Influence of Water in the Photogeneration and ... - ACS Publications

Oct 10, 2016 - and David Lee Phillips*,†. †. Department of Chemistry, University of Hong Kong, Pokfulam Road, Hong Kong S.A.R., P. R. China. ‡...
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Influence of Water in the Photogeneration and Properties of a Bifunctional Quinone Methide Lili Du,† Xiting Zhang,† Jiadan Xue,‡ WenJian Tang,§ Ming-De Li,† Xin Lan,† Jiangrui Zhu,∥ Ruixue Zhu,† Yuxiang Weng,∥ Yun-Liang Li,*,∥ and David Lee Phillips*,† †

Department of Chemistry, University of Hong Kong, Pokfulam Road, Hong Kong S.A.R., P. R. China Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, P. R. China § School of Pharmacy, Anhui Medical University, Meishan Road 81, Hefei 230032, P.R. China ∥ Key Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, P. R. China ‡

S Supporting Information *

ABSTRACT: Quinone methides (QM) are crucial reactive species in molecular biology and organic chemistry, with little known regarding the mechanism(s) for the generation of short-lived reactive QM intermediates from relevant precursors in aqueous solutions. In this study, several time-resolved spectroscopy methods were used to directly examine the photophysics and photochemical pathways of 1,1′-(2,2′dihydroxy-1,1′-binaphthyl-6,6′-diyl)bis(N,N,N-trimethylmethanaminium) bromide (BQMP-b) from initial photoexcitation to the generation of the key reactive binol QM intermediate (BQM) in aqueous solution. The fluorescence of BQMP-b is effectively quenched with a small amount of water, which suggests an excited state intramolecular proton transfer (ESIPT) occurs. The kinetics isotope effects observed in femtosecond and nanosecond time-resolved transient absorption experiments provide evidence for the participation of water molecules in the BQMP-b singlet excited state ESIPT process and in the subsequent −HNMe3+ group release and ground state intramolecular proton transfer that give rise to production of the reactive BQM intermediate. Nanosecond time-resolved resonance Raman (ns-TR3) measurements were also employed to investigate the structure and properties of several intermediates, including the key reactive BQM in aqueous solution. The ns-TR3 and density functional theory (DFT) computational results were compared, and this indicates the binol moiety and water molecules both have important roles in the characteristics and structure of the key reactive BQM intermediate produced from BQMP-b. The results presented here also provide new benchmark characterization of bifunctional quinone methide intermediates that can be utilized to guide direct time-resolved spectroscopic study of the alkylation and interstrand cross-linking reactions of quinone methides with DNA in the future.

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INTRODUCTION DNA replication and gene expression can be inhibited by DNA interstrand cross-linking (denoted here as IStrandC) which makes melting of the two strands much more difficult.1−15 DNA alkylation reactions that result in IStrandC which inhibit DNA replication are among the most cytotoxic of alkylations and thus have much promise in a variety of applications in molecular biology and medicine.1−15 A great deal of research effort has been put toward understanding how IStrandC can take place, and a number of substances have been found to undergo DNA IStrandC such as some antitumor antibiotics3−6 and synthetic antitumor agents such as cis-platinum-like organometallics,7−10 bizelesin,11,12 and others.13−15 Photoactivated substances that were able to undergo DNA IStrandC have been relatively less explored, with some work reported for psoralens16 and bifunctional quinone methides (QMs).17−22 A number of bifunctional QMs have recently been employed to do alkylation of a nucleoside that goes on to DNA IStrandC via means of photochemistry,18−21 oxidation,23,24 thermal digestion,25 and fluoride-induced activation.26,27 © XXXX American Chemical Society

For photoactivated QMs, ortho- and para-QM species were produced from suitable precursor compounds containing quaternary ammonium salts (X = NMe3+I−) or benzyl alcohols (X = OH) or Mannich bases (X = NMe2) (see Scheme 1) by several different research groups, including Wan and coworkers,28−30 Kresge and co-workers,31,32 Popik and coScheme 1. Structures of o-NQMPs, p-NQMPs, and oBQMPs and p-BQMPs

Received: August 29, 2016 Revised: October 8, 2016

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The Journal of Physical Chemistry B workers, 33,34 and Richter and Freccero and co-workers.20,21,25,35−38 However, most o-QMs and p-QMs have a small degree of absorbance over 350 nm and thus are not appropriate for use as the photoactivated alkylation compounds in biological systems. In order to have a greater degree of absorbance above 350 nm, some compounds of naphthol derivatives and binol counterparts of these naphthol derivatives (denoted here as o-NQMPs, p-NQMPs, and o-BQMPs and pBQMPs, respectively, and depicted in Scheme 1) have been developed as QM precursors.17−22,39−41 Pioneering work by Richter and Freccero and co-workers21 showed that o-BQMPs can undergo bis-alkylation in water and DNA IStrandC reactions via ultraviolet/visible photoactivation. More recent studies found that some p-BQMPs can be photoactivated and give efficient production of binol QM species in water that can undergo efficient alkylation and IStrandC reactions with singleand double-stranded DNA and also display encouraging photocytotoxic versus cytotoxic characteristics.41 In particular, p-BQMPs were found to be better photoalkylation species than p-NQMPs and it was speculated that this substantial difference in chemical reactivity may have something to do with intramolecular hydrogen bonding within the binol derivatives which would not take place in the naphthol compounds.41 Another difference in chemical reactivity is that p-BQMPs undergo mono- and bis-alkylation without competing side reactions while p-NQMPs produce side products attributable to the presence of a 6-naphthylmethyl radical intermediate after photoexcitation.41 Nanosecond timeresolved transient absorption (ns-TA) measurements have been done for selected p-NQMPs and p-BQMPs, and intermediates were observed and attributed to quinone methide (QM) species.41 The p-BQMP compound, 1,1′-(2,2′-dihydroxy-1,1′binaphthyl-6,6′-diyl)bis(N,N,N-trimethylmethanaminium) bromide (denoted hereafter as BQMP-b) was found to be a particularly good photoactivated DNA intrastrand cross-linker, with concentrations as little as 0.3 μM leading to noticeable amounts of intrastrand cross-linking.41 Alkylation experiments using photoactivated BQMP-b indicated it had a preference for dG which is different from many quinone methides such as the benzo o-QM that prefers dC.27,42 Based on a variety of product analysis results, it was postulated that the quinone methide reactive intermediate produced from photoexcitation of BQMP-b acts in a manner very different from typical quinone methide species.41 There are several unresolved issues. How are the reactive QM intermediates photogenerated from pBQMPs? What are the structure and properties of these unusual reactive QM intermediates formed from photoactivated p-BQMPs which display significantly different chemical reactivity than typical quinone methides? Here, we are pleased to report the BQMP-b compound results of time-resolved spectroscopic and quantum mechanical computational studies that directly examine the photogeneration of its unusual reactive binol quinone methides (BQM) intermediate and that characterize its structure and properties (Scheme 2). Femtosecond time-resolved transient absorption spectroscopy (fs-TA) was used to directly observe the electronic excited states and intermediates that lead to the production of the key BQM intermediate previously observed by Richter and Freccero and co-workers41 in their ns-TA experiments. This new fs-TA data combined with results from quantum mechanical calculations provides new knowledge for how water influences the photogeneration of the key reactive BQM precursor. To acquire further information regarding the

Scheme 2. Structure of the BQMP-b Precursor Molecule with Selected Atoms Numbered and the Proposed Structure of the BQM Intermediate Produced from Photolysis in Aqueous Solutions

identity and nature of the excited states and transients, femtosecond time-resolved infrared (fs-TRIR), nanosecond transient resonance Raman (ns-TR2), and nanosecond timeresolved resonance Raman (ns-TR3) spectroscopy methods were used to examine the reaction. These are likely the first time-resolved vibrational spectroscopy studies of bifunctional quinone methide transient species. These new experimental results along with results from DFT computations indicate that both the binol moiety and water molecules play crucial roles in the properties, structure, and reactivity of the key reactive BQM intermediate produced from BQMP-b and lead this key intermediate to have a chemical reactivity substantially different than monofunctional quinone methides. These BQMP-b results also provide new benchmark characterization of the bifunctional quinone methides that can be utilized to guide the future direct time-resolved spectroscopic investigation of alkylation and IStrandC reactions of quinone methides with DNA.

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EXPERIMENTAL AND COMPUTATIONAL METHODS The BQMP-b compound was prepared according to a previously reported procedure,41 and the NMR properties are in accordance with the structures proposed (NMR data given in Figures S1, S2, and S3 and UV/vis data in Figure S4, Supporting Information). Spectroscopic grade acetonitrile (MeCN), distilled water, and BQMP-b were utilized in the experiments. The mixed solution ratios are given as volume ratio unless otherwise indicated. Fs-TA and ns-TA Experiments. These experiments employed the same experimental setups and methods described previously.43,44 Fs-TRIR Experiments. These were done using the pump− probe beam geometry in a recently developed setup. The light came from a Ti:sapphire amplifier apparatus which delivered 35 fs, 800 nm pulses (1 kHz repetition rate). The 267 nm (15 μJ) used for the sample excitation was generated by sum-frequency generation between 800 and 400 nm in a nonlinear way. To avoid damage of the sample from the higher power pump beam, the 267 nm pulse was not further compressed into a shorter pulse and was reasonably attenuated with a neutral density filter. The broadband Mid-IR pulse (3−10 μm) was used as the probe pulse, which was facilitated by a nonlinear four-wave optical rectification of the 800, 400, and 267 nm through filamentation in the air.45 The intense fundamental pulse and other residual wavelengths in the generated Mid-IR beam were filtered with the space filter and a silica wafer to purify the Mid-IR probe pulse. The time-resolved Mid-IR spectra were collected in a single shot manner by a spectrograph with a 64 channel mercury−cadmium−telluride (MCT) detector. With the help of a chopper running at 500 Hz in the laser pump path, a transient spectrum of the sample was recorded with ΔA = −log Ipumpon/Ipumpoff, and the variability B

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this is the case.49 We note that a nonlinear water concentration dependence of fluorescence quenching has been observed previously in naphthol and some related systems, and it has been suggested that water trimers may be involved in a longrange proton relay excited state proton transfer (ESPT)47 and would be more noticeable at higher concentrations of water present. While it is likely that more than one water molecule is involved in the ESPT processes at higher water concentrations, the range of actual processes that occur at early times complicates extracting a clear physical interpretation of the quenching data. Agmon50 has reviewed a variety of likely steps involved in excited state proton transfer processes in 2-napthol and other molecules and noted that the initial photoexcitation induces an intramolecular charge rearrangement in the molecule that then interacts with the surrounding solvent environment, so there is some hydrogen bonding rearrangement collectively in the surrounding water molecules to assist the proton transfer and a number of solvent properties and dynamics can influence this.50 In the future, it may be interesting to attempt quantum simulations of the S1 excited state with explicit solvent molecules with varying ratios of water to acetonitrile in the system to try and find the degree of fluorescence versus ESPT as a function of water concentration to gain some further insight into the physical meaning of the fluorescence quenching concentration behavior observed experimentally. Fs-TA, ns-TA, and TD-DFT Study of BQMP-b. Figure 2 shows the fs-TA spectra of BQMP-b in MeCN. In order to

of the delay time between the pump and probe pulses was directed using a mechanical translation stage. Ns-TR2 and ns-TR3 measurements. The ns-TR2 data was found using the difference between Raman spectra from the different powers of the 309.1 nm pump laser (high power to low power) by subtracting the Raman bands for the precursor and solvents. The ns-TR3 measurements were also described in detail previously.43,44 DFT and Time-Dependent DFT (Denoted as TD-DFT) Computations. The computations employed the (U)B3LYP method and a 6-311G** basis set. A simulated bandwidth for the spectra was determined using a Lorentzian of 10 cm−1 bandwidth for the vibrational band frequencies. A 0.975 scaling factor was used to scale the vibrational frequencies. The Gaussian 09 program suite46 was employed, and more details were discussed previously.43,44 NBO calculation was performed with the same method and basis set.

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RESULTS AND DISCUSSION Fluorescence Quenching Experiments. The fluorescence of BQMP-b was examined after 266 nm excitation in mixed aqueous solutions (MeCN:H2O) of varying water concentrations (see Figure 1, left). In Figure 1, the addition

Figure 1. Representative fluorescence quenching traces of BQMP-b (left) and Stern−Volmer data for fluorescence emission changes in intensity BQMP-b (●) by H2O in MeCN (right). The line represents a best fit to I/I0 = 1 + Ksv[H2O] + K′[H2O]2 + K″[H2O]3.

of a small amount of H2O (1.11 mol L−1) to a MeCN solution of BQMP-b efficiently quenched the fluorescence emission. With an increasing concentration of water, the intensity of the fluorescence decreases significantly, and this may indicate that the singlet excited state(s) of the BQMP-b may be involved in a reaction with H2O. At higher water content, the quenching of fluorescence may possibly be assigned to the competitive formation of naphtholates BQMP-b− via water-assisted excited state intramolecular proton transfer (ESIPT).47,48 At high water concentration, no new emissive spectrum is achieved, which indicates that BQMP-b−, if formed, is not emissive. Another possibility is that the singlet excited state(s) of BQMP-b undergoes an ESIPT process to produce BQM intermediates. An adapted Stern−Volmer plot of the strength of the fluorescence of BQMP-b versus the amount of added water is shown in Figure 1 (right). At higher water content, the quenching of the fluorescence emission occurs for BQMP-b in a nonlinear manner. The Stern−Volmer plot can fit the following polynomial function reasonably well: I0/I = 1 + Ksv[H2O] + K′[H2O]2 + K″[H2O]3, where Ksv = 1.83 M−1, K′ = −0.09 M−2, and K″ = 0.002 M−3. It is possible higher order terms are required to model the data with water content over 5.55 M. However, the experimental error in measuring the very small changes of fluorescence makes it difficult to determine if

Figure 2. Fs-TA of BQMP-b achieved after a 267 nm excitation (a, b, and c) in MeCN. Kinetics at 530 nm is shown in d.

demonstrate the spectra changes detailed, the spectra before 1.5 ps, from 1.6 to 19.2 ps, and at late (19.2−2823 ps) times are displayed in Figure 2. The bands at 350 and 439 nm show up quickly within 1.5 ps. The variation from 0.9 to 1.5 ps is due to the internal conversion (IC) from the Sn to S1, whose lifetime is not resolved within the experiment resolution and will not be discussed further here. The initial intermediate at 1.5 ps could be attributed to S1 to Sn transient absorption due to the excited singlet state of BQMP-b. In Figure 2b, the 350 nm band decreases a bit, when a small band at 530 nm accompanied by a broad feature at 600 nm appears. Meanwhile, the band at 439 nm blue-shifts to 437 nm and becomes narrower. This behavior is assigned to vibrational cooling of higher energy S1 molecules C

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The Journal of Physical Chemistry B losing heat to the solvent.51 In the next 3 ns (Figure 2c) the strengths of the 437 nm, 530 nm, and 600 nm features decrease, which is attributed to the decay of S1. As displayed in Figure 2d, the kinetics at 530 nm could be modeled with a biexponential function that results in 7.6 ps (τ1) and 526 ps (τ2), time constants, respectively. Therefore, the vibrational cooling process for the S1 state takes place in 7.6 ps and the decay from S1 to S0 happens in 526 ps. A small amount of the S1 state undergoes ISC to the BQMP-b triplet which has a 442 nm absorbance band. Furthermore, the low ISC efficiency makes the clear transformation between these two excited states to not be easily discerned in the data. The fs-TA data around 3 ns are similar to those achieved from the very early time ns-TA spectra of BQMP-b in both the air saturated and nitrogen saturated MeCN solutions. The nsTA spectra of BQMP-b in saturated and nitrogen saturated MeCN solutions are given in Figure S5. As shown in Figure S5, the band at 442 nm, which is found in the late time delay fs-TA data, also shows up in the ns-TA spectra at the very beginning in both the air saturated and nitrogen saturated MeCN solvents. However, the 442 nm band disappears very quickly in an air purged condition while it decays much more slowly in the nitrogen purged MeCN solvent. Therefore, the intermediates obtained in the fs-TA late time data and in the ns-TA early time data can be attributed to the triplet of BQMP-b from the evidence that it could be quenched by oxygen. The ISC of the S1 state to the BMQP-b triplet appears to be inefficient in MeCN solution. Therefore, the main decay processes observed for BMQP-b are the fluorescence or/and IC process of the S1 state to the singlet ground state after 266 nm excitation in organic solutions such as MeCN. Although the quantum yield of the fluorescence was not calculated here, it seems that the efficiency of the fluorescence transition is much higher than the ISC process for the BMQP-b. Figure 3 and Figure S6 display the transient absorption spectra of BQMP-b obtained after 267 nm photolysis in a 1:1 MeCN:H2O solvent from 0.75 ps to 3 ns. Immediately after the pump 267 nm excitation, a wide transient absorption with 350 and 440 nm features appears (see Figure S6(a)). This species is

assigned to the IC transition from Sn to S1 after 267 nm excitation. In Figure S6(b), both bands at 350 and 440 nm blue-shift a little with a slight change of the intensities and become narrower. This is attributed to the vibrational cooling process as discussed above. In Figure 3(a), the 437 nm intensity decreases rapidly, and a narrower absorption at lower wavelength increases to have a bathochromic change of 350 to 362 nm with two shoulder bands seen at 388 and 488 nm. These changes are accompanied by a ∼410 nm isosbestic point, which suggests a transformation between two species. After 28.4 ps, the transient band at 362 nm decreases with a red shift to 367 nm over the next 3 ns in Figure 3(b). To help discern the role water molecules have in the formation and decay of the 437 nm species, which is the precursor to produce the proposed BQM intermediate, corresponding experiments were also done in a MeCN:D2O = 1:1 solution, and Figure S7 shows these spectra. The solvent kinetics isotope effects were determined by fitting intensities at 437 nm in the fs-TA spectra in both Figures 3c and S7. The best fit to this data is a two-exponential function that has 7.4 and 220 ps time constants in the MeCN:H2O = 1:1 solution and 12.3 and 289 ps in the MeCN:D2O = 1:1 solution. The calculated NBO results for the singlet excited state of BQMP-b with two explicit water molecules in the system are given in Figure S8 and show that the C18 position probably has the most negative character due to some charge transfer character between the two naphthol rings and the surrounding water molecules. Therefore, a tentative interpretation of these results is that, after photoexcitation of the BQMP-b to its singlet excited state, the water molecules permit a proton to leave the hydroxyl group O23 and then provide a proton to the carbon C18 on another naphthol ring to generate a zwitterionic species intermediate 1, and this water-assisted ESIPT process takes place within 7.4 ps to produce intermediate 1 from the singlet excited state of BQMP-b.52−54 The time constant for the generation of 1 (D) in the 1:1 MeCN:D2O solution is 12.3 ps. Therefore, the kinetics isotope effect of k1,H/k1,D = 1.66 for the first reaction process, which provides evidence for water molecules participating directly in the ESIPT process from the singlet excited state of BQMP-b to form intermediate 1. The time constants for the generation of intermediates 2 (H/ D) in the 1:1 MeCN:H2O and 1:1 MeCN:D2O samples are 220 and 289 ps, respectively, which is due to the leaving of the HNMe3+ group on intermediate 1 to form intermediate 2, and this presumably involves the participation of water molecules in the solvation of the HNMe3+ leaving group. Thus, the kinetics isotope effect of k2,H/k2.D = 1.31 for this second reaction process also gives support to the participation of water molecules to induce intermediate 2 to form the next transient species. The proposed photophysics and water assisted reaction processes deduced from the fs-TA experiments are shown in Scheme 3. We note that the results we have so far are an initial characterization and are only a preliminary interpretation that can be refined further with additional work. For example, further experiments such as D-exchange experiments like those performed by Wan and co-workers48 in BINOL derivatives and femtosecond two-dimensional time-resolved infrared (fs-2DTRIR) to better characterize the structure and dynamics combined with more advanced computations like quantumdynamics simulations for the S1 excited state with a more comprehensive explicit water solvation shell should lead to a deeper understanding of the ESIPT taking place at early times.

Figure 3. Fs-TA data of BQMP-b achieved in 1:1 MeCN:H2O following 267 nm photolysis (a) from 1.97 to 28.4 ps and (b) from 28.4 ps to 2.99 ns; (c) kinetics at 437 nm both in 1:1 MeCN:H2O and in 1:1 MeCN:D2O. The time dependences of the 437 nm band are fitted by a two-exponential function with 7.4 and 220 ps in 1:1 MeCN:H2O solution and with 12.3 and 289 ps in 1:1 MeCN:D2O. D

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Figure 5. Ns-TA spectra of BQMP-b achieved in 1:1 MeCN:H2O following 266 nm excitation of BQMP-b from 0 to 30 μs (left), kinetics at 367 nm in both 1:1 MeCN:H2O and 1:1 MeCN:D2O (right). The time dependences of the 367 nm band are fitted by a twoexponential function with 1.8 and 20.4 μs in 1:1 MeCN:H2O solution and 3.6 and 30.1 μs in 1:1 MeCN:D2O.

and 30.1 μs, respectively) from the kinetics fitted with a similar two-exponential function. Therefore, it is proposed that the zwitterionic intermediate 2 also undergoes a water-assisted ground state intramolecular proton transfer process (GSIPT) with the proton transferring from O22 to O23 and to produce the zwitterionic intermediate 3 (see Scheme 4), whose resonance structure is BQM. The kinetics isotope effect of kBQM,H/kBQM,D = 2 observed in Figure 5 (right) indicates that water molecules appear to take part in the GSIPT process, which is slower than the water assisted ESIPT process due to the higher energy barrier for a GSIPT process.56,57 Later, 4 is produced by adding H2O to BQM41 with a kinetics isotope effect of k4,H/k4,D = 1.48 (see Figure 5, right). Therefore, the results obtained by both fs-TA and ns-TA appear in accordance with results from fluorescence quenching experiments depicted in Figure 1, which suggests that water molecules take part in several reaction steps. More structural information from fsTRIR, ns-TR2, and ns-TR3 spectra described in a subsequent section also supports this view. TD-DFT computations performed to estimate the electronic absorbance bands of intermediate 2 and BQM gave the results presented in Figure S10, displaying the comparisons between the spectrum obtained at 0 ns and the calculated spectrum for intermediate 2 as well as the spectrum obtained at 25 μs and the calculated spectrum for BQM. These experimental data correlate with the calculated spectra, which indicate that the generation of intermediate 2 and the BQM species occur on the nanosecond to microsecond time scales. Fs-TRIR, ns-TR2, and ns-TR3 Experimental Characterization of the Excited States and Intermediates. To probe the vibrational structure and nature of the transient species produced from photoexcitation of BQMP-b in 1:1 MeCN:H2O, fs-TRIR, ns-TR2, and ns-TR3 were employed here to provide fingerprint information for the species observed in the timeresolved spectra. First, fs-TRIR measurements were studied by using a 267 nm pump and the mid-IR spectral region as the probe. Figure S11 presents the fs-TRIR data of BQMP-b acquired in a 1:1 MeCN:D2O solution. The TRIR data examined (Figure S11) indicated that the dynamics can be mainly divided into two periods: 0−50 ps and longer than 50 ps. The results for the earlier time before 50 ps were mainly dominated by the two bleached ground state signals of BQMPb in 1602 and 1633 cm−1, which correspond to the naphthol ring stretching vibrational modes. These two bands shifted to 1604 and 1618 cm−1 when the delay time is longer than 50 ps. After 50 ps, a new species increases in intensity until 900 ps, whose reaction correlates with the fs-TA results observed in a 1:1 MeCN:D2 O solvent displayed in Figure S7. Therefore, the

In addition, TD-DFT calculation has been illustrated as a useful tool in evaluating the absorption bands for intermediates previously.51,55 In order to assign the intermediates obtained in the fs-TA results, TD-DFT calculation was employed to evaluate the electronic absorption spectra of the BQMP-b S1 state and intermediate 1 as presented in Figure 4. The

Figure 4. (Left) Fs-TA spectrum at 1.97 ps (top) and the calculated electronic spectrum of the singlet of BQMP-b; (right) fs-ta spectrum at 28.4 ps (top) and the computed electronic spectrum of intermediate 1 from TD-B3LYP/6-311G** calculations.

calculated S1 absorption spectrum of BQMP-b gives two bands at 350 and 417 nm over 300−650 nm, which agrees with the experiment spectral bands at 350 and 437 nm at 1.97 ps (Figure 4 left). Besides, the computed absorption spectrum for 1 shows obvious absorption at 345, 390, and 480 nm, which is also consistent with the experimental spectrum obtain at 28.4 ps in 1:1 MeCN:H2O after excitation (Figure 4 right). Therefore, the TD-DFT results provide further evidence for the generation of intermediate 1 from the singlet excited state of BQMP-b as proposed above. Ns-TA experiments were also employed to distinguish the later species obtained in the 1:1 MeCN:H2O solution in Figure 5 (left) and in the 1:1 MeCN:D2O solution in Figure S9. The 367 nm species at 3 ns in Figure 3b can still be obtained in the early time ns-TA spectra with peaks at 313 and 367 nm. As discussed above, the initial species could be assigned to intermediate 2 (Scheme 3), which decays and gives rise to the next transient species at 381 and 500 nm. The second transient species can be attributed to the proposed BQM intermediate previously observed by Richter and Freccero and co-workers in an aqueous solution due to its very close resemblance to the previously reported TA spectra over a similar time scale.41 The kinetics obtained at 367 nm in the 1:1 MeCN:H2O solution could be modeled with a two-exponential function that gives 1.8 and 20.4 μs time constants. However, the time constants obtained in the MeCN:D2O solution are noticeably longer (3.6 E

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Scheme 4. Proposed Reaction Pathway of BQMP-b Connecting the Time-Resolved Spectroscopic Data Presented Here

900 ps TRIR spectrum with bands at 1618, 1593, 1576, 1534, and 1524 cm−1 (Figure 6) appears to be mainly due to the

Figure 6. TRIR data of BQMP-b obtained in 1:1 MeCN:D2O (at 900 ps) compared with the DFT calculated IR spectrum of intermediate 2.

Figure 7. Ns-TR2 data of BQMP-b acquired in 1:1 MeCN:H2O (obtained using a difference of the high and low power 309 nm resonance Raman spectra) compared to the DFT computed Raman data of BQM. The stars represent the bands caused by solvent subtraction artifacts.

generation of intermediate 2. These TRIR bands can be in large part assigned with the C−C bonds on both the naphthol ring and the zwitterion quinone methide ring stretching modes. The reasonable correlation of the DFT computed IR frequencies with the experiment results compared in Figure 6 indicates that intermediate 2 is generated in hundreds of picoseconds and appears to be formed from the cleavage reaction of intermediate 1. As discussed above, if intermediate 2 is produced, it may also be observed on the nanosecond time scale. Therefore, a ns-TR2 spectrum of BQMP-b acquired in 1:1 MeCN:H2O after high and low power 309.1 nm photoexcitation can also provide additional vibrational information. Figure 7 presents the 309.1 nm ns-TR2 data comparison to a computed DFT normal Raman spectrum for intermediate 2. This comparison shows reasonable correlation for the vibrational frequency pattern of calculated and experimental Raman bands although their intensities are different due to the resonance enhancement effects on the experimental data whereas the computed data does not have this effect. The vibrational feature at 1618 cm−1 obtained in Figure 6 is also seen in the TR2 data of Figure 7,

which is mostly attributed to the stretch motions of the C19− C20, C13−C17, and C18−C21 bonds. The feature at 1376 cm−1 may be correlated with the H−C21−H scissoring as well as the C−H rocking modes, while the 1180 and 856 cm−1 feature may be mainly ascribed to the C−H rocking and wagging modes. Therefore, comparing the IR spectrum with the ns-TR2 spectrum provides us more fingerprint information for intermediate 2. Ns-TR3 experiments were also employed using a 266 nm pump and 416 nm probe to explore the later time reaction pathway for BQMP-b in 1:1 MeCN:H2O. Figure S12 presents ns-TR3 data of BQMP-b in 1:1 MeCN:H2O from 10 ns to 250 μs. As shown in Figure S12, only one species was clearly observed with this 416 nm probe wavelength from 10 ns to 250 μs, and its intensity increases from 10 ns to 5 μs, and then decreases in the next 250 μs, and the changes with time for the 1624 cm−1 feature integrated area are shown in Figure S13 and appear correlated with the ns-TA results depicted in Figure 5. As discussed above, results from the ns-TA experiments here and those previously reported by Richter and Freccero and coworkers41 both suggest that the species obtained on the microseconds time scale could be a BQM intermediate. F

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H (H2O) scissoring mode showing up at 1587 cm−1, which could explain the vibration mode for the experimental Raman band at 1581 cm−1. However, two water molecules do not cause too much further difference compared to one molecule on either the dihedral angle or the Raman band shifts. As a result, many Raman features of the BQM TR3 results could be correlated to vibrational modes associated with ring C−C stretching and C−H bending. The 1624 cm−1 Raman feature is mostly contributed by the quinone methide ring stretching. The 1566 cm−1 Raman feature contributed mostly by the naphthyl ring stretch modes. The 1327 cm−1 feature is associated with the O−H rocking, and the 1233 cm−1 feature is correlated to a C−H in-plane rocking of the rings vibrational modes. Table S3 lists the resonance Raman measurement data and computed normal Rama frequencies for the 1100 cm−1 to 1700 cm−1 region. By obtaining the first time-resolved vibrational spectrum of BQM and comparison of its structural information in the form of the vibrational frequency pattern to those predicted from DFT calculations for probable intermediates in Figure 8, we have confirmed that BQM is indeed a short-lived quinone methide species, as proposed by Richter and Freccero and coworkers41 based on some earlier ns-TA data. More importantly, the sensitive nature of vibrational spectroscopy to the structure, properties, and environmental effects on the intermediates of interest enables a very detailed characterization of these properties and effects so that they can be correlated to each other to determine structure, properties, and chemical reactivity relationships in the future. Our present study clearly shows water is intimately influencing the photogeneration of bifunctional quinone methide intermediates such as the BQM examined here, and water molecules also noticeably influence its structure, properties, and likely its chemical reactivity in light of the results of alkylation reaction investigations that utilized photoactivated BQMP-b and found it had a preference for dG that is different from many quinone methides, such as the benzo o-QM that has a preference for dC.27,42 Based on a variety of product analysis results, Richter and Freccero and coworkers proposed that the quinone methide reactive intermediate produced from photoexcitation of BQMP-b behaves in a way very different from typical quinone methide species.41 Our work here shows that the absence or presence of water molecules significantly influences the relative dihedral angle of the two ring systems and the degree of conjugation in the quinone methide ring with the presence of water molecules enhancing the degree of conjugation in the quinone methide ring accompanied by twisting of the two ring systems about 90° from each other. The ESIPT, cleavage, and GSIPT processes involved in the photoactivation of BQMP-b to produce the reactive BQM intermediate of interest can be influenced by substituent and position effects in other related derivatives insofar as they change the structure and properties of the two ring systems and their interaction with each other. Judicious choices of substituents on either or both ring systems can be envisioned to enable the pKa of the two OH groups, the degree of twisting or interaction between the two ring systems, and the degree of conjugation in the quinone methide ring to all be varied and hence the chemical reactivity of BQM reactions to be varied as well. The demonstration of time-resolved vibrational spectroscopy techniques such as TR3 spectroscopy to examine the BQM transients here provides a platform to directly characterize BQM derivatives along with their

Therefore, the DFT computations are used to estimate the normal Raman frequencies of BQM, and the comparison results seen at 5 μs are shown in Figure 8.

Figure 8. Experiment TR3spectrum (at 5 μs) of BQMP-b observed in 1:1 MeCN:H2O (266 nm pump, 416 nm probe) compared to DFT computed Raman frequencies of BQM. Stars represent features caused by artifacts from solvent subtraction.

Six Raman bands, 1624 cm−1, 1581 cm−1, 1566 cm−1, 1521 cm−1, 1233 cm−1, and 1139 cm−1, in the 5 μs spectrum are seen in Figure 8D. The computed Raman data for the BQM without explicit water molecules gives three main bands at 1624 cm−1, 1567 cm−1, and 1480 cm−1 between 1700 cm−1 and 1400 cm−1. The features at 1624 and 1566 cm−1 correlate with the experiment data well (Figure 8A). However, the features at 1581 and 1521 cm−1 do not match as much with the calculated Raman bands. As recently discussed by Winter,58 utilizing a high correlated theory level and a big basis set combined with the addition of one or two explicit solvent molecules59 to start to build a solvation shell can provide an improved description of the solvated intermediate of interest. Thus, we considered the possibility that the BQM intermediate was influenced noticeably by hydrogen bonding with water molecules which might alter the Raman shift of some vibrational bands. Indeed, with the explicit addition of one or two waters into the system, the computed DFT Raman spectra of BQM changed noticeably to give better agreement with the experimental Raman bands. The DFT calculated results reveal that, with the absence of water molecules, the hydroxyl group and the carbonyl group are inclined to form a hydrogen bond and form a conjugated structure between H−O23−C9−C10−C11−C16-O22. However, with addition of explicit water molecule(s), both the carbonyl group and hydroxyl group are inclined to form hydrogen bonding with the solvent water molecules themselves, which induces a rotation of the dihedral angle from 59.5° with the absence of water to 94.4° with one water molecule and 92.4° with two water molecules, respectively (Figure S14 and Table S1). Therefore, the conjugated structure between theformer heptatomic ring is broken and the conjugation effects for the quinone methide ring are enhanced by addition of one or two explicit water molecules. Thus, compared to the BMQ intermediate without water molecule(s), the bond lengths for both C16O22 and C11C12 decrease from 1.2541 and 1.38631 Å to 1.2508 and 1.3799 Å with one water molecule involved in the system as shown in Table S2. Therefore, the stretching mode for both Raman bands shifted from 1480 to 1501 cm−1 when one water molecule is added into the calculated system. Besides, we also observe the H−O− G

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subsequent reactions, and in conjunction with corresponding quenching and product analysis studies, researchers can begin to develop structure/chemical reactivity relationships at a new level of detail for short-lived quinone methide intermediates.

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Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.6b08705. Description of the synthesis of BQMP-b and its characterization data (NMR, UV−vis, and FT-IR), fsTA, ns-TA, ns-TR 3 , fs-IR, NBO, and Cartesian coordinates for the DFT calculated species described in this study (PDF)

CONCLUSION

A combination of time-resolved spectroscopy methods has been used to study the photochemistry of BQMP-b from initial photoexcitation to generation of the key reactive binol QM intermediate BQM in aqueous solutions. In MeCN, the singlet excited state of BQMP-b is obtained after irradiation by 266 nm light and it depopulates with a 526 ps time constant mainly through the fluorescence and IC process as well as with a very small population via an inefficient ISC process. With the presence of water, the fluorescence of the BQMP-b is effectively quenched with a small amount of water, which suggests that a water-assisted ESIPT process takes place, and this is supported by fs-TA and ns-TA results. The kinetics isotope effects obtained from fs-TA and ns-TA experiments provide evidence for the participation of water molecules in the BQMP-b ESIPT, the release of the −HNMe3+ group, and GSIPT processes to subsequently produce the reactive BQM species. This study permits a direct observation of the photoreaction pathway of BQMP-b (see Scheme 4) in aqueous solution: the waterassisted ESIPT process takes place from O23 to C18 to form intermediate 1 within 7 ps, followed by the leaving of the HNMe3+ group to generate zwitterionic intermediate 2 within 220 ps; then it undergoes the GSIPT process from O22 to O23 to produce the BQM species within about 2 μs. Therefore, the efficient intramolecular proton transfer processes between hydroxyl groups of p-BQMPs provide a more efficient formation of BQM than p-NQMPs.41 In this study, we also characterized some of the intermediates for the first time with fs-IR, ns-TR2, and ns-TR3, which gave more in depth characterization of the identity, structural character, and properties of these intermediates produced from photoexcitation of BQMP-b. The DFT results show that, in the absence of water molecules, the hydroxyl group and the carbonyl group form a hydrogen bond that induces a conjugated structure between H−O23−C9−C10−C11−C16O22. The presence of an explicit water molecule changes this dramatically so that the carbonyl group and the hydroxyl group form hydrogen bonding with the solvent water molecules themselves and this induces a rotation of the dihedral angle from 59.5° with the absence of water to 94.4°. Therefore, the conjugated structure of the former heptatomic ring is broken and the conjugation effects for the quinone methide rings are enhanced with the bond lengths for both C16O22 and C11C12 decreasing from 1.2541 and 1.38631 Å to 1.2508 and 1.37993 Å with one water molecule involved in the system. The demonstration of time-resolved vibrational spectroscopy methods such as TR3 spectroscopy to investigate the BQM transient here provides a way to directly characterize BQM derivatives, and their reactions that are used in conjunction with corresponding quenching and product analysis studies can enable researchers to start to develop structure/chemical reactivity relationships at a greater level of detail for shortlived quinone methide intermediates reacting with DNA in alkylation and IStrandC processes in future studies.

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AUTHOR INFORMATION

Corresponding Authors

*Phone: +86-1082648118. E-mail: [email protected]. *Phone: +852-28592160. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from Research Grants Council of Hong Kong (grant HKU 7035/13P) to DLP and partial support from the Grants Committee Areas of Excellence Scheme (AoE/P-03/ 08) and the Special Equipment Grant (SEG HKU/07) and the National Science Foundation of China (grants 21433014 and 21573281) are gratefully acknowledged.

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REFERENCES

(1) Noll, D. M.; Mason, T. M.; Miller, P. S. Formation and Repair of Interstrand Cross-links in DNA. Chem. Rev. 2006, 106, 277−301. (2) Rajski, S. R.; Williams, R. M. DNA Cross-linking Agents as Antitumor Drugs. Chem. Rev. 1998, 98, 2723−2795. (3) LePla, R. C.; Landreau, C. A. S.; Shipman, M.; Hartley, J. A.; Jones, G. D. D. Azinomycin Inspired Bisepoxides: Influence of Linker Structure on in Vitro Cytotoxicity and DNA Interstrand Cross-linking. Bioorg. Med. Chem. Lett. 2005, 15, 2861−2864. (4) Armstrong, R. W.; Salvati, M. E.; Nguyen, M. Novel Interstrand Cross-Links Induced by the Antitumor Antibiotic Carzinophilin Azinomycin-B. J. Am. Chem. Soc. 1992, 114, 3144−3145. (5) Wolkenberg, S. E.; Boger, D. L. Mechanisms of in Situ Activation for DNA-targeting Antitumor Agents. Chem. Rev. 2002, 102, 2477− 2495. (6) Benbow, J. W.; Mcclure, K. F.; Danishefsky, S. J. Intramolecular Cycloaddition Reactions of Dienyl Nitroso-Compounds - Application to the Synthesis of Mitomycin-K. J. Am. Chem. Soc. 1993, 115, 12305− 12314. (7) Jamieson, E. R.; Lippard, S. J. Structure, recognition, and processing of cisplatin-DNA adducts. Chem. Rev. 1999, 99, 2467− 2498. (8) Ang, W. H.; Myint, M.; Lippard, S. J. Transcription Inhibition by Platinum-DNA Cross-Links in Live Mammalian Cells. J. Am. Chem. Soc. 2010, 132, 7429−7435. (9) Reissner, T.; Schneider, S.; Schorr, S.; Carell, T. Crystal Structure of a Cisplatin-(1,3-GTG) Cross-Link within DNA Polymerase eta. Angew. Chem., Int. Ed. 2010, 49, 3077−3080. (10) Ober, M.; Lippard, S. J. A 1,2-d(GpG) Cisplatin Intrastrand Cross-link Influences the Rotational and Translational Setting of DNA in Nucleosomes. J. Am. Chem. Soc. 2008, 130 (9), 2851−2861. (11) McHugh, M. M.; Kuo, S. R.; Walsh-O’Beirne, M. H.; Liu, J. S.; Melendy, T.; Beerman, T. A. Bizelesin, a Bifunctional Cyclopropylpyrroloindole Alkylating Agent, Inhibits Simian virus 40 Replication in Ttrans by Induction of an Inhibitor. Biochemistry 1999, 38, 11508−11515. (12) Lee, S. J.; Seaman, F. C.; Sun, D.; Xiong, H. P.; Kelly, R. C.; Hurley, L. H. Replacement of the Bizelesin Ureadiyl Linkage by a Guanidinium Moiety Retards Translocation from Monoalkylation to Cross-linking Sites on DNA. J. Am. Chem. Soc. 1997, 119, 3434−3442. H

DOI: 10.1021/acs.jpcb.6b08705 J. Phys. Chem. B XXXX, XXX, XXX−XXX

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Quinone Alpha, Alpha-diphenylmethide in Aqueous Solution. J. Phys. Org. Chem. 2004, 17, 579−585. (32) Chiang, Y.; Kresge, A. J.; Zhu, Y. Generation of o-Quinone Alpha-carbomethoxymethide by Photolysis of Methyl 2-hydroxyphenyldiazoacetate in Aqueous Solution. Phys. Chem. Chem. Phys. 2003, 5, 1039−1042. (33) Arumugam, S.; Popik, V. V. Photochemical Generation and the Reactivity of o-Naphthoquinone Methides in Aqueous Solutions. J. Am. Chem. Soc. 2009, 131, 11892−11899. (34) Kostikov, A. P.; Malashikhina, N.; Popik, V. V. Caging of Carbonyl Compounds as Photolabile (2,5-Dihydroxyphenyl)ethylene Glycol Acetals. J. Org. Chem. 2009, 74, 1802−1804. (35) Colloredo-Mels, S.; Doria, F.; Verga, D.; Freccero, M. Photogenerated Quinone Methides as Useful Intermediates in the Synthesis of Chiral BINOL Ligands. J. Org. Chem. 2006, 71, 3889− 3895. (36) Doria, F.; Percivalle, C.; Freccero, M. Vinylidene−Quinone Methides, Photochemical Generation and β-Silicon Effect on Reactivity. J. Org. Chem. 2012, 77, 3615−3619. (37) Doria, F.; Nadai, M.; Folini, M.; Scalabrin, M.; Germani, L.; Sattin, G.; Mella, M.; Palumbo, M.; Zaffaroni, N.; Fabris, D.; et al. Targeting Loop Adenines in G-Quadruplex by a Selective Oxirane. Chem. - Eur. J. 2013, 19, 78−81. (38) Doria, F.; Lena, A.; Bargiggia, R.; Freccero, M. Conjugation, Substituent, and Solvent Effects on the Photogeneration of Quinone Methides. J. Org. Chem. 2016, 81, 3665−3673. (39) Weinert, E. E.; Dondi, R.; Colloredo-Melz, S.; Frankenfield, K. N.; Mitchell, C. H.; Freccero, M.; Rokita, S. E. Substituents on Quinone Methides Strongly Modulate Formation and Stability of their Nucleophilic Adducts. J. Am. Chem. Soc. 2006, 128, 11940−11947. (40) Modica, E.; Zanaletti, R.; Freccero, M.; Mella, M. Alkylation of Amino Acids and Glutathione in Water by o-Quinone Methide. Reactivity and Selectivity. J. Org. Chem. 2001, 66, 41−52. (41) Verga, D.; Nadai, M.; Doria, F.; Percivalle, C.; Di Antonio, M.; Palumbo, M.; Richter, S. N.; Freccero, M. Photogeneration and Reactivity of Naphthoquinone Methides as Purine Selective DNA Alkylating Agents. J. Am. Chem. Soc. 2010, 132, 14625−14637. (42) McCrane, M. P.; Weinert, E. E.; Lin, Y.; Mazzola, E. P.; Lam, Y. F.; Scholl, P. F.; Rokita, S. E. Trapping a Labile Adduct Formed between an ortho-Quinone Methide and 2 ’-Deoxycytidine. Org. Lett. 2011, 13, 1186−1189. (43) Du, L.; Li, M.-D.; Zhang, Y.; Xue, J.; Zhang, X.; Zhu, R.; Cheng, S. C.; Li, X.; Phillips, D. L. Photoconversion of β-Lapachone to αLapachone via a Protonation-Assisted Singlet Excited State Pathway in Aqueous Solution: a Time-Resolved Spectroscopic Study. J. Org. Chem. 2015, 80, 7340−7350. (44) Du, L. L.; Zhu, R. X.; Xue, J. D.; Du, Y.; Phillips, D. L. Timeresolved Spectroscopic and Density Functional Theory Investigation of the Photochemistry of Suprofen. J. Raman Spectrosc. 2015, 46, 117− 125. (45) Fuji, T.; Suzuki, T. Generation of Sub-two-cycle Mid-infrared Pulses by Four-wave Mixing Through Filamentation in Air. Opt. Lett. 2007, 32, 3330−3332. (46) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; et al. Gaussian 09; Gaussian, Inc.: Wallingford, CT, USA, 2009. (47) Lukeman, M.; Veale, D.; Wan, P.; Munasinghe, V. R. N.; Corrie, J. E. T. Photogeneration of 1,5-Naphthoquinone Methides via Excitedstate (Formal) Intramolecular Proton transfer (ESIPT) and Photodehydration of 1-Naphthol Derivatives in Aqueous Solution. Can. J. Chem. 2004, 82, 240−253. (48) Flegel, M.; Lukeman, M.; Wan, P. Photochemistry of 1,1 ’-Bi-2naphthol (BINOL) - ESIPT is Responsible for Photoracemization and Photocyclization. Can. J. Chem. 2008, 86, 161−169. (49) Valiulin, R. A.; Lakkakula, S.; Kutateladze, A. G. A Peculiar Quenching Concentration Dependence of Photoinduced Fragmentation in Dithiane-carbonyl adducts: A Mechanistic Experimental and Theoretical study. J. Photochem. Photobiol., A 2009, 206, 80−86.

(13) Fan, Y. H.; Gold, B. Sequence-specificity for DNA Interstrand Cross-linking by Alpha,Omega-alkanediol Dimethylsulfonate Esters: Evidence for DNA distortion by the initial monofunctional lesion. J. Am. Chem. Soc. 1999, 121, 11942−11946. (14) Vedejs, E.; Naidu, B. N.; Klapars, A.; Warner, D. L.; Li, V. S.; Na, Y.; Kohn, H. Synthetic Enantiopure Aziridinomitosenes: Preparation, Reactivity, and DNA Alkylation Studies. J. Am. Chem. Soc. 2003, 125, 15796−15806. (15) Cullis, P. M.; Mersondavies, L.; Weaver, R. Conjugation of a Polyamine to the Bifunctional Alkylating Agent Chlorambucil Does Not Alter the Preferred Cross-Linking Site in Duplex DNA. J. Am. Chem. Soc. 1995, 117, 8033−8034. (16) Cimino, G. D.; Gamper, H. B.; Isaacs, S. T.; Hearst, J. E. Psoralens as Photoactive Probes of Nucleic-Acid Structure and Function-Organic-Chemistry, Photochemistry, and Biochemistry. Annu. Rev. Biochem. 1985, 54, 1151−1193. (17) Rokita, S. E. Reversible Alkylation of DNA by Quinone Methides. Quinone Methides; John Wiley & Sons, Inc.: New York, 2009; pp 297−327. (18) Lukeman, M. Photochemical Generation and Characterization of Quinone Methides; John Wiley & Sons: Hoboken, 2009. (19) Doria, F.; Richter, S. N.; Nadai, M.; Colloredo-Mels, S.; Mella, M.; Palumbo, M.; Freccero, M. BINOL-amino Acid Conjugates as Triggerable Carriers of DNA-targeted Potent Photocytotoxic Agents. J. Med. Chem. 2007, 50, 6570−6579. (20) Verga, D.; Richter, S. N.; Palumbo, M.; Gandolfi, R.; Freccero, M. Bipyridyl Ligands as Photoactivatable Mono- and Bis-alkylating Agents Capable of DNA Cross-linking. Org. Biomol. Chem. 2007, 5, 233−235. (21) Richter, S. N.; Maggi, S.; Mels, S. C.; Palumbo, M.; Freccero, M. Binol Quinone Methides as Bisalkylating and DNA Cross-linking Agents. J. Am. Chem. Soc. 2004, 126, 13973−13979. (22) Wang, P.; Liu, R. P.; Wu, X. J.; Ma, H. J.; Cao, X. P.; Zhou, P.; Zhang, J. Y.; Weng, X. C.; Zhang, X. L.; Qi, J.; et al. A Potent, Watersoluble and Photoinducible DNA Cross-linking Agent. J. Am. Chem. Soc. 2003, 125, 1116−1117. (23) Weng, X. C.; Ren, L. G.; Weng, L. W.; Huang, J.; Zhu, S. G.; Zhou, X.; Weng, L. H. Synthesis and Biological Studies of Inducible DNA Cross-linking Agents. Angew. Chem., Int. Ed. 2007, 46, 8020− 8023. (24) Liu, J.; Liu, H.; van Breemen, R. B.; Thatcher, G. R. J.; Bolton, J. L. Bioactivation of the Selective Estrogen Receptor Modulator Acolbifene to Quinone Methides. Chem. Res. Toxicol. 2005, 18, 174−182. (25) Di Antonio, M.; Doria, F.; Richter, S. N.; Bertipaglia, C.; Mella, M.; Sissi, C.; Palumbo, M.; Freccero, M. Quinone Methides Tethered to Naphthalene Diimides as Selective G-Quadruplex Alkylating Agents. J. Am. Chem. Soc. 2009, 131, 13132−13141. (26) Wang, H.; Wahl, M. S.; Rokita, S. E. Immortalizing a Transient Electrophile for DNA Cross-linking. Angew. Chem., Int. Ed. 2008, 47, 1291−1293. (27) Pande, P.; Shearer, J.; Yang, J. H.; Greenberg, W. A.; Rokita, S. E. Alkylation of Nucleic Acids by a Model Quinone Methide. J. Am. Chem. Soc. 1999, 121, 6773−6779. (28) Basaric, N.; Zabcic, I.; Mlinaric-Majerski, K.; Wan, P. Photochemical Formation and Chemistry of Long-Lived Adamantylidene-Quinone Methides and 2-Adamantyl Cations. J. Org. Chem. 2010, 75, 102−116. (29) Flegel, M.; Lukeman, M.; Huck, L.; Wan, P. Photoaddition of Water and Alcohols to the Anthracene Moiety of 9-(2 ’-hydroxyphenyl)anthracene via Formal Excited State Intramolecular Proton Transfer. J. Am. Chem. Soc. 2004, 126, 7890−7897. (30) Brousmiche, D. W.; Xu, M. S.; Lukeman, M.; Wan, P. Photohydration and Photosolvolysis of Biphenyl Alkenes and Alcohols via Biphenyl Quinone Methide-type Intermediates and Diarylmethyl Carbocations. J. Am. Chem. Soc. 2003, 125, 12961−12970. (31) Chang, J. A.; Kresge, A. J.; Zhan, H. Q.; Zhu, Y. Flash Photolytic Generation and Study of p-Quinone Alpha-phenylmethide and pI

DOI: 10.1021/acs.jpcb.6b08705 J. Phys. Chem. B XXXX, XXX, XXX−XXX

Article

The Journal of Physical Chemistry B (50) Agmon, N. Elementary Steps in Excited-State Proton Transfer. J. Phys. Chem. A 2005, 109, 13−35. (51) Li, M. D.; Albright, T. R.; Hanway, P. J.; Liu, M. Y.; Lan, X.; Li, S. B.; Peterson, J.; Winter, A. H.; Phillips, D. L. Direct Spectroscopic Detection and EPR Investigation of a Ground State Triplet Phenyl Oxenium Ion. J. Am. Chem. Soc. 2015, 137, 10391−10398. (52) Chiang, Y.; Kresge, A. J.; Zhu, Y. Kinetics and Mechanisms of Hydration of o-Quinone Methides in Aqueous Solution. J. Am. Chem. Soc. 2000, 122, 9854−9855. (53) Chiang, Y.; Kresge, A. J.; Zhu, Y. Flash Photolytic Generation of ortho-Quinone Methide in Aqueous Solution and Study of its Chemistry in That Medium. J. Am. Chem. Soc. 2001, 123, 8089−8094. (54) Chiang, Y.; Kresge, A. J.; Zhu, Y. Flash Photolytic Generation of o-Quinone alpha-Phenylmethide and o-Quinone Alpha-(p-anisyl)methide in Aqueous Solution and Investigation of Their Reactions in That Medium. Saturation of Acid-catalyzed Hydration. J. Am. Chem. Soc. 2002, 124, 717−722. (55) Li, M. D.; Hanway, P. J.; Albright, T. R.; Winter, A. H.; Phillips, D. L. Direct Spectroscopic Observation of Closed-Shell Singlet, OpenShell Singlet, and Triplet p-Biphenylyloxenium Ion. J. Am. Chem. Soc. 2014, 136, 12364−12370. (56) Shizuka, H.; Machii, M.; Higaki, Y.; Tanaka, M.; Tanaka, I. Excited-state and Ground-state Intramolecular Proton-transfer Reactions of 6-(2-Hydroxy-5-methylphenyl)-s-triazines in Poly(methyl methacrylate). J. Phys. Chem. 1985, 89, 320−326. (57) Annaraj, B.; Pan, S.; Neelakantan, M. A.; Chattaraj, P. K. DFT Study on the Ground State and Excited State Intramolecular Proton Transfer of Propargyl Arm Containing Schiff Bases in Solution and Gas Phases. Comput. Theor. Chem. 2014, 1028, 19−26. (58) Winter, A. Making a Bad Calculation. Nat. Chem. 2015, 7, 473− 475. (59) Bondesson, L.; Mikkelsen, K. V.; Luo, Y.; Garberg, P.; Agren, H. Hydrogen Bonding Effects on Infrared and Raman Spectra of Drug molecules. Spectrochim. Acta, Part A 2007, 66, 213−224.

J

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