Synthesis and characterization of a new class of phenothiazine molecules with 10H-substituted morpholine & piperidine derivatives: A structural insight

Article abstract of DOI:10.1016/j.molstruc.2020.128546

A series of 10H-substituted phenothiazine-based molecules were prepared by the base-catalyzed reactions. The synthesized compounds are characterized by Mass spectroscopy, NMR, and SCXRD to examine the role of different functional groups involved in the intermolecular interactions and conformational geometries. The crystal packing of the compounds is governed by O–H?O, C–H?O, and π–π interactions. A complete understanding of the intermolecular interactions is studied employing the Hirshfeld analysis, 2D Fingerprint plot. Furthermore, the density functional theory (DFT/B3LYP) method at the 6–311++G(d,p) basis set was performed to support and compare experimental & theoretical geometrical parameters of phenothiazine derivatives.

Full text of DOI:10.1016/j.molstruc.2020.128546

Journal Pre-proof
Synthesis and characterization of a new class of phenothiazine molecules with 10H-
substituted morpholine & piperidine derivatives: A structural insight
Javeena Hussain, Deekshi Angira, Tanya Hans, Pankaj Dubey, Sivapriya
Kirubakaran, Vijay Thiruvenkatam
PII:
S0022-2860(20)30871-1
DOI:
https://doi.org/10.1016/j.molstruc.2020.128546
MOLSTR 128546
Reference:
To appear in: Journal of Molecular Structure
Received Date: 23 April 2020
Revised Date: 25 May 2020
Accepted Date: 26 May 2020
Please cite this article as: J. Hussain, D. Angira, T. Hans, P. Dubey, S. Kirubakaran, V. Thiruvenkatam,
Synthesis and characterization of a new class of phenothiazine molecules with 10H-substituted
morpholine & piperidine derivatives: A structural insight, Journal of Molecular Structure (2020), doi:
https://doi.org/10.1016/j.molstruc.2020.128546.
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Credit Author Statement
Javeena Hussain (JH): Synthesized all the molecules, Crystallized the molecules and writing-
original draft preparation, Deekshi Angira (DA): Crystallographic analysis and writing of the
manuscript, Tanya Hans (TH): Synthesized the molecules Pankaj Dubey (PD): DFT
calculation and analysis, Sivapriya Kirubakaran (SK): Idea of synthesis of the new class of
phenothiazine molecules with morpholine substitution and proof reading of the manuscript,
Vijay Thiruvenkatam (VT): Conceptualization the idea, designed the manuscript contents and
crystallographic data analysis and curation.
S1

Synthesis and characterization of a new class of phenothiazine molecules with
0H-substituted morpholine & piperidine derivatives: A structural insight
1
1
1
1
1
1
Javeena Hussain , Deekshi Angira , Tanya Hans , Pankaj Dubey , Sivapriya Kirubakaran and
2
,
Vijay Thiruvenkatam *
1
Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat-
3
82355, India
2
Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar,
Gandhinagar, Gujarat-382355, India
E-mail: vijay@iitgn.ac.in
Graphical abstract:

Synthesis and characterization of a new class of phenothiazine molecules with
0H-substituted morpholine & piperidine derivatives: A structural insight
1
1
1
1
1
1
Javeena Hussain , Deekshi Angira , Tanya Hans , Pankaj Dubey , Sivapriya Kirubakaran and
2
,
Vijay Thiruvenkatam *
1
Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat-
3
82355, India
2
Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar,
Gandhinagar, Gujarat-382355, India
*
E-mail: vijay@iitgn.ac.in
Abstract:
A series of 10H-substituted phenothiazine-based molecules were prepared by the base-catalyzed
reactions. The synthesized compounds are characterized by Mass spectroscopy, NMR, and
SCXRD to examine the role of different functional groups involved in the intermolecular
interactions and conformational geometries. The crystal packing of the compounds is governed
by O–H…O, C–H…O, and π–π interactions. A complete understanding of the intermolecular
interactions is studied employing the Hirshfeld analysis, 2D Fingerprint plot. Furthermore, the
density functional theory (DFT/B3LYP) method at the 6–311++G(d,p) basis set was performed
to support and compare experimental & theoretical geometrical parameters of phenothiazine
derivatives.
Keywords: Phenothiazine, Crystal packing, Hirshfeld, 2D Fingerprint plot, DFT, HOMO-
LUMO
Introduction:
The investigation of 10H substituted phenothiazine derivatives has steadily grown fast because
they exhibit a wide range of applications in medicinal chemistry. Phenothiazine moiety is present
in a wide range of synthetic compounds and is considered as one of the most important
‘privileged substructures’ because of the wide spectrum of biological activities displayed by
many of its derivatives. It is the parent molecule of a significant series of drugs called the major
1
tranquilizers. The crystallographic elucidation of the structures of phenothiazine and some of
2
3
the derivatives was initiated in McDowell’s laboratory. Bernthsen was the first one who
synthesized phenothiazine called thiodiphenylamine in 1883 during the proof of structural
studies of dyes such as methylene blue. Later, it has played an important function in dye
4
chemistry. Phenothiazine and its derivatives have found several applications in other fields also,
1

and this has inspired further study on these compounds. These are heterocyclic molecules
containing two benzene rings connected in a tricyclic system through nitrogen and sulfur atom.
The slight change in substitution in the phenothiazine nucleus causes a distinguishable difference
in their biological activities. Phenothiazine related structures are building blocks for many drugs
5
that have shown diverse biological activities such as insecticidal properties in 1934; further
6
7
work demonstrated its usefulness as an antiseptic and an antihelmintic. Its derivatives have
8
been particularly valuable in human medicine as antihistamines in the treatment of Parkinson’s
9
10
11
12, 13
14
15
disease , and as antimalarial , antipsychotic , antimicrobial
antitubercular , antitumor ,
1
6
17
antifungal , and antioxidants. Due to the increased importance of these heterocyclic
compounds, several attempts were made during the past few years in the synthesis of a new
generation of 10H substituted phenothiazine’s scaffolds that exert a wide range of biological
1
8
effects. Together with their psychotic effects, other biological effects such as cancer
1
9
chemotherapy were very well documented. The mechanisms of these effects have been
previously well known and related to the chemical structure of derivatives synthesized from the
phenothiazine family. The presence of intermolecular interactions and the conformational
2
0–22
geometry implemented by the molecules influence the level of biological activity.
To examine the function of different functional groups engaged in the intermolecular interactions
and conformational geometries, a series of five 10H substituted phenothiazine derivatives have
been synthesized, crystallized, and studied for their structural feature. Adding to the list of next-
generation of 10H-substituted phenothiazine’s derivatives, we report the synthesis and analytical
characterization of the compounds along with structural analysis via single-crystal X-ray
diffraction and DFT calculation of the morpholine and piperidine based phenothiazine scaffolds,
2
-(10H-phenothiazine-10-yl)-1-(piperidine-1-yl)
phenothiazine-10-yl) ethanone (2b), 2-bromo-1-(10H-phenothiazine-10-yl) ethanone (3), 1-
10H-phenothiazine-10-yl)-2-(piperidine-1-yl) ethanone (3a) and 2-morpholino-1-(10H-
ethanone
(2a),
1-morpholino-2-(10H-
(
phenothiazin-10-yl) ethanone (3b) (Figure 1.). Here, we report the new phenothiazine
derivatives of pharmacological interest, which are attractive scaffolds in terms of biological
studies and would be the part of numerous important therapeutic applications.
2

Figure 1. Different variations of the R group.
Experimental
General Considerations for the synthesis of all the 5 compounds
All the chemicals were of analytical grade procured from Sigma, Merck, Finar, and SD Fine. The
reaction was done in a round-bottomed flask with a Teflon-coated and magnetic stirring bar
under inert condition. The monitoring of the progress of the reactions was done by Thin-layer
chromatography (TLC) carried on Merck TLC silica gel 60 F254 and visualized by ultraviolet
irradiation. Infrared (IR) spectra were performed on a Perkin Elmer FTIR Spectrometer
−
1
Spectrum 2 and absorption bands were reported in wavenumbers (cm ). The mass spectrums of
all the synthesized compounds were obtained by Waters Synapt-G2S ESI-Q-TOF Mass
instrument in the positive mode. The NMR of the synthesized compounds was recorded on
1
13
Bruker AVANCE III 500 ( HNMR: 500 MHz, CNMR: 125 MHz). Melting points (mp) for
solid compounds were recorded using LAB INDIA Visual Melting Range Apparatus (MR-Vis)
instrument in an open glass capillary.
3

Synthesis
Scheme 1. General synthetic routes for the synthesis of 1a-1b and 2a-2b.
Synthesis of 1a and 1b
To a solution of piperidine/morpholine (100 mg, 1.1 mmol) in dry dichloromethane (5 mL) in a
round-bottomed flask, triethylamine (111 mg, 1 mmol) was added under an inert atmosphere.
The 2-bromoacetyl bromide (221 mg, 1 mmol) was added dropwise and stirred for 4-5 h at RT.
The completion of the reaction was monitored by TLC. After the completion, the workup was
done by dichloromethane (DCM) and aqueous sodium chloride solution (NaCl). The organic
layer was dried over sodium sulfate (Na SO ), filtered and the solvent was evaporated in a rotary
2
4
evaporator to obtain a desired product, which was used as such without further purification for
the next step.
Synthesis of 2a and 2b
To a solution of phenothiazine (100 mg, 0.5 mmol) in a 5 mL of dry N, N-dimethyl formamide
(DMF) in a round-bottomed flask, sodium hydride (48 mg, 2 mmol) was added slowly under the
inert condition at 0-5 °C. The reaction mixture was stirred at room temperature for 15-20 min
followed by the addition of 1a/1b (0.5 mmol). The above reaction mixture was stirred for 12-15
hours at room temperature. The reaction towards completion was monitored by TLC. Then the
solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over
Na SO and evaporated on a rotary evaporator and the residue was purified by silica gel column
2
4
chromatography (10-25 % ethyl acetate/Hexane, as eluent) to afford desired products.
4

2
-(10H-phenothiazin-10-yl)-1-(piperidin-1-yl) ethanone, 2a
S
N
O
N
2a
-1
1
Yield (78 mg , ~ 47 %) ; mp -196 – 198 ºC; IR (ν, cm ): 1651 (C=O), 1220 (C–N); H NMR
(500 MHz, chloroform-d): δ 7.1 (d, J = 7.5 Hz, 4H), 6.9 (t, J = 7.3 Hz, 2H), 6.7 (d, J = 8.0 Hz,
1
3
2
H ), 4.5 (s, 2H), 3.6 (t, J = 5.5 Hz, 2H), 3.5 (d, J = 4.9 Hz, 2H), 1.6 (m, 4H), 1.5 (m, 2H); C
NMR (125 MHz, chloroform-d): δ 166.05, 144.56, 127.41, 127.00, 123.98, 122.91, 115.23,
5
21 2
3.43, 52.11, 46.48, 43.48, 29.72, 26.61, 25.71, 24.46; ESI-MS: m/z, calculated for C19H N OS
+
[
M+H] 325.13, found: 325.11.
1
-morpholino-2-(10H-phenothiazin-10-yl) ethanone, 2b
-1
Yield (70 mg , ~ 42%); mp-194 – 196 ºC ; IR (ν, cm ): 1648 (C=O), 1232 (C–N), 1112 (C–O);
1
H NMR (500 MHz, chloroform-d): δ 7.1 (m, 4H), 6.9 (m, 2H), 6.8 (d, J = 9.3 Hz, 2H ), 4.5 (s,
1
3
2
1
3
H), 3.5 (m, 8H); C NMR (125 MHz, chloroform-d): δ 166.50, 144.31, 127.53, 127.32, 124.55,
+
23.31, 115.30, 66.91, 66.86, 46.04, 42.72. ESI-MS: m/z, calculated for C H N O S [M+H]
18
19
2
2
27.11, found: 327.12.
5

Scheme 2. Synthetic route of 3, 3a, and 3b.
Synthesis of 3, (2-bromo-1-(10H-phenothiazine-10-yl) ethanone)
To a solution of phenothiazine (200 mg, 1 mmol) in toluene, 2-bromoacetyl bromide (201.84 mg,
1
.00 mmol) was added slowly under the inert condition at 0-5 °C. The reaction mixture was
refluxed at 120-130 °C for 5-6 h, the progress of the reaction was monitored by TLC. Then the
solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over
2 4
Na SO and evaporated on a rotary evaporator at 45-50 °C and the crude product was purified by
silica gel column chromatography (5 % ethyl acetate: Hexane) to yield 3.
2
-bromo-1-(10H-phenothiazin-10-yl)ethanone, 3
-1
1
Yield (194 mg , ~ 60 %) ; mp-128 – 130 ºC; IR (ν, cm ): 1666(C=O), 698(C–Br); H NMR (500
MHz, chloroform-d): δ 7.5 (d, J = 8.0 Hz, 2H), 7.4 (d, J = 7.5 Hz, 2H), 7.3 (t, J = 8.0 Hz, 2H),
1
3
7
1
3
.2 (t, J = 7.5 Hz, 2H), 3.93 (s, 2H); CNMR (125 MHz, chloroform-d): δ 164.73, 137.10,
+
27.10, 126.36, 126.26, 125.48, 25.87; ESI-MS: m/z, calculated for C H BrNOS [M+2H]
1
4
11
21.99, found: 321.96.
6

Synthesis of 3a and 3b
To a solution of piperidine or morpholine (3 eq.) was taken in a dry round-bottomed flask in
dichloromethane and triethylamine, NEt (2 eq.) was added. Followed by the addition of 3 (1 eq.)
3
at room temperature and the reaction mixture was stirred for 15-16 h. After completion, the
reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was
2 4
dried over Na SO and evaporated on a rotary evaporator at 45-50 °C. The crude product was
purified by silica gel column chromatography (5-10 % ethyl acetate: Hexane) to get 3a and 3b as
pure solid.
1
-(10H-phenothiazin-10-yl)-2-(piperidin-1-yl) ethanone, 3a
-1
1
Yield (133 mg , ~ 65 %); mp-156 – 158 ºC; IR (ν, cm ): 1668 (C=O), 1260 (C–N); H NMR
(500 MHz, chloroform-d): δ 7.5 (d, J = 7.9 Hz, 2H), 7.4 (dd, J = 6.5 Hz, 2H), 7.3 (m, 2H), 7.3
1
3
(
m, 2H), 3.2 (s, 2H), 2.3 (m, 4H), 1.5 (m, 4H), 1.3 (m, 2H); CNMR (125 MHz, chloroform-d):
δ 169.16, 138.93, 127.82, 126.67, 61.17, 54.10, 25.94, 23.89; ESI-MS: m/z, calculated for
+
C H N OS [M+H] 325.13, found: 325.21.
19
21
2
2
-morpholino-1-(10H-phenothiazin-10-yl) ethanone, 3b
-1
1
Yield ~ 58 %; mp-132 – 134 ºC; IR (ν, cm ): 1678 (C=O), 1262 (C–N), 1115 (C–O); HNMR
(500 MHz, chloroform-d) δ 7.55 (d, J = 7.9 Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H), 7.34 – 7.29 (m,
1
3
2
H), 7.25 – 7.21 (m, 2H), 3.58 (t, J = 4.7 Hz, 4H), 3.30 (s, 2H), 2.42 (t, J = 4.7 Hz, 4H); CNMR
7

(125 MHz, chloroform-d) δ 168.48, 138.79, 127.91, 126.93, 126.83, 126.74, 66.85, 60.71, 53.26.
+
ESI-MS: m/z, calculated for C H N O S: [M+H] 327.11, found: 327.07.
1
8
19
2
2
Crystallographic analysis
The characterization and quantification of the intermolecular interactions in these molecules
were carried out by the Hirshfeld surface(HS) analysis and 2D (two-dimensional) fingerprint
2
3, 24
plots using the Crystal Explorer program
. The HS was mapped with dnorm, shape index, and
curvedness, which helps to reveal the intermolecular interactions and the crystal packing. The 2D
25
fingerprint plots give a measurement of the different intermolecular interactions.
Crystallization: The saturated solutions of newly synthesized compounds 2a, 2b, 3, 3a, and 3b
were prepared in appropriate solvents. The solutions were allowed for solvent evaporation in a
dust-free environment. The crystals were obtained in dichloromethane and tertiary butyl methyl
ether solvents (1:1) at ambient temperature using the slow evaporation method. The good quality
crystals were harvested and subjected to single-crystal X-ray diffraction analysis.
Single crystal X-ray diffraction data
The data were collected from a single crystal at 150/273/293 K on Bruker APEX-II CCD using Mo
2
6
Kα (λ = 0.7107 Å). All the crystal structures were solved using SHELXS97 refined using
27
SHELXL2014
and reduced by the full-matrix least-squares method using Bruker SAINT.
Molecular graphics were generated using Bruker SHELXTL and packing diagrams were generated
2
8
using Mercury CSD 4.0.0. The non-hydrogen atoms are refined anisotropically and the
hydrogen atoms bonded to C atoms were positioned geometrically and refined using a riding
2
3
model with distance restraints C—H = 0.93–0.98 Å with U (H) = 1.2U (Csp ) or 1.5U (Csp ).
iso
eq
eq
Table 1. Crystal data and structure refinement for the 2a, 2b, 3, 3a, and 3b.
2
a
2b
3
3a
3b
Crystal data
Chemical
formula
C
19
H
20
N
2
OS
C
18
H
18
N
2
O
2
S
C
14
H10BrNOS
C
19
H
20
N
2
OS
C H N O S
18 18 2 2
CCDC number 1918910
Mr
324.43
1918911
326.40
1884801
320.19
1918908
324.43
1953850
326.40
8

Crystal system, Monoclinic, P2
/n Monoclinic, P2
/n Orthorhombic,
Monoclinic, P2
/c Monoclinic, P2 /c
1
1
1
1
space group
Pca2
1
Temperature (K) 273
273
150
273
293
a, b, c (Å)
α, β, γ (°)
15.2521 (10),
13.155 (3),
15.606 (4),
15.836 (4)
10.8958 (13),
8.9037 (12),
26.023 (3)
15.5041 (4),
9.0491 (2),
12.7418 (3)
15.073 (10), 9.100
(3), 12.724 (8)
9
2
.7811 (6),
3.6183 (17)
90, 104.906 (3), 90, 105.271 (6),
90, 90, 90
90, 109.228 (1),
90
90, 107.94 (3), 90
9
0
90
3
V (Å )
3404.9 (4)
8
3136.3 (13)
8
2524.5 (5)
8
1687.93 (7)
4
1660.4 (16)
4
Z
Radiation type
Mo Kα
Mo Kα
Mo Kα
Mo Kα
Mo Kα
-
1
µ (mm )
0.20
0.22
3.41
0.20
0.21
Crystal size
0.30 × 0.20 × 0.10 0.30 × 0.10 × 0.01 0.18 × 0.17 × 0.14 0.40 × 0.20 × 0.10 0.1 × 0.05 × 0.03
(
mm)
Data collection
Diffractometer
Bruker APEX-II Bruker APEX-II Bruker APEX-II Bruker APEX-II Bruker SMART
CCD
CCD
CCD
CCD
APEX2 CCD area
detector
Absorption
correction
Multi-scan
0.684, 0.746
Multi-scan
Multi-scan
Multi-scan
Multi-scan
Tmin, Tmax
0.53, 1.00
0.543, 0.623
31834, 6282,
0.91, 0.98
0.632, 0.746
12833, 4072,
No. of measured, 17632, 10166,
34041, 9585,
12520, 4136,
independent and 4769 [I > 2σ(I)] 5191 [I > 2σ(I)] 5684 [I ≥ 2u(I)] 3633 [I > 2σ(I)] 3103 [I > 2σ(I)]
observed
reflections
R
int
0.039
0.060
0.719
0.049
0.667
0.022
0.667
0.048
0.666
-
1
(
sin θ/λ)max (Å ) 0.715
Refinement
2
2
R[F > 2σ(F )],
0.067, 0.216,
0.99
0.054, 0.188,
1.01
0.025, 0.050,
1.00
0.040, 0.151,
1.21
0.047, 0.164,
1.07
2
wR(F ), S
No. of reflections 10166
9585
6244
4136
4072
No. of
415
415
405
208
208
parameters
H-atom
treatment
H-atom
parameters
constrained
H-atom
parameters
constrained
All H-atom
parameters
refined
H-atom
parameters
constrained
H-atom
parameters
constrained
9

-
∆
)
〉max, ∆〉min (e Å 0.29, -0.37
0.32, -0.44
0.27, -0.38
0.26, -0.23
0.26, -0.24
3
Cambridge structure database search
2
9, 30
31
The Cambridge structure database
searches was carried out using ConQuest version 2.0.0
with 2a, 2b, 3, 3a, and 3b together with alkyl-substituted phenothiazine moiety to understand the
similarities, packing arrangement and dominant interactions in these kinds of chemical
compounds.
Hirshfeld surface analysis
The Crystal explorer software used to estimate the strength of contacts by analyzing the
interaction energies and evaluate these facts with the outputs of the Hirshfeld surface analysis.
Properties like curvedness, shape index, and dnorm were studied for all the four compounds. The
relative contribution of various contacts present in the individual crystal was plotted with respect
2
4, 25,32, 33
to their respective 2D decomposition plots.
Powder X-ray diffraction (PXRD)
All the synthesized compounds were characterized by X-ray diffraction employing a Bruker D8
Discover diffractometer with CuKα radiation. The PXRD patterns were recorded in a 2θ range of
5
to 90° with a step size of 0.02 and at a scanning rate of 0.2 second per step. The tube voltage
and current were 20 kV and 5 mA, respectively. The intense and sharp patterns of PXRD of all
compounds confirmed good crystalline properties.
Results and discussion
Chemistry
The synthesis of new derivatives of piperidine and morpholine bearing alkyl chains of the same
lengths, connected to the N atom of the heterocyclic system of phenothiazine was accomplished in
good or moderate yields by advancing and modifying usual procedures reported in the literature.
34
Compounds 2a, 2b, 3, 3a, and 3b were synthesized by reacting 1a and 1b with phenothiazine
in the presence of sodium hydride (NaH) as a base and N, N-dimethylformamide (DMF) as a
solvent (Scheme 1.). Another three compounds were synthesized by the acetylation of the
phenothiazine using appropriate halogen alkyl reagent. Bromo-acetyl bromide in toluene was
refluxed with 10H-phenothiazine; it afforded the corresponding 10-bromo acetyl phenothiazine
1
0

(3). To prepare 10H-substituted phenothiazine amine derivative compounds, the morpholine and
piperidine were selected for this synthetic approach (Scheme 2.) The reaction of 10-bromo
acetyl phenothiazine (3) with morpholine and piperidine substituents, took place at room
temperature in dry acetonitrile (ACN), in the presence of trimethylamine (NEt
3
) as a base gave
the corresponding products 3a and 3b. The structures of all the compounds were confirmed by
1
13
their H NMR, C NMR, and Mass spectrum.
Structure description
An extensive CSD survey was performed to understand the similarities and conformational
changes of the title compounds. There are no reports of the structures similar to the compounds
3
5
2
a, 2b, 3, 3a, and 3b in the crystal database. However, there was one hit DUBZUV4 for alkyl-
substituted phenothiazine moiety with few similarities concerning the puckered conformation of
the bent phenyl rings, typical to the chemical compounds under study.
3
6
ORTEP and capped stick diagrams for compounds 2a, 2b, 3, 3a and 3b are displayed in the
supplementary figure S1 and figure S2 respectively. The compounds 2a, 2b, 3a, and 3b
1
crystallize in the centrosymmetric monoclinic system with 2a and 2b having a P2 /n space group
and 3a and 3b having P2 /c space group. The compound 3 crystallizes in the orthorhombic
1
system and depicts Pca2 . The compounds 2a and 2b are solved and refined as a dimer. The
1
asymmetric unit is composed of two molecules with the molecular formula C19
20 2
H N OS and
C H N O S for 2a and 2b respectively. Both the compounds have a Z value of 8. Their
18
18
2
2
structures exhibit ‘T shaped’ morphology with phenothiazine ring plane located perpendicular to
the piperidine moiety. The molecular conformation of 2a is stabilized by C…H and O…H
contacts as seen in the packing diagram whereas in 2b the major driving interactions are O…H
and S---H contacts.
The compound 3a and 3b with the molecular formula of C H N OS and C H N O S are
1
9
20
2
18 18
2
2
solved as a monomer with one molecule in the asymmetric unit and Z value of 4. Their structure
displays a slight difference with ‘crooked T shape’ morphology where the piperidine moiety is
bent over the phenothiazine ring with the amide linker showing a torsion angle
N1…C13…C14…N2 of -65.53 ◌֯ for 3a and -62.11 ◌֯ for 3b. The packing is assisted by O…H
interactions playing the master role in both the cases.
1
1

The compound 3 is solved as a dimer with the molecular formula, C H BrNOS with 2
14
10
molecules in the asymmetric unit, and a Z value of 8. Unlike compounds 2a, 2b, 3a, and 3b, this
compound comprises of bromo acetyl moiety connected to phenothiazine via amide linker. The
major contacts participating in the packing of this derivative include O…H, S…H, and Br…Br
contacts.
One of the interesting features that we can notice in all these compounds is the folded butterfly-
3
7
like
phenothiazine ring moiety that has a characteristic bent along the N-S vector and the
dihedral angle between two planes lie in a range of 132-142◌
֯
that is again distinctive feature for
1
, 35
1
phenothiazine derivatives.
Also, as discussed in by McDowell in , the N and the S atoms are
located at a considerable distance from the two planes and are not exactly located at the axis
where the two planes intersect. As shown in the figure. 2, the distance calculated for 2a is
0
0
.002Å (N) and 0.206 Å(S), for 2b it is 0.041 Å (N) and 0.293 Å(S), for 3a it is 0.022 Å (N), and
.050 Å (S), for 3b it is 0.076 Å (N) and 0.117 Å (S) and for 3 it is 0.076 Å (N) and 0.030 Å (S).
Figure 2. Representation of plane angles of 2a, 2b, 3, 3a, and 3b.
Hirshfeld surface analysis
The structure files for all the five compounds in the CIF format were submitted in Crystal
Explorer software to generate the Hirshfeld surface (HS) as shown in figure 3. It encodes for the
intermolecular interactions based on the electron density map of the molecule for the electron
density of its neighboring molecule. The dnorm was mapped in the range of -0.227 to 1.401, shape
index was mapped in the range of -1.00 to 1.00, and curvedness had a range of -4.00 to 0.40 for
1
2

all the compounds. The intense red spots are indicating the places where the intermolecular
3
8,39
distances are shorter than the sum of van der Waals radii.
of the intermolecular contacts is also analyzed using the 2D fingerprint plots generated using di
versus d values. The blue, white, and red color contacts utilized for the dnorm mapped Hirshfeld
surfaces distinguish the interatomic conventions as longer, at van der Waals partitions and small
Also, the quantitative breakdown
e
4
0
interatomic contacts, correspondingly . We can see the strong C—H...O interactions as bright
red spots between the relevant donor and acceptor atoms on the Hirshfeld surfaces mapped over
dnorm (Figure 3).
The HS analysis of compound 2a depicted the presence of a strong hydrogen bond, C14-
O1…H13B-C13, between oxygen (amide linker of one molecule) and hydrogen (amide linker of
the neighboring molecule) with a bond distance of 2.129 Å. The compound 2b, which has a
carbon substituted with oxygen in the morpholine moiety did not illustrate much difference and
showed S1…H1-C1 (2.740 Å) in addition to the C14-O1…H13B-C13 (2.304 Å) hydrogen bond
in the form of electron-rich red spots on the molecular surface. On the other hand, in compound
3
a, major interactions were C13-O1…H9-C9, C13-O1…H2-C2, and C1-H1…C11 with the bond
distance of 2.353 Å, 2.478 Å, and 2.763 Å respectively. Likewise, compound 3b also showed
C13-O1…H9-C9 and C13-O1…H2-C2 contact with the bond distance of 2.679 Å, and 2.523 Å
respectively. Owing to the presence of bromo acetyl moiety, compound 3 shows a strong Br…Br
interaction between the two monomers with a bond distance of 3.346 Å. The θ (C14A-
1
Br1A…Br1B) and θ (C14B-Br1B…Br1A) angles for the interaction are calculated as 145.5 ◌
֯
2
and 161.7 ◌
֯
respectively, thereby confirming this contact as quasi-type 1 halogen-halogen
4
1
interaction. A hydrogen bond between C14A-H14a…O1B with a bond distance of 2.454 Å was
also present in compound 3. The fingerprint or the decomposition plot for all the title compounds
is given in figure 4. Based on the fingerprint plots, a table for the percentage contribution of
major interactions is highlighted in table 2.
1
3

Figure 3. Hirshfeld surfaces of 2a, 2b, 3, 3a, and 3b mapped with (a) dnorm, (b) shape index, and (c) curvedness.
The valuable measures of Hirshfeld surfaces mapped over shape-index and curvedness,
4
2
commenced by Koendrink and offer additional chemical insight into molecular packing. A
surface with low curvedness assigns a flat area and may be indicative of π–π stacking
43
interactions in the crystal. The occurrence of the π–π stacking interactions is also specified by
the emergence of red and blue spots on the shape indexed surfaces, documented and in the flat
areas on the Hirshfeld surfaces mapped with curvedness in Figure 3. The curvedness map
showed green flat areas and the shape index has corresponding red (negative) and blue (positive)
spots such as triangles, which are discrete for the identification of π–π stacking. Further, the
intermolecular interactions in the morpholine/piperidine attached derivatives of phenothiazine
1
4

are analyzed by the 2D fingerprint plot. It has been generated from the Hirshfeld surface analysis
illustrate the percentage contacts of strong and weak intermolecular interactions on the
compounds. The 2D fingerprint plot offered the frequency of each intermolecular interaction
take place in the crystal (Table 2).
Figure 4. The two-dimensional fingerprint plot analysis of 2a, 2b, 3, 3a, and 3b (a) all interactions, (b) HH contacts
(
c) CH contacts (c) OH contacts and (c) SH contacts.
According to the data, 0.2 to 3.3 percent of C...C contacts also confirms the presence of π–π
stacking in all the calculated system (Supplementary, Figure S14). The main intermolecular
1
5

interactions influencing the molecular packing of the studied phenothiazine derivatives are the
C–H…O and H...H and π–π interactions (Table 2). We can notice that in compound 2a, the
maximum contribution is from H…H contacts i.e. 55.4% followed by C…H, S…H, and O…H
with values of 27%, 9.6%, and 6.4% respectively. A similar pattern was observed in 2b with the
H…H, C…H, O…H, and S…H contacts having the percentage contribution of 48.5%, 28.5%,
1
1.5%, and 9.3% respectively. The presence of oxygen in the morpholine moiety of 2b is
majorly responsible for the increase in O…H contact contribution and a concomitant decrease in
H…H contribution when compared to 2a. The compound 3a, which is very similar to 2a and
differs only with respect to the position of oxygen in amide linker surprisingly, displays a
different pattern of contact contribution, hence, highlighting the importance of the position of
functional group and its effect in intermolecular interaction.
Table 2. The relative contribution of different close contacts for the overall intermolecular
interactions in 10H substituted phenothiazine derivatives.
Compounds
Contacts
H⋯H (%)
C⋯H (%)
O⋯H (%)
S⋯H (%)
C⋯C (%)
Br⋯H (%)
2a
55.4
27.0
9.6
6.4
0.2
-
2b
48.5
28.5
11.5
9.3
1.5
-
3
3a
63.3
18.1
8.2
7.0
3.0
-
3b
57.4
17.9
14.1
6.1
3.3
-
29.6
29.7
11.9
9.8
0.5
11.8
The H…H contributes to 63.3%, highest among all the four derivatives, followed by C…H,
O…H, and S…H with values of 18.1%, 8.2%, and 7% respectively. Compound 3b, which is
again similar to the 2b, has maximum contact contribution from H…H (57.4%) followed by
C…H (17.9%), O…H (14.1%), and S…H (6.1%). The slight increase in O…H contact
contribution can be owed to the presence of two oxygen atoms, in amide linker and morpholine
moiety respectively. Similarly, in compound 3, the presence of bromo acetyl moiety is
accountable for 11.8% Br…H and 2.3% Br…Br contacts in addition to the contribution by
H…H, C…H, O…H and S…H of 29.6%, 29.7%, 11.9%, and 9.8% respectively. A drastic
decrease in H…H contact contribution is noticed in 3, due to the structural difference as
compared to other derivatives.
1
6

Table 3. Selected Hydrogen bond parameters (Å, °) of 2a, 2b, 3, 3a, and 3b
Compound
D—H···A
C13A—H13B···O1Ab
C13B—H13C···O1B
C4B—H4B···S1A
C13A—H13B···O1Bd
C13B—H13D···O1A
C1A—H1A···S1A
C10A—H10A···Br1A
C14B—H14C···O1A
D—H (Å)
0.97
H···A (Å)
2.26
D···A (Å)
3.217 (2)
3.207 (2)
3.700 (2)
3.143 (3)
3.374 (2)
3.747 (3)
3.608 (4)
3.511 (4)
3.404(2)
3.424(3)
a
2
a
0.97
0.93
0.97
0.97
0.95
0.95
0.99
0.93
2.24
2.87
2.44
2.41
2.95
2.95
2.58
2.50
c
2
b
e
3
f
g
3
a
C2—H2···O1g
C2—H2···O1
3
b
0.93
2.25
Symmetry code(s): (a) −x+1/2, y+1/2, −z+3/2; (b) −x+3/2, y−1/2, −z+3/2; (c) x−1/2, −y+3/2, z+1/2; (d) x−1/2,
−
y+3/2, z−1/2; : (e) x−1/2, −y+1, z; (f) −x+3/2, y, z−1/2; (g) −x, 1−y, −z;
After analyzing the CIF for all the compounds, significant formation of supramolecular
assemblies was observed in compounds 2a, 3a, and 3b. As seen in compound 2b (Figure 5.), a
supramolecular synthon formation occurs utilizing 3 dimers (6 molecules) linked to each other
by hydrogen bonds, thus, forming an elliptical cavity in a two-dimensional arrangement. The
bond formation occurs between C13B-H13D…O1A, C13A-H13B…O1B, C7B-H7B…O2B with
the bond distance of 2.41 Å, 2.44 Å, and 2.67 Å respectively.
Figure 5. Crystal packing diagram depicting supramolecular synthon formation in compound 2b in a unit cell
viewed down the, b direction
1
7

In Compound 3a and 3b, a similar synthon formation occurs in the form of a zig-zag herringbone
pattern utilizing hydrogen bond being formed between C2-H2…O1 with a bond distance of 2.50
Å in 3A and 2.25 Å in 3B. Both of the herringbone chains run parallel to each other this holding
the molecules together as shown in Figure 6
.
Figure 6. Supramolecular structure formation of compound 3a in a unit cell viewed along the b direction
Density functional theory
The electronic structure calculations were performed at the DFTB3LYP level of theory
employing a 6–311++G(d,p) basis set. The theoretical calculations were carried out using the
4
4
45
Gaussian 09 program and visualized in GaussView program. Previous reports suggest that the
nature of electron density distribution around molecule and its reactivity can be understood in
terms highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital
4
6
(
LUMO). Furthermore, it is also stated that the molecular regions with the high density of the
HOMO determine the site for electrophilic attacks. Whereas, the region for the nucleophilic
4
7
attack is governed by the high density of the LUMO. The stability and reactivity of the
4
8,49
molecule can be understood in terms of the energy differences between HOMO and LUMO.
Figure 7 shows optimized geometry, HOMO, and LUMO of the 10H substituted derivatives of
Phenothiazine, and Table 4 shows the absolute energy, dipole moment, HOMO energy, LUMO
energy and gap between HOMO and LUMO orbitals, for all five derivatives of phenothiazine. The
1
8

HOMO and LUMO of all the compounds were plotted to scrutinize the main atomic
contributions and tells the possible sites of electronic transfer in which atoms are located. In all
these energy-optimized structures (Figure. 7), phenothiazine employed a puckered butterfly
structure. The HOMO lobes are distributed mostly over phenothiazine ring; whereas, the LUMO
lobes are almost homogeneously spread over phenothiazine and terminal amine group
somewhere. Based on the HOMO-LUMO energy gap, the MO theory of the chemical bond
5
0
explains the concept of hard-soft molecules. In the present study, all five compounds can be
classified into a hard-molecule category and have good kinetic stability, as each of them shows
large energy gap between HOMO and LUMO, i.e. ranging in between - 4.5 to - 4.9 eV.
Figure 7. The optimized geometries and the surfaces of the frontier molecular orbital of compound 2a, 2b, 3, 3a,
and 3b obtained at the B3LYP/6–311++G(d,p).
1
9

Thus, this analysis shows that the HOMO-LUMO orbital is localized in the nearly same region
of all compounds. Furthermore, the HOMO-LUMO energy gaps observed for all derivatives are
seen to be nearly the same, thus suggesting that all five compounds exhibit nearly equivalent
electronic structure properties.
Table 4. Energies of both HOMO and LUMO and their gaps (in eV) calculated for 2a, 2b, 3, 3a and 3b
Compound
Energy
Dipole moments,
µ (Debye)
5.4048
HOMO
(eV)
-5.1767
-5.26486 -0.72899
-6.27849 -1.71786
-5.98351 -1.08002
-6.10052 -1.18016
LUMO
(eV)
-0.6479
HOMO-LUMO
energy gap (eV)
-4.5288
(
Hartee)
2a
-1319.2632
-1355.16571
-3642.02853
-1319.2525
-1355.15645
2
b
3.5179
3.6014
2.934
3.3029
-4.53587
-4.56063
-4.90349
-4.92036
3
3a
3
b
Electrostatic Potential Surface (ESP), the region provides a detailed description of both electron
5
1
acceptor and electron donor areas. The different colors signify the diverse values of ESP such
as blue color represents the most positive electrostatic potential whereas red color represents the
most electronegative electrostatic potential region. It also relates to the total charge distribution
through dipole moment, partial charges, electronegativity, chemical reactivity sites of a
compound. ESP offers a visual technique to comprehend the basic polarity of a molecule and
acts as a valuable quantity to explain electrophilic and nucleophilic sites including hydrogen
bonding, reactivity, and SAR (structure-activity relationship) of molecules including bio-
molecules and drugs.
Table 5. Selected structural parameters by X-ray and theoretical calculations for all the compounds.
Bond lengths Experimental DFT/Theoretical
Å)
Bond angles
(º)
Experimental DFT/Theoretical
(º)
(
2
a
C1A—C2A
C1A—C12A
C2A—C3A
1.386 (4)
1.384 (3)
1.373 (4)
1.394
1.400
1.391
C12A—C1A—C2A
C11A—N1A—C12A
C6A—S1A—C5A
120.5 (3)
120.27 (17)
98.83 (11)
120.8
120.48
99.05
2
b
C1A—C12A
C1A—C2A
O1A—C14A
S1A—C6A
N1A—C11A
N1A—C12A
3
1.382 (3)
1.383 (4)
1.214 (2)
1.743 (2)
1.390 (3)
1.401 (3)
1.400
1.394
1.220
1.782
1.414
1.414
C12A—C1A—C2A
C6A—S1A—C5A
C11A—N1A—C12A
C11A—N1A—C13A
C12A—N1A—C13A
C3A—C2A—C1A
121.1 (2)
100.07 (10)
122.01 (16)
117.25 (16)
118.36 (17)
120.4 (3)
120.84
99.06
120.52
119.38
119.43
120.5
Br1A—C14A
S1A—C5A
1.951 (2)
1.771 (2)
1.979
1.787
C6A—S1A—C5A
C12A—N1A—C11A
98.32 (10)
115.52 (17)
97.99
115.70
2
0

S1A—C6A
O1A—C13A
N1A—C11A
N1A—C12A
1.767 (2)
1.223 (3)
1.442 (3)
1.430 (3)
1.783
1.214
1.434
1.437
C13A—N1A—C11A
C13A—N1A—C12A
C2A—C1A—H1A
C12A—C1A—H1A
123.42 (18)
120.21 (18)
119.4 (17)
120.5 (17)
124.90
118.58
120.80
119.43
3
a
C1—C2
C1—C12
S1—C6
S1—C5
O1—C13
N1—C13
1.382 (2)
1.392
1.395
1.782
1.787
1.216
1.398
C2—C1—C12
C6—S1—C5
C13—N1—C12
C13—N1—C11
C2—C1—C12
C12—N1—C11
119.34 (14)
98.15 (5)
120.08 (10)
123.68 (10)
119.34 (14)
115.47 (9)
119.89
97.97
119.51
124.24
120.33
115.80
1.3919 (17)
1.7573 (13)
1.7629 (12)
1.2209 (17)
1.3729 (16)
3
b
C1—C2
C1—C12
S1—C6
S1—C5
O1—C13
N1—C13
1.382 (2)
1.392
1.395
1.782
1.788
1.217
1.397
C2—C1—C12
C6—S1—C5
C13—N1—C12
C13—N1—C11
C12—N1—C11
N2—C19—C18
119.34 (14)
98.15 (5)
120.08 (10)
123.68 (10)
115.47 (9)
111.35 (14)
119.87
97.97
119.42
124.29
115.76
109.87
1.3919 (17)
1.7573 (13)
1.7629 (12)
1.2209 (17)
1.3729 (16)
The electrostatic potential surface (ESP) generated for these derivatives at B3LYP/6-
11++G(d,p) level of theory, is shown in the supplementary figure S13. The ESP analysis of all
3
derivatives shows that the nucleophilic sites are localized on carbonyl oxygen (C=O). Moreover,
in the case of compounds 2b and 3b, the cyclic oxygen atom of (morpholine) is also observed to
be an electron-rich region (nucleophile). Similarly, the electrophilic regions are concentrated
near the aromatic hydrogen’s of phenothiazine, in all compounds. Thus, the ESP analysis
suggests that electrophilic and nucleophilic sites in all five derivatives of phenothiazine are
nearly similar. We also conclude that the experimentally observed parameters such as bond
lengths and bond angles for all five compounds were found to be in good agreement with the
computed values. The theoretical structural and experimental data of the 10H substituted
phenothiazine derivatives are listed in Table 5.
Conclusion
The work includes synthesis, characterization, and crystal structure of five new 10H-substituted
phenothiazine derivatives bearing alkyl chains (with two carbon chain lengths) and tertiary
amino groups at the 10(H) position; subjected for the X-ray crystallography and DFT studies to
evaluate their structural properties. Good qualities of single crystals suitable for X-ray diffraction
analysis were obtained by recrystallization. The crystals were obtained in dichloromethane and
tertiary butyl methyl ether solvents (1:1) at ambient temperature using the slow evaporation
method. Our study identified that phenothiazine derivatives 2a & 2b crystallizes as the
2
1

1
Monoclinic, with space group P2 /n and 3a & 3b crystallizes as the Monoclinic, with space
group P2 /c respectively. Compound 3 crystallized as orthorhombic with Pca2 . The C–O
⋯H
1
1
and C–H⋯O hydrogen bond interactions, along with other weak interactions, stabilize the crystal
packing. The purpose of the study was to analyze the consequence of the dissimilar crystal
conformations of phenothiazine derivatives. In this connection, we compare the experimental and
theoretical results of 10H-substituted phenothiazine derivatives. The HOMO–LUMO gap implies
that these compounds have good kinetic stability and a high chemical reactivity whereas ESP
gives the information on charge density distribution. Moreover, the computational study also
suggests that all five derivatives of phenothiazine show nearly similar electronic structure
properties such as electrophilic and nucleophilic sites and regions of HOMO and LUMO orbital
localization.
Conflicts of interest
There are no conflicts of interest to declare.
Supporting Information
Supporting information includes the following
1
2
3
4
. NMR (1H and 13C) of all reported compounds
. Mass data of synthesized compounds
. Crystal packing figures
. Powder XRD pattern of the reported compounds
Acknowledgements
The authors would like to acknowledge the Indian Institute of Technology Gandhinagar for
laboratory facilities and DST-FIST Department of Science and Technology, India for Single
Crystal X-ray Diffraction Facility provided at IIT Gandhinagar (Project No. SR/FST/CSI-
2
77/2016). The authors would also express sincere thanks to DRDO for funding.
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Synthesis and characterization of a new class of phenothiazine molecules with
0H-substituted morpholine & piperidine derivatives: A structural insight
1
1
1
1
1
1
Javeena Hussain , Deekshi Angira , Tanya Hans , Pankaj Dubey , Sivapriya Kirubakaran and
2
,
Vijay Thiruvenkatam *
1
Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat-
3
82355, India
2
Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar,
Gandhinagar, Gujarat-382355, India
E-mail: vijay@iitgn.ac.in
Highlights:
•
•
A new series of 10H-substitited phenothiazine derivatives have been crystallized.
Interactions in crystal packing were supported by Hirsfeld surface and 2D-Fingerprint
plot analysis.
•
•
•
The crystal structure was investigated using DFT and the nature of HOMO and LUMO
was theoretically studied.
DFT study supports the formation of intermolecular hydrogen bonds and electrostatic
interactions.
Theoretical studies were performed with B3LYP/6–311++G(d,p) level to compare the
best correlation of both theoretical with experimental data.

Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐
The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: