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Article

Synthesis of Acetylated Phenolic Compounds with Promising Antifouling Applications: An Approach to Marine and Freshwater Mussel Settlement Control

by
Míriam C. Pérez
1,2,
Mónica García
1,
Gustavo Pasquale
3,
María V. Laitano
4,
Gustavo Romanelli
3,5 and
Guillermo Blustein
1,3,*
1
Centro de Investigación y Desarrollo en Tecnología de Pinturas (CIDEPINT), Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de La Plata, Calle 52 e/121 y 122, La Plata 1900, Argentina
2
Facultad de Ciencias Naturales y Museo, Universidad Nacional de La Plata, Calle 60 y 122, La Plata 1900, Argentina
3
Cátedra de Química Orgánica, Facultad de Ciencias Agrarias y Forestales, Universidad Nacional de La Plata, Calle 60 y 119, La Plata 1900, Argentina
4
Instituto de Investigaciones Marinas y Costeras (IIMyC), Universidad Nacional de Mar del Plata (UNMdP-CONICET), Dean Funes 3350, Mar del Plata B7602AYL, Argentina
5
Centro de Investigación y Desarrollo en Ciencias Aplicadas “Dr. Jorge J. Ronco” (CINDECA-CCT La Plata-CONICET), Universidad Nacional de La Plata, Calle 47 No 257, La Plata B1900AJK, Argentina
*
Author to whom correspondence should be addressed.
Compounds 2025, 5(4), 45; https://doi.org/10.3390/compounds5040045
Submission received: 6 August 2025 / Revised: 12 September 2025 / Accepted: 20 October 2025 / Published: 24 October 2025
(This article belongs to the Special Issue Phenolic Compounds: Extraction, Chemical Profiles, and Bioactivity)
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Versions Notes

Abstract

Biofouling by mussels is responsible for serious economic losses worldwide. In Argentina, Limnoperna fortunei (Dunker, 1857) and Brachidontes rodriguezii (d’Orbigny, 1842) are common and abundant bivalve species of great interest, inhabiting freshwater and marine coasts, respectively. Both species are considered fouling pests for coastal industrial facilities that use untreated water as part of their processes. To chemically control mussel biofouling, it is necessary to find efficient and environmentally friendly non-biocidal compounds. In this work, we report the antifouling activity of three phenolic compounds (hydroquinone, resorcinol, and catechol) and their respective acetylated derivatives against L. fortunei and B. rodriguezii mussels. Classic ecotoxicity tests with Artemia salina were also performed. Acetylated phenolic compounds were synthesized in the laboratory by sustainable chemistry procedures. Results revealed the importance of hydroquinone, resorcinol, and catechol and their diacetylated derivatives for preventing the settlement of both these mussels, in a non-biocide way. Ecotoxicity bioassays revealed that these compounds were not toxic, with the exception of resorcinol. We propose the incorporation of these compounds in solution into closed circuits and water sprinkler anti-fire systems to prevent the settlement of L. fortunei and their inclusion in antifouling paints to prevent the settlement of B. rodriguezii. These results highlight a new friendly alternative for controlling mussels.

1. Introduction

Biofouling control is of particular interest for maritime shipping. Biofouling is the result of a sequence of events that includes several steps. The submerged surface is first coated with biopolymers and then with microorganisms such as bacteria, fungi, and protozoa. The multiplication of these microorganisms, along with the production of exopolymers, leads to the formation of biofilms [1]. Biofilms also include yeasts and diatoms, which induce the subsequent arrival of larvae of macroorganisms [2].
Biofouling (marine and freshwater) and corrosion create serious and costly problems in various port facilities, such as shipping, power plants, and aquaculture structures [1]. Although some differences exist in the composition of fouling communities, in general terms, they all include algae, sponges, hydroids, barnacles, bivalves, bryozoans, polychaetes, and ascidians. Some of these species are cosmopolitan. Those that are not can cause serious ecological and economic problems when transported around the world by ship, settling on the hull or in ballast water. In all cases, the impact of biofouling is very detrimental to industries [3,4].
In particular, fouling by mussels is responsible for serious economic losses worldwide in several industries. Infestations by Dreissena polymorpha (‘zebra mussel’) continue to be a serious problem in Europe for industrial port facilities [5].
In South America, Limnoperna fortunei (Dunker, 1857) and Brachidontes rodriguezii (d’Orbigny, 1842) are common and abundant bivalve species of great interest in the freshwater and marine coastal environments, respectively. Both freshwater and marine mussels trigger severe problems for a variety of substrata. In China and South America, L. fortunei is a fouling pest for coastal industrial facilities that use untreated water as part of their processes [6]. Important damage to irrigation infrastructures is attributable to this prolific species, which results in significant maintenance costs. Hydroelectric binational power plants such as Yacyretá (Argentina–Paraguay) and Itaipú (Brasil–Paraguay) have been rapidly colonized by this mussel, causing periodic interruption of the electricity-generating turbines [7,8].
On the other hand, marine mussels commonly adhere to ships and piers and integrate into fouling communities with serious consequences for artificial structures. Mussels are a very adept group of organisms that colonize all types of structures, being extremely harmful to the cooling systems of power plants [9,10]. It has been reported that blue mussels can form calcareous deposits on the walls of intake structures that could reach thicknesses greater than one meter [11]. In the particular case of bivalve B. rodriguezii is also considered an ecosystem engineer, because it increases habitat complexity by facilitating available niches to the diversity of the intertidal community, as several species of seaweeds, other mollusks, crustaceans, and polychaetes, among others [12,13]. In this way, B. rodriguezii contributes to increasing the thickness of fouling.
Different strategies have been developed to control biofouling depending on whether they are in marine or freshwater environments.
Although various methods have been proposed to control mussel fouling (chemical, cleaning, temperature, etc.), the most widely used remains the application of chlorine [6]. However, some studies confirmed the inadequacy of intermittent chlorination to control fouling by both freshwater and marine mussels. The most obvious feature of a bivalve is the protective shell, and during periods of chlorination, mussels shut their valves and halt byssus production [14]. Furthermore, the use of chlorogenic products has the disadvantage of non-selectively chlorinating organic matter and producing compounds harmful to health. Therefore, it is imperative to explore new approaches to control mussel settlement [15].
The use of antifouling paints containing one or more biocides is the most common and effective method to control marine biofouling [4]. However, it has been known for more than two decades that traditional antifoulants such as cuprous oxide (Cu2O) and the banned tetrabutyltin (TBT) are highly toxic to non-target marine organisms [16].
In contrast, the use of antifouling paints in freshwater environments is not recommended. The release of biocides is not convenient because rivers are a source of water for human consumption and also for watering.
A viable and ecological friendly alternative is the lab-synthesis by sustainable-chemistry procedures or the use of commercially compounds with antifouling action ‘inspired’ by natural compounds. Phenolic compounds are widely distributed in nature. Their functions are very broad and include: antioxidant and antimicrobial activity, ion storage, among others. This is due to their redox capacity, their chelating properties, and their high capacity to interact with other materials, either chemically or physically [17].
Based on their bioactivity, we have selected three phenolic compounds, hydroquinone, resorcinol, and catechol to study them as possible antifouling agents (Figure 1).
Hydroquinone is a phenolic compound that occurs naturally in both plants and animals, and several properties have been described [18]. Among its biological activities, hydroquinone significantly inhibited the growth of marine diatoms, decreasing chlorophyll A and carotenoid contents in microalgae Phaeodactylum tricornutum and inducing changes in cellular physiological levels. For this reason, hydroquinone has been proposed as an algaecide to control algal blooms [19]. It has been found in the leaves of a wide variety of plants, where it is postulated to act as an antioxidant [20]. On the other hand, other phenolic compounds have been indicated with several properties. Catechol is also found naturally in fruits, vegetables, and trees, and has been found to have antibacterial and antifungal effects [21]. Resorcinol was recognized as a potent antioxidant together with caffeic acid, vanillic acid, ferulic acid, and catechin, all present in argan oil [22].
In the search for bioactive molecules, a large number of compounds with antifouling activity have been isolated from natural sources [23,24]. However, these products are generally difficult to produce on a large scale due to their limited availability in sufficient quantities, and their chemical synthesis at low costs and high yields is also very complex [25,26,27]. One solution to this dilemma could be to synthesize smaller molecules that resemble those complex ones found in nature. Hydroquinone-C acetate, a secondary metabolite isolated from the epibiont-free Mediterranean sponge, showed a strong antifouling activity Balanus amphitrite larvae [28].
This study is part of a broader project aimed at discovering and developing new, more environmentally friendly antifouling agents. In this work, we study the antifouling activity of three phenolic compounds (hydroquinone, resorcinol, and catechol) and their respective acetylated derivatives (Figure 2) against L. fortunei and B. rodriguezii mussels. Classic ecotoxicity test with Artemia salina was also performed.

2. Materials and Methods

2.1. General Procedures and Statements

The three phenols were purchased from commercial suppliers and purified before use. Catechol (Sigma-Aldrich Reagent Plus; Darmstadt, Germany), Resorcinol (Sigma-ACS Reagent; Darmstadt, Germany), and hydroquinone (Sigma-Aldrich Reagent Plus; Darmstadt, Germany).
The progress of the acetylation reactions (described later in Section 2.3) was monitored using the layer chromatography (TLC) technique. The plates used were the following: Silicagel 60 F254 TLC plate (aluminum TLC plate, silica gel coated with fluorescent indicator F254).
The compounds in the reaction mixture were separated using flash chromatography. This involves filling a glass column with a solid stationary phase, in our case silica technical grade, pore size 60 Å, 230–400 mesh, and then adding a solvent (hexane) or a solvent mixture as the mobile phase (hexane-ethyl acetate of increasing polarity).
The yields were calculated from crystallized products. The acetylated products were identified by comparison of physical data (mp, TLC, NMR) with those reported or with those of authentic samples prepared by the respective conventional methods using aqueous NaOH as a catalyst. Melting points of the compounds were determined in sealed capillary tubes and are uncorrected. 1H-RMN and 13C-RMN spectra were obtained on a Bruker spectrometer FT-300 BioSpin GmbH (Rheinstetten, Germany), using CDCI3 as solvent (depending on the solubility of the compound) and tetramethylsilane (TMS) as internal standard. The operating frequencies for protons and carbons were 400 and 100 MHz, respectively. Chemical shifts (δ) are given in ppm, and coupling constants (J) are given in Hz. The following abbreviations are used for multiplicity: s = singlet, d = doublet, t = triplet, and m = multiplet.

2.2. Catalyst Preparation

This section describes two procedures involved in the preparation of the catalyst used in the organic synthesis of acetylated phenols. Section 2.2.1 describes the synthesis of the heteropolyacid, and Section 2.2.2 describes how the synthesized heteropolyacid is embedded in a silica matrix to function as a heterogeneous catalyst. These are routine operations in heterogeneous synthesis.

2.2.1. Bulk Catalysts

Bulk catalyst H14[NaP5W29MoO110] (PWMo) was prepared essentially following a procedure recently described by our research group [29].
Potassium salt of Preyssler anion was prepared by dissolving 5.75 g of Na2WO4·2H2O (32.5 mmol) and 0.5 g of Na2MoO4·2H2O (2.5 mmol) in 5 mL of hot distilled water with constant agitation; the solution was kept under reflux. Then 6.75 mL of H3PO4, 85% (5 mmol), was added by dripping; the resulting solution was kept at reflux for 24 h. Afterwards, 0.25 mL of concentrated nitric acid was added to the mixture, followed by 2.5 g of KCl (32.5 mmol) with constant stirring. The suspension obtained was centrifuged for 15 min, and the solid was dissolved in 12.5 mL of hot distilled water and kept cooling (4 °C approx.) overnight. The precipitate obtained (K14[NaP5W29MoO110]) was filtered and dried under vacuum at room temperature.

2.2.2. Supported Catalyst, PWMo10SiO2

PWMo10SiO2 (supported catalyst containing 10 wt% of active phase) was prepared according to a procedure described by Ruiz et al. [30]. Silica gel-supported Preyssler acid was prepared by wet impregnation of Grace silica (SiO2) (Grade 59, specific area: 250 m2/g), with an acetone solution of PWMo synthesized heteropolyacid, respectively. After impregnation, samples were dried at room temperature in vacuum desiccators for 8 h.

2.3. General Procedure for the Acetylation of Phenols

A mixture of phenol (5 mmol), toluene (10 mL), acetic anhydride (12 mmol), and PWMo10SiO2 catalyst (0.5 mmol% of active phase) was stirred at 20 °C for the indicated time (Table 1), ranging from 1.5 to 3 h. The catalyst was removed by simple filtration and washed with a small amount of toluene (2 × 3 mL). The toluene phase was washed with water (2 × 5 mL) and dried over anhydrous Na2SO4. Water washings allow the removal of residual phenolic compounds from the toluene phase. The toluene was evaporated in a rotary evaporator under vacuum with controlled heating, and the residue (mostly acetylated phenols) was subjected to column chromatography on silica to obtain the desired product. The di-esters from catechol and hydroquinone can also be obtained pure from the reaction mixture by recrystallization without the need for liquid column chromatography.

2.4. Melting Point and NMR Spectra of Synthesized Compounds

Hydroquinone diacetate: Melting point 119–121 °C (reported 120 °C) [31]. The product 1,4-phenylene diacetate was obtained in a pure form with a yield of 98%. 1H-NMR (CDCl3, 400 MHz) δ ppm: 7.10 (s, 4H), 2.31 (s, 6H). 13C-NMR (CDCl3, 100 MHz) δ ppm: 169.4, 148.3, 122.5, 20.9.
Resorcinol diacetate: colorless oil. The product 1,3-phenylene diacetate was obtained in a pure form with a yield of 98%. 1H-NMR (CDCl3, 400 MHz) δ ppm: 7.35 (t, J = 8 Hz, 1H), 6.96 (dd, J = 2.5, 8.4 Hz, 2H, 6.92 (t, J = 2.4 Hz, 1H), 2.26 (s, 6H). 13C-NMR (CDCl3, 100 MHz) δ ppm: 168.9, 151.1, 129.8, 118,8, 115.6, 21.2.
Catechol diacetate: Melting point 63–64 °C (reported 62–64 °C) [32]. The product 1,2-phenylene diacetate was obtained in a pure form with a yield of 86%. 1H-NMR (CDCl3, 400 MHz) δ ppm: 7.26–721 (m, 2H), 7.18–7.16 (m, 2H), 2.28 (s, 6H). 13C-NMR (CDCl3, 100 MHz) δ ppm: 168.5, 143.1, 126.8, 123.5, 20.8.

2.5. Biological Assays

2.5.1. Mussel Specimens

Two species of mussels from Buenos Aires Province were collected for bioassays. One of them is the invasive freshwater mussel L. fortunei, which was collected during low tide at Punta Lara (34°49′00″ S–57°58′00″ O), and the other is the marine mussel B. rodriguezii collected by scraping of the rocky shore in Mar del Plata (38°02′30″ S–57°32′00″ W).
L. fortunei and B. rodriguezii grow and proliferate in highly contaminated environments. Terrestrial and freshwater ecosystems are usually contaminated by agrochemicals, particularly glyphosate (N-phosphonomethyl glycine), which was detected in rivers and lakes in Argentina. This is one of the main pollutants where L. fortunei develops [33]. On the other hand, B. rodriguezii is one of the dominant byssal species of rocky shores along the Argentinean marine coast. Dense populations of this mussel develop in waters contaminated by polycyclic aromatic hydrocarbons and products derived from the leaching of antifouling paints as organotins. The presence of this pollutant has been very harmful to the coastal marine ecosystem due to its high persistence in the environment and its ability to move up the food chain [34,35].
Mussels were transported to the laboratory and acclimatized for 24 h. Freshwater mussels were transferred to an aquarium with a mixture of both river and aged tap water. On the other hand, marine mussels were conditioned with artificial seawater, which was prepared according to ASTM D1141−98 (reapproved in 2021) [36]. All experiments were carried out at room temperature (20 °C) and natural sunlight, and mussels were fed daily. Every two days, half of the water in each aquarium was renewed. Mussels with active exploratory behavior were chosen for the experiments.

2.5.2. Settlement Assay

This test was carried out to evaluate the antifouling activity of hydroquinone, resorcinol, catechol, and their acetylated derivatives. For bioassays, dilutions of all compounds were obtained from a stock solution of 103 μM prepared with aged tap water or seawater to final concentrations between 103 μM and 10 μM. In this context, byssal thread production was the parameter registered for the settlement assay. Experiments were conducted in 6 cm-diameter crystallizing vessels with 40 mL of each solution and five mussels of uniform size (0.8–1.2 cm). The control group was also maintained separately with similar conditions but without adding any compound. The mussels were not fed during the bioassays, and all the experiments were carried out in quadruplicate. After 48 h exposure, concentrations that inhibit byssus production were subjected to a detailed experiment to examine the EC50 (effective concentration for 50% inhibition of attachment). Mussels from the experimental beakers, which completely inhibited the byssal attachment, were kept in the same conditions until reaching 72 h of exposure, and vital parameters (mobility, foot, and siphon activity) were recorded and evaluated as toxicity criteria [37].

2.5.3. Recovery Tests

Finally, a series of experiments to determine the degree of toxicity of these compounds on organisms was carried out. These tests determine if the effect of compounds was temporary or permanent. All mussels were washed three times and transferred to clean water (freshwater or seawater).
Then, they were kept there for 24 h. Unattached individuals were transferred directly, and in the case of attached individuals, byssus were previously cut. After 24 h, the vessels were carefully examined under a stereomicroscope, and the mussels were considered ‘dead’ if they did not move or respond when touched with a metal probe, remained motionless, and with the valves closed [37]. Then, byssal production and attachment were registered and recovery percentages calculated [38].

2.5.4. Ecotoxicity Assays

Artemia salina is commonly used for ecotoxicity tests [39]. The larval stage of A. salina is easy to rear, which facilitates the observation of its behavioral responses, making it particularly suitable for toxicity assessments and quantitative analyses. This microcrustacean is frequently used as an indicator organism in ecotoxicity tests to evaluate the safety and ecological impact of antifouling compounds [40].
Ecotoxicity test conducted with A. salina was carried out at a concentration 10% above the highest EC50 found in the mussel settlement assay (600 μM). This provides a safety margin for screening of antifouling and non-toxic compounds. Brine shrimp eggs were bought from AQUABREED, Caseros, Buenos Aires, Argentina.
Brine shrimp eggs were allowed to hatch in artificial seawater, 20 °C, and after 48 h, the phototropic nauplii were collected by a Pasteur pipette from the light side. Toxicity test was performed in the darkness in 24-Multiwell plates containing 2 mL of 600 μM solutions. A volume of 20μL of culture containing nauplii was added. Experiments were carried out in sextuplicate. The plates were incubated for 24 h at room temperature, and then the percentage of dead nauplii was obtained. Larvae that were completely motionless were counted as dead organisms. All tests included K2Cr2O7 (13.6 μM) as a positive control and artificial seawater as a negative control [41].

2.5.5. Statistical Analysis

All statistical analyses were performed with IBM SPSS V22.0. The normality assumption was verified with the Shapiro–Wilk’s test. Comparisons of means between treatments and control for Settlement and Ecotoxicity tests were determined by one-way analysis of variance (ANOVA) followed by Dunnet. Differences were considered to be significant at p < 0.05. Calculations of EC50 with 95% confidence intervals were performed with Probit analysis.

3. Results and Discussion

3.1. Acetylation of Phenols

Acetylation of phenolic hydroxyl groups is a reaction commonly used to protect these groups during the organic synthesis of numerous chemical compounds. For this purpose, different procedures can be applied, involving an acid chloride or an acid anhydride with a base, or an acid anhydride in the presence of an acid catalyst [42]. Particularly, the synthesis of phenylene diacetates of the corresponding phenols: hydroquinone, resorcinol, and catechol is carried out regularly using acid anhydride and homogeneous protic acid, or based catalysts, including sulfuric acid, perchloric acid, aminosulfonic acid, methylenediphosphonic acid, pyridine, sodium hydroxide, sodium carbonate, among others [43,44]. In recent decades, great attention has been paid to reactions carried out under heterogeneous catalysis conditions, given the possibility of recovering, recycling, and reusing the catalyst, in order to reduce the environmental impact. A variety of noncorrosive materials have been used as heterogeneous catalysts. Some of them are: beta zeolite H-form, montmorillonite KSF, SBA-15-Ph-Pr-SO3H, sulfonated ordered mesoporous carbon (CMK-5-SO3H), and heteropolyacids. In general, the transformations have proved to be simpler and cleaner [45]. Particularly, heteropolyacids are formed by a close-packed framework of metal-oxygen octahedra MO6 (M = Mo6+, W6+) surrounding a central atom X (Si4+, P5+). Heteropolyacids catalyst exhibits super acidic properties, and can be used in bulk or supported form in reactions requiring electrophilic catalysis. Our research group has developed a procedure for the acylation of alcohols, phenols, amines, and thiols using a Keggin heteropolyacid supported on silica with very good yields [46]. More recently, the Preyssler heteropolyacids have shown great versatility as catalysts in organic synthesis processes, showing thermal stability and particularly greater hydrolytic stability than the Keggin and Wells-Dawson heteropolyacids. Our research group has studied the catalytic performance of bulk and silica-supported Preyssler heteropolyacids. The most relevant transformation including the protection of functional heterocyclic synthesis, and recently, transformations of building blocks present in biomass [29,47,48]. For this reason, in the present work, we have studied the diacetylation of three phenols (hydroquinone, resorcinol, and catechol) using acetic anhydride assisted by a Preyssler heteropolyacid (PWMo) supported on silica (PMoW10SiO2).
Optimal reaction conditions were initially evaluated using hydroquinone as a substrate, and varying: temperature, time, amount of catalyst, and anhydride acetic: substrate ratio. It was observed that after reusing the catalyst, the yields remained almost unchanged after three successive batches. Between each use, the catalyst was washed with toluene (Table 1).
The influence of temperature on the production of hydroquinone diacetate is shown in Table 1. Two experiments were performed (at 20, and 50° C) using PWMo10SiO2 as a catalyst (0.5 mmol %). The results show the best yield at 20° C (98%, 1.5 h, Table 1, entry 2). In this condition the reaction was 100% selective, and no secondary products were detected by TLC. Subsequently, a second experiment was carried out at 50 °C, in order to reduce reaction times. However, the reaction yield for a similar time (1.5 h) (Table 1, entry 1) was lower (90%), observing that although the conversion was 100%, small amounts of secondary products were detected, which were not identified by TLC. For this reason, the next optimization experiments were carried out at room temperature (20 °C).
The reaction time at constant temperature (20° C) was also studied as a variable, using two additionally times of 1 and 2 h (Table 1, entries 3 and 4). A good yield is obtained at 1 h of reaction (88%, Table 1, entry 4), reaching the optimal yields at 1.5 h (98%, Table 1, entry 2), without any variation at longer reaction times, such as 2 h (97%, Table 1, entry 3).
Another variable analyzed in this study was the amount of catalyst (PWMo10SiO2). Table 1 shows the results when two additional proportions of the catalyst were used at the previously defined optimal conditions. It can be seen that a lower amount of catalyst, 0.25 mmol % gives lower yields at 20 °C for 1.5 h (72%, Table 1, entry 5), and no relevant changes were observed when the catalyst increase was 0.75 mmol %, in the same reaction conditions (96%, Table 1, entry 6).
The optimal molar ratio of substrates for this procedure was hydroquinone/acetic anhydride: 1: 2.4 (98%, Table 1, entry 2), with no substantial change being observed when working with a ratio of 1:3 (98%, Table 1, entry 7), and lower yields with a 1:2 ratio (79%, Table 1, entry 8).
To study the reusability of the catalyst in the same reaction, the recovered catalyst was reused in the same conditions and proportions (20° C, 1.5 h, in toluene as solvent, 0.5 mmol % of PWMo10SiO2 and 1:2.4 hydroquinone/acetic anhydride molar ratio, over four consecutive tests). To make this possible, the recovered catalyst was washed with toluene (2 × 2 mL), water (2 × 2 mL), and dried in a vacuum at 20 °C. Then was activated at 120 °C for 2 h. The results, which are listed in Table 1 (entries 9, 10, and 11 are 97, 96, and 96%, respectively), suggest no appreciable variations for first, second, and threes reuses.
The scope and generality of this procedure are illustrated by two additionally examples using resorcinol and catechol as substrates. According to the results of optimization experiments for the reaction conditions, the resorcinol diacetylation was carried out in the presence of a catalyst (0.5 mmol %) at 20° C, 1.5 h, and using toluene as solvent, the corresponding 1,3-phenylene diacetate was obtained in very good yields (92% Table 1, entry 12). Comparable yields are obtained by increasing the reaction time to 2 h or the substrate/acetic anhydride molar ratio to 1:3. (Table 1, entries 13–15). Finally, catechol was used as the starting substrate in the diacetylation. Under identical conditions (Table 1, entry 16), the reaction products are obtained with a yield of 76%, which increases to 86% (maximum yield) by increasing the reaction time to 3 h (Table 1, entry 18).
Figure 3 summarizes the reaction scheme for obtaining the three acetylated phenols under optimal conditions.
The workup and catalyst recovery are simple, and all reactions have very high selectivity toward the corresponding diacetates. The TLC analysis shows only trace amounts of by-products. After completion of the reaction (monitored by TLC, eluent; EtOAc–hexane mixtures), the catalyst was separated by centrifugation and washed with toluene and water. After toluene evaporation, the crude product was easily isolated in an almost pure state. For solid compounds, further purification was performed by recrystallization. The reaction solvent can be recovered by simple distillation and reused. The products are known compounds and were characterized by 1H-NMR and 13C-NMR spectroscopy. For the solid compounds, the melting point was determined, resulting in concordance with the literature data. The characterization details of all compounds are shown in Section 2.4.

3.2. Biological Assays

Phenolic compounds are secondary metabolites that have broad-spectrum herbicidal and algaecide activity. In previous studies was confirmed that some polyphenols as hydroquinone and catechol, inhibited algal growth and induced changes in cellular physiological levels [49]. Particularly, the mechanism of action of hydroquinone is by altering the permeability of the cell membrane and inhibition of transcription of photosynthesis and respiration-related genes, suggesting the potential as an algaecide to control marine microalgae [19]. In addition, it was suggested that resorcinol plays a role as an allelochemical in interactions between macrophytes and other organisms of the aquatic ecosystem, and also certain resorcinol derivatives act as bactericidal in terrestrial plants [23].
Taking into account the mentioned properties, the experiments were focused on studying the antifouling activity of these compounds obtained by lab green synthesis or commercially. Ecotoxicity assays are frequently conducted simultaneously with settlement assays to assess the potential of active molecules to be included in environmentally benign coatings.
The results of the effect of hydroquinone, resorcinol, and catechol, and their acetylated derivatives indicate that all compounds showed antisettlement activity on L. fortunei and B. rodriguezii (Table 2). For L. fortunei acetylation has no marked effect on the EC50 except for resorcinol, but in the case of B. rodriguezii, acetylation has a strong impact on the EC50 for resorcinol and to a lesser extent for hydroquinone (Table 2).
Both species were highly affected by hydroquinone at low concentrations, although L. fortunei was more sensitive. For L. fortunei and B. rodriguezii the sequence of sensitivity was hydroquinone> catechol > resorcinol (Table 2). Sensitivity to acetylated compounds was dependent on the test organism. Thus, the following order was found for L. fortunei: hydroquinone diacetate > catechol diacetate > resorcinol diacetate, while for B. rodriguezii: hydroquinone diacetate > resorcinol diacetate > catechol diacetate (Table 2).
In Figure 4, settlement percentages at different concentrations of phenols and acetylated compounds for both species compared to the negative control are presented. Curves indicate that compounds presented highly significant antisettlement responses from a threshold concentration between 10 and 250 μM for phenols and 20–100 μM for acetylated compounds (p < 0.05).
Both hydroquinone and acetylated-hydroquinone (Figure 4a,b) were found to be the most potent compounds on L. fortunei, achieving total inhibition of settlement at a concentration close to 100 μM. In the case of B. rodriguezii, the most potent compound was catechol, which inhibited 100% of settlement at a concentration close to 100 μM (Figure 4a). It is also noteworthy that acetylated hydroquinone is able to completely inhibit the settlement of B. rodriguezii at concentrations less than 250 μM (Figure 4b).
After 72 h of exposure, signs of toxicity of the compounds were found in the mussels subjected to the settlement test, since the vital parameters were altered. The mussels had their valves completely closed and were immobile. In other words, these mussels could be counted as ‘dead’. However, recovery tests confirmed that all compounds studied have a temporary effect on mussels. A comparison made between treated and untreated mussels showed that they could recover immediately after exposure to each concentration, when placed in clean water. This indicates that the compounds had not caused any irreversible damage to the mussels.
Furthermore, ecotoxicity tests using A. salina showed that the values of dead nauplii ranged between 90 and 95% for the positive control, with significant differences with almost all the compounds tested and the negative control (Table 3). The percentage mortality of hydroquinone, catechol, acetylated hydroquinone, and acetylated catechol was always less than 10%. In the case of resorcinol and acetylated resorcinol, no significant differences in relation to the positive control were detected (Table 3). That is, both compounds were toxic to A. salina.
The studies presented in this article revealed the importance of hydroquinone, resorcinol, and catechol and their diacetylated derivatives to prevent the settlement of both freshwater and seawater mussels. Also, it was confirmed that the effect of all these compounds was reversible. Ecotoxicity bioassays with A. salina nauplii revealed that these promising compounds were not toxic, with the exception of resorcinol, because they caused less than 10% mortality at concentrations above and below the EC50 value. Lethality observed was not significantly different from the negative control (p < 0.05), and thus it could be concluded that these compounds are non-toxic to this non-target species [24]. It is noteworthy that the most potent compounds, both on L. fortunei and B. rodriguezii, reach a total inhibition of settlement at a concentration close to 100 mM, which turns out to be non-toxic on A. salina.
In earlier laboratory studies was suggested that hydroquinone, catechol, resorcinol, and other phenolic compounds have a mechanism of action that probably depends on factors related to structural properties such as the number of hydroxyl-groups and their relative location in the phenolic ring [50]. However, further structure-activity-relationship (SAR) trials should be conducted to determine this idea.
It is interesting to note that results obtained with acetylated or unacetylated compounds did not reveal significant differences in relation to antifouling response. However, acetylation makes compounds less soluble, and this is clearly an advantage from the point of view of antifouling coatings. Undoubtedly, the use of antifouling coatings would be adequate to prevent the settlement of B. rodriguezii, but not for L. fortunei.
A common problem in fire prevention systems is a consequence of using non-treated water. Several marine and freshwater organisms arrive as planktonic larvae and settle inside pipes. There are several methods to control marine/freshwater growth in a firewater pumping system, such as electrical fields, coatings, and biocide injection with varying degrees of success.
This type of accumulation is particularly serious in raw water systems used for fire, and the most important effects are the restriction of flow or complete blockage of the pipes [51]. Particularly, mussels are responsible for this accumulation not only when they are alive but also detached shells of those that have died. In this sense, it has been reported that severe blocking by Corbicula fluminea in fire protection lines in processing plants at Browns Ferry and McGuire power plant [11].
We propose the incorporation of these compounds in solution to closed circuits and water sprinkler anti-fire systems to prevent the settlement of L. fortunei.
In summary, it can be stated that water-soluble phenolic compounds are more suitable for water-recirculation systems. That is, they can be used to control L. fortunei in port structures that take water from the natural environment for their operation. On the other hand, acetylated phenolic compounds, which are poorly soluble in water, are promising candidates for the formulation of marine antifouling paints.
In addition, hydroquinone, catechol, and resorcinol are easily degradable under anaerobic conditions [52]. Several microorganisms catalyze mineralization and/or transformation of hydroquinone either by aerobic or anaerobic processes, although the last one being less frequent [53]. Biodegradation using microbial biomass is an effective strategy for removing hydroquinone and can be degraded by different pathways depending on the oxygen availability. It has been reported that degradation of hydroquinone is caused by certain fungi, and resorcinol is degraded by bacteria (Pseudomonas sp.). Based on the results obtained in aerobic and anaerobic conditions, resorcinol was classified as readily biodegradable by bacteria and fungi (IPS, International Programme on Chemical Safety, Resorcinol, IOMC, 2006) [53,54]. There have been several reports on the biodegradation of catechol by some microbial strains under aerobic conditions, such as Pseudomonas putida, the fungi Aspergillus awamori and Candida parapsilopsis [55]. Moreover, catechol may be released to the environment during its manufacture and use [56]. Although resorcinol can be biodegraded, in our ecotoxicity test, it was found to be a toxic compound. Taking this into account, it does not seem reasonable to introduce it into the environment. Perhaps a possible application would be to use it in closed water circulation systems, as long as adequate effluent treatment is carried out.

4. Conclusions

Acetylated phenols were obtained using an environmentally friendly methodology, through the use of recoverable solid catalysts of heteropolyacids type with excellent yields.
This study highlighted a new, safe alternative to control the settlement of freshwater and marine mussels. Phenol compounds (hydroquinone, resorcinol, and catechol) are suitable for the control of freshwater bivalve L. fortunei in different structures, while acetylated phenolic compounds are promising antifoulants for the formulation of marine paints to control B. rodriguezii. This paper summarizes an approach to the control of the mussels studied. However, further ecotoxicity testing, bioremediation, and effluent treatment are needed before these compounds can be safely introduced into the environment.

Author Contributions

Conceptualization, M.C.P., G.R. and G.B.; methodology, investigation, and formal analysis, M.C.P., M.G., G.P., M.V.L., G.R. and G.B.; writing—original draft preparation, writing—review and editing, M.C.P., G.R. and G.B.; supervision, project administration and funding acquisition, G.R. and G.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by MINCYT: PICT-2021-GRF-TII-00438; UNLP: Project A349 FCAyF and Project I268 F.I; CONICET: PIP-0111.

Institutional Review Board Statement

Both the University and CONICET have Institutional Committees for the Care and Use of Laboratory Animals (CICUAL) that adhere to international regulations regarding this matter. Also, in our research work we adhere to the document Estrategia Nacional sobre Especies Exóticas Invasoras signed in 2022 by the Ministry of Environment of the Nation in relation to a design and implementation of a system for early detection, prevention of spread, and early action against invasive species in ports and surrounding areas of the Atlantic coast (https://www.argentina.gob.ar/sites/default/files/2021/05/estrategiacexoticas_final.pdf accessed on 20 October 2025). In accordance with the guidelines of the Institutional Animal Care and Use Committee and relevant national regulations. We confirm that the use of these invertebrates does not require, at least not yet, an ethical approval statement.

Data Availability Statement

All data obtained and analyzed during this study are available from the corresponding author upon reasonable request.

Acknowledgments

We thank MINCyT, UNLP, CONICET, and CICPBA for their support. In memory of our Friend and Colleague, Diego Ruiz.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Compounds 05 00045 g001
Figure 1. Chemical structure of phenols.
Figure 1. Chemical structure of phenols.
Compounds 05 00045 g001
Compounds 05 00045 g002
Figure 2. Chemical structure of acetylated phenols.
Figure 2. Chemical structure of acetylated phenols.
Compounds 05 00045 g002
Compounds 05 00045 g003
Figure 3. Scheme of the acetylation of phenolic compounds assisted by Preyssler heteropolyacid.
Figure 3. Scheme of the acetylation of phenolic compounds assisted by Preyssler heteropolyacid.
Compounds 05 00045 g003
Compounds 05 00045 g004
Figure 4. (a) Settlement percentage of L. fortunei and B. rodriguezii exposed to hydroquinone (H), resorcinol (R), and catechol (C). Bars = mean ± SE. (b) Settlement percentage of L. fortunei and B. rodriguezii exposed to hydroquinone diacetate (Ac-H), resorcinol diacetate (Ac-R), and catechol diacetate (Ac-C). Bars = mean ±SE.
Figure 4. (a) Settlement percentage of L. fortunei and B. rodriguezii exposed to hydroquinone (H), resorcinol (R), and catechol (C). Bars = mean ± SE. (b) Settlement percentage of L. fortunei and B. rodriguezii exposed to hydroquinone diacetate (Ac-H), resorcinol diacetate (Ac-R), and catechol diacetate (Ac-C). Bars = mean ±SE.
Compounds 05 00045 g004
Table 1. Acetylation of phenols: optimization of reaction conditions (temperature, time, catalyst mass, reactant ratio) and yields.
Table 1. Acetylation of phenols: optimization of reaction conditions (temperature, time, catalyst mass, reactant ratio) and yields.
EntrySubstrateTemp
(°C)		Time
(h)		Catalysts Mass
(mmol %)		Ratio Substrate/Ac2OYield
(%)
1Hydroquinone5010.52.490
2 201.50.52.498
3 2020.52.497
4 2010.52.488
5 201.50.252.472
6 201.50.752.496
7 201.50.5398
8 201.50.5279
9 201.50.5 a2.497
10 201.50.5 a2.496
11 201.50.5 a2.496
12Resorcinol 201.50.52.492
13 501.50.52.489
14 2020.52.492
15 201.50.5391
16Catechol201.50.52.475
17 2020.52.479
18 2030.52.486
19 2030.5385
a Catalyst reuse (first, second, and third reuse).
Table 2. EC50 values of phenols and acetylated derivatives for mussels.
Table 2. EC50 values of phenols and acetylated derivatives for mussels.
EC50 (μM)
CompoundLimnoperna fortuneiBrachidontes rodriguezii
Hydroquinone2263
Resorcinol514320
Catechol110145
Acetylated hydroquinone3625
Acetylated resorcinol26891
Acetylated catechol121120
Table 3. Ecotoxicity test using A. salina expressed as mortality (average).
Table 3. Ecotoxicity test using A. salina expressed as mortality (average).
CompoundMortality (%)
Negative control (artificial seawater)2.2
Hydroquinone6.0
Resorcinol29.4
Catechol4.9
Acetylated hydroquinone5.9
Acetylated resorcinol39.6
Acetylated catechol5.7
Positive control (K2Cr2O7 13.6 μM)92.5
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Pérez, M.C.; García, M.; Pasquale, G.; Laitano, M.V.; Romanelli, G.; Blustein, G. Synthesis of Acetylated Phenolic Compounds with Promising Antifouling Applications: An Approach to Marine and Freshwater Mussel Settlement Control. Compounds 2025, 5, 45. https://doi.org/10.3390/compounds5040045

AMA Style

Pérez MC, García M, Pasquale G, Laitano MV, Romanelli G, Blustein G. Synthesis of Acetylated Phenolic Compounds with Promising Antifouling Applications: An Approach to Marine and Freshwater Mussel Settlement Control. Compounds. 2025; 5(4):45. https://doi.org/10.3390/compounds5040045

Chicago/Turabian Style

Pérez, Míriam C., Mónica García, Gustavo Pasquale, María V. Laitano, Gustavo Romanelli, and Guillermo Blustein. 2025. "Synthesis of Acetylated Phenolic Compounds with Promising Antifouling Applications: An Approach to Marine and Freshwater Mussel Settlement Control" Compounds 5, no. 4: 45. https://doi.org/10.3390/compounds5040045

APA Style

Pérez, M. C., García, M., Pasquale, G., Laitano, M. V., Romanelli, G., & Blustein, G. (2025). Synthesis of Acetylated Phenolic Compounds with Promising Antifouling Applications: An Approach to Marine and Freshwater Mussel Settlement Control. Compounds, 5(4), 45. https://doi.org/10.3390/compounds5040045

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