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Photochemical Activation of Tertiary Amines for Applications in Studying Cell Physiology Naeem Asad,† Davide Deodato,† Xin Lan,‡ Magnus B. Widegren,† David Lee Phillips,*,‡ Lili Du,*,‡ and Timothy M. Dore*,†,§ †

New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, United Arab Emirates Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong 999077, People’s Republic of China § Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States ‡

S Supporting Information *

ABSTRACT: Representative tertiary amines were linked to the 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group (PPG) to create photoactivatable forms suitable for use in studying cell physiology. The photoactivation of tamoxifen and 4-hydroxytamoxifen, which can be used to activate Cre recombinase and CRISPR-Cas9 gene editing, demonstrated that highly efficient release of bioactive molecules could be achieved through one- and two-photon excitation (1PE and 2PE). CyHQprotected anilines underwent a photoaza-Claisen rearrangement instead of releasing amines. Time-resolved spectroscopic studies revealed that photorelease of the tertiary amines was extremely fast, occurring from a singlet excited state of CyHQ on the 70 ps time scale.

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INTRODUCTION Amine groups are frequently critical to the function of biologically active molecules, especially neurotransmitters and neuromodulators such as glutamate, GABA, serotonin, dopamine, and others. As a result, photoactivatable versions of these have been created to study important aspects of physiology.1−8 Many strategies for the release of primary and secondary amines in a biological context have been reported,9−20 but there are few protocols for photoreleasing tertiary amines19,21−23 efficiently and in ways that are amenable to studying biological systems, although some examples of photobase generators for polymer systems exist.24−28 Photoactivatable forms of tertiary amines are interesting targets to pursue, because they are prevalent in a variety of biologically active compounds, such as atropine, codeine, morphine, and nicotine. The dimethylalkylamine motif is common among the pharmaceuticals chlorpromazine, sumatriptan, psilocin, and tamoxifen to mention a few. Tamoxifen, a cancer chemotherapeutic,29 has also been used to temporally regulate gene expression in the Cre-recombinase30−32 and CRISPR-Cas933 systems, and photoactivatable versions of tamoxifen and its analogs are useful tools to achieve spatiotemporal control over gene expression.22,34−39 Photoremovable (photoreleasable, photocleavable, or photoactivatable) protecting groups (PPGs) have been extensively used in different contexts to selectively release chemical entities with light.40−45 Photoactivation of signaling molecules is a powerful technique that enables the study of dynamic physiological processes in cell culture, intact tissues, and whole animals.46−52 A wide variety of PPGs have been © 2017 American Chemical Society

developed for the selective protection and release of a variety of functional groups such as alcohols, amines (as carbamates), metal cations, esters, diols, phosphates, and amides. Quinoline-based PPGs have been used for the release of physiologically active messengers in response to irradiation with ultraviolet light (365 nm) and one-photon excitation (1PE) or near-visible light (740 nm) and two-photon excitation (2PE).53−57 They protect a range of biologically relevant functional groups, and many possess excellent photochemical and physiological properties like solubility in aqueous media, high quantum efficiencies for 1PE, fast release kinetics, and moderate two-photon uncaging action cross sections.58−65 These properties make quinoline-based PPGs prime entities to study the dynamics of biological systems. The 8-bromo- and 8-cyano-7-hydroxyquinolinyl PPGs (BHQ and CyHQ, respectively, Figure 1) release carboxylates, amines (via the carbamate), phosphates, diols, and phenols. The pKa of the leaving group is critical for effective photorelease of the biologically active messenger; a threshold of 10.1 has been established for BHQ and slightly higher for CyHQ.57 Because

Figure 1. Structures of 8-bromo- (BHQ) and 8-cyano-7-hydroxyquinolinyl (CyHQ) PPGs. X = biological effector. Received: June 19, 2017 Published: August 14, 2017 12591

DOI: 10.1021/jacs.7b06363 J. Am. Chem. Soc. 2017, 139, 12591−12600

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probed the photolysis reaction mechanism through Stern− Volmer quenching experiments and absorption, resonance Raman, and time-resolved spectroscopy, revealing an extremely fast C−N bond cleavage from a singlet excited state, a mechanistic shift from the triplet state engaged in the photolysis of the BHQ PPG.59,67−69

ammonium and alkyl ammonium ions have a pKa of 9−11, a quaternary ammonium salt of CyHQ would release a tertiary amine upon exposure to light. The idea has some precedent in the work of Givens and Klán,19 who showed that irradiation of N-protected para-hydroxyphenacyl ammonium derivatives at 313 nm released primary and secondary amines or ammonia in nearly quantitative yields through the photo-Favorskii reaction. Wang et al.66 have also demonstrated release of primary amines from trityl-conjugated ammonium ions. A CyHQ-based approach would be one of the few examples involving the release of tertiary amines for use in biologically relevant systems. We have expanded the repertoire of functional groups released post photoactivation of CyHQ to include tertiary aliphatic amines, including a drug and its metabolite, tamoxifen and 4-hydroxytamoxifen (Figure 2). CyHQ-protected amines

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RESULTS AND DISCUSSION Synthesis. The CyHQ-protected tertiary amines 1a−r (Figure 2) were prepared from either the MOM-CyHQ-OMs (9a) or the MOM-CyHQ-Cl (9b) common intermediate (Scheme 1). Compounds 9a and 9b were synthesized from Scheme 1. Synthesis of CyHQ-Protected Aminesa

Reagents and conditions: (a) 6 N HCl, FeCl3, butanol, 85−95 °C, then TsOH, 35%; (b) NBS, MeOH, rt, 16 h, 80%; (c) AcCl, Et3N, CH3CN, 0−5 °C, then CuCN, DMA, reflux, 1 h; (d) 33% NH4OH, rt, 1 h, 60% over two steps; (e) MOMCl, Et3N, CH2Cl2, 10 °C, 12 h, 90%; (f) SeO2, t-BuOOH, dioxane, 55 °C, 3 h; (g) NaBH4, EtOH, rt, 6 h, 85% over three steps; (h) MsCl, TEA, CH2Cl2, rt; (i) NR3, CH3CN, reflux, 5 h, then TFA, CH2Cl2, rt, 5 h. a

MOM-CyHQ-OH (8),60 which was prepared through a new, high-yielding, and scalable protocol (Scheme 1). The reaction of 3-aminophenol (2) with crotonaldehyde (3) in the presence of HCl and FeCl3 afforded 2-methylquinolin-7-ol, which was subsequently treated with para-toluene sulfonic acid (p-TSA), expediting the purification process, and quinolinium 4 was isolated as the p-TSA salt. Treatment of 4 with Nbromosuccinimide resulted in bromination of C-8 on the quinoline. The bromine in 5 was replaced with a cyano group in a one-pot procedure of first protecting the phenolic position with an acetyl group, followed by treatment with CuCN in DMA and then hydrolyzing the acetate and liberating the free quinoline 6. MOM protection of the phenol in 6 followed by SeO2 oxidation and subsequent reduction furnished MOMCyHQ-OH (8), which was converted to CyHQ-protected amines 1a−r. Purification of compounds 1a−r was carried out by either trituration with tetrahydrofuran or column chromatography. The CyHQ-protected tamoxifen and 4-hydroxytamoxifen derivatives underwent isomerization of the double bond during the deprotection step with TFA. To circumvent this problem, the MOM group in MOM-CyHQ-OMs (9a) and MOM-

Figure 2. Quaternary CyHQ salts of tertiary amines.

photolyzed with large quantum efficiencies at biologically compatible wavelengths (>360 nm). They were sufficiently sensitive to 2PE at 740 nm for use in biological systems and stable in the dark in simulated physiological buffer. Instead of releasing the corresponding amine, aryl alkyl ammonium salts of CyHQ underwent an interesting rearrangement reaction. We 12592


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pH 7.2) was assayed. Less than 1% of any of the CyHQprotected amines 1a−t degraded during a period of 1 week. Photochemistry through 1PE. Upon exposure to 365 nm light, CyHQ-protected amines 1a−i and 1s,t in simulated physiological buffer (pH 7.2 KMOPS) successfully released their respective tertiary amines 12a−i and 12s,t (Scheme 3).

CyHQ-Cl (9b) was removed prior to coupling with tamoxifen and 4-hydroxytamoxifen (Scheme 2) to provide 1s−u. In the case of 4-hydroxytamoxifen, a small amount of isomerization was still observed. Scheme 2. Synthesis of CyHQ-Protected Tamoxifen and 4Hydroxytamoxifena

Scheme 3. Photolysis of CyHQ-Protected Amines

a

Reagents and conditions: (a) TFA, CH2Cl2, rt, 5h, 40−65%; (b) 4hydroxytamoxifen or tamoxifen, CH3CN, rt, 5 h.

The time course of the photolysis reaction was monitored by HPLC, quantifying the disappearance of the starting material by comparison with calibration curves of 1a−i and 1s,t (Figure 3). The quantum efficiency (Qu) and photochemical sensitivity (product of ε and Qu) at 365 nm of each CyHQ-protected tertiary amine 12a−i and 12s,t were calculated as previously described (Tables 1 and S1).10,57,60 The time courses for the photolysis of 1a−i and 1s,t (Figures 3 and S1−S11) showed that the amine derivatives 1a−i were efficiently photolyzed with 1PE at 365 nm. Excellent quantum efficiencies (Qu = 0.30−0.50) were obtained for caged-amines bearing a benzylic group (compounds 1d−f), whereas the efficiencies for 1a−c and 1g−i were slightly lower (0.10−0.25). Good quantum efficiencies were also found for the biologically relevant derivatives 1s,t; upon irradiation, they successfully release 4-hydroxytamoxifen and tamoxifen, with chemical yields of 81% and 91%, respectively. Both compounds were released as single isomers (Z), but upon prolonged irradiation (>40 s) Z/E photoisomerization occurred (60:40 Z/E ratio in 180 s for tamoxifen). LC−MS/MS was used to monitor the increase in photoreleased amine from compounds 1d−g, because the low extinction coefficients of the amines did not allow UV quantification. The yields for these latter derivatives were moderate to good (43−74%). The aromatic amines 1m−r displayed no conversion of the starting material after 15 min of UV exposure (365 nm) with high lamp intensity. Only minor oxidation byproducts were identified by LC−MS in the case of the two CyHQ-protected imidazoles 1n and 1o after prolonged irradiation. This result was unexpected, because the low pKa values of the conjugate

Aqueous Solubility of CyHQ-Protected Amines. The CyHQ-protected amines 1a−r exhibited good solubility (>0.1 mM) in the KMOPS buffer (KCl 100 mM, MOPS 10 mM, pH 7.2) used to simulate physiological conditions in the photochemistry experiments. Derivatives 1s−u were less soluble in KMOPS, because of the presence of the poorly soluble tamoxifen and 4-hydroxytamoxifen moieties (tamoxifen water solubility is 24 μg/mL70). The solubility of the mesylate and the chloride salts of CyHQ-protected tamoxifen 1t and 1u, respectively, which are less soluble than the 4-hydroxytamoxifen analog 1s, was found to be 27 ± 3 μM (18 μg/mL) for 1t and 18 ± 3 μM (11 μg/mL) 1u in KMOPS buffer. These values were not sufficient for the photochemistry experiments; therefore, a 30% solution of ethanol in KMOPS buffer was used to dissolve 1s,t and perform the photochemical characterizations. Molar Absorptivity and λmax of CyHQ-Protected Amines. UV−vis spectra of 1a−t were recorded in KMOPS, and all of the compounds exhibited λmax near 370 nm (Tables 1 and S2), which indicates that the phenoxy anionic forms of 1a− t predominate at pH 7.2. From the spectra, the molar absorptivities at 365 nm (ε365) were calculated using the Beer−Lambert law (Table 1). The values of ε365 range from 5770 to 8270 M−1 cm−1. The λmax and ε365 values are similar to those reported for CyHQ-protected acetate and phenols.57,60 Stability of CyHQ-Protected Amines in the Dark. The stability of compounds 1a−t in the dark at room temperature and under simulated physiological conditions (KMOPS buffer

Table 1. Photophysical and Photochemical Data for the CyHQ-Protected Tertiary Amines Successfully Photolyzeda

a

compound

λmax (nm)

ε365 (M−1 cm−1)

Qu

sensitivity (ε·Qu)

δu (GM)b

yield (%)c

CyHQ-TEA (1a) CyHQ-NMMo (1b) CyHQ-NMPip (1c) CyHQ-DMBnA (1d) CyHQ-BnPyr (1e) CyHQ-DEtBnA (1f) CyHQ-DMPhEtA (1g) CyHQ-AllylPip (1h) CyHQ-PropargylPip (1i) CyHQ-N-TMX-4OH (1s)e CyHQ-TMX (1t)e

371 373 372 372 369 368 372 372 371 386 373

7640 6670 7030 5030 4810 6540 6220 7480 8270 6880 7660

0.18 0.10 0.21 0.37 0.50 0.30 0.25 0.20 0.15 0.13 0.21

1400 660 1500 1800 2400 2000 1500 1500 1200 910 1600

0.26 0.23 0.23 0.38 0.38 0.35 0.31 0.24 0.27 0.29 0.36

n.d.d n.d. n.d. 59 74 74 43 n.d. n.d. 81 91

0.1 mM solution in KMOPS buffer (KCl 100 mM, MOPS 10 mM, pH = 7.2). bGM = 10−50 (cm4 s)/photon. cChemical yield of released amine. Not determined. eMeasured in 30% EtOH in KMOPS buffer.

d

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Figure 3. Time courses for the photolysis reaction of (left) 1a, 1d, 1e, and 1g and (right) biologically relevant caged amines 1s,t. Also shown is the appearance of the released tertiary amines. Tamoxifen (TMX) and 4-hydroxytamoxifen (4OH-TMX) were released as a mixture of E/Z isomers. Concentrations were determined by uHPLC and are the average of three runs. Lines are least-squares fits of a simple exponential decay (solid lines) or of an exponential rise to max (dashed lines). Error bars represent the standard deviation of the measurement.

consistent with the structure 13k and excludes other possibilities (Scheme 4).

acids of the aromatic amines make them good leaving groups, and the molar absorptivity is high enough for productive excitation. We assume that the CyHQ-protected amines dissipated the absorbed energy through different pathways rather than undergoing photochemistry, but to corroborate this hypothesis, in-depth studies on the decay paths of the singlet excited state (which are outside the scope of this work) need to be performed. Irradiation of KMOPS solutions of three CyHQ-protected anilines 1j−l at 365 nm led to the consumption of the starting material, but no formation of uncaging remnant 11, which is evidence of productive photolysis to release an amine, was observed (Scheme 3). A new compound was identified instead, having the same molecular weight of the starting material, but different uHPLC retention time, indicating that an intramolecular rearrangement had occurred. A large-scale photolysis of each substrate 1j−l enabled the isolation of a sufficient quantity of their respective unknown product for spectroscopic characterization. We acquired 1H, 13C, and DEPT-135° NMR spectra plus gCOSY, HMBC, HSQC-TOCSY, HSQC, and COSY twodimensional spectra. Comparing the one-dimensional NMR spectra of the starting material with the new product revealed that the quinoline was intact in the product. Taking 1k as an example, the spectrum of the starting material showed a quinoline ring proton at 8.22 ppm (d, J = 8.3 Hz, 1H) coupled to a single proton in the doublet at 6.88 ppm (d, J = 8.2 Hz, 1H). Another proton at 8.07 ppm (d, J = 9.1 Hz, 1H) is coupled to a proton in the multiplet at 7.38−7.48 ppm. The expected quinoline ring coupling pattern was present in the spectrum of the product as well: a proton at 7.93 ppm (d, J = 8.4 Hz, 1H) coupled to a proton at 6.97 ppm, and a proton at 7.80 ppm (d, J = 9.0 Hz, 1H) coupled to a proton at 7.08 ppm. The other aromatic proton signals indicated a switch from a monosubstituted benzene to an ortho-substituted one. Integration of the aromatic region of the 1H NMR spectrum of 1k contained 5 aromatic protons of the aniline, whereas that of the product showed only 4. The 13C NMR of 1k showed only 4 resonances for the aniline, yet there were 6 aromatic resonances in the product, consistent with an ortho-substituted benzene. Further, the 1H NMR spectrum of the product showed a triplet of doublets at 6.83 ppm with coupling constants J = 7.4 and 1.3 Hz, which is only possible if the substituents on the benzene ring are ortho. Two-dimensional NMR enabled full assignment of the 1H and 13C NMR peaks in a manner that is fully

Scheme 4. Rearrangement Reaction of CyHQ-Protected Anilines

Different reaction conditions were explored (solvent, irradiation time, and concentration of substrate) to optimize the photorearrangement reaction of 1k for synthetic viability (Table S1). We successfully identified synthetically useful conditions (10 mM in water and 1 h of UV irradiation) that gave the rearranged product 13k in 70% isolated yield. We hypothesize that photolysis products 13j−l arose from a photoaza-Claisen rearrangement (Scheme 5). The generation of the cationic intermediate 15 is well-precedented in the 7hydroxyquinoine-based PPGs59,67−69 and is supported by our studies on the photolysis reaction mechanism (vide infra), so it is reasonable that the aryl ring could trap the cation prior to trapping by water. Following the excited-state C−N bond Scheme 5. Proposed Mechanism for the Rearrangement

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Journal of the American Chemical Society cleavage, the rearrangement could occur through ground- or excited-state singlet or triplet species 15 and 16. A similar reaction of a photoactivatable phenol was reported by Wong and co-workers for coumarin-protected hydroxytamoxifen.39 This is interesting, because Claisen sigmatropic rearrangements of allylic and benzylic ethers have been extensively studied,71,72 whereas their photochemical equivalents have received less attention because of the low yields and extensive polymerization typically associated with them. Aza-Claisen reactions are far less common due to the high temperatures required to effect them,73 and alternative pathways are favored under irradiation,74,75 although Kraus, Schell, and co-workers reported a photoaza-Claisen rearrangement of cyclic enaminones.76 A radical mechanism could also be possible, because the rearrangement could be effected in acetonitrile, in which homolytic cleavage of the C−N bond predominates (vide infra). Additionally, some evidence77−81 suggests that the photo-Claisen rearrangement is mechanistically related to the photo-Fries rearrangement, which is known to proceed via a radical mechanism.82,83 More work is necessary to better understand the rearrangement mechanism. Photochemistry through 2PE. The ability to undergo photolysis through 2PE was investigated for the CyHQprotected compounds that released tertiary amines (1a−i and 1s,t). The parameter used to quantify the sensitivity of the PPG toward 2PE is the two-photon uncaging action cross-section (δu), generally expressed in Goeppert−Mayer (GM).84,85 Solutions of 1a−i and 1s,t in KMOPS were irradiated with a fs-pulsed laser at 740 nm for different time intervals (Figures S1−S11), and the value of δu was calculated using fluorescein as an external standard as previously described (Tables 1 and S1).10,57,60 All of the compounds evaluated successfully released the tertiary amines through 2PE with an average cross-section of 0.30 GM, which is in line with the reported values for CyHQ-protected acetate and phenols (0.32 and 0.25 GM, respectively).57,60 This result further validates CyHQ as a valuable PPG with good sensitivity toward 2PE, which is a very important property for successful employment in a biological setting, where deep light penetration and low phototoxicity are required. Stern−Volmer Quenching Experiments. To probe the nature of the excited state involved in the photolysis reaction (Scheme 3), we conducted Stern−Volmer quenching experiments on representative CyHQ-protected amines 1a and 1d plus CyHQ-60 and BHQ-protected acetates58,59,67 (Scheme 6).

Table 2. Stern−Volmer Quenching Experiments quantum efficiencies (Qu) of the photolysis reactionsa quencher: [quencher] (μM): CyHQ-TEA (1a) CyHQDMBnA (1d) CyHQ-OAc BHQ-OAc

potassium sorbate (PS)

sodium 2-naphthalenesulfonate (SNS)

0

500

1000

1500

500

1000

1500

0.18

0.18

0.15

0.14

0.17

0.16

0.15

0.37

0.35

0.33

n.d.b

0.36

0.38

n.d.b

0.27 0.24

0.28 0.21

0.32 0.22

n.d.b n.d.b

0.27 n.d.b

0.28 n.d.b

0.28 n.d.b

Photolyses performed at 365 nm on 100 μM substrate in KMOPS buffer. bNot determined.

a

at concentrations up to 15 times higher than 1a and up to 10 times higher than 1d or CyHQ-OAc. BHQ-OAc, which Stern−Volmer quenching experiments and time-resolved spectroscopic studies indicate photolyzes through a triplet excited state,67,68 did not show a statistically significant change in Qu at concentrations of PS up to 10 times that of BHQ-OAc (Figure S20), or an indication of reaction quenching in the UV−vis spectra at a concentration of PS 50 times higher than BHQ-OAc (Figure S25) when irradiated at 365 nm. The discrepancy between the reported quenching67 and the results we report here lies in the wavelength of excitation, 254 versus 365 nm. PS has a large absorbance at 254 nm (Figure S27), so photolysis was not observed at this wavelength in the previously reported work67 because PS served as a filter of 254 nm light and prevented excitation of BHQ-OAc, not because PS quenched a triplet-excited state of BHQ-OAc, although the time-resolved studies support a triplet state intermediate that is likely too short-lived (5 ns)67,68 to be quenched by PS. To summarize the results, the Stern−Volmer quenching experiments indicated that the photorelease of CyHQ-caged tertiary amines is likely to occur via a singlet excited state or, if a triplet excited state is involved, the lifetime is too short to be quenched by PS or SNS thorough energy transfer. Time-Resolved Spectroscopic Studies. To reveal the photoinduced C−N bond cleavage mechanism of 1a, timeresolved spectroscopies were employed. The UV−vis absorption spectra for 1a in 1:1 pH 7.2 PBS/acetonitrile and acetonitrile were measured and compared to the respective TDDFT calculated absorption spectra (Figure 4). The calculated spectra were computed for the optimized geometries of the ground states of 1a and its oxyanion form 1a (A). In acetonitrile, the main absorption bands appear at 230 and 338 nm, but red shift to 248 and 380 nm in pH 7.2 PBS/ acetonitrile (Figure 4b and c). Similarly, red-shifting of the absorption bands was observed in the calculated TD-DFT spectra (Figure 4a and d), which indicates that a deprotonation process takes place in aqueous solvents to produce some 1a (A). Considering that the electronic absorption spectra are generally broad and structureless, the resonance Raman spectroscopy technique was used to provide more information regarding the structure and identity of the prototropic form(s) of 1a present in each solvent. In accord with the absorption spectra results, the resonance Raman spectra also revealed that 1a is present mainly in the oxyanionic form 1a (A) in neutral aqueous conditions, whereas it is mostly in the neutral form in acetonitrile (Figure S29).

Scheme 6. Photolysis Reaction of CyHQ- and BHQ-OAc

The quantum efficiencies of the 1PE-mediated photolysis at 365 nm were determined in the presence of increasing concentrations of the well-known triplet quenchers potassium sorbate (PS) and sodium 2-naphthalenesulfonate (SNS) (Table 2, Figures S17−S20). The course of the photolyses was also monitored by comparing the UV−vis absorption spectra before and after irradiation in the presence of the quenchers (Figures S21−25). No statistically significant change in the quantum efficiency was observed in the presence of PS or SNS quenchers 12595


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Figure 5. Left: Time-resolved fluorescence (TRF) spectra of 1a in 1:1 pH 7.2 PBS/acetonitrile after 267 nm excitation. Right: Timedependence of the fluorescence decay dynamics at 439 (blue ○) and 538 nm (□). The fluorescence decay at 538 nm recorded before 400 ps is enlarged to display the details of the fluorescence intensity changes at early picosecond delay times as shown in the inset of the right kinetics figure.

Figure 4. Comparison of UV−vis absorption spectra of 1a in (b) pH 7.2 PBS/acetonitrile (1:1) and (c) acetonitrile with (a) the calculated absorption spectra (TD-B3LYP/6-311G(d,p)) of the ground-state singlet oxyanion precursor 1a (A) and (d) the protonated form 1a. The relevant molecular structures are displayed near the related spectra.

wavelength-dependent character of the fluorescence kinetics. Therefore, the relaxation processes producing emission appear to involve more than one fluorescent singlet state. Global analysis of the fluorescence decay kinetics at all wavelengths observed indicates that a satisfactory fitting requires three exponential functions with time constants of ∼30 ps (τ1) for the rising intensity and ∼70 ps (τ2) and ∼3000 ps (τ3) for the intensity decay processes. The rapid rise of the intensity of the spectra can be attributed to an internal conversion (IC) from the higher singlet excited state of the precursor 1a (Sn) (Scheme 7) to the first singlet excited-state

Excited-state proton transfer has been observed for 7hydroxyquinoline86 and 8-bromo-7-hydroxyquinoline67 after photoexcitation, and 8-hydroxyquinoline exists as the phenolic form in the absence of irradiation.87 As compared to these precursors, the phenolic hydroxyl group on 1a behaves differently. This may be a result of the enhanced acidity of the phenolic oxygen induced by the electron-withdrawing effect of the 8-cyano group (pKa of CyHQ-OAc is 4.9,88 as compared to 7.3 for BHQ-OAc69), which then results in a greater tendency toward deprotonation of the hydroxyl group. Because different ground-state precursors are formed in aqueous solution and in acetonitrile, different photochemical and photophysical processes likely occur after photoexcitation of 1a in these different solvents. The irradiation of 1a in acetonitrile gave starting material. Even after 1 h, no discrete photolysis products (CyHQ-OH, NR3, or other compounds) were observed, which could have resulted from homolytic cleavage and rapid recombination to reform 1a or decay to the ground state through photophysical processes. The former process is supported by the fact that the rearrangement proceeds to the ortho-substituted aniline in acetonitrile (vide supra) and ultrafast time-resolved spectroscopy (vide infra). We will therefore focus on the photochemistry of 1a in the aqueous environment (1:1 pH 7.2 PBS/acetonitrile) in subsequent sections of this Article. The combined application of ultrafast broadband timeresolved fluorescence (TRF) and transient absorption (TA) spectroscopy techniques has proven to be a powerful tool for investigating and elucidating the photophysics and photochemistry of biological molecules and small organic compounds.89−91 The dynamics of the fluorescent singlet excited states were monitored using TRF spectroscopy using a fluorescence up-conversion technique. The fs-TA spectroscopy was applied to not only identify the singlet excited states, but also to observe triplet states and conversion processes between different electronic states. The TRF spectra of 1a obtained after 267 nm excitation in 1:1 pH 7.2 PBS/acetonitrile (Figure 5) show the fluorescence signal of the transient species as one broad band (λmax ≈ 476 nm) and one long tail extending to ∼600 nm, which can still be observed at 7 ns, indicating a long-lived deactivation process. Spectral changes on going from earlier to later time delays reveal a gradual spectral red shift as the intensity decreases, and comparison of decay dynamics at 439 and 538 nm indicates the

Scheme 7. Proposed Photolysis Reaction Mechanism

1a (Shot) over less than about 100 fs (Figure 6). In the next 30 ps, the newly created hot 1a (Shot) then converts to the vibrationally cooled singlet excited-state species 1a (S1) through vibrational cooling (VC) to the surrounding solvent.92,93 The time constants τ2 and τ3 are thought to indicate the formation and subsequent decay of the singlet intermediate 17 (S1) (Scheme 7), which is formed after the cleavage of the C− N bond. Although this photocleavage can produce cation or radical species (or both) as a result of heterolysis or homolysis, respectively, the generation of a carbocation by a photoheterolysis of the C−N bond likely plays a more important role in the photorelease of the amine.94,95 Therefore, the intermediate observed at later delay times in the TRF spectra might be attributed to the singlet hydroxyquinolinyl carbocation 17 (S1), which is supported by additional evidence from 12596


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to increase at ∼338 nm, and decrease at ∼400 nm simultaneously, which is readily assigned to the internal conversion from 1a (Sn) to 1a (Shot). After 12 ps (Figure 7, upper right), the sharp band at ∼338 nm slightly decays followed by a small redshift of the band at 468−472 nm. This typical spectral change on the picosecond time scale may be attributed to a VC process.96−98 At time delays later than 101 ps (Figure 7, lower left), the sharp absorption band at 338 nm decays noticeably accompanied by a small redshift, and when the broad negative band at 472 nm disappears, two isosbestic points appear at 425 and 550 nm. This suggests a clean conversion between two transient species. Furthermore, the kinetics at 338 nm (Figure 7, lower right) is satisfactorily fitted by a three-exponential function to yield time constants (τ1 = ∼30, τ2 = ∼80, and τ3 = ∼3400 ps) that are similar to those obtained from the fs-TRF spectra. The agreement of the time constants from both the TRF and the TA spectra indicates that both ultrafast spectroscopy methods are probing the same excited-state processes and corresponding transient species.89−91 Taken together, the results from the TA and TRF spectroscopy corroborate the formation of the long-lived (∼3000 ps) fluorescent species 17 (S1) from photoheterolysis of the C−N bond over ∼70 ps. The ns-TA spectra of 1a in 1:1 pH 7.2 PBS/acetonitrile after 266 nm irradiation were measured at 3 μs intervals for 30 μs (Figure 8). They revealed that the sharp band at ∼338 nm

Figure 6. Proposed deactivation and photochemical reaction pathways for excited 1a in aqueous solution. The solid line represents the excitation, the dashed lines represent decay via fluorescence, and the wavy lines indicate nonradiative pathways. Corresponding lifetime constants (τ) are given for each nonradiative step.

the time-resolved spectroscopy experiments described in the next sections. The fs-TA spectra of 1a after 267 nm excitation in 1:1 pH 7.2 PBS/acetonitrile at 1.08−11.8, 11.8−101, and 101−2870 ps delay times were measured (Figure 7). A broad negative band

Figure 8. Left: Temporal evolution of ns-TA spectra 1a in argonpurged 1:1 pH 7.2 PBS/acetonitrile after 266 nm irradiation. Right: Comparison of the kinetics of the characteristic TA band at 521 nm in open air and argon-purged conditions.

continues to decay. The data collection system on the ns-TA instrument enables subtraction of the fluorescence band from the background. This revealed a new band at ∼521 nm not observed in the fs-TA spectra that decreases in step with the decay of the ∼338 nm band. The time dependence of the TA decay dynamics at 521 nm in air was compared to that observed in argon-purged conditions (Figure 8). With the presence of the oxygen, the lifetime for the transient species is 0.3 μs, while it reaches to 4 μs without oxygen. The results indicate that the decay dynamics are sensitive to the concentration of oxygen in the solution and suggest that the transient intermediate giving rise to the peak at 521 nm in the ns-TA spectra has triplet character99 and can be assigned as 17 (T1). It is generated from 17 (S1) through ISC. This assignment is further corroborated by the fact that the calculated UV−vis spectra of 17 (T1) and a hydrogen-bonded complex of 17 (T1) with water match the experimentally determined TA spectra at the shortest delay time (Figure S30). To more accurately confirm the observed triplet carbocation 17 (T1), the ns-TR2 spectrum of 1a in 1:1 pH 7 PBS/ acetonitrile was measured and compared to the calculated

Figure 7. fs-TA spectra of 1a after 267 nm excitation in 1:1 pH 7.2 PBS/acetonitrile from (upper left) 1.08−11.8 ps, (upper right) 11.8− 101 ps, and (lower left) 101−2870 ps time delays and (lower right) kinetics at 338 nm. Red line is a fit of the data to a three-exponential function.

peaking near 468 nm significantly influences the observation of the transient absorption spectral characteristics, because of overlap of a strong stimulated emission band with an absorption band at the nearly same wavelength. Hence, the analysis concentrates mainly on the kinetics of the characteristic TA bands. The initial TA spectra (Figure 7, upper left) appear 12597


Article

Journal of the American Chemical Society normal Raman spectrum of 17 (T1) (Figure 9). Seven major Raman bands at 1576, 1539, 1472, 1407, 1379, 1328, and 1297

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Detailed experimental procedures, including spectroscopic and analytical data, Figures S1−S30, Tables S1− S4, and DFT calculations (PDF)

AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] *[email protected] ORCID

Xin Lan: 0000-0002-6745-2154 David Lee Phillips: 0000-0002-8606-8780 Timothy M. Dore: 0000-0002-3876-5012

Figure 9. Comparison of the ns-TR2 spectrum of 1a in 1:1 pH 7.2 PBS/acetonitrile (black) and the calculated normal Raman spectrum of 17 (T1) (red).

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was sponsored in part by a grant from the National Science Foundation (CHE-1317760) to T.M.D. and New York University Abu Dhabi. Also acknowledged is partial support from the Hong Kong Research Grants Council grants GRF 17301815, AoE/P-03/08, SEG HKU/07, and The University of Hong Kong Development Fund 2013-2014 297 project “New Ultrafast Spectroscopy Experiments for Shared Facilities” to D.L.P. We thank Cyril Herbivo and Adna Muliawan for technical assistance. Part of the work was carried out using Core Technology Platform resources at New York University Abu Dhabi.

cm−1 were observed that are reproduced reasonably well in the calculated Raman spectrum of the π,π* triplet carbocation 17 (T1). The DFT computations indicate that 17 (T1) has a delocalized triplet π,π* diradical configuration.100 This configuration has been observed recently in the 7-(diethylamino)-4-methyl-2H-chromen-2-one-based PPG.101

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CONCLUSION We have developed an efficient method for the extremely rapid release of tertiary amines with light through 1PE or 2PE that is well suited to be employed in studying and probing biological systems. The photoactivatable forms of tamoxifen and 4hydroxytamoxifen, two biologically active tertiary amines, could be used to control gene expression in the Cre-recombinase or CRISPR-Cas9 systems.22,34−39 Amines with sp2 hybridization did not photolyze, despite being good leaving groups, probably because photophysical decay processes out-competed C−N bond cleavage. CyHQ-protected tertiary anilines underwent a photoaza-Claisen rearrangement instead of photolysis to reveal a tertiary amine. This rearrangement is synthetically useful for accessing diaryl methanes with quinolinyl and anilinyl substituents. Further studies to prevent the rearrangement and effect the release of dialkylanilines are in progress. Product studies, Stern−Volmer quenching experiments, and ground-state and time-resolved spectroscopy support a photolysis reaction mechanism that proceeds through the scission of the C−N bond from a singlet state intermediate with an estimated time constant of 70 ps. Solvent likely influences whether the cleavage is homolytic or heterolytic in nature. This is 70 times faster than acetate release from the related BHQprotected acetate, which releases carboxylates from a triplet excited state with a time constant of ∼5 ns.67 The rapid release of the amine is much faster than diffusion in aqueous media, which would enable tightly localized activation of biologically active amines through 2PE, because photolysis would occur only within the excitation volume of the laser beam. CyHQprotected tertiary amines might find applications in polymer and materials science, where micropatterning in three dimensions requires tight localization of the release of a photobase.

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REFERENCES

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