Photolytic and photocatalytic degradation of nitrofurantoin and its photohydrolytic products

Journal Pre-proof Photolytic and photocatalytic degradation of nitrofurantoin and its photohydrolytic products ´ ´ ardos, ´ ´ ˝ Orsolya Erzsebet Szabo-B Andrea Cafuta, Peter Hegedus, ˇ ´ ´ Fonagy, Gyula Kiss, Sandra Babi´c, Irena Skori´ c, Otto´ Horvath

PII:

S1010-6030(19)30175-3

DOI:

https://doi.org/10.1016/j.jphotochem.2019.112093

Reference:

JPC 112093

To appear in:

Journal of Photochemistry & Photobiology, A: Chemistry

Received Date:

28 January 2019

Revised Date:

31 August 2019

Accepted Date:

14 September 2019

´ ardos ´ ´ ˝ P, Fonagy Please cite this article as: Szabo-B E, Cafuta A, Hegedus O, Kiss G, Babi´c S, ˇ ´ O, Photolytic and photocatalytic degradation of nitrofurantoin and its Skori´ c I, Horvath photohydrolytic products, Journal of Photochemistry and amp; Photobiology, A: Chemistry (2019), doi: https://doi.org/10.1016/j.jphotochem.2019.112093

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Photolytic and photocatalytic degradation of nitrofurantoin and its photohydrolytic products Erzsébet Szabó-Bárdosa, Andrea Cafutaa, Péter Hegedűsa, Orsolya Fónagya, Gyula Kissb, Sandra Babićc, Irena Škorićd, Ottó Horvátha* a

Department of General and Inorganic Chemistry, Institute of Chemistry,

University of Pannonia, P. O. Box 158, 8201 Veszprém, Hungary b

MTA-PE Air Chemistry Research Group, H-8201 Veszprém, POB. 158, Hungary

Department of Analytical Chemistry, dDepartment of Organic Chemistry, Faculty of

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Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, 10000 Zagreb, Croatia *Corresponding

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Graphical abstract

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author (Department of General and Inorganic Chemistry, Institute of Chemistry, University of Pannonia, P. O. Box 158, 8201 Veszprém, Hungary, E-mail: [email protected], phone: +36 70 247 1061) E-mail addresses: [email protected] (E. Szabó-Bárdos), [email protected] (A. Cafuta), [email protected] (P. Hegedűs), [email protected] (O. Fónagy), [email protected] (Gy. Kiss), [email protected] (S. Babić), [email protected] (I. Škorić), [email protected] (O. Horváth) 1 Present name and address: Andrea Knežević, Reichenbachstraße 18, 86169 Augsburg, Germany

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Highlights photocatalyzed decomposition of nitrofurantoin was compared to its photolysis

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the first stage involved photoisomerization and photohydrolysis in both cases

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the photoisomer underwent dark hydrolysis too, giving two primary intermediates

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aerobic photocatalysis decomposed both nitrofuraldehyde and aminohydantoin

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several intermediates were detected to reveal degradation pathways

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Abstract

TiO2 based photocatalytic degradation of nitrofurantion (NFT), a widely used drug, and its

primary decomposition products, nitrofuraldehyde (NFA) and aminohydantoin (AHD) was

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investigated and compared to their photolysis in aerobic systems. UV-vis spectrophotometry, pH, IC, and HPLC measurements were applied to follow the changes during the irradiations

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and subsequently, in the dark. After a fast anti→syn (or trans→cis) photoisomerization of NFT (giving i-NFT), a slower photohydrolysis of both isomers took place upon UV

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excitation, leading to the formation of NFA and AHD. i-NFT proved to be more reactive than NFT; it underwent hydrolysis in the dark, too. While photolysis could not totally convert NFT and i-NFT within 120 min, they disappeared within 90 min during the photocatalysis

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under the same irradiation conditions, along with the degradation of NFA and AHD, and the accumulation of a rather stable intermediate identified as 5-hydroxyfuran-2-carbaldehyde, formed from NFA.

The direct photolysis of NFA also gave this characteristic intermediate

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along with its several derivatives formed via addition or condensation then redox transformations. They very slowly decomposed in photolysis, while totally disappeared

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during photocatalysis of NFA, producing polar aliphatic intermediates. Direct irradiation could not convert AHD, while photocatalysis led to its significant degradation in aerobic system. These results indicate that TiO2 based photocatalysis is suitable for the efficient decomposition of NFT and their photoderivatives.

Keywords: Nitrofurantoin derivatives; Photocatalysis; Photolysis; Intermediates; Thermal instability

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1. Introduction It has been well established that continuous input and persistence of pharmaceuticals in the environment could have a great impact not only on animals and micro-organisms but also on human health [1]. Therefore, public and scientific concern on this topic has progressively

increased. The main point of collection and subsequent release of pharmaceuticals into the environment are wastewater treatment plants (WWTPs) [2–4], where they enter via domestic and hospital sewages or through industrial discharges [1,5,6]. As a consequence, pharmaceutical residues were detected in different environmental compartments [7], in WWTP effluents, surface, ground and drinking waters [8], river sediments and wastewater sludge [9].

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Nitrofurans belong to a series of synthetic broad spectrum antibiotics which all contain 5nitrofuran ring and various substituents in the 2-position. Several thousands of nitrofurans have been evaluated as antimicrobial agents and of these, the hydantoin derivative,

nitrofurantoin (1-[(5-nitrofurfurylidene)amino]hydantoin), has achieved widest clinical

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applications [10].

It is rapidly absorbed from the gastrointestinal tract, well concentrated in the urine and

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active against a variety of common urinary tract pathogens [10–13]. An important property of nitrofurantoin is that usually sensitive microorganisms do not readily become resistant to the

Essential Medicines [15].

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drug [11–14]. Accordingly, it is included in the World Health Organization’s List of

In addition to their use in human medicine, nitrofurans (mainly furazolidone,

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nitrofurazone, furaltadone and nitrofurantoin) were frequently used in animal husbandry as feed additives and growth promoters to prevent and treat gastrointestinal infections [16,17]. However, nitrofurans and their metabolites have shown potential carcinogenic and mutagenic

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effects [18,19]. As a consequence, nitrofurans have been banned from using in animal husbandry both in the European Union [20] and in the US [21]. Nevertheless, in many

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countries nitrofurans are still used as a therapeutic or prophylactic medicine in animal husbandry. Hence, numerous studies proved the presence of nitrofurans and their metabolites in products of animal origin, but only a few papers dealt with NFT in environmental samples [22–24]. Quite recently, the thermal hydrolytic degradation of nitrofurantoin was studied at various temperatures and naturally occurring pH values [25]. Similarly, the photochemical behavior of nitrofurans, including NFT, was scarcely investigated [26,27]. According to these studies, upon UV irradiation the nitrofurans studied underwent a fast anti→syn photoisomerization followed by a slow photohydrolysis. The primary product of the latter 3

process was nitrofuraldehyde (NFA) (Scheme 1), which also proved to be photolabile upon UV excitation [27]. The other product of the photohydrolysis of NFT was aminohydantoin (AHD). However, no study was carried out with photocatalytic degradation of nitrofurans, although it is important to hinder these bioactive compounds to get into our environments. Notably, other methods have already investigated for the removal of NFT or other nitrofuran derivatives. Although NFT is an antibiotics, some bacterial cultures were isolated, which could partially decompose this pharmaceutical in 28 days [28]. However, the presence of NFT highly decreased the cell’s viability of these microbes, due to the change of their cell membrane’s

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permeability. Metal-organic frameworks (MOFs) proved to be useful for adsorption of various organic contaminants [29]. Two types of Zr(IV)-based MOF were found to be promising for sensing and removal of nitrofuran type antibiotics, due to their strong

adsorptivity toward these compounds [30]. After the removal, however, the adsorbent needs recovery and the collected contaminant a further treatment. Nitrofurans’ aromatic bond and

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nitrogen content may promote their degradation by ozonation [31]. Ozonation alone,

however, cannot reach the efficiency of the so-called advanced oxidation processes (AOPs).

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Based on the facts that nitrofurantoin is a frequently used drug with a relatively high excretion rate [10], the main objective of the present study was to investigate its

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photocatalytic degradation, using TiO2 as a catalyst. Advanced oxidation processes (AOPs) have proven to be among the most effective techniques for removing personal care products [32] and pharmaceuticals from water samples [33–36]. Oxidation processes in the case of

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TiO2 mediated photocatalysis, one of the most effective AOPs, are based on the generation of highly reactive radicals such as HO• and O2•- used for the unselective oxidation of pollutants, producing biologically more degradable and less toxic degradation products [37–

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39]. This efficient and environmentally benign procedure has not been previously applied for the degradation of NFT and related nitrofurans. Beside investigation of kinetics and pathways

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for the photocatalytic decomposition of nitrofurantoin and its degradation intermediates, the aim of this work was to compare these processes to those taking place in the direct photolysis of these species under the same irradiation conditions (similarly to the sunlight in the absorption range of NFT). In order to have a deeper insight into the photoinduced transformations, a careful analysis of the degradation products was also carried out. Since our preliminary experiments indicated that, in several cases, the compositions of the irradiated solutions underwent considerable changes in the dark, systematic stability measurements were realized, too. The results of this work could contribute to the 4

characterization of both the parent compound and the intermediates formed in the various photoinduced processes in these systems, and to the developments of efficient photocatalytic procedures for their decomposition in various wastewaters by potential usage of solar radiation.

2. Experimental 2.1. Materials and irradiations The following materials were used for the experiments: nitrofurantoin (abbreviated as NFT) (Acros Organics), nitrofuraldehyde (abbreviated as NFA), aminohydantoin (abbreviated as (AHD) (Sigma-Aldrich), Degussa P25 TiO2 (now called Evonik

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AEROXIDE® P25 TiO2), HPLC grade methanol (Honeywell, Riedel-de Haen). High purity water used in this study as solvent was double distilled and then purified with a Milli-Q

system. The solutions to be irradiated contained 10 mg dm-3 NFT, NFA, or AHD. 1g dm-3 TiO2 was applied for the photocatalytic systems.

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Irradiations of the reaction mixtures were carried out in a flat, round, two-neck duran-glass reactor (with 100 cm3 volume and 2 cm thickness (optical path length), see Fig. S1B in the

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Supplementary Information (SI)) under aerobic conditions, unless otherwise stated. A continuous bubbling of air at constant flow rate of 10 dm3 h-1 provided dissolved oxygen.

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Besides, a magnetic stirrer served for the homogenization of the reaction mixture. The reactor was vertically located in front of the light source (at a distance of 6.5 cm, Fig. S1A). The latter one was a Philips metal-halide lamp with an emission in the 350-750 nm range (I0=

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10.9 mW cm-2; I0(UVA)= 1.4 mW cm-2; I0(vis)= 9.5 mW cm-2; its emission spectrum is shown in Fig. S2). The irradiances were measured with a thermopile, using a 400-nm cut-off filter for

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the visible range.

2.2. Analytical procedures

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For analysis, 4 cm3 samples were taken. After photocatalytic experiments, the solid phase

was removed by filtration using Millipore Millex-LCR PTFE 0.45 m and 0.25 m filters. The absorption spectral changes of the reaction mixtures irradiated were followed with a SCINCO S-3100 spectrophotometer in 1-cm quartz cuvettes. HPLC analyses of the samples were carried out with a Shimadzu UFLC equipment. An Agilent 1100 Series LC/MSD Trap VL System was used for mass spectrometric measurements. (Details are given in the SI).)

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Nitrite and nitrate anions formed were determined by a Dionex DX300 ion chromatographic system using suppressed conductivity detection. The injection volume was 50 μl. Separations were carried out by a Dionex IonPac AS4A-SC (250×4 mm) column of medium hydrophobicity. The concentration, pH and flow rate of the carbonate eluent were 3.5 mM, 10.2 and 1.2 cm3 min-1. The pH of the aqueous phase of the reaction mixture was determined by a SP 10T

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electrode connected to a Consort C561 equipment.

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3. Results and Discussion 3.1. Direct photolysis and photocatalysis of NFT 3.1.1. Spectral changes Although a thorough study also dealing with the direct photolysis of NFT in aerated systems appeared in 2006 [27], before the photocatalytic degradation experiments, for a comparison, under the same irradiation conditions, we also applied this type of treatment in aerated solutions. Beside the spectral changes, nitrite and nitrate concentrations as well as pH were monitored during the irradiation period. As Fig. 1A indicates, confirming the previous results [27], within the first 4-6 minutes a very fast spectral change took place, which can be

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attributed unambiguously to the anti→syn (or trans→cis) photoisomerization giving i-NFT. (The spectrum of i-NFT can be found in Fig S3 of ref 27). The much slower process

following the fast photoisomerization was decomposition of i-NFT as the monotonous

decrease of absorbance in the 230-420-nm range indicates. Besides, the photohydrolysis of

the starting compound (NFT) may also take place. This spectral change indicates that the sum

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of the molar absorbances of the intermediates formed in the degradation process is lower than ε of the isomer mixture of the initial compound in this range of wavelength. The primary

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degradation process in the direct photolysis of nitrofurans (including NFT) is photoinduced hydrolysis producing nitrofuraldehyde (NFA, a common product of the hydrolysis of all

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nitrofurans) [27]. The other product of this reaction is aminohydantoin (AHD) in the case of NFT, according to Scheme 1. Since neither NFA nor AHD absorb above 400 nm, the increase of absorbance in the 420-530-nm range indicates the formation of another

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intermediate (Fig. 1A). This could not be formed by the degradation of NFT or AHD because during their direct photolysis no absorption was observed above 400 nm. Besides, at the direct photolysis of NFT, applying a filter cutting off the irradiation wavelengths below 400

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nm, only a spectral change corresponding to the photoisomerization was detected. Neither hydrolysis nor formation of another product absorbing above 420 nm could be observed. This

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phenomenon suggests that both processes needs excitation of NFT at wavelength much below 400 nm. Notably, this increase of absorbance in the 420-530-nm range was also observed in argon-saturated solution, while nothing similar occurred in the photocatalytic degradation of NFT (Fig. 1B). The spectral change during the photocatalytic treatment of NFT in the first period (up to ca. 20 min) was very similar to that observed in the case of the direct photolysis (Fig. 1). Photoisomerisation followed by photohydrolysis took place also in this system. These reactions may be a bit slower than in the homogeneous solution, due to the inner filter effect 7

of the suspended TiO2. However, degradation of NFT and its hydrolysis products was much faster during the photocatalysis as the spectral change in the second period (beyond the 20th minute) indicates (Fig. 1B). The absorption in the 350-450-nm range totally vanished within 120 min, while in the photolyzed solution the maximum absorbance in this range did not decrease below 0.3, besides, a significant increase above 420 nm took place. These deviations clearly show that in the direct photolysis no appreciable decomposition happened, even if nitrite formation took place in the aerated system, whereas the photocatalysis totally degraded not only NFT, but also the intermediates absorbing in the 350-450-nm range within 120 min. 3.1.2. Changes of NO2-, NO3-, and H+ concentrations

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Monotonous decreases of pH, i.e., increases of the H+ concentration, accompanied the degradation of NFT in aerated systems during the photolysis (from pH=6.5 to 5.0) and

photocatalysis (from pH=6.5 to 4.5) of NFT. This acidification originated from the formation of nitrous and nitric acid, and its order of magnitude was in accordance with the accumulation

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of nitrite and nitrate ions during the irradiations (Fig. 2).

Nitrous acid was formed via photoinduced substitution of the nitro group of NFT, its

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isomer (i-NFT) or their hydrolysis product, NFA, with a hydroxyl group. According to Fig. 2A, the nitrite formation was rather slow in the first 30 min of the photolysis (with the

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average rate of 2.8×10-4 mM min-1), then it accumulated almost linearly with an order of magnitude higher rate (4.5×10-4 mM min-1). It suggests that nitrite primarily originated from NFA. Earlier ESR measurements in the photolysis of 5-nitro-2-furoic acid (with the same

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basic structure as NFA) indicated that nitrite is produced via formation of a nitro cation radical (NFA.+ in our case), which reacts with water to form a hydroxyl radical adduct (in which the HO and NO2 groups connect to the same carbon atom), followed by the very fast elimination of the nitro

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group [40].

Nitrate generation was much slower because it was formed from nitrite. In the photocatalytic

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system the nitrite formation was much faster, and took place already from the very beginning of the irradiation, deviating from the photolysis. This phenomenon can be interpreted by the reaction between the photocatalytically generated HO radicals and the ground-state NFA molecules, producing the same type hydroxyl adduct, which was formed in the photolysis from the nitro cation radical. Accordingly, also the nitrate generation dramatically (by an order of magnitude) increased, compared to the photolysis (Fig. 2). This increase was accompanied by a similarly fast decrease of nitrite concentration from the 40th minute (Fig.

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2B). Scavenging experiments demonstrated that HO radicals played a determining role in the generation of NO2- from NFT and NFA in the photocatalytic system. Methanol, an efficient HO scavenger [41], strongly depressed the nitrite formation in the photocatalytic system (Fig. 3). In the presence of benzoquinone, an effective scavenger of O2- [42], the accumulation of nitrite dramatically increased, indicating the important role of superoxide in the oxidation of NO2- to NO3-. Addition of sodium azide, a scavenger of 1O2 [43], just slightly enhanced the nitrite formaton, suggesting a minor role of singlet oxygen in this oxidation process.

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3.1.3. HPLC and stability measurements

The concentrations of the starting material and the primary intermediates formed in the photoinduced reactions in these systems were followed by HPLC technique. Having

commercially available standards of NFT, NFA, and AHD, their concentration could be

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easily determined, using their specific area/concentration values regarding their peaks in the chromatogram. In the case of the photoisomer of NFT (i-NFT), this specific value was

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determined from the peak areas measured in the first 3 min of the irradiation (see Fig. S1 and the corresponding description in the SI), where the degradation of the primary intermediates

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(i-NFA, NFA, and AHD) was negligible. Thus, also the concentration of i-NFT could be determined in the samples taken during the irradiation. The concentrations of NFT and the intermediates formed were also measured in these samples after keeping them in the dark for

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various periods at 5oC or 25oC, in order to gain some pieces of information regarding the stability of these species.

In accordance with the spectral changes, during the photolysis, the decrease of the NFT

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concentration was rather fast in the first 5-6 min (with an initial rate of 7.8×10-3 mM min-1), then became much slower (6.9×10-5 mM min-1), keeping this rate for 110 min (Fig. 4A). The

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formation rate of i-NFT (7.8×10-3 mM min-1) well agreed with that of the NFT decay, indicating that the predominant transformation way of the excited NFT was isomerization. From the concentrations of NFT and i-NFT at 9 min (Fig. 4A), at the breakpoint of the CNFT vs. time plot, where the system reached a quasi photostationary state slightly affected by the photohydrolysis of these species, the equilibrium constant (K) for the photoisomerization (vs. very slow thermal back reaction) can be estimated. [i-NFT]/[NFT] = 1.89, taking also the effect of the photohydrolysis into account. This value is 1.8 times higher than that given in ref. 27, due to the different irradiation conditions and initial concentration. 9

After a steep concentration increase of i-NFT, its accumulation gradually slowed down, followed by a linear decay, the rate of which (1.40×10-4 mM min-1) is about twice as high as as that of NFT. This suggests that i-NFT is more reactive than its parent compound, due to the higher energy content gained via photoisomerization. Also in the photocatalytic system, NFT underwent a fast transformation (isomerization) within the first 8 minutes (Fig. 4B). The initial decay rate of NFT was 6.0×10-3 mM min-1. The fast decay of NFT was accompanied by a similarly quick formation of its isomer. However, the initial formation rate of this isomer (3.9×10-3 mM min-1) was considerably lower than the decay rate of its parent compound, indicating that other, competing reactions

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(such as hydrolysis and oxidation with hydroxyl radicals) consumed both species. Accordingly, after ca. 8 minutes the photoisomer also displayed a decay, the rate of which well agreed with that of the starting compound. Deviating from the photolysis, the

disappearance of NFT and i-NFT was much faster, completed within 120 min (Fig. 4B).

NFT, not surprisingly, did not change in the dark, in accordance with the observations

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of Biošić et al. [25], while the concentration of i-NFT significantly decreased during 1 day

(kept in the dark) at 25oC, after both photolysis (Fig. 5A) and photocatalysis (Fig. 5B). The

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temperature dependence was demonstrated in the previous case; the concentration changes regarding 7 days at 5oC were smaller than the corresponding ones after 1 day at 25oC. The

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decay of i-NFT was significantly faster after the photocatalysis (Fig.5); at 25oC it almost totally disappeared already within 24 hrs, clearly demonstrating its instability, due to the higher reactivity (energy content) of the syn (cis) structure.

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The decay of NFT and i-NFT was accompanied by the formation of NFA and AHD, due to photoinduced hydrolysis.. The concentration vs. irradiation time plots for NFA in both photolysis and photocatalysis of NFT are shown in Fig. 6A,B, along with the concentrations

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after standing in the dark for various periods of time at 5oC or 25oC. In the case of AHD, the sensitivity of HPLC was much lower than that for NFA, hence it

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could not be reliably detected right after the irradiations during the photolysis (Fig. 6C). In the photocatalysis of NFT, the initial rate for the formation of NFA (9.15×10-4 mM min-1) was moderately lower than that for AHD (1.12×10-3 mM min-1), indicating a faster photocatalytic degradation of the previous one. Accordingly, the concentration vs. time plot for NFA displayed a maximum at about 20 min (Fig. 6B), while that for AHD at 30 min (Fig. 6D). This phenomenon is in accordance with the fast nitrite formation from NFA (and from NFT as well), which shifts the maximum concentration toward shorter times compared to that of AHD, and slightly decreased the apparent formation rate of NFA. 10

The values in Fig. 6 clearly indicate that both NFA and AHD were formed in the dark, too, i.e., thermal hydrolysis of i-NFT took place after both photolysis and photocatalysis. Besides, the decay of i-NFT (Fig. 5) and the formation of NFA and AHD are in accordance, even quantitatively, especially regarding the samples irradiated for 6-40 min in both methods. The spectral changes in the dark agree with the HPLC results. The samples of 2.5-, 7-, and 30-min irradiations in the photocatalyis of NFT displayed significant changes corresponding to the decay of the photoisomer and the formation of NFA and AHD (Fig. S2). The spectrum belonging to the 7-min sample shows the biggest change because initially it contained the highest concentration of the photoisomer.

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Beside NFA and AHD, in the case of the photocatalysis of NFT, a third compound (intermediate) formed and accumulated in an appreciable amount (Fig. S3). Its relative concentration given by the area of its chromatografic peak (at 3.4-min retention time)

reached a maximum within 120 min, suggesting that it formed from NFA. On the basis of our MS measurements, this degradation product has been identified as 5-hydroxyfuran-2-

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carbaldehyde (MW = 112) and designated as PD-1. This intermediate exists in equilibrium

with its keto type tautomer (5-hydroxymethylene-2(5H)-furanone, DP-1'). This observation

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confirms the main photolytic degradation pathway suggested by Edhlund et al. [27], who supposed (but not proved) the formation of this compound. Also the concentration of this

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intermediate perceptively increased in the dark, indicating a moderate thermal conversion of NFA after the photocatalysis of NFT.

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3.2. Photolysis and photocatalysis of NFA

From the products of the hydrolysis, AHD did not show any reaction upon irradiation in

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aerobic system, while NFA proved to be photolabile. The latter observation agreed with the results in ref. 27. Hence, the photochemistry of NFA and the thermal stability of its irradiated

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solutions were also investigated in the presence of oxygen.

3.2.1. Spectral change During the direct irradiation of NFA, a fast decay of the 310-nm band took place in the first 15 min, along with the similarly rapid rise of a new band at 210 nm (Fig. 7A). Much slower changes of absorbance can be observed at longer irradiation periods, indicating the

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formation of relatively stable intermediates (or end-products). This is well demonstrated by the double band at 305 and 355 nm. Keeping the irradiated solutions in dark at 25oC for 24 hrs, the double band significantly decreased, while the peak at 210 nm did not change (Fig. S4 compared to Fig. 7), suggesting that the previous one belonged to labile intermediates, while the latter one to a stable product. The spectral changes during the photocatalytic degradation of NFA (Fig. 7B) significantly deviate from those observed for the photolysis. Surprisingly, the decrease of the main band at 310 nm was much slower in the photocatalysis than in the direct photolysis of NFA in the first 15 min. This may be attributed to the inner filter effect (also involving light scattering)

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of the suspended TiO2 photocatalyst. In the subsequent 60 min, however, this band totally disappeared. Besides, the absorption increase in the 190-220-nm range is much smaller than that observed during the photolysis. The latter two phenomena indicate that most of the intermediates formed in the photocatalytic system were also degraded within 120 min.

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3.2.2. HPLC and stability measurements

In accordance with the spectral changes, the photoinduced conversion of NFA took place

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rather fast in the photolysis (with the initial rate of 8.6×10-3 mM min-1); its concentration decreased by ca. 75% during 15 min and totally disappeared within 40 min (Fig. 8A). The

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decay of NFA was accompanied by the formation of intermediates detected at 2.9- and 3.4min retention times. On the basis of our MS measurements, the latter one was identified as 5-hydroxyfuran-2-carbaldehyde (m/z = 113 in the positive mode, i.e., MW=112), i. e., DP-1,

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similarly to the photolysis of NFT. The previous one, designated as DP-2, resulted in a much higher m/z value (225, i.e., MW=224), which indicated a product formed by the addition of two DP-1 molecules (Fig. S5 shows the suggested structure). The relative

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concentrations (given by the peak areas) vs. time plots display that these intermediates slowly degraded after the total disappearance of NFA (Fig. 8A), indicating their relatively low

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photolability – also in agreement with the spectral changes. Keeping the irradiated samples in the dark, considerable concentration decreases could be observed for both the parent compound and, much more remarkably, the intermediates, especially at 25oC (Fig. S6 compared to Fig. 8A). These results clearly indicate that the intermediates formed during the photolysis of NFA are thermally labile. Besides, they may promote a moderate thermal conversion of NFA, too, which is, otherwise, stable in the dark. Surprisingly, the decay of NFA in the photocatalysis (with the initial rate of 2.8×10-3 mM min-1, Fig. 8B) was significantly slower than in its photolysis (Fig. 8A), thus its total disappearance took ca. 60 12

min. Some intermediates were detected in the photocatalyzed system, too. The relative concentration (i.e., the chromatographic peak area) of the most abundant one (with 3.4-min retention time) monotonously increased for about 30 min, then decreased and disappeared in about 120 min (Fig. 8B). The shape of this plot suggests that this intermediate was directly formed from NFA. Similarly to the previous cases, this intermediate has been identified MS measurements as 5-hydroxyfuran-2-carbaldehyde (MW = 112), i. e., DP-1. This conclusion is in full accordance with the spectral changes in Fig 7A, where the appearance of a rather persistent double band at 305 and 355 nm was observed. Since the absorption spectrum of 5-

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hydroxyfuran-2-carbaldehyde (DP-1) displays a band at 305 nm and a shoulder at 355 nm [44], this is one of the relatively stable degradation products in the photolysis. The band at 355 nm covers the shoulder of DP-1, and could be attributed to another, relatively stable

intermediate, possibly with the retention time of 2.9 min. Besides, several intermediates with 1.7-1.9-min retention times formed and decayed at longer irradiation times. These may be

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related to the spectral changes (increase of absorbance) in the 190-220-nm range and to the m/z values below 100 in the MS spectra. The short retention times and absorption

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wavelengths, along with the low molecular weights indicate that these intermediates are polar aliphatic compounds formed via cleavage of the furan rings. The relative concentration vs.

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irradiation time plot for a representative one (with 1.7-min retention time) of these intermediates confirms this interpretation (Fig. 8B). Beside the above mentioned intermediates, further photoproducts were also detected by MS measurements (as DP-3, 4, 5,

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6, and 7 with MW values of 206, 222, 238, 178, and 150, respectively). They are discussed in Section 3.4, in the frame of a summary of the compounds identified in the photolytic and photocatalytic degradation of NFT and NFA.

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As for the thermal stability of the irradiated samples, deviating from the direct photolysis

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of NFA, no appreciable concentration change was observed, even after 48h at 25oC.

3.3. Photocatalysis of AHD As mentioned earlier, AHD did not change upon direct UV irradiation in both aerated and argon-saturated systems. This could be accounted for the minimal overlap of the absorption spectrum of AHD and the emission spectrum of the light source. However, it did not show any conversion in the deaerated photocatalytic system. It underwent degradation only via 13

aerobic photocatalysis. This observation suggested that hydroxyl radicals are not enough for the decomposition of AHD. It needs hydroperoxyl radicals (HO2) too, which are formed through electron scavenging with dissolved O2 molecules. During the photocatalytic degradation of AHD in aerated system, a monotonous increase of the absorbance could be observed in the 190-310-nm range, characterized by two bands (at about 205 and 260 nm, Fig. 9). This phenomenon indicates that the absorbance of the products formed in photoinduced ways in this system is higher than that of the starting compound throughout in this range of wavelength. As measured by HPLC, the initial decay rate of AHD was 7.7×10-4 mM min-1 (Fig. S7).

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This value is almost 3 times smaller than the corresponding one observed for NFA, and, hence, AHD could not be totally degraded in this system within 120 min. This result, in accordance with the stability of AHD observed in other systems applied in this study,

indicates that its structure is much more resistant to photoinduced oxidation or oxygenation

processes involving dissolved oxygen or to attacks by photocatalytically generated oxidative

-p

species such as hydroxyl and hydroperoxyl radicals, or singlet oxygen.

Unfortunately, no intermediate could be detected by HPLC in this system. Besides, after

re

the irradiation no spectral or concentration change was observed within 24 hr at 5oC or 25oC

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(Fig. S7).

3.4. Characterization of nitrofurantoin (NFT) photodegradation products

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In order to define the degradation process, it was necessary to investigate possible degradation products that evolve during such degradations. Seven degradation products were detected and proposed during the investigated degradation processes as newly formed peaks

ur

on the chromatogram. In order to elucidate the nitrofurantoin photolytic/photocatalytic degradation pathways, structures of degradation products (DP) were suggested, primarily on

Jo

the basis of mass spectra which were very informative. Photolytic/photocatalytic degradation processes of nitrofurantoin (together with nitrofuraldehyde, the primary product of its photohydrolysis), gave products DP1 – DP7, as shown in Scheme 2.

Several processes can be suggested primary from NFT showing the molecular ion m/z 239 (in the positive mode). These are the primary photoisomerization followed by the 14

photohydrolysis to NFA and AHD confirmed by their characteristic masses. From the NFA the degradation product DP-1 could be formed by aromatic photosubstitution (nucleophilic in the photolysis and electrophilic in the photocatalysis) having the characteristic lower mass and in equilibrium with DP-1' as supposed in ref. 27. The further transformations could lead to two pathways: a) to the secondary degradation product DP-2 obtained by nucleophilic addition to the carbonyl group of DP-1. The structure of the photodegradation product DP-2 is supported by the molecular ion m/z 225 (in the positive mode, i.e., MW = 224) being 112 higher than that for DP-1, b) to further substitution (or condensation) to the ether type DP-3. The next paths include the photochemical hydroxylation to the transformation product DP-4

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showing molecular ion m/z 223 (MW=222) being16 higher than the m/z for DP-3, or oxygenation by dissolved oxygen, giving the detected doubly carboxylated transformation

product DP-5. The latter one was suggested according to the mass spectrum by molecular ion m/z 239 (MW=238) being 32 higher than the m/z for DP-3.-It is possible that some reversible substitution/reduction happens at the very reactive positions of the two furan rings, giving the

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179 (MW=178) and 151 (MW=150), respectively.

-p

signals for the photodegradation products DP-6 and DP-7 with the corresponding masses m/z

As auxiliary pieces of information, the individual mass spectra of NFT and AHD are provided in the SI (Figs. S8 and S9), together with those of the samples taken after various

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irradiation times, regarding both the photolysis (Fig. S10) and the photocatalysis (Fig. S11) of NFA. Besides, the intensity vs. irradiation time plots of the characteristic MW or m/z values

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are also given as Figs S12 and S13. The plots regarding NFA, DP-1, DP-2, and DP-4 show very good correlations with the results of the corresponding HPLC measurements (see Fig. 8). The concentration maximum for most of the intermediates were at about 40 min. (DP-4 is

ur

a characteristic exception, due to its slower accumulation.)

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4. Conclusion

Our results clearly indicate that TiO2 based photocatalysis much more efficiently degrade

NFT and the products of its photohydrolysis, NFA and AHD as primary intermediates, than their direct photolysis does. Nevertheless, also in photocatalysis, NFT undergoes photoisomerization and photohydrolysis. As stability measurements indicated, the photoisomer (i-NFT) is much more reactive than the starting compound (NFT); it efficiently hydrolyzes in the dark, too. A careful analysis of the degradation products indicated that various derivatives were formed via addition and redox transformation processes. Some of 15

them may biologically more dangerous than NFT. While NFA can be directly photolyzed, degradation of AHD takes only place in photocatalysis. Scavenging experiments indicated that HO, HO2, and 1O2 as well participate in the oxidation processes resulting in decomposition via cleavage of the aromatic rings. TiO2 based photocatalysis proved to be suitable for an efficient degradation of NFT and its photodecomposition products. Since NFT is a characteristic representative of nitrofurans, these results can be important for a reliable removal of such environmentally dangerous compounds by even commercially available titanium dioxide and potential usage of solar radiation.

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Competing interest statement The authors declare no conflict of interest.

Acknowledgment

This work was supported by the Széchenyi 2020 under the GINOP-2.3.2-15-2016-00016

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and the Croatian Science Foundation under the project Fate of pharmaceuticals in the

environment and during advanced wastewater treatment (PharmaFate) (IP-09-2014-2353).

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The competent help by Dr. Krisztián Horváth and Martina Biošić in the HPLC measurements

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is also appreciated.

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20

Figure captions

0 1 2 3 6 12 20 30 40 50 90 120

0.4

0.2

Time / min

B

0 1 2.5 4 7 11 15 20 30 40 50 60 75 90 120

0.6

Absorbance

0.6

0.4

0.2

0.0

0.0 200

300

400

500

200

600

300

400

500

600

Wavelength / nm

Wavelength / nm

6.0E-3

na

4.0E-3

0.0E+0 0

ur

2.0E-3

40

80

2.0E-2

B

1.5E-2 4.0E-3 1.0E-2

2.0E-3 5.0E-3

0.0E+0

0.0E+0 0

40

80

120

Irradiation time / min

Jo

Irradiation time / min

120

c(NO2-) / mM

lP

A

c(NO3-) / mM

6.0E-3

re

-p

Fig. 1. Spectral change of NFT during direct photolysis (A) and photocatalysis (B) in aerated systems (C0(NFT)=10 mg dm-3, 4.2×10-2 mM).

c(NO2-), c(NO3-) / mM

Absorbance

0.8

Time / min

A

ro of

0.8

Fig. 2. Formation of nitrite and nitrate during direct photolysis (A) and photocatalysis (B) of NFT in aerated systems (C0(NFT)=10 mg dm-3, 4.2×10-2 mM).

21

1.2E-2

without scavenger

benzoquinone methanol

c(NO2-) / mM

9.0E-3

sodium azide

6.0E-3

ro of

3.0E-3

0.0E+0 0

40

80

120

Irradiation time / min

re

-p

Fig. 3. Formation of nitrite during the photocatalysis of NFT in aerated systems containing 2.9 M methanol, 1.25×10-3 M benzoquinone, or 5×10-3 M sodium azide compared to the case without scavenger (C0(NFT)=10 mg dm-3, 4.2×10-2 mM).

5.0E-2

A

NFT-isomer

lP

NFT

na

3.0E-2

2.0E-2

1.0E-2

0.0E+0 0

ur

Concentration / mM

4.0E-2

40

80

NFT

NFT-isomer

3.0E-2

2.0E-2

1.0E-2

0.0E+0 0

40

80

120

Irradiation time / min

Jo

Irradiation time / min

120

B

4.0E-2

Concentration / mM

5.0E-2

Fig 4. Concentration vs. time plots for the starting compound and its photoisomer during the direct photolysis (A) and photocatalysis (B) of NFT in aerobic systems.

22

A

after irradiation

1 day-25°C

7 days-25°C

7 days-5°C

2.0E-2

1.0E-2

B

2.0E-2

Concentration / mM

after irradiation

24h-5°C

48h-5°C

1.5E-2

1.0E-2

5.0E-3

0.0E+0

0.0E+0 0

40

80

0

120

Irradiation time/ min

40

80

120

ro of

Concentration / mM

3.0E-2

Irradiation time / min

Jo

ur

na

lP

re

-p

Fig. 5. Concentration change of the photoisomer (i-NFT) in the dark (at 5oC or 25oC ) within various periods of time after direct photolysis (A) and photocatalysis (B). The uppermost plots in both diagrams display the concentrations of i-NFT right after the actual irradiation times, while the plots below them indicate the corresponding concentrations in these samples kept in the dark (after the irradition) for 1 day, 2 days or 7 days at 5oC or 25oC.

23

3.0E-2

A

1.0E-2

B

after irradiation

24h-25°C

Concentration / mM

Concentration / mM

after irradiation

1 day-25°C

8.0E-3

7 days-5°C

6.0E-3

4.0E-3

48h-25°C

2.0E-2

24h-5°C 48h-5°C

1.0E-2

ro of

2.0E-3

0.0E+0

0.0E+0 0

40

80

0

120

40

Irradiation time / min 2.4E-2

3.0E-2

D

after irradiation

1 day-25°C

-p

2.0E-2

48h-25°C 24h-5°C 48h-5°C

re

7 days-5°C

24h-25°C

Concentration / mM

7 days-25°C

8.0E-3

1.0E-2

lP

Concentration / mM

120

Irradiation time / min

C

1.6E-2

80

0.0E+0

0.0E+0 0

40

80

0

40

80

120

Irradiation time / min

na

Irradiation time / min

120

Jo

ur

Fig. 6. Concentration change of NFA and AHD in the dark (at 5oC or 25oC) within various periods of time after direct photolysis (A - NFA, C - AHD) and photocatalysis (B - NFA, D AHD) of NFT.

24

0.9

0.9

Time / min

A

Time / min

B

0

0

2

2

4

0.6

6

9

0.6

Absorbance

Absorbance

4 15 20 30 40

0.3

50

10 15

20 30 40

0.3

50

60

60

90

90

120

120

0.0

0.0 200

300

200

400

250

300

350

400

450

500

Wavelength / nm

ro of

Wavelength / nm

ret=3.4 min

Jo

0.02

5.0E+4

40

0.0E+0 80

Irradiation time / min

NFA

rt=3.4 min

ret=1.7 min

0.07

6.0E+3

0.06

5.0E+3

0.05 4.0E+3 0.04 3.0E+3

0.03 2.0E+3 0.02 1.0E+3

0.01

0.00

0

Concentration / mM

1.0E+5

Area

1.5E+5

na

0.06

ur

Concentration / mM

2.0E+5

0.04

B

ret=2.9 min

0.08

120

Area

NFA

lP

A

re

-p

Fig. 7. Spectral changes during the direct photolysis (A) and photocatalysis (B) of NFA in aerated systems.

0.00

0.0E+0 0

40

80

120

Irradiation time / min

Fig. 8. Concentration changes of the starting compound and the intermediates formed during the direct photolysis (A) and photocatalysis (B) of NFA in aerobic systems.

25

0.4

Time / min 0

Absorbance

0.3

6 9 15

0.2

20 30 40 50

0.1

60

0.0 250

300

350

ro of

200

Wavelength / nm

Jo

ur

na

lP

re

-p

Fig. 9. Absorption spectra of aminohydantoin during photocatalysis in the presence of oxygen, C0(AHD)=10 mg dm-3, 1 g dm-3 TiO2.

26

Scheme captions

Jo

ur

na

lP

re

-p

ro of

Scheme 1. Photoinduced hydrolysis of NFT.

27

ro of -p re lP na ur Jo Scheme 2. Tentative molecular structures of nitrofurantoin photodegradation products.

28