Self-sorting under solvent-free conditions: One-pot synthesis of a hetero[3]rotaxane

Article abstract of DOI:10.1021/ol201870h

The one-pot synthesis of a hetero[3]rotaxane, assembled from five different molecular components under solvent-free conditions, through "self-sorting" of the bead and stopper units during the threading and stoppering processes, is reported.

Full text of DOI:10.1021/ol201870h

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4660–4663
Self-Sorting under Solvent-Free Conditions:
One-Pot Synthesis of a Hetero[3]rotaxane
Pei-Nung Chen,† 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., and Institute of Molecular Biology,
National Chung Hsing University and Department of Medical Genetics,
China Medical University Hospital, Taichung, Taiwan, R.O.C.
shchiu@ntu.edu.tw
Received July 12, 2011
ABSTRACT
The one-pot synthesis of a hetero[3]rotaxane, assembled from five different molecular components under solvent-free conditions, through “self-
sorting” of the bead and stopper units during the threading and stoppering processes, is reported.
The growing realization that mechanically interlocked
molecules, such as rotaxanes, can be used to develop
mesoscale devices and artificial molecular machinery on
the nanoscale has drawn much attention to their
syntheses.1 In Nature, important biomolecules (e.g., pairs
of DNA strands forming double helices) assemble through
selective recognition (e.g., of AꢀT and CꢀG base pairs);
the same “self-sorting” concept also allows the efficient,
selective self-assembly of non-natural systems (e.g., in
rotaxane-like systems, the threading of two different
macrocyclic components onto a single thread-like unit in
solution).2 The classical “threading-followed-by-stopper-
ing” approach for rotaxane synthesis generally involves
noncovalent threading of bead(s) onto a rod and then
sealing the assembly through covalent attachment of stopper
units.3 We wished to test whether we could realize the self-
sorting concept in both steps;threading and stoppering;to
form a hetero[3]rotaxane from five different molecular com-
ponents (one thread, two beads, two stoppers) through
selective assembly in a simple stepwise one-pot reaction
(Figure 1). Because the use of less-hazardous substances
and the generation of lower amounts of waste are important
issues in organic synthesis,4 we sought to take the challenge to
the next level by assembling such a hetero[3]rotaxane under
solvent-free conditions; that is, we wanted the self-sorting
processes in both the threading and stoppering steps to occur
in the absence of solvent molecules. Herein, we report the
one-pot synthesis of a hetero[3]rotaxane, assembled from five
different molecular components under solvent-free condi-
tions, through “self-sorting” of the bead and stopper units
during the threading and stoppering processes.
† National Taiwan University.
Although concentrating a solution containing a mixture
of a single thread and two macrocycles can result in
‡ National Chung Hsing University and China Medical University
Hospital.
(1) (a) Molecular Electronics: Science and Technology; Aviram, A.,
Ratner, M., Eds.; New York Academy of Sciences: New York, 1998. (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. (c) Saha,
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Mater. 2007, 17, 685. (d) Green, J. E.; Choi, J. W.; Boukai, A.;
Bunimovich, Y.; Johnston-Halperin, E.; DeIonno, E.; Luo, Y.; Sheriff,
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(2) (a) Lehn, J.-M. Science 2002, 295, 2400. (b) Wu, A. X.; Isaacs, L.
J. Am. Chem. Soc. 2003,125, 4831. (c) Mukhopadhyay, P.; Wu, A. X.; Isaacs,
L. J. Org. Chem. 2004, 69, 6157. (d) Jiang, W.; Winkler, H. D. F.; Schalley,
C. A. J. Am. Chem. Soc. 2008, 130, 13852. (e) Jiang, W.; Schaefer, A.; Mohr,
P. C.; Schalley, C. A. J. Am. Chem. Soc. 2010, 132, 2309.
(3) For recent examples, see: (a) Collin, J.-P.; Durola, F.; Heitz, V.;
Reviriego, F.; Sauvage, J.-P.; Trolez, Y. Angew. Chem., Int. Ed. 2010, 49,
10172. (b) Busseron, E.; Romuald, C.; Coutrot, F. Chem.;Eur. J. 2010,
16, 10062. (c) Hsueh, S.-Y.; Kuo, C.-T.; Lu, T.-W.; Lai, C.-C.; Liu,
Y.-H.; Hsu, H.-F.; Peng, S.-M.; Chen, C.-h.; Chiu, S.-H. Angew. Chem.,
Int. Ed. 2010, 49, 9170. (d) Strutt, N. L.; Forgan, R. S.; Spruell, J. M.;
Botros, Y. Y.; Stoddart, J. F. J. Am. Chem. Soc. 2011, 133, 5668. (e)
Yoshii, T.; Kohsaka, Y.; Moriyama, T.; Suzuki, T.; Koyama, Y.;
Takata, T. Supramol. Chem. 2011, 23, 65. (f) Leontiev, A. V.; Jemmett,
C. A.; Beer, P. D. Chem.;Eur. J. 2011, 17, 816.
(4) (a) Trost, B. M. Science 1991, 254, 1471. (b) Tanaka, K.; Toda, F.
Chem. Rev. 2000, 100, 1025. (c) Solvent-Free Organic Synthesis; Tanaka,
K., Ed.; Wiley-VCH: Weinheim, 2004.
r
10.1021/ol201870h
Published on Web 08/09/2011
2011 American Chemical Society

Scheme 1
Figure 1. Using two sequential self-sorting steps to construct a
hetero[3]rotaxane.
isolation of the corresponding hetero[3]pseudorotaxane in
solid form,5 this approach does not fit into the strict definition
of solvent-free “self-sorting.” Instead, we turned our atten-
tion to the melting approach, reported more than a decade
ago, for the synthesis of slippage [2]rotaxanes,6 expecting that
self-sorting in the threading process would proceed smoothly
upon melting a mixture of a single thread and two different
macrocycles. To avoid possible decomposition of these com-
ponents at their high melting temperatures, we chose to
employ one of the recognition components that is naturally
a liquid at room temperature to improve the degree of contact
between the components and thereby ensure that the thread-
ing process would proceed at relatively lower temperatures.
With regard to a solvent-free self-sorting stoppering process,
we required two different stoppers to be placed selectively at
their appropriate termini, adjacent to the two well-organized
macrocycles, in the absence of solvent molecules. Although
using two orthogonal stoppering reactions would likely solve
this problem, we sought the challenge of using the same types
of chemical functionalities but controlling their relative re-
activities under solvent-free conditions. We have previously
demonstrated that the DielsꢀAlder reactions between pro-
pargyl and tetrazine units occur smoothly when grinding the
corresponding solid mixtures; the same reactions between
para-substituted phenylacetylene and diphenyltetrazine units,
however, require heating and do not proceed under the same
grinding conditions.7 Therefore, we selected these compo-
nents to realize self-sorting stoppering in the solid state.
To begin our quest toward the one-pot synthesis of a
hetero[3]rotaxane under solvent-free conditions, we per-
formed some model reactions on simple two-component
tetrazine derivatives under solid-to-solid grinding conditions
(Scheme 1). We heated a neat mixture of the solid 1-H PF6
3
and the liquid 21C7 at 323 K while mixing with a spatula
until the sample solidified completely. We presumed that
this solid contained predominantly the corresponding
[2]pseudorotaxane [21C7⊃1-H][PF6], which we used di-
rectly in the ball-milling process. Grinding an equimolar
mixture of this solid [2]pseudorotaxane and solid tetrazine
for 6 h gave a mixture of the [2]rotaxanes 2-H PF6 and
3
3-H PF6 and the ammonium salt 4-H PF6 (Figure 2),
suggesting that both the passage of 21C7 onto the thread-
3
3
like salt 1-H PF6 and the DielsꢀAlder reactions at its
3
termini proceeded efficiently through this sequential treat-
ment process, albeit with poor reaction selectivity of tetra-
zine toward the two terminal alkyne units. A similar ball-
milling reaction of a mixture of solid tetrazine and the solid
[2]pseudorotaxane obtained after concentrating an equi-
molar mixture of 21C7 and 1-H PF6 in CH3NO2 gave almost
3
identical results to those from our heating/mixing/grinding
approach. Therefore, we suspected that [2]pseudorotaxane
formation from 1-H PF6 and 21C7 occurred during the
3
heating-and-mixing process performed in the absence of
solvent, encouraging us to investigate the self-sorting of two
different macrocycles onto a single thread-like salt using such a
solvent-free heating-and-mixing method.
systems. We selectedthe solid thread-like salt1-H PF6 and
3
the liquid macrocycle 21C7 as a model to investigate the
possibility of forming a [2]pseudorotaxane when heating
their mixture in the absence of solvent and then tested
the selectivities of the two terminal alkyne units toward
Next, we evaluated the reactivities of tetrazine and alkyne
units so that we could position appropriate stoppers during the
grinding process. To ensure a difference in reactivity of the two
(5) A similar method has been used to generate pseudorotaxanes as
solids for the efficient syntheses of [2]- and [4]rotaxanes; see: Hsueh,
S.-Y.; Cheng, K.-W.; Lai, C.-C.; Chiu, S.-H. Angew. Chem., Int. Ed.
2008, 47, 4436.
terminal alkyne units of the thread-like salt 1-H PF6, we
3
performed the grinding reaction using an equimolar mixture
of solid diphenyltetrazine and the solid [2]pseudorotaxane
[21C7⊃1-H][PF6] obtained after heating and mixing. As
expected, the reaction did not proceed, even after 6 h of ball-
milling; in contrast, heating this ground solid mixture at 373 K
€
€
(6) Handel, M.; Plevoets, M.; Gestermann, S.; Vogtle, F. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1199.
(7) (a) 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. (b) Hsu, C.-C.; Lai,
C.-C.; Chiu, S.-H. Tetrahedron 2009, 65, 2824.
Org. Lett., Vol. 13, No. 17, 2011
4661

Scheme 2
Figure 2. Partial 1H NMR spectra (400 MHz, CD3CN, 298 K) of
(a) an equimolar (40 mM) mixture of 21C7, 1-H PF6, and
3
tetrazine; (b) the crude product after solid state ball-milling for
6 h of an equimolar mixture of tetrazine and the [2]pseudorotaxane
[(21C7⊃1-H) PF6] formed by heating and mixing; (c) purified 3-
3
H PF6; and (d) purified 2-H PF6.
3
3
for 72 h gave the ammonium salt 5-H PF6 as the predominant
3
product. This result suggested that the phenylacetylene termi-
nus of the [2]pseudorotaxane was more reactive toward
diphenyltetrazine than was the propargyl terminus during this
solid-to-solid heating process. Initially, we suspected that the
difference in selectivity of tetrazine and diphenyltetrazine
toward the two different terminal alkynes was due to their
reactivity;with the more-reactive tetrazine providing
poorer selectivity. Grinding an equimolar solid mixture
Figure 3. 1H NMR spectra (400 MHz, CD3CN, 298 K) of (a) an
equimolar (40 mM) mixture of 21C7, 6-H PF6, and tetrazine;
3
(b) the crude product after solid state ball-milling for 9 h of an
equimolar mixture of tetrazine and the [2]pseudorotaxane
[(21C7⊃6-H)][PF6] formed by heating and mixing; and (c)
purified 7-H PF6. The descriptors “c” and “uc” refer to com-
3
plexed and uncomplexed states, respectively, of the components.
of the thread-like salt 1-H PF6 and tetrazine, however,
3
gave predominantly the salt 4-H PF6, suggesting that
in a rotaxane; therefore, we designed our one-pot, solvent-free
synthesis of a hetero[3]rotaxane such that the smaller tetrazine
would react with the propargyl terminus, leaving the phenyla-
cetylene end to react with diphenyltetrazine. The resulting
pyridazine and diphenylpyridazine stoppers would both be of
sufficient size to interlock their adjacent crown ether units.
One approach toward minimizing the inductive effect of
the NH2þ center on the propargyl unit would be to distance
the acetylene group farther from the positive charge. There-
3
tetrazine does react selectively with the phenylacetylene
terminus when the NH2þ unit is not encircled by a 21C7 unit.
The reaction of an electron-deficient tetrazine with an
alkyne most likely occurs between the lowest unoccupied
molecular orbital (LUMO) of the diene and the highest
occupied molecular orbital (HOMO) of the dienophile.8
Therefore, we suspect that the improved selectivity of
fore, we synthesized the thread-like salt 6-H PF6 (see the
3
tetrazine toward the phenylacetylene unit in 1-H PF6 in
the absence of complexation to 21C7 arose from the
greater electron-withdrawing effect of the NH2 unit,
3
Supporting Information), which features an oct-7-ynyl group
in place of the propargyl group in 1-H PF6 (Scheme 2).
þ
3
Gratifyingly, grinding an equimolar mixture of tetrazine and
the solid [2]pseudorotaxane [21C7⊃6-H][PF6] (obtained after
heating and mixing a 1:1 mixture of the thread-like salt
thereby decreasing the HOMO energy level of the propar-
gyl unit (decreasing its reactivity toward tetrazine and
resulting in greater selectivity). This result suggested that
if we could decrease the inductive effect of the NH2þ unit
even more, we might have a chance to reverse the reactivity
of the two alkyne units by having tetrazine react selectively
with the propargyl group under the grinding conditions.
The product of the reaction of tetrazine with a propargyl
unit;a pyridazine;is an efficient stopper for a 21C7 unit
6-H PF6 and 21C7) led to reaction of the oct-7-ynyl unit in
3
preference to the phenylacetylene unit with a selectivity as high
as 9:1, based on integration of pertinent signals in 1H NMR
spectra (Figure 3).9
Encouraged by this result, we synthesized the bis-
(ammonium) thread-like salt 8-H2 2PF6, expecting its
3
(8) (a) Boger, D. L. Chem. Rev. 1986, 86, 781. (b) Hamasaki, A.;
Ducray, R.; Boger, D. L. J. Org. Chem. 2006, 71, 185. (c) Blackman,
M. L.; Royzen, M.; Fox, J. M. J. Am. Chem. Soc. 2008, 130, 13518.
(9) We recovered 21% of the thread-like salt 6-H PF6 during the
3
purification process, possibly because of the loss of tetrazine through
sublimation under the reaction conditions.
4662
Org. Lett., Vol. 13, No. 17, 2011

Scheme 3
Figure 4. 1H NMR spectra (400 MHz, CD3CN, 298 K) of (a) an
equimolar (10 mM) mixture of 21C7, DB24C8, 8-H2 2PF6,
3
diphenyltetrazine, and tetrazine; (b) the crude product obtained
after subjecting the neat mixture of compounds in (a) to a one-
pot heating/mixing/grinding (9 h) process; (c) the crude product
obtained after heating the mixture in (b) for 72 h at 373 K; and
corresponding [3]pseudorotaxane [DB24C8⊂8-H2⊃21C7]
[2PF6] to be generated selectively through solvent-free
heating and mixing (because a phenyl group is an efficient
stopper for 21C7,7a this crown ether could encircle only the
NH2þ center adjacent to the oct-7-ynyl terminus, leaving the
other NH2þ center free for complexation with a DB24C8 unit).
(d) purified 9-H2 2PF6.
3
contains the same types of bead-like (crown ether) and
stopper (pyridazine) units; therefore, judicious selection of
the components was necessary to prevent the production
of a messy mixture of products.
We have achieved the selective synthesis of a hetero-
[3]rotaxane from five discrete components by applying the
concept of self-sorting to sequential threading and stoppering
processes in the absence of solvent molecules. Thus, the power
of self-sorting can be extended into solvent-free conditions,
allowing future integration of many molecular components
through selective transformations to form complicated func-
tional molecules in a simple, efficient, and waste-free manner.
We also anticipated that the oct-7-ynyl terminus of 8-H2 2PF6
3
would react selectively with tetrazine under solid-to-solid grind-
ing conditions, leaving its less-reactive phenylacetylene termi-
nus to react with diphenyltetrazine in the subsequent heating
process. If so, we would obtain a hetero[3]rotaxane, featuring
interlocked macrocyclic and stopper units placed precisely,
under solvent-free conditions through sequential self-sorting
processes in both the threading and stoppering steps.
We heated an equimolar mixture of the thread-like dica-
tionic salt 8-H2 2PF6 and the crown ethers DB24C8 and
3
21C7 at 373 K while mixing with a spatula until the sample
completely solidified to form, presumably, primarily the
[3]pseudorotaxane [DB24C8⊂8-H2⊃21C7][2PF6] in the first
self-sorting process (Scheme 3). The 1H NMR spectrum of
the solid obtained after grinding an equimolar mixture of the
solid [3]pseudorotaxane, tetrazine, and diphenyltetrazine for
9 h revealed the absence of the signal of tetrazine together
with the appearance of signals for the alkylpyridazine
(Figure 4b). The presence of signals for the relatively intact
diphenyltetrazine after grinding, but their significant decrease
after heating the solid mixture at 373 K for 72 h, indicated the
success of the second DielsꢀAlder reaction. The new signals
that formed were similar to those in the 1H NMR spectrum of
Acknowledgment. We thank the National Science Council
(Taiwan) for financial support (NSC-98-2113-M-002-004-
MY3).
Supporting Information Available. Synthetic proce-
dures and characterization data for the hetero[3]rotaxane
9-H2 2PF6. This material is available free of charge via
the Internet at http://pubs.acs.org.
3
(10) The tedious purification process of the hetero[3]rotaxane
9-H2 2PF6 appeared to significantly decrease its isolated yield. Using
3
CH2Br2 as an external reference in a coaxial insert NMR tube, we
estimated the yield of 9-H2 2PF6 in the crude product to be 13%.
3
Similarly, we determined the yield of 9-H2 2PF6 to be 18% in the crude
3
product obtained from sequential ball-milling and heating of diphenyl-
tetrazine and tetrazine with the solid formed after concentrating an
equimolar mixture of 21C7, DB24C8, and 8-H2 2PF6 in CH3NO2.
the salt 5-H PF6, suggesting that diphenyltetrazine had
reacted with the phenylacetylene unit to form a stopper under
these conditions. Purification of the resulting solid mixture
3
3
Thus, the efficiency of the passage of the macrocycles around the
threadlike component in the solid state should not be significantly lower
than that in solution. We did not observe signals corresponding to
afforded the hetero[3]rotaxane 9-H2 2PF6 in 9% yield.10
3
9-H2 2PF6 after heating an equimolar (50 mM) mixture of 21C7,
3
Therefore, applying two self-sorting processes sequen-
tially;one for threading and the other for stoppering;
allowed five different molecular components to assemble
precisely into a hetero[3]rotaxane in one pot under com-
pletely solvent-free conditions. This hetero[3]rotaxane
DB24C8, 8-H2 2PF6, diphenyltetrazine, and tetrazine in CD3NO2 at
3
373 K for 48 h. We did, however, observe (1H NMR) decomposition of
the pyridazine unit generated from the reaction of tetrazine with the oct-
7-ynyl terminus in CD3NO2 at 373 K. Therefore, thermal decomposition
might also be a factor responsible for the low yields under solvent-free
conditions.
Org. Lett., Vol. 13, No. 17, 2011
4663