Some new sulfur containing chelating agents

J. im,rg, nucl. Chem., 1974.Vol.36, pp. 1213-1216.PergamonPress.Printedin Great Britain.

SOME NEW SULFUR CONTAINING

CHELATING

AGENTS

MARK M. JONES, THOMAS H. PRATT and C. HENDRICKS BROWN Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235 (Received 2 August 1973)

Abstract--Nine new sulfur containing chelating agents have been prepared by the reaction of aldehydes with appropriate compounds containing sulfhydryl groups. These compounds all contain thioether donor groups and several contain carboxylate groups as well. Three of the compounds which are tetracarboxylic acids have carboxyl groups whose ionization is practically independent and give titration curves with but a single inflection point. A method is presented for obtaining all four dissociation constants in such cases.

INTRODUCTION THE SEARCH for chelating agents which are highly selective for certain metal ions is pursued to facilitate the separation or characterization of such metal ions from multicomponent systems. The present work was undertaken as part of the larger program to develop selective chelating agents for use in the removal of toxic heavy metals from the human body. The basic problem here is to administer a metal complex which will remove the toxic metal from the human body and simultaneously have a minimal effect on the distribution of the essential metal ions. The problem can be stated in terms of the process desired : Chelate of various essential metal ions

/ Human body ] | containing | ! toxic metal, / + ~ Ca 2+, Mg 2+, Fe 2+, ~-" ] Mn 2 +, Cu 2 +, Zn 2 + | I. K +, Na +, Fe a+, etc.J

Toxic metal chelate in excreta

/ Human body ] | with a normal | J distribution l, + -~Ca2+, Mg 2+,Fe 2 + , [ [ F e 3+, Mn 2+, Cu 2+, | / Z n 2+, Na +, K +, etc.)

for the toxic metals might have some real therapeutic advantages. Selectivity in analytical work is often achieved by adjustment of the pH, addition of a large amount of a second coordinating agent, solvent extraction, or a variety of techniques not feasible in therapy. The selectivity of a therapeutic chelating agent must arise almost exclusively from the structure it has over a pH range of 7.30 to 7.50. In this paper we describe some chelating agents which were synthesized in a search for new molecules which possess a greater selectivity for mercury than most of the compounds currently used in the therapy of mercury poisoning. These have all been prepared via a general reaction of the type H

H

I

I

SR /

R - - C = 0 + 2HSR ~ R - - C \

+ H20.

SR Most of the aldehydes used were, in fact, dialdehydes. The reaction has been previously characterized in some detail[4-7]. The compounds prepared in this paper are shown in Table 1 ; the numbering system is a continuation of that used in an earlier paper from this laboratory.

EXPERIMENTAL

Most of the chelating agents presently used for the removal of toxic metals from the human body are quite unselective in their action. Thus EDTA, administered as the calcium complex to facilitate the removal of lead also increases the excretion of zinc[l] and iron[2]. The same problems arise with penicillamine, which enhances the excretion of mercury, copper, and lead in therapy, but also increases the excretion of cobalt and zinc[3]. It is thus obvious that selective chelating agents

The synthetic procedures used were patterned after the previous syntheses. Because these compounds were sometimes low melting waxy solids or viscous liquids, the actual purification steps varied from compound to compound. The detailed synthetic procedures are given here to provide explicit instructions for the preparation of pure samples of each of the compounds. (Propanediylidenetetrathio)tetrapropionic acid (VI

1213

Malonaldehyde bis(dimethylacetal) (16.4 g., 0.10 mole),

1214

MARK M. JONES, THOMAS H. PRATT and C. HENDRICKS BROWN

mercaptopropionic acid (70.8 g, 0.667 mole), and concentrated hydrochloric acid (15 ml.) were mixed and placed on a stirring hot plate. After 1 hr, the mixture had become a thick white paste, which solidified to a white wax on cooling. The solid was broken up and stirred for two hours with anhydrous ethyl ether, (150 ml.) which converted the wax to a white powder. The solution was filtered, the solid collected and rewashed with ether, again filtered, and recrystallized from water-methanol. Yield: 22 g (48~). m.p. 148-151 °. Anal. Calcd for CzsH24S408 : C, 39.12: H, 5.25; S, 27.84~. Found: C, 39.36: H, 5.38; S, 28.099/00.

(Butanediylidenetetrathio)tetrapropionic acid (VI) Dimethoxytetrahydrofuran (13.2 g, 0.10 mole), mercaptopropionic acid (70.8 g, 0-667 mole), and concentrated hydrochloric acid (15 mll were mixed and placed on a stirring hot plate. After 3 hr, the mixture was a thick, slightly yellow liquid, which solidified on cooling. The solid was broken up and stirred with 400 ml of anhydrous ethyl ether, and filtered. The solid was rewashed with ether, dried in vacuum, and recrystallized from water-methanol. Yield: 25 g (53~). m.p. 110-114 °. Anal. Calcd for C I 6 H 2 6 5 4 0 8 : C, 40.49; H, 5.52; S, 27.02~. Found: C, 40.70; H, 5.52; S, 27.14~o.

(Pentanediylidenetetrathio)tetrapropionic acid (VII) Glutaraldehyde (21 g of a 50~ aqueous solution, 0.10 mole), mercaptopropionic acid (70-8 g, 0.667 mole), and concentrated hydrochloric acid (15 ml) were mixed and placed on a stirring hot plate. After 1/2 hr, the mixture had solidified. It was broken up and stirred with 400 ml ether, filtered, and rewashed with ether. The resulting white powder was dried in a vacuum and recrystallized from water-methanol. Yield : 20 g (40~). m.p. 148-150 °. Anal. Calcd for C~7H2sS,Os : C, 41.79; H, 5.78; S, 26.23~. Found: C, 42.00; H, 5-79; S, 26.45~.

Malonaldehyde bis(diphenylmercaptal) (VIII) Malonaldehyde bisIdimethylacetal) [16.4 g, 0.10 mole), thiophenol (74 g of a 9 7 ~ solution), and concentrated hydrochloric acid (15 ml) were mixed and heated over steam with stirring. The mixture changed from a clear solution to a red liquid after 2 hr. The liquid was placed in a vacuum dessicator (40°C) for 3 days. Yield: 45 g (95~). Anal. Calcd for C2THz4Sa: C, 68.02: H, 5.07; S, 26.90~. Found: C, 67.88; H, 5.08; S, 27-09°/0.

Succinaldehyde bis(diphenylmercaptal) (IX) Dimethoxytetrahydrofuran (13.2 g, 0.10 mole), thiophenol (74 g of a 97% solution, 0.667 mole), and concentrated hydrochloric acid (15 ml) were mixed and placed on a stirring hot plate. The reaction mixture solidified after 2 hr. The product was recystallized 4 times from 95'/o ethanol. Yield : 15 g (30~). m.p. 92.5-93.5 °. Anal. Calcd for C28H26S,, : C, 68.53; H, 5.34; S, 26.14~o. Found: C, 68.77: H, 5.54; S, 26.37 ~.

Glutaraldehyde bis(diphenlmercaptal) (X) Glutaraldehyde (21 g of a 50~ aqueous solution, 0.10 mole), thiophenol (74 g ofa 97~ solution), and concentrated hydrochloric acid (15 ml) were mixed and placed on a stirring hot plate. After 2 hr the mixture had become a dark brown liquid, which became very viscous but did not solidify on cooling. The product was placed in a vacuum dessicator (40°C) for 3 days. Yield : 43 g (85~). Anal. Calcd for C 29H2 aSa : C, 69.00; H, 5-59; S, 24.40%. Found: C, 69.04; H, 5.71; S, 24.54%.

o-Phthaldehyde bis(diphenylmercaptal) (XI) o-Phthaldehyde (13-4 g, 0.10 mole), thiophenol (74 g, of a 97~ solution), and concentrated hydrochloric acid (15 ml) were mixed and placed on a steam bath with stirring. After 3 hr the mixture had become a yellow-brown viscous liquid which solidified on cooling. The product was recrystallized 4 times from 9 5 ~ ethanol. Yield: 26 g (48~o). m.p. 83,2 84.4°. Anal. Calcd for C32H26S4: C, 71.33; H, 4.86; S, 23-80~. Found: C, 70.95 ; H, 4.80; S, 23.95 9,~.

1,1,3,3- Tetra(butylthio)propane (Xll) Malonaldehyde bis(dimethylacetyl) (16.4 g, 0.10 mole), butanethiol (60.15 g, 0.667 mole), and concentrated hydrochloric acid (15 ml) were mixed and placed on a stirring hot plate. After 3 hr two layers had formed; the bottom layer was clear yellow, the top layer was clear and colorless. The top layer was water soluble, the bottom layer was not. The mixture was placed on a steam bath and heated for 12 hr, after which only the yellow layer remained. An attempt was made to vacuum distill the yellow oil, but at 150°C and 0.50 mm, the product would not distill, and darkened to a red liquid. Yield: 33 g (84~). Anal. Calcd for C191-[40S 4 : o/ Found: C, 57.35; H, 10.34: C, 57.51; H, 10.16; S, 32.33/0. S, 32.55~. 1,1,4,4-Tetra(butylthio)butane (XIII) Dimethoxytetrahydrofuran (13.2 g, 0.10 mole), butanethiol (60.15 g, 0.667 mole), and concentrated hydrochloric acid (15 mll were mixed and heated with stirring. Two layers formed after 3 hr, the top clear and colorless, the bottom clear yellow. The mixture was placed on a steam bath and heated for 12 hr, after which only the yellow layer remained. An attempt to vacuum distill the product was made, but at 95°C and 0.50 mm only 1 ml of a clear, water soluble liquid was obtained. The yellow product was removed from distillation and cooled. Yield : 37 g (90~). Anal. Calcd for C2oH42S4 :C, 58.42; H, 10.30; S, 31.28 ~o. Found:C, 58.27; H, 10.20: S, 31-42 ~. IONIZATION C O N S T A N T S The ionization constants of V, VI, and VII were determined by titration at 25 ° in a medium held at an ionic strength of 0-10 by the addition of reagent grade sodium nitrate. A Beckman Research Model pH meter was used which had previously been standardized with a standard phthalate buffer of pH 4-00. The titration curves exhibited only a single inflection point corresponding to the consumption of four equivalents of hydrogen per mole of acid (Fig. 1). This indicates that the four ionization constants are quite close together. The calculation of acid dissociation constants involves transforming the titration data to a function of p H vs ~, the average n u m b e r of acidic hydrogens attached to the ligand. Since there are four carboxylic acid groups per molecule, 4 . CLig -- [ O H - ] - [ H 3 0 + ] , f i > 0. CLig

Hobs ~ - -

(1)

In terms of the acid dissociation constants, this becomes =

m=l

m [H30+]"K,,

1+

Z

m=l

[H30+]mKm

(2)

1215

Some new sulfur containing chelating agents II

Table 1. Compounds prepared

T i t r a t i o n of

HOOCCHzCH2~ H I0

H ~CH2CH2COOH

CC%CH~ / ?oocc.~c.p S C . ~ C H ~ C O 0 . / ' -

HOOCCH2CH2S

\

9

SCHzCH2COOH

/

8 pH 7

HOOCCH2CHzS

SCH2CHzCOOH

6

(v) 5 4 I I

t 2

I 3

I 4

I 5

ml

I 6

I ?

L 8

I 9

I I0

HOOCCH2CH2S

\

SCH2CH2COOH

/

/.'CCH2CH2C

base

Fig. 1. Titration curve for compound VI vs standard base.

HOOCCH2CH2S

in which

SCH2CH2COOH (VI)

ki

K m = i

m

Multiplication by the denominator in the second equation results in a linear least squares problem, whose solutions to the four unknowns were used as initial values, To achieve convergence, correction terms were calculated with a quasi-Newton method[8]. Use of a first order Taylor series expansion of Eqn (2) involving the four independent functions of the acid dissociation constants, produced an overdetermined system of equations solvable by generalized inverses[9]. To increase stability, it was found necessary to multiply these correction terms by a positive constant a, chosen to decrease the total variation between observed and predicted values of & This method normally provided convergence within two or three iterations, with mean differences and standard deviations between the two sets of h's being less than 0.03; no individual value differed by more than 0.06.

HOOCCH2CH2S

\

/

SCH2CH2COOH

CCH2CH2CH2C

.'\

HOOCCH2CH2S

SCH2CH2COOH (VII)

C6H5S

\

/ ~

SC6H5

CH2C

C6H6S

SC6Hs (vm)

RESULTSANDDISCUSSION The structures of the compounds which have been prepared are shown in Table 1. Each of these molecules has at least four donor atoms and three of them have eight (V, VI and VII). The compounds VIII through XIII are essentially insoluble in water, compounds V, VI and VII have solubilities, for the free acids, of about 5 × 10 -4 M in water at 25°, and in this respect are similar to EDTA. They dissolve much more readily as the pH is increased. The pK, values of these compounds are presented in Table 2. The reproducibility of these values is about +0.10. The fact that these ionization constants cover such a narrow range is a good indication that the ionization processes are largely independent of each other and differ primarily because of statistical effects. An examination of the stability constants of these chelating agents with Hg(II), Pb(lI), Cd(II) and the

C6H5S

\

/

SC6H5

/~_t-CH2CH2-~_t~ C6H5S

SC6H5 0x)

C6H5S

\

/

SC6Hs

CCH2CH~CH2C

C6HsS

SC6Hs (x)

1216

MARK M. JONES,THOMASH. PRATTand C. HENDRICKSBROWN

Table 2. pKa values

Table 1 (continued) H SC6H5 \ / C\ SC6H 5 /L\ H

pK 2

pK 3

pK,~

V VI VII

4.19 3-91 3.88

4.34 4.14 4-29

4.94 4.82 4.80

5.63 5.38 5.45

(T = 25 °, u = 0.10 in NaNO3t

\

SCH2CH2CH2CH3

/ ~ CH2C

CH3CH2CH2CH2S

SCH2CH2CH2CH3

\

/

SCH2CHzCHzCH 3

C-CH2CH2C CH3CH2CH2CH2S

Acknowledgements--This work was performed under the auspices of the Center of Toxicology, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, 37235 and supported by United States Public Health Services Center Grant ES00267. REFERENCES

(xH) CHaCH2CH2CH2S

pK l

SC6H 5

ix1) CH3CH2CH2CH2S

Compound

SCH2CH2CH2CH 3 (XII1)

metal ions essential in the normal physiology of the human body is currently under way.

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