Isotopic effect on tautomeric behavior of 5-(2,6-disubstituted-aryloxy)- tetrazoles

Article abstract of DOI:10.1002/mrc.2790

Isotopic effect on tautomeric behaviors of the synthesized 5-phenoxy- (1a), 5-(2,6-dimethylphenoxy)- (1b), 5-(2,6-diisopropylphenoxy)- (1c), 5-(2,6-dimethoxyphenoxy)- (1d) and 5-(4-methylphenoxy)-tetrazole (1e) were investigated in DMSO-d₆ by adding one drop of D₂O. Among 1a-e, 1a, 1d and 1e show small rotational barrier around C5-O1 and O1-C6 while in 1b and 1c there are distinguishable rotational barrier about that bonds. The ¹H NMR spectra of 1b and 1c show slightly different chemical shifts for two methyl and isopropyl groups on those phenyl ring, respectively, while the chemical shifts difference (Δδ) between two methyl and two isopropyl groups were enhanced by adding D₂O. The ¹³C NMR spectra of 1b show two overlapped singlets for methyl groups after adding D ₂O. Representatively, the calculations of compound 1c were performed with GAUSSIAN-03and the rotational barrier about C5-O1 and between isopropyl group and phenyl ring in 1c was calculated with B3LYP/6-31G(d) basis set.

Full text of DOI:10.1002/mrc.2790

Research Article
Received: 3 April 2011
Revised: 28 May 2011
Accepted: 2 June 2011
Published online in Wiley Online Library: 5 August 2011
(wileyonlinelibrary.com) DOI 10.1002/mrc.2790
Isotopic effect on tautomeric behavior of
5-(2,6-disubstituted-aryloxy)-tetrazoles
Nader Noroozi Pesyan∗
Isotopic effect on tautomeric behaviors of the synthesized 5-phenoxy- (1a), 5-(2,6-dimethylphenoxy)- (1b), 5-(2,6-
diisopropylphenoxy)- (1c), 5-(2,6-dimethoxyphenoxy)- (1d) and 5-(4-methylphenoxy)-tetrazole (1e) were investigated in
DMSO-d6 by adding one drop of D2O. Among 1a–e, 1a, 1d and 1e show small rotational barrier around C5–O1 and O1–C6
while in 1b and 1c there are distinguishable rotational barrier about that bonds. The 1H NMR spectra of 1b and 1c show slightly
different chemical shifts for two methyl and isopropyl groups on those phenyl ring, respectively, while the chemical shifts
difference (ꢀδ) between two methyl and two isopropyl groups were enhanced by adding D2O. The 13C NMR spectra of 1b
show two overlapped singlets for methyl groups after adding D2O. Representatively, the calculations of compound 1c were
performed with GAUSSIAN-03and the rotational barrier about C5–O1 and between isopropyl group and phenyl ring in 1c was
c
calculated with B3LYP/6-31G(d) basis set. Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: NMR; 1H NMR; 13C NMR; rotational barrier; isotope effect; tautomeric behavior; 5-aryloxy tetrazole
Introduction
0.19 Hz/data point, d1 = 1 s, td = 32768, ns = 16, experimental
time = 64 s, spectral width = 6172.8 Hz, dw = 81 µs, de = 6 µs;
13C NMR: pulse width (90◦) = 6.3 µs, acq. time = 1.82 s, digital
resolution = 0.27 Hz/data point, d1 = 2 s, td = 65536, ns =
1200, experimental time = 4800 s, spectral width = 17985.6 Hz,
dw = 27.8 µs, de = 6 µs.
5-Substituted tetrazoles are reported to possess antibac-
terial,[1–3] antifungal,[4] antiviral,[5–7] analgesic,[8–11] anti-
inflammatory,[12–15] antiulcer[16–18] and antihypertensive[19,20] ac-
tivities. The tetrazole function is metabolically stable.[21,22] This
feature and a close similarity between the acidic character of the
tetrazole group and carboxylic acid group[23–25] have inspired
medicinal chemists to synthesize substituted tetrazoles as poten-
tial medicinal agents. Tetrazoles are an increasingly important
functionality, not only as precursors to a variety of nitrogen-
containing heterocycles[26] but also as materials with applications
in explosives[27] and even as increasive lubricants.[28]
Several works were reported about tetrazole tauto-
merization[29–34] and isomerization.[35,36] But as part of investiga-
tions of 5-(2,6-disubstituted-aryloxy)-tetrazoles, there is no report
about isotope effect on tautomerization of these compounds. We
report herein the protium/deuterium isotope effect on tautomeric
behavior of these compounds in DMSO as suitable solvent with
adding one drop of D2O.
Syntheses
Tetrazoles1a–eweresynthesizedbasedonreportedliteraturesby
the reaction of phenol and its derivatives with cyanogen bromide
and subsequently 1,3-dipolar cycloaddition reaction with sodium
azide then acidified with HCl (37%).[29,30] All Attempts was failed in
results for the synthesis of tetrazoles 1f and 1g in similar manner
based on reported literatures.[29,30]
Computational details
Representatively, the calculations of compound 1c were per-
formed with GAUSSIAN-03 packages.[37] Molecular geometries
was calculated at DFT (B3LYP)[38–40] at 6-31G(d) basis set.
Experimental
Results and Discussion
Instruments and materials
This paper presents results on the tautomeric behavior of 5-
aryloxy-tetrazole derivatives (1a–e) via deuteration of exchange-
able proton on those tetrazole rings. Tetrazole ring can exist in two
tautomeric forms of (1H)- and (2H)-tetrazole in polar and nonpolar
Compounds 1a–e were dissolved in DMSO-d6 (99.8%) and
deuteration was achieved by the addition of a drop of D2O
(99.95%). The 1H NMR and 13C NMR spectra were recorded on
Bruker 300 FT-NMR spectrometer (300 MHz for 1H, 75 MHz for 13C)
in DMSO-d6 at ambient temperature (26 ◦C) using 5 mm direct
detection broadband probes and deuterium lock. The center of
the solvent signal was used as an internal standard which was
related to tetramethylsilane with δ 2.49 ppm (1H) and δ 39.5 ppm
∗
Correspondence to: Nader Noroozi Pesyan, Department of Chemistry, Faculty
of Science, Urmia University, 57159, Urmia, Iran.
E-mail: n.noroozi@urmia.ac.ir;pesyan@gmail.com
(
13C). The 1H signal of DOH appeared at δ 3.99 ppm (variable).
The recording conditions were the following: 1H NMR: pulse
Department of Chemistry, Faculty of Science, Urmia University, 57159, Urmia,
Iran
width (90◦) = 8.2 µs, acq. time = 2.65 s, digital resolution =
c
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Copyright ꢀ 2011 John Wiley & Sons, Ltd.

Isotopic effect on 5-(2,6-disubstituted-aryloxy)-tetrazoles
adding D2O while 5-phenoxy-(1H)-tetrazole (1a) do not. Before
adding D2O, two methyl groups upon phenyl ring in 1b show
a singlet at δ 2.09 ppm and have a shoulder in the peak’s
right side while these methyl groups show two distinct peaks
at δ 2.064 and 2.050 ppm after adding D2O (ꢀδ = 0.014 ppm;
Fig. 2). The appearance of a shoulder in the peak’s right side
can attribute to slightly nonequivalency of methyl groups upon
phenyl ring in 1bA tautomer (tetrazole-H) before adding D2O (in
comparison with 1e that showed a singlet for methyl group
on para-position). This observation indicated the equilibrium
mixture of two tautomers 1bA and 1bB (fast equilibrium) and
two methyl groups having equivalent chemical shift in 1bB
(2H-tetrazole-H), slightly nonequivalent in 1bA tautomer (1H-
tetrazole-H), respectively (Fig. 2(a)). After adding D2O, two methyl
groups became slightly nonequivalent in 1bB (2H-tetrazole-D)
and obviously nonequivalent in 1bA (1H-tetrazole-D), respectively
(Fig. 2(b)). The rotational barrier increased around C5–O1 and also
O1–C6 bonds due to substitution of deuterium on tetrazole ring
(Fig. 2(b)andScheme1(a)).Generally,deuterationontetrazolering
is fast and our aim for partial deuteration of tetrazole ring were
unsuccessful.Thereforetwomethylgroupshavedifferentchemical
shift on phenyl ring moiety where N1 atom was deuterated (1bA
form). Nonequivalency of the chemical shifts of two methyl groups
on 1bA corresponds to the slightly restriction of the rotation
Figure 1. The general formula structures of tetrazoles 1a–g.
solvents, respectively.[29] The general formula structure of 5-
aryloxy-tetrazoles 1 that studied in this work, are shown in Fig. 1.
5-Substituted tetrazoles are existed as equilibrium mixtures of
those 1H- and 2H-tautomers.[29] Buttler[32] discussed the rapid
equilibrium of 5-substituted 1H- and 2H-tetrazoles. Dabbagh and
Lwowski reported[29] that 15N NMR spectra of 5-methoxytetrazole
indicate only two signals (rapid equilibrium) at δ −19.0 and at
−126.0 ppm corresponding to N N and N–H, respectively. The
proton on tetrazole ring is delocalized due to fast tautomerization
on N1 and N2 atoms.
The 1H and 13C NMR spectra of 5-(2,6-dimethylphenoxy)-(1H)-
tetrazole (1b) shows interesting phenomenon before and after
(a)
(b)
Figure 2. Expanded 1H NMR spectra of methyl group of 1b before (a) and after adding D2O (b) in DMSO-d6.
c
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N. Noroozi Pesyan
Scheme 1. Comparison of the rotational barrier in deuterated tetrazoles 1bA (a), 1cA (b), 1dA (c) and 1eA (d).
around the ether linkage between tetrazole and phenyl ring
bearing methyl groups on ortho-positions (Fig. 2(b) and Scheme
1(a)). The covalent bond length of N–D is longer than that of
N–H bond (dN−H = 0.80 Å vs dN−D = 1.01 Å)[41] and caused to
increasing the rotational barrier of tetrazole ring around C5–O1
and also O1–C6 bonds (ether linkage bond). In 13C NMR spectrum
of 1b, before adding D2O, the chemical shifts of two methyl
groups are equivalent at δ 16.07 ppm while after adding D2O, the
chemical shifts of those methyl groups are slightly nonequivalent
(at δ 15.98 ppm and has a shoulder in the peak’s right side;
Fig. 3).
after adding D2O. The methyl groups show two peaks, a slightly
broadened singlet at δ 2.064 and two overlapped peaks at
2.050 ppm (Fig. 2(b)). It seems that this peak at δ 2.064 ppm
corresponds to deuterated 2H-tetrazole tautomer 1bB (2H-
tetrazole-D) form in which two methyls have chemical shift
equivalent. The substitution of deuterium on N2 atom upon
tetrazole ring has no steric effect to the methyl groups (lower
than that of 1H-tetrazole-D). Two overlapped peaks at 2.050 ppm
corresponds to methyl groups with different chemical shift
on phenyl ring in deuterated 1H-tetrazole tautomer 1bA due
to steric repulsion between deuterium and methyl groups.
This observation confirms that the equilibrium mixture of two
deuterated 1H- and 2H-tetrazoles have enough life time in NMR
time scale, approximately (Fig. 2). Quantitatively determination of
In 1b, the substitution of deuterium on tetrazole ring also
restricted the rapid tautomerization (Scheme 1a) and thus, the
equilibrium mixture of 1bA and 1bB were existed in solution
c
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Isotopic effect on 5-(2,6-disubstituted-aryloxy)-tetrazoles
Table 1. Chemical shifts of carbon atoms in tetrazoles 1a–e before
and after adding D2Oa
Atom
1a
1b
1c
1d
1e
C5b
d
166.80
166.69
154.59
154.39
119.41
119.41
130.48
130.55
126.01
126.20
–
166.60
166.50
151.07
151.01
130.14
130.11
129.57
129.58
126.78
126.86
16.07
167.70
167.62
148.47
148.39
140.44
140.40
125.02
125.03
127.52
127.61
27.11
C
166.84
166.80
152.46
152.34
119.30
119.31
130.73
130.77
135.26
135.43
20.73
C
C6
152.36
152.31
131.40
131.31
127.37
127.46
105.90
105.88
56.52
56.50f
–
C7
C8
C9
C10
C11
15.98e
27.09
20.68
–
–
23.42
23.34f
–
a One drop of D2O was added.
b The chemical shift(s) before adding D2O.
c The peak intensity was low and unclear.
d The chemical shift(s) after adding D2O.
e The peak has a shoulder in the peak’s right side.
f The peak has a shoulder in the peak’s left side.
their sulfur analogs.[57] The 13C NMR data of 1a–e are summarized
in Table 1 before and after adding D2O.
From 1b to 1c the rotational barrier was enhanced with
substitution of the bulky substituent of isopropyl at ortho position
in1c.The1HNMRanalysesof5-(2,6-diisopropylphenoxy)-tetrazole
1c proved that the phenyl ring bearing two isopropyl groups are
forced to lie out of the plane of the tetrazole due to the steric
hindrance exerted by the presence of two isopropyl groups. This
conformation was clearly deduced by the X-ray crystallographic
analysis and calculation of 1c (Fig. 4). Before adding D2O, Fig. 5(a)
show a doublet and having a shoulder at the peak’s right side
and indicates the two isopropyl groups are slightly nonequivalent
1
on phenyl ring. After adding D2O, the H NMR spectrum shows
two environments for isopropyl groups [δ 1.040 and 1.052 ppm
in which two equal coupling constants (J = 6.3 Hz)], which can
be ascribed to the frozen rotation about the aryl-oxygen bonds
on the NMR time scale and equilibrium mixture of two tautomers
(1cA and 1cB) as shown in Fig. 5.
Figure 3. Expanded 13C NMR spectra of 1b before (a) and after adding D2O
(b) in DMSO-d6.
However, expectedly, the 1H NMR spectrum of 5-(2,6-
diisopropylphenoxy)-tetrazole 1c must show only one doublet
peak belonging to the methyl groups indicating that the NMR
time scale rotation around the ether linkage is allowed or fast
enough to be detected at room temperature. Therefore, there is
no exactly one doublet for isopropyl groups before adding D2O
in 1c. This may be attributed to the absence of a hydrogen atom
on N2-position (in case of tetrazole) in the non-peripheral phenyl
positions, which clearly exert an additional steric hindrance in case
of 1c and hence preventing rotation around the aryloxy bond. In
addition, in the 1H-tautomer the steric hindrance is higher than
that of 2H-tautomer and exerts the restricted rotation around the
aryloxy bond. Before adding D2O, the 1H NMR spectrum of 1c
shows a doublet at δ 1.083 ppm (J = 6.3 Hz) and another over-
lappeddoubletappearedasashoulderatthepeak’srightside. The
methine proton of isopropyl group shows an overlapped septet at
δ 2.890 ppm (Fig. 5(a)). The 13C NMR spectrum shows a peak at δ
23.42and27.12 ppmformethylandmethinecarbonsonisopropyl
each tautomers in equilibrium mixtures of 1bA and 1bB is difficult
because of the peak overlapping.
In 13C NMR spectrum of deuterated 1b, the ipso-carbon atom
on phenyl ring (bonded to O1) show two peaks at δ 151.01 and
at ≈150.94 ppm correspond to C6 and C6ꢁ in equilibrium mixture
of 1bA and 1bB forms (Fig. 3(b) and Scheme 1(a)). The carbon
atom of tetrazole ring (C5) show a multiplet and can attributed
to equilibrium mixture of 1bA and 1bB (C5 and C5ꢁ). There is no
probability of β-isotope effect in 1H-tetrazole-D tautomer because
of no partial deuteration of this tautomer (full deuteration and
no formation of isotopomers). Of course, several works have been
reported about protium/deuterium β- and γ -isotope effects in
13C NMR spectroscopy of other organic compounds, e.g. carbohy-
drates, amines, ammonium salts, amino acids,[42–50] amides,[51–55]
barbiturate azo dyes[56] and also β-isotope effect and tautomeric
forms of 3-arylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones and
c
Magn. Reson. Chem. 2011, 49, 592–599
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N. Noroozi Pesyan
Figure 4. The crystal structure (a) and optimized structure of 1c calculated at B3LYP/6-31G(d) level of theory (b).
Figure 5. Expanded 1H NMR spectra of isopropyl groups of 1c before (a) and after adding D2O (b) in DMSO-d6.
c
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Magn. Reson. Chem. 2011, 49, 592–599

Isotopic effect on 5-(2,6-disubstituted-aryloxy)-tetrazoles
groups, respectively. In contrast, after adding D2O, the two iso-
propyl groups show obviously two overlapped doublets at δ 1.040
and 1.052 ppm with the same coupling constants (J = 6.3 Hz),
respectively. The methine proton on isopropyl groups appeared
as a multiplet that indicated minimum two overlapped septets
(Fig. 5(b)). These observations revealed that slow tautomerization
occurred and the equilibrium mixtures of two deutereted tau-
tomers have enough life time in NMR time scale (Scheme 1(b)
and Fig. 5(b)). Similar to 1b, quantitatively determination of each
tautomers in equilibrium mixtures of 1cA and 1cB is difficult be-
cause of the peak overlapping. This circumstance confirms the
equilibrium mixtures of two 1H-tetrazole-D and 2H-tetrazole-D
tautomers in 1c.
For instance, two isopropyl groups in 2,6-diisopropylphenol
(propofol, is a short-acting, intravenously administered hypnotic
agent)[58] are equivalent in chemical shifts[59] because of the low
rotational barrier. Therefore, it seems that the appearance of
1
approximately two doublets in H NMR spectrum of 1c (before
adding D2O)eitherattributedtothehindranceeffectbetweentwo
isopropyls and tetrazole groups upon phenyl ring and restricted
rotation around ether linkage bonds in 1c or presumably to
the equilibrium mixture of 1H- and 2H-tautomers that slightly
have enough life time in NMR time scale. It seems that the
hindrance effect of isopropyl groups is predominant. Presumably,
two methyls upon isopropyl group are slightly nonequivalent in
chemical shift because of the hindrance repulsion with tetrazole
group and restriction of the rotation around the ether linkage
bond and also rotation around the bond between isopropyl and
phenyl ring (this case depends to temperature).
Figure 6. Diagram of rotational barriers around the bond between O1
and C5 (a) and between isopropyl group and phenyl ring (b) in optimized
structure of 1c. Calculated at B3LYP/6-31G(d) level of theory.
For further study about 1c, the molecular geometry of
compound 1c was optimized by the calculation at DFT (B3LYP)
at 6-31G(d) basis set (Fig. 4(b)). A rotational barrier around the
bond between O1 and C5 was calculated and is shown in Fig. 6(a).
The maximum and minimum energies calculated with B3LYP/6-
31G(d) basis set derived from dihedral angles (ϕ) of 93◦ and
178◦ that equals to 7.36 and 0.00 kcal/mol, respectively (Fig. 6(a)).
These energies were also calculated for rotational barrier between
phenyl ring and isopropyl group (Fig. 6(b)). In the later case, the
maximum and minimum energies for rotation around C7–C10
(between phenyl ring and isopropyl group) derived from dihedral
angles (ϕ) of 158◦ and 64◦ that equals to 8.73 and 0.00 kcal/mol,
respectively (Fig. 6(b)). These calculated results demonstrate that
the rotational barrier around ether linkage bond is slightly lower
than that of those between isopropyl group and phenyl ring
(7.36 vs 8.73 kcal/mol).
In contrast, in 5-(2,6-dimethoxyphenoxy)-tetrazole 1d, the
rotational barrier about C5–O1 and O1–C6 was lower than 1b
because of the less interaction of oxygen lone pairs with hydrogen
and/or deuterium atom upon N1 of tetrazole ring (Scheme 1c).
1
Before adding D2O, the H NMR spectrum of 1d show a singlet
for two methoxy groups and indicating two methoxy groups have
chemical shift equivalent and each tautomer (1dA and 1 dB) has
no life time long enough in NMR time scale in equilibrium mixture
(fast tautomerization). After adding D2O, a shoulder at the peak’s
left side appeared for methoxy groups upon phenyl ring and
indicated that two tautomers slightly having enough life time in
NMR time scale, approximately (slow tautomerization; Fig. 7(A)).
We also performed the isotope effect experiment on 5-(4-
methylphenoxy)-tetrazole 1e. Similar to 1a, 1e has no rotational
barrier around O1–C5 and O1–C6 bonds (Table 1). On the other
hand, the methyl group of 1e shows a singlet at δ 2.295 and a
broadened singlet δ 2.270 ppm (including a shoulder at the peak’s
left side) before and after adding D2O, respectively (Fig. 7(B)).
Similar to 1d, especially in 1e, the appearance of a shoulder
in the peak’s left side demonstrates the equilibrium mixture of
two deuterated tautomers (1eA and 1eB) that have enough
life time in NMR time scale. This observation confirms the slow
tautomerization of deuterated tetrazole ring (tetrazole-D) than
that of tetrazole ring consisting of hydrogen atom (tetrazole-H).
For the further information and comparison with the calculated
data, the crystal structure of 1c is shown in Fig. 4(a). For the crystal
structure determinations, single-crystals of 1c were used for data
collection on Oxford Diffraction Gemini E diffractometer. Mea-
surements were made at 150 K with graphite monochromated
Cu Kα radiation (λ = 1.54184 Å). The computing details; Data
collection: Gemini, (Oxford Diffraction, 2006)[60]; cell refinement:
CrysAlis RED, (Oxford Diffraction, 2002)[60]; data reduction: CrysAlis
RED, (Oxford Diffraction, 2002)[60]; program(s) used to solve struc-
ture: SIR92[61]; program(s) used to refine structure: CRYSTALS[62]
;
molecular graphics: CAMERON[63] and software used to prepare
material for publication: CRYSTALS.[62] The crystallographic data
for structure 1 were deposited to the Cambridge Crystallographic
Data Center (entry no. CCDC-819010) and are available free of
charge upon request to CCDC, 12 Union Road, Cambridge, UK
(Fax: +44-1223-336033, e-mail: deposit@ccdc.cam.ac.uk).
Conclusion
In summary, the replacement of methyl, methoxy and isopropyl
groups with hydrogen atom on ortho position of phenyl ring
in deuterated 5-aryloxy tetrazoles restricted the rotation around
c
Magn. Reson. Chem. 2011, 49, 592–599
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
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N. Noroozi Pesyan
Figure 7. Expanded 1H NMR spectra of methoxy group of 1d (A) and methyl group of 1e (B) before (a) and after adding D2O (b) in DMSO-d6.
C5–O1 and O1–C6 bonds. The substitution of deuterium on N1
atom upon tetrazole ring also restricted the mentioned above
rotation due to N–D bond lengthening. Substitution of deuterium
on tetrazole ring also slightly slowed down the tautomerization
and caused each tautomers of 1H- and 2H-tetrazoles-D to have
enough life time in NMR time scale in equilibrium mixture.
The rotational barrier was enhanced by increasing the bulk
of substituent on ortho position (from hydrogen to isopropyl).
The rotational barrier was also slowed down by replacing
methoxy with methyl group on ortho position upon phenyl
ring.
Bavafa (from International University of Chabahar (IUC), Chabahar,
Iran) for helping in calculating data and to X-ray crystallography
lab of Universiti Putra Malaysia (UPM) for X-ray crystallographic
data of compound 1c.
Supporting information
Supporting information may be found in the online version of this
article.
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