A theoretical and experimental study to unequivocal structural assignment of tetrahydroquinoline derivatives

Article abstract of DOI:10.1007/s11224-013-0297-y

The tetrahydroquinoline derivatives can be easily synthesized through Povarov reaction and have several important biological activities. This work describes a comparative study for the unequivocal assignment of molecular structure of different tetrahydroq

Full text of DOI:10.1007/s11224-013-0297-y

Struct Chem
DOI 10.1007/s11224-013-0297-y
ORIGINAL RESEARCH
A theoretical and experimental study to unequivocal structural
assignment of tetrahydroquinoline derivatives
•
Bruno Henrique Sacoman Torquato da Silva
•
Naiara Letıcia Marana Ana Carolina Mafud
•
´
Luiz Carlos da Silva-Filho
Received: 11 February 2013 / Accepted: 10 June 2013
Ó Springer Science+Business Media New York 2013
Abstract The tetrahydroquinoline derivatives can be
easily synthesized through Povarov reaction and have
several important biological activities. This work describes
a comparative study for the unequivocal assignment of
molecular structure of different tetrahydroquinoline deriv-
atives, through a complete analysis of NMR 1D and 2D
NMR spectra (1H, 13C, COSY, HSQC, and HMBC), and
the correlation this data with theoretical calculations of
energy-minimization and chemical shift (d), employing the
theory level of DFT/B3LYP with set of the cc-pVDZ basis.
For these derivatives the experimental analyses and the
theoretical model adopted were sufficient to obtain a good
description of its structures, and these results can be used to
assign the structure of various others tetrahydroquinoline
derivatives.
biological activities [1–5], among them: psychotropic [6],
antiallergic [7], anti-inflammatory [8], and estrogenic
activity [9]. The pyranquinolines and furanquinolines
derivatives exhibit a pharmacological potential [10].
Recently published studies demonstrated that quinoline
derivatives also show good applications in solar cells, due
to the high number of conjugated p electrons in its structure
[11–15].
The tetrahydroquinoline derivatives can be easily syn-
thesized through Povarov’s reaction (single or multi-step)
using several kinds of catalysts, such as: NbCl5, InCl3,
LiBF4, and BF3ꢀEt2O [16–29]. The Povarov’s reaction is
derived from aza-Diels–Alder reaction and it is an excel-
lent tool for the synthesis of natural products and hetero-
cyclic. In this reaction, imines react with dienophiles to
obtain the tetrahydroquinolines derivatives through of a
concerted mechanism (Fig. 1).
Keywords Tetrahydroquinoline derivatives ꢀ Theoretical
study ꢀ NMR ꢀ Chemical shifts calculations ꢀ Poravov
adducts
Povarov‘s reaction for obtaining the tetrahydroquinoline
derivatives generally lead to the formation of a pair of
diastereoisomers, with stereochemistry cis and trans
between the hydrogens H-1 and H-2, providing different
proportions between these isomers, depending on the
conditions used [16–29]. However, even with the wide
variety of these catalysts used to the obtention of these
derivatives, we did not find, at the literature, more detailed
studies about the structure determination of these com-
pounds. Therefore, this work had an objective to realize a
theoretical and experimental study, in order to determine
unequivocally the structure assignment and the conforma-
tion of the different tetrahydroquinoline derivatives, using
ab initio calculations and nuclear magnetic resonance
experiments, and then correlating these two methods. This
was achieved by the use of several techniques, such as
COSY, HMQC, HMBC analysis, associated with theoret-
ical calculations.
Introduction
As an important class of natural products, the tetrahydro-
quinolines derivatives are compounds that have the basic
structure of quinolines and have several important
B. H. S. T. da Silva ꢀ N. L. Marana ꢀ L. C. da Silva-Filho (&)
Laboratory of Organic Synthesis and Catalysis (LOSC),
POSMAT-Sa˜o Paulo State University (UNESP), Bauru,
SP 17033-360, Brazil
e-mail: lcsilva@fc.unesp.br
A. C. Mafud
Institute of Physics of Sa˜o Carlos (IFSC), University of Sa˜o
Paulo (USP), Sa
˜o Carlos, SP, Brazil
123

Struct Chem
Fig. 1 Preparation of
tetrahydroquinoline derivatives
through Povarov’s reaction
O
H
H
(CH2)n
H
N
H
H
O
N
O
Lewis
acid
Lewis
acid
H
(CH2)n
cis
O
O
(CH2)n
NH2
(CH2)n
H
N
H
H
trans
O
O
H
H
O
(CH2)n
H
(CH2)n
H
NH2
+
O
NbCl5
+
H
+
CH3CN
ta.
(CH2)n
N
H
N
H
H
H
3 n=1
4 n=2
2
1
5 n=1
7 n=2
6 n=1
8 n=2
Scheme 1 Reaction of preparation of tetrahydroquinolines derivatives studied
The nuclear magnetic resonance (NMR) has been one of
the most powerful methods in structural elucidation, and it
is proving to be a versatile technique to solve a lot of
chemical problems. The data obtained from NMR spectra
are largely used to characterize chemical environment of
the individual atoms [30–32].
(1), benzaldehyde (2), 2,3-dihydrofuran (3) or 3,4-dihyd-
ropyran (4), using NbCl5 -as Lewis acid (Scheme 1)
[16–18].
To a solution of niobium pentachloride (10 or 25 mol%)
in 2.0 mL of anhydrous Acetonitrile, maintained at room
temperature under a nitrogen atmosphere, we added a
solution of the benzaldehyde (2) (1.0 mmol), 2,3-dihydro-
furan (3) or 3,4-dihydropyran (4) (1.0 mmol), and aniline
(1) (1.0 mmol) in 3.0 mL of anhydrous acetonitrile. After
completion of the addition, stirring was continued at room
temperature. The reaction mixture was quenched with
water addition (3.0 mL). The mixture was extracted with
However, the correct attribution of signal, as well as the
understanding of the relationship between chemical shifts
and molecular structure, can be difficult problems to solve.
Ab initio calculations are increasingly precise, being pos-
sible to use them as tool to help in the solution of many
problems. Thus, the use of two techniques together can be
very useful to make correct assignment, and to understand
the molecule chemical structure [33–38].
4
4
O
5
O
5
H
H
6
7
3
7
3
2
6
2
8
9
8
9
Experimental and theoretical methods
H 13
H 13
11
1
11
1
14
15
14
15
N
H
N
H
12
17
10
12
17
All reactions were performed under an atmosphere of N2,
unless otherwise specified. Acetonitrile was distilled with
calcium hydride. All commercially available reagents were
used without further purification. Thin-layer chromatogra-
phy was performed on AldrichÒ silica gel aluminum
sheets, which were visualized with a vanillin/methanol/
water/sulfuric acid mixture. AldrichÒ silica gel 60 was
employed for column chromatography.
10
H
H
16
16
5
6
5
5
4
4
O
6
O
6
H
8
H
3
8
3
2
1
7
2
7
9
9
H 14
H
12
14
12
1
13
10
13
10
15
16
N
H
15
16
N
H
11
H
11
H
18
18
Synthesis of tetrahydroquinoline derivatives
17
17
7
8
The tetrahydroquinolines (5, 6, 7 and 8) were prepared,
through Povarov multicomponent reaction, among aniline
Fig. 2 Structure of tetrahydroquinoline derivatives 5, 6, 7 and 8
123

Struct Chem
Table 1 Attribution of 1D and 2D NMR data for compound 5
Attribution dC
(ppm)
HSQC dH
(ppm)
Multiplicity J (Hz)
COSY
H2
H1, H30, H300,
H5
HMBC
C1
C2
56.5
44.8
H1
H2
4.71
2.80
d
J1 = 3.0
H2, H30, H13, H17
H1, H30, H300, H40, H400,
H5
dddd
J1 = 10.4; J2 = 8.1; J3 = 8.0;
J4 = 3.0
C3
23.7
H30
2.21
1.55
dddd
dddd
J1 = 11.9; J4 = 10.4; J3 = 8.8;
J4 = 8.6
H2, H300, H40,
H400
H2, H30, H40,
H400
H1, H2, H40, H400, H5
H300
J1 = 11.9; J2 = 8.1; J3 = 7.5;
J4 = 3.4
C4
C5
65.8
74.9
H40
H400
H5
3.84
3.74
5.29
ddd
ddd
d
J1 = 8.8; J2 = 8.3; J3 = 3.4
J1 = 8.6; J2 = 8.3; J3 = 7.5
J1 = 8.0
H30, H300, H400
H30, H300, H40
H2
H30, H5
H1, H2, H300, H40, H400,
H10
C6
121.7
129.1
118.2
127.3
113.9
143.9
141.2
127.6
125.5
126.6
125.5
127.6
–
–
–
–
–
H2, H5, H8, H9, H10
C7
H7
H8
H9
H10
–
7.47
6.82
7.10
6.61
–
d
J1 = 7.6
H8
H5, H8, H9
C8
dd
dd
d
J1 = 7.6; J2 = 7.0
H7, H9
H9, H10
C9
J1 = 8.0; J2 = 7.0
H8, H10
H5, H7, H8, H10
C10
C11
C12
C13
C14
C15
C16
C17
J1 = 8.0
H9
H7, H8, H9
–
–
–
–
–
–
–
–
–
H1, H5, H7, H8, H9, H10
–
–
–
–
H1, H13, H17
H13
H14
H15
H16
H17
7.36
7.36
7.36
7.36
7.36
m
m
m
m
m
H14
–
–
–
–
–
H13, H15, H16
H14, H16
H14, H15, H17
H16
Table 2 Attribution of 1D and 2D NMR data for compound 6
Atribuition dC HSQC dH Multiplicity J (Hz)
(ppm) (ppm)
COSY
H2
HMBC
C1
C2
C3
58.2
43.8
29.7
H1
3.74
2.40
1.95
1.65
d
J1 = 11.2
H2, H30, H300, H5, H13,
H17
H2
dddd
dddd
dddd
J1 = 11.2; J2 = 7.7; J3 = 4.9;
J4 = 2.1
H1, H30, H300 H5 H1, H30, H300, H40, H400
H30
H300
J1 = 13.2; J2 = 8.3; J3 = 6.0;
J4 = 2.1
H2, H300, H40,
H400
H2, H30, H40,
H400
H2, H40, H400, H5
J1 = 13.2; J2 = 9.2; J3 = 7.7;
J4 = 6.2
C4
65.6
H40
H400
H5
–
3.96
3.77
4.54
–
ddd
ddd
d
J1 = 8.8; J2 = 8.3; J3 = 6.2
H30, H300, H400
H30, H300, H40
H2, H30, H300
J1 = 9.2; J2 = 8.8; J3 = 6.0
C5
76.6
120.5
131.6
118.8
129.6
115.1
145.8
142.1
129.1
128.7
J1 = 4.9
H2
H300, H40, H400, H7, H10
H5, H7, H8, H9, H10
H5, H8, H9, H10
H7, H9, H10
H1, H7, H8
C6
–
–
–
C7
H7
H8
H9
H10
–
7.37
6.73
7.06
6.56
–
d
J1 = 7.0
H8
C8
dd
dd
d
J1 = 8.3; J2 = 7.7
H7, H9
C9
J1 = 8.3; J2 = 7.0
H8, H10
C10
C11
C12
C13
C14
J1 = 7.7
H9
H7, H8, H9
–
–
–
–
–
–
H1, H5, H7, H8, H9
H1, H2, H13, H17
–
–
–
–
–
H13
H14
7.31
7.31
m
m
H14
H13, H15, H16
–
123

Struct Chem
Table 2 continued
Atribuition dC
HSQC dH
(ppm)
Multiplicity J (Hz)
COSY
HMBC
(ppm)
C15
C16
C17
128.6
128.7
129.1
H15
H16
H17
7.31
7.31
7.31
m
m
m
–
–
–
H14, H16
H14, H15, H17
H16
–
–
–
ethyl acetate (10.0 mL). The organic layer was separated
and washed with saturated sodium bicarbonate solution
(3 9 10.0 mL), saturated brine (2 9 10.0 mL), and then
dried over anhydrous magnesium sulfate. The solvent was
removed under vacuum, and the products were purified by
column chromatography through silica gel using mainly a
mixture of hexane and ethyl acetate (9.0:1.0) as eluent.
spectrometer (5 mm z-gradient BBI probe) operating at
500.13 MHz (1H) or 125.78 MHz (13C), using as internal
standard the tetramethylsilane (TMS), using CDCl3 as
solvent.
Computational calculations
NMR spectra
The structure of tetrahydroquinolines derivatives studied
was optimized with the chloroform solvent effect by IE-
FPCM method on the level B3LYP with the set of func-
tions of cc-pVDZ basis [39]. The chemical shifts were
calibrated with values calculated to TMS, using the GIAO
For obtaining spectra the NMR 1D (1H and 13C) and 2D
(COSY, HSQC and HMBC) of synthesized compounds,
was used an equipment Bruker AVANCE DRX 500
Table 3 Attribution of 1D and 2D NMR data for compound 7
Atribuition dC
(ppm)
HSQC dH
(ppm)
Multiplicity J (Hz)
COSY
HMBC
C1
C2
C3
59.7
39.3
25.8
H1
H2
4.69
2.16
d
J1 = 2.3
H2
H2, H30, H300, H6, H14,
H18
H1, H30, H300, H40, H400,
H6
H1, H2, H40, H400, H50,
H500
dddd
J1 = 11.9; J2 = 5.6; J3 = 4.0;
J4 = 2.3
H1, H30, H300, H6
H2, H300, H40, H400
H2, H30, H40, H400,
H50
H30
H300
1.46
1.43
m
m
–
–
C4
C5
18.4
61.0
H40
H400
H50
1.55
1.31
3.58
m
–
H30, H300, H400, H50, H1, H2, H30, H300, H50,
H500
H500, H6
dddd
dddd
J1 = 10.4; J2 = 5.0; J3 = 3.5;
J4 = 2.5
H30, H300, H40, H500
J1 = 11.4; J2 = 4.3; J3 = 2.0;
J4 = 2.0
H300, H40, H400, H500 H2, H30, H40, H6
H500
H6
–
3.43
5.33
–
td
d
J1 = 11.4; J2 = 11.4; J3 = 2.5
H40, H400, H50
C6
73.2
120.3
129.2
118.7
128.8
114.8
145.6
141.5
128.7
128.0
127.2
127.9
128.5
J1 = 5.6
H2
H1, H30, H50, H500, H8, H9
C7
–
–
–
H6, H8, H9, H11
C8
H8
H9
H10
H11
–
7.30
6.79
7.09
6.60
–
dd
ddd
ddd
dd
–
J1 = 7.7; J2 = 1.0
H9, H10
H8, H10, H11
H8, H9, H11
H9, H10
–
H7, H9, H10, H11
C9
J1 = 7.7; J2 = 7.1; J3 = 0.8
H8. H10, H11
C10
C11
C12
C13
C14
C15
C16
C17
C18
J1 = 8.0; J2 = 7.1; J3 = 1.0
H8, H9, H11
J1 = 8.0; J2 = 0.8
H8, H9, H10
–
–
–
–
–
–
–
H1, H6, H8, H9, H10
–
–
–
–
H1, H14, H18
H14
H15
H16
H17
H18
7.40
7.40
7.40
7.40
7.40
m
m
m
m
m
H15, H16
H14, H16. H17
H14, H15, H17, H18
H15, H16, H18
H16, H17
–
–
–
–
–
123

Struct Chem
Table 4 Attribution of 1D and 2D NMR data for compound 8
Atribuition dC
(ppm)
HSQC dH
(ppm)
Multiplicity J (Hz)
COSY
H2
HMBC
C1
C2
55.2
39.3
H1
H2
4.72
2.11
d
J1 = 10.9
H30, H300, H6, H14, H18
ddt
J1 = 10.9; J2 = 4.8, J3 = 2.8;
J4 = 2.8
H1, H30, H300, H6 H1, H30, H300, H40, H400
C3
24.5
H30
H300
H40
H400
H50
1.65
1.47
1.84
1.33
4.10
ddt
J1 = 13.6; J2 = 13.4; J3 = 4.8;
J4 = 4.8
H2, H300, H40, H400 H2, H40, H400, H50, H500
dtdd
tddd
dddd
ddt
J1 = 13.6; J2 = 4.3; J3 = 4.3;
J4 = 2.8; J5 = 2.3
H2, H30, H40, H400,
H50
C4
22.4
J1 = 13.4; J2 = 13.4; J3 = 11.4,
J6 = 4.3; J5 = 2.3
H30, H300, H400,
H50, H500
H1, H2, H30, H300, H50,
H500, H6
J1 = 13.4; J2 = 4.8; J3 = 4.3;
J4 = 2.5
H30, H300, H40,
H500
C5
C6
69.0
74.9
J1 = 11.4; J2 = 4.3; J3 = 2.3;
J4 = 2.3
H300, H40, H400,
H500
H2, H30, H40
H500
H6
3.72
4.39
td
d
J1 = 11.4; J2 = 11.4; J3 = 2.5
J1 = 2.8
H40, H400, H50
H2
H1, H30, H50, H500, H8,
H9
C7
121.0
131.3
117.9
129.8
114.5
145.1
142.7
129.0
128.3
128.2
–
–
–
–
–
H6, H9, H11
C8
H8
H9
H10
H11
–
7.22
6.71
7.09
6.53
–
dd
ddd
ddd
dd
–
J1 = 7.7; J2 = 1.3
H9, H10
H8, H10, H11
H8, H9, H11
H9, H10
–
H9, H10, H11
C9
J1 = 7.7; J2 = 7.3; J3 = 0.7
H10, H11
C10
C11
C12
C13
C14
C15
C16
J1 = 8.1; J1 = 7.3; J1 = 1.3
H8, H9
J1 = 8.1; J2 = 0.7
H8, H9, H10
–
–
–
–
–
H1, H6, H8, H9, H10
–
–
–
–
H1, H2, H14, H18
H14
H15
H16
7.37
7.37
7.37
m
H15, H16
H14, H16. H17
–
–
–
m
m
H14, H15, H17,
H18
C17
C18
128.3
129.0
H17
H18
7.37
7.37
m
m
–
–
H15, H16, H18
H16, H17
–
–
method and same level of theory. All the calculations were
made using the Gaussian09 program [40]. The graphics and
the correlation coefficients between the theoretical and
experimental data were obtained with the aid of the Ori-
ginTM program [41].
Through NMR analysis, it was possible to determinate
all chemical shifts for carbons and hydrogens, and another
important information obtained by NMR analysis was the
determination of the relative stereochemistry of the
hydrogens H1 and H2, by determination of its coupling
constants. The cis adducts, compounds 5 and 7, show
smaller coupling constants (J1/2 = 3.0 and 2.3 Hz,
respectively), typical for a cis conformation between this
hydrogens. In trans adducts, compounds 6 and 8, the
coupling constants are significantly higher (J1/2 = 11.2 and
10.9 Hz, respectively), indicative of the trans orientation of
H-1 and H-2.
To analyze the ring conformation, the parameters were
calculated using the standards of Cremer and Pople [42],
for implementation CONFORM [43]. The input data was
the same of calculated by GIAO level, without shifts,
which caused an extrapolation of the data.
Results and discussion
To confirm the correct attribution of all chemical shifts
obtained experimentally, a theoretical study was realized
1
The unequivocal assignment of all chemical shifts of carbons
and hydrogens, and measured hydrogen coupling constants
to the tetrahydroquinoline derivatives 5, 6, 7, and 8, are
shown in Fig. 2 and Tables 1, 2, 3, and 4, respectively.
for calculation of all H and 13C NMR chemical shifts of
the tetrahydroquinoline derivatives studied. The structure
of tetrahydroquinolines was initially optimized using
B3LYP level of theory and with the basis set functions
123

Struct Chem
cc-pVTZ as input, and the minimum energy obtained for
all structures are shown in Fig. 3.
the relationship between the dihedral angle and the vicinal
coupling constant J [45–47] (Table 6).
3
The optimized structures of the tetrahydroquinoline
derivatives show that the pyran ring, in compounds 7 and 8,
take on twist-boat conformation, due to the rigidity of the
quinolinic ring and the ‘‘syn’’ addition mechanism of the
aza-Diels–Alder reaction, that occur on the multicompo-
nent Povarov reaction. The bond length and the bond
angles between the atoms oxygen and nitrogen obtained in
calculated structures for compound 5 (Table 5), are similar
with the experimental data values obtained through of
X-ray crystallography [44], which proves that the theory
utilized for the simulation of these compounds was ade-
quate, and the data obtained are near of the real com-
pounds. The calculated dihedral angles, between the
hydrogens H2/H5 to compounds 5 and 7, and H2/H6 to
compounds 6 and 8, near the 0° justified the values of
coupling constant measured for this hydrogens, because
they are in accordance to Karplus equations, that correlate
About the ring conformation, in the calculated com-
pounds 5 and 6, the furan ring adopts a twist conformation
˚
with puckering parameters q2 = 20.875 (3) A and
˚
U2 = 314.984 (9)° for compound 5, and q2 = 19.755 (6) A
and U2 = 164.92 (1)° for molecule 6; and the piperidine
ring exists in a half-boat conformation for both structures
[h = 43.323 (1)° and U = 240.046 (1)° for compound 5,
˚
and Q = 5150.372 (4) A, h = 136.774 (1)° and
U = 60.022 (1)° for compound 6]. For the calculated
compounds 7 and 8, the pyran rings adopts a half-boat
˚
conformation [Q = 3990.713 (4) A, h = 136.546 (1)° and
U = 59.574 (1)° for compound 7, and Q = 3990.713
˚
(4) A, h = 136.546 (1)° and U = 59.574 (1)° for com-
pound 8], like the piperidine rings for the same compounds
˚
[Q = 1813.727 (6) A, h = 136.396 (1)° and U = 59.983
˚
(1)° for compound 7, and Q = 582.962 (6) A, h = 44.159
(1)° and U = 239.887 (1)° for compound 8].
5
6
7
8
Fig. 3 Structure optimized for the tetrahydroquinoline derivatives
123

Struct Chem
160
140
120
100
80
A
C
E
B
10
8
6
60
4
40
2
20
0
0
0
1
1
1
8
2
3
4
5
6
7
0
20
40
60
80
100
120
140
160
experimental δ (ppm)
experimental δ (ppm)
D 10
160
140
120
100
80
8
6
4
2
0
60
40
20
0
0
20
40
60
80
100
120
140
160
0
2
3
4
5
6
7
8
experimental δ (ppm)
experimental δ (ppm)
F
160
10
140
120
100
80
8
6
4
2
0
60
40
20
0
0
20
40
60
80
100
120
140
160
0
2
3
4
5
6
7
8
experimental δ (ppm)
experimental δ (ppm)
G
H
10
160
140
120
100
80
8
6
4
2
0
60
40
20
0
0
1
2
3
4
5
6
7
8
0
20
40
60
80
100
120
140
160
experimental δ (ppm)
experimental δ (ppm)
Fig. 4 Correlation graphics for: a (compound 5—NMR 13C); b (compound 5—NMR 1H); c (compound 6—NMR 13C); d (compound 6—NMR
1
1
1H); e (compound 7—NMR 13C); f (compoundo 7—NMR H); g (compound 8—NMR 13C)e; h (compound 8—NMR H)
123

Struct Chem
´
˚
Table 5 Calculated and experimental bond length (A) and bond angle (8) for the tetrahydroquinoline derivatives
Compound
Bond
Calculated bond
length (A)
Experimental bond
length (A)*
Calculated bond
angle (°)
Experimental bond
angle (°)*
´
˚
´
˚
5
O–C4
1.42
1.44
1.47
1.40
1.42
1.44
1.47
1.40
1.43
1.44
1.47
1.40
1.43
1.43
1.46
1.40
1.425
C4–O5–C5
C1–N5–C11
C4–O6–C5
C1–N6–C11
C5–O7–C6
C1–N7–C12
C5–O8–C6
C1–N8–C12
108.15
114.92
108.15
114.92
112.48
118.20
111.90
116.92
107.84
O–C5
N–C1
1.429
1.457
120.02
N–C11
O–C4
1.386
6
7
8
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
O–C5
N–C1
N–C11
O7–C5
O7–C6
N7–C1
N7–C12
O–C5
O–C6
N–C1
N–C12
* Ref [44]
Table 6 Calculated dihedral angle for the tetrahydroquinoline
derivatives
Table 7 Theoretical and experimental 1H and 13C chemical shifts
(ppm) for compound 5
a
dC
b
a
dH
b
Compound
Hydrogens
Diedral angle (°)
Jexp (Hz)
C
dC
H
dH
5
H1/H2
H2/H5
H1/H2
H2/H5
H1/H2
H2/H6
H1/H2
H2/H6
26.0
-10.1
166.2
3.0
8.0
1
2
3
56.5
44.8
23.7
61.54
51.90
37.93
1
4.71
2.80
2.21
1.55
3.84
3.74
5.29
–
5.36
4.05
2.60
1.89
6.89
4.31
5.76
–
2
6
7
8
11.2
7.7
30
300
40
400
5
-10.1
46.5
2.3
4
65.8
73.82
-27.7
-180.0
-34.1
5.6
10.9
2.8
5
74.9
121.7
129.1
118.2
127.3
113.9
143.9
141.2
127.6
125.5
126.6
125.5
127.6
80.45
133.75
133.21
122.61
131.40
119.19
147.52
141.94
135.70
131.13
128.79
131.80
133.21
6
–
7
7
7.47
6.82
7.10
6.61
–
8.31
7.53
7.69
7.02
–
8
8
9
9
The calculated NMR shielding tensors were converted
into chemical shifts, considering the isotropic values of the
shielding tensors of H and 13C of TMS (dC = 196.70 and
dH = 32.23), calculated at the same levels of theory. The
values obtained from chemical shifts for the four structures
are shown in Tables 7, 8, 9, and 10.
10
11
12
13
14
15
16
17
a
10
–
1
–
–
–
13
14
15
16
17
7.36
7.36
7.36
7.36
7.36
9.38
7.71
7.99
7.98
7.82
Analyzing the Tables 7, 8, 9, and 10, it is verified that
there is a good agreement between experimental and
theoretical data, thus, the theoretical level utilized for the
simulation of the compounds was appropriate, and pro-
vided us a more precise analysis in relation to the
chemical shifts, However, a comparison between experi-
mental and theoretical data was realized from the graphics
(Fig. 4) and correlation coefficients (Table 11) to confirm
a good correlation existing between the two methods
utilized.
Experimental values
b
Theoretical values
The analysis of Fig. 4 and Table 11 allows us to confirm
the excellent concordance between the results, since all the
correlation coefficients are close to 1, which indicates that
123

Struct Chem
Table 8 Theoretical and experimental 1H and 13C chemical shifts
(ppm) for compound 6
Table 9 continued
a
dC
b
a
dH
b
C
dC
H
dH
a
dC
b
a
dH
b
C
dC
H
dH
17
18
a
127.9
128.5
131.68
130.93
17
18
7.40
7.40
8.08
7.95
1
2
3
58.2
43.8
29.7
68.50
59.22
37.48
1
3.74
2.40
1.95
1.65
3.96
3.77
4.54
–
3.99
3.28
2.57
2.49
4.60
4.41
5.78
–
2
Experimental values
30
300
40
400
5
b
Theoretical values
4
65.6
69.31
Table 10 Theoretical and experimental 1H and 13C chemical shifts
(ppm) for compound 8
5
76.6
120.5
131.6
118.8
129.6
115.1
145.8
142.1
129.1
128.7
128.6
128.7
129.1
81.44
130.72
132.84
122.14
130.84
117.80
149.87
149.55
132.77
131.29
130.61
131.49
132.74
C
dCa
dCb
H
dHa
dHb
6
–
7
7
7.37
6.73
7.06
6.56
–
8.29
7.61
7.85
7.35
–
1
2
3
55.2
67.99
1
4.72
2.11
1.84
1.33
1.65
1.47
4.10
3.72
4.39
–
4.33
2.53
2.11
1.85
2.55
2.21
4.94
4.69
5.03
–
8
8
39.3
24.5
53.97
29.29
2
30
300
40
400
50
500
6
9
9
10
11
12
13
14
15
16
17
a
10
–
4
5
22.4
69.0
28.99
71.57
–
–
–
13
14
15
16
17
7.31
7.31
7.31
7.31
7.31
8.52
8.26
8.17
8.12
8.06
6
74.9
121.0
131.3
117.9
129.8
114.5
145.1
142.7
129.0
128.3
128.2
128.3
129.0
75.75
126.96
135.46
121.10
131.82
117.71
149.97
148.11
133.11
132.60
131.30
131.48
130.41
7
–
8
8
7.22
6.71
7.09
6.53
–
8.06
7.51
7.85
7.23
–
9
9
Experimental values
b
10
11
12
13
14
15
16
17
18
a
10
11
–
Theoretical values
Table 9 Theoretical and experimental 1H and 13C chemical shifts
(ppm) for compound 7
–
–
–
a
dC
b
a
dH
b
C
dC
H
dH
14
15
16
17
18
7.37
7.37
7.37
7.37
7.37
8.42
8.22
8.15
8.11
8.11
1
2
3
59.7
39.3
25.8
67.04
49.09
29.80
1
4.69
2.16
1.46
1.43
1.55
1.31
3.58
3.43
5.33
–
4.71
3.30
2.33
2.24
2.65
2.34
5.01
4.76
5.23
–
2
30
300
40
400
50
500
6
4
5
18.4
61.0
29.16
71.25
Experimental values
b
Theoretical values
Table 11 Correlation coefficient (R) for H and 13C chemical shifts
1
Compound
R–13C
R–1H
6
73.2
120.3
129.2
118.7
128.8
114.8
145.6
141.5
128.7
128.0
127.2
74.39
127.85
134.11
120.94
131.97
118.37
146.90
147.21
133.22
131.76
130.55
7
–
5
6
7
8
0.99682
0.99610
0.99794
0.99706
0.96042
0.99576
0.98581
0.99437
8
8
7.30
6.79
7.09
6.60
–
8.11
7.46
7.73
6.95
–
9
9
10
11
12
13
14
15
16
10
11
–
–
–
–
Therefore, we can to conclude that the theoretical level
adopted in our studies to describe the structure of tetra-
hydroquinolines derivatives was appropriate, showing a
good theoretical–experimental correlation, which helped us
in the determining the structure of studied derivatives.
The correlation between the experimental and theo-
retical data show to be an excellent tool to help the
structural elucidation and unequivocally attribution of all
14
15
16
7.40
7.40
7.40
7.89
8.02
8.80
all the experimental data are in good agreement with the
theoretical data, for both the chemical displacements
(carbon and hydrogen).
123

Struct Chem
12. Arisawa M, Theeraladanon C, Nishida A, Nakagawa M (2001)
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NMR signals of tetrahydroquinolines studied. Other point
to be detached in this work is that the values of NMR
chemical displacement obtained with the theoretical level
B3LYP/cc-pVDZ allows the association of a computa-
tional cost not so high and an accurate precision of
results obtained.
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(2008) Synthesis 16:2527–2536
Based on the results mentioned above, we can conclude
that the theoretical data showed an excellent correlation
with the experimental data and reinforce the structural
elucidation and assignments of all NMR signals for
Povarov adducts treated in this work. For these derivatives,
the experimental analyses and the theoretical model
adopted were sufficient to obtain a good description of its
structures, and these results can be used to assign the
structure of various others tetrahydroquinoline derivatives
synthetized by Povarov reaction. The theory-level B3LYP/
cc-pVDZ proved to be an effective model to perform the
´
19. Vicente-Garcıa E, Ramon R, Lavilla
14:2237–2246
R (2011) Synthesis
´
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1
calculation of the chemical shift of H and 13C-NMR.
´
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Acknowledgments The authors would like to thank Fundac¸a˜o de
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6861–6865
`
Amparo a Pesquisa do Estado de Sa˜o Paulo (FAPESP) (Procs. N8
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de Desenvolvimento Cientıfico e Tecnologico (CNPq), Coordenado-
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´
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financial support.
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