One-step aldehyde group transformation by using guanidine and aminoguanidine: Synthetic, structural and computational studies

Article abstract of DOI:10.1016/j.molstruc.2014.02.002

New triazine derivatives 2,4-diamino-3,6-dihydro-6-(2-chlorophenyl)-1,3,5- triazine (1) and 1-(2-chlorobenzyl)-5-(2-chlorophenyl)-N-[(1E)-(2-chlorophenyl) methylene]-1,2,4-triazolidin-3-amine (2) were synthesized by a one-pot synthesis using 2-chlorobenzaldehyde, guanidine and aminoguanidine, respectively. The FTIR, multinuclear NMR, and single crystal X-ray characteristics of these compounds have been determined experimentally and rationalized on the basis of DFT calculation method.

Full text of DOI:10.1016/j.molstruc.2014.02.002

Journal of Molecular Structure 1064 (2014) 44–49
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
One-step aldehyde group transformation by using guanidine
and aminoguanidine: Synthetic, structural and computational studies
⇑
Jacek E. Nycz , Grzegorz J. Malecki
Institute of Chemistry, University of Silesia, ul. Szkolna 9, PL-40007 Katowice, Poland
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
ꢀ
ꢀ
We report new synthetic
methodologies of triazine derivatives.
Structure of 1-(2-chlorobenzyl)-
5-(2-chlorophenyl)-N-[(1E)-(2-
chlorophenyl)methylene]-1,2,4-
triazolidin-3-amine.
ꢀ
2,4-Diamino-3,6-dihydro-6-(2-
chlorophenyl)-1,3,5-triazine was
synthesized.
ꢀ
ꢀ
Multinuclear NMR, X-ray and DFT
characterization.
High yield from low cost starting
materials.
a r t i c l e i n f o
a b s t r a c t
Article history:
New triazine derivatives 2,4-diamino-3,6-dihydro-6-(2-chlorophenyl)-1,3,5-triazine (1) and 1-(2-chloro-
benzyl)-5-(2-chlorophenyl)-N-[(1E)-(2-chlorophenyl)methylene]-1,2,4-triazolidin-3-amine (2) were
synthesized by a one-pot synthesis using 2-chlorobenzaldehyde, guanidine and aminoguanidine, respec-
tively. The FTIR, multinuclear NMR, and single crystal X-ray characteristics of these compounds have
been determined experimentally and rationalized on the basis of DFT calculation method.
Ó 2014 Elsevier B.V. All rights reserved.
Received 9 December 2013
Received in revised form 1 February 2014
Accepted 4 February 2014
Available online 10 February 2014
Keywords:
Aldehyde
Aldazines
Guanidine
Aminoguanidine
Triazine
Schiff base
1. Introduction
equilibrium is strongly thermodynamically driven, and at room
temperature the keto form is favored. The conversion between
Aldehydes are a class of compounds of great interest from the
synthetic, theoretical and application point of view. They can be
transformed into a wide range of structures through applying a
variety of reactions. Like ketones, aldehydes are sp2 hybridized
and could exist in the form of keto or enol tautomer. The
the two forms can be catalyzed by either acids or bases. As
electrophiles, they are subject to be attacked by nucleophiles,
and participate in many nucleophilic addition reactions.
In this paper, we reported the transformation of aldehyde group
by guanidine and aminoguanidine to new triazine derivatives.
Despite its potential value there are many papers describing this
conversion. In most cases products are Schiff bases [1–13]. How-
ever, there are only few works showing the ring closure reaction
⇑
Corresponding author. Tel.: +48 323591206; fax: +48 322599978.
E-mail address: jnycz@us.edu.pl (J.E. Nycz).
http://dx.doi.org/10.1016/j.molstruc.2014.02.002
0022-2860/Ó 2014 Elsevier B.V. All rights reserved.

J.E. Nycz, G.J. Malecki / Journal of Molecular Structure 1064 (2014) 44–49
45
similar to ours, all without NMR and X-ray characteristics [14]. The
presented discussion is particularized by computational and spec-
troscopic studies. The triazines have been found broad applications
in pharmaceutical and agrochemical industries [15–19]. They have
also attracted considerable attentions due to their biological and
medicinal activities, such as antileukemic, against resistant malar-
ial strains, antitumor, diuretic, herbicides or in cancer therapy [20–
26]. Triazine derivatives are cytotoxic to parasites since they offer
excellent selectivity between parasites and host cells [27–29].
(M)+ = 441 (100%), 443 (100%), 442 (25%), 444 (25%) 445 (43%);
CCDC 921074.
2.2. Crystallization
The crystal of 2 suitable for X-ray analysis was obtained from
hot MeOH solution.
2.3. DFT calculations
The calculations were carried out by using Gaussian 09 [30]
program. The DFT/B3LYP [31,32] method was used for the geome-
try optimization and electronic structure determination. The
geometry optimization was made for gas phase molecule and a fre-
quency calculation was carried out, verifying that the optimized
molecular structure obtained corresponds to energy minimum,
thus only positive frequencies were expected. The absence of the
imaginary frequencies, as well as of negative eigenvalues of the
second derivative matrix has been obtained in geometry optimiza-
tion of all compounds. The calculations were performed using the
polarization functions for all atoms: 6-31G** – carbon, nitrogen,
oxygen, chloride and hydrogen. Natural charges were calculated
with use of the NBO 5.0 package included in Gaussian 09.
2. Experimental
2.1. General
NMR spectra were obtained with Bruker Avance 400 and 500
operating at 500.18 or 400.13 MHz (1H), 125.78 or 100.5 MHz
(
13C) at 21 °C. Chemical shifts referenced to ext. TMS (1H, 13C). Cou-
pling constants are given in Hz. Mass spectra were obtained with a
Varian 500 MS with applied ESI technique. Melting points were
determined on MPA100 OptiMelt melting point apparatus and
uncorrected. 2-Chlorobenzaldehyde, guanidine sulfate and amino-
guanidine bicarbonate were purchased from Sigma–Aldrich, and
were used without further purification.
2.4. Crystal structure determination and refinement
2.1.1. Synthesis of compounds
The crystal of 2 was mounted in turn on a Gemini A Ultra,
Oxford Diffraction automatic diffractometer equipped with a CCD
detector for data collection. X-ray intensity data were collected
2.1.1.1. Synthesis of 2,4-diamino-3,6-dihydro-6-(2-chlorophenyl)-
1,3,5-triazine (1). Guanidine sulfate (30.3 g, 0.28 mol) was partially
dissolved in a mixture of methanol (300 mL) and DMSO (5 mL).
Subsequently, K2CO3 (38.7 g, 0.28 mol) was added, and the
reagents were heated under reflux for an hour, then 2-chlorobenz-
aldehyde (39.2 g, 0.28 mol) in a solution of methanol (50 mL) was
added. After the addition, the reaction mixture was stirred under
reflux overnight, followed by filtration. The solvent was evaporated
from the resulting solution. The crude product was purified by
extraction at Soxhlet apparatus using EtOH:
with graphite monochromated Mo K radiation (k ¼ 0:71073Å) at
a
temperature of 295.0(2) K 2, with
x scan mode. Ewald sphere
reflections were collected up to 2h = 50.10. Details of crystal data
and refinement are gathered in Table 1, and selected bond lengths
and angles for compounds are listed in Table 2. During the data
Table 1
1; 32.47 g (0.146 mol; 52%); (white); m.p.dec. = 177–178 °C; 1H
NMR (DMSO-d6; 400.2 MHz; 75 °C) d = 5.44 (bs, 4H, NH), 5.99 (s,
1H, CH), 7.29 (d, J = 7.6 Hz, 1H, aromatic), 7.34 (t, J = 7.5 Hz, 1H,
aromatic), 7.38 (d, J = 7.8 Hz, 1H, aromatic), 7.49 (d, J = 7.5 Hz,
1H, aromatic); 13C{1H} NMR (DMSO-d6; 100.5 MHz; 60 °C)
d = 65.32, 126.87, 128.38, 128.60, 128.86, 131.01, 142.13 (bs),
158.15; MS (MeOH + AcOH): (ESI) (M + H)+ = 224 (100% 35Cl) and
226 (32% 37Cl).
Crystal data and structure refinement details for 2.
2
Empirical formula
Formula weight
Temperature (K)
Radiation
Color, habit
Crystal system
Space group
C22H15Cl3N4
441.73
295.0(2) K
Mo K k = 0.71073 Å
Colorless, plate
Monoclinic
P21/n
a
Unit cell dimensions
a (Å)
b (Å)
10.8119(9)
13.4154(9)
15.4186(13)
110.016(9)
2101.3(3)
2.1.1.2. Synthesis of 1-(2-chlorobenzyl)-N-(2-chlorobenzylidene)-5-
(2-chlorophenyl)-1H-1,2,4-triazol-3-amine
(2). Aminoguanidine
c (Å)
bicarbonate (38.1 g, 0.28 mol) was partially dissolved in water
(100 mL). Subsequently, K2CO3 (38.7 g, 0.28 mol) was added, and
the reagents were heated under reflux for an hour. Then the water
was evaporated and 2-chlorobenzaldehyde (78.7 g, 0.56 mol) in
solution of methanol (100 mL) was added. After the addition, the
reaction mixture was stirred overnight (16 h), followed by filtra-
tion. The solvent was evaporated from the resulting solution. The
crude product was purified by crystallization from MeOH:
b (°)
Volume (Å3)
Z
4
Calculated density (Mg/m3)
Absorption coefficient (mmꢁ1
F(000)
1.396
0.452
904
)
Crystal dimensions (mm)
h range for data collection (°)
Index ranges
0.27 ꢂ 0.19 ꢂ 0.06
3.35–25.05
ꢁ8 6 h 6 12
ꢁ15 6 k 6 13
ꢁ18 6 l 6 15
7993
3714 [R(int) = 0.0326]
3714/0/262
1.073
R1 = 0.0528
wR2 = 0.1190
R1 = 0.0944
wR2 = 0.1524
0.765 and ꢁ0.501
921074
2; 21.4 g (48.5 mmol; 26%); (beig); m.p. = 124–125 °C; 1H NMR
(DMSO-d6; 500.18 MHz) d = 3.34 (s, 2H, CH2), 7.28–7.33 (m, 2H,
aromatic), 7.34 (dd, J = 5.9, 2.9 Hz, 1H, aromatic), 7.41 (dd, J = 6.0,
2.9 Hz, 1H, aromatic), 7.48–7.55 (m, 2H, aromatic), 7.58–7.62 (m,
2H, aromatic), 7.65 (td, J = 7.2, 1.8 Hz, 2H, aromatic), 7.68 (dd,
J = 8.0, 0.7 Hz, 1H, aromatic), 8.23 (d, J = 7.7 Hz, 1H, aromatic),
9.58 (s, 1H, CHN); 13C{1H} NMR (DMSO-d6; 125.78 MHz)
d = 50.09, 126.83, 127.43, 127.60, 127.81, 128.35, 129.37, 129.86,
130.04, 130.22, 130.94, 131.89, 132.05, 132.45, 132.50, 132.53,
132.92, 133.85, 135.79, 152.66, 159.75, 164.72; MS: (ESI)
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2
r
(I)]
R indices (all data)
Largest diff. Peak and hole (e Åꢁ3
CCDC number
)

46
J.E. Nycz, G.J. Malecki / Journal of Molecular Structure 1064 (2014) 44–49
Table 2
Selected bond lengths and angles for 2 (Å and °).
Exp.
Calc.
Bond lengths (Å)
Cl(1)–C(9)
Cl(2)–C(15)
Cl(3)–C(22)
N(1)–C(2)
N(1)–N(2)
N(1)–C(3)
N(2)–C(1)
N(3)–C(2)
N(3)–C(1)
N(4)–C(16)
N(4)–C(1)
1.740(5)
1.691(5)
1.744(4)
1.343(5)
1.352(4)
1.463(5)
1.312(5)
1.315(5)
1.353(5)
1.266(5)
1.398(5)
1.84
1.83
1.84
1.34
1.38
1.39
1.34
1.35
1.38
1.30
1.38
Angles [°]
C(2)–N(1)–N(2)
C(2)–N(1)–C(3)
N(2)–N(1)–C(3)
C(1)–N(1)–N(2)
C(2)–N(3)–C(1)
C(16)–N(4)–C(1)
N(2)–C(1)–N(3)
N(2)–C(1)–N(4)
N(3)–C(1)–N(4)
109.7(3)
128.5(3)
121.7(3)
102.5(3)
103.1(3)
115.7(3)
114.8(3)
121.5(3)
123.7(3)
110.0
126.4
119.2
102.9
104.3
120.3
113.6
120.4
125.9
Hydrogen bonds
D–Hꢃ ꢃ ꢃA
Fig. 1. ORTEP drawing of molecule 2 with 50% probability displacement ellipsoids.
d(D–H)
d(Hꢃ ꢃ ꢃA)
d(Dꢃ ꢃ ꢃA)
<(DHA)
C(8)–H(8)ꢃ ꢃ ꢃN(3) #1
C(16)–H(16)ꢃ ꢃ ꢃCl(3)
C(16)–H(16)ꢃ ꢃ ꢃN(3)
0.93
0.93
0.93
2.58
2.68
2.35
3.488(6)
3.042(4)
2.723(5)
167.0
104.2
103.8
Symmetry transformations used to generate equivalent atoms: $1 1/2ꢁx, 1/2 + y,
1/2ꢁz.
reduction, the decay of the correction coefficient was taken into ac-
count. Lorentz, polarization and empirical absorption correction
using spherical harmonics implemented in SCALE3 ABSPACK
scaling algorithm [33] were applied. The structures were solved
by direct method. All the non-hydrogen atoms were refined aniso-
tropically using full-matrix, least-squares technique on F2. All the
hydrogen atoms were found from the difference of the Fourier syn-
thesis after four cycles of anisotropic refinement, and refined as
‘‘riding’’ on the adjacent atom with individual isotropic tempera-
ture factor equal to 1.2 times the value of equivalent temperature
factor of the parent atom, with geometry idealization after each cy-
cle. The Olex2 [34] and SHELXS97, SHELXL97 [35] programs were
used for all the calculations. Atomic scattering factors were those
incorporated in the computer programs.
2.5. X-ray and DFT studies
Fig. 2. Interaction between parallel phenyl rings in the unit cell of 2.
2 Crystallizes in monoclinic P21/n space group and its molecular
structure is displayed as ORTEP representation in Fig. 1.
between parallel phenyl C(10)–C(15) rings, with centroid–centroid
distance 3.842 Å and shift distance equal to 1.114 Å, (Fig. 2) also
exert influence on the crystal structure of the compound.
The heterocyclic triazole ring is planar within experimental er-
ror and the N(2)–C(1) and N(3)–C(2) distances of 1.312(5) Å and
1.315(5) Å, respectively, clearly indicate they are double bonds.
The N(1)–N(2) bond (1.352(4) Å) is somewhat shorter than the
standard ordinary bond N–N (1.451 Å), which can be explained
by the delocalization of double bond in the triazole fragment.
The bond’s lengths of triazole molecule are the same with the tab-
ulated values. The C–N–N angles in the ring show large deviations
from the value of 120° usually found in the trigonal planar arrange-
ment, which is common in five-membered rings. The angles be-
tween the planes defined by the triazole cycle and the benzene
rings are 37.21°, 66.85° and 84.85°, respectively. In the molecule
of 2 can be found intra- and intermolecular short contact (Table 2)
which, according to Desiraju & Steiner, can be classified as weak
hydrogen bond [36]. However the hydrogen bonds do not form
any substructures. Nevertheless some electronic interactions
2.6. DFT
The geometry of the compound 2 was optimized in singlet
states using the DFT method with the B3LYP functional and the
predicted bond lengths and angles are over-estimated by about
0.1 Å and 5°, respectively.
The calculated IR frequencies of the compound 2 show good
agreement with the experimental spectrum (see Fig. 3); the
differences can be explained by the neglect of intermolecular inter-
actions for the gas phase. From the data collected in Table 2, the
major differences between the experimental and calculated

J.E. Nycz, G.J. Malecki / Journal of Molecular Structure 1064 (2014) 44–49
47
Fig. 3. IR spectroscopic data of 2.
geometries are found in the Cl(2)–C(15) distance (ꢄ0.13 Å) and
C(16)–N(4)–C(1) angle (4.6°).
The atomic charge calculations can give a feature for the reloca-
tion of the electron density of the compounds, but the local con-
centration and local depletion of electron charge density allow us
to determine whether the nucleophile or electrophile can be
attracted.
Fig. 4. The electrostatic potential (ESP) surface for 2 plotted with use of gOpenmol
program.
Table 3
Fig. 4 presents the plots of the electrostatic potential for 2. The
isoelectronic contour is plotted at 0.05 a.u. (13 kJ/mol). The color
code of the map is in the range of 0.05 a.u. (deepest red) to
ꢁ0.05 a.u. (deepest blue), where blue indicates the strongest
attraction and red indicates the strongest repulsion. Regions of
negative V(r) are usually associated with the lone pair of electro-
negative atoms. The negative potentials (ꢁ0.5 to ꢁ0.2) are mainly
localized on the nitrogen atoms. Chlorine substituents have
charges close to zero (ꢁ0.04) similarly to our previous results
[37–39]. The natural charges of nitrogen and chloride atoms in
molecule of 2 compounds are collected in Table 3 and as one can
see the triazole N(3) and azomethine N(4) atoms have comparable
most negative charges.
The natural charges of selected atoms in molecule of 2.
Atom
N(1)
N(2)
N(3)
N(4)
Cl(1)
Cl(2)
Cl(3)
Natural charge ꢁ0.19 ꢁ0.27 ꢁ0.51 ꢁ0.46 ꢁ0.05 ꢁ0.04 ꢁ0.04
of intramolecular hydrogen bonds between >NH and chloride
which could make the methine carbon atom slightly more positive.
The existence of intramolecular hydrogen bonds in constitution of
similar triazines has been already demonstrated by Rihn et al. [41].
This in consequence should support the presence of tautomer ‘‘B’’
rather than postulated by Ujjinamatada and Hosmane ‘‘A’’ [40].
Another ring closure reaction was presented during the synthe-
ses of 2. The protocol was based on previously described synthesis
of 1. Reaction between 2-chlorobenzaldehyde with excess of ami-
noguanidine freshly liberated from the corresponding bicarbonate
salt in methanol smoothly led to 2. Product was quantitatively pre-
pared and characterized by MS, and multinuclear NMR spectros-
copy together with their X-ray structure (Fig. 1).
3. Results and discussion
We report herein an efficient one-pot conversion of an aldehyde
group into triazine derivatives. In literature there was only one pa-
per describing reaction between benzaldehyde with excess of gua-
nidine freshly liberated from the corresponding hydrochloride salt
in methanol leading to triazine derivatives [40].
We carried out analogous reaction between 2-chlorobenzalde-
hyde with excess of guanidine freshly liberated from the corre-
sponding sulfate salt in methanol. Conversion was unambiguous
and leads to 1 (Scheme 1). Our studies demonstrated that there
were three possible tautomeric forms; two symmetric A, B and
one unsymmetrical C (Scheme 2).
In order to improve the understanding of the chemical behavior
or the structure of species like 1 or 2, and similar molecules, it
would be desirable if one could employ a technique or a method
rather than an execution of experiments which could require com-
plex synthesis and a consumption of expensive materials.
The simplicity of 1H NMR and 13C NMR characteristics ruled out
the presence of unsymmetrical C tautomer. Similarly to Ujjinamat-
ada and Hosmane [40], our compound possesses characteristic
methine signal showing a single resonance at d(1H) = 5.99 and
d(13C) = 65.32 ppm (Table 4). The analysis of the trend in 1H NMR
and 13C NMR chemical shifts of 1 and their literature analogues re-
vealed that the presence of chloride atom in phenyl ring signifi-
cantly decreased the shielding effect (downfield effect, larger d)
(Table 4) [40]. One of the interpretations could be the existence
Scheme 1. The synthesis of 1 and 2; Reagents and conditions: (i) guanidine, MeOH,
reflux; (ii) aminoguanidine, MeOH, reflux.

48
J.E. Nycz, G.J. Malecki / Journal of Molecular Structure 1064 (2014) 44–49
4. Conclusions
The presented research focused on the synthesis of selected
crystalline triazine derivatives containing chloro substituent,
which showed high yield of products. The compounds were further
characterized by analytical methods and rationalized on the basis
of DFT calculation method with B3LYP functional. Chlorine
substituents have charges close to zero similarly to our previous
results. For future studies, we plan to extend this work and inves-
tigate the efficiency of the synthesis of triazine derivatives for
various biomedical applications.
Scheme 2. Tautomers of 1.
Table 4
The experimental 1H and 13C chemical shifts of methine signal of 1 and their literature
analogues.
Acknowledgments
Compound Solvent
1H NMR
5.99
13C NMR Substituent
1
DMSO-
d6
65.32
62.4
Cl in 2 position
The GAUSSIAN 09 calculations were carried out in the Wrocław
Centre for Networking and Supercomputing, WCSS, Wrocław,
Poland (http://www.wcss.wroc.pl Grant Number 18).
[40]
[40]
DMSO-
d6
DMSO-
d6
5.77
only H
5.74 or 5.73 59.7
OCH3 in 2 and 4 position
Appendix A. Supplementary data
CCDC 921074 for 2 contains the supplementary crystallographic
data for the compound. These data can be obtained free of charge
from http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336 033; or e-mail:
deposit@ccdc.cam.ac.uk. Calculations have been carried out in
Wroclaw Centre for Networking and Supercomputing (http://
www.wcss.wroc.pl).
Table 5
NICS(0) and NICS(1) values for symmetric A and B tautomers of 1 obtained with use of
the GIAO procedure at B3LYP/6-31G** level.
A
B
NICS(0)
NICS(1)
ꢁ2.51
ꢁ 0.67
ꢁ 1.33
ꢁ 5.99
References
The aromaticity is an important parameter used frequently as a
measure of reactivity of many organic compounds. The majority of
organic compounds may be characterized by more or less pro-
nounced aromatic character, which is especially important for het-
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have been proposed, but resonance energy was the first quantita-
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teristics of aromaticity [42]. Magnetic properties of organic
molecules arise from the diamagnetic ring currents of aromatic
systems. The nucleus independent chemical shift (NICS) was de-
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