Novel Phospholium-Type Cationic Surfactants: Synthesis, Aggregation Properties and Antimicrobial Activity

Article abstract of DOI:10.1007/s11743-016-1908-6

A series of novel phospholium amphiphilic compounds with straight alkyl chains with different numbers of carbon atoms (12, 14, 15, 16, 17, 18) were synthesized. The quaternary phosphorus, phosphonium cation, is incorporated into a five-membered heterocyclic ring. Their physicochemical properties were investigated by measurements of surface tension, conductivity and dynamic light scattering. The critical micelle concentration (c_M), the surface tension value at the c_M (γ_cmc), the surface area at the surface saturation per head group (A_cmc), the ionization degree of micelle (α), the free energy of micellization (ΔG°_mic), and hydrodynamic diameter (d_h) were determined. Antimicrobial activity was tested against bacteria and yeast. The structure–activity relationship was determined.

Full text of DOI:10.1007/s11743-016-1908-6

J Surfact Deterg
DOI 10.1007/s11743-016-1908-6
ORIGINAL ARTICLE
Novel Phospholium-Type Cationic Surfactants: Synthesis,
Aggregation Properties and Antimicrobial Activity
1
1
•
•
•
•
ˇ
´ˇ1
Milos Lukac Ferdinand Devınsky Martin Pisarcik Aspasia Papapetropoulou1
´
Marian Bukovsky Branislav Horvath
´ ˇ
2
3
•
´
´
´
Received: 1 February 2016 / Accepted: 3 November 2016
Ó AOCS 2016
Abstract A series of novel phospholium amphiphilic
compounds with straight alkyl chains with different num-
bers of carbon atoms (12, 14, 15, 16, 17, 18) were syn-
thesized. The quaternary phosphorus, phosphonium cation,
is incorporated into a five-membered heterocyclic ring.
Their physicochemical properties were investigated by
measurements of surface tension, conductivity and
dynamic light scattering. The critical micelle concentration
(cM), the surface tension value at the cM (ccmc), the surface
area at the surface saturation per head group (Acmc), the
ionization degree of micelle (a), the free energy of
micellization (DG°mic), and hydrodynamic diameter (dh)
were determined. Antimicrobial activity was tested against
bacteria and yeast. The structure–activity relationship was
determined.
Introduction
Cationic surfactants have long been studied for their
antimicrobial effect. They possess antimicrobial activities
against bacteria [1–3], yeast [1, 4, 5], fungi [6] and pro-
tozoa [7, 8]. The most studied cationic surfactants are
quaternary ammonium compounds (QACs) which also
have interesting physicochemical properties. They are
widely used in pharmacy, medicine, industry or house-
holds [9]. They have been studied for their solubilization
properties, e.g., for transferring poorly soluble compounds
into aqueous solutions [10, 11], as nonviral transfectors
[12], which is supported by their interaction with nega-
tively charged DNA [13, 14], or as phase transfer cata-
lysts [15].
Quaternary phosphonium compounds (QPCs) are simi-
lar compounds to QACs and the most common are alkyl-
triphenylphosphonium halides. They are used in organic
synthesis, e.g., in Wittig reactions [16]. QPCs possess
interesting antimicrobial activities against bacteria [17, 18],
fungi [17, 19] Leishmania spp. [20], and Trypanosoma spp.
[21]. Kanazawa et al. [17] investigated several series of
QPCs with different molecular architecture. They observed
that Gram-positive bacteria and yeast were more sensitive
than Gram-negative bacteria and filamentous fungi. The
antimicrobial activities of QPCs have also been studied in
various composites. Their activities were investigated
when QPCs were sorbed on montmorillonites [22] or when
quaternary phosphonium cations were part of amphiphilic
polymers [23–25]. Some compounds that contain triph-
enylphosphonium cations have a tendency to accumulate in
mitochondria: e.g., mitoQ [26] and chlorambucil [27] with
an attached triphenylphosphonium cation are mitochon-
dria-targeted compounds with antioxidant or antineoplastic
activity, respectively.
Keywords Antimicrobial activity Á Conductivity Á Critical
micelle concentration Á Hydrodynamic diameter Á
Phosphole Á Phospholium amphiphilic compounds Á
Structure–activity relationship Á Surface tension
ˇ
´ˇ
& Milos Lukac
lukac@fpharm.uniba.sk
1
2
Department of Chemical Theory of Drugs, Faculty of
Pharmacy, Comenius University, Bratislava 832 32, Slovakia
Department of Cellular and Molecular Biology of Drugs,
Faculty of Pharmacy, Comenius University,
Bratislava 832 32, Slovakia
3
Central NMR Laboratory, Faculty of Pharmacy, Comenius
University, Bratislava 832 32, Slovakia
123

J Surfact Deterg
Characterization of biodegradation of QACs and QPCs
is necessary for practical applications. One of the most
studied quaternary ammonium and phosphonium com-
pounds are ionic liquids which persist for a long time in the
environment and are toxic to different types of organisms
[28]. They can be degraded by microorganisms [29], by
physical [30] or chemical agents [31]. Morawski et al. [30]
observed that phosphonium salts are decomposed by pho-
tocatalysis more easily than ammonium salts.
and 31P NMR spectra were decoupled against protons. The
spectra were measured in CDCl3. The chemical shifts were
referenced with respect to an internal TMS (d1H = 0,
d13C = 0) or 85% H3PO4 (d31 P = 0 for
31P = 40.4807420 MHz).
N
Molecular surface area, minimal projection area and 3D
alignment of compounds were calculated using molecular
modeling software, Marvin 16.9.12. Calculations of low-
energy conformers were performed in vacuo.
Alkyltriphenylphosphonium halides are representatives
from the group of amphiphilic compounds containing qua-
ternary phosphorus whose physicochemical properties have
been the most studied [32–35]. They can be readily syn-
thesized and the triphenylphosphine used in their synthesis
is cheap and relatively stable in air (aliphatic phosphanes
are extremely sensitive to oxygen). Although the alkylt-
riphenylphosphonium halides contain three rigid phenyls in
the head group, they have good solubility in water. This
allows the measuring of the aggregation properties of series
of compounds with variable alkyl chains up to long-chain
analogs (even octadecyltriphenylphosphonium bromide is
still soluble) [35]. Their self-assembling properties have
been investigated in individual solutions [35], their mixtures
with alkyltriphenylphosphonium halides with different alkyl
chains [33, 34], or with cationic surfactants [32, 36]. The
influence of the head group on physicochemical properties
has been investigated by solubilization experiments [35, 37]
or by different types of reactions which were catalyzed by
the micellar environment [38, 39].
Synthesis
Synthesis of 2,3-Dimethylbuta-1,4-diene
2,3-Dimethylbuta-1,4-diene was synthesized according to
the procedure described by Allen and Bell [40]. The yield
of the reaction was 53%. Physical constants and spectral
characterization were as follows: b.p. = 69–70 °C;
n2D0 = 1.4365; 1H NMR (300 MHz, CDCl3) d: 1.92 (s, 6H),
4.97 (s, 2H), 5.06 (s, 2H).
Synthesis of 3,4-dimethyl-1-phenylphosphole
3,4-dimethyl-1-phenylphosphole was synthesized accord-
ing the procedure described by Breque et al. [41]. The yield
of the reaction was 79%. The final compound was char-
acterized by NMR spectra: 1H NMR (CDCl3, TMS) d: 2.11
(d, J = 2 Hz, 6H), 6.48 (d, J = 38.4 Hz, 2H), 7.20–7.38
(m, 5H); 31P NMR (CDCl3, 85% H3PO4) d: -1.7.
The aim of the present work is the synthesis of six novel
amphiphilic phosphonium salts with 3,4-dimethyl-1-
phenylphospholium moiety, the study of their physico-
chemical properties and antimicrobial activity, and the
relationship between their structure (focusing on the length
of the alkyl chain, n), lipophilicity (represented here by the
cM) and biological activity (given by minimum microbi-
cidal concentration). The physicochemical properties were
evaluated by surface tension, conductivity and dynamic
light scattering measurements of aqueous solutions. The
antimicrobial activity was studied against the bacteria
Staphylococcus aureus and Escherichia coli and yeast
Candida albicans. This work extends the knowledge about
a poorly known group of phosphonium amphiphilic
compounds.
Synthesis of 1-alkyl-3,4-dimethyl-1-phenylphospholium
Bromides
1-Bromoalkane
(0.012 mol)
and
3,4-dimethyl-1-
phenylphosphol (0.01 mol) were dissolved in 10 ml acetoni-
trile. The reaction mixture was heated under nitrogen at 80 °C
for 24 h. After cooling, the solvent was evaporated and the
crude product was recrystallized from a mixture of dry sol-
vents (acetone and diethyl ether or propan-2-ol and diethyl
ether). The evaporated residue of mother liquor of compound
12 after crystallization was purified by column chromatog-
raphy (silica gel; CHCl3 ? CHCl3: CH3OH–9: 1).
Compound 12 Yield 18% (crystallization) ?40%
(chromatography); 1H NMR (CDCl3, TMS) d: 0.87 (t,
3JH,H = 6.7 Hz, 3H, CH3 of alkyl chain), 1.13–1.38 (m,
16H, 8 9 CH2 of alkyl chain), 1.38–1.63 (m, 4H, b, c CH2
of alkyl chain) 2.29 (s, 6H, 2 9 = C–CH3), 3.06–3.20 (m,
Materials and Methods
2
All chemicals used in the synthesis were obtained from
commercial suppliers and were of p.a. purity.
1H, 13C and 31P NMR spectra were measured on a
Varian MERCURY plus spectrometer working at fre-
quencies of 300, 75, and 121.5 MHz, respectively. 13C
2H, a CH2 of alkyl chain), 7.13 (d, JHP = 30.9 Hz,
2H, = CHP), 7.54–7.61 (m, 2H, Ph Hmeta), 7.61–7.76 (m,
1H, Ph Hpara), 8.17–8.25 (m, 2H, Ph Hortho); 13C NMR
(CDCl3, TMS) d: 14.1 (CH3 of alkyl chain), 18.5 (d,
1
3JCP = 17.2 Hz, = C–CH3) 22.5 (d, JCP = 46.1 Hz, a
123

J Surfact Deterg
CH2 of alkyl chain), 22.6 (d, 2JCP = 4.1 Hz, b CH2 of alkyl
chain), 22.7 (x CH2 of alkyl chain), 29.0, 29.3, 29.5, 29.6
(m, 24H, 12 9 CH2 of alkyl chain), 1.38–1.61 (m, 4H, b, c
CH2 of alkyl chain) 2.29 (s, 6H, 2 9 = C–CH3), 3.07–3.22
3
2
(d–x-2 CH2 of alkyl chain), 30.5 (d, JCP = 15.4 Hz, c
(m, 2H, a CH2 of alkyl chain), 7.10 (d, JHP = 31,0 Hz,
CH2 of alkyl chain), 31.9 (x-1 CH2 of alkyl chain), 113.5
(d, JCP = 80.2 Hz, = CHP), 115.9 (d, JCP = 83.6 Hz,
2H, = CHP), 7.57–7.63 (m, 2H, Ph Hmeta), 7.63–7.77 (m,
1H, Ph Hpara), 8.17–8.24 (m, 2H, Ph Hortho); 13C NMR
(CDCl3, TMS) d: 14.1 (CH3 of alkyl chain), 18.5 (d,
1
1
3
Ph C1), 130.0 (d, JCP = 13.1 Hz, Ph Cmeta), 133.6 (d,
4
1
2JCP = 10.4 Hz, Ph Cortho), 134.6 (d, JCP = 3.0 Hz, Ph
3JCP = 17.1 Hz, = C–CH3) 22.4 (d, JCP = 43.3 Hz, a
2
C
para), 163.2 (d, JCP = 16.1 Hz, = C–CH3); 31P NMR
CH2 of alkyl chain), 22.5 (d, 2JCP = 4.0 Hz, b CH2 of alkyl
chain), 22.7 (x CH2 of alkyl chain), 29.0, 29.3(0), 29.3(4)
29.4(8), 29.5(8), 29.6(3), 29.7 (d–x-2 CH2 of alkyl chain),
(CDCl3, H3PO4) d: 38.6; IR tmax/cm-1: 2922, 2852, 1540,
1466, 1438, 1385, 1311, 1116, 996, 853, 823, 746, 719,
691.
3
30.5 (d, JCP = 15.3 Hz, c CH2 of alkyl chain), 31.9 (x-1
CH2 of alkyl chain), 113.5 (d, JCP = 80.3 Hz, = CHP),
1
1
Compound 14 Yield 35%; H NMR (CDCl3, TMS) d:
0.88 (t, 3JH,H = 6.7 Hz, 3H, CH3 of alkyl chain), 1.13–1.38
(m, 20H, 10 9 CH2 of alkyl chain), 1.38–1.63 (m, 4H, b, c
CH2 of alkyl chain) 2.29 (s, 6H, 2 9 = C–CH3), 3.07–3.20
115.9 (d, 1JCP = 84.2 Hz, Ph C1), 130.0 (d,
2
3JCP = 13.0 Hz, Ph Cmeta), 133.5 (d, JCP = 10.7 Hz, Ph
4
C
ortho), 134.6 (d, JCP = 2.9 Hz, Ph Cpara), 163.3 (d,
2
(m, 2H, a CH2 of alkyl chain), 7.10 (d, JHP = 30.9 Hz,
2JCP = 16.4 Hz, = C–CH3); 31P NMR (CDCl3, H3PO4) d:
38.5; IR tmax/cm-1: 2919, 2851, 1541, 1467, 1438, 1380,
1310, 1116, 996, 853, 801, 750, 719, 695.
2H, = CHP), 7.53–7.61 (m, 2H, Ph Hmeta), 7.61–7.76 (m,
1H, Ph Hpara), 8.17–8.25 (m, 2H, Ph Hortho); 13C NMR
(CDCl3, TMS) d: 14.1 (CH3 of alkyl chain), 18.6 (d,
1
Compound 17 Yield 38%; H NMR (CDCl3, TMS) d:
1
3JCP = 17.3 Hz, = C–CH3) 22.5 (d, JCP = 46.2 Hz, a
0.88 (t, 3JH,H = 6.7 Hz, 3H, CH3 of alkyl chain), 1.18–1.39
(m, 26H, 13 9 CH2 of alkyl chain), 1.39–1.62 (m, 4H, b, c
CH2 of alkyl chain) 2.29 (s, 6H, 2 9 = C–CH3), 3.08–3.21
CH2 of alkyl chain), 22.6 (d, 2JCP = 4.1 Hz, b CH2 of alkyl
chain), 22.7 (x CH2 of alkyl chain), 29.1, 29.3, 29.4, 29.5,
29.6(0), 29.6(4), 29.7 (d–x-2 CH2 of alkyl chain), 30.5 (d,
3JCP = 15.6 Hz, c CH2 of alkyl chain), 31.9 (x-1 CH2 of
2
(m, 2H, a CH2 of alkyl chain), 7.08 (d, JHP = 30.9 Hz,
2H, = CHP), 7.58–7.62 (m, 2H, Ph Hmeta), 7.62–7.76 (m,
1H, Ph Hpara), 8.17–8.24 (m, 2H, Ph Hortho); 13C NMR
(CDCl3, TMS) d: 14.1 (CH3 of alkyl chain), 18.5 (d,
1
alkyl chain), 113.6 (d, JCP = 80.0 Hz, = CHP), 115.9 (d,
3
1JCP = 83.9 Hz, Ph C1), 130.0 (d, JCP = 12.9 Hz, Ph
2
meta), 133.6 (d, JCP = 10.7 Hz, Ph Cortho), 134.6 (d,
1
C
3JCP = 17.3 Hz, = C–CH3) 22.5 (d, JCP = 46.1 Hz, a
4JCP = 3.0 Hz, Ph Cpara), 163.2 (d, 2JCP = 16.4 Hz, = C–
CH3); 31P NMR (CDCl3, H3PO4) d: 38.5; IR tmax/cm-1
CH2 of alkyl chain), 22.6 (d, 2JCP = 4.1 Hz, b CH2 of alkyl
chain), 22.7 (x CH2 of alkyl chain), 29.1, 29.3, 29.4, 29.5,
29.6(0), 29.6(5) 29.7 (d–x-2 CH2 of alkyl chain), 30.5 (d,
3JCP = 15.4 Hz, c CH2 of alkyl chain), 31.9 (x-1 CH2 of
:
2920, 2851, 1540, 1467, 1438, 1381, 1311, 1116, 996, 853,
801, 750, 718, 694.
1
1
Compound 15 Yield 31%; H NMR (CDCl3, TMS) d:
alkyl chain), 113.6 (d, JCP = 80.0 Hz, = CHP), 115.8 (d,
3
0.88 (t, 3JH,H = 6.7 Hz, 3H, CH3 of alkyl chain), 1.13–1.38
(m, 22H, 11 9 CH2 of alkyl chain), 1.38–1.62 (m, 4H, b, c
CH2 of alkyl chain) 2.29 (s, 6H, 2 9 = C–CH3), 3.08–3.22
1JCP = 83.9 Hz, Ph C1), 130.0 (d, JCP = 12.9 Hz, Ph
2
meta), 133.5 (d, JCP = 10.7 Hz, Ph Cortho), 134.7 (d,
C
4JCP = 3.0 Hz, Ph Cpara), 163.2 (d, 2JCP = 16.5 Hz, = C–
CH3); 31P NMR (CDCl3, H3PO4) d: 38,5; IR tmax/cm-1
2919, 2851, 1541, 1467, 1438, 1380, 1311, 1116, 996, 853,
2
(m, 2H, a CH2 of alkyl chain), 7.08 (d, JHP = 30.9 Hz,
:
2H, = CHP), 7.54–7.61 (m, 2H, Ph Hmeta), 7.61–7.75 (m,
1H, Ph Hpara), 8.15–8.23 (m, 2H, Ph Hortho); 13C NMR
(CDCl3, TMS) d: 14.1 (CH3 of alkyl chain), 18.5 (d,
802, 750, 719, 695.
1
Compound 18 Yield 93%; H NMR (CDCl3, TMS) d:
1
3JCP = 17.3 Hz, = C–CH3) 22.5 (d, JCP = 46.1 Hz, a
0.88 (t, 3JH,H = 6.7 Hz, 3H, CH3 of alkyl chain), 1.15–1.38
(m, 28H, 14 9 CH2 of alkyl chain), 1.38–1.61 (m, 4H, b, c
CH2 of alkyl chain) 2.29 (s, 6H, 2 9 = C–CH3), 3.08–3.22
CH2 of alkyl chain), 22.6 (d, 2JCP = 4.1 Hz, b CH2 of alkyl
chain), 22.7 (x CH2 of alkyl chain), 29.1, 29.3, 29.4, 29.5,
29.6, 29.7 (d–x-2 CH2 of alkyl chain), 30.5 (d,
3JCP = 15.4 Hz, c CH2 of alkyl chain), 31.9 (x-1 CH2 of
2
(m, 2H, a CH2 of alkyl chain), 7.07 (d, JHP = 30.9 Hz,
2H, = CHP), 7.57–7.63 (m, 2H, Ph Hmeta), 7.63–7.77 (m,
1H, Ph Hpara), 8.16–8.23 (m, 2H, Ph Hortho); 13C NMR
(CDCl3, TMS) d: 14.1 (CH3 of alkyl chain), 18.5 (d,
1
alkyl chain), 113.6 (d, JCP = 80.0 Hz, = CHP), 115.8 (d,
3
1JCP = 83.8 Hz, Ph C1), 130.0 (d, JCP = 12.9 Hz, Ph
2
meta), 133.5 (d, JCP = 10.4 Hz, Ph Cortho), 134.7 (d,
1
C
3JCP = 17.3 Hz, = C–CH3) 22.5 (d, JCP = 46.2 Hz, a
4JCP = 3.0 Hz, Ph Cpara), 163.2 (d, 2JCP = 16.5 Hz, = C–
CH3); 31P NMR (CDCl3, H3PO4) d: 38.5; IR tmax/cm-1
CH2 of alkyl chain), 22.6 (d, 2JCP = 4.1 Hz, b CH2 of alkyl
chain), 22.7 (x CH2 of alkyl chain), 29.1, 29.3(0), 29.3(6)
29.4, 29.5(0), 29.5(5), 29.6(0), 29.6(6) 29.7 (d–x-2 CH2 of
alkyl chain), 30.5 (d, 3JCP = 15.4 Hz, c CH2 of alkyl chain),
31.9 (x-1 CH2 of alkyl chain), 113.6 (d,
:
2918, 2851, 1540, 1467, 1437, 1380, 1312, 1116, 996, 852,
802, 749, 718, 691.
1
Compound 16 Yield 68%; H NMR (CDCl3, TMS) d:
0.88 (t, 3JH,H = 6.7 Hz, 3H, CH3 of alkyl chain), 1.16–1.38
1JCP = 80.0 Hz, = CHP), 115.8 (d, JCP = 83.8 Hz, Ph
1
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J Surfact Deterg
3
C1), 130.0 (d, JCP = 12.9 Hz, Ph Cmeta), 133.5 (d,
Tetracon 325). The cM was determined from the break
point of the conductivity versus the concentration curve.
The ratio of the slope of the postmicellar region to that of
the premicellar region gives the ionization degree a. The
free energy of micellization, DG°mic, was calculated
according to the equation:
4
2JCP = 10.4 Hz, Ph Cortho), 134.7 (d, JCP = 3.0 Hz, Ph
2
C
para), 163.2 (d, JCP = 16.5 Hz, = C–CH3); 31P NMR
(CDCl3, H3PO4) d: 38.5; IR tmax/cm-1: 2917, 2850, 1541,
1467, 1438, 1385, 1311, 1116, 996, 853, 802, 750, 719, 689.
DGꢀmic ¼ ð2ÀaÞRT ln cM
ð3Þ
Measurements of Physicochemical Properties
where a is the ionization degree, T the absolute tempera-
ture, and R the gas constant.
Equilibrium Surface Tension Measurements
The equilibrium surface tension measurements were car-
ried out according to the previously described procedure
[42]. The solvent surface tension values were measured by
the Wilhelmy plate technique using a Kru¨ss 100 MK2
tensiometer. Deionized water was used in the preparation
of all samples. The temperature of the measurements was
kept at 25 0.1 °C. Measurements of equilibrium surface
tension were taken repeatedly (every 6 min) until the
change in surface tension was less than 0.05 mN m-1. The
critical micelle concentration (cM) and surface tension at
the cM (ccmc) were determined from the break point of the
surface tension vs. log c curve. Surface tension data points
used for cM determination were taken from the linear part
of the surface tension vs. log surfactant concentration curve
in the premicellar region close to the cM point and were
fitted by a straight line. The adsorbed amount of surfactant
Ccmc has been calculated from the surface tension data
using the Gibbs adsorption isotherm:
Measurement of Hydrodynamic Diameter
The measurements of hydrodynamic diameter (dh) were
carried out according to the previously described procedure
[43]. The Brookhaven BI 9000 light scattering system with
argon laser (wavelength 514.5 nm) was used for dynamic
light scattering measurements. The scattered intensity was
registered at a constant scattering angle of 90° and at a tem-
perature of 25 °C. Solutions for the light scattering experi-
ments were prepared using deionized water which was
additionally filtered for mechanical impurities through syr-
inge filters with 0.45-lm pore size. The translation diffusion
coefficient was calculated from the time correlation function
using the method of cumulants. The method of cumulants in
dynamic light scattering data analysis was introduced by
Koppel [44] who showed that the decay rate C_ is proportional
to the z-average of the diffusion coefficient D as follows
Ccmc ¼ À½dc=d log cŠs=ð2:303iRTÞ
ð1Þ
2
ꢀ
C ¼ q Dz
ð4Þ
The logarithm of the electric field autocorrelation
where c is the surface tension (mN m-1), c is the surfactant
concentration, i is the prefactor (i = 2; surfactants are
ionized into two ions), T is the absolute temperature, and R
the gas constant. Surface excess may be determined from
the slope below the cM in the surface tension versus log c
plots. Surface area at the surface saturation per head group
(Acmc) is obtained from the equation:
function g(1)(t) can be expanded into a series as follows:
ꢀ
ꢁ
1
ln gð1ÞðtÞ ¼ ÀCt þ l2t2 þ Á Á Á
ð5Þ
ꢀ
2!
The term l2 is called the second cumulant. For a perfect
single exponential decay, it would be near zero. A measure
of the polydispersity of the distribution can be given in
Acmc ¼ 1018=NACcmc
where NA is the Avogadros constant.
ð2Þ
2
ꢀ
terms of the unitless quotient l2=C . It is also referred to as
the polydispersity parameter
´
ꢀ2
polydispersity ¼ l2=C
ð6Þ
Electrical Conductivity Measurements
The decay term U was calculated from the expansion of
the logarithm of the autocorrelation function up to the
second term using the first linear term in Eq. (5) for the
calculation. The diffusion coefficient was determined using
Eq. (4) from the decay rate U and the hydrodynamic
diameter was calculated from the diffusion coefficient
using the Stokes–Einstein formula
The measurements were performed in a conductivity cell
which was tempered at 25 °C 0.1 °C. The stock solution
of surfactant in deionized water was prepared in a 100-ml
volumetric flask. The conductivity cell was filled with
20 ml of deionized water before the measurement. The
stock solution was added to deionized water in the con-
ductivity cell by an automatic burette (765 Dosimat) and
was controlled by a computer. The solution was stirred by a
magnetic stirrer during the measurements. The conductiv-
ity of the solution was recorded by a conductimeter (WTW
dh ¼ kT=ð3pgDÞ
ð7Þ
g is the solvent viscosity, k is the Boltzmann constant,
and T is the absolute temperature. Five independent
123

J Surfact Deterg
measurements and calculations of the time correlation
function were carried out for each investigated surfactant
concentration. The mean value and standard deviation of dh
for each sample were calculated.
Results and Discussion
Synthesis
An alternative to the method of cumulants was applied to
the light scattering data analysis, especially in the case of
bimodal particle size systems. A numerical algorithm based
on the inverse Laplace transformation was applied on the
autocorrelation function. Micelle diameters were evaluated
from the partition distributions utilizing the CONTIN algo-
rithm [45] with the rejection probability parameter set to 0.5.
Due to the large number of processed data, a custom appli-
cation software written in Visual Basic was used for auto-
mated data format conversion from the measurement files.
A series of six QPCs derived from phosphole with different
lengths of alkyl chains were prepared. According to our
best knowledge, 1-alkyl-3,4-dimethyl-1-phenylphospho-
lium bromides represent a new type of amphiphilic phos-
phonium compounds. They contain quaternized
phosphorus in a five-membered unsaturated heterocycle.
Some phospholium salts have been prepared previously but
they were quaternized only with short alkyl chains, e.g.,
methyl or benzyl [47, 48]. Therefore, the compounds
synthesized and characterized here represent a unique type
of cationic surfactants.
Determination of Minimum Bactericidal
and Candidacidal Concentrations
The synthesis was performed according to Scheme 1.
The phosphorus heterocycle was prepared by McCormack
reaction of 2,3-dimethylbuta-1,3-diene with phenyldichlo-
rophosphine. The reaction was performed in a basic envi-
ronment of 2-methylpyridine. This base provides the high-
est yield as was investigated by Breque et al. [41]. 2,3-
dimetyl-1,3-diene was prepared from pinacol by an elimi-
nation reaction with HBr [40]. The last step of the prepa-
ration of QPCs was the quaternization of the phosphorus
heterocycle with 1-bromoalkanes. The reaction was per-
formed in acetonitrile. The compounds were obtained as
white solid powders or crystals. Compounds 12 and 14 were
extremely hygroscopic, while compound 12 liquefied in
several seconds in air. Similar behavior was observed in the
case of compound 14 but the liquefying was not so fast. This
property of the compounds makes them harder to crystal-
lize. Compound 12 was obtained in a very low yield and
therefore the mother liquor was evaporated after crystal-
lization and the residue was purified using chromatography
on silica gel. Compound 14 crystalized with surface active
impurity when an acetone/diethyl ether mixture was used.
Therefore, it had to be repeatedly crystalized from the
mixture propan-2-ol/diethyl ether. The structures of the
Measurements of minimum microbicidal concentrations
were performed as previously described [46]. The micro-
bicidal activity was tested against Gram-negative bacteria
Escherichia coli ATCC 11229, Gram-positive bacteria
Staphylococcus aureus CNCTC 29/58 and yeast Candida
albicans CCM 8186. Solutions of QPCs, BAB (benzalko-
nium bromide) and BDDAB (N-benzyl-N,N-dimethyldo-
decane-1-aminium bromide) serving as the standards were
prepared in deionized water. A suspension of the standard
microorganism prepared from 24-h cultures of bacteria in
blood agar and from 24-h cultures in Sabouraud agar for
yeast had a concentration of 5 9 107 cfu ml-1 of bacteria
and 5 9 105 cfu ml-1 of Candida. The suspensions were
prepared in physiological solution (pH 7.2). The concen-
tration of microorganisms was determined spectrophoto-
metrically and the suspensions were adjusted to the
˚
absorbance A = 0.35 at k = 540 nm. The microorganism
suspension (5 lL) was added to solutions containing the
compound tested (100 lL) and to a double-concentrated
peptone broth medium (8%) for bacteria or Sabouraud
medium (12%) for Candida (100 lL). The stock solutions
of the tested compounds 14, 15, 16, 17, 18 and BAB had a
concentration of 1 mmol dm-3. The stock solution of 12
was prepared with a concentration of 10 mmol dm-3. For a
testing assay, the solutions were serially diluted by half and
used. The cultures were placed in 96-well microtiter plates
and the microorganisms were incubated for 24 h at 37 °C.
Then, from each well, 5 lL of the suspension was taken
and cultured on blood agar (bacteria) or on Sabouraud agar
(yeast). Petri dishes were incubated for 24 h at 37 °C. The
lowest concentration of QPCs BAB or BDDAB that pre-
vented colony formation was defined as the minimum
bactericidal concentration (MBC) or minimum candidaci-
dal concentration (MCC).
1
compounds were confirmed by H, 13C, 31P NMR spec-
troscopy and IR spectroscopy. 2-D NMR experiments,
gDQCOSY and gHSQC, were measured for compound 17.
This helped us to assign signals to atoms/atomic groups.
Aggregation Properties
The physicochemical properties of QPCs were investigated
by the measurements of surface tension, conductivity and
dynamic light scattering of aqueous solutions of phospho-
lium salts. Figure 1 depicts the surface tension versus the
logarithm of concentration and conductivity versus con-
centration plots. The results obtained from the measure-
ments are summarized in Table 1.
123

J Surfact Deterg
Scheme 1 Synthesis of 1-alkyl-
3,4-dimethyl-1-
phenylphospholium bromides
The cM values were obtained from the breakpoints of the
curves. The values for each compound obtained from the
surface tension and conductivity are approximately the
same. However, the cM obtained from the measurements of
conductivity are a little higher than the cM obtained from
surface tension measurements. In the series of compounds,
the values of cM decreased with the increasing number of
carbon atoms in the long alkyl chain. The influence of the
length of the alkyl chain on log cM is depicted in Fig. 2 and
is expressed by the Kleven’s equations. B values were
found to be 0.29 and 0.30, respectively. They express the
influence of the methylene group on the decrease of cM
when increasing the length of an alkyl chain. The values
are in accordance with the results obtained for monovalent
QACs [9]. The cM of phospholium salts are comparable
with the cM of alkyltriphenylphosphonium bromides with
the same alkyl chains which have been previously inves-
tigated [32–35]. This means that the 3,4-dimethyl-1-
phenylphospholium cation has an influence on the
lipophilicity of amphiphilic compounds which is similar to
that of the triphenylphosphonium cation.
head group allows a denser arrangement of 1-alkyl-3,4-
dimethyl-1-phenylphospholium bromide molecules at the
water/air interface than the triphenylphosphonium head
group of alkyltriphenylphosphomium bromides. This dense
arrangement of head groups prevents long alkyl chains (16,
17, 18 carbon atoms) from having higher conformational
freedom. Therefore, the Acmc of phospholium surfactants is
not influenced by these phenomena. The organization of
1-alkyl-3,4-dimethyl-1-phenylphospholium bromides at the
water/air interface can also be affected by p–p stacking
interactions of aromatic parts of the head groups (phenyl
and 3,4-dimethylphospholium). This interaction results in a
regular arrangement of surfactant molecules at the water/
air interface without being affected by the presence of alkyl
chains.
The ionization degree of micelle (a) and the free energy
of micellization (DG°mic) were also obtained from the
conductivity measurements. The micelle ionization degree
increased with the increasing length of the alkyl chain. This
means that more counterions are localized in the Gouy–
Chapman layer of a micelle with the increasing length of
the alkyl chain. The micelle ionization degree results from
the variation in the electronic charge density on the cation,
which in turn depends on the positive inductive effect of
the alkyl group and bulkiness of the cation [49]. The ion-
ization degree of micelles in water solutions of alkylt-
riphenylphosphonium bromides is practically independent
of the alkyl chain length. Values in the range 0.60–0.68
were found for the investigated compounds with alkyl
chains of 12, 14 or 16 carbon atoms [32, 34]. Triph-
enylphosphonium cation is relative bulky in comparison
with 3,4-dimethyl-1-phenylphospholium cation, as shown
from the molecular modeling calculations. The van der
Waals surface area of the methyltriphenylphosphonium
Acmc and ccmc were also obtained from the measure-
ments of surface tension. The ccmc values were in the range
of 36.5–39.9 mN m-1. Acmc was not significantly affected
by the length of the alkyl chain. The values of Acmc were
found to be in the range 0.97 0.12 nm2. This means that
the organization of the head group at the air/water interface
is the most important factor affecting the value of this
parameter. According to the literature [32, 34], however,
Acmc of alkyltriphenylphosphonium bromides, which are
the most studied phosphonium surfactants, is strongly
affected by the length of the alkyl chain. Their Acmc values
increase with the increasing length of the alkyl chains. The
number of carbon atoms in the lipophilic part of the
molecule has an influence on the area value. The differ-
ences between the results obtained for surfactants with the
3,4-dimethyl-1-phenylphospholium head group and with
the triphenylphosphonium head group can be supported by
molecular modeling. Figure 3 shows that 1-alkyl-3,4-
dimethyl-1-phenylphospholium bromides are organized
more tightly than alkyltriphenylphosphonium bromides,
with the differences being related to the head group area.
2
2
˚
cation (Aw = 422.60 A ) is approximately 100 A larger
˚
than the surface area of the 1,3,4-trimethyl-1-phenylphos-
2
pholium cation (Aw = 313.48 A ). This means that the
˚
counterion can be bound to a smaller head group more
strongly than to a larger one. Therefore, the ionization
degree of micelles of alkyltriphenylphosphoniumbromides
is practically independent of the alkyl chain length, and its
values are mainly affected by the head group size. The free
energy of micellization increases with the number of car-
bon atoms in the alkyl chain in the case of compounds with
shorter alkyl chains (12, 14, 15). The values of QPCs with
longer alkyl chains (16, 17, 18) are not so strongly affected.
3,4-dimethyl-1-phenylphospholium head group has
a
2
smaller minimal projection area (Aproj = 39.54 A ) than
˚
2
triphenylphosphonium head group (Aproj = 58.35 A ).
˚
This means that the 3,4-dimethyl-1-phenylphospholium
123

J Surfact Deterg
c[mol.dm-3]
0,0010
c[mol.dm-3]
0,004
12 0,000
0,002
0,006
0,008
0,0000
0,0005
0,0015
0,0020
140
500
400
300
200
100
0
14 54
54
52
50
48
46
44
42
40
38
36
34
52
50
48
46
44
42
40
38
36
120
100
80
60
40
20
0
-3,6
-3,4
-3,2
-3,0
-2,8
-2,6
-2,4
-2,2
-4,0
-3,8
-3,6
-3,4
-3,2
-3,0
log c
log c
c[mol.dm-3 ]
c[mol.dm-3]
15 0,0000 0,0002 0,0004 0,0006 0,0008 0,0010 0,0012
0,0000
0,0002
0,0004
0,0006
16
50
40
30
20
10
0
58
56
54
52
50
48
46
44
42
40
38
54
52
50
48
46
44
42
40
38
36
80
70
60
50
40
30
20
10
0
-4,6
-4,4
-4,2
-4,0
-3,8
-3,6
-3,4
-3,2
-3,0
-2,8
-4,8
-4,6
-4,4
-4,2
-4,0
-3,8
-3,6
-3,4
log c
log c
c[mol.dm-3]
c[mol.dm-3]
0,00010
17 0,00000 0,00005 0,00010 0,00015 0,00020 0,00025 0,00030
18 0,00000
0,00005
0,00015
0,00020
18
54
24
22
20
18
16
14
12
10
8
56
52
50
48
46
44
42
40
38
-5,4
54
52
50
48
46
44
42
40
38
16
14
12
10
8
6
6
4
4
2
2
-4,8
-4,6
-4,4
-4,2
-4,0
-3,8
-3,6
-5,2
-5,0
-4,8
-4,6
-4,4
-4,2
-4,0
-3,8
log c
log c
Fig. 1 Surface tension versus log c and conductivity versus concentration of 1-alkyl-3,4-dimethyl-1-phenylphospholium bromides in aqueous
solutions. (Bottom x axis is for surface tension measurements and upper x axis is for conductivity measurements)
These values provide information about the effectiveness
of micellization of QPCs in an aqueous environment. QPCs
with a longer alkyl chain form micelles more sponta-
neously in water than their more hydrophilic analogues.
The literature data for the free energy of micellization of
surfactants similar to those containing a triphenylphos-
phonium cation show inconsistent results. For alkyltriph-
enylphosphoniumbromides, the values increase with the
123

J Surfact Deterg
Table 1 Physicochemical
properties of 1-alkyl-3,4-
dimethyl-1-phenylphospholium
bromides
Comp.
cM [mmol dm-3
]
ccmc [mN m-1
]
Acmc [nm2]
a
DG°mic [KJÁmol-1
-22.7 0.1
]
12
3.35 0.06a
4.14 0.04b
0.55 0.01a
0.96 0.01b
0.37 0.01a
0.47 0.01b
0.16 0.01a
0.25 0.01b
0.10 0.01a
0.13 0.01b
0.050 0.001a
0.070 0.006b
36.5 0.3
0.89 0.06
0.33 0.01
14
15
16
17
18
a
38.1 0.1
39.9 0.1
37.3 0.2
39.4 0.1
39.0 0.5
0.96 0.08
1.08 0.03
0.95 0.03
0.97 0.02
0.85 0.01
0.46 0.01
0.46 0.01
0.54 0.01
0.57 0.01
0.75 0.02
-26.8 0.1
-29.2 0.1
-29.9 0.2
-31.7 0.4
-29.2 0.7
Value obtained from surface tension measurements
b
Value obtained from conductivity measurements
-2,5
-3,0
-3,5
log cM = -0,29n + 1,13
R2 = 0,998
log cM= -0,30n + 1,03
R2 = 0,986
-4,0
-4,5
12
14
16
18
n
Fig. 2 Relationship between the log cM and the alkyl chain length
(n) of the 1-alkyl-3,4-dimethyl-1-phenylphospholium bromides
(squares are values obtained from surface tension measurements
and dots are values obtained from conductivity measurements)
Fig. 3 3-D alignment of surfactants with p-phenylphospholium head
group (dark gray) and with triphenylphosphonium group (light gray)
Polydispersity (defined in the light scattering section of
‘‘Materials and Methods’’) was found to be in the range
between 0.21 and 0.31 which justifies the application of the
method of cumulants for the light scattering data analysis.
It might be assumed that the formed aggregates are vesicles
due to the presence of sufficiently long chain of 17 and 18
carbon atoms in the surfactant molecular structure which is
required for the intensive hydrophobic aggregation.
Moreover, electrostatic or p–p stacking interactions should
be taken into account in the process of aggregation of the
investigated surfactants. These forces were also assumed in
the analysis of self-assembling properties of other types of
surfactants with aromatic rings [50]. The size of the
aggregates was almost constant or slightly decreased with
the increasing concentration of QPCs in the solution, which
indicates the formation of stable micellar and possible
increasing length of alkyl chain [32, 33] or do not depend
on it [34].
In Fig. 4, micelle diameters of phospholium salts are
plotted as a function of surfactant concentration c/cM, as
obtained from the dynamic light scattering experiments.
The results obtained from the measurements are also
summarized in Table 2.
The investigated surfactants molecules aggregate into
small spherical micelles in all cases except for compounds
12, 17, and 18, where the presence of large aggregates was
observed. The long-chain homologs 17 and 18 formed
large aggregates with dh = 220 nm even at the lowest
concentration c/cM = 5 (Fig. 4), as calculated using the
method of cumulants described in ‘‘Materials and Meth-
ods’’. This confirms the importance of the hydrophobic
interaction in the process of formation of aggregates.
123

J Surfact Deterg
12
14
15
16
17
18
100
10
1
0
5
10
15
20
25
30
35
40
c/cM
Fig. 4 Hydrodynamic diameter of micelles of phospholium salts
plotted as a function of surfactant concentration c/cM as determined
from dynamic light scattering measurements
vesicular phases throughout the range of the investigated
surfactant concentrations.
Fig. 5 Particle size distribution of surfactant 17
We also carried out data analysis utilizing the numerical
CONTIN algorithm which provided the particle size
spectra of the investigated surfactant aggregates. An
example from the results is shown in the following particle
size spectrum for surfactant 17 and the concentration c/
cM = 5 (Fig. 5).
presence of large aggregates in the case of surfactants with a
dodecyl chain. The first possible explanation could be
related to intermicellar interactions resulting from sponta-
neous aggregation of small micelles into more complex
aggregates. Formation of such larger aggregates could be
driven by p–p stacking interactions of the aromatic parts of
the head groups. Another possible explanation come from
the high concentrations of the samples used for dynamic
light scattering experiment with dodecyl surfactant 12 (in
the range 0.01–0.1 mol/L); these high concentration values
resulted from the high cM value of the dodecyl chain sur-
factant. Such high concentrations in the light scattering
experiment could lead to multiple scattering effects, and the
observed large aggregates are only apparent.
The aggregate size at the concentration c/cM = 5 for
compound 17 corresponds well with the value obtained by
the method of cumulants plotted in Fig. 4. Surfactant 12
forms aggregates with two different sizes in aqueous solu-
tion. Small aggregates with the diameter 2–3 nm are
attributed to the presence of spherical micelles. Surprisingly,
large aggregates were also found in the system as a result of
the dynamic light scattering data analysis. The size of
aggregates was virtually independent of surfactant concen-
tration. The dodecyl chain, however, is expected to be too
short to form large aggregates such as vesicles and bilayers.
We assume two possible reasons being responsible for the
The remaining investigated compounds, the homologues
14, 15, and 16 form only small spherical micelles with
dh = 3.1–5.8 nm. As seen from Fig. 4, the formed micelles
are stable in size and almost no concentration-dependence
Table 2 Micelle size of
c/cM dh [nm]
1-alkyl-3,4-dimethyl-1-
phenylphospholium bromides
12
14
15
16
17
18
2.5
5
2.7 0.6/163.3 13.6
2.3 0.6/157.0 13.4
221.9 11.8 221.3 7.6
10
15
20
25
30
35
40
2.1 0.3/161.0 15.6 5.5 0.6
214.3 6.0
159.8 10.9
137.3 4.7
123.9 10.7
116.0 7.0
2.6 0.4/160.8 18.7 4.8 0.7 4.0 1.1 4.5 1.5 193.1 4.3
2.8 0.4/150.0 19.6 5.3 1.6 4.6 2.3 4.2 1.2 188.9 1.6
3
0/173.0 21.0
4.7 0.3 4.8 1.9 5.8 0.6 183.7 5.9
4.5 0.7 3.3 0.5 3.1 0.4
4.6 0.5
3.9 0.8
123

J Surfact Deterg
the cM value for compound 10 calculated from Kleven’s
equation is higher than 1 9 10-2 mol dm-3 (the estimated
cM value as obtained from the Kleven’s equation for
compound 10 is cM = 1.7 9 10-2 mol dm-3). Therefore,
we suppose that compound 12 reaches the maximum
microbicidal activity against E. coli and C. albicans in the
series of 1-alkyl-3,4-dimethyl-1-phenylphospholium bro-
mides. Consequently, compounds with shorter alkyl chains
with even numbers of carbon atoms should be less active.
Until now, antibacterial activity of amphiphilic com-
pounds with quaternary phosphorus has not been suffi-
ciently studied. Kanazawa et al. [17] studied several series
of QPCs with a different structure of cationic parts of
molecules. The compounds with a phenyl moiety in a head
group showed trends in antibacterial activity similar to
those observed by us. Gram-positive bacteria were found to
be the most sensitive to phosphonium salts. Lower activi-
ties were observed in the case of Gram-negative bacteria
and fungi.
Table 3 Minimum bactericidal and candidacidal concentrations of
1-alkyl-3,4-dimethyl-1-phenylphospholium bromides
Compound
S. aureus (lM)
E. coli (lM)
C. albicans (lM)
12
625
250
250
16
156
250
500
500
500
500
26
78
250
500
500
500
500
26
14
15
16
17
16
18
31
BDDAB
BAB
26
26
260
26
is observed. This situation is similar to conventional
alkyltriphenylphosphonium bromides that form micelles
with similar hydrodynamic diameters. Their size slightly
increases from 1.8 to 4.2 nm with the increase in the alkyl
chain [35].
Antimicrobial Activity
Conclusions
Antimicrobial activity was tested on the Gram-positive
bacteria Staphylococcus aureus, Gram-negative bacteria
Escherichia coli and yeast Candida albicans. The results
are summarized in Table 3.
A novel family of cationic surfactants, 1-alkyl-3,4-dimethyl-
1-phenylphospholium bromides, were successfully synthe-
sized. The physicochemical properties were determined by
the measurements of surface tension and conductivity of
their aqueous solutions. A linear relationship was observed
between log cM and the length of the alkyl chain. Within the
series of compounds, the values of cM decreased with the
increasing number of carbon atoms in the alkyl chain. An
opposite effect of the dependence on the alkyl chain length
was observed in the case of the degree of micelle ionization.
Its values increased with the increasing number of carbon
atoms in the alkyl chain. In contrast, there was no evident
relationship between the length of the alkyl chain and the
surface area at the surface saturation per head group.
Hydrodynamic diameters of aggregates of the investigated
phospholium salts depended on the alkyl chain length.
Compounds 14, 15, and 16 aggregated into small micelles
while compounds 17 and 18 formed large aggregates.
Compound 12 formed both types of aggregates. The
microbicidal activities of QPCs were tested against bacteria
and yeast. Compounds 16 and 17 were found to be the most
active against S. aureus and compound 12 showed the
highest microbicidal activity against E. coli and C. albicans.
The most active compounds from the series of 1-alkyl-3,4-
dimethyl-1-phenylphospholium bromides showed better
bactericidal activity (compounds 16 and 17 for S. aureus and
compound 12 for E. coli) than the standard BAB. Com-
pounds 16 and 17 also displayed higher activities against S.
aureus than the standard BDDA.
S. aureus was the most sensitive tested microorganism
to the action of QPCs. Compounds 16 and 17 showed the
lowest MBC. They were more active than the standards
BAB and BDDAB. Other compounds with alkyl chains
shorter or longer than 16 or 17 carbon atoms were less
active. As with numerous types of sets of compounds
possessing long alkyl chains [1, 2, 46, 51, 52, 53], the so-
called cut-off effect [54] was observed. The Gram-negative
bacteria E. coli was the strain most sensitive to compound
12. The MBC of this QPC was lower than the standard
BAB. However, it did not reach the activity of BDDAB,
the compound with dodecyl alkyl chain which is present in
BAB. Compound 14 had an MBC comparable to that of
BAB. Compound 12 was also the most active against C.
albicans. However, its activity did not reach the activity of
the standards. It was approximately 3 times less active than
BAB and BDDAB. The cut-off effect was not observed in
the case of the action of the synthesized QPCs against
E. coli and C. albicans. The possible reason is related to the
fact that we did not investigate the compounds with alkyl
tails even shorter (i.e., more hydrophilic) than compound
12. They should have a lower microbicidal activity than
compound 12. This assumption corresponds with the
´
results of the study of Devınsky et al. [55] where the most
microbicidally efficient compounds were found to have cM
values in the range 1 9 10-2 - 1 9 10-4 mol dm-3 The
cM value for compound 12 fits into this range. However,
123

J Surfact Deterg
ˇ´
´
´
´
´
Acknowledgements This publication is the result of the project
implementation: Centre of Excellency in Security Research supported
by the Research and Development Operational Programme funded by
the ERDF Grant Number: ITMS 26240120034. This work was sup-
ported by the Slovak Research and Development Agency under the
Contract No. APVV-0516-12 and by the Grant Agency of Ministry of
Education and Academy of Science of Slovak republic (VEGA),
Project No. 1/0298/16.
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DNA—DOPC—gemini surfactants complexes: effect of ionic
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´ˇ
Milos Lukac is an associate professor in Pharmaceutical Chemistry at
the Department of Chemical Theory of Drugs, Faculty of Pharmacy,
Comenius University, Bratislava. He received his PhD in pharma-
ceutical chemistry at Comenius University in 2010, associate
professorship in 2016, and a study stay 2012 at Institute of Organic
Chemistry and Biochemistry, The Czech Academy of Science. His
research interests include organic synthesis, phosphorus chemistry,
properties of surfactants and lichenology.
40. Allen CFH, Bell A. 2,3-dimethyl-1,3-butadiene. Org Synth.
1942;22:39–43. doi:10.15227/orgsyn.022.0039.
41. Breque A, Mathey F, Savignac P. An improved one-pot synthesis
of phospholes. Synthesis. 1981;1981:983–5. doi:10.1055/s-1981-
29670.
´ˇ
42. Lukac M, Garajova M, Mrva M, Devınsky F, Ondriska F,
Kubincova J. Novel fluorinated dialkylphosphonatocholines:
´
´
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synthesis, physicochemical properties and antiprotozoal activities
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systems based on cationic gemini amphiphiles utilizing various
experimental techniques.
Ferdinand Devınsky is professor in Pharmaceutical Chemistry, head
of Department of Chemical Theory of Drugs, Faculty of Pharmacy,
Comenius University, Bratislava. Received his PhD in Organic
Chemistry at Comenius University in 1980, professor in 1992, DSc in
1993, and a study stay 1986–1987 at King’s College London,
University of London. Research interests: organic synthesis, organic-
physical chemistry, membrane active compounds, relationships
between optical activity and biological activity.
Aspasia Papapetropoulou received her MSc at Faculty of Pharmacy,
Comenius University in Bratislava in 2015.
´
´
Marian Bukovsky is associate Professor in microbiology, deputy
head of Department of cellular and molecular biology of drug,
Faculty of Pharmacy, Comenius University, Bratislava. He received
his PhD in Microbiology at Comenius Universitya in 1985, and
associate professorship in Microbiology at Comenius University in
1997. Research interests: microbiology, immunology, immunochem-
istry and immunodiagnostics.
´ ˇ
Martin Pisarcik is an associate professor in Macromolecular
Chemistry at the Department of Chemical Theory of Drugs at the
Faculty of Pharmacy, Comenius University, Bratislava. He received
his PhD in Macromolecular Chemistry in 1992 at the Faculty of
Chemical Technology, Slovak Technical University, Bratislava. He
gained his professional experience during long-term research stays in
the research groups in the field of colloid chemistry—University of
Bayreuth, Germany, University of Nagoya, Japan and Brooklyn
College, USA. His research interests are focused on the investigations
of physicochemical and aggregation properties of biologically active
´
Branislav Horvath is research fellow at the NMR laboratory, Faculty
of Pharmacy, Comenius University, Bratislava. He received his PhD
in organic chemistry at Comenius University in 2002.
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