Photodegradation of metoprolol using a porphyrin as photosensitizer under homogeneous and heterogeneous conditions

Accepted Manuscript Title: Photodegradation of metoprolol using a porphyrin as photosensitizer under homogeneous and heterogeneous conditions Authors: Cl´audia M.B. Neves, Olga M.S. Filipe, Nuno Mota, S´onia A.O. Santos, Armando J.D. Silvestre, Eduarda B.H. Santos, M. Grac¸a P.M.S. Neves, M´ario M.Q. Sim˜o es PII: DOI: Reference:

S0304-3894(18)31081-1 https://doi.org/10.1016/j.jhazmat.2018.11.055 HAZMAT 19977

To appear in:

Journal of Hazardous Materials

Received date: Revised date: Accepted date:

28 February 2018 13 October 2018 15 November 2018

Please cite this article as: Neves CMB, Filipe OMS, Mota N, Santos SAO, Silvestre AJD, Santos EBH, Neves MGPMS, Sim˜o es MMQ, Photodegradation of metoprolol using a porphyrin as photosensitizer under homogeneous and heterogeneous conditions, Journal of Hazardous Materials (2018), https://doi.org/10.1016/j.jhazmat.2018.11.055 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Photodegradation of metoprolol using a porphyrin as photosensitizer under homogeneous and heterogeneous conditions

Cláudia M. B. Nevesa, Olga M. S. Filipeb, Nuno Motac, Sónia A. O. Santosd, Armando J. D.

a

QOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal

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Silvestred, Eduarda B. H. Santosc,*, M. Graça P. M. S. Nevesa,*, Mário M. Q. Simõesa,*

CERNAS – Research Centre for Natural Resources, Environment and Society, College of Agriculture, Polytechnic

b

c

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Institute of Coimbra, Bencanta, 3045-601 Coimbra, Portugal

CESAM, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal

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CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal

*

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Corresponding authors: [email protected] (E. B. H. Santos), [email protected] (M. G. P. M. S. Neves), [email protected]

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(M. M. Q. Simões)

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Graphical abstract

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Highlights 

Metoprolol photodegradation in water with H2TF5PP as the photosensitizer

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H2TF5PP photosensitizer is efficient under homogeneous and heterogeneous conditions Singlet oxygen is the main ROS involved in the photodegradation process

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Metoprolol degradation under real sunlight is in accordance with the simulated data

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The main resulting products were identified by HPLC-UV-ESI–MSn

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

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Abstract

Porphyrins are known as effective photosensitizers and can be an interesting key in phototreatment of water contaminated with micropollutants such as pharmaceuticals. They already showed to be

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efficient photocatalysts for the degradation of dyes, chlorophenols and other pollutants. This work demonstrates the applicability of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (H2TF5PP) as

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photosensitizer for treatment of water contaminated with metoprolol, a highly prescribedβ-blocker,

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which is not completely removed in sewage treatment plants. Studies were firstly developed under

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homogeneous conditions with simulated solar radiation and porphyrin was found to be efficient in the photodegradation of metoprolol, following a pseudo-first order kinetics with ca. 90% metoprolol

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degradation after 12 h. Experiments in presence of scavengers confirmed the mechanism of degradation via singlet oxygen. Appearance of several new peaks in HPLC chromatograms indicates the formation of products, identified by HPLC-MSn. Furthermore, the porphyrin was

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immobilized on a silica support and used as heterogeneous photocatalyst in degradation of metoprolol. Experiments using this heterogeneous photocatalyst under real solar irradiation were

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also performed, and similar results were obtained. Kinetic comparison of metoprolol photodegradation in buffer solution and in real wastewater treatment plant effluent showed that the efficiency of the immobilized porphyrin was not decreased by the complex matrix of the effluent.

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Keywords: Photodegradation, Photocatalysis, Metoprolol, Porphyrin, Wastewater

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Introduction The presence of chemicals in wastewater effluents and in surface and ground waters

represents a negative impact on ecosystems and human health. Among the various chemicals commonly found in the aquatic environment, pharmaceuticals were considered emerging contaminants and have aroused great concern, since they are extensively consumed worldwide and reach the environment either by inadequate disposal or by their excretion (unchanged or as metabolites) into sewage waters [1]. In addition, they can be extremely resistant to degradation and

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often escape intact from conventional sewage treatment plants due to their high chemical stability and low biodegradability [2]. Therefore, alternative treatments such as the use of photocatalysts must be investigated to complement the existing gaps in the conventional treatment processes.

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Porphyrins are known to be highly effective photosensitizers, as they possess triplet states of appropriate energy to allow, under light irradiation, an efficient energy transfer to ground state oxygen, producing high yields of oxygen reactive species such as 1O2 [3]. Such properties are responsible for the application of these compounds in different areas such as medical photodynamic

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therapy (PDT) [4–11], and photodynamic inactivation (PDI) of different microorganisms [12–16].

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These features make porphyrins also good candidates in the photooxidation of organic compounds

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[17–20], namely as photocatalysts for the degradation of organic pollutants in a water remediation context [21,22]. In fact, the use of this class of compounds in the treatment of pollutants has been a

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subject of great attention in the last years, and considerable work has been described in the photodegradation of target molecules such as textile dyes [23–28], chlorophenols [29–35], and

pharmaceuticals [41,42].

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pesticides [36–40]. However, only a few studies have been reported on the photodegradation of

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Recently, Mathon et al. [43] selected 13 xenobiotics (pharmaceuticals and pesticides) commonly found in secondary effluents to be relevant to sewage polishing treatment. Five of the

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selected xenobiotics were -blockers, including metoprolol, which can be detected in a range of 5 × 10-3 to 3 μg L-1. Under direct photolysis, atenolol and metoprolol were classified as slowphotodegradable, and propranolol was classified as medium-photodegradable [43]. Direct photolysis of organic micropollutants, specifically β-blockers, may occur by the direct absorbance

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of photons, when the compound absorption spectrum overlaps with the solar spectrum but only if the radiation is strong enough [44]. Thus, since most of the β-blockers only absorb in the UV-C range, their direct photolysis in aquatic environment is not remarkable [44,45], but indirect photodegradation may occur induced by photosensitizers present in natural waters, such as humic substances [46]. However, even when indirect photodegradation may help to reduce β-blockers concentration in natural waters, their discharge should be avoided in the sources, among which outstand the effluents of sewage treatment plants. Given that β-blockers, and specifically 3

metoprolol, are not completely degraded in conventional biological treatments, photocatalytic processes have been tested for their elimination from wastewaters, generally using TiO2 as photocatalyst [47–62]. However, a main drawback of this photocatalyst is that solar energy for exciting TiO2 ( λ ≤ 387nm) accounts for less than 5% of the whole sunlight reaching the surface of the Earth [63]. Another challenge is its immobilization on solid supports. The immobilization often reduces the photocatalytic efficiency of TiO2 and the small particle size leads to high filtration costs for the photocatalyst removal [64]. For this reason, the search for efficient photocatalysts able to use

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sunlight, in a broader range of wavelengths, associated with an easy and efficient separation after use, is an issue of great importance. In this context, porphyrins are considered promising photocatalysts due to their strong absorption in several wavelengths of the sunlight range, showing

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in general an intense absorption (Soret band) in the 400-450 nm region and four additional bands (Q-bands) in the 500-800 nm region. A possible side effect, from the environmental point of view, can be the potential phototoxicity of the photocatalyst, which can be minimized by its decomposition in the presence of 1O2 [3], or alternatively by its immobilization on a solid support.

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The immobilization of porphyrins onto solid supports has received great attention on the last years

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due to their practicability in the water purification process, especially their easy removal by

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filtration and, ultimately, the possibility of reuse [22].

In the present work, and considering our research interest on β-blockers photodegradation

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[65], we decided to evaluate for the very first time the potential of the synthetic 5,10,15,20tetrakis(pentafluorophenyl)porphyrin (H2TF5PP) (Scheme 1) as photosensitizer for the removal of

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metoprolol in wastewater treatment systems. The efficiency under heterogeneous conditions was also evaluated by using the same photocatalyst covalently attached to an amino functionalized silica

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(Scheme 1).

Scheme 1. Synthesis to prepare and to attach the H2TF5PP onto the silica support [66,67].

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Experimental

2.1

Chemicals and solutions Nitrobenzene and 2,3,4,5,6-pentafluorobenzaldehyde used in the synthesis of the free-base

porphyrin were acquired from Acros and Fluka, respectively. Pyrrole was obtained from SigmaAldrich and was previously distilled. Diethylene glycol dimethyl ether (diglyme, ≥ 99%) used as solvent for the immobilization of the porphyrin was purchased from Fluka, whereas 3-aminopropylfunctionalized silica gel 9% was obtained from Aldrich.

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Metoprolol tartrate salt (≥ 98%), propan-2-ol and sodium azide were acquired from SigmaAldrich. Formic acid (HCO2H, 98%) was obtained from Panreac and acetonitrile (HPLC quality) and dimethyl sulfoxide (≥ 99,5%; DMSO) were purchased from Lab-Scan Analytical Sciences.

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Potassium dihydrogen phosphate (KH2PO4) and sodium hydroxide (NaOH) were obtained from Merck and di-sodium hydrogen phosphate anhydrous (Na2HPO4) from Fluka.

The stock solution of H2TF5PP (1000 mg L-1) was prepared by dissolving the porphyrin in dimethyl sulfoxide (DMSO) and the stock solution of metoprolol was prepared by dissolving the

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compound in ultrapure water (Milli-Q). The stock solutions were protected from light with

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aluminum foil and stored at 4 ºC until use.

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The stock solution of phosphate buffer 0.1 M was prepared in 250 mL of Milli-Q water with a mixture of 0.0125 mol of KH2PO4 and 0.0125 mol of Na2HPO4. The pH of the solution was

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adjusted to 7.5 with NaOH solutions (1 M and 0.1 M).

Irradiation apparatus

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2.2

The irradiations of metoprolol solutions were performed under simulated solar radiation,

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using a Solarbox 1500 (Co.fo.me.gra, Italy) equipped with a 1500 W arc xenon lamp and outdoor filters that restrict the transmission of light with wavelengths < 290 nm. The irradiance was kept

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constant at 55 W m-2 in the wavelength range 295-400 nm, corresponding to 550 W m-2 in the whole spectrum. A multimeter (Co.fo.me.gra, Italy), equipped with temperature and UV 290-400 nm large band sensors, was used to control the temperature and the irradiance, respectively. The samples (20 mL) were placed in 19.5 cm quartz or glass tubes with an internal diameter of 1.8 cm

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and the tubes were disposed inside the chamber using a home-made metallic support which keeps the tubes leaning positioned under the lamp. In the heterogeneous experiments, the irradiations were also performed under stirring and, for this purpose, a stirring plate was positioned below the Solarbox.

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2.3

Photodegradation experiments in aqueous solutions For the homogeneous photodegradation experiments, the solutions were prepared in order to

obtain a final metoprolol concentration of 50 mg L-1 and 1.0 × 10-5 mol L-1 of the porphyrin by dilution with Milli-Q water. In the case of HPLC-MSn analysis the solutions were prepared with a metoprolol concentration of 250 mg L-1 for a better detection of the degradation products. Solutions of metoprolol with the porphyrin were irradiated under the same conditions in the presence of selective scavengers. For the quenching of the hydroxyl radical (•OH), propan-2-ol was added to the

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solution to obtain a final concentration of 20 mM, and for the quenching of both hydroxyl radical (•OH) and singlet oxygen (1O2), sodium azide was added to attain a final concentration of 2 mM. Samples of 20 mL were placed in the tubes and irradiated during different time periods.

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For the heterogeneous photodegradation experiments, 20 mL of the 50 mg L-1 metoprolol solution were added to the tubes containing 1.23 × 10-5 M of the photosensitizer (2.5 g L-1 of H2TF5PP-silica with a porphyrin content of 4.9 mol g-1). Aliquots of 500 L were removed from

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the tubes and filtered through a Millex-GV syringe filter from Millipore (0.22 µm pore size, PVDF membrane) into a 2 mL glass vial for further analysis. Experiments with and without stirring were

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performed. To evaluate the pH effect, experiments were also made with 20 mL of metoprolol

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solution buffered at pH 7.5 with 0.01 M phosphate buffer under stirring.

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Replicates of the experiments were non-simultaneous in order to better evaluate reproducibility. For both homogeneous and heterogeneous photocatalysis experiments, metoprolol solutions (50 mg L-1) without the photosensitizer, and photosensitizer in water without metoprolol

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were also irradiated. Dark controls with the same amount of metoprolol and photosensitizer in tubes covered with aluminum foil were also prepared and submitted to the same irradiation conditions

Solar irradiation experiments

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inside the Solarbox.

Experiments under real sunlight were carried out at the roof of the Department of Chemistry

of the University of Aveiro, using the heterogeneous photosensitizer in buffered metoprolol solutions at pH 7.5 under stirring. For these experiments, the tubes and the volumes of solution were

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the same as those used in the experiments made in the Solarbox. They were also kept in a leaning position relatively to sunlight, in order to assure that the exposition area was the same as in the Solarbox. In parallel, a dark control in the same place was also performed involving the tube in an aluminum foil. The solar irradiation was performed during 6 h in a typical day of summer between 11 a.m. and 5 p.m. (higher solar irradiation period). Solar irradiance (W m-2) was measured with a Campbell-Stokes recorder and the data obtained every 10 min were supplied by the Meteorological Tower of the University of Aveiro. Solar energy 6

(J m-2) received by the samples was calculated as ∑𝑛𝑖=1 𝐼̅𝑖 × 600, where n is the number of 10 min intervals corresponding to the total time of samples exposition under sunlight and 𝐼̅𝑖 is the medium solar irradiance in each 10 min interval.

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Photodegradation experiments in wastewater Photodegradation experiments were also performed in a sample of the secondary effluent of

the municipal wastewater treatment plant (WWTP) located at Gafanha da Encarnação (ETAR de

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Ílhavo), which treats urban effluents from the municipalities of Ílhavo and Mira and from part of the municipalities of Aveiro, Cantanhede and Vagos, in Portugal. It treats an average of 25600 m3 per day. Data on the characterization of the effluent were provided by the WWTP Direction and are

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presented in Table S1 of the Supplementary Material. The effluent was filtered immediately after arrival at our laboratories (0.2 m filter after pre-filtration through larger pore filter) and kept in the refrigerator at 4ºC. Aliquots of the filtered effluent were spiked with metoprolol (50 mg L-1) and 20

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mL of the spiked effluent were added to 0.05 g of H2TF5PP-silica (2.5 g L-1) and irradiated in the Solarbox as described previously in section 2.3. For these experiments, a new batch of immobilized

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porphyrin was prepared, following the same immobilization procedure described in the

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Supplementary Material. Additional assays of the photodegradation of metoprolol in buffered

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aqueous solution were also performed with the second batch of immobilized porphyrin for

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comparison.

HPLC-UV analysis

The metoprolol samples were analyzed by HPLC in a Shimadzu apparatus equipped with a

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DGU-20A5 degasser, a LC-20AD pump, a UV-Vis SPD-20A detector, a CTO-10ASVP column oven (with constant temperature at 25 ºC), a PFP ACE® C18 column (150 × 4.60 mm, 5 μm), and a

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20 μL loop. The mobile phase was acetonitrile:water (acidified with HCO2H 0.1%) 20:80 (v/v) for kinetic studies of the metoprolol degradation and acetonitrile:water (acidified with HCO2H 0.1%) 10:90 (v/v) for the detection and identification of the photodegradation products and was previously

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filtered by a membrane filter 0.2 μm NL16 (Schleicher & Schuell). The flow rate was 0.7 mL min-1 and the detection wavelength was 222 nm. The calibration of the HPLC apparatus was made using metoprolol standards prepared in

Milli-Q water with concentrations in the range of 10 mg L-1 to 50 mg L-1. The calibration curve was validated daily, analyzing two standards. The calibration was considered valid whenever the difference between the calculated and the real concentration of the standard did not differ more than 5%. 7

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HPLC-MSn analysis The HPLC system consists of a variable loop Accela autosampler (set at a temperature of 16

°C), an Accela 600 LC pump and an Accela 80 Hz PDA detector (Thermo Fisher Scientific, San Jose, Ca, USA). The analyses were carried out using a PFP ACE® C18 column (150 mm x 4.6 mm, 5 μm). The separation of the compounds was carried out with a mobile phase of acetonitrile: water (with 0.1% HCO2H) 10:90 (v/v), at a flow rate of 0.7 mL min−1, at 25 ºC. The injection volume in the HPLC system was 20 μL. Single online detection was carried out in the PDA detector, at 222

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nm, and UV spectra in a range of 200-600 nm were also recorded. The HPLC system was coupled to a LCQ Fleet ion trap mass spectrometer (ThermoFinnigan, San Jose, CA, USA), equipped with an ESI source and operating in positive mode. The nitrogen

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sheath and auxiliary gas were 40 and 10 (arbitrary units), respectively. The spray voltage was 5 kV and the capillary temperature was 350 °C. The capillary and tune lens voltages were set at 32 V and 110 V, respectively. CID-MSn experiments were performed on mass-selected precursor ions in the

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range of m/z 50-1000. The isolation width of precursor ions was 1.0 mass units. The scan time was equal to 100 ms and the collision energy was optimized between 15-40 (arbitrary units), using

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helium as collision gas. The data acquisition was carried out by using Xcalibur ® data system

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(ThermoFinnigan, San Jose, CA, USA).

Data analysis

was calculated as

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The residual percentage of metoprolol remaining in solution after a certain time of irradiation 𝐶 × 100 % 𝐶0

(𝐸𝑞 1)

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𝑅𝑒𝑠𝑖𝑑𝑢𝑎𝑙 𝑝𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒 𝑜𝑓 𝑚𝑒𝑡𝑜𝑝𝑟𝑜𝑙𝑜𝑙 =

where C0 is the initial metoprolol concentration (calculated from the quantity dissolved for the

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preparation of the solution) and C is the concentration measured (HPLC analysis) after irradiation. All the experimental kinetic data obtained in different days were fitted by non-linear

regression analysis using the program GraphPadPrism7® (Trial version; http://www.graphpad.com). The data for the metoprolol photodegradation in the presence of porphyrin under homogeneous

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conditions were adjusted to the first order kinetics equation, 𝐶 = 𝑒 −𝑘1 𝑡 𝐶0

(𝐸𝑞 2)

where k1 is the first order rate constant and t is the irradiation time. For the metoprolol photodegradation in the presence of the supported porphyrin (H2TF5PPsilica) an exponential decay equation model was used to fit the data,

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𝐶 = (1 − 𝐴)𝑒 −𝑘2𝑡 + 𝐴 𝐶0

(𝐸𝑞 3)

where k2 is the rate constant and A corresponds to the ratio between C value at infinite time (plateau) and C0.

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Results and discussion

3.1

Preparation of the photocatalysts The

5,10,15,20-tetrakis(pentafluorophenyl)porphyrin

(H2TF5PP)

was

selected

as

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photocatalyst considering the following aspects: i) easy synthesis [68]; ii) high photostability [69]; iii) high efficiency to generate singlet oxygen [70]; iv) facile immobilization in solid supports by

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nucleophilic substitution of p-fluorine atoms [67,68].

After purification, the spectroscopic data of the non-immobilized H2TF5PP (1H NMR, MS and UV-Vis spectra) were consistent with the literature data [71–74]. The immobilization of the porphyrin on a solid support allows an easy removal of the photosensitizer from the water and

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consequently its potential phototoxicity is minimized. The synthesis used to prepare the non-

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immobilized and the immobilized porphyrin is described in the Supplementary Material and is summarized in Scheme 1. The amount of porphyrin immobilized onto the silica support was 4.9

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mol g-1 and it was determined considering the amount of unreacted porphyrin, as described in the

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Supplementary Material.

The solid material resulting from the immobilization of the porphyrin exhibits a yellowish-

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brown color due to the presence of the porphyrin, as can be seen in Figure 1, which shows the silica before and after the immobilization of the porphyrin. The supported material was characterized by

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diffuse reflectance UV-Vis spectroscopy (Figure 2). The UV-Vis spectrum of H2TF5PP in THF solution, also given for comparison, is characterized by the strong Soret band around 410 nm and

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the three typical Q-bands between 500 and 650 nm (Figure 2). The diffuse reflectance spectrum of the H2TF5PP powder (the non-immobilized H2TF5PP solid) was similar to that observed in solution, showing exactly the same bands, although with the relative intensity of the Soret band comparatively diminished. A similar diffuse reflectance spectrum was obtained in the case of

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H2TF5PP-silica material, thus indicating that the porphyrin H2TF5PP was successfully incorporated onto the silica support. Finally, the diffuse reflectance spectrum obtained for the 3aminopropyl-functionalized silica was also added to Figure 2, confirming that the bands observed are not from the support. The solid material was also characterized by powder X-ray diffraction and infrared spectroscopy (Figures S1 and S2 of the Supplementary Material, respectively).

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Figure 1. Appearance of the functionalized silica before the immobilization (left) and after the porphyrin immobilization (right).

a) Silica b) H2TF5PP powder

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c) H2TF5PP-silica

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0.3 0.2

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Absorbance (a.u.)

d) H2TF5PP in THF 0.4

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 (nm)

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Figure 2. Diffuse reflectance UV-Vis spectra obtained for: a) Silica (the 3-aminopropyl-functionalized silica support); b) H2TF5PP powder (the non-immobilized H2TF5PP solid); c) H2TF5PP-silica (the porphyrin immobilized on the silica support). UV–Vis spectrum of d) H2TF5PP in solution (dissolved in THF), evidencing the porphyrins’ characteristic Soret (around 410 nm) and Q bands (between 500 and 650 nm).

3.2

Evaluation of H2TF5PP as photosensitizer for metoprolol degradation under

homogeneous conditions

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Figure 3A shows the decrease of metoprolol concentration with the irradiation time in the

presence and absence of porphyrin. After 12 h a decrease of ca 90% of metoprolol was observed in the presence of porphyrin and, after 24 h, the metoprolol concentration was almost negligible. Without porphyrin, no detectable degradation of metoprolol occurred after 24 h of irradiation. There was also no degradation in the dark control containing porphyrin and metoprolol. The almost complete photodegradation of metoprolol after 24 h of irradiation in the presence of H2TF5PP is clearly seen in the chromatogram presented in Figure S3. 10

The photosensitized degradation of metoprolol follows a pseudo-first order kinetics with k = 0.262 ± 0.014 h-1 (95% confidence interval), as confirmed by the good fitting of Eq. (2) to the experimental data values (Figure 3A).

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A C/C0

With H2TF5PP

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Dark control Without H2TF5PP

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Time (h)

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C/C0

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Azide Propan-2-ol Kinetic curve calculated in the absence of scanvengers

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1.0

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Figure 3. Photodegradation of 50 mg L-1 metoprolol solutions A) in the absence and in the presence of 1.0 × 10-5 mol L-1 of H2TF5PP in homogeneous conditions; B) in the presence of scavengers. Propan2-ol was used with a final concentration of 20 mM and sodium azide with a concentration of 2 mM. Data correspond to mean values and the vertical bars correspond to the standard deviations. 11

In order to identify the type of mechanism involved in the metoprolol photodegradation, additional assays were performed in the presence of reactive oxygen species scavengers, namely propan-2-ol and sodium azide. While propan-2-ol is a •OH selective quencher, azide ion is a quencher of both hydroxyl radical (•OH) and singlet oxygen (1O2) [75]. The results obtained (Figure 3B) show that metoprolol degradation in the presence of propan-2-ol follows the same kinetics as in the absence of the scavenger, as confirmed by the coincidence of the experimental points with the pseudo-first order kinetic curve in the absence of the scavenger. A different situation

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occurred in the presence of sodium azide, where a metoprolol decrease of only 35% was observed after 24 h of irradiation, which lead to the assumption that 1O2 is the main reactive oxygen species

3.3

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involved in this process.

Metoprolol degradation in the presence of H2TF5PP-silica as photosensitizer Despite the observed efficiency of the porphyrin as photosensitizer in the degradation of

metoprolol under homogeneous conditions, the porphyrin has the drawback of being insoluble in

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water thus requiring its previous solubilization in DMSO before dilution in water. This fact hampers

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its large scale application in wastewater treatment as homogeneous sensitizer. The immobilization

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of the porphyrin overcomes this problem and, as referred in section 3.1, allows an easier recovery of the photosensitizer from water after treatment.

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The photodegradation of metoprolol in unbuffered solutions in the presence of H2TF5PPsilica and without stirring follows an exponential decay, in accordance to Eq. (3), with k2 = 0.190 ±

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0.045 h-1 (95% confidence interval, n = 17) and A = 0.586 ± 0.040 as shown in Figure 4. Using these conditions, the residual percentage of metoprolol was ≈ 63 % after 12 h of irradiation.

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Since the porphyrin absorbs in the visible range spectrum (Soret band max ≈410 nm and the Q bands ranging 500-650 nm), we decided to verify if the efficiency of the photodegradation was the

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same using glass tubes, which are cheaper than quartz tubes. Since the use of the glass tubes in the irradiation experiments resulted in the same degradation of metoprolol, all the other assays were performed in this type of tubes. In order to improve the contact of the immobilized photosensitizer with the solution and to

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avoid some depletion of dissolved oxygen at its surface, extra experiments for 6 h and 12 h of irradiation were performed under stirring (data not shown). The results show an improvement in the photodegradation with a residual percentage of metoprolol of ≈ 65 % after 6 h and of ≈ 57 % after 12 h (data not shown). Another aspect that merited some attention was the attenuation of the yellowish-brown color of the solid support, although there was no evidence of the presence of free porphyrin in solution by UV-Vis spectrophotometry. We suspected that this fact was probably due to the photodegradation 12

of the porphyrin either at the solid support or after its release into the solution associated to the alteration of the pH during irradiation.

With stirring and buffer pH 7.5 Unbuffered solution and without stirring Kinetic curve

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C/C0

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2

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Time (h)

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Figure 4. Photodegradation of 50 mg L-1 metoprolol solutions catalysed by H2TF5PP-silica under different conditions. The vertical bars correspond to the standard deviations.

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In fact, during the assays it was observed that the pH of the solutions decreased from pH ≈6 before the irradiation, to pH ≈4 after 12 h of irradiation. The acidic environment of the solutions can give rise to the protonation of the amino group responsible for the linkage of the porphyrin to the

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solid support and consequently the cleavage of the photocatalyst by a nucleophilic attack would be facilitated (Scheme 2). In order to minimize this leaching process, the irradiations were performed

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in aqueous solutions buffered with 0.01 M phosphate at pH 7.5.

Scheme 2. Putative protonation under acidic conditions and cleavage of the covalent bond linking the porphyrin to the support

The kinetics of the photodegradation of metoprolol, taking into account the two previous aspects, namely stirring in a buffered solution, follows an exponential decay as shown in Figure 4. Table 1 compares the kinetic parameters obtained under these conditions with the ones previously obtained (no-stirring in unbuffered solution). 13

Table 1 – Kinetic parameters obtained for the photodegradation of 50 mg L -1 metoprolol catalysed by H2TF5PP-silica under different conditions. Experimental conditions k2 (h-1) Ac Without stirring in unbuffered solutionsa

0.190 ± 0.045

0.586 ± 0.040

With stirring in buffered solutionsb

0.388 ± 0.049

0.384 ± 0.022

a

95% confidence interval, n = 17; b 95% confidence interval, n = 22; c A corresponds to the ratio between C value at infinite time and C0 (see Data analysis in the Experimental section for more information).

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The results show that, in the second conditions, the efficiency of the photosensitizer was improved and the residual percentage of metoprolol was only ≈38 % after 12 h of irradiation.

Thus, the metoprolol photodegradation at infinite time increased from 41% without stirring in

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unbuffered solution to 62% in buffered solution under stirring. The considerable improvement

in the stability of the photocatalyst was confirmed by diffuse reflectance UV-Vis spectroscopic analysis of the H2TF5PP-silica material recovered by filtration after 2, 4, 6, 8,

U

and 12 hours of irradiation. As can be seen in Figure 5, the porphyrin’s characteristic Soret and Q bands are still present in the H2TF5PP-silica material, even after 12 hours of

A M

0.8

T0 2h 4h 6h 8h 12h

ED

0.7 0.6

PT

0.5 0.4 0.3

CC E

Absorbance (a.u.)

N

irradiation, although less intense.

0.2

A

0.1 0.0

300

400

500

600

700

800

 (nm)

Figure 5. Diffuse reflectance UV-Vis spectra of the H2TF5PP-silica after each period of photoirradiation, for the experiments using buffered solutions of metoprolol, under stirring.

14

3.4

Metoprolol degradation under real sunlight, photosensitized by H2TF5PP-silica Since the rate constant expressed in h-1 depends on the irradiance of the light source, the

irradiation time was converted into energy received by the solutions in order to predict the percentage of degradation under real sunlight. Since the lamp irradiance of the Solarbox was 550 W m-2, 1 h of irradiation corresponds to 1.98 × 106 J m-2. Thus, the rate constant 0.388 ± 0.049 h-1 (Table 1) corresponds to (1.96 ± 0.25) × 10-7 J-1 m2. Thus, as the energy received by the solutions exposed to real sunlight, calculated as described

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in section 2.4, was 1.43 × 107 J m-2, and as the exposed area of the irradiated solutions was the same as in the Solarbox, the expected residual metoprolol fraction in solution after sunlight exposition can be calculated as (𝐸𝑞 4)

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𝐶 = (1 − 𝐴)𝑒 −𝑘𝐸 + 𝐴 𝐶0

where k = 1.96 × 10-7 J-1 m2, E, the energy received from the sun, is 1.43 × 107 J m-2 and A = 0.384 𝐶

± 0.022 (Table 1). So, the predicted residual fraction of metoprolol (𝐶 ) in solution after 6 h of solar

U

0

exposition (1.43 × 107 J m-2) is 0.421 ± 0.026. From the experiments of metoprolol degradation

N

under real sunlight, the residual fraction of metoprolol obtained after the solar exposition was 0.425

A

± 0.022 (n = 2), in very good agreement with the predicted value. The results indicate that the

M

kinetic parameters for the degradation of metoprolol photosensitized by H2TF5PP-silica, obtained under simulated sunlight, can be used to predict the residual fraction of metoprolol obtained in

ED

solutions exposed to natural sunlight conditions.

In order to use these data to predict the degradation percentage under other conditions of irradiance and different configurations of the sample containers with different areas of exposition to

PT

light, the rate constant was converted into the units J-1 L. Taking into account that the volume of solution irradiated was 20 mL and the area exposed to sunlight was 22.6 × 10-4 m2 (calculation

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explained in Figure S4), then the rate constant 1.96 × 10-7 J-1 m2 corresponds to 1.73 × 10-6 J-1 L. The predicted residual fraction after solar exposition can be calculated using this rate constant in equation (4) and replacing E by the energy received per liter of solution. In the present work, the

A

energy received per liter of solution was 1.62 × 106 J L-1.

3.5

Comparison of metoprolol photodegradation in wastewater treatment effluent and in buffered aqueous solution Figure 6 shows the photodegradation of metoprolol in the WWTP effluent and in buffer

solution, using H2TF5PP-silica as photosensitizer. The results obtained in buffer solution using the second batch of H2TF5PP-silica are similar to those obtained in the several assays performed with 15

the first batch of catalyst, as can be seen in Figure 6, where the individual results which gave rise to the mean values presented in Figure 4 are also shown. Besides, the results obtained in the effluent are almost coincident with those obtained in the buffer solution, using the same batch of H2TF5PPsilica.

st

Buffer; 1 batch of H2TF5PP-Silica

1.0

nd

Buffer; 2 batch of H2TF5PP-Silica nd

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Effluent 2 batch of H2TF5PP-Silica Kinetic curve in buffer solution

0.8

C/C0

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0.6

0.4

0.0 2

4

6

8

10

12

14

A

0

N

U

0.2

M

Time (h)

Figure 6. Photodegradation of 50 mg L-1 metoprolol solutions prepared in ultrapure water (with buffer) and

ED

in WWTP effluent: experimental data and kinetic curve fitted to all the experimental data (with the two batches of immobilized porphyrin) obtained in buffer solution (kinetic parameters k = 0.347 ± 0.072 h-1 A=

PT

0.404 ± 0.040).

Thus, it can be stated that the complicated matrix of the effluent did not decrease the

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efficiency of H2TF5PP-silica in metoprolol photodegradation. Kim et al [42] also observed a low effect of the matrices of wastewater treatment effluents on the efficiency of a tin porphyrin immobilized onto silica, for degradation of cimetidine and propranolol. This is an advantage

A

relatively to photoactive materials capable of generating OH radicals, such as semiconductor based photocatalysts (ex: TiO2), whose efficiency in pollutants degradation is usually decreased by the components of wastewater matrices [42, 61]. Wastewater components, namely the background organic substances, can compete for reactive oxygen species, and the lower matrix effects observed with porphyrin photosensitizers, relatively to semiconductor based photocatalysts, can be attributed to the higher selectivity of 1O2 relatively to OH radicals.

16

3.6

Identification of the photodegradation products by HPLC-UV-MSn Figure S5A shows the HPLC-UV-MSn chromatogram obtained with detection at 222 nm

when 250 mg L-1 metoprolol solutions in the presence of 1.0 × 10-5 mol L-1 of H2TF5PP were irradiated for 12 h. Simultaneously, the samples were analysed using the UV detection in a range of 200-600 nm (Figure S5B). At least 18 products have been detected and identified based on their [M + H]+ ions and on their MSn spectra. The proposed structures are presented in Scheme 3. The main products identified here have already been detected in our previous work [65] concerning

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metoprolol photodegradation sensitized by natural fulvic acids, in which the fragmentation pathways of 16 compounds were proposed. As in the presence of natural fulvic acids, compounds resulting from: ring-opening oxidative processes (1 and 2), modifications of the aliphatic ether

15), and from the loss of propene (18), were also detected.

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moiety (4, 5, 6, 8, 12, 14 and 16), successive hydroxylation reactions of the phenoxy unit (7 and

In the presence of the non-immobilized porphyrin, compounds 3, 9, 10, 11, 13 and 17 were

U

also detected and their structures were proposed based on their MS2, MS3 and in some cases MS4 spectra (Table S2). The proposed fragmentation pathways for these compounds are presented in

N

Schemes S1-S5. In the presence of the heterogeneous H2TF5PP-silica only the over oxidized

A

compounds 1, 7, 9, 10, 13, 15, and 17 were not detected. All the other products previously referred

M

were detected. Since in the presence of the heterogeneous porphyrin the photodegradation of metoprolol is lower, the products should appear in lower concentrations and this is probably the

ED

reason why the minor degradation products were not detected. In the MS2 spectra of the new compounds (see Table S2 and Schemes S1-S6), the presence of the metoprolol characteristic product ions at m/z 116, 98 and 74, and the typical losses of 18 Da

unchanged.

PT

(H2O) and 42 Da (CH3CH=CH2) indicate that the aminopropanol moiety of metoprolol is

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In the MSn spectra of 3, with [M + H]+ at m/z 242, the absence of the product ions at m/z 159

and 133 and the absence of methanol losses means that the phenoxy and ether moieties of metoprolol are changed. Compound 3 was identified as a di-hydroxylated benzene derivative with

A

the OH groups either with a 1,2 and/or 1,4 relative position (Scheme 3). The MSn fragmentation profile of the compound is consistent with both proposed structures (Scheme S1, exemplified for the case of the 1,2-dihydroxybenzene derivative). The MSn fragmentation of 13 with the molecular ion [M + H]+ at m/z 240, similarly to 3, does not generate the product ions at m/z 159 and 133. The aminopropanol moiety of metoprolol is maintained, due to the presence of the product ions at m/z 116 and 98. The difference of 2 Da in relation to 3 leads us to propose the corresponding 1,2-benzoquinone or 1,4-benzoquinone as the 17

most likely structures of 13 (Scheme 3) and may result from an oxidation of 3 or directly from metoprolol (Scheme 4). The mechanism of formation and the MSn fragmentation profile of the compound are consistent with both proposed structures (Scheme 4 and Scheme S2, exemplified for the case of the 1,2-benzoquinone derivative). In addition to 6 already identified in a previous study [65], three other derivatives resulting from the photodegradation of metoprolol with [M + H]+ ion at m/z 254 were detected at 9.1 min (9), 10.0 min (11) and 16.5 min (17). Their MS2 spectra are similar, however the product ions show

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different relative abundances and their MSn fragmentation presents some differences. In the MS2 spectra of the three compounds, the presence of product ions at m/z 212 (-42 Da, loss of propene) and 177 (-77 Da, loss of water and isopropylamine) can be observed. The absence of methanol

of the molecule.

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losses (32 Da), characteristic of the ether moiety, indicates that a modification occurred in this part Compound 11 presents a MS2 spectrum of the molecular ion at m/z 254 and MS3 fragmentation

patterns

very

similar

to

6,

therefore

it

was

identified

as

1-[4-(2-

U

hydroxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol (2-hydroxyethyl isomer of 6) (Table S2

N

and Scheme S3). This compound has already been identified by Armaković et al. [76] and their

A

results are in accordance with our MSn spectra fragmentation profile. In fact, from the MSn fragmentation pattern of [M + H]+ ion at m/z 254, the presence of product ions at m/z = 159, 133

M

and 105 shows that the aromatic ring of metoprolol is preserved. The loss of two molecules of water and ammonia in the MS3 spectrum of the product ion at m/z 212 (product ion at m/z 159) suggests

ED

the presence of another hydroxyl group. Also, the product ions at m/z = 159 and 133 observed in the MS3 spectrum of the product ion at m/z 177, resulting from the loss of 18 Da (water) and the loss of

PT

44 Da (CH3CHO), respectively, are indicative of the presence of a hydroxyethyl moiety. The MSn fragmentation of [M + H]+ ion at m/z 254 for 9 is in accordance with the structure of

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the hydroxy derivative of 4-[2-hydroxy-3-(propan-2ylamino)propoxy]benzaldehyde (Table S2 and Scheme S4). This compound has been identified in the photodegradation of atenolol using TiO2 and photo-Fenton reaction, under natural light [77]. The same product was also detected in the photodegradation of metoprolol in the presence of TiO2-based photocatalysts [50,76]. The presence

A

of the product ion at m/z 166 in the MS3 fragmentation pattern of [M + H]+ ion at m/z 212 (loss of 28 Da and water) and in the MS3 fragmentation pattern of [M + H]+ ion at m/z 194 (loss of 28 Da) may indicate the presence of a formyl group. In electrospray ionization mass spectrometry, protonated aldehydes can show loss of CO (-28 Da) as a major fragmentation pathway [78]. The presence of the product ion at m/z 147 in the MS3 fragmentation patterns of [M + H]+ ion at m/z 212 and m/z 194 may indicate that the hydroxyl group of the aromatic ring should be positioned meta to 18

the formyl group. Compound 17 presents a MS2 spectrum and MS3 fragmentation pattern of [M + H]+ ion at m/z 212 similar to 9 and is probably the ortho-isomer (Table S2 and Scheme S5). Compound 10, with [M + H]+ at m/z 318 may result from the hydroxylation of the aromatic ring of metoprolol and demethylation of the ether moiety. In the previous work with fulvic acids a product resulting from the hydroxylation of the aromatic ring of metoprolol was identified (compound with [M + H]+ at m/z 332) [65]. However, in the present study, this compound was only detected in trace amounts, which may indicate that it has been converted into 10. Compound 10 has

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a difference of 14 Da with respect to the derivative detected in the work with fulvic acids, which is in accordance with the absence of the methyl group. In addition, in the MS2 spectrum of 10, with the molecular ion [M + H]+ at m/z 318, the presence of the product ions at m/z 116 and 98 and the

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losses observed in the MSn spectra of 42 Da (CH3CH=CH2), 44 Da (CH3CH2CH3) and 59 Da

A

CC E

PT

ED

M

A

N

U

(NH2CH(CH3)2) indicate that the aminopropanol moiety of metoprolol is preserved (Scheme S6).

19

I N U SC R A M ED PT CC E A

Scheme 3. Proposed structures of the main photodegradation products of metoprolol obtained using H2TF5PP as photosensitizer.

20

4

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Scheme 4. Mechanism proposed for the formation of 13 from metoprolol.

Conclusions

In this study the photodegradation of metoprolol was performed, for the first time, in the

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presence of a porphyrin (H2TF5PP) as photosensitizer, both under homogeneous conditions and immobilized on a silica support.

The main photoproducts formed were identified by HPLC-UV-ESI-MSn. At least 18 products

U

have been tentatively identified based on MSn experiments and fragmentation patters, including: i) several compounds which have already been previously identified in our work concerning the

N

photodegradation of metoprolol in the presence of natural fulvic acids; ii) the 3 isomeric compounds

A

with m/z 254, previously identified in the literature as being formed by photocatalysis using TiO2,

240, m/z 242 and m/z 318.

M

and iii) 3 new compounds which were tentatively identified for the first time in this work, with m/z

ED

In homogeneous conditions and under simulated solar light the degradation of metoprolol follows a pseudo-first order kinetics with a decrease in metoprolol of ca 90% after 12 h. The irradiation experiments in the presence of scavengers revealed that singlet oxygen is the main

PT

reactive oxygen species involved in the photooxidation process. In the presence of H2TF5PP-silica in buffered and stirring conditions, the photodegradation of metoprolol follows an exponential

CC E

decay with a decrease in metoprolol of ca 60% after 12 h. Besides being an improvement over the direct photolysis, there is no need for solvents for it solubilization and the porphyrin is easily removed. The irradiation time was converted into energy received by the solutions in order to predict the percentage of degradation under real sunlight. The predicted residual fraction of

A

metoprolol in solution using the kinetic parameters obtained under Solarbox irradiation is in accordance with the results obtained under real solar exposition. Finally, studies performed in a sample from the secondary effluent of a wastewater treatment plant fortified with metoprolol revealed that the efficiency of H2TF5PP-silica was not decreased by the complex matrix of the effluent.

21

Conflicts of interest: none

Acknowledgments Thanks are due to National Foundation for Science and Technology / Ministério da Educação e Ciência − FCT/MEC (POPH/FSE) for the financial support to QOPNA (UID/QUI/00062/2013), CERNAS (UID/AMB/00681/2013), CESAM (UID/AMB/50017 - POCI-01-0145-FEDER-007638)

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and CICECO (UID/CTM/50011/2013), through national funds (PIDDAC) and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement and Compete 2020, and also to the Portuguese NMR Network. The authors are also grateful to FCT and POPH/FSE for the PhD

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Grant to C.M.B. Neves (PD/BD/52531/2014). S.A.O. Santos thanks to AgroForWealth project (CENTRO-01-0145-FEDER-000001) funded by Centro2020. The authors also thank “Águas do Centro Litoral, S.A.” (ETAR de Ílhavo) and its responsible, Eng. Milton Fontes, for the collection

N

U

of the effluent sample and for providing data on its chemical characterization.

M

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