Molecular structure and vibrational spectroscopic investigation of secnidazole using density functional theory.

Abstract

Secnidazole (alpha,2-dimethyl-5-nitro-1H-imidazole-1-ethanol) is an antimicrobical drug, and it is particularly effective in the treatment of amebiasis, giardiasis, trichomoniasis, and bacterial vaginosis. Secnidazole crystallizes as a hemihydrate, which belongs to a monoclinic system having space group P2(1)/c, with a = 12.424 A, b = 12.187 A, c = 6.662 A, and beta = 100.9 degrees. The optimized geometries and total energies of different conformers of the secnidazole molecule have been determined by the method of density functional theory (DFT). For both geometry and total energy, it has been combined with B3LYP functionals having extended basis sets 4-31G, 6-31G, and 6-311++G(d,p) for each of the three stable conformers of secnidazole. Using this optimized structure, we have calculated the infrared and Raman wavenumbers and compared them with the experimental data. The calculated wavenumbers are in an excellent agreement with the experimental values. Based on these results, we have discussed the correlation between the vibrational modes and the crystalline structure of the most stable conformer of secnidazole. A complete assignment is provided for the observed Raman and IR spectra.

Full text

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Molecular Structure and Vibrational Spectroscopic Investigation of Secnidazole Using
Density Functional Theory
Soni Mishra, Deepika Chaturvedi, Poonam Tandon,* and V. P. Gupta
Department of Physics, UniVersity of Lucknow, Lucknow 226007, India
A. P. Ayala and S. B. Honorato
Departamento de Fı ´sica, UniVersidade Federal do Ceara ´, C. P. 6030, 60.455-900 Fortaleza, CE, Brazil
H. W. Siesler
Department of Physical Chemistry, UniVersity of Duisburg-Essen, Essen D45117, Germany
ReceiVed: June 19, 2008; ReVised Manuscript ReceiVed: October 7, 2008
Secnidazole (R,2-dimethyl-5-nitro-1H-imidazole-1-ethanol) is an antimicrobical drug, and it is particularly
effective in the treatment of amebiasis, giardiasis, trichomoniasis, and bacterial vaginosis. Secnidazole
crystallizes as a hemihydrate, which belongs to a monoclinic system having space group P21/c, with a )
12.424 Å, b ) 12.187 Å, c ) 6.662 Å, and ? ) 100.9°. The optimized geometries and total energies of
different conformers of the secnidazole molecule have been determined by the method of density functional
theory (DFT). For both geometry and total energy, it has been combined with B3LYP functionals having
extended basis sets 4-31G, 6-31G, and 6-311++G(d,p) for each of the three stable conformers of secnidazole.
Using this optimized structure, we have calculated the infrared and Raman wavenumbers and compared them
with the experimental data. The calculated wavenumbers are in an excellent agreement with the experimental
values. Based on these results, we have discussed the correlation between the vibrational modes and the
crystalline structure of the most stable conformer of secnidazole. A complete assignment is provided for the
observed Raman and IR spectra.
I. Introduction
Secnidazole (R,2-dimethyl-5-nitro-1H-imidazole-1-ethanol;
Figure 1) is used as an antiprotozoal, antiamebic, and antibacte-
rial drug.1It is an antimicrobic agent which is structurally related
to the commonly used 5-nitromidazoles metronidazole and
tinidazole. Secnidazole is particularly effective in the treatment
of amebiasis, giardiasis, trichomoniasis, and bacterial vaginosis2
as it is rapidly and completely absorbed after oral administration
and has a longer terminal elimination half-life (17-29 h) than
commonly used drugs in this class.3In these cases, the treatment
with secnidazole is shorter and significantly more effective than
the treatment using other imidazole drugs and the adverse effects
are not very drastic.4
As an anhydrous solid, secnidazole is not stable at standard
conditions. Single crystal structure determinations showed that
this compound crystallizes in a hemihydrate form having four
secnidazole molecules per unit cell (Z ) 4) and two water
molecules. Secnidazole hemihydrate belongs to a monoclinic
system, space group P21/c, with a ) 12.424 Å, b ) 12.187 Å,
c ) 6.662 Å, and ? ) 100.9°.5The water molecules present in
the structure are shared among four half-occupied sites and are
linked to a propyl radical forming hydrogen bonds of the form
head-tail. The molecules are held together forming dimers by
means of a hydrogen bond between the OH group and a water
molecule.5The structure of secnidazole is of some interest as it
possesses a strong electron attracting nitro group as well as a
strong electron donating OH group and has the possibilities of
intramolecular as well as intermolecular hydrogen bonding.
Internal rotation about a C-C bond may result in several
isomeric conformations.
In the present work, the conformational stability of the
secnidazole molecule was investigated through quantum me-
chanical calculations. Geometry optimizations of the possible
stable rotamers were performed, and the corresponding relative
energies were compared. A complete vibrational analysis of
secnidazole was performed by combining Raman and infrared
data with quantum mechanical calculations. Infrared and Raman
spectroscopies are among the traditional methods of analysis,
and particularly powerful for nondestructive characterization of
substances including living material.6The calculated vibrational
spectra were analyzed on the basis of the potential energy
distribution (PED) of each vibrational mode, which allowed us
to obtain a quantitative as well as qualitative interpretation of
the infrared and Raman spectra.
* Author for correspondence. E-mail: poonam_tandon@hotmail.com.
Figure 1. Schematic of the secnidazole molecule.
J. Phys. Chem. A 2009, 113, 273–281
273
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 2009 American Chemical Society
Published on Web 12/15/2008

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II. Experimental Details
Secnidazole samples were characterized by X-ray powder
diffraction in order to identify the corresponding solid form.
The experimental and simulated powder diffraction patterns of
secnidazole are shown in Figure 2. The FULLPROF program7
was used to fit the simulated pattern to the experimental one,
and some instrumental parameters (overall intensity, background,
zero shift, etc.) were also adjusted. An excellent agreement
between the simulated powder pattern based on the reported
crystalline structure and the experimental data clearly show that
our samples are in the hemihydrate form.
Infrared spectra were recorded on a Bruker IFS28 FT-IR
spectrometer with a spectral resolution of 4 cm-1. KBr pellets
of solid samples were prepared from mixtures of 200 mg KBr
with 1 mg of sample using a hydraulic press. Raman spectra
were measured using a Jobin Yvon T6400 subtractive triple
spectrometer equipped with a liquid nitrogen cooled CCD
detector, and the 514.5 nm radiation from an Ar+laser was
used as the excitation line.
III. Computational Details
The electronic structure and optimized geometries of the
stable conformers of the molecule were computed by the DFT
method8using the Gaussian 03 program9package employing
6-311++G(d,p) basis sets and Becke’s three parameter (local,
nonlocal, Hartree-Fock) hybrid exchange functionals with
Lee-Yang-Parr correlation functionals (B3LYP).10-12The
basis set 6-311++G(d,p) augmented by d polarization functions
on heavy atoms and p polarization functions on hydrogen atoms
as well as diffuse functions for both hydrogen and heavy atoms
were used.13,14The absolute Raman intensities and infrared
absorption intensities were calculated in the harmonic ap-
proximation, at the same level of theory as used for the
optimized geometries, from the derivatives of the dipole moment
and polarizability of each normal mode, respectively. The
normal-mode analysis was performed, and the PED was
calculated for each of the internal coordinates using localized
symmetry.15,16For this purpose a complete set of 66 internal
coordinates was defined using Pulay’s recommendations.15,16The
vibrational assignments of the normal modes were proposed on
the basis of the PED calculated using the program GAR2PED.17
Raman and infrared spectra were simulated using a pure
Lorentzian band profile (fwhm ) 8 cm-1) using indigenously
developed software. Visualization and confirmation of the
calculated forms of the vibrations were done using the CHEM-
CRAFT program.18
IV. Results and Discussion
A. Geometry Optimization and Energies. Geometry op-
timization calculations were started taking the secnidazole
conformation determined by single crystal X-ray diffraction5
as the initial geometry. The geometry optimization produced a
molecule which is remarkably similar to one of the crystal-
lographic asymmetric unit. The optimized and experimental
structures of the molecule were compared by superimposing
them using a least-squares algorithm that minimizes the
distances between the corresponding non-hydrogen atoms
(Figure 3a). The agreement between the optimized geometry
and the experimental crystal structure is excellent showing that
the geometry optimization almost exactly reproduces the
experimental conformation (overall average deviation 0.078 Å).
The main differences lie in the misorientation of the methyl
and hydroxyl groups. The latter one exhibits the largest deviation
from the experimental results, but this effect may be associated
with the O13H···Ow and O13H···N4 hydrogen bonds, which
stabilize the crystalline structure.
There is a chiral carbon in the molecular geometry of
secnidazole, but racemic secnidazole is used in clinical trials at
the present time. Three different configurations have been
obtained based on the orientations of the ethanol moiety. The
equilibrium geometry of each conformer has been determined
by the energy minimization. These calculations were carried
out with the basis sets 4-31G, 6-31G, and 6-311++G(d,p). The
relative energies of these three conformers for which optimized
geometries were found are given in Table 1. The different
conformers are shown in Figure 3b. Conformer I is more stable
than conformers II and III. The energy difference between
conformer I and conformer II is 0.8838 kcal mol-1, and that
between conformer I and conformer III is 2.6738 kcal mol-1
for the basis set 6-311++G(d,p). Since these energy differences
are much larger than kT (at room temperature), there is almost
Figure 2. Comparison of the experimental and calculated (from secnidazole hemihydrate crystalline structure) X-ray powder pattern.
274
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Mishra et al.

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no possibility of coexistence of different conformers at room
temperature. The total energies are found to decrease with the
increase of the basis set dimension.
The presence of negative charge on O12 atom, net positive
charge on H24 atom, and small intermolecular distance (≈2
Å) between these two atoms suggests the presence of intramo-
Figure 3. (a) Comparison of the experimental (from single crystal X-ray diffraction) and optimized conformations of secnidazole. (b) Equilibrium
conformers of secnidazole.
Investigation of Secnidazole Using DFT
J. Phys. Chem. A, Vol. 113, No. 1, 2009 275

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lecular hydrogen bonding in the crystalline phase. Using
compiled data for a large number of C-H...O contacts, Desiraju
et al.19found significant statistical directionality even as far out
as 3.0 Å, and they concluded that these are to be legitimately
viewed as “weak” hydrogen bonds with a greater contribution
to packing forces than simple van der Waals attractions. In
conformer II, there exists the possibility of a much stronger
intramolecular hydrogen bond O13H24...O12 owing to a smaller
distance of 2.106 Å between atoms H24 and O12. But in
conformers I and III, the distances between atoms H24 and
O12 are 4.810 and 4.316 Å, respectively, which confirm a much
weaker intramolecular hydrogen bond O13H24...O12. In con-
former I, however, there exists the possibility of another stronger
intramolecular hydrogen bond C7H17...O12 owing to a smaller
distance of 2.613 Å between atoms H17 and O12.
It may be seen that the DFT calculations yield comparable
geometries using the same basis set for the three conformers
which differ from each other by not more than 0.02 Å in bond
length and 2° in bond angle except for the bond angles directly
related to the moieties associated with the conformational change
(the bond angle C6C7O13 increases by 6.03°, while the angle
O13C7H17 decreases by 5.41° in conformer II).
B. Vibrational Assignments. The molecular structures of
all the three equilibrium conformers of secnidazole are shown
in Figure 3b. The total number of atoms in this molecule is 24;
hence, it gives 66 (3n - 6) normal modes. The molecular
conformation obtained from the crystalline structure, as well
as the one yielded by geometry optimization, exhibits no special
symmetries, and hence the molecule belongs to the C1point
group. As a consequence, all the 66 fundamental vibrations of
the free molecule belong to the A irreducible representation and
are both IR and Raman active. As a crystalline solid, secnidazole
and water molecules are placed in general sites (4e in the
Wickoff notation) of the centrosymmetric space group P21/c
(C2h5). Considering that every crystalline structure has four
molecules of secnidazole and four water molecule per unit cell
(H2O sites are half-occupied), this gives 3N - 3 ) 321, [N )
4 × 27 ) 108] vibrational modes (rotations of the free molecule
become librational phonons; translations become acoustic
phonons, which have zero frequency at the gamma point). Using
the site symmetry, in accordance with the site group analysis
proposed by Rousseau et al.,20the vibrational modes of
secnidazole hemihydrate are distributed in the irreducible
representations of the C2hpoint group as follows
Γvib(309))78Ag+78Bg+77Au+76Bu
and the remaining 12 modes are librational modes of the water
molecule. According to the mutual exclusion principle, in the
case of a centrosymmetric structure, Raman active representa-
tions are not infrared active, and vice versa. Thus, 156 and 153
vibrational modes exhibit Raman (Agand Bg) and infrared (Au
and Bu) activity, respectively. However, in an organic crystal,
the crystalline field is usually not strong enough to split the
internal modes of the molecule, which become accidentally
degenerate. Thus, the vibrational spectrum is mainly determined
by the modes of the free molecule observed at higher frequen-
cies, together with the lattice (translational and librational)
modes in the low frequency spectral region.
(1)
The Raman scattering cross sections, ∂σj/∂Ω, which are
proportional to the Raman intensities, may be calculated from
the Raman scattering amplitude and predicted wavenumbers for
each normal modes using the relationship21,22
∂Ω)(24π4
∂σj
45)(
(υ0-υj)4
1-exp[
-hcυj
kT])(
h
8π2cυj)Sj
(2)
where Sjand υjare the scattering activities and the predicted
frequencies (in cm-1), respectively, of the jthnormal mode, υ0
is the Raman exciting frequency (in cm-1), and h, c, and k are
universal constants.
The calculated Raman and infrared intensities were used to
convolve each predicted vibrational mode with a Lorentzian line
shape (fwhm ) 8 cm-1) to produce simulated spectra. Assign-
ments have been made on the basis of relative intensities, line
shape, and potential energy distribution. The assigned wave-
numbers for the most stable conformer (conformer I) along with
the PED for each normal mode are given in Table 2.
C. Vibrational Wavenumbers. Comparison of calculated
wavenumbers at the B3LYP/6-311++G(d,p) level with experi-
mental values (Table 2) reveals an overestimation of the
wavenumber of the vibrational modes due to neglect of
anharmonicity present in a real system. Inclusion of electron
correlation in density functional theory to a certain extent makes
the wavenumber values smaller in comparison with the
Hartree-Fock wavenumber data. The vibrational wavenumbers
were obtained from the DFT calculations using a dual scaling
procedure for the fingerprint region (below 1800 cm-1) and
X-H stretching (above 1800 cm-1) regions, respectively.24,25
All the calculated vibrational wavenumbers reported in this
paper are scaled values. Experimental and calculated (scaled)
Raman and infrared absorbance spectra are shown in Figures 4
and 5, respectively.
1. C-OH Vibrations. In the FT-IR spectrum of secnidazole
(Figure 5), the characteristic peak corresponding to the stretching
mode of the OH group is identified at 3452 cm-1, whereas it is
calculated to be 3667 cm-1. In the Raman spectra, this band is
present as a broad and weak band around 3460 cm-1. In
conformer II, this mode is calculated to be 3584 cm-1with
smaller intensity in comparison to the corresponding intensities
in conformers I and III. The smaller value of OH stretching
wavenumber can be attributed to intrachain hydrogen bonding
(O13H24...O12) in conformer II. OH deformation modes are
calculated to be 1279 and 1210 cm-1, and they are observed at
1271 and 1196 cm-1in the IR spectra and at 1272 cm-1in the
Raman spectra.
The stretching modes υ(CO) at the calculated wavenumbers
1124 and 932 cm-1correspond to the observed bands at 1138
and 935 cm-1in the IR spectra and at 1138 and 937 cm-1in
the Raman spectra. These two modes have nearly 20% contribu-
tion from υ(CO), although the contribution from F(CH3) is
nearly 30%. This is because of heavy mixing of the modes.
The vibrational modes calculated to be 486 and 468 cm-1have
a major contribution from the internal coordinate corresponding
to the deformation of CCO. These modes are observed at 495
and 476 cm-1in the Raman spectra and approximately at the
TABLE 1: Theoretically Computed Energies (in Hartree) of Equilibrium Conformers of Secnidazole
conformer4-31G6-31G6-311++G(d,p)
-663.390 815 9
-663.389 408 3
-663.386 555
I
II
III
-662.281629 9
-662.280 808 8
-662.276 145 3
-662.970 642 9
-662.969 564 7
-662.965 239 2
276
J. Phys. Chem. A, Vol. 113, No. 1, 2009
Mishra et al.

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TABLE 2: Theoretical and Experimental Vibrational Wavenumbers (cm-1) of Conformers of Secnidazolea
DFT
unscaledscaledRamanIRPEDb
3842
3262
3158
3145
3101
3097
3096
3090
3037
3032
3028
1562
1540
1504
3667
3114
3014
3002
2960
2956
2955
2949
2899
2894
2890
1538
1516
1481
s
3452
3133
3015
2998
2984
2974
2937
2918
2896
2871
2850
1529
OH[υ(OH)](100)
R[υ(C3H)](99)
CH2[υa(CH2)](99)
Me1[υa(CH3)](97)
Me2[υa(CH3)](96)
Me1[υa(CH3)](74) + Me2[υa(CH3)](15) + CH2[υ(CH2)](7)
Me2[υa(CH3)](71) + Me1[υa(CH3)](22)
CH2[υs(CH2)](83) + Me2[υa(CH3)](14)
CH[υ(C7H)](94)
Me1[υs(CH3)](99)
Me2[υs(CH3)](100)
NO2[υa(NO) + δ(N10C2) + δ(NO2)](63)+ R[υ(CC) + υ(NC)](26)
R[υa(NC) + δ(C3H)](34) + NO2[υa(NO)](22) + Me1[δa(CH3) + υ(CC)](14)
R[υ(NC) + δring+ υ(CC)](36)
+ Me1[υ(CC) + δa(CH3)](27) + CH2[δ(CH2)](8) + Me2[δ(CH3)](6)
R[υ(CC) + δring](36) + NO2[υa(NO)](24) + Me1[δa(CH3)(16)]
Me2[δa(CH3) + F(CH3)](80)
Me2[δa(CH3) + F(CH3)](81) + Me1[δ(CH3)](5)
Me1[δa(CH3) + δ(CH3)](89)
CH2[δ(CH2)](54) + Me1[δa(CH3)](21)
R[υ(NC)](32) + CH2[δ(CH2) + υ(NC)](25) + Me1[δa(CH3)(15)
+ NO2[δ(N10C2) + υ(CN) + υ(NO)](12)
CH2[ω(CH2) + δ(CH2)](34) + CH[F(CH) + υ(CC)](32) + Me2[δs(CH3)](19) + OH[δ(OH)](7)
Me1[δs(CH3)(49)] + CH2[γ(CH2)](6) + CH[F(CH)](5) + Me2[δs(CH3)](5) +
R[υa(CN)](5) + NO2[υ(C2N10)](5)
Me2[δs(CH3)](70) + υ(CC)(9) + CH[F(CH)](5)
NO2[υ(C2N10) + υa(NO) + δ(NO2)](25) + CH[F(CH)](20) + R[υ(CN)
+ δ(C3H)](25) + CH2[γ(CH2)](15)
NO2[υ(NO) + υ(C2N10) + δ(NO2)](31) +
Me1[δs(CH3) (29)] + CH[F(CH)](16) + CH2[ω(CH2)](7) + R[υ(CN)(5)]
R[υ(NC)](36) + CH2[γ(CH2)](22) + CH[F(CH)](11)
CH[F(CH)](49) + CH2[ω(CH2)](32)
R[υ(NC) + δring](28) + CH2[γ(CH2)](21) + OH[δ(OH)](20) + CH[F(CH)](7)
R[υ(CN) + δ(C3H) + δring+ υ(NC)](53) + NO2[υ(NC) + υa(NO) + δ(NO2)](37)
CH2[F(CH2)](21) + OH[δ(OH)](20) + R[υ(NC) + δ(C3H) + δring](20) + CH[F(CH)](17)
R[υ(CN) + υ(CC) + δring+ υ(NC) + δ(C3H)](55) + CH2[υ(NC)](19) + NO2[υ(NO)](11)
+ Me1[υ(CC)](5)
R[δring+ δ(C3H) + υa(CN)](68) + NO2[υ(C2N10)](9) + CH2[υ(NC)](5)
Me2[F(CH3)](30) + OH[υ(CO)](22) + δ(C8OC7)(14) + υ(CC)(7) + CH2[F(CH2)](8)
υ(CC)(28) + Me2[F(CH3)](25) + OH[υa(CO) + δ(OH)](19) + δ(CCO)(11)
+ CH2[δ(NC7C6)](6)
υ(CC)(32) + OH[δ(OH) + υa(CO)](24) + CH2[F(CH2)](12) + δ(CCO)(6) + Me2[F(CH3)](5)
Me1[F(CH3) + δa(CH3) + δoop(C9C5)](85) + R[τring](5)
Me1[F(CH3)](46) + R[υ(NC)](20)
R[δring+ υ(NC) + δ(C3H)](50) + Me1[F(CH3) + υ(CC)](20) + CH2[F(CH2) + δ(C6N1)](7)
Me2[F(CH3)](37) + υ(CC)(30) + OH[υa(CO)](20)
CH2[F(CH2)](40) + Me2[δ(CH3)](14) + υ(CC)(9) + R[υ(NC)](11)
R[δoop(C3H) + τring](94)
OH[υ(CO)](31) + υ(CC)(27) + Me2[F(CH3)](12) + CH2[δ(NC7C6) +F(CH2)](12) + CH[F(CH)](5)
NO2[δ(NO2) + υ(NC) + υ(NO2)](71) + R[δring](15)
CH2[υ(NC) + δ(NC7C6)](35) + R[δring+ υ(NC)](19) + Me1[υ(CC)](13) + δ(C6C8C7)(5)
NO2[δoop(NO2) + δoop(N10C2)](92) + R[τring](6)
R[τring+ δring](50) + Me1[δoop(C9C5) + υ (CC)](26)
R[τring+ δring](57) + Me1[δoop(C9C5) + υ(CC)](24)
R[τring](70) + NO2[δoop(N10C2)](14) + CH2[δoop(C6N1)](8)
NO2[F(NO2) + δ(N10C2)](52) + CH2[δ(C6N1)](12) + Me1[δ(C5C9)](12) + R[υ(CC)](5)
δ(CCO)(25) + CH2[δ(NC7C6)](11) + Me1[δ(C5C9)](10)
+ NO2[υ(C2N10)](7) + υ(CC)(6) + R[τring](5)
δ(CCO)(59) + CH2[τ(N1C6) + F(CH2)](19) + δ(C6C8C7)(8)
NO2[υ(C2N10) + δ(NO2) + F(NO2)](31) + δ(CCO)(24) + R[δring](10) + CH2[δ(C6N1)](9)
NO2[δ(OC2N10) + υ(C2N10)](28) + Me1[δ(C5C9)](24)
+ CH2[δ(C6N1)](16) + R[υ(N1C2)](8)
CH2[δ(C6N1) + δ(CH2) + δoop(C6N1)](32) + Me1[δ(C5C9)](22) + δ(C6C8C7)(18)
CH2[δ(C6N1) + υ(N1C6)](16) + δ(C6C8C7)(15)
+ δ(CCO)(12) + Me1[δoop(C9C5)](12) + NO2[F(NO2)](10)
Me1[δoop(C9C5)](32) + NO2[δoop(N10C2)](28) + CH2[τ(N1C6)](8) + R[τring](7)
CH2[δoop(C6N1) + δ(C6N1) + δ(NC7C6)](30) + NO2[δoop(N10C2)](20) + δ(C6C8C7)(18)
+ δ(CCO)(13) + Me1[δ(C5C9)](5)
OH[τ(CO)](83)
Me2[τ(C7C8)](59) + NO2[δ(N10C2)](15) + OH [τ(CO)](10) + Me1[δ(C5C9)](5)
NO2[δ(N10C2) + F(NO2)](43) + Me2[τ(C7C8)](33) + Me1[δ(C5C9)](6) + δ(C6C8C7)(5)
Me1[τ(C5C9)](86)
NO2[δoop(N10C2)](41) + CH2[δ(NC7C6)
+ δoop(C6N1) + τ(N1C6)](30) + Me1[δoop(C9C5)](8) + R[τring](5)
CH2[τ(N1C6) + δoop(C6N1) + δ(NC7C6)](42) + NO2[τ(C2N10)](39)
CH2[τ(N1C6) + δoop(C6N1) + δ(NC7C6)](77) + NO2[δoop(N10C2)](8)
(C6C7)(55) + NO2[τ(C2N10)](14) + CH2[τ(N1C6) + δ(C6N1)](14)
CH2[τ(N1C6) + δoop(C6N1)](47) + NO2[τ(C2N10) + δoop(N10C2)](31) + τ(C6C7)(9)
lattice
3137
3015
3003
2984
2975
2934
s
2906
2878
2849
1536
ss
14891489
1499
1496
1493
1484
1472
1454
1476
1474
1470
1462
1450
1432
14891488
s
s
s
s
1471
1461
1437
1468
1448
1430
1421
1415
1400
1395
1408
1390
s
1392
1411
1391
1390
1371
s
s
s
1379
1387136713691357
1379
1350
1297
1292
1226
1216
1360
1331
1279
1275
1210
1201
1345
1307
1272
1265
1333
1305
1271
1264
1196
1184
s
1192
1176
1136
1117
1164
1124
1105
1155
1138
1111
1151
1138
1110
1074
1065
1018
983
940
902
890
849
840
783
736
697
681
607
574
481
1063
1054
1008
975
932
896
884
844
835
780
733
695
681
609
576
486
1086
1044
1007
983
937
906
879
842
829
775
743
691
675
609
572
495
1085
1039
1008
981
935
904
878
842
827
777
742
691
675
609
569
495
463
423
391
468
429
398
476
428
395
475
432
s
336
309
344
318
351
331
s
s
284
260
284
271
298
278
s
s
232
226
211
147
136
243
237
223
161
150
ss
s
s
s
s
234
221
169
147
101
77
60
43
s
117
93
76
60
s
123
92
75
60
43
s
s
s
s
s
aProposed assignment and potential energy distribution (PED) for vibrational normal modes. Types of vibration: υ, stretching; δ, deformation; oop, out-of-plane bending; ω, wagging; γ, twisting; F,
rocking; τ, torsion. The imidazole ring modes are labeled following Wilson’s notation.23 bPotential energy distribution (contributing g5) for conformer I.
Investigation of Secnidazole Using DFT
J. Phys. Chem. A, Vol. 113, No. 1, 2009 277

Page 6

same positions in the IR spectra also. The torsion around CO
is calculated to be 243 cm-1.
2. CC and CH Vibrations. CC stretches are calculated to
be 1105, 1063, and 844 cm-1, and the corresponding bands are
observed at 1111, 1086, and 842 cm-1in both the IR and Raman
spectra. The C7-H stretch predicted at 2899 cm-1by DFT
calculation is in an excellent agreement with the experimental
recorded bands at 2906 cm-1in the Raman spectra and 2896
cm-1in the IR spectra. The CH rocking mode is calculated to
be 1331 cm-1. The corresponding band is observed at 1305 cm-1
in the IR spectra and at 1307 cm-1in the Raman spectra.
3. N-CH2Group Vibrations. The molecule contains a CH2
group connected to the ring. The asymmetric CH2stretching
vibration is calculated to be 3014 cm-1and matches well with
the IR and Raman wavenumbers. The symmetric CH2stretching
mode is calculated to be 2949 cm-1, and it is assigned to the
2918 cm-1band in the IR spectra. The CH2deformation mode
is calculated to be 1450 cm-1, and the corresponding peak is
observed at 1461 cm-1in the Raman spectra and at 1448 cm-1
in the IR spectra. The CH2wagging mode occurs at 1305 cm-1
in the IR spectra and at 1408 and 1307 cm-1in the Raman
spectra. The calculated values are 1400 and 1331 cm-1. The
rocking modes of the CH2 group give rise to the medium
intensity bands at 1196 and 904 cm-1in the IR spectra, and
only one Raman band at 906 cm-1is observed. The corre-
sponding calculated wavenumbers are 1210 and 896 cm-1, as
shown in Table 2.
4. C-CH3 Group Vibrations. Two methyl groups are
present in the molecule. One of them is directly connected to
the ring, and the other one is connected to the CH group. The
CH3 group has several modes associated with it, such as
symmetric and asymmetric stretches, bends, and rock and
torsional modes. Assignments of all these fundamentals are
given in Table 2. In the first methyl group υs(CH3) mode is
observed at 2878 cm-1and υa(CH3) modes are observed at 3003
and 2975 cm-1in the Raman spectra. A υs(CH3) stretching mode
is calculated to be 2894 cm-1, and two υa(CH3) asymmetric
stretching modes are calculated to be 3002 and 2956 cm-1. In
Figure 4. Experimental and calculated (scaled) Raman spectra of the secnidazole in the regions 300-1650 and 2600-3900 cm-1. (Inset shows
Raman spectra in the region 30-300 cm-1.)
Figure 5. Experimental and calculated (scaled) infrared absorbance spectra of the secnidazole in the regions 400-1650 and 2700-3900 cm-1.
278
J. Phys. Chem. A, Vol. 113, No. 1, 2009
Mishra et al.

Page 7

the IR spectra, υa(CH3) modes are observed at 2998 and 2974
cm-1and a υs(CH3) mode is observed at 2871 cm-1. The peak
corresponding to symmetric stretching mode is relatively strong.
We have observed the asymmetric deformation modes
Me1[δa(CH3)] at 1468 and 1448 cm-1in the IR spectra and at
1471 and 1461 cm-1in the Raman spectra. These modes are
calculated to be 1462 and 1450 cm-1. The symmetric
Me1[δs(CH3)] modes are assigned to the observed peaks at 1390
and 1369 cm-1in the Raman spectra and at 1392 and 1357
cm-1in the IR spectra. The corresponding calculated values
are 1395 and 1367 cm-1. The CH3rocking modes are assigned
to weak Raman peaks at 1044 and 1007 cm-1and the IR peaks
at 1039 and 1008 cm-1for the first methyl group. The calculated
values of CH3rocking mode are obtained at 1054 and 1008
cm-1. The calculated wavenumber at 161 cm-1shows a major
contribution from CH3torsion around the C5-C9 bond, and
this matches well with the observed wavenumber (169 cm-1)
in the Raman spectra. A comparatively low value of this mode
is due to the heavy imidazole ring attached with the C5-C9
bond. We have calculated the out-of-plane deformation at 284
cm-1, and it is observed at 298 cm-1in the Raman spectra.
The asymmetric stretch mode of second methyl group is
calculated to be 2955 cm-1and matches well with the peak
observed at 2934 cm-1in the Raman spectra and approximately
at the same position in the IR spectra. The symmetric stretch
of methyl group is calculated to be 2890 cm-1and matches
well with 2849 cm-1observed in both Raman and IR spectra.
The symmetric methyl deformation mode Me2[δs(CH3)] is
calculated to be 1390 cm-1and the asymmetrical Me2[δa(CH3)]
are calculated to be 1474 and 1470 cm-1, their intensities being
less than the corresponding intensities in the two other conform-
ers. The CH3modes calculated for conformer I are in better
agreement with the observed spectra in comparison to that for
the other two conformers. This may be due to the different
orientations of the CH3 group in these two conformers in
comparison to single crystal data. The CH3rocking mode is
assigned to weak Raman peaks at 1138 and 1111 cm-1and
strong IR peaks at 1138 and 1110 cm-1. These two rocking
modes are calculated to be 1124 and 1105 cm-1. The torsional
mode C7-C8 for the second methyl group is calculated to be
237 cm-1, and it matches well with the observed band in the
Raman spectra.
5. C-NO2Vibrations. The molecule under investigation
possesses only one NO2 group, and hence one expects a
symmetric and an asymmetric N-O stretching vibration of the
NO2group. The symmetric and asymmetric stretching modes
appear at 1367 and 1538 cm-1, respectively, and both the modes
are highly mixed modes. Symmetrical and asymmetrical de-
formations of the NO2group appear at 827/829 cm-1and 742/
743 cm-1in IR/Raman spectra. These modes are calculated to
be 835/733 cm-1, respectively. The rocking mode of the NO2
group is observed at 572 cm-1in the Raman spectra. It is
calculated to be 576 cm-1and is assigned to the peak at 569
cm-1in the IR spectra. It is also a mixed mode containing the
contribution from C-N deformation. The stretching mode of
C-N band (connecting NO2group and ring) is calculated to be
1371 cm-1and has been assigned to the 1379 cm-1band in the
IR spectra. The C-N deformation is calculated to be 223 cm-1.
The C-N out-of-plane deformation is calculated to be 150 cm-1,
and it is assigned to a band at 147 cm-1in the Raman spectra.
The mode with the lowest wavenumber is the torsion mode of
C-N. C-N torsions are calculated to be 117 and 60 cm-1, and
they are observed at 123 and 60 cm-1in the Raman spectra.
6. Ring Vibrations. The C-H stretching vibration in ring
is usually strong in both the IR and Raman spectra. The υ(CH)
wavenumber in ring is assigned at 3137 cm-1in the Raman
spectra and at 3133 cm-1in the IR spectra. It is calculated to
be 3114 cm-1, and thus coincides well with the experimental
observations. The calculated wavenumber at 1516 cm-1has
major contribution from CN asymmetric stretching in the
imidazole ring. The major contribution of the symmetric
stretching mode of CN in imidazole ring is obtained in the
vibrational modes at 1432 and 1360 cm-1, and these are
observed at 1430 and 1333 cm-1in the IR spectra and at 1437
and 1345 cm-1in the Raman spectra. The symmetric stretching
mode R[υ(CN)] is calculated to be 1275 and 1201 cm-1mixed
with R[υ(CC)] symmetric stretch and other modes. It corre-
sponds to the peaks at 1265 and 1192 cm-1in the Raman spectra
and at 1264 and 1184 cm-1in the IR spectra. R[υ(CC)]
symmetric stretches are calculated to be 1538 and 1476 cm-1
and are assigned to the bands at 1529 and 1488 cm-1in the IR
spectra and at 1536 and 1489 cm-1in the Raman spectra.
Ring deformations are calculated to be 1164 and 975 cm-1,
and these are observed at 1155 and 983 cm-1in the Raman
spectra and at 1151 and 981 cm-1in the IR spectra. Out-of-
plane deformation of R[δoop(C3H)] is calculated to be 884 cm-1
and matches well with IR and Raman spectra. The torsions of
the ring are calculated to be 695, 681, and 609 cm-1. These are
also in excellent agreement with the experimentally observed
IR and Raman values.
By using a subtractive triple spectrometer, the low energy
region of the Raman spectrum is easily recorded (inset of Figure
4).26This equipment provides an excellent rejection of the
excitation line lowering the spectral limit down to 30 cm-1when
compared with single and Fourier transform spectrometers. The
extended spectral range allows us to observe the lattice and
skeleton vibrational modes, which are expected to be directly
related to the crystal structure. Our results show an excellent
agreement between the calculated and experimental values in
this spectral region, allowing us to establish a detailed assign-
ment of all these bands. Just one band, located at 43 cm-1, could
not be associated with any vibrational mode of the single
molecule, and this has been classified as a lattice vibration. It
is interesting to notice that usually the lattice vibrations are
observed below 200 cm-1. However, our results show that these
types of modes are in the very low wavenumber region, probably
below 50 cm-1. All the modes above 50 cm-1were classified
as deformations and torsions of the secnidazole molecule. On
the other hand, the lattice modes associated with the translations
and librations of the whole molecule lie below 50 cm-1and
can only be observed by dispersive Raman (in a subtractive
spectrometer), far-infrared, or terahertz spectroscopy.
By comparing the rest of the vibrational spectra of secnidazole
with the help of the PED distribution presented in Table 2, we
find a very good overall agreement. The difference between the
observed and scaled wavenumber values of most of the
fundamentals is quite small.
Finally, in Figure 6, a selected spectral region of the calculated
Raman spectrum is compared with experimental data obtained
at 30 and 90 °C. The room temperature Raman spectrum
corresponds to the hemihydrate form discussed previously. On
the other hand, secnidazole is in the melted form at 90 °C since
its melting point is 70 °C.2As stated previously, our DFT results
reproduce very well the experimental data, but interesting
features may be identified between the two experimental spectra
recorded at 30 and 90 °C. First, we notice that the band at 1192
cm-1remains approximately unaltered in the melted state. This
Investigation of Secnidazole Using DFT
J. Phys. Chem. A, Vol. 113, No. 1, 2009 279

Page 8

band is associated with the breathing of the imidazole ring. In
the solid form, this ring participates in the hydrogen bond pattern
that stabilizes the crystalline structure through a OH···N bond.
However, this interaction does not seem to be strong enough to
affect the ring breathing frequency. The neighboring bands,
located at 1265 and 1272 cm-1, exhibit a different behavior.
At room temperature they split into two bands (1265 and 1272
cm-1) and merge into just one band (1265 cm-1) at 90 °C.
According to Table 2, the first one at 1265 cm-1is related to
the deformation of the imidazole ring of the nitro group, whereas
the second one at 1272 cm-1has contributions from the
deformations of the ring as well as methylene and hydroxyl
groups. Even though DFT calculations have predicted a
negligible Raman intensity for the latter, this is one of the most
intense bands in the Raman spectrum. This anomalous behavior
could be explained by considering that the hydroxyl group
participates in all the main intermolecular interactions in the
solid hemihydrate form. The change in the vibrational mode
polarizability due to these interactions may easily affect its
Raman cross section. Nevertheless, the loss of the intermolecular
hydrogen bonds in the melted form reduces the intensity of this
band since the molecule now acquires a configuration which is
closer to single molecule approximation that is taken in the
theoretical model. The remaining bands observed in the spectral
region presented in Figure 6 do not present any evidence of
other effects that produce shift and line broadening, which are
expected in a completely disordered liquid.
V. Conclusions
Geometry optimizations show that there are three conformers
of secnidazole having very close total energies. Thus, calcula-
tions using DFT at the B3LYP level with extended basis sets
4-31G, 6-31G, and 6-311++G(d,p), show that the energy
differences between the reported conformers are as small as
0.5-3.0 kcal mol-1. However, these energy differences are
much larger than kT, so there is almost no possibility of
coexistence of different conformers at room temperature. X-ray
diffraction study also confirms that just one of them (conformer
I) was identified in the crystalline structure of secnidazole
hemihydrate. The optimized structure of this conformer is very
close to the one observed experimentally (bond lengths differ
by less than 0.01 Å and bond angles differ by about 1°, except
for the moieties where the difference is almost 6°). In conformer
I, there exists the possibility of stronger intramolecular hydrogen
bond C7H17...O12 owing to a smaller distance of 2.613 Å
between atoms H17 and O12. Vibrational spectroscopy and DFT
calculations have been applied for investigating the most stable
conformer of secnidazole. Raman and infrared spectra were
recorded, and the vibrational bands were assigned on the basis
of the PED obtained from the DFT calculations. In general, a
very good agreement between experimental and calculated
modes was observed. A striking feature of the work is that the
study of vibrational spectra and DFT calculations reveals that
the lattice modes of secnidazole lie below 50 cm-1. However,
such low-lying modes can only be observed by using high
performance spectroscopic techniques.
Acknowledgment. The financial support to one of the authors
(P.T.) from the Alexanded von Humboldt Foundation, Germany,
is gratefully acknowledged. A.P.A. and S.B.H. acknowledge the
financial support of the Brazilian agencies CNPq, CAPES and
FUNCAP. Authors would like to thank Vineet Gupta for
computational support.
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