Synthesis of 4,6-dichloro-2-(4-(dodecyloxy) phenyl)pyrimidine (2)

A solution of 1 (0.300 g, 0.72 mmol) in POCl₃ (1 mL, 10.84 mmol) was taken to reflux in an oil bath under inert atmosphere. After 8 h, 3 mL of a water-ice mixture was added, then extracted with Ethyl acetate and finally dried with sodium sulfate. After filtrating, the solvent was evaporated under reduced pressure. The resulting compound was purified using column chromatography with heptane/diethyl ether 20:1, a light yellow liquid was obtained with a 60% yield. ¹H NMR (400 MHz, chloroform-d) δ/ppm: 8.37 (d, J = 8.9 Hz, 2H), 7.17 (s, 1H), 6.96 (d, J = 8.9 Hz, 2H), 4.03 (t, J = 6.6 Hz, 2H), 1.85 - 1.76 (m, 2H), 1.52 - 1.43 (m, 2H), 1.41 - 1.21 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H). NMR ¹³C-{¹H} (101 MHz, chloroform-d) δ 165.75, 162.90, 161.94, 130.91, 127.40, 117.73, 114.70, 68.40, 32.08, 29.82, 29.79, 29.75, 29.72, 29.54, 29.51, 29.33, 26.17, 22.85, 14.27. Elemental analysis C 64.54 (64.52); H 7.39 (7.41); N 6.84 (6.81); O 3.91 (3.94).

Synthesis of 2-(4-(dodecyloxy)phenyl)-4,6-dihydrazinylpyrimidine (3)

Three mL of hydrazine monohydrate were added to 150 mg (0.37 mmol) of 2 under argon atmosphere. The solution was taken to reflux for 3 h, then, the excess of hydrazine monohydrate was removed under reduced pressure and the product was dissolved in chloroform. The resulting solution was treated with K₂CO₃ (2 equivalents) under stirring for 10 min; the liquid phase was extracted with CHCl₃ (3 x 50 mL) and, after drying the different portions, compound 3 was obtained quantitatively as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J = 8.7 Hz, 2H), 7.48 (s, 2H), 6.92 (d, J = 9.1 Hz, 2H), 5.92 (s, 1H), 4.16 (s, 4H), 3.98 (t, J = 6.5 Hz, 2H), 1.70 (p, J = 6.8 Hz, 2H), 1.47 - 1.03 (m, 18H), 0.84 (t, J = 6.6 Hz, 3H). NMR ¹³C-{¹H} (101 MHz, DMSO-d₆) δ 166.45, 161.18, 160.09, 131.06, 129.15, 113.70, 99.63, 77.16, 67.54, 31.37, 29.10, 29.08, 29.07, 28.84, 28.78, 25.59, 22.17, 14.04. Elemental analysis C 65.97 (65.94); H 9.06 (9.01); N 20.98 (20.96); O 3.99 (4.01).

Synthesis of 2-(4-(dodecyloxy)phenyl)-4,6-bis(2-((E)-pyridin-2-ylmethylene) hydrazinyl) pyrimidine (4)

100 mg of 3 were dissolved in ethanol (3 mL) and, under inert atmosphere, an ethanolic solution of 2-pyridinecarboxaldehyde (2 equivalents, 1 mL) was added dropwise. The resulting solution was taken to reflux for 12 h. After cooling, it was recrystallized in cold ethanol. After 12 h crystals were obtained in a 79% yield. ¹H NMR (400 MHz, chloroform-d) δ 9.23 (s, 2H), 8.63 (d, J = 4.8 Hz, 2H), 8.32 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 7.9 Hz, 2H), 8.01 (s, 2H), 7.79 (t, J = 7.6 Hz, 2H), 7.29 (dd, J = 7.5, 5.1 Hz, 2H), 7.07 (s, 1H), 6.97 (d, J = 8.7 Hz, 2H), 4.01 (t, J = 6.6 Hz, 2H), 1.80 (p, J = 6.8 Hz, 2H), 1.50 - 1.43 (m, 2H), 1.35 - 1.27 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H). NMR ¹³C-{¹H} (101 MHz, chloroform-d) δ 162.05, 153.44, 149.69, 143.39, 136.59, 129.90, 123.88, 120.71, 114.59, 100.14, 81.55, 77.37, 68.35, 32.08, 29.82, 29.80, 29.76, 29.74, 29.56, 29.51, 29.37, 26.18, 22.85, 14.27. Elemental analysis C 70.56 (70.55); H 7.31 (7.33); N 19.36 (19.34);O 2.76 (2.79).

General procedure to obtain metallogrids

Hydrazone 4 (10 mg) was dissolved in acetonitrile (2.0 mL) under argon atmosphere. Then, a solution of acetonitrile (3.0 mL) of the respective salt, Fe(BF₄)₂6H₂O or Co(BF₄)₂6H₂O, was added dropwise. In both cases an equivalent of the metallic ion was added with respect to the hydrazone. The resulting solution was stirred for 48 h. then concentrated to half the initial volume and 10 mL of ethyl ether were added; a black precipitate was obtained in both cases. The precipitate was dried under reduce pressure for 12 h, yielding 88% and 90% for Fe(II) and Co(II) complexes, respectively. Once dried, the solids were subject to elemental analysis and NMR. Elemental analysis: [Co₄(1)₄](BF₄)₈ ●6־H₂O C 48.71 (48.65); H 5.41 (5.47); N 13.37 (13.30); O 4.47 (4.80). [Fe₄(1)₄](BF₄)₈ ●6־H₂O C 48.89 (48.83); H 5.43 (5.48); N 13.42 (13.40); O 4.79 (4.82).

Synthesis of bis(hydrazone) 4

This work began with the design of a ditopic organic ligand of easy preparation and with the requirement of high solubility in common organic solvents. For that purpose, a protocol similar to the one found in the literature ¹⁹, which implied four synthetic steps towards compound 1 (See Figure 2) was carried out. This compound exhibited the same ¹H NMR signals as the one reported, therefore, no further characterization was performed ²⁶. Subsequently, 1 was reacted with POCl₃ to obtain 2 in an 86% yield. The chloride compound was subjected to a nucleophilic aromatic substitution reaction, using hydrazine monohydrate as solvent with reflux for 3 h. Excess of hydrazine was removed under reduced pressure and the obtained product was re-dissolved in chloroform. The resulting solution was treated with K₂CO₃ (2 equivalents) under constant stirring for 10 min. The liquid phase was extracted with CHCl₃ (3 x 50 mL) and the extracts were taken to dryness obtaining compound 3 quantitatively as a white solid. This compound proved to be sensitive to air and had to be used as soon as possible in the following reaction because it tended to decompose into a black substance, which was insoluble in common organic solvents.

Once compound 3 was obtained, it was dissolved in ethanol and added dropwise to an ethanolic solution of 2 equivalents of 2-pyridinecarboxaldehyde. The resulting solution was taken to reflux for 12 h. After cooling, compound 4 was recrystallized in cold ethanol (after ~12 h crystallization begins) and compound 4 in a 79% yield as a beige solid soluble in ethanol, methanol (partially), chloroform, DMSO, acetonitrile, dichloromethane, DMF, acetone, nitromethane, THF, and ethyl acetate, was obtained. Figure 3 shows ¹H NMR spectra of compounds 2, 3 and 4 which, to the best of our knowledge, have not been reported in literature. Compound 4 is a new type of organic ligand, which can be seen as two arms system whose frawso/d-conformation is capable of, via two bonds rotation, change to a c«o/d-conformation and coordinate metallic ions through the nitrogen atoms of the pyrimidine, imine and pyridine moieties, acting similar to a terpyridine ligand (Figure 2). Through such coordination molecular metallogrids of high solubility can be obtained, allowing the study of electronic and electrochemical properties as it is reported in the present work.

Figure 3 ¹H NMR (400 MHz) spectra expansion of compounds 2 (in CDCl₃), 3 (in DMSO-d₆) and 4 (in CDCl₃). 

Compounds 2, 3, and 4 showed the right number of characteristic signals of each molecule. At high field, four signals integrate for 23 protons, which correspond to those of the alkyl chain. Besides, around 4.0 ppm a triplet integrating for two protons was observed. This triplet corresponded to the methyl group bonded directly to oxygen. As expected, the signals of the alkyl chain were not affected by the substitution occurring in the pyrimidine ring and, therefore, they were observed at similar chemical shifts in the three compounds. At downfield the protons corresponding to the aromatic rings were seen. For the case of 2, two doublets (8.37 and 6.96 ppm, J = 8.90), which corresponded to the protons of the aromatic ring, are bonded to the pyrimidine center. Furthermore, there was a singlet at 7.17 ppm integrating for one proton corresponding to H-5 in the pyrimidine ring. In the case of 3, additionally to signals observed for 2, there were two new signals at 7.50 and 4.18 ppm integrating for two and four protons corresponding to the two of hydrazine units, respectively.

For the case of bis(hydrazone) 4, five additional signals correspond to the imine group protons and those of the pyridine ring. All the signals integrated correctly. The two N-H protons appeared as a wide band due to the rapid proton exchange in solution.

The ¹³C NMR spectrum showed the 25 expected signals, 14 of which appear at downfield and correspond to aromatic carbons and the alpha carbon to oxygen. At high field (14-32 ppm) there were 11 signals corresponding to the alkyl chain. The HSQC (Figure 4) allows the assignment of the corresponding signals.

Figure 4 HSQC spectrum (400 MHz) of bis(hydrazone) 4 in CDCl₃ 

Formation of metallogrids

Once prepared the bis(hydrazone) 4, the formation of Fe(II) and Co(II) metallogrids was carried out. Such compounds were prepared through a self-assembly process between hydrazone and M²⁺ ions (M = Fe or Co) at room temperature. The elemental analysis for structures [Co₄(4)₄] (BF₄)₈ -6H₂O and [Fe₄(4)₄](BF₄)₈ 6H₂O agreed well with the theoretical values (Table 1). This result is proof of the thermodynamic stability of the metallogrids and how these are the product of the self-assembly of several molecular components by molecular cooperativity ^{21 , 29}.

Figure 5 shows how four molecules of bis(hydrazone) and four metallic centers are organized. The M²⁺ cations coordinate octahedrically to six nitrogen atoms from two perpendicular bis(hydrazones). The four alkyl chains are orientated outside the metallogrid.

Figure 5 A) Computed structure of metallogrids of 1. B) and C) top and side view of the metallogrids; for simplicity, alkyl chains were removed. Carbon atoms are represented in grey, oxygen in red, nitrogen in blue and metallic ions in orange. 

¹ H NMR of metallogrids

The obtained metallogrids were analyzed by 1H NMR in deuterated acetonitrile (Figures 5 and 6). In the case of Co(II) metallogrid, a paramagnetic complex is obtained with signals from -60 to 220 ppm. The large number of signals were interesting because they indicate that not all the metallic centers had the same spin and, thus, the protons of the four bis(hydrazones) were not equivalent. The same phenomena has been observed in other metallogrids and coordination complexes previously published. It has been largely attributed to the influence exerted by the Co(II) ions over the local magnetic field and to the relaxation rate of protons ^{30 - 35}.

Figure 6 ¹H NMR (400 MHz) spectra of Co(II) metallogrid in deuterated acetonitrile. Concentration 50 mM. 

In the case of Fe(II) complex, wide signals were observed. However, these were not localized over a broad range of chemical shift as it was obtained for the Co(II) counterpart. This suggests that the metallogrid is under low/high spin crossover, as it was also observed by Lehn et al.^{34 - 37}. However, although supported by the literature, this assertion will keep being a conjecture until Mössbauer spectroscopy, Light-Induced Excited Spin-State Trapping (LIESST) and thermomagnetic experiments can be carried out. In this regard, paramagnetism in metallogrids can occur for at least four reasons:

1) inter and intramolecular steric effects of the ligands ^{38 - 39}, 2) electronic effects of the ligands and their substituents ^{40 - 42}, 3) protonation state of the ligand ⁴³, and 4) the type of counterion of the grid ^{44 - 45}. All these factors affect in different degrees the magnetic properties of the metallogrids and, thus, its ability to exhibit the spin crossover phenomena ²⁵.

Figure 7 ¹H NMR (400 MHz) spectrum of Fe(II) metallogrid in deuterated acetonitrile. Concentration 50 mM. 

E/Z photoisomerization

To follow the occurrence of isomers in the Z and E configurations, a 100.0 mM solution of 4-E,E in CDCl₃ was prepared and introduced in a quartz NMR tube, which was irradiated with a mercury vapor lamp of 250 W for different times, varying between 0 to 21 min. The photoisomerization was monitored by ¹H NMR spectroscopy to quantify the amounts of the formed isomers. When examining the ¹H NMR spectrum, the singlet at 7.13 ppm, corresponding to the 8-proton on the structure, split as the isomers were formed, indicating the formation of intramolecular hydrogen bonds. Pho-toisomerization was monitored over time and the relative amounts of each isomer were calculated (see Figure 8) and used to determine a first order reaction with a kinetic constant k = 9.5 x 10^-4 s^-1. The percentages of the E,E' and E,Z isomers were 29.6 and 70.4% respectively, after irradiating the sample during 21 min. No Z,Z was observed during this time window.

Figure 8 Photoisomerization of 4. Top: Scheme of photochemically activated isomerization. Bottom: ¹H NMR (400 MHz) spectrum of bis(hydrazone) 4 in CDCl₃ at different irradiation times in a quartz tube. 

Electronic studies (UV-Vis)

Methanol, chloroform, and dichloromethane solutions of the bis(hydrazone) and its metallogrids were analyzed by UV-Vis spectroscopy. Figure 9 shows the spectra in methanol and Table 2 the characteristic absorptions.

Figure 9 UV-Vis spectra of the free ligand 4 and its corresponding Fe(II) and Co(II) complexes in methanol. 

For the bis(hydrazone) 4 a very intense band was observed at 303 nm with a shoulder at 334 nm. This absorption is associated to a π ( π* electronic transition which exhibited a hypochromic shift when reducing the polarity of the solvent. The same transitions were observed for Fe(II) and Co(II) complexes but with lower intensities. Besides, additional absorption bands were detected in the visible region of the spectra, which are attributed to d ( d transitions.

In the case of the Co(II) complex, according to the NMR results, [Co₄(4)₄](BF₄)₈ corresponds to a (d⁷) complex of high spin (low field). Therefore, , and transitions were expected. The last two are of high energy (according to Tanabe-Sugano diagram) and thus they are not observable within the measured window. The d-d transitions exhibit Jahn-Teller distortions in dichloromethane, probably due to the interactions of the solvent with the organic ligands, which are evident because of the hypochromic shift, increasing the solvent polarity (Figure 10). By contrast, the Fe(II) (d ⁶ ) complex exhibited only one allowed transition. However, in methanol an additional electronic transition was observed, which is likely due to formation of a complex (via hydrogen bond) between the solvent and the metallogrid.

Figure 10 UV-Vis spectra of Fe(II) (left) and Co(II) (right) metallogrids in methanol, dichloromethane and chloroform. 

Figure 11 Squared wave voltammetry of the bis(hydrazone) 4 (in black) and Fe²⁺ (in blue) y Co²⁺ (in red) metallogrids. Scan rate 100 mV s^-1. 

Figure 12 Cyclic voltammetry of the bis(hydrazone) 4 (in black) and Fe²⁺ (in blue) y Co²⁺ (in red) metallogrids. Scan rate 100 mV s^-1. 

Electrochemical Studies

Cyclic and squared wave voltammetry studies were carried out for ligand 4 and its corresponding metallogrids, in 0.1 M solutions of NBu₄PF₆ in DMF. A 3 mm glassy carbon electrode was used as working electrode, a silver wire as pseudo-reference electrode, and a wire of platinum as a counter electrode. Ferrocene was added at the end of the experiment and its oxidation potential was taken as internal reference.

Bis(hydrazone) 4 exhibited two irreversible oxidative processes, which shift slightly towards cathodic potentials after coordination with Fe(II) and Co(II). These oxidations are probably located at the -N-H moiety of the hydrazone framework ⁴⁶. The inherent acidity of the N-H protons facilitates the oxidative process. However, the relative oxidation potentials do not seem to be affected by the metal ion present in the complex, suggesting that the central pyrimidine group would play an active role during the oxidation mechanism ^{47 , 48}.

Besides that, compound 4 exhibited five irreversible reduction potentials, going from -1.10 V until -2.54 V. When comparing with other reports, these potentials can be attributed to reduction of the imine groups from the hydrazone framework and the lateral pyridines. Such reduction potentials were also observed for Fe(II) and Co(II) complexes and have been summarized in Table 3. In the case of Co(II) metallogrid, two additional reductions were observed, presumably due to the reduction processes in the metallic centers. Whereas for Fe(II) metallogrid only one additional reduction was observed.

Table 3 Anodic and cathodic potentials of bis(hydrazone) 1 and its complexes. Potentials reported in volts vs ferrocene. 

In general, these compounds exhibit electrochemistry mainly characterized by processes occurring on the hydrazone framework (amine or imine groups). It is interesting that oxidation of Fe(II)/Fe(III) was not observed, probably because of a shielding effect of the hydrazones which anodically shifts such process. Noteworthy, these compounds exhibit multiple reduction states, which can be further studied, along with the above mentioned paramagnetic properties, for the development of multi-responsive devices ⁴⁹.