Synthesis and inclusion properties of pillar[n]arenes

Article abstract of DOI:10.1007/s10847-012-0242-5

A detailed study of the reaction conditions revealed that a quantitative cyclocondensation of 1,4-dialkoxy-2,5-bis(alkoxymethyl)-benzenes to pillar[n]arenes can be achieved by catalysis of p-toluenesulfonic acid in CH₂Cl₂. Major product of this new reaction is in each case a cyclopentamer (n = 5), but small amounts of the pillar[n]arenes with n = 6, 7 and 10 can be obtained as well. Different alkoxy groups in 1- and 4-position lead to regioisomers. All cyclooligomers exist in pillar structures as pair of enantiomers, which show a racemisation at room temperature, which is fast in terms of the NMR time scale. The racemisation process occurs by rotation of the 1,4-phenylene segments in the macrocyclic rings. Pillar[n]arenes exhibit novel host-guest behavior. Springer Science+Business Media B.V. 2012.

Full text of DOI:10.1007/s10847-012-0242-5

J Incl Phenom Macrocycl Chem
DOI 10.1007/s10847-012-0242-5
ORIGINAL ARTICLE
Synthesis and inclusion properties of pillar[n]arenes
•
Yuhui Kou Derong Cao Hongqi Tao
•
•
•
•
•
Lingyun Wang Jianquan Liang Zhizhao Chen
Herbert Meier
Received: 16 July 2012 / Accepted: 16 August 2012
ꢀ Springer Science+Business Media B.V. 2012
Abstract A detailed study of the reaction conditions
revealed that a quantitative cyclocondensation of 1,4-
dialkoxy-2,5-bis(alkoxymethyl)-benzenes to pillar[n]arenes
can be achieved by catalysis of p-toluenesulfonic acid in
CH2Cl2. Major product of this new reaction is in each case
a cyclopentamer (n = 5), but small amounts of the pil-
lar[n]arenes with n = 6, 7 and 10 can be obtained as well.
Different alkoxy groups in 1- and 4-position lead to re-
gioisomers. All cyclooligomers exist in pillar structures as
pair of enantiomers, which show a racemisation at room
temperature, which is fast in terms of the NMR time scale.
The racemisation process occurs by rotation of the 1,4-
phenylene segments in the macrocyclic rings. Pil-
lar[n]arenes exhibit novel host–guest behavior.
hydrocarbons 1n–3n (Fig. 1) is laborious and not very
efficient: 14 [1], 15 [1], 24 [2], 34 [3], 35 [4], 36 [4].1
Hydroxy or alkoxy derivatives 4n–6n, such as the veratr-
ylenes 44 [5], 45 [5], 46 [5], calixarenes 54 [6], 55 [7], 56 [8]
and pillararenes 65 [9–13], are somewhat easier to obtain
and are important host systems for host–guest chemistry.
We published recently [14] a short paper on a novel type
of cyclocondensation reaction, which provides a facile and
efficient preparation of pillar[5]arenes 65 (Scheme 1).
The reaction 7 ? 65 is quite unusual since an ipso-
substitution on benzene rings occurs by an alkylation/
dealkylation process. Moreover, CH2OR2 and OR2 are
normally not the best leaving groups. We assume a radical-
cation mechanism [14]. After a further systematic study,
we report here the detailed results, such as the influences of
the reaction conditions on the synthetic method, and syn-
thesis of a series of novel pillar[n]arenes by the facile
method.
Keywords Catalysis ꢀ Host–guest chemistry ꢀ Pillararene ꢀ
Calixarene ꢀ Inclusion
Introduction
Results and discussion
Ortho-, meta- and para-cyclophanes, which represent
macrocyclic ring systems with 4–6 phenylenemethylene
repeat units, are fascinating compounds in theoretical as
well as in practical respect. The preparation of the parent
We studied now the role of the acidic catalysis and the
influence of different substituents R1 and R2 on this new
reaction type. The results are summarized in Table 1.
Entries 1 and 9 with 10–15 mol % p-toluenesulfonic
acid in CH2Cl2 at room temperature proved to be the best
variant for 7a ? 65a (yield 89–92 %). Other solvents such
as BrCH2Cl, ClCH2CH2Cl or BrCH2CH2Br (entries 2–5)
reduced the yield, requested higher reaction temperatures
and/or longer reaction times. The reaction worked to a very
low extent or not at all in toluene, CCl4 or THF. Sulfuric
Y. Kou ꢀ D. Cao (&) ꢀ H. Tao ꢀ L. Wang ꢀ J. Liang ꢀ Z. Chen
School of Chemistry and Chemical Engineering, State Key Lab
of Luminescent Materials and Devices, South China University
of Technology, Guangzhou 510641, China
e-mail: drcao@scut.edu.cn
H. Meier (&)
Institute of Organic Chemistry, Johannes Gutenberg-Universitat
¨
1
Mainz, Duesbergweg 10-14, 55099 Mainz, Germany
e-mail: hmeier@uni-mainz.de
The parent compounds 16, 25 and 26 are, to our best knowledge, not
known.
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J Incl Phenom Macrocycl Chem
acid (entry 6) or phosphoric acid (entry 7) could be used
instead of p-toluenesulfonic acid, but then the reaction was
much slower. Non-oxidizing acids or acids with an extre-
mely low oxidizing potential (HCl, HCOOH, H3CCOOH)
gave at most traces of 65a. Polymerization is the major
competing process to cyclo oligomerization.
The next question concerned the influence of the leaving
groups CH2OR2 and OR2. It turned out that small alkyl
groups (R2 = Me, Et) are best suited. Free hydroxy groups
(R2 = H) or bulkier alkyl groups (R2 = n-Bu, Bn) gave
somewhat lower yields (entries 1, 9–12)—even when
higher reaction temperatures and/or longer reaction times
were used.
Fig. 1 [1.1.1.1…]Ortho-, meta- and para-cyclophanes 1n–3n and
their derivatives: veratrylenes 4n, calixarenes 5n and pillararenes 6n
(n = 4, 5, 6; R = H, alkyl)
The substituents R1 of the starting compounds (entries 1,
13 and 14) have a certain influence on the size of the
formed macrocycles. A fourfold cyclocondensation was
never observed, because the strain of a [1.1.1.1]paracy-
clophane is too high. The formation of cyclopentamers was
in each case the major process but some higher pil-
lar[n]arenes with n = 6, 7 and 10 were minor byproducts.
The yields of the larger ring systems (n [ 5) are low, but
the presently described method represents the first access to
these hitherto unknown pillar[n]arenes (Scheme 2).
From the crystal structure of pillar[5]arene 65b, 65a and
65c (Fig. 2), we know their cavity is more or less the same,
with the length of R1 increases, the volume of pil-
lar[5]arenes become bigger, so the more solvent molecules
included [15]. The details of the X-ray crystal structure
analyses of pillar[5]arenes 65a–65c are summarized in
Table 2.
Scheme 1 Formation of pillar[5]arenes 65 by catalytic cycloconden-
sation reactions of ethers 7 (R1: alkyl, R2: H, alkyl, aralkyl)
Table 1 Synthetic optimization of the cyclocondensation 7 ? 65
Entry
Starting
compound 7
R1
R2
Catalyst
Solvent
Reaction
temperature (ꢁC)
Reaction
time (h)
Isolated
yield (%)
1
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
7d
7e
7f
Et
Et
TsOH
CH2Cl2
rt
3–4
24
89
61
18
–
2
Et
Et
TsOH
ClCH2CH2Cl
BrCH2Cl
BrCH2CH2Br
BrCH2CH2Br
CH2Cl2
rt
3
Et
Et
TsOH
rt
22
4
Et
Et
TsOH
rt
48
5
Et
Et
TsOH
53
rt
30
25
89
19
14
92
84
75
75
95
86
6
Et
Et
H2SO4(98 %)
H3PO4(85 %)
CF3COOH
TsOH
27
7
Et
Et
CH2Cl2
41
rt
64
8
Et
Et
CH2Cl2
21
9
Et
Me
H
CH2Cl2
rt
3–4
5–6
24
10
11
12
13
14
Et
TsOH
CH2Cl2
rt
Et
n-Bu
Bn
Et
TsOH
CH2Cl2
41
41
rt
Et
TsOH
CH2Cl2
28
Me
n-Bu
TsOH
CH2Cl2
3–4
15
7g
Et
TsOH
CH2Cl2
rt
123

J Incl Phenom Macrocycl Chem
would have an angle strain. Cyclohexane has a chair con-
formation (D3d) and two conformations with higher energy
which are called boat (C2v) and twisted boat (D2d). Chair
(Cs), twisted chair (C2) and twisted boat (C2) conformers
are discussed for cycloheptane. Finally, boat–chair-boat
(C2v), boat–chair-chair (C2), chair–chair-chair (C2v) and
crown conformers (D5d) are relevant for cyclodecane [17].
It is not known which conformations of the pil-
lar[n]arenes as ‘‘extended cycloalkanes’’ have the lowest
energies, but irrespective of that, the diameter of the inte-
rior cavities increases strongly with increasing numbers n
of the pillar[n]arenes (Fig. 3). This is an important feature
for the encapsulation of guest molecules. Since the energy
differences between the different conformers are low, we
can assume that host and guest conformers can be adapted
to each other.
Scheme 2 Yields [%] of pillar[n]arenes 6na-c (entries 1, 13 and 14)
The cyclocondensation of 1,4-dialkoxy-2,5-bis(methoxy-
methyl)benzenes with different alkoxy groups leads to a
mixture of regioisomers [15]. Scheme 3 demonstrates this for
the 1-methoxy-4-n-octyloxy compound 7 h. Product 65d is
the regular cyclopentamer with a repeat unit which corre-
sponds to the general formula 65 in Scheme 1. The other re-
gioisomers 85, 95 and 105 donot have regular repeat units. The
statistical ratio of 65d:85:95:105 is 1:5:5.2:5.0 (total yield
about 84 %). Column chromatography permitted a separation
and elution in the sequence 85, 105, 95, 65d.
The alkoxy chains are arranged in the crystals of 65 so
that they avoid an interaction with each other [9–13, 15].
When we consider the diphenylmethane segments, then the
two OC4H9 chains in the ortho-positions to the CH2 bridge
have always different orientation (up and down). This
orientation is also present in solution since the ROESY
spectra exclude an alkoxy–alkoxy interaction [15, 18].
Accordingly, just one of four possible pairs of enantiomers
is realized in 65a-d. This statement comprises the presence
of a C5 axis. One of 16 possible pairs of enantiomers is
populated in each of the non-symmetric systems 85, 95 and
105.
In contrast to the low yields of the originally published
mode of preparation [9], Scheme 2 demonstrates that the
process 7a ? 6na is nearly quantitative (total yield: 97 %).
However, 7a has to be prepared in preceding steps from
1,4-diethoxybenzene 11. Therefore we tried to improve the
procedure (Scheme 4).
When 2.5 9 10-2 M solutions of 11 in CH2Cl2 were
used, the amount of linear oligomers and polymers is very
low compared to the reported results [9]. Thus, the yield of
65a could be improved up to 82 % with FeCl3 as catalyst.
The molecular structure of pillar[n]arenes can be regarded
on the basis of two models. Diphenylmethane provides the first
model. It accepts a gable conformation with C2v symmetry [16].
Its dehedral angles subtended between the least-squares
planes of the two benzene rings and the central plane,
defined by the ipso-C atoms and the methylene carbon
atom, amount to 90ꢁ. The bond angle i-C-C-i-C is about
112ꢁ (force field and semiempirical quantum chemical
calculations for the free molecule) [16]. This geometry fits
excellently to the generation of pillar[5]arenes.
1
Figure 4 shows the comparison between the H NMR
spectra of 65d with a C5 axis and its isomer 105 without
symmetry axis. Instead of two signals (6.860, 6.767 ppm)
for the aromatic protons, 105 has ten partially superim-
posed signals (6.832, 6.826, 6.810, 6.810, 6.810, 6.800,
6.796, 6.790, 6.790. 6.772 ppm). The CH2 bridge protons
give in 65d one (3.737 ppm) and in 105 five singlets (3.775,
3.737, 3.737, 3.737, 3.707 ppm).
In general the CH2 bridges of 65a-d, 85, 95, and 105 give
at room temperature in the 1H NMR spectra singlet signals,
each. The splitting of these signals of non-symmetric sys-
tems up to 110 ꢁC was an error2 [15, 18]. These geminal
protons are homotopic for 65a-c and enantiotopic for 65d,
85, 95, and 105. The latter statement means that the com-
pounds have a de facto symmetry plane, because the
rotation of the benzene rings is fast in terms of the NMR
time scale. We assume that the OCH3 groups of the non-
symmetric pillararenes 65d, 85, 95, and 105 may move
through the cavity, because the rotation of the n-octyloxy
group through the cavity would be more stericly chal-
lenging. The two benzene ring protons are in the ‘‘frozen’’
The second model is related to the conformations of
cycloalkanes. Instead of the single bonds in cycloalkanes, 1,4-
phenylene segments have to be considered (Fig. 3). Cyclo-
pentane has an envelope conformation (Cs) and an energeti-
cally slightly higher half-chair conformation (C2) [17]. Both
are not far from planarity. Thus, an essentially planar mac-
rocycle can be assumed for 65, 85, 95 and 105 in which the
benzene rings are perpendicular to the plane of the macrocy-
cle. The crystal structure analyses proved this model [9, 15].
The pillar structures of 66, 67, and 610 seem to be more
complicated. Planar systems can be excluded because they
2
A definite structure proof of the four regioisomers was provided by
four crystal structure analyses in the case of the methoxy/n-butoxy
compounds [see ref. 15]
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J Incl Phenom Macrocycl Chem
Fig. 2 Crystal structure of pillar[5]arene 65bꢀCH3CN, 65aꢀ2CH3CN and 65cꢀ2CH3CNꢀH2O (All of them were prepared in acetonitrile) [15]
123

J Incl Phenom Macrocycl Chem
Table 2 Details of the X-ray
crystal structure analyses of
pillar[5]arenes 65a–65c
65a
65b
65c
Empirical formula
Formula weight
Crystal system
Space group
C118 H152 N4 O20
1946.44
C47H50NO10
788.88
C79H118N2O11
1271.75
Triclinic
P-1
Tetragonal
I41/a
Triclinic
P-1
˚
a/A
13.3205(16)
21.185(3)
21.202(3)
77.613(2)
87.610(2)
83.748(2)
5807.9(12)
2
14.930(2)
14.930(2)
39.341(8)
90
12.1821(16)
14.6959(19)
21.725(3)
89.543(2)
89.862(2)
75.068(2)
3757.9(9)
2
˚
b/A
˚
c/A
a/8
b/8
c/8
90
90
3
˚
V/A
8769(2)
8
Z
D
calcd/g cm-3
1.113
1.195
1.124
F(000)
2096
3352
1388
h Range/8
2.61-25.03
41982
3.09-25.19
33531
2.55-25.03
25979
Reflections collected
R(int)
0.0185
0.0959
0.0224
R1, wR[I [ 2r(I)]
R1, wR(all data)
0.0557,0.1584
0.0682,0.1693
0.0694,0.2127
0.1266,0.2375
0.1285,0.4368
0.1445,0.4861
Scheme 3 Formation of regioisomeric pillar[5]arenes from 7h which bears different alkoxy substituents (the numbers 2 and 5 in the
cyclopentamers correspond to the carbon atoms in 7h)
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J Incl Phenom Macrocycl Chem
conformers as well as in the case of fast exchange homo-
topic for the symmetric and diastereotopic for the non-
symmetric systems. The OCH2 protons are in the ‘‘frozen’’
conformers diastereotopic and become chemically equiv-
alent in the case of fast exchange. Thus, the OCH2 groups
and in principle also their neighboring CH2 groups are
excellent probes for the benzene ring rotation [18–20]. The
chain packing effect [20] at the rim of the pillars is in our
opinion a minor effect if present at all. Table 3 summarizes
the topicity of several indicative pairs of protons for the
corresponding symmetry classes.
OEt
(CH2O)n
65a (67-82%)
acid/ CH2Cl2
OEt
11
Scheme 4 Direct preparation of 65a from 11 and paraformaldehyde
X
X
X
X
X
X
X
X
X
X
An effective symmetry plane, horizontal to the major
axis Cn, has for n = 6, 7, 10 two preconditions: the fast
inversion of the macrocyclic ring (Fig. 3) and the fast
rotation of the benzene rings. Both preconditions are ful-
filled for 66a, 66c, 67b and 610b at room temperature. These
X
o
o
65 Cs (d = 8.1 A)
66
D3d (d = 9.5 0.5 A)
X
X
X
X
X
X
X
X
1
compounds have in the H NMR spectra a set of signals
X
X
X
X
X
X
X
which corresponds to the repeat units. The bridge protons
as well as the benzene protons give one singlet, each, and
the OCH2 protons provide a triplet. Table 4 summarizes
X
X
o
o
67 C2 (d = 11.0 1 A)
610 D5d (d = 16.0 1 A)
1
the H and 13C NMR data of the pillar[n]arenes with reg-
ular repeat units.
Concerning the arrangement of the alkoxy chains in 65, 66,
67 and 610, the preference of one conformer, namely that one
with the lowest steric interaction, significates a far-going ste-
reoselectivity, since the theoretical number N of diastereomeric
conformers increases strongly with increasing numbers n:
:
X
Fig. 3 Selected conformers of 65 (almost planar), 66 (chair), 67
(twisted chair), and 610 (crown). The diameters da of the internal
cavities correspond to the crystal structure analysis of 65 [9, 15] and to
a
model considerations for the higher pillar[n]arenes. The diameter d
n 5 6 7 8 9 10
does not take into account the Van der Waals radii and the torsion of
the benzene rings [15]. Thus, the available space for guest molecules
is somewhat smaller
N 4 8 9 18 23 46
Pillar[n]arenes as host systems have the possibility to
include guests in their cavities. Since pillararenes have high
electron density in the pillar structure, electron deficient
guests are ‘‘welcome’’. Besides acetonitrile many
compounds can also become the guests of pillar[5]arenes,
such as ammonium salts [9], dibromoalkanes [13], etc. Due
to the different sizes of their cavities, pillar[5]arenes and
pillar[6]arenes show specific encapsulations respectively.
For example, a,x-dibromoalkanes are firmly encapsulated in
pillar[5]arene 65a, but not in the larger host pillar[6]arene
[25]. The even larger hosts pillar[7]arene and pillar[10]arene
might show different host–guest behavior. The study on their
host–guest properties is under progress.
Conclusion
We report here on a new type of condensation reaction of
ethers 7 ? 6n (Scheme 1 and 2) which leads to an unex-
pected ipso-substitution on benzene rings by an alkylation/
dealkylation process. A detailed study of the reaction con-
ditions revealed that p-toluenesulfonic acid in CH2Cl2 is the
best catalyst for the elimination of CH2OR2 and OR2 groups
present in the ethers 7. A quantitative formation of the
Fig. 4 1H NMR spectra (low-field part) of 65d (top) and 105 (bottom)
(CDCl3 as solvent, TMS as internal standard)
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J Incl Phenom Macrocycl Chem
Table 3 Topicity of pairs of
protons of 65a-d, 85, 95 and 105
and the resulting spin patterns
(h: homotopic, e: enantiotopic/
chemically equivalent, d:
diastereotopic)
Compd.
Symmetry
CH2 bridges
OCH2
Ar–H
65a-c
D5
h [A2, s]
h [A2, s]
d [AB]
d [AB of ABX2…]
e [A2 of A2X2…]
d [AB of ABX2…]
e [A2 of A2X2…]
d [5AB of 5ABX2…]
e [5A2 of 5A2X2…]
h [A2, s]
D5h (fast exchange)
h [A2, s]
65d
C5
d [AB, 20s0]a
d [AB, 20s0]a
d [5AB, 100s0]a
d [5AB, 100s0]a
C5h (fast exchange)
C
e [A2, s]
d [5AB]
e [5A2, s]
85, 95, 105
Para coupling (5J) not
detectable in 400 MHz spectra
a
Cs (fast exchange)
Table 4 1H and 13C NMR data of 65a-d, 66a, 66c, 67b and 610b (d values in CDCl3, Me4Si as internal standard)
Compd.
CqO
Cq
CH
CH2
OR
65a
1H
13C
1H
13C
1H
13C
1H
13C
1H
13C
1H
13C
1H
13C
1H
6.71
3.75
29.8
3.76
29.6
3.74
29.3
3.74
29.4
3.78
30.9
3.77
30.7
3.82
31.0
3.83
30.0
3.81 1.25
149.8
128.5
115.1
6.75
63.8 15.0
65b
65c
65d
66a
66c
67b
3.64
150.7
128.2
113.9
6.83
55.7
3.84, 1.76, 1.52, 0.96
67.9, 32.0, 19.5, 14.0
149.7
128.1
114.6
6.86, 6.77
114.5, 113.8
6.68
3.84, 3.68, 1.76, 1.47, 1.30, 1.18, 1.02, 1.02, 0.73
150.4, 149.8
150.4
128.0, 128.0
127.8
68.0, 55.5, 31.5, 29.6, 29.1, 26.2, 22.4, 22.4, 14.0
3.81 1.27
115.2
6.69
64.0 15.2
3.74, 1.65, 1.41, 0.89
150.4
127.8
114.9
6.61
68.2, 31.9, 19.4, 13.9
3.59
56.1
3.63
56.1
151.5
127.5
114.0
6.62
610
b
13C
151.3
127.6
113.7
cyclooligomers 6n can be obtained for R2 = CH3, C2H5,
n-C4H9, whereby cyclopentamers are always the major
products (86–95 %). Additionally to this pillar[5]arenes 65,
small amounts (2–11 %) of the members of higher pil-
lar[n]arenes 6n (n = 6, 7, 10) can be obtained as well. Pil-
lar[n]arenes represent a novel class of host molecules for
host–guest chemistry.
400 spectrometer using CDCl3 as solvent and TMS as
internal standard. Mass spectra were obtained on the fol-
lowing spectrometers: Agilent-t 5975(GC–MS), HCT PLUS
(APCI), Acquity UPLC-Q-TOF (ESI), Autoflex III Smart-
beam (MALDI-TOF). TLC was performed on silica gel
plates (Merck GF 254), visualization at 254 nm. SiO2
(200–300 mesh) was used for the column chromatographies.
Unsymmetrical starting products, such as 7h, lead to a
statistical mixture of regioisomers (Scheme 3), but all reac-
tions 7 ? 6n are highly stereoselective, in so far as only the
conformers with the lowest interaction of the alkoxy side-
chains are formed. All systems, which are studied here show a
racemization which is fast in terms of the NMR time scale.
The original preparation [9] of 65 by the catalytic
reaction of 1,4-dialkoxybenzenes 11 and paraformaldehyde
could be improved to three fold yield (Scheme 4).
1,4-Diethoxy-2,5-bis(ethoxymethyl)benzene (7a)
The starting compound 7a was prepared from 1,4-dieth-
oxy-2,5-bis(chloromethyl)benzene [20, 21] according to ref
[20, 22]. Crystallization from ethanol afforded a colorless
product. Yield 90 %; mp 70–71 ꢁC (lit [20] 69–70 ꢁC).
1,4-Diethoxy-2,5-bis(methoxymethyl)benzene (7b)
A mixture of 1,4-diethoxy-2,5-bis (chloromethyl)benzene
(1.58 g, 6.0 mmol) and CH3ONa (4.32 g, 80 mmol) was
vigorously stirred in methanol (50 mL) and refluxed for
3–5 h [23]. The mixture was concentrated, treated with H2O
Experimental
Melting points are uncorrected. 1H NMR (400 MHz) and 13
NMR (100 MHz) spectra were recorded on a Bruker DRX
C
123

J Incl Phenom Macrocycl Chem
and filtered to deliver the crude product. Crystallization from
ethanol afforded colorless crystals. Yield 1.34 g (87 %); mp
and concentration, the residue was treated with ethanol to
give 7e as colorless solid (2.44 g, yield 85 %); mp
108–109 ꢁC (ethanol). 1H NMR (CDCl3): d = 1.37 (t,
3J = 6.8 Hz, 6 H, CH3), 4.01 (q, 3J = 6.8 Hz, 4 H,
OCH2CH3), 4.61 s, 4 H/4.62, s, 4 H (CH2O), 7.00 (s, 2 H,
3-H, 6-H), 7.29–7.41 (m, 10 H, phenyl). 13C NMR
(CDCl3): d = 15.0 (CH3), 64.5 (1-OCH2, 4-OCH2), 66.9
(2-CH2O), 5-CH2O), 72.4 (OCH2Ph), 112.9 (C-3, C-6),
126.8, 127.5, 127.7, 128.3 (C-2, C-5 and CH, phenyl),
138.6 (Cq, phenyl), 150.5 (C-1, C-4). GC–MS: m/z
(%) = 406 (20) [M]?, 105 (18), 91 (100). Anal. Calcd for
C26H30O4: C, 76.82; H, 7.44. Found: C, 76.75; H, 7.49.
1
3
72 ꢁC. H NMR (CDCl3): d = 1.36 (t, J = 6.8 Hz, 6 H,
CH3), 3.40 (s, 6 H, OCH3), 4.00 (q, J = 6.8 Hz, 4 H,
3
OCH2CH3), 4.47 (s, 4 H, CH2O), 6.90 (s, 2 H, 3-H, 6-H). 13
C
NMR (CDCl3): d = 15.0 (CH3), 58.4 (OCH3), 64.5 (1-
OCH2, 4-OCH2), 69.2 (2-CH2O, 5-CH2O), 112.5 (C-3, C-6),
126.6 (C-2, C-5), 150.3 (C-1, C-4). GC–MS: m/z (%) = 254
(100) [M?], 225 (31), 194 (22), 134 (31), 109 (16), 67 (14).
Anal. Calcd for C14H22O4: C, 66.12; H, 8.72. Found: C,
66.01; H, 8.70.
2,5-Bis(ethoxymethyl)-1,4-dimethoxybenzene (7f)
(2,5-Diethoxy-4-hydroxymethyl-phenyl)-methanol (7c)
Preparation according to ref [20, 22]. yield: 70 %, mp
Preparation according to ref [22]. yield: 70 %, mp
57–58 ꢁC (lit. 55 ꢁC).
167–169 ꢁC.
1,4-Di-n-butoxy-2,5-bis(ethoxymethyl)benzene (7 g)
2,5-Bis(n-butoxymethyl)-1,4-diethoxy benzene (7d)
Preparation according to ref [20, 22]. yield: 95 %, colorless
oil.
Na (3.3 g, 143 mmol) and n-butanol (50 mL, 40.5 g,
546 mmol) was stirred till Na had completely reacted. 1,4-
Diethoxy-2,5-bis (chloromethyl)benzene [20, 21] (1.91 g,
7.26 mmol) was added and refluxed for 3–4 h. The con-
centrated mixture was treated with ice-water and neutralized
with acetic acid. The water layer was separated and extracted
with CH2Cl2 (3 9 15 mL). The combined organic phase
was dried with Na2SO4 and purified by column chromatog-
raphy (3 9 50 cm SiO2, petroleum ether (bp 60–90 ꢁC)/
ethyl acetate 20:1). Crystallization from EtOH afforded 7d
1-Methoxy-2,5-bis(methoxymethyl)-4-(n-
octyloxy)benzene (7 h)
Preparation analogous to the preparation of 7b. Yield
622 mg (80 %) when 1-methoxy-4-(n-octyloxy)-2,5-
bis(chloromethyl)benzene [24] was used (850 mg,
2.55 mmol); mp 44 ꢁC (ethanol). 1H NMR (CDCl3):
3
1
d = 0.87 (t, J = 6.8 Hz, 3 H, CH3), 1.27–1.31 (m, 8 H,
(2.10 g, 85 %) as colorless crystals, mp 30 ꢁC. H NMR
(CDCl3): d = 0.91 (t, 3J = 7.4 Hz, 6 H, CH3), 1.34–1.42 (m,
10 H, CH3, CH2), 1.59 (m, 4 H, CH2), 3.49 (t, 3J = 6.6 Hz, 4
H, OCH2), 3.99 (q, 3J = 6.8 Hz, 4 H, OCH2CH3), 4.51 (s, 4
H, 2-CH2O, 5-CH2O), 6.91 (s, 2 H, 3-H, 6-H). 13C NMR
(CDCl3): d = 14.0, 15.0 (CH3), 19.4, 31.9 (CH2), 64.5, 67.2
(OCH2), 70.4 (2-CH2O, 5-CH2O), 112.5 (C-3, C-6), 127.0
(C-2, C-5), 150.3 (C-1, C-4). GC–MS: m/z (%) = 338 (100)
[M]?, 265 (41), 237 (18), 191 (9), 165 (40), 123 (24), 107
(14), 57 (30), 41 (18). Anal. Calcd for C20H34O4: C, 70.97; H,
10.12. Found: C, 70.67; H, 10.20.
CH2), 1.43 (m, 2 H, CH2), 1.74 (m, 2 H, CH2), 3.40, s, 3
H/3.41, s, 3 H (OCH3), 3.80 (s, 3 H, 1-OCH3), 3.92 (t,
3J = 6.6 Hz, 2 H, OCH2), 4.46, s, 2 H/4.48, s, 2 H (2-
CH2O, 5-CH2O), 6.89, s, 1 H/6.91, s, 1 H (3-H, 6-H). 13C
NMR (CDCl3): d = 14.1 (CH3), 22.7, 26.1, 29.3, 29.3,
29.4, 31.8 (CH2), 56.1, 58.3, 58.4 (OCH3), 69.0, 69.2, 69.3
(OCH2), 111.2, 112.7 (C-3, C-6), 126.2, 126.8 (C-2, C-5),
150.4, 151.0 (C-1, C-4).
GC–MS: m/z (%) = 324 (36) [M]?, 180 (100), 150 (60).
Anal. Calcd for C19H32O4 (324.5): C, 70.34; H, 9.94.
Found: C, 70.21; H, 10.05.
2,5-Bis(benzyloxymethyl)-1,4-diethoxy benzene (7e)
General procedure for the preparation of pillar[n]arenes
6n from 7 (Entry 1)
A mixture of 2,5-diethoxy-1,4-bis(chloromethyl)benzene
[20, 21] (1.86 g, 7.07 mmol), (n-Bu)4NBr (142 mg,
0.44 mmol), benzyl alcohol (1.8 mL, 1.88 g, 17.4 mmol),
KOH (1.08 g, 15.8 mmol), H2O (1 mL) and chlorobenzene
(40 mL) was stirred vigorously at 75 ꢁC for 48 h. H2O
(50 mL) was added to the mixture. The separated water
layer was extracted with CH2Cl2 (3 9 10 mL). The com-
bined organic phase was dried with Na2SO4. After filtration
Starting compound 7a, f–h (20.6 mmol) and p-toluene-
sulfonic acid monohydrate (500 mg, 2.63 mmol) were
stirred in 400 mL CH2Cl2 at room temperature for 3–4 h.
Then H2O (100 mL) was added and the water layer sepa-
rated and extracted with CH2Cl2 (3 9 15 mL). The com-
bined organic phase was dried (Na2SO4) and purified by
column chromatography (4 9 60 cm SiO2, gradient
123

J Incl Phenom Macrocycl Chem
elution, petroleum ether bp 60–90 ꢁC/ethyl acetate from
500:1 to 10:1). Elution yielded two fractions for the reac-
tion of 7a and 7 g, three fractions for 7f and four fractions
for 7 h, which are described below. The chromatography
has to be repeated for difficult separations, in particular for
the separation of 105 and 95.
[M ? Na]?. MS (APCI): m/z = 1051.5 [M ? H]?. MS
(MALDI-TOF):): m/z calcd for [M]? C63H70O14: 1050.5;
found 1050.6; calcd for [M ? Na]?: 1073.5; found 1073.6.
Pillar[10]arene 610b: Third fraction, yield: 56 mg
(1.8 %); colorless crystals, mp 249–250 ꢁC (CH2Cl2/
petroleum ether) [See foot note 3]. MS (APCI): m/z =
1537.1 [M ? HCl]?. MS (MALDI-TOF): m/z calcd for
[M]? C90H100O20: 1500.7; found 1500.3; calcd for
[M ? Na]?: 1523.7; found 1523.3; calcd for [M ? K]?:
1539.6; found 1539.3.
Pillar[5]arene 65c: First fraction, yield: 4.15 g (86 %)
(Ref [19]. mp 131.5 ꢁC); colorless crystals, mp
133–135 ꢁC [See foot note 3]. MS (MALDI-TOF): m/z
calcd for [M]? C75H110O10: 1170.8; found 1170.6; calcd
for [M ? Na]?: 1193.8; found 1193.6.
Pillar[6]arene 66c: Second fraction, yield: 530 mg
(11 %); colorless crystals, mp 87–89 ꢁC (Ref [25]. mp
89–91 ꢁC). (CH2Cl2/EtOH) [See foot note 3]. MS (APCI):
m/z = 1406.2 [M ? H]?. MS (MALDI-TOF): m/z calcd
for [M]? C90H132O12: 1405.0; found 1404.9; calcd for
[M ? Na]?: 1428.0; found 1427.9; calcd for [M ? K]?:
1443.9; found 1443.9.
The entries 2–4 with 7a (Table 1) and 9–10 with 7b-c
were performed in an analogous mode. Higher tempera-
tures were used for the entries 5 and 7 with 7a, 11 with 7d
and 12 with 7e. Slightly higher amounts of catalyst did not
significantly enlarge the reaction rates. The reaction times
are listed in Table 1. In the entries 6–8 with 7a, p-tolu-
enesulfonic acid as catalyst was replaced by other acids
with moderate success. Only conc. H2SO4 gave a high
yield when a reaction time of 27 h was used at ambient
temperatures (Table 1).
Procedure for the Preparation of Pillar[5]arenes
65a from 11 (Scheme 4)
A mixture of 11 (500 mg, 3.0 mmol), paraformaldehyde
(270 mg, 9 mmol) and p-toluenesulfonic acid monohydrate
(86 mg, 0.45 mmol) was stirred in 120 mL CH2Cl2 at
room temperature for 10–15 h. 50 mL water was added,
and the water layer was extracted with CH2Cl2
(3 9 25 mL). The combined organic phase was dried
(Na2SO4) and purified by column chromatography
(2 9 20 cm SiO2, petroleum ether (bp 60–90 ꢁC)/ethyl
acetate 30:1), dried under vacuum to give 65a as colorless
crystals (358 mg, yield 67 %).
Pillar[5]arene 65a: First fraction, yield: 3.27 g (89 %);
colorless crystals, mp 154–156 ꢁC (Ref [19]. mp
157.5 ꢁC). (CH2Cl2/petroleum ether)3. GC–MS: m/z
(%) = 890 (100) [M]?, 862 (5), 667 (3), 503 (3), 445 (40),
355 (5), 221 (5), 207 (10). HRMS: m/z calcd for
C55H71O10: 891.5047 [M ? H]?; found 891.5049.
Pillar[6]arene 66a: Second fraction, yield: 294 mg
(8 %); colorless crystals, mp 172–173 ꢁC (Ref [25]. mp
172–173 ꢁC). (CH2Cl2/petroleum ether) [See foot note 3].
MS (APCI): m/z [M ? H]? = 1069.8. MS (MALDI-TOF):
m/z calcd for C66H84O12: 1068.6; found 1069.1; calcd for
[M ? Na]?: 1091.6; found 1092.1; calcd for [M ? K]?:
1107.6; found 1108.0.
Pillar[5]arene 85: Isolated as first fraction, yield: 1.22 g
(23.8 %); crystallization from ethyl acetate/EtOH gave
colorless crystals, mp 103–104 ꢁC. 1H NMR (CDCl3):
d = 0.72–0.82 (m, 15 H, CH3), 1.01–1.19 (m, 20 H, CH2),
1.12–1.19 (m, 20 H, CH2), 1.41 (m, 10 H, CH2), 1.77 (m,
10 H, CH2), 3.70 (m, 15 H, OCH3), 3.75 (m, 10 H, CH2),
3.83 (m, 10 H, OCH2), 6.83 (m, 10 H, aromat. H)4 [30]. 13
C
NMR (CDCl3): d = 14.0 (CH3), 22.5, 22.6, 26.3, 26.3,
29.1, 29.2, 29.4, 29.5, 29.8, 29.8, 29.9, 31.4, 31.5, 31.5,
31.7 (CH2), 55.4, 55.5, 55.6 (OCH3), 68.3, 68.4 (OCH2),
113.6, 113.7, 113.8, 113.9, 114.4, 114.5, 114.8 (aromat.
CH), 128.0, 128.0, 128.1, 128.2, 128.2 (aromat. Cq), 149.9,
149.9, 150.0, 150.3, 150.4 (CqO) [30]. MS (MALDI-TOF):
m/z calcd for [M]? C80H120O10: 1240.9; found 1240.8.
Calcd for [M ? Na]?: 1263.9; found 1263.8. Calcd for
[M ? K]?: 1279.9; found 1279.8.
Pillar[5]arene 105: Isolated as second fraction, yield:
1.28 g (25.0 %); crystallization from ethyl acetate/EtOH
gave colorless crystals, mp 101–102 ꢁC. 1H NMR (CDCl3):
d = 0.73–0.81 (m, 15 H, CH3), 1.10–1.27 (m, 40 H, CH2),
1.48 (m, 10 H, CH2), 1.76 (m, 10 H, CH2), 3.67 (m, 15 H,
OCH3), 3.71–3.78 (m, 10 H, CH2), 3.82 (m, 10 H, OCH2),
6.77–6.83 (m, 10 H, aromat. H) [See foot note 4]. 13C
NMR (CDCl3): d = 14.0 (CH3), 22.4, 22.5, 26.2, 26.2,
26.3, 29.1, 29.2, 29.2, 29.4, 29.5, 29.6, 29.8, 29.8, 31.5,
31.6 (CH2), 55.5, 55.6 (OCH3), 68.3, 68.4, 68.4 (OCH2),
113.7, 113.9, 114.7, 114.8, 115.0 (aromat. CH), 128.0,
128.1, 128.2, 128.3 (aromat. Cq), 149.9, 150.4 (CqO) [See
Pillar[5]arene 65b: First fraction, yield: 2.94 g (95 %);
colorless crystals, mp 194–195 ꢁC (Ref [9]. mp
248.8 ꢁC).(CH2Cl2/petroleum ether) [See foot note 3]. MS
(MALDI-TOF): m/z calcd for C45H50O10: 750.3; found
750.3.
Pillar[7]arene 67b: Second fraction, yield: 75 mg (2.4 %);
colorless crystals, mp 281–282 ꢁC (CH2Cl2/petroleum
ether) [See foot note 3]. MS (ESI): m/z = 1073.5
4
1
Due to the lack of symmetry, the H and 13C NMR signals of the
five phenylene methylene subunits are strongly superimposed.
3
1H and 13C NMR data are listed in Table 3.
123

J Incl Phenom Macrocycl Chem
foot note 4]. MS (MALDI-TOF): m/z calcd for [M]?
C80H120O10: 1240.9; found 1240.9. Calcd for [M ? Na]?:
1263.9; found 1263.9. Calcd for [M ? K]?: 1279.9; found
1279.8.
The ether cleavage of 65a gave under the same condi-
tions a somewhat lower yield. The identification of 65e was
performed by comparison with an authentic sample [9].
Pillar[5]arene 95: Isolated as third fraction, yield: 1.33 g
(26.0 %); crystallization from ethyl acetate/EtOH gave
colorless crystals, mp 49–51 ꢁC.
Acknowledgments The financial support by the National Natural
Science Foundation of China (20872038, 21072064) and the Natural
Science Foundation of Guangdong Province, China (06025664) is
gratefully acknowledged.
1H NMR (CDCl3): d = 0.69–0.78 (m, 15 H, CH3),
1.05–1.19 (m, 30 H, CH2), 1.28 (m, 10 H, CH2), 1.46 (m,
10 H, CH2), 1.76 (m, 10 H, CH2), 3.67 (m, 15 H, OCH3),
3.74 (m, 10 H, CH2), 3.84 (m, 10 H, OCH2), 6.83 (m, 10 H,
aromat. H) [See foot note 4]. 13C NMR (CDCl3): d = 14.0
(CH3), 19.5, 22.4, 22.5, 26.1, 26.3, 29.1, 29.2, 29.3, 29.5,
29.6, 29.6, 29.7, 31.4, 31.6, 31.9, 31.9, 32.0 (CH2), 55.5,
55.6, 55.7, 55.8 (OCH3), 67.9, 68.0, 68.2, 68.5 (OCH2),
113.7, 113.8, 113.9, 114.0, 114.1, 114.5, 114.8, 114.9,
114.9, 115.0 (aromat. CH), 128.0, 128.1, 128.2, 128.3
(aromat. Cq), 149.9, 150.1, 150.5, 150.6 (CqO) [See foot
note 4]. MS (MALDI-TOF): m/z calcd for [M]?
C80H120O10: 1240.9; found 1240.9. Calcd for [M ? Na]?:
1263.9; found 1263.9. Calcd for [M ? K]?: 1279.9; found
1279.8.
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