Four new amide derivatives of pyridinecarboxylic acids. Synthesis, structure and spectroscopic characterization

Article abstract of DOI:10.1016/j.molstruc.2017.05.080

This study treats about four new pyridine amide derivatives obtained by a simple and inexpensive method of synthesis which consisted in amide coupling of pyridine-2-carboxylic acid and pyridine-4-carboxylic acid chlorides and aromatic amines: methyl 2-amino-3-methylbenzoate (Ea), methyl 3-amino-2-methylbenzoate (Eb), methyl 3-amino-4-methylbenzoate (Ec). All products of synthesis: L1, L2, L3, L4 were analyzed in detail by FT-IR, ¹H, ¹³C, COSY 2D, HSQC, HMBC NMR spectroscopy, elemental, TGA and X-ray analysis. The excitation and emission spectra for obtained amides were also registered. An exact examination of results confirmed receiving four amide compounds with higher potential ability to metal ion coordination than the substrates alone.

Full text of DOI:10.1016/j.molstruc.2017.05.080

Accepted Manuscript
Four new amide derivatives of pyridinecarboxylic acids. Synthesis, structure and
spectroscopic characterization
Dorota Kwiatek, Maciej Kubicki, Piotr Barczyński, Stefan Lis, Zbigniew Hnatejko
PII:
S0022-2860(17)30694-4
10.1016/j.molstruc.2017.05.080
MOLSTR 23821
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 4 January 2017
Revised Date: 16 May 2017
Accepted Date: 17 May 2017
Please cite this article as: D. Kwiatek, M. Kubicki, P. Barczyński, S. Lis, Z. Hnatejko, Four new amide
derivatives of pyridinecarboxylic acids. Synthesis, structure and spectroscopic characterization, Journal
of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.05.080.
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ACCEPTED MANUSCRIPT

Four new amide derivatives of pyridinecarboxylic acids. Synthesis, structure and spectroscopic
ACCEPTED MANUSCRIPT
characterization
Dorota Kwiateka, Maciej Kubickia, Piotr Barczyńskia, Stefan Lisa and Zbigniew Hnatejkoa*
aFaculty of Chemistry, Adam Mickiewicz University in Poznań, Umultowska 89b, 61-614 Poznań, Poland
Zbigniew Hnatejko* - zbychuh@amu.edu.pl +48 61 829 1679
Faculty of Chemistry, Adam Mickiewicz University in Poznań, Umultowska 89b, 61-614 Poznań, Poland
*Corresponding author
1

Abstract
ACCEPTED MANUSCRIPT
This study treats about four new pyridine amide derivatives obtained by a simple and inexpensive
method of synthesis which consisted in amide coupling of pyridine-2-carboxylic acid and pyridine-4-
carboxylic acid chlorides and aromatic amines: methyl 2-amino-3-methylbenzoate (Ea), methyl 3-amino-2-
methylbenzoate (Eb), methyl 3-amino-4-methylbenzoate (Ec). All products of synthesis: L1, L2, L3, L4
1
13
were analyzed in detail by FT-IR, H, C, COSY 2D, HSQC, HMBC NMR spectroscopy, elemental, TGA
and X-ray analysis. The excitation and emission spectra for obtained amides were also registered. An exact
examination of results confirmed receiving four amide compounds with higher potential ability to metal ion
coordination than the substrates alone.
Keywords: amides; synthesis; pyridinecarboxylic acids; spectroscopy; heterocyclic compounds
1. Introduction
Pyridine carboxylic acids are one of the most frequently and successfully used ligands in
coordination chemistry syntheses [1]. These organic ligands possess two donor atoms: nitrogen and oxygen
which correspond with good coordination ability for metal ions [2].
Pyridine-2-carboxylic acid is an endogenous metabolite of L-tryptophan [3]. It was reported that
antranilic acid and picolinic thiole derivatives revealed the bioactivity on Mycobacterium Tuberculosis
pathogenic action [4,5]. Moreover, antranilic acid derivatives naturally occurring in jasmine oil found
application in perfume and pigment industry. They were also used as analgesic, antipyretic drugs and
sensitive environmental probes for detecting cancer cells. Some of them belong also to nonsteroidal, anti-
inflammatory drugs successfully used in the field of pharmaceutics [6-10].
In connection with two potential groups such as d- and f- electron metal ions, which can be
coordinated by pyridinecarboxylic acids, many complexes with various properties were obtained in previous
studies. Depending on the metal ion coordinated by pyridine derivatives the complexes exhibit luminescence,
magnetic properties, proteasome inhibition, insulin-mimetic activity, DNA binding ability and antibacterial,
antifunginal, insecticidal or plant growth stimulation properties. Some of the complexes reveal also the
ability to create more topological developed structures like MOF’s [11-21]. However, in the field of
2

pyridinecarboxylic acid amides the number of detailed and specific studies is still developing. There are
ACCEPTED MANUSCRIPT
reports about simple amides of pyridine-2-carboxylic, pyridine-3-carboxylic and pyridine-4-carboxylic acids
and their N-oxides, but there is a deficiency of information about more different and branched aromatic
derivatives and their properties [22-32].
According to the reported research listed above, this field is interesting due to many potential
applications such as magnetic and optical devices, imaging probes, antifungal, pharmaceutics, gas absorption
or catalytic compounds. In order to meet this interesting research area the work presented here is to introduce
a straight synthesis of new amide ligands in order to increase the number of function groups rich in nitrogen
and oxygen donor atoms. Accordingly the optimization of this method was aimed for receiving a rewarding
effect by involving minimum effort.
In this article we present structural and spectroscopic studies on four novel amides of methyl 2-
amino-3-methylbenzoate, methyl 3-amino-2-methylbenzoate, methyl 3-amino-4-methylbenzoate with
pyridine-2-carboxylic and pyridine-4-carboxylic acids: L1, L2, L3 and L4 as shown in Scheme 1. The
obtained compounds and their complexes with d metal ions will be used in further research related to the
antifungal properties i.e. studies of the growth inhibition zone of plant pathogen (Fusarium culmorum).
Ec
O
O
O
N
NH2
NH2
L4
L3
H
O
O
N
N
O
Eb
O
O
O
N
H
O
O
O
O
HO
Cl
Cl
N
N
SOCl2
O
+
O HN
O
O
N
N
L2
HO
Ea
O
N
O
NH2
O
O HN
O
N
Cs2CO3+CH3I+DMF
L1
HO
O
NH2
Scheme 1. Synthesis of amide ligands, derivatives of pyridine-2-carboxylic and pyridine-4-carboxylic acids
L1, L2, L3, L4.
3

2. Experimental
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The commercially available chemicals: 2-amino-3-methylbenzoic acid, methyl 3-amino-2-
methylbenzoate, methyl 3-amino-4-methylbenzoate, pyridine-2-carboxylic and pyridine-4-carboxylic acids,
SOCl2 (Sigma Alrdich), DMF, CHCl3, CH3I (POCh) and CsCO3 (ACROS ORGANICS) were of analytical
grade and used as received.
The results of elemental analysis of carbon, nitrogen and hydrogen were obtained with the use of Elementar
model Vario EL III CHN analyzer. The FT-IR spectra were registered for KBr disks on Jasco FT/IR-4200
spectrophotometer in the spectral range 4000–400 cm-1. NMR spectra were carried out on Varian VNMR-S
1
13
400 MHz and Varian Mercury 300 MHz spectrometers for H and C NMR and Bruker Avance 600 MHz
for COSY 2D, HSQC and HMBC NMR. The thermogravimetric analysis were conducted on Discovery
TGA analyzer or Setsys 1200-Setaram under air atmosphere at heating rate of 10 ̊C/min to 550.00 ̊C in an
Al2O3 crucibles (sample mass L1: 0.5645 mg, L2: 2.8343 mg, L3: 15 mg, L4: 0,9501 mg). Excitation and
emission spectra were registered on Hitachi F-7000 spectrofluorometer at ambient conditions.
2.1 Preparation of methyl 2-amino-3-methylbenzoate (Ea)
The synthesis of amides of pyridine-2-carboxylic and pyridine-2-carboxylic acids were started with
aromatic amine methyl ester (Ea) preparation by methylation of 2-amino-3-methylbenzoic acid [33]. The
synthesis was conducted in a round bottom flask where the 2-amino-3-methylbenzoic acid (0.3041 g; 2.0116
mmol) was suspended in 15 mL dry DMF and mixed with the catalyst Cs2CO3 (0.9887 g; 3.0345 mmol) in
room temperature. After 1 hour the appropriate amount of CH3I (0,3098 g; 2.1826 mmol) was added. After
24h of stirring the suspension was dissolved in distilled water. Then the extraction with the use of diethyl
ether was performed. The brown oil ester product (Ea: yield ca. 77%; 0.2544 g; 1.5402 mmol) was obtained
after the solvent evaporation.
Anal. Calc. C9H11N1O2 : C, 65.44; H, 6.71; N, 8.48. Found: C, 65.14; H, 6.99; N, 8.36. FT-IR (KBr): 3491,
3373 cm-1 ν(N-H), 3075, 2950, 2857 cm-1 ν(C-H), 1692 cm-1 ν(C=O), 1614 – 1437 cm-1 ν(ringC=C), δ(N-H)
and δ(C-H) overlapped, 1303 – 1087 cm-1 ν(C-O) and ν(C-N) overlapped, 845 cm-1 δ(N-H), 753 cm-1
1
δ(ringC=C)oop. H NMR (400 MHz, CDCl3, ppm) δ: 7.77 (ddd, J = 8.09, 1.60, 0.53 Hz, 1H), 7.26 (CDCl3
signal), 7.19 (ddd, J = 7.12, 1.60, 0.80 Hz, 1H), 6.59 (m, 1H), 5.82 (s, 2H amine), 3.86 (s, 3H), 2.17 (s, 3H).
13C NMR (400 MHz, CDCl3, ppm) δ: 169.00, 148.77, 134.72, 128.93, 122.86, 115.47, 110.18, 51.37, 17.49.
4

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2.2 Preparation of (L1)
The amide coupling of pyridine-2-carboxylic and pyridine-4-carboxylic acids with Ea were
conducted in similar procedure as in previous reports [23,24,26]. The reaction was carried out under inert gas
environment in a round bottom flask with reflux. First step was the carboxylic acid chloride synthesis with
the use of thionyl chloride SOCl2. The mixture of pyridine-2-carboxylic acid (1.1255 g; 9.1422 mmol)
dissolved in thionyl chloride (10 mL; 137.8498 mmol) was mixed and refluxed for 1-3h. Then the excess of
thionyl chloride was distilled under vacuum and the aromatic amine methyl ester Ea (1.5100 g ; 9.1421
mmol) dissolved in CHCl3 (20 mL; 249.6231 mmol) was added. The mixture was heated and stirred under
reflux for 3-6 h. After evaporation of solvent the white needles of amide (L1: yield ca. 53%; 1.3195 g;
4.8819 mmol) was adjusted by washing the brown oil with diethyl ether to orange precipitate purified with
recrystallization by n-hexane (m.p. 82 ̊C).
Anal. Calc. for C15H14N2O3: C, 66.66; H, 5.22; N, 10.36. Found: C, 66.18; H, 5.50; N, 10.11. FT-IR (KBr):
3418 cm-1 ν(O-H KBr), 3339 cm-1 ν(N-H), 3055, 2949, 2843 cm-1 ν(C-H), 1714 and 1690 cm-1 ν(C=O), 1621
1
– 1435 cm-1 ν(ringC=C), 1302 – 1085 cm-1 ν(C-O) and ν(C-N) overlapped, 755 cm-1 δ(ringC=C)oop. H NMR
(300 MHz, CDCl3, ppm) δ: 10.99 (s, 1H) - 9, 8.72 (ddd, J = 4.78, 1.72, 0.92 Hz, 1H) - 4, 8.27 (m, 1H) - 1,
7.88 (td, J = 7.71, 1.73 Hz, 1H) - 2, 7.83 (m, 1H) - 14, 7.48 (ddd, J = 7.61, 4.78, 1.24 Hz, 2H) – 3/12, 7.24 (t,
13
1H) - 13, 3.86 (s, 3H) - 20, 2.37 (s, 3H) - 16. C NMR (75 MHz, CDCl3, ppm) δ: 167.59-17, 162.37-7,
150.08-6, 148.66-4, 137.48-2, 136.20-10, 136.03-11, 135.45-12, 128.63-14, 126.50-3, 125.82-13, 124.15-15,
122.80-1, 52.43-20, 19.50-16.
2.3 Preparation of (L2)
The mixture of pyridine-4-carboxylic acid (1.1199 g; 9.0967 mmol) dissolved in thionyl chloride (15
mL; 206.7748 mmol) were mixed and refluxed for 1-3h. Then the excess of thionyl chloride was distilled
under vacuum and the aromatic amine methyl ester Ea (1.500 g; 9.0816 mmol) dissolved in CHCl3 (20 mL;
249.6231 mmol) was added. The mixture was heated and stirred under reflux for 3-6 h. The amide (L2: yield
ca. 50%; 1.2212 g ; 3.5627 mmol) was precipitated as yellow crystals after washing the dark yellow oil with
diethyl ether and recrystallization with the mixture of acetone and methanol (m.p. 180 ̊C).
5

Anal. Calc. for (C15H15N2O3)Cl(H2O)2: C, 52.56; H, 5.59; N, 8.17. Found: C, 52.39; H, 6.30; N, 8.16. FT-IR
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(KBr): 3435 cm-1 ν(O-H), 3218 cm-1 ν(N-H), 3056, 2924, 2852 cm-1 ν(C-H), 1730 and 1640 cm-1 ν(C=O),
1603 – 1441 cm-1 ν(ringC=C), 1317 – 1088 cm-1 ν(C-O) and ν(C-N) overlapped, 803/750 cm-1 δ(ringC=C)oop.
1H NMR (403 MHz, d-DMSO, ppm) δ: 10.71 (s, 1H) - 9, 9.04 (dd, J = 4.98, 1.52 Hz, 2H) – 2/4, 8.28 (dd, J =
4.96, 1.54 Hz, 2H) -1/5, 7.71 (m, 1H) - 14, 7.57 (ddd, J = 7.64, 1.53, 0.72 Hz, 1H) - 12, 7.38 (t, 1H) - 13,
4.41 (s, 12H N+-H protone – fast chemical exchange with water molecules) - 3, 3.72 (s, 3H) - 20, 2.30 (s,
3H) -16. 13C NMR (151 MHz, d-DMSO, ppm) δ: 166.32–17, 162.88–7, 146.52–2/4, 145.42–6, 136.54–11,
134.61–10, 134.33–12, 128.25–15, 127.95–14, 126.95–13, 123.44–1/5, 52.10-20, 17.86-16.
2.4 Preparation of (L3)
An appropriate amount of pyridine-4-carboxylic acid (1.0017g; 8.1366 mmol) was placed in a round
bottom flask and the thionyl chloride (10 mL; 137.8499 mmol) was added. The reaction mixture was stirred
under reflux for 1-3h. Then the excess of thionyl chloride was distilled under vacuum. The amine methyl
ester Eb (1.1700 mL; 8.1168 mmol) dissolved in CHCl3 (40 mL; 499.2462 mmol) was added into the flask
and the solution of substrates was stirred and heated for 4h under reflux. The white powder precipitated
(2.5152g; 95%) from the reaction mixture and was recrystallized from acetonitrile giving white needle
crystals (m.p.183 ̊C.
Anal. Calc. for (C15H15N2O3)Cl(H2O): C, 57.06; H, 5.11; N, 8.87. Found: C, 57.26; H, 5.38; N, 8.78. FT-IR
(KBr): 3423 cm-1 ν(O-H), 3186 cm-1 ν(N-H), 3104, 3052, 2953, 2847 cm-1 ν(C-H), 1720 and 1685 cm-1
ν(C=O), 1638 – 1453 cm-1 ν(ringC=C), 1300 – 1049 cm-1 ν(C-O) and ν(C-N) overlapped, 846/755/697 cm-1
δ(ringC=C)oop. 1H NMR (300 MHz, d-DMSO, ppm) δ: 10.75 (s, 1H) - 9, 9.00 (d, J = 6.31 Hz, 2H) – 2/4, 8.27
(dd, J = 5.09, 1.31 Hz, 2H) -1/5, 7.70 (dd, J = 7.76, 1.31, 1H) - 13, 7.56 (dd, J = 7.84, 0.92 Hz, 1H) - 11, 7.38
(t, J = 7.80, 1H) - 12, 4.48 (s, 12H N+-H protone – fast chemical exchange with water molecules) - 3, 3.85
(s, 3H) - 20, 2.37 (s, 3H) -16. 13C NMR (75 MHz, d-DMSO, ppm) δ: 167.66–17, 162.90–7, 146.40–6,
145.36-2, 136.62–10, 134.74–15, 131.73–14, 130.58–11, 128.09–13, 126.00–12, 123.69–1, 52.21-20, 15.29-
16.
6

2.5 Preparation of (L4)
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The mixture of pyridine-4-carboxylic acid (2.0030g, 16.2700 mmol) and thionyl chloride (10 mL;
137.8499 mmol) were stirred and refluxed for 1.5h. After distillation of thionyl chloride excess the solution
of Ec (2.6850g; 16.2540 mmol) in CHCl3 (45 mL; 561.6520 mmol) was added. The reaction mixture was
heated and refluxed for 3h. The bright – yellow product solidified from the mixture in room temperature. The
white powder precipitated after washing the product by diethyl ether (4.3821g; 88%). The white crystals
were obtained by recrystallization from ethanol/methanol mixture (m.p. 212 ̊C).
Anal. Calc. for (C15H15N2O3)Cl: C, 58.73; H, 4.93; N, 9.13. Found: C, 58.62; H, 5.41; N, 9.11. FT-IR (KBr):
3442 cm-1 ν(O-H KBr), 3211 cm-1 ν(N-H), 3028, 2974, 2950, 2922 cm-1 ν(C-H), 1708 and 1673 cm-1 ν(C=O),
1636 – 1412 cm-1 ν(ringC=C), 1341 – 1053 cm-1 ν(C-O) and ν(C-N) overlapped, 842/803/753 cm-1
δ(ringC=C)oop. 1H NMR (403 MHz, d-DMSO, ppm) δ: 10.83 (s, 1H) - 9, 9.06 (d, J = 3.57 Hz, 2H) – 2/4, 8.38
(d, J = 6.26 Hz, 2H) -1/5, 8.03 (d, J = 1.58, 1H) - 15, 7.80 (dd, J = 7.93, 1.81 Hz, 1H) - 13, 7.46 (d, J = 8.06,
1H) - 12, 3.85 (s, 3H) - 20, 2.35 (s, 3H) -16. 13C NMR (151 MHz, d-DMSO, ppm) δ: 165.82–16, 162.65–7,
146.58-6, 145.14–2/4, 139.61–11, 135.79–10, 131.05–12, 127.75–14, 127.12–15/13, 124.57–1/5, 52.16-19,
18.16-20.
2.6 X-ray crystal structure determination
Diffraction data were collected by the ω-scan technique, for L1 at room temperature on Agilent
Technologies SuperNova four-circle diffractometer with Atlas CCD detector and mirror-monochromated
CuKα radiation (λ=1.54178 Å), and for L2 at 100(1) K and for L3 and L4 at room temperature on Agilent
Technologies Xcalibur four-circle diffractometer with Eos CCD detector and graphite-monochromated
MoKα radiation (λ=0.71073 Å). The data were corrected for Lorentz-polarization as well as for absorption
effects [34]. Precise unit-cell parameters were determined by a least-squares fit of reflections of the highest
intensity, chosen from the whole experiment. The structures were solved with SIR92 [35] and refined with
the full-matrix least-squares procedure on F2 by SHELXL-2014/7 [36]. All non-hydrogen atoms were refined
anisotropically, positions of hydrogen atoms involved in hydrogen bonds (NH and OH) were found in the
difference Fourier maps and freely refined with isotropic displacement parameters, all other hydrogen atoms
7

were placed in idealized positions and refined as ‘riding model’ with isotropic displacement parameters set at
ACCEPTED MANUSCRIPT
1.2 (1.5 for methyl groups) times Ueq of appropriate carrier atoms.
Crystal data: L1: C15H14N2O3, Mr=270.28, orthorhombic, Pna21, a=8.8026(2) Å, b=30.771(2) Å, c=
4.9655(2) Å, V= 1345.00(11) Å3, Z=4, dx=1.34 g·cm-3, ꢀ=0.78 mm-1, F(000)=568. 3185 reflections collected
up to Θ = 75.7°, 1777 symmetry independent (Rint=0.014), 1708 with I>2σ(I). Final R[I>2σ(I)]=3.03%,
wR2[I>2σ(I)]=8.16%, R[all refl.]=3.15%, wR2[all refl.]=8.27%, S=1.10, max/min ꢁρ = 0.11/-0.13 e·Å-3.
+
L2: C15H15N2O3 ·Cl-·2H2O, Mr=342.77, monoclinic, P21/c, a= 16.0911(10) Å, b= 7.2356(4) Å, c = 13.904(2)
Å, β= 94.221(11)°, V= 1614.4(3) Å3, Z=4, dx=1.41 g·cm-3, ꢀ=0.26 mm-1, F(000)=720. 6408 reflections
collected up to Θ = 28.02°, 3347 symmetry independent (Rint=2.50%), 2950 with I>2σ(I). Final
R[I>2σ(I)]=5.54%, wR2[I>2σ(I)]=13.87%, R[all refl.]=6.33%, wR2[all refl.]=14.40%, S=1.14, max/min ꢁρ
=1.05/-0.31 e·Å-3.
+
L3: C15H15N2O3 ·Cl-·H2O, Mr=324.76, monoclinic, P21/c, a= 16.0620(5) Å, b= 12.8491(6) Å, c = 7.3928(2)
Å, β= 98.264(3)°, V= 1509.90(9) Å3, Z=4, dx=1.43 g·cm-3, ꢀ=0.27 mm-1, F(000)=680, 6111 reflections
collected up to Θ = 28.34°, 3109 symmetry independent (Rint=1.54%), 2485 with I>2σ(I). Final
R[I>2σ(I)]=3.99%, wR2[I>2σ(I)]=9.96%, R[all refl.]=5.32%, wR2[all refl.]=10.85%, S=1.05, max/min ꢁρ
=0.22/-0.36 e·Å-3.
+
L4: C15H15N2O3 ·Cl-, Mr=306.74, tetragonal, P41, a= 7.2951(3) Å, c = 27.091(3) Å, V= 1441.7(2) Å3, Z=4,
dx=1.41 g·cm-3, ꢀ=0.28 mm-1, F(000)=640, 2837 reflections collected up to Θ = 27.25°, 2266 symmetry
independent (Rint=1.13%), 2123 with I>2σ(I). Final R[I>2σ(I)]=3.90%, wR2[I>2σ(I)]=8.10%, R[all
refl.]=4.30%, wR2[all refl.]=8.31%, S=1.13, max/min ꢁρ =0.17/-0.16 e·Å-3.
Crystallographic data (excluding structure factors) for the structural analysis have been deposited
with the Cambridge Crystallographic Data Centre, Nos. CCDC-1472237 (L1), CCDC-1472238 (L2),
CCDC-1497670 (L3) and 1497671 (L4). Copies of this information may be obtained free of charge from:
The Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK. Fax: +44(1223)336-033, e-
mail:deposit@ccdc.cam.ac.uk, or www: www.ccdc.cam.ac.uk.
8

3. Results and Discussion
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3.1. Crystal structure description
The crystal structures of all four ligands were obtained from single-crystal X-ray analysis.
Interestingly, the 2-pyridyl derivative L1 crystallized as a free base, while for three ligands with 4-pyridyl
fragment the appropriate crystals were obtained as salts (chlorides); moreover in the structures of L2 and L3
additionally two (L2) or one (L3) water molecules have been found. Figure 1 collects the perspective views
of ligand L1 and cations of L2 – L4.
The conformations of these molecules can be described by dihedral angles between the planar
fragments: pyridine ring (A), C-C(=O)-NH-C linker (B) and phenyl ring (C) – cf. Table 1. It might be noted,
that the mutual orientation of B and C is similar in all four molecules, while the other angles are different,
leading to either almost perpendicular orientation of the rings (as in L2 and L4) or nearly parallel disposition
in L3 (Figure 1). The uniqueness of a free base L1, for which systems A and B are almost coplanar, is
caused by the intramolecular NH···N hydrogen bond in L1 and H···H repulsion in L2 (so by a steric
hindrance, related to the position of N atom in the ring). Moreover, in L1 there is another intramolecular H-
bond, NH···O, with carbonyl oxygen atom from the ester group, which is not observed in the cations,
probably due to the competition with the intermolecular hydrogen bonds with chloride anion and – for L2
and L3 - water molecules (hydrogen bond data are listed in Table 2).
(a)
9

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(b)
(c)
(d)
Figure 1. Perspective views of the ligand L1 (a) and cations of L2 (b), L3 (c) and L4 (d); ellipsoids are
drawn at the 50% probability level, hydrogen atoms are shown as spheres of arbitrary radii. Intramolecular
hydrogen bonds are shown as thin blue lines.
Table 1. Selected geometrical parameters (Å, °) with s.u.’s in parentheses (A, B and C – mean planes of
pyridine ring, linker, and phenyl ring, resp.).
L1
L2
L3
L4
C7-O8
C17-O18
C-N-C(pyr)
C10-C15-C17-O18
C14-C15-C17-O18
C11-C12-C17-O18
C13-C12-C17-O18
C13-C14-C17-O18
C15-C14-C17-O18
A/B
1.218(3)
1.205(2)
117.06(19)
23.1(3)
1.231(3)
1.211(3)
123.1(2)
140.4(3)
-40.7(4)
1.220(2)
1.199(2)
122.62(15)
1.213(5)
1.203(5)
122.2(4)
-155.7(2)
-10.2(3)
168.32(18)
176.2(4)
-1.0(6)
20.9(2)
2.52(16)
34.53(12)
50.74(7)
10

B/C
A/C
60.54(7)
60.71(8)
53.94(9)
88.41(7)
61.58(6)
11.74(6)
66.96(12)
87.85(11)
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In the crystal structure of L1 only weak specific interactions C-H···O can be found, in contrast, ionic
structures of L2 – L4 have – besides probably the most important Coulombic interactions - the rich hydrogen
bond networks, which connect the elements of the structure into 3D network (Table 1, Figure 2).
(a)
(b)
11

ACCEPTED MANUSCRIPT
(c)
Figure 2. Crystal packing of salt structures L2 (a), L3 (b), and L4 (c). Hydrogen bonds are shown as thin
blue lines.
Table 2. Hydrogen bond data (Å, °).
D
H
A
D-H
H···A
D···A
D-H···A
L1
N9
N9
H9
H9
N5
O18
0.81(3)
0.81(3)
L2
2.24(3)
2.27(3)
2.653(3)
2.733(2)
112(2)
117(2)
N3
N3
N9
O1W
O1W
O2W
O2W
H3
H3
H9
H1W1
H1W2
H2W1
H2W2
O1Wi
Cl1ii
O2W
Cl1iii
Cl1
0.88(4)
0.88(4)
0.85(3)
0.88(5)
0.88(5)
0.85(4)
0.81(4)
L3
0.95(3)
0.79(2)
0.83(4)
0.82(3)
L4
2.26(4)
2.45(4)
2.02(3)
2.34(5)
2.26(5)
2.41(4)
2.05(4)
2.921(3)
3.227(2)
2.869(3)
3.087(3)
3.138(2)
3.260(2)
2.868(3)
131(3)
147(3)
173(3)
143(4)
172(4)
175(4)
178(4)
Cl1
O8iv
N3
N9
O1W
O1W
H3
H9
H1W1
H1W2
Cl1v
O1W
Cl1ii
Cl1vi
2.11(3)
2.09(2)
2.31(4)
2.40(3)
2.9975(15)
2.871(2)
3.1384(16)
3.1966(18)
156(2)
172.1(19)
174(3)
163(2)
N3
C5
N9
H3
H5
H9
Cl1vii
Cl1
1.01(5)
0.93
0.89(5)
2.06(5)
2.66
2.42(5)
2.995(4)
3.582(4)
3.292(4)
154(4)
172
167(4)
Cl1
Symmetry codes: i x,3/2-y,1/2+z; ii –x,1-y,1-z; iii –x,1/2+y,1/2-z; iv x,-1+y,z, v x,y,1+z; vi –x,-1/2+y,1/2-z, vii
–
y,1+x,1/4+z.
12

3.2. The analysis of IR and NMR spectra
ACCEPTED MANUSCRIPT
All of the obtained products: intermediate and final compounds, were identified by analysis of FT-IR
and NMR spectra characteristic bands. This analysis for Ea, Eb, Ec, pyridine-2-carboxylic and pyridine-4-
carboxylic acids helped to determine all of the amide products from the second step of reaction.
In the IR spectra of obtained esters were observed two intensive amine bands at 3491, 3373, and
3467, 3382 and 3458, 3372 cm-1, respectively for Ea, Eb and Ec. After coupling the pyridine-2-carboxylic
acid with Ea the one strong band occurred at 3339 cm-1. In the final amide products L2-L4 the amide
bonding stretching bands appeared at 3218, 3186, 3211cm-1, respectively. Amide L1 was obtained with any
additional water molecules in the structure. For this reason the band responsible for the peptide bonding
became a narrow and intensive signal. For the amides L2 and L3 these signals were overlapped with
stretching bands corresponding to – OH groups from water molecules present in their molecular structures.
Amides L2, L3 and L4 were obtained as protonated forms compensated by chloride anion. There is
possibility that this protonated pyridine ring (N+-H) was reflected in the IR spectra at the same range of
wavelength causing an overlap [37,38]. The two strong and narrow carbonyl group stretching bands coming
from methyl esters and pyridinecarboxylic acids were also visible at 1714 and 1690 cm-1 (L1),1730 and 1640
cm-1 (L2), 1720 and 1685 cm-1 (L3) and 1708 and 1673 cm-1 (L4) [39]. All of the IR spectra for obtained
amides L1-L4 and ester Ea with additional spectra of esters Eb and Ec (reagents from Sigma–Aldrich) are
available in Supporting Information File 1 (Fig. S1. – Fig. S6.).
1
The H and 13C NMR spectra of obtained compounds were registered in CDCl3 and d-DMSO
solutions. Both of NMR spectra confirmed the purity of obtained ester and are in accordance with the
previous report [40]. The shift of N-H signal from δ5.82 (s, 2H) - Ea to δ10,99 (s, 1H) - L1, δ10.71 (s, 1H) –
L2, δ10,75 (s, 1H) – L3, δ10,83 (s, 1H) – L4 confirmed the amide bond formation in all new ligands which
were indicated in the IR spectra.
The obtained amides were characterized in detail by the analysis of COSY 2D, HSQC and HMBC
NMR spectra. COSY 2D NMR spectra allowed to observe the conjugation between neighboring hydrogens
1
in the amide structures. Then all of the chemical shifts from the simple H NMR spectra were properly
assigned to the hydrogens in the analyzed structure. The problem showed up also with the primary 13C NMR
spectra in case of distinction of each carbon signal. The overall amount of the signals in the L1 spectrum
13

confirmed the lack of symmetry in this structure of pyridine-2-carboxylic acid derivative. In the case of
ACCEPTED MANUSCRIPT
products L2, L3 and L4 a reduced number of carbon shifts in the NMR spectra reflected the symmetry of
pyridine-4-carboxylic acid pyridine ring. Moreover in the 13C NMR spectrum of amide L4 carbon atoms
number 13 and 15 are overlapped. Due to the narrow range of the signals occurrence and strong influence of
carbonyl, methyl and amide groups on the electron structure of aromatic rings; for all of these compounds
only detailed analysis of HSQC NMR in combination with HMBC NMR spectra allowed to attribute each of
1
carbon atoms to appropriate shift in the primary 13C NMR spectra. The primary H and 13C NMR spectra
were registered separately. For this reason in the COSY 2D, HSQC and HMBC NMR spectra a slight signal
shifts can be observed. This minor effect did not influence on the spectra analysis results and all of the
signals were easily attributed and characterized. In the example of compound L4 the COSY 2D NMR
spectrum allowed to discover few couplings between hydrogen atoms of neighboring carbons in the structure
of the ligand: (H2/4 with H1/5, H13 with H12, H1/5 with H15 and H15 with H13). Analysis of those signals
1
confirmed the positions of hydrogen atoms in the H NMR spectrum: H2/4 (9.06 ppm), H1/5 (8.38 ppm),
H15 (8.03 ppm), H13 (7.80 ppm) and H12 (7.46 ppm). The HSQC NMR analysis gave one of the most
important information about the overlapping of 13C NMR signals for carbons C13 and C15. This signal
position helped significantly in further reconsideration of carbons position in the aromatic ring. The detailed
analysis of HMBC NMR spectra (Figure 3) allows to assign the coupling effects between hydrogen atoms
H13, H15 and carbons C10, C11, C13, C15, C16. As one can observe the three positions 11, 13 and 15
revealed most intensive signals, which are responsible for three bond couplings between carbon and
hydrogen atoms in the aromatic ring. Moreover we can also clearly observe three signals related to H20
hydrogen atom coupling with carbons: C12, C10 and C11. As indicated the first two carbons are related by
three bond coupling and the last one by two bond coupling with H20 hydrogen atoms which confirms the
position of methyl group in the aromatic ring. The position of this methyl group is confirmed as well by four
signals responsible for H12 hydrogen atom couplings with C20, C14, C10, C16 carbon atoms. First three
carbons are related by three bond coupling. Atom C16 reveals a weaker signal than other three carbons,
which points out the more distant – four bond coupling with H12 hydrogen atom. Considering the pyridine
ring in the structure, atoms C2, C4 and C1, C5 are equivalent on all analyzed NMR spectra. On the HMBC
NMR we can observe the two and three bond coupling signals related to H1/5 hydrogen and C2/4, C1/5, C7
carbons impacts respectively. The last carbon C7 belongs to a peptide group. The peptide hydrogen atom H9
14

is also coupled by three bonds with C11 and C15 carbon atoms. What is more the two bond aliphatic
ACCEPTED MANUSCRIPT
coupling is observed for this hydrogen atom in relation with carbon C7. All of the detailed NMR spectra
analysis is available in the Supporting Information File 2 (Fig. S7 – S34 and Table S1-S4). The values of
HMBC NMR shifts and coupling rates (xJHC : x – bonded couplings) for L4 are shown in Table 3.
Figure 3. HMBC NMR spectra of L4 - narrow range (black - 2JHC, red – 3JHC, green – 4JHC).
Table 3. HMBC NMR shifts values and coupling rates for L4.
Hx
20
19
H [ppm]
Cx
12
10
11
C [ppm]
131.19
135.61
139.54
xJHC
3
3
2
2.35
3.86
16
20
14
10
16
165.88
18.08
3
3
3
3
4
127.72
135.92
165.95
12
13
7.48 - 7.46
7.80 – 7.81
15
10
127.10
135.31
3
4
15

11
3
3
ACCEPTED MANUSCRIPT139.55
16
165.99
13
10
11
16
127.07
135.83
139.54
165.97
3
2
3
3
15
8.03
1/5
2/4
7
124.52
145.32
162.20
3
2/4
3
1/5
9
8.39
15
11
7
127.09
139.43
162.59
3
3
2
10.80
3.3. The luminescence properties and thermal stability
Furthermore, the solid-state luminescent properties of compounds L1-L4 have been determined at
room temperature. Figure 4 shows excitation and emission spectra of a microcrystalline sample of L1. This
compound displays a broad emission band with the maximum intensity at 410 nm, after excitation with 354
nm light (the excitation spectrum was measured by monitoring the emission at 410 nm). Excitation and
emission slits during the measurements were equal 2.5 and 1 nm, respectively. Samples L2-L4
(Supplementary materials Fig S35-S37) exhibit similar emission profiles under the same experimental
conditions (excitation and emission slits equal 5 nm). A luminescence band at 468 nm was evidenced for L2
when the excitation wavelength was set at 354 nm. The emission spectrum of L3 displays the emission bands
centered at 462 nm with excitation maxima at 365 nm. The emission spectrum of L4 contains two peaks at
412 and 438 nm (λex=370 nm). The emission bands of L2-L4 are red-shifted compared to the sample L1.
The emission peaks of L1-L4 can be ascribed to π*-π transitions of L ligands. Notably, compound L1
showed more intense emissions than L2-L4. This may be a result of the presence of pyridine-2-carboxylic
acid in the structure of L1 [13].
16

ACCEPTED MANUSCRIPT
Figure 4. Excitation (black line) and emission (grey line) spectra of L1 in solid state.
Thermal stability of the synthesized ligands were examined by thermogravimetric analysis (TGA).
From TG of the amide ligands (Figure 5), the mass loss for the investigated ligands were calculated
within the temperature range at which pronounced decreases in mass were observed. In the IR spectra
of compounds L2 and L3 there are broad absorption bands of ν(OH) with a max.at around 3400 cm-1 that are
characteristic for hydrates [39,41]. From TG curves the loss of one and two water molecules was designated
(Calc: 10.51%, Found: 10.44% and Calc: 5.55%, Found: 5.84% of starting probe mass, respectively for L2
and L3) .
The probe decomposition analysis of L1 confirmed the presence of pure amide ligand in the crystal structure.
The weight loss of mass starts at 124 and finished at 389
amide molecules of L2-L4 took place at a higher temperature than for L1. For anhydrous compound L2,
the compound begins to decompose at 148 C (Calc: 86,95%, Found: 85,75%.). For L3, the departure of
organic components occurs from 230 C (Calc: 94,45%. Found: 94.17%). The decomposition of compound
L4 starts at 152 C.
̊C. The main decomposition of the anhydrous
̊
̊
̊
Such behavior of L2-L4 ligands, on the one hand, is most probably caused by their different
structures. Thanks to the hydrogen bond, they form a 3D structure that is not observed in L1. On the other
hand, ligands L2, L3 and L4 were obtained as the ionic compounds, where one hydrogen proton creates
positive charge on pyridine ring, which is compensated by opposite chloride anion
.
17

ACCEPTED MANUSCRIPT
Figure 5. TG curves for compounds L1, L2 and L4.
4. Conclusion
In this work we presented a simple method of obtaining four new amide derivatives of pyridine-2-
carboxylic and pyridine-4-carboxylic acids. Three of the obtained products revealed a protonated pyridine
ring equilibrated by a chloride ion in their molecular structure. This protonation is also indicated on FT-IR
and NMR spectra of appropriate compounds. The detailed analysis of amides showed up also the presence of
water molecules in L2 and L3. The combination of two dimensional NMR spectra allowed to fully
characterize all of amides distinguishing each of hydrogen and carbon atoms in their structures.
The TGA, elemental and X-Ray analysis confirmed all of conclusions put forward from FT-IR and NMR
spectra analysis. In the way expected all of obtained products have better coordination features because of
the presence of function groups coming from both of substrates used in the synthesis. Meeting the interesting
field of pyridinecarboxylic amides in this work we presented a detail spectroscopic characterization of more
branched derivatives, which is a good contribution to the understanding of the reactivity and finding
applications for these type of heterocyclic compounds.
5. Acknowledgments
This work was financed by the National Science Centre:
18

grant Preludium DEC-2014/15/N/ST5/00597.
ACCEPTED MANUSCRIPT
Supplementary Information
Appendix A: FT-IR spectra of Ea, Eb, Ec, L1, L2, L3, L4;
Appendix B: 1H,13C, HSQC, HMBC, COSY 2D NMR spectra of L1, L2, L3, L4;
Appendix C: excitation, emission spectra of L2, L3, L4;
Appendix D: checkCIF_L1, L2, L3, L4
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Schemes and Figures Captions:
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Scheme 1. Synthesis of amide ligands, derivatives of pyridine-2-carboxylic and pyridine-4-carboxylic acids
L1, L2, L3, L4.
Figure 1. Perspective views of the ligand L1 (a) and cations of L2 (b), L3 (c) and L4 (d); ellipsoids are
drawn at the 50% probability level, hydrogen atoms are shown as spheres of arbitrary radii. Intramolecular
hydrogen bonds are shown as thin blue lines.
Figure 2. Crystal packing of salt structures L2 (a), L3 (b), and L4 (c). Hydrogen bonds are shown as thin
blue lines.
Figure 3. HMBC NMR spectra of L4 - narrow range (black - 2JHC, red – 3JHC, green – 4JHC).
Figure 4. Excitation (black line) and emission (grey line) spectra of L1 in solid state.
Figure 5. TG curves for compounds L1, L2 and L4.
24

ACCEPTED MANUSCRIPT
Highlights
•
•
•
•
Studies on four new pyridinecarboxamides
Amide coupling synthesis of picolinic and isonicotinic acids
Detailed 1H, 13C, COSY 2D, HSQC, HMBC NMR analysis
Characterization of obtained compounds by elemental, X-Ray diffraction, TGA, FT-
IR, excitation and emission spectra analysis