Protonation of antamanide: Experimental and theoretical study

Journal of Molecular Liquids 196 (2014) 163–166

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Protonation of antamanide: Experimental and theoretical study Emanuel Makrlík a, Stanislav Böhm b, Petr Vaňura b,⁎, Paolo Ruzza c a b c

Faculty of Environmental Sciences, Czech University of Life Sciences, Prague, Czech Republic Institute of Chemical Technology, Prague, Czech Republic Institute of Biomolecular Chemistry of CNR, Padua Unit, Padua, Italy

a r t i c l e

i n f o

Article history: Received 7 January 2014 Received in revised form 11 March 2014 Accepted 14 March 2014 Available online 28 March 2014 Keywords: H3O+ cation Antamanide Protonation DFT calculations Structures

a b s t r a c t On the basis of extraction experiments and γ-activity measurements, the extraction constant corresponding to the equilibrium H3O+(aq) + 1·Na+(nb) ⇆ 1·H3O+(nb) + Na+(aq) occurring in the two-phase water–nitrobenzene system (1 = antamanide; aq = aqueous phase, nb = nitrobenzene phase) was evaluated as log Kex (H3O+, 1·Na+) = −0.4 ± 0.1. Further, the stability constant of the 1·H3O+ complex in nitrobenzene saturated with water was calculated for a temperature of 25 °C: log βnb (1·H3O+) = 5.7 ± 0.2. Finally, by using quantum mechanical DFT calculations, the most probable structure of the cationic complex species 1·H 3O+ was derived. In the resulting complex, the “central” cation H3O+ is bound by two linear hydrogen bonds and one bifurcated hydrogen bond to the corresponding four oxygens of the parent ligand 1. Besides, the whole 1·H3O+ complex structure is stabilized by two intramolecular H-bonds. The interaction energy of the considered 1·H 3O + complex was found to be − 458.7 kJ/mol, confirming also the formation of this cationic species. © 2014 Elsevier B.V. All rights reserved.

1. Introduction The cyclic decapeptide antamanide, cycl[-Val(1)-Pro(2)-Pro(3)Ala(4)-Phe(5)-Phe(6)-Pro(7)-Pro(8)-Phe(9)-Phe(10)-], consisting entirely of L-amino acids (see Scheme 1), forms 1:1 complexes with a variety of metal cations [1,2]. Antamanide was isolated from the poisonous mushroom Amanita phalloides [3] and it has the unique property of counteracting the toxin phalloidin, produced by the mentioned mushroom. Furthermore, it should be emphasized that antamanide also prevents the inhibition of depolymerization of F-actin and G-actin in the liver cell membranes of mammals [4]. The dicarbollylcobaltate anion (DCC−) [5] and some of its halogen derivatives have been applied very often for the solvent extraction of various metal cations (especially Cs+, Sr2 +, Ba2 +, Eu3 +, and Am3 +) from aqueous solutions into a polar organic phase, both under laboratory conditions for theoretical or analytical purposes [6–13], and on the technological scale for the separation of some high-activity isotopes in the reprocessing of spent nuclear fuel and acidic radioactive waste [14–16]. Recently, protonation of valinomycin, some calix[4]arenes, dibenzo18-crown-6, a hexaarylbenzene-based receptor, and beauvericin has been investigated in detail [17–21]. On the other hand, in the current work, the solvent extraction of H3O+ into nitrobenzene by means of a synergistic mixture of sodium dicarbollylcobaltate (NaDCC) and antamanide (abbrev. 1; see Scheme 1) was studied. Moreover, the ⁎ Corresponding author. E-mail address: [email protected] (P. Vaňura).

http://dx.doi.org/10.1016/j.molliq.2014.03.019 0167-7322/© 2014 Elsevier B.V. All rights reserved.

stability constant of the proved 1·H3O+ complex species in the organic phase of the water–nitrobenzene extraction system was determined. Finally, applying quantum mechanical DFT calculations, the most probable structure of this cationic complex species was predicted. 2. Experimental section 2.1. Chemicals Compound 1 (see Scheme 1) was prepared by the method described in Ref. [22]. Cesium dicarbollylcobaltate (CsDCC) was synthesized by means of the method published by Hawthorne et al. [23]. The other chemicals used (Lachema, Brno, Czech Republic) were of reagent grade purity. A nitrobenzene solution of sodium dicarbollylcobaltate (NaDCC) was prepared from CsDCC by the procedure described elsewhere [24]. The radionuclide 22Na+ was obtained from DuPont, Belgium; its radionuclidic purity was 99.9%. 2.2. Extraction The extraction experiments were carried out in 10 mL polypropylene test-tubes with polypropylene stoppers: 2 mL of an aqueous solution of HCl of a concentration in the range from 1 × 10− 3 to 3 × 10 − 3 mol/L and 10 kBq of 22Na + were added to 2 mL of a nitrobenzene solution of 1 and NaDCC, whose initial concentrations varied also from 1 × 10− 3 to 3 × 10− 3 mol/L (in all experiments, , was equal to the initial concentration of 1 in nitrobenzene, Cin,nb 1 the initial concentration of NaDCC in this medium, C in,nb NaDCC ). The

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test-tubes filled with the solutions were shaken for 3 h at 25 ± 1 °C, using a laboratory shaker. Then the phases were separated by centrifugation. Finally, 1 mL samples were taken from each phase and their γ-activities were measured by means of a well-type NaI(Tl) scintillation detector connected to a γ-analyzer Triathler (Hidex, Turku, Finland). The equilibrium distribution ratios of sodium, DNa, were determined as the ratios of the corresponding measured radioactivities of 22Na+ in the nitrobenzene and aqueous samples. 3. Results and discussion 3.1. Extraction experiments Previous results [5,17,25–27] indicated that the two-phase water–HCl–nitrobenzene–1 (antamanide)–sodium dicarbollylcobaltate (NaDCC) extraction system (see Experimental section), chosen for determination of the stability constant of the 1·H3O+ complex in nitrobenzene saturated with water, can be characterized by the main chemical equilibrium þ

þ

þ

nbÞV1H3 O ðnbÞ H3 O ðaqÞ þ 1Na ð þ þ þ þ Na ðaqÞ; K ex H3 O ; 1Na

ð1Þ

with the respective extraction constant Kex(H3O+, 1·Na+):  þ  þ   1H3 O nb Na aq þ þ K ex H3 O ; 1Na ¼ ½H3 Oþ aq ½1Naþ nb

ð2Þ

where aq and nb denote the presence of the species in the aqueous and nitrobenzene phases, respectively. At this point it should be noted that 1 is a considerably lipophilic ligand, practically present in the nitrobenzene phase only, where this ligand forms – with H3O+ and Na+ – the relatively stable complexes 1·H3O+ and 1·Na+, as given below. Employing the conditions of electroneutrality in the organic and aqueous phases of the system under study, the mass balances of the univalent cations studied at equal volumes of the nitrobenzene and aqueous phases, as well as the measured equilibrium distribution

ratio of sodium, DNa = [1·Na+]nb/[Na+]aq, combined with Eq. (2), we gain the final expression for Kex(H3O+, 1·Na+) in the form   1 þ þ K ex H3 O ; 1Na ¼ DNa

C in;nb NaDCC ð1 þ DNa Þ C in;aq −C in;nb NaDCC HCl

ð3Þ

where C in,aq HCl is the initial concentration of HCl in the aqueous phase and C in,nb NaDCC denotes the initial concentration of NaDCC in the nitrobenzene phase of the system under consideration. In this work, from the extraction experiments and γ-activity measurements (see Experimental section) by means of Eq. (3), the following value of the constant Kex (H3O+, 1·Na+) was determined as log Kex (H3O+, 1·Na+) = − 0.4 ± 0.1 (see Table 1). This constant experimentally proves the justifying of the extraction mechanism and the presentation of the corresponding species, expressed by the two-phase chemical equilibrium (1). Furthermore, with respect to our previous results [5,17,27], for the extraction constant Kex (H3O+, Na+) corresponding to the equilibrium H3O+(aq) + Na+(nb) ⇆ H3O+(nb) + Na+(aq) and for the extraction constant Kex (H3O+, 1·Na+) defined above, as well as for the stability constants of the complexes 1·H3O + and 1·Na+ in nitrobenzene saturated with water, denoted by βnb (1·H3O+) and βnb (1·Na+), respectively, one gets     þ þ logβnb 1H3 O ¼ logβnb 1Na     þ þ þ þ þ logK ex H3 O ; 1Na – logK ex H3 O ; Na : ð4Þ Using the value log Kex(H3O+, Na+) = 0.3 inferred from Ref. [25], the constant log Kex (H3O+, 1·Na+) given above, log βnb (1·Na+) = 6.4 ± 0.1 [28], determined from the distribution of sodium picrate in the water–nitrobenzene extraction system containing the ligand 1, and applying Eq. (4), we obtain the stability constant of the 1·H 3O + complex in water-saturated nitrobenzene at 25 °C as log βnb (1·H3O+) = 5.7 ± 0.2. This means that in the mentioned nitrobenzene medium, the stability of the 1·H3O+ complex under study is somewhat lower than that of the cationic complex species 1·Na+. In this context it is necessary to note that the stability constant of the complex species 2·H3O+, where 2 denotes valinomycin (see Scheme 2), in nitrobenzene saturated with water is log βnb (2·H3O+) = 5.3 ± 0.1 [17]. Thus, in this medium, the stabilities of the complexes 1·H3O+ and 2·H3O+ under consideration are nearly comparable. 3.2. DFT calculations The theoretical calculations were performed at the density functional level of theory (DFT, B3LYP functional) [29,30], employing the Gaussian 09 suite of programs [31]. The 6-31G(d,p) basis set was used and the optimizations were unconstrained. In order to increase the numerical accuracy and to reduce oscillations during the molecular geometry optimization, two-electron integrals and their derivatives were calculated by using the pruned (99,590) integration grid, having 99 radial shells and 590 angular points per shell, which was requested by means of the Gaussian 09 keyword “Int = UltraFine”. The most probable structure of the 1·H3O+ cationic complex was predicted on the basis of the thorough conformational analysis (i. e., different initial mutual positions of the ligand 1 and the hydroxonium cation H3O+ were considered Table 1 Experimental data concerning determination of log Kex (H3O+, 1·Na+) on the basis of Eq. (3). Cin,aq HCl (mol/L)

Scheme 1. Structural formula of antamanide (abbrev. 1).

1.0 1.5 2.0 2.5 3.0

× × × × ×

−3

10 10−3 10−3 10−3 10−3

Cin,nb NaDCC (mol/L) 1.0 1.5 2.0 2.5 3.0

× × × × ×

−3

10 10−3 10−3 10−3 10−3

DNa

log Kex (H3O+, 1·Na+)

1.49 1.60 1.48 1.66 1.72

−0.3 −0.4 −0.3 −0.4 −0.5

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165

Scheme 2. Structural formula of valinomycin (abbrev. 2).

during the geometry optimization) and the respective vibrational frequency calculations. In the model calculations, we optimized the molecular geometries of the parent antamanide ligand 1 and its complex with H3O+, similarly as in our previous papers [32–36]. The optimized structure of the free ligand 1 with the carbonyl oxygen bonding sites O(1), O(2),…, O(10) is illustrated in Fig. 1. It is necessary to emphasize that this free ligand 1 structure is stabilized by two strong intramolecular hydrogen bonds O(3)⋯H(6)N (2.11 Å) and O(8)⋯H(1)N (1.86 Å) (see Fig. 1). In Fig. 2, the structure obtained by the full DFT optimization of the 1·H3O+ complex is depicted. In the resulting cationic complex species, which is most energetically favored, the “central” cation H3O+ is bound by two strong linear hydrogen bonds (1.63 and 1.38 Å) and one relatively strong two-center H-bond (2.87 and 1.56 Å) to the respective four oxygen atoms of the parent ligand 1 (see Fig. 2). Besides, as follows from Fig. 2, the whole 1·H3O+ complex structure is also stabilized by two intramolecular H-bonds: O(3)⋯H(6)N (2.14 Å) and O(8)⋯H(1)N (2.15 Å). Thus, these H-bonds are somewhat longer (and therefore weaker) than those stabilizing the free ligand 1 structure. Cartesian coordinates (in Å) for the free ligand 1 and the 1·H3O+ complex are presented in Supplementary data. Finally, the interaction energy, E(int), of the 1·H3 O+ complex [calculated as the respective difference between of the pure electronic

Fig. 2. DFT optimized structure of the 1·H3O+ complex [B3LYP/6-31G(d,p)]; hydrogen atoms of 1 are omitted for clarity except two hydrogens taking place in two intramolecular hydrogen bonds O(3)⋯H(6)N (2.14 Å) and O(8)⋯H(1)N (2.15 Å); the lengths of the H-bond interactions H1⋯O(3), H1⋯O(6), H2⋯O(8), and H3⋯O(1) are 2.87, 1.56, 1.63, and 1.38 Å, respectively.

energies of 1·H3O+ and isolated 1 and H3O+ species: E(int) = E(1·H3O +) − E(1) − E(H3 O+ )] was found to be − 458.7 kJ/mol, which confirms the formation of the considered cationic complex 1·H3O+ as well. 4. Conclusions In this work, we have shown that the combination of theoretical DFT calculations and an experimental extraction method in the two-phase water–nitrobenzene system can provide relevant complementary data on the noncovalent interactions of the hydroxonium cation H3O+ with the antamanide ligand (1). By using this extraction method, the stability constant of the cationic complex 1·H3O+ in nitrobenzene saturated with water was determined as log β nb (1·H 3 O + ) = 5.7 ± 0.2 (t = 25 °C). On the other hand, by applying DFT calculations, the most probable structure of the 1·H3O+ cationic species was predicted. In the resulting complex, the “central” cation H3O+ is bound by two strong linear hydrogen bonds and one relatively strong bifurcated H-bond to the corresponding four oxygens of the parent ligand 1. Besides, the whole 1·H3O+ complex structure is stabilized by two intramolecular H-bonds. It is apparent that the present work may be an important contribution predominantly to both theoretical and experimental studies of the investigated antamanide ligand, as well as to supramolecular chemistry in general. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.molliq.2014.03.019. Acknowledgments This work was supported by the Grant Agency of Faculty of Environmental Sciences, Czech University of Life Sciences, Prague, Project No.: 42900/1312/3114 “Environmental Aspects of Sustainable Development of Society,” and by the Czech Ministry of Education, Youth, and Sports (Project MSM 6046137307). References

Fig. 1. DFT optimized structure of free ligand 1 [B3LYP/6-31G(d,p)]; hydrogen atoms are omitted for clarity except two hydrogens taking place in two intramolecular hydrogen bonds O(3)⋯H(6)N (2.11 Å) and O(8)⋯H(1)N (1.86 Å).

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