Fast, ligand- and solvent-free copper-catalyzed click reactions in a ball mill

Article abstract of DOI:10.1039/c0cc05657j

A new, ligand- and solvent-free method for the Huisgen 1,3-dipolar cycloaddition (click reaction) was developed using a planetary ball mill. Besides various alkynes and azides, a propargyl functionalized polymer was converted by mill clicking. Moreover, it was possible to carry out a click polymerization in a ball mill.

Full text of DOI:10.1039/c0cc05657j

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 4370–4372
www.rsc.org/chemcomm
COMMUNICATION
Fast, ligand- and solvent-free copper-catalyzed click reactions in
a ball millw
Rico Thorwirth,a Achim Stolle,*a Bernd Ondruschka,a Andreas Wildb and Ulrich S. Schubertb
Received 18th December 2010, Accepted 23rd February 2011
DOI: 10.1039/c0cc05657j
A new, ligand- and solvent-free method for the Huisgen
1,3-dipolar cycloaddition (click reaction) was developed using
a planetary ball mill. Besides various alkynes and azides, a
propargyl functionalized polymer was converted by mill clicking.
Moreover, it was possible to carry out a click polymerization in
a ball mill.
reaction with phenylacetylene (1a) forming 1-decyl-4-phenyl-
1H-1,2,3-triazole (3a; Scheme 1). First, the influence of different
copper salts and sodium ascorbate on the conversion of 2a
and the selectivity to 3a was investigated (Table S1, ESIw).
Additionally, fused quartz sand (SiO2) was used as inert
milling auxiliary to enable small batch sizes. Remarkably,
the use of copper acetate (Cu(OAc)2) and sodium ascorbate
quantitatively yielded the product within 5 min reaction
time only. Without sodium ascorbate the reaction is
completed in 10 min. Thus, sodium ascorbate as an additive
is useful for the reaction of less active substrates. Other
copper salts like cuprous iodide and cupric sulfate showed
similar results. In the absence of copper salts, no reaction
occurred during the tested reaction times. Competing
homo-coupling reaction of 1 (Glaser reaction) has not been
observed.
Metal-catalyzed bond forming reactions represent the state-of-
the-art synthetic tool in organic chemistry. An important class
of copper-catalyzed reactions are the Huisgen 1,3-dipolar
cycloadditions.1 This reaction between alkynes and azides as
dipolarophiles and 1,3-dipoles, respectively, fulfils the criteria
for a click reaction (high chemical yield, simple reaction
conditions, stereospecificity)2 and is a highly important method
for the straightforward synthesis of pharmaceuticals, polymers
and for the derivatization of biomolecules.3 However, only a
few very recent articles discuss solvent-free procedures for this
type of chemistry.4 In this contribution, a solvent-free imple-
mentation of the Huisgen 1,3-dipolar cycloaddition between
alkynes and azides in a planetary ball mill is reported.
With Cu(OAc2) showing the best results, a screening of
different alkynes (1) and azides (2) was performed (Table 1).
Almost all tested combinations revealed high conversions and
selectivities. Furthermore, the triazole products were pure
according to 1H NMR spectroscopy after extraction of the
reaction mixtures. Even ethynylpyridines 1g and 1h yielded the
corresponding triazoles (3g,h) while they were not reactive in
Sonogashira reactions operated under similar conditions in a
planetary ball mill.10b
Synthetic chemistry carried out in ball mills has attracted
increasing attention within the last years, as indicated by the
rising number of publications in this area of research.5,6
Throughout evolution of this field of chemistry, in the last
decade catalyzed bond-forming reactions became the most
prominent examples.6a,c,7–10 Ball mill protocols are often as
capable as their solvent-based counterparts in solution.
Categorization of catalysis in ball mills leads to two major
groups: organocatalysis6b,7 and Pd-mediated cross-coupling
reactions.6c,8–10 Amongst the last group of reactions such
prominent examples have shown to work: Mizoroki–Heck,8
Suzuki–Miyaura6c,9 and Sonogashira reactions.10
Besides (hetero)aryl alkynes (1a–h), decyne (1i) and
propargyl alcohols (1j,k), also 4-ethynyl[2.2]para-cyclophane
(1m) was successfully reacted with 2a, but with lower
conversion as the other alkynes. It was also possible to prove
that other azides can be employed in the reaction with 1a.
1-Mesityl- (3n), 1-benzyl- (3o) and 1-adamantyl-4-phenyl-1H-
1,2,3-triazole (3p) were obtained almost quantitatively from
the reaction with the respective azides. Functionalization of
1-ethoxy-2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azide (2d)
with 1a was successful, demonstrating the capability of this
method to handle also complex molecules. In addition,
the electron poor dimethylacetylenedicarboxylate (1n) was
Due to the fact that azides with small number of carbons are
sensitive to shock, decyl azide (2a) was used for a model
a Institute for Technical Chemistry and Environmental Chemistry
(ITUC), Friedrich-Schiller University Jena, Lessingstr. 12,
D-07743 Jena, Germany. E-mail: achim.stolle@uni-jena.de;
Fax: +49 3641 948402
b Laboratory for Organic and Macromolecular Chemistry (IOMC)
and Jena Center for Soft Matter (JCSM), Friedrich-Schiller
University Jena, Humboldtstr. 10, D-07743 Jena, Germany
w Electronic supplementary information (ESI) available: Complete
experimental procedure, analytical characterization of the products,
catalyst screening as well as analytical data of polymers 12a and 12b.
See DOI: 10.1039/c0cc05657j
Scheme 1 Cu-catalyzed 1,3-dipolar cycloaddition of alkynes (1) with
azides (2) forming 1,4-substituted-1H-1,2,3-triazoles (3).
c
4370 Chem. Commun., 2011, 47, 4370–4372
This journal is The Royal Society of Chemistry 2011

View Online
Table 1 Selected results of screening 1,3-dipolar cycloadditions
between alkynes (1) and azides (2; Scheme 1)a
3
R1
Azideb X(2)c (%) S(3)c (%)
3a C6H5 (1a)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
499
94
91
96
95
499
499
99
98
499
98
98
84
98
95
93
93
94
95
98
93
94
93
87
90
89
89
92
94
97
96
3b p-Me-C6H4 (1b)
3c o-Me-C6H4 (1c)
3d p-OMe-C6H4 (1d)
3e o-OMe-C6H4 (1e)
3f p-F-C6H4 (1f)
3g 2-C5H4N (1g)
3h 3-C5H4N (1h)
Scheme
3
Schematic representation of the click reaction of a
propargyl-functionalized polystyrene (6, 0.05 mmol) and decyl azide
(2a, R2 = n-decyl, 0.15 mmol; conditions cf. Table 1).
the single coupled product 1-decyl-4-(p-ethynylphenyl)-1H-
1,2,3-triazole (5d) was isolated with high selectivity. The bis-
ethynyl educts (4) were converted quantitatively in every case.
The products could not be investigated by GC-FID analysis;
3i
3j
n-C8H17 (1i)
Propan-2-ol-1-yl (1j)
3k But-3-en-2-ol-1-yl (1k)
3l
3m [2.2]Para-cyclophane-1-yl (1m) 2a
6-Methylhept-5-en-2-ol-1-yl (1l) 2a
1
as alternative H NMR spectroscopy of the extracted crude
3n C6H5 (1a)
3o C6H5 (1a)
3p C6H5 (1a)
3qd C6H5 (1a)
2b
2c
2d
2e
products was used to calculate the yields. Using similar
reaction conditions, 1,3,5-tris-ethynylbenzene was tested in
the click reaction with 2a. As a result the threefold clicked
triazole (cf. ESIw) was obtained as the only product with 97%
yield; neither single nor twofold clicked products could be
obtained.
499
98
98
a
Reaction conditions: 1.1 mmol 1, 1 mmol 2, 5 mol% Cu(OAc)2,
5 g SiO2; ZrO2 beaker (45 mL), 6 Â ZrO2 milling balls (15 mm),
800 minÀ1, 10 min. 2a = decyl azide, 2b = mesityl azide, 2c =
benzyl azide, 2d = adamantyl azide, 2e = 1-ethoxy-2,3,4,6-tetra-O-
b
Furthermore, a terminal propargyl-functionalized polystyrene
(PS2500, 6) was tested in a cycloaddition with 2a (Scheme 3),11
the extracted product (7) was analyzed with matrix assisted
laser desorption/ionization-time of flight mass spectrometry
(MALDI-TOF-MS; Fig. 1) and size exclusion chromato-
graphy (SEC; Fig. 2). The SEC analysis (PS standard) revealed
c
acetyl-b-D-glucopyranosyl azide. Conversion (X) and selectivity (S)
based on GC-FID analysis. Yields were determined by 1H NMR
d
analysis of the extracted crude product. 5 mol% Na-ascorbate are added.
an increase of the average molar mass of 9 (2720 g molÀ1
compared to 6 (2470 g molÀ1) while the PDI value (1.08)
)
Scheme 2 Synthesis of dimethylester 3r from dimethylacetylendi-
carboxylate (1n) and decyl azide (2a; conditions cf. Table 1).
suitable for cycloaddition reaction, but with slightly lower
conversion (3r, Scheme 2) than other examples (Table 1).
Subsequently, bis-ethynyl compounds were employed in the
reaction with 2a (Table 2). To force the reaction to the double
clicked product, sodium ascorbate and a 2.2-fold excess of 2a
were used. This approach worked well for 1,3-bis-ethynylbenzene
(4a) and 1,4-bis-ethynyl-2,5-bis-octyloxybenzene (4c), but in
the case of the symmetrically 1,4-bis-ethynylbenzene (4b), only
Table 2 Click reaction of bis-ethynyl benzenes (4) and decyl azide (2a)a
Fig. 1 MALDI-TOF-MS of polymers 6 and 7 (Scheme 3).
Entry
R
Yield (5)b (%)
5a
5b
5c
1,3-C6H4 (4a)
1,4-C6H4 (4b)
1,4-C6H2-2,5-OC8H17 (4c)
96
97c
95
a
Reaction conditions: 0.5 mmol 4, 1.1 mmol 2a (R2 = n-decyl),
5 g SiO2; ZrO2 beaker (45 mL), 6 Â ZrO2 milling balls (15 mm).
Calculated by 1H NMR analysis of the extracted crude products.
One ethynyl function was converted only: 1-decyl-4-(p-ethynyl-
phenyl)-1H-1,2,3-triazole (5d).
b
c
Fig. 2 SEC of polymers 6 and 7 (Scheme 3).
Chem. Commun., 2011, 47, 4370–4372 4371
c
This journal is The Royal Society of Chemistry 2011

View Online
Table 3 Polymerization of 1,12-diazidododecane (8) and bis-ethynyl
compounds (4c and 9)a
MALDI-TOF MS and HR-MS measurements as well as
Henning Hopf (TU Braunschweig), Justyna Czaplewska and
Omur Be-sir for the synthesis of 1m, 2e and 6, respectively.
Notes and references
1 R. Huisgen, Proc. Chem. Soc., London, 1961, 357.
2 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int.
Ed., 2001, 40, 2004.
3 (a) S. Chassaing, M. Kumarraja, A. S. Souna Sido, P. Pale and
J. Sommer, Org. Lett., 2007, 9, 883; (b) M. W. M. Fijten,
C. Haensch, B. van Lankvelt, R. Hoogenboom and
U. S. Schubert, Macromol. Chem. Phys., 2008, 209, 1887;
(c) F. Amblard, J. H. Cho and R. F. Schinazi, Chem. Rev., 2009,
109, 4207; (d) C. R. Becer, R. Hoogenboom and U. S. Schubert,
Angew. Chem., Int. Ed., 2009, 48, 4900; (e) Y. Kasuga, M. Ito,
W. Onoda, Y. Nakamura, S. Inokuma, T. Matsuda and
J. Nishimura, Heterocycles, 2009, 78, 983; (f) M. A. P. Martins,
C. P. Frizzo, D. N. Moreira, L. Buriol and P. Machado, Chem.
Rev., 2009, 109, 4140; (g) Click chemistry – Function follows form,
ed. M. G. Finn and V. Fokin, themed issue in Chem. Soc. Rev.,
2010, 39, 1221–1408; (h) A. Coelho, P. Diz, O. Caamano and
E. Sotelo, Adv. Synth. Catal., 2010, 352, 1179; (i) A. Wild,
C. Friebe, A. Winter, M. D. Hager, U. W. Grummt and
U. S. Schubert, Eur. J. Org. Chem., 2010, 6, 1859; (j) P. Cintas,
A. Barge, S. Tagliapietra, L. Boffa and G. Cravotto, Nat. Protoc.,
2010, 5, 607.
4 (a) J. Hong, Q. Luo and B. K. Shah, Biomacromolecules, 2010, 11,
2960; (b) D. Wang, N. Li, M. Zhao, W. Shi, C. Ma and B. Chen,
Green Chem., 2010, 12, 2120; (c) H. Kang, H. J. Lee, J. C. Park,
H. Song and K. H. Park, Top. Catal., 2010, 53, 523; (d) H. Elamari,
I. Jlalia, C. Louet, J. Herscovici, F. Meganem and C. Girard,
Tetrahedron: Asymmetry, 2010, 21, 1179.
5 (a) A. Bruckmann, A. Krebs and C. Bolm, Green Chem., 2008, 10,
1131; (b) G. Kaupp, J. Phys. Org. Chem., 2008, 21, 630;
(c) K. Tanaka, Solvent-Free Organic Synthesis, Wiley-VCH,
Weinheim, 2nd edn, 2009.
6 (a) V. Declerck, P. Nun, J. Martinez and F. Lamaty, Angew.
Chem., Int. Ed., 2009, 48, 9318; (b) A. Bruckmann, B. Rodriguez
and C. Bolm, CrystEngComm, 2009, 11, 404; (c) F. Schneider,
A. Stolle, B. Ondruschka and H. Hopf, Org. Process Res. Dev.,
2009, 13, 44; (d) G.-W. Wang and J. Gao, Org. Lett., 2009, 11,
2385; (e) D. C. Waddell, I. Thiel, T. D. Clark, S. T. Marcum and
J. Mack, Green Chem., 2010, 12, 209; (f) W. Yuan, T. Fricic,
D. Apperley and S. L. James, Angew. Chem., Int.Ed., 2010, 49,
3916; (g) T. Szuppa, A. Stolle, B. Ondruschka and W. Hopfe,
Green Chem., 2010, 12, 1288; (h) R. Thorwirth, F. Bernardt,
A. Stolle, B. Ondruschka and J. Asghari, Chem.–Eur. J., 2010,
16, 13236; (i) T. Szuppa, A. Stolle, B. Ondruschka and W. Hopfe,
ChemSusChem, 2010, 3, 1181.
7 (a) B. Rodriguez, T. Rantanen and C. Bolm, Angew. Chem., Int.
Ed., 2006, 45, 6924; (b) B. Rodriguez, A. Bruckmann, T. Rantanen
and C. Bolm, Adv. Synth. Catal., 2007, 349, 2213; (c) B. Rodriguez,
A. Bruckmann and C. Bolm, Chem.–Eur. J., 2007, 13, 4710.
8 (a) E. Tullberg, D. Peters and T. Frejd, J. Organomet. Chem., 2004,
689, 3778; (b) E. Tullberg, F. Schachter, D. Peters and T. Frejd,
Synthesis, 2006, 1183.
9 (a) S. Feldbæk Nielsen, D. Peters and O. Axelsson, Synth.
Commun., 2000, 30, 3501; (b) F. Schneider and B. Ondruschka,
ChemSusChem, 2008, 1, 622; (c) F. Schneider, T. Szuppa, A. Stolle,
B. Ondruschka and H. Hopf, Green Chem., 2009, 11, 1894;
(d) F. Bernhardt, R. Trotzki, T. Szuppa, A. Stolle and
B. Ondruschka, Beilstein J. Org. Chem., 2010, 6, No. 7.
10 (a) D. A. Fulmer, W. C. Shearouse, S. T. Medonza and J. Mack,
Green Chem., 2009, 11, 1821; (b) R. Thorwirth, A. Stolle and
B. Ondruschka, Green Chem., 2010, 12, 985.
Entry
R
Mnb/g molÀ1
PDIb
10a
10b
n-C4H8 (9)
1,4-C6H2-2,5-OC8H17 (4c)
2200
7500
2.43
2.44
a
Reaction conditions: 1 mmol 8, 1 mmol 4c or 9, 5 g SiO2; ZrO2
b
beaker (45 mL), 6 Â ZrO2 milling balls (15 mm). Calculated by SEC
analysis (PS standard) of the extracted crude.
remained unaffected. MALDI-TOF-MS indicated a shift
between the main mass distribution signals of 6 and 7 which
is fitting to the mass of 2a. The solvent-free click reaction is
obviously also possible for polymer modification reactions
without any notable influence of the high-energy ball milling
process on the integrity of the polymer chain as proven
by SEC.
Based on the results (polymer functionalization and reactions
with bis-functional molecules 4) we also investigated a poly-
merization in the ball mill. For this purpose, 1,12-diazidodo-
decane (8) was reacted with bis-ethynyl compounds 4c and 9
and the extracted crude products were analyzed with SEC
(Table 3, PS standard). The reaction with the rigid 1,4-bis-
ethynyl-2,5-bis-octyloxybenzene (4c) led to a significantly
higher average molar mass than the reaction with the flexible
octa-1,7-diyne (9). PDI values are in the expected range for a
step-growth polymerization. Assumedly, the higher amount of
oligomers in 10a (Fig. S1, ESIw) can be explained by possible
formation of cyclic systems due to the flexible alkyl spacers
preventing further chain growth. With the rigid phenyl spacer
in 10b, formation of cyclic systems should be more unlikely.
In conclusion, a fast, ligand- and solvent-free method for
the Huisgen 1,3-dipolar cycloaddition using a planetary ball
mill was developed. Almost no side products were formed due
to the gentle reaction conditions and the short reaction times
(10 min). The isolated crude products were pure according to
1H NMR spectroscopy and MALDI-TOF mass spectrometry.
The broad variety of suitable substrates enables a wide range
of potential applications of this protocol for complex substrates
and reactions. For instance, a terminal ethynyl functionalized
polystyrene could be modified in the ball mill without destroying
the polymer backbone. Moreover, polymerizations could be
performed in the future.
This study was supported by the German Federal Environ-
mental Foundation (DBU; grant No. 27281-31) and by the
Dutch Polymer Institute (DPI; technology area HTE). We
would like to thank Anja Baumgartel and Nicole Fritz for
11 P. L. Golas and K. Matyjaszewski, Chem. Soc. Rev., 2010, 39,
1338.
c
4372 Chem. Commun., 2011, 47, 4370–4372
This journal is The Royal Society of Chemistry 2011