Mercury, Lead, and Cadmium Complexation by Sulfhydryl-Containing

21 M e r c u r y , Lead, a n d C a d m i u m C o m p l e x a t i o n b y S u l f h y d r y l - C o n t a i n i n g A m i n o a c i d s . Implications for

Downloaded by RUTGERS UNIV on March 12, 2016 | http://pubs.acs.org Publication Date: January 12, 1979 | doi: 10.1021/bk-1978-0082.ch021

H e a v y - M e t a l Synthesis, Transport, a n d T o x i c o l o g y ARTHUR J. CARTY Guelph-Waterloo Centre for Graduate Work in Chemistry, Waterloo Campus, University of Waterloo, Waterloo, Ontario, N2L 3G1, Canada According to the A and Β classification of Ahrland and Chatt (1) or the Hard and Soft Acid and Base nomenclature of Pearson (2) the polarisable heavy metal ions Hg , Cd and Pb should form their strongest complexes with donor atoms from elements i n the second or subsequent periods of the periodic table. It comes as no great surprise therefore that these elements appear i n nature predominantly as their sulfides and that the interaction of sulfur containing molecules and ions with these metals plays a major role in their environmental and bio-chemistry. The advent of man-made heavy metal pollution of natural waters has brought to light significant new aspects of heavy-metal sulfur chemistry and re-emphasised the need for a clear under standing of metal ion behaviour towards sulfur containing ligands. The purpose of this article is to summarise and contrast recent results on the complexation of methylmercury (CH3Hg ) inorganic mercury (Hg(II)),cadmium (Cd(II)) and lead (Pb(II)) as well as methyllead (IV) with small sulfhydryl containing aminoacids and to place these results i n an environmental, biochemical and toxicological context. For mercury there is much evidence pointing to the relevance of mercurial complexes with sulfur aminoacids i n the microbiologi cal transformation of Hg to C^Hg"** and i n the biotransport, metabolism and toxicity of both inorganic and methyl mercury. Thus homocysteine (HSCH CH CH(NH)COO)and cysteine (HSCH CH(NH3) COO)complexes may be implicated i n one mechanism for the methylation of Hg(IT) (as HgCl ) by aerobic cultures of Neurospora Crassa (2) while the synthesis of methylmercury thiomethyl (CH3 Hg SCH3) i n shellfish may involve an L-cysteine complex of methylmercury (Scheme 1) (4). There i s l i t t l e doubt that the simple alkylmercurials (e.g. C^Hg"*", C H Hg ) exert their toxic effects principally by inactivating specific sulfhydryl sites of cysteine residues i n proteins and enzymes. Indeed, the methyl mercury cation C^Hg* has been used for decades by biochemists as a highly selective probe for sulfhydryl groups owing to the specific 1:1 stoichiometry of C^Hg*/sulfhydryl complexation (5). 2+

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0-8412-0461-6/78/47-082-339$05.00/0 © 1978 American Chemical Society Brinckman and Bellama; Organometals and Organometalloids ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

Brinckman and Bellama; Organometals and Organometalloids ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

Hg -h C H ,

(Methylcobalamin)

^CHgCHNH^ÎCOO

CH^CHWH^COO

CH^

s

s

(Methylcobalamin)

OOaNH^CHCHgSHg 1 , 4

Scheme I. Environmental synthesis of CH HgSCH

CH 3 HaSCH 3

'(Methyl Cobolomin)

CH^HgSCHjCHjCHd^ycOO

HSCH 2 CH 2 CH(NH^C00

CHj-Hg1,

CKjHgSC^CHiNK^KXK)

HSCH2CH(NiyC00


HSCH 2 CH(NH^COO +

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As an example, human albumin has been shown to c o n t a i n 0.65 - 0.70 S-H groups per mole as determined by r e a c t i o n s w i t h organic m e r c u r i a l s ( 6 ) . The s t r e n g t h and s t a b i l i t y of mercury-sulfur i n t e r a c t i o n s i n simple t h i o l complexes i s a l s o s i g n i f i c a n t i n the context of c h e l a t i o n therapy treatment f o r " i n o r g a n i c " mercury p o i s o n i n g and development of p o t e n t i a l a n t i d o t e s to Q^Hg**" p o i s o n i n g , s u b j e c t s d e a l t w i t h elsewhere i n t h i s volume (7). Despite the extremely h i g h values of the formation constants f o r CH3Hg /thiol complexes +

H

(log [ c H f f ] [ L ]

^

1 5

*

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°

r

C H

H

3 S

S C H

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C H ( N H

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) C 0 0

( 8 )


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and % 22 f o r the CH^Hg - mercaptalbumin complex (9) there i s evidence t h a t exchange of the methylmercury c a t i o n between s u l f h y d r y l s i t e s may be r a p i d . Thus f r e e g l u t a t h i o n e anion (G~) r a p i d l y exchanges w i t h bound l i g a n d i n the CH^Hg G complex (10) presumably v i a n u c l e o p h i l i c a t t a c k at 2-coordinate mercury generating a pseudo 3-coordinate i n t e r m e d i a t e . Although the r e s i d u a l Lewis a c i d i t y i n CI^HgSR complexes i s low ( v i d e i n f r a ) i t i s c l e a r l y of major s i g n i f i c a n c e i n the context of methylmercury m o b i l i t y i n b i o l o g i c a l systems. Small molecular weight s u l f h y d r y l c o n t a i n i n g molecules such as g l u t a t h i o n e f a c i l i t a t e m e r c u r i a l t r a n s p o r t i n b l o o d ; albumin, which i s present at the 5 gram per cent l e v e l i n mammals may a l s o p l a y a r o l e as a m e r c u r i a l c a r r i e r (11)· Inorganic mercury a l s o forms exceedingly s t r o n g bonds w i t h s u l f u r anions. The s t a b i l i t y constant l o g k f o r the 1:1, H g / L c y s t e i n e complex i s 45.4 a value which can be a p p r e c i a t e d when compared to l o g k =6.74 f o r c h l o r i d e i o n (12). B i s (mercaptides) of mercury are u s u a l l y s t a b l e over the e n t i r e pH range and i t i s evident that the complexation of H g by L - c y s t e i n e residues i n p r o t e i n s and enzymes dominates the biochemistry and t o x i c o l o g y of i n o r g a n i c mercury. " B i s ( c y s t e i n a t o ) mercury" i s a metabolic product of c e r t a i n m e r c u r i a l d i u r e t i c s (13) and mercury may be bound to two (or p o s s i b l y three) c y s t e i n y l s u l f u r atoms i n kidney m e t a l l o t h i o n e i n (14). Considerable evidence e x i s t s f o r b i o l o g i c a l l y and environmentally s i g n i f i c a n t H g complexes of the type RSHgX (X - a n i o n i c or n e u t r a l n o n - t h i o l l i g a n d ) (13,15), and i t i s l i k e l y that s t r u c t u r a l , p h y s i c a l and chemical d i f f e r e n c e s between RHg and H g complexes of L - c y s t e i n e and g l u t a t h i o n e are r e s p o n s i b l e i n l a r g e p a r t f o r d i f f e r e n c e s i n organ d i s t r i b u t i o n , t o x i c i t y and b i o l o g i c a l behaviour f o r these mercurials. I n c o n t r a s t to the b i o c h e m i s t s , i n o r g a n i c chemists showed l i t t l e i n t e r e s t i n the simple aminoacid, peptide or t h i o l complexes of KHg o r Hg u n t i l very r e c e n t l y . A 1972 review (16) of H g / a m i n o a c i d complexes i s almost t o t a l l y devoid of r e l i a b l e s t r u c t u r a l i n f o r m a t i o n e i t h e r i n s o l u t i o n or the s o l i d s t a t e . We thus s e t out to s y n t h e s i z e model compounds w i t h the f o l l o w i n g goals i n mind: (a) to provide q u a n t i t a t i v e i n f o r m a t i o n on the 2+

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mercury-sulfur interaction, (b) to investigate the importance of secondary mercury-ligand binding, (c) to contrast the structures and properties of C^Hg"*" and Hg complexes with sulfur aminoacids i n a search for features pertinent to mercurial transport and toxicity, and (à) to f u l l y characterise mercury species directly implicated i n environmental synthesis of CH3 Hg and metabolism of CH3Hg+ and H g . +

+

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L-Cysteine and PL-Homocysteine Complexes Strange as i t may seem the crystalline compound C^Hg SCH2 ~ CH(NH )C00" H 0 was f i r s t described only i n 1974 (17) although the formation constant for 1:1 C^Hg^/L-cysteine was reported i n 1961 (fi). NMR data have shown that O^Hg " binds to the sulfhydryl site over the entire pH range 1 - 1 3 (10, 18). The structure of CH Hg SCH CH(NH )C00' H 0 (Figure l f s o l v e d by X-Ray analysis i n our laboratory (19) i l l u s t r a t e s a number of important points : (i) mercury i s linearly 2-coordinate with strong C-Hg (2.09(4) A) and Hg-S (2.35(1) A) bonds, ( i i ) the molecule i s essentially molecular with only weak intermolecular hydrogen bonds between cysteines and water molecules/ and (iil) secondary intramolecular interactiois are weak (Hg-0 (carboxylate) = 2.84(2) Â ) . It i s unlikely that the Hg...0 interaction i s maintained i n solution (18) . This structure illustrates nicely the weak residual Lewis acidity associated with a mercury atom coordinated by one RS~ group and an alkyl group, a key feature of Q^Hg"*" coordination chemistry in biological systems. The molecule CH Hg SCH CH(NH )C00 i s obviously a reasonable model for tissue bound CH3Hg #and displacement of L-cysteine from this complex might well be used as an i n i t i a l test of antidote effectiveness. Finally CH3 Hg SCH CH(NH3)C00 i s a key intermediate en route to CH3 Hg SCH3 (Scheme 1) although,to our knowledge, the experiments to confirm the conversion to me thyImercury thiomethyl via methylcobalamin generated CH^" have not yet been carried out.


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Although the dominant feature of CH3Hg binding to proteins is the formation of strong Hg-S (cysteine) bonds, the nature of weak secondary interactions from neighbouring sites i s pertinent to the impact of CH Hg on protein structure and conformation. Our single crystal X-Ray diffraction results for the related molecule CH Hg SCMe CH(NH )C00 (Fig. 2) show that intermolecular Hg S (thio-ether type) contacts are barely significant (20). The shortest of these Hg...S distances (Hg.. .S of 3.35(1) &) i s the same as the sum of Van der Waals r a d i i for Hg and S (3.35 &). A recently solved structure of CF Hg SCMe CH(NH )C00-0.5 H 0 (21) (Fig. 3) i l l u s t r a t e s rather dramatically the increase in residual Lewis acidity of mercury which accompanies replacement of an alkyl by a fluoroalkyl group. The arrangement of mercury and sulfur atoms in this structure resembles a distorted cubane +

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Figure 1. The structure of CH HgSCH CH(NH )COO · H O. The dashed line from Hg to Ο (2) represents a weak intra molecular interaction and 0(3) is the oxy gen atom of the water molecule of crys tallization. s

s

t

t

Figure 2. A portion of the crystal struc ture of CH HgSCMe CH(NH )COO · 0.5 H O drawn to show the nature of weak inter- and intramolecular interactions. For clarity only on penicillamine molecule is illustrated. s

2

s

g


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although only the v e r t i c a l mercury-sulfur edge bonds are s t r o n g . Secondary Hg...O and Hg....S i n t e r a c t i o n s are both stronger here than i n the D L - p e n i c i l l a m i n e d e r i v a t i v e . Refinement of t h i s s t r u c t u r e ( c u r r e n t R of 0 JLO based on 1462 independent observed r e f l e c t i o n s measured on a GE-XRD-6 Datex automated d i f f r a c t o meter) i s c o n t i n u i n g . Our e f f o r t s to s y n t h e s i s e CHjHg* and HgCl2 d e r i v a t i v e s of DL-homocysteine HSOH CH CH(NH3)C00 were motivated by the o b s e r v a t i o n that t h i s aminoacid s t i m u l a t e s m e t h y l a t i o n of H g i n Neurospora Crassa, a cobalamin independent organism Q ) . Methyl group t r a n s f e r to a homocysteine complex of H g would generate methylmercury homocysteinate i n the proposed mechanism (3). The 1:1 MeHg complex, formed as a p r e c i p i t a t e on adding MeHgOH (0.86 g) i n ethanol (80 ml) to a b a s i c s o l u t i o n of DL-homocysteine (0.5 g i n a mixture of ethanol (5 ml) and water 50 m l ) , r e c r y s t a l l i s e d as t h i n p l a t e s from 30% aqueous e t h a n o l . Microanalyses, i n f r a r e d and Raman s p e c t r a (v(Hg-C) 535 i r , 5 3 8 R cm j v(Hg-S) 334 i r , 3 3 6 R cmT^vtS-H) absent i n Raman) of CH3HgSCH CH2CH(NH3)C00 and the deuterated complex, together w i t h the H nmr i n D 0 which showed a l a r g e downfield s h i f t of the Εγ protons (Δδ - +0.51) and a J H _ Hg ' 2

2

2 +

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+

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1

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l S 9

C

o f

1 8 6

H z

3

confirmed a s t r u c t u r e e s s e n t i a l l y the same as t h a t of the L - c y s t e i n e d e r i v a t i v e (10., 19) . Under s i m i l a r c o n d i t i o n s but employing 2:1 molar r a t i o s of CH3Hg : homocysteine, a c r y s t a l l i n e 2:1 complex (CH3Hg) S CH CH CH(NH )C00 was obtained. P r e l i m i n a r y X-Ray measurements have e s t a b l i s h e d that t h i s compound i s m o n o c l i n i c , space group C2/c w i t h a = 28.33, b - 11.24, c « 7.31 A; £ - 87° I I and Ζ - 8. From H nmr measurements (22) the two methyl groups appear to be a s s o c i a t e d w i t h one s u l f h y d r y l and one amino s i t e at n e u t r a l pH (Δδ Ηγ= + 0.53 ppm; ΔόΗ =+ 0.37 ppm; J c H - H g = 198 H z ) , as f o r the corresponding DL - p e n i c i l l a m i n e d e r i v a t i v e ( 10»20) . As observed by Rabenstein (10) f o r glutathione/C^Hg^complexation, at a c i d pH < 4 both CH3Hg groups probably become a s s o c i a t e d w i t h the s u l f h y d r y l group. Unfortunately, c r y s t a l l i n e samples of (CH3Hg) SCH CH CH(NH )C00 obtained from a c i d s o l u t i o n are u n s u i t a b l e f o r i n t e n s i t y data c o l l e c t i o n . The " i n o r g a n i c " complexes of homocysteine, prepared from d i l u t e aqueous s o l u t i o n s at n e u t r a l pH are i n t r a c t a b l e powders. Compounds of apparent formulae Hg[SCH CH CH(NH )C00H] CI2 and HgCl[SCH CH CH(MÎ3)C00> % H 0 have been s a t i s f a c t o r i l y analysed from 2:1 and 1:1 mixtures of aminoacid and H g C l . Using HgBr2 and DL-homocysteine under s t r o n g l y a c i d c o n d i t i o n s a complex of unusual s t o i c h i o m e t r y , HgBr2 [SCH2 CH CH(NH )C0] 2HBr was obtained (22) . A f u H 3-dimensional X-Ray study revealed a s t r u c t u r e c o n s i s t i n g of polymeric HgBr|~ ions s h a r i n g two b r i d g i n g bromides packed together w i t h c a t i o n s of homocysteine l a c t o n e SCH CH CH(NH )C0 ( F i g u r e 4 ) . C l e a r l y on a c i d treatment, cleavage of strong Hg-S (homocysteine) bonds occurs to generate the l a c t o n e , i n marked c o n t r a s t to the +

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Figure 4. An ORTEP II plot of the molecular structure of [ÉCH CH CH(NH )CO] · HgBr showing the atomic numbering. Bridging bromine atoms are indicated by an additional dashed bond. 2

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L - c y s t e i n e and D L - p e n i c i l l a m i n e complexes of Hg*"*. In view of d i f f i c u l t i e s i n s t r u c t u r a l l y c h a r a c t e r i s i n g the " i n o r g a n i c " complexes of homocysteine p u r p o r t e d l y i n v o l v e d i n CH3Hg s y n t h e s i s we began work on the L - c y s t e i n e and DLpeni c i l l amine d e r i v a t i v e s of HgCl2. Compounds of formulae Hg[SCH CH(NH )C00][SCH CH(NH )C00H] * C l . 0.5 H 0 ( 1 ) , H g C l [SCH CH(NH )C00H](2), Hg[SCH CH(NH )C00](3) [HgCl ] +

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[SCMe CH(NH )C00H] 2H 0 ( 4 ) , [Hg{SCMe CH(NH )C00H> C l ] C1.H 0 (£), and HgCl [SCMe CH(NH )C00H](6) have been s y n t h e s i z e d and c h a r a c t e r i z e d by s p e c t r o s c o p i c methods. S y n t h e t i c and s p e c t r o s c o p i c d e t a i l s w i l l be p u b l i s h e d elsewhere ( 2 X 2JÙ but i t i s p e r t i n e n t here to summarise the major s t r u c t u r a l f e a t u r e s of these compounds as r e v e a l e d by s i n g l e c r y s t a l X-Ray d i f f r a c t i o n . P i c t o r i a l r e p r e s e n t a t i o n s of 1^ 1^ 4· and 5_ are shown i n F i g u r e 5. There are s e v e r a l important s t r u c t u r a l f e a t u r e s to emphasize: ( i ) I n _1 and _5, n e g l e c t i n g the r e l a t i v e l y weak i n t e r a c t i o n s between cEloridê" ions and mercury, the b a s i c s t r u c t u r a l u n i t s present are the c l a s s i c a l two coordinate A^S-Hg- S'VWstereochemistry long thought to represent the bound s t a t e of H g i n p r o t e i n s and dimercaptides. S i g n i f i c a n t l y , l o s s of H and C l " from i would generate "mercury c y s t e i n a t e " , Hg[SCH CH(NH )C00] (13_, 16). The environment of mercuric i o n i n human kidney métallothionein, which binds H g more s t r o n g l y than e i t h e r Z n o r C d , may resemble t h a t i n 1 and w i t h two very s t r o n g Hg-S(cysteine) i n t e r a c t i o n s p r o v i d i n g the main b i n d i n g . I f bond-lengths are used as a rough c r i t e r i o n of bond s t r e n g t h , comparison of Hg-S d i s t a n c e s i n the "2-coo r d i n a t e " H g ^ and C H H g complexes of L - c y s t e i n e and DLpeni c i l l a m i n e , r e v e a l s l i t t l e d i f f e r e n c e between the a f f i n i t i e s of CH Hg and H g f o r deprotonated s u l f h y d r y l groups, ( i i ) Two types of mercapto b r i d g e s , one h i g h l y unsymmetrical i n 4 (Hg(l)S of 2.822(5)1 and Hg(2)-S of 2.356(5)1) ang one almost symmetrical i n £ (Hg-S - 2.490(4), Hg-S = 2.453(4)A) are e v i d e n t . C l e a r l y t h i o l s are q u i t e capable of p r o v i d i n g s i t e s f o r two mercury atoms. This a b i l i t y to b r i d g e mercury atoms may be m e c h a n i s t i c a l l y s i g n i f i c a n t i n s i t e exchange and t r a n s p o r t of i n o r g a n i c m e r c u r i a l s . I t i s noteworthy t h a t sulphur b r i d g i n g i s a l s o a r e c u r r i n g f e a t u r e of simple m e r c u r y - t h i o l chemistry, l e a d i n g to s t r u c t u r e s i n which the degree of p o l y m e r i z a t i o n v a r i e s c o n s i d e r a b l y (25,26). ( i i i ) C h l o r i d e i o n i n t e r a c t i o n s of v a r y i n g s t r e n g t h s are present ( c f H g - C l ( l ) of 2.582(4) i n 2., H g - C l ( l ) of 2.850(5)1 i n 5, H g ( l ) - C l ( 3 ) o f 2.348(5)1 i n 4, and Hg(l) - C l ( 2 ' ) of 3.335(6)1 i n 4) suggesting that c h l o r i d e i o n can compete favourably f o r m e r c u r i a l c o o r d i n a t i o n s i t e s and hence modify the p o l a r i t y and s o l u b i l i t y of the bio-complexes. The d i f f e r e n t d i s t r i b u t i o n r a t i o s of H g and CH Hg between plasma and red blood cells(27,28)may w e l l r e f l e c t the greater C l ~ content i n plasma. T r a n s p o r t a t i o n and membrane p e r m e a b i l i t y of d i f f e r e n t m e r c u r i a l s depend on m e r c u r i a l p o l a r i t y and s o l u b i l i t y , two parameters s e n s i t i v e to h a l i d e i o n i n t e r a c t i o n s . 2

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With the complete c h a r a c t e r i z a t i o n of the H g / L - c y s t e i n e d e r i v a t i v e s above,we f e e l c o n f i d e n t that the homocysteine complexes Hg[SCH2CH2CH(NH )C00H]Cl and HgCl[SCH2CH2CH(NH )C00]. 0.5 H2O have c l o s e l y r e l a t e d s t r u c t u r e s based e s s e n t i a l l y on d i g o n a l S-Hg-S or Cl-Hg-S bonds. I n l i n e w i t h our aim to assess the relevance of these c y s t e i n e and homocysteine compounds to environmental mercury methylation, we are c a r r y i n g out m e t h y l a t i o n s t u d i e s u s i n g a c t i v e sediments s p i k e d w i t h the mercury complexes and a l s o w i t h c u l t u r e s of Neurospora Crassa growing i n the presence of these compounds. 3

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Comparison of B i n d i n g Preferences Cadmium and Lead (11).

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2

2+

A comparison of s o l u b i l i t y products f o r M / S ~ or M /0H~ and s t a b i l i t y constants f o r ethylenediamine complexes ( F i g . 6 ) gives an i n d i c a t i o n of the r e l a t i v e a f f i n i t i e s one might expect to f i n d f o r mercury, cadmium and l e a d i n t h e i r aminoacid complexes. Mercury c l e a r l y has a very h i g h a f f i n i t y f o r s u l f u r , w i t h cadmium and l e a d having approximately equal but much lower a t t r a c t i o n s . As a converse to t h i s one might expect that i n complexes w i t h s u l f u r aminoacids where Hg-S bonding would predominate, cadmium and l e a d might e x h i b i t c o n s i d e r a b l y more d i v e r s e behavior, b i n d i n g simultaneously to s e v e r a l d i f f e r e n t s i t e s . This i s e x a c t l y the p i c t u r e which has emerged from X-Ray s t u d i e s of mercury^cadmium and l e a d complexation w i t h s u l f u r aminoacids. I n Figure 7 we i l l u s t r a t e s c h e m a t i c a l l y the modes of i n t e r a c t i o n r e c e n t l y found i n a v a r i e t y of complexes. Some r e l a t e d bond d i s t a n c e s are shown i n Table I . Although d i r e c t comparisons between metals are d i f f i c u l t owing to d i f f e r e n t complex s t o i c h i o m e t r i e s and s t a t e s of aminoacid i o n i z a t i o n , the s t r u c t u r e of Cd[SCMe2 CH(NH )C00] H2O ( 3 D i l l u s t r a t e s the a b i l i t y of cadmium to i n t e r a c t w i t h S, Ν and 0 s i t e s of the aminoacid. Comparison of the Cd-S d i s t a n c e s (av 2.565(7)1) w i t h Hg-S bond lengths i n Table I show that the weaker cadmium-sulfur i n t e r a c t i o n s i n the cadmium species are compensated by bonding c a p a c i t y d i r e c t e d to oxygen and n i t r o g e n donors. This tendency of cadmium to p r e f e r a combination of b i n d i n g s i t e s i m p l i e s a much l e s s e r s p e c i f i c i t y than mercury f o r s u l f h y d r y l s i t e s i n p r o t e i n s and i s c o n s i s t e n t w i t h the f a i l u r e o f reagents such as D- p e n i c i l l a m i n e to act as good a n t i d o t e s t o cadmium p o i s o n i n g . These observations a l s o suggest that the stereochemistry of C d i n métallothionein i s l i k e l y to d i f f e r s i g n i f i c a n t l y from that of H g i n the same m e t a l l o p r o t e i n . The l e a d (IT) compound Pb[SCMe CH(NH )COO](29) c l o s e l y resembles Cd[SCMe2CH(NH2)COO] H 0 i n s t o i c h i o m e t r y , and each metal i o n i s pseudooctahedrally coordinated by l i g a n d atoms, w i t h a 3S, 20, Ν donor s e t f o r l e a d and 30, 2S,N f o r cadmium. L i k e cadmium, l e a d seems to favour b i n d i n g to a combination of S, Ν and 0 s i t e s i n aminoacids and thus i t a l s o d i f f e r s from mercury i n t h i s respect. 2

2 +

2 +

2

2

2

American Chemical Society Library st. N. w. Brinckman and 1155 Bellama;16th Organometals and Organometalloids ACS Symposium Series; American Chemical Washington, D. C. Society: 20036Washington, DC, 1979.

348

ORGANOMETALS

A N D ORGANOMETALLOIDS

Cl Cl \ / Hg

~0L Ό-Η- 0 >C-CH-Ch£S-Hg-S-C^CH-c£

'

Hg(L-cystH)(L.cystHJ.CI. ο·5Η 0

(I)


2

Cl Cl \ / Hg^

CH$CH-Cf

HgCL(^.S.L.cystH )

(2)

cr

r

Me I C-CH— C-5—Hg—S-C-CH-C / I I I I V HO NH Me Me NH ΌΗ

HgCKpenH^.CI.HgO

(5)

(HgCI ) U-S.penH ).2H 0 2

2

2

2

(4)

Figure 5. Schematic representations of the crystal structures of Hg[SCH CH(NH )COO][SCH CH(NH )COOH]Cl · 0.5 H 0 (1), HgCl [SCH CH(NH )COOH] (2), [HgCl ] [SCMe CH(NH )COOH] -2H 0 (4), and [Hg—{SCMe CH(NH )COOH) Cl] Cl · H O (5). 2

s

2

s

s

2

2

2

2

2

2

s

s

t

2

2

t

Log Κ so-

\ t t I t

Figure 6. Stabilities of divalent metalligand complexes as indicated by sta bility constants or solubility products. For sulfides and hydroxides log k refers to solubility products; and for ethylenediamine complexes log k refers to sta bility constants. Key: (O) sulfide; (A) nitrogen; (X) oxygen.

Mn 1% Co Ni Cu Zn

Ag Cd

Hg


Pb


21.


CARTY

349

CH,

I s -

ry—s

œ

ο Pb(p-pen)

(Ref. 29) 0

Ι

Br

Cd--

/

0

H

2 . C — CH

Ο

C d " ^

C H ^

^ C H ,

0 Cl:H,

Jb

Cd Cd

Cd(loL-penH)Br.H 0).2H 0 (Ref. 30) 2

2

Cd(o-pen). H 0 (Ref. 31) 2

Figure 7. Pictorial representations of metal-ligand interactions in lead and cadmium-penicillamine complexes. For comparison with mercury complexes, see Figure 5.


350

ORGANOMETALS


Table I


M-X Bond Lengths i n Amino A c i d Complexes Compound

M-S

C H H g ( S C H C H (NH ) C O O ^ O 3

HgCl

2

2

2

3

M-0 2.84(2)

2,352(12)

3

[SCH CH ( N H )

M-N

19

M

2.490(4)

C00H]

Ref.

2.453(4) H g [ S C H C H ( N H ) C O O ] H C 1 *0.5 2

3

24

2.355(3)

H 0

2

2

2.329(5) (HgCl ) [SC(CH ) CH(NH )C00H]2H 0 2

2

3

2

3

2

23

2.822(5) 2.356(5)

CdBr [SC(CH ) CH(NH ) COO] 3H 0

2.444(2)

Cd[SC(CH ) CH(NH )COO]H 0

2.563(7)

3

2

3

2

2.262(5) 30 2.715(5) 2.490(6) 31

2.567(7)

2.38(2) 2.57(2) 2.51(2) 2.40(2)

Pb[SC(CH ) CH(NH )COO]

2.716

2.444

29

Me Pb[SCH CH(NH )C00]

2.50(1)

2.46(3) 2.55(4)

3

2

3

2

2

2

2

2

2

2

2.444 2.768


39

21.

351


CARTY


METHYLATION AND DEMETHYLATION OF LEAD Recently there has been a major upsurge i n i n t e r e s t i n environmental l e a d chemistry w i t h r e p o r t s t h a t t r i m e t h y H e a d ( I V ) (32) and lead(TT) n i t r a t e (33) can be b i o l o g i c a l l y methylated to t e t r a m e t h y l l e a d contrary t o e a r l i e r p r e d i c t i o n s . The m e t h y l a t i o n o f environmental l e a d t o t o x i c Me^Pb would pose a p o t e n t i a l h e a l t h t h r e a t i f proven^since l e a d , p a r t i c u l a r l y i n the form o f l e a d ( I I ) , continues t o accumulate i n the environment as a product of i n t e r n a l combustion engines. Although an i n i t i a l controversy (34) arose concerning the chemical ( i . e . d i s p r o p o r t i o nation) o r b i o l o g i c a l nature o f processes e f f e c t i n g the Me3Pb(IV) Me4Pb conversion, recent experiments appear to have c o n c l u s i v e l y proven the e x i s t e n c e o f a b i o l o g i c a l m e t h y l a t i o n sequence (35). For Pb(TT) s a l t s there are, on the s u r f a c e , cogent reasons f o r r e j e c t i n g the p o s s i b i l i t y o f b i o m e t h y l a t i o n to tetramethylead. With the e x c e p t i o n o f a few a i r and moisture s e n s i t i v e compounds w i t h bulky groups (36)r l e a d ( X I ) a l k y l s are unknown. Even monomethyllead(IV) species are unstable i n the absence o f s t a b i l i s i n g l i g a n d s . Furthermore, the o x i d a t i o n r e d u c t i o n p o t e n t i a l f o r Pb(XI)/Pb(IV) d i s f a v o u r s e l e c t r o p h i l i c mechanisms f o r Pb (ΤΙ) , p e r t i n e n t i n b i o l o g i c a l m e t h y l a t i o n o f other metals (e.g., H g ( l l ) , P d ( I l ) ) (37).Thus t r a n s f e r o f a methyl group as Οΐβ" (say frcm methylcobalamin) would y i e l d a h i g h l y unstable M e - P b ( I l ) s p e c i e s from which MePb(lV) could o n l y be generated by an unfavourable 2 - e l e c t r o n o x i d a t i o n o r v i a d i s p r o p o r t i o n a t i o n . I n our view a much more l i k e l y mechanism i s what can e s s e n t i a l l y be d e s c r i b e d as o x i d a t i v e a d d i t i o n o f CH3"** t o an uncharged ( o r a n i o n i c ) l e a d ( I X ) complex : +

CH

3

+ 3

+

[ r P b " L ]< - > - [ C H 3 2

n

n

+

+

- Pb

I V

L ] n

( 3

-

n ) +

(L = uninegative l i g a n d ) A v a r i e t y o f b i o l o g i c a l m e t h y l a t i n g agents (compare f o r example the recent paper o f McBride and C u l l e n on a r s e n i c m e t h y l a t i o n (38)) capable o f t r a n s f e r r i n g carbonium ions a r e p o t e n t i a l l y capable of s y n t h e s i s i n g CH3Pb(JV)in t h i s way. The P b ( I I ) - p e n i c i l l a m i n e complex ( F i g u r e 7) i s a p o t e n t i a l model f o r the l e a d ( I X ) c h e l a t e . However, i t would c l e a r l y be advantageous i f the lead(XT) lone p a i r was s t e r e o c h e m i c a l l y a v a i l a b l e f o r f a c i l e m e t h y l a t i o n , as i n J7 where X simply represents the backbone o f a t r i p o d - l i k e t r i d e n t a t e l i g a n d . -


ORGANOMETALS



352

Figure 8. A perspective view of the molecular structure of (CH ) Pb[SCH CH(NH )COO] · H0 s

2

g

8

2



21.

CARTY


353

Experiments designed to e s t a b l i s h the best choice of l i g a n d and methylation c o n d i t i o n s f o r the Pb(IT) -> Me^Pb i n t e r c o n v e r s i o n are c u r r e n t l y i n progress i n our l a b o r a t o r y i n c o l l a b o r a t i o n w i t h Drs. Y.K. Chau and P.T.S. Wong at CCIW B u r l i n g t o n . Although l e a d ( I I ) s a l t s are the major l e a d p o l l u t a n t s i n the environment, o c c a s i o n a l l y high concentrations of tetramethyHead or t r i m e t h y l l e a d species accumulate from g a s o l i n e s p i l l s , improperly burnt f u e l , e t c . I n such cases, the i n f l u e n c e of n a t u r a l l i g a n d s on the r a t e of environmental degradation to l e s s t o x i c lead(IT) s a l t s i s p e r t i n e n t . There i s evidence that s u l f u r l i g a n d s may f a c i l i t a t e the cleavage of l e a d ( I V ) - a l k y l bonds. Thus (CH3)3 PbOAc r e a c t s s l o w l y w i t h L - c y s t e i n e or DLp e n i c i l l a m i n e i n aqueous s o l u t i o n to g i v e dimethyllead(IV) c y s t e i n a t e ( F i g . 8) or p e n i c i l l a m i n a t e (39). By c o n t r a s t , t r i m e t h y l l e a d i n a c i d i c , n e u t r a l and b a s i c aqueous s o l u t i o n shows very l i t t l e decomposition to i n o r g a n i c l e a d over a p e r i o d of s e v e r a l months (40). The dimethyllead(IV) c y s t e i n a t e i s polymeric w i t h each c y s t e i n a t e coordinated to one l e a d atom v i a S and Ν s i t e s and to a second l e a d atom v i a a carboxylate oxygen. This conversion of ( O ^ ^ P b l V to (CH3) Pb(cyst) under m i l d c o n d i t i o n s may have b i o l o g i c a l i m p l i c a t i o n s ; a l k y l l e a d s are potent neurotoxins, and may exert t h e i r e f f e c t s v i a b i n d i n g to a c t i v e s u l f h y d r y l s i t e s i n t i s s u e s (cf F i g . 8 ) . 2

Acknowledgements I would very much l i k e to acknowledge the major c o n t r i b u t i o n s which Dr. Nicholas J . T a y l o r a research a s s o c i a t e at Waterloo, has made to t h i s work. Most of the s y n t h e t i c and X-Ray s t r u c t u r a l work quoted i n t h i s a r t i c l e has been c a r r i e d out by Dr. T a y l o r . I n i t i a l s t u d i e s of methylmercury complexation were undertaken by a graduate student (now Dr) Y.S. Wong and the homocysteine work i n progress i s due to L.F. Book. I would a l s o thank my colleague Dr. P.C. Chieh who has c o l l a b o r a t e d w i t h me i n some of t h i s work. F i n a n c i a l support has been provided by Environment Canada, p r i n c i p a l l y through the Water Resources Support Program.


354

organometals and organometalloids

Literature Cited 1. Ahrland S., Chatt J., and Davies N.R., Quarterly Rev. Chem. Soc., (1958), 12, 265. 2.

Pearson R . G . , J. Amer. Chem. Soc., (1963), 85, 3533.

3.

Landner L., Nature, (1971), 230, 452.

4.

Wood J . M . , Adv. Environmental S c i . Technol. (1971), 2, 39.


5. Hoch F.L., and Vallee B . L . , Arch. Biochem. Biophys., 91, 1. 6.

(1960),

Hughes W.L. Jr., J. Amer. Chem. Soc., (1947), 69, 1836.

7. Canty, A.J., "Chemical Problems i n the Environment: Occurrence and Fate of Organoelements" ACS Advances i n Chemistry Series, F . E . Brinckman and J . M . Bellama, Eds., (1978) 8.

Simpson R . B . , J. Amer. Chem. Soc., (1961), 83, 4711.

9. Hughes W.L. Jr., Cold Spring Harbour Symposium on Quantitative Biology, (1950), 14, 79. 10. Rabenstein D.L. and Fairhurst M . T . , J. Amer. Chem. Soc., (1975), 97, 2086. 11. Webb J.L., "Enzyme and Metabolic Inhibition", V o l . 2, Academic Press, New York (1969). 12. Schwarzenbach G. and Schellenberg Μ., Helv. Chim. A c t a . , (1965), 48, 28. 13. Weiner I . M . , Levy R . I . and Mudge G . H . , J. Pharmacol. Exp. Ther. (1962) 138, 96. 14. Kagi J.H.R. and Vallee B.L., J. B i o l . Chem., (1961), 236, 2435. 15. Hilton B . D . , Man Η . , Hsi Ε., and Bryant R . G . , J. Inorg. Nucl. Chem., (1975), 37, 1073. 16. McAuliffe C . A . , and Murray S . G . , Inorg. Chim. Acta Rev., (1972) 6, 103. 17. Wong Y.S., Taylor N.J., Chieh P.C. and Carty A.J. J. Chem. Soc. Chem. Commun., (1974), 625. 18. Rabenstein D . L . , Accounts Chem. Res., (1978), 11, 100.


21. carty


355

19. Taylor N.J., Wong Y.S., Chieh P . C . and Carty J. Chem. Soc. Dalton Trans., (1975), 438.

A.J.,

20. Wong Y.S., Carty A.J. and Chieh C . , J. Chem. Soc. Dalton Trans., (1977), 1801. 21. Carty A.J. and Taylor N.J., unpublished


22. Book L.F., Chieh C . , and Carty

A.J.,

results.

unpublished

results.

23. Taylor N.J., Carty A.J. and Wong Y.S., J. Chem. Soc. Dalton Trans., to be published. See also Taylor N.J. and Carty A.J., J. Chem. Soc. Chem. Commun., (1976) 214. 24. Carty A.J. and Taylor N.J., unpublished r e s u l t s . preliminary account see : Carty A.J. and Taylor N.J., Chem. Soc., (1977), 99, 6143. 25. Canty 24, 109.

A.J.

For a J. Amer.

and Kishimoto R . , Inorg. Chim. A c t a . , (1977)

26. Canty A.J. and Tyson

R.K.,

Inorg. Chim. A c t a . , (1977) 24, L77.

27. Aberg B., Ekman L., Falk R . , Grietz U., Pearson G . , and Snihs J.O., Arch. E n v i r . H e a l t h . , (1969) 19, 478. 28. Lundgren K.D., Swensson A . and Ulfvarson, U . Lab. I n v e s t . , (1967), 20, 164. 29. Freeman H.C., Stevens G . N . , and Taylor Chem. Commun., (1974), 366. 30. Taylor N.J. and Carty

A.J.,

I.F.

Scand J. Chim. Jr.,

J.

Chem. S o c . ,

Inorg. Chem., (1977), 16, 177.

31. Freeman H.C., Huq F., and Stevens G . N . , J. Chem. Soc. Chem. Commun., (1976), 90. 32. Wong P.T.S., 253, 263.

Chau, Y . K . and Luxon, P.L., Nature (1975),

33. Schmidt U., and Huber Η . , Nature, (1976) 259, 177. 34. Jarvie A . W . P . , Markall R . N . and Potter H . R . , Nature (1975), 225, 217. 35. Chau Y . K . and Wong P.T.S., "Chemical Problems in the Environment: Occurrence and Fate of Organoelements" ACS Advances in Chemistry S e r i e s , F . E . Brinckman and J . M . Bellama, Eds., (1978)


ORGANOMETALS

356 36. Davidson P.J. and Lappert M.F., (1973), 317. 37. R i d l e y W.P., 183, 1049. 38. C u l l e n W.R., and Reimer M.,


ORGANOMETALLOIDS

J . Chem. Soc., Chem. Commun.,

D i z i k e s L . J . and Wood J.M.,

Science

(1977),

Froese C.L., L u i Α., McBride B.C., Patmore J . Organometal. Chem., (1977), 139, 61.

39. Carty A . J . and T a y l o r , N.J., 40. S a y e r T.L., R a b e n s t e i n D.L.,

AND

unpublished

D.J.,

results.

B a c k s S., E v a n s C.A., Millar E.K. Can. J . Chem., (1977) 55, 3255.

and

Discussion F. E. BRINCKMAN ( N a t i o n a l Bureau of Standards): To emphasize your l a s t p o i n t concerning the appropriate c o o r d i n a t i o n of l e a d , the J a r v i e mechanism [Nature, (1975) 255, 217] , i n v o l v e s an a b i o t i c r e d i s t r i b u t i o n , presumably to form tetramethyllead. We reported t h a t i n Chesapeake Bay anoxic sediments w i t h h i g h biogen i c s u l f u r content, not only d i d gaseous elemental mercury form from b i o l o g i c a l a c t i v i t y , but mercury a l s o p a r t i t i o n e d i n t o the l i p i d or o i l phases i n the sediment body. The mercury was p r i n c i p a l l y i n s o l u b l e form; about 2% or so as the element and/or methylm e r c u r i a l s but p r i n c i p a l l y i n much l a r g e r molecules not yet char a c t e r i z e d by us or anybody e l s e . But the p o i n t here i s b i o a v a i l a b i l i t y . I t h i n k we w i l l f i n d a number of c o o r d i n a t i o n s i t e s which w i l l h o l d the metal a v a i l a b l e f o r other a c t i v i t y besides simple m i n e r a l i z a t i o n as the s u l f i d e . S u l f u r doesn't seem to be the only key element i n understanding t h i s c o o r d i n a t i o n chemistry and the b i o a v a i l a b i l i t y i n these systems.

ever

R. H. FISH ( U n i v e r s i t y of C a l i f o r n i a , B e r k e l e y ) : looked at t h i o e t h e r s ?

Have you

CARTY: We looked at both the methylmercury and the i n o r g a n i c complexes i n methionine, and the c r y s t a l l i n e methylmercury complex contains the methionine bound t o mercury by the n i t r o g e n . In s o l u t i o n i t i s l i n e a r . I t ' s w i t h t h i s z w i t t e r i o n i c complex w i t h a p o s i t i v e charge on mercury and a negative charge on the c a r b o x y l ate. FISH:

What about H g C l ? 2

2+ CARTY: In Hg , the p e r c h l o r a t e contains the methionine bound through two t h i o e t h e r s and two carboxylates. FISH: Yes, because we looked at a p y r i d y l e t h y l - c y s t e i n e molecule. We found a nine-numbered r i n g w i t h the p y r i d y l - n i t r o g e n and the amino f u n c t i o n . The s u l f u r never i n t e r a c t e d .


21.

CARTY


357

CARTY: I t h i n k the t h i o e t h e r i n t e r a c t i o n s are much l e s s s t r o n g . In f a c t , i n s o l u t i o n s of methionine w i t h CH«Hg , the t h i o e t h e r c o o r d i n a t i o n o n l y occurred at pH of l e s s than 2, o t h e r wise i t i s NH or c a r b o x y l a t e t h a t i n t e r a c t s . +

2

F. HUBER ( U n i v e r s i t y of Dortmund): We examined compounds of organolead and organotin mercaptocarboxylic a c i d s . We observed that the l e a d species can coordinate to the s u l f u r , or t o oxygen, or to even both. We d i d experiments w i t h mercaptopropionic a c i d as a model compound f o r c y s t e i n e , without an NH group, and observed that i n many cases there i s c o o r d i n a t i o n between l e a d and s u l f u r . The c a r b o x y l i c a c i d d i d n ' t r e a c t . With t r i m e t h y l l e a d ( I V ) and dimethyHead(IV) compounds, e s p e c i a l l y w i t h the t r i m e t h y l l e a d compounds, there was an a c i d o l y s i s r e a c t i o n g i v i n g methane and dimethyllead(IV).


2

CARTY: I n s o l u t i o n s of t r i m e t h y l l e a d a c e t a t e and L - c y s t e i n e , i f you look by nmr techniques at the r e a c t i o n w i t h a pH of 6 or 5, you f i n d only weak c o o r d i n a t i o n of the s u l f h y d r y l group. At a l k a l i n e pH, d i m e t h y l a t i o n occurs. HUBER: We t r y t o work i n n e u t r a l s o l u t i o n s . W. P. RIDLEY ( U n i v e r s i t y of Minnesota): Your suggestion t h a t we should not ignore the p o s s i b i l i t y t h a t l e a d ( I I ) c o u l d accept a carbonium methyl group from some b i o l o g i c a l methyl donor should c e r t a i n l y be i n v e s t i g a t e d . T h a l l i u m ( I ) could be methylated i n the same f a s h i o n , assuming a proper complex c o u l d be formed, i . e . , the t r a n s f e r of CH to T1(I) t o g i v e m o n o m e t h y l t h a l l i u m ( I I I ) . The standard r e d u c t i o n p o t e n t i a l s of the l e a d ( I I ) t o l e a d ( I V ) and t h a l l i u m ( I ) t o t h a l l i u m ( I I I ) couples are very s i m i l a r , suggesting t h a t they may proceed i n a s i m i l a r f a s h i o n . 3

HUBER: On the p o s s i b i l i t y of m e t h y l a t i o n of P b ( I I ) , i n many complexes we do not see an a v a i l a b l e lone p a i r ; the P b ( I I ) adopts o c t a h e d r a l c o o r d i n a t i o n . Nonetheless, I t h i n k the p o s s i b i l i t y exists for this reaction. W. R. CULLEN ( U n i v e r s i t y of B r i t i s h Columbia): I f the s u l f u r was a l r e a d y coordinated t o the l e a d , then m e t h y l a t i o n of the s u l f u r could o f f e r means f o r t r a n s f e r of methyl onto the l e a d or onto the t h a l l i u m . This might be a v i a b l e route by which o x i d a t i v e a d d i t i o n might take p l a c e . HUBER: When s u l f u r i s coordinated to l e a d , there might be a p o s s i b i l i t y t h a t the lone p a i r could be s t e r e o c h e m i c a l l y d i r e c t e d . H a l i d e complexes u s u a l l y have an o c t a h e d r a l geometry, but there are some complexes, e s p e c i a l l y w i t h thiophosphates, where the lone p a i r i s a c t i v e .


358

ORGANOMETALS

AND

ORGANOMETALLOIDS

CARTY: C e r t a i n l y , w i t h the a b i l i t y that i n o r g a n i c chemists have these days t o tailor-make l i g a n d s , one would not be s u r p r i s e d to f i n d that you can make a l i g a n d which would a c t u a l l y t i e the bonds back and l e t the lone p a i r be f r e e f o r m e t h y l a t i o n .


G. E. PARRIS (Food and Drug A d m i n i s t r a t i o n ) : Potassium antimony t a r t r a t e has a s t r u c t u r e i n which one s i d e of the a n t i mony i s open, and i t i s o f the few s o l u b l e compounds of i n o r g a n i c antimony. The p o s s i b i l i t y of t r a n s f e r r i n g CH^ t o t h i s p o t e n t i a l n u c l e o p h i l e i s i n t e r e s t i n g . However, s i n c e antimony Mossbauer has shown t h a t the lone p a i r i s probably more i n a S-type o r b i t a l , as i t i s i n t r i m e t h y l s t i b i n e , there i s some question whether o r not these are good n u c l e o p h i l e s f o r accepting CH^*. M. L. GOOD ( U n i v e r s i t y o f New O r l e a n s ) : That's a good p o i n t ; the Mossbauer i s d e f i n i t i v e on the character o f those e l e c t r o n s . CARTY: There are some a l k y l compounds of l e a d ( I I ) , c o n t a i n i n g bulky a l k y l groups, which have been prepared by P r o f e s s o r M.F. Lappert ( U n i v e r s i t y of Sussex). I n those compounds the P b ( I I ) behaves as a donor t o t r a n s i t i o n metals, so the lone p a i r i s available. RECEIVED

August 22,

1978.


Mercury, Lead, and Cadmium Complexation by Sulfhydryl-Containing

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