Studies on complex compounds. V. Coordination compounds of mercury and biologically active amines

Studies on complex compounds. V. Coordination compounds of mercury and biologically active amines'

Department of Pharmacology and Therapelltics, King George's Medical College, Luckrlobv U~zi~iersiry, Llickrto~v, and Departrnenf of Clzentistry, Lucknow University, Llickrzorv, India

Received August 8, 1967

Five mercury complexes were synthesized by condensation of mercuric chloride with different biologically active amines. In the present study D-amphetamine, L-amphetamine, DL-amphetamine, methylamphetamine, ephedrine, and tyramine were used where a stereoisomeric effect was observed during the formation of the mercury complexes. The complex compound synthesized from DL-amphetamine was found to be a mixture of the mercury complexes of D-amphetamine and L-amphetamine, and the difference in their solubilities was utilized for their separation. The estimation of the carbon, hydrogen, and nitrogen content, the determination of the amount of chlorine and mercury, and measurements of the infrared absorption spectra at 700-3500 cm-' indicated the ratio of 2:l for anline to mercury in these coordination compounds. Further characterization of these mercury complexes was done by ultraviolet absorption spectra and conductance measurements.

Canadian Journal o f Chemistry, 46, 2685 (1968)

Interference with cellular metabolism by in- hibition of certain enzyme systems has been shown to be the property of various organo- mercury compounds (1). Mercury has also been reported to combine with ligands of physiological importance such as phosphoryl, carboxyl, amido, and amino groups. The present study describes the synthesis of mercury complexes of biologically active amines with a view to studying the relative coordinating abilities of nitrogen and oxygen and to investigate their effects on certain enzyme systems for obtaining a better knowledge of their physiological significance (2). The in- volvement of a stereoisomeric effect was observed during the formation of such mercury complexes with isomeric amphetamines.

Experimental Materials

Most of the amines and mercuric chloride (B.D.H.) used in the present study were of analytical grade and were available commercially. Stereoisomeric arnpheta- mines (D-amphetamine and L-amphetamine), DL-amphetamine, and methylamphetamine were used as bases after separation from their respective sulfates by treating with an equivalent amount of dilute sodium hydroxide solution and subsequent extraction with ether. Tyramine base was separated from its hydrochloride with a dilute solution of liquor ammonia while ephedrine, as a base, was used without further purification. The purity of the amines was checked by their boiling or melting points. Absolute ethanol, ether dried over sodium wire, and

'This investigation was supported by a research grant from the Indian Council of Medical Research, New Delhi.

=Inquiries should be addressed to Professor S. S. Parmar.

purified anhydrous nitrobenzene (3) were used throughout these experiments.

Arzalyses The mercury content of the complexes was estimated

volumetrically (4) and gravimetrically (5). The chlorine content was determined gravimetrically as AgC1. The carbon, hydrogen, and nitrogen contents of these complexes were determined by well-known combustion methods.

Preparations Mercury complexes were prepared by lllixing 2.2 moles

of the appropriate amine with 1 mole of mercuric chloride in absolute ethanol as described earlier (4). The analyses and melting points are summarized in Table I.

Results

Properties of Mercury Coordinatio~z Con~po~~nds All com~lexes are white in color except the

tyramine-mercury complex which is of slightly brownish color. Complexes of D-amphetamine, DL-amphetamine, and methylamphetamine were obtained as fine powders while those synthesized from L-amphetamine, tyramine, and ephedrine were crystalline in nature. Complexes synthesized from D-amphetamine, DL-amphetamine, ephedrine, and tyramine are insoluble in water while complexes of L-amphetamine and methylamphetamine are sparingly soluble in boiling water. All complexes are soluble in acetone except those synthesized from ephedrine and tyramine. Mercury complexes of L-amphetamine and methylamphetamine are soluble in solvents like cyclohexane, cyclohexanol, dioxane, and nitrobenzene. All complexes undergo decom- position on boiling with dilute sodium hydroxide

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CANADIAN JOURNAL OF CHEMISTRY. VOL. 46, 1968

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MISRA ET AL.: STUDIES ON COMPLEX COMPOUNDS. V 2687

solution, as is indicated by the appearance of a TABLE I1

characteristic smell of the original amine. These Conductivity of mercury complexes mercury complexes, though soluble in dilute -

nitric acid, are oxidized with concentrated nitric Molar Solvent conductance

acid (4) where a definite change in the color of Complex used (mho) the compounds is observed. The mercury complex obtained from DL-amphetamine could be D$!~$$$~~&~t- Nitrobenzene 0.95 separated into complexes of D-amphetamine and Dichloro-bi(~-amphet- L-amphetamine by taking advantage of their arnine)mercury(II) Ethanol 0.75

Dichloro-bi(~~-amphet- solubility differences. The ethanol soluble por- arnine)mercury(II)* Nitrobenzene 0.58 tion contained the complex of L-amphetamine. Dichloro-bi(methy1amphet- On isolation these complexes were found to be , , ;~3, '~[~~!~~!L,- Ethanol 1.05 identical with those synthesized from either D- mercury(II) Nitrobenzene 0.35 amphetamine or L-amphetamine. Such a possi- Dichloro-bi(tyramine)-

bility was further confirmed by determining the Nitrobenzene 0.45 specific rotation of the ethanol soluble compound an~~,";~s,~o~;~;~,"~;~~;a~f~;;~~",$&j~m~hctamine)mercur~Or) obtained from the mixture of D-amphetamine and L-amphetamine complex. This complex Elmer UV-VIS spectrophotometer. Such studies showed a laevorotatory nature [a] = -20. with complexes of D-amphetamine, DL-amphet-

amine, and tyramine could not be undertaken Conductivity Measurements due to the lack of proper solvent. No definite

The conductance measurements were made peaks could be observed with complexes ob- with a Mullard conductivity bridge El3001 tained from ~ - ~ ~ ~ h ~ t a ~ i ~ ~ and methylamphet- at 20" with a having a ,mine. The characteristic wavelengths and the constant of 1.05. All complexes were used at a log of their extinction for the final concentration 1 pmole and were taken ephedrine-mercury complex were found to be in nitrobenzene, except the complexes of L- 215 mp and 4-71 and 265 mp and 3.48 for the amphetamine and methylamphetamine where first and second maxima respectively, as corn- ethanol was used as a solvent. The results of the pared with the absorption peak at 205 mp for conductance measurements are given in Table 11. the first maxima and 258 mp for the second

maxima observed with ephedrine. Absorption Spectra

The ultraviolet absorption spectra of com- I~frared Spectra plexes synthesized from L-amphetamine, methyl- The infrared spectra were obtained with a amphetamine, and ephedrine were carried out in Perkin-Elmer Infra-cord spectrophotometer ethanol with a Beckman G-2400 spectropho- model 137 equipped with NaCl optics. The tometer in the range of 200 mp-300 mp. These spectra of those complexes examined in KBr results were checked with a Hitachi Perkin- films in the range 700 to 3500 cm-I have been

TABLE 111 Frequency (crn-I) assignments for D-amphetamine, L-amphetamine, and their

mercury complexes

D-Amphetamine L-Amphetamine

Assignment Hg Hg

Ligand complex Ligand complex

N H Asymmetric stretching 3338 b 3178 sh 3325 s 3151 s N H Symmetric stretching 3231 sh 3124 s 3231 sh 3151 s NH2 Degenerate deformation - 1603sh 1599b 1585s

1599b 1611s - - NH, Svm~netric deformation 1468 rn 1491 m 1468 rn 1491 m - .

1451 s i452 s 1451 s 1468 s NH, Rocking 742 s 746 s 742 s 748 s

ABBREVIATION^: b = broad; m = medium; s = sharp; sh = shoulder.

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2688 CANADIAN JOURNAL OF CHEMISTRY. VOL. 46, 1968

TABLE I V Frequency (cm-l) assignments for methyl amphetamine, ephedrine, tyramine, and their nlercury colnplexes

Methylamphetamine Ephedrine Tyramine

Hg Hg Ligand complex Ligand complex

Hg Ligand coni~lex

N H Asymmetric stretching 3283 w 3178 s - 3145 b 3270w 3124m N H Svmmetric stretching - - - 3205 w - - NH2 begenerate deformation 1497 m 1596 m 1138 m 1596 b 1514 s 1611 sh

1456 m 1491 s 1491 s 1483 s 1462m 1600s NH2 Symmetric deformation 1379 s 1341 s 1391 w 1387 w 1392s 1370 w

1341 m 1333 m 1379 m 1316 w 1263w 1243s NH, Rocking 742 b 752 s - 751 s 781 n~ 787 w

ABnnEvrATlONs: b = broad; rn = medium; s = sharp; sh = shoulder; w = weak.

compared with their corresponding ligands. These results are recorded in Tables I11 and IV. For detailed investigation, the spectra of the complexes of ephedrine and tyramine were mea- sured with a Perkin-Elmer 337 grating infrared spectrophotometer in KBr and N~ijol mull phase.

Discussion

The ratio of the ligand with HgCl,, found to be 2:l in these complexes (Table I), indicates that these complexes exist as

Conductance measurements have indicated the nonelectrolytic nature (6) of all the coordination compounds which presumably exist as mono-

mers. At present, the probability for the existence of a polymeric structure due to halogen bridging (7, 8) cannot be ruled out. Furthermore, the low affinity of mercuric ion for oxygen as compared with its affinity for nitrogen, could account for the coordination through nitrogen preferentially over oxygen (9). The presence of the OH group in tyramine and ephedrine could render oxygen available to take part in the formation of the complex compound. However, the positive shift in the OH stretching vibration observed in the infrared spectrum of the ephedrine complex has indicated that coordination does not occur through the oxygen. The frequency assignments for OH stretching and NH asymmetric stretching vibrations could not be clearly established in the infrared spectrum of ephedrine. On the other hand, the OH stretching vibration was found to occur at 3373 cm-' (Fig. 1) with dichloro-

W A V E L E N G T H (MICRONS) FIG. 1. Infrared spectra of dichloro-bi(epl~edrine)n~ercury(II) in KBr (solid line), ephedrine in CHC13 (broken line).

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4 0 0 0 3 0 0 0 2 0 0 0 1500 C M-I 1000 9 0 0 BOO 7 0 0

100 I I I 1 c L I I I I I I I I I I l , ~ l t ~ t ~ ~ > ~ l ~ l t ! ~ ~ ! l l . a 1 2 0

FIG. 7. Infrared spectra of dichloro-bi(tyramine)mercury(II) in KBr (solid line), tyramine in Nujol (broken line).

bi(ephedrine)mercury(II). The possibility of co- valent bonding by replacement of hydrogen from the OH group is ruled out due to the in- ability of the alcoholic group to undergo ioniza- tion (10). Such a change in the spectrum was not observed with the tyramine-mercury complex (Fig. 2). The interaction of the free phenolic group with KBr during grinding (11) could presumably account for such a difference, since a negative shift was actually observed in the OH stretching vibration. Further support for such an explanation was provided by the positive shift in the OH stretching vibrations observed during measurement of the infrared spectra of

the complex in Nujol mull phase. The OH- stretching vibration at 3309 cm-' observed with tyramine was found to be at 3385 cm-' for dichloro-bi(tyramine)mercury(II). The infrared spectra of the complexes obtained from D- amphetamine (Fig. 3), L-amphetamine (Fig. 4), methylamphetamine (Fig. 5), ephedrine (Fig. l), and tyramine (Fig. 2) have indicated a negative shift in the NH stretching vibration and in the NH, degenerate deformation by comparison with their ligands (Tables I11 and IV). Donation of a pair of electrons from the primary and secondary amino groups to the metal ion may possibly account for such a negative shift. The

4 0 0 0 3 0 0 0 2 0 0 0 1 5 0 0 C M-I 1000 9 0 0 8 0 0 7 0 0 l l l l l . l i l l l t l l l l l . . # I 1 I , I 1 I , I I I 1 I

0 C, I I I I I I I 1 I 1 I I 3 4 5 6 7 8 9 I0 11 12 13 14 15

WAVE LENGTH (MICRONS)

FIG. 3. Infrared spectra of dichloro-bi(~-amphetamine)mercury(II) in KBr (solid line), D-amphetamine (broken line).

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2690 CANADIAN JOURNAL O F CHEMISTRY. VOL. 46, 1968

FIG. 4. Infrared spectra of dichloro-bi (L-aniphetan~ine)mercury(II) in KBr (solid line), L-aniphetaniine (broken line).

observed shifts in NH, sylninetric deformation and NH, rocking vibration (12, 13) have provided further support for such an explanation. The ability of D-amphetamine and L-amphetamine to form different complexes points to- wards the existence of stereoisomeric effects during complex formation. Solubility differences have been utilized for separation of the complexes of stereoisomeric amphetamines from dichloro-bi(~~-amphetamine)mercury(II). At present the possibility of the formation of a mixed complex presumably through the following re-

versible equilibrium cannot be ruled out. The reaction thus could possibly be driven to the right in a solvent in which one of the compounds is insoluble.

However, further experimental evidence will be required to elucidate such a mechanism where liberation of the ligands from the mixed complex is necessary before the formation of the complexes of D- and L-amphetamine separately.

WAVELENGTH (MICRONS)

FIG. 5. Infrared spectra of dichloro-bi(niethylamphetamine)mercury0I) in KJ3r (solid line), metliylamplletaniine in D r (broken line).

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Acknowledgments 1. S. M. A. SMOLT, C. W. KREKE, and E. S. COOK. J. Biol. Chem. 224,999 (1957).

The authors wish to express their thanks to 2. S. S. PARMAR, C. H. MISRA, and S. N. SHUKLA. In preparation. Dr. M. L. Dhar, Dr. Nitya Anand, and Dr. S. C. 3. A. I. VOGEL. Practical organic chemistry. Long-

Agarwal from the Central Drug Research Insti- mans, Green and Co., Ltd., London. 1948. p. 173. tute, Lucknow, for providing facilities for micro- 4. C. H. M~SRA, S. S. PARMAR, and S. N. SHUKLA. J.

Inorg. Nucl. Chem. 28,147 (1966). analysis and infrared and ultraviolet absorption 5. C. H. M ~ ~ ~ ~ , S. S. pARMAR, and S. N. sHUKLA. J. measurements respectively. Grateful acknowl- Inorg. Nucl. Chem. 29,2589 (1967). edgment is made to Professor K. P. Bhargava 6. R. BLACKHOUSE, M. E. FOSS, and R. S. NYHOLM. J.

Chem. Soc. 1714 (1957). and Dr. J. P. Barthwal for their advice and en- 7. G. J. SUTTON. Australian J. Chem. 15,563 (1962). couragelnent and to the University Grants 8. G. E. COATES and D. RIDLEY. J. Chem. SOC. 166

(1964). Commission, New Delhi, for Retired 9. T. W. W~RTH and N. D A ~ ~ ~ S O N . J. An,. Chem. Sot. Scientist Award to one of us (S. N. S.). A 86,4325(1964). generous gift of a Hitachi Perkin-Elmer UV- 10. I. C. SMITH. Dissertation, Kansas State University,

Manhattan, Kansas. 1961. VIS s~ectrO~hOtOmeter the Perkin-E1mer 11. V. C. FARMER. Spectrochim. Acta, 8,374 (1957). Corporation, Norwalk, Connecticut, and of 12. C. N. R. RAO. Chemical application of infrared

spectroscopy. Academic Press, Inc., London. 1963. chemicals by Riker Laboratories, Northridge, p. 361.

California, is gratefully acknowledged. 13. S. MIZUSHIMA, I. NAKAGAWA, and J. V. QUAGLIANO. J. Chem. Phys. 23, 1367 (1955).

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Documents

Studies on complex compounds. V. Coordination compounds of mercury and biologically active amines