Photochemical Reaction Mechanism Of Naproxen And Its Photoproducts In Aquatic Environment

Pharmaceuticals and personal care products(PPCPs)as emerging pollutants have attracted considerable interest for their environmental fates and toxicological properties.Pharmaceuticals in the environment have become the focus of attention due to the characteristics of frequent detection,pseudo-persistence and ecological risk.Photochemical transformation is the main degradation way of pharmaceuticals in environment.It is important to study the photochemical transformation mechanism of pharmaceuticals in water environment for the safety of ecological environment.Therefore,a typical non-steroidal anti-inflammatory drugs naproxen(NP)and its two important photoproducts 1-(6-Methoxynaphthalen-2-yl)ethanol(4a)and 2-Acetyl-6-methoxy naphthalene(13a)were chosen as models.The effects of decarboxylation of NP with different protonated forms,and reactive oxygen species(ROS),such as hydroxyl radical(·OH),singlet oxygen(1O2)and superoxide anion radicals(·O2-),on photochemical reaction kinetics and photolysis pathways were investigated by means of photochemistry experiments and quantum chemical calculations.At the same time,the effects of inorganic nitrogen,organic cosolvents and 1,4-Diazabicyclo[2.2.2]octane(DABCO),a quencher of singlet oxygen on the photolysis system of NP were studied to clarify the photochemical reaction mechanism of NP and its photoproducts in aqueous solutions.The main contents and results are as follows:(1)Photodegradation mechanisms of NPA DFT calculation combined with experiments was performed to explore the inner working of the naproxen photolysis.Contributions of different reactive oxygen species in the photolysis reaction also have been clarified.?The triplet deprotonated form of naproxen is much more reactive than the protonated one,as the free energy barrier(?G(?)=9.8 kcal·mol-1)of the intramolecular decarboxylation process with deprotonated naproxen is much lower than the free energy barrier(?G(?)=64.4 kcal·mol-1)of the protonated naproxen.The experimental results show that the higher the initial pH(pH>7.2),the faster the reaction rate,which indicates that the photochemical reaction rate is faster when NP exists in the form of dephosphorization.? By investigating the energy difference between the lowest singlet state(S1)and the lowest triplet state(T1),it is proved that NP forms the excited state through n??*transition and that the T1 state occupies the main position,while la,4a and 13a form the excited state through ???*transition,and the singlet state occupies the main position.Namely,the decarboxylation of NP is likely to occur in the T1 state,while the photolysis of la,4a and 13a is likely to occur in the S1 state.? According to the relative free energy barriers and quenching experimental outcomes,·OH plays an absolutely dominant role in the indirect photolysis process of la(?G(?)eff=7.6 kcal·mol-1)and 4a(?G(?)eff=7.0 kcal·mol-1),while 1O2 and ·O2-have a similar effect on the photolysis(?G(?)eff=30.8?35.9 kcal·mol-1).?Prediction about the reactive sites of ketone derivative(13a)has been made,the C2 and C7 sites may be attacked by ·OH,while the C6-C11 bond may break.And the predicted products coincide with the characterized intermediates very well.To sum up,the experimental and theoretical investigation on the photolysis reaction pathways from naproxen to ketone derivative enhances our understanding of naproxen photolysis and sheds new light to study the photochemical reaction mechanism of naproxen.(2)The effect of inorganic nitrogen on the photolysis of NP,4a and 13aDifferent forms of inorganic nitrogen in natural water plays an important role in the photochemical transformation of pharmaceutical contaminants.The effects of different forms of inorganic nitrogen in water on the photodegradation of NP and its two important photolysis intermediates 4a and 13a were studied.The experimental results showed that NH4+ had little effect on the photolysis of NP and its photoproducts,while NO2-and NO3-had inhibitory effects on the photodegradation of NP,4a and 13a.The influences of NO2-and NO3-on NP were mainly the light shielding effect,while the dominant influence for the photolysis of 4a and 13a was the indirect inhibition caused by the competition among ·NO,·NO2 and ·OH produced in the photochemical reaction system.The free energy barriers of·OH,·No2 and ·NO oxidizing 4a and 13a showed an upward trend(4a:7.0,21.2 and 54.4 kcal·mol-1;13a:34.5,47.1 and 70.3 kcal·mol-1).The differences of free energy barrier indicated that ·NO2 and ·NO generated in the reaction system would lead to the decrease of reaction rate.This explained well the differences of NO2-and NO3-on the photolysis of 4a and 13a.(3)The effect of organic solventsOrganic solvents such methanol are often used as cosolvents to improve the solubility of some insoluble pharmaceuticals in photochemical research.As a result,a small amount of organic solvents are introduced into the reaction system.Little attention is reserved to the effect of cosolvents adopted for solubilization on photochemical experiments.NP and its major photoproducts 4a and 13a were studied in aqueous solutions under monochromatic irradiation at pH=7.0 and T=25?.The photochemical reaction kinetics in pure water,pure water-1%cosolvents(methanol,ethyl alcohol and acetonitrile)and pure water-1%isopropanol were compared.The obtained results indicated a remarkable suppression effect of ethyl alcohol and methanol on the photodegradation rates of NP and its photoproducts 4a and 13a.Acetonitrile had the least effect on the photolysis of NP and its photoproducts,while isopropanol had the greatest effect.The activation energy barriers of ·OH attacking methanol,ethanol,acetonitrile and isopropanol for abstracting hydrogen were calculated,which were 8.54,7.61,12.52 and 7.17 kcal·mol-1,respectively.Thus,the reaction rate of isopropanol with ·OH was the fastest,followed by ethanol,and acetonitrile with ·OH was the slowest.Therefore,the theoretical calculation results are in good agreement with the experimental phenomena.These organic solvents can influence the photochemical reaction rate by quenching ·OH.Therefore,when studying the effect of reactive oxygen species on the photolysis mechanism of water-insoluble drugs,we must consider the quenching effect of cosolvents such as methanol,ethanol,acetonitrile on ·OH,and try to avoid the misunderstanding of the experimental results caused by residual organic solvents in the reaction system.(4)The effect of quencher DABCOIt is proved by experiments that DABCO,a quencher of singlet oxygen can be photoreduced with ketone 13A in aqueous solution.A photoreduction process is proposed,which can be divided into four parts,and verified by the theoretical calculation.?13a is excited to the S1 state by ultraviolet irradiation,and then the intersystem crossing from S1 to the triplet state T1 occurs,followed with the electron transfer between T1 state 13A and DABCO.?DABCO abstracts hydrogen from aqueous solution and then becomes protonated.By comparing the protonation processes of four water cluster models,it is proved that DABCO protonation process is barrierless.?There are two kinds of electron transfer reactions between triplet 13 A and DABCO.One is photoinduced electron transfer of T1 state 13A and DABCO to generate 13a radical anion(13a·-)and DABCO radical cation(DABCO·+);the other is that ion pairs of 13a·-and DABCO·+ return to ground state 13A and DABCO through the thermal back electron transfer.?There are two mechanisms of proton transfer between 13a·-and protonated DABCO.One is that DABCOH+ transfers a hydrogen to 13a·-to form 13a carbonyl radical.Secondly,DABCOH2+transfers a hydrogen to 13a,making 13a protonate to form a carbonium ion.?13a carbonyl radical can be coupled to form pinacol product.The carbonium ion can reacts with H2O to form a diol.Mass spectrometry showed that both pinacol and diol were formed in the reaction system.Therefore,DABCO,a quencher of singlet oxygen,can photoreduce 13a in aqueous solution.