Selective lithiation of 2,4-lutidine: Role of transition states of lithium dialkylamides

Article abstract of DOI:10.1016/j.jorganchem.2021.121691

The lithiation of 2,4-lutidine (1) with non-nucleophilic bases, such as lithium diisopropylamide (LDA) and lithium diethylamide (LDEA) affords different regioisomers under similar reaction conditions. The mechanism of these reactions and the factors determining selectivity have not been well understood. The present endeavor explores experimental and quantum chemical approaches to investigate factors that determine regioselectivity of the reaction. It has been found that transition states of LDA/LDEA determine regioselectivity and the presence of acatalyst (LiCl) plays a vital role. The LDA mediated lithiation of 1 proceeds through a disolvated open dimer of LDA, leading to a 2-methyl lithiated product. LDEA mediated lithiation is dominated by a route involving interception of 1 with a trisolvated monomer-based transition state of LDEA resulting in a 4-methyl lithiated product. The mechanism is supported by LiCl catalyzed reactions. LiCl has also been found to effect a change in selectivity of the lithiation of BF₃-complexed 2,4-lutidine.

Full text of DOI:10.1016/j.jorganchem.2021.121691

Journal of Organometallic Chemistry 936 (2021) 121691
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Selective lithiation of 2,4-lutidine: Role of transition states of lithium
dialkylamides
Neha Sharmaa,b, Jaspreet S. Dhaub,∗, Avtar Singhc,d, Sheenu Abbate, Prasad V. Bharatamf,
Ashok K. Malika,b, Amritpal Singhf
a Multani Mal Modi College, Patiala 147002, India
b Department of Chemistry, Punjabi University, Patiala 147002, India
c Molekule Inc. San Francisco 94103, CA, USA
d Department of Chemistry, Sri Guru Teg Bahadur Khalsa College, Anandpur Sahib 140118, India
e Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar 160062, Punjab, India
f Department of Chemistry, Mata Gujri College, Fatehgarh Sahib 140406, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The lithiation of 2,4-lutidine (1) with non-nucleophilic bases, such as lithium diisopropylamide (LDA)
and lithium diethylamide (LDEA) affords different regioisomers under similar reaction conditions. The
mechanism of these reactions and the factors determining selectivity have not been well understood.
Received 22 November 2020
Revised 3 January 2021
Accepted 5 January 2021
Available online 9 January 2021
The present endeavor explores experimental and quantum chemical approaches to investigate factors that
determine regioselectivity of the reaction. It has been found that transition states of LDA/LDEA determine
regioselectivity and the presence of acatalyst (LiCl) plays a vital role. The LDA mediated lithiation of 1
proceeds through a disolvated open dimer of LDA, leading to a 2-methyl lithiated product. LDEA mediated
lithiation is dominated by a route involving interception of 1 with a trisolvated monomer-based transition
state of LDEA resulting in a 4-methyl lithiated product. The mechanism is supported by LiCl catalyzed
reactions. LiCl has also been found to effect a change in selectivity of the lithiation of BF3-complexed
2,4-lutidine.
Keywords:
Lithiation
Lutidine
Reaction mechanism
Density functional theory
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
shown that treatment of 1 with n-BuLi furnishes 2-methyl lithiated
product. Evans et al. [11] have found that regioselectivity of the n-
Lithiation of methyl substituted pyridines (picolines and lu-
tidines) has always attracted tremendous interest as it is a gateway
to many useful materials [1,2] and biological active agents [3,4].
These pyridine derivatives pose tremendous challenge in obtaining
lithiation at the desired site and different strategies have been em-
ployed to achieve lithiation either at the methyl group or pyridine
ring moiety [4–9].
BuLi mediated reaction changes in the presence of diethylamine,
affording a 4-methyl lithiated product. They have also demon-
strated exclusive 4-methyl lithiation when 1 is directly reacted
with lithium diethylamide (LDEA). It is assumed that diethylamine
facilitates equilibration between the 2- and 4-methyllithio species
that leads to a thermodynamically more stable 4-methyl lithio
species [16]. Interestingly, the treatment of 1 with another non-
nucleophilic base, lithium diisopropylamide (LDA), affords lithia-
tion at the 2-methyl carbon [14]. It is suggested that complexation
of the Li atom with the ring N atom prior to lithiation promotes 2-
methyl lithiation [11]. However, the reason for the presence Li•••N
interaction in LDA mediated reactions and its absence in the case
of the LDEA has never been explained. Also, no explanation is pro-
vided on why a more stable 4-methyl lithio species is not formed
in an LDA mediated reaction. It is clear here that neither of the
above-mentioned factors entirely explain the observed selectivity.
Therefore, there is a need to look into other factors, such as the
role of solvent and the nature and structure of lithiated species,
in explaining the selectivity achieved. The present work is an en-
We have explored various aspects of lithiation of methyl substi-
tuted pyridines and found that the lithiation of 2,4-lutidine (1) has
not been well characterized, and therefore, not well understood. It
is not yet clear what factors and intermediate species determine
the regioselectivity in the lithiation of 1. As shown in Scheme 1,
2,4-lutidine has been selectively lithiated at the 4-methyl and 2-
methyl carbon with different lithiating reagents [10–14]. For ex-
ample, 2,4-lutidine when treated with phenyllithium in diethyl
ether affects lithiation at the 2-methyl carbon [15]. Kaiser [13] has
∗
Corresponding author.
E-mail address: jdhau@molekule.com (J.S. Dhau).
https://doi.org/10.1016/j.jorganchem.2021.121691
0022-328X/© 2021 Elsevier B.V. All rights reserved.

N. Sharma, J.S. Dhau, A. Singh et al.
Journal of Organometallic Chemistry 936 (2021) 121691
Table 1
LDA and LDEA mediated lithiation of 2,4-lutidine.
Reaction
Product Yield
Entry Base
Solvent
Condition
2a (%)
2b (%)
1.
2.
3.
4.
5.
6.
7.
8.
LDA (1.1 eq.)
THF
-78oC
-78oC
-78oC
-78oC
-78oC
-78oC
-78°C, -70°C, -78oC
-78oC
72
54
54
60
70
30∗
52
11
-
LDA (1.1 eq.)
Et2O
-
LDA (1.1 eq.) + LiCl (0.01 eq.)
LDA (1.1 eq.) + LiCl (0.1 eq.)
LDA (1.1 eq)
THF
17
20
-
THF
THF + Toluene (1:1)
LDA (0.5 eq.)
THF
THF
THF
-
LDA (1.1 eq.)
-
55
LDEA (1.1 eq)
9.
LDEA (1.1 eq.) + LiCl (0.01 eq.)
LDEA (1.1 eq.) + LiCl (0.1 eq.)
LDEA (1.1 eq.)
THF
-78oC
-78oC
-78oC
-78oC
-78oC
-78oC
9
63
70
44
34
44
40
10.
11.
12.
13.
14
THF
18
10
23
8
THF + Toluene (1:1)
LDEA (1.1 eq.)
THF + Toluene (1:3)
LDEA (1.1 eq.) + DIPA (1.1 eq.)
LDA (1.1 eq.) + DEA (1.1 eq.)
THF
THF
28
DIPA: Diisopropylamine
DEA: Diethylamine
∗The yield of this reaction was calculated based on the amount of LDA used and for the rest of other reactions the
yield was calculated based on the amount of 2,4-lutidine used
a 4-methyl lithiated product has been reported in earlier studies
through gentle warming [16], however the same observation could
not be generated in our lab. In two separate experiments, reac-
tion mixture containing lithiated 2,4-lutidine at –78°C was gently
warmed to –70°C and –50°C, and in none of the cases, product cor-
responding to 4-methyl lithiation was obtained even after stirring
the reaction mixture at the respective temperature for ½h and 2h.
We thought it worthwhile to investigate the role of transition
states of LDA in the observed selectivity. Similar to Hoepker et al.
[20], our Density Function Theory (DFT) analysis, using Becke3, Lee,
Yang, Parr (B3LYP) level in combination with the 6-31+G(d) basis
set using the IEF-PCM solvent model, indicate that LDA exists as a
disolvated dimer (3), both in THF and dimethyl ether (Scheme 3).
The dimer then deaggregates into a disolvated open dimer, 4 and
a trisolvated monomer, 5. The interception of 1 with 4, or 5, may
explain the observed selectivity. LiCl has been shown to facilitate
the deaggregation of LDA dimer 3 to a trisolvated LDA monomer,
5 [18,20]. If lithiation of 1 proceeds through 4, then LiCl should
have no impact on the selectivity and if it progressed through 5
then a change in the selectivity should be observed. The addition
of LiCl, 0.01 and 0.1 eq., to LDA followed by reaction with 1 and
quenching with benzaldehyde afforded both 2a and 2b in a 3:1
ratio. Surprisingly, the selectivity changed even in the case of BF3-
complexed 2,4-lutidine as 2a and 2b were again obtained in a 3:1
ratio (Scheme 2, Table 2, entry 3). Clearly, lithiation of 1 with LDA
proceeds through a dimer-based pathway involving interception of
1or BF3-complexed 1 with the disolvated dimer transition state, 4
(Scheme 3) and is substrate (uncomplexed 1 or BF3-complexed 1)
independent.
Scheme 1. Lithiation of 2,4-lutidine [11,13–16].
deavor to identify reaction pathway and factors controlling the se-
lectivity of the lithiation of 1 with LDA and LDEA by employing ex-
perimental and quantum chemical approaches. The role of catalyst,
LiCl, complexing reagent, BF3.Et2O, and solvation in the regioselec-
tivity of the reaction has been studied. The structural features of
transition states, free energy, and energy barriers of the reactions
were explored by quantum chemical analysis to predict the types
of chemical species generated in these reactions.
2. Results and discussion
2.1. Lithiation of 1 with LDA
LDA mediated reactions with a variety of organic substrates
have been shown to proceed through an open dimer- or monomer-
based transition state of LDA [17–19]. Hoepker et al. [20] have
demonstrated that in an LDA-mediated ortholithiation of 1-chloro-
3-(trifluoromethyl)benzene, LDA dimer undergo various deaggre-
gation processes leading to dimer- and monomer-based transi-
tion states. The interception of 1-chloro-3-(trifluoromethyl)benzene
with these transition states determines the selectivity of the re-
action. [20]. As discussed in the Introduction section, lithiation of
1 is also a very complex reaction and different regioisomers are
obtained with different lithiating agents. Our investigation showed
that the lithiation of 1 or its BF3-complexed adduct (1-BF3) with
LDA at –78°C followed by reaction with benzaldehyde exclusively
affords 2-(4-methylpyridin-2-yl)-1-phenylethanol (2a) (Scheme 2,
Table 1). The yields are significantly higher with 1-BF3 adduct than
with uncomplexed 1. Conversion of 2-methyl lithiated product to
It has been found that the selectivity of the reaction is also in-
dependent of THF and LDA concentrations, however the product
formation was found to be dependent on LDA concentration. The
use of THF-toluene (1:1) solvent mixture afforded 2a in a yield
similar to the reaction in the THF alone (Table 1, entry 5). On the
other hand, the use of 0.5 eq. of LDA exclusively afforded 2a, how-
ever in a much lower yield (Table 1, entry 6). The reduction in the
yield is consistent with the inference that the lithiation proceeds
through the open dimer, 4.
2.2. Lithiation of 1 with LDEA
The LDEA mediated lithiation of 1 and quench with PhCHO
has been reported to exclusively yield 2-(2-methylpyridin-4-yl)-1-
2

N. Sharma, J.S. Dhau, A. Singh et al.
Journal of Organometallic Chemistry 936 (2021) 121691
Scheme 2. LDA mediated lithiation of 2,4-lutidine and BF3-complexed 2,4-lutidine.
Scheme 3. DFT computations of transition states of LDA and reaction pathway based on experimental data.
phenylethanol (2b) [11]. Contrary to this, the lithiation of 1 with
dination between the lithium on the 2-methyl carbon and the flu-
oride of BF3, will generate a more stable- 2-methyl lithiated prod-
uct. However contrary to our expectation, the lithiation of 1-BF3
adduct with LDEA followed by reaction with benzaldehyde also af-
forded 2b and 2a in a 5:1 ratio (Scheme 4, Table 2, entry 4). As
explained earlier, the later result was surprising as we were ex-
pecting a higher proportion of 2a. It appears that deaggregation
of LDEA dimer is substrate independent and transition structures
LDEA followed by the reaction with benzaldehyde afforded both
2b and 2a in 55% and 11% yields (Scheme 4). The reaction was per-
formed a couple of times and each time 2a and 2b were obtained
in a 5:1 ratio. We also performed lithiation of 1 in the presence
of BF3 etherate, hoping that the complexation of 1 with BF3 will
allow preferential lithiation of 2-methyl carbon. This is based on
postulate that the complex-induced proximity effect [6], i.e., coor-
3

N. Sharma, J.S. Dhau, A. Singh et al.
Journal of Organometallic Chemistry 936 (2021) 121691
Table 2
LDA and LDEA mediated lithiation of BF3-complexed 2,4-lutidine.
Reaction
Product Yield
Entry
Solvent
Base
Condition
2a (%)
2b (%)
1.
2.
3.
4.
5.
6.
THF
Et2O
THF
THF
THF
THF
LDA (1.1 eq.)
-78oC
-78oC
-78oC
-78oC
-78oC
-78oC∗
86
65
46
8
-
LDA (1.1 eq.)
-
LDA (1.1 eq.) + LiCl (0.1 eq.)
LDEA (1.1 eq.)
15
45
9
n-BuLi (1.2)
50
51
Buli (1.2) + DEA
24
∗
½ h stirring after addition of n-BuLi at -78°C followed by addition of DEA and ½ h stirring
Scheme 4. LDEA mediated lithiation of 2,4-lutidine and its BF3 adduct.
Scheme 5. DFT computations of transition states of LDEA and reaction pathway based on experimental data.
of LDEA dominate the role in the observed selectivity. It is postu-
proportion than that obtained in pure THF (Table 1, entries 11
lated that formation of 2b is achieved through the interception of
1 with a trisolvated monomer-based transition structures of LDEA,
8, rather than the open disolvated dimer 7. The hypothesis was
tested by performing the LDEA mediated reactions in the pres-
ence of a trace amount of LiCl. It was expected that if the lithia-
tion proceeded through 8, then addition of LiCl should enhance the
proportion of 2b formed. The addition of LiCl (0.01 mol) to LDEA
followed by reaction with 1 and quenching with benzaldehyde af-
forded both 2b and 2a in 63% and 7% yields (9:1), respectively. The
use of 0.1 eq. of LiCl further improved the yield of 2b (Table 1, en-
try 10). All these results indicate that the 4-methyl lithiation of
1 is achieved through its reaction with the trisolvated monomer
(8) of LDEA (Scheme 5). Contrary to LDA mediated reaction, lithia-
tion of 1 with LDEA is dependent on THF concentration. The lithia-
tion of 1 with LDEA under varying solvent concentrations, 1:1 and
1:3 THF : Toluene mixture, afforded 2b in a significantly lower
and 12).
2.3. Equilibration and role of Et2NH and i-Pr2NH
It is clear now that both 1-2L and 1-4L exist in equilibrium in
a LDEA mediated lithiation which may not be the case with an
LDA mediated reaction. We investigated the role of dialkylamine,
a major by-product of the lithiation reaction in the lithiation of
1 with LDA and LDEA. For the later objective, we studied lithia-
tion reactions in the presence of i-Pr2NH and Et2NH. Reaction of
1 with LDEA at –78°C, stirring for 30 min, and subsequent addi-
tion of i-Pr2NH (1.1 eq.) did not show any change in selectivity as
2b and 2a were obtained in a 5:1 ratio (Table 1, entry 13). On the
other hand, lithiation of 1 with LDA in the presence of Et2NH re-
versed the selectivity as 2b was the major product formed and 2a
was obtained in a minor quantity only (Table 1, entry 14). In an-
4

N. Sharma, J.S. Dhau, A. Singh et al.
Journal of Organometallic Chemistry 936 (2021) 121691
Scheme 6. Equilibration of lithiated products of 2,4-lutidine.
Fig. 1. DFT computations of transition states with explicit solvent dimethyl ether (DME) in the metalation of 1. Atom color scheme: Nitrogen as blue, Oxygen as red, Lithium
as purple, carbon as gray, hydrogen as white.
other variation, we investigated the lithiation of BF3-complexed 1
with n-BuLi both in the presence and absence of Et2NH. We found
that addition of Et2NH to the reaction mixture increases the pro-
portion of 2b formed in the reaction mixture (Table 2, entries 5
and 6). All these results indicate that the addition of Et2NH to
an LDA mediated reaction initiates the conversion of 1-2L to 1-4L
as shown in Scheme 6. These results also demonstrate that for-
mation of Et2NH as a by-product in a LDEA mediated reaction is
partly responsible for the generation of 4-methyl lithiated product,
whereas i-Pr2NH does not play a similar role in an LDA mediated
reaction.
do not account for exclusive formation of 2a in an LDA mediated
reaction.
Next, we investigated three parameters: structural features of
transition states, free energy, and energy barriers of the reac-
tions by using quantum chemical methods. The activation bar-
rier involving possible transition states of lithiated 2,4-lutidine
species were calculated using the 6-311+G(d,p) basis sets.
A
number of possible reaction pathways through various transition
states (activation barrier) were considered. Based on theoretical
data from a LDEA mediated reaction, the most preferred transi-
tion state appears to be TS-LDEA-2L(solvent)1(Fig. 1). However,
the free energy of activation is only 0.5 kcal/mol lower than
the non-solvated transition structure TS-LDEA-2L, implying that
both TS-LDEA-2L(solvent)1and TS-LDEA-2L may exist in equilib-
rium. The corresponding 4-methyl lithiated transition structure TS-
LDEA-4L(solvent)1 is 6.7 kcal/mol higher in energy. Similar data
was obtained for LDA mediated reaction (Fig. 2) demonstrating
a lower energy barrier for 2-methyl lithiation than the 4-methyl
lithiation. Based on these results, selectivity can be explained
for the LDA mediated reaction, but not for an LDEA mediated
reaction.
2.4. Theoretical analysis of 2,4-lutidine
The observed selectivity in these reactions was investigated by
performing quantum chemical analysis. Computational calculations
on 1 indicate that the deprotonation energy of the 4-methyl carbon
(333.83 kcal/mol) is lower than the deprotonation energy of the 2-
methyl carbon (337.28 kcal/mol). The differences in these values
are very small and partly explain the experimental result when
LDEA is used as the lithiating reagent, however, these observations
5

N. Sharma, J.S. Dhau, A. Singh et al.
Journal of Organometallic Chemistry 936 (2021) 121691
Fig. 2. DFT computation of 1-2L transition states with explicit solvent dimethyl ether (DME) in a LDA mediated reaction. Atom color scheme: Nitrogen as blue, Oxygen as
red, Lithium as purple, carbon as gray, hydrogen as white.
Table 3
Relative energy of the lithiated product(s) obtained from the reaction of 1 with LDA and LDEA
under explicit solvent conditions and relative to 1.
Reactant
Solvent
1-2L(solvent)2࢞G, kcal/mol
1-4L(solvent)2࢞G, kcal/mol
1 + LDEA
1 + LDEA
1 + LDA
1 + LDA
THF
0.31
6.2
-0.5
5.2
Dimethyl ether
THF
0.37
12.6
-0.5
11.7
Dimethyl ether
Further, the relative stability of the lithiated products, 1-2L and
1-4L were determined. In the case of LDEA (THF), the free energy
change is negative during the conversion of 1 to a disolvated 1-4L,
however only a small difference, ≤1 kcal/mol, exists between 1-4L
and 1-2L, which is also the case for the LDA mediated lithiation of
1 (Table 3).
a minor quantity only. The concentration of the coordinating sol-
vent, THF, is vital for a LDEA mediated reaction, whereas it seems
not important in an LDA mediated reactions. DFT analysis demon-
strates lower energy barrier for 2-methyl lithiation than the 4-
methyl lithiation supporting results obtained from LDA mediated
reactions.
Based on DFT analysis, it can be inferred that the difference
in the regioselectivity for these two reactions cannot be fully ex-
plained based on the transition structures and thermodynamic sta-
bility of the lithiated products, especially the LDEA mediated reac-
tion.
4. Experimental
All the experiments were carried out in dry oxygen-free nitro-
gen atmosphere. All the reagents and solvents were procured from
Sigma Aldrich and purified by standard operating procedures and
were freshly distilled prior to use [21]. LDA and LDEA was pre-
pared by the reaction of n-BuLi with diisopropylamine and diethy-
lamine, respectively [22,23]. The solvents were dried before use.
1H NMR and 13C NMR spectra were recorded on Bruker 400 MHz
spectrophotometer in CDCl3 using tetramethylsilane (TMS) as an
internal standard. The ESI mass spectra were taken on Water Q-
TOF Micro spectrometer. EI mass spectra were taken by using Shi-
madzu GC-Mass Spectrometer [GCMS QP-2010 plus] with Rtx-1MS
(30m x 0.25mm ID x 0.25μm) capillary column.
3. Conclusion
In conclusion, it has been found that LDA and LDEA mediated
lithiation of 1 proceed through different reaction pathways. It has
been demonstrated that:
1) the transition states of LDA determine the selectivity of the
lithiation of 1. 2-Methyl lithiation is achieved due to a reac-
tion between the disolvated open dimer of LDA and 1.
2) in an LDEA mediated reaction, 4-methyl lithiation is
achieved through the interception of 1 with a trisolvated
monomer-based transition state of LDEA.
4.1. General procedure: lithiation of uncomplexed 2,4-lutidine
3) deaggregation of LDA/LDEA dimer is substrate independent
and transition states of LDA/LDEA dominate the role in the
observed selectivity.
A solution of 1 (1.60 g, 1. 64 mL, 15.0 mmol) in THF (50 mL)
was cooled to -78°C in a three-necked 100 mL round-bottom flask
(RBF). LDA and LDEA (16.5 mmol) was slowly added via cannula
to this solution. The resulting pale-yellow solution containing the
carbanion was then stirred for 15-20 min at -78°C and quenched
with benzaldehyde (1.7 g, 1.67 mL, 16.5 mmol). The temperature
was slowly raised to room temperature and hydrolyzed with
cold distilled water (20 mL). The organic layer was extracted
with diethyl ether, washed with water, brine solution and then
again with water. The organic layer was dried over anhydrous
sodium sulphate. The solvent was removed and the crude product
obtained was purified by column chromatography (60-120 mesh
silica gel and hexane-ethyl acetate as an eluent, 5:1) to afford the
pure product.
The above conclusions have been supported by investigating
LiCl catalyzed lithiation reactions, where it has been shown that
addition of LiCl changes the selectivity of the LDA mediated reac-
tion. Additionally, it was also found that the selectivity of the lithi-
ation of BF3-complexed 2,4-lutidine also changes in the presence
of LiCl.
The presence of reaction by-product, dialkylamine, is also criti-
cal in the achieved selectivity of the reaction. Where i-Pr2NH plays
no role, Et2NH facilitates the conversion of 1-2L to 1-4L. The pres-
ence of Et2NH in an LDA mediated reaction reversed the selectiv-
ity as 2b was the major product formed and 2a was obtained in
6

N. Sharma, J.S. Dhau, A. Singh et al.
Journal of Organometallic Chemistry 936 (2021) 121691
4.2. General procedure: lithiation of BF3-complexed 2,4-lutidine
Declaration of Competing Interest
A solution of 1 (1.60 g, 1. 64 mL, 15.0 mmol) in THF (50 mL)
was cooled to 0°C in a three-necked 100 mL RBF. Boron triflu-
orideetherate (BF3.Et2O) in diethyl ether (2.34 g, 2.07 mL, 16.5
mmol) was added to it. The resulting white suspension was stirred
for 10 min. The temperature of the RBF containing 1-BF3 adduct
was lowered to -78°C and LDEA or LDA was added slowly via can-
nulation. The resulting reddish-brown solution containing the BF3-
complexed carbanion was stirred for 15-20 min at -78°C. Benzalde-
hyde (1.7 g, 1.67 mL, 16.5 mmol) was added dropwise to this so-
lution at -78°C. The temperature was slowly raised to room tem-
perature and hydrolyzed with cold distilled water (20 mL). The or-
ganic layer was extracted with diethyl ether, washed with water,
brine solution and then again with water. The organic layer was
dried over anhydrous sodium sulphate. The solvent was removed,
and the crude product was purified by column chromatography us-
ing 60-120 mesh silica gel and hexane-ethyl acetate as an eluent
(5:1).
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgments
We are thankful to Mr. Avtar Singh of CIL Department of Panjab
University, Chandigarh for the NMR spectra and Mr. Gurpreet Singh
of Department of Chemistry, Punjabi University, Patiala for GCMS
analysis.
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2-(2-Methylpyridin-4-yl)-1-phenylethanol (2b) [11]
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1
NMR (400 MHz, CDCl3): δ (ppm): 8.18-8.19 (d, J = 5.0 Hz, 1H),
7.32-7.33 (m, 5H), 6.95 (s, 1H), 6.87-6.88 (d, J = 5.96 Hz, 1H), 4.88-
4.90 (dd, J = 2.32, 5.48 Hz, 1H), 2.93-2.94 (m, 2H), 2.43 (s, 3H) 13C
NMR: (400 MHz, CDCl3): δ (ppm):157.9, 148.5, 147.9, 143.7, 128.4,
127.6, 125.7, 124.5, 121.9, 74.2, 45.1, 23.9. MS (EI): 212 (M+, 7), 194
(56), 136 (2), 107 (100), 94 (17), 77 (16), 65 (3), 51 (4). Anal. Calcd
(%) for C14 NOH15(213):C, 78.87, H, 7.04, N, 6.57; Found: C, 78.62, H,
7.31, N, 6.84.
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4.3. Theoretical studies
Complete optimization and frequency calculations were carried
out by Density Functional Theory (DFT) with Becke3, Lee, Yang,
Parr (B3LYP) level of theory in combination with the 6-31+G(d)
basis set using the Gaussian 09 software package [24]. A scal-
ing factor of 0.9806 was used for thermal corrections to Gibbs
free energy [25]. Solvent level optimization studies have been per-
formed using the IEF-PCM solvent model for diethyl ether as a
solvent [26].
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7