摘要:
1977 1141Torsional Barriers in 6-Amino-5-formamidopyrimidin-4(3H)-onesBy Felix Bergmann and Miriam Rahat, Department of Pharmacology, The Hebrew University, HadassahMedical SchoolMordecai Rabinovitz, Department of Organic Chemistry, The Hebrew University, Jerusalem, IsraelThe chemical shifts of 6-amino-5-formamidopyrimidin-4(3H)-ones show that two rotamers are present in solution,their formyl signals being of unequal intensity. The two forms are stable both as neutral molecules and as cations,in contrast to the behaviour of N-alkylformamides. Exchange rates and barriers to rotation have been calculated.The reasons for the unequal distribution of the rotamers are discussed.6-AMINO-5-FORMAMIDOPYRIMIDIN-4(3H)-ONES are Usefulintermediates in the synthesis of hypoxanthines andrelated purines.They belong to the class of N-substitu-ted formamides which have served as classical models forthe study of exchange rates of amide r~tamers.l-~ Herewe report the n.m.r. spectra of four derivatives of 6-amino-5-formamidopyrimidin-4(3H)-one and of one ura-cil derivative (5). In these derivatives the formamido-group, owing to a dipolar contribution, exhibits a slowrotation about the C-N bond. This process is tempera-ture-dependent and its rate is within the n.m.r. time-scale.The chemical shifts of the neutral and cationic formsof compounds (1)-(5) are given in Table 1. Assignmentswere made as follows. In the spectra of the cations of(1) and (2), the formyl bands can be identified by com-H. Gutowsky and C.H. Holm, J . Chem. Phys., 1956, 25,1228.parison with the cations of (3) and (4) (see Table 1). Inthat of the neutral form of (2), the 2-H band was assignedwith the aid of the nuclear Overhauser effect. Irradi-ation at the frequency of the NMe signal ( 6 3.47) in-creased the area of the band at 8.24 by 44%, while thesum of the areas of the bands at 6 8.29 and 7.99 wasenlarged by an amount not more than corresponded tothe intrinsic error in the measurements (ca. 10%). Inthe spectrum of the neutral form of (l), assignment of thethree signals between 6 8.14 and 7.85 was based on inte-gration. The area underneath the band at 6 7.85 wasequal to the sum of the areas of the bands at 8.14 and8.02.Table 1 shows that in the spectra of all compoundsA. G.Whittaker and S. Siegal, J . Chem. Phys., 1965, 42,T. Drakenberg and S. Forsen, J . Phys. Chem., 1970, 74. 1 .33201142 J.C.S. Perkin Istudied two formyl proton signals are observed, while the two bands serve as a measure of the population distribu-protons in the pyrimidine moiety (2-H, 3-Me, and 2-SMe) tion in the equilibrium (A) (B). It is assumed thatR~-N A NHaCHO ,$AN YN HH(C)[cations of ( I )give rise to singlets.in both neutral andH( A ' )0H( 010Hin the ground state, form (A) is stabilised by an intra-molecular hydrogen bond and therefore is the predomin-ant conformer, i.e. it is represented by the lower fieldsignal (Figure).8.188-28 JL39'c 60 'C 74'C 84' CCoalescence of the two formyl signals of 6-amino-5-formamido-2-thiouracil (5) with increasing temperature ; the rotamer withthe more shielded formyl proton disappears around 84 "CIn general, acid lowers the barrier for rotation aboutthe amide bond to such a degree that interconversion ofconformers becomes very rapid and the signals coale~ce.~-~In N-methylformamide this applies to both the formyland the NMe signals.8 Although in the cations of suchsimple amides the proton is bound predominantly to the( € 1Separate formyl signals are presentcationic forms.TABLE 1U.v. and n .m. r. spectra of 6-amino-5-f ormamidopyrimidin-4 (3H) -oneshnllx.lnm-7 N a Aa C a263 266 257260 255 256231 266274228 i27524314 > - 228112 6257285232295PK- 1.4>130- 1.4>13#-28.0 + 1.76 (neutral form) *ZH CHO ANMe SM: Ratio7.85 8.14 4 : 38.028.24 8.29 3.47 6 : 17.998.11 2.61 6 : 57.938.15 3.42 2.60 4 : 17.938.18 5 : 17.876 ( cation) d'2-H CHO NMe SM; Ratio"9.08 f 8.52 4 : 88.349.109 8.54 3.848.358.43 2.79 6 : 58.278.53 3.75 2.87 4.5: 18.308.84 j 7 : 18.53N, neutral molecule; A, anion; C, cation.b Measurements at 30 "C in (CD,),SO-D,O (9 : 1 v/v). Approximate evaluationd In CF,CO,D.VThese measurements have to beTherefore evaluation of the ratioThe anion of (3) was studied in buffer of pH 11 : GCHO 8.34 and 7.97; 8 9 ~ ~ 2.50; tautomer3 Since this compound is only very slightly soluble in CF,CO,H, the chemical shiftsfrom the areas underneath the two formyl signals.performed rapidly, since in acidic solutions slow cyclisation to 1-methylhypoxanthine takes place.[(A)] : [(B)] in the cation is not possible.ratio 6 : 1.of the cation were determined in 27~-D,S0,.The first figure always relates to the more deshielded band.Unstable a t pH values above 13.f Similar chemical shifts were obtained in 2'7~-D,S0,.8 Unstable in alkaline solutions.The two formyl bands have different shapes andintensities, owing to the presence of unequal populationsof the two rotamers (Figure). The areas underneath theM. Liler, J . Chem. Soc. (B), 1971, 334.L. M. Jackman, T. E. Kavanagh, and R. C. Haddon, Org.G. Fraenkel and C. Niemann, Proc. Nat. Acad. Sci. U.S.A.,Magnetic Resonance, 1969, 1, 109.1958, 44, 688.carbonyl oxygen, lowering of the rotational barrier isthought to be due to the presence of the minor N-proton-ated form, which is in equilibrium with the major 0-protonated species.In contrast, in the formamidesA. Berger, A. Loewenstein, and S. Meiboom, J . Amer.Chem. Soc., 1959, 81, 62.8 G. Fraenkel and C. Franconi, J . Amer. Chem. SOC., 1960, 82,44781977 1143studied here, the barrier is maintained in the cations.This is due to the fact that protonation takes placeoutside the amide group. For compounds (1)-(4),N-1 is involved in cation formation, as shown by thefollowing data. In (1) and (2), protonation is character-ised by a downfield shift of the 2-H signal of ca. 1 p.p.m.(Table 1). This implies formation of an amidinium-likecation (C), in agreement with earlier assignments ofamidinium-like structures to the cations of 1- and3-methylpyrimidin-4(3H)-one 9 and of 3-methylhypoxan-thine.1° For compounds (3) and (4), protonation at N-1is indicated by the relatively large shift of the 2-SMesignal to lower field (0.18 and 0.27 p.p.m., respectively),We have previously shown for 2-methylthiohypoxan-thines that protonation in the pyrimidine moiety shiftsthe SMe band downfield by 0.204.30 p.p.m., whilecation formation in the imidazole ring deshields the 2-SMe signal by only 0.02-4.1 p.p.m.ll Thus we concludethat in compounds (1)-(4) protonation takes place out-side the formamido-group.In the cation of compound (5) (pK > -2), bothformyl resonances are shifted downfield by 0.66 p.p.m.,i.e.about twice the difference observed for cation form-ation in compounds (1)-(4). It appears possible thatthe cation of (5) is a mixture of tautomers (D) and (E),but this cannot be decided at present.The exchange between rotamers (A) and (B) becomesfaster with increasing temperature and finally the formylproton signals coalesce. The rate constants kc [for thereaction (A) + (B)] and k-, [for the conversion of (B)into (A)] at the coalesence point were evaluated with thehelp of the approximations (i) and (ii) where AV represents(ii) x x k, = AV (i); k-, = - AV@Keathe difference between the two formyl signals and Kes isthe equilibrium constant = population ratio [(A)]/[(B)].It has been shown that free energies of activation (AGX)derived from the above approximations are in goodagreement with the results of complete lineshape analy-sis,l2 even for the coalescence of signals with unequalintensities, i.e.when the two rotamer populations differ.According to the results of Kost et aZ.12 an error of 25%in rate constants produces deviations of AGt of only 0.1kcal mol-l at 300 K and an experimental error of &2 Kin the temperature measurements corresponds to adeviation of about 1% in AGI or ca. 0 . 1 4 . 2 kcal mol-l.Our experimental data and the calculated values of AGIand AGO are given in Table 2. For compound (2),coalescence of the formyl signals was not reached at 95 “C.which is the upper limit attainable with the solvent used.In this case the coalescence temperature was estimatedby extrapolation.Our data reveal a striking parallel between the differ-Y .Inoue, N. Furutachi, and K. Nakanishi, J . Org. Chem.,lo Il. Lichtenberg, F. Bergmann, and 2. Neiman, Israel J .l1 U. Reichman, F. Bergmann, and D. Lichtenberg, J.C.S.1966, 31, 175.Chem., 1972, 10, 805.Perkin I, 1973, 2647.ence in rotamer populations (Table 1) and the height ofthe rotation barriers (Table 2). This may be explained asfollows. A strong hydrogen bond between the 6-amino-group and the carbonyl of the formamido-substituent ,as shown in structure (A), raises the barrier by stabilisingthe ground state of one rotamer over that of the other.TABLE 2Dynamic n.m.r. parameters of the unchanged forms ofsome 6-amino-5-forrnamidopyrimidin-4( 3H) -ones aAv ofCHO AG(T,)r/ AG(T,)*/ AGO/Compd. T,/K a signals C kcal mol-1 kcal mol-1 e kcal mol-l f(1) 332 12 17.3 f 0.2 17.5 f 0.2 0.2(2) >365g 30 18.4 f 0.4 19.7 f 0.4 1.3(3) 343 18 17.6 f 0.2 17.8 f 0.2 0.122 17.8 f 0.2 18.6 f 0.2 1.0 1:; E 31 18.2 f 0.2 19.3 f 0.2 1.1In (CD,) ,SO-D,O (9 : 1 v/v) .The coalescence temperatureswere determined only for the neutral molecules; the cations inacid solution undergo slow hydrolysis, which is accelerated byraising the temperature. f 3 K. At very low exchangerates. Calculated from k,. e Calculated from k-l. f Cal-culated from AGO = RT In ITeq. f 6 K ; this value of T , wasobtained by extrapolation and therefore is only approximate.Furthermore, the dipolar structure (A’) increases theenergy of the transition state, in which rotation about theC-N bond has to take place.In addition, in the dipolarform (A’) the hydrogen bond is strengthened still further.A combination of these various factors is operative whenthe more stable rotamer (A) is to be converted into (B).Qn the other hand, for the reverse reaction (B) + (A)only the dipolar form of (B) raises the barrier. Tables1 and 2 show that compounds (2), (4), and (5) exhibitlarge differences in rotamer populations as well as higherbarriers to rotation in either direction. In the case of(2) and (4) we may assume that 3-methylation, by polar-king the grouping CH3-N(3)-C(4)=0 - CH,-N+=C-O-,stabilises the dipolar forms of both (A) and (B). In thisway the energy of the ground states is lowered and thatof the transition states is elevated, i.e.the barrier for thereaction in either direction is raised. However the in-creased contribution of the dipolar structure in turnstabilises the hydrogen bond in (A’), The correspondingeffect is missing for rotamer (B).No explanation is put forward at present for the highratio of (A) to (B) in compound ( 5 ) , since other pyrimid-ines with related structures have not been studied.EXPERIMENTALMicroanalyses were performed by M. Goldstein, Jerusalem.N.m.r. spectra were measured with a JEOL MH-100 instru-ment (sodium 3-trimethylsilyl[2,2,3, 3-2HJpropionate asinternal standard). Because of limited solubility of theneutral compounds in water, a 9 : 1 mixture of (CD,),SO andD,O was used as solvent. Cations were studied in trifluoro-acetic acid or in D,SO,. pK Values were derived fromplots of A,,, or log cmaZ against pH.l2 D. Kost, E. H. Carlson, and M. Raban, Chem. Comm., 1971,6561144 J.C.S. Perkin IPyrimidines.-Compounds (1) ,I3 (2) ,14 (4) ,15 and (5)'s weresynthesised by known methods.6-Amino-5- formamido- 2-methylthiopyrimidin-4( 3H) -one(3). A solution of 6-amino-5-formamido-2-thiouracil (5) l5(1 g ) in N-sodium hydroxide (10 ml) and dimethyl sulphate(0.5 ml) was stirred at 5-10 "C for 45 min. After neutralis-ation with hydrochloric acid, the product (3) precipitated,13 L. F. Cavalieri and A. Bendich, J . Amer. Chem. Soc., 1950,72, 2587.and gave needles (98%), m.p. 292-293" (from water);RF (butan-l-ol-acetic acid-water, 12 : 3 : 5 v/v) 0.34 (Found:C, 34.3; H, 4.45; N, 26.95. Calc. for C,H,N,02S,0.5H,0:C, 34.45; H, 4.3; N, 26.8%).[6/1536 Received, 5th August, 19761l4 G. B. Elion, J . Org. Chem., 1962,27, 2478.15 W. Traube, Annalen, 1904, 64, 331
ISSN:1472-7781
DOI:10.1039/P19770001141
出版商:RSC
年代:1977
数据来源: RSC