Synthesis and investigation of catalytic affinities of water-soluble amphiphilic calix[n]arene surfactants in the coupling reaction of some heteroaromatic compounds

Article abstract of DOI:10.1016/j.tet.2016.08.066

Six water-soluble calix[n]arene-based Br?nsted acid-type catalysts with amphiphilic groups were successfully synthesized by incorporating sulfonic acid moieties. Their structures were characterized using FTIR,¹H NMR,¹³C NMR, APT-NMR, and elemental analysis techniques. Moreover, their catalytic capabilities were evaluated in the coupling reaction of 2-methylfuran and/or N-methylindole with some sec-alcohols in aqueous media. The association of their surfactant abilities, and the effects of water amount used and reaction durations on the catalytic activities of these amphiphilic calix[n]arene derivatives were also investigated. Observations indicated that these amphiphilic calix[n]arene catalysts exhibited high catalytic activities in the coupling reactions of 2-methylfuran and N-methylindole with some alcohols in water.

Full text of DOI:10.1016/j.tet.2016.08.066

Accepted Manuscript
Synthesis and investigation of catalytic affinities of water-soluble amphiphilic
calix[n]arene surfactants in the coupling reaction of some heteroaromatic compounds
Serkan Sayin, Mustafa Yilmaz
PII:
S0040-4020(16)30851-1
10.1016/j.tet.2016.08.066
TET 28047
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 April 2016
Revised Date: 9 August 2016
Accepted Date: 23 August 2016
Please cite this article as: Sayin S, Yilmaz M, Synthesis and investigation of catalytic affinities of
water-soluble amphiphilic calix[n]arene surfactants in the coupling reaction of some heteroaromatic
compounds, Tetrahedron (2016), doi: 10.1016/j.tet.2016.08.066.
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ACCEPTED MANUSCRIPT
Graphical Abstract
___________________________________________________________________________
Synthesis and Investigation of Catalytic Affinities of Water-soluble Amphiphilic Calix[n]arene Surfactants in
the Coupling Reaction of Some Heteroaromatic Compounds
Serkan Sayin* and Mustafa Yilmaz
SO3Na
SO3Na
NaO3
S
NaO3S
n
O
O
OH
O
O
or
O
n
N
21a
21b
20
N
O
or
or
oC,
H O
150 r
, 50
pm
2
O
O
O
17a
O
17b
OH
or
O
N
O
O
18
19b
19a
________________________________________________________________________________

ACCEPTED MANUSCRIPT
Synthesis and Investigation of Catalytic Affinities of Water-soluble
Amphiphilic Calix[n]arene Surfactants in the Coupling Reaction of Some
Heteroaromatic Compounds
Serkan Sayina* and Mustafa Yilmazb
aDepartment of Environmental Engineering, Faculty of Engineering, Giresun University,
Giresun-28200, Turkey
bDepartment of Chemistry, Selcuk University, Konya-42075, Turkey
ABSTRACT
Six water-soluble calix[n]arene-based Brønsted acid-type catalysts with amphiphilic groups
were successfully synthesized by incorporating sulfonic acid moieties. Their structures were
characterized using FTIR, 1H-NMR, 13C-NMR, APT-NMR, and elemental analysis
techniques. Moreover, their catalytic capabilities were evaluated in the coupling reaction of 2-
methylfuran and/or N-methylindole with some sec-alcohols in aqueous media. The association
of their surfactant abilities, and the effects of water amount used and reaction durations on the
catalytic activities of these amphiphilic calix[n]arene derivatives were also investigated.
Observations indicated that these amphiphilic calix[n]arene catalysts exhibited high catalytic
activities in the coupling reactions of 2-methylfuran and N-methyl indole with some alcohols
in water.
Keywords: Water-soluble calix[n]arene, Brønsted acid type catalyst, alkylation of
heteroaromatic compounds, green chemistry.
___________________________________________________________________________
To whom correspondence should be addressed. Tel: +90 454 3101740 ; fax: +90 454 3101749
E-mail: serkan.sayin@giresun.edu.tr (S. Sayin).
1

ACCEPTED MANUSCRIPT
1. Introduction
Reactions involving carbon-carbon bond formation for arenes and heteroarenes
represent a substantial approach for the efficient fabrication of diversely functionalized
complex compounds such as dyestuffs, perfumes, flavors, agricultural aids, and
pharmaceuticals.1-3 In traditional methods, carbon-carbon bond formation is carried out
through the reaction between an electrophile (C-X, X= triflate, halide, mesylate, etc.) with a
reactive center of arenes or heteroarenes in the presence of a metallic/organometallic reagent.4
However, owing to toxicity, a limited number of functional group tolerance, and the poor
water-solubility of most metallic/organometallic reagents, developing a reaction for C-C bond
construction for arenes/heteroarenes using an alcohol as an electrophile in water is a
challenge.4-6 To perform this kind of reaction, a water-soluble organic-based catalyst with
excellent reusability, which catalyzes the coupling reaction by reducing activation energy, is a
requirement in terms of environmental toxicology.
Calixarenes, known as the third generation of supramolecules, represent very useful
building blocks in that they possess tunable and different cavity sizes and exhibit versatile
applications in supramolecular chemistry.7-10 Because of their easy synthesis,
functionalization, and special properties such as having different-sized cavities, including
hydrophilic -OH moieties at their lower rim and hydrophobic aromatic subunits along with
tert-butyl groups, attempts to design and synthesis of new calix[n]arene derivatives have been
made.11-14 It has been reported lately that some of the water-soluble calix[n]arene derivatives
acting as surfactant-type Brønsted acid catalysts exhibited substantial catalytic abilities for C-
C bond formation.3a,10,14
With the goal of translating in aqueous media some organic reactions requiring the
usage of a catalyst, in our previous study we have designed p-sulfonatocalix[n]arenes (n= 4, 6
and 8) as a catalyst for the alkylation of 2-methylfuran and N-methylindole with some
alcohols.3a We have preliminarily taken a strategy involving the introduction of hydrophobic
2

ACCEPTED MANUSCRIPT
groups with different straight alkyl chains to Brønsted acid-type calix[n]arene derivatives in
order to investigate the effects of amphiphilic groups on the catalytic efficacies of water-
soluble calixarenes. Thus, six water-soluble podands, bearing a calix[n]arene backbone with
various amphiphilic groups at the lower rim, were successfully synthesized. Furthermore,
their catalytic activities were evaluated for the first time in the coupling reaction of 4,4'-
dimethoxybenzhydrol and/or (E)-trans-1,3-diphenyl-2-propen-1-ol with 2-methyl furan and/or
N-methylindole in water without co-solvents.
SO3Na
NaO3S
SO3Na
NaO3S
O
O
O
O
iv
O
O
O
O
(5)
(6)
v
vi
OH
HO
OH
OH
HO
HO OH
OH
HO
HO OH HO
OH
iv
i
ii
HO3S
HO3S
SO3H
SO3H
(2)
(1)
(4)
iii
SO3H
SO3H
O
SO3H
HO3S
O
O
O
O
O
O
O
SO3H
HO3S
SO3H
(3)
SO3H
Scheme 1. Synthesis of Brønsted acid-type calix[4]arene derivatives. Reaction conditions; i)
HCHO, NaOH; ii) AlCl3, phenol; iii) 1,3-propanesultone, NaH; iv) H2SO4; v) propyliodide,
NaH; vi) propylbromide, NaOH.
2. Results and discussion
3

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2.1. Synthesis and characterizations of water-soluble calix[n]arene derivatives
OH
i
HO
OH
OH
OH
OH
HO
(7)
ii
OH HO
OH
OH
OH
HO
(8)
iii
NaO3S
SO3Na
SO3Na
SO3Na
SO3Na
NaO3S
NaO3S
NaO3S
SO3Na
SO3Na
SO3Na
SO3Na
SO3Na
NaO3S
NaO3S
SO3Na
SO3Na
iv
NaO3S
v
HO
OH
O
OH
O
OH
O
O
O
O
O
O
OH
O
O
HO
O
O
(9)
(10)
(11)
Scheme 2. Synthesis of Brønsted acid-type calix[6]arene derivatives. Reaction conditions; i)
HCHO, KOH; ii) AlCl3, phenol; iii) H2SO4; iv) propylbromide, NaOH; v); dodecyliodide,
NaOH.
With the aim of developing new water-soluble organic-based catalysts, a large number
of studies have been published in the last few decades.3a,14-18 In our previous study, catalytic
capabilities of p-sulfonatocalix[n]arenes (n=4, 6 or 8) were evaluated in the coupling reactions
4

ACCEPTED MANUSCRIPT
of some electron-rich arenes with sec-alcohols in water.3a Inspired by our results,3a in this
study we investigated the effects of hydrophobic groups of amphiphilic calix[n]arene
derivatives. For this purpose, six water-soluble podands, including calix[n]arene backbones
bearing different lipophilic subunits, were synthesized and characterized in order to
investigate their catalytic efficiencies in the coupling reactions for 4,4'-dimethoxybenzhydrol
and/or (E)-trans-1,3-diphenyl-2-propen-1-ol with 2-methyl furan and/or N-methylindole in
water without co-solvents. Thus, p-tert-Butylcalix[4]arene (1), calix[4]arene (2),
calix[4]aryloxy-25,26,27,28-tetrakis(propane-3-sulfonic acid) (3), calix[4]arene-p-sulfonate
(4), 25,26,27,28-tetrakis(propoxy)calix[4]arene (5), 5,11,17,23-tetrasulfonato-25,26,27,28-
tetrakis(propoxy)calix[4]arene (6), p-tert-butylcalix[6]arene (7), calix[6]arene (8),
calix[6]arene-p-sulfonate
(9),
5,11,17,23,29,35-hexasulfonato-37,38,39,40,41,42-
hexakis(dodecyloxy)calix[6]arene (11), p-tert-butylcalix[8]arene (12), calix[8]arene (13),
calix[8]arene-p-sulfonate(14), 5,11,17,23,29,35,41,47-octasulfonato-49,50,51,52,53,54,55,56-
octakis(dodecyloxy)calix[8]arene (16) were synthesized according to literature
1
procedures15,19-23 (Schemes 1-3). FTIR, H-NMR, 13C-NMR spectroscopy and elemental
analysis techniques were performed to characterize the structures of the synthesized
compounds.
However,
5,11,17,23,29,35-hexasulfonato-37,38,39,40,41,42-
and 5,11,17,23,29,35,41,47-octasulfonato-
hexakis(propoxy)calix[6]arene
(10)
49,50,51,52,53,54,55,56-octakis(propoxy)calix[8]arene (15) were synthesized for the first
time (Schemes 2 and 3). Typically, an aqueous solution of calix[6]arene-p-hexasulfonate (9)
was treated with propyl bromide and NaOH in DMSO, affording amphiphilic p-
sulfonatocalix[6]arene 10, concurrently appended with the hydrophobic propyl chains at the
lower rim of p-sulfonatocalix[6]arene with a yield of 58% (Scheme 2). An FT-IR spectrum of
10 confirmed the existence of sulfonate groups in which characteristic peaks for the stretching
vibrations of S-O, the symmetric and asymmetric vibrations of the SO2 bands of derivative
10, appeared at 861, 1050, 1163, and 1111 cm-1, respectively (see Supporting information).
5

ACCEPTED MANUSCRIPT
1
The H-NMR spectrum of amphiphilic p-sulfonatocalix[6]arene 10 showed that the
hydrophobic subunits were successfully attached to the p-sulfonatocalix[6]arene, which
resonances at 0.88-1.27 (18H), 1.62-2.01 (12H), and 4.25-4.61 (12H) ppm for the protons of
the -CH3, -CH2, and -OCH2 groups, respectively (see Supporting information). The APT-13C-
NMR spectrum of derivative 10 clearly showed that the peaks at the positive region belonging
to the -CH3 and -CH groups appeared at 9.81 and 124.99-125.77 ppm.
Figure 1. APT-NMR (D2O) spectrum of amphiphilic hexapropoxyl-p-sulfonatocalix[6]arene
10.
6

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OH
i
OH
HO
OH
OH
OH
HO
HO
OH
(12)
ii
OH
HO
OH
OH
OH
HO
HO
OH
(13)
iii
NaO3S
NaO3S
SO3Na
NaO3S
NaO3S
NaO3S
SO3Na
SO3Na
SO3Na
SO3Na
OH
OH
OH
HO
HO
SO3Na
NaO3S
SO Na
3 SO3Na
SO Na
3 SO3Na
OH
OH
iv
OH
v
SO3Na
SO3Na
SO3Na
SO3Na
O
O
O
SO3Na
NaO3S
O
O
O
O
O
NaO3S
O
O
O
O
O
O
O
O
SO3Na
(14)
(15)
(16)
Scheme 3. Synthesis of Brønsted acid-type calix[8]arene derivatives. Reaction conditions; i)
paraformaldehyde, NaOH; ii) AlCl3, phenol; iii) H2SO4; iv) propylbromide, NaOH; v);
dodecyliodide, NaOH.
The substitution of calix[8]arene-p-sulfonate (14) at the lower rim was conducted with
propyl bromide and NaOH in a mixture of H2O/DMSO to afford 5,11,17,23,29,35,41,47-
octasulfonato-49,50,51,52,53,54,55,56-octakis(propoxy)calix[8]arene (15) with a yield of
48% (see Scheme 3). The structure of amphiphilic p-sulfonatocalix[8]arene 14 was confirmed
7

ACCEPTED MANUSCRIPT
not only by the appearance of notably characteristic IR peaks at 1175, 1050, and 879 cm-1 for
the asymmetric and symmetric vibrations of the SO2 bands, and the stretching vibrations of S-
O, respectively on the FT-IR spectrum (see Supporting information), but also by the
appearance of the peaks at 0.42-0.87 (24H, -CH3) and the peaks of -CH2, which belong to the
propyl moieties on the 1H-NMR spectrum (see Supporting information).
APT-13C-NMR experiment provided valuable information about the type of C atoms
for amphiphilic p-sulfonatocalix[8]arene 14 (see Fig. 2). On the APT spectrum, the peaks for
the -CH3 and -CH groups appeared at 9.89 and 126.26 ppm at the positive region, while the
peaks for the -CH2 and quaternary C groups appeared at the negative region.
Figure 2. APT-NMR (D2O) spectrum of amphiphilic octapropoxyl-p-sulfonatocalix[8]arene
15.
2.2. Evaluation of catalytic efficiencies of amphiphilic calix[n]arene derivatives
8

ACCEPTED MANUSCRIPT
In our previous study, p-sulfonatocalix[n]arenes (n= 4,6 and 8) were used as Brønsted
acid type catalysts in the coupling reaction for 4,4'-dimethoxybenzhydrol and/or (E)-trans-1,3-
diphenyl-2-propen-1-ol with 2-methyl furan and/or N-methylindole in water without co-
solvents.3a It was observed that calix[n]arene sulfonic acids exhibited substantial catalytic
activity for the substitution reactions. This study aimed to provide an insight into how
hydrophobic groups affected the catalytic properties of water-soluble calixarenes in the
coupling reaction for sec-alcohols with some heteroaromatic compounds. Thus, we are
interested, for the first time, in a study on the catalytic capabilities of six different amphiphilic
water-soluble calix[n]arene derivatives in water, which have comprehensive prospects in
green synthesis. Considering that C-C bond formation for heteroaromatic compounds has
important applications in the fabrication of dyestuffs, perfumes, flavors, agricultural aids,
pharmaceuticals, etc.,3a the replacement of sec-alcohol -OH by aromatic compounds in the
o
coupling reaction of 2-methylfuran or N-methylindole at 50 C in water was chosen as a
substitution reaction system to determine the catalytic efficacies of six amphiphilic
calix[n]arene derivatives. From the experimental results presented in Tables 1, 2 and 3, it can
be seen that the corresponding products (19a-b and 21a-b) were not synthesized when
calixarene based catalyst was not added. However, when Brønsted acid-type calix[n]arene
derivatives (Calix-6, Calix-10, Calix-11, Calix-15, or Calix-16) were employed as catalysts,
the corresponding products (19a-b and 21a-b) were isolated in good to excellent yields (see
Tables 1-3), whereas the lowest yields of the corresponding products (19a-b and 21a-b) were
obtained when Brønsted acid-type calix[n]arene derivative (Calix-3) was used as a catalyst.
To determine the effects on the reaction by changing the amount of water used and reaction
durations, various water amounts and different reaction durations were also performed.
9

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Table 1. The coupling reaction of 17a-b with 18 in H2O
O
O
O
O
N
O
OH
17a
17b
Calix-Cat.
H2O, 50 oC, 150 rpm
O
N
Calix-Cat.
H2O, 50 oC, 150 rpm
O
O
18
19b
19a
Entry Catalyst
Catalyst loading Ar-H
sec-Alcohol
18
Time (h) H2O (mL)
Product Yield (%)a
1
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
-
15
30
30
15
15
15
30
15
15
15
15
15
15
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
48
2
22
32
36
46
78
54
84
33
100
42
50
62
97
71
74
88
100
88
66
85
77
89
87
85
77
63
63
28
0
Calix-3
Calix-3
Calix-3
Calix-11
Calix-11
Calix-11
Calix-11
Calix-16
Calix-16
Calix-16
Calix-4b
Calix-9b
Calix-14b
Calix-3
Calix-3
Calix-6
Calix-6
Calix-10
Calix-10
Calix-11
Calix-11
Calix-15
Calix-15
Calix-16
Calix-16
Calix-4b
Calix-9b
Calix-14b
none
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17a
17b
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19a
19b
2
1
18
3
1
18
4
0.5
18
5
1
18
6
2
18
7
1
18
8
0.5
18
9
1
18
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2
18
1
18
1
18
1
18
1
18
2
18
1
18
2
18
1
18
2
18
1
18
2
18
1
18
2
18
1
18
2
18
1
18
1
18
1
18
1 or 2
1 or 2
18
none
-
0
18
aReaction conditions: 17a-b (0.18 mmol), 18 (22 mg, 0.09 mmol); isolated yield.
bReference3a
10

ACCEPTED MANUSCRIPT
The yields of product 19a in the presence of catalysts Calix-11 and Calix-16 were as
high as 84% and 100% in entries 7 and 9, respectively. In addition, the maximum yields of
product 19b in the presence of catalysts Calix-3, Calix-6, Calix-10, Calix-11, Calix-15, and
Calix-16 were observed as 74, 100, 88, 85, 89 and 85% in entries 15, 17, 18, 20, 22, and 24,
respectively (see Table 1).
Table. 2 The coupling reaction of 17a with 20 in H2O
OH
O
Calix-Cat.
+
O
H2O, 50 oC, 150 rpm
17a
20
21a
Entry
1
Catalyst
Calix-6
Catalyst loading
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
-
Ar-H
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
sec-Alcohol
Time/h H2O/mL
Product Yield (%)a
61
61
86
61
61
86
61
61
86
61
86
61
61
86
61
61
61
86
1
77
95
100
54
87
100
45
87
57
46
58
45
87
57
81
86
42
0
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
2
2
Calix-6
3
1
Calix-6
4
1
Calix-10
Calix-10
Calix-10
Calix-11
Calix-11
Calix-11
Calix-15
Calix-15
Calix-16
Calix-16
Calix-16
Calix-4b
Calix-9b
Calix-14b
None
5
2
6
1
7
1
8
2
9
1
10
11
12
13
14
15
16
17
18
1
1
1
2
1
2
2
1
1 or 2
aReaction conditions: 17a (0.18 mmol), 20 (19 mg, 0.09 mmol). Isolated yield.
bReference3a
The experimental results, which were obtained from the coupling reactions of 2-
methylfuran or N-methylindole with (E)-trans-1,3-diphenyl-2-propen-1-ol in the presence of
11

ACCEPTED MANUSCRIPT
water-soluble calix[n]arene catalysts, are depicted in Tables 2 and 3. Although Calix-15
catalyzed this coupling reaction to afford product 21a with a yield of 58%, this percentage is
the lowest percentage yield when compared with the yields achieved by the results of the rest
of the catalysts (see Table 2). When Calix-6, Calix-10, Calix-11, or Calix-16 were used as
catalysts, the maximum yields for product 21a were as high as 100, 100, 87, and 87% in
entries 3, 6, 7, and 13, respectively. In addition, the maximum yields of product 21b in the
presence of catalysts Calix-3, Calix-6, Calix-10, Calix-11, Calix-15, or Calix-16 were
observed as 87, 100, 100, 100, 100, and 100% in entries 2, 6, 9, 12, 16, and 19, respectively
(see Table 3). It can be concluded that Brønsted acid-type amphiphilic calix[n]arene
derivatives exhibited excellent catalytic activities for coupling reactions of 2-methylfuran or
N-methylindole in water. Moreover, the results can also be summarized that the catalytic
abilities of calixarene-based catalysts were increased when the long alkyl groups such as
dodecyl moieties attached to the lower rim of calix[n]arenes. In addition, reaction durations
and amount of water also affected the yields of the products.
12

ACCEPTED MANUSCRIPT
Table.3 The coupling reaction of 17b with 20 in Water
OH
N
Calix-Cat.
+
H2O, 50 oC, 150 rpm
N
17b
20
21b
Time/h H2O/mL
Entry
1
Catalyst
Calix-3
Calix-3
Calix-3
Calix-6
Calix-6
Calix-6
Calix-6
Calix-10
Calix-10
Calix-10
Calix-11
Calix-11
Calix-11
Calix-15
Calix-15
Calix-15
Calix-15
Calix-16
Calix-16
Calix-16
Calix-4b
Calix-9b
Calix-14b
None
Catalyst loading
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
-
Ar-H
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
sec-Alcohol
20
Product Yield (%)a
15
61
61
6
1
82
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
21b
2
1
87
20
3
2
43
20
4
1
89
20
5
15
61
61
15
61
61
15
61
61
6
1
99
20
6
1
100
100
85
20
7
2
20
8
1
20
9
1
100
100
49
20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2
20
1
20
1
100
100
90
20
2
20
1
20
15
61
61
15
61
61
15
15
15
86
1
95
20
1
100
100
49
20
2
20
1
20
1
100
100
96
20
2
20
1
20
1
23
20
1
74
20
1 or 2
0
20
aReaction conditions: 10a-b (0.18 mmol), 13 (19 mg, 0.09 mmol). Isolated yield.
bReference3a
3. Conclusion
In summary, six Brønsted acid-type amphiphilic calix[n]arene derivatives were
synthesized and characterized. Moreover, these amphiphilic calix[n]arene derivatives were
employed as catalysts in a coupling reaction of 2-methylfuran or N-methylindole with two
13

ACCEPTED MANUSCRIPT
activated sec-alcohols in water. The experiments of aromatic substitution catalysis in aqueous
media reflected these amphiphilic calix[n]arene catalysts possessed excellent catalytic
capabilities. Especially, long alkyl groups attached to the lower rim of calix[n]arenes the
catalytic efficacy of calixarene were dramatically increased. Worthy of note is the fact that
this effective catalysis system provided by six amphiphilic calix[n]arene catalysts for C-C
bond formation reactions in water may open potential prospects in ‘green’ synthesis.
4. Experimental
4.1. General
Melting points of the synthesized compounds was determined using an Ez-Melt apparatus in a
sealed capillary. FTIR and NMR spectra were recorded on a Perkin-Elmer 100 spectrometer
and a Varian 400 MHz spectrometer, respectively. Elemental analyses were performed at
Leco CHNS-932 analyzer.
4.2. Synthesis
p-tert-Butylcalix[4]arene (1), calix[4]arene (2), calix[4]aryloxy-25,26,27,28-
tetrakis(propane-3-sulfonic acid) (3), calix[4]arene-p-sulfonate (4), 25,26,27,28-
tetrakis(propoxy)calix[4]arene
tetrakis(propoxy)calix[4]arene (6), p-tert-butylcalix[6]arene (7), calix[6]arene (8),
calix[6]arene-p-sulfonate (9), 5,11,17,23,29,35-hexasulfonato-37,38,39,40,41,42-
(5),
5,11,17,23-tetrasulfonato-25,26,27,28-
hexakis(dodecyloxy)calix[6]arene (11), p-tert-butylcalix[8]arene (12), calix[8]arene (13),
calix[8]arene-p-sulfonate(14), 5,11,17,23,29,35,41,47-octasulfonato-49,50,51,52,53,54,55,56-
octakis(dodecyloxy)calix[8]arene (16) were synthesized according to the literature
procedure.15,19-23
5,11,17,23,29,35-Hexasulfonato-37,38,39,40,41,42-
hexakis(propoxy)calix[6]arene
(10)
and
5,11,17,23,29,35,41,47-octasulfonato-
14

ACCEPTED MANUSCRIPT
49,50,51,52,53,54,55,56-octakis(propoxy)calix[8]arene (15) were synthesized for the first
time.
4.2.1. Synthesis of 5,11,17,23-Tetrasulfonato-25,26,27,28-tetrakis(propoxy)calix[4]arene
(6).21
Method 1; A mixture of 5 (0.2 g, 0.269 mmol) in H2SO4 (2.5 mL) was stirred at rt for
10 min. A precipitate was formed by addition of a large amount of Et2O, filtered and dried.
White colored product was obtained in 69% yield.
Method 2; Calix[4]arene-p-sulfonate (4) (0.2 g, 0.269 mmol) H2O (1.5 mL) containing
NaOH (0.23 g, 5.802 mmol) and propyl bromide (0.3 mL, 3.303 mmol) in DMSO (10 mL)
was mixed, and the reaction mixture was heated at 85 oC for 30 h. After cooling, the solution
was precipitated by addition of acetone, filtered and dried. White powder was synthesized in
o
99% yield. Melting points >350 C. FTIR (ATR) cm-1: 1639 (VH2O), 1594, 1462 ve 1301
(VC=C), 1175 (VSO2 asymmetric), 1044 (VSO2 symmetric) and 797 (VS-O). 1H-NMR (400 MHz,
D2O): δ 0.87 (t, 12H, J= 7.6 Hz, -CH3), 1.81-1.86 (m, 8H, -CH2-), 3.25 (d, 4H, J= 13.2 Hz,
Ar-CH2-Ar), 3.73 (t, 8H, J= 7.2 Hz, O-CH2-), 4.25 (d, 4H, J= 13.2 Hz, Ar-CH2-Ar), 7.16 (s,
13
8H, ArH). C-NMR (100 MHz, D2O): δ 10.12, 23.05, 31.80, 76.99, 125.92, 133.76, 137.19,
155.61. Anal. Calcd. For C40H44O16S4 Na4·4H2O (%): C, 44.03; H, 4.99; S, 11.76. Found (%);
C, 44.10; H, 4.88; S, 11.83.
4.2.2.
Synthesis
of
5,11,17,23,29,35-hexasulfonato-37,38,39,40,41,42-
hexakis(propoxy)calix[6]arene (10). Calix[6]arene-p-hexasulfonate (9) (0.2 g, 0.179 mmol) in
H2O (5 mL) containing NaOH (0.24 g, 5.907 mmol) was mixed a solution of propyl bromide
o
(0.3 mL, 3.043 mmol) in DMSO (20 mL), and the mixture was stirred at 85 C for 30 min.
After cooling, a precipitate was formed by addition of acetone, and filtered. The residue was
15

ACCEPTED MANUSCRIPT
o
recrystallized from MeOH, and dried. Yield: 58%, m.p. >350 C. FTIR (ATR) cm-1: 1630
(VH2O), 1407 (VC=C), 1163, 1111 (VSO2 asymmetric), 1050 (VSO2 symmetric) and 861 (VS-O).
1H-NMR (400 MHz, D2O): δ 0.88-1.27 (m, 18H, -CH3), 1.62-2.01 (m, 12H, -CH2-), 3.77-3.97
(m, 12H, Ar-CH2-Ar), 4.25-4.61 (m, 12H, O-CH2-), 7.69-8.04 (m, 12H, ArH). 13C-NMR (100
MHz, D2O): δ 9.81, 21.90-22.70, 38.52, 75.53, 124.95-125.77, 128.96-130.15, 135.01-137.69,
156.38. Anal. Calcd. For C60H66O24S6Na6·6H2O (%): C, 44.77; H, 4.88; S, 11.95. Found (%);
C, 44.71; H, 4.91; S, 12.07.
4.2.3.
Synthesis
of
5,11,17,23,29,35,41,47-octasulfonato-49,50,51,52,53,54,55,56-
octakis(propoxy)calix[8]arene (15). Calix[8]arene-p-sulfonate (14) (0.2 g, 0.134 mmol) H2O
(5 mL) containing NaOH (0.24 g, 5.907 mmol) and propyl bromide (0.3 mL, 3.043 mmol) in
o
DMSO (20 mL) was mixed, and the reaction mixture was heated at 85 C for 30 h. After
cooling, the solution was precipitated by addition of acetone, and filtered. The residue was
recrystallized from MeOH and dried. White powder was synthesized in 48% yield, m.p. >350
oC. FTIR (ATR) cm-1: 1413 (VC=C), 1175 (VSO2 asymmetric), 1050 (VSO2 symmetric) and 879
1
(VS-O). H-NMR (400 MHz, D2O): δ 0.42-0.87 (m, 24H, -CH3), 1.73 (brs, 16H, -CH2-), 3.65-
3.93 (m, 32H, Ar-CH2-Ar ve O-CH2-), 7.09-7.48 (m, 16H, ArH). 13C-NMR (100 MHz, D2O):
δ 9.89, 22.76, 38.55, 74.74, 126.26, 134.17, 137.76, 157.37. Anal. Calcd. For
C80H88O32S8Na8·8H2O (%): C, 44.77; H, 4.88; S, 11.95. Found (%); C, 44.64; H, 4.85; S,
12.07.
4.3. Typical procedure for nucleophilic substitutions of two sec-alcohols in the presence
of Brønsted acid-type calix[n]arene catalysts
A previously reported literature procedure was performed.3a,14,24 Typically, to a
solution of catalyst in water (as listed in the tables) were added sec-alcohol (18 or 20) and a
o
hetero-aromatic compound (17a-b). The reaction mixture was stirred vigorously at 50 C for
16

ACCEPTED MANUSCRIPT
the period of time indicated in the tables. It is worth noting that water soluble catalysts were
separaed by centrifugation of the mixture in order to use next reactions. Then, the mixture was
treated with NaHCO3 aq. and extracted by Et2O. The organic phase was washed with H2O to
adjust pH to 7, and dried over anhydrous MgSO4, and evaporated under reduced pressure to
obtain the crude product that was purified by column chromatography.
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20

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Figure captions:
Figure 1. APT-13C-NMR (D2O) spectrum of amphiphilic hexapropoxyl-p-
sulfonatocalix[6]arene 10.
Figure 2. APT-13C-NMR (D2O) spectrum of amphiphilic octapropoxyl-p-
sulfonatocalix[8]arene 15.
Scheme 1. Synthesis of Brønsted acid-type calix[4]arene derivatives. Reaction conditions; i)
HCHO, NaOH; ii) AlCl3, phenol; iii) 1,3-propanesultone, NaH; iv) H2SO4; v) propyliodide,
NaH; vi) propylbromide, NaOH.
Scheme 2. Synthesis of Brønsted acid-type calix[6]arene derivatives. Reaction conditions; i)
HCHO, KOH; ii) AlCl3, phenol; iii) H2SO4; iv) propylbromide, NaOH; v); dodecyliodide,
NaOH.
Scheme 3. Synthesis of Brønsted acid-type calix[8]arene derivatives. Reaction conditions; i)
paraformaldehyde, NaOH; ii) AlCl3, phenol; iii) H2SO4; iv) propylbromide, NaOH; v);
dodecyliodide, NaOH.
21

ACCEPTED MANUSCRIPT
Figure 1
22

ACCEPTED MANUSCRIPT
Figure 2
23

ACCEPTED MANUSCRIPT
Scheme 1
SO3Na
NaO3S
SO3Na
NaO3S
O
O
O
O
iv
O
O
O
O
(5)
(6)
v
vi
OH
HO
OH
OH
HO
HO OH
OH
HO
HO OH HO
OH
iv
i
ii
HO3S
HO3S
SO3H
SO3H
(2)
(1)
(4)
iii
SO3H
SO3H
O
SO3H
HO3S
O
O
O
O
O
O
O
SO3H
HO3S
SO3H
(3)
SO3H
24

ACCEPTED MANUSCRIPT
Scheme 2
OH
i
HO
OH
OH
OH
OH
HO
(7)
ii
OH HO
OH
OH
OH
HO
(8)
iii
NaO3S
SO3Na
SO3Na
SO3Na
SO3Na
NaO3S
NaO3S
NaO3S
SO3Na
SO3Na
SO3Na
SO3Na
SO3Na
NaO3S
NaO3S
SO3Na
SO3Na
iv
NaO3S
v
HO
OH
O
OH
O
OH
O
O
O
O
O
O
OH
O
O
HO
O
O
(9)
(10)
(11)
25

ACCEPTED MANUSCRIPT
Scheme 3
OH
i
OH
HO
OH
OH
OH
HO
HO
OH
(12)
ii
OH
HO
OH
OH
OH
HO
HO
OH
(13)
iii
NaO3S
NaO3S
SO3Na
NaO3S
NaO3S
NaO3S
SO3Na
SO3Na
SO3Na
SO3Na
OH
OH
OH
HO
HO
SO3Na
NaO3S
SO Na
3 SO3Na
SO Na
3 SO3Na
OH
OH
iv
OH
v
SO3Na
SO3Na
SO3Na
SO3Na
O
O
O
SO3Na
NaO3S
O
O
O
O
O
NaO3S
O
O
O
O
O
O
O
O
SO3Na
(14)
(15)
(16)
26

ACCEPTED MANUSCRIPT
Table 1. The coupling reaction of 17a-b with 18 in H2O
O
O
O
O
N
O
OH
17a
17b
Calix-Cat.
H2O, 50 oC, 150 rpm
O
N
Calix-Cat.
H2O, 50 oC, 150 rpm
O
O
18
19b
19a
Entry Catalyst
Catalyst loading Ar-H
sec-Alcohol
18
Time (h) H2O (mL)
Product Yield (%)a
1
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
-
15
30
30
15
15
15
30
15
15
15
15
15
15
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
48
2
22
32
36
46
78
54
84
33
100
42
50
62
97
71
74
88
100
88
66
85
77
89
87
85
77
63
63
28
0
Calix-3
Calix-3
Calix-3
Calix-11
Calix-11
Calix-11
Calix-11
Calix-16
Calix-16
Calix-16
Calix-4b
Calix-9b
Calix-14b
Calix-3
Calix-3
Calix-6
Calix-6
Calix-10
Calix-10
Calix-11
Calix-11
Calix-15
Calix-15
Calix-16
Calix-16
Calix-4b
Calix-9b
Calix-14b
none
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17b
17a
17b
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19b
19a
19b
2
1
18
3
1
18
4
0.5
18
5
1
18
6
2
18
7
1
18
8
0.5
18
9
1
18
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2
18
1
18
1
18
1
18
1
18
2
18
1
18
2
18
1
18
2
18
1
18
2
18
1
18
2
18
1
18
2
18
1
18
1
18
1
18
1 or 2
1 or 2
18
none
-
0
18
aReaction conditions: 17a-b (0.18 mmol), 18 (22 mg, 0.09 mmol); isolated yield.
bReference3a
27

ACCEPTED MANUSCRIPT
Table. 2 The coupling reaction of 17a with 20 in H2O
OH
O
Calix-Cat.
+
O
H2O, 50 oC, 150 rpm
17a
20
21a
Time/h H2O/mL
Entry
1
Catalyst
Calix-6
Catalyst loading
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
-
Ar-H
sec-Alcohol
Product Yield (%)a
61
1
77
95
100
54
87
100
45
87
57
46
58
45
87
57
81
86
42
0
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
17a
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
2
61
86
61
61
86
61
61
86
61
86
61
61
86
61
61
61
86
2
Calix-6
3
1
Calix-6
4
1
Calix-10
Calix-10
Calix-10
Calix-11
Calix-11
Calix-11
Calix-15
Calix-15
Calix-16
Calix-16
Calix-16
Calix-4b
Calix-9b
Calix-14b
None
5
2
6
1
7
1
8
2
9
1
10
11
12
13
14
15
16
17
18
1
1
1
2
1
2
2
1
1 or 2
aReaction conditions: 17a (0.18 mmol), 20 (19 mg, 0.09 mmol). Isolated yield.
bReference3a
28