Rearrangement of Meta-Bridged Calix[4]arenes Promoted by Internal

Mar 14, 2019 - The meta-bridged calixarenes possess a rigidified and highly distorted cavity, where the additional single bond bridge imposes an extre...
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Rearrangement of Meta-Bridged Calix[4]arenes Promoted by Internal Strain Petr Slavík, Martin Krupicka, Vaclav Eigner, Lukas Vrzal, Hana Dvorakova, and Pavel Lhotak J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00107 • Publication Date (Web): 14 Mar 2019 Downloaded from http://pubs.acs.org on March 14, 2019

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The Journal of Organic Chemistry

Rearrangement

of

Meta-Bridged

Calix[4]arenes

Promoted

by

Internal Strain Petr Slavík,† Martin Krupička,† Václav Eigner,§ Lukáš Vrzal,‡ Hana Dvořákovᇠand Pavel Lhoták†* †

Department of Organic Chemistry, University of Chemistry and Technology, Prague (UCTP), Technická

5, 166 28 Prague 6, Czech Republic §



Institute of Physics AS CR v.v.i., Na Slovance 2, 182 21 Prague 8, Czech Republic. Laboratory of NMR spectroscopy, UCTP, 166 28 Prague 6, Czech Republic.

Table of Contents Graphic

ABSTRACT The meta-bridged calixarenes possess a rigidified and highly distorted cavity, where the additional single bond bridge imposes an extreme internal strain on the whole system. As a consequence, these compounds exhibit a reasonably amended reactivity, compared with common calix[4]arene derivatives, and which is governed by the release of internal strain. This can be documented by the reaction of the bridged calix[4]arene with P2O5 or Nafion-H® leading (apart from polymers) to a macrocyclic product with a rearranged basic skeleton. The methylene bridge next to the fluorene moiety is intramolecularly shifted from position 2 to position 4 of the phenolic subunit to minimize the tension. As revealed by single crystal X-ray analysis and by application of the RDC (Residual Dipolar Couplings) method, the rearrangement occurs without altering the original conformation.

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INTRODUCTION Calix[n]arenes1 (where n = 4,5,6,7,8 etc.) represent a family of macrocyclic oligophenols frequently used as building blocks and molecular scaffolds in the design of various receptors.2 They have become popular starting points in modern supramolecular chemistry, as they are easily available with a different size of the cavity (from 4 to 8 phenolic moieties) on a multigram scale. At the same time, the reasonably well developed derivatization techniques, together with a unique opportunity to tune their 3-D shapes (conformations) in the case of calix[4]arenes, make these molecules good candidates for many applications in supramolecular functional systems.1,2 Contrary to all other electrophilic substitution reactions yielding always para-substituted products, direct mercuration3 of calix[4]arene 1 provides corresponding meta isomer 2 (see Scheme 1). This unprecedented regioselectivity4 makes available so far inaccessible derivatization patterns5 in calixarene chemistry. Moreover, intramolecular bridging of the organomercury intermediate using Pdcatalyzed C-H activation led to a novel type of calixarenes 3 possessing an additional single bond bridge between the meta positions of two neighboring phenolic subunits.6 Such compounds possess rigidified and highly distorted cavities that are amenable to unusual reactivity never before observed in the case of common calix[4]arenes. Recently, the cleavage of macrocyclic systems using various acids/electrophiles was described (Scheme 1), where acyclic oligophenolic derivatives of type 4 and 5 could be isolated in very good yields.7 As follows from our DFT calculations, such a cleavage is a consequence of an extreme internal strain, the releasing of which is the driving force for the whole phenomenon.

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Scheme 1. Unusual reactivity of the meta-bridged calix[4]arenes

In this paper we report another very unusual behavior of meta-bridged systems leading to the formation of quasi- calix[4]arenes with a rearranged basic skeleton. As supported by single crystal Xray analysis and by the residual dipolar coupling measurements, the shift of the methylene moiety from position 2 to position 4 of phenolic subunit took place with high regio- and stereoselectivity.

Scheme 2. Rearrangement of the meta-bridged calix[4]arenes

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RESULTS AND DISCUSSION The starting meta-bridged calix[4]arene 3a was prepared using the recently published procedure based on the meta-mercuration3 of 1 and subsequent intramolecular bridging6 (C-H activation) using Pd(OAc)2/AsPh3/Cs2CO3 in toluene under reflux. Propoxy derivative 3a immobilized in the cone conformation was obtained at a gram scale after column chromatography on silica gel. To study the influence of the conformational freezing the conformationally mobile tetramethoxy derivative 3b was obtained by the analogous procedure. As we recently published, the reaction of 3a with hydrochloric acid led almost quantitatively to the cleavage of macrocyclic skeleton resulting in unusual oligophenylene derivative 4a (95% isolated yield). A thorough inspection of a crude reaction mixture revealed the formation of an unknown compound (less than 1%) possessing the identical molecular mass as the starting derivative 3a. The survey of the reaction conditions and the acidic agents led to finding that stirring with P2O5 in chloroform at room temperature for 30 min provided compound 6a in 35% yield as the only isolable product apart from polymers. A slightly lower yield of 6a was also achieved with Nafion-H® under similar reaction conditions (3 days at rt). The analogous methoxy derivative 6b was isolated in 20% yield from the reaction of 3b with P2O5 in CHCl3 (Scheme 2). The HRMS ESI+ analysis of 6a showed a signal at m/z = 613.3293, which was in accordance with the [M+Na]+ (613.3288) cation predicted for the starting compound 3a, thus indicating that the unknown compound was the product of the rearrangement. The 1H NMR spectra of 6a (CDCl3) showed the presence of several doublets resembling the typical splitting of the methylene bridges in the cone conformation of calix[4]arenes. On the other hand, the values of the geminal coupling constants (J  15.3-18.4 Hz) and the corresponding chemical shifts made the overall spectral pattern rather untypical. A noteworthy feature of the 1H NMR spectra of 6a was represented by the presence of two triplets from the methyl groups at a remarkably higher field (0.50 and 0.64 ppm) than one could expect for the cone conformation (usually around 1.00 ppm). This indicates the spatial proximity of two propyl

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moieties and aromatic subunits, the arrangement usually observed in the 1,3-alternate conformation of calix[4]arenes. Consequently, we were unable to assign the structure/conformation using the characteristic splitting pattern, chemical shifts and/or the coupling constants. The final proof of the cone conformation of 6a and 6b in solution was achieved by measuring of RDCs or by single crystal Xray analysis (vide infra). The single crystal X-ray analysis of methoxy analogue 6b revealed that the crystal of 6b belonged to the monoclinic system, space group P21/c. As shown in Figure 1a, the methylene bridge next to the fluorene moiety migrated from position 2 of one phenolic subunit (with respect to phenolic oxygen) to position 4 of the same unit. As a result, the fluorene moiety which in starting compound 3b was far from being planar (interplanar angle of fluorene phenolic rings was found to be 127.90°) became much more planarized (163.55°). This indicates that the driving force for the rearrangement is the relief of geometrical restrictions imposed by the single bond bridge in the calixarene precursor.

a)

b)

Figure 1. Single crystal X-ray structures of rearranged calix[4]arene 6b: (a) side-view, (b) top-view.

If we define the main plane of the molecule by the three C atoms from the CH2 bridges outside the fluorene moiety (C4, C13, C24), the corresponding interplanar angles with aromatic subunits are 74.56°, 67.55°, 89.36° and 124.18° starting from fluorene and continuing clockwise from the top-view (see Figure 1b). As shown in Figure 1a, one half of the fluorene moiety is well below the main plane.

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Consequently, the cavity of 6b is formed mostly by the remaining three phenolic subunits leading to the approximately triangular shape of the cavity. As all of the phenolic functions are oriented towards the same side of the main plane the overall conformation can be called cone using normal calixarene nomenclature. Since calix[4]arenes bearing methoxy groups at the lower rim are conformationally mobile, we carried out dynamic 1H NMR measurements to find the conformational preferences of rearranged calixarene 6b. However, heating of the C2D2Cl4 solution up to 413 K did not show any changes in the 1H NMR spectra, indicating that 6b is fixed in the cone conformation even at the highest accessible temperatures. Similarly, cooling of the sample (CDCl3) down to 213 K did not reveal any significant changes in the 1H NMR spectra of 6b (Figure S1).

Scheme 3. Rearrangement of the partial cone conformation

Compound 6a was originally presumed to be an intermediate in the pathway from the meta-bridged 3a to a cleaved oligophenylene 4a (Scheme 2). Surprisingly, stirring 6a with HCl at room or even at elevated temperatures did not give any trace of the expected cleaved compound 4a as simply no reaction occurred. This means that the inner strain in this molecule is already released to such an extent that no further cleavage is possible, and that the compound itself is stable enough under reaction conditions used.

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Table 1. The comparison of fitting results of 6a, 8 and 9 in PBLG/PELG alignment medium. 6a RMS [Hz]a

8 R2

RMS [Hz]a

[%]a

a

9 R2

RMS [Hz]a

[%]a

R2 [%]a

Cone

2.2

99.0

14.0

87.4

31.0

43.1

1,2-alt

18.0

38.6

14.1

92.2

20.8

82.9

C-paco

15.5

52.8

9.6

93.9

4.1

99.1

D-paco

15.8

59.8

5.1

98.7

34.9

38.3

The lower is the root mean square (RMS) and the higher is the square of correlation coefficient (R2),

the better is the fit.

Compound 7, prepared analogously to 3a/3b from the partial cone conformer of tetrapropoxy calix[4]arene,8 was used to ascertain if the rearrangement depends on the conformation of starting calixarenes. As shown in Scheme 3, the partial cone conformer 7 can generally provide two different products from the acid-catalyzed reaction depending on the position of the methylene bridge being shifted. The rearrangement of the blue colored bond in 7 leads to the formation of isomer 8, while the shift of the red colored bond gives isomer 9. The reaction of 7 with Nafion-H® in CHCl3 led to successful isolation (preparative TLC) of these two expected products 8 (D-paco) and 9 (C-paco) in 14% and 15% yields, respectively, showing no regioselectivity (red versus blue). To distinguish between the two possible structures of 8 (D-paco) and 9 (C-paco), and also to confirm independently the cone conformation of 6a, NMR techniques were utilized. Unfortunately, the NOE experiments, the most frequently used method for distinguishing among various conformers, failed due to a number of overlaps in the aromatic region. Thus, we used the method of measuring the RDCs

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(Residual Dipolar Couplings),9 which was recently successfully applied in the field of conformational analysis of calixarenes.10

Figure 2. The fitting procedure results of 9 for the C-paco, D-paco, cone and 1,2-alt – correlation between back-calculated and experimental RDCs in PELG alignment medium. Structural proposals were optimized by ab initio calculation in Gaussian03* (RB3LYP/6-31G level).

This technique is based on the measuring of an anisotropic through-space dipole-dipole interaction, which is averaged to zero in the solution due to a fast molecular tumbling. In the case that a sample is partially aligned, the anisotropic interaction becomes observable and contributes to the J scalar interaction. Due to the fact that the dipolar interaction (D) depends on the distance of the coupled nuclei and their orientation within the external magnetic field, the values of RDCs include the detailed spatial information. Thus, the RDCs method provides “long-range” information in contrast to data obtained from 3J scalar coupling constants or NOE experiments. To prepare the partially aligned samples of the calix[4]arenes 6a, 8 and 9, poly-γ-benzyl-l-glutamate (PBLG) or poly-γ-ethyl-l-glutamate (PELG), a lyotropic liquid crystal based alignment medium was used. 11 The one-bond heteronuclear residual dipolar coupling constant 1DC-H needed for the calculation of RDCs was obtained from the following equation: 1TC-H = 21DC-H + 1JC-H, where 1TC-H is the one-bond

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heteronuclear coupling constant (total splitting) elucidated from coupled

13

C NMR or CLIP-HSQC

spectra of anisotropic solution and 1JC-H represents the one-bond heteronuclear scalar coupling constant elucidated from coupled 13C NMR or CLIP-HSQC spectra of isotropic solution. We used the ab initio calculation (RB3LYP/6-31G level in Gaussian03)12 to generate four initial input structures (structural proposals) of 6a, 8 and 9 (C-paco, D-paco, cone and 1,2-alt). Afterwards, the four optimized structure of 6a, 8 and 9 (Figure 2 for 9 and Figures S2 and S3 for 6a and 8) together with the experimental one bond RDCs (1DC-H) were used for the fitting procedure in the program MSpin.13 The comparison of the observed and the back calculated RDCs for all four structural proposals resulted in excellent linear correlations for cone of compound 6a, D-paco of compound 8 and for C-paco of compound 9 (Figure 2, S2, S3 and Table 1). The correlations for other conformers gave poor agreement between the experimental and the calculated data. Thus, using the RDCs it was possible to unambiguously determine the spatial structures of 6a (cone) and both 8 (D-paco) and 9 (C-paco), which was not possible to establish by using other NMR techniques. The findings described above suggest several assumptions: i) the rearrangement does not depend on the starting conformation as the same reaction was observed for the cone, partial cone and even the mobile starting compounds (6a, 7 and 6b, respectively); ii) no regioselectivity was observed in the case of partial cone conformation, indicating, that the main driving force is the release of the internal strain and planarization of the distorted fluorene moiety, irrespective of the position being cleaved; iii) the starting conformation (cone, partial cone) is fully conserved in the rearranged products suggesting that the rearrangement does not proceed via a benzylic carbocation of type F (Scheme 4) where the conformational changes could occur.

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Scheme 4. Tentative mechanism of the rearrangement

To explain the above described findings we have carried out quantum chemical calculations using ORCA 4.0.0.2.14 The geometries were optimized using B3LYP DFT functional15 with def2-TZVP basis set16 and def2/J fitting basis,17 employing RIJCOSX approximation18 for evaluation of Hartree-Fock exchange, using the default values for DFT and GridX4 COSX grid. The dispersion correction with Becke-Johnson damping scheme (D3BJ) has been applied.19. The protonated calixarene A (Scheme 4) resembles the typical Wheland intermediate of electrophilic aromatic substitution with its reactivity. Due to the ring strain of 24 kcal/mol,7 the system is prone to relaxation via the substituent migration/rearrangement. The relative energies of the corresponding rearranged species B, C, E and F are shown in Table 2 and combine the effects of a ring strain and electron donating propoxy group in position 1- of the fluorene moiety. The most favorable position for the carbocation migration is 4- (structure B), in accordance with the experimental findings. Upon the migration, the ring strain is reduced by 7 kcal/mol. The final deprotonation (the formation of product 6a) leads to overall stabilization by 15 kcal/mol, removing most of the ring strain. The electronic effects are most pronounced at line 3 of Table 2; the system would relax by 8.2 kcal/mol in neutral compound D, on the other hand, the corresponding cationic intermediate C is strongly disfavored.

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Table 2. Relative electronic energies of possible reaction intermediates in kcal/mol calculated at B3LYP/def2-TZVP. Species

Protonated

Neutral

1

3a (starting)

6.5 (A)

15.2 (3a)

2

6a (product)

0 (B)

0 (6a)

3

1,2-rearr.

25.3 (C)

7.0 (D)

4

1,3-rearr.

10.9 (E)

-

5

open structure

15.5 (F)

-

The overall reaction mechanism is supposed to be practically identical for all starting conformations. The conservation of the starting conformation could be explained by considering the side reactions. Should conformation change occur, the phenyl ring rotation demands de-cyclization, leading ultimately to degradation and polymer products. The barrier for this process can be estimated from the open structure, similar to π-complex, where the benzylic cation is weakly bound to the aromatic system and is almost free to interact with other molecules. Obviously, any isolable product keeps its original conformation as the migration happened faster than the ring flipping. The open structure energy could also serve as an estimation of the upper limit of the reaction barrier.

CONCLUSIONS In conclusions, the meta-bridged calixarenes exhibit a reasonably amended reactivity, compared with common calix[4]arene derivatives, which is induced by the release of internal strain. As documented

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by the reaction of bridged calix[4]arene with P2O5 or Nafion-H® the macrocyclic product is formed where the methylene bridge next to the fluorene moiety is shifted from position 2 to position 4 of the phenolic subunit. As revealed by single crystal X-ray analysis and by application of the RDC method, the rearrangement occurs without altering the original conformation of starting calixarenes.

EXPERIMENTAL SECTION General Information. All chemicals were purchased from commercial sources and used without further purification. Melting point were measured on Heiztisch Mikroskop-Polytherm A (Wagner & Munz, Germany). The IR spectra were measured on FT-IR spectrometer Nicolet 740 in KBr transmission mode. NMR spectra were recorded on spectrometers Agilent 400-MR DDR2 (1H: 400 MHz, 13C: 100 MHz), Bruker Avance DRX 500 (1H: 500 MHz, 13C: 125 MHz) and Bruker 600 AvanceIII (1H: 600.1 MHz, 13

C: 150.9 MHz) spectrometers. The mass analyses were performed using ESI technique on a FT-MS

(LTQ Orbitrap Velos) spectrometer. Purity of the substances and courses of the reactions were monitored by TLC using TLC aluminum sheets with Silica gel 60 F254 (Merck) and analyzed at 254 or 365 nm. Preparative TLC chromatography was carried out on 20x20 cm glass plates covered by Silica gel 60 GF254 (Merck).

The starting compounds and intermediates were prepared according to the published procedures: 23a, 3a6, 3b6, 78. All organomercurial derivatives are considered potentially hazardous and require special consideration.

General procedure for the intramolecular methylene shift

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Bridged calixarene was dissolved in chloroform (30 mL) and Nafion-H or P2O5 was added. The mixture was stirred at room temperature and the progress of the reaction was monitored by TLC. After the disappearance of the starting compound (in the case of P2O5 usually 30 minutes, in the case of NafionH 3 days), a saturated solution of NaHCO3 (5 mL) was added, the organic layer was washed with water (10 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by preparative TLC. Calixarene 6a: Calixarene 6a was prepared according to general procedure for the methylene shift using calixarene 3a (0.037 g, 0.063 mmol) and P2O5 (0.010 g, 0.071 mmol). The title compound (0.013 g, 35%) was obtained as a colourless, highly viscous oil by preparative TLC (hexane:CH2Cl2 1:1). 1H NMR (600.1 MHz, CDCl3, 298 K): δ = 7.17 (2H, 2 x d, J (3,4) ≈7.8, CH-A3 and CH-C3), 7.10 – 7.05 (2H, m, CHC3 and CH-D3), 6.94 – 6.89 (2H, m, CH-D5, CH-D4), 6.88 (1H, dd, J (3,4)= J (4,5)= 7.5, CH-C4), 6.74 (1H, d, J (2,3) =8.0, CH-A2), 6.00 (1H, d, J (2,3) = 8.2, CH-B4), 5.66 (1H, d, J (3.4) =8.2, CH-B3), 4.59 (1 H, d, J =18.2, bridge-CH2-AD), 4.42 (1 H, d, J =18.2, bridge-CH2-AD), 4.28 (1 H, d, J =15.4, bridge-CH2-BC), 4.17 - 4.08 (2 H, m, OCH2-A), 4.11 (1 H, overlapped d, J =12.3, bridge-CH2-CD), 4.05 – 4.02 (2 H, m, OCH2-B), 3.89 (1 H, d, J =21.6, bridge-CH2-AB), 3.78 (1 H, d, J =21.6, bridge-CH2-AB), 3.46 (1 H, d, J =15.4, bridgeCH2-BC), 3.44 – 3.40 (1H, m, OCH2-C), 3.26 – 3.22 (1H, m, OCH2-C), 3.11 – 3.07 (1H, m, OCH2-D), 3.06 – 3.03 (1H, overlapped m, OCH2-D), 3.03 (1 H, overlapped d, J =12.3, bridge-CH2-CD), 1.99 – 1.79 (4H, 2 x m, CH2-A, CH2-B), 1.40 – 1.29 (2H, m, CH2-C), 1.14 (3 H, t, J =7.6, CH3-A), 1.12 (3 H, t, J =7.4, CH3-B), 1.09 – 1.01 (1H, m, CH2-D), 0.76 – 0.68 (1H, m, CH2-D), 0.66 (3 H, t, J =7.6, CH3-C), 0.66 (3 H, t, J =7.4, CH3-D). 13C NMR (150.9 MHz, CDCl3, 298 K): δ = 157.9 (kv. C-C1), 156.4 (kv. C-D1), 156.0 (kv. C- B1), 154.0 (kv. C-A1), 143.7 (kv. C-A5), 141.5 (kv. C-B5), 139.8 (kv. C-C2), 136.5 (kv. C-C6), 134.7 (kv. C-D6), 133.2 (kv. C-B2), 133.4 (kv. C-B6), 131.4 (kv. C-A6), 130.9 (kv. C-D2), 130.0 (CH –A3), 129.3 (CH –D5), 129.04 (CH –D3), 128.99 (CH –B3), 128.5 (CH –C3), 127.9 (CH –C5), 125.9 (kv. C-A4), 123.2 (CH –D4), 121.8 (CH –C4), 119.3 (CH –B4), 108.4 (CH –A2), 75.81 and 75.76 (OCH2- B and OCH2- D), 75.1 (OCH2C), 69.9 (OCH2- A), 40.8 (bridge CH2- AD), 32.5 (bridge CH2-BC), 31.9 (bridge CH2-AB), 29.2 (bridge CH2CD), 23.7 (CH2- B), 22.7 and 22.6 (CH2- C and CH2- A), 22.3 (CH2- D), 10.7 and 10.6 (CH3- A and CH3- B),

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10.1 and 9.9 (CH3- C and CH3- D). IR (KBr): ν 1456.0, 1206.1 cm-1. HRMS (ESI+): C40H46O4 calcd for 613.3288 [(M+Na)+]; found: 613.3293 [(M+Na)+]. Calixarene 6b: Calixarene 6b was prepared according to general procedure for the methylene shift using calixarene 3b (0.056 g, 0.12 mmol) and P2O5 (0.017 g, 0.12 mmol). The title compound (0.011 g, 20%) was obtained as a colourless amorphous solid by preparative TLC (hexane:ethyl acetate 100:15), mp: 206-208 °C. 1H NMR (CDCl3, 600 MHz, 298 K): 1H NMR (600.1 MHz, CDCl3, 298 K): δ = 7.24 (1H, d, J (2,3) =8.2, CH-A3), 7.13 (1H, d, J (4,5) =7.5, CH-C5), 7.10 (2H, br d, CH-D, CH-C3), 6.92 – 6.83 (3H, m, CHD, CH-D4, CH-C4), 6.74 (1H, d, J (2,3) =8.2, CH-A2), 6.17 (1H, d, J (3,4) =8.2, CH-B4), 5.82 (1H, d, J (3,4) =8.2, CH-B3), 4.63 (1 H, d, J =18.1, bridge-CH2-AD), 4.40 (1 H, d, J =18.1, bridge-CH2-AD), 4.33 (1 H, d, J =14.6, bridge-CH2-BC), 4.00 (3 H, s, CH3-A), 3.98 (3 H, s, CH3-B), 3.96 (1 H, overlapped d, J =12.3, bridgeCH2-CD), 3.93 (1 H, d, J =21.8, bridge-CH2-AB), 3.86 (1 H, d, J =21.8, bridge-CH2-AB), 3.53 (1 H, d, J =14.6, bridge-CH2-BC), 3.15 (3 H, s, CH3-C), 3.02 (1 H, d, J =12.3, bridge-CH2-CD), 2.90 (3 H, s, CH3-D). 13C NMR (150.9 MHz, CDCl3, 298 K): δ = 158.6 (kv. C-C1), 157.6 (kv. C-B1), 157.3 (kv. C- D1), 154.5 (kv. C-A1), 143.7 (kv. C-A5), 142.2 (kv. C-B5), 139.2 (kv. C-C2), 136.8 (kv. C-C6), 134.9 (kv. C-D6), 133.4 and 133.3 (kv. C-B2 and B6), 131.0 (kv. C-D2), 130.6 (kv. C-A6), 130.0 (CH –A3), 129.29, 129.28 and 129.1(CH –B3, D3 and D5), 128.7 (CH –C3), 127.8 (CH –C5), 126.2 (kv. C-A4), 123.4 (CH –D4), 122.2 (CH –C4), 119.9 (CH –B4), 106.7 (CH –A2), 61.7 (CH3- B), 61.0 (CH3- D), 59.9 (CH3- C), 55.3 (CH3- A), 40.3 (bridge CH2AD), 32.0 (bridge CH2-BC), 31.7 (bridge CH2-AB), 29.5 (bridge CH2-CD). IR (KBr): ν 1466.7 cm-1. HRMS (ESI+): C32H30O4 calcd for 501.2036 [(M+Na)+]; found: 501.2040 [(M+Na)+]. Procedure for the synthesis of compound 8 and 9 Calixarenes 8 and 9 were prepared according to the general procedure for the methylene shift using calixarene 7 (0.091 g, 0.15 mmol) and Nafion-H (0.030 g, 0.12 mmol). The products were obtained by preparative TLC (hexane:CH2Cl2 1:1). Compound 8 (0.13 g, 14%) and compound 9 (0.14 g, 15%) were both obtained as colourless, highly viscous oils.

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Calixarene 8: 1H NMR (CDCl3, 600.1 MHz, 298 K): δ = 7.58 (d, 1H, J(3,4)= 8.1 Hz, CH-B4), 7.24 (d, 1H, J(3,4)= 7.4 Hz, CH-C3), 7.22 (d, 1H, J(3,4)= 8.0 Hz, CH-A3), 7.17 (d, 1H, J(4,5)= 7.4 Hz, CH-C5), 6.98 (dd, 1H, J(3,4)=J(4,5)= 7.4 Hz, CH-C4), 6.78 (d, 1H, J(4,5)= 7.4 Hz, CH-D5), 6.72 (d, 1H, J(2,3)= 8.0 Hz, CH-A2), 6.47 (dd, 1H, J(3,4)=J(4,5)= 7.4 Hz, CH-D4), 6.21 (d, 1H, J(3.5)= 7.4 Hz, CH-D3), 5.94 (d, 1H, J(3,4)= 8.1 Hz, CH-B3), 4.86 (d, 1H, J= 14.4 Hz, bridge-CH2-AD), 4.12 (d, 1H, J= 14.8 Hz, bridge-CH2-BC), 4.12–4.01 (m, 3H, OCH2-A, OCH2-B), 3.98–3.92 (m, 1H, OCH2-B), 3.84 (d, 1H, J= 15.9 Hz, bridge-CH2-CD), 3.78 (d, 1H, J= 15.9 Hz, bridge-CH2-CD), 3.77–3.62 (m, 1H, OCH2-D), 3.67 (d. 1H, J= 21.8 Hz, bridge-CH2-AB), 3.59 (d, 1H, J= 21.8 Hz, bridge-CH2-AB), 3.51 (2 x d overlapped, 2H, bridge-CH2-BC and bridge-CH2-AD), 3.28 (t, 2H, J= 6.9 Hz, OCH2-C), 1.94–1.86 (m, 2H, CH2-A), 1.86–1.71 (m, 4H, CH2-B and CH2-D), approx. 1.05 (m overlapped by methyls, 2H, CH2-C), 1.12 (t, 3H, J= 7.8 Hz, CH3-A), 1.10–1.03 (m, 6H, CH3-B and CH3D), 0.35 (t, 3H, J= 7.4 Hz, CH3-C) ppm.13C NMR (CDCl3, 150.9 MHz, 298 K): δ = 158.2 (kv. C-C1), 155.7 (kv. C-D1), 154.5 (kv. C-A1), 154.2 (kv. C- B1), 142.9 (kv. C-A5), 140.6 (kv. C-C2), 140.5 (kv. C-B5), 134.7 (kv. C6), 134.1(kv. C-B2), 133.9 (kv. C-D2), 132.8 (kv. C-D6), 131.7 (kv. C-A6), 131.4 (kv. C-B6), 130.4 (CH –B3), 130.2 (CH –A3), 129.8 (CH –C5), 129.7 (CH –C3), 129.7 (kv. C-A4), 129.5 (CH – D5), 129.2 (CH – D3), 122.2 (CH –D4), 121.8 (CH –C4), 119.2 (CH –B4), 108.1 (CH –A2), 75.2 (OCH2- D), 75.0 (OCH2- B), 73.3 (OCH2- C), 69.6 (OCH2- A), 38.7 (bridge CH2- CD), 32.9 (bridge CH2-BC), 32.3 and 32.2 (bridge CH2AB and bridge CH2-AD), 23.72 and 23.69 (CH2- B and CH2- D), 22.9 (CH2- A), 22.6 (CH2- C), 11.1, 10.64, 10.63 and 9.71 (CH3- A, CH3- B, CH3- C, CH3- D).IR (KBr): ν 1450.3 cm-1. HRMS (ESI+): C40H46O4 calcd for 613.3288 [(M+Na)+]; found: 613.3294 [(M+Na)+]. Calixarene 9: 1H NMR (CDCl3, 600.1 MHz, 298 K): δ = 7.23 (d, 1H, J(3,4)= 7.6 Hz, CH-D3), 7.19 (d, 1H, J(4,5)= 7.2 Hz, CH-D5), 7.12 (d, 1H, J(3,4)= 6.5 Hz, CH-C3), 7.08–7.03 (m, 2H, CH-A3, CH-D4), 7.00 (d, 1H, J(3,4)= 8.0 Hz, CH-B3), 6.67 (d, 1H, J(4,5)= 7.1 Hz, CH-C5), 6.62 (dd, 1H, J(2,3)= 8.1 Hz, CH-A2), 6.59 (dd, 1H, J(3.4)=J(4.5)= 7.5 Hz, CH-C4), 6.42 (d, 1H, J(3,4)= 8.0 Hz, CH-B4), 4.67 (d, 1H, J= 18.4 Hz, bridgeCH2-AD), 4.31 (d, 1H, J= 18.4 Hz, bridge-CH2-AD), 4.10–4.00 (m, 3H, OCH2-B, OCH2-A), 3.98–3.92 (m, 1H, OCH2-A), 3.81 (d, 1H, J = 11.6 Hz, bridge-CH2-BC), 3.72 (d, 1H, J= 11.6 Hz, bridge-CH2-BC), 3.83–3.60 (m, 2H, OCH2-C), 3.69 (d, 1H, J= 14.9 Hz, bridge-CH2-CD), 3.60 (d, 1H, J= 21.8 Hz, bridge-CH2-AB), 3.53

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(d, 1H, J= 21.8 Hz, bridge-CH2-AB), 3.45 (d, 1H, J= 14.9 Hz, bridge-CH2-CD), 3.05–2.98 (m, 1H, OCH2-D), 2.75–2.68 (m, 1H, OCH2-D), 1.99–1.85 (m, 6H, CH2-A, CH2-B, CH2-C), 1.14, 1.08 and 1.08 (3 x t, 9H, CH3A, CH3-B and CH3-C), 0.59–0.47 (m, 1H, CH2-D), 0.24 (t, 3H, J= 7.2 Hz, CH3-D), 0.23–0.12 (m, 1H, CH2-D) ppm.13C NMR (CDCl3, 150.9 MHz, 298 K): δ = 156.7 (kv. C-D1), 155.5 (kv. C-C1), 154.2 (kv. C-A1), 152.8 (kv. C- B1), 143.7 (kv. C-A5), 142.8 (kv. C-B5), 136.6 (kv. C-C2), 134.7 (kv. D6), 134.2 (kv. C-B6), 133.3 (kv. C-C6), 131.8 (kv. C-B2), 131.3 (CH –D5), 130.9 (kv. C-D2), 130.7 (kv. C-A6), 130.0 (CH –D3), 129.7 (CH –A3), 129.3 (CH –C5), 127.4 (CH – B3), 126.9 (CH –C3), 125.5 (kv. C-A4), 122.6 (CH –D4), 121.9 (CH –C4), 119.4 (CH –B4), 108.2 (CH –A2), 75.7 (OCH2- B), 75.3 (OCH2- C), 73.8 (OCH2- D), 69.7 (OCH2- A), 40.2 (bridge CH2- AD), 38.1 (bridge CH2-CD), 34.3 (bridge CH2-BC), 31.5 (bridge CH2-AB), 23.7, 23.6, 22.7 and 22.0 (CH2- A, CH2- B, CH2- C and CH2- D), 11.1, 10.8, 10.6 and 9.5 (CH3- A, CH3- B, CH3- C, CH3- D) ppm. IR (KBr): ν 1452.2 cm-1. HRMS (ESI+): C40H46O4 calcd for 613.3288 [(M+Na)+]; found: 613.3293 [(M+Na)+].

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Copies of 1H,

13

C, COSY, HMBC, HMQC NMR, HRMS and IR spectra of compounds 6a, 6b, 8, 9,

procedures for the preparation of anisotropic samples for RDC measurements, temperature dependant 1H NMR spectra, quantum chemical calculations and X-ray crystallography data.

AUTHOR INFORMATION Corresponding Author: * E-mail: [email protected] ORCID

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Petr Slavík: 0000-0002-3326-6169 Martin Krupička: 0000-0002-9132-5825 Pavel Lhoták: 0000-0003-3617-6596

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This research was supported by the Czech Science Foundation (Grant 16-13869S). Financial support from specific university research (MSMT No 20/2017) is also acknowledged. Access to computing and storage facilities owned by parties and projects contributing to the National Grid Infrastructure MetaCentrum provided under the program "Projects of Large Research, Development, and Innovations Infrastructures" (CESNET LM2015042) is greatly appreciated.

REFERENCES 1) For selected books on calixarenes and their applications, see: (a) Neri, P.; Sessler, J. L.; Wang M. X. Eds. Calixarenes and Beyond, Springer Int. Publishing Switzerland, 2016, ISBN 978-3-319-31865-3. (b) Gutsche C. D. Calixarenes An introduction 2nd Edition, The Royal Society of Chemistry, Thomas Graham House, Cambridge, 2008. (c) Vicens, J.; Harrowfield, J.; Backlouti, L. Eds. Calixarenes in the Nanoworld; Springer, Dordrecht, 2007. (d) Asfari, Z.; Böhmer, V.; Harrowfield, J.; Vicens, J.; Eds. Calixarenes 2001, Kluwer Academic Publishers, Dordrecht, 2001. (e) Mandolini, L.; Ungaro, R. Calixarenes in Action; Imperial College Press; London, 2000. (2) For selected reviews on various calixarene-based receptors, see: (a) Siddiqui, S.; Cragg, P. J. Design and Synthesis of Transition Metal and Inner Transition Metal Binding Calixarenes. Mini-Reviews in Org.

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Chem. 2009, 6, 283. (b) Leray, I.; Valeur, B. Calixarene‐Based Fluorescent Molecular Sensors for Toxic Metals. Eur. J. Inorg. Chem. 2009, 24, 3525. (c) Matthews, S. E.; Beer, P. D. in Calixarenes 2001; pp. 421 (in ref 1d). (d) Lhoták, P. Anion Receptors Based on Calixarenes. Top. Curr. Chem. 2005, 255, 65. (e) Coquiere, D.; Le Gac, S.; Darbost, U.; Seneque, O.; Jabin, I.; Reinaud, O. Biomimetic and self-assembled calix[6]arene-based receptors for neutral molecules. Org. Biomol. Chem. 2009, 7, 2485. (g) Lhotak, P.; Kundrat, O. in Artificial Receptors for Chemical Sensors, Mirsky, V.; Yatsimirsky, A. Eds.; Wiley-VCH, Weinheim, 2011, pp. 249. (3) (a) Slavik, P.; Dudič, M.; Flídrová, K.; Sýkora, J.; Císařová, I.; Böhm, S.; Lhoták, P. Unprecedented meta-Substitution of Calixarenes: Direct Way to Inherently Chiral Derivatives. Org. Lett. 2012, 14, 3628. (b) Flídrová, K.; Böhm, S.; Dvořáková, H.; Eigner, V.; Lhoták P. Dimercuration of Calix[4]arenes: Novel Substitution Pattern in Calixarene Chemistry. Org. Lett. 2014, 16, 138. (4) For a recent review on meta-substituted calixarenes, see: Kundrat, O.; Lhoták, P. in ref 1a), pp. 4373. (5) (a) Slavík, P.; Eigner, V.; Lhoták, P. meta-Bridged calix[4]arenes with the methylene moiety possessing in/out stereochemistry of substituents. New. J. Chem. 2018, 42, 16642. (b) Tlustý, M.; Slavík, P.; Kohout, M.; Eigner, V.; Lhoták, P. Inherently Chiral Upper-Rim-Bridged Calix[4]arenes Possessing a Seven Membered Ring. Org. Lett. 2017, 19, 2933. (c) Tlustý, M.; Slavík, P.; Dvořáková, H.; Eigner, V.; Lhoták, P. Synthesis and Study of Calix[4]arenes bearing Azo Moieties at the meta Position. Tetrahedron, 2017, 73. 1230. (d) Slavík, P.; Eigner, V.; Lhoták, P. Shaping of Calix[4]arenes via Double Bridging of the Upper Rim. Cryst. Eng. Comm. 2016, 18, 4964. (e) Slavík, P.; Eigner, V.; Lhoták, P. Intramolecularly Bridged Calix[4]arenes with Pronounced Complexation Ability toward Neutral Compounds. Org. Let. 2015, 17, 2788. (f) Slavík, P.; Flídrová, K.; Dvořáková, H.; Eigner, V.; Lhoták, P. Meta-Arylation of Calixarenes using Organomercurial Chemistry. Org. Biomol. Chem. 2013, 11, 5528. (6) Flídrová, K.; Slavík, P.; Eigner, V.; Dvořáková, H.; Lhoták, P. meta-Bridged Calix[4]arenes: A Straightforward Synthesis via Organomercurial ChemistryChem. Commun. 2013, 49, 6749.

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