′, prepared by
the same method of salt 1·2 (see Fig. S10 in ESI†), the wave-
number shift of the CvO group was not observed, indicating no
salt formation between 1 and 2′, as the acidity of 2′ is not strong
enough. In the PXRD experiment (see Fig. S11 in ESI†), the dif-
fraction patterns of the 1 and 2′ mixture were only the simple
addition of the patterns of the two individual compounds. Both
results demonstrated that fluorination was essential for the for-
mation of the salt 1·2.
Fig. 4 ORTEP drawing of the crystal structure of 1′·2 with 30% prob-
ability thermal ellipsoids along [100] (a) and [010] (b).
It was found that because of the electron-donating effect of
amino group, 1 could be easily transformed into ketone 3
through a hydration reaction when catalysed with acid, such as
hydrochloric acid, trifluoroacetic acid, perfluorobenzoic acid and
2. In solution, the hydration process took several hours at room
temperature. In the solid state it took about 24 hours to complete
the hydration under normal humidity. However, in the anhydrous
environment, hydration was suppressed and the yellow complex
1·2 gradually transformed into a pale white solid under normal
pressure in 1 month, which was no longer soluble in THF,
acetone and methanol, but soluble in DMSO. Raman and 1H
NMR spectra indicated that the main product was the cyclo-
addition product 4.
to the transition state of the 1,4-disubstituted cycloaddition. High
pressure was applied to accelerate the reaction by bring the func-
tional groups closer.
To further elucidate the pre-organization of the azide and
alkyne groups in the crystals, we attempted to grow crystals of
complex 1·2, but only obtained the co-crystal of 2 and 3 due to
the hydration reaction during the crystal growing process. There-
fore, as a model to evidence the arene–perfluoroarene and elec-
trostatic interactions, crystals of 1′·2 was successfully obtained.‡
Compound 1′ (4-iodoaniline) is the precursor of 1 and has a
similar size and electronic effect compared with 1. Single crystal
X-ray analysis (Fig. 4) revealed a columnar packing of the salt
1′·2 in the crystal. This columnar network structure is mainly
composed of the carboxylate oxygen atoms of the carboxylic
acid anions and the ammonium hydrogen atoms of the proto-
nated amine. The phenylene and tetrafluorophenylene stack alter-
nately in a face-to-face fashion and the distance between the two
parallel aromatic rings is ca. 3.5 Å. The shortest distance
between an iodine atom and an azide nitrogen atom within a
column is 3.6 Å. To validate such a comparison between 1·2 and
1′·2, we studied the PXRD of these two complexes. As shown in
Fig. S14, S16 and Table S1 (see ESI†), the PXRD of 1·2 and
1′·2 were very similar. Furthermore, the simulated crystal struc-
ture of 1·2 was obtained from 1′·2 by replacing the iodine atom
with the alkyne group using Materials Studio.17 It was found
that the simulated diffraction patterns of the crystal of 1·2 fits the
Because of the side reaction, heating was not suitable to accel-
erate the cycloaddition of the azide and alkyne groups in this
system. We chose to use high pressure to accelerate the reaction,
taking advantage of the pre-organization of the functional
groups, also avoiding the moisture. A hydraulic press and evacu-
able pellet die were used to produce the high pressure. Under 1
GPa pressure (Fig. 3), such a cycloaddition reaction was acceler-
ated and completed overnight with an 80–90% yield, as indi-
cated by 1H NMR. Only a small amount of hydration by-product
3 was observed. To certify the regioselectivity, a copper cata-
lyzed 1,3-dipolar cycloaddition of 1 and 2 was carried out to
1
yield compound 4′ which was the same as 4, confirmed by H
NMR and MS. Under the assumption that the CuAAC product is
1,4-disubstituted triazole, 4 should also be 1,4-disubstituted and
the pressure-accelerated cycloaddition is regioselective. Similar
to our previous study,5k we proposed that in the crystalline state
the azide and alkyne groups were in an arrangement that is close
2704 | Green Chem., 2012, 14, 2703–2705
This journal is © The Royal Society of Chemistry 2012

View Article Online
(d) T.-B. Yu, J. Z. Bai and Z. Guan, Angew. Chem., Int. Ed., 2009, 48,
1097.
experimental XRD result very well, which indicated that the
crystal structures of 1·2 and 1′·2 should be very similar. There-
fore, we reasonably assume that in the crystal of 1·2, both of the
arene–perfluoroarene interactions and electrostatic interactions
contribute significantly and the azide and alkyne groups are posi-
tioned suitably for the regioselective cycloaddition.5k
5 (a) S. S. van Berkel, A. J. Dirks, M. F. Debets, F. L. van Delft, J. J. L.
M. Cornelissen, R. J. M. Nolte and F. P. J. T. Rutjes, ChemBioChem,
2007, 8, 1504; (b) N. J. Agard, J. A. Prescher and C. R. Bertozzi, J. Am.
Chem. Soc., 2004, 126, 15046; (c) S. T. Laughlin, J. M. Baskin,
S. L. Amacher and C. R. Bertozzi, Science, 2008, 320, 664;
(d) W. L. Mock, T. A. Irra, J. P. Wepsiec and T. L. Manimaran, J. Org.
Chem., 1983, 48, 3619; (e) W. L. Mock and N.-Y. Shih, J. Org. Chem.,
1983, 48, 3618; (f) D. Tuncel and J. H. G. Steinke, Chem. Commun.,
1999, 1509; (g) T. C. Krasia and J. H. G. Steinke, Chem. Commun.,
2002, 22; (h) D. Tuncel and J. H. G. Steinke, Macromolecules, 2004, 37,
288; (i) R. Manetsch, A. Krasiński, Z. Radić, J. Raushel, P. Taylor,
K. B. Sharpless and H. C. Kolb, J. Am. Chem. Soc., 2004, 126, 12809;
( j) M. Whiting, J. Muldoon, Y.-C. Lin, S. M. Silverman, W. Lindstrom,
A. J. Olson, H. C. Kolb, M. G. Finn, K. B. Sharpless, J. H. Elder and
V. V. Fokin, Angew. Chem., Int. Ed., 2006, 45, 1435; (k) B.-B. Ni,
C. Wang, H. Wu, J. Pei and Y. Ma, Chem. Commun., 2010, 46, 782;
(l) F. Kloss, U. Köhn, B. O. Jahn, M. D. Hager, H. Görls and
U. S. Schubert, Chem.–Asian J., 2011, 6, 2816.
6 (a) D. Wang, N. Li, M. Zhao, W. Shi, C. Ma and B. Chen, Green Chem.,
2010, 12, 2120; (b) R. Hudson, C.-J. Li and A. Moores, Green Chem.,
2012, 14, 622; (c) K. Wang, X. Bi, S. Xing, P. Liao, Z. Fang, X. Meng,
Q. Zhang, Q. Liu and Y. Ji, Green Chem., 2011, 13, 562.
7 (a) Y. Mizobe, M. Miyata, I. Hisaki, Y. Hasegawa and N. Tohnai,
Org. Lett., 2006, 8, 4295; (b) Y. Mizobe, N. Tohnai, M. Miyata and
Y. Hasegawa, Chem. Commun., 2005, 1839; (c) T. Yuge, M. Miyata and
N. Tohnai, Cryst. Growth Des., 2006, 6, 1271; (d) N. Nishiguchi,
T. Kinuta, Y. Nakano, T. Harada, N. Tajima, T. Sato, M. Fujiki,
R. Kuroda, Y. Matsubara and Y. Imai, Chem.–Asian J., 2011, 6, 1092.
8 G. K. Kole, L. L. Koh, S. Y. Lee, S. S. Leeb and J. J. Vittal, Chem.
Commun., 2010, 46, 3660.
In summary, we have designed a supramolecular system to
pre-organize azide and alkyne functional groups in the crystal-
line state via electrostatic and arene–perfluoroarene interactions.
After pre-organization, high pressure was applied to accelerate
the cycloaddition of the azide and alkyne groups with reaction
times shortened from 1 month to 12 hours. A hydraulic press
was used as the high pressure equipment in AACs for the first
time. The orientation of the reacting functional groups might be
suitable to generate 1,4-disubstituted triazoles and therefore
promote a relatively well-controlled regioselective cycloaddition.
This is a good example of a pressure-accelerated reaction with
high regioselectivity, resulting from suitable packing through
two non-covalent interactions cooperatively, which also provides
a new direction to make chemistry “green” by using supramole-
cular chemistry.
This research was financially supported by National Natural
Science Foundation of China (No. 21074004) and the National
Basic Research Program (2007CB808000) of the Ministry of
Science and Technology of China.
9 Z. Li, F. W. Fowler and J. W. Lauher, J. Am. Chem. Soc., 2009, 131, 634.
10 M. Ayabe, T. Kishida, N. Fujita, K. Sada and S. Shinkai, Org. Biomol.
Chem., 2003, 1, 2744.
Notes and references
11 (a) J. H. Williams, Acc. Chem. Res., 1993, 26, 593; (b) J. Hernández-Tru-
jillo, M. Costas and A. Vela, J. Chem. Soc., Faraday Trans., 1993, 89,
2441; (c) J. Hernández-Trujillo, F. Colmenares, G. Cuevas and
M. Costas, Chem. Phys. Lett., 1997, 265, 503; (d) A. P. West, Jr.,
S. Mecozzi and D. A. Dougherty, J. Phys. Org. Chem., 1997, 10, 347;
(e) S. Lorenzo, G. R. Lewis and I. Dance, New J. Chem., 2000, 24, 295.
12 (a) C. R. Patrick and G. S. Prosser, Nature, 1960, 187, 1021;
(b) E. A. Meyer, R. K. Castellano and F. Diederich, Angew. Chem., Int.
Ed., 2003, 42, 1210.
13 (a) F. Ponzini, R. Zagha, K. Hardcastle and J. S. Siegel, Angew. Chem.,
Int. Ed., 2000, 39, 2323; (b) J. C. Collings, K. P. Roscoe, R. L. Thomas,
A. S. Batsanov, L. M. Stimson, J. A. K. Howard and T. B. Marder, New
J. Chem., 2001, 25, 1410; (c) V. R. Vangala, A. Nangia and V. M. Lynch,
Chem. Commun., 2002, 1304; (d) S. W. Watt, C. Dai, A. J. Scott,
J. M. Burke, R. L. Thomas, J. C. Collings, C. Viney, W. Clegg and
T. B. Marder, Angew. Chem., Int. Ed., 2004, 43, 3061; (e) A. Hori,
A. Shinohe, M. Yamasaki, E. Nishibori, S. Aoyagi and M. Sakata,
Angew. Chem., Int. Ed., 2007, 46, 7617; (f) W. J. Feast, P. W. Lövenich,
H. Puschmann and C. Taliani, Chem. Commun., 2001, 505;
(g) M. Gdaniec, W. Jankowski, M. J. Milewska and T. Połoñski, Angew.
Chem., Int. Ed., 2003, 42, 3903; (h) A. Sundararaman, L. N. Zakharov,
A. L. Rheingold and F. Jäkle, Chem. Commun., 2005, 1708; (i) S. Zhu,
S. Zhu, G. Jin and Z. Li, Tetrahedron Lett., 2005, 46, 2713.
‡Crystal data for 1′·2: C13H7F4IN4O2, M = 454.13, monoclinic, space
group, P21, a = 7.2406(14) Å, b = 6.3111(11) Å, c = 16.211(3) Å, β =
98.719(7)°, V = 732.2(2) Å3, T = 173 K, Z = 2, m = 2.249 mm−1, Dc =
2.060 g cm−3, F(000) = 436, λ = 0.71073 Å, total of 5741 reflections
collected, 3087 independent reflections (Rint = 0.0264), R1 [I > 2σ(I)] =
0.0261, wR2 [I > 2σ(I)] = 0.0618, R1 [all data] = 0.0265, wR2 [all data]
= 0.0621. CCDC 874309.† Crystal data for 2·3: C15H10F4N4O3, M =
370.27, triclinic, space group, P1, a = 5.7206(11) Å, b = 10.897(2) Å, c
= 12.306(3) Å, α = 86.60(3)°, β = 84.86(3)°, γ = 80.87(3)°, V =
753.5(3) Å3, T = 173 K, Z = 2, m = 0.149 mm−1, Dc = 1.632 g cm−3
,
F(000) = 376, λ = 0.71073 Å, total of 6742 reflections collected, 3423
independent reflections (Rint = 0.0400), R1 [I > 2σ(I)] = 0.0532, wR2
[I > 2σ(I)] = 0.1303, R1 [all data] = 0.0604, wR2 [all data] = 0.1360.
CCDC 874310.†
1 (a) C. Wilhelm, S. A. Boyd, S. Chawda, F. W. Fowler, N. S. Goroff,
G. P. Halada, C. P. Grey, J. W. Lauher, L. Luo, C. D. Martin, J. B. Parise,
C. Tarabrella and J. A. Webb, J. Am. Chem. Soc., 2008, 130, 4415;
(b) M. M. Caruso, D. A. Davis, Q. Shen, S. A. Odom, N. R. Sottos,
S. R. White and J. S. Moore, Chem. Rev., 2009, 109, 5755; (c) G. Jenner,
Tetrahedron, 1997, 53, 2669; (d) S. Hillers and O. Reiser, Chem.
Commun., 1996, 2197; (e) F.-G. Klärner and V. Breitkopf, Eur. J. Org.
Chem., 1999, 2757; (f) G. J. Kuster and H. W. Scheeren, Tetrahedron
Lett., 2000, 41, 515; (g) Y. Misumi and K. Matsumoto, Angew. Chem.,
Int. Ed., 2002, 41, 1031; (h) L. F. Tietze, M. Henrich, A. Niklaus and
M. Buback, Chem.–Eur. J., 1999, 5, 297.
14 A. Hori, A. Akasaka, K. Biradha, S. Sakamoto, K. Yamaguchi and
M. Fujita, Angew. Chem., Int. Ed., 2002, 41, 3269.
15 (a) M. Weck, A. R. Dunn, K. Matsumoto, G. W. Coates,
E. B. Lobkovsky and R. H. Grubbs, Angew. Chem., Int. Ed., 1999, 38,
2741; (b) K. Kishikawa, K. Oda, S. Aikyo and S. Kohmoto, Angew.
Chem., Int. Ed., 2007, 46, 764.
2 H. Al-Badri, N. Collignon, J. Maddaluno and S. Masson, Chem.
Commun., 2000, 1191.
3 Y. Hayashi, W. Tsuboi, M. Shoji and N. Suzuki, J. Am. Chem. Soc.,
2003, 125, 11208.
4 (a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless,
Angew. Chem., Int. Ed., 2002, 41, 2596; (b) C. W. Tornøe, C. Christensen
and M. Meldal, J. Org. Chem., 2002, 67, 3057; (c) H. C. Kolb,
M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed., 2001, 40, 2004;
16 (a) G. W. Coates, A. R. Dunn, L. M. Henling, D. A. Dougherty and
R. H. Grubbs, Angew. Chem., Int. Ed. Engl., 1997, 36, 248;
(b) G. W. Coates, A. R. Dunn, L. M. Henling, J. W. Ziller,
E. B. Lobkovsky and R. H. Grubbs, J. Am. Chem. Soc., 1998, 120, 3641.
17 Materials Studio Release Notes, Release 5.0, Accelrys Software, San
Diego, USA, 2010.
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 2703–2705 | 2705