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Chemistry of 2,14-Dithiacalix[4]arene: Alkylation and Conformational Behavior of Peralkylated Products Daniel Kortus, Jiri Miksatko, Ondrej Kundrat, Martin Babor, Vaclav Eigner, Hana Dvorakova, and Pavel Lhotak J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01493 • Publication Date (Web): 23 Aug 2019 Downloaded from pubs.acs.org on August 26, 2019

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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The Journal of Organic Chemistry

Chemistry of 2,14-Dithiacalix[4]arene: Alkylation and Conformational Behavior of Peralkylated Products Daniel Kortus,† Jiří Mikšátko,† Ondřej Kundrát,† Martin Babor,ǂ Václav Eigner,§ Hana Dvořáková‡ and Pavel Lhoták†* †Department

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

5, 166 28 Prague 6, Czech Republic ǂSolid

State Department, UCTP, 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.

Corresponding Author: * E-mail: [email protected]

Table of Contents Graphic But

But

R O

R

But

But

But

But

R

O

O

S

S O

But

But

R

alkylation

alkylation

O

S O

R But

But

H

O H

O H

O

S

S

H

R O S

O R

O R But

But

ABSTRACT 2,14-Dithiacalix[4]arene, prepared on a multigram scale, was alkylated using the reaction conditions well-known from the chemistry of classical calixarenes or thiacalixarenes to study the specific conformational preferences and dynamic behavior of the corresponding tetraalkylated derivatives. As proved by the combination of the X-ray crystallography and dynamic NMR techniques, the presence of mixed bridges (-CH2- and -S- groups) within the basic skeleton brings about considerable changes in

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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

the mutual ratios of the individual conformers compared to the parent macrocycles. Interestingly, certain conformers, hardly accessible for common calixarenes/thiacalixarenes (e.g. 1,2-alternates) are easily prepared in very good yields in the case of 2,14-dithiacalix[4]arene, which makes this mixed-bridge system attractive as molecular scaffold for supramolecular applications.

INTRODUCTION In supramolecular chemistry, calixarenes1 have an important role, especially due to their preorganized structures with a tunable size and different 3D shapes of their cavity and particularly due to diverse ways of their chemical derivatization, which makes them popular as molecular scaffolds to design new self-assembly systems and/or receptors.2 The introduction of other moieties instead of methylene bridges has enriched a calixarene family with new members like thia-, aza-, oxa- and selena-calixarenes.3 Obviously, the presence of heteroatoms has resulted in different behavior of those systems showing sometimes highly unexpected properties;3 nevertheless, the most studied and the most common new members are so called thiacalixarenes,4 having four sulfur bridges. The presence of these sulfur moieties substantially changes the conformational preferences4b and, moreover, also leads to the dramatic shifts in chemical behavior of the system: while the common electrophilic aromatic substitutions (formylation, nitration, halogenation) of peralkylated calix[4]arenes yield para-substituted products,1b meta-substituted compounds can be principally obtained from thiacalix[4]arenes treated under almost the same reaction conditions.5 Therefore, a new system comprising simultaneously both methylene and sulfide bridges (Figure 1) could both possess features of the parent systems and bring its utilization in host-guest chemistry due to yet unexplored chemical properties, conformational preferences and complexation abilities. For


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example, the above-mentioned differences in regioselectivity can enable so far unknown or hardly accessible substitution patterns of calixarene scaffold applicable to design new types of receptors.

But

O H

But But

But

O O O H H H

But S

H

O

But But

But S

O O O H H H

But

But But

S

S

H

O

But

S O O O S H H H

Figure 1. Calix[4]arene, thiacalix[4]arene and the system possessing mixed bridges.

To the best of our knowledge, there are only few reports6 on the preparation of the mixed S/CH2 calixarenes. The synthetic approach to 2,14-dithiacalix[4]arene 1 shown in Scheme 1 uses the stepwise construction6a of linear tetraphenol III, starting from tert-butylphenol I, with acid-catalyzed macrocyclization as the final step (approach A). Obviously, this approach is time demanding and provides a very low overall yield. The reaction of formaldehyde with bisphenol II gives a mixture of cyclic oligomer containing 4, 6 and 8 phenols, which corresponds to 2+2, 3+3 and 4+4 condensation products, respectively (approach B).6b However, the necessity of chromatographic separation of the resultant mixture makes this approach unsuitable for a large-scale preparation. During our on-going research on thiacalixarene functionalization, we published6c a simple and scalable synthesis of the mixed-bridge system 1 which comprises of the alternating sulfide and methylene bridging moieties. The condensation of an appropriate linear bisphenol building blocks II and IV which are easily accessible (Scheme 1), is used in the approach C. The final macrocyclization step can be accomplished with 58% yield, moreover giving substantially pure calixarene 1, which makes this approach easily scalable. Although the preparation of compound 1 has been described, the properties of this system were not studied at all. Nothing is known about its conformational behavior, complexation properties or the



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chemistry and/or reactivity patterns of the basic macrocycle. In this contribution, our research of the alkylation of 2,14-dithiacalixarene 1, the conformational preferences and dynamic behavior of peralkylated products is reported, since elucidating these properties is the key prerequisite for further applications of these compounds in supramolecular chemistry.

Scheme 1. Three different approaches to 2,14-dithiacalix[4]arene 1 But

But

But

But

But

But

But

SCl2 OH I

OH

II

OH CH2=O PTSA B

CH2=O KOH Bu

t

Bu

OH

S OH

OH

OH

HCl/AcOH

S OH OH HO OH

+ II HO

III OH

A

But

t

OH

OH

But

OH

S

S

S

S 1

PTSA C

But

But

IV

RESULTS AND DISCUSSION The starting 2,14-dithiacalix[4]arene 1 was prepared on a multigram scale using the recently published procedure6c based on the fragment condensation of building blocks II and IV (Scheme 1). This basic scaffold was then investigated for the exhaustive alkylation to find the conformational preferences and the yields of the corresponding conformers (atropisomers) in the reaction mixtures. Since the lower rim alkylation (phenolic hydroxyls) is the most widely applied method for the immobilization of calix[4]arene/thiacalix[4]arene conformers, the standard protocols well-known from the literature1-3 were applied. Tetramethyl ether 2 was prepared in 84 % yield via alkylation of compound 1 with methyl iodide in the presence of NaH in DMF (Scheme 2). The HRMS ESI+ spectrum of 2 showed a signal at m/z = 763.3833


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which is in good agreement with the [M+Na]+ cation predicted for the product (m/z = 763.3825). The 1H

NMR spectrum acquired at room temperature (298 K, CDCl3) revealed a simple set of five singlets

seemingly reflecting the C2 symmetry of the system. However, the noticeable broadening of the peaks indicated the time-averaged nature of signals resulting from fast chemical exchange between several conformations. In this context, the behavior of mixed bridge system resembles that of both parent macrocycles, which are also conformationally mobile in the form of methoxy derivatives.7 To gain better insight into this equilibrium, the conformational behavior of 2 was studied by means of temperature dependent 1H NMR spectroscopy in CD2Cl2. However, even at the lowest accessible temperature (173 K) the large width of the resonances did not allow the assignment of individual conformers (see ESI). Scheme 2. Alkylation of 2,14-dithiacalix[4]arene 1 But

But

R O S Bu

t

Bu

O

O

S OH 1

O

or NaH, R-I

2

R O

+

S

S O

But

Bu

Bu

t

But

Bu 1,3-alternate

+

But

S

But

But R

O R

O

O

R

OMe

OMe 2

2

+

S

t

Bu

6Et R = Et 6Pr R = Pr 6Bu R = Bu

R O S

O R

R

partial cone

S

O S

But


But O

R

t

R

NaH/DMF CH3I

O

R t


But

O

R

1,2 (S)-alternate


R

O

R

R

R

R O

S

S

+

cone

M2CO3, R-I

OH

O

R

R

t

S

O

But

But

But

But

But

But

O R

1,2 (C)-alternate

But

But


As indicated in Scheme 2, the introduction of bulkier substituents into the lower rim of compound 1 could afford up to five theoretically possible conformers 3-7. Compared to calix[4]arene or thiacalix[4]arene chemistry, the conformational diversity is more complex due to the lower symmetry of the basic skeleton, leading to the appearance of two different 1,2-alternate conformers. Depending on the bridges used for the inversion, one can recognize either isomer 4 (S-bridges between anti-



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oriented aromatic rings, called 1,2-(S) alternate) or isomer 7 (CH2-bridges between anti-oriented aromatic subunits, assigned as 1,2-(C) alternate), see Fig. 2.

syn-orientation (4)

anti-orientation (7) R

H O H R

O

R

equatorial (e)

O

H

H O H R

O

R

axial (a)

O H R isoclinal (i)

Figure 2. Mutual orientation of the neighboring aromatic rings in the 1,2-alternate conformers 4 and 7, with stereochemical assignments of the corresponding C-H bonds in methylene bridges.

To introduce ethyl groups into the lower rim of compound 1, we applied the same conditions as for methylation. Stirring 1 with EtI/NaH in DMF at room temperature afforded the 1,2-(S) alternate 4Et in a low yield (column chromatography on silica gel, 15% isolated yield) accompanied by an inseparable mixture of 1,3-alternate 5Et and partial cone 6Et conformers (53%). Interestingly, the cone conformer 3Et, which is typically obtained as the major product in the case of calix[4]arene,1b was not observed at all in the crude reaction mixture, and the same holds for the 1,2-(C) alternate 7Et. The reaction of 1 with ethyl iodide in the presence of K2CO3 (acetone, 7 days reflux) gave 1,2-(S) alternate 4Et as the main product (58%) and essentially the same result was obtained for Cs2CO3 as the base. Again, the inseparable mixture of 5Et and 6Et was obtained as the byproduct in both cases (20%). The formation of the 1,2-alternate conformer in direct peralkylation reaction is unique8 for the calixarene/thiacalixarene chemistry. On the other hand, ethyl group is too small to immobilize conformation completely, as documented for tetraethoxy-tert-butylcalix[4]arene which was isolated7a as the partial cone conformer, but could be isomerized into an equilibrium mixture of all possible conformers7a by heating at 405 K for 12 hours. Bearing this in mind, we heated isomer 4Et in CDCl2-


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CDCl2 at 403 K for two days observing no changes in the 1H NMR spectrum. The same result was obtained upon heating 4Et to 443 K overnight in o-dichlorobenzene-d4. The above results suggested that 1,2-(S) alternate 4Et is thermodynamically the most stable conformer. To support this assumption, conformational behavior of the crude reaction mixture formed by the alkylation of 1 with EtI/NaH was studied using dynamic NMR technique. Thus, the solution of the partial cone 6Et, 1,3-alternate 5Et and 1,2-(S) alternate 4Et in 62%:23%:15% ratio, respectively, was gradually heated in CDCl2-CDCl2 up to 393 K. As shown in Fig. 3, the ratio of 4Et gradually increased, finally leaving 4Et as the only conformer present in the mixture at this temperature. Cooling the NMR sample back to room temperature had no impact affording the 1,2-(S) alternate 4Et as a single isomer. Thus, by means of thermal isomerization of the crude reaction mixture the 1,2-alternate conformer was obtained as the sole product of the alkylation reaction which is unprecedented for calixarene/thiacalixarene chemistry.

Figure 3. The variable temperature 1H NMR spectra (400 MHz, C2D2Cl4) of the crude mixture of 6Et (green circles), 5Et (blue) and 4Et (red) in 62%:23%:15% ratio (at 298 K).



The corresponding conformation assignment for 4Et-6Et was easily accomplished by analogy with classical calixarenes owing to the presence of methylene bridges. The number of signals and splitting patterns are characteristic for an individual conformer and represent a perfect tool for the structure elucidation. Thus, the presence of equatorial and axial methyleme protons in 4Et results in two doublets in the CH2 region of the 1H NMR spectrum (4.32 ppm, eq. and 3.18 ppm, ax.) with a typical geminal coupling constant (12.6 Hz). The single-crystal X-ray study of 4Et provided the ultimate structural evidence and revealed the molecule in the 1,2-alternate conformation adopting the monoclinic system, space group P21/n. As shown in Figure 4, the presence of two sulfur bridges gave rise to the rhombic shape of the cavity with remarkably elongated main diagonal (S···S distance = 8.409 Å) compared to the minor C···C diagonal (6.582 Å). The difference in both diagonals (about 1.8 Å) is quite noteworthy, especially if we consider similar values for the 1,2-alternates in calix[4]arene (~ 1.2 Å)8a or thiacalix[4]arene (~ 1.4 Å)9 series.

a)

b)

Figure 4. Single crystal X-ray structures of 1,2-(S) alternate 4Et: (a) side-view, (b) top-view (the bridging atoms are shown as balls for better clarity). To gain a deeper insight into the thermodynamic stability of individual conformers, we also attempted to evaluate free energies of all possible conformations 3Et-7Et using the B3LYP/6-311G(d,p) level in


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ORCA).10 The computation suggested the partial cone 6Et to be the most stable conformer (0 kcal/mol, relative energy), followed by the 1,3-alternate 5Et (3.5 kcal/mol) and the cone 3Et (4.3 kcal/mol) conformers. The free energy of both 1,2-alternates 4Et and 7Et was approximately equal (7.9 kcal/mol), suggesting 4Et and 7Et to be the least stable of all five conformers. The sharp contrast of the theoretical predictions to the experimental results, therefore, indicates the overall unsuitability of the above method for mixed-bridge systems, despite previous successful applications for thiacalixarene analogues.5a, 5b, 11 To introduce propyls to the lower rim of 1, the standard alkylation protocol was used again. Thus, reaction with propyl iodide in the presence of NaH in DMF (see Table 1) led to the formation of the cone 3Pr in 59% yield. While the preparation of cone conformers within classical calix[4]arene series is routine,1b the same reaction on thiacalix[4]arene analogues does not lead to the cone at all.12 Consequently, p-tert-butylthiacalix[4]arenes immobilized in the cone conformation by lower alkyls are so far entirely inaccessible. In this perspective, the facile isolation of the cone conformer 3Pr makes mixed-bridge system 1 a very good candidate for further supramolecular applications.

TABLE 1. Reaction Conditions for Alkylation of 1 with Alkyl Iodides Base

R-I

Solvent

Reaction time (days)

3R (%)

4R (%)

5R (%)

6R (%)

(cone)

(1,2(S)-alt)

(1,3-alt)

(paco)

Temp.

Cs2CO3

EtI

acetone

7

reflux

0

58

a)

a)

NaH

PrI

DMF

7

rt

59

0

0

0

K2CO3

PrI

acetone

7

reflux

0

6

17

20

K2CO3

PrI

CH3CN

7

reflux

0

17

16

19

Cs2CO3

PrI

acetone

7

reflux

0

12

52

2

Cs2CO3

PrI

CH3CN

7

reflux

0

32

52

4

NaH

BuI

CH3CN

7

rt

49

0

0

0

K2CO3

BuI

CH3CN

7

reflux

0

19

26

23



a)

Inseparable mixture of 1,3-alternate 5Et and partial cone 6Et conformers (20%).

The alkylation with PrI in the presence of carbonates (K2CO3, Cs2CO3) in boiling solvent (acetone or acetonitrile) afforded a mixture of three conformers 4Pr, 5Pr, and 6Pr, the ratio of which was highly dependent on the reaction conditions (Table 1). The individual isomers 4Pr and 5Pr were separated using radial chromatography (Chromatotron®) on silica gel with cyclohexane:CH2Cl2 15/1 (v/v), compound 6Pr was crystallized from dichloromethane /methanol. It is worth mentioning that the partial cone conformers based on 2,14-dithiacalix[4]arene 1 are inherently chiral systems which makes them unique among other conformations. The formation of 6Pr thus represents the straightforward procedure for preparation of inherently chiral calixarene-based platforms. All four tetrapropoxy isomers were identified using the combination of HRMS ESI+ and 1H/13C NMR spectroscopy. Thus, the 1H NMR spectrum (CDCl3) of 3Pr exhibited two doublets with typical geminal coupling constants (12.9 Hz) at 3.12 and 4.56 ppm, respectively, corresponding to the equatorial and axial methylene protons. Moreover, the singlet from the upper rim tert-butyl (1.08 ppm), together with the triplet (1.02 ppm) from the methyl hydrogens of propyl groups, are in a perfect agreement with the symmetry of the cone conformation. While the propyl groups are bulky enough to prevent calix[4]arene scaffold from any thermally induced conformation switching,1b the corresponding derivatives of thiacalix[4]arene are still able to flip through the cavity at high temperatures. For instance, refluxing tetrapropoxy thiacalix[4]arene (1,3alternate) in 1,1,2,2-tetrachlorethane for 15 days yields a mixture containing cone (27%), partial cone (52%), 1,3-alternate (12%) and 1,2-alternate (8%) conformers.8c Since dithiacalixarene 1 comprises intrinsic features of both calixarene and thiacalixarenes, we wondered what type of behavior would prevail in this case. Thus, heating the cone 3Pr in C2D2Cl4 at 403 K for 30 days provided a complete


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transformation into the partial cone 6Pr conformer (Fig. 5). On the other hand, 1,2-alternate 4Pr, 1,3alternate 5Pr and the partial cone 6Pr remained unchanged under identical conditions.

Figure 5. Heating of cone 3Pr in C2D2Cl4 at 403 K for 20 days.

When cone 3Pr was heated in o-dichlorobenzene-d4 at 443 K for 72 h, the formation of a mixture containing partial cone 6Pr (83%), 1,3-alt 5Pr (8 %) and remaining 3Pr (9%) was observed. The same conditions applied to 1,3-alternate 5Pr slowly led (in 21 days) to a mixture with the partial cone 6Pr in 41:59 ratio, while 1,2-alternate 4Pr and the partial cone 6Pr remained unchanged under these conditions. Based on the above findings, we can conclude that propyl groups are not bulky enough for the complete immobilization of the corresponding conformers in the mixed-bridge systems based on macrocycle 1. Nevertheless, very harsh conditions are needed for their equilibration. Combined with the results obtained for ethyl substituted derivatives, one can draw the tentative stability of the



individual propyl substituted conformations: 1,2-(S) alt 4Pr > partial cone 6Pr > 1,3-alternate 5Pr > cone 3Pr. Again, the formation of the remaining 1,2-(C) alternate 7Pr conformer was never observed during all these experiments. To confirm that a longer alkyl chain is able to fix dithiacalixarene conformers, we have also introduced butyl groups into our system. Alkylation of 1 with butyl iodide in the presence of NaH in DMF has led to cone 3Bu isolated in 49 % yield, whereas the alkylation with BuI/Cs2CO3 system in refluxing MeCN has led to a mixture of 4Bu, 5Bu, and 6Bu in 19%, 26%, and 23% yields, respectively. Each conformer was purified using chromatography on silica gel with C6H12:CH2Cl2 20:1 v/v as the mobile phase. The heating experiments were carried out in o-dichlorobenzene-d4 at 443 K for 8 weeks period and did not reveal any changes in the 1H NMR spectra. These results suggest that the n-butyl group is bulky enough to prevent any thermal isomerization of butylated 2,14-dithiacalixarene conformers, thus, resembling the effect on the conformational behavior in thiacalix[4]arene series.13 A single crystal X-ray diffraction structure study has confirmed the solid state structures of all four propoxy conformers isolated (3Pr, 4Pr, 5Pr and 6Pr). The 1,2-(S) alternate 4Pr crystallized in a triclinic system, space group P-1. The structure is very similar to that of 4Et, again with strikingly elongated main diagonal (the S···S distance = 8.377 Å versus C···C distance 6.587 Å) leading to a distinctive rhombus shape (Fig 6a). The distance between the CH2 bridge and the two neighboring sulfur atoms are 5.35 and 5.34 Å, correspondingly, thus, indicating that the size of the cavity is between that of thiacalix[4]arene (distance between two neighbour S atoms approx. 5.55 Å)12 and calix[4]arene (typical distance between two proximal CH2 groups in the 1,2-alternate is 5.13 Å).8a Almost identical structural parameters were found for 4Bu as well (See ESI).


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a)

b)

d)

c)

e) Figure 6. Single crystal X-ray structures of propoxy substituted conformers: (a) 1,2-(S) alternate 4Pr top-view; (b) 1,3-alternate 5Pr – top view; (c) cone 3Pr – top view; (d) partial cone 6Pr – top view; (the bridging atoms are shown as ball for better clarity). (e) dimeric motif of 6Pr (interacting atoms are shown as balls for better clarity).



The corresponding 1,3-alternate 5Pr crystalized in a triclinic system, space group P-1. The cavity adopted almost ideal square shape with nearly identical lengths of both diagonals (S···S = 7.732 Å vs C···C 7.671 Å). If we define the main plane of the molecule by the four bridging atoms, the corresponding interplanar angles  with aromatic subunits are 61.04°, 66.58°, 72.80° and 69.59° with all aromatic moieties pointing by the propoxy groups out of the cavity (see Figure 6b). The cone conformer 3Pr was found to crystallized in trigonal system, space group P3221. The molecule adopted a considerably distorted pinched cone conformation (Figure 6c) with two opposite aromatic subunits being almost perpendicular to the main plane of the molecule ( = 88.46°), with the other two pointing outside of the cavity ( = 51.24°). Very similar structural features were also found for the corresponding butoxy derivative 3Bu (see ESI). Partial cone 6Pr crystallized in monoclinic system, space group C 2/c (Fig. 6d), with the long (S···S) and short (C···C) diagonals being 7.788 and 7.140 Å, respectively. While three of four phenolic subunits are nearly perpendicular to the main plane ( = 85.56°, 84.71°, and 84.89°), the remaining one is pointing into the cavity with its propoxy group ( = 45.25°). An interesting dimeric motif was found in the packing of 6Pr with two close contacts between the sulfur bridge and neighboring C-H bond of aromatic subunits. Moreover, the intermolecular S···S distance 3.523 Å indicated the presence of chalcogen bond in mixed-bridge system (Fig. 6e). It's a well-known fact that the 1H NMR spectra of teraalkylated cone conformers of calix[4]arene7a or thiacalix[4]arene7b (with intrinsic C4v symmetry), in reality, represent time averaged signals of two other structures of lower C2v symmetry, called pinched cone conformers. These structures are in fast equilibrium under ambient conditions, thus, realizing oscillations of two pairs of opposite aromatic subunits. This so called pinched cone – pinched cone interconversion usually becomes observable at lower temperatures (Fig. 7).


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X = S or CH2 X

X

X

O O

O R

O

O R

R

X

X

R

R

X

X O

O R

X

O R

R

C2v

C4v

X

X

X

O R OO O R R

X

R

C2v'

Figure 7. Pinched cone-pinched cone interconversion of (thia)calix[4]arenes.

To study the influence of mixed bridges on the activation free energy (G*) of the corresponding pinched cone – pinched cone interconversion we performed a dynamic NMR study of 2,14dithiacalixarene series. The temperature dependent 1H NMR spectra in the range of 143 K (or 153 K) – 298 K in CD2Cl2 were acquired for both cone conformers 3Pr and 3Bu, respectively. The corresponding activation free energy (G*) was computed using Eyring equations for the rate constant k: G 

k

k BTC  RTC e h

k

 2

where kB is the Boltzmann constant, TC is the coalescence temperature, h is the Planck constant, R is the gas constant, and ν is the chemical shift difference of the exchanging signals in the absence of chemical exchange.



t But Bu

But

RR

But

Page 16 of 28

RR

R R

R

R

3

5

S

S

O O

O R

R

O R

A

B

R

S O Pr

S

OO Pr

A

R = But S

O Pr

Pr

O

B O O

S

O Pr Pr Pr Pr

Figure 8. Partial 1H NMR spectra (aromatic region 6.0-8.0 ppm) of 3Bu in the range of 153 - 298 K (CD2Cl2, 500 MHz).


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As shown in Figure 8, cone conformer 3Bu revealed only two signals in the aromatic region (at 7.22 and 6.87 ppm, respectively) for the time-averaged structure at room temperature. As expected, lowering the temperature induced extensive broadening of both peaks leading finally to their disappearance at around 173 K (coalescence temperature). Further cooling resulted into four distinct signals corresponding to inequivalent aromatic rings A and B found within the two pinched cone conformations. Due to the symmetry of the molecule both pinched cone conformations were populated equally and the resultant value of G* for compound 3Bu was approx. 32 kJ·mol-1. The same value was obtained for 3Pr derivative as well. In this context, it is noteworthy that this value is slightly lower than that of tetrapropoxycalix[4]arene7a without tert-butyl groups (36 kJ·mol-1), while the corresponding tetrapropoxythiacalix[4]arene exhibited much higher G* (54 kJ·mol-1). This suggests the dynamic behavior of the macrocycle is mostly defined by the presence of methylene rather than sulfur bridges.

CONCLUSIONS 2,14-Dithiacalix[4]arene was alkylated using standard protocols for classical calixarenes or thiacalixarenes to study the specific conformational preferences and dynamic behavior of the corresponding tetraalkylated derivatives. As proved by the X-ray crystallography and dynamic NMR studies, the presence of mixed bridges (-CH2- and -S- groups) within the basic scaffolds brings about considerable changes in the mutual ratios of the individual conformers compared to parent macrocycles. Remarkably, certain conformers which are hardly accessible in common calixarene/thiacalixarene chemistry, e.g. 1,2-alternates, were prepared in very good yields, thus making the mixed-bridge calixarene a very attractive molecular scaffold for supramolecular applications.



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 6700 in KBr transmission mode. NMR spectra were recorded on spectrometers Varian Gemini 300 HC (1H: 300 MHz, 13C: 75 MHz), 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, 13C: 150.9 MHz) spectrometers. The signal assignment was supported by 1H-1H COSY, 1H-13C HMQC or 1H-13C HMBC 2D NMR using the standard pulse sequences provided by Bruker. 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.

The starting compound and intermediates were prepared according to the published procedure: 16c. Dithiacalixarene 2: Compound 1 (200 mg, 0.29 mmol) and sodium hydride (117 mg of 60% suspension in mineral oil, 2.93 mmol) were dissolved in dry DMF (20 mL) at 0 °C. After few minutes, iodomethane (0.36 mL, 5.8 mmol) was added to the solution and the mixture was stirred at room temperature. After 48 hours, the solvent was evaporated under reduced pressure, the residue was neutralized with 1 M HCl and extracted with dichloromethane. The organic layer was washed with 10% aqueous solution of sodium sulfite (30 mL), washed with water (30 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure to yield the crude product which was purified by radial chromatography on silica-gel (eluent = cyclohexane:CH2Cl2:acetone 240:20:1, v/v). The product was obtained as white powder in 84% yield (181 mg), m.p: 230-233 °C. 1H NMR (300 MHz, CDCl3, 298 K): δ = 7.33 (4H, s, CH-arom), 7.08 (4H, s, CH-arom), 3.70 (4H, br s, bridge CH2), 3.45 (12H, s, OCH3), 1.22 (36H, s, tBu). 13C{1H} NMR (125.8 MHz, CD2Cl2, 298 K): 188.7 (quart. C), 157.3 (quart. C), 145.1 (quart.


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C), 134.0 (quart. C), 130.3 (CH), 128.2 (CH), 59.8 (OCH3 - Me), 34.1 (bridge CH2), 31.6 (quart. C- tBu), 29.9 (tBu). IR (KBr): ν 2959 cm-1, 1634 cm-1, 1459 cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C46H60O4S2Na 763.3825; Found 763.3832. Dithiacalixarene 3Pr: Compound 1 (200 mg, 0.29 mmol) and sodium hydride (117 mg of 60% suspension in mineral oil, 2.93 mmol) were dissolved in dry DMF (20 mL) at 0 °C. After few minutes, iodopropane (0.57 mL, 5.8 mmol) was added to the solution. The mixture was stirred at room temperature. After 7 days, the solvent was evaporated under reduced pressure, the residue was neutralized with 1 M HCl and extracted with dichloromethane. The organic layer was washed with 10% aqueous solution of sodium sulfite (30 mL), washed with water (30 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure to yield the crude product which was purified by radial chromatography on silica-gel (eluent = cyclohexane:CH2Cl2=15:1, v/v). Dithiacalixarene 3Pr was obtained in 59% yield (147 mg), m. p: 250-254 °C. 1H NMR (300 MHz, CDCl3, 298 K): 7.22 (4H, d, J= 2.93 Hz, CH-3-arom), 6.87 (4H, d, J= 2.93 Hz, CH-arom), 4.56 (2H, d, J= 12.89 Hz, bridge CH2-ax), 4.26 – 4.16 (4H, m, OCH2-a - Pr), 3.94 – 3.84 (4H, m, OCH2-b - Pr), 3.12 (2H, d, J= 12.89 Hz, bridge CH2-eq), 2.15 – 1.86 (8H, 2 x m, 2 x CH2- Pr), 1.08 (36H, s, tBu), 1.02 (12H, t, J= 7.62 Hz, CH3 - Pr). 13C{1H} NMR (75 MHz, CDCl3, 298 K): 156.8 (quart. C-1), 144.7 (quart. C-4), 134.2 and 131.9 (quart. C-2 and quart. C-6), 129.1 and 127.4 (CH -5 and CH-3), 77.4 (OCH2 - Pr), 33.9 (bridge CH2), 31.3 (quart. C- tBu), 31.0 (tBu), 23.3 (CH2- Pr), 10.4 (CH3 - Pr). IR (KBr): ν 2961 cm-1, 2873 cm-1, 1476 cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C54H76O4S2Na 875.5077; Found 875.5081. Dithiacalixarene 3Bu: Compound 1 (170 mg, 0.247 mmol) and sodium hydride (99 mg of 60% suspension in mineral oil, 2.36 mmol) were dissolved in dry DMF (15 mL) at 0 °C. After few minutes, iodobutane (0.56 mL, 4.9 mmol) was added to the solution. The mixture was stirred at room temperature. After 7 days, the solvent was evaporated under reduced pressure, the residue was neutralized with 1 M HCl and extracted with dichloromethane. The organic layer was washed with 10% aqueous solution of sodium sulfite (30 mL), washed with water (30 mL) and dried over magnesium



sulfate. The solvent was removed under reduced pressure to yield the crude product which was purified by column chromatography on silica-gel (eluent = cyclohexane:CH2Cl2=20:1, v/v). Dithiacalixarene 3Bu was obtained in 49% yield (110 mg), m.p: 194.6-197.7 °C. 1H NMR (500.1 MHz, CD2Cl2, 298 K): 7.23 (4H, d, J= 2.2 Hz, CH-3-arom), 6.92 (4H, d, J= 2.0 Hz, CH-arom), 4.55 (2H, d, J= 12.7 Hz, bridge CH2-ax), 4.28 – 4.20 (4H, m, OCH2-a - Bu), 4.00 – 3.92 (4H, m, OCH2-b - Bu), 3.13 (2H, d, J= 12.7 Hz, bridge CH2-eq), 2.11 – 1.86 (8H, 2 x m, 2 x CH2- Bu), 1.59 – 1.44 (8H, m, 2 x CH2- Bu), 1.10 (36H, s, tBu), 1.04 (12H, t, J= 7.4 Hz, CH3 - Bu). 13C{1H} NMR (125.8 MHz, CD2Cl2, 298 K): 156.7 (quart. C-1), 144.9 (quart. C-4), 134.4 and 129.2 (quart. C-2 and quart. C-6), 131.9 and 127.6 (CH -5 and CH-3), 75.9 (OCH2 - Bu), 33.9 (bridge CH2), 32.4 (quart. C- tBu), 31.1 (tBu), 30.5 and 19.4 (2 x CH2- Bu), 14.3 (CH3 Bu). IR (KBr): ν 2953 cm-1, 2869 cm-1, 1453 cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C58H84O4S2Na 931.5703; Found 931.5706. Dithiacalixarenes 4Et, 5Et and 6Et: Compound 1 (200 mg, 0.29 mmol) and potassium carbonate (1.0 g, 7.2 mmol) were dissolved in dry acetone (20 mL). After few minutes, iodoethane (0.58 mL, 7.2 mmol) was added to the solution and the mixture was stirred under reflux. After 7 days, the solvent was evaporated under reduced pressure, the residue was neutralized with 1 M HCl and extracted with dichloromethane. The organic layer was washed with 10% aqueous solution of sodium sulfite (30 mL), washed with water (30 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure to yield the crude product which was purified by radial chromatography on silica-gel (eluent = cyclohexane:CH2Cl2=12:1, v/v). Dithiacalixarene 4Et was obtained in 58% yield (133 mg) as white powder. Additionally, 45 mg (20%) of dithiacalixarenes 5Et and 6Et was isolated as byproduct. Dithiacalixarene 4Et: m.p: 276-280 °C. 1H NMR (500.1 MHz, C2D2Cl4, 343 K): 7.36 (4H, d, J= 2.2 Hz, CH3), 7.27 (4H, d, J= 2.2 Hz, CH-5), 4.32 (2H, d, J= 12.6 Hz, bridge CH2-ax), 4.03 – 3.89 (4H, m, OCH2-a - Et), 3.59 – 3.50 (4H, m, OCH2-b - Et), 3.18 (2H, d, J= 12.6 Hz, bridge CH2-eq), 1.36 (36H, s, tBu), 0.72 (12H, t, J= 7.0 Hz, CH3 - Et). 13C{1H} NMR (125.8 MHz, C2D2Cl4, 343 K): 154.6 (quart. C-1), 144.7 (quart. C-4), 134.6 and 126.9 (quart. C-2 and quart. C-6), 127.0 (CH -3), 126.9 (CH -5), 66.8 (OCH2 - Et), 34.1 (quart. C-tBu), 31.6 (tBu), 29.6 (bridge CH2), 15.0 (CH3 - Et). IR (KBr): ν 2962 cm-1, 2925 cm-1, 1459 cm-1. HRMS


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(ESI-TOF) m/z: [M + Na]+ Calcd for C50H68O4S2Na 819.4451; Found 819.4457. Dithiacalixarene 5Et: 1H

NMR (600.1 MHz, CD2Cl2): 7.35 (4H, d, overlapped by paco, CH-3), 7.12 (4H, d, J= 2.5 Hz, CH-5), 3.84

(4H, s, bridge CH2), 1.31 (36H, s, tBu), 0.73 (12H, t, J= 7.0 Hz, CH3 - Et). Protons of OCH2-a – Et and OCH2b – Et (8H) are overlapped by the corresponding signals of 1,2-alt a paco. 13C{1H} NMR (150.9 MHz, CD2Cl2): 155.8 (quart. C-1), 144.5 (quart. C-4), 134.0 and 127.4 (quart. C-2 and quart. C-6), 127.4 (CH 5), 127.3 (CH-3), 66.6 (OCH2 - Et), 39.3 (bridge CH2), 33.9 (quart. C-tBu), 31.1 (tBu), 14.9 (CH3 - Et). Dithiacalixarene 6Et: 1H NMR (600.1 MHz, CD2Cl2): 7.62 (1H, d, J= 2.6 Hz, CH-D5), 7.56 (1H, d, J= 2.5 Hz, CH-B5), 7.40 (1H, d, J= 2.6 Hz, CH-D3), 7.35 (1H, overlapped by 1,2-alt a 1,3-alt, CH-A3), 7.29 (1H, overlapped by 1,2-alt, CH-B3), 7.04 (1H, d, J= 2.5 Hz, CH-C5), 6.90 (1H, d, J= 2.5 Hz, CH-C3), 6.81 (1H, d, J= 2.4 Hz, CH-A5), 4.17 (1H, d, J= 12.7 Hz, bridge CH2 – AB), 3.73 (1H, d, J= 13.2 Hz, bridge CH2 – CD), 3.68 (1H, d, J= 13.2 Hz, bridge CH2 – CD), 4.35 – 3.40 (8H, several overlapped m, OCH2 – Et), 3.07 (1H, d, J= 12.8 Hz, bridge CH2 – AB), 1.42 (9H, s, tBu-D), 1.38 (9H, s, tBu-B), 1.14 (9H, s, tBu-A), 1.00 (9H, s, tBu-C), 1.54 – 0.99 (12H, m, 4 x CH3 - Et). 13C{1H} NMR (150.9 MHz, CD2Cl2): 157. 5 (quart. C-D1), 156.83 and 156.81(quart. C-C1 and quart. C-B1), 155.4 (quart. C-A1), 145.6 (quart. C-B4), 144.18 and 144.16 (quart. C-C4 and quart. C-A4), 143.8 (quart. C-D4), 136.3 (quart. C-B2), 134.2 (quart. C-D2), 133.6 (quart. C-A6), 132.1 (CH -C3), 131.7 and 131.5 (quart. C-C6 and quart. C-B6), 131.47 and 131.47 (CH – B5 and CH –D5), 130.5 (CH -D3), 130.2 (CH -A3), 128.7 (CH –C5), 128.4 (CH -B3), 127.8 and 127.7 (quart. C-D6 and quart. C-C2), 127.4 (CH –A5), 127.9 (quart. C-A2), 69.0, 68.5, 67.1 and 64.4 (4xOCH2 - Et), 37.6 (bridge CH2– CD), 34.1, 34.0, 33.8 and 33.6 (4x quart. tBu), 31.3, 31.23, 31.23 and 31.1 (4xtBu), cca 31.2 (overlapped bridge CH2– AB), 14.3, 16.0, 15.8 and 15.7 (4xCH3 – Et). Dithiacalixarenes 4Pr and 5Pr: Compound 1 (200 mg, 0.29 mmol) and cesium carbonate (2.35 g, 7.2 mmol) were dissolved in dry acetonitrile (20 mL). After few minutes, iodopropane (0.7 mL, 7.2 mmol) was added to the solution. The mixture was stirred and heated under reflux. After 7 days, the solvent was evaporated under reduced pressure, the residue was neutralized with 1 M HCl and extracted with dichloromethane. The organic layer was washed with 10% aqueous solution of sodium sulfite (30 mL), washed with water (30 mL) and dried over magnesium sulfate. The solvent was removed



under reduced pressure to yield the crude product which was purified by radial chromatography on silica-gel (eluent = cyclohexane:CH2Cl2=15:1, v/v). Dithiacalixarene 4Pr was obtained in 32 % yield (79 mg) and dithiacalixarene 5Pr in yield 52 % (128 mg), both as white powder. Dithiacalixarene 4Pr: m.p: > 300 °C. 1H NMR (600.1 MHz, C2D2Cl4): 7.29 (4H, d, J= 2.2 Hz, CH-3), 7.22 (4H, d, J= 2.2 Hz, CH5), 4.28 (2H, d, J= 12.6 Hz, bridge CH2-ax), 3.85 – 3.77 (4H, m, OCH2-a - Pr), 3.34 – 3.26 (4H, m, OCH2-b - Pr), 3.12 (2H, d, J= 12.6 Hz, bridge CH2-eq), 1.30 (36H, s, tBu), 1.22 – 1.12 and 1.93 – 0.73 (8H, 2 x m, CH2- Pr), 0.79 (12H, t, J= 7.4 Hz, CH3 - Pr). 13C{1H} NMR (125.8 MHz, C2D2Cl4, 343 K): 154.6 (quart. C-1), 144.5 (quart. C-4), 134.3 and 126.9 (quart. C-2 and quart. C-6), 126.9 and 126.8 (CH -3 and CH -5), 73.3 (OCH2 - Pr), 34.1 (quart. C-tBu), 31.5 (tBu), 29.1 (bridge CH2), 22.3 (CH2 - Pr), 15.0 (CH3 - Pr). IR (KBr): ν 2960 cm-1, 2873 cm-1, 1456 cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C54H76O4S2Na 875.5077; Found 875.5080. Dithiacalixarene 5Pr: m.p: > 300 °C. 1H NMR (600.1 MHz, CDCl3): 7.31 (4H, d, J= 2.5 Hz, CH-3), 7.08 (4H, d, J= 2.5 Hz, CH-5), 3.92 – 3.87 (4H, m, OCH2-a - Pr), 3.87 (4H, s, bridge CH2), 3.37 – 3.31 (4H, m, OCH2-b - Pr), 1.30 (36H, s, tBu), 1.08 – 1.00 (8H, m, CH2- Pr), 0.66 (12H, t, J= 7.5 Hz, CH3 - Pr). 13C{1H} NMR (150.9 MHz, CDCl3): 155.8 (quart. C-1), 144.4 (quart. C-4), 133.6 and 127.2 (quart. C-2 and quart. C-6), 127.1 (CH -5), 126.6 (CH-3), 70.6 (OCH2 - Pr), 39.4 (bridge CH2), 33.9 (quart. C-tBu), 31.2 (tBu), 22.1 (CH2- Pr), 9.8 (CH3 - Pr). IR (KBr): ν 2957 cm-1, 2918 cm-1, 1455 cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C54H76O4S2Na 875.5077; Found 875.5082. Dithiacalixarenes 4Pr, 5Pr and 6Pr: Compound 1 (200 mg, 0.29 mmol) and potassium carbonate (1 g, 7.2 mmol) were dissolved in dry acetonitrile (20 mL). After few minutes, 0.7 mL of iodobutane (7.2 mmol) was added to the solution. The mixture was stirred and heated under reflux. After 7 days, the solvent was evaporated under reduced pressure, the residue was neutralized with 1 M HCl and extracted with dichloromethane. The organic layer was washed with 10% aqueous solution of sodium sulfite (30 mL), washed with water (30 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure to yield the crude product which was purified by radial chromatography on silica-gel (eluent = cyclohexane:CH2Cl2=20:1, v/v). Dithiacalixarenes 4Pr, 5Pr and 6Pr were obtained in 17 % (45 mg), 16 % (44 mg) and 19 % (50 mg) yields, respectively. Dithiacalixarene


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6Pr: m.p: 255.2-258,4 °C. 1H NMR (600.1 MHz, C2D2Cl4): 7. 57 (1H, d, J= 2.5 Hz, CH-D5), 7.52 (1H, d, J= 2.5 Hz, CH-B5), 7.34 (1H, d, J= 2.5 Hz, CH-D3), 7.29 (1H, d, J= 2.5 Hz, CH-A3), 7.24 (1H, d, J= 2.4 Hz, CHB3), 7.00 (1H, d, J= 2.5 Hz, CH-C5), 6.89 (1H, d, J= 2.5 Hz, CH-C3), 6.78 (1H, d, J= 2.4 Hz, CH-A5), 4.25 – 4.14 (2H, m, OCH2 (1H) – Pr, bridge CH2 – AB (1H)), 4.02 – 3.87 (3H, m, OCH2 – Pr), 3.87 – 3.79 (1H, m, OCH2 – Pr), 3.78 – 3.73 (1H, m, OCH2 – Pr), 3.73 – 3.63 (2H, m, bridge CH2 – CD), 3.62 – 3.55 (1H, m, OCH2 – Pr), 3.54 – 3.46 (1H, m, OCH2 – Pr), 3.06 (1H, d, J= 12.8 Hz, bridge CH2 – AB), 2.11 – 1.53 (8H, m, CH2 – Pr), 1.42 (9H, s, tBu-D), 1.36 (9H, s, tBu-B), 1.13 (9H, s, tBu-A), 0.99 (9H, s, tBu-C), 1.12 – 0.72 (12H, m, CH3 - Pr). 13C{1H} NMR (150.9 MHz, C2D2Cl4): 157.4 (quart. C-D1), 157.1 (quart. C-C1), 156.6 (quart. C-B1), 155.5 (quart. C-A1), 145.4 (quart. C-B4), 144.1 (quart. C-C4), 144.0 (quart. C-A4), 143.7 (quart. C-D4), 136.1 (quart. C-B2), 133.9 (quart. C-D2), 133.4 (quart. C-A6), 132.1 (CH -C3), 131.7 (CH – B5), 131.7 (quart. C-C6), 131.5 (CH –D5), 131.0 (quart. C-B6), 130.2 (CH -D3), 129.9 (CH -A3), 128.8 (CH –C5), 128.5 (CH -B3), 127.3 (quart. C-D6), 127.28 (quart. C-C2), 127.25 (CH –A5), 127.2 (quart. C-A2), 77.7, 75.5, 75.1 and 74.2 (4xOCH2 - Pr), 37.7 (bridge CH2– CD), 34.2, 34.1, 33.9 and 33.7 (4x quart. tBu), 31.73, 31.69, 31.44 and 31.35 (4xtBu), 31.3 (bridge CH2– AB), 24.03, 23.99, 23.7 and 21.6 (4xCH2 - Pr), 11.0, 10.9, 10.6 and 9.8 (4xCH3 - Pr). IR (KBr): ν 2958 cm-1, 2922 cm-1, 1453 cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C54H76O4S2Na 875.5077; Found 875.5077. Dithiacalixarenes 4Bu, 5Bu and 6Bu: Compound 1 (200 mg, 0.29 mmol) and potassium carbonate (1 g, 7.2 mmol) were dissolved in dry acetonitrile (20 mL). After few minutes, 0.82 mL of iodobutane (7.2 mmol) was added to the solution. The mixture was stirred and heated under reflux. After 7 days, the solvent was evaporated under reduced pressure, the residue was neutralized with 1 M HCl and extracted with dichloromethane. The organic layer was washed with 10% aqueous solution of sodium sulfite (30 mL), washed with water (30 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure to yield the crude product which was purified by radial chromatography on silica-gel (eluent = cyclohexane:CH2Cl2=20:1, v/v). Dithiacalixarenes 4Bu, 5Bu and 6Bu were obtained in 19 % (52 mg), 26 % (70 mg) and 23 % (61 mg) yields, respectively. Dithiacalixarene 4Bu: m.p: 287-290 °C. 1H NMR (600.1 MHz, CDCl3): 7.33 (4H, d, J= 2.4 Hz, CH-3), 7.26



(4H, d, J= 2.4 Hz, CH-5), 4.31 (2H, d, J= 12.6 Hz, bridge CH2-ax), 3.40 – 3.34 (4H, m, OCH2-a - Bu), 3.42 – 3.34 (4H, m, OCH2-b - Bu), 3.13 (2H, d, J= 12.6 Hz, bridge CH2-eq), 1.33 (36H, s, tBu), 1.27 – 1.19, 1.18 – 1.09 and 1.91 – 0.81 (16H, 3 x m, 2 x CH2- Bu), 0.79 (12H, t, J= 7.4 Hz, CH3 - Bu). 13C{1H} NMR (150.9 MHz, CDCl3): 154.7 (quart. C-1), 144.5 (quart. C-4), 134.3 and 126.9 (quart. C-2 and quart. C-6), 126.8 and 126.7 (CH -5 and CH-3), 71.5 (OCH2 - Bu), 34.1 (bridge CH2), 31.5 (tBu), 29.0 (quart. C-tBu), 30.8 and 18.9 (2 x CH2- Bu), 13.8 (CH3 - Bu). IR (KBr): ν 2955 cm-1, 2866 cm-1, 1456 cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C58H84O4S2Na 931.5703; Found 931.5705. Dithiacalixarene 5Bu: m.p: 289.6-291.4 °C. 1H NMR (600.1 MHz, CDCl3): 7.30 (4H, d, J= 2.4 Hz, CH-3), 7.03 (4H, d, J= 2.4 Hz, CH-5), 3.98 – 3.92 (4H, m, OCH2-a - Bu), 3.81 (4H, s, bridge CH2), 3.42 – 3.34 (4H, m, OCH2-b - Bu), 1.30 (36H, s, tBu), 1.20 – 1.07 (16H, m, 2 x CH2- Bu), 0.84 (12H, t, J= 7.0 Hz, CH3 - Bu). 13C{1H} NMR (150.9 MHz, CDCl3): 155.9 (quart. C-1), 144.3 (quart. C-4), 133.6 and 127.2 (quart. C-2 and quart. C-6), 127.2 (CH -5), 127.1 (CH3), 69.4 (OCH2 - Bu), 39.5 (bridge CH2), 34.0 (quart. C-tBu), 31.4 (tBu), 31.2 and 19.0 (2 x CH2- Bu), 14.0 (CH3 - Bu). IR (KBr): ν 2955 cm-1, 2868 cm-1, 1454 cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C58H84O4S2Na 931.5703; Found 931.5707. Dithiacalixarene 6Bu: m.p: 257.4-260.1 °C. 1H NMR (600.1 MHz, CDCl3): 7.60 (1H, d, J= 2.6 Hz, CH-D5), 7.52 (1H, d, J= 2.5 Hz, CH-B5), 7.38 (1H, d, J= 2.5 Hz, CHD3), 7.30 (1H, d, J= 2.5 Hz, CH-A3), 7.23 (1H, d, J= 2.4 Hz, CH-B3), 7.00 (1H, d, J= 2.5 Hz, CH-C5), 6.87 (1H, d, J= 2.5 Hz, CH-C3), 6.76 (1H, d, J= 2.4 Hz, CH-A5), 4.28 – 4.17 (3H, m, OCH2 – Bu, bridge CH2 – AB (1H)), 4.04 – 3.92 (3H, m, OCH2 – Bu), 3.82 – 3.62 (4H, m, OCH2 – Bu, bridge CH2 – CD), 3.58 – 3.52 (1H, m, OCH2 – Bu), 3.02 (1H, d, J= 12.7 Hz, bridge CH2 – AB), 2.08 – 1.73 (8H, m, CH2 – Bu), 1.62 – 1.18 (8H, m, CH2 – Bu), 1.42 (9H, s, tBu-D), 1.36 (9H, s, tBu-B), 1.13 (9H, s, tBu-A), 0.97 (9H, s, tBu-C), 1.10 – 0.78 (12H, m, CH3 - Bu). 13C{1H} NMR (150.9 MHz, CDCl3): 157.4 (quart. C-D1), 157.1 (quart. C-C1), 156.4 (quart. C-B1), 155.7 (quart. C-A1), 145.0 (quart. C-B4), 144.1 (quart. C-C4), 144.0 (quart. C-A4), 143.6 (quart. C-D4), 136.2 (quart. C-B2), 133.8 (quart. C-D2), 133.4 (quart. C-A6), 132.2 (CH -C3), 131.8 and 131.7 (CH –B5 and CH –D5), 131.5 (quart. C-C6), 130.9 (quart. C-B6), 130.2 (CH -D3), 130.0 (CH -A3), 128.5 (CH –C5), 128.2 (CH -B3), 127.5 (quart. C-D6), 127.4 (quart. C-C2), 127.3 (quart. C-A2), 127.1 (CH –A5), 75.8, 73.6, 72.6 and 72.2 (4xOCH2 - Bu), 37.4 (bridge CH2– AB), 34.2, 34.1, 33.8 and 33.7 (4x quart.


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tBu), 33.1, 33.0, 32.7 and 30.2 (4xCH2 - Bu), 31.62, 31.59, 31.32 and 31.26 (4xtBu), 31.52 (bridge CH2– CD), 19.6, 19.43, 19.36 and 18.9 (4xCH2 - Bu), 14.09, 14.07, 14.0 and 13.9 (4xCH3 - Bu). IR (KBr): ν 2955 cm-1, 2867 cm-1, 1454 cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C58H84O4S2Na 931.5703; Found 931.5701.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Copies of 1H, 13C NMR, HRMS and IR spectra of synthesized compounds, temperature dependent 1H NMR spectra, quantum chemical calculations, the numbering or the dithiacalixarene system, and X-ray crystallography data.

AUTHOR INFORMATION Corresponding Author: * E-mail: [email protected] ORCID Ondrej Kundrat: 0000-0003-0298-1108 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 19-08273S). Financial support from specific university research (MSMT No 21/2019) 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.

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Chemistry of 2,14-Dithiacalix[4]arene: Alkylation ... - ACS Publications

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