A rapid metal free synthesis of 5-substituted-1H-tetrazoles using cuttlebone as a natural high effective and low cost heterogeneous catalyst

Article abstract of DOI:10.1039/c5ra08147e

A convenient, rapid and metal free synthesis of 5-substituted-1H-tetrazoles is described by [3 + 2] cycloaddition reaction of nitriles with sodium azide. The reaction was catalyzed by cuttlebone in DMSO at 110°C. Cycloaddition reaction of nitriles with sodium azide happened in the presence of mesoporous cuttlebone by "electrophilic activation" of nitriles through hydrogen bond formation between the cuttlebone and nitrile. Cuttlebone as a natural low cost heterogeneous catalyst with high porosity, high flexural stiffness, high compressive strength and high thermal stability affords 5-substituted-1H-tetrazoles rapidly with high efficiency.

Full text of DOI:10.1039/c5ra08147e

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A rapid metal free synthesis of 5-substituted-1H-tetrazoles using cuttlebone
as a natural high effective and low cost heterogeneous catalyst
Sara S. E. Ghodsinia, Batool Akhlaghinia*
Abstract:
A convenient, rapid and metal free synthesis of 5ꢀsubstitutedꢀ1Hꢀtetrazoles is described by
[3+2] cycloaddition reaction of nitriles with sodium azide. The reaction was catalyzed by
o
cuttlebone in DMSO at 110 C. Cycloaddition reaction of nitriles with sodium azide was
happened in the presence of mesoporous cuttlebone by “electrophilic activation” of nitriles
through hydrogen bond formation between cuttlebone and nitrile. Cuttlebone as a natural low
cost heterogeneous catalyst with high porosity, high flexural stiffness, high compressive
strength and high thermal stability affords 5ꢀsubstitutedꢀ1Hꢀtetrazoles rapidly with high
efficiency.
Keywords: Metal free synthesis, 5ꢀSubstitutedꢀ1Hꢀtetrazoles, Nitriles, Sodium azide,
Cycloaddition reaction, Mesoporous cuttlebone, Heterogeneous catalyst.
Introduction
Tetrazoles have been known for over a hundred years. They are important and useful class
of heterocycles with wide range of applications in medicinal chemistry,1ꢀ8 coordination
chemistry9 and material science.10 Tetrazoles as precursors of different nitrogen containing

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heterocycles (triazoles, oxazolidones and thiazoles)9a,11 have been studied as lipophilic
spacers12, ion and peptide chelating agents13, cisꢀpeptide bond mimics14 and catalysts in
asymmetric synthesis15. Because of their usefulness, the research on the catalytic preparation
of tetrazoles has been attracted great attention. The first method involves the [3+2]
cycloaddition of an azide with a nitrile which was reported by Hantzsch and Vagt in 1901.16
So far, most of reported methods contain the cycloaddition of nitrile with an azide moiety,
under the influence of several efficient catalysts. For a long time proton acidꢀcatalyzed
cycloaddition was the main routes to 5ꢀsubstitutedꢀ1Hꢀtetrazoles which was suffered from
explosion of large amounts of harmful hydrazoic acid.17ꢀ27 Some of different homogenous and
heterogeneous catalyst systems were also applied in 5ꢀsubstitutedꢀ1Hꢀtetrazoles synthesis via
cycloaddition of nitrile with azide. Numbers of these new catalysts are Pd(OAc)2/ZnBr2,28
ZnO,29 ZnBr2,30 ZnCl2/ tungstates,31 Zn/Al hydrotalcite,32 Zn(OTf)233, Zn hydroxyapatite,34
41
ZnS,35 Cu2O,36 nano ZnO/Co3O4,37 FeCl3ꢀSiO2,38 Fe(OAc)2,39 Fe(HSO4)340 , nano CuFe2O4
, CdCl242, BF3.OEt243, InCl344, I245, (CH3)2SnO,46 TBAFza,47 AgNO3,48 copper triflates,49 βꢀ
cyclodextrin,50 COY zeolites,51 Pd(PPh3)4,52 AgNPs,53 WAlPOꢀ5 microspheres,54
Fe3O4@SiO2/salen of Cu(II),55 CuFe2O4 nano particles,41 B(C6F5)3,56 AlCl3,57 Zn–Cu alloy,58
CAES,59 CuSO4.5H2O,60 In(OTf)3,61 But, in this ways, there are problems including the use of
expensive and toxic metals, highꢀcost reagents, long reaction times (several hours to days) in
combination with high reaction temperatures, strong Lewis acids, low yield, harsh reaction
conditions, boring workꢀups and difficulty in separation and recovery of the catalyst.
Today, as employing the metal catalysts are not always ecoꢀfriendly and because of this,
serious environmental pollution often results,62 and also because of the strict environmental
legislation, there is a huge demand for metalꢀfree, green and safe synthetic methods that not
only reduce the use of toxic and corrosive reagents and stop the formation of inorganic
wastes but also leading to high yield of the desired product.63 In continuation of our studies

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and to promote the methods of tetrazoles preparation,59,60 herein we report an efficient rapid
metal free synthesis of 5ꢀsubstitutedꢀ1Hꢀtetrazoles in the presence of mesoporous cuttlebone
as a new green heterogeneous catalyst with super catalytic activity.
Results and Discussion
Cuttlebone signifies a special class of ultraꢀlight weight, high stiffness and high
permeability cellular biomaterials, which was provided from cuttlefish with an efficient
means of maintaining neutral buoyancy at considerable habitation depths.64,65 Cuttlebone as a
natural material possessing the multifunctional properties with high porosity, high flexural
stiffness, high compressive strength and high thermal stability functions as a rigid buoyant
tank in animal. Cuttlebone with an inorganic–organic composite framework composed of
aragonite, protein and βꢀchitin.66,67 Following our interest in the synthesis of 5ꢀsubstitutedꢀ
1Hꢀtetrazoles, we speculated on the possibility of using cuttlebone to achieve 5ꢀsubstitutedꢀ
1Hꢀtetrazoles by [3+2] cycloaddition reaction of nitriles with sodium azide (Scheme 1).
N
R
Cuttlebone (0.05 g)
DMSO, 110 °C
N
R C N
Na
N N N
+
HN N
1-18
R = Ph, 4ꢀBrC6H4, 4ꢀClC6H4, 4ꢀCNC6H4, 4ꢀNO2C6H4, 2ꢀNH2 5ꢀNO2C6H3,
4ꢀEtOC6H4, 3,5ꢀdiꢀMeOC6H4, 3ꢀMeC6H4, 4ꢀOHC6H4, 2ꢀOHC6H4, 9ꢀphenanthrene,
2ꢀthiophene, 4ꢀpyridine, 2ꢀpyridine, (CH3)2CHCH2, (CH3)2CH(CH2), PhCH2
Scheme 1 Synthesis of different structurally 5ꢀsubstitutedꢀ1Hꢀtetrazoles in the presence of
cuttlebone in DMSO.
Cuttlebone was taken out from cuttlefish (Sepia esculenta),64,65,68,69 which is commonly
found in saltwater beaches like Persian Gulf in Iran. This sample was in a fairly good

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condition with minimal external damage. In order to remove pollution on the surface of
cuttlebone, the catalyst was powdered, washed with distilled water and dried at 100 °C for 2h.
The model reaction was carried out by taking the mixture of benzonitrile with sodium azide
in the presence of cuttlebone. Table 1 gives the details about the amount of cuttlebone, molar
ratios of benzonitrile / NaN3, solvent and temperature which were used to optimize the
reaction conditions. Only 30% addition product is obtained when the reaction is carried out
without catalyst in DMSO at 140 ºC (Table 1, entry 1), despite of prolonged reaction time. At
the same reaction condition, 100% conversion was obtained after 20 min in the presence of
cuttlebone (Table 1, entry 2). This result highlights the specific role of cuttlebone in [3+2]
cycloaddition reaction of benzonitrile with sodium azide. In an effort to develop better
reaction conditions, different solvents were screened for cycloaddition reaction in the
presence of cuttlebone (Table 1, entries 3ꢀ9). Other solvents, such as DMF, toluene, H2O,
CH3CN gave the desired product in low yield (Table 1, entries 4ꢀ6) but no product was
obtained when the reaction was performed in 1,4ꢀdioxane, CH3NO2 and CHCl3 (Table 1,
entries 7ꢀ9). As shown in Table 1 among the different solvents tested DMSO was found to be
the solvent of choice for [3+2] cycloaddition reaction in the presence of cuttlebone. At lower
reaction temperature (130 ºC and 110 ºC) the reaction was progressed as the same as at 140
ºC (Table 1, entries 10ꢀ12). To investigate the effect of catalyst loading, the formation of 5ꢀ
phenylꢀ1Hꢀtetrazole was carried out in DMSO at 110 ºC in the presence of 0.07 g and 0.03 g
of catalyst. According to this study, increasing the catalyst loading did not lead to higher
conversion (Table 1, entry 13), while lower catalyst loading has lessened the reaction yield
even after longer reaction time (Table 1, entry 14). To improve [3+2] cycloaddition reaction,
the effect of different molar ratio of benzonitrile / sodium azide was also examined in DMSO
at 110 ºC. It is noteworthy that additional amount of sodium azide cannot improve the
reaction rate (Table 1, entry 15). By considering the cuttlebone structure66,67 and to

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understand which segment of cuttlebone catalyzed [3+2] cycloaddition reaction, the
optimized reaction conditions were applied on the cyclization of benzonitrile with sodium
azide in the presence of CaCO3 and freshly extracted βꢀchitin from cuttlebone70 respectively
(Table 1, entries 16, 17). In comparison, a trace amount of product was produced in the
presence of CaCO3 while in the presence of βꢀchitin the reaction was completed after longer
reaction time.
Table 1 Synthesis of 5ꢀphenylꢀ1Hꢀtetrazole in the presence of different amounts of
cuttlebone, different molar ratios of benzonitrile / NaN3 in various solvents at
different temperatures.
Entry
Molarratio
Catalyst
(g)
Solvent
Temperature
(ºC)
Time
(h)
Isolated
(Benzontrile / NaN3)
Yield (%)
1
2
3
4
5
6
7
8
9
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
ꢀ
DMSO
DMSO
DMF
140
10
30
98
65
10
5
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
140
20 min
140
2
2
2
2
2
2
2
CH3CN
Toluene
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
10
0
CH3NO2
1,4ꢀDioxane
CHCl3
0
0

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10
11
12
13
14
15
16a
17b
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1/5
1 : 1
1 : 1
0.05
0.05
0.05
0.07
0.03
0.05
0.05
0.05
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
130
110
100
110
110
110
110
110
20 min
20 min
20 min
20 min
2
98
98
95
98
65
20 min
20 min
20/40 min
98
Trace
85/98
a The reaction was performed in the presence of CaCO3.
b The reaction was performed in the presence of freshly extracted βꢀchitin from cuttlebone.
It can be seen from Table 2 that, admirable yields of the desired 5ꢀsubstitutedꢀ1Hꢀ
tetrazoles were obtained rapidly by using 0.05 g of cuttlebone in solution of 1:1 molar ratio of
organic nitriles / NaN3 in DMSO at 110 °C. The reaction times and product yields of
aromaric nitriles bearing electron withdrawing and electron donating groups have a
significant difference, because of the obvious difference in electrophilic character of nitrile.
The aromatic nitriles containing electron withdrawing substituents such as –Cl, –Br, −CN, –
NO2 at para position took less time (15ꢀ30 min) for complete conversion of starting material
(Table 2, entries 2ꢀ5). 2ꢀAminoꢀ5ꢀnitrobenzonitrile results the desired product in longer
reaction time due to steric effect and electron donation of –NH2 substitution at ortho position
(Table 2, entry 6). Moreover, aromatic rings with electron donating groups (–NH2, −OCH3,

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CH3, −OCH2CH3 and –OH) gave the corresponding tetrazoles in high yields, although longer
reaction times (40 minꢀ 2 h) were required (Table 2, entries 7ꢀ11). Interestingly, aryl nitrile
containing a free hydroxy group at ortho or para positions gave desired product in high yield
after 1 h or 40 min respectively (Table 2, entries 10 and 11). Hydroxy group at ortho position
render inductive effect which accelerates the cycloaddition reaction of 2ꢀhydroxybenzonitrile.
Phenanthreneꢀ9ꢀcarbonitrile with steric hindrance at 9 position produced the corresponding
tetrazole after 2 h (Table 2, entry 12). Similarly, heteroaryl nitriles were found to be
extremely reactive substrate affording the relative tetrazole rapidly in the presence of
cuttlebone (Table 2, entries 13ꢀ15). We next examined the cycloaddition of alkyl nitriles such
as 3ꢀmethylbutanenitrile, 4ꢀmethylpentanenitrile and 2ꢀphenylacetonitrile with azide ion in
the presence of cuttlebone. It was found that alkyl nitriles in the presence of cuttlebone
reacted smoothly to give the corresponding 1Hꢀtetrazoles in excellent yields after 1ꢀ1.5 h
(Table 2, entries 16ꢀ18). The results obtained from Table 2 indicate that [3+2] cycloaddition
reaction of nitriles with sodium azide in the presence of cuttlebone proceeds rapidly
irrespective of the electronic nature of nitrile compound.
Table 2 Synthesis of different structurally 5ꢀsubstitutedꢀ1Hꢀtetrazoles in the
presence of cuttlebone in DMSO.
Entry
1
Substrate
Product
Time (min) Isolated Yield (%)
20
98

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30
95
2
15
18
15
97
98
98
3
4
5
50
96
6
40
90
95
7
8
2 (h)

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2 (h)
95
9
1 (h)
87
95
10
11
40
2 (h)
85
12
40
30
90
97
13
14
15
40
92

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1.5 (h)
1.5 (h)
1 (h)
95
95
98
16
17
18
FTꢀIR spectroscopy of all purified products revealed an absorption band at 3485ꢀ3329 cmꢀ1
(NꢀH) and group of bands at 1469ꢀ1430 cmꢀ1 (scissoring bending CꢀH), 1293–1233 cmꢀ1 ( N–
N=N– ), 1189–1110 and 1106ꢀ1041 cmꢀ1 (tetrazole ring) and absence of band at 2200 cmꢀ1
1
due to CN group. In H NMR and 13C NMR spectra, a signal at 16.9 and 161–155 ppm are
assigned to the NH and quaternary carbon NH–C=N respectively.
All of the products were known compounds and characterized by the FTꢀIR spectroscopy,
mass spectrometry and comparison of their melting points with known compounds.The
structure of selected products was further confirmed by 1H NMR and 13C NMR spectroscopy.
A plausible mechanism for the reaction methodology under current development is shown in
Scheme 2. The fact that after a long reaction time, lower yield of product was observed in the
absence of cuttlebone (Table 1, entry 1) established the catalytic activity of cuttlebone in [3 +
2] cycloaddition reactions of various organic nitriles with sodium azide. Although the role of
cuttlebone in [3+2] cycloaddition reaction is not clear definitively, it is speculated that a
ternary complex A among nitrile compound, azide ion and cuttlebone (βꢀchitin as organic
segment of catalyst) would be generated in the transition state immediately as shown in
Scheme 2. In accordance with Scheme 2 the following steps are postulated to occur: the
hydrogen bonding of βꢀchitin with nitrogen atom of nitrile compound accelerates the

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cyclization step via increasing the electrophilicity of nitrile group. The [3 + 2] cycloaddition
between the C≡N bond of nitrile compound and azide ion takes place readily to form the
intermediate B. After removing the catalyst by simple filtration, C was produced as sodium
salt which upon acidic workꢀup, leads to formation of D and E. Finally the more stable
tautomer E (5ꢀsubstitutedꢀ1Hꢀtetrazole) was obtained as major product. Further investigation
on the elucidation of the mechanism and scope of this reaction are currently underway in our
laboratory.
Scheme 2 Proposed mechanism for the synthesis of 5ꢀsubstitutedꢀ1Hꢀtetrazoles in the
presence of cuttlebone.

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[3+2] Cycloaddition reaction of organic nitriles with sodium azide in the presence of
cuttlebone was vigorously dependent on physical form of the catalyst. Excellent yield of
product was obtained in the presence of fine powdered cuttlebone, while 5ꢀphenylꢀ1Hꢀ
tetrazole was obtained in 20 % yield in the presence of nonꢀpowdered cuttlebone. On the
basis of the results obtained from Table 1 (entries 16, 17), organic segment of cuttlebone (βꢀ
chitin) has an essential role in catalytic activity of cuttlebone. So, in the presence of βꢀchitin
(which was extracted from cuttlebone according the method reported previously)65 the
reaction was completed after longer reaction time, and in the presence of CaCO3 (as
inorganic segment of cuttlebone) a trace amount of product was produced. Performing the
reaction in the presence of βꢀchitin suffered from long reaction time and tedious workꢀup
procedure, because of gelation of βꢀchitin in the reaction mixture. Also, βꢀchitin is not
reusable catalyst in [3+2] cycloaddition reaction. Interestingly, cuttlebone matrix improved
the catalytic activity of βꢀchitin significantly with providing easy and simple removing of
catalyst which could be reusable several times (Fig.1).
Recyclability is important for industrial application of a catalyst. Therefore, the reuse
performance of cuttlebone was investigated. After completion of [3+2] cycloaddition reaction
of benzonitrile with sodium azide, cuttlebone was separated by simple filtration from the
reaction mixture, washed with distilled water and ethanol several times to remove the organic
products. The catalyst was dried at 100°C for 1 h. The heterogeneous catalyst was used for 6
successive times in the new experiments without dramatic yield loss and generate product
with purity similar to that obtained in the first run (Fig.1).

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100
100
100
100
100
95
90
98
98
95
95
92
90
100
80
60
40
20
0
85
First
Second
Third
Fourth
Fifth
Sixth
Seventh
Isolated yield
Conversion
Fig. 1 [3 + 2] Cycloaddition reactions of benzonitrile with sodium azide in the presence of
reused cuttlebone.
The FTꢀIR spectrum of cuttlebone and the 6th recovered cuttlebone was shown in Fig. 2. As
can be seen, the shape, position and relative intensity of all characteristic peaks are well
preserved. The results indicate no considerable changes were observed on the chemical
structure of functional groups and the hydrogen bonding network (Fig. 2).
120
(a)
100
80
60
40
(b)
20
0
-20
-40
-60
3900
3400
2900
2400
1900
1400
900
400
Wavenumbers ( cm-1)
Fig. 2 FTꢀIR spectrum of cuttlebone and 6th recovered cuttlebone.

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In comparison, [3+2] cycloaddition reaction of nitriles with sodium azide in the presence
of cuttlebone affords 5ꢀsustitutedꢀ1 ꢀtetrazole rapidly in high yield than the earlier reported
H
catalysts (Table 3). As can be seen from Table 3, all of the previously reported methods
suffer from long reaction times to achieve suitable yields as well as use of strong Lewis acids,
expensive and toxic metals and tedious workꢀup procedure.
Table 3 Comparison of various catalysts in [3+2] cycloaddition reaction of nitriles with
sodium azide
Entry
Catalyst
Solvent
DMF
DMF
ꢀ
Temp. ºC Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
Mesoporous ZnS 35
120
Reflux
120
36
5
96
88
84
87
83
90
90
84
78
Silica sulfuric acid 71
Imidazoleꢀbased zwitterionicꢀtype molten salts72
Chitosan derived magnetic ionic liquid 73
12
7
ꢀ
70
48
AgNO3
DMF
DMF
DMF
DMF
DMF
120
5
CoY zeolite 74
Fe3O4@SiO2/Salen Cu(II)55
Zn/Al hydrocalcite 32
Zn Hydroxyapatite34
120
14
7
120
120ꢀ130
120
12
12

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10
11
12
13
14
AgNPs 53
DMF
120
120
130
140
110
8
92
94
95
98
98
56
B(C6F5)3
DMF
8
CAES59
DMSO
DMSO
DMSO
1
1
CuSO4.5H2O60
Cuttlebone
20 min
Experimental
General
The purity determinations of the products were accomplished by TLC on silica gel
polygram STL G/UV 254 plates. The melting points of products were determined with an
Electrothermal Type 9100 melting point apparatus. The FTꢀIR spectra were recorded on an
Avatar 370 FTꢀIR Therma Nicolet spectrometer. The NMR spectra were provided on Brucker
Avance 100 and 400 MHz instruments in acetoneꢀd6, DMSOꢀd6 and CD3CN. Elemental
analyses were performed using a Thermo Finnegan Flash EA 1112 Series instrument. Mass
spectra were recorded with Agilent Technologies (HP) 5973 Network Mass Selective
Detector, Shimadzu GCꢀMSꢀQP5050 instruments and a CH7A Varianmat Bremem
instrument (Germany) at 70 eV. Elemental compositions were determined with a Leo 1450
VP scanning electron microscope equipped with an SC7620 energy dispersive spectrometer
(SEMꢀEDS) presenting a 133 eV resolution at 20 kV. All of the products were known
compounds and characterized by the FTꢀIR spectroscopy and comparison of their melting
points with known compounds. The structure of selected products was further confirmed by
1H NMR, 13C NMR spectroscopy, and mass spectrometry. Cuttlebone was taken out from

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cuttlefish (Sepia esculenta),64,65,68,69 which is commonly found in saltwater beaches like
Persian Gulf in Iran.
Pre-Preparation of cuttlebone
In order to remove pollution on the surface of cuttlebone, the catalyst was powdered,
washed with distilled water and dried at 100 °C for 2h.
Characterization of cuttlebone
Cuttlebone was identified by FTꢀIR spectroscopy, scanning electron microscope and
energy dispersive spectrum (SEMꢀEDS). The FTꢀIR spectrum of the cuttlebone (Sepia
esculenta) shows absorption bands between 3440ꢀ699 cmꢀ1(Fig. 3). The observed absorptions
bands for aragonite phases (calcium carbonate) in cuttlebone structure are due to the planar
CO3ꢀ2 ion. There are four vibrational modes in the free CO3ꢀ2 ion:75 the symmetric stretching
vibration of the carbonate ion at about 1082 cm−1 (ν1); the outꢀofꢀplane bending absorption at
about 857 cm−1 (ν2); the asymmetric stretching vibrations at about 1400ꢀ1500 cm−1 (ν3); the
split inꢀplane bending vibrations at about 700 cm−1 (ν4). Also, as shown in the FTꢀIR
spectrum of cuttlebone (Fig. 3), the bands at 3448 and 3318 cmꢀ1 are attributed to the OH and
NH stretching vibrations respectively, which are related to absorption bands of βꢀchitin
segment of cuttlebone. The hydrogen bonding network of βꢀchitin in cuttlebone would
change the shape and intensity of the above mentioned absorption bands. The absorption
bands ranging from 2977 to 2855 cm−1 were related to symmetric stretching of CH, CH3 and
asymmetric stretching vibrations of CH2. The CH bending, CH3 symmetric deformation and
CH2 wagging bands were appeared at 1384 to 1312 cm−1. The absorption bands at 1662 and
1644 cmꢀ1 are assigned to amide I band (two types of hydrogen bonds in a C=O group with
the NH group of the adjacent chain and the OH group of the interꢀchain). Amide II band (inꢀ
plane N–H bending and C–N stretching mode) at about 1550 and 1360 cmꢀ1 and amide III

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band (inꢀplane mode of the CONH group) are observed at 1315 cmꢀ1. The absorption bands
ranging from 1160 to 1030 cm−1 are attributed to the asymmetric bridge oxygen and C–O
stretching vibrations.76,77
(b)
(a)
Fig. 3 FTꢀIR spectrum of the (a) cuttlebone and (b) extracted βꢀchitin from cuttlebone.
Scanning electronic microscopy (SEM) of transverse section of cuttlebone commonly
reveals an approximately periodic microstructure. The most common base cell (or smallest
representative volume element ꢀ RVE) has a bridgeꢀlike configuration (Fig. 4). This base cell
geometry can be used to approximate the mechanical properties for cuttlebone.66
Lamella
Pillar
Fig. 4 SEM image of cuttlebone.

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Also, as was shown in Fig. 5 scanning electronic microscopy (SEM) of finely powdered
cuttlebone shows an amorphous morphology.
Fig. 5 SEM image of finely powdered cuttlebone.
The energy dispersive spectrum (EDS) indicates the presence of Ca, C, O and Cl elements in
cuttlebone structure (Fig. 6).
Fig. 6 EDS of finely powdered cuttlebone.
Typical procedure for the preparation of 5-phenyl-1H-tetrazole in the presence of
cuttlebone

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Finely powdered cuttlebone (0.050) was added to a mixture of benzonitrile (0.1031 g, 1
mmol) and sodium azide (0.0650 g, 1 mmol) in DMSO (2 mL) with stirring at room
temperature. The reaction temperature was raised up to 110 °C for 20 min. The progress of
the reaction was monitored by TLC. After completion of reaction (monitored by thinꢀlayer
chromatography, TLC), the reaction mixture was cooled and the catalyst was filtered. The
filtrate was treated with HCl (4 N, 10 mL) and then ethyl acetate (2×10 mL). The resultant
organic layer was washed with distilled water, dried over anhydrous sodium sulfate, and
concentrated to give the crude solid crystalline 5ꢀphenylꢀ1
recrystallized from ꢀhexane/ethylacetate (1:1) obtaining 0.1430 g of colourless crystals
(98% Isolated Yield).
Hꢀtetrazole. The crude product was
n
5-Phenyl-1H-tetrazole (Table 2, Entry 1). White solid; mp 214ꢀ216 ºC (Lit.75 214ꢀ216 ºC);
FTꢀIR (KBr): νmax/cmꢀ1 3125, 3043, 2982, 2913, 2835, 2765, 2692, 2606, 2557, 2488, 1613,
1
1563, 1485, 1465, 1409, 1163, 1056, 726, 703, 687; H NMR (400 MHz, DMSOꢀ
d
6, ppm)
δ
13
7.61 (s, 3H, Ph), 8.05 (s, 2 H, Ph); C NMR (100 MHz, DMSOꢀ
d6, ppm) δ 124.6, 127.4,
129.9, 131.7, 155.7.
5-(4-Boromophenyl)-1H-tetrazole (Table 2, Entry 2). White solid; mp 264ꢀ265 ºC (Lit.79
265 ºC); FTꢀIR (KBr): νmax/cmꢀ1 3089, 3063, 2996, 2900, 2844, 2761, 2729, 2633, 1652,
1
1604, 1560, 1482, 1431, 1405, 1157, 1076, 1054, 1018, 829, 744, 502; H NMR (100 MHz,
DMSOꢀd6, ppm) δ
8.00 (q, 4H, Ph); MS, m/z (%): 226 [M+ + 2], 224 [M+], 198 [(M+ + 2) ꢀ
N2], 196 (100) [M+ ꢀ N2], 185 [(M+ + 2) ꢀ N3], 183 [M+ ꢀ N3].
5-(4-Chlorophenyl)-1H-tetrazole (Table 2, Entry 3). White solid; mp 261ꢀ262 ºC (Lit.76
261ꢀ263 ºC). FTꢀIR (KBr): νmax/cmꢀ1 3092, 3060, 3007, 2978, 2907, 2851, 2725, 2622, 2537,
2471, 1609, 1564, 1486, 1435, 1160, 1096, 1053, 1020, 990, 833, 745, 508; 1H NMR (400

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MHz, DMSOꢀ
d
6, ppm)
δ
7.68 (d,
J
= 8.4 Hz, 2H, Ph), 8.05 (d, J
= 8.8 Hz, 2H, Ph); 13C NMR
(100 MHz, DMSOꢀ
d
6, ppm) δ 123.5, 129.2, 130.0, 136.4, 155.3.
4-(1H-tetrazol-5-yl)benzonitrile (Table 2, Entry 4). White solid; mp 190ꢀ191 ºC (Lit.80 192
ºC); FTꢀIR (KBr): νmax/cmꢀ1 3150, 3092, 3013, 2928, 2861, 2758, 2610, 2231, 1585, 1560,
1494, 1433, 1279, 1153, 1014, 976, 944, 850, 749, 554; 1H NMR (100 MHz, CD3CN, ppm)
δ
13
7.90 (d,
ppm)
J
= 7.5 Hz, 2H, Ph), 8.20 (d,
J
= 7.5 Hz, 2H, Ph); C NMR (100 MHz, DMSOꢀd6
,
δ
113.8, 118.6, 128.0, 129.1, 133.7, 155.6; MS, m/z (%): 171 [M+], 142 (100) [M+ ꢀ
N2], 114 [M+ ꢀ 2N2].
5-(4-Nitrophenyl)-1H-tetrazole (Table 2, Entry 5).Yellow solid; mp 218ꢀ219 ºC (Lit.80
219ꢀ220 ºC). FTꢀIR (KBr): νmax/cmꢀ1 3448, 3334, 3235, 3109, 3080, 2974, 2900, 2819, 2659,
1
1562, 1532, 1488, 1357, 1340, 1315, 1143, 1106, 995, 867, 853, 730, 710; H NMR (400
MHz, DMSOꢀ
d
6, ppm)
δ
8.31 (d,
125.1, 128.6, 131.0, 149.2, 155.9.
J = 8.4 Hz, 2H, Ph), 8.46 (d, J
= 8.8 Hz, 2H, Ph); 13C NMR
(100 MHz, DMSOꢀ
d
6. ppm)
δ
4-Nitro-2-(1H-tetrazol-5-yl)benzenamine (Table 2, Entry 6). White solid; mp 268ꢀ270 ºC
(Lit.81 270ꢀ271 ºC); FTꢀIR (KBr): νmax/cmꢀ1 3411, 3321, 3199, 3084, 2937, 1645, 1616, 1572,
1
1477, 1325, 1278, 1141, 1041, 910, 831, 751, 722; H NMR (400 MHz, DMSOꢀ
d
6, ppm)
= 9.2, J = 2,4 Hz, 1H, Ph), 8.81
104.4, 116.3, 126.1, 127.6,
δ
7.00 (d,
(d,
136.3, 153.0, 154.4.
J
= 9.2 Hz, 1H, Ph), 7.94 (br s, 1H, NH), 8.10 (dd, J
13
J
= 2.4 Hz, 1H, Ph); C NMR (100 MHz, DMSOꢀ
d
6, ppm)
δ
5-(4-Ethoxyphenyl)-1H-tetrazole (Table 2, Entry 7). White solid; mp 234ꢀ235 ºC (Lit.60
234ꢀ235 ºC); FTꢀIR (KBr): νmax/cmꢀ1 3145, 3101, 3060, 2986, 2921, 2868, 2737, 2647, 1613,
1
1505, 1470, 1394, 1293, 1262, 1189, 1056, 1041, 923, 827, 751, 653, 522; H NMR (100
MHz, acetoeꢀ
d
6, ppm)
δ 1.40 (t, J = 5 Hz, 3H, ꢀOEt), 4.20 (q, 2H, ꢀOEt), 7.15 (d, J = 9.5 Hz,
2H, Ph), 8.07 (d,
J
= 9.5 Hz, 2H, Ph).

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5-(3,5-Dimethoxyphenyl)-1H-tetrazole (Table 2, Entry 8). White solid; mp 204ꢀ205 ºC
(Lit.41 204ꢀ206 ºC); FTꢀIR (KBr): νmax/cmꢀ1 3129, 3064, 3011, 2975, 2941, 2843, 2757, 2712,
2634, 1605, 1562, 1480, 1430, 1287, 1208, 1167, 1162, 1054, 827, 747; 1H NMR (400 MHz,
DMSOꢀ
16.91 (br s, 1H, NH); 13C NMR (100 MHz, DMSOꢀ
156.3, 161.5; MS, m/z (%): 207 [M + H], 149 (100) [M+ ꢀ 2N2].
d
6, ppm)
δ
3.84 (s, 6H, ꢀOMe), 6.73 (t,
J
= 2 Hz, 1H, Ph), 7.21 (d,
J
= 2 Hz, 2H, Ph),
d
6, ppm) δ 56.0, 103.4, 105.3, 125.7,
5-m-Tolyl-1H-tetrazole (Table 2, Entry 9).White solid; mp 149 ꢀ150 ºC (Lit.31 151ꢀ152 ºC);
FTꢀIR (KBr): νmax/cmꢀ1 3120, 3061, 2979, 2917, 2871, 2746, 2611, 2490, 1728, 1605, 1565,
1486, 1463, 1150, 1060, 1038, 802, 741, 705, 687; 1H NMR (100 MHz, CD3CN, ppm)
(s, 3H, CH3), 7.40ꢀ7.90 (m, 4H, Ph).
δ 2.43
4-(1H-tetrazol-5-yl)phenol (Table 2, Entry 10). White solid; mp 218ꢀ219 ºC (Lit.82 219ºC);
FTꢀIR (KBr): νmax/cmꢀ1 3252, 3101, 3066, 3019, 3000ꢀ2200, 1615, 1599, 1511, 1466, 1413,
1282, 832, 752, 514; 1H NMR (400 MHz,
7.87 (d, = 8.8 Hz, 2H, Ph), 10.20 (br s, 2H, OH); C NMR (100 MHz, DMSOꢀ
115.0, 116.6, 129.2, 155.2, 160.5.
d
6 DMSOꢀ
d
6, ppm)
δ
6.97 (d,
J
= 8.4 Hz, 2H, Ph),
6, ppm)
13
J
d
δ
2-(1H-tetrazol-5-yl)phenol (Table 2, Entry 11).White solid; mp 218ꢀ219ºC (Lit.82 219 ºC):
FTꢀIR (KBr): νmax/cmꢀ1 3175, 2970, 2855, 2721, 2561, 1616, 1545, 1490, 1467, 1392, 1365,
1298, 1071, 999, 837, 745, 465; MS, m/z (%): 162 [M+], 161 [M+ ꢀ H], 133 (100) [M+ ꢀ 2N2].
5-(Phenanthren-9-yl)-1H-tetrazole (Table 2, Entry 12). White solid; mp 241ꢀ242 ºC (Lit.83
243ꢀ244 ºC); FTꢀIR (KBr): νmax/cmꢀ1 3105, 3076, 3016, 2978, 2878, 2830, 2724, 2686, 2622,
2590, 2520, 2478, 1612, 1565, 1450, 1399, 1246, 1112, 1053, 1038, 992, 934, 771, 737, 721,
1
424; H NMR (100 MHz, DMSOꢀ
d
6. ppm)
δ
7.79ꢀ7.82 (m, 4H, Ph), 8.08ꢀ8.20 (m, 1H, Ph),
8.40ꢀ8.52 (m, 2H, Ph), 8.92ꢀ9.10 (m, 2H, Ph); Ms, m/z (%): 246 [M+], 218 (100) [M+ ꢀ N2],
190 [M+ ꢀ 2N2].

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5-(Thiophen-2-yl)-1H-tetrazole (Table 2, Entry 13). White solid; mp 205ꢀ207 ºC (Lit.84
205ꢀ207 ºC); FTꢀIR (KBr): νmax/cmꢀ1 3109, 3074, 2974, 2891, 2780, 2722, 2628, 2569, 2500,
2456, 1830, 1595, 1503, 1411, 1233, 1139, 1046, 962, 853, 740, 719; 1H NMR (100 MHz,
CD3CN, ppm)
δ 7.20ꢀ7.30 (m, 1H, Tiophen), 7.67ꢀ7.80 (m, 2H, Tiophen); Ms, m/z (%): 152
[M+], 124 (100) [M+ ꢀ N2], 97 [M+ ꢀ 2N2].
4-(1H-tetrazol-5-yl)pyridine (Table 2, Entry 14). White solid; mp 255ꢀ258 ºC (Lit.78 255ꢀ
258 ºC); FTꢀIR (KBr) νmax/cmꢀ1 3485, 3264, 3099, 3035, 2966, 1624, 1529, 1435, 1388,
1123, 1096, 1042, 1022, 845, 730, 674, 593, 465.
2-(1H-tetrazol-5-yl)pyridine (Table 2, Entry 15). White solid; mp 211ꢀ213 ºC (Lit.76 210ꢀ
213 ºC); FTꢀIR (KBr): νmax/cmꢀ1 3088, 3060, 2959, 2929, 2864, 2737, 2692, 2622, 2582,
1728, 1602, 1557, 1483, 1449, 1405, 1284, 1158, 1068, 1024, 955, 795, 743, 726, 703, 637,
1
496; H NMR (400 MHz, DMSOꢀ
d
6, ppm)
δ
7.65 (s, 1H, Py), 8.10 (s, 1H, Py), 8.24 (d, J =
6.4 Hz, 1H, Py), 8.81 (s, 1H, Py); 13C NMR (100 MHz, DMSOꢀ
138.7, 144.0, 150.6, 155.3.
d6, ppm) δ 123.1, 126.7,
5-Isobutyl-1H-tetrazole (Table 2, Entry 16). White solid; mp 52ꢀ54 ºC (Lit.26b 53.5ꢀ54 ºC);
FTꢀIR (KBr): νmax/cmꢀ1 3089, 3063, 2971, 2901, 2845, 2765, 2729, 2633, 1605, 1482, 1454,
1430, 1156, 1075, 1053, 1017, 990, 829, 772, 743, 502.
5-Isopentyl-1H-tetrazole (Table 2, Entry 17). White solid; mp 94 ºC (Lit.26b 95ꢀ96 ºC); FTꢀ
IR (KBr): νmax/cmꢀ1 2962, 2931, 2874, 2709, 2618, 2482, 1867, 1583, 1553, 1469, 1404,
1110, 1048, 772. 1H NMR (100 MHz, CDCl3, ppm)
(m, 3H, ꢀCHꢀ, ꢀCH2ꢀ), 3.10 (t, 6 Hz, 2H, ꢀCH2ꢀ).
δ 1.00 (d, J 5 Hz, 6H, 2 CH3), 1.40ꢀ2.05
J
5-Benzyl-1H-tetrazole (Table 2, Entry 18). White solid; mp 117ꢀ119 ºC (Lit.85 118ꢀ120 ºC);
FTꢀIR (KBr): νmax/cmꢀ1 3109, 3031, 2984, 2945, 2863, 2778, 2704, 2594, 1768, 1707, 1638,

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1
1549, 1533, 1494, 1457, 1241, 1108, 1074, 772, 734, 695; H NMR (100 MHz, CD3CN,
ppm) 4.30 (s, 2H, ꢀCH2ꢀ), 7.31 (s, 5H, Ph).
δ
Conclusion
In conclusion, a convenient and highly efficient metal free synthesis of 5ꢀsubstitutedꢀ1H-
tetrazoles has been developed by reacting nitriles with sodium azide in the presence of
cuttlebone as a green and effective catalyst. This new type of low cost and reusable catalyst
plays a crucial role by “electrophilic activation” of nitrile through hydrogen bond formation
between cuttlebone and nitrile. Excellent yields of product, short reaction time, elimination of
dangerous and harmful hydrazoic acid, avoidance of toxic metal derivatives, a simple workꢀ
up procedure, simple preꢀpreparation, and easy handling of the catalyst are the notable and
valuable features of this metal free methodology. This procedure can be used to convert aryl,
heteroaryl and alkyl nitriles, sterically hindered orthoꢀsubstituted aryl nitriles, organic nitriles
containing bulky aryl groups and halo aryl nitriles to corresponding 5ꢀsubstitutedꢀ1H-
tetrazoles. Thus, it provides a better and more practical alternative to the existing
methodologies.
Acknowledgements
The authors gratefully acknowledge the partial support of this study by Ferdowsi University
of Mashhad Research Council.
Notes and references
Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad
9177948974, Iran.
* Corresponding author: Phone: +98-51-3880-5527, Fax: +98-51-3879-5457,
E-mail: akhlaghinia@um.ac.ir

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