Determination of energy barriers and racemization mechanisms for thermally interconvertable barbituric and thiobarbituric acid enantiomers

Article abstract of DOI:10.1016/S0957-4166(03)00306-9

The enantiomers of the 5,5-dimethyl-1-(o-aryl)barbituric and 2-thiobarbituric acid derivatives have been separated by micropreparative liquid chromatography on the Chiralcel OD-H column. The activation barriers for the conversion of one enantiomer to its

Full text of DOI:10.1016/S0957-4166(03)00306-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1857–1864
Determination of energy barriers and racemization mechanisms
for thermally interconvertable barbituric and thiobarbituric acid
enantiomers
:
S. Funda Og˘uz and Ilknur Dog˘an*
Bog˘azic¸i University, Chemistry Department, Bebek, Istanbul, Turkey
Received 18 March 2003; accepted 3 April 2003
Abstract—The enantiomers of the 5,5-dimethyl-1-(o-aryl)barbituric and 2-thiobarbituric acid derivatives have been separated by
micropreparative liquid chromatography on the Chiralcel OD-H column. The activation barriers for the conversion of one
enantiomer to its counterpart (M ? P) have been determined upon thermal racemization of the separated enantiomers by
following the intensity changes in the HPLC chromatograms with time. The activation barrier of the 1-(o-tolyl)barbituric acid has
been determined by temperature-dependent NMR. The racemization mechanisms are discussed with reference to the determined
barriers. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
(Table 1) and 13C (Table 2) NMR signals. The protons
at C-5 on the other hand showed AB type splittings
(Table 3). These results indicate that the R groups on
C-5 (Fig. 1) are diastereotopic which in turn demon-
strates the chirality of these compounds in their ground
states. Enantioselective liquid chromatography has
been used to resolve the enantiomers for which NMR
anisochrony has been observed. The Chiralcel OD-H
column proved to be the most efficient for this purpose,
on which the enantiomers of 1–6 which are the 5,5-
dimethyl derivatives, have been micropreparatively sep-
Barbituric acid derivatives are a well-known class of
compounds with various pharmacological activities.1
Chiral barbituric acid derivatives having asymmetric
substitution on 5-position of the ring have been
resolved by enantioselective liquid chromatography on
triacetylcellulose.2 The N-o-aryl substituted barbituric
and thiobarbituric acid derivatives studied in this work
(Fig. 1) are axially chiral due to nonplanar ground
states of the molecules,3 the CarylꢀN bond being the
2
sp
chiral axis and all of them exist as a pair of thermally
interconvertable M and P enantiomers (Fig. 1). The
work covers the determination of the energy barriers of
these compounds by either thermal racemization of the
micropreperatively separated enantiomers or by tem-
perature-dependent NMR and discussion of the mecha-
nism of racemization based on the found values.
arated or highly enriched. Table
4 shows the
chromatographic parameters of the separation.
The barriers to partial rotation about the CꢀN bond in
1-6 were determined by thermal racemization of prepar-
atively enriched enantiomers. The rate constants for
enantiomerization have been calculated using reversible
first order kinetics with the equation ln([M]−[M]eq/
[M]o−[M]eq)=−2kt,4 [M] being the molar concentration
of the enantiomer at time t, [M]o the initial and [M]eq
the equilibrium concentration. In place of [M] and [M]o
the percentage values of the enantiomers obtained from
HPLC chromatograms have been used where [M]eq is
fifty percent. The free energy of activation values, DG"
for the interconversion of the enantiomers have been
calculated using the Eyring equation DG"=RT ln(kbT/
kh). The rate constants and barriers found are listed in
Table 5.
2. Results and discussion
1H and 13C NMR spectra of the synthesized barbituric
and thiobarbituric acids showed that the methyl groups
on C-5 of the heterocyclic ring had two distinct 1H
* Corresponding author. Fax: +90-212-287-2467; e-mail: dogan@
boun.edu.tr
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00306-9

:
S. F. Og˘uz, I. Dog˘an / Tetrahedron: Asymmetry 14 (2003) 1857–1864
1858
Figure 1. The structure of the N-o-aryl substituted barbituric and -2-thiobarbituric acid derivatives studied.
The energy barriers for enantiomerization of 1–6 are
comparable to each other in spite of somewhat different
temperatures. As can be seen from the Table 5 the
rotation barrier for the compound 1, the oxo derivative,
is 102.8 kJ/mol, which is lower than the one observed for
the compound 2, the thioxo derivative at 116.1 kJ/mol.
Kashima et al. have reported the activation energies for
the racemization for the structurally similar compounds,
namely ortho substituted 1-aryl-4,6-dimethylpyrimidin-
2(1H)-ones and the corresponding thiones.5 They unex-
pectedly observed a lower activation energy for the
racemization of the thione derivatives compared to the
oxo derivatives, although the standard bond length of the
posed that the greater single bond character would
promote bond bending, which will cause a decrease in the
inter-atomic repulsion between the sulphur atom and the
ortho-methyl group on the aryl ring. Roussel et al.
however proposed a ring opening-ring closure mecha-
nism for the racemization of those pyrimidine deriva-
tives.6 In compounds 1–6 which we synthesized, since two
methyl groups are attached to C-5, the ring-opening–
ring-reclosure mechanism is impossible, so there is no
possibility for a 3,3-electrocyclic reaction that had been
suggested by Roussel et al.6 The result, which shows that
the barrier for racemization is higher in the thioxo
derivative, 2, than in oxo derivative, 1, is consistent with
the racemization for these compounds via rotation about
the CꢀN bond and does not agree with Kashima’s
suggestion,5 that the greater single bond character of the
thiocarbonyl group results in a lower energy barrier for
the heterocycles with the thioamide group.
,
CꢁO double bond (1.22 A) is shorter than that of the CꢁS
,
(1.71 A), and the van der Waals radius of oxygen (1.4
,
,
A) is smaller than that of the sulphur atom (1.85 A). They
explained this behaviour in terms of the greater single
bond character of the carbonꢀsulphur bond. They pro-

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S. F. Og˘uz, I. Dog˘an / Tetrahedron: Asymmetry 14 (2003) 1857–1864
1859
1
Table 1. 400 MHz H NMR spectral data for the 5,5-dimethyl-1-(o-aryl)barbituric and -2-thiobarbituric acids in CDCl3
Compd
X
Ar
l (ppm) of 5-CH3
l (ppm) aromatic H
l (ppm) 3-NH
l (ppm) o-CH3
( )-1
( )-2
( )-3
( )-4
( )-5
( )-6
O
S
S
S
S
S
o-Tolyl
o-Tolyl
o-Fluorophenyl
o-Methoxyphenyl
o-Chlorophenyl
a-Naphtyl
1.68a and 1. 70a
1.69a and 1.70a
1.59a and 1.62a
1.66a and 1.70a
1.68a and 1.75a
1.75a and 1.81a
7.07–7.38
7.04–7.39
7.10–7.62
7.00–7.45
7.24–7.54
7.30–8.00
8.04
9.08
9.09
9.14
9.13
9.17
2.16
2.16
–
3.81b
–
–
a Diastereotopic groups.
b l (ppm) of o-OCH3.
Table 2. 13C NMR spectral data for the 5,5-dimethyl-1-(o-aryl)barbituric and -2-thiobarbituric acids in CDCl3
Carbon no.
( )-1
( )-2
( )-3
( )-4
( )-5
( )-6
2
4, 6
5
148.89
171.98, 172.59
48.10
177.71
169.75, 171.13
48.67
177.68
169.53, 171.08
48.83
178.36
169.78, 171.20
48.76
177.28
169.60, 170.78
48.75
178.11
169.65, 171.53
48.86
7, 8
Aromatic
o-(CH3)
24.34, 25.67,
127.40–135.90
17.78
24.07, 25.38
127.47–136.93
17.74
23.40, 25.65
116.47–131.57
–
23.19, 25.86
112.41–154.50
56.22
23.18, 26.26
128.10–135.38
–
24.49, 25.27
121.16–134.58
–
1
Table 3. 400 MHz H NMR spectral data for the 1-(o-aryl)barbituric and -2-thiobarbituric acids in CDCl3
Compd
Xa Ra, R¦a=H, R%a=H
l (ppm) of 5-CH2
l (ppm) aromatic H
l (ppm) 3-NH
l (ppm) o-CH3
( )-7
( )-8
( )-9
( )-10
O
O
S
CH3
Cl
CH3
Cl
3.84; 3.68 and 3.87b,c
3.84 and 3.88b
7.09–7.38, 7.14–7.29c
7.25–7.57
7.06–7.40
8.11, 11.46c
8.04
9.38
2.18; 2.08c
–
2.16
–
3.87 and 3.89b
S
3.88 and 3.91b
7.62–7.98
9.31
a For the descriptions, see Figure 1.
b AB type splitting.
c 1H NMR spectral data in DMSO-d6.
of the heterocyclic ring and the chlorine atom. This
repulsion might increase the free energy of the transi-
tion state of the compound with a chlorine atom as the
ortho substituent relative to that of the methyl group as
the ortho substituent. For arylrhodanines and for aryl-
hydantoins the difference was found to amount to 6–7
kJ/mol, whereas for N-aryl-2(1H)quinolones and N-
aryl-6(5H)-phenanthridinones,8 it was only 0.2 kJ/mol.
In 2,4-quinolinediones,10 on the other hand, the ortho-
methyl derivative caused a higher barrier by 0.8 kJ/mol
The energy barriers for racemization of the o-methyl
and the o-chloro derivatives, compounds 2 and 5, were
found to be similar (115.8 kJ/mol). When the steric
effects of a methyl and a chlorine atom are compared in
different types of N-ortho-aryl substituted heterocyclic
systems, for arylhydantoins,7 arylquinolones,8 and aryl-
rhodanines,9 it had been observed, that a chlorine atom
exerts a greater energy barrier than a methyl group in
restricted internal rotation. These results were explained
by the dipolar repulsion between the exocyclic oxygen

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S. F. Og˘uz, I. Dog˘an / Tetrahedron: Asymmetry 14 (2003) 1857–1864
1860
Table 4. Chromatographic data for the separation of
(Fig. 3) in DMSO-d6. This barrier is considerably low
compared with that of 1, which is 102.8 kJ/mol and
cannot be explained by a solvent effect.
enantiomers on Chiralcel OD-H
Compound
k%
1
k%
2
h
The only structural difference between the compounds
1 and 7 is at the 5 position of the heterocyclic ring. The
reason for the higher barrier with the 5,5-dimethyl
compound ( )-1 compared to that of ( )-7 may be
partly due to the buttressing effect of the methyl
groups. In addition to this 1 is unable to undergo a
keto-enol tautomerization (Fig. 4), whereas 7, in princi-
ple, can. Although 13C NMR did not show any sign of
tautomerization for 7, a fast equilibrium with respect to
NMR time scale cannot be excluded. The enol tau-
tomer on the other hand may be expected to stabilize
the planar transition state by resonance, thus lowering
the DG". Also over the enol form (Fig. 4, tautomer D)
the ring opening–reclosure mechanism that had been
suggested by Roussel may also be operating.6 The fast
tautomerization equilibrium may be shifted to the enol
side as the heterocycle ring opens over the enol form.
( )-1a
( )-2b
( )-3b
( )-4b
( )-5b
( )-6b
0.66
2.22
1.23
2.78
3.22
3.79
1.00
3.49
1.83
3.41
5.27
4.67
1.52
1.57
1.49
1.23
1.64
1.23
a Eluent: ethanol, flow rate 0.2 ml/min.
b Eluent: hexane:ethanol mixture=80:20, flow rate: 0.5 ml/min.
than the ortho-chloro derivative. It can be argued that
the difference in the steric effects of these two groups
depends on the geometries of the transition states that
the two rings assume in passing one another. The
tetrahedral nature of the methyl substituent may allow,
depending on the geometry, a lower barrier despite its
larger reported van der Waals radius11 than the spheri-
cal chlorine atom.
For 1-(o-chlorophenyl)barbituric acid, 8, the coales-
cence temperature could not be reached even at 423 K
in dideuterated tetrachloroethane, C2D2Cl4, which
would correspond to a barrier >88 kJ/mol.
The energy barrier for the o-methoxy derivative, 4 has
been found to be less than the o-methyl, 2 and o-
chloro, 5 and a-naphthyl, 6 derivatives as had previ-
ously been observed in literature.8,10 The o-fluoro
derivative, 3 has the lowest energy barrier where
fluorine is the ortho substituent with the smallest van
der Waals radius.11
Excellent separation of the enantiomers (Fig. 2) gave
rise to enantiopurities close to 100%. The high barriers
of the thioxo derivatives would not allow rapid rotation
at ordinary NMR probe temperatures. The structure of
the 2-thiobarbituric acid derivative, 6 shows an NꢀH
bond capable of H-bonding, a naphthyl group for p–p
interaction and carbonyl groups for possible H-bond-
ing. This may make the separated enantiomers of the
( )-6 good candidates for chiral auxiliary, which is
cheap and easily synthesizable to be used in enan-
tiomeric purity determinations by NMR.
Attempts to resolve racemic 1-(o-aryl)barbituric and
-2-thiobarbituric acids 7–10 (unsubstituted at C-5) on
TAC and OD-H columns failed. The activation barrier
to enantiomerization for compound 7, 1-(o-tolyl)-
barbituric acid, has been determined by temperature-
dependent NMR as 70.7 kJ/mol observing the coales-
cence (at 350 K) of the diastereotopic 5-CH2 AB signal
Table 5. Results of the thermal racemization experiments followed by the change in HPLC chromatograms at a constant
temperature with time (column: Chiralcel OD-H; solvent: ethanol)
Compd
X
R
R¦
T (K)
k (10−5 s−1
)
DG", energy barrier (kJ/mol)
( )-1
( )-2
( )-3
( )-4
( )-5
( )-6
O
S
S
S
S
S
CH3
CH3
F
OCH3
Cl
H
H
H
H
H
Benzo
313
343
297
321
345
343
4.0
1.7
22.9
8.8
2.1
1.5
102.8 0.3
115.8 0.3
93.1a
103.7 0.3
115.8 0.4
116.1 0.4
Benzo
a Only two data were available because of fast racemization.

:
S. F. Og˘uz, I. Dog˘an / Tetrahedron: Asymmetry 14 (2003) 1857–1864
1861
Figure 2. The liquid chromatograms of second eluted enantiomer of 5 during thermal racemization at 345 K. column: Chiralcel
OD-H. solvent: hexane:ethanol=80:20. flow: 0.5 ml/min. UV detection at u=240 nm. Inset: The plot of ln([M]−[M]eq/[M]0−
[M]eq) versus time at 345 K for 5.
D (Fig. 4) as suggested by Roussel for 1-arylpyrimidine-
3. Conclusion
2-thione and 3-arylthiazoline-2-thione derivatives.6
The energy barriers for 5,5-dimethyl-1-(o-tolyl)-
barbituric and 5,5-dimethyl-1-(o-tolyl)-2-thiobarbituric
acids were found to be 102.8 and 114.5 kJ/mol, respec-
tively. The racemization barrier for the thioxo deriva-
tive is found to be higher than the oxo derivative. This
result is consistent with the racemization for the 5,5-
dimethyl-1-(o-aryl)barbituric and 5,5-dimethyl-1-(o-
aryl)-2-thiobarbituric acids occuring via rotation about
the C(aryl)ꢀN(sp2) bond.
4. Experimental
1H and 13C NMR spectra were recorded on a Varian
400 NMR spectrometer. Melting points were recorded
using an Electrothermal 9100 melting point apparatus
or Fisher Jones melting point apparatus. The UV spec-
tra were recorded on a Unicam UV2-100 spectrophoto-
meter. Liquid chromatography analyses were
performed on a Cecil 2100 instrument (pump and UV
detector model) using the chiral sorbent, cellulose tris-
The 1-(o-aryl)barbituric and 1-(o-aryl)-2-thiobarbituric
acids could not be resolved by liquid chromatography
on an optically active sorbent. The energy barrier for
the 1-(o-tolyl)barbituric acid was determined as 70.7
kJ/mol by temperature-dependent NMR. This barrier is
rather low compared with that of 5,5-dimethyl-1-(o-
tolyl)barbituric acid, being 102.8 kJ/mol. This low bar-
rier could be explained either by the stabilization of the
planar transition state by resonance due to enol tau-
tomer formation (Fig. 4) or by the ring opening–reclo-
sure mechanism that may take place over the enol form
(3,5-dimethyl)phenylcarbamate,
Chiralcel
OD-H,
(Daicel Ltd, particle size: 5 mm, column size: 250×4.6
mm).
4.1. Thermal racemization
The thermal racemization is performed in the following
way: First each fraction is collected separately. As soon
as the fraction is collected, the solvent is evaporated by

:
S. F. Og˘uz, I. Dog˘an / Tetrahedron: Asymmetry 14 (2003) 1857–1864
1862
into the column to determine the initial concentration.
The solution left is kept in a constant water or oil bath,
and the racemization process is followed by taking 30
ml of the sample at regular time intervals and injecting
to the column after quenching in an ice bath. This
process is repeated until equilibrium is reached or for at
least two half lives.
4.2. Syntheses
The compounds, 2–6, 5,5-dimethyl-1-(o-aryl)-2-thiobar-
bituric acids were prepared from the reaction of 2,2-
dimethyl malonic acid and the appropriate arylthiourea
by heating in a large excess of acetyl chloride for 24 h
under reflux.3 Ice water was added at the end of the
reflux period and the solution was concentrated by
vacuum evaporation. The precipitated crystals were
collected by filtration and the crude product was
purified by either successive recrystallisations from eth-
anol or by flash chromatography. Yields (unoptimized)
were in the range 15–35%.
The compounds,
1 and 7–10, 5,5-dimethyl-1-(o-
tolyl)barbituric acid, 1-(o-aryl)-barbituric and 1-(o-
aryl)-2-thiobarbituric acids were synthesized by the
reaction of 2,2-dimethyldiethylmalonate or diethyl-
malonate with the appropriate arylurea or arylthiourea
in sodium ethoxide solution.3 The crude products were
purified by recrystallization from ethanol.
4.2.1. 5,5-Dimethyl-1-(o-tolyl)barbituric acid, ( )-1. The
compound has been synthesized using o-tolylthiourea
and 2,2-dimethylmalonic acid. Yield: 6.5%. Mp 148–
1
150°C (dec.). H NMR (CDCl3): l=2.16 ppm (3H, s),
1.68 ppm (3H, s), 1.70 ppm (3H, s), 7.07–7.38 ppm (4H,
m), 8.04 ppm (1H, b). 13C NMR (CDCl3): 148.89 ppm
(C-2), 171.98 ppm (C-4 or C-6), 172.59 ppm (C-4 or
C-6), 48.10 ppm (C-5), 24.34 ppm (C-7 or C-8), 25.67
ppm (C-7 or C-8), 127.40–135.90 ppm (aromatic C’s),
17.78 ppm (o-CH3). UV data (EtOH): umax, (log mmax)=
206 nm, (4.16). IR data: w¯ NꢀH stretching: 3571, 3254
cm−1, w¯ NꢀCꢁO stretching: 1692 cm−1, w¯ CꢀN stretch-
ing: 1349 cm−1.
Figure 3. The temperature-dependent 1H NMR spectrum of
5-CH2 protons of compound 7 in DMSO-d6 showing the
coalescence of the AB type splittings.
blowing nitrogen gas to the sample. This procedure is
done successively, until about 0.2 mg of each enan-
tiomer is collected. Then the solid is dissolved in 200 ml
of absolute ethanol, and 30 ml of the solution is injected
Figure 4. Possible tautomers of barbituric and 2-thiobarbituric acid derivatives in ethanol.

:
S. F. Og˘uz, I. Dog˘an / Tetrahedron: Asymmetry 14 (2003) 1857–1864
1863
4.2.2. 5,5-Dimethyl-1-(o-tolyl)-2-thiobarbituric acid, ( )-
2. The compound has been synthesized using o-tolylth-
iourea and 2,2-dimethylmalonic acid. Yield: 35%. Mp
NꢀH stretching: 3248 cm−1, w¯ NꢀCꢁO stretching: 1721,
1695 cm−1, w¯ CꢀN stretching: 1334 cm−1, w¯ CꢁS stretch-
ing: 1211 cm−1. Mass (EI+): C12H11ClN2O2S (M+),
found (M+−Cl): m/z, 247, calculated for (M+−Cl): m/z,
247.
1
146–147°C. H NMR (CDCl3): l=2.16 ppm (3H, s),
1.69 ppm (3H, s), 1.70 ppm (3H, s), 7.04–7.39 ppm (4H,
m), 9.08 ppm (1H, b). 13C NMR (CDCl3): 177.71 ppm
(C-2), 169.75 ppm (C-4 or C-6), 171.13 ppm (C-4 or
C-6), 48.67 ppm (C-5), 24.07 ppm (C-7 or C-8), 25.38
ppm (C-7 or C-8), 127.47–136.93 ppm (aromatic C’s),
17.74 ppm (o-CH3). UV data (EtOH): umax, (log mmax)=
238 nm, (6.7); 252 nm, (5.8); 288 nm, (6.38); 405 nm,
(5.4). IR data: w¯ of NꢀH stretching: 3247 cm−1, w¯ of
NꢀCꢁO stretching: 1715, 1691 cm−1, w¯ of CꢀN stretch-
ing: 1335 cm−1, w¯ of CꢁS stretching: 1212 cm−1. Mass
(EI+): C13H14N2O2S (M+), found: m/z, 262, calculated
for (M+): m/z, 262.
4.2.6. 5,5-Dimethyl-1-(a-naphthyl)-2-thiobarbituric acid,
( )-6. The compound has been synthesized using a-
naphthylthiourea and 2,2-dimethylmalonic acid. Yield:
1
33%. Mp 209°C. H NMR (CDCl3): l=1.75 ppm (3H,
s), 1.81 (3H, s), l=7.30–8.00 ppm (4H, m). 9.17 ppm
(1H, b). 13C NMR (CDCl3): 178.36 ppm (C-2), 169.78
ppm (C-4 or C-6), 171.20 ppm (C-4 or C-6), 48.76 ppm
(C-5), 23.19 ppm (C-7 or C-8), 25.86 ppm (C-7 or C-8),
112.41–154.50 ppm (aromatic C’s), 56.22 ppm (o-CH3).
UV data (EtOH): umax, (log mmax)=236 nm, (7.7); 253
nm, (7.05); 289 nm, (7.3); 406 nm, (6.6). IR data: w¯
NꢀH stretching: 3274 cm−1, w¯ NꢀCꢁO stretching: 1716,
1692 cm−1, w¯ CꢀN stretching: 1334 cm−1, w¯ CꢁS stretch-
ing: 1211 cm−1. Mass (EI+): C16H14N2O2S (M+), found:
m/z, 298, calculated: m/z, 298.
4.2.3. 5,5-Dimethyl-1-(o-fluorophenyl)-2-thiobarbituric
acid, ( )-3. The compound has been synthesized for the
first time using o-fluorophenylthiourea and 2,2-
dimethylmalonic acid. Yield: 34%. Mp 159°C. 1H
NMR (CDCl3): l=1.59 ppm (3H, s), 1.62 ppm (3H, s),
l=7.10–7.62 ppm (4H, m), l=9.09 ppm (1H, b). 13C
NMR (CDCl3): 177.68 ppm (C-2), 169.53 ppm (C-4 or
C-6), 171.08 ppm (C-4 or C-6), 48.83 ppm (C-5), 23.40
ppm (C-7 or C-8), 25.65 ppm (C-7 or C-8), 116.47–
4.2.7. 1-(o-Tolyl)barbituric acid, ( )-7. The compound
has been synthesized using o-tolylurea and diethyl-
malonate. Yield: 12.8%. Mp 234–235°C. 1H NMR
(CDCl3): l=2.18 ppm (3H, s), 3.84 (2H, s), l=7.09–
7.38 ppm (4H, m), 8.11 ppm (1H, b); 1H NMR
(DMSO-d6): l=2.08 ppm (3H, s), 3.68, 3.87 (2H, AB),
l=7.14–7.29 (4H, m), 11.46 (1H, b). 13C NMR
(CDCl3): 148.57 (C-2), 163.42 (C-4 or C-6), 164.60 (C-4
or C-6), 39.84 (C-5), 127.46–135.50, (aromatic C’s),
17.05 (o-CH3). UV data (EtOH): umax, (log mmax); 203.5
nm, (4.54); 259.5 nm, (4.33). IR data: w¯ NꢀH stretching:
3224 cm−1, w¯ NꢀCꢁO stretching: 1720 cm−1, w¯ CꢀN
stretching: 1342 cm−1. Elemental analysis: found C,
60.31; H, 4.39; N, 12.57, calculated for C11H10N2O3: C,
60.31; H, 4.62; N, 12.89.
131.57 ppm (aromatic C’s). UV data (EtOH): umax
,
(log mmax)=235 nm, (5.23); 252 nm, (5.29); 288 nm,
(5.36); 392 nm, (2.83). IR data: w¯ NꢀH stretching: 3292
cm−1, w¯ NꢀCꢁO stretching: 1747cm−1, w¯ CꢀN stretching:
1358 cm−1, w¯ CꢁS stretching: 1185 cm−1. Mass (EI+):
C12H11FN2O2S (M+), found: m/z, 266, calculated for
(M+): m/z, 267.
4.2.4. 5,5-Dimethyl-1-(o-methoxyphenyl)-2-thiobarbituric
acid, ( )-4. The compound has been synthesized for the
first time using o-methoxyphenylthiourea and 2,2-
dimethylmalonic acid. Yield: 15%. Mp 160°C. 1H
NMR (CDCl3): l=1.66 ppm (3H, s), 1.70 (3H, s),
l=3.81 ppm (3H, s), l=7.00–7.45 ppm (4H, m), l=
9.09 (1H, b). 13C NMR (CDCl3): 178.36 ppm (C-2),
169.78 ppm (C-4 or C-6), 171.20 ppm (C-4 or C-6),
48.76 ppm (C-5), 23.19 ppm (C-7 or C-8), 25.86 ppm
(C-7 or C-8), 112.41–154.50 ppm (aromatic C’s), 56.22
ppm (o-CH3). UV data (EtOH): umax, (log mmax)=226
nm, (5.62); 243 nm, (5.76); 294 nm, (5.14); 393 nm,
(2.81), IR data: w¯ NꢀH stretching: 3137 cm−1, w¯ NꢀCꢁO
stretching: 1747, 1709 cm−1, w¯ CꢀN stretching: 1330
cm−1, w¯ CꢁS stretching: 1211 cm−1. Mass (EI+):
C13H14N2O2S (M+), found: m/z, 277, calculated for
(M+): m/z, 278.
4.2.8. 1-(o-Chlorophenyl)barbituric acid, ( )-8. The com-
pound has been synthesized using o-chlorophenylurea
and diethylmalonate. Yield: 5.8%. Mp 224.5°C (dec.).
1H NMR (CDCl3): l=3.84, 3.88 ppm (2H, AB), l=
7.25–7.57 ppm (4H, m), 8.04 ppm (1H, b). 13C NMR
(CDCl3): 163.58 ppm (C-4 or C-6), 164.17 ppm (C-4 or
C-6), 39.82 ppm (C-5), 128.18–131.22 ppm (aromatic
C’s). UV data (EtOH): umax, (log mmax); 204.5 nm,
(4.18); 259 nm, (3.86). IR data: w¯ NꢀH stretching: 3218
cm−1, w¯ NꢀCꢁO stretching: 1724 cm−1, w¯ CꢀN stretch-
ing: 1346 cm−1. Elemental analysis: found C, 50.41; H,
3.03; N, 11.48, calculated for C10H7ClN2O3: C, 50.31;
H, 2.96; N, 11.78.
4.2.5. 5,5-Dimethyl-1-(o-chlorophenyl)-2-thiobarbituric
acid, ( )-5. The compound has been synthesized using
o-chlorophenylthiourea and 2,2-dimethylmalonic acid.
Yield: 29%. Mp 178°C. 1H NMR (CDCl3): l=1.68
ppm (3H, s), 1.75 ppm (3H, s), l=7.24–7.54 ppm (4H,
m), 9.13 ppm (1H, b). 13C NMR (CDCl3): 177.28 ppm
(C-2), 169.60 ppm (C-4 or C-6), 170.78 ppm (C-4 or
C-6), 48.75 ppm (C-5), 23.18 ppm (C-7 or C-8), 26.26
ppm (C-7 or C-8), 128.10–135.38 ppm (aromatic C’s).
UV data (EtOH): umax, (log mmax)=237 nm, (5.9); 253
nm, (5.08); 288 nm, (5.6); 407 nm, (4.6). IR data: w¯
4.2.9. 1-(o-Tolyl)-2-thiobarbituric acid, ( )-9. The com-
pound has been synthesized using o-tolylthiourea and
diethylmalonate. Yield: 31.5%. Mp 137°C (dec.). 1H
NMR (CDCl3): l=2.16 ppm (3H, s), 3.87, 3.89 ppm
(2H, AB), l=7.06–7.40 ppm (4H, m), 9.38 ppm (1H,
b). 13C NMR (CDCl3): 178.46 ppm (C-2), 162.19 ppm
(C-4 or C-6), 163.37 ppm (C-4 or C-6), 40.29 ppm
(C-5), 127.62–138.46 ppm (aromatic C’s), 17.78 ppm
(o-CH3). UV data (EtOH): umax, (log mmax); 203 nm,
(3.86); 267 nm, (3.28); 285 nm, (3.27); 450 nm, (3.30).
IR data: w¯ NꢀH stretching: 3228 cm−1, w¯ NꢀCꢁO

:
S. F. Og˘uz, I. Dog˘an / Tetrahedron: Asymmetry 14 (2003) 1857–1864
1864
stretching: 1728 cm−1, w¯ CꢀN stretching: 1332 cm−1, w¯
CꢁS stretching: 1193 cm−1. Elemental analysis: found C,
55.28; H, 4.25; N, 11.52, calculated for C11H10N2O2S:
C, 56.37; H, 4.30; N, 12.0.
References
1. Jovanovic, M. V.; Biehl, E. R. J. Org. Chem. 1987, 24,
191–204.
2. Allenmark, S. G. Chromatographic Enantioseparation, 1st
ed.; Ellis Horwood: New York, 1988; p. 96.
4.2.10. 1-(o-Chlorophenyl)-2-thiobarbituric acid, ( )-10.
The compound has been synthesized using o-
chlorophenylthiourea and diethylmalonate. Yield: 32%.
Mp 164°C (dec.). 1H NMR (CDCl3): l=3.88, 3.91 ppm
(2H, AB), l=7.62–7.98 ppm (4H, m), 9.31 ppm (1H,
b). 13C NMR (CDCl3): 177.87 ppm (C-2), 161.26 ppm
(C-4 or C-6), 163.01 ppm (C-4 or C-6), 40.34 ppm
(C-5), 126.16–134.88 ppm (aromatic C’s). UV data
(EtOH): umax, (log mmax); 206 nm, (4.09); 244 nm, (3.53);
268 nm, (3.66); 427 nm, (3.21). IR data: w¯ NꢀH stretch-
ing: 3429 cm−1, w¯ NꢀCꢁO stretching: 1710 cm−1, w¯ CꢀN
stretching: 1343 cm−1, w¯ CꢁS stretching: 1189 cm−1.
Elemental analysis: found C, 46.45; H, 2.59; N, 10.59,
calculated for C10H7ClN2O2S: C, 47.14; H, 2.77; N,
11.04.
:
3. Og˘uz, F. S.; Berg, U.; Dog˘an, I. Enantiomer 2000, 5,
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Perkin Trans. 2 1993, 1557–1560.
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Acknowledgements
11. Carey, A. F.; Sundberg, R. Advanced Organic Chemistry,
Part A: Structure and Mechanism; Plenum Press: New
York, 1990; p. 120.
We thank Dr. Andreas Ritze´n for valuable discussions.
This project has been supported by Bog˘azic¸i University
Research Fund (Project No. 99B508D).