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J. Org. Chem. 1997, 62, 5592-5599
Efficient and Highly Selective Copper(II) Transport across a Bulk Liquid Chloroform Membrane Mediated by Lipophilic Dipeptides Marco C. Cleij,†,§ Paolo Scrimin,‡ Paolo Tecilla,† and Umberto Tonellato*,† Department of Organic Chemistry and Centro CNR Meccanismi di Reazioni Organiche, University of Padova, Via Marzolo 1, 35131 Padova, Italy, and Department of Chemical Sciences, University of Trieste, Via Giorgieri 1, 34127 Trieste, Italy Received February 19, 1997X
Several structurally simple N-monoalkylated and -dialkylated dipeptides made of R-amino acids Gly, Phe, and Leu, 1-11, were synthesized and investigated as carriers for the transport of Cu(II), Zn(II), and Ni(II) from an aqueous pH ) 5.6 buffer source to a 0.1 M HCl receiving phase across a bulk chloroform membrane. The proton-driven translocation was followed during the process by analyzing the metal ion concentrations in the three phases. The transport efficiency depends on the ease of formation of a neutral complex with Cu(II) (the peptide group and carboxylic acid being deprotonated) at the source-chloroform interface and on that of its disruption by protonation at the receiving phase: the carrier’s lipophilicity favors the metal ion uptake and not the release. By modulating the length of the N-alkyl chains and the hydrophobicity of the dipeptide moiety, a quite remarkable transport efficiency was observed for Cu(II), in most cases superior to that of the industrial extractant Kelex 100. Moreover, using L,L- and L,D-N-octyl-PheLeu as carriers, remarkable diastereomeric effects were observed in the rate of uptake and release of Cu(II) ion although the differences mutually compensate in the overall transport rate. Under the conditions used the carriers are much less effective in the translocation of Zn(II) and Ni(II) and their transport efficiency drops dramatically in the presence of Cu(II), the latter being favored by factors of 1.2 × 103 and >104, respectively. Such very high selectivities depend on the fact that only Cu(II) among other transition metal ions can form neutral complexes at the pH value of the source phase. The selective transport of metal ions across a membrane is known to play an essential role in many biological processes.1 Over the years, a large number of molecules featuring proper binding sites, particularly crown ethers, have been synthesized and demonstrated to act as selective carriers of alkali or ammonium ions across a membrane.2 Theoretical models aimed at correlating the efficacy and selectivity of the transport with the structure of the carrier molecules have been also proposed and experimentally tested.3 In the case of transition metal ions, although a large number of effective ligands have been characterized and utilized in
selective extractions4 from an aqueous into an organic phase, fewer studies dealing with their transport across a membrane have been reported5-13 in spite of a growing demand for these systems in waste water treatment, medicine, and metallurgy. Investigations of the permeation of biological membranes or of closely related vesicular double layers are not easily accessible,9 and most studies in the field have been addressed to liquid membranes, made usually of chloroform. As pointed out by Menger,10 liquid bulk organic solvents bear very little similarity with biological membranes; however, they may be useful for evaluating the factors playing a role in the translocation from and to aqueous pools through an
*Corresponding author. Phone: +39-49-8275269. Fax: +39-498275239. E-mail:
[email protected]. † University of Padova. ‡ University of Trieste. § European E.C. Research Fellow (1993-1994). X Abstract published in Advance ACS Abstracts, July 1, 1997. (1) (a) Westley, J. W.; Evans, R. H.; Williams, T.; Stempel, A. J. Chem. Soc., Chem. Commun. 1970, 71. (b) Maier, C. A.; Paul, I. C. J. Chem. Soc., Chem. Commun. 1971, 181. (c) Ring, K. Angew. Chem., Int. Ed. Engl. 1970, 9, 345. (d) Ovchinnikov, Y. A.; Ivanov, V. T.; Shkrob, A. M. Membrane Active Complexons; Elsevier: Amsterdam, 1974. (e) Urry, D. W. Top. Curr. Chem. 1985, 128, 175. (f) Linder, M. C. Biochemistry of Copper; Plenum: New York, 1991. (2) Selected examples: (a) Chrisstoffels, L. A. J.; Struijk, W.; de Jong, F.; Reinhoudt, D. N. J. Chem. Soc., Perkin Trans. 2 1996, 1617. (b) Gokel, G. W.; Murillo, O. Acc. Chem. Res. 1996, 29, 425. (c) Xie, Q.; Gokel, G. W.; Hernandez, J.; Echegoyen, L. J. Am. Chem. Soc. 1994, 116, 690. (d) Pregel, M. J.; Jullien, L.; Lehn, J. M. Angew. Chem., Int. Ed. Engl. 1992, 31, 1637. (e) Izatt, R. M.; Gypzy, C. L.; Biernat, J. F.; Bochenska, M.; Bruening, R. L.; Bradshaw, J. S.; Christensen, J. J. J. Inclusion Phenom. Mol. Recognit. Chem. 1989, 7, 487. (f) Masushima, K.; Kobayashi, H.; Nakatuji, Y.; Okahara, M. Chem. Lett. 1983, 792. (g) Schchori, E.; Grodzinskira, J. J. J. Appl. Polym. Sci. 1976, 20, 773. (h) Choy, E. M.; Evans, D. F.; Cussler, E. L. J. Am. Chem. Soc. 1974, 96, 7085. (3) (a) Lamb, J. D.; Izatt, R. M.; Garrick, D. G.; Bradshaw, J. S.; Christensen, J. J. J. Membr. Sci. 1981, 9, 83. (b) Izatt, R. M.; Clark, G. A.; Bradshaw, J. S.; Lamb, J. D.; Christensen, J. J. Sep. Purif. Methods 1986, 15, 21. (c) Behr, J. P.; Kirch, M.; Lehn, J. M. J. Am. Chem. Soc. 1985, 107, 241. (d) Visser, H. C.; Reinhoudt, D. N.; de Jong, F. Chem. Soc. Rev. 1994, 75 and references cited therein.
(4) Reviews: (a) Freiser, H. Anal. Sci. 1995, 11, 191. (b) Freiser, H. Chem. Rev. 1988, 88, 611. (c) Lobana, T. S.; Sandhu, S. S. Coord. Chem. Rev. 1982, 47, 283. (d) Uhlig, E. Coord. Chem. Rev. 1982, 43, 299. (5) (a) Hiratani, K.; Taguchi, K.; Ohhashi, K.; Nakayama, H. Chem. Lett. 1989, 2073. (b) Hiratani, K.; Hirose, T.; Fujiwara, K.; Saito, K. Chem. Lett. 1990, 1921. (c) Hiratani, K.; Taguchi, K. Chem. Lett. 1990, 725. (d) Hiratani, K.; Hirose, T.; Saito, K. J. Org. Chem. 1992, 57, 7083. (e) Kasuga, K.; Hirose, T.; Takahashi, T.; Hiratani, K. Chem. Lett. 1993, 2183. (f) Hiratani, K.; Sugihara, H.; Kasuga, K.; Fujiwara, K.; Hayashita, T.; Bartsch, R. A. J. Chem. Soc., Chem. Commun. 1994, 319. (6) Di Casa, M.; Fabbrizzi, L.; Perotti, A.; Poggi, A.; Riscassi, R. Inorg. Chem. 1986, 25, 3984. (7) (a) Tsukube, H.; Adachi, H.; Morosawa, S. J. Chem. Soc., Perkin Trans. I 1989, 89. (b) Maruyama, K.; Tsukube, H. J. Am. Chem. Soc. 1980, 102, 3246. (8) (a) Kishii, N.; Araki, K.; Shiraishi, S. J. Chem. Soc. Dalton Trans. 1985, 373. (b) Kishii, N.; Araki, K.; Shiraishi, S. J. Chem. Soc., Chem. Commun. 1984, 103. (9) (a) Moss, R. A.; Byeong, D. P.; Scrimin, P.; Ghirlanda, G. J. Chem. Soc., Chem. Commun. 1995, 1627. (b) Ghirlanda, G.; Scrimin, P.; Tecilla, P.; Tonellato, U. J. Org. Chem. 1993, 58, 3025. (c) Scrimin, P.; Tecilla, P.; Tonellato, U. J. Am. Chem. Soc. 1992, 114, 5086. (d) Kragten, U. F.; Roks, M. F. M.; Nolte, R. J. M. J. Chem. Soc., Chem. Commun. 1985, 1275. (10) Menger, F. M.; Lee, J. J. J. Org. Chem. 1993, 58, 1909. (11) Ameerunisha, S.; Zacharias, P. S. Polyhedron 1994, 13, 2327. (12) (a) Scrimin, P.; Tonellato, U.; Zanta, N. Tetrahedron Lett. 1988, 29, 4967. (b) Scrimin, P.; Tecilla, P.; Tonellato, U. Tetrahedron 1995, 51, 217. (13) Kimura, E.; Dalimunte, C. A.; Yamashita, A.; Machida, R. J. Chem. Soc., Chem. Commun. 1985, 1041.
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Efficient and Highly Selective Cu(II) Transport Chart 1
organic phase. From the published studies, also from this laboratory,12 the transport through liquid membranes is a more complicated process than it may appear, involving a subtle interplay of many factors that are not easy to estimate: thus it has been shown that a ligand that is very efficient and selective in extracting transition metal ions from an aqueous phase into an organic phase may be extremely poor in its transport ability5a,b and vice versa.5b,c In this paper, we report our efforts to produce simple ligands that are highly effective and selective carriers in the transport of Cu(II) across a bulk chloroform membrane. We focused our attention on simple dipeptides, like glycylglycine, which are known to strongly bind Cu(II) in aqueous solution to give a neutral complex in which the amido group is deprotonated14-16 also under slightly acidic conditions. The dipeptide coordinates with its amino and amide nitrogens and with a carboxylate oxygen to three of the four square-planar coordination sites of the Cu(II) ion as schematically represented in Chart 1. Deprotonation of the amide group under slightly acidic or neutral pH only occurs upon coordination with Cu(II) and not with Ni(II), Zn(II), or Co(II).16 Therefore, dipeptide derivatives are potential candidates for the selective transport of Cu(II) across a membrane, and their selectivity may be modulated on changing the pH of the solution. On these premises, we synthesized and investigated the dipeptides listed in Chart 1. Compounds 1-5 are GlyGly derivatives with the amino group alkylated with a pair of paraffinic chains of increasing (from ethyl to n-dodecyl) length and, hence, lipophilicity. The struc(14) Dobbie, H.; Kermack, W. O. Biochem. J. 1955, 59, 246. (15) Datta, S. P.; Rabin, B. R. Trans. Faraday Soc. 1956, 52, 1117, 1123. (16) Sigel, H.; Martin, R. B. Chem. Rev. 1982, 82, 385.
J. Org. Chem., Vol. 62, No. 16, 1997 5593 Scheme 1
tures of compounds 6-9 are just variations of that of 4 aimed at increasing its lipophilicity: in 6 the N-terminal amino acid is Phe, in 7 and 8 the C-terminal amino acids are Leu and Phe, respectively, and in 9 both amino acids of the dipeptide are Phe. A special case is that of 10 and 11: they are the L,L and L,D diastereomers of the N-octylPheLeu and were conceived to verify the possible effect of diastereoselectivity on the Cu(II) transport. Moreover, to compare the effectiveness of these carriers to that of extractants used in industry, we included in our study the active component of the industrial extractant Kelex 100,17 i.e, the 7-(4-ethyl-1-methyloctyl)-8-hydroxyquinoline. Results and Discussion Synthesis of the Carriers. Scheme 1 shows the synthetic routes followed to obtain the ligands. Route a, involving as a first step the alkylation of the proper symmetrically substituted amine with the ethyl ester of bromoacetic acid, was convenient for the synthesis of 1-5, and 7, and 8. Compound 6 was obtained following route b through the dialkylation of the ethyl ester of L-phenylalanine with octyl bromide. Compounds 9-11 were prepared via route c, by reacting the Boc-protected phenylalanine with the phenylalanine or leucine ethyl ester and, after deprotection, by alkylating the amino group of the dipeptide with octyl bromide. The yields of the latter step were very low (
