Intramolecular interactions (O-H∙∙∙O, C-H∙∙∙N, N-H∙∙∙π) in isomers of neutral, cation, and anion dopamine molecules: A DFT study on the influence of solvents (water and ethanol)

Dopamine (DA) is one of the most important neurotransmitters associated with numerous neural disorders. This investigation reports the intramolecular interactions present in the isomers of neutral (DA0), anionic (DA−), and cationic (DA+) dopamine isomers in gas, water, and ethanol mediums. Neutral and anion isomers have O-H∙∙∙O, C-H∙∙∙N intramolecular hydrogen bonds and N-H∙∙∙π interactions. All the interactions are electrostatic in nature. Isomers of cation dopamine show no intramolecular interactions in the solvent. Natural charges from natural bond orbital (NBO) analysis show that O-H∙∙∙O bonds and the N-H∙∙∙π interactions are the most and least polar, respectively. 1H NMR study reveals the inverse linear correlation between shielding constant and electron density in a solvent medium. HOMO-LUMO energy gap indicates higher stability for neutral and cationic forms of dopamine isomers in water and ethanol medium. We have optimized all the structural forms of dopamine molecule using the Becke three hybrid exchange and Lee-Yang-Parr correlation functional with Grimme’s dispersion correction, B3LYP-D3(BJ), and aug-cc-pVTZ basis set using the Gaussian16 software. Vibrational frequency analysis with no imaginary frequencies confirms the nature of global minima. The solvent studies (water and ethanol) were carried out using the SCRF keyword and the polarisable continuum model (PCM) of Miertus and Tomasi. NBO analysis and NMR studies were also performed for all conformers. Topology analysis was explored using the software Multiwfn.


Introduction
Neurotransmitters play a crucial role in human body functions by exchanging electrochemical signals from one neural cell to another [1]. Dopamine (DA) is one of the most important neurotransmitters associated with numerous neural disorders and psychiatric conditions, such as drug addiction, Huntington's disease, Alzheimer's disease, Parkinson's disease, anxiety, depression, and bipolar disorder [1][2][3][4][5][6]. Furthermore, the dopamine molecule is a natural catecholamine and an essential precursor for neurotransmitters like noradrenaline and epinephrine [7]. Therefore, early detection and treatment for these disorders associated with neurotransmitters (dopamine, noradrenaline, and epinephrine) depend on the measurement of dopamine concentration. Besides, in the drug design process for the above disease, dopamine receptors are targets. Hence, understanding the molecular forms of dopamine will augment the chemical study of dopamine hydrochloride (salt form), which is necessary for developing drugs and expanding neuro and medicinal chemistry knowledge.
In the human brain, the cationic and neutral forms of molecular dopamine are predominant [8]. Experimental and theoretical studies have reported molecular dopamine in cationic (DA + ), neutral (DA 0 ), and anionic (DA − ) structural forms. Cationic and anionic forms of dopamine molecule result from the amine group's protonation and deprotonation of the keto group, respectively, in the neutral form. Their tautomeric and isomeric structures are shown in Fig. 1. Therefore, understanding these dopamine molecules' structural and reactivity properties is vital for designing and developing drugs and dopamine sensors materials. Intramolecular hydrogen bonding plays a pivotal role in establishing the molecular stability and reactivity of the system depending upon their interaction energy [9,10]. Intramolecular hydrogen bonds under distinct chemical environments alter the molecular properties of a chemical system. The strength of the hydrogen bonds (H-bonds) is an important feature of intramolecular hydrogen bonds [11]. It has been reported that intramolecular hydrogen bonds are advantageous for analyzing molecular conformations and inspecting how they interact with solvents [2,12,13]. In addition, the intramolecular hydrogen bonds are responsible for holding the molecule to a suitable configuration for binding to a drug, enzyme, or some other guest molecules [14,15].
Several theoretical and experimental approaches have explored the chemical properties of dopamine molecules through studies such as conformational analysis, rotational isomerization, potential energy distributions, hydration effects, Raman analysis, oxidation properties, and electrochemical behaviour [8,[16][17][18][19][20][21][22][23][24][25][26][27][28]. However, the intramolecular hydrogen bonds formed through the hydroxyl interactions with the carbonyl group and amino groups with the C-H moiety remain unexplored. These intramolecular hydrogen bonds within dopamine govern the reactivity and guest molecule interactions. In addition, these intramolecular hydrogen bonds in dopamine also play a critical role in molecular conformation and stability. Besides, dopamine functions within the brain with water as the primary component. Likewise, ethanol, a universal solvent and the primary ingredient in alcoholic beverages, have a strong negative influence on brain activity. Therefore, investigation of the chemical nature of intramolecular hydrogen bonds under the influence of solvents like water and ethanol is crucial.
The principal objective of this study is to examine intramolecular hydrogen bonds formed in different tautomers and isomers derived from neutral, cation, and anion forms of dopamine molecules in both gas and solvent phases. We anticipate that this study on intramolecular hydrogen will lead to a further understanding of guest molecule interactions with dopamine. More specifically, the results will support understanding the dopamine-drug interaction mechanism.

Computational details
A schematic diagram of the generated dopamine (DA) structural forms is shown in Fig. 1. [29]. We have optimized all the structural forms of dopamine molecule using the Becke three hybrid exchange [30] and Lee-Yang-Parr correlation functional with Grimme's dispersion correction, B3LYP-D3(BJ), and aug-cc-pVTZ basis set [31]. Vibrational frequency analysis with no imaginary frequencies confirms the nature of global minima [32]. The optimized coordinates are provided in the supplementary information. The studies were carried out in the gaseous and solvent phases (water and ethanol) by using the SCRF [33] keyword along with the polarisable continuum model (PCM) of Miertus and Tomasi [34][35][36]. Natural bond orbital (NBO) analysis [37] and GIAO NMR studies [38,39] were also performed for all conformers. Density functional theory (DFT) calculations on all dopamine (DA) forms were carried out using the Gaussian16 software [40]. Atom in a molecule (AIM) analysis were performed using the software Multiwfn [41].

Structural information
The most stable conformer (shown in Fig. 1) of the dopamine molecule in neutral, cationic, and anionic forms was optimized in a gas and solvent medium. Their structural parameters, such as the bond length and angle from the gas medium, have been compared with experimental results [17] and are in good agreement (given in Supplementary Information Tables S1-S3). Furthermore, the isomers and tautomers of these three stable conformers were investigated. Neutral dopamine molecular structure demonstrates ketoimine tautomerization, consequently, exhibits two tautomers, KI-1 and KI-2, due to the migration of the H atom from the keto to the amine group (shown in Fig. 1). Furthermore, the KI-1 chemical structure is similar to the zwitterionic form of dopamine tautomer with a cationic RNH3 group and deprotonation of the hydroxyl group (at meta position) to ethylamine as reported in the previous experimental study [8]. Hence, KI-1 and KI-2 tautomers are pertinent for this study. On the other hand, cation and anion dopamine molecular forms have two isomers, each Iso-1, Iso-2 and Iso-3, Iso-4, respectively, due to the migration of H atom from keto to C-H moiety (shown in Fig. 1).
In total, nine molecular dopamine forms were considered for this study. The nine molecular forms of dopamine were optimized in gas and solvents. The optimized structures in the gas phase are given in Fig. 2, while for the solvent medium, they are given in the supporting information (S1-S3). All isomers with atom numbering in gas and solvents are shown in Supplementary Figures S1-S3. Among these nine conformers, seven structures possess intramolecular hydrogen bonds and N-H•••π interaction, shown in Fig. 2 and Table 1. The bond lengths (in Å) and bond angle for intramolecular hydrogen bond and N-H•••π interaction are given in Fig. 2 and Table 2  In addition to hydrogen bonds, we observed N-H•••π bonds in the gas phase with a distance of 1.7 to 2.3Å. From the above, it is inferred that intramolecular hydrogen bond lengths are more elongated in the solvent medium than in the gas phase. Consequently, the elongation of bonds indicates that polar solvents may have weakened the intramolecular hydrogen bonds, which is ascertained from the topological study.
The total electronic energy and HOMO-LUMO (HL) energy gap is provided in the supplementary Table S4. The stability of all the isomers cannot be compared based on the electronic energy in the present work due to the difference in the number of atoms. Nevertheless, the HOMO-LUMO energy gap, a reactivity parameter, can indicate its stability. Here, the HL energy gap has increased for all the isomers from the gas to solvents, demonstrating reduced reactivity or increased stability. Further, neutral and cationic dopamine isomers are more stabilized in solvents than anion isomers. This trend agrees that neutral and cation forms of dopamine molecules are dominant in the brain. Besides, it is noticeable that neutral and cation dopamine isomers reflect a similar HL energy gap. This indicates that neutral and cation dopamine molecular forms are equally stable in water and ethanol.
In the infrared (IR) spectrum, the O-H stretching frequency generally lies in the range of 3700-3600 cm −1 [42]. Here, the alcoholic O-H makes an intramolecular hydrogen bond with the neighbouring O-atom of the carbonyl group, reducing the stretching frequency to 3600-3300 cm −1 . The frequency decrease indicates the O-H bond's weakening during hydrogen bond formation. The experimental IR stretching frequency for C-H is 3100-3000 cm −1 . In this study, C-H stretching falls between 3000 and 2800 cm −1 . The decrease in frequency indicates that the C-H bond is red-shifted and forms a weak hydrogen bond with amine nitrogen. Typically, the N-H stretching frequency falls in the range of 3400-3300 cm −1 after N-H•••π with carbon or π electrons in the molecule's benzene ring, showing a decrease in stretching vibrations in the range of 2000-3300 cm −1 .

AIM analysis
Atoms in molecules (AIM) analysis is a reliable tool to determine the nature of hydrogen bonds in a structure [43][44][45]. The main parameters provided by AIM analysis are electron density ρ and Laplacian of electron density ∇ 2 ρ at bond critical points (BCPs) [46]. The covalent nature and electrostatic interactions can be distinguished with the sign of (∇ 2 ρ). If ∇ 2 ρ > 0, there is an electrostatic interaction, and if ∇ 2 ρ < 0, the bond shows a covalent nature [14]. In general, for hydrogen bond formation, the ρ and ∇ 2 ρ values lie between 0.002 and 0.340 a.u. and 0.016-0.130 a.u. respectively [47]. The values associated with the electron density classify strong and weak interactions at bond critical points (BCP) and impede the conformer's stability and reactivity. The topological parameters, electron density (ρ), Laplacian of electron density (∇ 2 ρ), and total energy density (H(r)) for O-H•••O, C-H•••N hydrogen bonds and N-H•••π interactions along with the IR stretching frequency are given in Table 1.
The values of ρ and ∇ 2 ρ for the intramolecular hydrogen bond are in the range of 0.008-0.058 and 0.027-0.120 a.u., respectively, indicating the presence of hydrogen  [46]. Besides, the local energy density H(r) is greater than zero (H(r) > 0); hence, based on the Cremer-Kraka criterion [48], the intramolecular hydrogen bond and N-H•••π interactions are electrostatic. Furthermore, the correlation between electron density and hydrogen bond length is inverse. The corresponding linear regression coefficient values confirm a good correlation between both properties and are shown in Fig. 3; in the gas medium, the value is 0.997, and for water, 0.967 and 0.968 in ethanol. For the N-H•••π interactions in all mediums, the correlation coefficient is 0.971.

NBO analysis
Natural bond orbital (NBO) analysis has been used for hydrogen bond analysis, providing information about charge densities in electron donors and acceptors [49][50][51]. For example, in a system of (X-H•••Y) hydrogen bonds, NBO discloses the charge transfer between the antibonding orbital X-H and the lone pair of acceptor Y [52]. Here, the occupation numbers and stabilization energy E 2 for all conformers are given in

Dipole moments (D)
The dipole moment is an important physical property of the molecular system and is very helpful in assessing the quality of the electron probability distribution [54]. For example, the theoretically determined dipole moment of neutral dopamine is 1.864 Debye [17], and our most stable neutral conformer of dopamine has a dipole moment of 1.641 Debye. The (orientation of the) dipole moment vector of the neutral molecule is shown in Fig. 5. This suggests that the aggregation of dopamine molecules will be planar and moreover agrees with the crystal data study of Laura Cruickshank et al. [8]. Table S5 shows that the dipole moment of all conformers increases in the solvent medium. This increase in dipole moment is a result of the solute-solvent interaction. Although the dipole moments of the two solvents are nearly equal, the water's higher polarity causes a slight increase when compared to ethanol. Cationic dopamine in water has the highest dipole moments among all molecular forms. The dipole moments of anionic dopamine and its isomers are relatively low. Author contribution T. Sangeetha: conceptualization, methodology, formal analysis, writing -review and editing; Senthilkumar Lakshmipathi: conceptualisation, methodology, formal analysis, writing -review and editing.