Threading of an Inherently Directional Calixarene Wheel with Oriented Ammonium Axles

Article abstract of DOI:10.1021/acs.joc.7b01388

The threading of monostoppered alkylbenzylammonium axles 7⁺ and 8⁺ with the calix[6]-wheel 3 can occur by both routes of entering the macrocycle 3 in the cone conformation: passage through the upper rim and the through the lower rim. Thus, under thermodynamic conditions, with both the axles 7⁺ and 8⁺, the two possible orientations of calix[2]pseudorotaxane, namely, endo-benzyl and endo-alkyl, are formed by a stereoselectivity controlled by the 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-wheel adopts 1,2,3-alternate and cone conformations, which represent the kinetic and thermodynamic species, respectively. Finally, the synthesis of ammonium-based oriented calix[2]rotaxane is here described.

Full text of DOI:10.1021/acs.joc.7b01388

Subscriber access provided by UNIV OF UTAH
Article
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
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry 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.

Page 1 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
On the Threading of an Inherently Directional
7
8
9
10
11
12
13
Calixarene Wheel with Oriented Ammonium Axles
Pellegrino La Manna, Carmen Talotta,* Carmine Gaeta, Annunziata Soriente, Margherita De Rosa,
and Placido Neri
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
Dipartimento di Chimica e Biologia “A. Zambelli”, Università di Salerno, Via Giovanni Paolo II 132,
Iꢀ84084 Fisciano (Salerno), Italy,
eꢀmail: ctalotta@unisa.it
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 monoꢀstoppered 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:
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 31
throughꢀtheꢀupperꢀrim and the throughꢀtheꢀlowerꢀrim passage. Thus, under thermodynamic conditions,
with both the axles 7+ and 8+ the two possible oriented calix[2]pseudorotaxane, namely endoꢀbenzyl and
endoꢀalkyl, are formed with a stereoselectivity controlled by endoꢀalkyl rule. Interestingly, by 1H NMR
monitoring of the threading process between 8+ and 3, we revealed two calix[2]pseudorotaxane isomers
in which the calixꢀweel adopts 1,2,3ꢀalternate and cone conformations and which represent the kinetic
and thermodynamic species, respectively. Finally, the synthesis of ammoniumꢀbased oriented
calix[2]rotaxane is here described.
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
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 smallꢀmolecule
synthetic walker7d and a chemicallyꢀfueled unidirectional circular motor.7e
2
ACS Paragon Plus Environment

Page 3 of 31
The Journal of Organic Chemistry
In the last three decades, calixarene macrocycles have found many applications as supramolecular
1
2
hosts8cꢀm 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 calixꢀwheel 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 triphenylureidoꢀcalix[6]arene wheel 1 (Figure 2) by a oriented monoꢀ
stoppered 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).
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
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
alkylbenzylꢀammonium axles (e.g. 4+, Figure 2) are threaded through a directional calix[6]arene wheel
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 31
(e.g., 3) by exploiting of the soꢀcalled “endoꢀalkyl rule”:12 threading of a directional
alkylbenzylammonium axle through a hexaalkoxycalix[6]arene occurs with an endoꢀalkyl preference.
By exploiting this “endoꢀalkyl rule”, we have recently reported the stereoselective synthesis of the first
examples of calixareneꢀbased 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 endoꢀalkyl 5+ orientational pseudorotaxane stereoisomer (Figure 2) over the endoꢀbenzyl 6+ one was
observed.11b
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
Figure 2. Oriented interpenetrated architectures based on the threading of directional calixꢀwheels.
In a more general case, an endoꢀalkyl pseudorotaxane (e.g.: 5+) could be formed by two different
routes of entering of the alkylbenzylammonium axle into the calixꢀwheel (e.g.: 3): the benzyl-through-
the-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
4
ACS Paragon Plus Environment

Page 5 of 31
The Journal of Organic Chemistry
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.
1
2
3
4
5
6
7
8
In order to get information on this threading directionality with the larger calix[6]arene wheel we
designed the monoꢀstoppered 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 monoꢀstoppered 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 endoꢀalkyl rule?
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
Figure 3. Possible pathways for the formation of endoꢀalkyl 5+ 11b pseudorotaxane by threading 3 with
4+.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 31
RESULTS AND DISCUSSION
1
2
3
4
5
Synthesis of TFPB− salts of monoꢀstoppered axles 7+ and 8+. The synthetic pathway to 7+•TFPB−
6
7
salt is outlined in Scheme 1.13
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
10
Br
Br
OH
4
O
Br
a)
O
H
b)
11
9
OH
OH
H2N
Cl-
4
O
O
O
O
CHO
N
H2
OH
+
c,d)
13
12
e)
F3C
CF3
CF3
TFPB-
F3C
F3C
CF3
CF3
TFPB- =
O
O
7+
B
N
+
OH
H2
F3C
Scheme 1. Synthesis of thread 7+. Reagents and conditions: a) K2CO3, NaI, CH3CN, reflux, 18 h;
b) K2CO3, [18]crownꢀ6, 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, 4ꢀtritylphenol 9 was treated with K2CO3 and reacted with 1,6ꢀdibromohexane 10 to give
monobromide 11. A mixture of 4ꢀhydroxybenzaldehyde and 11 in acetonitrile, in the presence of K2CO3
and 18ꢀcrown[6], was refluxed for 18 h to give aldehyde 12. This compound was then coupled with 6ꢀ
aminoꢀ1ꢀhexanol, 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.
6
ACS Paragon Plus Environment

Page 7 of 31
The Journal of Organic Chemistry
O
O
O
N-K+
1
2
b)
a)
Br
N
O
Br
N
Br
+
4
4
4
O
O
O
3
4
5
OH
14
10
15
16
9
c)
6
7
8
9
Cl-
N
e)
d,
O
H2N
O
O
HO
4
4
H2
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
O
19
17
H
HO
O
4
18
f)
F3C
F3C
CF3
TFPB-
CF3
TFPB- =
B
O
F3C
F3C
CF3
N
O
HO
4
H2
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 1,6ꢀdibromohexane 10, in DMF as solvent led to the formation of monobromide 15.
Compound 15 was then reacted with 4ꢀtritylphenol 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.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 31
Directional threading of calix[6]areneꢀwheel 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 endoꢀalkyl 20+ or endoꢀbenzyl 20+ (Scheme 3).
1
2
3
4
5
6
7
8
9
Preferred
HO
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
But
But
But
But
But
But
+
N
O
HO
H
O O
R
R
O
R
O
R
R
O
R
TFPB-
3 + 7+
+
O
CDCl3
But
O
But
But
But
But
But
O
+
N
O
HO
O O
R
R
O
O
R
H
R
R
R
TFPB-
HO
R = n-C6H13
endo-alkyl 20+
endo-benzyl 20+
Scheme 3. Formation of the oriented endoꢀalkyl and endoꢀbenzyl 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
endoꢀalkyl and endoꢀbenzyl 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 calixꢀwheel 3 takes place from
both rims of the macrocycle. The preferential formation of the endoꢀalkyl 20+ stereoisomer, in
accordance with the endoꢀalkyl rule,12 occurs by throughꢀtheꢀlowerꢀrim passage of calixꢀwheel 3.
8
ACS Paragon Plus Environment

Page 9 of 31
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
1
Figure 4. Significant portions of the H NMR spectra (400 MHz, CDCl3, 298 K) of: (a) 3; (b) 1:1
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
mixture (3.0×10ꢀ3 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
1
exchanging H NMR signals, was 3.5×102 Mꢀ1 (SI, page S21).14 DFT calculations (Figure 5) at the
B3LYP/6ꢀ31G(d,p) level of theory using Grimme’s dispersion corrections (IOp(3/124 = 3))15 indicated
the greater stability of the endoꢀalkyl 20+ stereoisomer over the endoꢀbenzyl one. In detail, endoꢀalkyl
20+ results stabilized by two Hꢀbonding interactions (Figure 5) between the ammonium group of 7+ and
the oxygen atoms of the calixꢀwheel 3, with an average N···O distance of 3.02 Å and an average Nꢀ
H···O angle of 159.5°.16 Additional four CꢀH···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
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 31
3,16 with an average CꢀH···πcentroid distance of 3.16 Å16,17 and an average CꢀH···πcentroid angle of 155°.16
As concerns the DFTꢀoptimized structure of the endoꢀbenzyl 20+ pseudorotaxane (Figure 5, right), two
1
2
3
4
5
6
+
Hꢀbonding interactions were detected between the NH2 group of 7+ and the oxygen atoms of 3, with a
7
8
9
longer average distance of 3.15 Å (with respect to that found in endoꢀalkyl 20+ stereoisomer of 3.02 Å)
and an average angle of 157°.16 Finally, two aromatic CꢀH···π interactions were observed between the
aromatic CꢀH of 7+ and the aromatic rings of calixꢀwheel 3, with an average distance CꢀH···πcentroid of
2.97 Å and an average CꢀH···πcentroid angle of 155.0°.16,17
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
Figure 5. DFTꢀoptimized structures16 of the oriented endoꢀalkyl (left) and endoꢀbenzyl (right) 20+
calix[2]pseudorotaxanes (B3LYP/6ꢀ31G(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 endoꢀalkyl and endoꢀbenzyl 21+, could be formed
(Figure 6).
10
ACS Paragon Plus Environment

Page 11 of 31
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
Figure 6. Chemical drawing of the oriented endoꢀalkyl and endoꢀbenzyl 21+ calix[2]pseudorotaxanes,
that could be formed by threading of 3 with axle 8+.
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
1
Interestingly, immediately after mixing of 3 with 8+ in CDCl3, the H 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 calixꢀwheel adopts a 1,2,3ꢀalternate conformation.18 After equilibration of the
mixture of 3 and 8+ in CDCl3 at 55 °C for 12 h, the signals of 21+
disappeared while those of endoꢀ
1,2,3
alkyl 21+
and endoꢀbenzyl 21+
(Scheme 4 and Figure 7cꢀd) emerged. Interestingly, 1D and 2D
cone
cone
NMR studies16 indicated that the oriented pseudorotaxane endoꢀalkyl 21+cone was preferentially formed
16
over endoꢀbenzyl 21+cone in a 98/2 ratio (Scheme 4). 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
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 31
21+
(Scheme 4). Indeed, the 1,2,3ꢀalternate conformation of free 3 is a preferred conformation in
1,2,3.
1
2
3
4
5
solution as evidenced by VT NMR studies (see SI,16 pages S35ꢀS38). Therefore, the threading of 31,2,3
by 8+ is faster than that of 3cone (Scheme 4)
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
Figure 7. Significant portions of the 1H NMR spectra (400 MHz, CDCl3, 298 K) of: a) 3; b) 1:1 mixture
(3.0×10ꢀ3 M) of 3 and 8+ immediately after mixing and c) after 12 h at 55 °C; d) Inserts: enlargement of
1
the H 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 endoꢀcavity benzylammonium unit of the
pseudorotaxane endoꢀbenzyl 21+.
12
ACS Paragon Plus Environment

Page 13 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
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 deꢀthreading of axle 8+ from 21+
can occur and a subsequent reꢀthreading
1,2,3
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
from the lower and upper rim of 3cone, would take place to give endoꢀbenzyl 21+
and endoꢀalkyl
cone
21+cone, respectively (Scheme 4). Second, a mechanism for the conversion of 21+1,2,3 to 21+cone (Scheme
4) based on a throughꢀtheꢀannulus 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 throughꢀtheꢀannulus passage of both the
hexyl chains and the tertꢀbutyl groups.13b In conclusion, under thermodynamic control, after 12 h at 55
°C, the pseudorotaxane 21+
initially formed is consumed in favor of the more stable 21+
only
cone
1,2,3
through a deꢀthreading/reꢀthreading mechanism (Scheme 4).
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Scheme 4. Mechanism for the formation of the oriented endoꢀalkyl and endoꢀbenzyl 21+
calix[2]pseudorotaxanes by threading of 8+ with 3.
Page 14 of 31
cone
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
1
The preferential formation of endoꢀalkyl 21+cone stereoisomer was indicated by the presence in the H
NMR spectrum (Figure 7c) of the typical signature at highfield negative values (α, β, γ, and δ protons,
in red) characteristic of an endoꢀcomplexation of the alkyl chains of 8+. The apparent association
constant for endoꢀalkyl 21+cone, calculated by integration of its slowly exchanging H NMR signals, 16
1
was 5.5×102 M−1.16 The presence of endoꢀbenzyl 21+
was indicated by the expected upfield AX
cone
system between 4.0 and 5.0 ppm (see insets in Figure 7d) of ArH protons of the shielded endoꢀcavity
benzylammonium unit (in magenta in Scheme 3 and Figure 7d). All the above results clearly indicate
that the monoꢀstoppered alkylbenzylammonium axle 8+ is able to thread the inherently directional
calix[6]areneꢀwheel 3 by entering from both rims (upper and lower) and that under thermodynamic
conditions the endoꢀalkyl pseudorotaxane prevails in accordance with the known endoꢀalkyl rule.
Summarizing, the formation of pseudorotaxane endoꢀalkyl 21+
passage of calixꢀwheel 3.
occurs by throughꢀtheꢀupperꢀrim
cone
14
ACS Paragon Plus Environment

Page 15 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Figure 8. DFTꢀoptimized structures of the oriented endoꢀalkyl (left) and endoꢀbenzyl (right) 21+
calix[2]pseudorotaxanes (B3LYP/6ꢀ31G(d,p) level of theory and using Grimme’s dispersion corrections
(IOp(3/124 = 3)).15
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
DFT calculations at the B3LYP/6ꢀ31G(d,p) level of theory using Grimme’s dispersion corrections
(IOp(3/124=3) 15 indicated a greater stability of the endoꢀalkyl 21+cone, over the endoꢀbenzyl one. A close
inspection of the optimized endoꢀalkyl 21+cone structure (Figure 8, left) reveals the presence of two Hꢀ
bonds between the ammonium group of the axle 8+ and the oxygen atoms of the calixꢀwheel 3, with an
average N···O distance of 3.0 Å and an average NꢀH···O angle of 159.2°.16 An extra stabilization of the
endoꢀalkyl 21+
structure was brought by CꢀH···π interactions17 between the
α and β methylene
cone
groups of the alkyl chain of 8+ inside the calix cavity and aromatic rings of 3, 16,17 with an average Cꢀ
H···πcentroid distance of 3.25 Å16,17 and an average CꢀH···πcentroid angle of 160°.16,17 A similar analysis of
the DFTꢀoptimized structure of endoꢀbenzyl 21+cone structure (Figure 8, right) revealed the presence of
two Hꢀbonding interactions between the ammonium group of 8+ and the oxygen atoms of the calixꢀ
wheel 3 with an average N···O distance of 3.0 Å and a narrower NꢀH···O angle of 152.3°.16 In addition,
two aromatic CꢀH···π interactions were detected between the aromatic ring of 8+, as CꢀH donor, and the
aromatic rings of the calixꢀwheel 3, as CꢀH acceptors, with an average distance CꢀH···πcentroid of 3.10 Å
and an average CꢀH···πcentroid angle of 145.8°.16
Synthesis of oriented calix[2]rotaxanes. The treatment of the mixture of the two
pseudorotaxanes endoꢀalkyl and endoꢀbenzyl 20+ with 4ꢀtriphenylmethylphenylisocyanate gave the
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 31
oriented [2]rotaxanes endoꢀalkyl 22+ and endoꢀbenzyl 22+ in 13 % total yield, in addition to the free
1
2
3
stoppered axle (Scheme 5).
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
Scheme 5. Synthesis of the oriented calix[2]rotaxanes 22+. a) Diꢀnꢀbutyltindilaurate, 4ꢀ
triphenylmethylphenylisocyanate, dry CHCl3, 55 °C, 72 h.
The isomeric mixture of endoꢀalkyl and endoꢀbenzyl 22+ was identified by 1D and 2D16 NMR
1
spectroscopy but not separated by chromatography. Integration of the H NMR signals of the two
isomeric rotaxane revealed a 96/4 endoꢀalkyl/endoꢀbenzyl ratio. The presence of the endoꢀalkyl 22+
1
rotaxane was confirmed by typical shielded resonances between 1.0 and −1.0 ppm in the H NMR
spectrum (Figure 9). Analogously, the presence of the endoꢀbenzyl 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 endoꢀcavity benzylammonium unit.
16
ACS Paragon Plus Environment

Page 17 of 31
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
1
Figure 9. (a) Significant portion of the H NMR spectrum of 22+ (600 MHz, CDCl3, 298K). b)
1
Enlargement of the 4.0ꢀ5.0 ppm section of the H NMR spectrum in (a): the signals of the oriented
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
[2]rotaxane endoꢀbenzyl 22+ are marked in magenta and in blu.
In a similar way, the mixture of endoꢀalkyl 21+
and endoꢀbenzyl 21+
pseudorotaxanes,
cone
cone
obtained after equilibration, was reacted with 4ꢀtriphenylmethylphenylisocyanate (Scheme 6) to give
directional endoꢀalkyl and endoꢀbenzyl 23+ calix[2]rotaxanes (Scheme 6) in 39 % total yield, in addition
to the free stoppered axle. The isomeric mixture of endoꢀalkyl and endoꢀbenzyl 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 endoꢀalkyl and endoꢀbenzyl 23+ stereoisomers. The presence of endoꢀ
alkyl 23+ stereoisomer was indicated by a typical signature at highfield negative values (in red
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 31
1
α, β, γ, δ, from 1.0 to −1.0 ppm) of the H NMR spectrum (Figure 10a), which is characteristic of an
1
2
3
endoꢀcavity alkylammonium moiety.
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
Scheme 6. Synthesis of the oriented calix[2]rotaxanes 23+. a) Diꢀnꢀbutyltindilaurate, 4ꢀ
triphenylmethylphenylisocyanate, dry CHCl3, 55 °C, 72 h.
A close inspection of the 1D and 2D NMR spectra16 also revealed the presence of the endoꢀ
benzyl 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 endoꢀcavity benzylammonium unit. This was confirmed by an AX
system attributable to the ArCH2Ar groups of the calixꢀwheel of endoꢀbenzyl 23+ rotaxane (in blu,
Figure 10b).
18
ACS Paragon Plus Environment

Page 19 of 31
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
Figure 10. Relevant portions of the 1H NMR spectra (600 MHz, CDCl3, 298 K) of (a) [2]rotaxane endoꢀ
alkyl 23+. (b) Enlargement of the 4.0ꢀ5.0 ppm section of the 1H NMR spectrum in (a): the signals of the
oriented endoꢀbenzyl 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: throughꢀtheꢀupperꢀrim and throughꢀtheꢀlowerꢀrim passages. Under
thermodynamic conditions, the two possible oriented calix[2]pseudorotaxane, namely endoꢀbenzyl and
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 31
endoꢀalkyl, are obtained for both 7+ and 8+ axles. Under those conditions, the stereoselectivity is
controlled by the endoꢀalkyl rule with the observed prevalence of the endoꢀalkyl stereoisomer.
Interestingly, in the threading of 3 with 8+ two calix[2]pseudorotaxane isomers are observed in which
the calixꢀwheel adopts a 1,2,3ꢀalternate and a cone conformation, which represent the kinetic and
thermodynamic species, respectively. In fact, the preferred 1,2,3ꢀalternate conformer of 3 is quickly
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
threaded by 8+ to give the calix[2]pseudorotaxane 21+
Upon equilibration, this initiallyꢀformed
1,2,3 .
pseudorotaxane is consumed in favor of the more stable 21+
only via a deꢀthreading/reꢀthreading
cone
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 ammoniumꢀbased oriented calix[2]rotaxanes 22+ and
23+. The stereoselective synthesis of these oriented interpenetrated architectures could allow the design
of novel and intriguing calixareneꢀbased molecular machines with expanded properties or functions.
Experimental Section
General Information.
ESI(+)ꢀMS measurements were performed on a Micromass BioꢀQ 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, 40ꢀ63 ꢁm). 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 H2SO4ꢀCe(SO4)2 or phosphomolybdic acid. Derivatives 3,11b
15,19 1813b were synthesized according to literature procedures. NMR spectra were recorded on a Bruker
Avanceꢀ600 spectrometer [600 (1H) and 150 MHz (13C)], Bruker Avanceꢀ400 spectrometer [400 (1H)
20
ACS Paragon Plus Environment

Page 21 of 31
The Journal of Organic Chemistry
and 100 MHz (13C)], Bruker Avanceꢀ300 spectrometer [300 (1H) and 75 MHz (13C)], or Bruker Avanceꢀ
250 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, COSYꢀ45, HSQC,
ROESY. COSYꢀ45 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 phaseꢀsensitive mode using an Echo/AntiechoꢀTPPI procedure. Typically, 20 scans with 113
increments of 2048 points each were acquired.
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
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 1,6ꢀdibromohexane 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
1
mmol, 67%), which was sufficiently pure for subsequent synthetic manipulations. mp 85ꢀ86 °C; H
NMR (250 MHz, CDCl3, 298 K): δ 1.50ꢀ1.52 (overlapped, 4H), 1.79ꢀ1.92 (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). 13C 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
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 31
Derivative 11 (0.13 g, 1.04 mmol) was dissolved in CH3CN (80 mL) and K2CO3 (0.55 g, 4.00 mmol),
[18]crownꢀ6 (catalytic amounts) and pꢀhydroxybenzaldehyde (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
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
1
derivative 12 (0.28 g, 0.52 mmol, 50%) as a yellow oil. H NMR (250 MHz, CDCl3, 298 K): δ 1.82ꢀ
1.83 (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).
13C 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 6ꢀaminoꢀ1ꢀhexanol (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
22
ACS Paragon Plus Environment

Page 23 of 31
The Journal of Organic Chemistry
cooled at room temperature and it was collected by filtration, washed with CH3OH and dried under
1
2
3
vacuum to give ammonium chloride derivative 13 (0.21 g, 0.31mmol, 63% compared to amine
4
5
6
1
intermediate) as a white solid. mp 101ꢀ102 °C; H NMR (400 MHz, CDCl3, 298 K): δ 1.37ꢀ1.40
7
8
9
(overlapped, 4H), 1.55ꢀ1.60 (overlapped, 8H), 1.82ꢀ1.84 (overlapped, 4H), 2.66 (t, J = 7.2 Hz, 2H), 3.64
(t, J = 6.4 Hz, 2H), 3.77 (s, 2H), 3.95ꢀ3.99 (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), 7.21ꢀ7.29 (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.
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
Synthesis of Derivative 7+ꢁTFPB˗
Ammonium chloride derivative 13 (0.12 g, 0.18 mmol) and sodium tetrakis[3,5ꢀ
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+
1
·TFPBꢀ (0.17 g,0.11 mmol, 61%) as a brown solid. Decomposes above 105°C; H NMR (250 MHz,
CDCl3, 298 K): δ 1.39ꢀ1.56 (overlapped, 6H), 1.53ꢀ1.84 (overlapped, 10H), 3.02 (m, 2H), 3.69 (m, 2H),
3.96ꢀ3.99 (overlapped, 6H), 6.78 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 7.21ꢀ7.27 (overlapped,
19H), 7.56 (s, 4H),7.72 (s, 8H), 13C 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
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 31
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
1
2
3
4
5
6
1
evaporated under reduced pressure to give derivative 16 (3.12 g, 5.49 mmol, 96%). mp 78ꢀ79 °C H
7
8
9
NMR (400 MHz, CDCl3, 298 K): δ 1.40ꢀ1.55 (overlapped, 4H), 1.69ꢀ1.75 (overlapped, 4H), 3.66ꢀ3.71
(m, 2H), 3.89ꢀ3.92 (m, 2H), 6.72ꢀ7.75 (m, 2H), 7.05ꢀ7.08 (m, 2H), 7.16ꢀ7.26 (overlapped, 15H), 7.68ꢀ
7.70 (m, 2H), 7.82ꢀ7.84 (m, 2H). 13C 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.
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
Synthesis of compound 17
A solution of derivative 16 (1.45 g, 2.64 mmol) and hydrazine (150 mmol, 24.8 mL, 50ꢀ60% 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 1.38ꢀ
1.45 (overlapped, 6H), 1.71ꢀ1.75 (overlapped, 2H), 2.65 (t, J = 5.7 Hz, 2H), 3.88 (t, J = 6.3 Hz, 2H),
13
6.72 (d, J = 9.0 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 7.14ꢀ7.22 (overlapped, 15H). 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
24
ACS Paragon Plus Environment

Page 25 of 31
The Journal of Organic Chemistry
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%
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
1
compared to amine intermediate). mp 110ꢀ115 °C; H NMR (300 MHz, CD3OD, 298K): δ 1.41ꢀ1.54
(overlapped, 10H), 1.65ꢀ1.76 (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), 7.10ꢀ7.20
13
(overlapped, 15H), 7.34 (d, J = 8.4 Hz, 2H). 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[3,5ꢀbis(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 yellowꢀbrownish solid, derivative 8+· ꢀ
(0.20 g, 0.13 mmol, 87%). Decomposes above 108°C; 1H NMR (300 MHz, CD3OD, 298K): δ 1.47ꢀ1.54
(overlapped, 10H), 1.62ꢀ1.76 (overlapped, 6H), 2.96 (t, J = 7.5 Hz, 2H), 3.51 (t, J = 6.3 Hz, 2H), 3.82ꢀ
3.96 (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), 7.10ꢀ7.21 (overlapped, 15H), 7.34 (d, J = 8.6 Hz, 2H), 7.55 (s, 12H). 13C NMR (75 MHz,
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 31
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.
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
Preparation of 20+ꢁTFPB˗ and 21+ꢁTFPB˗ pseudorotaxanes for 1D and 2D NMR studies:
Derivative 3 (3.0×10ꢀ3 M) and thread 7+ꢁTFPB˗ or 8+ꢁTFPB˗ (3.0×10ꢀ3 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.
Diꢀnꢀbutyltindilaurate (3 drops) was added to the above mixture and subsequently 4ꢀ
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 22+ꢁTFPB˗
1
[2]rotaxanes as a yellow pale oil (0.07 g, 0.02 mmol, 13 %): H NMR (600 MHz, CDCl3, 298 K): δ ꢀ
0.76ꢀ0.71 (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), 1.28ꢀ1.35 (overlapped, 36H,), 1.60ꢀ1.64 (overlapped, 4H), 1.72ꢀ1.76
(overlapped, 12H), 1.77ꢀ1.94 (overlapped, 4H), 3.21 (broad, 2H), 3.46 and 4.51* (AX, ArCH2Ar, J =
14.4 Hz, 12H), 3.47ꢀ4.58 (AX, J = 14.4 Hz 12H), 3.49 (t, ζ, J = 6.8 Hz, 2H), 3.78 (t, J = 8.0 Hz, 12H),
3.99ꢀ4.05 (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), 7.07ꢀ7.13 (overlapped, 4H), 7.20ꢀ7.28 (overlapped, 46H), 7.54 (s, 4H),
13
7.74 (s, 8H), 7.86 (d, J = 8.5 Hz, 2H). 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.
26
ACS Paragon Plus Environment

Page 27 of 31
The Journal of Organic Chemistry
*Signals attributable to endoꢀbenzylꢀ22+ꢁTFPB˗ stereoisomer. Anal. Calcd for C204H239BF24N2O10:
1
2
3
C,73.23; H, 7.20; N, 0.84. Found: C,73.26; H, 7.25; N, 0.83.
4
5
6
7
8
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. Diꢀnꢀbutyltindilaurate (3 drops) was added to the above mixture and
subsequently 4ꢀtriphenylmethylphenylisocyanate (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+coneꢁTFPB˗:
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
1H NMR (600 MHz, CDCl3, 298 K): δ ꢀ0.72 (overlapped,
β and γ, 4H,), ꢀ0.38 (broad, δ, 2H), 0.36
(broad, , 2H), 0.81 (broad, , 2H), 0.96 (t, J = 6.5 Hz, 18H), 1.20 (s, 54H), 1.30ꢀ1.38 (overlapped,
α
ε
36H), 1.56ꢀ1.61 (overlapped, 4H), 1.78ꢀ1.79 (overlapped, 14H), 1.93ꢀ1.96 (m, 2H), 3.27 (m, 2H), 3.33
, J = 6.2 Hz, 2H), 3.48 and 4.55* (AX, ArCH2Ar, J = 12.2 Hz, 12H), 3.49 and 4.60 (AX, ArCH2Ar,
(t,
ζ
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,
13
2H), 7.20ꢀ7.30 (overlapped, 48H), 7.56 (s, 4H), 7.76 (s, 8H), 7.89 (d, J = 8.2 Hz, 2H). 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 endoꢀbenzylꢀ23+ꢁTFPB˗
stereoisomer
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 31
1
2
3
Acknowledgements
4
5
6
7
8
9
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.
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
1
Supporting Information: H 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.
REFERENCES
(1) (a) Raymo, F. M.; Stoddart, J. F. Chem. Rev.1999, 99, 1643–1664. (b) Sauvage, J. P.; Dietrichꢀ
Buchecker, C., Molecular Catenanes, Rotaxanes and Knots: A Journey Through the World of Molecular
Topology. Wiley: 1999.
(2) (a) Leigh, D. A. Angew. Chem. Int. Ed. 2016, 55, 14506–7441. (b) Balzani, V.; Venturi, M.;
Credi, A., Molecular Devices and Machines: A Journey Into the Nano World. WileyꢀVCH: 2003.
(3) (a) Lewis, J. E. M.; Galli, M.; Goldup, S. M. Chem. Commun. 2017, 53, 298–312. (b) Yu, H.;
Luo, Y.; Beverly, K.; Stoddart, J. F.; Tseng, H.; Heath, J. R. Angew. Chem. Int. Ed. 2003, 42, 5706–
5711. (c) Green, J. E.; Choi, J.W.; Boukai, A.; Bunimovich, Y.; Halperin, E.; Delonno, E.; Luo, Y.;
Sheriff, B. A.; Xu, K.; Shin, Y. S.; Tseng, H.; Stoddart, J. F.; Heath, J. R. Nature, 2007, 445, 414–417.
(4) (a) Beswick, J.; Blanco, V.; De Bo, G.; Leigh, D. A.; Lewandowska, U.; Lewandowski, B.;
Mishiro, K. Chem. Sci. 2015, 6, 140–143. (b) Blanco, V.; Leigh, D. A.; Marcos, V. Chem. Soc. Rev.
28
ACS Paragon Plus Environment

Page 29 of 31
The Journal of Organic Chemistry
2015, 44, 5341–5370. (c) Blanco, V.; Leigh, D. A.; Lewandowska, U.; Lewandowski, B.; Marcos, V. J.
Am. Chem. Soc. 2014, 136, 15775−15780.
1
2
3
4
5
(5) Fuller, A.ꢀM. L.; Leigh, D. A.; Lusby, P. J. J. Am. Chem. Soc. 2010, 132, 4954−4959.
6
7
8
9
(6) (a) Bordoli, J. R.; Goldup, S. M. J. Am. Chem. Soc. 2014, 136, 4817−4820. (b) Neal, E. A.;
Goldup, S. M. Chem. Commun. 2014, 50, 5128−5142.
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
(7) (a) Kassem, S.; van Leeuwen, T.; Lubbe, A. S.; Wilson, M. R.; Feringa, B. L.; Leigh, D. A.
Chem. Soc. Rev. 2017, 46, 2592˗2621. (b) Leigh, D. A.; Wong, J. K. Y.; Dehez, F.; Zerbetto, F. Nature
2003, 424, 174−179. (c) Beves, J. E.; Blanco, V.; Blight, B. A.; Carrillo, R.; D'Souza, D. M.; Howgego,
D.; Leigh, D. A.; Slawin, A. M. Z.; Symes, M. D. J. Am. Chem. Soc. 2014, 136, 2094−2100. (d)
Lewandowski, B.; De Bo, G. W.; Ward, J.; Papmeyer, M.; Kuschel, S.; Aldegunde, M. J.; Gramlich, P.
M. E.; Heckmann, D.; Goldup, S. M.; D’Souza, D. M.; Fernandes, A. E.; Leigh, D. A. Science 2013,
339, 189−193. (e) Wilson, M. R.; Solà, J.; Carlone, A.; Goldup, S. M.; Lebrasseur, N.; Leigh, D. A.
Nature 2016, 534, 235˗240.
(8) (a) Neri P., Sessler J. L., Wang M.ꢀX., (Eds.), Calixarenes and Beyond, Springer, Dordrecht,
2016. (b) Gutsche, C. D. Calixarenes, An Introduction; Royal Society of Chemistry: Cambridge, UK,
2008. For recent applications in molecular recognition and sensing: (c) Sun, Y.; Mei, Y.; Quan, J.; Xiao,
X.; Zhang, L.; Tian, D.; Li, H.Chem. Commun. 2016, 52, 14416ꢀ14418. (d) Yeon, Y.; Leem, S.; Wagen,
C.; Lynch, V. M.; Kim, S. K.; Sessler, J. L. Org. Lett. 2016, 18, 4396−4399. For applications in selfꢀ
assembly processess: (e) Asfari, Z., Böhmer, V., Harrowfield, J., Vicens J., (Eds.), Calixarenes 2001,
Kluwer, Dordrecht, 2001. For applications as catalysts: (f) Homden, D. H.; Redshaw, C. Chem. Rev.
2008, 108, 5086−5130. (g) De Rosa, M.; Talotta, C.; Soriente, A. Lett. Org. Chem. 2009, 6, 301−305.
(h) De Rosa, M.; Soriente, A.; Concilio, G.; Talotta, C.; Gaeta, C.; Neri, P. J. Org. Chem. 2015, 80,
7295−7300.
29
ACS Paragon Plus Environment