Na+ ion templated threading of Oligo(ethylene glycol) chains through BPX26C6 Allows synthesis of [2]rotaxanes under solvent-free conditions

Article abstract of DOI:10.1021/ol403602j

Threading of di-, tri-, and tetra(ethylene glycol) through the macrocycle BPX26C6 in the presence of templating Na⁺ ions was proven by the synthesis of the corresponding [2]rotaxanes under solvent-free conditions. Among them, a [2]rotaxane featuring both tetra(ethylene glycol) and carbamate stations behaves as a molecular switch that can be controlled reversibly through the application of the KTFPB/[2.2.2]cryptand reagent pair.

Full text of DOI:10.1021/ol403602j

Letter
pubs.acs.org/OrgLett
Na+ Ion Templated Threading of Oligo(ethylene glycol) Chains
through BPX26C6 Allows Synthesis of [2]Rotaxanes under Solvent-
Free Conditions
Ke-Dian Wu,† You-Han Lin,† Chien-Chen Lai,‡ and Sheng-Hsien Chiu*,†
†Department of Chemistry, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei, Taiwan, 10617, R.O.C.
‡Institute of Molecular Biology, National Chung Hsing University and Department of Medical Genetics, China Medical University
Hospital, Taichung, Taiwan, R.O.C.
S
* Supporting Information
ABSTRACT: Threading of di-, tri-, and tetra(ethylene glycol) through the macrocycle BPX26C6 in the presence of templating
Na+ ions was proven by the synthesis of the corresponding [2]rotaxanes under solvent-free conditions. Among them, a
[2]rotaxane featuring both tetra(ethylene glycol) and carbamate stations behaves as a molecular switch that can be controlled
reversibly through the application of the KTFPB/[2.2.2]cryptand reagent pair.
thylene glycol and its oligomers and polymers are applied
widely in many fields, from industrial manufacturing to
E
biological production.1 In supramolecular chemistry, oligo-
(ethylene glycol) units have long been critical motifs within
crown ethers, endowing them with the ability to complex
various metal ions and to form pseudorotaxanes with various
cationic guests, including dialkylammonium,2 pyridinium,3 and
imidazonium ions.4 Oligo(ethylene glycol) motifs also
commonly appear in the molecular structures of typical
crown ether−like macrocycles in interlocked molecular
switches, not only for their ability to conveniently adjust the
ring size but also to confer residual guest complexation
properties. In contrast, although the threading of poly(ethylene
glycol) chains through cyclodextrins has been applied to
generate polypseudorotaxanes and polyrotaxanes in aqueous
solution,5 linear oligo(ethylene glycol)s are rarely applied as
primary guest recognition units for synthetic hosts in the
formation of interweaved and/or interlocked structures in
common organic solvents.6 Recently, we reported the self-
assembly of a [2]catenane based on the orthogonal placement
of two di(ethylene glycol) chains templated by the Na+ ion.7
We wished to test whether such a templating strategy could be
applied to direct the threading of an oligo(ethylene glycol)
chain through an oligo(ethylene glycol)-containing macrocycle,
thereby facilitating the synthesis of corresponding rotaxanes
(Figure 1). If relatively chemically inert, yet readily accessible
and derivatized, oligo(ethylene glycol)s could become primary
recognition units within rotaxanes, and it would also be possible
to synthesize molecular switches having relatively simple and
robust structures. Herein, we report the construction of
[2]rotaxanes based on the threading of di-, tri-, and
tetra(ethylene glycol) through bis-para-xylyl[26]crown-6
(BPX26C6),8 templated by Na+ ions, under solvent-free
Figure 1. Chemical structure of 1 and the concept of threading
oligo(ethylene glycol)s through the cavity of BPX26C6 with the
assistance of templating Na+ ions.
conditions; one such [2]rotaxane, featuring both tetra(ethylene
glycol) and carbamate stations, behaves as a K+-controllable
molecular switch.
To investigate the possibility of assembling two oligo-
(ethylene glycol)-containing species, a linear guest and a
macrocyclic host, linked by a Na+ ion as the template, we
synthesized the threadlike molecule 1 from di(ethylene glycol)
and p-tert-butylbenzyl bromide (see the Supporting Informa-
1
tion). The H NMR spectrum of an equimolar mixture (10
mM) of BPX26C6, the threadlike species 1, and sodium
tetrakis(3,5-trifluoromethylphenyl)borate (NaTFPB) in CDCl3
featured signals for the macrocyclic component that were
almost identical to those of an equimolar mixture of BPX26C6
and NaTFPB (i.e., in the absence of 1) under similar
conditions; in addition, the shifts in the signals for the aromatic
and ethylene glycol units of 1 in the presence of BPX26C6 and
NaTFPB were minor relative to those of 1 alone in the same
Received: December 12, 2013
Published: February 5, 2014
© 2014 American Chemical Society
1068
dx.doi.org/10.1021/ol403602j | Org. Lett. 2014, 16, 1068−1071

Organic Letters
Letter
1
solvent. Nevertheless, the H NMR spectrum of an equimolar
(10 mM) mixture of 1 and NaTFPB revealed significant upfield
shifts for the signals of the aromatic and ethylene glycol units of
1. Taken together, these features suggest that the Na+ ions in
the mixture of BPX26C6, 1, and NaTFPB were complexed
predominately with BPX26C6 rather than with 1 (not
surprisingly, as would be expected for the macrocyclic effect)9
and that the association of 1 with the BPX26C6·Na+ complex
was not particularly strong. Thus, to prove the existence of
[2]pseudorotaxanes formed through Na+ ion templated
complexation of the oligo(ethylene glycol)-containing macro-
cycle and oligo(ethylene glycol)-containing threadlike mole-
cules in solution, it was necessary to synthesize and isolate the
corresponding [2]rotaxanes (Scheme 1). To do so, we
demonstrated that the efficiency of synthesizing [2]rotaxanes
from weakly interacting host/guest systems can be improved
significantly under solvent-free conditions, where the concen-
tration of the host/guest complexes can be increased
significantly and their unfavorable dissociation, induced by
reagents or side products, can be minimized;10 therefore, we
turned our attention to preparing the [2]rotaxanes 12−14
under solvent-free conditions. Because the isocyanate 11 is a
liquid and relatively sensitive to moisture in the air, instead of
coating the materials on a solid support to perform ball-milling,
we concentrated a CH2Cl2 solution of a threadlike oligo-
(ethylene glycol) (8, 9, or 10), the macrocycle BPX26C6,
NaTFPB, and the isocyanate 11 (1:2.5:2.5:5) to give a sticky
liquid, which we presumed comprised the isocyanate stopper
and the [2]pseudorotaxane [(BPX26C6·Na+)⊃8−10].11 After
adding the neat catalyst di-n-butyltin dilaurate (DBTDL), we
stirred/ground the neat liquid mixture using a strong magnet to
manually control the motion of the magnetic stirrer inside the
sealed flask. After the liquid mixture had solidified completely
(typically less than 30 min), we ground the solid mixture for an
additional 5 min. Subsequent chromatographic purification of
the solid mixture gave the desired [2]rotaxane (12, 13, or 14;
yield: 23, 33, or 2%, respectively).
Scheme 1. Synthesis of the [2]Rotaxanes 12−14
To exclude the possibility of the [2]rotaxanes 12−14 having
been synthesized from intermediates formed from the Na+ ion
templated association of the isocyanate 11 and BPX26C6, we
wished to perform a stoppering reaction under similar solvent-
free conditions but instead using a stoppering reagent lacking
functional groups capable of strongly chelating Na+ ions (unlike
the CO group in the isocyanate). Because the “click” reaction
between an azide and a strained alkyne can proceed smoothly
in the absence of a catalyst,12 which itself might have disturbed
our host/guest recognition, we selected such a reaction for our
control experiment. Thus, we mixed the azide-terminated
tri(ethylene glycol) derivative 15 with BPX26C6 and NaTFPB
in CH2Cl2 and then concentrated the mixture to give a solid,
which we ball-milled in the presence of the benzannulated
cyclooctyne 1612b (a solid) to afford the [2]rotaxane 17 in 13%
yield after column chromatography (Scheme 2). This result
Scheme 2. Synthesis of the [2]Rotaxane 16 through a Click
Reaction under Solvent-Free Conditions
synthesized the threadlike molecules 8−10 in three steps
from their corresponding oligo(ethylene glycol)s. The oligo-
(ethylene glycol)s were first alkylated with 3,5-di-tert-
butylbenzyl bromide to give the alcohols 2−4, which we
subsequently alkylated with methyl 4-bromomethylbenzoate to
afford the esters 5−7. We obtained the alcohols 8−10 after
LiAlH4-mediated reduction of these esters.
Possibly because of weak association of the host and guest
components, the 1H NMR spectra of the crude products
obtained after adding the isocyanate 11 into an equimolar
mixture of BPX26C6, a threadlike oligo(ethylene glycol) (8, 9,
or 10), and NaTFPB in CH2Cl2 featured no obvious signals
belonging to the [2]rotaxanes 12−14; subsequent purification
afforded no such [2]rotaxanes, instead yielding the correspond-
ing dumbbell-shaped oligo(ethylene glycol)s and free
BPX26C6 as major products. In a previous study, we
supports our proposed mechanism for the formation of
[2]pseudorotaxane structures through the recognition of linear
oligo(ethylene glycol) chains by BPX26C6, stabilized by a
templating Na+ ion, in concentrated solutions or in the absence
of solvent (Scheme 1). The absence of any detectable signals
1
for the [2]rotaxanes 12−14 in the H NMR spectra of the
crude products obtained when we repeated their syntheses
under otherwise identical conditions, but in the absence of
NaTFPB, suggested that the Na+ ion template was crucial for
1069
dx.doi.org/10.1021/ol403602j | Org. Lett. 2014, 16, 1068−1071

Organic Letters
Letter
efficient threading of each oligo(ethylene glycol) unit through
the cavity of BPX26C6.
component to complex a Na+ ion, the addition of NaTFPB
into CDCl3 solutions of the [2]rotaxanes 12−14 led to
broadening of the signals to various degrees, suggesting
shuttling of the BPX26C6 component (or its Na+ ion
complexed form) between the oligo(ethylene glycol) and
carbamate stations. Possibly because of its larger size and lower
charge density, the K+ ion is a weaker template than the Na+
ion when mediating the threading of urea or amide
functionalities through BPX26C6;13 we suspected, however,
that its weaker interactions in the binding pocket generated
from the CO group of the carbamate station and the
BPX26C6 component and its higher coordination number
might result in its preference for the ethylene glycol station
(i.e., higher number of oxygen atoms), thereby making the K+
ion a suitable agent for switching the [2]rotaxanes between
their two different states.
The success in synthesizing the [2]rotaxanes 12−14
confirmed that the di-, tri-, and tetra(ethylene glycol)
derivatives reside favorably within the cavity of BPX26C6 in
the presence of templating Na+ ions. The higher yield of the
[2]rotaxane 13 relative to that of the [2]rotaxane 12 under
similar conditions was presumably due to the tri(ethylene
glycol) motif of the threadlike molecule 9 containing one more
oxygen atom than the di(ethylene glycol) unit of the threadlike
molecule 8, thereby increasing its affinity to the templating Na+
ion and stabilizing the corresponding [2]pseudorotaxane to a
greater extent. Interestingly, however, extending the threadlike
molecule by one more ethylene glycol unit, forming 10, led to
increased flexibility that disrupted the synthesis of the
[2]rotaxane 14. We suspect that the very low yield of the
[2]rotaxane 14 also resulted from its tetra(ethylene glycol)-
derived threadlike precursor having the ability to almost fulfill
the coordination number of the Na+ ion, thereby decreasing its
need to cooperate with BPX26C6 in the binding of the
template. This observation supports our original design and
implies that similar strategies based on metal ion−templated
threading might be inefficient when the host or guest can, by
itself, largely fulfill the coordination number of the templating
metal ion.
1
Because the H NMR spectra of the [2]rotaxane 14 (Figure
3a) and its free dumbbell-shaped component (Figure 3d) in
As displayed in Figure 2, the 1H NMR spectra of the
[2]rotaxanes 12−14 are quite similar, except for the signals of
1
Figure 3. H NMR spectra (400 MHz, CDCl3, 298 K) of (a) the
[2]rotaxane 14 (10 mM); (b) the mixture obtained after adding
KTFPB (1 equiv) to the solution in (a); (c) the mixture obtained after
adding [2.2.2]cryptand (1 equiv) to the solution in (b); and (d) the
free dumbbell-shaped component of the [2]rotaxane 14. *Signals of
[2.2.2]cryptand.
Figure 2. 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a) the free
dumbbell-shaped component of the [2]rotaxane 12 and (b−d) the
[2]rotaxanes (b) 12, (c) 13, and (d) 14.
CDCl3 were similar to those of the [2]rotaxane 12 (Figure 2b)
and its free dumbbell-shaped component (Figure 2a),
respectively, we suspect that the interlocked BPX26C6
component of 14 also encircled its carbamate station under
these conditions. Figure 3b reveals that the addition of KTFPB
(1 equiv) to the solution of the [2]rotaxane 14 in CDCl3
migrated the relatively upfield and downfield signals of its
benzylic (Hg, Hh) and carbamate NH protons, respectively,
back to positions similar to those in the spectrum of the free
dumbbell-shaped component of the [2]rotaxane 14 (Figure
3d), suggesting that the interlocked BPX26C6 component no
longer resided around the carbamate station under these
conditions.14 In addition, the spreading and upfield shifts of the
signals of the ethylene glycol protons and the downfield shift of
the signals of the aromatic xylyl protons suggested that the
BPX26C6 component had moved away from the carbamate
station and most likely resided at the tetra(ethylene glycol)
station to allow cooperative chelation of the K+ ion. This
concept was supported by the corresponding 2D NOESY
spectra, in which cross signals appeared between the xylyl
protons of the BPX26C6 component and the terminal benzylic
their oligo(ethylene glycol) units in the range δ 3.35−3.70. We
used 2D COSY and NOESY experiments to identify most of
1
the signals in the H NMR spectra of the [2]rotaxanes 12−14
1
in CDCl3 at 298 K (Figure 2). Relative to the H NMR
spectrum of its free dumbbell-shaped component, the spectrum
of the [2]rotaxane 12 features significant upfield shifts of the
two carbamate-adjacent benzylic protons (Hg, Hh), from δ 5.1
and 4.36 to δ 4.52 and 3.80, respectively, together with a
downfield shift of the carbamate’s NH proton, from δ 4.99 to
5.80, suggesting the encircling of the BPX26C6 component
around the carbamate station and the existence of possible [N−
H···O] hydrogen bonds between the components under these
conditions. The presence of cross peaks for the signals of the
aromatic protons (HAr) of BPX26C6 and the terminal benzylic
protons (Hh) adjacent to the carbamate station in the 2D
NOESY spectrum of the [2]rotaxane 12 in CDCl3 at 298 K
(see the Supporting Information) is consistent with the
encircling of the macrocyclic component around the carbamate
unit under these conditions. Because the CO group in the
carbamate unit can also combine with the BPX26C6
1070
dx.doi.org/10.1021/ol403602j | Org. Lett. 2014, 16, 1068−1071

Organic Letters
Letter
protons (Hc) adjacent to the tetra(ethylene glycol) station in
the presence of K+ ions. Thus, it appears that the addition of K+
ions induced the migration of the interlocked BPX26C6
component from its original position, encircling the carbamate
station, to a new position, encircling the tetra(ethylene glycol)
station, generating the new translational structure [14·K]+
(Scheme 3). Subsequent addition of [2,2,2]cryptand (1
REFERENCES
■
(1) Harris, J. M., Zalipsky, S., Eds. Poly(ethylene glycol): Chemistry and
Biological Applications; ACS: San Francisco, 1997.
(2) (a) Fyfe, M. C. T.; Stoddart, J. F. Adv. Supramol. Chem. 1999, 5,
1. (b) Clifford, T.; Abushamleh, A.; Busch, D. H. Proc. Natl. Acad. Sci.
U.S.A. 2002, 99, 4830. (c) Gibson, H. W.; Yamaguchi, N.; Jones, J. W.
J. Am. Chem. Soc. 2003, 125, 3522. (d) Zhang, M.; Xu, D.; Yan, X.;
Chen, J.; Dong, S.; Zheng, B.; Huang, F. Angew. Chem., Int. Ed. 2012,
51, 7011.
(3) (a) Allwood, B. L.; Spencer, N.; Shahriari-Zavareh, H.; Stoddart,
J. F.; Williams, D. J. J. Chem. Soc., Chem. Commun. 1987, 1064.
(b) Loeb, S. J.; Wisner, J. A. Angew. Chem., Int. Ed. 1998, 37, 2838.
(c) Huang, F.; Zakharov, L. N.; Rheingold, A. L.; Ashraf-Khorassani,
M.; Gibson, H. W. J. Org. Chem. 2005, 70, 809. (d) Cheng, P.-N.; Lin,
C.-F.; Liu, Y.-H.; Lai, C.-C.; Peng, S.-M; Chiu, S.-H. Org. Lett. 2006, 8,
435. (e) Wang, F.; Zhang, J.; Ding, X.; Dong, S.; Liu, M.; Zheng, B.; Li,
S.; Wu, L.; Yu, Y.; Gibson, H. W.; Huang, F. Angew. Chem., Int. Ed.
2010, 49, 1090.
Scheme 3. [2]Rotaxane 14 Behaves as a K+ Ion Controllable
Molecular Switch
́
(4) (a) Castillo, D.; Astudillo, P.; Mares, J.; Gonzalez, F. J.; Vela, A.;
Tiburcio, J. Org. Biomol. Chem. 2007, 5, 2252. (b) Li, L.; Clarkson, G.
J. Org. Lett. 2007, 9, 497. (c) Noujeim, N.; Zhu, K.; Vukotic, V. N.;
Loeb, S. J. Org. Lett. 2012, 14, 2484.
(5) (a) Harada, A.; Kamachi, M. Macromolecules 1990, 23, 2821.
(b) Wenz, G.; Han, B.-H.; Muller, A. Chem. Rev. 2006, 106, 782.
̈
(6) Chiu, S.-H.; Stoddart, J. F. J. Am. Chem. Soc. 2002, 124, 4174.
(7) Tung, S.-T.; Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.; Chiu, S.-H.
Angew. Chem., Int. Ed. 2013, 52, 13269.
(8) (a) Cheng, P.-N.; Huang, P.-Y.; Li, W.-S.; Ueng, S.-H.; Hung, W.-
C.; Liu, Y.-H.; Lai, C.-C.; Peng, S.-M.; Chao, I.; Chiu, S.-H. J. Org.
Chem. 2006, 71, 2373. (b) You, Y.-C.; Tzeng, M.-C.; Lai, C.-C.; Chiu,
S.-H. Org. Lett. 2012, 14, 1046.
(9) (a) Sun, Y.; Kollman, P. A. J. Am. Chem. Soc. 1995, 117, 3599.
(b) Haack, K.-J.; Goddard, R.; Poerschke, K.-R. J. Am. Chem. Soc.
1997, 119, 7992.
equiv), a very strong binder of K+ ions, to the solution
provided a H NMR spectrum similar to that obtained in the
absence of any additives, suggesting the regeneration of the
original state of the [2]rotaxane 14 (Figure 3c). Thus, the
[2]rotaxane 14 is a molecular switch that can be controlled
reversibly through application of the KTFPB/[2.2.2]cryptand
reagent pair.
We have demonstrated that relatively chemically inert and
readily accessible oligo(ethylene glycol)s can function as
primary recognition units for the assembly of [2]rotaxanes
under solvent-free conditions. In addition, we have found that
one such interlocked molecule, the [2]rotaxane 14, behaves as a
metal ion controllable molecular switch, where the addition and
removal of K+ ions results in the interlocked BPX26C6
component in the [2]rotaxane encircling the tetra(ethylene
glycol) and carbamate stations, respectively, of the dumbbell
component. We believe that this simple recognition system will
have great potential for application in the development of
robust interlocked structures and molecular switches exhibiting
new functions.
1
(10) (a) Hsueh, S.-Y.; Cheng, K.-W.; Lai, C.-C.; Chiu, S.-H. Angew.
Chem., Int. Ed. 2008, 47, 4436. (b) Hsu, C.-C.; Chen, N.-C.; Lai, C.-C.;
Liu, Y.-H.; Peng, S.-M.; Chiu, S.-H. Angew. Chem., Int. Ed. 2008, 47,
7475.
(11) No signals representing the [2]rotaxane were present in the 1H
NMR spectrum of this mixture (see the Supporting Information). The
reaction between an isocyanate and an alchohol proceeds extremely
slowly at room temparature in the absence of a suitable catalyst; see:
Furusho, Y.; Sasabe, H.; Natsui, D.; Murakawa, K.-i.; Takata, T.;
Harada, T. Bull. Chem. Soc. Jpn. 2004, 77, 179.
(12) (a) Agard, N. J.; Prescher, J. A.; Bertozzi, C. R. J. Am. Chem. Soc.
2004, 126, 15046. (b) McKay, C. S.; Moran, J.; Pezacki, J. P. Chem.
Commun. 2010, 46, 931.
(13) Lin, Y.-H.; Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.; Chiu, S.-H. Angew.
Chem., Int. Ed. 2013, 52, 10231.
(14) The 1H NMR spectrum of an equimolar mixture of KTFPB and
the [2]rotaxane 12 or 13 in CDCl3 featured broadening of the signals.
ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic procedures and characterization data for the [2]-
rotaxanes. This material is available free of charge via the
Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: shchiu@ntu.edu.tw.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported by the National Science Council of
Taiwan (NSC-102-2119-M-002-007) and National Taiwan
University (NTU-102-R890913).
1071
dx.doi.org/10.1021/ol403602j | Org. Lett. 2014, 16, 1068−1071