Synthesis, solid-state structure, and electrochemical properties of thienodipyrimidine-2,4,5,7-tetra(thi)ones

Thienodipyrimidine-2,4,5,7-tetra(thi)ones were prepared by one-pot photocyclization from barbituric acid derivatives. The structures of these tricyclic molecules with multiple (thio)carbonyl groups were determined by NMR and single-crystal X-ray diffraction analysis, and the electrochemical properties were studied by cyclic voltammetry and DFT calculations. The solid-state structures of these molecules feature dipolar C=S (or C=O), chalcogen-bonding


Results and Discussion
With the aim of investigating the photophysical properties of barbituric acid chromophores with varying degrees of thionation, N,N'-dimethyl-2-thiobarbituric acid was treated with Lawesson's reagent, 21 which unexpectedly yielded 5 (4%) and 1a-S4 (4%; Scheme 1). Structural determination of both molecules was supported by 1 H and 13 C NMR spectroscopy, high-resolution mass spectrometry, and single-crystal X-ray diffraction (see later for discussion). Following this discovery, the reaction conditions were then varied to improve the yield of 1a-S4 (Table 1); under a normal atmosphere, the yield of 1a-S4 increased with increasing equivalents of Lawesson's reagent and the reaction time (entries 1-3, 4-44%). When the reaction was conducted in CH2Cl2 at reflux, 1a-S4 was not detected after 24 h (entry 4), suggesting high temperatures are required for thionating barbituric acid. Finally, various irradiation sources were implemented under either an aerated or N2 atmosphere to determine whether irradiation is necessary for the cyclization process (entries 5-10). UV irradiation (365 nm LED) in the presence of oxygen yielded 1a-S4 in the highest yield (44%, entry 7), indicating that either natural or artificial UV

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irradiation is essential to initiate the dimerization and cyclization processes. To ensure reproducible light exposure, the synthesis of other structural analogues was carried out under UV irradiation.

Scheme 1.
Unexpected formation of 1a-S4. Oxo analogues 2a-4a can be prepared using N,N'-dimethylbarbituric acid as the starting material or through oxidative desulfurization 22,23 of suitable precursors (Scheme 2). Specifically, treating N,N'dimethylbarbituric acid with Lawesson's reagent yielded compound 2a-O2S2, with two urea-type C=O groups (i.e. 2,7-dioxo), along with 6 as a minor product. Compound 6 has been previously reported and it appears as a mercaptothione instead of a structurally symmetric dithione tautomer by NMR, in agreement with the literature. 22 Successive Cu-mediated oxidation of 1a-S4 gave 3a-OS3 and 4a-O4 at room and high temperatures, respectively. Other oxo-isomers, such as 4,5-dioxo (found 341.01 m/z for C12H13N2O2S3 + ) and 2,4,5-trioxo (325.06 m/z for C12H13N2O3S2 + ) may have been generated according to mass spectrometry analysis; however, these compounds were not isolated. It is of interest to note that Senga and co-workers previously reported the synthesis of 4a-O4 by thermolysis of [1,2,3] Ethyl analogues 1b-S4, 2b-O2S2, and 3b-OS3 were also prepared using similar reaction conditions. The ethyl analogue of 6 was observed by mass spectrometry (219.0244 m/z for C8H12N2OS2 + ), but could not be isolated. The yield for each ethyl-substituted thienodipyrimidine tetra(thi)one is generally lower than that for the methyl derivatives, and 4b-O4 could not be obtained (see experimental), highlighting the reduced reactivity affected by bulkier ethyl substituents.
Compounds 5 and 6 are likely intermediates in the course of 1 and 2 formation. The observation of these species suggests a one-pot, two-step mechanism shown in Scheme 3. In the first step, mercaptothione intermediate A, produced through thionation of the barbituric precursor with Lawesson's reagent, reacts with its dithione tautomer A' to give thioether B upon elimination of H2S. 21,25,26 This reaction may proceed through a photochemical (upper pathway in Step 1) or thermal (lower pathway) route. In the photochemical route, the photoexcited A' abstracts a hydrogen atom from the thiol group of A; 25,27,28 the two radicals then combine to form the thioether linkage. As negligible 5 was observed in the dark reactions (Table 1, entries 9 and 10), this putative photochemical route may be significant. Notably, when N,N'-dimethylbarbituric acid was used as the starting material, thionation does not occur at the urea-like C=O group, indicating a substantial energy barrier for thionation at this position. Trace water in the solvent or the activated methylene group of barbituric acid provides a proton source for tautomerization. As light irradiation and an aerated atmosphere facilitate the formation of 1, it is believed that photon absorption of B initiates cyclization to give C, which then undergoes air oxidation to afford the aromatic thieno unit in 1 and 2 (Scheme 3, step 2). This oxidative photocyclization is akin to the reported thiophene synthesis from aryl vinyl sulfides or divinyl sulfides. [29][30][31][32] Page 5 of 14 © AUTHOR(S) Scheme 3. A plausible mechanism for the formation of thioether and thienodipyrimidine-2,4,5,7-tetra(thi)one.
Crystals of 1-4 with suitable qualities for X-ray diffraction analysis were obtained by solvent diffusion or slow evaporation (see experimental details for crystallization methods). Compounds 1a/b-S4 (crystallized in Pc and Pbca, respectively), 2a-O2S2 (Pca21), and 3a-OS3 (P21/n), with at least one sulfur atom on the 4 or 5 position of thienodipyrimidine, display a twisted geometry; large dihedral angles θ(E4-C4-C5-S5) in the range 32-63° were observed (E = S or O, Table 2). In the absence of C=S groups, tetraone 4a-O4 is nearly planar, with a small θ(O4-C4-C5-O5) of about 2°. Therefore, the non-planar, helicene-like structure of 1-3 should be caused by the steric congestion between the large chalcogen atoms in the 4/5 bay region.  The small size of the methyl substituent and a large number of chalcogen atoms in 1a-4a permit various intermolecular short contacts. In the herringbone packing of 1a-S4, one C=S group on the 2/7 position forms  33,34 On the other hand, one C=S group on the 4/5 position is in short contact with the thiophene S (d(S⋯S) = 3.55 Å), indicative of chalcogen bonding between lone-pair electrons of thione C=S and *C-S orbital of the thiophene unit. 35 Within each columnar stack of 1a-S4, the molecules are spaced by about 3.68 Å from each other. 2a-O2S2 also observes herringbone packing, with similar orthogonal interactions between the 2/7 C=O groups of neighboring molecules (d(O⋯C=O) = 3.12 Å and φ(O⋯C=O) = 87.7°; Figure 2c) and molecular stacking distances (3.51 Å); no chalcogen-bond-type interaction is observed. Ethyl-substituted 1b-S4 similarly exhibits a herringbone-like packing; however, the distance between the orthogonal 2/7 C=S groups of neighboring molecules is longer than the sum of the van der Waals radii of S and C (d(S⋯C=S) = 3.62 Å; Figure 2d). Additionally, the presence of ethyl groups increases the intermolecular distances between both the C=S and thiophene S and the π-stacking molecules (4 Å); therefore, it may be assumed that 1b-S4 would exhibit poor electron mobilities and air-stability owing to the negligible intermolecular interactions. The solid of 3a-OS3 instead shows sheet-like packing, with small intermolecular spacing (3.58 Å; Figure  2e). Such a sheet arrangement is incompatible with forming orthogonal interactions between the 2/7 C=S groups of neighboring molecules. The distance between the C=S group on the 5 position and the thiophene S (d(S⋯S) = 3.45 Å; Figure 2f) is shorter than the chalcogen bonds observed for 1a-S4. We note that the C=S group acts as the chalcogen bond acceptor in 3a-OS3 rather than the C=O group. This observation contradicts the common expectation, given a more substantial negative charge on C=O's oxygen but highlights the potential for C=S to engage in non-covalent interactions. The UV-Vis absorption spectra for thienodipyrimidine tetra(thi)ones 1-4 and thioether 5 in CH2Cl2 are shown in Figure 3 (Table 3). Each molecule shows absorption between 300-400 nm and no solvatochromic behavior was observed upon changing solvent polarity. The absorption intensity of the lower-energy band for each chromophore increases as the number of thiocarbonyls increases ( 9 700 M -1 cm -1 per thionation). The shape of the absorption bands changes negligibly when the alkyl group is converted from methyl to ethyl groups. Thioether 5 absorbs strongly at 360 nm ( = 36 410 M -1 cm -1 ) in agreement with the 365 nm LEDs required to maximize the yield of 1a-S4.   (M -1 cm -1 ) ΔGneu-ox [c] θneutral [d]  The electrochemical properties of 1-4 are summarized in Table 3 and the cyclic voltammograms shown in Figure 3. The reduction potentials become more positive as the degree of thionation increases, indicating that thionation of a carbonyl molecule makes it a better electron acceptor, as discussed in our recent study. 37 Although the number of C=S (and hence C=O) units in 3-OS3 is between that in 1-S4 and 2-O2S2, the oxidation potentials for 3-OS3 are higher than those for 1-S4 or 2-O2S2. This surprising observation is in line with the much larger energy difference (ΔGneu-ox) between the neutral and the 1-eoxidized forms of 3-OS3 in comparison to 1-S4 or 2-O2S2, computed at the (U-)ωB97X−D/6-31G(d,p) level of theory (Table 3). These results indicate that the oxidation potential is governed by the heteroatom composition on the 4 and 5 positions.
A closer examination of the optimized molecular geometry offers a clue for the explanation. Similar to the twisted structures found in the solid-state X-ray structure, the computed geometry shows a large dihedral angle θ(S4-C4-C5-S5)  64° for 1-S4 and 2-O2S2 and a slightly smaller one θ(O4-C4-C5-S5)  50° for 3-OS3, due to the presence of large sulfur atoms. The deviation between the corresponding values in Tables 2 and 3 is likely a consequence of packing effects. However, upon 1-eoxidation, the dihedral angle for radical cation 1-S4 •+ and 2-O2S2 •+ reduced substantially to θ(S4-C4-C5-S5)  30° whereas that for radical cation 3-OS3 •+ remain at θ(O4-C4-C5-S5)  50° (a minor change was also found for 4-O4 •+ ). The reduction in the dihedral angle also manifests in the shortening of the d(S4⋯S5) distance in 1-S4 •+ and 2-O2S2 •+ . The d(S4⋯S5)  2.7 Å in these radical cations is, in fact, significantly shorter than the sum of van der Waals radius of two sulfur atoms (3.8 Å). 38 The electron spin density plots of radical cations of 1a-4a in Figure 4 reveal the localization of the unpaired electron between the S4 and S5 atoms of 1-S4 •+ and 2-O2S2 •+ ; the distribution resembles a σ-type orbital interaction between S4 and S5. On the other hand, the spin density of 3-OS3 •+ and 4-O4 •+ spreads the entire molecule and is of π symmetry (see also Figure S2). The localization of the spin density and the small d(S4⋯S5) point at a two-center three-electron (2c/3e) bonding interaction between the thiocarbonyl units on the 4 and 5 Page 9 of 14 © AUTHOR(S) position (-C=SS=C-), a phenomenon that was reported for intermolecular systems. [39][40][41] In other words, the 2c/3e hemi-bonding between the two adjacent thiocarbonyl groups provides a stabilizing interaction 42 in the radical cation form of 1-S4 and 2-O2S2, allowing 1-eoxidation of these species to occur at a much milder potential than the other derivatives.

Conclusions
In summary, a series of thienodipyrimidine tetra(thi)ones have been synthesized via a one-pot photocyclization reaction of (2-thio)barbituric acid and successive Cu-mediated oxidation reactions. It was determined that both irradiation and aerated conditions are required for the cyclization process to occur. These molecules show photoabsorption mainly in the UV region and amphoteric electrochemical activities. In the presence of two C=S groups on the 4 and 5 positions, facile oxidation of these derivatives was observed, due to stabilizing intramolecular 2c/3e interaction in the radical cations. In the solid state, the molecular packing features dipolar C=S (or C=O), chalcogen-bonding, and π-stacking interactions, resulting in various short contacts between molecules. These favorable characteristics suggest the promising use of thienodipyrimidine tetra(thi)ones as field effect transistors. Our future study will identify which S-S interactions play a significant role in achieving air-stable transistors with superior electron mobilities.

Experimental Section
Materials and general methods. Materials were purchased at the reagent grade and used as received. resonance multiplicity was described as s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). Infrared spectra (IR) were recorded on a Shimadzu IR Affinity 1S FTIR spectrometer with a Specac Quest ATR accessory; vibration modes are reported in cm -1 . High-resolution mass spectra (HR-MS) were performed on a Waters LCT HR TOF mass spectrometer; signals are reported in m/z units.