Solid State Separation and Isolation of Tautomers of Fused-Ring

Article pubs.acs.org/joc

Solid State Separation and Isolation of Tautomers of Fused-Ring Triazolotriazoles Roberto Centore,*,† Carla Manfredi,*,† Amedeo Capobianco,*,‡ Sabato Volino,† Maria Vittoria Ferrara,† Antonio Carella,† Sandra Fusco,† and Andrea Peluso‡ †

Department of Chemical Sciences, University of Naples Federico II, Via Cintia, I-80126 Naples, Italy Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II, 132, I-84084 Fisciano, Salerno, Italy

‡

S Supporting Information *

ABSTRACT: Fine control of the tautomeric forms of [1,2,4]triazolo[3,2-c][1,2,4]triazole derivatives in acidic conditions has been achieved by acting on the electronic character of the substituent at position 7 of the heterobicycle and on the counterion. Strong electron releasing or electron withdrawing substituents lead almost exclusively to a single tautomeric form, the 1H-3H or the 2H-3H, respectively. In the case of the phenol substituent, both tautomeric forms are present in comparable amount in solution; the two tautomers can also be selectively precipitated in different crystalline salts using suitable counterions.

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INTRODUCTION N-rich fused-ring aromatics are an interesting class of compounds. Besides their paramount biological importance (e.g., adenine and guanine bases of DNA) they have been investigated in the field of advanced materials as high energy compounds,1 organic semiconductors,2,3 optoelectronic compounds,4,5 and nonfullerene acceptors in organic solar cells.6 The relevance of these compounds in so many fields depends on both molecular and supramolecular features. As concerns single molecule properties, the replacement of C−H groups of acenes with N atoms can significantly affect the electron donor−acceptor character of the compounds and tune their frontier orbital energy levels, making them stable to one electron reduction and then suitable candidates for n-type organic semiconductors.7 On the other hand, the strong inplane H bonding acceptor capability of pyridine-like N atoms or in-plane donor capability of N−H groups can be exploited for the realization of specific supramolecular architectures, such as H bonded chains or ribbons and tight π-stacked structures,8 as compared with the face-to-edge intermolecular architecture typical of all-carbon aromatic hydrocarbons.9 The possible coexistence of acidic N−H groups and basic N ring atoms in N-rich aromatics can induce tautomerism,10 which affects the chemical and biological properties of molecules, as well-known for DNA bases, where noncanonical tautomeric forms are believed to be responsible for base mismatch, mutagenesis, and genetic damage.11,12 Switching among tautomeric forms, induced by chemical or physical factors,13−17 can be exploited, in principle, for the synthesis of multifunctional molecular compounds for bio© 2017 American Chemical Society

logical or material applications, making the search for simple molecules exhibiting two or more low energy tautomeric forms worthy of attention. The N-rich fused-ring triazolo[3,2-c]triazole is a system with a rich tautomeric behavior.18−20 Three low energy tautomeric forms are predicted for the neutral molecule and many others for the singly or double protonated species.20

We have studied several compounds of the series with R and R′ groups differing for their electron donor or acceptor character (compounds TT1-TT4 of the structure block below).19,20 In particular, we proved that the acidity of the N−H proton is considerably high, approaching that of carboxylic acids, and can be modulated within 5−6 units of pKa by acting mainly on the electron donor/acceptor nature of the group at position 7.20 In all the compounds of the series studied so far, one tautomeric form was by far predominant in solution, both for the neutral and for the singly protonated system. In this article we report the synthesis of a new triazolotriazole compound, 4-methyl-7-(4-hydroxyphenyl)-2H-[1,2,4]triazolo[3,2-c][1,2,4]triazole (TT5), which exhibits two singly protonated nearly degenerate tautomeric forms, present in comparable amount in solution. We also record the successful Received: February 17, 2017 Published: April 28, 2017 5155

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The Journal of Organic Chemistry Scheme 1. Two Synthesis Routes to TT5

separation and isolation of the tautomeric forms in the solid state by selective precipitation.

Table 1. Computed Relative Energies (kJ/mol), in Reference to 2H, of Tautomers 3H and 5H of TT2, TT4, and TT5a gas TT2 TT4 TT5

water

3H

5H

3H

5H

28.5 41.0 39.7

72.4 95.4 96.2

8.8 14.6 13.4

45.2 58.6 58.2

a

Data for TT2 are taken from reference 19 and for TT4 from reference 20.

molar ratio between 3H and 2H tautomers in water is 0.45% at 25 °C for TT5. The presence of an electron donor group, as in TT4, further decreases the ratio to 0.27%, while an electron withdrawing group at position 7, as in TT2, stabilizes the 3H tautomer increasing its abundance to 2.9%. The solid state X-ray molecular structure of TT5 is reported in Figure 1, confirming that the 2H tautomer is obtained.

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RESULTS AND DISCUSSION

Synthesis. The synthesis of TT5 was performed according to two different routes, shown in Scheme 1. In the first route, starting from 4-hydroxybenzoic acid, reaction with diaminoguanidine monohydrochloride in polyphosphoric acid (PPA), according to a procedure already described by us,19 affords 5-(4-hydroxyphenyl)-3,4-diamino1,2,4-triazole. Reaction of the diaminotriazole with acetic anhydride at reflux gives the diacetylatedtriazolo-triazole that, after basic hydrolysis and acid recovery, affords TT5. The second route starts from TT4 that is diazotized at low temperature by reaction with sodium nitrite in the presence of concentrated sulfuric acid. Hydrolysis of the diazonium salt affords TT5 as well. Tautomers of Neutral TT5. The relative stability of the three tautomeric forms of neutral TT5 can be inferred from the energy data of Table 1, in which predicted relative energies of the tautomeric forms of TT2 and TT4 are also given, as two representative examples in which a strong electron withdrawing or donor group is attached at position 7 of the heterobicycle. Although the polar medium significantly stabilizes the 3H and 5H tautomers with respect to the gas phase, the energy difference between the most stable 2H tautomer and the 3H is still high enough to assume that for TT5 only the former is actually present. In fact, from the data of Table 1, the calculated

Figure 1. X-ray molecular structure of TT5 at 298 K, showing the two crystallographically independent molecules. Thermal ellipsoids are drawn at 30% probability level. Selected bond lengths (Å): N1−C7 1.315(2), 1.317(2); N2−C8 1.341(3), 1.334(3); N3−C8 1.332(2), 1.329(3); N3−C9 1.379(3), 1.376(3); N4−C9 1.326(3), 1.320(3); N5−C7 1.380(2), 1.373(3); N5−C8 1.338(3), 1.344(2).

It must also be stated that another crystal structure of neutral TT5 has been studied in the present work (acetic acid disolvate) and also in that case the tautomer 2H is present in the crystals (see Supporting Information, henceforth SI). Acid−Base Behavior of TT5 in Solution. The absorption spectra of TT5 at different pH values are shown in Figure 2. The change of λmax with pH is not monotonic; it can be accounted for by the last three equilibria of Scheme 2: neutral TT5 can accept a proton, forming the cationic species H3L+, and can release up to two protons, forming the species HL− and L2−. Starting from low pH, in which H3L+ is the predominant species, a hypsochromic shift is observed in the pH range 0.3− 5156

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triazole derivatives among the most acidic organic compounds in which the acidic proton is delivered by a N−H group. Protonation of triazolo-triazole-fused ring can take place at different nitrogen atoms of the heterobicycle, and different tautomers can be formed.20 The computed energies of the most relevant tautomers of singly protonated TT5 (and also TT2 and TT4 for comparison) are reported in Table 3. Computational results concerning many other tautomers, including also those relative to quinoidal forms, are reported and discussed in the SI. Figure 2. UV−vis absorption spectra of TT5 at constant total concentration, cM = 4.0 × 10−5 M, in NaCl 0.5 M/ethanol 4% (v/v) recorded at 0.3 ≤ pH ≤ 9.7.

Table 3. Computed Relative Energy (kJ/mol) of the Most Relevant Tautomers of Singly Protonated TT2, TT4, and TT5, Referred To the Most Stable Speciesa

Scheme 2. Acid−Base Equilibria in the Triazolo-Triazole System

TT2 1H-2H 1H-3H 1H-5H 2H-3H 2H-5H 3H-5H

2.6 (λmax from 280 to 272 nm), while for pH > 2.6 the λmax shift is bathochromic (from 272 nm up to 296 nm at pH = 9.7). These changes are related to the different distribution of the species with pH and to their different degree of conjugation. The equilibrium constants Ka2−Ka4 of TT5, determined by the analysis of the UV−vis absorbance as a function of the pH (see Experimental Section and SI) and reported in Table 2, are

TT1 TT2 TT3 TT4 TT5

pKa2

pKa3 b

3.43(3)b 1.30(3)b

1.18(5) 0.77(5)b 7.69(1)b 3.10(1)b 2.02(5)

gas

water

gas

water

gas

water

91.2 0.0 50.2 17.2 32.6 118.8

74.5 4.6b 45.6 0.0 30.5 66.9

63.6 0.0 65.7 27.6 56.5 158.2

52.3 0.0 47.7 7.9c 43.5 90.0

71.1 0.0 67.8 22.6 53.6 152.3

57.7 0.0 48.5 3.8d 39.7 84.5

Concerning the acid behavior of neutral TT5, the question arises whether the first proton released is the amino N−H or the phenol O−H. The comparison among the protolytic equilibrium constants reported in Table 2 for TT1-TT4 and the acid constants of phenols reported in literature21 suggests that the N−H proton is more acidic than the O−H proton. This is confirmed by the computed relative energies of the singly deprotonated isomers of TT5, reported in Table 4, which predict that all singly deprotonated species in which the proton is released by the O−H group are at higher energy than those with proton released by the N−H one.

pKa4 b

6.20(3) 5.70(1)b 10.54(5)b 7.10(5)b 6.97(5)

TT5

a Data for TT4 are taken from reference 20. b5.4 kJ/mol including zero-point vibrational energy (ZPVE). c9.2 kJ/mol including ZPVE. d 2.5 kJ/mol including ZPVE; −0.4 kJ/mol including thermal effects (vibrational energy and entropy) at T = 298.15 K.

Table 2. Acid Constants, in the Form of pKa, for Compounds of Scheme 2, with Estimated Standard Deviations in Parenthesesa pKa1

TT4

9.00(5)

The constants are measured at T = 25 °C, in NaCl 0.5 M/ethanol 4% (v/v). bTaken from ref 20. a

Table 4. Computed Relative Energies (kJ/mol) of Singly Deprotonated Isomers of TT5

substantially intermediate between those of TT1/TT2, in which an electron acceptor group is attached at position 7 of the heterobicycle, and of TT3/TT4 in which an electron donor group is present instead. This is expected on the basis of the nature of the 4-hydroxyphenyl substituent of TT5. The distribution diagram of TT5 is reported in Figure 3. We also remark that data of Table 2 allow to classify neutral triazolo-

−

HOLN OLNH(1H) − OLNH(2H) − OLNH(3H) − OLNH(5H) −

gas

water

0 1.3a 5.4b 72.4 96.7

0 19.7 11.7c 31.8 72.0

a

2.9 kJ/mol including zero-point vibrational energy (ZPVE). b4.6 kJ/ mol including ZPVE. c10.9 kJ/mol including ZPVE.

Separation and Isolation of Tautomers of Singly Protonated TT5 in the Solid State. The computed relative energies of Table 3 indicate that for singly protonated TT5 in water the most stable species are the two tautomers 1H-3H and 2H-3H, with the former slightly more stable than the latter (by 2.5−3.8 kJ/mol). As shown in Figure S11 of SI, the bandwidth of the absorption at 280 nm recorded in very acidic ambient (pH = 0.3) is significantly larger than all the other ones recorded at higher pH (see also Figure 2). According to the computed electronic transitions of 1H-3H and 2H-3H, the

Figure 3. Distribution diagram of TT5. 5157

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The Journal of Organic Chemistry observed broad absorption band could be compatible with the coexistence in solution of both species. Furthermore, the 13C NMR spectrum in solution at very low pH (figure S9 of SI) is also compatible with the presence of two species in solution. On the basis of the above considerations, we have successfully accomplished selective precipitation of the two tautomers by using different counterions. Crystallization of TT5 in solution of HCl yields exclusively the 1H-3H tautomer, whereas in solution of H2SO4 only the 2H-3H tautomer is obtained in crystal form. The X-ray molecular structures of the 1H-3H tautomer with chloride counteranion and of the 2H-3H with sulfate anion are shown in Figures 4 and 5 (see SI for a detailed discussion of the X-ray molecular and crystal structures of the two tautomers).

Figure 5. X-ray molecular structure of (TT5)2·(H2SO4)·3H2O at 298 K. Thermal ellipsoids are drawn at 30% probability level. Some hydrogen bonds are shown as dashed lines. Selected bond lengths (Å): N1−C7 1.321(4), 1.318(4); N2−C8 1.313(5), 1.312(5); N3−C8 1.333(5), 1.327(5); N3−C9 1.384(4), 1.373(5); N4−C9 1.309(4), 1.314(4); N5−C7 1.373(4), 1.371(4); N5−C8 1.338(4), 1.330(4). The hanging contacts from the sulfate ion are hydrogen bonds with two other tautomer molecules.

The observation of different tautomers in the solid state is, in general, a rare phenomenon. It has been estimated that only around 0.5% of molecules present in the Cambridge Structural Database (CSD) and able to tautomerize are observed in different tautomeric forms in the solid state.22 This is related with the fact that in many tautomeric systems, one tautomer has energy considerably lower than the others. Even in the case of tautomers close in energy, cocrystallization of two different tautomers in the same lattice or concomitant precipitation of different polymorphs, each one containing a different tautomer, are possible outcomes.22,23 The selective precipitation of tautomers of singly protonated TT5 in different salts is an even more rare example of complete separation of tautomers in the solid state24 and was not achieved for the other triazolotriazole derivatives, in which the computed energy difference between the two singly protonated tautomers is higher (see Table 3): for TT4, only the 1H-3H tautomer was isolated in the solid state,20 while for TT2 only the 2H-3H is obtained, Figure 6. The complex behavior of TT5 upon protonation and single deprotonation is summarized in Scheme 3. A more complete discussion of the resonance forms of singly protonated TT5, in which the X-ray molecular structures are compared with the optimized DFT geometries, is reported in the SI.

Figure 4. X-ray molecular structure of TT5·HCl at 298 K. Thermal ellipsoids are drawn at 30% probability level. Hydrogen bonds are shown as dashed lines. Selected bond lengths (Å): N1−C7 1.330(4); N2−C8 1.304(4); N3−C8 1.341(3); N3−C9 1.370(4); N4−C9 1.308(3); N5−C7 1.346(3); N5−C8 1.359(3). Selected H bonding parameters: N1−H···Cl 0.98(3) Å, 2.10(3) Å, 3.069(2) Å, 168(3)°.

Both crystal structures are driven by the formation of H bonds. In the two tautomers 1H-3H and 2H-3H, the H bonding directionality of the N−H donor groups is different and also the geometric features of the counterions Cl− and SO42− as H bonding acceptors are different. This can explain the selectivity in the crystallization of the two tautomers. In particular, in the crystal structure of the 1H-3H tautomer, each chloride ion accepts H bonding from three different tautomer molecules, while in the crystal structure of the 2H-3H tautomer, each sulfate ion is acceptor from four tautomer molecules (packing diagrams are shown in Figures S17 and S18 of SI, while full geometric parameters of the H bonds are given in Tables S7 and S8 of SI). The selective precipitation of the tautomers has been carefully confirmed also by comparing the experimental X-ray powder diffraction patterns of bulk samples with the powder diffraction patterns calculated from the single crystal X-ray data (see SI). In particular, with hydrochloric acid, the tautomer 1H3H was exclusively obtained, even in the presence of other solvents, such as acetic acid, ethanol, or dimethyl sulfoxide (see SI for the description of the crystal structure of TT5·HCl· DMSO in which the 1H-3H tautomer is present); in a similar way, different crystallization experiments in the presence of sulfuric acid exclusively gave the 2H-3H tautomer.

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CONCLUSIONS The triazolo[3,2-c]triazole-fused ring exhibits interesting acid− base properties, with the involvement of different tautomeric forms. By changing the nature of the substituents on the heterobicycle it is possible to modulate the acid−base equilibrium constants over a very wide range, even approaching the acid strength of carboxylic acids. Separation and isolation of tautomers in the solid state relies on two basic points: tuning the energies of the different tautomers in such a way that they are present in comparable amount in solution and developing strategies for crystallizing separately the tautomers, avoiding cocrystallization in the same lattice or concomitant precip5158

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described can be relevant in the design of functional molecules with spatial anisotropy in proton delivery.

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EXPERIMENTAL SECTION

All reagents were analytical grade and were used without further purification. Melting points were determined by temperature controlled optical microscopy (Zeiss Axioskop polarizing microscope equipped with a Mettler FP90 heating stage). NMR spectra were recorded with Bruker or Varian spectrometers operating at 400 or 500 MHz, in CDCl3 or [D6]DMSO. Synthesis. 5-(4-Hydroxyphenyl)-3,4-diamino-1,2,4-triazole. 4Hydroxybenzoic acid (5.012 g, 3.63 × 10−2 mol) and diaminoguanidinemonohydrochloride (6.101 g, 4.86 × 10−2 mol, 30% excess by mol) were finely ground in a mortar. The mixture was added in portions, under mechanical stirring, to a beaker containing polyphosphoric acid (PPA, 60 g) at 100 °C. After a few minutes, evolution of gaseous HCl was observed from the reaction mixture. The temperature of the pasty reaction mixture was increased to 150 °C and the mixture was allowed to react for 12 h, under stirring. After, the mixture was poured in water (150 mL) and the pH of the resulting solution was increased to 5 by addition of a concentrated solution of NaOH. A pale pink solid was obtained that was filtered, washed with water, and dried in oven at 100 °C. Yield was 4.733 g (68%). mp 269− 272 °C. 1H NMR (400 MHz, D6-DMSO) δ 5.69 (s, 2H), 6.04 (s, 2H), 6.84 (d, J = 8.8 Hz, 2H), 7.77 (d, J= 8.8 Hz, 2H), 9.8 (s broad, 1H). 13 C NMR (100 MHz, D6-DMSO) δ 115.7, 121.0, 129.5, 149.0 (CPh), 154.9, 159.4 (Ctriaz). HRMS (MALDI FT-ICR) m/z: [M+Na]+ Calcd for C8H9N5ONa 214.0704; Found 214.0681. 2-Acetyl-4-methyl-7-(4-acetyloxyphenyl)-[1,2,4]triazolo[3,2-c][1,2,4] Triazole. 5-(4-Hydroxyphenyl)-3,4-diamino-1,2,4-triazole (1.011 g, 5.29 × 10−3 mol) and acetic anhydride (20 mL) were placed in a round bottomed flask equipped with a condenser. The mixture was heated at reflux for 3 h under stirring. After, the brown solution was cooled to room temperature and poured in water (150

Figure 6. X-ray molecular structure of TT2·HCl at 173 K. Thermal ellipsoids are drawn at 30% probability level. Hydrogen bonds are shown as dashed lines. Only one orientation of the disordered pentafluorophenyl group is shown. Selected bond lengths (Å): N1− C7 1.307(3); N2−C8 1.316(4); N3−C8 1.335(4); N3−C9 1.380(4); N4−C9 1.309(3); N5−C7 1.374(4); N5−C8 1.333(3). Selected H bonding parameters: N2−H···Cl 0.96(3) Å, 2.03(3) Å, 2.992(2) Å, 177(3)°.

itation of different crystal forms, each containing a different tautomer. With reference to the class of triazolo[3,2-c]triazoles, we have shown a successful example of application of molecular and crystal strategies, achieving complete separation of singly protonated tautomers of TT5 in the solid state. Moreover, if we consider that different tautomers of singly protonated triazolotriazoles (e.g., 1H-3H and 2H-3H) deliver the acidic proton from different molecular sites, we note that the system here Scheme 3. Dancing of Protons in TT5

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The Journal of Organic Chemistry mL). A white solid formed that was filtered, washed with water, and dried in oven at 100 °C. Recrystallization from DMF/water gave 1.219 g (3.68 × 10−3 mol) of the product. Yield was 70%. mp 220−223 °C. 1 H NMR (500 MHz, CDCl3) δ 2.33 (s, 3H), 2.57 (s, 3H), 2.76 (s, 3H), 7.30 (d, J = 7.0 Hz, 2H), 8.42 (d, J= 7.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 15.4 (Me), 21.1, 21.8 (acetyl Me), 121.2 (CPh), 122.5 (CPh), 128.8 (CPh), 139.3 (C7triaz), 153.5 (C2′triaz), 155.1 (CPh), 165.9 (CO) 168.7 (CO), 170.3 (C4triaz). HRMS (MALDI FT-ICR) m/z: [M +H]+ Calcd for C14H14N5O3 300.1091; Found 300.1089. 4-Methyl-7-(4-hydroxyphenyl)-2H-[1,2,4]triazolo[3,2-c][1,2,4]triazole (TT5). 2-Acetyl-4-methyl-7-(4-acetyloxyphenyl)-[1,2,4]triazolo[3,2-c][1,2,4] triazole (0.610 g, 1.82 × 10−3 mol) was suspended in 40 mL of an aqueous solution of KOH (15% by weight) in a round bottomed flask equipped with a condenser and a magnetic stirrer. The mixture was heated at reflux under stirring and, after few minutes, a colorless solution was obtained. The solution was kept at reflux for 2 h. After, it was cooled to room temperature and poured in water (50 mL). The pH of the resulting solution was adjusted to 5 by addition of drops of 37% HCl, and a white solid formed that was filtered, washed with water, and dried in oven at 100 °C. Yield was 0.380 g (97%). mp 326−330 °C. 1H NMR (500 MHz, D6-DMSO) δ 2.39 (s, 3H), 6.98 (d, J = 8.8 Hz, 2H), 8.08 (d, J= 8.8 Hz, 2H), 10.09 (s, 1H), 13.51 (s broad, 1H). 13C NMR (100 MHz, D6-DMSO) δ 15.5 (Me), 116.4 (CPh), 116.6 (CPh), 127.7 (CPh), 137.9 (C7triaz), 157.7 (C2′triaz), 159.8 (CPh), 168.6 (C4triaz). HRMS (MALDI FT-ICR) m/z: [M+H]+ Calcd for C10H10N5O 216.0880; Found 216.0879. 4-Methyl-7-(4-hydroxyphenyl)-2H-[1,2,4]triazolo[3,2-c][1,2,4]triazole (TT5). 4-Methyl-7-(4-aminophenyl)-2H-[1,2,4]triazolo[3,2-c][1,2,4]triazole (TT4, 0.710 g, 3.32 × 10−3 mol) was suspended in a solution obtained by mixing conc. H2SO4 (0.7 mL) and water (9 mL), and the temperature of the mixture was lowered to 0−4 °C by using a water-ice bath. To the mixture, under stirring, a solution of sodium nitrite was added drop by drop, while keeping the temperature between 0 and 4 °C. The solution had been prepared by solving NaNO2 (0.241 g, 3.49 × 10−3 mol, 5% molar excess) in water (5 mL). After the addition of sodium nitrite was completed, the solution was kept at low temperature under stirring for 20 min. Then, the solution was gradually heated to 80 °C and kept to this temperature for 1 h. After, it was cooled to room temperature and the pH was increased to ca. 5 by addition of a solution of NaOH. A white solid formed that was filtered, washed with water, and dried in oven at 100 °C. Yield was 0.571 g (80%). Thermal and spectroscopic data are coincident with the preceding preparation. Acid−Base Equilibria. The protolytic equilibria of TT5 were studied by UV−vis absorption spectroscopy in 0.5 M NaCl, 4% ethanol (v/v), as the ionic medium, following the same procedure described in ref 21 that is also detailed in SI. The experiments were performed as acid−base titrations at constant total concentration of TT5 without varying the 0.5 M concentration of Cl−. The investigated pH range extends from 0.3 to 12. For each experimental point, the equilibrium free proton concentration was evaluated from the measured electromotive force at the ends of the galvanic cell GE/ TS/RE, where TS indicates the Test solution, GE is the glass electrode, and RE is a reference electrode (0.5 M NaCl|Hg2Cl2| Hg(Pt)) placed outside but electrically connected to TS through a salt bridge. All the experiments were carried out in air in a thermostat, at 25.00 ± 0.03 °C. Potentiometric experimental data were collected by means of an automatic data acquisition system based on HewlettPackard (HP) instrumentation. Coulometric variations of the solution composition were carried out using a Hewlett-Packard “DC Power Supply”. Absorption spectra were recorded with a Varian Cary 50 UV−vis spectrophotometer using 1 cm cell. The primary spectrophotometric data (A, pH, λ) were numerically analyzed by the HYPERQUAD program.25 The protolysis constants were also determined from the analysis of the plots of absorbance versus pH at fixed wavelength (see SI for a more detailed description). X-ray Analysis. All data for crystal structure determinations were measured on a Bruker-NoniusKappaCCD diffractometer equipped with Oxford Cryostream 700 apparatus, using graphite monochro-

mated Mo Kα radiation (λ = 0.71073 Å). Reduction of data and semiempirical absorption correction were done using SADABS program.26 The structures were solved by direct methods (SIR97 program27) and refined by the full-matrix least-squares method on F2 using SHELXL97 program28 with the aid of the program WinGX.29 H atoms bonded to C were generated stereochemically and refined by the riding model. After having placed C-bound H atoms, those bonded to O and N, that are essential in the identification of tautomers, were clearly found in difference Fourier maps as the first maxima and their coordinates were refined without constraints on bond length. For all H atoms Uiso was set at 1.2 times Ueq of the carrier atom (1.5 in the case of methyl group). The analysis of the crystal packing was performed using the program Mercury,30 which was also used for the calculation of the powder diffraction patterns. Crystal and refinement data are summarized in Table S6 of SI. CCDC 1486970-1486975 contain the supplementary crystallographic data fort this article. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Powder X-ray diffraction patterns were recorded with a Philips X′Pert diffractometer using Ni filtered Cu Kα radiation. Computational Details. Quantum chemical computations were carried at the density functional level of theory (DFT) by using the Gaussian 09 package.31 The 6-31+G** basis set was used throughout. The meta BMK functional32 was employed because of its high fraction (42%) of HF exchange which mitigates the self-interaction problem affecting standard hybrid functionals;33 moreover BMK has proven to give excellent performance nearly reproducing experimental electrical and optical properties for donor−acceptor systems,34 matching the quality of high level correlated and ad hoc parametrized methods.35−37 Solvent (water) effects were included by the polarizable continuum model (PCM).38 The nature of located stationary points was verified by computing the eigenvalues of the Hessian matrix; all the minimum energy structures have only positive eigenvalues. Excitation energies and oscillator strengths of the ten lowest excited states of 1H-3H and 2H-3H protonated tautomers of TT5 (see SI) have been calculated by the time dependent DFT approach, using the same functional, solvation method and basis set adopted for ground state calculations.

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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/acs.joc.7b00380. 1 H NMR and 13 C NMR spectra of TT5 and intermediates, NMR spectra of TT5 in very acidic ambient, experimental and calculated UV−vis spectra of TT5 in very acidic ambient, discussion of the X-ray molecular structures and resonance forms of singly protonated TT5, analysis of the crystal packing, details of the experimental apparatus for the study of acid−base equilibria, plot of absorbance versus pH at fixed different wavelengths for TT5, used in the determination of pKa values (PDF) Crystal structure of TT5·DCl as D6-DMSO solvate. (XYZ) Crystal structure of TT5·2CH3COOH (XYZ) X-ray powder diffraction patterns of TT5·HCl and TT5· H2SO4·3H2O (XYZ) X-ray crystallographic data of TT2·HCl, TT5·DCl, TT5, TT5·H2SO4, TT5·HAc, and TT5·HCl (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] *[email protected] 5160

DOI: 10.1021/acs.joc.7b00380 J. Org. Chem. 2017, 82, 5155−5161

Article

The Journal of Organic Chemistry ORCID

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Roberto Centore: 0000-0002-2797-0117 Amedeo Capobianco: 0000-0002-5157-9644 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Thanks are due to University of Naples “Federico II” and University of Salerno for RX, NMR and UV−vis. R. C. thanks the COST Association for support and critical discussions within the COST Action CM-1402-Crystallize. A. C. acknowledges the CINECA award HP10CYW18T under the ISCRA initiative for the availability of high-performance computing resources.

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DOI: 10.1021/acs.joc.7b00380 J. Org. Chem. 2017, 82, 5155−5161