Synthesis, Characterization, and Computational Studies of Selenium Derivatives of 3,5-Dichloropyridine

Article abstract of DOI:10.1002/jhet.2804

A methodology that can be tailored to incorporate selenium at the C-2 or C-4 position of 3,5-dichloropyridine (1) was developed. For this, the lithiation of 1 with and without prior boron trifluoride complexation was utilized. The use of 1.3 equiv of LDA in the reaction did not give the desired product; however, the use of 2.3 equiv of LDA successfully inserted selenium into the C─Li bond. The observed regioselectivity in these reactions has been explained in light of relative stability of the lithiated species formed in dimethyl ether solution. Quantum chemical analysis was used to calculate the deprotonation energy and pK_a values and correlated with the observed regioselectivity. Theoretical analysis (B3LYP/6-311++G(d,p)) of the synthesized compounds was performed to predict the effect of structural variations on the molecular properties of pyridylselenium derivatives. Various thermodynamic parameters and HOMO-LUMO energies in the gas and solvent phases were calculated. When compared with 1, the insertion of selenium into a pyridine moiety drastically reduces the HOMO-LUMO energy gap, which clearly explains photochemical liability of selenium-containing pyridine derivatives. The ¹H- and ¹³C-NMR chemical shifts were also calculated by using gauge-including atomic orbital method, and the results were validated with the experimental data.

Full text of DOI:10.1002/jhet.2804

Month 2017
Synthesis, Characterization, and Computational Studies of Selenium
Derivatives of 3,5-Dichloropyridine
a
b
c
Neha Sharma, Avtar Singh, and Jaspreet S. Dhau *
a
Department of Chemistry, Punjabi University, Patiala 147002, India
b
Department of Chemistry, Sri Guru Teg Bahadur Khalsa College, Anandpur Sahib 140118, India
c
Department of Chemistry, Florida Polytechnic University, Lakeland, FL 33805, USA
*
E-mail: jdhau@flpoly.org
Additional Supporting Information may be found in the online version of this article.
Received July 19, 2016
DOI 10.1002/jhet.2804
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A methodology that can be tailored to incorporate selenium at the C-2 or C-4 position of 3,5-
dichloropyridine (1) was developed. For this, the lithiation of 1 with and without prior boron trifluoride
complexation was utilized. The use of 1.3 equiv of LDA in the reaction did not give the desired product;
however, the use of 2.3 equiv of LDA successfully inserted selenium into the C─Li bond. The observed
regioselectivity in these reactions has been explained in light of relative stability of the lithiated species
formed in dimethyl ether solution. Quantum chemical analysis was used to calculate the deprotonation energy
and pK
a
values and correlated with the observed regioselectivity. Theoretical analysis (B3LYP/6-311++G
(
d,p)) of the synthesized compounds was performed to predict the effect of structural variations on the molec-
ular properties of pyridylselenium derivatives. Various thermodynamic parameters and HOMO-LUMO ener-
gies in the gas and solvent phases were calculated. When compared with 1, the insertion of selenium into a
pyridine moiety drastically reduces the HOMO-LUMO energy gap, which clearly explains photochemical
1
13
liability of selenium-containing pyridine derivatives. The H- and C-NMR chemical shifts were also
calculated by using gauge-including atomic orbital method, and the results were validated with the
experimental data.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
3,5-dichloropyridine (1) both in the presence and
absence of boron trifluoride etherate (BF .Et O) and
3
2
Although a variety of substituted and unsubstituted
pyridylselenium compounds have been reported in the
literature [1–5], to the best of our knowledge, there
is no report on the selenium derivatives of
have successfully inserted a selenium atom into the
C─Li bond of lithiated 3,5-dichloropyridine.
In addition, the present study attempts to develop
quantum computation models, using Hartree-Fock (HF)
and Density Functional Theory (DFT) methods to
study HOMO-LUMO energy gap, thermodynamic
3
,5-dichloropyridine. This, in part, may be due to
nonavailability of a suitable synthetic methodology.
Therefore, we thought of developing a methodology
that could be tailored to incorporate selenium atom(s)
at different positions in 3,5-dichloropyridine. The
lithiation of mono-, di-, and tri-halopyridines is well
developed and documented in literature [6–9]; however,
these methodologies fail to incorporate selenium into
the C─Li bond [10]. We have explored the lithiation of
1
parameters, and spectroscopic properties such as H-
1
3
and C-NMR spectra of the synthesized compounds.
The results of spectroscopic properties have been
computed and validated with the experimental data.
The impact of structural variations on the molecular
properties of the pyridylselenium compounds has been
reported.
©
2017 Wiley Periodicals, Inc.

N. Sharma, A. Singh, and J. S. Dhau
Vol 000
RESULTS AND DISCUSSION
Scheme 1. Synthesis of selenium derivatives of 3,5-dichloropyridine
through boron trifluoride complexation of 1.
Synthesis of selenium derivatives of 3,5-dichloropyridine
with and without prior boron trifluoride complexation.
Reaction of 1 with boron trifluoride etherate (BF .Et O) in
3
2
THF at 0°C gave
a white suspension of 3,5-
dichlorpyridine-BF adduct (2). Reaction of 2 with 1.2
3
equiv of LDA at ꢀ78°C gave a red solution indicating the
formation of a carbanionic species. Elemental selenium
was added to this solution. The reaction mixture was
slowly brought to room temperature and stirred from 30 to
4
5 minutes. Contrary to the expectation, most of the
selenium remained unreacted which suggests failure of
selenium insertion into the C─Li bond. Hydrolysis of the
reaction mixture followed by usual work-up procedure
from 1.2 to 2.3 equiv, and it was found that there was a
substantial increase in the yield of products formed
(Table 1, entry 4). All these suggest preferential lithiation
afforded 3,3′,5,5′-tetrachloro-2,2′-bipyridine (3),
a
of C-2 position in the BF -complexed 3,5-dichloropyridine.
3
coupled product of 1, as the only product in a 40% yield.
Similar result was obtained when lithiation of 1 was
attempted without the use of BF .Et O. Again, most of
The above result was corroborated with quantum
chemical analysis. First, deprotonation energy (DPE) and
pK values of BF -complexed 1were calculated at the
3
2
a
3
the selenium powder remained unreacted, and a coupled
product of 1 was obtained in a 58% yield (Table 1, entry
C-2, C-4, and C-6 positions (Fig. 1a). The result obtained,
shown in Table 2, indicates that the most favorable site
for deprotonation and the most acidic position is the C-4
position, which does not explain the observed
regioselectivity. Next, the relative stability of lithiated
species at different positions was calculated. The results
indicate that the lithiated species at the C-2 position is the
most stable species (Table 3), confirming the experimental
observations. From the results depicted in Table 3 and
Figure 2, it can be inferred that thermodynamic stabilities
of the lithiated species play a major role in dictating the
product formation rather than the pKa or the C─H
dissociation process. A strong coordination between the
2
). It appears that insertion of selenium into the C─Li
bond is a slow process, and the lithiated species formed in
the reactions react preferentially with each other or with
unreacted starting material to form the dimers.
The dilithiation of 1 was attempted to check this
hypothesis. Treatment of 3,5-dichloropyridine-BF adduct
3
with 2.3 equiv of LDA at ꢀ78°C gave a dark reddish
solution. Elemental selenium (1.2 equiv) was added to the
reaction mixture, and the solution was slowly brought to
room temperature. At this temperature, all of the selenium
got dissolved which indicated successful incorporation of
the selenium atom into the C─Li bond, resulting in the
formation of the corresponding selenolate anion. This is
contrary to the earlier experiments where most of the
selenium remained unreacted. The reaction of the
selenolate anion with iodomethane (1.2 equiv) gave two
products, 3,5-dichloro-2-(methylselenenyl)pyridine (4)
and 3,5-dichloro-2,6-bis(methylselenenyl)pyridine (5) in
lithium (on α-carbon) and the fluoride of BF , leading to
3
the formation of a 5-member chelating ring (Fig. 2), is the
major contributor to the observed regioselectivity.
Synthesis of C-4-substituted selenium derivatives of
3,5-dichloropyridine. The reaction of 1 with LDA (2.2
equiv) at ꢀ78°C afforded a dark reddish solution which
on quenching with elemental selenium followed by
treatment with iodomethane (1.2 equiv) furnished 3,5-
dichloro-4-(methylselenenyl)pyridine (6) and 3,5-
2
8% and 12% yields, respectively (Scheme 1). In a
different reaction, the amount of electrophile was increased
Table 1
Synthesis of Selenium Derivatives of 3,5-Dichloropyridine.
Entry
BF
3
·Et
2
O (equiv)
Lithiating reagent (equiv)
Electrophile (equiv)
Product
1
2
3
4
5
6
7
8
1.1
–
1.1
1.1
–
–
–
–
LDA (1.2)
LDA (1.2)
LDA (2.2)
LDA (2.2)
LDA (2.2)
LDA (2.2)
LDA (2.2)
LDA (2.2)
Se + CH
Se + CH
Se + CH
Se + CH
Se + CH
Se + CH
3
3
3
3
3
3
I (1.2)
I (1.2)
I (1.2)
I (2.3)
I (1.2)
I (2.3)
Coupled product (40%)
Coupled product (58%)
4 (28%), 5 (12%)
4 (34%), 5 (20%)
6 (39%),7 (17%)
6 (46%), 7 (23%)
8 (39%)
Se + C
2
H
5
I (2.3)
Cl (2.3)
Se + PhCH
2
9 (49%)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis, Characterization, and Computational Studies of Selenium Derivatives
of 3,5-Dichloropyridine
Figure 1. Three-dimentional view of (a) boron trifluoride-complexed 3,5-dichloropyridine (2) and (b) 3,5-dichloropyridine (1). [Color figure can be
viewed at wileyonlinelibrary.com]
Table 2
3
Deprotonation Energy (DPE) Studies on 3,5-Dichloropyridine (1) and its Coordinated Complexes with BF (2).
3
,5-Dichloropyridine
3,5-Dichloropyridine-BF
3
Site of deprotonation
DPE (kcal/mol)
pK
a
DPE (kcal/mol)
pK
a
C-2
C-4
C-6
342.36
327.12
342.36
1.47
1.20
1.47
320.53
314.31
320.53
1.08
0.98
1.08
Table 3
dichloro-2,4-bis(methylselenenyl)pyridine (7) in 39% and
17% yields, respectively (Scheme 2). The isolation of
these 2 products clearly shows that the first attack of LDA
on 1 takes place at the C-4 position, and the second attack
takes place at the C-2 position. It was observed that with
the increase in the amount of electrophile from 1.2 to 2.3
equiv, there was a substantial increase in the yield of
products (Table 1, entries 6). The use of iodoethane and
Relative Stability of the Lithiated Species of 1and 2.
Relative stability
Lithiation
site
Lithiated 3,5-
dichloropyridine
Lithiated 3,5-
dichloropyridine-BF
3
C-2
C-4
C-6
8.30
0
8.30
0
1.30
0
(
chloromethyl)benzene, instead of iodomethane, exclusively
afforded 3,5-dichloro-4-(ethylselenenyl)pyridine (8) and
-(benzylselenenyl)-3,5-dichloropyridine (9), respectively
Table 1, entries 7 and 8). All these results indicate that C-4
4
(
is the preferred lithiation site in the case when the lithiation
is carried out in the absence of BF ·Et O. The results
3
2
obtained here were corroborated through quantum chemical
analysis. The deprotonation energy and pKa values of
uncomplexed 1 were calculated at the C-2, C-4, and C-6
positions (Fig. 1b). The result obtained, shown in Table 2,
indicates that the most favorable site for deprotonation and
the most acidic position is the C-4 position. The relative
stability of lithiated species at different positions also
indicates that the lithiated species at the C-4 position is the
most stable species (Table 3). All these results are in well
agreement with the experimental findings.
Spectral studies. All the synthesized compounds were
1
13
characterized by elemental analysis, NMR ( H and C),
Figure 2. Optimized structure of lithiated 2 showing Li─F interaction.
Color figure can be viewed at wileyonlinelibrary.com]
1
[
and mass spectral techniques. The H-NMR spectrum of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Sharma, A. Singh, and J. S. Dhau
Vol 000
Scheme 2. Synthesis of C-4 selenium derivatives of 3,5-dichloropyridine.
Table 4
1
13
Experimental and Theoretical Probable H- and C-NMR Chemical
Shifts of 4.
Experimental
Theoretical
B3LYP
1
3
Atom
C-NMR
HF
C1
C2
C3
C4
C5
C12
147.3
128.2
136.1
134.2
157.9
6.4
168.3
132.0
140.3
128.6
150.3
13.5
153.9
125.7
121.3
123.1
133.0
7.7
1
H-NMR
8.40
8.30
HF
9.6
8.9
3.0
B3LYP
8.6
H7
H10
H(CH
7.7
2.5
4
8
showed two singlets in the aromatic region at δ 8.30 and
.40 ppm corresponding to H-4 and H-6 protons,
3
)
2.46
respectively. The signal corresponding to ─SeCH3
protons appears as a singlet at δ 2.46 ppm. In the
diselenated product, 5, a singlet appeared in the aromatic
region at δ 7.36 ppm. Due to the symmetrical nature of
the molecule, only a singlet peak corresponding to six
protons of two ─SeCH3 units was observed at δ
Table 5
1
13
Experimental and Theoretical Probable H- and C-NMR Chemical
Shifts of 5.
Experimental
Theoretical
B3LYP
13
Atom
C-NMR
HF
2
.49 ppm. In the spectrum of 6, only one singlet is seen
C1
C2
C3
C4
C5
C10
C16
152.6
127.4
134.1
127.4
152.6
6.0
162.2
140.3
141.2
140.3
162.2
15.6
149.9
133.8
123.4
133.8
149.9
9.2
at δ 8.41 ppm due to two hydrogens attached to C-2 and
C-6 carbons indicating their electronic equivalency. The
structure of 3,5-dichloro-2,4-bis(methylselenenyl)pyridine
(
7) was established by the appearance of two peaks
flanked by selenium satellites, one at δ 2.47 ppm and the
6.0
15.6
9.2
other at δ 2.46 ppm due to two ─SeCH units attached to
3
1
H-NMR
HF
2.9
9.0
2.9
B3LYP
2.5
the C-2 and C-4 positions of the pyridine ring.
H11
H14
H17
2.4
7.3
2.4
13
In the C-NMR spectrum of 4, five signals corresponding
to aromatic carbons appear at δ 157.9, 147.3, 136.1, 134.2,
and 128.0 ppm. The signal due to C-6 is the most downfield
due to the direct attachment with the electronegative
nitrogen atom. The signal corresponding to ─SeCH3
appeared at δ 6.4 ppm. Compound 5 is a symmetrical
8.0
2.5
Table 6
1
13
Experimental and Theoretical Probable H- and C-NMR Chemical
13
Shifts of 6.
molecule, and only three signals appear in the C-NMR
spectrum. In the aliphatic region, only a single peak
Experimental
Theoretical
B3LYP
corresponding to carbons of two ─SeCH units appears at δ
13
3
Atom
C-NMR
HF
6.0 ppm. In 7, the signals corresponding to two ─SeCH3
C1
C2
C3
C4
C5
C12
146.8
136.6
141.0
136.6
146.8
9.9
151.1
139.7
153.2
138.8
151.1
16.4
134.1
135.4
138.3
134.0
134.3
10.0
units appear at different positions (δ 6.7 and 7.2 ppm).
Computational studies. Nuclear magnetic resonance
1
13
spectra and calculations.
The theoretical H- and C-
NMR chemical shift values have been compared with the
experimental data (Tables 4–7). Chemical shifts are
1
1
H-NMR
HF
9.7
9.7
2.9
B3LYP
8.8
reported in parts per million relative to TMS for H- and
13
H7
H8
H(CH
8.30
8.30
2.51
C-NMR spectra. The atom statues were numbered
8.8
2.6
according to Figure 3. First, full geometry optimizations
of the studied compounds were performed at the gradient-
corrected density functional level of theory by using the
Becke’s three-parameter hybrid functional combined with
Lee–Yang–Parr correlation functional (B3YLP) level of
3
)
basis set with integral equation formalism variant (IEF)
polarizable continuum model (PCM)/CDCl solution. The
correlations between experimental and calculated
chemical shifts obtained by B3LYP and HF methods are
depicted in Figures 4–7 (for 4-7, respectively).
3
1
13
DFT. Next, gauge-including atomic orbital H and
C
chemical shift calculations of the compounds (4, 5, 6, and 7)
were made by the same method by using 6-311++G(d,p)
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Month 2017
Synthesis, Characterization, and Computational Studies of Selenium Derivatives
of 3,5-Dichloropyridine
Table 7
For the compound 5, the relation between the calculated
and experimental chemical shifts can be described by the
following equation:
1
13
Experimental and Theoretical Probable H- and C-NMR Chemical
Shifts of 7.
Experimental
Theoretical
B3LYP
13
δcal:ðppmÞ ¼ 0:980δexp:
Atom
C-NMR
HF
þ 1:773ðR² ¼ 0:995Þfor B3LYP method (3)
C1
C2
C3
C4
C5
C12
C16
146.2
129.6
135.6
132.6
153.6
6.7
165.1
146.1
154.6
139.2
149.3
15.0
153.0
140.4
139.8
132.9
132.4
9.9
δcal:ðppmÞ ¼ 1:043δexp:
þ 4:272ðR² ¼ 0:997Þfor HF method (4)
For the compound 6, the relation between the calculated
and experimental chemical shifts can be described by the
following equation:
7.2
16.5
9.6
1
H-NMR
8.3
HF
9.6
2.9
2.9
B3LYP
8.7
H7
H13
H17
2.4
2.4
2.6
2.6
δcal:ðppmÞ ¼ 0:948δ
exp:
þ 0:867ðR² ¼ 0:996Þfor B3LYP method (5)
δcal:ðppmÞ ¼ 1:021δexp:
The relations between the calculated and experimental
chemical shifts of the studied compounds are linear and
described by the following different equations. For the
compound 4, the relation between the calculated and
experimental chemical shifts can be described by the
following equation:
þ 2:215ðR² ¼ 0:998Þfor HF method (6)
For the compound 7, the relation between the calculated
and experimental chemical shifts can be described by the
following equation:
δcal:ðppmÞ ¼ 0:983δexp:
δcal:ðppmÞ ¼ 0:930δexp:
þ 1909ðR² ¼ 0:985Þfor B3LYP method (7)
þ 0:589ðR² ¼ 0:996Þfor B3LYP method (1)
δcal:ðppmÞ ¼ 1:005δ
δcal:ðppmÞ ¼ 1:050δexp:
exp:
þ 2:372ðR² ¼ 0:987Þfor HF method (2)
þ 4:024ðR² ¼ 0:989Þfor HF method (8)
Figure 3. Optimized geometric structures of 3,5-dichloropyridylselenium compounds. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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N. Sharma, A. Singh, and J. S. Dhau
Vol 000
Figure 4. Correlation graph of calculated and experimental chemical shifts of 4. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 5. Correlation graph of calculated and experimental chemical shifts of 5. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 6. Correlation graph of calculated and experimental chemical shifts of 6. [Color figure can be viewed at wileyonlinelibrary.com]
The investigation has proven that the performances of
B3LYP method with respect to prediction of compounds
HOMO and LUMO is indicative of chemical reactivity,
polarizability, and chemical hardness/softness of
molecule [12,13]. To evaluate the energetic behavior of
3,5-dichloropyridylselenium compounds (4-7), we carried
out calculations in dimethyl sulfoxide (DMSO),
a
13
were quite close to the experimentally determined
chemical shift values.
C
Frontier molecule orbitals.
The highest occupied
molecular orbitals (HOMOs) and the Lowest Unoccupied
Molecular Orbitals (LUMOs) are named as frontier MOs
and play an important role in molecular properties such
as electronic transitions [11]. The energy gap between
chloroform (CHCl ), and gas phases. The energies of 4
3
important MOs of compounds 1, 4, 5, 6, and 7; the
second highest and the highest occupied MOs (HOMO
and HOMO ꢀ 1); and the lowest and the second lowest
Journal of Heterocyclic Chemistry
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Month 2017
Synthesis, Characterization, and Computational Studies of Selenium Derivatives
of 3,5-Dichloropyridine
Figure 7. Correlation graph of calculated and experimental chemical shifts of 7. [Color figure can be viewed at wileyonlinelibrary.com]
unoccupied MOs (LUMO and LUMO + 1) were calculated
by using B3LYP/6-311++G(d,p) basis set (Tables 8–11).
The HOMO and LUMO orbitals of compounds 4 to 7,
computed with the B3LYP/6-311++G(d,p) method, are
illustrated in Figures 8 to 12. The positive phase is
represented in red and the negative in green. The plots in
Figures 9 to 12 indicate that the HOMO of all molecules
is localized mostly on the selenium atoms and is mainly
nonbonding in nature. Interestingly, the LUMO of all
molecules is spread over the entire molecule.
Table 8
Calculated Energy Values of 4 in the Gas Phase, DMSO, and Chloroform.
B3LYP/6-
311++G(d,p)
Gas
DMSO
CHCl
3
E
E
E
E
Total (Hartree)
HOMO (eV)
LUMO (eV)
ꢀ3606.2233 ꢀ3606.2247 ꢀ3606.2234
ꢀ0.2272
ꢀ0.0588
0.1684
ꢀ0.2282
ꢀ0.0585
0.1697
ꢀ0.2273
ꢀ0.0588
0.1685
HOMO
ꢀ E
LUMO
gap
(eV)
E
E
E
HOMOꢀ1
LUMO+1
ꢀ0.2850
ꢀ0.0430
0.2420
ꢀ0.2857
ꢀ0.0429
0.2428
ꢀ0.2851
ꢀ0.0430
0.2421
The compound
0.2269 eV and an ELUMO value of ꢀ0.0717 eV. In the
case of compound 4, the E and E values are
7 shows an EHOMO value of
ꢀ
HOMOꢀ1
LUMO+1
gap
HOMO
LUMO
ꢀ E
Dipole moment
Debye)
1.04
1.09
1.05
ꢀ
0.2272 and ꢀ0.0588 eV, respectively. A higher band
(
gap of 0.1684 eV in 4 indicates higher stability and
lower chemical reactivity than the compound 7.
Interestingly,
the
precursor
molecule,
3,5-
Table 9
dichloropyridine (1), with EHOMO and ELUMO values of
Calculated Energy Values of 5 in the Gas Phase, DMSO, and Chloroform.
ꢀ
0.2716 and ꢀ0.0618 eV, has the largest band gap
(
(
0.2098 eV) than any of its selenium derivatives
Fig. 8). This suggests that insertion of selenium in the
B3LYP/6-
311++G(d,p)
Gas
DMSO
CHCl
3
pyridine scaffold reduces the band gap. The later results
clearly explain photochemical liability of selenium-
containing pyridine derivatives. Insertion of another
atom of selenium further reduces the band gap, although
the difference is not large.
E
Total (Hartree)
ꢀ6044.9462 ꢀ6044.9781 ꢀ6044.9464
EHOMO (eV)
ꢀ0.2287
ꢀ0.0664
0.1623
ꢀ0.2297
ꢀ0.0661
0.1636
ꢀ0.2289
ꢀ0.0664
0.1625
ELUMO (eV)
E
HOMO
ꢀ
ELUMO gap
(eV)
Thermodynamic parameters.
Various thermodynamic
E
E
E
ꢀ
HOMOꢀ1
LUMO+1
HOMOꢀ1
ꢀ0.2313
ꢀ0.0631
0.1682
ꢀ0.2318
ꢀ0.0629
0.1689
ꢀ0.2315
ꢀ0.0632
0.1683
parameters (such as zero-point vibrational energy,
thermal energy, specific heat capacity, rotational
constants, and entropy and dipole moment) of the
compounds 4 to 7 are listed in Table 12. The global
minimum energy obtained for the structure optimi-zation
of 4 with B3LYP/6-311++g(d,p) method is ꢀ3606.22 au.
With 5, 6, and 7, B3LYP/6-311++G(d,p) method
provides ꢀ6044.94, ꢀ3606.21, and ꢀ6044.94 au of
energies, respectively. Dipole moment reflects the
molecular charge distribution and is given as a vector in
ELUMO+1 gap
Dipole moment
Debye)
2.22
2.28
2.22
(
moment vector in a molecule depends on the positive and
negative charges. As a result of DFT calculations, 7 has
the highest dipole moment for all the studied compounds,
and the lowest dipole moment was observed for 5 and is
very close to that of the precursor molecule 1, which is
3
dimensions, which can be used to depict the charge
movement across the molecule. Direction of the dipole
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Sharma, A. Singh, and J. S. Dhau
Vol 000
Table 10
Table 12 that the Cv values of the aforementioned
compounds increase with increase in the number of
selenium atoms, and the position of selenium atom on the
pyridine moiety has no significant effect on the variation
of specific heat under constant volume conditions.
Similarly, entropy increases with the increase in number
of selenium atoms, and the position of the selenium
atom(s) has no effect.
Calculated Energy Values of 6 in the Gas Phase, DMSO, and Chloroform.
B3LYP/6-
311++G(d,p)
Gas
DMSO
CHCl
3
E
E
E
E
Total (Hartree)
HOMO (eV)
LUMO (eV)
ꢀ3606.2146 ꢀ3606.2166 ꢀ3606.2148
ꢀ0.2351
ꢀ0.0710
0.1641
ꢀ0.2355
ꢀ0.0707
0.1648
ꢀ0.2351
ꢀ0.0709
0.1642
HOMO
ꢀ
ELUMO gap
eV)
(
E
E
E
ꢀ
HOMOꢀ1
LUMO+1
HOMOꢀ1
ꢀ0.2706
ꢀ0.0486
0.2220
ꢀ0.2705
ꢀ0.0482
0.2223
ꢀ0.2706
ꢀ0.0486
0.2220
EXPERIMENTAL
ELUMO+1 gap
Dipole moment
Debye)
2.22
2.40
2.24
General. All experiments were carried out in a dry
(
oxygen-free nitrogen atmosphere. All the solvents were
1
13
dried before use. The H-NMR and C-NMR spectra
were recorded on Bruker 400 MHz spectrophotometer
Table 11
Calculated Energy Values of 7 in the Gas Phase, DMSO, and Chloroform.
(Fallanden, Switzerland) in CDCl by using TMS as an
3
internal standard. Electron Ionization (EI) mass spectra
were taken by using Shimadzu GC-Mass Spectrometer
B3LYP/6-
311++G(d,p)
Gas
DMSO
CHCl
3
[
(
GCMS QP-2010 plus] with Rtx-1MS (Tokyo, Japan)
30 m × 0.25 mm id × 0.25 μm) capillary column. The
E
E
E
E
Total (Hartree)
HOMO (eV)
LUMO (eV)
ꢀ6044.9419 ꢀ6044.9439 ꢀ6044.9422
ꢀ0.2269
ꢀ0.0717
0.1552
ꢀ0.2278
ꢀ0.0715
0.1563
ꢀ0.2271
ꢀ0.0717
0.1554
elemental analysis was carried out by using Elemantar
Vario MICRO analyzer (Langenselbold, Germany).
HOMO
ꢀ
ELUMO gap
eV)
Theoretical studies. Density functional theory (DFT)
with Becke’s three-parameter hybrid functional combined
with Lee -Yang -Parr correlation functional (B3LYP) level
of theory in combination with the 6-31 + G(d) basis set by
using the Gaussian 03 software package [16] was used for
the quantum chemical study of 1. The IEF-PCM solvent
(
E
E
E
ꢀ
HOMOꢀ1
LUMO+1
HOMOꢀ1
ꢀ0.2365
ꢀ0.0574
0.1791
ꢀ0.2370
ꢀ0.0573
0.1797
ꢀ0.2366
ꢀ0.0574
0.1792
ELUMO+1 gap
Dipole moment
Debye)
3.82
3.88
3.86
(
model for Et O was used for solvent level optimization
2
studies [17], and a scaling factor of 0.9806 was used for
thermal corrections to the Gibbs free energy. Dimethyl
ether (2 units) was used as the model solvent to study the
probably due to the symmetrical nature of the molecule.
B3LYP/6-311++G(d, p) level was utilized to calculate
standard statistical thermodynamic parameters such as
molar heat capacity (C , C ) and entropy (S) of
compounds 1 and 4 to 7; values for various temperatures
are listed in Tables 13 and 14. It is evident from
Figure 13a to f that thermodynamic functions increase
with the increase in temperature. This is probably due to
increase in the intensity of molecular vibrations with the
increase in temperature [14,15]. It is clearly evident from
explicit solvent effect in the reaction. For pK calculations,
a
v
p
the ab initio geometries were employed in calculating the
solvation free energies by using the B3LYP/6-31 + G(d)
level. The pKa value is calculated by using equations
shown in the Supplementary Information [18,19].
pK ¼ ΔG =2:303RT
a
R
[18,19]
Figure 8. Frontier molecular orbital diagram of 1. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis, Characterization, and Computational Studies of Selenium Derivatives
of 3,5-Dichloropyridine
Figure 9. Frontier molecular orbital diagram of 4. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 10. Frontier molecular orbital diagram of 5. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 11. Frontier molecular orbital diagram of 6. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 12. Frontier molecular orbital diagram of 7. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Sharma, A. Singh, and J. S. Dhau
Vol 000
Table 12
Calculated Thermodynamical Parameters of the Compounds.
Atom
1
1g
1h
1j
1k
ꢀ6044.94
0.6683
SCF energy
Rotational constant
A
ꢀ1167.49
ꢀ3606.22
ꢀ6044.94
ꢀ3606.21
2.8762
1.3090
0.7334
0.8833
B
C
0.8358
0.6476
47.74
23.91
83.18
1.03
0.3870
0.2992
67.53
35.63
103.06
1.04
0.2160
0.1717
86.97
47.82
124.43
2.22
0.7173
0.3968
67.49
35.71
103.82
2.22
0.2642
0.1898
87.02
47.76
125.04
3.82
Total energy
Specific heat at constant volume (C
Entropy (S) (cal mol
Dipole moment (Debye)
ꢀ
1
ꢀ1
v
) (cal mol
K
)
ꢀ
1
ꢀ1
K
)
continued until complete dissolution of selenium was
obtained. The dark red solution indicating the formation
of the selenolate anion was recooled to ꢀ78°C, and
iodomethane (2.20 g, 0.96 mL, 15.54 mmol) was added
to it. The reaction mixture was slowly brought to room
temperature, hydrolyzed with chilled water, and purified
by column chromatography by using silica gel (60-120
mesh) and hexane-ethyl acetate as an eluent. After
purification, two products (4 and 5) were obtained.
Table 13
Thermodynamic Properties of 4 at Different Temperatures at B3LYP/6-
11++G(d,p) level.
3
ꢀ
1
ꢀ1
ꢀ1 ꢀ1
ꢀ1 ꢀ1
T (K) C
v
(cal mol
K
) C
p
(cal mol
K
) S (cal mol
K )
1
2
3
4
5
6
7
00
00
00
00
00
00
00
17.30
27.06
34.18
40.38
44.51
47.61
48.77
19.28
73.37
29.04
36.16
42.36
46.49
49.58
50.75
89.84
109.84
124.35
139.42
150.29
162.68
3,5-Dichloro-2-(methylselenenyl)pyridine (4).
Yield:
.56 g (34%), red viscous liquid. Proton nuclear magnetic
resonance (400 MHz, CDCl ): δ (ppm): 8.40 (s, 1H),
0
3
8
.30 (s, 1H), 2.46 (s, 3H). Carbon-13 nuclear magnetic
resonance: (400 MHz, CDCl ): δ (ppm): 157.9, 147.3,
3
Table 14
Thermodynamic Properties of 5 at Different Temperatures at B3LYP/6-
11++G(d,p) level.
136.1, 134.2, 128.0, 6.4. Mass spectrometry (EI, 70 eV)
m/z (relative intensity): 247 (2), 245 (16), 241 (100), 226
(36), 206 (5), 161 (10), 146 (3). Anal. (%) Calcd for
C H NCl Se: C, 29.87, H, 2.07, N, 5.80. Found: C,
3
ꢀ1
ꢀ1
ꢀ1 ꢀ1
ꢀ1 ꢀ1
6
5
2
T (K)
C
v
(cal mol
K
) C
p
(cal mol
K
) S (cal mol
K )
2
9.77, H, 2.11, N, 5.89.
,5-Dichloro-2,6-bis(methylselenenyl)pyridine (5). Yield:
.45 g (20%), white semi-solid. Proton nuclear magnetic
1
2
3
4
5
6
7
00
00
00
00
00
00
00
25.10
37.90
48.92
57.76
65.12
71.05
75.98
27.08
84.23
3
39.88
50.90
59.74
67.10
73.03
77.96
106.82
124.79
140.76
154.60
167.37
179.10
0
resonance (400 MHz, CDCl ): δ (ppm): 7.36 (s, 1H),
3
2.49 (s, 6H). Carbon-13 nuclear magnetic resonance:
(
400 MHz, CDCl ): δ (ppm): 152.6, 134.1, 127.4. Mass
3
spectrometry (EI, 70 eV) m/z (relative intensity): 335
62), 333 (47), 331 (24), 300 (68), 149 (100). Anal. (%)
Calcd for C H NCl Se : C, 25.07, H, 2.08, N, 4.17.
(
7
7
2
2
Synthesis of selenium derivatives of 3,5-dichloropyridine
through boron trifluoride-directed lithiation route.
Found: C, 25.17, H, 2.19, N, 4.31.
A
Synthesis of selenium derivatives of 3,5-dichloropyridine
solution of 3,5-dichloropyridine (1) (1 g, 6.75 mmol) in
dry THF (30 mL) was taken in a 3-necked 100-mL round
bottom flask (RBF) under inert atmosphere. Boron
trifluoride etherate (1.05 g, 0.91 mL, 7.43 mmol) was
added to the solution at 0°C. A white suspension of 3,5-
dichloropyridine-adduct (2) was formed which was then
stirred for 10 minutes. The temperature of the RBF
using direct lithiation of 1.
A solution of 1 (1g,
6.75 mmol) in dry THF (30 mL) was taken in a 3-necked
100-mL RBF under inert atmosphere. The temperature of
the RBF containing 1 was lowered to ꢀ78°C, and LDA
(15.54 mmol) was added slowly to the solution. The
orange-red solution was stirred for 5 minutes at ꢀ78°C,
and elemental selenium (1.22 g, 15.54 mmol) was added
to it. The reaction mixture was slowly warmed to the
ambience temperature and stirred for 15 minutes. The
color of the reaction mixture on complete dissolution of
selenium changed to dark red. Different electrophiles
(15.54 mmol) were added to the selenolate anion at ꢀ78°C
to obtain the desired products.
containing
2
was lowered to ꢀ78°C, and LDA
(15.54 mmol) was added slowly to the solution. The
orange-red solution was formed and stirred for 5 minutes
at ꢀ78°C. Elemental selenium (1.22 g, 15.54 mmol) was
added to this solution at ꢀ78°C. The temperature was
slowly raised to ambience temperature, and stirring was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis, Characterization, and Computational Studies of Selenium Derivatives
of 3,5-Dichloropyridine
Figure 13. Variation of thermodynamic parameters with temperature; (a) C
of 5. [Color figure can be viewed at wileyonlinelibrary.com]
v p v p
of 4, (b) C of 4, (c) entropy of 4, (d) C of 5, (e) C of 5, and (f) entropy
Preparation of 3,5-dichloro-4-(methylselenenyl)pyridine and
,5-dichloro-2,4-bis(methylselenenyl)pyridine. In the above
solution, iodomethane (2.20 g, 0.96 mL, 15.54 mmol)
was added at ꢀ78°C. The reaction mixture was slowly
brought to room temperature, hydrolyzed with chilled
water, and purified by column chromatography by using
silica gel (60-120 mesh) and hexane-ethyl acetate as an
eluent. After purification of the crude mixture, two
products (6 and 7) were obtained.
3
3,5-Dichloro-4-(methylselenenyl)pyridine (6).
Yield:
0.76g (46%), light red liquid. Proton nuclear magnetic
resonance (400 MHz, CDCl ): δ (ppm): 8.41 (s, 2H),
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Sharma, A. Singh, and J. S. Dhau
Vol 000
2
.51 (s, 3H). Carbon-13 nuclear magnetic resonance:
mode analysis. The optimized structural parameters
have been evaluated for calculations at different level
of theories. At the optimized geometry, no imaginary
frequency modes were obtained, so there is a true
minimum on the potential energy surface. Gauss view
program [23] was considered to obtain a visual
animation. Thermodynamic parameters were calculated
with HF and DFT theories by using a variety of basis
sets. The HOMO-LUMO energies were calculated by
using B3LYP/6-311++G(d,p) level of theory in gas
and DMSO and CHCl3 phases. Molecular orbital
energies were also illustrated with the help of
diagrams at B3LYP/6-311++G(d,p) level of theory.
For NMR calculations, compounds 4 to 7 were
optimized with 6-311++G(d,p) basis set at the DFT
(400 MHz, CDCl ): δ (ppm):146.8, 141.0, 136.6, 9.9.
3
Mass spectrometry (EI, 70 eV) m/z (relative intensity):
2
47 (1), 245 (16), 241 (100), 239 (46), 226 (35), 165 (4),
1
63 (7), 161 (10), 76 (6). Anal. (%) Calcd for
C H NCl Se: C, 29.87, H, 2.07, N, 5.80. Found: C, 29.78,
6
5
2
H, 2.17, N, 5.88.
,5-Dichloro-2,4-bis(methylselenenyl)pyridine (7). Yield:
.52 g (23%), white solid, mp 63 to 65°C. Proton nuclear
magnetic resonance (400 MHz, CDCl ): δ (ppm): 8.30 (s,
3
0
3
1
H), 2.47 (s, 3H), 2.46 (s, 3H). Carbon-13 nuclear
magnetic resonance: (400 MHz, CDCl ): δ (ppm): 153.6,
3
1
46.2, 135.6, 132.6, 129.6, 7.2, 6.7. Mass spectrometry
EI, 70 eV) m/z (relative intensity): 335 (63), 331 (62),
00 (100), 240 (25), 145 (4), 76 (50). Anal. (%) Calcd
for C H NCl Se : C, 25.07, H, 2.08, N, 4.17. Found: C,
(
3
1
13
7
7
2
2
and HF levels of theory. The H- and
C-NMR
2
5.19, H, 2.21, N, 4.29.
chemical shifts were calculated by using gauge-
including atomic orbital method in a gas phase and
solvent phase of CDCl3 by IEF-PCM method. The
observed theoretical results were compared with the
experimental data.
3
,5-Dichloro-4-(ethylselenenyl)pyridine (8).
Iodoethane
(2.42 g, 1.24 mL, 15.54 mmol) was added to the
selenolate anion, formed as described above. The reaction
mixture was slowly brought to room temperature,
hydrolyzed, and purified. Yield: 0.67g (39%), reddish
yellow liquid. Proton nuclear magnetic resonance:
(
(
400 MHz, CDCl ): δ (ppm): 8.43 (s, 2H), 3.12 to 3.19
q, 2H), 1.35 to 1.43 (m, 3H). Carbon-13 nuclear
3
CONCLUSIONS
magnetic resonance: (400 MHz, CDCl ): δ (ppm): 146.3,
3
In summary, we have developed a methodology that
can be tailored to direct incorporation of selenium at the
C-6/C-2 or C-4 positions. The lithiation of BF3-
complexed 3,5-dichloropyridine with 2.3 equiv of LDA
followed by selenium addition successfully incorporated
selenium at the C-2 position of 3,5-dichloropyridine (1).
On the contrary, the direct lithiation of 1 with LDA (2.3
equiv) and reaction with selenium afforded selenation at
the C-4 position. The observed regioselectivity in these
reactions has been explained in light of relative stability
of the lithiated species. Under the BF3 complexed
condition, the relative stability of the lithiated species
achieved through Li⋯F interaction guides lithiation and
subsequent selenation at the C-6/C-2 position. In the
1
40.0, 137.4, 23.4, 15.5. Mass spectrometry (EI, 70 eV)
m/z (relative intensity): 259 (16), 257 (64), 255 (100),
26 (12), 146 (2), 76 (5). Anal. (%) Calcd for
C H NCl Se: C, 32.94, H, 2.74, N, 5.49. Found: C,
2
7
7
2
3
2.99, H, 2.69, N, 5.44.
4
-(Benzylselenenyl)-3,5-dichloropyridine (9).
(Chloro-
methyl)benzene (1.96 g, 1.78 mL, 15.54 mmol) was
added to a solution of selenolate anion, formed as above.
The reaction mixture was slowly brought to room
temperature, hydrolyzed, and purified. Yield: 1.05 g
(
(
(
49%), red liquid. Proton nuclear magnetic resonance:
400 MHz, CDCl ): δ (ppm): 8.31 (s, 2H), 7.15 to 7.24
3
m, 5H), 4.31 (s, 2H). Carbon-13 nuclear magnetic
resonance: (400 MHz, CDCl ): δ (ppm): 146.8, 140.1,
3
absence of BF complexation, the C-4 lithiated species is
3
1
37.6, 136.9, 128.9, 128.6, 127.5, 31.7. Mass
spectrometry (EI, 70 eV) m/z (relative intensity): 321 (2),
17 (10), 91 (100). Anal. (%) Calcd for C H NCl Se:
the most stable species that explains the formation of the
C-4 selenated products. Computationally, a complete
3
1
2
9
2
description
of
the
3,5-dichloropyridylselenium
C, 45.42, H, 2.83, N, 4.41. Found: C, 45.20, H, 2.79,
N, 4.37.
compounds was achieved by using techniques and
tools derived from the DFT and HF theories. The
performances of the B3LYP method with respect to
1
13
prediction of the H and C chemical shift values were
quite close to the experimentally determined values.
Also, calculations of various thermodynamic parameters
and HOMO-LUMO energies established that the
insertion of selenium into a pyridine moiety drastically
reduces the HOMO-LUMO band gap, which clearly
explains the photochemical liability of selenium-containing
pyridine derivatives.
COMPUTATIONAL DETAILS
Gaussian 03 program [16] was used to perform quantum
chemical calculations. HF and DFT computations were
carried out by using the closed-shell B3LYP in
combination with 6-311++G(d,p) basis set [20–22] to
perform complete geometry optimizations and normal
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis, Characterization, and Computational Studies of Selenium Derivatives
of 3,5-Dichloropyridine
Acknowledgment. The authors like to thank Dr P.V. Bharatam
NIPER, Mohali, India) for providing useful insight during the
course of this work.
[14] Chocholousova, J.; Spirko, V. V.; Hobza, P. Physiol Chem
Phys 2004, 6, 37.
(
[15] Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F.
NBO Version 3.1.
[16] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. J. A.; Vreven, T.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene,
M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. J.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck,
A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul,
A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko,
A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, Y.; Wong, M. W.; Gonzalez, C.; Pople,
J. A. GAUSSIAN 03 Program, Gaussian Inc Wallingford, CT, 2004.
[17] Cances, E.; Mennucci, B.; Tomasi, J. J Chem Phys 1997, 107,
3032.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet