Structural investigations of a series of 1,6-aryl-7-hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-ones with potential antinociceptive activity

Article abstract of DOI:10.1016/j.molstruc.2015.04.005

The structural investigations of a series of new bioactive imidazo[1,2-a]pyrimidines 1-6 were undertaken using IR, ¹H and ¹³C NMR spectroscopic analysis, X-ray crystal structure determinations and theoretical calculations. The compounds 1-6 were obtained by condensation of the respective 1-aryl-4,5-dihydro-1H-imidazol-2-amine hydrobromide and diethyl phenylmalonate in presence of sodium methoxide in methanol and for these compounds the equilibrium between possible O10-enol/O11-keto (a), O11-enol/O10-keto (b) and O10,O11-diketo (c) tautomeric forms were investigated in the gaseous phase, solution and crystalline state. Spectroscopic studies ¹H, ¹³C NMR and IR allowed for the identification of the compounds 1-6 but they did not indicate explicitly their tautomeric forms present in solution and in the solid state. The X-ray analysis showed that the molecules of all investigated compounds exist as the O10-enol/O11-keto (a) tautomeric form in the crystalline state. The hydroxyl and carbonyl groups characteristic for existing tautomeric form are involved in a strong intra- and/or intermolecular O-H?O and O-H?N hydrogen bonds. The theoretical calculations at DFT/B3LYP/6-311++G(d,p) level showed that two tautomeric forms (a) and (c) can coexist both in gas phase and the solution with the population of them being in the relation (a) > (or ?) (c). The comparison of the experimentally recorded IR, ¹H and ¹³C spectra with the corresponding spectra theoretically calculated for all possible tautomeric forms of 1-6 shows that the correlation of experimental and theoretical spectra can be used to a limited extent for the identification of tautomeric forms.

Full text of DOI:10.1016/j.molstruc.2015.04.005

Journal of Molecular Structure 1094 (2015) 137–147
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Structural investigations of a series of 1,6-aryl-7-hydroxy-2,3-
dihydroimidazo[1,2-a]pyrimidin-5(1H)-ones with potential
antinociceptive activity
b
b
Waldemar Wysocki a, Zbigniew Karczmarzyk a, , Marzena Rza˛dkowska , Elzbieta Szacon ,
⇑
_
´
b
c
c
´
Dariusz Matosiuk , Zofia Urbanczyk-Lipkowska , Przemysław Kalicki
a Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland
b
´
Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University, Chodzki 4A, 20-093 Lublin, Poland
c Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warszawa 42, Poland
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
ꢀ
ꢀ
ꢀ
Structural analysis of new bioactive
imidazo[1,2-a]pyrimidines were
undertaken.
All compounds were characterized by
IR, 1H and 13C NMR, X-ray and DFT
methods.
Keto–enol tautomeric equilibrium
were investigated using DFT method.
a r t i c l e i n f o
a b s t r a c t
Article history:
The structural investigations of a series of new bioactive imidazo[1,2-a]pyrimidines 1–6 were undertaken
using IR, 1H and 13C NMR spectroscopic analysis, X-ray crystal structure determinations and theoretical
calculations. The compounds 1–6 were obtained by condensation of the respective 1-aryl-4,5-dihydro-
1H-imidazol-2-amine hydrobromide and diethyl phenylmalonate in presence of sodium methoxide in
methanol and for these compounds the equilibrium between possible O10-enol/O11-keto (a),
O11-enol/O10-keto (b) and O10,O11-diketo (c) tautomeric forms were investigated in the gaseous phase,
solution and crystalline state. Spectroscopic studies 1H, 13C NMR and IR allowed for the identification of
the compounds 1–6 but they did not indicate explicitly their tautomeric forms present in solution and in
the solid state. The X-ray analysis showed that the molecules of all investigated compounds exist as the
O10-enol/O11-keto (a) tautomeric form in the crystalline state. The hydroxyl and carbonyl groups char-
acteristic for existing tautomeric form are involved in a strong intra- and/or intermolecular OAHÁ Á ÁO and
OAHÁ Á ÁN hydrogen bonds. The theoretical calculations at DFT/B3LYP/6-311++G(d,p) level showed that
two tautomeric forms (a) and (c) can coexist both in gas phase and the solution with the population of
them being in the relation (a) > (or ꢁ) (c). The comparison of the experimentally recorded IR, 1H and
13C spectra with the corresponding spectra theoretically calculated for all possible tautomeric forms of
1–6 shows that the correlation of experimental and theoretical spectra can be used to a limited extent
for the identification of tautomeric forms.
Received 11 December 2014
Received in revised form 6 March 2015
Accepted 6 April 2015
Available online 11 April 2015
Keywords:
Imidazo[1,2-a]pyrimidine derivatives
Keto–enol tautomerism
X-ray structure
DFT calculations
Correlation analysis
Ó 2015 Elsevier B.V. All rights reserved.
⇑
Corresponding author. Tel.: +48 25 643 1017; fax: +48 25 644 20 45.
E-mail address: kar@uph.edu.pl (Z. Karczmarzyk).
http://dx.doi.org/10.1016/j.molstruc.2015.04.005
0022-2860/Ó 2015 Elsevier B.V. All rights reserved.

138
W. Wysocki et al. / Journal of Molecular Structure 1094 (2015) 137–147
16.7% solution of sodium methoxide in methanol (60 ml) were
Introduction
refluxed for 3 h. The solvent was evaporated. After cooling the
crude product was dissolved in water and neutralized with 10%
solution of hydrochloric acid. The solid product was filtrated off
and recrystallized from propan-2-ol.
Both synthetic and natural compounds containing imidazo[1,2-
a]pyrimidine system exhibit wide spectrum of biological activity
such as anticonvulsant and tranquilizer [1], antineoplastic [2],
anti-inflammatory [3,4] and antimicrobial [5]. Dioxo derivatives
of fused imidazoline ring systems, e.g. imidazo[1,2-a]imidazoles,
imidazo[1,2-a][1,3,5]triazines and imidazo[2,1-c][1,2,4]triazines,
were found to have significant analgesic opioid-like action but
without the typical narcotic side-effects [6,7]. Modification of their
structure led us to the synthesis a series of 1-aryl-6-phenyl-5,7-
dioxo-imidazo[1,2-a]pyrimidines 1–6 (Scheme 1), which in the
pharmacological tests show antinociceptive and serotonergic
activity in CNS system with an average or low acute toxicity. One
of the method to synthesize these compounds is condensation of
respective 1-aryl-4,5-dihydro-1H-imidazol-2-amine hydrobro-
mide, diethyl phenylmalonate in alkaline media [8]. Obtained
derivatives can exist in 7-enol–5-keto (a), 5-enol–7-keto (b) and
5,7-diketo (c) tautomeric forms (Scheme 1).
Spectroscopic data of compounds 1–6
7-Hydroxy-1-(2-methylphenyl)-6-phenyl-2,3-dihydroimidazo[1,2-
a]pyrimidin-5(1H)-one (1)
1H NMR: (400 MHz, DMSO-d6, ppm) d = 10.90 (s, 1H, OH), 7.45
(m, 1H, CH), 7.40 (m, 2H, 2 Â CH), 7.30 (m, 5H, 5 Â CH), 7.12 (t,
1H, CH, J = 7.2 Hz), 4.15 (t, 2H, CH2, J = 9.2 Hz), 4.01 (t, 2H, CH2,
J = 9.2 Hz), 2.30 (s, 3H, CH3);
13C NMR: (100 MHz, DMSO-d6, ppm) d = 166.9 (C@O), 161.2
(CAOH), 153.5 (C@N), Ar (CH): 136.9, 136.5, 134.0, 131.0, 130.6,
128.2, 127.8, 127.1, 127.0, 125.1, 93.3, (C@CO), 47.9 (CH2), 41.1
(CH2), 17.5 (CH3);
IR: (KBr, cmÀ1
) m = 3171 (OH), 1640 (C@O), 1606, 1566, 1504,
In order to determine the keto–enol tautomeric equilibrium
within a series of imidazo[1,2-a]pyrimidines 1–6, IR, 1H and 13C
NMR spectroscopic analysis, X-ray crystal structure determina-
tions and theoretical calculations were undertaken for all 1–6
investigated compounds. The tautomerism of the oxo groups
would be responsible for the selectivity of action, as we have
already confirmed for structurally related imidazo[2,1-c][1,2,4]
triazines [9]. We report here the structural characterization of
compounds 1–6 in terms of their tautomeric equilibrium in
crystalline state, in solution and in gaseous phase.
1409, 1316, 1213, 1175, 1126, 1099, 767, 737, 701, 587, 458.
1-(4-Chlorphenyl)-7-hydroxy-6-phenyl-2,3-dihydroimidazo[1,2-
a]pyrimidin-5(1H)-one (2)
1H NMR: (400 MHz, DMSO-d6, ppm) d = 11.05 (s, H, OH), 7.90
(m, 2H, 2 Â CH), 7.45 (m, 4H, 4 Â CH), 7.43 (m, 2H, 2 Â CH), 7.16
(m, 1H, CH), 4.11 (m, 4H, 2 Â CH2);
13C NMR: (100 MHz, DMSO-d6, ppm) d = 165.9 (C@O), 160.9
(CAOH), 151.2 (C@N), Ar (CH): 138.1, 133.5, 130.5, 128.6, 127.1,
127.0, 125.4, 120.2, 94.7 (C@CO), 45.1 (CH2), 40.0 (CH2);
IR: (KBr, cmÀ1
) m = 3431 (OH), 3068, 2958, 2914, 2868, 1735,
Experimental
1660 (C@O), 1600, 1552, 1503, 1401, 1257, 1233, 1006, 826, 716,
534, 512.
General methods
The 1H and 13C NMR spectra were recorded at room temperature
on a Varian 400-MR spectrometer at 399.67 and 100.50 MHz,
respectively. Chemical shift (d) are given in ppm, referenced to the
residual proton (2.50 ppm) and carbon (39.51 ppm) resonance of
the DMSO-d6. IR spectra were recorded on a FTIR MAGNA-IR 760
Nicolet spectrometer for 1–6 in the solid state (KBr) and for 4 in
chloroform (CHCl3).
1-(2,6-Dichlorphenyl)-7-hydroxy-6-phenyl-2,3-dihydroimidazo[1,2-
a]pyrimidin-5(1H)-one (3)
1H NMR: (400 MHz, DMSO-d6, ppm) d = 11.08 (s, 1H, OH), 7.67
(d, 2H, 2 Â CH, J = 8.0 Hz), 7.51 (t, 1H, CH, J = 8.0 Hz), 7.39 (d, 2H,
2 Â CH, J = 7.2 Hz), 7.26 (t, 2H, 2 Â CH, J = 8.0 Hz), 7.13 (t, 1H, CH,
J = 7.2 Hz), 4.26 (t, 2H, CH2, J = 8.8 Hz), 4.01 (t, 2H, CH2, J = 8.8 Hz);
13C NMR: (100 MHz, DMSO-d6, ppm) d = 166.9 (C@O), 160.9
(CAOH), 153.0 (C@N), Ar (CH): 135.4, 133.6, 132.3, 131.5, 130.6,
129.3, 127.0, 125.3, 94.0 (C@CO), 45.4 (CH2), 41.5 (CH2);
Synthesis of compounds 1–6 [8]
IR: (KBr, cmÀ1
) m = 3435 (OH), 2899, 2637, 1668 (C@O), 1557,
The mixture of respective 1-aryl-2-aminoimidazoline hydro-
bromide (0.02 mol), diethyl phenylmalonate (0.02 mol), 15 ml of
1423, 1341, 1308, 1247, 1182, 1092, 849, 784, 741, 698, 592,
536, 450.
Scheme 1.

W. Wysocki et al. / Journal of Molecular Structure 1094 (2015) 137–147
139
1-(3,4-Dichlorphenyl)-7-hydroxy-6-phenyl-2,3-dihydroimidazo[1,2-
1-Benzyl-7-hydroxy-6-phenyl-2,3-dihydroimidazo[1,2-a]pyrimidin-
a]pyrimidin-5(1H)-one (4)
5(1H)-one (6)
1H NMR: (400 MHz, DMSO-d6, ppm) d = 11.22 (s, 1H, OH), 8.29
(d, 1H, CH, J = 2.4 Hz), 7.77 (dd, 1H, CH, J = 8.8, J = 2.8 Hz), 7.64 (d,
1H, CH, J = 9.2 Hz), 7.45 (m, 2H, 2 Â CH), 7.28 (t, 2H, CH,
J = 7.2 Hz), 7.16 (m, 1H, CH), 4.11 (m, 4H, 2 Â CH2);
13C NMR: (100 MHz, DMSO-d6, ppm) d = 165.8 (C@O), 160.8
(CAOH), 150.9 (C@N), Ar (CH): 139.2, 133.4, 131.3, 130.5, 130.4,
127.1, 125.5, 124.6, 119.8, 118.2, 95.0 (C@CO), 45.1 (CH2), 40.1
(CH2);
1H NMR: (400 MHz, DMSO-d6, ppm) d = 10.90 (s, 1H, OH), 7.36
(m, 7H, 7 Â CH), 7.28 (t, 2H, 2 Â CH), 7.11 (t, 1H, 1 Â CH), 4.58 (s,
2H, 1 Â CH2), 3.97 (t, 2H, 1 Â CH2), 3.57 (t, 2H, 1 Â CH2);
13C NMR: (100 MHz, DMSO-d6, ppm) d = 167.2 (C@O), 161.6
(CAOH), 154.8 (C@N), Ar (CH): 136.1, 130.6, 128.7, 127.7, 127.5,
127.0, 126.6, 124.9, 83.3 (C@CO), 47.3 (CH2), 44.3 (CH2), 40.7 (CH2);
IR: (KBr, cmÀ1
) m = 3435 (OH), 3048, 1652 (C@O), 1606, 1551,
1417, 1359, 1298, 1172, 1081, 989, 860, 780, 740, 703, 582, 495,
459.
IR: (KBr, cmÀ1
) m = 3434 (OH), 3032, 2654, 1637 (C@O), 1541,
1509, 1416, 1385, 1332, 1274, 1238, 1185, 1136, 1114, 1042,
791, 705, 592, 494;
X-ray structure analysis
IR: (CHCl3, cmÀ1
) m = 3072, 3028, 2927, 2854, 1659 (C@O), 1551,
1482, 1308, 1178, 795, 787, 701, 693, 678, 667.
Colorless prismatic crystals of 1–3 suitable for X-ray diffraction
analysis were grown by slow evaporation of a methanol solution,
while the needle crystals of 4 were obtained from DMSO and pris-
matic crystals of 5 and 6 were crystallized from propan-1-ol. X-ray
data of 1–3 were collected on the Kuma KM-4 four-circle diffrac-
tometer at room temperature; crystal sizes: 0.60 Â 0.40 Â
0.30 mm (1), 0.50 Â 0.30 Â 0.20 mm (2) and 0.20 Â 0.20 Â
7-Hydroxy-1,6-diphenyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-
one (5)
1H NMR: (400 MHz, DMSO-d6, ppm) d = 10.98 (s, 1H, OH), 7.85
(m, 2H, 2 Â CH), 7.43 (m, 4H, 4 Â CH), 7.29 (m, 2H, 2 Â CH), 7.16
(m, 2H, 2 Â CH), 4.14 (m, 4H, 2 Â CH2);
0.10 mm (3); Cu K
a
(k = 1.54178 Å) radiation,
x
À2h scans. Data col-
13C NMR: (100 MHz, DMSO-d6, ppm) d = 166.0 (C@O), 160.9
(CAOH), 151.4 (C@N), Ar (CH): 133.7, 130.5, 128.8, 127.1, 125.3,
123.4, 119.0, 94.3 (C@CO), 45.2 (CH2), 40.1 (CH2);
lections for 4, 5 and 6 were performed on the Bruker SMART APEX II
CCD diffractometer at room temperature; crystal sizes
0.28 Â 0.19 Â 0.14 mm (4), 0.28 Â 012 Â 0.02 mm (5) and
IR: (KBr, cmÀ1
)
m
= 3430 (OH), 2905, 1632 (C@O), 1591, 1545,
0.59 Â 0.17 Â 0.07 mm (6), Cu K
a (k = 1.54178 Å) radiation, u and
x scans. The structures were solved by direct methods using
1509, 1493, 1405, 1317, 1244, 1177, 790, 760, 583, 516.
Table 1
Crystal data and structure refinement for 1–6.
1
2
3
4
5
6
Empirical formula
Formula weight
Crystal system
Space group
C
19H17N3O2
C18H14ClN3O2
339.77
Monoclinic
P21/c
C18H13Cl2N3O2
374.21
Orthorhombic
Pbca
C18H13Cl2N3O2
374.21
Triclinic
C18H15N3O2
305.33
Orthorhombic
Pbca
C19H17N3O2
319.36
Monoclinic
P21/c
319.36
Monoclinic
P21/c
P1
Unit cell parameters
a (Å)
b (Å)
c (Å)
8.1089(15)
26.857(4)
7.1988(16)
7.2078(10)
14.4418(15)
14.9765(15)
11.699(3)
11.568(4)
24.584(3)
11.7174(4)
11.9012(4)
13.6483(4)
94.461(2)
112.577(1)
104.891(2)
1664.86(9)
4
13.6856(3)
10.3389(3)
20.8395(6)
15.7968(2)
5.8142(1)
18.6854(3)
a
(°)
b (°)
94.35(4)
98.973(10)
115.860(1)
c
(°)
V (Å3)
1563.3(5)
4
1.357
1539.9(3)
4
1.466
3326.8(1)
8
1.494
2948.67(14)
8
1.376
1544.32(4)
4
1.374
Z
Dcalc (g cmÀ3
F(000)
)
1.493
768
672
704
1536
1280
672
Cell parameters from
h range for lattice
parameters (°)
25 reflections
18.86–37.60
25 reflections
18.77–35.51
25 reflections
20.33–34.66
3538 reflections
3.58–65.18
4970 reflections
4.24–66.72
6619 reflections
3.11–68.53
Absorption coefficient
l
0.728
2.336
3.663
3.660
0.747
0.737
(mmÀ1
)
Absorption correction
Tmin/Tmax
h range for data
collection (°)
Refdelf [11]
0.619/0.804
0.619/0.804
Multi-scan [12]
0.442/0.663
4.28–80.32
Refdelf
0.435/0.693
3.60–80.47
Multi-scan
0.581/0.756
3.92–65.08
Multi-scan
0.8575/0.9996
4.2–67.6
Multi-scan
0.712/0.988
3.11–66.60
Index ranges h, k, l
No. of measured
reflections
0/10, À34/0, À9/9 À8/9, À1/18, À1/19 0/14, À14/0, 0/31
3576 3959 3633
À13/13,À13/13,À16/16 À16/14, À11/12,À24/25 À18/18, À6/5, À21/21
17,583
26,210
13,830
No. of independent
reflections
No. of observed
reflections
3347 (Rint = 0.048) 3323 (Rint = 0.016)
3633 (Rint = 0.000) 5273 (Rint = 0.063)
(I) 2706 with I > 2 (I) 4044 with I > 2 (I)
Full-matrix least-squares on F2
2641 (Rint = 0.054)
2679 (Rint = 0.032)
2982 with I > 2
r
(I) 2928 with I > 2
r
r
r
2171 with I > 2
r(I)
2419 with I > 2r(I)
Refinement method
Final R indices: R, wR(F2) 0.052,0.137
0.046, 0.128
1.075
0.070, 0.207
1.111
0.052, 0.138
1.049
0.0384, 0.0982
1.037
2641/212
0.00053(8)
+0.164/À0.127
0.035, 0.095
1.036
2679/221
0.0033(4)
+0.179/À0.134
Goodness-of-fit on F2, S
Data/parameters
1.037
3347/268
None
+0.363/À0.298
3323/260
0.0082(7)
+0.474/À0.441
3633/229
None
5273/457
None
Extinction coefficient
Largest diff. peak
+0.631/À0.497
+0.308/À0.437
and hole (eÅÀ3
)
(D
/
r
)
0.000
0.001
0.000
0.000
0.000
0.001
max

140
W. Wysocki et al. / Journal of Molecular Structure 1094 (2015) 137–147
Table 2
Selected bond lengths (Å) and angles (°) for 1–6.
1
2
3
4A
4B
5
6
N1AC21a
N1AC2
C2AN3
C2AN6
C7AO10
C9AO11
1.4251(17)
1.3512(18)
1.3631(17)
1.3090(17)
1.3287(16)
1.2347(17)
125.63(11)
110.14(11)
122.22(11)
145.47(15)
À46.5(2)
–
1.407(2)
1.360(2)
1.356(2)
1.309(2)
1.332(2)
1.239(2)
128.32(14)
110.12(14)
121.36(15)
165.43(17)
À38.1(3)
–
1.418(3)
1.348(3)
1.352(3)
1.314(3)
1.331(3)
1.223(3)
125.1(2)
111.3(2)
121.4(2)
À76.5(3)
À96.5(3)
–
1.406(4)
1.367(4)
1.357(3)
1.301(3)
1.325(3)
1.244(3)
127.3(2)
110.5(2)
122.1(2)
À4.4(5)
49.9(4)
–
1.403(4)
1.366(4)
1.352(3)
1.302(3)
1.331(3)
1.245(3)
128.1(2)
110.2(2)
121.3(2)
À0.3(4)
À42.4(4)
–
1.413(2)
1.3596(19)
1.3539(18)
1.3029(19)
1.3341(17)
1.2423(17)
127.91(13)
110.30(12)
121.72(13)
À178.03(14)
À42.7(2)
–
1.4532(17)
1.3351(16)
1.3529(16)
1.3210(16)
1.3149(16)
1.2283(15)
126.01(11)
110.47(11)
122.11(11)
–
C2AN1AC21a
C2AN1AC5
C5AN1AC21a
C2AN1AC21AC22
C7AC8AC31AC32
C2AN1AC12AC21
N1AC12AC21AC22
À116.02(14)
À98.93(15)
À22.27(17)
–
–
–
–
–
–
a
N1AC12, C2AN1AC12 and C5AN1AC12 in 6.
Fig. 1. A view of the molecules of compounds 1–6 in conformation observed in their crystals with the atom labeling scheme. Displacement ellipsoids are drawn at the 50%
probability level.
SHELXS97 [10] and refined by full-matrix least-squares with
SHELXL97 [10]. In 1 and 2 all hydrogen atoms were located by dif-
ference Fourier synthesis. For compounds 3–6 the OAbounded H
Computational details
The theoretical calculations at the DFT/B3LYP level with
6-311++G(d,p) basis set implemented in GAUSSIAN 03 [16] were
carried out to investigate the tautomeric equilibrium of 1–6 in
gaseous phase and water, DMSO, methanol, n-octanol, chloroform
and tetrachloromethane solutions (The Conductor Polarizable
Continuum Model; CPCM [17]). The structures of all possible tau-
tomeric forms were fully optimized without any constraint and
the initial geometries were built from crystallographic data of
1–6. The energy of each tautomeric form of 1–6 in solutions with
CPCM model was calculated for geometry of respective molecule
atoms were located in
Dq maps and the remaining H atoms were
positioned geometrically and treated as riding on their C atoms
with CAH distances of 0.93 Å (aromatic), 0.97 Å (CH2) and 0.96 Å
(CH3). All H atoms were refined with isotropic displacement
parameters taken as 1.5 times those of the respective parent atoms.
Crystal and experimental data of 1–6 are listed in Table 1. Molecular
graphics were prepared using ORTEP3 for Windows [13]. PARST
[14] and PLATON [15] were used for geometrical calculations. All
calculations were performed using WINGX package [13].

W. Wysocki et al. / Journal of Molecular Structure 1094 (2015) 137–147
141
Table 3
Hydrogen bonding geometry (Å, °) for 1–6.
DAHÁ Á ÁA
DAH
HÁ Á ÁA
DÁ Á ÁA
DAHÁ Á ÁA
Symmetry codes
1
C32AH321Á Á ÁO10
C36AH361Á Á ÁO11
O10AH101Á Á ÁO11i
0.98(2)
0.97(2)
0.85(3)
2.56(2)
2.53(2)
1.84(3)
2.900(2)
2.967(2)
2.5992(16)
100.1(16)
107.1(17)
147(3)
i = x, y, 1 + z
2
C26AH261Á Á ÁN6
C32AH321Á Á ÁO10
C36AH361Á Á ÁO11
O10AH101Á Á ÁO11i
C22AH221Á Á ÁO11ii
C26AH261Á Á ÁO10iii
3
0.98(3)
0.95(3)
1.01(3)
0.85(3)
0.96(3)
0.98(3)
2.39(3)
2.43(3)
2.39(3)
1.92(3)
2.49(3)
2.59(3)
2.988(2)
2.849(2)
2.936(3)
2.6773(18)
3.247(2)
3.495(2)
118.7(17)
106.4(19)
113.2(19)
147(3)
136(2)
153(2)
i = 1 + x, y, z
ii = 1Àx, À1/2 + y,1/2Àz
iii = 2Àx, 2Ày, Àz
O10AH101Á Á ÁN6i
0.91(4)
1.84(3)
2.740(3)
170(5)
i = 1Àx, 1Ày, 1Àz
4
O10AAH10AÁ Á ÁO11B
C22AAH22AÁ Á ÁN6A
C22BAH22BÁ Á ÁN6B
C32BAH32BÁ Á ÁO10B
C36BAH36BÁ Á ÁO11B
O10BAH10BÁ Á ÁO11Ai
C5AAH51AÁ Á ÁO11Bii
C5BAH52BÁ Á ÁO11Aiii
0.79(5)
0.93
0.93
0.93
0.93
0.96(5)
0.97
0.97
1.86(5)
2.23
2.25
2.51
2.55
1.71(5)
2.59
2.37
2.636(3)
2.878(4)
2.891(4)
2.892(4)
2.952(4)
2.644(3)
3.501(4)
3.287(4)
165(6)
126
125
105
107
162(7)
157
158
i = x, y, 1 + z
ii = 1Àx, 1Ày, Àz
iii = 1Àx, 2Ày, Àz
5
C26AH26Á Á ÁN6
C32AH32Á Á ÁO10
C36AH36Á Á ÁO11
O10AH10Á Á ÁO11i
C5AH52Á Á ÁO11ii
0.93
0.93
0.93
0.97(2)
0.97
2.25
2.48
2.58
1.72(2)
2.57
2.892(2)
126
108
106
167.5(19)
2.9052(19)
2.9777(18)
2.6737(15)
3.3311(18) 136
i = 1/2 + x, y, 3/2Àz
ii = 1Àx, 1/2+y, 3/2Àz
6
C22AH22Á Á ÁN1
O10AH10Á Á ÁN6i
C12AH12BÁ Á ÁO10i
C36AH36Á Á ÁO11ii
0.93
0.91(2)
0.97
2.60
1.87(2)
2.36
2.908(2)
100
168(2)
142
2.7626(16)
3.1839(18)
3.3245(17)
i = Àx, 1Ày, 2Àz
i = Àx, 1Ày, 2Àz
ii = x, 1 + y, z
0.93
2.40
171
obtained in gaseous phase. Calculated energies in gaseous phase
for all tautomeric forms were corrected for the zero-point energy
(ZPE). The population analysis of tautomeric forms was estimated
using non-degenerate Boltzmann distribution. The vibrational fre-
quencies calculated for all possible tautomeric forms of 1–6 were
scaled by 0.9679 for DFT/B3LYP/6-311++G(d,p) [18]. All experi-
mental and calculated vibrational frequencies were compared for
the model compound 5, while for the other compounds this
comparison was limited to the characteristic bands of OH and
C@O groups. The calculated chemical shifts of the 1H NMR and
13C NMR spectra were obtained from the GIAO method [19,20]
using TMS as reference. The visualization of theoretical calculation
results was made using GaussView [21].
Results and discussion
Synthesis
The synthesis of compounds 1–6 is shown in Scheme 1. These
compounds were obtained by condensation of the respective
1-aryl-4,5-dihydro-1H-imidazol-2-amine
hydrobromide
and
diethyl phenylmalonate in presence of sodium methoxide in
methanol [8]. The synthesized compounds 1–6 were characterized
by elemental analysis, IR, 1H and 13C NMR, as well as X-ray analysis.
Spectroscopic analysis
The spectroscopic studies 1H and 13C NMR performed for com-
pounds 1–6 confirmed their structure, but they do not allowed to
explicitly indicate the tautomeric forms present in solution. In
the 1H NMR spectra of investigated compounds broadened reso-
nance signals are observed, which may indicate a high rate of pro-
ton exchange processes between the different tautomeric forms, so
only the ‘‘average’’ spectrum can be recorded. The process of pro-
ton exchange is fast in the time scale of the NMR experiment
and it does not allow for a classical one-dimensional NMR spectra
unambiguously identify the tautomeric forms present in solution.
Moreover, the protons bonded to heteroatoms may be involved
in hydrogen bonds. Increasing the strength of such hydrogen bond
Fig. 2. Overlay of X-ray molecules of compounds 1–6 by least-squares fitting of the
atoms of imidazopyrimidine rings (RMS = 0.0596 Å).

142
W. Wysocki et al. / Journal of Molecular Structure 1094 (2015) 137–147
Fig. 3. The energy effect of the free-rotation between the phenyl ring and imidazo[1,2-a]pyrimidine system (C8AC31,
u2) for the molecule 4 calculated using DFT/B3LYP/6-
311++G(d,p) method.
results in a reduction of the electron density around a proton and
resonance signal is shifted toward higher frequencies. The charac-
teristic chemical shifts of OH groups in compounds 1–6 vary
within the range of 10.90–11.22 ppm. 1H NMR spectra exclude tau-
tomeric form (c), because the hydrogen atom attached to the car-
bon atom C6 cannot resonate in this range. 13C NMR spectra also
did not allow to establish the tautomeric equilibrium, due to high
similarity of surroundings of carbon atoms in the tautomeric forms
of 1–6. The chemical shifts for the C atom with a hydroxyl and car-
bonyl groups being in the ranges of 160.8–162.0 and 161.1–
170.4 ppm, respectively, exclude tautomeric form (c), while forms
(a) and (b) appear to be equally probable and can coexist in the
solution.
1668–1632 cmÀ1 corresponding to the stretching vibration of the
carbonyl group for a fused imidazopyrimidine system. The broad
absorption band characteristic of the hydroxyl group present in
the range 3435–3171 cmÀ1 confirms the possibility of the forma-
tion of hydrogen bonds. These observations allow to conclude that
in the solid phase all forms (a)–(c) of 1–6 can occur. IR spectrum
recorded in the solvent (CHCl3) for compound 4 does not reveal a
stretching vibration characteristic for the hydroxyl group, which
may indicate a potentially existence diketo form (c) in solution.
Spectroscopic studies 1H, 13C NMR and IR, although allowed for
the identification of the compounds 1–6 but they did not indicate
explicitly their tautomeric forms present in solution and in the
solid state. Therefore, for a full analysis of tautomeric equilibria a
simulation of NMR and IR spectra using theoretical calculation
were performed, in order to compare them with the experimental
data.
The IR spectra were performed in solid state (KBr) for all inves-
tigated compounds 1–6 and chloroform solution for 4. IR spectra in
KBr show the characteristic narrow absorption bands in the range
Fig. 4. The energy effect of the free-rotation between the phenyl ring and imidazo[1,2-a]pyrimidine system (N1AC21,
u1) for the molecules 1, 4 and 5 calculated using DFT/
B3LYP/6-311++G(d,p) method.

W. Wysocki et al. / Journal of Molecular Structure 1094 (2015) 137–147
143
X-ray investigations
Selected geometrical parameters for the X-ray investigated crys-
tal structures of (1)–(6) are summarized in Table 2. The X-ray struc-
ture analysis of 4 revealed, that the asymmetric part of the unit cell
contains two independent molecules A and B. View of the mole-
cules with numbering of the atoms is shown in Fig. 1.
Difference electron-density maps for 1–6 revealed the position
of the H atom in the vicinity of atom O10 with the bond lengths for
C7AO10 and C9AO11 (Table 2) comparable with those for hydro-
xyl and carbonyl groups, respectively, clearly indicating that all
molecules exist as the O10-enol/O11-keto (a) tautomeric form in
the crystalline state. It is worth emphasizing that the hydroxyl
and carbonyl groups in 1, 2, 4 and 5 are involved in a strong inter-
molecular O10AH101Á Á ÁO11 (Table 3) hydrogen bond.
The bond lengths and angles in the imidazopyrimidine system
are very similar in 1–6 and close related structures of 6-benzyl-
7-hydroxy-1-(2-methoxyphenyl)-2,3-dihydro-1H,7H-imidazo[1,
2-a]pyrimidin-5(1H)-one [22] and 6-(2-chlorobenzyl)-1-(4-chloro-
phenyl)-7-hydroxy-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5
(1H)-one [23]. The aromatic pyrimidine rings are planar to within
0.053(16) Å in 1, 0.0354(17) Å in 2, 0.013(2) Å in 3, 0.028(3) and
0.032(3) Å in molecules A and B of 4, respectively, 0.0355(15) Å
in 5 and 0.0165(12) Å in 6. In 1, 2 and 6, the partially saturated
imidazoline rings exist in an intermediate conformation between
sofa and half-chair with respective characteristic asymmetry
parameters [24] for these conformations of
D
CsC4 = 2.64(19)° and
CC22 = 2. 1(2)° in 2 and
D
CC22 = 2.48(16)° in 6, while in 3, 4 and 5
D
CC22 = 2.31(19)° in 1,
D D
CsC5 = 4.1(2)° and
D
CsC5 = 3.50(16)° and
the imidazoline rings are nearly planar to within 0.016(2) Å in 3,
0.003(3) and 0.0015(4) Å in molecules A and B of 4, respectively
and 0.0209(6) Å in 5.
The orientation of the 1-(un)substitutedphenyl substituent in
relation to the imidazo[1,2-a]pyrimidine system in 1–5, as shown
by the torsion angle
u1 = C2AN1AC21AC22 of 145.47(15)° in 1,
165.44(17)° in 2, À76.5(3)° in 3, À4.4(5) and À0.3(4)° in molecule
A and B of 4, respectively, À178.03(14)° in 5, is strongly influenced
by the steric effect of respective 2-methyl, 4-chloro, 2,5-dichloro
and 3,4-dichloro substituents in phenyl ring. The orientation of
the phenyl substituent at C8 position of the imidazopyrimidine
ring changes from gauche for 1, 2, 4, 5 and 6 to nearly perpendicu-
lar for 3, as evidenced by the torsion angle
u2 = C7AC8AC31AC32
of À46.5(2) for 1, À38.1(3) for 2, 49.9(4) and À42.4(4)° for A and B
of 4, respectively, À42.7(2)° for 5, 65.19(18)° for 6 and À96.5(3)°
for 3. The weak intramolecular CAHÁ Á ÁN and CAHÁ Á ÁO hydrogen
bonds (Table 3) giving slightly puckered six-ring fused system for
1, 2, 5 and 4B, and four-ring fused system for molecule 4A can be
probably responsible for the conformations of molecules 1, 2, 4
and 5. In 6, the benzyl substituent has a gauche–trans conformation
with the torsion angles C2AN1AC12AC21 of À98.63(15)° and
N1AC12AC21AC22 of À22.27(17)°. This position of the benzyl
group with respect to the imidazo[2-a]pyrimidine system is stabi-
lized by the intramolecular C22AH22Á Á ÁN1 hydrogen bond
(Table 3). The differences between conformations of molecules
1–6 are illustrated in Fig. 2 showing the overlay of all molecules
by fitting of pyrimidine rings.
The X-ray structure analysis of 4 showed, that the asymmetric
part of the unit cell contains two independent molecules A and
B. The conformations of these molecules described by the torsion
angles u1 [À4.4(5)° in A and À0.3(4)° in B] and u2 [49.9(4)° in A
and À42.4(4)° in B] differ significantly by a rotation of phenyl ring
around C8AC31 bond by about 90°. The theoretical calculations at
the DFT/B3LYP/6-311++G(d,p) level show that the conformation of
molecules A and B as observed in their crystal are not equi-ener-
getic, with a difference in energy between A and B conformation
of
DE = 30.423 kcal/mol (single-point energy calculations).

144
W. Wysocki et al. / Journal of Molecular Structure 1094 (2015) 137–147
However, the energy minimization and full geometry optimization
with initial geometries obtained from the X-ray analysis for mole-
cules A and B yielded a very small difference in energy of
In the crystal structure of 4 the pairs of hydrogen bonding mole-
cules A and B from asymmetric part of the unit cell form molecular
chains along
c
axis by the O10AAH10AÁ Á ÁO11B and
0.012 kcal/mol between the conformations of molecule
A
O10BAH10BÁ Á ÁO11A strong resonance-assisted hydrogen bonds.
These molecular chins are linked in three-dimensional network
through the weak C5AAH51AÁ Á ÁO11B and C5BAH52BÁ Á ÁO11A
hydrogen bonds. Additionally, the pyrimidine and C21Á Á ÁC26 ben-
zene rings in inversion-related molecules A and inversion-related
molecules B overlap each other in head-to-tail orientation. The
(
u
1 = À21.6° and
u
2 = 44.6°) and B (
u
1 = À22.7° and
u
2 = À45.6°)
without changing significantly the conformations of these mole-
cules in relation to the conformations observed in crystal.
Therefore the energy effect of the free-rotation between the phenyl
ring and imidazo[1,2-a]pyrimidine system, taking into account the
one degree of freedom described by the torsion angle
u
2, were cal-
p p distances in the pair of molecules A are 3.3933(11) Å between
Á Á Á
pyrimidine/benzene (1Àx, 1Ày, Àz) and 3.5181(14) Å between ben-
zene/pyrimidine (1Àx, 1Ày, Àz) rings. Corresponding ÁÁÁ dis-
culated using DFT/B3LYP/6-311++G(d,p) method. The energies of
conformations were minimized and all geometrical parameters
optimized for each rotation with a 10° increment from À180 to
180° of u2 (Fig. 3). The conformations of molecules A and B
observed in the crystalline state are in good agreement with calcu-
lated conformations with minima of energy for u2 of À50° and
+50°. These two minima, similarly as two other minima at
p
p
tances for overlapping molecules B in (x, y, z) and (1Àx, 2Ày, 1Àz)
positions are 3.4005(13) and 3.4900(17) Å, respectively. In the crys-
tal structure of 5, molecules related by the a glide plane and 21 sym-
metry axis are linked into chains parallel to [100] and [010]
direction via strong O10AH10Á Á ÁO11 and weak C5AH52Á Á ÁO11
intermolecular hydrogen bonds, respectively. The combinations of
the [100] and [010] chains gives hydrogen-bonded molecular lay-
u
2 = À130° and +130°, are separated by the energy barrier esti-
mated to about 2.7 kcal/mol for the phenyl ring to pass through
mutual parallel position with pyrimidine ring 2 = 0° and
(
u
ers in the (001) crystallographic plane. The p-electron systems of
180°). The presented value of energy shows that the molecule 4
can rotate freely about C8AC31 bond in the room temperature.
The same can be concluded for molecules 1, 2, 3, 5 and 6 noting
that their conformations in crystal described by torsion angle u2
are very close to the conformations corresponding the calculated
minima of energy for molecule 4. The similar conformational
analysis performed for torsion angle u1 for compounds 1, 4 and
5 (Fig. 4) shows, that the position of the phenyl substituent with
respect to the imidazo[1,2-a]pyrimidine system and the energy
value of the rotation barrier are related with the type and place
of the substituent in the benzene ring. The calculated energy min-
the pairs of pyrimidine and benzene rings belonging to the mole-
cules related by c glide plane overlap each other, with centroid-
to-centroid separation of 3.6447(9) Å between pyrimidine ring at
(x, y, z) and benzene ring at (1/2Àx, 1/2+y, z) and benzene ring at
(x, y, z) and pyrimidine ring at (1/2Àx, À1/2+y, z). The
pÁ Á Áp dis-
tances are 3.5284(5) and 3.4743(7) Å, respectively, and the angle
between overlapping planes is 7.52(8)°. In the crystal structure of
6 the dimers formed from inversion-related molecules by two pairs
of O10AH10Á Á ÁN6 and C12AH12BÁ Á ÁO10 hydrogen bonds are linked
into molecular chains along b axis by weak C32AH32Á Á ÁO11 hydro-
gen bond. It is noticeable, that in the all analyzed crystal structures
ima for
u
1 are in good agreement with the value of
u
1 observed in
the numerous weak CAHÁ Á Á
p intermolecular contacts are observed
(Table S1 in Supplementary Materials).
the crystals of compounds 1, 4 and 5.
The molecular packing in the crystals of 1–6 is presented in
Figs. S1–S6 in Supplementary Materials. In the crystal structure of
1 the strong intermolecular O10AH101Á Á ÁO11 hydrogen bond links
the translation-related molecules into chains along the [001] direc-
tion. In the crystal structure of 2 the inversion-related molecules
form dimers via pair of the C26AH261Á Á ÁO10 hydrogen bonds.
Similarly as in 1, the strong O10AH101Á Á ÁO11 resonance-assisted
hydrogen bond links translation-related molecules into molecular
chains along the [100] direction. Additionally, the molecules
related by the 21 symmetry axis are joined in molecular chains par-
allel to the [010] direction by a weak C22AH221Á Á ÁO11 hydrogen
bond. These two last intermolecular hydrogen bonds links the
dimers in molecular layers parallel to the (001) crystallographic
plane. Pairs of the pyrimidine rings belonging to inversion-related
The molecular packing in the crystals of investigated com-
pounds is determined by intermolecular hydrogen bonds,
CAHÁ Á Á
p
,
p p and van der Waals interactions. A special role is
Á Á Á
played by a strong OAHÁ Á ÁO and OAHÁ Á ÁN intermolecular hydro-
gen bonds, which on one hand stem from the tautomeric form,
and on the other hand affects the occurrence of well-defined tau-
tomeric forms in the crystals of investigated compounds.
Theoretical calculations
In order to find the relative stabilities of the tautomeric forms of
analyzed 1,6-aryl-7-hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidin-
5(1H)-ones, energy calculations for each of the three possible tau-
tomeric forms of compounds 1–6 were performed in the gas phase
and water, DMSO, methanol, n-octanol, chloroform and tetra-
chloromethane solutions using DFT method. The stabilization
energy for each tautomeric form, expressed as the energy differ-
ence between the energy of given tautomeric form and the energy
molecules partially overlap, with the
p
Á Á Áp(i) distance of 3.6594(6)
Å; symmetry code: (i) = 1Àx, 2Ày, Àz and slippage of 1.637 Å. In
the crystal structure of 3 the molecules related by centre of inver-
sion form dimers through strong O10AH101Á Á ÁN6 hydrogen bond.
Table 5
Comparison of experimental (E) and theoretical (Tsc) characteristic stretching bands
m
(cmÀ1) of the OH and C@O groups in the tautomeric forms (a)–(c) of compounds 1–6.
Tautomer
E
Tsc
E
Tsc
E
Tsc
a
b
c
a
b
c
a
b
c
Compound
1
2
3
m
m
OH
C@O
3171
1640
3660
1665
3602
1673
–
3431
1660
3669
1668
3602
1674
–
3435
1668
3662
1667
3602
1678
–
1721
1694
1724
1698
1726
1699
Compound
4
5
6
m
m
OH
C@O
3434
1637
3669
1670
3602
1675
–
3430
1632
3665
1666
3602
1672
–
3435
1652
3664
1666
3602
1672
–
1726
1700
1722
1685
1720
1694
Tsc .– Theoretical oscillation frequency scaled by a literature scaling factor 0.9679.

W. Wysocki et al. / Journal of Molecular Structure 1094 (2015) 137–147
145
Fig. 5. The linear regression of experimental and calculated (GIAO DFT/B3LYP/6-311++G(d,p) method) chemical shifts in 1H (column left) and 13C (column right) NMR spectra
for 1–6. The signals derived from the protons of the hydroxyl group and methine atom C8 are omitted.

146
W. Wysocki et al. / Journal of Molecular Structure 1094 (2015) 137–147
of the tautomeric form with lowest energy, was calculated and the
population (fractional participation), pi, of each form in the tau-
tomeric form distribution was estimated using a non-generate
Boltzmann distribution. The results of these calculations are pre-
sented in Table 4. As can be seen from Table 4, the population of
the tautomeric form (b) in considered environments is below the
threshold of the detectability of conventional analytical methods
with the stabilization energy within the range from 8.5 to
13.0 kcal/mol for 2 in DMSO solution and 3 in gaseous phase,
respectively. The other two tautomeric forma (a) and (c) can coex-
ist both in gas phase and the solution, wherein the population of
them is according with the relation (a) > (or ꢁ) (c). Influence of
solvent polarity on tautomeric equilibrium is negligible resulting
in changes in the population forms within a few percent and an
explicit relationship between population form and the polarity of
the solvent is not observed. Nevertheless one can see that the pop-
ulation of the form (c) for 1, 2 and 6 increased slightly with the
polarity of the solvent and an inverse relationship can be observed
for form (c) in 4 and 5. The results of the theoretical calculations of
tautomeric equilibrium in gaseous phase and solutions for 1–6 are
in good agreement with the experimental data obtained for these
compounds in crystalline state. Although, the tautomeric form
O10-oxo/O11-hydroxy (a), and form O10-oxo/O11-oxo (c), can be
observed in gaseous phase and solutions and only tautomeric form
(a) is observed in crystalline state, but due to proton-acceptor
character of both oxo groups in tautomeric form (c), the lack of
intermolecular OAHÁ Á ÁO hydrogen bonds can be an important fac-
tor destabilizing the structure of the potential crystal of form (c).
Theoretical IR spectra calculated for possible tautomeric forms
of 1–6 using DFT/B3LYP/6-311++G(d,p) method were compared
with the experimental spectra recorded in KBr for these com-
pounds. Since the calculated ‘‘raw’’ spectra usually significantly
overestimate harmonic frequencies in comparison to experimental
values, the scaling method was applied to best fit calculated and
experimentally determined vibrational frequencies. Calculated
vibrational frequencies were scaled by the scaling factor of
0.9679 recommended for the method and the basis set used in
theoretical calculation [18].
(Supplementary Materials; atoms numbers used for GIAO-DFT
calculations are shown in Scheme S1). Comparison of experimental
and calculated 1H NMR and 13C NMR spectra for compound 5 are
shown in Figs. S8 and S9, respectively (Supplementary Materials).
The comparison of the 13C NMR spectra for compounds 1–6
obtained from theoretical calculation with those recorded experi-
mentally (Fig. 5) gave a good fit factors, for which the values of
R2 are in the ranges 0.9946–0.9736, 0.9861–0.9675 and 0.9754–
0.9396 for tautomeric forms (a), (b) and (c), respectively. This indi-
cates a slightly better fit 13C NMR spectra for oxo-hydroxy tau-
tomeric forms (a) and (b) in relation to the spectrum for dioxo
form (c). Also calculated and experimentally recorded chemical
shifts of all protons in 1H NMR spectra for 1–6 show very good cor-
relation (Fig. 4), except chemical shifts for the proton of the
hydroxy group in tautomeric forms (a) and (b) and the proton of
the methine C(8)H group in tautomeric form (c), which differences
between theoretical and experimental values are within the range
5.01–6.76 and 6.52–6.84 ppm, respectively. This discrepancy
between experimental and theoretical shifts is caused by the
incapacity of polarizable continuum model in calculations of
NMR spectra for systems with hydrogen bonds between solute
and solvent. Omitting these protons, the values of correlation
coefficients R2 vary from 0.9983 to 0.9557 for tautomeric form
(a), from 0.9964 to 0.8953 for tautomeric form (b) and from
0.9958 to 0.9198 for tautomeric form (c). The best fit of the experi-
mental and theoretical 1H NMR spectra is observed for tautomeric
form (a) of compounds 2–5 and tautomeric form (b) of compound
1. In practice, slight differences in the values of R2 for tautomeric
forms (a), (b) and (c) are not capable of identifying tautomeric
forms based on their NMR spectra in the set of investigated com-
pounds 1–6. It should be noted that the inclusion of protons of
groups AOH and C(8)H in correlation analysis give the correlation
coefficients R2 less than 0.32, which means that the chemical shifts
of theoretical and experimental spectra are uncorrelated.
Conclusion
In this paper, the structural characterization of a series of imi-
dazo[1,2-a]pyrimidine derivatives 1–6 with antinociceptive activ-
ity is reported. The compounds 1–6 can exist in three tautomeric
forms and the tautomeric equilibrium between them in gaseous
phase, solution and crystalline state was examined using IR, 1H
and 13C NMR spectroscopic analysis, X-ray crystal structure
determinations and theoretical calculations at DFT Level. The cor-
relation analysis of the experimentally recorded IR, 1H and 13C
spectra and the corresponding spectra theoretically calculated for
all possible tautomeric forms of 1–6 show limited possibilities of
use of these methods to identify their tautomeric forms in different
environments. This may be due to the fact, that polarisable contin-
uum model PCPM used for theoretical calculation may fail in
describing the properties of systems with hydrogen bonds between
solute and solvent. The obtained results of the structural investiga-
tion of compounds 1–6 may be helpful in the study of relations
between chemical structure and biological activity (SAR and
QSAR analysis) of the analyzed bioactive imidazo[1,2-
a]pyrimidine.
As noted above (Part 3.2) the IR spectra recorded in KBr for all
investigated compounds show the bands characteristic for OAH
and C@O groups occurring in the tautomeric forms (a)–(c). All
experimental and calculated vibrational frequencies were com-
pared for the model compound 5 (Table S2 and Fig. S7 in
Supplementary Materials), while for all compounds 1–6 this com-
parison limited to the characteristic bands of the groups OH and
C@O is shown in Table 5.
As can be seen in Tables 5 and S2, the comparison of the experi-
mental with theoretically calculated vibrational frequencies gave a
difference of several cmÀ1 in
Dm for all tautomeric forms (a)–(c).
The great similarity in the oscillation frequencies of both hydroxy
and carbonyl groups at various positions 5 and 7 of the imi-
dazo[1,2-a]pyrimidine ring confirms the difficulty in distinguish-
ing three tautomers (a), (b) and (c) using IR spectra.
Although NMR spectroscopy is a widely used experimental
method for structural analysis of organic compounds, it encounters
a series of interpretation difficulties, particularly in the analysis of
polyatomic molecules that can also exist as various tautomeric or
isomeric forms. In such cases, it happens that the experimental
spectrum does not give a full and explicit analysis of the structure
of these compounds. However, the NMR spectra obtained from
theoretical calculation allow the unambiguous assignment of sig-
nals from individual nuclei of atoms, and comparing it with the
experimental spectrum can confirm or rule out the existence of
various forms of the investigated compounds.
Appendix A. Supplementary material
CCDC-1038738 for 1, CCDC-1038739 for 2, CCDC-1038740 for 3,
CCDC-1038741 for 4, CCDC-1038742 for 5 and CCDC-1038743 for 6
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.
uk/conts/retrieving.html [or from the Cambridge Crystallographic
Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(0) 1223 336 033; email: deposit@ccdc.cam.ac.uk].
All experimental and theoretical calculated 1H and 13C NMR
chemical shifts for compounds 1–6 are presented in Table S3

W. Wysocki et al. / Journal of Molecular Structure 1094 (2015) 137–147
147
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The weak CAHÁ Á Á
p intermolecular contacts geometry for 1–6
(Table S1). The comparison of experimental and calculated stretch-
ing and bending vibrational frequencies in the IR spectra of the
tautomeric forms (a)–(c) of the model compound 5 (Table S2).
Experimental and calculated 1H and 13C NMR chemical shifts for
compounds 1–6 (Table S3). Unit-cell packing in crystals of 1–6
(Fig. S1–S6). Comparison of experimental and calculated IR spectra
for compound 5 (Fig. S7). Comparison of experimental and calcu-
lated 1H NMR spectra for compound 5 (Fig. S8). Comparison of
experimental and calculated 13C NMR spectra for compound 5
(Fig. S9). Atom numbers used for GIAO calculation of 1H and 13C
NMR chemical shifts (Scheme S1).
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2015.04.
005.
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