Self-assembly of calix[4]arene amine derivatives

Article abstract of DOI:10.1016/j.tet.2013.06.103

Self-assembly can occur spontaneously in solution for calix[4]arenes substituted at both the upper and lower rims with flexible pendant groups containing aromatic rings. This self-assembly occurs in both a head-to-tail and head-to-head manner, as proven by NOESY experiments.

Full text of DOI:10.1016/j.tet.2013.06.103

Tetrahedron 69 (2013) 7220e7226
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Tetrahedron
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Self-assembly of calix[4]arene amine derivatives
,
b
Laura O’Toole a, John McGinley a , Bernadette S. Creaven
*
a Department of Chemistry, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland
b Department of Science, Institute of Technology Tallaght Dublin, Dublin 24, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Self-assembly can occur spontaneously in solution for calix[4]arenes substituted at both the upper and
lower rims with flexible pendant groups containing aromatic rings. This self-assembly occurs in both
a head-to-tail and head-to-head manner, as proven by NOESY experiments.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 19 February 2013
Received in revised form 13 June 2013
Accepted 27 June 2013
Available online 4 July 2013
Keywords:
Calix[4]arene
Self-assembly
Synthesis
NMR
SEM
1. Introduction
of calix[4]arenes has been reported by Gutsche,25 Ungaro26 and
Pochini27 for calix[4]arene derivatives containing two tert-butyl
The concept behind self-assembly is the spontaneous and re-
versible association of building blocks into well-defined structures
via non-covalent interactions.1 The study of these non-covalent in-
teractions has been greatly enhanced by research into macrocyclic
calixarene molecules.2e6 Calix[4]arenes are one of the most versa-
tile building blocks in supramolecular chemistry, in the fabrication
of molecular devices and supramolecular architectures, as they
possess a framework, which allows the introduction of appropriate
binding cores at either the upper or the lower rim.7e14 Indeed, over
the past 20 years, a great deal of interest has been generated in the
self-assembly of calix[4]arenes resulting in the inclusion of small
molecules, which can then be separated from the bulk solution.15e22
As part of our on-going research into calix[4]arene derivatives as
potential ligands for energy transfer studies,23,24 we targeted the
attachment of functional groups containing nitrogen donor atoms to
both the upper and lower rims of our calix[4]arene scaffolds directly,
without using the nitration route we had previously published.23
This paper reports on the unexpected and spontaneous self-
assembly in solution of these calix[4]arene derivatives.
groups on the upper rim and alkyl derivatives on the lower rim. These
methods involved the use of either SnCl4 with chloromethyl n-octyl
ether or the formation of the methyl alcohol and its conversion to the
chloromethyl derivative with thionyl chloride. However, neither of
these reactions was successful when we started with tetrahydrox-
ycalix[4]arene (1). On the other hand, the reaction of 1 with formal-
dehyde in the presence of ZneHBr in glacial acetic acid28e30 resulted
in the formation of 2 in almost quantitative yield. The 1H NMR spec-
trum of 2 shows sharp signals for the aromatic and hydroxyl protons
but broad signals for both the methylene bridges and bromo-
methylene group, which was taken to be an indication of conforma-
tional change in solution since the lower rim and two positions of the
upper rim are unsubstituted. The signal for the hydroxyl protons is
almost the same in compounds 1 and 2, indicating that hydrogen
bonding between the hydroxyl groups is occurring in both cases,
which would suggest that the major form of 2 in solution is the cone
conformation.
Derivatisation of the lower rim of 2 with either benzyl groups or
methylpyridine groups, using previously reported methods,23
resulted in the formation of the cone conformers of both 3 and 6.
The attachment of both of those groups was evident in the 1H NMR
spectra of both 3 and 6 as a result of the OCH2 signal at 5.12 and
5.16 ppm, respectively. We have ascertained that the benzyl or
pyridylmethyl groups are not attached to the oxygen atom para to
the bromomethyl substituents through an HMBC NMR experiment.
The reaction at the upper rim of either 3 or 6 with 2-
aminomethylpyridine resulted in 4 and 7, which were waxy
2. Results and discussion
Scheme 1 shows the synthetic approach chosen for the benzyl
(3e5) and pyridyl (6e8) derivatives. The upper rimchloromethylation
* Corresponding author. E-mail address: john.mcginley@nuim.ie (J. McGinley).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.103

L. O’Toole et al. / Tetrahedron 69 (2013) 7220e7226
7221
Scheme 1. Reaction conditions: (i) formaldehyde, ZneHBr, glacial acetic acid, 90 ꢀC, 72 h; (ii) K2CO3, benzyl bromide or 2-aminomethylpyridine hydrochloride, MeCN,
D, 18 h; (iii)
2-aminomethylpyridine, MeCN,
D, 6 h; (iv) 2-aminomethylpyridine hydrochloride, DCM, D, 8 h.
solids in both cases. CHN analyses confirmed the formation of 4 and
7. However, the 1H NMR spectra of both 4 and 7 did not show the
expected signals for the proposed structures (see Fig. 1). There
appeared to be several species present in solution, which could not
be accounted for, given the CHN results. Furthermore, TLC analysis
suggested the presence of a single species. Therefore, two possi-
bilities that could explain this unexpected increase in signals in the
1H NMR spectra of 4 and 7 were (i) conformational change in so-
lution, that is, forming the partial cone, 1,2-alternate or 1,3-
alternate conformers in solution, or (ii) self-assembly. We did not
believe that conformational change was occurring, as such a change
had never been previously observed in our laboratory and there
was no metal ion present in the reaction to initiate that type of
transformation. The alternative explanation of self-assembly was
a possibility but required further investigation.
We decided to react 3 and 6 with 2-aminoethylpyridine to give 9
and 10 (see Scheme 2) to see if the 1H NMR spectra obtained would
be similar to those obtained for 4 and 7. We synthesised 9 and 10 in
good yields using similar procedures to those for 4 and 7 (see
Scheme 2). A similar increase in the number of signals observed in
the 1H NMR spectra of compounds 9 and 10 were observed. Again,
CHN analyses confirmed the formation of 9 and 10.
These observations led us to believe that some kind of self-
assembly was occurring in solution. To investigate how this
self-assembly was occurring, we began by carried out a dilution
experiment on 9 using 1H NMR spectroscopy on a 500 MHz in-
strument to see whether the self-assembly could be prevented if
a very dilute solution of the compound was present. We started off
with a 1 mM solution of 9 in CDCl3 and obtained the 1H NMR
spectrum. Then we carried out a 10-fold dilution and re-ran the
spectrum. We repeated this until we had a 1
sults of the dilutions are shown in Fig. 2.
mM solution. The re-
It is clearly evident, from Fig. 2, that as the concentration of 9
decreases, so also does the number of signals in each spectrum until
the spectrum is simplified to what should be expected for the cone
conformation of 9 (Fig. 2). Two distinct doublets for the methylene
bridges can be clearly seen as well as four other signals (singlet,
doublet, triplet and multiplet) for the remaining methylene groups.
A similar effect was observed when this experiment was carried out
on either of the compounds 4, 7 or 10, which showed this similar
phenomenon in solution.
Using NOESY experiments, it should be possible to ascertain
whether the self-assembly is occurring in a head-to-tail manner or
in a head-to-head/tail-to-tail manner (see Fig. 3). We will define the
processes as being either a Homo process, where like ends are
connected together, either head-to-head or tail-to-tail, or a Hetero
Fig. 1. The 1H NMR spectrum of 4 obtained in CHCl3.

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L. O’Toole et al. / Tetrahedron 69 (2013) 7220e7226
Scheme 2. Reaction conditions: (i) 2-aminoethylpyridine, MeCN, 6 h; (ii) 2-aminomethylpyridine hydrochloride, DCM, 8 h.
Fig. 2. 1H NMR spectra of 9 in CDCl3 at various concentrations of 9 with assignment of 1ꢁ10ꢂ6
purple¼1ꢁ10ꢂ6 M.
M
spectrum: blue¼1ꢁ10ꢂ3 M, red¼1ꢁ10ꢂ4 M, green¼1ꢁ10ꢂ5
M and
process, where opposite ends join together, as in head-to-tail,
in the self-assembly process occurring. Further correlation was
observed between the methylene group attached to the amine
(CH2eNHR group) and the singlet at d 5.06, which is the CH2 of the
similar to those reported on tetraurea calix[4]arene systems by
11
€
Bohmer. The upper and lower rim substituents are colour coded
blue (upper) and red (lower) to make it easier to distinguish the
different possible self-assembly processes. These experiments were
initially carried out on the 500 MHz instrument using compound 9.
Analysis of the 2D NOESY spectra was initiated at H2 of the
benzyl group again. The key NOESY correlations for 9 are outlined
in Fig. 4 and include the interactions between the benzyl linker and
the pyridyl protons (green line), the pyridyl protons and the benzyl
ring (purple line) and a second pyridyl proton and the benzyl linker
(red line) suggesting a hetero dimerisation and the interactions of
the calix[4]arene ring protons with the pyridyl group and benzyl
group (blue line) and the pyridyl proton and a pyridine ring (red
line) suggesting a homo dimerisation. The orange line indicates the
interactions of the AreCH2eNHR protons with both the pyridyl ring
and the benzyl linker, suggesting both homo and hetero dimer-
isations are evident. So from the NOE studies, it is clear that both
homo and hetero dimerisations are occurring and that both pro-
cesses are present in solution.
pyridine ring (d 8.50). This is a convenient starting point from
which conformational assignments can be inferred, as any in-
teraction with the lower rim benzyl protons can only occur if
a head-to-tail self-assembly mechanism has occurred. The NOESY
correlation observed with the doublets at
proximity to the methylene bridges of the calix[4]arene and, more
importantly, observed with the singlet at 5.06 indicated proximity
d 4.35 and 3.39 indicated
d
to the methylene bridge of the benzyl group. This latter NOE in-
teraction supports the theory of a head-to-tail interaction resulting

L. O’Toole et al. / Tetrahedron 69 (2013) 7220e7226
7223
Fig. 3. The three possible head-to-head, head-to-tail and tail-to-tail dimerisations that could occur for 9 in solution. The head-to-head and tail-to-tail dimerisations are homo
dimerisations and the head-to-tail dimerisation is a hetero dimerisation.
Fig. 5. Scanning electron micrograph of self-assembled 9.
Fig. 4. Key NOSEY correlations observed for 9.
sputter coated with gold under argon for 10 cycles and then
transferred into the main chamber of the SEM where the sample
Efforts to grow crystals of 4, 5, 9 and 10, suitable for an X-ray
crystallography study, were unsuccessful. However, long, strand-
like growths were observed at the bottom of the flasks in all
cases after evaporation of most of the solvent. The difficulty in
trying to obtain single crystals suitable for an X-ray structural de-
termination is that, as the amount of solvent decreases, the con-
centration of the compounds increase and promotes the self-
assembly process, resulting in polymeric materials. These poly-
meric strands were analysed using scanning electron microscopy
(SEM, Hitachi S-3200N at 14 kV), as shown in Fig. 5. The sample was
was subjected to high vacuum conditions at room temperature. The
sample was viewed between 14 and 16 kV. The images for 4, 5, 9
and 10 were all similar and showed these long strand-like mor-
phologies with smooth surfaces.
The subsequent reaction of 4 and 7 with 2-picolyl chloride
afforded 5 and 8. Again, CHN analyses confirmed the formation of 5
and 8. The 1H NMR spectra of 5 and 8 show an increase in the
number of signals in both the aromatic and methylene bridge re-
gions of the spectra, suggesting that self-assembly in solution is
also occurring in these materials.

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L. O’Toole et al. / Tetrahedron 69 (2013) 7220e7226
3. Conclusions
5.12 (4H, s, OCH2Bn), 4.54 (4H, s, CH2Br), 4.38 (4H, d, J¼13.1 Hz,
CH2), 3.42 (4H, d, J¼13.1 Hz, CH2). 13C NMR (75 MHz, CDCl3): 153.4,
151.9, 136.8, 133.2, 129.0, 128.7, 128.5, 128.0, 127.5, 125.5, 118.4, 78.4,
76.6, 31.4. Found C 66.65, H 4.42; C44H38Br2O4 requires C 66.85, H
4.84%.
In conclusion, we have shown that self-assembly can occur
spontaneously in solution for calix[4]arenes substituted at both the
upper and lower rims with flexible pendant groups containing ar-
omatic rings. This self-assembly occurs in a head-to-tail and head-
to-head manner, as proven by NOESY experiments.
4.2.3. Compound 4. To compound 3 (0.65 g, 0.89 mmol) dissolved
in acetonitrile (60 mL) were added triethylamine (0.18 g,
1.77 mmol) and 2-aminomethylpyridine (0.28 mL, 1.77 mmol). The
resulting solution was heated to reflux for 6 h under nitrogen. After
cooling, the solvent was removed under reduced pressure to give
an oil. The oil was washed with dichloromethane (3ꢁ25 mL) to
remove any unreacted starting material and the volatiles were re-
moved under reduced pressure to give a waxy red oil (4). Yield:
0.72 g, 95%. IR (KBr, cmꢂ1): 3414 (OH), 3388, 3028, 1590, 1448, 1089,
755. 1H NMR (300 MHz, CDCl3): 8.59 (2H, d, J¼3.8 Hz, PyeH), 7.79
(4H, d, J¼2.0 Hz, BneH), 7.73 (2H, t, J¼2.1 Hz, PyeH), 7.42 (2H, t,
J¼1.9 Hz, PyeH), 7.39 (2H, s, AreOH), 7.37 (2H, d, J¼2.1 Hz, PyeH),
7.34 (4H, t, J¼2.3 Hz, BneH), 7.14 (2H, t, J¼1.8 Hz, BneH), 7.10 (4H, s,
AreH), 6.89 (4H, d, J¼6.9 Hz, AreH), 6.57 (2H, t, J¼8.2 Hz, AreH),
5.13 (4H, s, OCH2Bn), 4.79 (4H, s, CH2NH), 4.41 (4H, d, J¼13.2 Hz,
CH2), 3.91 (4H, s, CH2Py), 3.23 (4H, d, J¼13.2 Hz, CH2), 2.43 (2H, br s,
NH). 13C NMR (75 MHz, CDCl3): 149.2, 135.6, 134.0, 133.3, 130.0,
128.9, 128.7, 128.5, 128.4, 128.3, 128.3, 128.1, 128.0, 123.7, 121.4, 75.3,
71.7, 54.6, 31.5. Found C 79.64, H 5.97, N 6.82; C56H52N4O4 requires C
79.59, H 6.20, N 6.63%.
4. Experimental
4.1. Equipment and materials
1H and 13C NMR (
d ppm; J Hz) spectra were recorded on either
a Bruker Advance DPX-300 spectrometer or a Bruker Advance
500 MHz spectrometer using saturated CDCl3 solutions with Me4Si
reference, unless indicated otherwise, with resolutions of 0.18 Hz
and 0.01 ppm, respectively. Infrared spectra (cmꢂ1) were recorded
as KBr discs or liquid films between KBr plates using a Nicolet
Impact 410 FT-IR spectrometer. Melting point analyses were carried
out using a Stewart Scientific SMP 1 melting point apparatus and
are uncorrected. Electrospray (ESI) mass spectra were collected on
an Agilent Technologies 6410 Time of Flight LC/MS. Compounds
were dissolved in acetonitrile/water (1:1) solutions containing 0.1%
formic acid, unless otherwise stated. The interpretation of mass
spectra was made with the help of the program ‘Agilent Mass-
hunter Workstation Software’. Microanalyses were carried out at
the Microanalytical Laboratory of the National University of Ireland
Maynooth. Standard Schlenk techniques were used throughout.
The particle morphologies of the as-prepared samples were ob-
served by JSM-5610LV scanning electron microscopy (SEM) at
20 kV. Starting materials were commercially obtained and used
without further purification.
4.2.4. Compound 5. To compound 4 (1.0 g, 1.18 mmol) dissolved in
dichloromethane (60 mL) were added triethylamine (0.21 g,
2.12 mmol) and 2-picolyl chloride hydrochloride (0.35 g,
2.12 mmol). The resulting solution was then heated to reflux under
nitrogen for 8 h. After cooling, the solvent was removed under
reduced pressure to give an oil. The oil was washed with chloro-
form (3ꢁ25 mL) to remove any unreacted starting material and the
volatiles were removed under reduced pressure to give a waxy red
solid (5). Yield: 1.04 g, 96%. IR (KBr, cmꢂ1): 3388 (OH), 1590, 1571,
1448, 1384, 1090, 758. 1H NMR (300 MHz, CDCl3): 8.56 (4H, d,
J¼5.5 Hz, PyeH), 7.85 (2H, s, AreOH), 7.65 (4H, t, J¼7.8 Hz, PyeH),
7.63 (4H, t, J¼5.1 Hz, PyeH), 7.58 (4H, d, J¼8.1 Hz, PyeH), 7.43 (4H,
d, J¼1.7 Hz, BneH), 7.37 (4H, t, J¼1.3 Hz, BneH), 7.19 (2H, t, J¼2.6 Hz,
BneH), 7.05 (4H, d, J¼6.6 Hz, AreH), 6.84 (4H, d, J¼7.7 Hz, AreH),
6.65 (2H, t, J¼5.8 Hz, AreH), 5.05 (4H, s, OCH2Bn), 4.68 (8H, s,
CH2Py), 4.27 (4H, d, J¼13.8 Hz, CH2), 3.89 (4H, s, NCH2), 3.34 (4H, d,
J¼13.8 Hz, CH2). 13C NMR (75 MHz, CDCl3): 149.2, 137.7, 137.2, 136.8,
135.6, 134.8, 133.3, 133.1, 131.1, 128.8, 128.6, 128.5, 128.4, 128.2,
128.0, 124.1, 123.7, 78.6, 76.9, 52.9, 31.4. Found C 79.42, H 6.01, N
7.90; C68H62N6O4 requires C 79.51, H 6.08, N 8.18%.
4.2. Syntheses
4.2.1. Compound 2. Zinc powder (0.18 g, 2.8 mmol) was added to
glacial acetic acid (100 mL) followed by HBr (33% in acetic acid,
12 mL) and stirred for 30 min under nitrogen. Compound 1 (3.0 g,
7.1 mmol), paraformaldehyde (0.11 g, 3.5 mmol) and HBr (60 mL)
were added and heated to reflux at 90 ꢀC for 72 h. On cooling, the
solvent was removed under reduced pressure and the residue was
washed with water (30 mL) and ether (30 mL) to give a brown solid
(2). Yield: 2.98 g, 99%; mp 255e260 ꢀC. IR (KBr, cmꢂ1): 3175 (OH),
1608, 1594, 1448, 753. 1H NMR (300 MHz, CDCl3): 10.19 (4H, s,
AreOH), 7.26 (1H, d, J¼12.1 Hz, AreH), 7.05 (1H, d, J¼12.1 Hz,
AreH), 6.72 (1H, t, J¼8.6 Hz, AreH), 4.73 (4H, s, CH2Br), 4.24 (4H, d,
J¼14.0 Hz, CH2), 3.51 (4H, d, J¼14.0 Hz, CH2). 13C NMR (75 MHz,
CDCl3): 148.8, 131.6, 129.0, 128.2, 122.2, 76.6, 34.1, 31.7. ESI-MS
(DMSO/MeOH) calcd for C30H26Br2O4 [Mꢂ1]þ 609.3280, found
609.3280. Found C 59.10, H 4.31; C30H26Br2O4 requires C 59.04, H
4.29%.
4.2.5. Compound 6. 2-Aminomethylpyridine hydrochloride (0.27 g,
1.6 mmol) was dissolved in acetonitrile (10 mL) and to this was
added Na2CO3 (0.17 g, 1.6 mmol) to remove the hydrochloride salt
and the resulting suspension was stirred for 30 min. The resulting
inorganic salts were removed by filtration and to the filtrate were
added 2 (0.50 g, 0.8 mmol) and NaH (0.04 g, 1.6 mmol) in aceto-
nitrile (60 mL). This suspension was then heated to reflux under
nitrogen overnight. After cooling, the inorganic solids were re-
moved by filtration and the volatiles were removed under reduced
pressure to give an oil. The oil was washed with dichloromethane
(3ꢁ25 mL) to remove any unreacted starting material and the
volatiles were removed under reduced pressure to give a sticky red
solid (6). Yield: 1.24 g, 95%; IR (KBr, cmꢂ1): 3404, 2919, 1592, 1448,
1247, 1089, 909, 757. 1H NMR (300 MHz, CDCl3): 8.51 (2H, d,
J¼7.5 Hz, PyeH), 7.59 (2H, t, J¼4.8 Hz, PyeH), 7.51 (2H, s, AreOH),
7.39 (2H, t, J¼5.3 Hz, PyeH), 7.15 (2H, d, J¼6.8 Hz, PyeH), 7.09 (4H, s,
AreH), 6.89 (4H, d, J¼6.9 Hz, AreH), 6.63 (2H, t, J¼8.6 Hz, AreH),
5.16 (4H, s, CH2ePy), 4.64 (4H, s, CH2eBr), 4.37 (4H, d, J¼13.2 Hz,
4.2.2. Compound 3. To compound 2 (1.00 g, 1.64 mmol) dissolved
in acetonitrile (100 mL) were added benzyl bromide (0.39 mL,
3.28 mmol) and potassium carbonate (0.45 g, 3.28 mmol) and the
resulting suspension was heated to reflux under nitrogen over-
night. The suspension was allowed to cool, the inorganic salts were
removed by filtration and the volatiles were removed under re-
duced pressure to give an oil. The oil was washed with dichloro-
methane (3ꢁ25 mL) to remove any unreacted starting material and
the volatiles were removed under reduced pressure to give a waxy
burgundy solid (3). Yield: 0.65 g, 89%; IR (KBr, cmꢂ1): 3361 (OH),
1608, 1595, 1448, 1088, 753. 1H NMR (300 MHz, CDCl3): 7.94 (2H, s,
AreOH), 7.72 (4H, t, J¼2.8 Hz, BneH), 7.43 (4H, s, AreH), 7.40 (2H, t,
J¼2.2 Hz, BneH), 7.12 (4H, d, J¼6.9 Hz, BneH), 6.96 (4H, d, J¼7.7 Hz,
AreH), 6.77 (2H, t, J¼10.0 Hz, AreH), 6.72 (4H, d, J¼10.0 Hz, AreH),

L. O’Toole et al. / Tetrahedron 69 (2013) 7220e7226
7225
CH2), 3.42 (4H, d, J¼13.4 Hz, CH2); 13C NMR (75 MHz, CDCl3): 156.2,
155.6, 152.6, 148.7, 136.6, 133.6, 132.4, 128.7, 128.6, 128.2, 125.1,
125.0, 120.9, 78.2, 46.3, 31.6. Found C 63.54, H 4.49, N 3.48;
PyeH), 7.37 (4H, d, J¼6.7 Hz, BneH), 7.34 (4H, s, AreH), 7.31 (2H, t,
J¼7.8 Hz, BneH), 7.14 (4H, t, J¼6.7 Hz, BneH), 7.05 (4H, d, J¼7.7 Hz,
AreH), 6.87 (4H, d, J¼7.6 Hz, AreH), 6.70 (2H, t, J¼7.7 Hz, AreH),
6.65 (2H, t, J¼7.7 Hz, AreH), 5.05 (4H, s, OCH2Bn), 4.31 (4H, d,
J¼13.7 Hz, CH2), 4.12 (4H, s, CH2Py), 3.93 (4H, s, CH2Py), 3.33 (4H, d,
J¼13.7 Hz, CH2), 2.91 (2H, br m, NH). 13C NMR (75 MHz, CDCl3):
158.6, 154.1, 152.3, 149.3, 135.6, 135.2, 133.1, 130.0, 128.8, 128.3,
127.7, 127.5, 127.0, 125.0, 123.7, 74.3, 53.4, 48.9, 36.1, 31.0. Found C
79.56, H 6.08, N 6.21; C58H56N4O4 requires C 79.79, H 6.47, N 6.42%.
C
42H36Br2N2O4 requires C 63.64, H 4.58, N 3.53%.
4.2.6. Compound 7. To compound 6 (0.44 g, 0.55 mmol) dissolved
in acetonitrile (70 mL) were added triethylamine (0.112 g,
1.11 mmol) and 2-aminomethylpyridine (0.11 mL, 1.11 mmol). The
resulting solution was heated to reflux overnight under nitrogen.
After cooling, the solvent was removed under reduced pressure to
give an oil. The oil was washed with chloroform (3ꢁ25 mL) to
remove any unreacted starting material and the volatiles were re-
moved under reduced pressure to give a waxy red-brown solid (7).
Yield: 0.46 g, 99%; IR (KBr, cmꢂ1): 3418, 2923, 1591,1571,1467, 1435,
1088, 755. 1H NMR (300 MHz, CDCl3): 8.59 (2H, d, J¼4.8 Hz, PyeH),
8.50 (2H, d, J¼4.3 Hz, PyeH), 7.52 (2H, t, J¼5.5 Hz, PyeH), 7.49 (2H,
t, J¼6.6 Hz, PyeH), 7.47 (2H, t, J¼7.6 Hz, PyeH), 7.27 (2H, d, J¼7.8 Hz,
PyeH), 7.21 (2H, d, J¼7.4 Hz, PyeH), 6.94 (2H, d, J¼7.6 Hz, PyeH),
6.81 (4H, d, J¼7.1 Hz, AreH), 6.54 (2H, t, J¼7.1 Hz, AreH), 5.16 (4H, s,
OCH2Py), 4.5 (2H, s, CH2NH), 4.35 (4H, d, J¼12.6 Hz, CH2), 3.95 (4H,
s, NHCH2Py), 3.43 (4H, s, J¼12.6 Hz, CH2); 13C NMR (75 MHz, CDCl3):
158.3,156.0, 154.7,152.3, 50.8,149.9, 136.4, 135.6, 133.4, 131.9, 128.4,
127.8, 127.5, 126.9, 125.1, 124.6, 120.7, 120.5, 77.7, 59.2, 53.7, 30.9.
Found C 76.41, H 5.74, N 9.56; C54H50N6O4 requires C 76.57, H 5.95,
N 9.92%.
4.2.9. Compound 10. Compound 6 (1.24 g, 1.56 mmol), triethyl-
amine (0.32 g, 3.12 mmol) and 2-aminoethylpyridine (0.37 mL,
3.12 mmol) were heated to reflux in a 1:1 acetonitrile/chloroform
mixture (50 mL) under nitrogen overnight. The solution was
allowed to cool to room temperature, filtered and the volatiles re-
moved under reduced pressure. The residue was then washed with
dichloromethane and water to remove any remaining triethyl-
amine to give an oil. The oil was washed with dichloromethane
(3ꢁ25 mL) to remove any unreacted starting material and the
volatiles were removed under reduced pressure to give a waxy red-
brown solid (10), yield¼1.20 g, 63%; IR (KBr, cmꢂ1): 3404, 3007,
2916, 1591, 1569, 1435, 1088. 1H NMR (300 MHz, CDCl3): 8.62 (2H, d,
J¼4.6 Hz, PyeH), 8.51 (2H, d, J¼5.5 Hz, PyeH), 7.75 (2H, t, J¼8.0 Hz,
PyeH), 7.63 (2H, d, J¼7.6 Hz, PyeH), 7.59 (2H, t, J¼6.4 Hz, PyeH),
7.41 (2H, t, J¼6.3 Hz, PyeH), 7.08 (4H, d, J¼7.2 Hz, AreH), 7.06 (2H, t,
J¼7.53 Hz, PyeH), 7.04 (2H, d, J¼7.6 Hz, PyeH), 6.99 (4H, d,
J¼6.8 Hz, AreH), 6.89 (2H, s, AreH), 6.62 (2H, t, J¼7.7 Hz, AreH),
5.14 (4H, s, OCH2Py), 4.36 (4H, d, J¼13.4 Hz, CH2), 3.94 (4H, s,
CH2eNHR), 3.33 (4H, d, J¼14.0 Hz, CH2), 3.04 (4H, t, J¼6.7 Hz,
NeCH2CH2ePy), 2.94 (4H, t, J¼6.1 Hz, NCH2CH2epy); 13C NMR
(75 MHz, CDCl3): 160.0, 159.6, 156.1, 153.4, 149.4, 149.1, 136.6, 136.5,
133.7,130.0,128.5,128.2,127.8,125.5,123.9,123.5,123.3,122.9, 78.7,
55.0, 53.6, 38.8, 31.3. Found C 76.52, H 6.14, N 9.12; C56H54N6O4
requires C 76.86, H 6.22, N 9.60%.
4.2.7. Compound
8. 2-Aminomethylpyridine
hydrochloride
(0.209 g, 1.27 mmol) was dissolved in acetonitrile (20 mL) and to
this was added Na2CO3 (0.135 g, 1.27 mmol) to remove the hydro-
chloride salt and the resulting suspension was stirred for 10 min.
The resulting inorganic salts were removed by filtration and to the
filtrate were added 7 (0.54 g, 0.64 mmol) and NaH (0.03 g,
1.27 mmol) in acetonitrile (50 mL). This suspension was then
heated to reflux under nitrogen overnight. After cooling, the in-
organic solids were removed by filtration and the volatiles were
removed under reduced pressure to give an oil. The oil was washed
with dichloromethane (3ꢁ25 mL) to remove any unreacted starting
material and the volatiles were removed under reduced pressure to
give a sticky red solid (8). Yield¼0.52 g, 76%; IR (KBr, cmꢂ1): 3432,
1630, 1592, 1448, 1384, 1091, 757. 1H NMR (300 MHz, CDCl3): 8.60
(2H, d, J¼4.5 Hz, PyeH), 8.49 (4H, d, J¼4.5 Hz, PyeH), 7.90 (2H, s,
AreOH), 7.69 (2H, t, J¼8.2 Hz, PyeH), 7.52 (4H, t, J¼7.4 Hz, PyeH),
7.23 (2H, t, J¼5.8 Hz, PyeH), 7.17 (4H, t, J¼5.4 Hz, PyeH), 7.09 (4H, s,
AreH), 7.03 (2H, t, J¼5.7 Hz, PyeH), 7.00 (4H, t, J¼6.7 Hz, PyeH),
6.74 (4H, d, J¼7.7 Hz, AreH), 6.50 (2H, t, J¼7.5 Hz, AreH), 5.21 (4H, s,
OCH2ePy), 4.62 (12H, s, CH2ePy), 4.36 (4H, d, J¼13.7 Hz, CH2), 3.39
(4H, d, J¼12.1 Hz, CH2); 13C NMR (75 MHz, CDCl3): 154.5, 153.9,
151.4, 150.0, 149.0, 148.7, 136.5, 136.2, 132.7, 131.3, 127.6, 127.3, 127.1,
126.8,126.5,126.0,120.6,120.0, 76.5, 48.8, 44.9, 29.9. Found C 76.85,
H 5.65, N 10.78; C66H60N8O4 requires C 77.02, H 5.88, N 10.89%.
4.2.10. Compound
11. 2-Aminomethylpyridine
hydrochloride
(0.07 g, 0.46 mmol) was dissolved in acetonitrile (20 mL) and to this
was added Na2CO3 (0.048 g, 0.457 mmol) to remove the hydro-
chloride salt and the resulting suspension was stirred for 10 min.
The resulting inorganic salts were removed by filtration and to the
filtrate were added 9 (0.2 g, 0.23 mmol) and NaH (0.01 g,
0.46 mmol) in acetonitrile (50 mL). This suspension was then
heated to reflux under nitrogen overnight. After cooling, the in-
organic solids were removed by filtration and the volatiles were
removed under reduced pressure to give an oil. The oil was washed
with dichloromethane (3ꢁ25 mL) to remove any unreacted starting
material and the volatiles were removed under reduced pressure to
give a waxy yellow solid (11), yield¼0.24 g, 92.3%; IR (KBr, cmꢂ1):
3429 (OH), 2921, 1592, 1456, 1195, 1089, 759; 1H NMR (300 MHz,
CDCl3): 8.50 (2H, d, J¼4.6 Hz, PyeH), 8.47 (2H, d, J¼4.9 Hz, PyeH),
7.86 (2H, s, AreOH), 7.65 (4H, d, J¼6.8 Hz, BneH), 7.57 (6H, t,
J¼7.7 Hz, BneH), 7.50 (2H, t, J¼4.7 Hz, PyeH), 7.43 (2H, t, J¼8.0 Hz,
PyeH), 7.38 (2H, d, J¼4.6 Hz, PyeH), 7.31 (2H, t, J¼6.4 Hz, PyeH),
7.25 (2H, t, J¼7.7 Hz, PyeH), 7.20 (2H, d, J¼6.7 Hz, PyeH), 7.13 (4H, s,
AreH), 7.08 (4H, d, J¼7.7 Hz, AreH), 6.76 (2H, t, J¼8.1 Hz, AreH),
5.06 (4H, s, OCH2Bn), 4.75 (4H, s, CH2NR2), 4.31 (4H, d, J¼13.0 Hz,
CH2), 3.91 (4H, s, CH2Py), 3.34 (4H, d, J¼13.0 Hz, CH2), 3.15 (4H, t,
J¼14.4 Hz, CH2CH2Py), 3.02 (4H, t, J¼14.4 Hz, CH2CH2Py); 13C NMR
(75 MHz, CDCl3): 160.4, 159.4, 154.1, 151.9, 149.0, 148.6, 137.7, 136.5,
136.4, 134.0, 129.0, 128.8, 128.6, 128.4, 128.2, 127.7, 127.2, 126.4,
125.4, 123.1, 122.3, 121.2, 71.6, 60.2, 58.6, 54.4, 39.2, 31.9. Found C
79.31, H 6.13, N 7.86; C70H66N6O4 requires C 79.67, H 6.30, N 7.96%.
4.2.8. Compound 9. Compound 3 (0.50 g, 0.71 mmol), triethyl-
amine (0.14 g, 1.42 mmol) and 2-aminoethylpyridine (0.17 g,
1.42 mmol) were heated to reflux in acetonitrile (60 mL) under
nitrogen for 2 days. The suspension was allowed to cool to room
temperature. The triethylammonium bromide was removed by
filtration and the volatiles were removed under reduced pressure
to give an oil. The oil was washed with chloroform (3ꢁ25 mL) to
remove any unreacted starting material and the volatiles were re-
moved under reduced pressure to give an oil. The oil was washed
with dichloromethane (3ꢁ25 mL) to remove any unreacted starting
material and the volatiles were removed under reduced pressure to
give a waxy dark yellow solid (9). Yield: 0.72 g, 66.7%. IR (KBr,
cmꢂ1): 3394, 3351, 2926, 1608, 1594, 1448, 1088, 753. 1H NMR
(300 MHz, CDCl3): 8.55 (2H, d, J¼3.6 Hz, PyeH), 7.63 (2H, t,
J¼7.4 Hz, PyeH), 7.61 (2H, t, J¼8.5 Hz, PyeH), 7.59 (2H, d, J¼7.4 Hz,
4.2.11. Compound
12. 2-Aminomethylpyridine
hydrochloride
(0.28 mL, 2.74 mmol) was dissolved in acetonitrile (20 mL) and to
this was added Na2CO3 (0.29 g, 2.74 mmol) to remove the

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L. O’Toole et al. / Tetrahedron 69 (2013) 7220e7226
6. Sansone, F.; Baldini, L.; Cassnati, A.; Ungaro, R. New J. Chem. 2010, 34,
2715e2728.
hydrochloride salt and the resulting suspension was stirred for
10 min. The resulting inorganic salts were removed by filtration and
to the filtrate were added 10 (1.20 g, 1.37 mmol) and triethylamine
(0.23 g, 2.74 mmol) in acetonitrile (50 mL). This suspension was
then heated to reflux under nitrogen overnight. The solution was
allowed to cool to room temperature, filtered and the volatiles re-
moved under reduced pressure. The residue was then washed with
DCM and water to remove any residual triethylamine to give a dark
red/brown waxy solid (12), yield¼0.95 g, 65%; IR (KBr, cmꢂ1): 3431,
1591, 1570, 1466, 1435, 1088, 755; 1H NMR (300 MHz, CDCl3): 8.70
(2H, d, J¼5.1 Hz, PyeH), 8.63 (2H, d, J¼5.0 Hz, PyeH), 8.52 (2H, d,
J¼5.1 Hz, PyeH), 8.22 (2H, t, J¼5.9 Hz, PyeH), 8.16 (2H, t, J¼7.6 Hz,
PyeH), 7.86 (2H, d, J¼1.7 Hz, PyeH), 7.79 (2H, t, J¼6.0 Hz, PyeH),
7.60 (2H, t, J¼1.7 Hz, PyeH), 7.57 (2H, t, J¼1.6 Hz, PyeH), 7.55 (2H, t,
J¼1.7 Hz, PyeH), 7.53 (2H, d, J¼1.9 Hz, PyeH), 7.40 (2H, s, AreOH),
7.29 (2H, d, J¼1.9 Hz, PyeH), 7.06 (4H, s, AreH), 7.04 (4H, d,
J¼2.8 Hz, AreH), 6.49 (2H, t, J¼7.1 Hz, AreH), 5.18 (4H, s, CH2Py),
4.24 (4H, d, J¼14.9 Hz, CH2), 3.94 (4H, s, R2NCH2Py), 3.44 (4H, d,
J¼13.7 Hz, CH2), 3.05 (4H, t, J¼4.6 Hz, CH2CH2Py), 3.00 (4H, t,
J¼3.8 Hz, CH2CH2Py); 13C NMR (75 MHz, CDCl3): 159.9, 159.4, 156.8,
156.6, 156.1, 154.4, 149.4, 149.0, 148.7, 137.2, 136.6, 136.3, 133.7,
128.8, 128.5, 128.2, 127.9, 125.4, 123.8, 123.5, 123.2, 121.9, 121.5,
121.1, 78.7, 63.5, 60.1, 54.3, 38.4, 32.2. Found C 76.91, H 6.05, N
10.45; C68H64N8O4 requires C 77.25, H 6.10, N 10.60%.
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