Selective transmembrane carriers for hydroxycarboxylic acids: Influence of a macrocyclic calix[4]arene platform

Article abstract of DOI:10.1016/j.mencom.2012.03.009

Selective transmembrane carriers for a-hydroxy acids, acyclic a-amino phosphonates and calix[4]arenes containing a-aminophosphonate substituents at the lower rim have been synthesized; analytical HPLC has been used to monitor the selective separation of dicarboxylic, a-hydroxy and a-amino acid mixtures by membrane extraction; the attachment of a-aminophosphonate fragments to the macrocyclic calix[4]arene platform results in receptors with markedly modified efficiency and selectivity relative to those of only aminophosphonates.

Full text of DOI:10.1016/j.mencom.2012.03.009

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 80–82
Selective transmembrane carriers for hydroxycarboxylic
acids: influence of a macrocyclic calix[4]arene platform
Maria N. Agafonova, Olga A. Mostovaya, Igor S. Antipin, Alexander I. Konovalov and Ivan I. Stoikov*
A. M. Butlerov Chemical Institute, Kazan (Volga Region) Federal University, 420008 Kazan, Russian Federation.
Fax: +7 8432 92 4330; e-mail: ivan.stoikov@mail.ru
DOI: 10.1016/j.mencom.2012.03.009
Selective transmembrane carriers for a-hydroxy acids, acyclic a-amino phosphonates and calix[4]arenes containing a-aminophosphonate
substituents at the lower rim have been synthesized; analytical HPLC has been used to monitor the selective separation of dicarboxylic,
a-hydroxy and a-amino acid mixtures by membrane extraction; the attachment of a-aminophosphonate fragments to the macrocyclic
calix[4]arene platform results in receptors with markedly modified efficiency and selectivity relative to those of only aminophosphonates.
Phosphoryl compounds functionalized by oxygen- and nitrogen-
containing substituents in the a- and b-positions relative to the
phosphorus atom are of considerable current interest.1–8 They
can be used as improved extraction agents and carriers.3,9–18
Acyclic amino phosphoryl compounds with various substi-
tuents can selectively bind oxalic acid amongst a series of struc-
turally similar dicarboxylic acids.19 The combination of different
binding sites, namely, a proton donor (NH) and two proton
acceptors (P=O and a lone electron pair on the N atom) and the
possibility of varying the lipophilicity and steric hindrance of
the binding sites make these compounds potentially versatile
receptor molecules.20–23 Thus, it is promising to investigate the
influence of a calix[4]arene macrocyclic platform on the com-
plexation properties of a-aminophosphoryl derivatives towards
a series of dicarboxylic, a-hydroxy- and a-amino acids. In this
work, the complexation properties of aminophosphonates 1 and
2 with alkyl or aryl fragments towards such organic acids are
compared with those of 1,3-disubstituted calix[4]arenes 3 and 4
containing similar a-aminophosphonate groups at the lower rim.
Acyclic a-aminophosphonates 1 and 2 were synthesized by
the Kabachnik–Fields reaction (Scheme 1).†
O
O
C18H37 NH
R1
O
H
P(OEt)2
+
C18H37NH2 + (EtO)2P
R1
R2
R2
1 R1 = R2 = Me
2 R1 = Ph, R2 = H
Scheme 1
Table 1 Mass transfer flux (ji/kmol m–2 s–1) of substrates 5–13 through a
liquid-impregnated membrane (25°C).
Substrate pKa j0a
j1b
1.3×10–11 1.8×10–11 2.0×10–11 1.4×10–11 1.5×10–11
1.25 5.0×10–12 3.3×10–9 6.6×10–9 1.6×10–10 5.2×10–12
j2b
j3b
j4b
Sodium
—
acetate 5
Oxalic
acid 6
Aspartic 1.99 5.7×10–12 2.5×10–11 4.6×10–11 2.3×10–11 4.0×10–10
acid 7
Glutamic 2.10 2.8×10–12 3.8×10–11 4.2×10–11 3.0×10–12 2.9×10–12
acid 8
Malonic
acid 9
Tartaric
2.85 2.9×10–11 1.4×10–8 1.3×10–8 3.6×10–10 6.1×10–11
3.03 4.4×10–11 1.9×10–9 2.4×10–9 5.8×10–9 4.2×10–10
Transport through lipophilic liquid membranes induced by
compounds1and2wasstudiedfordicarboxylicanda-substituted
carboxylic acids. To estimate the influence of the carboxylate
function, as distinct from that of the carboxylic acid unit, the
membrane extraction of sodium acetate was studied.‡
acid 10
Mandelic 3.37 1.5×10–9 4.4×10–8 3.5×10–8 1.5×10–8 1.7×10–9
acid 11
Glycolic 3.83 9.4×10–12 5.6×10–10 5.5×10–10 4.5×10–10 1.5×10–10
acid 12
Succinic 4.21 1.3×10–11 3.9×10–9 3.8×10–9 2.9×10–10 1.6×10–9
Table 1 summarizes the fluxes of substrates 5–13. A com-
parison of the mass transfer data with that for control experiments
acid 13
a Mass transfer flux through a liquid-impregnated membrane without carrier.
b Fluxes j1–j4 relate to carriers 1–4, respectively.
†
Synthesis of a-amino phosphonates 1 and 2 (general procedure). A mix-
ture of octadecylamine (3.7 mmol) and an appropriate carbonyl compound
(3.7 mmol) in acetone (15 ml) for 1 or toluene (15 ml) for 2 was refluxed
with stirring for 1 h. Then, diethyl phosphite (4.7 mmol) and a catalytic
amount of p-toluenesulfonic acid were added. The reaction mixture was
stirred for 6 h at 80°C. The reaction progress was monitored by 31P NMR
spectroscopy. The solvent was evaporated in vacuo. The residue was dis-
solved in hexane. The excess hydrophosphoryl compound was extracted
with water. The organic phase was separated and dried with molecular
sieves 3 Å. The molecular sieves were filtered off, and the solvent was
evaporated.
without carrier showed that the introduction of carriers 1 and 2
into the membrane phase leads to a 10–1000 fold-increase in the
flux. The highest enhancement of the transport rate was observed
for oxalic acid in both cases. The mass transfer flux of sodium
acetate was insignificantly influenced by the test receptor. The
For 2: yield, 0.65 g (35%); mp 28°C. 31P NMR (121.5 MHz, CDCl3)
1
3
d: 24.29. H NMR (300 MHz, CDCl3) d: 0.91 (t, 3H, MeC17H34, JHH
For 1: yield, 1.07 g (65%); mp 32°C. 31P NMR (121.5 MHz, CDCl3)
6.5 Hz), 1.18 (t, 3H, POCH2Me, 3JHH 7.1 Hz), 1.25 (br.s, 32H, MeC16H32),
1.31 (t, 3H, POCH2Me, JHH 7.1 Hz), 1.48 (m, 2H, CH2CH2NH), 2.03
1
3
3
d: 32.09. H NMR (300 MHz, CDCl3) d: 0.87 (t, 3H, MeC17H34, JHH
6.1 Hz), 1.25 (br.s, 32H, MeC16H32), 1.27 (d, 6H, PCMe2, 3JPH 15.1 Hz),
1.31 (t, 6H, POCH2Me, 3JHH 7.3 Hz), 2.69 (t, 2H, NHCH2CH2, 3JHH 7.3 Hz),
4.13 (m, 4H, POCH2). IR (KBr, n/cm–1): 961 (P–O–C), 1028 (P–O–C),
1164 (P–O–Et), 1230 (P=O), 3100–3400 (OH, NH). Found (%): C, 68.16;
H, 11.26; N, 3.06. Calc. for C25H54NO3P (%): C, 67.07; H, 12.16; N, 3.13.
(br.s, PCHPh), 2.43–2.62 (m, 2H, NHCH2CH2), 3.82–4.14 (m, 4H,
POCH2), 7.31–7.47 (m, 5H, Ph). IR (KBr, n/cm–1): 966 (P–O–C), 1030
(P–O–C), 1164 (P–O–Et), 1244 (P=O), 3200–3400 (OH, NH). Found (%):
C, 70.58; H, 10.16; N, 2.86; P, 6.60. Calc. for C29H54NO3P (%): C, 70.26;
H, 10.98; N, 2.83; P, 6.25.
© 2012 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2012, 22, 80–82
(a)
1400
1200
1000
800
600
400
200
0
But
But
OH
But
But
OH
O
O
2
n
n
1
H2N
NH2
n = 2 or 4
i
ii
But
But
But
But
But
But
But
But
OH
(b)
140
120
100
80
60
40
20
0
OH
OH
Ph
O
O
P
O
O
OH
4
3
NH
HN
Ph
EtO
O
O
NH
P
P
HN
P
Me
Me
Me
Me
OEt
OEt
EtO
O
O
4
EtO OEt
EtO OEt
3
Figure 1 Transport enhancement coefficients (e = ji/j0) for organic substrates
6–13 through a liquid-impregnated membrane containing carriers (a) 1, 2
and (b) 3, 4.
Scheme 2 Reagents and conditions: i, acetone, diethyl phosphite, p-toluene-
sulfonic acid, 56°C; ii, benzene, benzaldehyde, diethyl phosphite, p-toluene-
solfonic acid, 80°C.
results testify that the interaction energy of the carboxylate group
with the a-aminophosphonate fragment is insufficient for the
transport of highly hydrophilic carboxylate anions across a lipo-
philic membrane.
reflects the higher degree of pre-organization of the carrier func-
tional substituents; as a consequence, the characteristics of structural
and geometric correlations between the binding sites and substrates
become more important than the single factor of acid strength.
As an additional method of assessing the transport selectivity
by different receptors, the concentrations of acids reaching the
receiver phase from a source phase containing a mixture of
tartaric, malonic and succinic acids were monitored by analytical
Compounds 1 and 2 and dicarboxylic acids exhibit a clear
correlation between the flux enhancement and the acid strength
[Table 1, Figure 1(a)]. Note that, although aminophosphonate 2
with an aryl fragment at the a-carbon atom is the most effective
carrier for oxalic acid,19 both compounds 1 and 2 demonstrated
relatively high efficiency and selectivity for oxalic acid transport.
To modify this selectivity by the preorganisation of binding
sites, we used macrocyclic p-tert-butylcalix[4]arene as a plat-
form. Calixarenes are versatile molecular building blocks for
the creation of three-dimensional structures with various internal
cavity sizes and numbers and types of binding sites.16,24–26
Synthetic receptors§ 3 and 4 were obtained from the amino
alkyl derivatives of p-tert-butylcalix[4]arene (Scheme 2).27 Their
transport ability towards substrates 5–13 was very different from
that of acyclic carriers 1 and 2 (Table 1, Figure 1).
§
Synthesis of calix[4]arenes 3 and 4 (general procedure). Carbonyl
compounds (2.6 mmol) were added to 1.3 mmol of an appropriate disub-
stituted p-tert-butylcalix[4]arene dissolved in 5 ml of acetone (for 3) or
benzene (for 4). The mixture was stirred for 1 h. Then, diethyl phosphite
(3.25 mmol) and a catalytic amount of p-toluenesulfonic acid were added.
The reaction mixture was stirred for 25 h at 80°C. The reaction progress
was monitored by 31P NMR spectroscopy. The solvent was evaporated
in vacuo and the residue was dissolved in benzene. The excess hydro-
phosphoryl compound was extracted with water. The organic phase was
separated and dried with molecular sieves 3 Å. The molecular sieves were
filtered off, and the solvent was evaporated.
For the macrocyclic receptors, a decrease in the enhanced
transport coefficient e for oxalic acid was observed. There was
also a switch in selectivity for tartaric acid by compound 3, and
for succinic and aspartic acids by compound 4 [Figure 1(b)]. This
For 3: yield, 0.96 g (67%); mp 58°C. 31P NMR (121.5 MHz, CDCl3)
d: 31.8. 1H NMR (300 MHz, CDCl3) d: 0.96 (s, 18H, But), 1.21 (t, 12H,
3
MeCH2OP, JHH 4.9 Hz), 1.28 (s, 18H, But), 1.32 (d, 12H, Me2CP,
3JPH 7.1 Hz), 1.75 [m, 4H, O(CH2)2CH2CH2N], 2.06 [m, 4H, OCH2CH2-
3
(CH2)2N], 2.83 [t, 4H, O(CH2)3CH2N, JHH 6.8 Hz], 3.29 (d, 4H,
‡
General method for membrane extraction. The fluxes of the substrate
2
3
Ar–CH2–Ar, JHH 12.9 Hz), 3.98 [t, 4H, OCH2(CH2)3N, JHH 6.8 Hz],
4.14 (m, 8H, MeCH2OP), 4.27 (d, 4H, Ar–CH2–Ar, 2JHH 12.9 Hz), 6.78
(s, 4H, HAr), 7.03 (s, 4H, HAr), 7.42 (s, 2H, Ar–OH). IR (KBr, n/cm–1):
956 (P–O–C), 1054 (P–O–C), 1163 (P–O–Et), 1240 (P=O), 3100–3400
(OH, NH). Found (%): C, 67.58; H, 10.10; N, 2.31; P, 4.92. Calc. for
C66H104N2O10P2 (%): C, 69.1; H, 9.1; N, 2.4; P, 5.4.
transport through the liquid-impregnated membranes were measured in a
thermostated vertical diffusion glass cell with a movable cylinder. Porous
Millipore Type FA Teflon filters (thickness, 1 mm; pore size, 100 nm;
porosity, 85%; the filters were reinforced with a carbon net) were used as
the hydrophobic matrix of an impregnated liquid membrane. The volume
ratio of the source and receiving phases was 5:1. This provided equal
solution levels to eliminate the osmotic transport of an acid. The mass
transport measurements were carried out under normal conditions (25°C).
A pure solvent (o-nitrophenyl octyl ether) or a 0.05 m solution of carrier
1–4 in o-nitrophenyl octyl ether was used as a liquid membrane. The
initial concentration of substrates 5–13 in source phase was 0.1 mol dm–3.
The concentrations were determined conductometrically. The fluxes (ji)
through the membrane were calculated from the initial linear regions of
the time dependence of the concentration of transported substance in the
receiving phase.
For 4: yield, 0.49 g (31%); mp 74°C. 31P NMR (121.5 MHz, CDCl3)
d: 23.80. 1H NMR (300 MHz, CDCl3) d: 0.93 (s, 18H, But), 1.09 (t, 6H,
MeCH2OP, 3JHH 7.1 Hz), 1.17 (t, 6H, MeCH2OP, 3JHH 7.1 Hz), 1.28 (s, 18H,
3
But), 2.97 (t, 4H, OCH2CH2N, JHH 6.2 Hz), 3.25 (d, 4H, Ar–CH2–Ar,
2JHH 13.2 Hz), 3.79–3.88 (m, 4H, OCH2CH2N), 3.93–4.22 (m, 8H,
2
MeCH2OP), 4.35 (d, 4H, Ar–CH2–Ar, JHH 13.2 Hz), 6.70–7.50 (m,
20H, HAr, OH). IR (KBr, n/cm–1): 965 (P–O–C), 1027 (P–O–C), 1163
(P–O–Et), 1243 (P=O), 3300–3400 (OH, NH). Found (%): C, 69.71;
H, 8.46; N, 2.37. Calc. for C70H96N2O10P2 (%): C, 70.8; H, 8.2; N, 2.4.
– 81 –

Mendeleev Commun., 2012, 22, 80–82
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HPLC (Figure 2). The samples of the receiving phase were taken
at regular intervals of 1 h.
During the first 3 h, only the peak of tartaric acid was detected.
After 4 h, succinic acid became detectable. Malonic acid was not
detected. The data are consistent with results of the membrane
extraction of separate species. Hence, receptor 3 can selectively
transport only tartaric acid through the membrane, as it decreases
e by a factor of 6 (cf. succinic acid).
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liquid-impregnated membranes, selective carriers for tartaric, suc-
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experiment make it possible to control the receptor abilities of
1,3-disubstituted calix[4]arenes by varying their substituents. The
attachment of aminophosphonate groups to a calixarene platform
switches the selectivity of complexation properties of amino-
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This work was supported by the Federal Programme ‘Research
and Scientific-Pedagogical Cadres of Innovative Russia’ for
2009–2013 (project no. 16.740.11.0472), the Russian Founda-
tion for Basic Research (project no. 09-03-00426-a) and the
Programme of the President of the Russian Federation for the
State Support ofYoung Russian Scientists – Doctors of Sciences
(MD-2747.2010.3).
Received: 26th August 2011; Com. 11/3787
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