Synthesis and characterization of macrocyclic polyether N,N′-Diallyl-7,16-diaza-1,4,10,13-tetraoxa-dibenzo-18-crown-6

Article abstract of DOI:10.3390/molecules21020171

In this study an efficient and direct production procedure for a macrocyclic polyether N,N′-diallyl-7,16-diaza-1,4,10,13-tetraoxa-dibenzo-18-crown-6 from the reaction of catechol and N, N-bis(2-chloroethyl)prop-2-en-1-amine in n-butanol in the presence of a strong base is reported. The synthesis involves a two-step addition of sodium hydroxide to enhance the cyclization process, and at the end of the reaction, the reaction mixture is neutralized and the solvent replaced with water in-situ through distillation to afford a relatively pure precipitate that is easily recrystallized from acetone. The yield of the macrocycle was 36%-45% and could be scaled-up to one-mole quantities. The structure and purity of this compound was verified on the basis of elemental analysis, IR, UV-Vis,¹ H-, ¹³C-NMR, 2D-NMR, mass spectroscopy, and thermal analysis. The white crystalline compound has a sharp melting point of 124 °C and a crystallization temperature of 81.4 °C determined by differential scanning calorimetry. Our motivation behind the synthesis of the bibracchial lariat azacrown polyether ligand was to examine its possible applications in ion-selective polymer-supported materials.

Full text of DOI:10.3390/molecules21020171

molecules
Article
Synthesis and Characterization of Macrocyclic
1
Polyether N,N -Diallyl-7,16-diaza-1,4,10,13-tetraoxa-
dibenzo-18-crown-6
Julius Toeri 1,2,* and Marie-Pierre Laborie 1,2
1
Freiburg Materials Research Center, Stefan-Meier-Straße 21, 79104 Freiburg, Germany;
marie-pierre.laborie@biomat.uni-freiburg.de
Chair of Forest Biomaterials, University of Freiburg, Werthmanstr. 6, 79085 Freiburg, Germany
2
*
Correspondence: ratumo.toeri@biomat.uni-freiburg.de or ratumojt@gmail.com;
Tel.: +49-761-203-9239; Fax: +49-761-203-3763
Academic Editor: Derek J. McPhee
Received: 14 December 2015 ; Accepted: 27 January 2016 ; Published: 29 January 2016
Abstract: In this study an efficient and direct production procedure for a macrocyclic polyether
1
N,N -diallyl-7,16-diaza-1,4,10,13-tetraoxa-dibenzo-18-crown-6 from the reaction of catechol and
N,N-bis(2-chloroethyl)prop-2-en-1-amine in n-butanol in the presence of a strong base is reported.
The synthesis involves a two-step addition of sodium hydroxide to enhance the cyclization process,
and at the end of the reaction, the reaction mixture is neutralized and the solvent replaced with
water in-situ through distillation to afford a relatively pure precipitate that is easily recrystallized
from acetone. The yield of the macrocycle was 36%–45% and could be scaled-up to one-mole
quantities. The structure and purity of this compound was verified on the basis of elemental
1
13
analysis, IR, UV-Vis, H-, C-NMR, 2D-NMR, mass spectroscopy, and thermal analysis. The white
˝
crystalline compound has a sharp melting point of 124 C and a crystallization temperature of
8
˝
1.4 C determined by differential scanning calorimetry. Our motivation behind the synthesis of the
bibracchial lariat azacrown polyether ligand was to examine its possible applications in ion-selective
polymer-supported materials.
Keywords: N-substituted azacrown polyether; 4,16-diaza-18-crown-6; synthesis; lariat azacrown
ether; molecular recognition
1
. Introduction
Macrocyclic compounds containing oxygen and nitrogen as donor atoms have been extensively
investigated for their ability to form stable complexes with ions within their central cavity [
research oriented towards the application of these lariat azacrown ether compounds, a special emphasis
has been directed at finding suitable chemical compounds that can selectively bind metal ions [ ]. It
1–6]. In the
7
has been established that nitrogen-containing crown ethers have stronger complexation properties
for heavy-metal ions than all-oxygen crowns, which strongly complex alkali and alkaline earth metal
ions [
ability for ammonium salts and transition-metal ions over the all-oxygen crown compounds, partly
due to differences in polarizability [ 10]. These selective complexing properties have influenced
their incorporation into polymeric matrices to produce unique and novel polymer-supported crown
ethers [ 11 15]. This is normally achieved by tailoring the macrocycle with appropriate side arms
1,4,8]. The nitrogen-containing lariat azacrowns were also found to possess enhanced complexing
3,4,8–
9, –
that covalently bind to the prospective polymer backbone. However, practical applications of these
compounds are still limited due to the complexity of reactions used in the synthesis and the yields of
1
the isolated products often being moderate [
3,
5,
6
]. For instance, the N,N -Bis(substituted) derivatives
Molecules 2016, 21, 171; doi:10.3390/molecules21020171
www.mdpi.com/journal/molecules

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of 4,13-diaza-18-crown-6 polyether macrocycle are prepared via the macrocycle ring closure reactions
with the participation of secondary amine (“pre-formed side-arm” method) [ ]. However, this method
often leads to contamination by difficult-to-remove inorganics and the formation of linear and lager
cyclic byproducts that cause their instability and difficulty in purification [ ]. Moreover, in spite of the
5
5
popularity of these macrocycle compounds based on the proven ability to achieve a strong, selective,
and dynamic three-dimensional binding of metal cations, most authors report their synthesis in the
scale of a few grams or milligrams normally not sufficient for further application processes [16].
1
Of particular interest is the synthesis of macrocycle polyether N,N -diallyl-7,16-diaza-
1,4,10,13-tetraoxa-dibenzo-18-crown-6. The synthesis of this macrocycle as a potential metal ion
chelating ligand in a polymer-supported network has been reported previously [17], albeit the yield
and purity were not documented. Our attempts at exactly reproducing this procedure gave 6% yield
or less of the targeted compound. Therefore, the method was not found to be particularly versatile.
In the present paper, we report for the first time the synthesis of this macrocyclic polyether directly
1
from catechol and the precursor compound N,N -bis(2-chloroethyl)prop-2-en-1-amine in a scaled-up
batch size of up to one mole of reactants (corresponding to a product mass of ca. 91 g). The purpose
of this work was therefore to improve the overall efficiency and yield of this synthesis and increase
the batch size to one mole of the reactants. In addition to the optimized and up-scaled procedure, we
1
13
provide a full structural and physical characterization of the product including H-, C-, and 2D-NMR
as well as mass spectroscopy, FT-IR, UV-Vis and thermal analysis to support the proposed molecular
structure and its purity. By establishing the spectroscopic properties of the macrocyclic polyether and
the reaction pathway that leads to improved yields, it is hoped that this compound can find more
widespread use in ion-selective materials.
2
. Results and Discussion
1
Bis(2-hydroxyethyl)amine (
1
) is reacted with allyl bromide to form 2,2 -(prop-2-en-1-ylimino)
1
diethanol (
2
), which is then chlorinated to yield the precursor N,N -bis(2-chloroethyl)prop-2-en-1-amine
(3), followed by reaction with catechol in dry n-butanol in the presence of a strong base to afford
1
the desired product N,N -diallyl-7,16-diaza-1,4,10,13-tetraoxa-dibenzo-18-crown-6 (
Scheme 1. The macrocycle was reported to have been previously prepared from catechol and the
precursor compound 17]. The cyclization reaction involved the generation of catecholate salt by
addition of 2-mol. equivalent of sodium hydroxide in n-butanol before the slow addition of under
4), as shown in
3
[
3
reflux to yield the desired product. In our experience, this method affords low yields and the crude
product was not easily crystallized, suggesting the presence of impurities. We were able, through some
modifications, to improve the overall efficiency of this process and scale up the synthesis to afford the
desired product as white fibrous crystals (Figure 1a).
Figure 1.
(a) SEM image of the azacrown polyether showing fibrous crystals after crystallization (b) a
photograph of the synthesized azacrown ether precipitate in distilled water before crystallization.

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Scheme 1. Synthesis of the azacrown polyether.
First, it has been proposed that the ring closure reaction step is facilitated by the presence of
sodium ion, which is solvated by the intermediate acyclic polyether [18]. In previous studies, it was
concluded that the “coordination template effect” is operating and the probability of the ring-closing
step is greatly increased by the sodium ion [19]. The results of further experiment appeared to support
this assumption. We found yields to be poor in experiments where we added 2 mol. equivalent of
sodium hydroxide to catechol/butanol solution all at once. The yields were significantly improved
when two aliquots of 1 mol. equivalent of sodium hydroxide was added in two steps, according to
Pedersen [18]. Therefore it was assumed that the high yields are ascribed to the sodium ion which
is a strong complexer [20] to a “template effect” involving a cation which is not too bulky guiding
together the termini of an intermediate, thus increasing the rate of cyclization. Secondly, after refluxing
for 21 h, the reaction is neutralized with concentrated hydrochloric acid and the solvent distilled off
while it is slowly replaced with distilled water. This step was critical in obtaining the crude product in
relatively pure form (Figure 1b) especially when scaling up the production by avoiding an oily phase
that is difficult to crystallize. Reactant amounts and yields according to both the previously reported
method and the present procedure are included in Table 1. In addition to the improved and scaled
up procedure of synthesizing the macrocycle, its spectroscopic and thermal properties have not been
reported in detail before, as described in the following sections.
Table 1. Comparison of the reaction amounts and the respective yields of the azacrown according to
two procedures.
Catechol (Moles)
1.0 g (0.10 mol.)
10.11 g (1.00 mol.)
1.0 g (0.10 mol.)
10.11 g (1.00 mol.)
Moles of 3
Method of Adding NaOH
Yield (%)
1
1
1
1
0.10
1.00
0.10
1.00
One step 2-mol equivalent
One step 2-mol equivalent
Two step 1-mol equivalent
Two step 1-mol equivalent
5 ˘ 1
3–6
36
42
2
.1. Spectroscopic Characterization of the Azarown Polyether
The structures of compounds and
were completely assigned by H-, 13C-NMR and 2D-NMR
1
2,
3
4
spectroscopy and supported with infrared signal assignments. The IR spectroscopic data (Figure S1)
indicate that the precursor compounds and the synthesized title compound were formed [21–23].
´
4
The UV-Vis spectrum of
has two UV maxima of 236 nm (
4
(Figure S2) was recorded in cyclohexane (2.28
ˆ
10 M). The product
ε
12368) and 278 nm (
ε
11184) both of which are πÑπ* and can be
attributed to the benzene fragment of the crown ether cavity. A related macrocycle, dibenzo-18-crown-6
polyether, which was synthesized by Pedersen [18], and has all-oxygen crown ether cavity was reported
with similar absorption values hence supporting the possibility that the two signals arise as a result of
the presence of benzene ring.
The H-, 13C-NMR and the heteronuclear single quantum coherence (HSQC)-NMR spectra
1
of the synthesized compound were consistent with the assigned structure in all cases. In the

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proton-NMR spectra (Figure 2), compounds
2
and
3
displayed very well defined resonance signals
for the -CH -CH=CH allyl and -CH CH -X (X = OH or Cl) aliphatic units corresponding to the
2
2
2
2
typical signals of the precursor compounds. In compound
m, J = 19.9 Hz, 1H10a) and the trans ( = 5.20 ppm; dq, J = 17.22, 1.71 Hz, 1H10b) protons are observed,
while the signal at = 5.90 ppm (m, J = 17.00 Hz, 10.35 Hz, 6.57 Hz, 1H ) represents the single
2 (Figure 2a), the cis (δ = 5.08–5.15 ppm;
δ
δ
9a
proton of C9. The two equivalent protons at C8 are clearly represented by the signal at 3.21 ppm (dt,
J = 6.42 Hz, 1.32 Hz, 2H). The four equivalent protons next to the more electronegative nitrogen atom
(
H3a,3b & H5a,5b) are observed at
next to –OH groups (H2a,2b & H6a,6b) appear downfield at
of the proton signals as shown in Table 2 was consistent with the population. The corresponding
δ
= 2.65 ppm (J = 5.74 Hz, 4H), while the other four equivalent protons
δ
= 3.57 ppm (t, J = 5.74 Hz, 4H). Integration
1
3
C-NMR spectrum of compound
2 (Figure 3a) indicates the expected five carbon environments and
their correct positions, i.e., 136.27 ppm (C9), 116.4 ppm (C10), 59.50 ppm (C3 & C5), 57.8 ppm (C8),
5
6.1 ppm (C2 & C6).
Figure 2. 1H-NMR spectra of: (
a
1 1
) 2,2 -(prop-2-en-1-ylimino)diethanol (2) (b) N,N -bis(2-chloroethyl)
prop-2-en-1-amine (3); and (c) N,N -diallyl-7,16-diaza-1,4,10,13-tetraoxa-dibenzo-18-crown-6 (4).
1

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Figure 3. 13C-NMR spectra of: (
a
1
) 2,2 -(prop-2-en-1-ylimino)diethanol (2); (b) N,N-bis(2-chloroethyl)
prop-2-en-1-amine (3) and (c) N,N -diallyl-7,16-diaza-1,4,10,13-tetraoxa-dibenzo-18-crown-6 (4).
1
After chlorination of compound
spectra (Figure 2b) with the following shifts:
H), 3.56–3.66 (m, 4H), 5.10–5.20 (m, 1H), 5.22–5.32 (m, 1H), 5.80–5.97 (m, 1H). The corresponding
2, compound
3 was produced and had it displayed proton NMR
δ
ppm 2.88–2.99 (m, 4H), 3.30 (dt, J = 6.35, 1.36 Hz,
2
13
C-NMR data was as follows (Figure 3b):
δ (ppm): 135.94 (C9) 116.88 (C10), 57.42 (C8), 55.89 (C2 &
C5), 42.00 (C3 & C6) whereby we observed the significantly shifted signal of the carbon atoms attached
1
13
to the chloride. On the other hand, H- and C-NMR signals (Figures 2c and 3c) together with
1
13
the corresponding long-range H- C correlations (Figure 4) of the synthesized azacrown polyether
confirmed the proposed structure. The signal for HDO (deuterated water) due to exchange of protons
1
with the solvent deuteriums occurs at
δ
= 2.80 ppm as a singlet. Comparison of the H-NMR spectra
of the precursor compounds and those of the azacrown polyether reveals that the new signals in the
region between 6.81 ppm and 7.00 ppm are characteristic of the eight benzene protons (19, 20, 21,

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22 and 23, 24, 25, 26). The rest of the proton signals can be assigned to the allyl fragments and the
polyether ring cavity as already discussed in the precursor compounds. Integration of the signals
for all the compounds (Table 2) confirms the assignments and proves the purity of the synthesized
compounds. In 13C-NMR spectrum, the 8 chemical shifts for the crown polyether reveal 8 carbon
1
13
environments (Figure 3c). Using the HSQC ( H- C correlation) spectrum in Figure 4, the seven
protonated carbon environments were assigned according to Table 3 while the unprotonated carbons
environment (C8, C9, C17 and C18) was then assigned to δ = 148.88 ppm.
Figure 4. HSQC-NMR for the azacrown polyether macrocycle.
Table 2. Proton NMR signal integration for compounds 2–4.
Compound
2
Proton Position
Integral
Multiplicity
9
a
0.07
0.14
0.28
0.14
0.28
1
2
4
2
4
1
0a & 10b
2a, 2b, 6a, & 6b
a & 8b
a, 3b, 5a & 5b
8
3
9
a
0.07
0.14
0.28
0.28
1
2
4
4
1
0a & 10b
a, 3b, 6a & 6b
a, 2b, 5a & 5b
3
4
3
2
1
9, 20, 21, 22, 23, 24,
5 & 26
8, 31
9a, 32a
9b, 32b
, 6, 11, & 15
7 & 30
, 5, 12 & 14
0
.08
8
2
2
2
2
0.02
0.02
0.02
0.08
0.04
0.08
2
2
2
8
4
8
2
2
3

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Table 3. 13C-NMR signal assignments for the azacrown polyether.
Entry
Carbon Position
Chemical Shift (ppm)
a
b
c
Solvent (Acetone)
C3, C5, C12, C14
C27, C30
40.00
53.43
57.63
d
e
f
g
h
i
C2, C6, C11, C15
C20, C21, C24, C25
C29, C32
C19, C22, C23, C26
C28, C31
67.63
113.41
117.39
121.14
137.08
148.88
C8, C9, C17 and C18
The NMR spectroscopy clearly revealed that the synthesis of the targeted molecule was achieved.
There was no evidence revealing any impurities in the NMR spectra and the proton signal integration
matched proton populations thus proving the purity of the molecule. Further evidences were however
sought by mass spectroscopy (Figure 5) and elemental analysis (results for the latter are presented in
the Experimental Section). The mass spectrum of the macrocycle revealed several peaks: some of them
had m/z greater than the molecular mass of the synthesized compound suggesting that the ions may
have resulted from the molecular recombination within the fragmentation process.
These peaks include m/z = 461.6, 477.5, 500.8, 545.5, 671.4, and 858.4. For the analyzed peaks
we have proposed structures shown in Figure 5; they include m/z = 109.8, 167.1, 220.1, 273.9, 332.8,
+
3
74.7, 439.6. The detection of the molecular ion peak [M + H] for the azacrown polyether at m/z 439.6
confirmed its molecular mass which is 438.6 g/mol.
Figure 5. MS spectrum of the azacrown polyether macrocycle (solvent used; THF); (Inset are the
important MS fragments of the macrocycle).
Also the detection of m/z = 109.8 suggests that the compound could possibly fragment into its
starting reactant fragments—catechol and compound 3—both of which have similar m/z values. The
catechol ion fragment has been detected in a different crown ethers; dibenzo-18-crown-6 polyether [18].
Other important fragments observed at m/z 374.7, 332.8, 273.9, 220.1 and 167.1, correspond to the

Molecules 2016, 21, 171
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proposed structures suggesting the existence of compound
4
. The fragmentation pattern shows that
the ether chains are fragile under the experimental conditions leading to most of the fragmentation
patterns suggested. Similar hypothesis suggesting fragmentation patterns proceeding by the loss of
ether chain segments are in accordance with other studies relating to the synthesis of benzo-15-crown-5
moiety [24]. Furthermore, allyl fragments were not detected in the MS spectrum.
2
.2. Thermal Analysis of the Azacrown Polyether Macrocycle
Figure 1a shows the SEM image of the solid-state crystalline morphology of the macrocycle.
They are white, fibrous needle-like crystals. In terms of its thermal properties, the melting point and
crystallization temperatures were determined by means of a heating and cooling scan in differential
˝
scanning calorimetry (Figure 6a). The crystallization temperature was 81.45 C (
˘
0.03) while the
˝
melting point was precisely determined to be 124.00 C (
˘
0.17) in the second heating run and could
be verified using a melting point apparatus. The enthalpy of fusion (Hfus) was calculated to be
0.63 kJ/mol while the crystallization enthalpy change was 36.27 kJ/mol. The sharp melting and
crystallization temperatures are consistent with high purity of the synthesized compound. The thermal
stability of the azacrown ether was also determined using TGA. The thermograms are shown in
Figure 6b. The TGA data shows that there is only one major degradation step at 340 C and it is
4
´
˝
˝
accompanied by a complete weight loss of the whole molecule above 400 C. The onset of degradation
at 290 C demonstrates that no decomposition occurs before its melting temperature at 124.0 C.
˝
˝
Figure 6.
(a) DSC heating and cooling thermogram (b) TGA and DTG curves of the azacrown
polyether macrocycle.
3
. Experimental Section
3
.1. General Information
The melting point of the crown ether was initially determined using a B-540 Melting Point
apparatus (Büchi, Flawil, Switzerland) equipped with capillary tubes and programmable temperature
control. Differential scanning calorimetry was used as a main tool to confirm this m.p as well as
the crystallization temperature using a DSC-8500 instrument (Perkin-Elmer, Rodgau, Germany) with
˝
samples (4–5 mg) sealed in high-pressure steel pans. The DSC temperature ramp was 10 C/min
under N flow of 20 mL/min while TGA data was recorded on a Pyris 1 thermo-gravimetric analyzer
2
˝
Perkin-Elmer) at 10 C/min under N flow. H- and C-NMR as well as 2D-NMR were recorded
2
1
13
(
using an Avance DPX 300 MHz nuclear magnetic resonance spectrometer (Bruker, Wien, Austria)
with acetone-d as solvent. For elemental analysis, dried samples were analyzed on a Vario elemental
6
analyzer (Elementar Analysensysteme GmbH, Hanau, Germany). FT-IR was performed on ATR crystal
mode on a FT-IR spectrometer 65 (Perkin Elmer, Waltham, MA, USA) using 32 scans at a resolution of

Molecules 2016, 21, 171
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2
cm 1. The electronic spectra of the macrocycle polyether were recorded in the region 700–200 nm
´
using a PerkinElmer double beam model Lambda 35 spectrometer with a quartz cell of 1 cm path
length in cyclohexane. Bis(2-hydroxyethyl)amine, allyl bromide, thionyl chloride and catechol were
purchased from Sigma-Aldrich (Munich, Germany) and used without further purification. Potassium
carbonate, sodium hydroxide pellets, n-butanol, acetone, methanol, diethyl ether and all other solvents
were reagent grade and used without further purification.
3
.2. Synthesis of the Azacrown Polyether Macrocycle
1
3
.2.1. Synthesis of 2,2 -(Prop-2-en-1-ylimino)diethanol (2)
Bis(2-hydroxyethyl)amine (105.14 g, 1.0 mol) was mixed with potassium carbonate (1.00 mol)
in a three-neck round-bottomed flask under mechanical stirring. 3-Bromopropene (allyl bromide,
21.0 g, 1.00 mol) was added dropwise by means of a dropping funnel over a period of 1–2 h. The
reaction between the bis(2-hydroxyethyl)amine and the allyl bromide was allowed to proceed for 6 h
1
˝
˝
at 170 C under reflux. The reaction mixture was cooled to 70 C, dissolved in ethanol (100 mL) and
˝
filtered. The filtered solution was distilled under vacuum and collected at 111 C/1000 mbar. Yield
10.8 g (76.3%), as a yellowish viscous oil. H-NMR (acetone-d )
1
1
δ
(ppm): 2.65 (t, J = 5.74 Hz, 4H), 3.21
6
(
1
1
dt, J = 6.42, 1.32 Hz, 2H), 3.57 (t, J = 5.74 Hz, 4H), 5.08–5.15 (m, J = 19.9 Hz, 1H), 5.20 (dq, J = 17.22,
13
.71 Hz, 1H), 5.90 (m, J = 17.00, 10.35, 6.57, 6.57 Hz, 1H). C-NMR (acetone-d )
δ
(ppm): 135.27 (C9),
6
´
1
16.42 (C10), 59.50 (C2, 6), 57.78(C8), 56.08 (C3, C5); IR (ν/cm ): 3080 (alkene =C-H stretch), 2947
and 2828 (methylene stretch), 1642 (C=C stretch), 1450, (aliphatic C-H bend), 1354 and 1141 (C-N
stretch aliphatic amines), 1060 (C-OH stretch), 921 (=C-H bend alkenes); Anal. Cacl. for C H NO
7
15
2
(145.2 g/mol): C, 57.90; H, 10.41; N, 9.65; O, 22.04. Found. C, 57.60; H, 10.64; N, 9.57.
1
.2.2. Synthesis of N,N -Bis(2-chloroethyl)prop-2-en-1-amine (3)
3
1
The chlorinated product N,N -bis(2-chloroethyl)prop-2-en-1-amine (
3) was obtained by reaction of
2
with thionyl chloride in chloroform solution. In details, a 1.03% w/v solution of
2
(102.80 g equivalent
to 0.71 mol) in chloroform (100 mL) was carefully added by means of a dropping funnel to ice-cooled
warning!: the reaction is very exothermic) thionyl chloride (1.42 mol, 168.76 g) contained in a two-neck
round-bottomed flask. After all the funnel contents had been added, the ice bath was replaced with a
(
˝
water bath set at 40 C and the reaction was continued at reflux for 4 h with magnetic stirring. Then,
˝
the reactor flask was cooled to room temperature (~23 C) and distilled to remove excess SOCl and
chloroform. The entire contents of the reaction were then put under an ice bath and cooled to 0 C.
2
˝
NaOH (2.5 M, 100 mL) was then added to the reactor. The pH of the mixture was adjusted to neutral
with saturated solution of sodium carbonate, leading to two immiscible liquid phases. The oily layer
was separated from the aqueous one by mean of a separatory funnel and afterwards distilled under
˝
pressure. A clear liquid distillate was obtained at 78–79 C/1000 mbar with a total yield of 91.6%
118.15 g). The N,N -bis(2-chloroethyl)prop-2-en-1-amine product was designated as compound 3.
(
'
˝
It was used immediately for the next reaction or stored in a brown glass bottle and kept under 4 C.
1
H-NMR (acetone-d )
δ
ppm 2.88–2.99 (m, 4 H), 3.30 (dt, J = 6.35, 1.36 Hz, 2 H), 3.56–3.66 (m, 4 H),
.10–5.20 (m, 1 H), 5.22–5.32 (m, 1 H), 5.80–5.97 (m, 1 H). 13C-NMR (DMSO-d )
ppm: 135.94 (C9),
/cm ): 3080 (alkene =C-H stretch), 2957
and 2816 (methylene stretch), 1642 (C=C stretch), 1450, (aliphatic C-H bend), 1257 (C-Hwag of the
CH Cl), 1354 and 1107 (aliphatic amine C-N stretch), 921 (alkene =C-H bend), 740 (C-Cl stretch); Anal.
6
5
1
δ
6
´
1
16.88 (C10), 57.42 (C8), 55.89 (C3, C6), 42.03 (C2, C5); IR (ν
-
2
Calc. for C H Cl N (182.1 g/mol): C, 46.17; H, 7.20; N, 7.69; Cl, 38.94. Found. C, 46.13; H, 7.48;
7
13
2
N, 7.65.
1
3
.2.3. Synthesis of N,N -Diallyl-7,16-diaza-1,4,10,13-tetraoxa-dibenzo-18-crown-6 (4)
A dry, 2-L, three-necked flask was fitted with a reflux condenser, a 250-mL, pressure-equalizing
dropping funnel, and a nitrogen inlet tube. The flask was charged with catechol (110.11 g, 1.00 mol)

Molecules 2016, 21, 171
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and n-butanol (300 mL) before stirring was started, and sodium hydroxide pellets (40 g, 1.00 mol) were
˝
added. The mixture was rapidly heated to reflux at ~115 C thereby producing the corresponding salt of
the catechol (sodium catecholate). Afterwards, a solution of N,N-bis(2-chloro- ethyl)prop-2-en-1-amine
(3, 91.05 g, 0.50 moles) in n-butanol (90 mL) was added dropwise with continuous stirring and heating
over a 2 h period. After the resulting mixture had been refluxed with stirring for an additional hour, it
˝
was cooled to 90 C and another 40 g of NaOH pellets were added. The mixture was further refluxed
for 30 min, and another solution of (91.05 g 0.50 moles) in n-butanol (90 mL) was added dropwise
with continuous stirring and heating over 2 h period. Finally, the reaction mixture was refluxed for
1 h, then acidified by the dropwise addition of concentrated hydrochloric acid (7 mL) The reflux
3
2
condenser was replaced with a distillation column and approximately 250 mL of solvent was distilled
from the mixture. As the distillation was continued water was added to the flask from the dropping
funnel at a sufficient rate to maintain a constant volume in the reaction flask. The distillation was
˝
continued until the temperature of the distilling vapor reached ~100 , and the resulting slurry was
cooled to room temperature to precipitate. The solid was dissolved in acetone (250 mL) and stirred
to coagulate it and then filtered off on a glass frit. The residual crude was stirred with 1 L of water,
˝
decanted and recrystallized three times from acetone and dried at 60 C to yield 91.38 g (42.0%) of
˝
1
white fibrous crystals, m.p. 124 C; UV (cyclohexane) λmax (log
acetone-d6) ppm 3.22 (t, J = 6.07 Hz, 8 H), 3.34 (dt, J = 6.22, 1.44 Hz, 4 H), 4.12 (t, J = 6.23 Hz, 8 H),
.09–5.20 (m, 2 H), 5.20–5.34 (m, 2 H), 5.85–6.04 (m, 2 H), 6.81–7.00 (m, 8 H); 13C-NMR (acetone-d6)
ppm: 148.88 (C28, C31), 137.08 (C29, C32), 121.14 (C8, C9, C17, C18), 117.39 (C19, C22, C23, C26) 113.41
ε) 236 (2.82), 278 (2.55) nm; H-NMR
(
δ
5
δ
´
1
(
C20, C21, C24, C25) 67.63 (C2, C6, C11, C15), 57.63 (C27, C30), 53.4 (C3, C5, C12, C14); IR (
068 (aromatic C-H stretch), 2926 and 2855 (methylene stretch), 1634 (C=C stretch), 1596, 1496 and 1456
C=C aromatic ring stretch), 1334 and 1120 (C-N stretch), 1238 (aryl-O-CH2 stretch), 1024 (in-plane
C-H bend), 728 (out-of-plane C-H bend); Anal. Calc. for C H N O (438.6 g/mol): C, 71.21; H, 7.81;
ν/cm ):
3
(
26
34
2
4
N, 6.39; O, 14.59. Found C, 71.03; H, 7.82; N, 6.22.
4
. Conclusions
In this paper we have described an optimized and scaled-up synthesis of the bibracchial
1
lariat azacrown ether N,N -diallyl-7,16-diaza-1,4,10,13-tetraoxa-dibenzo-18-crown-6. The production
scale-up to one-mole batch of reactants is demonstrated in yields up to 35%–45%. This is a large
improvement compared to the prior art, where batch sizes of ~0.1 moles and yields of about 3%–6%
are obtained. The improvement is made possible by implementing a two-step addition of strong base
under anhydrous conditions to improve the cyclization process. The combination of neutralization
of the reaction mixture and distillation of the excess solvent and its subsequent replacement with
distilled water was key in the formation of a high purity precipitate that crystallizes from acetone.
The convergent results obtained by elemental analysis, FTIR, UV-Vis, NMR MS, and thermal analysis
allowed us to confirm the structural formula of the crown ether and its purity. With the availability of
a new synthesis on a larger scale and the good yields of this azacrown ether, its use in supramolecular
chemistry and ion-selective complexation is made possible.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/
2
1/2/171/s1.
Acknowledgments: The authors gratefully acknowledge the financial support of the German Federal Ministry of
Education and Research (Grant No. 8454), the National Council of Science and Technology (NACOSTI, Kenya)
and the Germany Academic Exchange Program (DAAD). The article processing charge was funded by the Open
Access Publication Fund of the Albert Ludwigs University of Freiburg.
Author Contributions: Julius Toeri conceived and designed the experiments. Marie-Pierre Laborie guided the
experiments and evaluated the data. Julius Toeri and Marie-Pierre Laborie wrote the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2016, 21, 171
11 of 12
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Sample Availability: Samples of the compounds 2´4 are available from the authors.
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(