First X-ray structural characterization of isatin Schiff base derivative. NMR and theoretical conformational studies

Article abstract of DOI:10.1016/j.molstruc.2014.07.008

Isatin (1H-indole-2,3-dione) is an endogenous natural compound under intense development in medicinal chemistry. Here, we characterize isatin Schiff base derivative by X-ray crystallography. We describe a derivative that crystallizes E-isomer form in the triclinic space group P 1ˉ; a = 5.9580 (4) A?, b = 8.4184 (7) A?, c = 14.1801 (14) A?, α = 73.962 (8)°, β = 83.184 (7)°, γ = 81.143 (6)°. NMR data show that E-conformer interconverts to the Z-conformer when dissolved, this equilibrium weakly depends on the solvent type. The Z-isomer geometry and the energetics of ΔE_E-Zinterconversion barriers were determined by quantum chemical calculations. The isomers are further characterized by means of FT-IR and UV-Vis spectroscopy.

Full text of DOI:10.1016/j.molstruc.2014.07.008

Journal of Molecular Structure 1075 (2014) 450–455
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
First X-ray structural characterization of isatin Schiff base derivative.
NMR and theoretical conformational studies
b
b
c
d
Pavel Davidovich a, , Daria Novikova , Vyacheslav Tribulovich , Sergey Smirnov , Vlad Gurzhiy ,
⇑
Gerry Melino b,e, Alexander Garabadzhiu b
a Laboratory of Cell Biotechnology, Saint-Petersburg Technological Institute, 26, Moskovskii av., Saint-Petersburg 190013, Russia
b Laboratory of Molecular Pharmacology, Saint-Petersburg Technological Institute, 26, Moskovskii av., Saint-Petersburg 190013, Russia
c Center for Magnetic Resonance, Saint-Petersburg State University, 26, Universitetsky av., Saint-Petersburg 198504, Russia
d Crystallography Chair, Geology Department, Saint-Petersburg State University, University emb. 7/9, Saint-Petersburg 199034, Russia
e Medical Research Council Toxicology Unit, Leicester LE1 9HN, UK
h i g h l i g h t s
ꢀ
ꢀ
ꢀ
X-ray structure of isatin Schiff base derivative E-isomer determined.
E/Z ratio in different solvents investigated by NMR spectroscopy.
Conformational analysis was performed by theoretical methods.
a r t i c l e i n f o
a b s t r a c t
Article history:
Isatin (1H-indole-2,3-dione) is an endogenous natural compound under intense development in medic-
inal chemistry. Here, we characterize isatin Schiff base derivative by X-ray crystallography. We describe a
derivative that crystallizes E-isomer form in the triclinic space group P 1; a = 5.9580 (4) Å, b = 8.4184
Received 9 December 2013
Received in revised form 4 July 2014
Accepted 4 July 2014
ꢀ
(7) Å, c = 14.1801 (14) Å,
interconverts to the Z-conformer when dissolved, this equilibrium weakly depends on the solvent type.
The Z-isomer geometry and the energetics of EE–Z interconversion barriers were determined by quan-
a = 73.962 (8)°, b = 83.184 (7)°, c = 81.143 (6)°. NMR data show that E-conformer
Available online 15 July 2014
D
Keywords:
tum chemical calculations. The isomers are further characterized by means of FT-IR and UV–Vis
spectroscopy.
Isatin Schiff base
Molecular structure
Isomerism
Ó 2014 Elsevier B.V. All rights reserved.
X-ray
NMR
Conformational analysis
Introduction
Among the investigated isatin derivatives of particular interest
are Schiff bases, their synthesis, structure, and biological activity.
Isatin (1H-indole-2,3-dione) derivatives are currently of great
interest in the field of medicinal chemistry [1,2]. Isatin is an endog-
enous natural compound [3], which possesses anticonvulsant and
anxiolytic activity [4]. Isatin derivatives, such as substituted isa-
tins, hydrazones, Mannich bases, Schiff bases, and spiroindolinones
exhibit a broad spectrum of biological activities [5,6]. Accordingly,
some derivatives act as antimicrobial [7], antiviral [8] antioxidant
[9], and tumor supressive [10–13] compounds; anticonvulsant
properties allow regarding the isatin derivatives as promising
anti-epileptic [14,15] drug candidates.
It has been found that the isatin Schiff base derivatives (ISBD) pos-
sess analgesic effects in in vivo experiment [16]. In addition, large
amount of research is done on the antimicrobial activity of these
derivatives [17–24]. ISBD coupled with trimethoprim showed good
activity against a variety of microorganisms [25]. Coupled deriva-
tives of isatin and fluoroquinolones are potential antimicrobial
agents, Schiff base with norfloxacin and ciprofloxacin show signif-
icant antimicrobial activity [20–22]. Schiff bases with pyrimidine
in turn possess significant antifungal activity [23]. Anti-tuberculo-
sis activity of ISBD has been studied by Varma and Pandeya [26].
Last but not least, ISBD exhibit anti-HIV activity [8,27]. Cytotoxic
activities of ISBD were recently evaluated by Reddy et al. [28].
Not only the biological effects were determined for ISBD, but
also the potential set of protein targets was studied. ISBD based
⇑
Corresponding author. Tel.: +7 (812)4949266, mobile: +7 (911)2245487; fax: +7
81231646 48.
E-mail address: davidovich.pavel@technolog.edu.ru (P. Davidovich).
http://dx.doi.org/10.1016/j.molstruc.2014.07.008
0022-2860/Ó 2014 Elsevier B.V. All rights reserved.

P. Davidovich et al. / Journal of Molecular Structure 1075 (2014) 450–455
451
analysis. The structure was also confirmed in various solvents by
NMR spectroscopy and quantum-chemical calculations.
Experimental
Materials
All necessary chemicals were of analytical grade obtained from
Sigma Aldrich and were used without further purification.
3-(3,4-dimethylphenyl)imino-1-methylindol-2-one was prepared
analogically to the previously described method [32].
Fig. 1. Possible Z,E-isomerism of isatin Schiff base derivatives.
on dibromoizatin were tested for their ability to inhibit the activity
of cyclin-dependent kinase 2, caspases 3 and 7 [29]. Accordingly,
phenyl ring-unsubstituted ISBD (R3 = H, Fig. 1) inhibit activity of
the vascular endothelial growth factor receptor VEGFR-2, which
is involved in the processes of cell proliferation and angiogenesis
[30]. Earlier it was shown that these type of derivatives can selec-
tively bind to cannabinoid receptors CB1 and CB2 [31] and inhibit
the transthyretin fibrillogenesis [32]. These derivatives are also
capable of inhibiting the activity GAL3 receptor and crossing
blood–brain-barrier [33]. Isatin core is a promising scaffold for
the design of protein–protein interaction inhibitors between
MDM2 E3-ligase and the transcription factor protein p53 [34,35].
Accordingly, the broad spectrum of biological effects that exhibit
ISBD may suggest these compounds as promising drug candidates.
Isatin scaffold serves as a convenient base for the design of
target-oriented molecules. The central flat core allows distinct
chemical substitution modifications (Fig. 1) without resorting to
complex synthetic schemes, as outlined in Fig. 2. The resulting
Schiff base derivatives can exist in the form of two conformers,
E-and Z-forms, differing in the orientation of substituents at the
double bond, see Fig. 1.
The design of a target-associated drugs based on isatin scaffold
requires an evaluation of the possible isomeric form derivatives.
Clearly, isatin Schiff bases Z- and E-isomers greatly differ topolog-
ically, that conformation flexibility reduces the target-specificity of
compound and increases the number of ineligible biological
targets. Consequently, the structural studies of ISBD should be per-
formed and proper suggestions on isomer form stabilization should
be made.
Previously ISBD were structurally characterized by NMR solu-
tion studies [32,33], and the only one Schiff base like isatin oxime
derivative was crystallized with the protein JNK3 MAP kinase both
in Z-and E-conformations depending on the indole nitrogen substi-
tuent [36]. In several works [30,37] the in silico docking studies
were performed for a number of isatin Schiff base derivatives, how-
ever, the actual isomer distribution was less investigated.
In this paper we present the results of structural investigation
of one of isatin Schiff base derivatives, namely, 3-(3,4-dimethyl-
phenyl) imino-1-methylindol-2-one (Fig. 2 compound II). Hence,
we characterize the derivative by means of X-ray diffraction
Physical methods
For single crystal X-ray diffraction experiment, crystal of com-
pound II was fixed on a micro mount and placed on an Agilent
Technologies Excalibur Eos diffractometer and measured at a tem-
perature of 100 K using monochromatic Mo Ka radiation. The unit
cell parameters (Table 1) were refined by least-squares techniques
using 4944 reflections in the 2h range of 5.18–50.00°. The structure
has been solved by the direct method and refined till R1 = 0.043
(wR2 = 0.089) for 1784 unique reflections with |Fo| P 4rF by means
of the SHELXL-97 [38] program incorporated in the OLEX2 program
package [39]. The carbon-bound H atoms were placed in calculated
positions and were included in the refinement in the ‘rider’ model
approximation, with Uiso(H) set to 1.5Ueq(N) and C–H 0.96 Å for the
CH3 groups and Uiso(H) set to 1.2Ueq(N) and C–H 0.93 Å for the CH
groups. Empirical extinction correction was applied in CrysAlisPro
[40] program complex using spherical harmonics, implemented in
SCALE3 ABSPACK scaling algorithm. Supplementary crystallo-
graphic data for this paper have been deposited at Cambridge
Crystallographic Data Centre (CCDC 974716) and can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif.
Elemental analysis of II was performed on Perkin Elmer 2400
Series II CHNS/O analyzer. The FT-IR spectra were recorded using
pellets with KBr in the range 4000–400 cmÀ1 on a Shimadzu IR-
Affinity-1 spectrometer at room temperature. UV–Vis spectra were
recorded at room temperature in 1 cm cell on Shimadzu UV-1800
spectrophotometer on 1 nm resolution in the range from 190 to
1100 nm. All 1H and 13C NMR spectra were recorded on a spec-
trometer Bruker Avance III at 400.13 and 100.61 MHz respectively
in three different solvents (DMSO-d6, chloroform-d1, and metha-
nol-d4).
Calculation methods
Calculations were made by DFT method with B3LYP functional
(calculations with PBE0, B2PLYP [41] and CAM-B3LYP functionals
or in second order Møller–Plesset perturbation theory did not
empove the results Table S5) and in cc-PVTZ basis set using Gauss-
ian 09 [42] program package. Solvation effect was considered using
Fig. 2. General synthetic scheme for the preparation of isatin Schiff base derivative.

452
P. Davidovich et al. / Journal of Molecular Structure 1075 (2014) 450–455
Table 1
Crystallographic and structure refinement data for II.
dimethylformamide at room temperature 7.5 mL of methyl iodide
(120 mmol) were added under stirring in inert atmosphere. After
12 h the reaction mixture was neutralized with hydrochloric acid
and the precipitate of corresponding N-methyl derivative (com-
pound I) separated as an orange amorphous powder. Compound I
was dissolved in absolute ethanol, 3,4-dimethylaniline was added
to the solution, and the mixture was stirred and refluxed for
another 24 h. The evaporation in a vacuum yielded compound II
as an orange powder. Yield: 70%. Prismatic orange crystals suitable
for the X-ray diffraction analysis were obtained after crystalliza-
tion from methanol. Anal.: Calcd. C17H16N2O (%): C À 77.25;
H À 6.10; N À 10.60; O À 6.05; found (%): C À 77.78; H À 6.69;
Compound
II
Formula
Crystal system
a (Å)
b (Å)
c (Å)
C
17H16N2O
Triclinic
5.9580(4)
8.4184(7)
14.1801(14)
73.962(8)
83.184(7)
81.143(6)
673.22(10)
264.32
a
(°)
b (°)
c
(°)
V (Å3)
Molecular weight
Space group
P À 1
N À 10.37. M.p. 156–157 °C. IR (KBr)
1656, 1602, 1470, 1371, 1333, 1101, 764. UV–Vis (methanol),
nm, cmÀ1 MÀ1: (249,
= 245,050; 299, = 96,106; 420, = 66,210).
m : mC=O 1730, mC=N
, cmÀ1
l
(mm–1
)
0.082
Temperature (K)
Z
100(2)
2
1.304
e
e
e
Dcalc (g/cm3)
Crystal size (mm3)
Radiation
Total reflections
Unique reflections
Angle range 2h (°)
Reflections with |Fo| P 4rF
Rint
0.32 Â 0.24 Â 0.18
Mo K
4944
2358
a
NMR spectroscopy in solution
All NMR assignments were made on the basis of 2D NMR exper-
iments (geCOSY, geNOESY, geHSQC, geHMBC). The stereochemistry
of the ISBD was established by NMR using 2D geNOESY experiment
(spectrum is shown in Fig. 3b). The hydrogen and carbon number-
ing and spectrum are represented in Fig. 3a.
The E-isomer shows a correlation between hydrogen H-9 and
H-14, H-18 and also the weaker correlation between atoms H-9
and H-15. In addition, the signal for H-9 of E-isomer was consider-
ably shifted upfield (approx. by 1 ppm) relative to the H-9 signal of
the Z-isomer.
5.18–50.00
1784
0.0323
R
r
0.0600
R1 (|Fo| P 4rF
)
0.0429
wR2 (|Fo| P 4rF
R1 (all data)
wR2 (all data)
S
)
0.0888
0.0678
0.1004
1.036
qmin
,
qmax (e/Å3)
||Fo|–|Fc||/ |Fo|; wR2 = {R R .
[w(Fo2–Fc2)2]/ [w(Fo2)2]}1/2
À0.204, 0.234
R1
=
R
R
w = 1/[
R
2(F2o) + (aP)2 + bP], where P = (Fo2 + 2Fc2)/3; s = { [w(Fo2–
R
NMR shifts in ppm, spin–spin coupling constants, and isomers
ratio in different solvents are presented below.
F2c)]/(n À p)}1/2 where n is the number of reflections and p is the
number of refinement parameters.
1H, (CDCl3), E-isomer: 6.852 (d, J = 7.9 Hz, 1H, H-6), 7.356 (ddd,
J = 7.9, 6.6, 2.3 Hz, 1H, H-7), 6.770(m, 1H, H-8), 6.790(1H, H-9),
3.301 (s, 3H, H-10), 6.753(1H, H-14), 7.167 (d, J = 7.9 Hz, 1H, H-
15), 6.819 (d, J = 2.1 Hz, 1H, H-18), 2.308 (s, 3H, H-19), 2.280 (s,
3H, H-20). Z-isomer: 6.820 (1H, H-6), 7.452 (td, J = 7.8, 1.3 Hz,
1H, H-7), 7.115 (dd, J = 7.6, 7.6 Hz, 1H, H-8), 7.704 (dm, J = 7.5 Hz,
1H, H-9), 3.162 (s, 3H, H-10), 6.820 (1H, H-14), 7.115 (d,
J = 7.9 Hz, 1H,H-15), 6.889 (d, J = 2.1 Hz, 1H, H-18), 2.269 (s, 3H,
H-19), 2.263 (s, 3H, H-20) E to Z isomer ratio = 9.1:0.9.
implicit solvent approximation in the polarization continuum
model PCM (calculations using other solvation models SMD [43]
and CPCM [44] gave almost the same solvation energies as PCM)
[45] in seven different solvents: water, 1,2-dichloroethane, ace-
tone, acetonitrile, methanol, dimethyl sulfoxide, and chloroform.
Results and discussion
1H, (MeOD), E-isomer: 7.067 (ddd, J = 8.0, 0.8, 0.8 Hz, 1H, H-6),
7.444 (ddd, J = 7.8, 7.8, 1.3 Hz, 1H, H-7), 6.815 (ddd, J = 7.6, 7.6,
0.9 Hz, 1H, H-8), 6.730 (ddd, J = 7.7, 1.3, 0.6, 1H, H-9), 3.304 (s,
3H, H-10), 6.767 (dd, J = 7.9, 2.2 Hz, 1H, H-14), 7.240 (d,
J = 7.9 Hz, 1H, H-15), 6.835 (1H, H-18), 2.343 (s, 3H, H-19), 2.321
Synthesis of Schiff base isatin derivative
To 17.7 g of indole-2,3-dione (100 mmol) and 20.9 g of
potassium carbonate (150 mmol) in 60 mL of anhydrous
Fig. 3. Representation (a) of the hydrogen/carbon atom numbering for compound II ISBD, and (b) geNOESY spectrum of II in chloroform-d1.

P. Davidovich et al. / Journal of Molecular Structure 1075 (2014) 450–455
453
13C, (CDCl3), E-isomer: 163.44 (C-2), 153.88 (C-3), 115.79 (C-4),
147.83 (C-5), 109.15 (C-6), 133.73 (C-7), 122.57 (C-8), 125.96 (C-9),
26.33 (C-10), 147.97 (C-13), 115.29 (C-14), 130.36 (C-15), 133.74
(C-16), 137.66 (C-17), 119.28 (C-18), 19.39 (C-19), 19.90 (C-20)
Z-isomer: 157.52 (C-2), 151.36 (C-3), 121.62 (C-4), 146.32(C-5),
108.56 (C6), 133.46 (C-7), 123.13 (C-8), 122.77 (C-9), 25.78 (C-
10), 146.74 (C-13), 116.74 (C-14), 129.61 (C-15), 133.91 (C-16),
136.67 (C-17), 120.89 (C-18), 19.88 (C-19), 19.43 (C-20).
1H (DMSO), E-isomer: 7.110 (d, J = 7.9 Hz, 1H, H-6), 7.439 (ddd,
J = 7.8, 7.8, 1.3 Hz, 1H, H-7), 6.824 (ddd, J = 7.7, 7.7, 1.0 Hz, 1H, H-8),
6.555 (d, J = 7.7 Hz, 1H, H-9), 3.209 (s, 3H, H-10), 6.712 (dd, J = 7.9,
2.3 Hz, 1H, H-14), 7.228 (d, J = 7.9 Hz, 1H, H-15), 6.794 (d,
J = 2.0 Hz, 1H, H-18), 2.274 (s, 3H, H-19), 2.254 (s, 3H, H-20); Z-iso-
mer:7.080 (d, J = 7.9 Hz, 1H, H-6), 7.537 (ddd, J = 7.8, 7.8, 1.3 Hz,
1H, H-7), 7.133 (ddd, J = 7.6, 7.6, 0.9 Hz, 1H, H-8), 7.611 (d,
J = 7.5 Hz, 1H, H-9), 3.100 (s, 3H, H-10), 6.779 (d, J = 2.3 Hz, 1H,
H-14), 7.080 (d, J = 7.9 Hz, 1H, H-15), 6.854 (d, J = 2.0 Hz, 1H,
H-18), 2.224 (s, 3H, H-19), 2.207 (s, 3H, H-20). E to Z isomer
ratio = 8.5:1.5.
To stabilize molecule Z-conformation we suggest using differ-
ent N12 substituents, which can form the intermolecular hydrogen
bonds with carbonyl oxygen O11 atom. Complex formation with
d-elements could also contribute to the stabilization of one of iso-
meric forms, thought the complexation can strongly influence the
ligands electron density distribution and solubility.
X-ray crystallography
Fig. 4. ORTEP view of the molecular structure of (3E)-(3,4-dimethylphenyl)imino-
1-methylindol-2-one. Atoms are represented as ellipsoids of thermal displacements
with 50% probability. Angle between atoms C3–N12–C13 is 120.98, dihedral angle
between atoms C2–C3–N12–C13 is 172.06, the angle between the planes formed by
isatin core and dimethylphenyl-ring is 63.63.
The initial geometry for calculations was taken directly from
the resolved crystal structure of 3-(3,4-dimethylphenyl) imino-1-
methylindol-2-one. The starting ‘‘X-ray’’ geometry (Fig. 4, refine-
ment details in Table 1) was found not to be the optimal for gas-
eous state in a vacuum, and lies 6.44 kJ/mol higher than the
calculated minimum (comparison of X-ray data with calculated
parameters represented in Table S1, Supporting Information). In
the optimized structure the dihedral angle C2–C3–N12–C13 is
174.34 and the angle between the planes formed by isatin core
and 3,4-dimethylphenyl-ring is 65.15. It can be considered that
(s, 3H, H-20); Z-isomer: 7.021 (ddd, J = 8.0, 0.8, 0.8 Hz, 1H, H-6),
7.532 (ddd, J = 7.8, 7.8, 1.3 Hz, 1H, H-7), 7.161 (ddd, J = 7.6, 7.6,
0.9 Hz, 1H, H-8), 7.684 (ddd, J = 7.5, 1.3, 0.6, 1H, H-9), 3.181 (s,
3H, H-10), 6.815(1H, H-14), 7.111 (d, J = 8.0 Hz, 1H, H-15), 6.886
(d, J = 2.2 Hz, 1H, H-18), 2.288 (s, 3H, H-19), 2.281 (s, 3H,H-20)) E
to Z isomer ratio = 9.4:0.6.
Fig. 5. Representation of the short contact network between the three molecules of compound II. Atoms are shown as ellipsoids of thermal displacements with 50%
probability. Some atoms are not shown for clarity.

454
P. Davidovich et al. / Journal of Molecular Structure 1075 (2014) 450–455
Table 2
this conversion is not favorable. The isomerization from the E- to
the Z-conformer (Fig. 6) may be caused by the transitions between
electronic ground and excited states [46].
E- and Z-isomer energy gaps in different conditions.
E-isomer, a.u.
Z-isomer, a.u.
D
E = EE–EZ (kJ/mol)
Calculations performed for free molecule show that Z-con-
former is more stable than E-conformer and the energy difference
is approximately 6.1 kJ/mol. Topological analysis of the calculated
electron density distribution with QTAIM [47] has not shown any
significant intramolecular interactions (Fig. S3, Supporting Infor-
mation). Increase in the dielectric constant of the solvation media
leads to the stabilization of E-form. In nonpolar chloroform more
preferable isomer is still Z one, but going to more polar dichloro-
X-ray (single point) À842.2156129
–
–
Vacuum (
e
= 1.00)
À842.4781770 À842.4803950
À842.4869129 À842.4870422
5.85
0.31
CHCl3
EtCl2
(
e
e
= 4.71)
(
= 10.13)
À842.4891479 À842.4888348 À0.83
À842.4902876 À842.4897932 À1.30
À842.4907294 À842.4901677 À1.48
À842.4907954 À842.4902250 À1.51
À842.4909902 À842.4903689 À1.62
À842.4911232 À842.4901677 À2.52
Me2CO (e = 20.49)
MeOH (
CH3CN (
e
e
= 32.62)
= 35.69)
e = 46.83)
DMSO (
*H2O (
e
= 78.36)
*
ethane (e = 10.13) E conformer becomes more stable; the DE = EE–
Calculation with doubly hybrid functional B2PLYP resulted almost the same
EZ values in Table 2 represent the qualitative trend of the solvent
influence on the stabilization of the appropriate isomeric form.
energy difference À2.86 kJ/mol; SMD and CPCM models resulted À1.84 kJ/mol and
À1.51 kJ/mol energy gaps.
Conclusion
the X-ray geometry is stabilized by the short contacts (Table S2,
Supporting Information) formed between neighboring molecules
in crystal (Fig. 5).
As isatin Schiff base derivatives are potent scaffolds for drug
design it is crucial to understand the geometry of the target com-
pound in solution as well as in solid state. In this study the X-ray
structure of E-conformer isatin Schiff base derivative is described.
By NMR spectroscopy we show that dissolution of E-isomer is
accompanied with partial isomerization to Z-form. The QM calcu-
lations showed that more preferable form in a vacuum is Z-isomer,
while moving to the solvents with higher polarities the isomeric
preference changes. The E- to Z-form barrier was calculated and
methyl and phenyl rotation PES was achieved. The isomeric inter-
conversion (flexibility) is a disadvantage for the compound that is
considered to become drug, as more flexible drug is less specific.
That is why further studies on the substituent effect on geometry
and electronic structure of isatin Schiff base are needed. It is now
evident that in order to make these compounds suitable candidates
for drugs, the understanding of all possible conformation stabiliza-
tion is paramount.
In order to understand the energy difference between conform-
ers the energy gap between the two isoforms was calculated
(Table 2) in different conditions. Potential energy surface (PES)
scan and normal mode vibration analysis were performed to
approve that the optimized structures are in the local minima.
The calculated barrier for the N-methyl group rotation around
N1–C10 bond is 6.4 kJ/mol and is reached every 120° of the rota-
tion; it is equal for both isomers. The rotation barriers of 3,4-
dimethylphenyl ring differs between two isomeric forms: there
are two equal barriers at 2.5 kJ/mol and 6.9 kJ/mol for the Z-form
(calculated geometry in Table S4, Supporting Information); the
rotation of the 3,4-dimethylphenyl ring in the E-isomer is less
favorable, the PES also has two barriers: one with 1.3 and another
with 35.8 kJ/mol. The barrier for the rotation around the double
bond C3–N12 has very high activation energy (ꢁ150 kJ/mol), so
Fig. 6. Calculated geometry of free isatin Schiff base Z-conformer (a) and E-conformer (b). For the Z-conformer dihedral angle between atoms C2–C3–N12–C13 is 352.51 and
the angle between the planes is 41.03°.

P. Davidovich et al. / Journal of Molecular Structure 1075 (2014) 450–455
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