An Approach to Paracyclophane-Based Tetrathiafulvalenes: Synthesis and Characterization of a Pseudo-Geminal [2.2]Paracyclophane 1,3-Dithia-2-Thione

The synthesis of paracyclophane-based tetrathiafulvalene precursors is described in the context of the importance of these compounds in the field of material chemistry. Pseudo-geminal bis(1,3-dithia-2-thione) was synthesized via the corresponding 1,3-dithiol-2-ylium salt. The latter was obtained by a synthetic procedure that involves 4,15-bis(acetyl)[2.2]paracyclophane, a new compound of interest for many researchers.


Introduction
Paracyclophane derivatives have been the subject of particular interest since their first appearance in the literature, more than seven decades ago [1][2][3]. Since then, most studies have been devoted to the elucidation of the structural characteristics of [2.2]paracyclophanes, particularly their geometry and steric properties, transannular interactions, and ring strain [4][5][6]. Most of the unique properties of these cyclophanes are the result of the rigid framework and the short distance between the two aromatic rings within the [2.2]paracyclophane unit. In one such application, unsaturated cyclophane bis(esters) provided the corresponding ladderanes by intramolecular photocyclization [7]. The [2.2]paracyclophane core can undergo chemical transformations specific to both aliphatic and aromatic compounds, resulting in a wide variety of functionalized [2.2]paracyclophanes. Both the parent hydrocarbon and its derivatives have been used in asymmetric catalysis [8][9][10][11], optoelectronics [12], and polymer synthesis [13].
Special attention has been paid to the ability of these compounds to form charge transfer complexes [14]. Tetrathiafulvalene (TTF) and its derivatives have been extensively studied with respect to their applications as organic metals and superconductors [15,16]. These properties are a consequence of the π-donor properties of TTF and of its important intermolecular interactions in the solid state through extended π-orbitals. The design of new tetrathiafulvalene derivatives has targeted those systems where the intermolecular interactions between planar molecules are more efficient and the solid-state architecture tends to organize as stacks or layers, with their long axes mutually parallel [17].
As can be seen in Scheme 1, pseudo-geminal derivative 1 [18] was converted to the pseudo-geminal bis(acetyl) derivative 2 by treatment with methyl lithium in the presence of copper(I) cyanide. We note that 4,15-bis(acetyl) [2.2]paracyclophane is a new derivative that has great potential to become an important synthetic intermediate in [2.2]paracyclophane chemistry. After the reaction workup, the desired product was isolated in 93% yield. Single crystals of 2 were obtained by layering hexane over a solution of 2 in dichloromethane; the structure of 2 is shown in Figure 1. Several bromination methods of 2 were investigated, involving molecular bromine, copper(I) bromide, and N-bromosuccinimide as brominating agents. Among these, N-bromosuccinimide proved to be the most efficient, providing the corresponding bis(dibromide) 3 in reasonable yield (52%) as well as the tribrominated derivative 4 as a side-product (10% yield). Single crystals of both 3 and 4 have been obtained by the same method and the structures are shown in Figure 2.

Results and Discussion
The synthetic pathway for the synthesis of pseudo-geminal [2.2] As can be seen in Scheme 1, pseudo-geminal derivative 1 [18] was converted to the pseudo-geminal bis(acetyl) derivative 2 by treatment with methyl lithium in the presence of copper(I) cyanide. We note that 4,15-bis(acetyl) [2.2]paracyclophane is a new derivative that has great potential to become an important synthetic intermediate in [2.2]paracyclophane chemistry. After the reaction workup, the desired product was isolated in 93% yield. Single crystals of 2 were obtained by layering hexane over a solution of 2 in dichloromethane; the structure of 2 is shown in Figure 1. Several bromination methods of 2 were investigated, involving molecular bromine, copper(I) bromide, and N-bromosuccinimide as brominating agents. Among these, N-bromosuccinimide proved to be the most efficient, providing the corresponding bis(dibromide) 3 in reasonable yield (52%) as well as the tribrominated derivative 4 as a side-product (10% yield). Single crystals of both 3 and 4 have been obtained by the same method and the structures are shown in Figure 2. We report here the synthesis and characterization of pseudo-geminal [2.2]paracyclophane 1,3-dithia-2-thione as a precursor for hybrid [2.2]paracyclophane-tetrathiafulvalene systems.

Results and Discussion
The synthetic pathway for the synthesis of pseudo-geminal [ As can be seen in Scheme 1, pseudo-geminal derivative 1 [18] was converted to the pseudo-geminal bis(acetyl) derivative 2 by treatment with methyl lithium in the presence of copper(I) cyanide. We note that 4,15-bis(acetyl) [2.2]paracyclophane is a new derivative that has great potential to become an important synthetic intermediate in [2.2]paracyclophane chemistry. After the reaction workup, the desired product was isolated in 93% yield. Single crystals of 2 were obtained by layering hexane over a solution of 2 in dichloromethane; the structure of 2 is shown in Figure 1. Several bromination methods of 2 were investigated, involving molecular bromine, copper(I) bromide, and N-bromosuccinimide as brominating agents. Among these, N-bromosuccinimide proved to be the most efficient, providing the corresponding bis(dibromide) 3 in reasonable yield (52%) as well as the tribrominated derivative 4 as a side-product (10% yield). Single crystals of both 3 and 4 have been obtained by the same method and the structures are shown in Figure 2.  2]paracyclophane (4) (right); ellipsoids represent 50% probability levels [20]. O1 and O2 represent the two oxygen atoms and Br1, Br2 and Br3 the bromine atoms.
The next step involved the synthesis of bisdithiocarbamate derivative 6 is by treatment of 3 with dimethylammonium N,N-dimethyldithiocarbamate 5, as presented in Scheme 2. The reaction proceeds readily in refluxing acetone, providing the desired product in 79% yield. From a series of various aminocarbodithioates derived from secondary amines (pyrrolidine, piperidine, morfoline), the use of the dimethylammonium derivative provided the best yield and a cleaner crude reaction product. Dithiocarbamate 6 was then converted into bis(1,3-dithiolium) perchlorate 7 through a method extensively used by us in the past [21][22][23][24], which involved heating 6 in a mixture of sulfuric and acetic acid over a period of 10 min, followed by addition of perchloric acid to the reaction mixture. Bis(1,3-dithiolium) perchlorate 7 was thereby obtained in 96% yield.  The cyclization of dithiocarbamates 6 was accompanied by important spectral changes. The IR spectra revealed the disappearance of the absorption band corresponding to the carbonyl group (1676 cm −1 ) and the presence of new, strong, and broad absorption bands at 1100-1200 cm −1 , corresponding to the perchlorate anion. Heterocyclization of dithiocarbamates 6 is also supported by the NMR spectrometry. Thus, the 1 H-NMR spectrum of the 1,3-dithiol-2-ylium perchlorate indicates the disappearance of the signal of the α-carbonyl hydrogen atom from compound 6 (4.08 ppm). The 13 C-NMR spectrum also supports the synthesis of 1,3-dithiolium salt 7 by the disappearance of the carbonyl and thiocarbonyl carbon atoms and the appearance of a new signal at very low field (186 ppm) which corresponds to the electron-deficient C-2 atom (see supplementary material). Finally, the desired bis(1,3-dithia-2-thione) 8 was obtained by treatment of 7 with ammonium sulfide. Although sodium sulfide was also investigated as a sulfur nucleophile, ammonium sulfide provided 2]paracyclophane (4) (right); ellipsoids represent 50% probability levels [20]. O1 and O2 represent the two oxygen atoms and Br1, Br2 and Br3 the bromine atoms. The next step involved the synthesis of bisdithiocarbamate derivative 6 is by treatment of 3 with dimethylammonium N,N-dimethyldithiocarbamate 5, as presented in Scheme 2. The reaction proceeds readily in refluxing acetone, providing the desired product in 79% yield. From a series of various aminocarbodithioates derived from secondary amines (pyrrolidine, piperidine, morfoline), the use of the dimethylammonium derivative provided the best yield and a cleaner crude reaction product. Dithiocarbamate 6 was then converted into bis(1,3-dithiolium) perchlorate 7 through a method extensively used by us in the past [21][22][23][24], which involved heating 6 in a mixture of sulfuric and acetic acid over a period of 10 min, followed by addition of perchloric acid to the reaction mixture. Bis(1,3-dithiolium) perchlorate 7 was thereby obtained in 96% yield. 2]paracyclophane (4) (right); ellipsoids represent 50% probability levels [20]. O1 and O2 represent the two oxygen atoms and Br1, Br2 and Br3 the bromine atoms.
The next step involved the synthesis of bisdithiocarbamate derivative 6 is by treatment of 3 with dimethylammonium N,N-dimethyldithiocarbamate 5, as presented in Scheme 2. The reaction proceeds readily in refluxing acetone, providing the desired product in 79% yield. From a series of various aminocarbodithioates derived from secondary amines (pyrrolidine, piperidine, morfoline), the use of the dimethylammonium derivative provided the best yield and a cleaner crude reaction product. Dithiocarbamate 6 was then converted into bis(1,3-dithiolium) perchlorate 7 through a method extensively used by us in the past [21][22][23][24], which involved heating 6 in a mixture of sulfuric and acetic acid over a period of 10 min, followed by addition of perchloric acid to the reaction mixture. Bis(1,3-dithiolium) perchlorate 7 was thereby obtained in 96% yield.  The cyclization of dithiocarbamates 6 was accompanied by important spectral changes. The IR spectra revealed the disappearance of the absorption band corresponding to the carbonyl group (1676 cm −1 ) and the presence of new, strong, and broad absorption bands at 1100-1200 cm −1 , corresponding to the perchlorate anion. Heterocyclization of dithiocarbamates 6 is also supported by the NMR spectrometry. Thus, the 1 H-NMR spectrum of the 1,3-dithiol-2-ylium perchlorate indicates the disappearance of the signal of the α-carbonyl hydrogen atom from compound 6 (4.08 ppm). The 13 C-NMR spectrum also supports the synthesis of 1,3-dithiolium salt 7 by the disappearance of the carbonyl and thiocarbonyl carbon atoms and the appearance of a new signal at very low field (186 ppm) which corresponds to the electron-deficient C-2 atom (see supplementary material). Finally, the desired bis(1,3-dithia-2-thione) 8 was obtained by treatment of 7 with ammonium sulfide. Although sodium sulfide was also investigated as a sulfur nucleophile, ammonium sulfide provided The cyclization of dithiocarbamates 6 was accompanied by important spectral changes. The IR spectra revealed the disappearance of the absorption band corresponding to the carbonyl group (1676 cm −1 ) and the presence of new, strong, and broad absorption bands at 1100-1200 cm −1 , corresponding to the perchlorate anion. Heterocyclization of dithiocarbamates 6 is also supported by the NMR spectrometry. Thus, the 1 H-NMR spectrum of the 1,3-dithiol-2-ylium perchlorate indicates the disappearance of the signal of the α-carbonyl hydrogen atom from compound 6 (4.08 ppm). The 13 C-NMR spectrum also supports the synthesis of 1,3-dithiolium salt 7 by the disappearance of the carbonyl and thiocarbonyl carbon atoms and the appearance of a new signal at very low field (186 ppm) which corresponds to the electron-deficient C-2 atom (see Supplementary Materials). Finally, the desired bis(1,3-dithia-2-thione) 8 was obtained by treatment of 7 with ammonium sulfide.
Although sodium sulfide was also investigated as a sulfur nucleophile, ammonium sulfide provided the best yield (76%) and a better quality of the crude reaction mixture. NMR spectra support the formation of compound 8 by the disappearance of the signals of the dimethylamino groups in 1 H NMR. The 13 C-NMR spectrum also indicates the disappearance of the signals of the methyl carbon atoms and that of the electron-deficient C-2 atom. The formation of the carbon-sulfur double bond is accompanied by the appearance of a new signal at 211.1 ppm (see Supplementary Materials).
1,3-Dithia-2-thiones derivatives are important precursors for the corresponding substituted tetrathiafulvalenes either by a homocoupling or heterocoupling approach. Under homocoupling conditions, pseudo-geminal derivative 8 should provide paracyclophane-based tetrathiafulvalenes, one of the possible stereoisomers being depicted in Figure 3. Preliminary investigations on phosphite-mediated homocoupling of 8 have not provided convincing results so far. These studies are still under evaluation.
the best yield (76%) and a better quality of the crude reaction mixture. NMR spectra support the formation of compound 8 by the disappearance of the signals of the dimethylamino groups in 1 H NMR. The 13 C-NMR spectrum also indicates the disappearance of the signals of the methyl carbon atoms and that of the electron-deficient C-2 atom. The formation of the carbon-sulfur double bond is accompanied by the appearance of a new signal at 211.1 ppm (see supplementary material).
1,3-Dithia-2-thiones derivatives are important precursors for the corresponding substituted tetrathiafulvalenes either by a homocoupling or heterocoupling approach. Under homocoupling conditions, pseudo-geminal derivative 8 should provide paracyclophane-based tetrathiafulvalenes, one of the possible stereoisomers being depicted in Figure 3. Preliminary investigations on phosphite-mediated homocoupling of 8 have not provided convincing results so far. These studies are still under evaluation.

Chemistry
Melting points were obtained on a KSPI melting-point meter (A. KRÜSS Optronic, Hamburg, Germany) and are uncorrected. IR spectra were recorded on a Bruker Tensor 27 instrument (Bruker Optik GmbH, Ettlingen, Germany). NMR spectra were recorded on a Bruker 500 MHz spectrometer (Bruker BioSpin, Rheinstetten, Germany). Chemical shifts are reported in ppm downfield from TMS. Mass spectra were recorded on a Thermo Scientific ISQ LT instrument (Thermo Fisher Scientific Inc., Waltham, MA, USA). All reagents were commercially available and used without further purification.

Bromination of 4,15-bis(acetyl)[2.2]paracyclophane
NBS (1.2 g, 6.7 mmol) and p-TsOH (0.25 g, 1.34 mmol) were added to a solution of 2 (0.978 g, 3.35 mmol) in CHCl3 (30 mL). The reaction mixture was refluxed for 30 min and then cooled to rt. Subsequent washing with water and sodium bicarbonate solution (5%) provided the crude reaction mixture, which was purified by column chromatography on silica gel using dichloromethane/pentane 1:1 as the eluent. Compounds 3 and 4 were isolated following this procedure.

Chemistry
Melting points were obtained on a KSPI melting-point meter (A. KRÜSS Optronic, Hamburg, Germany) and are uncorrected. IR spectra were recorded on a Bruker Tensor 27 instrument (Bruker Optik GmbH, Ettlingen, Germany). NMR spectra were recorded on a Bruker 500 MHz spectrometer (Bruker BioSpin, Rheinstetten, Germany). Chemical shifts are reported in ppm downfield from TMS. Mass spectra were recorded on a Thermo Scientific ISQ LT instrument (Thermo Fisher Scientific Inc., Waltham, MA, USA). All reagents were commercially available and used without further purification.

4,15-Bis(acetyl)[2.2]paracyclophane (2)
MeLi (1.6 M in Et 2 O, 12.5 mL, 20 mmol) was added dropwise to a suspension of CuCN (0.9 g, 10 mmol) in Et 2 O (20 mL). After 5 min, 4,15-bis(carboxyl)[2.2]paracyclophane 1 (0.296 g, 1 mmol) was added and the reaction mixture was left at 0 • C for 20 min. A solution of NH 4 Cl was then added and the organic layer was extracted with CH 2 Cl 2 and dried over Na 2 SO 4 . Evaporation and recrystallization from ethanol gave 2 (0.272 g, 93%) as colorless crystals. NBS (1.2 g, 6.7 mmol) and p-TsOH (0.25 g, 1.34 mmol) were added to a solution of 2 (0.978 g, 3.35 mmol) in CHCl 3 (30 mL). The reaction mixture was refluxed for 30 min and then cooled to rt. Subsequent washing with water and sodium bicarbonate solution (5%) provided the crude reaction mixture, which was purified by column chromatography on silica gel using dichloromethane/pentane 1:1 as the eluent. Compounds 3 and 4 were isolated following this procedure.  (7) Dithiocarbamate 6 (0.7 g, 1.3 mmol) was added to a mixture of sulfuric acid (1 mL) and acetic acid (3 mL), and the resulting solution was heated to 80 • C for 10 min. The reaction mixture was then left to cool to room temperature and HClO 4 70% (0.5 mL) was added. The resulting precipitate was then filtered off, washed thoroughly with water, and recrystallized from ethanol, yielding the desired 1, 3-

X-ray Structure Determination
Crystals were mounted in inert oil on glass fibers and transferred to the cold gas stream of an Oxford Diffraction diffractometer (Oxford Diffraction Limited, Abingdon, UK) (2: Nova A using mirror-focussed Cu Kα radiation; 3 and 4: Xcalibur E using monochromated Mo Kα radiation). Absorption corrections were implemented on the basis of multi-scans. The structures were refined anisotropically on F 2 using the programs SHELXL-1997 [25] (2) or -2018 [26] (3 and 4). Due to the inherent strain of cyclophane systems, hydrogen atoms of the cyclophane rings were refined freely but with C-H distance restraints; other hydrogens were included using rigid methyl groups or a riding model starting from calculated positions (see Supplementary Materials).
Special features: Structure 3 was refined as a pseudo-merohedral twin based on a pseudo-orthorhombic cell generated by the matrix -1 0 0/1 0 2/0 1 0. The TWIN matrix was 1 0 0/-1 0 0/-1 0 -1, and the scale factor (relative volume of the smaller twin component) was refined to 0.0791 (8). For structure 4, the largest difference peaks (1.3 and 1.0 e/A 3 ) may correspond to an alternative position for the entire molecule (e.g., with the CHBr 2 and CH 2 Br groups exchanged) or to contamination by a more highly brominated species. However, attempts to refine the peaks as alternative bromine positions led to occupation factors of only ca. 1%.

Conclusions
The synthesis of paracyclophane-based tetrathiafulvalenes precursors is described in the context of the importance of these compounds in materials chemistry. Pseudo-geminal bis(1,3-dithia-2-thione) was synthesized via the corresponding 1,3-dithiol-2-ylium perchlorate. The latter was obtained by a synthetic procedure that involves 4,15-bisacetyl [2.2]paracyclophane, a new derivative that opens up a new range of possibilities in [2.2]paracyclophane chemistry. We hope to report on the conversion of 8 into its TTF-derivative in the near future.