Coordination Chemistry of Alkali and Alkaline-Earth Cations with Macrocyclic Ligands Bernard DieMch Universite Louis Pasteur, Strasbourg, France The solution chemistry of the groups IA and IIA was mainlvdeveloped onlv in the last 15 vears excent for oreanolithium and organa-magnesium reagents, wkch we; explored quite early in this century. The lack of complexes of alkali cations (AC) and alkaline-earth cations (AEC) with simple neutral ligands (such as those which ammonia, ethylene diamine, etc., form with transition metal cations) the absence of spectroscopic (UV, visible) and magnetic properties are the major explanations for this deferred expioraiion of AC's and AEC's. In coniunction with the develonment of X-rav diffraction ~~, ---methods", the discovery of AC and^^^ complexing agents in living systems opened a new field of investigation. Because of the valence configurations (respectively ns' and ns2) and the low ionization potentials, the cations M+ and M2+ are easily formed. The chemistry of these cations is essentially ionic (with some exceptions for Li+, Be2+,and Mg2+). Important properties of the AC's and AEC's are collected in Table 1. ~~
~
Alkall and Alkallne-Earth Catlons In Blology The four cations, Na+, K+, Mg2+, and CaZ+,are widely distributed in all living- organisms. The uptake of these elements by biological systems has been reviewed recently ( I ) . The preeminence of these four cations will he reflected in this discussion. The other cations belonging to these two groups will be cited only for comparative purposes. The . . catims of interest play a tremendous variety of roles such as in the tn~nsmijiionoiner\,cimpul~e;;,in musclecontraction. and as enzyme activators as structural factors, to mention just a few. In Table 2 one may note that the extra- and intracellular concentrations of Na+, K+, Mg2+ are very different (the values for CaZf beine.. m. i t e similar). This observation raises the questions: I ) how is this diisymmetry rstablisherl and purpose maintained? 2) what is the . of this distribution'? H'r will try to give some answers to the former question. ~
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Naturally Occurring lonophores In the early 1950's several antibiotics were isolated from microorganisms (spores). Over the years the chemical structures of some of these quite complicated compounds were elucidated (2, 3). A few years later biochemical studies showed thedramatic effects of some of these products on mitochondria. Finally, in 1964, Pressman et al. established that the mode of action of the antibiotic valinomycin was related to its ahilitv to induce the transnort of K+ across the lipophilic membraneof the mitorhondrin 14).' As many antibiotics were a\.ailable this area of research wicklv exnanded and many groups worked on this subject including .Simon et al. ( 5 ) and Ovchinnikov et al. (6) among others (7).
Presented at the 189th ACS meeting. "State-of-the-Art Sympcsium: Bioinorganic Chemistry," Miami, May 1. 1985. 'We will not, in most cases, cite the original paper, but rather, when available, a more recent and general review by the same author.
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Table 1. Ionic Radii, Hydration Numbers, and Free Energles ol Hydration -A@
Cation Li+ Na+ Kt Rbt
Cs+ Be2+ Mg2+
Ca2+ SrZt Ba2+
ionic. Radius (A)#
Hydration
0.78 0.98 1.33 1.49 1.65 0.34 0.78 1.08
6
numberb
6
6 6 6 4
6 8 8 8
1.27
1.43
(kcallmole) (25°C)C 122
98.5 80.5 75.5 68 582 454 379
340 314
.Gaidschrnldt. V. M., Skriner Naske Videnskeps-Aka& Oda. MatAa*. (19261. Wori. W. E.. and Siman. W.. Helv Chlm. Acts, 54,794(19711. CNWBS. R. M.. J. A m Chem Sm..84.513 119821.
Kt.. 2
Table 2. Concentrations of Cations In Extracellular and InIracellular Fluids (in Mequivalent per liter)' Cations
Extracellular
lnhacelluiar
Na+ Kt M$+
145 5 2
10 150 15 2
ca2+
2
King, E. J.. and Woonon. I. D. P.. in"Micmana1pis in Medical Bbchemistry." Churchill. London.
3rdsd..
All the naturally occurring ion carriers or ionophores share some common chaacteristics. The most important originate from the problem of transporting a very~hydrophilic ion across a lipophilic membrane. These two opposite requirements imply that the carrier bears, a t the same time, a polar part interacting with the cation and a nonpolar part able to solubilize it in the lipophilic membrane. I t is therefore obvious that the polar part must be inside, the nonpolar one outside. The ionophores usually transport only one specific cation. This means that the structural features of the carrier allow selectiuity to be achieved. This aspect and others such as conformational flexibility and stability of the 'complex will be detailed later. We will first focus on structural aspects. X-ray Structures of the lonophores Depending upon their structure and the nature of the transported cation the natural ionophores may be classified into several families. Cyclic neutral carriers. This group consists of many species and may be further subdivided. 1) Macrotetrolides (nonactin, dinactin, etc.). The general formula of these compounds appears in Figure 1. The X-ray structures of the free nonactin (8)and of its K+ complex show the important
0~ - V - o J + o ~ R . n
CH,
0
-
\
'
'C
I
\*:
,.
4 n
Figure 1. Macrotetroiides. Figure 4. Enniatin B and its Kt campiax.
Figure 2. Nonactin and its Kt complex
Figure 3. Vaiinomycin and its K+ campiex.
conformational changes that occur when complexation takes place Wig. 2) ( 5 ) .The 32-membered ring wraps around the cation; four carbonyl oxygens and four tetrahydrofuran oxygens bind the cation which is maintained inside the hydrophilic central cavity. I t is clear also that the outside becomes very lipophilic ( R 1=~CH3). 2) Cyclodepsipeptides. Valinomycin, a typical example (Fig. 3a) has 36 atoms in its ring. Its K+ complex (Fig. 3b) shows the very efficient encircling of the cation (9).Note that binding is achieved in this case by only six donor sites. Note also that the ligand conformation is reenforced by several intramolecular hydrogen bonds. The enniatin class of depsipeptides has only 18 atoms in the ring, the complex with K+ having avery simple structure (Fig. 4) (10).
Figure 5. Carboxylic acid ionophores.
Volume 62 Number 11 November 1985
955
Figure 7. Replacement around the Cation of the water molecules by a ligand.
Figure 8 . Terminal donor group llgands
Synthetic Complexing Agents tw GIFigure 6. Nat-Monensin complex.
All of these neutral cyclic carriers form complexes with monovalent alkali metal cations. Open-chain carboxylic acid ionophores. A large number of antibiotics belong to this class; examples are given in Figure 5. They all have a carboxylic acid function which may be ionized a t physiological pH values. The monensin Na+ c o m ~ l e xshown in Firmre 6 has a cvclic structure which is maintained by two htramolecular- hydrogen bonds (11). This i s a ceneral characteristic of all these t w e s ofantibiotics. I t is important to note that the resulting complex with a monovalent cation is neutral. Lasalocid can complex mono and divalent cations but with low selectivity in all cases (12). Ionophores that achieve high specificity for divalent cations are rare; A 23187 (calcimycin) is one example. I t transports calcium across membranes and can form 1:1 or 1:2 cation:ligand complexes, the latter being neutral (13). Physicochemical Studles Much effort has been made t o gain insight into the underlying parameters of complexation, selectivity, transport, etc. Some selected, but fundamental properties are collected in Table 3. Three antibiotics display selectivity for K t (or Rb+),monensin being selective for Na+. From the very large volume of data on the natural ionophores we have chosen just several illustrative examples for the following discussions which will concern the chemical approach to cation complexation.
IA and IIA Several hundreds of ligands have been synthesized and studied in the last 15 years. I t would be impossible to give even a small summary of all the interesting contributions in this area. The approach we have chosen is expressed by the following questions: 1)how to obtain very stable complexes, receptors of group IA and IIA cations; 2) how to obtain complexes capable of transporting these ions across natural or svnthetic membranes. carriers. This verv narrow aDproach should allow us to give a useful discussion on coordination of e r o u ~IA and IIA cations. We will limit our discussion strict& to-the synthetic chemical approach. Thus, modified natural ionophores and peptides will not be treated here. T h e discussion will not be developed in chronological order but will begin with the simplest systems and finish with the most complicated. AC and AEC Receptors (or How to Obtain Very Stable
Complexes) The several X-ray structures described previously show clearlv that the donor sites of the ligand have replaced the u~atermolerulesaroundthe cationasshown s r h e ~ a t i c a l l in y Figure 7. Synthetic ligands should therefore be able to as-
Table 4.
Nonactln Valinomycin Enniattn B Monensin
KC
Rb+
Ga2+
2.4 0.7 2.4 5.8
3.7 4.9 2.9 5.0
3.6 5.3 2.7
.. .
. ..
2.7 2.95
2.2 2.65
.. .
. ..
+
Sr2+
...
Ba2+ 1.7 3.3 2.9
.. .
Journal of Chemical Education
Na+
Kt
I
1.28
1.72
11
1.47
2.20
1.60
2.55
1.67
2.87
L Y "w'LY
'Inrne.ompiexationsq~~tion:M+ L + M + L ~a t a b i ~ i t y c o ~ t a n t i s e n p r e s ~ e d ~ ~ ~ = [M+L]I[Mtl[L]. The llpsndsslsnivityotcomplexatlanofmeoation Mlfovara cation M i ' is sxpressea bythe ratio of the stability mnsmnts of he complexes LM3+and LMlf. 1.e.. s = K(SM,+)IMSM,+). dwell.E.. Funck. Th., and Eggsn. F.. b "Membtanes." Vol. Ill, (Edi~or:Eisenman. G.) Wkksr. New Y a k . 1974, p. 1.
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Table 3. Stability Constantse(log K.) lor lonophore iMeOH. 25°C)b Nat
Stability Constants (log K . ) fw Olymes (MeOH. 2S°C)*
cr
111
Figure 9. Structures of several types of poiyethers bearing end groups ( 16).
sure the same water replacement and, to achieve strong complexation, provide an optimal donor-atom distribution around the cation. This discussion will be concerned with several types of synthetic ligands and it will he shown how the structural constitution of the ligand affects the stability of the complex obtained. Conventional lzgands. Ligands, such as EDTA, 1,3-diketonates, etc., are well-known complexing agents. An extensive review of these compounds is available (14). Linear polydentate lgands. These compounds, which are structurally quite simple and which may be obtained by short step syntheses, have been seriously studied only in the last 10 years (in fact after the more elaborated macrocycles and macrobicycles we shall describe below). The oligoethylene glycol dimethyl ethers (glymes) are the simplest neutral complexing agents for AC. The examples in Table 4 show the following trends: 1) stahility constants are low; 2) log K, increases as the number of donor sites increases, i.e., improved encircling of the cation; 3) the selectivities of complexation are low (15). The end-group concept was introduced by Vogtle et al. (16). They found that polyethylene glycol chains hearing a termmol donor group improved complexation ability with both AC's and AEC's. Suitable end-groups are 8-quinolyloxy, 0-nitrophenoxy, etc. (see Fig. 8). As VBgtle said, "the terminal groups function as anchoring points with locally fixed donor centers on which the cation can take hold" (16). The efficiency of interaction with the cations depends on the number of ethyleueoxy units as shown by the X-ray structures in Figure 9. The ligand can wrap around the cation in several ways: planar in (a)-since the ligand has only five donating sites, additional interactions with anions are necessary; helical in (b)-the anion does not interact this case; spherical-the cation is nicely coordinated in (c) by the 10 donor sites. In all these three cases the ligand adopts a conformation that optimizes all of the interactions with the cation. Structure (c) illustrates the optimal distribution of binding sites mentioned a t the beginning of this section. However the ligand has too many degrees of freedom to form, very stable complexes. Stability constants of compounds Table 5.
Stabllny Conslants (log K,) for Polyethers Bearing a Donor End Group (methanol, 2S°C) ( 1 7 ) Lii
V VI VII Vill
2.37
