An example of green surfactant systems based on inherently biodegradable IL-derived amphiphilic oximes

Article abstract of DOI:10.1016/j.molliq.2020.112857

Progress in the development of biodegradable ionic liquids (ILs) leads to designing green surfactant formulations for miscellaneous applications. In this work, we present synthesis of a series of novel IL-derived amphiphilic pyridinium oximes composed by

Full text of DOI:10.1016/j.molliq.2020.112857

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An example of green surfactant systems based on inherently
biodegradable IL-derived amphiphilic oximes
Subhashree Jayesh Pandya, Illia V. Kapitanov, Zeba Usmani,
Reshma Sahu, Deepak Sinha, Nicholas Gathergood, Kallol K.
Ghosh, Yevgen Karpichev
PII:
S0167-7322(19)36198-7
DOI:
https://doi.org/10.1016/j.molliq.2020.112857
MOLLIQ 112857
Reference:
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
9 November 2019
5 March 2020
6 March 2020
Please cite this article as: S.J. Pandya, I.V. Kapitanov, Z. Usmani, et al., An example
of green surfactant systems based on inherently biodegradable IL-derived amphiphilic
oximes,
Journal
of
Molecular
Liquids(2020),
https://doi.org/10.1016/
j.molliq.2020.112857
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An Example of Green Surfactant Systems Based on
Inherently Biodegradable IL-derived Amphiphilic Oximes
†
a
†b1
b
a
c
Subhashree Jayesh Pandya , Illia V. Kapitanov , Zeba Usmani , Reshma Sahu , Deepak Sinha ,
b,d
a
b
Nicholas Gathergood , Kallol K. Ghosh* , Yevgen Karpichev*
a
b
School of Studies in Chemistry, Pt. Ravishankar Shukla University, Raipur (C.G.) 492010, India
Department of Chemistry and Biotechnology, Tallinn University of Technology (TalTech),
Tallinn 12618, Estonia
c
Government Nagarjuna Post Graduate College of Science, Raipur (C.G.) 492010, India
School of Chemistry, University of Lincoln, Lincoln, Lincolnshire, LN6 7DL, United Kingdom
b
†
contributed equally to the publication
Authors for correspondence:
Dr. Yevgen Karpichev, phone: +372 620-4382; fax: +372 620-2994
E-mail: yevgen.karpichev@ttu.ee
*
*
Prof. Kallol K. Ghosh, phone: +91 771-2263146, fax: +91 771-2262583
E-mail: kallolkghosh@yahoo.com
1Current address: Gemini PharmChem Mannheim GmbH, 68305 Mannheim, Germany
1

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Abstract
Progress in the development of biodegradable ionic liquids (ILs) leads to designing green
surfactant formulations for miscellaneous applications. In this work, we present synthesis of a series
of novel IL-derived amphiphilic pyridinium oximes composed by octylamide tail linked to the
headgroup by means of amide, 4-((hydroxyimino)methyl)-1-(2-(octylamino)-2-oxoethyl)pyridin-1-
iumbromide, 4-PyC8), alanyl ((S)-4-((hydroxyimino)methyl)-1-(2-((1-(octylamino)-1-oxopropan-2-
yl)amino)-2-oxoethyl) pyridin-1-ium bromide, 4-PyAlaC8), or phenylalanyl ((S)-2-
((hydroxyimino)methyl)-1-(2-((1-(octylamino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-
pyridin-1-ium bromide, 2-PyPheC8), S)-3-((hydroxyimino)methyl)-1-(2-((1-(octylamino)-1-oxo-3-
phenylpropan-2-yl)amino)-2-oxoethyl)pyridin-1-iumbromide, 3-PyPheC8), and (S)-4-((hydroxy-
imino)methyl)-1-(2-((1-(octylamino)-1-oxo-3-phenylpropan-2yl)amino)-2-oxoethyl) pyridin-1-ium
bromide, 4-PyPheC8) moiety. Their biodegradability examined in the closed bottle test shown the
dependence on the amino acid structure and follows the tendency Phe> Ala> amide. Phenelalanine-
based oximes demonstrate >30% of degradation in the CBT after 42 days and can be considered as
inherently degradable. The acid ionization constant (pK ) of studied oximes determined by means of
a
UV-vis spectroscopy at 27 ̊ C were found to be in the range from 8.00 to 9.00. The pKa,app values of
oximes in the presence of cationic gemini surfactants, 12-4-12- and 16-10-16, change insignificantly
whereas they shifted upwards in the presence of anionic surfactant SDS. The nucleophilic cleavage of
organophosphorus triester PNPDPP under optimal concentration conditions of 4-PyC8 come about
with half-life times 40 s under mild condition (pH 9.00). These results provide new information on
control the green microorganized nucleophilic systems for chemical decontamination.
Keywords
Ionic liquids; oximes; biodegradability; closed bottle test ; acid dissociation constant ; chemical
decontamination.
2

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1
. Introduction
Ionic liquids (ILs) are increasingly seen nowadays as an integral part of green chemistry applications
1-3] with a particular attention to their biocompatibility and biodegradability [4-7]. An attractive
[
feature of ILs is the ability to refine the structure, to tailor the properties for a desired application. The
ILs with long chains are capable to form aggregates in aqueous solutions similar to that of
conventional surfactants and are called the surface-active ionic liquids (SAILs) [8, 9]. This
overlapping between surfactant and IL chemistry causes the increased interest to the synthesis, self-
organization, and applications of SAILs, including developing micellar catalytic systems [10, 11].
Progress in the development of biodegradable ionic liquids ILs allowed finding sustainable fragments
to assist the synthesis of sustainable molecules by means of “benign by design” approach [12, 13].
The novel SAILs are expected to combine advanced colloid properties with lowered risk for the
environment [14]. We have reported recently a versatile approach towards the synthesis of
biodegradable amino acid derived ILs [12, 13] to open the opportunities for developing SAILs with
optimized environmental toxicity [15] and tunable properties [16] in their self-assembly,
antimicrobial activity, and biodegradability. Among the L-phenylalanine (Phe) derived SAILs
reported in our recent report [16], the medium chain length (namely, n-hexyl and n-octyl esters)
derivatives bearing pyridinium headgroup were pointed out to be the prospective green alternatives
for conventional surfactants and to be considered as the base for miscellaneous applications.
A problem of both theoretical and practical importance is the fast and irreversible detoxification of
organophosphorus compounds (OP), either used as pesticides or chemical warfare agents (CWA) [17-
2
1]. The comprehensive approach of solving problems related to the crisis management, e.g. remedial
measures to mitigate manmade disasters or a terrorist attack towards civilians [22, 23] is also far from
complying with the principles of green chemistry. During an incident involving exposure of civilians,
it's usually exists a delay between initial exposure of poisonous agents and on-scene arrival of the
effective countermeasures and trained personnel to apply best military practices [17]. Formulations,
which are environmentally friendly and easy-to-use by both first responders or volunteers are on
demand, and they are far from being fully fitted to the green chemistry criteria. The significance of
the international efforts towards environmentally benign methods of chemical decontamination was
sharply highlighted by the OPCW’s Initiative on Green and Sustainable Chemistry [24] aimed at
enhancing implementation of the Chemical Weapons Convention.
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The non-functionalized SAILs aggregates have been published to solubilize OP pesticides [25] or act
as micellar hydrolytic system bringing together OP pesticide and a weak nucleophile in the micellar
pseudophase [26]. Oximes are among the most effective nucleophiles providing high rate of the
detoxification of OPs under mild pH [27-29]. One of the promising ways to advance micellar
catalytic system is attaching specific functional moiety to the surfactant headgroup. It allows one to
produce high “local” concentration of the reactive species in the region close to the micellar interface
[
30]. The commonly used antidotes [31, 32] and functionalized surfactants [33] for effective cleavage
and degradation of toxic organophosphorus compounds (OP) are zwitterionic salts (in their reactive
form oxime group is deprotonated) containing quaternary ammonium (pyridinium, in essence) group.
The results on studies of oxime supernucleophilic systems in the reactions toward toxic
organophosphorus esters have been rationalized in a terms of micellar kinetic in relation to the oxime
structure and basicity [31, 34-39]. The CMC values for the Phe-derived SAILs reported in [16], see
Scheme 1, are significantly (up to 10 times) lower than those for conventional surfactants with the
same length of the side chain. This phenomenon was supposed to be related with the role the aromatic
ring of Phe moiety plays in the aggregation. The pyridinium headgroup non-functionalized Phe-
derived ester IL with n-butyl chain (R= C H ) has considerably high, as for practical use, CMC value
4
9
of 60 mM, but n-octyl derivative (R= C H ) was reported to demonstrate CMC ca. 2 mM that is
8
17
comparable with much less (bio)degradable conventional cationic surfactants with tetradecyl or
hexadecyl chains. Combined with data on toxicity and biodegradability [15, 16], it makes octyl
derivatives among the most suitable SAILs for practical applications. The short-chain Phe-derived
oxime (n-butyl esters and amides, see Scheme 1) have been recently reported as the potential
antidotes-reactivators of human acetyl cholinesterase inhibited by OP insecticide paraoxon and nerve
agents sarin and VX [40]. Our approach presented in this work includes extension of the side chain of
the hydroximinopyridinium IL-based short-chain salts [40] in order to obtain amphiphilic oximes
/
functional surfactants [41], which may lead to the environmentally benign micellar systems for
chemical decontamination [31]. Since oxime possess alpha effect properties in its deprotonated form,
the acid dissociation constant (pK ) [29] is an important physicochemical parameter to analyze the
a
“effective pH” allowing oximate ion (zwitterionic species of the structures represented on the Scheme
1
) attack the unsaturated center of a substrate [42, 43]. The apparent pK of oxime values may vary in
a
the presence of an added surfactant of different structure in the mixed micellar systems [38, 39].
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Scheme 1. Phe-derived non-functionalized SAILs [15] (top left), their short chain oxime-
functionalized antidotes [34] (top right), and oxime-functionalized IL-derived surfactants with n-octyl
chain reported in this work.
Analysis of acid-base equilibria of the environmentally benign amphiphilic oximes and observed
effects towards OP, either real agents or their low toxic simulants, may give a clue to the designing
biodegradable constituents for chemical decontamination systems.
Scheme 2. Structure of surfactants and OP substrate used in the present work.
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We report here the synthesis and characterization of a series of novel IL-derived amphiphilic
oximes 4-PyC8, 4-PyAlaC8, 2-PyPheC8, 3-PyPheC8, and 4-PyPheC8 (Scheme 1) followed by the
studies of their biodegradability under aerobic aquatic condition using Closed Bottle Test (OECD
3
01D). We present determination of pK values of oximes studied in the bulk and in the presence of
a
gemini (16-4-16 and 12-10-12) and anionic (SDS) surfactants (see Scheme 2), along with kinetics of
the oximolysis of model OP, 4-nitrophenyl diphenyl phosphate (PNPDPP) in the presence of one of
the above surfactants at “mild” pH values of 8.35 and 9.00.
2
. Experimental Section
2
.1 Materials
All commercial chemicals and solvents were purchased from Sigma Aldrich, Alfa Aesar, or TCI
Europe and used without further purification. Silica gel 60 F254 plates were used for TLC. Gemini
surfactants were synthesized in the laboratory of Dr. P. Quagliotto, Department of Chemistry,
University of Torino, Italy. PNPDPP was prepared at Defence Research Development Establishment,
Gwalior (India), sodium dodecylsulphate (SDS), potassium dihydrogen phosphate and dipotassium -
hydrogen phosphate were purchased from Sigma - Aldrich and used without further purification. All
the reagents used were of analytical grade. Double distilled or demineralized water was used
throughout the experiments.
2
.1.1. Characterization of products. Melting points were determined with Stuart SMP40 apparatus
with parameters for the melting point analysis set at 2°C per minute ramp; values are expressed in °C.
The HRMS identification of compounds was performed on Agilent 6540 UHD Accurate-Mass Q-TOF
LC/MS G6540A Mass Spectrometer. Bruker Avance III 400 MHz spectrometer operating at 400 MHz
1
13
for H-NMR and 101 MHz for C-NMR. Samples were recorded in deuterated chloroform (CDCl ) or
3
dimethyl sulfoxide (DMSO-d ) where appropriate. All chemical shifts δ are reported in parts per
6
million (ppm) are relative to the internal standard TMS and coupling constants (J) are measured in
Hertz (Hz).
2
.1.2. Synthesis of the IL-derived amphiphilic oximes
We report synthesis of the series of novel SAILs-derived oximes obtained from corresponding amines
similar to a general Scheme 3 similarly to the method published for amide ILs [44, 45] and a series of
L-phenylalanine (Phe) ILs we have published previously [13, 16]
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Scheme 3. General method of synthesis of oximes studied in this work.
Precursors C AlaNH and C PheNH were synthesized from corresponding commercially available
8
2
8
2
Boc-protected amino acids (see Scheme 4).
Scheme 4. Synthesis of key precursors for studied oximes.
Boc-protected octylamides. The corresponding N-(Boc)-L-amino acid (0.05 mol; Boc-N-Phe or Boc-
N-Ala) was dissolved in dry DMF (25 mL) under argon atmosphere and the reaction mixture was
cooled to 0ºC. Then to stirred solution was added portionwise carbonyldiimidazole (8.11 g; 0.05 mol).
The reaction mixture was stirred 15 min more after stopped of gas formation. After that, solution of 1-
octylamine (8.26 mL; 0.05 mol) in alcohol-free amilene-stabilized chloroform (25 mL) was added
dropwise to reaction mixture. The reaction mixture was stirred 24 hours at room temperature under
argon atmosphere. After that, solvents from reaction mixture was evaporated in vacuo, residue
dissolved in chloroform (100 mL) and washed with 0.1 N HCl (2 x 50 mL), 0.1 N Na CO (2 x 50
2
3
mL) and water (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and
concentrated in vacuo to afford the title compounds. The yields were 95–97 %.
Boc-deprotection of C AlaNH and C PheNH ). To a solution of corresponding N-(Boc)-L-amino acid
8
2
8
2
octyl amide (0.05 mol) in ethanol (150 mL) was added PTSA∙H O (12.36 g; 0.065 mol) and refluxed
2
with stirring for 12 hours. Then solvent was removed in vacuo. Residue was dissolved in chloroform
(
150 mL) and washed with solution of Na CO (0.1 mol; 10.6 g) in water (150 mL), and then with
2 3
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water (2 x 100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in
vacuo to afford the title compounds (yield 96–98 %).
Synthesis of N-bromoacetyl derivatives.To a stirred solution of the corresponding substituted amine
(
0.05 mol) in alcohol-free chloroform (50 mL) was added solid Na CO (7.95 g, 0.075 mol). To this
2 3
mixture was added dropwise bromoacetyl bromide (5.65 mL, 0.065 mol) and stirred for 12 hours.
Then 50 mL of water added carefully to reaction mixture and then transferred to a separating funnel.
The organic layer was separated, washed with 0.1 N Na CO (2 x 50 mL) and water (3 x 50 mL). The
2
3
organic phase was dried over sodium sulphate, filtered, and volatiles were removed in vacuo to afford
the title compounds. The yields were 94–98 %.
Synthesis of pyridinium aldoximes. The stirring solution of corresponding N-bromoacetyl derivative
(0.01 mol) and corresponding pyridinealdoxime (1.22 g; 0.01 mol) in 25 mL of acetone (for 2- and 3-
pyridine aldoxime) or 25 ml of methanol (for 4-pyridinealdoxime) was refluxed for 12 hours. After
cooling to room temperature the solid product was filtered, washed with cold acetone(3 x 10 mL), then
with diethyl ether (2 x 20 mL), and dried in vacuo. The titled compounds was isolated with yields 38 –
1
13
7
0 %. H and C NMR spectra, HRMS and mp of the obtained compounds are collected in the
Appendix A.
2
.2 Methods
2
.2.1. Aerobic biodegradation test.
Biodegradation was studied using the Closed Bottle Test (CBT) method OECD 301D described in
the previous papers [12, 13]. Effluent from wastewater treatment plant was collected from a municipal
wastewater treatment plant in Tallinn, Estonia (Paljassaare wastewater treatment plant, 59°27'55.5"N
2
4°42'08.8"E). WWTP effluent was filtered through a Whatman cellulose filter paper (90 mm
diameter, Grade 1, pore size 11µm) before being used as inoculum. Aerobic biodegradation testing
was done using modified CBT (OECD 301D). CBT setup with modification where biological oxygen
consumption is measured with an optode oxygen sensor system using PTFE-lined PSt3 oxygen sensor
spots (Fibox 3 PreSens, Regensburg, Germany) allows measuring BOD without opening the flasks and
thereby reducing the number of parallels needed for each compound and increasing test throughput. It
has also shown to improve reproducibility compared to the original OECD 301D guideline [46]. Each
CBT run consisted of four different series, each have been repeated in duplicates. First was „reference
-1
series“ in which readily biodegradable sodium acetate in known concentration (6.41 mg L ) was
added to a flask of mineral medium inoculated with effluent from wastewater treatment plant. In „test
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series“ test compound, as a source of carbon was added to the inoculated mineral medium. The test
compound was added in concentration corresponding to theoretical oxygen demand (ThOD) of
approximately 5 mg/L. ThOD was calculated assuming nitrification would take place as each of the 25
studied compounds included nitrogen atom(s) in their structure. „Toxicity series“ containing both
sodium acetate and test compound in their respective concentrations were used to evaluate test
compounds’ toxicity against inoculum – if biodegradation values in these bottles were significantly
lower compared to reference series it was concluded that test compound could be inhibiting or even
toxic to microbes in WWTP effluent. Each run was extended from 28 days (suggested by OECD 301D
protocol) to 42 days.
Results from each run were accepted if following criteria were met: i) difference of extremes of
replicate values at the plateau is less than 20%, ii) oxygen concentration in test series bottles must not
fall below 0.5 mg/L at any time, iii) sodium acetate in reference series must be degraded ≥ 60% by day
1
4. Blank bottles oxygen consumption was also monitored to avoid possibility of system turning from
aerobic to anaerobic
2
.2.2. pH measurements
The pH of the buffer solutions was determined using a pH meter Eutech pH 700, equipped with an
Inlab@ Expert Pro glass electrode with an accuracy of ±0.01 units. The pH meter was calibrated
using the two-point calibration method with commercially available standard buffer solutions at pH
4
.00 and 9.00.
2
.2.3. UV-Visible spectroscopy
The spectrophotometric measurements were recorded by Cary 60 UV–Vis spectrophotometer
Agilent Technologies) in the range of 200 – 400 nm. All the spectra were recorded at 27 °C. The
(
solutions of different pH (6.20-10.50) were used in spectrometric analysis. The quartz cells were
attached to Peltier element for maintaining the constant temperature (27 ± 0.5 °C). The stock solution
of the oxime-functionalized salt 4-PyC8 was prepared solution in water, and the stock solutions of
other oximes 4-PyAlaC8, 2-PyPheC8, 4-PyPheC8, and 3-PyPheC8 were prepared in 25% (v/v)
ethanol-water, as they were sparingly soluble in water. An aliquot of 3 mL from stock solution of
0
6
.5mM of oxime in double distilled water was diluted with 25 mL phosphate buffer solution of pH
.2 and the spectrum was recorded using buffer solution as a blank. The pH was calibrated to the
desired value by using sodium hydroxide (NaOH) solution. After balancing each pH, the absorption
spectra were recorded at selected wavelengths 200 to 400 nm (Fig. 1). Similarly, the effect of
9

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surfactants (gemini and anionic) with functionalized oximes based ionic liquids were done. The
concentration of surfactants was 10 mM.
2
.2.4. Determination of acid dissociation constant (pKa)
The pK values of all oximes studied in this work have been determined by spectrophotometric
a
method described by Albert and Sergeant [47]. All the spectrophotometric measurements were made
at 27 °C and the spectra were recorded within the range of 200-400 nm. The absorbance spectra of all
the compounds where noted in aqueous solution 4-PyC8 and in 25% (v/v) ethanol-water 4-PyAlaC8,
2
-PyPheC8, 4-PyPheC8, 3-PyPheC8 of different pH, see Fig 1. The shorter wavelength absorption
maximum, appearing at lower pH values, reflects the absorption of the non-ionized oxime group(s) in
all investigated compounds, whereas the longer wavelength maximum, observed at higher pH values,
is due to the absorption of the reactivator with an ionized oxime group(s). The pH-dependent
absorption spectra show the presence of isosbestic point. The pK values have been evaluated from
a
the absorbance vs. pH data by the general method of Albert and Sergeant using eq. 4.
The ionization behavior of oxime may be represented as,
HA ⇌ H ꢀ A−
+
(1)
Then the apparent acidity constant K of the acid HA is defined as the equilibrium constant
a
ꢂ
ꢄ
[
ꢁ ] [ꢃ ]
퐾a =
(2)
[ꢁꢃ]
By taking the logarithms and reconstructing the equation. (2) we get the Henderson- Hasselbalch
equation
[
ꢃ_]
pH = p퐾 ꢀ log [
(3)
a
ꢁꢃ]
This equation can be written as shown in equation (4)
ꢃbs −ꢃbs
φ
ꢇOꢈ
p퐾 = pH ꢆ log
(4)
a
exꢅ
ꢃbsOꢈ−ꢃbsφ
where, AbsHOx is the absorbance of unionized form of an oxime, Abs is the absorbance of
Ψ
partially ionized form of oxime, and AbsOx is the absorbance of completely deprotonated form of
oxime at particular pH.
2
.2.5. Reaction kinetics
The pseudo-first order rate constants for the hydrolysis of PNPDPP phosphate esters in the presence of
different composition of concentration of the oxime 4-PyC8 were determined at 8.35 and 9.00 pH at
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◦
2
7 C. The reaction were monitoring as the appearing of the leaving p-nitrophenoxide anion at
wavelength 400 nm shown in Fig. 1 recorded by Cary 60 UV–Vis spectrophotometer (Agilent
Technologies) with a temperature controller (Peltier element). Phosphate buffer (0.1 M) was employed
to control the pH for all the reaction process. All the pH measurements were obtained using a pH
meter Eutech pH 700, equipped with an Inlab@ Expert Pro glass electrode with an accuracy of ±0.01
units. All kinetic reactions were conducted under pseudo-first order conditions, i.e. with large excess
of oximate anions over the PNPDPP.
Fig. 1. UV-vis spectra collected at different reaction times showing the increase in absorbance of p-
nitrophenoxide anion for the cleavage of PNPDPP with 4-PyC8.
[
PNPDPP] = 0.5 mM; [4-PyC8] = 1.0 mM; pH 9.00; 27 °C.
Each experiment was repeated until observed rate constants were reproducible within an accuracy
of ±5% or better. For all the kinetic reaction run, the plots of absorbance verses rate results fits very
well for the first–order rate equation (5).
ln(퐴 ꢆ 퐴 ) = ln(퐴 ꢆ 퐴 ) ꢆ 푘푡 (5)
∞
t
∞
ꢉ
The progressive reaction of pseudo-first–order rate constants (k ) were determined from the plots
obs
of absorbance verses time with
,
, and
being the absorbance significance at zero, time and
infinite time, respectively. The substrate (PNPDPP) concentration was being kept constant for all the
kinetic runs (0.05 mM). The reaction were performed at various concentration of functionalized
1
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oxime-based 4-PyC8 to explore the effect of an amphipnilic oxime on the cleaving potency of
PNPDPP.
3
. Results and Discussion
3
.1. Biodegradability of IL-derived oximes
Studies into the ultimate biodegradability of studied amphiphilic oximes have been set a
requirement for implementation of the EU regulation on detergents [48]. Ultimate biodegradation, or
mineralisation, is achieved when the test compound is totally utilized by microorganisms (inoculum)
resulting in the production of primarily carbon dioxide, water, mineral and salts. In the stringent tests,
such as CBT, it is used to operate the term “readily biodegradable” for those chemicals which have
passed CBT showing 60% of biodegradability or more. It is assumed that such compounds will
rapidly and completely biodegrade in aquatic environments under aerobic conditions. Compounds for
which there is unequivocal evidence of biodegradation in the extent from 20% to 60% are called
inherently biodegradable. An extension of the time of the experiment (e.g. from the standard 28 days
to 33 or 42 days) may provide an additional insight into the inherent biodegradability of the sample.
The “traffic light” classification [49] is used to facilitate recognition of the certain biodegradability, to
place the green light for readily biodegradable chemicals, amber light for inherently biodegradable,
and red light – for those that have not reached 20% threshold of the biodegradability during the test.
The studied oximes have different solubilities in water so only in the case of 4-PyC8 water was used
to prepare its stock solution. For the oximes 4-PyAlaC8, 2-PyPheC8, 3-PyPheC8, and 4-PyPheC8
the DMSO was added along with MilliQ water to overcome this solubility issue and prepare their
stock solutions. To negate the effect of inoculum, blank bottles containing only inoculum and mineral
medium were added to the CBT run and the values of these bottles were subtracted from other bottles
of IL-derived oximes (“blank DMSO”). Another set of DMSO constituting blank was also added to
negate the effect of inoculum and DMSO. The data on CBT within 28 days and 42 days are collected
in the Table 1. It’s worth noting that none of the samples passed CBT within 28 days whereas
extension to 42 days demonstrate tendency of the studied salts to biodegrade, see Table 1, Fig. 2, and
Fig. S1-S2. The amide salt 4-PyC8 demonstrate low biodegradability (11%) even after 42 days, even
since the biodegradation slightly accelerates (ascending curve to develop) after the induction period
about 20 days of the no plateau reached yet upon the 42 days, see Fig. 2a. Alanine derivative 4-
PyAlaC8 shows better results (19% after 42 days) but not overcoming 20% threshold, Fig. 2b. All
three phenylalanine derivatives demonstrate comparable tendency to biodegradability: 20% (3-
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PyPheC8), 24% (2-PyAlaC8), 25% (4-PyAlaC8) after 28 days, and 34% (3-PyPheC8), 37% (2-
PyAlaC8), and 39 % (4-PyPheC8) after 42 days, Fig. 2c, Figs. S1-S2. The biodegradability for all
oximes are inferior to that of the parent phenylalanine SAIL, see Table 1. Thus, short-chain ethyl Phe
IL is a readily biodegradable (mineralisible) compound within standard 28-days CBT [12, 13], and
the decanoyl (C10) derivative SAIL can be characterized as inherently biodegradable based on 28-
day run [16]. The data presented in Table 1 confirms that the Phe ILs-derived oximes can be
considered as inherently biodegradable amphiphiles.
Table 1. CBT results on biodegradability of studied oximes and their non-functionalized Phe-derived
IL precursors; color coded according to the traffic light classification [49]
Structures
D% 28 days
D% 42 days
4
-PyC8
4
11
19
37
34
39
4
-PyAlaC8
9
2
3
4
-PyPheC8
-PyPheC8
-PyPheC8
24
20
25
-
-
6
3
3 [13]
6 [16]
PhePyC2
PhePyC10
There are several possible resons causing lower biodegradability for the IL-derived oximes, compared
to parent ILs. The PhePyCn salts reported in our recent paper [16] have been prepared based on the
-
Phe esters (from C2 to C16), and are not tolerant to the nucleophilic attack of OH under alkaline
conditions or to the esterolysis by oximate ion. To expand the window of pH for potential application
(
chemical decontamination, in essence), the C8 oximes have been prepared as amides, tolertant to
hydrolysis in the wide interval of pH. Enzymatic cleavage of the amide bond of the shorter chain salts
C4) by the inoculum microorganisms occurs slower than esterolysis [50].
(
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a
1
00
90
80
70
60
50
40
30
20
10
0
Test Substance
Quality Control
Meas. Toxicity Control
Calc. Toxicity Control
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
TIME (DAYS)
1
00
b
90
80
70
60
50
40
30
20
10
0
Test Substance
Quality Control
Meas. Toxicity Control
Calc. Toxicity Control
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
TIME (DAYS)
1
00
c
90
80
70
60
50
40
30
20
10
0
Test Substance
Quality Control
Meas. Toxicity Control
Calc. Toxicity Control
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
TIME (DAYS)
1
4

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Fig. 2. Biodegradability data for 42 days CBT experiment; a - 4-PyC8; b - 4-PyAlaC8; c - 4-PyPheC8
An additional factor one should take into account is an order of cleaving two amide bonds present in
the IL-derived oxime stucture. It was pointed out [13] that it is amide bond from the N-side of Phe to
be cleaved first to provide readily biodegradation of the PhePyC2 salt. Cleavage of the C-side bond
resulted in accumulation of the corresponding pyridinium linked phenylalanine carboxylic acid that is
more persistent than pair of the transformation product Phe-ester (Phe-amide) + N-
carboxymethylpyridinium salt. Another reason of the retardation of biodegradation as compared to
the parent ILs could be introducing oxime moiety into the pyridinium ring that makes the
biotransformation process more complex, as compared to pyridinium itself. The abilities of most
fungi and bacteria to metabolize Z-oximes to use them as a source of reduced nitrogen is described
eslewhere [51], the most usual mechanism to be conversion into the corresponding nitrile, amide, and
carboxylic acid with a concomitant release of ammonia. Therefore, this process is expected to occur
in the presence of oximinomethyl pyridinium salts irrespectively of the side chain structure. Indeed,
the position of the oximino moiety does not affect the CBT results. At the same time, the
biodegradability is dependent on the amino acid structure and follows the tendency Phe> Ala> amide.
This tendency supports that the introducing amino acid fragment into the surfactant structures
increases its biodegradability, compared to the amide salts. We suggest that better biodegradability
of the Phe-containing salts as compared to Ala analogs may be related to facilitated enzymatic
aminolysis of the Phe salts as the first transformation stage. Therefore, the Phe-containing oximes are
the most promising functional compounds in the series. Due to their inherent biodegradability, they
can be among prospective candidates for environmental application, in particular, to use as a basis for
chemical decontamination formulations. Even if they did not fulfil the criterion of ultimate
biodegradation within the stipulated period, these amphiphilic oximes can be considered, according to
current detergent regulation [48] for special applications, i.e. those the chemical decontamination can
be referred to.
3
.2. Acid dissociation constant (pKa)
The acid base equlibrium of oxime can be represented as below (Scheme 5).
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5

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Scheme 5. Schematic representation of the acid-base equilibrium of the amphiphilic oxime 4-
PyC8.
A number of approaches have been used to determine the pK value including potentiometry,
a
conductometry, spectrophotometry, solubility, and liquid–liquid partitioning. Out of all the
techniques UV–Vis absorption spectrophotometry is used to be more reproducible and required lesser
amount of analyte. This technique requires very low analyte concentrations and can measure
absorbance in aqueous solution even for products with low solubility in water [52-57]. There are
number of the studies on oximes with reported pK values determined by means of spectrophotometry
a
in water [28, 58] as well as in aqueous mixture with organic solvent [29] (e.g. 50% (v/v) water-
acetonitrile [58]). Mixture of water with water-miscible organic solvent are used to apply to
determine the pK values for compounds imperfectly soluble in water [59-62]. We considered the
a
average values of ten measurements as the pK of the compound with respect to oxime group,
a
following the recommendations of the paper [63].
The absorption spectra of different oximes at various pH values 6.20 - 10.50 are shown in Fig. 3.
The change in the absorption spectra with the change in the pH indicates that the dissociation of the
oxime group into the oximate occurs in the studied pH range. The absorption spectra of all studied
salts show mainly two pH dependent absorption maxima: (i) the shorter wavelength absorption
maximum, appearing at lower pH values in the range from 280 to 300 nm, reflects the absorption of
the non- ionized oxime group in all the analyzed compounds, (ii) the longer wavelength maximum,
observed at higher pH values in the range from 345 to 350 nm, is due to the absorption of the
ionized oxime group [64]. Both maxima are in accordance with the change of π→π ⃰ transitions within
the aromatic ring of pyridinium ring. Upon increasing the pH, the absorbance of the shorter band
decreases, while that of the longer band increases. A typical effect of pH on the absorption spectra of
all functionalized oxime based ionic liquids were reflected by the dissociation of either oxime groups
exhibits a well organized by overlapping ionization equilibria i.e., isosbestic point at 310 nm denoting
-
the existence of an equilibrium essentially an acid base between the NO , which has an absorption
maximum at 345 to 350 nm and the other form NOH, which has an absorption maximum at 280 to
3
00 nm [64]. It was observed that the resulting pK values revealed that pH of the oximes were
a
between the pH range of 7.89-8.48 which had the oxime group at ortho and para position whereas
1
6

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when the oxime was present at meta position its pH was found to be have pK values 9.00. The pK
a
a
values are collected in Table 2.
The absorbances of 4-PyC8 at 280 and 350 nm, for 4-PyAlaC8 at 280 and 350 nm, for 2-
PyPheC8 at 300 and 350 nm, for 4-PyPheC8 at 285 and 345 nm and for 3-PyPheC8 at 245 and 290
nm were plotted against pH values of the buffer solution shows the solid curves represent the non
linear regression square fit curves (inset of Fig. 2) is obtained. It was seen that the pK of 3-PyPheC8
a
(
9.05) was moderately higher as compared to the pK of 4-PyC8, 4-PyAlaC8, 2-PyPheC8, and 4-
a
PyPheC8 (8.08-8.48) were found to be in lower range. These differences in the pK values can be
a
explained with the help of resonating concepts in which the meta position of oxime group of 3-
PyPheC8 having comparatively lesser resonating structure than that of 4-PyC8, 4-PyAlaC8 and 4-
PyPheC8 in which oxime having oximino group at para position and compound 2-PyPheC8 having
oximino group at ortho position respectively. As they proceed through a resonating structure where
the positive charge of pyridinium ring have established oneself on the carbon atom at second and
forth (ortho and para position) isomers. These circumstances allow oxime to demonstrate more
remarkable electron withdrawing effect as compared to 3-PyPheC8, i.e, third isomer (meta position)
which lead to the lower pK values of second and forth (ortho and para position) isomers [63].
a
Apparently, the pK value was ruled by the position of oximino function in pyridinium ring and the
a
position of linker had a little effect in corresponding pK value. In structure of functionalized oxime
a
based ionic liquid, presence of oxime along with their position (ortho and para) play an important
role on the reactivation and detoxification of OP compounds [33].
3
.2 Effects of added surfactants on the pKa,app of oxime
The micellar systems can be regarded to be a system consisting of an aqueous phase and a micellar
pseudophase [65, 66]. Micelles can influence the pK values of protogenic groups due to the
a
combination of electrostatic and minute environmental effects of the micellar system [67-70]. The
effect of micellar systems on acid-base equilibria has been suggested to arise from an intrinsic factor
(due to the energy difference between the aqueous and the nonpolar media) and a potential effect that
is due to the electrically charged micellar surface [68].
The incorporation of the studied oximes into the mixed surfactant aggregate can affect their the
acid-base equilibrium. The appeared effects will depend on hydrophilic-lipophilic balance of oxime
amphiphile and nature of micellar surface [67]. For analysis of this influence we have chosen two
gemini surfactants with different properties of the aggregate surface (12-4-12, 16-10-16) and one
1
7

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anionic surfactant (Scheme 2) and have studied an ionization process in pH range 6.20 - 10.50. The
absorption spectra are shown in Fig. 4. The pK for each wavelength was calculated using Eq. 4. The
a
pK values of studied salts, which were determined without any added surfactant, are used as a
a
reference in presented analysis, see Table 2.
a
b
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8

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c
Fig. 3. Representative absorption spectra of oximes (a – 4-PyC8; b – 4-PyAlaC8; c - 4-PyPheC8; at
different pH values; water, 27 °C. Inset: plots against pH and absorbance for oximes in
aqueous solution of [Ox] = 50 mM; pH = 6.20...10.50.
0
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9

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The data indicate that the interchange of the neutral form of functionalized oxime based ionic liquids
-
(
HA) is stronger than that of the anionic species (deprotonated oximes A ) [71]. The effect of SDS on
the observed dissociation constant of oxime based ionic liquids, having higher pK . It is of interest to
a
explain the increase in the pK values in the micellar phase, because SDS as an anionic surfactant and
a
form the anionic micelles so as to concentrate the protons in the aggregate’s interface and slightly
suppressed the protonation of the aromatic oxime group [72-74].
The presence of cationic surfactants in mixed micellar system with oxime-functionalized
surfactants was reported previously elsewhere [37, 39] to cause decreasing of apparent pK value
a
(pKa,app) of the oxime moiety. In this study, we did not report a significant effect of the surfactant on
the deprotonation constant, they remain within the standard experimental errors, see Table 2. We also
report here that the role of the gemini head group structure on the pK of oximes is negligible, in spite
a
of the fact that 12-4-12 with relatively rigid spacer tend to form different aggregates as compared to
1
6-10-16, gemini surfactant with a long flexible spacer. We may suggests that levelling this
difference off is a result of interaction of amide bond with micellar surface repulsing oxime moieties
outside the micellar surface. The moderate hydrophobic properties of n-octyl chain and introduction
of the amino acid fragments (in essence, hydrophobic phenyl ring of Phe promoting micellization of
the Phe SAILs [16], see Scheme 1), the factors promoting micelle formation, seems not to be factors
sufficient to outweigh this interaction and move oxime moiety closer to the micellar surface. SDS
increased basicity of the hydroximino groups could be explained in terms of electrostatic interactions
at the negatively charged SDS aggregate interface (anion repulsion and cation attraction). This
surfactant affected the oxime group of all examined functionalized oxime based ionic liquids in the
same manner; that is, an increase of basicity due to its negatively charged interface acted to stabilize
the protonated hydroximino group. Decreasing apparent oxime basicity in the presence of anionic
SDS suggested hydrophobic interactions under the experimental analysis and lipophilic hydrocarbon
chain that takes oxime group apart [74]. In other words, these two effects are against each other and
showed higher variation in the pK values. The positively charged pyridinium headgroup undergo
a
repulsion in the interaction to the cationic gemini headgroups so hydrophobic interaction remain the
only driving force to form the mixed aggregates in such a system. This may not cause sufficient shift
of the pKa,app value of the oxime group.
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0

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Table 2. Acid dissociation constants of studied oximes in the absence and in the presence of
surfactants; 27 °C, [D] = 10 mM.
0
pKa,app
b
Sr.No.
Oxime
Medium
pKa
(in presence of surfactants)
1
2-4-12
8.21
16-10-16
8.22
SDS
8.93
1
2
.
.
4-PyC8
Water
8.08
8.12
4-PyAlaC8
25% (v/v)
8.27
8.24
8.82
Ethanol-Water
3.
4.
5.
4-PyPheC8
3-PyPheC8
2-PyPheC8
25% (v/v)
Ethanol- water
8.48
9.00
7.89
8.21
-
8.25
9.21
7.98
9.25
-
25% (v/v)
Ethanol- water
25% (v/v)
8.01
9.40
Ethanol- water
a
a
a
6
7
8
.
.
.
2-PAM
3-PAM
4-PAM
b
Water (1M KCl)
Water (1M KCl)
Water (1M KCl)
8.04 + 0.05
8.61 + 0.04
9.51 + 0.06
-
-
-
-
-
-
-
-
-
a
Notes: - ref. [28, 75]; water; CMC of 12-4-12, 16-10-16 and SDS reported in literature are 1.17 mM [76],
.051 mM [77] and 8.2 mM [78], correspondingly
0
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Fig. 4. Absorbance spectra of mixtures of IL-derived oximes (a – c, 4-PyC8; d – f, 4-PyAlaC8) with gemini surfactants 16-10-16
and 12-4-12, and anionic surfactant SDS. [Oxime] =50 mM; [D] = 10 mM; 27 °C. Inset: Plots of absorbance vs pH for
0
0
studied oximes in micellar solution.
2
2

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4
. Effect on cleavage of PNPDPP
The main expected advantages of low toxicity/biodegradable functional surfactant systems is an
opportunity to ensure environmentally benign decontamination. PNPDPP is a phosphotriester
which has been widely recruited as a stimulant (surrogate) and its hydrolytic reactions have been
investigated [30, 38, 79, 80], see Scheme 6. Since PNPDPP is water insoluble,
microheterogenerous (micellar, in essence) systems have been generally enroll as a reaction
mechanism for the cleavage of PNPDPP. In such a medium, the organic reactants are partitioned
into the surfactant aggregates by electrostatic and hydrophobic interactions. The observed rate
assistance occurs mainly due to the increased localization of the reactants as well as the typical
physical chemical properties of the micellar environment, which is remarkably different from
those of the bulk solvents.
Scheme 6. Nucleophilic attack at phosphorus atom of PNPDPP
The 4-PyC8 was taken to estimate the reactivity in process of OP cleavage. In order to
determine the efficiency of IL-derived oxime 4-PyC8 in decomposition of PNPDPP, kinetic
studies have been performed at two different pH. The first-order rate constants been determined at
pH 8.35 and 9.00, see Fig. 5. The nucleophilic concentration dependent first-order rate constants
were determined spectrophotometrically for the reaction of PNPDPP with oxime in excess (Table
3
; Scheme 6). The rate constant increases in both the concentration of nucleophilie and pH of the
system. The obtained kinetic data entirely supports the hypothesis that oximate ion acting as a
reactive species and possesses its α-effect properties. The observed reaction rates at pH 9.0 are
substantially higher than reported in our previous study [38] for all oxime-functionalized
surfactants (N-alkylated oximino pyridinium salts with C10 to C14 side chain), and comparable
-1
-1
(
but still higher, 0.0177 s vs 0.0162 s ) to cetyl derivative.
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3

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Table 3. Hydrolysis of p-nitrophenyl diphenyl phosphate (PNPDPP) in the presence of 4-PyC8.
Reaction condition: [PNPDPP] = 0.5 mM; 27 °C.
3
-1
1
0 k (s )
obs,
pH
Sr. No.
[D] mM
8.37
9.00
1
2
3
4
5
.
.
.
.
.
0
0.76
2.57
5.44
11.10
9.67
5.72
9.27
0.5
1.0
3.0
5.0
13.30
17.70
15.90
-1
Fig. 5. Observed pseudo-first order rate constants (k , s ) vs. [4-PyC8] for reaction of PNPDPP
obs
0
cleavage; water, 27
̊C ; [PNPDPP] = 0.5 mM.
Taking into account binding constant K of PNPDPP, a very hydrophobic OP substrate to be
S
4
-1

10 M [37], the second-order rate constant can be estimated from k according to Eq. 6
obs
'
2
m
2
kobs,max  (k /V )  (k /V ) 
(6)
m
m
m
−1 −1
where k , M
s
is the second-order rate constant characterizing the nucleophilicity of the
2
−
1
oximate fragment, V , M is the partial molar volume of surfactant, which for this type of
m
2
4

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−
1
surfactants usually 0.4 M , α – degree of deprotonation of the nucleophilic moiety. With the
m
parameter α equal to 0.66 and 0.89 at pH 8.4 and 9.0, correspondingly, the k2 values can be
−
1
−1
−1 −1
calculated from kinetic data, which gives the values of 6.7 M s (pH 8.4) and 7.9 M s (pH
−
1 −1
9
.0) M s .
The practical procedure of chemical decontamination requires the smallest time possible for
detoxification of an agent. The half-life times for oxymolysis of PNPDPP in optimal concentration
conditions of [4-PyC8] calculated from the kinetic data (Table 3) are found to be ca. 62 s (pH
8
.37) and ca. 40 s (pH 9.00), respectively. The values testify this system is capable to cleave by
half the model OP within one minute of less under mild experimental conditions.
4
. Conclusion
In this work, we presented synthesis of a series of novel IL-derived amphiphilic pyridinium
oximes composed by octylamide tail linked to the headgroup by means of amide (4-PyC8), alanyl
4-PyAlaC8), or phenylalanyl (2-PyPheC8, 3-PyPheC8, and 4-PyPheC8) moiety. The
(
biodegradability has been examined in the closed bottle test (CBT) to demonstrate that it is
dependent on the amino acid structure and follows the tendency Phe> Ala> amide. Phe oximes
demonstrate 34-39% of degradation in the CBT after 42 days and can be considered as inherently
degradable. The acid ionization constant (pK ) of studied oximes determined by means of UV-vis
a
spectroscopy at 27
oximes changes insignificantly in the presence of cationic gemini surfactants, 12-4-12- and 16-
0-16, and shifted upwards in the presence of anionic surfactant SDS. The oxymolysis of OP
̊ C were found to be in the range from 8.00 to 9.00. The pKa,app of studied
1
triester PNPDPP under optimal concentration conditions of 4-PyC8 occurs with half-life times
ca. 62 s and ca. 40 s at pH 8.37 and 9.00, respectively. Therefore, by means of nucleophilic attack
of the alpha effect nucleophile, this IL-derives oxime system can provide cleavage one half of the
model OP within one minute of less under mild experimental conditions. Results of this study can
be useful in developing green and biodegradable compounds for chemical decontamination
systems.
Acknowledgment
Financial support of this work by the DST-FIST [No.SR/FST/CSI-259/2014(C)] and UGC-SAP
[
No.F-540/7/DRS-II/2016 (SAP-I)] is gratefully acknowledged. IK, NG, and YK acknowledge
funding from EU FP7 under grant agreement No. 621364 (TUTIC-Green). YK acknowledges
NATO SPS MYP No. G5565 (DEFIR). The authors are grateful to Prof. Shamsh Pervez, Head,
2
5

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School of Studies in Chemistry, Pt. Ravishankar Shukla University, Raipur (C.G), India, for
providing laboratory facility.
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