Sequence stereoisomerism in calixarene-based pseudo[3]rotaxanes

Article abstract of DOI:10.1021/ol2005159

Two calix[6]arene directional wheels can be ordered in the right stereosequence by their through-the-annulus threading with a rationally designed bis(benzylalkylammonium) axle. These stereoisomeric pseudo[3]rotaxanes can be considered as a minimal "inform

Full text of DOI:10.1021/ol2005159

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2098–2101
Sequence Stereoisomerism in
Calixarene-Based Pseudo[3]rotaxanes
Carmen Talotta, Carmine Gaeta,* Teresa Pierro, and Placido Neri*
ꢀ
Dipartimento di Chimica e Biologia, Universita di Salerno, Via Ponte don Melillo,
I-84084 Fisciano, Salerno, Italy
cgaeta@unisa.it; neri@unisa.it
Received February 25, 2011
ABSTRACT
Two calix[6]arene directional wheels can be ordered in the right stereosequence by their through-the-annulus threading with a rationally designed
bis(benzylalkylammonium) axle. These stereoisomeric pseudo[3]rotaxanes can be considered as a minimal “informational system” because the
“written information” on the thread is transferred to a specific sequence stereoisomer.
The most important and marvelous biological “infor-
mational systems”, such as DNA, RNA, and proteins, rely
on the diverse and precise sequences of a limited set of
covalently linked building blocks, which Leigh and co-
workers have defined as a sort of “sequence isomerism”.1
Obviously, in such biological systems control of the se-
quential order of the constitutive building blocks is crucial
to the transmission and translation of genetic information.
A conceptually comparable sequence isomerism can be
obtainedin the caseofmechanicallyinterlocked molecules,
such as rotaxanes and catenanes,2 if two or more different
rings are in a different sequential order along the threading
element (Figure 1), provided that their relative position is
Figure 1. Sequence isomerism in rotaxane and pseudorotaxane
structures.
maintained by mechanical restrictions. This isomerism is
of a stereochemical nature and can be related to conforma-
tional isomerism, which can be also maintained by intra-
molecular mechanical restrictions.
In the case of rotaxanes or pseudorotaxanes the
minimal structural requirements to observe a sequence
stereoisomerism is to have two different rings and a direc-
tional (asymmetric) thread (type I, Figure 1a) or three rings
of two different types and a symmetrical thread (type II,
Figure 1b).3 Another possibility is linked to the use of three-
dimensional nonsymmetrical rings (directional wheels),
which minimally requires only one type of ring, but in two
different orientations (type III, Figure 1c). In this latter
instance three different stereoisomers can be obtained, which
could be termed as head-to-head (H,H), head-to-tail (H,T),
and tail-to-tail (T,T) (Figure 1c).
(1) Fuller, A.-M. L.; Leigh, D. A.; Lusby, P. J. J. Am. Chem. Soc.
2010, 132, 4954.
(2) Molecular Catenanes, Rotaxanes and Knots: A Journey Through
the World of Molecular Topology; Sauvage, J. P., Dietrich-Buchecker, C.,
Eds.; Wiley-VCH: Weinheim, 1999.
(3) An example of sequence-specific formation of heteropseudo-
[3]rotaxane in which two different crown-ethers were threaded with a
directional (asymmetric) thread was reported by Schalley: (a) Jiang, W.;
Winkler, H. D. F.; Schalley, C. A. J. Am. Chem. Soc. 2008, 130, 13852.
Instead, examples have been reported in which two different wheels were
threaded with a symmetrical thread and consequently no isomerism was
ꢁ
ꢂ
displayed: (b) Amabilino, D. B.; Ashton, P. R.; Belohradsky, M.;
Raymo, F. M.; Stoddart, J. F. J. Chem. Soc., Chem. Commun. 1995,
747. (c) Chen, L.; Zhao, X.; Chen, Y.; Zhao, C. X.; Jiang, X. K.; Li, Z. T.
J. Org. Chem. 2003, 68, 2704.
r
10.1021/ol2005159
Published on Web 03/22/2011
2011 American Chemical Society

Figure 3. Structures of (H,H)-,(T,T)-,and(H,T)-pseudo[3]rotaxanes
obtained by threading hexamethoxy-p-H-calix[6]arene 1b with axles
3a, 3b, and 3c, respectively.
of the weakly coordinating tetrakis[3,5-bis(trifluoromethyl)
phenyl]borate (TFPB) anion8 that gives free “naked” dialkyl-
ammonium cations. In particular, we observed that the
complexation of a nonsymmetrical alkylbenzylammonium
cation (e.g., 2) by hexaalkoxycalix[6]arenes (e.g., 1a) can lead
to a preference for the endo-alkyl stereoisomer (2⊂1a) overthe
endo-benzyl one up to a 30:1 ratio (Figure 2).6a
On this basis we envisioned that the appropriate cova-
lent linkage of two such alkylbenzylammonium recogni-
tion motifs could allow good control of the consequent
sequence stereoisomerism.
As a first step we decided to connect two alkylben-
zylammonium motifs by the alkyl ends to give a thread
exposing benzyl units at the two extremities (3a).9 We
expected that the endo-alkyl stereochemistry should
be favored at both ammonium centers resulting in a
head-to-head pseudo[3]rotaxane (Figure 3). In accor-
dance with this expectation, the 1H NMR spectrum of
a 1:2 mixture of the TFPB salt of dicationic thread 3a
and hexamethoxy-p-H-calix[6]arene 1b in CDCl3
(Figure 4b) showed a typical 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. This result and the
absence of shielded benzylic resonances in the 4ꢀ6
ppm region, typical of endo-benzyl complexation,
were clear-cut proof that head-to-head pseudo-
[3]rotaxane (H,H)-3a⊂1b2 (Figure 3) had been exclu-
sively formed.
Figure 2. Structures of calix[6]arene wheels 1aꢀc and alkylben-
zylammonium axles 2 and 3aꢀc.
More complex and more informative sequence stereo-
isomerism is obtained with longer sequences of identical or
different directional wheels (Figure 1dꢀe). Obviously, for
a larger number of identical wheels the sequence stereo-
isomerism will resemble the tacticity of polymers.4
Currently only a few examples of sequences of type I1,3
have been described, whereas no instances of stereocon-
trolled directed synthesis of II and III5 have been reported.
Here, we wish to report some examples of sequence
stereoisomerism of type III, in which the rational choice
of the threading elements allows the stereocontrolled direct
preparation of given sequence diastereoisomers of type III
in Figure 1.
Our approach is based on our recent observation6 that the
through-the-annulus threading of simple calix[6]arene7 hosts
1aꢀc (Figure 2) can be obtained through the inducing effect
(4) Young, R. J.; Lovell, P. A. Introduction to Polymers, 3rd ed.; CRC
Press: Boca Raton, FL, 2011.
(5) Orientational isomers of a cyclodextrin [3]rotaxane have been
obtained by linking two cyclodextrin-pseudo[2]rotaxane units. Thus, all
three possible diastereoisomers have been obtained in a statistical ratio:
(a) Cheetham, A. G.; Claridge, T. D. W.; Anderson, H. L. Org. Biomol.
Chem. 2007, 5, 457. A single directional isomer of a cyclodextrin-based
pseudo[3]rotaxane was obtained under kinetic control: (b) Oshikiri, T.;
Takashima, Y.; Yamaguchi, H.; Harada, A. Chem.;Eur. J. 2007, 13,
7091. For other examples of orientational isomers of [3]rotaxane
systems, see: (c) Saudan, C.; Dunand, F. A.; Abou-Hamdan, A.;
Bugnon, P.; Lye, P. G.; Lincoln, S. F.; Merbach, A. E. J. Am. Chem.
Soc. 2001, 123, 10290. (d) Eliadou, K.; Yannakopoulou, K.; Rontoyianni,
A.; Mavridis, I. M. J. Org. Chem. 1999, 64, 6217. (e) Qu, D. H.; Wang,
Q. C.; Ma, X.; Tian, H. Chem.;Eur. J. 2005, 11, 5929. (f) Craig, M. R.;
Claridge, T. D. W.; Hutchings, M. G.; Anderson, H. L. Chem. Commun.
1999, 1537.
The formation of pseudo[3]rotaxane (H,H)-3a⊂1b2
(Figure 3) was confirmed by a prominent peak at 898 m/z
in the ESI(þ) mass spectrum,9 corresponding to the
doubly charged supramolecular ion. The double endo-
alkyl stereochemistry was fully confirmed by a 2D ROESY
spectrum coupled to a full signal assignment by 2D COSY
analysis.9 In particular, diagnostic cross-peaks were
(6) (a) Gaeta, C.; Troisi, F.; Neri, P. Org. Lett. 2010, 12, 2092. (b) For
the first examples of calixarene-based molecular shuttles obtained by
using the same approach, see: Pierro, T.; Gaeta, C.; Talotta, C.;
Casapullo, A.; Neri, P. Submitted.
(7) Gutsche, C. D. Calixarenes, An Introduction; Royal Society of
Chemistry: Cambridge, UK, 2008.
(8) (a) Strauss, S. H. Chem. Rev. 1993, 93, 927. (b) For a review on
counterion effects in supramolecular chemistry, see: Gasa, T. B.;
Valente, C.; Stoddart, J. F. Chem. Soc. Rev. 2011, 40, 57.
(9) See Supporting Information for further details.
Org. Lett., Vol. 13, No. 8, 2011
2099

Figure 5. Structures of (T,T)-pseudo[3]rotaxanes obtained by
threading hexamethoxy-p-t-Bu-calix[6]arene 1c with axles 3a,
3b, and 3c.
squares fitting11 of the integration data led to a value of
16 923 ( 2599 and 342 ( 30 Mꢀ1 for the first (K1) and
the second (K2) association constant, respectively, in
good agreement with the previously reported mono-
meric 1:1 complexation constants.6a
Figure 4. 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a) 1b;
(b) 1:2 mixture of 3a and 1b; (c) 1:2 mixture of 3b and 1b; and (d)
1:2 mixture of 3c and 1b. In some structure drawings an
aromatic ring of the wheel has been removed for clarity.
The logical extension of the above approach was the
connection of two alkylbenzylammonium moieties by
the benzyl ends to give a thread exposing alkyl chains at
the terminations (3b). In this case the orientation of the
calixarene cavity toward the exterior should be favored
leading to a tail-to-tail pseudo[3]rotaxane (Figure 3). In
present in the ROESY spectrum of (H,H)-3a⊂1b2 (400
MHz, CDCl3, 298 K) between the shielded aliphatic Rꢀε
protons (Figure 4b) of the axle and ArH protons of the two
equivalent calix-wheels. Another cross-peak indicative
of the head-to-head orientation of the two calix-wheels
was present at 3.60/7.59 ppm between OMe protons at
the lower rim of calix[6]arene macrocycle and ArH protons
of the benzyl units of the thread. The stereochemical
preference was also confirmed by molecular mecha-
nics calculations10 (OPLS force field, CHCl3, GB/SA
model solvent), which indicated the (H,H) sequence
isomer of 3a⊂1b2 as the lowest in energy with respect to
(H,T) and (T,T) ones by 3.6 and 4.3 kcal/mol, respectively
(see Figure S49 in the Supporting information).
It is interesting to point out that the formation of
pseudo[3]rotaxane (H,H)-3a⊂1b2 occurs with high effi-
ciency and only a minimal amount of uncomplexed calix-
[6]arene host 1b was present, while the singly threaded
species was below the detection limit.
Under these conditions the association constant can-
not be determined by simple integration methods;
therefore we resorted to a dilution experiment of the
1:2 mixture of 3a and 1b in CDCl3.9 A nonlinear least-
1
fact, the H NMR spectrum of a 1:2 mixture of the
TFPB salt of 3b and hexamethoxy-p-H-calix[6]arene 1b
in CDCl3 (Figure 4c) showed again the presence of
shielded alkyl resonances at negative values typical of
endo-alkyl complexation. Also in this instance, no
shielded benzylic signals could be traced confirming
the exclusive formation of tail-to-tail pseudo[3]rotaxane
(T,T)-3b⊂1b2.
As above the structure of (T,T)-3b⊂1b2 was fully con-
firmed by an ESI(þ) MS spectrum, which showed a
prominent peak at 942 m/z corresponding to the doubly
charged supramolecular ion, and by a 2D COSY NMR
spectrum.9 In this instance the values of the single association
constants (K1 and K2) could not be determined by dilution
experiments and only the total binding constant (Ktot
=
K1 K2) could be evaluated by signal integration. A value of
3
7.4 ꢁ 105 Mꢀ2 was obtained for Ktot of (T,T)-3b⊂1b2,whichis
lower than that calculated for (H,H)-3a⊂1b2 (5.8ꢁ 106 Mꢀ2).
Finally, thread 3c bearing an alkyl and a benzyl unit at the
two extremities was synthesized in order to direct the calix-
[6]arene wheels 1b in the head-to-tail stereosequence
1
(Figure 3). As expected, the H NMR spectrum of a 1:2
mixture of the TFPB salt of dicationic thread 3c and
hexamethoxy-p-H-calix[6]arene 1b in CDCl3 (Figure 4d)
was indicative that head-to-tail pseudo[3]rotaxane (H,T)-
3c⊂1b2 had been exclusively formed.
(10) MacroModel-9.0/Maestro-4.1 program: Mohamadi, F.;
Richards, N. G.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield,
C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11,
440.
(11) Elizarov, A. M.; Chiu, S.-H.; Glink, P. T.; Stoddart, J. F. Org.
Lett. 2002, 4, 679.
In fact, it showed a typical signature at highfield
negative values (from 1.0 to ꢀ1.0 ppm) characteristic of
Org. Lett., Vol. 13, No. 8, 2011
2100

rise to a head-to-head stereosequence with hexame-
thoxycalix[6]arene 1b bearing H-atoms at the upper
rim. The 1H NMR spectrum (Figure 6b) of a 1:2
mixture of the TFPB salt of 3a and p-t-Bu-calix[6]-
wheel 1c in CDCl3 revealed the presence of shielded
benzylic resonances in the 4ꢀ6 ppm region, which was
clear proof of a double endo-benzyl complexation of 3a,
to give tail-to-tail pseudo[3]rotaxane (T,T)-3a⊂1c2
(Figure 5). As above, the formation of this pseudo-
[3]rotaxane was confirmed by the doubly charged su-
pramolecular peak at 1235 m/z in the ESI(þ) mass
spectrum, while a total binding constant of 2.5 ꢁ 105
M
ꢀ2 was evaluated by signal integration.9
Clearly, the change of thread 3a from the head-to-head
to the tail-to-tail stereosequence by replacing p-H-1b with
p-t-Bu-calix[6]-wheel 1c has to be attributed to the steric
encumbrance of the t-Bu groups in 1c. This conclusion was
also confirmed by OPLS calculations (in CHCl3, GB/SA
model solvent), which favored (T,T)-3a⊂1c2 with respect
to the (H,H)-3a⊂1c2 stereoisomer by an energy difference
of 4 kcal/mol and evidenced a steric crowding between
facing calixarene t-Bu groups in the latter (see Figure S50
in the Supporting Information).9
An analogous study with threads 3b and 3c evidenced
that the tail-to-tail stereosequence is again preferred with
p-t-Bu-calix[6]-wheel 1c to give (T,T)-3b⊂1c2 and (T,T)-
3c⊂1c2 (Figures 5 and 6), thus confirming the strong role
played by the t-Bu groups on this wheel.
In conclusion, the first examples of calixarene-based
pseudo[3]rotaxane systems have been obtained by the
through-the-annulus threading of alkoxycalix[6]arene
macrocycles with bis(benzylalkylammonium) ions coupled
to the weakly coordinating TFPB anion. In addition, we
have here reported the first example of rational control
of the stereosequence of two threaded directional wheels,
which can be considered as a minimal “informational
system” whose “written information” on the thread
is transferred to a specific pseudorotaxane sequence
stereoisomer.
In analogy to natural informational systems, such as
DNA, where the sequence of nucleic bases encodes the
genetic information, control of the sequence (stereo)-
isomerism in threaded structures, such as rotaxane and
pseudorotaxane, could allow the design of “informational
devices” in which each sequence isomer corresponds to a
specific physical or chemical output. Further studies in this
direction are in progress in our laboratory.
Figure 6. 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a) 1c;
(b) 1:2 mixture of 3a and 1c; (c) 1:2 mixture of 3b and 1c; and (d)
1:2 mixture of 3c and 1c. In some structure drawings an aromatic
ring of the wheel has been removed for clarity.
an endo-alkyl complexation. In addition, the absence of
shielded endo-benzyl resonances in the 4ꢀ6 ppm region
was a clear indication that head-to-head or tail-to-tail
sequential isomers have not been formed. Again, the pre-
sence of pseudo[3]rotaxane (H,T)-3c⊂1b2 was confirmed
by a prominent peak at 906 m/z in the ESI(þ) mass
spectrum,9 corresponding to the doubly charged supra-
molecular ion.
From the above three examples we can conclude that the
rational choice of the axle allows preparation of all three
possible (H,H)-, (T,T)-, and (H,T)-stereosequences of two
threaded calix-wheels 1b. In other words, the “information
written” on the thread is transferred to a specific pseudor-
otaxane sequence stereoisomer, which can be consideredas
a minimal “informational system”.
In this regard it is interesting to examine how the
structure of the calix-wheel could influence the transfer
of the written information. In particular, we speculated
that the presence of bulky groups on the wheel could
alter the stereopreference of a given thread. Thus, we
decided to study the complexation of hexamethoxy-
calix[6]arene 1c, bearing tert-butyl groups at the upper
rim, with the benzyl-exposing thread 3a, which gives
Acknowledgment. Thanks are due to Dr. Patrizia Ian-
ꢀ
nece (Dipartimento di Chimica e Biologia, Universita di
Salerno) for ESI-MS measurements.
Supporting Information Available. Synthetic details, 1D
and 2D NMR spectra, details on molecular modeling and
on stability constant determination. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 8, 2011
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