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Here we employed ciprofloxacin (CIP, Figure 1), a widely prescribed fluoroquinolone antibiotic,(18, 19) as a model compound to test our basic hypothes...
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Distinct Photolytic Mechanisms and Products for Different Dissociation Species of Ciprofloxacin Xiaoxuan Wei,† Jingwen Chen,†,* Qing Xie,† Siyu Zhang,†,‡ Linke Ge,†,§ and Xianliang Qiao† †

Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, China ‡ State Key Joint Laboratory of Environment Simulation and Pollution Control, School of Environment, POPs Research Center, Tsinghua University, Beijing 100084, China § Key Laboratory for Ecological Environment in Coastal Areas (SOA), National Marine Environmental Monitoring Center, Dalian 116023, China S Supporting Information *

ABSTRACT: As many antibiotics are ionizable and may have different dissociation forms in the aquatic environment, we hypothesized that the different dissociation species have disparate photolytic pathways, products, and kinetics, and adopted ciprofloxacin (CIP) as a case to test this hypothesis. Simulated sunlight experiments and matrix calculations were performed to differentiate the photolytic reactivity for each dissociation species (H4CIP3+, H3CIP2+, H2CIP+, HCIP0, and CIP−). The results prove that the five dissociation species do have dissimilar photolytic kinetics and products. H4CIP3+ mainly undergoes stepwise cleavage of the piperazine ring, while H2CIP+ mainly undergoes defluorination. For H3CIP2+, HCIP0, and CIP−, the major photolytic pathway is oxidation. By density functional theory calculation, we clarified the defluorination mechanisms for the five dissociation species at the excited triplet states: All the five species can defluorinate by reaction with hydroxide ions (OH−) to form hydroxylated products, and H2CIP+ can also undergo C−F bond cleavage to produce F− and a carbon-centered radical. This study is a first attempt to differentiate the photolytic products and mechanisms for different dissociation species of ionizable compounds. The results imply that for accurate ecological risk assessment of ionizable emerging pollutants, it is necessary to investigate the environmental photochemical behavior of all dissociation species.

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INTRODUCTION Antibiotics, such as fluoroquinolones, are frequently detected in environmental waters as emerging pollutants.1−3 Although antibiotics have short environmental half-lives, they are constantly introduced into the aquatic environment.4 Some antibiotics can induce bacterial resistance even at environmental concentrations.5 Especially, the recent emergence of “superbugs” makes their environmental fate and ecological risk of acute concern.6,7 The molecular structures of most antibiotics contain ionizable groups (e.g., −COOH, −OH, and −NHn), rendering the aqueous presence of antibiotics in various dissociation forms. Previous studies show that organic pollutants in different dissociation forms have unique physicochemical properties (e.g., vapor pressure and lipophilicity) and toxicity that depend on the composition of the aquatic medium in which the chemicals reside.8,9 The environmental behavior, for example photochemical behavior, of antibiotics in different dissociation forms can also be disparate. The photochemical behavior of antibiotics is of concern as many antibiotics are resistant to microbial degradation and © 2013 American Chemical Society

photodegradation becomes a pivotal factor in determining their fate and ecological risk.10−13 Previous studies showed that the observed photolytic rate constants (kobs) of ionizable antibiotics were pH-dependent. For example, with pH increasing from 5 to 11, kobs of sarafloxacin, and gatifloxacin increased to a peak and then decreased.14 For tetracycline, kobs increased with pH increasing from 4.7 to 9.5.15 The kobs values of sulfonamides also varied with pH, but no general trends could be observed.16,17 The variation of kobs with pH is an integrative appearance of the photochemical reactions for different dissociation states of antibiotics that may exist in the aqueous solution at a given pH value. Thus, we hypothesized that different dissociation states of antibiotics possessed different photochemical reactivity (reaction kinetics, pathways, and products distributions). Received: Revised: Accepted: Published: 4284

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was used to simulate sunlight with λ > 290 nm. The emission spectrum of the light source (Figure S1 of the Supporting Information (SI)) was measured by a monochromator (SP300i, Acton Research Corporation). The irradiance measured by a UV-365 radiometer (Photoelectric Instrument Factory of Beijing Normal University, China) was 294 μW/cm2 in the center of the tubes. Aqueous solutions of CIP (5 μmol/L) were adjusted to the desired pH with HCl/NaOH only in order to avoid possible effects of buffers.31 The pH values changed slightly (0.02 (SI Figure S2), the kobs values were corrected for lightscreening.32 Photolytic quantum yields (Φ) were calculated as follows:33

Here we employed ciprofloxacin (CIP, Figure 1), a widely prescribed fluoroquinolone antibiotic,18,19 as a model com-

Figure 1. Molecular structure and dissociation positions of ciprofloxacin. The pKa values are taken from ref 20.

pound to test our basic hypothesis. The molecular structure of CIP has four ionizable functionalities, and CIP may exhibit five dominant dissociation forms in water.20 Previous studies have observed that kobs of CIP is pH-dependent.14,21 The underlying mechanism of this pH-dependence need to be clarified further. The light absorption characteristics, photolytic kinetics, and products for different dissociation forms of CIP need to be determined. In addition, defluorination at electronically excited states, a process that can hardly be observed for fluorobenzenes under sunlight irradiation due to the high strength of the C−F bond (ca. 120 kcal/mol, which corresponds to 238 nm of wavelength),22 was observed to be a main photoreaction pathway for most fluoroquinolones under neutral conditions.23−25 Further studies are needed to understand the mechanisms of the excited-state defluorination reaction and to know whether different protonated states of CIP have different defluorination pathways. In this study, simulated sunlight experiments and matrix calculations16 were performed to differentiate the absorption spectra, light-screening corrected photolytic rate constants (k), and quantum yields (Φ) of different dissociation forms of CIP. Photoproducts of CIP under different pH conditions were identified by the use of a Q-TOF mass spectrometer. To elucidate the excited-state defluorination pathways for the five dissociation states of CIP, density functional theory (DFT)26,27 calculations were employed. DFT calculations can provide important information on reaction intermediates or active species involved in chemical reactions,28−30 which are necessary for mechanism clarification but are difficult to be detected experimentally. We finally aim to test whether the photolytic kinetics, defluorination mechanisms, and product distribution for the different dissociation species of CIP are disparate, and discuss the consequences of the findings for ecological risk assessment of ionizable emerging pollutants like pharmaceuticals and personal care products.

ΦCIP =

k CIP ∑ Lλελ ,a Φa ka ∑ Lλελ ,CIP

(1)

where the subscript a stands for the chemical actinometer (pnitroanisole/pyridine); Lλ is the incident light intensity at a given wavelength λ, calculated by the emission intensity of the light source and the transmissivity of the Pyrex tube; ελ is the molar absorptivity at λ. The wavelength range was 250−400 nm. The chemical actinometer and CIP were placed in different tubes. Dark controls were performed under the same conditions. All the experiments were carried out at least in triplicate. Ignoring the mutual influence of the different dissociation species, the light-screening corrected photolytic rate constants for each dissociation species of CIP (ki) can be calculated by solving the matrix equation A·B = C (detailed in the SI), where the elements of matrix A, B, and C are αi f i, ki, and kobs, respectively; αi is the fraction of each dissociation form under different pH conditions, as calculated on the basis of the pKa of each species; and f i is the correction factor for light-screening. UV-vis absorption spectra for the five dissociation species of CIP were differentiated with an analogous method. Analytical Determinations. The concentration of CIP was determined by an Agilent 1100 HPLC with a ZORBAX SB-C18 column (2.1 × 150 mm, 3.5 μm). CIP was excited at λ = 280 nm and recorded at λ = 445 nm with a fluorescence detector. The mobile phases were acetonitrile (A) and trifluoroacetic acid in water (pH 2.4) with the following gradient elution: 5% A (0 min) to 20% A (3 min) to 40% A (15 min) to 5% A (17− 20 min). The flow rate was 0.2 mL/min, injection volume was 5 μL, and column temperature was 30 °C. Photolytic products were analyzed by an Agilent 1200 HPLC with an Agilent 6510 Q-TOF mass spectrometer equipped with a dual-spray electrospray ionization (ESI) source. The gradient eluting condition of HPLC was changed to: 2% A (0 min) to 12% A (3 min) to 20% A (28 min) to 38% A (43 min) to 2% A (44−50 min). The other analytical separation conditions were the same as the method mentioned above. The mass spectrometer conditions were: ionization mode: ESI, positive mode; scan range: m/z 50−1000; drying gas flow: 9 L/min; drying gas temperature: 350 °C; fragmentor: 150 V; nebulizer

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MATERIALS AND METHODS Chemicals and Reagents. Ciprofloxacin (CIP) with 98.0% purity was provided by Zhejiang Guobang Pharmaceutical Co., Ltd. Acetonitrile, trifluoroacetic acid, and pyridine were of HPLC grade and purchased from Tedia Inc. p-nitroanisole with 97% purity was obtained from Alfa Aesar. Other reagents (purity >99.0%) were purchased from Kermel Chemical Reagent Co., Ltd. Ultrapure water was obtained with a Millipore-Milli Q system. Photodegradation Experiments. An XPA-7 merry-goround photoreactor (Xujiang Electromechanical Plant, China) with a water-refrigerated 1000 W xenon lamp and Pyrex tubes 4285

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pressure: 40 psi; capillary voltage: 4000 V; skimmer voltage: 65 V; octapole radio frequency voltage: 750 V. DFT Computation Methods. The possible defluorination reactions were calculated for the five dominant dissociation species at the lowest excited triplet states, as the lowest excited triplet states were found to be long-lived photochemical reaction precursors for many compounds.22,23 All the calculations were performed with the Gaussian 09 program suite,34 using the M06-2X hybrid meta exchange-correlation functional35 in conjunction with the 6-31+G(d,p) basis set. The solvent effect of water was considered by the integral equation formalism of polarized continuum model (IEFPCM) based on the self-consistent-reaction-field (SCRF) method.36 The geometries at the lowest triplet states were calculated with a spin multiplicity of 3.37 Frequency calculations were performed with the same method to determine the character of stationary points. Transition states (TS) were characterized with one imaginary vibrational frequency. Intrinsic reaction coordinate (IRC) analysis38 was executed to verify that each TS uniquely connected the designated reactants with the products. The profiles of the free energy surface (FES) were depicted by employing relative free energies to the reactants (R). The values of Gibbs free energy and enthalpy were corrected by zero-point energy and thermal energy at 298 K. The atomic charges were evaluated by the Natural Bond Orbital (NBO) analysis.39

Figure 3. Light-screening corrected photolytic rate constants (ki), quantum yields (Φi) and cumulative light absorption (ΣLλελ,i) for each dissociation form of ciprofloxacin (CIP). The error bars represent the 95% confidence interval (n = 3); Lλ is the incident light intensity at a given wavelength λ, ελ,i is the molar absorptivity of CIP in the dissociation form i at λ.

Thus, the magnitude of k depends on the cumulative light absorption (ΣLλελ) and Φ. As can be seen from Figure 3, the ΣLλελ values for the five species vary insignificantly under the light source employed. It is Φ for the different dissociation species that dominates their k values. Photoproducts and Pathways for the Different Dissociation Species. We identified seven photolytic products among which three products (P346, P293, and P275) were newly identified in the current study (Figure 4). The molecular structures of these products were derived from the accurate mass determined by Q-TOF (Table S1, detailed in the SI). P346 was produced by oxidation of the quinolone ring. P293 and P275 were nitro-products, which were formed by oxidation of the piperazine ring. The formation of these oxidation products suggests that CIP can undergo selfsensitized photooxidation, which was also proved in our previous study.14 Although self-sensitized photooxidation is not a main process under the condition of low environmental CIP concentrations, it may occur in sunlit wastewaters with high CIP concentrations (up to 31 mg/L).41 Furthermore, light absorption of dissolved organic matters (DOMs) and some inorganic ions can produce reactive oxygen species (e.g., 1O2 and ·O2−) that can also oxidize CIP to generate these oxidation products. P288 was identified as a defluorination product, which was formed by cleavage of the C−F bond and the piperazine ring. P330 is also a defluorination product, which could be generated by photoinduced solvolysis. Previous studies detected P288 and P330 as the main photolytic products of CIP under neutral pH conditions.24,25,31,42 P306 and P263 were formed by cleavage of the piperazine ring. Mella et al. also detected these two products from the photolysis of CIP in 0.1 mol/L HCl solutions.31 Accordingly, the primary photolytic pathways for CIP include (I) photooxidation, (II) defluorination, and (III) cleavage of the piperazine ring (Figure 4). The evolution profiles of the products at different pH conditions (pH 2, 4.5, 7.5, 9.5, and 12) are depicted in Figure 5. We found that the products varied evidently under the different pH conditions. Based on the distribution of the dissociation species of CIP under the different pH conditions employed in this study (SI Figure S4), we determined the major products and degradation pathways for the five dissociation species (Figure 4). P306 and P263 were only detected in the pH 2 solutions, where H4CIP3+ was dominant (>91%). P263 was not observed in the initial period of irradiation, indicating that it was a secondary cleavage product. Thus, stepwise cleavage of the piperazine ring is a major pathway for the photodegradation

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RESULTS AND DISCUSSION Photolytic Kinetics of Each Dissociation Species. No obvious loss of CIP ( 0.99, p < 0.05). In the pH range of 2−12, the light-screening corrected photolytic rate constants (k) and quantum yields (Φ) were found to be pH-dependent and to exhibit a maximum value at around pH 8 (Figure 2). Torniainen et al.40 also found that

Figure 2. Light-screening corrected photolytic rate constants (k) and quantum yields (Φ) of ciprofloxacin at different pH conditions. The error bars represent the 95% confidence interval (n = 3).

under the irradiation of a high-pressure mercury lamp at 313 nm, kobs and Φ of CIP depended on the pH of the buffer solutions. The UV-vis absorption spectrum of CIP also varies at different pH conditions (SI Figure S2). We differentiated ki, Φi (Figure 3), and UV-vis absorption spectra (SI Figure S3) for each dissociation species of CIP. Theoretically, k for organics in transparent dilute solutions can be expressed as:32 k = 2.303Φ ∑ Lλελ

(2) 4286

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Figure 4. Primary photolytic products and pathways for the five dissociation species of ciprofloxacin (CIP). The three photolytic pathway types (I), (II), and (III) stand for photooxidation, defluorination, and cleavage of the piperazine ring, respectively.

Figure 5. Evolution profiles of the photoproducts of ciprofloxacin under different pH conditions. P275 and P293 were detected by a diode array detector (DAD) at 254 nm; the other photoproducts were detected by a fluorescence detector (FLD).

clarified by the DFT calculations in the next part. When CIP− was dominant (>96%, pH 12), two nitro-products (P293 and P275) as well as P346 and P330 were detected. Thus, CIP− not only undergoes photooxidation of the quinolone ring and photoinduced solvolytic defluorination, but also undergoes photooxidation of the piperazine ring. The reactivity of photooxidation at the piperazine ring can be attributed to the deprotonation of the amino substituents that can increase the electron donating ability and decrease the steric hinerance.43,44 Mechanisms of Defluorination of the Different Dissociation Species. Based on the structures of the two

of H 4 CIP 3+. One oxidation product (P346) and two defluorination products (P330 and P288) were detected at pH 4.5, 7.5, and 9.5, where H3CIP2+, H2CIP+, and HCIP0 were the dominant species (SI Figure S4). The amount of P346 in the pH 4.5 and 9.5 solutions was higher than that in the other solutions, implying that both H3CIP2+ and HCIP0 could generate P346 through photooxidation of the quinolone ring. P330 and P288 were mainly detected at pH 7.5, indicating that the primary photolytic pathway of H2CIP+ was defluorination. The reactivity of defluorination of H3CIP2+ and HCIP0 is hard to evaluate due to the coexistence of H2CIP+ and this will be 4287

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character. Thus, F− and a C12-centered radical were formed by intramolecular charge transfer during the C−F bond cleavage of H2CIP+. For the reactions of the five CIP species at their excited triplet state with OH− at its ground state, we identified two transition states (TS1 and TS2), and one intermediate (IM) (SI Table S3), indicating that the reactions are stepwise. The reactions are initiated by formation of reactant complexes (RCs) between the CIP dissociation species and OH− with different interactions. For H4CIP3+, H3CIP2+, and H2CIP+, we found that intermolecular hydrogen bonds were formed between O in OH− and H44 in CIP,45,46 and negative charges were transferred from OH− to CIP in the RC. For HCIP0 and CIP−, intermolecular hydrogen bonds were formed in the RC between H in OH− and N15 in CIP, and charge transfers occurred in TS1. The subsequent reaction processes were similar for the five dissociation species, that is, O in OH− gradually approached C12 and the distances of C12−O in the IM reduced to about 1.39 Å, falling in the range of a C−O single bond length. In the following step, the distances of C12− F bonds elongated to about 2.00 Å and negative charges were transferred to the F atom in TS2. Finally, F− and hydroxy products were produced, with the C12−O bond length being 2.35 Å. Thus, by the DFT calculation, we further clarified that the five dissociation species at their excited triplet states have different defluorination pathways (OH− reaction or C−F bond cleavage) and reaction channels (different transition states and intermediates), in addition to their disparate photolytic kinetics and products observed in the experiment. Environmental Implications. In this study, we first differentiated and confirmed that the five dissociation species of CIP have different photodegradation pathways, products and kinetics. In the normal pH range (6−9) of surface waters,47 H2CIP+ is the predominant dissociation species of CIP. H2CIP+ can photodegrade fast by defluorination. The carbon-centered radical generated from the C−F bond cleavage of H2CIP+ can cause DNA cleavage.48 We also estimated the genotoxic potential of CIP and the two defluorination products, P288 and P330, according to the QSAR model of Hu et al.,49 and found P330 is more genotoxic than CIP. Under some extreme conditions (e.g., acid lakes and hypertrophic lakes), the pH can range from 4 to 10.47 Thus, for accurate risk assessment of ionizable organic chemicals, like many antibiotics, it is necessary to unveil the different photolytic reactivity for the different dissociation species that are dominant under different pH conditions.

defluorination products (P288 and P330), three possible reaction pathways were considered in the calculation of defluorination at the excited triplet states,22 including cleavage of the C−F bond, defluorination caused by H2O addition, and defluorination caused by addition of hydroxide ions (OH−). The computed Gibbs free energy changes (ΔG), enthalpy changes (ΔH), and activation free energies (ΔG‡) for the three defluorination reaction pathways are listed in Table 1. As Table 1. Computed Gibbs Free Energy Changes (ΔG, kcal/ mol), Enthalpy Changes (ΔH, kcal/mol), and Activation Free Energies (ΔG‡, kcal/mol) for Defluorination of Different Dissociation Species of Ciprofloxacin (CIP) species

H4CIP3+

H3CIP2+

H2CIP+

HCIP0

Cleavage of the C−F Bonds 10.2 −4.8 22.6 10.5 −2.8 23.7 45.4 27.3 10.7, 16.3

ΔG ΔH ΔG‡

−4.3 −1.4 71.2

ΔG ΔH ΔG‡

−22.1 −25.0 60.1

ΔG ΔH ΔG‡

Defluorination caused by OH− Addition −23.7 −9.0 −68.8 −55.4 −26.7 −13.2 −71.9 −59.5 9.4, 17.4 7.6, 14.1 0.8, 6.0 1.7, 4.7

Defluorination caused by H2O Addition −12.4 −11.2 −12.7 −14.8 −14.6 −17.1 59.6 58.2 39.5, 6.7

CIP− 18.4 20.4 9.0, 14.6

−18.2 −23.1 37.9, 5.7

−28.5 −35.1 2.2, 6.2

indicated by the ΔG values, only H4CIP3+, and H2CIP+ can undergo cleavage of the C−F bonds spontaneously. However, the ΔG‡ value of this reaction for H4CIP3+ is too high to overcome. H2CIP+ can defluorinate via cleavage of the C−F bond due to the much lower ΔG‡ value. Cleavage of the C−F bond of H2CIP+ leads to P288, which is consistent with the experimental results that P288 was mainly detected in the H2CIP+-dominant solution. According to the ΔG values, the reactions of CIP with H2O and OH− are spontaneous for all the five dissociation species. The ΔG and ΔH values for the reactions of CIP with OH− are more negative than the other two pathways, indicating that OH− addition is thermodynamically favorable and strongly exothermic. Furthermore, the ΔG‡ values for the OH− addition are much lower than that of H2O addition, indicating that the OH− addition is more favorable. The addition of OH− leads to the final product P330 that has been detected experimentally. However, P330 was not detected in the strong acid solution (pH 2) due to the extremely low concentration of OH−. All the possible reactions mentioned above were simulated, but only the favorable ones are detailed here. The structures, atomic charges (q) and spin densities (ρ) of the reactants (R), transition states (TS), intermediates (IM), and products (P) for the C−F bond cleavage of H2CIP+ at excited triplet states are shown in SI Table S2. The distance of C12−F13 was elongated from 1.35 Å in R to 1.48 Å in TS, and to 3.86 Å in P, indicating the rupture of the C−F bond. The calculated q values show obvious intramolecular charge transfer in the cleavage of the C−F bond. The q values of atom F (qF) and of the quinolone ring moiety (qQ) show that the negative charge is transferred mainly from the quinolone ring to the F-atom, leading to the formation of F− in P. The ρ values on C12 are 1.22 and 1.00 in the TS and P, respectively, revealing that C12 has a radical

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ASSOCIATED CONTENT

S Supporting Information *

Details of the analysis of dissociation species and identification of photoproducts; irradiance spectra of the simulated sunlight; UV-vis absorption spectra of CIP; CIP dissociation speciation distribution; HPLC-Q-TOF for accurate determination of the mass spectrum; molecular structures, atomic charges and spin densities for the reaction species. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Phone/fax: +86-411-84706269; e-mail: [email protected]. 4288

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Notes

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Rong Zhang for assisting in product identification, and Prof. Dr. Willie Peijnenburg (RIVM) for improving the English expression and suggestions. The study was supported by the National Basic Research Program (2013CB430403) and National Natural Science Foundation (21137001) of China.

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