Synthesis of eugenol derivative by the ring opening of epoxide eugenol and its analysis through chemical reactivity: a DFT approach

Abstract Eugenol, a plant bioactive component, is frequently found in a variety of medicinal plants with well-defined functional attributes. Essential oils containing eugenol were extracted from buds of Eugenia caryophyllata commonly named clove using hydrodistillation. Afterwards, the analysis of the essential oils using gas chromatography/mass spectrometry (GC/MS) shows that eugenol is the major constituent with 70.14% of it. The alkene group in eugenol was epoxidised using m-chloroperbenzoic acid leading to the synthesis of epoxide eugenol. The epoxide ring was cleaved to vanillyl glycol by mixed the epoxide eugenol with aluminum chloride hydrate in an ethanolic medium. A Density Functional Theory (DFT) study was investigated to understand the reactivity of the epoxide eugenol with the aluminum chloride hydrate. The results obtained from DFT based reactivity descriptors were in good agreement with the experiment results. Graphical Abstract

Density functional theory (DFT) can help us to understand many useful and important theoretical concepts in chemistry (Elshakre et al. 2020;Geerlings et al. 2020).To study the chemical reactivity of organic compounds, the DFT approach is a very useful and convenient setting of the discussion (Belaidi et al. 2012).Among the diverse computational methodologies, DFT has now become famously for calculating molecular properties, which has been widely used to calculate excited electronic states of molecules in the gas and aqueous phases and electronic structure properties in the ground (Cohen et al. 2012).
In the present work, we extracted and analysed the essential oil of Eugenia caryophyllata using gas chromatography/mass spectrometry.The eugenol was isolated and converted to epoxide eugenol then to vanillyl glycol.A DFT study was used to investigate the ring opening of epoxide eugenol with aluminum chloride hydrate.The results obtained from DFT based reactivity descriptors were in good agreement with the experiment results.
The eugenol was isolated from the essential oil using chemical treatment (Khalil et al. 2017).The structure of the starting material was confirmed by NMR and infrared spectroscopy (See supplementary information).The alkene group of eugenol was converted to the epoxide eugenol in a good yield by stirring a solution of eugenol in dichloromethane and m-chloroperbenzoic acid during 24 hours at room temperature (Eyambe et al. 2011).The ring opening of the epoxide eugenol was investigated using AlCl 3 hydrate in ethanolic solution to afford the vanillyl glycol (Figure 1).A theoretical study was conducted to investigate the ring opening of the epoxide eugenol using AlCl 3 .

Optimisation of interatomic distances and determination of the density of charges and the angles of the reagents
The optimised structures provide easy access to all parameters linked to the geometry of the molecules, including: charge densities, interatomic distances and angles (Zeroual and Hajbi 2015).Firstly, the reactants epoxide eugenol and aluminum chloride hydrate were optimised (Figure S13).Then the charge densities, the interatomic distances and the angles were studied.We noted that the heteroatom (Oxygen) presented the lowest charge density in all used reagents, while the high density of charge was observed for the carbon 3 of the epoxide eugenol .For aluminum chloride hydrate, aluminum presents the high charge density compared to the other atoms (Table S1).All angles are more than 100 excepted the epoxide angle A(C 18 -C 19 -O 20 ) ¼ 60.51 which is the bond that is targeted to be opened (Table S2).

Theoretical analysis of reagents by global properties
The static global properties of the reagent epoxide eugenol and aluminum chloride hydrate, namely the electronic chemical potential l, Mulliken Electronegativity v, chemical hardness g, softness s, global electrophilicity x and global nucleophilicity N were studied (Table 1).
The electronic chemical potential of epoxide eugenol (l¼ À2.6581 eV) is significantly higher than that of aluminum chloride hydrate (l¼ À4.8859 eV) which implies that electron transfer takes place from epoxide eugenol to aluminum chloride hydrate (G azquez 2008).The same result was shown from the values of Mulliken Electronegativity.The global nucleophilicity of epoxide eugenol (N ¼ 3.6153 eV) is upper than that of aluminum chloride hydrate (N ¼ 1.3425 eV) which means that epoxide eugenol behaves as a nucleophile whereas aluminum chloride hydrate plays the role of electrophile.The same conclusion can be made based on the values of the global electrophilicity x.The chemical hardness of epoxide eugenol (g ¼ 5.6945 eV) is lower than that of aluminum chloride hydrate (g ¼ 5.7845 eV).This means that epoxide eugenol retains few electrons in its environment (Pearson 2005).Then, the softness of the two reagents has close values.
Consequently, we can deduce that the transfer of electrons takes place from epoxide eugenol to aluminum chloride hydrate.In conclusion, HOMO/LUMO Gap calculations, electronic chemical potentials, and global electrophilicity and nucleophilicity indices show the nucleophilic nature of epoxide eugenol and the electrophilic character of aluminum chloride hydrate globally.
The Figure S14 and Table S3 show that DE(I) is upper than DE(II).This result allows us to conclude that the epoxide eugenol plays the role of nucleophile, while the aluminum chloride hydrate behaves like an electrophile.

Mechanism of the reaction
The ring opening of epoxide eugenol using AlCl 3 and H 2 O can be achieved through two steps, leading to the formation of vanillyl glycol (P).The reaction was catalyst using AlCl 3 (Figure S16).
The sum of energies of the isolated reactants (R) epoxide eugenol, AlCl 3 and H 2 O were set to zero.The first step was the coordination of the epoxide to the AlCl 3 , which forms a complex (C) which present the transition state.Followed by nucleophilic attack from an oxygen atom of H 2 O on the most substituted carbon (Int 1) or the least substituted carbon (Int 2) of complex.Based on the sum of energies of the two intermediates product we can deduce that the reaction favorites the formation of intermediate (Int 1) by 25.48 Kcal.molÀ1 compared to (Int 2) product.Both of the intermediate's products lead to the vanillyl glycol and the regeneration of the catalyst.

Thermodynamic study
The nature of the reaction is exothermic based on the value of the enthalpy DH ¼ 79.0812 Kcal.molÀ1 .The reaction causes a decrease in entropy DS ¼ À0.08325 Kcal.molÀ1 .K À1 which means that the disorder is decreasing in the system.The free enthalpy variation DG is negative (DG ¼ À9.897707 Kcal.molÀ1 ) and that indicate that the reaction is spontaneous (Zhao and Truhlar 2004;Ouattara et al. 2021).

General experimental procedures
Solvents and all organic reagents were purchased from Sigma Aldrich and Merck, they were used without purification.All reactions were monitored with thin-layer chromatography (TLC) while spots were visualised under UV light.Purification of products was carried out by column chromatography on silica gel using hexane-ethyl acetate (80:20) as eluent.The IR absorption spectra were recorded using a Shimadzu spectrometer (Fourier Transform Infrared spectrophotometer). 1 H-NMR and 13 C-NMR spectra were obtained on AVANCE 300 Bruker ( 1 H NMR: 300 MHz, 13 C NMR: 75 MHz) instrument for solutions in CDCl 3. Finally, Gas Chromatography 2010 Shimadzu (GC) equipped with a capillary column BP-5 (30 m Â 0.25 mm with a film thickness of 0.25 lm.The carrier gas is helium set at a flow rate of 1.27 mL/min and adjust to a linear velocity of 31.7 cm/s.The column temperature was programmed at 3 C/min from 80 to 250 C (2 min).The volume injected is 5 lL.

Synthesis of epoxide eugenol
In a 100 mL flask containing (500 mg, 2.77 mmol) of eugenol solubilised in 30 mL of CH 2 Cl 2 , (680 mg, 2.77 mmol) of m-chloroperoxybenzoic acid is added.The mixture was stirred at room temperature for 24 h.Then it was diluted with CH 2 Cl 2 (20 mL) and washed twice with a solution of 10% NaHCO 3 (20 mL).The organic phase was combined and washed twice with 20 mL of distilled water, dried over Na 2 SO 4 , filtered, and concentrated under vacuum.The crude material was purified by silica gel column chromatography (Yadav and Banik 2018) using n-hexane-ethyl acetate (80:20) as eluent.

Synthesis mode of vanillyl glycol
In a 100 mL flask containing 5 mmol of eugenol epoxide solubilised in 10 mL of ethanol, 1% mmol of AlCl 3 hydrate is added under nitrogen, the reaction mixture was followed by TLC.The raw reaction mixture was diluted in 10 mL of ethanol then treated with sodium hydrogen carbonate 10% NaHCO 3 .The organic phases are collected dried on magnesium sulphate MgSO 4 and concentrated under reduced pressure (Deshpande et al. 2019).The raw material was purified by silica gel column chromatography using n-hexane-ethyl acetate (70:30) as eluent.

Computational methods
All computations calculations were performed using the Gaussian 06 W series of program (Al Zoubi et al. 2021).The geometries of optimised reagents were performed by the density functional theory DFT with the Becke's three parameters exchange functional and the Lee Yang Parr correlation functional (B3LYP) (Becke 1988;Lee et al. 1988 ), where the standard 6-31 G (d, p) basis set was employed (Martell et al. 1997).Solvation effects were accounted by employing the Density-based Solvation Model (SMD) method (Marenich et al. 2009).The global reactivity parameters give information about the general behavior of molecules.The global electrophilicity index x (Parr et al. 1999), is given by Parr was calculated using the following expression, x ¼ (l 2 / 2g), where l presented the electronic chemical potential and g the chemical hardness (Chakraborty and Chattaraj 2021).In terms of the energies of the highest occupied (E HOMO ) and the lowest unoccupied (E LUMO ) molecular orbitals the chemical potential and the chemical hardness expressed as follow, l¼ (E HOMO þ E LUMO )/2 and g¼ (E LUMO -E HOMO ), respectively (Maynard et al. 1998).The Mulliken Electronegativity v is defined as the negative of the chemical potential (Marco and G azquez 2019).The Softness (s) could be expressed as the reciprocal of chemical hardness as follows (s ¼ 1/g) (Xu et al. 2017).The nucleophilicity index N was introduced based on the HOMO energies obtained within the Kohn-Sham scheme (Zeroual et al. 2016), and expressed as N ¼ EHOMO (Nu) -EHOMO (TCE) , where tetracyanoethylene (TCE) was taken as reference, because it presents the lowest HOMO energy in a large series of organic molecules (Domingo and Patricia 2011).

Conclusion
The current study aimed to synthesis a new compound from eugenol, starting by the extraction of essential oils from clove bud.The essential oils present four principal compounds namely; eugenol (70.14%) as the major compound, caryophyllene (17.09%), acetyleugenol (6.45%) and isoeugenol (5.80%).The double bond present in the later chain of eugenol was converted to epoxide.The ring opening of epoxide eugenol using aluminum chloride hydrate in an ethanolic medium lead to vanillyl glycol.The DFT study of the chemical reactivity's epoxide with AlCl 3 hydrate approves and explain the experimental outcomes.The synthesised product vanillyl glycol is a bioactive compound that can be a new potential resource for future research to design new activities.

Figure 1 .
Figure 1.Synthesis of vanillyl glycol from eugenol via the opening ring of epoxide eugenol.