A theoretical study of the structural and electronic properties of trans and cis structures of chlorprothixene as a nano-drug

Accepted Manuscript A theoretical study of the structural and electronic properties of trans and cis structures of chlorprothixene as a nano-drug Samaneh Bagheri Novir PII:

S1567-1739(17)30239-0

DOI:

10.1016/j.cap.2017.08.020

Reference:

CAP 4574

To appear in:

Current Applied Physics

Received Date: 19 July 2017 Revised Date:

24 August 2017

Accepted Date: 28 August 2017

Please cite this article as: S. Bagheri Novir, A theoretical study of the structural and electronic properties of trans and cis structures of chlorprothixene as a nano-drug, Current Applied Physics (2017), doi: 10.1016/j.cap.2017.08.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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ACCEPTED MANUSCRIPT

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A theoretical study of the structural and electronic properties of trans and cis structures of chlorprothixene

Samaneh Bagheri Novir a,* a

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as a nano-drug

Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry,

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Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran

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*Corresponding author: S. Bagheri Novir; E-mail: [email protected],

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[email protected], Tel: +98-9123548308, Fax: +98-21-22600099

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ACCEPTED MANUSCRIPT Abstract Geometrical structure, electronic and optical properties, electronic absorption spectra, thermodynamic properties, natural charge distribution, MEP analysis, and charge transfer analysis of trans and cis structures of chlorprothixene drug have been

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investigated with DFT and TDDFT methods. The results of the computations show that the calculated quantum quantities of the cis isomer of chlorprothixene are in agreement with the activity of cis-chlorprothixene as a drug. Cis structure of

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chlorprothixene has slightly better absorption properties than the trans structure on the basis of TDDFT calculations. The NLO quantities of the cis structure are higher than

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the trans structure, and the chemical hardness of the cis isomer, is smaller than the trans isomer which specifies that the reactivity and charge transfer of the cis structure of chlorprothixene is higher than the trans structure. The MEP maps of both conformations of chlorprothixene show that the top of the N atom and the around of the

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S and Cl atoms of the molecule are proper regions for electrophilic reactions. The calculated thermodynamic parameters illustrate that these parameters are improving with increasing temperature because of the enhancement of molecular vibrational

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intensities with temperature.

Keywords: chlorprlothixen; schizophrenia; TDDFT; Absorption spectra; charge transfer

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ACCEPTED MANUSCRIPT 1. Introduction Chlorprothixene (CPX), with Cloxan, Truxal and Taractan trading names, and 3-(2chloro-9H-thioxanthen-9-ylidene)-N,N-dimethylpropan-1-amine IUPAC name is an antipsychotic drug which belongs to the group of thioxanthene drugs [1,2].

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Thioxanthene derivatives, which are a group of bioactive compounds, have been presented into medicine as strong tricyclic aromatic psychotherapeutic effective in the treatment of organic psychoses, idiopathic psychotic diseases, schizophrenia and other illnesses

[3-6].

Chlorprothixene

medicine,

because

of

its

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neuropsychiatric

comparatively low toxicity and extensive pharmacological action has been extensively

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used as a main tranquillizer in psychiatry in the treatment of anxiety and distress because of its strong relaxing effect. It is also used for the treatment of depression, phobic diseases, neurosis, personality disorders, alcoholic psychosis, schizophrenia and general medical practice. Moreover the influence of chlorprothixene on the central

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nervous system, chlorprothixene with effects on cardiac function, blood pressure, cardiovascular system and the sensory organs as a whole, can be prescribed as a medicine [1,3,7]. The elimination of the medicine from the blood happens in the liver

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via biotransformation. For younger people, the elimination half-life is 12–24 h, but for elderly people it can be found significantly enhanced due to decreased metabolic

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activity [1,7].

The chemical structures of chlorprothixene which consist of the tricyclic aromatic ring and a side chain which is linked to the thioxanthene ring by a C=C double bond, have been shown in Fig. 1. As shown in Fig. 1, because of the existence of a C=C double bond in the molecular structures of chlorprothixene and the presence of chlorin atom in one ring of this molecule, chlorprothixene can exist as two trans (E) and cis (Z) isomers, which the cis isomer of chlorprothixene is biologically more active compound than the

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ACCEPTED MANUSCRIPT trans isomer and trans isomer of chlorprothixene is almost inactive [3,8-10]. Generally, investigations of thioxanthene derivatives display that generally cis structures of these medicines are biologically more active than the trans structures [5,11-13]. Possibility of trans(E)/cis(Z) isomerization around C=C double bond in chlorprothixene, as a result of

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the radiation of ultraviolet–visible light, can change its biological activities. Though chlorprothixene is suggested as a pure cis-isomer as a medicine, the photoinduced isomerization to its trans-isomer can change its strengthen the phototoxic response and

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pharmacokinetics of this drug [5,7,14,15]..

Quantum chemical methods can be a proper technique for the consideration and the

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relation between the molecular structures of drugs and their biological and pharmacological activities. Some experimental and theoretical studies on the molecular and spectroscopic properties of antipsychotic and antidepressant drugs have been performed, previously [16-20]. Chlorprothixene have been experimentally studied

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before by some authors. Such as: Chlorprothixene in bodies after exhumation by B. Madea et al [1], Photophysics and Photochemistry of z-Chlorprothixene in Acetonitrile by C. Garcı´a et al [2], Solvent Dependence of the Photophysical Properties of 2-

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Chlorothioxanthone, the Principal Photoproduct of Chlorprothixene by C. Garcı´a et al [7], High-performance thin-layer chromatographic determination of cis- and trans-

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chlorprothixene and two oxidation products by S. Tammilehto et al [8], ThreeDimensional

Structure

and

Molecular

Dynamics

of

cis(Z)-

and

trans(E)-

Chlorprothixene by S. G. Dah et al [9], Determination of chlorprothixene and amitryptyline hydrochlorides by UV-derivative spectrophotometry and UV-solid-phase spectrophotometry by J. Karpi´nska et al [21], Sensitive determination of phenylephrine and chlorprothixene at poly(4-aminobenzene sulfonic acid) modified glassy carbon electrode by J. Kong et al [22]. But, chlorprothixene medicine has not been studied by

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ACCEPTED MANUSCRIPT quantum chemistry methods, to date. In this work, both trans and cis structures of chlorprothixene were studied with computational chemistry methods to evaluate the calculated quantities of trans and cis structures of chlorprothixene. Also, the explanation and the correlation between the biological activities of trans and cis conformations of

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chlorprothixene and their computed quantum parameters, can be evaluated by quantum chemical computations. The main purpose of this investigation is to study the molecular structure, nonlinear optical properties such as polarizability and hyperpolarizability,

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electronic absorption spectra, thermodynamic parameters, charge transfer and other

dependent DFT (TDDFT) methods.

2. Computational methods

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molecular properties on the basis of density functional theory (DFT) and time-

All quantum chemical calculations in this study, have been performed with the Gaussian

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03 package [23]. In this study water is chosen as solvent and solvent effect have been considered with the conductor polarizable continuum model (CPCM) [24-26]. Trans

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and cis structures of chlorprothixene have been optimized with DFT [27] using the Becke’s three-parameter hybrid function (B3) and the Lee–Yang–Parr nonlocal

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correlation function (B3LYP) and 6-311+G** basis set [28-30]. 6-311+G** basis set has been used with the aim of achieving more accurate results by applying triple split valence basis set along with polarization fnctions (**), which adds p functions to hydrogen atoms in addition to the d functions on heavy atom and diffuse function (+) which adds diffuse functions to the heavy atoms. Frequency calculations at the same level have been performed on the optimized structures to confirm that the optimized structures reached to a stationary point with minimum energy and to compute non-linear optical properties (NLO) such as polarizability, hyperpolarizability and thermodynamic 5

ACCEPTED MANUSCRIPT parameters. Absorption spectra, excitation energies, maximum absorbances (λmax) and oscillator strengths (f) of two conformations of chlorprothixene were estimated with time-dependent DFT (TDDFT) method at B3LYP/6-311+G** level of theory for the lowest 30 singlet–singlet transitions based on optimized ground state structures. Natural

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bond orbital (NBO) calculations of two isomers of chlorprothixene and also the reactive sites of this molecule which have been estimated with the molecular electrostatic potential (MEP), have been considered by the B3LYP/6-311+G** method. The charge

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transfer analysis was also analyzed by Multiwfn 3.2.1 [31-33]. The results of these

program [34].

3. Results and discussion

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3.1. Geometrical structures

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calculations were analyzed and presented with the GaussView molecular visualization

Ground-state structures of both trans and cis isomers of chlorprothixene were optimized with the B3LYP/6-311+G** method in both gas and water phases. The optimized

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geometries of the two configurations are shown in Fig. 2. Chlorprothixene belongs to C1 point group symmetry. The selected bond lengths, bond angles and dihedral angles

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of the two structures are presented in Table 1. The results in Table 1 display that the optimization in water doesn't vary the structural parameters, considerably. All the CC lengths in the two phenyl rings, are between the distance of a single bonded and a double bonded which show that there exist resonance bonds in the rings of the cis and trans structures of this molecule. The aromaticity of the benzene rings is distorted from the hexagonal structure of the benzene because of the substitutions. It is obvious from the difference in bond length between C6-C10 & C12-C16 that is 0.019 Å and 0.014 Å

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ACCEPTED MANUSCRIPT in the trans and cis structures, respectively. Also, the difference in bond length between C7-C11 & C13-C17 that is 0.016 Å and 0.015 Å in the trans and cis structures, respectively. The difference in bond angle between C14-C10-C6 and C10-C6-C12 in the solvent phase is 2.38̊ and 2.55̊ in the trans and cis structures, respectively. Also, the

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difference in bond angle between C7-C11-C15 and C13-C7-C11 in the solvent phase is 3.27̊ and 3.04̊ in the trans and cis structures, respectively. Calculations show that in both trans and cis conformations of the molecule, the C6–C10 and C7–C11 bond lengths, are

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slightly larger than the other CC bond lengths of the phenyl rings. The S2–C10 and S2– C11 bond lengths in the middle ring are longer than the other bond lengths in this ring.

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Viewed from the results of Table 1, the C6-C4-C8 bond angle of the trans structure is slightly smaller than that of the cis structure and the C7-C4-C8 bond angle in the trans structure is slightly larger than the cis structure. The other bond lengths and bond angles in the trans and cis structures are almost close to each other. The calculated dihedral

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angles C6-C4-C8-C5, C7-C4-C8-C5, C12-C6-C4-C8, C13-C7-C4-C8 and C4-C8-C5C9 in the solvent phase, corresponding to the trans and cis structures, are -175.75, 2.05, -42.84, 45.33, 135.19̊ and 1.84, -175.92, 45.39, -42.78, 134.37̊, respectively. It has been

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observed that the dihedral angles are significantly affected by the isomerization of

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chlorprothixene from trans isomer to the cis isomer.

3.2. Energy levels

The EHOMO, ELUMO, HLG (ELUMO − EHOMO), total molecular energies and the relative energies calculated with B3LYP/6-311+G** method, for trans and cis stuctures of chlorprothixene are shown in Table 2. As seen in Table 2, in the presence of water as solvent, the HOMO and the LUMO energy levels of trans structure of chlorprothixene decreased about 0.104 eV, and 0.039 eV, respectively, and the HOMO and the LUMO 7

ACCEPTED MANUSCRIPT energy levels of the cis structure decreased about 0.105eV and 0.048 eV, respectively. The HOMO energy levels of the trans and cis structures in the gas phase (water) are located at -5.868 and -5.866 eV (-5.972 and -5.971 eV), and their corresponding LUMO energy levels are located at -1.504 and -1.508 eV (-1.543 and -1.556 eV), respectively.

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In the presence of both gas and solvent phases, the HOMO energy levels of trans structure of chlorprothixene are lower than the HOMO energy level of cis structure, while, the LUMO energy levels of the trans structure are higher than the cis structures.

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Therefore, the HLG of the trans structure of chlorprothixene is larger than the HLG of the cis structure. The relationship between the smaller HLG values and better activity of

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cis structure of the molecule have been explained in section 3.4, through discussion on some parameters effective on the activity of the cis structure such as chemical hardness and polarizabilty which these parameters have been correlated to the HLG values. The relative energies of the structures in both gas and solvent phase show that because of

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very small relative energies we cannot conclude that the cis structure has more stability than trans structure, certainty. Since the cis structure of chlorprothixene is known as an active drug, the relative lower energy level of cis structure of this drug compared to the

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trans structure may be a good parameter for justification of the activity of cis structure of chlorprothixene, but it cannot be a certain parameter. Other parameters that justify

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the better activity of the cis structure have been discussed in the next section.

3.3. Electronic absorption spectra Electronic absorption spectra of trans and cis conformations of chlorprothixene have been evaluated by the time-dependent DFT (TDDFT) method at B3LYP/6-311+G** level of theory in the gas phase and water phase based on the optimized ground state structures of the molecule. TDDFT calculations of this molecule in the solvent phase 8

ACCEPTED MANUSCRIPT have been performed with the CPCM model. The excitation energies, maximum wavelengths (λmax), oscillator strengths (f), main transition and electronic transition configurations of trans and cis isomers of chlorprothixene in both gas and water phases are listed in Table 3 and the UV-Vis absorption spectra of both structures of

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chlorprothixene in the two phases are shown in Fig. 3. The maximum absorption wavelengths (λmax) of trans and cis geometries of chlorprothixene in the gas phase are observed at 232.86 nm with an oscillator strength f=0.3028 and at 233.17 nm with an

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oscillator strength f=0.3281, respectively. Also, The λmax of trans and cis structures of this compound in water are observed at 234.95 nm with an oscillator strength f=0.3022

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and 235.07 nm with an oscillator strength f=0.4561, respectively. The results of Table 3 and Fig. 3 shows that the presence of water as solvent shifts the absorption bands of trans and cis structures of chlorprothixene toward longer wavelengths and larger oscillator strengths. With enhancing solvent polarity, the energy of the excited state is

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decreased more than that of the ground state. Therefore, the λmax of both isomers of chlorprothixene has somewhat red-shift by solvent effects [35]. The electronic absorption spectra shows that the maximum absorption wavelengths are related to the

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HOMO-2 → LUMO+2 transitions. The HOMO-2 and LUMO+2 frontier molecular orbitals of trans and cis structures of chlorprothixene in the solvent phase which are

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presented in Fig. 4., show that for this compound the frontier molecular orbitals are usually composed of p atomic orbitals. Thus, these electronic transitions correspond to π→π*. These results are almost in qualitative agreement with the experimental results [2,36]. We cannot get the precise quantitative results from the TDDFT calculations, because of a little difference between TDDFT methods and experimental results caused by the difference between the DFT exchange and correlation function and the computational model of solvent effects [37-40].

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ACCEPTED MANUSCRIPT From Table 3 and Fig. 3., we can find that, the absorption bands and oscillator strength and therefore the absorption peak intensity of cis structure of chlorprothixene are almost slightly higher than the trans structure. Practically no difference is observed between the absorption spectra of the trans and cis isomers of chlorprothixene. The small differences

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can be attributed to the difference in the dihedral angles of the trans and cis isomers of chlorprothixene. Consequently, cis structure of chlorprothixene shows slightly better absorption properties than the trans structure. The better properties of cis structure of

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chlorprothixene can be attributed to the better properties of cis-chlorprothixene as a

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medicine.

3.4. Nonlinear optical properties and other molecular properties The total static dipole moment (µ), mean polarizability (α), anisotropy of polarizability (∆α) and first order hyperpolarizability (β) are nonlinear optical (NLO) properties of the

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molecule, which have been calculated for both isomers of chlorprothixene. Dipole moment, which can be used as a descriptor to determine the charge transfer within the

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molecule, is one of the key parameters which are of main significance in structural chemistry [41]. The total dipole moment could be calculated via the following equation

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[42,43]:

(1)

where µx , µy , µz are the vector components of the dipole moment. Polarizabilities and hyperpolarizabilities characterize the reaction of a molecule in an applied electric field. The mean polarizability, α, the anisotropy of polarizability, ∆α, and the total first-order hyperpolarizability, βtot, are computed by the following formulas [41,42,44]: 10

ACCEPTED MANUSCRIPT (2)

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(3)

(4)

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where αxx, αyy, αzz are tensor components of polarizability, and βxxx, βxyy, βxzz, βyyy, βyzz ,βyxx, βzzz, βzxx and βzyy are tensor components of hyperpolarizability, which can be in Gaussian.

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found via a frequency calculation output

Polarizability and

hyperpolarizability values of the Gaussian output file are presented as atomic units (a.u.), but they have been altered into the electronic units (esu) ( α; 1 a.u. = 1.48176 *10 -25

esu, β; 1 a.u. = 8.63993 * 10-33 esu) [42].

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In order to consider the correlation among NLO properties, HLG and chemical reactivity descriptors such as electronegativity (χ), chemical hardness (η) and softness (σ), chemical potential (ρ) and electrophilicity index (ω) of the molecule, the following

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equations by Koopman’s theorem [45-47] have been used to compute these parameters.

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Electronegativity (χ) that is a measure of the power of an atom or a group of atoms to attract electrons [48,49] can be calculated from the HOMO and LUMO energy level via this equation [42,44]: χ= −

1 ( E HOMO + E LUMO ) 2

(5)

The chemical hardness (η) which is a measure of the resistance of a system to charge transfer and the reactivity of a compound can be computed by this formula [42,44]:

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ACCEPTED MANUSCRIPT 1 1 η= [ IP − EA] ≈ [ E LUMO − E HOMO ] 2 2

(6)

On the basis of Koopman’s theorem IP≈EHOMO and EA≈ELUMO which IP is ionization potential and EA is electron affinity [42,44,48].

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The chemical softness (σ) which is a measure of the easiness of charge transfer can be calculated with the inverse of hardness (Eq. 7): 1

(7)

η

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σ=

The softness which is correlated with polarizability, means that the soft molecules have

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high polarizability and the hard molecules have low polarizability [42,48,50]. The electronic chemical potential (ρ) that is the evasion affinity of an electron from equilibrium are calculated from the equation [50,51]: 1 2

ρ = − χ = [ E HOMO + E LUMO ]

(8)

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The stabilization energy of the systems when it becomes saturated by electrons, is called electrophilicity index (ω) and can be computed from the electronegativity and chemical

ω=

χ2 2η

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hardness via the following formula [42,50,52]: (9)

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All the above parameters for both trans and cis structures of chlorprothixene in the gas and solvent phases are calculated with the B3LYP/6-311+G** method and are listed in Table 4.

The results in Table 4 show that dipole moments µ, polarizability α, anisotropy of polarizability ∆α and the total first-order hyperpolarizability βtot of the cischlorprothixene is higher than the trans-chlorprothixene in both gas and solvent phases and these values in the solvent phase are higher than those of in the gas phase. The

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ACCEPTED MANUSCRIPT higher dipole moment, polarizability, and hyperpolarizability exhibit that cis structure of chlorprothixene has better NLO properties than the trans structure. The calculated dipole moment for the trans and cis conformations of chlorprothixene is 1.953 and 2.052 Debye in the gas phase and 2.285 and 2.957 Debye in the solvent phase,

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respectively. These parameters show that cis structure of chlorprothixene molecule has stronger intermolecular interactions than the trans structure because a molecule with the higher dipole moment, has stronger intermolecular interactions [42]. The calculated

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polarizability, anisotropy of the polarizability and first hyperpolarizability of transchlorprothixene in the gas phase (solvent phase) is 0.390*10-22 (0.544*10-22) esu,

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0.129*10-22 (0.140*10-22) esu and 0.018*10-28 (0.059*10-28) esu, respectively. Also, the values of α, ∆α and βtot of cis-chlorprothixene in the gas phase (solvent phase) is 0.391*10-22 (0.545*10-22) esu, 0.145*10-22 (0.171*10-22) esu and 0.056*10-28 (0.104*1028

) esu, respectively. Therefore, we can conclude that cis structure of chlorprothixene

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which has been used as a pharmacologically and biologically active molecule, constitutes a better NLO molecule than trans-chlorprothixene. Chemical hardness of the isomers of the molecules, which are associated to the HLG of

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these structures, determines the charge transfer and the reactivity of the molecule. Hard molecules have the larger HLG than soft molecule and therefore will be less reactive

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than soft molecules [42,50,51,53]. The data in Table 4 show that the chemical hardness of cis structure of chlorprothixene, in both gas and solvent phases, is smaller than the trans structure. It means that trans structure of chlorprothixene is harder than the cis structure and the chemical softness of the cis structure is higher than the trans structure, that means that the charge transfer and the reactivity of cis-chlorprothixene is higher than trans-chlorprothixene. Also, the results in Table 4 display that there is an opposite correlation between polarizabilities values and the chemical hardness (η) of the

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ACCEPTED MANUSCRIPT molecule. The cis structure of chlorprothixene with the smaller HLG, shows the lower chemical hardness (η), the higher λmax and the larger polarizability and hyperpolarizability than the trans structure. The reduced chemical hardness demonstrates that the electron density is more simply influenced and the molecule could

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be more reactive. The better polarizabilities increase the distortion of the electron cloud by an electric field to the acceptor group and cause a much higher intramolecular charge transfer ability [35,53]. Consequently, the lower chemical hardness of cis structures of

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chlorprothixene is in agreement with the higher polarizability and hyperpolarizability

and therefore the activity of cis structure of this molecule.

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From Table 4, it is clear that the electronegativity of trans-chlorprothixene is 3.686 eV in the gas phase and 3.687 eV in water. This quantity for cis-chlorprothixene has been increased from 3.757 to 3.764 eV from gas to solvent phase. The electrophilicity index of trans and cis structures of chlorprothixene in the gas phase is 3.113 and 3.120 eV,

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respectively, and this parameter in the solvent phase is observed to be increased from 3.187 to 3.209 eV from trans to cis structure of chlorprothixene. Regarding to these results, we can conclude that the electronegativity, chemical potential and

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electrophilicity index of cis structure of chlorprothixene, in both gas and solvent phases, are more than those of the trans structure. It means that cis structure of chlorprothixene

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has better reactivity on the basis of these chemical reactivity descriptors.

3.5. Thermodynamic properties The thermodynamic parameters of trans and cis structures of chlorprothixene such as total thermal energy (E), zero point vibrational energy, heat capacity (C), entropy (S) and enthalpy change (∆H) have been evaluated with the frequency calculations in different temperatures from 100 K to 500 K, by the B3LYP/6-311+G** method in the 14

ACCEPTED MANUSCRIPT solvent phase and listed in Table 5. The correlation between the total thermal energy, heat capacity, entropy and enthalpy changes and temperature, and also the correlation equations fitted by quadratic formula and the corresponding fitting factors (R2) are shown in Figs. 5-8. According to Table 5, there is no obvious difference between the

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thermodynamic parameters of trans and cis structures of chlorprothixene and these parameters are almost close to each other. Total thermal energies, entropies and enthalpy changes of trans-chlorprothixene are a little more than those of cis-

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chlorprothixene, while heat capacities of cis-chlorprothixene is a little more than those of trans-chlorprothixene. Since cis structure of chlorprothixene can act as an active

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medicine, we can find that the higher heat capacity is an appropriate parameter for the compound which can be used as an active drug. Figs. 5-8 show that all these thermodynamic parameters, except zero point vibrational energy, are increasing with enhancing temperature from 100 to 500 K, because the molecular vibrational intensities

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enhance with temperature but zero point vibrational energy dose not change with temperature [51,54]. The regression agents (R2) of the equations of theses thermodynamic properties are not fewer than 0.99. These equations have been used to

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evaluate the values of every thermodynamic parameters for any temperature and to

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calculate the other thermodynamic energies for more studies of the molecule [51].

3.6. Natural charge distributions and Molecular electrostatic potential (MEP) The natural atomic charges of trans and cis isomers of chlorprothixene calculated with B3LYP/6-311+G** method in the solvent phase, are listed in Table 6. In chlorprothixene molecule, all hydrogen atoms have positive natural atomic charges, and all the carbon atoms and chlorine and nitrogen atoms have negative atomic charges. The N atom shows the highest negative atomic charge and the S atom shows the highest 15

ACCEPTED MANUSCRIPT positive atomic charges among all the atoms of the molecule. Molecular electrostatic potential (MEP) is an appropriate method to specify the charge distributions of molecules as three dimensional. This counter map is very useful to determine the reactive sites of molecules in both electrophilic and nucleophilic reactions for

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investigation of biological systems [42,55,56]. The molecular electrostatic potential for both conformations of chlorprothixene at the B3LYP/6-311+G** optimized geometry was calculated and presented in Fig. 9., to characterize the reactive sites of electrophilic

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and nucleophilic attacks for trans and cis structures of chlorprothixene molecule. Usually, the various values of the electrostatic potential are shown by different colors,

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that the order of potential values is: red < orange < yellow < green < blue. The maximum positive area that is the preferred site for nucleophilic attack is presented by blue color. The negative regions of MEP which are suitable sites for electrophilic reactivity are specified with red and yellow colors, which the preferred site for

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electrophilic attack is shown by red color [42,55]. According to the Fig. 9, the color of trans structure of chlorprothixene in this map is in the range between -0.03915 a.u. (dark red) and +0.03915 a.u. (dark blue), and for cis structure of chlorprothixene this range is

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between -0.04163 a.u. and +0.04163 a.u. The MEP maps of chlorprothixene molecule show that the yellow and red colors are observed around of the N, S and Cl atoms.

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Therefore, these areas of the molecule are proper regions for electrophilic reactivity, particularly the red color region of MEP that is observed at the top of the N atom, are the preferred sites for electrophilic reactions. The other regions of the molecule are neither dark blue nor dark red. It means that these regions are practically neutral. The more electronegativity of the nitrogen and chlorine atoms makes them the most reactive portions for electrophilic reactivity in the molecule.

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ACCEPTED MANUSCRIPT 3.7. Charge transfer An easy methodology to evaluate intramolecular charge transfer has been suggested that this approach is relatively general and only ground state (GS) and excited state (ES) total electronic densities have been needed. For this purpose, ground state density and

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excited state density have been obtained using DFT and TD-DFT calculations, respectively. The difference between ground state electronic densities (ρGS(r)) and

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excited state electronic densities (ρES(r)) is revealed as [31,57]: (10)

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The quantity of transferred charge, qCT, can be obtained by: (11)

+

Which ρ (r) is a measure of the increase of density as a result of the photon absorption

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which can be defined as:

-

(12)

-

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density.

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That there is a comparable equation for ρ (r) that ρ (r) is a measure of the decrease of

The charge transfer distance, dCT, can be obtained from the difference between the barycenters of the ρ+ (r) and ρ-(r) by the following formula: (13)

Which the barycenters of the ρ+ (r) and ρ-(r) are defined as: (14)

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ACCEPTED MANUSCRIPT (15) The half of the summation of the centroids axis along x axis, H, is calculated by the

(16)

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equation:

Which the root-mean-square deviation (rms) for the positive portion along the x axis,

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can be applied to evaluate the extension of the charge on the acceptor and donor groups of the molecule:

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(17)

H can be compared to dCT, if a good overlap between the electron-donating and electron-accepting areas has been observed. If H ≥ dCT, an overlap between the centroids along x axis can be foreseeable [31,57-60].

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The ground state geometries of both trans and cis isomers of this drug were optimized at the B3LYP/6-311+G** level and the excited state calculations have been carried out

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with the TD-DFT at the B3LYP/6-311+G** level on the based on optimized ground state structures in the solvent phase. The qCT, dCT and H quantities and dipole moment

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variation between ground and excited state, which are computed by Multiwfn 3.2.1 program [32], are gathered in Table 7. As observed from Table 7, the values of transferred charge (qCT), charge transfer length (dCT), H values and dipole moment variation (µCT), of the cis structure of chlorprothixene are higher than those of the trans structure. We can conclude that the strength of the charge transfer that measured by qCT, are related to the geometrical structures of the medicine. The larger dCT is because of the higher delocalization of the transferred charge. The improved dipole moment can enhance the distance between the charge centers, which results the improve of electron 18

ACCEPTED MANUSCRIPT delocalization [38,61]. The overlap between the centroids can be evaluated with H. The order of H is equivalent to the order of qCT, dCT and dipole moment variation. Therefore, by variation of the geometrical structure of this drug, the values of qCT, dCT, H and dipole moment variation could be changed. Therefore, we can find that cis structure of

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chlorprothixene has a superior structure for electron delocalization and intramolecular charge transfer.

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4. Conclusions

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In this study, the geometries, electronic properties, electronic absorption spectra, nonlinear optical properties, thermodynamic properties, natural charge distribution, MEP analysis and charge transfer analysis of cis and trans structures of chlorprothixene medicine, have been considered by DFT methods to compare trans and cis structures of chlorprothixene and clarify why cis structure of chlorprothixene is more active than the

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trans structure. Geometrical investigation shows that in the phenyl rings of this compound, the C-C bonds where substitution groups are linked are longer than the other

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C-C bond lengths of the phenyl rings, because the hexagonal structure of the phenyl rings are distorted. The energy levels and the relative energy of trans and cis structures

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of chlorprothixene show that the cis structure of chlorprothixene is more stable than the trans structure with a small energy difference. The LUMO energy levels of the trans structure of chlorprothixene are higher than the cis structure, while the HOMO energy levels of trans structure of chlorprothixene are slightly lower than the HOMO energy level of the cis structure. So, the HLG of the trans structure of chlorprothixene is larger than the HLG of the cis structure. TDDFT calculations show that cis structure of chlorprothixene has almost the better absorption properties, which the better properties of cis structure of chlorprothixene can be attributed to the better properties of cis 19

ACCEPTED MANUSCRIPT structure of chlorprothixene as an active drug. The properties such as dipole moment (µ),

polarizability

(α),

anisotropy

of

polarizability

(∆α)

and

first

order

hyperpolarizability (β), electronegativity (χ), chemical hardness (η) and softness (σ), chemical potential (ρ) and electrophilicity index (ω) of the molecule, show that dipole

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moment and NLO properties of cis structure of chlorprothixene is higher than the trans structure, therefore, this structure has the better NLO properties than the trans structure and has stronger intermolecular interactions. The chemical hardness of cis structure of

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chlorprothixene, is lower than the trans structure and the electronegativity, chemical softness and electrophilicity index of cis structure of chlorprothixene, are larger than

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those of the trans structure. It means that the reactivity and charge transfer of cis isomer of chlorprothixene is higher than the trans isomer. Also, Charge transfer analysis with Multiwfn program show that the transferred charge of cis structure of chlorprothixene is higher than the trans structure. Moreover, an opposite correlation has been seen between

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chemical hardness and polarizabilities values of the molecule. The thermodynamic parameters such as total thermal energy, heat capacity, entropy and enthalpy change from 100 K to 500 K show that all these thermodynamic parameters are increasing with

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enhancing temperature. The MEP maps of the molecule indicate that the around of the

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N, Cl and S atoms of the molecule are suitable areas for electrophilic reactions. All these quantum parameters justify the more reactivity of the cis structure of chlorprothixene relative to the trans structure of chlorprothixene.

Acknowledgement

20

ACCEPTED MANUSCRIPT We would like to thank Pharmaceutical Sciences Branch, Islamic Azad University of Tehran.

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181-185.

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Figure captions: Figure. 1. Molecular structure of trans- and cis-chlorprothixene

Figure. 2. Optimized molecular structure of a) trans-chlorprothixene and b) cis-

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chlorprothixene at B3LYP/6-311+G** level of theory

Figure. 3. Electronic absorption spectra of trans- and cis- chlorprothixene in the gas phase and water with TDDFT method using B3LYP/6-311+G** level of theory.

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B3LYP/6-311+G** level in the solvent phase.

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Figure. 4. HOMO and LUMO plots of trans- and cis-chlorprothixene computed at

Figure. 5. Correlation graphic of total thermal energy and temperature for trans- and cischlorprothixene

Figure. 6. Correlation graphic of heat capacity and temperature for trans- and cis-

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chlorprothixene

chlorprothixene

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Figure. 7. Correlation graphic of entropy and temperature for trans- and cis-

Figure. 8. Correlation graphic of enthalpy and temperature for trans- and cis-

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chlorprothixene

Figure. 9. MEP map of a) Trans- chlorprothixene and b) Cis-chlorprothixene

26

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Table 1

311+G** level of theory. Chlorprothixene Trans

gas / water

Chlorprothixene

Cis

Trans

gas / water

Bond lengths

gas / water Bond angles

Cis

gas / water

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Parameters

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Selected bond lengths (in Å), bond angles (in degree) and dihedral angles (in degree) of trans and cis structures of chlorprothixene at the B3LYP/6

1.760 / 1.765

1.760 / 1.764

C12-C16-C20

121.30 / 121.65

C16-C12

1.388 / 1.388

1.388 / 1.388

C16-C20-C14

118.80 / 118.63

C12-C6

1.401 / 1.402

1.401 / 1.402

C20-C14-C10

C6-C10

1.406 / 1.407

1.401 / 1.402

C14-C10-C6

C10-C14

1.396 / 1.397

1.396 / 1.397

C10-C6-C12

C14-C20

1.390 / 1.391

1.390 / 1.390

C6-C12-C16

C20-C16

1.391 / 1.391

1.391 / 1.391

Cl1-C16-C12

C10-S2

1.781 / 1.783

1.780 / 1.782

Cl1-C16-C20

119.42 / 119.25

119.46 / 119.30

S2-C11

1.782 / 1.785

1.783 / 1.786

C4-C6-C10

120.11 / 120.22

120.00 / 120.13

C11-C7

1.406 / 1.406

1.405 / 1.406

C6-C10-S2

120.76 / 120.57

120.83 / 120.68

C7-C4

1.484 / 1.485

1.486 / 1.487

C10-S2-C11

99.83 / 99.87

99.81 / 99.89

C4-C6

1.486 / 1.487

1.484 / 1.485

S2-C11-C7

120.79 / 120.64

120.69 / 120.56

C11-C15

1.397 / 1.397

1.397 / 1.397

C11-C7-C4

120.04 / 120.09

110.7 / 110.9

C15-C21

1.390 / 1.391

1.390 / 1.392

C7-C4-C6

115.33 / 115.33

115.29 / 115.33

C21-C17

1.394 / 1.395

1.394 / 1.395

C7-C11-C15

120.89 / 121.05

120.84 / 121.00

C17-C13

1.390 / 1.391

1.390 / 1.391

C11-C15-C21

120.05 / 119.94

120.02 / 119.91

C13-C7

1.402 / 1.403

1.401 / 1.402

C15-C21-C17

119.86 / 119.85

119.89 / 119.87

C4-C8

1.347 / 1.347

1.347 / 1.347

C21-C17-C13

119.89 / 119.96

119.89 / 119.96

C8-C5

1.501 / 1.500

1.501 / 1.500

C17-C13-C7

121.35 / 121.29

121.26 / 121.22

gas / water

Cis

gas / water

Dihedral angles C6-C4-C8-C5

-175.12 / -175.75

118.80 / 118.62

C7-C4-C8-C5

2.33 / 2.05

120.57 / 120.47

120.59 / 120.50

C12-C6-C4-C8

-43.14 / -42.84

45.90 /45.39

120.54 / 120.74

120.55 / 120.76

C13-C7-C4-C8

45.64 / 45.33

-43.31 /-42.78

118.42 / 118.36

118.28 / 118.21

C4-C8-C5-C9

134.11 / 135.19 132.39 / 134.37

120.30 / 120.08

120.38 / 120.17

119.27 / 119.08

119.26 / 119.07

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EP

AC C

Trans

121.27 /121.62

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Cl1-C16

Chlorprothixene

2.23 / 1.84 -175.14 /-175.92

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1.538 / 1.537

1.538 / 1.538

C13-C7-C11

117.84 / 117.78

118.02 / 117.96

C9-N3

1.461 / 1.465

1.460 / 1.465

C7-C4-C8

124.62 / 124.68

120.22 / 120.21

N3-C18

1.458 / 1.461

1.458 / 1.462

C6-C4-C8

119.99 / 119.95

124.43 / 124.42

N3-C19

1.457 / 1.462

1.457 / 10462

C4-C8-C5

128.76 / 128.76

128.98 / 129.02

C8-C5-C9

111.07 / 111.07

110.99 / 111.00

C5-C9-N3

113.36 / 113.42

113.34 / 113.39

C9-N3-C18

111.42 / 110.84

111.45 / 110.87

C9-N3-C19

113.04 / 112.60

113.01/ 112.52

C18-N3-C19

110.90 / 110.46

110.93 / 110.42

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C5-C9

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Table2 EHOMO (eV), ELUMO (eV), HLG (eV), total energy (eV) and relative energy ∆E = E cis - E trans (eV) of trans and cis structures of chlorprothixene with B3LYP/6-311+G** method in the gas and water phases. EHOMO

ELUMO

HLG

Total energy

Gas Trans

-5.868

-1.504

4.364

-43814.558

Cis

-5.866

-1.508

4.358

-43814.563

Trans

-5.972

-1.543

4.429

-43814.771

Cis

-5.971

-1.556

4.416

-43814.775

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Water

Relative energy ∆E = E cis - E trans

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Chlorprothixene

-0.005

-0.004

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Table 3 Calculated excitation energies, maximum wavelengths (λmax) (nm), oscillator strengths (f), main transition and electronic transition configurations of trans and cis structures of chlorprothixene, with the TDDFT-

Chlorprothixene

excitation energies

λmax

f

RI PT

B3LYP/6-311+G** method. main transition (electronic transition configurations)

Gas 5.3244

232.86

0.3028

H-2→L+2 (34.95 %)

Cis

5.3173

233.17

0.3281

H-2→L+2 (36.68 %)

Trans

5.2770

234.95

0.3022

H-2→L+2 (37.79 %)

Cis

5.2743

235.07

0.4561

H-2→L+2 (39.73 %)

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Water

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Trans

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Table 4 Calculated dipole moment µ (Debye), isotropic polarizability α, anisotropy of polarisability ∆α, total firstorder hyperpolarizability βtot, chemical hardness η and softness σ (eV), Electronegativity (χ), Chemical B3LYP/6-311+G** method.

Gas

Chlorprothixene

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potential (ρ) and Electrophilicity index (ω) values of trans and cis structures of chlorprothixene, with the

Water

Cis

Trans

Cis

Dipole moment µ

1.953

2.052

2.285

2.957

α (10-22 esu)

0.390

0.391

∆α (10-22 esu)

0.129

0.145

βtot (10-28 esu)

0.018

Chemical hardness η

2.182

Chemical softness σ

0.458

Electronegativity χ

3.686

Chemical potential ρ

-3.686

Electrophilicity index ω

3.113

SC

Trans

0.545

0.140

0.171

0.059

0.104

2.179

2.214

2.207

0.459

0.451

0.453

3.687

3.757

3.764

-3.687

-3.757

-3.764

3.187

3.209

AC C

EP

0.056

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0.544

3.120

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Table 5

(K)

Zero point energy -1

(kcal mol )

Total thermal energy (E)

Heat Capacity (C) -1

-1

-1

(cal mol K )

(kcal mol )

Trans-Chlorprothixene 196.638

198.442

29.967

200

196.638

202.574

52.539

298.15

196.638

208.830

75.048

300

196.638

208.970

400

196.638

500

196.638

-1

Enthalpy changes (∆H)

-1

(cal mol K )

(kcal mol -1)

92.265

198.626

121.389

202.956

147.334

209.407

75.475

147.812

209.549

217.644

97.633

173.184

218.421

228.393

116.761

197.534

229.368

29.975

91.692

198.619

52.549

120.822

202.951

75.057

146.770

209.402

75.483

147.248

209.545

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Cis-Chlorprothixene

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100

Entropy (S)

SC

Temperature

RI PT

Thermodynamic properties at different temperatures of trans and cis structures of chlorprothixene, at the B3LYP/6-311+G** level in water.

196.638

198.436

200

196.638

202.569

298.15

196.638

208.826

300

196.638

208.966

400

196.638

217.640

97.640

172.623

218.418

500

196.638

228.390

116.766

196.974

229.347

AC C

EP

100

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Table 6 Natural atomic charges of trans and cis isomers of chlorprothixene in water. Chlorprothixene

RI PT SC

M AN U

Cis -0.01328 0.31438 -0.57055 -0.06626 -0.43640 -0.05510 -0.06717 -0.11533 -0.15968 -0.16339 -0.16500 -0.20948 -0.18590 -0.19720 -0.21751 -0.03892 -0.20811 -0.35872 -0.36439 -0.21969 -0.20002 0.21326 0.21883 0.19712 0.16839 0.20432 0.23526 0.22087 0.23056 0.22408 0.21852 0.16479 0.19497 0.19531 0.16552 0.19698 0.19426 0.23540 0.21926

TE D

EP

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

Trans -0.01512 0.31414 -0.57017 -0.07042 -0.43619 -0.04119 -0.07712 -0.11494 -0.15964 -0.16716 -0.16131 -0.21230 -0.18302 -0.19687 -0.21775 -0.03731 -0.20900 -0.35867 -0.36446 -0.22379 -0.19585 0.21451 0.21872 0.19702 0.16812 0.20349 0.23659 0.21969 0.23004 0.22461 0.21907 0.16470 0.19489 0.19530 0.16547 0.19696 0.19431 0.23506 0.21960

AC C

Cl S N C C C C C C C C C C C C C C C C C C H H H H H H H H H H H H H H H H H H

Water

ACCEPTED MANUSCRIPT

Table 7 Transferred charge (qCT in the e-), charge transfer length (dCT in Å), dipole moment variation (µCT in Debye) and H (in Å) of trans and cis structures of chlorprothixene at the TD-B3LYP/6-

Chlorprothixene

qCT

dCT

µCT

0.772

1.064

3.025

Cis

0.878

1.427

3.545

H

3.964

3.994

AC C

EP

TE D

M AN U

SC

Trans

RI PT

311+G**//B3LYP/6-311+G** level in the solvent phase.

SC

RI PT

ACCEPTED MANUSCRIPT

Cis-chlorprothixene

AC C

EP

TE D

M AN U

Trans-chlorprothixene

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

(a)

(b)

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

LUMO+2 Cis-Chlorprothixene

AC C

EP

TE D

LUMO+2 Trans-Chlorprothixene

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

HOMO-2 Trans-Chlorprothixene

HOMO-2 Cis-Chlorprothixene

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

(a)

(b)

ACCEPTED MANUSCRIPT

Highlights

Trans and cis structures of chlorprothixene were studied by quantum methods.

•

Cis structure of chlorprothixene is more stable than the trans structure.

•

Cis structure of chlorprothixene has more charge transfer than trans structure.

•

Cis structure of chlorprothixene has better reactivity.

AC C

EP

TE D

M AN U

SC

RI PT

•