Synthesis, click reaction, molecular structure, spectroscopic and DFT computational studies on 3-(2,6-bis(trifluoromethyl)phenoxy)-6-(prop-2-yn-1-yloxy)phthalonitrile

Article abstract of DOI:10.1016/j.molstruc.2016.01.078

The compound 3-(2,6-bis(trifluoromethyl)phenoxy)-6-(prop-2-yn-1-yloxy)phthalonitrile has been synthesized and confirmed by different characterization techniques such as elemental analysis, IR, UV-vis spectroscopy, and X-ray single-crystal determination. The molecular geometry from X-ray determination of this compound in the ground state has been compared using the Hartree-Fock (HF) and density functional theory (DFT) with the 6-31G(d) basis set. This compound reacted with sugar azide via click reaction to form triazol ring. The synergy between carbohydrate molecule and fluorinated organic compound achieved novel synthetic pathways, properties, and applications in chemistry science.

Full text of DOI:10.1016/j.molstruc.2016.01.078

Accepted Manuscript
Synthesis, Click reaction, Molecular structure, Spectroscopic and DFT computational
studies on 3-(2,6-bis(trifluoromethyl)phenoxy)-6-(prop-2-yn-1-yloxy)phthalonitrile
Muhammad Hasan, Mona Shalaby
PII:
S0022-2860(16)30078-3
10.1016/j.molstruc.2016.01.078
MOLSTR 22194
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 15 October 2015
Revised Date: 27 January 2016
Accepted Date: 27 January 2016
Please cite this article as: M. Hasan, M. Shalaby, Synthesis, Click reaction, Molecular structure,
Spectroscopic and DFT computational studies on 3-(2,6-bis(trifluoromethyl)phenoxy)-6-(prop-2-yn-1-
yloxy)phthalonitrile, Journal of Molecular Structure (2016), doi: 10.1016/j.molstruc.2016.01.078.
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ACCEPTED MANUSCRIPT
Synthesis, Click reaction, Molecular structure, Spectroscopic
and
DFT
computational
studies
on
3-(2,6-
bis(trifluoromethyl)phenoxy)-6-(prop-2-yn-1-
yloxy)phthalonitrile
*
Muhammad Hasan and Mona Shalaby
Department of Chemistry, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait
13
1
KEYWORDS Fluorinated phthalonitrile, FT-IR, FT-Raman, C and H NMR, Click chemistry, and DFT.
*
Corresponding author. Tel.: +96599686945; fax: +96524816482.
E-mail address: m.hasan@ku.edu.kw.
ABSTRACT:
The compound
3-(2,6-bis(trifluoromethyl)phenoxy)-6-(prop-2-yn-1-
yloxy)phthalonitrile has been synthesized and confirmed by different
characterization techniques such as elemental analysis, IR, UV-vis
spectroscopy, and X-ray single-crystal determination. The molecular
geometry from X-ray determination of this compound in the ground state
has been compared using the Hartree-Fock (HF) and density functional
theory (DFT) with the 6-31G(d) basis set. This compound reacted with sugar
azide via click reaction to form triazol ring. The synergy between
carbohydrate molecule and fluorinated organic compound achieved novel
synthetic pathways, properties, and applications in chemistry science.
phthalonitrile. In order to overcome this problem, a
terminal alkyne was prepared to represent a new building
block for further preparation of versatile functionalized
phthalonitriles. Superior combination of fluorine
substituents with other functional groups in their
structures, such as sugars led to novel molecules possessing
outstanding phototoxicity in both in vitro and in vivo
studies. [6]
The Huisgen 1,3-dipolar cycloaddition reaction of organic
azides and alkynes has gained considerable attention in
recent years due to the using of Cu(1) as a catalyst by
Tornøe and Meldal,[7, 8] leading to a major improvement
in both rate and regioselectivity for the click reaction.[9, 10]
Huisgen click reaction is using here to functionalize
phthalonitrile with sugar molecule. Two advantages could
appears from functionalizing the photosensitizers with
carbohydrates substituent, in addition to water-solubility: a
potential selective recognition by the targeting cancer cells
and an increased uptake due to the high energy
requirements of cancer cells that consume much more
carbohydrate than other cells, as it is a readily available
energy source.[11] In recent years, density functional theory
(DFT) has been a shooting star in theoretical modeling.
Many important chemical and physical properties of
Introduction
Phthalonitrile is considered as petals of a dye molecule
which form a ring around an atom to create a flower-like
dye molecule called phthalocyanine.[1] This unique
reaction is but one of the fascinating properties that make
phthalonitrile so promising for producing an important
class of molecules with various application possibilities in
sensors, catalysis, non-linear optics (NLO), optical data
storage, photodynamic cancer therapy (PDT), bio-imaging
and nanotechnology .[2-5] These leads to developments of
new synthetic efforts for enlarge the access to new
derivatives.
The insertion of fluorine atom to the phthalocyanine
precursor may enrich the pharmacokinetic features,
lipophilicity, and high level of singlet oxygen production
and selective accumulation of photosensitizer in tumor
cells which make from this photosensitizer potential entity
for photodynamic therapy. Noteworthy, the fluorinated
compounds possess a remarkable magnetic resonance
which constitutes excellent probe for sensitive and
minimally invasive imaging. [6] Unfortunately, the initial
attempts for synthesizing di-substituted phthalonitrile
didn't succeed and gave only
a
monosubstituted

ACCEPTED MANUSCRIPT
biological and chemical systems can be predicted by
various computational techniques.[12]
collected by filtration and washed several times with
distilled water, then dry in oven and recrystallized by Ethyl
acetate (EA)/ n-hexane to give white crystals yield (1 gm,
Vibrational studies for the precursor molecules are
considered important and extremely valuable when
performing these studies on larger composite molecular
Systems. [13]
In this paper, we designed fluorinated phthalonitrile with
terminal alkyne and grafted by carbohydrate azide. This
phthalonitrile can used for the preparation of
unsymmetrical phthalocyanines, which has become the
focus of interest [14] as well as the theoretical studies on
the phthalonitrile with terminal alkyne by using the HF/6-
−
1
58.82 %). Mp: 219.9 °C; IR (KBr) ν/cm : 3277.43 (OH),
1
2251.49 (CN); HNMR (400 MHz, DMSO), δ/ppm: 6.97 (1H,
d, H ); 7.23(1H, d, H ); 7.83(1H, t, H ); 8.26(2H, d, H );
ar
ar
ar
ar
13
11.85(1H, br, OH). C NMR (DMSO), δ/ppm: 156.95 (O-C-
Ar); 153.09 (O-C-Ar); 147.57 (O-C-Ar); 133.01 ,132.98, 132.95,
132.91 (C-Ar); 128.51 (C-CF3); 124.96 (C-Ar); 124.80, 124.59,
124.38, 124.16 ( CF ); 123,41, 123.15 (C-Ar) ; 121.90, 121.34 (C-
3
*
Ar) ; 113.62, 112.69 (C≡N); 102.14, 100.52 (C -CN). Anal. Calcd
(%) for C H F N O : C 51.63; H 1.62; N 7.53. Found: C 51.77;
16
6
6
2
2
3
1G(d) and DFT/B3LYP/6-31G(d) methods.
H 1.71; N 7.55.
-(2,6-bis(trifluoromethyl)phenoxy)-6-(prop-2-yn-1-
yloxy)phthalonitrile (4) to solution of 3-(2,6-
bis(trifluoromethyl)phenoxy)-6-hydroxyphthalonitrile (3, 1
gm, 2.6 mmol) in dry acetone (20 ml) anhydrous
3
Experimental and theoretical methods
General Procedures. Among the starting materials, 2,3-
a
Dicyano-1,4-hydroquinone,
2,6-Bis-
potassium carbonate (K2CO3, 1.8 gm , 5 equiv) was added,
and the mixture was refluxed, then propagyl bromide (1 ml)
was added drop by drop while refluxing. The resulting
mixture was stirred and refluxed for 20 h. the mixture was
cooled and evaporated under vacuum and then add water
with stirring then filter. The crude product was purified
with column chromatograph on silica gel eluted with
(
2
trifluoromethyl)fluorobenzene, 1,4-dihydroxynaphthalene-
,3-dicarbonitrile, 3-Bromoprop-1-yne 80% w/w in toluene
were purchased from Sigma-Aldrich, Matrix Scientific and
Alfa Aesar and used directly without further purification.
Sugar azide was synthesized according to the literature
method.[15-17] TLC was performed using Polygram sil
G/UV 254 TLC plates and visualization was carried out by
ultraviolet light at 254 nm and 350 nm. Column
chromatography was performed using Merck silica gel 60 of
mesh size 0.040–0.063 mm. Anhydrous solvents were either
supplied from Sigma-Aldrich and used as they were
Dichloromethane (DCM): n-hexane (3:5, v/v)
to
give a white ppt, which was recrystallized by DCM/ n-
hexane. Yield: (0.8 gm , 72.72 %). Mp: 151.2 °C; IR (KBr)
−
1
ν/cm :
2
3300(C≡C-H),3083.62,
3056.62
(
C-H ),
ar
1
1
234.13(C≡N), 2131.92 (C≡C); HNMR (400 MHz, DMSO)
received or dried as described by Perrin. [18] The H NMR
and C NMR Spectra (400 MHz) were recorded using
Bruker DPX 400 and IR spectra were obtained from Jasco
13
δ/ppm: 8.30 (2H, d, H ); 7.87 (1H,t, H ); 7.57(1H, d, H );
ar
ar
ar
1
3
7
2
.26(1H, d, Har); 5.08 (2H, d, CH ), 3.75 (1H, s, HC=C). C
NMR (DMSO), δ/ppm: 155.07 (O-C-Ar); 154.22 (O-C-Ar);
47.31 (O-C-Ar); 133.02 (C-Ar); 128.68 (C-CF3); 124.94 (C-
Ar); 124.70, 124.48, 124.27 , 124.06 ( CF ); 123.13 (C-Ar) ;
6
300 FTIR. UV–Vis studies were done on a Varian Cary 5
1
spectrometer and Shimadzu UV-2401Pc
spectrophotometer. Elemental analyses were carried out
using Elementar Vario Micro Cube. Mass analyses were
done by electron impact (EI) on a Thermo DFS mass
spectrometer. A high resolution mass analysis (HRMS) was
measured on Xevo G2-S QTof. Differential scanning
calorimetry (DSC) analyses were carried out on Shimadzu
DSC-50. Single crystal data collections were made on a
Bruker X8 Prospector using filtered Cu- Kα radiation. The
diffraction data were collected at room temperature.
Raman spectra and images were obtained using a confocal
microprobe Raman system (Invia, Renishaw). Ar laser (514
nm) was used for compound (4) and Diode (Semi-
conductor) laser (785 nm) for compound (8) for the Raman
measurement. The laser power at the sample was 10% for
compound (4) and 100% for compound (8). Typical
exposure time for cell measurement was 20 s for compound
3
1
1
;
21.64, 121.31, 120.97 (C- Ar) ; 112.84, 112.25 (C≡N); 103.81,
*
*
2
03.28 (C -CN); 79.99 (H-C ≡C-); 77.48 (C≡C-H); 57.71 (CH )
+
m/z (EI) = 410.1 [M ]; Anal. Calcd (%) for C H F N O : C
19
8
6
2
2
55.62; H 1.97; N 6.83, Found: C 55.58; H 2.07; N 6.76
;
TOF-
+
ES-MS: found (m/z) 411.0583 [M+H] , calcd for
+
C19H9N2O2F6 (m/z) 411.0568 [M+H] .
Synthesis of glucose with spacer. The synthesis
protocol of the glucose spacer was performed in three steps
according to literatures [15-17]
1,2,3,4,6-penta-O-acetyl-β-D-gulcopyranoside
was synthesized as in literature. [15]
(5)
(2-chloroethyl)-2,3,4,6-tetra-O-acetyl-β-D-
glucopyranoside (6) was synthesized as in literature [16]
with some modification. 1,2,3,4,6-penta-O-acetyl-β-D-
gulcopyranoside (5, 5 gm, 12.8 mmol) was dissolved in 100
(
4) and 1 s for compound (8). The laser spot was focused on
the sample surface using a long working distance x100
objective. Raman spectra were collected on numerous spots
on the sample and recorded with Renishaw CCD camera.
Syntheses.
ml dry DCM with adding molecular sieves 4
Å (2.5 gm). 2-
iodoethanol was added drop wisely to the pervious mixture
with stirring at room temperature for 0.5 h. The resulting
reaction mixture was cold at 0 °C in ice bath. BF3.etherate
(4 ml) was added drop wisely then the reaction mixture was
stirred at room temperature over night. After completion
K2CO3 (2.37 gm) was added and allowed to stir for 5 min.
Filter the salt and the reaction mixture extracted with 200
ml of water two times. DCM solution was collected and
dried over anhydrous sodium sulfate, filter and then
evaporated the solution. The crude product was purified
using column chromatograph on silica gel eluted with EA:
3
-(2,6-bis(trifluoromethyl)phenoxy)-6-
hydroxyphthalonitrile (3) To a stirred solution of 2,3-
Dicyano-1,4-hydroquinone (1, 1gm, 6.2 mmol) and
anhydrous potassium carbonate ( 4.3 gm, 5 equiv) in dry N-
Methyl-2-pyrrolidone (NMP) under nitrogen atmosphere,
2
,6-Bis-(trifluoromethyl)fluorobenzene (2, 1.4 gm, 1 equiv)
was added drop wisely. The reaction mixture was heated at
30 °C for 24 h. Then after being cooled, it was poured into
acidic distilled water and the resulting precipitate was
1

ACCEPTED MANUSCRIPT
1
result without any constraints. The DFT calculations with a
n-hexane (1:1, v/v). Yield: (2.5 gm, 39.06 %). HNMR (400
MHz, CDCl3) δ/ppm: 5.42 (1H, d); 5.280 (1H, dd); 5.06 (1H,
dd); 4.55 (1H, d); 4.22(1H, dd), 4.14 (2H, m), 3.954 ( 1H, t),
hybrid functional B3LYP (Becke’s three parameter hybrid
functional using the LYP correlation functional) with the 6-
31G(d) basis set and Hatree-Fock calculations with the 6-
3
.83 (1H, m), 3.31 (2H, m); 2.18, 2.12, 2.08, 2.01 (12H, s). m/z
+
31G(d) basis set using the Berny method[19, 20] were
performed with the Gaussian 09W program. [21] The
harmonic vibrational frequencies were calculated at the
same level of theory for the optimized structures and the
obtained frequencies were scaled by 0.9613 and 0.8929. [22]
Vibrational band assignments were made using the Gauss-
View molecular visualisation program. [23] The electronic
absorption spectra were calculated using the time-
dependent density functional theory (TD-DFT) and
Hartree- Fock (TD-HF) methods [24-27] in gas phase in
addition to the solvent (chloroform) effect which
stimulated using the polarizable continuum model
(
EI) = 442.1 [M -OAc].
(
2-azidoethyl)-2,3,4,6-tetra-O-acetyl-β-D-
glucopyranoside (7) was synthesized as in literature. [17]
(
2S,3S,5R)-2-(acetoxymethyl)-6-(2-(4-((4-(2,6-
bis(trifluoromethyl)phenoxy)-2,3-
dicyanophenoxy)methyl)-1H-1,2,3-triazol-1-
yl)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate
(
8) alkynylphthalonitrile (4, 0.4 gm, 0.975 mmol) dissolved
in 20 ml chloroform then add Copper iodide(I) (1 eq, 0.185
gm) and N,N-Diisopropylethylamine (DIPEA , 6 eq, 1.67
gm) to the solution with stirring. Sugar aztide (7, 1.5 eq,
(
PCM).[28-30] To investigate the reactive sites of the
compound (4) the molecular electrostatic potential was
0.61 gm) was then added to the solution and refluxed
evaluated using the B3LYP/6-31G(d) method.
overnight. After completion, the reaction mixture was
washed with ammonium hydroxide solution then washed
two times with water and the organic phase was collected
and dried over sodium sulfate. The solution was evaporated
and the crude product purified by chromatograph on silica
gel eluted with EA: n-hexane (1:1, v/v). Yield: (0.2 gm, 25
1
13
For NMR calculations, after optimization, H and C NMR
chemical shifts were calculated using the gauge-invariant
atomic orbital (GIAO) method [31, 32] in DMSO. The GIAO
method is one of the most common approaches for
calculating nuclear magnetic shielding tensors. The GIAO
approach allows the computation of the absolute chemical
shielding due to the electronic environment of the
individual nuclei and this method is often more accurate
than those calculated with other approaches for the same
−
1
%
). Mp: 73.1
C≡N), 1752.98 ( C=O); HNMR (400 MHz, DMSO) δ/ppm:
.309 (2H, d, H ); 8.161 (1H, s, triazole-CH); 7.875 (1H, t,
̊C ; IR (KBr) ν/cm : 3097.12(C≡C-H), 2237.02
1
(
8
ar
H ); 7.798 (1H, d, H ); 7.243 (1H, d, H ), 5.391 (1H, s), 5,229
1
13
ar
ar
ar
basis set size. The H and C NMR chemical shifts were
converted into the TMS scale by subtracting the calculated
absolute chemical shielding of TMS the values of which are,
respectively, 32.59 and 199.98 ppm for HF/6-31G(d).
(
1H, t), 4.925 (1H, t), 4.876 (1H, d), 4.750 (1H, t), 4.598 (2H,
m), 4.165(2H, m), 4.053 (2H, m), 3.971 (2H, m), 2.106, 2.002,
+
1
.901, 1.866 (12H, 5s, 5x OC(O)CH3); m/z (EI) = 827.0 [M ];
+
TOF-ES-MS: found (m/z) 828.1939 [M+H] , calcd for
+
C35H32N5O12F6( m/z ) 828.1952 [M+H] .
Results and Discussion
Synthesis. The direct reaction between 2,3-dicyano-1,4-
hydroquinone
(1)
and
2,6-Bis-
(
trifluoromethyl)fluorobenzene
(2) produce
mono-
substituted fluorinated phthalonitrile precursor (3) instead
of forming di-substituted fluorinated phthalonitrile as
shown in scheme (1). The propargylation of phenolic
hydroxyl groups using propargyl bromide through an
aromatic nucleophilic substitution (SN ) mechanism such
Ar
as compound (4) is particularly important because of being
a terminal alkyne moiety can be used as a prospective
component for “click chemistry” along with an organic
azide (7). Grafting carbohydrates on to this precursor via
click reaction offers several advantages for the resulting
photosensitiser: besides the hydrophilicity of such moieties
which aids delivery in aqueous systems, potential selective
recognition and enhanced cell uptake by cancer cells
having elevated receptor densities for these species are
possible.
Scheme 1. Reagents and conditions. (i) NMP, anhydrous
K2CO3, 130 °C, 24 h; (ii) acetone, propagyl bromide,
2 3
anhydrous K CO , reflux, 24 h; (iii) Acetic anhydride,
CH COONa; (iv) CH Cl , iodoethanol, BF .OEt ; (v) DMF,
3
2
2
3
2
Description of the Crystal Structure. The crystal
structure of compound (4) is shown in Fig. 1a and selected
bond distances and angles are summarized in Table 2. The
compound (4) crystallizes in the monoclinic space group P
3
NaN , 80°C; (vi) chloroform, CuI, reflux, 24 h.
Crystal structure determination and refinement.
Single crystals of phthalonitrile 4 suitable for X-ray diffraction
technique were grown by solvent diffusion method. A summary
of the key crystallographic information is given in Table 1.The
ball and stick representation of crystal structure derived from 4
is depicted in Fig. 1.
1
21/n 1 with eight molecules in the unit cell. A great
attention has been focus to understand the nature of short
contacts involving halogens of the type C-X…X (where X =
F, Cl, Br, I) and contacts of the type C-X…O, C-X…N, and C-
X…H (where X= C, N, O).[33-40] Such contacts have been
known for some time in crystallographic literature, wherein
Computational Methods. The molecular geometry was
taken directly from the X-ray diffraction experimental

ACCEPTED MANUSCRIPT
a short contact between two atoms, A and B, signifies that
C16 is 82.8, C1-O1-C7-C12 is 100.2, C1-O1-C7-C8 is -87.2
which confirms that the dihedral angles between the
phenyl ring containing phthalonitrile functional groups are
more or less 90 degrees to the plane of those phenoxy and
alkynoxy substituents. The 3-dimensional packing structure
of this molecule, viewing along a-, b- and c- directions are
given in Fig. 2.
the distance A…B is less than the sum of the van der Waals
radii.[39] Regarding the crystal structure of compound (4)
there is short contact shown in fig. 1c. between C15…F5,
N1…H3, O1…C17 and F5…H15A. This phthalonitrile linked by
an O atom, forming non-planar molecular structure. The
calculated torsion angles of the chain of atoms C4-O2-C15-
Table 1. Crystal data and refinement parameters for
compound (4)
Table 2. Selected structural parameters by X-ray and
theoretical calculations for compound (4)
Formula
C19H8F6N2O2
410.27
Experimental Calcd.
Formula weight (g)
Temperature (K)
Wavelength
Crystal system
Space group
Unit cell dimensions
a, b, c (Å)
296(2) K
HF
DFT/B3LYP
1.54178 Å
Monoclinic
P 1 21/n 1
Bond lengths
Å)
F1-C13
F3-C13
F5-C14
O2-C4
(
1.312(7)
1.311(7)
1.308(4)
1.358(3)
1.376(3)
1.142(3)
1.158(5)
1.437(5)
0.97
1.393(3)
1.433(3)
1.379(4)
1.362(6)
1.379(4)
0.93
1.32267
1.31612
1.32443
1.34237
1.36206
1.13496
1.18600
1.47316
1.08398
1.39223
1.44177
1.38983
1.38200
1.38158
1.07219
1.51003
0.14219
179.455
113.347
110.435
125.093
118.884
119.134
119.853
120.586
115.818
119.725
120.513
119.178
119.420
120.479
107.433
120.038
107.404
179.711
2.717
1.35006
1.34324
1.35409
1.35836
1.37645
1.16274
1.20677
1.46422
1.09869
1.41017
1.42975
1.40207
1.39261
1.39270
1.08362
1.51233
0.15362
7.9163(2), 18.0585(4) , 12.7302(3)
O1-C1
β(°)
90.087(2)°
1819.86(7)
4
N1-C18
C17-C16
C16-C15
C15-H15B
C4-C5
C5-C18
C7-C12
C10-C9
C3-C2
3
Volume (Å )
Z
_
3
Calculated density (g cm
)
1.497
_
1
)
µ (mm
1.243
F(0, 0,0)
824
Crystal size (mm)
θ Ranges (°)
Index ranges
0.050 x 0.150 x 0.250
4.25 - 66.38°
-9<=h<=9
C2-H2
1.480(6)
C8-C13
Max.
difference
a
180.0
112.9(3)
109.0
179.223
113.756
109.826
125.277
119.281
119.402
119.477
120.706
115.510
119.733
120.399
119.571
119.432
120.389
107.460
120.470
107.435
179.765
2.831
Bond angles (ᵒ)
C16-C17-H17
C16-C15-O2
O2-C15-H15B
O2-C4-C3
C3-C4-C5
-
-
21<=k<=21
14<=l<=14
126.0(2)
119.3(2)
120.7(2)
119.9(2)
119.8(2)
114.8(2)
119.3(3)
123.2(3)
119.9
118.9(3)
121.6(4)
105.5(6)
119.8
Reflections collected
20082
Independent reflections
3165 [R(int) = 0.0427]
2456
C4-C5-C18
C1-C6-C5
Reflection observed (I > 2σ)
Absorption correction
Refinement method
multi-scan
C5-C6-C19
O1-C1-C6
C12-C7-O1
C7-C12-C14
C3-C2-H2
C9-C8-C7
2
Full-matrix least-squares on F
3165 / 0 / 262
1.046
Data/restrains/parameters
2
Goodness-of-fit on F
Final R indices [Ih2r(I)]
R indices (all data)
0.0590
C7-C8-C13
F3-C13-F2
C10-C9-H9
F4-C14-F5
N1-C18-C5
Max.
106.9(3)
177.9(3)
0.0757
_
3
)
Largest diff. Peak and hole (e A
0.417 and -0.321
a
difference
a
Maximum differences between the bond lengths and angles computed using
theoretical methods and those obtained from X-ray diffraction.

ACCEPTED MANUSCRIPT
(
a)
(b)
(c)
Fig.1. (a) The ball and stick representation of crystal structure 4, (b) unit cell, (c) short contact
(a)
(b)
(c)
Fig.2. 3-dimensional packing pattern of compound (4) along (a) a-, (b) b- and (c) c- directions
Optimized structure
The atomic numbering scheme for the title crystal is shown
in fig.1 a. B3LYP/6-31G(d) and HF/6-31G(d) calculations were
performed on compound (4) and a selected calculated
geometric parameters are listed in Table 3 along with the
experimental data. The molecular structure of this
compound is not planar. A superposition of the molecular
structure of compounds as established by quantum
mechanical calculations and X-ray study shows an excellent
agreement as seen in Fig. 3. Comparing the theoretical data
with the experimental ones indicates that optimized bond
lengths and angle values are slightly different with the
experimental results. The largest difference between
experimental and calculated DFT bond length is 0.15362 Å for
CF3 groups. The aromatic structure shows the presence of
-
1
C−H stretching vibrations in the region 2900–3150 cm ,
which is the characteristic region for the C−H stretching
vibrations. The C-H aromatic stretching mode was observed
‒
1
at 3083.62 cm experimentally, and calculated at 3087.27
‒
1
‒1
cm for B3LYP and at 3019.93 cm for HF. The experimental
‒1
C N stretching mode was observed at 2234.13cm as a strong
≡
band, which have been calculated at 2258.71 cm for B3LYP
and 2330.34 cm for HF. In the phthalonitrile, the C
stretching modes were observed to be 2232 - 2237cm [13]
‒1
‒1
≡
N
‒1
‒1
and 2230 cm [42] as experimentally. The C
vibrations have a characteristic region 2100–2260cm . The
experimental C C stretching mode was observed at 2131.92
cm as a weak band, which have been calculated at 2153.74
≡
C stretching
‒1
≡
‒1
(
C2–H2), whereas this difference for HF method is 0.14219 Å
‒1
‒1
for (C2–H2), which suggest that the calculation precision is
satisfactory. These theoretical results indicate that the HF
method gives geometric parameters, which are much closer
to experimental ones. Similar situation is also observed for
calculated bond angles with HF and DFT method.
cm for B3LYP and 2154.41 cm for HF. The identification of
C−O and CF3 vibrations is a very difficult task, since the
mixing of several bands are possible in this region. The band
‒
1
observed at 994.12 cm in FT-IR spectrum is assigned to C–O
‒1
stretching vibration and calculated at 977.26 cm for B3LYP
‒1
and 905.36 cm for HF while the band observed at 1061.62
‒1
IR and Raman frequencies
cm in FT-IR spectrum is assigned to CF3 stretching
‒1
IR and Raman frequencies of compound (4) were calculated
using the DFT/B3LYP and HF methods with the 6-31G (d)
basis set. The vibrational band assignments were made using
the Gauss-View molecular visualisation program. Figure 4
and 5 shows the observed and calculated IR and Raman
spectra of this compound. Calculated vibrational frequencies
of compound (4) at DFT/B3LYP and HF levels were scaled by
vibration and calculated at 1044.60 cm for B3LYP and
‒1
1056.30 cm for HF. It should be noted that the calculations
were made for a free molecule in vacuum, while the
experiments were performed for the solid samples.
Moreover, two factors may be responsible for the
discrepancies between the experimental and computed
spectra of this compound. The first is caused by the
environment and the second reason for these discrepancies is
the fact that the experimental value is an anharmonic
0.96 and 0.89, respectively. [41] The experimental FT-IR
spectrum of the title compound is shown in Fig. 4. The IR
spectra contain some characteristic bands of the stretching
frequency
while
the
calculated
value
is
a
vibrations of the C−H, C N, C C, C−O and
≡
≡

ACCEPTED MANUSCRIPT
(
a)
(b)
Fig. 3. Atom-by-atom superimposition of the 3-(2,6-bis(trifluoromethyl)phenoxy)-6-(prop-2-yn-1-yloxy)phthalonitrile calculated
a = HF (red); b = B3LYP (blue) over the X-ray structure (black).
1
harmonic frequency. [43, 44] In FT-Raman spectrum, the
Table 3. H chemical shift values are calculated to be 2.752–
8.325 ppm B3LYP/6-31G(d) level, while the experimental
-
1
vibration mode at 2234.073 cm is corresponding to
stretching mode of C N group. The calculated vibration by
B3LYP is 2258.88 and by HF are 2334.47 cm . The second
≡
-
1
-1
characteristic vibration mode at 2132.77 cm
is
corresponding to stretching mode of C C group. The
≡
-1
calculated vibration by B3LYP is 2155.20 cm and by HF are
-
1
2
158.25 cm .
Fig.5. Observed and calculated FT-Raman spectra of 3-(2,6-
bis(trifluoromethyl)phenoxy)-6-(prop-2-yn-1-
yloxy)phthalonitrile.
results are observed to be 3.755–8.306 ppm. The atom
positions were numbered as in Fig. 1. It is clear from Table 3
that the agreement with experimental data is good. The
Fig.4. Observed and calculated FT-IR spectra of 3-(2,6-
bis(trifluoromethyl)phenoxy)-6-(prop-2-yn-1-
yloxy)phthalonitrile.
13
largest differentiation in C chemical shifts is observed for
1
3
1
C(13) and C(14), amounting to about 10 ppm while, the
differentiation in H NMR is observed for H(17) about 1.003
C and H NMR calculations
1
1
13
The experimental H and C NMR spectra of compound (4)
are shown in Fig. 6. GIAO H and C chemical shift values
were calculated using the DFT/B3LYP method with 6-
ppm . The terminal alkynyl carbons C(16) and C(17) are
coupled at 77.48 and 79.99 ppm respectively, whereas the
1
13
1
3
corresponding values are 77.748 and 82.288 ppm. C NMR
spectra of the compound show signals at 112.84 and 112.25
ppm due to the C(18) and C(19) atoms of the cyano groups.
These signals were calculated at 115.538 and 115.257 ppm.
1
13
C
3
1G(d) basis set and generally compared with H and
chemical shift values. The calculated results are given in

ACCEPTED MANUSCRIPT
The chemical shift value of C(13) and C(14) atoms bounded
UV–vis spectrum and electronic properties
the trifluoromethyl group is observed as quartet at 124.70
ppm, whereas the corresponding value is 135.436 and
The electronic absorption spectra of the compound (4) in
chloroform solvent were recorded within the 200 - 600 nm
range and representative spectrum is shown in Fig. 5. As
can be seen from the figure, electronic absorption spectra
of this compound show three bands at 240, 333, and 341
nm. Electronic absorption spectra of compound (4) were
calculated using the TD-DFT and TD-HF methods based on
the B3LYP/6-31G(d) and HF/6-31G(d) level optimized
structure in gas phase, respectively. For the TD-HF
calculations, the absorption wavelengths are obtained at
1
35.465 ppm for B3LYP level. As can be seen from Table 3,
1
13
the theoretical H and C chemical shift results for
compound (4) are generally closer to the experimental H
and C shift data.
1
13
1
13
Table.3 Theoretical and experimental H and C isotropic chemical
shifts (with respect to TMS, all values in ppm) for compound (4).
Atom
Experim
Calculat-
ed(ppm)
B3LYP 6-
31G(d)
Atom
Experi-
mental
(ppm)
Calculat
ed (ppm)
B3LYP
-
(
(
ental
ppm)
DMSO)
1
57.95, 176.44, and 242.29 nm. It is obvious that these bands
are not corresponding to the experimental results, which
shows that to use TD-HF method here to predict the
electronic absorption spectra is not reasonable. For TD-
DFT calculations, the theoretical absorption bands are
predicted at 199.72, 224.84 and 312.75 nm and it can easily
be seen that they are corresponding to the experimental
absorption ones. In addition to the calculations in gas
phase, TD-DFT calculations of this compound in
chloroform solvent were performed using the PCM model
are obtained at 230 and 323 nm.
(DMSO)
6-31G(d)
C1
C4
C7
155.07
154.22
147.31
161.368
160.168
152.614
136.980
136.969
135.465
135.436
133.778
133.767
131.838
126.439
123.886
115.538
115.257
111.087
111.008
82.288
H11
H9
H10
H3
H2
H15B
8.306
8.286
7.873
7.578
7.269
5.081
8.325
8.321
8.105
7.723
6.938
5.410
5.079
2.752
C11 133.02
C9 133.02
C14 124.70
C13 124.70
H15A 5.077
H17 3.755
C8
128.68
C12 128.68
C10 124.94
C2
C3
C18 112.84
C19 112.25
C5
C6
1
.2
1
123.13
121.64
0.8
103.81
103.28
0
0
.6
.4
C17 79.99
C16 77.48
C15 57.71
77.748
65.922
0.2
0
2
35
335
435
Wavelength/ nm
A
Fig. 7. UV-vis spectrum of the studied compound in
chloroform solution.
The experimental and computed electronic values, such as
absorption wavelength, excitation energies, frontier orbital
energies, and oscillator strengths are tabulated in Table 4.
The frontier orbitals are important in determining the
electric and optical properties, as well as in UV–vis spectra
and chemical reactions.[45, 46] Fig.
6 shows the
distributions and energy levels of the HOMO-1, HOMO,
LUMO and LUMO+1 orbitals computed at the B3LYP/6-
31G(d) level for compound (4). From Fig. 6, the HOMO is
mainly localized on the phthalonitrile ring and oxygen as
well as cyano group. The LUMO are localized on
phthalonitrile ring. The value of the energy separation
between the HOMO and LUMO is 4.328 eV.
B
Table
4 Experimental and calculated wavelengths λ (nm),
excitation energies (eV), oscillator strengths (f) and major
contributions in chloroform solution for compound (4)
Exp. (in
chlorofor
B3LYP/DFT
(in
Major contributions
E (eV)
f
-
(
m) λ
nm)
chloroform)
λ (nm)
230
1
13
240
H-3→L, H-2→L,H-1→L+2,
H→L+3
H→L, H-2→L+3
5.400
3.833
0.7508
0.1889
Fig.6. The experimental (A) H NMR and (B) C spectra of
compound (4).
3
3
33
41
323

ACCEPTED MANUSCRIPT
reactivity.[51] The MEP at the B3LYP/ 6-31G(d) optimized
geometry was calculated to predict the reactive sites for
electrophilic and nucleophilic attack for the investigated
molecule. The total electron density mapped with
electrostatic potential surface and the electrostatic
potential contour maps are shown in Fig. 8a and b,
respectively. The different values of the electrostatic
potential at the surface are represented by different colors.
Potential increases in the order red < orange < yellow <
green < blue. The color code of these maps is in the range
between -0.05976 a.u (deepest red) to 0.05976 a.u (deepest
blue) for the investigated compound. As can be seen from
the figure, this molecule has two possible sites for
electrophilic attack. Negative regions are mainly localized
over the N1 and N2 atoms of the cyano groups while; the
maximum positive region is localized on the C17-H17 bond,
indicating a possible site for nucleophilic attack.
LUMO+1 (-1.379 ev)
LUMO (-2.318 ev)
Click reaction
Placing terminal alkynyl group on phthalonitrile facilitate
alkyne-azide click chemistry. The click reaction serves as a
new approach for incorporation of a new functional group
to get a new compound with new physical properties. With
this approach, the original preparation of terminal-
alkynylphthalonitrile was accomplished using the
nucleophilic displacement reaction between 3-(2,6-
bis(trifluoromethyl)phenoxy)-6-hydroxyphthalonitrile and
propagyl bromide to give the target ‘clickable’ compound
HOMO-1 (-7.661 ev)
HOMO(-6.646 ev)
Fig. 8. Molecular orbital surfaces and energy levels using the
DFT/B3LYP method for the, HOMO, HOMO−1, LUMO and LUMO
+
1 of compound(4).
Molecular electrostatic potential maps
The MEP is related to the electronic density and is very
important for describing and determining the sites for
electrophilic and nucleophilic reactions as well as hydrogen
bonding interactions.[47, 48] The importance of MEP is
due to the displaying of molecular size, shape as well as
positive, negative and neutral electrostatic potential
regions in terms of color grading (Fig. 8a) and it is a very
useful tool in research of molecular structure with its
physiochemical property relationship. [49, 50] The negative
regions (red and yellow) were related to electrophilic
reactivity and the positive (blue) ones to nucleophilic
(
4). Click reaction between terminal-alkynyl substituted
phthalonitrile and (2-azidoethyl)-2,3,4,6-tetra-O-acetyl-β-
D-glucopyranoside form triazole ring. The experimental
evidence for this reaction is described as follow:
Accurate mass measurement
The resulting compound (8) from click reaction could be
identified by means of exact mass measurement (Fig. 10).
This
compound
shows
a
remarkable
pattern.
-0.05976 a.u
0.05976 a.u
(a)
(b)
Fig.9. (a) The total electron density mapped with electrostatic potential of compound (4). (b) The contour surface of electrostatic potential of
compound (4).

ACCEPTED MANUSCRIPT
Conclusion
In this paper, we designed fluorinated phthalonitrile
with terminal alkyne grafted by carbohydrate azide as
well as the theoretical studies on this fluorinated
phthalonitrile with terminal alkyne compound by
using the HF/6-31G(d) and DFT/B3LYP/6-31G(d)
methods. A good agreement between experimental and
calculated normal modes of vibrations has been
observed. Grafting carbohydrates on to this precursor
via click reaction offers several advantages for the
resulting asymmetrical photosensitiser: besides the
increasing possibility in the hydrophilicity for such
compounds which aids delivery in aqueous systems,
potential selective recognition and enhanced cell
uptake by cancer cells for these species are possible.
Fig. 10. ESI-Q-TOF product ion scans of 8 (m/z =
28.1939).
8
Acknowledgement
FT-IR and FT Raman measurements
The infrared and Raman spectra of this compound are
compared in Fig. 11. FT-IR shows the presence of C≡N
The author acknowledges the support of this work by
the Research Administration of Kuwait University,
under the Grant Number SC02/14, the facilities of GFS
(Chemistry Department, GS01/05, GS02/10, GS01/01,
-1
stretching vibration in the region at 2237.02 cm and
-1
ester group at 1758.76 cm . The FT Raman band found
GS03/08, GS01/10 and GS01/03).
-
1
at 2237 and 1761.86 cm due to the stretching vibration
of C N and ester group, respectively.
≡
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ACCEPTED MANUSCRIPT
Highlights
•
The spectroscopic properties of the compound were investigated by DFT
method.
•
•
The DFT theoretical results were compared experimental results.
Click reaction between terminal-alkynyl substituted phthalonitrile and (2-
azidoethyl)-2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside to form triazole
ring.