Calix[6]arenes incorporating functionalised substituents at the methylene bridges

Article abstract of DOI:10.1080/10610278.2010.500728

The hexabromocalix[6]arene 5 reacts with p-tert-Bu-phenol, thymol and propargyl alcohol to afford the corresponding hexasubstituted methylene-functionalised calixarenes. The substituents at the bridges were further functionalised via acetylation or click

Full text of DOI:10.1080/10610278.2010.500728

Supramolecular Chemistry
Vol. 22, Nos. 11–12, November–December 2010, 704–709
Calix[6]arenes incorporating functionalised substituents at the methylene bridges†
Katerina Kogan, Norbert Itzhak and Silvio E. Biali*
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
(Received 6 May 2010; final version received 27 May 2010)
The hexabromocalix[6]arene 5 reacts with p-tert-Bu-phenol, thymol and propargyl alcohol to afford the corresponding
hexasubstituted methylene-functionalised calixarenes. The substituents at the bridges were further functionalised via
acetylation or click chemistry. Reaction of the hexahydroxy derivative 10 with DAST afforded 11, a first example of a
calixarene with all bridges monofluorinated.
Keywords: calixarenes; methylene-functionalised; synthesis
Introduction
method is that, when applied to larger calixarenes, in some
cases, the cyclocondensation step affords macrocycles of
different sizes than the one targeted (4). Recently,
optically active methylene-functionalised calixarenes
have been prepared by Wulff and co-workers (3f) via the
reaction of a biscarbene complex with a bisalkyne. In the
second approach, the substituents are directly introduced on
a preformed calix[n]arene, thus avoiding the need to find
out the proper reaction conditions for conducting the
macrocyclisation step with the functionalised fragments.
Methylene-functionalised systems have been prepared by
this approach via a homologous anionic ortho-Fries
rearrangement, (5) via a lithiation/alkylation sequence, (6)
via a spirodienone route (7) and via the addition of
organolithium reagents to a ketocalixarene derivative (8, 9).
We have recently reported that the bromocalixarene
derivatives 2–5 (10) are useful intermediates for the
preparation of a wide array of methylene-functionalised
derivatives (11). Under SN1 conditions, these compounds
undergo nucleophilic substitution at the carbon bridges.
O-, N-, S- and even some C-nucleophiles can be introduced
by this route. The reaction does not require dry reagents or
an inert atmosphere and is usually conducted by refluxing
solutions of the bromocalixarene and the nucleophile in
ionising solvents such as 2,2,2-trifluoroethanol (TFE) or
hexafluoroisopropanol (HFIP). Due to its high ionising
power and low nucleophilicity, HFIP can be considered as
the ideal solvent for conducting the reactions, but it is
relatively expensive. Mixtures of HFIP and chloroform can
be used instead of the pure fluorinated solvent to reduce the
costs (and in some cases, to increase the solubility of the
Most supramolecular applications of the calixarenes
require modification of the parent p-tert-butylcalix[n]ar-
ene scaffold (1) (1). Usually, the calixarene macrocycle
can be functionalised via derivatisation or even replace-
ment of the OH groups at the lower rim, or via substitution,
oxidation or reduction of the aryl rings (2). In contrast to
the large number of known synthetic routes allowing the
chemical modification of the calix scaffold at the upper or
lower rim, only a handful of methods are known allowing
the incorporation of substituents at the methylene bridges.
Such modifications are of interest since the substituents at
the bridges may modify the physical and chemical
properties of the macrocycle, and may preorganise and
rigidify the calix skeleton in a desired conformation.
R
R
n
n
Br
OMe
OH
2: R = t-Bu, n = 4
3: R = H, n = 4
4: R = t-Bu, n = 5
5: R = t-Bu, n = 6
1
Two main different approaches have been used for the
preparation of calixarenes substituted at the bridges. In the
first approach (e.g. the fragment condensation method) (3),
fragments possessing the proper functionalities at the
bridges are synthesised and then cyclocondensed to afford
the functionalised calixarenes. A disadvantage of the
*Corresponding author. Email: silvio@vms.huji.ac.il
†In memoriam of Prof. Dmitry Rudkevich.
ISSN 1061–0278 print/ISSN 1029-0478 online
q 2010 Taylor & Francis
DOI: 10.1080/10610278.2010.500728
http://www.informaworld.com

Supramolecular Chemistry
705
reagents), but this results in slower reactions due to the
decrease in the ionising power of the medium.
In this paper, we report some additional reactions of
the hexabromocalix[6]arene derivative 5, and the deriva-
tisation/chemical modification of the functional groups at
the bridges of selected methylene-substituted calix[6]ar-
ene derivatives.
To increase the solubility in organic solvents, the crude
6a was acetylated, affording the hexasubstituted derivative
7a (Equation (1)). Calixarene 7a is sufficiently soluble in
CDCl3 to allow the determination of its spectra at room
temperature. Compound 7a displayed in the 1H NMR
spectrum pairs of singlets for the t-Bu, methoxy and
aromatic protons of the macrocycle, but single signals for
the substituents attached at the bridges. This pattern,
indicating three-fold symmetry of the molecule, is
consistent with a frozen ‘pinched cone’ conformation on
the NMR timescale. In this conformation, the six bridges
are symmetry equivalent, but the rings at positions 1, 3 and
5 are less twisted than the rings at positions 2, 4 and 6. We
have hypothesised previously that this conformation,
observed in the crystal structure of two hexasubstituted
(all-cis) methylene-functionalised calix[6]arene deriva-
tives, is adopted also in solution (11c).
Results and discussion
Reaction of 5 with phenols
In principle, reaction of 5 with an ambident nucleophile
should yield methylene-functionalised calixarenes with
functionalised substituents. These functional groups may
further contribute to the binding properties of the ligand
and may allow a facile modification of the additional
functionality. Ideally, the two nucleophilic sites at the
t-Bu
t-Bu
Ac2O
ArH / TFE
(1)
5
6
6
Ar
Ar′
OMe
OMe
(rc5)
6a Ar = 2-OH, 5-t-Bu-C6H3
7a Ar′ = 2-OAc, 5-t-Bu-C6H3
6b Ar = 2-Me, 4-OH, 5-i-Pr-C6H2
7b Ar′ = 2-Me, 4-OAc, 5-i-Pr-C6H2
ambident nucleophile should react at different rates,
otherwise mixtures of compounds are to be expected. We
have previously shown that 4 reacts with p-tert-Bu-phenol
and thymol via C-alkylation (11d). Since, as observed with
4, the ambident nucleophile reacts para to the OH group in
the case of thymol, but ortho in the case of p-tert-Bu-
phenol, the two phenols should afford derivatives differing
in the relative location of the OH group at the side arms.
The reaction of 5 with p-tert-butylphenol was
conducted by refluxing a mixture of the compounds in
TFE. An extremely insoluble product precipitated from the
reaction mixture. The low solubility of this product
(ascribed to the hexasubstituted derivative 6a) is most
likely due to intramolecular hydrogen bonds between the
OH groups at the side arms in the solid state. To determine
the NMR spectra of 6a, it was necessary to use pyridine-d5
(a hydrogen-bond-accepting solvent) and a high tempera-
ture (381 K). Lowering the temperature by 58C resulted in
the fast precipitation of the compound. The 1H NMR
spectra of 6a at 381 K displayed two t-Bu signals and a
single methoxy signal, in agreement with a hexasubstituted
derivative of rc5 configuration (i.e. all cis). Precluding
accidental isochrony, and assuming a preferred pinched
cone conformation, the high symmetry indicated by the
NMR spectra of 6a at high temperatures (consistent
with six-fold symmetry) indicates that the pinched
cone/pinched cone interconversion is fast on the NMR
timescale (see below).
Upon raising the temperature, pairs of signals of 7a
broadened and eventually coalesced. The dynamic process
responsible for these spectral changes can be ascribed to a
pinched cone/pinched cone interconversion (Figure 1)
involving rotation of the aryl rings, and mutually exchanging
the two types of rings on the macrocycle. From the chemical
difference under slow exchange conditions for the pair of
methoxy signals at 400 MHz (Dn ¼ 222.6 Hz) and the
16.9kcalmol21 was calculated for the dynamic process.
The reaction of 5 with thymol was conducted in a
similar fashion to that with t-Bu phenol (Equation (1)).
The crude mixture was acetylated yielding 7b.
Notably, while both 6b and 7b display in the 1H NMR
spectrum a signal pattern indicating three-fold symmetry,
the isopropyl groups display two doublets for its CH3
groups (Figure 2). The diastereotopicity of the CH3 groups
of the isopropyls is in full agreement with a preferred
pinched cone conformation. In such conformation, the six
bridges are symmetry equivalent, but since there are no
mirror planes bisecting each substituted bridge, the two
CH3 groups of a given isopropyl are diastereotopic, even
under fast rotation around the Ar-i-Pr bonds.
coalescence temperature (362.3 K),
a
barrier of
Click chemistry on the substituent at the bridge
The Huisgen 1,3-dipolar cycloaddition of azides with
acetylenes to yield 1,2,3-triazoles (click chemistry) (12) is

706
K. Kogan et al.
t-Bu
Ar
Ar
MeO
Ar
Ar
t-Bu
t-Bu
Ar
t-Bu
OMe
OMe
MeO
MeO
t-Bu
OMe
t-Bu
t-Bu
Ar
Ar
Ar
t-Bu
MeO
OMe
MeO
OMe
t-Bu
MeO
t-Bu
t-Bu
Ar
OMe
Ar
Ar
Ar
t-Bu
OAc
Ar=
t-Bu
Figure 1. Pinched cone/pinched cone interconversion in 6b. This dynamic process mutually exchanges the two types of rings of the
calixarene skeleton.
a versatile reaction which has proved very useful for the
modification of the calixarene scaffold (13). The six-fold
incorporation of 1,2,3-triazol groups was conducted
according to Equation (2):
Bromocalix[6]arene 5 readily reacts with neat primary
and secondary alcohols (no additional fluorinated alcohol
is needed). The first step was conducted simply by heating
at reflux a mixture of 5 and propargyl alcohol. On the basis
t-Bu
t-Bu
PhCH2N3
HOCH2C≡CH
(2)
5
CuI, toluene, ∆
∆
6
6
R
R
OMe
OMe
(rc5)
(rc5)
O CH2
9 R =
8 R = OCH2C≡CH
N
N
N
Ph
of the 1H and 13C NMR patterns indicating six-fold
symmetry, an rc5 (i.e. all-cis) configuration is ascribed to
the product. The reaction of the hexapropargyloxy
derivative 8 with azidomethyl benzene proceeded readily
and afforded the derivative incorporating triazole rings at
all bridges (9).
Full monofluorination of the bridges of calix[6]arene
The hydroxyl group of a calix[6]arene possessing a single
hydroxymethylene bridge can be replaced by a fluorine by
means of the deoxofluorinating agent DAST (Et2NSF3)
(14). To test whether this reaction can be conducted at all
bridges in a stereoselective fashion, we reacted the
hexahydroxycalix[6]arene 10 (previously obtained by
acetolysis of 5 followed by LiAlH4 reduction of the
resulting hexaacetate derivative) (11c) with DAST
(Equation (3)). As observed in most of the reactions of
5, a single major product was obtained. Hexafluoro-
calix[6]arene 11 displayed a doublet for the methylene
bridges (J ¼ 46.6 Hz) as a result of the geminal coupling
Figure 2. 500 MHz 1H NMR spectrum (CDCl3, r.t.) of 7b (high-
field region). The two isopropyl methyls are diastereotopic and
appear as separate signals (doublets) at 1.10 and 0.89 ppm.

Supramolecular Chemistry
707
between the proton and the fluorine of each bridge. On the
basis of the high symmetry of the NMR pattern, the all-cis
configuration is ascribed to this derivative.
6H), 7.47 (s, 12H), 7.38 (s, 6H), 7.17 (dd, J ¼ 8.5, 2.0 Hz,
6H), 6.93 (d, J ¼ 8.1 Hz, 6H), 3.35 (s, 18H), 1.41 (s, 54H),
1.34 (s, 54H) ppm. 13C NMR (pyridine-d5, 381 K,
125 MHz): d 155.6, 153.9, 145.2, 142.2, 137.6, 133.4,
128.1, 126.9, 116.8, 61.1, 38.4, 35.1, 34.8, 32.5, 32.2 ppm.
HR-MS (ESI): m/z 1947.2649 (M þ Hþ). Calcd for
t-Bu
t-Bu
DAST
(3)
C132H169O12: 1947.2648.
CH2Cl2, 0°C
6
6
6b. Yield: 0.055 g (43%) mp 3558C. 1H NMR
F
OH
OMe
OMe
11
(rc5)
(rc5)
(acetone-d6, 500 MHz, r.t.): d 7.77 (s, 6H), 7.13 (s, 6H),
6.95 (s, 6H), 6.92 (s, 6H), 6.54 (s, 6H), 6.46 (s, 6H), 3.18
(h, J ¼ 6.8 Hz, 6H), 2.95 (s, 9H), 2.52 (s, 9H), 2.08 (s,
18H), 1.17 (d, J ¼ 6.8 Hz, 18H), 1.1 (s, 27H), 1.06 (s,
27H), 1.01 (d, J ¼ 6.8 Hz, 18H) ppm. 13C NMR (acetone-
d6, 125 MHz, r.t.): d 155.07, 155.01, 153.5, 146.1, 145.9,
138.2, 136.9, 136.1, 135.2, 132.5, 127.8, 127.7, 127.0,
118.5, 61.2, 61.1, 40.5, 35.6, 35.4, 32.5, 32.3, 28.0, 24.0,
23.8, 21.0, 19.7 ppm. HR-MS (ESI): m/z 1969.2462 (M þ
Naþ). Calcd for C132H168O12Na: 1969.2467.
10
Cleavage and reaction with hydrazine of acetylacetonyl
groups
We also examined the chemical modification of the
acetoacetonyl groups of calixarene 12, previously obtained
via reaction of 5 with the ambident nucleophile
acetylacetone (11c). We found that, as previously observed
for the calix[5]arene analogue of 12, the acetoacetonyl
groups are readily cleaved in the presence of a base,
affording the corresponding hexa(2-propanonyl) derivative
13 and reaction of 12 with hydrazine affords the
hexapyrazolyl derivative 14 (Equation (4)).
Acetylation of 6a and 6b
A stirred mixture of 6a or 6b (0.10 g, 0.05 mmol) in acetic
anhydride (4 ml) containing 0.1 ml H2SO4 was heated
t-Bu
NH2NH2
(4)
NaOH
MeOH
6
R
OMe
t-Bu
t-Bu
12 R = CH(COMe)2
Me
Y =
Me
HN
N
6
6
R
Y
OMe
OMe
14
13 R = CH2COMe
Conclusions
to reflux for 3 h. The hot solution was poured into crushed
ice and extracted with chloroform (20 ml). The organic
solution was washed successively with brine, aq. NaHCO3
and brine, dried on Na2SO4 and evaporated. The crude
residue was recrystallised from acetone yielding 0.066 g
(62%) 7a, mp 3388C (dec), and 0.062 g (60%) 7b, 3588C
(dec).
The hexabromocalix[6]arene 5 reacts with the ambident
nucleophiles to afford the corresponding hexasubstituted
derivatives. The functional group at the substituent (OH,
triple bond, acetylacetonyl) can be derivatised or
functionalised.
7a. 1H NMR (CDCl3, 400 MHz, r.t.): d 7.13 (br, 15H),
6.88 (br, 15H), 6.42 (s, 6H), 2.17 (br s, 18H), 1.15 (s, 54H),
0.98 (br s, 54H) ppm. 13C NMR (C2D2Cl4, 410 K,
125 MHz): d 168.1, 153.8, 147.5, 146.5, 144.7, 135.7,
135.2, 126.9, 126.1, 123.2, 121.9, 60.4, 37.7, 34.1, 33.9,
31.2, 31.0, 20.4 ppm. HR-MS (ESI): m/z 2199.3276
(M þ H). Calcd for C144H181O18: 2199.3281.
Experimental section
Reaction of bromocalixarene 5 with p-tert-butylphenol or
thymol
A stirred mixture of 5 (0.10 g, 0.07 mmol), the
corresponding phenol (12 equivalents) in TFE (6 ml) and
chloroform (6 ml) was heated at reflux overnight. On
cooling to room temperature, a white solid was separated.
The crude product was filtered, triturated successively with
chloroform and methanol, and dried.
6a. Yield: 0.070 g (54%), mp 3028C. 1H NMR
(pyridine-d5, 381 K, 500 MHz): d 7.56 (d, J ¼ 2.0 Hz,
1
7b. H NMR (CDCl3, 400 MHz, r.t.): d 7.04 (s, 6H),
6.96 (s, 6H), 6.74 (s, 6H), 6.67 (s, 6H), 6.41 (s, 6H), 2.87
(s, 9H), 2.83 (h, J ¼ 6.9 Hz, 6H), 2.45 (s, 9H), 2.21 (s,
18H), 2.11 (s, 18H), 1.09 (d, J ¼ 6.8 Hz, 18H), 1.02 (s,
27H), 0.96 (s, 27H), 0.89 (d, J ¼ 6.8 Hz, 18H) ppm.

708
K. Kogan et al.
13C NMR (CDCl3, 125 MHz, r.t.): d 169.4, 153.8,
164.9 ppm. HR-MS (ESI): m/z 1187.6534 (M þ Na)þ.
153.4, 145.8, 145.1, 144.9, 141.4, 136.2, 136.1, 135.0,
134.3, 126.6, 126.2, 125.8, 123.7, 60.8, 59.9, 39.5, 34.2,
34.1, 31.2, 31.1, 30.2, 30.1, 30.0, 27.0, 23.3, 23.1, 20.9,
18.8 ppm. HR-MS (ESI): m/z 2199.3279 (M þ H). Calcd
for C144H181O18: 2199.3281.
Calcd for C72H90F6NaO6, 1187.6539.
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-
hexamethoxy-2,8,14,20,26,32-hexa(2-propanonyl)-
calix[6]arene (13)
A solution of 1.5 M NaOHaq (10 ml) was added to a
suspension of 12 (0.20 g, 0.12 mmol) in 20 ml of warm
methanol. The mixture was refluxed for 15 min and left to
cool overnight. After vacuum filtration, the white solid was
recrystallised from CHCl3/MeOH to afford compound 13
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-
hexamethoxy-2,8,14,20,26,32-hexapropargyloxy-
calix[6]arene (8)
A mixture of 5 (0.50 g, 0.33 mmol) and 35 ml of propargyl
alcohol was refluxed for 2 h. After evaporation, the residue
was recrystallised from CHCl3/MeOH affording 0.21 g
(47%) of 8, mp 265–2678C (dec); 1H NMR (CDCl3,
400 MHz, r.t.): d 7.28 (s, 18H), 6.40 (s, 6H), 4.16 (d,
J ¼ 2.31 Hz, 12H), 3.18 (s, 18H), 2.46 (t, J ¼ 2.24 Hz,
6H), 1.09 (s, 54H) ppm. 13C NMR (CDCl3, 125 MHz, r.t.):
d 154.7, 146.3, 132.8, 125.5, 79.8, 74.7, 70.7, 62.0, 56.4,
34.4, 31.3 ppm. HR-MS (ESI): m/z 1403.7733 (M þ Na)þ.
Calcd for C90H108NaO12: 1403.7738.
1
(82 mg, 48%), mp 215–2178C (dec); H NMR (CDCl3,
500 MHz, r.t.): d 6.95 (s, 12H), 5.28 (t, J ¼ 7.84 Hz, 6H),
3.55 (s, 18H), 2.99 (d, J ¼ 7.84 Hz, 12H), 2.06 (s, 18H),
1.05 (s, 54H) ppm. 13C NMR (CDCl3, 125 MHz, r.t.): d
206.9, 152.9, 146.0, 135.7, 123.5, 60.6, 50.6, 34.31, 33.52,
31.3, 29.8 ppm; HR-MS (ESI): m/z 1415.8672 (M þ Na)þ.
Calcd for C90H120NaO12, 1415.8677.
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-
hexamethoxy-2,8,14,20,26,32-hexa(dimethylpyrazolyl)-
calix[6]arene (14)
Click chemistry reaction of 8
A suspension of 12 (0.10 g, 0.061 mmol), 15ml of ethanol
and 1 ml of hydrazine monohydrate was refluxed for 3 h.
The white solid was vacuum filtered and washed several
times with water to afford 14 (54 mg, 55%), mp 420–4228C
(dec); 1H NMR (DMSO-d6, 500 MHz): d 12.02–11.84 (m,
6H), 7.00 (br s, 6H), 6.91 (s, 6H), 6.04 (s, 6H), 3.15 (s, 9H),
2.24 (s, 9H), 1.86 (br s, 18H), 1.71 (s, 18H), 1.18 (s, 27H),
0.82 (s, 27H) ppm. 13C NMR (DMSO-d6, after addition
of p-toluenesulphonic acid, 125 MHz): d 153.3, 151.9,
145.6, 145.3, 142.5, 139.5, 135.4, 134.7, 125.6, 117.4, 59.5,
33.8, 33.7, 33.1, 30.5, 11.3, 10.1ppm; HR-MS (ESI):
m/z 1623.0499 (M þ H)þ. Calcd for C102H133N12O6,
1623.0505. Anal. Calcd for C102H132N12O6: C, 75.52; H,
8.20. Found: C, 75.65; H, 8.54.
A mixture of 8 (0.1 g, 0.072 mmol), azidomethyl-benzene
(0.28 g, 2.10 mmol), CuI (85.4 mg, 0.45 mmol) and 20 ml
of toluene was refluxed overnight. After evaporation, the
residue was washed several times with acetone to afford
0.13 g (82%) of 9 as a greenish powder, mp 193–1958C
1
dec; H NMR (CDCl3, 500 MHz, r.t.): d 7.46 (s, 6H),
7.38–7.28 (m, 42H), 6.21 (s, 6H), 5.52 (s, 12H), 4.64 (s,
12H), 2.90 (s, 18H), 1.03 (s, 54H) ppm. 13C NMR (CDCl3,
125 MHz, r.t.): d 154.4, 146.3, 145.2, 135.3, 134.6, 133.0,
129.1, 128.9, 128.8, 128.7, 128.6, 128.2, 128.1, 127.3,
125.4, 122.8, 70.8, 62.7, 61.3, 54.8, 54.1, 34.3, 31.2,
31.8 ppm; HR-MS (ESI): m/z 1091.0927 (M þ 2H)2þ
.
Calcd for C132H152N18O12/2, 1091.0935.
Acknowledgement
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-
hexamethoxy-2,8,14,20,26,32-hexafluoro-calix[6]arene
(11)
This research was supported by the Israel Science Foundation
(Grant No. 257/07).
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suspension of 10 (0.40 g, 0.35 mmol) and dichloromethane
(30 ml). The reaction was left to warm to room
temperature for 4 h and quenched with water. After
phase separation, drying (MgSO4) and evaporation of the
solvent, the residue was recrystallised from CHCl3/MeOH
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1
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Supramolecular Chemistry
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