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Cooperativity between various types of polar solute–solvent interactions in aqueous media Pedro P. Madeira a,∗ , Ana Bessa a , Joana A. Loureiro b , Luís Álvares-Ribeiro c , Alírio E. Rodrigues a , Boris Y. Zaslavsky d a Laboratory of Separation and Reaction Engineering, Department of Chemical Engineering, Faculty of Engineering of the University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal b LEPABE, Department of Chemical Engineering, Faculty of Engineering of the University of Porto, 4200-465 Porto, Portugal c Requimte, Dep. Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua Campo Alegre 687, 4169-007 Porto, Portugal d AnalizaDx Inc., 3615 Superior Avenue, Suite 4407B, Cleveland, OH 44114, USA

a r t i c l e

i n f o

Article history: Received 14 May 2015 Received in revised form 29 June 2015 Accepted 1 July 2015 Available online xxx Keywords: Aqueous two-phase partitioning Salt additives Hofmeister effect Solute–water interactions Solvatochromic comparison method

a b s t r a c t Partition coefficients of seven low molecular weight compounds were measured in multiple aqueous two-phase systems (ATPSs) formed by pairs of different polymers. The ionic composition of each ATPS was varied to include 0.01 M sodium phosphate buffer (NaPB), pH 7.4 and 0.1 M Na2 SO4 , 0.15 M NaCl, and 0.15 M NaClO4 all in 0.01 M NaPB, pH 7.4. The differences between the solvent features of the coexisting phases in all the ATPSs were estimated from partitioning of a homologous series of dinitrophenylatedamino acids and by the solvatochromic method. The solute-specific coefficients for the compounds examined were determined by the multiple linear regression analysis using the modified linear solvation energy relationship equation. It is established that the solute specific coefficients characterizing different types of the solute–water interactions (dipole–dipole, dipole–ion, and H-bonding) for a given solute change in the presence of different salt additives in the solute specific manner. It is also found that these characteristics are linearly interrelated. It is suggested that there is a cooperativity between various types of solute–water interactions governed by the solute structure. © 2015 Elsevier B.V. All rights reserved.

1. Introduction It is well known that interactions of any substance from small organic compounds to biological macromolecules with aqueous environment are fundamentally important for their functions in vivo [1–3]. Our current understanding of aqueous solvent–solute interactions is very limited, however. Recognizing the difficulties in describing water and its interactions with solutes on the molecular level led us to propose a new approach to quantify and understand these interactions based on solute partitioning in aqueous two-phase systems (ATPS) [4–6]. Mixtures of aqueous solutions containing two or more polymers (e.g., dextran (Dex) and polyethylene glycol (PEG)) above certain concentrations commonly separate to form two or more coexisting aqueous phases [7–9]. Phase separation occurs in aqueous mixtures of different polymers, including proteins and nucleic acids [10]. The coexisting phases have different solvent properties governing unequal distribution of solutes between the phases, and

∗ Corresponding author. Tel.: +351 225081669; fax: +351 225081674. E-mail address: [email protected] (P.P. Madeira).

aqueous two-phase systems have been suggested as a model for compartmentalization in cells [9–12]. The distribution of a solute in an ATPS is characterized in terms of the partitioning coefficient, K, defined as the ratio of the concentration of the solute in the top phase to that in the bottom phase. The solute preferential distribution between the aqueous phases is mainly driven by different solute–solvent interactions [13–17] and it can be described as [4–6,15–17]: log K = Ss  + Bs ˛ + As ˇ + Cs c

(1)

where K is the solute partition coefficient; , ˛, ˇ and c are the differences between the solvent properties of the top and bottom phases (solvent dipolarity/polarizability, hydrogen-bond donor acidity, hydrogen-bond acceptor basicity, and electrostatic interactions, respectively); Ss , Bs , As , and Cs are constants (solute specific coefficients) that describe the complementary interactions of the solute with the solvent media in the coexisting phases; the subscript s designates the solute. It has been shown recently that the solute specific coefficients may be determined for a given compound (including proteins) by analysis of partition coefficients of the compound in multiple ATPS with different polymers but the same ionic composition

http://dx.doi.org/10.1016/j.chroma.2015.07.002 0021-9673/© 2015 Elsevier B.V. All rights reserved.

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[4–6,15–17]. Once , ˛, ˇ, and c parameters in multiple ATPS are determined, the solute specific coefficients can be calculated by multiple linear regression analysis. It was also shown [6] that the partition coefficients of compounds with pre-determined solute specific coefficients in new ATPS with established solvent properties of the phases could be predicted with 90–95% accuracy. Recent studies [18–22] suggested that the solute properties in aqueous solutions of different ionic composition are linearly interrelated according to: SPsalt-1 = k1 + k2 × SPsalt-2 + k3 × SPsalt-3

(2)

where SP is the solute property (logarithm of partition coefficient in octanol–water system [21], in polymer–polymer or polymer–salt ATPSs [18,20], solubility [19], optical rotation [23]); k1 , k2 , and k3 are constant coefficients dependent on the solute property and salt compositions. These results led us to suggest [18–22] that different solutes respond to different ionic composition by changes in the solute–solvent interactions in the solute structure specific manner. The purpose of the present work was to explore if and to what extent the intensities of the different types of solute–solvent interactions change in the presence of different salts in aqueous solution. For this end partitioning of several different organic compounds was examined in multiple ATPS in the presence of different salt additives. 2. Material and methods

Table 1 Polymer compositionsa of aqueous two-phase systems used for partitioning. ATPS

Polymer 1

[Polymer 1], %wt.

Polymer 2

[Polymer 2], %wt.

S1 S2 S3 S4 S5 S6 S7 S8 S9 S10

Dextran-70 Dextran-70 Dextran-70 Dextran-70 Dextran-70 Ficoll-70 Ficoll-70 Ficoll-70 Ficoll-70 PEG-8000

12.90 13.67 20.00 16.23 12.39 22.99 24.67 23.08 19.12 15.00

Ficoll-70 PEG-4000 PEG-1000 PEG-600 Ucon PEG-10000 PEG-8000 PEG-6000 Ucon Ucon

18.10 6.15 13.57 16.87 10.08 9.90 10.42 9.87 15.47 29.97

a Polymer 1, predominant polymer in the bottom phase; polymer 2, predominant polymer in the top phase; all concentrations of polymers are in %wt.

probes 4-nitroanisole, 4-nitrophenol and Reichardt’s carboxylated betaine (the carboxylated form of the dye of 2,6-diphenyl-4(2,4,6-triphenyl-1-pyridinio)phenolate) were used to measure the dipolarity/polarizability *, H-bond acceptor (HBA) basicity ˇ, and H-bond donor (HBD) acidity ˛ in both phases of each particular ATPS using the technique previously described [6]. The results of the solvatochromic studies were used to calculate *, ˇ and ˛ as described by Marcus [24].(a) Determination of the solvent dipolarity/polarizability * ␲* was determined from the wave number ((1) ) of the longest wavelength absorption band of the 4-nitroanisole dye using the relationship:

2.1. Material

∗ = 0.427(34.12 − (1) )

2.1.1. Polymers Dextran 75 (lot 124339), weight-average molecular weight (Mw) ∼ = 75,000 was purchased from USB (Cleveland, OH, USA). Polyethylene glycol 8000 (lot BCBJ3787V), Mw = 8000; and polyethylene glycol 4000 (lot BCBD2874), Mw = 4000; were purchased from Sigma–Aldrich (St. Louis, MO, USA). Ucon 50-HB-5100 (lot SJ1955S3D2), Mw = 3930 was purchased from Dow-Chemical (Midland, MI, USA). Ficoll 70 (lot 10085600), Mw ∼ = 70 000 was purchased from GE Healthcare Biosciences AB (Uppsala, Sweden). All polymers were used without further purification.

(b) Determination of the solvent hydrogen-bond acceptor basicity ˇ ˇ values were determined from the wave number ((2) ) of the longest wavelength absorption band of the 4-nitrophenol dye using the relationship:

2.1.2. Solvatochromic dyes The solvatochromic probes 4-nitrophenol (reagent grade, >98%), and 4-nitroanisole (GC, >97%) were supplied by Sigma–Aldrich (St. Louis, MO, USA). Reichardt’s carboxylated betaine dye was kindly provided by Professor C. Reichardt (Philipps University, Marburg, Germany). 2.1.3. Dinitrophenylated amino acids Dinitrophenylated (DNP) amino acids – DNP–glycine, DNP–alanine, DNP–norvaline, DNP–norleucine, DNP-DL-␣-aminon-octanoic acid (DNP-AO), were purchased from Sigma–Aldrich (St. Louis, MO, USA). 2.1.4. Other chemicals Phenol, benzyl alcohol, 2-phenylethanol, vanillin, 4nitrophenyl-␣-d-glucopyranoside, coumarin (2H-chromen-2-one) and methyl anthranilate were purchased from Sigma–Aldrich (St. Louis, MO, USA). All salts and other chemicals used were of analytical-reagent grade. 2.2. Methods 2.2.1. Solvatochromic studies The ATPSs of the compositions shown below (see in Table 1) were prepared as previously described [4–6]. The phases were separated and used for solvatochromic analysis. The solvatochromic

ˇ = 0.346(35.045 − (2) ) − 0.57∗

(3)

(4)

(c) Determination of the solvent hydrogen-bond donor acidity ˛ ␣ values were determined from the longest wavelength absorption band of Reichardt’s betaine dye using the relationship: ˛ = 0.0649ET (30) − 2.03 − 0.72∗

(5)

The ET (30) values are based on the solvatochromic pyridinium N-phenolate betaine dye as probe, and are obtained directly from the wavelength (, nm) of the absorption band of the carboxylated form, as ET (30) = 1/0.932(28591/ − 3.335)

(6)

Note that although the ET (30) parameter is described and defined here, it is used only as an intermediary to calculate the value of parameter a, hence the corresponding data for ET (30) are not given. 2.2.2. Partitioning Solutions of each compound were prepared in water at concentrations of 1–5 mg/mL. Varied amounts (e.g., 0, 10, 20, 30, 40 and 50 ␮L) of a given compound solution and the complementary amounts (e.g., 100, 90, 80, 70, 60 and 50 ␮L) of water were added to a set of the same polymer/buffer/salt mixtures using a Multipette Xstream pipette (Eppendorf, Hamburg, Germany). Systems were vortexed and centrifuged (HIMAC, CT15RE, VWR, Radnor, Pennsylvania, USA) for 30 min at 3500 × g at 23 ◦ C to accelerate phase settling. Aliquots of 20–70 ␮L from the upper and lower phases were withdrawn with a Multipette Xstream pipette in duplicate for analysis. Two aliquots from both phases were diluted with water up to 250 ␮L in microplate wells. Following moderate shaking at room temperature (23 ◦ C), a Synergy-2 UV–vis plate reader (BioTek Instruments, Winooski, VT, US) was used to measure optical

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Table 2 Difference between the solvent properties of aqueous media in the coexisting phases of aqueous two-phase systems (ATPS) indicated. ˛

ˇ

0.01 M NaPB, pH 7.4 −0.0015 ± 0.0003 S1 S2 −0.038 ± 0.001 S3 −0.038 ± 0.002 − 0.021 ± 0.005 S4 −0.028 ± 0.013 S5 −0.053 ± 0.001 S6 −0.062 ± 0.003 S7 S8 −0.045 ± 0.001 S9 −0.069 ± 0.004 S10 −0.097 ± 0.009

−0.030 ± 0.006 −0.028 ± 0.005 −0.046 ± 0.008 −0.027 ± 0.001 −0.175 ± 0.020 −0.006 ± 0.001 0.021 ± 0.006 0.006 ± 0.003 −0.124 ± 0.010 −0.084 ± 0.002

0.012 ± 0.0002 0.009 ± 0.005 0.022 ± 0.021 −0.010 ± 0.006 0.034 ± 0.006 −0.0032 ± 0.0002 −0.004 ± 0.004 −0.004 ± 0.001 0.043 ± 0.004 0.062 ± 0.010

0.15 M NaCl in 0.01 M NaPB, pH 7.4a S1 0.003 S2 −0.041 S3 −0.052 −0.040 S4 −0.023 S5 −0.050 S6 −0.061 S7 S8 −0.047 −0.065 S9 −0.117 S10

−0.028 −0.024 −0.061 −0.017 −0.181 −0.014 −0.026 −0.023 −0.138 −0.091

0.010 0.007 0.018 0.005 0.015 −0.029 0.000 −0.001 0.045 0.070

0.10 M Na2SO4 in 0.01 M NaPB, pH 7.4 S1 0.009 ± 0.004 −0.043 ± 0.001 S2 −0.043 ± 0.001 S3 −0.032 ± 0.001 S4 −0.046 ± 0.003 S5 −0.062 ± 0.002 S6 −0.068 ± 0.003 S7 S8 −0.062 ± 0.003 −0.097 ± 0.007 S9

−0.049 ± 0.002 −0.047 ± 0.001 −0.057 ± 0.002 −0.022 ± 0.001 −0.208 ± 0.012 −0.015 ± 0.002 −0.006 ± 0.003 0.004 ± 0.002 −0.152 ± 0.034

0.15 M NaClO4 in 0.01 M NaPB, pH 7.4 −0.059 ± 0.007 S1 −0.026 ± 0.005 S2 −0.048 ± 0.003 S3 S4 −0.032 ± 0.001 −0.044 ± 0.002 S5 S6 −0.054 ± 0.006 −0.064 ± 0.001 S7 −0.053 ± 0.001 S8 −0.084 ± 0.006 S9 −0.082 ± 0.005 S10

0.020 ± 0.008 −0.030 ± 0.006 −0.030 ± 0.011 −0.011 ± 0.001 −0.139 ± 0.007 −0.004 ± 0.002 0.012 ± 0.006 0.004 ± 0.001 −0.106 ± 0.010 −0.087 ± 0.024

ATPS

a



E

c 0.0105 0.0232 0.0442 0.0277 0.0632 0.0267 0.030 0.0195 0.088 0.0968

± ± ± ± ± ± ± ± ± ±

0.0002 0.0001 0.003 0.0008 0.0006 0.0009 0.003 0.0008 0.001 0.0006

0.1095 0.0558 0.093 0.076 0.214 −0.130 −0.056 −0.086 0.134 0.504

± ± ± ± ± ± ± ± ± ±

0.0006 0.0005 0.009 0.003 0.002 0.003 0.005 0.003 0.003 0.002

0.0130 0.0234 0.042 0.0221 0.072 0.01844 0.025 0.0221 0.0903 0.091

± ± ± ± ± ± ± ± ± ±

0.0001 0.0007 0.002 0.0001 0.001 0.00006 0.002 0.0005 0.0006 0.006

0.0481 −0.0371 −0.018 −0.0148 0.041 −0.1262 −0.157 −0.135 0.085 0.60

± ± ± ± ± ± ± ± ± ±

0.0005 0.0003 0.006 0.0004 0.003 0.0002 0.005 0.002 0.002 0.02

−0.008 ± 0.004 0.004 ± 0.002 −0.009 ± 0.007 −0.020 ± 0.014 0.044 ± 0.001 −0.002 ± 0.004 −0.017 ± 0.001 −0.002 ± 0.001 0.046 ± 0.004

0.0194 0.0333 0.060 0.046 0.085 0.0351 0.0431 0.0305 0.121

± ± ± ± ± ± ± ± ±

0.0004 0.0009 0.002 0.001 0.003 0.0005 0.0001 0.0006 0.003

0.139 0.070 0.215 0.139 0.357 −0.020 −0.0070 −0.011 0.456

± ± ± ± ± ± ± ± ±

0.002 0.003 0.006 0.005 0.007 0.004 0.0004 0.002 0.009

0.040 ± 0.005 −0.001 ± 0.003 0.007 ± 0.004 −0.013 ± 0.004 0.046 ± 0.002 0.002 ± 0.001 0.005 ± 0.005 −0.002 ± 0.001 0.049 ± 0.013 0.047 ± 0.003

0.00872 0.0245 0.051 0.037 0.075 0.0315 0.0365 0.0305 0.098 0.082

± ± ± ± ± ± ± ± ± ±

0.00008 0.0003 0.001 0.001 0.003 0.0008 0.0008 0.0003 0.004 0.003

−0.0032 −0.085 −0.140 −0.116 −0.11 −0.192 −0.215 −0.176 −0.16 0.19

± ± ± ± ± ± ± ± ± ±

0.0003 0.001 0.005 0.004 0.01 0.003 0.003 0.001 0.01 0.01

Data reported previously [6].

absorbance at maximum wavelength of each compound. Phases of blank systems at corresponding dilutions were measured for comparison. The partition ratio, K, is defined as the ratio of the compound concentration in the upper phase to the compound concentration in the lower phase. The partition ratio value for each solute was determined as the slope of the plot of the solute concentration in the upper phase as a function of the solute concentration in the bottom phase, obtained from six partition experiments carried out at different concentrations of the solute and at the fixed composition of the system. Deviation from the average K value was consistently below 5%. 3. Results Polymer compositions of ATPS employed in this study are listed in Table 1. For analysis of the solvent properties of the aqueous media in the coexisting phases of ATPS we used the data obtained from partitioning of the homologous series of sodium salts of dinitrophenylated (DNP-) amino acids with aliphatic side-chains of different length (glycine, alanine, norvaline, norleucine, and ␣amino-n-octanoic acid). Partition coefficients of the sodium salts of DNP-amino acids in the ATPS used are presented in Table S1.

Typical experimental data obtained for sodium salts of DNP-amino acids in Ficoll-Ucon ATPS (S18) with different salt additives are plotted in Figure S1, and the linear curves observed may be described as: (i)

log KDNP-AA = C (i) + E (i) NC

(7)

where KDNP-AA is the partition coefficient of a DNP-amino acid with aliphatic side-chain; superscript (i) denotes the particular ith ATPSs used for the partition experiments; NC is equivalent number of CH2 groups in the aliphatic side-chain of a given DNP-amino acid; E is an average log K increment per CH2 group; C represents the total contribution of the non-alkyl part of the structure of a DNP-amino acid into log KDNP-AA and is used to characterize the difference between the electrostatic properties of the coexisting phases as described previously [6,9]. The coefficients E(i) and C(i) values determined for the ATPSs examined are listed in Table 2. As the standard free energy of transfer of a solute from the bottom phase to the top phase is described as: G0 = −RT ln K

(8)

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Table 3 Partition coefficients of organic compounds in aqueous two-phase systems (ATPS) indicated. ATPS

Partition coefficients of organic compounds Phenol

NaPB 0.01 M, pH 7.4 1.29 ± S1b 1.690 ± S2b 2.00 ± S3 S4 1.697 ± b S5 3.16 ± 1.70 ± S6 1.84 ± S7b 1.61 ± S8 3.55 ± S9b S10b 3.35 ±

Benzyl alcohol

2-Phenylethanol

Glucosidea

Vanillin

Coumarin

Methyl anthranilate

1.16 1.370 1.60 1.351 2.09 1.434 1.553 1.361 2.29 2.21

± ± ± ± ± ± ± ± ± ±

0.01 0.006 0.02 0.005 0.01 0.001 0.004 0.009 0.02 0.01

1.17 1.48 1.63 1.37 1.93 1.46 1.51 1.36 2.22 2.43

± ± ± ± ± ± ± ± ± ±

0.05 0.04 0.02 0.07 0.08 0.02 0.03 0.01 0.08 0.04

1.308 1.65 2.15 1.59 3.19 1.572 1.632 1.461 3.14 2.59

± ± ± ± ± ± ± ± ± ±

0.008 0.01 0.01 0.02 0.02 0.009 0.008 0.006 0.02 0.02

1.127 1.122 1.213 1.10 1.508 1.059 1.099 1.021 1.63 2.22

± ± ± ± ± ± ± ± ± ±

0.003 0.004 0.004 0.01 0.006 0.003 0.003 0.005 0.01 0.01

1.244 1.378 1.60 1.32 2.55 1.263 1.363 1.195 2.67 2.92

± ± ± ± ± ± ± ± ± ±

0.002 0.004 0.02 0.01 0.01 0.003 0.004 0.005 0.02 0.02

1.266 1.583 2.065 1.54 3.34 1.46 1.57 1.342 3.65 4.41

± ± ± ± ± ± ± ± ± ±

0.004 0.004 0.007 0.01 0.02 0.01 0.01 0.009 0.01 0.03

1.16 1.41 1.77 1.44 2.245 1.44 1.54 1.33 2.34 2.54

± ± ± ± ± ± ± ± ± ±

0.01 0.01 0.01 0.01 0.006 0.01 0.01 0.01 0.02 0.03

1.03 1.48 1.77 1.40 2.4 1.55 1.60 1.40 2.50 3.11

± ± ± ± ± ± ± ± ± ±

0.03 0.02 0.05 0.05 0.1 0.02 0.01 0.03 0.06 0.07

1.19 1.69 2.15 1.677 3.37 1.75 1.90 1.57 3.98 3.85

± ± ± ± ± ± ± ± ± ±

0.01 0.01 0.01 0.006 0.04 0.02 0.02 0.01 0.05 0.04

1.155 1.106 1.31 1.175 1.61 1.108 1.133 1.070 1.87 2.685

± ± ± ± ± ± ± ± ± ±

0.002 0.005 0.01 0.005 0.01 0.002 0.004 0.005 0.01 0.004

1.164 1.34 1.67 1.37 2.51 1.298 1.402 1.17 2.94 3.92

± ± ± ± ± ± ± ± ± ±

0.007 0.01 0.01 0.01 0.05 0.008 0.004 0.02 0.05 0.02

1.253 1.623 2.037 1.49 3.52 1.613 1.694 1.478 4.81 5.92

± ± ± ± ± ± ± ± ± ±

0.006 0.008 0.006 0.02 0.02 0.008 0.007 0.007 0.08 0.07

Na2 SO4 0.1 M, NaPB 0.01 M, pH 7.4 1.41 ± 0.01 1.18 ± 0.02 S1b 2.004 ± 0.006 1.649 ± 0.008 S2b 2.438 ± 0.008 1.85 ± 0.08 S3 S4 2.18 ± 0.02 1.72 ± 0.01 5.14 ± 0.05 2.85 ± 0.03 S5b S6 2.15 ± 0.01 1.720 ± 0.006 b 2.316 ± 0.006 1.79 ± 0.02 S7 1.931 ± 0.007 1.643 ± 0.005 S8 6.56 ± 0.04 3.63 ± 0.02 S9b

1.36 1.46 2.71 1.77 2.32 1.69 1.54 1.65 3.72

± ± ± ± ± ± ± ± ±

0.02 0.07 0.05 0.05 0.06 0.03 0.04 0.02 0.08

1.475 1.94 2.87 2.01 5.11 2.05 2.168 1.79 5.23

± ± ± ± ± ± ± ± ±

0.004 0.01 0.01 0.04 0.03 0.03 0.005 0.01 0.05

1.21 1.242 1.347 1.323 2.03 1.178 1.25 1.150 2.37

± ± ± ± ± ± ± ± ±

0.02 0.008 0.008 0.008 0.01 0.007 0.01 0.002 0.02

1.358 1.684 2.11 1.76 3.60 1.549 1.686 1.499 4.679

± ± ± ± ± ± ± ± ±

0.005 0.006 0.02 0.01 0.02 0.004 0.008 0.007 0.009

1.463 2.015 2.78 2.15 6.54 1.80 2.10 1.84 7.47

± ± ± ± ± ± ± ± ±

0.005 0.003 0.02 0.02 0.02 0.01 0.02 0.01 0.04

NaClO4 0.15 M, NaPB 0.01 M, pH 7.4 S1b 1.282 ± 0.002 1.121 S2b 1.81 ± 0.01 1.48 S3 2.48 ± 0.02 1.88 S4 1.91 ± 0.02 1.60 S5b 3.84 ± 0.02 2.31 S6 1.952 ± 0.006 1.557 S7b 2.14 ± 0.01 1.664 S8 1.889 ± 0.006 1.512 b S9 4.21 ± 0.02 2.49 b 3.04 ± 0.02 2.15 S10

1.13 1.46 1.60 1.52 2.66 1.60 1.66 1.48 2.65 2.46

± ± ± ± ± ± ± ± ± ±

0.04 0.02 0.06 0.02 0.07 0.02 0.04 0.02 0.07 0.05

1.223 1.758 2.51 1.83 3.62 1.84 1.862 1.700 3.72 2.559

± ± ± ± ± ± ± ± ± ±

0.008 0.008 0.01 0.03 0.02 0.02 0.006 0.006 0.04 0.006

1.079 1.214 1.54 1.303 1.585 1.138 1.187 1.151 1.771 2.02

± ± ± ± ± ± ± ± ± ±

0.005 0.006 0.01 0.006 0.006 0.003 0.003 0.008 0.007 0.01

1.219 1.54 2.08 1.610 3.09 1.465 1.573 1.38 3.24 2.977

± ± ± ± ± ± ± ± ± ±

0.005 0.01 0.01 0.002 0.02 0.007 0.004 0.01 0.02 0.009

1.294 1.828 2.61 2.03 4.69 1.79 1.935 1.66 5.02 4.25

± ± ± ± ± ± ± ± ± ±

0.008 0.004 0.01 0.04 0.02 0.01 0.004 0.01 0.01 0.04

0.02 0.006 0.01 0.007 0.03 0.01 0.01 0.01 0.05 0.06

NaCl 0.15 M, NaPB 0.01 M, pH 7.4 S1b 1.21 ± 0.03 S2b 1.663 ± 0.003 S3 2.38 ± 0.01 S4 1.64 ± 0.01 b S5 3.23 ± 0.02 S6 1.71 ± 0.01 S7b 1.74 ± 0.01 S8 1.63 ± 0.01 S9b 3.82 ± 0.01 S10b 4.28 ± 0.05

a b

± ± ± ± ± ± ± ± ± ±

0.004 0.02 0.02 0.01 0.01 0.004 0.005 0.002 0.01 0.01

Glucoside-p-nitrophenyl-␣-d-glucopyranoside. Data reported previously [26].

where R is the universal gas constant and T is the absolute temperature in Kelvin, it follows that G0 (CH2 ) = −RTE ∗

(9)

where G0 (CH2 ) is the standard free energy of transfer of a methylene group from one phase to another, E* is parameter E (Eq. (7)) expressed in natural logarithmic units. The salt effects observed here are similar to those reported previously [25] in the similar ATPS of different polymer composition in the presence of 0.01 M universal buffer, pH 7.4. The difference between the electrostatic properties of the phases characterized by the parameter C value (Table 2) as expected changes with the salt additive type more dramatically than the E value. Each of the solvent parameters *, ˛, and ˇ were obtained from a set of single solvatochromic probes as previously described [4–6,25]. The differences between the solvatochromic parameters values found for the top phases and for the corresponding bottom phases are presented in Table 2. The data reported earlier [6] for the same ATPSs with 0.15 M NaCl in 0.01 M sodium phosphate buffer (NaPB), pH 7.4 is also presented in Table 2 for comparison. The changes in the differences between the solvatochromic solvent

properties of the coexisting phases in the presence of different salt additives agree with the data reported previously [25]. The partition coefficients of nonionic organic compounds and vanillin in all the ATPS employed are presented in Table 3. The data reported earlier [26] for the ATPS S1, S2, S5, S7, S9 and S10 are also presented in Table 3 for comparison.

4. Discussion It has been reported [27] by some of us recently that different polymers (dextran, polyethylene glycol, Ficoll, Ucon, and polyvinylpyrrolidone) used for ATPS formation change the solvent dipolarity/polarizability, hydrogen bond donor acidity and hydrogen bond acceptor basicity of water in their solutions with the polymer concentration up to 40%w/w. Polymer-induced changes in these features were found to be polymer type and concentration specific, and, in case of polyethylene glycol, molecular mass specific. It has been shown [27] that the polymer-induced changes in the solvent properties of water may explain some of the effects of these polymers when used as macromolecular crowding agents.

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It should be emphasized that as mentioned above partition coefficients of organic compounds and even proteins in ATPS formed by different pairs of these polymers are described by Eq. (1) with the constant solute-specific coefficients indicating that the different types of solute–solvent interactions in all these systems are similar. This experimental fact indicates that the solute-specific coefficients represent the different types of solute–water interactions. The solvent properties of water are varied in ATPS due to the polymer- and salt additive-induced changes in the solvent properties of the phases. Analysis of the parameter E values using Eq. (1) (replacing log K with E value) shows that this parameter is interrelated with the solvent properties of the coexisting phases as: EiNaPB = −0.58±0.06 i∗ NaPB − 0.24±0.05 ˛NaPB + 0.3±0.16 ˇiNaPB i (10a) N = 11; SD = 0.006; F = 211.8 EiNaCl = −0.34±0.03 i∗ NaCl − 0.35±0.02 ˛NaCl + 0.29±0.06 ˇiNaCl i (10b) N = 11; SD = 0.004; F = 577.5 2 SO4 EiNa2 SO4 = −0.55±0.02 i∗ Na2 SO4 − 0.09±0.03 ˛Na i

− 0.24±0.06 ˇiNa2 SO4 + 0.14±0.01 CiNa2 SO4

(10c)

N = 10; SD = 0.002; F = 1436

Fig. 1. Interrelationship between the logarithms of partition coefficients for organic compounds in different ATPSs in the presence of 0.15 M NaCl in 0.01 M NaPB, logarithms of partition coefficients of the same compounds in the same ATPSs in the presence of 0.10 M Na2 SO4 in 0.01 M NaPB and logarithms of partition coefficients for the same compounds in the same ATPSs in the presence of 0.15 M NaClO4 in 0.01 M NaPB. NaPB—0.01 M sodium phosphate buffer, pH 7.4.

4 EiNaClO4 = −0.68±0.05 i∗ NaClO4 − 0.52±0.05 ˛NaClO i

− 0.4±0.1 ˇiNaClO4

(10d)

N = 11; SD = 0.006; F = 252.7; where EiNaPB , EiNaCl , EiNa2 SO4 , and EiNaClO4 are parameters E in the ith ATPS in the presence of 0.01 M NaPB, 0.15 M NaCl, 0.10 M Na2 SO4 , and 0.15 M NaClO4 correspondingly; i∗ salt , ˛i∗ salt , ˇi∗ salt , and ci∗ salt are as defined above with i salt denoting that each characteristic is determined for the ith ATPS in the presence of salt additive indicated; N – is the total number of Eisalt -values in different ATPSs of the same ionic composition employed (including the theoretical zero point); SD – standard deviation, and F – ratio of variance. The relationships described by Eqs. (10a)–(10d) indicate that the difference between the hydrophobic character of the two phases interpreted sometimes [13,14] also as the difference between the free energy of the cavity formation in the coexisting phases of the ATPS used depends to the most part on the solvent dipolarity/polarizability, *, solvent hydrogen bond acidity, ˛, and solvent hydrogen bond basicity, ˇ, of the aqueous media in the coexisting phases. The relationship determined in the presence of Na2 SO4 includes additionally parameter c representing the difference between the electrostatic properties of the phases likely due to pronounced polarization effect of Na2 SO4 on water in its solutions [28]. It seems reasonable that the free energy of cavity formation in an aqueous medium, resulting in rearrangement of the highly cooperative hydrogen-bonds network, would involve all types of solvent–solvent interactions. An explanation for the observed differences in the contributions of different types of these interactions in the presence of different salts additives may be obtained from further studies but is currently beyond the scope of the present work. It has been reported recently [19] that different properties of organic compounds in aqueous media with different salt additives, such as salting-out and salting-in coefficients, optical rotation, partition coefficients in PEG–sodium sulfate ATPS with different salt additives, are linearly interrelated as described by Eq. (2). We examined the presence of similar interrelationship for the partition coefficients presented in Tables S1 and 3, and found that such

interrelationship does exists as shown graphically in Figs. 1 and 2. These interrelationships may be described as: j NaCl

log Ki

= −0.029±0.005 + 0.35±0.02 log Kij Na2 SO4 + 0.54±0.02 log Kij NaClO4

(11)

Fig. 2. Interrelationship between the logarithms of partition coefficients for organic compounds in different ATPSs in the presence of 0.01 M NaPB, logarithms of partition coefficients of the same compounds in the same ATPSs in the presence of 0.15 M NaClO4 in 0.01 M NaPB and logarithms of partition coefficients for the same compounds in the same ATPSs in the presence of 0.15 M NaCl in 0.01 M NaPB. NaPB—0.01 M sodium phosphate buffer, pH 7.4.

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Table 4 Solute specific coefficients in the presence of different salt additives. Compound

Ss

As

Bs

0.01 M NaPB, pH 7.4 Phenol Benzyl alcohol 2-Phenylethanol Vanillin Glucoside Coumarin Methyl anthranilate DNP-Gly Na DNP-Ala Na DNP-norVal Na DNP-norLeu Na DNP-AO Na

−4.7 −3.1 −3.2 −3.9 −1.0 −2.5 −3.8 −0.14 −0.78 −1.7 −2.3 −3.8

± ± ± ± ± ± ± ± ± ± ± ±

0.3 0.2 0.2 0.4 0.1 0.1 0.2 0.07 0.06 0.15 0.2 0.3

−2.3 ± −1.3 ± – −2.7 ± 1.3 ± – – – – – – –

0.15 M NaCl in 0.01 M NaPB, pH 7.4 Phenol Benzyl alcohol 2-Phenylethanol Vanillin Glucoside Coumarin Methyl anthranilate DNP-Gly Na DNP-Ala Na DNP-norVal Na DNP-norLeu Na DNP-AO Na

−3.6 −2.4 −2.9 −3.5 −1.3 −2.2 −3.4 0.10 −0.38 −0.92 −1.3 −2.1

± ± ± ± ± ± ± ± ± ± ± ±

0.2 0.2 0.1 0.2 0.1 0.2 0.3 0.04 0.06 0.08 0.1 0.2

– – −1.1 ± – – – – – 0.5 ± 0.9 ± 1.1 ± 1.8 ±

0.10 M Na2 SO4 in 0.01 M NaPB, pH 7.4 −4.6 ± 0.2 Phenol −3.4 ± 0.1 Benzyl alcohol −3.0 ± 0.4 2-Phenylethanol Vanillin −3.9 ± 0.2 −1.1 ± 0.1 Glucoside Coumarin −2.89 ± 0.07 Methyl anthranilate −3.9 ± 0.2 – DNP-Gly Na −0.71 ± 0.03 DNP-Ala Na DNP-norVal Na −1.47 ± 0.05 DNP-norLeu Na −2.1 ± 0.1 DNP-AO Na −3.2 ± 0.2

−3.0 ± −1.7 ± −2.8 ± −4.7 ± – −1.7 ± −2.8 ± – −0.62 ± −0.9 ± −0.8 ± −1.8 ±

0.6 0.4 0.9 0.6

−3.1 ± −3.6 ± −2.6 ± −2.8 ± −2.4 ± −2.1 ± −3.5 ± – −0.5 ± −1.3 ± −2.0 ± −2.8 ±

0.7 0.5 0.5 1.0 0.8 0.7 0.8

0.15 M NaClO4 in 0.01 M NaPB, pH 7.4 Phenol Benzyl alcohol 2-Phenylethanol Vanillin Glucoside Coumarin Methyl anthranilate DNP-Gly Na DNP-Ala Na DNP-norVal Na DNP-norLeu Na DNP-AO Na

−4.8 ± −3.8 ± −3.5 ± −4.0 ± −2.7 ± −3.6 ± −5.3 ± – −0.8 ± −1.8 ± −2.7 ± −4.3 ±

0.3 0.2 0.2 0.5 0.4 0.3 0.3 0.1 0.2 0.3 0.5

0.8 0.6 1.2 0.6

0.4

0.2 0.3 0.4 0.8

0.2 0.6 0.08 0.1 0.3 0.7

0.2 0.5 0.7 1.1

N = 108; r2 = 0.9744; SD = 0.029; F = 1980; and j NaPB

log Ki

j NaCl

= −0.002±0.006 + 0.54±0.05 log Ki

+ 0.33±0.05 log Kij NaClO4

(12) j NaCl

N = 70; r2 = 0.9775; SD = 0.023; F = 1459; where Ki j NaPB Kij NaClO4 , and Ki

, Kij Na2 SO4 ,

are partition coefficients of jth compound in ith ATPS in the presence of 0.15 M NaCl, 0.10 M Na2 SO4 , 0.15 M NaClO4 , and 0.01 M NaPB, correspondingly; N is the total number of K-values in the different ATPSs employed, r is the correlation coefficient. The other parameters are as defined above. It should be emphasized that Eq. (11) describes the relationship between partition coefficients for all compounds examined (nonionic as well as sodium salts of DNP-amino acids), while Eq. (12) describes the relationship between partition coefficients for only

Cs

Na

0.06 0.04 0.06 0.02 0.02 0.05 0.06 0.11

11 11 11 11 11 11 11 11 11 11 11 11

0.04 0.04 0.03 0.04 0.06 0.01 0.02 0.03 0.05 0.08

11 11 11 11 11 11 11 11 11 11 11 11

−2.6 −1.6 −1.2 −2.9 −0.3 −1.8 −2.2 0.17 −0.34 −0.7 −1.0 −2.0

± ± ± ± ± ± ± ± ± ± ± ±

0.3 0.2 0.1 0.4 0.1 0.1 0.2 0.06 0.05 0.1 0.1 0.3

– – – – 0.27 ± 0.17 ± 0.22 ± 1.12 ± 1.05 ± 1.08 ± 1.14 ± 1.2 ±

−2.4 −1.6 −1.79 −2.6 −1.00 −2.0 −2.7 −0.08 −0.46 −0.89 −1.3 −2.2

± ± ± ± ± ± ± ± ± ± ± ±

0.1 0.1 0.09 0.1 0.08 0.1 0.2 0.03 0.04 0.07 0.09 0.2

– – 0.11 ± −0.08 ± 0.33 ± 0.28 ± 0.23 ± 0.98 ± 0.97 ± 0.96 ± 1.01 ± 1.00 ±

−2.5 ± −1.4 ± – −3.6 ± −0.6 ± −1.5 ± −2.8 ± – −0.20 ± −0.26 ± −0.4 ± −1.9 ±

0.3 0.2

−3.4 −2.4 −2.6 −3.3 −1.7 −3.1 −4.2 −0.18 −0.62 −1.3 −1.9 −3.4

± ± ± ± ± ± ± ± ± ± ± ±

0.12 0.09 0.13

0.05 0.07 0.16 0.4

0.27 ± 0.22 ± 0.95 ± – 0.37 ± 0.54 ± 0.5 ± 1.03 ± 1.16 ± 1.38 ± 1.51 ± 1.55 ±

0.2 0.2 0.2 0.3 0.3 0.3 0.3 0.03 0.07 0.15 0.2 0.4

−0.29 ± – – −0.35 ± 0.30 ± – – 1.01 ± 0.97 ± 1.00 ± 1.04 ± 1.0 ±

0.09

0.2 0.2 0.1 0.3

0.08 0.04 0.1 0.01 0.02 0.03 0.06 0.14

0.13 0.10

0.01 0.03 0.06 0.08 0.1

10 10 10 10 10 10 10 10 10 10 10 10 11 11 11 11 11 11 11 11 11 11 11 11

nonionic compounds. This finding agrees with the results obtained for proteins [20] and with the model suggested by Ninham et al. (see in [29]) that dispersion ion-solute interactions dominate at relatively high salt concentrations (exceeding 0.1–0.2 M) in contrast to electrostatic interactions dominant at low ionic concentrations (as in the presence of 0.01 M NaPB). Partition coefficients of polar organic compounds examined in all the ATPSs presented in Table 3 were used to determine solute specific coefficients Ss , As , Bs , and Cs in Eq. (1) by the multiple linear regression analysis. We followed the procedure described by Ab Rani et al. [30] using the p-value as a test for significance for each solute specific coefficient in Eq. (1) for a given compound. If all coefficients (Ss , As , Bs , and Cs ) were found to be statistically significant (p < 0.05), then the corresponding correlation was accepted. If one or more values reveal a p-value of greater than 0.05, then the equations containing different trios or pairs of coefficients

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were examined. The equation with a set of coefficients providing p-values for all parameters below 0.1 was accepted. The solute specific coefficients determined for each compound are presented in Table 4. As can be seen from the data in Table 4, the solute specific coefficients may have different signs. The sign of each coefficient is affected by the choice of the partition coefficient definition. We define the solute partition coefficient as the ratio of the solute concentration in the top phase to that in the bottom phase. Hence the positive sign of a given descriptor means that the energy of a given type of the solute–solvent interactions in the top phase exceeds that in the bottom phase, while the negative sign of the same descriptor represents the opposite situation. It should be emphasized here that the solute specific coefficients derived from the solvatochromic solvent features of the phases (Ss , As , and Bs ) are not related strictly to the free energy of the solute–water interactions as the solvatochromic shift observed for a given dye represents the energy between the ground and excited states for the dye but the issue of the solvent effect on just one or both of these states remains an open question [31]. Analysis of the solute specific coefficients presented in Table 4 shows that the coefficients for a given compound differ in the presence of different salt additives. This finding agrees with the aforementioned interrelationship between the solute specific responses of different polar compounds to various ionic environments reported previously [18–21] and confirmed above. The electrostatic nature of dipole–dipole and hydrogen bonding interactions [32–34] explains why the relative intensities of these solute–water interactions may vary with the ionic composition of the media. It seems that the different effects of salt additives on the solute-specific coefficient Cs might be related to the differences in anion–solute dipole interactions. These interactions appear to be both solute- and anion-specific. The data in Table 4 show that for pnitrophenyl-␣-d-glucopyranoside the solute-specific coefficient Cs value is constant (0.32 ± 0.043) in all ionic compositions explored. For other compounds examined here the Cs value increases in the sequence Na2 SO4 > NaCl > NaPB > NaClO4 , i.e., in the Hofmeister series, except for benzyl alcohol (Cs measurable only in the presence of NaCl). The limited experimental data obtained so far prevent any general conclusion. It was suggested earlier [18–21] that the aforementioned relationships imply that the abilities of various solutes to participate in each type of solute–solvent interactions in the presence of different salt additives are also interrelated. Analysis of the solute specific coefficients Ss characterizing the solute–water dipole-dipole interactions shows that the interrelationships in question do exist as Fig. 3a and b demonstrate. The interrelationships shown may be described as: j,NaPB

Ss

j,NaCl

= −0.41±0.17 Ss

+ 1.36±0.15 Ssj,Na2 SO4

(13)

N = 9; r2 = 0.9880; SD = 0.18; F = 247; and j,NaCl

Ss

= 0.58±0.22 Ssj,Na2 SO4 + 0.29±0.21 Ssj,NaClO4

(14) j,NaCl

N = 10; r2 = 0.9369; SD = 0.33; F = 52.0; where Ss j,NaPB Ss

, Ssj,Na2 SO4 ,

Ssj,NaClO4 , and are solute specific coefficients for jth compound in the presence of 0.15 M NaCl, 0.10 M Na2 SO4 , 0.15 M NaClO4 , and 0.01 M NaPB, correspondingly; all other parameters as defined above. It should be indicated that two compounds, coumarin and benzyl alcohol, do not fit Eq. (13), and one compound, DNP-␣-amino-n-octanoic acid sodium salt, does not fit Eq. (14). Similar linear interrelationships were found for the solutespecific coefficient Bs characterizing the solute–water hydrogen bonding with the solute serving as the hydrogen bond acceptor.

7

Fig. 3. (A) Interrelationship between the solute specific coefficient Ss in the presence of 0.01 M NaPB, the solute specific coefficient Ss for the same compounds in the presence of 0.15 M NaCl in 0.01 M NaPB and the solute specific coefficient Ss for the same compounds in the presence of 0.10 M Na2 SO4 in 0.01 M NaPB. NaPB—0.01 M sodium phosphate buffer, pH 7.4. (B) Interrelationship between the solute specific coefficient Ss obtained in the presence of 0.15 M NaCl in 0.01 M NaPB, the solute specific coefficient Ss for the same compounds obtained in the presence of 0.15 M NaClO4 in 0.01 M NaPB and the solute specific coefficient Ss for the same compounds obtained in the presence of 0.10 M Na2 SO4 in 0.01 M NaPB. NaPB—0.01 M sodium phosphate buffer, pH 7.4.

These interrelationships are shown in Fig. 4a and b, and they may be described as: j,NaPB

j,NaCl

Bs

N = 8; j,NaCl Bs

= 0.68±0.12 Bs

r2

+ 0.34±0.08 Bsj,Na2 SO4

(15)

= 0.9920; SD = 0.09; F = 311; and

= 0.23±0.05 Bsj,Na2 SO4 + 0.47±0.05 Bsj,NaClO4

N = 10;

r2

= 0.9906; SD = 0.09; F = 370; where j,NaPB

Bsj,NaClO4 , and Bs

(16) j,NaCl Bs ,

Bsj,Na2 SO4 ,

are solute specific coefficients Bs for jth

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Fig. 5. Interrelationship between the solute specific coefficient Ss , the solute specific coefficients Bs , and the solute specific coefficients Cs for the same compounds determined in the presence of 0.15 M NaCl in 0.01 M NaPB. NaPB—0.01 M sodium phosphate buffer, pH 7.4.

The relationships between the solute specific coefficients in the presence of 0.15 M NaCl and 0.15 M NaClO4 are illustrated graphically in Figs. 5 and 6. These relationships may be describes as: j,NaCl

Ss

j,NaCl

= −0.7±0.28 + 0.87±0.23 Cs

j,NaCl

+ 1.0±0.11 Bs

(17)

N = 10; r2 = 0.9740; SD = 0.23; F = 130.8; and j,NaClO4 4 + 0.82 Ssj,NaClO4 = 0.52±0.09 Aj,NaClO ±0.08 Bs s

(18)

r2

N = 11; = 0.9892; SD = 0.15; F = 366; where all the parameters are as defined above.

Fig. 4. (A) Interrelationship between the solute specific coefficient Bs determined in the presence of 0.01 M NaPB, the solute specific coefficient Bs for the same compounds in the presence of 0.15 M NaCl in 0.01 M NaPB and the solute specific coefficient Bs for the same compounds in the presence of 0.10 M Na2 SO4 in 0.01 M NaPB. NaPB—0.01 M sodium phosphate buffer, pH 7.4. (B) Interrelationship between the solute specific coefficient Bs determined in the presence of 0.15 M NaCl in 0.01 M NaPB, the solute specific coefficient Bs for the same compounds in the presence of 0.15 M NaClO4 in 0.01 M NaPB and the solute specific coefficient Bs for the same compounds in the presence of 0.10 M Na2 SO4 in 0.01 M NaPB. NaPB—0.01 M sodium phosphate buffer, pH 7.4.

compound in the presence of 0.15 M NaCl, 0.10 M Na2 SO4 , 0.15 M NaClO4 , and 0.01 M NaPB, correspondingly; all other parameters as defined above. It should be noted that two compounds, pnitrophenyl-␣-d-glucopyranoside and methyl anthranilate, do not fit Eq. (15). As can be seen from Table 4 the number of compounds with determined solute specific coefficients As and Cs in the presence of different salts is too small to establish the presence or absence of the interrelationships under consideration. Further analysis of the solute specific coefficients listed in Table 4, however, shows that these coefficients are interrelated.

Fig. 6. Interrelationship between the solute specific coefficient Ss , the solute specific coefficients Bs and the solute specific coefficients As determined for the same compounds in the presence of 0.15 M NaClO4 in 0.01 M NaPB. NaPB—0.01 M sodium phosphate buffer, pH 7.4.

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There are two important though preliminary conclusions to be drawn from the above relationships. First, the relative contributions of different types of solute–water interactions represented by the solute-specific coefficients for nonionic and even mono-charged compounds appear to be interrelated. These interrelationships may be explained by the cooperativity of the different types of polar solute–water interactions into the solute partition coefficient. There are multiple examples of cooperativity between different physicochemical features of organic compounds [34–41] supporting the above conclusion. The number of compounds examined here is insufficient, however, to make a decisive general conclusion. Secondly, the solute specific coefficients for the nonionic compounds examined and even for ionizable compound such as vanillin change in the presence of different salt additives in the solute specific manner. These coefficients for various compounds in the presence of different salt additives are linearly interrelated as has been suggested previously [18–21]. It seems reasonable that all the solute specific coefficients as well as the ionic responsiveness of the solute in aqueous media are defined by the solute structure. The generality of the above conclusions remains uncertain at present. It is beyond doubt, however, that the approach described here opens up new possibilities to gain better insight into peculiarities of solute–water interactions unattainable with currently existing techniques. The results presented here raise the question of what structural properties of the compounds under study might govern different aspects of the solute–water interactions under the conditions employed. In our view, more experimental data and extensive analyses are needed to better understand the effects of the solute structural features on the contributions of different types of solute–water interactions (solute-specific coefficients) into partition coefficient of a solute. In fact, although we analyzed seven solutes with different chemical structures in this study, this set is still too limited for gaining statistically meaningful information that can be added to the list of structural features of compounds defining their partitioning and interaction with water under the various conditions. On the other hand, the existing list of structural, topological, and physico-chemical descriptors used for the characterization of chemical compounds includes close to five thousand descriptors. Finding a correlation between those descriptors and partitioning behavior of solutes in different systems and the peculiarities of interaction of those compounds with water under the variety of conditions represents an interesting and challenging task. We are working on the exploration of these issues, and the results of these studies will be reported elsewhere.

Acknowledgments Financial support for this work was in part provided by (i) FCT/MEC, FEDER under Programe PT2020 (Project UID/EQU/50020/2013), (ii) national research grant PTDC/EQUEQU/112812/2009, (iii) QREN, ON2 and FEDER, under Programe COMPETE (Project NORTE-07-0124-FEDER-0000011) for which the authors are thankful. A. Bessa acknowledges the scholarship within the Project PTDC/EQU-EQU/112812/2009 from Fundac¸ão para a Ciência e a Tecnologia (FCT). J.A. Loureiro acknowledges FEDER postdoctoral grant (NORTE-07-0124-FEDER-000025/FEUPON2-25MC - Enga QuimicaBiologica). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.chroma.2015.07. 002 References [1] [2] [3] [4] [5] [6]

[7] [8]

[9] [10] [11] [12] [13] [14] [15] [16] [17] [18]

5. Conclusions

[19] [20]

Effects of three salt additives, Na2 SO4 , NaCl and NaClO4 , in sodium phosphate buffer, pH 7.4, on partition behavior of seven different organic compounds in multiple different polymer–polymer ATPSs were examined. The differences between the solvent features of aqueous media of the coexisting phases were characterized. It was established that the responses of all the compounds toward different salt additives are linearly interrelated. The solute-specific coefficients, representing the contributions of dipole–dipole, dipole–ion, and H-bonding solute–water interactions were determined for each compound. It is established that the solute specific coefficients examined change in the presence of different salt additives in the solute specific manner and that they are linearly interrelated. It is suggested that the observed interrelationships are due to the cooperativity of the different types of polar solute–water interactions into the solute partition behavior.

9

[21] [22] [23] [24] [25] [26] [27]

[28] [29] [30]

[31]

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