Reaction of chlorine dioxide with emergent water pollutants: Product study of the reaction of three β-lactam antibiotics with ClO2

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Reaction of chlorine dioxide with emergent water pollutants: Product study of the reaction of three b-lactam antibiotics with ClO2 Sergio Navalon1, Mercedes Alvaro1, Hermenegildo Garcia Department of Chemistry, Universidad Polite´cnica de Valencia, Camino de Vera S/N, 46022 Valencia, Spain

art i cle info

ab st rac t

Article history:

This work deals with the chlorine dioxide (ClO2) reactivity with three representative b-lactam

Received 27 July 2007

antibiotics (penicillin, amoxicillin and cefadroxil) that can be present in natural aquatic

Received in revised form

resources. Due to the wide use of ClO2 as disinfection agent our work is of interest to

14 November 2007

determine the fate of these antibiotics during the water treatment process. Our study shows

Accepted 19 November 2007

that antibiotics react stoichiometrically with ClO2 because increasing amounts of ClO2 lead to

Available online 24 November 2007

increasing antibiotic disappearance. Concerning the influence of antibiotic structure,

Keywords: Chlorine dioxide Water treatment Trihalomethane formation b-Lactam antibiotics in water

penicillin reacts sluggishly with ClO2, whereas amoxicillin and cefadroxil are highly reactive at either neutral or basic pH. For both reactive antibiotics, hydroquinone together with a wide range of 4-substituted phenols were detected as products. Pretreatment with ClO2 before chlorination of aqueous solutions of antibiotics reduces the trihalomethane formation as compared with analogous chlorination without ClO2 pretreatment.

Emergent pollutants in water

1.

Introduction

There is an increasing concern about the presence of pharmaceutically active drugs in water resources due to their adverse effects on human health upon continued ingestion (Richardson and Bowron, 1985; Heberer and Stan, 1996; Hirsch et al., 1999). It has been shown that conventional urban sewage treatment does not completely remove the most widely used therapeutic drugs (Ternes, 1998; Ternes et al., 2002; Carballa et al., 2004; Stackelberg et al., 2004; Bendz et al., 2005) and control analyses reveal their presence downstream of conventional wastewater treatment plants. There is also an increasing concern by the occasional detection of therapeutical drugs in underground water resources caused by urban waste water infiltration. Chlorine dioxide (ClO2) is one of the disinfectant agents used in water treatment plants as an alternative to chlorine (Aieta

& 2007 Elsevier Ltd. All rights reserved.

and Berg, 1986; Myers, 1990; White, 1998; Rav-Acha, 1998). One of the major advantages of ClO2 over chlorine is the reported inability of ClO2 to form trihalomethanes (THMs) (Lykins and Griese, 1986; McVeigh et al., 1985). Current European regulations (EU, 1998) limits THM content in drinking waters and in order to minimize THM formation the use of chlorine in disinfecting water treatment is being reduced and replaced by alternative disinfection agents worldwide. In view of the increasing use of ClO2 in water treatment, it is of interest to determine the reactivity of this disinfectant agent with organic compounds that could be present in water resources (Huber et al., 2005). More specifically, it is of interest to gain information about the reaction of ClO2 with highly consumed pharmaceutical drugs that have been detected in groundwater, because some of the resulting products can have an adverse biological effect. It is particularly relevant to determine the consequences of chronic, low-level dosage to

Corresponding author. Tel.: +34 96 387 78 07; fax: +34 96 387 78 09.

E-mail addresses: [email protected] (S. Navalon), [email protected] (M. Alvaro), [email protected] (H. Garcia). 1 Tel.: +34 96 387 7007; fax: +34 96 387 9349. 0043-1354/$ - see front matter & 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.watres.2007.11.023

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the products derived from ClO2 reaction with some common pharmaceutical drugs. In this context, the present work studies the reactivity of ClO2 with three of the bestselling b-lactam antibiotics under conditions that can be of some relevance in water treatment. In particular, we have studied the stoichiometry of the reaction between these antibiotics and ClO2 to determine whether ClO2 can catalytically decompose this type of antibiotics under aerobic conditions. It is also important to characterize the resulting reaction products and the effects of ClO2 on THM formation from these antibiotics. Considering the extensive use of ClO2 in drinking water treatment plants, our work demonstrates that ClO2 does affect the stoichiometric degradation of antibiotics, transforming them into other derivatives and occasionally reducing the THM content of the treated water.

2.

Experimental

2.1.

Materials

Penicillin G potassium salt (PEN), amoxicillin (AMO), cefadroxil (CEF) and N,O-bis(trimethylsilyl)trifluoroacetamide with 10% trimethylchlorosilane (BSTFA+10% TMCS) were supplied by Sigma-Aldrich. Tris(p-bromophenyl)ammonium hexafluoroantimonate (TPAd+AsF 6 ) was supplied by Scharlab. The other reagents used were of analytical or HPLC grade.

2.2.

Product identification

Prior to the analysis, the reaction mixture containing the antibiotic and the corresponding amount of ClO2 was quenched for the required time using an excess of thiosulphate with respect to ClO2. Then, antibiotic disappearance was determined by reverse-phase HPLC (Waters 600 Series adapted to a photodiode array detector) using a Kromasil-C18 column under isochratic conditions. PEN (25 ppm) was analysed using 20% acetonitrile and 80% water (pH 3; 1% acetic acid) as mobile phase. In the case of AMO (1.6 ppm) and CEF (1.89 ppm) the eluent was 10% methanol and 90% water (pH 4.8; 0.02 M KH2PO4). In both cases the flow was 0.9 mL/min and the injection volume was 200 mL. The detection limit depends on the absorbance of each antibiotic at the monitoring wavelength (PEN 225 nm and AMO and CEF 229 nm). The detection limit for PEN, AMO and CEF was 5, 0.5 and 0.5 ppm, respectively. For product identification the reaction mixtures were acidified to pH 2 with HCl, concentrated at 40 1C and lyophilized. The residue was suspended in BSTFA+ 10% TMCS and the solution stirred at 80 1C for 8 h. The resulting silylated mixture was dissolved in anhydrous acetonitrile, filtered through a 0.45 mm membrane and injected in a gas chromatography (GC)–MS system (Hewlett Packard HP6890 Chromatograph and mass detector Agilent 5973). The capillary column (30 m) contains crosslinked (5%) phenylmethylsilicone (HP-5MS) as stationary phase. It was used as a carrier gas (1.2 mL/min). The injection volume was 1 mL. The injection and detector temperatures were 250 and 280 1C, respectively. The oven temperature programme starts at 50 1C for 3 min, then it increases at a rate of 8 1C/min up to 90 1C, maintains

this temperature for 2 min and subsequently rises again at a rate of 15 1C/min up to 280 1C for 10 min. Product identification was done using the mass spectra of the silylated derivative present in the reaction mixture. Penillic acid was identified by comparison of the chromatographic retention time, 1H-NMR and 13C-NMR (recorded on a Varian Gemini 3000, 300 MHz) as well as ESI–MS spectroscopic data with those of an authentic sample prepared by acid hydrolysis of PEN. The transformation of PEN into penillic acid has been reported in the literature (Kessler et al., 1983). N-(2-phenylacetyl) glycine was identified through the alternative synthesis of this product obtained by reacting glycine and phenylacetyl chloride and comparing the retention time of the synthesized product with that present in the reaction with ClO2. The mass spectra of the silylated products recorded in the present work are given as Supplementary information. THM content was determined by GC-ECD (Carlo-Erba 8139 chromatograph with ECD coupled to a Thermo Finnigan autosampler HS 2000) following the procedure of the UNE-EN ISO 10301 standard. In all cases, the almost exclusive THM detected was chloroform, this being in agreement with the lack of bromine atoms in the synthetic waters used. GC for THM analysis was performed using He as carrier gas (85 kPa), and N2 as make-up gas (110 kPa) in a DB.624 capillary column, injecting 0.4 mL of the head gas. The injection and detector temperatures were 220 and 330 1C, respectively. The oven temperature programme started at 50 1C for 1 min, then increased at a rate of 3 1C/min up to 180 1C and subsequently at a rate of 10 1C/min up to 210 1C. For THM analysis, sealed vials (20 mL) containing 10 mL of the water sample chlorinated at 10 ppm with a stock solution of NaClO (1000 ppm) were sealed and stored in the dark at 20 1C for 24 h. After this time the reaction was stopped, reducing the residual chlorine with 0.1 g of thiosulphate and adding 0.1 g of NaCl. The stock NaClO solution was prepared by diluting commercial NaClO (10–13%). Free chlorine was determined by the N,N0 -diethyl-1,4-phenylenediamine (DPD) method (ISO 7393-2:1985).

2.3.

Reaction conditions and procedure

Three commercially available antibiotics with a b-lactam structure were selected as probes to study their reactivity with ClO2. The reactions were carried out in buffered water (pH 7; HCO 3 /HCl) at thermostated temperature (20 1C) containing 25 (PEN), 1.6 (AMO) and 1.89 ppm (CEF) of the drugs. Although these concentrations are considerably larger than those expected in water resources (0.1 ppm) (Huang et al., 2001) we have tried to keep them as low as possible while still allowing product characterization by chromatography. The reactions were carried out in triplicate and the results shown correspond to the average of the individual runs. In general, variations among individual runs were lower than 5%. ClO2 was generated by reacting potassium chlorate and hydrogen peroxide in sulphuric acid (Eq. (1)). The resulting gas was collected in water and the resulting concentrated aqueous ClO2 solution was titrated by measuring the optical absorption (Perkin-Elmer’s Lambda 35 UV/Vis) of the solution at 360 nm (for ClO2 e360 ¼ 1250 cm1 M1) after buffering at pH 7. ClO2 production was checked for the absence of significant

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chlorine concentration by titration before and after treatment with glycine, which is a selective reagent for chlorine. 2 KClO3 þ H2 O2 þ H2 SO4 ! 2 ClO2 þ O2 þ K2 SO4 þ 2 H2 O:

(1)

Corresponding volumes of this ClO2 stock solution were added to the antibiotics under study dissolved in water, controlling the initial ClO2/substrate molar ratio at the required value (between 0.1 and 3). The reaction was observed by monitoring ClO2 concentration using optical spectroscopy (PEN) or DPD colorimetric titration (AMO and CEF). This difference in the ClO2 analytical method was due to the absorbance of the reaction products derived from AMO and CEF at 360 nm. At the same time as ClO2, antibiotic concentration was determined in the three cases by HPLC analysis of the aqueous solution. At the end of the reaction the mixture was concentrated and exposed to exhaustive silylation using a BSTFA+10% TMCS mixture, at 80 1C before GC–MS analysis of the resulting products. Scheme 1 illustrates the protocol used to perform the reaction of ClO2 with b-lactam antibiotics. Several ClO2/substrate molar ratios were assayed to determine the stoichiometry of the reaction and to find out whether or not catalytic ClO2 amounts can affect antibiotic degradation to a significant extent. Some experiments were purposely performed at acidic or basic pH to determine the relative proportion between reaction and spontaneous disappearance for ClO2. ClO2 is a disinfecting agent that exhibits low persistence in water. Moreover, the stability of ClO2 aqueous solutions is strongly dependent on pH and, therefore, ClO2 disappearance cannot completely be associated in its reaction with the b-lactam antibiotic.

3.

Results and discussion

3.1.

Reaction of ClO2 with PEN

At pH 7, PEN reacts sluggishly with ClO2. The reactivity of ClO2 towards PEN even decreases further as pH increases in the

1937

range of 7–9 units. In contrast to this lack of reactivity at neutral or basic pH, ClO2 attacks PEN at acidic pH values. We have studied the reactivity in the pH range between 3.5 and 6.4 units. The tendency observed is that the reaction rate and PEN disappearance increase progressively as the pH value decreases. Fig. 1(a) shows the percentage of PEN disappearance versus the concentration of ClO2 added when the reaction is conducted at pH 3.5. As it can be seen there, the reaction at this acidic pH value seems to exhibit a 1:1 stoichiometry, proportionally increasing the percentage of PEN disappearance after 2 h reaction with the ClO2 dose. The kinetics of the reaction of PEN with ClO2 at three different pH values in the range 3.5–6.4 was studied by observation of the time conversion plot. Figs. 1(b) and 2 show ClO2 concentration and percentage of PEN disappearance versus time. In these plots, the results of two control experiments, namely the spontaneous disappearance of ClO2 and PEN at their corresponding pH values, have also been included. These blank controls show that about 10% PEN decomposes spontaneously in the absence of ClO2 in this pH range. Similarly, ClO2 is stable in this pH range for the time interval of PEN reaction. In contrast to the blank controls, the reaction of PEN with ClO2, characterized by the initial reaction rate and the percentage of disappearance at 60 min reaction time, was strongly dependent on pH. The maximum initial reaction rate and percentage of PEN disappearance at 100 min time is obtained at the lowest pH, while at higher pH values the decay of ClO2 concentration is not coupled with a concomitant increase in the percentage of PEN disappearance. At high pH values most ClO2 disappears in the presence of b-lactam, while the concentration of the antibiotic remains unaltered. Apparently the b-lactam is playing the role of an organocatalyst promoting ClO2 decomposition but without reacting itself in the same extent. The product formed upon reaction of PEN with ClO2 was characterized by spectroscopic means including 1H NMR, 13C NMR spectroscopy and HPLC–MS. The data indicate that the

B-lactam antibiotics (diluted and buffered aqueous solutions)

+ ClO 2

Optical Spectroscopy ClO2 measurement at 360 nm ClO2 measurement by DPD method at 515 nm Chlorine measurement by DPD method (for chlorination to measure THMs) at 515 nm

HPLC-reverse phase Antibiotic disappearance by reaction with ClO2 at different pH’s.

NMR 1H and 13C for Penillic Acid characterization

GC with Headspace THMs analysis

GC-MS Product reaction analysis after silylation with BSTFA+10 % TMCS

HPLC-MS. Penillic acid characterization

Scheme 1 – Procedure for the analysis of the reaction products resulting from ClO2 treatment of antibiotics.

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a

b 100 % Disappearance

% Disappearance

100 80 60 40

80 60 40 20

20

0

0 0.25 0.50 0.75 1.00 ClO2/PEN

1.50

0

20

40 60 t (min)

80

100

Fig. 1 – PEN disappearance by ClO2 at pH ¼ 3.5 after 2 h of reaction (a). Time–conversion plot for the reaction of PEN with one equivalent ClO2 at pH 3.5 (b). .: Disappearance of PEN in the absence of ClO2. ’: PEN disappearance by reaction with ClO2. &: ClO2 consumption in the presence of PEN. J: Disappearance of ClO2 in the absence of PEN.

a

b 100 % Disappearance

% Disappearance

100 80 60 40

80 60 40 20

20 0

0 0

100

200 300 t (min)

400

500

0

100

200 300 t (min)

400

500

Fig. 2 – Time–conversion plot for the reaction of PEN with one equivalent ClO2 at pH 5.4 (a) and at pH 6.4 (b). .: Disappearance of PEN in the absence of ClO2. ’: PEN disappearance by reaction with ClO2. &: ClO2 consumption in the presence of PEN. J: Disappearance of ClO2 in the absence of PEN.

O

C

H N O

ClO2/H+ ClO2-

S N

O

C

H N

S N

COOH

.+

(Ph)3N PEN

TPA

O

COOH

(TPA.+)

S

+H2 O N

COOH O

C

H COOH N S

O C

H N

CH C O

HN COOH + H2 O

-H2O HOOC

H N

S N

N

COOH

O COOH

<2 % N-(2-phenylacetyl) glycine

Penillic acid

70 %

Scheme 2 – Reaction and proposed mechanism of PEN promoted by ClO2 or TPAd+.

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predominant product was penillic acid accompanied with small quantities of N-(2-phenylacetyl) glycine (Scheme 2). It is worth noting that penillic acid (but in much lower percentages) is also formed in the absence of ClO2 due to the disappearance of PEN at acidic pH values. The possibility for penillic acid to result from purely acid reactions even in the presence of ClO2 was rejected based on the previously commented blank controls at pH 3.5 in which minor spontaneous PEN disappearance occurs. Concerning the mechanism of the reaction between PEN and ClO2, which we have shown to react with a 1:1 stoichiometry, one possible explanation reported in the literature is the occurrence of an initial electron transfer from PEN as donor to ClO2 as acceptor (Rav-Acha, 1998). Subsequently PEN’s radical cation undergoes further transformations (see below). To provide some experimental support to this mechanism, PEN was also made to react at pH 7 with TPAd+AsF 6 , which is a well-known single-electron acceptor reagent (Bell et al., 1969). In the presence of TPAd+AsF 6 as electron acceptor we observed again a complete conversion of PEN to penillic acid, as indicated in Scheme 2. Based on the reactivity of PEN with TPAd+ and the known ability of ClO2 to act as a single-electron acceptor reagent, we consider that penillic acid is formed following the reaction mechanism shown in Scheme 2. N-(2-phenylacetyl) glycine results from the [2+2] cycloreversion of the b-lactam ring generating a ketene intermediate that after hydration will give the carboxylic acid (Scheme 2).

The time conversion of the reactions of AMO and CEF with ClO2 was also studied at different pH values. Fig. 4 shows the time profiles of ClO2 consumption and antibiotic disappearance versus the reaction time at pH 4. Both AMO and CEF antibiotics behave similarly in all the pH range studied and exhibit the same 1:1 stoichiometry. Interestingly, AMO and CEF show different reactivity with pH from that of PEN. Thus, while acidic pH values are required to observe reaction with PEN, AMO and CEF do not decompose completely in the presence of ClO2 at acidic pH and they only reach high conversions at pH 8 (100% conversion in less than 4 min, time–conversion plot not shown). The relevance of the influence of pH on the reactivity with ClO2 is that while PEN should not react with ClO2 in the process of water treatment, both AMO and CEF will be readily and completely transformed by ClO2 under the conditions of ClO2 disinfection. These results, particularly the significant differences in reactivity, can be explained by the structural differences between PEN on the one hand and AMO and CEF on the other. We consider that the common 2-(4-hydroxyphenyl)-2-aminoacetyl moiety present in AMO and CEF are responsible for this behaviour. On the one hand, the presence of a hydroxy group on the aromatic ring increases the overall reactivity of AMO and CEF, while the presence of a basic amino group that will be protonated at acidic pH strongly disfavours the reaction of AMO and CEF at low pH values. Scheme 3 illustrates the proposal to rationalize the different behaviour to pH between AMO and CEF and PEN. The reaction products were determined under those conditions in which ClO2 reacts completely with the two b-lactam

Reaction of ClO2 with AMO and CEF

We extended our study to two other bestselling b-lactam antibiotics that are among the emerging water contaminants, namely AMO and CEF. The chemical structures of AMO and CEF are drawn in Scheme 3. Their common main difference with PEN is the presence of two highly reactive moieties, i.e. a primary amino group and a phenolic ring. Therefore, a higher reactivity towards to ClO2 could be anticipated. We proceeded in the same way as above to determine the stoichiometry of the reaction between ClO2 and AMO or CEF. Fig. 3 shows a bar plot presenting the percentage of antibiotic disappearance at pH 8 as a function of the number of ClO2 equivalents added to the reaction medium. From these data it can be concluded that the stoichiometry of the reaction, of these two antibiotics, also is 1 mol of ClO2 reacting with 1 mol of these two b-lactamic compounds.

AMO

100

CEF % Disappearance

3.2.

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80 60 40 20 0 0.25

0.50

0.75

1.00

1.50

2.00

ClO2/Antibiotic Fig. 3 – Stoichiometry of the reaction at pH 8 between ClO2 and b-lactam antibiotics after 1 min reaction.

NH 2

HO

NH 2

H N

O

N O

AMO

S COOH

HO

H N

O

S N

O COOH CEF

Scheme 3 – Structures of AMO and CEF and reactive sites with ClO2 highlighted in squares. The amino group is an unreactive site at low pH and a reactive site at basic pH. Hydroxyl group increases the overall reactivity of the phenyl ring at any pH.

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b 100

100

80

80

% Disappearance

% Disappearance

a

60 40 20 0

60 40 20 0

0

40

80 120 t (min)

160

200

0

50

100 150 200 250 300 350 t (min)

Fig. 4 – Time–conversion plot for the reaction of AMO (a) and CEF (b) (1 ppm TOC) with ClO2 (2 ClO2 to substrate) at pH 4 and room temperature. .: Disappearance of antibiotic in the absence of ClO2. ’: Disappearance of antibiotic by reaction with ClO2. &: ClO2 consumption in the presence of antibiotic. J: Disappearance of ClO2 in the absence of antibiotic. Table 1 – Products detected (and their percentages) in the reaction of AMO and CEF with ClO2 (substrate to ClO2 ratio 1:2) at different pHs valuesa N

OH

O NH O

HO OH

OH Hydroquinone

4-(3,4-dihydroxyphenyl)-

8 2 3

3(2H)-one-1,2,5-oxadiazol 0 6 0.5

AMO pH 8, 10 ppm AMO pH 8, 100 ppm AMO pH 4, 100 ppmb CEF pH 8, 10 ppm

13.4

0

CEF pH 8, 100 ppm CEF pH 4, 100 ppm

2.5 1

4 1.5

NH COOH 2-(4-hydroxyphenyl)-2-iminoacetic OH

HO

NH2

acid (o0.5%), and

, 2-hydroxy-

HO

cation will evolve into a radical by N–H deprotonation. This radical can couple with ClO2, oxygen or other radical-like oxygen species to form hydroxylamine and hydroxylimines. Thus, four of the products observed result from the functionalization of the benzylic amino group. Eventually, all these derivatives will end up in hydroquinone.

O

2-(4-hydroxyphenyl)acetamide (o0.5%), were also detected. a The disappearance of initial materials was complete. Other unidentified products were also observed by GC–MS after silylation. The possibility that some reaction products are not detectable by GC is likely. b Detected compounds for the reaction of AMO at pH 4 and 100 ppm.

antibiotics (pH 8). Product identification was based on the MS spectra of the reaction mixture after silylation with BSTFA+TMCS. Table 1 shows the products characterized in the reaction of AMO and CEF with ClO2. A likely reaction mechanism compatible with all the available data is indicated in Scheme 4. In both cases, the reaction starts by single-electron transfer from the lone electron pair of the amino group to ClO2, forming the corresponding radical cation and chlorite. This aminyl radical

3.3.

Influence of ClO2 pre-treatment on THM formation

One of the main advantages of the use of ClO2 as a disinfectant agent in water treatment is the reduction of THM content with respect to conventional treatments based on the extensive use of chlorine (Rav-Acha, 1998). Therefore, it is of interest to determine whether pre-treatment of the three antibiotics under study with ClO2 results in a reduction of THM formation. Considering our previous product determination upon reaction of antibiotics with ClO2 we want to correlate the reactivity of ClO2 with antibiotics to any variation in THM content. In order to analyse the influence of ClO2 pre-treatment on THM formation, aqueous solutions of the antibiotics in MilliQ water at pH 8 and at 1 or 2 ppm concentration were prepared and treated with different doses of ClO2. After disappearance of ClO2, the samples were chlorinated and THM formation after 24 h at 20 1C was measured. The results obtained are summarized in Table 2. We observed that the addition of ClO2 at pH 8 in various doses does not influence THM formation when PEN is treated with chlorine. This result is consistent with the lack of ClO2 reaction with PEN at pH 8 commented above. By contrast, both AMO and CEF reduce THM formation if they are previously treated with ClO2 at pH 8. The higher the dose of ClO2, the higher the reduction percentage of THM. This reduction in THM formation after ClO2 treatment was observed at the two concentrations of antibiotics under study, indicating that THM reduction by ClO2 pre-treatment is a general phenomenon. Also remarkable is the fact that THM formation strongly depends on the nature of the antibiotic. AMO and CEF having a phenolic substructure are the antibiotics giving the highest THM content. On the other hand, PEN, unreactive with ClO2, is also highly reluctant to form THMs. Furthermore, pre-treatment with ClO2 does not affect the THM value of PEN-containing waters.

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NH2

H N

ClO 2-

ClO2

S

NH 2 H N

Q O

HO

S Q

N O

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42 (2008) 1935 – 1942

COOH

HO

O

N O

COOH

Radical cation NH H N

-H +

+ O2

S

Oxidized products (Table 1)

Q O

HO

N O

COOH

Aminyl radical Q AMO:

C(CH3)2

CEF:

CH2-C(CH3)2

Scheme 4 – Proposed mechanism for the reaction of AMO and CEF with ClO2. Table 2 – THM formation upon chlorination (10 ppm) at 20 1C of antibiotic synthetic water (TOC, 2 and 1 ppm) at pH ¼ 8 ClO2/antibiotic molar ratio reduction

THMs (ppb)

% THM

AMO (2 ppm TOC)

0 3 7.5 8

27.1 25.1 17.5 13.4

– 7.6 35.6 46.2

AMO (1 ppm TOC)

0 0.35 0.75 1 4 8

23.9 14.3 15.3 16.4 14.1 10

– 40 36 32 41 59

0 0.35 0.75 1 2 4 8

47 47.2 42.4 42.2 43.4 38.2 42.5

– 3.3 6.2 10.2 7.7 10.1 9.6

CEF (2 ppm TOC)

0 4 8

63.5 47.8 30.6

– 24.8 51.9

PEN (2 ppm TOC)

0 1 2 4 6 8

10.3 10.7 12 10.3 10.44 14.68

– 0 0 0 0 0

CEF (1 ppm TOC)

higher the decomposition of the initial antibiotic because as, we have demonstrated, they react stoichiometrically. Then, if after treatment with ClO2, chlorine is added the tendency to form THMs (measured in ppb) is significantly reduced simply because ClO2 has already reacted and degraded the most reactive part of the antibiotic. Worth noting is the fact that THM (ppb) corresponds only to a very small fraction of TOC (ppm). Thus, our study sheds light about the mechanism of action of ClO2 and why this disinfectant agent is effective in reducing the THM content of treated water in those cases in which ClO2 reacts.

4.

Conclusions

In the present work, we have shown that under conditions similar to those used for drinking water treatment (pH 8 and diluted concentrations): 1. ClO2 reacts stoichiometrically with AMO and CEF but not with PEN. 2. In the case of AMO and CEF, product isolation shows the formation of phenolic compounds in which the b-lactam ring has been degraded. 3. When chlorine is added after ClO2 treatment, a reduction in THM value is observed in those cases in which ClO2 reacts. 4. Overall, the above results are relevant in the understanding of how ClO2 reacts with drugs that are emerging water pollutants. 5. This work raises the question about how the by-products resulting from antibiotics may affect consumers and microorganism resistance to antibiotics.

Contact time 3 h for ClO2 and 24 h for ClO.

Acknowledgements The previous results about THM formation can be explained by the fact that ClO2 reacts with the original molecule giving rise to decomposition products. The higher the ClO2 dose, the

Financial support by the Spanish DGI (Project CTQ06,0658) is gratefully acknowledged. S.N. also thanks the Technical University of Valencia for a contract (Programa Cantera).

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Appendix A.

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Supplementary materials

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.watres.2007.11.023

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