Control of conformational flexibility in calix[6]arenes: Synthesis and characterisation of triply bridged calix[6]arene - 10, 15-dihydro-5H-tribenzo [a,d,g]cyclononene conjugates

Article abstract of DOI:10.3184/030823408X324724

A series of triply bridged symmetrical terf-butylcalix[6]arene-10,15- dihydro-5H-tribenzo[a,d,g]cyclononene conjugates have been synthesised in excellent yields. It has been observed that the synthesised multi-cavity molecular receptors retain the calix[6

Full text of DOI:10.3184/030823408X324724

JOURNAL OF CHEMICAL RESEARCH 2008
JUNE, 347–353
RESEARCH PAPER 347
Control of conformational flexibility in calix[6]arenes: synthesis and
characterisation of triply bridged calix[6]arene—10,15-dihydro-5h-tribenzo
[a,d,g]cyclononene conjugates
H.Mohindra Chawla* and Rahul Shrivastava
Department of Chemistry, Indian Institute of Technology, Hauz Khas, New Delhi-110 016, India
A
series of triply bridged symmetrical tert-butylcalix[6]arene—10,15-dihydro-5H-tribenzo[a,d,g]cyclononene
conjugates have been synthesised in excellent yields. It has been observed that the synthesised multi-cavity
molecular receptors retain the calix[6]arene and derivatised 10,15-dihydro-5H-tribenzo[a,d,g]cyclononene units in
their cone conformations in solution. While the employed alkyl spacers confer flexibility to the conjugate units at
room temperature, the synthesised receptors have been observed to exist in flattened cone conformations at low
temperatures as determined by variable temperature NMR measurements. It has been observed that 6b shows
+
a significant selectivity towards Ba2+ over other metal ions while compound 6c shows selectivity towards NH4
ions from amongst alkali, alkaline-earth and transition metal picrates. Alkali and transition metal ions are poorly
extracted by the hosts 6a–c. The extraction abilities of host molecules 5a–c towards metal picrates were found to be
much less than that of 6a–c.
Keywords: calix[6]arene, 10,15-dihydro-5H-tribenzo[a,d,g]cyclononene, conjugate receptors, extraction, recognition
t-Bu
OH
The design and synthesis of molecular receptors represented by
macrocyclic molecules containing hydrophobic or hydrophilic
cavities has generated considerable interest in scientific
community in recent years. Calixarenes, resorcinarenes,
cyclodextrins, cyclotriveratrylenes and porphyrins are suitable
macrocyclic building blocks.1-7 Coupling of two or more
building blocks via covalent linkages can provide artificial
receptor molecules with large well defined structural motifs
for useful applications. For example, synthetic receptors
have been obtained by covalently linking calix[4]arenes,
n
Fig. 1 p-tert butyl calix[n]arene (n = 2, 4, 6…20).
Likewise 10,15-dihydro-5H-tribenzo[a,d,g]cyclononene are
intrinsically rigid macrocycles that possess a shallow 3-fold
symmetric core associated with functional groups at the upper
rim. While calix[6]arenes possess numerous conformations
that are difficult to control, the 10,15-dihydro-5H-tribenzo
[a,d,g]cyclononene are known to be present in their cone
or the saddle form (Fig. 3) which needs to be controlled.
Such difficulties pose serious hurdles in the synthesis and
characterisation of calix[6]arene—10,15-dihydro-5H-tribenzo
[a,d,g]cyclononene conjugates for molecular recognition
despite the fact that both calix[6]arene and 10,15-dihydro-5H-
tribenzo[a,d,g]cyclononene are known to form endo cavity
inclusion complexes in solution.18,19
resorcinarenes,8–10
β-cyclodextrins,11
porphyrins,12,13
cryptophans14 and carbohydrates15 to give ‘conjugate
molecules’ for drug delivery, stabilisation of reactive
intermediates, catalysis, ionic or molecular recognition and
separations in the recent past. In this context, it was envisaged
that if one could ‘couple’ calix[n]arenes (n>4) (Fig. 1) and
10,15-dihydro-5H-tribenzo[a,d,g]cyclononene (Fig. 2), it would
provide unique molecular architectures with distinct upper
and lower rims with hydrophilic and hydrophobic regions.
The linking spacer units can act as structural corridors that
would present a third cavity or hollow space. Although such
molecular scaffolds would adopt numerous conformations
due to calix[n]arenes and nature of substitutents in derivatised
10,15-dihydro-5H-tribenzo[a,d,g]cyclononene, they would
provide an opportunity to encapsulate molecular and ionic
species in a multitopic manner. We envisaged that out of three
kinds of hollow spaces in their molecular architecture for
encapsulating bioactive organic species, the seat of actual host
guest complexation would depend upon the conformational
mobility of such receptors that provide a judicious balance of
hydrophobicity, hydrophilicity and flexibility necessary for an
ideal molecular receptor. Additionally, the spacer units can in
principle provide windows or gates for efficient applications.
Previous studies using mass spectrometry and X-ray
diffraction techniques have amply demonstrated that the π-
basic cavity of calix[4]arene is too small to accept biologically
important organic molecules as guests while their higher
homologues are too flexible for ionic/molecular recognition.
It is also known that rotational freedom of calix[6]arenes
and calix[8]arenes can be suppressed by anchoring them
to different molecular scaffolds or by introduction of bulky
substituents at their lower rim.16,17
In such molecular scaffolds, it is understood that while
the cavity size of 10,15-dihydro-5H-tribenzo[a,d,g]
15
14
R2
5
10
R1
R2
1
9
11
12
6
2
4
8
R3
7
R1
R3
R1
13
3
R2
R3
Fig.2 Substituted10,15-dihydro-5H-tribenzo[a,d,g]cyclononene.
X
Y
Y
Y
X
X
Y
Y
X
X
Y
X
saddle conformation
Bowl conformation
Fig. 3 Bowl and saddle conformation of 10,15-dihydro-5H-
tribenzo[a,d,g]cyclononene.
* Correspondent. E-mail: hmchawla@chemistry.iitd.ernet.in

348 JOURNAL OF CHEMICAL RESEARCH 2008
cyclononene and calix[6]arene would remain largely
unchanged with reduced conformational flexibility, one
can employ functionalised connecting corridors to provide
different structural motifs for exploring molecular selectivities
and allosteric sites in the multi cavity receptors. To the best
of our knowledge, such calix[6]arene and 10,15-dihydro-
5H-tribenzo[a,d,g]cyclononene coupled molecular receptors
have not been examined so far, possibly due to structural
and conformational complexity as explained above and also
because of difficulties in identification of guests at specific
sites in the synthesised multi-cavity receptors.
CHCl3. Similarly when cyclisation of 5b was effected with
10% TFA in CHCl3, it provided 6b in excellent yield (85%) as
compared to when cyclisation was carried out with perchloric
acid (yield 39%). Analogously cyclisation of 5c gave 6c in
high yield (85%) in the selected solvent system. The use of
other acids (H2SO4, HNO3 and HCl) in acetic acid did not
provide the target cyclised derivatives (Table 1).
Characterisation of the products
1
The formation of 6a–c was confirmed by recording their H
NMR, 13C NMR, DEPT-135 and Mass spectra. For instance,
1
In this paper, we discuss our attempts to immobilise calix[6]
arene and 10,15-dihydro-5H-tribenzo[a,d,g]cyclononene
units and to couple them through variable alkyl spacer units.
The resultant molecular scaffolds have three point linkages
through alkyl (ethyl, propyl and 1,4-dimethyl phenyl) spacer
units to provide a preorganised platform for wider binding
sites. In order to obtain a fine host–guest complexation in
such receptors, stepwise changes in the cross section of wall
have been achieved by varying the length and structure of
the linking bridges to produce receptors with varied binding
abilities and allosteric properties. The synthesised multi cavity
molecular receptors have been analysed for conformational
analysis by NMR spectroscopy. They have also been examined
for recognition of different metals and ammonium cations
when they are present in the form of their picrates. Since
target molecular scaffolds are complex chemical entities, one
needs to achieve good yields and be able to identify specific
spectral properties that can signal the recognition event. It has
been observed that multicavity receptors 6a–c can be obtained
in good yield through the use of p-toluenesulfonic acid and
trifluoroacetic acid as per reaction Scheme 2. This paper
presents our initial efforts to achieve these objectives.
the H NMR spectrum of 6a gave distinct signals for tert-
butyl and aromatic protons at δ 0.71, δ 1.31 and δ 6.64, δ
7.20 respectively indicating two types of O-substitutions in
the calix[6]arene core. The protons of the methylene bridge
of calix[6]arene appeared as a pair of doublets at δ 3.33 and
δ 4.57 while the protons of the methylene bridge of 10,15-
dihydro-5H-tribenzo[a,d,g]cyclononene appeared as a pair of
doublets at δ 3.49 and δ 4.69. It was observed that the chemical
shift of the methoxy protons of calix[6]arene appeared at a
higher field (δ 2.1) than the methoxy protons of the 10,15-
dihydro-5H-tribenzo[a,d,g]cyclononene core (δ 3.7). Two
doublets at δ 7.3 and 7.46 could be assigned to the aromatic
protons of the 1,4-dimethyl phenyl spacer unit. Two singlets at
δ 6.73 and δ 6.91 could be ascribed to the aromatic protons of
the 10,15-dihydro-5H-tribenzo[a,d,g]cyclononene core. Two
pairs of doublets between δ 4.79 and 5.25 could be attributed
to the diastereotopic protons of the methylene group attached
to the phenolic oxygen which was confirmed by recording the
DQF-COSY spectrum of 6a.
1
Likewise, the H NMR spectra of 6b exhibited the tertiary
butyl protons as two singlets at δ 0.63 and δ 1.23. Protons of
the methoxy group of calix[6]arene unit could be discerned
at δ 1.57 while the methoxy protons of the 10,15-dihydro-
5H-tribenzo[a,d,g]cyclononene core appeared at δ 3.69
ppm plausibly due to the shielding of the methoxy group
of calix[6]arene unit. Well defined two pairs of doublets for
methylene bridge protons of calix[6]arene appeared at δ 3.19
and 4.46, δ 3.44 and 4.73. This was confirmed by its HSQC
spectrum in which these pairs of doublets were correlated
with three types of methylene carbons. The signals at δ 6.54,
6.66, 7.15 and 7.24 for aromatic protons of calix[6]arene and
signals at δ 6.83 and δ 6.89 for aromatic protons of 10,15-
dihydro-5H-tribenzo[a,d,g]cyclononene core could be easily
discerned in the IH NMR spectrum of 6b. This was confirmed
by recording its 13C NMR spectrum which exhibited aromatic
carbon signals at δ 112, 113, 126 and 128 which could be
attributed to calix[6]arene unit and signals at δ 122.3, and
123.1 for aromatic carbons of 10,15-dihydro-5H-tribenzo
[a,d,g]cyclononene unit. A pair of doublets at δ 3.57 and 4.83
could be assigned to the methylene bridge protons of 10,15-
dihydro-5H-tribenzo[a,d,g]cyclononene unit. Two triplets
between δ 3.9–δ 4.0 and δ 4.38–δ 4.51 could be assigned to
methylene protons of the spacer unit.
Results and discussion
Vanillin 1 was alkylated with dibromoalkanes in refluxing
acetone using K2CO3 as a base to provide 3a–c in good yields
(3a, 95%; 3b, 92%; 3c, 97%). 3a–c were subjected to reduction
with NaBH4 in methanol to provide 4a-c in more than 90%
yield (Scheme 1). Symmetrical 5,11,17,23,29,35-hexa-tert-
butyl-37,39,41-trimethoxy-38,40,42-trihydroxycalix[6]arene
(prepared from hexa-tert-butylcalix[6]arene by reaction
with methyl iodide and potassium carbonate under reaction
conditions reported in the literature20) was then reacted with 4
equivalents of 4a–c in refluxing anhydrous DMF using Cs2CO3
as a base to provide 5a–c in excellent yields (Scheme 2)
which on cyclisation gave 6a–c.
It has been determined that cyclisation of 5a–c to 6a–c is an
important key step for synthesis. The reaction was found to be
markedly affected by the nature of acid used for cyclisation to
provide varying yields of 6a–c. For example, it was observed
that cyclisation of 5a in the presence of p-toluenesulfonic acid
gave 6a in moderate yield (62%) as compared to 25% yield
obtained when cyclisation was carried out with 10% TFA in
HOH2C
OCH3
OCH3
OCH3
OH
OHC
OHC
(a)
(b)
O-R1-Br
O-R1-Br
4a–4c
1
3a–3c
3a, R1 = –CH2(C6H4)CH2–
3b, R1 = –(CH2)2–
3c, R1 = –(CH2)3–
4a, R1 = –CH2(C6H4)CH2–
4b, R1 = –(CH2)2–
4c, R1 = –(CH2)3–
Scheme 1 Synthesis of 4a–c; reagents: (a) a,a’-dibromo-p-xylene/dibromoethane/dibromopropane, acetone, K2CO3, reflux,
5–12 h. (b) NaBH4, methanol: dichloromethane (2:1), 0°C, 4 h.

JOURNAL OF CHEMICAL RESEARCH 2008 349
OCH3
HOH2C
+
3
O-R1-Br
OH
4a-4c
OR2
(a)
R2O
R O
O
2
OR2
O
R1
O
R1
OR
O
1
OCH3
O
H3CO
OCH3
OH
5a R1=CH2(C6H4)CH2; R2=CH3
OH
OH
5b R1= (CH2)2;
5c R1= (CH2)3;
R2=CH3
R2=CH3
5a–5c
(c)
(b)
(d)
O
OR2
OR2
OR2
OR2
O
O
OR2
OR2
OR2
CH2
O
O
O
OR2
OR2
OR2
O
O
CH2
CH2
O
H2C
CH2
H2C
CH2
H2C
CH2
CH2
H2C
R2O
CH2
O
H2C
H2C
CH2
O
H2C
R2O
CH2
CH2
H2C
O
H2C
O
H2C
R2O
OR2
O
O
O
OR2
O
O
R2O
R2O
R2O
6b
6a
6c
R2= CH3
R2= CH3
R2= CH3
Scheme 2 Synthesis of 6a–c; Reagents and reaction conditions: (a) Cs2CO3, Dry DMF, 90°C, 72 h. (b) p-toluene sulfonic acid,
CHCl3, r.t, 96 h. (c) 10% TFA in CHCl3, r.t., 48 h. (d) 10% TFA in CHCl3, r.t, 72 h.
The identification of 6c could be achieved by detailed analysis
calix[6]arene could be observed as a triplet and a doublet at
δ 3.25 and δ 4.32 respectively while protons of methyl-
ene bridge of 10,15-dihydro-5H-tribenzo[a,d,g]cyclononene
moiety appeared as a pair of doublets at δ 3.49 and δ 4.69.
Two broad signals at δ 2.23 and δ 3.73 – δ 4.26 could be
assigned to spacer methylene protons.
1
of its H NMR and 13C NMR spectrum. The tertiary butyl
protons appeared as two singlets at δ 0.67 and δ 1.32. The
methoxy protons of calix[6]arene core could be observed at
δ 1.94 while methoxy protons of 10,15-dihydro-5H-tribenzo
[a,d,g]cyclononene core appeared at δ 3.73. A doublet
and a singlet at δ 6.45 and δ 7.18 respectively could be
assigned to aromatic protons of calix[6]arene core while two
singlets observed at δ 6.88 and δ 6.92 could be ascribed to
the aromatic protons of 10,15-dihydro-5H-tribenzo[a,d,g]
cyclononene unit. The protons of methylene bridge of
Variable temperature NMR studies
1
The H NMR spectrum of receptor 6c has been recorded at
different temperatures varying between 223 and 298 K in
deuterated chloroform. It was observed that the position
Table 1 Percentage yield (%) of compound 6a–c in various conditions
Entry No.
Reactant
Acids
Solvent
Temperature
Product
Percentage yield/%
1.
2.
3.
4.
5.
5a
5a
5b
5b
5c
p-toluenesulfonic acid
10% TFA in CHCl3
10% TFA in CHCl3
HClO4
CHCl3
CHCl3
0oC
R.T.
R.T.
0oC
0oC
6a
6a
6b
6b
6c
62%
25%
85%
39%
85%
CHCl3
CH3COOH
CHCl3
10% TFA in CHCl3

350 JOURNAL OF CHEMICAL RESEARCH 2008
of a pair of doublets for ArCH2Ar protons of calix[6]arene
and 10,15-dihydro-5H-tribenzo[a,d,g]cyclononene appeared
consistently between –40°C and 25°C while a portion of
signals for spacer protons between δ 3.73 and 3.99 (methylene
protons attached to phenolic oxygen of calix[6]arene and
10,15-dihydro-5H-tribenzo[a,d,g]cyclononene
platforms)
displayed a splitting to different extents in the proton NMR
spectrum of 6c between –40°C and 25°C. On the other
hand a broad signal of –CH2–CH2–CH2– at δ 2.23 got
broadened in the above temperature range as shown in Fig. 4.
This splitting of spacer methyl protons observed at low
temperatures in 6c could be attributed to the freezing of
the spacer unit while calix[6]arene and 10,15-dihydro-5H-
tribenzo[a,d,g]cyclononene units remained stable in their
cone conformations at all temperatures in the studied range.
In the case of 6a and 6b, no spectral changes were observed in
their proton NMR spectrum. Different NMR signals that can
be used for identification of plausible recognition event are
summarised in Table 2.
▼
d 223 K
c
253 K
Discussion
b 273 K
▼
The methylene bridge protons of 10,15-dihydro-5H-tribenzo
[a,d,g]cyclononene unit were observed as a pair of doublets
1
in H NMR spectrum. One signal for methylene carbon in
its 13C NMR spectrum suggested that the conformation of
10,15-dihydro-5H-tribenzo[a,d,g]cyclononene unit does not
alter after its attachment with calix[6]arene and it retains its
cone conformation with C3V symmetry intact in 6a–c. These
observations strongly favour the trimerisation mechanism for
preparation of 6a–c for which derivatives of benzyl alcohol
have been used as the starting materials. These derivatives of
benzyl alcohol provide a significant advantage of generation
of a single benzylic cation in the first step (Scheme 3) to
eventually lead to the formation of a single 10,15-dihydro-5H-
tribenzo[a,d,g]cyclononene analogue having C3 symmetry as
described previously.21 Although 10,15-dihydro-5H-tribenzo
[a,d,g]cyclononene is known to exist in the bowl and saddle
conformation, the saddle conformation could not be detected
in the reaction mixture. On the other hand, a clear splitting
of methylene protons (Table 2) for calix[6]arene in 6a–c was
found to be significantly different from that of the parent
trimethoxy calix[6]arene which showed only one singlet for
methylene protons due to conformational flexibility. Spectral
analysis thus indicated that flexibility of calix[6]arenes is
suppressed when they get connected to 10,15-dihydro-5H-
tribenzo[a,d,g]cyclononene in 6a–c.
a 298 K
▼
Fig. 4 Temperature dependence of protons of methylene
region (shown by ▼) of 6c in CDCl3 at (a) 298 K, (b) 273 K,
(c) 253 K and (d) 223 K.
1
of doublets for methylene bridge protons in H NMR, three
signals for methylene bridge carbons in the 13C NMR and
no spectral change at different temperatures (between 223
and 298 K) suggested that the angle of flattening of anisole
moieties in calix[6]arene is different in 6b.
Since chemical shift of methoxy group shifted upfield
to δ 1.94 and typical signals of other conformations
were not observed,22 it appears that the calix[6]arene
unit in 6c predominantly exists in a flattened cone
conformation. This was supported by the HSQC spectrum
which exhibited correlating cross peaks of axial and
equatorial protons connected to methylene bridge carbons
of calix[6]arene with one methylene bridge carbon at δ 29.4
(shown in Fig. 5). It was further observed that the axial proton
of the methylene bridge carbon of calix[6]arene exhibited
The methylene bridge protons of calix[6]arene in 6a
appeared as a pair of doublets. A significant upfield shift of
methoxy group as compared to trimethoxycalix[6]arene20
(δ 2.1, Δδ = 1.37) revealed that 6a is present in its flattened
cone conformation. In 6b, the methoxy protons shifted more
1
upfield (δ 1.5) in its H NMR spectrum indicating that the
anisole units are more flattened in 6b than in 6a. Two pairs
Table 2 1H NMR for methylene protons and 13C NMR data for methylene carbons (d, 300 MHz, 25°C) of synthesised molecular
receptors 6a–c
1H NMR values for ArCH2Ar protons
13C NMR values for ArCH2Ar carbons
Product
calix[6]arene
tbc
calix[6]arene
29.3
tbc
6a
6b
3.33 (6H, d, J = 14.8 Hz)
4.57 (6H, d, J = 14.8 Hz)
3.19(4H, d, J = 13.9 Hz)
4.46 (4H,d, J = 13.9 Hz)
3.44 (2H, d, J = 14.0 Hz)
4.73 (2H, d, J = 14.0 Hz)
3.25 (6H, t, J = 15.3 Hz)
4.32 (6H, d, J = 15.3 Hz)
3.49 (3H,d, J = 13.4 Hz)
4.69 (3H,d, J = 13.4 Hz)
3.57 (3H, d, J = 16.1 Hz)
4.83 (3H, d, J = 16.1 Hz)
36.4
36.6
28.0, 28.8, 29.2
6c
3.49 (3H,d, J = 13.5 Hz)
4.69 (3H, d, J = 13.5 Hz)
29.4
36.0
tbc = 10,15-dihydro-5H-tribenzo[a,d,g]cyclononene.

JOURNAL OF CHEMICAL RESEARCH 2008 351
Two-phase solvent extraction
Y
Y
X
Y
X
X
Y
X
CH2
The synthesised molecular receptors 6a–c and 5a–c were
examined for their efficiency in extraction of alkali, alkaline-
earth, transition metals and ammonium ion picrates. The
results of extraction of metal ions in the organic phase as
well as aqueous phase are summarised in Table 3. It has been
observed that 6b shows a significant selectivity towards Ba2+
as compared with other metal ions while compound 6c shows
CH2
+
selectivity towards NH4 ions from amongst alkali, alkaline-
Y
CH2OH
earth, and transition metal picrates. Alkali and transition metal
ions are poorly extracted by the hosts 6a–c. The extraction
abilities of host molecules of 5a–c towards metal picrates
were found to be much less as compared to those of 6a–c,
which may be explained by the 10,15-dihydro-5H-tribenzo
[a,d,g]cyclononene capping the lower rim of calix[6]arenes to
adopt a more convenient cone conformation suitable for the
complexation event.
X
Y
X
Y
X
X
Y
C3
Scheme 3
a strong correlation with the aromatic proton of calix
[6]arene. On the other hand, it has been observed that methoxy
protons of 10,15-dihydro-5H-tribenzo[a,d,g]cyclononene
unit have a weak connectivity with its aromatic protons
through space as revealed from the NOESY spectrum of
6c (Fig. 6).
Conclusion
It has been observed that better yields of 6a, 6b and 6c are
obtained from 5a, 5b and 5c when cyclisation step was
accomplished by p-toluenesulfonic acid or trifluroacetic
acid as compared to when cyclisation is effected by using
1
other acids (HClO4, HCl and H2SO4). The H NMR studies
He
Ha
Hd
Ha
He
O
OCHJ
OR
CH2
Hh
OR
Hg
3
O
Hb
Hb
Hd
Hd
O
C
CH2
H2C
Hc
Hc
H2C
C
CH2
O
CH2
O
C
O
OR
Hc
OCHf3
RO
Hh
Hb
Hg
6c
Fig. 5 Two-dimensional HSQC spectrum of compound 6c in CDCl3 in 298 K.
1
7
8
4
2
H
H
3
1
H
6
2
5
2
6
O
OCH3
O
H
7
CH2
CH2
H2C
O
6
H2C
(CH2)3
O
CH2
H3CO
3 3
H
CH2
H3CO
H
4
8
O
H
3 4
5
7
1
H
8
H
5
Fig. 6 Partial NOESY spectrum of compound 6c in CDCl3 at 298 K (shown by arrow).

352 JOURNAL OF CHEMICAL RESEARCH 2008
General procedure for synthesis of 5a–c
solution of trimethoxycalix[6]arene (0.5 g, 0.038 mmol)
Table
3
Percentage extraction (%E) of metal picrates
(2.5 ¥ 10-5 M) by host 5b–5c, 6b–6c (2.5 ¥ 10-5 M) from water
A
and Cs2CO3 (0.962 g, 2.3 mmol) in 20 ml of anhydrous DMF.
The reaction mixture was heated at 70°C for 30 min, compounds
4a–c (4.5 equivalents) were added to it and heated at 70°C for
72 h. The reaction mixture was diluted with CHCl3 (40 ml) and
water (20 ml) was added to it. The organic layer was separated
and the aqueous layer extracted again with CHCl3 (20 × 3 ml). The
organic extracts were combined, washed with water and dried over
anhydrous Na2SO4. After filtration and removal of solvent under
reduced pressure, the resulting crude products 5a–c were purified by
column chromatography (silica gel) to give 5a–c.
into dichloromethane
% Extraction
Metals
5b
6b
5c
6c
Li+
ne
ne
ne
ne
ne
ne
ne
ne
ne
ne
ne
ne
ne
ne
3
3
4
ne
ne
ne
ne
ne
ne
ne
ne
ne
ne
ne
ne
ne
ne
5
5
3
ne
4
ne
ne
ne
ne
3
4
2
ne
ne
4
Na+
K+
2
Rb+
Cs+
4
5
3a: Column chromatography of the crude product by using hexane-
ethyl acetate (7:3) as an eluent to afford 3a as a white solid (9.13 g,
95%), m.p. 92–94°C. (Found: C 57.2, H 4.6%. C16H15O3Br requires
C 57.3 H 4.5%.) νmax (KBr pellet)/cm-1 1720 (CO). δH (300 MHz,
CDCl3, 25°C) 9.83 (1H, s, CHO), δ 7.7–7.3 (6H, m, ArH), 6.95 (1H, d,
J = 8.1 Hz, ArH), 5.22 (2H, s, CH2Br), 4.48 (2H, s, OCH2), 3.94 (3H,
s, OCH3). δC (75 MHz, CDCl3, 25°C) 173, 147.9, 147, 146, 134, 119.3,
117.2, 113.6, 112, 111, 65.7, 64.1, 54.8. FAB- MS m/z: 336 (M+).
4a: White solid (3.16 g, 90%), m.p. 83–85°C. (Found: C 56.7,
H 5.2%. C16H17O3Br requires C 57.0 H 5.1%.) νmax (KBr pellet)/cm-1
3344 (OH). δH (300 MHz, CDCl3, 25°C) 7.39–7.30 (6H, m, ArH),
6.18 (1H, d, J = 8.1 Hz, ArH), 5.22 (2H, s, CH2Br), 4.60 (2H, s,
CH2OH), 4.44 (2H, s, OCH2), 3.89 (3H, s, OCH3), 1.25 (1H, s, OH).
δC (75 MHz, CDCl3, 25°C) 148, 147.4, 146.3, 118.4, 134, 117.8,
113.5, 112, 111, 65.3, 64.3, 54.3, 31.3. FAB-MS m/z: 338 (M+).
5a: Column chromatography of the crude reaction mixture by using
hexane-ethyl acetate (7:3) as an eluent afforded 5a as a white solid
(7.9 g, 90%), m.p. 293–297°C. (Found: C 78. 7, H 7.7%. C117H138O15
requires C 78.8 H 7.8%) νmax (KBr pellet)/cm-1 3354 (OH). δH (300
MHz, CDCl3, 25°C) 7.55–7.52 (6H, d, J = 7.2 Hz, dimethyl phenyl
ArH), 7.44–7.42 (6H, d, J = 7.2 Hz, ArH), 7.27 (6H, s, calixareneArH),
6.93 (3H, s, ArH), 6.81–6.76 (6H m, dimethyl phenyl ArH), 6.68 (6H,
s, calixarene ArH), 5.19 (6H, s, ArOCH2Ar), 4.94 (6H, s, ArOCH2Ar),
4.63 (6H, s, CH2OH), 4.63–4.57 (6H, bs, calixarene ArCH2Ar), 3.88 (9
H, s, OCH3), 3.42–3.37 (6H, d, J = 14.5 Hz, calixarene ArCH2Ar), 2.23
(9H, s, calixarene OCH3), 1.63 (3H, s, OH), 1.37 (27H, s, t-butyl), 0.81
(27H, s, t-butyl). δC (75 MHz, CDCl3, 25°C) 133.6, 133, 127, 126, 123,
119, 118, 117, 113.4, 113, 111.8, 111, 108, 73, 71, 69, 64, 58, 54, 31.2,
31, 29.3. FAB-MS m/z: 1782 (M+).
Mg2+
Ca2+
Sr2+
Ba2+
Fe2+
Co2+
Ni2+
Cu2+
Cd2+
Pb2+
ne
ne
ne
33
2
3
ne
ne
ne
ne
ne
ne
ne
ne
52
8
+
NH4
ne
ne
ne
ne
ne
ne
+
CH3NH3 +
n-PrNH3
ne
ne = No extraction.
demonstrated that the a 10,15-dihydro-5H-tribenzo[a,d,g]
cyclononene cap at the lower rim of calix[6]arene can
immobilise the conformation of calix[6]arene. It has been
determined that the calix[6]arene and 10,15-dihydro-5H-
tribenzo[a,d,g]cyclononene units remain stable in their cone
conformation in 6a and 6c. The alkyl spacers in 6c are able to
confer flexibility at room temperature which can be suppressed
by lowering the temperature. The cavities provided by these
receptors are rigid and conformationally defined to be used
for ionic and molecular recognition.
6a: A solution of 5a (100 mg, 0.0056 mmol) and p-toluene sulfonic
acid (70 mg, 0.0036 mmol) in 15 ml of dry CHCl3 was stirred at room
temperature in the presence of molecular sieves (4 Å) for 3 days.
After filtration of the reaction mixture, it was diluted with CHCl3
(40 ml) and water (25 ml) was added. The organic layer was separated
and the aqueous layer was extracted with CHCl3 (20 × 3 ml). The
organic extracts were combined, washed with water and dried over
anhydrous Na2SO4. After filtration and removal of the solvent
under reduced pressure, the resulting crude product 6a was purified
by column chromatography using ethyl acetate-hexane, (1:4) as an
eluent to give 6a as a white solid (44 mg, 62%), m.p. 287–290°C.
(Found: C 80.9, H 7.3%. C117H132O12 requires C 81.2, H 7.7%.) δH
(300 MHz, CDCl3, 25°C) 7.46 (6H, d, J = 7.2 Hz, dimethyl phenyl
ArH), 7.31 (6H, d, J = 7.2 Hz, dimethyl phenyl ArH), 7.20 (6H, s,
calixarene ArH), 6.91 (3H, s, tbc ArH), 6.73 (3H, s, tbc ArH), 6.64
(6H, s, calixarene ArH), 5.25–5.12 (6H, m, ArOCH2Ar), 4.98–4.79
(6H, m, ArOCH2Ar), 4.69 (3H, d, J = 13.4 Hz, tbc ArCH2Ar), 4.57
(6H, d, J = 14.8 Hz, calixarene ArCH2Ar), 3.7 (9H, s, tbc OCH3),
3.49 (3H, d, J = 13.4 Hz, tbc ArCH2Ar), 3.33 (6H, d, J = 14.8 Hz,
calixarene ArCH2Ar), 2.1 (9H, s, calixarene OCH3), 1.31 (27H, s,
t-butyl), 0.71 (27H, s, t-butyl). δC (75 MHz, CDCl3, 25°C) 155.2,
151.2, 149.6, 147.5, 145, 133.8, 133.7, 133.3, 133.1, 132.9, 132.6,
131.3, 129.8, 129, 127, 123, 116, 114, 67.7, 67.4, 60.3, 55.4, 36.4,
30.8, 29.4, 29.3. FAB-MS m/z: 1728 (M+).
3b: Column chromatography of the crude reaction mixture by
using hexane-ethyl acetate (7:3) as an eluent afforded 3b as a
white solid (7.9 g, 92%), m.p. 89–91°C. (Found: C 46.5, H 4.2%.
C10H11O3Br requires C 46.4 H 4.3%.) νmax (KBr pellet)/cm-1 1731
(CO). δH (300 MHz, CDCl3, 25°C) 9.86 (1H, s, CHO), 7.46–7.42
(2H, bs, ArH), 7.02–6.99 (1H, d, J = 8.0 Hz, ArH), 4.4–4.0 (2H, t,
J = 6.7 Hz, CH2Br), 3.94 (3H, s, OCH3), 3.73–3.68 (2H, t, J = 6.7
Hz, OCH2) δC (75 MHz, CDCl3, 25°C) 164, 149.7, 147, 134, 119.3,
113.6, 111, 66.8, 65.1, 55.8, 32.3. FAB-MS m/z: 259 (M+).
4b: White solid (3.6 g, 90%), m.p. 84–87°C. (Found: C 45.8,
H 5.1%. C10H13O3Br requires C 46.0 H 5.0%.) νmax (KBr pellet)/cm-1
3364 (OH). δH (300 MHz, CDCl3, 25°C) 6.9 (1H, s, ArH) 6.8 (2H,
bs, ArH), 4.6 (2H, s, CH2OH), 4.34–4.30 (2H, t, J = 6.6 Hz, CH2Br),
3.88 (3H, s, OCH3), 3.67–3.62 (2H, t, J = 6.6 Hz, OCH2), 1.67 (1H,
Experimental
All the regents used in the experiments were purchased from Sigma-
Aldrich or Merck and were chemically pure. The solvents were
distilled and dried. Column chromatography was performed on
silica gel (60–120 mesh) obtained from Merck. H and 13C NMR,
1
DEPT-135, HSQC, DQF-COSY, NOESY spectra were recorded on
a 300 MHz Brucker DPX 300 instrument at different temperatures
using tetramethylsilane (TMS) at δ 0.00 as internal standard. IR
spectra were recorded on a Nicolet Protégé 460 spectrometer in KBr
disks while CHN analysis was obtained by using a Perkin-Elmer
240C elemental analyser. The FAB mass spectra were recorded on
a JEOL SX 102/DA-6000 Mass spectrometer/Data System using
Argon/Xenon (6 kV, 10 mA) as the FAB gas. Melting points were
determined on an electrothermal Toshniwal melting point apparatus
and were uncorrected.
General procedure for synthesis of 3a–c
A solution of vanillin (5.0 g, 0.32 mol) and K2CO3 (18.2 g, 0.13 mol)
in 25 ml of anhydrous acetone was refluxed for 10 min and then a
solution of alkyl dibromide (2a–2c, 1.5 equivalents) in acetone
(10 ml) was introduced. After refluxing for 18 h, the solvent was
removed under reduced pressure and the resulting mixture dissolved
in chloroform and washed with water (25 ml). The organic layer was
separated and the aqueous layer extracted with CHCl3 (20 × 3 ml).
The organic extracts were combined, washed with water and dried
over anhydrous Na2SO4. It was filtered to give a crude product (3a–c)
which was then purified by column chromatography (silica gel) to
give pure 3a–c.
General procedure for synthesis of 4a–c
A solution of 3a–c (4.0 g, 0.015 mol) in anhydrous methanol-
dichloromethane (2:1) was cooled at 0°C for 20 min. NaBH4 (1.8 g,
0.046 mol) was slowly added at 0°C within 1 h. It was stirred at the
same temperature for 5 h and then chloroform (20 ml) was added and
the organic layer washed with water (25 ml). The organic layer was
separated and dried over anhydrous Na2SO4 followed by evaporation
of the solvent under reduced pressure to yield 4a–c as a white solid.

JOURNAL OF CHEMICAL RESEARCH 2008 353
bs, OH). δC (75 MHz, CDCl3, 25°C) 149.7, 147, 134, 119.3, 113.6,
111, 66.8, 32.3, 55.8, 65.1, 29.7. FAB-MS m/z: 260.9 (M+).
H 8.2%.) δH (300 MHz, CDCl3, 25°C) 7.18 (6H, s, calixarene ArH),
6.92 (3H, s, tbc ArH), 6.88 (3H, s, tbc ArH), 6.45 (6H, d, J = 18 Hz,
calixarene ArH), 4.69 (3H, d, J = 13.5 Hz, tbc ArCH2Ar), 4.37–4.2
(12H, m, ArOCH2 + calixarene ArCH2Ar), 3.9 (6H, m, ArOCH2),
3.73 (9H, s, tbc OCH3), 3.49 (3H, d, J = 13.5 Hz, tbc ArCH2Ar), 3.25
(6H, t, J = 15.3 Hz, calixareneArCH2Ar), 2.23 (6H, bs, CH2CH2CH2),
1.94 (9H, s, calixarene OCH3), 1.31 (27H, s, t-butyl), 0.67 (27H, s,
t-butyl), δC (75 MHz, CDCl3, 25°C) 155, 151, 149.5, 147.6, 145.2,
133.3, 132.6, 131.3, 128, 127.6, 123.2, 119.5, 114.9, 68.9, 68.4, 60.5,
56.5, 36.0, 31.4, 30.8, 29.8, 29.4. FAB-MS m/z: 1542 (M+).
5b: Column chromatography of the crude product by using hexane-
ethyl acetate (1:4) as an eluent gave 5b as a white solid (8.2 g,
89%), m.p. 284–287°C. (Found: C 76.4, H 8.1%. C99H126O15 requires
C 76.4 H 8.2%) νmax (KBr pellet)/cm-1 3341 (OH). δH (300 MHz,
CDCl3, 25°C) 7.24 (6H, s, calixarene ArH), 6.89 (9H, bs, ArH),
6.62 (6H, s, calixarene ArH), 4.64 (6H, s, CH2OH), 4.60–4.49 (12H,
m, ArOCH2 + calixarene ArCH2Ar), 4.28 (6H, t, J = 12.0 Hz, Ar-
OCH2), 3.70 (9H, s, OCH3), 3.38 (6H, d, J = 14.8 Hz, calixarene Ar-
CH2Ar), 2.1 (9H, s, calixarene OCH3), 1.61 (3H, bs, OH), 1.37 (27H,
s, t-butyl), 0.77 (27H, s, t-butyl). δC (75 MHz, CDCl3, 25°C) 154.4,
145.7, 134.4, 133.9, 133.6, 127, 126, 123, 119.8, 119, 111.8, 111, 71,
68, 65, 59, 55, 31, 30.3, 29.5. FAB-MS m/z: 1555 (M)+.
6b: A solution of 10% TFA and in CHCl3 (10 ml) was cooled
and stirred at 0°C temperature for 30 min. Compound 5b (200 mg,
0.12 mmol) dissolved in CHCl3 (2.0 ml) was added drop wise (within
2 h) to it. After 12 h stirring, the reaction mixture was diluted with
CHCl3 (40 ml) and water (20 ml) was added to it. The organic layer was
separated and the aqueous layer was extracted with CHCl3 (20 × 3 ml).
The organic extracts were combined, washed with water and dried
over anhydrous Na2SO4. After filtration and removal of solvent
under reduced pressure, the crude product was purified by column
chromatography using ethyl acetate and hexane (2:4) as the eluent
to give pure 6b as a white solid (83 mg, 85%), m.p. 292–294°C.
(Found: C 79.4, H 8.3%. C99H120O12 requires C 79.2, H 8.1%.) δH
(300 MHz, CDCl3, 25°C) 7.24–7.11 (6H, m, calixarene ArH), 6.89
(3H, s, tbc ArH), 6.83 (3H, s, tbc ArH), 6.66 (3H, s, calixarene ArH),
6.54 (3H, s, calixarene ArH), 4.95–4.7 (5H, m, calixarene ArCH2Ar +
tbc ArCH2Ar), 4.42–4.51 (10H, m, calixarene ArCH2Ar + ArOCH2),
4.0–3.9 (6H, m, ArOCH2), 3.69 (9H, s, tbc OCH3), 3.57 (3H, d,
J = 16.1 Hz, tbc ArCH2Ar), 3.44(2H, d, J = 14.0 Hz, calixarene
ArCH2Ar), 3.19 (4H, d, J = 13.9 Hz, calixarene ArCH2Ar), 1.57 (9H,
bs, calixarene OCH3), 1.23 (27H, s, t-butyl), 0.63 (27H, s, t-butyl).
δC (75 MHz, CDCl3, 25°C) 154, 149, 148, 147, 145, 144, 133.6, 133,
132, 131, 130, 128, 126, 123.01, 122.3, 113, 112, 71, 67, 58, 54, 31.1,
36.6, 30.4, 29.2, 28.8, 28.0. FAB-MS m/z 1501 (M+).
3c: Column chromatography of the crude product by using hexane-
ethyl acetate 7:3 as an eluent afforded 3c as a white solid (7.8 g, 97%),
m.p. 94–96°C. (Found: C 48.6, H 4.7%. C11H13O3Br requires C 48.4,
H 4.8%.) νmax (KBr pellet)/cm-1 1723 (CO). δH (300 MHz, CDCl3,
25°C) 9.86 (1H, s, CHO), 7.46–7.42 (2H, m, ArH), 7.02–6.99 (1H,
d, J = 8.0 Hz, ArH), 4.27–4.23 (2H, t, J = 5.8 Hz, CH2Br), 3.92 (3H,
s, OCH3), 3.65–3.60 (2H, t, J = 6.24 Hz, OCH2CH2), 2.45–2.17 (2H,
quint, CH2CH2CH2). δC (75 MHz, CDCl3, 25°C) 172, 149.8, 147,
136, 116.4, 115.6, 112.2, 66.8, 63.1, 53.8. FAB-MS m/z: 273 (M+).
4d: White solid (3.56 g, 93%), m.p. 82–87°C. (Found: C 48.21, H
5.65%. C11H15O3Br requires C 48.02, H, 5.50%.), νmax (KBr pellet)/
cm-1 3349 (OH). δH (300 MHz, CDCl3, 25°C) 6.83–6.86 (3H, m,
ArH), 4.5 (2H, s, CH2OH), 4.09–4.06 (2H, t, J = 5.8 Hz, CH2Br),
3.79 (3H, s, OCH3), 3.57–3.53 (2H, t, J = 6.2 Hz, OCH2CH2), 2.3–2.2
(2H, quint, CH2CH2CH2), 1.68 (1H, s, OH). δC (300 MHz, CDCl3,
25°C) 149.7, 148, 135, 119.4, 114.6, 111.2, 65.8, 63.1, 54.8,31.3.
FAB-MS m/z: 274 (M+).
5c: Column chromatography of the crude reaction mixture by
using hexane-ethyl acetate (2:8) as the eluent gave 5c as a white solid
(8.2 g, 98%), m.p. 278–284°C. (Found: C 76.8, H 7.9%. C102H132O15
requires C, 76.7 H, 8.3%.), νmax (KBr pellet)/cm-1 3419 (OH). δH
(300 MHz, CDCl3, 25°C) 7.16 (6H, s, calixarene ArH), 6.89–6.75
(9H, m, ArH), 6.53 (6H, s, calixarene ArH), 4.49 (6H, s, CH2OH),
4.43–4.32 (12H, m, ArOCH2 + calixarene ArCH2Ar), 4.32 (6H,
bs, ArOCH2), 3.75 (9H, s, OCH3), 3.31–3.26 (6H, d, J = 14.8 Hz,
calixarene ArCH2Ar), 2.33 (6H, bs, CH2CH2CH2), 2.06 (9H, s,
calixarene OCH3), 1.63 (3H, s, OH), 1.31 (27H, s, t-butyl), 0.69
(27H, s, t-butyl). δC (75 MHz, CDCl3, 25°C) 155, 151.1, 149.5, 147.6,
145.2, 133.4, 133, 132.9, 132, 131, 126, 127.8, 123, 118, 113, 68.9,
68.4, 64.5, 60, 56, 31.2, 30.4, 29.4, 29. FAB-MS m/z: 1597 (M+).
6c: A solution of 10% TFA and in CHCl3 (10.0 ml) was cooled
and stirred at 0°C temperature for 30 min and compound 5c (300 mg,
0.18 mmol) dissolved in CHCl3 (7 ml) was added drop wise (within
1 h) to it. After 12 h stirring, the reaction mixture was diluted with
CHCl3 (40 ml) and water (25 ml) was added. The organic layer
was separated and the aqueous layer was extracted with CHCl3
(20 × 3 ml). The organic extracts were combined, washed with water
and dried over anhydrous Na2SO4. After filtration and removal of
solvent under reduced pressure, the resulting crude product 6c was
purified by column chromatography using ethyl acetate and hexane
(1:4) as the eluent to provide 6c as a white solid (82 mg, 85%), m.p.
295–299°C. (Found: C 79.6, H 8.0%. C102H126O12 requires C 79.3
Solvent extraction
The general extraction procedures employed were similar to those
described previously23. Distilled dichloromethane and demineralised
water were used. The solvents were saturated with each other
before use in order to prevent volume changes of the phase during
extraction. Equal volumes (5 ml) of dichloromethane solution of
the respective host 6a–c as well as 5a–c (2.5 ¥ 10-5 M) and of an
aqueous solution of the corresponding metal picrate (2.5 ¥ 10-5 M)
were stirrered for 10 h at 25°C in a round bottom flask. The mixture
was then allowed to stand for at least half an hour at that temperature
for complete phase separation. The extractability was determined
spectrophotometrically from the decrease in the absorbance of picrate
ion in the aqueous phase. In control runs, no detectable amounts of
picrates were extracted into the organic phase in the absence of host
molecules.
The authors thank the Council for Scientific and Industrial
Research for a senior research fellowship (RS) and Department
of Science and Technology and Department of Biotechnology,
Govt. of India for financial assistance. We also thank
Sophisticated Analytical Instrumentation Facility (SAIF),
Central Drug Research Institute, Lucknow for low temperature
NMR spectra and FAB mass spectra reported in this paper.
Received 9 April 2008; accepted 14 May 2008
Paper 08/5210 doi: 10.3184/030823408X324724
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