Reactivity of phosphorus esters in supramolecular systems based on surfactants containing an uracil residue and polyethylenimine

Article abstract of DOI:10.1134/S1070428014040095

The reactivity of phosphorus esters with different hydrophobicities was studied in aqueous solutions of cationic surfactants containing an uracil residue, as well as in binary systems based on polyethylenimine. Pronounced substrate specificity was reveale

Full text of DOI:10.1134/S1070428014040095

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 4, pp. 500–505. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © D.R. Gabdrakhmanov, F.G. Valeeva, L.Ya. Zakharova, R.Kh. Giniyatullin, V.E. Semenov, V.S. Reznik, A.I. Konovalov, 2014,
published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 4, pp. 512–517.
Reactivity of Phosphorus Esters in Supramolecular
Systems Based on Surfactants Containing an Uracil
Residue and Polyethylenimine
D. R. Gabdrakhmanov, F. G. Valeeva, L. Ya. Zakharova, R. Kh. Giniyatullin,
V. E. Semenov, V. S. Reznik, and A. I. Konovalov
Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
e-mail: lucia@iopc.ru
Received January 14, 2014
Abstract—The reactivity of phosphorus esters with different hydrophobicities was studied in aqueous
solutions of cationic surfactants containing an uracil residue, as well as in binary systems based on poly-
ethylenimine. Pronounced substrate specificity was revealed in all supramolecular systems examined; in
particular, acceleration of the hydrolysis of more hydrophobic substrate and inhibition of the reaction with less
hydrophobic analog were observed. Aggregation in the examined systems was confirmed by tensiometric and
conductometric measurements. The aggregation threshold considerably decreased in going from monocationic
amphiphile to more hydrophobic dicationic analog due to the presence in the latter of two additional alkyl
radicals.
DOI: 10.1134/S1070428014040095
Reactivity control constitutes one of the most im-
portant problems of organic chemistry. Among numer-
ous catalytic systems, a particular place is occupied by
catalysis of chemical reactions in organized media
based on amphiphilic compounds; such systems may
be regarded as biomimetic, and they make it possible
to simulate factors responsible for the reactivity of sub-
strates in biological media [1, 2]. Two main factors are
generally distinguished for catalytic reactions in syn-
thetic supramolecular systems and enzymatic catalysis:
(1) concentrating of the reactants (cage effect) and
(2) change of their microenvironment (effect of the
medium). These factors originate from the capability
of amphiphilic compounds for self-organization and
transfer of the reactants from the bulk solution to
aggregates [3, 4]. Although catalytic reactions in
organized media have been extensively studied [4–6],
only a few examples of selective acceleration of reac-
tions with structurally related substrates, i.e., substrate
specificity typical of enzymatic catalysis, have been
reported.
arenes and polymers) and mixed amphiphile–polymer
systems, which showed a high catalytic or inhibitory
activity in nucleophilic substitution reactions with
phosphorus esters [4, 7–9]. Phosphoryl group transfer
is the key biochemical reaction in metabolic processes
[10]. The applied aspect of relevant studies is equally
important; for example, environmentally hazardous
toxic phosphorus esters are decomposed by hydrolysis
[11, 12]. Cationic surfactants are capable of accelerat-
ing alkaline hydrolysis of esters by enhancing the
concentration of hydroxide ions on the surface of
cationic micelles.
In the present work we studied the hydrolysis of
two p-nitrophenyl alkyl chloromethylphosphonates I
and II with different lengths of the alkyl radical (R =
Et, C6H13) in aqueous solutions of acyclic surfactants
APB-1 and APB-2 containing uracil fragments and
bromide ions as counterions (Scheme 1). We previ-
ously reported [13–15] on the synthesis and aggrega-
tion properties of acyclic and macrocyclic amphiphiles
containing pyrimidine fragments; these compounds
were shown to constitute a new class of cationic
surfactants possessing specific properties that differ
from the properties of classical surfactants. Introduc-
We previously described various supramolecular
catalytic systems based on conventional surfactants
(micelles and microemulsions) and macrocycles (calix-
500

REACTIVITY OF PHOSPHORUS ESTERS IN SUPRAMOLECULAR SYSTEMS
501
Scheme 1.
OR
O
OH
OR
CH2Cl
H2O
HO
P
CH2Cl
+
P
O
O
O2N
O2N
I, II
I, R = Et; II, R = C6H13.
O
O
Et
Et
Et
Et
Et
Et
Br–
Br–
N
Br–
N
N
N
N
N
C10H21
C10H21
C10H21
Me
N
H
O
O
Me
C10H21
APB-2
APB-1
tion into an amphiphile molecule of a 6-methyluracil
fragment structurally related to the nucleobase uracil
was expected to further highlight the biomimetic
aspect of these studies and provide the possibility for
the design of nanocontainers for targeted DNA
delivery.
referred to as CMC. Two critical concentrations were
found for APB-1, 3.0 and 10.0 mM, whereas one bend
was observed for APB-2 at a concentration of
0.045 mM. The sharp decrease of CMC in going from
the monocationic surfactant to dicationic analog may
be rationalized by considerably increased hydropho-
bicity of APB-2 molecules possessing three decyl
radicals. Comparison of the data for APB-2 and
previously studied amphiphile containing a pyrimidine
residue and two decyl radicals at the ammonium head
groups [9] showed that the key factor is the presence of
a hydrophobic substituent in the pyrimidine fragment,
which strongly enhances the aggregation ability (the
CMC decreases from 3 to 0.045 mM). We previously
substantiated the assumption [13] that increase in the
aggregation ability is determined not only by increased
hydrophobicity of the surfactant due to the presence of
an additional lipophilic substituent but also by the pos-
The formation of aggregates in solutions of APB-1
and APB-2 was confirmed by tensiometry and conduc-
tometry. Apart from surfactant solutions, we examined
the system surfactant–polyethylenimine (PEI). The use
of polymers allows one to replace micellar catalysts on
the basis of non-covalently bound aggregates by
immobilized nanoreactors. In addition, amino groups
in polyethylenimine may enhance micellar catalysis
factors due to the contribution of homogeneous cata-
lytic mechanisms (base catalysis). The catalytic effect
of polyethylenimine in the hydrolysis of phosphonates
I and II was studied in [7].
2
Aggregation behavior. The reactivity of com-
pounds in micellar surfactant solution is determined by
aggregation [2–5]. We have studied those properties of
the systems that are responsible for their catalytic
effect. In particular, the critical micelle concentrations
(CMC) and the degrees of counterion binding (β) were
determined. The critical micelle concentration is the
concentration of a surfactant corresponding to forma-
tion of micelles which act as nanosized reactors, and
the degree of counterion binding determines the sur-
face charge of aggregates and hence the concentration
of nucleophile (hydroxide ion) in the reaction zone.
1
70
3
60
50
40
10–8
10–6
10–4
csurf, M
10–2
0
The tensiometric and conductometric data are pre-
sented in Figs. 1 and 2 as concentration dependences
of the surface tension γ and electrical conductivity χ of
aqueous surfactant solutions. These dependences have
a bend at a definite surfactant concentration which is
Fig. 1. Surface tension isotherms of aqueous solutions of
(1) APB-1 and (2) APB-2 and (3) of binary system APB-2–
polyethylenimine; cPEI = 0.05 M, 25°C.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014

GABDRAKHMANOV et al.
502
1500
2
follows SN2 (P) mechanism [16] with second-order
rate constants of 4.0 and 3.0 L mol–1 s–1 for phospho-
nates I and II, respectively. Addition of surfactants
does not change the reaction mechanism, and cationic
micelles generally accelerate the process [4]. Figures 3
and 4 show the kinetic data for alkaline hydrolysis of
phosphonates I and II in APB-1 and APB-2 micellar
systems. The hydrolysis of phosphonate II was accel-
erated in both systems, by 3.8 and 27.7 times for
micellar solutions of APB-1 and APB-2, respectively.
This acceleration is determined by the concentration
factor: the substrate is solubilized by the aggregates,
and hydroxide ions bind to positively charged micelle
surface via electrostatic forces.
1
1200
900
600
300
0
2000
1000
0
cAPB-1, M
0.00
0.01
0.02
0.03
0.000
0.005
0.010
csurf, M
0.015
0.020
Phosphonate I displayed an anomalous micellar
effect: the rate of its hydrolysis decreased in APB-1
solution, while APB-2 did not affect the reaction rate.
Rare examples of such substrate specificity, including
inversion of the catalysis/inhibition effect, were noted
in our earlier publications [17], in particular for surfac-
tants containing a pyrimidine fragment. The following
reasons for the anomalous micellar effect were pre-
sumed: (1) spontaneous acidification of the reaction
solution; (2) steric hindrances to the attack by nucleo-
phile; (3) low reagent–micelle binding constant. Our
experiments showed that in the absence of alkali all
solutions retained pH ~7 throughout the examined
range of surfactant concentrations.
Fig. 2. Plots of the specific electrical conductivity of
(1) aqueous solution of APB-2 and (2) binary system
APB-2–polyethylenimine versus surfactant concentration;
cPEI = 0.05 M, 25°C. The corresponding dependence for
APB-1 is shown in the insert.
sibility for more compact molecular packing. The data
for the APB-2–polyethylenimine system (Fig. 1) show
that addition of a polymer reduces the CMC even more
strongly.
By quantitative analysis of the surface tension
isotherms we calculated parameters characterizing
micelle formation by the surfactants and adsorption at
the water–air interface. The data in Table 1 show
a good agreement between the trends in the variation
of CMC and free energy of micelle formation in the
examined systems. The conductometric data (Fig. 2)
are consistent with those obtained by tensiometry;
they confirm the CMC value of APB-1 close to 10 mM
(Table 1).
In order to estimate the substrate binding constants
we analyzed the kinetic data in terms of the pseudo-
phase model using Eq. (1), which is widely used in
micellar catalysis [2]. This model implies formation of
a substrate–micelle catalytic complex.
One of the most important characteristics of ionic
surfactants is the degree of counterion binding. By
potentiometric measurements with the aid of
a bromide-selective electrode we estimated the β value
of APB-2 at 0.65–0.90; it decreases as the surfactant
concentration increases.
kw + kcat K′ csurf
S
kobs
=
.
(1)
1 + K′ csurf
S
Here, kobs is the observed pseudofirst-order rate
constant, kw and kcat are the first-order rate constants in
water and catalytic complex, respectively, K′ (L/mol)
S
Catalytic activity. In the absence of a surfactant,
is the reduced micelle–substrate binding constant, and
alkaline hydrolysis of phosphorus esters (Scheme 1)
csurf (mol/L) is the surfactant concentration.
Table 1. Maximum surface excesses (Γmax), minimum surface areas per surfactant molecule (Amin), surface pressures (πCMC),
free energies of micelle formation (ΔGm), and standard free energies of adsorption (ΔGad) for surfactant systems
System
CMC, M
Γmax ×107, mol/m2
Amin., nm2 πCMC, mN m–1 –ΔGm, kJ/mol –ΔGad, kJ/mol
APB-1
APB-2
3.0, 10.0
0.045
8.16
5.62
6.09
2.03
2.96
2.73
32.93
21.70
31.43
25.8
31.3
48.3
62.4
62.7
APB-2–polyethylenimine
0.027
100.00
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014

REACTIVITY OF PHOSPHORUS ESTERS IN SUPRAMOLECULAR SYSTEMS
503
10
8
II
II
35
30
25
20
15
10
5
6
4
I
2
I
0
0.000
0.002
0.004
0.006
0.0000
0.0001
0.0002
cAPB-2, M
0.0003
c
APB-1, M
Fig. 3. Plots of the observed rate constant of alkaline hydrol-
ysis of phosphonates I and II versus concentration of APB-1;
0.01 M NaOH, 25°C.
Fig. 4. Plots of the observed rate constant of alkaline hydrol-
ysis of phosphonates I and II versus concentration of APB-2;
0.001 M NaOH, 25°C.
It is seen from the data in Table 2 that the binding
constants of phosphonates I and II in both systems are
comparable. Therefore, the concentrating effect cannot
be responsible for the different effects of APB-1 and
APB-2 on the reactivity of substrates differing by their
hydrophobicity, and the observed substrate specificity
is likely to be controlled by microenvironment of the
phosphonates in micelles. This assumption may be
regarded as fairly reasonable since molecules of phos-
phonates I and II, due to their different hydropho-
bicities, may be localized at different distances from
the aggregate surface. Phosphonate I is likely to reside
in the polar Stern layer, and more hydrophobic phos-
phonate II, in nonpolar micelle core. Furthermore,
spatial proximity of phosphonate I molecules to the
surface layer favors formation of hydrogen bond
between the NH hydrogen atom of uracil and phos-
phoryl oxygen atom (Scheme 2), which could weaken
polarization of the phosphoryl group and reduce the
electrophilicity of the phosphorus atom and thus
inhibit alkaline hydrolysis in the presence of APB-1.
Comparison of the micellar effects of APB-1 and
APB-2 shows that the latter is a more efficient catalyst
which selectively accelerates alkaline hydrolysis of
Table 2. Results of quantitative analysis of the kinetic data for the hydrolysis of phosphonates I and II in surfactant-based
systems with the use of Eq. (1)
System
Phosphonate
kcat ×103, s–1
KS, L/mol
kcat/kw
APB-1
APB-2
I
000.3
121.7
004.1
090.6
000.4
003.7
0369
0499
7059
1496
1022
0424
00.01
03.80
II
I
01.00
II
I
27.70
APB-1–polyethylenimine
00.30
II
4.5 (10.0)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014

GABDRAKHMANOV et al.
hydrolysis of phosphonate II by an order of magnitude
504
Scheme 2.
relative to the rate of hydrolysis in the absence of
surfactant, the high substrate specificity being retained.
In fact, the alkaline hydrolysis of phosphonate I slows
down in going from aqueous solution to both APB-1
solution and ABP-1–PEI binary system.
ClCH2
EtO
O
N
P
HO–
O
·
NO2
·
·
H
Me
N
O
C10H21
To conclude, our study of the aggregation behavior
and catalytic activity of new amphiphiles containing
an uracil fragment, taken alone and in a combination
with PEI, revealed a stepwise reduction of the critical
micelle concentration in the series monocationic sur-
factant > dicationic surfactant > binary system di-
cationic surfactant–polyethylenimine. The supra-
molecular systems thus formed considerably affect the
reactivity of alkyl p-nitrophenyl chloromethylphos-
phonates, so that the rate of their hydrolysis can be
varied over a wide range (from inhibition to accelera-
tion). All catalytic systems examined displayed high
substrate specificity: they selectively accelerated the
hydrolysis of more hydrophobic phosphonate II at
low surfactant concentrations.
Br–
N
Et
Et
O
phosphonate II by a factor of ~30, whereas the reac-
tivity of less hydrophobic analog I remains unchanged.
It is important that the micellar effect of APB-2 is
observed at a considerably lower concentration (μM
level) as compared to APB-1. In keeping with the data
in Table 2, the higher catalytic activity of APB-2 is
related to the higher micelle–substrate binding con-
stants which exceed those observed for APB-1 by
a factor of 4–5.
Immobilization of micelles on a polymer matrix
may enhance the catalytic efficiency of APB-1 and
facilitate separation of the catalyst (which is important
from the practical viewpoint). The data in Table 2
show that the system APB-1–PEI accelerates alkaline
EXPERIMENTAL
Phosphonates I and II were synthesized according
to the procedure described in [18]. Surfactants APB-1
and APB-2 were prepared as reported [15]. Branched
polyethylenimine (M 25000, Aldrich) was used; its
molar concentrations are given with respect to the
monomer unit.
II
3.0
The kinetic measurements were performed under
pseudofirst-order conditions by spectrophotometry
using a Specord UV-Vis spectrophotometer; the ab-
sorbance of p-nitrophenoxide ion was monitored at
λ 400 nm. The observed rate constants (kobs) were cal-
culated by Eq. (2):
2.4
1.8
1.2
ln(A∞ – A) = –kobsτ + const.
(2)
Here, A and A∞ are, respectively, the optical
densities of reaction solution at a time τ and by the end
of the process. The data were processed according to
the weighted least-squares; mean values from three
parallel measurements differing by no more than 5%
were taken.
I
0.6
0.000
0.003
0.006
cAPB-1, M
0.009
The surface tension was measured at 25°C by the
du Noüy ring detachment method with the aid of
a Krüss K6 tensiometer.
Fig. 5. Plots of the observed rate constant of alkaline hy-
drolysis of phosphonates I and II versus concentration of
APB-1 in the binary system APB-1–polyethylenimine, cPEI
The maximum surface excess Γmax was calculated
=
0.05 M, 25°C.
from the Gibbs adsorption equation (3):
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014

REACTIVITY OF PHOSPHORUS ESTERS IN SUPRAMOLECULAR SYSTEMS
505
1
2. Berezin, I.V., Martinek, K., and Yatsimirskii, A.K., Usp.
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Γmax
=
lim(∂π/∂logc),
(3)
2.3nR T
c→CMC
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a solution with a given surfactant concentration (π =
γ0 – γ). The constant n is equal to 2 for ionic surfac-
tants consisting of a singly charged micelle-forming
ion and counterion, and n = 3 for dimeric surfactants
consisting of a doubly charged micelle-forming ion
and two singly charged counterions.
2007.
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The minimum surface area per surfactant molecule
(Amin), the free energy of micelle formation (ΔGm), and
the standard free energy of adsorption (ΔGad) were
calculated by formulas (4) and (5):
1018
Amin
=
;
(4)
(5)
N Γmax
ΔGm = (1 + β)RTln(CMC),
where N is the Avogadro number, and β is the degree
of counterion binding.
10. Jencks, W.P., Catalysis in Chemistry and Enzymology,
New York: McGraw–Hill, 1969.
The specific electrical conductivity was measured
using an Inolab conductometer (Germany). The con-
centration of free bromide ions was determined with
the aid of an I-160MI ionometer using an ELIS-131Br
bromide-selective electrode and an ESR-10101 refer-
ence electrode. The concentration of bromide ions was
calculated from the known Nernst equation (6) which
relates the electrode potential (ΔE) to the activity of
11. Yang, Y. and Bakker, J., Chem. Rev., 1992, vol. 92,
no. 8, p. 1729.
12. Franke, S., Franz, P., and Warnke, W., Lehrbuch der
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bromide ions (aBr ):
–
14. Voronin, M.A., Gabdrakhmanov, D.R., Semenov, V.E.,
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RT
F
ΔE = –
log(aBr–) + const.
(6)
Here, R is the universal gas constant, T is the
temperature, and F is the Faraday constant; in an ideal
case, the slope of this dependence RT/F = 59.2 mV×
equiv–1 at 298.2 K.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 13-03-00709).
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014