Catechin and Epicatechin. What’s the More Reactive?

Catechin and epicatechin are two isomeric flavonoids. Despite the vital properties highlighted by numerous scientific studies, very little data is available on the intrinsic reactivity of these compounds. To provide more details on the stability and reactivity of catechin and epicatechin, this study is performed by means of theoretical calculation methods. For this purpose, geometry optimizations and frequency calculations at the B3LYP/6-31 + G (d, p) level of theory has been carried out and Natural Bond Orbital (NBO) analysis and VEDA (Vibrational Energy Distribution Analysis). The geometric and energy parameters and NBO analysis show that catechin appears more stable than epicatechin. The hydroxyl group position on the ring C of the catechol structure represents a factor that influences this relative stability. The global and local reactivity parameters reveal that epicatechin becomes more reactive than catechin. They indicate that their hydroxyl groups correspond to their most receptive sites. Fukui indices, VEDA and acidity study establish that O28–H29 remains the most reactive.

Computational Chemistry and tea [2] [5]. With the consumption of these foods, humans benefit from antioxidant properties [6] [7] [8] [9] [10]. These delay cell damage and combat certain chronic diseases including cardiovascular and neurodegenerative diseases ones [6] [7] [11] [12] [13] [14]. These molecules also possess anti-cancer, anti-inflammatory and anti-viral properties [15] [16] [17] [18]. The wide spectrum of polyphenols' biological activities gives them a great importance in therapeutic processes. Besides, only 2% of these alcohols consumed reach the plasma. This underperformance thus represents a problem of bioavailability [19]. Increasing their proportion in this organism would make them much more efficacious. For better control and improvement of polyphenols' therapeutic effects, it's advisable to discover ways to grow their concentration in plasma. The development of medicines incorporating polyphenols would be an asset in providing effective remedies for these illnesses that ruin human populations. Tests to manufacture catechin-specific anti-inflammatory drugs weren't as conclusive as expected. The reasons are related to the failures of the very limited clinical tests because of their stability, their short half-life in the plasma and their low bioavailability [20] [21].
The properties exhibited by catechin and epicatechin emanate from their many hydroxyl groups [22]. The aromatic rings and their OH associated makes it possible to build several types of interactions. These permit polyphenols to scavenge hydroxyl radicals, inhibit reactions such as lipid peroxidation and Computational Chemistry prevent oxidation reactions. This process happens in a state of transition [22]; the latter promotes the occupation of their specific molecular orbitals [23]. These foster some CHO bond at three centres. However, despite the large number of studies on the biological mechanisms explaining the beneficial effects of polyphenols on human health, few quantitative data are available on the polyphenol's reactivity. This research aims to fill this gap through the following question: Which isomer is the most reactive between catechin and epicatechin?
Its response fulfills the gap in numerical data relating to the reactivity of the two compounds. But it's difficult to identify all the factors involved in the instability of the two isomers. To correct this shortcoming, the work wants to address another question: What are the most receptive sites of isomers?
The research plans to suggest avenues that will contribute to a better integra-

Materials and Methods
This part includes the descriptors of global and local reactivity. It explains those of acidity. It describes how to assess load transfers using NBO analysis. For the moment, it specifies the method of calculations. The bond lengths, the bond angles and the standard dihedral angle constitute the initial geometrical parameters. The geometry optimizations and the frequency calculations were carried out with the Density Functional Theory (DFT) method at the B3LYP/6-31 + G(d, p) level of theory [24] in gas and aqueous phases.

Calculation Method
The

Global Reactivity Descriptors
The energies of these two frontier orbitals lead to the determination of several reactivity parameters. According to Koopmans theorem [29], the ionization energy I and the electronic affinity A are directly related to the energy of the HOMO and the LUMO respectively.
The chemical electron potential μ and chemical hardness η are defined in terms of ionization energy and electron affinity [30]: Also, global index of electrophilicity ω, introduced by Parr [31], is defined by the following formula: Local reactivity index is also accessible by calculation. While the global reactivity parameters evaluate that of a molecule, Fukui [32] introduces indices (Fukui parameters) to describe the reactivity of each atom.

Local Reactivity Descriptors
These parameters denote either a nucleophilic attack ( k f + ), an electrophilic attack ( k f − ), or a radical attack ( 0 k f ). The following equations [33] help to determine them:   The acidity represents an important parameter to integrate the intermolecular interactions. The calculations give access to the pKa.

Acidity
Catechin and epicatechin represent polyphenols with both five hydroxyl groups. They're therefore likely to exchange one or more protons with other molecules, either during hydrogen bonding interactions or "antiradical" mechanisms [34].
The value of ( )  Lewis-type orbital: lone pairs (n), natural bond (σ and π) to an electron acceptor one (anti-Lewis orbital: σ* and π*). This electron delocalization is with a decrease in the donor electronic density and an increase in the acceptor one. For each donor NBO (i) and acceptor NBO (j), the electron delocalization i → j is evaluated by the stabilization energy E (2) using second-order perturbation theory [39]. This latter is expressed as:

NBO Analysis
where i q denotes the electronic density in the donor orbital,

Results and Discussion
This section discusses those related to indicators of global and local responsiveness. Its analysis concerns acidity and NBO comprise results of calcula-

Spectroscopic Parameters
These vibrations are divided into 34 stretching, 33 deformations and 32 torsions. The 34 stretching is repartitioned into five O-H, nine C-H, 13 C-C and seven C-O. This agrees with the structure of the two molecules ( Figure 1). The analysis of the potential energy distribution (PED) by VEDA can efficiently assign the calculated normal modes of vibration.

UV-Visible Spectral Analysis
The TD-DFT method at the level of the theory B3LYP/6-31 + G (d, p), in the gas phase evaluates the electron transitions of catechin or epicatechin in the ultraviolet and visible regions. It gives molecule excitation energy. This latter quantity permits comparing the reactivity of two molecules. Its higher value corresponds to the more stable compound. Table 2 shows the results of the TD-DFT calculations. It displays the first three excited states of both molecules as presented in Figure 2.

Global Reactivity Descriptors
To access the chemical reactivity of catechin or epicatechin, it's necessary to determine their molecular border orbital HOMO and LUMO [27]. More, the first orbitals can explain the physical and chemical properties of molecules [23].
Here, they help to provide insight into intramolecular charge transfers; an electron-rich HOMO orbital acts as a donor; an electron-poor LUMO functions as an acceptor. Figure 3 and Figure 4 illustrate the HOMO − 3 to LUMO + 3 boundary orbitals of catechin and epicatechin. These molecular orbitals have a π character.
For HOMO, the π character is distributed over all the catechin and epicatechin. This means that the delocalization of electrons occurs through the molecules of catechin and epicatechin. Unlike LUMO, the π character of these molecules is concentrated on the B-cycle with a residual contribution of its oxygen atoms. The global reactivity indices are presented in Table 3. The smaller the energy gap (∆E) between HOMO and LUMO is, the more reactive is the molecule [27].

Local Reactivity Descriptors
Fukui indices are used to assess the reactivity of atoms or functional groups (nucleophilic or electrophilic attack site) of a molecule [33]. This work is based on a natural population analysis (NPA) in gas and aqueous phase to estimate the electron population [41]. This leads to the Fukui indices, reported in Tables 4-6.
The Molecular Electrostatic Potential (MEP) map displays the electron density of a molecule as a function of colour. It constitutes a descriptor of the local reactivity for a molecule. Colours indicate the electron density of areas of the molecule [42]. A red region illustrates an electron-rich site. A blue zone describes an electron-poor site. A green area is a neutral site. Figure 5 gives the plots of the catechin and epicatechin electrostatic potential.       Table 8 and Table 9 collate the second-order perturbation energies E (2) , the electron density (ED), the energy difference E(j) -E(i) of the donor NBO (i) and of the acceptor NBO (j) related to catechin and epicatechin. They show their elements of the Fock matrix F(i, j). These results indicate that for catechin and epicatechin, the main interactions are of two types. They're intramolecular interactions of the types ( ) ( )

Conclusions
The research plans to compare the reactivity of two isomers, catechin and epicatechin, using the resources of theoretical chemistry. It's carried out at the TD-DFT/B3LYP/6-31 + G(d, p) level. It's interesting in the parameters of global and local responsiveness. The MEP and the Fukui indices make it possible to specify the latter. It also harnesses the distribution of potential energy through VEDA. It contrasts the acidity. It ends with an NBO analysis. These statistics probe that epicatechin remains the more reactive compound of the two. More, the Fukui indices and the analysis of vibration energies establish that hydroxyl group reactivity of two isomers varies in the following order: O 28