An oriented handcuff rotaxane

Article abstract of DOI:10.1021/ol4026974

The first example of an oriented handcuff rotaxane has been obtained by through-the-annulus threading of a double-calix[6]arene system with a bis-ammonium axle. The relative orientation of the two calix-wheels can be predefined by exploiting the "endo-alkyl rule" which controls the directionality of the threading of alkylbenzylammonium axles with calixarene macrocycles.

Full text of DOI:10.1021/ol4026974

ORGANIC
LETTERS
2
013
Vol. 15, No. 22
694–5697
An Oriented Handcuff Rotaxane
5
†
†
,†
Roberta Ciao, Carmen Talotta, Carmine Gaeta,* Luigi Margarucci,
‡
‡
Agostino Casapullo, and Placido Neri*
,†
Dipartimento di Chimica e Biologia and NANO_MATES Research Center,
Universit aꢀ di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano (Salerno), Italy, and
Dipartimento di Farmacia, Universit aꢀ di Salerno, Via Giovanni Paolo II 132,
I-84084 Fisciano (Salerno), Italy
cgaeta@unisa.it; neri@unisa.it
Received September 18, 2013
ABSTRACT
The first example of an oriented handcuff rotaxane has been obtained by through-the-annulus threading of a double-calix[6]arene system with a
bis-ammonium axle. The relative orientation of the two calix-wheels can be predefined by exploiting the “endo-alkyl rule” which controls the
directionality of the threading of alkylbenzylammonium axles with calixarene macrocycles.
Macrocyclic hosts with multiple cavities and/or multiple
recognition sites haveattractedincreasing attentionthanks
to their usefulness for developing nontrivial interlocked
1
architectures. In this regard, interpenetrated systems in
which two rings are linked to one another in a hand-
cuff-like fashion have represented a significant synthetic
2
1,3
challenge. Based on the template-directed threading of
linear axles through such double-macrocycles, beautiful
handcuff-like architectures have been reported to date,
which shows interesting properties and functions.
The first example dates back to 1993 when Stoddart
4
a
et al. reported the handcuff architecture A(Figure1), which
4
b
was followed by similar [2]catenane polymers B. Succes-
5
sively, Becher reported an example of architecture C, in
Figure 1. Schematic representation of the currently known pro-
totypical examples of handcuff-derived architectures (AꢀE) and the
proposed stereoisomeric oriented handcuff (pseudo)-[2]rotaxanes
which the two connected rings are threaded through the same
large ring to form a handcuff [2]catenane. A similar topology
(
FꢀH).
6
,2b
†
Dipartimento di Chimica e Biologia and NANO_MATES Research
was built in 2005 by Sauvage, through the template effect
7
of Cu(I), and more recently by Beer, through the templation
Center.
‡
Dipartimento di Farmacia.
1) Molecular Catenanes, Rotaxanes and Knots: A Journey Through
8
of the chloride anion. In 2000 V o€ gtle et al. reported a
(
the World of Molecular Topology; Sauvage, J. P., Dietrich-Buchecker, C.,
Eds.; Wiley-VCH: Weinheim, 1999.
molecular ‘‘pretzelane’’ D in which the two connected rings
are mutually interpenetrated to give a [1]catenane.
Regarding rotaxane architectures such as E (Figure 1),
only very recently an example has been reported in which
two flat crown-rings, rigidly linked to one another, were
(2) (a) Zhang, Z.-J.; Han, M.; Zhang, H.-Y.; Liu, Y. Org. Lett. 2013,
5, 1698. (b) Frey, J.; Kraus, T.; Heitz, V.; Sauvage, J.-P. Chem.;Eur. J.
1
2
a
2
007, 13, 7584. (c) Balzani, V.; Clemente-Le oꢁ n, M.; Credi, A.; Lowe,
J. N.; Badji ꢁc , J. D.; Stoddart, J. F.; Williams, D. J. Chem.;Eur. J. 2003,
, 5348.
3) Templated Organic Synthesis; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, 1999.
4) (a) Ashton, P. R.; Reder, A. S.; Spencer, N.; Stoddart, J. F. J. Am.
9
(
(6) Frey, J.; Kraus, T.; Heitz, V.; Sauvage, J.-P. Chem. Commun.
2005, 5310.
(
Chem. Soc. 1993, 115, 5286. (b) Weidmann, J.-L.; Kern, J.-M.; Sauvage,
J.-P.; Muscat, D.; Mullins, S.; K o€ hler, W.; Rosenauer, C.; R €a der, H. J.;
Martin, K.; Geerts, Y. Chem.;Eur. J. 1999, 5, 1841.
(7) Evans, N. H.; Serpell, C. J.; Beer, P. D. Angew. Chem., Int. Ed.
2011, 50, 2507.
(8) Reuter, C.; Mohry, A.; Sobansky, A.; V o€ gtle, F. Chem.;Eur. J.
(5) Li, Z.-T.; Becher, J. Chem. Commun. 1996, 5, 639.
2000, 6, 1674.
1
0.1021/ol4026974 r 2013 American Chemical Society
Published on Web 11/01/2013

Figure 2. Structures of calix[6]arene wheels 1and 2, bis(alkylbenzyl-
ammonium) axles 3 and 4 , TFPB anion, and alkylbenzylam-
monium axle 5 .
2þ
2þ
þ
14
Figure 3. The “endo-alkyl rule” and some related examples of
oriented interpenetrated architectures reported.
1
0,13
threaded with a bis-ammonium axle to mimic a double-leg
elevator. To the best of our knowledge, this is the only
example of handcuff rotaxane so far reported.
2
þ
Scheme 1. Handcuff Threading of 2 with 3
With respect to the use of flat macrocycles in E
Figure 1), a further synthetic challenge is represented by
(
the use of three-dimensional nonsymmetrical rings (directional
9
wheels), such as in double-calixarene 2 (Figure 2), because of
the inherent difficulty in controlling their relative orienta-
10
tion within the entire system. In fact, the threading of 2
2þ
with a bis-ammonium axle (e.g., 3 ) could give rise to three
stereoisomeric handcuff pseudo[2]rotaxane structures, in
which the two calix-wheels could show three different
relative orientations, head-to-head (H,H), tail-to-tail (T,T),
and head-to-tail (H,T), respectively represented by FꢀH in
Figure 1. Based on these considerations, the following
questions arise: which stereochemistry (F, G, or H) of the
handcuff pseudo[2]rotaxane formed between 2 and thread
a non-tert-butylated hexaalkoxycalix[6]arene (e.g., 1) oc-
1
curs with an endo-alkyl preference.
4
1
4
On the basis of this “endo-alkyl rule”, we envisioned
that the appropriate encoding of a sequence of alkylben-
zylammonium binding sites along a bis-ammonium thread
could allow the stereoprogrammed preparation of a given
oriental isomer F, G, or H of a calixarene-based handcuff
pseudorotaxane.
Naturally, the presence of the short m-xylylene spacer
between the two wheels in 2 could favor a different
anomalous stereochemistry with respect to that predicted
by the “endo-alkyl rule”. Prompted by these considerations,
we decided to study the threading properties of double-
calix[6]arene 2 with bis-ammonium axles 3 and 4 and
we wish to report here the results of our studies.
As a first step we decided to use thread 3 in which two
alkylbenzylammonium moieties are connected by the ben-
zyl ends to expose the alkyl chains at the terminations
(Figure 2). On the basis of the above endo-alkyl rule, the
2
þ
2þ
3
or 4 can be expected? Are we able to deliberately form
only one of them?
1
Recently, we have shown that the threading of a direc-
1
þ
tional alkylbenzylammonium cation (e.g., 5 , Figure 2) by
a calix[6]arene (e.g., 1) leads to a preference for the endo-
alkyl stereoisomer 6 over the endo-benzyl one (Figure 3).
þ
12
Successively, we showed that by encoding the appropriate
alkylbenzyl sequence along bis-ammonium axles it was
possible to obtain a specific stereosequence (e.g., H,H or
H,T, Figure 3) of the two calix-wheels in pseudo[3]rotaxane
15
2þ
2þ
2
þ
2
þ
2þ 10
architectures 7 and 8 . Analogously, the stereopro-
grammed synthesis of a calix[2]catenane orientational isomer
þ
9 was obtained by macrocyclization, upon using a direc-
tional alkylbenzylammonium axle.
13
2þ
threading of 2 with 3 should result in a tail-to-tail
oriented handcuff pseudo[2]rotaxane such as G. To verify
From these studies we have generalized the following
stereochemical “endo-alkyl rule” (Figure 3): threading of a
1
this prediction, the TFPB salt of 3 was equilibrated
6
2þ
2þ
directional alkylbenzylammonium axle (e.g., 5 ) through
(
15) Saadioui, M.; B o€ hmer, V. In Calixarenes; Asfari, Z., B €o hmer, V.,
Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht, 2001; pp 130ꢀ154 and
11,12
(
9) Gutsche, C. D. Calixarenes, An Introduction; Royal Society of
Chemistry: Cambridge, U.K., 2008.
10) (a) Talotta, C.; Gaeta, C.; Pierro, T.; Neri, P. Org. Lett. 2011, 13,
098. (b) Talotta, C.; Gaeta, C.; Neri, P. Org. Lett. 2012, 14, 3104.
references cited therein.
(
16) As reported by us,
the through-the-annulus threading of scarcely
(
efficient calix[6ꢀ8]arene hosts with dialkylammonium axles can only be
obtained through the inducing effect of the superweak anion TFPB
(Tetrakis[3,5-bis(triFluoromethyl)Phenyl]Borate). For a review on super-
2
(11) Gaeta, C.; Troisi, F.; Neri, P. Org. Lett. 2010, 12, 2092.
ꢀ
(12) Analogously, the threading of a directional alkylbenzylammo-
weak anion TFPB , see: (a) Strauss, S. H. Chem. Rev. 1993, 93, 927. For
nium cation by calix[8]arene lead to a preference for the endo-alkyl
stereoisomer over the endo-benzyl one: Gaeta, C.; Talotta, C.; Margarucci,
L.; Casapullo, A.; Neri, P. J. Org. Chem. 2013, 78, 7627.
recent examples on the use of the TFPB superweak anion in supramolecular
chemistry, see (b) Pierro, T.; Gaeta, C.; Talotta, C.; Casapullo, A.; Neri, P.
Org. Lett. 2011, 13, 2650. (c) Li, C.; Shu, X.; Li, J.; Fan, J.; Chen, Z.; Weng,
L.; Jia, X. Org. Lett. 2012, 14, 4126. (d) Gaeta, C.; Talotta, C.; Farina, F.;
Camalli, M.; Campi, G.; Neri, P. Chem.;Eur. J. 2012, 18, 1219. (e) Gaeta,
C.; Talotta, C.; Farina, F.; Teixeira, F. A.; Marcos, P. A.; Ascenso, J. R.;
Neri, P. J. Org. Chem. 2012, 77, 10285.
(
13) Gaeta, C.; Talotta, C.; Mirra, S.; Margarucci, L.; Casapullo, A.;
Neri, P. Org. Lett. 2013, 15, 116.
14) Talotta, C.; Gaeta, C.; Qi, Z.; Schalley, C. A.; Neri, P. Angew.
(
Chem., Int. Ed. 2013, 52, 7437.
Org. Lett., Vol. 15, No. 22, 2013
5695

2þ
Figure 5. ESI(þ) mass spectrum of (T,T)-10 and its AMBER
energy-minimized structure (inset).
the ESI(þ) mass spectrum (Figure 5). In fact, the Δ spacing
of 0.5 m/z between the peaks in the isotopic envelop
(Figure 5, inset) solely accounts for a doubly charged
species of 10, excluding architectures with higher charges
such as I or J represented in ref 18.
1
3
Figure 4. Portions of the H NMR spectra (400 MHz, CDCl ,
2
3
4
98 K) of (a) 2, (b) an equimolar mixture (3 mM) of 2 and
2
2
þ
þ
ꢀ
ꢀ
2TFPB , (c) an equimolar mixture (3 mM) of 2 and
2TFPB , and (d) handcuff [2]rotaxane (T,T)-12
3
3
2þ
.
1
7
A COSY-45 spectrum (CDCl , 400 MHz, 298 K) of
3
1
with double-calix[6]arene 2 (Scheme 1) and the resulting
7
2þ
the 1:1 mixture of thread 3 and double-calix[6]arene 2
solution was investigated by 1D and 2D NMR spectro-
scopy and ESI(þ) mass spectrometry.
allowed a complete confident assignment of all shielded
alkyl resonances. Thus, R-protons at 0.17 ppm show a
coupling with the β-methylene group at ꢀ0.96 ppm, which
presents a cross-peak with γ-protons at ꢀ0.03 ppm, finally
1
In particular, the H NMR spectrum (CDCl , 400 MHz,
98 K) of the 1:1 mixture (Figure 4b) showed a typical
3
2
signature at highfield negative values (from 1.0 to ꢀ1.0 ppm)
characteristic of an endo-complexation of the alkyl chains
shielded by calixarene aromatic rings and indicative of the
coupled with δ CH at 0.39 ppm, which was coupled with
2
ε-protons at 0.40 ppm. In addition, the ArCH Ar region
2
1
9
(3ꢀ5 ppm) revealed the presence of three AX systems at
2þ
formation of pseudorotaxane (T,T)-10 . This result and the
absence of shielded benzylic resonances in the 4ꢀ6 ppm
4.43/3.58, 4.38/3.49, and 4.31/3.49 ppm relative to three
1
ArCH Ar groups. On the other hand, the H NMR
2
1
0ꢀ14
region, typical of endo-benzyl complexation,
were a
clear-cut proof that the tail-to-tail isomer G of handcuff-
spectrum showed three singlets in a 2:1:2 ratio at 3.77,
3.63, and 3.33 ppm relative to OMe groups and a singlet at
4.95 ppm relative to OCH groups of the m-xylylene
2þ
pseudo[2]rotaxane (T,T)-10 (Scheme 1) had been stereo-
selectively formed. An apparent total association constant
2
bridge. These data indicate the presence of a symmetry
plane bisecting the m-xylylene bridge and the 1,4-diphe-
noxybutane chain, which is perfectly compatible with a
handcuff threading of 2.
3
ꢀ1
(
formation 58%) was determined for (T,T)-10 by integra-
K ) of 1.6 ( 0.3 ꢁ 10 M in CDCl (percentage of
tot
3
2þ
1
tion of the slowly exchanging H NMR signals. These results
show that the presence of the short m-xylylene spacer between
the two calix-wheels of 2 does not generate any anomalous
stereopreference with respect to the endo-alkyl rule.
Molecular mechanics calculations revealed that a fold-
2þ
ing of the thread 3 is required to simultaneously thread
the two calixarene-wheels of 2. Thus, the folded conforma-
2þ
Certainly, the presence of the typical highfield signature
in Figure 4b could also be compatible with a cyclic or
tion adopted by 3 in handcuff pseudo[2]rotaxane (T,T)-
2þ
10 was characterized by unfavorable gauche conforma-
tions around C(1)ꢀC(2) and C(2)ꢀC(3) bonds (dihedral
angles of 45° and 55°, respectively, Figure 6) of the central
1
8
square-type supramolecular architecture I or an unde-
fined supramolecular oligomer or polymer J (see ref 18).
2þ
17
The formation of handcuff pseudo[2]rotaxane 10 was
unequivocally confirmed by the base peak at m/z 979.83 in
1,4-diphenoxybutane fragment. Simulated Annealing (SA)
1
7
experiments clearly evidenced that ∼75% of the coconfor-
mers in the 4 kcal/mol lowest energy window (200 indepen-
dent annealing experiments) showed a dihedral angle in the
42°ꢀ87° range around the C(1)ꢀC(2) bond. Analogously,
(
(
17) See Supporting Information for further details.
18) Structures I and J.
∼
85% of the same structures gave a C(2)ꢀC(3) dihedral
angle in the 50°ꢀ75° range (Figure S15). This situation
(
2
19) The presence of well-defined AX systems for ArCH Ar groups in
þ
the COSY-45 spectrum is a clear indication that the thread 3a gave a
handcuff-through-the-annulus-threading with double-calix[6]arene 2 in
CDCl . In fact, the ArCH Ar protons appear as singlets for the conforma-
tionally mobile free host 2 (see H NMR spectrum of 2 in Figure 3a),
whereas each of them gives rise to a couple of doublets (AX system) when the
wheel is conformationally blocked by pseudorotaxane formation.
3
2
1
5
696
Org. Lett., Vol. 15, No. 22, 2013

Figure 6. (a) Lowest energy structure of handcuff pseudo-
[
2
2]rotaxane (T,T)-10 found by Monte Carlo search associated
þ
with Simulated Annealing experiments (MacroModel V. 9.0,
AMBER force field). (b and c) Newman projections along the
C(2)ꢀC(3) and C(1)ꢀC(2) bonds, respectively, showing the
unfavorable gauche conformations.
2þ
Figure 7. ESI(þ) mass spectrum of (T,T)-12 and its AMBER
energy-minimized structure (inset).
2þ
2
0
Scheme 2. Synthesis of Handcuff [2]Rotaxane (T,T)-12
resembles those observed by Rebek in the encapsulation of
long alkanes in a coiled form inside a self-assembled capsule
16e
and recently by us in the endo-complexation of large di-n-
alkylammonium cations inside the narrow cavity of the
18-membered dihomooxacalix[4]arene ring. In analogy to
those complexes, in the present case the energy loss due to the
unfavorable folding of the thread is counterbalanced by
the gain in H-bonding energy due to the double threading
of the two calix[6] cavities.
In order to permanently trap the above handcuff
2]rotaxanearchitecture, wedecidedtoinvestigatethethread-
[
2þ
ing of 2 with axle 4 encoding again the external alkyl
chains, which are now terminated by two easily stopper-
able OH groups (Scheme 2). Therefore, 1 equiv of the
2þ
TFPB salt of 4 was equilibrated with 1 equiv of double-
calix[6]arene 2 in CDCl to give handcuff pseudo[2]-
3
2þ
1
2þ
rotaxane (T,T)-11 (Scheme 2). The H NMR spectrum
of this mixture (Figure 4c) showed again the presence of
shieldedalkylresonances atnegative valuestypical ofendo-
alkyl complexation and confirming the exclusive form-
ation of tail-to-tail handcuff pseudo[2]rotaxane (T,T)-
Analogously to pseudorotaxane (T,T)-10 , SA experi-
ments clearly evidenced that ∼65% of the coconformers in
the 4 kcal/mol lowest energy window (200 independent
experiments) showed a dihedral angle in the 45°ꢀ70° range
around the C(1)ꢀC(2) bond (Figure S16). Analogously,
∼50% of the same structures gave a C(2)ꢀC(3) dihedral
angle in the 59°ꢀ84° range (Figure S16).
2þ
11 . Thus, the validity of the above endo-alkyl rule was
again confirmed. An apparent total association constant
5
ꢀ1
(
formation 84%) was determined for (T,T)-11 by integration
K ) of 1.7 ( 0.3 ꢁ 10 M in CDCl (percentage of
In conclusion, we have reported here the first examples of
calixarene-based handcuff pseudorotaxane and rotaxane
architectures. In addition, we have showed the possibility
to control the threading directionality by exploiting the
“endo-alkyl rule” to give a predefined orientational isomer.
Therefore, it is conceivable that the extension of this ap-
proach could lead to novel mechanically interlocked archi-
tectures with high-order topologies.
tot
3
2
þ
1
of the slowly exchanging H NMR signals. Pseudorotaxane
T,T)-11 was then stoppered by a reaction with 4-tritylphenyl
isocyanate to give the first example of predefined orienta-
tional handcuff [2]rotaxane (T,T)-12
Scheme 2). Its formation was confirmed by a prominent
2þ
(
2þ
in 28% yield
(
peak at 1370.1 m/z in the ESI(þ) mass spectrum (Figure 7),
corresponding to the doubly charged interlocked ion. As
above, a combined 1D and 2D NMR study confirmed the
tail-to-tail stereosequence of the two calix-wheels in hand-
Acknowledgment. We thank the Italian MIUR (PRIN
0109Z2XRJ_006) for financial support.
2
2þ
cuff [2]rotaxane (T,T)-12 . Also in this case molecular
mechanics calculations (AMBER force field, CHCl , GB/SA
Supporting Information Available. Synthetic details,
D and 2D NMR spectra, and details on molecular
3
1
model solvent) indicated a folded conformation of the thread
(
modeling. This material is available free of charge via
the Internet at http://pubs.acs.org.
Figure 6).
(
20) (a) Scarso, A.; Trembleu, L.; Rebek, J., Jr. Angew. Chem., Int.
Ed. 2003, 42, 5499. (b) Rebek, J., Jr. Chem. Commun. 2007, 2777.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5697