Synthesis of sulfuric macrocycles and a rotaxane through thiol-yne click and dithiol coupling reactions

Article abstract of DOI:10.1021/ol1014569

A macrocycle and a rotaxane were constructed by virtue of the thiol-yne click reaction under the irradiation of light in high yield, which can proceed at ambient temperature and humidity under an air atmosphere. Two disulfide macrocycles were synthesized through a simple dithiol coupling reaction, which exhibited high stability and a weak assembly interaction with a dialkylammonium ion.

Full text of DOI:10.1021/ol1014569

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4078-4081
Synthesis of Sulfuric Macrocycles and a
Rotaxane through Thiol-yne Click and
Dithiol Coupling Reactions
Weidong Zhou, Haiyan Zheng, Yongjun Li,* Huibiao Liu, and Yuliang Li*
National Laboratory for Molecular Sciences, Key Laboratory of Organic Solids,
Institute of Chemistry and Graduate School, Chinese Academy of Sciences,
Beijing, 100190, P. R. China
ylli@iccas.ac.cn; liyj@iccas.ac.cn
Received July 19, 2010
ABSTRACT
A macrocycle and a rotaxane were constructed by virtue of the thiol-yne click reaction under the irradiation of light in high yield, which can
proceed at ambient temperature and humidity under an air atmosphere. Two disulfide macrocycles were synthesized through a simple dithiol
coupling reaction, which exhibited high stability and a weak assembly interaction with a dialkylammonium ion.
Biological molecular machines, such as the supramolecular
system in photosynthesis, which are able to transform
chemical energy into mechanical motion, have been well
studied during the past few years. To simulate these
biological machines with synthetic systems, many simple
prototypes of artificial molecular motors, consisting of a few
components capable of moving in a controllable way, have
been proposed in recent years.1 Mechanically interlocked
molecules, such as catenanes and rotaxanes, have become
typical candidates in the design of artificial molecular machines
because some of their components have the ability of reversibly
moving among two or more stations on application of external
stimuli.1 “Threading followed by stopping” and “clipping” are
two efficient strategies for the construction of rotaxanes.2 As
for the clipping method, several reactions have been employed
for pseudorotaxanes to form rotaxanes, such as olefin metathe-
ses3 and imine formation.4 However, in practice, the use of
metal catalysts or reducing agent limits their application.
Therefore, the development of mild and high yielding reactions
suitable for the construction of2 rotaxanes is still important for
scientists in this field.
The thiol-yne reaction involves addition of a thiol to an
alkyne followed by addition of another thiol to the resulting
alkene, giving a fully saturated specie.5-7 Although the thiol-
yne reactions were reported more than 50 years ago to be
facile processes,5-7 there has been little effort to capitalize
on what could be an exceptional opportunity for materials
fabrication. Recently, it had new life for materials synthesis
(2) Amabilino, D. B.; Stoddart, J. F. Chem. ReV. 1995, 95, 2725–2828.
(3) (a) Fuller, A.-M.; Leigh, D. A.; Lusby, P. J.; Oswald, I. D. H.;
Parsons, S.; Walker, D. B. Angew. Chem., Int. Ed. 2004, 43, 3914–3918.
(b) Leigh, D. A.; Lusby, P. J.; Slawin, A. M. Z.; Walker, D. B. Angew.
Chem., Int. Ed. 2005, 44, 4557–4564. (c) Mullen, K. M.; Mercurio, J.;
Serpell, C. J.; Beer, P. D. Angew. Chem., Int. Ed. 2009, 48, 4781–4784.
(d) Guidry, E. N.; Cantrill, S. J.; Stoddart, J. F.; Grubbs, R. H. Org. Lett.
2005, 7, 2129–2132. (e) Li, S.; Liu, M.; Zheng, B.; Zhu, K.; Wang, F.; Li,
N.; Zhao, X.; Huang, F. Org. Lett. 2009, 11, 3350–3353.
(1) (a) Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, J. F. Angew.
Chem., Int. Ed. 2000, 39, 3348–3391. (b) Stoddart, J. F. Acc. Chem. Res.
2001, 34 (6), 409–522, special issue. (c) Balzani, V.; Credi, A.; Venturi,
M. Molecular DeVices and Machines: A Journey into the Nano World;
Wiley-VCH: Weinheim, Germany, 2003. (d) Kay, E. R.; Leigh, D. A.;
Zerbetto, F. Angew. Chem., Int. Ed. 2006, 41, 72–191. (e) Credi, A.; Tian,
H. AdV. Funct. Mater. 2007, 17 (5), 671–840, special issue. (f) Tian, H.;
Wang, Q.-C. Chem. Soc. ReV. 2006, 35, 361–374.
(4) (a) Glink, P. T.; Oliva, A. I.; Stoddart, J. F.; White, A. J. P.; Williams,
D. J. Angew. Chem., Int. Ed. 2001, 40, 1870–1875. (b) Horn, M.; Ihringer,
J.; Glink, P. T.; Stoddart, J. F. Chem.sEur. J. 2003, 9, 4046–4054. (c)
Arico´, F.; Chang, T.; Cantrill, S. J.; Khan, S. I.; Stoddart, J. F. Chem.sEur.
J. 2005, 11, 4655–4666.
10.1021/ol1014569  2010 American Chemical Society
Published on Web 08/16/2010

from the recognition by Bowman,8 Lowe and Hoyle,9
Perrier,10 Stenzel,11 etc. that the reaction possessed excep-
tional qualities including rapid, high-yield reactions that
proceeded under ambient conditions. These conditions for
the thiol-yne radical reaction purport to be a facile method
for the rapid fabrication of macrocycles and interlocked
molecules. To date, thiol-yne reactions have not been used
for making macrocycles, though this reaction has recently
attracted significant attention in the materials area8-11
because it displays many attributes of click chemistry. The
reaction proceeds by reacting 2 equiv of thiol with the alkyne,
via a two-step process. Therefore, after the reaction, each
alkyne functional group will be combined with two thiols,
which is very attractive and advantageous in the synthesis
of macrocycle and rotaxane through the “clipping” method.
We proposed herein a new method to construct a macrocycle
and an interlocked molecule via a thiol-yne reaction based on
templates of secondary dialkylammonium ions. The template-
induced clipping reaction was conducted under the irradiation
of UV light in apolar solvent with high yield. The reaction could
proceed at high rate under ambient humidity and atmospheric
oxygen conditions to high conversion, thereby providing an
extremely efficient methodology for fabricating macrocycles and
interlocked molecules. In addition, we also synthesized two
other disulfide macrocycles through a simple methodsa thiol
coupling reactionsin high yield, which exhibit higher stability
compared with linear disulfide compounds.
sembled with secondary dialkylammonium ions in CH2Cl2/
THF (1/1, v/v) with high concentration. After the addition
of prop-2-ynyl benzoate, the mixture was irradiated with
UV light for 15 min in the presence of 2 × 10-3 M 2,2-
dimethoxy-2-phenylacetophenone (DMPA) as the initiator,
giving the target macrocycle in a yield of 80%. Reducing
the concentration of dithiol 2 did not enhance the yield
significantly but depressed the rate and enlarged the
reaction time, which can be attributed to the radical
mechanism of thiol-yne reaction. In this reaction, one
intermediate thiyl radical must collide with another thiol
molecule to abstract a hydrogen atom and induce another
thiyl radical in a chain transfer reaction. When we reduced
the quantity of initiator DMPA to 1% of compound 2,
the reaction still reached 70% conversion within 5 min
and was complete after 20 min. The NH4PF6 could also
function as the effective template with the yield of 75%
in the same condition as the template of secondary
dialkylammonium ions, which indicated the effective
hydrogen bonding between the -(OCH2CH2)- unit and
the -NH+- core (Scheme 1).
When a dumbbell-shaped thread containing a secondary dialk-
ylammonium ion was utilized as a template, interlocked molecule
R-1 was obtained in high yield (75%) as shown in Scheme 2. Since
Scheme 2. Synthetic Route Towards Rotaxane R-1
The thiol-yne addition based sulfuric macrocycle was
designed and synthesized as outlined in Scheme 1. The
Scheme 1. Synthetic Route Toward Macrocycle M-1
the xylylene parts of the macrocycle shields encapsulated
regions of the thread, the position of the macrocycle could
esterification of 1 with thioglycolic acid in the presence of
4-methylbenzenesulfonic acid gave dithiol 2. 2 was as-
(9) (a) Chan, J. W.; Zhou, H.; Hoyle, C. E.; Lowe, A. B. Chem. Mater.
2009, 21, 1579–1585. (b) Chan, J. W.; Hoyle, C. E.; Lowe, A. B. J. Am.
Chem. Soc. 2009, 131, 5751–5753. (c) Lowe, A. B.; Hoyle, C. E.; Bowman,
C. N. J. Mater. Chem. 2010, 20, 4745–4750. (d) Yu, B.; Chan, J. W.; Hoyle,
C. E.; Lowe, A. B. J. Polym. Sci., Polym. Chem. 2009, 47, 3544–3557.
(10) Konkolewicz, D.; Gray-Weale, A.; Perrier, S. J. Am. Chem. Soc.
2009, 131, 18075–18077.
(5) (a) Blomquist, A. T.; Wolinsky, J. J. Org. Chem. 1958, 23, 551–
554. (b) Sauer, J. C. J. Am. Chem. Soc. 1957, 79, 5314–5315.
(6) Griesbaum, K. Angew. Chem., Int. Ed. 1970, 9, 273–287.
(7) Behringer, H. Ann. Pharm. 1949, 564, 219–234.
(8) (a) Fairbanks, B. D.; Scott, T. F.; Kloxin, C. J.; Anseth, K. S.;
Bowman, C. N. Macromolecules 2009, 42, 211–217. (b) Chan, J. W.; Shin,
J.; Hoyle, C. E.; Bowman, C. N.; Lowe, A. B. Macromolecules 2010, 43,
4937–4942. (c) Fairbanks, B. D.; Sims, E. A.; Anseth, K. S.; Bowman,
C. N. Macromolecules 2010, 43, 4113–4119.
(11) (a) Chen, G.; Kumar, J.; Gregory, A.; Stenzel, M. H. Chem.
Commun. 2009, 6291–6293. (b) Hensarling, R. M.; Doughty, V. A.; Chan,
J. W.; Patton, D. L. J. Am. Chem. Soc. 2009, 131, 14673–14675.
Org. Lett., Vol. 12, No. 18, 2010
4079

be determined by comparing the chemical shift of the
protons in the rotaxane with those of the corresponding
thread. The 1H NMR spectra (Figure 1) of thread T-1 and
Scheme 3. Synthetic Route Toward Macrocycles M-2 and M-3
obtained from a highly concentrated solution (shown in
Supporting Information). Obviously, the potential polymer-
ization has been prevented by the templation effect of K+,
which facilitates the formation of crown ether macrocycles
M-2 and M-3.
Figure 1
.
Partial 1H NMR spectra (600 MHz, 298 K, CDCl3, 1 ×
It has been reported that disulfide bonds can be cleaved
by various stimulation,13 i.e., nucleophile, photoirradiation,
and heating. Takata has reported a method for the
preparation of dynamic controlled [2]rotaxane and [3]ro-
taxane by utilizing the reversible dithiol-disulfide inter-
change reaction.14 It gave us inspiration that we might be
able to utilize this dithiol-disulfide interchange reaction
of disulfide macrocycles M-2 and M-3 for the construction
of a [2]rotaxane, using a so-called thermodynamic-control
method. Unfortunately, we did not find any significant
change of M-2 and M-3 under the initiator of benzenethiol
and template of dialkylammonium ion for 14 days. In
addition, when macrocycles M-2 and M-3 were irradiated
by UV light (365 nm) for 30 min with DMPA as the
initiator and prop-2-ynyl benzoate as the capturing reagent,
no new product could be detected, and all reactants did
not exhibit any reduction. All of these phenomena
indicated the high stablility of the disulfide macrocycles
M-2 and M-3.
10-3 M) of (a) M-1, (b) R-1, and (c) T-1.
macrocycle M-1 confirm the interlocked nature of R-1
and show that in the form of R-1 the macrocycle is largely
localized on the dialkylammonium ion region of the thread
(Scheme 2). The upfield shifts of the methylene resonances
of the dialkylammonium ion station (HH 0.36, HG 0.11)
in R-1 are characteristics of aromatic shielding by the
encapsulating macrocycle. The thread dialkylammonium
ion resonance, HK, is shifted downfield by 0.55 ppm in
the rotaxane as a result of the hydrogen bonds between
the macrocycle and corresponding protons.12 All these
features confirm the interlocked nature of R-1, which
indicates the synthetic approach presented here is a rapid
and effective approach for interlocked molecules contain-
ing sulfur.
When we tried to synthesize the dithiol 5, a precursor for
a smaller macrocycle M-2, according to the synthetic strategy
in Scheme 3, surprisingly, we obtained disulfide macrocycles
M-2 and M-3 directly. This phenomenon tells us that dithiol
5 was very difficult to isolate because of its oxidative
macrocyclization reaction to either M-2 or M-3. Compound
4 was obtained from the nucleophilic substitution reaction
between potassium ethanethioate and compound 3 in THF/
EtOH (1/1) at 70 °C. The hydrolysis of compound 4 in the
presence of K2CO3 resulted in the formation of disulfide
macrocycle M-2 and M-3 directly in yields of 80 and 8%,
respectively. Interestingly, this high yield of M-2 (80%) was
The binding affinities between disulfide macrocyles
(M-2, M-3) and ammonium ion have been recorded. The
results show that, compared to the 24-crown-8, two
disulfide macrocyles exhibit much lower binding affinities
toward the ammonium ion. Mixing disulfide macrocycle
M-2 and dialkylammonium ion in CDCl3/CD3CN (1/1,
1
v/v), no significant change in the H NMR spectra was
detected (shown in Supporting Information), which indi-
cated that there was no interaction between the disulfide
marocycle and -NH2+- in this condition. Mixing disul-
fide M-3 and dialkylammonium ion in CDCl3/CD3CN (1/
1, v/v) (Scheme 4), slight changes in the 1H NMR spectra
(12) (a) Liu, M.; Yan, X.; Hu, M.; Chen, X.; Zhang, M.; Zheng, B.;
Hu, X.; Shao, S.; Huang, F. Org. Lett. 2010, 12, 2558–2561. (b) Domoto,
Y.; Fukushima, A.; Kasuga, Y.; Sase, S.; Goto, K.; Kawashima, T. Org.
Lett. 2010, 12, 2586–2589. (c) Yin, J.; Dasgupta, S.; Wu, J. Org. Lett. 2010,
12, 1712–1715. (d) Jiang, Q.; Zhang, H.; Han, M.; Ding, Z.; Liu, Y. Org.
Lett. 2010, 12, 1728–1731.
(13) Organic Chemistry of Sulfur; Field, L., Oae, S., Eds.; Plenum Press:
New York, 1977; Chap. 7.
(14) (a) Furusho, Y.; Hasegawa, T.; Tsuboi, A.; Kihara, N.; Takata, T.
Chem. Lett. 2000, 18–19. (b) Furusho, Y.; Oku, T.; Hasegawa, T.; Tsuboi,
A.; Kihara, N.; Takata, T. Chem.sEur. J. 2003, 9, 2895–2903. (c) Oku,
T.; Furusho, Y.; Takata, T. Angew. Chem., Int. Ed. 2004, 43, 966–969.
4080
Org. Lett., Vol. 12, No. 18, 2010

phenyl unit, which increases the bulky effect and prevents
the threading process for the dialkylammonium ion. Huang
et al. have reported that the phenyl group is big enough
to work as a stopper for 21-crown-7 derivatives.15 It is
surprising that the addition of one disulfide bond did not
cause conspicuous cavity increase of the macrocycle
compared with 21-crown-7. As for the weak interaction
between M-3 and -NH2+-, this phenomenon can be
attributed to the incorporation of the disulfide bond owning
less hydrogen bonding ability. Previously, Shinkai had
researched the coordination ability of the similar macro-
cycle toward alkali metal ions compared with 21-crown-
7.16 They also found obvious negative results for binding
of alkali metal ions, meaning that introduction of the long
noncoordinative unit is very unfavorable to ion binding.
Scheme 4
.
Interaction between Macrocycle M-3 and
Dialkylammonium Ion
In conclusion, we exploited a novel synthesis method for
the construction of a macrocycle and interlocked rotaxane
to take advantage of the thiol-yne click reaction in high yield,
which can proceed under facile conditions (at ambient
temperature and humidity under an air atmosphere). The mild
condition of this reaction provides extensive opportunity for
the construction of [2]rotaxane. In addition, two disulfide
macrocycles were synthesized through a simple method, a
thiol coupling reaction, which exhibit weak assembly inter-
action with dialkylammonium ion and high stability under
the irradiation of the UV light or benzenethiol.
were observed (Figure 2), which indicated that there was
weak interaction between disulfide marocycle M-3 and
Acknowledgment. This work was supported by the
National Nature Science Foundation of China (20831160507,
20971127, and 20721061) and the National Basic Research
973 Program of China and NSFC-DFG joint fund (TRR 61).
Supporting Information Available: Full experimental
details pertaining to the preparation and characterization of
R-1, M-1, M-2, and M-3. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL1014569
Figure 2.
Partial 1H NMR spectra (400 MHz, 298 K, CDCl3/CD3CN
(1/1, v/v), 1 × 10-3 M) of (a) M-3, (b) M-3 + 1 equiv of
dialkylammonium ion, (c) M-3 + 2 equiv of dialkylammonium
ion, and (d) dialkylammonium ion.
(15) (a) Zhang, C.; Li, S.; Zhang, J.; Zhu, K.; Li, N.; Huang, F. Org.
Lett. 2007, 9, 5553–5556. (b) Zhang, C.; Zhu, K.; Li, S.; Zhang, J.; Wang,
F.; Liu, M.; Li, N.; Huang, F. Tetrahedron Lett. 2008, 49, 6917–6920. (c)
Jiang, W.; Winkler, H. D. F.; Schalley, C. A. J. Am. Chem. Soc. 2008,
130, 13852–13853. (d) Hsu, C.-C.; Chen, N.-C.; Lai, C.-C.; Liu, Y.-H.;
Peng, S.-M.; Chiu, S.-H. Angew. Chem., Int. Ed. 2008, 47, 7475–7478.
(16) (a) Shinkai, S.; Inuzuka, K.; Miyazaki, O.; Manabe, O. J. Org.
Chem. 1984, 49, 3440–3442. (b) Shinkai, S.; Inuzuka, K.; Miyazaki, O.;
Manabe, O. J. Am. Chem. Soc. 1985, 107, 3950–3955.
+
-NH2 - in this condition. Both phenomena indicated that
the macrocycle M-2 is spatially small compared with the
Org. Lett., Vol. 12, No. 18, 2010
4081