One pot synthesis, molecular structure and spectroscopic studies (X-ray, IR, NMR, UV-Vis) of novel 2-(4,6-dimethoxy-1,3,5-triazin-2-yl) amino acid ester derivatives

Article abstract of DOI:10.1016/j.saa.2016.01.051

Novel series of 2-(4,6-dimethoxy,1,3,5-triazin-2-yl) amino acid ester derivatives were synthesized using simple one pot method in methanol. The products were obtained in high yields and purities as observed from their spectral data, elemental analyses, GC-MS and X-ray crystallographic analysis. The B3LYP/6-311G(d,p) calculated molecular structures are well correlated with the geometrical parameters obtained from the X-ray analyses. The spectroscopic properties such as IR vibrational modes, NMR chemical shifts and UV-Vis electronic transitions were discussed both experimentally and theoretically. The IR vibrational frequencies showed good correlations with the experimental data (R² = 0.9961-0.9995). The electronic spectra were assigned based on the TD-DFT results. Intense electronic transition band is calculated at 198.1 nm (f = 0.1389), 204.2 nm (f = 0.2053), 205.0 (f = 0.1704) and 205.7 (0.2971) for compounds 6a-i, respectively. The molecular orbital energy levels contributed in the longest wavelength transition band were explained. For all compounds, the experimental wavelengths showed red shifts compared to the calculations due to the solvent effect. The NMR chemical shifts were calculated using GIAO method. The NBO analyses were performed to predict the stabilization energies due to the electron delocalization processes occur in the studied systems.

Full text of DOI:10.1016/j.saa.2016.01.051

One pot synthesis, molecular structure and spectroscopic studies (X-ray, IR,
NMR, UV–Vis) of novel 2-(4,6-dimethoxy-1,3,5-triazin-2-yl) amino acid
ester derivatives
Ayman El-Faham, Saied M. Soliman, Sameh M. Osman, Hazem A.
Ghabbour, Mohammed R. Siddiqui, Hoong-Kun Fun, Fernando Albericio
PII:
DOI:
Reference:
S1386-1425(16)30051-8
doi: 10.1016/j.saa.2016.01.051
SAA 14261
To appear in:
Received date:
Revised date:
Accepted date:
10 November 2015
10 January 2016
23 January 2016
Please cite this article as: Ayman El-Faham, Saied M. Soliman, Sameh M. Osman,
Hazem A. Ghabbour, Mohammed R. Siddiqui, Hoong-Kun Fun, Fernando Albericio, One
pot synthesis, molecular structure and spectroscopic studies (X-ray, IR, NMR, UV–Vis)
of novel 2-(4,6-dimethoxy-1,3,5-triazin-2-yl) amino acid ester derivatives, (2016), doi:
10.1016/j.saa.2016.01.051
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ACCEPTED MANUSCRIPT
One pot synthesis, molecular structure and spectroscopic studies (X-
ray, IR, NMR, UV-Vis) of novel 2-(4,6-dimethoxy-1,3,5-triazin-2-yl)
amino acid ester derivatives
Ayman El-Faham,a,c,* Saied M. Soliman,*b,c Sameh M. Osman,a,dHazem A.
Ghabbour,eMohammed R. Siddiqui,aHoong-Kun Fun,e,f Fernando Albericioa,g,h,i,j
aDepartment of Chemistry, College of Science, King Saud University, P.O.Box 2455,Riyadh11451, Saudi Arabia;
aelfaham@ksu.edu.sa.
bDepartment of Chemistry, Rabigh College of Science and Art, King Abdulaziz University, P.O. Box 344, Rabigh
21911, Saudi Arabia.
cDepartment of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321,
Egypt; aymanel_faham@hotmail.com
dAdvanced Materials Research Chair, Department of Chemistry, College of Science, King Saud University, P.O.
Box 2455, Riyadh 11451, Saudi Arabia
eDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box. 2457, 11451
Riyadh, Saudi Arabia.
fX-ray Crystallography Unit, School of Physics, UniversitiSains Malaysia, 11800 USM, Penang, Malaysia.
g School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa
h Institute for Research in Biomedicine (IRB Barcelona), BaldiriReixac 10, Barcelona 08028, Spain.
i
CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park,
Barcelona 08028, Spain.
jDepartment of Organic Chemistry, University of Barcelona,Barcelona 08028, Spain.
Abstract
Novel series of 2-(4,6-dimethoxy,1,3,5-triazin-2-yl) amino acid ester derivatives were
synthesized using simple one pot method in methanol. The products were obtained in high yields
and purities as observed from their spectral data, elemental analyses, GC-MS and X-ray
crystallographic analysis. The B3LYP/6-311G(d,p) calculated molecular structures are well
correlated with the geometrical parameters obtained from the X-ray analyses. The spectroscopic
properties such as IR vibrational modes, NMR chemical shifts and UV-Vis electronic transitions
were discussed both experimentally and theoretically. The IR vibrational frequencies showed
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good correlations with the experimental data (R2 =0.9961-0.9995). The electronic spectra were
assigned based on the TD-DFT results. Intense electronic transition band is calculated at 198.1
nm (f=0.1389), 204.2 nm (f=0.2053), 205.0 (f=0.1704) and 205.7 (0.2971) for compounds 6a-i,
respectively. The molecular orbital energy levels contributed in the longest wavelength transition
band were explained. For all compounds, the experimental wavelengths showed red shifts
compared to the calculations due to the solvent effect. The NMR chemical shifts were calculated
using GIAO method. The NBO analyses were performed to predict the stabilization energies due
to the electron delocalization processes occur in the studied systems.
Keywords: Amino acid esters, dimethoxy-1,3,5-triazine derivatives, X-ray crystallographic
analysis, NBO, B3LYP, TD-DFT.
1. Introduction
The chemistry of s-triazine (1,3,5-triazine) derivatives has been intensively used for the
synthesis of nitrogen containing heterocycles compounds and it is the subject of many articles
reviews[1].The triazine scaffold has provided the starting point for the design of biologically
molecules with broad biomedical applications[1-4].Several derivatives of s-triazine showed
antimicrobials[5-8], herbicidal activities [9],anticancer agents [10-13], antiviral [14], estrogen
receptor modulators[15],antimalarials [16],cyclindependent kinase modulators[17] and
antibacterial [18].s-Triazine derivatives also reported as templates for molecular imprinting [19]
and for the construction of three-helix bundle protein [20]. Very recently, a new series of 4,6-
disubstituted -1,3,5-triazin-2-yl) amino acid derivatives were reported as monoamine oxidase
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inhibitors (MAOs). The results showed that they have more selective inhibitory activity toward
MAO-A than MAO-B with no significant acute toxicity [21].
The starting reagent for obtaining these compounds is an inexpensive commercially
available reagent 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) which makes it more attractive
to be used for synthetic chemistry[1]. The increasing interest in this reagent lies in the different
reactivity of the substituent chlorine atoms, which are controlled by temperature[1].This property
allows substitution of the three chlorine atoms by different nucleophiles onto the triazine core
which provides an enormous selection of derivatives[2-4, 22-27]. As a general rule, which
depends on the reactivity of the nucleophile chosen, the first substitution occurs at low
temperature (0-5°C), the second substitution at approximately room temperature, and the third at
elevated temperature,70–100°C (Scheme 1)[1].
Scheme 1.Reaction of cyanuric chloride with different amines.
Several specific synthetic protocols were developed for the preparation of a range of
symmetric and non-symmetric di- and tri-substituted 1,3,5- triazines [28].Recently, many studies
have focused on the use of triazine moiety for enantioseparation of a few selected amino acids by
the reversed-phase high-performance liquid chromatography (RP-HPLC)[29-36].To the best of
our knowledge, most of the reported method goes through the stepwise preparation; which need
to separate and purify each intermediate.
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The aim of this work is to study the structure, electronic and spectroscopic features of the
newly synthesized4,6-dimethoxy-2-triazinyl amino acid ester derivatives in high yields and
purities via simple one pot eco-friendly method.
2. Experimental Section
2.1. Material and methods
The solvents used were of HPLC reagent grade. Melting points were determined with a
Mel-Temp apparatus. A Fourier transform infrared spectroscopy (FTIR) spectrum was recorded
on Nicolet 560 spectrometer. Nuclear magnetic resonance spectra (1H NMR and 13C NMR
spectra) were recorded on a JEOL 400 MHz spectrometer. Elemental analyses were performed
on Perkin-Elmer 2400 elemental analyzer, and the values found were within ±0.3% of the
theoretical values. Follow-up of the reactions and checks of the purity of the compounds were
done by TLC on silica gel-protected aluminum sheets (Type 60 GF254, Merck). The compounds
were named using ChemDraw Ultra version 11, Cambridge Soft Corporation (Cambridge, MA,
USA). Gas chromatography–mass spectrometry (GC-MS) analysis was accomplished using a
Thermo Trace GC Ultra gas chromatograph equipped with AI 3000 injector and linked to a
Thermo TSQ Quantum mass spectrometer. Peaks were scanned in the mass range from m/z 100
to 500. For the separation of target compounds, a TR-1 capillary column (60 m× 0.25 mm i.d.,
phase thickness 0.25 µm) was used with helium as the carrier gas (at a flow rate of 1 ml min-1).
The GC temperature programming was 40 °C for one min, at 5 °C min-1 with a final hold at 300 °C for 1
min. Data were collected online with use of Xcalibur software version. The electronic spectra of the
studied compounds were measured using UV-Vis spectroscopy (Perkin Elmer Lambda 35;
Waltman, MA, USA).
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2.2. General procedure for the synthesis of 2-(4,6-dimethoxy-1,3,5-triazin-2-yl) amino acid
ester:
To a solution of α-amino acid ester HCl (10 mmol) and Na2CO3 (50 mmol) in methanol (100
o
mL), cyanuric chloride 1 (10 mmol) was added portionwise at 0 C. The reaction mixture was
stirred at this temperature for 1 h, and then the temperature was raised gradually to room
temperature and kept at the same temperature for three hours, finally the reaction mixture was
heated at 70-80 oC for 12h. The reaction mixture was concentrated under vacuum and the residue
was dissolved in dichloromethane (100 mL). The solvent washed with 1N HCl (2x10 mL), sat.
NaCl (2x 10 mL), dried over MgSO4 anhydrous, filtered and the solvent was removed under
vacuum and then the residue was recrystallized from dichloromethane and hexane (2:1).
2.2.1. Methyl 4-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)benzoate (3)
The product was obtained as off white solid; yield 80.0%; mp 168-170 oC; IR (KBr): 3309 (NH,
amine), 1697 (CO, ester), 1615, 1571 (C=N), 1369 (O-CH3) cm-1; 1H NMR (CDCl3) ppm: δ 3.83
13
(s, 6H, 2 OCH3), 3.92 (s, 3H, OCH3 ester), 7.87-7.90 (m, 4H, H-Ar), 10.46 (s, 1H, N-H); C
NMR (DMSO-d6) ppm: 51.9, 55.6, 120.0, 123.9, 130.6, 144.2, 166.5, 166.6, 172.6. Anal.Calcd
for C13H14N4O4 (290.27): C, 53.79; H, 4.86; N, 19.30; found:C, 53.98; H, 4.99; N, 19.54.
2.2.2. Methyl 2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)acetate (6a)
o
The product was obtained as a white crystal; yield 84%; mp 115-6 C; λmax= 231 nm; IR (KBr):
3270 (NH, amine), 1757 (CO, ester), 1628 (C=N), 1361 (O-CH3) cm-1; 1H NMR (CDCl3) ppm: δ
3.74 (s, 3H, OCH3 ester), 3.91 (s, 3H, O-CH3), 3.92 (s, 3H, O-CH3), 4.19(d, 2H, α-CH2), 6.47
(brs, 1H, N-H) ppm; 13C NMR (CDCl3) ppm: 42.6, 42.3, 54.7, 54.75, 16.7.7, 170.2, 171.9, 172.4
ppm. Anal.Calcd for C8H12N4O4 (228.21): C, 42.10; H, 5.30; N, 24.55; found: C, 42.00; H, 5.18;
N, 24.72; m/z found 282.26.
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2.2.3. Methyl 2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)propanoate (6b)
o
The product was obtained as a white crystal from ethanol; yield 83%; mp 90-91 C; λmax= 234
nm ; IR (KBr): 3256 (NH, amine), 1735 (CO, ester), 1620 (C=N), 1371 (O-CH3) cm-1; 1H NMR
(CDCl3) ppm: δ 1.45 (d, 3H, CH3), 3.72 (s, 3H, OCH3 ester), 3.90 (s, 3H, OCH3), 3.91 (s, 3H, O-
13
CH3), 4.68 (q, 1H, α-CH2), 6.10 (d, 1H, N-H); C NMR (CDCl3) ppm: 18.2, 49.5, 52.4, 54.3,
54.7, 167.0, 171.8, 172.3, 173.2. Anal.Calcd for C9H14N4O4 (242.23): C, 44.63; H, 5.83; N,
23.13; found: C, 44.91; H, 5.98; N, 23.40; m/z found 242.27.
2.2.4. Methyl 2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)-3-methyl butanoate (6c)
The product was obtained as a white solid; yield 81%; mp sticky solid; IR (KBr): 3263 (NH,
1
amine), 1741 (CO, ester), 1600 (C=N), 1371 (O-CH3) cm-1; H NMR (CDCl3) ppm: δ 0.87 (dd,
6H, 2CH3), 2.13 (m, 1H, CH), 3.64 (s, 3H, O-CH3 ester), 3.82 (s, 3H, OCH3), 3.83 (s, 3H, O-
CH3), 4.58-4.59 (m, 1H,α-CH), 5.89 (d, 1H, N-H); 13C NMR (CDCl3) ppm: 17.9, 18.9, 31.2,
52.1, 54.7, 58.8, 168.1, 172.1, 172.3, 172.4 ppm. Anal.Calcd for C11H18N4O4 (270.1): C, 48.88;
H, 6.71; N, 23.68; found: C, 49.08; H, 6.631; N, 23.49; m/z found 270.26..
2.2.5. Methyl 2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)-2-methyl propanoate (6d)
o
The product was obtained as a white crystals; yield 86%; mp 96 C; IR (KBr): 3263 (NH,
1
amine), 1735 (CO, ester), 1625 (C=N), 1371 (O-CH3) cm-1; H NMR (CDCl3) ppm: δ 1.55 (s,
6H, 2CH3), 3.65 (s, 3H, OCH3 ester), 3.86 (s, 3H, O-CH3), 3.89 (s, 3H, OCH3), 6.13 (s, 1H, N-
H); 13C NMR (CDCl3) ppm: 25.4, 52.5, 54.8, 55.4, 56.9, 166.5, 171.7, 172.0, 173.6, 174.7 ppm.
Anal.Calcd for C10H16N4O4 (256.26): C, 46.87; H, 6.29; N, 21.86; found: C, 46.98; H, 6.41; N,
22.01; m/z found 256.32.
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2.2.6. Dimethyl 2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)succinate (6e)
o
The product was obtained as a white crystals; yield 81%; mp 97 C; IR (KBr): 3249 (NH,
amine), 1743, 1738 (CO, ester), 1612 (C=N), 1365 (O-CH3) cm-1; 1H NMR (CDCl3) ppm: δ 2.94
(dd, 1H, CHa-COOMe), 3.00 (dd, 1H, CHb-COOMe), 3.65 (s, 3H, OCH3 ester), 3.72 (s, 3H,
OCH3 ester), 3.89 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 5.00-5.03(qm, 1H, α-CH), 6.39 (d, 1H, N-
H); 13C-NMR (CDCl3) ppm: 50.1, 52.1, 52.9, 54.8, 55.4, 167.44, 171.1, 171.2, 172.2,
172.5.Anal.Calcd for C15H18N4O4 (300.27): C, 44.00; H, 5.37; N, 18.66; found: C, 44.23; H,
5.51; N, 18.89; m/z found 300.14.
2.2.7. Methyl 2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)-3-phenyl propanoate (6f)
o
The product was obtained as a white solid; yield 85%; mp102-3 C; IR (KBr): 3275 (NH,
1
amine), 1738 (CO, ester), 1628 (C=N), 1366 (O-CH3) cm-1; H NMR (CDCl3) ppm: δ 3.11 (dd,
1H, CHa-Ph), 3.20 (dd, 1H, CHb-Ph), 3.70 (s, 3H, OCH3 ester), 3.88 (s, 3H, OCH3), 3.91 (s, 3H,
OCH3), 4.96(q, 1H, α-CH), 6.00 (d, 1H, N-H); 7.10 (d, 2H, Ar-H), 7.18-7.25 (m, 3H, Ar-H); 13C
NMR (CDCl3) ppm: 38.1, 52.4, 54.8, 65.9, 127.2, 128.7, 129.3, 135.8,167.2, 171.9, 172.0,
172.4Anal. Calcd for C15H18N4O4 (318.8): C, 56.60; H, 5.70; N, 17.60; found: C, 56.89; H, 5.64;
N, 17.41; m/z found 318.76.
2.2.8. Methyl 4-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)butanoate (6g)
The product was obtained as a white crystal; yield 86%; mp 94 oC; λmax= 238 nm
1
; IR (KBr): 3262 (NH, amine), 1740 (CO, ester), 1627 (C=N), 1372 (O-CH3) cm-1; H NMR
(CDCl3) ppm: δ 1.91 (t, 2H, CH2), 2.37 (t, 2H, CH2), 3.48 (t, 2H, CH2), 3.63 (s, 3H, OCH3 ester),
3.91 (s, 3H, O-CH3), 3.95 (s, 3H, O-CH3), 6.47 (t, 1H, N-H) ppm; 13C NMR (CDCl3) ppm: 24.6,
31.2, 40.2, 51.6, 54.6, 54.7, 167.3, 171.4, 172.3, 173.5. Elemental Analysis Calcd for
C10H16N4O4 (256.26): C, 46.87; H, 6.29; N, 21.86; found: C, 47,01; H, 6.42; N, 21.73; m/z found
256.26.
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2.2.9. Methyl 3-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)propanoate (6h)
o
The product was obtained as a white crystal; yield 83%; mp126-7 C; IR (KBr): 3270 (NH,
1
amine), 1736 (CO, ester), 1628 (C=N), 1366 (O-CH3) cm-1; H NMR (CDCl3) ppm: δ 2.60 (t,
2H, CH2), 3.66 (s, 3H, OCH3 ester), 3.71 (t, 2H, CH2), 3.88 (s, 3H, OCH3), 3.93 (s, 3H, OCH3),
6.19 (t, 1H, N-H) ppm; 13C NMR (CDCl3) ppm: 33.7, 36.5, 51.8, 54.6, 54.7, 167.5, 171.5, 172.5.
Anal.Calcd for C9H14N4O4 (242.10): C, 44.63; H, 5.83; N, 23.13; found: C, 44.8; H, 5.96; N,
23.41; m/z found 242.22.
2.2.10. Dimethyl 2,2'-(4,6-dimethoxy-1,3,5-triazin-2-ylazanediyl) diacetate (6i)
o
The product was obtained as a white crystal; yield 82%; mp 92-4 C ; λmax=239 nm; IR (KBr):
1751 (CO, ester), 1565 (C=N), 1382 (O-CH3) cm-1; 1H NMR (CDCl3) ppm: δ 3.72 (s, 6H, OCH3
13
ester), 3.91 (s, 6H, O-CH3), 4.43 (s, 4H, 2 α-CH2); C NMR (CDCl3) ppm: 49.3, 52.2, 167.8,
169.8, 172.2 ppm. Elemental Analysis Calcd for C11H16N4O4 (300.27): C, 44.00; H, 5.37; N,
18.66; found: C, 44.21; H, 5.52; N, 18.89; m/z found 300.13.
3. Crystal structures determination and refinement.
Three dimensional X-ray intensity diffraction data for single crystal of the title
compounds were collected on Bruker APEX-II D8 venture Single Crystal X-ray Diffractometer
equipped with a CMOS detector. The diffractometer provides reflections of a large number of
individual planes, and their corresponding intensities were recorded electronically with the help
of a COMS camera. All non-hydrogen atoms of the molecule were located using the best E-map.
Data collection: APEX2 [37];cell refinement: SAINT[37]; data reduction: SAINT; program(s)
used to solve structure: SHELXS97 [38]; program(s) used to refine structure:
SHELXL2013[38];molecular graphics: SHELXTL [38]; software used to prepare material for
publication: SHELXTL and PLATON [39].
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4. Computational details
All calculations for the studied compounds were carried out using Gaussian 03 software
[40]. Without any symmetry restrictions and starting with the X-ray structures as input files,
geometry optimization followed by frequency calculations were performed by DFT/B3LYP
method using 6-311G(d,p) basis set. No negative vibrational modes were obtained.
GaussView4.1 has been used to draw the structures of the optimized geometries [41]. Optimized
structural parameters were used in the electronic properties and isotropic chemical shift
calculations. The charge distribution on the atomic sites was deduced using natural bond orbital
(NBO) method [42] at the DFT/B3LYP level. The nuclear magnetic resonance (NMR) chemical
shifts calculations were performed using GIAO method [43,44].
5. Results and Discussion
5.1. Synthesis
The chlorine atoms of cyanuric chloride 1 were replaced first by α-amino acid ester,
while the second and third chlorine had been replaced by two methoxy group in one step.
Accordingly, 4,6-dimethoxy,1,3,5-triazine amino acid ester derivatives were prepared by
subsequent displacement of chlorine atoms.
The first attempt was performed by the reaction of cyanuric chloride 1with methyl 4-
aminobenzoate 2 in the presence of Na2CO3and methanol as a solvent (Scheme 2). The reaction
o
was kept at 0 C for 1 h and then the temperature was increased gradually to room temperature
and kept for 3-4h at the same temperature; finally the reaction mixture was heated at 70-80 oC for
12h. The progress of the reaction was followed by TLC (ethyl acetate-hexane; 1:2). After
completion of the reaction the solvent was removed and the product 3 was purified by
9

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crystallization from dichloromethane-hexane (1:2).
Scheme 2. Synthesis of methyl 4-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)benzoate.
The 1H and 13C NMR of 3 in a good agreement with the proposed structure and with an
authentic sample obtained from the reaction of 2-chloro-4,6-dimethoxy, 1,3,5-triazine 4 with
methyl 4-aminobenzoate (Scheme 2).
Accordingly, small library of (4,6-dimethoxy-1,3,5-triazin-2-yl) amino acid ester
derivatives 6a-i were prepared by reaction of cyanuric chloride 1 with α-amino acid esters 5a-i
in presence of Na2CO3 as a scavenger for the HCl and methanol as a solvent (Scheme 3). The
reaction started by dropwise addition of cyanuric chloride to a solution of amino acid ester
o
derivatives and Na2CO3in methanol as a solvent at 0 C, and then followed the same method
described above.
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Scheme 3. Synthesis of (4,6-dimethoxy-1,3,5-triazin-2-yl) amino acid ester derivatives.
The 1H NMR spectra of 6e in CDCl3 showed two doublet of doublet (dd) peaks at δ 2.94
ppm and 3.00 ppm, corresponding to the two diastereotopic methylene protons Ha and Hb,
respectively, as shown in Figure 1. Ha showed a doublet of doublet peak caused by coupling
with the germinal proton Hb with 2J = 12.44 Hz, then with the vicinal proton Hc (α-proton) with
3J = 4.40 Hz. Similarly, Hb showed a doublet of doublet peak as a result of coupling with the
2
3
germinal proton Ha with J = 12.30 Hz, then with the vicinal proton Hc (α-proton) with J =
4.44 Hz. Also, two singlet peaks at δ 3.65 ppm and 3.72 ppm corresponding to the methyl ester
group, and another two singlet peaks at δ 3.89 ppm and 3.91 ppm corresponding to the two
methoxy groups were observed. A multiplet peak appeared at δ 5.00-5.03 ppm and δ 6.39 ppm
corresponding to the α-proton and NH respectively was observed.
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Fig. 1.Dimethyl 2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino) succinate, 6e.
1
The same behaves was observed for compound 6f,where the H NMR spectra of 6f in
CDCl3 showed two doublet of doublet (dd) peaks at δ 3.11 ppm and 3.20 ppm, corresponding to
the two diastereotopic methylene protons Ha and Hb, respectively, as shown in Figure 2. Ha
2
showed a doublet of doublet peak caused by coupling with the germinal proton Hb with J =
3
13.92 Hz, then with the vicinal proton Hc with J = 7.32 Hz. Similarly, Hb showed a doublet of
doublet peak as a result of coupling with the germinal proton Ha with 2J = 13.86 Hz, then with the
3
vicinal proton Hc with J = 5.12 Hz. Two singlet peaks at δ 3.88 ppm and 3.91 ppm
corresponding to the two methoxy groups were observed. A quartet peak appeared at δ 4.96 ppm
corresponding to the α-proton. The peaks corresponding to the aromatic protons and the NH
appeared at the expected positions.
Fig. 2. Methyl 2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)-3-phenylpropanoate, 6f.
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Samples for x-ray crystallography for compounds 6a, 6b, 6g, and 6i were obtained from
ethanol with the slow evaporation of the solvent at room temperature. The x-ray data was an
excellent tool to proof their structures.
The crystal structures of methyl 2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)acetate,
6a(Fig. 3a),methyl 2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)propanoate, 6b (Fig. 3b),, methyl
3-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)propanoate, 6g (Fig. 3c),and dimethyl 2,2'-(4,6-
dimethoxy-1,3,5-triazin-2-ylazanediyl)diacetate, 6i (Fig. 3d), with ORTEP view of the
compounds with atomic labeling are shown in Figure 3, the crystals and experimental data was
shown in Table 1.
The geometry of the molecule was determined and selected bond lengths and bond
angles are given in Tables S1-4 (Supplementary data). The packing views of the molecules in
the unit cell are shown in Figure 4.
Fig.3a.
Fig.3b
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Fig.3c
Fig.3d
Fig. 3. ORTEP representation of the crystal structures with displacement ellipsoids drawn at
40%. H atoms are shown as small spheres of arbitrary radii. (Fig.3a)Ortep of Methyl 2-(4,6-
dimethoxy-1,3,5-triazin-2-ylamino)acetate, 6a CCDC 1052720. (Fig.3b)Ortep of Methyl 2-
(4,6-dimethoxy-1,3,5-triazin-2-ylamino)propanoate, 6b CCDC 1049423. (Fig.3c)Methyl 4-
(4,6-dimethoxy-1,3,5-triazin-2-ylamino)butanoate, 6g CCDC1054326.(Fig.3d) Dimethyl 2,2'-
(4,6-dimethoxy-1,3,5-triazin-2-ylazanediyl)diacetate, 6i CCDC 1049298.
Table 1. Crystal and experimental data for compounds 6a, 6b, 6g, and 6i
Crystal data
Chemical formula C16H24N8O8
6a
6b
C18H28N8O8
484.48
6g
6i
C22H32N8O12
600.56
C10H16N4O4
Mr
456.43
256.27
Crystalsystem,
spacegroup
Temperature (K)
Triclinic, P-1 Triclinic, P1
Monoclinic, P21/n
Triclinic, P-1
150
150
100
150
10.0836 (3),
10.1723 (4),
11.0404 (4)
100.840 (1),
101.461 (1),
105.791 (1)
1032.18 (6)
2
7.4824 (3),
8.3505 (3),
9.5365 (4)
95.0509 (10),
99.9500 (11),
98.3466 (11)
576.75 (4)
1
4.4397 (2), 11.5085
(5), 23.9833 (10)
6.0102 (2), 7.9786
(3), 15.9994 (6)
a, b, c (Å)
90.918 (1), 99.893
(1), 108.815 (1)
α, β, γ (°)
90.183 (2)
V (Å3)
Z
1225.40 (9)
4
713.32 (4)
1
Radiationtype
µ (mm−1)
Mo Kα
0.12
Mo Kα
0.11
Mo Kα
0.11
Mo Kα
0.12
Crystalsize (mm) 0.58 × 0.24 × 0.62 × 0.60 ×
0.86 × 0.72 × 0.08
0.68 × 0.66 × 0.31
14

ACCEPTED MANUSCRIPT
0.12
0.934, 0.986
0.32
Data collection
Tmin, Tmax
No. of measured,
independent and
0.935, 0.965
0.912, 0.991
18778, 5940, 3062
0.074
0.926, 0.965
50791, 6325, 39733, 10980,
observed [I> 2σ(I)] 4510
14062, 3215,
3006
10622
reflections
Rint
0.037
0.020
0.018
Refinement
R[F2> 2σ(F2)],
wR(F2), S
0.046, 0.140, 0.031, 0.089,
0.067, 0.154, 1.02
0.039, 0.114, 1.01
1.03
1.06
No. of reflections 6325
No. of parameters 303
10980
323
5940
170
3215
194
No. of restraints
0
3
0
0
Δρmax, Δρmin (e Å−3) 0.32, −0.27
0.33, −0.33
0.37, −0.32
0.32, −0.20
Fig.4a
Fig.4b
15

ACCEPTED MANUSCRIPT
Fig.4c
Fig.4d
Fig. 4.The packing arrangement of 6a (Fig.4a);the packing arrangement of 6b (Fig.4b);the
packing arrangement of 6g (Fig.4c); the packing arrangement of 6i (Fig.4d).
6. Calculated Geometrical Structures
The optimized structures, the calculated bond lengths and bond angles obtained from the
DFT computations are given in Figure5 and Table 2, respectively. All structures have C1 point
group. On comparison with the experimental X-ray structure data, the root mean square
deviation (RMSD), the mean absolute deviation (MAD) and the correlation coefficient (R2)
16

ACCEPTED MANUSCRIPT
values were computed (Table 2). The small MAD and RMSD values as well as the high
correlation coefficients (R2) indicated good agreement between the calculated and experimental
geometric parameters. We noted that 6a has one weak O---H interaction with intramolecular
distance of 2.276Å (Figure5). The calculated dihedral angles of the triazine ring are calculated in
the range of 0.00-0.03˚ for the compound 6a indicating perfectly planar ring structure. In the rest
of the studied compounds, the ring dihedral angles are predicted to be higher. It is found to reach
upto 0.370, 0.355 and 0.412˚ for 6b-i, respectively. These results indicated that the deviation of
the triazine ring from planarity increased with increase the bulky of the N-substituents. It is the
maximum for 6i.
6a
6b
6g
6i
Fig. 5.The optimized molecular structure of the studied systems.
17

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Table 2: Comparison between the calculated bond distances and bond angles of the studied
compounds with the experimental X-ray structure data.
Parametera
DFT X-ray Parametera
6a
DFT X-ray Parametera
6b
DFT X-ray Parametera
6g
DFT X-ray
6i
R(1-9)
1.336
1.433
1.336
1.434
1.341
1.442
1.206
1.327
1.345
1.34
1.335
1.322
1.347
1.348
1.441
1.515
1.337 R(1-9)
1.441 R(1-19)
1.333 R(2-10)
1.448 R(2-15)
1.34 R(3-14)
1.454 R(3-27)
1.194 R(4-14)
1.333 R(5-9)
1.339 R(5-11)
1.335 R(6-9)
1.333 R(6-10)
1.322 R(7-10)
1.351 R(7-11)
1.344 R(8-11)
1.437 R(8-12)
1.518 R(12-14)
R(12-23)
1.334
1.436
1.333
1.437
1.345
1.439
1.204
1.331
1.338
1.332
1.335
1.327
1.348
1.355
1.457
1.539
1.530
1.337 R(1-9)
1.439 R(1-26)
1.332 R(2-10)
1.438 R(2-30)
1.334 R(3-21)
1.448 R(4-21)
1.207 R(4-22)
1.334 R(5-9)
1.354 R(5-11)
1.327 R(6-9)
1.343 R(6-10)
1.322 R(7-10)
1.350 R(7-11)
1.338 R(8-11)
1.454 R(8-12)
1.529 R(12-15)
1.524 R(15-18)
R(18-21)
1.334
1.434
1.334
1.436
1.205
1.351
1.439
1.327
1.350
1.335
1.332
1.330
1.341
1.353
1.457
1.534
1.527
1.514
1.335 R(1-17)
1.441 R(1-18)
1.338 R(2-17)
1.450 R(3-25)
1.202 R(3-26)
1.343 R(4-25)
1.445 R(5-11)
1.323 R(5-30)
1.357 R(6-12)
1.336 R(6-34)
1.331 R(7-11)
1.334 R(7-13)
1.353 R(8-11)
1.331 R(8-12)
1.454 R(9-12)
1.525 R(9-13)
1.525 R(10-13)
1.498 R(10-14)
R(10-22)
1.346
1.441
1.204
1.346
1.441
1.204
1.334
1.433
1.334
1.433
1.332
1.344
1.330
1.330
1.332
1.344
1.364
1.447
1.447
1.523
1.524
1.333
1.456
1.193
1.336
1.443
1.199
1.333
1.443
1.329
1.443
1.324
1.349
1.333
1.336
1.327
1.349
1.347
1.450
1.450
1.516
1.511
R(1-20)
R(2-10)
R(2-24)
R(3-15)
R(3-16)
R(4-15)
R(5-10)
R(5-11)
R(6-9)
R(6-10)
R(7-9)
R(7-11)
R(8-11)
R(8-12)
R(12-15)
R(14-17)
R(22-25)
(MAD,RMSD) Å 0.005, 0.007
0.006, 0.008
0.995
0.007, 0.009
0.994
0.007, 0.009
0.995
R2
0.998
118.1
A(9-1-20)
A(1-9-6)
117.4 A(9-1-19)
119.3 A(1-9-5)
113.4 A(1-9-6)
118.4 A(10-2-15)
113.4 A(2-10-6)
118.7 A(2-10-7)
116.7 A(14-3-27)
124.4 A(3-14-4)
110.0 A(3-14-12)
125.6 A(4-14-12)
113.3 A(9-5-11)
127.8 A(5-9-6)
125.2 A(5-11-7)
118.9 A(5-11-8)
112.3 A(9-6-10)
127.3 A(6-10-7)
114.0 A(10-7-11)
115.8 A(7-11-8)
123.0 A(11-8-12)
113.1 A(8-12-14)
A(8-12-23)
117.7
114.4
118.7
117.9
114.4
119.3
115.8
124.1
111.1
124.7
113.5
126.9
125.7
116.8
113.5
126.4
113.9
117.5
124.9
112.6
113.6
117.6 A(9-1-26)
117.9
119.2
114.1
117.6
118.7
114.4
123.5
125.9
115.7
110.7
113.8
126.7
125.5
118.1
113.4
126.9
113.7
116.4
125.1
114.3
117.2 A(17-1-18)
115.9
124.3
109.7
126.0
115.8
124.3
109.8
125.9
118.1
118.8
114.2
118.1
114.2
118.8
114.3
127.0
124.5
117.8
113.0
127.0
114.3
117.7
114.5
118.6
114.7
117.9
114.5
118.8
115.9
124.5
110.6
124.9
113.6
126.7
125.9
117.5
113.6
126.7
113.6
116.6
123.8
109.0
113.3 A(1-9-5)
118.6 A(1-9-6)
117.2 A(10-2-30)
112.9 A(2-10-6)
119.8 A(2-10-7)
116.0 A(3-21-4)
124.5 A(3-21-18)
110.9 A(21-4-22)
124.4 A(4-21-18)
113.1 A(9-5-11)
128.0 A(5-9-6)
125.1 A(5-11-7)
116.7 A(5-11-8)
112.4 A(9-6-10)
127.3 A(6-10-7)
114.0 A(10-7-11)
118.2 A(7-11-8)
123.7 A(11-8-12)
112.4 A(8-12-15)
119.2 A(1-17-2)
112.9 A(1-17-14)
116.9 A(2-17-14)
119.1 A(25-3-26)
113.3 A(3-25-4)
122.6 A(3-25-22)
126.0 A(4-25-22)
115.3 A(11-5-30)
111.4 A(5-11-7)
113.7 A(5-11-8)
127.9 A(12-6-34)
124.6 A(6-12-8)
118.5 A(6-12-9)
112.4 A(11-7-13)
127.5 A(7-11-8)
113.8 A(7-13-9)
117.0 A(7-13-10)
123.2 A(11-8-12)
112.5 A(8-12-9)
112.3 A(12-9-13)
113.2 A(9-13-10)
123.6
111.5
124.9
115.5
125.0
109.4
125.6
117.9
119.4
113.1
117.9
113.0
119.6
113.3
127.5
125.8
116.8
112.8
127.4
113.2
117.4
118.8
119.9
120.5
111.0
113.0
109.5
109.4
A(1-9-7)
A(10-2-24)
A(2-10-5)
A(2-10-6)
A(15-3-16)
A(3-15-4)
A(3-15-12)
A(4-15-12)
A(10-5-11)
A(5-10-6)
A(5-11-7)
A(5-11-8)
A(9-6-10)
A(6-9-7)
A(9-7-11)
A(7-11-8)
A(11-8-12)
A(8-12-15)
114.2 A(12-15-18) 113.3
106.1 A(15-18-21) 113.1
A(13-12-14) 104.7
A(13-12-23) 108.7
A(14-12-23) 111.4
106.1 A(4-21-18)
111.3 A(9-5-11)
A(5-9-6)
110.7
113.8
126.7
125.5
118.1
113.4
126.9
113.7
116.4
125.1
114.3
111.4 A(13-10-14) 121.0
113.7 A(13-10-22) 120.9
127.9 A(14-10-22) 118.2
124.6 A(10-14-17) 112.8
118.5 A(10-22-25) 112.7
112.4 A(15-14-17) 108.7
127.5 A(16-14-17) 108.9
113.8
117.0
123.2
112.5
112.3
113.2
A(5-11-7)
A(5-11-8)
A(9-6-10)
A(6-10-7)
A(10-7-11)
A(7-11-8)
A(11-8-12)
A(8-12-15)
A(12-15-18) 113.3
A(15-18-21) 113.1
(MAD,RMSD) ˚
0.9, 1.2
0.975
0.7, 0.9
0.990
0.7, 0.9
0.988
0.8, 1.0
0.999
R2
18

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6.1.Atomic Charge distribution
The atomic charges obtained using NBO calculations were collected in Table 3. All
hydrogen atoms have positive charge densities where the NH protons are the most
electropositive H-atoms. For compounds 6a-g, the natural charge values at the NH-proton are in
the range 0.3989-0.4179. It has the least charge value for 6a probably due to the intramolecular
N-H…O interaction. The O and N-atoms possesses the highest negative natural charge values of
the O-atoms, the carbonyl O-atoms have the most negative charge values. Since the O- and N-
atoms are more electronegative than carbon atoms, so all carbon atoms bonded to these high
electronegative atoms are predicted to have positive charges. The most electropositive C-atoms
are those lying in between three strong electronegative atoms. For example, the C9, C10 and C11
of 6a have the highest positive charge values (0.6419-0.7855). In case of 6a, the charge values at
the N5, N6 and N7-atoms of the triazine ring are calculated to be -0.6191, -0.6820 and -0.5961,
respectively while the corresponding N7, N6 and N5-atoms of 6b have natural charges of -
0.6648, -0.6326 and 0.6105, respectively. Two of these N-atoms are shifted to more negative
natural charges due to varying the substituent. Similar conclusions were predicted for 6g and 6i.
Molecular electrostatic potential (MEP) indicates the net electrostatic effect produced at a
point by the total charge distribution of the molecule. It correlates with the dipole moment,
electronegativity, partial charge and chemical reactivity of the molecules. It provides a visual
method to depict the size, shape, charge density and the sites of chemical reactivity of the
molecules. The molecular electrostatic potential (MEP) Maps shown in Figure 6 were used to
visualize the atomic charge density distribution of 6a-g.MEP values increase in the order red <
orange < yellow < green < blue. The MEP Map showed the most negative (red) regions around
the carbonyl oxygen and N atoms while the maximum positive (blue) regions are localized on
19

ACCEPTED MANUSCRIPT
the hydrogen atoms of the NH group. MEP regions with red are the most suitable for
electrophilic attack. In contrast, the blues spaces represent the sites of the highest reactivity
towards the nucleophilic attack [45]. MEP is used to understand the relative polarity of the
molecule. The dipole moment of the studied compounds is 1.9528D (6a), 1.5229 D (6b), 2.2394
D (6g) and 4.8758 D (6i). We could conclude that 6i which has the largest number of
heteroatoms has the highest polarity.
Table 3 The calculated natural atomic charge densities of the studied compounds.
Atom
NAC
Atom
NAC
Atom
NAC
Atom
NAC
6a
6b
6g
6i
O1
O2
O3
O4
N5
N6
N7
N8
C9
C10
C11
C12
H13
H14
C15
C16
H17
H18
H19
C20
H21
H22
H23
C24
H25
H26
H27
H28
-0.5037 O1
-0.5044 O2
-0.5407 O3
-0.6066 O4
-0.6191 N5
-0.6820 N6
-0.5961 N7
-0.5882 N8
-0.5038 O1
-0.5028 O2
-0.5481 O3
-0.6031 O4
-0.6015 N5
-0.6326 N6
-0.6648 N7
-0.5925 N8
0.7747 C9
-0.5031 O1
-0.5050 O2
-0.6021 O3
-0.5518 O4
-0.6642 O5
-0.6343 O6
-0.6069 N7
-0.5988 N8
0.7867 N9
-0.5484
-0.6018
-0.5483
-0.6019
-0.4999
-0.4998
-0.6651
-0.5775
-0.6650
-0.4311
0.7812
0.7812
0.6744
-0.2836
0.2558
0.2288
0.8271
-0.2017
0.1821
0.1782
0.1802
-0.2832
0.2548
0.2297
0.8269
-0.2017
0.1820
0.1783
0.1801
-0.1976
0.1813
0.1749
0.1754
0.7802 C 9
0.7855 C10
0.6419 C11
-0.2730 C12
0.2226 H13
0.2226 C14
0.8322 C15
-0.2014 H16
0.1835 H17
0.1805 H18
0.1805 C19
-0.1968 H20
0.1804 H21
0.1750 H22
0.1750 C23
-0.1970 H24
0.1800 H25
0.1756 H26
0.1756 C27
0.4179 H28
H29
0.7895 C10
0.6522 C11
-0.0882 C12
0.2170 H13
0.8352 H14
-0.1990 C15
0.1800 H16
0.1756 H17
0.1843 C18
-0.1977 H19
0.1786 H20
0.1791 C21
0.1786 C22
-0.5749 H23
0.1971 H24
0.2110 H25
0.2148 C26
-0.2003 H27
0.1817 H28
0.1771 H29
0.1791 C30
0.4037 H31
H32
0.7737 N10
0.6471 C11
-0.1678 C12
0.1854 C13
0.2099 C14
-0.3820 H15
0.2035 H16
0.2110 C17
-0.4857 C18
0.2137 H19
0.2221 H20
0.8416 H21
-0.2020 C22
0.1801 H23
0.1772 H24
0.1781 C25
-0.1974 C26
0.1803 H27
0.1783 H28
0.1755 H29
-0.1976 C30
0.1781 H31
0.1787 H32
0.1786 H33
H30
H31
H33
20

ACCEPTED MANUSCRIPT
H34
0.3989 C34
-0.1976
0.1812
0.1747
0.1757
H35
H36
H37
Fig. 6: Molecular Electrostatic potentials (MEP) mapped on the electron density surface
calculated by the DFT/B3LYP method for the studied compounds.
Frontier molecular orbitals (FMOs) and Electronic absorption spectra
The HOMO and LUMO are also called frontier molecular orbital since they lie at the
outermost electron boundaries of the molecules. The HOMO and LUMO energy levels are found
21

ACCEPTED MANUSCRIPT
related to the nucleophilic and electrophilic characters of compound, respectively. Also, they
have great importance in describing the electronic transitions and excitation properties of
molecules. The orbital energy level analysis of the studied compounds showed EHOMO values of -
6.6500, -6.6851, -6.6287 and - 6.6097 eV and ELUMO values of -0.2874, -0.2868, -0.1837 and -
0.2732, for compounds 6a-i, respectively (Figure S5; Supplementary data).As a result, 6g has the
lowest electrophilic behavior (electron acceptor) while 6i is the most nucleophilic one (electron
donor). Also the negative values of the HOMO and LUMO energies indicate the stability of the
studied systems [46].
It is well known that; the lower the energy gap between the FMOs, the more ease the
electronic transition. The energy gap is predicted to be 6.3626, 6.3983, 6.4451 and 6.3365 eV for
6a-i, respectively. This energy gap characterizes the stability and explains the eventual charge
transfer interactions occurring within the compounds. The high values of the energy gaps
indicated the high stability of the systems towards electron transfer where 6g is the most stable
one. The HOMO and LUMO plots drawn by DFT-B3LYP method is shown in Figure S5;
Supplementary data. Since the distribution of the HOMO and LUMO levels are mainly localized
over the π-system of the molecules so the lowest energy transition belongs mainly to π→π*
transition.
The theoretically computed electronic spectra of the studied compounds are given in
Table S6 (Supplementary data) while the experimentally measured electronic spectra were
shown in Figure S7 (Supplementary data). The most important electronic transitions are shown
in bold in this Table. Of the most intense transition bands predicted, the longest wavelength band
at 198.1 nm (f=0.1389), 204.2 nm (f=0.2053), 205.0 (f=0.1704) and 205.7 (0.2971) for
compounds 6a-i, respectively were considered. Experimentally these bands were detected at 231
22

ACCEPTED MANUSCRIPT
nm, 234 nm, 238 nm and 239 nm, respectively. The red shift of the experimental wavelengths
compared to the calculated values could be attributed to the solvent effect. The molecular orbital
energy levels involved in the above mentioned electronic transitions and their major
contributions are shown in Figure 7.
Fig. 7: The molecular orbital contributed in the longest wavelength transition band of the studied
compounds.
23

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6.2. Chemical reactivity
According to Pearson, [47,48] many electronic aspects of molecule such as
electronegativity (χ), chemical potential (μ), chemical hardness (η), global softness (S) and
global electrophilicity index (ω) could be calculated using the energies of the frontier molecular
orbitals [49-51]. These chemical reactivity descriptors could be used for describing the different
pharmacological aspects of drug molecules. Based on the molecular orbital calculations of the
studied compounds, these reactivity descriptors are given in Table 4. Almost, the studied
molecules have very close reactivity. The most significant results are the negative chemical
potential values which indicate the stability of molecules. The chemical hardness is in the order
6g>6b>6a>6i. From this point of view the hardest molecule is 6g while the softest one is 6i.
Based on the results given in Table 4, 6b has the highest electrophilicity index so it has higher
electrophilic behavior compared to the others [52].
Table 4: The calculated global reactivity descriptors of the studied compounds
Descriptor
6a
6b
6g
6i
I
A
χ
μ
η
s
6.6500
0.2874
3.4687
-3.4687
3.1813
0.1572
1.8910
6.6851
0.2868
3.4859
-3.4859
3.1991
0.1563
1.8992
6.6287
0.1837
3.4062
-3.4062
3.2225
0.1552
1.8002
6.6097
0.2732
3.4415
-3.4415
3.1682
0.1578
1.8691
ω
6.3. Natural bond orbital analysis
The NBO calculations were used to calculate the stabilization energies E(2) due to
electron delocalization processes occurred in the investigated structures. This gives indication on
the strength of the intramolecular charge transfer (ICT) in the studied molecules. High E(2) value
indicates strong electron delocalization from the donor NBO to acceptor one [53,54]. The most
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important ICT interactions and their stabilization energies were presented in Table 5. The π→π*
electron delocalization causing stabilization of the system upto 47.68, 44.62, 45.05 and 45.70
kcal/mol for compounds 6a-i, respectively. The maximum stabilization in the studied systems
due to the π→π* ICT is for 6a as it has the most planar triazine ring. Strong n→π* ICT from the
lone pair of the amine nitrogen atom to the adjacent π*-orbital of the C=N bond of the triazine
ring. This ICT leads to maximum stabilization of the system by 66.56 kcal/mol for 6a. Moreover,
the stabilization of the system due to the n→σ* ICT from the LP(O) of the carbonyl O-atom to
σ*(C-O) and σ*(C-N) anti-bonding orbitals having maximum E(2) values of 32.42 kcal/mol for
6g. It is clear that, the ICT interaction energies due to the electron delocalization from the
LP(2)O4 of the carbonyl group to the BD*(1)N8-H28 is very small (0.72 kcal/mol) indicating
the weak N-H…O intramolecular interaction in 6a.
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Table 5: The stabilization energy E(2) (kcal/mol) occurred within the studied systems using
B3LYP/6-311G(d,p) method.
E(2)
E(2)
Donor NBO (i) Acceptor NBO (j)
Donor NBO (i) Acceptor NBO (j)
6b
kcal/mol
kcal/mol
6a
BD(2)N5-C11
BD(2)N6-C10
BD(2)N7-C9
LP(2)O1
LP(2)O2
LP(2)O3
LP(1)N8
LP(2)O4
LP(2)O4
LP(1)N5
LP(1)N5
BD*(2)N6-C10
BD*(2) N7-C9
BD*(2)N5-C11
BD*(2)N7-C9
BD*(2)N6-C10
BD*(2)O4-C15
BD*(2)N5-C11
BD*(1)O3-C15
BD*(1)C12-C15
BD*(1)N6-C10
BD*(1)N7-C11
BD*(1)N5-C0
BD*(1)N7-C9
BD*(1)N5-C11
BD*(1)N6-C9
BD*(1)N8-H28
6g
47.68
41.21
39.23
42.96
45.57
49.16
66.56
31.10
18.98
11.19
11.34
10.45
10.21
11.60
11.52
0.72
BD(2)N5-C11
BD(2)N6-C9
BD(2)N7-C10
LP(2)O1
LP(2)O2
LP(2)O3
LP(1)N8
LP(2)O4
LP(2)O4
LP(1)N5
LP(1)N5
BD*(2)N 6-C 9
BD*( 2)N7-C10
BD*(2)N5-C11
BD*(2)N6-C9
BD*(2)N7-C10
BD*(2)O4-C14
BD*(2)N5-C11
BD*(1)O3-C14
BD*(1)C12-C14
BD*(1)N6-C9
BD*(1)N7-C11
BD*(1)N5-C9
BD*(1)N7-C10
BD*(1)N5-C11
BD*(1)N6-C10
44.62
43.16
38.09
45.44
46.37
46.03
59.93
31.76
20.36
11.02
12.13
10.96
10.86
10.73
10.55
LP(1)N6
LP(1)N6
LP(1)N7
LP(1)N7
LP(1)N6
LP(1)N6
LP(1)N7
LP(1)N7
LP(2)O4
6i
BD(2)N5-C9
BD(2)N6-C10
BD(2)N7-C11
LP(2)O1
LP(2)O2
LP(2)O4
LP(1)N8
LP(2)O3
LP(2)O3
LP(1)N5
LP(1)N5
BD*(2)N7-C11
BD*(2)N5-C9
BD*(2)N6-C10
BD*(2)N5-C9
BD*(2)N6-C10
BD*(2)O3-C21
BD*(2)N7-C11
BD*(1)O4-C21
BD*(1)C18-C21
BD*(1)N6-C9
BD*(1)N7-C11
BD*(1)N5-C9
BD*(1)N7-C10
BD*(1)N5-C11
BD*(1)N6-C10
37.93
43.14
45.05
45.70
45.17
46.89
62.50
32.42
18.68
10.77
10.77
10.88
10.92
11.97
11.06
BD(2)N7-C 11 BD*(2)N9-C13
40.97
45.70
43.96
43.15
45.90
47.75
64.97
47.72
31.83
19.77
31.82
19.77
10.50
11.01
11.48
11.48
11.01
10.50
BD(2)N8-C12
BD(2)N9-C13
LP(2)O6
LP (2)O5
LP(2)O3
LP(1)N10
LP(2)O1
LP(2)O2
LP(2)O2
LP(2)O4
LP(2)O4
LP(1)N7
LP(1)N7
LP(1)N8
LP(1)N8
LP(1)N9
LP(1)N9
BD*(2)N7-C11
BD*(2)N8-C12
BD*(2)N8-C12
BD*(2)N7-C11
BD*(2)O4-C25
BD*(2)N9-C13
BD*(2)O2-C17
BD*(1)O1-C17
BD*(1)C14-C17
BD*(1)O3-C25
BD*(1)C22-C25
BD*(1)N8-C11
BD*(1)N9-C13
BD*(1)N7-C11
BD*(1)N9-C12
BD*(1)N7-C13
BD*(1)N8-C12
LP(1)N6
LP(1)N6
LP(1)N7
LP(1)N7
6.4. IR Vibrational Spectra
The theoretical and experimental IR spectra of the studied molecules are shown in Figure
8 and Figure S8 (Supplementary data). The calculated wave numbers and intensities of 6a-i
obtained from the B3LYP/6-311G(d,p) method were collected in Table S9 (Supplementary
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Information). Since the calculated frequencies are in general overestimate the experimental data
so the vibrational frequencies calculated at B3LYP/6-311G(d,p) level of theory were scaled by
0.9670 in order to correct the calculated harmonic frequencies[55].Generally, the scaled infrared
vibrational frequencies showed good agreement with the experimental data. Figure 9 showed
good correlations between the calculated and the experimental wave numbers (R2= 0.9961-
0.9995).The IR fundamental modes were collected and assigned in Table 6. Herein the
descriptions of the most important modes were presented.
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Fig. 8: The calculated scaled [39] infrared vibrational spectra of the studied compounds.
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