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Analytical reactions of substituted pyrimidines
0039-9140/82/02w95-0!3so3.co/Q Copyright 0 I982 Perpamon Press Lid
rulunt~. Vol. 29. pp. 95 to IOX I982 Printed in Great Britam. All rights reserved
ANALYTICAL REACTIONS OF SUBSTITUTED PYRIMIDINES AJAI K.slNcxi* Department of Chemistry, M.D. University, Rohtak-124001, India BANI
MUKHEWE, R. P. S~NGHand M. KATYAL
Department of Chemistry, University of Delhi, Delhi-l 10007, India
(Received 3 Jury 1979. Reuised 15 June 1981. Accepted 6 Jury 1981) Qmry-Analytical
aspacts of the chemistry of substituted pyrimidincs are reviewed.
bituric and 2-thiobarbituric acids,” and polarography for phenobarbital and methyl phenobarbital in human plasma (detection limit 3.5-5.5 c1B/ml).19Diallyl and isopropyl barbituric acids can be potentiometrically titratedzo by using bromination reactions, the titrant being lead tetra-acetate in presence of excess of bromide. Phenobarbital, amobarbital, barbital, ally1 isobutyl barbituric acid, pentobarbital and secobarbital can be dc&rmined by dif’fffcntiating nonaqueous titration in methyl isobutyl ketone with sodium methoxide in -methanol mixture.21 Plienobarbital, amobarbital and secobarbital h&e been similarly determined in tetramethylurea2* and sulpholam? media with tetrabutylammonium hydroxide, the recovery for 0.1-0.3 mmole of compound being 97%104.4% and 99-lOlo/, respectively. In Emethyloxazolidin-2-one medium, barbitone, amylobarbitone and quinalbarbitone can also be titrated.” Barbituric acid in acetic acid medium can be titratedzs potentiometrically with mercury(I) acetate. A conductometric method for the determination of alo-, amo- and phenobarbital in pharmaceuticals has been reported. 26 Barbituric acid derivatives can be determined amperometrically2’ and coulometrically2* in aqueous and water-acetone media. Sodium barbiturate has been used to give a colour reaction with the product of reaction between chloramine-T and cyanide or thiocyanate. 29 2-Thiobarbituric acid has be-en used for amperometric titration of copper.3o
Pyrimidine can be considered as derived from pyr idine. It is a weaker base @K, 1.3) than the related compounds pyridazine, pyridine and imidazole. Considering the distribution of n-electron densities and the resonance hybrids representing the pyrimidine and pyridine molecules, it is inferred that the C5 position of pyrimidine should correspond to C, in pyridine and be the most susceptible to electrophilic attack. Similarly, positions 2, 4 and 6 in pyrimidine should correspond to 2 and 4 in pyridine. Substituents at these. positions should have comparable reactivities. l
Pyrimidine (pK, 1.3)
Pyridazine (pK, 2.33)
Pyridine (PK, 5.23)
Imidazole (pK, 7.2)
Pyrimidine derivatives and compounds in which the pyrimidine ring is a part of a more complex system were amongst the first compounds to be synthesized. They are vital compounds, widely distributed in living organisms. The chemistry2-a and the biochemical aspects 9- ‘* of the pyrimidincs have been extensively reviewed Recently, the stereochemistry of metal-pyrimidine complexes has also been reviewed. *5 The compounds have long been extensively used for analytical work, and these aspects are reviewed in this article, together with methods for analysis of the compounds themselves.
Violuric acids
Barbituric acids
Applications of violuric acids as analytical reagents have been reviewed by Singh et al.” Little work of analytical interest has since been reported.
Their determination and applications have been reviewed.16 The electrochemical methods are more sensitive than calorimetric and titrimetric methods for their determination. Differential pulse polarography has been used for determination of phenobarbital in blood (detection limit 0.1 ~g/ml),” and traces of bar* To whom correspondence
D&uric acids
Dilituric acid was first prepared in 1845.32 Many of its salts were examined32*33 but up to 1940 almost no work except its examination as a precipitant for or-
should be addressed. 95
96
AJAIK. S~NGH er
alkaline earth metals. The precipitates dissolve in alkaline medium; giving intense yellow colours. The compound is not very suitable for gravimetric determination, errors being as high as 2..50/, but the intense yellow colour of the potassium salt in alkaline medium is suitable for spectrophotometric determination at 410 or 420 nm.
ganic and inorganic bases” was reported.
09’ HO
al.
; H Dilituric acid (Snitrobarbituric acid)
Uracils
The nearly white crystalline acid gives a yellow solution in water (A,,, at 218 and 318 run, shoulder at 237 nm). The peaks at 218 and 318 nm have been attributed to primary and secondary ionization of the acid respectiveiy. 35 The acid decomposes explosively at about 185” on heating. Js The optical properties of the diliturates of primary and secondary amines and amino-acids have been utilized for identification of these compounds;36-3* alkaloids have been similarly characterized.39 Dilituric acid has been used for gravimetric determination of potassium*“*41 and indirect calorimetric determination of potassium4f*43 and of magnesium” from the absorbance of the residual dilituric acid after precipitation of the cation. Copper, nickel, cadmium and cobalt have been determined gravimetrically4s and lead, potassium and magnesium thermogravimetrically.46 The diliturates of the alkali metals,*’ silver, lead, thorium and manganese ‘s have also been examined thermogravimetrically. Their thermal stability is adequate for
X-Ray diffraction studiesS5 have shown that the arrangement of atoms in crystalline uracil (2&Ghydroxypyrimidine) is analogous to that in pyridone. Complexation of paliadium(I1) with uracil,56*s7 2-thiourac#’ and 6-methyl-2-thiouracils7 has been investigated photometrically. All the complexes have maximum absorption at 380 nm and are suitable for determination of palladium in acidic medium (pH < 2.0). Platinum and gold interfere. Uracil forms a 1:l metai:ligand complex, the other two form 1:2 complexes. s ’ SAminouracil forms a red complex with Ru(III) at pH 2.9-4.0 (&,, 480 nm. E 7.6 x 10’ l.mole-‘. cm-‘) on heating for 1 hr on a steam-bath. and a red complex with Os(VII1) in alkaline medium, without heating ss Its azo-dye (I) is used as an indicator in chelatometric titrationss8 of Zn, Cd and Hg. l-(2,4Dihydroxy-5-pyrimidylazo)-2-naphthol (II), obtained by coupling fl-naphthol with diazotized S-aminouracil, finds use as an indicators8 in titration of MoOt-. WO:- and PO:- with lead nitrate. / ..-(;I
OH
(1)
gravimetric determinations but the lithium, sodium and silver salts are too soluble for gravimetric purposes. The other metals can be determined with an average deviation of 0.5%. Rubidium and caesium can be determined by X-ray Ruorescence.49 The solubilities and thermolysis curves of ethylenediamine, polymethylenediamine and quinine diliturates have been examined.s0 Ethylenediamine and quinine can be determined gravimetrically, but the solubilities of the polymethylenediamine diliturates increase with increasing number of carbon atoms in the chain. Trimethylenediamine diliturate is an exception, however, being more soluble than expected, .presumably because of the internal hydrogen-bonding possible in this polymethylenediamine.5’ The crystalline nature of these organic salt diliturates makes it easy to identify them by X-ray powder diffraction methodsS2 Nutiu and co-workers53.54 synthesized the 2-thio derivative of dilituric acid and studied its analytical potentialities. It gives precipitates with alkali and
N?
/-\ -
N-N
\
OH
\
8 OH
(II)
5.6Diaminouracii G,,,., 255-265 nm, c = 2 x lo4 l.mole-‘.cm-‘) has been used for the spectrophotometric determination of Ru(II1) and 0s(VIII)s9~60 but tolerance for other platinum metals in these determinations is poor. CAminouracil can be hydrolysed by hydrochloric or ptoluenesulphonic acid to barbituric acid, which in turn can be condensed with Ehrlich’s reagent to give a benzylidene compound. This reaction has been used to determine the uracil colorimetrically.6’ Metal complexes of thiouracils are used for determination of the ligands. 5-Iodo-6~benzyland 5-butyl-6methyl-2-thiouracil can. be potentiometritally titrated with mercury(I1) acetate.62 2-Thiouracil. 6-methyl-2-thiouracil and t&dithiouracil can be similarly determined with silver nitrate.“3 Rtiifka and LyEka64 prepared 1,3-dimethylnitroso&aminouracil and characterized its salts with alkali metals, Cu(II), Ag(I), Hg(I), Hg(II), Ni(I1) and Pd(I1). Copper and nickel were determined gravi-
91
Analytical reactions of substituted pyrimidines
metrically and polarographically. 1,3-Dimethyl-4.5: diaminouracil (DAL)65 is a very selective and sensitive coiorimetric reagent for Co(i1) in alkaline medium (phosphate buffer, pH 11.2X but Fe(iIiX Cu(ii) and Ag(i) interfere at fairly low levels6’ A4iii) is coiorimetricaliy determined with 5-@-ethoxyanilino)-5,6dihydrouracii66 at pH 6.0-6.5. The complex (&,_ 520 nm) is extractable into a 1: 1 mixture of chloroform and toiuene. Orotic acids Orotic acid (2,6-dihydroxypyrimidine4carboxyiic acid, iii) was first studied analytically by Seller+ and Caidini6’ They determined sodium and potassium gravimetrically (at pH 6.5-8.5 and 3’ in 5 80% methanol or ethanol medium), the reagents being the highly soluble ammonium or substituted ammonium salts of erotic acid. Potassium can be determined in presence of NH:, Li+. Cuz+, alkaline earth metals A13+, Fe’+ and Ni’ +. Babbie and Wagner ‘* used N:N-dimethylethanolammonium orotate for the gravimetric determination of rubidium and caesium at pH 6.8. The error obtained was within *Oo.5% but the precipitation mixture had to be kept in the refrigerator for 2 hr before filtration. Several substituted erotic acids (as the N,Ndimethyiethanoiammonium salts) were extensively studied69 as potential reagents for precipitation of alkali metals, but it appeared that substitution generally results in an increase in the soiubihty of the alkali metal salts. However, it was found that uracil-Eacetic acid was selective for lithium, 5-ethylorotic acid for sodium and 5-methyluracii-3-acetic acid for potassium. COOH I
2.4,5-Trihydroxypyrimidine’* (isobarbituric acid) undergoes reactions similar to those of 2,3-dihydroxypyridine79**0 and reacts with iron(iii) to form blue 1:2 (il, 590 nm, l 600) and red 1:3 (i,,,, 500 nm, E 4.8 x 103) complexes at pH 2.0-4.5 and 4.6-11.0, respectively. The complexes can be used as acid-base indicators. iron is determined spectrophotometrically as the red complex. The Ru(iii)-@diamino-6-pyrimidinol complex (I,, 530 nm E 6.5 x 10’) formed in acidic medium is suitable for spectrophotometric determination of the metal, *i but the other platinum metals interfere and a preliminary separation is necessary. The iigand forms a highly unstable brown complex (i,, 470 nm) with Ck(Viii),*z but the addition of mercury(i1) perchlorate to this complex gives a pink coiour (&,., 500 rim; 0s:Hg:iigand = 1:2:2) which can be employed to determine osmium at pH 8.5-l 1.0. 2,4,5-Triamino-6-pyrimidinol is used to determine Ru(iii) and Os(VIiI) photometricaliy.*3~84 It reacts to give a purple complex (I,,, with ninhydrin” 555 nm) that can be used to determine it in plants. The complexation reactions of Fe(H), Co(H), Ru(Ii1) and Rh(ii1) with 2-amino-5-nitroso-4&-pyrimidinediol (IV) and 6-amino-5-nitroso-2,4-pyrimidinediol (V) have been studied spectrophotometrically and used in determination of these metais.s”s8 For ruthenium reagent (V) is more sensitive and sekctive than (IV) but for determination of iron (IV) is superior.*6s7 OH
OH
COOH I
Grotic acid forms 1: 1 complexes with copper(i1) at pH 3-8,” with cobalt(i1) at pH 6-10” and zinc at pH 6-9.” Nickel and cadmium also react. 2-Thioerotic acid has also been examined.73.‘4 it reacts with 17 metals in ammoniacal medium but with only a few at pH < 3, and gives better sensitivity than erotic acid.73 It has been used as developing reagent in the paper chromatographic separation of metal ions present in alloys.‘* Thallium(i) can be determined amperometrically or gravimetricaily74 without interference from Cu(ii), Co(ii) and Ni(i1). Pa&y et a1.75-77 have examined the complexes of 2-thio-orotic acid with Ag(i), Cu(I), Ti(i), Hg(i), Zn(Ii), Cd(H), Hg(ii), Fe(ii), Co(H), Ni(ii), Pd(O,ii,iV), Pt(O,Ii,iV) and Rh(i,iii). Other ppimidinofs Many other types of hydroxypyrimidines (pyrimidinols) also find wide use as analytical reagents.
4-Amino-5-nitroso_2,6_pyrimidinediol forms complexes with Fe(H), Co(H), Ru(iii) and Rh(iii)8”90 and can be used as an indicator for EDTA titration of iron.” The cobalt complex is inert and does not decompose when the solution is made 6N with respect to hydrochloric, perchloric or sulphuric acid, making the reagent very selective for cobalt. Generally, nitrosopyrimidinols have been found to be more sensitive than nitrosophenols for cobalt, iron and ruthenium. 4-Amino-5-nitroso-2,6-pyrimidinediol is the most sensitive for cobalt. iron(i1) gives a 1:4 complex with 2$diamino-5nitroso4pyrimidinol (I.,,,.,,653, E 2.0 x lo*) which is used for spectrophotometric determination of iron.9 1 2,4-Diamino-5-nitroso-&pyrimidinol forms a bluish green complex (A,, 650 nm) with iron(i1) and is used for the photometric determination of 0.9-3.7 ppm of the metal at pH 7.0-8.5 or as indicator in the EDTA titration.” it is also used for spectrophotometric determination of Ru(II1) and Rh(ili).sQ~“* This reagent and 2,6-diamino4pyrimidinol are fairly sensitive for nitrite detection93 by diazotixation and coupling to
98
AJAI
K. SINGH et al.
axe dyes. The closely related 2+diamino-6-pyrimidinol has long been used for this purpo5z9* Complexation with 2+nercap@5-(4-methoxybenxyl)4.6pyrimidinediol has been used for potentiometric, conductometric and amperometric titration of gold (III) in hydrochloric acid medium.9s AS-Diamino3mercapto+pyrimidinol acts as a very selective and sensitive reagent for detection and determination of osmium(VII1) in 1.0-6.OM sodium hydroxide.96 The red 1:2 (0s:ligand) complex (&,., 520 nm. E 2.7 x 104) obeys Beer’s law up to 8.0 ppm metal concentration. The iron and platinum group metals do not interfere. Ruthenium(II1) forms a red I:2 complex (L,,,, 540 nm, E 9.6 x 10’) on heating at pH 2.2-3.3, which is also used for determination of the metal, but the method is not very selective. Both the Ru and OS complexes are cationic and not extractable into organic solvents. 4,5-Diamino-2-methyl4pyrimidinol with rutheniumS9 and also gives complexes osmium6’ suitable for their spectrophotometric determination. Cu(II), Fe(H), Co(H), Ni(II), Ru(III), Rh(III), Pd(I1) and Os(VII1) form complexes with 4-amino-2-mercapto-5-nitroso-6-pyrimidinol. suitable for their spectrophotometric &termination.97-‘01 The complexes are not extractable into organic solvents, contain the metal and the l&and in 1: l-l : 3 ratio and conform to Beer’s law. A comparative study with 4-amino-2methyl-S-nitroso-6-pyrimidinol shows that the thiol derivative is more sensitive (e 6.1 x 10’4.8 x 104) and forms the metal complexes at higher pH. On the
Pyrimidinethiok Pyrimidine-tthiol, 2,4diaminopyrimidine-dthiol. 2.6-diaminopyrimidine-2-thiol and Zfidiaminopyrimidine-26-dithioI have been synthesized and explored for their analytical utility.‘04~10s They give many useful reactions with metal ions-the most significant (sensitivity given in parentheses, ppm) are those of pyrimidine-2-thiol with Pd (1) Cu (2), Hg+ (2), Bi (2) and Cd (10); 2,4-diaminopyrimidine&thiol with Pd (1) and Co (2); 2,6diaminopyrimidine-2-thiol with Co (1) and Pd (2) and 2,5diaminopyrimidine-2.6dithiol with Se4’ (0.4) and Bi (5). The introduction of the 2-amino group does not significantly a&t the reactivity, but a thiol group at Cg has a stronger reducing character than at C2. Chanio6 used 4,5-diamino-6-pyrimidinethiol for spectrophotometric determination of Se(IV) at pH 1.2-2.5 or still lower. The yellow complex formed (L,,, 380 nm E 1.92 x 104) conforms to Beer’s law from 0.1 to 2.5 ppm of selenium. The absorbance is measured within 30 min of addition of the reagent to avoid precipitation of elemental selenium. Though Bi(II1) and Te(IV) interfere, the presence of a 50-fold amount of transition metals does not al&t the determination. The method is used to determine traces of Se in semiconductors. Alkyl and aryl substituted 4,4,6-trimethyLlH,4Hpyrimidine-2-thiols (VI-XVII)‘o7 react selectively with palladium(H); forming yellow complexes extractable into non-polar solvents.
I (VI) (IX) (XI) (XII)
R R R R
= = = =
H; (VII) R = C,H,: (VIII) R = C,H,; n-C,H,; (X) = R = CzHS; C6H40CHs (anisyl) p-C6H4ND1 ; (XIII) R = C6H,, (cyclohexyl); (XIV) R = C,oH,(a-naphthyl): HzN
(XV) R =
/ \ CH, +- (XVI) R = p-C,H40CzH5 (phenacyl); SH
(XVII) R =
-2 -4‘N
H
OH
I
HzN
other hand, the methyl derivative is a more selective reagent, particularly for determination of iron. In a recent study, the blue water-soluble Fe(H)-1,3dimethyl-5-nitroso-2-thio-oxoperhydropyrimidine-4. 6-dione complex (L,,,, 630 nm ; metal-ligand 1: 3) has been found suitable for the spectrophotometric determinationlO’ of iron at pH 5.5-6.8. Large amounts of Cu(I1) and Co(I1) do not interfere. 6-Amino-2-benzylthio-5-nitroso-3.4-dihydropyrimidine’03 is also used for determination of iron(I1) at pH 5-6.5.
By extractive procedures, microgram amounts of Pd can be photometrically determinedio8-’ i3 in presence of milligram amounts of many metal ions, including platinum group metals. The abovementioned pyrimidine-Zthiols except (XV) are also used for the spectrophotometric determination of osmium.L’2-1’6 With the a-naphthyl derivative (XIV) palladium and osmium can each be determined in presence of large amounts of the other, because at acidity lower than 4M (hydrochloric acid) .
99
Analytical reactions of substituted pyrimidines osmium cannot be extracted with a chloroform solution of the thiol, but palladium can be completely extracted. Simultaneous determination, without prior separation of the metals, is also reported. Bismuth(III) and tellurium(W) react with the thiol (VI) forming orange-red (RIIUII500 nm, t 1.27 x lo*) and yellow (i.,,, 385 nm, e 1.26 x 104) complexes”’ respectively. The other derivatives (VII-XII) do not undergo compiexation with these metals. It appears that steric effects become operative because Bi and Te are larger than Pd. The orange-red bismuth complex formed in 1.5-3.OM perchloric acid is extracted into chloroform and the metal determined accurately in the concentration range 4.0-14.6 ppm. The tellurium complex (not extractable) is also used in determination of 1.5-7.0 ppm of the metal in 1.8-2.W perchloric acid medium. Palladium(H) and osmium(VIII) react with l-amino-, I-anilino- and 1_(2’.4’-dinitroanilino~,4,6trimethyl-lH,4H-2-pyrimidinethiols in 1:2 metalligand ratio, forming coloured complexes extractable into non-polar solvents. 1i * The ligands are very selective and the two metals can be determined in presence of large amounts of several ions, including FeWI), Co(H), Ni(II), Ru(IIIX Rh(III), Ir(II1) and I%(W). The anllino and 2’,#-dinitroanilino derivatives form two coloured complexes with ruthenium(III), iridium(III), rhodium(II1) and platinum(W), depending upon the acidity of the solution. ‘1g-121 The yellow complexes formed in acidic medium (pH < 3) are anionic and may be assigned structures of the type [MLsC$](for the Ru, Rh and Ir-complexes) and [MLCI* J- (for Pt), if LH represents the bidentate ligand. The extractable complexes formed at pH > 3 may be regarded as ML3 (for Rh, Ru and Ir) and ML&J, (for Pt). If reduction of Pt(IV) to Pt(I1) occurs during the complexation with thiol, the probable structures will be [PtLClJand PtLI for the yellow and the extractable complex respectively. Possibilities for use of these complexes for analytical purposes have been explored. Alloxans The reactions of alloxan (the degradation product of uric acid) with Ag(I), Hg(II), Pb(II), Fe(H) and Fe(II1) were reported 12z in 1940. Alloxan was subsequently used for the calorimetric determination of and identification of amino-acids’2* thiophene”’ after their chromatographic separation. It is, however, less sensitive than ninhydrin for this purpose. Alloxan is reduced to alloxantin (XVIII) by hydrogen sulphide. The reaction of iron(I1) with alloxantin
+CN--
to form dihydroxydiferrodialloxantin has been usedizs to detect iron (limit of identification 1.7 pg).
VW
(XVIII)
The l&and forms a yellow complex with molybdatelz6 (A 400 nm) at pH 3.3-3.9, which obeys Beer’s lawyp to 25 ppm of MO. Up to at least a IO-fold amount of tungstate, &fold amount of Zn(II), Co(II) or Ni(II) and 20-fold amount of Mn(I1) will not interfere, but Cr(III), oxalate, tartrate. citrate and vanadate should be absent. The thiosemicarbazone of alloxan has also been prepared and usediz7 for the detection of Cu(II), WI), AgfI), Hg(I1) and Ni(I1). 1,3-Dimethyl4imino-5-oximino alloxan (XIX) finds use as a reagent for spectrophotometric determination of copperiz9 (&_ 382 nm, 1: 1 complex at pH 7-9.5) and gravimetric determination of palladium.‘29 Fe(H), Co(H), Ni(I1) and Pd(I1) interfere in the copper determination. The red palladium complex is precipitated quantitatively at pH I-3 and dried at 100-l lo”. It may be dissolved in formamide and the metal determined calorimetrically. Cu(II), Au(III), Co(H), Ni(II), Os(ViII), lr(IV) and Pt(IV) interfere. Bipyrimidines
Bly and Mellon prepared’“~ 2,2’-bipyrimidine (m.p. 113-l 15”. pK 0.6) and studied’ 31 its complexation reactions with 30 metals, those with CufI) and Fe(II) being particularly useful. The absorption characteristics of the Fe(IIkomplex (i.,, 490 nm, c 5.0 x 103, stability constant 3.4 x 10’) are similar to those of Fe(H) complexes with 2,2’-bipyridyl and l,lO-phenanthroline. The complex is insensitive to pH in the range 26, contains metal and the ligand in 1:3 ratio (dominant species) and conforms to Beer’s law from I to 10 ppm of iron. Many ions, but not Cu(1). do not interfere.
5&+5~ 4
:
@S-S+;2 3’
Bipyrimidine
N
Dithiodipyrimidine
2J’Dithiodipyrimidine is used to determine the thiol grou~“~ and cyanide ioni33 on the basis of the reactions:
_N)-3+c+-S,. CI”\
100
AJAI K.
SINGH et al.
The absorbance of the thioi is measured photometrically and related to the concentration of RSH or CN-. Other subsritured pyrimidines The complexation of Fe(U), Co(IIX Ru(III) and Ir(II1) with S-nitroso-2,4,6_triaminopyrimidine has been studied.“4 The ligand is particularly useful for sensitive determination of ruthenium without interference from IO-fold amounts of other platinum metals. 2,4,5&i-Tetra-aminopyrimidine is also used for ruthenium and osmium determination. l 35 2-Amino-6-methylthio4pyrimidine carboxylic acid and 6-methoxy-2-methylthio4pyrimidine carboxylic acid”’ have been used for photometric determination of Ag(I)“’ and Mn(VII).‘3* respectively. The silv’er complex (1,, 375 nm, E 2.09 x lo’), obeys Beer’s law up to 5 x 10e4M Ag. However, many cations partially destroy the complex or are precipitated and adsorb the colour. The manganese determination is baaed on reduction of permanganate to green manganate (in alkaline medium) by 6-methoxy-2-methylthiopyrimidinedcarboxylic acid and measurement of the absorbance of the Mn(V1) at 580 nm (e 1.48 x 10’). Metal ions do not interfere unless they precipitate as hydroxides and adsorb some of the manganese. The fluorescence intensity of 4,6-bis(methylthio)& aminopyrimidine decreases in proportion to the amount of osmium tetroxide added to it.“’ I?t liquid-nitrogen temperature, as little as 10 ng of 0~04 per ml can be detected. The intensity is not affected by variation in pH from 3 to 12. In determination of 0~0~ at the I-ppm level, 10 ppm of Ir(III), 1 ppm of Fe(II1) and 1 ppm of Pd(I1) do not interfere. The metal : ligand ratio is 2 : 3. The decrease in fluorescence is attributed to complexation, with the first site of reaction at the NH2 group. Sheppard and Brigham14’ have synthesized 2-thio-5-keto4carbethoxy-1,3-dihydropyrimidine (XX) and its metal complexation reactions have been investigated.‘40.‘4’ The reagent is suitable for silver(I) in acidic medium (detection limit 1 part in 10”) and employed in its calorimetric determination.14’ For 20 gg of Ag(I), the tolerance limits (in mg) for other metals are: 2.0 for Fe(II1); 1.5 for Zn(II), Cu(II), Pb(II), Mn(I1) and Ni(I1); 1.0 for Cd(I1); 0.5 for Co(I1). COOC,H, 0
I
(XX) Conclusions In general, this class of reagents tends to be versatile in the sense of a wide range of application, but to
suffer from a lack of selectivity in many of the uses. A few of the reagents, however. do show considerable promise.
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23. T. L. Buxton and J. A. Caruso, Talanra, 1973.28.254. 24. G. M. Davis, J. E. Taphorn and J. A. Caruso. J. Pharm. Sci.. 1974. 63. 1136. 25. S. L. Belenkaya and G. P. Tikhomirova, Zacodsk. Lab.. 1971, 37, 907.
26. S. Stefek and M. ZahradniEtk. Cesk. Farm,, 1973, 22, 158. 27. L. Murea M. Beral, E. Cuciureanu and M. Madgearu Rev. Chim. Bucharest, 1966, 17, 46. 2s. J. R. Monforte and W. C. Purdy. Anal. Chim. Acta. 1970, 52, 25.
29. S. Nagashima, ibid.. 1978,99, 197. 30. R. J. Murphy and G. Svehla. ibid., 1978, 99, 115. 31. A. K. Singb M. Katyal and R. P. Singh. Curr. Sci. (Indiu). 1976. 45, 405. 32. A. Schlieper, Ann., 1845. 56, 24. 33. A. Baeyer, ibid., 1863, 127, 220. 34. C. E. Redemann and C. Niemann. J. Am. Chem. Sot.. 1940. 62, -590. 35. A. Berlin, M. E. Taylor and R. J. Robinson, Anal. Chim. Acta, 1961, 24,427. 36. E. M. Plain and B. T. Dewey, Ind. Eng. Chem.. Anal. Ed., 1943, 15. 534; 1946, 18, 1515. 37. Idem, Anal. Chem.. 1955.27, 307, 862. 38. J. Larsen, C. F. Poe and N. F. Witt, Mikrochim. Acra. 1949.351. 39. U. F. UlTelie, Chem. Weekblad. 1945, 41. 101. 40. C. L. deGraff and E. C. Noyons. ibid.. 1947. 43. 300.
Analytical reactions of substituted pyrimidines 41. F. Modreanu and N. Iorga, Anulele Stiint. Unir. “AI. 1. Cura” lasi, Sect. I., 1958. 4, 143. 42. R. Palo& V. Pavelka and M. Mbra. Naturwissenschafren. 1958. 45. 627. 43. I. G. Izhak, Zacwdsk. Lab, 1963, 29, 1060. 44. M. MPra, R. PalouS and V. Pavelka Collecrion C:ech. Ckem. Convnun.. 1960. 25,2240. . 45. I. Dick and F. Mihai. &ad. Rep. Populare Romine Bata Cercetari Stiint, Timisoada Ser. Stiinr. Chim.. 1956.3.67; 1957,4,61.67. 73. 46. A. Berlin and R. J. Robinson. Anal. Chim. Acta, 1961, 24,224. 47. M. W. Goheen and R. J. Robinson, ibid., 1964, 30,
101
84. P. Jain. M. Katyal and R. P. Singh, J. Indiun Chem. Sot.. 1980,56,944. 85. K. R. Mohan, G. Kanjilal, S. N. Mahajan and G. R. Rao, Curr. Sri. (India), 1976, 45, 154. 86. S. K. Kundra, M. Katyal and R. P. Singh. ibid., 1975, 44.81. 87. P. Mathur, M. Katyal, D. P. Goel and R. P. Singh, ibid., 1976, 45, 5 15. 88. A. K. Singh and R. P. Singh. Ann. Chim. (Rome), 1979, 69,409. 89. A. K. Singh. M. Katyal and R. P. Singh. ibid., 1975, 65, 109. 90. A. K. Singh, M. Katyal. K. C. Trikha and R. P. Singh, J. 1ndianChem. So& 1975,32, 891.
460.
48. idem, ibid., 1964, 31, 175. 49. K. E. Daugherty. M. W. Goheen, R. J. Robinson and J. I. Mueller, Anal. Chem., 1964, 36, 2373. 50. A. Berlin and R. J. Robinson, Anal. Chim. Acta. 1961,
91. C. W. McDonald and T. Rhodes. Mikrochim. Actu. 1971, 767. 92. P. Jain, M. Katyal and R. P. Singh. Ann. Chim.
24,319. 51. A. Gero, J. Am. Chem. Sot., 1954, 76, 5159. 52. A. Berlin, Thesis, University of Washington.
93. ldem, Acta Ciencia lndicu, 1977, 3, 218. 94. G. Gutzeit, He/c. Chim. Acta, 1927, 12, 713. 95. G. N. Shaposhnikova. V. M. Tarayan and N. G. Galfayan, Dokl. Akad. Nauk Arm. SSR, 1973, 56,
53. 54. 55. 56.
142. 96. A. K. Singh, M. Katyal and R. P. Singh, Indian
57. 58. 59. 60. 61. 62.
63. 64. 65.
Seattle. 1960. R. Nutiu and J. Scbe, Rev. Roum. Chim., 1971.16.919. R. Nutiu, I. Sebe and M. Nutiu, ibid., 1974, 19, 679. G. S. Parry, Acta Cryst., 1954, 7, 313. V. Croitoru and G. PoDa An. Univ. Bucuresti Ser. Stiint. Natur., 1966, 15, iii. Idem ibid., 1966, 15, 23. S. K. Kundra. _. P. Jain. _._.. V. Kushwaha M. Katyal and R. P. &i;gh. J. Indian C&em. S&., 1976, 33, 7i5. P. Jain. Ph.D. Thesis, University of Delhi. 1977. P. Jain, M. Katyal and R. P. Singh. Sci. Cult. (India), 1978, 44, 85. K. Nakaahima, Yakugaku Zasshi, 1977.97.906. S. Pinzauti, V. Dal Piaz and E. La Porta Farmaco. Ed. Prat, 1973, 28, 396;~EIecrroanal. Abstracts. 1974, 12, 3354. M. T. Neshkova, V. P. Izvekov, M. K. Pipay, K. T&h and E. Pungor, Anul. Chim. Acta, 1975. 75,439. E. RtiEka and K. LyEka, Collecrion Czech. Chem. Commun., 1962,27, 1790. E. RtiPka and V. Do&l, Mikrochim. Acta. 1968, 938.
66. D. A. Marshall and C. E. Meloan. Anal. Len.. 1969. 2. 595.
67. R. Selleri and 0. Caldini, Anal. Chem., 1961,33, 1944. 68. N. Z. Babbie and W. Wagner, Talanra, 1965, 12, 105. 69. B. C. Lewis and W. I. Stephen, Anal. Chim. Acra. 1966.36.234. 70. F. Capit&Garcia and A. Arrebola, Rec. Unir. ind. Sanmnder, 1965, 7. 241. 71. Idem, In/. Quim. Anal. Pura Apl. Ind., 1967, 21, 1. 72. ldem, Ars. Pharm., 1967, 8, 49. 73. F. Capitin-Garcia, M. R. Ceba and A. Arrebola, Inf: Quim. Anal. Pura Apl. lnd., 1971, 25, 111. 74. G. S. Pandey. Presinted at Seminar on Metallurgical Analysis, Raipur. India 7-8 Feb. 1976. 75. G. S: Pandey, G. C. Pandey, P. C. Nigam and U. Agarwala, Indian J. Chem., 1976, 15A, 884. 76. G. S. Pandey, P. C. Nigam and U. Agarwala, ibid., 1977, 16A, 537.
77. Idem, J. lnorg. Nucl. Chem., 1977, 39, 1877. 78. M. Katyal, S. K. Kundra and R. P. Singh, Mikrochim. Acta, 1974, 973. 79. V. Kushwaha, M. Katyal and R. P. Singh, Talanta, 1974, 21, 763. 80. V. Kuahwaha, Ph.D. Thesis, University of Delhi, 1973. 81. C. G. Raghuveer. T. Rhodes and C.‘W. McDonald, Mikrochim. Acta, 1974, 611. 82. S. K. Kundra, Ph.D. Thesis, University of Delhi, 1976. 83. E. L. Wittle, B. L. O’Dell, J. M. Vandenbelt and J. J. Pfiffner, J. Am. Chem. Sot., 1947,69, 1786.
(Rome), 1979,69,201.
97.
98. 99. 100. 101. 102.
J.
Chem.. 1976, 14A, 367. S. Przeszlakowski and M. Przeszlakowska Ann. Unit. Mariae Curie-SklodoH-ska, Dublin-Polonia Sect. AA, 1964. 19.69. S. Przeszlakowski and A. Waksmundzki, Chem. Anal. (Warsaw), 1964. 9, 69. ldem, ibid., 1964, 9, 919. V. Kushwaha, P. Jain, M. Katyal and R. P. Singh, J. Chinese Chem. Sot. (Taiwan), 1976,.23,43. P. Jain, V. Kushwaha. M. Katyal and R. P. Singh, Curr. Sri. (India), 1976, 45. 178. M. Tsuchiya and H. Sasaki, Nippon Kugaku Kaishi, 1977, 504.
103. K. Nakashima and H. Hirahara, Bunseki Kauaku,, _ 1977.26, 798. 104. A. Izquierdo and E. Bosch. Inform. Quim. Anal. (Madrid).
105. 106. 107. 108.
109. 110. 111. 112. 113. 114.
1971. 25. 203.
A. Izqui&do and M. D. Prat, ibid., 1973, 27, 38. F. L. Chan, Talanta, 1965, 11, 1019. R. A. Mathes. J. Am. Chem. Sot.. 1953.75. 1747. A. K. Singh, A. M. Bhatti and R. P. Sing;, Presented at the Annual Convention of Chemists, Roorkee. India, 18-21 Dec. 1975. A. K. Singh, M. Katyal, A. M. Bhatti and N. K. Ralhan. Talanta, 1976, 23, 337. D. Nath. A. K. Singh, M. Katyal and R. P. Singh, Indian J. Chem.. 1978. 16A. 451. P. Jain, M. Katyal, R. P. Singh and N. K. Ralhan, J. Insr. Chemists (India), 1978, 50, 217. B. Mukherjee, M. Phi/. Dissertation, University of Delhi, 1978. B. Mukherjee, R. P. Singh and A. K. Singh, J. lndian Inst. Sci. (Chem. Sec.), 1581, 62, in the p&s. A. K. Sinnh. R. P. Sinah and M. Katval. J. Indian _ Chem. SW:, i976,53,65%
115. A. K. Singh and R. P. Singh, ibid., 1979, 56, 423. 116. P. Jain. M. Katyal and R. P. Singh. J. lndian inst. Sci. (Chem. Sec.). 1979. 61, 195. 117. A. K. Singh, R. P. Singh and M. Katyal, Indian J. Chem., 1977, MA, 257. 118. A. K. Singh, M. Katyal, R. P. Singh and N. K. Ralhan, Talanta, 1976, 23, 851. 119. A. K. Singh, M. Katyal and R. P. Singh, Rec. Roum. Chim.. 1978.23, 1153. 120. ldem, lndian J. Chem., 1980, 19A, 712. 121. A. K. Sin& Ph.D. Thesis. Universitv of Delhi. 1976. 122. J. V. D&l& K. J. Keuding and VI Sindelhi, Chem. Obror., 1940, 15, 17. 123. K. H. V. French, J. Appl. Chem., 1952, 2, 664.
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AJAI K. SINGH er al.
124. J. Opienska-Blauth. H. Kowalska and M. Pietrusiewin, C’hem. Anul. (Wkuwl 1957.2. 266. 125. G. Denigb, Compr. Rend., 1925. 180, 519. 126. Y. Dutt and R. P. Singh. Proc. Indian Acad. Sci., 1962, 55, 195. 127. S. S. Guha-Sirkar and S. Satpathy, J. Indian Chem. sot.. 1954. 31, 450. 128. K. Burger. Tulanta, 1961, 8, 77. 129. ldem, Acta Chim. Acad. Sci. Hung., 1961, 36, 305. 130. D. D. Bly and M. C. Mellon, J. Org. Chem., 1962.27, 2945. 131. ldem, Anal. Chem., 1963.35, 1386. 132. D. R. Grassetti and J. F. Murray Jr., Anuf. Chim. Acra, 1969, 46. 139. 133. R. E. Humphrey and W. Hinze, Tulanra. 1971, IS, 491.
134. A. K. Singh, M. Katyal and R. P. Singh, J. Indian Chem. Sot.. 1976. U. 69 1. 135. P. Jai% M: Kat&.‘V. Kushwaha and R. P. Singh. Indian J. Chem.. 1976, 14A, 811. 136. G. D. Daves, Jr.. F. Baioeehi. R. K. Robins and C. C. Cheng, J. Org. Chem., 1%1,26,2755. 137. 0. K. Chung and C. E. Mcloan, Anul. Chem.. 1967. 39, 383. 138. Idem, ibid.. 1967, 39, 525. 139. S. Burchett and C. E. Meloan. Anal. Letr.. 1971. 4, 471. 140. S. E. Sheppard and H. R. Brigham, J. Am. Chem. Sot.. 1936.58, 1046. 141. J. H. Yoe and L. G. Overholser. fnd. Eng. Chrm.. Awl. Ed.. 1942 14, 148.
rulunt~. Vol. 29. pp. 95 to IOX I982 Printed in Great Britam. All rights reserved
ANALYTICAL REACTIONS OF SUBSTITUTED PYRIMIDINES AJAI K.slNcxi* Department of Chemistry, M.D. University, Rohtak-124001, India BANI
MUKHEWE, R. P. S~NGHand M. KATYAL
Department of Chemistry, University of Delhi, Delhi-l 10007, India
(Received 3 Jury 1979. Reuised 15 June 1981. Accepted 6 Jury 1981) Qmry-Analytical
aspacts of the chemistry of substituted pyrimidincs are reviewed.
bituric and 2-thiobarbituric acids,” and polarography for phenobarbital and methyl phenobarbital in human plasma (detection limit 3.5-5.5 c1B/ml).19Diallyl and isopropyl barbituric acids can be potentiometrically titratedzo by using bromination reactions, the titrant being lead tetra-acetate in presence of excess of bromide. Phenobarbital, amobarbital, barbital, ally1 isobutyl barbituric acid, pentobarbital and secobarbital can be dc&rmined by dif’fffcntiating nonaqueous titration in methyl isobutyl ketone with sodium methoxide in -methanol mixture.21 Plienobarbital, amobarbital and secobarbital h&e been similarly determined in tetramethylurea2* and sulpholam? media with tetrabutylammonium hydroxide, the recovery for 0.1-0.3 mmole of compound being 97%104.4% and 99-lOlo/, respectively. In Emethyloxazolidin-2-one medium, barbitone, amylobarbitone and quinalbarbitone can also be titrated.” Barbituric acid in acetic acid medium can be titratedzs potentiometrically with mercury(I) acetate. A conductometric method for the determination of alo-, amo- and phenobarbital in pharmaceuticals has been reported. 26 Barbituric acid derivatives can be determined amperometrically2’ and coulometrically2* in aqueous and water-acetone media. Sodium barbiturate has been used to give a colour reaction with the product of reaction between chloramine-T and cyanide or thiocyanate. 29 2-Thiobarbituric acid has be-en used for amperometric titration of copper.3o
Pyrimidine can be considered as derived from pyr idine. It is a weaker base @K, 1.3) than the related compounds pyridazine, pyridine and imidazole. Considering the distribution of n-electron densities and the resonance hybrids representing the pyrimidine and pyridine molecules, it is inferred that the C5 position of pyrimidine should correspond to C, in pyridine and be the most susceptible to electrophilic attack. Similarly, positions 2, 4 and 6 in pyrimidine should correspond to 2 and 4 in pyridine. Substituents at these. positions should have comparable reactivities. l
Pyrimidine (pK, 1.3)
Pyridazine (pK, 2.33)
Pyridine (PK, 5.23)
Imidazole (pK, 7.2)
Pyrimidine derivatives and compounds in which the pyrimidine ring is a part of a more complex system were amongst the first compounds to be synthesized. They are vital compounds, widely distributed in living organisms. The chemistry2-a and the biochemical aspects 9- ‘* of the pyrimidincs have been extensively reviewed Recently, the stereochemistry of metal-pyrimidine complexes has also been reviewed. *5 The compounds have long been extensively used for analytical work, and these aspects are reviewed in this article, together with methods for analysis of the compounds themselves.
Violuric acids
Barbituric acids
Applications of violuric acids as analytical reagents have been reviewed by Singh et al.” Little work of analytical interest has since been reported.
Their determination and applications have been reviewed.16 The electrochemical methods are more sensitive than calorimetric and titrimetric methods for their determination. Differential pulse polarography has been used for determination of phenobarbital in blood (detection limit 0.1 ~g/ml),” and traces of bar* To whom correspondence
D&uric acids
Dilituric acid was first prepared in 1845.32 Many of its salts were examined32*33 but up to 1940 almost no work except its examination as a precipitant for or-
should be addressed. 95
96
AJAIK. S~NGH er
alkaline earth metals. The precipitates dissolve in alkaline medium; giving intense yellow colours. The compound is not very suitable for gravimetric determination, errors being as high as 2..50/, but the intense yellow colour of the potassium salt in alkaline medium is suitable for spectrophotometric determination at 410 or 420 nm.
ganic and inorganic bases” was reported.
09’ HO
al.
; H Dilituric acid (Snitrobarbituric acid)
Uracils
The nearly white crystalline acid gives a yellow solution in water (A,,, at 218 and 318 run, shoulder at 237 nm). The peaks at 218 and 318 nm have been attributed to primary and secondary ionization of the acid respectiveiy. 35 The acid decomposes explosively at about 185” on heating. Js The optical properties of the diliturates of primary and secondary amines and amino-acids have been utilized for identification of these compounds;36-3* alkaloids have been similarly characterized.39 Dilituric acid has been used for gravimetric determination of potassium*“*41 and indirect calorimetric determination of potassium4f*43 and of magnesium” from the absorbance of the residual dilituric acid after precipitation of the cation. Copper, nickel, cadmium and cobalt have been determined gravimetrically4s and lead, potassium and magnesium thermogravimetrically.46 The diliturates of the alkali metals,*’ silver, lead, thorium and manganese ‘s have also been examined thermogravimetrically. Their thermal stability is adequate for
X-Ray diffraction studiesS5 have shown that the arrangement of atoms in crystalline uracil (2&Ghydroxypyrimidine) is analogous to that in pyridone. Complexation of paliadium(I1) with uracil,56*s7 2-thiourac#’ and 6-methyl-2-thiouracils7 has been investigated photometrically. All the complexes have maximum absorption at 380 nm and are suitable for determination of palladium in acidic medium (pH < 2.0). Platinum and gold interfere. Uracil forms a 1:l metai:ligand complex, the other two form 1:2 complexes. s ’ SAminouracil forms a red complex with Ru(III) at pH 2.9-4.0 (&,, 480 nm. E 7.6 x 10’ l.mole-‘. cm-‘) on heating for 1 hr on a steam-bath. and a red complex with Os(VII1) in alkaline medium, without heating ss Its azo-dye (I) is used as an indicator in chelatometric titrationss8 of Zn, Cd and Hg. l-(2,4Dihydroxy-5-pyrimidylazo)-2-naphthol (II), obtained by coupling fl-naphthol with diazotized S-aminouracil, finds use as an indicators8 in titration of MoOt-. WO:- and PO:- with lead nitrate. / ..-(;I
OH
(1)
gravimetric determinations but the lithium, sodium and silver salts are too soluble for gravimetric purposes. The other metals can be determined with an average deviation of 0.5%. Rubidium and caesium can be determined by X-ray Ruorescence.49 The solubilities and thermolysis curves of ethylenediamine, polymethylenediamine and quinine diliturates have been examined.s0 Ethylenediamine and quinine can be determined gravimetrically, but the solubilities of the polymethylenediamine diliturates increase with increasing number of carbon atoms in the chain. Trimethylenediamine diliturate is an exception, however, being more soluble than expected, .presumably because of the internal hydrogen-bonding possible in this polymethylenediamine.5’ The crystalline nature of these organic salt diliturates makes it easy to identify them by X-ray powder diffraction methodsS2 Nutiu and co-workers53.54 synthesized the 2-thio derivative of dilituric acid and studied its analytical potentialities. It gives precipitates with alkali and
N?
/-\ -
N-N
\
OH
\
8 OH
(II)
5.6Diaminouracii G,,,., 255-265 nm, c = 2 x lo4 l.mole-‘.cm-‘) has been used for the spectrophotometric determination of Ru(II1) and 0s(VIII)s9~60 but tolerance for other platinum metals in these determinations is poor. CAminouracil can be hydrolysed by hydrochloric or ptoluenesulphonic acid to barbituric acid, which in turn can be condensed with Ehrlich’s reagent to give a benzylidene compound. This reaction has been used to determine the uracil colorimetrically.6’ Metal complexes of thiouracils are used for determination of the ligands. 5-Iodo-6~benzyland 5-butyl-6methyl-2-thiouracil can. be potentiometritally titrated with mercury(I1) acetate.62 2-Thiouracil. 6-methyl-2-thiouracil and t&dithiouracil can be similarly determined with silver nitrate.“3 Rtiifka and LyEka64 prepared 1,3-dimethylnitroso&aminouracil and characterized its salts with alkali metals, Cu(II), Ag(I), Hg(I), Hg(II), Ni(I1) and Pd(I1). Copper and nickel were determined gravi-
91
Analytical reactions of substituted pyrimidines
metrically and polarographically. 1,3-Dimethyl-4.5: diaminouracil (DAL)65 is a very selective and sensitive coiorimetric reagent for Co(i1) in alkaline medium (phosphate buffer, pH 11.2X but Fe(iIiX Cu(ii) and Ag(i) interfere at fairly low levels6’ A4iii) is coiorimetricaliy determined with 5-@-ethoxyanilino)-5,6dihydrouracii66 at pH 6.0-6.5. The complex (&,_ 520 nm) is extractable into a 1: 1 mixture of chloroform and toiuene. Orotic acids Orotic acid (2,6-dihydroxypyrimidine4carboxyiic acid, iii) was first studied analytically by Seller+ and Caidini6’ They determined sodium and potassium gravimetrically (at pH 6.5-8.5 and 3’ in 5 80% methanol or ethanol medium), the reagents being the highly soluble ammonium or substituted ammonium salts of erotic acid. Potassium can be determined in presence of NH:, Li+. Cuz+, alkaline earth metals A13+, Fe’+ and Ni’ +. Babbie and Wagner ‘* used N:N-dimethylethanolammonium orotate for the gravimetric determination of rubidium and caesium at pH 6.8. The error obtained was within *Oo.5% but the precipitation mixture had to be kept in the refrigerator for 2 hr before filtration. Several substituted erotic acids (as the N,Ndimethyiethanoiammonium salts) were extensively studied69 as potential reagents for precipitation of alkali metals, but it appeared that substitution generally results in an increase in the soiubihty of the alkali metal salts. However, it was found that uracil-Eacetic acid was selective for lithium, 5-ethylorotic acid for sodium and 5-methyluracii-3-acetic acid for potassium. COOH I
2.4,5-Trihydroxypyrimidine’* (isobarbituric acid) undergoes reactions similar to those of 2,3-dihydroxypyridine79**0 and reacts with iron(iii) to form blue 1:2 (il, 590 nm, l 600) and red 1:3 (i,,,, 500 nm, E 4.8 x 103) complexes at pH 2.0-4.5 and 4.6-11.0, respectively. The complexes can be used as acid-base indicators. iron is determined spectrophotometrically as the red complex. The Ru(iii)-@diamino-6-pyrimidinol complex (I,, 530 nm E 6.5 x 10’) formed in acidic medium is suitable for spectrophotometric determination of the metal, *i but the other platinum metals interfere and a preliminary separation is necessary. The iigand forms a highly unstable brown complex (i,, 470 nm) with Ck(Viii),*z but the addition of mercury(i1) perchlorate to this complex gives a pink coiour (&,., 500 rim; 0s:Hg:iigand = 1:2:2) which can be employed to determine osmium at pH 8.5-l 1.0. 2,4,5-Triamino-6-pyrimidinol is used to determine Ru(iii) and Os(VIiI) photometricaliy.*3~84 It reacts to give a purple complex (I,,, with ninhydrin” 555 nm) that can be used to determine it in plants. The complexation reactions of Fe(H), Co(H), Ru(Ii1) and Rh(ii1) with 2-amino-5-nitroso-4&-pyrimidinediol (IV) and 6-amino-5-nitroso-2,4-pyrimidinediol (V) have been studied spectrophotometrically and used in determination of these metais.s”s8 For ruthenium reagent (V) is more sensitive and sekctive than (IV) but for determination of iron (IV) is superior.*6s7 OH
OH
COOH I
Grotic acid forms 1: 1 complexes with copper(i1) at pH 3-8,” with cobalt(i1) at pH 6-10” and zinc at pH 6-9.” Nickel and cadmium also react. 2-Thioerotic acid has also been examined.73.‘4 it reacts with 17 metals in ammoniacal medium but with only a few at pH < 3, and gives better sensitivity than erotic acid.73 It has been used as developing reagent in the paper chromatographic separation of metal ions present in alloys.‘* Thallium(i) can be determined amperometrically or gravimetricaily74 without interference from Cu(ii), Co(ii) and Ni(i1). Pa&y et a1.75-77 have examined the complexes of 2-thio-orotic acid with Ag(i), Cu(I), Ti(i), Hg(i), Zn(Ii), Cd(H), Hg(ii), Fe(ii), Co(H), Ni(ii), Pd(O,ii,iV), Pt(O,Ii,iV) and Rh(i,iii). Other ppimidinofs Many other types of hydroxypyrimidines (pyrimidinols) also find wide use as analytical reagents.
4-Amino-5-nitroso_2,6_pyrimidinediol forms complexes with Fe(H), Co(H), Ru(iii) and Rh(iii)8”90 and can be used as an indicator for EDTA titration of iron.” The cobalt complex is inert and does not decompose when the solution is made 6N with respect to hydrochloric, perchloric or sulphuric acid, making the reagent very selective for cobalt. Generally, nitrosopyrimidinols have been found to be more sensitive than nitrosophenols for cobalt, iron and ruthenium. 4-Amino-5-nitroso-2,6-pyrimidinediol is the most sensitive for cobalt. iron(i1) gives a 1:4 complex with 2$diamino-5nitroso4pyrimidinol (I.,,,.,,653, E 2.0 x lo*) which is used for spectrophotometric determination of iron.9 1 2,4-Diamino-5-nitroso-&pyrimidinol forms a bluish green complex (A,, 650 nm) with iron(i1) and is used for the photometric determination of 0.9-3.7 ppm of the metal at pH 7.0-8.5 or as indicator in the EDTA titration.” it is also used for spectrophotometric determination of Ru(II1) and Rh(ili).sQ~“* This reagent and 2,6-diamino4pyrimidinol are fairly sensitive for nitrite detection93 by diazotixation and coupling to
98
AJAI
K. SINGH et al.
axe dyes. The closely related 2+diamino-6-pyrimidinol has long been used for this purpo5z9* Complexation with 2+nercap@5-(4-methoxybenxyl)4.6pyrimidinediol has been used for potentiometric, conductometric and amperometric titration of gold (III) in hydrochloric acid medium.9s AS-Diamino3mercapto+pyrimidinol acts as a very selective and sensitive reagent for detection and determination of osmium(VII1) in 1.0-6.OM sodium hydroxide.96 The red 1:2 (0s:ligand) complex (&,., 520 nm. E 2.7 x 104) obeys Beer’s law up to 8.0 ppm metal concentration. The iron and platinum group metals do not interfere. Ruthenium(II1) forms a red I:2 complex (L,,,, 540 nm, E 9.6 x 10’) on heating at pH 2.2-3.3, which is also used for determination of the metal, but the method is not very selective. Both the Ru and OS complexes are cationic and not extractable into organic solvents. 4,5-Diamino-2-methyl4pyrimidinol with rutheniumS9 and also gives complexes osmium6’ suitable for their spectrophotometric determination. Cu(II), Fe(H), Co(H), Ni(II), Ru(III), Rh(III), Pd(I1) and Os(VII1) form complexes with 4-amino-2-mercapto-5-nitroso-6-pyrimidinol. suitable for their spectrophotometric &termination.97-‘01 The complexes are not extractable into organic solvents, contain the metal and the l&and in 1: l-l : 3 ratio and conform to Beer’s law. A comparative study with 4-amino-2methyl-S-nitroso-6-pyrimidinol shows that the thiol derivative is more sensitive (e 6.1 x 10’4.8 x 104) and forms the metal complexes at higher pH. On the
Pyrimidinethiok Pyrimidine-tthiol, 2,4diaminopyrimidine-dthiol. 2.6-diaminopyrimidine-2-thiol and Zfidiaminopyrimidine-26-dithioI have been synthesized and explored for their analytical utility.‘04~10s They give many useful reactions with metal ions-the most significant (sensitivity given in parentheses, ppm) are those of pyrimidine-2-thiol with Pd (1) Cu (2), Hg+ (2), Bi (2) and Cd (10); 2,4-diaminopyrimidine&thiol with Pd (1) and Co (2); 2,6diaminopyrimidine-2-thiol with Co (1) and Pd (2) and 2,5diaminopyrimidine-2.6dithiol with Se4’ (0.4) and Bi (5). The introduction of the 2-amino group does not significantly a&t the reactivity, but a thiol group at Cg has a stronger reducing character than at C2. Chanio6 used 4,5-diamino-6-pyrimidinethiol for spectrophotometric determination of Se(IV) at pH 1.2-2.5 or still lower. The yellow complex formed (L,,, 380 nm E 1.92 x 104) conforms to Beer’s law from 0.1 to 2.5 ppm of selenium. The absorbance is measured within 30 min of addition of the reagent to avoid precipitation of elemental selenium. Though Bi(II1) and Te(IV) interfere, the presence of a 50-fold amount of transition metals does not al&t the determination. The method is used to determine traces of Se in semiconductors. Alkyl and aryl substituted 4,4,6-trimethyLlH,4Hpyrimidine-2-thiols (VI-XVII)‘o7 react selectively with palladium(H); forming yellow complexes extractable into non-polar solvents.
I (VI) (IX) (XI) (XII)
R R R R
= = = =
H; (VII) R = C,H,: (VIII) R = C,H,; n-C,H,; (X) = R = CzHS; C6H40CHs (anisyl) p-C6H4ND1 ; (XIII) R = C6H,, (cyclohexyl); (XIV) R = C,oH,(a-naphthyl): HzN
(XV) R =
/ \ CH, +- (XVI) R = p-C,H40CzH5 (phenacyl); SH
(XVII) R =
-2 -4‘N
H
OH
I
HzN
other hand, the methyl derivative is a more selective reagent, particularly for determination of iron. In a recent study, the blue water-soluble Fe(H)-1,3dimethyl-5-nitroso-2-thio-oxoperhydropyrimidine-4. 6-dione complex (L,,,, 630 nm ; metal-ligand 1: 3) has been found suitable for the spectrophotometric determinationlO’ of iron at pH 5.5-6.8. Large amounts of Cu(I1) and Co(I1) do not interfere. 6-Amino-2-benzylthio-5-nitroso-3.4-dihydropyrimidine’03 is also used for determination of iron(I1) at pH 5-6.5.
By extractive procedures, microgram amounts of Pd can be photometrically determinedio8-’ i3 in presence of milligram amounts of many metal ions, including platinum group metals. The abovementioned pyrimidine-Zthiols except (XV) are also used for the spectrophotometric determination of osmium.L’2-1’6 With the a-naphthyl derivative (XIV) palladium and osmium can each be determined in presence of large amounts of the other, because at acidity lower than 4M (hydrochloric acid) .
99
Analytical reactions of substituted pyrimidines osmium cannot be extracted with a chloroform solution of the thiol, but palladium can be completely extracted. Simultaneous determination, without prior separation of the metals, is also reported. Bismuth(III) and tellurium(W) react with the thiol (VI) forming orange-red (RIIUII500 nm, t 1.27 x lo*) and yellow (i.,,, 385 nm, e 1.26 x 104) complexes”’ respectively. The other derivatives (VII-XII) do not undergo compiexation with these metals. It appears that steric effects become operative because Bi and Te are larger than Pd. The orange-red bismuth complex formed in 1.5-3.OM perchloric acid is extracted into chloroform and the metal determined accurately in the concentration range 4.0-14.6 ppm. The tellurium complex (not extractable) is also used in determination of 1.5-7.0 ppm of the metal in 1.8-2.W perchloric acid medium. Palladium(H) and osmium(VIII) react with l-amino-, I-anilino- and 1_(2’.4’-dinitroanilino~,4,6trimethyl-lH,4H-2-pyrimidinethiols in 1:2 metalligand ratio, forming coloured complexes extractable into non-polar solvents. 1i * The ligands are very selective and the two metals can be determined in presence of large amounts of several ions, including FeWI), Co(H), Ni(II), Ru(IIIX Rh(III), Ir(II1) and I%(W). The anllino and 2’,#-dinitroanilino derivatives form two coloured complexes with ruthenium(III), iridium(III), rhodium(II1) and platinum(W), depending upon the acidity of the solution. ‘1g-121 The yellow complexes formed in acidic medium (pH < 3) are anionic and may be assigned structures of the type [MLsC$](for the Ru, Rh and Ir-complexes) and [MLCI* J- (for Pt), if LH represents the bidentate ligand. The extractable complexes formed at pH > 3 may be regarded as ML3 (for Rh, Ru and Ir) and ML&J, (for Pt). If reduction of Pt(IV) to Pt(I1) occurs during the complexation with thiol, the probable structures will be [PtLClJand PtLI for the yellow and the extractable complex respectively. Possibilities for use of these complexes for analytical purposes have been explored. Alloxans The reactions of alloxan (the degradation product of uric acid) with Ag(I), Hg(II), Pb(II), Fe(H) and Fe(II1) were reported 12z in 1940. Alloxan was subsequently used for the calorimetric determination of and identification of amino-acids’2* thiophene”’ after their chromatographic separation. It is, however, less sensitive than ninhydrin for this purpose. Alloxan is reduced to alloxantin (XVIII) by hydrogen sulphide. The reaction of iron(I1) with alloxantin
+CN--
to form dihydroxydiferrodialloxantin has been usedizs to detect iron (limit of identification 1.7 pg).
VW
(XVIII)
The l&and forms a yellow complex with molybdatelz6 (A 400 nm) at pH 3.3-3.9, which obeys Beer’s lawyp to 25 ppm of MO. Up to at least a IO-fold amount of tungstate, &fold amount of Zn(II), Co(II) or Ni(II) and 20-fold amount of Mn(I1) will not interfere, but Cr(III), oxalate, tartrate. citrate and vanadate should be absent. The thiosemicarbazone of alloxan has also been prepared and usediz7 for the detection of Cu(II), WI), AgfI), Hg(I1) and Ni(I1). 1,3-Dimethyl4imino-5-oximino alloxan (XIX) finds use as a reagent for spectrophotometric determination of copperiz9 (&_ 382 nm, 1: 1 complex at pH 7-9.5) and gravimetric determination of palladium.‘29 Fe(H), Co(H), Ni(I1) and Pd(I1) interfere in the copper determination. The red palladium complex is precipitated quantitatively at pH I-3 and dried at 100-l lo”. It may be dissolved in formamide and the metal determined calorimetrically. Cu(II), Au(III), Co(H), Ni(II), Os(ViII), lr(IV) and Pt(IV) interfere. Bipyrimidines
Bly and Mellon prepared’“~ 2,2’-bipyrimidine (m.p. 113-l 15”. pK 0.6) and studied’ 31 its complexation reactions with 30 metals, those with CufI) and Fe(II) being particularly useful. The absorption characteristics of the Fe(IIkomplex (i.,, 490 nm, c 5.0 x 103, stability constant 3.4 x 10’) are similar to those of Fe(H) complexes with 2,2’-bipyridyl and l,lO-phenanthroline. The complex is insensitive to pH in the range 26, contains metal and the ligand in 1:3 ratio (dominant species) and conforms to Beer’s law from I to 10 ppm of iron. Many ions, but not Cu(1). do not interfere.
5&+5~ 4
:
@S-S+;2 3’
Bipyrimidine
N
Dithiodipyrimidine
2J’Dithiodipyrimidine is used to determine the thiol grou~“~ and cyanide ioni33 on the basis of the reactions:
_N)-3+c+-S,. CI”\
100
AJAI K.
SINGH et al.
The absorbance of the thioi is measured photometrically and related to the concentration of RSH or CN-. Other subsritured pyrimidines The complexation of Fe(U), Co(IIX Ru(III) and Ir(II1) with S-nitroso-2,4,6_triaminopyrimidine has been studied.“4 The ligand is particularly useful for sensitive determination of ruthenium without interference from IO-fold amounts of other platinum metals. 2,4,5&i-Tetra-aminopyrimidine is also used for ruthenium and osmium determination. l 35 2-Amino-6-methylthio4pyrimidine carboxylic acid and 6-methoxy-2-methylthio4pyrimidine carboxylic acid”’ have been used for photometric determination of Ag(I)“’ and Mn(VII).‘3* respectively. The silv’er complex (1,, 375 nm, E 2.09 x lo’), obeys Beer’s law up to 5 x 10e4M Ag. However, many cations partially destroy the complex or are precipitated and adsorb the colour. The manganese determination is baaed on reduction of permanganate to green manganate (in alkaline medium) by 6-methoxy-2-methylthiopyrimidinedcarboxylic acid and measurement of the absorbance of the Mn(V1) at 580 nm (e 1.48 x 10’). Metal ions do not interfere unless they precipitate as hydroxides and adsorb some of the manganese. The fluorescence intensity of 4,6-bis(methylthio)& aminopyrimidine decreases in proportion to the amount of osmium tetroxide added to it.“’ I?t liquid-nitrogen temperature, as little as 10 ng of 0~04 per ml can be detected. The intensity is not affected by variation in pH from 3 to 12. In determination of 0~0~ at the I-ppm level, 10 ppm of Ir(III), 1 ppm of Fe(II1) and 1 ppm of Pd(I1) do not interfere. The metal : ligand ratio is 2 : 3. The decrease in fluorescence is attributed to complexation, with the first site of reaction at the NH2 group. Sheppard and Brigham14’ have synthesized 2-thio-5-keto4carbethoxy-1,3-dihydropyrimidine (XX) and its metal complexation reactions have been investigated.‘40.‘4’ The reagent is suitable for silver(I) in acidic medium (detection limit 1 part in 10”) and employed in its calorimetric determination.14’ For 20 gg of Ag(I), the tolerance limits (in mg) for other metals are: 2.0 for Fe(II1); 1.5 for Zn(II), Cu(II), Pb(II), Mn(I1) and Ni(I1); 1.0 for Cd(I1); 0.5 for Co(I1). COOC,H, 0
I
(XX) Conclusions In general, this class of reagents tends to be versatile in the sense of a wide range of application, but to
suffer from a lack of selectivity in many of the uses. A few of the reagents, however. do show considerable promise.
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134. A. K. Singh, M. Katyal and R. P. Singh, J. Indian Chem. Sot.. 1976. U. 69 1. 135. P. Jai% M: Kat&.‘V. Kushwaha and R. P. Singh. Indian J. Chem.. 1976, 14A, 811. 136. G. D. Daves, Jr.. F. Baioeehi. R. K. Robins and C. C. Cheng, J. Org. Chem., 1%1,26,2755. 137. 0. K. Chung and C. E. Mcloan, Anul. Chem.. 1967. 39, 383. 138. Idem, ibid.. 1967, 39, 525. 139. S. Burchett and C. E. Meloan. Anal. Letr.. 1971. 4, 471. 140. S. E. Sheppard and H. R. Brigham, J. Am. Chem. Sot.. 1936.58, 1046. 141. J. H. Yoe and L. G. Overholser. fnd. Eng. Chrm.. Awl. Ed.. 1942 14, 148.