Hexameric capsule of a resorcinarene bearing fluorous feet as a self-assembled nanoreactor: A Diels-Alder reaction in a fluorous biphasic system

Article abstract of DOI:10.1002/ejoc.201300652

A Diels-Alder reaction in a fluorous biphasic system was accelerated by a hexameric capsule of resorcinarene bearing fluorous feet. The reaction takes place predominantly within the capsule, which can be recovered as a fluorous solution and recycled after simple decantation. Copyright

Full text of DOI:10.1002/ejoc.201300652

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300652
Hexameric Capsule of a Resorcinarene Bearing Fluorous Feet as a Self-
Assembled Nanoreactor: A Diels–Alder Reaction in a Fluorous Biphasic
System
Shoichi Shimizu,*[a] Asuka Usui,[a] Masae Sugai,[a] Yuki Suematsu,[a] Seiji Shirakawa,[b] and
Hayato Ichikawa[a]
Keywords: Calixarenes / Perfluorinated solvents / Solvent effects / Self-assembly / Supramolecular chemistry
A Diels–Alder reaction in a fluorous biphasic system was ac-
celerated by a hexameric capsule of resorcinarene bearing
fluorous feet. The reaction takes place predominantly within
the capsule, which can be recovered as a fluorous solution
and recycled after simple decantation.
liquid–liquid separation process,[9] the unique solubilizing
properties have solved numerous problems in synthesis, ca-
talysis, and molecular recognition/assembly.[10] Recently, we
also demonstrated that a resorcinarene bearing fluorous
feet (i.e., 1) was soluble in wet fluorous solvents owing to
the formation of hexameric capsules, 16·(H2O)8,[11] and that
in fluorous solvents these capsules exhibit more selective
and/or enhanced properties as a result of fluorophobic ef-
fects through encapsulation (Figure 1).[12]
Introduction
Artificial receptor molecules and self-assembled molec-
ular structures have attracted considerable attention over
the past two decades because of potential applications in
many branches of supramolecular chemistry.[1] In particu-
lar, many research groups have intensively investigated the
application of self-assembled nanocapsules based on non-
covalent bonds such as hydrogen bonds and metal–ligand
interactions as nanoreactors.[2] These nanocapsules bear an
internal cavity, and their interior can provide new and spe-
cific chemical environments. Indeed, in most cases remark-
able acceleration of the reactions and/or change in selectiv-
ity were observed as a result of the steric requirements of
the host’s cavity. Selectivity rarely approached the level ob-
served in natural enzymes.[3] However, catalytic turnover
was inhibited because of the binding of the products, with
the exception of a limited number of self-assembled nano-
capsules,[3b,4–9] particularly a few that involved carbon–
carbon bond-forming reactions.[3b,4b,5a,5c,7,8]
The use of highly fluorinated and perfluorinated
(fluorous) solvents and reagents has grown over the past
decade. Most perfluoroaliphatic solvents are not miscible
even with the most common organic solvents at room tem-
perature. At elevated temperatures, however, a homogene-
ous system is formed, which separates again on cooling.
Since Horváth and Rábai developed a fluorous biphasic
system for the recycling of a fluorous catalyst through a
Figure 1. Structures of Teflon-footed resorcinarene 1 and tetra-
acetyl derivative 2 and model of hexameric assembly 16·(H2O)8,
encapsulating eight benzene molecules. Peripheral highly fluorin-
ated alkyl groups (Rf) are removed for clarity.
In this context, it was hypothesized that supramolecular
capsules may more effectively accelerate a reaction in
fluorous solvents than in organic solvents. Furthermore,
provided that an adequate release rate of the product from
the capsule is realized at the reaction temperature without
an extinguishing rate acceleration by the fluorophobic ef-
fect, a substantial catalytic turnover may be attained.
Herein, we report the application of fluorous resorcinarene
1 to a Diels–Alder reaction in a fluorous biphasic system to
realize an efficient catalytic reaction within a nanocapsule.
[a] Department of Applied Molecular Chemistry
College of Industrial Technology, Nihon University
Izumi-cho, Narashino, Chiba 278-8575, Japan
E-mail: shimizu.shouichi@nihon-u.ac.jp
Homepage: http://www.cit.nihon-u.ac.jp/
[b] Department of Chemistry
Graduate School of Science, Kyoto University
Sakyo, Kyoto 606-8502, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300652.
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Capsule of a Resorcinarene as a Self-Assembled Nanoreactor
ity of 16·(H2O)8 as a self-assembled nanoreactor and/or to
acid catalysis by the hydroxy groups of 1. No rate accelera-
tion was observed when tetraacetylated resorcinarene 2 was
added to the reaction mixture as a monomeric counterpart
of 1, as 2 could not form a hexameric capsule (Table 1, En-
try 8). Consequently, it is clear that the cavity of hexameric
capsule 16·(H2O)8 provides an isolated space that promotes
the Diels–Alder reaction and attains efficient catalytic turn-
over (38 times; Table 1, Entry 5); thus, the reaction takes
place preferentially in the cavity of 16·(H2O)8.[16] Inciden-
tally, adequate yields were obtained at reaction tempera-
Results and Discussion
Initially, the activity of fluorous resorcinarene 1 was ex-
amined by conducting the model Diels–Alder reaction in
perfluorohexane (FC-72), and the results are summarized
in Table 1. Treatment of methyl vinyl ketone with 2,3-di-
methyl-1,3-butadiene in FC-72 at 50 °C for 6 h afforded
only a small amount of adduct (10%; Table 1, Entry 9),
which is comparable to that afforded under neat reaction
conditions (13%; Table 1, Entry 11). However, in the pres-
ence of fluorous resorcinarene 1, the yield of the adduct
increased to 74% (Table 1, Entry 5). Kumar and co-
worker[13] reported that Diels–Alder reactions of N-ethyl-
maleimide with 9-(hydroxymethyl)anthracene showed dras-
tic rate accelerations in fluorous solvents with enhance-
ments approaching those in water.[14] In the absence of 1,
no such fluorous acceleration was observed in this reaction,
because the diene had no functional substituent to form a
hydrogen bond with the dienophile in the transition state.[15]
This acceleration has been attributed to catalysis by the cav-
Table 2. Diels–Alder reaction using various reagents.[a,b]
Table 1. Diels–Alder reaction.[a]
Entry Host (mol-%) Solvent T [°C] Time [h] Yield [%][b]
1
2
3
4
5
6
7
8
9
1 (10)[c]
1 (10)
1 (10)
1 (10)
1 (10)
1 (5)
1 (2.5)
2 (10)
none
FC-72
FC-72
FC-72
FC-72
FC-72
FC-72
FC-72
FC-72
FC-72
THF
60
50
40
50
50
50
50
50
50
50
50
4
4
4
8
6
6
6
6
6
6
6
61
62
37
73
74
56
38
Ͻ18
10
Ͻ18
13
10
11
none
none
none
[a] Reaction conditions: 2,3-dimethyl-1,3-butadiene (4.9 mmol,
10 equiv.), 3-buten-2-one (0.49 mmol), host compound, H2O
(0.30 μL, 1.7ϫ10–2 mmol), solvent (2.0 mL), 800 rpm. [b] Isolated
yield. [c] 16 (1.67 mol-%).
[a] Reaction conditions: diene (4.9 mmol, 10 equiv.), dienophile
(0.49 mmol), 16 (1.67 mol-%), H2O (0.30 μL, 1.7ϫ10–2 mmol), FC-
72 (2.0 mL), 50 °C, 6 h, 800 rpm. [b] Yield and endo/exo ratio in
parentheses were obtained in a control reaction without 1. [c] Iso-
1
Figure 2. Effect of the solvent on the yield of Diels–Alder adduct
for the reaction of methyl vinyl ketone with 2,3-dimethyl-1,3-buta-
diene.
lated yield. [d] Determined by H NMR spectroscopy (400 MHz).
[e] Diene (1.0 equiv.). [f] Reaction time = 2 h. [g] Reaction time =
24 h.
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S. Shimizu et al.
SHORT COMMUNICATION
tures higher than or equal to 50 °C, probably because FC- transition state, which results in the formation of the endo
72 shows fair miscibility with the reactants at 50 °C adduct.[18]
(Table 1, Entries 1–3).
The feasibility of the recovery and reuse of the fluorous
The effect of fluorous solvents on the reaction rate was resorcinarene in a fluorous solvent (FC-72) was evaluated.
examined for various C6F6/FC-72 solvent ratios (Fig- The results are summarized in Table 3. Although the yields
ure 2).[17] It is interesting that in the absence of 1, the yield of the adduct were rather low because of the lack of an
was not affected by changes in the FC-72 content of the extraction procedure, the activity of the hexameric capsule
solvent. However, if the same reaction was carried out in was retained after being consecutively recycled, even in the
the presence of hexameric capsule 16·(H2O)8, the yield in- fifth run, and the yield was practically identical to that ob-
creased as the fluorous content was increased with a plateau served if a fresh hexameric capsule was used (Table 3, En-
region at approximately 50% FC-72 (C6F6/FC-72 = 1:1, v/ tries 1–5).
v). The increase in yield was attributed to an increase in
the association constant[12] of the capsule for the reactants
because of fluorophobic effects. Those effects can be
thought of as a reflection of the higher concentration of the
Conclusions
reactants and a higher internal pressure inside the cavity of
the capsule. Thus, the increase indicates that the reaction
takes place predominantly within the cavity of the hexa-
meric capsule. Furthermore, the nonlinear increase in the
yield can be mainly correlated to preferential solvation of
the interior and exterior of the hexameric capsule with C6F6
and FC-72. That is, it could be associated with preferential
encapsulation of C6F6 molecules by the capsule and compe-
tition with the substrate molecules.
To probe the scope of the diene and dienophile compo-
nents of the reaction in a fluorous biphasic system, nine
other Diels–Alder reactions were conducted (Table 2). In all
reactions, a rate acceleration (2.3- to 21-fold increase in
yield) was observed in the presence of a hexameric capsule
[1.67 mol-% as 16·(H2O)8], and the corresponding adducts
were obtained. Bulkier adducts were formed in low yields,
We demonstrated herein that a hexameric capsule of re-
sorcinarene bearing fluorous feet accelerates a Diels–Alder
reaction much more effectively in a fluorous biphasic sys-
tem than in an organic homogeneous system. The reaction
takes place predominantly within the capsule, which can be
recovered as a fluorous solution and recycled after simple
decantation. Thus, as the concept of a fluorous biphasic
system was effective in the Diels–Alder reaction with a
supramolecular capsule, this tool provides the possibility of
a new catalytic process through supramolecular catalysis.
Experimental Section
Typical Procedure for the Diels–Alder Reactions: Diene (4.9 mmol),
dienophile (0.49 mmol), and H2O (0.30 μL) were added to a solu-
which may be ascribed to steric factors (Table 2, Entries 7 tion of 1 (0.049 mmol in the case of 10 mol-%) in FC-72 (2 mL),
and the mixture was stirred at 800 rpm at 50 °C for 4–8 h. The
reaction mixture was diluted with FC-72 (5 mL), extracted with
CHCl3 (5 mL), and washed with FC-72 (5 mL). The combined ex-
tract was dried with anhydrous MgSO4, and the solvents were evap-
orated. The product was purified by preparative GPC.
and 9). Moreover, the presence of the hexameric capsule
gave rise to higher endo/exo ratios than those obtained in
the control reactions. For instance, in the reaction between
methyl acrylate and cyclopentadiene, the endo/exo ratio in-
creased from 2.9:1 to 5.5:1 (Table 2, Entry 7). The increase
in the endo selectivity indicates that the reaction took place
predominantly in the cavity of the hexameric capsule and
that the internal pressure was rather high, because a high
internal pressure in a water solution favors a more compact
2: Rf = 0.16 [hexane/EtOAc/HFE-7100, 2:7:1 (v/v)], m.p. 56–57 °C.
1H NMR [400 MHz, (CD3)2CO/C6F6, 3:1 (v/v)]: δ = 7.60 (br. s, 4
H), 7.34 (s, 2 H), 7.08 (br. s, 2 H), 6.68 (s, 2 H), 6.00 (br. s, 2 H),
3
4.62 [t, J(H,H) = 7.6 Hz, 4 H], 2.68 (br. s, 4 H), 2.54–2.18 (m, 36
H), 1.76 (br. s, 8 H) ppm. Partial 13C NMR [125 MHz, (CD3)2CO/
C6F6, 3:1 (v/v)]: δ = 170.0, 154.7, 148.4, 135.3, 126.9, 126.7, 123.0,
118.3, 103.1, 36.0, 35.6 [t, 2J(C,F) = 21.1 Hz], 34.4, 33.6, 27.2,
Table 3. Recovery and reuse of 1 in FC-72.[a]
21.2 ppm. IR (KBr): ν = 3448, 2950, 2877, 1215, 1153, 652,
˜
555 cm–1. C139H64F168O12 (5081.69): calcd. C 32.14, H 1.27; found
C 31.80, H 1.25.
Recycling Experiment: 2,3-Dimethyl-1,3-butadiene (4.9 mmol), 3-
buten-2-one (0.49 mmol), and H2O (0.30 μL) were added to a solu-
tion of 1 (0.049 mmol) in FC-72 (2 mL), and the mixture was
stirred at 800 rpm at 50 °C for 6 h. The mixture was allowed to
stand at 0 °C for 1 h, and then the fluorous phase (FC-72) contain-
ing 16·(H2O)8 was transferred by syringe to a new flask for direct
reuse in the next cycle. From the remaining organic phase, the prod-
uct was isolated by preparative GPC.
Entry
Host 1[b]
Yield [%][c]
1
2
3
4
5
1st use
2nd use
3rd use
4th use
5th use
50
55
61
58
60
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic route for 2, characterization data and spectra of 2
and its synthetic intermediates, characterization data of the Diels–
Alder adducts.
[a] Reaction conditions: 2,3-dimethyl-1,3-butadiene (4.9 mmol,
10 equiv.),
3-buten-2-one
(0.49 mmol),
H2O
(0.30 μL,
1.7ϫ10–2 mmol), FC-72 (2.0 mL), 50 °C, 6 h, 800 rpm. [b] 16
(1.67 mol-%). [c] Isolated yield.
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Capsule of a Resorcinarene as a Self-Assembled Nanoreactor
drogen-bonded hexameric capsule changes the selectivity of a
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A. Scarso, P. Sgarbossa, G. Strukul, J. N. H. Reek, J. Am.
Chem. Soc. 2011, 133, 2848–2851.
Acknowledgments
This work was supported by the Japan Society for the Promotion
of Science (JSPS), through a Grant-in-Aid for Scientific Research
(C) (no.22550125).
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[16] To obtain circumstantial evidence that the reaction takes place
in the cavity of 16·(H2O)8, we studied encapsulation of the sub-
strates, methyl vinyl ketone and 2,3-dimethyl-1,3-butadiene, by
the capsule in FC-72. If 2,3-dimethyl-1,3-butadiene was used
as the sole guest at a molar ratio of 7.2:1 (diene/1), the methyl
signal of the encapsulated diene appeared at δ = 0 ppm with
an upfield shift of about 1.4 ppm. Integration of the signal
showed that an average of 4.6 diene molecules was detained in
the capsule. To our surprise, in the case of methyl vinyl ketone
at a molar ratio of 7.1:1 (dienophile/1), only a trace of the
methyl signal of the encapsulated dienophile appeared at δ =
0.78 ppm with an upfield shift of about 0.9 ppm. However, if
both the diene and dienophile were used as double guests at a
molar ratio of 100:1:1 (diene/dienophile/1), integration of the
signals showed that 0.63 diene and 10.8 dienophile molecules
were detained in the capsule at the same time. This result indi-
cates that the presence of 2,3-dimethyl-1,3-butadiene promotes
encapsulation of methyl vinyl ketone by the capsule in the fluo-
rous FC-72 solvent. That is, a large excess amount of the diene
may improve solubility of the dienophile in the fluorous sol-
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Received: May 4, 2013
Published Online: July 1, 2013
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