Organic & Biomolecular Chemistry Tetrathiafulvalene Mono-and Bis-1,2,3-triazole Precursors by Click Chemistry: Structural Diversity and Reactivity †

PAPER Thomas Biet and Narcis Avarvari Tetrathiafulvalene mono-and bis-1,2,3-triazole precursors by click chemistry: structural diversity and reactivity The donor ortho-dimethyl-TTF-(N-n-Bu-1,2,3-triazole) 1,5-isomer has been synthesized by click chemistry following a ruthenium-catalyzed azide–alkyne cycloaddition procedure. The single crystal X-ray analysis showed a planar conformation between the TTF and triazole units and a set of intermolecular interactions at the supramolecular level in the solid state. The same procedure allowed the preparation of the corresponding ortho-dimethyl-TTF-bis(triazole) which was also structurally characterized. Because of the steric hindrance, the triazole units are no longer planar with the TTF backbone. The reactivity of the triazole ring has been investigated in protonation and alkylation reactions, monitored by UV-visible spec-troscopy, which clearly showed the red shift of the intramolecular charge transfer band. A TTF-methyl-triazolium salt has been isolated and analyzed by single crystal X-ray analysis. All of the TTF-triazoles and triazolium salts are valuable precursors for radical cation salts due to their oxidation potentials and variety of possible intermolecular interactions.


Introduction
Synthetic methods based on click chemistry strategies have developed increasingly over the last decade, 1 with one of the most useful reactions being the copper-catalyzed azide-alkyne cycloaddition (CuAAC) that allows the straightforward preparation of 1,2,3-triazoles (1,4-isomers). 2 These heterocycles have proved to be useful units in chemical sensing 3 and peptidomimetic research, 4 and are also interesting ligands towards transition metals. 5 Alternatively, the 1,5-isomers of 1,2,3-triazoles have been efficiently prepared by the azide-alkyne cycloaddition mediated by a ruthenium(II)-based catalyst. 6 We have recently employed both strategies for the synthesis of the new electroactive ligands TTF-1,2,3-triazoles as 1,4-and 1,5-isomers (Scheme 1), 7 respectively, where the electroactive part is represented by the TTF (tetrathiafulvalene) unit, and in which TTF and triazoles are directly connected. A large difference in their electrochemical behavior was observed, e.g. much easier oxidation for the 1,4-isomers than for the 1,5-isomers, and, accordingly, in their relative kinetic stability. Moreover, coordination of the more stable 1,5-isomers to Cu(hfac) 2 (hfac = hexa-fluoroacetylacetonate) fragments induced an unusual cathodic shift of the oxidation potentials of TTF.
In the other few published examples of TTF-triazole systems, with linkers of various lengths between TTF and triazole, 8 the latter serves mainly to connect other electroactive moieties to TTF, such as perylene diimide 9 or ferrocene. 10 From a general point of view, the association of TTF with coordinating groups within electroactive ligands 11 represents a powerful strategy to access either multifunctional molecular materials, in which a combination of different physical properties can be achieved, 12 or electroactive catalysts. 13 In this respect, nitrogen-containing five-membered rings, such as oxazolines, 14 pyrazoles 15 or imidazoles 16 have been attached to TTF, while the synthesis and coordination chemistry of TTFtriazole ligands has been reported much more recently. 7 Beside their use as ligands, the basicity and nucleophilicity of the triazole ring should in principle allow for the modulation of the intramolecular charge transfer and the electrodonating Scheme 1 TTF-1,2,3-triazoles. † Electronic supplementary information (ESI) available. CCDC 982420-982423.
For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob00148f character of TTF upon protonation or reaction with electrophiles. 16b Moreover, the versatility of the two "click" strategies, i.e. Cu versus Ru catalysis, guarantees the preparation of a whole library of TTF-triazoles by the appropriate choice of the acetylene and azide units. The substitution pattern, type of isomers, i.e. 1,4-versus 1,5-, and number of triazole units should have an important influence not only on the electrochemical properties and coordination ability, but also on the supramolecular architectures in crystals, which ultimately determines the solid state properties of the derived materials. We report herein the synthesis, reactivity and solid state structures of TTF-mono and -bis(1,2,3-triazoles), together with those of a TTF-triazolium salt.

Results and discussion
The TTF-triazole 1 (Schemes 1 and 2), with Me groups on TTF and a benzyl (Bn) substituent on the nitrogen atom N1, was synthesized as previously described by a Ru-catalyzed azidealkyne cycloaddition (RuAAC) reaction between the dimethyl-TTF-acetylene and benzyl azide. 7 In order to evaluate the influence of different substituents on the triazole ring, the ligand TTF-triazole 2 with an n-butyl (n-Bu) group instead of Bn was prepared following the same procedure by using n-butyl azide (Scheme 2).
The donor ortho-dimethyl-TTF 3 is well suited for a selective bis-functionalization, allowing us to attempt the preparation of TTF-bis(triazoles) through both strategies. Accordingly, the diiodo derivative 4 has been prepared upon the double lithiation of 3 followed by treatment with perfluorohexyl iodide. Then, a double Sonogashira coupling under classical conditions with trimethylsilyl acetylene afforded the bis(acetyl-enic) compound 5 which was further deprotected in the presence of (n-Bu) 4 NF. The resulting TTF-bis(acetylene) 6 was then rapidly engaged in a double cycloaddition reaction with benzyl azide following either the copper or the rutheniumbased catalysis (Scheme 3).
While in the case of the Ru-catalyzed reaction the TTF-bis-(triazole) 8 was obtained in low yield (15%) as the bis(1,5isomer), the Cu-based catalysis afforded only the TTF-triazoleacetylene 7 as the 1,4-isomer in even lower yield (10%) with no trace of the bis(triazole). The low yields are very likely attributed to the sensitivity of the TTF-diacetylene 6 which partially degrades under the reaction conditions. Moreover, as previously mentioned, the 1,4-isomers are less stable than the 1,5isomers, 7 therefore compound 7, which is an intermediate towards the desired bis(triazole), degrades before the second acetylene unit reacts in the cycloaddition reaction. Nevertheless, a small amount of 7 could be purified by column chromatography and characterized by 1 H NMR and mass spectrometry, yet the compound has a limited stability in air even in the solid state.
Cyclic voltammetry measurements (see ESI †) show that the oxidation potentials for the donor 2, of 0.45 and 0.85 V versus SCE for E 1 1/2 and E 2 1/2 respectively, are identical to those for the benzyl derivative 1. In the case of the bis(triazole) 8, anodic shifts of 0.13 and 0.11 V for the first and second oxidation processes are observed when compared to the mono(triazole) 1 (e.g. E 1 1/2 = 0.44 V (1) and 0.57 V (8), E 2 1/2 = 0.85 V (1) and 0.96 V (8)), thus evidencing the withdrawing effect of the triazole ring when connected to TTF as the 1,5-isomer.
The solid state structures of the mono(triazole) 2, bis(triazole) 8, as well as the intermediate 5 (see ESI †), have been determined by single crystal X-ray diffraction analysis.
The crystal structure of 1-butyl-5-(ortho-dimethyl-TTF)-1,2,3-triazole (2) The solid state structure of the benzyl derivative 1, previously described, 7 shows quasi-planarity between the TTF and triazole units, with a dihedral angle of 6.0°and the s-trans conformation, and the existence of short intermolecular S⋯S contacts. In the case of 2, suitable crystals, as orange needles, for X-ray analysis were obtained by the slow evaporation of the solvent from a 1 : 1 MeOH-CH 2 Cl 2 solution. The compound crystallizes in the monoclinic system, space group P2 1 /c, with one independent molecule in the unit cell. The conformation between the TTF and triazole is s-trans when considering the double bonds C5vC6 and C7vC8, with a very small value of 7.4°for the TTF⋯triazole dihedral angle (Fig. 1). The central C3vC4 bond measures 1.260(4) Å, in agreement with the neutral state of the donor.
At the supramolecular level the formation of columns is observed, in which the donors are shifted with respect to each other along the longitudinal axis in such a way that a triazole ring stacks with the TTF unit below, with N⋯S and S⋯S contacts of 3.55 and 3.72 Å, respectively (Fig. 2).
This arrangement is different to that encountered in the structure of 1, where the formation of head-to-tail dimers was observed. The columns of 2 further interact laterally along the c axis through short N⋯S contacts and N⋯H vinyl hydrogen bonds of 2.87 and 2.83 Å, respectively (Fig. 3). Thus, the overall supramolecular architecture results from the interplay of S⋯S, N⋯S and N⋯H intermolecular interactions. As a general feature of the TTF-mono(triazole) donors, when comparing the structures of 1 7 and 2, one can disclose the planarity of the system, suggesting conjugation between the two units.
The crystal structure of ortho-dimethyl-TTF-bis(1-benzyl-1,2,3-triazol-5-yl) (8) Single crystals of 8 as orange plates were obtained by vapour diffusion of pentane into a solution of the compound in methylene chloride. The donor crystallizes in the orthorhombic system, with the non-centrosymmetric space group P2 1 2 1 2 1 , with one independent molecule in the asymmetric unit. The most striking peculiarity in the structure is the non-planarity of the two triazole rings with respect to the TTF backbone, with dihedral angles of 87.9°and 37.0°f or TTF⋯triazole N1N2N3 and TTF⋯triazole N4N5N6 , respectively ( Fig. 4). This feature is very likely due to the steric hindrance caused by the vicinity of the two heterocycles, which is comparable to the situation observed in the solid state structures of TTF-mono(oxazolines) 14a and TTF-bis(oxazolines). 17 Moreover, the intramolecular π-stacking interaction established between the triazole N4N5N6 and the Ph ring of the other triazole unit, which are parallel at a distance of 3.4 Å, probably also contributes to the stabilization of this conformation. Bond lengths, such as the central C3vC4 bond and the internal C-S bonds, have typical values for a neutral donor (see ESI †).     At the supramolecular level there is no short S⋯S intermolecular contact, very likely because of the presence of the bulky benzyl groups on TTF. However, a network of intermolecular N⋯H interactions develops, particularly involving the benzylic protons (see ESI †).
For the use of precursors such as the TTF-bis(triazole) 8 in electrocrystallization experiments for the preparation of radical cation salts, the replacement of the benzyl groups by less bulky substituents, e.g. n-Bu as in 2, can be envisaged in order to allow the occurrence of TTF⋯TTF intermolecular interactions which are crucial for the establishment of conductivity paths. It is clear that, when analysing the structures of 1, 7 2 and 8, and also the other TTF-triazole derivatives, 7 the presence of the triazole ring on TTF provides additional possibilities for intermolecular interactions such as hydrogen bonding, π-π stacking and donor-acceptor, and thus results in the emergence of original architectures. Moreover, the unsubstituted nitrogen atoms can in principle be protonated or alkylated, which should allow for the modulation of the electron donor character of TTF, the intra-and intermolecular charge transfer, and the geometry of the compound.
Protonation and alkylation studies with 1 and 8 The protonation of the mono(triazole) 1 and bis(triazole) 8, both possessing benzyl substituents, has been monitored by UV-vis spectroscopy. As previously described, in the UV-vis spectra of TTF-triazoles, an absorption band is observed at around λ max = 388-394 nm, corresponding to a partial charge transfer from TTF to triazole, as determined by TD DFT calculations. 7 In the bis(triazole) 8, this band is centered at 415 nm (Fig. 5), with the red shift with respect to the mono(triazole) 1 being in agreement with a smaller HOMO-LUMO gap when compared to 1. Since the oxidation of 8 occurs at a more anodic potential than the oxidation of 1, indicating a lower energy HOMO level for 8 than for 1, it can be concluded that the variation ΔE LUMO is larger than ΔE HOMO when going from 1 to 8. The protonation or alkylation of the triazole ring is expected to increase its withdrawing character, and, consequently, result in a red shift of the charge transfer band. The stepwise addition of up to 1 equivalent of HBF 4 in a CH 2 Cl 2 solution of 1 indeed leads to a red shift of the charge transfer band from 394 nm (1) (Fig. 5).
In order to isolate and characterize in detail a triazolium salt, the precursor 1 was reacted with trimethyloxonium tetrafluoroborate (Me 3 O)BF 4 to afford 9 (Scheme 4).
The triazolium salt 9 was obtained as an analytically pure brown solid, and suitable single crystals, as red blocks, were grown by the slow diffusion of diethyl ether into a solution of 9 in acetonitrile. The cyclic voltammetry measurements show anodic shifts of 0.07 and 0.06 V for the first and second oxidation potentials respectively, when compared to the neutral precursor 1 (see ESI †). In line with the observations from the protonation experiment, a large red shift of 57 nm in the UVvis spectrum is observed for the charge transfer band which is now centred at 451 nm (see ESI †).
The final proof for the cationic structure of 9 was provided by the single crystal X-ray analysis. The compound crystallizes in the triclinic system, space group P1, with one independent TTF-triazolium cation and one BF 4 anion in the asymmetric unit. As clearly observed (Fig. 6), the methylation took place at the N3 atom, which is the most nucleophilic. There is now perfect planarity between the TTF and triazolium units, while the Ph ring is perpendicular to the rest of the molecule.
The central C3vC4 bond length of 1.351(4) Å is in the normal range for a neutral donor and compares very well with  the value of 1.350(5) Å in the neutral precursor 1. Nevertheless, the most important structural effect of the methylation concerns, as expected, the triazole ring, since in 9 the N-N distances have closer values, i.e. 1.326(4) Å for N1-N2 and 1.306(4) Å for N2-N3, as an effect of the conjugation, and, moreover, are shorter than the distances of 1.353(4) and 1.316(4) Å, respectively, observed in the neutral triazole. In the packing there is no short intermolecular S⋯S contact (see ESI †), yet hydrogen bonds of F⋯H-type are established between the BF 4 anions and vinylic, benzylic and NMe protons (see ESI †).

Conclusions
The synthesis of TTF-bis(triazoles) as 1,4-and 1,5-isomers was attempted following copper and ruthenium-catalyzed azidealkyne cycloaddition reactions, respectively. The access to these bis(triazole) precursors proved to be much more problematic than the preparation of TTF-mono(triazoles), very likely because of the sensitivity of the TTF-bis(acetylene) precursor and the TTF-triazole-acetylene intermediate, since only the 1,5-isomer of the ortho-dimethyl-TTF-bis(triazole) could be prepared by ruthenium-based catalysis. The same reaction allowed the preparation of TTF-mono(triazoles) with benzyl or n-butyl substituents on the triazole ring. The substitution patterns and number of triazole units greatly influences the solid state structures of these electroactive precursors. As a general structural feature, the triazole units engage in the solid state in intermolecular π-π interactions and hydrogen bonding, thus competing with the classical TTF⋯TTF interactions. Modulation of the intramolecular charge transfer, TTF → triazole, was achieved by protonation of the triazole units with HBF 4 , monitored by UV-visible spectroscopy. Moreover, a triazolium salt was isolated and structurally characterized by methylation with the strong electrophilic agent (Me 3 O)BF 4 . All of these TTF-triazoles and derivatives constitute valuable precursors for radical cation salts since they all possess good electron donating properties. The coordinating properties of triazoles can be also exploited, especially when associated to pyridines within chelating ligands. 18 These possibilities are actively being investigated in our laboratory. 1-Butyl-5-(ortho-dimethyl-tetrathiafulvalenyl)-1,2,3-triazole 2

X-Ray structure determination
Details of the data collection and solution refinement are given in Table 1 (see also ESI † for 5). X-ray diffraction measurements were performed on a Bruker Kappa CCD diffractometer, operating with a Mo Kα (λ = 0.71073 Å) X-ray tube with a graphite monochromator. The structures were solved (SHELXS-97) by direct methods and refined (SHELXL-97) by full matrix least-square procedures on F 2 . 21 All of the non-hydrogen atoms were refined anisotropically. Hydrogen atoms were introduced at calculated positions (riding model) and included in structure factor calculations, but not refined. Crystallographic data for the four structures have been deposited with the Cambridge Crystallographic Data Centre, with the deposition numbers CCDC 982420 (2), CCDC 982421 (5), CCDC 982422 (8) and CCDC 982423 (9).