Development of Turn-On Probes for Acids Triggered by Aromaticity

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Development of Turn-On Probes for Acids Triggered by Aromaticity Enhancement Using Tricyclic Amidine Derivatives Shota Matsumoto, Yasufumi Fuchi, Kazuteru Usui, Go Hirai, and Satoru Karasawa J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00023 • Publication Date (Web): 16 May 2019 Downloaded from http://pubs.acs.org on May 20, 2019

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The Journal of Organic Chemistry

Development of Turn-On Probes for Acids Triggered by Aromaticity Enhancement Using Tricyclic Amidine Derivatives Shota Matsumoto,1 Yasufumi Fuchi,1 Kazuteru Usui,2 Go Hirai,2 and Satoru Karasawa1*

1Faculty

of Pharmaceutical Sciences, Showa Pharmaceutical University, 3-3165

Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan

2Graduate

School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi,

Higashi-Ku, Fukuoka 812-8582, Japan

*Corresponding Author: [email protected] (S. K.) Financial Declaration: The authors declare no competing financial interests.

Abstract Two fluorophores consisting of tricyclic amidine derivatives (DHIm and DHPy) were prepared as selective turn-on probes for acid, which were triggered by an aromaticity enhancement. Both amidine derivatives were expanded rings prepared by condensed-

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reactions between the corresponding dibromoalkanes and an aminonaphthylidine analogue. In X-ray analyses, DHIm, in which the dihydroimidazole ring was condensed into aminonaphthyridine, showed a high planarity, compared to DHPy, with condensed dihydropyirimidine. The fluorescence property of DHIm exhibited a higher quantum yield than DHPy due to the difference in planarity. Under acidic conditions such as in the presence of H+ and M(II), protonations and complexations occurred, exhibiting a higher quantum yield than the neutral DHX (X = Im or Py). The nucleus-independent chemical shift (NICS) values from the density functional theory (DFT) calculations suggested that the protonations and complexations caused an enhancement of the aromaticity within the frameworks. These aromaticity changes led to intense fluorescence, and DHX behaved as selective turn-on probe for acids and metal ions. Interestingly, this fluorescence turnon system triggered by the aromaticity-based enhancement is not a typical system such as the photo-induced electron transfer, aggregation-induced enhanced emission, and twisted intramolecular charge transfer systems, but is classified as a novel turn-on system.

1. Introduction Because of their various uses, emissive compounds have been given much attention in both the materials and biological fields. For example, in the former, organic electron 2


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luminescence (OEL)1 and light emitting diodes (LEDs)2 are widely applied as emissive materials. In the latter field, they are used in cell and tissue strainers and are widely applied as biological imaging tools. Moreover, in fundamental research, probes with responsiveness to heat, light, pH, and other factors are widely studied.3–10 In addition, probes emitting near infrared wavelengths, which are capable of passing through biowindows, are greatly desired as promising non-invasive probes.11–13

Scheme 1. Molecular Structures of TFMAQ, 1,8-Nap, DHIm, and DHPy CF3

F3C

N TFMAQ

CF3

CF3

NH2

F3C

N

N

NH2

1,8-Nap

F3C

N

CF3

N

DHIm

N

F3C

N

N

N

DHPy

We have been studying electron properties using push–pull-type fluorophores as the diverse stimuli-responsive emissive materials.14,15 Recently, the aminoquinoline derivatives, TFMAQ,16 and the aminonaphthylidine derivatives, 1,8-Nap,17 which introduce an amino group as a donor and a trifluoromethyl group as an acceptor group into mother frameworks, were prepared, and their fluorescence changes in response to various external stimuli were investigated (Scheme 1). For example, solvatochromic

3



behaviors that depended on the polarity of a solvent were observed using derivatives that introduced the alkyl groups and/or phenyl group into the amino groups in TFMAQ or 1,8-Nap frameworks.16–21 In contrast, when using single-crystals containing those fluorophores, thermal phase transitions and fluorescence changes were observed as single-crystal-to-single-crystal transformations (SC-to-SC). Moreover, diTFMAQ derivatives, where two TFMAQ frameworks are linked at the amino group, showed light responsiveness, which led to a new C-C bond between two quinoline rings at the C8 positions.22 In derivatives that introduced the p-anisole ring instead of the phenyl ring, many crystal polymorphs were present, and mechanical phase transitions within these polymorphs occurred, accompanied by fluorescence changes.23 In relation to pH dependence, the fluorescence based on TFMAQ or 1,8-Nap derivatives was easily quenched by protonations using a relatively strong acid. Accordingly, until now, turn-ontype fluorophores that respond to acidic conditions such as photo-induced electron transfer (PET)24–26 have been missing from our fluorescent analogues. The microenvironments of tumor tissues show pH values of approximately 6.5, whereas normal tissues show pH values of approximately 7.4.27 In cells, lysosome is an acidic organelle.28 Therefore, compounds that respond to weaker acidic conditions are of significance and promising approaches for bio-imaging tools. In this study, two emissive 4


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tricyclic amidine derivatives, DHIm and DHPy, into which the amidine group was introduced as a basic functional group, were prepared as acid responsive probes (Scheme 1). Because of its basic properties, DHX (X = Im or Py) are capable of responding to acidic conditions such as those found in tumor tissues and/or lysosomes. Many fluorophores possess switchable functions such as turn-on and -off functions, which have been used to advantage in well-known systems such as photo-induced electron transfer (PET), aggregation-induced enhance emission (AIEE),29–31 and twisted intramolecular charge transfer (TICT) systems32–34 (Figure 1). However, turn-on and -off systems that take advantage of aromaticity changes have not yet been reported. At this time, we suggest a novel turn-on system using DHX, which takes advantage of aromaticity enhancement (Figure 1). We will herein describe the X-ray structures, electron properties in solutions, results of computational analyses, and acid responsiveness triggered by aromaticity changes for both fluorophores (DHX).

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Figure 1. Various fluorescence “turn-on and -off” systems, including that shown in this work, with well-known mechanisms (PET, AIEE, and TICT).

2. Results and Discussion 2-1. Syntheses and Recrystallizations (Scheme 2) 2,4-bis(trifluoromethyl)-8,9-dihydroimidazo[1,2-a][1,8]naphthyridine (DHIm) and 2,46


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bis(trifluoromethyl)-9,10-dihydro-8H-pyrimido[1,2-a][1,8]naphthyridine (DHPy) were prepared in a one-step synthesis from 1,8-Nap using the corresponding dibromoalkanes in the presence of a reductant NaH in a THF solution. Using 1,2-dibromoethane or 1,3dibromopropane, DHIm or DHPy, which condensed with dihydroimidazole or dihydropyrimidine rings, was produced in a 14% or an 83% yield, respectively. However, when using 1,4-dibromobutane in a manner similar to DHX, a five member-ring of pyrrolidine was formed at the amine position in 1,8-Nap, and was prepared as 1,8-Nappyrro with a 94% yield. Therefore, no tricyclic amidine compound such as DHX was prepared. The synthetic routes of DHX and 1,8-Nap-pyrro are shown in Scheme 2.

Scheme 2. Synthetic routes and recrystallization conditions of DHX and 1,8-Nap-pyrro. Single-crystals

CF3

CF3

d)

a) F3C

N

N

NH2

1,8-Nap

N

N

e)

DHIm DHIm-2

c)

CF3 e)

CF3

CF3

N

N

b)

c)

F3C

DHIm-1 F3C

F3C N

N F3C

N

N

N

N

N

DHPy

DHPy

N

d)

1,8-Nap-pyrro

1,8-Nap-pyrro-blue 1,8-Nap-pyrro-green

a) 1,2-dibromoethane. NaH, THF, reflux. b) 1,3-dibromopropane. NaH, THF, reflux. c) 1,4-dibromobutane, NaH, THF, reflux. d) AcOEt/n-hexane, r.t. e) CH2Cl2/n-hexane, r.t.

7



In recrystallizations, two single-crystal forms of DHIm were obtained with block and needle shapes, together with similar yellowish colors, from different mixtures of AcOEt/n-hexane and CH2Cl2/n-hexane, respectively. The two crystals obtained from the different solvent mixtures were suitable for conducting single-crystal X-ray analyses. In DHPy, only one single-crystal form appeared with a block shape and a yellowish color, and the given crystal was also suitable for X-ray analysis. 1,8-Nap-pyrro gave two single-crystal forms, which could be described as having platelet and prism shapes with a deep yellowish color. The synthetic routes and recrystallization conditions of DHIm, DHPy, and 1,8-Nap-pyrro are shown in Scheme 2.

2-2. X-ray Analyses Single-crystal X-ray analyses of DHX and 1,8-Nap-pyrro were performed at -180 °C using an imaging plate method. ORTEP drawings and crystal packings are shown in Figures 2, 3, and S2, respectively. In the results, a platelet crystal of DHIm had a molecular structure wherein P21/n (no. 14) had a symmetry center, and Z = 4. In contrast, a needle crystal of DHIm gave P21 (no. 4) without a symmetry center, and Z = 2, indicating that the two single-crystals from different mixed-solvents were crystal 8


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polymorphs. We will represent the former and latter as DHIm-1 and DHIm-2, respectively. A single-crystal of DHPy gave P21/c (no. 14) with Z = 4. In the molecular structures of each DHIm-X, the planarity of the rings between the naphthylidine and dihydroimidazole rings was high and showed the co-planarity. Furthermore, because of the five-member-ring to be condensed with a naphthylidine ring, the dihydroimidazole rings in both DHIm-X were distorted by similar angles of 109° and 108° at Cimi-N-C9 (Figure 2). In contrast, the planarity of DHPy was lower than those of the DHIm-Xbased polymorphs because of the distortion of the dihydropyrimidine ring, which consisted of three sp3 C atoms. The bond distances of two pyridines in the naphthylidine ring were evaluated (Figure S3-1). In DHIm-1, the ring 1 carrying CF3 groups showed that the average bond distance was approximately 1.38 Å. Similar difference of bond distances was found in DHIm-2 and DHPy. In contrast, the corresponding distances in ring 2 was 1.41 Å, giving rise to the difference approximately 0.03 Å between rings 1 and 2.

Table 1. Crystallographic and Refinement Parameters of Single-Crystal Analyses of DHIm-X and DHPy. DHIm-1

DHIm-2 9


DHPy


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Class

Monoclinic

Monoclinic

Monoclinic

Space Group (no.)

P21/n (14)

P21 (4)

P21/c (14)

a/Å

4.7639(3)

4.5879(3)

11.7160(4)

b/Å

10.5335(6)

10.6241(5)

5.0426(2)

c/Å

23.717(2)

11.9829(6)

21.6594(7)

β / deg

94.668(7)

92.543(7)

103.028(8)

V / Å3

1186.1(1)

583.49 (5)

1246.69 (8)

Z

4

2

4

R1 (%)

5.97

4.41

3.99

wR2 (%)

12.86

10.66

12.48

GOF

0.916

1.013

0.896

Figure 2. ORTEP drawings with 50% provability of (a) DHIm-1, (b) DHIm-2, and (c) DHPy. The top and bottom figures are the top and side views of the corresponding molecules, respectively. The gray, blue, green, and white colors indicate C, N, F, and H 10


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atoms, respectively. The broken quarter circles indicate the bond angles of Cimi-N-C9 in the dihydroimidazole or dihydropyrimidine rings, with angles of 109°, 108°, and 118° shown in (a), (b), and (c), respectively.

In the crystal packings, all of the crystals possessed hydrogen bonds between the N atoms in the imine group and H atoms at the C6 positions. The bond lengths corresponding to the weak hydrogen bonds were 2.44, 2.54, and 2.42 Å for DHIm-1, DHIm-2, and DHPy, respectively, forming a dimer and polymer for DHIm-1 and DHPy, and for DHIm-2, respectively, within the same planes (Figure 3). Those intermolecular weak hydrogen bonds arose as a result of the strong basic property of the N atoms in the imine groups. Furthermore, - stacking between the resulting planes was observed. In the dimer-type of DHIm-1 and DHPy, the distances within the resulting planes were 3.36 and 3.48 Å, respectively. The corresponding distance in the polymer-type of DHIm-2 was 3.49 Å. In addition, distinguishable overlaps between the  orbitals in the rings were observed, with larger and smaller overlaps in the polymer- and dimer-based structures, respectively. Comparing the bond distances of two pyridines in the naphthylidine ring of 1,8-Nappyrro (Figure S4-2), the average bond distance was approximately 1.38 and 1.39 Å in the rings 1 and 2. The difference bond distances were approximately 0.01 Å, which were 11



considerable smaller compared to those of DHX (vide supra). ORTEP drawings with top and side views are shown in Figure 1. In addition, the crystal packings of the given dimerand polymer-based structures, and the - stackings, are shown in Figures 3 and S3-2, respectively. The main crystallographic and refinements parameters are summarized in Table 1. The corresponding polymorphous crystals and the given structural data of 1,8Nap-pyrro are shown in Figure S4 and summarized in Table S1.

12


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Figure 3. Ball-and-stick models of crystal packings of (a) DHIm-1, (b) DHIm-2, and (c) DHPy. Graphics of (a) and (c), and (b), represent dimer and polymer forms based on the hydrogen bonds, respectively. The red dotted lines in (a)–(c) indicate the hydrogen bonds between the N atoms in the imine groups and H atoms in C6, with values of 2.44, 2.54, and 2.42 Å for DHIm-1, DHIm-2, and DHPy, respectively. The gray, blue, green, and white colors indicate the C, N, F, and H atoms, respectively.

2-3. Absorption and Emission Spectra The absorption spectra in the solid and solution states of DHIm-1, DHIm-2, and DHPy, together with 1,8-Nap-pyrro, were obtained in the range of 200–700 nm, and these spectra are presented in Figures 3 and S5. In the solid samples prepared by dilutions using KBr, the diffuse reflection spectra were obtained, and the resulting spectra were converted using the KM function (Figure 3a). Amorphous sample of DHIm showed that maxAb was 13



423 nm, accompanied by the vibration structures. In contrast, DHPy showed a spectrum with a shape similar to that of DHIm with a distinguishable maxAb value at 387 nm. A vibration structure was also seen. It was confirmed that the solvatochromic behavior was similar to those of the TFMAQ and 1,8-Nap derivatives previously reported,16,17 with the absorption and fluorescence spectra obtained in 100 M solutions using various solvents, including n-hexane, CHCl3, AcOEt, and MeOH. However, the typical solvatochromism, which strongly depended on the polarity of the solvent, was missing for both DHX. In the case of DHIm, all of the solvent conditions gave maxAb values of approximately 410 nm, which were similar to those for one of the solid samples (Figure 3b). In contrast, DHPy exhibited solvent dependences but polarity independence, together with broadening maxima for maxAb (Figure 3c). Under the conditions of n-hexane and AcOEt, maxAb values of approximately 390 nm were observed. Under the conditions of CHCl3 and MeOH, however, the maxAb values shifted to a lower wavelength of approximately 360 nm. To reveal the solvent dependence, spectra with a concentration dependence at 10–100 M were found for the previously mentioned whole solvents. In the AcOEt, spectral changes with isosbestic points at 314 and 382 nm were clearly observed (Figure 3d). Upon increasing the concentration, the maxAb values shifted to a lower wavelength, which was similar to those for CHCl3 and MeOH. Except for AcOEt, no concentration 14


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dependences of the spectra changes were observed. The different behaviors with the concentration dependence might have resulted from the presence of the N atom in the imine group, which has a basic property. In the case of n-hexane, the spectra with a longer wavelength (maxAb = 412 nm) and no spectral change in the concentration dependence suggested that the monomer-form was maintained in the solution. In contrast, in the cases of MeOH and CHCl3, which possessed H atoms capable of dissociating from C atoms, spectra with a lower wavelength (maxAb = 404–408 nm) and no spectral change in the concentration dependence were found, suggesting the formation of complexes with the corresponding solvent molecules. In the AcOEt, spectral changes with a concentration dependence appeared, suggesting the formation of the dimmer or polymer, like the results from the X-ray analyses (vide supra). These spectral differences will be discussed in detail in the next section based on DFT calculations.

15



Figure 4. (a) Diffuse reflection spectra of DHIm and DHPy. (b) and (c) Absorption (dotted lines on left axis) and fluorescence (solid lines on right axis) spectra in various solvents (100 M). The purple, sky-blue, light green, and red lines indicate conditions using n-hexane, CHCl3, AcOEt, and MeOH, respectively. (d) Absorption spectral change of DHPy in AcOET solutions after changing concentration in range of 10–100 M. The corresponding concentration is given in the figure. Thick gray arrows indicate an increase or a decrease in the absorption when the concentration is increased from 10 to 100 M.

The fluorescence spectra for DHIm and DHPy in various solvents were performed at 23 °C (Figures 3(b) and (c)). Because of the lower emission intensities of both DHXs, a 100 16


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M solution was prepared and used for the spectra examinations. In DHIm, fluorescence spectra with maxFl = 513–534 nm were observed, indicating a small solvatochromic behavior similar to that of the given absorption spectra. The fluorescence intensities of the solvents were estimated by the absolute quantum yields (Fl) using a calibrated integrating sphere system, exhibiting weak fluorescence intensities with Fl values of 1.4–2.3%. In DHPy, similar weak solvent dependences were observed at maxFl = 380– 440 nm. Furthermore, the fluorescence intensities were low and Fl = 0.14–0.74%, which was one tenth of the value for DHIm. In n-hexane excited at 412 nm, which was the maxAb value, the fluorescence was quenched. However, when it was excited at 365 nm, which was similar to the maxAb absorption using CHCl3 and MeOH, a weak fluorescence was observed, with maxFl and Fl values of 402 nm and 0.14%, respectively. These different behaviors might cause the different circumstances for the N atoms in the imine groups such as the monomer in n-hexane, dimer or polymer in AcOEt, and complexes between the DHPy and solvent molecules in CHCl3 and MeOH. On the other hand, 1,8-Nap-pyrro showed a strong solvatochromic behavior related to the absorption and fluorescence spectra, giving rise to shifts to longer wavelengths, along with the higher polarity in solvents (Figure S5). Furthermore, the Fl values were larger than those of DHX, with values of 34, 41, 15, and 1.6% for the n-hexane, CHCl3, AcOEt, 17



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and MeOH, respectively. This strong solvatochromic behavior was the same as that of the 1,8-Nap analogs reported previously.17,18 The absorption and fluorescence spectra of DHIm, DHPy, and 1,8-Nap-pyrro are shown in Figures 3(b), 3(c), and S5, respectively. Furthermore, the values obtained from the absorption and fluorescence spectra, together with the Fl values of their compounds, are summarized in Table 2.

Table 2. Values of maxAb, maxFl, and  Fl for DHX (X = Im or Py) and Their Protonated Analogues [DHX-H]+ in Various Solvents. solvents

n-hexane

CHCl3

AcOEt

MeOH

DHPy maxAb/nm maxFl /nm (Fl %)*

402

354

382

368

380 (0.14)

440 (0.34)

443 (0.24)

435 (0.74)

[DHPy-H]+ maxAb/nm maxFl/nm (Fl %)*

―

―

―

351

―

―

―

402 (1.7)

DHIm maxAb/nm

412

408

416

404

maxFl/nm (Fl %)*

513 (1.8)

518 (1.8)

534 (1.4)

513 (2.3)

[DHIm-H]+

18


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maxAb/nm

―

―

―

372


―

―

―

442 (7.8)

1,8-Nap-pyrro maxAb/nm

388

396

396

396


425 (34)

450 (41)

470 (15)

479 (1.6)

[1,8-Nap-pyrro-H]+ maxAb/nm

―

―

―

362


―

―

―

n.d. (n.d.)

*excitation

at maximum of the corresponding excited spectra under individual conditions. n.d.: not determined

2-4. Computational Analyses by DFT To precisely investigate the electron states obtained from the absorption spectra for DHX, a DFT calculation was performed at the B3LYP/6-311+G**(SMD: MeOH)//B3LYP/6311+G**(SMD: MeOH) level, and the highest occupied molecular orbital (HOMO) and lowest occupied molecular orbital (LUMO) were estimated (Figure 4). Furthermore, using TD-DFT at the same level, the expected absorption spectra in various solvents were estimated and are shown in Figures S6–S8. In addition, to evaluate the aromaticities of both DHXs, the NICS and HOMA values were estimated and are shown in Tables 3 and S3, respectively. 19



Figure 5. Molecular structures of (a) DHIm and DHPy, and (b) their protonated [DHImH]+ and [DHPy-H]+ with HOMO and LUMO calculated by DFT (B3LYP/6311+G**(SMD: MeOH) //B3LYP/6-311+G**(SMD: MeOH) level). Different color in individual orbitals indicate different sign. Red arrows indicate the tertiary N atoms.

The molecular structures with the HOMO and LUMO values for DHX are depicted in Figure 5(a). In the LUMOs, the orbital coefficients of the tertiary N atoms for both compounds were smaller than those of the other atoms in the naphthylidine ring, suggesting a smaller aromaticity for the pyridine rings next to the dihydroimidazole and dihydropyrimidine rings. Based on the TD-DFT results, the expected absorptions in 20


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various solvents are shown in Figure S6. For DHIm, spectra for the whole solvents similar to the experimental results with calc.-expe. = 10–25 nm (calc.-expe: the different maxab values between the calculations and the experiments) were obtained, suggesting that the given spectra in the experiments could be assigned as the monomer-induced spectra (Figure S6). Furthermore, the longest absorptions at approximately 410 nm were attributed to the HOMO–LUMO transitions. For DHPy, however, the calculated spectra were only comparable to the spectrum from n-hexane. The spectra obtained from other solvents were shifted to lower wavelengths compared to that of the calculated spectra (calc.-expe. = 20–50 nm). Therefore, to consider the presence of complexes between DHPy and the solvent molecules, DFT calculations were again performed using the models of the complexes, namely [DHX-solvent]. The given calculated spectra in CHCl3 and MeOH were shifted to a lower wavelength of approximately 10 nm compared to those of the monomer models (Figure S7-1). In addition, the dimer model (DHX)2 was used to show that the spectrum was also shifted to a lower wavelength than the monomer models (Figures S7-2, -3, and -4). However, the complexation energy of (DHX)2 in MeOH was much higher compared to those in AcOEt and MeOH, suggesting no formation of the dimer, but the formation of [DHX-MeOH] was preferred. Expectedly, the given experimental spectra for the DHPy in n-hexane, AcOEt, CHCl3, and MeOH could be 21



assigned as the spectra based on the monomer, dimer (DHPy)2, polymer (DHPy)n, and complexes of [DHPy-CHCl3] or [DHPy-MeOH], respectively. Both DHXs have three N atoms that are capable of the protonation. The individual stabilities of the protonated isomers were estimated by a DFT calculation (B3LYP/6-311+G**) and showed the extremely large difference among three isomers (Figure S9 and Table S2). The isomers protonated at N atom in the imine group showed the smallest values of relative energies (ΔE), relative enthalpies (ΔΔH), and relative free energies (ΔΔG). Interestingly, the models protonated at N atoms belonging to the imine group, namely, [DHIm-H]+ and [DHPy-H]+, showed exclusive spectral changes with a drastically lower shift than the spectra in both neutral compounds (DHX), and the given maxAb values were 358 and 337 nm, which were 72 and 63 nm lower than those of DHX, respectively (Figure S10). In the LUMOs of both protonated compounds [DHX-H]+, the orbital coefficient values increased, suggesting that an aromaticity enhancement occurred among the rings (Figure 5(b)). The calculated spectra for the individual models of the complexes, dimers, and protonated monomers are shown in Figures S7 and S8.

Table 3. NICS Values of DHIm and DHPy, and Their Complexes under Various Conditions. 22


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NICS(1)up

NICS(1) ring 1

1

1

2

1Å

CF3 F 3C

2

1

N

N

NICS(0)

Solvents or ring* complexes

1

F 3C

ring 2

ring 1

ring 2

CF3

1Å

N

2

N

2

N

N

H 2C

C H2

CH2

NICS(1)down

Location of dummy atom

NICS values (ppm) DHIm

DHPy (up or down)**

1 MeOH 1 2 2 Complexes; 1 [DHIm1 MeOH] or 2 [DHPy2 MeOH] 1 CHCl3 1 2 2

NICS(0) NICS(1) NICS(0) NICS(1) NICS(0) NICS(1) NICS(0) NICS(1)

-5.8194 -7.8205 1.8713 -1.2369 -6.4222 -8.3687 0.9448 -1.9901

-6.5065 -8.3687 (up), -8.3732 (down) 1.8717 -1.4418(up), -1.2081(down) -7.0378 -8.8634(up), -8.9077(down) 1.0295 -2.0912(up), -1.8983(down)

NICS(0) NICS(1) NICS(0) NICS(1)

-5.8484 -7.8377 1.8351 -1.2544

-6.5069 -8.3593(up), -8.3593(down) 1.6610 -1.4775(up), -1.1685(down)

Complexes; 1 [DHIm1 CHCl3] or 2 [DHPy2 CHCl3]

NICS(0) NICS(1) NICS(0) NICS(1)

-6.3365 -8.2506 1.2020 -1.6819

-6.8853 -8.741(up), -8.7515(down) 1.3490 -1.7988(up), -1.5771(down)

*Results

for rings 1 and 2 are shown using black and deep blue letters, respectively. terms “up” and “down” indicate that the dummy atom is 1 Å up or down from the plane consisting of individual ring 1 or 2, which is the individual center of the rings. **The

To evaluate the aromaticity of each ring, the NICS and HOMA values were calculated by 23



DFT, and are shown in Tables 3, 4, and S3. Significantly different values within the two rings, rings 1 and 2, in the naphthyridine framework were revealed (Table 3). NICS (0) and (1) are estimated values as follows: one dummy atom was placed on the plane for NICS (0) or at a location far from the plane and up or down 1 Å for NICS (1). Under MeOH, in ring 1, which is the pyridine ring carrying trifluoromethy groups, NICS (0) and NICS (1) for DHIm and DHPy showed negative values that ranged from -8.4 to -5.8 ppm, suggesting that ring 1 had sufficient aromaticity. In contrast, for ring 2, which fused the dihydroimidazole or dihydropyrimidine rings, the NICS (0) and NICS (1) values showed near values close to zero in the range of -1.2 to 1.9 ppm, suggesting that the aromaticity was insufficient compared to ring 1. Similar NICS values under CHCl3 were observed. Interestingly, the complexes connected with MeOH or CHCl3, [DHX-CHCl3] or [DHX-MeOH], showed much larger negative values, especially in ring 2, compared to those of DHX, suggesting that the complexations gave rise to the aromaticity enhancement. Furthermore, [DHX-H]+, which were protonated compounds at the N atoms in the imine groups, showed the exclusive enhancement of the aromaticity in the entire naphthylidine framework (Table 4). Those results based on the DFT were supported from the X-ray results of the different bond distances in the naphthylidine rings between DHX and 1,8-Nap-pyrro (vide supra). The HOMA values also indicated that 24


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an aromaticity enhancement occurred, triggered by the protonations (Table S2).

Table 4. NICS Values of [DHIm-H]+ and [DHPy-H]+ in MeOH and CHCl3. NICS(1)up

NICS(1) ring 1

1

2

1

1Å

CF3 F 3C

1

N

NICS(0)

Solvents complexes

2

N

N

CF3

1Å H

1

F 3C

ring 2

ring 2

2

ring 1

2

N

N

1

2

N

MeOH

CHCl3

C H2

CH2

NICS values (ppm) [DHIm-H]+

NICS(0) NICS(1) NICS(0) NICS(1) NICS(0) NICS(1) NICS(0) NICS(1)

H 2C

NICS(1)down

or ring Location of dummy atom 1 1 2 2 1 1 2 2

H

-8.785 -10.6463 -4.2945 -6.035 -8.7864 -10.6427 -4.3362 -6.0656

[DHPy-H]+ (up or down)* -9.0087 -10.7541 (up), -10.7947 (down) -3.7793 -5.8304(up), -5.521(down) -9.0137 -10.7285(up), -10.8239(down) -3.809 -5.8561(up), -5.5392(down)

*Results

for rings 1 and 2 are shown by black and deep blue letters, respectively. **The terms “up” and “down” indicate that the dummy atom was 1 Å up or down from the plane consisting of ring 1 or 2, which was the individual center of the rings.

2-5. Protonations and Complexations Inspired by the DFT results, in which protonation caused an aromaticity enhancement, the absorption and fluorescence spectral changes by protonation and complexation for metal ions were determined, with the expectation of a fluorescence enhancement. In the 25



absorption spectra of DHIm and DHPy, upon adding HCl solutions in MeOH, the original absorption with maximum (maxAb) values at 404 and 368 nm disappeared, and a new absorption appeared at 372 and 351 nm, together with isosbestic points (Table 2 and Figures 6(a-1) and (a-2)). Compared to the spectra of neutral analogues (DHX), the ab (maxAbDHX - maxAbDHX-H+) values were 32 and 17 nm. These spectral changes shifted to lower wavelengths, suggesting the formations of [DHX-H]+, which had values similar to those found in the DFT calculations. The inflection points for the protonation were estimated to be approximately 0.5 M (insets of Figures 6(a-1) and (a-2)). In the fluorescence spectra, the fluorescence maxima (maxFl) also shifted to lower wavelengths, maxFl = 442 and 404 nm, and Fl (maxFlDHX - maxFlDHX-H+) were 72 and 33 nm for DHIm and DHPy (Table 2 and Figures 6(b), (c) and (d)), respectively. Moreover, the fluorescence quantum yields (Fl) increased and became 7.8 and 1.7% for [DHIm-H]+ and [DHPy-H]+, respectively. These values were approximately five and two times larger than those for the DHX. In the spectrum of 1,8-Nap-pyrro, however, a fluorescence quench occurred, and no spectrum was depicted because of the formation of [1,8-Nappyrro-H]+ after adding H+, which was a behavior similar to that of the 1,8-Nap analogues reported previously.17,18 The absorption and fluorescence spectra in the presence or absence of H+ are shown in Figure S10, and the given maxAb values of [1,8-Nap-pyrro26


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H]+ are summarized in Table 2.

Figure 6. Absorption (a) and fluorescence (b) spectral changes upon adding HCl 27



solutions in range of 0–27 M into 100 M MeOH solutions for DHIm (a-1 and b-1) and DHPy (a-2 and b-2). The black and red lines, together with the gradual color changes, depict the values before and after adding H+. The insets of (a-1) and (a-2) represent the titration results of the protonations using the normalized absorptions at 371 nm for (a-1) and 351 nm for (a-2) as a function of the concentration of H+, accompanied by the fitting curves according to a sigmoidal function as a visual guide. In (b-1) and (b-2), the excitation wavelength were 404 and 351 nm for DHIm (b-1) and DHPy (b-2). In (c), the absorption (dotted lines) and fluorescence (solid lines) spectral changes are shown before and after additions of 27 M HCl solutions for DHIm (c-1) and DHPy (c-2). [H+] was defined from the dropped volume of HCl solution.

Using five transition metal ions, Mn(II), Fe(II), Co(II), Ni(II), and Zn(II), which are Lewis acids, the absorption and fluorescence changes were monitored. The job’s plots35 were created using the absorption spectral changes of 100 M ([DHX] + [MII]) MeOH solutions (Figure S11). The molar ratio in the complexations between DHX and metal ions were estimated to be 1:1 to form the complexes consisted of DHX, M(II) ions and MeOH molecules. However, the structures of the complexes (octahedral, tetrahedral, and square) have not yet been determined. To investigate the complexation effect using the 28


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absorption and fluorescence spectral changes, the following examinations were performed using solutions upon additions in a molar ratio of DHX:M(II) = 1:10. The absorption and fluorescence spectral changes by the additions of H+ are shown in Figure S12, and the resulting Fl values are summarized in Table S4. In DHIm, the solutions containing individual metal ions shifted to lower wavelengths in both the absorption and fluorescence spectra, accompanied by a reduction of absorption at approximately 240 nm, suggesting the formation of metal complexes [DHIm-M]2+. In particular, the absorptions of the solutions containing Fe(II) and Zn(II) ions, and the fluorescence spectra of the solution containing Fe(II), Co(II), Ni(II), and Zn(II) ions, produced extensively shifted spectra. Individual Fl values of 3.2–7.3% were obtained, which were two–four times larger than one without the metal ions (Table S4). In the DHPy solutions, similar absorption spectral changes were observed. In particular, the solutions containing Fe(II), Zn(II), and Ni(II) exhibited large shifts to lower wavelengths. In the fluorescence spectra, the maxFl values were slightly shifted to lower or higher wavelengths. Surprisingly, all of the Fl values were extensively enhanced by the addition of individual metal ions (Table S4). In the case of Fe(II), especially, the Fl values became greater than 12% and approximately twenty times larger than one without Fe(II). The solutions containing Zn(II) exhibited larger Fl values than the solutions containing other metal ions (except 29



for [DHPy-Fe]2+). This strong emission could be attributed to the exclusion of the fluorescence quench based on an unpaired electron.36 The unexpected enhancement of the Fl values obtained from [DHPy-Fe]2+ is currently being studied. The absorption and fluorescence spectral changes before and after the additions of various metal ions are shown in Figure S12, and the given Fl values are summarized in Table S4

2-6. NMR Spectral Changes Before and After Additions of H+ To precisely investigate the protonation behavior such as the location where the protonation occurs in the framework, the 1H NMR spectral changes were monitored in the presence or absence of CF3COOH as a proton source. The 1H NMR spectral changes in the presence or absence of H+ are shown in Figure S13, and plausible chemical reactions in the presence of H+ are shown in Scheme 3. Upon the addition of H+, all of the peaks belonging to the aromatic and alkyl regions shifted to lower fields for both DHXs. The DHI chemical shifts for DHIm in the presence and absence of H+ were 0.5– 0.7 and 0.2–0.6 ppm in the aromatic and alkyl regions, respectively (Figure S13-1). For DHPy, similar DHP chemical shifts with and without H+ were observed, with values of 0.5–1.0 and 0.2–0.5 ppm in the aromatic and alkyl regions, respectively (Figure S13-2). On the other hand, for 1,8-Nap-pyrro, smaller 1,8-Nap-pyrro chemical shifts in the presence 30


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and absence of H+ were observed compared to those of DHX. In particular, the 1,8-Nappyrro values

in the alkyl region had subtle values. The 1,8-Nap-pyrro values were 0.3–0.4 and

0.1–0.2 ppm in the aromatic and alkyl regions, respectively (Figure S13-3). Those results suggested that the aromaticity enhancement took place by protonations in DHX, Furthermore, the protonation occurred at the N atoms in the imine groups for DHX. In contrast, smaller deshielding shifts in the alkyl region were observed in 1,8-Nap-pyrro, suggesting that the protonation of 1,8-Nap-pyrro took place at the N atom at position 8 in the naphthylidine ring, not a N atom in the amino group (Scheme 3). The 1H NMR spectral changes in the presence or absence of H+ are shown in Figure S13.

Scheme 3. Protonated structures of DHX and 1,8-Nap-pyrro. CF3

CF3 H+

F3C

N

N

N

F3C

N

N

N

n

H

Turn-ON Fluorescence

n

n = 1: DHIm n = 2: DHPy CF3

CF3 Turn-OFF

H+ F3C

N

N

N

F3C

1,8-Nap-pyrro

N

N H

N

Fluorescence

3. Conclusion We successfully prepared two novel turn-on type fluorophores, DHIm and DHPy, which were capable of responding to acids such as H+ and metal ions, using tricyclic amidine 31



derivatives. In X-ray analyses of both DHXs, the dimer or polymer structures produced by intermolecular weak hydrogen bonds between the N atoms in the imine and H atoms at C6 atoms were observed, suggesting that the corresponding N atoms have a relatively strong basic property. When examining the fluorescence properties of DHX, weak emissions with small solvatochromic behaviors were obtained, whereas 1,8-Nap-pyrro showed a strong fluorescence compared to those of DHX, accompanied by the solvatochromic behavior. Upon additions of H+, the Fl values increased by approximately five and two times for DHIm and DHPy compared to those before the H+ additions as a result of the formation of [DHX-H]+. Furthermore, upon the addition of M(II) ions, which are Lewis acids, fluorescence increases were also obviously observed, and the Fl values that were approximately 2–20 times larger were observed, due to the formation of [DHX-M]2+. On the other hand, 1,8-Nap-pyrro quenched the fluorescence by the H+. In DFT calculations, the aromaticity values of the corresponding rings were estimated using the NICS and HOMA values. Before the H+ additions, the rings next to the dihydroimidazole or dihydropyrimidine rings showed a lower aromaticity, to afford non-aromaticity, whereas after the H+ additions, aromaticity enhancements were clearly observed. These results indicated that the aromaticity enhancement caused enhancements of the Fl values. This turn-on fluorescence system derived from the aromaticity enhancement is not classified among the well-known systems of PET, AIEE, and TICT. In addition, the system does not belong to one, in which after protonation, it successively gives rise to chemical reactions.37,38 Accordingly, to the best of our knowledge, no turnon system like ours, which takes advantage of an aromaticity change, has yet been reported. To increase the Fl values for practical applications, modifications of the molecular design of DHX are currently underway. 32


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4. Experimental Section 4-1. General Information Infrared spectra were recorded using a JASCO 420 FT-IR spectrometer. UV-vis spectra were recorded using JASCO V570 and V760 spectrometers. The fluorescence spectra and quantum yields were recorded on a JASCO FP8500 spectrofluorimeter equipped with a calibrated integrating sphere system. The 1H and 13C NMR spectra were measured by a Bruker Biospin AVANCE III 300 spectrometer using CD3OD as the solvent and tetramethylsilane as the reference. High-resolution electrospray ionization mass spectra were recorded using a JEOLJMS-T 100LP spectrometer. The melting points were found using a Yanako MP-J3. 4-2. Single Crystal X-ray Diffraction (SXRD) The crystallographic data are summarized in Tables 1 and S1. Suitable single crystals were glued onto a glass fiber using epoxy resin. All of the X-ray data were collected on a Rigaku R-AXIS rapid diffractometer with graphite monochromated CuK radiation ( = 1.54187 Å). Reflections were collected at 93 ± 1 K. The molecular structures were solved using direct methods (SIR 92 or SHELXL 97).39,40 The refinements were performed using the full-matrix least squares method from the Crystal Structure software package41 to give

33



P21/n (no. 14), P21 (no. 4), P21/c (no. 14), Pbca (no. 61), and P21/n (no. 14) for DHIm-1, DHIm-2, DHPy, 1,8-Nap-blue, and 1,8-Nap-green, respectively. All of the nonhydrogen atoms were refined anisotropically, and the hydrogen atoms were refined isotropically. The crystallographic data for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Center as supplementary publications no. CCDC 1884054, 1884055, 1884056, 1884058, and 1884057 for DHIm1, DHIm-2, DHPy, 1,8-Nap-blue, and 1,8-Nap-green, respectively.

4-3. DFT calculation Geometries of the studied molecules were optimized at the B3LYP/6-311+G** level of theory using the 16A. 03 revision of the Gaussian 16 program package. The all optimized geometries were further confirmed as minima by carrying out frequency calculations. No imaginary frequencies were found. TD-DFT calculations of the studied molecules for UV spectra were performed at the same level of theory. Various solvation effects on the ground and excited states were included using the solvation model of density (SMD). The interaction energies for the complexes between DHX and the solvent molecules [DHXsolvent] and the dimer model (DHX)2 computed at the same level of theory and basis set superposition error correction (BSSE) corrected. The aromaticities of both DHXs were 34


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calculated by nucleus-independent chemical shifts (NICS)42 and harmonic oscillator model of aromaticity (HOMA)43 index. The NICS were calculated through the gaugeincluding atomic orbital (GIAO) method. The HOMA index was applied as a geometrybased indicator of local aromaticity. The optimized structures were employed for the HOMA index calculations.44

4-4. Titrations of Absorption Spectra Using HCl Solutions A 10% HCl solution was added to 100 M MeOH solutions containing DHX (X = Im or Py), and 2.7 × 10-2, 2.7 × 10-3, 8.1 × 10-4, 5.4 × 10-4, 2.7 × 10-4, 2.7 × 10-5, 2.7 × 10-6, and 2.7 × 10-7 mM HCl solutions were prepared. Using 2 mL of each of the corresponding solutions, the absorption spectra were found in the range of 200–700 nm.

4-5. Absorption and Fluorescence Spectral Change Using Solutions Containing Proton and Transition Metal Ions A 10% HCl solution was added to 100 M MeOH solutions containing DHX (X = Im or Py), and a 2.7 × 10-2 mM HCl solution was prepared. Using 2 mL of this solution, the absorption in the range of 200–700 nm and the fluorescence spectra excited at the maxima in the excited spectra were found. A 20 L quantity of a 100 mM solution containing 35



MnCl2, FeCl2, CoCl2, NiCl2, or ZnCl2 was added to 100 M MeOH solutions containing DHX (X = Im or Py), and DHX and MCl2 mixture solutions were prepared. Using 2 mL of each of the corresponding solutions, the absorption in the range of 200–700 nm, and the fluorescence spectra excited at the maxima in the excited spectra were found. 4-7. Job’s plot. A 100 mM solution containing MnCl2, NiCl2, or ZnCl2 was added to MeOH solutions containing DHX (X = Im or Py), and then by changing the molar ratio, the total concentration of individual solutions was set to 100 M ([DHX] + [M2+]). Using 2 mL of each of the corresponding solutions, the absorption spectra were performed and the resulting absorption was plotted as a function of the molar ratio. 4-7. Materials Unless otherwise stated, all of the reagents and solvents were used as received without further purification. 5,7-bis(trifluoromethyl)-1,8-naphthyridin-2-amine (1,8-Nap) was prepared according to the procedure previously reported.15,16 Thin layer chromatography (TLC) was performed on silica gel plates, using a 60 F254 (Merck). Synthesis

of

2,4-bis(trifluoromethyl)-8,9-dihydroimidazo[1,2-a][1,8]naphthyridine,

DHIm: To a THF solution (20 mL) containing 1,8-Nap (1 g, 3.56 mmol) and NaH (0.41 g, 17.8 mmol), 1,2-diboromoethane (3.54 g, 17.8 mmol) was added dropwise and heated 36


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at 80 °C in a sealed tube for 3 h. The reaction mixture was quenched by a 10% HCl solution in an ice bath and extracted with CHCl3 three times. The combined organic layers were dried over MgSO4, and the organic solution was evaporated. The crude residue was purified by silica gel column chromatography using n-hexane/AcOEt (30:1) as the eluent, to afford a yellowish solid in a 14% yield (161 mg, 0.52 mmol, 14% yield). The resulting solid was recrystallized using mixtures of AcOEt/n-hexane or CH2Cl2/n-hexane, to afford single crystals labeled as DHIm-1, which had the appearance of a yellowish block, and -2, which had the appearance of a yellowish needle; 1H NMR (CD3OD, 300 MHz) δ 7.88 (d, J = 10.0 Hz, 1H), 7.70 (s, 1H), 7.04 (d, J = 10.0 Hz, 1H), 4.41 (t, J = 9.97 Hz, 2H), 4.13 (t, J = 9.97 Hz, 2H); 13C{1H}NMR (CD3OD, 75 MHz) δ 157.4, 152.2, 148.7 (q, JCF

= 35.9 Hz), 136.5 (q, JC-F = 33.0 Hz), 131.6, 123.8 (q, JC-F = 274.6 Hz), 123.6, 122.2 (q,

JC-F = 273.62 Hz), 117.0, 109.7, 53.9, 46.9; HRMS (ESI) m/z [M+H]+ calcd for C12H8F6N3 308.0622, found: 308.0623. Single crystal of DHIm-1: (KBr) 3020, 1650, 1577, 1486, 1285, 1211, 1128, 1072, 994, 872, 741, 645, 476 cm-1. M.p.111−113 °C. Single crystal of DHIm-2: IR (KBr) 2876, 1644, 1578, 1483, 1283, 1211, 1140, 1071, 988, 877, 741, 644, 476 cm-1. M.p.102 −106 °C.

37



Synthesis

of

2,4-bis(trifluoromethyl)-9,10-dihydro-8H-pyrimido[1,2-

a][1,8]naphthyridine, DHPy: DHPy was prepared in a manner similar to the procedure for DHIm using 1,8-Nap (1 g, 3.56 mmol) and 1,3-dibromopropane instead of 1,2dibromoethnane. The reaction yield was 83% (1 g, 3.56 mmol), and the resulting solid was recrystallized using CH2Cl2/n-hexane, to afford single crystals with a yellowish block appearance; 1H NMR (CD3OD, 300 MHz) δ 7.77 (s, 1H), 7.53 (dd, J = 10.1, 1.82 Hz, 1H), 6.74 (d, J = 10.1 Hz, 1H), 4.26 (t, J = 6.02 Hz, 2H), 3.55 (t, J = 5.60 Hz, 2H), 2.03 (quin, J = 5.87 Hz, 2H); 13C{1H} NMR (CD3OD, 75 MHz) δ152.9, 151.1, 147.4 (q, JC-F = 35.9 Hz), 136.5 (q, JC-F = 33.0 Hz), 131.1, 127.2, 123.2 (q, JC-F = 274.6 Hz), 123.0 (q, JC-F = 274.6 Hz), 117.5, 110.9, 44.8, 43.4; HRMS (ESI) m/z [M+H]+ calcd for C13H10F6N3 322.0779, found: 322.0781; IR (KBr) 2975, 1645, 1612, 1430, 1280, 1213, 1135, 1037, 919, 874, 840, 737, 658 cm-1. M.p. 120−124 °C.

Synthesis of 2,4-bis(trifluoromethyl)-8,9-dihydroimidazo[1,2-a][1,8]naphthyridine, 1,8Nap-pyrro: 1,8-Nap-pyrro was prepared in a manner similar to the procedure for DHIm using 1,8-Nap (1 g, 3.56 mmol) and 1,4-dibromobutane instead of 1,2-dibromoethnane. The reaction yield was 94% (1 g, 3.56 mmol), and the resulting solid was recrystallized using CH2Cl2/n-hexane, to afford different crystal forms that looked like a pale yellowish 38


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platelet (1,8-Nap-pyrro-blue) and needle (1,8-Nap-pyrro-green); 1H-NMR (CD3OD, 300 MHz) δ 8.16 (ddd, J = 1.8, 1.9, 9.5 Hz, 1H), 7.66 (s, J = 1H), 7.00 (d, J = 9.5 Hz, 1H), 3.90 (s, 2H), 3.58 (s, 2H), 2.10 (d, J = 12.1 Hz, 4H);

13C{1H}

NMR (CD3OD) δ

159.3, 158.4, 150.5 (q, JC-F = 35.4 Hz), 138.1 (q, JC-F = 32.3 Hz), 133.8, 124.3 (q, JC-F = 272.3 Hz), 122.4 (q, JC-F = 272.8 Hz), 117.5, 115.1, 110.1, 26.7, 25.9; HRMS (ESI) m/z [M+H]+ calcd for C14H12F6N3 336.0935, found: 336.0918. Single crystal of 1,8-Nap-pyrro-blue: IR (KBr) 2965, 2869, 1633, 1561, 1427, 1385, 1280, 1140, 884, 801, 662, 445 cm-1. M.p.121−124 °C. Single crystal of 1,8-Nap-pyrro-green: IR (KBr) 2971, 2877, 1626, 1588, 1430, 1279, 1146, 868, 800, 662, 445 cm-1. M.p.122−126 °C.

ASSOCIATED CONTENT Supporting Information Supporting information is available free of charge on the ACS Publications website at DOI: 10.1021/ The following files are available free of charge: Copies of the 1H,

13C

NMR, and IR

spectra for DHX and 1,8-Nap-pyrro; the X-ray structures, and the absorption and 39



fluorescence spectra of 1,8-Nap-pyrro; the TD-DFT calculation results for DHX; and the absorption, fluorescence, and 1H NMR spectral changes in the presence of protons or metal ions in MeOH for DHX and 1,8-Nap-pyrro; cartesian coordinates obtained from DFT calculation; Job’s plots of metal complexes consisted of DHX and various metal ions. Thermal ellipsoid plots of single crystals for DHX. ORCID Satoru Karasawa: 0000-0002-3107-442X Kazuteru Usui: 0000-0002-2175-5221 Go Hirai: 0000-0003-3420-555X ACKNOWLEDGMENT This work was partially supported by the PRESTO Program on Molecular Technology from the Japan Science Technology Agency (JST). The authors thank Dr. Kenji Higashiguchi of Kyoto University for the useful discussion. REFERENCES 1.

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Development of Turn-On Probes for Acids Triggered by Aromaticity

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