Synthesis and characterisation of macromolecules containing multiple tetrazole functionalities

Article abstract of DOI:10.1016/j.tet.2012.04.062

The synthesis of tetra-tetrazole macromolecules, containing various aromatic cores including benzene, pyridine and pyrazine directly attached to the tetrazole moieties, is described. This variation allowed for the generation of ligands with greater potent

Full text of DOI:10.1016/j.tet.2012.04.062

Tetrahedron 68 (2012) 5935e5941
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and characterisation of macromolecules containing multiple tetrazole
functionalities
,
a
a
Jackie Gaire a, John McGinley b , Adrienne Fleming , Fintan Kelleher
*
a Molecular Design and Synthesis Group, Department of Science, Institute of Technology Tallaght, Dublin 24, Ireland
b Department of Chemistry, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of tetra-tetrazole macromolecules, containing various aromatic cores including benzene,
pyridine and pyrazine directly attached to the tetrazole moieties, is described. This variation allowed for
the generation of ligands with greater potential for metal ion complexation. Metal ion complexation
reactions of the tetra-tetrazole macromolecules with the chelating pyridyl-tetrazole arms result in the
formation of metal complexes where the metal ion was bound at the pendant arms rather than at the
central core.
Received 19 January 2012
Received in revised form 27 March 2012
Accepted 16 April 2012
Available online 3 May 2012
Keywords:
Tetrazole
Ó 2012 Elsevier Ltd. All rights reserved.
Macromolecules
Synthesis
Metal ion complexation
NMR
1. Introduction
benzene14 (1), 2,6-bis(2H-tetrazol-5-yl)pyridine13 (2) and 2,3-
bis(1H-tetrazol-5-yl)pyrazine (3) as the starting building blocks
The development of ‘click’ chemistry, as described by Sharpless
and co-workers,1,2 has resulted in an increase in the number of
publications involving tetrazoles.3e7 There are also several reviews
on tetrazoles in the literature, including their use as carboxylic acid
bioisosteres in drug discovery and as functional ligands in co-
ordination chemistry.8e10 Our interest in tetrazoles stems from
their use as precursors for the formation of new functionalised
polytetrazole macrocycles, which could find application, for ex-
ample, as sensors or in molecular recognition. We have previously
reported the synthesis and structural characterisation of several
tetra-tetrazole macrocycles from 1,2-, 1,3- and 1,4-dicyanobenzene
and 2,6-pyridinedicarbonitrile derivatives, as well as the first ex-
ample of a hosteguest interaction between a tetra-tetrazole
macrocycle and a solvent molecule.10e14 In order to increase the
flexibility of tetra-tetrazole ligands, we have removed some of the
rigidity of the system by synthesising macromolecules to include
flexible pendant arms, thus allowing the pendant arms to adapt
their conformation for complexation to a metal ion more easily
than analogous macrocycles. Macromolecules containing several
tetrazole groups have been previously reported.15e17 This paper
focuses on the synthesis and characterisation of tetra-tetrazole
macromolecules using the bis-tetrazoles 1,3-bis(tetrazol-5-yl)
(see Schemes 1 and 2). Preliminary studies on the complexation
reactions of these macromolecules with several metal salts have
also been conducted.
2. Results and discussion
The bis-tetrazole compounds (1, 2 and 3) were synthesised fol-
lowing reported procedures from 1,3-dicyanobenzene, 2,6-
pyridinedicarbonitrile and 2,3-pyrazinedicarbonitrile, respecti-
vely.13,14,18 The 13C NMR spectra of the three compounds showed
a signal at w158 ppm for 1, at w155 ppm for 2 and at w150 ppm,
confirming the formation of the tetrazole systems.11e16 The synthesis
of 2-(60-bromohexyl)-5-phenyl-2H-tetrazole (4) and 2-(600-bromo-
hexyl)-(2-tetrazol-5-yl)pyrazine (6) was carried out using a similar
procedure to that previously reported for the synthesis of 2-(600-bro-
mohexyl)-(2-tetrazol-5-yl)pyridine (5).19 In the 1H NMR spectra of 4
and 6, two triplet signals, at w4.9 ppm and at w3.4 ppm, corre-
sponding to the expected shift for the side-chain NeCH2 and CH2eBr
signalswereobserved.The13CNMRspectraof4and 6showed that the
tetrazole carbon signal resonated at w162 ppm indicative of N2
alkylation.
The phenyl macromolecules 7 and 8 were synthesised by
reacting 2-(60-bromohexyl)-5-phenyl-2H-tetrazole (4) with 1,3-
bis(tetrazol-5-yl)benzene (1) in acetonitrile with triethylamine as
base to afford the tetra-tetrazole macromolecules, as in Scheme 1.
* Corresponding author. E-mail address: john.mcginley@nuim.ie (J. McGinley).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.062

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J. Gaire et al. / Tetrahedron 68 (2012) 5935e5941
Scheme 1. Reagents and conditions: (i) Et3N, MeCN,
D, 24 h.
Both the symmetric 7 and asymmetric 8 tetra-tetrazole macro-
molecules were isolated from the crude reaction mixture. The
symmetric compound 7 was the major product of the reaction and
was isolated, as a white solid, in 41% yield with a melting point of
107d109 ꢀC. The 1H NMR spectrum of 7 had a small number of
signals due to the plane of symmetry within the molecule. The
signals associated with bis(tetrazol-5-yl)benzene region were as
expected with a singlet, doublet and triplet signal being observed at
8.93, 8.26 and 7.64 ppm, respectively. The signals of the phenyl
moiety attached to the mono-tetrazole appeared as a multiplet at
7.47 ppm, similar to that observed in the starting material 4. The
symmetry of the molecule was confirmed by a single triplet signal
observed for the eight protons of the N2 substituted methylene
carbons at 4.66 ppm. The other methylene signals were observed at
2.09 and 1.46 ppm. The 13C NMR spectrum confirmed one signal for
the four N2 substituted tetrazoles at 165.1 ppm. The alkyl region
was uncomplicated with three signals observed at 25.7, 29.1 and
52.9 ppm, respectively.
The asymmetric macromolecule 8 was also isolated as a white
solid, in 23% yield, with a melting point of 111e114 ꢀC. The 1H NMR
spectrum confirmed the asymmetric nature of the compound as
most signals were doubled due to the asymmetry. The four signals
at 8.83, 8.36, 8.13 and 7.69 ppm for the central phenyl ring were
indicative of asymmetric alkylation. A triplet was observed for the
methylene attached to the N2 substituted tetrazoles at 4.65 ppm
and a second triplet was observed at 4.48 ppm for the N1
substituted tetrazole. The remaining methylene signals were ob-
served as multiplets. The 13C NMR spectrum confirmed the
substitution pattern with the appearance of three peaks for the
tetrazoles at 165.5 and 163.6 ppm for the N2 substituted tetrazoles
and at 153.9 ppm for the N1 substituted tetrazole. The signals for
the methylene carbons adjacent to the tetrazole moieties were seen
at 53.1 and 52.8 ppm for the carbons adjacent to the N2 substituted
tetrazoles and at 47.9 ppm for the N1 substituted tetrazole.
The pyridyl-substituted phenyl macromolecule 9 was syn-
thesised by reacting 2-(600-bromohexyl)-(2-tetrazol-5-yl)pyridine
(5) with 1,3-bis(tetrazol-5-yl)benzene (1) in acetonitrile with trie-
thylamine as base, as in Scheme 1. The tetra-tetrazole macromol-
ecule 9 was isolated as a white solid in 28% yield. The mass balance
of the reaction was unreacted starting materials and intractable
side products, which could not be fully separated or characterised.
The product 9 was readily identified by 1H NMR and 13C NMR
spectroscopy, which showed a simple splitting pattern as a result of
the plane of symmetry in the molecule. If asymmetry had been
observed, there would have been a doubling of signals in the NMR
spectra, as were observed in the case of compound 8. In the 1H NMR
spectrum, the signals associated with bis(tetrazol-5-yl)benzene
region were again observed at 8.92, 8.23 and 7.62 ppm, re-
spectively, as a singlet, doublet and triplet signal, as had been
previously observed in compound 7. The formation of the tetra-
tetrazole macromolecule 9 was confirmed by the disappearance
of the CH2eBr signal at ca. 3.40 ppm and the retention and dou-
bling of the integration of the N2eCH2 signal. This signal was ob-
served as a double-triplet at 4.69 ppm. The 13C NMR spectrum
showed two peaks at 164.8 ppm and at 164.6 ppm, identifying that
the compound was N2 substituted, with the difference in the

J. Gaire et al. / Tetrahedron 68 (2012) 5935e5941
5937
Scheme 2. Reagents and conditions: (i) Et3N, MeCN,
D, 24 h.
signals being due to the attachment to either a pyridyl system or
a phenyl system. Further peaks, which identified the formation of
the macromolecule, were the appearance of the two methylene
signals adjacent to the tetrazole nitrogens at 53.2 and 52.9 ppm,
respectively.
nitrogens at 53.4 ppm, which again confirmed the structure of 10.
The 1H NMR analysis of 11 confirmed the asymmetric nature as
nearly all the signals were split due to the lack of a plane of sym-
metry. All the proton signals of the central pyridine ring were ob-
served. The splitting of the 2,6-di(2H-tetrazol-5-yl)pyridine moiety
was as observed in the symmetric analogue 10. As seen in the
previous asymmetric phenyl macromolecules, two triplet signals
were observed at 5.39 ppm for the N1eCH2 substituted tetrazoles
and at 4.70 ppm for the N2eCH2 substituted tetrazoles. The 13C
NMR spectrum confirmed the tetrazole carbon signals at 164.8 and
163.9 ppm for the N2 substituted tetrazoles and the N1 substituted
tetrazole carbon was seen at 154.4 ppm. The signals at 53.2 ppm
(N1) and 49.9 ppm (N2) of the carbons adjacent to the tetrazoles
were as expected.
2,3-Bis(1H-tetrazol-5-yl)pyrazine 3 was reacted with 2-(2-(6-
bromohexyl)-2H-tetrazol-5-yl)pyrazine 6 to yield the symmetric
(12) and asymmetric (13) regioisomers, as shown in Scheme 2. The
asymmetric product was expected to be the minor product due to
the steric effect of the bulky aromatics at the end of the alkyl chain,
but both products were obtained as slightly yellow oils in 8% yields.
The IR spectra of both products 12 and 13 were nearly identical due
to their similar chemical structure. Both the asymmetric and
symmetric compounds were confirmed by mass spectrometry and
elemental analysis. The 1H NMR spectrum of 12 confirmed the
symmetric nature of the compound as the signal for the pyrazine
hydrogens of the central ring was observed as a single singlet at
8.88 ppm. The symmetric nature was further identified by the ap-
pearance of a single signal for the methylene group adjacent to the
The next tetra-tetrazole macromolecules involved the re-
placement of 1,3-bis(tetrazol-5-yl)benzene 1 with 2,6-bis(2H-tet-
razol-5-yl)pyridine 2 (see Scheme 2). This change offered a further
point where metal ion complexation may occur. The isolated yields
of both the symmetric (10) and asymmetric (11) compounds were
11% and 8%, respectively. The IR spectra of both products were very
similar due to their near identical chemical structure, and con-
tained stretches at 2953 and 2857 cmꢁ1 for the pyridyl aromatic
CeH stretches and the typical tetrazole stretches at 1651 cmꢁ1
(>C]Ne), 1593 cmꢁ1 (eN]Ne) and 1260 cmꢁ1 (CeN). The mo-
lecular formula of both the symmetric and asymmetric compounds
was confirmed by mass spectrometry and elemental analysis. The
1H NMR spectrum of 10 confirmed its symmetric nature as the
protons on the central pyridine ring appeared as a single doublet
and a triplet at 8.35 ppm and at 8.05 ppm, respectively. The signals
associated with the 2-(1H-tetrazol-5-yl)pyridine part of the mole-
cule were observed as two doublets at 8.47 and 8.32 ppm and
a triplet at 8.07 ppm, respectively. The appearance of a single
multiplet at 4.72 ppm for the methylene protons adjacent to the
tetrazole carbons confirmed the plane of symmetry in 10. The 13C
NMR analysis confirmed the tetrazole carbon signals at 165.0 and
164.4 ppm for the N2 substituted tetrazoles. A single carbon signal
was observed for the methylene carbons adjacent to the tetrazole

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J. Gaire et al. / Tetrahedron 68 (2012) 5935e5941
tetrazoles, which was observed as a multiplet at 4.74 ppm. The 13
C
course of the titration experiment. The main shifts, however, were
observed for the pyridyl-tetrazole moiety. The clearest indication of
complexation was observed for the proton beside the pyridyl ni-
trogen b, which had shifted downfield by 0.18 ppm. The remaining
pyridyl signals all showed large shifts downfield and the signals for
protons c and e were observed to gradually merge into one signal
after the addition of 15 equiv of Zn2þ ion. No further significant
shift was observed on addition of five more equivalents, which may
signify that one species now predominated in solution or that all
the complexation sites had now been occupied by the metal ion.
Another clear sign that complexation involved the pyridyl nitrogen
and tetrazole nitrogen was the shift of the methylene proton signal
attached to the tetrazole ring. A multiplet, consisting of overlapping
triplets, was observed in the free ligand due to all the tetrazoles
being N2 substituted. On addition of the Zn2þ ion, these two signals
began to differentiate from one another with the signal for the N2
substituted tetrazoles attached to the pyridine rings shifting
downfield from 4.76 to 4.83 ppm. Although a small shift was ob-
served, the multiplicity was clearly shown. The fact this was a clear
triplet might indicate that a symmetric species predominated in
solution. If complexation had occurred on only one of the pendant
arms, then the triplet signal would have been further split, but as
this was not the case it was assumed the predominant species in
solution was symmetric in nature.
NMR analysis confirmed the tetrazole carbon signals at 162.7 and
162.4 ppm for the N2 substituted tetrazoles. A single carbon signal
was also observed for the methylene carbons adjacent to the tet-
razole nitrogens at 53.4 ppm. In the case of compound 13, the 1H
NMR spectrum confirmed the asymmetric nature of the compound
as nearly all the signals were doubled due to this asymmetry. Two
signals were observed for the pyrazine hydrogens of the central
ring of the macromolecule at 8.97 and 8.88 ppm. Two triplet signals
were observed for the methylene carbons adjacent to the tetrazole
nitrogens, one at 4.74 ppm for the N1 substituted tetrazoles and the
second for N2 substituted tetrazoles at 4.63 ppm, similar to what
was observed for the asymmetric macromolecules previously dis-
cussed (8 and 10). The 13C NMR analysis confirmed the tetrazole
carbon signals at 162. and 162.4 ppm for the N2 substituted tetra-
zoles, while the N1 substituted tetrazole was seen at 151.4 ppm. The
asymmetry of the central pyrazine ring was also observed with four
signals at 145.7, 144.7, 143.0 and 142.9 ppm. Two signals at 53.4
(N1) and 48.2 ppm (N2) for the methylene carbons adjacent to the
tetrazoles were also observed.
As the yields of several of the macromolecules were very low,
metal ion complexation studies were only undertaken in earnest
with 9. The tetra-tetrazole macromolecule 9 was designed with the
chelating site between the pendant pyridine and tetrazole rings, as
this has the ability to form five-membered rings.19 It was found that
when metal ion complexation reactions were attempted with the
tetra-tetrazole macromolecules containing the phenyl moieties (7
and 8) in solution, no shifts in either 1H NMR spectra or UVevis
spectra resulted. When complexation reactions were attempted
with the pyridyl tetra-tetrazole macromolecule 9, it suggested that
complexation had resulted as examined by 1H NMR and UVevis
titrations.
Based on this 1H NMR complexation study, two transition metal
complexes of the ligand 9 were synthesised and characterised. The
tetra-tetrazole macromolecule 9 was reacted with CuCl2$2H2O and
Co(SCN)2 metal salts. The macromolecule was dissolved in CHCl3.
To this was added a MeOH solution of the metal salt. The resulting
highly coloured solution was then stirred for one hour and after
several days a highly coloured solid was obtained (Fig. 2).
The IR spectra of both 14 and 15 showed several clear differ-
ences in peak position when compared to that of 9. In 15, there was
a thiocyanate peak at 2073 cmꢁ1, which was not present in 9. Fur-
thermore, this band has shifted from 2152 cmꢁ1 in the metal salt
Co(SCN)2 to 2073 cmꢁ1. The spectra of both 14 and 15 showed that
the stretches of the pyridine and tetrazole rings of the pendant
arms had shifted to higher wavenumber upon complexation to
both the Cu2þ and Co2þ ion, respectively. The shifts in wavenumber
were similar to those observed for the complexation of 5 with
CuCl2$2H2O and Co(SCN)2 as previously reported.19 In the UVevis
The aromatic region of the 1H NMR spectrum of compound 9
(bottom) and the shifts induced by the addition of varying numbers
of molar equivalents of Zn(ClO4)2 are shown in Fig. 1. All spectra
were run in CD3OD, as Zn(ClO4)2 has considerable solubility in this
solvent. Fig. 1 also shows a labelled structure of the tetra-tetrazole
macromolecule 9. The perchlorate salt was chosen as it was hoped
that crystals of any metal complex formed might crystallise more
easily from solution using this anion. However, no crystals were
observed.
An immediate shift was observed on addition of 0.5 mol equiv of
Zn(ClO4)2 and shifts were observed up to 10 mol equiv of Zn(ClO4)2.
The phenyl signals a, d and f did not shift significantly over the
spectra of 14 and 15, a ded transition was observed at 760 nm and
*
751 nm, respectively, which tailed into the visible region similar to
that described by Gallardo.17 We have shown the pyridine-tetrazole
Fig. 1. Aromatic region in 1H NMR spectra of 9 and those obtained upon addition of Zn2þ ion equivalents (CD3OD as solvent), with molecule showing labelled protons for partial
spectra.

J. Gaire et al. / Tetrahedron 68 (2012) 5935e5941
5939
Fig. 2. Suggested structures for the copper (14) and cobalt (15) complexes of macromolecule 9.
moiety can form a five-membered ring when being complexed to
metal ions, and in particular the use of CuCl2 has led to dimeric
copper species.19 The spectroscopic results along with the ele-
mental analysis, in combination with the crystallographic data
previously reported for metal complexes of 5,19 suggest the struc-
tures of complexes 14 and 15, as shown in Fig. 2.
There is also the possibility that both the metal ions in com-
plexes 14 and 15 could bind intermolecularly, rather than in-
tramolecularly as shown in Fig. 2, which would result in an
oligomeric structure. This type of structure would also be consis-
tent with the analytical data. Without an X-ray crystal structure, it
is impossible to prove, which structure is correct. However, based
on the crystallographic data previously reported for metal com-
plexes of 5,19 it is impossible to favour intramolecular binding over
intermolecular binding, as the position of the pendant alkyl chain
has no influence on the binding of the metal ion as previously
discussed.
of 0.18 Hz and 0.01 ppm, respectively. Infrared spectra (cmꢁ1) were
recorded as KBr discs or liquid films between KBr plates using ei-
ther a Nicolet Impact 410 FT-IR spectrometer. Melting point anal-
yses were carried out using a Stewart Scientific SMP 1 melting point
apparatus and are uncorrected. Mass spectrometry was carried out
at the Centre for Synthesis and Chemical Biology (CSCB), University
College, Dublin using Quattro microÔ LCeMS/MS and LCT mass
spectrometers. Microanalyses were carried out at the Microana-
lytical Laboratory of University College, Dublin. Magnetic suscep-
tibility measurements were carried out at room temperature using
a
Johnson Matthey Magnetic Susceptibility Balance with
[HgCo(SCN)4] as reference. UVevis spectra were recorded using
a T80 UVevis spectrophotometer in MeOH (spectrophotometric
grade) unless stated. Spectra were recorded from 210 to 900 nm.
Standard Schlenk techniques were used throughout. Starting ma-
terials were commercially obtained and used without further pu-
rification. The synthesis of compounds 1, 2, 3 and 5 has been
described previously.13,14,18,19 Caution! Nitrogen-rich compounds
such as tetrazole derivatives are used as components for explosive
mixtures.8 In our laboratory, the reactions described were run on
several gram scales, and no problems were encountered. However,
great caution should be exercised when heating or handling com-
pounds of this type. Caution! Although not encountered in our ex-
periments, perchlorate salts of metal ions are potentially explosive and
should be manipulated with care and used only in small quantities.
3. Conclusions
The synthesis of tetra-tetrazole macromolecules, containing
benzene, pyridine and pyrazine as the central ring in the macro-
molecule, are described. This variation has allowed for the gener-
ation of ligands with greater potential for metal ion complexation.
The tetra-tetrazole macromolecules with the benzene core, con-
taining a chelating pyridine-tetrazole pendant arm, lead to the
formation of several metal complexes. In all cases, complexation is
only observed at the pendant arm and not at the central core. This
would suggest that the central core is redundant. We are currently
undertaking further metal ion complexation reactions with the
macromolecules containing the pyridine and pyrazine central core,
as these compounds now contain several potential binding sites.
The results of these studies will be reported in due course.
4.2. 2,3-Bis(1H-tetrazol-5-yl)pyrazine (3)
A suspension of 2,3-pyrazinedicarbonitrile (2.60 g, 0.02 mol),
sodium azide (2.90 g, 0.043 mol), ammonium chloride (2.30 g,
0.043 mol) and lithium chloride (0.60 g, 0.014 mol) in anhydrous
dimethylformamide (60 mL) was stirred for 10 h at 110 ꢀC. After
this time, the solution was cooled and the insoluble salts were re-
moved by filtration. The solvent was then evaporated under re-
duced pressure and the residue was dissolved in deionised water
(200 mL) and acidified with concentrated HCl (3 mL), to initiate
precipitation. The product was filtered, washed with water
(3ꢂ40 mL) and dried to afford a brown solid, which was recrys-
tallised from hot ethanol to afford a yellow crystalline solid (3.27 g,
76%), mp 268e270 ꢀC (lit. 265 ꢀC).18 Found: C, 33.38; H, 1.98; N,
64.80. C6H4N10 requires C, 33.34; H, 1.87; N, 64.79%; nmax (KBr) 3415
4. Experimental
4.1. General
1H and 13C NMR (
d ppm; J Hz) spectra were recorded on a JEOL
JNM-LA300 FT-NMR spectrometer using saturated CDCl3 solutions
with Me4Si reference, unless indicated otherwise, with resolutions
(NeH), 2928, 2855, 1651, 1601, 1452, 1278 cmꢁ1
; dH (300 MHz,

5940
J. Gaire et al. / Tetrahedron 68 (2012) 5935e5941
DMSO-d6) 9.16 (2H, s, pyz-H), 3.56 (2H, br s, NH); dC (75 MHz,
DMSO-d6) 150.3 (CN4), 146.1, 139.8.
125.2, 52.9 (CH2N), 29.1, 25.7; HRMS (ES): [Mþ1]þ, found 671.3543.
C34H39N16 requires 671.3544.
4.3. 2-(60-Bromohexyl)-5-phenyl-2H-tetrazole (4)
4.5.2. 5-Phenyl-2-(6-(5-(3-(1-(6-(5-phenyl-2H-tetrazol-2-yl)hexyl)-
1H-tetrazol-5-yl)phenyl)-2H-tetrazol-2-yl)hexyl)-2H-tetrazole
(8). White solid (0.35 g, 23%), mp 111e114 ꢀC. Found: C, 60.84; H,
5.68; N, 33.42. C34H38N16 requires C, 60.88; H, 5.71; N, 33.41%; Rf
(99:1 chloroform/methanol) 0.48; nmax (KBr) 2927, 2855, 1618,
To 5-phenyl-1H-tetrazole (1.00 g, 6.80 mmol) dissolved in ace-
tonitrile (30 mL) was added potassium carbonate (9.40 g,
68.0 mmol). The resulting suspension was stirred at reflux for
30 min and to the hot solution was added 1,6-dibromohexane
(6.10 g, 25.0 mmol). The reaction mixture was then stirred at
reflux temperature for a further 24 h. After cooling and removal of
inorganic solids, the solvent was removed under reduced pressure
to afford an oil, which was purified by column chromatography on
silica gel (initially at a ratio of petroleum ether/ethyl acetate 4:1,
followed by the ratio of 3:2) to give a waxy white solid (3.2 g, 50%),
mp 42e44 ꢀC. Found: C, 50.46; H, 5.51; N, 18.09. C13H17BrN4 re-
quires C, 50.50; H, 5.54; N, 18.12%; Rf (3:2 petroleum ether/ethyl
1528, 1465, 1261 cmꢁ1
; dH (300 MHz, CDCl3) 8.44 (1H, s, PheH),
8.36 (1H, d, J¼7.7 Hz, PheH), 8.13 (4H, d, J¼7.7 Hz, PheH), 7.80 (1H,
d, J¼7.8 Hz, PheH), 7.69 (1H, t, J¼7.8 Hz, PheH), 7.48e7.46 (6H, m,
PheH), 4.65 (6H, t, J¼7.1 Hz, CH2N2), 4.48 (2H, t, J¼7.2 Hz, CH2N1),
2.06e2.05 (8H, m, CH2), 1.41e1.40 (8H, m, CH2); dC (75 MHz, CDCl3)
165.5 (CN4), 163.6 (CN4), 153.9 (CN4), 130.5, 130.3, 129.4, 128.9,
128.7, 127.4, 126.8, 126.7, 53.1 (CH2N2), 52.8 (CH2N2), 47.9 (CH2N1),
29.0, 25.7; HRMS (ES): [Mþ1]þ, 671.3545. C34H39N16 requires 671.
3544.
acetate) 0.74; nmax (KBr) 2957, 2855,1663,1514,1458,1255 cmꢁ1
; dH
(300 MHz, CDCl3) 8.15 (2H, br d, AreH), 7.48e7.45 (3H, m, AreH),
4.66 (2H, t, J¼7.0 Hz, CH2N), 3.37 (2H, t, J¼6.2 Hz, CH2Br), 2.08e2.06
(2H, m, CH2), 1.85e1.83 (2H, m, CH2), 1.41e1.39 (4H, m, CH2); dC
(75 MHz, CDCl3) 164.9 (CN4), 130.2, 128.9, 127.4, 126.7, 52.9 (CH2N),
33.5 (CH2Br), 32.3, 29.1, 27.4, 25.5.
4.6. 2-(2-(6-(5-(3-(2-(6-(5-(Pyridin-2-yl)-2H-tetrazol-2-yl)
hexyl)-2H-tetrazol-5-yl)phenyl)-2H-tetrazol-2-yl)-2H-
tetrazol-5-yl))pyridine (9)
Compound 1 (0.10 g, 0.06 mmol) was dissolved in acetonitrile
(50 mL). To this was added triethylamine (0.30 mL, 0.16 mmol).
The resulting solution was stirred at reflux for 30 min and to the
hot solution 5 (0.40 g, 0.18 mmol) was added and heating was
continued for a further 24 h. After cooling and removal of in-
organic solids, the solvent was removed under reduced pressure
to afford a yellow oil, which was then purified by column chro-
matography on silica gel (initially at a ratio of chloroform/meth-
anol 99:1, followed by the ratio 19:1). This gave the product 9 as
a white solid (0.12 g, 28%), mp 88e90 ꢀC. Found: C, 57.23; H, 5.41;
N, 37.23. C32H36N18 requires C, 57.13; H, 5.39; N, 37.48%; Rf (19:1
chloroform/methanol) 0.54; nmax (KBr) 2965, 2851, 1629, 1515,
4.4. 2-(600-Bromohexyl-(2-tetrazol-5-yl))pyrazine (6)
To 2-(1H-tetrazol-5-yl)pyrazine (1.00 g, 6.80 mmol) dissolved in
acetonitrile (30 mL) was added potassium carbonate (9.40 g,
68.0 mmol). The resulting suspension was stirred at reflux for
30 min and to the hot solution was added 1,6-dibromohexane
(6.10 g, 25.0 mmol). The reaction mixture was then stirred at
reflux temperature for a further 24 h. After cooling and removal of
inorganic solids, the solvent was removed under reduced pressure
to afford an oil, which was purified by column chromatography
on silica gel (initially at a ratio of petroleum ether/ethyl acetate 4:1,
followed by the ratio of 3:2). This gave the product 6 as a clear
oil (0.55 g, 26%). Found: C, 42.53; H, 4.91; N, 26.95. C11H15BrN6
requires C, 42.46; H, 4.86; N, 27.01%; Rf (3:2 petroleum ether/ethyl
1452, 1249 cmꢁ1
; dH (300 MHz, CDCl3) 8.92 (1H, s, PheH), 8.78
(2H, d, J¼7.7 Hz, pyr-H), 8.26 (2H, d, J¼7.7 Hz, pyr-H), 8.23 (2H, d,
J¼7.7 Hz, PheH), 7.89 (2H, t, J¼7.7 Hz, pyr-H), 7.62 (1H, t, J¼7.8 Hz,
PheH), 7.41 (2H, t, J¼7.7 Hz, pyr-H), 4.69 (8H, t, J¼6.9 Hz, CH2N),
2.11e2.10 (8H, m, CH2), 1.46e1.45 (8H, m, CH2); dC (75 MHz,
CDCl3) 164.8 (CN4), 164.6 (CN4), 150.3, 146.8, 137.1, 129.5, 128.5,
128.2, 125.2, 124.8, 122.0, 53.2 (CH2N), 52.9 (CH2N), 29.0, 25.7;
HRMS (ES): [Mþ1]þ, found 673.3444. C32H37N18 requires
673.3448.
acetate) 0.29; nmax (KBr) 2956, 1663, 1514, 1458, 1255 cmꢁ1
; dH
(300 MHz, CDCl3) 9.62 (1H, s, pyz-H), 8.73 (2H, br d, pyz-H), 4.94
(2H, t, J¼6.9 Hz, CH2N), 3.37 (2H, t, J¼6.2 Hz, CH2Br), 2.02e2.00 (2H,
m, CH2), 1.70e1.68 (2H, m, CH2), 1.42e1.40 (4H, m, CH2); dC
(75 MHz, CDCl3) 162.6 (CN4), 146.2, 145.7, 143.7, 141.8, 49.6 (CH2N),
33.7 (CH2Br), 32.4, 29.7, 27.5, 25.5.
4.7. Preparation of pyridyl macromolecules (10 and 11)
4.5. Preparation of phenyl macromolecules (7 and 8)
Compound 2 (1.40 g, 1.78 mmol) was dissolved in acetonitrile
(50 mL) and to this was added triethylamine (1.20 mL, 8.90 mmol).
The resulting solution was stirred at reflux for 30 min and to this
was added 5 (1.70 g, 5.35 mmol). The solution was then refluxed for
24 h. After cooling, the solvent was removed under reduced pres-
sure to afford a yellow oil, which was then purified by column
chromatography on silica gel using the ratio of chloroform/meth-
anol (99:1).
Compound 1 (0.50 g, 2.30 mmol) was dissolved in acetonitrile
(50 mL). To this was added triethylamine (1.50 mL, 11.0 mmol). The
resulting solution was stirred at reflux for 30 min and to the hot
solution 4 (2.10 g, 7.00 mmol) was added and heating was contin-
ued for a further 24 h. After cooling, the solvent was removed under
reduced pressure to afford a yellow oil, which was then purified by
column chromatography on silica gel (initially at the ratio of chlo-
roform/methanol 99:1, followed by the ratio 95:5).
4.7.1. 2-(2-(6-(5-(6-(2-(6-(5-(Pyridine-2-yl)-2H-tetrazol-2-yl)
hexyl)-2H-tetrazol-5-yl)pyridin-2-yl)-2H-tetrazol-1-yl)hexyl)-2H-
tetrazol-5-yl)pyridine (10). White solid (0.10 g, 8%); mp
132e135 ꢀC. Found: C, 55.22; H, 5.28; N, 39.48. C31H35N19 requires
C, 55.26; H, 5.24; N, 39.50%; Rf (99:1 chloroform/methanol) 0.70;
4.5.1. 5-Phenyl-2-(6-(5-(3-(2-(6-(5-phenyl-2H-tetrazol-2-yl)hexyl)-
2H-tetrazol-5-yl)phenyl)-2H-tetrazol-2-yl)hexyl)-2H-tetrazole
(7). White solid (0.63 g, 41%), mp 107e109 ꢀC. Found: C, 60.75; H,
5.73; N, 33.44. C34H38N16 requires C, 60.88; H, 5.71; N, 33.41%; Rf
(99:1 chloroform/methanol) 0.30; nmax (KBr) 2920, 2851, 1648,
nmax (KBr) 2952, 1651, 1593, 1466, 1418, 1263 cmꢁ1
; dH (300 MHz,
1527, 1465, 1263 cmꢁ1
;
dH (300 MHz, CDCl3) 8.93 (1H, s, PheH),
CDCl3) 8.78 (2H, d, J¼7.7 Hz, pyr-H), 8.35 (2H, d, J¼7.6 Hz, pyr-H),
8.26 (2H, d, J¼7.7 Hz, pyr-H), 8.05 (1H, t, J¼7.7 Hz, pyr-H), 7.87
(2H, t, J¼7.7 Hz, pyr-H), 7.40 (2H, br t, pyr-H), 4.72 (8H, t, J¼6.9 Hz,
CH2N), 2.10e2.09 (8H, m, CH2), 1.44e1.43 (8H, m, CH2); dC (75 MHz,
CDCl3) 165.0 (CN4), 164.4 (CN4), 150.3, 147.5, 146.8, 138.3, 137.1,
8.26 (2H, d, J¼7.7 Hz, PheH), 8.13 (4H, d, J¼7.7 Hz, PheH), 7.64 (1H,
t, J¼7.7 Hz, PheH), 7.47e7.46 (6H, m, PheH), 4.66 (8H, t, J¼7.0 Hz,
CH2N), 2.09e2.08 (8H, m, CH2), 1.46e1.45 (8H, m, CH2); dC (75 MHz,
CDCl3) 165.1 (CN4), 130.3, 129.6, 128.9, 128.5, 128.2, 127.4, 126.8,

J. Gaire et al. / Tetrahedron 68 (2012) 5935e5941
5941
124.8, 123.5, 122.4, 53.4 (CH2N), 29.9, 29.2, 25.9; HRMS (ES): [M]þ,
4.9. Metal complexes of 9
found 673.3379. C31H35N19 requires 673.3323.
To a chloroform solution (10 mL) of 9 (0.02 g, 0.03 mmol) was
added a solution of the appropriate metal salt (0.03 mmol) in
methanol (5 mL). The resulting highly coloured solution was stirred
at room temperature for 1 h. It was then allowed to stand for sev-
eral days, which resulted in highly coloured solids, which were
removed by filtration.
4.7.2. 2-(2-(6-(5-(6-(2-(6-(5-(Pyridine-2-yl)-2H-tetrazol-2-yl)
hexyl)-2H-tetrazol-5-yl)pyridin-2-yl)-1H-tetrazol-1-yl)hexyl)-2H-
tetrazol-5-yl)pyridine (11). White solid (0.12 g, 11%); mp
129e132 ꢀC. Found: C, 55.20; H, 5.21; N, 39.53. C31H35N19 requires
C, 55.26; H, 5.24; N, 39.50%; Rf (99:1 chloroform/methanol) 0.74;
nmax (KBr) 2953, 2857, 1651, 1593, 1465, 1418, 1260 cmꢁ1
; dH
(300 MHz, CDCl3) 8.77 (2H, br d, pyr-H), 8.47 (1H, d, J¼7.7 Hz, pyr-
H), 8.32 (1H, d, J¼7.7 Hz, pyr-H), 8.23 (2H, d, J¼7.7 Hz, pyr-H), 8.07
(1H, t, J¼7.8 Hz, pyr-H), 7.86 (2H, br t, pyr-H), 7.42 (2H, br t, pyr-H),
5.39 (2H, t, J¼7.3 Hz, CH2N1), 4.70 (6H, t, J¼7.4 Hz, CH2N2),
2.12e2.11 (8H, m, CH2), 1.45e1.44 (8H, m, CH2); dC (75 MHz, CDCl3)
164.8 (CN4), 164.7 (CN4), 155.4 (CN4), 150.3, 147.5, 146.8, 138.7, 137.1,
124.8, 124.2, 123.8, 122.3, 53.2 (CH2N2), 49.9 (CH2N1), 29.7, 29.0,
25.8, 25.6; HRMS (ES): [Mþ1]þ, found 674.3394. C31H36N19 requires
674.3401.
4.9.1. [Cu2(9)Cl4]. Dark green solid (0.02 g, 65%); mp >300 ꢀC.
Found: C, 41.12; H, 3.76; N, 26.92. C32H36Cl4Cu2N18 requires C,
40.82; H, 3.85; N, 26.77%; nmax (KBr) 2957, 2854, 1669, 1522, 1460,
1363, 1262 cmꢁ1
;
meff 2.8 B.M.; UVevis (MeOH): 760 nm,
3
¼70 Mꢁ1 cmꢁ1
.
4.9.2. [Co(9)(SCN)2]. Dark blue solid (0.02 g, 65%); mp >300 ꢀC.
Found: C, 45.12; H, 4.35; N, 31.12. C34H36CoN20S2 requires C, 45.03;
H, 4.00; N, 30.89%; nmax (KBr) 2957, 2854, 2073, 1606, 1502, 1459,
1380, 1248 cmꢁ1
3
;
meff 4.4 B.M.; UVevis (MeOH): 751 nm,
¼32 Mꢁ1 cmꢁ1; 508 nm,
3
¼65 Mꢁ1 cmꢁ1
.
4.8. Preparation of pyrazyl macromolecules (12 and 13)
Compound 3 (0.10 g, 0.64 mmol) was dissolved in acetonitrile
(50 mL) and to this was added triethylamine (0.20 mL, 1.60 mmol).
The resulting solution was stirred at reflux for 30 min and to this
was added 6 (0.60 g, 1.90 mmol). The solution was then refluxed for
24 h. After cooling, the solvent was removed under reduced pres-
sure to afford a yellow oil, which was then purified by column
chromatography on silica gel using the ratio of chloroform/meth-
anol (99:1).
Acknowledgements
J.G. thanks the Postgraduate R&D Skills programme (Techno-
logical Sector Research, Strand I) and IT Tallaght Dublin for financial
assistance.
References and notes
1. Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945e7950.
2. Himo, F.; Demko, Z. P.; Noodleman, L.; Sharpless, K. P. J. Am. Chem. Soc. 2003,
125, 9983e9987.
3. Gundugola, A. S.; Chandra, K. L.; Perchellet, E. M.; Waters, A. M.; Perchellet, J.-P.
H.; Rayat, S. Bioorg. Med. Chem. Lett. 2010, 20, 3920e3924.
4. Habibi, D.; Nasrollahzadeh, M.; Faraji, A. R.; Bayat, Y. Tetrahedron 2010, 66,
3866e3870.
4.8.1. 2,3-Bis(2-(6-(5-(pyrazin-2-yl)-2H-tetrazol-2-yl)hexyl)-2H-tet-
razol-5-yl)pyrazine (12). Yellow oil (0.09 g, 8%). Found: C, 49.76; H,
4.71; N, 45.48. C28H32N22 requires C, 49.70; H, 4.77; N, 45.54%; Rf
(99:1 chloroform/methanol) 0.35; nmax (KBr) 2923, 2852, 1653,
1534, 1455, 1260 cmꢁ1
; dH (300 MHz, CDCl3) 9.48 (2H, s, pyz-H),
5. Lakshman, M. K.; Singh, M. K.; Parrish, D.; Balachandran, R.; Day, B. W. J. Org.
Chem. 2010, 75, 2461e2473.
6. Pachfule, P.; Das, R.; Poddar, P.; Banerjee, R. Cryst. Growth Des. 2010, 10,
2475e2478.
7. Li, Q.-Y.; Yang, G.-W.; Tang, X.-Y.; Ma, Y.-S.; Zhou, F.; Liu, W.; Chen, J.; Zhou, H.
Inorg. Chem. Commun. 2010, 13, 254e257.
8. Butler, R. N. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Permagon: Oxford, UK, 1996; Vol. 4, pp 621e678.
9. Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379e3393.
10. McGinley, J.; Fleming, A. J. Inclusion Phenom. Macrocycl. Chem. 2008, 61, 1e10.
11. Bond, A. D.; Fleming, A.; Kelleher, F.; McGinley, J.; Prajapati, V.; Skovsgaard, S.
Tetrahedron 2007, 63, 6835e6842.
12. Bond, A. D.; Fleming, A.; Gaire, J.; Kelleher, F.; McGinley, J.; McKee, V. Tetrahe-
dron 2009, 65, 7942e7947.
13. Fleming, A.; Gaire, J.; Kelleher, F.; McGinley, J.; McKee, V. Tetrahedron 2009, 67,
3260e3266.
8.88 (2H, s, pyz-H), 8.74 (2H, br d, pyz-H), 8.71 (2H, br d, pyz-H),
4.74 (4H, t, J¼7.1 Hz, CH2N), 4.69 (4H, t, J¼7.1 Hz, CH2N), 2.11e2.10
(8H, m, CH2), 1.45e1.44 (8H, m, CH2); dC (75 MHz, CDCl3) 162.7
(CN4), 162.4 (CN4), 145.7, 144.9, 144.8, 143.8, 142.8, 142.6, 53.4
(CH2N), 53.2 (CH2N), 29.0, 25.7; HRMS (ES): [Mþ1]þ, found
677.3261. C28H33N22 requires 677.3259.
4.8.2. 2-(1-(6-(5(-(Pyrazine-2-yl)-2H-tetrazol-2-yl)hexyl)-1H-tetra-
zol-5-yl)-3-(2-(6-5-(pyrazin-2-yl)-2H-tetrazol-2-yl)hexyl)-2H-tetra-
zol-5-yl)pyrazine (13). Yellow oil (0.09 g, 8%). Found: C, 49.74; H,
4.83; N, 45.60. C28H32N22 requires C, 49.70; H, 4.77; N, 45.54%; Rf
(99:1 chloroform/methanol) 0.40; nmax (KBr) 2926, 2854, 1653,
1536, 1465, 1261 cmꢁ1
; dH (300 MHz, CDCl3) 9.48 (2H, s, pyr-H),
14. Fleming, A.; Kelleher, F.; Mahon, M. F.; McGinley, J.; Prajapati, V. Tetrahedron
2005, 61, 7002e7011.
15. Bethel, P. A.; Hill, M. S.; Mahon, M. F.; Molloy, K. C. J. Chem. Soc., Perkin Trans. 1
1999, 3507e3514.
16. Hill, M.; Mahon, M. F.; Molloy, K. C. J. Chem. Soc., Dalton Trans. 1996, 1857e1865.
17. Gallardo, H.; Meyer, E.; Bortoluzzi, A. J.; Molin, F.; Mangrich, A. S. Inorg. Chim.
Acta 2004, 357, 505e512.
18. Reid, W.; Aboul-Fetouh, S. Tetrahedron 1988, 44, 3399e3404.
19. Bond, A. D.; Fleming, A.; Gaire, J.; Kelleher, F.; McGinley, J.; McKee, V.; Sheridan,
U. Polyhedron 2012, 33, 289e296.
8.97 (1H, d, J¼7.7 Hz, pyz-H), 8.88 (1H, d, J¼7.7 Hz, pyz-H), 8.74
(2H, br d, pyz-H), 8.70 (2H, br d, pyz-H), 4.74 (4H, t, J¼6.9 Hz,
CH2N2), 4.63 (2H, t, J¼6.8 Hz, CH2N2), 4.53 (2H, t, J¼7.1 Hz, CH2N1),
2.08e2.07 (8H, m, CH2), 1.41e1.40 (8H, m, CH2); dC (75 MHz, CDCl3)
162.8 (CN4), 162.4 (CN4), 151.4 (CN4), 145.9, 145.8, 145.7, 144.7, 144.5,
143.8, 143.0, 142.9, 53.4 (CH2N2), 48.2(CH2N1), 29.2, 29.0, 28.9, 25.5;
HRMS (ES): [Mþ1]þ, found 677.3258. C28H33N22 requires 677.3259.