Next Article in Journal
Characterization of the Key Aroma-Active Compounds in Yongchuan Douchi (Fermented Soybean) by Application of the Sensomics Approach
Next Article in Special Issue
Diels–Alder Cycloaddition Reactions in Sustainable Media
Previous Article in Journal
Effect of Saffron Extract on the Hepatotoxicity Induced by Copper Nanoparticles in Male Mice
Previous Article in Special Issue
Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 26
Issue 10
10.3390/molecules26103047
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis of the [11]Cyclacene Framework by Repetitive Diels–Alder Cycloadditions

by
John B. Bauer
1,
Fatima Diab
1,
Cäcilia Maichle-Mössmer
2,
Hartmut Schubert
2 and
Holger F. Bettinger
1,*
1
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
2
Institut für Anorganische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(10), 3047; https://doi.org/10.3390/molecules26103047
Submission received: 14 April 2021 / Revised: 11 May 2021 / Accepted: 14 May 2021 / Published: 20 May 2021
(This article belongs to the Special Issue Diels-Alder Reaction in Organic Synthesis)
Browse Figures
Versions Notes

Abstract

:
The Diels–Alder cycloaddition between bisdienes and bisdienophile incorporating the 7-oxa-bicyclo[2.2.1]heptane unit are well known to show high diastereoselectivity that can be exploited for the synthesis of molecular belts. The related bisdiene 5,6,7,8-tetramethylidene-2-bicyclo[2.2.2]octene is a valuable building block for the synthesis of photoprecursors for acenes, but it has not been employed for the synthesis of molecular belts. The present work investigates by computational means the Diels–Alder reaction between these bisdiene building blocks with syn-1,4,5,8-tetrahydro-1,4:5,8-diepoxyanthracene, which shows that the diastereoselectivity of the Diels–Alder reaction of the etheno-bridged bisdiene is lower than that of the epoxy-bridged bisdiene. The reaction of the etheno-bridged bisdiene and syn-1,4,5,8-tetrahydro-1,4:5,8-diepoxyanthracene in 2:1 ratio yields two diastereomers that differ in the orientation of the oxa and etheno bridges based on NMR and X-ray crystallography. The all-syn diastereomer can be transformed into a molecular belt by inter- and intramolecular Diels–Alder reactions with a bifunctional building block. The molecular belt could function as a synthetic intermediate en route to a [11]cyclacene photoprecursor.

Graphical Abstract

1. Introduction

The Diels–Alder (DA) reaction developed into a powerful synthetic method since its discovery more than 100 years ago [1,2,3,4,5,6]. As a member of the class of pericyclic reactions, this cycloaddition is particularly valuable due to its stereospecificity and the often observed high diastereoselectivity. This last feature is highly desirable and turned out to be the key to the successful synthesis of molecular belts [7,8,9,10]. In a series of classic papers, Stoddart et al. reported their results of the detailed analysis of the diastereoselectivity of DA reactions involving epoxy bridged bisdiene 1a and bisepoxy bridged bisdienophile 2 (Scheme 1) [7,11,12,13,14,15].
The DA reaction of a 1:1 mixture of 1a and 2 exclusively yields the syn/endo-H isomer 3a out of four possible diastereoisomers due to stereoelectronic effects, as discussed by Stoddart et al. (Scheme 1b) [7]. We follow their nomenclature and use the descriptors syn and anti for the relative configurations of the endoxide bridges and exo and endo for the relative configurations of the hydrogen atoms of the bisdiene after DA reaction.
As a consequence of the pronounced diastereoselectivity of the DA reaction involving strained bisdiene 1a and bisdienophile 2, the reaction in 2:1 ratio also yields a single diastereomer of the 2:1 adduct 5a (Scheme 1c). Remarkably, the reaction in 1:1 ratio does not produce polymers since the reactivity of the second diene unit is reduced once the first diene unit has undergone a DA reaction, as discussed by Stoddart et al. [7]. Due to the diminished reactivity, the reaction with another bisdienophile building block requires high pressure (Scheme 1c). In this way, it was possible to synthesise molecular belt 7a, a potential precursor of [12]cyclacene (8) (Scheme 1c).
First envisioned by Heilbronner [16], fully conjugated molecular belts consisting solely of linearly fused benzene rings, cyclacenes ([n]CA, where n is the number of benzene rings), have not yet been synthesised although related systems have been achieved, for example, by Gleiter et al. [17,18] and by Itami et al. [19]. Seminal work by Stoddart [7,11,12,13,14,15], Schlüter [9,20], and Corey [8,21] demonstrated the significant resistance of the belts toward full conjugation. More recent attempts by on-surface synthesis using a tetraepoxy precursor further demonstrated the challenge in achieving full conjugation [10]. Synthesis of conjugated molecular belts and structurally related molecules has been reviewed in the literature [22,23,24,25,26]. Computational analyses of the strain energies arrive at values around 123 kcal mol−1 for [10]CA and 103 kcal mol−1 for [12]CA, indicating that the final reaction step in a CA synthesis will result in a substantial energy penalty due to the buildup of strain [27,28,29].
The resistance of cyclacene formation also under the conditions of on-surface synthesis is remarkable as the combination of ultrahigh vacuum, submonolayer coverage, and catalytically active single crystal transition metal surface is employed. These conditions previously allowed the production of acenes [30,31,32,33,34], the highly reactive linear analogues of cyclacenes [35]. Acenes could be obtained up to undecacene under matrix isolation conditions by photocleavage of α-diketone bridges. These were installed synthetically by DA reactions involving bisdiene 1b that is closely related to 1a employed by Stoddart. If this shows similar diastereoselectivity, then it should be possible to employ it in the synthesis of molecular belts as well. However, the high diastereoselectivity of 1a is ascribed to the distortion of the diene unit from planarity, which causes the ‘lower’ side to be more reactive, thus favoring the formation of syn diastereomers [7]. The larger etheno bridge of 1b causes less distortion of the diene moieties according to single-crystal X-ray crystallography [36] and thus reduced diastereoselectivity is anticipated.
Indeed, Wegener and Müllen reported that the DA reaction of bisdiene 1b with the closely related monodienophile 1,4-dihydro-1,4-epoxynaphthalene gave two diastereomers in a ratio of 4:1 under high-pressure conditions [37,38]. The major isomer was identified as having all bridges syn standing with hydrogen atoms at the newly formed bonds in endo position with respect to the epoxy bridge. The minor isomer had the corresponding H atoms also in endo position, but one epoxy bridge was anti to the other bridges, as evidenced by X-ray crystallography [37,38]. This observation confirms the reduced diastereoselectivity in DA reactions of bisdiene 1b and bisdienophile 2 under high-pressure conditions. The reaction did not result in cyclic materials, according to Müllen, but in polymeric materials for which elucidation of the stereochemistry was impossible [37,38].
We here report a computational analysis of the DA reactions involving bisdienes 1a and 1b with bisdienophile 2 that confirm the reduced diastereoselectivity in their Diels–Alder reaction. We demonstrate that diastereomer 6a can be obtained from 1b and 2 (Scheme 1c) with sufficient diastereomeric excess to employ it in the synthesis of a molecular belt, as described in the second part of this paper.

2. Results and Discussion

2.1. Computations

The computational analysis employed the M062X functional and the 6-311+G** basis set. The effects of the solvent toluene were taken into account with a polarisable continuum model for geometry optimisation and subsequent computation of harmonic vibrational frequencies (see SI for comparison with other computational methods and Tables S6 and S7 for energy data). The Diels–Alder reaction between the bisdienes 1 and the bisdienophile 2 in a 1:1 ratio can result in four diastereomeric products 3a–d (from 1a) and 4a–d (from 1b) (see Scheme 1b).
The syn/endo-H isomer 3a, the sole reaction product observed by Ashton et al. [7], is the least stable diastereomer, while the anti/exo-H isomer 3d is the most stable one. The energy difference (ΔΔG°(298.15 K) = 1.9 kcal mol−1) between these isomers is small. Among the diastereomers, 4 the syn/endo-H product 4a is the most stable one, while the syn/exo-H isomer 4b is the least stable. The free energy difference between these isomers, ΔΔG°(298.15 K) = 0.9 kcal mol−1, is smaller than in the case of 3.
Since two transition states (TS) are conceivable for the formation of each diastereomer, eight TS each are relevant for the formation of 3 and 4. The expected TS could each be located on the corresponding potential energy surfaces. Among diastereomers 3, the least stable 3a is formed with the lowest energy barrier (ΔG‡ = 24.8 kcal mol−1) (Figure 1). The second-lowest barrier (ΔG‡ = 27.8 kcal mol−1) is associated with the formation of the anti/endo-H isomer 3c. Most importantly, the energy difference between the lowest and the second-lowest barrier (formation of 3a and 3c) is ΔΔG‡ = 3.0 kcal mol−1. The computations also show that the subsequent DA reaction of the syn/endo-H adduct 3a, with its remaining dienophile and a second equivalent of bisdiene in a syn/endo-H fashion to give 5 has almost the same barrier (ΔG‡ = 24.7 kcal mol−1) as the first syn/endo DA reaction. The large energetic preference of the syn/endo-H cycloaddition mode is in accord with the observation of the diastereoselective DA reaction between 1a and 2 by Ashton et al. [7].
The desired syn/endo-H isomer 4a and the anti/endo-H isomer 4c are almost isoenergetic. As a consequence, the barriers of their formations are more much more similar, although the formation of the isomer 4a still is preferred by ΔΔG‡ = 1.9 kcal mol−1. The barrier height for the formation of 4a is lower than that of 3a by 1.0 kcal mol−1, indicating that the endoxide bridge of 1a reduces reactivity. Formation of the syn/exo-H (4b) and anti/exo-H (4d) isomers are associated with barriers that are higher than that for 4a by 7.5 kcal mol−1 and 6.2 kcal mol−1, respectively, which excludes the corresponding stereochemical modes of reaction. As in the case of 3a, the subsequent DA reaction of 4a with the second equivalent of bisdiene 1b has a similar barrier to the first one for both the syn/endo (ΔG‡ = 24.3 kcal mol−1 to give 6a) and the anti/endo (ΔG‡ = 25.8 kcal mol−1 to give 6b) fashion (see Figure S65). In consequence, the computations suggest that the 2:1 DA reaction will likely give a mixture of twofold syn/endo and syn/endo plus anti/endo diastereoselectivity.
To summarise, the results of the computations of the DA reactions involving 1a and 2 are in full accord with the observations of Ashton et al. [7] regarding the high diastereoselectivity of the DA reaction. The computations suggest that the diastereoselectivity is reduced in the DA reaction of 1b and 2, in accord with the reports by Wegener and Müllen [37,38]. The formation of a molecular belt was not observed by them, but we reason that it should be possible to achieve if the proper diastereomer 6a can be isolated and employed in subsequent DA reactions.

2.2. Synthesis

The required bisdiene 1b and bisdienophile 2 were synthesised, as reported in [7,39]. The DA reaction of 2 with 2.2 equivalents of 1b in boiling toluene resulted in the formation of isomers 6a and 6b (Scheme 2). Integration of aromatic protons of the crude product reveals the ratio of diastereomers 6a:6b to be 1.9:1.
The stereochemistry of isomers 6a and 6b was determined by NMR spectroscopy and single-crystal X-ray crystallography. According to the Karplus equation, the coupling constant with a dihedral angle around 90° is close to zero, compared to dihedral angles of 0° and 180°. For the exo-H-isomers, the strong coupling would be expected, as opposed to no or weak coupling in the endo-H-isomers. In the COSY NMR spectra of 6a (Figure S5) and 6b (Figure S11), no coupling can be observed for the corresponding atoms. The NOESY NMR spectra, however, show an interaction between the corresponding atoms (for 6a: Figure S6, for 6b: Figure S12). An assignment of the 1H and 13C NMR signals to the corresponding atoms of 6a (Table S1) and 6b (Table S2) and the computed dihedral angles between the corresponding protons for the four diastereomers 4a–d (Figure S21) can be found in the Supplementary Materials. The conclusions based on NMR spectroscopy were confirmed by single-crystal X-ray crystallography (Figure 2).
The reaction of an equimolar ratio of compounds 2 and 1b leads to the formation of both 2:1 adducts 6a and 6b, and additionally, to two 1:1 adducts under these conditions (Scheme 2). The COSY NMR spectra (Figure S22) of the mixture of 1:1 adducts do not show any coupling for the corresponding atoms, which indicates the formation of the endo-H isomers. One 1:1 adduct could be isolated through preparative chromatography. Based on the preferred syn/endo-H diastereoselectivity, it is assigned as 4a. The minor 1:1 adduct, likely isomer 4c, could not be isolated, but the separation of 4c can be achieved with HPLC–MS chromatography where the [M + H]+ and [M + H-H2O]+ ions can be detected (see Figure S63).
Diels–Alder reaction of compounds 6a and 2 could in principle lead to macrocycle 8b. After employing three different reaction conditions (Scheme 3), MS measurements of all crude reaction mixtures could detect m/z of 733.1, 715.4, 697.4, and 679.4, which could result from the ions [M + H]+, [M-H2O + H]+, [M-2H2O + H]+, and [M-3H2O + H]+. Not enough product could be gained for NMR experiments. After heating 2 and 6a for 168 h at 120 °C and 85 bar the chromatogram of the crude product shows 2 signals at 35.16 min and 36.20 for the m/z of 733.1, 715.4, 697.4, and 679.4 (Figure S64), indicating a rearrangement of 8b. It appears that the higher temperatures employed in this reaction, compared to those for the synthesis of 4a, resulted in significant thermal degradation. Unfortunately, we were not able to find milder conditions for this transformation to proceed in better yields.
We, therefore, sought a different way to construct a molecular belt. Ashton et al. [7] showed that the final DA reaction can proceed under mild conditions as it is an intramolecular reaction. We thus resorted to a more reactive dienophile than 2 willing to sacrifice the high diastereoselectivity. For this purpose, we chose an aryne that we generated from 10. Macrocycle 12 was obtained from 6a and 10 in an overall yield of 7% upon heating a mixture of 6a and 10 with a fluoride source, which generates the aryne from 10 to react with 6a in a Diels–Alder reaction to afford compound 11a (Scheme 4). This in turn undergoes an intramolecular Diels–Alder reaction to yield 12. Compound 10 was obtained in a yield of 66% after treating commercially available 9 with furan and CsF in MeCN for 1 h at 45 °C (Scheme 5).
The products 11a and 11b could be obtained and characterised after treatment of 6a and 10 with KF and 18-crown-6 for 24 h at room temperature. All the ether and olefin bridges in the target molecule 11a are syn to each other. Additional side products were formed during the reaction, which were more polar than 11a and 11b, and were not isolated or characterised. The formation of 2:1 adducts 13, with different orientations of the newly installed endoxide bridges would be expected.
Since compounds 11a and 11b could not be differentiated by NMR and MS, both compounds were heated in boiling toluene for 2 h, respectively, with 11a affording 12 as product and 11b remaining unchanged. This indicates that 11a has all the bridges on the same side. The chemical transformation from 11a to 12 can be proven by the changes in the 1H and 13C NMR spectra. For CS symmetric compound 11a all the required 13C signals can be observed, but due to the very similar chemical shifts of the bridgehead carbon atoms (C-8) and (C-12), their assignment is interchangeable (Table 1). Likewise, the diastereotopic hydrogen atoms at (C-6) and (C-14) can only be assigned pairwise (Figure S49). The same is true for a number of 13C and 1H signals of 12, but the required amount of 13C resonances for CS symmetric 12 is observed (Table 1). The terminal carbon of the diene of 11a can easily be identified with a DEPT-135 measurement, which shows a negative signal at δC 101.2 (C-1). After the intramolecular DA reaction to 12, the signal is shifted to δC 31.2 (C-1). The methylene protons of the diene unit of 11a at δH 4.86 and 4.70 (H-1) are transformed to diastereotopic protons in 12, which can be found in the range between 2.5 and 2.0 ppm (H-1) (Figure S50). The protons for the dienophile at δH 6.91 (H-24) in 11a are shifted to the range between 1.36 and 1.20 ppm (H-24) in 12. Analogously a shift takes place from δC 143.0 (C-24) to δC 46.3/45.8 (C-24). The assignment to 11a and 12 are in agreement with the 2D NMR and DEPT spectra and with the high-resolution APCI measurements.

2.3. Properties of Macrocycle 12

Since we were not able to obtain single crystals suitable for X-ray crystallography, we computed the structure of 12 (Figure 3). The distances between the internal endo hydrogen atoms range between 3.3–5.3 Å. The molecular belt 12 is significantly more stable than precursor 11a as indicated by the heat of reaction for cyclisation, ΔH°(298.15 K) = −42.5 kcal mol−1.
The molecular belt 12 decomposes both in toluene solution during heating within a few hours and in substance during storage in a refrigerator within a few weeks to unidentified products.

3. Materials and Methods

3.1. General Methods

All commercially available reagents were used as received. Air and/or water-sensitive reactions were carried out under N2 in oven-dried glassware. Solvents for chromatography and workup including diethyl ether (Et2O), ethyl acetate (EtOAc), hexane, methanol, and dichloromethane (DCM) were purchased as high-performance liquid chromatography (Sigma-Aldrich, Steinheim, Germany) grade. DCM and toluene used for the synthetic reactions were purified by an SPS system (MBraun MB-SPS-800). Acetonitrile and n-BuLi (1.6 M in hexane) used in the synthetic reactions were bought anhydrous and under an inert atmosphere from Sigma-Aldrich (Steinheim, Germany). KF was dried under vacuum at 150 °C for 1.5 h. For deactivated aluminium oxide for column chromatography, 8 g of water was added to 100 g of activated aluminium oxide. Compound 1b was synthesised according to the reported literature and showed the same spectroscopic properties as reported [39]. Thin-layer chromatography (TLC) was performed on silica TLC plates (Polygram Sil G/UV, Macherey-Nagel, Düren, Germany) and visualised by illumination with a UV lamp (Analytikjena, Jena, Germany) 254 and 365 nm wavelength). TLC plates were stained with phosphomolybdic acid, 10 wt% solution in ethanol. Silica gel (Macherey-Nagel, 0.04–0.063 mm) was used as received. All NMR spectra were recorded at 298 K on 400 and 700 MHz Bruker Avance III spectrometers. 1H and 13C shifts were referenced to the residual solvent signal of CDCl3, 1H-NMR: δ = 7.26 ppm, 13C NMR: δ = 77.16 ppm [40]. 1H-NMR gave signals at 1.52 (water), 1.26 (grease), and 0.08 (grease) ppm. 13C NMR gave signals at 1.2 (grease) ppm [40]. Mass spectrometry measurements were recorded on a maXis 4G-UHR-TOF Bruker Daltonics spectrometer using the electrospray ionisation (ESI) or the atmospheric-pressure chemical ionisation (APCI) technique; the chromatogram in Figure S63 was obtained on an Esquire 3000 plus Bruker Daltonics spectrometer with an Agilent 1100 Series HPLC using linear-gradient conditions: from 90% A (H2O/0.1% formic acid) and 10% B (MeOH/0.1% formic acid) to 0% A and 100% B in 20 min, then keeping 0% A and 100% B for 10 min. The flow rate was 0.3 mL/min with eluent monitoring at 254 nm. Column: Macherey-Nagel EC 125/4 Nucleosil 100-5 C18. The chromatogram in Figure S64 was obtained on an amaZon SL Bruker Daltonics spectrometer with an Agilent 1260 Series HPLC using linear-gradient conditions: from 60% A (H2O/0.1% formic acid) and 40% B (MeOH/0.1% formic acid) to 5% A and 95% B in 30 min, then keeping 5% A and 95% B for 20 min. The flow rate was 0.3 mL/min with eluent monitoring at 254 nm. Column: Agilent InfinityLab Poroshell 120 EC-C18 4.6 × 100 mm 2.7 Micron with Column ID.

3.2. Synthetic Procedures

rel-(1R,4S,5R,8S)-1,4,5,8-Tetrahydro-1,4:5,8-diepoxyanthracene (2)
A solution of 36.6 mL (500 mmol) furan, 10 g (25.4 mmol) 1,2,4,5-tetrabromobenzene in 400 mL of toluene was cooled to −25 °C under argon and a solution of 33.3 mL n-butyllithium (1.6 M in hexane) was added dropwise within 1 h. After the addition, the reaction mixture was stirred at room temperature for 12 h. Then, 12.5 mL of methanol was added and the reaction mixture was washed three times with 50 mL of water and three times with 50 mL of saturated sodium chloride solution. After drying over MgSO4, the solvent was removed under reduced pressure. The residue was purified by column chromatography (aluminium oxide deactivated, neutral; hexane/DCM/Et2O 1:2:1). Product 2 was obtained as a yellow solid. Yield: 1.15 g (5.47 mmol, 21%). 1H-NMR (400 MHz, CDCl3) δ [ppm]: 7.19 (2H, s), 7.04-7.02 (4H, apparent t, J = 0.96 Hz), 5.63 (4H, broad s). 13C-NMR (100 MHz, CDCl3) δ [ppm]: 147.7, 143.5, 113.8, 82.5. RF (aluminium oxide, hexane/DCM/Et2O 1:2:1): 0.35. Spectral data are in accordance with literature information [7].
rel-(1R,4S,5aS,6S,8R,8aR,10R,13S,14aS,15S,17R,17aR)-2,3,11,12-Tetramethylene-1,4,5,5a,6,8,8a,9,10,13,14,14a,15,17,17a,18-hexadecahydro-6,17:8,15-diepoxy-1,4:10,13-diethenoheptacene (6a) and rel-(1R,4S,5aR,6R,8S,8aS,10S,13R,14aR,15R,17S,17aS)-2,3,11,12-tetramethylene-1,4,5,5a,6,8,8a,9,10,13,14,14a,15,17,17a,18-hexadecahydro-6,17:8,15-diepoxy-1,4:10,13-diethenoheptacene (6b)
A solution of 150 mg (0.71 mmol) bisdienophile 2 and 265 mg (1.70 mmol) bisdiene 1b in 70 mL anhydrous toluene was heated under reflux for 18 h. After removing the solvent under reduced pressure, the residue was purified by column chromatography (silica; hexane/DCM 18:1). Both products were obtained as colourless solids. Yield: for 6a: 90 mg (0.17 mmol, 24%), for 6b: 60 mg (0.12 mmol, 16%). 6a: 1H-NMR (400 MHz, CDCl3) δ [ppm]: 6.98 (2H, s), 6.41-6.37 (4H, m), 4.94 (4H, s), 4.89 (4H, s), 4.75 (4H, s), 3.92–3.88 (4H, m), 2.64–2.56 (4H, m), 2.22–2.14 (4H, m), 1.90–1.83 (4H, m). 13C-NMR (100 MHz, CDCl3) δ [ppm]: 144.8, 144.4, 137.7, 133.8, 110.3, 101.3, 85.2, 53.7, 43.5, 30.8. RF (silica, DCM:EtOAc 18:1): 0.47. HRMS (ESI) m/z: [M + Na]+ calcd for C38H34NaO2+ 545.24510; found 545.24537. 6b: 1H-NMR (400 MHz, CDCl3) δ [ppm]: 7.00 (2H, s), 6.41–6.36 (4H, m), 5.04 (2H, s), 4.94 (2H, s), 4.90 (2H, s), 4.89 (2H, s), 4.80 (2H, s), 4.75 (2H, s), 3.92–3.85 (4H, m), 2.65-2.55 (4H, m), 2.24–2.11 (4H, m), 1.94–1.86 (4H, m). 13C-NMR (100 MHz, CDCl3) δ [ppm]: 144.8, 144.6, 144.4, 144.3, 137.7, 136.8, 133.9, 133.8, 110.3, 101.6, 101.3, 85.2, 85.2, 53.6, 53.5, 43.3, 41.4, 30.8, 30.1. RF (silica, DCM:EtOAc 18:1): 0.53. HRMS (ESI) m/z: [M + Na]+ calcd for C38H34NaO2+ 545.24510; found 545.24542.
rel-(1R,4S,6R,6aR,8R,11S,12aS,13S)-16,17-Dimethylene-1,4,6,6a,7,8,11,12,12a,13-decahydro-1,4:6,13-diepoxy-8,11-ethanopentacene (4a)
A solution of 100 mg (0.48 mmol) bisdienophile 2 and 74 mg (0.48 mmol) bisdiene 1b in 60 mL anhydrous toluene was heated under reflux for 18 h. After removing the solvent under reduced pressure, the residue was purified by column chromatography (silica; DCM:EtOAc 25:1). The product 4a was obtained as a colourless solid. Yield: 22 mg (0.06 mmol, 13%). 1H-NMR (400 MHz, CDCl3) δ [ppm]: 7.07 (2H, s), 7.01–6.99 (2H, m), 6.42–6.38 (2H, m), 5.63 (2H, s), 4.94 (2H, s), 4.88 (2H, s), 4.75 (2H, s), 3.93–3.89 (2H, m), 2.65–2.56 (2H, m), 2.23–2.14 (2H, m), 1.94–1.87 (2H, m). 13C-NMR (100 MHz, CDCl3) δ [ppm]: 148.7, 144.4, 143.5, 143.4, 137.7, 133.7, 112.1, 101.3, 85.0, 82.5, 53.6, 43.4, 30.7. RF (silica, DCM:EtOAc 18:1): 0.34. HRMS (ESI) m/z: [M + Na]+ calcd for C26H22NaO2+ 389.15120; found 389.15130.
7-(Trimethylsilyl)-1,4-dihydro-1,4-epoxynaphthalen-6-yl-trifluoromethanesulfonate (10)
A solution of 52 mg (0.34 mmol) CsF was added over a solution of 120 mg (0.23 mmol) bistriflate 9 and 33 μL (0.46 mmol) furan in 6 mL of dry MeCN. The mixture was stirred for 1 h at 45 °C. After the evaporation of the solvent under reduced pressure, the residue was purified by column chromatography (silica, hexane:EtOAc 7:3). The product 10 was obtained as a colourless solid. Yield: 56 mg (0.15 mmol, 66%) 1H-NMR (700 MHz, CDCl3) δ [ppm]: 7.33 (1H, s), 7.24 (1H, s), 7.07-7.02 (2H, m), 5.72 (2H, broad s), 0.34 (9H, s). 13C-NMR (176 MHz, CDCl3) δ [ppm]: 153.9, 152.5, 148.2, 143.4, 142.7, 128.6, 126.2, 121.3, 119.5, 117.7, 115.9, 113.2, 82.4, 82.1, −0.6. RF (silica, hexane:EtOAc 7:3): 0.72. Spectral data are in accordance with literature information [41].
rel-(1R,4S,7R,8aS,9S,11R,11aR,13R,16S,17aS,18S,20S,20aR,22S)-14,15-Dimethylene-1,4,6,7,8,8a,9,11,11a,12,13,16,17,17a,18,20,20a,21,22,23-icosahydro-1,4:9:20,11:18-triepoxy-7,22:13,16-diethenodecacene (11a) and rel-(1R,4S,7S,8aR,9R,11S,11aS,13S,16R,17aR,18R,20R,20aS,22R)-14,15-dimethylene-1,4,6,7,8,8a,9,11,11a,12,13,16,17,17a,18,20,20a,21,22,23-icosahydro-1,4:9:20,11:18-triepoxy-7,22:13,16-diethenodecacene (11b)
A suspension of 15 mg (0.26 mmol) KF and 63 mg (0.24 mmol) 18-crown-6 in dry MeCN was cooled to 0 °C and a solution of 83 mg (0.16 mmol) diene 6a and 58 mg (0.16 mmol) triflate 10 in 10 mL of dry DCM was added dropwise within 10 min. The reaction mixture was stirred for 1 h at 0 °C and then at room temperature for 18 h. After the evaporation of the solvent under reduced pressure, the residue was purified by column chromatography (silica, DCM:EtOAc 25:1). Both products were obtained as colourless solids. Yield: for 11a: 7 mg (0.011 mmol, 7%), for 11b: 8 mg (0.012 mmol, 8%). 11a: 1H-NMR (700 MHz, CDCl3) δ [ppm]: 6.95 (2H, s), 6.93 (2H, s), 6.91 (2H, s), 6.77–6.75 (2H, m), 6.39–6.37 (2H, m), 5.61 (2H, s), 4.87 (2H, s), 4.86 (2H, s), 4.85 (2H, s), 4.70 (2H, s), 4.15–4.13 (2H, m), 3.88–3.86 (2H, m), 3.49–3.33 (4H, m), 2.70–2.65 (2H, m), 2.60–2.55 (2H, m), 2.18–2.12 (2H, m), 2.12–2.06 (2H, m), 1.92–1.87 (2H, m), 1.77–1.71 (2H, m). 13C-NMR (176 MHz, CDCl3) δ [ppm]: 146.6, 144.8, 144.7, 144.4, 143.8, 143.0, 140.8, 139.5, 137.5, 133.8, 130.7, 120.9, 110.2, 101.2, 85.2, 85.2, 82.2, 55.3, 53.6, 43.1, 42.9, 33.7, 31.4, 30.7. RF (silica, DCM:EtOAc 18:1): 0.36. HRMS (APCI) m/z: [M + H]+ calcd for C48H41O3+ 665.30502; found 665.30606. 11b: 1H-NMR (700 MHz, CDCl3) δ [ppm]: 6.97 (2H, s), 6.93 (2H, s), 6.93 (2H, s), 6.74–6.72 (2H, m), 6.39–6.36 (2H, m), 5.60 (2H, s), 4.89 (2H, s), 4.87 (2H, s), 4.86 (2H, s), 4.70 (2H, s), 4.14-4.12 (2H, m), 3.88–3.86 (2H, m), 3.43–3.37 (4H, m), 2.73–2.68 (2H, m), 2.60–2.56 (2H, m), 2.19–2.12 (2H, m), 2.12–2.05 (2H, m), 1.90–1.83 (4H, m). 13C-NMR (176 MHz, CDCl3) δ [ppm]: 146.6, 144.7 (2 isochronous nuclei), 144.3, 143.5, 142.9, 140.7, 139.6, 137.6, 133.8, 130.7, 120.9, 110.2, 101.4, 85.3, 85.2, 82.2, 55.3, 53.6, 43.3, 42.5, 33.7, 31.4, 30.8. RF (silica, DCM:EtOAc 18:1): 0.39. HRMS (APCI) m/z: [M + H]+ calcd for C48H41O3+ 665.30502; found 665.30625.
Macrocycle 12
A solution of 7 mg (0.011 mmol) 11a in 5 mL toluene was stirred for 5 h at 75 °C. After the evaporation of the solvent under reduced pressure, the residue was purified by column chromatography (silica, DCM:EtOAc 25:1). The product 12 was obtained as a colourless solid. The yield could not be determined reliably due to the small reaction scale but is estimated to be around 80 to 90%. 1H-NMR (700 MHz, CDCl3) δ [ppm]: 6.85 (2H, s), 6.82–6.80 (2H, m), 6.77 (2H, s), 6.75–6.73 (2H, m), 4.82 (2H, s), 4.81 (2H, s), 4.79 (2H, s), 4.23–4.21 (2H, m), 4.14–4.12 (2H, m), 3.53–3.46 (2H, m), 3.26–3.19 (2H, m), 2.57–2.48 (6H, m), 2.23–2.17 (2H, m), 2.20–2.04 (4H, m), 1.36–1.31 (2H, m), 1.31–1.25 (2H, m), 1.25–1.20 (2H, m). 13C-NMR (176 MHz, CDCl3) δ [ppm]: 147.8, 147.5, 147.4, 145.2, 145.1 143.7, 143.3, 139.8, 139.0, 133.5, 118.8, 110.0, 84.3, 84.1, 84.0, 57.0, 56.3, 47.2, 46.3, 45.8, 34.3, 31.7, 31.2, 31.2. RF (silica, DCM:EtOAc 18:1): 0.34. HRMS (APCI) m/z: [M + H]+ calcd for C48H41O3+ 665.30502; found 665.30521.

3.3. X-ray Crystallographic Data

Suitable crystals for 6b were grown from a solution of chloroform and toluene at 5 °C. Data were collected on a Bruker SMART APEX II instrument equipped with a fine focus sealed tube and TRIUMPH monochromator using MoKα radiation (λ = 0.71073 Å). The data collection strategy was determined using COSMO [42] employing ω- and ϕ scans. Raw data were processed using APEX [43] and SAINT [44] corrections for absorption effects were applied using SADABS [45].
Suitable crystals for 6a were grown from a solution of dichloromethane and hexane at room temperature. Data collections were therefore performed on a Bruker APEX DUO instrument equipped with an IμS microfocus sealed tube and QUAZAR optics for MoKα radiation (λ = 0.71073 Å). The Data collection strategy was determined using COSMO [42] employing ω- scans. Raw data were processed using APEX [46] and SAINT [47], corrections for absorption effects were also applied using SADABS [45].
The structures were solved by direct methods and refined against all data by full-matrix least-squares methods on F2 using SHELXTL [48] and Shelxle [49]. All atoms (except hydrogen) were refined anisotropically. All methyl groups were refined as rigid and rotating (difference Fourier density optimisation) CH3 groups with Uiso(H) = 1.5Ueq(C) and all other hydrogen atoms were placed in calculated positions and refined using a riding model with Uiso(H) = 1.2Ueq(C) for aromatic and Uiso(H) = 1.5Ueq(C) for all other hydrogen atoms.
Crystal Data for C38H34O2 6b (M = 522.65 g/mol): monoclinic, space group P2/c (no. 13), a = 14.0261(2)Å, b = 6.81100(10) Å, c = 28.6971(5) Å, β = 95.4760(10)°, V = 2728.97(7) Å3, Z = 4, T = 100(2) K, μ(MoKα) = 0.077 mm−1, Dcalc = 1.272 g/cm3, 30,286 reflections measured (6.628° ≤ 2Θ ≤ 54.279°), 6017 unique (Rint = 0.0358, Rsigma = 0.0525), which were used in all calculations. The final R1 was 0.0453 (I > 2σ(I)) and wR2 was 0.12162 (all data).
Crystal Data for C38H34O2 6a (M = 522.65 g/mol): monoclinic, space group C2/c (no. 15), a = 27.338(2) Å, b = 6.6749(7) Å, c = 29.531(3) Å, β = 91.711(6)°, V = 5386.4(8) Å3, Z = 8, T = 100(2) K, μ(CuKα) = 0.601 mm−1, Dcalc = 1.289 g/cm3, 15,880 reflections measured (6.468° ≤ 2Θ ≤ 130.032°), 4425 unique (Rint = 0. 1130, Rsigma = 0. 1406), which were used in all calculations. The final R1 was 0.0797 (I > 2σ(I)) and wR2 was 0.2122 (all data).
The X-ray crystal structures of compounds 6a and 6b were uploaded to the Cambridge Crystallographic Data Centre with the deposition numbers CCDC 2076991 for 6a and CCDC 2076992 for 6b. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif, accessed on 19 May 2021.

3.4. Computational Chemistry

The computations were performed using the M062X [50] functional along with the 6-311+G** basis set. Although the DA reaction is not very sensitive to solvent polarity, we took into account the effect of the toluene solvent in our computations. For this purpose, the polarisable continuum model using the integral equation formalism variant (IEFPCM) [51], as implemented in Gaussian 16 [52], was employed. Computations of harmonic vibrational frequencies confirm the nature of stationary points as minima or saddle points.

4. Conclusions

In summary, the computational investigation of the diastereoselectivity of the Diels–Alder reaction of strained bisdiene 1a with strained bisdienophile 2 is in agreement with the experimental observations reported by Stoddart et al. [7,11,13,14,15]. The computations suggest that the geometrically more flexible bisdiene 1b should undergo the DA reaction with bisdienophile 2 with lower diastereoselectivity, but the concave all-syn diastereomer 6a required for construction of a molecular belt should be dominant. This is confirmed experimentally since 6a is the dominant 2:1 cycloaddition product, while 6b is a minor by-product. The concave 6a can be chemically transformed into a molecular belt 12 by two subsequent DA reactions. The novel belt 12 could function as a synthetic intermediate for the synthesis of a photoprecursor for [11]cyclacene.

Supplementary Materials

Charts of NMR spectra (1H, 13C, selected COSY and NOESY), mass spectra, chromatograms, computational method evaluation, relative energies, figures of transition states discussed in the text, Cartesian coordinates of stationary points are available online.

Author Contributions

Conceptualisation, H.F.B.; methodology, J.B.B., F.D., C.M.-M., H.S. and H.F.B.; writing, J.B.B. and H.F.B. All authors have read and agreed to the published version of the manuscript.

Funding

The authors acknowledge support by the state of Baden-Württemberg through bwHPC and the German Research Foundation (DFG) through grant no INST 40/467-1 FUGG (JUSTUS 2 cluster).

Acknowledgments

We thank the Fonds der chemischen Industrie for support.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not available.

References

  1. Diels, O.; Alder, K. Synthesen in der hydroaromatischen Reihe. Liebigs Ann. Chem. 1928, 460, 98–122. [Google Scholar] [CrossRef]
  2. Diels, O.; Alder, K. Synthesen in der hydroaromatischen Reihe, III. Liebigs Ann. Chem. 1929, 470, 62–103. [Google Scholar] [CrossRef]
  3. Diels, O.; Alder, K. Synthesen in der hydroaromatischen Reihe, IV. Ber. Dtsch. Chem. Ges. 1929, 62, 2081–2087. [Google Scholar] [CrossRef]
  4. Diels, O.; Alder, K. Synthesen in der hydroaromatischen Reihe, V. Ber. Dtsch. Chem. Ges. 1929, 62, 2087–2090. [Google Scholar] [CrossRef]
  5. Ichihara, A. Retro-Diels–Alder strategy in natural product synthesis. Synthesis 1987, 1987, 207–222. [Google Scholar] [CrossRef]
  6. Nicolaou, K.C.; Snyder, S.A.; Montagnon, T.; Vassilikogiannakis, G. The Diels–Alder reaction in total synthesis. Angew. Chem. Int. Ed. 2002, 41, 1668–1698. [Google Scholar] [CrossRef]
  7. Ashton, P.R.; Brown, G.R.; Isaacs, N.S.; Giuffrida, D.; Kohnke, F.H.; Mathias, J.P.; Slawin, A.M.Z.; Smith, D.R.; Stoddart, J.F.; Williams, D.J. Molecular LEGO. 1. Substrate-directed synthesis via stereoregular Diels–Alder oligomerizations. J. Am. Chem. Soc. 1992, 114, 6330–6353. [Google Scholar] [CrossRef]
  8. Cory, R.M.; McPhail, C.L.; Dikmans, A.J.; Vittal, J.J. Macrocyclic cyclophane belts via double Diels–Alder cycloadditions: Macroannulation of bisdienes by bisdienophiles. Synthesis of a key precursor to an [8]cyclacene. Tetrahedron Lett. 1996, 37, 1983–1986. [Google Scholar] [CrossRef]
  9. Neudorff, W.D.; Lentz, D.; Anibarro, M.; Schlüter, A.D. The carbon skeleton of the belt region of fullerene C84 (D2). Chem. Eur. J. 2003, 9, 2745–2757. [Google Scholar] [CrossRef]
  10. Schulz, F.; García, F.; Kaiser, K.; Pérez, D.; Guitián, E.; Gross, L.; Peña, D. Exploring a route to cyclic acenes by on-surface synthesis. Angew. Chem. Int. Ed. 2019, 58, 9038–9042. [Google Scholar] [CrossRef] [Green Version]
  11. Ashton, P.R.; Isaacs, N.S.; Kohnke, F.H.; Slawin, A.M.Z.; Spencer, C.M.; Stoddart, J.F.; Williams, D.J. Towards the making of [12]collarene. Angew. Chem. Int. Ed. Engl. 1988, 27, 966–969. [Google Scholar] [CrossRef]
  12. Girreser, U.; Giuffrida, D.; Kohnke, F.H.; Mathias, J.P.; Philip, D.; Stoddart, J.F. The structure-directed synthesis of cyclacene and polyacene derivatives. Pure Appl. Chem. 1993, 65, 119–125. [Google Scholar] [CrossRef]
  13. Kohnke, F.H.; Mathias, J.P.; Stoddart, J.F. Structure-directed synthesis of new organic materials. Angew. Chem. Int. Ed. Engl. 1989, 28, 1103–1110. [Google Scholar] [CrossRef]
  14. Kohnke, F.H.; Slawin, A.M.Z.; Stoddart, J.F.; Williams, D.J. Molecular belts and collars in the making: A hexaepoxyoctacosahydro [12]cyclacene derivative. Angew. Chem. Int. Ed. Engl. 1987, 26, 892–894. [Google Scholar] [CrossRef]
  15. Kohnke, F.H.; Stoddart, J.F. The evolution of molecular belts and collars. Pure Appl. Chem. 1989, 61, 1581–1586. [Google Scholar] [CrossRef]
  16. Heilbronner, E. Molecular Orbitals in homologen Reihen mehrkerniger aromatischer Kohlenwasserstoffe: I. Die Eigenwerte von LCAO-MO’s in homologen Reihen. Helv. Chim. Acta 1954, 37, 921–935. [Google Scholar] [CrossRef]
  17. Gleiter, R.; Hellbach, B.; Gath, S.; Schaller, R.J. From superphanes to beltenes. Pure Appl. Chem. 2006, 78, 699–706. [Google Scholar] [CrossRef]
  18. Hellbach, B.; Rominger, F.; Gleiter, R. Synthesis of beltenes by reactions of 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctene with [CpCo(CO)2] derivatives. Angew. Chem. Int. Ed. 2004, 43, 5846–5849. [Google Scholar] [CrossRef]
  19. Takaba, H.; Omachi, H.; Yamamoto, Y.; Bouffard, J.; Itami, K. Selective synthesis of [12]cycloparaphenylene. Angew. Chem. Int. Ed. 2009, 48, 6112–6116. [Google Scholar] [CrossRef]
  20. Stuparu, M.; Lentz, D.; Rüegger, H.; Schlüter, A.D. Exploring the chemistry of a double-stranded cycle with the carbon skeleton of the belt region of the C84 fullerene. Eur. J. Org. Chem. 2007, 2007, 88–100. [Google Scholar] [CrossRef]
  21. Cory, R.M.; McPhail, C.L. Transformations of a macrocyclic cyclophane belt into advanced [8]cyclacene and [8]cyclacene triquinone precursors. Tetrahedron Lett. 1996, 37, 1987–1990. [Google Scholar] [CrossRef]
  22. Chen, H.; Miao, Q. Recent advances and attempts in synthesis of conjugated nanobelts. Phys. Org. Chem. 2020, 33, 1–20. [Google Scholar] [CrossRef]
  23. Cheung, K.Y.; Segawa, Y.; Itami, K. Synthetic strategies of carbon nanobelts and related belt-shaped polycyclic aromatic hydrocarbons. Chem. Eur. J. 2020, 26, 14791–14801. [Google Scholar] [CrossRef] [PubMed]
  24. Shi, T.-H.; Wang, M.-X. Zigzag hydrocarbon belts. CCS Chem. 2020, 2, 916–931. [Google Scholar] [CrossRef]
  25. Gleiter, R.; Esser, B.; Kornmayer, S.C. Cyclacenes: Hoop-shaped systems composed of conjugated rings. Acc. Chem. Res. 2009, 42, 1108–1116. [Google Scholar] [CrossRef] [PubMed]
  26. Tahara, K.; Tobe, Y. Molecular loops and belts. Chem. Rev. 2006, 106, 5274–5290. [Google Scholar] [CrossRef]
  27. Gupta, D.; Omont, A.; Bettinger, H.F. Energetics of formation of cyclacenes from 2,3-didehydroacenes and implications for astrochemistry. Chem. Eur. J. 2021, 27, 4605–4616. [Google Scholar] [CrossRef]
  28. Sadowsky, D.; McNeill, K.; Cramer, C.J. Electronic structures of [n]-cyclacenes (n = 6–12) and short, hydrogen-capped, carbon nanotubes. Faraday Discuss. 2010, 145, 507–521. [Google Scholar] [CrossRef]
  29. Segawa, Y.; Yagi, A.; Ito, H.; Itami, K. A theoretical study on the strain energy of carbon nanobelts. Org. Lett. 2016, 18, 1430–1433. [Google Scholar] [CrossRef]
  30. Zuzak, R.; Dorel, R.; Kolmer, M.; Szymonski, M.; Godlewski, S.; Echavarren, A.M. Higher acenes by on-surface dehydrogenation: From heptacene to undecacene. Angew. Chem. Int. Ed. 2018, 57, 10500–10505. [Google Scholar] [CrossRef] [Green Version]
  31. Krüger, J.; García, F.; Eisenhut, F.; Skidin, D.; Alonso, J.M.; Guitián, E.; Pérez, D.; Cuniberti, G.; Moresco, F.; Peña, D. Decacene: On-surface generation. Angew. Chem. Int. Ed. 2017, 56, 11945–11948. [Google Scholar] [CrossRef] [PubMed]
  32. Krüger, J.; Eisenhut, F.; Skidin, D.; Lehmann, T.; Ryndyk, D.A.; Cuniberti, G.; García, F.; Alonso, J.M.; Guitián, E.; Pérez, D.; et al. Electronic Resonances and Gap Stabilization of Higher Acenes on a Gold Surface. ACS Nano 2018, 12, 8506–8511. [Google Scholar] [CrossRef] [PubMed]
  33. Eisenhut, F.; Kühne, T.; García, F.; Fernández, S.; Guitián, E.; Pérez, D.; Trinquier, G.; Cuniberti, G.; Joachim, C.; Peña, D.; et al. Dodecacene generated on surface: Reopening of the energy gap. ACS Nano 2020, 14, 1011–1017. [Google Scholar] [CrossRef]
  34. Urgel, J.I.; Mishra, S.; Hayashi, H.; Wilhelm, J.; Pignedoli, C.A.; Di Giovannantonio, M.; Widmer, R.; Yamashita, M.; Hieda, N.; Ruffieux, P.; et al. On-surface light-induced generation of higher acenes and elucidation of their open-shell character. Nat. Commun. 2019, 10, 861. [Google Scholar] [CrossRef] [PubMed]
  35. Tönshoff, C.; Bettinger, H.F. Pushing the limits of acene chemistry: The recent surge of large acenes. Chem. Eur. J. 2021, 27, 3193–3212. [Google Scholar] [CrossRef]
  36. Geiger, T.; Schundelmeier, S.; Hummel, T.; Ströbele, M.; Leis, W.; Seitz, M.; Zeiser, C.; Moretti, L.; Maiuri, M.; Cerullo, G.; et al. Modulating the electronic and solid-state structure of organic semiconductors by site-specific substitution: The case of tetrafluoropentacenes. Chem. Eur. J. 2020, 26, 3420–3434. [Google Scholar] [CrossRef]
  37. Wegener, S.; Müllen, K. 5,6,7,8-Tetramethylenebicyclo [2.2.2]oct-2-ene as “Bis(diene)” in repetitive Diels–Alder reactions. Chem. Ber. 1991, 124, 2101–2103. [Google Scholar] [CrossRef]
  38. Wegener, S.; Müllen, K. New ladder polymers via repetitive Diels–Alder reaction under high pressure. Macromolecules 1993, 26, 3037–3040. [Google Scholar] [CrossRef]
  39. Gabioud, R.; Vogel, P. Synthesis and Diels–Alder reactivity of 5,6,7,8-tetramethylidene-2-bicyclo [2.2.2]octanol and -octanone. Selective oxidations of the corresponding bis(irontricarbonyl) complexes. Helv. Chim. Acta 1983, 66, 1134–1147. [Google Scholar] [CrossRef]
  40. Fulmer, G.R.; Miller, A.J.M.; Sherden, N.H.; Gottlieb, H.E.; Nudelman, A.; Stoltz, B.M.; Bercaw, J.E.; Goldberg, K.I. NMR chemical shifts of trace impurities: Common laboratory solvents, organics, and gases in deuterated solvents relevant to the organometallic chemist. Organometallics 2010, 29, 2176–2179. [Google Scholar] [CrossRef] [Green Version]
  41. Krüger, J.; Eisenhut, F.; Alonso, J.M.; Lehmann, T.; Guitian, E.; Perez, D.; Skidin, D.; Gamaleja, F.; Ryndyk, D.A.; Joachim, C.; et al. Imaging the electronic structure of on-surface generated hexacene. Chem. Commun. 2017, 53, 1583–1586. [Google Scholar] [CrossRef] [PubMed]
  42. Bruker AXS Inc. COSMO v. 1.61; Bruker AXS Inc.: Madison, WI, USA, 2012. [Google Scholar]
  43. Bruker AXS Inc. APEX 2 v. 2012.10_0; Bruker AXS Inc.: Madison, WI, USA, 2012. [Google Scholar]
  44. Bruker AXS Inc. SAINT v. 8.34A; Bruker AXS Inc.: Madison: WI, USA, 2013. [Google Scholar]
  45. Krause, L.; Herbst-Irmer, R.; Sheldrick, G.M.; Stalke, D. Comparison of silver and molybdenum microfocus X-ray sources for single-crystal structure determination. J. Appl. Crystallogr. 2015, 48, 3–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Bruker AXS Inc. APEX 3 V. 2017.3-0; Bruker AXS Inc.: Madison, WI, USA, 2017. [Google Scholar]
  47. Bruker AXS Inc. SAINT v. 8.38A; Bruker AXS Inc.: Madison, WI, USA, 2017. [Google Scholar]
  48. Sheldrick, G. SHELXT-Integrated space-group and crystal-structure determination. Acta Cryst. 2015, 71, 3–8. [Google Scholar] [CrossRef] [Green Version]
  49. Hübschle, C.B.; Sheldrick, G.M.; Dittrich, B. ShelXle: A Qt graphical user interface for SHELXL. J. Appl. Crystallogr. 2011, 44, 1281–1284. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Zhao, Y.; Truhlar, D. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: Two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 2008, 120, 215–241. [Google Scholar]
  51. Tomasi, J.; Mennucci, B.; Cammi, R. Quantum mechanical continuum solvation models. Chem. Rev. 2005, 105, 2999–3094. [Google Scholar] [CrossRef]
  52. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Petersson, G.A.; Nakatsuji, H.; et al. Gaussian 16 Rev. C.01; Gaussian: Wallingford, CT, USA, 2016. [Google Scholar]
Molecules 26 03047 sch001 550
Scheme 1. (a) Structures of bisdiene 1a–b and bisdienophil 2; (b) cycloaddition of compounds 2 and 1a,b in 1:1 ratio could in principle result in four diastereoisomeric 1:1 adducts 3a–d and 4a–d. For 1a only isomer 3a could be detected by Stoddart’s group; (c) Diels–Alder reaction between 1 and 2 (2:1 ratio) yields 5a (from 1a) or 6a and 6b (from 1b) and synthesis of kohnkene (7a), a precursor of [12]cyclacene (8), by Stoddart’s group; (i) 1a + 2, toluene, reflux, 14 h, 61%; (ii) 5a + 2, CH2Cl2, 10 kbar, 200 h, 55–60 °C, 20%.
Scheme 1. (a) Structures of bisdiene 1a–b and bisdienophil 2; (b) cycloaddition of compounds 2 and 1a,b in 1:1 ratio could in principle result in four diastereoisomeric 1:1 adducts 3a–d and 4a–d. For 1a only isomer 3a could be detected by Stoddart’s group; (c) Diels–Alder reaction between 1 and 2 (2:1 ratio) yields 5a (from 1a) or 6a and 6b (from 1b) and synthesis of kohnkene (7a), a precursor of [12]cyclacene (8), by Stoddart’s group; (i) 1a + 2, toluene, reflux, 14 h, 61%; (ii) 5a + 2, CH2Cl2, 10 kbar, 200 h, 55–60 °C, 20%.
Molecules 26 03047 sch001
Molecules 26 03047 g001 550
Figure 1. Lowest energy transition states for the formation of diastereomers 3 (a) and 4 (b) as computed at the M062X/6-311+G**/toluene level of theory. Distances between reacting carbon atoms are given in Å (blue), enthalpies (normal print), and free energies (italics) at 298.15 K are given in kcal mol−1. Note that for the formation of each diastereomer, there is another transition state that is higher in energy and that is not depicted for clarity: Red, oxygen; dark gray, carbon; light gray, hydrogen.
Figure 1. Lowest energy transition states for the formation of diastereomers 3 (a) and 4 (b) as computed at the M062X/6-311+G**/toluene level of theory. Distances between reacting carbon atoms are given in Å (blue), enthalpies (normal print), and free energies (italics) at 298.15 K are given in kcal mol−1. Note that for the formation of each diastereomer, there is another transition state that is higher in energy and that is not depicted for clarity: Red, oxygen; dark gray, carbon; light gray, hydrogen.
Molecules 26 03047 g001
Molecules 26 03047 sch002 550
Scheme 2. Diels–Alder reaction of 1b and 2. Reaction conditions and isolated yields (a) 2.2 equivalent of 1b, 1 equivalent of 2, toluene, reflux, 18 h; (b) equimolar ratio of 1b and 2, toluene, reflux, 18 h. 4c could not be isolated.
Scheme 2. Diels–Alder reaction of 1b and 2. Reaction conditions and isolated yields (a) 2.2 equivalent of 1b, 1 equivalent of 2, toluene, reflux, 18 h; (b) equimolar ratio of 1b and 2, toluene, reflux, 18 h. 4c could not be isolated.
Molecules 26 03047 sch002
Molecules 26 03047 g002 550
Figure 2. X-ray molecular structures of (a) 6a and (b) 6b (50% thermal ellipsoids; side views (top) and perspective views (bottom); hydrogen atoms are removed for clarity.
Figure 2. X-ray molecular structures of (a) 6a and (b) 6b (50% thermal ellipsoids; side views (top) and perspective views (bottom); hydrogen atoms are removed for clarity.
Molecules 26 03047 g002
Molecules 26 03047 sch003 550
Scheme 3. (a) Decalin, 150 °C, 18 h; (b) microwave: DCM, BMIM–PF6, 140 °C, 3 h, 14 bar; (c) autoclave: toluene, 120 °C, 168 h, 85 bar.
Scheme 3. (a) Decalin, 150 °C, 18 h; (b) microwave: DCM, BMIM–PF6, 140 °C, 3 h, 14 bar; (c) autoclave: toluene, 120 °C, 168 h, 85 bar.
Molecules 26 03047 sch003
Molecules 26 03047 sch004 550
Scheme 4. Synthesis of macrocycle 12: (a) KF, 18-crown-6, DCM, MeCN, RT, 18 h; (b) toluene, 75 °C, 5 h. Overall yield from 6a: 7%.
Scheme 4. Synthesis of macrocycle 12: (a) KF, 18-crown-6, DCM, MeCN, RT, 18 h; (b) toluene, 75 °C, 5 h. Overall yield from 6a: 7%.
Molecules 26 03047 sch004
Molecules 26 03047 sch005 550
Scheme 5. (a) Furan, CsF, MeCN, 45 °C, 1 h; (b) 6a, KF, 18-crown-6, DCM, MeCN, 18 h RT.
Scheme 5. (a) Furan, CsF, MeCN, 45 °C, 1 h; (b) 6a, KF, 18-crown-6, DCM, MeCN, 18 h RT.
Molecules 26 03047 sch005
Molecules 26 03047 g003 550
Figure 3. Molecular structure of macrocycle 12 as computed at the M062X/6-311+G**/toluene level of theory. Distances between endo-H atoms are given in Å (blue): Red, oxygen; dark gray, carbon; light gray, hydrogen.
Figure 3. Molecular structure of macrocycle 12 as computed at the M062X/6-311+G**/toluene level of theory. Distances between endo-H atoms are given in Å (blue): Red, oxygen; dark gray, carbon; light gray, hydrogen.
Molecules 26 03047 g003
Table
Table 1. 1H NMR and 13C NMR (DEPT 135) data for compounds 11a and 12.
Table 1. 1H NMR and 13C NMR (DEPT 135) data for compounds 11a and 12.
No.11a12
δCδHδCδH
1101.2, CH2Ha: 4.70, Hb: 4.8631.16a, CH2 or 31.19a, CH2Ha/Hb: 2.57–2.48/2.20–2.04
2144.4, C-147.5, C or 147.4, C-
353.6, CH3.88–3.8657.0, CH4.14–4.12
4133.8, CH6.39–6.37139.8, CH6.75–6.73
5137.5, C-147.5, C or 147.4, C-
630.7, CH2Ha/Hb: 2.60–2.55/2.18–2.1231.16a, CH2 or 31.19a, CH2Ha/Hb: 2.57–2.48/2.20–2.04
743.1, CH1.36–1.31 or 1.31–1.25 or 1.25–1.2046.3, CH or 45.8, CH1.36–1.31 or 1.31–1.25 or 1.25–1.20
885.19 a, CH or 85.24 a, CH4.8784.3, CH or 84.0, CH4.79
9144.8, C or 144.7, C-145.2, C or 145.1, C-
10110.2, CH6.95110.0, CH6.85
11144.8, C or 144.7, C-145.2, C or 145.1, C-
1285.19 a, CH or 85.24 a, CH4.8584.3, CH or 84.0, CH4.82
1342.9, CH1.77–1.7147.2, CH1.36–1.31 or 1.31–1.25 or 1.25–1.20
1431.4, CH2Ha/Hb: 2.70–2.65/2.12–2.0631.7, CH2Ha/Hb: 2.57–2.48/2.23–2.17
15143.8, C-147.8, C-
1655.3, CH4.15–4.1356.3, CH4.23–4.21
17139.5, CH6.77–6.75139.0, CH6.82–6.80
18140.8, C-143.3, C-
1933.7, CH2Ha, Hb: 3.49–3.3334.3, CH2Ha/Hb: 3.53–3.46/3.26–3.19
20130.7, C-133.5, C-
21120.9, CH6.93118.8, CH6.77
22146.6, C-143.7, C-
2382.2, CH5.6184.1, CH4.81
24143.0, CH6.9146.3, CH or 45.8, CH1.36–1.31 or 1.31–1.25 or 1.25–1.20
a chemical shifts are rounded to two decimals to distinguish them.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Bauer, J.B.; Diab, F.; Maichle-Mössmer, C.; Schubert, H.; Bettinger, H.F. Synthesis of the [11]Cyclacene Framework by Repetitive Diels–Alder Cycloadditions. Molecules 2021, 26, 3047. https://doi.org/10.3390/molecules26103047

AMA Style

Bauer JB, Diab F, Maichle-Mössmer C, Schubert H, Bettinger HF. Synthesis of the [11]Cyclacene Framework by Repetitive Diels–Alder Cycloadditions. Molecules. 2021; 26(10):3047. https://doi.org/10.3390/molecules26103047

Chicago/Turabian Style

Bauer, John B., Fatima Diab, Cäcilia Maichle-Mössmer, Hartmut Schubert, and Holger F. Bettinger. 2021. "Synthesis of the [11]Cyclacene Framework by Repetitive Diels–Alder Cycloadditions" Molecules 26, no. 10: 3047. https://doi.org/10.3390/molecules26103047

Article Metrics

Back to TopTop