Catenation of calixarene annulus

Article abstract of DOI:10.1021/ol303142c

Through-the-annulus-catenated calixarenes have been obtained, for the first time, by exploiting the "superweak anion" approach that allows the threading of the calix cavitywith functionalized dialkylammoniumaxles. In addition, the first example of a stere

Full text of DOI:10.1021/ol303142c

ORGANIC
LETTERS
2013
Vol. 15, No. 1
116–119
Catenation of Calixarene Annulus
Carmine Gaeta,*,† Carmen Talotta,† Silvia Mirra,† Luigi Margarucci,‡
Agostino Casapullo,† and Placido Neri*,†
Dipartimento di Chimica e Biologia and NANO_MATES Research Center, and
ꢀ
Dipartimento di Scienze Farmaceutiche e Biomediche, Universita di Salerno, Via Ponte
don Melillo, I-84084 Fisciano (Salerno), Italy
cgaeta@unisa.it; neri@unisa.it
Received November 14, 2012
ABSTRACT
Through-the-annulus-catenated calixarenes have been obtained, for the first time, by exploiting the “superweak anion” approach that allows the
threading of the calix cavity with functionalized dialkylammonium axles. In addition, the first example of a stereoprogrammed synthesis of a catenane
orientational isomer (an oriented calix[2]catenane) has been obtained, after macrocyclization, by using a directional alkylbenzylammonium axle.
In the last two decades, research interest in mechanically
interlocked molecules (MIMs),1 such as rotaxanes, cate-
nanes, and knots, has increased dramatically thanks to
their applications in nanotechnology2 and as molecular
machines3 and sensors.4 Among them, the catenanes, con-
stituted by two or more mechanically interlocked rings, have
attracted considerable attention as the basic component of
switches,5 unidirectional motors,6 and electronic displays.2
Various kinds of macrocycles, including crown-ethers,2,7
azacyclophanes,2,7 cyclodextrins,8 cucurbiturils,9 and macro-
lactams,6,10 have been used as the basic macroring under-
going catenation, after threading with a complementary
component and exploiting various preorganizing supramo-
lecular interactions.
Regarding calixarene11 macrocycles, only a few exam-
ples of catenanes have been reported in which the calixar-
ene annulus is not catenated but simply acts as an “inert”
scaffold on which a different kind of macrocycle is con-
structed, leaving the calix cavity completely unexploited
(Figure 1A).12 Consequently, to the best of our knowledge,
no examples of through-the-annulus-catenated calixarene
systems (calix-catenane, Figure 1B) are currently known.
Here we describe the first examples of catenation through a
calixarene annulus (i.e., a calix[6]arene) to give either a
symmetrical system or a nonsymmetrical catenane with a
stereoprogrammed orientation of the calix wheel.
† Dipartimento di Chimica e Biologia and NANO_MATES Center.
‡ Dipartimento di Scienze Farmaceutiche e Biomediche.
(1) Molecular Catenanes, Rotaxanes and Knots: A Journey through
the World of Molecular Topology; Sauvage, J. P., Dietrich-Buchecker, C.,
Eds.; Wiley-VCH: Weinheim, Germany, 1999.
(2) (a) Ikeda, T.; Saha, S.; Aprahan, I.; Leung, K. C.-F.; Williams, A.;
Deng, W.-Q.; Flood, A. H.; Goddard, W. A.; Stoddart, J. F. Chem.
Asian J. 2007, 2, 76. (b) Collier, C. P.; Mattersteig, G.; Wong, E. W.;
Luo, Y.; Beverly, K.; Sampaio, J.; Raymo, F. M.; Stoddart, J. F.; Heath,
J. R. Science 2000, 289, 1172.
(3) (a) Balzani, V.; Credi, A.; Venturi, M. Molecular Devices and
Machines, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2008. (b) Saha, S.;
Stoddart, J. F. Chem. Soc. Rev. 2007, 36, 77.
The synthetic strategy undertaken to catenate the
calix[6]arene macrocycle 1a was based on the so-called
(4) Caballero, A.; Zapata, F.; White, G. N.; Costa, P. J.; Felix, V.;
Beer, P. D. Angew. Chem., Int. Ed. 2012, 51, 1876.
(5) For a recent review, see: Fahrenbach, A. C.; Bruns, C. J.; Cao, D.;
Stoddart, J. F. Acc. Chem. Res. 2012, 45, 1581.
(6) (a) Leigh, D. A.; Wong, J. K. Y.; Dehez, F.; Zerbetto, F. Nature
2003, 424, 174. (b) Hernandez, J. V.; Kay, E. R.; Leigh, D. A. Science
2004, 306, 1532.
(7) For a recent report, see: Fahrenbach, A. C.; Hartlieb, K. J.; Sue,
C.-H.; Bruns, C. J.; Barin, G.; Basu, S.; Olson, M. A.; Botros, Y. Y.;
Bagabas, A.; Khdary, N. H.; Stoddart, J. F. Chem. Commun. 2012, 48,
9141.
(8) (a) Lim, C. W.; Sakamoto, S.; Yamaguchi, K.; Hong, J.-I. Org.
Lett. 2004, 6, 1079. (b) Armspach, D.; Ashton, P. R.; Ballardini, R.;
Balzani, V.; Godi, A.; Moore, C. P.; Prodi, L.; Spencer, N.; Stoddart,
J. F.; Tolley, M. S.; Wear, T. J.; Williams, D. J. Chem.;Eur. J. 1995, 1, 3.
(9) Park, K.-M.; Kim, S.-Y.; Heo, J.; Whang, D.; Sakamoto, S.;
Yamaguchi, K.; Kim, K. J. Am. Chem. Soc. 2002, 124, 2140.
(10) (a) White, N. G.; Beer, P. D. Chem. Commun. 2012, 48, 8499.
(b) Leigh, D. A.; Lusby, P. J.; Slawin, A. M. Z.; Walker, D. B. Chem.
Commun. 2012, 48, 5826.
(11) Gutsche, C. D. Calixarenes, An Introduction; Royal Society of
Chemistry: Cambridge, UK, 2008.
r
10.1021/ol303142c
Published on Web 12/18/2012
2012 American Chemical Society

designed and synthesized diisocyanate 3b (Scheme 1)17
containing more rigid elements and meta-substituted aryl
rings that should induce a certain favorable curvature.
Figure 1. Schematic representation of the currently known pro-
totypical examples of catenanes with unthreaded calix cavity (A)
and the proposed calix[2]catenane with a through-the-annulus
catenation (B).
“superweak anion” approach13 that allows the through-
the-annulus threading of such simple calix[6]arene hosts
with dialkylammonium ions13 by exploiting the inducing effect
of the “superweak” tetrakis[3,5-bis(trifluoromethyl)phenyl]-
borate (TFPB) anion (Figure 2).14 The corresponding pseu-
dorotaxane thus obtainable should then be cyclizable to a
catenane form (clipping) if appropriate functional groups are
present at the two terminations of the threading element.
Therefore, theTFPBsaltofadibenzylammonium cation
Figure 2. Structures of calix[6]arene wheels 1a,b, alkylbenzylammo-
nium axles 2þ and 5þ, TFPB anion, and aliphatic diisocyanate 3a.
Scheme 1
bearing two terminal OH groups 2þ TFPBꢀ (Figure 2)13f
3
was equilibrated with hexamethoxy-p-tert-butylcalix[6]-
arene 1a, at 60 °C for 72 h, to give pseudo[2]rotaxane
[2⊂1a]þ TFPBꢀ (Scheme 1) (percentage of formation
3
23% and apparent association constant Kass = 90 Mꢀ1
,
as determined by integration of the slowly exchanging 1H
NMR signals). This pseudorotaxane is an ideal candidate
to attempt the synthesis of a calix-threaded [2]catenane
by [1 þ 1] cyclocondensation clipping with appropriate
diisocyanate derivatives. Initially, we attempted this
cyclocondensation by using aliphatic diisocyanate 3a15
(Figure 2). However, under various conditions, the puta-
tive catenane could not be traced. To explain this unex-
pected result, we hypothesized that 3a was not sufficiently
preorganized to give the macroring closure.16 Thus, we
Therefore, pseudo[2]rotaxane [2⊂1a]þ TFPBꢀ, pre-
3
viously formed in a 6 ꢁ 10ꢀ3 M total concentration of each
precursor in dry CHCl3, and diisocyanate 3b (6 ꢁ 10ꢀ3 M
in dry CHCl3) were addedat a rateof 0.6 mL/min from two
distinct dropping reservoirs to 2.0 mL of dry CHCl3 under
stirring in the presence of dibutyltin dilaurate (DBTDL) as
the catalyst. Under these conditions, the first example of
(12) For recent examples of calixarene-based catenane systems in
which the calixarene annulus is unthreaded (type A in Figure 1), see:
(a) Schlesier, T.; Metzroth, T.; Janshoff, A.; Gauss, J.; Diezemann, G.
J. Phys. Chem. B 2011, 115, 6445. (b) Phipps, D. E.; Beer, P. D.
Tetrahedron Lett. 2009, 50, 3454. (c) Li, Z.-T.; Zhao, X.; Shao, X.-B.
In Calixarenes in the Nanoworld; Harrowfield, J., Vicens, J., Eds.; Springer:
Dordrecht, The Netherlands, 2007; Chapter 3, pp 47ꢀ62 and references
cited therein. (d) Wang, L.; Vysotsky, M. O.; Bogdan, A.; Bolte, M.;
through-the-annulus-threaded calix[2]catenane 4þ TFPBꢀ
3
(Scheme 1) was formed and isolated by semipreparative
HPLC in 30% yield.17
The ESIþ MS spectrum of 4þ TFPBꢀ gave sharp peaks
þ3
€
Bohmer, V. Science 2004, 304, 1312.
centered at m/z 2060.21 [M] (see Figure S11 in the
Supporting Information) corresponding to the singly
charged interlocked molecule. This [2]catenane nature
(13) (a) Gaeta, C.; Troisi, F.; Neri, P. Org. Lett. 2010, 12, 2092. In
addition, see: (b) Talotta, C.; Gaeta, C.; Neri, P. Org. Lett. 2012,
14, 3104. (c) Gaeta, C.; Talotta, C.; Farina, F.; Camalli, M.; Campi,
G.; Neri, P. Chem.;Eur. J. 2012, 18, 1219. (d) Gaeta, C.; Talotta, C.;
Farina, F.; Teixeira, F. A.; Marcos, P. A.; Ascenso, J. R.; Neri, P. J. Org.
Chem. 2012, 77, 10285. (e) Talotta, C.; Gaeta, C.; Pierro, T.; Neri, P.
Org. Lett. 2011, 13, 2098. (f) Pierro, T.; Gaeta, C.; Talotta, C.;
Casapullo, A.; Neri, P. Org. Lett. 2011, 13, 2650.
(14) (a) Strauss, S. H. Chem. Rev. 1993, 93, 927. (b) Gasa, T. B.;
Valente, C.; Stoddart, J. F. Chem. Soc. Rev. 2011, 40, 57.
(15) Ovalos, M.; Babiano, R.; Cintas, P.; Gomez-Carretero, A.;
Jimenez, J. L.; Lozano, M.; Ortiz, A. L.; Palacios, J. C.; Pinazo, A.
Chem.;Eur. J. 2008, 14, 5656.
1
was confirmed by the expected H and 13C NMR reso-
nances of all components and by a typical upfield AX
system at 5.08 and 4.50 ppm (d, J = 8.3 Hz, 2H each) (red
signals in Figure 3) for ArH protons of the shielded
endocavity benzylammonium unit of the axle,17 similar
tothatobservedfor the related pseudorotaxanecomplex.13
In addition, a 2D ROESY17 experiment showed the pre-
sence of diagnostic cross-peaks between these shielded
ArH protons of the axle and the calixarene ArH and
t-Bu resonances at 7.16 and 1.12 ppm, respectively. These
(16) A similar reasoning also explained the unsatisfactory results
obtained in some preliminary attempts using the more popular ring-
closing metathesis (RCM) approach, which was not further pursued.
(17) See Supporting Information for further details.
Org. Lett., Vol. 15, No. 1, 2013
117

data are a clear evidence that the calix[6]arene macrocycle
ispositionedaroundthebenzylammonium center towhom
it is bonded by hydrogen bonds between ethereal OMe
atoms and the ammonium þNH2 group.
them in a stereoprogrammed mode. To the best of our
knowledge, no examples of such stereoprogrammed synth-
esisoforientedcatenane stereoisomershavebeendescribed
in the chemical literature to date.21 To address this issue, on
the basis of previous work,13a,b we designed directional
alkylbenzylammonium axle 5þ TFPBꢀ (Figure 2) having
3
two different moieties attached to the ammonium center
and bearing two terminal OH groups.17
As above, the new directional axle 5þ TFPBꢀ was
3
equilibrated with hexamethoxy-p-tert-butylcalix[6]arene
1a to obtain the corresponding pseudorotaxane.17 How-
ever, 1H NMR spectroscopy revealed no hint of threading
of 5þ under various conditions. Therefore, we resorted to
hexamethoxy-p-H-calix[6]arene1b (Figure 2) as an alternative
wheel. In this instance (Figure 4), clear evidence of threading
was observed in a 1:1 host/guest solution in CDCl3 (9 ꢁ 10ꢀ3
M each) by NMR.17 In fact, the complexation equilibrium
was reached, at room temperature, within a few minutes with
a percentage of formation of 25% and an apparent associa-
tion constant Kass = 6.2 ꢁ 102 Mꢀ1 (determined by integra-
tion of the slowly exchanging 1H NMR signals).
Figure 3. 1H NMR spectrum (400 MHz, CDCl3, 298 K) of
4þ TFPBꢀ and its B3LYP/6-31G* energy-minimized structure18
(inset).
3
This location was fully confirmed by DFT calculations
at the B3LYP/6-31G* level of theory,18 which evidenced
the two strongly stabilizing NꢀH O hydrogen bonds
3 3 3
(see inset in Figure 3). In addition, these interactions
contribute to held the calix[6]arene macrocycle in a cone
conformation as demonstrated by a well-spaced AX sys-
tem at 3.44 and 4.38 ppm (d, J = 14.4 Hz, 6H each) for
ArCH2Ar protons (Figure 3). Interestingly, all of these
spectral features remained practically unaltered either by
changing the temperature or by adding anions (Clꢀ) or
polar solvents (CH3CN)19 that usually led to decomplexa-
tion of the related pseudorotaxanes.13a,20
Because of the symmetrical nature of its constitutive
components 2þ and 3b, the newly formed macroring of
catenane 4þ is also symmetrical, and consequently, no
stereochemical problems are present here. Of course, a
different situation would be obtained if one of the above
components isconstitutionally nonsymmetrical (oriented).
In fact, this orientation coupled to the directional nature of
the cone-shaped calixarene wheel would give rise to two
possible catenane orientational isomers.8b
Figure 4. 1H NMR spectrum (400 MHz, CDCl3, 298 K) of an
equimolar mixture (9 ꢁ 10ꢀ3 M) of 5þ TFPBꢀ and 1b.
3
The relative orientation of the thread 5þ with respect to
calixarene 1b (see Scheme 2) was established by 1D and 2D
NMR experiments.17 In particular, the presence in the
1H NMR spectrum (CDCl3, 400 MHz, 298 K) of
[5⊂1b]þ TFPBꢀ of a typical signature at high field or
3
In this instance, it would be quite challenging to find a
way to direct the synthesis specifically toward one of
negative values (0.51, 0.25, 0.05, and ꢀ0.95 ppm; see
Figure 4), characteristic of an endo-complexation of the
alkyl chains shielded by calixarene aromatic rings, and the
absence of shielded benzylic resonances in the 4ꢀ6 ppm
region (Figure 4), typical of endo-benzyl complexation,
(18) DFT calculations were performed at the B3LYP level, using the
6-31G* basis set for the entire system (GAUSSIAN 09 Software
Package, see page S43 in the Supporting Information for additional
details).
was clear-cut proof that [(endo-alkyl)-5⊂1b]þ TFPBꢀ
3
(19) As previously reported in ref 13f, the addition of 10 equiv of
n-Bu4NþClꢀ is sufficient to give a coþmplete dethreading of [2⊂1a]þ
pseudo[2]rotaxane, while [2]catenane 4ꢀ retains its structure even after
the addition of 30 equiv of n-Bu4NþCl . Analogously, the addition of
300 equiv of CD3CN leads to complete dethreading of [2⊂1a]þ,13f while
pseudo[2]rotaxane (Scheme 2) had been formed in a
stereocontrolled way. These conclusions were further con-
firmed by a COSY-45 spectrum17 that allowed a complete
confident assignment of all upfield shielded alkyl resonances
4
þ retains its structure even after the addition of 700 equiv of CD3CN.
(20) To investigate the behavior of [2]catenane 4þ upon deprotona-
of [(endo-alkyl)-5⊂1b]þ TFPBꢀ pseudo[2]rotaxane. In the
3
tion of its ammonium center, it was neutralized using phosphazene base
P1-t-Bu to give the corresponding neutral [2]catenane 4. The 1H NMR
spectrum of 4 (CDCl3, 233 K) evidenced the presence of signals at
negative values characteristic of an endo-alkyl inclusion.17 Thus, upon
deprotonation, the calix[6]arene wheel moves from the original diben-
zylammonium site to new positions in which aliphatic chains are inside
the calix cavity. On the basis of previous results,13b,f the most favored
one is very likely that stabilized by H-bonds between calixarene OR
atoms and urethane NH group.17
2D ROESY spectrum17 (400 MHz, CDCl3, 298 K), the
[(endo-alkyl)-5⊂1b]þ TFPBꢀ complex gives rise to ROE
3
correlations among the shielded R, β, γ, and δ signals and
the host ArH at 6.99 ppm (d, J = 8.0 Hz, 6H).
In conclusion, the threading of p-H-calix[6]arene macro-
cycle 1b with alkylbenzylammonium axle 5þ TFPBꢀ led
3
Org. Lett., Vol. 15, No. 1, 2013
118

Scheme 2
Scheme 3
confirmed the endo-alkyl stereochemistry by giving ROE
correlations among the shielded R, β, γ, and δ signals and
the calix ArH protons (Figure S35).
exclusively to the endo-alkyl orientational isomer, while no
trace of the endo-benzyl one could be detected by 1H NMR
spectroscopy even after heating at 50 °C for 48 h. In good
accord, DFT calculations (Figure S30) at the B3LYP/
6-31G* level of the theory indicated that [(endo-alkyl)-
DFT calculations at the B3LYP/6-31G* level of theory
were in good accordance with this result, indicating that
(endo-alkyl)-12þ TFPBꢀ stereoisomer was more stable
3
than the endo-benzyl one by 3.1 kcal/mol (Figure 5).18
5⊂1b]þ TFPBꢀ stereoisomer was more stable than the
3
endo-benzyl one by 3.5 kcal/mol.18,22
Thus, having secured the stereocontrol of intermediate
pseudo[2]rotaxane [5⊂1b]þ TFPBꢀ, we decided to test the
3
[1 þ 1] cyclocondensation with diisocyanate derivative
3b, under the same conditions used above to obtain
calix[2]catenane 4þ TFPBꢀ.17 Unexpectedly, no traces of
3
the putative catenane could be detected, under these
conditions, with various analytical techniques. To explain
this result, we reasoned that, very likely, the dilution
caused by the slow dropping in a larger volume favored a
quick dethreading process of the [5⊂1b]þ TFPBꢀ pseudo-
Figure 5. Energy-minimized structures of (endo-alkyl) (left) and
(endo-benzyl) (right) orientational isomers of calix-threaded
[2]catenane 12þ (B3LYP DFT calculations using the 6-31G*
basis set).
3
[2]rotaxane. On the other hand, the contrasting positive
result obtained for 4þ TFPBꢀ can be rationalized by the
3
slow kinetics of dethreading of [2⊂1a]þ TFPBꢀ, which
3
requires more than 2 days to reach the new equilibrium.
Therefore, in a second experiment, diisocyanate deriva-
tive 3b was added dropwise to a solution 6 ꢁ 10ꢀ3 M of
In conclusion, the first examples of through-the-annulus-
catenated calixarenes (calix[2]catenanes) have been ob-
tained by exploiting the “superweak anion” approach that
allows the threading of the calix cavity with functionalized
dialkylammonium axles. In addition, we have shown that
directional alkylbenzylammonium axles can be threaded
in a stereoprogrammed way to give, after macro-
cyclization, the first example of oriented calix-catenane.
Considering the current enormous interest in mechanically
interlocked molecules1 and the large variety of shapes
and dimensions obtainable with calix[n]arene macrocycles,
it is conceivable that our approach to calixarene-based
MIMs will pave the way to a quickly expanding new area
of research.
pseudo[2]rotaxane [(endo-alkyl)-5⊂1b]þ TFPBꢀ in dry
3
CHCl3 at 55 °C, in the presence of dibutyltin dilaurate
(DBTDL) as the catalyst.17 Under these conditions, the
first example of oriented calix[2]catenane 12þ TFPBꢀ was
3
isolated in 23% yield (Scheme 3). The ESIþ MS spectrum
of 12þ TFPBꢀ gave sharp peaks centered at m/z 1722.92
3
[M]þ (Figure S31), confirming its catenane nature.17 The
endo-alkyl stereochemistry of the pseudorotaxane precur-
sor [5⊂1b]þ was retained after the macrocyclization reac-
1
tion (Scheme 3) as evidenced by the H NMR spectrum
of 12þ TFPBꢀ in CDCl3, which showed very similar
3
spectral features in the pertinent diagnostic regions.
As above, a COSY-45 spectrum17 allowed a complete
confident assignment of all upfield shielded alkyl reso-
Supporting Information Available. Synthetic details,
1D and 2D NMR spectra, and details on molecular
modeling. This material is available free of charge via
the Internet at http://pubs.acs.org.
nances of 12þ TFPBꢀ. Also in this case, the 2D ROESY
3
spectrum17 (400 MHz, CDCl3, 298 K) of 12þ TFPBꢀ
3
(21) Oriented [2]catenane stereoisomers have been reported8b in
which a constitutionally asymmetrical diamine was threaded through
a constitutionally asymmetrical cyclodextrin. In this case, the two
possible diastereoisomers were obtained in a statistical ratio and no
stereocontrol could be evidenced.8b
(22) For possible explanations on this higher stability, see ref 13a.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
119