Experimental and theoretical studies on thermodynamics and properties of tautomers of 2-substituted 6(4)-methyl-1,4(1,6)-dihydropyrimidine-5-carboxylates

Article abstract of DOI:10.1016/j.tet.2018.03.032

Experimental and theoretical studies on the thermodynamics and properties of 2-substituted 6(4)-methyl-1,4(1,6)-dihydropyrimidine-5-carboxylates were undertaken by ¹H NMR measurements and DFT (density functional theory) calculations. The ratios

Full text of DOI:10.1016/j.tet.2018.03.032

Accepted Manuscript
Experimental and theoretical studies on thermodynamics and properties of tautomers
of 2-substituted 6(4)-methyl-1,4(1,6)-dihydropyrimidine-5-carboxylates
Hidetsura Cho, Yoshio Nishimura, Hiroshi Ikeda, Mitsuhiro Asakura, Shinji Toyota
PII:
S0040-4020(18)30275-8
10.1016/j.tet.2018.03.032
TET 29372
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 February 2018
Revised Date: 12 March 2018
Accepted Date: 14 March 2018
Please cite this article as: Cho H, Nishimura Y, Ikeda H, Asakura M, Toyota S, Experimental and
theoretical studies on thermodynamics and properties of tautomers of 2-substituted 6(4)-methyl-1,4(1,6)-
dihydropyrimidine-5-carboxylates, Tetrahedron (2018), doi: 10.1016/j.tet.2018.03.032.
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Experimental and theoretical studies on thermodynamics
and properties of tautomers of 2-substituted 6(4)-methyl-
1,4(1,6)-dihydropyrimidine-5-carboxylates
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Hidetsura Cho*, Yoshio Nishimura, Hiroshi Ikeda, Mitsuhiro Asakura, Shinji Toyota*

1
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Tetrahedron
journal homepage: www.elsevier.com
Experimental and theoretical studies on thermodynamics and properties of
tautomers
of
2-substituted
6(4)-methyl-1,4(1,6)-dihydropyrimidine-5-
carboxylates
Hidetsura Choa,b*, Yoshio Nishimurac, Hiroshi Ikedad,e, Mitsuhiro Asakurab and Shinji Toyota e*
a Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan
b NARD Institute, LTD., 2-6-1, Nishinagasu-cho, Amagasaki, Hyogo, 660-0805, Japan
c Faculty of Pharmacy, Yasuda Women’s University, 6-13-1, Yasuhigashi, Asaminami-ku, Hiroshima, 731-0153, Japan
dTokyo Metropolitan College of Industrial Technology, 1-10-40, Higashi-Ohi, Shinagawa-ku, Tokyo, 140-0011, Japan
eTokyo Institute of Technology, Department of Chemistry, School of Science, 2-12-1-E1-4, Ookayama, Meguro-ku, Tokyo, 152-8551, Japan
ARTICLE INFO
Abstract: Experimental and theoretical studies on the thermodynamics and properties of 2-
substituted 6(4)-methyl-1,4(1,6)-dihydropyrimidine-5-carboxylates were undertaken by 1H
NMR measurements and DFT (density functional theory) calculations. The ratios of tautomers
a/b of dihydropyrimidines (DPs) 1, 2, and 3 were determined under various conditions to reveal
the effects of temperature, solvent, and concentration on the thermodynamic data. The observed
Article history:
Received
Received in revised form
Accepted
Available online
results, the free energy differences (
S), are discussed in terms of the molecular structures, dipole moments (DM), and the
electrostatic potential maps calculated by the DFT to clarify the nature of the DPs.
∆G), enthalpy differences (∆H), and entropy differences
(
∆
Keywords:
Dihydropyrimidine;
Tautomerism;
Tautomer;
2009 Elsevier Ltd. All rights reserved
.
Thermodynamics;
DFT calculation
1. Introduction
Dihydropyrimidines (DPs) have received much attention from
synthetic and medicinal chemists owing to their biological
activities and unique physical and chemical characteristics.1 They
exhibit a wide range of activities for possible medicinal
applications, such as calcium antagonists,2 anti-MRSA agents
(emmacin),3 and selective and orally bioavailable inhibitors of
Rho kinase (ROCK1).4 The chemical structure of DPs is
ambiguous and complicated owing to tautomerism and the
isomerization of double bonds, because DPs theoretically have
nine isomeric mixtures including tautomers.1,5 Tautomerism in
the DP system has not been sufficiently investigated to date.6 A
DP is usually observed as a single compound in an NMR
spectrum. Namely, a proton transfer from one nitrogen atom to
the other is very fast, and the NMR spectrum usually exhibits an
average spectrum of two tautomers and so resembles the
spectrum of a single compound just like that of an imidazole
derivative. Therefore, it is unusual to observe separated isomers
of 1,4-DP and 1,6-DP (Fig. 1).
Fig. 1. Tautomerism of dihydropyrimidine.
tautomers of DPs are sometimes independently observed in 1H
NMR spectra are shown in Fig. 2. For instance, Weis and co-
workers studied the tautomerism of 6(4)-methyl-2,4(6)-diphenyl-
1,4(1,6)-dihydropyrimidine A and observed two individual
tautomers at −50 °C in a highly diluted CDCl3 solution [0.001–
0.003 M (mol L–1)].7 On the other hand, Cho and co-workers
synthesized DP derivatives B having various 2-substituents and
an o-nitrophenyl group at the 4(6)-position and observed the
individual tautomers of 2-CF3 and 2-SMe derivatives from 25 °C
to 70 °C at higher concentrations (0.007–0.212 M in C6D6),8
although it is generally presumed that tautomers could sometimes
be observed at very low temperatures below 0 °C and in highly
diluted solutions.7 They reported in the supporting data that the
ratio of individual 1,4- and 1,6-tautomers changes regularly
depending on temperature and concentration.8
Representative examples demonstrating that both 1,4- and 1,6-
*Corresponding author. (H. Cho).; Tel: +81-22-795-6812; Fax:
+81-22-795-6811 e-mail address: hcho@mail.pharm.tohoku.ac.jp
*Corresponding author. (S. Toyota).; Tel: +81-3-5734-2294; e-
mail address: stoyota@cms.titech.ac.jp

2
Tetrahedron
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Recently, Cho, Nishimura and co-workers reported that
individual tautomers of 2-SMe derivative C and derivatives D
were also observed over some ranges of temperatures in DMSO-
d6 and CDCl3 (0.012–0.050 M).9,10 However, experimental and
theoretical studies of the thermodynamics and properties of DPs
have not been carried out in detail.
Scheme 1. Synthesis of dihydropyrimidine 1.
DPs 2 and 3 were synthesized as follows (Scheme 2). 2-
Methoxy derivative 2 was synthesized in 51% yield by heating 1
in MeOH. 2-Dimethylamino derivative 3 was prepared from 4 in
four steps. Regioselective protection with
a Boc group
(NaH/Boc2O) afforded 5 in 90% yield, followed by methylation
(MeI/Et3N) to give 6 in 87% yield. Subsequently, the substitution
reaction of 6 with dimethylamine hydrochloride under basic
condition provided 7 in 50% yield, followed by deprotection of
the N-Boc group under acidic condition to yield 3 in 95% yield. 9
Fig. 2. Examples of dihydropyrimidines observed as their individual
tautomers.
1
Therefore, further H NMR studies should be undertaken to
clarify the nature of tautomers of novel DPs at various
temperatures, in polar or nonpolar solvents, and at several
concentrations. In addition, DFT (density functional theory)
calculations may prove interesting to explain the cause of the
ratio of tautomers regularly changing and to determine their
properties.
Hence, we will report experimental results on the regular
changes in the ratios of tautomers a and b of DPs 1, 2, and 3 (Fig.
3) under various conditions (temperature, solvent, and
concentration) and describe the findings obtained from
thermodynamic studies and the properties of several DPs using
van't Hoff equations, free energy differences (∆G), enthalpy
differences (∆H), dipole moments (DM), and electrostatic
potential maps.
Scheme 2. Synthesis of dihydropyrimidines 2 and 3.
The 1H NMR spectra of SMe-DP 1 and OMe-DP 2 exhibited a
mixture of tautomers a and b at 20 °C (293 K) in DMSO-d6,
respectively. Prior to an NOE study of SMe-DP 1, the singlet
(2.11 ppm) was ascribed to the 6-Me group by the heteronuclear
multiple bond coherence (HMBC) correlation between the 6-Me
group and 5-carbon (93.9 ppm) (Fig. 4 and Supplementary data
Fig. S1). Subsequently, an NOE (2.2%) was observed between
the 1-NH proton (9.28 ppm) and the 6-Me group. Thus, the major
tautomer was assigned as 1,4-DP. Similarly, an NOE (2.3%) of
OMe-DP 2 was found between the 1-NH proton and the 6-Me
group, and the major tautomer was assigned to be 1,4-DP; in
addition, an NOE (2.6%) was observed between the 1-NH proton
and 6-H in the minor tautomer 1,6-DP (Fig. 5). However, in the
case of NMe2-DP 3, the spectrum suggested a sole isomer, 1,6-
DP (Fig. 6). This should not be an average spectrum of 1,4- and
1,6-DP but a single 1,6-tautomer because of the presence of NOE
(3.1%) correlations between the NH proton and the NMe protons,
and the observed NOE (1.9%) between the NH proton and 6-H
(Fig. 6), as well as the results of the theoretical studies described
in the later section.
Fig. 3. Chemical structures of dihydropyrimidines 1–3 and their tautomers.
2. Results and Discussion
2.1. Synthesis of DPs 1, 2, and 3
DP 1 was prepared according to a modified procedure based on
our previous method.9 Namely, a three-component Biginelli
reaction of thiourea, formaldehyde, and ethyl acetoacetate using
aluminum trichloride hexahydrate as
a
catalyst gave
dihydropyrimidine-2-thione 4. The S-methylation reaction of 4
furnished HI salts of 1, and following basic workup and
purification with SiO2 chromatography gave DP 1.

3
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Fig. 4. 1H NMR spectrum of dihydropyrimidine 1 [DMSO-d6, 0.012 M, 20 °C (293 K)].
Fig. 5. 1H NMR spectrum of dihydropyrimidine 2 [DMSO-d6, 0.012 M, 20°C (293 K)].
Fig. 6. 1H NMR spectrum of dihydropyrimidine 3 [DMSO-d6, 0.012 M, 25 °C (298 K)].

4
Tetrahedron
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Table 1. Ratios of 1,4- and 1,6-tautomers of 1 at various
temperatures and concentrations (DMSO-d6)
Temp.(°C) /
5.92:1.00 at 20 °C to 2.74:1.00 at 90°C (Table 1). This trend was
also observed in the measurements of 1 in CDCl3 and C6D6
(Supplementary data). Similarly, the ratios of 1,4-DP to 1,6-DP
of 2 in DMSO-d6 decreased as shown in Table 2, as well as in
CDCl3 and C6D6 (Supplementary data).
Ratio 1,4-DP:1,6-DP
(K: kelvin)
0.012 M
0.050 M
0.12 M
20/293
25/298
30/303
35/308
40/313
45/318
50/323
55/328
60/333
65/338
70/343
75/348
80/353
85/358
90/363
5.92:1.00
5.51:1.00
5.32:1.00
4.83:1.00
4.65:1.00
4.30:1.00
3.87:1.00
3.85:1.00
3.60:1.00
3.47:1.00
3.43:1.00
3.12:1.00
2.99:1.00
2.80:1.00
2.74:1.00
6.49:1.00
6.18:1.00
6.05:1.00
5.72:1.00
5.38:1.00
5.00:1.00
4.79:1.00
4.48:1.00
4.22:1.00
4.00:1.00
3.85:1.00
3.64:1.00
3.43:1.00
3.19:1.00
3.11:1.00
6.93:1.00
6.67:1.00
6.29:1.00
5.97:1.00
5.64:1.00
5.30:1.00
5.04:1.00
4.83:1.00
4.73:1.00
4.56:1.00
4.33:1.00
4.02:1.00
3.88:1.00
3.74:1.00
3.55:1.00
2.3. Thermodynamics of tautomers of DPs from van't Hoff plots
The thermodynamics of tautomerization was analyzed using
van't Hoff plots by observing the equilibrium constant K ([1,4-
DP]/[1,6-DP]) as a function of temperature T (K). The van’t Hoff
plots of 1 and 2 in DMSO-d6 at 0.012 M are shown in Figs. 7 and
8, respectively, as typical cases (other plots are given in the
supplementary data). Both plots showed
a nearly linear
correlation between 1/T and ln K, and the enthalpy difference
(∆H°) and entropy difference (∆S°) were obtained by least
squares fitting (experimental section 4.3). The thermodynamic
parameters as well as the chemical shifts of the NH protons are
compiled in Table 3.
For each entry, the ∆H° and ∆S° values are positive. This
means that 1,4-DP is enthalpically favorable to 1,6-DP, and that
the conversion from 1,4-DP to 1,6-DP results in an increase in
molecular freedom in solution. The positive ∆G° values (namely
K < 1) mean that 1,4-DP is more abundant than 1,6-DP at 298 K.
Under the same conditions, the ∆G° value of 1 is always larger
than that of 2 (e.g., 4.24 and 2.48 kJ mol–1 for 1 and 2,
respectively, in DMSO-d6 at 0.012 M). The ∆G° values decrease,
namely the population of 1,4-DP increases, in the order DMSO-
d6, CDCl3, and C6D6 at the same concentration for each
compound. There are small effects of concentration on the
tautomer population: the population of the 1,4-isomer constantly
increases with increasing concentration except for 1 in C6D6.
These results will be discussed later with the aid of theoretical
calculations.
Table 2. Ratios of 1,4- and 1,6-tautomers of 2 at various
temperatures and concentrations (DMSO-d6)
Temp.(°C) /
Ratio 1,4-DP:1,6-DP
(K: kelvin)
0.012 M
0.050 M
0.12 M
20/293
25/298
30/303
35/308
40/313
45/318
50/323
55/328
60/333
65/338
70/343
75/348
80/353
85/358
90/363
2.74:1.00
2.69:1.00
2.62:1.00
2.57:1.00
2.52:1.00
2.44:1.00
2.37:1.00
2.33:1.00
2.28:1.00
2.22:1.00
2.14:1.00
2.06:1.00
2.00:1.00
1.97:1.00
1.90:1.00
2.93:1.00
2.86:1.00
2.79:1.00
2.67:1.00
2.60:1.00
2.55:1.00
2.49:1.00
2.37:1.00
2.31:1.00
2.19:1.00
2.13:1.00
2.06:1.00
1.99:1.00
1.90:1.00
1.87:1.00
3.09:1.00
3.03:1.00
2.91:1.00
2.84:1.00
2.77:1.00
2.68:1.00
2.58:1.00
2.49:1.00
2.42:1.00
2.34:1.00
2.31:1.00
2.23:1.00
2.17:1.00
2.10:1.00
2.05:1.00
2.4. DFT calculations of DP tautomers
In order to obtain further insight into the experimental results,
we carried out DFT calculations for the two tautomers of DPs 8–
12 (Fig. 9). Compounds 9–11 are model compounds of 1–3,
respectively, where the ethyl group in the ester moiety is replaced
by a methyl group for simplification.11 Substituent-free derivative
8 and CF3-substituted derivative 12 (an analog of B: R1 = CF3 in
Fig. 2) were also treated as a series of compounds, although the
synthesis of the corresponding ethyl esters was unsuccessful. The
structures of the two tautomers were optimized at the M06-2X/6-
31G(d) level, because this function tended to give reliable
thermochemical parameters for common organic compounds.12
The thermodynamic parameters were obtained by a frequency
analysis of each energy-minimum structure.
2.2. Determination of the population of DP tautomers
1
The H NMR spectra of 1 and 2 were measured at various
temperatures in three solvents, such as a polar solvent (DMSO-
d6), a less polar solvent (CDCl3), and a nonpolar solvent (C6D6).
To investigate the effect of concentration, the measurements
were independently performed at three different concentrations
(0.012 M, 0.050 M, and 0.12 M in DMSO-d6 and CDCl3, and
0.0050 M, 0.012 M, and 0.050 M in C6D6). All the measurements
were carried out under an argon atmosphere in order to prevent
oxidation to pyrimidines. The ratios of 1,4- and 1,6-DPs were
determined using integrated intensities of their NH signals. The
data for 1 and 2 in DMSO-d6 are provided in Tables 1 and 2,
respectively, and the data from the other solvents (CDCl3 and
C6D6) at three concentrations are given in the supplementary
data. The ratios (1,4-DP vs 1,6-DP) of 1 and 2 regularly changed
2.4.1. Calculations of tautomers of 8
The structural optimization of 8a and 8b gave one energy-
minimum structure each, as shown in Fig. 10. In the optimized
structures of 8a and 8b, the six-membered rings are almost planar
regardless of the positions of the double bonds. The two
compounds have similar conformations with respect to the ester
moiety: the plane consisting of the COO moiety is coplanar with
the six-membered ring so as to the carbonyl oxygen atom is away
from the ring methyl group. These structural features are
common in the X-ray structures of the other 1,4-DP and 1,6-DP
derivatives.9, 13
o
o
as the temperature increased from 20 C to 90 C at 0.012 M,
0.050 M, and 0.12 M in DMSO-d6. For instance, the ratios of the
1,4-DP to 1,6-DP of 1 decreased in 0.012 M DMSO-d6 from

5
-0.60
ACCEPTED MANUSCRIPT
-0.80
-1.00
-1.20
-1.40
-1.60
-1.80
-2.00
-0.70
y = –559.71x + 0.8766
R² = 0.98409
y = –1183.5x + 2.2586
R² = 0.99324
-0.80
-0.90
-1.00
-1.10
0.0027
0.0029
0.0031
1/ T
0.0033
0.0035
0.0027
0.0029
0.0031
1/
Fig. 7. van’t Hoff plot of 1 in DMSO-d6 (0.012 M).
0.0033
0.0035
T
Fig. 8. van’t Hoff plot of 2 in DMSO-d6 (0.012 M).
Table 3. Effects of solvents and concentration on thermodynamic parameters for tautomerization of 1 and 2. a
c
Compound
Solvent b
Concentration
∆H°
∆S°
∆G° c
K298
δ
NH d
δ
NH d
(mol L–1)
(kJ mol–1)
(J mol–1 K–1)
(kJ mol–1)
1,4-DP
1,6-DP
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
CDCl3
CDCl3
C6D6
0.012
0.050
0.12
9.84 ± 0.49
9.70 ± 0.49
8.43 ± 0.32
7.38 ± 0.57
7.25 ± 0.51
7.93 ± 0.39
5.12 ± 0.32
4.79 ± 0.36
3.84 ± 0.28
4.65 ± 0.35
5.87 ± 0.41
5.31 ± 0.19
4.91 ± 0.44
4.47 ± 0.25
4.86 ± 0.46
1.56 ± 0.10
1.50 ± 0.05
2.06 ± 0.13
18.8 ± 1.5
17.2 ± 1.6
12.6 ± 1.0
13.7 ± 1.9
12.5 ± 1.7
13.2 ± 1.3
8.5 ± 1.1
7.5 ± 1.2
3.3 ± 0.9
7.3 ± 1.1
10.8 ± 1.3
8.6 ± 0.6
9.2 ± 1.5
7.1 ± 0.9
7.3 ± 1.6
2.4 ± 0.4
2.1 ± 0.2
3.8 ± 0.5
4.24
4.59
4.69
3.31
3.51
4.00
2.59
2.55
2.85
2.48
2.64
2.75
2.16
2.35
2.69
0.86
0.89
0.92
0.180
0.157
0.151
0.263
0.242
0.199
0.351
0.357
0.316
0.368
0.344
0.330
0.419
0.387
0.338
0.707
0.699
0.691
9.25
9.25
9.25
5.89
6.00
6.15
5.03
5.06
5.23
8.89
8.89
8.89
5.60
5.67
5.79
4.79
4.80
4.93
8.20
8.20
8.19
5.16
5.24
5.37
3.77
3.79
0.012
0.050
0.12
0.0050
0.012
0.050
0.012
0.050
0.12
C6D6
e
C6D6
–
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
CDCl3
CDCl3
C6D6
7.63
7.63
7.63
4.71
4.77
4.87
3.54
3.56
3.69
0.012
0.050
0.12
0.0050
0.012
0.050
C6D6
C6D6
a. Symbol ° refers to the standard condition (298 K, 1 atm).
b. See footnote of Table 6 for dielectric constants of these solvents.
c. Calculated according to the equations of ∆G° = ∆H° – T∆S° and ∆G° = –RTlnK (298 K).
d. At 298 K.
e. Overlapped with other signals.

6
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ACCEPTED MANUSCRIPT
in nearly the same direction to enhance the net dipole moment.
On the other hand, the two dipole moments cancel out to some
extent in 1,6-DP 8b. The difference in molecular polarity can be
confirmed from the electrostatic maps in Fig. 10. In the two
compounds, electron-rich regions are distributed around the
carbonyl oxygen atom and sp2 nitrogen atom, and electron-
deficient regions are distributed around NH moiety. This feature
is well understood in terms of the resonance structures shown in
Fig. 11 where the C=O and NH moieties contribute negative and
positive charges, respectively.
Fig 9. Chemical structures of dihydropyrimidines 8–12 for DFT calculations.
Table 4. Calculated data for the optimized structures of tautomers 8a
and 8b at M06-2X/6-31G(d) level. a
E° (au)
H° (au)
G° (au)
µ
(D)b
8a
8b
–532.481181
–532.481439
–532.295543
–532.295693
–532.344546
–532.345024
5.25
1.70
8b–8a
–0.000257
(–0.68)c
–0.000150
(–0.39)c
–0.000478
(–1.25)c
a
b
c
In au (atomic unit) unless otherwise noted. 1 au = 2625.50 kJ mol–1.
Dipole moment in debye (D), 1 D = 3.33564×10ꢀ 30 C m.
In kJ mol–1.
Fig.11. Resonance structures of 8a and 8b.
2.4.2. Calculations for 2-substituted derivatives
Similar calculations were also carried out for the 2-substituted
derivatives 9–12. For 9 and 10, we calculated structures from the
conformers shown in Fig. 12 that differ in the conformation of
the OMe or SMe group. We obtained two energy-minimum
structures of 9a and 9b, where the Me group in the SMe group is
nearly coplanar with the attached C=N bond in either syn or anti
conformation. The syn forms, 1,4-DP syn-9a and 1,6-DP syn-9b,
are much more stable than the corresponding anti forms, 1,4-DP
anti-9a and 1,6-DP anti-9b, in the two tautomers. Therefore, we
can ignore the presence of the anti forms under ordinary
conditions. The anti forms are destabilized by the steric
interaction between the Me group and the adjacent NH group.
For the methoxy derivatives 10, only syn forms were obtained as
energy-minimum structures. Although 10b gave two structures
that differ in the conformation of the six-membered ring, only the
stable one is considered in the following discussion.
O
O
N
N
O
O
N
N
8a
8b
O
O
NH
N
NH
N
8a
8b
Fig. 10. Calculated structures of 8a and 8b at M06-2X/6-31G(d) level and
their electrostatic potential maps (red: electron-rich, blue: electron-deficient).
The thermodynamic parameters and dipole moments of
optimized 8a and 8b are listed in Table 4. The data indicate that
8b is slightly more stable than 8a; the energy differences are 0.39
kJ mol–1 in H° and 1.25 kJ mol–1 in G°. The comparable
stabilities of the two tautomers of the parent DP were predicted
in a previous theoretical study.14 From the free energy difference
(∆G°), the equilibrium constant K298 ([8b]/[8a]) was calculated to
be 1.66 (Table 5). The thermodynamic preference for 1,6-DP 8b
is attributable to the extended conjugation along the three double
bonds. The calculated dipole moments mean that 8a (5.25 D) is
much more polar than 8b (1.70 D). Qualitatively, this difference
can be explained by the dipole moments of the two polar C=O
and C=N double bonds. In 1,4-DP 8a, the dipole moments direct
Fig. 12. Two energy-minimum conformers of 9a and 9b. Values are relative
energies to the syn forms in kJ mol–1.

7
The calculated energies of 8–12 are compiled in Table 5,
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where only relative energies of 1,4-DP and 1,6-DP are given. The
free energy differences increase in the order of 11(NMe2) <<
10(OMe) < 8(H) ≈ 9(SMe) < 12(CF3). The value of 11 is large
and negative, meaning that most molecules should exist as 1,6-
DP in equilibrium. In contrast, the positive value of 12 means
that 1,6-DP is less stable than 1,4-DP. These results mean that
electron donating groups tend to stabilize 1,6-DP relative to 1,4-
DP. In 1,6-DP, the substituent at the 2-position is bonded to a
terminal carbon of the three conjugated double bonds. Therefore,
the electron donating group should result in stabilization by
resonance, as shown as the resonance structures of 11b in Fig.
13. The dipole moment of 1,4-DP is larger than that of its
tautomer 1,6-DP in all the substituted derivatives as discussed for
8. As for 1,6-DP, the dipole moment of 11b (4.41 D) is much
larger than those of the other derivatives (1.42–1.99 D). This
feature also supports the significant contribution of the charge-
separated resonance structure mentioned previously. In fact, the
NMe2 nitrogen atom is nearly planar in the optimized structure of
11b, where the single bonds in the conjugated moiety are
significantly shorter than the corresponding bonds of 11a (Fig.
14). For example, the Me2N–C single bond of 11b is shorter by
0.033 Å than that of 11a.
Fig. 13. Resonance structures of 11b.
O
O
1.466
1.457
N
N
O
O
1.350
1.366
[114.0]
N
[121.6]
N
N
N
[111.9]
1.392
1.377
[116.3]
[116.9]
[120.1]
1.399
1.366
11a 1,4-DP(NMe2)
11b 1,6-DP(NMe2)
Fig. 14. Calculated structures of 11a and 11b. Selected bond lengths (Å) and
bond angles [°]
Table 5. Thermodynamic data and dipole moments of 2-substituted DP derivatives 8–12 calculated at M06-2X/6-31G(d) level. a
0
c
∆E (kJ mol–1)
∆H° (kJ mol–1)
∆G° (kJ mol–1)
K298([b]/[a])
µ
(D) b
σp
a
b
8
–0.68
–2.84
–6.47
–13.6
1.28
–0.39
–3.00
–5.89
–13.6
1.69
–1.25
–1.21
–3.52
–16.3
2.18
1.66
1.63
2.46
714
5.25
3.44
3.98
4.76
4.98
1.70
1.42
1.99
4.41
1.59
0.00
9
0.12
10
11
12
–0.10
–0.43
0.51
0.41
a
b
c
Energies are relative values, b(1,6-DP)–a(1,4-DP), in kJ mol–1. Negative and positive values mean the preference of 1,6-DP and 1,4-DP, respectively.
Dipole moment in debye (D), 1 D = 3.33564×10ꢀ 30 C m.
Hammett constants of the 2-substituents (Ref. 15).
Table 6. Solvent effects on standard free energy differences (∆G°) and standard enthalpy differences (∆H°) of 2-substituted DP derivatives 8–
12 calculated at M06-2X/6-31G(d) level in kJ mol–1 a
ε b
Solvent
8
9
10
11
12
∆H°
–0.39
0.68
1.56
2.00
2.60
2.83
∆G°
–1.25
–0.80
0.00
∆H°
–3.00
–1.85
–0.86
–0.45
0.08
∆G°
–1.21
0.16
∆H°
–5.89
–5.10
–4.36
–3.99
–3.48
–3.30
∆G°
–3.52
∆H°
–13.6
∆G°
–16.3
–18.6
–19.2
–19.1
–18.7
–18.5
∆H°
1.69
∆G°
2.18
vacuum
C6H6
1
2.27
4.71
7.58
20.5
46.8
–4.60
–4.77
–4.58
–3.83
–3.53
–15.6
–16.5
–16.7
–17.0
–17.1
2.46
2.87
3.07
3.33
3.42
1.96
2.71
2.86
3.00
3.00
CHCl3
THF
1.25
0.50
1.04
Acetone
DMSO
1.30
0.74
1.63
0.27
0.68
a Relative values, b(1,6-DP)–a(1,4-DP).
b Dielectric constants as parameters for solvent polarity.

8
Tetrahedron
ACCEPTED MANUSCRIPT
2.4.3. Solvent effects
concentration. The underestimation of the stability of 1,4-DP
mentioned is also attributable to intermolecular interactions
because this polar tautomer should form strong hydrogen bonds
in solution. These treatments are too difficult in conventional
In order to consider solvent effects, the calculations were
performed by adopting the polarizable continuum model
(PCM).16 The structures and energies of two tautomers of 8–12
(only stable conformers for 10 and 11) were calculated with the
parameters for benzene, chloroform, THF, acetone, and DMSO.
The calculated free energy and enthalpy differences between the
two tautomers are listed in Table 6. For 8, the ∆G° values slightly
increase with increasing solvent polarity. The positive value in
DMSO means that 1,4-DP is more stable than 1,6-DP, contrary to
the value in vacuum. This tendency means that the polar 1,4-DP
tautomer is more stabilized by solvation in polar solvents than the
1,6-DP tautomer. A similar tendency was observed for 12, even
though the solvent effect was rather small. The solvent effects on
the free energy differences were irregular for compounds 9, 10,
and 11: the value in CHCl3 was maximum for 9 while the values
were minimum for 10 and 11. In contrast, the ∆H° values change
regularly with solvent polarity. Polar solvents tend to stabilize
1,4-DP relative to 1,6-DP for 8–10, and 12, and vice versa for 11.
The irregular changes in the relative free energies are attributed
to entropy factors, although it is not straightforward to
understand this tendency from available data.
theoretical
calculations
to
reproduce
the
observed
thermodynamic data quantitatively.
3. Conclusion
Experimental and theoretical studies on the thermodynamics
and properties of 2-substituted 6(4)-methyl-1,4(1,6)-
1
dihydropyrimidine-5-carboxylates were undertaken by H NMR
1
measurements and DFT calculations. For 1 and 2, the H NMR
spectra revealed the presence of two tautomers, and the major
and minor tautomers were assigned to 1,4-DPs and 1,6-DPs
based on the NOE experiments. The ratios of the two tautomers
regularly changed depending on the temperature, solvent, and
concentration. In contrast, the NMe2 compound existed solely as
1,6-DP. The observed tautomer ratios at various temperatures
were analyzed using van’t Hoff plots to give the enthalpy
differences (∆H°), entropy differences (∆S°), and free energy
differences (∆G°) for tautomerization of 1 and 2, where 1,4-DP
was found to be enthalpically favored and entropically disfavored
relative to 1,6-DP. In general, 1,4-DP was the major tautomer
and its population increased at low temperatures, in polar
solvents, and at high concentrations.
2.5. Comparison with the experimental data
The calculated results for a series of compounds were
compared with the experimental results of 1–3. The fact that
NMe2 compound 3 exists only as 1,6-DP is consistent with the
calculation for 11, in which 1,6-DP is much more stable than 1,4-
DP (>18 kJ mol–1 in solution). The calculations for 9 showed that
1,6-DP was more stable than 1,4-DP in vacuum and vice versa in
solution. This trend means that polar 1,4-DP is stabilized by
solvation in solution compared with 1,6-DP. In fact, the observed
entropy differences are large and positive especially in polar
DMSO, and these values mean effective solvation for 1,4-DP
molecules. The observed free energy differences for 1 were not
always reproduced by the theoretical calculations for 9, where the
calculated values are smaller by 2–4 kJ mol–1 than the observed
values in the three solvents. These differences between the
experimental and theoretical data are larger for the OMe
compounds (ca. 5 kJ mol–1 for 2 and 10) than for the SMe
compounds (1 and 9). These inconsistencies suggest that factors
stabilizing 1,4-DP should be underestimated or not be considered
in the theoretical calculations. This is attributable to the
limitations of the PCM method that lacks specific solvation
effects such as hydrogen bonds. Intermolecular interactions
should be important in these molecules, which have polar
moieties as well as hydrogen bond donor and acceptor moieties.13
The structures and properties of these tautomers were
investigated by DFT calculations of analogous derivatives 8–12
having various 2-substituents. The calculated thermodynamic
data revealed the effects of 2-substituents on the tautomer ratios,
and explained well the predominance of 1,6-DP for the NMe2
compound. The calculated large dipole moments of 1,4-DPs were
consistent with the preference for this polar tautomer in polar
solvents due to solvation. The theoretical calculations tended to
underestimate the stability of 1,4-DPs relative to 1,6-DPs. This
finding as well as the presence of concentration effects is
attributable to strong hydrogen bonds of 1,4-DP molecules with
other substrate and solvent molecules. Further calculations with
precise solvation models will reveal the role of these
intermolecular interactions in determining the thermodynamic
characteristics.
Few experimental and theoretical studies on the tautomerism
have been carried out so far and our works may provide useful
information to researchers in the near future who will study the
tautomerism of dihydropyrimidines, imidazoles and other
tautomeric heterocycles.
Weis et al. pointed out that DP derivatives form oligomers or
complexes with solvent molecules via hydrogen bonds in
solutions.7 The chemical shift of the NH protons is a good
indication of the formation of hydrogen bonds. The data of 1 and
2 in Table 3 show that the deshielding of the NH protons in polar
aprotic DMSO-d6 (ca. δ 9) is due to strong hydrogen bond with
solvent molecules at any concentration. If each molecule behaves
independently as solvated species, the concentration effect on the
tautomer ratios should be absent. The presence of the small
concentration effect indicates the presence of interactions
between solvated species or changes in the solvation state so as
to stabilize the polar 1,4-DP at high concentrations. In CDCl3 and
C6D6, the chemical shifts of the NH protons (δ 4.8–6.0) are
smaller than those in DMSO-d6, and they increase with
increasing concentration. The latter phenomenon can be
explained by intermolecular interactions: namely, the populations
of monomer, dimer, and possibly higher oligomers depend on the
4. Experimental section
4.1. General
Melting points were determined on Yanaco micro melting
point apparatus and uncorrected. IR spectra were measured on
SHIMADZU FTIR-8300 spectrometer. 1H NMR spectra were
recorded on a Varian Mercury (300, 400 MHz) or a Bruker
AVANCE III 600 (600 MHz) with tetramethylsilane (0 ppm),
CD3OD (3.30 ppm), DMSO-d6 (2.49 ppm), or C6D6 (7.15 ppm),
as an internal standard. The abbreviations of signal patterns are
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad. 13C NMR spectra were recorded on a Varian Mercury
(75, 100 MHz) or a Bruker AVANCE III 600 (150 MHz) with
CD3OD (49.0 ppm) or DMSO-d6 (39.7 ppm) as an internal

9
standard. Mass spectra were recorded on a JMS-DX303, JMS-
acetic acid (36 µL, 0.629 mmol) in CH2Cl2 (3 mL) was stirred
ACCEPTED MANUSCRIPT
700
or
JMS-T100GC
spectrometer.
Flash
column
at rt for 63 h. To complete the reaction, dimethylamine
hydrochloride (156 mg, 1.91 mmol), and triethylamine (0.270
mL, 1.94 mmol) were added, and the reaction mixture was heated
at reflux for 9 h. EtOAc (15 mL) and saturated NaHCO3 aqueous
solution (5 mL) were added, and the organic layer was separated.
The organic layer was washed with brine (5 mL), and dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by flash silica gel column
chromatography [n-hexane-EtOAc (5:1 to 1:1)] to give 7 (99.4
chromatography was performed on silica gel 60N (Kanto, 40-60
µm) using indicated solvent. Reactions and fractions of
chromatography were monitored by employing pre-coated silica
gel 60 F254 plates (Merck).
4.2. Synthesis of compounds 1–4
4.2.1. Ethyl 6-methyl-2-(methylthio)-1,4-dihydropyrimidine-5-
carboxylate and ethyl 4-methyl-2-(methylthio)-1,6-
dihydropyrimidine-5-carboxylate (1)
1
mg, 0.319 mmol, 50%) as a colorless oil. H NMR (CDCl3) δ:
1.28 (3H, t, J = 7.2 Hz), 1.47 (9H, s), 2.34 (3H, s), 2.98 (3H, brs),
3.15 (3H, brs), 3.42 (1H, brs), 4.18 (2H, q, J = 7.2 Hz), 5.07 (1H,
brs). To a solution of 7 (99.0 mg, 0.318 mmol) in CH2Cl2 (2 mL)
was added trifluoroacetic acid (0.5 mL, 6.53 mmol) at rt. The
reaction mixture was stirred at rt for 44 h, and 1 M NaOH
aqueous solution (10 mL) and EtOAc (15 mL) were added. The
organic layer was separated, and the aqueous layer was extracted
with EtOAc (10 mL x 2). The combined organic layers were
washed with water (5 mL), brine (5 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure to give 3 (63.8
mg, 0.302 mmol, 95%) as colorless crystals. Analytical sample of
3 was obtained by recrystallization (n-hexane-EtOAc). Mp 69–72
ºC; IR (KBr) cm−1: 3505, 2985, 1670, 1601, 1507, 1204, 1089;
1H NMR (DMSO-d6) δ: 1.15 (3H, t, J = 7.2 Hz), 2.10 (3H, s),
2.90 (6H, s), 3.89 (2H, s), 3.98 (2H, q, J = 7.2 Hz), 6.86 (1H, s);
13C NMR (DMSO-d6) δ: 14.9, 23.2, 37.5, 41.4, 60.3, 95.4, 157.8,
162.3, 168.9; HRMS-CI (m/z): [M+] calcd for C10H17N3O2,
211.1321; found, 211.1323. Exact structure assignment of 3 as a
sole isomer (1,6-isomer) was made using NOE experiment: the
NOE (3.1%) was observed between 2-NMe2 protons (2.90 ppm)
and 1-NH proton (7.14 ppm), and the NOE (1.9%) was observed
6-CH2 protons (3.89 ppm) and 1-NH proton (7.14 ppm). As such,
its structure was determined to be 1,6-isomer (Fig. 6).
A mixture of thiourea (1.98 g, 26.0 mmol), 37% formaldehyde
aqueous solution (1.62 g, 20.0 mmol), ethyl acetoacetate (2.60
mL, 20.6 mmol), and aluminum trichloride hexahydrate (483 mg,
2.00 mmol) in EtOH (40 mL) was heated at reflux for 6 h. After
cooled in ice bath for 1 h, the precipitate was collected by
filtration. The filtrate was washed with EtOH, and dried to give
1
the dihydropyrimidine-2-thione 4 (1.74 g, 8.69 mmol, 43%). H
NMR (DMSO-d6) δ: 1.18 (3H, t, J = 7.2 Hz), 2.16 (3H, s), 3.87
(2H, s), 4.06 (2H, q, J = 7.2 Hz), 8.96 (1H, s), 9.95 (1H, s). To a
suspension of 4 (1.74 g, 8.69 mmol) in MeOH (17 mL) was
added MeI (1.40 mL, 22.5 mmol) at rt, and the reaction mixture
was heated at reflux for 3 h. CHCl3 (30 mL) and saturated
NaHCO3 aqueous solution (15 mL) were added, and the organic
layer was separated. The organic materials were extracted with
CHCl3 (30 mL), and combined organic layers were washed with
brine (10 mL), and dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was purified by
flash silica gel column chromatography [CH2Cl2-EtOAc (10:1 to
1.5:1)] to give 1 (1.44 g, 6.72 mmol, 77%) as a pale yellow solid.
Mp 113–115 ºC (n-hexane-CHCl3); IR (KBr) cm−1: 3318, 1668,
1647, 1171; 1H NMR (0.012 M, 20°C in DMSO-d6) δ: 1.17 (3He
and 3He’, t, J = 7.2 Hz), 2.11 (3Hf, s), 2.13 (3Hf’, s), 2.26 (3Hb, s),
2.35 (3Hb’, s), 3.92 (2Hc’, s), 4.04 (2Hd and 2Hd’, q, J = 7.2 Hz),
4.10 (2Hc, s), 8.22 (1Ha’, s), 9.27 (1Ha, s); 13C NMR (average
spectrum of tautomers in CD3OD) δ: 13.4, 14.7, 18.1, 46.7, 60.9,
96.9, 150.1 (br), 157.6 (br), 168.2; HRMS-EI (m/z): [M+] calcd
for C9H14N2O2S, 214.0776; found, 214.0770.
4.3. Thermodynamic Analysis.
An NMR sample at 0.050 M was prepared by dissolution of
7.0 mg of 1 in 0.65 mL of DMSO-d6, CDCl3 C6D6. or CD3OD.
For CDCl3, the solvent was passed through a short alumina
before use to remove acidic impurities. The solution and the
sample tube were purged by argon gas before the measurement.
NMR samples at other concentrations and those of 2 were
similarly prepared. The 1H NMR spectra were measured at
variable temperatures (0–90 °C, 5° intervals). After the
thermometer reached the set temperature, the sample was kept at
the conditions for at least 10 min before the measurement. The
populations of the two tautomers were determined by the
intensities of NMR signals due to NH protons. The errors in the
population ratios in Tables 1, 2, and S1–S4 were estimated to be
within 3%. It was confirmed that the ratios were not affected by
using DMSO-d6 dried over MS 4A. In CD3OD, the exchange
between the two tautomes was so fast on the NMR time scale that
only averaged signals were observed.
4.2.2. Ethyl 2-methoxy-6-methyl-1,4-dihydropyrimidine-5-
carboxylate and ethyl 2-methoxy-4-methyl-1,6-
dihydropyrimidine-5-carboxylate (2)
A solution of 1 (447 mg, 2.09 mmol) in MeOH (10 mL) was
heated at reflux for 3 h. After concentration under reduced
pressure, the residue was purified by flash silica gel column
chromatography [CH2Cl2-MeOH (50:1 to 20:1)] to give 2 (213 g,
1.07 mmol, 51%) as a colorless solid. Mp 89–90 ºC (not
recrystallized because of its instability); IR (KBr) cm−1: 2988,
1
1699, 1510, 1229, 1089; H NMR (0.012 M, 20°C in DMSO-d6)
δ: 1.16 (3He, t, J = 7.2 Hz), 1.17 (3He’, t, J = 7.2 Hz), 2.10 (3Hf,
s), 2.13 (3Hf’, s), 3.58 (3Hb, s), 3.68 (3Hb’, s), 4.00 (2Hc’, s), 4.03
(2Hd and 2Hd’, q, J = 7.2 Hz), 4.09 (2Hc, d, J = 0.6 Hz), 7.66
(1Ha’, s), 8.92 (1Ha, s); 13C NMR (average spectrum of tautomers
in CD3OD) δ: 14.7, 18.4, 45.8, 54.3, 60.8, 96.8, 151.5 (br), 155.2
(br), 168.3; HRMS-CI (m/z): [(M+H)+] calcd for C9H15N2O3,
199.1083; found, 199.1074.
The observed equilibrium constants (K = [1,4-DP]/[1,6-DP])
and the temperatures (T/K) were used for the van’t Hoff plot:
ln K = –∆H°/RT + ∆S°/R ,
4.2.3. Ethyl 2-(dimethylamino)-4-methyl-1,6-dihydropyrimidine-
5-carboxylate (3)
Dihydropyrimidine 3 was prepared from 4 for four steps
according to the procedure in reference 9. A mixture of 6 (200
mg, 0.636 mmol), dimethylamine hydrochloride (156 mg, 1.91
mmol), sodium hydrogen carbonate (160 mg, 1.91 mmol), and
where –∆H° is the standard enthalpy difference, –∆S° is the
standard entropy difference, and R is the gas constant. The free
energy differences ∆G° were calculated by the equation of ∆G° =
–RTlnK or ∆G° = ∆H° – T∆S°. The original data and the
thermodynamic parameters are shown in Table 3 and Tables in
Supplementary data.

10
Tetrahedron
ACCEPTED MANUSCRIPT
2014;13:1450056;
(c) Memarian HR, Rezaie F, Sabzyan H, Ranjbar M. J Iranian
Chem Soc. 2014;11:1265–1274.
15. Exner, O. Correlation Analysis of Chemical Data, Springer, New
York, 1988.
16. Tomasi J, Mennucci B, Cammi R. Chem Rev. 2005;105:2999–
3093.
17. Frisch MJ, Trucks GW, Schlegel HB, et al. Gaussian 09, Revision
C.01. Wallingford, CT: Gaussian, Inc.; 2009.
18. Foresman JB, Keith TA, Wiberg KB, Snoonian J, Frisch MJ. J
Phys Chem. 1996;100:16098–16104.
4.4. DFT calculations
Calculations were carried out with Gaussian 09W17 program
on a Windows computer. The structures were optimized by the
hybrid DFT method at the M06/6-31G(d) level. The frequency
analysis gave no imaginary frequency for each energy-minimum
structure, and gave thermodynamic parameters. The calculations
of each energy minimum structure in several solvents were
18
carried out by the PCM SCRF method at the same level. The
19. Cancès E, Mennucci B, Tomasi J. J Chem Phys. 1997;107: 3032–
3041.
PCM using the integral equation formalism variant (IEFPCM19)
is the default of the SCRF method. The detailed data of the
calculations are shown in Tables and Figures in Supplementary
data.
Supplementary Material
1H spectra of all compounds, HMBC spectrum of DP 1, van’t
Hoff plots of 1 and 2 in various solvents, and the detailed data of
the calculations are available, and the data can be found online at
xxxxxx. Scientific articles:
Acknowledgments
We (Y. N and H. C) appreciate the financial support of the
JSPS KAKENHI Grant Number 16K08335.
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