Transformation of Organic Compounds during Water Chlorination/Bromination: Formation Pathways for Disinfection By-Products (A Review)

Abstract

The purity of drinking water is an important issue of the human life quality. Water disinfection has saved millions people from the diseases spread with water. However, that procedure has a certain drawback due to formation of toxic organic disinfection products. Establishing the structures of these products and the mechanisms of their formation and diminishing their levels in drinking water represent an important task for chemistry and medicine, while mass spectrometry is the most efficient tool for the corresponding studies. The current review throws light upon natural and anthropogenic sources of the formation of disinfection by-products (DBPs) and the mechanisms of their formation related to the structural peculiarities and the presence of functional groups. In addition to chlorination, bromination is discussed since it is used quite often as an alternative method of disinfection, particularly, for the purification of swimming pool water. The benefits of the contemporary GC/MS and LC/MS methods for the elucidation of DBP structures and study of the mechanisms of their formation are discussed. The reactions characteristic for various functional groups and directions of transformation of certain classes of organic compounds in conditions of aqueous chlorination/bromination are also covered in the review.

INTRODUCTION

More than 71% of the Earth’s surface is covered with water, but only 1% of all its reserves are available for direct human consumption for food and household purposes. However, even this water often cannot be used directly for its intended purpose due to the presence of pathogenic bacteria and viruses in it. Approximately half of the population in developing countries suffers from one or more of the six major water and sanitation diseases (diarrhea, ascariasis, dracunculiasis, hookworms, schistosomiasis, and trachoma). About 400 children under the age of 5 in the world die every hour from an acute intestinal infection transmitted through water [1]. In this regard, one of the most important stages of water treatment is disinfection, which is the most effective way to prevent these diseases [2]. Disinfection is an effective barrier to many pathogens (especially bacteria) in the treatment of drinking water, and it should be used for surface water and groundwater. The destruction of pathogens and parasites through disinfection has greatly contributed to the reduction of the incidence of diseases transmitted through water and food [3]. The destruction of microbial pathogens very often involves the use of chemically active substances. To date, a number of options for water disinfection are used. Chlorination remains the most common method worldwide. It has been used for over 100 years and has saved the lives of hundreds of millions of people. For a long time, only positive aspects of water chlorination were considered. However, in the mid-1970s, chloroform was found in drinking water; then, a significant range of other halogen-containing organic substances [4, 5] that are toxic or genotoxic to both animals and humans [6] were detected. These compounds are disinfection by-products (DBPs). Their range and concentration determine the quality of drinking water. The best known (regulated) DBPs are small molecules: trihalomethanes, haloacetic acids, N-nitrosodimethylamine, bromates, etc. Their cytotoxicity, genotoxicity, and carcinogenicity for mammalian cells have been studied, and maximum permissible concentrations (MPCs) have been established [3, 6–12]. However, in addition to them, according to various estimates, the structures of more than 700 [13, 14] or even 800 [15] DBPs have been established to date and this list continues to expand [16–21].

Recently, approximately 266 new DBPs were identified in the study of aqueous chlorination of natural organic matter dissolved in river water using two-dimensional gas chromatography/mass spectrometry (GC × GC/MS) [22]. It is important to emphasize that more than half of the total organic chlorine, that is, chlorinated organic compounds in drinking water, remained unidentified [23]. It is likely that most brominated and iodinated DBPs also remain unknown or poorly understood. At the same time, the brominated and iodinated analogues of chlorinated compounds have a significantly higher toxicity, which varies in the order Cl-DBP $\ll$ Br-DBP < I-DBP [24, 25]. Note that, as a rule, the toxicity of nitrogen-containing DBPs is much higher than that of hydrocarbon derivatives, and haloaromatic DBPs are more dangerous than their haloaliphatic counterparts [26].

Epidemiological studies have found that the consumption of chlorinated drinking water leads to an increased risk of developing bladder cancer [27–29], reproductive pathologies, and growth retardation [30, 31]. However, it should be emphasized that the toxicity of the vast majority of even established disinfection products remains unexplored, and known DBPs cannot explain the increased risk of diseases associated with the consumption of poor-quality drinking water.

There are certain differences in the reactivity of chlorinating agents. In particular, the most popular sodium hypochlorite and molecular chlorine (chlorine water) exist in aqueous solution in the form of mixtures of molecules and ions due to equilibrium reactions with water. Gaseous chlorine in water is a mixture of molecular chlorine, hydrochloric and hypochlorous acids, and their anions:

$${\text{C}}{{{\text{l}}}_{2}} + {{{\text{H}}}_{{\text{2}}}}{\text{O}} \rightleftarrows {\text{HOCl}} + {{{\text{H}}}^{ + }} + {\text{C}}{{{\text{l}}}^{ - }};$$

$${\text{HOCl}} \rightleftarrows {{{\text{H}}}^{ + }} + {\text{Cl}}{{{\text{O}}}^{ - }}.$$

Sodium hypochlorite occurs in water mainly in the form of hypochlorous acid and the hypochlorite anion:

$$\begin{gathered} {\text{NaOCl}} \rightleftarrows {\text{N}}{{{\text{a}}}^{ + }} + {\text{OC}}{{{\text{l}}}^{ - }}; \\ {\text{Cl}}{{{\text{O}}}^{ - }} + {{{\text{H}}}_{{\text{2}}}}{\text{O}} \rightleftarrows {\text{HOCl}} + {\text{O}}{{{\text{H}}}^{ - }}. \\ \end{gathered} $$

These forms are characterized by addition, substitution, and oxidation reactions [32].

Molecular chlorine is a stronger oxidizing agent (E° = 1.59) than hypochlorous acid (E° = 1.50) and much stronger than hypochlorite anion (E° = 0.89). Therefore, the ranges of products and their yields can differ significantly upon aqueous chlorination of organic substrates. For example, sodium hypochlorite exhibits a higher chlorinating activity in electrophilic aromatic substitution reactions, especially, in the presence of activating substituents in the ring. On the contrary, molecular chlorine is more active in oxidation reactions, and it leads to the splitting of the initial substrate structure with the formation of low-molecular-weight chlorination products. In particular, when molecular chlorine is used as a chlorinating agent, the concentrations of controlled halomethanes can be tens and hundreds of times higher than those in reactions with sodium hypochlorite [33].

Both reagents are effective, stable, and cheap, but they have a fundamental disadvantage associated with the formation of organochlorine compounds, primarily, trihalomethanes (THMs) and haloacetic acids (HAAs). The presence of these compounds is monitored at water treatment plants. Because this monitoring requires adequate equipment, often the control of water quality and the amount of DBPs is carried out only for chloroform as the major component of this group. In Russia, the MPC of chloroform in drinking water was 0.2 mg/L for a long time; however, this value was reduced to 0.06 mg/L in March 2021. Compliance with the new standard for chloroform required a change in the technology of water disinfection at a number of regional water treatment plants. Drinking water supply stations around the world are gradually switching from chlorine gas to hypochlorite because sodium hypochlorite is less toxic and easier to transport, and it produces less chloroform.

The level of chloroform formed can also be reduced by using other agents with active chlorine: dichloroisocyanuric and trichloroisocyanuric acids, chlorine dioxide, and chloramine. Chloramine leads to a significant decrease in the THM and HAA levels; because of this, it is popular in many countries, such as the United States. However, chloramine also has its drawbacks. In particular, it increases the level of highly carcinogenic N-dimethylnitrosamine and results in the leaching of lead from metal water pipes. Chlorine dioxide, acting primarily as an oxidizing agent, significantly decreases the formation of organochlorine products. Its disadvantage is the formation of inorganic anions (bromites, bromates, chlorates, and chlorites), the levels of which are also regulated. Isocyanuric acids are significantly more expensive, and they are not used to treat large volumes of water.

There is an opinion that ozone is an ideal disinfectant. Indeed, ozone is a very powerful oxidizing agent and disinfectant, and no organochlorine compounds are formed with the use of it. The disadvantages of its use include low solubility in water, high cost, and instability. It is effective in the disinfection of small volumes of water, for example, in individual plots and in small settlements. However, in large cities with extensive water supply networks, ozone instability forces the use of additional chlorination at the outlet of the water treatment plant to prevent the formation of pathogens directly in the water distribution systems. This significantly reduces the attractiveness of ozonation as a method of disinfecting drinking water in large cities. A similar problem is typical for UV irradiation of water. Organic peracids (RCOOOH) are extremely promising for water disinfection. They are highly effective for the destruction of microorganisms, and organochlorine compounds are not formed as a result of their use. The main disadvantage of peracids is related to economic rather than chemical aspects because their cost is several orders of magnitude higher than that of other disinfectants.

Today, gas chromatography–mass spectrometry is the most informative and reliable method for solving the problems of detection, identification, and control of DBPs. Currently, all options for connecting gas and liquid chromatographs with mass spectrometers are widely used to study the processes that occur in the disinfection of drinking water and pool water. In particular, Wawryk et al. [34] considered the currently available mass-spectrometric approaches to the detection of new toxicologically significant DBPs.

This review is devoted to studying the processes of chlorination/bromination of various organic substrates and establishing the structures of DBPs using gas chromatography/mass spectrometry (GC/MS) and high performance liquid chromatography/mass spectrometry (HPLC/MS). In many works, the authors used high resolution mass spectrometry and tandem mass spectrometry methods.

TRANSFORMATION OF HUMIC SUBSTANCES AND THEIR FRAGMENTS

What is the source of carbon for the formation of disinfection by-products even in the purest natural water? Humic substances are the most common natural polymer on Earth. They are formed upon the decomposition of plant and animal residues as a result of metabolic processes and abiotic environmental factors [35]. As early as 1970, Kleinhempel [36] proposed the tentative formula of humic matter. It is a combination of lignin residues, sugars, peptides, fats, aliphatic fragments, and even metals. This is the most complex mixture of organic compounds in nature, surpassing even oil in complexity. Figure 1 shows a small common fragment of humic matter identified by NMR spectroscopy [35]. The presence of 13 optically active atoms in the structure of this compound suggests the presence of 2¹³ diastereomers even without rearrangement of substituents.

Fig. 1.

The most common fragment of humic substance according to NMR-spectroscopic data [35].

Humic substances are present in any of the purest natural water. If they are exposed to disinfecting agents, they transform into a huge number of products, the structures of which are very difficult, if not impossible, to predict. The interaction of a disinfectant with natural compounds dissolved in water results in the formation of DBPs [37]. Most of the currently known DBPs are formed as a result of numerous sequential reactions of the original natural substance; that is, they represent the final part of the transformation chain. Primary DBPs, which are formed at the first stages of the reaction, are almost not studied, and their composition varies greatly depending on the structure of the initial organic substrate.

In 2006, Bull et al. [38] simulated the reactions of disinfectants with structural fragments of natural organic matter in combination with a quantitative analysis of the structure–toxicity relationship in order to predict the relative toxicological significance of DBPs as probable carcinogens. This study identified several potential classes of DBPs to look for in chlorinated water: haloquinones, halocyclopentenoic acids, organic N-haloamines, nitrosamines, nitrosamides, halonitriles, and haloamides. Many representatives of these groups have previously been found in drinking water, and their belonging (with the exception of haloquinones) to DBPs has been proven. To confirm the hypothesis on the formation of haloquinones in the course of water chlorination, Zhao et al. [39] developed an HPLC–MS/MS method, where 2,6-dichloro-1,4-benzoquinone, 2,6-dichloro-3-methyl-1,4-benzoquinone, 2,3,6-trichloro-1,4-benzoquinone, and 2,6-dibromo-1,4-benzoquinone were chosen as target compounds. All four substances were identified in the water subjected to disinfection, thus confirming their belonging to the DBPs in some drinking water treatment systems. Further works showed their toxicity and carcinogenicity [40].

Because aqueous chlorination is primarily an oxidative process, organic acids are a significant fraction of DBPs. To date, numerous carboxylic acids with carbon skeleton lengths from three to nine atoms are classified as DBPs in addition to haloacetic acids, which are regulated in many countries of the world. Previously unknown products belonging to the group of carboxylic acids were found in a large-scale study [23] on the assessment of DBP levels at various water treatment and disinfection stations in the United States and the identification of new DBPs. For example, by repeated measurements of the concentration of 3,3-dichloropropanoic acid, it was proved that it belongs to the DBP group, regardless of the type of water and the method of water disinfection. The lengths of the carbon skeletons of other acids found ranged from three to nine atoms, and the most common were acids containing three and four carbon atoms, which also contained C=C double bonds or an additional carboxyl group. A lot of brominated acids were found in chlorinated water when water with a high concentration of bromide ions was used as a source. Some of these acids are characteristic of Israeli drinking waters with a high bromide content, treated with chlorine or chlorine dioxide and chloramines [41]. Among acids, the most unusual bromo derivatives of DBPs were halogenated oxo acids, 3,3-dibromo-4-oxopentanoic and 3-bromo-3-chloro-4-oxopentanoic acids, which were detected only at two water disinfection stations, although 3,3-dibromo- and 3,3-dichoro-4oxopentanoic acids were found earlier in the drinking water of Israel [41]. The only earlier mention of halooxo acids refers to the identification of 2,3-dichloro-4-oxopentanoic and trichloro-4-oxopentanoic acids in a laboratory study of the chlorination of humic acids [42]. In the cited work, the following iodo derivatives of acids were also detected for the first time: iodoacetic, bromoiodoacetic, (E)- and (Z)-3-bromo-3-iodopropenoic, and (E)-2-iodo-3-methylbutenedioic acids.

Krasner et al. [23] determined haloketones (tri- and tetrahalopropanones), haloaldehydes (dichloroacetaldehyde, iodobutanal, and 4-chlorobut-2-enal), halonitromethanes (chloropicrin and bromopicrin), halogenated furanones, haloacetamides, and haloacetonitrile among other DBPs representing the end products of transformation.

A significant amount of brominated and iodinated compounds found among the primary products of aqueous chlorination is the most important fact established in recent years. What is the source of bromine and iodine if disinfection is carried out using active chlorine? Bromide anions are always present in natural water. Their concentration in fresh water is usually in a range of 0.1–1.0 mg/L; sometimes, it reached 2 mg/L in Israel and even 4.13 mg/L in Australia [16]. Particular care should be taken when disinfecting desalinated sea waters, in which the concentration of bromides can be very high [43]. The ingress of wastewater from oil and gas production into surface waters also leads to elevated levels of halides from geogenic bromides and iodides [44].

Depending on pH, bromides reacting with active chlorine form hypobromous acid (HOBr) or hypobromite anion (OBr^–) [45–47], which are nothing more than active bromine. They react with organic compounds to form the corresponding organobromine products. Moreover, HBrO/BrO^– is much more active than HClO/ClO^– in reactions with dissolved natural matter [47–49]. The rates of reactions under conditions of aqueous bromination of natural organic matter (k_app = 1.6 × 10⁶ M^–1 s^–1) significantly exceed the rates of similar aqueous chlorination reactions with HClO/ClO^– (k_app = 41 M^–1 s^–1) [49]. This means that chlorination at water treatment plants begins with the reaction of all available active bromine with activated aromatic groups of humus to form a large mass of brominated natural substance; then, the reaction with chlorine comes into play. Because the amount of chlorine in the reaction mixture is greater and its oxidizing ability is much higher, chlorine not only enters into the composition of the molecules of natural matter but decreases the size of the molecules by breaking C–C bonds. The greater the number of stages of aqueous chlorination, the smaller the size of the resulting molecules and the higher chlorine content of them. Long-term observations of the Ufa water treatment station clearly demonstrated that the fraction of bromine in semivolatile DBPs (four to six carbon atoms) is greater than that of chlorine, whereas the fraction of chlorine in volatile DBPs is much higher [50]. In addition, bromine is easily eliminated from aromatic substrates under conditions of aqueous chlorination or chloramination, being replaced by chlorine as a result of electrophilic aromatic substitution according to the ipso mechanism [51–53].

Iodides are also always present in natural water, and they are even more easily oxidized by active chlorine. However, the main oxidation product is the nonreactive iodate anion ${\text{IO}}_{3}^{ - }$ [54]. Nevertheless, hypoiodide can still form and instantly react with organic substrates. In addition, it promotes the chlorination of aromatic substrates [55]. It has recently been shown that iron trichloride, which is often used for coagulation in water treatment, can lead to the formation of organoiodine compounds if the treated water contains reactive substrates (such as resorcinol) and inorganic iodides [56]. Dong et al. [57] studied the processes and factors that determine the formation of known and unknown iodinated DBPs. They analyzed the mechanisms of formation of iodinated DBPs upon oxidation, disinfection, and distribution of drinking water. Particular attention was paid to the inorganic and organic sources of iodine, the kinetics of iodide oxidation, and the pathways for the formation of these products.

Bromides can also be oxidized to nonreactive ${\text{BrO}}_{3}^{ - }$ ions; however, it should be remembered that both iodates and bromates are very toxic, and their presence is controlled throughout the world [58]. Sufficiently high levels of bromine may be present in a chlorinating agent itself because these agents are technical products. For example, the amount of bromine in sodium hypochlorite used by the Ufa water utility was three times higher than the amount of bromides in the water intake [50].

With the development of civilization, another group of compounds, which are subjected to aqueous chlorination one way or another, becomes more and more important. These are anthropogenic compounds, the range of which increases from year to year. More than 160 million substances have been registered in the CAS system by 2020 [59]. They enter into a variety of reactions in the environment under the influence of physicochemical and biological factors (sunlight and contacts with oxidizing agents and microorganisms), and the products can be more toxic than the starting compounds [60, 61]. Even if we do not take into account the obvious pollution of natural water by discharges from industrial enterprises, many thousands of organic compounds enter water bodies with precipitations [62–68]. These are particular compounds that occur in the intakes of drinking water supply stations and react with disinfectants. Knowing the exact structure of a precursor, one can more efficiently determine the structures of its transformation products; that is, the situation is much simpler than in the case of aqueous chlorination reactions of humic substances of unknown composition.

In this regard, several main areas of study of the processes of aqueous chlorination and the formation of DBPs can be distinguished:

(1) Identification of new DBPs and study of kinetics, additives, and reaction conditions in the process of aqueous chlorination/bromination of humic substances.

(2) Identification of new DBPs and study of kinetics, additives, and reaction conditions in the simulation of the process of aqueous chlorination/bromination of known structural fragments of humic substances.

(3) Study of the transformation and identification of new DBPs and study of kinetics, additives, and reaction conditions in the process of aqueous chlorination/bromination of particular organic compounds that often occur in water intakes.

(4) Study of the reaction mechanisms of aqueous chlorination/bromination of organic compounds depending on their structure and the presence of certain functional groups.

(5) Study of the possibility of decreasing the range and levels of (primarily regulated) DBPs with changes in the process conditions of chlorination/bromination.

TRANSFORMATION OF HYDROCARBONS

Petroleum hydrocarbons are the most common pollutants entering water treatment plants with water intake. They enter natural water as a result of fuel spills, discharges and emissions from enterprises, and with precipitation. The main components of petroleum hydrocarbons are alkanes, naphthenes, aromatic hydrocarbons of the benzene series, and polycyclic aromatic hydrocarbons, including alkylated ones. In 2004, Shaidulina and Lebedev [69] carried out a laboratory experiment with light diesel fuel. Water chlorination was carried out under laboratory conditions similarly to a procedure used at the Rublevskaya water treatment plant in Moscow. GC × GC/MS was used as an analysis method, which makes it possible to separate the most complex mixtures of organic compounds and eliminate the overlapping of the mass spectra of components [70]. Figure 2 shows three-dimensional total ion current chromatograms of the samples before and after chlorination. The peaks of saturated alkanes and naphthenes remained unchanged; that is, these compounds did not react under the experimental conditions. The peak intensity of alkylbenzenes decreased by about 50%, and a large group of chlorinated alkylbenzenes was formed. The initial alkylnaphthalenes reacted completely to form a set of low-intensity peaks of mono- to tetrachlorinated products.

Fig. 2.

Three-dimensional total ion current chromatograms of light diesel fuel samples (left) before and (right) after aqueous chlorination.

It would seem that this experiment revealed the whole picture of aqueous chlorination of hydrocarbons. However, the subsequent studies have shown that the situation is much more complicated. Theoretically, radical reactions with saturated compounds are really unlikely under conditions of aqueous chlorination, which occurs in the dark and for a limited time. Nevertheless, Hao et al. [71] established the radical mechanism of pyridine chlorination. We made an attempt to check the possibility of aqueous chlorination and bromination of benzalkonium chloride. Alkyldimethylbenzylammonium (BA) cations are a set of quaternary ammonium compounds differing in the lengths of saturated alkyl chains (8–18 carbon atoms). They have antibacterial, antiviral, and antifungal activity; in the form of chlorides, they are widely used in personal hygiene products, cosmetics, and pharmaceuticals [72]. BA is also considered as a promising disinfectant for the destruction of SARS-CoV-2 in wastewater [73, 74]. Benzalkonium salts are very actively used as an algicide preventing the development of microalgae in pool water [75]. They are frequently detected in the samples of natural water. Despite the saturated structure, BA undergoes a number of transformations in the course of the disinfection of tap water and wastewater [76, 77].

The target-oriented analysis of pool water in Arkhangelsk to search for potential products of BA chlorination based on the ions [C₂₁H₃₇ClN]⁺ and [C₂₃H₄₁ClN]⁺ (Fig. 3) revealed their presence in an amount of about 1% on the initial BA basis [20].

Fig. 3.

High-resolution HPLC-ESI(+) mass chromatograms of pool water for (a) characteristic ions BA-12 and BA-14 and (b) their monochlorinated derivatives.

Laboratory experiments on the aqueous chlorination and bromination of BA demonstrated the formation of mono- and polyhalogenated and oxygen-containing products [20, 21]. The collisionally activated dissociation (CAD) spectra of the protonated molecules of halogenated products (Fig. 4) showed that neither the aromatic ring nor the benzyl and methyl groups at the nitrogen atom contained halogen atoms. One or more halogen atoms were introduced only into the alkyl chain by the mechanism of radical substitution. Because most of the positions of the long aliphatic chain are almost equivalent, halogenation leads to a wide range of isomeric products with close retention times.

Fig. 4.

CAD mass spectrum of monobromo derivative BA-15 (m/z 382.2093) and assignment of product ions.

The reaction proceeds slowly in the absence of light, but the reaction rate increases significantly in the presence of light, especially, in the case of bromination. Then, the resulting halogen derivatives react with water and oxidizing agents to form hydroxyl and keto derivatives due to nucleophilic substitution and oxidation reactions. The process ends with the formation of a wide range of semivolatile polyhalogenated compounds, which can be easily detected in the GC/MS mode [20, 21].

TRANSFORMATION OF OLEFINS AND COMPOUNDS WITH C=C BONDS

Compounds with multiple C=C bonds are often present in environmental materials as natural and anthropogenic pollutants, for example, ionones, β-cyclocitral, microcystins, etc. [78–81]. Cyclohexene was one of the simplest alkenes studied in the reaction of aqueous chlorination with gaseous chlorine and sodium hypochlorite [33]. Figure 5 shows a reaction scheme of the transformation of this compound. Over 20 products, including polyhalogenated compounds, were identified by GC/MS.

Fig. 5.

Reaction products of the aqueous chlorination of cyclohexene.

Although 1,2-dichlorocyclohexane is a major product of the reaction, its concentration at all substrate/active chlorine ratios was lower by one or two orders of magnitude than that of dominant 2-chlorocyclohexanol (Table 1). This result indicates that the conjugated addition reaction proceeds predominantly, when the chloronium cation is opened by a water molecule rather than by the chloride anion at the second stage of the process (Fig. 6). This is absolutely reasonable because the amount of water in the reaction mixture is immeasurably greater than that of chloride anions.

Table 1.   Levels of some products in the aqueous chlorination of cyclohexene with gaseous chlorine and sodium hypochlorite at different substrate/active chlorine ratios

Fig. 6.

Reaction scheme of the opening of the chloronium ion at the second stage of an electrophilic addition reaction.

Chlorine derivatives of cyclohexanone, hydroxycyclohexanone, and cyclohexanedione were identified among the products. The formation of chlorocyclohexene as a result of the reactions of allyl chlorination or elimination (of HCl or H₂O) from primary addition products is a key step, which explains the appearance of the subsequent generations of transformation products, primarily, polychlorinated compounds. Attention should also be paid to significant differences in the amounts of chloroform depending on the chlorinating agent used (Cl₂ or NaClO). The results clearly confirm the advantage of sodium hypochlorite for decreasing the formation of this ecotoxicant (Table 1).

D-Limonene, which is both a naturally occurring and industrial compound included in many commercial products, is widespread in the environment [64, 65, 68]. It has two double bonds in its structure; therefore, the formation of four primary and four secondary products of chlorination is possible (Fig. 7). Note that the substrate/active chlorine ratio was small because the task of the experiment was to study the initial stages of chlorination. Under these conditions, only conjugated addition products were detected [82].

Fig. 7.

Reaction scheme of the transformation of limonene under conditions of aqueous chlorination.

The identification of products was complicated by the lack of library spectra and reference standards. Nevertheless, Lebedev et al. [82] managed to correlate specific structures to all of the four primary isomeric products using the Markovnikov rule and laws of the fragmentation of organic compounds under electron ionization (EI) conditions. As in the case of cyclohexene, the processes of water elimination from the addition products play a significant role in the transformation. As a result, the double bond is regenerated and the reaction continues with the formation of numerous isomeric polychlorinated compounds, the exact structures of which cannot be established, especially, with consideration for the absence of peaks due to molecular ions from the spectra. With an increase in the dose of hypochlorite, the levels of the end products of chlorination, primarily, haloforms, sharply increased.

A study of organic substances in the drinking water of Arkhangelsk by high-performance liquid chromatography/high-resolution mass spectrometry (HPLC/HRMS) revealed a group of halogenated nitrogen-containing compounds, which could not be attributed to any of the disinfection by-products known at that time. Measurements of exact masses showed that these were the compounds C_nH_2nNO₂X, C_nH_{2n – 2}NO₂X, and C_nH_{2n – 1}NOX₂ (X = Cl or Br; n = 16, 18, or 22); in all cases, they were represented by two (sometimes four) isomers with close retention times and similar intensities. The use of tandem mass spectrometry made it possible to hypothesize that these compounds were the halogen derivatives of fatty acid amides of natural or anthropogenic origin [18].

The aqueous chlorination of model oleamide with Cl₂ or NaClO under laboratory conditions led to the formation of two isomeric chlorohydrins formed in accordance with the Markovnikov rule. Both variants of addition were almost equally probable because substituents at the double bond differed only in the presence of a carboxamide group at the end of the alkyl chain, and this led to peaks of equal intensity in the chromatograms. In addition to these major products, the bromo derivatives of a corresponding amide were also identified in the reaction mixture due to bromine impurities in the reagents mentioned above [18].

Li et al. [83] selected 12 model compounds with C=C bonds to study the kinetics and mechanisms of their aqueous chlorination and bromination. Among them were sorbic acid, (E,E)-hexadien-2,4-ol-1, (E,E)-hexadien-2,4-al, and various derivatives of cinnamic acid. Identified products were presented only for cinnamic acid: these were the expected two isomeric products of the addition of HClO at the double bond (2-chloro-3-hydroxy3-phenyl- and 2-hydroxy-3-chloro-3-phenylpropionic acids) and also a compound with the formula C₈H₇Cl—chlorostyrene, a product of the chlorodecarboxylation of cinnamic acid. Comparison of the reactivity of a number of disinfectants with respect to selected olefins made it possible to propose the following order: HOCl < HOBr < Br₂O < Cl₂O ≈ Cl₂. The introduction of various substituents in cinnamic acid derivatives led to a 3–100-fold acceleration of the reaction for electron-donating substituents and a 3–10 000-fold slowdown for electron-withdrawing substituents.

The study of aqueous chlorination in the case of more complex substrates with a double bond showed its high reactivity, and the reaction of electrophilic addition to the double bond successfully competes even with electrophilic substitution reactions in the activated aromatic ring.

Lebedev and coauthors [84, 85] studied the deep stages of aqueous chlorination of cinnamic acid with chlorine water and sodium hypochlorite. They found the high reactivity of the double bond, when less than 1% of the starting substance remained in the reaction mixture at a substrate/active chlorine ratio of 1/5 or higher. Initial products were also actively transformed further. Therefore, only 2,2-dichloro-3-hydroxy-3-phenylpropionic acid was detected among them. At low substrate/active chlorine ratios, the main product was chlorostyrene, which was formed as a result of chlorodecarboxylation. Sykes [86] described the mechanism of this reaction for the case of α,β-dibromo-substituted carboxylic acids. The presence of a double bond in this compound leads to the addition of HOCl, and 1-hydroxy-2,2-dichloroethylbenzene becomes the dominant product (~50% of the total organic chlorine) at high substrate/active chlorine ratios. Benzoic acid is formed at the next step. The benzene ring is much more stable, and the corresponding products of aromatic electrophilic substitution were not found. Chlorine water results in a greater number products and higher degree of conversion, including the formation of chloroform. A conclusion on the possible contribution of radical processes leading to the formation of benzaldehyde, chlorobenzene, and 2-phenylacetic acid was also made [85].

UV filters are most common substances in swimming pool water. They are widely used in everyday life as components of commercial skin care products. As a rule, UV protectors are not very toxic, but they react with active chlorine in water to form a wide variety of products many of which can potentially be significantly more toxic. Avobenzone, 4-tert-butyl-4'-methoxy-dibenzoylmethane, is the most common UV-A filter (400–320 nm) used in sunscreen products [87]. It is characterized by keto–enol tautomerism, and avobenzone in sunscreens mainly exists in the enol form (Fig. 8), which has an absorption maximum at wavelengths in a range from 350 to 365 nm depending on the solvent used [88, 89].

Fig. 8.

Keto–enol tautomerism of 4-tert-butyl-4'-methoxy-dibenzoylmethane.

In the first work devoted to the aqueous chlorination of avobenzone, Santos et al. [90] used LC/MS and found the formation of mono- and dichloro derivatives of this compound as primary products. Because the methoxy group is one of the most powerful orientants of the first kind, Crista et al. [91] made a logical conclusion on the incorporation of chlorine into the ring activated by the methoxy group in the ortho position to it without data of tandem mass spectrometry. For example, ortho-methoxybenzoic acid is easily chlorinated at the ring with the formation of ortho- and para-chloro derivatives as the main products [92]. Moreover, a 3-chlorophenyl derivative was the dominant reaction product upon the aqueous chlorination of dibenzoylmethane [85]; therefore, even the passivated ring entered into the electrophilic substitution reaction, especially, at a high dose of chlorinating agents (both chlorine water and sodium hypochlorite). Indeed, the reaction also actively proceeded at the methylene group of dibenzoylmethane; that is, active chlorine attacked the double bond of the enol form of the diketone [85].

However, the subsequent detailed studies on the aqueous chlorination of avobenzone by GC/HRMS showed that both of the aromatic rings do not contain chlorine atoms because the main peaks in the spectrum upon the fragmentation of the molecular ions of mono- and dichlorinated products under electron ionization conditions were due to methoxy- and tert-butyl-benzoyl cations with m/z 135 and 161 (Fig. 9), respectively; that is, they remained the same as in the spectrum of avobenzone itself [93–95]. Consequently, the aqueous chlorination reaction proceeded at the double bond of the enol form of avobenzone rather than at the activated benzene ring. The primary products 1-(tert-butyl)-2-chloro-3-(4-methoxyphenyl) -1,3-dione and 1-(tert-butyl)-2,2-dichloro-3-(4-methoxyphenyl)propan-1,3-dione were synthesized, and their spectra and retention times coincided with those observed upon the aqueous chlorination of avobenzone [96].

Fig. 9.

EI mass spectrum of 1-(tert-butyl)-2-chloro-3-(4-methoxyphenyl)propan-1,3-dione.

The reactivity of the double bond becomes comparable to the reactivity of aromatic rings only in the presence of the most active substituents, which activate electrophilic aromatic substitution. In particular, the aqueous chlorination of resveratrol proceeds simultaneously at the double bond and at the rings with hydroxyl groups [97]. More than 80 DBPs, including polychlorinated biphenyls and monoaromatic compounds, were identified by GC/HRMS analysis; addition, substitution, ring-opening, and cyclization reactions took place (Fig. 10).

Fig. 10.

Transformations of resveratrol under conditions of aqueous chlorination.

AROMATIC COMPOUNDS

According to Liu et al. [98], unsubstituted aromatic hydrocarbons behave inertly under the conditions of aqueous chlorination and bromination. They studied in detail the kinetics of processes and determined a significant number of the products of oxidation and aromatic substitution reactions; the identification was confirmed by the synthesis and the subsequent analysis of more than 40 chlorine-, bromine-, and oxygen-containing products. Liu et al. [98] found that HOBr reacts faster than HOCl with polyaromatic hydrocarbons (PAH) both by the electrophilic substitution mechanism and by the oxidation mechanism of one-electron transfer with second-order constants higher by factors of 10²–10³. In this case, HOBr enters into substitution reactions better than HOCl. Unfortunately, Liu et al. [98] failed to reliably establish the reasons for the significant difference in the rates of aqueous chlorination/bromination of PAHs and the tendency to substitution or oxidation depending on the structure despite the use of a wide range of physicochemical parameters to characterize various properties of the used hydrocarbons. For example, anthracene is easily oxidized to form anthraquinone, while pyrene is active in substitution reactions; the rate of aqueous bromination of benzopyrene is significantly higher than the rate of bromination of naphthalene or phenanthrene. Of course, additional studies are required to understand the processes.

The situation changes dramatically in the presence of a substituent with at least minimal activating properties at the aromatic nucleus. The aqueous chlorination of ethylbenzene affected both the aromatic ring and the ethyl group [69]. The degree of conversion of ethylbenzene was 10% under the experimental conditions. Although the sets of transformation products were identical with the use of gaseous chlorine and sodium hypochlorite, their levels were different. The use of chlorine water facilitated a more active oxidation of the substrate with the formation of 1-phenylethanol and acetophenone, whereas sodium hypochlorite increased the yield of the products of electrophilic substitution in the aromatic nucleus: ortho- and para-chloroethylbenzenes. Indane behaved similarly under these conditions. Sodium hypochlorite accelerated the processes of electrophilic substitution into the aromatic ring, while chlorine water led to the oxidation of a saturated ring with the formation of a corresponding alcohol and ketone [69].

2-Methylnaphthalene behaved much more actively under the experimental conditions. The degrees of its conversion at an equimolecular substrate/active chlorine ratio were 50% in the reaction with chlorine water and 65% in the reaction with sodium hypochlorite. The main processes with both agents were explained by ortho substitution in the aromatic ring; however, in addition to these processes, many detected products were related to the initial 1,2- or 1,4-addition characteristic of dienes. As a result, a large number of quinoid structures were formed [69]. Moreover, both substitution and addition can affect both rings to form polychlorinated products containing to six chlorine atoms per molecule. The destruction of one of the rings leads to phthalic anhydride or its substituted analogues. More than 60 products of 2-methylnaphthalene chlorination were detected in the reactions with different doses of chlorine water [99].

In the case of diphenylmethane [100], both the benzene rings activated by the alkyl substituent and the methylene group are sufficiently reactive. The reaction takes place at these reaction centers. In addition to polychlorophenyl derivatives of diphenylmethane, 1‑chloro- and 1,1-dichlorodiphenylmethanes and their hydrolysis products, diphenylmethanol and benzophenone, were identified in the reaction mixture. Moreover, for all of the four derivatives of the methylene group, chlorinated products with chlorine atoms in the rings were also found. Next, the molecules were degraded with the formation of monoaromatic compounds, for example, benzaldehyde or chlorobenzene. With the use of a large dose of chlorine, polychlorinated products with open benzene rings were also detected with chloroform as the final product [100]. As in many other studies, bromine-containing reaction products were also found; it is likely that they were formed due to the presence of bromine impurities in sodium hypochlorite.

The presence of stronger activating substituents, for example, the methoxy groups, leads to an increase in the degree of conversion. In the case of anisole, even a small dose of chlorine leads to a high conversion, and the main reaction products are ortho- and para-substituted chloroanisols. The reaction goes further with the formation of corresponding dichloro and trichloro derivatives. A study of the effect of pH on the aqueous chlorination of anisole showed that the rate of reaction and the degree of conversion reached maximum values in an acidic medium [101]. An increase in the rate of chlorination in acidic solutions suggests that this reaction is catalyzed by an acid [102]. However, the trimolecular reaction of any substrate with HOCl and H₃O⁺ requires a significant change in entropy; that is, it is unlikely. It could be assumed that protonated hypochlorous acid is the main chlorinating agent at acidic values of pH [102]. To test this hypothesis, Lebedev et al. [101] carried out quantum chemical calculations and computed the thermal effect of the reaction of HOCl with the hydroxonium ion H₃O⁺ using the DFT method at the B3LYP/6-31(d)+G level and the semiempirical AM1 and PM3 methods. They found that the reaction HOCl + H₃O⁺ → H₂OCl⁺ + H₂O is endothermic (11.4 kcal/mol). Consequently, the protonation of hypochlorous acid is energetically unfavorable. On the other hand, calculations at the B3LYP/6-31(d)+G and MP2/6-31(d)+G levels showed that the reaction of HOCl with H₃O⁺ gives a stable hydrogen-bonded complex. The influence of other hydration spheres on the structure of this complex was estimated using the Onsager continuum model. Figure 11 shows the optimized structure. The influence of an aqueous medium on the structure of this complex was modeled taking into account the participation of one water molecule in the structure of the reaction particle [101].

Fig. 11.

Structures of the complexes HOCl–H₃O⁺ and HOCl–H₃O⁺–H₂O.

Unfortunately, the authors [101] failed to develop an appropriate model for the aromatic substitution reaction with molecular chlorine.

ortho-Methoxybenzoic acid is readily chlorinated to form 3-chloro-2-methoxybenzoic acid and 5-chloro-2-methoxybenzoic acid (the main reaction product with sodium hypochlorite). The corresponding disubstituted product, 3,5-dichloro-2-methoxybenzoic acid, is also formed (the main product of the reaction with chlorine water) [92]. Interestingly, an ipso substitution, more precisely, chlorodecarboxylation reaction with the formation of 2-chloroanisole occurs along with these classical electrophilic substitution reactions [92]. This process is especially active with the use of chlorine water. The subsequent chlorination products are also formed: two isomeric dichloroanisoles and one of the isomeric trichloroanisoles. The ring opening and formation of trihalomethanes is detected only at a high dose of active chlorine.

Lebedev et al. [103] studied the aqueous chlorination of aromatic compounds with nitrogen atoms in the ring or as substituents (aniline, benzidine, azobenzene, 2-methylindole, 8-hydroxyquinoline, and 2,2'-dipyridyl). Aniline, as one of the most active substrates in electrophilic substitution reactions, almost completely reacts with active chlorine even at the lowest concentrations of the latter. 2-Chloroaniline, 4-chloroaniline, 2,4-dichloroaniline, 2,6-dichloroaniline, 2,4,6-trichloroaniline, aminodichlorophenol, azobenzene, and monochloroazobenzene were identified among the products of aniline chlorination; that is, oxidation and dimerization reactions take place in addition to the electrophilic substitution reaction in the aromatic nucleus. Despite the structural similarity between benzidine and aniline, only 3-chloro-substituted and 3,3'-dichloro-substituted products were found in the former. 2-Methylindole gave only one transformation product, 3-chloro-2-methylindole. The presence of a phenolic fragment in the structure of 8-hydroxyquinoline significantly increased its reactivity. Already at the ratio Cl : substrate = 2 : 1, more than half of 8-hydroxyquinoline is converted into 7-chloro- and 5-chloro-8-hydroxyquinolines as major products of the classical electrophilic substitution reaction in the aromatic nucleus (ortho- and para-positions to the activating hydroxyl group). With an increase in the amount of chlorinating agent, these primary products undergo a profound transformation, including ring cleavage and the formation of pyridine derivatives. Similar results were also found in the chlorination of 2,2'-dipyridyl.

The most active group promoting electrophilic aromatic substitution reactions is hydroxyl. Phenols were the first organic compounds used as examples for studying aqueous chlorination reactions. Phenols (especially, 1,3-dihydroxyaromatic compounds) were identified as the main precursors for the formation of trihalomethanes in the first studies of DBPs [4, 5, 32, 104, 105]. The reaction begins with the rapid chlorination of activated aromatic ring to form a polychlorinated derivative in the keto form. The ring opening is followed by the loss of a CO₂ molecule by the resulting keto acid and the closing of a pentachloropentanone ring, which undergoes a haloform reaction with the formation of chloroform and trichlorobutenoic acid (Fig. 12).

Fig. 12.

Reaction scheme of the transformation of resorcinol under conditions of aqueous chlorination.

Tretyakova et al. [106] demonstrated the wide variety of reactions accompanying the aqueous chlorination of 1,3-dihydroxyaromatic compounds using orcinol (3,5-dihydroxytoluene) as an example. More than 80 products of aqueous chlorination are formed by the mechanisms of electrophilic substitution and electrophilic addition at a double bond, as a result of cyclization, in reactions with ring opening and a decrease in ring size according to Favorsky, etc.

The aqueous chlorination reaction of α-naphthol is very fast, but it mainly affects only the activated phenol nucleus [99]. The corresponding chain of transformations based on substitution, addition, and hydrolysis reactions leads to its complete destruction with the formation of phthalic anhydride, benzoic acid, and ortho-chlorobenzoic acid. A chlorine atom in the second ring appeared only in 2 of 50 identified products at a substrate/active chlorine ratio of no smaller than 1/5.

An interesting variant of aromatic electrophilic substitution reactions under conditions of aqueous chlorination is the replacement of one halogen by another. In particular, bromine and iodine are easily eliminated from aromatic substrates under conditions of aqueous chlorination or chloroamination, being replaced by chlorine in activated substrates as a result of electrophilic aromatic substitution according to the ipso mechanism [51, 52, 107].

In our laboratory, a model study of the substitution of iodine and bromine for chlorine in the simplest aromatic substrates with activating substituents (OH, OCH₃, and NH₂) was carried out under conditions of aqueous chlorination with sodium hypochlorite. Detenchuk et al. [53] found that, in the case of organoiodine compounds, ipso substitution is the dominant process if the halogen is in the ortho- or para-position to the activating substituent. For example, in the case of 4-iodoanisole, the fraction of the corresponding 4‑chloroanisole is higher than 75% of all reaction products. This is due to the easy oxidation of the eliminated ion I⁺ to nonreactive ${\text{IO}}_{3}^{ - }$. The replacement of bromine with chlorine is not so active, but such products are present in the reaction mixture. Moreover, due to its high activity [49] and slower oxidation to the bromate anion, the eliminated Br⁺ cation can attack aromatic substrates in the reaction mixture to form, for example, polybrominated products [53]. Due to the activity of Br⁺, bromine can also displace chlorine from activated aromatic substrates under aqueous bromination conditions, although the yields of such reactions are very low.

TRANSFORMATION OF AMINO ACIDS AND PEPTIDES

Amino acids are widespread natural compounds; they occur in a wide range of concentrations (from 20 to 10 000 μg/L) in natural waters and cover from 2 to 13% of dissolved organic carbon and to 75% of dissolved organic nitrogen [108, 109]. The concentration of amino acids bound in the forms of peptides and proteins, in general, is higher by a factor of 4–5 than the concentration of free amino acids [108, 110]. Despite this fact, free amino acids are poorly removed in the course of biological filtration [111], and their concentrations may even increase after filtration through sand [112]. In this regard, free amino acids are usually present in natural water in the course of its disinfection. Organic chloramines are the main subclass of nitrogen-containing chlorination products formed as a result of the reactions of nitrogen-containing organic substances with free chlorine [113] or inorganic chloramines [114, 115], including reactions of amino acids and dipeptides [116–119]. However, the resulting N-chloroamino acids are very unstable [120, 121]. During the full cycle of disinfection and water delivery, it is very likely that only their degradation products will reach the end user. To assess possible risks, these products have been studied. It was found that chloramines formed from leucine, phenylalanine, and valine lead to numerous compounds both containing structural fragments of the initial amino acids [122–124] and products of deeper transformation—trihalomethanes [125], haloacetic acids [125], and haloacetonitriles [126]. The main identified degradation products of monochloramines were the corresponding aldehydes, while organic dichloramines were converted into nitriles, N-chloraldimines, and acids [123]. The transformation pathways of amino acids under water chlorination conditions, the transformation of primary and secondary degradation products, and the effect of secondary functional groups on the formation of organic chloramines were studied in more detail with the use of valine, lysine, and tyrosine [127]. The N,N-dichloramine derivatives of lysine and valine were not detected due to their likely instability, but alternative dichloramine derivatives of lysine and tyrosine were found. The presence of additional functional groups (the amino groups of lysine and the phenolic fragment of tyrosine) led to additional attack sites for active chlorine. For example, in the chlorination of lysine, two monochloramine derivatives were formed due to the participation of the second amino group. At higher ratios between a chlorinating agent and amino acid (Cl : substrate = 1.2), N,N'-dichlorolysine was found, which was subsequently converted into the corresponding aldehyde and 5-chloroaminopentanal. An increase in the ratio Cl : substrate to 2.4 resulted in the formation of an aldehyde corresponding to N,N′,N′-trichlorolysine and 5-dichloroaminopentanal; in this case, no peaks of dichlorolysine were observed. The presence of an activated aromatic ring in the case of tyrosine leads to the appearance of products of electrophilic substitution in the aromatic ring (N-monochloro-3-chlorotyrosine) along with N-monochlorotyrosine and N,N-dichlorotyrosine.

TRANSFORMATION OF SOLAR PROTECTORS AND UV FILTERS

As noted above, in recent years, more and more attention has been paid to the environmental transformation of UV protectors. These are organic compounds used as ingredients in skin care products. While bathing, they occur in natural reservoirs or in the water of pools, in which chlorinating or brominating agents are usually used for disinfection. They penetrate into natural waters as a result of seepage from landfills and with sewage. As a result, they occur in the intakes of drinking water treatment plants. Currently, UV filters are considered as emerging pollutants [128]. They are also subject to photolytic reactions in the light [90].

Two primary products of the aqueous chlorination of 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoate (DHHB, Fig. 13) with sodium hypochlorite [129] were obvious and associated with ortho-substitution in the benzene ring activated with diethylamine and hydroxyl groups. However, the third detected product corresponded to the substitution of the ethyl group for chlorine. Grbović et al. [129] were unable to unambiguously establish the structure of this compound, assuming the transformation of the diethylamine group into a monoethylamine group in the structure of the monochlorinated product. An alternative could be the formation of an N–Cl bond with the elimination of the ethyl group, but the CAD spectra used in the work could not give an unambiguous answer to this question.

Fig. 13

Structures of the test substrates.

Fig. 13

(Contd.)

The transformation of oxybenzone and sulisobenzone (Fig. 13) upon chlorination in fresh water [130] and sea water [131] includes a series of consecutive reactions of aromatic electrophilic substitution in the methoxyphenol ring. First, substitution at the 3- and 5-positions (ortho- and para-positions relative to the hydroxy group) occurred; then, or if these positions are occupied by other functional groups, the carbonyl group is converted into an ester group due to the Baeyer–Villiger reaction. Only then does the subsequent electrophilic substitution become possible with the formation of a trichloro-/tribromo-substituted derivative. Further, the cleavage of the resulting ester is followed by another electrophilic substitution reaction with the formation of 2,4,6-trihalo-3-methoxyphenol (Fig. 14) or other halogen derivatives of 3-methoxypyrocatechol [132]. Oxybenzone and sulisobenzone do not form tetrahalo-substituted DBPs due to the absence of an activating group in the second benzophenone ring.

Fig. 14.

Reaction scheme of the transformation of oxybenzone in the course of chlorination in sea water [131].

The chlorination of the UV filter dioxybenzone (Fig. 13) in sea water resulted in the formation of only brominated DBPs [133]. According to Manasfi et al. [133], this is a natural result of the reactions of molecular bromine, hypochlorous acid, or other forms of active bromine arising from the interaction of chlorine and bromide ions, which are always present in sea water. Dioxybenzone undergoes a series of successive aromatic electrophilic substitution reactions, which leads to the formation of mono-, di-, tri- and tetrabromo derivatives of dioxybenzone. In this case, the bromine atoms occupy the ortho- and para-positions in both aromatic fragments relative to the hydroxy and methoxy groups. Tribromodioxybenzone can be further oxidized according to Baeyer–Villiger and converted into the corresponding 3,5-dibromo-2-hydroxy-4-methoxyphenyl ester of 2-hydroxybromobenzoic acid. Transformations of this type were previously described in the chlorination reactions of other UV filters of benzophenone derivatives, including oxybenzone [131] and sulisobenzone [130, 132]. Further bromination of the oxidized form of tribromodioxybenzone leads to the formation of an unstable tetrabromo derivative, which is cleaved into more stable 2,4-dibromosalicylic acid and 2,4,6-tribromo-3-methoxyphenol. The retention times and the mass spectra of reference standards were used to confirm the structure of the last two DBPs.

The chlorination of octyl-4-methoxycinnamate (Fig. 13) in sea water led to the formation of mono- and dibromo derivatives. The monobromo derivatives were represented by four isomers due to the presence of a mixture of Z and E isomers in the initial substrate and substitution at two possible positions in the aromatic ring. The dibromo-substituted products were represented by two isomers. Similar results were obtained in the reaction of octyl-4-methoxycinnamate with sodium hypochlorite under the conditions of pool water disinfection [134], where four monochlorine-substituted and two dichlorine-substituted products were recognized. Note that the products of the addition of chlorine or bromine to the C=C bond of the cinnamic acid ester fragment were not observed.

It was shown above that the primary products of the chlorination or bromination of avobenzone (Figs. 8, 9, and 13) are derivatives mono- and dibromo-substituted at the methylene group, and the electrophilic substitution reaction does not occur in activated benzene rings. All stages of the transformation of avobenzone under conditions of chlorination and bromination in fresh and sea water in the presence of additives of inorganic anions (Br^– and I^–) and cations (Cu²⁺ and Fe³⁺) were studied in detail; more than 100 transformation products including substituted aldehydes, acetophenones, acids, and phenols were identified [93–96, 135, 136]. The range and levels of reaction products significantly depend on the experimental conditions. Although organoiodine compounds are easily transformed under conditions of aqueous chlorination with the substitution of iodine for chlorine [51–53, 107], two organoiodine products were detected in experiments with the addition of iodide anions [135]. Iron ions and iodides accelerate the chlorination reaction, and the presence of copper ions under bromination conditions leads to an almost 100-fold increase in the yield of bromoform [135, 136].

Octocrylene (Fig. 13) does not form DBPs under conditions of aqueous chlorination and bromination. Two electron-withdrawing groups (cyano and ester groups) greatly decrease the reactivity of octocrylene with respect to an electrophilic attack; as a result of this, it is stable under the conditions of water disinfection [133].

The chlorination of octyl dimethyl-p-aminobenzoate (Fig. 13) under the conditions of pool water disinfection mainly leads to the introduction of chlorine atoms through the aromatic electrophilic substitution reaction [137]. The formation of mono- and dichloro derivatives of the octyl esters of dimethyl-p-aminobenzoic, methyl-p-aminobenzoic, and p-aminobenzoic acids was observed. Therefore, along with the reaction of electrophilic substitution, the dealkylation of the substrate at the nitrogen atom in the para-position of the aromatic ring occurs. Note that Negreira et al. [138] did not detect dichloro/dibromo derivatives; that is, it is likely that a long reaction time (60 h) and solar radiation play a key role in the formation of these products.

TRANSFORMATION OF PHARMACEUTICALS

Narcotic and Psychoactive Substances

Narcotic and psychoactive substances are regularly detected in the wastewater of large cities, and they occur in natural water and often in the intakes of drinking water treatment plants because treatment systems are usually not designed for these ingredients. Under the conditions of aqueous chlorination of cocaine, the main direction of reactions is reduced to hydrolytic and N-dealkylation processes [139]. The main transformation products of cocaine are monochloro cocaine derivatives, norcocaine, norbenzoylecgonine, and N-formylcocaine [139, 140].

In the case of nicotine (Fig. 13), the pyrrolidine fragment is mainly subject to transformations in the course of chlorination, and the main substitution, elimination, and oxidation reactions [141] lead to the formation of cotinine, nicotinic acid, nornicotine, nicotirine, and myosmin, as well as chlorinated DBPs such as 5-chloronicothyrine and 5-chloromyosmine.

Aqueous chlorination of the main metabolite and biomarker of cannabis, 11-nor-9-carboxy-9-tetrahydrocannabilol, leads to an electrophilic attack of chlorine at the para- and/or ortho-positions of the phenolic group [142]. The introduction of a chlorine atom into psychostimulants of the amphetamine series (3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, and 3,4-methylenedioxyethylamphetamine) also occurs as a result of an electrophilic substitution reaction but only after the corresponding cleavage of the amine side chain [143]. This leads to the formation of 3-chloropyrocatechol and 4-chlorobenzo[1,3]dioxol. In the chlorination of compounds of the benzodiazepine series (diazepam and oxazepam), the attack of chlorine occurs at the carbon atom in the 3-position of the 1,4-diazepine structure. Further oxidation with oxygen transfer gives 7-chloro-1-methyl-5-phenyl-1,3dihydro-2H-1,4-benzodiazepine-2,3-dione as the main DBP. The transformation of oxazepam under aqueous chlorination conditions is initiated by the abstraction of one proton followed by a rearrangement and contraction of the diazepine ring to form 6-chloro-4-phenyl-2(1H)-quinazolinone [144, 145]. Quinazoline derivatives were also formed upon the chlorination of diazepam and nordazepam. Further transformation led to the opening of the 1,4-diazepine ring with the formation of benzophenone derivatives as final minor DBPs [145]. A study of the aqueous chlorination of the antidepressant citalopram showed that one of the main products is desmethylcitalopram, which is formed by the demethylation of a tertiary amine to a secondary amine [146]. This compound can be further oxidized first at the furan ring and then at the nitrogen of the secondary amine to form an N‑oxide derivative, which is extremely stable in solution.

Antibiotics

The formation of the DBPs of antibiotics under conditions of aqueous chlorination in many cases leads to the preservation of their bactericidal properties. This, in turn, allows them, along with the original antibiotics, to play an important role in the selection of resistant forms of microorganisms in the environment [147, 148].

The chlorination of tetracycline antibiotics mainly leads to the formation of chlorine- and hydroxy-substituted DBPs without ring cleavage [149]. In particular, the DBPs of doxycycline (Fig. 13) are formed as a result of double demethylation, subsequent chlorination in the para- and ortho-positions relative to the hydroxyl group of the phenolic ring, and N-chlorination of the amide group [150].

Studies on the chlorination products of sulfonamide antibiotics revealed many transformation pathways including substitution with chlorine, S–C bond cleavage, S–C bond hydrolysis, desulfurization, hydroxylation, oxidation, and coupled reactions [151, 152]. In this case, chlorine-substituted DBPs and those formed due to S–C bond hydrolysis and desulfurization are typical of all compounds of this series, while other specific reactions may occur with some substances. For example, DBPs formed by S–C bond rupture are characteristic of only sulfamethoxazole (Fig. 13). The presence of a strong electrophilic center at carbon in the α-position relative to the sulfonyl or sulfonamide group determines the course of this reaction [153]. However, even the common substitution with chlorine for many sulfonamide derivatives proceeds differently depending on the molecular structure. For example, sulfamethoxazole [152], sulfamethazine [151], sulfamerazine, and sulfadiazine [154] (Fig. 13) are characterized by N-chlorination of the aniline fragment, while substitution for chlorine in sulfathiazole (Fig. 13) takes place at the thiazole fragment and in sulfadimethoxine (Fig. 13), at the dimethoxypyrimidine fragment [152].

In studies on the transformation of fluoroquinolone antibiotics under conditions of aqueous chlorination, it was found that chlorine primarily attacks the piperazine ring, while the quinolone fragment does not react [155, 156]. The absence of the piperazine ring, apparently, is the reason why the reaction of flumequine (Fig. 13) with chlorine does not proceed. Flumequine transformation occurs only after the interaction of its quinolone fragment with reactive intermediates formed upon chlorination of other fluoroquinolones (for example, levofloxacin or enrofloxacin) [155, 156]. The secondary amino group in the piperazine ring of ciprofloxacin (Fig. 13) is rapidly converted into the corresponding N-chloro derivative, which then undergoes piperazine ring cleavage. On the contrary, enrofloxacin (Fig. 13), which has a tertiary amino group in the piperazine ring, slowly reacts with chlorine to form a chloro ammonium intermediate capable of further catalyzing the halogenation of both enrofloxacin itself and other compounds in solution, for example, halodecarboxylation in the case of flumequine [156]. For norfloxacin, ofloxacin, and levofloxacin (Fig. 13), similar trends were observed in reactions with chlorine [155, 157]. In the chlorination of ciprofloxacin (Fig. 13), after the rupture of the piperazine ring, further oxidation occurs with the formation of a 7-amino-8-chloro derivative of the fluoroquinolone fragment, which probably retains the antimicrobial activity of ciprofloxacin.

The secondary amino group of chloramphenicol (Fig. 13) also reacts rapidly with chlorine to form an N-chloro derivative. Some DBPs are formed as a result of electrophilic substitution reactions in the aromatic ring. Similar substitution reactions can also occur with DBPs obtained after amide cleavage [158].

The interaction of cefazolin, an antibiotic of the cephalosporin series (Fig. 13), with chlorine occurs by the oxidation of the thioether sulfur atom with the formation of sulfoxide and disulfoxide derivatives. Only after that the electrophilic substitution of chlorine for α-hydrogen with respect to the amide group takes place [159].

The reactivity of trimethoprim (Fig. 13) under conditions of aqueous chlorination is determined by its 2,4-diamino-5-methylpyrimidine fragment. Al-though significant degradation to final DBPs was not observed, some chlorine- and hydroxy-substituted isomeric products were identified [160].

Other Pharmaceutical Preparations

The presence of an activated aromatic system in the molecule, as a rule, leads to products of electrophilic substitution reactions. For example, the attack of a halogen occurs at the ortho-position relative to the hydroxyl group in the benzene ring in the chlorination or bromination of salbutamol [161] and paracetamol [162] (Fig. 13) or at the naphthalene fragment in the case of propranolol [161]. A similar substitution reaction with atenolol (Fig. 13) proceeds only after the hydrolysis of the amide group with the formation of a carboxylic acid [161]. Other transformation pathways for β-blockers/β-agonists include hydroxylation and dealkylation reactions. Thus, paracetamol (Fig. 13) can also be converted into toxic 1,4-benzoquinone and N-acetyl-p-benzoquinoneimine [162].

Carbamazepine is one of the pharmaceuticals best studied under aqueous chlorination conditions [163–167] (Fig. 13). N-Chloramide-carbamazepine and 10,11-epoxycarbamazepine are two key intermediates formed in the competing processes of N-chlorination and epoxidation of carbamazepine [167]. Both primary products are highly reactive, and this results in the formation of various chlorinated and hydroxylated derivatives. Some of the final transformation products, iminostilbene and acridine, can be further oxidized to oxoiminostilbene, 9-formylacridine, and 9(10)-H-acridone, respectively. On the chlorination of oxcarbazepine, a keto analog of carbamazepine, chlorine sequentially replaces hydrogen atoms at the α-carbon atom to finally form a carbonyl group in this position [168]. The hydrolysis of mono- and dichloro derivatives of oxcarbazepine gives 1-(2-benzaldehyde)-(1Н,3Н)-quinazolin-2,4-dione, which accumulates in solution by the end of the reaction, and the amide group does not interact with chlorine at all [168].

Phenazone and propyphenazone (Fig. 13), which belong to the pyrazolone type of analgesics, are converted into the corresponding halogen derivatives due to the reactions in the pyrazolone ring. Further transformations occur as a result of hydroxylation and dealkylation reactions [169, 170]. Aminopyrine (Fig. 13) undergoes pyrazolone ring cleavage, hydroxylation, dehydrogenation, and halogenation in the course of chlorination [171].

The chlorination of the anti-inflammatory drug diclofenac (Fig. 13) is accompanied by hydroxylation and subsequent oxidation of the phenol group, decarboxylation of the parent molecule, and electrophilic substitution with chlorine in the nonhalogenated ring [172]. Similar transformations lead to the formation of decarboxylated, brominated, and iodinated DBPs when chlorination is carried out in the presence of bromide and iodide ions. In this case, hydroxylated derivatives are formed only in the presence of the bromide ion in the initial solution. For naproxen (Fig. 13), the substitution for chlorine mainly occurs in the 7-position of the naphthalene fragment. After that, another 13 different DBPs are formed as a result of demethylation, decarboxylation, hydroxylation, and dehydrogenation reactions [173].

Iodine-containing radiopaque agents, which are often used in soft tissue medical imaging, were designed to be chemically inert toward the human body to be eliminated from the body in its original form within 24 h. However, in turn, this stability led to their significant concentrations (to μg/L) not only in wastewater [174] but also in drinking water [175]. For this reason, the study of the transformation of this class of substances under conditions of water disinfection has become relevant. Wendel et al. [107] studied the transformation of radiopaque substances in the course of water disinfection with chloramine, chlorine dioxide, and hypochlorite using iopamidol, iopromide, iohexol, iomeprol, and diatrizoate as examples (Fig. 13). They established the structures of the main conversion products of iopamidol by a combination of mass-spectrometric methods (HRMS and HPLC–MS/MS) and ¹H and¹³C NMR spectroscopy and proposed a reaction scheme of its transformations under aqueous chlorination conditions. They found that the hydrolysis of an amide bond, the breaking of a side chain (C–N bonds) with the retention of the amide group, the inversion of the amide substituent to an ester one, and the oxidation of the NH₂ group to the NO₂ group can occur in the course of chlorination. The hydrolysis of the amide fragment leads to the formation of a substituted aniline, which, in turn, undergoes oxidative dimerization to form a substituted azobenzene structure. In addition, iodine can be replaced by chlorine as a result of ipso-aromatic substitution stimulated by an oxidizing medium at all stages of the transformation of iopamidol. Iopamidol is also a source of toxic iodinated DBPs (iodine-containing acids and trihalomethanes) formed upon chlorination. Iodine released in the course of chlorination becomes available in solution, and this fact stimulates its incorporation into natural organic matter [176].

Significant amounts of controlled trihalomethanes and haloacetic acids and noticeable concentrations of iodinated trihalomethanes (CHBrClI, CHCl₂I, and CHBr₂I) were formed under the conditions of aqueous chloramination of water containing iopamidol and bromides. Low concentrations of iodoacetic acids were found, especially, at low pH. In general, it is likely that high concentrations of bromide suppressed the formation of iodine derivatives of DBPs in the chloramination of iopamidol in the presence of natural organic matter [177]. Ackerson et al. [178] studied changes in the levels of possible halogenated DBPs depending on the concentrations of bromides and iopamidol.

Electrophilic substitution in the ortho- and para-positions relative to the amino group is the predominant process in the interaction of phenamic acids (Fig. 13) with chlorine under water disinfection conditions. Monohalo- and dihalo-substituted derivatives are formed among the products. In addition, an attack of chlorine at the nitrogen atom, nucleophilic substitution in the aromatic ring, and oxidation reactions, which lead to N-chloro, hydroxyl, and oxidized derivatives, respectively, are possible [179].

Glucocorticoid DBPs formed upon chlorination also exhibit biological activity along with the parent molecules [180]. 9-Chloroprednisone, Δ1-adrenosterone, and a chlorinated derivative of Δ1-adrenosterone are the main DBPs of prednisone reactions with chlorine, and prednisone itself is a product of the aqueous chlorination of prednisolone and cortisol. In the case of prednisolone, 11β-hydroxybaldione is formed after cleavage of the side chain at a carbon atom in the 17-position. Chlorinated prednisone and prednisolone, Δ1-adrenosterone, and its chlorinated derivative are also formed at high ratios of chlorine to prednisolone. Chlorinated derivatives of prednisone, a hydroxylated derivative of cortisone, adrenosterone, and Δ1-adrenosterone are also formed in the chlorination of cortisone, while cortisone is a DBP of cortisol [180].

Electrophilic substitution in the phenol ring is the main driving process for the transformation of 17α-ethinylestradiol under aqueous chlorination conditions. The resulting monochloro and dichloro derivatives are further converted into DBPs with cleaved phenol rings [181].

Tamoxifen (Fig. 13) is resistant to chlorination; therefore, DBPs were not identified for it. However, its main metabolites, 4-hydroxytamoxifen and 4‑hydroxy-N-desmethyltamoxifen, are highly reactive, and this fact can be explained by the presence of a hydroxyl group in the benzene ring, which strongly activates the ring to electrophilic substitution. Chlorination of tamoxifen metabolites results in the formation of several monochloro-, dichloro-, and hydroxylated derivatives. Because the reactivity of the amino group is lower than that of the phenolic fragment, the formation of N-chlorinated compounds was not observed [182].

The chlorination of the antacid drug cimetidine (Fig. 13) leads to the formation of cimetidine sulfoxide, 4‑hydroxymethyl-5-methyl-1H-imidazole, 4-chloro-5-methyl-1H-imidazole, and a product that is presumably β- or δ-sultam. The formation of cimetidine sulfoxide is a natural consequence of the chlorination process, whereas the other three DBPs are generated through less common reactions of C–C bond cleavage and intramolecular nucleophilic substitution [183].

The indole derivative umifenovir (Arbidol) (Fig. 13) is one of the most popular drugs in Russia against COVID-19 and a number of other viruses. Its active use has led to its accumulation in activated sludge and river sediments. In particular, in Arkhangelsk, umifenovir was detected in concentrations of 1.3 mg/kg and 1 μg/L in activated sludge and treated wastewater, respectively, at the beginning of 2021 [184]. A laboratory experiment on the aqueous chlorination of this compound revealed 15 bromine-containing products (umifenovir contains a bromine atom in its composition) formed at the initial stages of chlorination and 14 volatile and semivolatile DBPs with bromoform as the main product using GC/HRMS and HPLC/HRMS analysis. A detailed reaction scheme for the transformation of umifenovir was proposed. The only chlorine derivative was formed at the initial stages of chlorination when the alkylamine group was replaced by chlorine. This is due to the fact that the activated benzene ring of umifenovir already has five substituents and only one free site not very accessible for steric reasons. Two main products formed upon the oxidation of the thioether group to sulfoxide and as a result of the elimination of a thiophenol fragment were also detected along with their precursor in the wastewater of Arkhangelsk [184].

OTHER STUDIES ON DBP FORMATION

Worldwide, tea is the second most consumed soft drink after drinking water. When boiled tap water is used to brew tea, the residual chlorine reacts with the compounds of tea. Li et al. [185] measured the levels of 60 regulated and priority DBPs in Twinings green tea, Earl Gray tea, and Lipton tea, which were brewed using tap water or simulated tap water (nanopure water with chlorine). In many cases, the levels of DBPs in tea were lower than those in the tap water itself due to volatilization and sorption onto the tea leaves. Products formed as a result of the reaction of residual chlorine with tea compounds accounted for approximately 12% of the total DBP amount in real tea brewed with tap water, and the remaining 88% occurred in the initial tap water. The total number of organic halogens in tea has nearly doubled, as compared to that in tap water; in this case, 96% of halogenated DBPs remained unknown. The exception is dichloroacetic acid, trichloroacetic acid, and chloroform. Most of the products may be high-molecular-weight haloaromatic compounds resulting from the reactions of chlorine with polyphenols present in tea leaves. This is also evidenced by the identification of 15 haloaromatic DBPs with the use of GC/HRMS analysis.

CONCLUSIONS

Although a wealth of material on the processes and products of chlorination and bromination of water has been accumulated to date with the use of mass spectrometry methods, the issue is still very far from a final solution. More than half of organic chlorine and bromine are the constituents of compounds whose structures are unknown. Some directions of transformation of even simple organic compounds, for example, PAHs, with the formation of a number of disinfection products remain unclear. The presence of inorganic salts has a significant effect on the range and levels of disinfection products. The toxicity of the vast majority of disinfection products remains unexplored, and the known DBPs cannot explain the entire range of diseases associated with the consumption of poor-quality drinking water. However, the use of high-resolution mass spectrometry and tandem mass spectrometry methods has recently made significant progress in the study of disinfection by-products. The list of identified DBPs is growing rapidly; detailed reaction schemes for the transformation of anthropogenic compounds, which often occur in the intakes of drinking water treatment plants and undergo chlorination, are being established, and active research is underway to study the mechanisms of transformations of natural substances and anthropogenic compounds under conditions of aqueous chlorination/bromination.