Synthesis, crystal structure and dft studies of polyfunctionalized alkenes: A transition metal-free c(sp2)-h sulfenylation of electron deficient alkyne

Article abstract of DOI:10.1016/j.molstruc.2020.129089

An efficient, novel and transition metal-free protocol has been developed for the synthesis of polyfunctionalized aminothioalkenes via direct C[sbnd]H sulfenylation of in situ generated enamines. The reaction was performed using a catalytic amount of inex

Full text of DOI:10.1016/j.molstruc.2020.129089

Journal of Molecular Structure 1225 (2021) 129089
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, Crystal structure and DFT studies of Polyfunctionalized
2
Alkenes: A transition Metal-Free C(sp )-H Sulfenylation of electron
deficient Alkyne
Mohit Sarohaa,b, Jayant Sindhu , Parvin Kumar , J.M. Khurana
c,∗
d
a
a
Department of Chemistry, DCRUST, Murthal, Sonipat, 131001 India
b
Department of Chemistry, University of Delhi, Delhi 110007
c
Department of Chemistry, COBS&H, CCS Haryana Agricultural University, Hisar 125004
d
Department of Chemistry, Kurukshetra University, Kurukshetra 136119
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, novel and transition metal-free protocol has been developed for the synthesis of polyfunc-
tionalized aminothioalkenes via direct C–H sulfenylation of in situ generated enamines. The reaction was
performed using a catalytic amount of inexpensive and nontoxic K2CO3 under mild reaction condition.
All the reactions resulted in good to excellent yields. The cross-coupling reaction has been achieved by
in situ aerobic oxidation at room temperature with good functional group tolerance. The molecular archi-
tecture and stereochemistry has been established by spectral data, X-ray single crystal diffraction studies
and supported by Density Functional theory (DFT). Hirshfeld surface analysis has been used to explore
the intramolecular and intermolecular interactions present in the case of 4a. Moreover, the intramolecu-
lar hyperconjugative interactions have been investigated using natural bond orbitals (NBOs) analysis and
their intensity was categorized according to their second-order stabilization energy (E(2)). The electro-
static properties such as global reactivity descriptors, local reactivity descriptors, ESP and NLO have been
investigated using DFT method and B3LYP/6–311+G(d) level of theory.
Received 16 April 2020
Revised 5 August 2020
Accepted 14 August 2020
Available online 17 August 2020
Keywords:
Transition metal-free
DFT
Hirshfeld
Fingerprint
NBO
NLO
Fukui function
©
2020 Elsevier B.V. All rights reserved.
1. Introduction
formation via C–H activation or CDC reactions has become more
important.
Development of novel, green and accessible procedures for the
synthesis polyfunctionalized functionalities is a worthwhile con-
tribution in organic synthesis. The progression of new C-S cross-
dehydrogenative coupling (CDC) strategies attract synthetic organic
chemists due to wide application of organosulfur compounds in
pharmaceuticals, agrochemicals, organic dyes, and materials chem-
istry [1–6]. The C–H activation is a class of organic transforma-
tions [7–9], wherein the Heck reaction has established itself with
high practicality [10,11]. Lately, the cross-coupling (CC) reaction of
aryl halides with aryl thiols has become one of the most efficient
method for C-S bond formation. A number of CDC reactions have
been developed recently to form Csp-Csp, Csp-Csp2 and Csp -Csp2
bonds [12–19]. With the focus on emergence of “atom-economy”
Several CDC reaction based methodologies have been devel-
oped for thiolation/sulfenylation via C–H activation which, how-
ever, require synthesis of thiolation reagents initially [23–31]. Di-
rect utilization of arylthiols as sulfenylating agent in metal-free
protocols have not been explored to a significant extent. Thi-
olation/sulfenylation of five and six membered heterocycles has
been reported using transition metal-free reagents viz. I /BSA
2
[32], K CO /DMSO [33], I /DMSO [34], N-chlorosuccinimide [35],
2
3
2
I /DMSO [36], and KClO /ethylacetate [37]. Molecular oxygen has
2
3
been utilized as mild oxidant in organic synthesis by various re-
search groups in C–H oxygenation [38], C–H amination [39] and
C–H thiolation of enamines/enaminones [40,41]. To the best of our
knowledge, synthesis of polyfunctionalized alkenes via CDC medi-
ated sulfenylation of enamines by using environmentally benign
method has not been explored yet.
2
[
20,21] and “green chemistry”[22] in organic synthesis, transition
metal-free functionalization and specially, the C–C and C-X bond
The non-covalent interactions largely affect the molecular archi-
tecture by controlling the aggregation process in crystals. [42] The
∗
role of strong hydrogen bonds (O—H
••••O, N—H••••H, N—H••••O
Corresponding author.
etc.) is very significant in crystal packing [43]. Further, crystal pack-
E-mail addresses: jayantchem@gmail.com (J. Sindhu), jmkhurana1@yahoo.co.in
(J.M. Khurana).
https://doi.org/10.1016/j.molstruc.2020.129089
022-2860/© 2020 Elsevier B.V. All rights reserved.
0

2
M. Saroha, J. Sindhu and P. Kumar et al. / Journal of Molecular Structure 1225 (2021) 129089
Table 1
Optimization of reaction conditionsa.
chromatographed over silica gel (230–400) using EtOAc: Pet ether
2:98, v/v) as eluent. The solid thus separated was characterized as
(
Entry
Base (equiv.)
Solvent
Time(h)
Yield(4a)
dimethyl 2-((4-methoxyphenyl)amino)-3-(phenylthio)fumarate (4a)
using 1H NMR, 13C NMR and X-ray single crystal diffraction studies
(XCDS) and was obtained in 42% yield (Table 1, entry 2).
1
2
3
4
5
6
7
8
9
1
1
1
.
–
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
24 h
24 h
24 h
24 h
24 h
24 h
24 h
12 h
09 h
24 h
24 h
24 h
No reaction
42b
.
K2CO3 (2)
K2CO3 (1)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
NaOH (4)
Cs2CO3 (4)
K2CO3 (4)
.
32b
42b
42b
20b
36b
76
In order to develop a highly efficient and convenient method-
ology for the synthesis of aminothioalkenes (4), the scope of the
same model reaction was further explored using different concen-
.
.
.
THF
tration of base i.e., 1 eq. and 4 eq. of K CO3 (Table 1, entries 3 & 4).
.
DCM
2
.
DMF
It was observed that reaction went to completion with high yield
when higher concentration of base was used (Table 1, entry 4).
A variety of solvents i.e., EtOH, THF, DCM, DMF and DMSO were
explored in the same model reaction using K2CO3 (4 equiv.) as a
base (Table 1, entry 5–9). In first three cases, reactions did not pro-
ceed to completion even after 24 h and gave 42%, 20% and 36% of
4a, respectively (Table 1, entries 5–7) while in case of DMF, the
reaction was complete in 12 h but gives 4a in 76% yield (Table 1,
entry 8). To our delight, the reaction carried out in DMSO at room
temperature under ideal conditions resulted in 83% yield of 4a in
.
DMSO
DMSO
DMSO
DMSO
83
0.
1.
2.
68
78
No reactionc
a
Conditions: 1a (1.0 mmol), 2a (1.0 mmol) and 3a (2.0 mmol),
base in 5 mL of solvent at room temperature;
b
Incomplete Reaction;
c
reaction was attempted under N2 atmosphere.
Table 2
Synthesis of polyfunctionalized aminothioalkenes (4a-4i).
9
h (Table 1, entry 9). The effect of different bases like NaOH and
Compound no
R1
R2
Ar
Time (h)
Yield (%)
Cs2CO3 (Table 1, entries 10 & 11) was also explored. However, no
significant improvement in yield and reaction time was observed
in both the conditions. In order to explore the role of air, the reac-
tion was carried out under N2 atmosphere and no desired product
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
OMe
OMe
OMe
Cl
H
H
H
H
H
H
H
H
Cl
C6H5
09
08
12
10
24
12
12
24
12
83
82
85
85
78
86
81
80
82
4-ClC6H4
2-Naphtyl
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
2-Naphthyl
(4a) were detected (Table 1, entry 12). It can be inferred that thiol
Br
3a undergoes aerobic oxidation in situ to disulfide. This shows that
Me
H
the reactions occurring via an aerobic oxidative cross-coupling.
It can be inferred from above results that the reaction of
dimethylacetylenedicarboxylate (1a) (1 mmol), p-anisidine (2a)
g
h
i
F
Cl
(
1 mmol) and thiophenol (3a) (2 mmol) in presence of 4 equiv.
of K CO3 using DMSO as solvent is the standardized reaction
2
ing in molecules devoid of these strong directional forces depends
mainly upon weak interactions. The role of -CH group in self-
assembly is well established and plays a significant role in crystal
packing [44]. DFT based theoretical methods provide an alternative
to crystallography for molecular structure prediction. The detailed
exploration of structural features from optimized molecular geom-
etry using DFT based methods is one of our interest [45]. [46]
Keeping in view the need of development of novel transition
metal-free methodologies and continuing our interest in the same
field [47–50], we have carried out metal free C–H sulfenylation of
in situ prepared enamines and their detailed structural study using
X-ray single crystal diffraction studies (XCDS) and DFT methods
condition for the synthesis of dimethyl 2-(phenyl)thio)-3-((4-
methoxyphenyl)amino)fumarate (4a).
The developed methodology was then extended to other sub-
strates by carrying out reactions of dimethylacetylenedicarboxylate
(1a) with substituted thiophenol and aniline under otherwise iden-
tical conditions (Scheme 2). All the reaction gave the correspond-
ing polyfunctionalized alkenes in high yields in 8–24 h under sim-
ilar condition (4b-4i). The developed methodology failed to yield
desired product when aliphatic thiol (n-hexanethiol) was reacted
with in situ generated enamine under identical conditions.
We believe that the thioarylation proceeds by a nucleophilic
attack of in situ generated enamine on diphenyldisulfide linkage
followed by isomerization to give the desired product (Scheme 3).
The initial formation of enamine from dialkyl acetylenedicarboxy-
late and aromatic amine in ethanol was followed by removal
of ethanol under reduced pressure. This was followed by addi-
tion of 2 eq. of thiophenol which undergoes aerial oxidation in
K2CO3/DMSO, followed by attack of enamine on disulphide to give
the desired compound polyfunctionalized aminothioalkenes.
2. Results and discussion
2
.1. Chemistry
The direct sulfenylation of in situ generated enamine was
investigated using a one-pot, three-component protocol, where
dimethylacetylenedicarboxylate (1a), p-anisidine (2a) and thiophe-
nol (3a) were used as model substrates. Firstly, a mixture of
dimethylacetylenedicarboxylate (1a) (1.0 mmol) and p-anisidine
(
2a) (1.0 mmol) was stirred at room temperature in ethanol for
min. After the formation of enamine, as monitored by TLC
2.2. Molecular structure (X-ray diffraction)
5
using EtOAc: Pet ether (10:90, v/v) as solvent, ethanol was re-
moved under reduced pressure and 2.0 mmol of thiophenol (3a)
The detailed molecular structure of dimethyl 2-((4-
methoxyphenyl)amino)-3-(phenylthio)fumarate (4a) was explored
using XCDS. The trans stereochemistry of double bond in 4a was
confirmed from the structure derived from diffraction studies
(Fig. 1). The ORTEP view of the asymmetric unit along with the
optimized structure of 4a are shown in Fig. 1. The refinement
details and crystallographic parameters are provided as sup-
plementary material (Table S1). The molecule 4a crystallises in
monoclinic system within p21/n space group with lattice parame-
in 5 mL of CH CN was added to the reaction mixture. The con-
3
tents were stirred at room temperature and the progress of the
reaction was monitored using TLC for 24 h. No new product for-
mation was observed in the reaction even after 24 h (Table 1,
entry 1) (Scheme 1). The same model reaction was further ex-
plored using K CO (2 equiv.) as a base. A new spot was ob-
2
3
served on TLC, however, the reaction was incomplete even af-
ter 24 h. The reaction was quenched by adding ice. The reaction
mixture was extracted using DCM, dried over anhyd. Na SO and
˚
˚
˚
ter a = 10.8877(2) A, b = 20.6639(3) A, c = 8.1934(8) A with β=
90.502(3)° respectively.
2
4

M. Saroha, J. Sindhu and P. Kumar et al. / Journal of Molecular Structure 1225 (2021) 129089
3
Scheme 1. Synthesis of dimethyl 2-((4-methoxyphenyl)amino)−3-(phenylthio)fumarate(4a).
Scheme 2. One-pot synthesis of polyfunctionalized aminothioalkenes (4a-4i).
Scheme 3. Mechanism for the synthesis of polyfunctionalized aminothioalkenes (4a-4i).
Fig. 1. (a) Crystal structure of dimethyl 2-((4-methoxyphenyl)amino)-3-(phenylthio)fumarate(4a); (b) Optimized geometry using DFT B3LYP/6–311+G(d) theory.

4
M. Saroha, J. Sindhu and P. Kumar et al. / Journal of Molecular Structure 1225 (2021) 129089
Fig. 2. Hirshfeld Surface analysis of dimethyl 2-((4-methoxyphenyl)amino)−3-(phenylthio)fumarate (4a) (a) di; (b) de; (c) dnorm; (d) Shape index; (e) Curvedness.
Fig. 3. 2D fingerprint regions for 4a showing per atom intermolecular interactions.
2
.3. Hirshfeld surface analysis
hydrogen bonding are represented by diminutive spots on the sur-
face (Fig. 2).
Structural descriptions using crystallographic techniques would
The summary of intermolecular contacts in the crystal struc-
tures was extracted from crystallographic data by generating 2D
fingerprint plots by a combination of de and di and binding them
be incomplete without Hirshfeld surfaces (HS) analysis as it ex-
plains different types of interactions existing within the crystals.
Furthermore, HS analysis can also be used to investigate the lo-
cations and quantitative ratios of atom…atom contacts with po-
tential weak hydrogen bond and intramolecular interactions. The
HS analysis of 4a was done using crystal explorer 17.5. HS is gen-
erally three-dimensional (3D) colored maps generated with dnorm
using a color combination of blue, white and red. The color used
in these 3D maps indicates the strength of intermolecular contacts
comparable with the Van der Waals (vdW) contacts where blue
color represents longer contacts, white shows vdW and red indi-
cates shorter intermolecular contacts. The π-π stacking interac-
tions in a molecule can be visualized with the help of a shape in-
dex tool in HS by the presence of adjacent red and blue triangles.
The distance of an atom external or internal to the surface can be
mapped using de and di respectively. The dnorm surface resulted
˚
into intervals of 0.01 A. The HS was decomposed further into fin-
gerprint plots, which defines all significant intermolecular interac-
tions and their contribution to HS. The H–H type of interaction
contributes 57.2% of the total HS. However, the contribution made
by hydrogen bonding interactions in the form of O–H and S-H is
25.9% and 5.6% of the total interaction respectively. The C–H type
of interaction contributes 30.7% in the total Hirshfeld surface and
represented by outermost spikes present in the fingerprint plot
(Fig. 3).
2.4. Molecular self-assembly
Various inter and intramolecular interactions present in the
case of 4a are calculated using PARST [51]. The presence of eight
potential hydrogen bond donor –CH groups establish C—H•••O
as the most significant intermolecular interactions in case of 4a.
The molecules of 4a form dimers associated with a crystallo-
graphic glide plane (Fig. 4) and linked through moderate O10…H26
from the normalization of d and de pair with respect to vdW radii
i
of corresponding atoms. The HS was mapped over dnorm (−0.064
˚
˚
˚
to 1.138 A), d (1.063 to 2.548 A), de(1.063 to 2.505 A), shape index
i
˚
˚
(
−0.998 to 0.996 A) and curvedness (−3.803 to 0.487 A) to visu-
alize the molecular structure around which these properties were
calculated. HS is a practical tool for defining the surface character-
istics of molecules along with the hydrogen bonding interactions
and close contacts present in them. Intermolecular hydrogen bonds
are the close contacts represented by deep-red large circular spots
visible on HS mapped over dnorm, whereas, contacts weaker than
˚
˚
(2.705 A) and C14 …H6C (2.773 A) hydrogen bond. Due to the ab-
sence of strong -OH and -NH based hydrogen bond donor, the 4a
assembled mainly through C–H interactions. The main D-H—A type
interactions present in 4a along with close contacts are tabulated
in Table 3.

M. Saroha, J. Sindhu and P. Kumar et al. / Journal of Molecular Structure 1225 (2021) 129089
5
Fig. 4. (a) Dimer of 4a associated with a crystallographic glide plane; (b) Crystal packing along ab plane.
Table 3
Potential non-covalent interactions present in case of 4a [ A˚ and o].
∗
D-H–A type interactions
D-H—A
d(D-H)
d(H—A)
d(D—A)
<(DHA)
∗
∗
∗
∗
N11–H11–O9
1.030
1.080
1.080
1.080
1.080
1.080
1.080
1.080
1.080
1.080
1.080
1.080
1.080
1.080
1.080
1.080
1.080
1.080
2.659
3.205
2.651
2.651
2.607
2.607
3.206
3.849
3.286
3.120
3.377
3.328
3.120
3.499
3.864
3.728
3.820
3.668
1.893
2.496
2.604
2.660
2.590
2.576
2.508
2.773
2.680
2.859
2.730
2.622
2.735
2.707
2.873
2.798
2.831
2.712
128.55
122.28
80.60
C26–H26–O7
C6–H6A-O10
C6–H6B-O10
77.81
∗
C5–H5B-O9
78.89
∗
C5–H5c-O9
79.62
C14–H14–O9#1
C5–H5B-O10#1
C15–H15–O9#1
C6–H6c-O10#2
C27–H27–O10#2
C26–H26–O10#2
C6–H6B-O10#2
C18–H18–O8#3
C41–H41c-O40#4
C6–H6A-O7#4
C16–H16-S12#5
C5–H5A-O40#6
Close contacts
Interaction
121.39
173.76
115.05
93.67
118.23
122.46
100.64
129.90
152.56
144.21
152.25
147.32
Distance ( A˚ )
Interaction
O10…H27#4
O8…H18#3
H14…H6C#4
O10…H6C#4
H41A…H41C#4
H41C…H41A#4
Distance ( A˚ )
Fig. 5. Potential energy scan applied along dihedral angle N11 –C –C –C for 4a.
1
2
3
O9…H14#1
H26…H6B#2
H11…H15#1
O10…H26#4
O10…H6B#4
C14…H6C#4
2.589
2.8037
2.8056
2.859
2.5931
2.6825
2.7051
2.7596
2.7727
trans form is −1564.478472 a.u and −1564.481937 a.u respectively.
The results of DFT based optimization suggest that trans form of 4a
is more stable than its cis form which are in line with the results
obtained from x-ray single crystallography.
2.8694
2.8718
2.8718
Values normalized following R.Taylor et al. [52].
∗
intramolecular interactions; Symmetry transformations used to generate
equivalent atoms: #1 -x + 1,-y,-z; #2 x,-y + 1/2,+z + 1/2; #3 -x,-y,-z; #4 x,-
y + 1/2,+z-1/2; #5 x,+y,+z-1; #6 -x + 1,+y-1/2,-z + 1/2.
3
. Electrostatic results
3
.1. Global reactivity descriptors
2
.5. DFT based conformational studies
The geometries of polyfunctionalized aminothioalkenes (4a-4i)
were optimized using DFT method with B3LYP/6–311+G(d) level
of theory and frontier molecular orbitals (FMO’s) were computed.
According to FMO theory the stability, reactivity, electronic transi-
tions and intermolecular interactions of a compound are contained
within well known quantum chemical parameters i.e., HOMO and
LUMO [53–55]. These orbitals signify that the electron accepting
and donating behavior of a molecule can be utilized for ciphering
the reactivity of π-electron framework in conjugated systems [56].
The distribution of FMO’s in a molecule decides the biological re-
In order to explore the most stable conformation of 4a,
potential energy scan (PES) was applied along dihedral angle
N11 –C –C –C (Fig. 5). It has been revealed from PES that the trans
1
2
3
form of 4a is 2.3 kcal/mol more stabilized than the cis form. The
extra stabilization in case of trans over cis form was attributed
due to the presence of steric hindrance in later case. The geome-
try of both cis and trans form were optimized using the same DFT
method. The sum of electronic and zero-point energy for cis and

6
M. Saroha, J. Sindhu and P. Kumar et al. / Journal of Molecular Structure 1225 (2021) 129089
Fig. 6. Pictorial representation of (A) HOMO-LUMO; (B) Density of states for 4a.
tential. The energy change associated with the flow of electrons
from HOMO to LUMO is defined mathematically by electrophilicity
index (ω). The energy of HOMO and LUMO along with global reac-
tivity descriptors calculated for all the polyfunctionalised aminoth-
ioalkenes (4a-4i) are summarized in Table 4.
The local reactivity of a molecule can be defined in terms of lo-
cal reactivity descriptors i.e., Fukui function, which can be defined
as the distortion of electron density upon accepting and donat-
ing electrons in particular nuclei. Fukui functions in its condensed
form is the most practical way to investigate the ability of an atom
to serve as a reactive site in the molecule. The nucleophilic, elec-
trophilic and radical sites in a molecule can be expressed using
Fukui functions in its condensed form by fx , fx and fx0 as respec-
tively. Following expressions are used to access these condensed
Fukui function
−
+
ꢀ
ꢁ
fx = q − q ; fx+ = q − q and fx = q − q /2
−
N
A
C
N
0
C
A
The electronic population in neutral, cationic and anionic
species can be represented by q , qC and q . The charge present on
Fig. 7. FMO of polyfunctionalized aminothioalkenes (4a-4i) and their energy gap.
N
A
each atom in neutral, positive and negative state of the molecule
was accessed using natural charge derived from NBO analysis. Mor-
rel et al. had proposed a new dual descriptor ꢀf(r) for differenti-
ating reactive sites within a molecule, where electrophilic sites are
associated with positive ꢀf(r) and nucleophilic sites are with nega-
tive ꢀf(r) values. [60] The results calculated for 4a are summarized
in Table S2. The new dual descriptor is defined by following equa-
tion.
sponse associated with it, their presence on the same side strongly
reduces the biological activity. The distribution pattern of FMO’s
along with density of states (DOS) for 4a is shown in Fig. 6.
The green and red lines represent the energy levels for occu-
pied and empty orbitals respectively. It has been revealed that π-
electron cloud of HOMO is mainly distributed over phenyl ring at-
tached to sulfur, however, the LUMO is mainly concentrated over
ester and phenyl ring attached with the nitrogen atom. The energy
difference between these FMO’s for polyfunctionalized aminoth-
ioalkenes is shown in Fig. 7.
ꢀ
f (r) = fx+ − fx−
3.2. Molecular electrostatic potential (MEP)
The chemical reactivity descriptors includes chemical potential
(
μ), chemical Hardness (η), electrophilicity index (ω), Fukui func-
The reactive and hydrogen bonding sites along with electron
density can be significantly recognised visually using MEP and can
be used for the evaluation of reactive sites in a molecule [61]. Fur-
thermore, the electronegativity and dipole moment are some of
the significant properties that can be predicted using DFT based
MEP calculations. The electrostatic potential over the surface of the
molecule was mapped using different color combinations. The re-
gion of zero, positive and negative potential are represented using
white, red and blue color respectively (Fig. 8.) It can be seen from
MEP plot that the negative electrostatic potential was spread over
carbonyl oxygen atom and sulfur indicating possible electrophilic
sites while electropositive region is mainly distributed over nitro-
gen atom attached to double bond. The presence of positive charge
tion (ꢀf) and Nucleophilicity index (N) which provide a deep in-
sight into the chemical reactivity and stability of polyfunctionalised
aminothioalkenes [57,58,59]. The properties associated with these
descriptors are further categorised into global and local reactiv-
ity descriptors. Hardness is one of the important terms which re-
late to the biological activity of a compound. The molecules as-
sociated with a large HOMO-LUMO energy gap are comparatively
harder and more stable than the molecules with a small gap. The
chemical potential (μ) describes the intramolecular charge trans-
fer phenomenon in the ground state and the tendency of elec-
trons to escape from the equilibrium state. Hence, chemically re-
active molecules are associated with large values of chemical po-

M. Saroha, J. Sindhu and P. Kumar et al. / Journal of Molecular Structure 1225 (2021) 129089
7
Table 4
Electrostatic properties of polyfunctionalized aminothioalkenes (4a-4i).
a
2
Nucleophilicity index (N)b
S.No
HOMO
LUMO
Chemical potential (μ)= (I + A)/2
Chemical hardness (η)= (I-A)/2
Electrophilicty Index (ω)= μ /2η
4
4
4
4
4
4
4
4
4
e
d
i
−6.011
−6.008
−5.875
−5.993
−5.907
−5.833
−5.628
−5.698
−5.644
−1.832
−1.816
−1.871
−1.716
−1.661
−1.492
−1.469
−1.383
−1.438
−3.921
−3.912
−3.873
−3.854
−3.784
−3.662
−3.549
−3.541
−3.541
2.090
2.096
2.002
2.138
2.123
2.17
3.679
3.65
3.477
3.48
3.747
3.474
3.373
3.09
3.613
3.495
3.581
3.655
3.86
h
g
b
c
a
f
2.079
2.158
2.103
3.028
2.906
2.981
3.79
3.844
a
I= -EHOMO, A= -ELUMO.
b
Calculated using N = EHOMO (Compound)-EHOMO(Tetracyanoethylene) [59].
Fig. 8. ESP surface mapped over electron density for polyfunctionalized aminothioalkenes (4a-4i).
on H36 and negative on O9 indicates the probability of intramolec-
ular hydrogen bonding between them. The findings of MEP plot
supports the presence of intramolecular hydrogen bonding in the
crystal structure of 4a. Moreover, the contribution of O–H interac-
tion is 25.9% of the overall interactions present in the crystal struc-
ture quantified using 2D fingerprint.
tions like optical modulation, telecommunication, signal process-
ing, optical memories and optical interconnections [63]. The dipole
moment of the system rearranges upon exposure to an external
electric field, where linear and non-linear optical behavior of the
molecule can be predicted using polarizability (α) and hyperpolar-
izibility (β) values. The NLO properties related to a molecule can
be predicted in an inexpensive way by DFT based calculations. First
hyperpolarizability (β ) of a molecule is the basis of NLO prop-
3
.3. NBO & NLO analysis (DFT based)
0
erties and urea is used as a prototype for comparative studies.
The hyperpolarizability tensors (βxxx, βxxy, βxyy, βyyy, βxxz, βxyz,
The different properties like stability, basicity, reactivity, inter-
β
yyz, βxzz, βyzz, βzzz) of 4a were obtained from Gaussian log file
molecular charge transfer, the relationship between donor and ac-
ceptor associated with a molecule can be explored in an efficient
way by Natural Bond orbital (NBO) analysis [62]. Second order per-
turbation theory explains the nature of non-Lewis acceptors and
Lewis donor, and can be used to explore hyperconjugative inter-
action energies. The intensity of hyperconjugative interactions can
be ascertained using E(2) value. The intensive interactions are as-
sociated with a large E(2) values, and the intense values of E(2)
present in case of 4a are given in Table S3.
as calculated using DFT method (Table S4). The hyperpolarizabil-
ity (β) values obtained in atomic units have been converted into
electronic units (e.s.u) (β; 1 a.u.= 8.6393 × 10 33esu). The value
−
of first order hyperpolarizibility (β ) calculated for all the com-
0
−30
pounds is listed in Table 5. The β0 of 4b is 2.03 × 10
e.s.u
−30
is 17 times greater than urea 0.12 × 10
e.s.u and is listed in
Table 5.
Development of non-linear optical material attracts scientific
community as these materials can be used in various applica-
ꢂ
ꢃ
1/2
2
2
2
)
β
0 = (βxxx+βxyy+βxzz) +(βyyy+βxzz+βyxx) +(βzzz+βzxx+βzyy

8
M. Saroha, J. Sindhu and P. Kumar et al. / Journal of Molecular Structure 1225 (2021) 129089
Table 5
Non-linear optical properties of polyfunctionalised aminothioalkenes (4a-4j).
Compounds
0 (e.s.u) x 10
4a
4b
4c
4d
4e
4f
4 g
4h
4i
Urea
0.12
−
30
β
1.27
2.03
1.75
0.81
0.89
0.35
0.97
0.72
1.48
4. Conclusion
5.1.2 Spectral data
A transition metal-free protocol has been developed for the
Dimethyl 2-((4-methoxyphenyl)amino)-3-(phenylthio)fumarate (4a)
synthesis of novel polyfunctionalized aminothioalkenes via direct
C–H sulfenylation of in situ generated enamines. The reaction was
performed using a catalytic amount of inexpensive and nontoxic
K2CO3 under mild reaction conditions. All the reactions resulted
in good to excellent yields. The cross-coupling reaction has been
achieved by aerobic oxidation without any additional oxidant at
room temperature with good functional group tolerance. We be-
lieve that this is one of the simplest methodologies that provide
a straightforward approach for thiolation. The molecular architec-
ture and stereochemistry has been established using X-ray single
crystal diffraction and DFT based studies. Hirshfeld surface analy-
sis has been used to explore the intramolecular and intermolecular
interactions present in the case of 4a. Moreover, the intramolecu-
lar hyperconjugative interactions have been investigated using nat-
ural bond orbitals (NBOs) analysis and their intensity was catego-
rized according to their second order stabilization energy (E(2)).
The electrostatic properties such as global reactivity descriptors,
local reactivity descriptors, ESP and NLO have been investigated
using DFT method and B3LYP/6–311+G(d) level of theory. Crystal
data reveals strong intramolecular hydrogen bond in the molecule
and DFT studies suggest that these molecules can be explored as
potential candidates in excited state proton transfer phenomenon.
Off white solid; 1H NMR (400 MHz, CDCl )δ 10.73 (s, 1H, NH),
3
H
7.25 (d, J = 3.2 Hz, 4H, ArH), 7.20–7.05 (m, 3H, ArH), 6.84 (d,
J = 9.2 Hz, 2H, ArH), 3.79 (s, 3H, COOCH ), 3.71 (s, 3H, COOCH ),
3
3
13
3.64–3.57 (s, 3H, ArOCH ); C NMR (100 MHz, CDCl )δ 170.60,
3
3
C
162.94, 159.90, 158.09, 138.63, 130.99, 128.55, 126.12, 125.26,
125.11, 114.40, 84.30, 55.37, 52.39, 52.03.
Dimethyl
2-((4-chlorophenyl)thio)-3-((4-methoxyphenyl)amino)fumarate (4b)
Off white solid; 1H NMR (400 MHz, CDCl3)δH 10.73 (s, 1H, NH),
7.20 (m, 4H, ArH), 7.11 (d, J = 8.7 Hz, 2H, ArH), 6.85 (d, J = 9.2 Hz,
2H, ArH), 3.80 (s, 3H, COOCH3), 3.71 (s, 3H, COOCH3), 3.60 (s,
3H, ArOCH3); 13C NMR (100 MHz, CDCl3)δC 170.42, 162.88, 160.11,
158.23, 137.34, 131.13, 130.86, 128.71, 127.47, 125.21, 114.45, 83.87,
55.41, 52.50, 52.12.
Dimethyl
2-((4-methoxyphenyl)amino)-3-(naphthalen-2-ylthio)fumarate(4c)
Off white solid; 1H NMR (400 MHz, CDCl3)δH 10.80 (s, 1H, NH),
7.75 (m, 3H, ArH), 7.67 (d, J = 8.2 Hz, 1H, ArH), 7.41 (m, 3H, ArH),
7.14 (d, J = 8.7 Hz, 2H, ArH), 6.85 (d, J = 8.2 Hz, 2H, ArH), 3.79 (s,
13
3H, COOCH3), 3.69 (s, 3H, COOCH3), 3.59 (s, 3H, ArOCH3); C NMR
(
100 MHz, CDCl ) δC 170.69, 162.98, 158.15, 136.25, 133.69, 131.61,
3
1
31.02, 128.16, 127.68, 127.11, 126.27, 125.14, 124.66, 123.89, 114.45,
5
Experimental
8
4.17, 55.41, 52.47, 52.12.
5
.1 Chemistry
Dimethyl 2-((4-chlorophenyl)amino)-3-((4-chlorophenyl)thio)fumarate
4d)
Off white solid; 1H NMR (400 MHz, CDCl )δ 10.88 (s, 1H, NH),
(
All the chemicals, solvents and reagents are commercial and
3
H
procured from Sigma-Aldrich, Merck and Spectrochem and were
used as received. The Progress of the reaction was monitored
by thin layer chromatography by using Pre-coated thin layer
aluminum sheets (GF-254). The 1H NMR and proton decoupled
13C spectra were recorded on JEOL JNM ECX-400 P at 400 and
7
.30 (d, J = 8.7 Hz, 2H, ArH), 7.21 (m, 4H, ArH), 7.14–7.04 (m,
13
2
H, ArH), 3.72 (s, 3H, COOCH ), 3.67 (s, 3H, COOCH ); C NMR
3
3
(
100 MHz, CDCl )δC 170.28, 162.79, 158.45, 136.71, 131.89, 131.43,
3
129.59, 128.80, 124.81, 123.91, 86.53, 52.73, 52.30.
1
00 MHz respectively, using TMS as an internal standard. The
Dimethyl
chemical shifts values are recorded on δ scale and the coupling
constants (J) are in Hz.
2
-((4-bromophenyl)amino)-3-((4-bromophenyl)thio)fumarate (4e)
Off white solid; 1H NMR (400 MHz, CDCl )δ 10.89 (s, 1H, NH),
3
H
7
.45 (d, J = 6.9 Hz, 2H, ArH), 7.37 (d, J = 8.7 Hz, 2H, ArH), 7.12
5
.1.1 Typical procedure for the synthesis of polyfunctionalized
(d, J = 8.2 Hz, 2H, ArH), 7.02 (d, J = 8.7 Hz, 2H, ArH), 3.72 (s,
aminothioalkenes (4a-4i)
3H, COOCH ), 3.67 (s, 3H, COOCH ); 13CNMR (100 MHz, CDCl )δ
3
3
3
C
170.25, 162.77, 158.33, 137.48, 137.20, 132.57, 131.70, 127.96, 124.09,
A mixture of dimethylacetylenedicarboxylate (1) (1.0 mmol),
aromatic amine (2a) (1.0 mmol) in 5 mL of EtOH was added to a
119.62, 119.28, 84.45, 52.78, 52.34.
5
0 mL round-bottomed flask mounted over a magnetic stirrer. The
Dimethyl 2-(p-tolylamino)-3-(p-tolylthio)fumarate (4f)
Off white solid; 1H NMR (400 MHz, CDCl )δ 10.81 (s, 1H, NH),
reaction was monitored by TLC using EtOAc: Pet ether (10:90, v/v)
as eluent. After the disappearance of reactant in the reaction mix-
ture, the solvent was removed under reduced pressure and 2 equiv.
of thiophenol (3a) was added to the reaction mixture in 5 mL of
DMSO. The mixture was stirred at room temperature. The reaction
was monitored by TLC using EtOAc: Pet ether (20:80, v/v) as eluent.
After completion of the reaction, 50 mL of water was added to the
reaction mixture. The reaction mixture was extracted using DCM
3
H
7.18 (d, J = 8.2 Hz, 2H, ArH), 7.12 (d, J = 8.2 Hz, 2H, ArH), 7.05
(m, 4H, ArH), 3.71 (s, 3H, COOCH ), 3.66 (s, 3H, COOCH ), 2.31 (s,
3
3
6H, 2xArCH ); 13C NMR (100 MHz, CDCl )δC 170.66, 163.14, 158.89,
3
3
136.05, 135.68, 135.24, 134.90, 129.94, 129.40, 126.66, 122.65,
85.79, 52.46, 52.09, 20.95, 20.89.
Dimethyl 2-((4-chlorophenyl)thio)-3-(phenylamino)fumarate (4 g)
(
2 × 10 mL), dried over anhyd. Na SO and chromatographed over
Off white solid; 1H NMR (400 MHz, CDCl )δ 10.94 (s, 1H, NH),
2
4
3
H
silica gel (230–400) using EtOAc: Pet ether (2:98, v/v) as eluent.
to afford pure polyfunctionalized aminothioalkenes (4a-4i). Vari-
ous spectral techniques like 1H NMR and 13C NMR were used for
the characterization of compound.
7.33 (t, J = 8.0 Hz, 2H, ArH), 7.25–7.18 (m, 5H, ArH), 7.17–7.12 (m,
13
2H, ArH), 3.72 (s, 3H, COOCH ), 3.65 (s, 3H, COOCH ); C NMR
3
3
(100 MHz, CDCl )δC 170.34, 162.95, 158.89, 138.10, 137.13, 131.27,
3
129.46, 128.75, 127.64, 126.32, 122.58, 85.54, 52.57, 52.20.

M. Saroha, J. Sindhu and P. Kumar et al. / Journal of Molecular Structure 1225 (2021) 129089
9
Dimethyl 2-((4-chlorophenyl)thio)-3-((4-fluorophenyl)amino)fumarate
4 h)
Off white solid; 1H NMR (400 MHz, CDCl )δ 10.79 (s, 1H, NH),
Acknowledgement
(
The authors thanks SAIF, PU for spectral data
3
H
7
.27–7.12 (m, 6H, ArH), 7.03 (t, J = 8.5 Hz, 2H, ArH), 3.72 (s, 3H,
13
Supplementary materials
COOCH ), 3.63 (s, 3H, COOCH ); C NMR (100 MHz, CDCl )δ
C
3
3
3
1
70.34, 162.74, 161.03(d, 1 C-F
J
= 246 Hz), 159.39, 137.01, 134.14,
= 24.7 Hz), 85.57,
31.38, 128.77, 127.72, 125.33, 116.26 (d, 2
J
C-F
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2020.129089.
1
5
2.54, 52.15.
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