The template effect of solvents on high yield synthesis, co-cyclization of pillar[6]arenes and interconversion between pillar[5]- and pillar[6]arenes

Article abstract of DOI:10.1039/c4cc01968g

We have synthesized a pillar[6]arene in high yield and a co-pillar[6]arene using chlorocyclohexane as a solvent. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01968g

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The template effect of solvents on high yield
synthesis, co-cyclization of pillar[6]arenes and
interconversion between pillar[5]- and
pillar[6]arenes†
Cite this: Chem. Commun., 2014,
50, 5774
Received 17th March 2014,
Accepted 7th April 2014
Tomoki Ogoshi,*ab Naosuke Ueshima,a Tomohiro Akutsu,a Daiki Yamafuji,a
DOI: 10.1039/c4cc01968g
Takuya Furuta,a Fumiyasu Sakakibaraa and Tada-aki Yamagishia
www.rsc.org/chemcomm
We have synthesized a pillar[6]arene in high yield and a co-pillar[6]arene
using chlorocyclohexane as a solvent.
The properties of host–guest complexes based on macrocycles such
as cyclodextrins,1 crown ethers,2 calixarenes3 and cucurbiturils4
have been studied extensively. The development of methods for the
high yield synthesis of macrocyclic host homologues possessing
different cavity sizes has extended this field of chemistry consider-
ably, because of different host–guest properties depending on their
cavity sizes. The selective synthesis of the macrocyclic homologues,
however, is generally difficult by the kinetically controlled cycliza-
tion process. The use of template compounds (thermodynamically
controlled cyclization process) is therefore necessary for the selec-
tive synthesis of particular homologues.
Pillar[n]arenes, which were first reported by our group in
2008,5 are some of the new macrocyclic compounds at the core
of supramolecular chemistry. A cyclic pentamer, pillar[5]arene,
was prepared in high yields by the condensation reaction of
1,4-dialkoxybenzene with paraformaldehyde and BF3ÁOEt2 in
1,2-dichoroethane (DCE) because DCE acts as a templating
solvent. The high yield synthesis of pillar[5]arenes has led to
the rapid development of the chemistry of pillar[5]arenes.5–7
Pillar[6]arenes, which are cyclic hexamers, have been synthe-
sized, but their yields were not high (o45%) even under the
optimized conditions because the cyclization process is kineti-
cally controlled.8–10 The low yields encountered in the synthesis
of pillar[6]arenes compared to pillar[5]arenes represent a bottle-
neck in terms of further expanding the field of pillar[6]arene
chemistry. Herein, we described our research towards developing a
thorough understanding of the exact role of the template effect of
solvents on the synthesis of a pillar[6]arene. By the thermo-
dynamically controlled cyclization process, we successfully synthesized
Fig. 1 (a) Synthesis of pillar[5]- and pillar[6]arenes from dialkoxybenzene
monomers (M1–M4). (b) Pillar[n]arenes with tri(ethylene oxide) groups
(TEO[5] n = 5; TEO[6] n = 6).
a pillar[6]arene in high yield, and a co-pillar[6]arene by the
co-cyclization approach for the first time.
DCE is a suitable solvent for the synthesis of pillar[5]arenes.
Pillar[5]arene P1[5] (Fig. 1) was obtained in high yield (71%)
when DCE was used as the solvent with 1,4-dimethoxybenzene (M1)
as the monomer (Table 1, entry 1). The cavity size of pillar[5]arenes
is ca. 5.5 Å and generally fits linear alkanes containing electron-
withdrawing groups.6 The linear dihaloalkane DCE therefore fits
well into the pillar[5]arene cavity and acts as the template for the
synthesis of the pillar[5]arene, indicating a thermodynamically
controlled cyclization process. In contrast, the reaction of
1,4-diethoxybenzene (M2) with paraformaldehyde in the presence
of BF3ÁOEt2 in chloroform (Table 1, entry 2) resulted in a mixture of
pillar[5–10]arenes,10 with P2[5] and P2[6] being isolated in yields of
20 and 15%, which prevented the pillar[5]arene from forming
stable complexes.6 This indicates that the cyclization is carried out
under kinetic control. In this study, several other reaction solvents
capable of fitting the pillar[6]arene cavity were also investigated for
a Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma-machi, Kanazawa, 920-1192, Japan. E-mail: ogoshi@se.kanazawa-u.ac.jp
b JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
† Electronic supplementary information (ESI) available: Experimental section,
characterization data, DFT calculations and 1H NMR spectra. See DOI: 10.1039/
c4cc01968g
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Table 1 Solvent effects
Pillar[n]arenes (yield%)
Entry
Monomer
Solvent
n = 5
n = 6
16b
29
3a
4b
5c
M1
M2
M3
M3
M3
M3
DCE
Chloroform
DCE
Chloroform
CyC6
Cl-CyC6
P1[5] (71)
P2[5] (20)
P3[5] (3)
P3[5] (10)
P3[5] (0)
P3[5] (3)
P1[6] (0)
P2[6] (15)
P3[6] (0)
P3[6] (8)
P3[6] (0)
P3[6] (87)
6c
a
The same reaction conditions as in ref. 6b. b The same reaction conditions
c
as in ref. 9. Detailed experimental conditions are provided in the ESI.
the synthesis of pillar[6]arenes. The cavity size of pillar[6]arenes is
greater than that of pillar[5]arenes, which is ca. 7.5 Å, and this
large cavity size allows pillar[6]arenes to bind various bulky hydro-
carbons.9 Based on the host–guest chemistry of pillar[6]arenes,
it was envisaged that bulky hydrocarbon solvents would be ideal
solvents for the synthesis of pillar[6]arenes. Thus, we evaluated the
use of cyclohexane (CyC6), chlorocyclohexane (Cl-CyC6), cyclooctane
and decaline as solvents. 1,4-Bis(methylcyclohexyl ether)benzene
(M3) was used as a monomer in these reactions to overcome the
poor solubility of 1,4-dialkoxybenzenes in the hydrocarbon solvents
because monomer M3 contained bulky lipophilic moieties that
would enhance its solubility in the hydrocarbon solvents. We
initially examined the reaction of M3 in DCE under the same
Fig. 2 1H NMR spectra of (a) DCE, and 1 : 1 mixtures of DCE with
(b) TEO[5] or (c) TEO[6], (d) Cl-CyC6, and 1 : 1 mixtures of Cl-CyC6 with
(e) TEO[5] or (f) TEO[6] at 25 1C.
In an attempt to examine the solvent template effect on the
conditions used for the high yield synthesis of pillar[5]arenes selective formation of pillar[5]- and pillar[6]arenes, we recorded the
(Table 1, entry 1). Although the conditions were suitable for the 1H NMR spectra of mixtures of DCE and Cl-CyC6 with P3[5] and
synthesis of pillar[5]arenes, the yield of P3[5] was much lower, about P3[6] in CDCl3 (Fig. S3 and S4, ESI†). It was not possible, however, to
3% (Table 1, entry 3). This low yield was attributed to steric detect clear peak shifts in these spectra because the complexation
hindrance of the bulky cyclohexylmethyl groups, which would have was too weak in CDCl3. We recently found that pillar[5]- and pillar-
prevented the formation of P3[5] and also P3[6]. When M3 was [6]arenes carrying tri(ethylene oxide) chains (Fig. 1b, TEO[5] and
reacted in chloroform, P3[5] and P3[6] were formed with yields of 10 TEO[6]) exist as liquids at room temperature.11 We proceeded to
and 8%, respectively (Table 1, entry 4). Chloroform does not act as a evaluate the bulk state host–guest complexation process by 1H NMR
template for the synthesis of both pillar[5]- and pillar[6]arenes,6 thus with guest molecules using TEO[5] and TEO[6] as solvents. The
the reaction in chloroform resulted in the formation of P3[5] and proton signal from the ethylene moiety of DCE in the bulk state was
P3[6]. This result therefore displayed a similar trend to that of the observed at 3.64 ppm (Fig. 2a). When DCE was mixed with TEO[5]
reaction of M2 in chloroform (Table 1, entry 2). Pleasingly, when (Fig. 2b), the signal of the ethylene moiety underwent a significant
Cl-CyC6 was used as the solvent with M3, the pillar[6]arene P3[6] upfield shift of 2.53 ppm. In contrast, no upfield shift was observed
was isolated as the major product in 87% yield (Table 1, entry 6). for this peak in a 1 : 1 mixture of DCE and TEO[6] (Fig. 2c). These
This high yield represents a significant improvement over those results indicated that DCE formed a strong complex with TEO[5] in
previously reported for the synthesis of pillar[6]arenes (35–45%).8 the bulk state but not with TEO[6]. In contrast, when Cl-CyC6 and
This method therefore allowed for the selective and high yield TEO[5] were mixed (Fig. 2e), only small up-field shifts were observed
synthesis of a pillar[6]arene using Cl-CyC6 as a bulky hydrocarbon in the proton signals belonging to Cl-CyC6. In the case of a mixture of
solvent. Several other bulky hydrocarbon solvents were also inves- Cl-CyC6 and TEO[6] (Fig. 2f), large upfield shifts were observed in the
tigated, including CyC6 (Table 1, entry 5), but did not afford any of signals belonging to Cl-CyC6. Cl-CyC6 can form much stronger
the desired pillar[n]arene products. The use of halogenated solvents interaction with TEO[6] than that with TEO[5]. From these results, it
is also suitable for the synthesis of pillar[n]arenes, because the can be inferred that DCE acts as a template for pillar[5]arenes but not
cavities of pillar[n]arenes are electron-rich spaces and can there- for pillar[6]arenes, and Cl-CyC6 behaves as a template in the synthesis
fore readily accommodate guest molecules containing electron- of pillar[6]arenes but not in the synthesis of pillar[5]arenes. DFT
withdrawing groups such as cyano and halogen moieties.6 The calculations (Fig. S5, ESI†) also supported these experimental data.
haloalkane Cl-CyC6 would therefore be included in the pillar[6]arene
To examine the mechanism of the reaction leading to the
cavity where it would act as a template for the synthesis of a pillar[6]arene using Cl-CyC6 (Table 1, entry 6), we monitored the size-
pillar[6]arene. As with pillar[6]arenes, P3[6] also forms a host–guest exclusion chromatography (SEC) profiles of the products obtained
complex with a DABCO cation9 (Fig. S2, ESI†) and deprotection from the reaction over time (Fig. 3a). After 1 min, peaks of P3[6] and
of cyclohexylmethyl groups by BBr3 afforded per-hydroxylated P3[5] were observed with retention times of 19.0 and 19.5 min.
pillar[6]arene in high yield (yield 95%).
Peaks of the corresponding oligomers were also observed in the
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Fig. 4 Interconversion between pillar[5]arene P3[5] and pillar[6]arene P3[6].
Ratios of P3[5] (blue circles), P3[6] (red squares) and the oligomers (black
triangles) by cleaving (a) P3[6] in DCE and (b) P3[5] in Cl-CyC6 at 80 1C, which
were monitored by 1H NMR analysis of the reaction mixtures over time.
Fig. 3 Monitoring the reaction of entry 6 (Table 1). (a) SEC traces, (b)
partial 1H NMR spectra (CDCl3, 25 1C) and (c) ratios of M3 (green
diamonds), pillar[5]arene P3[5] (blue circles), pillar[6]arene P3[6] (red
squares) and oligomers (black triangles) determined by 1H NMR of the
reaction mixtures over time.
subsequently observed as the reaction progressed, indicating that
P3[6] was converted to P3[5]. We also examined the conversion of
P3[5] to P3[6] in Cl-CyC6 (Fig. 4b). Heating at 80 1C was also required
for the cleavage of the P3[5] ring. As the reaction proceeded, we
observed a decrease in the amount of P3[5] together with a simulta-
neous increase in the amount of P3[6], even though the ratio of
oligomers in the reaction mixture was high. This result indicated that
P3[5] was converted to P3[6].12 By contrast, conversions did not take
place (Fig. S5, ESI†) in combinations of host–guest complexes (P3[5]
in DCE or P3[6] in Cl-CyC6), meaning ‘‘freezing’’ by inclusion of a
template solvent. We can reversibly carry out interconversion using
different template solvents, in which P3[6] can be converted to P3[5]
using DCE, and P3[5] can be converted back to P3[6] using Cl-CyC6.
The co-cyclization method, which involves the co-cyclization of
different monomers, represents a useful approach for the synthesis
of functionalized pillar[5]arenes. This method, however, cannot be
applied to the synthesis of functionalized pillar[6]arenes because
pillar[5]arenes are formed as the major products when DCE is used
as the solvent.13 In this study, however, we found that a pillar[6]arene
was formed as the major product using Cl-CyC6. We investigated
the development of a co-cyclization method for the synthesis of a
co-pillar[6]arene (Fig. 5). A large amount of M4 is found to be best
range of 17–20 min. As the reaction proceeded, the sizes of the peaks
corresponding to P3[5] and the oligomers decreased, whereas the
peak corresponding to P3[6] increased in size. After 1.5 min, we
detected peaks of P3[6] and the oligomers. Beyond this time point,
the trace remained largely unchanged. The reaction was also
monitored using 1H NMR (Fig. 3b). After 20 s, the proton signal of
M3 (green peak, 6.80 ppm) and multiple other proton signals
(6.60–6.73 ppm) of the oligomers were observed. After 1 min, the
spectrum contained proton signals of P3[5] (blue peak, 6.84 ppm),
P3[6] (red peak, 6.75 ppm) and the oligomers. After 3 min, the
proton signal of M3 completely disappeared, with the main signal in
the spectrum belonging to P3[6]. The integration ratios of the
different species were investigated over time (Fig. 3c). At the
beginning of the reaction, M3 was converted to linear oligomers.
Following the formation of these oligomers, there was a reduction
in the amount of oligomers and an increase in the amount of
P3[6] as the reaction progressed. This reaction behaviour indi-
cated that pillar[n]arenes are constructed by a reversible reaction
between the oligomer and the macrocyclic compounds and the
reaction proceeds under thermodynamic control.
Based on the solvent template effect and the reversible reaction
behaviour, we examined the ‘‘dynamic’’ interconversion between the
pillar[5]arene and pillar[6]arene with BF3ÁOEt2. Firstly, we examined
conversion of P3[6] to P3[5] in DCE. The reaction was monitored by
1H NMR measurements (Fig. 4a). At 25 1C, the ring-opening reaction
of P3[6] did not proceed, but, when the mixture was heated at 80 1C,
new peaks corresponding to P3[5] and the oligomers were observed.
It was necessary to heat the reaction to provide the energy required to
overcome the kinetic barrier to the ring-opening reaction. A decrease
Fig. 5 Synthesis of co-pillar[6]arene by the co-cyclization of different
in the ratio of P3[6] together with an increase in the ratio of P3[5] was monomers in Cl-CyC6.
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for the synthesis of co-pillar[6]arene P3[5]P4[1].14 A mixture of M3
and M4 (M3 :M4 = 1 : 16) with paraformaldehyde and BF3ÁOEt2
was stirred in Cl-CyC6 at room temperature. After purification by
column chromatography, co-pillar[6]arene P3[5]P4[1] was isolated
in 9% yield, which was higher than the yields observed for
homopillar[n]arenes P3[5] (1%) and P3[6] (8%). The use of
Cl-CyC6 as a solvent therefore allowed for the synthesis of
P3[5]P4[1] by the co-cyclization method for the first time.
In conclusion, we demonstrated the template effect of different
solvents on the formation of pillar[5]- and pillar[6]arenes, and
discovered that Cl-CyC6 is a good solvent for synthesis of
pillar[6]arenes. Cl-CyC6 is an inexpensive and commercially avail-
able solvent, and we therefore believe that our new procedure could
be used to provide better access to pillar[6]arenes. We have also
demonstrated for the first time the synthesis of co-pillar[6]arene
using the co-cyclization method. The success of this solvent-
templated synthesis in the construction of pillar[6]arenes suggests
that a similar strategy could be applied to the selective synthesis of
the other pillar[n]arene homologues with larger ring sizes. This is
currently underway in our laboratory.
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