Highly functionalised 3,4,5-trisubstituted 1,2,4-triazoles for future use as ligands in coordination polymers

Article abstract of DOI:10.1016/j.tetlet.2009.11.098

An optimised synthesis of 3,4,5-trisubstituted 1,2,4-triazoles, that can be used as linkers for metal organic frameworks (MOFs), is described. The substituents in 3- and 5-position of the triazole have a significant impact on the torsion angles between the aromatic rings and therefore influence on solubility and coordination behaviour of these ligands.

Full text of DOI:10.1016/j.tetlet.2009.11.098

Tetrahedron Letters 51 (2010) 653–656
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly functionalised 3,4,5-trisubstituted 1,2,4-triazoles for future use
as ligands in coordination polymers
*
Daniel Lässig, Jörg Lincke, Harald Krautscheid
Fakultät für Chemie und Mineralogie, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
An optimised synthesis of 3,4,5-trisubstituted 1,2,4-triazoles, that can be used as linkers for metal organic
frameworks (MOFs), is described. The substituents in 3- and 5-position of the triazole have a significant
impact on the torsion angles between the aromatic rings and therefore influence on solubility and coor-
dination behaviour of these ligands.
Received 30 October 2009
Revised 19 November 2009
Accepted 20 November 2009
Available online 27 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1,3,4-Oxadiazoles
1,2,4-Triazoles
Crystal structures
Microporous materials such as coordination polymers, so called
MOFs, but also microporous organic polymers such as polymers of
intrinsic microporosity (PIMs) have gained increasing interest in
the last decade.1,2 MOFs possess a narrow pore size distribution
due to the underlying crystallinity of these materials. In addition,
they can reach high surface areas making them interesting for
adsorption applications as impressively demonstrated by Cu3(btc)2
(btc = 1,3,5-benzene tricarboxylate).3,4
Carboxylate ligands have been extensively studied as polyfunc-
tional linkers.5–7 Apart from this, MOFs containing linkers with a
combination of both neutral donor groups such as pyridines or
1,2,4-triazoles and charged functional groups such as carboxylates
are of interest.8–13 A convenient way for the preparation of 3,5-
unsubstituted 1,2,4-triazoles was reported by Bartlett and Hum-
phrey in 1967 (Scheme 1).14
et al.16 Because of the limited stability of these azines a further
modification does not appear to be promising.
The synthesis of 3 was first reported by Guo et al. using a more
complicated approach.12 We obtained compounds 3–7 (Scheme 2)
in good yields using Bartlett’s method, 5 was obtained as the
respective monodimethyl ammonium salt. Nevertheless, a more
sophisticated approach to the synthesis of 3,5-disubstituted
1,2,4-triazoles is the reaction of 2,5-disubstituted 1,3,4-oxadiaz-
oles with respective primary amines (Scheme 4). 1,3,4-Oxadiazoles
can be easily obtained either through reaction of carboxylic acid
hydrazides with triethyl orthoacetate or by reaction of 5-substi-
tuted tetrazoles with carboxylic anhydrides or acid chlorides
(Scheme 3).17,18 Following up a modified procedure of Brooker
et al. involving a condensation reaction of thioamides and hydra-
zides we were not able to obtain the respective products.19
2,5-Dimethyl-1,3,4-oxadiazole as the simplest 1,3,4-oxadiazole
was obtained on a molar scale in 85% optimised yield from acetyl
hydrazine and triethyl orthoacetate following the known reaction
procedure.20,21 In a similar manner, we obtained the corresponding
3- and 4-pyridine-substituted oxadiazoles 12 and 13. Although
these oxadiazoles are known in the literature, our route combines
An optimised procedure was presented by Naik et al. in 2008.15
This method involves the reaction of N,N-dimethyl formamide
azine 1 with primary amines mediated by p-toluene sulfonic acid.
The driving force of this reaction is the release of dimethyl amine
as well as the stability of the aromatic heterocycle formed. 1 can
be obtained through reaction of the Vilsmeier–Haack reagent with
hydrazine hydrate. As we observed, simple adaptations of this
method using different N,N-dimethyl-substituted amides in order
to obtain the corresponding azines failed. Eventually N,N-dimethyl
acetamide azine 2 was obtained in 25% yield by using anhydrous
hydrazine and phosphorus oxychloride instead of hydrazine hy-
drate and thionyl chloride similarly to a procedure of Zelenin
* Corresponding author. Tel.: +49 341 97 36172; fax: +49 341 9736199.
E-mail address: Krautscheid@rz.uni-leipzig.de (H. Krautscheid).
Scheme 1. General procedure for synthesis of 3,5-unsubstituted 1,2,4-triazoles.14,15
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.098

654
D. Lässig et al. / Tetrahedron Letters 51 (2010) 653–656
tration. Scheme 4 summarises the syntheses of 6–10 and 14–19
with yields ranging from 34% to 85%. The products were character-
ised by standard proton and carbon NMR and IR spectroscopy as
well as by mass spectrometry and elemental analysis.
1. Single crystal structure determinations
Suitable crystals for single crystal X-ray structure analysis were
obtained in case of eight 1,2,4-triazolyl benzoic acids by hydrother-
mal recrystallisation. The X-ray diffraction data were collected on
R1
R3
Pro-
duct
compound
yield Mp. in °C
in %
(decomp.)
diffractometers IPDS-I and IPDS-2T (STOE) using Mo-K radiation
a
H
H
H
p-CO2H
m-CO2H
m,m’-
3
4
5
H(trz-pba)
H(trz-mba)
(H2NMe2)H(trz-ia)
70
65
45
327
264
238
(k = 71.073 pm). The structures were solved by direct methods
and refined using SHELX.
27 Non-hydrogen atoms were refined aniso-
CO2H
tropically. Hydrogen atoms of the water molecule in 5 were located
and refined isotropically, whereas the coordinates of the remaining
hydrogen atoms were calculated for idealised positions.
CH3 p-CO2H
CH3 m-CO2H
6
7
H(Me2trz-pba)
H(Me2trz-mba)
77
81
322
257
Despite the fact that the molecular structures of the ligands
show no exceptional specialities, the crystal structures reveal
interesting details due to the packing in solid state.
Scheme 2. Synthesis of 3–7.
In general, the single molecules are hydrogen-bonded via the
carboxylic functions and triazole rings, in case of 16 additionally
Scheme 3. Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles.
Pro-
duct
6
7
8
compound
yield
in %
58
62
85
Mp. in °C
(decomp.)
322
257
261
R1
R3
p-CO2H
m-CO2H
m,m’-CO2H
m-CO2H, m’-NH2
CH3
CH3
CH3
CH3
H(Me2trz-pba)
H(Me2trz-mba)
H2(Me2trz-ia)
H(3-Me2trz-5-
NH2-ba)
9
72
287
CH3
m-CO2H,
m’-Me2trz
p-CO2H
m-CO2H
p-CO2H
m-CO2H
p-CO2H
m-CO2H
10
H(3,5-(Me2trz)2-
ba)
54
326
Figure 1. Hydrogen bonding of 5 in solid state.
2py
2py
3py
3py
4py
4py
14
15
16
17
18
19
H(Me-2py-pba)
H(Me-2py-mba)
H(Me-3py-pba)
H(Me-3py-mba)
H(Me-4py-pba)
H(Me-4py-mba)
48
52
45
41
68
34
287
234
293
211
275
253
Scheme 4. Synthesis of 6–10 and 14–19.
both easier access and higher yields.22–24 Nevertheless, applying
this method, the respective 2-pyridine-substituted oxadiazole 11
is not accessible making it necessary to switch to a more general
approach. Therefore the corresponding pyridyl-substituted tetra-
zoles were synthesised starting from the nitriles according to the
literature methods.25
Eventually the synthesis of the 1,2,4-triazoles was performed
applying a modified method of Meyer, who achieved the triazole
synthesis by the condensation of 2,5-dialkyl- or 2-alkyl-5-aryl-
substituted 1,3,4-oxadiazoles and highly reactive primary amines
such as aniline and methyl amine.26 In our case, the reactivity of
the amines used is not sufficient to succeed in the formation of tri-
azoles, hence we improved the reaction by the addition of p-tolu-
ene sulphonic acid to enable the reaction.
Performing the reaction in xylene under reflux the reaction time
is about two days. The desired products were isolated by simple fil-
Figure 2. Four-membered macrocycles in 7 formed by hydrogen bonds.

D. Lässig et al. / Tetrahedron Letters 51 (2010) 653–656
655
Figure 3. Molecular structure of 14.
the pyridine ring is involved. Whereas carboxylic acids typically
Table 1
form hydrogen-bonded dimers, this behaviour is not observed in
case of the present ligands. Nevertheless, the carboxylic acids be-
have as donors while the triazole and pyridine rings act as
acceptors.
Selected torsion angles
Torsion angle phenyl–triazole (°)
33.80(7), 20.77(7)
Torsion angle triazole–pyridine (°)
3a
4
—
—
30.2(1)
Although there are the same functional groups in very similar
arrangements, a large variety of hydrogen-bonded networks is ob-
served. In the solid state structure of 5 (Fig. 1) a three-dimensional
network is formed by hydrogen bonding of both the carboxylic
functions and the triazole groups with the water molecules present
in the crystal structures. In contrast, 7 contains four-membered
macrocycles (Fig. 2) formed by hydrogen bonds.
5
47.4(3)
59.40(5)
70.25(5), 80.84(5)
59.86(6)
56.11(5)
—
—
—
—
6
7a
8
14
16
25.59(6)
16.11(7)
74.81(4)
a
Two different torsion angles are observed due to two crystallographic inde-
pendent molecules in the asymmetric unit.
While 3, 4, 6, 14 and 16 form simple chains, 8 builds up layers
due to the second carboxyl group. Interestingly, the one-dimen-
sional network of 16 is built up by the combination of carboxyl
and pyridyl groups exclusively (Fig. 3), leaving out triazoles,
whereas in the other cases only carboxyl and triazole groups
interact.
gles between the phenyl and the triazole ring. This results in
weaker
p–p stacking interactions of the aromatic rings in solid
state leading to lower melting points and to an increase of solubil-
ity in common organic solvents.
As an example, 3 shows a relatively small torsion angle of
20.77(7)° or 33.80(7)°, respectively, and has the highest melting
point of 327 °C due to the unsubstituted ring. Molecules containing
3,5-dimethylated triazol rings with a higher sterical demand lead
to torsion angles of 56–81°. The dimethylated derivative 5 shows
a lower melting point associated with the observed torsion angles.
Furthermore, pyridyl substituents do not significantly influence
the torsion angles between the triazole and the phenyl ring in com-
parison with the dimethylated compounds. The torsion angle be-
tween the triazole and the pyridine is about 16–26°. Therefore
Furthermore, different p–p stacking interactions, especially off-
set-face to face arrangements are observable in most of the struc-
tures.28 The crystal structure of 13 displays short distances of
335 pm between the triazole rings (Fig. 4).
The crystal structures allow to draw conclusions on solubility
and melting points taking into account the torsion angles between
the aromatic rings (Table 1). Sterically more demanding substitu-
ents in 3- and 5-position of the triazole lead to higher torsion an-
the presence of isolated
p-systems on each aromatic ring can be
concluded. As can be seen from the decomposition temperatures
the pyridine substituted molecules 14 and 16 have the lowest ther-
mal stability.
2. Conclusions
We presented the syntheses of 3,5-disubstituted 1,2,4-triazolyl
benzoic acids, that might be potentially useful ligands for the prep-
aration of coordination polymers. We established a straightfor-
ward route for the synthesis of ligands combining the properties
of both functional groups. Furthermore, we introduced pyridine
substituents as additional nitrogen donor groups into the 1,2,4-tri-
azole ring. Up to now, the combination of these substituents has
been unknown in the literature to our knowledge. Currently, we
Figure 4.
p–p stacking interactions between triazole rings of 16.

656
D. Lässig et al. / Tetrahedron Letters 51 (2010) 653–656
5. Li, H.; Eddaoudi, M.; O’Keeffe, M.; Yaghi, O. M. Nature 1999, 402, 276–279.
6. Férey, G.; Mellot-Draznieks, C.; Serre, C.; Millange, F.; Dutour, J.; Surblé, S.;
Margiolaki, I. Science 2005, 309, 2040–2042.
are investigating coordination polymers incorporating these
ligands.
7. Latroche, M.; Surblé, S.; Serre, C.; Mellot-Draznieks, C.; Llewellyn, P. L.; Lee, J.-
H.; Chang, J.-S.; Jhung, S. H.; Férey, G. Angew. Chem. 2006, 118, 8407–8411.
8. Klingele, M. H.; Brooker, S. Coord. Chem. Rev. 2003, 241, 119–132.
9. Beckmann, U.; Brooker, S. Coord. Chem. Rev. 2003, 245, 17–29.
10. Haasnoot, G. Coord. Chem. Rev. 2000, 200, 131–185.
Acknowledgements
We gratefully acknowledge the helpful assistance of Professor
Dr. J. Sieler, Dr. L. Hennig, R. Oehme and G. Reinhardt. We thank
Deutsche Forschungsgemeinschaft (SPP 1362—Poröse metall-
organische Gerüstverbindungen) and the graduate school Build-
MoNa for financial support.
11. Lukashuk, L. V.; Lysenko, A. B.; Rusanov, E. B.; Chernega, A. N.; Domasevitch, K.
V. Acta Crystallogr., Sect. C 2007, 63, m140–m143.
12. Zou, R.-Q.; Cai, L.-Z.; Guo, G.-C. J. Mol. Struct. 2005, 737, 125–129.
13. Bondar, O. A.; Lukashuk, L. V.; Lysenko, A. B.; Krautscheid, H.; Rusanov, E. B.;
Chernega, A. N.; Domasevitch, K. V. Cryst. Eng. 2008, 10, 1216–1226.
14. Bartlett, R. K.; Humphrey, I. R. J. Chem. Soc. C 1967, 1664–1667.
15. Naik, A. D.; Marchand-Brynaert, J.; Garcia, Y. Synthesis 2008, 1, 149–154.
16. Zelenin, K. V.; Khrustalev, V. A.; Sergutina, V. P. Zh. Org. Khimii 1980, 16, 276–
281.
Supplementary data
17. Jursic, B. S.; Zdravkovskif, Z. Synth. Commun. 1994, 24, 1575–1582.
18. Vereshchagin, L. I.; Petrov, A. V.; Kizhnyaev, V. N.; Pokatilov, F. A.; Smirnov, A. I.
Russ. J. Org. Chem. 2006, 42, 1049–1055.
19. Klingele, M. H.; Brooker, S. Eur. J. Org. Chem. 2004, 3422–3434.
20. Curtius, Th.; Schöfer, G.; Schwan, N. J. Prakt. Chem. 1892, 51, 180–196.
21. Ainsworth, C.; Hackler, R. E. J. Org. Chem. 1966, 31, 3442–3444.
22. Efimova, Y. A.; Artamonova, T. V.; Koldobskii, G. I. Russ. J. Org. Chem. 2008, 44,
1345–1347.
CCDC 751484–751491 contain the supplementary crystallo-
graphic 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.
Supplementary
data
(experimental and spectroscopic data) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2009.11.098.
23. Rigo, B.; Fasseur, D.; Cauliez, P.; Couturier, D. Synth. Commun. 1989, 19, 2321–
2335.
24. Navarrete-Vazquez, G.; Molina-Salinas, G. M.; Duarte-Fajardo, Z. V.; Vargas-
Villarreal, J.; Estrada-Soto, S.; Gonzalez-Salazar, F.; Hernandez-Nunez, E.; Said-
Fernandez, S. Bioorg. Med. Chem. 2007, 15, 5502–5508.
References and notes
25. Finnegan, W. G.; Henry, R. A.; Lofquist, R. J. Am. Chem. Soc. 1958, 80, 3908–3911.
26. Meyer, R. DRP No. 574944, 1933.
27. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112–122.
28. Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem. 2003, 115, 1244–
1287.
1. Carta, M.; Msayib, K. J.; Budd, P. M.; McKeown, N. B. Org. Lett. 2008, 10, 2641–
2643.
2. McKeown, N. B.; Budd, P. M. Chem. Soc. Rev. 2006, 35, 675–683.
3. Chui, S. S.-Y.; Lo, S. M.-F.; Charmant, J. P. H.; Guy Orpen, A.; Williams, I. D.
Science 1999, 283, 1148–1150.
4. Hartmann, M.; Kunz, S.; Himsl, D.; Tangermann, O.; Ernst, S.; Wagener, A.
Langmuir 2008, 24, 8634–8642.