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Singlet Versus Triplet Excited State Mediated Photoin-duced Dehalogenation Reactions of Itraconazole in Acetonitrile and Aqueous Solutions Ruixue Zhu, Ming-De Li, Lili Du, and David Lee Phillips J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.6b11934 • Publication Date (Web): 10 Mar 2017 Downloaded from http://pubs.acs.org on March 13, 2017

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The Journal of Physical Chemistry

Singlet Versus Triplet Excited State Mediated Photoinduced Dehalogenation Reactions of Itraconazole in Acetonitrile and Aqueous Solutions Ruixue Zhu, † Ming-de Li*, †‡ Lili Du† and David Lee Phillips*† †

Department of Chemistry, the University of Hong Kong, Pokfulam Road, Hong Kong S.A.R. ‡Department of Chemistry, Shantou University, Shantou 515063, China

RECEIVED DATE Supporting Information Place holder ABSTRACT: The photoinduced dehalogenation of the antifungal drug Itraconazole in acetonitrile and acetonitrile/water mixed solutions was investigated using femtosecond and nanosecond time-resolved transient absorption (fs-TA and ns-TA) and nanosecond time-resolved resonance Raman spectroscopy (ns-TR3) experiments. An excited resonance energy transfer was found to take place from the 4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-one part of the molecule to the 1,3-dichlorobenzene part of the molecule when Itraconazole is excited by ultraviolet light. This photoexcitation is followed by a fast carbon-halogen bond cleavage that leads to the generation of radical intermediates via either triplet and/or singlet excited states. It was found that the singlet excited state mediated carbon-halogen cleavage is the predominant dehalogenation process in acetonitrile solvent while a triplet state mediated carbon-halogen cleavage prefers to occur in the acetonitrile/water mixed solutions. The singlet to triplet energy gap was decreased in the acetonitrile/water mixed solvents and this helps to facilitate an intersystem crossing (ISC) process and thus the carbonhalogen bond cleavage happens mostly through an excited triplet state in the aqueous solutions examined. The ns-TA and ns-TR3 results also provide some evidence that radical intermediates are generated through a homolytic carbon-halogen bond cleavage via predominantly the singlet excited state pathway in acetonitrile but via mainly a triplet state pathway in the aqueous solutions. In strong acidic solutions, protonation at the oxygen and/or nitrogen atoms of the 1, 2, 4-triazole-3-one group appear to hinder the dehalogenation reactions. This may offer the possibility that phototoxicity of ITR due to the generation of aryl or halogen radicals can be reduced by protonation of certain moieties in suitably designed ITR halogen containing derivatives.

INTRODUCTION The antifungal drug Itraconazole (see Scheme 1 and denoted as ITR hereafter) is a triazole derivative of the azole family which may have less toxicity than some other oral triazole antifungal drugs. However, ITR has also been reported to cause heartburn, headaches, sweating and other unwanted side effects.1 Indeed, many side effects of photosensitive agents have been reported due to the reactive intermediates generated under exposure to solar radiation, such as radicals or ions, especially for drugs which contain an aryl halide structure.2-4 Photoinduced dehalogenation reactions can occur when exposed to light and then cause the carbon-halogen bond to cleave and generate halogen ion or radical intermediates.5-7 The generation of these halogen ions or radicals may be responsible for many relevant photosensitivity disorders, such as fever, headache or even cutaneous adverse reactions.1, 7-10 More importantly, the carbon-halogen bond exists widely in many drug molecules,11-12 thus the detailed understanding of the photoinduced dehalogenation process is needed to develop a better understanding for how unwanted photoinduced drug side effects occur. There have been a lot of studies for aryl halide structure containing compounds regarding carbon-halogen bonds cleavage reactions that take place after direct irradiation of light.13-16

Scheme 1. Chemical structure of Itraconazole (ITR).

Some of our previous studies examined how water can assist several kinds of dehalogenation processes that lead to production of strong acid leaving moieties and scission of C-H, O-H and C-X bonds17-19 and how a C-halogen bond cleavage occurs in photosubstitution reactions of some benzophenone derivatives.20 The dissociation of the C-halogen bond can take place from either excited singlet or triplet states and the generated singlet or triplet intermediates can lead to different final products since they may affect the reaction pathways differently. In some cases they can be used as viable intermediates in synthetic chemistry which are accessible under mild conditions.21 Investigations have been performed to explore the character of the excited states which are responsible for the dehalogenation process(es).12, 22-28 Early studies of the photocleavage reaction of several iodine and bromine substituted aromatic compounds found that the dissociation of the C-I bond is much faster than the C-Br bond and that both of these two processes appear to take place from excited triplet states.25

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Due to the electrons of the excited triplet state being localized on the carbon-halogen bond, the dissociation via the triplet state is more likely to occur than that based on an excited singlet state. The consideration of the triplet excitation energy also supports this conclusion.29 As the polarity of the solvent can affect the energies of the singlet and triplet states,30 this property may be possible to use to regulate the intermediates generated from which type of excited states by using different solvents. It has been reported that ITR can undergo a primary dehalogenation process under UV light irradiation to form a biologically reactive aryl radical that may induce phototoxicity or photoallergy side effects. Some basic photochemical properties of ITR have been investigated by using UV spectrophotometric, HPLC and/or chromatography methods,31-35 and a photoreaction product analysis has also been done by Miranda and coworkers.2 However there is no in depth time-resolved spectroscopic investigation about the specific mechanism of its photoreaction. In this work, exploratory studies were conducted by choosing acetonitrile and acetonitrile/water solutions with different water proportions as solvents to investigate how the characteristics of the excited state affect the two C-Cl bonds that may undergo dissociation in ITR after UV photoexcitation. Ultrafast laser spectroscopy methods and density functional theory (DFT) computations were employed to investigate the dehalogenation process(es) of ITR. By using different solvents, we observed that the dehalogenation of ITR processes can occur via both singlet and triplet state pathways where the singlet excited state mediated carbon-halogen cleavage is the predominant process in acetonitrile solvent while a triplet state mediated carbon-halogen cleavage process prefers to occur in acetonitrile/water mixed solutions. The dehalogenation rates and efficiencies appear to be influenced by the properties of the excited singlet or triplet states. The solvent acidity was also observed to affect the dehalogenation processes of ITR. EXPERIMENTAL AND COMPUTATIONAL DETAILS Materials. ITR (≥98%, TLC) was purchased commercially and used as received. Spectroscopic grade solvents acetonitrile, perchloric acid and distilled water were utilized to make samples. The concentration of ITR was prepared to be ~1 OD at 267 nm used in the ultrafast spectroscopy experiments. During the experiments, in order to keep the ITR solutions fresh, the sample solutions were flowed through a flow cell or stirred by a magnet bar. All the given proportion of water containing solvents are of volume ratio unless specified otherwise. Sample degradation was kept to less than 5%. Instrumentation. The femtosecond transient absorption experiments (fs-TA) were done with a femtosecond Ti:sapphire regenerative amplifier laser and transient absorption spectrometer.36-37 For the present experiments, part of these fundamental 800 nm pulse (approximately 95%) were employed to pump a third harmonic generator to obtain the laser of 267 nm used as the pump pulse while the probe was gained by utilizing the remaining 5% 800 nm light to produce a white-light continuum (330-700 nm) with a one dimensional moveable CaF2 crystal. A flow cell with a 2 mm optical path length was used to hinder the build-up of photoproducts. The instrument resolution of this setup was determined to be 150 fs.

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A commercial spectrometer was employed to do the nanosecond transient absorption (ns-TA) experiments.38 The 266 nm pump was produced by a Nd: YAG laser system equipped with a fourth harmonic generator. The probe light was supplied from the continuous light source of a 450 W Xeon lamp. The light of the probe and pump light were both focused through the sample with right angles to each other. The laser power was monitored by a power meter, and the power should be keep reasonably constant in different experiments. Both the spectra and single wavelength kinetics were recorded. The time resolution of this instrument is around 5 ns. All the samples were conducted in open air conditions except where otherwise specifically noted. The nanosecond time-resolved resonance Raman (ns-TR3) spectra were collected employing a home build setup 39-41 that used two Nd:YAG lasers electronically synchronized via a pulse delay generator to set the time delay between the pump and probe laser pulses. A 500 MHz oscilloscope and fast photodiode were utilized to measure the pump and probe time delay. A hydrogen shifter (containing around 100 kpa of hydrogen gas) was used to generate Raman shifted laser beams. In the ns-TR3 experiments, around 100 ml of the sample in a conical flask were circulated by a micro-pump based flow jet system. The probe and pump pulses were focused on the flowing sample so that these two beams should be spatially overlapped on the flowing liquid. The Raman scattering was acquired with reflective optics. The spectra were calibrated by the known Raman shifts of acetonitrile features. The TR3 experiments time resolution was approximately 5 ns. DFT calculations. DFT computations used the B3LYP method with the 6-31G(d) basis set to obtain the optimized geometries and vibrational wavenumbers of the proposed intermediates. To estimate the calculated Raman spectra, a Lorentzian with a 16 cm-1 bandwidth was utilized along with the Raman vibrational frequencies. When the calculated spectra were compared to the experimental spectra, a frequency scaling factor 0.965 was used. TD-DFT computations found molecular orbitals of various energy levels. The Gaussian (G09) programs were used for all of the computations reported here. RESULTS AND DISCUSSION A. Photochemical Reactions of ITR in Acetonitrile (ACN) and ACN/water Mixed Solvents with Different Water Proportions Monitored by Absorption and Fluorescence The UV-Vis spectra of ITR in different solvents were acquired to evaluate its absorption in different wavelength regions (see Figure S1 in the supporting information). ITR in ACN exhibits an intense absorption band with a maximum at ~ 260 nm. The spectrum experiences a blue shift when water was added (the electronic transition has n→* character). The pH can also affect the absorption spectra significantly (see Figure S2), which suggests a protonation process can occur in a strongly acidic solution. The 266 nm excitation utilized in the time resolved experiments is also denoted in Figure S1. We have used TD-DFT calculations to examine the excited states of the donor (the 4-phenyl-4,5-dihydro-3H-1,2,4-triazol3-one part of ITR) and acceptor (the 1,3-dichlorobenzene moiety of ITR) groups of the ITR molecule. These results indicate that the donor group of the ITR molecule will be excited to higher level excited states when 266 nm wavelength excitation


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is used as the pump laser in the experiments while the acceptor group of the molecule will not absorb the 266 nm wavelength appreciably due to its low oscillator strengths above 260 nm range (see Figure 1 right-hand part). The donor may be excited to S14 (or nearby excited states) when 266 nm was used as the pump laser wavelength and then undergo internal conversion (IC) to S11, at this point, an energy transfer may take place mainly from S11 of the donor part of ITR to S3 of the acceptor part of ITR since the energy difference between these two excited states is very low (eg 0.022 eV and see Figure 1 lefthand part). After that, relaxation from S3 to S1 of the acceptor part of the molecule can occur. The detailed excitation energies and oscillator strengths of the energy donor part of ITR and the acceptor part of ITR are given in Table S1. That such an energy transfer may be able to take place is also supported by the examination of the LUMO, LUMO-1 and HOMO orbitals of ITR. Figure S3 shows that the LUMO orbital appears located on the donor part of the molecule and the LUMO-1 orbital seems located on the bridge part of ITR which may help favor an energy transfer from donor to acceptor groups of ITR while the HOMO orbital appears located on the acceptor moiety of ITR. 10 9 8 7 6 5 13 9 7

14 12 11 10 8 6

4 3 2

donor acceptor

absorption

Vertical Transition Energy/ eV

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


5 4 3 1 2 1

donor

acceptor

250

275

300

Wavelength/ nm

325

350

Figure 1. Shown are the comparison of the excitation energies of donor (the 4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3one part of ITR) and acceptor (the 1,3-dichlorobenzene moiety of ITR) groups of the ITR molecule (left) and the calculated absorption spectra of the donor and acceptor components of ITR from the TD-DFT calculations. Scheme 2. Molecular formulae of ITR photochemical reaction products reported in reference 2.

Product analysis results reported by Miranda and coworkers2 indicate there are three main final products for ITR after irradiation, the molecular formulae of these products are shown in Scheme 2. Primary C-Cl bond scission at ortho or para of the 2, 4’-dichlorophenyl group takes place after photolysis and the para is favored.2 Furthermore, the quantitative distribution of the products was demonstrated to be solvent dependent with the major product from ITR photolysis in the aprotic non-hydrogen bonding solvent ACN being generated by intramolecular reaction of the nascent aryl radical to the adjacent triazole ring to produce the compound a photoproduct while in ethanol or water, the proportion of the reductive dehalogenation products compounds b and c increase.2 We performed in-situ photochemistry experiments for argon saturated solutions of ITR in ACN and ACN/water mixed aqueous solutions to observe the photochemical reactions and the steady state absorption and fluorescence spectra acquired using 266 nm photolysis are shown in Figures S4-S5. Figure S4 shows that the UV-Vis absorption spectra of ITR in ACN (a) and ACN/water mixtures (b) under different irradiation times, as shown in Figure S4-a, the bands at 205 nm and 265 nm due to the absorption of ITR decrease and a new broad feature appears in the 216-236 nm region generated due to the final products (see Scheme 2 – a) with an isobestic feature ~212 nm. Moreover, the blue shift of the 205 nm band attributed to the cyclization product was also observed. When the volume ratio of 50% water was added (Figure 4S-b), a broad band is still generated in the 216-236 nm region with an isobestic point at 212 nm. However, the 205 nm band intensity is dramatically decreased without any shift of this band’s wavelength and there is only a noticeable blue shift for the 265 nm band. These observations indicate that the cyclization process is not favored anymore after the addition of water. It also appears that the addition of water greatly increases the chances for the reductive reaction with the hydrogen provided by solvent or the intermediate which leads to a distinctly different distribution of the major final products. In short, the different spectra characteristics indicate that the final products of ITR in ACN and ACN/water mixture are significantly different from one another. If polar hydrogen bonding solvents were used (like water), the major photoproducts are produced from a reductive dehalogenation process, which agrees with the previous photoproduct analysis data of Miranda and coworkers.2 The steady state fluorescence of ITR in ACN/water mixed solutions exhibit weaker initial emission centered at 378 nm than that seen in neat ACN. The fluorescence spectra under different 266 nm irradiation times are depicted in Figure S5. As the fluorescence quantum yield of ITR in ACN was reported to be 0.0122, emission is not the predominant way for deactivation of the singlet excited state of ITR in ACN and this is even less the case in the ACN/water mixed aqueous solutions that display even weaker fluorescence emission. With the increasing of the irradiation time, the fluorescence intensity of ITR in ACN decreased (Figure S5-a) while it increased in ACN/water mixture (Figure S5-b) and all of the spectra experienced a blue shift until they were stable at 357 nm. This indicates that the final products have a different identity and/or population distribution in the ACN and ACN/water mixed aqueous solutions consistent with the absorption spectra changes in the above analogous photochemistry experiments. To further investigate the influence of the excited state properties and their relationship to the final products, the excited state differences between ITR in ACN and ACN/water mixed



B. Photoinduced Dehalogenation Reactions of ITR in ACN and ACN/water Solutions with Different Water Proportions Observed by Time Resolved Transient Absorption Spectroscopy Fs-TA spectra of ITR in ACN (a) and the mixed solvent of ACN/water (1:1 by volume, b) are shown in Figure 2 with the spectra at the early and later times presented separately. For the spectra of ITR in ACN (Figure 2a), after 267 nm excitation, the ground state of ITR was stimulated up to a high singlet excited state Sn and then experienced an internal conversion (IC) to populate S1 (denoted here as ITRS), the time constant of the IC process was not resolved in our fs-TA experiments. The initial broad band at around 650 nm whose spectral profile changes within tens of picoseconds may due to an energy transfer process from the donor 4-phenyl-4,5-dihydro-3H1,2,4-triazol-3-one group of ITR to the acceptor 1,3dichlorobenzene moiety of ITR with some contributions from vibrational cooling and/or solvent orientation processes of the excited singlet state. Next, a new band at 485 nm grew in conspicuously as a simultaneous decrease in the 650 nm band intensity was observed. The clear isobestic point at 522 nm suggests this is a conversion between two different species and this process may be assigned to a dehalogenation reaction. The previously reported products analysis results2 indicate that a dehalogenation at the ortho-position chlorine is the predominant process in ACN and thus the second species is likely the radical intermediate (denoted here as the ortho-ITR radical) which is generated from the excited singlet state by the dehalogenation. Time evolution analysis of the absorbance intensity changes at 350, 485, 650 nm with two exponential decay function fitted parameters are shown in Table 1. The reasonable correlation between the ITRS (1230 ps) decay time constant and the growth time constant of the ortho-ITR radical (1880 ps) indicates some transformation relationship between them. When water is added to the solution (volume ratio of 1:1, Figure 2b), the early spectra of the photoinduced process resembles the analogous spectra of ITR in the ACN solvent. The ground state of ITR was excited to an excited singlet state (ITRS) and then underwent a similar energy transfer process from the donor 4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-one

group of ITR to the acceptor 1,3-dichlorobenzene moiety of ITR with some contributions from vibrational cooling and/or solvent orientation processes of the excited singlet state. Meanwhile, a novel phenomenon is that there is a small amplitude increasing at 350 nm along with a growth time constant of 5 ps and a possible isobestic point at 379 nm, this dynamic conversion can be assigned to a very fast ISC from S 1 to the triplet T1 state (denoted here as ITRT). Results from DFT calculations show the energy gap between the excited singlet and triplet states of ITR in aqueous solution (0.85 eV) is smaller than that in pure ACN (0.9 eV). This indicates that intersystem crossing process can proceed more easily in aqueous solution. This is consistent with the much weaker fluorescence in polar hydrogen bonding solvents like ethanol and water compared to that in a polar non-hydrogen bonding solvent like acetonitrile.2 These preceding results imply that ITRT state is likely responsible for the subsequent C-Cl cleavage and give rise to the radical intermediate. Since the transient absorption at late delay time (3 ns) for ITR in ACN/water aqueous solution is almost the same with ITR in ACN, the generated intermediates are similar with that in ACN but with a lower yield. The analysis of the time evolution at 650 nm shows two components of 11 ps and 386 ps corresponding to vibrational relaxation/energy transfer and the excited state decay processes separately. Kinetics analysis also indicates that the triplet state mediated dehalogenation reaction is faster than that via the singlet state, as it’s noted that the decay rate of ITRT in ACN/water aqueous solution is much faster than that of ITRS in ACN, but with a lower yield. a 0.03 1ps 0.02 1 ps 2 ps 5 ps 9 ps 19 ps 29 ps

29ps 0.01

A (a.u.)

aqueous solutions were studied using time resolved spectroscopy techniques. Please note that the UV/VIS and fluorescence data discussed above are not intended to determine the products structure or identity. The UV-Vis and fluorescence spectral changes following photolysis were only used to monitor the changes of the ground state absorption for the disappearance of ITR being photolyzed and the appearance of the presence of some final products. This simple photochemistry experimental data shows that the photochemical conversion of ITR to final products in the two different solvents are not identical for a polar non-hydrogen bonding solvent (acetonitrile) and a polar hydrogen bonding solvents (50% acetonitrile/ 50% water here) and this is similar to previously reported photochemistry results in similar polar non-hydrogen bonding and polar hydrogen bonding solvents (acetonitrile and ethanol) of reference 2. The detailed products analysis of ITR in acetonitrile and ethanol have been reported before by Miranda and coworkers2 and the reader is referred to this study for the characterization of the structural and identity of the photoproducts produced in polar non-hydrogen bonding (acetonitrile) and polar hydrogen bonding (ethanol) solvents.2

39 ps 59 ps 99 ps 209 ps 409 ps 609 ps 809 ps 1009 ps 1509 ps 2109 ps 3109 ps

0.03

0.02

39ps

485nm

0.01 3109ps 350

400

450

500

550

600

650

Wavelength (nm)

b 0.03 5 ps

0.02

0.01

A (a.u.)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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5 ps 7 ps 9 ps 11 ps 13 ps 23 ps

23 ps

0.00 43 ps 63 ps 83 ps 103 ps 213 ps 413 ps 613 ps 813 ps 1013 ps 1513 ps 2113 ps 3113 ps

0.032 0.024 0.016 0.008 0.000 350

*

400

33 ps

3113 ps

450

500

550

600

650

Wavelength (nm)

Figure 2. Femtosecond transient absorption spectra (fs-TA) of ITR in ACN (a) and ACN/water (b, volume ratio is 1:1) obtained after 267 nm irradiation of the samples. The asterisk (*) marks the back-ground subtraction artifact of 400 nm scattered laser light.


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Table 1. Shown are the two exponential function fitting parameters for the fs-TA kinetics curves of ITR in ACN and ACN/water mixed solutions. 350 nm

485 nm

650 nm

1 /ps

2 /ps

1 /ps

2 /ps

1 /ps

2 /ps

ACN

65

1067

8

-1880

8

1230

3ACN-1H2O

-3.6

328

46

352

8.6

455

1ACN-1H2O

-5

159

19

199

11

386

1ACN-3H2O

-6.4

89

11

89

12

396

tion reaction can be mediated by both singlet and triplet excited states via a homolytic cleavage to produce long lived ITR radical intermediate species. a

1.2

1.0

CN 3A O 1H 2

O 3H 2

N-

0.6

O 1H 2

O -1H 2

0.2

ACN

0.8 N-

CN 3A

O -3H 2

0.4

485nm

C 1A

ACN

0.6

b

1.0

C 1A

0.8

Nomallized Intensity (a.u.)

350nm

O -1H 2

Nomallized Intensity (a.u.)

1.2

N 1AC

0.4 0.2 0.0

0.0 10

100

Time Delay (ps)

1000

10

100

Time Delay (ps)

1000

Figure 3. Comparison of normalized transient decay kinetics of ITR in ACN and ACN/water mixtures with different water proportions as indicated beside the kinetic curves (given as volume ratios) monitored at 350 nm (a) and 485 nm (b). 487 nm

0.008

A (a.u.)

The fs-TA experiments for ITR in ACN/water mixtures with different water proportions (25%, 75% volume ratio of water) were also performed to make a comparison and these data are provided in Figure S6, all the fitted lifetime time constants are shown in Table 1. It can be ascertained that the higher concentration of water can significantly accelerate the dehalogenation reaction mediated by the ITRT intermediate. To clearly discern the temporal evolution changes of the spectra of ITR in different solvents, the normalized representative kinetic curves observed at 350 nm and 485 nm in mixed solvents with different water proportions are compared in Figure 3 and the kinetics at 650 nm are given in Figure S7. The exponential decay fitted parameters are listed in Table 1. The values of the fitted time constant parameters are quite different for the temporal dependence behaviors of ITR in ACN and ACN/water mixed solvents. In ACN, the cleavage of the C-Cl bonds occurs via the singlet state and the two components are attributed to the energy transfer with contributions from some vibrational cooling/solvent orientation processes (eg the fast component, ca. 8 ps) and the dehalogenation reaction (the slow component, ca. 1200 ps). The kinetics at 650 nm seen in the ACN/water aqueous solutions display some similarity (see Figure S7). The energy transfer with contributions from some vibrational cooling/solvent orientation process lifetime is found to be ca. 11 ps. The initial growth of the kinetics curve at 350 nm with a fitting constant of ca. 5 ps can be assigned to an ISC process and then the absorption of ITRT started to decrease in intensity dramatically due to the dehalogenation reaction that forms the long lived ITR radicals. With regard to the kinetics at 485 nm, the lifetime of ITRT can be obtained and found to be ca. 352 ps for 25% water, ca. 199 ps for 50% water and ca. 89 ps for 75% water and obviously water appears to accelerate the decay of the ITR triplet state. The radical lifetime can be found from ns-TA spectroscopy experiment. To identify and characterize the new intermediate generated after the dehalogenation reaction, Cl- ion (from added NaCl) quenching experiments were done in the ACN solvent. These results indicate that the addition of Cl- has no significant effect on the spectra and the kinetics curves (see Figure S8), and the photodehalogenation reaction probably generates radical intermediates rather than ions. In order to further characterize the new species after the dehalogenation reactions of ITR in ACN and ACN aqueous solutions, the spectra with time delay of 3.1 ns were presented separately to make a comparison in Figure 4 which finds the late spectral profiles of ITR are almost the same in the different solvents. This suggests that the photoinduced dehalogena-

N 1AC

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ACN 3ACN_1H2O 1ACN_1H2O 1ACN_3H2O

0.006

0.004

*

0.002

0.000

400

500

Wavelength (nm)

600

Figure 4. Fs-TA of ITR in ACN and ACN/water mixtures with different water proportions (percent by volume are 25%, 50% and 75% respectively), obtained after 267 nm excitation and the time delay of 3.1 ns. Figure 5 presents the ns-TA spectra of ITR in ACN (a) and ACN/water (volume ratio is 1:1, b). The transient absorption bands and corresponding dynamics are substantially the same. There are two intense bands (~315 nm and ~ 480 nm) with long lifetimes and these two bands can be attributed to the absorption of intermediates generated after the dehalogenation reaction(s) occurs. The low wavelength bands have a small blue shift for ITR in ACN aqueous solution. A two exponential function was used to fit the ns-TA kinetics curve at 485 nm for ITR in ACN while a three exponential was employed to fit the kinetics curve for 485 nm of ITR due to there being likely both ortho and para dehalolgenation taking place in the


The Journal of Physical Chemistry ACN/water solution. The time constants from these fittings are listed in Table 2. Three kinds of radicals, the ortho-ITR radical, the para-ITR radical and the triazole radical are likely produced with different relative populations present in the ns-TA spectra. The results in Table 2 combined with the previously reported product analysis results for ITR and the fs-TA spectra results discussed earlier here indicate that the ns–TA spectra have mainly contributions from the absorption of the orthoITR radical and the triazole radical accompanied by small amounts of the para-ITR radial which is more significant in the ACN/water solution. The apparent preference for producing the ortho-ITR radical in the ACN solvent compared to the ACN/water solution may be related to the different hydrogen bonding environments of the ortho and para-Cl atoms of ITR in these solvent systems. In the ACN solvent the ortho-Cl atom may have some intramolecular hydrogen bonding to the nearby O atoms of ITR not available to the para-Cl atom while in the ACN/water solution there will also be intermolecular hydrogen bonding available to both the ortho- and paraCl atoms. At this time, it is difficult to assign the different kinetics observed to the different radicals that are likely formed in the photochemistry due to the complexity for how the solvent interactions influence their structure and reactivity for these radical species toward subsequent reactions whose transition state barriers determine their lifetimes. Further work will be needed to assign the three different radical species kinetics to the three different radicals that are apparently observed on the microsecond time scale in this study. We also note that these radicals undergo noticeable diffusion in the solutions due to their microsecond scale lifetimes and one would need to consider their reactions with both solvent molecules and possibly with each other which further complicates the assignment of the three radical decay lifetimes to specific radical species. 0.08

0 ns 200 ns 400 ns 0.8 s 20 s 60 s 100 s

a

A (a.u.)

0.06

0.04

0.02

20.15 kcal/mol higher than that of the triazole radical with an estimated error of a few kcal/mol. This means that the triazole radical appears to be more stable thermally than the para and ortho-benzene radicals. Table 2. Shown are the two exponential function fitted parameters for the ns-TA kinetics curves of ITR in ACN and ACN/water mixed solutions. 315 nm

485 nm

1/μs

2/μs

1/μs

2/μs

ACN

99

920

125

1276

1ACN-1H2O

129

800

237

1246

3/μs

48

C. Direct Observation of the Aryl Radical with Time Resolved Resonance Raman (TR3) Spectroscopy To gain more information for the reactive intermediates, nsTR3 experiments were done after 266 nm irradiation and a 299 nm probe wavelength and Figure 6 (left) gives the ns-TR3 spectra of ITR in ACN. The spectra exhibit three obvious Raman bands with at 818, 1192 and 1595 cm-1. The Raman band at 1595 cm-1 can be attributed to the two benzene rings skeletal vibrations while the bands at 818, 1192 cm-1 can be associated with mainly C-C stretch and C-H bend motions of the ITR radical. It appears that only one (or two very similar species) species was observed in the spectra. As the intensity of the Raman bands decayed somewhat by 5 s, this species can be attributed to the ortho-ITR radical and/or the para-ITR radical. The calculated normal Raman spectrum of the ortho-ITR radical shows good agreement with the experimental resonance Raman spectrum at 10 ns (see Figure 6, right) for its vibrational frequency pattern. Therefore it is reasonable to assign some of the population of the observed species that decays within tens of microseconds to the ortho-ITR radical that is generated from the dehalogenation reaction and then decays due to the subsequent cyclization to produce the compound a final product (see Scheme 2) that was observed in the photoproduct analysis work of reference 2.

600

700

800

*

b

0.04 0.03 0.02 0.01

1 s 500 ns 200 ns 100 ns 10 ns

800

1000

1200

1400-1

Raman Shift (cm ) 0.00 300

400

500

600

Wavelength (nm)

700

5 s

*

Relative Intensity (a.u.)

0 ns 200 ns 400 ns 30 s 50 s 70 s

800

Figure 5. Nanosecond transient absorption spectra of ITR in ACN (a) and in ACN/water (volume ratio is 1:1, b) obtained with 266 nm irradiation of the samples. The relative energies of the ortho-benzene radical, parabenzene radical and triazole radical were calculated using the B3LYP/6-31g* and a PCM continuum solvation model and these results are shown in Figure S9. The free energies of the para-benzene radical and ortho-benzene radical are 25.51 and

1600

1800

800

1192

500

Wavelength (nm)

818

400

Relative Intensity (a.u.)

300

0.05

1595

0.00

A (a.u.)

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*

*

1000

1200 1400-1 Raman Shift (cm )

1600

1800

Figure 6. (left) Ns-TR3 spectra of ITR obtained in ACN with a 266 nm pump and 299 nm probe at varying delay times are shown. (right) The experimental TR3 spectrum at 10 ns is compared to the calculated normal Raman spectrum of the ortho-ITR radical. We note that the para-ITR radical can also make a contribution in the ACN/water (1:1 by volume) solutions so we have we have calculated the normal Raman spectra of the pararadical and the ortho-radical and comparison of these results found that the main Raman features come from the skeleton stretching and wagging vibrations of the two benzene rings in


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the middle portion of the ITR molecule and the C-H bonds of 4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-one part of ITR. The 1,3-dichlorobenzene part seems to have little contribution to the Raman spectrum. This causes the calculated normal Raman spectra of the para-radical and the ortho-radical to look very similar with each other and their spectra are shown in Figure S10. These results suggest it would be hard to distinguish these two radicals in the ns-TR3 spectra in aqueous solutions and thus we cannot unambiguously assign the different kinetics of the radical species observed to specific radical species yet. D. The Effect of Acidity The oxygen atom of the carbonyl group and the nitrogen atom of 1, 2, 4-triazole-3-one moiety may undergo protonation in acidic solutions. The photochemical behaviors were measured as reported in the supporting information. Figure S3 depicts the comparison of the UV-Vis absorption spectra of ITR in ACN (black line) and ACN pH=3 (red line) and pH=1 (green line), the intensity diminution at the absorption maximum at 260 nm indicates a protonation occurs for ITR in a strong acidic solvent (pH=1), which also means the excitation efficiency by the UV light will be reduced dramatically. The fs-TA spectra of ITR in differing degrees of acidity solutions were recorded as detailed in Figure S11. It was found that the characteristic band at around 485 nm for the ITR radical disappeared gradually with the increase of the acidity (pH=1) of the solution. As expected, this indicates that the protonation of triazole and/or the carbonyl group can affect the energy transfer process and further alter the efficiency of photoinduced dehalogenation reactions. To make a more detailed comparison, the fs-TA spectra of ITR in ACN and ACN/H+ solvents with different pH values (pH = 6, 4, 3, 2, 1, 0.5), obtained after 266 nm excitation and at a 3.1 ns time delay are shown in Figure S12-a. When the concentration of H+ is very small (0.1 M), the protonated ITR will be the predominant form that is excited and this consequently leads to different reaction pathways compared to those for ITR

in ACN that is not acidic. The gradual changes seen in the kinetics curves under the maximum absorption bands of the above mentioned pH values (Figure S12-b) provides more pieces of evidence to support that the dehalogenation reactions are hindered in strongly acidic solutions and protonation of the carbonyl and/or nitrogen in ITR appears to lead to less radical formation due to the dehalogenation reactions.

AUTHOR INFORMATION

sponding molecular orbital with weighted coefficients are provided. This information is available free of charge via the Internet at http://pubs.acs.org.

Corresponding Author

CONCLUSIONS The photoinduced dehalogenation of the antifungal drug ITR in ACN and ACN/water mixed solutions was studied with fs-TA, ns-TA and ns-TR3 spectroscopy experiments as well as DFT computations. DFT calculation results suggest that UV excitation of ITR leads to an excited resonance energy transfer to occur from the 4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-one portion of the molecule to the 1,3-dichlorobenzene portion of the molecule. This photoexcitation leads to C-Cl bond scission that produces radical intermediates via either triplet and/or singlet excited states. The results presented here indicate that a singlet excited state carbon-halogen cleavage is the main dehalogenation process in ACN solvent while a triplet state carbon-halogen cleavage appears to be a major pathway in the ACN/water mixed solutions. The energy gap between the singlet and triplet states appears to become narrower in the ACN/water mixed solvents compared to acetonitrile solvent which significantly enhances an intersystem crossing (ISC) process so that the carbon-halogen bond cleavage appears to proceed noticeably through an excited triplet state in aqueous solution. The ns-TA and ns-TR3 results also indicate that radical intermediates are generated through a homolytic carbonhalogen bond cleavage mainly through a singlet excited state in ACN while the dehalogenation takes place more through a triplet state in aqueous solution. Moreover, the excited triplet state based dehalogenation reaction have fast reaction rate but lower efficiency. In strong acidic solutions, protonation at the oxygen and/or nitrogen atoms of the 1, 2, 4-triazole-3-one group were observed to result in much lower yields for the dehalogenation reactions. This effect may be useful to consider in the design of less phototoxic ITR derivatives.

*Phone: +852-2859-2160. Fax: +852-2857-1586. E-mail: [email protected]; [email protected]

REFERENCES

ACKNOWLEDGMENT This work was supported by grants from the Research Grants Council of Hong Kong (HKU 17301815), a Special Equipment Grant (SEG-HKU-07) and a University Development Fund grant for the “New Ultrafast Spectroscopy Experiments for Shared Facilities” from the University of Hong Kong to DLP. Partial support from the Grants Committee Areas of Excellence Scheme (AoE/P-03/08) is also gratefully acknowledged.

SUPPORTING INFORMATION AVAILABLE Description of the UV-Vis spectra of ITR in different solvents, the femtosecond time resolved transient absorption spectra and kinetic curves, additional spectra obtained under varying conditions, static absorption and fluorescence spectra of ITR under different photolysis time, DFT calculated transition energy and its corre-

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TOC Graphic

Sn

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Sn

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S1

266 nm

Fl

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T1 Water

Dehalogenation S0

S0

Energy Donor

Energy Acceptor

10 ACS Paragon Plus Environment

Singlet versus Triplet Excited State Mediated ... - ACS Publications

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