Synthesis of tris-(azacrown) ethers for carboxylic acid recognition

Article abstract of DOI:10.1016/j.tet.2012.10.067

The synergistic enhancement of metal ion extraction by azacrown ethers in the presence of carboxylic acids has been attributed to a ligand assembly effect in which these two ligands form a complex, facilitated by proton transfer, prior to complexation of the metal ion. In order to investigate the first steps in this multi-component complexation procedure, six tris-(azacrown) ethers were synthesised in high yields and their ability to complex mono- and tri-carboxylic acids was investigated by ¹H NMR in methanol-d₄. All six compounds bound to benzoic acid with 1:3 host-guest stoichiometry and four of them bound tricarboxylic acids with 1:1 host-guest stoichiometry, providing good support for the proposed first step in the ligand assembly effect.

Full text of DOI:10.1016/j.tet.2012.10.067

Tetrahedron 69 (2013) 38e42
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Tetrahedron
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Synthesis of tris-(azacrown) ethers for carboxylic acid recognition
y
z
*
Michael Lee, Hassan Zali-Boeini , Feng Li , Leonard F. Lindoy, Katrina A. Jolliffe
School of Chemistry, The University of Sydney, 2006, NSW, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2012
Received in revised form 3 October 2012
Accepted 23 October 2012
Available online 30 October 2012
The synergistic enhancement of metal ion extraction by azacrown ethers in the presence of carboxylic
acids has been attributed to a ligand assembly effect in which these two ligands form a complex, fa-
cilitated by proton transfer, prior to complexation of the metal ion. In order to investigate the first steps
in this multi-component complexation procedure, six tris-(azacrown) ethers were synthesised in high
yields and their ability to complex mono- and tri-carboxylic acids was investigated by 1H NMR in
methanol-d4. All six compounds bound to benzoic acid with 1:3 hosteguest stoichiometry and four of
them bound tricarboxylic acids with 1:1 hosteguest stoichiometry, providing good support for the
proposed first step in the ligand assembly effect.
Keywords:
Azacrown ether
Supramolecular chemistry
Molecular recognition
Tripodal receptor
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
However, only a few investigations of this type of association
between carboxylic acids and azacrown ethers have been reported
The ability of crown ethers and azacrown ethers to selectively
bind metal ions and (alkyl)ammonium ions has been widely
studied.1e7 Given their unique properties, these compounds are
frequently used in the formation of supramolecular and super-
molecular structures and a number of molecular hosts containing
multiple (aza)crowns have been investigated.8e18 They have been
employed as selective hosts for a wide range of guest molecules
and ions and many systems have been investigated as selective
extractants/ionophores in solvent extraction and/or bulk mem-
brane transport studies.19 In this context, it has been found that
synergistic enhancement of ion extraction can occur when aza-
crown ethers are employed in combination with carboxylic acid
derivatives.20 This synergy has been attributed to the assembly of
components required to occupy the coordination sphere of the
metal, prior to metal binding and termed the ‘ligand assembly
effect’ (Scheme 1).21e23 The first step in the ligand assembly effect
requires binding to occur between the azacrown ether and a car-
boxylic acid, facilitated by proton transfer between the acid and
amino groups, which results in the formation of both hydrogen
bonds and electrostatic interactions between the two species.23
previously and these have focused on single macrocycles.22,23 In
order to investigate this effect, we have designed a number of tris-
azacrown derivatives, which are expected to have multiple in-
teractions with appropriate tricarboxylic acids. We report here the
synthesis of these compounds and our preliminary investigations
into the ability of these compounds to bind to tricarboxylic acid
derivatives.
2. Results and discussion
Tripodal molecular receptors have frequently been observed to
provide multiple interactions with suitable guests and thus provide
stronger hosteguest interactions.24 We therefore designed tripodal
tris-azacrown derivatives to investigate the ability of the ligand
assembly effect to preorganise these polytopic systems for the
transport of multiple metal ions. 1,3,5-Substituted-benzene, -2,4,6-
trimethylbenzene and -2,4,6-triethylbenzene derivatives were se-
lected as ‘cores’ for the synthesis of a series of tripodal receptors to
enable an investigation of the effect of steric gearing25 on the
molecular recognition process. It was anticipated that an increase
in scaffold preorganisation, as expected for the sterically geared
2,4,6-triethylbenzene derivative25,26 would lead to improved rec-
ognition of an appropriately sized guest molecule.
* Corresponding author. Tel.: þ61 2 9351 2297; fax: þ61 2 9351 3329; e-mail
addresses: kate.jolliffe@sydney.edu.au, jolliffe@chem.usyd.edu.au (K.A. Jolliffe).
Reaction of either 1-aza-15-crown-5 (1) or 1-aza-18-crown-6
(2) with the appropriate tribromide 3e5 in the presence of Na2CO3
gave the tris-azacrown derivatives 6e11 in excellent yields
(93e95%) (Scheme 2).27
y
Current address: Department of Chemistry, University of Isfahan, 81746-73441
Isfahan, Iran.
z
Current address: School of Science and Health, University of Western Sydney,
Locked Bag 1797, Penrith 2751, NSW, Australia.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.067

M. Lee et al. / Tetrahedron 69 (2013) 38e42
39
Scheme 1. The ligand assembly effect: (a) formation of a hosteguest complex between a macrocycle and an organic acid. (b) Coordination of a metal ion in the hosteguest complex,
accompanied by the displacement of protons (X¼NR0, O or S. R0¼alkyl or aromatic group.).
Table 1
Apparent stability constants (Ka; Mꢀ1
) of the tris-azacrown ethers 6e11 for
tricarboxylic acids 12e14 determined by 1H NMR titration in methanol-d4 at 298 K,
following the protons adjacent to the azacrown nitrogen atom. Data fitted to a 1:1
binding model. Errors <15%
12
13
14
6
7
8
9
10
11
600
120
1010
470
da
330
430
670
880
da
115
140
70
190
da
da
da
da
a
Data could not be fit to 1:1, 1:2 or 1:3 hosteguest binding models.
downfield shifts of similar magnitude were also observed for the
aromatic protons in the case of receptors 6 and 7. Titration data for
compounds 6e9 fit well to a 1:1 binding model. The 1:1 stoichi-
ometry was confirmed by Job plots of the complexes with 6 and 7
(Fig. 1). However, data for the 2,4,6-triethylbenzene derivatives 10
and 11 could not be fit to a simple binding model, suggesting the
presence of multiple equilibria in solution. It appears that, in this
case, steric gearing does not provide improved recognition, but
instead the increased steric bulk around the benzene core in 10 and
11 results in the formation of complexes with different stoichi-
ometry to that observed for complexes of 6e9 with the same
guests. Given the multiple recognition sites present in both the
tripodal hosts and tricarboxylic acid guests, it is possible that
oligomeric complexes form in these cases. However, it was not
possible to determine the exact nature of the species formed. In all
cases, the apparent stability constants for complexes between the
0.20
0.16
0.12
0.08
0.04
0.00
Scheme 2. Synthesis of tris-azacrown ethers 6e11.
To determine whether the tris-azacrown ether derivatives
would bind to carboxylic acids, 1H NMR titrations were performed
in methanol-d4 solution with trimesic acid (12), citric acid (13),
Kemp’s triacid (14), and benzoic acid (15). Apparent stability con-
stants were obtained by non-linear curve fitting of the resulting
data using WinEQNMR2 computer software (Table 1).28 In all cases,
addition of tricarboxylic acids 12e14 to 6e11 resulted in downfield
shifts of the signals attributable to the protons adjacent to the
azacrown nitrogen atoms (Dd¼0.5e0.6 ppm in all cases), as would
be expected if this nitrogen atom is protonated. Additional
0.00
0.25
0.50
χ(Host)
0.75
1.00
Fig. 1. Job plot for the complex between receptor 7 and trimesic acid 12 showing the
observed 1:1 stoichiometry (ꢁ¼signal for protons adjacent to nitrogen atom; ꢂ¼signal
for protons on aromatic ring).

40
M. Lee et al. / Tetrahedron 69 (2013) 38e42
2,4,6-trimethylbenzene derivatives, 8 and 9, were higher than
those observed for the corresponding benzene derivatives 6 and 7
for the same carboxylic acids, suggesting that some preorganisation
of the scaffold is imposed by the methyl substituents. Similar effects
have been observed with other 1,3,5-substituted-2,4,6-
trimethylbenzene derived receptors.29 Of the tricarboxylic acid
guests, the 15-azacrown-5 derivatives 6 and 8 had binding affinity
in the order trimesic acid>citric acid>Kemp’s triacid, while the 18-
azacrown-6 derivatives 7 and 9 bound citric acid with higher af-
finity than trimesic acid. This may reflect the slightly larger size of 7
and 9 (compared to 6 and 8), which can better accommodate the
large and flexible citric acid guest. The relatively low affinity ob-
served for Kemp’s triacid with all receptors may be attributed to the
preferred all-axial conformation of the protonated form of this
acid,30 which is a poor geometric match to the tris-azacrown
receptors.
4. Experimental
4.1. General
Infrared absorption spectra were obtained using a Shimadzu
FTIR-8400S spectrometer as a thin film between sodium chloride
plates. NMR spectra were recorded on a Bruker Avance DPX 300
spectrometer. The solvent 1H and 13C signals, dH 3.31 and dC 49.0 for
methanol-d4 were used as internal references. Low resolution mass
spectra were recorded on a Finnigan LCQ ion trap mass spectrom-
eter (ESI). High resolution mass spectra were recorded on a BioApex
Fourier Transform Ion Cyclotron Resonance Mass Spectrometer
(ESI). Preparative column chromatography was carried out using
neutral aluminium oxide (Brockmann 1 standard grade w150
mesh) with the indicated solvents (v/v). Compounds 1,32 233 and
333 were prepared according to literature procedures.
4.2. 1,3,5-Tris[(10-aza-40,70,100,130-tetraoxapentadec-10-yl)met-
hyl]benzene (6)
A mixture of 1 (0.20 g, 0.56 mmol), 1-aza-15-crown-5 (0.43 g,
2.0 mmol) and sodium carbonate (0.52 g, 5.0 mmol) in dry aceto-
nitrile (15 mL) was stirred at room temperature under an atmo-
sphere of nitrogen for 20 h. The mixture was then heated at reflux
for 4 h. After cooling, the mixture was filtered and the filtrate was
evaporated under reduced pressure. The residue was purified by
column chromatography (9:1 v/v chloroform/methanol elution), to
give 6 (0.41 g, 95%) as a yellow oil. Found: [MþH]þ, 772.4954.
C39H70N3O12 requires 772.4959; found: C, 59.5; H, 9.1; N, 5.3.
C39H69N3O12$H2O requires C, 59.3; H, 9.1; N, 5.3%; 1H NMR
For comparison, compounds 6e11 were also titrated with ben-
zoic acid and in all cases the data fit to a 3:1 guestehost binding
model using WinEQNMR2. Stepwise stability constants indicate
that, in all cases, while binding of the first benzoic acid guest is
appreciable (K1¼760e1500 Mꢀ1), the apparent stability constants
for binding of the second and third benzoic acid guests are low
(K2¼10e50; K3ꢃ5). This reflects the increased difficulty in succes-
sive proton transfers upon addition of the second and third benzoic
acids. Potentiometric titrations indicated that while the first pro-
tonation constants (pKa1) for 6e11 are 8.51e9.36, which fall in the
expected range for azacrown ethers (previously reported pKa for 4
[9.17; 5¼9.28; in 95% methanol31); the second protonation con-
stants (pKa2) are 7.06e8.05 and the third protonation constants
(pKa3) vary from 3.28 to 6.79, depending on the substituents
present on the benzene ring and the size of the azacrown ether. The
differences in binding affinities between benzoic acid 15 and the
tricarboxylic acids 12e14 provides further evidence that binding of
the tricarboxylic acids occurs through interactions with more than
one of the azacrown units on each receptor. The lower affinity
observed for the tricarboxylic acids reflects the reorganisation re-
quired of the tripodal hosts 6e11 to accommodate these guests
though interactions with multiple azacrowns.
(300 MHz, CD3OD) d 7.24 (s, 3H), 3.69e3.58 (complex m, 54H), 2.77
(t, J¼5.8 Hz, 12H); 13C NMR (75.5 MHz, CD3OD)
d 139.9 (C), 130.5
(CH), 71.7 (CH2), 71.13 (CH2), 71.07 (CH2), 71.4 (CH2), 61.4 (CH2), 55.1
(CH2); IR nmax (NaCl)/cmꢀ1 3433 (m), 2864 (s), 1122(s); MS (ESI) m/z
794 [(MþNa)þ, 5%] 772 (100).
4.3. 1,3,5-Tris[(10-aza-40,70,100,130,160-pentaoxaoctadec-10-yl)
methyl]benzene (7)16
A mixture of 1 (0.20 g, 0.56 mmol), 1-aza-18-crown-6 (0.50 g,
1.9 mmol) and sodium carbonate (0.52 g, 5.0 mmol) in dry aceto-
nitrile (15 mL) was stirred at room temperature under an atmo-
sphere of nitrogen for 20 h. The mixture was then heated at reflux
for 4 h. After cooling, the mixture was filtered and the filtrate was
evaporated under reduced pressure. The residue was purified by
column chromatography (9:1 v/v chloroform/methanol elution), to
give 7 (0.47 g, 93%) as a yellow oil. Found: [MþH]þ, 904.5741.
C45H82N3O15 requires 904.5746; found: C, 55.2; H, 8.8; N, 4.3.
C45H81N3O15$4H2O requires C, 55.4; H, 9.2; N, 4.3%; 1H NMR
(300 MHz, CD3OD)
d 7.26 (s, 3H), 3.73e3.63 (complex m), 2.80 (t,
J¼5.3 Hz, 12H); 13C NMR (75.5 MHz, CD3OD)
d 139.7 (C), 130.6 (CH),
3. Conclusions
71.6 (CH2), 71.5 (CH2), 71.3 (CH2), 70.3 (CH2), 60.5 (CH2), 54.7 (CH2),
one signal obscured or overlapping; IR nmax (NaCl)/cmꢀ1 3495 (m),
2867 (s), 1116 (s); MS (ESI) m/z 927 [(MþNa)þ, 10%] 905 (100) 657
(10).
In summary, six tris-(azacrown) ethers 6e11 have been syn-
thesised in excellent yields. The ability of the tri-azacrown ethers to
bind to carboxylic acids has been investigated by 1H NMR titrations
in methanol-d4. All six compounds 6e11 were found to bind to
benzoic acid to give 1:3 hosteguest complexes. Compounds 6e9
were also found to bind to triscarboxylic acids with 1:1 stoichi-
ometry. These results support the proposed first step in the ligand
assembly effect, which requires that the carboxylic acid and aza-
crown ether form a complex in which proton transfer occurs. Fur-
ther studies on the ability of these complexes to bind alternative
guests, such as dicarboxylic acids, are in progress and studies on the
ability of these complexes to bind to metal ions will be reported in
due course.
4.4. 1,3,5-Tris[(10-aza-40,70,100,130-tetraoxapentadec-10-yl)meth-
yl]-2,4,6-trimethylbenzene (8)
A mixture of 2 (0.15 g, 0.38 mmol), 1-aza-15-crown-5 (0.26 g,
1.2 mmol) and sodium carbonate (67 mg, 0.64 mmol) in dry ace-
tonitrile (15 mL) was stirred at room temperature under an atmo-
sphere of nitrogen for 20 h. The mixture was then heated at reflux
for 15 h. After cooling, the mixture was filtered and the filtrate was
evaporated under reduced pressure. The residue was purified by
column chromatography (9:1 v/v chloroform/methanol elution), to

M. Lee et al. / Tetrahedron 69 (2013) 38e42
41
give 8 (0.29 g, 95%) as a yellow oil. Found: (MþH)þ, 814.5424.
C42H76N3O12 requires 814.5429; found: C, 61.68; H, 9.15; N, 5.12.
C45H75N3O12$0.25H2O requires C, 61.63; H, 9.30; N, 5.13%; 1H NMR
overlapping; IR nmax (NaCl)/cmꢀ1 3459 (s), 2867 (s),1117 (s); MS (ESI)
m/z 991 [(MþH)þ, 15%] 990 (100) 726 (5), 462 (3).
(300 MHz, CD3OD)
d
3.75e3.53 (complex m, 54H), 2.74 (t, J¼5.8 Hz,
4.8. NMR titrations
12H), 2.47 (s, 9H); 13C NMR (75.5 MHz, CD3OD)
d
139.1 (C), 135.1 (C),
72.3 (CH2), 71.9 (CH2), 71.5 (CH2), 56.3 (CH2), 55.5 (CH2), 17.6 (CH3),
one signal overlapping; IR nmax (NaCl)/cmꢀ1 3494 (w), 2863 (s),
1127 (s); MS (ESI) m/z 816 [(MþH)þ, 50%] 815 (100) 595 (10).
For trimesic, citric and benzoic acids, small aliquots of a solution
of acid/ligand (0.250 M/0.005 M) in methanol-d4 were added to
a solution of ligand (0.005 M) in methanol-d4 in an NMR tube and
1H NMR spectra were obtained after each addition. For Kemp’s
triacid, the acid was added in small portions as a solid to an NMR
tube containing the ligand (0.005 M). Data were analysed using
WinEQNMR2.28
4.5. 1,3,5-Tris[(10-aza-40,70,100,130,160-pentaoxaoctadec-10-yl)
methyl]-2,4,6-trimethylbenzene (9)
A mixture of 2 (0.13 g, 0.33 mmol), 1-aza-18-crown-6 (0.27 g,
1.03 mmol) and sodium carbonate (58 mg, 0.55 mmol) in dry
acetonitrile (15 mL) was stirred at room temperature under an at-
mosphere of nitrogen for 20 h. The mixture was then heated at
reflux for 4 h. After cooling, the mixture was filtered and the filtrate
was evaporated under reduced pressure. The residue was purified
by column chromatography (9:1 v/v chloroform/methanol elution),
to give 9 (0.29 g, 95%) as a pale yellow oil. Found: (MþH)þ,
946.6211. C48H88N3O15 requires 946.6215; found: C, 60.75; H, 9.49;
N, 4.36. C48H87N3O15$0.25H2O requires C, 60.64; H, 9.28; N, 4.42%;
4.9. Potentiometric titrations
The protonation constants were determined by potentiometric
(pH) titration. All measurements were performed in 95% methanol
at 25ꢄ0.1 ꢅC (I¼0.1; NEt4ClO4) under the same conditions as de-
scribed previously.34 Data are the average of two individual de-
terminations and were processed using
a local version of
MINIQUAD.35
1H NMR (300 MHz, CD3OD)
d 3.74e3.52 (complex m, 66H), 2.72 (t,
J¼5.8 Hz,12H), 2.47 (s, 9H); 13C NMR (75.5 MHz, CD3OD)
d 138.8 (C),
Acknowledgements
134.6 (C), 71.9 (CH2), 71.8 (CH2), 71.7 (CH2), 71.3 (CH2), 55.4 (CH2),
54.7 (CH2), 17.2 (CH3), one signal overlapping; IR nmax (NaCl)/cmꢀ1
3511 (w), 2864 (s), 1119 (s); MS (ESI) m/z 948 [(MþH)þ, 40%] 947
(100) 684 (10).
We thank the Australian Research Council for funding
(DP0555883).
References and notes
4.6. 1,3,5-Tris[(10-aza-40,70,100,130-tetraoxapentadec-10-yl)
methyl]-2,4,6-triethylbenzene (10)
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A mixture of 3 (1.10 g, 2.5 mmol), 1-aza-15-crown-5 (1.76 g,
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mosphere of nitrogen for 20 h. The mixture was then heated at
reflux for 4 h. After cooling, the mixture was filtered and the filtrate
was evaporated under reduced pressure. The residue was purified
by column chromatography (9:1 v/v chloroform/methanol elution),
to give 10 (2.03 g, 95%) as a yellow oil. Found: (MþH)þ, 856.5894.
C45H82N3O12 requires 856.5899; found: C, 62.2; H, 9.6; N, 4.7.
C45H81N3O12$0.5H2O requires C, 62.5; H, 9.55; N, 4.9%; 1H NMR
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(300 MHz, CD3OD)
d
3.76e3.51 (complex m, 54H), 3.10 (q, J¼7.3 Hz,
6H) 2.75 (t, J¼5.5 Hz, 12H), 1.09 (t, J¼7.3 Hz, 9H); 13C NMR
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overlapped), 71.1 (CH2), 55.2 (CH2), 54.3 (CH2), 23.2 (CH2), 16.4
(CH3); IR nmax (NaCl)/cmꢀ1 3481 (m), 2865 (s), 1126 (s); MS (ESI) m/z
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column chromatography (9:1 v/v chloroform/methanol elution), to
give 11 (2.08 g, 93%) as a pale yellow oil. Found: (MþH)þ, 988.6680.
C51H94N3O15 requires 988.6685; found: C, 58.7; H, 9.2; N, 4.0.
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(300 MHz, CD3OD)
d
3.70e3.52 (complex m, 66H), 3.10 (q, J¼7.3 Hz,
6H) 2.75 (t, J¼5.5 Hz,12H),1.09 (t, J¼7.3 Hz, 9H); 13C NMR (75.5 MHz,
CD3OD) d 146.1 (C),133.3 (C), 71.9 (CH2), 71.75 (CH2), 71.71 (CH2), 71.4
(CH2), 54.8 (CH2), 53.8 (NCH2), 23.2 (CH2), 16.5 (CH3), one signal

42
M. Lee et al. / Tetrahedron 69 (2013) 38e42
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