Charge transfer complex of some nervous and brain drugs-Part 1: Synthesis, spectroscopic, analytical and biological studies on the reaction between haloperidol antipsychotic drugs with π-acceptors

Article abstract of DOI:10.1016/j.molstruc.2012.08.045

Donor-acceptor interactions between the electron donor haloperidol (HPL) and π-acceptors like 7,7,8,8-tetracyanoquinodimethane (TCNQ) and picric acid (PA) have been studied spectrophotometrically in CH₃OH solvent. The donor-acceptor (charge tra

Full text of DOI:10.1016/j.molstruc.2012.08.045

Journal of Molecular Structure 1034 (2013) 1–18
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Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Charge transfer complex of some nervous and brain drugs – Part 1: Synthesis,
spectroscopic, analytical and biological studies on the reaction between
haloperidol antipsychotic drugs with p-acceptors
Abeer A. El-Habeeb a, Foziah A. Al-Saif a, Moamen S. Refat b,c,
⇑
a Department of Chemistry, Faculty of Science, Princess Nora Bint Abdul Rahman University, Riyadh, Saudi Arabia
b Department of Chemistry, Faculty of Science, Port Said, Port Said University, Egypt
c Department of Chemistry, Faculty of Science, Taif University, 888 Taif, Saudi Arabia
h i g h l i g h t s
"
"
"
"
Synthesis of charge transfer complex of some nervous and brain drugs.
Spectroscopic studies on the reaction between haloperidol with -acceptors.
The stoichiometry of these complexes was found to be 1:1 M ratio.
p
These complexes were also tested for their antimicrobial activity against six different microorganisms.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2012
Received in revised form 21 August 2012
Accepted 24 August 2012
Available online 6 September 2012
Donor–acceptor interactions between the electron donor haloperidol (HPL) and p-acceptors like 7,7,8,8-
tetracyanoquinodimethane (TCNQ) and picric acid (PA) have been studied spectrophotometrically in
CH3OH solvent. The donor–acceptor (charge transfer complexes) were discussed in terms of formation
constant (KCT), molar extinction coefficient (
sition dipole moment ( ), resonance energy (RN) and ionization potential (ID). The stoichiometry of these
eCT), standard free energy (D
Go), oscillator strength (f), tran-
l
complexes was found to be 1:1 M ratio and having the formulas [(HPL)(TCNQ)] and [(HPL)(PA)], respec-
tively. The charge transfer interaction was successfully applied to determine of HPL drug using men-
Keywords:
Haloperidol
TCNQ
tioned common
p-acceptors also, the results obtained herein are satisfactory for estimation of HPL
compound in the pharmaceutical form. The formed solid charge-transfer complexes were also isolated
and characterized using elemental analysis, conductivity, (infrared, Raman, and 1HNMR) spectra and
X-ray powder diffraction (XRD). The experimental data of elemental analyses are in agreement with cal-
culated data. The infrared spectra of both HPL complexes are confirming the participation of AOH of 4-
hydroxy-1-piperidyl moiety in the donor–acceptor chelation. The morphological surface of the resulted
charge transfer complexes were investigated using scanning electron microscopy (SEM). The thermo-
gravimetric analysis (TG/DTG) and differential scanning calorimetry (DSC) techniques were performed
to give knowledge about the thermal stability behavior of the synthesized charge transfer complexes.
Thermodynamic parameters were computed from the thermal decomposition data. These complexes
were also tested for their antimicrobial activity against six different microorganisms, and the results were
compared with the parent drug.
PA
Spectroscopic data
Charge transfer complex
Thermal analysis
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
is an older antipsychotic used in the treatment of schizophrenia
[2] and in the treatment of acute psychotic states and delirium. A
Haloperidol (Scheme 1) is a typical antipsychotic. It is in the
butyrophenone class of antipsychotic medications and has phar-
macological effects similar to the phenothiazines [1]. Haloperidol
long-acting decanoate ester is used as an injection given every
4 weeks to people with schizophrenia or related illnesses who have
a poor compliance with medication and suffer frequent relapses of
illness, or to overcome the drawbacks inherent to its orally admin-
istered counterpart that burst dosage increases risk or intensity of
side effects. In some countries, injections of antipsychotics such as
⇑
Corresponding author at: Department of Chemistry, Faculty of Science, Port
Said, Port Said University, Egypt.
E-mail address: msrefat@yahoo.com (M.S. Refat).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.08.045

2
A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
O
OH
Cl
N
F
HPL
N
N
N
O
N+ O-
O
N+
N
-O
HO
N+ O-
TCNQ
O
PA
Scheme 1. Haloperidol drug (HPL); IUPAC name 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one, acceptors; 7,7,8,8-tetracyanoquinodi
methane (TCNQ) and picric acid (PA).
Table 1
Analytical and physical data for haloperidol (HPL) charge transfer complexes.
Compound Empirical formula (M. Wt.)
Color Before ppt
Color After ppt
Km (
X
ꢀ1 cmꢀ1 molꢀ1
)
Elemental analysis (%) Found (Calcd.)
Yield (%)
C
H
N
HPL 375.86
[(HPL)(PA)]
(604.968)
[(HPL)(TCNQ)]
(579.043)
White
Yellow
White
Yellow
10
45
67.11
53.39
(53.60)
68.43
(68.45)
6.17
4.21
(4.33)
4.49
(4.53)
3.73
9.12
(9.26)
11.98
(12.09)
–
89
Olive
Green
Green
53
93
7
6
6
B
A
5
4
5
4
3
3
2
2
1
1
0
0
-1
-1
200
300
400
500
600
700
800
900
200
300
400
500
600
700
800
900
Wavelength/ nm
Wavelength/ nm
Fig. 1. Electronic absorption spectra of (A): [(HPL)(PA)] and [(HPL)(TCNQ)] charge transfer complexes in methanol solvent.
haloperidol can be ordered by a court at the request of a
psychiatrist.
tant processes in biological systems; for example, drug action, en-
zyme catalysis, and ion transfers through lipophilic membranes all
involve complexation [5]. Mulliken suggested that the formation of
molecular complexes from two aromatic molecules can arise from
Donor acceptor complexation is an important phenomenon in
biochemical and bioelectrochemical energy transfer process [3].
Charge transfer interactions between electron donors and accep-
tors are generally associated with the formation of intensely col-
ored CT complexes which absorb radiation in the visible region
[4]. Molecular complexation and structural recognition are impor-
the transfer of an electron from a
p-molecular orbital of a Lewis
base to vacant -molecular orbital of a Lewis acid, with resonance
p
between this dative structure and the no-band structure stabilizing
the complex [6]. Mulliken also noted the possibility of complex for-

A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
3
2.2
B
A
2.6
2.4
2.2
2.0
1.8
1.6
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
ml added of PA
ml added of TCNQ
Fig. 2. Photometric titration spectra of (A): [(HPL)(PA)] and [(HPL)(TCNQ)] charge transfer systems in methanol solvent at refereed peaks of 447 nm and 357 nm, respectively.
1.6
B
A 1.2
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
100
150
200
250
300
-6
350
400
100
150
200
250
300
-6
350
400
(Cdo +Cao )x10
(Cdo +Cao )x10
Fig. 3. The modified Benesi–Hildebrand plot of (A): [(HPL)(PA)] and [(HPL)(TCNQ)] charge transfer systems in methanol solvent at refereed peaks of 447 nm and 357 nm,
respectively.
mation through the donation of an electron from a non-bonding
molecular orbital in a Lewis base to a vacant -orbital of an
acceptor (n– ) [7] with resonance stabilization of the combination.
2.2. Synthesis of charge transfer complexes of HPL drug donor
p
p
The two haloperidol solid charge transfer complexes
[(HPL)(PA)] and [(HPL)(TCN)] were synthesized as a yellow and
green colors, respectively, by mixing a (3 mmol, 0.125 g) of halo-
peridol drug in 20 mL methanol to a 3 mmol of each acceptors;
PA (0.0763 g) and (0.0680 g of TCNQ in 10 mL chloroform solvent.
All mixtures were stirred for 45 min at room temperature and the
The CT complexation is an important technique that is cheaper,
simpler, and more efficient than the methods of drug determina-
tion described in the literature [8–16]. The solid charge transfer
products of HPL with TCNQ and PA have not yet been reported in
the literature; therefore the target of the present study was to
investigate these reactions. Results of elemental analysis for all
the HPL complexes are listed in Table 1. From this table, it can be
seen that values found are in agreement with the calculated ones
and the composition of the CT complexes are matched with the
molar ratios presented from the photometric titration occurring
between HPL and both p-acceptors. All of the complexes are insol-
uble in water and partially soluble in alcohols, but easily soluble in
dimethyl formamide (DMF) and dimethylsulfoxide (DMSO).
2. Experimental
2.1. Chemicals and reagents
[(HPL)(PA)]
[(HPL)(TCNQ)]
All chemicals and reagents used in this study were of analytical
grade. Haloperidol was received from Egyptian International Phar-
maceutical Industries Company EIPICO. Picric acid and 7,7,8,8-tet-
racyanoquinodimethane were obtained from Aldrich Chemical
Company.
4000
3500
3000
2500
2000
1500
-1
1000
500
Wavenumber/ cm
Fig. 4. IR spectra of [(HPL)(PA)] and [(HPL)(TCNQ)] charge transfer complexes.

4
A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
Table 2
Spectorophotometric data of the HPL charge transfer systems in methanol.
kmax (nm)
ECT (eV)
K (l molꢀ1
)
emax (l molꢀ1 cmꢀ1
)
f
l
Ip
D
RN
D
Go (25 °C) kJ molꢀ1
[(HPL)(PA)]
447
2.78
11468
26596
23
23
46.71
41.85
9.183
10.05
33
33
0.435
0.546
23163
25358
[(HPL)(TCNQ)]
357
3.48
27815
26738
Table 3
Assignments of the IR spectral bands (cmꢀ1) of HPL, PA, TCNQ, [(HPL)(PA)], and [(HPL)(TCNQ)] charge transfer complexes.
HPL
PA
TCNQ
[(HPL)(acceptor)] CT-complexes
PA
Assignments(b)
TCNQ
3129
3416
3103
2980
2872
3405
3502
3357
3030
3502
3364
3030
2944
m(OAH)
2968
2955
2917
2839
2824
3137
3050
2969
2851
ms(CAH)
ms(CAH)
+
+
mas(CAH) aliphatic
mas(CAH) aromatic
–
–
–
–
–
2220
–
2774
2597
2761
2604
Hydrogen bonding
–
2171
2112
m(C„N)
1682
1861
1686
1620
1692
m(C@O);
HPL
m(C@O); PA
1599
1505
1483
1471
1458
1411
1632
1608
1529
1432
1540
1567
1489
1436
1403
1600
1561
1495
1430
1404
m(C@C)
CAH deformation
1378
1363
1314
1255
1244
1235
1224
1199
1168
1343
1312
1263
1150
1352
1285
1205
1364
1332
1267
1240
1150
1364
1312
1267
1233
1155
m(CAC)
m(CAN)
m(CAO)
CH, in-plane bend
1137
1110
1087
1047
1013
1006
998
1086
917
829
781
732
703
652
1117
1044
997
962
860
1076
1036
1004
964
905
827
787
748
702
1076
1042
1010
976
906
827
787
748
702
CH-deformation
m(CACl) + m(CAF)
808
962
951
793
603
603
742
546
500
522
473
537
499
537
491
Skeletal vibration
CH bend
CH out of plane bend
CNC def.
dNO2
solid products were filtered off, washed with minimum amounts of
chloroform and dried under vacuum over anhydrous CaCl2.
conductivities of freshly prepared 1.0 ꢁ 10ꢀ3 mol/cm3 dimethyl-
sulfoxide (DMSO) solutions were measured for the dissolved HPL
complexes using Jenway 4010 conductivity meter. The electronic
absorption spectra of the resulted charge transfer complexes were
recorded in methanol within 800–200 nm range using a Perkin–El-
mer Precisely Lambda 25 UV/Vis double beam Spectrometer fitted
with a quartz cell of 1.0 cm path length. Infrared spectra within the
2.3. Physical measurements and analytical estimations
The elemental analyses of carbon, hydrogen and nitrogen con-
tents were performed using a Perkin Elmer CHN 2400. The molar

A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
5
range of 4000–400 cmꢀ1 for the free reactants and the resulted CT-
complexes were recorded from KBr discs using a Shimadzu FT-IR
Spectrometer with 30 scans and 2 cmꢀ1 resolution, while Raman
laser spectra of samples were measured on the Bruker FT-Raman
with laser 50 mW. 1HNMR was recorded as DMSO solutions on a
Bruker 600 MHz spectrometer using TMS as the internal standard.
DSC-TG thermograms of the HPL charge transfer complexes were
obtained on a NETZSCH STA 449F3. Samples in solid form were
placed in aluminum pans with a pierced lid, and heated rate of
15 °C minꢀ1 under a nitrogen flow. Scanning electron microscopy
(SEM) images and Energy Dispersive X-ray Detection (EDX) were
taken in Joel JSM-6390 equipment, with an accelerating voltage
of 20 kV. The X-ray diffraction patterns for both haloperidol com-
plexes were recorded on Bruker Advanced 8 X-ray powder diffrac-
alternatives because they are simpler and faster than broth meth-
ods [23,24].
3. Results and discussions
3.1. Analytical data and conductivity measurements
The molecular weights, molecular formula, conductance, yield,
color before and after precipitation as well as percentage of each
carbon, hydrogen and nitrogen contents of haloperidol charge
transfer complexes were listed in Table 1. The elemental analysis
technique support the stoichiomerty between HPL (donor) and
mentioned
p-acceptors (PA and TCNQ) is 1:1. The chelation pro-
cess occurs via AOH of 4-hydroxy-1-piperidyl moiety of haloperi-
dol drug toward accepting centers. Conductivity meter type
Jenway 4010 was used to measure conductivities of both charge
transfer complexes of HPL donor in DMSO with 1.0 ꢁ 10ꢀ3 mol/
dm3 concentration. The conductivities of the free reactants were
also measured at a similar condition in order to make comparison
between the free donor and acceptors with those of its charge
transfer complexes. The molar conductance of haloperidol CT-com-
plexes was reported in Table 1. The molar conductance values of
tion, target CuK radiation, step scan mode with step = 0.05° and
a
counting time 3.0 s/step.
2.4. Antibacterial and antifungal activities
Antimicrobial activity of the tested samples was determined
using a modified Kirby–Bauer disc diffusion method [17]. Briefly,
100
media until they reached a count of approximately108 cells/mL
for bacteria or 105 cells/mL for fungi [18]. 100 L of microbial sus-
lL of the best bacteria/fungi were grown in 10 mL of fresh
picric and TCNQ of HPL complexes have 45 and 53
X -
ꢀ1 cmꢀ1
molꢀ1, respectively. The conductance values indicate that the
charge transfer complexes have slightly electrolytic nature.
Slightly electrolytic complexes assigned to the formation of posi-
l
pension was spread onto agar plates corresponding to the broth in
which they were maintained. Isolated colonies of each organism
that might be playing a pathogenic role should be selected from
primary agar plates and tested for susceptibility by disc diffusion
method [19,20].
F
Of the many media available, National Committee for Clinical
Laboratory Standards (NCCLS) recommends Mueller–Hinton agar
due to: it results in good batch-to-batch reproducibility. Disc diffu-
sion method for filamentous fungi tested by using approved stan-
dard method (M38-A) developed by the NCCLS [21] for evaluating
the susceptibility of filamentous fungi to antifungal agents. Disc
diffusion method for yeast developed standard method (M44-P)
by the NCCLS [22]. Plates inoculated with filamentous fungi as
Aspergillus flavus at 25 °C for 48 h; Gram (+) bacteria as Staphylo-
coccus aureus, Bacillus subtilis; Gram (ꢀ) bacteria as Escherichia
coli, Pseudomonas aeruginosa they were incubated at 35–37 °C for
24–48 h and yeast as Candida albicans incubated at 30 °C for
24–48 h and, then the diameters of the inhabitation zones were
measured in millimeters [17]. Standard discs of Tetracycline (Anti-
bacterial agent), Amphotericin B (Antifungal agent) served as posi-
tive controls for antimicrobial activity but filter disc impregnated
N
Cl
O
H
O
H
O-
O
O
N+
N+
O-
O
N+
O-
O
with 10 lL of solvent (distilled water, chloroform, DMSO) were
used as a negative control.
Scheme 2. Suggested structure of [(HPL)(PA)] complex.
The agar used is Meuller–Hinton agar that is rigorously tested
for composition and pH. Further the depth of the agar in the plate
is a factor to be considered in the disc diffusion method. This meth-
od is well documented and standard zones of inhabitation have
been determined for susceptible values. Blank paper disks (Schlei-
cher & Schuell, Spain) with a diameter of 8.0 mm were impreg-
F
N
Cl
nated 10 lL of tested concentration of the stock solutions. When
a filter paper disc impregnated with a tested chemical is placed
on agar the chemical will diffuse from the disc into the agar. This
diffusion will place the chemical in the agar only around the disc.
The solubility of the chemical and its molecular size will determine
the size of the area of chemical infiltration around the disc. If an
organism is placed on the agar it will not grow in the area around
the disc if it is susceptible to the chemical. This area of no growth
around the disc is known as a ‘‘Zone of inhibition’’ or ‘‘Clear zone’’.
For the disc diffusion, the zone diameters were measured with slip-
ping calipers of the National for Clinical Laboratory Standers [19].
Agar-based methods such as Etest disk diffusion can be good
O
O
NH
C
NC
NC
CN
Scheme 3. Suggested structure of [(HPL)(TCNQ)] complex.

6
A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
Fig. 5. Raman laser spectra of (a) [(HPL)(PA)] and (b) [(HPL)(TCNQ)] charge transfer complexes.
tive and negative datives anions under the donor–acceptor chela-
tion [25].
HPL/TCNQ systems in CH3OH solvent. These concentrations pro-
duce HPL:acceptor (PA or TCNQ) ratios extending along the range
from 1:0.25 to 1:3.00. The electronic absorption spectra of the
1:1 ratios in methanol together with the reactants (PA and TCNQ)
are shown in Fig. 1a and b. The spectra reveal the characterization
of the real absorption bands which are not present in the spectra of
free reactants. These bands are assigned at 447 nm and (357, 418,
738 and 837 nm) due to the CT complexes formed in the reaction of
HPL with PA and TCNQ, respectively, in methanol solvent. Photo-
metric titration curves based on these characterized absorption
bands are given in Fig. 2a and b. These photometric titration curves
were obtained according to known methods [26] by the plot of the
3.2. Electronic spectra and physical data
The UV–vis spectra of PA and TCNQ of haloperidol charge-trans-
fer complexes were measured in CH3OH solvent. The CT complexes
are formed by adding X mL of 5.0 ꢁ 10ꢀ4 M (PA or TCNQ) where
(X = 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50 and 3.00 mL) to
1.00 mL of 5.0 ꢁ 10ꢀ4 M HPL. The total volume of each system
was completed to 5 mL with methanol solvent. The concentration
of HPL in the reaction mixture was kept fixed at 1.00 ꢁ 10ꢀ4 M in
CH3OH solvent, while the concentration of PA or TCNQ was varied
over the range of 0.25 ꢁ 10ꢀ4 M to 3.00 ꢁ 10ꢀ4 M for HPL/PA and
absorbance against the X mL added of the PA or TCNQ as
p-accep-
tors. The equivalence points shown in these curves clearly indicate

A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
7
Fig. 7. SEM images spectra of (a) [(HPL)(PA)] and (b) [(HPL)(TCNQ)] complexes.
CoaCodl
A
1
Coa þ Cod
¼
þ
ð1Þ
K
e
e
where Coa and Cod are the initial concentrations of the acceptors (PA
or TCNQ) and the donor HPL, respectively, K is a formation constant,
Fig. 6. Proton NMR spectra of (a) haloperidol free drug, (b) [(HPL)(PA)] complex,
and (c) [(HPL)(TCNQ)] complex.
e
is a molar extinction coefficient, and A is the absorbance of the
definite bands around 447 and 357 nm for HPL/PA and HPL/TCNQ
systems, respectively. The Cao ꢂ Cod=A values are plotted against the
corresponding Coa þ Cdo values, straight lines were obtained with a
that the formed CT complexes between HPL and PA or TCNQ are
1:1. It was of interest to observe that the solvent has a pronounced
effect on the spectral intensities of the formed [(HPL)(PA)] and
[(HPL)(TCNQ)] complexes. The 1:1 modified Benesi–Hildebrand
equation [27] was used in the calculations.
slope of 1/e and intercept of 1/ke as shown in Fig. 3a and b. The
oscillator strength f was obtained from the approximate formula gi-
ven in following equation [28]
f ¼ ð4:319 ꢁ 10ꢀ9
Þemax
ꢂ
m1=2
ð2Þ
Table 4
Assignments of the proton NMR spectral data (ppm) of HPL, [(HPL)(PA)], and [(HPL)(TCNQ)] charge transfer complexes.
Assignments
Shift (ppm)
A
B
C
D
E
F
G
J
K
L
M
N
HPL
PA
8.08
8.00
8.70
9.40
7.37
7.40
7.36
7.30
7.34
7.10
4.85
5.50
2.98
3.20
3.30
3.40
3.60
3.10
3.30
3.35
3.55
3.80
3.90
2.58
2.60
2.36
2.40
2.34
2.20
1.85
1.90
1.67
–
1.47
1.20
8.10
7.50
7.20
6.80
6.90
5.45
2.55
2.20
2.05
2.15
1.80
1.90
–
1.25
TCNQ

8
A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
001
free energy changes of complexation (
the association constants by following equation [36]
D
Go) were calculated from
2700
2400
2100
1800
1500
1200
900
a
D
Go ¼ ꢀ2:303RT log KCT
ð7Þ
where
D
Go is the free energy change of the complexes (kJ molꢀ1), R
is the gas constant (8.314 J molꢀ1 K), T is the temperature in Kelvin
degrees (273+ °C), and KCT is the association constant of the com-
plexes (l molꢀ1) in different solvents at room temperature, the val-
600
ues thus calculated are represented in Table 2. The data of
D
Go has a
300
negative value according to the higher values of formation constant,
and then the formation process of HPL charge transfer complexes is
exothermic feature reactions.
0
0.00
1.00
2.00
3.00
4.00
5.00
keV
6.00
7.00
8.00
9.00
10.00
002
b
3600
3200
2800
2400
2000
1600
1200
800
3.3. Infrared and Raman spectra
The Infrared spectra of the reactants HPL, PA, TCNQ and the
reaction products [(HPL)(PA)] and [(HPL)(TCNQ)] are presented in
Fig. 4. Their band assignments are given in Table 3. The resulted
charge transfer complexes produce from the interaction of HPL
with PA and TCNQ are containing the characteristic bands of the
HPL donor and acceptors (PA and TCNQ) with observed shift in
the frequencies (Table 3), as well as some change in their bands
intensities. This could be assigned to the expected symmetry and
electronic structure changes upon the formation of the CT-com-
plexes. The infrared interpretive for the formed CT-complexes are
concluded as follows; The infrared spectra of the donor as well
as the [(HPL)(PA)] formed CT complex is given in Fig. 4 and their
band assignments are reported in Table 3. However, the appear-
400
0
0.00
1.00
2.00
3.00
4.00
5.00
keV
6.00
7.00
8.00
9.00
10.00
Fig. 8. EDX spectra of (a) [(HPL)(PA)] and (b) [(HPL)(TCNQ)] complexes.
where m
1/2 is the band-width for half-intensity in cmꢀ1. The oscilla-
tor strength values together with the corresponding dielectric con-
stants, D, of the solvent used are given in Table 2. The trend of the
values in this table reveals two facts:
The [(HPL)(PA)] and [(HPL)(TCNQ)] shows high values of both
the equilibrium constant (K) and the extinction coefficient (e). This
high value of K reflects the high stability of the HPL complexes as a
result of the expected high donation of the HPL consequently high
value of
e
which is known to have a high absorptivity values
) of the HPL complexes
[29–31]. The transition dipole moment (
l
(Table 2) have been calculated from following equation [32]
1=2
l
¼ 0:0958½emaxm1=2
=
mmax
ꢃ
ð3Þ
where m1/2 is the bandwidth at half-maximum of absorbance, emax
and mmax are the extinction coefficient and wavenumber at maxi-
mum absorption peak of the CT complexes, respectively. The ioniza-
tion potential (Ip) of the free HPL donor was determined from the CT
energies of the CT band of its complexes with different p-acceptors
using the following relationships derived by Aloisi and Piganatro
[33,34].
ID ðeVÞ ¼ 5:76 þ 1:53 ꢁ 10ꢀ4mCT
ð4Þ
where ECT is the energy of the CT of the HPL complexes, the energy
of the
p
–
rꢄ, n–rꢄ pꢄ or n–pꢄ interaction (ECT) is calculated using
, p–
following equation [32]
ECT ðeVÞ ¼ ðhmCTÞ ¼ 1243:667=kCT ðnmÞ
ð5Þ
where kCT is the wavelength of the complexation band. Determina-
tion of resonance energy (RN), from Briegleb and Czekalla [35]
theoretically derived the relation given in following equation
emax ðl molꢀ1 cmꢀ1Þ ¼ 7:7 ꢁ 10ꢀ4=½h
mCT =½RNꢃ ꢀ 3:5ꢃ
ð6Þ
where
maximum CT absorption,
e
max is the molar extinction coefficient of the complex at the
CT is the frequency of the CT peak, and RN
m
is the resonance energy of the complex in the ground state, which
obviously is a contributing factor to the stability constant of the
complex (a ground state property). The values of RN for the PA
and TCNQ complexes under study are given in Table 2. The standard
Fig. 9. XRD powder diffraction spectra of (a) [(HPL)(PA)] and (b) [(HPL)(TCNQ)]
complexes.

A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
9
Fig. 10. TG/DTG and DSC curves of (a) [(HPL)(PA)] and (b) [(HPL)(TCNQ)] charge transfer complexes.
Table 5
Kinetic parameters of [(HPL)(PA)] and [(HPL)(TCNQ)] charge transfer complexes using the Coats–Redfern (CR) and Horowitz–Metzger (HM) equations.
Complex
DTGmax
Method
Parameter
r
E
A
D
S
D
H
DG
(J molꢀ1
)
(sꢀ1
)
(J molꢀ1 Kꢀ1
)
(J molꢀ1
)
(J molꢀ1)
PA
250
280
CR
HM
1.29 ꢁ 105
3.91 ꢁ 1010
ꢀ4.68 ꢁ 101
1.24 ꢁ 105
1.49 ꢁ 105
0.9041
0.9021
1.34 ꢁ 105
3.15 ꢁ 1011
ꢀ2.95 ꢁ 101
1.29 ꢁ 105
1.45 ꢁ 105
TCNQ
CR
HM
8.87 ꢁ 104
10.8 ꢁ 104
1.62 ꢁ 106
1.67 ꢁ 108
ꢀ1.31 ꢁ 102
ꢀ9.27 ꢁ 101
8.41 ꢁ 104
1.03 ꢁ 105
1.57 ꢁ 105
1.55 ꢁ 105
0.9967
0.9936
ance of a group of IR spectral bands in the spectrum of haloperidol
picric acid CT complex supports the conclusion that a deformation
of the electronic environment of haloperidol is occurred by accept-
ing a proton from AOH of PA acceptor. The IR spectrum of PA com-
plex is characterized by a group of bands appearing at 2774 and
2597 cmꢀ1, which are not appearing in the spectra of the free do-

10
A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
a
b
-12.0
-12.0
-12.5
-13.0
-13.5
-14.0
-14.5
-15.0
-15.5
-12.5
-13.0
-13.5
-14.0
-14.5
-15.0
-15.5
-16.0
CR
CR
-16.5
0.00180 0.00185 0.00190 0.00195 0.00200
1/T (K-1)
0.0017
0.0018
0.0019
1/T (K-1)
0.0020
0.0021
0.0
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.6
-1.8
HM
HM
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.6
-1.8
-2.0
-2.2
-20
-10
0
10
θ(K)
20
30
40
-80
-60
-40
-20
0
20
θ(K)
Fig. 11. Plots of Coats–Redfern (CR) and Horowitz–Metzger (HM) relations for (a) [(HPL)(PA)] and (b) [(HPL)(TCNQ)] charge transfer complexes.
nor and acceptors. These bands are attributed to the stretching
vibration of a proton attached to the donation site of the donor
[37]. These results caused by the intermolecular hydrogen bond
occur in PA acceptor from AOH group to the basic center oxygen
atom. The shift of the IR bands of the acceptor part to lower wave-
numbers and those of the donor part to higher values reflects a
Raman spectra of both [(HPL)(PA)] and [(HPL)(TCNQ)] com-
plexes were performed and recorded differentiation that the picric
acid complex has
a seven regions with wavenumbers data
3074 cmꢀ1 2949 cmꢀ1
,
, , (1594, 1560, 1489 and
1687 cmꢀ1
1436 cmꢀ1), (1362, 1332, 1296, 1206, 1184, and 1159 cmꢀ1),
(1083, 1040, 944, 907, 820, 739, and 708 cmꢀ1), and 631 cmꢀ1
donor to acceptor charge transfer of
p
–
pꢄ interaction, DHOMO
?
which assigned to
deformation), ( (CAC),
deformation, (CACl),
m
(OAH),
(CAN),
(CAF)) and (out-of-plane bend and
m
(CAH),
m(C@O), (m(C@C) and CAH
DLUMO transition [38]. Accordingly, the hydrogen bonding between
the donor and the acceptor, the suggested formula can be designed
as Scheme 2.
m
m
m
m(CAO), CH-in plane bend), (CH-
m
d(NO2). The blue shifted caused to the stretching vibration band
for AOH of HPL inside complexation led us to refer to the place
of charge transfer chelation via AOH of HPL and AOH of picric acid.
On the other hand, the spectrum of [(HPL)(TCNQ)] (Fig. 5b) has a
sharp broadening with distorted in the stretching vibration band
of cyano groups, this can be discussed under the knowledge that
Raman analysis of fluorescent materials and compounds is a chal-
lenging task experimentally due to the overlap of fluorescence
which, even when very weak, can overwhelm the inherently weak
Raman scattering signal [39,40].
Concerning of [(HPL)(TCNQ)] CT-complex, the IR spectrum of
the solid reaction product contains the characteristic bands for
both HPL (donor) and TCNQ (acceptor). The CN stretching of TCNQ
show a drastic shift to lower value. The distinguish stretching
vibration, m
(C„N), of the free TCNQ is observed at 2220 cmꢀ1 as
single peak, but in the case of [(HPL)(TCNQ)] charge transfer com-
plex, it means that after complexation, the two peaks at 2171 and
2112 cmꢀ1 values are detected and having a strong band intensi-
ties. This shift is indicative of higher charge density on the cyano
groups of TCNQ charge transfer complex. On the other hand, the
AOH stretching band of HPL was shifted to higher frequencies in
the spectrum of HPL/TCNQ complex. This is reasonable based on
the increasing polarity of the AꢀOACBNH+ band during complex-
ation. The interaction of TCNQ and haloperidol on the basis of
infrared spectra can be suggested as Scheme 3. The conductance
values at 1.0 ꢁ 10ꢀ3 molar concentrations indicated that these
complexes have a small limit of conductivity. The data of conduc-
tivity confirms that these complexes have a positive and negative
charge resulted from CT transition. The low conductivity values
for the two CT-complexes may be due to intermolecular hydrogen
bond formation.
3.4. 1HNMR spectra
The proton NMR spectra of the haloperidol free donor drug HPL
and their charge transfer complexes of picric acid and TCNQ (Fig. 6)
were recorded in DMSO-d6 solvent using tetramethylsilane (TMS)
as internal standard. The chemical shifts (d) of the different types
of protons of the ligand HPL and their charge transfer complexes
are listed in Table 4. In details the chemical shifts of different kinds
of protons in haloperidol drug can be justified in Fig. 6. The AOH
signal of 4-hydroxy-1-piperidyl moiety for proton in position hEi
(Fig. 6a) found at 4.85 ppm in the spectrum of the free haloperidol

A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
11
Table 6
The values of bond lengths and bond angles of HPL, [(HPL)(PA)] and [(HPL)(TCNQ)] charge transfer complexes.
Adducts
Bond length
Atoms
Bond angle
Atoms
Actual
Optimal
Actual
Optimal
HPL
C(1)AC(2)
C(1)AO(5)
C(1)AC(6)
C(2)AC(3)
1.509
1.208
1.517
1.523
1.113
1.113
1.523
1.113
1.113
1.438
1.113
1.113
1.42
1.42
1.42
1.1
1.42
1.1
1.42
1.32
1.42
1.509
1.208
1.517
1.523
1.113
1.113
1.523
1.113
1.113
1.438
1.113
1.113
1.42
1.42
1.42
1.1
1.42
1.1
1.42
1.32
1.42
C(2)AC(1)AO(5)
C(2)AC(1)AC(6)
O(5)AC(1)AC(6)
C(1)AC(2)AC(3)
122.331
114.835
122.832
109.998
108.8
122.5
115
123
110
C(2)AH(44)
C(2)AH(45)
C(3)AC(4)
C(3)AH(42)
C(3)AH(43)
C(4)AN(13)
C(4)AH(40)
C(4)AH(41)
C(6)AC(7)
C(6)AC(11)
C(7)AC(8)
C(7)AH(49)
C(8)AC(9)
C(1)AC(2)AH(44)
C(1)AC(2)AH(45)
C(3)AC(2)AH(44)
C(3)AC(2)AH(45)
H(44)AC(2)AH(45)
C(2)AC(3)AC(4)
C(2)AC(3)AH(42)
C(2)AC(3)AH(43)
C(4)AC(3)AH(42)
C(4)AC(3)AH(43)
H(42)AC(3)AH(43)
C(3)AC(4)AN(13)
C(3)AC(4)AH(40)
C(3)AC(4)AH(41)
N(13)AC(4)AH(40)
N(13)AC(4)AH(41)
H(40)AC(4)AH(41)
C(1)AC(6)AC(7)
C(1)AC(6)AC(11)
C(7)AC(6)AC(11)
C(6)AC(7)AC(8)
C(6)AC(7)AH(49)
C(8)AC(7)AH(49)
C(7)AC(8)AC(9)
C(7)AC(8)AH(46)
C(9)AC(8)AH(46)
C(8)AC(9)AC(10)
C(8)AC(9)AF(12)
C(10)AC(9)AF(12)
C(9)AC(10)AC(11)
C(9)AC(10)AH(47)
C(11)AC(10)AH(47)
C(6)AC(11)AC(10)
C(6)AC(11)AH(48)
C(10)AC(11)AH(48)
C(4)AN(13)AC(14)
C(4)AN(13)AC(18)
C(14)AN(13)AC(18)
N(13)AC(14)AC(15)
N(13)AC(14)AH(38)
N(13)AC(14)AH(39)
C(15)AC(14)AH(38)
C(15)AC(14)AH(39)
H(38)AC(14)AH(39)
C(14)AC(15)AC(16)
C(14)AC(15)AH(34)
C(14)AC(15)AH(35)
C(16)AC(15)AH(34)
C(16)AC(15)AH(35)
H(34)AC(15)AH(35)
C(15)AC(16)AC(17)
C(15)AC(16)AO(19)
C(15)AC(16)AC(21)
C(17)AC(16)AO(19)
C(17)AC(16)AC(21)
O(19)AC(16)AC(21)
C(16)AC(17)AC(18)
C(16)AC(17)AH(32)
C(16)AC(17)AH(33)
C(18)AC(17)AH(32)
C(18)AC(17)AH(33)
H(32)AC(17)AH(33)
N(13)AC(18)AC(17)
N(13)AC(18)AH(36)
N(13)AC(18)AH(37)
C(17)AC(18)AH(36)
C(17)AC(18)AH(37)
H(36)AC(18)AH(37)
C(16)AO(19)AH(20)
108.8
108.8
109.41
109.41
108.8
109.409
109.409
109.4
109.5
109.5
109.409
109.409
109.411
109.409
109.4
109.41
109.41
109.41
109.41
109.5
109.5
109.41
109.41
109.409
109.409
108.8
108.8
109.4
117.599
117.601
120
C(8)AH(46)
C(9)AC(10)
C(9)AF(12)
C(10)AC(11)
C(10)AH(47)
C(11)AH(48)
N(13)AC(14)
N(13)AC(18)
C(14)AC(15)
C(14)AH(38)
C(14)AH(39)
C(15)AC(16)
C(15)AH(34)
C(15)AH(35)
C(16)AC(17)
C(16)AO(19)
C(16)AC(21)
C(17)AC(18)
C(17)AH(32)
C(17)AH(33)
C(18)AH(36)
C(18)AH(37)
O(19)AH(20)
C(21)AC(22)
C(21)AC(26)
C(22)AC(23)
C(22)AH(31)
C(23)AC(24)
C(23)AH(28)
C(24)AC(25)
C(24)ACl(27)
C(25)AC(26)
C(25)AH(29)
C(26)AH(30)
1.1
1.1
1.1
1.1
117.6
117.6
120
120
120
120
120
120
120
120
121
121
120
1.438
1.438
1.523
1.113
1.113
1.514
1.113
1.113
1.514
1.421
1.497
1.524
1.113
1.113
1.113
1.113
0.942
1.42
1.42
1.42
1.1
1.42
1.1
1.42
1.719
1.42
1.1
1.438
1.438
1.523
1.113
1.113
1.514
1.113
1.113
1.514
1.421
1.497
1.523
1.113
1.113
1.113
1.113
0.942
1.42
1.42
1.42
1.1
1.42
1.1
1.42
1.719
1.42
1.1
120
119.998
119.998
120
119.998
119.998
120.001
119.998
119.998
120
120
120
120
120
120
119.998
119.998
107.701
107.701
107.701
109.5
107.7
107.7
107.7
109.5
108.8
108.8
109.41
109.41
109.4
109.5
109.41
109.41
109.41
109.41
109.4
109.47
107.5
109.47
107.5
109.47
109.5
109.5
109.41
109.41
109.41
109.41
109.4
109.5
108.8
108.8
109.41
109.41
109.4
106.9
108.8
108.8
109.411
109.411
110.899
109.5
109.409
109.409
109.411
109.409
109.689
109.47
107.5
1.1
1.1
109.47
107.5
109.47
113.35
109.717
109.409
109.411
109.409
109.411
109.468
109.426
108.8
108.799
109.409
109.411
110.97
106.9
(continued on next page)

12
A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
Table 6 (continued)
Adducts
Bond length
Atoms
Bond angle
Actual
Optimal
Atoms
Actual
Optimal
C(16)AC(21)AC(22)
C(16)AC(21)AC(26)
C(22)AC(21)AC(26)
C(21)AC(22)AC(23)
C(21)AC(22)AH(31)
C(23)AC(22)AH(31)
C(22)AC(23)AC(24)
C(22)AC(23)AH(28)
C(24)AC(23)AH(28)
C(23)AC(24)AC(25)
C(23)AC(24)ACl(27)
C(25)AC(24)ACl(27)
C(24)AC(25)AC(26)
C(24)AC(25)AH(29)
C(26)AC(25)AH(29)
C(21)AC(26)AC(25)
C(21)AC(26)AH(30)
C(25)AC(26)AH(30)
119.998
119.998
119.998
120
119.998
120
121.4
121.4
120
120
120
120
120
120
120
120
119.998
119.998
120
119.998
119.998
120
119.998
119.998
120
119.998
120
120
118.8
118.8
120
120
120
120
120
120
PA
C(1)AC(2)
C(1)AO(5)
C(1)AC(6)
C(2)AC(3)
1.509
1.208
1.517
1.523
1.113
1.113
1.523
1.113
1.113
1.438
1.113
1.113
1.42
1.42
1.42
1.1
1.42
1.1
1.42
1.32
1.42
1.509
1.208
1.517
1.523
1.113
1.113
1.523
1.113
1.113
1.438
1.113
1.113
1.42
1.42
1.42
1.1
1.42
1.1
1.42
1.32
1.42
C(2)AC(1)AO(5)
C(2)AC(1)AC(6)
O(5)AC(1)AC(6)
C(1)AC(2)AC(3)
122.332
114.833
122.832
109.998
108.8
122.5
115
123
110
C(2)AH(51)
C(2)AH(52)
C(3)AC(4)
C(3)AH(53)
C(3)AH(54)
C(4)AN(13)
C(4)AH(55)
C(4)AH(56)
C(6)AC(7)
C(6)AC(11)
C(7)AC(8)
C(7)AH(50)
C(8)AC(9)
C(1)AC(2)AH(51)
C(1)AC(2)AH(52)
C(3)AC(2)AH(51)
C(3)AC(2)AH(52)
H(51)AC(2)AH(52)
C(2)AC(3)AC(4)
C(2)AC(3)AH(53)
C(2)AC(3)AH(54)
C(4)AC(3)AH(53)
C(4)AC(3)AH(54)
H(53)AC(3)AH(54)
C(3)AC(4)AN(13)
C(3)AC(4)AH(55)
C(3)AC(4)AH(56)
N(13)AC(4)AH(55)
N(13)AC(4)AH(56)
H(55)AC(4)AH(56)
C(1)AC(6)AC(7)
108.8
108.8
109.41
109.41
109.4
109.5
109.41
109.41
109.41
109.41
109.4
109.5
109.41
109.41
108.8
108.8
109.4
117.6
117.6
120
120
120
120
120
120
120
120
121
121
120
120
120
120
120
120
107.7
107.7
107.7
109.5
108.8
108.8
109.41
109.41
109.4
109.5
109.41
109.41
109.41
109.41
109.4
109.47
108.8
109.411
109.409
110.409
109.5
109.409
109.409
109.409
109.409
109.689
109.5
109.411
109.411
108.8
108.8
110.9
C(8)AH(48)
C(9)AC(10)
C(9)AF(12)
C(10)AC(11)
C(10)AH(47)
C(11)AH(49)
N(13)AC(14)
N(13)AC(18)
C(14)AC(15)
C(14)AH(59)
C(14)AH(60)
C(15)AC(16)
C(15)AH(67)
C(15)AH(68)
C(16)AC(17)
C(16)AO(19)
C(16)AC(20)
C(17)AC(18)
C(17)AH(65)
C(17)AH(66)
C(18)AH(57)
C(18)AH(58)
O(19)AH(43)
O(19)AH(44)
C(20)AC(21)
C(20)AC(25)
C(21)AC(22)
C(21)AH(64)
C(22)AC(23)
C(22)AH(62)
C(23)AC(24)
C(23)ACl(26)
C(24)AC(25)
C(24)AH(61)
C(25)AH(63)
O(27)AC(28)
O(27)AH(44)
C(28)AC(29)
1.1
1.1
1.1
1.1
120
C(1)AC(6)AC(11)
C(7)AC(6)AC(11)
C(6)AC(7)AC(8)
C(6)AC(7)AH(50)
C(8)AC(7)AH(50)
C(7)AC(8)AC(9)
119.998
119.998
120
119.998
120
120.001
119.998
119.998
120.001
119.998
119.998
119.998
119.998
119.998
119.998
119.998
120
107.701
107.701
107.701
109.5
108.8
108.8
109.409
109.411
110.902
109.5
109.409
109.411
109.409
109.409
109.689
109.47
1.438
1.438
1.523
1.113
1.113
1.523
1.113
1.113
1.523
1.402
1.497
1.525
1.113
1.113
1.113
1.113
0.992
0.992
1.42
1.42
1.42
1.1
1.42
1.1
1.42
1.719
1.42
1.1
1.438
1.438
1.523
1.113
1.113
1.523
1.113
1.113
1.523
1.402
1.497
1.523
1.113
1.113
1.113
1.113
0.992
C(7)AC(8)AH(48)
C(9)AC(8)AH(48)
C(8)AC(9)AC(10)
C(8)AC(9)AF(12)
C(10)AC(9)AF(12)
C(9)AC(10)AC(11)
C(9)AC(10)AH(47)
C(11)AC(10)AH(47)
C(6)AC(11)AC(10)
C(6)AC(11)AH(49)
C(10)AC(11)AH(49)
C(4)AN(13)AC(14)
C(4)AN(13)AC(18)
C(14)AN(13)AC(18)
N(13)AC(14)AC(15)
N(13)AC(14)AH(59)
N(13)AC(14)AH(60)
C(15)AC(14)AH(59)
C(15)AC(14)AH(60)
H(59)AC(14)AH(60)
C(14)AC(15)AC(16)
C(14)AC(15)AH(67)
C(14)AC(15)AH(68)
C(16)AC(15)AH(67)
C(16)AC(15)AH(68)
H(67)AC(15)AH(68)
C(15)AC(16)AC(17)
1.42
1.42
1.42
1.1
1.42
1.1
1.42
1.719
1.42
1.1
1.1
1.41
0.992
1.42
1.1
1.42

A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
13
Table 6 (continued)
Adducts
Bond length
Atoms
Bond angle
Actual
Optimal
Atoms
Actual
Optimal
C(28)AC(39)
C(29)AN(30)
C(29)AC(33)
N(30)AO(31)
N(30)AO(32)
C(33)AC(34)
C(33)AH(46)
C(34)AN(35)
C(34)AC(38)
N(35)AO(36)
N(35)AO(37)
C(38)AC(39)
C(38)AH(45)
C(39)AN(40)
N(40)AO(41)
N(40)AO(42)
1.42
1.496
1.42
1.316
1.143
1.42
1.1
1.496
1.42
1.316
1.143
1.42
1.42
1.496
1.42
C(15)AC(16)AO(19)
C(15)AC(16)AC(20)
C(17)AC(16)AO(19)
C(17)AC(16)AC(20)
O(19)AC(16)AC(20)
C(16)AC(17)AC(18)
C(16)AC(17)AH(65)
C(16)AC(17)AH(66)
C(18)AC(17)AH(65)
C(18)AC(17)AH(66)
H(65)AC(17)AH(66)
N(13)AC(18)AC(17)
N(13)AC(18)AH(57)
N(13)AC(18)AH(58)
C(17)AC(18)AH(57)
C(17)AC(18)AH(58)
H(57)AC(18)AH(58)
C(16)AO(19)AH(43)
C(16)AO(19)AH(44)
H(43)AO(19)AH(44)
C(16)AC(20)AC(21)
C(16)AC(20)AC(25)
C(21)AC(20)AC(25)
C(20)AC(21)AC(22)
C(20)AC(21)AH(64)
C(22)AC(21)AH(64)
C(21)AC(22)AC(23)
C(21)AC(22)AH(62)
C(23)AC(22)AH(62)
C(22)AC(23)AC(24)
C(22)AC(23)ACl(26)
C(24)AC(23)ACl(26)
C(23)AC(24)AC(25)
C(23)AC(24)AH(61)
C(25)AC(24)AH(61)
C(20)AC(25)AC(24)
C(20)AC(25)AH(63)
C(24)AC(25)AH(63)
C(28)AO(27)AH(44)
O(27)AC(28)AC(29)
O(27)AC(28)AC(39)
C(29)AC(28)AC(39)
C(28)AC(29)AN(30)
C(28)AC(29)AC(33)
N(30)AC(29)AC(33)
C(29)AN(30)AO(31)
C(29)AN(30)AO(32)
O(31)AN(30)AO(32)
C(29)AC(33)AC(34)
C(29)AC(33)AH(46)
C(34)AC(33)AH(46)
C(33)AC(34)AN(35)
C(33)AC(34)AC(38)
N(35)AC(34)AC(38)
C(34)AN(35)AO(36)
C(34)AN(35)AO(37)
O(36)AN(35)AO(37)
C(34)AC(38)AC(39)
C(34)AC(38)AH(45)
C(39)AC(38)AH(45)
C(28)AC(39)AC(38)
C(28)AC(39)AN(40)
C(38)AC(39)AN(40)
C(39)AN(40)AO(41)
C(39)AN(40)AO(42)
O(41)AN(40)AO(42)
O(19)AH(44)AO(27)
109.47
109.47
109.47
109.474
109.472
109.666
109.409
109.409
109.409
109.409
109.521
109.426
108.799
108.8
109.411
109.409
110.972
106.999
109.47
109.47
120
119.998
119.998
120
119.998
119.998
120
119.998
119.998
120.001
119.998
119.998
119.998
120
119.998
120
119.998
119.998
109.47
120
119.998
119.998
119.998
120
119.998
119.998
120
119.998
120.001
119.998
119.998
119.998
120.001
119.998
119.998
119.998
119.998
119.998
120
109.47
109.47
1.42
1.1
1.496
1.42
109.5
109.41
109.41
109.41
109.41
109.4
109.5
108.8
108.8
109.41
109.41
109.4
107
1.42
1.1
1.496
1.1
1.496
1.316
1.143
121.4
121.4
120
120
120
120
120
120
120
120
118.8
118.8
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
119.998
120
119.998
119.998
119.998
119.998
119.998
109.472
TCNQ
C(1)AC(2)
C(1)AC(6)
C(1)AH(69)
C(2)AC(3)
C(2)AH(60)
C(3)AC(4)
1.337
1.503
1.1
1.503
1.1
1.337
1.503
1.1
1.503
1.1
C(2)AC(1)AC(6)
C(2)AC(1)AH(69)
C(6)AC(1)AH(69)
C(1)AC(2)AC(3)
C(1)AC(2)AH(60)
C(3)AC(2)AH(60)
120.001
119.998
119.998
120
120
119.998
120
120
120
120
120
120
1.42
1.503
(continued on next page)

14
A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
Table 6 (continued)
Adducts
Bond length
Atoms
Bond angle
Actual
Optimal
Atoms
Actual
Optimal
C(3)AC(7)
C(4)AC(5)
C(4)AH(59)
C(5)AC(6)
C(5)AH(68)
C(6)AC(8)
C(7)AC(12)
C(7)AC(14)
C(8)AC(9)
C(8)AC(10)
1.337
1.42
1.1
1.42
1.1
1.337
1.42
1.1
1.42
1.1
1.503
1.469
1.469
1.313
1.469
C(2)AC(3)AC(4)
C(2)AC(3)AC(7)
C(4)AC(3)AC(7)
C(3)AC(4)AC(5)
C(3)AC(4)AH(59)
C(5)AC(4)AH(59)
C(4)AC(5)AC(6)
C(4)AC(5)AH(68)
C(6)AC(5)AH(68)
C(1)AC(6)AC(5)
C(1)AC(6)AC(8)
C(5)AC(6)AC(8)
C(3)AC(7)AC(12)
C(3)AC(7)AC(14)
C(12)AC(7)AC(14)
C(6)AC(8)AC(9)
C(6)AC(8)AC(10)
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
119.998
119.998
120.001
119.998
119.998
120
1.503
1.469
1.469
1.313
1.469
1.446
1.158
1.158
1.158
1.316
1.02
1.509
1.208
1.517
1.523
1.113
1.113
1.523
1.113
1.113
1.438
1.113
1.113
1.42
120
119.998
119.998
120
C(9)AN(16)
C(10)AN(11)
C(12)AN(13)
C(14)AN(15)
N(16)AO(36)
N(16)AH(17)
C(18)AC(19)
C(18)AO(22)
C(18)AC(23)
C(19)AC(20)
C(19)AH(48)
C(19)AH(49)
C(20)AC(21)
C(20)AH(50)
C(20)AH(51)
C(21)AN(30)
C(21)AH(52)
C(21)AH(53)
C(23)AC(24)
C(23)AC(28)
C(24)AC(25)
C(24)AH(47)
C(25)AC(26)
C(25)AH(44)
C(26)AC(27)
C(26)AF(29)
C(27)AC(28)
C(27)AH(45)
C(28)AH(46)
N(30)AC(31)
N(30)AC(35)
C(31)AC(32)
C(31)AH(56)
C(31)AH(57)
C(32)AC(33)
C(32)AH(66)
C(32)AH(67)
C(33)AC(34)
C(33)AO(36)
C(33)AC(37)
C(34)AC(35)
C(34)AH(64)
C(34)AH(65)
C(35)AH(54)
C(35)AH(55)
C(37)AC(38)
C(37)AC(42)
C(38)AC(39)
C(38)AH(63)
C(39)AC(40)
C(39)AH(58)
C(40)AC(41)
C(40)ACl(43)
C(41)AC(42)
C(41)AH(61)
C(42)AH(62)
1.158
1.158
1.158
119.998
119.998
119.998
119.998
119.998
119.998
119.998
179.684
180
1.02
1.509
1.208
1.517
1.523
1.113
1.113
1.523
1.113
1.113
1.438
1.113
1.113
1.42
1.42
1.42
1.1
1.42
1.1
1.42
1.32
1.42
C(9)AC(8)AC(10)
C(8)AC(9)AN(16)
C(8)AC(10)AN(11)
C(7)AC(12)AN(13)
C(7)AC(14)AN(15)
C(9)AN(16)AO(36)
C(9)AN(16)AH(17)
H(17)AN(16)AO(36)
C(19)AC(18)AO(22)
C(19)AC(18)AC(23)
O(22)AC(18)AC(23)
C(18)AC(19)AC(20)
C(18)AC(19)AH(48)
C(18)AC(19)AH(49)
C(20)AC(19)AH(48)
C(20)AC(19)AH(49)
H(48)AC(19)AH(49)
C(19)AC(20)AC(21)
C(19)AC(20)AH(50)
C(19)AC(20)AH(51)
C(21)AC(20)AH(50)
C(21)AC(20)AH(51)
H(50)AC(20)AH(51)
C(20)AC(21)AN(30)
C(20)AC(21)AH(52)
C(20)AC(21)AH(53)
N(30)AC(21)AH(52)
N(30)AC(21)AH(53)
H(52)AC(21)AH(53)
C(18)AC(23)AC(24)
C(18)AC(23)AC(28)
C(24)AC(23)AC(28)
C(23)AC(24)AC(25)
C(23)AC(24)AH(47)
C(25)AC(24)AH(47)
C(24)AC(25)AC(26)
C(24)AC(25)AH(44)
C(26)AC(25)AH(44)
C(25)AC(26)AC(27)
C(25)AC(26)AF(29)
C(27)AC(26)AF(29)
C(26)AC(27)AC(28)
C(26)AC(27)AH(45)
C(28)AC(27)AH(45)
C(23)AC(28)AC(27)
C(23)AC(28)AH(46)
C(27)AC(28)AH(46)
C(21)AN(30)AC(31)
C(21)AN(30)AC(35)
C(31)AN(30)AC(35)
N(30)AC(31)AC(32)
N(30)AC(31)AH(56)
N(30)AC(31)AH(57)
C(32)AC(31)AH(56)
C(32)AC(31)AH(57)
H(56)AC(31)AH(57)
C(31)AC(32)AC(33)
180
180
180
179.684
180
109.47
109.47
109.468
122.332
114.833
122.832
110
122.5
115
123
110
1.42
1.42
1.1
1.42
1.1
1.42
1.32
1.42
108.8
108.8
108.8
108.8
109.41
109.41
109.4
109.5
109.41
109.41
109.41
109.41
109.4
109.5
109.41
109.41
108.8
108.8
109.4
117.6
117.6
120
120
120
120
120
120
120
120
121
121
120
120
120
120
120
120
109.409
109.407
110.409
109.5
109.409
109.409
109.409
109.411
109.689
109.5
109.411
109.412
108.799
108.799
110.899
119.998
119.998
120
1.1
1.1
1.1
1.1
1.438
1.438
1.523
1.113
1.113
1.523
1.113
1.113
1.523
1.41
1.497
1.523
1.113
1.113
1.113
1.113
1.42
1.42
1.42
1.1
1.42
1.1
1.42
1.719
1.42
1.1
1.438
1.438
1.523
1.113
1.113
1.523
1.113
1.113
1.523
1.497
1.523
1.113
1.113
1.113
1.113
1.42
1.42
1.42
1.1
1.42
1.1
1.42
1.719
1.42
1.1
120
119.998
120
120.001
119.998
120
120.001
119.998
119.998
119.998
120
119.998
120
119.998
119.998
107.702
107.701
107.699
109.502
108.799
108.8
107.7
107.7
107.7
109.5
108.8
108.8
109.41
109.41
109.4
109.5
1.1
1.1
109.409
109.409
110.9
109.5

A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
15
Table 6 (continued)
Adducts
Bond length
Atoms
Bond angle
Actual
Optimal
Atoms
Actual
Optimal
C(31)AC(32)AH(66)
C(31)AC(32)AH(67)
C(33)AC(32)AH(66)
C(33)AC(32)AH(67)
H(66)AC(32)AH(67)
C(32)AC(33)AC(34)
C(32)AC(33)AO(36)
C(32)AC(33)AC(37)
C(34)AC(33)AO(36)
C(34)AC(33)AC(37)
O(36)AC(33)AC(37)
C(33)AC(34)AC(35)
C(33)AC(34)AH(64)
C(33)AC(34)AH(65)
C(35)AC(34)AH(64)
C(35)AC(34)AH(65)
H(64)AC(34)AH(65)
N(30)AC(35)AC(34)
N(30)AC(35)AH(54)
N(30)AC(35)AH(55)
C(34)AC(35)AH(54)
C(34)AC(35)AH(55)
H(54)AC(35)AH(55)
N(16)AO(36)AC(33)
C(33)AC(37)AC(38)
C(33)AC(37)AC(42)
C(38)AC(37)AC(42)
C(37)AC(38)AC(39)
C(37)AC(38)AH(63)
C(39)AC(38)AH(63)
C(38)AC(39)AC(40)
C(38)AC(39)AH(58)
C(40)AC(39)AH(58)
C(39)AC(40)AC(41)
C(39)AC(40)ACl(43)
C(41)AC(40)ACl(43)
C(40)AC(41)AC(42)
C(40)AC(41)AH(61)
C(42)AC(41)AH(61)
C(37)AC(42)AC(41)
C(37)AC(42)AH(62)
C(41)AC(42)AH(62)
109.409
109.412
109.409
109.409
109.687
109.47
109.47
109.47
109.47
109.474
109.47
109.498
109.409
109.411
109.409
109.409
109.69
109.507
108.8
108.799
109.409
109.409
110.895
109.472
120
119.998
119.998
120.001
119.998
120
109.41
109.41
109.41
109.41
109.4
109.47
109.47
109.47
109.5
109.41
109.41
109.41
109.41
109.4
109.5
108.8
108.8
109.41
109.41
109.4
121.4
121.4
120
120
120
120
120
120
120
120
119.998
119.998
120.001
119.998
119.998
120.001
119.998
119.998
120
120
118.8
118.8
120
120
120
120
120
120
119.998
120
donor is completely downfield in the spectra of both PA and TCNQ
complexes, this support the sharing of the AOH group of (HPL) in
charge transfer chelation with AOH for (PA) and ACN for (TCNQ)
of acceptors via intermolecular hydrogen bond. In case of
[(HPL)(PA)] complex the proton NMR spectrum showed signal at
9.40 ppm is actually shifted downfield due to the involvement of
AOH proton (picric acid) towards the AOH proton of 4-hydroxy-
1-piperidyl moiety.
phologies in the form of a dispersed with particle size 20 lm is
exhibited in Fig. 7b. X-ray powder patterns of both representative
haloperidol charge transfer complexes have given in Fig. 9a and b
along with the prominent data. The peaks at 2h = 14° and 16° are
more target for the calculation of particle size, under Debye–Scher-
rer equation [41] using reflection from the XRD pattern. Debye–
Scherrer equation is given by D = 0.94k/bCosh, where D is size of
the particles, k is the wavelength of X-ray, b is the full width at half
maximum (FWHM), and h is the angle of the particles has been
found to be 60 or 30 nm, respectively, for PA or TCNQ haloperidol
charge transfer complexes.
3.5. Scanning electron microscopy, EDX, and XRD studies
Microstructure and morphology of the synthesized charge
transfer complexes were analyzed by electronic microscopy SEM,
EDX and XRD, the recorded images and diffractometry are shown
in Fig. 7–9, respectively. The electron micrograph shows that mor-
phology of the different haloperidol charge transfer complexes de-
pend on the acceptor present, due to the different chemical
structure of the adducts produced. The EDX spectra (Fig. 8a and
b) corroborates the presence of carbon, oxygen, halogens (chlorine
and fluorine) in the haloperidol adducts. The uniformity and simi-
larity between the particles forms of synthesized haloperidol
charge transfer complexes indicate that the existence of morpho-
logical phases of picric acid and TCNQ complexes have a homoge-
neous matrix. A spherical ball particles shape (Fig. 7a) is observed
3.6. Thermal and kinetic thermodynamic assessments
The data respected to the thermal decomposition of the syn-
thetic haloperidol charge transfer complexes are discussed as it
follows.
3.6.1. Thermal decomposition of [(HPL)(PA)] complex
The TG/DTG and DSC curves corresponding to the picric acid
complex heated in the 30–1200 °C temperature range are exhib-
ited in Fig. 10a. The thermal decomposition of [(HPL)(PA)] complex
has only one very strong peak recorded in both DTG and DSC
curves. This step is endothermic and assigned to the loss of organic
moiety (C7H26N4O9ClF) with weight loss 60%.
in case of the [(HPL)(PA)] with the particle size 5.0
lm. A homoge-
neous phase formation of [(HPL)(TCNQ)] complex has crack mor-

16
A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
Cl(27)
C(25)
C(24)
C(26)
H(20)
C(23)
O(19)
C(21)
O(5)
C(22)
C(16)
C(11)
C(1)
C(17)
C(15)
C(10)
C(9)
C(6)
C(7)
C(2)
C(18)
C(14)
C(3)
N(13)
C(4)
F(12)
C(8)
Fig. 12a. Optimized structure of haloperidol drug.
steps at 150, 280, and 450 °C, first one is exothermic due to starting
of melting points and decomposition, but the second and third
endothermic process assigned to the completely decomposition
of donor and acceptors with weight loss 68%.
In literature [42–44] there has been increasing interest in deter-
mining the rate-dependent parameters of solid-state non-isother-
mal decomposition reactions by analysis of TG curves. Several
equations [42–44] have been proposed as means of analyzing a
TG curve and obtaining values for kinetic parameters. Two major
different methods (Horowitz and Metzger (HM) approximation
method [43] and Coats and Redfern (CR) integral method [44])
are used for the evaluation of kinetic parameters. The enthalpy of
F(12)
C(9)
C(8)
C(7)
C(10)
C(11)
C(6)
C(1)
O(5)
Cl(26)
activation,
culated via following equation
D
H, and the free enthalpy of activation,
D
G, can be cal-
C(24)
D
H ¼ E ꢀ RTm; G ¼ H ꢀ TmD
D
D
S
ð8Þ
C(22)
C(21)
The kinetic parameters were evaluated using two of the above-
C(20)
mentioned methods by graphical means and are listed in Table 5.
The satisfactory values of correlation coefficients (ꢅ1) in all cases
indicates good agreement with experimented data and the values
of kinetic parameters are reasonable and in good agreement. The
calculated of activation energy
D
E⁄ values using Coats–Redfern
O(19)
and Horowitz–Metzger methods for the main decomposition stage
of both haloperidol charge transfer complexes are found to be the
average of Eꢄ[(HPL)(PA)] = 132 kJ molꢀ1 > Eꢄ[(HPL)(TCNQ)] = 98 kJ
molꢀ1 which is in accordance with type of acceptors. The negative
O(42)
O(27)
O(31)
N(30)
O(32)
N(40)
values of
D
Sꢄ (Table 5) indicate that the reaction rates are slower
C(28)
than normal [45]. Furthermore, these data indicate that the acti-
vated complexes have more ordered structure than the reactants
(see Fig 11).
C(38)
C(33)
3.7. Molecular modeling studies
O(37
Molecular modeling had been successfully used to detect three
dimensional arrangements of atoms in free haloperidol drug and
their charge transfer complexes. The bond lengths and bond angles
values of the chelation complexes were summarized and refereed
in Table 6 and Figs. 12a–c. This calculation for [(HPL)(PA)] and
[(HPL)(TCNQ)] complexes were obtained by using the commercial
available molecular modeling software Chem Office Ultra-7. These
statistical data have a good agreement with formula 2 and 3 con-
Fig. 12b. Optimized structure of [(HPL)(PA)] charge transfer complex.
3.6.2. Thermal decomposition of [(HPL)(TCNQ)] complex
Thermal analysis for [(HPL)(TCNQ)] complex has confirmed the
thermal stability and the number of degradation steps upon to the
DSC and DTG maximum peaks. According to TG and DSC curves
(Fig. 10b) profiles this step comprises at least three decomposition

A.A. El-Habeeb et al. / Journal of Molecular Structure 1034 (2013) 1–18
17
Cl(43)
H(44)
F(29
H(47)
C(40)
H(58)
H(61)
C(39)
C(38)
C(41)
C(42)
C(19)
H(50)
C(37)
C(33)
H(51)
H(54)
C(35)
C(21)
H(52)
H(65)
H(55)
N(16)
H(64)
C(9)
C(8)
H(69)
C(1)
C(5)
C(3)
H(60)
N(13)
C(14)
Fig. 12c. Optimized structure of [(HPL)(TCNQ)] charge transfer complex.
displayed a degree of antimicrobial activities greater than free hal-
operidol drug donor against all organisms tested. The most reasons
for lethal action of tested PA and TCNQ as well as similar charge
transfer complexes reported in literature survey may be due to
their interactions with critical interacellular sites causing the death
of cells [46–49]. The variety of antimicrobial activities of tested
compounds may due to a different degree of tested compounds
penetration through cell membrane structure of target organism.
In conclusion, the interaction between the HPL and
p-acceptors
in nano-structural form resulting developing of the effectiveness
of biological characters of free drug.
4. Conclusion
The interactions between the electron donor haloperidol drug
and the acceptors picric acid (PA) and 7,70,8,80-tetracyanoquinodi-
methane (TCNQ) were studied spectrophotometrically in methanol.
New charge-transfer complexes were isolated and characterized
through elemental analysis, (infrared, HNMR, electronic, and XRD
spectra) as well as thermal and kinetic thermodynamic studies.
The stoichiometry of the products was found to be 1:1 in all cases.
Accordingly, the formed CT-complexes have the formulas [(HPL)
(PA)] and [(HPL)(TCNQ)].
Fig. 13. Inhibition zone diameter of HPL, [(HPL)(PA)] and [(HPL)(TCNQ)] charge
transfer complex.
firmed the presence of intermolecular hydrogen bonding between
AOH of 4-hydroxy-1-piperidyl (drug donor) towards AOH of picric
acid and one cyano group of TCNQ acceptors.
Acknowledgement
3.8. Biological activity studies
This work was supported by grants from Princess Nora Bint
Abdul Rahman University, Riyadh, Saudi Arabia under project
Grants No. 25/32.
The biological assessment were studied in term antimicrobial
activities of free haloperidol drug and their charge transfer com-
plexes against gram-positive ( B. subtilis and S. aureus) and
gram-negative (E. coli and P. aeruginosa) and two strains of fungus
(A. flavus and C. albicans). Result from the agar disc diffusion tests
for antimicrobial activities of respective compounds are shown in
Fig. 13. All tested compounds displayed a different degree of anti-
microbial effect and both haloperidol charge transfer complexes
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