Thermodynamic Properties of Dopamine in Aqueous Solution. Acid

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Thermodynamic Properties of Dopamine in Aqueous Solution. Acid− Base Properties, Distribution, and Activity Coefficients in NaCl Aqueous Solutions at Different Ionic Strengths and Temperatures Clemente Bretti,† Francesco Crea,*,† Concetta De Stefano,† Claudia Foti,† Stefano Materazzi,‡ and Giuseppina Vianelli† †

Dipartimento di Scienze Chimiche, Università di Messina, viale Ferdinando Stagno d’Alcontres, 31, I-98166 Messina, Vill. S. Agata, Italy ‡ Dipartimento di Chimica, Università “La Sapienza” di Roma, Piazzale A. Moro 5, I-00185 Rome, Italy S Supporting Information *

ABSTRACT: The acid−base properties of dopamine were studied in different experimental conditions by potentiometry, UV-spectrophotometry, and spectrofluorimetry. The distribution measurements between 2-methyl-1propanol/pure water (or NaCl aqueous solutions up to I = 1.02 mol kg−1) were carried out at T = 298.15 K and 310.15 K. The potentiometric measurements were used to calculate the total concentration of the ligand in each phase, and from simple mass balance equations, using the free hydrogen concentration and the protonation constants, it was possible to calculate the ligand neutral species concentration and the distribution coefficient. The salting parameter and the activity coefficient of the neutral species were calculated by means of the Setschenow equation. Independently of the experimental conditions, a good agreement between the protonation constants obtained from the different techniques was obtained. The dependence of the protonation constants on ionic strength was modeled by means of the Debye−Hückel type and Specific ion Interaction Theory (SIT) approaches, and the specific interaction parameters of the ionic species were determined. For the protonation constants, the following thermodynamic values were obtained at T = 298.15 K, log K1H0 =10.886 ± 0.042; log K2H0 = 9.107 ± 0.032; at T = 310.15 K, log K1H0 =10.260 ± 0.024; log K2H0 = 8.418 ± 0.018. From the distribution measurements the following distribution coefficients at infinite dilution were obtained at T = 298.15 K, log KD00 = 0.705 ± 0.013; at T = 310.15 K, log KD00 = 0.983 ± 0.014.

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INTRODUCTION Dopamine [2-(3,4-dihydroxyphenyl)ethylamine] (see Scheme 1) is an important neurotransmitter that plays a fundamental

groups), it can form chelate complexes with metals of biological interest.1−12 Many biochemical processes that occur in living organisms involve the stages related to a change in the hydration (solvation) state of biomolecules participating in the chemical interaction. The solvation environment plays a considerable role in the complex multistage process of molecular recognition and fixation of physiologically active substances on receptor targets. When studying complexes of important biologically active molecules or biomimetic systems, it is fundamental to characterize either their solution or their gas/solid state properties. Authors extensively applied the combined approach13−20 and this work is the first step of a complete characterization of dopamine complexes. The knowledge of the thermodynamic solution properties of this kind of molecules is a very important task for pharmaceutical product design, because it affects the drug efficacy, its future development, and formulation efforts and also influences the pharmacokinetics,

Scheme 1. Chemical Structure of the 2-(3,4Dihydroxyphenyl)ethylamine (Dopamine)

role in the regulation of hormonal secretions in the central nervous system and in the peripheral organs implicated in the control of motor\cognitive and neuroendocrine functions. Its improper regulation is associated with neurological diseases such as parkinsonism, where dopamine levels are reduced, and schizophrenia, which can be related to excess dopamine activity.1−6 It is a precursor of adrenaline and forms in adrenergic nerve endings [tyrosine →3,4-dihydroxy-phenylalanine → dopamine → noradrenaline → adrenaline]. Owing to the presence in the molecule of three donor centers (two phenolic and one amino © XXXX American Chemical Society

Received: June 14, 2013 Accepted: September 9, 2013

A

dx.doi.org/10.1021/je400568u | J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

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APPARATUS Potentiometric Apparatus. The free hydrogen ion concentration was measured using a 713 Metrohm potentiometer (resolution ±0.1 mV, reproducibility ±0.15 mV) connected to a 665 Metrohm automatic buret and to a Orion glass electrode (8101 Ross type), coupled with a standard calomel electrode. The potentiometer and the buret were connected to a personal computer, and the whole system was controlled by a suitable computer program, which read and saved the emf values when the equilibrium was reached and allowed management of the titrant delivery, data acquisition, and emf stability checks. The measurement cells were thermostatted at T = ((288.15 ± 0.1), (298.15 ± 0.1), (310.15 ± 0.1) and (318.15 ± 0.1)) K by means of water circulation in the outer chamber of the titration cell, from a thermocryostat (model D1-G Haake). Purified N2(g) was bubbled into the solutions to exclude the presence of CO2(g) and O2(g). For each experiment, independent titrations of strong acid (HCl) solutions with carbonate-free NaOH solutions were carried out under the same ionic strength conditions as the systems to be investigated with the aim of determining the electrode potential (E0) and the acidic junction potential (Ej = ja [H+]). In this way, the free proton concentration scale was used, pH ≡ −log10[H+], where [H+] is the free proton concentration (not activity). The reliability of the calibration in the alkaline range was checked by calculating the ionic product of water (pKw). Spectrophotometric Apparatus. The spectrophotometric measurements were carried out using a Varian Cary 50 UV− vis spectrophotometer equipped with an optic fiber probe with a fixed 1 cm path length; preliminary absorbing spectra were recorded to know the wavelength interval where the ligand absorbs; the selected wavelength range was from λ = (200 to 400) nm. The spectrophotometer was connected to a PC and the acquisition of the couple of data absorbance (A) vs wavelength (λ/nm) was made by the Varian Cary WinUV (version 3.00) software. During these measurements, we introduced in the thermostatted measurement cell (total volume of 25 mL), a 602 Metrohm Biotrode combined metrosensor glass electrode, that was connected to a potentiometric apparatus (see previous section). In this way, we are also able to record simultaneously A vs λ (nm), and emf (mV) vs volume of titrant (mL) for each alkalimetric titration point; also in this case, the combined glass electrode was standardized as reported in the previous section. Spectrophotometric titrations were performed at T = (308.15 ± 0.1) K and I = (0.50 and 1.02) mol kg−1 in NaCl. The titrant was delivered in the measurement cell by means of a 665 Metrohm automatic buret, and the homogeneity of the solutions during the titration was maintained by a stirring bar. Before each experiment, N2(g) was bubbled in the solutions for at least 5 min in order to exclude the presence of CO2(g) and O2(g). Spectrofluorimetric Apparatus. A FluoroMax-4 spectrofluorometer by Horiba Jobin-Yvon equipped with an F-3006 Autotitration Injector with two Hamilton Syringes (models Gastight 1725 and 1001 TLLX, 250 μL and 1 mL capacity, respectively) was used to perform the spectrofluorimetric titrations. The resolutions of wavelength selectors and titrant additions were 0.3 nm and 0.25 μL, respectively. The instrument was also equipped with a Peltier Sample Cooler (model F-3004) controlled by a Peltier Thermoelectric Temperature Controller model LFI-3751 (5 A, 40 W). The

such as the release, transport, and the degree of absorption in the organism.3,21−23 The literature reports much information about the biological activity and the application of such molecules in medicine, while data regarding their thermodynamic properties appear till now doubtful and confusing. Moreover, in the literature there is the total absence of a modeling study regarding the dependence of the thermodynamic parameters of dopamine on ionic medium, ionic strength, and in part temperature. From modeling studies it is possible to obtain simple equations able to model or predict the behavior of such molecules in aqueous solutions over a wide range of experimental conditions.3,21,24 However, often, on the basis of the goodness of the experimental data, the predicted parameters, calculated from the empirical equations,3,21,24 may have low accuracy, and for this reason, the availability of experimental data is still fundamental for an appropriate model development and evaluation. For many years, our research group has undertaken a systematic study on the modeling of the thermodynamic properties in aqueous solution (acid−base properties, solubility and/or distribution between water/organic solvent) of different classes of ligands25−30 and some molecules of high interest from a biological point of view.27,31−33 Recently, the acid−base properties and the solubility of aminoacids27,31 and penicillin derivatives34 (amoxicillin, ampicillin, and (+)6-aminopenicillanic acid) were investigated, at different ionic strengths and temperatures. The activity coefficients of the ligands neutral species were calculated by means of the Setschenow equation.35 The main aim of this paper is to give a significant contribution to the knowledge of the solution thermodynamic properties of dopamine in NaCl at different temperatures and ionic strengths by using different instrumental techniques (UV−vis spectrophotometry, spectrofluorimetry, and ISE-[H+] potentiometry). The dependence of the protonation constants on ionic strength was modeled by means of the Debye−Hückel type and SIT (Specific ion Interaction Theory) approaches, and the specific interaction parameters of the ionic species were determined.

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MATERIAL AND METHODS Chemicals. The hydrochloride dopamine product (Fluka p.a.) was used without further purification. The ligand purity was checked by alkalimetric titration and resulted to be > 99.5 %. Sodium chloride solutions were prepared by weighing pure salt (Fluka, p.a.) previously dried in an oven at T = 383.15 K. Carbonate free sodium hydroxide solutions were prepared from concentrated (Fluka puriss. electrochemical grade) ampules and standardized against potassium biphthalate. Hydrochloric acid solutions were prepared from concentrated ampules (Fluka) and standardized against sodium carbonate. Distribution measurements were performed by using as organic phase, 2-methyl-1-propanol (Fluka, p.a.). Before each distribution measurement, the dopamine·HCl solutions were neutralized with an equivalent amount of NaOH standard solution. All solutions were preserved from atmospheric CO2 by means of soda lime traps. The standard stock solutions of dopamine were prepared by bubbling purified N2(g) into the solutions, in order to keep the environment inert. Grade A glassware and twice distilled water were employed in the preparation of all the solutions. B



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whole system was controlled by the FluorEssence 2.1 software by Horiba Jobin-Yvon. The titrations were performed directly in a Hellma type 101-OS precision cell (light path, 10 mm), where a magnetic stirrer, the ISE-[H+] microelectrode (model biotrode 6.0224.100 purchased from Metrohm) and the antidiffusion buret tip were inserted. The buret tip and the ISE-[H+] electrode were placed in a position that would not interfere with the light beam. The automatic data acquisition (fluorescence intensity vs λ(nm) for each titrant addition), was performed using the same FluorEssence 2.1 software, whereas the emf values were measured using the same procedure already described in previous section. The measurements were carried out by titration, with NaOH standard solutions, 2.5 mL of a titrand solution containing dopamine hydrochloride at a concentration of (0.04 to 0.12) mmol dm−3 and a suitable amount of NaCl to obtain the desired ionic strength value. After each NaOH addition, both the fluorescence intensity and the emf values were recorded when the potential was constant (within the instrumental resolution). All the experimental conditions were determined by preliminary evaluation of several parameters: equilibration time, scan rate, scan range, and integration time, wavelength of excitation, and emission; these parameters were systematically varied to select the values giving the best signal/noise ratio. Through a shrewd trial of these parameters, we decided to use the wavelength range of λ = (300 to 400) nm, the scan rate of 1 nm s−1, and an integration time of 0.5 s. The excitation wavelength used was λ = 284 nm.

γaq =

γaq0 =

=

KD00

(6)

KD00

where and have the same significance as in eq 3, but here they refer to the ligand neutral species. The activity coefficient of a neutral species in pure water or saline solution can be calculated by means of the Setschenow equation:35 log γ = kmmsalt

(7)

where km and msalt are the Sestschenow coefficient and the sodium chloride concentration (mol·kg−1), respectively. Rearranging eqs 6 and 7, we obtain for the ligand neutral species log KDm0 = log KD00 − kmmsalt

(8)

that allows a calculation of the Setschenow coefficient, and by means of the eq 6, the activity coefficient of the neutral species in the ionic strength range and at different temperatures is investigated. If the molar concentration scale was used, the distribution ratios of the neutral species can be indicated with KDc0. Some years ago, a modified version of the Setschenow equation was introduced,27,28 where the salting parameter k(c,m), depends on the electrolyte concentration, according to the equation:

(1)

⎛ k(c , m),0 − k(c , m), ∞ ⎞ k(c , m) = ⎜k(c , m), ∞ + ⎟ (c , m)MX + 1 ⎠ ⎝

(9)

where k0 and k∞ are the values at (c,m)MX → 0 and (c,m)MX → ∞, respectively, and MX is the supporting electrolyte concentration (m, molal concentration scale; c molar concentration scale). This equation was introduced since generally, as the concentration of the added salt increases, the apparent k value is not constant, but it is dependent on the ligand neutral species concentration and on the rate of change of ligand neutral species concentration with added salt concentration;25−28,31 using this simple equation, the non linear variation of k(c,m) with respect to the salt concentration can be modeled, as well as the corresponding activity coefficients. This approach tested on several classes of ligands, gave better results with respect to the application of the eq 7; in

(2)

KDmT KD0T

KDm0

KDm0

where KTD0 is the distribution ratio of the component for the organic phase and pure water. Substituting eq 2 in eq 1 we obtain:

γorg

(5)

In regard to the organic solvent, we assumed that the ligand that is dissolved in this phase is present only as neutral/ undissociated species (LH0), so that CorgT = Corg0. Using this approach, it is possible to determine the distribution coefficient of the neutral species (KD0) and the corresponding salt effect (salting-in or salting-out). Equation 4 can be also applied to the ligand neutral species, and in this case, we have

where μ0 is the standard chemical potential of the component in the aqueous (aq) and organic (org) phase, respectively; γ is the activity coefficient; m is the concentration in the molal concentration scale (mol kg−1 (H2O)) [the molar concentration scale, c can be used] and KDmT is the distribution ratio of the component between the organic phase and the saline solution. If the distribution measurements are carried out between an organic solvent/pure water mixture, eq 1 becomes

γaq

(4)

⎞ ⎛ 1 Caq T = Caq 0⎜1 + H + + K 2H[H+]⎟ K1 [H ] ⎠ ⎝

DISTRIBUTION MEASUREMENTS Theory. The chemical potential of a component dissolved in two phases in equilibrium can be expressed by26,29,36

⎛ μ0 − μ0 ⎞ m aq org ⎟ org exp⎜⎜ = = KD0T ⎟ RT m aq ⎠ ⎝

KD0T

The total and neutral species concentration (CaqT and Caq0, respectively) in the aqueous phase can be calculated from distribution measurements carried out in pure water and in salt solutions at different ionic strengths (up to pH ≈ 10.5, neglecting the third protonation step) and by means of eq 5:

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⎛ μ0 − μ0 ⎞ m γ γorg org org aq org ⎟ exp⎜⎜ = = KD mT ⎟ maq γaq γaq ⎝ RT ⎠

KDmT

(3)

In the organic phase, it can be assumed that the activity coefficient is γorg ≈ 1, so that eq 3 becomes C



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Table 1. Total Concentration of Dopamine in the Saline Solution (aq) at Different Ionic Strengths and in the Organic Phase (org), at T = 298.15 K and 310.15 K CNa+/mol kg−1

mmol kg−1(aq)

0.163 0.163 0.510 0.510 0.745 0.745 0.998 0.998

T=298.15 K 0.860 0.691 0.806 0.860 0.234 0.254 0.230 0.625

mmol kg−1

CNa+/mol kg−1

(org)

4.340 3.756 4.880 5.072 1.684 1.696 1.604 4.260

0.167 0.167 0.506 0.506 0.759 0.759 1.015 1.015

mmol kg−1

(aq)

T=310.15 K 1.161 0.533 0.484 0.292 0.533 0.731 0.652 0.451

mmol kg−1

(org)

10.968 5.476 5.672 3.640 6.388 8.304 8.652 6.388

conditions (i.e., ligand and supporting electrolyte concentration, pH range) are known. Along the manuscript, the protonation constants refer to the equilibrium:

the case of dopamine, we observed that the two models can be indifferently used, since similar results were obtained. Procedure. The distribution of the dopamine between the 2-methyl-1-propanol/aqueous solution mixtures was studied mixing and shaking an aliquot of 25 mL of pure water (or NaCl aqueous solution to adjust the ionic strength) containing the ligand at different concentrations with a equal volume of 2methyl-1-propanol. The solutions prepared in proper flasks were shaken for at least 2 h in a thermostatted homemade box at T = (298.15 ± 0.10) K and (310.15 ± 0.10) K without light exposition.37 The flasks were shaken by means of a IKA HS 260 Basic compact flat shaker with ideal swivel motion at 210 mot/min. Preliminary conductivity measurements on the aqueous solutions, carried out with a WTW INOLAB Cond Level 1 conductimeter equipped with a Tetracon 325 cell, established that this time is sufficient to reach the equilibrium. The temperature was controlled by means of a heater control box and the flow air was guaranteed by a fan. The two immiscible phases were separated by means of a separatory funnel, and potentiometric titrations were performed (some checks were also carried out on the organic phase suitably diluted with aqueous solution) to calculate the total ligand and hydrogen ion concentrations; these measurements were also used to calculate the log KiH of dopamine. To avoid systematic errors, independent experiments were performed at least two times, for each experimental condition. Calculations. The BSTAC computer program was used to refine all the parameters (protonation constants, analytical concentration of reagents, formal electrode potential, acid junction potential (Ej = Ja [H+]) and ionic product of water) of the potentiometric titrations of the ligand investigated and to check its purity. The general least-squares computer program LIANA was used for the refinement of both the parameters for the dependence of protonation constants on ionic strength, to calculate the concentration of the neutral species at infinite dilution, and the Setschenow parameters. Details for the BSTAC and LIANA computer programs are described in a previous work.38 The Hyperquad 2008 computer program39 was used to analyze the UV−vis and the spectrofluorimetric spectra, and to calculate the stability constants and the molar absorbance/emission spectrum of each formed species, using the experimental absorbance/fluorescence intensities, the analytical concentrations of the reagents, and the proposed chemical model as input. The ES4ECI program38 was used to draw the distribution diagrams and to calculate the formation percentages of the species, once the protonation constants and the experimental

K iH H+ + Hi − 1L(z − i + 1) − = LH i(z − i) −

(10)

The errors associated to the protonation constants and to the total and neutral species concentration in the aqueous and organic phase are expressed as a 95 % confidence interval, that is ± 1.96 standard deviation, if not differently reported in the text. Along the manuscript, the ligand concentration and the ionic strength were expressed both in the molar and molal concentration scale; the conversion from the molar to the molal concentration scale (and vice versa) was obtained using the appropriate density values40 or as already reported in previous papers,29,41 using the equation: c /m = d0 + a1c + a 2c 2

where d0 is the density of pure water. At T = 298.15 K and in NaCl, we have for example that a1 = −0.017765 and a2 = −6.525·10−4.29

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RESULTS AND DISCUSSION Distribution Coefficient. The distribution measurements of dopamine at different ligand concentrations were carried out following the procedures previously reported. From the knowledge of the total and neutral species ligand concentration, it is possible to calculate the distribution ratios between the two phases. As already reported in previous papers,26,29 the ligand concentration in the organic phase was calculated by the difference between the total ligand concentration, and that was determined by ISE-[H+] potentiometric titrations in the aqueous phase. Some titrations were also carried out on the organic phase, after suitable dilution with pure water or NaCl aqueous solution, to obtain the desired ionic strength value. Owing to the low ligand concentration, we can assume that CTORG ≈ C0ORG (ligand neutral species concentration in 2methyl-1-propanol); some experimental measurements confirmed this approximation over all the range of experimental conditions investigated. Table 1 reports the total concentration of the ligand at different ionic strength values both in the aqueous solutions and in 2-methyl-1-propanol, at T = 298.15 K and 310.15 K. Independently of the ionic strength value, the percentage of the neutral species in the aqueous phase is about 15 % of the total ligand concentration. Table 2 reports the log K0Dm values calculated in these conditions and the corresponding pH after the distribution tests. The dependence of the log K0Dm D



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0 Table 2. Distribution coefficient (log KDm ) of the dopamine neutral species at different ionic strengths, at T = 298.15 and 310.15 K

CNa+/mol kg−1

pHa

0 log KDm

CNa+/mol kg−1

T = 298.15 K 0 0.163 0.163 0.510 0.510 0.745 0.745 0.998 0.998

Protonation Constants. The protonation constants were calculated analyzing (i) the ISE-[H+] potentiometric data (up to I ≈ 1.02 mol kg−1) at T = 298.15 K and 310.15 K, collected from the alkalimetric titrations of the aqueous or saline solutions obtained from the distribution measurements, or (ii) dissolving known amounts of the ligand in NaCl aqueous solutions at different ionic strengths (fresh solutions). Using the second procedure, spectrofluorimetric titrations were made at the same ionic strength values and in the temperature range T = (288.15 to 318.15) K; in this case, lower ligand concentrations were used (CL ≅ 0.08 mmol dm−3) with respect to the potentiometric measurements; (iii) as a further check, UV−vis spectrophotometric measurements were also carried out at T = 310.15 K, I = 0.5 mol kg−1 and 1.0 mol kg−1. During the spectrophotometric and spectrofluorimetric titrations, the data absorbance (A) or fluorescence intensity (CPS) vs λ/nm and e.m.f vs mL were simultaneously collected. These experimental data were analyzed all together by means of the Hyperquad computer program, that also allows an estimation of the distribution of the species and the spectra fitting for each complex formed in the solution, only assuming the additivity of the absorbance or the fluorescence emission in the investigated concentration range. All the titrations were performed taking into account the results reported by some authors37,42 on the auto-oxidation of dopamine in alkaline medium and in the presence of O2(g). The solutions, prepared immediately before the titrations, were preserved from the light exposure, and presaturated N2(g) was bubbled to obtain an inert environment. Owing to the high number of data collected, the experimental log KiH obtained at different ionic strengths and temperatures were reported as Supporting Information in Table 1S. Table 3 reports the experimental log KiH calculated as mean values from the protonation constants obtained from the different techniques and at same ionic strength; it can be observed that despite that this data were obtained from measurements carried out at different ligand concentrations, a good agreement between them was obtained. As an example, Table 4 reports the calculated protonation constants at T = 310.15 K obtained, on the contrary, refining separately the log KiH values determined from (i) potentiometric titrations; (ii) spectrofluorimetric titrations, or (iii) refining altogether the

pHa

0 log KDm

T = 310.15 K

0.718 0.703 0.736 0.782 0.771 0.858 0.825 0.844 0.834

8.40 8.45 8.37 8.38 8.36 7.90 7.95 7.65 7.98

0 0.167 0.167 0.506 0.506 0.759 0.759 1.015 1.015

0.989 0.975 1.012 1.069 1.096 1.079 1.055 1.123 1.151

8.12 8.06 7.83 7.78 7.60 7.79 7.88 7.91 7.77

a

pH value of the aqueous solution after the distribution measurements.

on I/mol kg−1 is shown in Figure 1, where it is possible to observe a fairly linear variation of the distribution coefficient

Figure 1. Distribution coefficient of dopamine between 2-methyl-1propanol and NaCl aqueous solutions at different ionic strength values, at T = 298.15 K and 310.15 K.

with respect to the ionic strength, and that the two straight lines have about the same slope: 0.145 ± 0.08.

Table 3. Mean Protonation Constants at Different Ionic Strengths and Temperatures, Obtained from the ISE-[H+] Potentiometric, Spectrophotometric, and Spectrofluorimetric Data I/mol kg−1

log K1H

I/mol kg−1

log K2H

I/mol kg−1

9.495 8.919 8.945 9.010

± ± ± ±

0.062 0.010 0.045 0.024

0.163 0.198 0.497 0.510 0.747 1.001

10.563 10.570 10.435 10.394 10.300 10.253

± ± ± ± ± ±

0.024 0.012 0.017 0.044 0.017 0.052

8.372 8.686 8.463 8.505 8.502

± ± ± ± ±

0.013 0.023 0.022 0.036 0.025

0.150 0.503 0.768 1.016

9.513 9.128 9.202 8.785

± ± ± ±

0.023 0.025 0.021 0.023

log K1H

T = 288.15 K

a

0.147 0.496 0.757 1.000

10.686 10.739 10.935 11.021

± ± ± ±

0.051a 0.076 0.044 0.024

0.149 0.167 0.503 0.759 1.015 1.037

9.985 9.984 9.897 9.969 9.991 9.960

± ± ± ± ± ±

0.006 0.029 0.029 0.029 0.019 0.015

0.147 0.496 0.757 1.000

T = 310.15 K 0.149 0.167 0.505 0.762 1.011

I/mol kg−1

log K2H

T = 298.15 K 0.163 0.198 0.497 0.517 0.747 1.001 T = 318.15 K 0.150 0.503 0.768 1.016

9.206 8.960 9.061 9.114 8.964 8.869

± ± ± ± ± ±

0.024 0.021 0.031 0.044 0.016 0.015

8.138 8.249 8.296 8.299

± ± ± ±

0.021 0.057 0.021 0.013

95% C.I. E



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Table 4. Protonation Constants at T = 310.15 K and at Different Ionic Strength Values I/mol kg−1

log K1Ha

0.101 0.151 0.253 0.508 0.766 1.027

± ± ± ± ± ±

10.041 10.018 9.993 9.975 9.981 9.998

log K2Ha d

0.026 0.024 0.020 0.013 0.012 0.019

8.344 8.355 8.374 8.423 8.472 8.521

± ± ± ± ± ±

log K1Hb

0.012 0.011 0.009 0.005 0.004 0.007

10.007 9.985 9.962 9.949 9.960 9.982

± ± ± ± ± ±

log K2Hb

0.022 0.020 0.017 0.014 0.018 0.026

8.722 8.721 8.719 8.712 8.706 8.699

± ± ± ± ± ±

log K1Hc

0.020 0.018 0.016 0.010 0.008 0.012

10.005 9.985 9.964 9.959 9.978 10.005

± ± ± ± ± ±

0.006 0.006 0.005 0.004 0.006 0.008

log K2Hc 10.008 8.394 8.401 8.416 8.452 8.488

± ± ± ± ± ±

0.025 0.023 0.020 0.012 0.011 0.017

a

Calculated from spectrofluorimetric data. bCalculated from potentiometric data. cCalculated processing altogether the potentiometric and spectrofluorimetric data. d95 % C.I. (i.e., ± 1.96 standard deviation).

Table 5. Calculated Protonation Constantsa in the Molal Concentration Scale at Different Ionic Strengths and Temperatures I/mol kg−1

log KH1

log KH2

log KH1

log KH2

T = 288.15 K 0 0.1 0.15 0.25 0.5 0.75 1 0 0.1 0.15 0.25 0.5 0.75 1 a

10.813 ± 0.040 10.656 ± 0.025 10.656 ± 0.024 10.677 ± 0.021 10.773 ± 0.015 10.894 ± 0.010 11.025 ± 0.012 T = 310.15 K 10.260 ± 0.024 10.055 ± 0.013 10.031 ± 0.012 10.004 ± 0.011 9.981 ± 0.007 9.982 ± 0.003 9.994 ± 0.001 b

T = 298.15 K 9.453 9.402 9.376 9.325 9.198 9.070 8.942

± ± ± ± ± ± ±

0.036 0.024 0.022 0.020 0.015 0.015 0.020

10.886 10.641 10.597 10.529 10.405 10.305 10.216

8.418 8.427 8.432 8.441 8.463 8.486 8.509

± ± ± ± ± ± ±

0.018 0.020 0.019 0.016 0.010 0.007 0.008

9.841 9.571 9.514 9.421 9.235 9.072 8.921

± ± ± ± ± ± ±

0.042 0.002 0.001 0.002 0.008 0.015 0.021 T = 318.15 K ± 0.018 ± 0.008 ± 0.007 ± 0.008 ± 0.019 ± 0.033 ± 0.046

9.107 9.099 9.094 9.085 9.063 9.041 9.019

± ± ± ± ± ± ±

0.032 0.048 0.042 0.032 0.015 0.031 0.057

8.116 8.138 8.148 8.169 8.222 8.275 8.327

± ± ± ± ± ± ±

0.036 0.008 0.008 0.007 0.006 0.008 0.011

Calculated processing all together all the protonation constants determined by means of the different instrumental techniques. b95 % C.I.

neutralization of the strong acid and to the proton displacement (see Figure 1S of Supporting Information). Figure 2 reports the fluorescence intensity collected for each titration curve at the same wavelength: λ = 315 nm (wavelength

data collected from each technique. The results reported in this table confirm the agreement between them, within the experimental errors. Table 5 reports the protonation constants at infinite dilution and at different ionic strengths (molal concentration scale) and temperatures obtained by analyzing simultaneously the experimental data collected from potentiometric, spectrofluorimetric, and spectrophotometric measurements. The good agreement between the log KHi values obtained from the different instrumental techniques, and the unchanged profile of the fluorescence spectra when the pH goes from pH ≈ 6.5 to 10.5, is an indication that processes of photoinduced proton transfer do not occur.43 Despite that dopamine has three protonation equilibria, we in this work, as did some other authors,1,4,8−11,22,44,45 determined the protonation constants of only two steps, which refer to the protonation of the amine group in the lateral chain and the second phenolic group presents in the para position with respect to the lateral chain (log K2H).4,46 The other phenolic group (meta position) has a log KH value >13 and is less important from a biological point of view. A quite accurate discussion on the protonation steps of dopamine is reported in the literature section (see later). The fluorescence intensity of dopamine is strongly influenced by the change of pH. During our experiments, we observed that the addition of the titrant (NaOH standard solution), gave a significant lowering of the signal of different order of magnitudes, indicating that a reaction of fluorescence quenching occurs when the pH goes from the acidic to the alkaline medium (pH > 10.5). This is due both to the

Figure 2. Fluorescence intensity of dopamine vs pH in NaClaq 0.15 mol kg−1, T = 310.15 K, λecc= 284 nm, λemiss = 315 nm, cL = 0.08 mmol dm−3.

where the maximum fluorescence intensity was observed), I = 0.15 mol kg−1, and T = 310.15 K. The influence of the temperature on the fluorescence intensity can be investigated from the spectrofluorimetric titrations carried out in the range T = (288.15 to 318.15) K. Figure 3 reports the different titration curves collected for a F



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Figure 5. Plot of log KiH vs T/K at I = 0.5 mol kg−1 in NaCl aqueous solutions. Figure 3. Fluorescence intensity (CPS) of dopamine vs wavelength (λ/nm), at different temperatures (T/K).

freshly prepared dopamine solutions (CL = 0.08 mmol dm−3) at I = 0.15 mol kg−1 and for all the temperatures investigated. A quite significant lowering of the signal along the temperature range was observed; in fact, from Figure 4, it is possible to

Figure 6. Distribution diagram of the dopamine species at I = 0.15 mol kg−1 and at different temperatures: (a) T = 288.15 K; (b) T = 310.15 K. Species: 1, LH3+; 2, LH2; 3, LH− and 4, L2−.

Figure 4. Linear relationship between the fluorescence intensity and temperature in NaCl 0.15 mol kg−1. λemiss = 315 nm, λecc = 284 nm, and cL = 0.08 mmol dm−3.

observe that at the maximum emission wavelength (λem = 315 nm), the signal (CPS) varies linearly with respect to the temperature and it reduces over 50 %. A similar trend was also observed for the protonation constants reported in Table 3 and in Figure 5, where the dependence of log KHi on T/K at I = 0.5 mol kg−1 is shown. The dependence of the formation percentages on the temperature and on the ionic strength is reported in Figures 6 and 7, respectively. To obtain accurate information on the distribution of all the protonated/unprotonated dopamine species over the whole pH range, the most basic protonation step was also taken into account; in this case the literature value of log KH = 13.1 was used.47 Figure 6 shows the effect of the temperature on the distribution of the species at T = 288.15 K and 310.15 K, at I = 0.15 mol kg−1; as we can see, the maximum of all the curves has shifted at lower pH values. The shaded zone refers to pH values not experimentally investigated, where probably the oxidation of dopamine occurs (similar behavior was also observed at T = 298.15 K and 318.15 K). Figure 7 reports the dependence of the formation percentages on the ionic strength at T = 298.15 K; in this case the curves refer to

Figure 7. Distribution diagram of dopamine species at T = 298.15 K and at different ionic strengths: (a) I = 0.15 mol kg−1; (b) I = 1.00 mol kg−1. Species: 1, H3L+; 2, H2L; 3, HL−; 4, L2‑.

the ionic strength values: I = 0.15 mol kg−1 and 1.0 mol kg−1, respectively. The dependence of the protonation constants and of the species distribution on the ionic strength can be explained in terms of weak ion pair formation between the charged ligand species and the ions of the supporting electrolyte.48−50 Figure 8 shows a UV−vis spectrophotometric titration diagram recorded at a ligand concentration of 0.08 mmol dm−3, I = 0.5 mol kg−1, T = 310.15 K and at different pH values; the profile of the titration curves varies significantly with pH. This behavior can be explained taking into account that the ligand protonated species absorb in a different wavelength G



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means of eqs 7,8, and 9 using two different procedures (see Table 6). In the first procedure, the log KD00 was considered as a fitting parameter and by means of eqs 7 and 8 and of the LIANA computer program, we calculated its value and the corresponding Setschenow coefficients k(c,m) both for the molal and the molar concentration scale. In the second procedure, only k(c,m) was considered as a fitting parameter, while for log KD00, the experimental values in pure water reported in Table 2 (log KD00 = 0.718 and 0.989 at T = 298.15 and 310.15 K, respectively) were used. The differences can be explained taking into account that in aqueous solution and at the pH of dissolution, the dopamine dissociates significantly, and it is present for ∼85% as LH2+ species and only for ∼15% as neutral species; consequently, the experimental values in pure water differ significantly from that extrapolated at I → 0. The use of the different approaches for the calculation of the Sestchenow coefficients can be considered only as a check for the robustness of the procedures; this was confirmed by the good agreement between the different results, as already obtained in previous investigations.29,34 Dependence of the Protonation Constants on Ionic Strength. Since alkalimetric titrations were made up to pH ≈ 10.5, the protonation steps that must be taken into account are

Figure 8. Spectrophotometric titration of dopamine (CL = 0.08 mmol dm−3) in NaCl 0.5 mol kg−1, T = 310.15 K and at different pH values: 1, pH = 5.7; 2, pH = 8.9; 3, pH = 9.8; 4, pH = 10.5.

range and form in different pH regions; in particular we observe that (i) at λ ∼ 210 nm, a sharp increase in the absorbance occurs when the pH varies between 5.7 to 10.5; (ii) at λ ≈ 279 nm, the absorption band remains quite stable up to pH ≈ 8− 8.2; (iii) at pH > 8.5 a significant bathocromic shift and an increase of the absorbance up to pH ≈ 9.8 (curve 3) is observed; (iv) for higher pH values (>10.5−11), a decrease of the absorbance and an hipsochromic shift is observed up to λ = 290 nm; these pH values were not taken into account during the refinement of the experimental data (potentiometric, UV− vis and spectrofluorimetric), since probably in that conditions the oxidation of dopamine occurs, and the formation of the corresponding benzoquinone, that is not fluorescent is observed.42 The variation of the molar absorptivity of each species in the wavelength range from λ = (200 to 400) nm at I = 0.5 mol kg−1 and T = 310.15 K is reported in Figure 9. The values of the

0

log K1H = log K1H + log γH+ + log γL− − log γLH0

(11)

0

log K 2H = log K 2H + log γH+ + log γLH0 − log γLH + 2

(12)

where KH0 i refers to the protonation constant at infinite dilution and γi is the activity coefficient (expressed in the molal concentration scale) of the ith ionic species. The dependence of the protonation constants on ionic strength was modeled by means of the Specific ion Interaction Theory (SIT).51−54 This allowed us the determination of the specific interaction parameters of the ionic species present in solution. By using this approach, the activity coefficients of a cation or an anion can be expressed by log γ = −z 2

0.51 I + 1 + 1.5 I

∑ ε·mi

(13)

where ε is the interaction coefficient of a generic ionic species, while for a neutral species, the activity coefficient can be calculated by means of the Setschenow coefficient:35 log γ = kmI

(14)

km is the Setschenow coefficient that accounts for the variation of the activity coefficient of the neutral species with the ionic strength. Using the simple formulation and the molal concentration scale, the SIT approach is identical to the widely used Debye− Hückel equation:55

Figure 9. Molar absorbtivity of dopamine (cL = 0.08 mmol dm−3) in NaCl 0.5 mol kg−1 and at T = 310.15 K.

0

log K iH = log K iH − A ·z*

molar absorptivity (ε/ mol−1 L cm−1) in these conditions are εmax(L−) = 9810 (λ/nm =300); εmax(LH0) = 8300 (λ/nm =297); εmax(LH2+) = 5500 (λ/nm =279). These ε values, that are typical of aromatic ligands containing few polar substituents, refer only to the highest value of εmax at the corresponding wavelength. The uncertainty on εmax ranges between 2 and 8% (± 95 % C.I.), depending on the formation percentage of each complex species. Setschenow Coefficients. As already made in previous papers,31,34 the Setschenow coefficients k(c,m) were calculated by

I + Δε ·I 1 + 1.5 I

(15)

In this case, the Δε parameter is identical to the C parameter of the Debye−Hückel equation. By using a modified version of the SIT equation already proposed,49,56 the specific interaction coefficients ε can be considered dependent on the ionic strength, and not true constants; this modified version, that makes the model reliable over a wide ionic strength range, can be expressed according to the simple relationship: H



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Table 6. Distribution Coefficients of the Neutral Species at Infinite Dilution and Setschenow Coefficients 2-parameters T/K

a

k(c,m)∞

1-parameter σfitb

k(c,m)0

mol mol mol mol

dm−3 kg−1 dm−3 kg−1

0.140 0.106 0.176 0.109

± ± ± ±

0.043a 0.021 0.065c 0.010c

0.181 0.177 0.126 0.169

± ± ± ±

log = 0.705 ± 0.013 0.027a 0.017 0.017 0.006 0.044c 0.035 0.010c 0.018 log KD00 = 0.983 ± 0.014a,e) 0.048a 0.024 0.020 0.009 0.054c 0.017 0.017c 0.006

310.15

mol mol mol mol

dm‑3 kg−1 dm−3 kg−1

0.117 0.112 0.109 0.111

± ± ± ±

0.060a 0.026 0.063c 0.023c

0.170 0.169 0.182 0.168

± ± ± ±

σfitb

0.163 0.146 0.146 0.133

± ± ± ±

0.015a 0.007 0.005c 0.010c

0.017 0.008 0.019 0.006

0.145 0.142 0.148 0.131

± ± ± ±

0.018a 0.007 0.008c 0.002c

0.023 0.009 0.023 0.010

a,b

KD00

298.15

k(c,m)

Extrapolated values from eq 7. bMean deviation on the fit. cCalculated using the experimental values for log K0D0.

Table 7. Specific Interaction Coefficients of Dopamine Species at Different Temperatures SIT parameters T/K

species ‑

288.15

L HL0 H2L+ L‑ HL0 H2L+ L‑ HL0 H2L+ L‑ HL0 H2L+

298.15

310.15

318.15

ε

ε∞

ε0

0.647 ± 0.019 0.140 0.718 ± 0.024 −0.228 ± 0.012

1.016 ± 0.024 0.160 0.907 ± 0.046 −0.149 ± 0.070

0.312 ± 0.024 0.124 0.546 ± 0.046 −0.289 ± 0.062

0.385 ± 0.011 0.135 ± 0.011

1.062 ± 0.088 0.411 ± 0.092

−0.101 ± 0.049 −0.081 ± 0.058

0.113 ± 0.012 −0.530 ± 0.049 0.098 −0.010 ± 0.008

0.104 ± 0.066 −0.564 ± 0.094 0.178 0.202 ± 0.099

0.105 ± 0.061 −0.501 ± 0.094 0.029 −0.166 ± 0.092

interaction −

ε[ L , Na ] kmc ε[ H2L+,Cl−] ε[ L−, Na+] kmb ε[ H2L+,Cl−] ε[ L−, Na+] kmc ε[ H2L+,Cl−] ε[ L−, Na+] kmb ε[ H2L+,Cl−] +

a

a 95 % C.I. bSetschenow coefficients experimentally determined from distribution measurements at T = 298.15 K and 310.15 K. cSetschenow coefficient at T = 288.15 K and 318.15 K were estimated by considering for km, in the temperature interval T = (298.15 to 310.15) K, a linear dependence on temperature.

Δε = Δε∞ +

Δε0 − Δε∞ I+1

ε0 − ε∞ I+1

(20)

ε0 = 0.0848 − 0.1024f1 (T ) + 0.1970f2 (T )

(21)

(16)

where Δε = Σεreactants − Σεproducts; if the specific interactions of the ligand with the ions of the supporting electrolyte are taken into account, we can calculate the single specific interaction coefficients ε, by means of the eqs 13 or 17 ε = ε∞ +

ε∞ = 0.136 + 0.07165f1 (T ) + 0.1159f2 (T )

where

(17)

The ε0 and ε∞ parameters take into account the dependence of SIT parameters on ionic strength and are valid for I → 0 and I → ∞, respectively. In the case of dopamine, we have for the first and second protonation constants, respectively: Δε1 = ε(H+, Cl−) + ε(L−, Na +) − km

(18)

Δε2 = ε(H+, Cl−) + km − ε(LH+2 , Cl−)

(19)

f1 (T ) =

⎛1 1⎞ ⎜ − ⎟ ⎝θ T⎠

f2 (T ) =

⎛θ T⎞ ⎜ − 1 + ln ⎟ ⎝T θ⎠

where θ = 298.15 K, while T = (288.15, 310.15, or 318.15) K. The parameters calculated by means of eq 15 and eq 16 are reported in Table 2S of the Supporting Information. Similar calculations were made using different Debye−Hückel type equations already proposed in previous papers;48−50,55 the corresponding parameters calculated for the molar concentration scale are also reported in Table 2S. The SIT approach (eqs 13 and 17) was applied only to the protonation constants obtained refining altogether the spectrofluorimetric/ISE-[H+] potentiometric data; the specific interaction coefficient of each ion pair formed by the interaction of the different protonated or unprotonated species with the ions of the supporting electrolyte (NaCl) (see eqs 18 and 19) at different temperatures are reported in Table 7. The interaction coefficients of the neutral species (k(c,m)) at T =

where km = ε(LH0, Na+,Cl−). At T = 298.15 K, the values ε = 0.21, ε∞ = 0.136, and ε0 = 0.0848 were used for ε(H+, Cl−). The corresponding values at T = (288.15, 298.15, 310.15, and 318.15) K were calculated taking into account the dependence of the specific interaction coefficient of ε(H+, Cl−) on temperature and using eqs 20−21:56 I



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LITERATURE COMPARISON In the literature there are several papers containing information on the acid−base properties of dopamine and its ability to form complexes with metal ions.1,2,4,5,7−12,37,42,44−46,57 However, until now this information appeared quite confusing, probably because of the difficulty in determining the protonation constants of all the equilibrium steps. Another important problem is bound to the uncertainty of the association of the log KiH values to the correct functional groups. Corona− Avendaño et al.4 proposed some possible deprotonation processes for the three functional groups of dopamine. The best agreement between the results obtained from the theoretical and the 13C NMR investigation in aqueous solution was observed when the following deprotonation steps were taken into account: the first proton displacement involves the −NH3+ group, followed by the cathecol group in the para position with respect to the aliphatic lateral chain containing the amine group. Finally, the deprotonation of the second cathecol group was observed at high pH values (>12.5). The protonation constant of this group is difficult to determine by simple potentiometric titration, and is, however, less important from a biological point of view with respect to the other ones. Nagy et al.45 and Antikainen et al.44 report for some cathecol amine derivatives different deprotonation processes; in the case of dopamine, they assumed that the protonated form (H2L+) occupies a central position in the chemistry of the catechol amines in aqueous solutions and assumed that the first phenolic group is more acidic than the protonated amino group. On the basis of our expertise in the field of the speciation studies of similar molecules, we think that the results reported by Nagy et al.45 and Antikainen et al.44 are very reliable, so that they were taken into account for the calculation performed in the present paper. Cathecol derivatives are unstable molecules that tend to degrade under particular conditions.37,42 The effect of pH, light exposure, oxygen, and time on the stability and acid−base properties of dopamine was carefully investigated; from the analysis of the literature information, it appears that in the acidic environment and up to medium alkaline conditions, dopamine is stable. For pH values higher than 10.5, the molecule tends to degrade under the effect of oxygen and light; the auto-oxidation of dopamine in alkaline medium gives as product, the benzoquinone,37,42 that has completely different acid−base properties with respect to the dopamine, and is not fluorescent. For this reason during the investigation carried out in this paper, we followed the suggestion and results reported by these authors. This information is sufficient to highlight the difficulty in studying the acid−base properties of such a ligand. In the past, different approaches and instrumental techniques were used to investigate the acid−base properties of dopamine at different ionic strengths and temperatures; nevertheless, the results reported by many authors are quite different (see Table 9). It can be observed,6,12,44,45,57 that generally only two protonation constants were obtained, especially for the investigations carried out by potentiometry; in fact, the log KiH of the most basic protonation step is often neglected. The third protonation constant is obtained from spectrophotometric methods, and in some cases the log K3H values reported by different authors differ by more than one logarithm unit. In many cases, this is also observed for the other two protonation constants, making

288.15 K and 318.15 K were estimated by applying a linear dependence on the temperature to the k (c,m) values experimentally determined at T = 298.15 K and 310.15 K. Activity Coefficients. Once the Setschenow coefficients were calculated from the distribution measurements, the activity coefficients of the neutral species can be obtained indifferently at different salt concentrations using the two models expressed by eqs 7 and 9 (see Table 8). A rough Table 8. Activity Coefficients of Dopamine Neutral Species at T = 298.15 K and 310.15 K, Calculated by Using the One Parameter and Two Parameter Models I/mol kg−1

γNa

0.05 0.10 0.15 0.25 0.50 0.75 1.00

1.017 1.035 1.053 1.090 1.187 1.293 1.409

± ± ± ± ± ± ±

0.05 0.10 0.15 0.25 0.50 0.75 1.00

1.015 1.030 1.045 1.076 1.159 1.247 1.343

± ± ± ± ± ± ±

I/mol kg−1

T = 298.15 K 0.070c 0.05 0.062 0.10 0.048 0.15 0.050 0.25 0.038 0.50 0.048 0.75 0.084 1.00 T = 310.15 K 0.084 0.05 0.081 0.10 0.067 0.15 0.069 0.25 0.075 0.50 0.121 0.75 0.186 1.00

γNb 1.022 1.044 1.066 1.107 1.205 1.300 1.393

± ± ± ± ± ± ±

0.071 0.063 0.049 0.051 0.039 0.048 0.083

1.016 1.032 1.048 1.080 1.162 1.249 1.341

± ± ± ± ± ± ±

0.084 0.081 0.068 0.070 0.075 0.121 0.185

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a

Calculated by using the one parameter model (eq 6). bCalculated by using the two parameter models (eq 8). c95 % C.I.

comparison between the log γ values calculated by means of each model, allow us to observe a fairly good agreement between them. Figure 10 reports the trend of the activity

Figure 10. Activity coefficient values of the dopamine neutral species vs I/mol kg−1, calculated by means of eq 6. □, values at T = 298.15 K; ○, values at T = 310.15 K.

coefficient of the neutral species calculated by means of the one parameter model (eq 7) for the two temperatures investigated. As we can see, the activity coefficients of the dopamine neutral species are fairly coincident up to I = 0.5 mol kg−1, and only for higher ionic strength values the differences become significant; at I = 1.0 mol kg−1 we have for example Δlog γ = 0.066. This indicates that the activity coefficients of the dopamine neutral species are slightly temperature dependent. J



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Table 9. Literature Protonation Constants of Dopamine I/mol kg−1 0.5, 0.6, 0.1, 1.0, 0.2, 1.0, 0.5, 0.5,

NaCl NaCl KNO3 KNO3 KCl NaClO4 NaNO3 NaCl

0.2, KCl 0.15, KCl 0.1, KCl

T/K 298.15 298.15 298.15 298.15 298.15 298.15 293.15 293.15 298.15 298.15 298.15

log KH1

13.1 12.81 12.05 12.04 12.07 13.7

log KH2

log KH3

10.41 10.49 10.41 10.50 10.41 10.55 10.6 9.95 10.58 12.37 10.50 10.31

9.06 8.93 8.88 8.96 8.89 9.05 9.06 8.61 9.05 8.01 8.92 8.85

authors This work Sedeh et al.12 Zelano et al.57 Rajan et al.6 Kiss et al.9 Gerard et al.7 Grgas-Kuznar et al.8 Sanchez-Rivera et al.37 Kiss et al.10 Nagy et al.45 Antikainen and Witikainen44

The only information that we can give, as regards to dopamine, is that the lowering of the log KiH values with temperature indicate that the processes are exothermic. The only ΔH values reported in the literature47 were calculated at T = 298.15 K from the log KiH determined in the temperature range of T = (283.15 to 313.15) K in the KCl aqueous solution (I = 0.1 mol dm−3) and seem to be somewhat unreliable.

quite difficult an accurate comparison among the data reported in the literature and those here obtained. The results reported by several authors on the acid−base properties of dopamine in aqueous solution appear in many cases discordant; moreover there is an absence, in our knowledge, of data at physiological conditions, so that the log KiH values here reported can be considered an important upgrade to the knowledge of the acid−base properties of dopamine at different ionic strengths and temperatures. No investigation is reported in the literature about the modeling of the protonation constants and their dependence on the ionic strength. For the first time the specific interaction parameters, for each ion-pair formed by the interaction of the differently protonated/unprotonated dopamine species with the supporting electrolyte ions, are proposed. The Setschenow parameters were calculated from the distribution measurements carried out at T = 298.15 K and 310.15 K; by considering a linear dependence on the temperature of the experimental Setschenow parameters, the corresponding values at T = 288.15 K and 318.15 K were also estimated. The specific ion interaction parameters were determined by using the Setschenow parameters calculated at different temperatures for the ligand neutral species; this procedure allows the calculation of accurate ε values, since (i) the approximations that generally were made assigning an arbitrary value of zero to the activity coefficient of neutral species can be bypassed and (ii) for each temperature investigated, a different k(c,m) value was used, instead of a common value for each temperature. A lack of information in the literature is also observed for the knowledge of the total and neutral species concentration, as well as for the activity coefficients at different ionic strengths and temperatures. This information is fundamental for pharmaceutical product design, influencing the drug efficacy, future development and formulation efforts, and the pharmacokinetics, such as the release, transport, and the degree of absorption in the organism. The significant errors observed in some cases on the protonation constants and the rather short temperature range investigated did not allow us to calculate reliable temperature coefficient values. King58 reports for a temperature interval of ∼30 K, as here investigated, and for values of pK ± 0.02, that taking into account the propagation of errors in pK to errors in ΔH, it is possible to obtain ΔH values with a standard deviation not less than ± 200 cal mol−1.

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ASSOCIATED CONTENT

S Supporting Information *

Additional tables as described in the text. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +39(090)6765761. Fax. +39(090)392827. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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REFERENCES

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Thermodynamic Properties of Dopamine in Aqueous Solution. Acid

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