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DFT Study of Structure and Radical Scavenging Activity of Natural Pigment Delphinidin and Derivatives

Written By

Sumayya Pottachola, Arifa Kaniyantavida and Muraleedharan Karuvanthodiyil

Submitted: 08 May 2021 Reviewed: 31 May 2021 Published: 07 July 2021

DOI: 10.5772/intechopen.98647

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Density Functional Theory - Recent Advances, New Perspectives and Applications

Edited by Daniel Glossman-Mitnik

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A theoretical evaluation of the antioxidant activity of natural pigment delphinidin (1a) and derivatives 1b, 1c, 1d & 1e was performed using the DFT-B3LYP/6–311 + G (d, p) level of theory. Three potential working mechanisms, hydrogen atom transfer (HAT), stepwise electron transfer proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET), have been investigated. The physiochemical parameters, including O–H bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA), and electron transfer enthalpy (ETE), have been calculated in the gas phase and aqueous phase. The study found that the most suitable mechanism for explaining antioxidant activity is HAT in the gas phase and SPLET in the aqueous medium in this level of theory. Spin density calculation and delocalization index of studied molecules also support the radical scavenging activity. When incorporated into natural pigment delphinidin, the gallate moiety can enhance the activity and stability of the compounds.


  • DFT
  • Multiwfn
  • Delphinidin
  • Radical scavenger
  • Gallic acid

1. Introduction

Dietary polyphenols have interesting spectrum biological properties, including radical scavenging activity [1]. Anthocyanins are one of essential classes in the polyphenol family [2]. These are the plant pigments responsible for the bright red-orange to blue-violet colors of many fruits and vegetables [3]. Since these are natural colored compounds, many pieces of literature come with their application as coloring or coloring material, especially in the food industry [4, 5, 6, 7, 8, 9]. Naturally, these compounds found in glycoside form can collectively be called anthocyanins. At the same time, their aglycon forms are commonly called anthocyanidins [10]. The common aglycon forms are cyanidin, delphinidin, peonidin, petunidin, malvidin, and pelargonidin. The color pigments are most abundant in berries like black currants, elderberries, blueberries, strawberries, etc., red and purple grapes, red wine, sweet cherries, eggplants, black plums, and red cabbage, etc.

The basic structure of anthocyanins is the flavylium cationic ring in which oxygen carries a positive charge. The positively charged species exhibit several equilibrium structures due to different transformations like proton transfer, isomerization, and tautomerization under various pH conditions [11]. All molecules of a group of anthocyanins have their absorption range in the visible spectrum due to effective π conjugation within the molecule. These are the largest group of water-soluble pigments in the plant kingdom. Experimental and theoretical reports show an exponential increase in findings related to its properties, color, co-pigmentation, pH effect, antiradical properties, etc. [12, 13, 14, 15, 16, 17].

The delphinidin (1a) and its four modifications (1b, 1c, 1d & 1e) are selected for the study. The structure of 1a having three rings A, B, and C, where A & C are fused rings and B connected with A-C through a single bond. The structures of compounds under consideration are shown in Figure 1. The colored pigments with other colorless natural products are now proven to be very impressive due to their improved activity in the sense of color and property. Hence to enhance the property, the colorless, most important, small, widely studied polyphenol gallic acid is taken and coupled with 1a through their 3 and 4’ OH bonds and respectively formed delphinidin-3-O-gallate (1c) and delphinidin-4’-O-gallate (1e). Also, the results are compared with its glucose forms delphinidin-3-O-glucoside (1b) and delphinidin-4’-O-glucoside (1d).

Figure 1.

Structures of compound considered for the study.

Gallic acid (3,4,5- Trihydroxy benzoic acid) and its derivatives have been found in various natural sources like nuts, tea, grapes, gallnut, oak bark, etc. Biological studies show that gallic acid has variable effects, including antiviral, antioxidant, and anticancer activities [18, 19, 20]. Due to its potent antioxidant activity against free radicals is used in food, cosmetics, and pharmaceutical industries and as a source material for ink and paints [21]. GA possesses the most robust antiradical property than Trolox, and hence, in many cases, this molecule is widely used as a reference compound for antioxidant studies. Green tea contains the highest concentration of GA-based compounds responsible for the plant’s antioxidant capacity [22, 23].

Once the compound possesses potent antioxidant activity and a specific range of absorbance in the visible spectrum can be effectively used for various purposes, especially in the food industry, they seek less hazardous, highly protective materials for coloring purposes. Hence these are colored compounds, and this work concludes the antiradical property of delphinidin and its derivatives with the help of computational methods.


2. Materials and method

2.1 Materials

The present work has utilized a theoretical approach to study the structure and properties of all compounds under consideration. The molecular forms of 1a and 1b were downloaded from the PubChem database in SDF file format and converted to GJF file format by Open Babel [24]. The structures of 1c, 1d, and 1e were drawn using the Gaussview 5.0.8 graphical user interface [25]. All the computational works have been carried out through Gaussian 09 software package to get the output [26]. The spin density (SD) and electron delocalization (DI) analysis are explained with the help of the software Multiwfn 3.6 [27].

2.2 Computational methodology

The present work was carried out using density functional theory (DFT) because it is based on electron density, and antioxidant activity is mainly influenced by electron density [28, 29, 30, 31, 32]. In DFT calculation, 6–311+ G (d, p) basis set with B3LYP (Becke’s exchange functional in conjunction [33] with Lee-Yang–Parr [34]) correlational functional has been used for geometry optimization, computation of harmonic vibrational frequencies, BDE, IP, PDE, PA and ETE calculations. To obtain antioxidant parameters BDE, IP, PDE, PA, and ETE, the geometry optimization of neutral, radicals, anions, and radical cation structures of all the studied molecules are conducted in the ground state both in the gas phase and aqueous phases. Solvent effects on the calculated systems were investigated with the self-consistent reaction field (SCRF) method via the integral equation formalism polarized continuum model (IEF-PCM).

2.2.1 Frontier molecular orbital (FMO) analysis

Frontier molecular orbital theory is an application of MO theory that explains HOMO/LUMO interactions. HOMO is the highest occupied molecular orbital, and LUMO is the lowest unoccupied molecular orbital. Frontier molecular orbital analysis is fundamental because HOMO or LUMO energies and bandgap energies are the key factors that drive the antiradical property of molecules. Since HOMO is in the highest energy state, so easier to remove an electron from this orbital. So in a chemical reaction or bond formation, HOMO is donating electrons, or it acts as a Lewis base or undergoes oxidation. LUMO is the lower-lying orbital; it is empty, so it is easier for LUMO to accept electrons into its orbital or acts as a Lewis acid or undergoes reduction. Reactivity becomes lower when the molecule has a higher bandgap. The distribution of HOMO orbitals and energies is calculated using the DFT-B3LYP/6–311 + G (d, p) level of theory from the optimized structures of 1a and its derivatives.

2.2.2 Radical scavenging activity

Several mechanisms have theoretically explained the radical scavenging mechanism of phenolic compounds. The widely used mechanisms are hydrogen atom transfer (HAT) mechanism (Eq. (1)), single-electron transfer followed by proton transfer (SET-PT) mechanism (Eqs. (2)(4)), and sequential proton loss electron transfer (SPLET) mechanism (Eqs. (5) and (6)) [35, 36, 37, 38, 39, 40]. These mechanisms have been briefly addressed here.

  1. HAT (hydrogen atom transfer) mechanism


    By transferring the hydrogen atom of the –OH group to the radical species, the antioxidant (ArOH) scavenges the free radical (X) and transforms it into phenoxide radical. The descriptor associated with the HAT mechanism is bond dissociation enthalpy (BDE), and the lower value indicates good radical scavenging activity. The ArO∙ radical species’ stabilizing features, like the resonance delocalization of the electron within the aromatic ring, are the basis of lowest energy and increased antiradical activity.

  2. SET (single electron transfer) mechanism


    Here, the reactive free radicals are neutralized by transferring electrons to them, resulting in anions. The most reactive hydroxyl group in antioxidant compounds provides these electrons and finally becomes a radical cation. The descriptor associated with this mechanism is AIP (adiabatic ionization potential).

  3. SET-PT (single electron transfer followed by proton transfer) mechanism


    The first process involves an electron transfer from the antioxidant (Eq. (2)), and the second step consists of a proton transfer from the radical cation (Eq. (4)) generated in the first step. Proton dissociation enthalpy is the descriptor connected with the second phase (PDE).

  4. SPLET (sequential proton loss electron transfer) mechanism


    This is also a two-stage mechanism, with the dissociation of the antioxidant into phenoxide anion and proton as the first step (Eq. (5)). The first-step phenoxide anion then interacts with free radicals at a certain pH (Eq. (6)); the compounds generated are similar to those developed in the HAT mechanism. Proton affinity (PA) is the regulating descriptor for the first stage, and electron transfer enthalpy is the driving descriptor for the second stage (ETE).

The Eqs. (7)(11) are used for analyzing the type of mechanism involved by the compound


Thus, in the present study, BDE, IP, PDE, PA, and ETE values were used as the primary molecular descriptors to elucidate the radical scavenging activity of the investigated compounds. The enthalpies of hydrogen radicals in the water and gas phase are calculated by G09 software using the DFT/B3LYP/6–311 + G (d, p) level of theory. The enthalpies of the electron (e) and proton in the gas phase are taken from the commonly accepted values 0.00236 Hartree for proton and 0.00120 Hartree for electron. In contrast, for water, these corresponding values are calculated with the help of the DFT/B3LYP/6–311 + G(d, p) level of theory. The enthalpies of electron and proton in solvent water were computed using the same level of theory with methodology suggested by Markovic et al. (Eqs. (12) and (13)) [41, 42].


Where Ssol is the solvent molecule solvated by the same kind of molecule, SHsol+ and Sesol· are the charged particles formed. The solvation enthalpies of proton and electron are calculated using the Eqs. (14) and (15), respectively, and that of H by optimizing hydrogen atom using the same level of theory. The enthalpy of hydrogen radical taken for gas is −0.49764 Hartree and − 0.497466 Hartree for water. The enthalpies of proton and electron in water, respectively, are −0.37725431 Hartree and 0.093551 Hartree.


3. Results and discussion

3.1 Conformation analysis and geometry optimization

To elucidate the reactivity of the compounds towards free radicals, the conformational and geometrical features of compounds are very significant. The structures of 1a and 1b are downloaded from the PubChem database and 1c, 1d, and 1e are constructed from the optimized structure of 1a. The potential energy surface of all five molecules is scanned by using the B3LYP/3-21G level of theory by varying the dihedral angles values in 12 steps of 30° from 0 to 360°. The dihedral angle between aromatic ring B and AC bicyclic in 1a is performed on the dihedral Ф1 (C3, C2, C1ˈ, C2ˈ), and the five OH groups are also scanned as above mentioned procedure. All phenolic OH is in a position that forms hydrogen bonding with the nearest OH. The dihedral Ф1 about (C3, C2, C1ˈ, C2ˈ) of 1a completely reveals the planar geometry of the molecule, whereas other molecules are slightly becoming nonplanar because of the steric cloud around flavylium cationic ring. The dihedral (C3, C2, C1ˈ, C2ˈ) of 1a, 1b, 1c, 1d, and 1e respectively are −179.95499, −158.12940, −167.05569, −169.70713, and 171.29496 degrees.

The lowest energy conformer obtained after the last scan was then subjected to geometry optimization, and B3LYP/6–311 + G(d, p) level of theory with a correlation coefficient of 0.89281 are selected for the study. The crystal structure data of cyanidin are considered for experimental validation of results obtained from the computational analysis since these are not available for delphinidin molecules and tabulated in Table 1 [43]. But the basic structural unit of 1a is similar, except in cyanidin, one OH is missing from the 5′ position. The optimized structures of the five compounds are shown in Figure 2. These optimized structures are considered for further calculations.

BondExperimental bond length (AO)Theoretical
B3LYP 6–31 G (d)B3LYP 6–31+ G (d, p)B3LYP 6–311+ G (d, p)B3LYP 6–311++ G (d, p)
C 2-C1’1.4531.443801.443801.441731.44176
C6 - C71.4131.413921.413901.411071.41106
C2 –C31.3961.421731.421771.419181.41920
C7 – C81.3871.398601.398601.395171.39517

Table 1.

Comparison of bond length with experimental values in different basis sets.

Figure 2.

The obtained optimized structures of the compounds using B3LYP /6–311 + G(d, p) level of theory (delphinidin (1a), delphinidin-3-O-glucoside (1b), delphinidin-3-O-gallate (1c), delphinidin-4’-O-glucoside (1d), and delphinidin-4’-O-gallate (1e)).

3.2 Molecular orbital analysis

Frontier molecular orbital analysis gives a detailed account of HOMO/LUMO interactions in the molecule. It is very useful in describing optical and electronic properties as well as the reactivity of a molecule. The HOMO value of the molecule is strongly influenced by radical scavenging activity. The higher the HOMO energy, the easier the electron is being excited and acts substantial donor of the electron. The chemical reactivity of the molecule can be described by knowing the HOMO–LUMO gap. Like that, the distribution of orbitals among the molecule reveals probable sites for the attack of free radicals. The HOMO distribution among molecule 1a is completely distributed on each atom, whereas the LUMO orbitals have distributed all atoms except 3- OH, 3’- OH, and 5’-OH. For the molecules studied here, the distribution of the LUMO distributed among each atom other than 3- OH, 3′- OH, and 5’-OH. So these three bonds are involved in the HOMO-LUMO transition. In 1c and 1e, HOMO is present only on the gallate moiety, whereas the LUMO is distributed only in the flavylium ring. The HOMO of 1b and 1d occur throughout the flavylium ring though only negligible HOMO/LUMO contributions are present on glucoside moiety.

The increasing order of bandgap energies in the gas phase at 1e < 1c < 1d < 1a < 1b reveals that the gallate-based compounds have the lowest bandgap energies and higher in activity. In the aqueous phase, the band gaps are higher compared to the gas phase, and the difference between the bandgap of water and gas is also represented in Table 2. One of the difficulties associated with anthocyanins as color pigments is their stability in polar solvents. When the medium changes from the gas phase to water, the only difference in the bandgap is 0.17 for 1a and 0.20 for 1b, but it is more significant for its gallates. So gallates are stable than others; hence expect higher reactivity in water (Figure 3).

Gas (eV)Water(eV)
EHOMOELUMOBand gap (ΔEgas)EHOMOELUMOBand gap (ΔEwater)ΔEwater - ΔEgas

Table 2.

FMO analysis of studied compounds in gas and water media at B3LYP/6–311 + G(d, p) level of theory.

Figure 3.

FMO of 1a, 1b, 1c, 1d, & 1e in the gas phase at B3LYP/6–311 + G(d, p) level of theory.

3.3 Radical scavenging activity

The antioxidant activities of the compounds are studied using the antioxidant mechanism described in Section 2.2.2. The BDE, IP, PA, PDE, and ETE values obtained from the corresponding mechanism are used to analyze the activity of compounds. Among the five parameters, one with the lowest value and the corresponding mechanism is followed by the compound. The parameters of antioxidant activities are represented in the gas phase and aqueous phase, respectively, in Tables 3 and 4.


Table 3.

The antioxidant mechanism study of compounds 1a, 1b, 1c, 1d, and 1e in gas using B3LYP/6–311 + G(d, p) level of theory. All values are represented in kcal/Mol.


Table 4.

The antioxidant mechanism study of compounds 1a, 1b, 1c, 1d, and 1e in water using B3LYP/6–311 + G(d, p) level of theory. All values are represented in kcal/Mol.

5 OH7 OH3 OH3’ OH4’ OH5’ OH5” OH6”OH7”OH

Table 5.

The SD distribution for the O-radical and delocalization index (DI) of C-O bond computed for 1a, 1b, 1c, 1d, & 1e in the gas-phase at B3LYP/6–311 + G (d, p) level of theory.

3.3.1 Analysis of HAT mechanism

In the gas phase, all studied molecules follow the HAT mechanism because of its lower BDE values. Hence, all compounds tending to form radicals by donating hydrogen atoms in respective positions are higher in the gas phase. In the case of 1a, the positions 3-OH (81.56 kcal/mol), 4’-OH (83.19 kcal/mol), and 5’-OH (84.51 kcal/mol) have the lowest values of BDE, and hence these positions are involved in radical scavenging activity in the gas phase. For a compound possessing more than one phenolic hydroxyl group, its radical scavenging activity is determined by the one with the lowest value of BDE. Hence, in this case, 3-OH is the most active site, followed by 4’-OH and 5’-OH.

The glucose substituted derivatives of 1a, 1b, and 1d in the gas phase also follow the HAT mechanism due to its lowest value of BDEs comparing with other parameters. In 1b, 4’-OH has a higher tendency to participate in radical scavenging mechanism due to its lowest BDE value (82.15 kcal/mol) compared to other phenolic OH groups in the compound. When 4’-OH is substituted with glucose moiety or 1d, 3-OH is contributing to the radical mechanism. So in 1b and 1d radical scavenging activity is mainly through B-ring (4’-OH) and C-ring (3-OH).

As from Table 3 the antioxidant activity of compound 1c are through its phenolic hydroxyl group at 4’ OH (83.12 kcal/mol), 5’ OH (84.18 kcal/mol), 6”OH (83.09 kcal/mol), and 7” OH (83.60 kcal/mol) positions with an increasing order of 6”OH < 4’ OH < 7” OH < 5’ OH. The phenolic hydroxyl groups at 4’ OH and 5’ OH situates on the B-ring of 1a, whereas 6”OH and 7” OH at gallic acid moiety. Here, both rings, the gallate ring, and delphinidin ring moieties, contribute to the radical scavenging activity through the hydroxyl groups. Since an ester relation connects gallate and delphinidin moieties, the radicals produced in one ring do not delocalize much to another ring and acts as separate contributors to radical scavenging activity. Like that, 1e also shows antioxidant activity through 3’ OH (83.90 kcal/mol), 6” OH (82.80 kcal/mol) and 7” OH (83.22 kcal/mol). The 6” OH has a slightly lower value of BDE than the other two OH groups because the radical formed at para OH is highly stabilized through the aromatic system of gallate moiety. Similar to 1c, compound 1e also possesses radical scavenging activity through B-ring and gallic acid moiety. When comparing 1c and 1e with other molecules, when gallic acid is substituted, the number of hydroxyl groups under lower BDE values increases. Hence, the chance of enhancing activity is clear.

To explain the differences in BDE and consequently the differences in the reactivity of OH sites, the spin density distribution of radicals was calculated and presented in Table 5. The stability of radicals formed can be explained with the help of SD values; more delocalized SD means to be more stable is the radical formed. Moreover, the delocalization index is also a supporting parameter for explaining the stability of radicals created. The more stable the radical formed from an -OH bond, the more the corresponding C-O bond will be the delocalization index. The DI of C-O bonds in each radical site are calculated using Fuzzy atomic space analysis [44, 45, 46]. The SD contours of 1c are represented in Figure 4.

Figure 4.

Electronic spin density distributions and optimized structures of 1c radicals in the gas-phase at B3LYP/6–311 + G (d, p) level of theory.

3.3.2 Analysis of SET-PT mechanism

In the SET-PT mechanism, the parameters involved are IP and PDE. In all derivative IP is found to be higher in both media. The PDE values are higher in the gas phase but lower in the water medium. But the lower value in the water medium cannot be used for final judgment about contribution in antioxidant activity. In the SET-PT mechanism, the PDE comes from the second step of this mechanism, whereas the first step is the IP. Since all cases have the highest values for IP in the water medium, they have to overcome this large energy barrier of IP to reach the second step.

3.3.3 Analysis of SPLET mechanism

In water, the parameters BDE, IP, and ETE having higher enthalpy than PA and are represented in Table 4. Hence SPLET is the mechanism followed by each molecule in the water medium. In the SPLET mechanism, the heterolytic bond cleavage of the phenolic hydroxyl group is considered, and the neutral molecule is split into an anion and a proton. The numerical parameter associated with this step is PA. The anion produced donates one electron to free radical species, and the free radical receives one electron and forms an anion. The anion of free radical react with proton forms a neutral compound by leaving the anion starting compound as radical. The numerical parameter associated with this step is ETE. The values of PA are found to be lower than BDE and other parameters in all studied cases when the solvent was aqueous. In the case of 1a, 4’ OH possesses the lowest value of PA (35.27 kcal/mol), contributing to the radical scavenging mechanism.

In the case of 1b, the PA value of 7 OH (36.41 kcal/mol) has a lower value, and 5 OH (37.08 kcal/mol) and 4’ OH (37.11 kcal/mol) have valued at the nearest. When glucose at position 3 enhances the electron-donating capacity of A ring. When glucose at 4′ position called 1d, the lowest PA value at 3-OH (35.21 kcal/mol) and followed nearest at 7 OH (35.80 kcal/mol) and 5-OH (36.36 kcal/mol) also enhances the radical scavenging activity of A- ring. The lowest PA value of 1c in water is 4’ OH (34.39 kcal/mol), which is the lowest of all studied compounds in the water medium. The PA values 35.10 kcal/mol of 7 OH and 5 OH are near the 4’ OH. For 1e, the lowest value of PA at 5-OH (36.07 kcal/mol). In the water medium, the gallate moiety containing hydroxyl group does not affect radical scavenging activity due to its higher PA values. In the gas phase, a considerable contribution is provided by this group.


4. Conclusion

A theoretical study on the antioxidant activity of natural pigment delphinidin and its derivative has been evaluated. The antiradical properties of all studied molecules are finalized through an antioxidant mechanism. All compounds follow the HAT mechanism in the gas phase and the SPLET mechanism in the aqueous medium. In gas-phase gallic acid, substituted compounds possess considerable enhancement in activities by providing more hydroxyl groups of near BDEs. In the water medium, 1c posses a lower value of PA than other compounds. Frontier molecular orbital analysis also supports the radical scavenging activity of compounds. The HOMO-LUMO gap of each molecule increases when the medium changes from the gas phase to the water medium. Hence all these are more stable in water especially gallic acid-based pigments, so the stability issue of bare pigments in the solvent can be solved by its gallates.



The author, Sumayya Pottachola, expresses sincere gratitude to UGC-MANF for financial support and the central sophisticated instrumentation facility (CSIF) of the University of Calicut for Gaussian 09 software support.


Conflict of interest

The authors declare no conflict of interest.


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Written By

Sumayya Pottachola, Arifa Kaniyantavida and Muraleedharan Karuvanthodiyil

Submitted: 08 May 2021 Reviewed: 31 May 2021 Published: 07 July 2021