Synthesis of 5-Acyl-2-Amino-3-Cyanothiophenes: Chemistry and Fluorescent Properties

Article abstract of DOI:10.1002/asia.201700721

Independent of the substrate structure and reaction conditions, 3-amino-2-cyanothioacrylamides, which contain two active electrophilic centers, were shown to interact with various active halo methylene compounds under mild conditions to afford 5-acyl-2-amino-3-cyanothiophenes as the only products. A series of new polyfunctional thiophene derivatives with a rare combination of functionalities were synthesized, and their photophysical properties were experimentally and computationally investigated. The calculated electronic characteristics of the ground and excited states were compared to the experimental results, which provided a good understanding of the relationship between the optoelectronic properties and the molecular structures. After absorption of light quanta, the systems populate an intramolecular charge-transfer (ICT) Franck–Condon state, and emission occurs from a twisted ICT minimum.

Full text of DOI:10.1002/asia.201700721

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AN ASIAN JOURNAL
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Accepted Article
Title: New Promising Method for the Challenging Synthesis of 5-Acyl-2-
Amino-3-Cyanothiophenes: Chemisry and Fluorescent Properties
Authors: Kseniya I. Lugovik, Alexander K. Eltyshev, Enrico Benassi,
and Nataliya P. Belskaya
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10.1002/asia.201700721
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New Promising Method for the Challenging Synthesis of 5-Acyl-2-
Amino-3-Cyanothiophenes: Chemisry and Fluorescent Properties
Kseniya I. Lugovik,[a] Alexander K. Eltyshev,[a] Enrico Benassi,*[b] Nataliya P. Belskaya*[a]
Abstract: Independent of the substrate structure and reaction
conditions, 2-cyano-3-aminothioacrilonitriles, which contains two
active electrophilic centers, were shown to interact with various active
halo methylene compounds under mild conditions to afford 5-acyl-2-
amino-3-cyanothiophenes as the only products. A series of new
polyfunctional thiophene derivatives with a rare combination of
functionalities were synthesized and their photophysical properties
were experimentally and computationally investigated. The calculated
electronic characteristics of the ground and excited states were
compared to the experimental results, which provided a good
understanding of the relationship between the optoelectronic
properties and the molecular structures. After absorption of light
quanta, the systems populate an intramolecular charge transfer (ICT)
Franck-Condon state, and emission occurs from a twisted ICT (TICT)
minimum.
from the presence of additional fluorogenic heterocycles in their
structure.[7] In addition, the design and synthesis of new small
molecule fluorophores with a required set of functionalities or
substituents is interesting for understanding this phenomenon,
extending the fluorescent compound set, and broadening their
application in medicine and biology.
The classical approaches for the synthesis of substituted
thiophenes are based on subsequent functionalization of the
thiophene ring or condensation reactions, which directly afford
polyfunctionalized thiophenes.[1,2a,8] Stepwise modification of the
thiophene nucleus often consists of a prolonged, multistep
process.[2a] Additionally, the introduction of specific functionalities
(CN-group) or combinations of functionalities using this approach
is a challenge in thiophene chemistry. Furthermore, the synthesis
of thiophenes bearing acyl and amino group is also difficult. The
conventional method for regioselective formation of substituted
thiophenes that starts from acyclic precursors is based on
heterocyclization of functionalized alkynes.[8a,b] Nevertheless, this
method provides mainly alkyl- or aryl-substituted thiophenes and
only limited types of functionalized derivatives (e.g.,
alkoxycarbonyl). The most convenient method for preparing
thiophenes is the well-known Gewald method.[8b] This method is
the most suitable route for obtaining 2-aminothiophenes, which
are useful intermediates in the preparation of dyestuffs and
pharmaceuticals.[2a] However, this methodology is typically
associated with several drawbacks including harsh reaction
conditions as well as complex and tedious experimental
procedures, and limited yields are often obtained. A promising
alternative consists of a one-step straightforward method for the
synthesis of highly functionalized thiophene scaffolds based on
the heterocyclization of thioacetamide derivatives bearing
additional electrophilic centers with bromoketones.[8] According to
this mechanism, the typical transformation involves the cyclization
of arylhydrazonothioacetamides 1, which affords a series of 1-
Introduction
The thiophene ring is an attractive core among five-membered
heterocycles due to their broad use in various fields. Thiophenes
are a classical bioisostere for the benzene ring in medicinal
chemistry.[1] Many molecules bearing a thiophene ring exhibit
important pharmacological activities.[1,2] Some of these molecules
are biologically active natural compounds and plant pigments.[1]
Due to their unusual electronic nature and low aromaticity,[1,2]
thiophenes are an ideal molecule for applications in polymers,
liquid crystals and dyes which find wide applications in material
science[1,3] and coordination chemistry.[4] Thiophene and
polythiophene are also efficiently applied as π-bridges, which
improves the molecular hyperpolarizability of the push-pull
systems.[5] Unsubstituted thiophene and bithiophene are not
capable of emission,[1] and limited examples of thiophene
derivatives (functionalized mono- or bithiophenes) with
fluorescent properties have been reported.[6] Fluorescence of
heterocyclic systems including thiophenes rings typically arises
acyl-3-amino-4-arylazo-5-tert-cycloalkylaminothiophenes
(Scheme 1).[8d,e]
4
However, 3-cyclohexylamino-3-cyanopropenthioamide 6, which
is generated in situ from 3-morpholino-3-thioxopropane nitrile 5a
and cyclohexyl isocyanide, reacts with phenacyl bromides
followed by the subsequent formation of 2-morpholino-5-
aroylthiophenes 8. Scheme 2 outlines the route devised to
prepare compounds 8 via formation of enamine 6B followed by
alkylation, cyclization and aromatization, which is accomplished
by elimination of cyclohexylamine.[8c]
[a]
[b]
Ksenia, I. Lugovik, Alexander K. Eltyshev, Prof. Nataliya P.
Belskaya
Ural Federal University,
19 Mira Str., Yekaterinburg 620002 (Russian Federation)
E-mail: n.p.belskaya@urfu.ru
Dr. Enrico Benassi
Scuola Normale Superiore,
Piazza dei Cavalieri 7 56126, Pisa (Italy)
E-mail: enrico.benassi@sns.it
Supporting information and the ORCID identification numbers for the
authors for this article is given via a link at the end of the document.
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Scheme 1.
Scheme 2.
synthesis, we chose a two-step procedure based on the
condensation of readily available cyanothioacetamides[9a,10] with
dimethylformamide dimethylacetal (DMFDMA) followed by
nucleophilic substitution of the dimethylamine moiety by the
desired secondary or tertiary amines (Scheme 3, Table 1). The
method for the synthesis of the arylaminothioacrylamides was
previously described and verified.[9c]
The investigation of this reaction with a wide range of α-
haloketones, α-halonitrile, α-haloanilide and α-haloester allowed
for the preparation of thiophenes with phenacyl bromides and
chloroacetonitrile.[8c] However, 2-chloro-N-phenylacetamide and
ethyl-2-chloroacetate failed to take part in this methodology.
The aim of this investigation was to elaborate this method for
the synthesis of polyfunctionalized thiophenes involving various
3-aminothioacrylamides and different types of halogen
compounds with activated methylene group, determine the
potential for realizing two alternative synthetic mechanisms for
their heterocyclization (Schemes 1 and 2), and estimate the scope
and limitation of the investigated process. Therefore, we designed
the structure of the starting compounds along with the synthetic
tasks. The synthesized thiophene compounds were subsequently
characterized to determine their spectroscopic and photophysical
properties.
Results and Discussion
Availability, variability, safety, and environmental impact of
starting compounds are important factors to consider during the
design of a synthetic methodology. Cyanides (Scheme 2) are very
toxic and volatile compounds and difficult to synthesize.
Alternative reagents may include aminothioacrylamides, which
are readily accessible by a variety of different methods.[9] For their
Scheme 3.
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This approach allowed for the preparation of a series of various
aminothioacrylamides 9a-h and 11a-с for use in the research.
First, we focused on investigating the reaction of 3-
arylaminothioacrylamides 11a-c with phenacyl bromides 2a-d
under different conditions (Scheme 4). It is important to note that
thioamides 9 and 11 contain two electrophilic centers and can
formed thiophenes 12 and 13.
For thioamides 11a-c, the electrophilicity of the enamine carbon
atom (CCH) in intermediate B was expected to decrease in
contrast to intermediate A because the probability of involving the
CN-electrophilic center in the last stage of the cyclization may
increase (Scheme 4). To confirm this hypothesis, we initially
carried out the reaction of 11a-c with phenacyl bromide 2a-d in
DMF without base or in the presence of base (1 equiv. of TEA or
10% KOH) at 80 °C. These conditions were chosen due to the
better solubility of the starting reagents and according to the
Table 1. Conversion time and yields for the synthesis of
aminothioacrylamides 9a-h and 11a-c.
Entry
Comp
NR2R3
NMe2/HNR4
Time [h]
Yield[a]
[%]
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
11a
11b
11c
Morpholin-4-yl
Piperidin-1-yl
Pyrrolidin-1-yl
NHMe
NH-nBu
NHBn
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
2.0
2.0
2.0
2.0
3.0
2.0
2.0
4.0
3.0
2.5
3.0
75
86
92
65
67
84
57
50
75
65
87
NHPh
2-MeOC6H4
Morpholin-4-yl
Morpholin-4-yl
Morpholin-4-yl
9
10
11
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
[a] Isolated yields after purification.
literature
data
for
the
same
transformation
of
Newly synthesized compounds 9d-h and 11a-c were
characterized by elemental analyses, MS and NMR. These data,
which are provided in the Supplementary Information (SI, Figures
S1-11), are consistent with the suggested structures. It is
important to note that compounds 11 were isolated as a mixture
of Z- and E-isomers.
arylhydrazonothioamides 1.[8d,e] The reaction proceeded rather
quickly and independently of the presence base, the nature of the
substituent on the aromatic ring of enamine moiety (MeO, Cl or
NO2) or phenacyl bromide 2a-e (MeO, H, Cl, NO2), and
thiophenes 12a-d were uniquely obtained in all cases (Table 2).
Scheme 4.
Table 2. Reaction of 3-aminothioacrylamides and 11a-c with phenacyl bromides 2a-d.
Entry
1
Comp 11
R4
Comp 2
Comp 12
R1
Time [h]
0.5
Yield 12[a] [%]
11a
4-MeOC6H4
2a
12a
4-ClC6H4CO
87
2
3
4
5
6
11b
11c
11b
11b
11b
4-ClC6H4
4-NO2C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
2a
2a
2b
2c
2d
12a
12a
12b
12c
12d
4-ClC6H4CO
4-ClC6H4CO
4-MeOC6H4CO
4-C6H5CO
0.5
1.5
1.0
1.0
2.5
94
85
93
62
63
4-NO2C6H4CO
[a] Isolated yields after purification.
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The 1H and 13C NMR spectra, mass spectra, and FTIR spectra
were consistent with the expected structures for compounds 12a-
d (See Experimental part and SI, Figures S12-15). In the mass
spectra of compounds 12a-d, peaks for molecular ions with 46-
100% relative intensity were readily observed. All 5-
aryloxycarbonyl-substituted 2-aminothiophenes 12a-d exhibited
bands at 1600-1642 (C=O) and 2208-2215 cm-1 (CN) in their FTIR
spectra. The positions of these bands are not typical for CN and
CO bond stretching and may be due to their strong conjugation
with the thiophene ring. The 13C NMR spectra contained common
signals corresponding to carbon atoms in the carbonyl group, CN
groups and C4H thiophene ring at 169.3-169.9 ppm, 114.4-117.0
ppm and 136.9-149.0 ppm, respectively. The extreme shift in the
CO signal to high field suggests strong conjugation with the
heterocyclic scaffold. This interpretation of the spectral data was
subsequently supported by quantum mechanical calculations
(vide infra).
To highlight the differences in the two possible reaction curves
(via stage I or stage II) for reagents 11a and 2a, we performed
quantum chemical calculations using density functional theory
(DFT) and accounted for solvent effects (DMF) using IEF−PCM
(cf. Computational Details). The charge distribution and
electrostatic potential for all compounds (viz., reactants,
intermediates, and products) and the difference in the
thermochemical quantities (including the Gibbs free energies) for
the reactions including the last stage (I) leading to thiophene 12a
(ΔGI) and reaction with the last stage (II) leading to thiophene 13a
(ΔGII) were calculated (SI, Scheme S1). The ESP charge
distribution analysis (SI, Figure S37, Table S3) demonstrates that
the largest amount of charge was localized on carbon atom CCN
(q = 0.527 e), and this value should be compared to carbon atom
CCH of the enamine moiety (q = 0.365 e), which confirms the
significant decrease in its susceptibility to nucleophilic attack atom
CCH2. However, the electrostatic potential values for these atoms
intramolecular interaction between the sulfur atom and the
nitrogen atom of the enamine group (lS∙∙∙N = 3.005 Å, the sum of
van der Waals radiuses for these atoms is RΣvdW(S-N) = 3.355 Å).
The presence of this interaction was confirmed by the RDG plot
(Figure 1 c),[12] which is a state-of-the-art technique based on the
electron density that is particularly reliable for investigating weak
interactions.
a
b
c
Figure 1. Intermediate B (in solution of DMF). (a) MEP; (b) optimized geometry;
(c) RDG plot. Legend of MEP colors: red (negative potential) and blue (positive
potential). Legend for the elements: hydrogen (white), carbon (grey), nitrogen
(blue), and oxygen (red).
The synthetic results indicate the preferred participation of the
carbon atom in the =CHNHAr group and exclusion of the CN
function from the heterocyclization process. This behavior
indicates that the reaction mechanism is independent of the
substituent at the amino moiety in 3-aminopropene thioamides
11a-c. Therefore, further investigations involved only the use of
3-aminothioacrilamide 9a-i with a =CHNMe2 group. These
substrates provide the best reactivity due to the formation of
intermediate A (Scheme 4 and 5) and represent the most
convenient solution in term of atom economy and technological
arrangement of the process due to the elimination of a smaller
and more easily separated dimethylamine molecule with respect
to 4-chloraniline or 4-anisidine during the reaction.
Next, we used the optimal reaction conditions (DMF, 80 °C) to
synthesize a series of new functionalized thiophenes (Table 3).
To investigate the scope of this reaction, we employed a range of
halocarbonyl compounds 2a,b,e-g, 2-chloroacetonitrile 2h,
pycolyl chlorides 2i,j, and along with the 3-morpholinoderivatives,
we employed thioamides 9b-h with other tert-cycloalkylamino and
different secondary amino groups. Most of the condensed
reagents 2 afforded the desired thiophenes with satisfactory
yields and short reaction times. It is important to note that a
decrease in the activity of the CH2 group in halomethylene
compounds 2e-j and the use of chloro derivatives slow down the
process. Further improvement in the protocol was achieved by
addition of 1 equivalent of TEA (Table 3, entries 12-17) for all
these cases.
are much closer (-14.755 and -14.729 a.u. for atoms CCN and CCH
,
respectively) (SI, Table S3). The appreciably negative ΔGI = -
42.0 kJ/mol for the transformation of 11a and 2a to 12a compared
to Δ GII = -30.4 kJ/mol for the same transformation to 13a
indicates that the formation of thiophene 12a is the most
thermodynamically favorable (SI, Table S1). Therefore, the
reaction was under thermodynamic control and followed direction
I to more stable thiophenes 12.
A
very useful descriptor for determining the sites for
nucleophilic/electrophilic attack is a map of the molecular
electrostatic potential (MEP).[11] The MEP (Figure 1 a) provides a
visual representation of the chemical active sites and comparative
reactivity of atoms. The potential value increases according to a
continuum scale of colors from red (negative) to blue (positive). In
our case, negative regions in the MEP corresponded to
electrophilic reactive centers, and positive regions corresponded
to nucleophilic reactive centers. The MEP was calculated for
intermediate B and indicated that the CCN atom is the most
electrophilic site. In addition, the CCH2 atom was the most
nucleophilic site (Figure 1 a).
The optimized geometry of intermediate B (Figure 1 b)
possessed a CCH2 and CCH (3.112 Å) distance that was shorter
than that between another pair of electrophile and nucleophile
centers (CCH2-CCN = 5.120 Å). Such rapprochement of the two
active sites can be explained by the presence of a weak
Most of the heterocyclic compounds described herein are new
compounds whose structures were unambiguously confirmed
using elemental analysis, NMR, FTIR spectroscopy
(Experimental section and SI, Figures S16-31) and mass
spectrometry. The thiophenes were obtained as yellowish solids.
Their solutions in organic solvents exhibit fluorescence under
irradiation with UV light. (SI, Figures S45-47).
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Scheme 5. Conditions: a - DMF, 80 °C; b – DMF, 1 equiv. TEA, 80 °C
Table 3. Reaction of 3-aminothioacrylamides 9a-h with halo methylene compounds 2a,b,e-j.
Entry
Comp 9
NR2R3
Comp 2
Comp 12
R1
NR2R3
Time [h]
Yield[a] 12 [%]
1
9a
9b
9c
9c
9d
9d
9e
9f
Morpholin-4-yl
Piperidin-1-yl
Pyrrolidin-1-yl
Pyrrolidin-1-yl
NHMe
2a
2b
2b
2a
2b
2a
2a
2a
2a
2b
2a
2e
2f
12a
12e
12f
4-ClC6H4CO
Morpholin-4-yl
Piperidin-1-yl
Pyrrolidin-1-yl
Pyrrolidin-1-yl
NHMe
0.5
94
90
80
67
87
62
72
93
96
72
84
78
56
84
83
92
93
2
4-MeOC6H4CO
4-MeOC6H4CO
4-ClC6H4CO
0.5
3
0.5
4
12g
12h
12i
0.5
5
4-MeOC6H4CO
4-ClC6H4CO
0.5
6
NHMe
NHMe
0.5
7
NHnBu
12j
4-ClC6H4CO
4-ClC6H4CO
4-ClC6H4CO
4-MeOC6H4CO
4-ClC6H4CO
MeCO
NHnBu
0.5
8
NHBn
12k
12l
NHBn
0.5
9
9g
9g
9h
9a
9a
9a
9a
9a
9a
NHPh
NHPh
0.5
10
11
12
13
14
15
16
17
NHPh
12m
12n
12o
12p
12q
12r
12s
12t
NHPh
1.0
2-MeOC6H4
Morpholin-4-yl
Morpholin-4-yl
Morpholin-4-yl
Morpholin-4-yl
2-MeOC6H4
Morpholin-4-yl
Morpholin-4-yl
Morpholin-4-yl
0.5
0.5[b]
1.0[b]
1.0[b]
1.0[b]
1.0[b]
2.0[b]
EtOOC
2g
2h
2i
EtOOCCO
CN
Morpholin-4-yl
Morpholin-4-yl
Morpholin-4-yl
Morpholin-4-yl
Morpholin-4-yl
Pyridin-4-yl
Pyridin-2-yl
2j
[a] Isolated yields after purification. [b] Reaction carried out with 1 equiv. TEA.
The range of applicability of the reported method was extended
to the synthesis of bithienoketones 15a-e using dichloroacetone
under ambient conditions for condensation with thioamides 9a-
d,g. The reactions performed well with satisfactory rates and
product yields (Scheme 6). The 1H NMR spectra for newly
synthesized compounds 15a-e contain characteristic signals for
all the proton-containing groups. The 13C NMR spectra are shown
in Figures S32-36 (SI). The carbonyl carbon atom signal was
located at 164.9-173.7 ppm, the thiophenes C4H carbon signal
was located at 134.8-136.9 ppm, and the signal at 112.3-116.7
ppm was due to the CN carbon atom. Details of the experimental
procedures and data for structural characterization are provided
in the Experimental Section as well as the Supporting Information
(SI).
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Scheme 6.
UV-Vis Absorption and Fluorescence Spectra
of compounds is related to the equilibration between two
conformers (i.e., the former has a twisted geometry, and the latter
has a planar geometry).[13]
The photophysical properties of prepared compounds 12a-t and
15a-e were investigated using UV-Vis and fluorescence
spectroscopy in dioxane at room temperature (Table 4 and Figure
2). The UV-Vis spectra of thiophenes 12a-t, 15a-e exhibit a λmax
in the range of 321-418 nm (Table 4). The molar extinction
coefficients indicate that the main band in the absorption spectra
resulted from population of a charge transfer state, which was
primarily due to a π→π* transition. The change in the nature of
the substituent in the aroyl group at the C5Thioph position does not
significantly affect the absorption spectrum, and a small shift in
the longest wavelengths from 361 nm to 377 nm (1176 cm-1) was
observed (Table 4, entries 1-4, Figure 2 a). In contrast,
replacement of the aroyl group at the C5 thiophene carbon atom
to acetyl, ethoxycarbonyl, and CN groups resulted in a dramatic
hypsochromic effect for the longest wavelengths (Table 4, entries
15-18, Figure 2 e). In addition, introduction of 2- or 4-pyridine at
the C5 thiophenes ring causes the same effect (Table 4, entries
19, 20). Notably, bithienoketones 15a-e result in a redshift of the
longest wavelengths (Table 4, entries 21-25) in the 383-418 nm
region (Figure 2 g).
Similar to the UV-Vis absorption spectra, the fluorescence
spectra and their efficiencies can also be tuned by substituents
on positions 2 and 5 of the thiophene ring. Changes in the
substituents in the para position of the aroyl C5Thioph fragment as
well as the type of amine group in the C2 thiophene affect the
emission spectra and quantum yields. For example, the presence
of a 4-NO2-benzoyl moiety at the heterocycle C5 atom quenches
the efficiency of the emission (Table 4, entry 4). High quantum
yield values were obtained for thiophenes 12b,e,f,m (Table 4,
entries 2,5,6,13). Therefore, structures including
a
4-
methoxybenzoyl substituent may stabilize the excited state and
enhance the probability for electron transition. The structure of the
amine group attached to C2 thiopene is also important for the
fluorescence intensity. The presence of a tert-cycloalkylamino or
phenyl amino group enhances the fluorescence quantum yield.
It is important to note that an increase in the quantum yields of
bithienoketones 15a,c-e occurs along with a small bathochromic
shift and blue-green fluorescence (Table 4, entries 21-25 and
Figure 1 d). The largest Stokes shifts was observed for
thiophenes 12a,l,n,q and bithienoketone 15b. As observed in
related structures, this phenomenon indicates large differences
between the Franck-Condon state and the relaxed adiabatic
minimum from which the emission occurs.
The fluorescence spectra of all the studied compounds exhibit
a maximum wavelength for emission at 400–475 nm as well as
blue and blue-green light emission. The emission spectra of
compounds 12i-k,n,p,q,s exhibited dual fluorescence and were
broadened, especially for compound 12j and 12n (HWHM = 5759
and 6208 cm-1, respectively). The dual florescence of these types
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Table 4. Photophysical properties of compounds 12a-t and 15a-e in 1,4-dioxane.
ΦF [a] [%]
εmax [M-1∙cm-1]
Stokes shift [nm/cm-1]
Comp
λabs [nm]
λem [nm]
HWHM[b] [cm-1]
Entry
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
12q
12r
365, 254
361, 286
362, 285
377, 259
367, 286
371, 284
374, 250
385, 281
362, 281, 249
363, 249
362, 250
374
22645, 13358
22347, 11514
21311, 5807
24386, 17150
21311, 12582
26271, 13320
24146, 12582
26658, 13318
26148, 3828, 9823
22745, 12016
21970, 10925
11584
456
441
450
1.53
6.62
1.58
-
3175
2737
3051
-
91/5467
80/5025
88/5402
-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
[c]
-
442
441
460
7.78
6.40
0.90
0.90
1.64
0.80
0.80
4.04
3.77
0.30
0.65[d]
0.31[d]
0.23
2.33[d]
0.64
1.85
3.1
2623
2623
3293
3097
4490
5759
4672
3314
3409
6208
3045
2690
4130
3199
4269
3097
2261
2215
75/4624
70/4248
86/4999
86/4999
46/2826
84/5177
87/5353
91/5233
80/4781
89/6312
56/4070
79/5983
90/5088
79/6153
59/4233
61/4286
56/3144
92/5057
432
408, 448
415, 447
415, 449
465
451
423, 462
400
387(sh), 405
432, 468
400
388, 404
409
371, 291
373
23524, 13628
20776
344, 285
326, 286
378, 286
321
345, 281
348, 293
395, 329, 283
383, 294
18847, 5564
19348, 6200
15655, 5089
14979
20385, 16599
20345, 6835
12115, 8335, 8807
13018, 9830
30617, 6311,
10953
12s
12t
15a
15b
451
475
1.2
15c
15d
418, 360, 291
465
465
3.9
3.9
2087
2147
47/2418
61/2418
23
24
403, 291
412
12248, 4560
24311
25
15e
468
3.3
2020
56/2904
[a] - The fluorescence quantum yields (Φ) were estimated with quinine sulfate (ΦF) 0.55 in a 1 N H2SO4 solution as a standard, λex = 366 nm (5×10-5 М) (dioxane,
5×10-6 М).[14] [b] – Half-Width at Half Maximum. [c] - No emission. [d] - The fluorescence quantum yields (ΦF) were estimated with anthracene (ΦF) as a standard,
λex = 376 nm (solvent in EtOH).[14].
a
b
c
d
e
f
g
h
Figure 2. Absorption (c = 5×10-5 M) and normalized fluorescence spectra (c = 5×10-6 M) of thiophenes 12a-g (a,b), 12h-n (c,d), 12o-t (e,f) and bithienoketones 15a-
e (g,h) in 1,4-dioxane at room temperature.
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New thiophene derivatives 12 and 15 exhibit good solubility in
common polar and non-polar organic solvents, such as n-hexane,
1,4-dioxane, toluene, chloroform, acetone, acetonitrile, alcohols,
DMF and DMSO. To evaluate the effect of the solvent polarity on
the absorption and emission of the synthesized thiophenes, the
spectra of compounds 12a,b were measured in solvents with
different polarities (Table 5, Figure 3). The (fluoro)solvatochromic
results indicate that a long-wavelength absorption band is located
in the 355 to 374 nm region in more polar solvents. Thiophenes
12a and 12b absorb in the UV-Vis region between 355 and 374
nm and 359 and 370 nm, respectively.
Table 5. Absorption and emission maxima, quantum yield and Stokes shift of thiophenes 12a and 12b in different solvents at room temperature.
ΦF [a] [%]
εmax [M-1∙cm-1]
Comp
Solvent
Hexane
λabs [nm]
λem [nm]
HWHM[b] [cm-1]
Entry
1
Stokes shift [nm/cm-1]
12a
21461, 13254,
24244
355, 255, 212
439
0.74
3454
84/5390
2
3
4
5
6
7
Toluene
1,4-Dioxane
CHCl3
AcOEt
CH2Cl2
365
365, 254
365
364
367, 356
374
26052
22645, 13358
25325
22520
18596, 10360
23430
450
456
460
421, 464
417, 464
433
2.17
1.53
1.05
0.52
0.73
0.48
2982
3175
3478
3475
3571
3729
85/5175
91/5467
95/5658
100/5921
97/5696
59/3643
DMSO
22991, 13296,
26112
21363
22832, 13961,
28483
8
9
iPrOH
DMF
367, 257, 213
371
416, 459
424, 475
423, 463
0.40
0.20
0.23
3806
4839
4411
92/5462
104/5902
95/5576
10
EtOH
368, 256, 210
11
12
13
14
15
16
17
18
19
20
21
22
23
24
MeCN
Aceton
THF
Toluene
1,4-Dioxane
CHCl3
AcOEt
DMSO
DMF
368, 253
366
365, 252
360
361
361
359
370
364
364
21707, 12060
22828
22828, 13860
21623
421, 466
422, 475
416, 463
431
441
442
443
461
455
455
0.14
0.24
1.00
6.47
6.62
6.11
3.69
1.84
3.02
0.73
1.04
2.54
1.72
4.91
5485
3695
3888
2737
2656
2757
2757
2989
3204
3245
3026
2856
3065
2737
98/5714
109/6270
98/5799
71/4576
80/5025
81/5076
84/5282
91/5335
91/5495
91/5495
93/5618
90/5528
87/5326
83/5204
12b
22347
24055
20484
19303
20744
20435
20153
19950
EtOH
MeCN
Acetone
iPrOH
363
361
363
360
456
451
450
443
21547
23287
THF
[a] - The fluorescence quantum yields (Φ) were estimated with quinine sulfate (ΦF) 0.55 in a 1 N H2SO4 solution as a standard, λex = 366 nm (5×10-5 М)
(dioxane, 5×10-6 М).[14] [b] - Half-Width at Half Maximum.
a
b
c
d
Figure 3. UV-Vis absorption (5×10-5 M) and normalized fluorescence spectra (5×10-6 M) of thiophenes 12a (a,b) and 12b (c,d) in different solvents at room
temperature.
Although the absorption spectra are slightly dependent on the
solvent polarity (shift of 995 and 1432 cm-1 for 12a and 12b,
respectively), the emission spectra exhibit more remarkable
upon photoexcitation. Compounds 12a and 12b exhibit
remarkable Stokes shifts in the 3643-6270 cm-1 and 4576-5618
cm-1 ranges, respectively. The largest Stokes shifts for thiophenes
fluorosolvatochromic effects (2042 and 1510 cm-1 for 12a and 12b, 12a,b were observed in polar solvents (i.e., acetone and
respectively), which suggests that emission is occurring from an
ICT minimum in the excited state. The extent of the
solvatochromic shift strongly depends on the nature of the
substituent on the aroyl group. The increasingly red-shifted
emission may be due to the higher electron acceptor strength of
the Cl substituent and an increased degree of charge transfer
acetonitrile, respectively), which supports the hypothesis that an
ICT transition occurs during the photoexcitation. The fluorescence
intensity is very sensitive to the solvent polarity for compound 12a
and 12b. The quantum yields for 12a and 12b were in the 0.14-
2.17% and 0.73-6.62% ranges, respectively. For compound 12a,
in addition to the principal band, an additional band in the 416-
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423 nm range was observed when the spectra were recorded in
polar solvents (i.e., MeCN, AcOET, EtOH, THF, iPrOH, DMF,
acetone and DCM), suggesting that highly polar solvents favor
rotational isomerization of the substrate to a polar TICT minimum
(Figure 3 b).
representative thiophenes (i.e., 12a-d,i,l,m,n,s,t and 15a,d).
Notably, most of the synthesized thiophenes (12 and 15) may
exist as a mixture of several conformers (Figure 4 and more
additional examples in SI, Figure S38). After studying the
rotameric equilibria, the same global minimum rotamer was
revealed within the same group of compounds. For example, the
cis-SO rotamer (i.e., B) with a C=O group and S-atom of the
heterocycle ring in a cis conformation was predicted to be the
most stable form for thiophenes 12a-d. For the bithienoketones,
the S-atom in the thiophene ring (cis-SO-trans-S) of the most
stable rotamer (i.e., B) has the opposite orientation. The
stabilization is supported by the presence of weak attractive
intramolecular interactions.
Quantum mechanical calculations
To confirm the trends revealed by the experimental investigations
and their interpretation, quantum mechanical calculations were
performed using time-dependent density functional theory (details
are provided in the dedicated section) for
a number of
12a (rotamer А)
12a (rotamer B)
12i (rotamer A)
12i (rotamer B)
Δ(E+ZPE) = 1.8 kcal/mol
ΔH = 1.6 kcal/mol
ΔG = 1.8 kcal/mol
f = 0.049
Δ(E+ZPE) = 0.0 kcal/mol
ΔH = 0.0 kcal/mol
ΔG = 0.0 kcal/mol
f = 0.954
Δ(E+ZPE) = 1.7 kcal/mol
Δ(E+ZPE) = 0.0 kcal/mol
ΔH = 0.0 kcal/mol
ΔG = 0.0 kcal/mol
f = 0.942
ΔH = 1.8 kcal/mol
ΔG = 1.2 kcal/mol
f = 0.053
12l (rotamer C)
12l (rotamer D)
15d (rotamer A)
15d (rotamer B)
Δ(E+ZPE) = 5.1 kcal/mol
ΔH = 5.2 kcal/mol
ΔG = 5.3 kcal/mol
f = 0.000
Δ(E+ZPE) = 3.1 kcal/mol
ΔH = 3.2 kcal/mol
ΔG = 3.6 kcal/mol
f = 0.005
Δ(E+ZPE) = 2.0 kcal/mol
ΔH = 2.0 kcal/mol
ΔG = 2.0 kcal/mol
f = 0.032
Δ(E+ZPE) = 0.0 kcal/mol
ΔH = 0.0 kcal/mol
ΔG = 0.0 kcal/mol
f = 0.969
Figure 4. Rotameric study. Relative electronic energy plus zero point energy (Δ(E+ZPE)), Gibbs free energy (ΔG), enthalpy (ΔH) and Boltzmann factor (f) computed
at 300 K for ground state of possible thiophene rotamers in 1,4-dioxane. Level of theory: DFT M06-2X (SMD) / aug-cc-pVTZ.
The preference for the same rotamer was confirmed in other
solvents (i.e., DCM, acetone, MeCN, and DMSO). The origin of
the stability of the different rotamers was investigated by
analysing the intramolecular interactions via a reduced density
gradient (RDG)[12] for compounds 12a,b,g,n,s,t, and 15a (SI,
Figure S39). Within thiophene molecules, various weak
intramolecular interactions were detected, and these interactions
are responsible for the stabilization of the rotamers and affect the
vibronic relaxation after excitation. The strongest of these
interactions was observed between the aromatic and thiophene
rings, which stabilizes the cis-conformation of the C=O group and
S-atom of thiophenes 12 and 15 (SI, Figure S39).
of thiophene and the O-atom of the carbonyl group (2.922-2.950
Å) (SI, Tables S4-6). Hypervalent non-bonded interactions of a
divalent sulfur atom and a nearby heteroatom were previously
reported in organic compounds.[15] The directionality of the
interaction strongly suggests the importance of the orbital
interaction between the interacting atoms for stability. For the S•
••O interactions, the stabilization primarily arises from the n(O) →
σ*(S) orbital interaction. The electrostatic nature of the 1,4-type S
•••O interactions between a positively charged S atom and a
negatively charged carbonyl O atom was proposed by Burling and
Goldstein.[15c]
Any substituents that are attached to thiophenes (CN, NR1R2,
C=O) participate in conjugation and extend the π-network in the
ground state. A small twist θ from planarity is also indicative of
extended π-electron delocalization. Only an aromatic ring bound
to the carbonyl fragment in the C5-position of thiophenes exhibits
a significant deviation from planarity (30.3-37.7 degs; SI, Tables
S4-6).
In addition, we investigated the stabilization of rotamer B for
derivatives 12a-d,i,l-n and 15d in the ground (S0) and excited (S1)
states. The RDG analysis confirmed
a series of internal
interactions (SI, Figure S39) that are responsible for this particular
conformation. Along with the S∙∙∙H-CMorph (2.922-2.959 Å) and
C=O∙∙∙H-CAr (2.571-2.656 Å) hydrogen bonds in the ground state,
additional weak interactions were observed between the S-atom
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Remarkable changes occur when S1 is populated upon
excitation and relaxes towards the emissive minimum of the
excited state PES. S∙∙∙H-CMorph becomes shorter in compounds
12a-d (from 2.527-2.617 Å in S0 to 2.475-2.484 Å in S1) but
elongates in compounds 12i,l,n (from 2.453-3.030 Å in S0 to
2.487-3.275 Å in S1). The interaction between the S and O atoms
weakens, which results in an increase in the interatomic distance
(from 2.932-2.950 Å in S0 to 3.328-3.357 Å in S1). The exception
is compound 12l, where excitation leads to this weak interaction
strengthening (from 2.922 Å in S0 to 2.784 Å in S1). In general, we
can conclude that photoexcitation leads to weakening of the
intramolecular interactions in favor of a more twisted conformation
in excited state S1 than in the ground state. The dihedral angle
between the aroyl fragment and the thiophene ring increases (up
to 82.2-86.1degs) due to the electronic structure separating into
two independent parts. It is important to note that the C=O bond
lengths are shorter in the ground state than in S1 (from 1.248 Å in
S0 to 1.290 Å in S1; SI, Tables S5-7), which typically occurs due
to a decrease in conjugation during the excitation.
Table 6. Calculated absorption and emission properties[a] for most stable rotamer of thiophenes 12a-d,i,l,m,n,s,t and 15d.
Entry
Comp
12a
12b
12c
12d
12i
c
λa [nm]
f01
μ0 [D]
μ1v [D]
θ0,1v [°]
c’
λe, [nm]
Δν [kK]
f10
μ1r [D]
θ0,1r [°]
1
2
0.67978
0.68518
0.61115
0.70446
0.66541
0.69881
0.69184
0.69999
0.69876
0.70017
0.70222
365.9
362.1
363.0
378.1
363.2
375.1
371.8
373.2
346.4
348.9
403.9
0.4011
0.5243
0.2759
0.1162
0.3538
0.5522
0.6457
0.5661
0.4864
0.5302
0.5471
2.7
1.9
6.3
6.6
3.9
3.5
4.5
5.1
3.4
3.9
4.0
9.4
3.1
28.7
145.8
118.6
15.3
20.9
19.6
111.6
6.3
-0.69667
0.69371
0.69568
0.69983
-0.69621
-0.69868
0.68595
-0.69178
-0.69765
0.69620
-0.69781
457.4
442.3
451.1
898.9
448.9
466.7
452.3
462.6
404.8
410.1
464.6
5.47
5.01
5.38
13.93
5.26
5.23
4.79
5.18
4.16
4.27
3.23
0.0216
0.0229
0.0114
0.0081
0.0157
0.0230
0.0930
0.0012
0.0056
0.0087
0.0251
9.4
10.6
5.0
28.7
133.6
118.6
14.5
21.9
17.1
65.1
7.8
3
5.0
4
28.4
9.7
33.3
12.7
21.4
11.2
19.0
9.2
5
6
12l
11.5
5.1
7
12m
12n
12s
12t
8
15.3
7.0
9
43.2
99.3
27.9
38.9
109.8
104.7
10
11
2.7
5.1
15d
4.6
12.5
[a] Computed orbital’s coefficient (c and c’), absorption wavelength (λa, nm), fluorescence wavelength (λe, nm), oscillator strength (f01 and f10), modulus of the
electric dipole moments of the ground state (μ0, D) and of the vertical FC excited state (μ1v, D), angles formed by the dipole moment vectors (θ0,1v and θ0,1r).
UV-Vis absorption and emission spectra of molecules 12a-
l-n and 15d were computationally simulated in solvent
Interestingly, compound 12a tends to preserve the same
d
,
i
,
,
s
,
t
electric dipole moment value in the excited state when
(1,4-dioxane) at the TD-DFT level (SI, Figure S40). Excellent
agreement between the computed wavelengths and the
experiment values was obtained (Table 4,6). The cH-L
coefficients confirm that the first absorption band is
surrounded by a solvent of increasing polarity. This
characteristic was observed in DCM, acetone, acetonitrile,
and DMSO (SI, Table S7). This behavior indicates the
difference between the charge distribution in the ground and
excited states in the solute with stabilization of the excited
state in polar solvents and provides support for a charge-
transfer transition.[13]
dominated by the HOMO
→ LUMO transition.
The calculated oscillator strengths are larger for absorption
than for emission. These results are in agreement with the
To better understand the nature of the excited state and the ICT
process, the FMOs are shown in Figure 5 for compounds
12a,b,d,m,n,s and 15d (additional examples are presented in the
SI, Figure S41). Based on these plots, the ICT nature of the
transition is evident and explains the redshifted emissions for
most of the thiophenes.
experimental data and confirm that compounds 12b,l,m and
bithienoketone 15d exhibit better fluorescence than 12d and
12n, which exhibit limited emissivity.
With regards to the thiophene polarity and how it changes
after photoexcitation and relaxation on the excited state
potential energy hypersurface, the molecular electric dipole
moment exhibits a slight change after photon absorption in
The HOMOs of compounds 12a-d
localized on the thiophene moiety and attached CN and
amine groups. However, in compounds 12s and
bithienoketone 15d, the HOMOs are delocalized over the
entire molecule. Upon HOMO-LUMO excitation,
,i,l,m are primarily
some cases (e.g., thiophenes 12c
remarkable change in other cases (e.g., compounds
12a ). Furthermore, for most compounds, the
,m,t and 15d) but
,
t
,b,d,i,l,n,s
a
electric dipole moment increases after geometry relaxation.
Along with an increase in the polarity after photoexcitation
(i.e., increase in the intensity of the dipole moment),
considerable transfer of electron density from the aryl
substituent to the thiophene skeleton was observed. The
LUMO densities were shifted onto the thiophenes and
aromatic ring and CN, and the substituent on the amino
group exhibit depleted electron density.
thiophenes 12b
,c,m,t and bithienoketone 15d exhibit a
remarkable change in the dipole moment direction.
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GS
ES
S1
HOMO
LUMO
HOMO
LUMO
S0
12a
12b
12d
12m
12n
12s
15d
Figure 5. Frontier molecular orbitals (FMOs) HOMO and LUMO in ground and excited states for rotamers B of thiophenes 12a,b,d,m,n,s and 15d (|Isovalue(MO)|
= 0.02; |Isovalue(ρ)| = 0.0004).
According to the computed excited state optimized
geometries, the presence of a twisted intramolecular charge
transfer (TICT) exists where the two subunits that participate
in the charge transfer process (the donor and acceptor of
electron density) are orbitally decoupled. Emission from the
TICT state to the ground state involves orbitals that are
localized in different, spatially orthogonal π-systems.
Therefore, their overlap is negligible, and this transition has
a small transition moment and effectivity, which explains the
origin of the low fluorescence quantum yield and the large
Stokes shift. The most remarkable geometrical change after
TICT was observed for compound 12n
In bithienoketones 15, the first absorption band was
dominated by the HOMO LUMO transition. Therefore,
.
→
analysis of the HOMO−LUMO overlap provides useful insight
into the transition effectivity. The overlap between the
HOMOs and LUMOs in the ground state is relatively large in
all cases. In contrast, the overlap between the HOMOs and
LUMOs in the excited state is smaller in all cases.
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S0
S1v
S1r
S0
S1v
12b
S1r
12a
12d
12m
12n
15d
Figure 6. Molecular electric potential (MEP) calculated in solution (1,4-dioxane) for the most stable rotamer of thiophenes 12a,b,d,m,n and 15d in the ground and
excited states. Legend of MEP colours: red (negative potential) and blue (positive potential). Legend of elements: hydrogen (white), carbon (grey), nitrogen (blue),
and oxygen (red)..
Additional confirmation of the change in polarity and the
ICT nature of the excited state comes from analysis of the
MEP plots, which are shown in Figure 6 for several examples
(additional examples are presented in the SI, Figure S42,
conditions, suggesting that this protocol may provide a valid
alternative to previously reported protocols, which are
tedious, time consuming, and result in poor yields using
dangerous harsh conditions. Furthermore, the current
protocol can be readily extended to the synthesis of libraries
of new thiophene compounds incorporating various
combinations of secondary or tert-cyclic amines as well as a
range of halogen partners.
43). In their ground state, compounds 12a-d,i,l-n,s,t and 15d
possess carbonyl and CN groups that are surrounded by a
slightly negative electrostatic potential, and therefore, these
groups may represent suitable sites for electrophilic attack.
In contrast, a positive potential surrounds the amino group.
Based on the MEP computed for the excited state (both after
absorption and for the emissive minimum), these results
confirm the increase in the charge separation after photon
absorption and further increase after relaxation.
Another important result of this work is the photophysical
properties of the newly synthesized mono- and
bithienoketones. Most of these compounds exhibit
fluorescence that is sensitive to the nature of the solvent
polarity. Among the reported examples, the most efficient
combinations of thiophene attached fragments is the anisoyl
functionality at C5 thiophene and cycloalkylamine or
phenylamine group at C2 thiophene. The experimental data
and quantum chemical calculations revealed the presence of
an ICT state during absorption that converts to a TICT state
after geometry relaxation in the excited state. This behavior
clarifies the origin of the remarkable fluorosolvatochromism
of the new compounds. The TICT fluorescence has great
promise in materials chemistry and life science research (i.e.,
biomedical imaging and diagnostics, in optoelectronic
devices, and photovoltaic application).[13a] Due to their
photophysical properties and environmental sensitivity,
these new compounds may find important applications in
many fields, especially in biology, due to their structural
similarity to biologically active thiophenes.
Conclusions
In this study, we developed an efficient, two-step
alternative procedure for the synthesis of thiophenes with
remarkable optical and fluorescence properties. The carbon
atom of enamine group thioamides 11 was proven to be a
better electrophilic centre than the carbon atom of the CN
group. The heterocyclization results in the formation of a
series of 5-acetyl-2-aminothiophenes. The proposed
synthesis of trisubstituted thiophenes starts from simple
initial compounds, such as 3-amino-2-cyanopropene
thioamides,
DMFDMA,
and
various
halocarbonyl
compounds, e.g., 2- and 4-pycolyl chlorides. Trisubstituted
thiophenes were produced in excellent yields. The current
method is also promising due to its simple reaction
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5-(4-Chlorobenzoyl)-2-morpholinothiophene-3-carbonitrile
(12a):
Experimental Section
Beige color powder (method А, 72 %); mp 175-177 °С; IR (ATR, ZnSe): ν
= 3055, 3008, 2957, 2913, 2871, 2217, 1633 cm-1; 1Н NMR (400 MHz,
DMSO-d6, TMS): δH = 7.64 (s, 1H, CH), 7.78 and 7.54 (AA′XX′, 4H, J = 8.4
Hz, HAr), 3.84-3.82 (m, 4H, 2CH2), 3.71-3.69 ppm (m, 4H, 2CH2); 13С NMR
(100 MHz, DMSO-d6) δC = 184.4 (+), 170.5 (+), 140.3 (-), 137.5 (+), 135.8
(+), 131.0 (2C) (-), 129.3 (2C) (-), 125.8 (+), 116.7 (+), 86.7 (+), 65.5 (2C)
(+), 50.5 ppm (2C) (+); MS (EI) m/z (%): 332 (M+, 100); elemental analysis
calcd (%) for C16H13ClN2O2S: C 57.74, H 3.94, N 8.42; found: C 57.5, H
4.2, N 8.1.
General information and materials
All reactants were obtained from Acros Organics (Geel, Belgium) and used
without further purification. The 1Н NMR and 13C NMR spectra were
recorded using a Bruker Avance II (Karlsruhe, Germany) (400 MHz for 1H,
100 MHz for 13C) spectrometer. The chemical shifts are reported in parts
per million (ppm) relative to TMS for the 1H NMR spectra and the residual
solvent signals for the 13C NMR spectra. The coupling constant (J) values
are given in hertz (Hz). The signal splitting patterns are described as a
singlet (s), doublet (d), triplet (t), quartet (q), sextet (sext), quintet (quin),
multiplet (m), broad (br), doublet of doublets (dd), doublet of triplets (dt) or
AA'XX' - spin system of para-substituted benzene with two different
substituents. The major isomer signal is highlighted with an asterisk (*).
The 13C NMR signal patterns for several compounds were performed using
the APT (attached proton test) and are described as follows: + for
secondary or quaternary carbon atoms (positive signal) and - for primary
or tertiary carbon atoms (negative signal). The mass spectra were
recorded on a Shimadzu GCMS-QP 2010 “Ultra” (Kyoto, Japan) mass
spectrometer using the electron impact (EI) ionization technique (40-
200 °C, 70 eV). The [M]+ abbreviation refers to the molecular ion. The IR
spectra were obtained on an FTIR-ATR (attenuated total reflection, ZnSe)
spectrometer (neat) in the 4000-400 cm-1 region (Ettlingen, Germany).
Elemental analysis was conducted on a CHNS/O Perkin-Elmer 2400
Series II analyser instrument (Shelton, CT USA). The melting points were
determined on a Stuart SMP3 apparatus (Staffordshire, ST15 OSA, UK).
The reactions were monitored by analytical thin-layer chromatography
(TLC) on aluminium-backed silica gel plates (Sorbfil UV–254). The
components were visualized using a short wavelength UV light (254 nm).
The solvents were dried and distilled according to common procedures. All
solvents were of spectroscopic grade.
5-(4-Methoxybenzoyl)-2-morpholinothiophene-3-carbonitrile (12b):
White crystals (method А, 93 %); mp 113-115 °С; IR (ATR, ZnSe): ν = 2971,
2913, 2878, 2843, 2208, 1624 cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS):
δH = 7.58 (s, 1H, CH), 7.77 and 7.03 (AA′XX′, J = 8.8 Hz, 4H, HAr), 3.89 (s,
3Н, ОМе), 3.84-3.81 (m, 4H, 2CH2), 3.68-3.66 ppm (m, 4H, 2CH2); 13С
NMR (100 MHz, DMSO-d6) δC = 183.7, 169.6, 162.6, 138.2, 130.9 (2C),
129.1, 126.3, 116.3, 114.0 (2C), 86.0, 65.0 (2C), 55.5, 50.0 ppm (2C); MS
(EI) m/z (%): 328 (M+, 70); elemental analysis calcd (%) for C17H16N2O3S:
C 62.18, H 4.91, N 8.53, found: C 61.9, H 5.0, N 8.3.
5-Benzoyl-2-morpholinothiophene-3-carbonitrile (12c): White crystals
(method А, 62 %); mp 146-148 °С; IR (ATR, ZnSe): ν = 3101, 3054, 2991,
2947, 2868, 2215, 1625 cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS): δH
7.79 (d, J = 7.4 Hz, 2H, HAr), 7.72 (s, 1H, CH), 7.65 (t, J = 7.3 Hz, 1H, HAr),
7.55 (t, J = 7.4 Hz, 2H, HAr), 3.81-3.78 (m, 4H, 2CH2), 3.69-3.67 ppm (m,
4H, 2CH2); 13С NMR (100 MHz, DMSO-d6) δC = 185.1, 169.9, 139.3, 136.7,
132.2, 128.7 (2C), 128.6 (2C), 125.8, 116.2, 86.2, 65.0 (2C), 50.1 ppm
(2C); MS (EI) m/z (%):298 (M+, 91); elemental analysis calcd (%) for
C16H14N2O2S: C 64.41, H 4.73, N 9.39; found: C 64.2, H 5.0, N 9.2.
=
2-Morpholino-5-(4-nitrobenzoyl)thiophene-3-carbonitrile
(12d):
Bright-yellow crystals (method А, 63 %); mp 197-199 °С; IR (ATR, ZnSe):
ν = 3104, 3091, 3043, 2993, 2877, 2210, 1628 cm-1; 1Н NMR (400 MHz,
DMSO-d6, TMS): δH = 8.35 and 7.99 (AA′XX′, J = 8.7 Hz, 4H, HAr), 7.72 (s,
1H, CH), 3.84-3.81 (m, 4H, 2CH2), 3.74-3.71 ppm (m, 4H, 2CH2); 13С NMR
(100 MHz, DMSO-d6) δC = 183.6 (+), 170.3 (+), 149.2 (+), 142.0 (+), 141.0
(-), 129.9 (2C) (-), 124.8 (+), 123.8 (2C) (-), 116.1 (+), 86.4 (+), 65.0 (2C )
(+), 50.2 ppm (2C) (+); MS (EI) m/z (%): 343 (M+, 100); elemental analysis
calcd (%) for C16H13N3O4S: C 55.97, H 3.82, N 12.24; found: C 55.7, H 4.0,
N 11.9.
The title products were purified by column chromatography on silica gel
(0.035–0.070, 60 Å) and recrystallized from ethanol.
Cyanothioacetamides (5a-h) and aminothioacrylamides (9a-h and 11a-
c) were prepared according to previously published procedures.[9,10] Full
experimental details for the synthesis of aminothioacrylamides (9a-h and
11a-c), as well as the 1H NMR and 13C NMR spectra of new compounds
9a-h, 11a-c, 12a-t and 15a-d, photophysical characterization, and
quantum mechanical calculation data are reported in the Supporting
Information.
5-(4-Methoxybenzoyl)-2-(piperidin-1-yl)thiophene-3-carbonitrile
(12e): White powder (method А, 90 %); mp 108-109 °С; IR (ATR, ZnSe):
ν = 2951, 2923, 2844, 2206, 1628 cm-1; 1Н NMR (400 MHz, DMSO-d6,
TMS): δH = 7.50 (s, 1H, CH), 7.75 and 7.01 (AA′XX′, J = 8.8 Hz, 4H, HAr),
3.89 ppm (s, 3Н, ОМе), 3.73-3.71 (m, 4H, 2CH2), 1.78-1.76 (m, 6H, 3CH2);
13С NMR (100 MHz, DMSO-d6) δC = 183.6 (+), 169.0 (+), 162.4 (+), 138.6
(-), 130.8 (2С) (-), 129.2 (+), 125.2 (+), 116.5 (+), 113.9 (2С) (-), 85.1 (+),
55.5 (-), 51.8 (2C) (+), 24.7 (2C) (+), 22.8 (+) ppm; MS (EI) m/z (%): 326
(M+, 100); elemental analysis calcd (%) for C18H18N2O2S: C 66.23, H 5.56,
N 8.58; found: C 65.9, H 5.7, N 8.3.
General procedure A to prepare compounds 12: Phenacyl bromides
2a-d (1.2 mmol) were added to a solution of thioamides 9a-h or 11a-d (1.1
mmol) in DMF (4.0 ml). The mixture was maintained at 80 °C for 0.5-4.0 h,
diluted with ethanol (10 ml) and maintained at 10-12 °C for 30 minutes.
The precipitate was collected by filtration.
5-(4-Methoxybenzoyl)-2-(pyrrolidin-1-yl)thiophene-3-carbonitrile
°
(12f): Beige color powder (method А, 80 %); mp 135-136 С; IR (ATR,
General procedure B to prepare compounds 12: Halomethylene
compounds (1.2 mmol) 2e-j and TEA (0.15 ml, 1.1 mmol) were added to
the solution containing thioamides 9a,d,g (1.1 mmol) in 4.0 ml of DMF. The
mixture was maintained at 80 °C for 0.5-4.0 h. The solution was diluted
with ethanol (10 ml) and maintained at 10-12 °C for 30 minutes. The
precipitate was collected by filtration.
ZnSe): ν = 2979, 2956, 2849, 2210, 1620 cm-1; 1Н NMR (400 MHz, DMSO-
d6, TMS): δH = 7.50 (c, 1H, CH), 7.73 and 7.00 (AA′XX′, J = 8.8 Hz, 4H,
HAr), 3.88 (s, 3Н, ОМе), 3.71-3.67 (m, 4H, 2CH2), 2.16-2.12 ppm (m, 4H,
2CH2); 13С NMR (100 MHz, DMSO-d6) δC = 183.4 (+); 165.3 (+), 162.4 (+),
138.4 (-), 130.7 (2С) (-), 129.5 (+), 124.0 (+), 116.9 (+), 113.9 (2С) (-), 83.5
(+), 55.4 (-), 51.9 (2C) (+), 25.4 ppm (2C) (+); MS (EI) m/z (%): 312 (M+,
100); elemental analysis calcd (%) for C17H16N2O2S: C 65.36, H 5.16, N
8.97; found: C 65.1, H 5.3, N 8.7.
5-(4-Chlorobenzoyl)-2-(pyrrolidin-1-yl)thiophene-3-carbonitrile (12g):
Beige color powder (method А, 67 %); mp 190-191 °С; IR (ATR, ZnSe): ν
=3 096, 3058, 2961, 2867, 2209, 1618 cm-1; 1Н NMR (400 MHz, DMSO-
d6, TMS): δH = 7.58 (s, 1H, CH), 7.75 and 7.52 (AA′XX′, J = 8.5 Hz, 4H,
HAr), 3.71-3.67 (m, 4H, 2CH2), 2.15-2.12 ppm (m, 4H, 2CH2); 13С NMR
(100 MHz, DMSO-d6) δC = 183.9 (+), 166.4 (+), 140.1 (-), 137.2 (+), 136.4
(+), 130.7 (2C) (-), 129.1 (2C) (-), 124.7 (+), 117.0 (+), 84.7 (+), 52.6 (2C)
General procedure to prepare compounds 15: To the solution
containing dichloroacetone 14 (0.26 g, 1.15 mmol), the solution containing
propentioamides 9a-c (0.25 g, 1.10 mmol) in DMF (3.0 ml) was added. The
mixture was maintained at 80 °C for 0.5-2.0 h, diluted with ethanol (10 ml)
and maintained at 10-12 °C for 30 minutes. The precipitate was collected
by filtration.
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°
(+), 25.8 ppm (2C) (+); MS (EI) m/z (%): 316 (M+, 100); elemental analysis
calcd (%) for C16H13ClN2OS: C 60.66, H 4.14, N 8.84; found: C 60.3, H 4.3,
N 8.6.
228 С; IR (ATR, ZnSe): ν = 3350, 3094, 3063, 3025, 2953, 2211, 1624
cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS): δH = 10.00 (s, 1Н, NH), 7.58 (s,
1Н, СН), 7.75 и 7.52 (AA′XX′, J=7.6Hz, 4H, HAr), 7.34-7.30 (m, 2H, HAr),
7.14 (d, J = 7.9 Hz, 1H, HAr), 7.02 (t, J = 7.0 Hz, 1H, HAr), 3.89 ppm (s, 3Н,
ОМе); 13С NMR (100 MHz, DMSO-d6) δC = 183.8 (+), 169.0 (+), 153.3 (+),
138.2 (-), 136.7 (+), 135.6 (+), 130.3 (2С) (-), 128.6 (2С) (-), 128.5 (-), 128.1
(+), 125.8 (-), 124.9 (+), 120.8 (-), 114.4 (+), 112.6 (-), 87.4 (+), 55.6 ppm
(-); MS (EI) m/z (%): 369 (M+, 68); elemental analysis calcd (%) for
C19H13ClN2O2S: C 61.87, H 3.55, N 7.60; found: C 61.5, H 3.8, N 7.3.
5-Acetyl-2-morpholinothiophene-3-carbonitrile (12o): Beige crystals
(method B, 78 %); mp 207-209 °С; IR (ATR, ZnSe): ν = 3059, 2953, 2928,
2907, 2874, 2208, 1642 cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS): δH =
7.91 (s, 1H, CH), 3.79-3.82 (m, 4H, 2CH2), 3.61-3.63 (m, 4H, 2CH2), 2.40
ppm (s, 3H, Me); 13С NMR (100 MHz, DMSO-d6) δC=189.4 (+), 170.3 (+),
138.3 (-), 127.6 (+), 116.8 (+), 85.9 (+), 65.5 (2C) (+), 50.5 (2C) (+), 25.5
ppm (-); MS (EI) m/z (%): 236 (M+, 100); elemental analysis calcd (%) for
C11H12N2O2S: C 55.92, H 5.12, N 11.86; found: C 55.7, H 5.3, N 11.6.
Ethyl 4-cyano-5-morpholinothiophene-2-carboxylate (12p): Beige
crystals (method B, 56 %); mp 136-138 °С; IR (ATR, ZnSe): ν = 3107, 3063,
2992, 2973, 2930, 2907, 2878, 2210, 1696 cm-1; 1Н NMR (400 MHz,
DMSO-d6, TMS): δH = 7.64 (s, 1H, CH); 4.25 (q, 2H, J = 7.1 Hz, CH2CH3),
3.82-3.79 (m, 4H, 2CH2), 3.59-3.57 (m, 4H, 2CH2), 1.32 ppm (t, J = 7.1Hz,
3H, CH3); 13С NMR (100 MHz, DMSO-d6) δC = 169.5 (+), 160.9 (+), 136.9
(-), 116.5 (+), 116.0 (+), 86.5 (+), 65.5 (2C) (+), 61.4 (+), 50.6 (2C) (+), 14.6
ppm (-); MS (EI) m/z (%): 266 (M+, 100); elemental analysis calcd (%) for
C12H14N2O3S: C 54.12, H 5.30, N 10.52; found: C 53.9, H 5.5, N 10.3.
Ethyl 2-(4-cyano-5-morpholinothiophen-2-yl)-2-oxoacetate (12q):
5-(4-Methoxybenzoyl)-2-(methylamino)thiophene-3-carbonitrile
(12h): White crystals (method А, 87 %); mp 236-237 °С; IR (ATR, ZnSe):
ν = 3289, 2916, 2885, 2212, 1615 cm-1; 1Н NMR (400 MHz, DMSO-d6,
TMS): δH = 8.60 (q, 1Н, J = 4.7 Hz, NH), 7.72 and 6.99 (AA′XX′, J = 8.7 Hz,
4H, HAr), 7.71 (s, 1H, CH), 3.88 (s, 3Н, OMe), 2.99 ppm (д, 3Н, J = 4.7 Hz,
NMe); 13С NMR (100 MHz, DMSO-d6) δC = 183.5 (+), 171.0 (+), 162.3 (+),
137.4 (-), 130.6 (2С) (-), 129.6 (+), 124.4 (+), 115.1 (+), 113.9 (2С) (-), 84.2
(+), 55.4 (-), 33.8 ppm (-); MS (EI) m/z (%):272 (M+, 58); elemental analysis
calcd (%) for C14H12N2O2S: C 61.75, H 4.44, N 10.29; found: C 61.5, H 4.6,
N 10.0.
5-(4-Chlorobenzoyl)-2-(methylamino)thiophene-3-carbonitrile (12i):
Beige color powder (method А, 62 %); mp 281-283 °С; IR (ATR, ZnSe): ν
= 3309, 3088, 2926, 2211, 1613 cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS):
δH = 8.75 (br s, 1Н, NH), 7.55 (s, 1Н, СН), 7.74 and 7.51 (AA′XX′, J = 8.5
Hz, 4H, HAr), 3.00 ppm (d, J = 4.7 Hz, 3H, NHMe); 13С NMR (100 MHz,
DMSO-d6) δC = 184.0 (+), 172.0 (+), 139.6 (-), 137.1(+), 136.3(+), 130.8
(2C) (-), 129.9 (2C) (-), 124.0 (+), 115.5 (+), 85.2 (+), 34.4 ppm (-); MS (EI)
m/z (%):276 (M+, 91); elemental analysis calcd (%) for C13H9ClN2OS: C
56.42, H 3.28, N 10.12; found: C 56.2, H 3.5, N 9.9.
2-(Butylamino)-5-(4-chlorobenzoyl)thiophene-3-carbonitrile
(12j):
Light-brown powder (method А, 72 %); mp 157-159 °С; IR (ATR, ZnSe): ν
= 3271, 3097, 2961, 2936, 2867, 2210, 1614 cm-1; 1Н NMR (400 MHz,
DMSO-d6, TMS): δH = 8.92 (br s, 1H, NН), 7.68 (s, 1H, CH), 7.77 и 7.58
(AA′XX′, J = 8.0 Hz, 4H, HAr), 3.28 (q, J = 6.5 Hz, 2H, CH2NH), 1.64 (sext,
J = 7.4Hz, 2H, CH2), 1.37 (quin, J = 7.3Hz, 2H, CH2), 0.93 ppm (t, J = 7.4
Hz, 3H, Me); 13С NMR (100 MHz, DMSO-d6) δC = 183.5, 170.4, 139.1,
136.6, 135.8, 130.3 (2С), 128.7 (2С), 123.2, 115.1, 84.8, 47.6, 29.7, 19.4,
13.5 ppm; MS (EI) m/z (%): 318 (M+, 65); elemental analysis calcd (%) for
C16H15ClN2OS: C 60.28, H 4.74, N 8.79; found: C 59.9, H 4.9, N 8.6.
2-(Benzylamino)-5-(4-chlorobenzoyl)thiophene-3-carbonitrile (12k):
Lemon color powder (method А, 93 %); mp 279-281 °С; IR (ATR, ZnSe):
ν = 3234, 3097, 3060, 3029, 3001, 2214, 1613 cm-1; 1Н NMR (400 MHz,
DMSO-d6, TMS): δH = 9.39 (t, 1Н, J = 5.8 Hz, NH), 7.53 (s, 1Н, СН), 7.72
и 7.50 (AA′XX′, J = 8.4 Hz, 4H, HAr), 7.42-7.34 (m, 4H, HAr), 7.31-7.27 (m,
1H, HAr), 4.50 ppm (d, J = 5.9 Hz, 2H, СН2); 13С NMR (100 MHz, DMSO-
d6) δC = 183.6, 170.3, 138.7, 136.6, 136.3, 135.7, 130.3 (2C), 128.7 (2C),
128.6 (2C), 127.7 (2C), 124.0, 114.9, 85.6, 50.6 ppm; MS (EI) m/z (%):
352 (M+, 6); elemental analysis calcd (%) for C19H13ClN2OS: C 64.68, H
3.71, N 7.94; found: C 64.4, H 3.9, N 7.6.
°
Yellow crystals (method B, 84 %); mp 131-132 С; IR (ATR, ZnSe): ν =
3105, 2978, 2907, 2873, 2211, 1738, 1642 cm-1; 1Н NMR (400 MHz,
DMSO-d6, TMS): δH = 8.18 (s, 1H, CH), 4.34 (q, J = 7.1 Hz, 2H, CH2CH3),
3.80-3.72 (m, 8H, 4CH2), 1.32 ppm (t, J = 7.1 Hz, 3H, CH3); 13С NMR (100
MHz, DMSO-d6) δC = 173.9, 170.4, 161.3, 142.9, 121.2, 115.9, 86.7, 65.0
(2C), 62.4, 50.3 (2C), 13.8 ppm; MS (EI) m/z (%): 294 (M+, 100); elemental
analysis calcd (%) for C13H14N2O4S: C 53.05, H 4.79, N 9.52; found: C 52.8,
H 4.9, N 9.6.
5-Morpholinothiophene-2,4-dicarbonitrile (12r): Beige color powder
(method B, 83 %); mp 150-152 °С; IR (ATR, ZnSe): ν = 2921, 2852, 2201,
1635 cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS): δH = 7.88 (s, 1H, CH),
3.79-3.82 (m, 4H, 2CH2), 3.58-3.61 ppm (m, 4H, 2CH2); 13С NMR (100
MHz, DMSO-d6) δC = 169.1 (+), 142.7 (-), 116.1 (+), 114.4 (+), 91.7 (+),
85.7 (+), 65.4 (2C) (+), 50.7 ppm (2C) (+); MS (EI) m/z (%): 219 (M+, 100);
elemental analysis calcd (%) for C10H9N3OS: C 54.78, H 4.14, N 19.16;
found: C 54.6, H 3.9, N 18.8.
5-(4-Chlorobenzoyl)-2-(phenylamino)thiophene-3-carbonitrile (12l):
Sand color powder (method А, 96 %); mp 195-197 °С; IR (ATR, ZnSe): ν
= 3261, 3095, 3062, 3022, 2980, 2218, 1614 cm-1;1Н NMR (400 MHz,
DMSO-d6, TMS): δH = 10.55 (s, 1Н, NH), 7.78 и 7.54 (AA′XX′, J = 8.4 Hz,
4H, HAr), 7.67 (s, 1Н, СН), 7.41–7.47 (m, 4H, HAr), 7.22 ppm (t, 1H, J = 4.6
Hz, HAr); 13С NMR (100 MHz, DMSO-d6) δC = 184.1, 166.3, 140.3, 138.0,
137.0, 135.5, 130.5 (2С), 129.7 (2С), 128.8 (2С), 125.5, 124.9, 121.1 (2С),
114.5, 89.7 ppm; MS (EI) m/z (%): 338 (M+, 100); elemental analysis calcd
(%) for C18H11ClN2OS: C 63.81, H 3.27, N 8.27; found: C 63.6, H 3.5, N
8.0.
2-Morpholino-5-(pyridin-4-yl)thiophene-3-carbonitrile (12s): Pale-
°
yellow powder (method B, 92 %); mp 117-119 С; IR (ATR, ZnSe): ν =
3054, 2957, 2867, 2202, 1598 cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS):
δH = 8.48 (br s, 2Н, HAr), 7.71 (s, 1H, CH), 7.41 (d, J = 5.0 Hz, 2Н, HAr),
3.84-3.82 (m, 4H, 2CH2), 3.55-3.52 ppm (m, 4H, 2CH2); 13С NMR (100
MHz, DMSO-d6) δC = 166.5, 150.2, 139.4, 127.8 (2С), 124.0, 118.3 (2С),
116.4, 87.1, 65.1 (2C), 50.5 ppm (2C); MS (EI) m/z (%): 271 (M+, 100);
elemental analysis calcd (%) for C14H13N3OS: C 61.97, H 4.83, N 15.49;
found: C 61.7, H 5.0, N 15.1.
5-(4-Methoxybenzoyl)-2-(phenylamino)thiophene-3-carbonitrile
(12m): Sand color powder (method А, 72 %); mp 194-196 С; IR (ATR,
2-Morpholino-5-(pyridin-2-yl)thiophene-3-carbonitrile (12t): White
crystals (method B, 93 %); mp 157-159 °С; IR (ATR, ZnSe): ν = 3064, 3000,
2928, 2872, 2206, 1585 cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS): δH =
8.40 (d, J = 4.7 Hz, 1Н, HAr), 7.71-7.79 (m, 2H, HAr), 7.67 (s, 1H, CH), 7.18-
7.15 (m, 1H, HAr), 3.81-3.83 (m, 4H, 2CH2), 3.52-3.54 ppm (m, 4H, 2CH2);
13С NMR (100 MHz, DMSO-d6) δC = 167.2 (+), 150.8 (+), 149.2 (-), 136.9
(-), 128.9 (+), 126.1 (-), 121.8 (-), 117.6 (-), 116.9 (+), 86.5 (+), 65.2 (2C)
(+), 50.2 ppm (2C) (+); MS (EI) m/z (%): 271 (M+, 100); elemental analysis
calcd (%) for C14H13N3OS: C 61.97, H 4.83, N 15.49; found: C 61.6, H 4.9,
N 15.3.
°
ZnSe): ν = 3278, 3149, 3095, 3069, 3026, 2980, 2919, 2828, 2216, 1600
cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS): δH = 10.39 (s, 1Н, NH), 7.77 (d,
J = 8.8 Hz, 2H, HAr), 7.59 (s, 1Н, СН), 7.46-7.41 (m, 4H, HAr), 7.17 (t, J =
7.0 Hz, 1H, HAr), 7.02 (d, J = 8.8 Hz, 2H, HAr), 3.89 ppm (s, 3Н, ОМе); 13
С
NMR (100 MHz, DMSO-d6) δC=184.5 (+), 166.0 (+), 163.1 (+), 141.0 (+),
136.9 (-), 131.4 (2С) (-), 130.1 (2С) (-), 129.8 (+), 126.4 (+), 125.7 (-), 121.3
(2С) (-), 115.1 (+), 114.5 (2С) (-), 90.1 (+), 56.0 ppm (-); MS (EI) m/z (%):
334 (M+, 63); elemental analysis calcd (%) for C19H14N2O2S: C 68.25, H
4.22, N 8.38; found: C 68.0, H 4.4, N 8.1.
5,5'-Carbonylbis(2-(methylamino)thiophene-3-carbonitrile)
(15a):
5-(4-Chlorobenzoyl)-2-((2-methoxyphenyl)amino)thiophene-3-
carbonitrile (12n): Bright-yellow crystals (method А, 84 %); mp 226-
Orange color powder (60 %); mp 326-327 °С; IR (ATR, ZnSe): ν = 3336,
3259, 3093, 2973, 2948, 2901, 2214, 1582 cm-1; 1Н NMR (400 MHz,
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DMSO-d6, TMS): δH = 8.63 (d, J = 4.7 Hz, 2H, 2NH), 8.11 (s, 2H, 2CH),
2.92 ppm (d, 6H, J = 4.7 Hz, 2CH3); 13С NMR (100 MHz, DMSO-d6) δC =
173.8 (+), 170.7 (2C) (+), 135.5 (2C) (-), 123.4 (2C) (+), 115.8 (2C) (+),
84.7 (2C) (+); 34.2 ppm (2C) (-); MS (EI) m/z (%): 302 (M+, 100); elemental
analysis calcd (%) for C19H14ClN3OS: C 51.64, H 3.33, N 18.53; found: C
51.3, H 3.5, N 18.3.
and different basis sets.[16] In particular, we chose hybrid (viz. B3LYP,[16a]
and M06−2X[16b]) and long−range corrected (viz. CAM−B3LYP[16c] and
ωB97X[16d]
) functionals coupled with the 6−31+G**, 6−311++G**,
aug−cc−pVDZ and aug−cc−pVTZ[17] basis sets. The D3 version of
Grimme’s semi-empirical dispersion with Becke-Johnson damping
GD3BJ[17f] was also included for the B3LYP, CAM-B3LYP, and ωB97X
functionals. The solvent effects were taken into account using the implicit
polarizable continuum model in its integral equation formalism (IEF−PCM).
5,5'-Carbonylbis(2-(phenylamino)thiophene-3-carbonitrile)
(15b):
Brown crystals (93 %); mp 282-283 С; 1Н NMR (400 MHz, DMSO-d6,
TMS): δH = 10.52 (s, 2H, 2NH), 8.27 (s, 2H, 2CH); 7.44 (d, J = 4.3 Hz, 8Н,
8СHAr); 7.21 ppm (quin, J = 4.2 Hz, 2Н, 2СHAr); 13С NMR (100 MHz,
DMSO-d6) δC = 174.0, 164.9 (2C), 155.8 (2C), 140.6 (2C), 134.9 (2C),
129.6 (4C), 125.1 (2C), 120.8 (4C), 114.8 (2C), 90.0 ppm (2C); MS (EI)
m/z (%): 426 (M+, 100); elemental analysis calcd (%) for C23H14N4OS2: C
64.77, H 3.31, N 13.14; found: C 64.4, H 3.5, N 12.9.
°
[18]
For geometry optimizations and frequency calculations, the PCM
molecular cavity was constructed according to the universal force field
(UFF)[19] radii within the value used in the last implementation of the PCM
(based on a continuum surface charge formalism). For topological analysis
and evaluation of the energetics, SMD parameterization was employed.[20]
The standard values for the dielectric constants and refractive indices were
always assumed. The vibrational frequencies and thermochemical values
were computed with the harmonic approximation at T = 298.15 K and p =
1 atm, and no imaginary frequencies were found.
The UV-Vis absorption spectra for the equilibrium geometries of the
ligand were calculated using time-dependent density functional theory
(TD-DFT) accounting for S0 → Sn (n = 1 to 5). The energy of the first 5
triplet states was also computed. The nature of the vertical excited
electronic state was analysed both in vacuum and in the solvated phase.
This investigation was performed by employing a long-range corrected
functional (CAM-B3LYP) coupled with the 6−31+G** basis sets. For the
solvated phase, state-specific (SS)[21] treatment of the solvent effects was
considered within both the non-equilibrium (neq) and equilibrium (eq)
solvation regimes.[22] In addition, the vibronic progressions[23] of the S0 →
S1 electronic transition were simulated including Duschinsky and
Herzberg–Teller effects. The first singlet excited state (S(π,π*)) geometry
was optimized using analytical gradients and the first transitions (S1 → S0)
of the emission transition. In this case, SS (both eq and neq) treatment of
the solvent effects was considered, and the electronic emission band was
simulated by accounting for the vibronic progressions, as performed for
absorption.
5,5'-Carbonylbis(2-(pyrrolidin-1-yl)thiophene-3-carbonitrile)
(15c):
Yellow powder (77 %); mp 323-324 °С; IR (ATR, ZnSe): ν = 3071, 2955,
2876, 2202, 1557 cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS): δH = 8.32 (s,
2H, 2СH), 3.62-3.65 (m, 8H, 4CH2), 2.04-2.10 ppm (m, 8H, 4CH2); 13
С
NMR (100 MHz, DMSO-d6) δC = 168.8, 158.2 (2C), 136.5 (2C), 123.5 (2C),
116.6 (2C), 83.9 (2C), 51.9 (4C), 25.3 ppm (4C); MS (EI) m/z (%): 382 (M+,
100); elemental analysis calcd (%) for C19H18N4OS2: C 59.66, H 4.74, N
14.65; found: C 59.4, H 4.9, N 14.3.
5,5'-Carbonylbis(2-morpholinothiophene-3-carbonitrile) (15d): Bright
yellow powder (76 %); mp 320-321 °С; IR (ATR, ZnSe): ν = 3056, 2955,
2912, 2873, 2214, 1602 cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS): δH =
8.19 (s, 2H, 2СH), 3.79-3.85 (m, 8H, 4CH2), 3.61-3.67 ppm (m, 8H, 4CH2);
13С NMR (100 MHz, DMSO-d6) δC = 169.9, 162.7 (2С), 136.9 (2С), 125.3
(2С), 116.7 (2С), 87.2 (2С), 65.6 (4С), 50.8 ppm (4С); MS (EI) m/z (%):
414 (M+, 100); elemental analysis calcd (%) for C19H18N4O3S2: C 55.06, H
4.38, N 13.52; found: C 54.8, H 4.5, N 13.2.
5,5'-Carbonylbis(2-(piperidin-1-yl)thiophene-3-carbonitrile)
(15e):
°
Sand color powder (75 %); mp 315-316 С. IR (ATR, ZnSe): ν = 2938,
2922, 2854, 2205, 1559 cm-1; 1Н NMR (400 MHz, DMSO-d6, TMS):
δH=7.71 (s, 2H, CH), 3.82-3.84 (m, 4H, 2CH2), 3.52-3.55 ppm (m, 12H,
6CH2); 13С NMR (100 MHz, DMSO-d6) δC = 168.7 (+), 157.0 (2С) (+), 136.5
(2С) (-), 123.8 (2С) (+), 116.4 (2С) (+), 85.7 (2С) (+), 51.9 (4С) (+), 24.7
(4С) (+), 22.7 ppm (2С) (+); MS (EI) m/z (%): 410 (M+, 100); elemental
analysis calcd (%) for C21H22N4OS2: C 61.44, H 5.40, N 13.65; found: C
61.2, H 5.6, N 13.3.
The atomic charge population analysis, electric multiple moments,
electronic density, and electrostatic potential were also computed within
the Mulliken and CHelpG procedure[24] for both the ground and S1 excited
(vertical and relaxed) states.
To investigate the presence and nature of the possible intramolecular
hydrogen bonding interactions, the non-covalent interaction (NCI) index
combined with the second derivative of the reduced density gradient and
the second main axis of variation were employed.[12] These procedures
were applied both to the ground and first singlet excited states.
For the topological and RDG analyses, the integration grid for the
electronic density was set to 150 radial shells and 974 angular points. For
the other calculations, the integration grid was set to 99 radial shells and
590 angular points. The convergence criteria for the self-consistent field
were set to 10-12 for the RMS change in the density matrix and 10-10 for
the maximum change in the density matrix. The convergence criteria for
optimizations were set to 2  10-6 a.u. for the maximum force, 1  10-6 a.u.
for the RMS force, 6  10-6 a.u. for the maximum displacement and 4  10-
6 a.u. for the RMS displacement.
Electronic absorption and emission spectroscopy
The UV-Vis absorption spectra were recorded on a Perkin-Elmer Lambda
35 UV-Vis spectrophotometer (Shelton, CT USA). The fluorescence of the
sample solutions was measured using
a
Hitachi F-7000
spectrophotometer (Tokyo, Japan). The absorption and emission spectra
were recorded in hexane, 1,4-dioxane, toluene, acetone, MeCN, THF,
AcOEt, DCM, CH2Cl2, DMF, DMSO, iPrOH, and EtOH using 10.00 mm
quartz cells. The excitation wavelength was equal to the absorption
maxima. The atmospheric oxygen that was contained in the solutions was
not removed. The concentrations of the compounds in the solution was 10-
All calculations were performed using the GAUSSIAN G09.D01
package.[25] The location of the BCPs and subsequent calculation of the
SF values were performed using a modified version of the PROAIMV
program.[26] The calculation of the RDG and its derivatives were performed
using homemade codes.
5
M and 10-6 M for the absorption and fluorescence measurements,
respectively. The relative fluorescence quantum yields (ΦF) were
determined using quinine sulfate (10-5 M) in 0.1 M H2SO4 as a standard
(ΦF = 0.546) or anthracene as a standard.[14]
Quantum mechanical calculations
Acknowledgements
The ground state molecular geometry of all possible rotamers of the
studied compounds was fully optimized using density functional theory
(DFT) both in vacuum and in solvent (1,4-dioxane for all compounds; DCM,
acetone, acetonitrile, and DMSO for a sub-set of the compounds, vide
infra). We have compared the results obtained using different functionals
The Government of the Russian Federation (Act 211, contract
#02.A03.21.0006) supported the research. K. L. Thanks RFBR for
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Entry for the Table of Contents
FULL PAPER
Kseniya I. Lugovik, Alexander K.
Eltyshev, Enrico Benassi,* Nataliya P.
Belskaya*
S1
FL
HOMO
LUMO
Page No. – Page No.
New Promising Method for the
Challenging Synthesis of 5-Acyl-2-
Amino-3-Cyanothiophenes:
Chemistry and Fluorescent
Properties
An efficient method for the synthesis of new polyfunctional thiophenes is reported.
Quantum mechanical calculations provide the explanation of the synthetic pathway
of this heterocyclization. Both experimental and computational spectral results
demonstrate that the particularities of the optic properties synthesized thiophenes are
caused by the presence of an ICT state during absorption and a TICT state after
geometry relaxation in the excited state.
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