The interaction of transition metals with the coenzyme α-lipoic acid: synthesis, structure and characterization of copper and zinc complexes

ELSEVIER

lnorganicaChimicaActa 252 (1996) 319-331

The interaction of transition metals with the coenzyme a-lipoic acid: synthesis, structure and characterization of copper and zinc complexes Markus R. Baumgartner, Helmut Schmalle, Erich Dubler * Institute of Inorganic Chei,..istry, Universityof Ziirich, Winterthurerstrasse 190. 8057Zurich, Switzerland Received23 April 1996;revised29 May 1996

Abstract The reaction of DL-a-lipoic acid or DL-a-lipoamide with copper(1) chloride in acidic aequeous solution leads to the copper(1) lipoic acid complexes catena-poly[Cul(lip°)CI] form I (A) and form II (B) and poly [Cu~3(lip°)2Cl3] (C). From an aqueous suspension oflipoic acid, crystals of the copper(ll) lipoic acid complex [ {Cun(lip- )2}2] (D) and of the zinc(II) complex [ZnU(iip- )2(H20)2] (E) can be grown on the surface of pressure pills of the corresponding insoluble metal hydroxide salts. The crystal structures of A, B, C and E have been established by X-ray diffraction. Crystal data are as follows. A: monoclinic, P2Jc, a=4.937(1), b=32.143(7), c=7.198(2) ,~, /3=90.39(2) °, V=1142.2(5) A 3, Z=4; B: triclinic, P-l, a=7.137(3), b= 13.120(4), c=!3.152(4) A, a=92.69(2),/3=94.45(3), 7 = 103.81 (2) °, V= 1195.6(7) ,~3,Z = 4; C: monoclinic, P2jc, a = 16.130(5),b =9.821 (3),c = 17.719(7) ,A,/3= 116.54(3) °, Vffi2511 (3) .~3 Z=4; D: triclinic, P-l, a = 14.390(9), b =27.202(14), c =5.264(2) A, a=92.55(4),/3=90.65(4), T=89.89(6) °, V=2058(3) ,~3, Z=4; E: monoclinic, C2/c, a=39.916(13), b = 5.344(1), c = 10.772(3) A,/3=95.76(2) °, V=2286(2) ,~3 Z=4. In the three copper(l) complexes A, B and C, a-lipoic acid is coordinating to the metal atom via its cyclic disulfide group and bridges two adjacent copper atoms. Five-membered rings of the type Cu-CI-Cu-S-S- are the building blocks in each of these three structures. A four-fold bridging/~-chlorine atom is observed in C. The structure of E is built up by neutral molecular [Znn(lip - )2(H20)2] units; the anionic a-lipoic acid ligand is coordinating via its bidentate, chelating carboxylate group. A trend is evident, whereby the S-S bond distance of the cyclic disulfide unit increases and the C-S-S-C torsion angle decreases upon coordination to metal ions. This geometrical influence upon coordination may be paralleled by an increase of the corresponding ring strain and, hence, by an enhanced redox reactivity of the disulfide moiety of a-Iipoic acid. Spectroscopic and variable temperature magnetic studies indicate the presence of a dimeric [CuU2(lip- )4] unit with antiferromagnetic coupling ( - 2 J = 315 cm- i) between the copper(!I) centers in D. Keywords: Crystalstructures; Coppercomplexes;Zinc complexes;Lip~icacidcomplexes;Disulfidecomplexes

o

1. I n t r o d u c t i o n

The cyclic disulfide a-lipoic acid (lip, 6,8-dithioctanoic acid, 1,2-dithiolane-3-pentanoic acid, vitamin Bs, line drawing see Fig. 1 ) is a molecule that is widely distributed in the biosphere and which occurs in higher plants and bacteria as well as in humans ( 16 mg I - t in the serum [ 1 ] ). The colnpound was isolated for the first time in 1951 by Reed et al. [ 2 ] from processed insoluble liver residues. It is very soluble in organic solvents, but only sparingly soluble in water, and it exhibits a melting point of about 48°{2 [2]. According to its high lipid solubility and acidic nature (pKa=4.7), the compound was named a-lipoic acid. A biological oxidation product of lipoic acid was identified as lipoic acid S-oxide and is nanted fl-lipoic acid (protogen B) [3]. a-Lipoic acid * Correspondingauthor. 0020-1693/96/$15.00 © 1996ElsevierScienceS.A. All rights reserved PIISO020- ! 693 ( 96 ) 05331-5

S--S

Fig. I. Chemical linedrawing of a-lipoicacid.

is termed a coenzyme; in nature it is found mainly in its protein-bound form by amide formation of the carboxyl function with amino groups. Some authors ascribe the status of a vitamin to aolipoic acid (vitamin Bs, vitamin N ) , although it can be naturally synthesized by humans in sufficient amounts [3,4]. a-Lipoic acid is involved in a wide range of reactions, such as hydrogen transfer and acyl group transfer in the oxidative decarboxylation of a-keto acids [3,5]. The absolute configuration in the naturally occurring isomer was determined in 1983 to be the R-( + )-configuration [6]. The Renantiomer of a-lipoic acid exhibits much more biological activity than its S-antipode [7].

320

M.R. Baumgartneret al./ lnorganica ChimicaActa 252 (1996)319-331

The most striking physical property of a-lipoic acid is the presence offing strain in the 1,2-dithiolane ring of about 1525 k.l mol-~ [3], which favors its reversible reduction to dihyd~o[~poic acid. Many biochemical reactions of a-lipoic acid directly or indirectly depend upon the ease with which it can be reduced according to this reaction. A great number of biological activity tests and pharmacological applications of a-lipoic acid have been reported, including the treatment of radiation-induced damage of DNA and of several liver diseases [3]. In addition, a-lipoic acid and derivatives have been applied in cancer chemotherapy. As a result of the metal complexing properties of a-tipoic acid and of dihydrolipoic acid, the most interesting pharmacological application of a-lipoic acid, however, is its successful use in the treatment of heavy-metal poisoning. The existence of a metal complex of mercury, for example, with the stoichiometry Hg(iip)(OH)z has indeed been reported [81. So far, it is not known whether a metal ion-disulfide interaction occurs during the biochemical reactions in which the lipoyl group is involved or not [9]. However, a general interest in the coordination of metal ions to disulfide moieties also originates from the well known fact that the conformation of peptide molecules containing disulfide bridges can be dramatically influenced by the interaction with metal ions. Preliminary structural data of [Znn(lip - )z(H20)2] (E) have been given earlier [10], and the existence of [Pd(lip)2Cl2], containing neutral a-lipoic acid molecules coordinated to palladium via its disulfide group and of [M(lip-)2(H20)2] (M =Zn, Cd), exhibiting carboxylate coordination, have been claimed in a conference report [ I l ]. No further X-ray structural information is available on metal complexes of a-lipoic acid, although t'~e metal ion coordinating properties of this molecule in solution have been extensively studied by Sigel et al. [ 9,12 ]. Based on the determination of the acidity constant of a-lipoic acid and of the stability constants of its metal complexes, the following conclusions concerning complex formation in solution may be drawn. The carboxylate group dominates the coordinating properties of a-lipoic acid towards the biologicallyimportant metal ions, but a disulfide-metal interaction is still possible and under sterically favorable conditions may become very important. Disulfide coordination may become more probable under enzymatic conditions, where the carboxylate group is amide-linked to the protein and therefore has a reduced coordination ability [9,12].

2,. Experimental 2. I. Materials and methods DL-a-lipoic acid and DL-6,8-thioctic acid amide (DL-alipoamide) were obtained from Fluka-Bioehemica. The racemic mixture was used always without furth,'r purification. CuICI was freshly prepared by the following procedure. 25.2

g of Na2SO 3 in 200 ml of oxygen-free water were added to a solution of 100 g of CuSO4"5n20 and 23.33 g of NaCI in 320 ml of oxygen-free water. The immediately formed white solid was filtered off and washed with ether. Cu~CI was used as a dark brown saturated solution in HC! (36.6 g of freshly prepared Cu~C! in 115 ml of 4 M HCI). The syntheses of compounds A - C were done under an inert atmosphere (N2). C, H, N, CI and S analyses were performed at the Institute of Organic Chemistry, University of Ziirich; Cu analyses were calculated from the CuO quantities obtained by the thermal decomposition of the compounds in an 02 atmosphere (see Section 2.10). 2.2. Preparation of catena-poly[Cu~(lip°)Cll, form l (A) 410 mg (2 mmol) of DL-a-lipoic acid were suspended in 20 ml of 0.5 M HCI. 5 ml of a saturated CuICI/4 M HC! solution (approx. 16 mmol Cu) were slowly added at 60°(2. Yellow lamellar needles crystallized after cooling to r.t. Anal. Calc. for CaHI4CICu02S2 (305.32): C, 31.47; H, 4.62; CI, 11.61; Cu, 20.81; S, 21.00. Found: C, 30.47; H, 4.74; CI, 12.33; Cu, 21.89 (TG analysis); S, 19.78%. IR data (KBr, c m - I ) : 2950 (w), 2930 (w), 1697 (vs), 1467 (w), 1429 (w), 1405 (m), 1267 (m), 1203 (w), 917 (m). 2.3. Preparation of catena-poly[Cut(lip°)Cl],form H (B) A saturated Cu~C1/4 M HCI solution, was diluted 1:10 with 4 M HCI. 18 ml of this solution (approx. 5.8 mmol Cu) were added to 1.19 g (5.81 mmol) of DL-a-lipoamide in 20 ml of 0.5 M HCI. This suspension was heated to boiling point for 10 min. After storing at 5°C in the refrigerator under Nz, orange-yellow plates crystallized. Anal. Calc. for CsHI4CICuO2S2 (305.32): C, 31.47; H, 4.62; Ci, 1i.61; Cu, 20.81; S, 21.00. Found: C, 30.54; H, 4.77; CI, 13.90; Cu, 21.41 (TG analysis); S, 19.25%. Obviously, the lipoamide used for the synthesis of B had been hydrolyzed to form lipoic acid during the process of the synthesis. IR data (KBr, c m - I ) : 2925 (w), 2859 (w), 1701 (vs), 1462 (w), 1413 (m), 1301 (w), 1259 (m), 1199 (m). 2.4. Preparation of polylCu~(lip°)2Cl3l (C) 410 mg (2 mmol) DL-a-lipoamide were suspended in 20 ml of 0.5 M HCI. At 60°C, 5 ml of a saturated CuICI/4 M HCI solution (approx. 16 mmol Cu) were slowly added. Very thin yellowish lens-shaped plates crystallized after some days at r.t. Anal. Calc. for CI6H2sClaCu304S4 (709.64): C, 27.08; H, 3.98; CI, 14.99; Cu, 26.86; S, 18.07. Found: C, 27.25; H, 3.98; CI, 15.4; Cu, 27.52 (TG analysis); S, 17.79%. No significant amount of N was observed.

M.K Baumgarmer et al./ hwrganica Chimica Acta 252 (1996) 319-331

2.5. Preparation of l{ Cun(lip- )z}2] (D) Compound D was obtained by slow crystallization of two insoluble starting materials in the solid phase with water as the transport medium: an aqueous suspension of lipoic acid was poured over. a plate fon,-led as a pressure pill of Cu:CO3 (OH)2 (s:inthetic or in the form of the mineral malachite) or CuO. After some days, dark green needles had grown at the surface of these plates. The crystals of D were then separated manually. Anal. Calc. for C16H26C~104S4(474.17): C, 40.54; H, 5.53; Cu, 13.40; S, 27.06. Foun6. C, 40.24; H, 5.66; Cu, 13.30 (TG analysis); S, 26.75%. IR data (KBr, c m - I ) : 2928 (m), 2855 (w), 1585 (vs, Vasym(COO- ) ), 1506 (m), 1433 (m, Psym(COO-)), 1410 (m), 1050 (w).

2.6. Preparation of [ZnU(lip- )2(H20)2] (E) Compound E was obtained by slow crystallization starting from two insoluble starting materials in the solid phase with water as the transport medium: an aqueous suspension of iipoic acid was carefully poured over a plate formed as a pressure pill of Zns(CO3) 2(OH)6, ZnO or natural Smithonite (ZnCO3). After some days, pale yellow needles had grown at the surface of these plates. The crystals of E were then separated manually. Anal. Calc. for C ic,H3oO~S4Zn(5 !2.03 ): C, 37.54; H, 5.9 i; S, 25.06; Zn, 12.77; H20, 7.03%. Found: C, 36.9; H, 6.19; S, 23.9; Zn, 12.61 I I'G analysis); H20 7.06% (TG analysis). IR data (KBr, c m - t ) : 2928 (m), 2856 (w), 1543 (vs, V,sym(COO- ) ), 1441 (m, Vsym(COO- )), 1410 (w), 1357 (w), 1256 (w), ! 124 (w). In addition to the methods described above, A can be synthesized by an analogous procedure to that used for the preparation of D and E. The pressure pill was made from freshly prepared Cu~CI and the water was saturated with N2. Small yellow needles grew within three weeks on the surface of the Cu~Cl-pills. All pro-lucts were characterized by powder Xray diffraction and microanalysis. Brown and Edwards [ 8] have described the synthesis of a solid product of inexact stoichiometry by the reaction of the reduced form of lipoic acid, dihydrolipoic acid H21ip, and CuCI2 in MeOH. Our experiments repeating this preparation method, however, did not result in characterizable products.

2.7. Infrared spectroscopy Solid state IR spectra in the range 341X)--400cm- t were obtained on a Perkin-Elmer spectrophotometer type 983. Spectra were run in a KBr or CsI matrix.

2.8. UV-Vis spectroscopy UV-Vis spectra of compound D were run in solution with a Varian Cary 2300 and, with a solid phase equipment reflec-

32I

tion technique, BaSO4 as internal standard, on a Beckman DK-2A.

2.9. Magnetic susceptibility measurements Magnetic susceptibility measurements of compound D were performed using the Faraday technique (Oxford Instruments) over the temperature range between r.t. and 80 K.

2.10. Thermalanalysis Thermogravimetric (TG) data in the temperature range 30-900°C were recorded in a flowing 02 atmosphere with heating rates of 10° min-J and sample weights of a few milligrams on a Perkin-Eimer TGS-2 thermobalance. X-ray powder diffraction diagrams of the intermediate and the final products were performed on a Guinier type camera with a Johansson monochromator (Cu Kam radiation). Alternatively, the thermal decomposition was monitored continuously by using a high-temperature Guinier-Lenn6 type camera (Cu Ka, radiation).

2.11. Crystallographicstudies Symmetry, preliminary cell parameters, and space groups of the complexes A-E were established by precession and Weissenberg photography. Final lattice parameters and crystal orientations of the compounds were obtained from leastsquares refinement of the 0 values of 25 reflections with 5.5 < 0 < 17.5° for A, 5.9 < 0 < 19.5° for B, 5.0 < 0 < ! 2.6" for C and 5.0 < 0< 20.0° for E on an Euraf-Nonius CAD-4 diffractometer. The lattice parameters of compound D were refined from X-ray powder data. Relevant crystallographic data and structure determination parameters are summarized in Table !. Intensity data for compounds A-C and E were collected using graphite-monochromated Mo Ka radiation on the diffractometer. Unit cell parameters refinement and crystal face indexing for absorption corrections were carried out with the Enraf-Nonius CAD-4 software [ 13]. Three standard reflections were measured every 180 rain daring each data collection. The observed decay of intensities of the standards were - 0 . 8 % for A, - 1.3% for B, and - 1.7% for C. In the latter case a decay correction was performed. Absorption corrections were based on six (A), eight (B), and again six ((C) and (E)) indexed and measured crystal faces. Data reduction, corrections for Lorentz and polarization, absorption and decay effects were carried out with the MolEN program package [ 14]. The structures of A and B were sob,ed using the Patterson interpretation routine SHELXS-86 [ 15] and by conventional Fourier techniques. Refinement of the structures of A and B on F 2 were performed using SHELXL93 [ 16]. The crystal of compound C used for data collection had an extremely small diffracting volume. Thus, this data collection was performed very slowly (the max. measuring time per reflection was 400 s). In spite of this effort, routine structure solution

322

M.R, Baumgarmer et al. / Inorganica Chimica Acta 252 (1996) 319-331

r-.

.~, _ ~ o .~

v

o

0

:ff

~ ~

~

ft.

o

d

I

~. --

~o~-~,~ ~

~.

~'~

'~

~

"

"6 "6

~

~

~

"~"

323

M.R. Baumgarmer et al./ lnorganica Chimica Acre 252 (1996) 319-331

Table 2 Positional parameters of catena-poly[Cut(lip°)CI] form 1 (A). catenapoly[CuX(lip°)CI] form II (B), poly[Cul3(lip°)2Cl~] (C) and [Znn(lip-)2(H20)2] (E) Atom

x/a

y/b

z/c

U¢q~/Uj~h

A Cu CI(I) S(I) S(2) C(I) C(2) C(3j C(4) C(5) C(6) C(7) C(8) O(1) 0(2) H(I)

0.0480(i) -0.1998(3) 0.2645(3) 0.3466(3) -0.0095(11) 0.0881(12) 0.1797(12) 0.3620(11) 0.2294(12) 0.3868(11) 0.2372(12) 0.3626(11) 0.2271(10) 0.5698(9) 0.275(11)

0.2503(1) 0.2749(I) 0.1911(I) 0.2000(I) 0.1553(2) 0.1268(2) 0.1516(2) 0.1303(2) 0.0930(2) 0.0755(2) 0.0407(2) 0.0235(2) -0.0071(2) 0.0362(!) -0.0186(17)

0.6347(1) 0.3863(2) 0.2503(2) 0.5339(2) 0.2960(7) 0.4499(7) 0.6144(7) 0.7527(7) 0.8428(6) !.0072(7) 1.0996(7) 1.2722(7) !.3399(6) 1.3422(6) 1.420(7)

0.039(I) 0.039(!) 0.033(I) 0.031(I) 0.042(!) 0.048(2) 0.042(I) 0.038(I) 0.043(I) 0.041(I) 0.045(2) 0.039(I) 0.075(2) 0.066(I) 0.048(18)

0.4934t' 1) 0.9953( I ) 0.7935(2) 0.2407(2) 0.1510(2) 0.4309(2) 0.2335(8) 0.4100(8) 0.5598(8) 0.7108(g) 0.8225(9) 0.9986(8) 1.0995(10) 1.2871(8) !.3673(14) 1.3741(14) 1.4218(29) 1.3280(26) 0.8127(2) 0.5284(2) 0.8425(11) 0.7374(14) 0.5532(16) 0.3884(16) 0.2869(14) 0.1028(10) -0.0035(10) -0.1990(9) -0.3128(23) -0.2757(16) 0.6923(19) 0.5268(20) 0.3A~5(22) 0.307(~(18) -0.2558(19) - 0.3263(16)

0.2160(I ) 0.2157( 1) 0.3285( i ) 0.2421 ( I ) 0.2673(I) 0.2442( 1) 0.4076(,~) 0.4452(5) 0.3826(4) 0.3888(4) 0.5006(5) 0.5137(5) 0.6282(5) 0.6504(5) 0.7506(6) 0.5856(7) 0.6624(23) 0.6524(14) 0.0458( i ) 0.0504( ! ) -0.0011(5) 0.0552(9) 0.0681(!1) 0.0342(8) -0.0805(7) -0.1097(6) -0.2160(6) -0.2515(4) -0.3424(10) -0.1876(8) -0.0051(20) 0.041 ! (13) -0.0481(14) -0.0512(16) -0.3533(8) - 0.2069(10)

0.4354( 1) 0.4360( ! ) 0.4178(1) 0.3283(I ) 0.5979(I) 0.6028(I ) 0.5883(6) 0.6596(6) 0.6414(5) 0.7279(5) 0.7559(5~ 0.8301(5) 0.8515(6) 0.9118(5) 0.9364(7) 0.9419(8) 0.8439(17) !.0021(9) 0.4195( I ) 0.3821( I ) 0.2917(5) 0.2174(8) 0.2544(8) 0.1716(8) 0.1650(12) 0.0877(7) 0,1099(6) 0.0566(6) 0.0749(14) 0.0146(9) 0.2067(13) 0.2319(12) 0.2065(10) 0.0919(9) 0.0248(10) 0.0697( 11 )

0.054(i ) 0.054(I ) 0.054(I ) 0.056(I ) 0.051(I) 0.046( I ) 0.068(2 ~ 0.075(2) 0.053(I) 0.058(I) 0.065(2) 0.063(2) 0.076(2) 0.069(2) 0.103(3)* 0.106(3)* 0.166(11)* 0.095(5)* 0.054(! ) 0.050(1) 0.089(2) 0.076(4) 0.100(5) 0.072(3) 0.081(5) 0.098(3) 0.077(2) 0.070(2) 0.147(6)* 0.097(4)* 0.159(13) 0.097(7) 0.080(6) 0.083(6) 0.091(4)* 0.098(4)*

0.185(I) -0.016( I ) 0.221(I) 0.117(3)

0.3177(6) 0.5172(7) 0.6135(6) 0.205(I)

0.032(4) 0.032(4) 0.034(4) 0.051(9)* (continued)

B

Cu( I ) Cu(2) CI( 1) CI(2) S(II) S(21 ) C( I 1) C(21) C(31) C(41) C(51) C(61) C(71) C(81) O(IIA) O(21A) O(lIB) O(21B) S(12) S(22) C(12) C(22A) C(32A) C(42A) C(52A) C(62) C(72) C(82) O(12A) O(22A) C(22B) C(32B) C(42B) C(52B) O(12B)

O(22B) c Cu(l) Cu(2) Cu(3) Cl( I )

0.4930(8) 0.5949(8) 0.4277(8) 0.516(2)

Table 2 (continued) Atom

ylb

zlc

Um=lU~o b

O(21) S(12) S(22) C(12) C(22) C(32) C(42) C(52) C(62) C(72) C(82) O(12) 0(22)

0.461(2) 0.379(2) 0.364(2) 0.318(2) 0.271(6) 0.237(6) 0.222(7) 0.179(7) 0.148(6) 0.099(6) 0.073(6) 0.027(6) -0.005(4) 0.033(4) 0.624(2) 0.689(2) 0.597(6) 0.669(7) 0.707(7) 0.776(6) 0.786(7) 0.838(6) 0.863(6) 0.917(6) 0.959(4) 0.913(4)

-0.021(3) 0.246(3) 0.185(3) 0.134(3) 0.31(!) 0.36(I) 0.25(!) 0.29(I) 0.17(I) 0.23( I ) 0.11(I) 0.16(I) 0.065(7) 0.278(7) 0.276(3) 0.146(3) 0.41 ( 1) 0.40( I ) 0.26( I ) 0.22( ! ) 0.32( 1) 0.24( ! ) 0.34( i ) 0.29( I ) 0.379(8) 0.174(8)

0.375(I) 0.470(!) 0.777(i) 0.648(2) 0.759(5) 0.671(5) 0.613(6) 0.521(6) 0.459(5) 0.370(6) 0.313(5) 0.223(5) 0.162(4) 0.204(4) 0.418(I) 0.519(I) 0.475(6) 0.567(6) 0.599(6) 0.687(5) 0.757(6) 0.835(5) 0.906(5) 0.996(5) 1.050(4) 1.004(3)

0.049(9)* 0.051(9)* 0.049(10) 0.049(10) 0.05(4)* 0.05(4)* 0.05(4)* 0.06(4)* 0.05(4)* 0.05(4)* 0.05(4)* 0.05(4)* 0.05(3)* 0.05(3)* 0.051(11) 0.049(11) 0.05(4)* 0.06(4)* 0.05(4)* 0.05(4)* 0.05(4)* 0.05(4)* 0.05(4)* 0.05(4)* 0.05(3)* 0.05(3)*

E Zn S(I) S(2) C(I) C(2) C(3) C(4) C(5) C(6) C(7) C(8) O( 1) 0(2) 0(3)

0.090 0.20861(9) 0.16085(9) 0.2215(3) 0.2015(3) 0.1715(3) 0.1434(3) 0.1153(3) 0.0886(3) 0.0674(3) 0.0412(2) 0.0380(2) 0.0241 (2) -0.0318(I)

0.1596(2) 0.8834(7) 0.8733(7) 0.593(2) 0.558(3) 0.733(3) 0.621(2) 0.807(3) 0.721(3) 0.527(2) 0.400(I) 0.463( I ) 0.223( I ) -0.0841(9)

0.250 0.9054(3) 0.8212(3) 0.837(!) 0.714(!) 0.685(1) 0.601(1) 0.566(1) 0.456(i) 0.4978(8) 0.3998(~) 0.2873(4) 0.4363(4) 0.3205(4)

0.0401(3) 0.104(I) 0.112(!) 0.108(4) 0.120(4) 0.109(4) 0.100(4) 0.108(4) 0.106(4) 0.106(4) 0.052(3) 0.066( 1) 0.054( 1) 0.049(l)

C1(2) C1(3) S(II) S(21) C(II) C(21) C(31) C(41) C(51) C(61 ) C(71.~ C(81) O(!1)

xla

aUeq =il3E,Y~jU~ja*a*a,aj. ~ Starred atoms are refined isotropically.

programs could not solve the structure. Finally, with the aid o f the program S I M P E L [ 17], a promising starting set for a refinement could be achieved. All further calculations for C were carded out with MolEN, refining the structure on F. Structure solution and refinement o f E also was based on the program package MolEN, refining the structure on F. For the structures o f A, B and C, hydrogen atoms ( w i t h the exception o f H ( 1 ) in A ) were relined using the riding model with calculated positional and fixed thermal parameters. N o h y d r o gen atom parameters were refined in E. In c o m p o u n d B, part o f the chain (C2B to CSB) and all o f the carboxyl groups appeared to be disordered and were refined using two distinct orientations. Positional parameters for all four cp,stal structures are given in Table 2. Interatomic b o n d distances and

324

M.R. Baumgartner et aL / h~organica Chhnica Acre 252 (1996)319-331

angles as well as hydrogen bonding contacts were calculated with ORFFE [ 181.

3. Results and d i s c u s s i o n

3. I. X-ray structures of the three copper(1) lipoic acid complexes, A, B and C In accordance with the HSAB principle, the copper(1) atoms in the complexes A and B (form I and form II of catena-polylCu~(lip°)CI]), as well as those of C (polyl Cu~ ( lip°) eel3] ), are coordinated via the 'soft' sulfur atoms of the disulfide group within the five-membered ring of lipoic acid and do not show any bonding interaction with the oxygen atoms of the carboxylate group. In addition, bridging C I anions are observed. In A and B, two/x2-bridging C I - are connected to each Cu atom to form an infinite (CuCI),, chain. Within this chain, two adjacent Cu atoms are bridged alternately by a disulfide unit, thereby forming a five-membered ring ( C u - C I - C u - S - S - ) . This ring represents a building subunit observed in each of the three structures described here. ORTEP [ 19 ] presentations of the 'molecular" structures of A, B and C containing this five-membered ( C u - C I - C u S - S - ) ring are shown in Figs. 2, 3 and 4, respectively. Selected interatomic bond distances and angles within the metal coordination polyhedra of A and B are given in Table 3. In both structures, all copper atoms are approximately tetrahedrally coordinated by two chlorine and two sulfur atoms. Analogous five-membered rings have been established by X-ray crystallography in two copper(I) complexes of a noncyclic disulfide. Cut(diethyl-disulfide)CI [20] exhibits a (CuCI),, chain structure with alternating pairs of Cu atoms bridged by two disulfide units. The Cu-Cu distances in this

H1~ 01 02 ~

complex are 3.22 .~ (linkage by one C I - and two disulfide bridges) and 3.68 A, (linkage by one p.-chloro bridge only). The structure of Cut2(diethyl-disulfide)I2 [21] consists of double chains of copp,.r atoms bridged by two iodine atoms, with alternative pairs of copper atoms also bridged by diethyldisulfide molecules. The Cu-Cu distances within the fivemembered ring in A and B, representing Cu atoms bridged by one C I - and one disulfide unit, range from 3.57 to 3.60

A.

The structures of the two polymorphic forms of catenapoly [Cu~(lip°)Ci] ), A and B, mainly differ in their packing of the (CuCI), chains and in their arrangement of the lipoic acid side chain. The lipoic acid ligand, as discussed above, bridges two adjacent copper atoms via its disulfide moiety.

O12A~ C82 O22AC72~z~ C52A% C 3 ~ S

l

1

22A

~ $11i

C21v G

4 ~

Fig. 3. The asymmetric unit and adjacentatomsin catena-poly [ Cu~( lip °) CI 1

form II (B) with numbering scheme. The superscripts correspond to the symmetry operatorsgiven in Table 3.

l C8 c,

~,

c~-~ 26

~,c4 C3

Clii /

~ i

2

,

S

Clliii St Cui

~cti Fig. 2. The asymmetricunitand adjacentatomsin catena-poly [Cut(lip°)1211 form I (A) with numbering scheme. The superscripts correspond to the symmetry operators given in Table 3.

iii

I

Fig. 4. Stereoplot of the Cu-CI-S framewurk in poly[Cut~(lip°)2CI3] (C)

with numberingscheme, indicatingtile p,4-bindingmode of C1(2). Cu and S atoms are drawn with vibrationalellipsoidsat the 50% probabilitylevel; the isotropicallyrefined chlorine atoms are represented by spheres. The superscripts ~::~¢espondto: t ! -x. -y, 1-z; " x, I/2-y. I/2+z; ,l x.

112-y,z-I/2.

M.R. Baumgartner et al, / Inorganica Chiraica Acta 252 f 1996) 319-331 Table 3 Selected bond distances (,~.) and angles (°) within the metal coordination polyhedra in catena-poly[Cul(lip°)CI], Form I (A)

325

form ! (A) and form il (B)

Form il (B)

Cu-Cu i~

3.599( I )

Ca( i )-Ca(2)

3.600(2)

Cu( I )--Cu(2) ti

3.573(2t

Cu-CI( 1) Cu-CI( 1)i Cu-S( I )~ Cu-S (2)

2.300( I ) 2.337(2) 2.317(2) 2.309(2)

Cu( I )-CI( I ) Ca( I ) - 0 ( 2 ) Cu( I )-S(21 ) Cu( I )-S(22)

2.336(2) 2.309(2) 2.311 (2) 2.328(2)

Cu(2)-CI( I ) Cu(2)-C1(2)* Cu(2)-S( I l )t Ca(2)-S(12)

2.312(2) 2.317(21 2.319(2) 2.291(21

S(2)-Ca-S( I Y C1( I )-Cu-CI ( 1)' S( 1)~-Cu-CI( I ) S( 1)l-Cu-Cl( I )i S( 2)-Cu-CI( I ) S(2 I-Cu-CI( I )i

112.84(5) 116.31 (7) 103.93(6) 104.26(5) 109.52(5) 109.84(6)

S(21 )-Cu( I )-S(22) CI(2)-Ca( I )-CI( I ) S(21 )-Cu( I )-CI( I ) S(22)-Cu( I )-CI( I ) S(21 )-Cu( I ) - 0 ( 2 ) S(22)-Cu( I ) - 0 ( 2 )

11,5.19(6) 115.30(6) 105.96(6) 104.15(5) 108.76(6) 104.83(6)

S( 12)-Cu(2)-S( I I )* CI( i )-q~n(2)--.Cl(2) ~ S( 12)-Cu(2)-C1( 1) S( I I )*-Cu(2)-CI( I ) S(12)-Cu(2)-C1(2) ~ S( I I )i-Cu(2)-Cl(2)i

114.01

Cu-CI( I )-Cuii

101.80(6)

Ca( I )-CI( i )-Cu(2) 'i

I01.54(6)

Cu( I )-C1(2)-Cu(2) ii

!01.12(7)

(7)

!14.53(6) 108.93(6) 102.56(6) ! !1.95(6) 104.56(6)

ix, - y + 1/2, z+ l/2;iix, - y + l12, z - 1/2.

u

n

A

b

) S

71

Fig, 5. Stereoplot of the Cu-CI chains running along c in catena-poly [Cul(lip° )CI ] form I (A), The disulfide moiety of the lipoic acid molecule bridges pa/rs of Cu atoms within these chains.

Z

Fig. 6. Stercoplot of the Cu--CI chains running parallel to a in catena-poly[Cu i(lip°)CI] form !! (B). The disulfide moiety of the lipoic acid molecule bridges pairs of Cu atoms within these chains.

326

M.R. Baumgartner et al. / Inorganica Chimica Acta 252 (1996) 319-331

c,,

a

jo

Fig. 7. Projectionalong the (Cu-CI), chains depictingdifferentpacking modes within the polymorphicforms ! (A, left) and II (B, right) of catenapoly[Cul(lip°)CI]. The side chain of the molecule extends at both sides of the (CuCI), chain, thus forming sheets, as demonstrated by the SCHAKAL stereopictures [22] of the structures of A (Fig. 5) and B (Fig. 6). Within the structure of A, the (CuCI), chains are running parallel to the c-axis, and all the lipoic acid carboxylate groups of the same sheet point in the same direction. In B, the (CuCl)n chains extend along the aaxis, and the lipoic acid carboxylate groups are oriented in opposite directions. The corresponding cell constants of the two compounds are fairly equal (Table 1 ). The differences in the packing modes within the two polymorphic forms A and B are elucidated by a comparative projection along the (CuCI) n chains in both structures, given in Fig. 7. The sheets formed by the arrangement of the lipoic acid side chains on both sides of the (CuCI), chain are held together via pairs of O H . - . O hydrogen bonds between the carboxylate groups defining the borders of the sheets with O---O distances of 2.662(6) ,~ in A and 2.61 ( 1)-2.77(2) ,g, in B. In compound B. there is some crystallographic disorder of the lipoic acid side chain. This disorder, however, does not significantly influence the mutual linkage of these sheets. The X-ray structural results of poly[Cu~3(lip°)2Cl3] (C) have to be considered as preliminary, since they are based on a weak data set. Nevertheless, they clearly show that the fivemembered ring of the type Cu--CI--Cu-S-S- is also observed in this structure. In addition, Cu-CI--Cu--CI- four-membered tings are formed by further/z-chloro bridges interconnecting the five-membered rings. Four-membered (Cu--CI-Cu--CI-)

rings represent a very general pattern in chloride containing copper(I) complexes. In C, the two building elements establish a two-dimensional framework which runs perpendicular to the a-axis. One copper atom (Cu(1) ) again is approximately tetrahedrally coordinated by two chloriue and two sulfur atoms, whereas the two other crystallographically independent copper atoms, Cu(2) and Cu(3), also show approximate tet~ahedral coordination, but by three chlorine and one sulfur atom only. The Cu-Cu bond distances are 2.86 and 2.97 A within the four-membered rings, and 3.41 and 3.73 ,~ within the five-membered rings. An interesting feature of the structure of C is the occurrence of a four-fold bridging /x4-cblorine atom within the (Cu3ClaS4) n framework. This chlorine atom exhibits a strongly distorted tetrahedral coordination by four copper atoms with a mean CI(2)--Cu distance of 2.50 ,&. This distance is significantly longer than the corresponding mean distances of the two other /.¢z-bridging chlorine atoms (CI ( 1)-Cu = 2.28 ,& and C I ( 3 ) - C u = 2.30/~ ), but it fits well with the values found in the few other otructures where/x 4chlorine atoms are observed (Table 4).

3.2. X-ray structure of the zinc lipoic acid complex E The structure of [ZnU(lip - )2(H20)2] (E) is built up by neutral molecular [ Zn ( l i p - ) 2(H20 ) 2] units (Figs. 8 and 9 ). The zinc atom exhibits a slightly distorted octahedral coordination by two bidentate carboxylate groups and two water

327

M.R. Baumgarmer et al. /Inorganica Chimica Acta 252 (1996) 319-331

Cl~

$1

03"~ . ~ o~

O0

c8-~

c~

Fig.8. The asymme~c unitand syrmmetryrelatedatoms formingthe z ~

t....

coordination polyhedron in [Zn(lip-)2(H20)2] (E) with numbering scheme. The superscriptscorrespondto the symmetryoperas given in Table6. Table5 Selected bond distances(,~) and angles (°) withinthe zinc coordination polyhedronin [Znn(lip- )2(H20)2] (E)

m e4

m~ ~

M M ~ N N

Zn-O( I ) Zn--O(2) Zn-O(3)

2.228(5)(2)<) 2.163(4)(2×) 2.021(4)(2×)

Zn-Znts Zn-Znm

5.653( I ) 5.348( I )

- x , y, l / 2 - z ; " - x , - y ,

- - z ; ta - x , y -

O( 1 )-Z¢-O(1) +

O( I )-Zn--O(2) O( 1)-Zn-O(2)' O( I )-Zn--O(3)l O( ! )-TJt--O(3) O(2)-Zn-O(2)* O(2)-Zn-O(3) O(2)-Zn--O(3)t O(3)-Zn-O(3)I

86.5(2) 59.2( ! ) 106.4(2) 147.5(1) 95.5(2) 161.9(2) 102.3(2) 89.4(2) 99.7(2)

1, l / 2 - z .

molecules. The Z n - O distances of the carboxylate group are 2.228(5) ,~ ( Z n - O ( 8 1 ) ) and 2.163(4) ,~ ( Z n - O ( 8 2 ) ) ; the Zn-OH2 distance is 2.021(4) A. Neighboring [ Zn (lip - ) 2(H20) 2] units are connected via O H - - . O hydrogen bonds between the coordinating water molecules and the carboxylate groups with an O--.O distance of 2.713(6) ,~. Selected bond distances and angles involving the coordination sphere of the Zn atom in E are summarized in Table 5.

.e >

o

3.3. Geometrical analysis o f the lipoic a c i d m o l e c u l e

6

The geometrical data of the lipoic acid ligand molecule in the crystal structures of A, B and E arc summarized and compared with the corresponding data of neutral, non-coordinating lipoic acid t27] in Table 6. The most interesting geometrical features of the lipoic acid molecule are the disulfide bond length S-S, the C - S - S - C torsion angle and further interplanar angles (see Table 7). The S-S distances are 2.098(2) ,~ in A, 2.097(2) and 2.076(2) ,~ in B, 2.12(5) and 2.06(5) ,A in C, 2.025(4) ,A in E and 2.053(4) ~ in free lipoic acid. A clear trend is

328

M.R. Baumgartner et al. / hu,rganica Chimica Acta 252 (1996) 319-331

Fig. 9. Stereoplot of the unit cell of [Zn(lip- )2(H20)2] tEL Table 6 Geometry of the lipoic acid molecule (bonding distances (A.) and angles (o)). Values involving only non-disordered atomic positions are given A

B Molecule 1

Molecule 2 2.076(2) 1.808(7)

S(11-S(2) S(I)-C(I) S(21--C(3) C(I)~(2) C(2)-C(3) C(3)-C(41 C(4)-C(5) C(5)42(6) C(6)-C(71 C(7)-C(81 C(81-0(11 c(g)~o(2)

2.098(2) 1.808(5) 1.855(5) 1.513(71 1.494(7) 1.502(71 1.516(7) 1.519(6) 1.497(71 1.491(71 1.285(7) 1.209(6)

2.097(2) 1.808(6) 1.857(51 1.483(8) 1.527(8) 1,495(81 1.507(8) 1.506(8) 1.506(9) 1.466(91 1.317(9) ~ 1.271(9)"

S(2)-S(I)-C(I) S(11-S(21-C(3) S(I)~2(I)-C(2) S(2)-C(3)-C(2) S(2)~2(3)-C(4) C(I)-C(2)-C(3) C(2)-C(3)-C(4) C(3)--C(4)-C(5) C(4)-C(5)---C(6) C(5)-C(6)-C(7) C(6)-C(7)-C(8) O(I)-C(8)-O(2) 0(I)-C(8)-C(7) 0(2)-C(8)-C(7)

92.8(2) 96.1(21 106.5(31 109.4(41 108.9(41 IIu.o(4) 117.4(4) 112.7(4) 114.0(4) 111.8(4) 116.4(5) 122.8(5) 112.7(5) 124.5(51

93.2(2) 96.7(2) 107.5(5) 111.5(41 108.3(41 111.7(5) 115.6(5) 111.6(5) 115.6(5~ 111.0(5) 116.0(6) 117.7(8) 115.4(7) 126.9(71

108.95(7) 106.35(6) 103.8(2) 101.7(21

109.49(81 106.67(71 lO0.a(2) 105.5(2)

M-S(I)-S(2) M-S(2)-S(I) M-S(I)-C(I) M-S(21-C(3)

Values given correspond to the A-labeled atoms (see Table 2).

!.475(9) 1.476(91 1.318(11) a 1.236(10) a 93.3(2)

114.8(6) ll7.1(li) 120.5(10) 120.0(7) 107.63(71 108,21(7) 104.4(2)

E

Lip°[27]

2.025(4) 1.819(91 1.743(9) 1.482(12) 1.524(14) 1.493(12) 1.520(131 1.578(!1) !.439(~1) 1.563(101 1.252(7) 1.255(7)

2.053(4) 1.79(I) !.83(1) 1.51(21 i,55(2) 1,53(11 !.51(I) i.53(I) 1.55(!) 1.50(I) 1.31(i) 1.20(I)

94.9(3) 95.2(3) 108.7(71 109.9(71 116.8(71 116.6(81 !13.7(9) !12.~(6) 114.7(8) 110.3(8) 122.3(6) 119.9(6) 122.3(6) 117.7(51

95.5(6) 92.8(4) 112.6(101 !12.6(111 106.7(81 111.3(71 112.8(9) 115.3(8) 109.2(8) !10.3(9) 112.9(9) 121.8(9) 113.3(9) 124.8(9)

M.R. Baumgartneret aL / lnorganica ChimicaActa 252 (1996) 319--331

329

Table 7 Torsion angles and interplanar angles ~depictingthe conformationalgeometryof the lipoicacid n ~lecule.V'quesinvolvingnon-disorderedatomicpositions only are given

A B mol. I E Lip° [27]

c( I )-s( I )-s(2)-c(3) torsion angle

Anglebetweenplane I and 2

Anglebetweenplane I and 3

Anglebetween plane2 and 3

20.5(3) 19.6(3) -- 34.0(4) - 34.5(6)

28.8(6) 30.6(5) 20. I (5) 28,4(6)

25.2(3) 20.9(4) b 89.9(6) 20.8(7)

4.5(8) 10.1(8) b 72.3(5) 9.0(5)

a Plane I: Ci I )-C(2)-C(3)-S(2)-S( I ); plane 2: C(4)-C(5)-C(6); plane 3: C(7)-C(8)-O( ! )--0(2). b Values givencorrespond to the A-labeledatoms (see Table 2). evident, whereby the S - S bond distances increase upon coordination of the disulfide moiety to metal ions (A, B and C) compared with those where carboxylate coordination of the lipoic acid occurs ( E ) or in the free iigand. The geometry of organic disulfides has been discussed in two papers. Bock et al. [ 28 ] have investigated the properties of the biochemicaUy active group of ot-lipoic acid - - the saturated five-membered ring containing two adjacent sulfur atoms, 1,2-dithiolane - by spectroscopic and quantum mechanical methods. Higashi et ai. [29] give a discussion of the geometrical data of symmetric disulfides whose sulfur atoms are bound to sp 2 carbon atoms (therefore excluding lipoic acid and 1,2-dithiolanes, where the adjacent carbon atoms are of the sp 3 type). The S-S bond lengths in 20 of these aromatic disulfides range from 2.00 to 2.11 ,~, with a mean value of 2.042 ~,, whereas the corresponding C-S-S--C torsion angles vary from 50 to 105 ° with a mean value of 81.7 °. The enhanced reactivity of cyclic disulfides is mainly attributed to their small C - S - S - C dihedral angles. In the open-chain disulfides, this angle assumes values close to 90 °, thus minimizing the interaction between adjacent sulfur lone pairs. In the case of a cyclic disulfide, (CHe)nS2, the C-S--S-C dihedral angle can be maintained at about 90 ° only i f n > 6. If this torsion angle goes from 90 to 0 °, the S-S bond is weakened as a result of the increasing antibonding contribution of the lone pair-lone pair interaction. In the unsubstituted 1,2-dithiolane ring (n = 3), the corresponding angle is about 30 ° [3]. Boek et al. [28] have documented a weakening of the S - S bond in cyclic 1,2-dithiolanes compared with open-chain disulfides by a correlation of increasing bond lengths with decreasing C-S-S--C dihedral angles. These torsion angles (see Table 7) are 20.5(3) ° in A, 19.6(3) ° in B, - 3 4 . 0 ( 4 ) ° in E and - 3 4 . 5 ( 6 ) ° in free lipoic acid. The corresponding S - S distances of 2.098(2), 2.097(2), 2.025(4) and 2.053(4) ,~,, respectively, confirm the trend of decreasing bond lengths with increasing C-S-S--C torsion angles. The optimum torsion angle of the unperturbed ot!ipoic acid molecule, realized in the free lipoic acid molecule [27] and in E, seems to be about - 34 °, whereas a reversal of the sign (the negative sign was defined as the anticlockwise arrangement of the two bonds C - S and S--C, viewed along the S-S bond in direction of the side chain of the R enantiomeric form) and a decrease of its absolute value to about 20 °

are observed upon coordination of metal ions to the disulfide group. This geometrical influence upon coordination may be paralleled by an increase of the corresponding ring strain and, hence, by an enhanced redox reactivity of the disulfide moiety of a-lipoic acid. To our knowledge, the only two further examples of metal complexes containing a cyclic disulfide moiety, whosecrystal structures have been solved, refer to two organometallic manganese complexes: ( ~ - C s H s ) (CO) 2MnS(CH2)~SMn(CO)2(~/5-CsHs) with x = 3 and 4, respectively [30]. Both complexes are diamagnetic molecules containing S - S bonds in relatively unstrained five- and six-membered rings. The disulfide group exhibits S - S distances of 2.202(3) and 2. ! 3 ! (6) A, respectively, and bridges two manganese atoms in each structure. These S--S distances are distinctly longer and therefore weaker than those in the ot-lipoic acid structures presented here, a fact which is supported by the finding via NMR and EPR spectra, that partial rupture of the S--S bonds of the manganese complexes into diradicals is observed [ 30]. 3.4. Spectroscopic properties and structural model o f [ { CuU(lip- )2}z/ (D) From compound D, no single crystal suitable for an X-ray structure analysis could be obtained. By means of spectroscopic investigations, we suggest that D has the same structural elements as observed in many other complexes of Cu(H) coordinated by carboxylate iigands. Magnetic measurements show a temperature dependent magnetic susceptibility with a Tc ( X ~ ) of 283__5 K This behavior represents a dimer of Cu(H) (3d 9 system) with antiferromagnedc coupling. A coupling constant of - 2 , / = 3 1 4 . 7 4 - 5 . 6 cm ~-I was observed. Similar values are well known for other [ C u ( R - C O O - )2] dimers [31]. The carboxylate group can act as a monodentate, a bidentare chelating or a bridging ligand. These different coordination abilities result in a distinct shift of the symmetric and the antisymmetric stretching vibrations o s ( C O O - ) and v ~ ( C O O - ) . The two IR bands appear in the ranges 1650-1550 cm -~ ( v ~ ( C O O - ) ) and 1450-1340 cm - ! ( os(COO- ) ), respectively. The difference A between these two viha~ons is related to the coordination behavior of the carboxylate group [ 32 ]. Whereas a large A (200-320 c m - t)

330

M.R. Baumgarmer et aL / lnorganica Chimica Acta 252 (1996) 319-331

On. : .,,~o

R-~'~,OO~cu.,,~O/~//~R ~ ~'O

the Cu(I) compounds in an inert N 2 atmosphere; in the case of compound E, ZnO was identified. As intermediates of the thermal degradation of A and D under oxygen, we observed the formation of CuSO4 and Cu20(SO4) in the temperature ranges 320-530°C and 450--590°C, respectively. No chloride containing products were detected during the decomposition of A, B and C in any atmosphere.

O~. : .,~O R--.~lo--Cu ~'O~/R

4. Conclusions o

;cu:

~'o

/

Fig. I0. Schematicrepresentationof the dimeric [Cu2(lip-) a] units,indicated by spectroscopicand magneticdata to occurin [Cu(lip- )2] (D). corresponds to monodentate coordination, a small one (40150 cm - I ) is assigned to a bidentate chelation; bridging carboxylate groups exhibit intermediate A values in the range 150-200 cm - 1 The experimental value of 102 c m - 1 for the zinc complex E indicates a bidentate chelating mode for the carboxylate group, which is in accordance with the X-ray structural results. From the corresponding value of the copper complex D ( 158 c m - i) it may be concluded that the lipoic acid acts as a bridging ligand. This result is supported by the magnetic measurements described above. The solid state UV-Vis spectrum of [ {Cu u ( lip - ) 2 }2] consists of a broad band with A M at 650 nm (probably a multiplet of d--d transitions), a CT band with Am~xat 255 nm and a weak band with A ~ at 370 nm. The latter band is assigned to a transition between orbitals resulting from Cu--Cu dimer formation [33]. The absence of this band in the spectrum of [{Cun(lip -)2}2] (D) measured in 1,4-dioxane solution indicates the presence of only monomers in solution. Fig. 10 gives a schematic representation of the suggested dimeric [Cun2(lip - )4] unit in [ {Cu"(lip- )2}2]" On the basis of our experimental data, however, it cannot be excluded that the dimers are not interconnected by weak Cu-.-O interactions as shown in Fig. 10, but are isolated by additional coordination of two disulfide groups of the side chains R. 3.5. T h e r m a l d e g r a d a t i o n reactions

Thermogravimetric investigations allow the stoichiometry of the compounds and possible thermal decomposition mechanisms to be characterized. The intermediate and final products of the thermal decomposition of all lipoic acid complexes described here were analyzed by X-ray powder diffraction. The zinc compound E exhibits a desolvation step with t~/2 at 80°(2, corresponding to the loss of the two water molecules coordinateo to the zinc atom. The subsequent decomposition of all solvent-free species A - D and E starts at about 180°C and proceeds via several steps to the final products. For both the Cu(I) and the Cu(II) compounds, the final product of the degradation was CuO when an oxidizing atmosphere was present. CuS was the final product for the decomposition of

Stoichiometric and air-stable complexes of the coenzyme ct-lipoic acid with copper or zinc may be crystallized from aqueous solution or on the surface of pressure pills of insoluble metal hydroxide salts. In copper(I) complexes of neutral ot-lipoic acid, coordination to the metal atom via its cyclic disulfide group with bridging of two adjacent copper atoms by a-lipoic acid is observed. Copper(II) and zinc(II) complexes of monodeprotonated t~-Iipoic acid do not exhibit any metal--disulfide interactions. Their structures consist of monomeric [ Zn u(lip- ) 2(H20) 2] and dimeric [cun2(iip - )4] units, respectively, with coordination of the anionic t~-lipoic acid ligand via its bidentate, chelating carboxylate group. Marked influences of the coordination of metal ions on the geometrical features of the a-lipoic acid ligand (increase of the S-S bond distance and decrease of the C - S - S - C torsion angle) are observed. In view of the fact that a decrease of the C - S - S - C torsion angle increases the ring strain of cyclic disulfides, an enhancement of the reactivity of t~-iipoic acid upon coordination of metal atoms to its disulfide moiety may be predicted.

5. Supplementary material Tables listing observed and calculated structure factors, anisotropic temperature parameters and atomic positional parameters of the hydrogen atoms of A, B, C and E, a stereovie~v oi' the unit cell content of C, and a table listing O H . . . O hydrogen bonding distances and angles are available from the authors on request.

Acknowledgements We thank Professor H.R. Oswald for continuous support of this project. Research grants from the Swiss National Science Foundation are gratefully acknowlegded.

References [ 1] A. Burgerand H. Wachter, Hunnius Pharmazeutisches WOrterbuch, W, de Gruyter,New York, 1993. [2] L.J. Reed,B,G.De Busk,1,C.GunsalusandCS. Hornberger,Science, 114 (1951) 93.

M.R. Baumgartner et al. / lnorganica Chimica Acta ?52 (1996) 319-331 [3] L. Teuber, SulfurRep., 9 (1990) 257, and Refs. therein. [4] W. Gross, K. Ring and E. Lodemano, Physiologische Chemie, VCH, Weinhein, Germany, 1989. [5] P.C. Bulman Page, CM. Rayner and I.O. Sutherland, J. Chem. Sac., Perkin Trans. I. (1990) 1615. [6] M.H. Brookes, B.T. Golding, D.A. Howes and A.T. Hudson, J. Chem. Sac.. Chem. Commun.. (1983) 1051. [7] J.C. Gunsalus, L.S. Barton and W. Gruber, J. Am. Chem. Sac.. 78 (1956) 1763. [ 8 ] P.R. Brown and J.O. Ed wards, J. lnorg. Nucl. Chem., 32 ( 1970 ) 2671. [9] H. SigeI, Angew. Chem.. Int. Ed. Engl.. 21 (1982) 389. [ 10 ] E. Dubler, G.B. Jameson, N. Cathomas, M. Baumgartner and A. Relier, Acta Crystallogr., Sect. A, 40 (1984) C-31 !. [ 11 ] H. Strasdeit, A. van D011en and A.K. Duhme, J. Inorg. Biochem., 59 (1995) 228. [ 12] H. Sigel, K.H. Scheller, V.M. Rheinberger and B.E. Fi. cher, J. Chem. Sac., Dalton Trans., (1980) 1022. [13] Enraf-Nonius CAD-4 Software, Version 5.0, Enraf-Nonius, Delft, Netherlands, 1989. [ 14] C.K. Fair, MoIEN, an interactive intelligent system for crystal structure analysis, Enraf-Nonius, Delft, Netherlands, 1990. [ 15] G.M. Sheldrick, Acta Crystallogr., Sect. A, 46 (1990) 467. [ 16] G.M. Sheldrick, SHELXL93, program for crystal structure refinement, University of G6ttingen, Germany. [ 17] A.R. Overbeek and H. Schenk, in H. Schenk, R. Olthof-Hazekantp, H. van Koningsveld and G.C. Bassi (eds.), SIMPEL: Computing in Crystallography, Delft University Press, Netherlands, 1978, p. 108.

331

[ 18] W.R. Busing, K.O. Martin, H.A. Levy, G.M. Brown, C.K. Johnson and W.A. Thiessen, ORFFE3, Rep. ORNL-TM-306, revised, Oak Ridg~ National Laboratory, TN, USA, 1970. [19] C.K. Johnson, ORTEPII, Rep. ORNL-5138, revised, Oak Ridge National Laboratory, TN, USA, 1976. [20] C.I. Br~And~n,Acta Chem. Scand. 21 (1967) 1000. [21] P.M. Boatman, K.A. Kerr, R.A. Kydd, K.J. Moynihan and K.A. Valentine, J. Chem. Sac., Dalton Trans., (1982) 1401. [22] E. Keller, SCHAKAL 86, Chem. UnsererZeit, 20 (1986) 178. [23] K.J. Oliver, T.N. Waters, D.F. Cook and C.E.F. Rickard, lnorg. Chim. Acre, 24 (1977) 85. [24] I.G. Dance, Aust. J. Chem.. 38 (1985) 1391. [25] S. Andersson and S. Jagner, Acta Chem. Scand, Set. A, 40 (1986) 177. [26] S. Wang, J.C. Huffman, K. Fairing, W.E. Streib, E.B. Lobkovsky and G. Christou, Anfew. Chem.. Int. Ed. Engl., 30 ( 1991 ) 1672. [27] R.M. Stroud and C.H. Carlisle, Aeta Crystallogr., Yecr. B, 28 (1972) 304. [28] H. Back, U. Stein and A. Semkow, Chem. Bet., 113 ~1980) 3208. [ 29] L.S. Higashi, M. Lundeen and K. Serf, J. Am. Chem. Sac., i00 (1978) 8101. [ 30] H. Bmunwarth, P. Lau, G. Huttner, M. Mineni, D. Giinauer, L. Zsolnai, 1. Jibril and K. Evertz, J. Organomer. ChenL. 411 ( 1991 ) 383. [31] R.L. Martin and H. Watermann, J. Chem. Soc., (1957) 2545; J.N.van Niekerk, Acta Crystallogr., Sect. B, 26 (1953) 1858; Y.A. Simonov, Soy. Phys.-Crysmllogr., 15 (1970) 310; M.J. Bird and T.R. Lamer, Acta Crystallogr.. Sect. B, 28 (1972) 242 [32] K. Nakamoto, Infrared Spectra of Inorganic and Coordination Compounds, Wiley, New York, 1978. [33] B.N. Figgis and R.L. Martin,,/. Chem. Sac., (1956) 3837.