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The Dissociation Constants of Some 155-Trisubstituted Barbituric Acids.

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319186
255
Dissociation Constants of Barbituric A c i h
4,9-Dimethoxy-5-o~o-SH-furo[3,2-g][lJbenzopyran-6-su~ons~ure
(9A)
3.0g (9.7mmol) 5 werden in 25ml Chloroform aufgeschlämmt. Nach Zugabe einer Suspension von
2.5 g (14.5 mmol) 3-Chlorperbenzoesäurein 25 ml Chloroform entsteht eine orange-gefärbte Lösung,
aus der beim Abkühlen orangefarbene Kristalle ausfallen, die beim Absaugen ander Luft eine gelbe
Farbe annehmen. Gelbe Kristalle, Schmp. 192-195", Ausb. 2.1 g (60 % d. Th.). C13Hlo0,S 2 H 2 0
(362.3) Ber. C 43.1 H 3.90 Gef. C 43.5 H 3.83. - MS: m/z = 326,(66 %, Mf). - IR (KBr): 36W-2500,
1635, 1605cm-'. - 'H-NMR ([DóIDMSO): 6 (ppm) = 3.94 (s, 3H), 4.09 (s, 3H), 7.18 (d, lH , J =
2.3Hz), 8.07 (d, l H , J = 2.3Hz), 8.48 (s, 1H).
-
-
5-Hydroxy-4,9-dimethoxy-furo[3,2-g][l]benzopyrylium-6-su~onat
(9B)
Verbindung 9A wird aus Eisessig umkristallisiert und upter LuftausschluR aufbewahrt. Orangerote
Kristalle, Schmp. 192-195", Ausb. 2.1 g (67 % d. Th.). C13H1OOgS (326.3) Ber. C 47.9 H 3.09 S 9.8
Gef. C47.7H3.00S9.7.MS: m/z= 326(67%,Mt
(KBr): 3600-2600,1600cm-'. - 'H-NMR
(CD3COOD): 6 (ppm) = 4.26 (s, 6H),
, 3 H z ) , 7.96 (d, lH , J = 2.3Hz), 9.25 (s,
1H).
-
Chromon-3-sulfonsäure(10)
-
'H-NMR ([D6]DMSO):vgl. Lit.*). '€3-NMR (CD3COOD): 6(ppm) = 7.6W.60 (m, 4H), 9.00 (s,
1H).
Literatur
* * Teil eines Vortrags auf dem Ersten GesamtkongreB der Pharmazeutischen Wissenschaften,
München 1983.
3 E. Späth und W. Gruber, Ber. Dtsch. Chem. Ges. 71,106 ($938).
4 R.B. Gammil, C. E. Day und P. E. Schurr, J. Med. Chem. 26, 1672 (1983).
[Ph 451
Arch. Pharm. (Weinheim) 319, 255-260 (1986)
The Dissociation Constants of Some 1,5,5-Trisubstituted
Barbituric Acids
Jerzy L. Mokrosz, Jacek Bojarski* and Wadaw Weha
Department of Organic Chemistry, Nicotaus Copernicus Academy of Mediciy , Dzierzynskiego
14 B st., 30048 Kraków,Poland I
Eingegangen am 18. Februar
03656233/86/0303-0255 $ 02.50/0
O VCH Verlqgsgesellschaft mbH,D-6940 Weinheim, 1986
256
Mokrosz, Bojarski and Welna
Arch. Pharm.
The pK, values of 15 N-substituted 5,s-diethylbarbituric acids containing phenyl, benzyl and benzoyl
moieties have been determined. The qualitative and quantitative effects of substitution at the N-1
atom on the pK, value are discussed.
Die Dissoziationskonstanten einiger 1,5,5-tnsubsîituierter Barbitursäuren
Die pK, Werte von 15 N-substitutierten 5,5-Diethylbarbitursäuren mit Phenyl-, Benzyl- und
Benzoylgruppen wurden bestimmt. Die qualitativen und quantitativen Effekte der Substituenten am
Stickstoffatom auf die ,pK, Werte werden diskutiert.
Hitherto the most attention has been focused on the dissociation constants of the 5-substituted
barbiturates'-''). The first ionization step for 5,5-disubstituted barbiturates containing phenyl,
alkenyl or alkyl substituents lies in the 7.3-8.9 pK, range and their acidity is strongly dependent on
the electronic and steric nature of substituents'-* ?O ) . "he inductive effect of the electron acceptor
On
substituents results in a decrease of the pKal value in relation to 5,5-diethylbarbituric
the other hand, large alkyl groups at the C-5 position hinder the solvation of the barbituric acid ring
shielding the C-4 and C-6 carbonyl groups, which results in an increase of the pKa;+). Recently,
successful correlations between the pKal values of 5,s-disubstituted barbiturates and Taft's polar (8%)
and steric (E,) substituent constants were also reported""*). However, the pK, values of
1,5,5-trisubstituted barbiturates were little investigated and only the effect of N-methylation in
5,5-disubstituted barbiturates was d i s ~ u s s e d ' * ~ ~ ~ ~ ' ~ * ~ ~ ) .
In this paper we discuss an influence of different phenyl, benzyl and benzoyl
substituents at the N-atom on the pK, of 1,5,5-trisubstituted barbiturates.
It is wel1 known that the l-methyl-5,5-disubstitutedbarbiturates show higher pK, by ca.
0.5 unit than their N-unsubstituted analogs41"). However, introduction of benzyl 5,
p-chlorobenzyl 6 or p-nitrobenzyl7 substituents at the N-1 position caused a decrease of
the pK, values in relation to the N-methyl derivative 2 by 0.18, 0.29 and 0.82 unit,
respectively (Table 1). Similarly, the N-(p-nitropheny1)derivative 4 shows a lower pK,
than the N-phenyl derivative 3, and moreover, this last is more acidic in relation to
5,ti-diethylbarbituric acid 1by 0.24 pK, unit. The pK, values of derivatives 8-17 containing
an N-benzoyl substituent or substituted N-benzoyl moiety are lower by 1.061.47 unit in
relation to 1.
The pK, data of the particular derivatives have been correlated with the substituent
constants using the following Hammett equation:
PKax = PKa,, + Q
.
where pK,,, and pKaa are values for substituted and unsubstituted derivatives,
respectively, while Q and u are reaction and substituent constants. The best straight-line
fits were calculated by the least squares method and correlation coefficients (r) were
evaluated by Student's test (C.L. - confidence level). The results of correlation analysis
are presented in Fig. 1 and 2.
An excellent correlation with the inductive substituent constants u* has been found for
compounds 1-5 and 8 (Fig. 1). The compounds 6 and 7 are excluded from this analysis
because their substituent constants have not been found in the literature but such highly
319186
257
Dissociation Constants of Barbituric Acids
R3
1-21
Table 1: p K , values and substituent constants for 1-subsf. 5,S-diethylbarbiturates
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
R3
H
methyl
phenyl
pnitxophenyl
benzyl
p-chlorobenzyl
p-ni trobenzyl
benzoyl
o-methylbenzoyl
m-methylbenzoyl
p-methylbenzoyl
o-methoxybenzoyl
m-methox ybenzoyl
p-methoxybenzoyl
o-bromobenzoyl
m-bromobenzoyl
p-brumobenzoyl
pKa
7.86 i 0.03
8.30 i 0.03
7.62 f 0.02
7.32 2 0.03
8.12 i 0.03
8.01 c 0.04
7.48 i 0.03
6.40 f 0.03
6.50 f 0.03
6.64 f 0.03
6.64 i 0.02
6.54 f 0.03
6.51 s 0.02
6.80 i 0.02
6.56 s 0.02
6.39 1. 0.02
6.55 i 0.03
o *a
o +b
0.49
0.00
0.75
1.26
0.27
2.26
0.00
-0.07
-0.31
0.05
-0.78
0.40
0.15
-
a
the inductive substituent constants for the whole N-substituent taken from ref.”)
the resonance substituent constants for substituents in the benzoyl moiety taken from ref.16)
significant results of correlation analysis (coefficient of determination rz = 0.996) and the
sequence of the individual pK, values enables determination - from the regression
equation in Fig. 1- of these inductive constants as o* = 0.35 and 0.99 for p-chlorobenzyl6
and p-nitrobenzyl7 substituents, respectively .
Thus, al1 these facts support our working hypothesis that the pK, changes within the
investigated 1-substituted 5,s-diethylbarbiturates are crucially affected by the inductive
effect of the N-substituents. The electron withdrawing N-substituents stabilize an anionic
form of the barbiturate ring and cause the decrease of the pK, value in relation to the
N-methyl derivative 2. It is noteworthy that for derivatives 3,4 and û-17 the conjugation
between the N lone electron pair and the phenyl or benzoyl moieties may occur. Such
conjugation has been als0 postulated earlier for l-(p-bromophenyl)-5,5-diallylbarbituric
acid from crystallographic data”). Although the correlation coefficient of the regression
line for meta and para substituted derivatives in the benzoyl moiety is rather poor, the
258
65
Mokrosz, Bojarski and Welna
Arch. Pharm.
-
Lmzï
o5
10
15
2'0
'U
Fig. 1: Relationship between pK, and the inductive substituent constants for 1-substituted
5,5-diethylbarbiturates1-5 and 8. The straight h e equation:
pK,,, = 8.303 -0.834.0*, r = 0.998, C.L.= 99.9%.
-0 8
-0 I
O
OL
a'
rn
Fig. 2: Relationship between pK, and the resonance substituent constants for the meta and para
acid substituted in the phenyl ring. The straight
derivatives of l-benzoyl-5,5-diethyIbarbituric
line equation:
pK,,x=6.534-0. 340. 0+ , r = 0. 878, C. L. =99%.
correlation with the resonance substituent constants u+ is still highly significant (Fig. 2)
which may additionalìy support the existence of the conjugation discussed above.
Comparison of the pK, values for different l-benzoyl-5,5-disubstitutedbarbiturates
with their N-unsubstituted analogs indicates that the inductive effect of the benzoyl
substituents dominates over other effects of the 5-substituents (Table 2).
The hyperconjugation effect of the C-5 methyl group causes an increase of the pK,
value7x9)(cf. 20 and 21). This effect is not observed when the N-benzoyl group is present in
the barbituric acid molecule (cf. 18, 19). An influence of the inductive effect of the
5-substituent is also not observed in the N-benzoyl derivatives (cf. 1, 21 and 8, 19).
However, smal1 changes in the pK,'s of the N-benzoyl derivatives 8,18 and 19 are difficult
to interpret. It should be also emphasized that the observed influence of the N-benzoyl
group on the pK, values of 1,5,5-trisubstituted barbiturates can be considered as the
319186
259
Dissociation Constants of Barbituric Acids
Table2: The effect of substitution
af
C-5 on the value of pKa,
~
No.
R’
8
ethyl
methyl
ethyl
ethyl
methyl
ethyl
18
19
1
20
21
R2
ethyl
phenyl
phenyl
ethyl
phenyl
phenyl
R3
benzoyl
benzoyl
benzoyl
H
H
H
PK,
’
6.40
6.35 * 0.06
6.5818)
7.86
7.634)
7.364)
superposition of the inductive and solvation effects. The solvation of the barbiturate ring
influences the pK,, of the 5,5-disubstituted barbiturates’-’).
The N-benzoyl group may be almost coplanar to the plane of the barbituric acid ring due
to the conjugation between that group and the lone electron pair of the nitrogen atom.
Thus, the solvation of the whole molecule may be facilitated and reflects in the
acid-strengthening effect of the derivatives discussed above.
Experimental Part
Materials and apparatus: Barbiturates 1 and 2 were commercial products of Polfa and Abbott
Laboratories, resp. Syntheses of other barbiturates than 6are described as follows: 3”),4”), 5”), 7*’),
ga), !L1724)and
Phosphate (pH 5.8-7.6) and tris(hydroxymethy1)methane (pH 7.4-8.8) buffers
were used with an addition of an appropriate vol. of 1M-NaOH to produce p = O. 1. Al1 reagents were
of analytica1 grade. Uncorr. m. p . : Boetius apparatus (PHMK VEB Analytik, Dresden). W
spectra: spectrophotometers Specord UV-VIS and VSU-2P (C. Zeiss, Jena). p H measuremenrs:
pH-meter N5122 (Mera Elwro, Poland) equipped with the glass and calomel electrodes.
1 -(p-chlorobenzyl)-5,5-diethylbarbituric
acid (6)
The mixture of the sodium sak of 7g, (0.034mole) 1 in 50mi of water and 5g (0.031mole)
p-chlorobenzylchloridein 90ml of ethanol was refluxed for 1h. Then the reaction mixture was cooled
to room temp. and the precipitate was washed with 50ml of lM-Na,CO,, twice with water and with
ethanol yielding after drying 3.5 g (33 %) of colourless needles of 1,3-bis(p-chlorobenzy1)5,5-diethylbarbituric acid. M. p. 142.5-143.5”C (lit.’@ m. p. 142-143°C). The filtrate from the
reaction mixture was kept overnight in a refngerator. Crystals were dissolved in 50ml of
0.5 M-NaOH, filtered off again and acidified with conc. hydrochloric acid. The precipitate was
recrystallized from ethanol giving 1.3g (8.8 %) of colourless crystals of 6 M. p. 146-147°C (the Same
compound obtained by condensation of the appropriate urea derivative and the diethylester of
diethylmalonic acid had m. p. 134”CZ7)).
(308.7) C,,Hl,C1N203 Calcd. C 58.3 H 5.55 N 9.1 Found C
58.2 H 5.56 N 9.1.
p K , measuremenis
The pK, values were determined spectrophotometrically28)at 20 k 0.2”C using 0.1 M-HCI and 0.1
M-NaOH for unionized and completely ionized species, respectively. Borate buffer (pH 10.40) was
used for determination of the UV absorbance for the monoionized form of 1. Phosphate (pH
5.80-7.60) andior tns(hydroxymethy1)aminomethane buffers (pH 7.40-8.80) were applied for partly
ionized species.
260
Mokrosz, Bojarski and Welna
Arch. Pharm.
Referenees
1 M. E. Krahl, J. Phys. Chem. 44, 449 (1940).
2 T. C. Butler, J. M. Ruth and G. F. Tucker, J. Am. Chem. Soc. 77, 1486 (1955).
3 D. A. Doornbos and R.A. de Zeeuw, Pharm. Weekbl. 104, 233 (1969).
4 D. A. Doornbos and R.A. de Zeeuw, Pharm. Weekbl. 106, 134 (1971).
5 J. M. A. Sitsen and J. A. Fresen, Pharm. Weekbl. 108, 1053 (1973).
6 H. Koffer, J. Chem. Soc. Perkin Trans 2 1974, 1429.
7 R. H. McKeown, J. Chem. Soc. Perkin Trans 2 1980,504.
8 R. H. McKeown, J. Chem. Soc. Perkin Trans 2 198I, 481.
9 J. Mokrosz and J. Bojarski, Pol. J. Chem. 56, 491 (1982); C. A. 100, 191036 g (1984).
10 D. A. Buckingham, C. R. Clark, R.H. McKeown and W. Ooi, J. Chem. Soc. Chem. Commun.
1984, 1440.
11 R.H. McKeown, J. Chem. Soc. Perkin Trans 2 1980,515.
12 J.L. Mokrosz, Arch. Pharm. (Weinheim) 317, 718 (1984).
13 T. C. Butler, J. Am. Pharm. Assoc. 44, 367 (1955).
14 P. Zuman, J. A. Vida, A. Kardos and M. Romer, Anal. Lett. 9, 849 (1976).
15 W. Y. Li, Z. R. Guo and E. J. Lien, J. Pharm. Sci. 73, 553 (1984).
16 H.C. Brown and Y. Okamoto, J. Am. Chem. Soc. 80, 4979 (1958).
17 D. Pyzalska, R.Pyzalski and T. Borowiak, Acta Crystallogr. B36, 1672 (1980).
18 M. Paluchowska, L.Ekierî, K. Jochym and J. Bojarski. Pol. J. Chem. 57,799 (1983); 102,5311m
(1985).
19 H. Aspelund and O. Backman, Acta Acad. Aboensis Set. B 14, No. 14 (1944); C. A. 42,573f
(1948).
20 J. S. Buck, J. Am. Chem. Soc. 59, 1249 (1937).
21 A. W. Dox and E.G.Jones, J. Am. Chem. Soc. 51, 316 (1929).
22 J. Bojarski, W.Kahl and M. Melzacka, Roczn. Chem. 42, 41 (1968).
23 L.P. Kulyev and A.L. Shesterova, Zhur. Obshch. Khim. 31, 1378 (1961); C.A. 55, 24758 f
(1961).
24 W. Welna and J . Bojarski, Pol. J. Chem. 52,987 (1978); C.A. 89, 146141 f (1978).
25A. Sucharda-Sobczyk and J . Bojarski, Roczn. Chem. 44, 2333 (1970).
26 M.E. Hultquist and C.F. Poe, Ind. Eng. Chem. Anal. Ed. 7, 398 (1935); C.A. 30, 1942
(1936).
27 J. P. Tnvedi and J. J. Tnvedi, J. Indian Chem. Soc. 35, 661 (1958); C. A. 53, 14112 g (1959).
28 A. Albert and E. P. Serjeant, Ionization Constants of Acids and Bases, Methuen and Co Ltd,
London 1962.
[Ph 461
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