Hofmeister Anion Effects on Thermodynamics of Caffeine Partitioning

Nov 21, 2016 - Specific anion effects on the thermodynamics of caffeine partitioning between aqueous and cyclohexane phases were studied in the presen...
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Hofmeister Anion Effects on Thermodynamics of Caffeine Partitioning Between Aqueous and Cyclohexane Phases Bradley A. Rogers, Tye S. Thompson, and Yanjie Zhang J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.6b07760 • Publication Date (Web): 21 Nov 2016 Downloaded from http://pubs.acs.org on November 27, 2016

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The Journal of Physical Chemistry

Hofmeister Anion Effects on Thermodynamics of Caffeine Partitioning between Aqueous and Cyclohexane Phases

Bradley A. Rogers,§ Tye S. Thompson, Yanjie Zhang* Department of Chemistry and Biochemistry, James Madison University, Harrisonburg, Virginia 22807, United States

§

Current address: Department of Chemistry, Penn State University, University Park, Pennsylvania 16801, United

States

November 20, 2016

*Authors to whom correspondence should be directed. E-mail: [email protected]

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ABSTRACT Specific anion effects on the thermodynamics of caffeine partitioning between aqueous and cyclohexane phases were studied in the presence of eleven sodium salts by utilizing UV-vis spectroscopy. It is observed that weakly hydrated anions such as ClO4-, SCN-, and I- salt caffeine into the aqueous phase and increase the standard Gibbs free energy for caffeine transfer. On the other hand, well-hydrated anions such as CO32- and SO42- salt caffeine molecules out of aqueous solution and promote the transfer process. Results suggest that weakly hydrated anions associate with the hydrophobic patches of caffeine including three methyl groups and a flat heteroatomic ring to solvate caffeine molecules. Well-hydrated anions are excluded from caffeine surface to salt caffeine molecules out of aqueous solution. Moreover, the enthalpy and entropy of caffeine transfer were obtained by measuring the standard Gibbs free energy for caffeine transfer at varied temperatures. The transfer of caffeine from the aqueous to cyclohexane phase was an endothermic process driven by the entropy of caffeine transfer. However, the trend in standard Gibbs free energy across the Hofmeister series was determined by the enthalpy of caffeine transfer. These results provide an enthalpic origin to explain the Hofmeister trends in aqueous solution.

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INTRODUCTION The ability of a new drug to partition and reach the action site is important to understanding drug behaviors in biological systems. An effective way to evaluate the partitioning ability of a new drug is to study its distribution in biphasic systems that are composed of two immiscible solvents.1,2 Typically, one phase is aqueous and the other phase is made of a semipolar or non-polar organic solvent. The thermodynamics of drug partitioning in biphasic systems helps interpret the mechanisms of drug partitioning and further predict important drug behaviors such as adsorption, cell membrane permeation, and in vivo distribution.3-8 Salt ions are naturally present in all living systems and play essential roles in maintaining normal cellular functions. Previous studies have shown that the behaviors of proteins, polymers, surfactants, and other molecules in aqueous solution are affected by added salts in a recurring pattern called the Hofmeister series.9-15 In recent years, a large amount of work has been devoted to understanding the underlying mechanisms by which the Hofmeister effects operate.16-43 However, how salt ions interact with drug molecules and influence their partitioning thermodynamics has not been investigated in great details. In the present study, we investigate the specific anion effects on caffeine partitioning between cyclohexane and aqueous phases as a model system for drug partitioning. Caffeine has significant biological relevance due to its well-known pharmaceutical application as a mild central nerve system stimulant.44-46 As a key component in tea, coffee, energy drinks, and some soft drinks, caffeine is the most widely used psychoactive substance in the world.47 Caffeine is classified as a methylated xanthine that contains two fused planar rings consisting of a 6membered pyrimidinedione and 5-membered imidazole. The chemical structure and atomic numbering of caffeine molecule is shown in Figure 1. When assessing caffeine partitioning

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O H3C

O

N1 6 5 2 3 4 N

7 N 9 N

CH3 8

H

CH3

Figure 1. Chemical structure and atomic numbering of caffeine molecule.

it is necessary to consider its hydration environment in the aqueous as well as the cyclohexane phase. Interactions between solvating water molecules and caffeine in the aqueous phase are highly complex.48-50 It has been suggested that the carbonyl oxygen atoms O2 and O6 as well as the lone pair baring nitrogen atom N9 participate in hydrogen bonds with hydrating water molecules. In addition, the proton H8 attached to C8 can interact with hydrogen acceptors to have a pseudo hydrogen bonding character. The three methyl groups and the flat hydrophobic ring make the molecule weakly hydrated in water so that it will be easily separated from water into non-polar solvents. Overall caffeine has limited solubility in water. 48-54 In the cyclohexane phase, caffeine interacts with the solvent molecules through non-specific interactions, namely, London dispersion forces. The presence of salts in the aqueous phase changes the hydration of caffeine and influences its partitioning thermodynamics between the aqueous and cyclohexane phases. Our results demonstrate that weakly hydrated anions such as SCN- and ClO4- make caffeine molecules more soluble in the aqueous phase and increase the standard Gibbs energy of caffeine transfer from the aqueous to cyclohexane phase. On the other hand, well-hydrated anions such as SO42- and CO32- decrease the standard Gibbs energy and enhance caffeine transfer from the aqueous to cyclohexane phase. The positive enthalpy and entropy for caffeine transfer suggest that the transfer process is entropy-driven and enthalpically unfavorable. The ordering in 4 ACS Paragon Plus Environment

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the standard Gibbs free energy for caffeine transfer as a function of anion identity is determined by the enthalpic contribution to the total standard Gibbs free energy. Our findings reported herein supply a fundamental understanding of specific anion effects on drug partitioning thermodynamics. Meanwhile, these studies provide novel thermodynamic insights into understanding the underlying mechanisms of the Hofmeister series.

MATERIALS AND METHODS Caffeine and all of the sodium salts used in this study, NaClO4, NaSCN, NaI, NaNO3, NaBr, NaCl, NaF, NaH2PO4, Na2S2O3, Na2SO4, and Na2CO3 were purchased from Fisher Scientific Inc. Low-conductivity water, produced from a NANOpure Ultrapure Water System (Barnstead, Dubuque, IA) with a minimum resistivity of 18 MΩ·cm, was used to prepare caffeine and salt solutions. Caffeine partitioning experiments were performed in 15-mL centrifuge tubes by a shake-flask method as a function of anion identity and concentration ranging from 0 to 2.0 M. In each extraction, 3 mL of a solution containing 10 mM caffeine and salt at desired concentration was first added to a centrifuge tube followed by addition of 3 mL of cyclohexane. The centrifuge tube was shaken for 1 min and then set at rest for 20 min to allow the phase separation to reach equilibrium. Approximately 2.5 mL of the cyclohexane phase on the top was transferred to a clean centrifuge tube for UV-vis analysis. The concentration of caffeine in the cyclohexane phase was evaluated at 273 nm using an Agilent 8453 UV-VIS diode array spectrophotometer. The molar extinction coefficient of caffeine in cyclohexane at 273 nm was determined to be 8508 M-1cm-1 by establishing a calibration curve in cyclohexane. Aqueous caffeine concentration was determined by subtracting the determined caffeine concentration in the cyclohexane phase from the original 10 mM concentration. Temperature dependence of

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caffeine partitioning in the presence of 0.5 M salts was studied at temperatures ranging from 298 to 319 K. The measurement of the partition coefficient at each salt concentration and temperature was repeated at least three times and the average was taken. The measured standard Gibbs free energy for caffeine transfer from the aqueous to cyclohexane phase had a typical standard error of ± 0.03 kJ/mol.

RESULTS AND DISCUSSION Standard Gibbs Free Energy of Caffeine Transfer vs. Salt Concentration Specific anion effects on caffeine partitioning between cyclohexane and aqueous phases was studied in the presence of sodium salts of 11 anions, namely, ClO4-, SCN-, I-, Br-, NO3-, Cl-, F-, H2PO4-, S2O32-, SO42-, and CO32-. In a partitioning model, the transfer of caffeine from the aqueous to cyclohexane phase is an equilibrium process represented below: (

) ⇌

(



)

eq. 1

The partition coefficient of caffeine, P, is the equilibrium constant representing the extent to which caffeine is distributed between two phases. The partition coefficient is calculated by the ratio of caffeine concentration in the cyclohexane phase to that in the aqueous phase as shown in eq. 2: =

[

] [

eq. 2

]

where [caf]cyclohexane and [caf]aqueous are the concentrations of caffeine in the cyclohexane and aqueous phases, respectively. Gibbs free energy for caffeine transfer under standard conditions at a specified temperature can be obtained by eq. 3: ∆

= −

eq. 3

where R is the gas constant (8.314 J mol-1 K-1) and T is the temperature (K). The standard 6 ACS Paragon Plus Environment

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o -1 -1 ΔtrsG (kJ K mol )

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16

NaClO4

14

NaSCN NaI NaNO3 NaBr NaCl NaF NaH2PO4

12

Na2S2O3 Na2SO4

10

Na2CO3

8 0.0

0.5

1.0

1.5

2.0

Salt Concentration (M) Figure 2. Standard Gibbs free energy of caffeine partitioning between the aqueous and cyclohexane phases vs salt concentration at room temperature (T = 295 K). All error bars are within the data points drawn. The order of the curves from top to bottom corresponds to the legend on the right of the figure. The solid lines are the linear fits to the data.

Table 1. Fitted c Values for the Change in standard Gibbs Free Energy for Caffeine Transfer as a Function of Anion Concentration together with Literature Values of Limited Partial Molar Volume, Gibbs Free Energy and Entropy of Hydration for Anions. anion ClO4SCNINO3BrClFH2PO4S2O32SO42CO32-

Vio (cm3 mol-1) 49.6 41.2 41.7 34.5 30.2 23.3 4.3 34.6 38.2 25.0 6.7

∆hydrGo (kJ mol-1) -214 -287 -283 -306 -321 -347 -472 -473 N/A -1090 -479

∆hydrSo (J mol-1 K-1) -57 -66 -36 -76 -59 -75 -137 -166 -180 -200 -245

Values of Vio, ∆hydrGo, and ∆hydrSo are from ref 55. 7 ACS Paragon Plus Environment

c (kJ mol-1 M-1) 1.50 1.24 1.15 0.36 0.22 -0.53 -1.56 -1.43 -1.95 -2.57 -2.79

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state is chosen to be 1 M of solute in aqueous solution and1 bar at the temperature of interest. The standard Gibbs free energy of caffeine transfer, ∆trsGo, at room temperature (T = 295 K) as a function of ion identity and concentration for 11 anions are shown in Figure 2. All obtained standard Gibbs free energies are positive, which means that the transfer of caffeine from the aqueous to cyclohexane phase is a non-spontaneous process under standard conditions. It can be observed that the ∆trsGo value changes linearly with the increase of salt concentration for all the anions studied. The data were fitted with a simple linear equation: ∆ where ∆

=∆

+ [ ]

eq. 4

is the standard Gibbs free energy for caffeine transfer in the absence of salt and

[M] is the molar concentration of salt. The slope of the curves, termed as c in kJ mol-1M-1, provide a quantitative description for the standard Gibbs free energy change as a function of anion concentration. Positive c values indicate that the standard Gibbs free energy of caffeine transfer increases as a function salt concentration, which correspond to ions’ ability to increase caffeine solubility in the aqueous phase and shift the equilibrium in eqn. 1 to the left. On the other hand, negative c values suggest that the standard Gibbs free energy of caffeine transfer decreases as salt concentration increases, which correspond to the ability of anions to push caffeine molecules into the cyclohexane phase. These results are consistent with the Hofmeister series that weakly hydrated anions solubilize (salt-in) proteins and well-hydrated anions precipitate (salt-out) proteins from aqueous solution, respectively.9-15 The anion effects on caffeine partitioning between aqueous and cyclohexane phases exhibit decreased slopes from weakly hydrated to well-hydrated anions. It should be noted that the data for NaClO4 and NaSCN show a small curvature at low salt concentrations, which suggests that binding of weakly hydrated ClO4- and SCN- to caffeine molecule may have occurred. However, the deviation from

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the linear fitting at low salt concentration for ClO4- and SCN- are not significant enough to change the overall dominating linear trend. The abstracted c values together with the physical properties of anions are compiled in Table 1. These c values are utilized to find the correlation between the anion effects on caffeine partitioning Gibbs free energy and physical properties of anions. These results are consistent with previously reported dependence of caffeine partitioning in biphasic ionic liquid-aqueous systems on the Hofmeister series.56 Moreover, previous studies with ionic liquid based aqueous biphasic systems indicated that caffeine partitioning is determined by the relative hydrophobicity of the two coexisting phases.57,58

Influence of Anion Hydration on Standard Gibbs Free Energy for Caffeine Transfer The c values are plotted against the hydration thermodynamic properties of anions to find out the influence of anion hydration on the caffeine partitioning between the aqueous and cyclohexane phases. Figure 3a shows that the c values for weakly hydrated anions are well correlated with limiting partial molar volume, Vio, of the anions. Limiting partial molar volume, Vio, is a physical property of anions that is interpreted as the volume of a hydrated ion.55 The hydration Gibbs free energy of anions is inversely proportional to the size;55 therefore, the c values for weakly hydrated anions are also correlated to the hydration Gibbs free energy of the anions as shown in Figure 3b. However, there are no correlations between the c values for wellhydrated anions and the size and hydration Gibbs free energy of the anions (Figure 3c, 3d). Instead, the c values for well-hydrated anions are correlated to the hydration entropy of the anions as plotted in Figure 3e. No correlation is observed between the c values for weakly hydrated anions and the hydration entropy of the anions as shown in Figure 3f. These results

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suggest that weakly hydrated and well-hydrated anions interact with caffeine molecule differently and further influence its partitioning behaviors.

ClO4

1.5

SCN

-

I

-

1.0 0.5

Br

-

NO3

-

0.0 Cl

-0.5

2.0

(a)

-

c (kJ mol-1 M-1)

c (kJ mol-1 M-1)

2.0

-

-1.0 20

25

30

35

40

45

50

(b)

ClO4-

1.5

SCN

0.5

Br

Cl

-0.5

-

o

-0.5

H2PO4

-

-2.0

-

S2O3

2-

-2.5 CO3

-3.0

2-

c (kJ mol-1 M-1)

c (kJ mol-1 M-1)

-1.0

SO4

5

10

15

20

25

30

35

(d)

-1.0

H2PO4-

-1.5

F-

-2.0 -2.5 2-

SO4

-3.0

40

o

o

-0.5

H2PO4FS2O32SO42-

-2.5

-3.5 -260

CO3

2-

(f)

-

c (kJ mol-1 M-1)

-1.0

-3.0

2.0

(e)

-2.0

-1

ΔhydrG (kJ mol )

Vi (cm3 mol-1)

-1.5

CO32-

-3.5 -1200 -1100 -1000 -900 -800 -700 -600 -500 -40

-3.5 0

-1

ΔhydrG (kJ mol )

(c)

2-

NO3-

-1.0 -360 -340 -320 -300 -280 -260 -240 -220 -20

55

-0.5

-1.5

-

-

0.0

o

F

-

I

1.0

Vi (cm3 mol-1)

c (kJ mol-1 M-1)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1.5

SCN-

ClO4

I-

1.0 NO3

0.5

-

Br

0.0 -0.5

-

Cl-

-1.0 -240

-220

-200 o

-180

-160 -1

-140

-120

-1

-80

-70

-60 o

ΔhydrS (J mol K )

-50 -1

-40

-30

-1

ΔhydrS (J mol K )

Figure 3. Plots of c values vs size and hydration thermodynamics of anions: (a) c vs limiting partial molar volume for weakly hydrated anions; (b) c vs and hydration Gibbs free energy for weakly hydrated anions; (c) c vs limiting partial molar volume for well-hydrated anions; (d) c vs and hydration Gibbs free energy for well-hydrated anions; (e) c vs hydration entropy for wellhydrated anions; (f) c vs hydration entropy for weakly hydrated anions. 10 ACS Paragon Plus Environment

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The Journal of Physical Chemistry

Standard Enthalpy and Entropy of Caffeine Transfer In order to further understand the anion effects on caffeine partitioning, the standard Gibbs free energy of caffeine transfer is measured for the 11 sodium salts mentioned above at 0.5 M concentration at temperatures ranging from 298 to 319 K as shown in Figure 4. The standard Gibbs free energy-temperature plots are fitted with a linear regression in eq. 5: ∆

=∆

− T∆

eq. 5

where the y-intercept and negative slope correspond to the standard enthalpy, ΔtrsHo, and the standard entropy, ΔtrsSo, for caffeine transfer, respectively. It is assumed that ΔtrsHo and ΔtrsSo do not vary significantly as a function of temperature. This method, the analysis of the temperature dependence for partitioning, has been widely used in the thermodynamic studies of pharmaceutical compounds, food components, and hydrophobic dye molecules.6,7,59 The extrapolated values for the enthalpy and entropy together with the standard Gibbs free energy for caffeine transfer at 298 K are summarized in Table 2. As can be seen in Table 2, both ΔtrsHo and

ΔtrsSo are positive for caffeine transfer in the presence of all of the anions studied. The positiveΔtrsHo values indicate that the caffeine transfer is an endothermic process. Caffeine molecules are hydrated in the aqueous phase. Energy is required to remove the hydration water away from caffeine as the molecules are transferred from the aqueous to cyclohexane phase. It has been previously reported that both apolar and polar solutes order water molecules in their hydration shells relative to the bulk solution indicated by the entropy decrease upon hydration.6064

The positive ΔtrsSo originates from the release of ordered water molecules as caffeine

molecules are dehydrated and transferred across the aqueous/cyclohexane interface. Both ΔtrsHo and ΔtrsSo being positive indicates that caffeine transfer from the aqueous to cyclohexane phase is an entropy-driven process. Previously reported molecular dynamic simulations on caffeine 11 ACS Paragon Plus Environment

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aggregation in NaCl solution have shown that the hydrophobic atomic sites of caffeine are dehydrated on addition of salt.50 Caffeine aggregation is enthalpy driven in pure water and entropy driven in the presence of NaCl especially as higher temperature.52 15 o -1 -1 ΔtrsG (kJ K mol )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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NaClO4 NaSCN NaI NaNO3

14

NaBr NaCl NaF NaH2PO4

13 12

Na2S2O3 Na2SO4

11

Na2CO3

10 300

305

310

315

320

Temperature (K) Figure 4. Gibbs free energy for caffeine transfer from the aqueous to cyclohexane phase vs temperature in the presence of 0.5 M of each salt.

Table 2. Summary of Enthalpy and Entropy of Caffeine Transfer Extracted from Linear Fits of the Gibbs Free Energy vs Temperature Plots at 0.5 M salt concentration. anion ClO4SCNINO3BrClFH2PO4S2O32SO42CO32-

∆trsGo (kJ mol-1) 14.36 13.87 13.67 13.45 12.98 12.44 12.19 12.27 11.83 11.45 11.28

∆trsHo (kJ mol-1) 36.70 31.23 30.70 30.00 28.53 24.80 27.09 26.50 25.10 24.58 23.30

∆trsSo (J mol-1 K-1) 74.7 58.0 56.8 55.6 52.1 41.1 49.8 47.6 44.3 43.8 40.2

T∆trsSo (kJ mol-1) 22.26 17.28 16.93 16.57 15.53 12.25 14.84 14.18 13.20 13.05 11.98

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ζH

ζTS

62.2 64.4 64.5 64.4 64.8 66.9 64.6 65.1 65.5 65.3 66.0

37.8 35.6 35.5 35.6 35.2 33.1 35.4 34.9 34.5 34.7 34.0

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Some interesting trends should be noted in Table 2. The standard Gibbs free energy for caffeine transfer at 298 K decreases from weakly hydrated anion ClO4- to well-hydrated anion CO32-. The enthalpy for caffeine transfer follows the same trend across the Hofmeister series. The enthalpy makes a positive contribution to the Gibbs free energy for caffeine transfer as indicated in eq. 5. On the other hand, the entropy of caffeine transfer also decreases from weakly hydrated ClO4- to well-hydrated CO32-. However, the contribution of entropy to the Gibbs free energy is negative TΔtrsSo, which means that more positive entropy in the presence of weakly hydrated anions such as ClO4- is expected to result in lower Gibbs energy for caffeine transfer. The balancing between the enthalpy and entropy determines the standard Gibbs free energy for caffeine transfer. The trend in the standard Gibbs free energy for caffeine transfer across the Hofmeister series is dominated by the enthalpy term. The entropy term compensates for the unfavorable enthalpy; however, the entropy contribution is not significant enough to overcome the enthalpy cost. It should be noted that the determined ΔtrsHo and ΔtrsSo values for Cl- deviate slightly from the general trend across the Hofmeister series. This may come from experimental error in the temperature dependence of ΔtrsGo for caffeine transfer in the presence of NaCl in the aqueous phase. The relative contributions of ΔtrsHo and -TΔtrsSo to the overall Gibbs free energy for caffeine transfer are determined by eq. 6a and 6b2,6,7 and the results are listed in Table 2. ζ = |∆ where ζ and ζ

|∆

| | | ∆

|

; ζ

= |∆

| ∆ | | | ∆

|

eq. 6a, b

represent the contributions of the enthalpy and entropy terms, respectively. It

can be observed that the relative contributions of ΔtrsHo and -TΔtrsSo stay roughly constant across the Hofmeister series and that ΔtrsHo is the major contribution to ΔtrsGo. The analysis of anion effects on caffeine transfer from the aqueous to cyclohexane phase provides thermodynamic insights into understanding the origin of Hofmeister ordering. The trends in thermodynamics for 13 ACS Paragon Plus Environment

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caffeine transfer across the Hofmeister series are shown in Figure 5. These results clearly demonstrate that the trend in the standard Gibbs free energy is determined by the contribution of the enthalpy for caffeine transfer. The entropy term compensates for the unfavorable enthalpy; however, the entropy contribution is not significant enough to overcome the enthalpy cost. 40 o ΔtrsJ (kJ/mol)

35

ΔtrsG

30

ΔtrsH

25

ο

o o

-TΔtrsS

20 15 10 -15 -20 CO32-

SO42-

2-

S2O3

H2PO4-

F-

-

Cl

-

Br

-

NO3

I-

SCN

-

-25 ClO4-

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Figure 5. Comparison of the thermodynamic results for caffeine transfer from the aqueous to cyclohexane phase at 298 K, where J = G (black), H (red), and S (green).

The enthalpy and entropy for caffeine transfer against the physical properties of anions are displayed in Figure 6. The enthalpy and entropy for caffeine transfer in the presence of weakly hydrated anions are found to correlate well with the limiting partial molar volume and hydration Gibbs free energy of anions. On the other hand, the enthalpy and entropy for caffeine transfer obtained in the presence of well-hydrated anions correlates with the hydration entropy of anions. The correlation of the determined enthalpy and entropy to the anions’ physical properties are strikingly consistent with the dependence of standard Gibbs free energy for caffeine transfer on anion properties as discussed above. Large weakly hydrated anions easily shed their hydration water to associate with the hydrophobic moieties of caffeine molecule. As a result, these anions

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ClO4

36

38

(a)

-

o ΔtrsH (kJ mol-1)

o

ΔtrsH (kJ mol-1)

38

34 32

SCN

-

-

NO3

30

Br

I

-

-

28 26

Cl

-

20

30

40

ClO4

50

36

32

NO3

30

ΔtrsS (J K-1 mol-1)

SCN

I-

Cl

40

-

26

Cl-

30

40

50

70 60 Br

ΔtrsS (J K-1 mol-1)

S2O3

-

2-

SO42-

22 -260

o

24 23

CO3

2-

-240

-220

-200 o

-180

-160 -1

-

SCNI-

50 Cl

-

40

-1

52

26 25

NO3

o

(e)

H2PO4

-

ΔhydrG (kJ mol ) F-

27

-

(d)

ClO4

o

Vi (cm3 mol-1)

28

-1

30 -360 -340 -320 -300 -280 -260 -240 -220 -200

30 20

-

I

-

Br

28

o

50

o

ΔtrsS (J mol-1 K-1)

-

Br

-

80

-

70 NO3-

SCN

o

(c)

-

-

ΔhydrG (kJ mol ) ClO4

60

(b)

34

o

Vi (cm3 mol-1)

80

-

24 -360 -340 -320 -300 -280 -260 -240 -220 -200

24

o ΔtrsH (kJ mol-1)

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-140

-120

F

50 H2PO4

48

(f)

-

46 S2O3

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CO3

2-

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2-

-240

-220

-200 o

-1

-

-180

-160 -1

-140

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ΔhydrS (J mol K )

ΔhydrS (J mol K )

Figure 6. The correlation between the enthalpy and entropy of caffeine transfer and the physical properties of the anions. (a) to (d) are for the weakly hydrated anions: (a) Enthalpy of caffeine transfer vs limiting partial molar volume of anions; (b) enthalpy of caffeine transfer vs hydration Gibbs free energy of anions; (c) entropy of caffeine transfer vs limiting partial molar volume of anions; (d) entropy of caffeine transfer vs hydration Gibbs free energy of anions. (e) to (f) are for the well-hydrated anions: (e) Enthalpy and (f) entropy of caffeine transfer vs hydration entropy of anions.

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solvate caffeine molecules into the aqueous phase and increase the standard Gibbs free energy for caffeine transfer. On the contrary, well-hydrated anions are excluded from the caffeine surface and promote caffeine transfer from the aqueous to the cyclohexane phase.

Proposed Model for Anion-Caffeine Interactions The interactions between anions and caffeine molecules are proposed in Figure 7. First, weakly hydrated anions are usually large and they can easily shed their hydration shells to associate with the hydrophobic surface of caffeine including three methyl groups and the hydrophobic planar structure.27,65,66 As a result, these anions salt caffeine molecules into the aqueous solution and increase the standard Gibbs free energy of caffeine transfer. Large anions

Figure 7. Schematic representation of interactions between caffeine and anions: (a) The association of weakly hydrated anions to the hydrophobic surface of caffeine increases the solubility of caffeine in water; (b) Well-hydrated anions are excluded from caffeine/water interface that makes caffeine less soluble in water. 16 ACS Paragon Plus Environment

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such as SCN-, ClO4-, and I- are the most effective ions to solvate caffeine molecules and prevent caffeine transfer. Well-hydrated anions affect caffeine transfer through an entropic effect.16,21,67 These well-hydrated anions are excluded from the caffeine/water interface and remain in the bulk solution. The volume exclusion effect of well-hydrated anions makes caffeine less soluble in the aqueous phase and promotes caffeine transfer to the cyclohexane phase. The proposed mechanisms are consistent with recent theoretical work of Shimizu on salt effects on caffeine dimerization.68 It was reported that caffeine dimerization was enhanced by the exclusion of additives from caffeine while dimerization was weakened by the binding of additives on caffeine.68 The interactions of anions studied herein with caffeine at the molecular level are being further explored by a combination of 1H and 13C NMR and ATR-FTIR spectroscopy in our recent work in progress.

CONCLUSION The thermodynamics of caffeine partitioning between aqueous and cyclohexane phases has been studied in the presence of various salts. We have demonstrated that caffeine transfer from the aqueous to cyclohexane phase is an endothermic process accompanied by an increase in entropy. Well-hydrated anions are excluded from caffeine surface and decrease the standard Gibbs free energy for caffeine transfer. Weakly hydrated anions associate with the hydrophobic moieties of caffeine and increase the standard Gibbs free energy for caffeine transfer. The enthalpic contribution dominates the ordering of the standard Gibbs free energy for caffeine transfer across the Hofmeister series. The mechanisms for anion-caffeine interactions proposed herein are applicable to understanding anion effects on the behaviors of other drugs or proteins in aqueous solutions.

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AUTHOR INFORMATION Corresponding Author E-mail: [email protected] Tel: (540)-568-6839 Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS We acknowledge the Donors of the American Chemical Society Petroleum Research Fund (51008-UNI4) and the National Science Foundation (CHE-1461175)-Research Experience for Undergraduates Program for their support of this research.

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