Reactivity of 6-methylthiopurin-8-ones. Properties of 6-methylsulphonylpurin-8-ones

摘要

470 J.C.S. Perkin IReactivity of 6-Methylthiopurin-8-ones. Properties of 6-Methylsulphon-yl purin-8-onesBy Felix Bergmann," Miriam Rahat. and llana Tamir. Department of Pharmacology, The Hebrew University-All 6-methylthiopurin-8-ones (except those bearing a 1 -methyl substituent, which decompose) are convertedby chlorine in methanol a t 0" into the corresponding sulphones. In a series of N-methyl6-methylthiopurin-8-ones.only the 1 -methyl, the 1.9- and 3.9-dimethyl, and the 3,7,9-trimethyl derivatives undergo thiohydrolysis. Incontrast, all the corresponding sulphones are attacked by hydrogen sulphide anion. A 6-methylsulphonylsubstituent weakens basicity and increases the acid strength of purines. In 6-methylsulphonylpurin-amp;one, anionformation follows the order N - 9 ---t N-7.A 3-methyl substituent, by virtue of reduction of the ring current inthe pyrimidine system, causes a diamagnetic shift of the 2-H signal.Hadassah Medical School, Jerusalem, IsraelPREVIOUS studies have suggested that introduction ofan 8-0x0-group may change the chemical reactivity of6-methylthiopurines profound1y.l This was shown for3-methyl-6-methylthiopurin-8-one (3), which was re-sistant to attack by hydrogen sulphide anion, whereas3-methyl-6-methylthiopurine itself underwent thiohydro-lysis readily.2 Furthermore, compound (3) was oxidisedby chlorine in absolute methanol at 0" to the correspond-ing sulphone (22),l whereas the analogue lacking the8-0x0-group was transformed under the same conditionsinto 6-chlor0-3-methylpurine.~In order to elucidate more thoroughly the factorsresponsible for this change in reactivity, we have nowexamined a number of N-methyl derivatives of 6-methyl-thiopurin-amp;one (1) (Table 1) .4TABLE 1Substitution patterns of the purines (1)-(28)Methylsubstituentsat positionsNone13791,93,73,97,93,7,96-Meth ylsul-phonyl-purin-8-ones(21)(25)(26) a(27)(28) bThiohydroZysis.-Six members of the series compound(l), its 3- (3), 7- (4), and 9-methyl derivatives (5), and1 D.Diller, 2. Neiman, and F. Bergmanil, J . Chem. SOC. ( C ) ,1968, 878.2. Neiman and F. Bergmann, Israel J . Chem., 1965, 3, 85.F. Bergmann, 2. Neiman, and M. Kleiner, J . Chem. SOC. ( C ) ,1966, 10.the 3,7- (7) and 7,9- (9) dimethyl derivatives are resistant to thiohydrolysis.On the other hand, fourmembers were converted into the corresponding 6-thioxo-purin-amp;ones: the 1-methyl derivative (2), the 1,9- (6)and 3,9- (8) dimethyl derivatives, and 3,7,9-trimethyl-6-methylthiopurinium cation (10) see Table 2(A) andScheme 11.Thus, with the exception of compound (2), all deriv-atives which can form anions, are resistant to attackby SH-. The negative charge on the anions not onlyrepels the nucleophilic reagent, but also reduces themesomeric effect of the N-methyl group, which plays afundamental role in nucleophilic attack on methyl-thiopurine~.~$6 In compounds (7) and (9), whichcannot form anions, polarisation of the 3- and 9-alkylsubstituents, respectively, places a partial negativecharge at N-1 (7b) and (9b) in Scheme 21.This effectmay be responsible for resistance to attack by SH-.A different situation is encountered with the 1,9-and 3,g-dimethyl derivatives. Above pH 6, compounds(6) and (8) exist as zwitterions? in which the effect ofthe negative charge at N-7 is neutralised by the positivecharge on the N-methyl groups (Scheme 1).3,7,9-Trimethy1-6-methylthio-8-oxopurinium cationcan be represented by the resonance forms (10a and b),analogous to (8a and b) (Scheme 1). The susceptibilityof (10) to nucleophilic attack is thus easily understood.The ready reaction of the 1-methyl derivative (2) issurprising. This compound is attacked not only underthe usual conditions (pH ca.l l ) , but also by aqueous* F. Bergmann, M. Rahat, and D. Lichtenberg, J.C.S. Perkin5 U. Reichman, F. Bergmann, D. Lichtenberg, and 2. Neirnan,U. Reichman, F. Bergmann, and 2. Neiman, J . Org. Chem.,I, 1973, 1226.J . Ovg. Chem., 1973, 38, 2066.1973, 38, 33671974 471hydrogen sulpliide, i.e. by a much weaker nucleophile(see Experimental section). The same applies to the1,g-dimethyl derivative (6), whereas (8) and (10) areMe H( 6 a ) 2 (12)Me( 6 b )Me(16)Me Me( 8a)Me Me(8b)(1Oa) IMe Me( l o b )Me Me(20)SCHEME 1resistant to hydrogen sulphide. Likewise the 3-methylderivative (3), although present as neutral molecule, isnot attacked by this reagent.D. Lichtenberg, F. Bergrnann, and 2. Neiman, J.C.S.Perkin I, 1973, 2445.It was thought that the reactions of (2) and (6) mightinvolve ring opening a t the lJ6-bond and recyclisationto (12) and (16) , respectively.However, monitoringof the U.V. spectrum during the reaction with hydrogensulphide revealed no other change besides the expectedrise ofLl,113X, in the conversion of (2) into (12).IStrong steric interference is observed between thel-methyl and 6-methylthio-s~bstituents.~ The reliefof steric strain that is achieved by conversion of (2)and (6) into (12) and (16), respectively, may be thedriving force for these reactions. Compounds (8) and(10) are much less reactive and undergo thiohydrolysisonly with the stronger nucleophile SH-.Reaction of 6-Methylthiopurin-8-ones with ChLorine.-In the reaction with chlorine in absolute methanolat or below O", the l-methyl derivatives (2) and (6)decompose.All other members of the series are con-verted into the corresponding 6-methylsulphonyl de-rivatives (21)-(28) (Table 3). In a few cases e g .in the conversion (7) --+ (25), the crude reactionmixture contained small amounts of a second, unstableproduct which was not isolated. These by-productsmay have been the 6-chloro-derivatives.In general, the reaction of 6-methylthiopurines withchlorine can take two different courses* (Scheme 3).Either the dichloro-derivative (B) reacts with solventto produce the sulphoxide (C) the latter again addschlorine (D) and is then converted by solvent into thesulphone (E), or (B) or (D) undergoes electrophilicsubstitution by C1+ to give (F), with elimination ofMeSCl (or MeSOC1).Under anhydrous conditions, theC. W. Noel1 and R. K. Robins, J . Amer. Chem. SOC., 1959,81,5997472 J.C.S. Perkin ITABLE 2Thiohydrolysis of 6-methylthio- and 6-methylsulphonyl-purin-8-onesN-MethylNo. of groups atpurine positions(A) 6-Methylthio a(2) 1(6) 1,9(8) 3,9(10) 3,7,9(21)(22) 3(23) 7(24) 9(25) 3,7(26) 3,9(27) 7,9(28) 3,7,9(B) 6-3Iethylsulphonyl cReaction 6-Thioxo- Crystal formtime (min) purine formed Yield (yo) M.p. ("C) and colour(12) 300 Rectangular 80(16) 80 300 YellowishplatesSH- 5H2S 5SH- (1H2S 10 prismsSH- 120 (18) 60 300 YellowprismsSH- 1 (go) 80 295 Yellowneedles300103030301203015GO60908090605080 300 300 300 300-300 300 300295Pale yellowneedlesYellowneed 1 e sYellowishprismsRectangularplatesYellowishprismsYellowprismsYellowishprismsYellowneedlesNeutral formr - - vA,,,./nni log E3872393302413442553502553322373372573352403332393402593442553362393502584.3 14.164.3 14.254.454.084.384.004.324-144-454-124.303-934.204-054.273.984.454-084.204.084-384.00Analysis of new 6-thioxopurin-amp;onesCalc.() Found ()c f h bsol;39.6 3.3 30.8 17.6 C,H,N,OS 39.3 3.4 31.1 17.842-65 3.9 28.7 16-542.7 4.8 28.3 16.742.6 4.2 28.3 16.642.8 4.3 28-65 17-045.7 4.8 26.7 15.2 C8Hl,N,0S 45.9 5.2 26.4 15.2ACompound C H N S Formula c H N 5(14) } 42.9 4.1 28.6 16.3 C,H,N,OS(19)(20)0 At room temp., compounds (2) and (6) reacted with both SH- and H,S; (8) and (10) reacted only with SH- and were resistantAll reactions with ammonium sulphide were carried out a t room temp., with thee See ref. 1.to H,S even at reflux temp.exception of the thiohydrolysis of (22), which required reflux temp.8 See ref.12.d See ref. 15. f See ref. 16.TABLE 3Formation of 6-methylsulphonylpurin-8-ones by chlorination of 6-methylthiopurin-onesReactiontime a(min)30306030105605Methanol 6-Methylsulphonyl-(ml per g) purine formed40 (21)12 (22)100 (23)40 (24)40 (26)10 (26)80 (27)10 (28)Calc.()Yield (()7077708036407040ALP. orkcomp. p. 300 300295245ca. 300("C)167 d194-1 95186Crystalform bPrismaticcolumnsPlatesPrismaticrodsPrismsHexagonalcolumnsPrismsRhombicplatesPrismsRB in solvent c --0.79 0.71 0.750.44 0.55 0.730-20 0-53 0.690-58 0.65 0-770.49 0.74 0.69(A) (B) (C) FluorescenceBrilliant violetViolet1 1 0-57 e 0.630.85 0.85 0.790-57 e 0.61Found ()L L r bsol; f 8 Compound C H N S Formula C H N 533.6 2-8 26.2 15.0 C,H,N403S 33.6 2.75 26-2 15.137.1 3.7 24.8 14.536.6 3.5 24-6 14.2(21) } 36.8 3.6 24-6 14.0 C,H8N40,S39.5 4.1 23.439.6 4-0 23.2 13.2 (24 1 39.7 4-1 23-1 13.2 C,HloN40,S35.7 2.8 20.8 6-8 C14H13N7010S 36.6 2.7 20.6637-1 3.1 20.2 6.6 Cl,Hl,N,O,OS 37.1 2.7 20.6(27)(26)(28)a All chlorinations at 0 to + 6'.b All methylsulphonyl derivatives were recrystallised from water. C For solvent conipositionsee Experimental section. These purines were isolated as picrates. e Decompose in solvent (B) 1974 473latter reaction usually takes place at or below O",whereas conversion into the sulphone requires warmingto 50-60".* The finding that the members of thepresent series are converted into sulphonyl derivativesat low temperatures suggests that electrophilic sub-stitution, to yield (F), is hampered because the 8-oxo-group reduces the electron density at C-6.Thiohydrolysis of 6-Methyls.ul+hony@urin-8-ones.-Allmembers of the 6-methylsulphonyl series (21)-(28)(Table 1) readily undergo thiohydrolysis to the corre-sponding 6-thiones (11)-(20) (Table 2B) and are thusmuch more susceptible to nucleophilic attack than thecorresponding 6-methylthio-derivatives.The same ap-plies to alkaline hydrolysis, as will be shown in a separatepublication. Apparently the strong electronegativecharacter of the methylsulphonyl group facilitatesnucleophilic substitution at C-6 and thus overcomes theadverse effect of anion formation in compounds (21)-Properties of 6-Methylsul~honyl~urin-8-ones.-( a)Tautomerism. The neutral forms of the mother sub-stance (21), its 7- (23) and 9- (24) methyl derivatives,and the 7,g-dirnethyl derivative (27) have very similarabsorption spectra (Table 4). Therefore they can berepresented by the common structure (I) (Scheme 4).The values of A, for the 3-methyl derivatives (22)and (25), which have the quinonoid structure (11)(Scheme 4), are higher than those of the purines re-presented by formula (I).structure (11) also explainsthe finding (Table 5) that the protons at C-2 in (22)and (25) are shielded relative to those in the derivatives(24) *Me Me Me Me( F )Me6+ pl q- s -CINM eI(+ MeSCl I ( E lSCHEME 3represented by structure (I). A similar relationshipis observed for the 6-methylthio-derivatives (3) and (7),although the difference between their 8 2 - ~ values andthat of (1) is much smaller (see Table 6). Calculationsaccording to the method of McWeeny9 show that thering current in the pyrimidine rings of compounds(3) and (22) is less than in compounds (1) and (21).Table 6 demonstrates that the ring current in the aro-matic pyrimidine ring of (21) is larger than in (1).It also indicates that the decrease in the J i value, dueto introduction of a 3-methyl substituent, is about twiceMeOS R'(21 I R'=R~HNo (23) RLMe, famp;HN ( 2 4 ) R'=H,RtMe(27) R'=RtMeR2(1)(22) R=HMeIo=s=oMe MeIY)SCHEME 4as large in (22) as in (3), in parallel with the relativeshifts of the 2-H signals.(b) Anion formation. All pK values in the 6-methyl-sulphonyl series are 1.4-2 units lower than those ofthe corresponding 6-met hylt hiopurin-ones (Table 4),owing to the pronounced electronegative character of themethylsulphonyl substituent .Anion formation in the sulphones (21)-(24) isaccompanied by a bathochromic shift of Amx.(Table 4),Dissociation of the 9-NH group in (23) is characterisedby AA,,,. 10 nm and pK 6.4. Ionisation of the 7-NHgroup in (24) leads to a AAmax. of 20 nm and a pk' of 7.5.From these values we may derive the sequence ofionisation of the mother substance (21). The lattercan form a mono- and a di-anion. The first dissociationstep of (21) is characterised by Ahmax. 12 nm and pK6.5, almost identical with the values for (23). Thedifference between the pK values of (23) and (24) is 1.1.We may thus estimate that the monoanion of (21) is atautonieric mixture of about 93 of the form bearingthe charge at N-9, and about 7 of the ion obtained bydissociation of the 7-NH group.Ionisation of the9-NH group is predominant because spreading of thecharge over both rings is now possible by participationof the pyrimidine nitrogen atoms. On the other hand,in the case of dissociation of 7-NH, a similar delocalisationof the negative charge would involve the carbon atomsof the pyrimidine ring. HMO calculations show,however, that the latter carry a positive charge. Anadditional factor making dissociation of 7-KH moredifficult may be loss of the hydrogen bond betweenR. McWecny, Mol. Phys., 1958, 1, 311474 J.C.S. Perkin ITABLE 4U.V. absorption niasiina and ph' values of 6-inethylsulphoiiylpuriin-8-onesA,,,./nni and log EN a7 - A -296 4.18316 4.1 1237 3.753 00 4.00297 4.0732 I -1.1 0242 3.71355 d (3.88)300 4.26250sh 3-56A7-A-308 4.2033 1 4.1 12452 3.63310 4.1 1317 4-12233 4-05A(A - N) C'+-I2 300-7 1 ti 313J 15+ l o i 3 0 6+20 300317338'279 305322 * (3.86)225 (4.33)pK for formation ofanion b cation1 h -- r6.5 (8.2) - 16.4 (8.35) -17.5 (9.0) - 18.5 (9.9) -k 0.3- 0.2CU. 8 - 7 f ca. 3.8(-1a N . - neutral form; A = anion; C = cation. b Figures in parentheses indicate the pK values of the corresponding B-niethylthio-derivatives 4 (see Table 1 ) . Approxi-mate Amax. of zwitterion; the compound decomposes above pH 9, before conversion into the zwitterioii is complete; therefore thevalue of log E is only approximate. Compound (26) forms also a dication with A,,,.317 nm. f pK for the conversion of cation intozwitterion.Compound (21) forms a dianion with Xmax. 325 nm (log E 4.19) ; A(A2 - A,) 17 nm; pK 11.9 pK for formation of dication. A,,,. of fixed cation. -4t pH values above 4, compound (28) decomposcs.TABLE 5K.rn.r. data of 6-inethylsulphonylpurin-8-ones in D,O at 70" Q:Coinpound positions N A A(N - A) C N A A(N - A) C N A A(N - A) C73 8.56 8.27 0.29 8.88 3-45 3.40 0.05 3.50 4-08 4.03 0-05 4.247 8.77 8-62 0.16 3.60 3.55 0.05 3.74 3.74 09 8.91 8.56 0.35 3.47 3-46 0.01 3-67 3-55 0.0282-H amp;-sO*Ye 6"Mer r Meat ,-. ~- I 1 bsol; r8.80 8.59 0.21 3-46 8-41 0.05 (21)(22,(23)(24)(25) 3,7 8.57 8.80 3.5fi 3.53 (3)4-07 4-24(7)3.73 3-77(9)3.93 3.93(26) 3,9 8-53 8.61 d 3.48 3.48 d (3)4*48c 4.50 d(37) 7,9 8.90 3-02 (7)3.79(9)3*62( B Y ) 3,7,9 8.92 e 3-70 (3) 4.6 13.864.05(7)(9)a For anion formation, NaOD was added; for cation, Cr.',.CO,H or I),SO, was used.The 8 values for the diaiiion were measured3.36. The corresponding values ford The dication ofa t room temp., because a t pH 14 the compound decomposed upon warming;the monomion a t room temp. were a2.= 8-52, 6 6-$OIamp; 3.37.compound (26) showed tS2-= 9.06, 8 ( l - ~ ~ z ~ e 3.57, amp;ge 4.67, a9-xe 4.04.8.27,C These values apply to the zwitterion (pH ca. 9.0).8 The value5 for fixecl cation a t pH 0.'7-NH and the 6-sulphonyl substituent see structures(111)-(IV) in Scheme 41.The second ionisation step in (21) involves mainly the7-NH group and is accompanied by a larger batho-chromic displacement (17 nm) of A,,,,..A similarsequence of anion formation (N-9 + N-7) has beenobserved previously for purin-8-ones lo and (?-methyl-thiopurin-8-0nes.~The diamagnetic shifts of the 2-H signals upon anionformation support the foregoing coiiclusions (Table 5).Thus A8(N - A)2-= = 0.16 p.p.m. for compound (23)and 0-35 for the 9-methyl isomer (24). For inono-anion formation of (21) the difference is 0.21, indicatingagain preferential dissociation of the 9-NH group, asin (23). For the transformation of the mono- into thedi-anion, A8(A, - A2)z-H = 0-25 p.p.m., i.e. the sum ofthe two shifts in (21) is approximately the same as thesum of the individual shifts in (23) and (24).Thegreater. upfield shift of the 2-H signal upon ionisation' 0 D. Lichtenberg, 17. Bergmann, M. Rahat, and 2. Neiman,J.C.S. Perkin I , 1972, 2950.of 7-NH may bc explained by the same factors whichare responsible for the relatively high pK of this group,TABLE 6Ring current (Ji) in purines *Ji Value for7 ----Appyriniidiiic imidazolone of neutralCon1 pou n t l ring ring riiolecule6-Methylthiopurin- 6-55 3.95 8.613-Methyl derivative (3) 5.66 3.46 8.483-Xethyl derivative (22) 5-06 6-72 8.56one (1)purin-8-one (21)6-Rkthylsulphonyl- 7.87 4.88 8.80* See Experinieiital section.i.e. participation of C-2 in charge distribution and lossof hydrogen bonding of the 6-sulphonyl substituent .The latter now exerts a stronger shielding effect on thepyrimidine proton.These considerations also explainthe large value of A8(N - A)~-H (0.29 p.p.m.) for (22)upon dissociation of 'I-'NH1974 475Protonation. -The bat hochromic shift indicatingcation formation in compounds (21), (23), (24), and(27) (Table 4) takes place only in extremely acidicR'YeMe Me Me Me(la) ( Y I t )SCHEME 5media (pH -1). The values, measured in 50sulphuric acid, were not significantly different from thoseof the neutral molecules and are not recorded in Table 5,because cation formation is still incomplete at pH -3.0H(291Protonation of these four purines may involve eithertlie 8-carbonyl group or the oxygen atoms of the 6-sul-phonyl substituent. HNO calculations of electrondensities indicate that the charge density on the sul-phonyl oxygen atoms (ca.-0.78) is substantially higherthan on the 8-carbonyl (ca. -0.42).On the other hand in the 3-methyl derivatives (22)and (25), a small hypsochromic displacement of A,,,.appears around pH 0. Protonation of these two com-pounds at N-1 would create an amidinium-like cationand would therefore cause deshielding of the 2-H signalby about 1 p.p.m.11J2 However the values of h8(N -C)2-= are 0.32 p.p.m. for (22) and 0.23 for (25) (Table 5).Thus protonation probably takes place a t position 9to yield the resonating structure (Va and b; R2 = H)(Scheme 5), (Va) making the greater contribution.This would explain the slight hypsochromic displace-ment of A,,,. and the paramagnetic shift of amp;-= in thecations of (22) and (25), so that these chemical shiftscome close to the 82-H values of the neutral moleculesrepresented by structure (I) (see Scheme 4 and Table 5 ) .Uponconversion of the zwitterion into the cation, A,, islowered to 338 nm; transformation into tlie dicationCompound (26) occupies a special position.l1 D.Lichtenberg, F. Bergmann, and 2. Neiman, IsraeZ J.l2 U. Reichman, F. Bergmann, I). Lichtenbcrg, and 2. Neiman,Chem., 1972, 10, 806.,J.C.S. Perkin I, 1973, 793.leads to A,,, 317 nm. This value is similar to thoseof the cations of (22) and (25) and not much differentfrom that of the fixed cation (28). The positivelycharged molecules of (22), (25), and (28) are shownin Scheme 5 (Va-b).This however leaves the processof conversion of zwitterion to cation in (26) unexplained.It may involve protonation of the 8-oxo-group (VI).If indeed the monocation of (26) is represented by (VI)and the dication by (VII), then the appearance of a7-NH group in the latter could explain the relativelylarge deshielding of the 2-H signal (A8 0.55 p.p.m.;Table 5). On the other hand, the transformationzwitterion structures (8a and b) in Scheme 11cation (VI) in Scheme 51 leaves the signal of 2-H in (2b)practically unchanged.Thesequence of N-methyl signals (upfield + downfield)for all molecular forms of the 6-met hylsulphonyl deriv-atives is 9 -+ 7 ---+ 3 (Table 5). This order is dueto the fact that the methyl groups at N-7 and N-9 areshielded by the 8-oxo-group. The absolute 6 valuesare close to those of the N-methyl substituents in thecorresponding 6-SMe derivatives: where the samesequence has been found. In both series, the 7-Megroup is deshielded relative to the 9-methyl group,because the former is under the influence of the mag-netic anisotropy of the substituent at C-6.Indeed,if this substituent is hydrogen, the two signals arepractically identical.l0The relative position of an N-methyl signal is onlyslightly influenced by the presence of other N-methylsubstituents (Table 5). Only compounds (26) and (28)show exceptional behaviour. Here the 3-methyl signalis shifted downfield by 045-060 p.p.m., relative tothe position of this signal in (22). Likewise, the9-methyl group is deshielded by 0-36-0-38 p.p.m.,relative to compound (24).These deviations can beascribed to steric interference between 3- and 9-methylsubstituents.13* l4The signals of the 6-methylsulphonyl group are 0.7-0-8 p.p.m. downfield of the SMe bands in the correspond-ing 6-methylthio-derivatives. In the 7-methyl deriv-atives (23), (25), (27), and (28), the MeSO, group isdeshielded by 0.10-020 p.p.m., relative to the othermembers of the series. We may attribute this para-magnetic shift to steric interference between the 7-and 6-substituents. An even greater steric effect maybe expected for 1 -met hyl-6-met h ylsulphonylpurines.However, so far we have been unable to synthesisesuch derivatives.Evidence for the Structures of New Purines.-Allnew methylsulphonylpurines were converted into thecorresponding 6-thioxopurin-amp;ones (1 1)-(20) (Table 2).The mother substance (11) l5 and its 1- (12),12 3- (13),land 9- (15) methyl 4 derivatives are known compounds.lH N.m.r.signals of NMe and MeSO, grou+s.l3 D. Lichtenberg, F. Bergmann, and 2. Neiman, J. Chem. SOC.l4 2. Neiman, F. Bergmann, and D. Lichtenberg, J. Chenz. SOC.l5 R. I. Robins, J. A~ner. Cham. Soc., 1958, 80, 6671.(C), 1971, 1676.(C), 1971, 1822476 J.C.S. Perkin IThe new members of the 6-thioxo-series (14) and (16)-(20)l were converted into the corresponding 6-methyl-thio-derivatives (4) and (6)-(10) (see Table l), whichhave been described b e f ~ r e . ~Noel1 and Robinss have reported a compoundderived from 6,8-bismethylthiopurine by reaction withchlorine in aqueous methanol, as ' 6-methylsulphonyl-8-oxopurine. ' However, the physical properties of thisproduct distinguish it clearly from (21) (see Experi-mental section).We conclude that the authors actuallyobtained the isomeric 8-methylsulphonylhypoxanthine(29). Indeed the absorption maximum of (29) (265nm) is closer to that of hypoxanthine (249 nm), whereasthe values of (1) and (21) are 299.5 and 296 nm, re-spectively. Presumably, 6,s-bismethylthiopurine isconverted into 6-chloro-8-methylsulphonylpurine, whichundergoes hydrolysis to (29).EXPERIMEST-4LM.p.s mere determined on a Fisher- Johns apparatus.Microanalyses were performed by M. Goldstein, Jerusalem,and F. Strauss, Oxford, England.U.V. spectra weremeasured on a Hitachi-Perkin-Elmer 124 spectrophoto-meter. pK Values were determined from a plot of A,,,as function of pH. For n.m.r. spectra, a JEOL MH-100instrument was used, with TSP (sodium 3-trimethylsilyl-2,2,3,3-2H4propionate; Merck, Sharp, and Dohme) asstandard. For paper chromatography by the descendingmethod, Whatman No. 1 paper was used with the followingsolvents: (A) (acidic) n-butanol-AcOH-H,O (12 : 3 : 5v/v) ; (B) (basic) propan-2-ol-Me2N*CHO-25 ammonia(13 : 5 : 2 v/v) ; (C) (neutral) ethanol-Me,N*CHO-water(3 : 1 : 1 v/v). Spots were located under a MineralightU.V. lamp ( A ca. 254 nm). All RF values are expressedrelative to theophylline (RP 0.68 in all solvents).General Procedures.-( 1) Preparation of 6-naetlzylsul~Jaonyl-pztrin-8-ones (2 1)-(28).Absolute methanol was saturatedat 0" with dry chlorine for 30 min. After addition of asuspension of the 6-methylthiopurin-8-one in cold methanol,the mixture was kept a t 0" while chlorine gas was bubbledthrough. Reaction times are specified in Table 3. Themixture was then concentrated in vacuo, first a t roomtemperature and finally on a water-bath a t 40". Theresidue was neutralised and the precipitate recrystallisedfrom water. With compounds (26) and (28), purificationproved difficult ; they were therefore characterised aspicrates. The properties of compounds (21)-(28) aredescribed in Table 3.(2) Thiohydrolysis. (a) Through a solution of ammonia(d 0.88) hydrogen sulphide gas was bubbled at roomtemperature for 30 min.After addition of the purine,more gas was passed through the solution for the periodstated in Table 2. The solution was then neutralised;the precipitate was filtered off and recrystallised from water.The properties of the 6-thioxopurin-amp;ones (1 1)-(20) aredescribed in Table 2.(b) Through a solution of the purine in water, hydrogenl6 H. P. Figeys and P. Dedieu, Theov. Chim. Acta, 1967, 9, 82.l7 G. Hafelinger, Tetrahedron, 1971, 27, 1635.l8 N. K. Ray and P. T. Narashina, Theor. Chim. Acta, 1966, 5,401.lS From ' Tables of Interatomic Distances and Configurations,'in ' Molecules and Ions,' Chem. SOC. Special Pztb?. No. 1 1 , 1958,s-9.sulpliide was bubbled for the time specified in Table 2.The precipitate formed was recrystallised from water.A solution of a 6-thioxopurin-8-onein dimethylformamide and methyl iodide (3 equiv.) wasgently refluxed for 30 min.The 6-methylthio-derivativesformed were isolated and purified as described previously.4Purines .-The following compounds were prepared byknown procedures : 6-thioxopurin-8-one (1 1) l6 and its1- (12),12 3- (13),l and 9- (15) methyl4 derivatives; 6-methylthiopurin-8-one (1) and its methyl derivatives ; 43-methyl-6-methylsulphonylpurin-8-one (22) ; 1 and 8-methylsulphonylhypoxanthine (29) ,* 82-= 8.14, 88-~~,3fIe3.40 (in Na,CO, a t pH 10).Calculation of Ring Currents.-Ring currents were cal-culated by the method of M~Weeny,~ as developed byFigeys and Dedieu.l6 These authors used (a) self-con-sistent iterative functions for the variation of the exchangeintegral @ with bond order, and (b) the relation of the latterwith bond length.They introduced iterative functionsfor different carbon-carbon bonds and for links of carbonwith nitrogen and oxygen, but not for carbon-sulphurand sulphur-oxygen bonds, which are needed for calcula-tions on the compounds included in Table 6.Hafelinger l7 has derived parameters for the resonanceintegrals of the carbon-sulphur bond, using HMO bond-bond polarisabilities in combination with bond order-bondlength relations. The iterative functions for the C-Sbonds which we have used in the present calculationswere based on Hafelinger's values, by assuming a linearrelation between exchange integral and bond length,and limiting the latter to the range 1.5-1.8 A.17 The(3) S-Methylation.@c-s = 0.405 + 0.077 Pc-s (9Pc=s = 0.517 + 0.063 Pc=s@-value of equation (i) ( P indicates bond order) was usedfor the S-Me bond; the p-value of equation (ii) was as-sumed to account better for the linkage between sulphurand the ' aromatic ' pyrimidine ring.Since the corresponding parameters for the S=O bondare not available, the exchange integral was derived fromthe proportionality between exchange and overlap inte-grals l8 equation (iii).Here SS=O represents the overlap(ii)integral for the 3px-orbital of sulphur and the 2px-orbitalof oxygen; Sc=a is the carbon-carbon overlap integral ofbenzene (0*245).18 Assuming rS=O = 0.145 A,19 and usingMulliken's 2o tables, we find SS=O = 0.168.The effect of the ring current emanates from the de-localised x-electrons in closed circuits ; its magnitudedepends on ring size.9 Since no crystallographic dataare available for the compounds included in Table 6, thearea of the two component rings was calculated from thedata of Ringertz 2l (for the pyrimidine system from X-raydata of purine and for the imidazolone system from thedata for uric acid).Initial parameters for all other bonds were taken fromthe data of Pullman and These parameterswere also used to calculate charge densities. All cal-*O R. S. Mulliken, C. A. Rieke, D. Orloff, and H. Orloff, J . Chem.Phys., 1949, 17, 1248.21 H. Ringertz, Acta Cvyst., 1966, 20, 397.*2 B. Pullman and A. Pullman, ' Quantum Biochemistry,'Interscience, London, 1963, p. 1081974 477culations were carried out with the computer program of Division, Niagara Falls, New York, for a gift of phosphorusFigeys and Dedieu,16 on a CDC 6400 digital computing pentasulphide. This research was supported by a grantmachine, using a Fortran IV program. from California Foundation for Biochemical Research(to M. R.).We thank Mr. R. Knafo for help with the U.V. measure-ments. We also thank Hooker Industrial Chemicals 3/1487 Received, 16th JuZy, 1973