Intramolecular C-H...O hydrogen bonding in 1,4-dihydropyridine derivatives

Article abstract of DOI:10.3390/molecules16098041

The diastereotopy of the methylene protons at positions 2 and 6 in 1,4-dihydropiridine derivatives with various substituents has been investigated. NMR spectroscopy and quantum chemistry calculations show that the CH...O intramolecular hydrogen bond is on

Full text of DOI:10.3390/molecules16098041

Molecules 2011, 16, 8041-8052; doi:10.3390/molecules16098041
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Intramolecular C-H···O Hydrogen Bonding in
1,4-Dihydropyridine Derivatives
Marina Petrova *, Ruslan Muhamadejev, Brigita Vigante, Brigita Cekavicus, Aiva Plotniece,
Gunars Duburs and Edvards Liepinsh
Latvian Institute of Organic Synthesis Aizkraukles 21 Street, Riga LV-1006, Latvia;
E-Mails: muhamadejev@osi.lv (R.M.); vigante@osi.lv (B.V.); arkady@osi.lv (B.C.);
aiva@osi.lv (A.P.); gduburs@osi.lv (G.D.); edv@osi.lv (E.L.)
* Author to whom correspondence should be addressed; E-Mail: marina@osi.lv;
Tel.: +371-67014900.
Received: 26 July 2011; in revised form: 8 September 2011 / Accepted: 9 September 2011/
Published: 19 September 2011
Abstract: The diastereotopy of the methylene protons at positions 2 and 6 in 1,4-
dihydropiridine derivatives with various substituents has been investigated. NMR
spectroscopy and quantum chemistry calculations show that the CH···O intramolecular
hydrogen bond is one of the factors amplifying the chemical shift differences in the
1H-NMR spectra.
Keywords: 1,4-dihydropyridines; bromination; nucleophilic substitution; hydrogen bond;
NMR spectra; quantum chemical calculations
1. Introduction
The 1,4-dihydropyridine (1,4-DHP) scaffold is a common component of pharmacologically active
molecules which possess a variety of biological activities [1]. Several 1,4-DHP derivatives play an
important role in regulating the decrease or increase of the penetration of calcium ions through
membranes into cells. Substituents at the 2,6-, 3,5-, 4- and 1- positions of 1,4-DHP derivatives
influence their structure-activity relationships, so structural and conformational investigations of these
systems are important to gain insight into the mechanisms of their physiological action [2].

Molecules 2011, 16
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2. Results and Discussion
In recent years many studies attempting to modify the 2,6-methyl groups of 1,4-DHP by introducing
various substituents have been performed [3-6]. On the other hand cationic amphiphilic 1,4-DHP
derivatives have gained significance as useful transport molecules for the delivery of nucleotides into
target cells [4,7].
Our attention was drawn to the fact that the CH2X protons of substituents in positions 2 and 6
of symmetrically substituted 1,4-dihydropyridine rings (compounds 1-3, 5, Table 1) become
diastereotopic in the presence of different substituents at position 4, thereby, providing an AB system
1
in the corresponding H-NMR spectra. The extent of the observed non-equivalence of the methylene
protons should be influenced by the spatial conformation of side chains in the molecule and/or the
anisotropy of the substituents.
Table 1. Characterization of compounds 1–5.
R1
R1
O
R1
O
O
R2OOC
R3CH2
COOR2
CH2R3
EtOOC
Me
4
3
2
5
6
O
1
O
O
N
N
H
N
H
R4
1-3
4
5
Comp.
R1
R2
R3
R4
H
Yield,% Reference
1a
1b
1c
1d
1e
1f
Me
Ph
Et
Et
Et
Br
Br
Br
Br
Cl
Br
Br
Br
Br
Py+Br−
Py+Br−
Py+Br−
Py+Br−
Py+Cl−
Py+Br−
Py+Br−
Py+Br−
Py+Br−
Py+Br−
Py+Br−
Py+Br−
Py+Br−
59
88
76
61
87
Me
H
PhCF3-o
PhOCHF2-o
COOMe
Ph
(CH2)2OC3H7-n
H
Et
H
Et
H
47
86
72
89
63
66
93
74
91
63
64
84
63
82
35
33
38
[3]
[3]
[5]
1g
1h
1i
PhOCHF2-o
Ph
Me
H
C12H25
H
PhOCHF2-o
Me
Me
Me
H
2a
2b
2c
2d
2e
2f
Et
Ph
Et
Me
H
PhCF3-o
PhOCHF2-o
COOMe
Ph
Et
(CH2)2OC3H7-n
Et
H
H
Et
H
[6]
[4]
2g
2h
3a
3b
3c
3d
3e
PhOCHF2-o
PhOCHF2-o
Ph
Me
H
Me
Me
H
C10H21
C12H25
C14H29
C16H33
C12H25
[4]
[4]
[4]
[7]
[7]
Ph
H
Ph
H
Ph
H
Ph
Me

Molecules 2011, 16
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Table 1. Cont.
Comp.
R1
R2
R3
R4
Yield,% Reference
4a
4f
Ph
20
33
50
60
[10]
[11]
[12]
[13]
PhOCHF2-o
Ph
5a
5f
PhOCHF2-o
The synthetic pathway for obtaining 1,4-dihydropyridine derivatives bearing substituents on the
2,6-methylene groups (Table 1) involved Hantzsch synthesis, followed by bromination of the methyl
groups with NBS and nucleophilic substitution of bromine by pyridine giving the target compounds
1a–d, i and 2a–d, h (Scheme 1).
Scheme 1. Synthesis of compounds 1 and 2.
R1
R1
R1
R2OOC
COOR2
R2OOC
COOR2
R2OOC
H3C
COOR2
CH3
N
NBS
Br
C
Br
C
H2
H2C
-
N
CH2
N+
MeOH
N
acetone
N+
R4
N
H2
-
Br
Br
R4
R4
1a-d,i
2a-d,h
A different approach was elaborated for the synthesis of 4-methoxycarbonyl derivative 1e
(Scheme 2). Thus, the condensation of ethyl 4-chloroacetoacetate with glyoxylic acid monohydrate in
methanol at rt in the presence of piperidine/acetate as catalyst provided (E,Z)-2-(2-chloroacetyl)-but-2-
enedioic acid 1-ethyl ester, which was used without isolation in the next reaction with ethyl 3-amino-4-
chlorobut-2-enoate. The obtained 3,5-diethyl 2,6-bis(chloromethyl)-1,4-dihydropyridine-3,4,5-tri-
carboxylate was esterified with methanol using conc. sulfuric acid as catalyst to afford compound 1e.
The target compound 2e was successfully obtained via nucleophilic substitution of chlorine by
pyridine in the presence of potassium iodide in dry acetone.
Scheme 2. Synthesis of compounds 1e, 2e.
O
OH
O
OEt
H
OH
MeOH
Cl
EtO
Cl
+
O
O
O
O
O
OEt
Cl
MeOH
NH2
O
O
O
O
O
O
O
O
O
OH
O
O
O
EtO
OEt
N
EtO
OEt
MeOH
conc.H2SO4
EtO
OEt
N
-
I
-
I
H
N+
N+
N
KI / acetone
N
H
H
Cl
Cl
Cl
Cl
1e
2e

Molecules 2011, 16
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Compounds 1f–h, 2f–g, 3a–e, 4a,f and 5a,f were prepared according to the literature, as mentioned
in Table 1. The 4-substituent in the molecule is located at a considerable distance from the 2- (6–)
1
methylene group, and the experimentally observed difference in the H-NMR chemical shifts of the
CH2 groups in cyclic lactones 4–5 does not exceed 0.08 ppm (Table 2); a similar value was observed
in [8]. However, its potential anisotropic influence on the 2,6-CH2 methylene proton chemical shifts
can’t be ignored. In monocyclic derivatives 1–3 the conformation of the 3,5-ethoxycarbonyl groups
should be another important factor in the anisotropy. Indeed in these compounds the chemical shift
difference for CH2X protons becomes very significant (Table 2), so we can assume that the difference
in chemical shifts of CH2X groups in 1–3 induced by the anisotropy of the 4-substituent may also be
influenced by the position of these protons relative to the 3,5-alkoxycarbonyl substituents. In order to
1
study the substituent influence on the magnetic nonequivalence of the mentioned H-NMR signals,
quantum chemical studies were carried out for some derivatives of 1,4-DHP (compounds 1–5). The
obtained data are presented in Table 3.
Table 2. 1H-NMR data of compounds 1–5.
Comp.
1a
Solvent
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDСl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
δNH
6.35
9.44
δHВ
4.89
4.69
4.96
5.17
4.81
4.61
4.86
4.67
5.19
4.93
4.91
4.67
4.86
4.62
4.92
4.68
4.91
5.18
6.28
5.99
6.82
6.45
6.35
5.97
6.16
5.90
6.30
5.97
1J(C,HB)
δHA
4.51
4.40
4.82
4.87
4.66
4.56
4.57
4.53
4.74
4.48
4.63
4.57
4.62
4.59
4.63
4.59
4.84
4.85
5.76
5.49
6.59
5.77
5.97
5.66
6.11
5.62
6.06
5.64
1J(C,HA)
2J(H,H)
11.5
9.6
159
157
11.0
11.3
11.6
9.9
1b
1c
1d
1e
1f
6.49
9.67
6.55
9.62
7.37
9.78
6.45
9.58
6.56
9.65
6.45
9.62
159
158
157
157
11.8
9.7
160
158
159
160
158
156
14.6
11.1
11.8
9.6
156.4
158.7
11.3
9.7
1g
1h
1i
158
159
156
157
11.5
9.7
11.0
11.4
14.1
15.0
15.6
16.0
13.6
15.1
14.1
14.9
14.1
15.6
10.88
10.10
2a
2b
2c
2d
2e
152.1
152.2
153.1
151.1
146.3
146.2
147.1
149.1
10.98
10.48
10.80
10.15
10.31
10.20
150.1
149.2

Molecules 2011, 16
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Table 2. Cont.
Comp.
2f
Solvent
δNH
10.92
10.34
10.88
10.31
δHВ
6.38
6.08
6.24
5.94
6.84
6.39
6.40
6.08
6.40
6.07
6.32
6.08
6.40
6.07
6.73
6.48
4.52
4.84
4.69
4.72
4.64
1J(C,HB)
δHA
5.92
5.63
6.10
5.46
6.62
5.77
5.89
5.56
5.89
5.53
5.86
5.56
5.89
5.53
6.56
5.78
4.47
4.74
4.65
4.65
4.60
1J(C,HA)
146.5
2J(H,H)
13.6
15.3
13.7
14.9
15.8
16.2
13.9
15.1
13.9
15.0
13.8
15.1
13.9
15.2
16.1
16.5
16.7
16.5
16.4
16.0
16.2
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
CDCl3
DMSO
DMSO
150.6
151.9
146.4
2g
2h
3a
3b
3c
3d
3e
4a
10.96
10.21
10.95
10.12
10.92
10.28
10.96
10.12
150.7
151.1
151.4
152.4
150.1
152.1
148.3
146.5
145.4
146.3
146.3
146.2
146.4
146.2
152.5
152.5
and
150.2
147.5
8.30
9.74
6.42
9.91
9.97
and
4f
5a
5f
and
and
and
Table 3. Comparison of H-bond parameters in model compounds 1f, 1b and 2b, 2f and 3b.
Compound
С2(СН···О)
2.508 Å,
(86.6°)
С6(СН···О)
2.511 Å,
(86.5°)
С2 pyr(СН···О)
С6 pyr(СН···О)
1f
-
-
2.376 Å,
(93.6°)
2.374 Å,
(93.7°)
2.032 Å,
(131.5°)
2.329 Å,
(99.6°)
2.073 Å,
(126.0°)
2.168 Å,
(117.7°)
2.198 Å,
(107.7°)
2.366 Å,
(96.979°)
1b
2f
-
-
2.629 Å,
(89.7°)
2.152 Å,
(137.3°)
2.913 Å,
(87.5°)
2.254 Å,
(103.9°)
2.341 Å,
(98.914°)
2.544 Å,
(94.0°)
2b
3b
2.591 Å,
(90.362°)
2.849 Å,
(82.121°)
Signals of the AB protons of the 2,6-methylene groups for compounds 1–5 are easily
distinguishable in the 1H-NMR spectra by their 11–15 Hz geminal 2J coupling constants. The values of
the constants for compounds 1 are less than for compounds 2 and 3. Neighbouring π-bonds of the
pyridines in 2, 3 usually result in an increase of the absolute value of the constants 2J.
According to literature data [9], increasing the polarity of the medium usually slightly increases the
negative contribution to the geminal coupling, and if its sign is negative, the absolute value increases.

Molecules 2011, 16
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Such effect is observed in the N-methyl-substituted derivatives 1b, 1i and in compounds 2, 3 where
2
|2Jcdcl3| < |2Jdmso|. However, for compounds 1a and 1c–h, contrary to the literature data, the J values
decrease by about 2 Hz on going from CDCl3 to DMSO solution. The unusual behaviour of the
geminal couplings for compounds 1a, 1c–h may be explained by the variation of the dihedral angle
between the methylene group protons and 1,4-DHP cycle in distribution of rotamers around the
C2,6-CH2X bond.
Formation of intermolecular hydrogen bonds between the NH group and solvent DMSO moves
the resonance signal of NH proton to a higher-frequency field ~3 ppm (Table 2). Contrary in
compounds 2a,c–g and 3a–d, the resonance signal of the NH proton moves to a lower-frequency field
~0.5–1.1 ppm on going from CDCl3 to DMSO. The reason for this anomalous behaviour of the NH
proton could be that in CDCl3 solutions of these compounds the CH2Py substituent is strongly oriented
and NH proton is located in a zone of negative anisotropy of the pyridinium ring. This is confirmed by
calculations (Figure 1).
Figure 1. The calculated optimal conformations in compounds 1f, 1b and 2f, 2b.
1f
1b
2f
2b

Molecules 2011, 16
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Analysis of NOEs in the 1H NOESY spectra of compounds 1–3 allows us to determine the relative
position of the AB protons for the methylene group—the NOE from NH to the more shielded proton HA
is twice as intense as the HB (Figure 2). This means that the HA proton resonating in a lower-frequency
field is located closer to the NH proton by about 0.3 angstroms.
1
Figure 2. Slice of Н-NMR NOESY spectrum for compound 3b. More intense NOE is
registered between NH and HA, showing preferable orientation toward the NH.
Such an arrangement of CH2 protons leads to an intramolecular contact between the hydrogen atom
HB and the carboxyl group at the C3 carbon, leading to the formation of a CHB···O=C hydrogen bond.
It is known that protons involved in hydrogen bonds are less shielded, as compared to free ones [14].
Short interactions of C-H···O play an important role in biology and have been observed in many cases
previously [15].
Additional confirmation for the existence of C-H···O hydrogen bonding in compounds 1–3 comes
from the different deuteration rates of the 2(6)-CH2 protons (Figure 3). In D2O solution the intensity of
the resonance signal of the more shielded proton HA of compound 3b decreases faster than for the
more deshielded HB. This is because the hydrogen-bonded protons are usually less influenced by the
intermolecular H-D exchange. This fact confirms the formation of a hydrogen bond between HB
methylene proton and the carboxyl group.
Figure 3. 1Н-NMR spectral data of D2O solutions of compound 3b at 25 °С.

Molecules 2011, 16
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The measured coupling constants J(13C, H) for each of the methylene protons also differ
1
1
1
1
1
1
1
1J(13C, HA) < J(13C, HB) (see Table 2). The smaller J(13C, H) value corresponds to the more
shielded proton HA. This is consistent with the literature data [16], which states that if the CH-proton is
involved in a hydrogen bond, the 1J(13C, 1H) value increases.
1H-13C-HMBC spectra reveal a more intensive magnetization transfer from the low field HB
proton to 13C3 carbon as compared to HA. It is known that the intensities of cross peaks in the HMBC
spectra are proportional to the value of the vicinal coupling constant J(13C, H), normally being
3
1
3J(C,H)trans > J(C,H)cis [17]. The delay value used to generate long-range spin-spin interaction
3
between 13C-1H in HMBC spectrum was 8 Hz. The higher intensity of HA cross peak to the carbon C3
(110.1 ppm) points to its trans-orientation relative to C3. Therefore, the orientation of the less shielded
proton HB favours its participation in the CH···O hydrogen bond.
Thus, on the basis of these data, we can unambiguously claim that the intramolecular CH···O
hydrogen bond is one of the reasons for the non-equivalence of the methylene protons in these
systems. In compounds 1 and 2 the difference in the chemical shifts of the AB methylene protons
(ΔδAB = δB − δA) vary in the range 0–0.5 ppm, rather randomly, depending on the nature of substituents
and the solvent used. In compounds 3a–d, with bulk aliphatic substituents at C3,5, the difference is
relatively constant and is equal to ~0.5 ppm (Table 2). To get more insight for the results obtained by
NMR quantum-chemical calculations were carried out.
The results obtained reveal that for compounds 2b, 2f the energy minima correspond to the
conformations with s-cis-s-cis carboxyl group orientation relative to the double bond in the
dihydropyridine cycle, indicating the dominant stabilizing effect of intramolecular hydrogen bond
on the conformation of molecules 2b, 2f the same as in case of 1b, 1f. Structures with s-cis-s-trans
and s-trans-s-trans carboxyl groups orientation are with higher energy, consequently the stabilizing
effect in solutions has to be attributed to the hydrogen bonds C-H···O. The calculated equilibrium
conformations and the internuclear distances R (CH···O) also reveal the formation of a hydrogen
bond (Table 3).
In description of hydrogen bonds of the CH···O type geometric characteristics are often used. In our
case, the calculated parameters of intramolecular hydrogen bonds for compounds 1b, 1f, 2b, 2f and 3b,
presented in Table 3, are consistent with the X-ray diffraction and NMR spectral data. According to
calculations, the distance d(CH···O) decreases, and the angle (C-H···O) increases on going from 1f, 1b
to 3b, indicating weakening of the hydrogen bond between the methylene HB proton and oxygen of the
carboxyl group. At the same time, in the most energetically favourable conformations of 2b, 2f and 3b
there exist additional H-bonds between the pyridine ortho protons and the oxygen atoms of the
carboxyl group (see Table 3). These additional H-bonds also stabilize the structure of the molecule. In
conformations with s-cis-s-trans and s-trans-s-trans orientation of the carboxyl groups relative to the
double bonds of DHP cycle there is a possibility to form H-bonds with a length of about 2.400 Å
between protons in position 4 and the ethoxycarbonyl oxygen. The latter contact is much weaker than
the ones with protons of the methylene groups and does not contribute significantly to the
conformation of the molecule.
In summary, some novel derivatives of 1,4-dihydropyridine bearing substituents at 2,6-methylene
groups were synthesized. It was shown that one of the reasons for the diastereotopy of the methylene
protons at positions 2 and 6 of symmetrically substituted 1,4-dihydropyridine rings is the formation of

Molecules 2011, 16
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an intramolecular hydrogen bond of the CH···O type, which was confirmed by NMR spectroscopy and
quantum-chemistry calculations.
3. Experimental
3.1. Chemicals
All reagents were purchased from Aldrich, Acros, Fluka or Merck and used without further
purification. TLC was performed on 20 × 20 cm silica gel TLC-PET F254 foils (Fluka). Melting points
were determined on an SRS OptiMelt apparatus (Stanford Research Systems, Sunnyvale, CA, USA).
Elemental analyses were performed on an EA 1106 (Carlo Erba Instruments, Milan, Italy).
Compounds were recrystallized from methanol, acetone or purified by column chromatography.
3.2. NMR Experiments (Table 2)
1
13
1
13
13
The one-dimensional H- and C- and two dimensional H-1H NOESY, C-1H HMBC, C-1H
HSQC of compounds 1–5 were recorded on a Varian-Mercury 400 MHz BB instrument. The mixing
13
time in the 2D-NOESY spectra was 800 ms. The C-HMBC were recorded with the evolution time
of 62.5 s delay for the generation of long-range correlations. For all two dimensional spectra a
4,096 × 1,024 data matrix was used. To improve the signal-noise ratio, the data matrix before Fourier
transformation was zero-filled twice and multiplied by a cosine function. The chemical shifts of the
hydrogen and carbon atoms are presented in ppm and referred to the residual signals of the solvent a
7.25 (1H) and 77.0 ppm (13C) ppm, respectively. Multiplicities are abbreviated as: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; br, broad. The coupling constants are expressed in Hertz.
3.3. Synthesis
General method for the synthesis of 2,6-di(bromomethyl)-3,5-bis(alkoxycarbonyl)-4-aryl(4-alkyl)-(or
N-methyl)-1,4-dihydropyridines 1a–d,i: To a solution of the appropriate 2,6-dimethyl-3,5-
bis(alkoxycarbonyl)-4-aryl(4-alkyl)-1,4-dihydro-pyridine (5 mmol) in methanol (50 mL) NBS (10
mmol) was added portionwise at ambient temperature. The reaction mixture was stirred at rt for 24 h.
The paleyellow precipitate was filtered and washed with water. The precipitate was crystallized from
ethanol giving 1a–d,i.
2,6-Di(chloromethyl)-3,5-bis(ethoxycarbonyl)-4-methoxycarbonyl-1,4-dihydropyridine (1e). A mixture
of ethyl 4-chloroacetoacetate (2.72 mL, 20 mmol) and glyoxylic acid monohydrate (1.74 g, 19 mmol)
in methanol (40 mL) was stirred at rt for 72 h in the presence of piperidine/acetate as catalyst. Then
ethyl (E,Z)-3-amino-4-chlorobut-2-enoate (3.27 g, 20 mmol) was added and the combined mixture was
stirred at rt additional 72 h. The solvent was removed under vacuum and the residue was washed with
water. The obtained yellow oil was crystallized from methanol yielding 3,5-diethyl 2,6-bis-
(chloromethyl)-1,4-dihydropyridine-3,4,5-tricarboxylate (4.98 g, 68%); m.p.164–166 °C; elemental
analysis calcd (%) for C14H17Cl2NO6: C 45.92, H 4,68, N 3.82; found: C 45.95, H 4.58, N 3.72. To
a solution of 3,5-diethyl 2,6-bis(chloromethyl)-1,4-dihydropyridine-3,4,5-tricarboxylate (1.83 g,
5 mmol) in methanol (30 mL) conc. sulfuric acid (0.1 mL) was added and the reaction mixture was

Molecules 2011, 16
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refluxed for 2 h. The solvent was removed under vacuum and the residual crude product was triturated
with water. After cooling the precipitate was filtered off and crystallized from methanol giving
compound 1e (1.65 g, 87%); m.p. 99–101 °C; p elemental analysis calcd. (%) for C15H19Cl2NO6: C
47.38, H 5.04, N 3.68; found: C 47.41; H 4.95; N 3.68.
General method for the synthesis of 1,1`-{[3,5-bis(alkoxycarbonyl)(3,5-bis(2-propoxyethoxycarbonyl)-
4-aryl(4-alkyl) (or N-methyl)-1,4-dihydropyridine-2,6-diyl] dimethylene} bispyridinium dibromides
2a–d,h: To a solution of compounds 1a–d,i (2 mmol) in dry acetone (20 mL) pyridine (0.20 mL, 2.2
mmol) was added and the reaction mixture was stirred at rt for 24 h. After cooling the precipitate was
filtered off, washed with dry acetone and crystallized from ethanol giving compounds 2a–d,h as pale
yellow powders.
1,1`-{[3,5-Bis(ethoxycarbonyl)-4-methoxycarbonyl-1,4-dihydropyridine-2,6-diyl]dimethylene}
bis-
pyridinium diiodide (2e). To a solution of compound 1e (0.38 g, 1 mmol) in dry acetone (4 mL)
pyridine (0.18 mL, 2 mmol) and potassium iodide (0.33 g, 2 mmol) were added and the mixture was
stirred at rt for 48 h. The mixture was diluted with acetone (20 mL), and the potassium chloride formed
was filtered off. Acetone was removed under vacuum, and the residue was crystallized from methanol
yielding compound 2e as a pale yellow powder, (0.65 g, 91%); m.p.137–139 °C; elemental analysis
calcd (%) for C25H29I2N3O6: C 41.63; H 4.05; N 5.83; found: C 41.49; H 3.98; N 5.65.
3.4. Computional Methods
The Firefly (7.1.G) software package [18] was used for calculation/optimisation of
structures/structures’ geometry. The structures of 1d, 1e, 1d and 2a were optimised using a combined
RHF/DFT (b3lyp) method and 6-31g basis set. In the calculation of compounds 1 and 2 the basis set
was supplemented by two polarization functions (**) and a diffuse (++) - 6–31g ++ ** (hybrid
DFT/RHF B3LYP/6-31++G**). For 3b the same method and theory level was used, only simplified by
using one polarization function and one diffuse - (hybrid DFT/RHF B3LYP/6-31+G*).
4. Conclusions
Some novel derivatives of 1,4-dihydropyridine were synthesized. Due to the presence of a prochiral
centre at C-4 in the heterocyclic ring magnetic non-equivalence of the diastereotopic methylene
protons in positions 2 and 6 was observed. NMR spectroscopy and quantum-chemistry calculations
confirmed that the formation of a CH···O intramolecular hydrogen bond amplifies the extent of the
anisochrony of the methylene protons.
Acknowledgments
This work was supported by the ESF project No.2009/0197/1DP/1.1.1.2.0./09/APIA/VIAA/014
“Design of new pharmacomodulators and studies of their nanoassociates as transport forms”,
VPP-4-02.2 and VPP-4-07-3.

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8051
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