Tautomerism in o-hydroxyanilino-1,4-naphthoquinone derivatives: Structure, NMR, HPLC and density functional theoretic investigations

Article abstract of DOI:10.1016/j.molstruc.2016.06.026

Structure and spectral characteristics of 'Ortho' ((E)-4-hydroxy-2-(2′-(4′-R)-hydroxyphenyl)-imino)-naphthalen-1(2H)-one) and 'para' (2-(2′-(4′-R)-hydroxyphenyl)-amino)-1,4-naphthoquinone) tautomers of o-hydroxyanilino-1,4-naphthoquinone derivatives (R=H,

Full text of DOI:10.1016/j.molstruc.2016.06.026

Journal of Molecular Structure 1123 (2016) 245e260
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Tautomerism in o-hydroxyanilino-1,4-naphthoquinone derivatives:
Structure, NMR, HPLC and density functional theoretic investigations
,
,
Sujit Bhand a 1, Rishikesh Patil a 1, Yogesh Shinde a, Dipali N. Lande a, Soniya S. Rao a,
Laxmi Kathawate a, Shridhar P. Gejji a, Thomas Weyhermüller b, Sunita Salunke-Gawali a
,
*
a Department of Chemistry, University of Pune, Pune 411007, India
b MPI für Chemische Energiekonversion, Stiftstrabe. 34-36, 45470 Mülheim an der Ruhr, Germany
a r t i c l e i n f o
a b s t r a c t
Structure and spectral characteristics of ‘Ortho’ ((E)-4-hydroxy-2-(20-(40-R)-hydroxyphenyl)-imino)-
naphthalen-1(2H)-one) and ‘para’ (2-(20-(40-R)-hydroxyphenyl)-amino)-1,4-naphthoquinone) tautomers
of o-hydroxyanilino-1,4-naphthoquinone derivatives (R]H, 1A; eCH3, 2A; and eCl, 3A) are investigated
using the 1H, 13C, DEPT, gDQCOSY, gHSQCAD NMR, HPLC, cyclic voltammetry techniques combined with
the density functional theory. The compound 2A crystallizes in monoclinic space group P21/c. wherein
the polymer chain is facilitated via OeH/O and CeH/O intermolecular hydrogen bonding. Marginal
variations in bond distances in quinonoid and aminophenol moieties render structural flexibility to these
compounds those in solution exist as exist in ‘ortho e para’ tautomers. 1H and 13C NMR spectra in DMSO-
d6 showed two sets of peaks in all compounds; whereas only the para tautomer of for 1A and 2A, the para
tautomer is predominant in CD3CN solution. Further the ortho-para interconversion is accompanied by a
large up-field signals for C(3)eH(3) in their 1H and 13C NMR spectra. These inferences are corroborated
by the density functional theoretic calculations.
Article history:
Received 23 March 2016
Received in revised form
6 June 2016
Accepted 7 June 2016
Available online 11 June 2016
Keywords:
Tautomer
Keto-enol
Lawsone
Aminonaphthoquinone
Aminophenol
Ortho-para conversion
DFT
© 2016 Elsevier B.V. All rights reserved.
1. Introduction
C, N, O or may be S. The migration of such proton involving carbon
atom being sufficiently slow so that the corresponding tautomers
Enzymatic activities, spontaneous mutation as well as biological
activities of organic, heterocyclic, biochemical compounds are due
to proton transfer in fundamental functional groups like ketone,
aldehyde, ester, amide, peptide and proteins. Tautomers are prime
important class of isomers which exerts potent pharmacological
activities outcomes from various molecular interactions. Classical
discrimination between isomerism and tautomerism is the only
relative low energy required for interconversion of tautomers.
Tautomers are easily interconvertable isomers of single molecule
by transfer of atom or group of atom usually the proton. Tautomeric
equilibrium are strongly affected by polarity of the solvent and
density. The accompanied energy difference up to 20 kcal molꢀ1
can be observed which can alter the concentration of either of the
tautomers significantly [1,2]. Isomerisation of prototrophic tauto-
mers refers to the migration of proton from atom to another such as
could be separated easily in solution. Contrary to this the proton
transfer involving nitrogen to oxygen or vice-versa are rapid and
the separation of tautomers in solution [3,4] become far from
straightforward. Tautomeric equillibria are dependent on the
dielectric constant of the medium and the ability of solvents to
hydrogen bond with each tautomer. The polar solvent usually fa-
vors the more polar tautomer. The equilibrium composition further
is influenced by temperature as well; with higher temperature
increasing the proportion of the less stable enol form can be
noticeable. The structural attributes and solvent polarity dictate the
tautomeric equillibria.
Hydroxynaphthoquinones are pharmacologically important
molecules they possess several biological activities which includes,
anticancer [5] and antibiotic [6] etc. Hydroxynaphthoquinones
exist in tautomeric equillibria in solutions contrary to only one
stable tautomeric form in solid [7]. The prototropic tautomerism of
2-hydroxy-1,4-naphthoquinone derivatives predicted the 1,4-
tautomer of naphthoquinone is observed to be of lower energy and
biologically relevant. It has further been inferred that the hydroxyl
group is crucial for its inhibitory action against quinol fumarate
* Corresponding author.
E-mail addresses: spgejji@chem.unipune.ac.in (S.P. Gejji), sunitas@chem.
unipune.ac.in (S. Salunke-Gawali).
1
Contributed equally.
http://dx.doi.org/10.1016/j.molstruc.2016.06.026
0022-2860/© 2016 Elsevier B.V. All rights reserved.

246
S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
Table 1
reductase [8]. Moreover tautomers of hydroxynaphthoquinones
can form as stable intermediate in biosynthesis of cis-3,4-
dihydroxy-1-tetralone [9]. Ortho-para naphthoquinone tautomers
Crystal data and structure refinement for 2A.
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system, space group
Unit cell dimensions
C17 H13 N O3
279.28
100(2) K
1.54178 Å
Monoclinic, P21/c
a ¼ 20.279(2) Å
rearrangement was inferred in the synthesis of ( )-g-Rubromycin
antibiotic [10]. Tautomers showing solid state fluorescence are also
reported [11]. Naphthoquinone tautomers are the intermediates in
the synthesis of Kermesic acid; a colorant [12].
b ¼ 3.7696(4) Å,
c ¼ 18.742(2) Å
1285.7(2) Å3
4, 1.443 Mg/m3
0.816 mmꢀ1
584
b
¼ 116.183(4)ꢁ
Recently we studied the tautomeric equillibria of naph-
thoquinoneoximes, by reversed phase chromatographic technique
[13,14]. The tautomeric equilibrium is shown to be dependent on
pH of mobile phase. The isolation of the tautomers carried out by
preparative HPLC and characterized by chromatographic (HPLC) as
well as spectroscopic techniques. Stability of tautomers depends on
solvent polarity which is used for solubility of compound [13].
Tautomeric equillibria further provide facile path for biological
activity.
In the present report we investigated the tautomers of anilino
derivatives of 2-hydroxy-1,4-aphthoquinone (1A-3A)(Scheme 1).
All compounds exist as ‘ortho’ and ‘para’ tautomers in polar solvent
such as DMSO-d6, however only the ‘para’ tautomer exists as stable
form in the less polar CD3CN. 1H and 13C chemical shifts were
assigned by gDQCOSY, gHSQCAD NMR experiments and by density
functional theory (DFT) on the theoretical front.
Volume
Z, Calculated density
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Limiting indices
Reflections collected/unique
Completeness to theta ¼ 67.679ꢁ
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
0.180 ꢂ 0.102 ꢂ 0.060 mm
2.428e67.447ꢁ
ꢀ23 ꢃ h ꢃ 24, ꢀ4 ꢃ k ꢃ 4, ꢀ22 ꢃ l ꢃ 22
27895/2322 [R(int) ¼ 0.0504]
99.1%
Gaussian
0.97333 and 0.88495
Full-matrix least-squares on F2
2322/2/198
1.062
R1 ¼ 0.0437, wR2 ¼ 0.1183
R1 ¼ 0.0523, wR2 ¼ 0.1265
0.260 and ꢀ0.209 e Aꢀ3
Largest diff. peak and hole
2. Experimental section
stirred for 15 min. The solids of 2-aminophenol; 1 mM (109 mg) in
1A, 4-methyl-2-aminophenol 1 mM (123 mg) in 2A and 4-chloro-2-
aminophenol, 1 mM (143 mg) in 3A, were dissolved in 10 ml dry
methanol. The aminophenol solutions were added drop wise in to
the solution of lawsone. The colour of reaction mixture turned from
yellow to brown. The mixture was stirred at room temperature
(26 ꢁC) for 24 h in 1A and refluxed for 62 h in 2A and 3A. The re-
action was monitored on TLC (9.5:0.5; toluene: methanol). Dark red
colour products obtained were filtered and washed with small
amount of methanol and dried in vacuum and purified by column
chromatography. Dark red band was separated as major product
(1Ae3A) by column chromatography. Details of synthesis and
characterizations of the compounds can be found in Ref. [16].
2.1. Material
All the chemicals used in synthesis are of analytical grade.
Lawsone (2-hydroxy-1,4-napthoquinone) and 2-aminophenol has
been obtained from Sigma-Aldrich and recrystallized from dry
methanol before use. 4-chloro-2-aminophenol and 4-methyl-2-
aminophenol are obtained from across chemicals. Anhydrous
methanol used in the synthesis has been purified by literature re-
ported procedure [15].
2.2. Analytical methods
The FT-IR spectra of the compounds were recorded between
4000 and 400 cmꢀ1 as KBr pellets on SHIMADZU FT 8400 Spec-
trometer. The elemental analyses were performed on Thermo Fin-
nigan EA 1112 Flash series Elemental Analyzer. 1H, (Figs. S3, S12 and
S22), 13C (Figs. S4, S13, S23), DEPT (Figs. S5, S14 and S24), gDQCOSY
(Figs. S15 and S25) and gHSQCAD (Fig. S6, S16 and S26) NMR of 1A,
2A and 3A were recorded in DMSO-d6, and for 1A (Figs. S7eS11) and
2A in eCD3CN(Figs. S17eS21) on Varian Mercury 500 MHz NMR
spectrometer with tetramethylsilane (TMS) as a reference.
2.4. X-ray diffraction studies of 2A
An orange single crystal of 2A were coated with per-
fluoropolyether, picked up with nylon loops and mounted in the
nitrogen cold stream of the Bruker APEX-II Diffractometer. Graphite
monochromated Cu-K
a
radiation (
l
¼ 0.71073 Å) was used. Final
cell constants were obtained from least squares fits of several
thousand strong reflections. Intensity data were corrected for ab-
sorption using intensities of redundant reflections with the pro-
gram SADABS [17]. The structure was solved readily by direct
methods and subsequent difference Fourier techniques. The
Siemens ShelXTL [18] software package was employed for solution
and artwork of the structures, ShelXL97 [19] was used for the
refinement. All non-hydrogen atoms were anisotropically refined
2.3. Synthesis of 1A and 3A
Recrystallized 2-hydroxy-1,4-naphthoquinone (lawsone) 1 mM
(174 mg) was dissolved in 20 ml dry methanol. The solution was
Scheme 1. Reaction scheme of synthesis of compounds 1Ae3A.

S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
247
and hydrogen atoms were placed at calculated positions and
Condition III:
refined as riding atoms with isotropic displacement parameters.
The crystallographic data is presented in Table 1.
Buffer Preparation 10 mM ammonium formate prepared in
HPLC grade water.
Mobile Phase A: 0.1% Formic Acid in 10 mM ammonium formate.
Mobile Phase B: 5% Mobile phase A and 0.1% Formic Acid in 95%
HPLC grade Acetonitrile.
2.5. Computational details
Condition IV:
Optimizations of 1A, 2A and 3A in ortho and para tautomers
Buffer Preparation: 10 mM ammonium formate in HPLC grade
water. Mobile Phase A: 0.1% ammonia in 10 mM ammonium
formate. Mobile Phase B: 5% Mobile Phase A and 0.1% ammonia in
95% HPLC grade Acetonitrile.
Above chromatographic parameters, gradient programme are
similar but only the mobile phase preparations are different
(Condition I to Condition IV) for the analysis of isomers of o-
hydroxyanilino-1,4-naphthoquinone derivatives.
were carried out using the dispersion corrected density functional
theory incorporating
uB97x and M06-2x exchange correlation
functionals [20] employing the analytical gradient method in which
all the geometrical parameters relaxed simultaneously. Gaussian-
09 suit of programs [21] with the internally stored 6-
311þþG(d,p) basis set [22] was used. Stationary point structures
thus obtained were confirmed to be local minima on the potential
energy surface through vibrational frequency calculations. The
normal vibrations were assigned by visualizing displacements of
atoms about their equilibrium (mean) positions. Besides the po-
tential energy distribution were derived specifying the internal
option in the Gaussian program. NMR chemical shifts were ob-
tained by subtracting the nuclear magnetic shielding tensors of
protons for the ortho or para tautomer from those of the tetra-
methyl silane (TMS) (as a reference) with the gauge invariant
atomic orbital (GIAO) [23] method. The effect of solvation on rela-
tive stabilization energies were simulated via the self-consistent
reaction field (SCRF) theory incorporating polarizable continuum
model [24].
2.7. Cyclic voltammetry studies
The electrochemical measurements were performed with CHI
6054E electrochemical analyzer. A commercial Pt disc electrode
(CHI Instruments, USA, 2 mm diameter), AgNO3 wire and Pt wire
loop were used as working, reference and counter electrodes
respectively. After fixing the electrodes to the cell 0.513 g of tetra
butyl ammonium perchlorate (100 mM in 15 mL solution) was
transferred to the cell through high purity argon gas. The blank or
controlled voltammograms were acquired in tetra butyl ammo-
nium perchlorateeDMSO mixture prior to the measurements.
Sample dispersed in small amount of solvent injected in the cell for
further measurement (analyte concentration 5 mg/15 ml). At the
end of each set of experiments the potentials were calibrated
relative to the normal hydrogen electrode (NHE) using ferrocene as
an internal standard.
2.6. HPLC
Apparatus: Shimadzu, LC-2010CHT liquid chromatograph was
used for separation of isomers/tautomers. The detector used is SPD-
M20A diode array and auto sampler injection system, connected
with LC-Solution with a multi-channel module.
Chromatography: A YMC Triart C18 column [length ¼ 100 mm,
3. Result and discussion
internal diameter ¼ 4.6 mm, particle size ¼ 3.5 , pore size ¼ 12 nm]
m
was used for separation of tautomers. The mobile phase consisted
of water: acetonitrile in various proportions. Water and acetonitrile
was acidified with mixture of ammonium formate and formic acid,
basified by using mixture of ammonium formate and ammonia.
Ammonium acetate was used for preparation of neutral mobile
phase. Detector was set at 254 nm.
Chemicals and materials: HPLC grade CH3CN and CH3OH was
obtained from Merck Chemicals. Chromatographic ammonium
acetate, ammonium formate was obtained from Merck.
3.1. Synthesis
Compounds 1Ae3A were synthesized by catalyst free reactions
of nucleophilic addition of aminophenol derivatives to C(2) carbon
of lawsone (2-hydroxy-1,4-naphthoquinone). The products were
purified by column chromatography using toluene: methanol (9:1)
as eluent. The chromatographic separation showed the resultant
red colored solid as the major product (1A-3A) with a yield of about
67%, the orange colour minor product (1Be3B) in 10% yield was
Chromatographic Parameters: Column: YMC-Triart C18
identified to be benzo[a]phenoxazine derivative [16]. The com-
(4.6 ꢂ 100) mm 3.5
m
m. Flow rate: 1 mL/min. Wavelength: 254 nm.
pounds 1A, 2A and 3A were further characterized by elemental
analysis, FT-IR and 1H NMR experiments. LC-MS analysis of 1A, 2A
and 3A were carried out from the. Liquid chromatogram of all
compounds that showed two peaks with the same molecular mass.
Run Time: 15 min.
Gradient Program:
Sr. no.
Time (Min.)
Mobile phase A (%)
Mobile phase B (%)
1
2
3
4
5
6
0.01
2.00
8.00
12.00
12.10
15.00
90
90
05
05
90
90
10
10
95
95
10
10
Diluent Preparation: Used methanol as diluent.
Condition I:
Mobile Phase A: Milli-Q Water. Mobile Phase B: HPLC grade
Acetonitrile.
Condition II:
Mobile Phase A: Buffer solution (50 mM, ammonium acetate in
HPLC grade water). Mobile Phase B: Acetonitrile.
Fig. 1. ORTEP plot of 2A. The ellipsoid was drawn with 50% of probability.

248
S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
Fig. 2. Bond distances in o-hydroxyanilino-1,4-naphthoquinone derivatives.
1H NMR investigations further led to two sets of resonance signals.
These observations prompted us to initialize the investigations
further on the 1H and 13C chemical shifts, chromatography sepa-
ration combined with theoretical investigations based on DFT.
naphthoquinone (~1.20 Å). Contrary to 1A which is planar, the
naphthoquinone and aminophenol rings of 2A and 3A make an
angle of 45.59ꢁ to one another (Fig. S1 in ESIy).
There is intra molecular hydrogen bonding observed to
O(1)(N(11)eH(11)/O(1)), while O(4) and O(18) involved in
3.2. Single crystal X-ray diffraction studies of 2A
2A crystallizes in monoclinic space group P21/c. ORTEP plot is
shown in (Fig. 1) and details of crystallography parameters are re-
ported in Table 1. The bond distances (C]O, CeC, C]C, CeN) of 2A
unlike 1A [25] and 3A [16] fall within the range of those corre-
sponding to the oxidized form of naphthoquinone ligands [26e30],
the marginal variations in bond distances being accounted for the
delocalization of charge in quinonoid ring and part of amino phenol
ring (Fig. 2). One of the carbonyl bond distances in 1A, 2A(C(4)(O4)),
and 3A is ~1.24 Å which is slightly longer compared to those in 1,4-
Table 2
Hydrogen bond geometries for 2A.
DeH/A
DeH(Å)
H/A(Å)
D/A(Å)
:DeH/A(ꢁ)
C(5)eH(5)/O(18)a
0.951(2)
0.86(2)
0.951(2)
0.89(2)
2.614(1)
2.624(1)
2.621(1)
2.190(1)
3.499(2)
2.725(2)
3.304(2)
2.629(2)
155.1(1)
177(2)
129.1(1)
110(1)
O(18)eH(18)/O(4)a
C(16)eH(16)/O(4)b
N(11)eH(11)/O(1)(intra)
a
x,1/2ꢀy,ꢀ1/2 þ z.
b
x,1/2ꢀy,ꢀ1/2 þ z.

S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
249
Fig. 3. Polymer like chain of 2A down b-axis formed by OeH/O and CeH/O interactions.
Fig. 4. Slipped
p-p interaction of quinonoid and benzenoid rings down a-axis.
O
OH
O
OH
H
N
N
H
H
O
OH
1A
1A
2-(2'-(hydroxyphenyl)-amino)-1,4-naphthoquinone
(E)-4-hydroxy-2-((2'-hydroxyphenyl)-imino)-naphthalen-1(2H)-one
O
OH
O
OH
H
N
N
H
H
OH
O
2A
(E)-4-hydroxy-2-(2'-(4'-methyl-hydroxyphenyl)-imino)-naphthalen-1(2H)-one
2A
2-(2'-(4'-methyl-hydroxyphenyl)-amino)-1,4-naphthoquinone
O
O
OH
Cl
O
OH
Cl
H
N
N
H
H
OH
3A
3A
(E)-4-hydroxy-2-(2'-(4'-chloro-hydroxyphenyl)-imino)-naphthalen-1(2H)-one
2-(2'-(4'-chloro-hydroxyphenyl)-amino)-1,4-naphthoquinone
Scheme 2. ‘Para’ (all left) and ‘ortho’ (all right) tautomeric forms of 1Ae3A.

250
S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
1'
OH
1'
OH
O
O
11
NH
2'
11
N
8
5
8
5
1'
1
4
1
1'
9
9
7
6
6'
5'
7
6'
5'
2
2'
2
3
3
6
10
3'
3'
10
4'
4
4'
R
O
4
R
OH
4
Scheme 3. ‘Para’ (left) and ‘ortho’ (right) tautomers of o-hydroxyanilino-1,4-
naphthoquinone derivatives, R]H, 1A; eCH3, 2A, eCl, 3A.
intermolecular hydrogen bonding (Table 2). Molecules of 2A
showed polymeric chain of molecules facilitated via OeH/O and
CeH/O interactions down the b-axis (Fig. 3). Oxygen O(4) en-
genders bifurcated hydrogen bonding interactions with H(18) and
H(16) of neighboring molecules The aromatic moieties of 2A viz.
benzenoid, quinonoid and aminophenol ring revealed p-p stacking
interactions when viewed down a-axis the centroid to centroid
distance found to be 3.770 Å to all the rings (Fig. 4). Molecules of 3A
void of such
p
-p
stacking interactions while 1A exhibit slipped
p-p
interaction [25,16]. Besides the presence of CeH/
p
interaction, by
amino phenol (H(15)) and benzenoid ring (H(8)) protons with
neighboring molecules of 2A (Fig. S2 in ESIy) are also noticed.
Molecular structures for 1A and 3A are known [25,16]. The
structures varied with respect the orientation of amino phenol ring.
Molecular NeH/O hydrogen bonding interactions are inferred in
the planar 1A structure. The planes of aminophenol ring and
naphthoquinone ring are nearly perpendicular to each other in 3A
and oriented with 45ꢁ in 2A. Thus the 1A, 2A and 3A are qualita-
Fig. 6. gHSQCAD NMR spectrum of 2A in CD3CN.
distances (Fig. 2) of quinonoid ring and part of aminophenol rings
suggest the delocalization of electron charge in this region. From
these crystallographic inferences it can be concluded that these
compounds are rendered with the structural flexibility and yield in
polar solvent.
tively different in terms of
are void of such interactions, the neighboring benzenoid and
quinonoid rings are stacked in 2A whereas the slipped
stacking interactions are inferred in 1A. Marginal variations in bond
p-p staking interactions. Molecules of 3A
p-
p
p-p
Fig. 5. gDQCOSY NMR spectra of 3A in DMSO-d6.

S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
251
3.3. FT-IR studies
resonance signals of H(6) and H(7) protons and accordingly these
protons revealed shielding from the signals near
d
¼ 7.79, and
FT-IR spectra of 1A, 2A and 3A showed sharp peaks at the 3279,
3293 and 3314 cmꢀ1, respectively, assigned to nNH vibration. A
broad band observed respectively, at the 3169, 3195, and 3061 cmꢀ1
results from the coupling of nOH and nC-H vibrations whereas the nCO
was observed at 1667 cmꢀ1 for 1A and 3A as well and as two
different vibrations near 1682 and 1645 cmꢀ1 in 2A. nC-N was
assigned to bands at 1620,1593 cmꢀ1 in 1A; 1618,1595 cmꢀ1 for 2A;
and 1624 cmꢀ1 for 3A. Lastly the nC-C was observed at 1554, 1568
and 1570 cmꢀ1 for 1A, 2A and 3A, respectively. The characteristics
p-naphthoquinone vibrations are located near 1275, 1249 and
1242 cmꢀ1, respectively in 1A and at the 1269 and 1253 cmꢀ1 for
2A. A single band ~1269 cmꢀ1 was observed in 3A.
7.85 ppm to those at 7.71 and 7.57 ppm in the ‘para’ to ‘ortho’ forms.
Compounds 1A and 2A led to similar trends for the proton chemical
shifts in DMSO. The presence of only para tautomer in the CD3CN
solution for 1A and 2A, facilitates these assignments in 1H and 13
spectra easier.
C
Two set of resonance peaks in the 13C NMR spectra are observed
in DMSO-d6 solvent. All the resonance peaks observed were finally
confirmed through the DEPT, gDQCOSY, gHSQCAD experiments.
3.5. gDQCOSY NMR spectra of 3A in DMSO-d6
The contouls marked with blue in Fig. 5 are the correlation of
para tautomer of 3A and the contouls marked with red are in cor-
relation of the ortho tautomer of 3A. There are four correlation of
observed in the 3A aromatic region. H(50) and H(60) shows corre-
lation with each other. The protons H(7), H(6) and H(8), H(5) cor-
relation with each other. The ortho tautomer peaks are H(50) and
H(60) are merged into each other. Likewise the gHSQCAD NMR
spectra show the correlation of proton and carbon. These spectra
confirmed the presence of ortho and para tautomers in DMSO.
Moreover, observed peaks of para tautomers in less polar CD3CN
points to restricted flexibility of the ortho-para tautomeric
equillibria.
3.4. 1H and 13C NMR studies of 1A, 2A and 3A
1H, 13C, gDQCOSY and gHSQCAD NMR spectra of the 1A, 2A and
3A recorded in DMSO and 2A and 3A recorded in CD3CN solvent. 3A
was not soluble in CD3CN. 1H NMR spectra in DMSO reveals two
sets of resonance peaks indicating the presence of ‘ortho’ and ‘para’
tautomers (Scheme 2). 1A, 2A and 3A are in both ortho and para
tautomeric forms in DMSO whereas in CD3CN, 1A and 2A exist only
as para tautomer (Scheme 3).
Selected NMR spectra of 1A, 2A and 3A were explained here-
with, exhaustive data have been represented in supplementary
section (Figs. S3eS26 in ESIy). The 1H NMR spectrum of 3A in
DMSO-d6, showed a singlet observed at 5.65 ppm which was
assigned to C(3)eH(3) proton. During interconversion of ‘ortho-
para’ form of the tautomers the electron density at C(3)eH(3) was
most affected and hence the chemical shift of the H(3) proton in the
3.6. gHSQCAD NMR spectrum of 2A in CD3CN
gHSQCAD a spectrum of the 2A in CD3CN is shown in Fig. 6. In
this spectrum, every proton is showing the signals for the carbon
attached to it. Hence by using gHSQCAD NMR spectra we can assign
the protonated carbon present in the structure. Spot (1) shows
ortho tautomer engenders an upfield shift at
Consequent reorganization in electron density affects the
d
¼ 5.54 ppm.
(Fig. 6) the correlation between the H(3), a singlet at
d
¼ 6.01 ppm
Fig. 7. gHSQCAD NMR spectra of 2A in DMSO-d6.

252
S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
1A
Fig. 8. 1H and 13C chemical shift of 1A, 2A and 3A.

S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
253
Fig. 9. Energy profile as a function of C1eC2eN11eC2’dihedral angle a) 1A,b) 2A and c) 3A of para tautomer.
and C(3) at
d
¼ 104.25 ppm. Spot (2) shows the correlation between
para tautomers protons. H(60) at
d
¼ 6.88 ppm and C(60) at
the H(50), a doublet at
d
¼ 6.91 ppm and the C(50) at
d
¼ 128.6 ppm.
d
¼ 116.1 ppm. Spot (6), H(50) proton a doublet
d
¼ 6.79 ppm and
Spot (3) shows the correlation between the H(60), a doublet at
C(50) at
d
d
¼ 116.50 ppm. Spot (7), H(30) a singlet at
d
¼ 6.97 ppm and
¼ 7.71 ppm
d
¼ 6.96 ppm and C(60) at
d
¼ 117.4 ppm. Spot (4) shows the cor-
C(30) at
and the C(7) at
¼ 102.7 ppm. Spot (10), H(7) proton triplet at
d
relation between the H(30), a singlet at
d
¼ 7.17 ppm and C(30) at
d
¼ 133.7 ppm. Spot (11), H(6) a triplet at
d
¼ 125.5 ppm. Spot (5) shows the correlation between the H(7), a
d
¼ 7.79 ppm in and C(6) at
d
¼ 135.5 ppm. Spot (12), H(8) proton
triplet at
d
¼ 7.76 ppm and C(7)observed at
d
¼ 133.8 ppm. Spot (6)
¼ 7.84 ppm
¼ 136.21 ppm. Spot (7) shows the correlation between
the H(8), a doublet at ¼ 127.5 ppm.
¼ 8.04 ppm and the C(8) at
Spot (8) shows the correlation between the H(5), a doublet at
8.12 ppm and the C(5) carbon observed at
¼ 126.93 ppm.
doublet at
Spot (14), H(5) a doublet at
d
¼ 7.87 ppm and the C(8) observed at
d
d
¼ 125.4 ppm.
¼ 125.4 ppm.
shows the correlation between the H(6), a triplet at
and C(6) at
d
d
¼ 7.94 ppm and C(5) at
d
From Fig. 7, for ortho tautomer the correlation between proton
d
d
and carbon resonance is as follows, spot (1) H(3) proton a singlet
d
¼ 5.51 ppm and C(3) observed at
d
¼ 87.86 ppm. Spot (3), H(50)
d
doublet
d
¼ 6.75 ppm and C(50) at
d
¼ 127.5 ppm. The merged spot
(4) shows correlation between the H(30) a singlet at
d
¼ 6.97 ppm
with C(30) at
d
¼ 124.5 ppm. Spot (5), H(60) a doublet at
3.7. gHSQCAD NMR spectra of 2A in DMSO-d6
There were two sets of peak observed in gHSQCAD NMR of 2A in
DMSO-d6. The 1H and 13C chemical shifts were assigned with the
help of these spectra for all compounds for assignment of 1A and 3A
shown in Supplementary Fig. S6 and Fig. S26. The assignments have
been done for respective protons and carbons for 2A and those for
1A and 3A they were presented in Fig. 7.
Table 3
Relative stabilization energies in kJ molꢀ1 in ortho and para conformers of 1A, 2A and
3A in gas as well as in solvents (DMSO and CDCl3). See text for details.
Gas
DMSO
CDCl3
Gas
DMSO
CDCl3
Para
Ortho
1A
2A
3A
ꢀ43.9
ꢀ42.2
ꢀ42.2
0.0
0.0
0.0
ꢀ13.4
ꢀ13.6
ꢀ12.6
ꢀ36.9
ꢀ36.8
ꢀ37.9
0.0
0.0
0.0
ꢀ11.0
ꢀ11.1
ꢀ11.3
From Fig. 7, for para tautomer the correlation between proton
and carbon resonance is, spot (2), H(3) proton of
d
¼ 5.70 ppm and
the C(3)
d
¼ 97.2 ppm. Spot (4) shows overlapping of the ortho and

254
S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
d
¼ 6.80 ppm in and the C(60) observed at
d
¼ 118.0 ppm. Spot (6),
obtained in d6-DMSO and CD3CN were summarized in Fig. 8.
H(50) proton a doublet at
d
¼ 6.75 ppm and C(50) at
d
¼ 127.5 ppm.
Spot (8), H(7) a triplet at
d
C(6) at
d
d
¼ 7.53 ppm and the C(7) at
3.8. DFT investigations
¼ 126.6 ppm. Spot (9), H(6) a triplet at
d
¼ 7.65 ppm in and the
¼ 132.5 ppm. Spot (13), the H(5) proton a doublet at
¼ 123.1 ppm. The chemical shifts
d
The conformational search on the potential energy surface (PES)
of para tautomers of 1A, 2A and 3A molecule was carried out using
¼ 7.94 ppm and the C(5) at
d
Table 4
Selected bond distances (in Å) and angles (in ꢁ) for paraand ortho conformers of 1A, 2A and 3A in gas as well in solvents (DMSO and CDCl3). See text for details.
Bond
Com
Para
Ortho
Observed
(Å)
Gas(Å)
CDCl3 (Å)
DMSO (Å)
Gas (Å)
CDCl3 (Å)
DMSO (Å)
C(4)]O(4)
1A
2A
3A
1A
2A
3A
1A
2A
3A
3A
1A
2A
3A
1.219
1.220
1.220
1.220
1.227
1.227
1.227
0.968
0.967
0.968
1.743
ꢀ170
ꢀ171
ꢀ170
1.220
1.220
1.220
1.230
1.230
1.229
0.968
0.968
0.968
1.744
ꢀ171
ꢀ172
ꢀ172
1.213
1.216
1.216
1.215
1.351
1.351
1.345
0.972
0.972
0.972
1.747
ꢀ176
ꢀ177
ꢀ177
1.217
1.217
1.216
1.348
1.348
1.343
0.971
0.971
0.971
1.747
ꢀ176
ꢀ176
ꢀ177
1.218
1.219
1.219
1.222
1.222
1.221
0.967
0.967
0.967
1.740
1.213
1.212
1.355
1.356
1.350
0.972
0.972
0.972
1.744
1.221(1)
1.225(3)
1.248
1.244(1)
1.241(3)
0.840
0.86(2)
0.820
1.744(3)
ꢀ178.95
179.49
179.7(3)
C(1)eO(1)
O(18)eH(18)
C(40)eCl40 :C(1)eC(2)eN(11)eC(20)(ꢁ)
ꢀ168
ꢀ177
169
ꢀ178
ꢀ178
ꢀ168
Fig. 10.
uB97x optimized geometries of para (a) and ortho (b) tautomers of 1A.

S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
255
the dihedral angle around the C2eN11 bond as the reaction coor-
dinate, within the frame work of
B97x/6-311þþG(d,p) density
through Fig. 12. The NeH/O hydrogen bonding parameters in
these structures are also given along with. Overall the structural
parameters in para tautomers of 1A-3A from the present theory
agree well with those in the crystal structure except for C]O and
OH bond distances which turn out to be 0.012 Å and 0.014 Å shorter
than their experimental counterparts. As opposed to this the ortho
isomer reveals relatively longer C]O or OH bonds are predicted
from the present calculations. Generally the bond angles agree well
within 2ꢁ except for the dihedral angle referring to C(1)eC(2)
eN(11) and C(2)eN(11)eC(20) planes which show a deviation upto
~8ꢁ in the para tautomer. The ortho tautomer turns out to be planar.
The ramifications of these structural attributes in their vibration
spectra have further been analyzed through the normal vibration
analyses. Calculated harmonic vibrational frequencies were scaled
by a factor of 0.9194.
The infra-red spectra from the experiment and theory are
compared in Fig. 13. As may readily be noticed the experimental
infrared spectra of 1A exhibits NH stretching vibration at
3279 cmꢀ1 and substitution of methyl (in 2A) or chlorine (in 3A) at
40 position reveals the frequency upshift of NH stretching to
3293 cmꢀ1 and 3314 cmꢀ1, respectively. A broad carbonyl stretch-
ing band was observed at ~1667 cmꢀ1 in 1A and 3A. The methyl
substituted 2A engenders two carbonyl stretching vibrations at
u
functional theory. Thus the C1eC2eN11eC20 angle was varied with
a step-size of 20ꢁ. The energy profiles corresponding to 1A, 2A and
3A tautomers thus obtained are shown in Fig. 9(a)e(c). Accordingly
1A emerge with three minima and two maxima as shown in its
potential energy curve with the lowest energy structure having
strong NeH/O interactions and aminophenol group being nearly
planar to napthaquinone functionality. These arguments which
concur with the X-ray crystal structure data can further be
extended to 2A and 3A tautomers as well. Noteworthy enough, the
stationary point structures representing the maxima on the energy
profiles (cf. Fig. 9aec) are void of intramolecular hydrogen bonding
interactions. It may, therefore, be conjectured that intramolecular
NeH/O hydrogen bonding interactions govern the stability of 1A-
3A tautomers.
SCF energies of the lowest energy ortho and para tautomers of
1A, 2A and 3A in the gas phase as well as in DMSO obtained from
the SCRF-PCM optimizations have been compared in Table 3.
Selected bond-distances and -angles in the lowest energy para
tautomers of 1A, 2A and 3A derived from the
theory are compared with those from the X-ray experiments in
Table 4. Atomic labelling scheme used has been depicted in Figs.10
u
B97x/6-31þþG(d,p)
Fig. 11.
uB97x optimized geometries of para (a) and ortho (b) tautomers of 2A.

256
S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
1682 cmꢀ1 and 1645 cmꢀ1; the latter being attributed to hydrogen
bonding from NH functionality as reported for lawsone derivatives
gradient approximation) M06-2x exchange correlation functional
in conjecture with the 6-311þþG(d,p) basis set. The inferences
drawn from density functional theory based on these two func-
tionals are qualitatively similar with the M06-2X predicted
N11eH11/O1 distance parameters in the para tautomers of 1A, 2A
and 3A respectively, being 2.153, 2.141, 2.184 Å, compared to 2.140,
earlier [30,31]. The
u
B97x/6-31þþG(d, p) derived vibrational fre-
quencies predict the blue shift of NH stretching in 3A relative to its
unsubstituted analogue. A marginal frequency downshift of NH
stretching in 2A can be inferred. The C]O stretching corresponding
to 1695 cmꢀ1 in the ortho isomers shows two near lying intense
bands separated by 23 cmꢀ1 to 27 cmꢀ1 in para isomers of 1A-3A.
The 1H and 13C NMR chemical shifts in ortho and para tautomers
of 1Ae3A are given in supporting information Table S5 through
Table S10. 1H NMR spectra of 1A in DMSO reveals dH signal at the
5.6 ppm that arises from the H(3) proton. As expected the redis-
tribution of electron density at the H(3) proton accompanying the
ortho e para interconversion influences the chemical shift of H(3)
proton significantly with the ortho tautomer showing an upfield
signal at dH 5.5 ppm. Concomitantly dH values of H(6) and H(7)
protons exhibit marginal upfield signals near 8.2 ppm. Similar in-
ferences are drawn for the 13C signals in the CMR spectra of ortho
and para tautomers. The 6-311þþG(d,p) bais set has widely been
employed to compute the dH values in the recent literature
2.137, 2.178 Å predicted from the
uB97x based calculations. More-
over the hierarchy of dH values in ortho as well as para tautomers of
1A-3A turns out to be nearly the same as evident from Table S12 of
the supporting information. It may thus be concluded that the
M06-2x theory predicts large deshielding in the calculated 1H NMR
spectra compared to the
uB97x theory.
3.9. Separation of tautomers of o-hydroxyanilino-1,4-
naphthoquinone derivatives by HPLC
The presence of tautomers in solution can also be revealed by
chromatographic technique like HPLC. Four methods were devel-
oped in order to separate the tautomers by HPLC. The buffer solu-
tions were used so as to maintain the pH of mobile phase.
[32e38].
A comparison of dH values calculated from 6 to
Fig. 14 shows the chromatograms of 1A. Four peaks were
observed (Fig. 14a) when method I was used for tautomer separa-
tion. The retention times of the peaks in minutes were; 7.0, 8.3, 8.8,
10.3 and the respective peak area were 7.60, 7.22, 59.88 and 25.30%.
The relative retention time (RRT) of isomers is 0.79, 0.94 and 1.15
with respect to major peak (Rt- 8.8 min). The resolutions between
the isomers are 6.403, 2.359, and 6.814 respectively. Similar chro-
matographic pattern was obtained when condition II was used for
separation (Fig. 14b) and the retention time in minutes were 7.8,
8.3, 8.8 and 10.3 with peak area 9.08, 6.92, 58.52 and 25.48%
31þþG(d,p) and 6-311þþG(d,p) are compared in Table S11. It may
readily be noticed that the 6-311þþG(d,p) basis reveal better
agreement with the measured 1H NMR spectra. Generally the
chemical shifts for the protons exhibit relatively large shielding
except for the H3 and H5 protons in the para tautomer of 1A with
the 6-311þþG(d,p) basis set. The 2A and 3A tautomers also reveal
more shielding. To validate these results we compare the intra-
molecular hydrogen bond distances and dH values with those
derived from the DFT incorporating the meta GGA (generalized
Fig. 12.
uB97x optimized geometries of para (a) and ortho (b) tautomers of 3A.

Fig. 13. Observed and optimized IR spectra of 1A, 2A and 3A.
6.0x105
4.0x105
pH~7
8.0x105
pH~6.8
2.0x105
0.0
4.0x105
0.0
6
8
10
12
6
8
10
12
Retention Time (Min.)
Retention Time (Min.)
pH Acidic
6.0x105
4.0x105
pH Basic
4.0x105
2.0x105
0.0
2.0x105
0.0
6
8
10
12
6
8
10
12
Retention Time (Min.)
Retention Time (Min.)
Fig. 14. HPLC Chromatogram for 1A Condition I (Neutral condition), Condition II (pH 6.8), Condition III (pH Acidic) and Condition IV (pH Basic).

258
S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
pH~6.8
Iso II
1.2x106
6.0x105
4.0x105
Iso II
pH~7
6.0x105
2.0x105
0.0
Iso I
Iso I
0.0
6
8
10
12
6
8
10
12
Retention Time (Min.)
Retention Time (Min.)
2.4x106
1.6x106
II
8.0x105
6.0x105
4.0x105
pH Basic
Iso
pH Acidic
8.0x105
0.0
o I
Is
2.0x105
0.0
6
8
10
12
6
8
10
12
Retention Time (Min.)
Retention Time (Min.)
Fig. 15. HPLC Chromatogram for 2A Condition I (Neutral condition), Condition II (pH 6.8), Condition III (pH Acidic) and Condition IV (pH Basic).
respectively. The relative retention times of isomers are 0.879,
0.946 and 1.161 with respect to major peak (Rt- 8.8 min). The res-
olutions between the peaks are 3.380, 3.277, and 9.517 respectively.
In acidic pH of the mobile phase (condition III, Fig. 14c), the peaks
are not well separated from each other. Four peaks are observed in
basic pH of mobile phase (condition IV, Fig. 14d), however these
peaks are not well separated from each other. It can therefore be
concluded that the method developed were inappropriate to
separate the tautomers of 1A.
Fig. 15aed shows the chromatogram of 2A at various
1.4x106
1.2x106
1.0x106
8.0x105
6.0x105
4.0x105
pH~6.8
1.2x106
pH~7
8.0x105
4.0x105
0.0
2.0x105
0.0
6
8
10
12
-2.0x105
Retnetion Time (Min.)
6
8
10
12
Retention Time (Min.)
1.8x106
1.2x106
pH Basic
Iso II
3x105
pH Acidic
2x105
6.0x105
0.0
1x105
0
Iso I
6
8
10
12
6
8
10
12
Retention Time (Min.)
Retention Time (Min.)
Fig. 16. HPLC Chromatogram for 3A Condition I (Neutral condition), Condition II (pH 6.8), Condition III (pH Acidic) and Condition IV (pH Basic).

S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
259
chromatographic conditions used for separation. Fig. 15a, a chro-
matogram shows two peaks where the experimental condition I
was used for tautomer separation. The two peaks were eluted at
retention time 8.7 and 9.2 min having peak area of 8.09% and 91.91%
respectively. Base to base separation of tautomers was not observed
and peak II is very broad. Resolution between the isomers is very
less 1.92 min. The relative retention time (RRT) of isomer II is
1.054 min with respect to isomer I.
In Fig. 15b there two peaks were observed and condition II was
used for separation of tautomers. The retention time of peak 1 was
8.7 min whereas for peak 2 it was 9.1 min with peak area of 8.72%
and 91.73% respectively. The resolution between two isomers is
2.893 min. The relative retention time of peak is 1.048 min with
respect to peak 1. Base to base separation between the tautomers
was observed with similar symmetry factor (Tailing- 1.3).
Tautomeric equillibria was observed when condition III, was
used for tautomer separation. Base to base separation diminished
in the acidic pH of mobile phase, which implies the tautomeric
instability. Only one peak is eluted at retention time 8.71 min
with area 99.94% for method IV (Fig. 15d) and thus this method is
not suitable for separation of tautomers of 2A. Peak first was
assigned to ortho tautomer while peak II was assigned to the para
tautomer.
Fig. 16 displays chromatogram of compound 3A. Chromatogram
in Fig. 16a, b, d showed only single peak where the methods I, II and
IV were used. The presence of single peak implies that, there is only
one isomer present in such experimental conditions; hence these
methods unable to separate the tautomers of 3A. There are two
peaks with experimental conditions of method III was used (In
Fig. 16c). The pH of mobile phase is acidic in method III. The
retention time of peak-1 is 8.3 min and peak-2 is 9.1 min with peak
area 1.47% and 98.53% respectively. Although the peak area is
negligible the nature of chromatogram is similar to what is
observed for tautomers13. Based on the peak areas it can be
concluded that the tautomer stability at peak II is maximum. Since
the separation between the two peaks is not base to base, the
chromatographic pattern suggests that there is interconversion of
tautomers. In this condition relative retention time (RRT) of isomer-
II is 1.10 with respect to isomer-I.
The mobile phase used in all the methods attempted for sepa-
ration of tautomers is CH3CN and water. The infra NMR experi-
ments suggests that, there is presence of only one stable tautomer
in CD3CN solution, this inference also proved by HPLC experiments.
Although the tautomeric equillibria is observed in 1A, 2A and 3A,
there was one predominant tautomer that prevails in CH3CN
solution.
Fig. 17. Cyclic Voltammogram of 1A, 2A and 3A in a) DMSO and b) CH3CN solution.
Tetra butyl ammonium perchlorate was used as supporting electrolyte.
4. Conclusions
The tautomers of o-hydroxyanilino-1,4-naphthoquinone de-
rivatives have been investigated in this report with the help of 1H,
13C, DEPT, gDQCOSY, gHSQCAD NMR experiments, HPLC and cyclic
voltammetry. All the compounds exists as ‘ortho’and ‘para’ tauto-
mers in DMSO-d6 solvent and only ‘para’ tautomer is predominant
in CD3CN solvent. Structural parameters of these tautomers derived
from the SCRF method within the framework of dispersion cor-
rected DFT agree well with the single crystal X-ray data. The 1H and
13C chemical shifts were assigned to all compounds and it was
observed that proton chemical shifts of ‘ortho’ tautomers showed
upfield shift. The H(3) proton facilitating intramolecular hydrogen
bonding in ’ortho’ tautomers of 1A-3A reveals largest deshielding in
the GIAO calculated 1H NMR spectra in consonance with the
experimental data. HPLC and cyclic voltammetry investigations
further corroborate ‘ortho’ and ‘para’ tautomeric equillibria.
3.10. Cyclic voltammetry studies
Fig.17 shows cyclic voltammogram of 1A, 2A and 3A, recorded in
DMSO and CH3CN solution containing neutral electrolyte tetrabutyl
ammonium perchlorate. The redox potentials were presented
Table S13(in ESIy) and scan variation plots for 1A, 2A and 3A were
presented in Fig. S27 and Fig. S28. More than one reduction peaks
were observed between ~ꢀ0.5 V to ꢀ0.7 V. This potential region
usually belongs to one electron reduction of naphthoquinone to
naphthosemiquinone forms of 1,4-naphthoquinone compounds
[20]. More than one cathodic peaks were observed in DMSO and
CH3CN solution, which suggests that more than one electroactive
species, is present in the solution. All compounds showed an irre-
versible anodic peak ~ þ0.5 V, this peak can be assigned to oxida-
tion reduced species formed in the solution. The presence of
multiple cathodic peaks in CH3CN and DMSO solution imply that
ortho-para equillibria does exist in solution for all compounds.
Acknowledgements
SSG thankful to RGYI scheme of Department of Biotechnology,

260
S. Bhand et al. / Journal of Molecular Structure 1123 (2016) 245e260
[19] G.M. Sheldrick, SHELX-97 Program for Crystal Structure Solution and
New Delhi, India. S. P. G. acknowledges the support from the Board
of Research in Nuclear Sciences (BRNS) India through the research
project 37(2)/14/11/2015-BRNS. S. S. R. is grateful to University
Grants Commission, New Delhi for award of the meritorious
research fellowship. D. N. L and S. B. acknowledges potential
excellence scheme, Savitribai Phule University of Pune. Authors
thank the Centre for Development of Advanced Computing (CDAC),
Pune for providing National Param Supercomputing Facility.
€
Refinement, University of Gottingen, Germany, 1997.
[20] J.D. Chai, M. Head-Gordon, J. Chem. Phys. 128 (2008) 084106.
[21] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb,
J.R. Cheeseman, J.A. Montgomery Jr., T. Vreven, K.N. Kudin, J.C. Burant,
J.M. Millam, S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi,
G. Scalmani, N. Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Akajima, Y. Honda, O. Kitao,
H. Nakai, M. Klene, X. Li, J.E. Knox, H.P. Hratchian, J.B. Cross, V. Bakken,
C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin,
R. Cammi, C. Pomelli, J.W. Ochterski, P.Y. Ayala, K. Morokuma, G.A. Voth,
P. Salvador, J.J. Dannenberg, V.G. Zakrzewski, S. Dapprich, A.D. Daniels,
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Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2016.06.026.
[22] G.A. Peterson, T.G. Tensfeldt, J.A. Montgomery, J. Chem. Phys. 94 (1991)
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