Key words Calixarenes - macrocycles - phenothiazine - host–guest chemistry - conformational flexibility
Introduction
Calix[n ]arenes[1 ]
[2 ] as “chalice-like” macrocycles have found widespread interest and applications, most prominently as receptors for ions and small molecules, but also in organic materials.[3 ] Calix[4]arenes are the most common, consisting of four 4-substituted phenols, methylene-bridged in the 2,6–positions. Incorporating other aromatics than phenol will alter the optoelectronic and host–guest properties of the calixarenes. Examples are calix[4]pyrroles,[4 ] calix[n ]furanes (n = 5–8),[5 ]
[6 ] calix[4]thiophenes,[7 ] calix[n ]triazoles (n = 4–6),[8 ] calix[n ]imidazolium salts (n = 4, 5),[9 ] calix[n ]indoles (n = 3, 4),[10 ]
[11 ]
[12 ] and the recently reported calix[n ]carbazoles (n = 3, 4).[13 ]
[14 ] Phenothiazine has long been of interest to chemists[15 ]
[16 ] due to its pharmacological and biological activity[15 ]
[16 ]
[17 ]
[18 ] and its use in dye chemistry,[19 ]
[20 ]
[21 ] among others. Phenothiazines are fluorescent and feature a reversible oxidation process, which makes them attractive for applications in organic electronics[22 ]
[23 ]
[24 ] and in batteries.[25 ]
[26 ]
[27 ]
[28 ] They are also strong excited-state reductants and have been used in photoredox catalysis.[29 ]
[30 ]
[31 ] Incorporating phenothiazines into calixarene structures will therefore endow the above-mentioned properties to the macrocycles. We herein report on the synthesis and optoelectronic and structural properties of calix[n ]phenothiazines [n ]CPT-Hex (n = 3, 4) and [3]CPT-Tol ([Scheme 1 ]) as well as the host–guest chemistry of the hexyl derivative. To the best of our knowledge, calix[n ]phenothiazines have not been reported in the literature before.
Scheme 1 Syntheses of calix[n ]phenothiazines [n ]CPT-Hex (n = 3, 4) and [3]CPT-Tol .
Results and Discussion
Calix[n ]phenothiazines [n ]CPT-Hex (n = 3, 4) and [3]CPT-Tol were accessed in a facile two-step synthesis ([Scheme 1 ]). Alkylation of phenothiazine (1 ) with 1-bromohexane furnished N -hexylphenothiazine (2 ) in excellent yield. This was then reacted with paraformaldehyde under acidic conditions and 5 mM dilution to yield calix[n ]phenothiazines [3]CPT-Hex and [4]CPT-Hex in 15% and 4% yield, respectively, after separation by semipreparative gel permeation chromatography. Similarly, N -(para -tolyl)phenothiazine (3 ), synthesized by Buchwald–Hartwig coupling of phenothiazine (1 ) with para -bromotoluene, was cyclized with paraformaldehyde under the same acidic conditions and afforded [3]CPT-Tol in a good yield of 30% ([Scheme 1 ]). Experiments to increase the yields of the cyclization reactions by adding tetraethylammonium bromide as a template molecule were not successful [see [Supporting Information ] (SI) for more details].
The NMR spectra confirmed the high symmetry of the formed calix[n ]phenothiazines ([Figure 1 ]). Each spectrum displayed only one set of signals for the phenothiazine units and the bridging CH2 -groups. Regarding their structures, for the calix[3]phenothiazines two conformers are possible with all phenothiazines oriented the same way (AAA) or one rotated the other way (AAB). Density-functional theory (DFT) calculations on the PW6B95-D3/def2-QZVP level of theory showed the AAB conformation to be slightly more stable by 1.2 kcal mol−1 for [3]CPT-Me (hexyl groups in [3]CPT-Hex were replaced by methyl) and 1.3 kcal mol−1 for [3]CPT-Tol . NMR spectra indicated a fast conformational isomerism and no change in signals for [3]CPT-Hex and [3]CPT-Tol in the temperature range of 233–300 K (see [Supporting Information ] for VT-NMR spectra).
Figure 1
1 H NMR spectra of calix[n ]phenothiazines [3]CPT-Tol (a), [3]CPT-Hex (b), and [4]CPT-Hex (c) in CD2 Cl2 (500 MHz).
For the calix[4]phenothiazine [4]CPT-Hex , four conformations (AAAA, AAAB, AABB, and ABAB) are possible (see [Supporting Information ] for structures) as for the commonly known calix[4]arenes.[3 ] Calculations on the PW6B95-D3/def2-QZVP level of theory on the methyl derivatives [4]CPT-Me of all four conformers showed AAAA to be most stable followed by AAAB (+ 1.2 kcal mol−1 ), ABAB (+ 2.3 kcal mol−1 ), and AABB (+ 3.4 kcal mol−1 ). Also in this case, the high symmetry of the NMR spectra indicated a fast conformational isomerism.
The molecular structure of [3]CPT-Tol in the solid state was resolved by X-ray diffraction. Single crystals were grown by layering a toluene solution with methanol. For comparison, the structure of 3 was also determined by X-ray diffraction (see [Supporting Information ] for details). [3]CPT-Tol crystallized in the AAB conformation ([Figure 2 ]). The structure had no symmetry elements, resulting in three different butterfly angles for the phenothiazine units. The butterfly angles amounted to 159.3° and 153.4° for the “A”-phenothiazines and 142.8° for the “B”-phenothiazine, similar to that of N -(para -tolyl)phenothiazine (3 ) of 151.1°. The space in the cavity (distances between the phenothiazine subunits) amounts to 7.44–7.87 Å and can accommodate a toluene solvent molecule, which co-crystallized ([Figure 2 ]).
Figure 2 Molecular structure of [3]CPT-Tol in the solid state (displacement ellipsoids are shown at the 50% probability level; hydrogen atoms are omitted for clarity).
The cyclic voltammograms of the calix[n ]phenothiazines confirmed reversible redox processes due to the phenothiazine units ([Figure 3 ]). In the smaller calix[3]phenothiazines, the first oxidation was split into two processes due to the close proximity of the phenothiazine units at E
1/2 = 0.25 and 0.37 V for [3]CPT-Tol and at E
1/2 = 0.15 and 0.29 V for [3]CPT-Hex (all vs. Fc/Fc+ ). In acyclic N -(para -tolyl)phenothiazine (3 ) and N -methylphenothiazine, these events are visible at E
1/2 = 0.25 V and 0.32 V, respectively, vs. Fc/Fc+ (see [Supporting Information ]). A split of the first oxidation has also been reported for linear phenothiazine oligomers[32 ] and cyclic phenothiazinophanes depending on the linking unit.[33 ]
[34 ] In the larger [4]CPT-Hex , no split of the first oxidation wave was observed. The second oxidations of the phenothiazine units to dications occurred at E
1/2 = 0.99 V (reversible), E
1/2 = 0.97 V (quasi-reversible), and 0.98 V (anodic peak potential) for [3]CPT-Tol , [3]CPT-Hex , and [4]CPT-Hex , respectively.
Figure 3 Cyclic voltammograms of calix[n ]phenothiazines (in CH2 Cl2 , 0.1 M n -Bu4 NPF6 , scan rate 0.1 V s−1 ). (a) [3]CPT-Tol (0.33 mM, glassy carbon electrode); (b) [3]CPT-Hex (0.33 mM, Pt electrode); and (c) [4]CPT-Hex (0.25 mM, Pt electrode).
DFT calculations of the calix[3]phenothiazines showed the relevant orbitals to be located on two respective ones of the phenothiazine units (shown for [3]CPT-Me in [Figure 4 ], for [3]CPT-Tol the same distribution was obtained). HOMO, HOMO−1, and HOMO−2 lie close in energy, which explains the appearance of several redox waves in the CVs.
Figure 4 Selected calculated orbitals for [3]CPT-Me with energies for orbitals of [3]CPT-Me and [3]CPT-Tol (B3LYP-D3/def2-TZVP) in the AAB conformation.
The absorption and emission properties of the calix[n ]phenothiazines strongly depended on the N -substituent on the phenothiazines ([Figure 5 ]). For [3]- and [4]CPT-Hex , the absorption maxima were found to be at 266 and 315 nm and 260 and 312 nm, respectively, while emission occurred with maxima at 445 and 454 nm, respectively. In addition, [4]CPT-Hex showed a shoulder peak at 532 nm. For [3]CPT-Tol , on the other hand, the absorption maxima were bathochromically shifted to 259 and 325 nm and occurred with a higher molar attenuation coefficient of log ε = 4.3. The emission of [3]CPT-Tol was significantly red-shifted to a maximum at 518 nm. This corresponds to a large Stokes shift of 1.67 eV. This is surprising in comparison to N -(para -tolyl)phenothiazine (3 ), where absorption occurred with similar maxima of 258 and 321 nm, while the emission maximum was at a much shorter wavelength of 448 nm.[35 ] For N -arylphenothiazines, emissions around or above 500 nm and such large Stokes shifts were only observed with electron-withdrawing substituents at the aryl group (CN or CF3 ),[35 ] imparting a donor–acceptor character to the molecule. The origin of this bathochromic shift in [3]CPT-Tol is unclear.
Figure 5 Absorption (solid lines) and emission spectra (dashed lines) of calix[n ]phenothiazines in CH2 Cl2 .
Finally, we performed host–guest studies of [3]CPT-Hex with different guests. For comparison with the recently reported calix[3]carbazole,[13 ] we chose the imidazole derivative 4 as a neutral guest, which shows high binding constants (up to 104 M−1 ) towards pillar[5]arenes,[36 ] as well as tetraalkylammonium cations, namely 5 and 6 ([Figure 6a ]). NMR titration experiments[37 ] of [3]CPT-Hex solutions with these guest molecules showed a shift in the phenothiazine 1 H NMR resonances with increasing guest concentrations (see [Figure 6b ], spectra for other titrations can be found in [Supporting Information ]).
Figure 6 (a) Structures of guest molecules used in host–guest studies with [3]CPT-Hex . (b) Selected region of 1 H NMR spectra during titration of [3]CPT-Hex (2 mM) with 6 (added eq. of 6 from top to bottom: 0, 0.41, 1.19, 4.33, 7.88, 14.01, solvent CDCl3 , 300 MHz, 300 K).
The fact that only one set of signals was visible indicated a fast exchange between free and complexed species. To obtain binding constants, we used a 1:1 binding model[38 ]
[39 ]
[40 ] and an online tool provided by Thordarson and coworkers.[37 ]
[41 ] The resulting binding constants were K = 50 ± 3, 91 ± 4, and 128 ± 9 M−1 for the complex formation between [3]CPT-Hex and 4 , 5 , and 6 , respectively. For the ammonium cations 5 and 6 , the binding constants are larger than that reported for calix[3]carbazole[13 ] with the tetraethylammonium cation (up to 66.8 M−1 ).
Conclusions
We herein presented three calix[n ]phenothiazines as novel macrocycles. These calixarene derivatives showed reversible redox events and emissive properties due to the presence of the phenothiazine units. The structures are flexible at room temperature, allowing for fast conformational changes. The calix[3]phenothiazines can bind both cations and neutral guest molecules with binding constants to ammonium ions of up to 128 M−1 . Due to their facile two-step synthesis, these novel macrocycles could find widespread interest as receptors or as organic materials.
