Bojarski, Jacek

Tarsa, Monika

Żuchowski, Grzegorz

Acta Poloniae Pharmaceutica - Drug Research

English

Jagiellonian Univeristy Repository

A cta  P o lo n ia e  P h arm ae eu tica  -  D rug  R esearch , V ol. 60  N o. 4  pp . 253- 2 5 6 , 2003 ISSN  0 0 0 1 -6 8 3 7  P olish  P h arm ac eu tica l S o cie tyHYDROLYSIS OF N ,N - AND N,S-DIMETHYL DERIVATIVES OF 2-THIOPHENOBARBITALMONIKA TARSA, GRZEGORZ ZUCHOWSKI and JACEK BOJARSKIDepartment of Organic Chemistry, Medical College, Jagiellonian University,9 Medyczna Str., 30-688 Krakow, PolandA bstract: K inetics o f  hydro lysis  o f  N ,N -  and  N ,S -d im e th y l-2 - th io p h en o b a rb ita l and products o f  this reac tion  w ere  investigated . T h e  UV spectroscopy  served  as a  tool fo r k inetic  investiga tions and chrom atog raphy  w as used to separate  and  iso late the m ain products o f  hydrolysis. T h ese  products w ere  identified  by spectro scop ic  m ethods and the co u rse  o f  hydro lysis  o f  both isom ers w as com pared .K eyw ords: N ,N -  and  N ,S --d im ethy l-2 -th iophenobarb itaI, hyd ro lysis , k inetic  param ete rs, hydro lysis  products, stab ility .In previous papers we reported investigations on kinetics of hydrolysis o f N -m ethyl-2-thiop- henobarbital (1) and its S-methyl isomer (2). We were interested to compare these results with those for N ,N -dim ethyl- (compound I) and N,S-dimet- hyl (compound II) derivatives of 2-thiophenobar- bital. Besides, N ,N -dim ethyl-2-thiophenobarbital has no possibility to ionize and thus may serve as model compound for hydrolysis of undissociated species of 2-thiobarbiturates. The separation of hydrolysis products could contribute to elucidation of hydrolysis course of this type of compounds.EXPERIM ENTALN ,N - and N ,S-dimethyl derivatives of 2-thio- phenobarbital (I and II, respectively) were ob­tained according to (3). Other experimental details, apparatuses and procedures were the same as desc­ribed in the preceeding paper. The solvent systems for TLC investigations were: a) chloroform, b) chloroform : toluene : acetone (2:1:1, v/v/v) and c) cyclohexane : ethyl acetate (4:1, v/v) for I and d) n-hexane : ethanol : triethylamine (7:1:1, v/v/v) and e) n-hexane : acetone (2:1, v/v) for II.F ig u re  I . A b so rb an ce-co n cen tra tio n  re la tionsh ip s fo r com pound  I (A ) and II  (B)253254 MONIKA TARSA et al.Figure 2. P se u d o -f irs t o rder p lo ts  fo r hydro lysis  o f  I (A ) and  II (B ) at d iffe ren t pH  values at 25°CF igure 3. T he log k /pH  profiles fo r hydro lysis  o f  I (A ) and II  (B) at 25"CT ab le  1. V au les o f  experim en tal rale constan ts  (k) for hyd ro ly sis  o fCompound IPH k x 10~5 [s-1] log k6.0 0.0699 -6.1567.0 0.0340 -6.4697.12 0.0441 -6.3567.52 0.0951 -6.0228.0 0.2823 -5.5498.5 0.7363 -5.1339.0 1.8470 -4.7349.3 2.8130 -4.5519.5 3.3270 -4.478buffers the sam e as in [2] experim en ta l pH  m easured  at 25UCRESULTSLinear UV absorbance-concentration relations­hip was checked in the 4.0 x  1(LS -  8.0 x  10~5 M range for buffer (pH = 8.5) and ethanol solutions of I  and I I  (Figure 1). Typical absorbance changes during degradations o f  I and II  are shown in Figure 2. Plots o f log (A -  A°°) vs. tim e were linear indicating the pseudo-first order reaction. The rate constants (k) (Table 1) were calculated from the expression:I and  II  at d iffe ren t pH * valuesCompound 11PH k x 10“5 [s '] log k1.01 90.3800 -3.0472.1 8.8910 —4.0513.0 0.9950 -5.0024.0 0.1158 -5.9365.02 0.0271 -6.5676.0 0.0498 -6.3037.1 0.3568 -5.4548.0 4.4210 -4.3609.3 19.2200 -3.716log (A -  A=°) = log (A„ -  A°=) -  ktl2.303 w here A„ is the absorbance at tim e t = 0; A°o is the final (residual) absorbance and A is the absorbance at tim e = t.The calculated  rate constants served for const­ruction o f log k/pH  profiles for hydrolysis o f both com pounds (Figure 3).The rate constants at different temperatures (bet­ween 20 and 45"C) and in various buffers are listed inH y d ro ly s is  o f  N ,N -  a n d  N ,S - d im e th y l  d e r iv a t iv e s  o f  2 - th io p h e n o b a r b i ta l 255T ab le  2. V alues o f  experim en tal rate constan ts  (k) fo r hydro lysis  o f  I and  II  at d iffe ren t tem peratu resCompound I (pH = 9.8) Compound II (pH = 8.5) Compound II (pH = 3.0)Temp. [KJ 1/T I ’/kI k x  10 4 log k k x 10-4 log k k x  10-* log k293 3.413 x 10 ' 2.3523 -3.639 0.5195 -4.282 0.0302 -5.521303 3.3 x 10 * 4.4875 -3.348 1.6220 -3.789 0.0831 -5.080308 3.25 x  HT3 6.2374 -3.205 2.3598 -3.627 0.1273 -4.895318 3.15 x  10 1 11.7689 -2.929 4.4450 -3.352 0.2172 -4.633E„ = 53.01 kJ/mol E„ = 67.96 kJ/mol Ea = 61.96 kJ/molT ab le  3. S pectroscop ic data  lo r degrada tion  products o f  com pound  I and  IIH 1 NMR (CDCfO [ppml MS (%) IR (KBr) ( c n r ’lCompound III0.972 (t, 3H, J = 7.5, C H ,-C H 2-) 250 (20) M+1.681-1.781 (m, 1H, C H ,-C H 2-) 249 (100) [C l3H l7N2OSJ +2.044-2.114 (m, 1H, C H ,-C H 2-) 178 (32) [C mH I(,NO] +3.180 (s, 3H, C H .,-N H -) 117 (8) [CkH,01+3.672 (s, 3H, C H ,-N = ) 91 (5) |C 7H7j +3.810 (t, 1H, J = 7.5, -C H 2-C H -C 6H5)7.297-7.378 (m, 5H, -C 6H 5)1 1.592 (s, 1H, -N H -)Compound IV0.962 (t, 3H, J = 7.5, C H ,-C H ,-) 246 (12) M+ 3199 N -H2.172 (s, IH, H O -) 231 (5) [CI2H mN20 ,P 3092 r  hC -H  aromat.30672.470 (q, 2H, J=7.5, C H ,-C H 2-) 128 (100) [C i2H ,4N20 21+3.340 (s, 3H, CH:,-N =) 7.253-7.381 (m, 5H, C6H 5)175 (6) LCnH,.,NOr 16 (7) [C.oH mNO]42979C -H  aliph.2885 18.447 (s, IH, -N H -) 146 (16) rC l0H„,O]+ 15751715 C = 0  1689117 (19) [C8H5OJ+91 (7) [C7H7]+77 (5) [C„H5]+ 1435 N -H|Compound V0.895 (t, 3H, J = 7.5, C H ,-C H 2-) 251 (2) [C,.,H„N2OS]+ 3212 N -H1.753-1.857 (m, IH, C H ,-C H ,-) 235 (2) [C i2H „N 2OS1+ 3080C -H  romat.30232.172-2.274 (m, IH, C H ,-C H 2-) 220 (2) [C ,,H l2N2OSJ+2.436 (s, 3H, C H ,-S -) 203 (2) [C12H i7N20 ] + 2967 C -H  aliph.2.915 (s, 3H, C H ,-N = ) 174 (2) LC m H ioN ^r 1591 C = 03.496 (t, IH, J = 7.5, -C H =) 159 (2) [GTTNjOT 1559 N -H7.171-7.385 On, 5H, -C«,H5) 146 (2) [C,„Hl0Ol+ 1354 C -N10.780 (s, IH, NH=C=) 131 (100) IC„Hm]+119 (2) [C4H7N2OS]+Table 2. The Arrhenius equation was used for calcu­lation of activation energies from these data (Table 2).The results of TLC monitoring of hydrolysis course for I  and II are shown in Figure 4. The structures of the main products of hydrolysis ofI (compound III) and II  (compound IV and V) separated by column and circular chromatography and identified by spectroscopic methods are shown in Figure 5. Their spectroscopic data are presented in Table 3.c h 3c h 2 hc h ,C „H f C —N— C— NH— CH, CKH,C2H5'c h 3,,N , , 0OIVC H 3 C H 2'*x  , H  C H aC6H / C --N — C = N HS— CH,Figure 5. S tructu res o f  m ain hydro lysis  products o f  I and II  in alkaline ( I I I ,  V ) and acid (IV ) m edium , respectively .256 MONIKA TARSA et al.F igure 4. TLC m onito ring  o f  hydro lysis  o f  I (A -  pH = 9 .5 , at 40°C, m obile  phase: ch lo rofo rm ) and II  [B -  pH = 2.5, C -  pH = 8.5, a t 40°C; m obile phase: n -h cx an e  : e thanol : trie thy lam ine  (7:1: l, v /v /v)[.D ISCUSSIONThe results presented above indicate that hydro­lysis of N ,N - and N,S-dimethyl derivatives of 2-thiophenobarbital (I and II, respectively) is a pseu­do-first order process. For both compounds the speci­fic hydroxyl ion catalysis was observed in the alkaline region but only for II  the specific acid catalysis was found. These results are in full agreement with those previously found for N - and S-methyl derivatives of 2-thiophenobarbital (see preceeding paper), but cont­rary to previous findings the rates of hydrolysis of I and II in the alkaline region were within the same order of magnitude and the N,S-dimethyl derivative was hydrolyzed even faster than the N,N isomer.In the alkaline region the hydrolytic pyramidi- ne ring opening is characteristic of both compounds but in the acidic region only désulfuration of II  was observed and the pyrimidine ring remained intact. Désulfuration was also observed for hydrolysis of S-m ethyl-2-thiophenobarbital (see preceeding pa­per) but the product o f ring opening and the structure of isourea derivative was also identified.Since compound I cannot ionize and its hydro­lysis is still catalyzed by hydroxyl ions, it is quite possible that the hydrolysis of undissociated species of other 2-th iobarbi tu rates and their oxo analogs follow the same pattern and not the kinetically equivalent attack of water on monoionized species, suggested by their log kJpH profiles. The mechanis­tic pathways of hydrolysis of N-methyl and N,N-di- methyl derivatives are quite similar to those of other barbiturates and 2-thiobarbiturates but those for S-methyl substituted isomers seem more complica­ted and their full elucidation requires further studies.AcknowledgmentThe work was supported by the Grant No. 4P05F02915 from the Polish State Committee for Scientific Research (KBN), Warszawa, Poland. The authors are indebted to Dr. hab. M. Klys, from the Department of Toxicology, Institute o f Forensic Medicine, Medical College of the Jagiellonian University for enabling LC/MS measurements.REFERENCES1. Tarsa M., Bojarski J.: Bull. Acad. Pol. Sci. Chemistry 45, 63 (1997).2. Tarsa M., Zuchowski G., Bojarski J.: Acta Polon. Pharm. -  Drug Res., preceeding paper.3. Kubaszek M., Paluchowska M., Chmiel E., Bo­jarski J.: Pol. J. Chem. 68, 117 (1994).Received: 10.02.2003

Hydrolysis of N,N- and N,S-dimethyl derivatives of 2-thiophenobarbital

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Hydrolysis of N,N- and N,S-dimethyl derivatives of 2-thiophenobarbital

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