Theoretical study on the phenylpropanolamine drug interaction with the pristine, Si and Al doped [60] fullerenes

Author’s Accepted Manuscript Theoretical study on the phenylpropanolamine drug interaction with the pristine, Si and Al doped [60] fullerenes Majid Eslami, Morteza Moradi, Reza Moradi www.elsevier.com/locate/physe

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S1386-9477(16)31215-2 http://dx.doi.org/10.1016/j.physe.2016.11.027 PHYSE12666

To appear in: Physica E: Low-dimensional Systems and Nanostructures Received date: 26 October 2016 Accepted date: 24 November 2016 Cite this article as: Majid Eslami, Morteza Moradi and Reza Moradi, Theoretical study on the phenylpropanolamine drug interaction with the pristine, Si and Al doped [60] fullerenes, Physica E: Low-dimensional Systems and Nanostructures, http://dx.doi.org/10.1016/j.physe.2016.11.027 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 galley proof before it is published in its final citable 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.

Theoretical study on the phenylpropanolamine drug interaction with the pristine, Si and Al doped [60] fullerenes Majid Eslami1, Morteza Moradi2, Reza Moradi3* 1. Infectious and Tropical Diseases Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran 2. Department of Semiconductors, Materials and Energy Research Center, P.O. Box 31787-316, Karaj, Iran 3. Department of Chemistry, Tuyserkan Branch, Islamic Azad University, Toyserkan, Iran

*Corresponding author; Email: [email protected]

Abstract Phenylpropanolamine (PPA) is a popular drug of abuse and its detection is of great importance for police and drug communities. Herein, we investigated the electronic sensitivity and reactivity of pristine, Al and Si doped C60 fullerenes to the PPA drug, using density functional theory calculations. Two adsorption mechanisms were predicted for PPA on the pristine C60 including cycloaddition and adsorption via –NH2 group. It was found that the pristine C60 has a good sensitivity to this drug but suffers from a weak interaction (adsorption energy ~ -0.1 kcal/mol) because of structural deformation and aromaticity break. The PPA is adsorbed on the Al or Si doped C60 from its –OH or –NH2 groups. The Al-doping significantly improves the reactivity of C60 but decreases its electronic sensitivity. Unlike the Al-doping, the Si-doping increases both the reactivity and electronic sensitivity to the PPA drug. At the presence of PPA drug, the conductivity of the Si-doped C60 considerably increases due to the HOMO-LUMO gap reduction by about 30.3%. Different analyses were used to obtain the results including nucleus independent chemical shift (NICS), density of states (DOS), molecular electrostatic potential (MEP), frontier molecular orbitals (FMO), etc. Keywords Sensor, Phenylpropanolamine, Abuse, Fullerene, DFT 1. Introduction

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Detection of illicit drugs is of increasing interest because of the dramatic consequences of their abuse [1-3]. Phenylpropanolamine (PPA) is a popular drug of abuse and its recognition in the biological specimens is of great importance for police and drug communities [4]. It has been demonstrated, in the cases of abuse, several problems such as psychological disorders, and traffic accidents may occur [4]. Thus, developing highly sensitive, fast response, hand-portability sensors for detection of this drug agent is an essential task. Up to date, several detection methods have been introduced including infra-red absorption spectroscopy, gas chromatography, field asymmetric ion mobility spectrometry, etc [5, 6]. By advent of nanotechnology, different nanostructures have found widespread applications as chemical sensors because of their surface/volume ratio which is much greater than that of the conventional micro detectors [7-14]. Carbon nanotubes (CNTs), graphene and fullerenes are popular nanomaterials which have been investigated as gas sensors extensively [15-20]. It has been experimentally and theoretically indicated that modification of fullerene surface by inserting impurity atoms is a promising method to improve its sensitivity to gas molecules [21, 22]. This strategy also has been frequently employed for increasing the sensitivity of different nanostructures to chemicals [23-31]. Also, the interaction of C60 fullerene and its derivatives with different drugs has been extensively studied because of the potential application of C60 in drug delivery [32-36]. In addition to the expensive experimental methods, the computational approaches effectively help to understand the mechanism and the nature of these interactions [37-39]. It has been revealed that replacing a carbon atom of C 60 by Al or Si atom is a useful strategy to improve the drug delivery properties [39]. Also, experimentally many kinds of impurity doped C60 fullerenes have been synthesized [40, 41]. Nishinaga et al. have synthesized Al-doped C60 fullerenes, growing on quartz glass and GaAs substrates by solid 2

source molecular beam epitaxy [42]. Herein, we investigate the reactivity and electronic sensitivity of the intrinsic and extrinsic Al and Si doped (Al-C60, and Si-C60) C60 fullerenes to the PPA drug, using density functional theory calculations. 2. Computational methods The all calculations were performed using the B3LYP functional augmented with an empirical dispersion term (B3LYP-D) and the 3-21G* basis set as executed in the GAMESS code [43]. It has been already shown that extending the basis set does not guarantee the improvement of the electronic properties compared to the experimental results, and 3-21G* results of the electronic properties are in good agreement with the experiment [44, 45]. Similarly, it gives dependable structures according to the different reports [46]. The structures which are investigated here, especially, the complexes are very large with very high degree of freedom which make it impossible using bigger basis sets. We think that the basis set does not have an effect on the analysis of the relative values of the electronic structures because the aberration can be compensated by the scissors approximation. The B3LYP is the commonest functional in the nanostructure examination, reproducing experimental data [47-50]. GaussSum code was used to attain density of states (DOS) plots [51]. The nucleus independent chemical shift (NICS) values, [52] were computed using gauge independent atomic orbital (GIAO) approach [53]. The NICS (0) is predicted as a negative value of the absolute shielding measured in the center of a definite ring. The adsorption energy (Ead) is expected as follows: Ead = E (adsorbent) + E (agent) – E (agent/ adsorbent) + E (BSSE)

3

(1)

where E (adsorbent) is the total energy of a intrinsic or extrinsic C60 molecule. E (agent/ adsorbent) is the total energy of the adsorbed PPA molecule on the adsorbent surface. E (BSSE) is the basis set superposition error (BSSE) corrected for all adsorption energies. 3. Results and discussion 3.1. The PPA molecule specifications Geometry of PPA (C9H13NO) molecule and its HOMO, and LUMO shapes, and the molecular electrostatic potential (MEP) plot are shown in Fig. 1. The MEP plot shows that the oxygen of hydroxyl group (-OH) has the highest negative electrostatic potential and thus, the highest tendency to the electrophilic agents compared to the nitrogen of the amine group (-NH2). Also, a negative region is predicted on the surface of phenyl group which indicates a πconjugated aromatic system. The NICS (0) value in the center of phenyl group is about -8.49 ppm which shows a high aromatic character while its aromaticity is somewhat smaller than that of benzene molecule (NICS (0) = 8.64 ppm at the same level of theory). The HOMO is nearly localized on the whole molecule especially on the oxygen atom and the LUMO is mainly located on the hexagonal ring. 3.2. The PPA adsorption on the pristine C60 The pristine C60 fullerene is made of 20 hexagonal and 12 pentagonal rings and two kinds of C-C bonds can be distinguished in its structure among 90 C-C bonds. One kind is shared by two hexagons ([6-6] bond) and the other shared between a hexagon and pentagon ([6-5] bond). The [6-6] bonds are smaller and have more double bond character, compared to the [6-5] bonds. The [6-6] and [6-5] bond lengths are calculated to be about 1.39 and 1.45 Å, which are in good agreement with the experimental values of 1.40 and 1.45 Å, respectively [54]. For the interaction

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between the PPA and C60, two mechanisms can be assumed including a cycloaddition from hexagonal ring of PPA to a [6-6] or [5-6] bond of C60, and adsorption from another part of molecule on the C60. These mechanisms are considered below. 3.2.1. Cycloaddition Many experimental works have shown that 1, 2 addition of olefins to a [6-6]-ring junction possesses a higher electron density than the [6-5]-ring junction [55-57]. Therefore, the [6-6]-ring junction cycloaddition is thermodynamically much more stable than the [6-5]-ring junction and most of the [6-5]-open derivatives undergo conversion, into the thermodynamically more stable [6-6]-closed isomers [57]. However, for the [6-6] bond cycloaddition of PPA, three configurations can be expected in which a PPA molecule is added to the ring from its α, β, and γ bonds (Fig. 1) of the hexagonal ring. Our calculations indicated that the addition from the γ bond is not possible because of a high steric effect and no local minimum is converged. While two local minima are predicted for α and β bonds addition to a [6-6] bond as shown in Fig. 2. The adsorption energy for the complex in which the cycloaddition occurs from β bond (complex B) is about 20.1 kcal/mol (Table 1) and this complex is more stable than the complex A (Fig. 2), by about 2.4 kcal/mol. However, both of the cycloadditions are endothermic and thermodynamically difficult processes. Upon the cycloaddition process, α and β bonds are enlarged from 1.39 Å to about 1.57 and 1.58 Å. The NICS (0) value (+5.82 ppm) of the hexagonal ring of PPA in the complex B is positive, indicating that the β bond becomes single bond after the cycloaddition, thereby, breaking the aromaticity of the ring. Also, the newly formed tetragonal ring between the PPA and C60 is anti-aromatic with a NICS (0) value of about +3.30 ppm. The NISC (0) values of two hexagons in both sides of the target [6-6] bond are changed from -2.95 ppm in the bare C60 to 5

+3.24 and +2.80 ppm in the complex, indicating an anti-aromaticity character. All of these aromaticity breakings, besides the structural deformation, make the complexes A and B unstable. After the cycloaddition because of the π-conjugated system breaking, the HOMO and LUMO levels are perturbed and the Eg is decreased from 2.94 eV to 2.40 and 2.45 in complexes A and B, respectively (Table 1). 3.2.2. Adsorption from amine and hydroxyl groups It is expected that the PPA drug interacts with the C60 via its –OH or –NH2 groups. While during the optimization process in which the oxygen atom is located near a carbon atom of the C60, the PPA escapes from the C60 surface due to the steric effects of the surrounding groups. However, we found a local minimum when the PPA attacks the C60 form the N atom as shown in Fig. 3 (Complex C). In the complex C, the N-C distance is about 1.65 Å, and the adsorbing carbon atom is slightly projected out of the surface of C60, increasing its adjacent [6-5] and [6-6] bonds from 1.45 and 1.38 to 1.53 and 1.48 Å, respectively. This reveals that the interaction is strong but the adsorption energy is small (less negative, ~ -0.1 kcal/mol) because much of the released energy is compensated by this deformation energy. Also, our NICS analysis indicates that the two hexagonal rings around the adsorbing site loss their aromaticity because of a structural deformation. The NICS (0) values for these rings are about + 2.27 and +1.97 ppm. Table 1 indicates that the electronic properties of C60 are significantly affected by the adsorption process. To explore the electronic sensitivity of C60 to PPA, we use a prevalent method which frequently was employed to relate the Eg to the electrical conductivity of a semiconductor as follows [58-60]: σ = A T3/2 exp(-Eg/2kT)

(2)

6

where k is the Boltzmann's constant and A (electrons/m3K3/2) is a constant. It has been demonstrated that the results of this technique are in a good agreement with the experiment [28]. Based on this equation, a change in the Eg exponentially modifies the population of conduction electrons, thereby, altering the electrical conductivity which can produce an electrical signal. Table 1 indicates that both of the LUMO and LUMO levels of C60 are meaningfully unstabilized by shifting to higher energies after the PPA adsorption via N atom. In accordance with this energy shift, the shape of the HOMO and LUMO is significantly changed by shifting from the C60 on the –OH and –phenyl groups of PPA molecule (Fig. 3). Subsequently, the Eg of the C60 is largely reduced (by about 23.8%, Table 1) which exponentially increases the conductivity. Overall, the electronic properties of C60 are highly sensitive to the presence of PPA drug, while the interaction in between is very weak, hindering the high adsorption capacity. To improve the reactivity, but retaining the sensitivity, we explored the strategy of replacing a C atom by Al or Si atom. 3.3. Adsorption of PPA on the Al- C60 A carbon atom is replaced by an Al atom and the structure was optimized as shown in Fig. 4. In the Al-C60, Al atom is protruded out of the surface of the C60 because of its larger size compared to the carbon atom. The formed [6-5] and [6-6] Al-C bonds are about 1.90 and 1.87 Å, respectively, being larger than the corresponding C-C bonds. The Al-doping process also significantly distributes the electronic properties of the C60. The HOMO and LUMO are largely shifted to higher energies and the Eg is decreased from 2.94 to 1.45 eV. The Eg is a value of kinetic stability and the lower value somewhat shows higher reactivity [61]. As shown in Fig. 4, two stable PPA/Al-C60 complexes were found in which the PPA attaches to the Al atom from its nitrogen (complex N-Al) or oxygen (complex O-Al) atom. The adsorption energy for complexes 7

N-Al and O-Al are calculated to be about -65.6 and -73.9 kcal/mol, which are significantly more negative than that of the PPA adsorption on the pristine C60. This is because of the more nucleophilic character, higher hybridization, and out of plan character of the Al atom compared to carbon atom. As it is shown by the MEP plot (Fig. 4), the electrostatic potential of the Al atom is significantly larger (more positive) compared to the other carbon atoms which makes it more electrophilic site for O or N atom of PPA. Also, the hybridization of the Al atom is nearly sp3 and it is projected out of the surface and is more accessible for nucleophilic attack. In the N-Al complex, the newly formed Al-N bond is about 1.96 Å and the Al-C bonds are enlarged slightly upon the adsorption process. For the O-Al complex, the mechanism of the adsorption is different in which upon the adsorption process, the hydrogen of –OH group transfers on the –NH2 group indicating that the –NH3+ is more stable than the –OH2+ group. The N atom can sustain positive charge easier than the much more electronegative oxygen atom. Overall, the interaction of –OH group is stronger than that of the –NH2 one. It is shown in Table 2 that the HOMO and LUMO of the Al-C60 are significantly changed upon the adsorption process but the value of Eg is very slightly increased (by about 7.5 or 8.6%). This shows that although the Al-doping significantly improves the interaction between the PPA and fullerene, it largely reduces the electronic sensitivity. 3.4. Adsorption of PPA on the Si- C60 Similar to the case of Al-doping, a carbon atom is replaced by a Si atom and the structure was optimized as shown in Fig. 5. In the Si-C60, Si atom is projected out of the surface of the C60 because of its larger size compared to the carbon atom (similar to the Al atom). The formed [6-5] and [6-6] Si-C bonds are about 1.83 and 1.78 Å, respectively, being smaller than the 8

corresponding Al-C bonds because of smaller size of Si compared to the Al. Compared to the Aldoping, the Si-doping process slightly distributes the electronic properties of the C60. The Eg is decreased from 2.94 eV in the pristine C60 to 2.30 eV in the Si-C60. As shown in Fig. 5, two stable PPA/Si-C60 complexes were found in which the PPA attaches to the Si atom from its nitrogen (complex N-Si) or oxygen (complex O-Si) atom. The adsorption energy for complexes N-Si and O-Si are about -52.3 and -86.0 kcal/mol, which are significantly more negative than that of the PPA adsorption on the pristine C60. In the N-Si complex, the newly formed Si-N bond is about 1.88 Å and the Si-C bonds are enlarged slightly upon the adsorption process. For the OSi complex, the hydrogen of –OH group transfers on a C atom which is adjacent to the Si atom. This is different from the adsorption mechanism in the Al-O complex. Overall, the interaction of –OH group with Si site is stronger than that of the –NH2 one and also is stronger than that of the –OH group with the Al-C60. Table 3 indicates that upon the adsorption process via –OH group, the HOMO level of the Si-C60 is significantly unstabilized by shifting from -6.24 to -4.23 eV and, also, the LUMO is slightly unstabilized by about 0.72 eV. Our frontier molecular orbital analysis (Fig. 6) demonstrates that the shape of these levels is also significantly changed in consistence with the energy change. In the Si-C60, the HOMO and LUMO are mainly localized on the Si atom and its surrounding environment with different orbital phase. While the –OH group interacts directly with the Si atom and influences both the HOMO and LUMO levels. The HOMO is distributed on the whole fullerene except Si atom and also slightly on the N atom in the complex O-Si. The LUMO is shifted from surface of Si site to the other sites of the fullerene. Consequently, the Eg of the Si-C60 is significantly reduced by about 30.3%, indicating that the sensitivity of the Si-C60 is higher than the pristine C60 to the PPA drug. This reduction of Eg exponentially increases the 9

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Figure captions Fig. 1. The optimized structure of phenylpropanolamine (PPA) drug, its molecular electrostatic potential (MEP) plot, HOMO, and LUMO profiles. The length of α, β, and γ is about 1.39 Å. Fig. 2. Optimized structures of cycloaddition of phenylpropanolamine (PPA) drug to the C60 fullerene. Complex A and B indicates the cycloaddition of PPA from its α and β bonds to the fullerene, respectively. Distance are in Å. Fig. 3. Optimized structures of adsorption of phenylpropanolamine (PPA) drug from its –NH2 group on the pristine C60 fullerene and its HOMO and LUMO profiles. Distance are in Å. Fig. 4. Optimized structures of (a) Al-C60 and (b) its molecular electrostatic potential (MEP) plot. Also, the optimized structures of phenylpropanolamine (PPA) adsorbed from its (c) N and (d) O atoms on the Al-C60. Distances in Å. Fig. 5. Optimized structures of (a) Si-C60 and (b) the complexes of phenylpropanolamine (PPA) adsorbed from its (b) N atom and (c) O atom on the Si-C60. Distances in Å. Fig. 6. The HOMO and LUMO profiles of Si-C60 before and after the adsorption of phenylpropanolamine (PPA) drug from its –OH group on the Si site.

18

Compound

Ead

EHOMO

ELUMO

Eg

%∆Eg

C60

-

-6.51

-3.57

2.94

-

A

22.5

-5.78

-3.38

2.40

-18.3

B

20.1

-5.82

-3.37

2.45

-16.6

C

-0.1

-5.21

-2.97

2.24

-23.8

Table 1. The adsorption energies in kcal/mol for cycloaddition of phenylpropanolamine drug to the C60 through complexes A and B (Fig. 2) and its adsorption from N atom through the complex C

(Fig. 3). Energies of HOMO, LUMO and Eg in eV. The ∆Eg indicates the change of Eg of C60 after the drug adsorption.

Table 2. The adsorption energies (Ead, kcal/mol), energies of HOMO, LUMO and Eg in eV for Al-

C60 and N-Al and O-Al (Fig. 4). The ∆Eg indicates the change of Eg of Al-C60 after the drug adsorption.

Cluster

Ead

EHOMO

ELUMO

Eg

%∆Eg

Al-C60

-

-5.79

-4.35

1.45

-

N-Al

-65.6

-5.10

-3.54

1.56

7.5

O-Al

-73.9

-4.92

-3.35

1.58

8.6

19

Table 3. The adsorption energies (Ead, kcal/mol), energies of HOMO, LUMO and Eg in eV for Si-

C60 and N-Si and O-Si (Fig. 5). The ∆Eg indicates the change of Eg of Si-C60 after the drug adsorption.

Cluster

Ead

EHOMO

ELUMO

Eg

%∆Eg

Si-C60

-

-6.24

-3.95

2.30

-

N-Si

-52.3

-5.19

-2.95

2.24

-2.6

O-Si

-86.0

-4.23

-2.67

1.56

-30.3

Fig. 1..

20

21

Fig. 2.

22

Fig. 3.

23

Fig. 4.

24

Fig. 5.

25

Fig. 6.

26

Highlights Adsorption of phenylpropanolamine (PPA) drug on the C60 is studied by DFT Two adsorption mechanisms were predicted for PPA on the pristine C60 The C60 has a good sensitivity to PPA but suffers from a weak interaction Si-doping makes the C60 much more sensitive and reactive to the PPA

27