Threading of an Inherently Directional Calixarene Wheel with Oriented

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On the Threading of an Inherently Directional Calixarene Wheel with Oriented Ammonium Axles Pellegrino La Manna, Carmen Talotta, Carmine Gaeta, Annunziata Soriente, Margherita De Rosa, and Placido NERI J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01388 • Publication Date (Web): 11 Aug 2017 Downloaded from http://pubs.acs.org on August 11, 2017

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The Journal of Organic Chemistry

On the Threading of an Inherently Directional Calixarene Wheel with Oriented Ammonium Axles Pellegrino La Manna, Carmen Talotta,* Carmine Gaeta, Annunziata Soriente, Margherita De Rosa, and Placido Neri

Dipartimento di Chimica e Biologia “A. Zambelli”, Università di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano (Salerno), Italy, e-mail: [email protected]

RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

ABSTRACT. The threading of mono-stoppered alkylbenzylammonium axles 7+ and 8+ with the calix[6]-wheel 3 can occur by both the routes of entering of the macrocycle 3 in the cone conformation:

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through-the-upper-rim and the through-the-lower-rim passage. Thus, under thermodynamic conditions, with both the axles 7+ and 8+ the two possible oriented calix[2]pseudorotaxane, namely endo-benzyl and endo-alkyl, are formed with a stereoselectivity controlled by endo-alkyl rule. Interestingly, by 1H NMR monitoring of the threading process between 8+ and 3, we revealed two calix[2]pseudorotaxane isomers in which the calix-weel adopts 1,2,3-alternate and cone conformations and which represent the kinetic and thermodynamic species, respectively. Finally, the synthesis of ammonium-based oriented calix[2]rotaxane is here described.

INTRODUCTION Interpenetrated architectures such as pseudorotaxanes, rotaxanes, and catenanes,1 beyond their potentiality as molecular machines,2 sensors,3 and catalysts,4 show fascinating structures which can present peculiar and unconventional forms of (stereo)isomerism. Special cases arise when structurally nonsymmetric (directional) threads and/or wheels are used. For example, Leigh and coworkers recently introduced the concept of sequence isomerism5 in which two different rings may have different positions along a directional thread (I and II, Figure 1). More recently, Goldup6 has reported the synthesis of a mechanically planar chiral rotaxane, composed by achiral components, in which the chirality arises by the presence of a rotationally asymmetrical macrocycle and a directional thread possessing nonequivalent ends (III and III', Figure 1). In this work, the two enantiomeric rotaxanes were obtained by using a chiral stopper, to give two rotaxane diastereoisomers, which was substituted with an achiral one after their separation. Interlocked architectures with directional components are fundamental for the realization of molecular motors showing a unidirectional motion.7a At this regard, Leigh has recently reported a small-molecule synthetic walker7d and a chemically-fueled unidirectional circular motor.7e


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In the last three decades, calixarene macrocycles have found many applications as supramolecular hosts8c-m thanks to their synthetic and conformational versatility.8a,b They can be considered as wheels endowed with an inherent directionality.9 An oriented axle (e.g.: 22+ and 4+, Figure 2) which is small enough to pass through both rims of a directional calix-wheel should generate two distinct orientational stereoisomeric pseudorotaxanes (IV and V, Figure 1). In these instances, a related point is to understand if the threading process occurs by axle entering from the upper (also called exo or wide) or from the lower (also called endo or narrow) rim. Arduini and coworkers10 have shown that the directionality of the threading process of a triphenylureido-calix[6]arene wheel 1 (Figure 2) by a oriented monostoppered viologen axle 22+, is affected by the polarity of the solvent used. Interestingly, it was shown that in apolar solvents, such as C6D6, the threading process of 22+ occurs through the upper rim of 1,10c while in more polar solvents, such as CD3CN, the threading occurs from both rims10c yielding a mixture of both IV and V stereoisomers (Figure 1).

Figure 1. Cartoon representation of some examples of (stereo)isomerism in (pseudo)rotaxane architectures generated by the use of oriented axles and/or directional wheels.

We have recently11 shown that a specific orientational stereoisomer11b can be obtained when oriented alkylbenzyl-ammonium axles (e.g. 4+, Figure 2) are threaded through a directional calix[6]arene wheel


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(e.g., 3) by exploiting of the so-called “endo-alkyl rule”:12 threading of a directional alkylbenzylammonium axle through a hexaalkoxycalix[6]arene occurs with an endo-alkyl preference. By exploiting this “endo-alkyl rule”, we have recently reported the stereoselective synthesis of the first examples of calixarene-based oriented interlocked architectures: calix[2]catenane (Figure 2),11e calix[3]rotaxane,11d and handcuff calixrotaxane.12a Following this empirical rule, a neat preference for the endo-alkyl 5+ orientational pseudorotaxane stereoisomer (Figure 2) over the endo-benzyl 6+ one was observed.11b

Figure 2. Oriented interpenetrated architectures based on the threading of directional calix-wheels.

In a more general case, an endo-alkyl pseudorotaxane (e.g.: 5+) could be formed by two different routes of entering of the alkylbenzylammonium axle into the calix-wheel (e.g.: 3): the benzyl-throughthe-upper-rim passage and the alkyl-through-the-lower-rim passage (Figure 3). Very recently, we have reported an unidirectional threading motion11g based on the alkyl-through-the-lower-rim passage of ACS Paragon Plus Environment

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alkylbenzylammonium axles with calix[5]-wheels.11g In this case, the benzyl group was too large to pass through the small calix[5]arene annulus. In order to get information on this threading directionality with the larger calix[6]arene wheel we designed the mono-stoppered alkylbenzylammonium axles 7+ and 8+ (Schemes 1 and 2), bearing a free OH group, which could be exploited to isolate the corresponding calix[2]rotaxane after a subsequent stoppering reaction. Now, the question arises as to whether these mono-stoppered axles 7+ and 8+ are capable of a selective direction of threading: do the axles will enter from the upper or from the lower rim of 3? The stereochemistry of the corresponding pseudorotaxane will still obeys the endo-alkyl rule?

+

Figure 3. Possible pathways for the formation of endo-alkyl 5+ 11b pseudorotaxane by threading 3 with 4+.


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RESULTS AND DISCUSSION

Synthesis of TFPB− salts of mono-stoppered axles 7+ and 8+. The synthetic pathway to 7+•TFPB− salt is outlined in Scheme 1.13

10 Br

Br OH

4

O

a)

4 Br

O b)

11

9

H

OH

O

O 4

13

OH

H2N

Cl-

4

O

N OH H2+ 4

c,d)

O

CHO

4

12 e) F3C

O

O 4

7+

TFPBN OH H2+ 4

CF3

F3C

CF3

TFPB- =

B F3C

CF3 F3C

CF3

Scheme 1. Synthesis of thread 7+. Reagents and conditions: a) K2CO3, NaI, CH3CN, reflux, 18 h; b) K2CO3, [18]crown-6, CH3CN, reflux, 18 h; c) CHCl3, 2 h, RT→NaBH4, THF, 2 h, RT; d) HCl, THF, RT, 1 h; e) TFPBNa, dry MeOH, 25 °C, 18 h.

In detail, 4-tritylphenol 9 was treated with K2CO3 and reacted with 1,6-dibromohexane 10 to give monobromide 11. A mixture of 4-hydroxybenzaldehyde and 11 in acetonitrile, in the presence of K2CO3 and 18-crown[6], was refluxed for 18 h to give aldehyde 12. This compound was then coupled with 6amino-1-hexanol, directly reduced with NaBH4, and treated with HCl/MeOH to give chloride salt 13. Finally, counterion exchange with NaTFPB led to the formation of 7+•TFPB− salt, bearing an external (with respect to the trityl stopper group) alkylammonium unit.


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The Journal of Organic Chemistry O

O

O

14

a)

Br

N K + Br O - +

Br

N

4

O

10

b)

N

4

O 4

O OH

15

16

9 c)

ClO

HO 4

N H2

d, e)

O

H2N

4

19

HO

O

O 4

O

17

H

4

18 f) F3C

TFPBO

HO 4

CF3

F3C

N H2

O

TFPB- =

4

CF3 B

F3C F3C

CF3 CF3

8+

Scheme 2. Synthesis of thread 8+. Reagents and conditions: a) dry DMF, RT, 48h; b) K2CO3, CH3CN, reflux, overnight; c) NH2NH2, EtOH, reflux, 2 h; d) CHCl3, 2h, RT→NaBH4, MeOH, 1 h, RT; e) HCl, THF, 0 °C→RT, 1 h; f) TFPBNa, dry MeOH, 25 °C, 24 h.

The synthetic pathway to 8+•TFPB− salt is outlined in Scheme 2.13 The reaction of potassium phthalimide 14 with 1,6-dibromohexane 10, in DMF as solvent led to the formation of monobromide 15. Compound 15 was then reacted with 4-tritylphenol 9 in the presence of K2CO3 to give 16, which was reacted with hydrazine to afford the primary amine 17 in almost quantitative yield. Derivative 17 was reacted with aldehyde 18 to give the corresponding imine, which was directly reduced with NaBH4 and treated with HCl to give the secondary ammonium chloride salt 19. The counteranion of 19 was then exchanged by treatment with NaTFPB in MeOH, to give 8+•TFPB− salt, bearing an external (with respect to the trityl stopper group) benzylammonium unit.


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Directional threading of calix[6]arene-wheel 3 with axles 7+ and 8+. Initially we studied the directionality of the threading of 3 with axle 7+. Two possible directional pseudo[2]rotaxanes are here expected, namely endo-alkyl 20+ or endo-benzyl 20+ (Scheme 3). Preferred HO t But But Bu

But

But But

+ HO O O O ON H O R R R R R R

O

TFPB-

3 + 7+

O

+

CDCl3 But But

But

ButO

But But

O + HO O O R O O ON HR R R R R

TFPB-

R = n-C6H13

endo-alkyl 20+

HO

endo-benzyl 20+

Scheme 3. Formation of the oriented endo-alkyl and endo-benzyl 20+ calix[2]pseudorotaxanes.

The 1H NMR spectrum of 1:1 mixture of 7+ and 3 in CDCl3 at 25 °C (Figure 4) showed, immediately after mixing, the sharpening of all signals and the peculiar features of the presence of two stereoisomeric endo-alkyl and endo-benzyl 20+ pseudorotaxanes in a 98/2 ratio (see SI, Figure S39). This means that the threading of 7+, bearing an external alkylammonium unit, with the calix-wheel 3 takes place from both rims of the macrocycle. The preferential formation of the endo-alkyl 20+ stereoisomer, in accordance with the endo-alkyl rule,12 occurs by through-the-lower-rim passage of calix-wheel 3.


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Figure 4. Significant portions of the 1H NMR spectra (400 MHz, CDCl3, 298 K) of: (a) 3; (b) 1:1 mixture (3.0×10-3 M) of 3 and 7+·TFPB− immediately after mixing.

The NMR spectrum of the 1:1 mixture in Figure 4b remained unchanged after 12 h at 55 °C, thus showing that the system has reached the equilibrium immediately after the mixing of 3 and 7+ in CDCl3. The apparent association constant for the complex, calculated by means of integration of the slowly exchanging 1H NMR signals, was 3.5×102 M-1 (SI, page S21).14 DFT calculations (Figure 5) at the B3LYP/6-31G(d,p) level of theory using Grimme’s dispersion corrections (IOp(3/124 = 3))15 indicated the greater stability of the endo-alkyl 20+ stereoisomer over the endo-benzyl one. In detail, endo-alkyl 20+ results stabilized by two H-bonding interactions (Figure 5) between the ammonium group of 7+ and the oxygen atoms of the calix-wheel 3, with an average N···O distance of 3.02 Å and an average NH···O

angle

of

159.5°.16 Additional

four

C-H···π

interactions

were

detected

between

the α and β methylene groups of the alkyl chain of 7+ inside the calix cavity and the aromatic rings of ACS Paragon Plus Environment

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3,16 with an average C-H···πcentroid distance of 3.16 Å16,17 and an average C-H···πcentroid angle of 155°.16 As concerns the DFT-optimized structure of the endo-benzyl 20+ pseudorotaxane (Figure 5, right), two H-bonding interactions were detected between the NH2+ group of 7+ and the oxygen atoms of 3, with a longer average distance of 3.15 Å (with respect to that found in endo-alkyl 20+ stereoisomer of 3.02 Å) and an average angle of 157°.16 Finally, two aromatic C-H···π interactions were observed between the aromatic C-H of 7+ and the aromatic rings of calix-wheel 3, with an average distance C-H···πcentroid of 2.97 Å and an average C-H···πcentroid angle of 155.0°.16,17

Figure 5. DFT-optimized structures16 of the oriented endo-alkyl (left) and endo-benzyl (right) 20+ calix[2]pseudorotaxanes (B3LYP/6-31G(d,p) level of theory and using Grimme’s dispersion corrections (IOp(3/124 = 3)).15

At this point we moved our attention to the threading of 3 with axle 8+. Also in this instance, two oriented pseudorotaxane stereoisomers, namely endo-alkyl and endo-benzyl 21+, could be formed (Figure 6). ACS Paragon Plus Environment

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Figure 6. Chemical drawing of the oriented endo-alkyl and endo-benzyl 21+ calix[2]pseudorotaxanes, that could be formed by threading of 3 with axle 8+.

Interestingly, immediately after mixing of 3 with 8+ in CDCl3, the 1H NMR analysis revealed the presence of shielded signals at negative values of chemical shifts (Figure 7b) indicative of the formation of a pseudorotaxane. In addition, a close inspection of the ArCH2Ar region revealed the presence of three AX systems (green in Figure 7b) compatible with the formation of pseudorotaxane 21+1,2,3 (Scheme 4) in which the calix-wheel adopts a 1,2,3-alternate conformation.18 After equilibration of the mixture of 3 and 8+ in CDCl3 at 55 °C for 12 h, the signals of 21+1,2,3 disappeared while those of endoalkyl 21+cone and endo-benzyl 21+cone (Scheme 4 and Figure 7c-d) emerged. Interestingly, 1D and 2D NMR studies16 indicated that the oriented pseudorotaxane endo-alkyl 21+cone was preferentially formed over endo-benzyl 21+cone in a 98/2 ratio (Scheme 4). 16 The above NMR spectra remained unchanged after 24 h at 55 °C, thus showing that the system had reached the equilibrium condition. A plausible explanation of these results is based on the initial formation of the kinetically favored pseudorotaxane ACS Paragon Plus Environment

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21+1,2,3. (Scheme 4). Indeed, the 1,2,3-alternate conformation of free 3 is a preferred conformation in solution as evidenced by VT NMR studies (see SI,16 pages S35-S38). Therefore, the threading of 31,2,3 by 8+ is faster than that of 3cone (Scheme 4)

Figure 7. Significant portions of the 1H NMR spectra (400 MHz, CDCl3, 298 K) of: a) 3; b) 1:1 mixture (3.0×10-3 M) of 3 and 8+ immediately after mixing and c) after 12 h at 55 °C; d) Inserts: enlargement of the 1H NMR and COSY sections (between 4.2 and 5.1 ppm) of the mixture in (c); marked in magenta the AX system for ArH protons of the shielded endo-cavity benzylammonium unit of the pseudorotaxane endo-benzyl 21+. ACS Paragon Plus Environment

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At this point, the formation of the two 21+cone pseudorotaxanes from 21+1,2,3 could take place through two possible routes. First, a de-threading of axle 8+ from 21+1,2,3 can occur and a subsequent re-threading from the lower and upper rim of 3cone, would take place to give endo-benzyl 21+cone and endo-alkyl 21+cone, respectively (Scheme 4). Second, a mechanism for the conversion of 21+1,2,3 to 21+cone (Scheme 4) based on a through-the-annulus reorganization of 3 could be envisioned. However, this latter mechanism can be ruled out because we have previously demonstrated that the presence of an ammonium axle inside the cavity of 3 (impedes) prevents the through-the-annulus passage of both the hexyl chains and the tert-butyl groups.13b In conclusion, under thermodynamic control, after 12 h at 55 °C, the pseudorotaxane 21+1,2,3 initially formed is consumed in favor of the more stable 21+cone only through a de-threading/re-threading mechanism (Scheme 4).


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Scheme 4. Mechanism for the formation of the oriented endo-alkyl and endo-benzyl 21+cone calix[2]pseudorotaxanes by threading of 8+ with 3.

The preferential formation of endo-alkyl 21+cone stereoisomer was indicated by the presence in the 1H NMR spectrum (Figure 7c) of the typical signature at highfield negative values (α, β, γ, and δ protons, in red) characteristic of an endo-complexation of the alkyl chains of 8+. The apparent association constant for endo-alkyl 21+cone, calculated by integration of its slowly exchanging 1H NMR signals, 16 was 5.5×102 M−1.16 The presence of endo-benzyl 21+cone was indicated by the expected upfield AX system between 4.0 and 5.0 ppm (see insets in Figure 7d) of ArH protons of the shielded endo-cavity benzylammonium unit (in magenta in Scheme 3 and Figure 7d). All the above results clearly indicate that the mono-stoppered alkylbenzylammonium axle 8+ is able to thread the inherently directional calix[6]arene-wheel 3 by entering from both rims (upper and lower) and that under thermodynamic conditions the endo-alkyl pseudorotaxane prevails in accordance with the known endo-alkyl rule. Summarizing, the formation of pseudorotaxane endo-alkyl 21+cone occurs by through-the-upper-rim passage of calix-wheel 3.


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Figure 8. DFT-optimized structures of the oriented endo-alkyl (left) and endo-benzyl (right) 21+ calix[2]pseudorotaxanes (B3LYP/6-31G(d,p) level of theory and using Grimme’s dispersion corrections (IOp(3/124 = 3)).15

DFT calculations at the B3LYP/6-31G(d,p) level of theory using Grimme’s dispersion corrections (IOp(3/124=3) 15 indicated a greater stability of the endo-alkyl 21+cone, over the endo-benzyl one. A close inspection of the optimized endo-alkyl 21+cone structure (Figure 8, left) reveals the presence of two Hbonds between the ammonium group of the axle 8+ and the oxygen atoms of the calix-wheel 3, with an average N···O distance of 3.0 Å and an average N-H···O angle of 159.2°.16 An extra stabilization of the endo-alkyl 21+cone structure was brought by C-H···π interactions17 between the α and β methylene groups of the alkyl chain of 8+ inside the calix cavity and aromatic rings of 3, 16,17 with an average CH···πcentroid distance of 3.25 Å16,17 and an average C-H···πcentroid angle of 160°.16,17 A similar analysis of the DFT-optimized structure of endo-benzyl 21+cone structure (Figure 8, right) revealed the presence of two H-bonding interactions between the ammonium group of 8+ and the oxygen atoms of the calixwheel 3 with an average N···O distance of 3.0 Å and a narrower N-H···O angle of 152.3°.16 In addition, two aromatic C-H···π interactions were detected between the aromatic ring of 8+, as C-H donor, and the aromatic rings of the calix-wheel 3, as C-H acceptors, with an average distance C-H···πcentroid of 3.10 Å and an average C-H···πcentroid angle of 145.8°.16

Synthesis of oriented calix[2]rotaxanes. The treatment of the mixture of the two pseudorotaxanes endo-alkyl and endo-benzyl 20+ with 4-triphenylmethylphenylisocyanate gave the ACS Paragon Plus Environment

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oriented [2]rotaxanes endo-alkyl 22+ and endo-benzyl 22+ in 13 % total yield, in addition to the free stoppered axle (Scheme 5).

Scheme 5. Synthesis of the oriented calix[2]rotaxanes 22+. a) Di-n-butyltindilaurate, 4triphenylmethylphenylisocyanate, dry CHCl3, 55 °C, 72 h.

The isomeric mixture of endo-alkyl and endo-benzyl 22+ was identified by 1D and 2D16 NMR spectroscopy but not separated by chromatography. Integration of the 1H NMR signals of the two isomeric rotaxane revealed a 96/4 endo-alkyl/endo-benzyl ratio. The presence of the endo-alkyl 22+ rotaxane was confirmed by typical shielded resonances between 1.0 and −1.0 ppm in the 1H NMR spectrum (Figure 9). Analogously, the presence of the endo-benzyl 22+ stereoisomer was proved by the presence of the typical upfield AX system between 4.0 and 5.0 ppm (in magenta in Figure 9b) for ArH protons of the shielded endo-cavity benzylammonium unit.


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Figure 9. (a) Significant portion of the 1H NMR spectrum of 22+ (600 MHz, CDCl3, 298K). b) Enlargement of the 4.0-5.0 ppm section of the 1H NMR spectrum in (a): the signals of the oriented [2]rotaxane endo-benzyl 22+ are marked in magenta and in blu.

In a similar way, the mixture of endo-alkyl 21+cone and endo-benzyl 21+cone pseudorotaxanes, obtained after equilibration, was reacted with 4-triphenylmethylphenylisocyanate (Scheme 6) to give directional endo-alkyl and endo-benzyl 23+ calix[2]rotaxanes (Scheme 6) in 39 % total yield, in addition to the free stoppered axle. The isomeric mixture of endo-alkyl and endo-benzyl 23+ was identified by 1D and 2D16 NMR spectroscopy, but not separated by chromatography. Integration of their 1H NMR signals indicated a 97/3 ratio between endo-alkyl and endo-benzyl 23+ stereoisomers. The presence of endoalkyl 23+ stereoisomer was indicated by a typical signature at highfield negative values (in red


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α, β, γ, δ, from 1.0 to −1.0 ppm) of the 1H NMR spectrum (Figure 10a), which is characteristic of an endo-cavity alkylammonium moiety.

Scheme 6. Synthesis of the oriented calix[2]rotaxanes 23+. a) Di-n-butyltindilaurate, 4triphenylmethylphenylisocyanate, dry CHCl3, 55 °C, 72 h.

A close inspection of the 1D and 2D NMR spectra16 also revealed the presence of the endobenzyl 23+ rotaxane by the expected upfield AX system between 4.0 and 5.0 ppm (in magenta, Figure 10b) for ArH protons of the shielded endo-cavity benzylammonium unit. This was confirmed by an AX system attributable to the ArCH2Ar groups of the calix-wheel of endo-benzyl 23+ rotaxane (in blu, Figure 10b).


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Figure 10. Relevant portions of the 1H NMR spectra (600 MHz, CDCl3, 298 K) of (a) [2]rotaxane endoalkyl 23+. (b) Enlargement of the 4.0-5.0 ppm section of the 1H NMR spectrum in (a): the signals of the oriented endo-benzyl 23+ [2]rotaxane are marked in magenta and in blu.

Conclusions The threading of calix[6]arene wheel 3 with alkylbenzylammonium axles can occur by both the two possible routes of entering: through-the-upper-rim and through-the-lower-rim passages. Under thermodynamic conditions, the two possible oriented calix[2]pseudorotaxane, namely endo-benzyl and ACS Paragon Plus Environment

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endo-alkyl, are obtained for both 7+ and 8+ axles. Under those conditions, the stereoselectivity is controlled by the endo-alkyl rule with the observed prevalence of the endo-alkyl stereoisomer. Interestingly, in the threading of 3 with 8+ two calix[2]pseudorotaxane isomers are observed in which the calix-wheel adopts a 1,2,3-alternate and a cone conformation, which represent the kinetic and thermodynamic species, respectively. In fact, the preferred 1,2,3-alternate conformer of 3 is quickly threaded by 8+ to give the calix[2]pseudorotaxane 21+1,2,3 . Upon equilibration, this initially-formed pseudorotaxane is consumed in favor of the more stable 21+cone only via a de-threading/re-threading mechanism. The control on the directionality of the threading of 3 with 7+ and 8+ is a prerequisite to the stereoselective synthesis of the first examples of ammonium-based oriented calix[2]rotaxanes 22+ and 23+. The stereoselective synthesis of these oriented interpenetrated architectures could allow the design of novel and intriguing calixarene-based molecular machines with expanded properties or functions.

Experimental Section

General Information.

ESI(+)-MS measurements were performed on a Micromass Bio-Q triple quadrupole mass spectrometer equipped with electrospray ion source, using a mixture of H2O/CH3CN (1:1) and 5% HCOOH as solvent. Flash chromatography was performed on Merck silica gel (60, 40-63 µm). All chemicals were reagent grade and were used without further purification. Anhydrous solvents were purchased from Aldrich. When necessary compounds were dried in vacuo over CaCl2. Reaction temperatures were measured externally. Reactions were monitored by TLC on Merck silica gel plates (0.25 mm) and visualized by UV light, or by sprying with H2SO4-Ce(SO4)2 or phosphomolybdic acid. Derivatives 3,11b 15,19 1813b were synthesized according to literature procedures. NMR spectra were recorded on a Bruker Avance-600 spectrometer [600 (1H) and 150 MHz (13C)], Bruker Avance-400 spectrometer [400 (1H)


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and 100 MHz (13C)], Bruker Avance-300 spectrometer [300 (1H) and 75 MHz (13C)], or Bruker Avance250 spectrometer [250 (1H) and 63 MHz (13C)]; chemical shifts are reported relative to the residual solvent peak (CHCl3: δ 7.26, CDCl3: δ 77.23; CD3OH: δ 4.87, CD3OD: δ 49.0; (CD3)2CO). Standard pulse programs, provided by the manufacturer, were used for 2D NMR experiments, COSY-45, HSQC, ROESY. COSY-45 spectra were taken using a relaxation delay of 2 s with 30 scans and 170 increments of 2048 points each. HSQC spectra were performed with the gradient selection, sensitivity enhancement, and phase-sensitive mode using an Echo/Antiecho-TPPI procedure. Typically, 20 scans with 113 increments of 2048 points each were acquired.

Synthesis of Derivative 11 K2CO3 (2.05 g, 14.8 mmol) and NaI (catalytic amounts) were added to a solution of derivative 9 (1.00 g, 2.97 mmol) in CH3CN (180 mL). The mixture was stirred for 30 min., then 1,6-dibromohexane 10 (1.45 g, 5.94mmol, 0.91 mL) was added. The mixture was refluxed for 18 h. The solution was cooled at room temperature and the solvent evaporated under reduced pressure. The residue was partitioned between 1M solution of HCl (150 mL) and CH2Cl2 (150 mL), the organic layer was washed successively with H2O and then dried over Na2SO4. Removal of the solvent under reduced pressure gave the crude product, which was precipitated in hexane. Derivative 11 was obtained as a white solid (0.99 g, 2.00 mmol, 67%), which was sufficiently pure for subsequent synthetic manipulations. mp 85-86 °C; 1H NMR (250 MHz, CDCl3, 298 K): δ 1.50-1.52 (overlapped, 4H), 1.79-1.92 (overlapped, 4H), 3.42 (t, J = 6.1 Hz, 2H), 3.94 (t, J = 6.2 Hz, 2H), 6.77 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 7.18 - 7.26 (overlapped, 15H).

13

C NMR (100 MHz, CDCl3, 298 K) : δ 25.6, 28.2, 29.4, 33.0, 34.1, 64.6, 67.8,

113.5, 126.1, 127.7, 131.4, 132.5, 139.1, 147.3, 157.3. Anal. Calcd for C31H31BrO: C, 74.54; H, 6.26. Found: C,74.63; H, 6.15. Synthesis of Derivative 12 ACS Paragon Plus Environment

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Derivative 11 (0.13 g, 1.04 mmol) was dissolved in CH3CN (80 mL) and K2CO3 (0.55 g, 4.00 mmol), [18]crown-6 (catalytic amounts) and p-hydroxybenzaldehyde (0.52 g, 1.04mmol) was added to the solution.The resulting mixture was refluxed for 18 h, the solvent was evaporated under reduced pressure and the reaction residue was partitioned between HCl 1 M (40 mL) and AcOEt (60 mL). The organic layer was washed with deionized H2O and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (SiO2, CH2Cl2) to give derivative 12 (0.28 g, 0.52 mmol, 50%) as a yellow oil. 1H NMR (250 MHz, CDCl3, 298 K): δ 1.821.83 (overlapped, 8H), 3.95 (t, J= 6.5 Hz, 2H), 4.05 (t, J= 6.3 Hz, 2H), 6.76 (d, J= 8.6 Hz, 2H), 6.98 (d, J= 8.6 Hz, 2H), 7.09 (d, J= 8.6 Hz, 2H), 7.21 (overlapped, 15H), 7.82 (d, J= 8.75 Hz, 2H), 9.88 (s, 1H). 13

C NMR (63 MHz, CDCl3, 298 K): δ 26.1, 29.2, 29.4, 64.5, 67.8, 68.4, 113.4, 114.9, 126.0, 127.6,

130.0, 131.3, 132.2, 132.3, 139.0, 147.2, 157.1, 164.4, 191.0. Anal. Calcd for C38H36O3: C, 84.41; H, 6.71. Found: C,84.45; H, 6.72. Synthesis of Derivative 13 A solution of derivative 12 (0.27 g, 0.50 mmol) and derivative 6-amino-1-hexanol (0.06 g, 0.50mmol) in CHCl3 was stirred for 2 h at room temperature. Solvent removal was performed in vacuo, to give the imine intermediate as a white solid in a quantitative yield, which was used in the next step without further purification. The imine was dissolved in THF (40 mL) and NaBH4 (0.39 g, 10.2 mmol) was added at 0 °C and then the mixture was allowed to warm at room temperature. The mixture was kept under stirring for 2 h and the solvent was removed under reduced pressure. The residue was partitioned between AcOEt (50 mL) and an aqueous saturated solution of NaHCO3 (60 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to give amine derivative (0.31 g, 0.49 mmol, 98%) as a yellow solid. Secondary amine derivative (0.31 g, 0.49 mmol) was dissolved in THF (40 mL) at room temperature and then an aqueous solution of HCl (37% w/w, 0.2 mL) was added dropwise. The mixture was kept under stirring for 1 h, then solvent was removed under reduced pressure. The residue was dissolved in hot CH3CN. A white precipitate was formed when solution was ACS Paragon Plus Environment

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cooled at room temperature and it was collected by filtration, washed with CH3OH and dried under vacuum to give ammonium chloride derivative 13 (0.21 g, 0.31mmol, 63% compared to amine intermediate) as a white solid. mp 101-102 °C; 1H NMR (400 MHz, CDCl3, 298 K): δ 1.37-1.40 (overlapped, 4H), 1.55-1.60 (overlapped, 8H), 1.82-1.84 (overlapped, 4H), 2.66 (t, J = 7.2 Hz, 2H), 3.64 (t, J = 6.4 Hz, 2H), 3.77 (s, 2H), 3.95-3.99 (overlapped, 4H), 6.80 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 7.21-7.29 (overlapped, 17H). 13C NMR (100 MHz, CDCl3, 298 K): δ 26.0, 27.0, 29.3, 29.4, 29.5, 29.8, 32.7, 48.9, 53.2, 62.7, 64.4, 67.8, 68.0, 113.3, 114.5, 125.9, 127.5, 129.7, 131.2, 138.9, 147.2, 157.1, 158.4. Anal. Calcd for C44H52ClNO3: C, 77.91; H, 7.73; N, 2.06. Found: C,77.95; H, 7.72; N, 2.05. Synthesis of Derivative 7+·TFPB˗ Ammonium

chloride

derivative

13

(0.12

g,

0.18

mmol)

and

sodium

tetrakis[3,5-

bis(trifluoromethyl)phenyl]borate (0.18 g, 0.20 mmol) were dissolved in dry MeOH (50 mL). The solution was stirred for 18 h in the dark, then the solvent was removed and deionized water was added, obtaining a light brown precipitate, that was filtered off and dried under vacuum to give thread 8+ ·TFPB- (0.17 g,0.11 mmol, 61%) as a brown solid. Decomposes above 105°C; 1H NMR (250 MHz, CDCl3, 298 K): δ 1.39-1.56 (overlapped, 6H), 1.53-1.84 (overlapped, 10H), 3.02 (m, 2H), 3.69 (m, 2H), 3.96-3.99 (overlapped, 6H), 6.78 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 7.21-7.27 (overlapped, 19H), 7.56 (s, 4H),7.72 (s, 8H),

13

C NMR (100 MHz, CDCl3, 298 K): δ23.9, 25.1, 26.0, 29.2, 29.4,

29.7, 47.4, 52.8, 63.0, 64.5, 67.9, 68.4, 113.4, 116.0, 117.8, 119.9, 122.0, 123.8, 125.6, 126.1, 127.5, 127.61, 127.6, 127.7, 129.0, 129.3, 130.9, 131.3, 132.4, 135.0, 139.2, 147.2, 157.2, 161.4, 161.7, 162.0, 162.4. Anal. Calcd for C76H64BF24NO3: C, 60.61; H, 4.28; N, 0.93. Found: C, 60.64; H, 4.26; N, 0.91. Synthesis of compound 16 To a suspension of 9 (1.93 g, 5.72 mmol) in CH3CN (100 mL) was added K2CO3 under stirring (0.99 g, 7.16 mmol). The mixture was refluxed for 1 h, then derivative 15 (1.85 g, 5.96 mmol) was added and


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mixture was refluxed for 12 h. After concentration under vacuum, the mixture was partitioned between CH2Cl2 (120 mL) and water (100 mL), then organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give derivative 16 (3.12 g, 5.49 mmol, 96%). mp 78-79 °C 1H NMR (400 MHz, CDCl3, 298 K): δ 1.40-1.55 (overlapped, 4H), 1.69-1.75 (overlapped, 4H), 3.66-3.71 (m, 2H), 3.89-3.92 (m, 2H), 6.72-7.75 (m, 2H), 7.05-7.08 (m, 2H), 7.16-7.26 (overlapped, 15H), 7.687.70 (m, 2H), 7.82-7.84 (m, 2H).

13

C NMR (100 MHz, CDCl3, 298 K): 25.9, 26.8, 28.7, 29.3, 38.1,

64.4, 67.7, 113.3, 114.4, 123.3, 126.0, 127.5, 131.3, 132.3, 132.6, 134.0, 138.9, 147.2, 157.1, 168.7. Anal. Calcd for C39H35NO3: C, 82.80; H, 6.24; N, 2.48. Found: C, 82.86; H, 6.25; N, 2.50. Synthesis of compound 17 A solution of derivative 16 (1.45 g, 2.64 mmol) and hydrazine (150 mmol, 24.8 mL, 50-60% v/v solution in H2O) in EtOH was refluxed for 2 h. The solution was cooled at room temperature and H2O (100 mL) was added. The product was extracted with CH2Cl2 (3 x 100 mL) and the organic layers were collected and dried over Na2SO4, filtered and evaporated under reduced pressure to give derivative 17 as a white solid (1.14 g, 2.61 mmol, 99%) as a yellow oil.;1H NMR (300 MHz, CDCl3, 298 K): δ 1.381.45 (overlapped, 6H), 1.71-1.75 (overlapped, 2H), 2.65 (t, J = 5.7 Hz, 2H), 3.88 (t, J = 6.3 Hz, 2H), 6.72 (d, J = 9.0 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 7.14-7.22 (overlapped, 15H).

13

C NMR (75 MHz,

CDCl3, 298 K): δ 26.1, 26.8, 29.5, 33.5, 42.1, 64.5, 67.9, 113.4, 126.0, 127.6, 131.3, 132.3, 138.9, 147.3,157.2. Anal. Calcd for C31H33NO: C, 85.48; H, 7.64; N, 3.22. Found: C, 85.50; H, 7.65; N, 3.23. Synthesis of compound 19 Derivative 18 (0.25 g, 1.13 mmol) was added to a solution of derivative 17 (0.49 g, 1.13 mmol) in CHCl3 (8.0 mL). The mixture was stirred at room temperature for 2 h, then solvent was removed under reduced pressure to give the imine intermediate as yellow oil, which was used in the next step without further purification. A solution of the imine in CH3OH (15 mL) was cooled to 0 °C, then NaBH4 (0.85 g, 22.60 mmol) was slowly added. The mixture was allowed to warm to room temperature and stirred for 1


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h. The solvent was removed under reduced pressure and the residue was partitioned between AcOEt (120 mL) and aqueous saturated solution of NaHCO3 (100 mL). The organic layer was removed under reduced pressure. The resulting crude was purified by flash chromatography on silica gel (CH2Cl2/CH3OH, 95/5, v/v) to give the amine derivative. Amine derivative (0.27 g, 0.42 mmol) was dissolved in THF (50 mL) at 0 °C and an acqueous solution of HCl (37% w/w, 0.50 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was kept under stirring for 1 h. The solvent was removed under reduced pressure to give a residue which was dissolved in hot CH3CN. The solution was cooled at room temperature to give a white precipitate, which was collected by filtration and dried under vacuum to give derivative 19 as a white solid (0.21 g, 0.31 mmol, 74% compared to amine intermediate). mp 110-115 °C; 1H NMR (300 MHz, CD3OD, 298K): δ 1.41-1.54 (overlapped, 10H), 1.65-1.76 (overlapped, 6H), 2.96 (m, 2H), 3.51 (t, J = 6.4 Hz, 2H), 3.92 (m, 4H), 4.06 (s, 2H), 6.72 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 7.10-7.20 (overlapped, 15H), 7.34 (d, J = 8.4 Hz, 2H).

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C NMR (75 MHz, CD3OD, 298 K): δ 27.0, 27.1, 27.3,

30.1, 30.3, 33.6, 48.2, 51.9, 62.9, 65.5, 68.6, 69.0, 114.3, 116.1, 124.2, 127.0, 128.4, 132.2, 132.5, 133.3, 140.2, 148.5, 158.6, 161.6. Anal. Calcd for C44H52ClNO3: C, 77.91; H, 7.73; N, 2.06. Found: C, 77. 90.; H, 7.74; N, 2.05. Synthesis of Derivative 8+·TFPB˗ Sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (0.13 g, 0.15 mmol) was added to a solution of derivative 19 (0.10 g, 0.15 mmol) in dry CH3OH (30 mL). The mixture was kept under stirring in the dark for 24 h, then the solvent was removed and deionized water was added, obtaining a precipitate which was filtered off and after liophilized overnight to give a yellow-brownish solid, derivative 8+· (0.20 g, 0.13 mmol, 87%). Decomposes above 108°C; 1H NMR (300 MHz, CD3OD, 298K): δ 1.47-1.54 (overlapped, 10H), 1.62-1.76 (overlapped, 6H), 2.96 (t, J = 7.5 Hz, 2H), 3.51 (t, J = 6.3 Hz, 2H), 3.823.96 (overlapped, 4H), 4.06 (s, 2H), 6.73 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 7.10-7.21 (overlapped, 15H), 7.34 (d, J = 8.6 Hz, 2H), 7.55 (s, 12H). ACS Paragon Plus Environment

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C NMR (75 MHz, 25


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CD3OD, 298 K): δ 26.7, 27.0, 27.1, 27.3, 30.1, 30.3, 30.7, 33.6, 51.9, 62.9, 65.6, 68.6, 69.1, 114.2, 116.1, 118.5, 120.4, 124.0, 124.2, 127.0, 127.6, 128.4, 130.3, 130.7, 131.2, 132.2, 132.4, 133.3, 135.8, 140.2, 148.4, 158.6, 161.9, 162.5, 163.2, 163.9. Anal. Calcd for C76H64BF24NO3: C, 60.61; H, 4.28; N, 0.93. Found: C,60.66; H, 4.29; N, 0.95. Preparation of 20+·TFPB˗ and 21+·TFPB˗

pseudorotaxanes for 1D and 2D NMR studies:

Derivative 3 (3.0×10-3 M) and thread 7+·TFPB˗ or 8+·TFPB˗ (3.0×10-3 M) were dissolved in CDCl3. The mixture was stirred at 55 °C for 12 h and were used for 1D and 2D NMR studies. Synthesis of oriented calix[2]rotaxane 22+·TFPB˗: Derivative 3 (0.20 g, 0.14 mmol) and thread 7+·TFPB˗ (0.21 g, 0.14 mmol) were dissolved in dry CHCl3 (15 mL). The mixture was stirred at 55 °C for 12 h and were checked by 1H NMR and the mixture was used for the subsequent stoppering reaction. Di-n-butyltindilaurate (3 drops) was added to the above mixture and subsequently 4triphenylmethylphenylisocyanate (0.25 g, 0.70 mmol) was added. The reaction was kept under stirring at 55 °C for 72 h, then the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (Hexanes/CH2Cl2, 70/30, v/v) to give 22+·TFPB˗ [2]rotaxanes as a yellow pale oil (0.07 g, 0.02 mmol, 13 %): 1H NMR (600 MHz, CDCl3, 298 K): δ 0.76-0.71 (overlapped, β and γ, 4H), -0.51 (m, δ, 2H), 0.27 (m, α, 2H), 0.71 (m, ε, 2H), 0.90 (t, J = 7.1 Hz, 18H), 1.21 (s, 54H, But), 1.28-1.35 (overlapped, 36H,), 1.60-1.64 (overlapped, 4H), 1.72-1.76 (overlapped, 12H), 1.77-1.94 (overlapped, 4H), 3.21 (broad, 2H), 3.46 and 4.51* (AX, ArCH2Ar, J = 14.4 Hz, 12H), 3.47-4.58 (AX, J = 14.4 Hz 12H), 3.49 (t, ζ, J = 6.8 Hz, 2H), 3.78 (t, J = 8.0 Hz, 12H), 3.99-4.05 (overlapped, 4H), 4.28 and 4.94* (AX, ArH, J = 9.1 Hz, 12H), 5.68 (broad, 2H), 6.3 (broad, 2H), 6.80 (d, J = 8.9 Hz, 2H), 7.07-7.13 (overlapped, 4H), 7.20-7.28 (overlapped, 46H), 7.54 (s, 4H), 7.74 (s, 8H), 7.86 (d, J = 8.5 Hz, 2H).

13

C NMR (150 MHz, CDCl3, 298 K): δ 14.2, 23.0, 25.7, 30.5,

31.6, 32.2, 34.4, 64.2, 64.5, 64.7, 67.8, 68.4, 75.8, 113.3, 113.4, 114.6, 117.6, 123.9, 125.7, 126.0,126.1, 126.2, 126.4, 126.5, 127.5, 127.6, 127.7, 127.8, 128.0, 128.5, 128.9, 129.1, 129.7, 131.0, 131.1, 131.3, 131.4, 132.0, 132.4, 132.5, 132.6, 135.0, 146.9, 147.0, 147.2, 152.0, 157.2, 161.0, 161.4, 161.7, 162.1. ACS Paragon Plus Environment

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*

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

Signals attributable to endo-benzyl-22+·TFPB˗ stereoisomer. Anal. Calcd for C204H239BF24N2O10:

C,73.23; H, 7.20; N, 0.84. Found: C,73.26; H, 7.25; N, 0.83. Synthesis of the oriented calix[2]rotaxane 23+·TFPB˗: Derivative 3 (0.20 g, 0.14 mmol) and thread 7+·TFPB˗ (0.21 g, 0.14 mmol) or 8+·TFPB˗ (0.21 g, 0.14 mmol) were dissolved in dry CHCl3 (15 mL). The mixture was stirred at 55 °C for 12 h and were checked by 1H NMR and the mixture was used for the subsequent stoppering reaction. Di-n-butyltindilaurate (3 drops) was added to the above mixture and subsequently 4-triphenylmethylphenylisocyanate (0.25 g, 0.70 mmol) was added. The reaction was kept under stirring at 55 °C for 72 h, then the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (Hexanes/CH2Cl2, 70/30, v/v) to give 23+·TFPB˗ [2]rotaxanes as a yellow pale oil (0.18 g, 0.05 mmol, 39 %).endo-alkyl 23+cone·TFPB˗: 1

H NMR (600 MHz, CDCl3, 298 K): δ -0.72 (overlapped, β and γ, 4H,), -0.38 (broad, δ, 2H), 0.36

(broad, α, 2H), 0.81 (broad, ε, 2H), 0.96 (t, J = 6.5 Hz, 18H), 1.20 (s, 54H), 1.30-1.38 (overlapped, 36H), 1.56-1.61 (overlapped, 4H), 1.78-1.79 (overlapped, 14H), 1.93-1.96 (m, 2H), 3.27 (m, 2H), 3.33 (t, ζ, J = 6.2 Hz, 2H), 3.48 and 4.55* (AX, ArCH2Ar, J = 12.2 Hz, 12H), 3.49 and 4.60 (AX, ArCH2Ar, J = 13.2 Hz, 12H), 3.80 (t, J = 7.7 Hz, 12H), 3.90* (t, OCH2calix, J = 6.1 Hz, 12H), 4.05 (t, J = 6.2 Hz, 2H), 4.16* (t, J = 6.1 Hz, 2H), 4.23 (t, J = 6.6 Hz, 2H), 4.25 and 4.91* (AX, ArH, J = 9.6 Hz, 4H), 4.27* (t, J = 7.2 Hz, 2H), 5.80 (broad, +NH2, 2H), 6.55 (d, J = 8.5 Hz, 2H), 6.60 (s, 1H) 7.09 (d, J = 8.2 Hz, 2H), 7.20-7.30 (overlapped, 48H), 7.56 (s, 4H), 7.76 (s, 8H), 7.89 (d, J = 8.2 Hz, 2H).

13

C NMR (150

MHz, CDCl3, 298 K): δ 15.5, 24.2, 25.3, 25.6, 26.88, 26.94, 27.2, 27.4, 29.5, 30.4, 31.1, 31.7, 33.4, 35.7, 49.4, 53.9, 65.7, 65.9, 66.5, 67.8, 69.6, 77.1, 114.5, 115.8, 118.8, 118.8, 119.0, 123.3, 125.07, 125.10, 126.9, 127.3, 127.4, 127.7, 127.8, 128.7, 128.8, 128.9, 130.0, 130.17, 130.19, 130.20, 130.38, 130.40, 130.41, 130.6, 132.5, 133.3, 133.4, 133.8, 136.3, 137.1, 140.3, 143.4, 148.2, 148.5, 153.2, 155.1, 158.0, 162.2, 162.7, 163.0, 163.3, 163.6. Anal. Calcd for C204H239BF24N2O10: C,73.23; H, 7.20; N, 0.84. Found: C,73.22; H, 7.19; N, 0.85. *Signals attributable to the endo-benzyl-23+·TFPB˗ stereoisomer ACS Paragon Plus Environment

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Acknowledgements

We thank the Italian MIUR (PRIN 20109Z2XRJ_006) for financial support and the Centro di Tecnologie Integrate per la Salute (Project PONa3_00138), Università di Salerno, for the 600 MHz NMR instrumental time. Supporting Information: 1H NMR spectra, and 2D NMR spectra of new compounds, details on the DFT calculations. This material is available free of charge via the Internet at http://pubs.acs.org.

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(9) In the calixarene chemistry the term “inherent” is particularly used to indicate a novel form of chirality which “arises from the introduction of a curvature in an ideal planar structure that is devoid of perpendicular symmetry planes in its bidimensional representation", see: Szumna, A. Chem. Soc. Rev. 2010, 39, 4274−4285. Thus, regarding the calix-wheel 3, we introduce the term “inherent directionality” to emphasize that its vase-like structure (a curvature with respect to its ideal planar structure) results in two structurally different rims (endo and exo). (10) (a) A. Arduini, G. Orlandini, A. Secchi, A. Credi, S. Silvi, M. Venturi in Calixarenes and Beyond, Eds.: Neri, P.; Sessler, J. L.; Wang M. –X., Eds., Springer: Dordrecht, 2016, pp. 761-781. (b) Arduini, A.; Bussolati, R.; Credi, A.; Secchi, A.; Silvi, S.; Semeraro, M.; Venturi, M. J. Am. Chem. Soc. 2013, 135, 9924−9930. (c) Arduini, A.; Calzavacca, F.; Pochini, A.; Secchi, A. Chem. Eur. J. 2003, 9, 793− 799. (d) Arduini, A.; Ciesa, F.; Fragassi, M.; Pochini, A.; Secchi, A. Angew. Chem. Int. Ed. 2005, 44, 278–281. (e) Arduini, A.; Credi, A.; Faimani, G.; Massera, C.; Pochini, A.; Secchi, A.; Semeraro, M.; Silvi, S.; Ugozzoli, F. Chem. Eur. J. 2007, 14, 98–106. (f) Arduini, A.; Bussolati, R.; Credi, A.; Monaco, S.; Secchi, A.; Silvi, S.; Ventura, M. Chem. Eur. J. 2012, 18, 16203–16213. (g) Zanichelli, V.; Ragazzon, G.; Arduini, A.; Credi, A.; Franchi, P.; Orlandini, G.; Venturi, M.; Lucarini, M.; Secchi, A.; Silvi, S. Eur. J. Org. Chem. 2016, 1033–1042. (h) Orlandini, G.; Ragazzon, G.; Zanichelli, V.; Secchi, A.; Silvi, S.; Venturi, M.; Credi, A. Chem. Commun. 2017, 53, 6172˗6174. (11) (a) Talotta, C.; Gaeta, C.; Neri, P. Org. Lett. 2012, 14, 3104–3107. (b) Gaeta, C.; Talotta, C.; Mirra, S.; Margarucci, L.; Casapullo, A.; Neri, P. Org. Lett. 2013, 15, 116–119. For other examples of stereoisomerism based on threading of calixarene macrocycles, see: (c) Gaeta, C.; Talotta, C.; Neri, P. Chem. Commun. 2014, 50, 9917–9920. (d) Talotta, C.; De Simone, N. A.; Gaeta, C.; Neri, P. Org. Lett. 2015, 17, 1006−1009. (e) De Rosa, M.; Talotta, C.; Gaeta, C.; Soriente, A.; Neri, P.; Pappalardo, S.; Gattuso, G.; Notti, A.; Parisi, M. F.; Pisagatti, I. J. Org. Chem. 2017, 82, 5162–5168. (12) (a) Ciao, R.; Talotta, C.; Gaeta, C.; Margarucci, L.; Casapullo, A.; Neri, P. Org. Lett. 2013, 15, 5694−5697. (b) Ciao, R.; Talotta, C.; Gaeta, C.; Neri, P. Supramol. Chem., 2014, 26, 569–578. ACS Paragon Plus Environment

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(13) TFPB = Tetrakis[3,5-bis(triFluoromethyl)Phenyl]Borate, superweak anion, see: (a) Strauss, S. H. Chem. Rev. 1993, 93, 927−942. (b) Gaeta, C.; Talotta, C.; Farina, F.; Teixeira, F. A.; Marcos, P. A.; Ascenso, J. R.; Neri, P. J. Org. Chem. 2012, 77, 10285–10293. (c) Gaeta, C.; Talotta, C.; Farina, F.; Camalli, M.; Campi, G.; Neri, P. Chem. Eur. J. 2012, 18, 1219–1230. (d) Talotta, C.; Gaeta, C.; Neri, P. J. Org. Chem. 2014, 79, 9842-9846. (e) Hou, H.; Leung, K. C.-F.; Lanari, D.; Nelson, A.; Stoddart, J. F.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 13358–13359. (f) For a review on counterion effects in supramolecular chemistry, see: Gasa, T. B.; Valente, C.; Stoddart, J. F. Chem. Soc. Rev. 2011, 40, 57– 78. (g) Talotta, C.; Gaeta, C.; De Rosa, M.; Ascenso, J. R.; Marcos, P. M.; Neri, P. Eur. J. Org. Chem. 2016, 158–167. (14) Hirose, K. in Analytical Methods in Supramolecular Chemistry; Schalley, C. A., Ed.; WileyVCH: Weinheim, 2007, Chapter 2, pp. 17–54 (15) Grimme, S. J. Comput. Chem.,2006, 27, 1787−1799. The Grimme’s dispersion correction has been already used for DFT calculations in calixarene-based pseudorotaxane structures, see reference 11f (16) See Supporting Information for further details. (17) These values are in accord with the C-H···π distance parameters indicated by Nishio in: Suezawa, H.; Ishihara, S.; Umezawa, Y.; Tsuboyama, S.; Nishio, M. Eur. J. Org. Chem. 2004, 4816–4822. (18) Previously our group reported an example of ammonium-based pseudorotaxane, in which the calix-wheel 3 adopted a 1,2,3-alternate conformation, see reference 11g. (19) Pfammatter, M. J.; Siljegovic, V.; Darbre, T.; Keese, R. Helvetica Chimica Acta 2001, 84, 678−689.


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Threading of an Inherently Directional Calixarene Wheel with Oriented

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