Proton and carbon-13 NMR studies of conformational preferences in N-(2-pyridinyl)-2-pyridinecarboxamides

Article abstract of DOI:10.1016/S1386-1425(98)00020-1

The ¹H and ¹³C NMR spectra, molecular conformation and intermolecular association of N-(2-pyridinyl)-2-pyridinecarboxamides and 2-pyridinecarboxamide are discussed. The ¹H NMR spectra have been analyzed with the aid of COSY spectra and the ¹³C spectra with the aid of HETCOR, proton coupled spectra and ¹³C-¹H coupling constants. In concentrated CDCl₃ solution, N-(2-pyridinyl)-2-pyridinecarboxamides dimerise by intermolecular association

Full text of DOI:10.1016/S1386-1425(98)00020-1

Spectrochimica Acta Part A 54 (1998) 1059–1065
Proton and carbon-13 NMR studies of conformational
preferences in N-(2-pyridinyl)-2-pyridinecarboxamides
Netai C. Singha, D.N. Sathyanarayana *
Department of Inorganic and Physical Chemistry, Indian Institute of Science, UGC Centre of Ad6anced Study,
Bangalore 560 012, India
Received 8 September 1997; received in revised form 6 January 1998; accepted 13 January 1998
Abstract
The 1H and 13C NMR spectra, molecular conformation and intermolecular association of N-(2-pyridinyl)-2-
1
pyridinecarboxamides and 2-pyridinecarboxamide are discussed. The H NMR spectra have been analyzed with the
aid of COSY spectra and the 13C spectra with the aid of HETCOR, proton coupled spectra and 13Cꢀ1H coupling
constants. In concentrated CDCl3 solution, N-(2-pyridinyl)-2-pyridinecarboxamides dimerise by intermolecular
association © 1998 Elsevier Science B.V. All rights reserved.
Keywords: NMR spectroscopy; COSY; HETCOR; Conformation; N-(2-pyridinyl)-2-pyridine carboxamides
1. Introduction
mation, intermolecular association and spectral
assignments.
N-pyridyl substituted 2-pyridinecarboxamides
(RCONHR1 where R and R1 are 2-pyridyl) form
an interesting class of aromatic secondary amides,
which can serve as model compounds for the
study of conformation of polypeptides and
proteins. In this context and in a continuation of
our previous studies on pyridine carboxamides
[1–3], this paper presents the proton and carbon-
13 NMR studies of N-(2-pyridinyl)-2-pyridinecar-
boxamides (1–3) and 2-pyridinecarboxamide (4)
(see Fig. 1). In addition to 1H and 13C NMR,
COSY and HETCOR measurements have been
utilised for the delineation of molecular confor-
2. Experimental
Simple acid-base neutralisation reaction in the
presence of N,N-dicyclohexylcarbobimide as a de-
hydrating agent was used for the synthesis of 1–4
employing appropriate pyridine carboxylic acid
and pyridyl amines (Aldrich chemicals). The m.p.
of compounds 1–4 are correspondingly 118, 126,
90 and 72oC. Elemental analyses for compounds
1–4 were in agreement with the calculated values.
1
The H and 13C NMR spectra were recorded at
ambient temperature on 270 (13C: 67.89 MHz)
and 200 MHz (13C: 50.32 MHz) Bruker AC and
WH FT spectrometers, respectively. The spectra
* Corresponding author. Tel.: +91 80 3092382; fax: +91
80 3341683; e-mail: dns@hamsadvani.serc.iisc.ernet.in
1386-1425/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved.
PII S1386-1425(98)00020-1

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N.C. Singha, D.N. Sathyanarayana / Spectrochimica Acta Part A 54 (1998) 1059–1065
were measured in CDCl3, CD3CN and/or
(CD3)2CO (approx. 0.02 M) using Me4Si as an
internal reference. The COSY spectra, 13C spec-
tra in coupled and decoupled mode and HET-
COSY spectra were recorded on 200 MHz
the 1H NMR spectra were measured in dilute
solutions (about 0.02 M). The chemical shift of
NꢀH proton of 1 occurs at 10.53 ppm while
that of N2PA and N2PB where intramolecular
hydrogen bonding is very unlikely is found in
the same region [5]. However in N-(2-pyridinyl)-
3-pyridinecarboxamide (Singha and Sathya-
narayana, unpublished results), the l value for
NH is 8.67 ppm. The higher deshielding of the
NꢀH proton of 1 may be attributed to in-
tramolecular hydrogen bonding. Intermolecular
hydrogen bonding was excluded since the NꢀH
resonance does not show any appreciable con-
centration dependence. For the amide group, the
stable form is usually the trans form. Secondary
amides and proteins generally occur in the trans
form [7]. Several possible conformations of 1
where the amide group orientation is trans are
shown in Fig. 4. The conformers I to V are
planar. The ring A/B is out of the plane of the
molecule in the other two conformations shown
in Fig. 4. Discrimination between the conform-
ers I to VI of 1 was made on the basis of the l
values of H3 and H3% and these protons appear-
ing at 8.28 and 8.42 ppm for 1, respectively ex-
perience strong deshielding of the carbonyl
group compared to 6.49 ppm in 2-aminopy-
ridine, 7.29 ppm in N,N-diacetyl 2-aminopy-
ridine and 6.80 ppm in N-(2-pyridyl),
N’-(3-pyridyl)urea [2,5]. Similar deshielding ef-
fects on H3 in acylated 2-aminopyridines have
1
spectrometer in CDCl3. The H and proton cou-
pled 13C spectra were analysed iteratively using
the LAOCOON-5 Program [4].
3. Results and discussion
1
3.1. H NMR spectra
1
The H chemical shifts and coupling constants
of 1–4 in different solvents are given in Tables
1 and 2, respectively along with the data for
closely related N-(2-pyridinyl)acetamide (N2PA)
and N-(2-pyridinyl)benzamide (N2PB) [5] for the
sake of comparison. The resolution enhanced
270 MHz 1H NMR spectrum of 1 in CDCl3
was simulated in excellent agreement with the
experimental spectrum (RMS errors for the pro-
tons of the rings A and B were respectively
1
0.082 and 0.053). The RE H NMR and COSY
spectrum of 1 are shown in Figs. 2 and 3, re-
spectively. From the correlation in the COSY
spectrum, the diagonal peaks at 7.75, 7.07 and
8.42 ppm are respectively assigned to H4%, H5%
and H6% of the ring B and the peaks at 7.48,
7.90 and 8.28 ppm (marked by asterisk) are sim-
ilarly assigned to H5, H4 and H3, respectively
1
of the ring A. The H NMR spectra of 2–4 in
CDCl3 were assigned by a comparison with that
of 1 and from their COSY spectra. The proton
chemical shifts of the pyridyl groups of 1 appro-
priately compare with those of N2PA [5] and
compound 4 (Table 1). The 1H coupling con-
stants for 1 to 4 are similar to those in other
pyridyl systems (Table 2) [6].
3.2. Conformation
Amides undergo self association by inter-
molecular hydrogen bonding between NꢀH and
the carbonyl oxygen. In dilute solutions, self as-
sociation is less likely due to solvation. Hence,
Fig. 1. Molecular geometry and numbering of atoms of N-(2-
pyridinyl)-2-pyridinecarboxamides (1–3) and 2-pyridinecar-
boxamide (4).

N.C. Singha, D.N. Sathyanarayana / Spectrochimica Acta Part A 54 (1998) 1059–1065
1061
Table 1
1H chemical shiftsa (in l ppm) of 1–4
Compoundb
Solvent
Groupc
H3,H3’
H4,H4’
H5,H5’
H6,H6’
NH
1
CDCl3
2-Py
(2-Py)
2-Py
(2-Py)
2-Py
(2-Py)
2-Py
8.28
8.42
8.35
8.48
8.30
8.40
8.24
8.35
7.90
7.75
8.19
7.95
8.16
7.95
8.01
7.83
7.48
7.07
7.78
7.25
7.75
7.25
7.61
7.14
8.63
8.36
8.82
8.46
8.79
8.42
8.69
8.36
10.53
(CD3)2CO
(CD3)2CO+ D2O
CD3CN
10.48
10.48
—
—
10.37
(2-Py)
2
3
4
CDCl3
2-Py
(2-Py)
2-Py
8.28
8.27
8.23
8.20
7.91
—
8.06
—
7.49
6.91
7.64
6.96
8.63
8.21
8.69
8.17
10.50
10.25
(CD3)2CO
(2-Py)
CDCl3
2-Py
(2-Py)
2-Py
8.29
8.22
8.22
8.14
7.91
7.65
8.05
7.69
7.49
6.94
7.65
6.98
8.63
—
8.69
—
10.47
10.31
(CD3)2CO
(2-Py)
CDCl3
2-Py
8.22
7.87
7.47
8.59
7.90(Ha)
5.96(Hb)
10.39
N2PA
N2PB
CDCl3
CDCl3
8.29
8.40
7.72
7.64
7.05
6.91
8.29
7.95
10.38
a Numbering follows from Fig. 1. b N2PA and N2PB are N-(2-pyridinyl)acetamide and N-(2-pyridinyl)benzamide, respectively [5],
c 2-Py is 2-pyridyl group; 2-Py group in parenthesis refers to the N-bonded group.
Table 2
1H coupling constantsa (in Hz) of 1–4
Compound Solvent
Groupc
3J34/3J3%4%
4J35/4J3%5%
5J36/5J3%6%
3J45/3J4%5%
4J46/4J4%5%
3J56/3J5%6%
5JNH,4%
1
CDCl3
2-Py
(2-Py)
2-Py
7.82
8.37
7.83
8.53
7.82
8.45
7.83
8.37
1.21
1.07
1.29
1.15
1.29
1.06
1.24
1.13
0.93
0.93
0.96
1.02
0.95
0.93
0.94
0.97
7.63
7.36
7.61
7.32
7.61
7.37
7.64
7.43
1.75
1.95
1.75
1.94
1.75
1.95
1.74
1.81
4.76
4.94
4.83
4.94
4.84
4.96
4.81
4.91
0.51
0.57
(CD3)2CO
(2-Py)
(CD3)2CO+ D2O 2-Py
(2-Py)
2-Py
CD3CN
(2-Py)
0.65
2
3
4
CDCl3
2-Py
(2-Py)
2-Py
7.81
1.22
1.54
1.25
1.55
0.92
0.77
0.96
0.79
7.63
—
7.63
—
1.71
—
1.74
—
4.77
5.10
4.80
5.07
(CD3)2CO
7.87
(2-Py)
CDCl3
2-Py
(2-Py)
2-Py
7.82
8.24
7.73
8.23
1.22
0.88
1.60
0.87
0.93
—
0.82
—
7.62
7.56
7.62
7.55
1.72
—
1.73
—
4.78
—
4.82
—
0.56
0.56
(CD3)2CO
(2-Py)
CDCl3
2-Py
7.78
7.65
1.21
1.35
0.84
1.01
7.57
7.65
1.67
1.85
4.77
4.87
a,c As in Table 1.
been attributed to the coplanar proximity of the
carbonyl group [5,8]. Therefore, conformer I shown
in Fig. 4 is expected in CDCl3. Recent theoretical
and experimental studies on N%-(2- pyridyl)N,N-
dimethyl formamidines [9] have indicated that
intramolecular dipole–dipole interactions could
play an important role in stabilizing a particular
conformation. Increased delocalization is expected
for rotamer I relative to the nonplanar conforma-
tions.

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N.C. Singha, D.N. Sathyanarayana / Spectrochimica Acta Part A 54 (1998) 1059–1065
Fig. 2. Resolution enhanced 270 MHz 1H NMR spectrum of 1 in CDCl3. The value in parenthesis is the chemical shift with
reference to TMS.
Fig. 3. Contour plot of 1H COSY spectrum of 1 in CDCl3 (on 270 MHz spectrometer). The diagonal peaks due to the protons of
the ring A are marked by an asterisk (*).

N.C. Singha, D.N. Sathyanarayana / Spectrochimica Acta Part A 54 (1998) 1059–1065
1063
Fig. 4. Molecular conformation of 1.
tions. Intramolecular hydrogen bonding, dipole–
dipole interactions and extended delocalization
seem to stabilize I for compounds 1–3 over the
other conformations. The NꢀH proton of 1 is
possibly hydrogen bonded to the pyridyl nitrogen
of ring A leading to a stable five-membered ring.
Hydrogen bonding with pyridyl nitrogen of the
ring B is unlikely since it leads to a highly strained
four-membered ring and severe nonlinearity of the
NꢀH…N moiety.
The NH2 protons of 4 in CDCl3 appear at l
5.96 and 7.9 ppm, respectively and the latter
signal overlaps with that of H4. The high fre-
quency shift of Hb relative to that of Ha suggests
intramolecular hydrogen bonding with the 2-
pyridyl nitrogen. Thus the conformation of 4 in
CDCl3 is predicted to be planar with Hb hydro-
gen bonded to the 2-pyridyl nitrogen.
3.3. Intermolecular association
Intermolecular association is a key factor in
stabilizing the molecular conformations of pep-
tides and proteins [10]. A study of intermolecular
association in small model systems is desirable for
understanding the role of hydrogen bonding in
more complex systems. Intermolecular association
for compounds 1 and 4 in CDCl3 was investigated
by studying the NMR spectra at different concen-
trations. The signals are much broader in the
spectrum of the concentrated solution (ca. 0.12
M) than those in the dilute solution (ca. 0.02 M).

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N.C. Singha, D.N. Sathyanarayana / Spectrochimica Acta Part A 54 (1998) 1059–1065
Table 3
13C chemical shiftsa (in l ppm) of 1–3 in CDCl3
Compoundb
Groupc
C2,C2%
C3,C3%
C4,C4%
C5,C5%
C6,C6%
CꢁO
ꢀCH3
1
2
3
2-Py
(2-Py)
2-Py
(2-Py)
2-Py
(2-Py)
(2-Py)
(2-Py)
2-Py
151.56
153.49
149.26
151.11
151.64
152.78
151.8
124.74
116.20
122.31
114.35
124.67
113.02
114.4
139.92
140.61
137.50
149.63
139.88
140.87
138.1
129.11
122.23
126.66
121.04
129.04
121.71
119.1
150.60
150.60
148.19
147.81
150.53
159.50
146.9
164.86
164.86
162.45
162.45
164.80
164.80
169.0
21.38
26.50
26.50
N2PA
N2PB
PYBr
151.6
141.97
114.4
128.13
138.3
138.66
119.4
122.87
147.1
150.10
166.0
a,c
As in Table 1.
b PyBr is2-bromopyridine [15]; rest as in Table 1.
Table 4
13Cꢀ1H coupling constantsa (in Hz) of 1–3 in CDCl3
Compoundb
Carbon atom
C2
JCꢀH3(H3%)
JCꢀH4(H4%)
JCꢀH5(H5%)
JCꢀH6(H6%)
1
3
Py
2
Py
2
Py
1
2
Py
2
3
Py
1
2
3
Py
1
3
Py
1
3
0.00
0.00
3.12
167.26
163.04
0.82
0.70
6.77
7.44
6.56
0.00
0.00
−0.92
0.93
0.00
0.00
3.12
170.30
170.05
163.04
0.00
6.90
7.2
6.85
0.00
0.84
163.42
162.41
1.44
0.80
0.84
7.02
7.04
6.85
8.98
0.00
0.00
−0.92
6.80
6.56
1.32
10.58
10.42
11.16
0.00
−1.65
6.07
6.34
8.44
7.75
8.47
180.78
180.74
177.63
11.95
12.36
C3
C4
C5
0.70
164.21
163.74
163.04
3.51
3.52
3.12
0.00
0.00
0.00
−0.92
6.60
C6
C2%
9.11
6.85
1.78
1.66
0.84
161.96
160.48
162.41
0.64
11.16
1.78
C3%
C4%
6.08
6.56
0.00
0.00
−1.65
6.45
0.00
0.00
6.44
6.56
0.00
−0.92
Py
1
Py
2
Py
0.70
6.34
7.90
8.47
177.32
177.63
C5%
C6%
164.75
163.04
3.52
0.84
6.85
3.12
a As in Table 1.
b Values for pyridine (Py) are taken from Ref. [15].
stacked one above the other in such a way that
the positively charged amide carbon of one
molecule faces the negatively charged amide oxy-
gen of the other. The protons of one molecule fall
inside the shielding zone of the pyridine ring(s) of
the other molecule and as a result the ring protons
would experience a low frequency shift. In this
The ring protons suffer low frequency shifts by
nearly 0.2 ppm in the concentrated solution when
compared to those in the dilute solution. How-
ever, the NꢀH of 1 does not show any significant
shift. Some specific association of the solute
molecules probably exists in the concentrated
CDCl3 solution. The molecules of 1 are probably

N.C. Singha, D.N. Sathyanarayana / Spectrochimica Acta Part A 54 (1998) 1059–1065
1065
arrangement, the coulombic, dipole–dipole and
London dispersive forces could stabilize the asso-
ciated forms [11,12]. The solvation of pyridine
and its derivatives in benzene is such that the
benzene molecule avoids the negative end of the
pyridine dipole with the two rings occurring in
parallel orientation [13]. Similar association be-
tween N,N-dimethylformamide and benzene has
compound, it is not [5,8] and the diacylamino
group adopts a less sterically hindered conforma-
tion with the carbonyl group out of the plane of
the pyridine ring. This supports the conclusion
obtained from the proton NMR that the com-
pounds 1–4 exists predominantly as planar con-
former I shown Fig. 4.
1
been predicted from H NMR studies [14].
1
The H coupling constants for the ring protons
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served for 1 in (CD3)2CO and CD3CN. It may be
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in solutions of relatively more polar solvents, such
as (CD3)2CO and CD3CN, compared to that in a
less polar solvent CDCl3. Intermolecular associa-
tion was also not observed for 4.
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The 13C NMR spectra of 1–4 were analysed
using HETCOR and proton coupled 13C spectra
and a knowledge of the chemical shifts in related
compounds [5,6]. The 13Cꢀ1H coupling constants
obtained by the simulation of the proton coupled
spectra are compared with those of pyridine
derivatives in Table 4. The signals due to C6 and
C6% of 1 overlap as noted from the HETCOR
spectrum. Comparison of the l values for C3 and
C3% of compounds 1–3 and 2-aminopyridine
(108.5 ppm) with those of N2PA (114.4 ppm) and
N2PB(114.4 ppm) indicates that in these com-
pounds the lone pair on amino nitrogen is conju-
gated to the pyridine ring while in the diacylated
.