Density Functional Theory, Atoms in Molecule and Becke ... · 1 Article 2 Density Functional...

Article 1

Density Functional Theory, Atoms in Molecule and 2

Becke Surface Studies on the Interaction Mechanism 3

in Dioxin Imprinted Polymers 4

Muntazir Saba Khan1*, Sourav Pal2 5 1Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, 400 076, India; 6

[email protected] 7 2Indian Institute of Science Education And Research Kolkata, Mohanpur, 741 246, West Bengal, India; 8

[email protected] 9 * Correspondence: [email protected]; Tel.: +91-8956111113 10

Abstract: We have presented a benchmark study of binding energies for dioxin-imprinted polymer 11 complexes. A density functional theory (DFT) approach was used for screening the polymerization 12 precursors in the rational design of molecularly imprinted polymers (MIPs). The 13 tetrachlorodibenzo-p-dioxin (TCDD) was taken as an imprinted molecule. The geometry 14 optimization, natural bond orbital (NBO) charge, and molecular electrostatic potential (MEP) of 15 TCDD and AM were studied at the M062X level and 6-31g (d,p) belonging to one of the hybrid 16 density functional theories. The results of MEP and NBO charge analysis were comparable. Among 17 functional monomers: acrylamide (AM), methacrylic acid (MAA), itaconic acid (IA), and 4-Vinyl 18 pyridine (VP); acrylamide (AM) was confirmed as the best functional monomer, because the 19 strongest interaction (the maximum number of hydrogen bonds and the lowest binding energy) 20 occurs between TCDD and AM. The stability property was excellent when the ratio of TCDD and 21 AM was 1:4. The polarizable continuum model (PCM) was used for solvent calculations. 22 Computational results showed that acetonitrile plays an important role in the MIP formation, as it 23 seems to control the size and the shape of the cavity. The atoms in molecule (AIM) and Becke 24 surface method have also been applied to understand the nature and strength of the hydrogen 25 bonding interactions in complexes. TCDD-AM complexes were found involving C-O···Cl and 26 N-H···Cl hydrogen bonds. Good correlations have been established between hydrogen bond 27 lengths versus AIM topological parameter like electron density (ρ (r)) and its Laplacian (▽2ρ (r)) at 28 the bond critical points. On ground of theoretical results, a series of MIPs were synthesized. The 29 MIP prepared using TCDD as the template, the functional monomer (AM), and the cross-linker 30 (TRIM) in acetonitrile solvent exhibited the highest adsorption capacity for TCDD. The maximum 31 binding capacity of TCDD on the MIP was 3.7 μg/mg. This research work can provide a theoretical 32 reference for the fabrication and characterization of novel TCDD-MIPs for environmental 33 applications. 34

35

Keywords: tetrachlorodibenzo-p-dioxin (TCDD); hybrid density functional theory; atoms in 36 molecule (AIM); becke surface method; molecularly imprinted polymer 37

38

1. Introduction 39

Molecular imprinting (MI) is an extremely efficient class in molecular recognition technologies. In 40 molecularly imprinted polymer approach, a specific protocol creates explicit nano-cavities with high 41 affinity and selectivity that are capable of recognizing and binding a probable target molecule. MIPs 42 have attracted lots of interests in many fields such as solid phase extraction [1-2], chiral separation 43

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[3], immune-like assay [4], antibody simulation [5], chemical sensors [6-7], drug delivery [8] and 44 wastewater treatment [9] due to its extremely high recognition performance, low cost, high physical 45 and chemical stability, and application tailor-made recognition sites. 46

Nevertheless, the selective recognition of MIPs is affected by various key factors such as the 47 functional monomer, cross-linker, porogen, and imprinted molar ratio, which remarkably affect the 48 recognition properties of the MIPs. Therefore, the choice of polymer precursors (functional 49 monomer, cross-linker, porogen, and imprinted molar ratio) must be very sensible to get a MIP with 50 high performance and selectivity. For selecting appropriate functional monomers and imprinted 51 molar ratios, the strengths of interactions between the functional monomers and the templates 52 should be evaluated based on binding energies. Usually, more interaction sites and lower values of 53 the binding energies should result in stronger interactions between template and the functional 54 monomers [10]. Moreover, the choice of cross-linker is another crucial step to the construction of 55 polymer systems selective. The strengths of the interactions between the template and the 56 cross-linkers should be weak, and between the functional monomers and the cross-linkers should be 57 strong. Else, the cross-linkers may compete with the functional monomers, which may result in poor 58 recognition properties of the MIPs for the targeted molecules. In practice, an attempt based on the 59 trial-and-error method is made. 60

Recently, the combinatorial and computational methods have been considered as alternative 61 approaches for the rational design of MIPs [11-14]. The characterization of molecular complexes 62 formed between templates and monomers, with the aim of attainment a clear picture of the 63 interactions that are the basis of MIP technology, have been the goal of numerous theoretical studies 64 [15]. Wei et al. investigated the mechanism of 17β-estradiol imprinting with dynamic simulations to 65 select most suitable monomers [16]. Del Sole et al. reported the prepolymerization interaction 66 between nicotinamide and methacrylic acid in different solvents and the computational 67 investigation on the complex to obtain a better understanding of hydrogen-bonding interactions 68 [17]. Yañez et al. offered a computation to screen commonly used monomers and select the most 69 suitable monomers for synthesizing cholate-imprinted and non-imprinted polymer [18]. Overall, the 70 theoretical calculations reduce the time required to understand the molecular imprinting mechanism 71 and also it helps us to achieve the active site for the targeted molecule. In most of the literature, it has 72 been noticed that the traditional methacrylic acid has been used as a functional monomer due to its 73 easy availability [19]. Furthermore, many scientific groups have studied the selection of appropriate 74 functional monomer and polymer precursors of MIP by using DFT method at the B3LYP/6-31G (d) 75 level. For example, Piacham et al. studied the molecularly imprinted nanospheres for selective 76 recognition of α-tocopherol succinate by employing the DFT/B3LYP method [20]. Khan et al. 77 designed a new computational model capable of understanding the nature of the interaction 78 between the template and the functional monomers by using the DFT/B3LYP method [21]. Diñeiro et 79 al. used the DFT/B3LYP method to design the MIPs for voltammetric sensing of homovanillic acid 80 [22]. However, it is well known that the accuracy and reliability calculated via different functional 81 theories are different in the matter of molecular calculation [23]. 82

It was documented during the 1970s that polychlorinated derivatives of dibenzo-p-dioxin (dioxins, 83 PCDDs) pose a serious concern as a ubiquitous and tremendously hazardous class of organic and 84 global pollutants [24-26]. The major emission sources of PCDDs to the environment are incineration 85 of domestic, industrial, and hospital waste, as well as natural combustion processes (e.g., volcanic 86 activity), with the main route of human exposure via food intake [27]. Exposure to these molecules 87 in living beings cause adverse health effects such as mutagenicity, carcinogenicity, reproductive 88 disorders, immune suppression, birth defects and they are also endocrine disruptors [28]. The most 89 toxic congener among PCDDs is 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD). Thus, there is a 90 necessity to develop an effective, yet economical method for the elimination of dioxins from the 91 environment; hence we have selected TCDD for our present study. 92



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In the present study, a DFT-based computational approach was used to design TCDD-MIPs with the 93 property of selective adsorption of TCDD. The presented model allows us to predict qualitatively 94 and quantitatively possible interactions in the MIP system. To select the appropriate DFT functional 95 method, the optimization of the structure of TCDD has been done with several methods (B3LYP, 96 BHandHLYP, M062X and ωB97xD) and basis sets (6-31G (d, p), 6-31++G (d, p). The optimized results 97 are analyzed and compared with the earlier experimental data available in the literature. The 98 binding sites, binding strength, and the mechanism of the interactions between TCDD and the 99 functional monomers were deliberated by NBO and MEP analysis. Topology analysis i.e. AIM and 100 Becke surface method have been performed to confirm the existence and strength of hydrogen 101 bonding and to find the information about charge transfer between the molecules. The theoretical 102 studies were further validated experimentally. Overall, this article aims to provide a simple 103 computational approach for the better understanding of the molecular architecture of MIPs, and 104 nature of interactions during molecular recognition of dioxins. 105

2. Results and Discussion 106

2.1. Selection of the Appropriate Method Based on Theoretical Calculations 107 In this work, we have optimized the geometry of TCDD (Figure 1) with four different DFT 108

functionals i.e. B3LYP, BHandHLYP, M062X and ωB97xD methods and basis sets (6-31G (d, p), 109 6-31++G (d, p)) in order to screen the optimum functional monomer for the fabrication of dioxin 110 imprinted polymers. The theoretical method was confirmed by comparing the theoretical results 111 and the experimental data [29]. The structural parameters of TCDD calculated by four different 112 functions and basis set are presented in Table 1. As can be observed in Table 1, the bond length 113 calculated by M062X of the four unique C-Cl, the four C-O, and the twelve C-C are 1.751, 1.389, and 114 1.370 respectively. However, the experimental data values of the four unique C-Cl, the four C-O, and 115 the twelve C-C are 1.73, 1.37, and 1.36 respectively. In contrast, the theoretical values obtained by the 116 B3LYP, BHandHLYP, and ωB97xD methods are all 1.801, 1.789 and 1.817 Å respectively for C-Cl. 117 Similarly, the experimental bond angle of C-O-C is 115.7° and the value obtained through B3LYP, 118 BHandHLYP, M062X and ωB97xD methods are 117.92, 118.42, 116.3, 119.13 respectively. In addition, 119 the basis sets cannot make significant changes in the molecular structure. From Table 1, it has 120 observed that the differences between the 6-31g (d, p) and 6-31++g (d, p) basis sets are 0~0.04 Å and 121 0~0.05° in bond lengths and angles, respectively. Further, we have also compared our results with 122 existing structural parameter of 2,3,7,8-TCDD calculated at the B3LYP/6-311+G(2d,2p) level [30]; and 123 11Ag ground states of 2,3,7,8-TCDD calculated at the CASSCF(16,14)/cc-pVDZ [31]. From the table 1, 124 it was observed that there is a very slight deviation in our results and also the computation time has 125 been saved by using M062X/6-31g(d,p) method as compared to the existing methods. Hence, we 126 have selected the M062X/6-31g(d,p) as the appropriate method for further calculations. 127

128 Figure 1. Optimized structure of Tetrachlorodibenzo-p-dioxin (TCDD) at M062X/6-31G(d,p) level 129

130



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Table 1. Bond Lengths (Å) and Bond Angles (°) calculated by the B3LYP, BHandHLYP, M062X 131 and ωB97xD with Basis Sets (6-31g(d, p), 6-31++g(d, p) and experimental data of TCDD. 132

Bond/

Angle

B3LYP BHandHLYP M062X ωB97xD a

Ref.30

b

Ref.31

c

Ref.29 6-31g

(d, p)

6-31++g

(d,p)

6-31g

(d,p)

6-31++g

(d,p)

6-31g

(d,p)

6-31++g

(d,p)

6-31g

(d,p)

6-31++g

(d,p)

R (Å)�

C-Cl 1.809 1.778 1.789 1.791 1.751 1.758 1.817 1.819 1.743 1.737 1.73

C-O 1.403 1.408 1.412 1.417 1.389 1.392 1.437 1.438 1.377 1.361 1.37

C-C 1.386 1.389 1.392 1.397 1.370 1.373 2.111 2.117 1.392 1.395 1.36

Φ (◦)�

C-O-C 117.9 117.9 118.4 118.4 116.3 116.3 119.1 119.2 116.2 116.6 115.7

*aStructural Parameter of 2,3,7,8-TCDD at the B3LYP/6-311+G(2d,2p) Level [Ref.30]; bGeometric Parameters of the 11Ag Ground States 133 of 2,3,7,8-TCDD at the CASSCF(16,14)/cc-pVDZ [Ref.31]; cExperimental geometry from crystallographic data (ref 29) 134 135 2.2. Selection of Functional Monomer and molar ration Based on Theoretical Calculations 136

We have selected AM, MAA, IA, and VP as the functional monomers because of their easy 137 availability and frequent use in MIP fabrication. Figure 2, represented the optimized structure and 138 MEP surface of the functional monomers (AM, MAA, MBA, and IA). For the selection of appropriate 139 functional monomer, we have compared the values of binding energies of TCDD and different 140 functional monomers (∆E) listed in Table 2. From the Table 2, it has been noticed that the values of 141 ∆E are in the order of ∆E (TCDD-AM) < ∆E (TCDD-MAA) < ∆E (TCDD-IA) < ∆E (TCDD-VP), which 142 may indicate that the interaction between TCDD and AM has the highest strength among the 143 complexes formed stable TCDD and AM pre-polymerized complex. Hence the results reveal that 144 among functional monomers, acrylamide (AM) should be the best functional monomer for the 145 synthesis of the MIPs with the properties of recognizing TCDD. 146

147 Figure 2. Optimized structure and MEP surface of the functional monomers 148



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149 Table 2. Binding energies (∆E, Kcal/mol) of TCDD and different functional monomer 150 complexes with and without BSSE correction in the gas-phase at the M062X/6-31G(d,p) level 151

T-M Complexes ΔΕB (non-corr.) ΔΕB (corr.) μ(Debye)

TCDD-AM -27.583 -25.918 2.27

TCDD-MAA -33.224 -29.744 1.35

TCDD-IA -53.793 -51.216 3.49

TCDD-VP -43.194 -38.339 3.68

152 Theoretical titrations for calculating the molar ratio for TCDD imprinting, using MAA 153

functional monomers, have been designed to create the more realistic view of functional monomer 154 template binding in MIPs. Figure. 3 clarify that the system has been saturated in all the binding sites 155 of TCDD by four functional monomers. Also, we have investigated the effect of the addition of 156 functional monomers to the complex system (Table 3). From the result, it was seen that the bond 157 distance value between Cl···H and Cl···O was 1.87 and 2.35 Å respectively, but as the number of 158 functional monomers was increased, the bond distance was reduced to 1.65 and 1.83 Å. This may 159 occur because of the reorientation and steric effect of other functional monomer molecules. This is in 160 agreement with the conclusion that the self-association might not seem in the low concentration of 161 the functional monomer. Hence the binding energy of the complex with the molar ratio of 1:4 was 162 the best ratio to create a successive TCDD-MIP with stronger stability. 163

164 Figure 3. The binding distance between T-FM complexes by varying the numbers of functional 165

monomers in the system. 166 Table 3. Theoretical titration parameters for optimization of fixed T/M ratio at the 167 M062X/6-31G(d,p) level 168

Molar Ratio Bond Numbers Action Sites Bond length (Å) ΔE (Kcal/mol)

1:1 2 Cl(22)···O(24)

Cl(21)···H(26)

2.35

1.87 -25.918

1:2 4 Cl(22)···O(24)

Cl(21)···H(26)

2.01

1.73 -38.730

1:3 6 Cl(22)···O(24) 1.96 -45.029



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Cl(21)···H(26) 1.70

1:4 8 Cl(22)···O(24)

Cl(21)···H(26)

1.83

1.65 -53.113

1:5 6 Cl(22)···O(24)

Cl(21)···H(26)

2.12

1.77 -47.291

169 2.3. Selection of Cross-Linker Based on Theoretical Calculations 170

The key role of the cross-linkers in the polymeric network is to shield the functionality of 171 functional monomers in specific sites and directions around the template molecules and thereby to 172 prevent the structure of the binding cavities [21]. Ethylene glycol dimethylacrylate (EGDMA), 173 pentaerythritol triacrylate (PETA), and trimethylolpropane trimethacrylate (TRIM) are most 174 commonly used as the cross-linkers in the synthesis of the MIPs; therefore we have selected them as 175 the cross-linkers for our study. The binding energies (∆E1) of pre-polymerized complexes and 176 cross-linkers calculated at the M062X/6-31G(d,p) level are reported in Table 4. The presence of the 177 cross-linker can affects the binding between the functional monomers and the template. The 178 molecular screening of the cross-linkers against TCDD-AM validated that the highest ∆E1 value 179 obtained with PETA (-42.184 kcal/mol) and EGDMA (-38.918 kcal/mol), and lower energy with 180 TRIM (-34.921 kcal/mol) (Table 4). It is possible to advise that TRIM would be considered as the best 181 cross-linker for the imprinting of TCDD as it formed the strong complex without disturbing the 182 arrangement of functional monomer around the template. At the same time, cross-linkers (EGDMA 183 and PETA) would most likely to compete with the functional monomer for binding of the template 184 and would possibly affect the formation of the molecular complex that is dominant for the success of 185 molecular imprinting. The study reveals that the most stable complex is formed between 186 TCDD-AM-TRIM; hence TRIM is acted as best cross-linker for the dioxin imprinted polymers. 187

Table 4. Binding energies (∆E1 & ∆E2) between TCDD-AM complexes and different cross-linkers 188 in a vacuum and in porogen at the M062X/6-31G(d,p) level (kcal/mol). 189

Complexes ∆E1in vac ∆E2in ACN ∆E2 in CHL ∆E2 in DCM ∆E2 in DMS

TCDD-AM-EGDMA -38.918 -38.827 -36.110 -36.786 -34.932

TCDD-AM-PETA -42.184 -40.154 -38.721 -37.982 -33.470

TCDD-AM-TRIM -34.921 -37.278 -36.011 -34.815 -36.634

2.4 Selection of porogen for template–monomer-cross-linker systems 190 It is crucial to mimic porogen in polymerization, as MIP process occurs in a porogenic solution. 191

In porogenic solution, however, the stability and order of binding energies are quite different. Table 192 4 lists the data for 1:1 complexes in a vacuum and in different porogen. As can be seen, a significant 193 decrease in the binding energy in each case was observed relative to that of the gas-phase. This 194 makes sense since solvation of a species involves also inter-molecular interactions of the same nature 195 as monomer–template, and so the solvent acts as a competitor. The trend of BE with complexes is as 196 follows: acetonitrile > chloroform > dimethylsulfoxide > dichloromethane. Table 4 shows that the ∆E2 197 value of the complex in ACN (-37.278 kcal/mol) is the highest, and the ∆E2 value of the complex in 198 DCM (-34.815 kcal/mol) is the lowest. Under the rule, the strength of complex with solvent should be 199 weak which leads the formation of a strongest interaction between the template and the FM to 200 generate control size and shape of the cavity. Thus, ACN was chosen as the best porogen in our 201 studies. Hence, the all above discussion provide a best-predicated MIP recipe for fabrication of high 202 performance and selective adsorbent for TCCD from the environment. 203



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2.5. Prediction of the Active Sites of complexes by NBO and MEP charge analysis 204 We have also investigated the active sites of molecules on the basis of NBO and MEP charge 205

analysis (Figure 4). NBO charge analysis (Figure 4a) shows that the O-24 with value -0.609 and N-25 206 with values -0.783 of AM carries a negative charge. As the nitrogen atoms belonging to the sp2 207 hybridization, it is difficult for nitrogen atoms of AM to accept a proton. Hence, the carbonyl oxygen 208 atom of AM monomer acceptors the proton and act as nucleophilic centers. The hydrogen atoms 209 associated with nitrogen atoms of AM carries a more positive charge with NBO charge values 0.407 210 (H-26), and 0.382 (H-27), respectively. Therefore, these two hydrogen atoms act as the proton 211 donors. However the other carbon, nitrogen and hydrogen atoms present in the AM have been not 212 taken part in proton donors or acceptors, they could be neglected in the simulation process. 213 Subsequently, the active sites of TCDD were mainly Cl-21 (-0.015), Cl-22 (0.033) respectively (Figure 214 4a). The negative charges were mainly distributed on the oxygen atoms of TCDD, because of the 215 steric factors and arrangement of electropositive and electronegative atoms. The oxygen atom of AM 216 easily approaches to one of the Cl atoms of the TCDD by accepting an electron. Whereas the other Cl 217 atom of TCDD forms week to bond with the hydrogen atom of AM by donating a proton. Thereby, 218 the main active sites of AM were O-24, H-26, and H-27. 219

220 Figure 4. 4(a) NBO charges and 4(b) MEP surface of TCDD-AM pre-polymerized complex. Red 221

regions of the map are the most electron-rich regions of the molecule, and blue regions are 222 electron poor. Order of increasing electron density is blue < orange < red. 223

Molecular electrostatic potential (MEP) maps use local electronic charge density to 224 systematically investigate a molecule’s ability to interact. Generation of MEP maps for this study is 225 ideal for predicting the nature of interactions and provides justification for molecular phenomena. 226 Conferring to the scattering of colors, we could judge the position of strong electropositive and 227 electronegativity atoms that aids to determine the active sites. From the color scale of MEP contour 228 in figure 4b, we identified that the –C=O group of AM surface closer to the red color shows dense 229 electron cloud of atoms (strong electronegative), whereas the –NH2 group of AM surface closer to 230 the blue color shows less electron cloud of atoms (strong electropositive). Obviously, the positive 231



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charges localized on the hydrogen atoms easily react with nucleophilic reagent and acquire 232 electrons. The negative charges distributed on the carbonyl oxygen atoms in AM easily react with 233 nucleophilic atoms and lose electrons. Additionally, electron deficient area of TCDD is at Cl-21 234 atoms in the blue region, and the electron efficient area of TCDD is at Cl-22 atoms in the red region. 235 The results of NBO and MEP charge analysis were coextensive. 236 2.6. AIM and Becke Surface analysis for strength of H-bonding 237

We have further explained the T-FM interaction with the help of Multiwfn software [25] based 238 on Bader's atoms in molecules (AIM) theory [26] and Becke Surface (BS) method in order to 239 understand the nature and strength of the hydrogen bonding interactions in complexes. Topology 240 analysis of electron density is the main ingredient of AIM theory. All critical points (CPs) have been 241 searched and it satisfied the Poincaré-Hopf relationship that means all critical points (CPs, (3, -3); 242 �(3, -1); (3, +1); (3, +3))�may have been found. From all the CPs, bond critical points (BCPs, (3, -1)) are 243 used to predict the interaction between two neighboring atoms bonded chemically. Figure 5., shown 244 T-FM interaction by plotting interbasin surfaces (IBS) corresponding to the BCP (3, -1) with an index 245 of 67 and 54 in AIM. The nature of chemical bonds and molecular reactivity are described by 246 total electronic density ρ (r), Laplacian electronic density ▽2ρ (r) and the electronic energy density (H), 247 which is composed by the electronic kinetic energy density (G) and the electronic potential energy 248 density (V). The interactions are studied by considering the values of the electron density (ρ (r)) and 249 Laplacian of the electron density (▽2ρ (r)) at the bond critical points (BCP) of the Cl(22)···O(24)-C and 250 Cl(21)···H(26)-N. If ▽2ρ (r) > 0 and H(r) > 0 at BCP, the molecules interacted via weak interaction 251 (electrostatic interaction). If, ▽2ρ(r) > 0 and H(r) < 0 indicated that the molecules interacted by 252 moderate interactions. ▽2ρ(r) < 0 and H(r) < 0 confirmed the presence of strong intermolecular 253 interaction (covalent interaction) [23]. The values of AIM topological parameters of the 254 intermolecular hydrogen bond for complexes are shown in Table 5. In the present study, the values 255 of ρ (r) and ▽2ρ (r) varies from 0.011 to 0.098 a.u and 0.209 to 0.921 a.u. Maximum electron density in 256 the self-association is 0.098 a.u and in cross-association is 0.033 a.u shows hydrogen bonds are 257 observed for Cl(21)···H(27)-N interaction with stability. The interaction of Cl(22)···O(24)-C belonged 258 to ▽2ρ (r) > 0 and H(r) > 0 i.e. 0.413 and 0.268 respectively. This result reveals that the interaction 259 belongs to electrostatic interaction as mentioned above. The Laplacian charge density value (Table 5) 260 for all molecules at BCPs are positive which reveal that electronic charges are depleted in the 261 interatomic path, which is characteristic of closed-shell interactions such as hydrogen bonds. Also, 262 the output indicates that the V(r) at Cl(22)···H(26), BCP is -0.022, therefore the hydrogen bond energy 263 could be evaluated as EHB= -0.022/2*2625.5= -29.8 KJ/mol. 264

265 Figure 5. AIM study of T-FM interaction by plotting interbasin surfaces (IBS) corresponding to 266

the (3, -1) with the index of 67 and 54 267



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Table 5. AIM Property of the TCDD-AM Complex (1:4) (a.u.) 268

Active sites ρ(r) ▽2ρ(r) V(r) G(r) H(r)

Cl(22)···O(24) 0.016 0.572 -0.386 0.045 0.723

Cl(22)···H(26) 0.011 0.218 -0.022 0.058 -0.0012

Cl(21)···O(34) 0.027 0.921 -0.303 0.012 0.268

Cl(21)···H(36) 0.098 0.352 -0.035 0.046 -0.0011

Cl(20)···O(44) 0.087 0.413 -0.683 0.086 0.700

Cl(20)···H(46) 0.033 0.314 -0.052 0.064 -0.0012

Cl(19)···O(54) 0.027 0.883 -0.302 0.041 0.305

Cl(19)···H(56) 0.059 0.209 -0.036 0.044 -0.0008

Becke surface (BS) analysis represents a unique approach towards an understanding of the 269 strength of interactions in the complex. In addition to the BS analysis, the fingerprint plots also 270 provide some useful quantitative information about the individual contribution of each 271 intermolecular interaction in the complexes. The three-dimensional BS generated for TCDD-AM 272 complex is presented in Figure 6. The red contacts highlight the intermolecular interactions with 273 distances closer than the sum of the van der Waals radii, while yellow indicates contacts near the van 274 der Waals. After analysis, we found numerous surface minima, which are meaningless in this case, 275 and at the same time, three surface maxima are found (Figure 6). The sequence of electron density at 276 these maxima is 0.009>0.008>0.005, one can expect that the sequence of H-bond strength is 277 Cl21-H26>Cl21-H27>Cl22-O24. This conclusion is identical to the analysis of AIM bond critical point 278 analysis. 279

280

Figure 6. Becke surface analysis to evaluate the strength of interaction between the TCDD-AM 281 complex 282

2.7. Comparison of Theoretical and Experimental Studies 283

The theoretical studies provided a platform to select the most appropriate polymer precursors for 284 fabrication of TCDD-imprinted polymer. To compliment the theoretical calculations, sets of MIPs 285



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(AM-MIP, MAA–MIP, IA-MIP and VP–MIP) were synthesized based on the theoretically predicated 286 composition. The binding capacity of series of MIPs was determined and found that the order of 287 binding capacity of the MIPs was AM-MIP>MAA-MIP>IA-MIP≥VP-MIP. Then, the MIPs were 288 synthesized in four different porogenic solvents (acetonitrile, chloroform, dichloromethane and 289 dimethylsulfoxide) to know the solvent implications on molecular imprinting. The experimental 290 results of binding capacities of MIPs were correlated with the binding energies of theoretical data 291 and presented in Figure 7. The result signifies that the high binding capacity was achieved with the 292 AM-MIP prepared in acetonitrile and the lowest adsorption capacity for IA-MIP synthesized in DMS. 293 These experiments verify that, according to the theoretical predictions, among different monomers 294 and solvents tested, AM is the best functional monomer and ACN is the most favorable solvent to 295 prepare an imprinting polymer for TCDD. The relationship between theoretically derived ΔE and 296 experimentally determined binding capacity k’ was established; the relationship is a linear with 297 r=0.986. Adsorption experiments confirmed the utility of computational approaches to select the best 298 polymer recipe for the fabrication of efficient and selective MIPs in an experimental free way. 299

300

301 Figure 7. The relationship between experimentally derived binding capacities versus theoretically 302 computed binding energies between functional monomers and TCDD in different solvents. 303

3. Materials and Methods 304 3.1. Computational Methods 305

Quantum mechanics calculation including ab-initio method, density functional theory (DFT), 306 semi-empirical method, and perturbation theory are the fundamental tool to calculate the molecular 307 properties. To understand the properties of MIP at the molecular level, the model of the template–308 monomer complexes were framed. The electronic contribution i.e. electron interaction cannot be 309 ignored, as they play an important role to calculate the molecular properties [27]. Thus, DFT has 310 been selected as the resourceful theory for all the theoretical calculations [28]. We have calculated the 311 electronic energies and other properties through density functional theory (DFT) via different 312 functional methods in order to get the more accuracy and reliability. The initial structure of TCDD 313 was optimized using different functional (B3LYP, BHandHLYP, M062X, and ωB97xD) methods and 314



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basis sets (6-31G (d, p), 6-31++G (d, p)) at Gaussian 09 software [29]. Then we compared the 315 theoretical values of bond length and bond angle of TCDD with experimental data, to screen out the 316 reliable method. Geometries of all the polymer precursors and their pre-complexes were optimized 317 followed by harmonic vibrational frequency calculations at the same level of theory to confirm that 318 all structures were at local minima on the potential energy surface. Additionally, the theoretical 319 titration of the complex at different imprinting molar ratios was also optimized. The T-M complexes 320 with the lowest value of binding energy (∆E) and the maximum number of hydrogen bond were 321 selected as the best recipe for MIP synthesis. The basis set superposition error (BSSE) was used to 322 correct the energies of the T-M complexes. The binding energy, ∆E of the T-M complexes was 323 calculated through Equation (1): 324

∆E = E template-monomer − E template − ΣE monomer (1) 325

The ∆E1 of the complexes of template or functional monomer and crosslinker was calculated by 326 Equation (2): � 327

∆E1 = E template-monomer-crosslinker − E template or monomer − E crosslinker (2) 328

As the polymerization and adsorption event headway in the solvent, we took into account the 329 effect of solvation on energy calculations. We have used PCM Solvation model based on polarizable 330 continuum dielectrics, which has proven to be flexible and accurate in particular because the solute 331 is accommodated in a molecular cavity of realistic shape [30]. The solvation binding energy (ΔEsolv) 332 of four different solvents (acetonitrile, dichloromethane, dimethylsulfoxide, and tetrahydrofuran) 333 was calculated by equation 3: 334

∆E2 = ∆E + ∆Esolv (3) 335

Additionally, The natural bond orbital (NBO) charge and molecular electrostatic potential 336 (MEP) of TCDD and AM were studied to predict the active sites without imaginary frequency. The 337 “atoms in molecules” (AIM) theory and Becke surface method were employed to reveal the 338 interaction mechanism involved in our study by using the multiwfn software. 339

3.2. Fabrication of TCDD Imprinted Polymers 340

3.2.1. Chemicals and Reagents 341

The chemicals used for TCDD imprinted polymer synthesis are: 2,3,7,8-tetrachlor- 342 odibenzo-p-dioxin as a template; acrylamide (AM), methacrylic acid (MAA), itaconic acid (IA), and 343 4-Vinyl pyridine (VP) was used as functional monomer; trimethylolpropane trimethacrylate (TRIM) 344 as the cross-linking agent and 2,2’-azobis isobutyronitrile (AIBN) as a polymerization reaction 345 initiator. All these chemicals were purchased from Sigma-Aldrich (Buchs, Switzerland) and stored in 346 the N2 atmosphere prior to use. Solvents: acetonitrile, chloroform, dichloromethane, and 347 dimethylsulfoxide HPLC grade were obtained from Merck (Darmstadt, Germany). 348

In glass vial 1mmol of TCDD, 4mmol of AM was added to the 10 mL of a solvent to this mixture 40 349 mmol of TRIM and 0.01 g AIBN (initiator) were added and mixed uniformly using ultrasonicator. 350 The sealed glass vial containing reaction mixture were freeze-thaw-degassed by submerging the vial 351 in liquid nitrogen and holding the frozen vial under a vacuum of 100 m Torr for a period of at least 352 15 min. The vial was thawed and charged with a positive pressure of argon, and were place in ice led 353 Dewar’s and temperature equilibrated. The glass vial was immersed into the isothermal water bath 354 and the mixtures were thermally polymerized at 60 °C for 24 h. The resultant polymer was grounded 355 in a ball mill and dry sieved to a size between 100 mesh (150 m) and 200 mesh (75 m). To remove 356 template molecule TCDD, the polymer particles were extracted with the mixture of methanol and 357 acetic acid (9:1, V/V) using Soxhlet extractor for 24h. The extracted polymer particles were then 358



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washed with methanol to remove acetic acid. Finally, the polymer (MIP) particle was dried at 60 °C 359 under vacuum for 24 h and stored in desiccators for further analysis. The similar procedure was 360 followed for preparation of other MIPs and NIPs using different solvents. 361

2.2.2. Binding Experiments 362

For the preparation of a calibration curve of TCDD, standard solution (50-200 μg/L) were prepared 363 by dilution of 500 μg/L solution in hexane. Then in separate vials, 5 mg of MIP and NIP were added 364 in 5 mL of (0.5-10 μg/L) of TCDD solution. The solutions were then sealed and shaken in a shaker at 365 25°C for 24 hrs. The suspension was then filtered using 0.22 μm PVDF filter. The free TCDD in the 366 filtrate were measured with a Varian 3800 gas chromatograph coupled to a Varian 4D MS ion trap 367 detector. The amount of analyte bound to the MIP was calculated using Equation 4. 368

= (4) 369

Where Qe is the amount of analyte adsorbed in an adsorbent (MIP or NIP), V is the volume of the 370 solution, Ci is the initial concentration and Ce is the concentration of target analyte at equilibrium or 371 after adsorption. 372

373

4. Conclusions 374 The fabrication of MIPs are modest and straightforward, the formulation of these polymers can be 375 achieved in the most economical possible way and the application of such polymers can result in 376 high efficiency and high level of selectivity in removing pollutants from the environment at 377 ultra-trace level. The results of the present study illustrated that the computer-assisted design of 378 MIPs based on the density functional theory (DFT) can be used as a powerful tool to select the 379 functional monomers and other polymer precursors for a specified template molecule. In this work, 380 TCDD was taken as a template molecule due to its carcinogenic property. By comparing the 381 calculated and experimental structure parameters of TCDD, the M062X method and 6-31G(d,p) were 382 preferred to be the appropriate calculation method, among the B3LYP, BHandHLYP, M062X and 383 ωB97xD methods. Based on theoretical and practical results, AM was confirmed as the appropriate 384 functional monomer among AM, MAA, IA, and VP; the best imprinting molar ratio of TCDD to AM 385 is determined to be 1:4; and TRIM was predicted to be the best cross-linker among EGDMA, PETA, 386 and TRIM. There were 8 hydrogen bonds in the cavity of stable complexes when the ratio was 1:4. At 387 PCM Solvation model, single point calculations performed in the solvent phase exhibit no effect on 388 stabilization energies. Besides, solvent phase calculations contributed to a decrease in energy and 389 formed the more stable complex, rather than as predicted in the gas phase. The BSSE correction had 390 no perceptible effect on the calculated binding energies for the systems. Further, NBO and MEP 391 surfaces were generated to predict the nature of realistic reaction regions. The NBO and MEP 392 surfaces revealed two negative potential regions that can take place in reaction. Because of the 393 geometry of these compounds, there are few structures where the negative potential around chlorine 394 is weak. 395 The topological parameters calculated using the AIM methodology gives a suitable justification for 396 the stability of the structure. The electron density and its Laplacian at BCPs correlate well with the 397 hydrogen bond length. AIM calculations also provide coherent means of determining the strength of 398 the hydrogen-bonding interactions and to demonstrate that our complex system of TCDD and AM 399 exhibits hydrogen-bond activity. The electron density at the bond critical points of each system 400 determined strong hydrogen-bonding interactions. Our results show that the interactions are more 401 van der Waals-type bonding rather than a dipole-dipole interaction. Significant hydrogen bonding 402 has been sensed and demonstrated to be an interaction that can stabilize these systems as well as the 403 reorientation of the functional groups. It is concluded that the EHB value calculated in AIM method 404



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indicates Cl(22)···H(26)-N hydrogen bonds are stronger. The Becke surface method was applied to 405 reveal the nature and the strength of the bond between TCDD with AM complex. This presented 406 article could provide the better understanding of important interaction to the development of 407 molecular imprinting technology. Moreover, This work will help to improve the affinity toward the 408 selective detection and remediation particular dioxin, in environmental samples. 409 410 Acknowledgments: M.S.K. acknowledges the Indian Institute of Technology Bombay, India, for funding of the 411 Institute Postdoctoral Fellowship. The authors also acknowledge Center of Excellence in Scientific Computing 412 at National Chemical Laboratory, Pune, India. S. P. acknowledges the J.C. Bose Fellowship grant of DST 413 towards partial fulfillment of this work. 414 Conflicts of Interest: The authors declare no conflict of interest. 415 416 417

Appendix B 418

419 Figure A1. Optimized structure of Tetrachlorodibenzo-p-dioxin (TCDD) at M062X/6-31G(d,p) level 420

421 Figure A2. Optimized structure and MEP surface of the functional monomers 422

423



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424 Figure A3. The binding distance between T-FM complexes by varying the numbers of 425

functional monomers in the system. 426

427 Figure A4. 4(a) NBO charges and 4(b) MEP surface of TCDD-AM pre-polymerized complex. 428

Red regions of the map are the most electron-rich regions of the molecule, and blue regions are 429 electron poor. Order of increasing electron density is blue < orange < red. 430

431 432



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433 Figure A5. AIM study of T-FM interaction by plotting interbasin surfaces (IBS) corresponding 434

to the (3, -1) with index of 67 and 54 435

436

Figure A6. Becke surface analysis to evaluate the strength of interaction between the TCDD-AM 437 complex 438



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439 Figure A7. The relationship between experimentally derived binding capacities versus theoretically 440

computed binding energies between functional monomers and TCDD in different solvents 441 442

443

444

445 Table A1. Bond Lengths (Å) and Bond Angles (°) calculated by the B3LYP, BHandHLYP, 446 M062X and ωB97xD with Basis Sets (6-31g(d, p), 6-31++g(d, p) and experimental data of TCDD. 447

Bond/

Angle

B3LYP BHandHLYP M062X ωB97xD a

Ref.30

b

Ref.31

c

Ref.29 6-31g

(d, p)

6-31++g

(d,p)

6-31g

(d,p)

6-31++g

(d,p)

6-31g

(d,p)

6-31++g

(d,p)

6-31g

(d,p)

6-31++g

(d,p)

R (Å)�

C-Cl 1.809 1.778 1.789 1.791 1.751 1.758 1.817 1.819 1.743 1.737 1.73

C-O 1.403 1.408 1.412 1.417 1.389 1.392 1.437 1.438 1.377 1.361 1.37

C-C 1.386 1.389 1.392 1.397 1.370 1.373 2.111 2.117 1.392 1.395 1.36

Φ (◦)�

C-O-C 117.9 117.9 118.4 118.4 116.3 116.3 119.1 119.2 116.2 116.6 115.7

*aStructural Parameter of 2,3,7,8-TCDD at the B3LYP/6-311+G(2d,2p) Level [Ref.30]; bGeometric Parameters of the 11Ag Ground States 448 of 2,3,7,8-TCDD at the CASSCF(16,14)/cc-pVDZ [Ref.31]; cExperimental geometry from crystallographic data (ref 29) 449 450



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Table A2. Binding energies (∆E, Kcal/mol) of TCDD and different functional monomer 451 complexes with and without BSSE correction in the gas-phase at the M062X/6-31G(d,p) level 452

T-M Complexes ΔΕB (non-corr.) ΔΕB (corr.) μ(Debye)

TCDD-AM -27.583 -25.918 1.35

TCDD-MAA -33.224 -29.744 2.27

TCDD-IA -53.793 -51.216 3.49

TCDD-VP -43.194 -38.339 3.68

453 454 Table A3. Theoretical titration parameters for optimization of fixed T/M ratio at the 455 M062X/6-31G(d,p) level 456

Molar Ratio Bond Numbers Action Sites Bond length (Å) ΔE (Kcal/mol)

1:1 2 Cl(22)···O(24)

Cl(21)···H(26)

2.35

1.87 -25.918

1:2 4 Cl(22)···O(24)

Cl(21)···H(26)

2.01

1.73 -38.730

1:3 6 Cl(22)···O(24)

Cl(21)···H(26)

1.96

1.70 -45.029

1:4 8 Cl(22)···O(24)

Cl(21)···H(26)

1.83

1.65 -53.113

1:5 6 Cl(22)···O(24)

Cl(21)···H(26)

2.12

1.77 -47.291

Table A4. Binding energies (∆E1 & ∆E2) between TCDD-AM complexes and different cross-linkers in 457 a vacuum and in porogen at the M062X/6-31G(d,p) level (kcal/mol). 458

Complexes ∆E1in vac ∆E2in ACN ∆E2 in CHL ∆E2 in DCM ∆E2 in DMS

TCDD-AM-EGDMA -38.918 -38.827 -36.110 -36.786 -34.932

TCDD-AM-PETA -42.184 -40.154 -38.721 -37.982 -33.470

TCDD-AM-TRIM -34.921 -37.278 -36.011 -34.815 -36.634

459 460 Table A5. AIM Property of the TCDD-AM Complex (1:4) (a.u.) 461

Active Sites ρ(r) ▽2ρ(r) V(r) G(r) H(r)

Cl(22)···O(24) 0.016 0.572 -0.386 0.045 0.723

Cl(22)···H(26) 0.011 0.218 -0.022 0.058 -0.0012

Cl(21)···O(34) 0.027 0.921 -0.303 0.012 0.268

Cl(21)···H(36) 0.098 0.352 -0.035 0.046 -0.0011



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Cl(20)···O(44) 0.087 0.413 -0.683 0.086 0.700

Cl(20)···H(46) 0.033 0.314 -0.052 0.064 -0.0012

Cl(19)···O(54) 0.027 0.883 -0.302 0.041 0.305

Cl(19)···H(56) 0.059 0.209 -0.036 0.044 -0.0008

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