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Selective Transformation of #-Lactam Antibiotics by Peroxymonosulfate: Reaction Kinetics and Non-Radical Mechanism Jiabin Chen, Cong Fang, Wenjun Xia, Tianyin Huang, and Ching-Hua Huang Environ. Sci. Technol., Just Accepted Manuscript • Publication Date (Web): 02 Jan 2018 Downloaded from http://pubs.acs.org on January 2, 2018

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Environmental Science & Technology

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Selective Transformation of β-Lactam Antibiotics by

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Peroxymonosulfate: Reaction Kinetics and Non-Radical Mechanism

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Jiabin Chen1, Cong Fang1, Wenjun Xia1, Tianyin Huang1,*, Ching-Hua Huang2,*

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1

School of Environmental Science and Engineering, Suzhou University of Science

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and Technology, Suzhou 215001, P. R. China 2

School of Civil and Environmental Engineering, Georgia Institute of Technology,

8

Atlanta, Georgia 30332, United States

9 10

*

Corresponding Authors Phone: 404-894-7694; Fax: 404-358-7087;

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E-mail: [email protected] (Ching-Hua Huang).

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Phone: +86 0512 68096895; Fax: +86 0512 68096895.

13

Email: [email protected] (Tianyin Huang).

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Manuscript submitted to

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October 30, 2017

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(Manuscript word count: 5495 + 1500)

19 20 21 22 1

ACS Paragon Plus Environment


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ABSTRACT

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While the β-lactam antibiotics are known to be susceptible to oxidative degradation by

25

sulfate radical (SO4·-), here we report that peroxymonosulfate (PMS) exhibits specific high

26

reactivity towards β-lactam antibiotics without SO4·- generation for the first time. Apparent

27

second-order reaction constants (k2, app) were determined for the reaction of PMS with three

28

penicillins, five cephalosporins, two carbapenems, and several structurally-related chemicals.

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The pH-dependency of k2, app could be well modeled based on species-specific reactions. On

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the basis of reaction kinetics, stoichiometry and structure-activity assessment, the thioether

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sulfur, on the six- or five-membered rings (penicillins and cephalosporins) and the side chain

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(carbapenems), was the main reaction site for PMS oxidation. Cephalosporins were more

33

reactive towards PMS than penicillins and carbapenems, and the presence of phenylglycine

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side chain significantly enhanced cephalosporins’ reactivity towards PMS. Product analysis

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indicated oxidation of β-lactam antibiotics to two stereoisomeric sulfoxides. A radical

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scavenging study and electron paramagnetic resonance (EPR) technique confirmed lack of

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involvement of radical species (e.g., SO4·-). Thus, the PMS-induced oxidation of β-lactam

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antibiotics was proposed to proceed through a non-radical mechanism involving direct

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two-electron transfer along with the heterolytic cleavage of the PMS peroxide bond. The new

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findings of this study are important for elimination of β-lactam antibiotic contamination,

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because PMS exhibits specific high reactivity and suffers less interference from the water

42

matrix than the radical process.

43 44 2


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INTRODUCTION

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Persulfates (PS), including peroxymonosulfate (HSO5-, PMS) and peroxydisulfate

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(S2O82-, PDS), have been increasingly considered as alternative oxidants for water treatment

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and soil remediation.1, 2 They are relatively stable and strong oxidants (E0 = 1.96 V for PDS,

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and 1.75 V for PMS),3 and the cleavage of their peroxide bonds can generate more reactive

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radical species, i.e., sulfate radical (SO4·-).4 SO4·- is a strong oxidant with a high redox

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potential (2.5-3.1 V) and thus can efficiently destruct a wide range of refractory organic

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contaminants.5 Various strategies have been developed to activate PS for SO4·- generation. For

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example, heating6, 7 and UV irradiation8, 9 can induce the homolytic cleavage of peroxide bond

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in PS via intramolecular electron transfer. Transition metal ions activate PS to generate SO4·-

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through intermolecular electron transfer.10, 11 All these activation strategies require external

56

energy or intensive chemical consumption.

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Some organic compounds are considered as potential activators for PS. Ahmad et al.

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reported that soil organic matter (SOM) significantly activated PDS at basic pH, with

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phenoxide moieties as the potential activator.12 Phenoxide was subsequently confirmed to

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activate PDS to generate SO4·- via reduction.13 Organic quinones14 and some other phenolic

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compounds 15 were regarded as potential activators for PDS to produce SO4·-. They were also

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effective to activate PMS but via a non-radical mechanism.16, 17 Indeed, some recent studies

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have shown that PS could accept electrons from contaminants with the help of electron

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mediator without SO4·- formation. Copper oxide (CuO),18 surface loaded-noble metal

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nanoparticles (e.g., Pd),4 and carbonaceous materials (e.g., carbon nanotubes and graphitized

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nanodiamonds)3 were reported as effective electron shuttles for PMS activation to avoid the 3



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generation of non-selective reactive radicals. This non-radical approach exhibited a lower

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oxidation potential but higher selectivity towards contaminants, thus providing a promising

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way for contaminant removal in the water treatment.18 In fact, the direct electron transfer from

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contaminants, e.g., cationic dyes, to PS was possible, even without the electron shuttles.19

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Such direct oxidation by PS could maximize the utilization efficiency of PS, and also

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minimize the adverse impact of water matrix.1 In this work, PMS was also found to

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effectively oxidize β-lactam antibiotics without electron mediator, catalyst or external energy.

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The β-lactam antibiotics are among the most frequently used antibiotics worldwide,

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accounting for 50-70% of the global antibiotic use.20 The high consumption inevitably leads

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to discharge of these antibiotics into the environment, thus becoming a worldwide concern.

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Indeed, several commonly used β-lactam antibiotics, e.g., cefalexin (CFX) and amoxicillin

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(AMX), have been frequently detected in wastewater,21 surface water,22 and coastal water at

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the concentrations of ng/L - µg/L.23, 24 Bacterial resistance to β-lactam antibiotics has been

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observed in the environment, which poses potential threats to living organism and human

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health.25 Various techniques have been explored to eliminate β-lactam antibiotics, including

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membrane separation,26 activated carbon adsorption,27 photo-degradation,28 and biological

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degradation.29,

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degradation owing to the presence of some electron-rich moieties, e.g., primary amine and

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thioether sulfur.31 Indeed, certain β-lactam antibiotics showed considerable reactivity with

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various oxidants, e.g., KMnO4,32 ClO2,33 ferrate (VI),34 ozone,35 and peracetic acid.36 SO4·-

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generated from UV/PDS was very reactive towards β-lactam antibiotics.37 However, the

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non-selective SO4·- was potentially scavenged by the water matrices (e.g., Cl- and HCO3-),

30

The β-lactam antibiotics are expected to be susceptible to oxidative

4


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thus generating some unexpected by-products (e.g., chlorinated (or brominated) products),38

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and reducing the efficiency of SO4·-. Note that SO4·- for β-lactam antibiotic destruction was

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primarily generated from the activated PDS (e.g., UV/PDS) in the previous studies, the

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reactivity of PMS towards β-lactam antibiotics has always been ignored. As will be discussed

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later, we discovered that PMS exhibited specific and high reactivity towards β-lactam

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antibiotics without SO4·- generation, which was almost unaffected by the water matrices, and

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thus showed high efficiency to eliminate β-lactam antibiotics in real water samples.

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This work examined a wide range of β-lactam antibiotics, including three penicillins

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[penicillin G (PG), ampicillin (AMP), and AMX], five cephalosporins [cefapirin (CFP),

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cephalothin (CFL), cefradine (CFD), cefotaxime (CFT), and CFX] and two carbapenems

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[meropenem (MPN) and imipenem (IPN)], and several structurally related substructure

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chemicals [6-aminopenicillanic acid (6-APA), 7-aminocephalosporanic acid (7-ACA),

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4-pyridineacetic

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2-(2-Aminothiazole-4-yl)-2-methoxyiminoacetic acid (ATMAA), 2-thiopheneacetic acid, and

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phenylglycine] (structures shown in Figure 1) to obtain a fundamental understanding of the

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reactivity of β-lactam antibiotics towards PMS. Based on the reaction kinetics, reaction

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stoichiometry, product identification, and structure-activity assessment, a two-electron

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transfer reaction pathway that has not been discovered before for β-lactam antibiotics towards

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PMS was proposed.

acid

(PTA),

3-methylcrotonic

acid

(3-MCA),

108 109 110

MATERIALS AND METHODS Chemicals. Sources of chemicals are provided in the Supporting Information (SI) Text 5



111

S1.

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Real Water Samples. Surface water (SW) from a river, groundwater (GW) from a

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drinking water well, and wastewater (WW) from the effluent of a municipal wastewater

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treatment plant were collected at locations in the southeast region of China. Samples were

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filtered through 0.45-µm glass fiber filters immediately upon arrival in the laboratory and

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stored at 5 °C before use. The characteristics of these water samples are shown in Table S1.

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Experimental Procedures. Batch reactions were conducted in 100-mL amber glass

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bottles wrapped with aluminum foil to prevent light. The solution was constantly mixed by

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magnetic stirring at room temperature (25 °C). Reaction pH was controlled by 10 mM

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phosphate buffer for all the experiments, and phosphate ions at 10 mM had no effect on

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PMS-induced oxidation of β-lactam antibiotics. Reaction was initiated by adding PMS

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(0.2-1.2 mM) to the solution containing 40 µM of β-lactam antibiotics at pH 7.0. Cl- (1-500

123

mM), HCO3- (1-50 mM), or humic acid (HA, 1-50 mg/L) was added into the above reaction

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systems to evaluate their impact on PMS-induced oxidation. For the pH impact, the reaction

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solution was controlled at pH 5.0-10.0 with phosphate buffer. The quenching agent (methanol

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(MeOH, 1000 mM), tert-butyl alcohol (TBA, 1000 mM), and furfuryl alcohol (FFA, 10 mM))

127

was added to investigate the mechanism. DI water was used in all the above experiments.

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Sample aliquots were taken at the predetermined time intervals, immediately quenched by

129

excess Na2S2O3. The quenched samples were filtered through 0.45 µm membrane

130

(GVWP01300, Millipore), stored in 2 mL amber vials at 5 °C, and analyzed within 24 h. The

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same experimental procedure was conducted in evaluating PMS-induced oxidation of CFX in

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real water matrices at pH 7.0. 6


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For comparison, the conventional radical processes, such as Co(II)/PMS and Ag(I)/PDS

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were also evaluated to degrade β-lactam antibiotics. Co(II) and Ag(I) are regarded as the most

135

efficient metal activators for PMS and PDS, respectively, to generate SO4·-.10 40 µM of Co(II)

136

was added into the DI water containing CFX (40 µM) and phosphate buffer (10 mM, pH 7.0),

137

and then PMS was added to initiate the reaction. For Ag(I)/PDS, the reaction was controlled

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at pH 3.0 with phosphate buffer owing to the solubility limitation of Ag(I) at neutral pH

139

condition. The experimental procedure was similar to that in PMS-induced oxidation. All the

140

experiments were conducted in duplicate or more.

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Analytical Methods. A high performance liquid chromatography (HPLC, 1260, Agilent

142

Technology, USA) equipped with a Zorbax SB-C18 column (4.6 × 250 mm, 5 µm), and a UV

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detector was used to monitor the concentration of β-lactam antibiotics. The mobile phase and

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detection wavelengths are detailed in Table S2. The HPLC system (Utimate 3000, Dionex,

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USA) was connected to a triple quadrupole mass spectrometry (TSQ Quantum Ultra EMR,

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Thermo Fisher Scientific, USA) to analyze the transformation products. The chromatographic

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and MS conditions are provided in Text S2. The EMX-8/2.7 spectrometer (BRUKER,

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Germany) was used to analyze the electron paramagnetic resonance (EPR) spectra, with the

149

detailed conditions described in Text S3. A UV/Vis spectrophotometer (UV-1600PC,

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Shanghai mapada Instruments Co., Ltd., China) was used to quantify PMS with the method

151

proposed by Liang et al.39 as detailed in Text S4.

152 153 154

RESULTS AND DISCUSSION PMS-Induced Rapid Degradation. Previous studies showed that the activated PS 7



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process was efficient to destruct contaminants by the generated SO4·-.10 Our experiments

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showed that PMS alone induced rapid degradation of β-lactam antibiotics without external

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energy or catalyst. As Figure 2A shows, CFX ([CFX]0 = 40 µM) was completely degraded

158

after 3 min at pH 7.0 by PMS alone ([PMS]0 = 400 µM), a much faster degradation than that

159

by the conventional radical process, such as the PDS/Ag(I) or PMS/Co(II) systems ([PMS]0 =

160

[metal ion] = 400 µM). On the other hand, the decomposition of PMS in the reaction

161

involving only CFX and PMS was much slower than that in the radical process of PMS/Co(II)

162

(Figure S1), indicating high efficiency of PMS-induced oxidation of CFX than the radical

163

process. Moreover, while PMS alone showed high reactivity towards CFX, it was inert for the

164

degradation of anisole, which was frequently used as a probe for SO4·- and HO· (kHO· = 5.4 ×

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109 M-1.s-1, kSO4-· = 4.9 × 109 M-1.s-1)40, 41 (data not shown). Hence, PMS exhibited a specific

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reactivity towards CFX, likely via a different mechanism from radical-induced oxidation.

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The effect of PMS concentration on CFX degradation was evaluated at pH 7.0. The

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degradation of CFX followed first-order kinetics at different initial concentrations of PMS

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(Figure S2A). The pseudo-first-order rate constant (kobs in equation (1)) increased as the

170

PMS/CFX ratio was increased from 5 to 30. Plot of log (kobs) vs log (CPMS) exhibited a linear

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relationship with the slope close to unity (Figure S2B). Hence kobs was first-order with respect

172

to PMS concentration. Apparent second-order rate constants (k2,app in equation (2)) were then

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obtained to be 71.7 ± (3.76) M-1.s-1 by dividing kobs by the concentration of PMS.

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−

[]

= k ∙ [CFX]

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−

[]

= k , ∙ [CFX] ∙ [PMS]

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(1) (2)

We further investigated the effect of common water matrix (e.g., Cl-, HCO3- and HA) on 8


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PMS-induced CFX degradation (Figure S3). The addition of HCO3- or HA showed negligible

178

effect on CFX degradation, while the presence of Cl- exhibited a slight promoting effect,

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which increased with increasing concentration of Cl-. Cl- was supposed to react with PMS to

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generate oxidative species, e.g., HClO, thus promoting the contaminant degradation.42 The

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PMS-induced CFX degradation was further evaluated in real water matrices, e.g., SW, GW,

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and WW samples. Results showed that the rapid degradation of CFX could be observed in the

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real water samples (Figure S4). Compared to the DI water, PMS-induced degradation of CFX

184

was only slightly affected in SW, GW, and WW matrices. Therefore, PMS is highly selective

185

to oxidize CFX, thus a promising technology to remove CFX in real water matrices.

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pH Impact. The impact of pH was examined for PMS-induced oxidation of CFX at pH

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5.0-10.0. Generally, k2,app-CFX slightly decreased with increasing pH from 5.0 to 8.0, and

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sharply decreased as pH was further increased to 9.0 and above (Figure 2B). CFX has two

189

pKa values at 2.56 and 6.88, corresponding to the carboxyl group on the dihydrothiazine ring

190

and the primary amine group on the phenylglycine side chain, respectively.28 PMS also

191

possesses two pKa values (pKa1 < 0, pKa2 = 9.4).8, 43 The speciation of PMS or CFX is strongly

192

influenced by solution pH (CFX ⇌ CFX + H , pKa2, CFX = 6.88; HSO ⇌ H + SO , pKa2,

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PMS

194

reactivity. For example, protonated phenylglycine primary amine in CFX always shows

195

negligible reactivity towards oxidants, such as Cu(II)44 and ferrate(VI);34 while SO52- is less

196

reactive than HSO5-.19 Hence, the species-specific reactions between CFX and PMS species

197

were thus used to account for the pH-dependent variation of k2, app-CFX. The PMS-induced

198

oxidation of CFX could be expressed as follows:

= 9.4; Figure S5A) Note that different species of CFX and PMS might exhibit different

9



−

d["#$] % = k , ∙ [CFX] % ∙ [PMS] % d&

*,+

= ' k (,) ∙ α( ∙ β) . ["#$] % ∙ [PMS] % (3) (,)

199

where [CFX]T and [PMS]T represent the total concentration of CFX and PMS, respectively;

200

ki,j is the species-specific second-order rate constant for the reaction between species i of CFX

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and species j of PMS; and αi and βj represent the equilibrium distribution coefficients of CFX

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and PMS species, respectively. The species-specific second-order rate constants (ki,j) were

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determined by fitting the experimental data of k2,app-CFX to equation (4) with least-squares

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nonlinear regressions by the Origin software. *,+

k , = ' k (,) ∙ α( ∙ β) (4) (,)

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Note that the reaction between CFX0 and SO52- species was negligible owing to the

206

lower oxidation capacity of SO52- than HSO5-19 and the extremely low mole fractions of α1 ×

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β2, i.e., CFX0-SO52- species (Figure S5B); thus, this reaction was not considered when fitting

208

experimental data to the kinetic model. As Figure 2B shows, the experimental k2,app-CFX across

209

the pH range could be well explained by the kinetic modeling (R2 = 0.9789), with the

210

obtained species-specific rate constants (ki,j) summarized in Table S3. The contribution of the

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apparent species-specific reaction rate constants to the overall k2, app-CFX is also depicted in

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Figure 2B. The results showed that the contribution of SO52- species to the overall reaction

213

was insignificant at pH lower than 8.0. SO52- exhibited relatively low reactivity to CFX (kCFX--

214

SO 52-

215

SO52- than HSO5-.19, 45 Compared to CFX- species, CFX0 was more susceptible to HSO5-

216

oxidation (76.81 ± (1.91) M-1.s-1 (kCFX0-HSO5-) vs 69.44 ± (2.18) M-1.s-1 (kCFX--HSO5-)). This result

= 8.01 ± (3.25) M-1.s-1), which could be attributed to the lower oxidation capacity of

10


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was opposite to previous reports that CFX0 was unreactive to oxidants such as Cu(II).44 It was

218

thus implied that reaction site on CFX by PMS oxidation was likely different from that by

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Cu(II) oxidation, which will be further discussed in the following section. The different

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reactivity trend observed in this study might be explained by electrostatic interactions. Indeed,

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PMS (HSO5-) was previously reported to be effective for cationic dye degradation but inert to

222

anionic dye oxidation owing to electrostatic repulsion.19 In analogy, PMS (HSO5-) could get

223

close to the neutral CFX0 more easily than to the negatively-charged CFX-; thus, PMS

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exhibited higher reactivity to CFX0. For PMS-induced oxidation of AMP and PG, the

225

pH-dependent k2,

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species-specific reactions (Text S5, Figures S6 and S7).

app

could also be well explained by the kinetic modeling based on

227

Structure-Dependent Degradation. The PMS-induced degradation was further

228

investigated for many β-lactam antibiotics, including cephalosporins, penicillins, and

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carbapenems, at pH 7.0. For all the selected compounds, the PMS-induced degradation

230

followed pseudo-first-order kinetics. The linear relationship between log (kobs) and log (CPMS)

231

with the slope close to unity confirmed their second-order reaction (Figures S8-S10), with the

232

obtained k2,app summarized in Figure 3. Generally, these k2,app values ranged from 2.0 to 71.7

233

M-1.s-1, which were comparable to k2,app of β-lactam antibiotics with peracetic acid

234

(15.56-44.38 M-1.s-1),36 but were smaller than those for their reaction with ferrate(VI)

235

(110-770 M-1.s-1),34 ozone (103-106 M-1.s-1),46 and radical species such as SO4·- and HO· (109

236

M-1.s-1).47

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As an oxidant, PMS is expected to attack the atoms/moiety with available electrons. The

238

thioether sulfur in the six- or five-membered ring, and the double bond in the six-membered 11



239

dihydrothiazine ring are electron-rich and thus are regarded as potential reactive sites for

240

various oxidants such as SO4·-,47 O3,35 and MnO4-.32 If present, the phenylglycine primary

241

amine on the side chain is also electron-rich, reactive towards oxidants such as Cu(II)44 and

242

ferrate(VI).34 We thus hypothesized that the above three moieties were potential reactive sites

243

for PMS oxidation. To assess whether the double bond on the six-membered ring of

244

cephalosporins was a reactive site to PMS, we investigated the reactivity of the substructure

245

compound 3-MCA towards PMS. The finding that PMS could not induce degradation of

246

3-MCA (Figure 3A) suggested that the double bond on the six-membered dihydrothiazine

247

ring was not reactive to PMS. The study to assess the reactivities of phenylglycine primary

248

amine and thioether sulfur are discussed below.

249

Phenylglycine primary amine moiety. As Figure 3B shows, the phenylglycine-type

250

cephalosporins were more susceptible to oxidation by PMS than their non-phenylglycine-type

251

counter parts (e.g., CFX/CFD vs CFL/CFT), suggesting that the phenylglycine side chain

252

might be a reactive site for PMS. However, the reactivity of penicillins towards PMS seems to

253

be not affected by the presence of phenylglycine side chain (e.g., AMP/AMX vs PG). In

254

addition, when phenylglycine was tested for its reactivity towards PMS, degradation of

255

phenylglycine was negligible after 1 h (Figure 3A), indicating very low reactivity towards

256

PMS. The above results together indicated that the phenylglycine moiety was not a reaction

257

site for PMS, but may affect the PMS-induced oxidation of cephalosporins through altering

258

molecular electron distribution. According to the density functional theory (DFT) calculation,

259

the highest occupied molecular orbital (HOMO), characteristic of compound nucleophilicity,

260

is located at the six-membered dihydrothiazine ring for cephalosporins and the 12


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five-membered thiazolidine ring for penicillins.36 The presence of phenylglycine moiety

262

increases the HOMO energy, and thus nucleophilicity at the six-membered ring of

263

cephalosporins.36 This could be the reason why the phenylglycine-type cephalosporins

264

showed higher reactivity towards PMS than the non phenylglycine-type cephalosporins,

265

similar to the reactivity trend of cephalosporins toward peracetic acid. In the case of

266

penicillins, the presence of phenylglycine moiety increases the HOMO energy but also shifts

267

the HOMO location away from the 5-membered thiazolidine ring, thus an overall less impact

268

of the phyenylglycine group on the compound reactivity was observed.36

269

In addition to phenylglycine, we also investigated the reactivity of PTA, ATMAA and

270

2-thiopheneacetic acid, substructure of CFP, CFT and CFL, respectively, towards PMS.

271

ATMAA and 2-thiopheneacetic acid were found to be inert towards PMS (Figure 3A). Hence,

272

CFT and CFL exhibited comparable reactivity towards PMS, and the reactive site was located

273

on the six-membered dihydrothiazine ring. PTA exhibited considerable reactivity towards

274

PMS, with k2,app = 6.8 ± (0.62) M-1.s-1. Hence, PTA significantly contributed to the higher

275

reactivity of CFP towards PMS than other non-phenylglycine cephalosporins.

276

Thioether sulfur. The thioether sulfur on the β-lactams’ five- or six-membered ring is

277

known to be susceptible to electrophilic attack by various oxidants.31 Thus, the thioether

278

sulfur on the ring was most likely the main reaction site for PMS. The thioether sulfur on the

279

six-membered dihydrothiazine ring showed higher reactivity towards PMS than that on the

280

five-membered thiazolidine ring (e.g., 6-APA vs 7-ACA). This difference could be explained

281

by the steric hindrance present in the latter. On the five-membered thiazolidine ring, the two

282

methyl groups adjacent to thioether might hinder the attack of oxidant on the thioether sulfur, 13



283

thus contributing to the observed lower reactivity to PMS.34

284

Compared to penicillins and cephalosporins, the transformation of carbapenems has been

285

largely overlooked before. Although the thioether sulfur is not present on the five-membered

286

ring of carbapenems (i.e., MPN and IPN), PMS-induced rapid degradation was still observed

287

(Figure 3B), probably due to the thioether sulfur present in the side chain of carbapenems.

288

This hypothesis was supported by the considerable reactivity of PTA towards PMS. Note that

289

MPN reacted with PMS at 9.5 times as fast as IPN. Since the structural difference of MPN

290

and IPN only lies in the neighboring moiety linked to the side-chain thioether sulfur, the

291

side-chain thioether sulfur is important for carbapenems’ reactivity towards PMS and the

292

impact of the neighboring moiety to the side-chain thioether sulfur will be further elucidated

293

in a later section.

294

Reaction stoichiometry. Reaction stoichiometry could be determined from reaction ratio

295

between PMS and β-lactam antibiotics, because their oxidation products were not reactive

296

towards PMS (see the following section about transformation products). Decomposition of

297

PMS was monitored along with the degradation of β-lactam antibiotics. As Figure S11 shows,

298

near 10% of initial PMS was decomposed after the complete degradation of penicillins and

299

cephalosporins, except for CFP. Note that the initial concentration of PMS was 10 times

300

higher than that of β-lactam antibiotics and thus the reaction stoichiometry between PMS and

301

antibiotics was around 1:1. This result implied that only one reaction site was present on

302

β-lactam antibiotics for PMS oxidation, most likely the thioether sulfur on the six

303

(five)-membered rings. For CFP, the deviation of 1:1 reaction stoichiometry suggests that an

304

additional reaction site was present, most probably the thioether sulfur on the side chain. For 14


Page 14 of 35

Page 15 of 35


305

carbapenems, however, the decomposition loss of PMS was around 20% and thus the reaction

306

stoichiometry between PMS and carbapenems was close to 2:1. This result implied that two

307

reaction sites were likely present on the carbapenem antibiotics.

308

Overall, the thioether sulfur, on the six- or five-membered rings and the side chain, was

309

the reaction site for PMS. The thioether sulfur on the six-membered dihydrothiazine ring

310

exhibited higher reactivity than that on the five-membered thiazolidine ring. Although the

311

phenylglyicine primary amine was not a direct reaction site, it could significantly enhance the

312

reactivity of the thioether sulfur on the six-membered dihydrothiazine ring towards PMS.

313

Transformation products. To facilitate discerning the reaction mechanism, the

314

transformation products of β-lactam antibiotics by PMS were analyzed by LC/MS/MS. The

315

primary products were with molecular weight (MW) of M+16 and M+32 (M: MW of the

316

parent β-lactam antibiotic) (Table S4). For most cephalosporin antibiotics except CFP, only

317

two MW 363 (M+16) products were observed. The 363a and 363b product might be isomers

318

because they had different LC retention times but the same MW and MS fragment patterns.

319

Previous study has reported two MW 363 products for ferrate(VI) oxidation of CFX to be the

320

stereoisomeric CFX-(R)-sulfoxide and CFX-(S)-sulfoxide.34 We subsequently analyzed the

321

oxidation products of CFX by ferrate(VI) using the analytical methods in this study and found

322

that the stereoisomeric CFX-sulfoxides generated by ferrate(VI) oxidation matched with the

323

363a and 363b products in LC retention time and MS spectra. This evidence verified 363a and

324

363b as the CFX-sulfoxides, with the thioether sulfur on the six-membered dihydrothiazine

325

ring oxidized by PMS (Figure 4). Compared to PMS-induced oxidation of CFX, much more

326

oxidation products were previously reported in the oxidation of CFX by SO4·-, including 15



327

oxidation of amine and thioether, hydroxylation of benzene and double bond, and β-lactam

328

ring opening of CFX.37

329

Different from the other cephalosporin antibiotics, oxidation of CFP by PMS yielded

330

three M+16 products and one M+32 product. Among the M+16 products, two products might

331

be the stereoisomeric sulfoxides of CFP from oxidation of the thioether sulfur on the

332

six-membered ring, and the other one likely from oxidation of the PTA side chain thioether

333

sulfur by PMS. For the M+32 product, both thioether sulfurs, on the six-membered ring and

334

the PTA side chain, were oxidized to the sulfoxides (Text S6, Figure S12 and S13).

335

For the PMS-induced oxidation of penicillin antibiotics, i.e., PG, AMP and AMX, two

336

M+16 products were also the only identified oxidation products. Similarly, they were

337

confirmed to be the corresponding sulfoxide products by matching their retention times and

338

MS spectra with those observed in the ferrate(VI)-induced oxidation.

339

Oxidation of the carbapenem antibiotic MPN by PMS yielded two M+16 products and

340

two M+32 products. Both pairs were likely the isomers because of the same MS fragments

341

but different retention times. Similar to MPN, the M+16 products also exhibited the MS

342

fragments of m/z 141 and 114, which were characteristics of the pyrrolidine side chain fused

343

to thioether sulfur and the β-lactam ring, respectively (Figure 4, Figure S14A and S14B). It

344

was thus suggested that the M+16 products possess intact pyrrolidine side chain and β-lactam

345

ring, and the reactive sites on MPN for PMS might be the thioether sulfur and the double

346

bond of the dihydropyrrole ring. However, since 3-MCA showed no reactivity towards PMS

347

(Figure 3A), the double bond on the dihydropyrrole ring was unlikely a reactive site for PMS.

348

Thus, the thioether sulfur on MPN was oxidized by PMS, generating the M+16 stereoisomeric 16


Page 16 of 35

Page 17 of 35


349

sulfoxide products. The M+32 products were previously proposed as the sulfone products for

350

oxidation of penicillins or cephalosporins.34 If the sulfone products of MPN were generated,

351

the fragments of m/z 68 and 141, representative of the intact pyrrolidine side chain, were

352

expected in the MS spectra of M+32 products. However, m/z 84 and 157 fragments were

353

observed instead from the M+32 products (Figure S14C). The occurrence of m/z 84 and 157

354

implied hydroxylation of the side chain pyrrolidine ring, that is, 84 = 68 + 16 and 157 = 141 +

355

16. All the above evidence suggested the thioether sulfur of MPN was susceptible to oxidation

356

by PMS to generate stereoisomeric sulfoxides, but without further oxidation to sulfone

357

products. The much higher intensity of the sulfoxide products than that of the M+32 products

358

(Figure S15) also indicated that the thioether sulfur was the main reactive site on MPN for

359

PMS.

360

Proposed mechanism. The conventional PS activation process always relies on SO4·-

361

generation for contaminant degradation. SO4·- exhibits high reactivity towards β-lactam

362

antibiotics (up to 109 M-1.s-1)47 to generate diverse products.48 In this work, PMS-induced

363

oxidation of β-lactam antibiotics primarily generated the M+16 products, quite different from

364

the SO4·--induced oxidation.37 Moreover, the reaction stoichiometry of PMS with penicillins

365

and most cephalosporins (except CFP) was around 1:1, contrary to the fact that SO4·- reacts

366

non-selectively with the antibiotics as well as coexisting solutes or even water molecules. All

367

the experimental evidence indicated that SO4·- was not involved in the oxidation of β-lactam

368

antibiotics by PMS. This hypothesis was further verified by the radical scavenging study and

369

EPR technique. Specifically, the PMS-induced oxidation of CFX was not affected after

370

addition of excess radical scavengers, i.e., MeOH and TBA (Figure S16). Moreover, EPR 17



371

analysis unambiguously demonstrated that SO4·- and HO· were not generated (Figure S17).

372

Thus, the PMS induced-oxidation of β-lactam antibiotics underwent via the non-radical

373

process rather than radical process. In the real water samples, such as WW, water matrix

374

could not activate PMS to generate radicals, on the basis that PMS decomposition was

375

negligible by water matrix alone, and both CFX degradation and PMS decomposition were

376

not affected by excess MeOH (Figure S18). Hence, the oxidation of CFX by PMS was still

377

via the non-radical process in real water matrix. Previous study reported that 1O2 likely acted

378

as the reactive species in the non-radical activation of PMS by BQ.17 However, addition of

379

FFA, an efficient 1O2 scavenger, did not influence the PMS-induced degradation of CFX

380

(Figure S16); thus, the involvement of 1O2 was excluded (Text S7).

381

The non-radical process might proceed through two-electron transfer (i.e., oxygen atom

382

transfer), which involves the heterolytic breakage of the peroxide bond in PMS and an oxygen

383

atom transfer from PMS to nucleophiles (Nu) (Scheme A in Figure 5).1, 49 The two-electron

384

transfer mechanism was verified by the 1:1 reaction stoichiometry between the thioether

385

sulfur and PMS. The oxidation of alkyl sulfides by PMS was previously assumed to proceed

386

via the attack of peroxide on the sulfur atom to form an intermediate, and the subsequent

387

rate-limiting heterolysis (and rearrangement) of the intermediate to form the sulfoxide.50

388

Similarly, a plausible mechanism for the oxidation of β-lactam antibiotics by PMS likely

389

underwent via the electrophilic attack of the peroxide on the thioether sulfur to generate an

390

intermediate, which was further decomposed to sulfoxide products by the rate-limiting

391

heterolysis and rearrangement (Scheme B in Figure 5). This reaction mechanism only

392

involves two electron transfer from the thioether sulfur to peroxide bond without formation of 18


Page 18 of 35

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393

radical species. Compared to the typical radical process, all of the oxidation capacity of PMS

394

was utilized in this non-radical process, rendering this technique cost-effective and highly

395

efficient for the oxidation of β-lactam antibiotics.

396

In fact, the above mechanism involving heterolysis and rearrangement was primarily

397

proposed for the mono-substituted peroxide, e.g., PMS.49 Unlike PMS, the rearrangement of

398

the intermediate between PDS and thioether sulfur was not likely to occur owing to the lack

399

of proton in PDS molecule. Hence, PDS exhibited low reactivity towards the thioether sulfur

400

in β-lactam antibiotics (Figure 2A). In this work, the sulfoxide products of β-lactam

401

antibiotics were the end products by PMS oxidation without further oxidation to a sulfone

402

product, quite different from the previous studies that the sulfoxide product (DMSO) of

403

dimethyl sulfide (DMS) was further oxidized to the corresponding sulfone product

404

(DMSO2).50 Compared to the simple DMSO molecule, it might be difficult for the second

405

PMS molecule to approach the sulfoxide sulfur on the strained five (or six)-membered ring

406

owing to the steric hindrance effect. Consequently, the stoichiometry reaction between the

407

thioether sulfur and PMS was around 1:1, and the PMS decomposition was almost ceased

408

after complete conversion of thioether sulfur to sulfoxide.

409

The reactivity of reduced sulfurs towards PMS was positively related to their electron

410

density, e.g., DES (DMS) < H2S < HS-.50 The fusion of β-lactam ring with the five (or

411

six)-membered ring made the molecule structure more strained, thus resulting in

412

non-planarity of the molecule with large angle and torsional rotation.31 As a result, more

413

electron density of the thioether sulfur on the ring is exposed outside, thus exhibiting high

414

reactivity towards oxidants, e.g., PMS. This hypothesis was verified by the larger k2, app for 19



415

penicillins and cephalosporins than those for carbapenem antibiotics or alkyl sulfides.50

416

Although the thioether sulfur is located at the side chain of MPN rather than on the ring, its

417

linkage with two five-membered rings makes the electron density more exposed to the

418

electrophilic attack, rendering the thioether sulfur on MPN more reactive towards PMS than

419

that on IPN.

420

Environmental Significance. To our best knowledge, this is the first study to report the

421

high reactivity and fast reaction of β-lactam antibiotics with PMS not relying on SO4·-

422

generation, highlighting a new and facile strategy for alleviating β-lactam antibiotic

423

contamination. Compared to the conventional PMS activation with SO4·- generation,

424

PMS-induced degradation exhibits low cost because no external energy or catalyst is required,

425

and high efficiency because of complete utilization of the oxidation capacity of PMS. In

426

contrast to the non-selective reactivity of SO4·-, PMS shows specific high reactivity towards

427

the thioether sulfur on β-lactam antibiotics, which is almost unaffected by background ions

428

and natural organic matter in water matrices. Hence, PMS maintains remarkable treatment

429

efficiency for β-lactam antibiotics in complicated environmental matrices, e.g., wastewater.

430

The β-lactam ring is responsible for the antibacterial activity of β-lactam antibiotics,51

431

and hydrolytic cleavage of the β-lactam ring could eliminate antibacterial activity.52 However,

432

the hydrolysis of β-lactam antibiotics is dependent on compound structure, pH and

433

temperature.53 Compared to the rapid oxidation of β-lactam antibiotics by PMS, the

434

hydrolysis could be neglected at environmental conditions. Although photodegradation may

435

be the most important route to eliminate cephalosporins in surface waters (t1/2 up to hours),

436

their transformation products were found to be more toxic than the parent cephalosporins.28 20


Page 20 of 35

Page 21 of 35


437

Recently, various oxidants, such as ferrate(VI),34 ozone,54 chlorine,55 and advanced oxidation

438

processes56, 57 have been investigated for eliminating β-lactam antibiotics and their biological

439

activity. The remarkable reduction of antibacterial activity of β-lactam antibiotics was

440

observed after treatment by ferrate(VI)34 and ozone.54 However, photocatalytic transformation

441

products of AMX with UV/TiO2 still exhibited significant activity to Enterococcus faecalis

442

(ATCC 14506), 57 and the oxidation of AMX by a photo-Fenton process (Fe2+/H2O2/stimulated

443

solar light) generated even more toxic products than AMX based on Daphnia magna

444

biossays.56 Free available chlorine (FAC) is among the most frequently utilized disinfectants,

445

but the oxidation of β-lactam antibiotics, e.g., cefazolin, by chlorine generated chlorinated

446

products, which might possess high genotoxicity.55 The rapid oxidation of β-lactam antibiotics

447

by PMS generated the stereoisomeric sulfoxide products, which were reported to exhibit

448

significantly lower antibacterial activity than the parent β-lactam antibiotics. For example,

449

PG-(R)-sulfoxide and CFX-(R)-sulfoxide were determined to be ∼15% and ∼83% as active

450

as PG and CFX, respectively, against B. subtilis ATTC 6051; while their corresponding

451

(S)-sulfoxides were found to possess less than 1% of their parent β-lactam antibiotics’

452

antibacterial activity.54 Therefore, PMS oxidation may effectively reduce the antibacterial

453

activity of β-lactam antibiotics, providing a promising way to rapidly eliminate β-lactam

454

antibiotics and significantly reduce their biological activity in water treatment.

455 456

ASSOCIATED CONTENT

457

Supporting Information.

458

Text S1-S7, Tables S1-S4 and Figures S1-S18. This material is available free of charge via the 21



459

Internet at http://pubs.acs.org.

460 461

ACKNOWLEDGMENTS

462

We sincerely thank the National Natural Science Foundation of China (51509175), Science

463

and Technology Planning Project of Suzhou (SS201666, SS201722) for financially supporting

464

this work.

465 466

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Figure 1. Structures of β-lactam antibiotics and related compounds examined in this study. 6-APA:

6-aminopenicillanic

4-pyridineacetic

acid,

acid,

7-ACA:

3-MCA:

7-aminocephalosporanic

3-methylcrotonic

acid,

acid,

PTA:

ATMAA:

2-(2-Aminothiazole-4-yl)-2-methoxyiminoacetic acid. Note: 7-ACA and 6-APA are the core structure for penicillins and cephaloporins, respectively; PTA, ATMAA, 2-thiopheneacetic acid represent the substructure on the side chain of CFP, CFT and CFL, respectively; phenylglcine is the substructure of phenylglycine-type β-lactam antibiotics, including CFX, CFD, AMP, and AMX.

30


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(A)

1.0

PMS PDS PMS + 400 µM Co(II) PDS + 40 µM Ag(I) PDS + 200 µM Ag(I) PDS + 400 µM Ag(I)

0.8

C/C0

0.6 0.4 0.2 0.0 0

30

60

90

120

150

180

t (min)

(B)

80

Experimental k2,app Modeled k2,app

60

kCFX -HSO .αCFX .βHSO 0

0

-1

_

5

-1

k2,app, M .s

_

5

40

kCFX -HSO .αCFX .βHSO _

_

_

5

20

_

5

kCFX -SO .αCFX .βSO _

2-

_

5

2-

5

0 5

6

7

8

9

10

pH Figure 2. Comparison of PS with the metal-activated PS process for CFX degradation (A), and effect of pH and kinetic modeling for the reaction rate constants of CFX with PMS (B). [CFX] = 40 µM, [PS] = 400 µM, 10 mM phosphate buffer used to control pH at 7.0 for PS or PMS/Co(II) system, but at pH 3.0 for PDS/Ag(I) system. Error bars indicate standard deviations of triplicates.

31



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(A)

0 7-ACA 6-APA PTA phenylglycine 3-MCA ATMAA 2-thiopheneacetic acid

ln(C/C0)

-1 -2 -3 -4 -5 0

500

1000

1500 3500

3600

t (s)

cephalosporin

penicillin carbapenem substructure (B)

75

45

-1

-1

k2, app (M .s )

60

30

15

0 CFX CFD CFP CFL CFT

PG

AMX AMP MPN IPN 6-APA7-ACA PTA

Figure 3. Degradation of structurally related chemicals by PMS (A), and the apparent second-order rate constants for various β-lactam antibiotics (B). [β-lactam antibiotic] = 40 µM, [PMS] = 400 µM, pH 7.0 (10 mM phosphate buffer). Error bars indicate standard deviations of triplicates. Note: Thioether sulfur exists in all the investigated β-lactam antibiotics, and phenylglycine only presents in CFX, CFD, AMP and AMX.

32


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Figure 4. Transformation products of β-lactam antibiotics by PMS oxidation. Note: R1 and R3 represent the side chain of β-lactam in pencillins and cephalosporins, and R2 is the side chain fused to six-membered dihydrothiazine ring of cephalosporins.

33



Figure 5. Proposed mechanism of PMS-induced oxidation of β-lactam antibiotics with cephalosporin as a representative. Nu: nucleophiles.

34


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Selective Transformation of Î²-Lactam Antibiotics by ... - ACS Publications

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