Synthesis of C3-symmetric tri(alkylamino) guests and their interaction with cyclodextrins

Article abstract of DOI:10.1007/s10847-014-0443-1

The synthesis of a series of star-shaped C₃-symmetric amines and their inclusion complexation properties toward α-, β-, γ-cyclodextrins and their permethylated derivatives has been described. The star molecules comprise of 1, 3, 5-trisubstited benzene core and the points formed by (alkylamino)methyl or 4-((alkylamino)methyl)phenyl groups. The modes of host-guest interaction were studied by UV-Vis spectroscopy, ITC, ¹H NMR and 2D-NMR (NOESY). It was found that star molecules containing (tert-butylamino)methyl, (adamantan-1-ylamino)methyl, 4-((isopropylamino)methyl) phenyl, 4-((tert-butylamino)methyl)phenyl and protonated 4-((adamantan-1-ylamino)methyl)phenyl points form strong host-guest complexes with β-cyclodextrin. It was also proved that the largest C₃-symmetric guest can form complexes with bcyclodextrin with stoichiometry 3 which is required for construction of dendrimer supramolecular structures. None of the investigated amines forms a strong complex with permethylated cyclodextrins.

Full text of DOI:10.1007/s10847-014-0443-1

J Incl Phenom Macrocycl Chem (2015) 81:141–152
DOI 10.1007/s10847-014-0443-1
ORIGINAL ARTICLE
Synthesis of C3-symmetric tri(alkylamino) guests and their
interaction with cyclodextrins
•
Tereza Bednarıkova Zdenek Tosner
•
ˇ´
Jirı Horsky Jindrich Jindrich
´
ˇ
ˇ
•
ˇ´
´
ˇ
ˇ
Received: 20 April 2014 / Accepted: 9 August 2014 / Published online: 20 August 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract The synthesis of a series of star-shaped C3-sym-
metric amines and their inclusion complexation properties
toward a-, b-, c-cyclodextrins and their permethylated deriv-
atives has been described. The star molecules comprise of
1,3,5-trisubstited benzene core and the points formed by
(alkylamino)methyl or 4-((alkylamino)methyl)phenyl groups.
The modes of host–guest interaction were studied by UV–Vis
spectroscopy, ITC, 1H NMR and 2D-NMR (NOESY). It was
found that star molecules containing (tert-butylamino)methyl,
(adamantan-1-ylamino)methyl, 4-((isopropylamino)methyl)
phenyl, 4-((tert-butylamino)methyl)phenyl and protonated
4-((adamantan-1-ylamino)methyl)phenyl points form strong
host–guest complexes with b-cyclodextrin. It was also proved
that the largest C3-symmetric guest can form complexes with b-
cyclodextrin with stoichiometry 3 which is required for con-
struction of dendrimer supramolecular structures. None of the
investigated amines forms a strong complex with permethy-
lated cyclodextrins.
Keywords Cyclodextrin Á Supramolecular interactions Á
C3-symmetric guests Á Inclusion complexes
Introduction
Cyclodextrins [1] (CDs) and their synthetic derivatives [2]
attract much attention due to their complexation abilities.
CDs are cyclic oligosaccharides consisting of a-1,4-linked
D-glucopyranose units, with a hydrophilic hydroxyl groups
located on their outer surface and a hydrophobic cavity in
the center. The most common CDs are a-, b- and c-CD
which consist of six, seven and eight glucopyranose units,
respectively. CDs have a shape of a hollow truncated cone.
The wider rim is composed of the secondary hydroxyl
groups and is ringed on the inside with H-3 protons. The
smaller rim is composed of the primary hydroxyl groups
´
and is ringed on the inside by H-6 and H-6 protons. The
H-5 protons form a ring around the inner hydrophobic core
of the CD molecule. Cyclodextrin hydrogens H-2 and H-4
are arranged as a band around the outside of the molecule
with H-2 near the wide rim and H-4 near to the narrow rim
[3] (Fig. 1).
Electronic supplementary material The online version of this
article (doi:10.1007/s10847-014-0443-1) contains supplementary
material, which is available to authorized users.
CDs are one of the most widely used systems in
supramolecular chemistry [4] due to their ability to include
a large variety of organic compounds inside their hydro-
phobic cavity (host–guest complexation). The structural
studies of CDs and of their complexes with guest mole-
cules has been carried out by different techniques such as
NMR spectroscopy [5] [6], UV–Vis spectroscopy [7],
fluorescence spectroscopy [8] or IR spectroscopy [9].
Wide variety of CD supramolecular complexes has been
described such as CD rotaxanes and polyrotaxanes [10],
supramolecular polymers formed by modified CDs
(intramolecular and intermolecular CD complexes, CD
ˇ´
´
ˇ
T. Bednarıkova Á J. Jindrich (&)
Department of Organic Chemistry, Faculty of Science, Charles
University in Prague, Hlavova 8, 128 43 Praha 2, Czech
Republic
e-mail: jindrich@natur.cuni.cz
ˇ
Z. Tosner
NMR Laboratory, Faculty of Science, Charles University in
Prague, Hlavova 8, 128 43 Prague 2, Czech Republic
´
J. Horsky
Institute of Macromolecular Chemistry, Heyrovsky Sq. 2,
162 06 Prague 6, Czech Republic
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OH
OH
OH
O
O
HO
H
O
OH
H
HO
3
2
OH
O
H
HO
1
4
5
O
H
HO
OH
OH
H
OH
O
6
O
H
H
OH
O
HO
HO
OH
n
O
OH
OH
H
OH
OH
OH
6
O
O
4
H
O
O
5
HO
1
H
HO
HO
2
H
OH
n = 1, α-CD
n = 2, β-CD
n = 3, γ-CD
3
H
OH
Fig. 1 Structure of cyclodextrins and illustration of the location of hydrogen atoms
dimers and trimers, cyclic ‘‘daisy chain’’ or branched
supramolecular polymers) [11], CD-based dendrimers and
networks or CD-based hydrogels [12].
a
b
R =
H
N
Here, we report on the synthesis of a series of C3-sym-
metric aromatic amines and their interaction with cyclo-
dextrins. The study suggests suitable guest groups which can
be used for preparation of building units containing planar
n
c
C3-symmetric core and bearing one CD and two guests or
H
H
N R
one guest and two CDs. Building units of this type are
intended for use in the construction of fully self-assembled
hyperbranched dendrimeric structures with the C3-symmet-
ric aromatic amines themselves serving potentially as cores.
R N
n
n
n = 0, 1
d
In
Fig. 2 General structure of the prepared C3-symmetric molecules
Results and discussion
Our long term objective is to study the ability of the star
shaped C3-symmetric molecules bearing CD and guest
terminal group to form self-assembled dendrimer struc-
tures. The first step in this study is to find the guest groups
which will form the strongest inclusion complex with CDs.
We decided to test the guest groups (a)–(d) depicted in the
Fig. 2. The idea was to select groups of different size and
groups which are known to form strong inclusion com-
plexes with CDs, prepare the model C3-symmetric mole-
cules (In) and evaluate strength of their interaction with
native and permethylated cyclodextrins. The combination
of the group and cyclodextrin which gives the strongest
interaction will be used in the synthesis of the further
derivatives with C3-symmetric core containing both—guest
and CD-groups.
Compounds of the structure I0 serve as models with the
following properties—(a) the studied guest groups are attached
to a larger structure, (b) only one guest group can be oriented
towards the approaching CD molecule. Compounds of the
structure I1 preserve these properties but are closer to the
envisaged dendrimer building blocks because—(a) they allow
easier concurrent interaction of more than one guest groups
with CD units due to the longer linker arms (b) they contain
linkers which can also act as guest groups and thus strengthen
the interaction with CD. For aromatic compounds of this type
quite low solubility could be expected; therefore, amine
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143
H
N R
O
OH
O
O
Br
1. LiAlH4, THF
reflux, 24 h
R
NH2,K2CO3
PhMe, rt
CH3OH, H2SO4
reflux, 24 h
2. 48% HBr, PhMe
reflux, 24 h
O
O
O
O
NH
R
NH
R
OH
OH
O
O
Br
Br
2
3a-d
1
93 %
94 %
3a
3b
3c
3d
,
,
,
R =
98 %
95 %
35 %
40 %
Scheme 1 Synthesis of I0 amines 3a–d
Scheme 2 Synthesis of I1
amines 7a–c
O
O
O
O
OH
(HO)2B
Br
Pd(OAc)2
LiAlH4
K2CO3,
PEG-400, rt
THF, 0 - 30°C
Br
Br
O
O
O
O
OH
OH
5
4
88 %
82 %
PBr3
THF, rt
H
N R
Br
7a
7b
7c
R
NH2,K2CO3
PhMe, rt
,
,
R =
97 %
93 %
59 %
7 a-c
NH
R
NH
R
Br
Br
6
70 %
connectivity of the structure components was chosen with the
potential to increase the solubility by protonation. On the other
hand, the protonation could substantially lower the strength of
the host–guest complex, especially for smaller guest groups,
therefore it was avoided whenever possible. In the planned
dendrimer building blocks the solubility is expected to not
cause such problems.
3a–d were synthesized from 1,3,5-tricarboxylic acid. First
step was esterification of 1,3,5-tricarboxylic acid with meth-
anol [13] to obtain the ester 1. This was followed by reduction
with lithium aluminum hydride in THF and treatment with
hydrobromic acid [13] which gave the corresponding bro-
momethyl derivative 2. Set of amines 3a–d was then prepared
from various amines and derivative 2 with K2CO3 in toluene.
‘‘Longer’’ amines 7a–c were synthesized from 1,3,5-trib-
romobenzene. The synthesis of ester 4 was achieved by Su-
Synthesis
zuki–Miyaura
cross-coupling
reaction
of
1,3,5-
tribromobenzene with 4-methoxycarbonylphenylboronic acid
The synthesis of C3-symmetric aromatic amines was carried
using Pd(OAc)2 and K2CO3 in PEG-400 [14]. The ester 4 was
out as described in Scheme 1 and Scheme 2. ‘‘Short’’ amines
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Fig. 3 UV-Vis spectra of
amines 7a and 7b (1 9 10-5 M)
in the presence of b-CD or c-
CD at pH = 7, at various molar
ratios
then converted to the corresponding alcohol 5 by reduction
with lithium aluminum hydride in THF [15]. Bromomethyl
derivative 6 was prepared by treatment of alcohol 5 with
phosphorus tribromide in THF [16]. Set of amines 7a–c was
then prepared from the corresponding amines and derivative 6
with K2CO3 in toluene.
Table 1 Absorption maxima kmax of amine/CD complexes in ratio
1/100
System
kmax System
(nm)
kmax (nm) System
kmax
(nm)
7a
257.5 7b
257.5
258.0
253.0
256.0
7c?
257.5
258.0
252.0
256.0
7a/aCD
7a/bCD
7a/cCD
257.5 7b/aCD
253.5 7b/bCD
256.0 7b/cCD
7c?/aCD
7c?/bCD
7c?/cCD
Determination of the extent of end-groups inclusion
7a/PMaCD 257.5 7b/PMaCD 257.5
7a/PMbCD 258.0 7b/PMbCD 257.5
7a/PMcCD 257.5 7b/PMcCD 257.0
7c?/PMaCD 258.0
7c?/PMbCD 258.0
7c?/PMcCD 258.0
The ability to form inclusion complexes is a common
property of cyclodextrins. We studied the formation of
host–guest complexes of native (a-, b-, c-CD) and per-
methylated CDs (PM-a-CD, PM-b-CD, PM-c-CD) with
C3-symmetric amines (3a–d and 7a–c). Methods for mea-
surements of inclusion abilities were UV–Vis spectros-
copy, 1H-NMR spectroscopy and 2D-NOESY (nuclear
Overhauser effect spectroscopy).
The bold values indicate the substantial shifts
complex between amine 7a or 7b and b-CD or c-CD. No
spectral changes were observed upon the addition of other
CDs to solutions of amines 7a and 7b. The negative effect
of permethylation on binding power of b-CD has been
noticed previously by Wenz [17]. The UV–Vis spectra of
amines 3a and 3b showed no changes with any of the
examined cyclodextrins.
In the case of UV–Vis spectroscopy we studied changes
in spectra after gradual addition of cyclodextrins (a-, b-, c-
CD, PM-a-CD, PM-b-CD and PM-c-CD) into the solution
of amines in phosphate buffer (pH = 7). We observed
substantial spectral changes just in the case of the amine 7a
and 7b with b-CD and c-CD (Fig. 3). It can be seen from
these spectra that the intensity of the UV absorption is
highly dependent on the CDs concentration. The main
bands in absorption spectra are hypsochromically shifted
(Table 1), which is also indicative of the formation of a
The UV–Vis spectra of amines 3c and 7c were measured
in phosphate buffer at pH = 2.5, because of their very low
solubility at pH = 7. These protonated amines were
labeled as 3c? and 7c?, respectively. Amine 7c? showed
spectral changes in the presence of b-CD and c-CD. These
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145
Fig. 4 Dependence of
absorbance (k = 253 nm) on
the concentration of amine 7a
and 7b. The molar ratio of
amine to b-CD was 1:100
spectral changes were identical to the changes observed for
amines 7a and 7b at pH = 7. The UV–Vis spectra of amine
3c? with b-CD showed no changes as in the case of amines
3a and 3b at pH = 7.
Table 2 Results of Isothermal Titration Calorimetry of I1 amines 7a–
c with b-CD
Amine pH K (mol-1
)
DH (cal mol-1
)
DS (cal mol-1
n
K-1
)
The UV–Vis spectrum of amine 3d was not measured,
because of its very low solubility in water and small
absorbance value in low concentration. This was also the
reason why compound 7d of I1 series (where even lower
solubility could be expected) was not prepared.
7a
7b
7c
7.0
7.0
6,890
9,710
-4280
-3270
-4430
3.2
7.3
3.3
0.78
0.48
4.90
2.5 12,200
The graph of the dependence of absorbance on amine
concentration at different pH (Fig. 4) shows that amines 7a
and 7b aggregate at higher concentrations (dependence of
absorbance on concentration is not linear). Taking into
consideration the aggregation and extinction coefficients,
concentration of amines 1 9 10-5 mol/L was selected as
optimal for the measurements. The graph on Fig. 4 also
shows that the presence of b-CD prevents aggregation of
the amine but only at pH = 7. Aggregation of amine 7b at
pH 7 was confirmed by dynamic light scattering which
detected objects with hydrodynamic diameter 250 nm.
Dynamic light scattering also confirmed the interaction of
b-CD with amine 7b since the observed hydrodynamic
diameter decreased to 1.8 nm in the presence of 7.5 mg/ml
of b-cyclodextrin.
Isothermal titration calorimetry of amine 7a and 7b at
pH 7 and amine 7c at pH 2.5 was carried out using b-CD as
a titrant. The general structure of used amines suggests the
model of three sequential binding sites as appropriate for
analysis of obtained data; nevertheless, a simpler model of
a set of identical sites provided better fit to experimental
data even though only 3 parameters are adjusted instead of
six required for three sequential binding sites. Therefore,
the results of a fit to the simpler model are reported in
Table 2. The key to the success of the simpler model is that
stoichiometry is treated as an adjustable parameter; other-
wise, the more general sequential model should reduce to
the simpler one. For all cases measured, the stoichiometry
found by fitting procedure strongly deviates from integer
values and thus has to be taken as apparent, probably
compensating for such effects as amines aggregation or
ionization. Nevertheless, low stoichiometry was found for
amines 7a, 7b with correspondence with their structure
which suggests strong anitcooperativity of binding. Values
of binding constants, even though affected by the same
phenomena as stoichiometry, are high for binding of an
alkyl group [18] binding thus suggesting that the aromatic
ring participates in the binding. Amine 7c has longer arms,
thus anticooperativity of the CD binding due to the steric
hindrance is less probable. In agreement with that a higher
stoichiometry is observed for 7c, in fact exceeding 3.
Again, the value can be affected by amine aggregation but
also by the fact that the longer arm can accommodate two
CD rings. Values of binding constant and binding enthalpy
roughly correspond to that of adamantylamonium [18].
The formation of the host–guest supramolecular com-
plexes with CDs can be observed by NMR spectroscopy,
one of the most powerful tools for describing complex
formation in solution [5], following chemical shifts in the
1
presence and absence of guest molecules. The H NMR
spectra of all guest/host combinations (amines 3a–3d and
7a–7c with a-, b-, c-CD, PM-a-CD, PM-b-CD and PM-c-
CD) were recorded but significant spectral changes were
observed only with b-CD. The profound differences in
chemical shifts of H-3 and H-5 protons (Fig. 5) indicate
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1
Fig. 5 The H-NMR spectra (600 MHz, D2O, 25 °C) of pure b-CD and b-CD in the presence of amines 3a–7c (concentration of b-CD was
6 9 10-3 mol/L and concentrations of amines were 2 9 10-3 mol/L)
that the complexation of amines occurs inside the cavity of
b-CD. The largest changes were observed for amines 7a,
7b, 7c? (in correspondence with the results of UV–Vis
measurements), and in the case of amine 3c. Smaller
changes in chemical shifts of CDs were observed in the
case of amine 3b. Also, the corresponding differences
caused by complex formation were found for the signals of
amines in aliphatic and aromatic proton areas (Fig. 6).
Further useful information about the structure of the
supramolecular system in solution can be obtained from two-
dimensional nuclear Overhauser spectroscopy (2D NOESY)
that reveals spatial proximity between protons (distances
with the interior of the b-CD cavity (no cross-peaks to H-1,
H-2 or H-4). For 7a/b-CD only weak cross-peaks were
observed between aromatic arm and H-3 proton of b-CD,
with no significant interaction of the methyl groups. Similar
behavior was obtained for the 7b/b-CD case and this sug-
gests that the aromatic rings of the linker arms of 7a or 7b are
located inside the cyclodextrin cavity rather than the meth-
yls. A different observation was done for the 7c? sample—
the adamantyl protons provide much stronger cross-peaks
with the H-3 and H-5 protons than the aromatic arms. That all
together suggests that while the tert-butyl group is capable to
form a strong complex, b-CD slips over it onto the aromatic
arm and forms even stronger inclusion complex there. On the
other hand, b-CD can remain on an adamantyl group at pH
2.5. Not only the relative attractivity of the aromatic ring for
b-CD is smaller in this case because adamantyl is one of the
strongest guest groups known [18] but also the binding to
aromatic rings is affected by steric hindrance. Other factors
which may play a role can be length of the end groups and
protonation of nitrogen which is known to restrict moving of
the CD host groups on the rotaxane axes [10].
˚
about 3–5 A) in cross-peak intensities [19]. Only selected
1
amines/CDs showing changes in the H NMR or UV–Vis
spectra were selected for such analysis, namely 3b/b-CD, 3c/
b-CD, 7a/b-CD, 7b/b-CD, 7c?/b-CD, 7a/c-CD, 7b/c-CD.
The resulting NOESY spectra with clear intermolecular
cross-peaks confirmed that amines 7a, 7b, 7c?, 3b and 3c
form inclusion complexes with b-CD while there were no
appreciable cross-peaks in the case of c-CD samples.
Example of 2D NOESY spectrum of 3c with b-CD is pre-
sented in Fig. 7. The aliphatic protons in 3b and 3c (tert-
butyl- and adamantyl-, respectively) show strong interaction
All UV–Vis and NMR measurements are summarized in
Table 3.
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147
Fig. 6 1H-NMR spectra (600 MHz, D2O, 25 °C) of amine 7a, b-CD and mixture of 7a with b-CD (concentration of b-CD was 6 9 10-3 mol/L
and concentration of amine was 2 9 10-3 mol/L)
Conclusion
Experimental section
General method for preparation of C3-symmetric planar
molecules containing three alkylamino end-groups con-
nected directly or by a rigid 1,4-phenylene linker arm to the
benzene core was developed. A series of such compounds
with different alkyl end-groups was synthesized with the
aim to find out, which group will show the strongest
interaction with which CD or permethylated-CD and
therefore will be the most suitable component for con-
struction of supramolecular dendrimer structures. The most
promising host–guest combination appears to be adamantyl
group and b-cyclodextrin. Nevertheless, tert-butyl could
also be used for formation of sufficiently strong complexes
with b-CD. We observed that adamantylamine end-group
forms strong complex with b-CD even if the amine group
is protonated and that the b-CD has a tendency to slip over
tert-butyl toward the phenylene arm group. We confirmed
that permethylated CDs form weaker complexes compared
to native CDs [17]. It was also confirmed that the largest
prepared C3-symmetric guest containing adamantyl end-
groups can form strong complexes with b-cyclodextrin
with stoichiometry 3 which is required for construction of
dendrimer supramolecular structures.
General
All reagents were purchased from commercial suppliers
without further purification. a-, b-, c-CD were purchased
from WAKO Chemicals (Germany) and per-Me-a-, b-, c-
CD were prepared according to literature [20]. The solvents
were purified and dried according to conventional methods
prior to use. H and 13C NMR spectroscopic data were
1
recorded with a Varian VNMRS 300 or a Bruker AVANCE
III 600 at 25 °C, 2D NMR measurements (NOESY) were
performed on Bruker AVANCE III at 600 MHz. Chemical
shifts (d) are given in ppm relative to the residual reso-
nance of the solvents (1H-NMR, d = 7.26 ppm for CHCl3;
13C-NMR, d = 77.00 ppm for CHCl3; 1H-NMR,
d = 3,31 ppm for CH3OH; 13C-NMR, d = 49.00 ppm for
CH3OH; H-NMR, d = 2.50 ppm for DMSO; 13C-NMR,
d = 39.50 ppm for DMSO; H-NMR, d = 4.80 ppm for
1
1
H2O; 1H-NMR, d = 7.16 ppm for C6H6; 13C-NMR,
d = 128.06 ppm for C6H6), and coupling constants (J) are
presented as absolute value in Hz. Mass spectra were
obtained on Bruker ESQUIRE 3000 ES-ion trap instrument
with electrospray ionization (ESI) in positive mode. All
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Fig. 7 NOESY spectrum of the host–guest complex 3c with b-CD (D2O, 25 °C)
samples were dissolved in methanol. Infrared spectroscopy
was performed on Thermo Nicolet AVATAR 370 FT-IR
instrument. Samples were prepared by mixing with KBr
and measured via DRIFT method. HRMS ESI spectra were
acquired on Thermo Fisher Scientific LTQ Orbitrap XL
instrument. Thin layer chromatography (TLC) was per-
formed on silicagel-coated aluminium sheets DC-Alufolien
Keisegel 60 F265 (Merck, Darmstadt, Germany). Sub-
stances were detected by UV-lamp (254 nm). Fluka Silica
gel 60 (40-63 am; Fluka, Neu-Ulm, Switzerland) was used
to perform preparative flash column chromatography.
Dynamic light scattering measurement were done at 25 °C
using Zetasizer Nano ZS (Malvern, UK). Phosphate buffer
0.02 M pH 7 was filtered through 0.2 lm PTFE filter. 0.4
lmol of Amine 7b was added to 1 mL of the filtered buffer,
shortly sonicated and shaken for 24 h. The aliquots of the
solution were diluted either by the buffer or by solution of
b-cyclodextrin in the buffer (15 mg/ml) and subjected to
dynamic light scattering measurement.
mixed and then refluxed for 24 h. The solvent was evap-
orated, and the residue was dissolved in chloroform
(50 mL) and then washed with a saturated solution of
potassium carbonate (40 mL). The solvent was removed
under reduced pressure to afford 1 as a white powder
(2.23 g, 93 % yield). 1H NMR (300 MHz, CDCl3):
d = 8.84 (s, 3H), 3.97 (s, 9H) ppm. 13C NMR (75.4 MHz,
CDCl3): d = 165.36, 134.54, 131.17, 52.58 ppm. MS (GC/
MS): m/z = 252 [M], 221 [M-OCH3]. The analytical data
are consistent with the literature [13].
1,3,5-Tris(bromomethyl)benzene (2)
A lithium aluminum hydride (0.45 g, 11.88 mmol) was
added to 20 mL of dry THF. Then solution of 1 (0.5 g,
1.98 mmol) in 20 mL of dry THF was added dropwise at
room temperature under stirring and an atmosphere of
Argon. After dropwise addition was completed, the mixture
was heated to reflux for 24 h. The excess of reducing agent
was destroyed by slow addition of water (5 mL) and the
solvent was evaporated. Then 15 mL of a 48 % HBr
solution and 25 mL of toluene were added and heated to
reflex for 24 h. The organic layer was separated and the
aqueous portion was extracted several times with diethyl
ether (3 9 50 mL). The organic layers were combined and
removed under reduced pressure. The crude material was
Synthesis
1,3,5-Tris(methoxycarbonyl)benzene (1)
1,3,5-Benzenetricarboxylic acid (2 g, 9.52 mmol), metha-
nol (40 mL), and concentrated sulfuric acid (0.5 mL) were
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149
Table 3 Results of UV–Vis and NMR measurements of guests 3a–7c? with CDs.a
a
‘‘??’’ complex is formed, ‘‘?’’ week complex is formed, ‘‘0’’ no complex observed, ‘‘--‘‘not measured, ‘‘n’’ number of 1,4-phenylene
groups (in In)
purified through a column chromatography of silica gel
with a 1:1 mixture of n-hexane: toluene as an eluent. The
solvents were evaporated under high vacuum to afford
3H), 7.77 (d, J = 8.47 Hz, 6H), 3.96 (s, 9H) ppm. 13C NMR
(75.4 MHz, CDCl3): d = 166.83, 144.95, 141.60, 130.25,
129.47, 127.27, 126.03, 52.21 ppm. MS (ESI): m/z 480.2 The
analytical data are consistent with those in the literature [21].
1
0.66 g (94 % yield) of 2. H NMR (300 MHz, CDCl3):
d = 7.35 (s, 3H), 4.46 (s, 6H) ppm. 13C NMR (75.4 MHz,
CDCl3): d = 139.06, 129.57, 32.16 ppm. MS (CG/MS): m/
z = 356 [M], 277 [M-Br], 196 [M-2Br], 115 [M-3Br]. The
analytical data are consistent with those in the literature
[13].
1,3,5-Tris[(4-hydroxymethyl)phenyl]benzene (5)
A lithium aluminum hydride (0.19 g, 5.0 mmol) was added
to 20 mL of dry THF. Then solution of 4 (0.4 g, 0.83 mmol)
in 20 mL of dry THF was added dropwise at 0 °C under
stirring and an atmosphere of argon. After dropwise addition
was completed, the mixture was heated to 30 °C for 24 h.
The excess of reducing agent was destroyed by slow addition
of 5 % HCl (5 mL) and the solvent was evaporated. Reac-
tion mixture was added to water (400 mL) and extracted
with chloroform (4 9 300 mL). The organic layers were
combined and removed under reduced pressure. The crude
material was purified through a column chromatography of
silica gel with a 50:1 mixture of chloroform: methanol as an
eluent. The solvent was evaporated under high vacuum to
afford 0.27 g (82 % yield) of 5. 1H NMR (300 MHz,
DMSO-d6): d = 7.85 (s, 3H), 7.82 (d, J = 8.21 Hz, 6H),
7.45(d, J = 8.25 Hz, 6H), 5.23 (t, J = 5.72 Hz, 3H), 4.57
(d, J = 5.68, 6H) ppm. 13C NMR (75.4 MHz, DMSO-d6):
1,3,5-Tris[(4-methoxycarbonyl)phenyl]benzene (4)
A mixture of 1,3,5-tribrombenzene (0.5 g, 1.59 mmol),
4-methoxycarbonylphenylboronic acid (1.14 g, 6.35 mmol),
Pd(OAc)2 (2 mol %, 7.0 mg, 3.18 9 10-2 mmol), K2CO3
(988 mg, 7.15 mmol) and PEG-400 (12.3 mL) was stirred at
room temperature overnight. The mixture was added to brine
(40 mL) and extracted four times with ethylacetate
(4 9 200 mL). The organic layers were combined and
removed under reduced pressure. The crude material was
purified through a column chromatography of silica gel with
chloroform as an eluent. The solvent was evaporated under
1
high vacuum to afford 0.67 g (88 % yield) of 4. H NMR
(300 MHz, CDCl3): d = 8.16 (d, J = 8.48 Hz, 6H), 7.86 (s,
123

150
J Incl Phenom Macrocycl Chem (2015) 81:141–152
d = 142.08, 141.48, 138.51, 126.99, 126.82, 123.89,
62.62 ppm. MS (ESI): m/z 396.1. The analytical data are
consistent with those in the literature [22].
-Ar), 3.71 (s, 6H, -CH2N), 1.22 (s, 27H, -CH3) ppm. 13C
NMR (125 MHz, CD3OD): d = 141.68, 128.77, 50.06,
47.78, 28.73 ppm. MS (ESI): m/z 334.3 [M ? H]?. HRMS
(ESI): calcd. for C21H40N3 334.32167; found 334.32174. IR
(KBr): 3306, 3055, 3019, 2959, 2896, 2863, 2830, 1598,
1,3,5-Tris[(4-bromomethyl)phenyl]benzene (6)
1473, 1452, 1383, 1362, 1227, 716 cm-1
.
To a stirred solution of the alcohol 5 (0.2 g, 0.5 mmol) in
dry THF (5 mL) was added dropwise a solution of phos-
phorus tribromide(0.54 g, 2.0 mmol) in dry ether (3 mL) at
room temperature and the mixture was stirred for 4 h at
room temperature under an atmosphere of argon. The
excess of phosphorus tribromide was destroyed by addition
of water (12 mL) and the solvent was evaporated. Reaction
mixture was added to water (100 mL) and extracted with
chloroform (4 9 100 mL). The organic layers were com-
bined and removed under reduced pressure. The crude
material was purified through a column chromatography of
silica gel with a 4:1 mixture of n-hexane: toluene as an
eluent. The solvent was evaporated under high vacuum to
afford 0.21 g (70 % yield) of 6. 1H NMR (300 MHz,
CDCl3): d = 7.76 (s, 3H), 7.66 (d, J = 8.15 Hz, 6H), 7.51
(d, J = 8.22 Hz, 6H), 4.58 (s, 6H) ppm. 13C NMR:
(75.4 MHz, CDCl3): d = 141.8, 141.0, 137.3, 129.6,
127.7, 125.3, 33.2 ppm. MS (ESI): m/z 504.9 [M-Br]?. The
analytical data are consistent with those in the literature
[22].
1,3,5-Tris(adamantylaminomethyl)benzene (3c)
The filtrate was concentrated in vacuo. The crude material
was purified through a column chromatography of silica
gel with a 5:1 mixture of n-hexane: ethylacetate ? 3 % of
triethylamine as an eluent. The solvent was evaporated
under high vacuum to afford 57 mg (35 % yield) of 3c. 1H
NMR (600 MHz, CD3OD): d = 7.21 (s, 3H, -Ar), 3.72 (s,
6H, -CH2N), 2.10 (s, 9H -Ad), 1.79 - 1.69 (m, 36H-Ad)
ppm. 13C NMR (125 MHz, CD3OD): d = 141.92, 128.73,
52.43, 45.62, 42.96, 37.74, 31.09 ppm. MS (ESI): m/z
568.5
C39H58N3 568.46253; found 568.46268. IR (KBr): 3010,
2899, 2845, 1598, 1455, 1356, 1308, 1144, 716 cm-1
[M ? H]?.
HRMS
(ESI):
calcd.
for
.
1,3,5-Tris([3,5-dimethylphenyl]aminomethyl)benzene (3d)
The filtrate was concentrated in vacuo. The crude material
was purified through a column chromatography of silica
gel with a 50:1 mixture of n-hexane: ethylacetate ? 3 % of
triethylamine as an eluent. The solvent was evaporated
under high vacuum to afford 54 mg (40 % yield) of 3d. 1H
NMR (600 MHz, C6D6): d = 7.17 (s, 3H, -Ar), 6.42 (s,
3H, -Ar), 6.23 (s, 6H, -Ar), 4.00 (s, 6H, -CH2-N), 2.18 (s,
General method for preparation of amines 3a–7c
A suspension of tribromomethyl derivative 2 (100 mg,
0.28 mmol, 1 equiv.) or 6 (100 mg, 0.17 mmol, 1 equiv.),
potassium carbonate (5 equiv.) and corresponding amine
(40 equiv.) in toluene (6 ml) was stirred at room temper-
ature for 48 h under an argon atmosphere. The reaction
mixture was filtered through Celite and washed with tolu-
ene (10 ml).
1
18H, -CH3) ppm. H NMR (300 MHz, CD3OD): d = 7.25
(s, 3H, -Ar), 6.29(s, 3H, -Ar), 6.25 (s, 6H, -Ar), 4.22 (s, 6H,
-CH2N), 2.13 (s, 18H, -CH3) ppm. 13C NMR (125 MHz,
C6D6): d = 148.48, 140.90, 138.75, 125.64, 120.27,
111.58, 48.53, 21.73 ppm. MS (ESI): m/z 478.3 [M ? H]?.
HRMS (ESI): calcd. for C33H40N3 478.32167; found
478.32172. IR (KBr): 3410, 3016, 2944, 2914, 2854, 1598,
1,3,5-Tris(isopropylaminomethyl)benzene (3a)
1518, 1479, 1329, 1192, 824 cm-1
.
The filtrate was concentrated in vacuo to afford 81 mg
(98 % yield) of 3a. 1H NMR (600 MHz, CD3OD):
d = 7.24 (s, 3H, -Ar), 3.77 (s, 6H, -CH2N), 2.86 (sep,
J = 6.0 Hz, 3H, -CH), 1.12 (d, J = 6.3 Hz, 18H, -CH3)
ppm. 13C NMR (125 MHz, CD3OD): d = 141.01, 128.65,
51.65, 48.93, 22.25 ppm. MS (ESI): m/z 292.3 [M ? H]?.
HRMS (ESI): calcd. for C18H34N3 292.27472; found
292.27483. IR(KBr): 3270, 3046, 2959, 2926, 2863, 2824,
1,3,5-Tris[(4-isopropylaminomethyl)phenyl]benzene (7a)
The filtrate was concentrated in vacuo to afford 87 mg
(97 % yield) of 7a. 1H NMR (600 MHz, CD3OD):
d = 7.74 (s, 3H, -Ar), 7.66 (d, J = 7.92 Hz, 6H, -Ar), 7.44
(d, J = 7.98 Hz, 6H, -Ar), 3.79 (s, 6H, -CH2N), 2.86 (sep,
J = 6.3 Hz, 3H, -CH), 1.12 (d, J = 6.3 Hz, 18H, -CH3)
ppm. 13C NMR (125 MHz, CD3OD): d = 143.35, 141.19,
139.97, 130.17, 128.35, 125.60, 51.45, 48.85, 22.28 ppm.
MS (ESI): m/z 520.3 [M ? H]?. HRMS (ESI): calcd. for
C36H46N3 520.36862; found 520.36877. IR (KBr): 3309,
3078, 3026, 2962, 2929, 2863, 2821, 1592, 1506, 1464,
1604, 1467, 1434, 1335, 1174, 743 cm-1
.
1,3,5-Tris(tert-butylaminomethyl)benzene (3b)
The filtrate was concentrated in vacuo to afford 89 mg (95 %
yield) of 3b. 1H NMR (600 MHz, CD3OD): d = 7.24 (s, 3H,
1440, 1377, 1335, 1171, 818 cm-1
.
123

J Incl Phenom Macrocycl Chem (2015) 81:141–152
151
1,3,5-Tris[(4-tert-butylaminomethyl)phenyl]benzene (7b)
reported in parts per million. Two-dimensional NOESY
experiments were recorded using vendor’s standard gradi-
ent enhanced pulse sequence with the mixing time of 0.5 s.
We prepared samples with molar host/guest ratio 3:1.
Solutions of CDs and of amines in D2O were prepared with
the help of sonication. Concentration of CDs was
6 9 10-3 mol/L. Protonated amine 7c? for NMR experi-
ments was prepared by addition of a drop of 5 % HCl in an
aqueous solution of the substance 7c.
The filtrate was concentrated in vacuo to afford 90 mg (93 %
yield) of 7b. 1H NMR (600 MHz, CD3OD): d = 7.78 (s, 3H,
-Ar), 7.71 (d, J = 8.1 Hz, 6H, -Ar), 7.48 (d, J = 7.98 Hz,
6H), 3.77 (s, 6H, -CH2N), 1.23 (s. 27H, -CH3) ppm. 13C
NMR (125 MHz, CD3OD): d = 143.45, 141.13, 140.93,
130.30, 128.33, 125.55, 52.09, 47.59, 28.74 ppm. MS (ESI):
m/z 562.5 [M ? H]?. HRMS (ESI): calcd. for
C39H52N3 562.41558; found 562.41568. IR (KBr): 3049,
3022, 2956, 2926, 2860, 2836, 1664, 1419, 1374, 1009,
833 cm-1
.
Supporting information
Supporting information is available, containing copies of
1H-NMR and 13C-NMR spectra of the new compounds and
UV spectra of the host-guest mixtures where interaction
was observed.
1,3,5-Tris[(4-adamantylaminomethyl)phenyl]benzene (7c)
The filtrate was concentrated in vacuo. The crude material
was purified through sublimation to afford 80 mg (59 %
yield) of 7c. 1H NMR (600 MHz, C6D6): d = 7.97 (s, 3H, -
Ar), 7.68 (d, J = 6 Hz, 6H, -Ar), 7.56 (d, J = 6 Hz, 6H, -
Ar), 3.76 (s, 6H, -CH2N), 2.00 (s, 9H, -Ad), 1.65-1.56 (m,
36H, -Ad) ppm. 13C NMR (125 MHz, C6D6): d = 143.34,
140.60, 129.50, 128.66, 128.00, 125.79, 45.45, 43.57,
37.48, 30.45 ppm. MS (ESI): m/z 796.6 [M ? H]?. HRMS
(ESI): calcd. for C57H70N3 796.55643; found 796.55650.
IR (KBr): 3045, 3022, 2902, 2842, 1595, 1515, 1452, 1392,
Acknowledgments This work was supported by the Ministry of
Education, Youth, and Sports of the Czech Republic (project No.
MSM0021620857) and Grant Agency of the Czech Republic (project
No. 13-01440S). Help of Dr. S. Filippov with ITC measurements is
appreciated.
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