Novel two step synthesis of bis/Mono 1-aryl-1H-tetrazole-5-carboxylic acid

Article abstract of DOI:10.1080/00397911.2019.1610176

Some novel compounds of bis/mono 1-aryl-1H-tetrazole-5-carboxylic acid are synthesized by the hydrolysis of two different synthesized esters, they are ethyl-1-aryl-1H-tetrazole-5-carboxylate and ethyloxo(1-aryl-1H-tetrazol-5-yl)acetate. The ethyl-1-aryl-1

Full text of DOI:10.1080/00397911.2019.1610176

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Novel two step synthesis of bis/Mono 1-aryl-1H-
tetrazole-5-carboxylic acid
Sambandam Chandrakumari, Dhanavel Sivakumar, Haridoss Manikandan &
Mannuthusamy Gopalakrishnan
To cite this article: Sambandam Chandrakumari, Dhanavel Sivakumar, Haridoss Manikandan &
Mannuthusamy Gopalakrishnan (2019): Novel two step synthesis of bis/Mono 1-aryl-1H-tetrazole-5-
carboxylic acid, Synthetic Communications, DOI: 10.1080/00397911.2019.1610176
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https://doi.org/10.1080/00397911.2019.1610176
Novel two step synthesis of bis/Mono 1-aryl-1H-tetrazole-5-
carboxylic acid
Sambandam Chandrakumari, Dhanavel Sivakumar, Haridoss Manikandan, and
Mannuthusamy Gopalakrishnan
Department of Chemistry, Annamalai University, Chidambaram, TN, India
ABSTRACT
ARTICLE HISTORY
Received 20 November 2018
Some novel compounds of bis/mono 1-aryl-1H-tetrazole-5-carboxylic
acid are synthesized by the hydrolysis of two different synthesized
esters, they are ethyl-1-aryl-1H-tetrazole-5-carboxylate and ethyloxo
(1-aryl-1H-tetrazol-5-yl)acetate. The ethyl-1-aryl-1H-tetrazole-5-carb-
oxylate is resistant to get hydrolyzed, whereas the ethyloxo(1-aryl-
1H-tetrazol-5-yl) acetate undergoes hydrolysis process and converts
the ester to title compound. All the synthesized compounds are
characterized by IR, 1H and 13C NMR, mass and elemental
analysis.The ethyl-1-aryl-1H-tetrazole-5-carboxylateis optimized by
DFT B3LYP method and the HOMO and LUMO energy is 5.14 eV and
also there is a formation of a weak bond between O18 and C8 as
observed from the AIM analysis result.
KEYWORDS
AIM; 1-aryl-1H-tetrazole-5-
carboxylic acid; DFT; ethyl-
1-aryl-1H-tetrazole-5-carb-
oxylate; ethyloxo(1-aryl-1H-
tetrazol-5-yl) acetate
GRAPHICAL ABSTRACT
Introduction
Carboxylic acids are small organic acid molecules found as amino acids, triglycerides,
and prostanoids, in many endogenous substances and play a vital role as pharmaco-
phore in therapeutic agents.[1] Tetrazoles (CN4H) are the aromatic heterocyclic com-
pounds. In recent days, researchers have shown their considerable attention
on tetrazoles and tetrazole derivatives because they have numerous multi-varieties of
biological applications such as antibacterial,[2] antifungal,[3] antiviral,[4–6] analgesic,[7]
CONTACT Gopalakrishnan Mannuthusamy
mgkrishnan61@gmail.com
Department of Chemistry, Annamalai
University, Medical Collage Rd, Sadagopan Nagar, Chidambaram 608002, TN, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
C. SAMBANDAM ET AL.
anti-inflammatory,[8–10] and antihypertensive activities[11]. A wide variety of tetrazole
moiety and its derivatives are important in medicinal chemistry research. Tetrazoles
draw more attention because of its potential biological activity and industrial applica-
tions.[12] Losartan, Valsartan, Irbesartan, and Candesartan are medicinally important
AII receptor antagonist hypotensive tetrazole containing drugs play an important role
in the regulation of blood pressure and homeostasis. Angiotensin II is an octapeptide
formed from Angiotensin I within the renin-angiotensin system (RAS) from the reac-
tion catalyzed by an angiotensin-converting enzyme and it is a powerful vasoconstrictor.
Losartan, Valsartan, and candesartan have (1 H-tetrazol-5-yl) biphenyl moiety as their
common structural fragment and have garnered attention from drug manufacturers for
almost 15 years in the pharmaceutical market.[13,14] The biphenyl moiety and its pos-
ition in the compound have efficient molecular docking energy.[15] The b-aderno block-
ers containing tetrazolone moiety in the molecular structure and is used in the
treatment of arterial hypertonia and concomitant diseases.[16,17] The structure of
Losartan, Irbesartan, Valsartan, Candesartan and b-adernoblockers are given below.
The DFT B3LYP is a computational method which calculates the geometries and
energies of the molecules. An organic synthetic chemist uses computational chemistry
to describe the optimized geometry structure and electronic behaviors of molecules.
DFT is very useful to predict the electronic structure (ground state) for atoms, mole-
cules and condensed phase which is used by physics and chemistry fellow due to its low
cost. By using this DFT theory, we are able to describe the properties of electron density
of an atom or molecules. DFT B3LYP is a very reliable method of calculating the geo-
metries and energies of heterocyclic molecules.[18,19] Bader’s QTAIM theory helps us to
define the structure of molecules.[20,21] The QTAIM theory is applicable to unravel the
atom–atom interaction in covalent and non-covalent interactions such as weak Vander
Waal’s, p–p, X–H–p, conventional hydrogen bonding, cation-p interactions, halogen
bonds, etc. and also other applications in chemistry.[22] The concept of assumption in

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atoms and bonds are useful in interpretation, classification, prediction, molecular struc-
ture and communication chemistry. This theory is about the molecular structure, atoms,
bonds and distribution function of electron density dealing with the probability of elec-
tronic charge in the real space and attraction between the charge and the nuclei. The
hypothesis concepts of molecular structure in QTAIM helps to define the bonds linked
to the atoms will result in impart the structure. QTAIM defines the structure, chemical
bonding based on the topology of density of electrons. Bader’s QTAIM theory help to
define the structure of molecules,[23–28] It exploits the electron or charge density of mol-
ecules. Distribution of electron density in molecules, mainly affects the interaction
between the two nuclei (chemical bonding). The results from both experimental[29] and
theoretical[30] density of electrons are used to know the nature of the chemical bonding
The structure of the synthesized compounds 4a–4f.
Results and discussion
A very well-known standard method to synthesize the acid molecule is the hydrolysis
process of an ester. Ester compounds are the best precursor to produce the acid com-
pound. Our objective here is to synthesize new types of aryl tetrazole acids through two
sets of reactions; one is aryl tetrazole with ethyl chloroformate and other is the aryl
tetrazole with ethyl-2-chloro-2-oxoacetate in THF solvent medium and DIPEA used as
a catalyst. Two different esters are formed, they are ethyl-1-aryl-1H-tetrazole-5-carboxyl-
ate 2a and ethyloxo(1-aryl-1H-tetrazol-5-yl) acetate 3a which is formed by dehydrohalo-
genation route (Scheme 1) (Alkyl tetrazole esters and alkyl tetrazole acids failed to
synthesize due to the poor yield of alkyl tetrazole). The compound ethyl-1-phenyl-1H-
tetrazole-5-carboxylate 2a was taken as a precursor to synthesize compound 4a. The 2a
was prepared by treating 1-phenyl-1H-tetrazole with ethyl chloroformate and diisopro-
pylethylamine in THF. The reaction mixture was refluxed at 80 ꢀC for 16 h. The syn-
thetic pathway is shown in Scheme 1. The ester was formed by the removal of HCl.
The dehydrohalogenation route was employed. Then, 2a (0.5 g) was treated with both
concentrated HCl in ethanol and 20% of an aqueous solution of NaOH separately.
However, the expected product of 1-phenyl-1H-tetrazole-5-carboxylic acid did not form.
The tetrazole ester 2a was resistant to hydrolyzation and to know the reasons; the
molecule was subjected to theoretical studies such as DFT B3LYP method, (631 G d, p)
as the basis set and AIM analysis. The molecule 2a was optimized with two different
conformers A and B. In conformer A (Fig. 1) the carbonyl bearing oxygen and phenyl
carbon are syn to each other and found vice–versa, in an anti position to each other in
conformer B (Fig. 2). The major conformer A has less enthalpy of reaction, whereas the
minor conformer B has more enthalpy of reaction.
The HOMO and LUMO energy of conformer A is 5.17 eV, which is relatively high
energy and energy gap. According to Pearson and Parr concept,[31,32] “Hardness meas-
ures the resistance to change in the electron distribution in a molecule”.[33] The energy
gap is found to be more between the HOMO and LUMO orbitals (Fig. 3), hence, there
is a rapid increase in the hardness of the molecule. Hardness and reactivity of the mol-
ecule are inversely proportional to each other. Therefore, more the hardness in the mol-
ecule lesser will be the reactivity in reaction. We found this as the main reason for

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C. SAMBANDAM ET AL.
Scheme 1. Synthesis of bis/mono 1-aryl-1H-tetrazole-5-carboxylic acid. Reactions conditions (i) 3a–h :
Reflux at 80 ꢀC for 16 h , (ii) 4a–h: 80 ꢀC for 6 h.
Figure 1. Major conformer A.

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Figure 2. Minor conformer B.
ethyl-1-phenyl-1H-tetrazole-carboxylate 2a which did not undergo hydrolysis reaction
under both acidic and basic condition.
Additionally, to strengthen the reason, the AIM analysis[34] was also performed for
the compound 2a. The results show a weak bond formation between the carbonyl oxy-
gen and the phenyl carbon (Fig. 4). This will decrease the reactivity of the oxygen
group. The lone pair of electrons on the oxygen atom was used for the formation of a
weak bond. Hence, it will block the reactivity of the molecule.
The contour map of Laplacian of electron density (qBCP) for conformer A (Fig. 5)
indicates that the weak bond of (3, ꢁ1) topology between C8 and O18 is found in the
positive (green) regions of Laplacian of electron density qBCP. The bond between C8
and H12 is strong and it lies in negative Laplacian of electron density (red). Thus, the
AIM analysis predicts the non-bonded electrons in the oxygen atom of the carbonyl
group used up for the weak bond formation between C8 and O18. This may be the rea-
son for the unreactivity of the carbonyl group in molecule A.
Hence, we synthesized the title compounds 4a–h using the precursors 3a–h.
(Schemes 1–3) All the newly synthesized compounds are confirmed by spectral data.
The 1-phenyl-1H-tetrazole 1a (1.46 g, 10 mmol) is treated with ethyl-2-chloro-2-oxoace-
tate (1.36 g, 10 mmol) and diisopropylamine (1 mL) in THF (100 mL). It was refluxed at
80 ꢀC for 16 h. The IR spectrum of compound 3a exhibited the tetrazole ring character-
istic frequency at 957 cmꢁ1, N¼N absorption band at 1543 cmꢁ1 and C¼N frequency
signal at 1644 cmꢁ1. The absorption bands at 1704 and 1741 cmꢁ1 confirmed the pres-
ence of the ester group and the keto group. The frequency at 2918–2954 cmꢁ1 revealed
the presence of ethyl group. The absorption signal at 3057 cmꢁ1 indicated the aromatic

6
C. SAMBANDAM ET AL.
Figure 3. HOMO and LUMO images of Conformer A.
1
C–H. In H NMR spectrum, the triplet signal at 1.71 ppm and the quartet signal at
4.13 ppm indicated the presence of methyl and methylene protons. The aromatic pro-
tons resonated multiplet signal from 7.50 to 7.80 ppm. In 13C NMR spectrum, the peak
at 13.95 and 60.56 ppm indicated the presence of methyl and methylene carbon. The
aromatic carbons appeared from 128.53 to 137.58 ppm. The tetrazole carbon appeared
at 157.43 ppm. The carbon signal at 169.82 ppm and 173.35 ppm confirmed the presence
of ester and keto carbon. The mass spectrum was obtained as [Mþ] peak. The calcu-
lated elemental analysis value was C, 52.17; H, 4.38; N, 20.28 and the experimental
elemental analysis value was C, 52.86; H, 4.26; N, 20.68.

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Figure 4. AIM analysis result – visualized using Multi wave function analyzer. Weak bond between
O18 and C8.
Figure 5. Contour diagram to identify the red and green region.

8
C. SAMBANDAM ET AL.
Scheme 2. Synthesis of 1, 1’-(1, 2-phenylene) bis (1 H-tetrazole-5-carboxylic acid) Reactions conditions
(i) 3g: Reflux at 80 ꢀC for 16 h, (ii) 4g: 80ꢀCfor 6 h.
Scheme 3. Synthesis of 1, 1’-(oxy bis (4, 1-phenylene) bis (1 H-tetrazole-5-carboxylic acid) Reactions
conditions (i) 3h : Reflux at 80 ꢀC for 16 h , (ii) 4h: 80 ꢀC for 6 h.
After confirming the structure of compounds, the hydrolysis process was preceded.
The synthesized ethyloxo(1-aryl-1H-tetrazol-5-yl) acetate (0.5 g) was treated with 1 mL
concentrated HCl and 10 mL of ethanol. The reaction mixture was refluxed for 6 h.
The solid product was filtered off and dried. The compound 1-aryl-1H-tetrazole-5-car-
boxylic acid 4a–4f was characterized by IR, NMR, mass technique and elemental ana-
lysis. The tetrazole ring characteristic peak appeared at 961 cmꢁ1, N¼N band at
1523 cmꢁ1, and C¼N frequency peak appeared at 1601 cmꢁ1. The stretching frequencies
appeared at 1716, 3079, and 3337 cmꢁ1 attributed to the presence of acid carbonyl
group, aromatic C–H and the hydroxyl group 4a. In proton NMR the aromatic protons
resonated multiplet signals from 7.60 to 7.93 ppm. The aliphatic protons signals have
vanished and the OH proton appeared as a sharp singlet in 10.13 ppm. In carbon NMR,
the aromatic carbons were in the range of 128.43 to 134.03 ppm. The tetrazole carbon
appeared at 142.63 ppm. The aliphatic carbon signals had vanished and the carbonyl
carbon appeared in 161.90 ppm. The mass spectrum obtained as [M þ H] peak at 191.1.

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The calculated elemental analysis value was C, 50.53; H, 3.18; N, 29.46 and the experi-
mental elemental analysis value was C, 50.86; H, 3.14; N, 29.53. The data for the com-
pound 3a-h, 4a-h are given in supplementary data.
Experimental procedure
Materials and methods
The melting points (ꢀC, uncorrected) of the synthesized compounds were checked by
using the digital auto melting point apparatus (Labtronics 110, India) in open capillary
tube. All the reagents and solvents were purchased in Sigma–Aldrich and Merck, India.
All the reactions were carried out at an appropriate temperature and the products were
checked by TLC silica gel 60 F 254 using the eluents pet ether and ethyl acetate in the
ratio 7:3. All the compounds were characterized by the FT-IR spectrometer (Agilent
1
Cary 650) using KBr pellets; H NMR spectroscopy in DMSO (400 MHz, Brucker), 13C
NMR spectroscopy in DMSO (100 MHz, Bruckner) using tetramethylsilane (TMS) as an
internal standard. GC- Mass spectra were measured by Saturn 2200 (Varian (CP-3800)).
Optimization using DFT, B3LYP method was performed in Gaussian 03 software pack-
age and the AIM analysis was performed in AIMALL software package.
General procedure for synthesis of Mono ethyloxo(1-aryl-1H-tetrazol-5-yl) acetate
(3a–f) and 1-aryl-1H-tetrazole-5-carboxylic acid 4a–f
The mono1-aryl-1H-tetrazoles 1a–f were synthesized by the literature method.[35,36] The
1-substituted-aryl-amine (10 mmol) was treated with sodium azide (10 mmol), triethyl
orthoformate (10 mmol) in 100 mL of acetic acid. It was refluxed for 24 h at 80 ꢀC. The
reaction progress was checked by TLC. Once the reaction was completed, the reaction
mixture was transferred into a beaker containing ice. The solid product was separated
on cooling, filtered and dried. The equimolar mixture of 1-substituted-aryl-tetrazole
(5 mmol) 1a–f is treated with ethyl-2-chloro-2-oxoacetate (5 mmol) in the presence of a
catalytic amount of DIPEA in THF (100 mL) (Scheme 1). It was refluxed for 16 h. The
process of the reaction was checked by TLC. After the formation of a product, the reac-
tion mixture was poured into ice. The solid product was separated, filtered and dried.
The compound was purified by column chromatography using the pet ether and ben-
zene in the ratio 7:3. The yield of the product was 88–95%. Then, the title compound
(0.5 g) was synthesized by hydrolysis of compounds 3a–f in the presence of
Concentrated HCl (1 mL) and 10 mL of ethanol (Scheme 1). The reaction was refluxed
for 6 h. The formation of the product was confirmed with the help of TLC and the reac-
tion was quenched by pouring the mixture into ice. The solid product was filtered off
and dried. The products 4a–f were obtained in good yield of 90%.
General procedure for the synthesis for the synthesis of bis phenyl-1-aryl-1H-
tetrazole-5-carboxylic acid 4 g–h
The bis-1-aryl-1H-tetrazoles 1 g–h were synthesized by the literature method.[24,25] O-
Phenylene diamines/4,4-oxydianiline (10 mmol) was treated with sodium azide

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C. SAMBANDAM ET AL.
(20 mmol), triethyl orthoformate (20 mmol) in acetic acid (100 mL) (Schemes 2 and 3)
The reaction mixture was refluxed for 24 h at 80 ꢀC. The reaction progress was checked
by TLC. Once the reaction was completed, the reaction mixture was transferred into a
beaker containing ice. The solid product separated on cooling was filtered and dried.
Then, the 1,2-di(1H-tetrazol-yl) benzene/1,1-(oxybis (4,1-phenylene) bis (1 H-tetrazole)
(5 mmol) was treated with ethyl-2-chloro-2-oxoacetate (10 mmol) in THF(100 mL) in
the presence of DIPEA. It was refluxed for 16 h. Again, the reaction progress was
checked by TLC. Once the reaction was completed, the reaction mixture was poured
into ice. The solid product separated on cooling was filtered and dried. The compound
was purified by column chromatography using 7:3 of pet ether and benzene. The yield
of the products 3g and 3h was 82–85%. Then, the title compound (0.5 g) was synthe-
sized by hydrolysis of compounds 3g and 3h in the presence of Concentrated HCl
(2 mL) and 20 mL of ethanol. It was refluxed for 6 h. The formation of the product was
confirmed with the help of TLC and the reaction was quenched by pouring the mixture
into ice. The solid product was filtered off and dried. The products 4g–h are obtained
in good yield of 90%.
Diethyl-1,1’-(oxybis(1,2-phenylene)bis(1H-tetrazole-5,1-diyl)bis(oxoacetate)),(3g)
1,2-di(1H-tetrazol-yl) benzene (2.14 g, 10 mmol) was treated with ethyl-2-chloro-2-oxoa-
cetate (2.73 mL, 20 mmol) in the presence of diisopropyl ethylamine (2 mL) as a catalyst
in THF(100 ml). Brown color solid; mp 102 ꢀC; IR (KBr, ꢀmax, cmꢁ1)942 (Characteristic
tetrazole ring),1520 (N¼N),1599 (C¼N), 1690 (ester group),1735 (keto group),
1
2926–2983 (aliphatic C–H), 3069 (aromatic C–H); H NMR (400 MHz, DMSO-d6): d
1.72 [6H, t], 4.20 [4H, q], 7.22–7.53 ppm [4H, m]; 13C NMR (100 MHz, DMSO-d6): d
13.95,60.56, 125.43, 125.53, 125.53, 125.65, 126.15, 129.67, 156.88, 169.82, 173.16,
ppm.MS, m/z (%): 415.1 [M þ H]þ; anal. Calcd. for. C16H14N8O6: C, 46.38; H, 3.41; N,
27.04. Found: C, 46.51; H, 3.54; N, 27.16.
1, 1’-(1, 2-phenylene) bis (1 H-tetrazole-5-carboxylic acid),(4g)
Diethyl-2,2’-(1,1’-(oxybis(1,2-phenylene)bis(1H-tetrazole-5,1-diyl)bis(2-oxoacetate)
(0.5 g) was treated with Concentrated HCl (2 mL) and 20 mL of ethanol. It was refluxed
for 6 h. Pale brown crystalline solid; mp 136–140 ꢀC; IR (KBr, ꢀmax, cmꢁ1
)
943(Characteristic tetrazole ring),1499 (N¼N),1608 (C¼N), 1663(C¼O group),
3045 cmꢁ1 (aromatic C–H), 3409 (OH group); 1H NMR (400 MHz, DMSO-d6): d
6.91–7.54 [4H, m],11.92 ppm [2OH, s]; 13C NMR (100 MHz, DMSO-d6): d 115.61,
123.51, 126.02,142.16, 161.55 ppm.MS, m/z (%): 298.5 [M þ H]þ; anal. Calcd. for.
C10H6N8O4: C, 39.74; H, 2.00; N, 37.08. Found: C, 39.81; H, 2.14; N, 37.13.
Conclusion
In conclusion two different types of esters are synthesized and used as a precursor to
synthesize bis/mono 1-aryl-1H-tetrazole-5-carboxylic acid (4a–h), they are Ethyl-1-phe-
nyl-1H-tetrazole-5-carboxylate (2a) and ethyloxo(1-aryl-1H-tetrazol-5-yl) acetate (3a–h).

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The ester 2a is resistant to hydrolyzation because of the formation of a weak bond
between the O18 and C8 whereas the esters (3a–h) undergo hydrolyzation process to
produce mono and bis 1-aryl-1H-tetrazole-5-carboxylic acid. All the synthesized 16
compounds are characterized by IR, NMR and mass spectra. Future studies may stress
on the biological activities of the synthesized compounds.
Funding
One of the authors, S. Chandrakumari is thankful to UGC-Rajiv Gandhi National Fellowship
[RGNF-2017-18-SC-TAM-31743] for financial support.
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