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Eugenol: Source, processing, and its derivative compounds

Eugenol (C10H12O2, Figure 1, a) is a phenylpropanoid compound with the IUPAC name of 4-allyl-2-methoxyphenol and biosynthesized from the phenylalanine amino acid. Eugenol has an aromatic odor of clove and unique spicy taste with colorless to pale yellow oily liquid. A large number of scientific evidences reported the bioactivities of eugenol, such as antioxidant (Gulcin, 2011), antibacterial (Jeyakumar and Lawrence, 2021), antifungal (Ju et al., 2020), anticancer (Fangjun and Zhijia, 2018), anti-inflammatory (Megalhaes et al., 2019), and others. Therefore, eugenol is widely used in the pharmaceutical, food, and cosmetic industries as well as a raw material for other chemical products due to its properties. Regarding to its toxicity, a dose of eugenol at 2.5 mg/kg body weight is reported as safe (Ulanowska and Olas, 2021).

Figure 1. Molecular structure of eugenol and its derivatives: (a) eugenol, (b) methyleugenol,

(c) isoeugenol, and (d) vanillin.

In 1929, eugenol was firstly isolated as a volatile compound from Eugenia caryophyllata (synonym of Syzygium aromaticum) and the name is supposedly derived according to this genus (Marchese et al., 2017). It is known that eugenol is the most important compound in the clove essential oil. This oil from clove flower buds contains a large amount of eugenol up to 180 mg per g of fresh material (Raja et al., 2015). The concentration of eugenol from other plant organs of clove is lower compared to the flower buds. Cinnamon, nutmeg, basil or tulsi, betel pepper, clover pepper, turmeric, thyme, oregano, ginger, and bay are another well known natural source of eugenol and their concentration in the essential oils are varied according the parts of these plant source. However, these sources have a low concentration of eugenol, namely less than 36 mg per g, compared to the clove (Giuliani, 2014, Raja et al., 2015, Marchese et al., 2017). Up to date, essential oils of clove from Indonesia remain as one potential source of eugenol in the market.

Essential oils from clove containing eugenol are extracted by using conventional extraction methods, solvent extraction, hydro distillation, and steam distillation (Khalil et al., 2017, Haro-Gonzalez et al., 2021). The use of solvent extraction method both in batch and soxhlet extractions faces major hindrances, such as the presence of solvent residue, other soluble residue undesirable flavor changes, and so on. On the other hand, hydro distillation and steam distillation are the most common methods for the extraction of essential oils from clove. Essential oils with eugenol contents of 50–87% were obtained from clove flower buds with high yields of 12–21% by hydro distillation method (Frohlich et al., 2019). These yields and eugenol contents using hydro distillation are similar to the extraction result by the use of supercritical CO2 which is known as a green and efficient extraction method. Another green techniques, microwave and ultra-sound assisted extractions can be also used for the extraction of eugenol to replace the conventional techniques (Khalil et al., 2017). To increase in the eugenol content, several methods purifying eugenol from the clove essential oil have been reported by employing some techniques, e.g., high performance liquid chromatography (Miller et al., 1979) and high-speed counter-current chromatography (Geng et al., 2007). PT Mitra Ayu Adi Pratama applies fractional distillation as another type of refining method to purify clove essential oil with eugenol content ≥ 99.5% to achieve the USP grade of eugenol.

Some experimental reports show eugenol is used as a target molecule for the structural modification in order to produce other derivatives with better and healthier biological effects, lower side effects, and new spectrum of activities and applications. da Silva et al. (2018) modified the eugenol structure using esterification reactions in the hydroxyl group and addition reactions in double bond of the allyl group to enhance antibacterial and antioxidant activities. Esterification and epoxidation reactions of eugenol could improve insecticidal activity (Fernandes et al., 2020). Some eugenol derivatives produced through the following reactions described below: (1) methylation (methyleugenol); (2) isomerization (isoeugenol); and (3) bioengineering (vanillin).

(1) Methyleugenol (Figure 1, b)

Methyleugenol is a natural compound of numerous essential oils of plant origin. The content of methyleugenol in essential oils varies within and between plant families as well as within plant organs. The following plants contain more than 90% methyleugenol as the main compound in essential oils: Melaleuca (M.) bracteata F.v.M. leaves, Cinnamomum (C.) oliveri Bail. leaves, Dacrydium franklinii, M. leucadendron, Crotonn malambo, C. cordatum, M. ericifolia, M. quinquenervia, Pimenta racemose, Piper divaricatum, and Clusena anisate (Burfield, 2004, Burdock, 2005, Tan and Nishida, 2012). Due to the increasing demand, methyleugenol is chemically produced by methylation of eugenol. This reaction involves an addition of a methyl group on the oxygen atom of the hydroxyl group of eugenol based on Williamson ether synthesis in the presence of methylation agent, such as dimethyl carbonate, methyl halides, dimethyl sulphate, etc., and catalyst, such as KOH, bentonite, etc. (Asnawati et al., 2015, Riyanto et al., 2016).

Methyleugenol is a colorless to pale yellow liquid with a clove-carnation odor and a bitter taste. In nature, methyleugenol has various roles related to the chemical defense of plants, namely antifungal, antibacterial, antinematoda, toxicant against pathogens and insect herbivores as well as insect attractant, and sex pheromone (Tan and Nishida, 2012). Gogoi et al. (2020) reported some potential bioactivities of methyleugenol as antioxidant, anti-inflammatory, antimicrobial, genotoxicity, and herbicidal activities. It is used as flavoring agents of ice cream, candy and so on, and a fragrance ingredient in perfumes, toiletries and detergents (National Toxicology Program, 2010b).

(2) Isoeugenol (Figure 1, c)

Some plants, i.e. calamus, savory, basil, clove, nutmeg etc., are source of isoeugenol. However, isoeugenol in nature is present in a small quantity (Galopin et al., 2006). Isoeugenol can be easily isomerized from eugenol wherein the double bond in alkenyl group of eugenol migrates to a position conjugated with the benzene ring. Isomerization of eugenol is carried out by potassium hydroxide in the presence of alcohol and also by a catalyst of rhodium chloride in aqueous alcohol solution at high temperature (Červený et al., 1987). Other modified catalysts, mesoporous silica of SBA-16 containing titanium chloride (Wróblewska et al., 2021) and hydrotalcite-like lattice (Kishore and Kannan, 2004) have a superior performance of isomerization yield compared to that using the conventional base isomerization.

Isoeugenol has a spicy, carnation-like odor which can be incorporated into numerous household and personal hygiene products (National Toxicology Program, 2010a). In addition, isoeugenol is used as sweetener, natural antioxidant, and storage agent in food and pharmaceutical processes (Zhang et al., 2017). Isoeugenol also exhibited the higher biological activities such as antioxidant and antibacterial activities as well as protective effect against DNA damage, than eugenol (Zhang et al., 2017). Isoeugenol is used as a starting material for the biotechnological production of vanillin (Ma et al., 2022).

(3) Vanillin (Figure 1, d)

Vanillin, the world most popular flavor compound, is obtained as a main ingredient of vanilla extract from the fermented pods of vanilla, Vanilla (V.) planifolia and V. tahitensis (Rao and Ravishankar, 2000). In cured vanilla pods, vanillin is present at a concentration of 1–2% (w/w) and due to its characteristic flavor and fragrance comes mainly from the vanillin, vanillin is called as the key component of vanilla extract (Gallage and Møller, 2018, Zhang and Mueller, 2012). Biotechnology-based vanillin synthesis with the use of eugenol, isoeugenol, and others natural compounds has been extensively investigated by many researchers due to its high demand, limited supply of vanilla pods and increasing the production cost of natural vanillin from the cured vanilla pods (Gallage and Møller, 2015, Ma et al., 2022). Bioengineering of vanillin from eugenol and isoeugenol by microorganisms has been reviewed by Gallage and Møller (2015). A higher vanillin production by Amycolatopsis sp. HR167 and Bacillus pumilus S-1 were obtained using eugenol (> 10 g/L, Overhage et al., 2006) and isoeugenol (32.5 g/L, Zhao et al., 2005) as substrates, respectively.

Vanillin is structurally a benzaldehyde substituted with a hydroxyl and methoxy group at positions of C4 and C3, respectively. It is a white crystalline powder with a pleasant, sweet, and intense aroma, offering a vanilla-like flavor as well as a strong milky fragrance. Therefore, vanillin is widely used as an important ingredients in foods, beverages, cosmetics, and pharmaceuticals with the market demand up to 15,000 ton annually (Ma et al., 2022). Bioactive properties of vanillin have been reported by Sinha et al. (2008) and Arya et al. (2021) and others. Some bioactivities of vanillin are as neuroprotection, anticarcinogenic, antioxidant, antimicrobial, hypolipidemic, antisickling, antimutagenic and so on.

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