Exploration of Molecular Shape-Dependent Luminescence Behavior

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Article Cite This: ACS Appl. Bio Mater. 2018, 1, 136−145

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Exploration of Molecular Shape-Dependent Luminescence Behavior: Fluorogenic Organic Nanoparticles Based on Bent Shaped Excited-State Intramolecular Proton-Transfer Dyes Mithun Santra,† Yong Woong Jun,† Ye Jin Reo,† Sourav Sarkar,† Wanuk Choi,‡ Ji Eon Kwon,§ Soo Young Park,*,§ and Kyo Han Ahn*,†

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†

Department of Chemistry and ‡Department of Environmental Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-Gu, Pohang, Gyungbuk 37673, Republic of Korea § Center for Supramolecular Optoelectronic Materials, Research Institute of Advanced Materials (RIAM), Department of Materials Science and Engineering, Seoul National University, 1 Gwanak-Ro, Gwanak-Gu, Seoul 08826, Republic of Korea S Supporting Information *

ABSTRACT: Fluorogenic materials that emit both in solution and in solid states have received special attention for their potential applicability to optoelectronic devices and biochemical sensing systems. To develop such materials, we have explored the molecular shape-dependent luminescence behavior for the bent-shaped molecules. We have synthesized several bentshaped 1-(benzo[d]thiazol-2-yl)-6-substituted-naphthalen-2-ol compounds, which also have an excited-state intramolecular proton-transfer (ESIPT) feature, which is expected to modulate their optical properties. All the compounds and their 2-methoxy derivatives showed luminescence both in solution as well as in solid states, plausibly due to unfavorable orbital interactions between stacked molecules nearby as suggested by single crystal structure packing pattern analysis. The naphthol compounds also showed large Stokes shifts due to the ESIPT feature, along with good optical brightness and tunable emission color by changing the 6-substituent. Fluorescent organic nanoparticles were then prepared from selected compounds, and their size distribution and polydispersity were analyzed by dynamic light scattering and transmission electron microscope. Photophysical properties of the new dyes and their nanoparticles in solution as well as in solid states (in powder and crystalline forms) were characterized by spectral analysis and fluorescence lifetime measurements. The new organic nanoparticles were shown to stain cells by both confocal and two-photon microscopic imaging. The approach of molecular shape control demonstrated here thus opens a door toward solid-state luminescent organic compounds and their nanoparticles. KEYWORDS: molecular shape-dependent luminescence, solid-state luminescence, fluorescent organic nanoparticles, excited-state intramolecular proton-transfer, fluorescence imaging to unfavorable molecular shape.30 A dye molecule with bent shape can have the unfavorable excited state resonance interaction with nearby molecules and thus can emit luminescence in the aggregated states even though it has a parallel stacking pattern (Figure 1a) as in the case of the resonant dimer (H-aggregation). As the origin of luminescence of such a class of dyes is not due to the conformational restriction, they can be emissive not only in solid states, but also in solution, a distinct feature from the AIE dyes (Figure 1b). In this contribution, we have explored the molecular shapedependent luminescence behavior by investigating solid-state luminescence properties of bent-shaped 1-(benzo[d]thiazol-2yl)-6-substituted-naphthalen-2-ol (BTN) compounds and their

1. INTRODUCTION Fluorescent organic nanoparticles (FONPs) have received increasing attention for their potential applications to optoelectronic nanodevices, biochemical sensing and imaging, and drug delivery.1−13 Conversion of organic fluorophores into the corresponding nanoparticles may accompany changes in their optical properties and biocompatibility.14−18 FONPs generated from small fluorescent molecules have gained special interest, as they can be readily synthesized and derivatized and are also more biodegradable.19−24 Such FONPs have potential for the detection and imaging of biological analytes.25−29 Most of the FONPs are based-on aggregation-induced emission (AIE) dyes; hence, they are nonemissive in solution but emissive upon aggregation mainly due to the conformational restriction. Recently, we have disclosed a different mechanism for the enhanced luminescence upon aggregation, that is, “non-resonant” stacking interaction or unfavorable exciton coupling of dyes due © 2018 American Chemical Society

Received: April 25, 2018 Accepted: June 19, 2018 Published: June 19, 2018 136

DOI: 10.1021/acsabm.8b00040 ACS Appl. Bio Mater. 2018, 1, 136−145

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ACS Applied Bio Materials

Figure 1. (a) Exciton energy diagram for the resonant (H-aggregation) and “non-resonant” dimers with parallel transition dipoles (Reproduced from ref 30. Copyright 2014 American Chemical Society). (b) A difference between “fluorescence-on” due to aggregation-induced emission and fluorescence change due to the nonresonant stacking interaction (NRSI) upon aggregation.

development of solid-state luminescent materials. Accordingly, fluorescent nanoparticles were also generated by precipitation of the dyes in aqueous media. A handful number of ESIPTbased FONPs have been developed, but all of them are based on the AIE/AIEE phenomenon.38−42 The AIE/AIEE based dyes or their FONPs are non- or very weakly emissive in solution but become more emissive upon aggregation due to the conformational restriction mechanism mostly. In contrast, the BTN dyes are emissive in solid states as well as in solution. This strategy opens up a new perspective for the design and synthesis of organic dyes that are emissive not only in solution, but also in solid states. Such dyes are readily transformed into the corresponding FONPs. We further show that the BTN dyes and their FONPs are potentially useful for fluorescence imaging of cells under one- as well as two-photon excitation conditions.

2-methoxy derivatives. The naphthol compounds also have an additional structure motif for the excited-state intramolecular proton-transfer (ESIPT) (Figure 2). We expected that the bent

2. RESULTS AND DISCUSSION 2.1. Synthesis and Structural Characterization. The designed compounds were synthesized following the synthetic procedure as shown in Scheme 1. Starting from compound 1, compounds 2 and 3 were synthesized through a substitution reaction with copper cyanide and a copper/L-proline-catalyzed aryl amination reaction, respectively.43,44 Next, condensation reactions of aldehydes 1−3 with 2-aminothiophenol in refluxing acetonitrile in the presence of 5% (v/v) acetic acid for 12−16 h produced the corresponding benzothiazoles in good yields CN-BTN-OMe (87%), Br-BTN-OMe (66%), and Pyr-BTNOMe (65%). Finally, demethylation of these compounds with 1-dodecanethiol and NaOH in N-methyl-2-pyrrolidone (NMP) at 130 °C for 2−3 h afforded the corresponding naphthols in good yields CN-BTN (92%), Br-BTN (88%), and Pyr-BTN (83%). During the isolation stage of the products, we observed that all the compounds showed bright luminescence in the amorphous solid state, as shown by the photos taken under UV irradiation (Figure 2).

Figure 2. Structures of the BTN dyes with different 6-substituents (R) with and their solid-state fluorescence images obtained under excitation at 365 nm.

shape of the molecules would endow them with luminescent behavior both in solution and in solid states, and the ESIPT feature would further modulate their photophysical properties. Fluorescent organic compounds that exhibit ESIPT states have attracted much attention for their potential applications in molecular switches, laser dyes, and UV photostabilizers, molecular probes, and imaging agents.31−37 We have found that the emission wavelengths of the BTN dyes can be also tuned by changing the 6-substituent (Figure 2). To our delight, the ESIPT dyes and their 2-methoxy derivatives showed fluorescence in solid states, highlighting the usefulness of the molecular shape control approach for the 137

DOI: 10.1021/acsabm.8b00040 ACS Appl. Bio Mater. 2018, 1, 136−145

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ACS Applied Bio Materials Scheme 1. Synthesis of Benzthiazolyl-Naphthol Compounds and Their 2-Methoxy Derivativesa

a Reagent and conditions: (a) CuCN, N-methyl-2-pyrrolidone (NMP), 135 °C, 10 h; (b) CuI, K2CO3, L-proline, pyrrolidine, DMSO, 100 °C, 12 h; (c) 2-aminothiophenol, CH3CO2H, CH3CN, reflux, 12−16 h; (d) n-C12H25SH, NaOH, NMP, 130 °C, 2−3 h.

Figure 3. DLS and PDI data for the BTN NPs: (a) CN-BTN, (b) Br-BTN, and (c) Pyr-BTN. (d) TEM image of Br-BTN NPs. (e) Fluorescence images of the nanoparticles of CN-BTN, Pyr-BTN, and Pyr-BTN-OMe in cell culture media DMEM, taken under irradiation at 365 nm using a UV lamp.

additional 5 min, the solution was cooled to and kept at room temperature for 30 min. The solution contained colloidal nanoparticles in uniform dimensions as evidenced by DLS analysis. The FONPs had quite different hydrodynamic diameters and polydispersity index values (HDD, PDI): NPs of CN-BTN (45.4 nm, 0.34), NPs of Br-BTN (22.7 nm, 0.11), and NPs of Pyr-BTN (141.8 nm, 0.059). An analysis by transmission electron microscopy (TEM) for the NPs of Br-BTN showed well-defined and monodispersed nanospheres with an average particle size of 20 nm (Figure 3d). 2.2. Photophysical Properties in Solution. Absorption and emission spectra for all the dyes were recorded in different organic solvents, from nonpolar 1,4-dioxane to polar DMSO and phosphate buffer solution (PBS buffer pH 7.4). Photophysical properties of these dyes revealed that both the absorption

The 6-cyano derivatives, CN-BTN-OMe and CN-BTN, emitted blue and cyan fluorescence, respectively, when irradiated with a UV lamp at 365 nm. The 6′-bromo-substituted dyes, Br-BTNOMe and Br-BTN, emitted blue and green fluorescence, respectively. The pyrrolidine analogues, Pyr-BTN-OMe and Pyr-BTN, emitted green and orange fluorescence, respectively. The emission band of BTNs shifted to the longer wavelength as the better electron-donor was substituted at the 6-position of the naphthalene ring. Given that BTNs emit in the solid state, we prepared the corresponding nanoparticles from three selected compounds (CN-BTN, Br-BTN, and Pyr-BTN) by a precipitation method. In a typical procedure, each dye in DMSO (5 mM, 100 μL) was quickly dropped into deionized water (10 mL) under vigorous sonication at 40 °C. After being sonicated for 138

DOI: 10.1021/acsabm.8b00040 ACS Appl. Bio Mater. 2018, 1, 136−145

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ACS Applied Bio Materials

Figure 4. (a) Absorption spectra, (b) normalized emission spectra of all the BTN dyes; all experiments were performed for 10 μM dye in EtOH (1% DMSO).

Table 1. Photophysical Properties of CN-BTN, Br-BTN, Pyr-BTN, and Pyr-BTN-OMe dyea CN-BTN Br-BTN Pyr-BTN Pyr-BTN-OMe

λ

abs (nm)

εb

373 400 410 405

17000 9700 4800 6000

λ

emc

ΦFd

ΦFe

ΦFf

brightness (ε × ΦF)e

Stokes shifte (nm)

ΦFσ2 (GM)g

460, 484 470, 495 540 532

0.031 0.001 0.015 0.234

0.373 0.084 0.411 0.307

0.076 0.001 0.008 0.033

6400 800 2000 1900

87, 111 70, 95 130 127

n.d.h n.d.h 2.2 2.0

All measurements were conducted at 25 °C with each of the compounds at 10 μM in DMSO. bLM−1 cm−1. cMeasured under excitation at maximum absorption wavelength for each compound in DMSO. dFluorescence quantum yield of dyes in EtOH. eFluorescence quantum yield of dyes in DMSO. fFluorescence quantum yield of nanoparticles in PBS buffer (pH 7.4). Quantum yield was measured considering fluorescein (ΦF = 0.79 in 0.1 M NaOH) as reference dye for Pyr-BTN and 9,10-diphenylanthracene (ΦF = 0.90 in cyclohexane) as reference dye for CN-BTN, Br-BTN and Pyr-BTN-OMe. gTwo-photon action cross section (TPACS) measured for each compound dissolved in DMSO (50 μM) using rhodamine B as a standard. hn.d., not determined. a

increasing the solvent polarity from 410 to 430 nm (Figure S1). In contrast, CN-BTN had a rather broad absorption band in the range of 350−450 nm depending on the solvent. Similar to the case of the methoxy analogue, the emission also showed a red-shift from 410 to 490 nm upon increasing the solvent polarity (Figure S2c). The bromo-substituted compounds also showed similar behavior: Br-BTN-OMe emitted in all the organic solvents as well as in PBS buffer with absorption maxima at 350 nm (Figure S3). In contrast, Br-BTN showed three absorption maxima at 320, 390, and 470 nm (Figure S4). Strong electron-donating pyrrolidine-substituted BTNs showed bathochromic shifts both in the absorption and emission wavelengths from the other fluorophores: Pyr-BTN-OMe showed an absorption maximum at 410 nm and fluoresces in all the organic and PBS buffer solution (Figure S5). The emission was red-shifted with increasing the solvent polarity, except in PBS buffer solution (Figure S5c). Pyr-BTN absorbed in the wavelength range of 400−500 nm and showed strong emission at 540 nm in DMSO that gave a homogeneous solution of the dye (Figure S6). This dye showed a little red-shift in the emission with increasing the solvent polarity, and in PBS buffer, the emission came from the aggregated nanoparticles at 560 nm (Figure S6c). In pure water, Pyr-BTN (10 μM) also existed as nanoparticles due to aggregation. The bathochromic shifts in the emission wavelengths of all the dyes with increasing solvent polarity indicate that they have intramolecular charge-transfer (ICT) excited states in polar media. The fluorescence quantum yields and optical brightness as well as Stokes shifts for selected dyes (CN-BTN, Br-BTN, PyrBTN, and Pyr-BTN-OMe) were determined in EtOH and DMSO, respectively, along with their NPs in PBS buffer (pH 7.4) (Table 1). Interestingly, the BTN series showed significantly higher quantum yields in DMSO but relatively lower quantum yields in EtOH. Their NPs also showed low

and emission properties of them are dependent on the 6-substituent, as noted above. Compared to the cyano-substituted dyes, the amino-substituted ones showed bathochromic shifts both in the absorption and emission bands, in accordance of the color changes observed. Moreover, the 2-methoxy and 2-hydroxy-derivatives had absorption and emission bands in different regions, as the latter compounds can generate ESIPT tautomers (the keto forms) that emit at the longer wavelengths compared to the phenol tautomers (Figure 4). A striking difference in the emission intensity dependent on solvent was observed between the hydroxyl and methoxy derivatives: for example, the BTN-OMe dyes emitted strongly regardless of the media, both organic and aqueous media, but the BTN analogues emitted strongly in DMSO, moderately in EtOH, but poorly in other solvents (dioxane, dichloromethane, acetonitrile, and PBS buffer). This contrasting emission behavior can be explained by the dyes’ ESIPT tendency that is dependent on media. It is known that the ESIPT process in a structurally related hydroxyphenyl−benzothiazole system (HBT) is promoted by the intramolecular hydrogen bonding between the hydroxyl hydrogen and the benzothiazole nitrogen. In a solvent that destabilizes the intramolecular hydrogen bond in the HBT dyes, the ESIPT is suppressed.45−47 The polar aprotic solvent DMSO destabilizes the intramolecular hydrogen bonding in the BTN dyes, which precludes the ESIPT process. In such a case, the dye can emit from the normal localized excited (LE) state. In other words, BTN dyes in DMSO behave as the corresponding BTN-OMe. In ethanol, the ESIPT occurs partially, hence the BTN dyes emit moderately. In the other organic solvents, the ESIPT occurs favorably, and the BTN dyes emit through the keto form with very lower quantum efficiency as usual (Φfl = 0.005 in the case of HBT).48 CN-BTN-OMe emitted in all the organic solvents examined and also in PBS buffer when excited at 340 nm, and its absorption and the emission wavelength maxima showed a bathochromic shift with 139

DOI: 10.1021/acsabm.8b00040 ACS Appl. Bio Mater. 2018, 1, 136−145

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ACS Applied Bio Materials

Figure 5. (a) Solid-state (powder form) normalized fluorescence spectra, and (b) solid-state (powder form) fluorescence lifetime data for CN-BTN, Br-BTN, Pyr-BTN-OMe, and Pyr-BTN; the fluorescence lifetime of Br-BTN was too short to be determined. (c) Solid-state (crystalline form) normalized fluorescence emission spectra of Pyr-BTN-OMe (λex = 410 nm) and Pyr-BTN (λex = 440 nm). (d) Solid-state (crystalline form) fluorescence lifetime data for Pyr-BTN-OMe and Pyr-BTN.

Table 2. Solid (Powder) State Photophysical Properties of CN-BTN, Br-BTN, Pyr-BTN, and Pyr-BTN-OMe lifetime a

dye

CN-BTN Br-BTN Pyr-BTN-OMe Pyr-BTN

λ

ex (nm) 370 390 410 440

λ

PL, max (nm)

ΦFc

τ1 (ns)

τ2 (ns)

498 541 515 585

0.143 Pyr-BTN (6.1%) ≫ Br-BTN (0.1%). The ΦF yields measured in the crystalline state of PyrBTN-OMe (2.2%) is lower than that in the powder state, whereas Pyr-BTN (7.3%) shows similar ΦF yields both in the crystalline and in the powder states (Table S1). The poor quantum efficiency of Br-BTN in the powder state can be explained by a very short fluorescence lifetime ( 2σ(I), 236 parameters, 1 restraint, 1.512 < θ < 28.436°, final R factors R1 = 0.0390 and wR2 = 0.0805, GOF = 1.048. CCDC deposit number: 1814396. 4.3.2. Crystallographic Data for Single Crystal Pyr-BTN. C21H18N2O1S1 Mr = 346.4, crystal dimensions 0.08 × 0.07 × 0.06 mm3, triclinic, space group P-1, a = 12.1809(9), b = 13.3983(9) Å, c = 16.9252(11) Å, α = 72.327(3)° β = 71.229(4)° γ = 73.535(4)°, V = 2438.5(3) Å3, Z = 6, ρcalcd = 1.415 g cm−3, μ = 0.211 mm−1, λ = 0.71073 Å (Mo Kα), T = 100(2) K, 7296 unique reflections out of 10052 with I > 2σ(I), 679 parameters, 0 restraints, 1.307 < θ < 26.472°, final R factors R1 = 0.0521 and wR2 = 0.1176, GOF = 1.045. CCDC deposit number: 1814397. 4.4. Two-Photon Action Cross-Section. TPACS values were measured following known method. Two equations are referred from the references as follows: Φcal η2cal σ2calCcal⟨Pcal(t )⟩2 ncal ⟨F(t )⟩cal = ⟨F(t )⟩new Φnew η2new σ2newCnew⟨Pnew(t )⟩2 nnew

(1)

Eq 1 is the main equation that calculates TPACS using a reference dye, and eq 2 could be extracted from eq 1: σ2new(λ)η2new =

Φcal η2cal σ2cal(λ)Ccal ⟨Pcal(t )⟩2 ⟨F(t )⟩2 new ncal Φnew Cnew ⟨Pnew(t )⟩2 ⟨F(t )⟩cal nnew (2)

Where σ2 = two photon absorption cross-section; η = quantum efficiency; σTPE (two photon action cross-section) = ση; = time averaged fluorescecne emission; C = fluorophore concentration; = time averaged laser power; n = reflective index of sample; Φ = fluorescence collection efficiency. Φcal and Φnew are the identical value in the same experimental setup, and , are also identical when same laser has been applied. TPACS values of samples could be calculated by adding values of known TPACS (Two-Photon Action Cross Section) (ση), concentration (C), detected emission (), and known reflective index (n). Rhodamine B in methanol (100 μM) was used as a reference, and 100 μM Pyr-BTN-OMe and Pyr-BTN in DMSO (dimethyl sulfoxide) were used for the measurement. Each refractive index of a given solvent was applied (assuming that the refractive index of sample is almost same as that of pure solvent). One-hundred microliter samples were loaded in well slides and covered with cover glass. 143

DOI: 10.1021/acsabm.8b00040 ACS Appl. Bio Mater. 2018, 1, 136−145

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ACS Applied Bio Materials Notes

The edge of cover glass was coated with transparent manicure to prevent the evaporation of solvent and then mounted on a vibration isolation table. Two-photon excitation was performed with a Ti-sapphire laser (Chameleon Vision II, Coherent) at 140 fs pulse width and 80 MHz pulse repetition rate. The emission intensity was collected through an HCX APO 10× objective lens (Leica, Germany) of a two-photon microscopy (TCS SP5 II, Leica, Germany) equipped with HyD detector (Leica, Germany), in the range of 400−665 nm. 4.5. Cytotoxicity Study. HeLa cells were thus seeded into 96-well plates at a density of 5000 cells/well and incubated for 24 h at 37 °C in a humidified atmosphere of 5% CO2 in air. The fluorophore solution with various concentrations (5, 10, 50, and 100 μM) was added into the culture media in the plate. The plate was incubated for 4, 8, 12, and 24 h and CCK-8 solution was added to each well of the plate. After the further incubation for 2 h, absorbance at 450 nm was measured using a microplate reader (Multiskan EX, Thermo Eletron). Cell viability was calculated by the ratio of the absorbance of control cells with that of dye-treated cells. 4.6. Cell Culture. HeLa human cervical cancer cells were obtained from Korean Cell Line Bank. HeLa cells were maintained in 10% (v/v) fetal bovine serum (FBS) and 1% (w/v) penicillin-streptomycin (PS) supplemented DMEM at 37 °C in a humidified atmosphere of 5% CO2 in air. Upon reaching approximately 80% confluence, cells were passaged. 4.7. Fluorescence Microscopic Imaging. Cells were seeded onto cell culture dish at a density of 1 × 105 cells. The cultured cells were incubated in DMEM-FBS buffer containing 50 μM of Pyr-BTNOMe and Pyr-BTN NPs for 30 min at 37 °C under 5% CO2. Next, cells were washed with PBS to remove the remaining NPs, and then fixed with 4% formaldehyde solution. The images of the cells were recorded by confocal microscopy. Confocal fluorescence imaging experiments were performed on Leica TCS SP5 II Advanced System. The microscope was equipped with multiple laser lines (405, 458, 476, 488, 496, 514, 561, 594, 633 nm). The 405 nm (for Pyr-BTNOMe NPs) and 450 nm (for Pyr-BTN NPs) lasers were used for the confocal imaging experiments. Fluorescence signals were obtained through Hyd PMT (Hybrid detector Photo Multiplier Tube; Leica) in green channel (420−555 nm) for Pyr-BTN-OMe NPs and in yellow channel (555−620 nm) for Pyr-BTN NPs. Prepared cells were mounted on the tight-fitting holder. The imaging field-of-view (FOV) was 97 × 97 μm2 consisting of 1024 × 1024 pixels. Acquired images were processed by using LAS AF Lite (Leica, Germany).

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was funded by the Global Research Laboratory Program (2014K1A1A2064569) through the National Research Foundation (NRF) funded by Ministry of Science, ICT & Future Planning, Republic of Korea. We thank Dr. Swapan Pramanik for determining the nanoparticles size with DLS.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsabm.8b00040. Methods and experimental details, optical properties of all dyes, HOMO−LUMO energy calculation, crystalline state fluorescence, side view crystal packing, TPACS graph, cytotoxicity value, copies of 1H and 13C NMR (PDF) Crystallographic information file for C22H20N2O1S1 (CIF) Crystallographic information file for C21H18N2O1S1 (CIF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Mithun Santra: 0000-0003-3165-4659 Yong Woong Jun: 0000-0001-9359-1265 Ji Eon Kwon: 0000-0001-5382-3690 Soo Young Park: 0000-0002-2272-8524 Kyo Han Ahn: 0000-0001-7192-7215 144

DOI: 10.1021/acsabm.8b00040 ACS Appl. Bio Mater. 2018, 1, 136−145

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ACS Applied Bio Materials

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DOI: 10.1021/acsabm.8b00040 ACS Appl. Bio Mater. 2018, 1, 136−145