5,7-Bis(2′-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles: Synthesis, and experimental and theoretical evaluation of the effects of substituents at 5,6,7-positions on the molecular configuration and spectral properties

Article abstract of DOI:10.1039/c5ob02098k

A series of novel 5,7-bis(2′-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles was synthesized through sequential aldol condensation reactions of 1,3-diketones with diaminomaleonitrile, and the resulting 5,7-dimethyl-6H-1,4-diazepines were condensed with aromatic aldehydes. The substituents' effects on the spectral properties and conformational states of the molecules in solution were studied using 2D NMR techniques and DFT calculations. Specific intramolecular steric interactions in derivatives substituted at the C6 position were discovered and investigated in detail. Differential scanning calorimetry and thermogravimetric analyses revealed the strong dependence of the thermal stability of the newly prepared diazepinodicarbonitriles on the nature of the substituents. This offers new insight into the structure-property relationships of arylethenyl-substituted diazepine derivatives.

Full text of DOI:10.1039/c5ob02098k

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Chem., 2015, DOI: 10.1039/C5OB02098K.
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5,7-Bis(2'-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles:
synthesis, experimental and theoretical evaluation of effect of
substituents at 5,6,7-positions on the molecular configuration and
spectral properties
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Pavel A. Tarakanov,a Anton O. Simakov,b Alexander V. Dzuban,c Vladimir I. Shestov,a Ekaterina N.
www.rsc.org/
Tarakanova,a Victor E. Pushkareva and Larisa G. Tomilovaa,c
A series of novel 5,7-bis(2'-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles was synthesized through sequential aldol
condensation reactions of 1,3-diketones with diaminomaleonitrile, and the resulting 5,7-dimethyl-6H-1,4-diazepines were
condensed with aromatic aldehydes. Substituent effects on the spectral properties and conformational states of the
molecules in solution were studied using 2D NMR techniques and DFT calculations. Specific intramolecular steric
interactions in derivatives substituted at C6 position were discovered and investigated in detail. Differential scanning
calorimetry and thermogravimetric analysis revealed the strong dependence of the thermal stability of the newly prepared
diazepinodicarbonitriles on the nature of the substituents. This offers new insight into the structure-property relationships
of arylethenyl-substituted diazepine derivatives.
diketones, which allow the introduction of various additional
functional groups into the structure of the resulting 5,7-bis(2'-
arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles.
Herein, we describe the preparation, physicochemical
properties, thermal behavior, and structure–property
relationships of a series of novel 5,7-bis(2'-arylethenyl)-6H-1,4-
diazepine-2,3-dicarbonitriles with an emphasis on the
conformational behavior additionally supported by the DFT
study.
Introduction
The synthesis of tetrapyrrolic macrocycles containing 1,4-
diazepine moieties is a promising direction for the generation
of new photosensitizers.1-3 The physicochemical properties of
these compounds can easily be changed by introducing various
substituents into the 1,4-diazepine heterocycle.4-9 Thus, the
development of synthetic approaches to form various
substituted 1,4-diazepine-2,3-dicarbonitriles should greatly
improve the accessibility of precursors for the synthesis of
macroheterocyclic photosensitizers with annulated 1,4-
diazepine rings.10
Results and discussion
5,7-Bis(2'-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles
can be considered as promising precursors for
Synthesis
A
condensation reaction between diaminomaleonitrile
macrocyclization.
A convenient method of varying the
(DAMN) and acetylacetone 111 or its alkylated derivative
afforded 5,7-dimethyl-6H-1,4-diazepine-2,3-dicarbonitriles
2
3
peripheral substituents in these heterocycles involves
application of different commercially available aromatic
aldehydes in the aldol condensation reaction with 5,7-
dimethyl-6H-1,4-diazepine-2,3-dicarbonitrile. Moreover, the
substrate scope can be expanded with C-substituted-1,3-
and
corresponding aromatic aldehydes, giving products 5a–c and
6b , respectively (Scheme 1). The condensation of and 4
4, which were used for further condensation with the
,d
3
with the corresponding aldehydes was performed under
modified conditions compared to the standard technique.12
Increasing the temperature from 80 to 111°C, owing to
changing the reaction solvent from benzene to toluene, as
suggested earlier,6 provided a significant increase in the yields
a.Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1
Severny proezd, 142432 Chernogolovka, Russian Federation.
Fax: +7 49652 49508; E-mail: paveltar369@gmail.com.
b.Centre for Theoretical and Computational Chemistry (CTCC), Department of
Chemistry, University of Oslo, P. O. Box 1033 Blindern, N-0315 Oslo, Norway.
c. Department of Chemistry, M.V. Lomonosov Moscow State University, 1 Leninskie
Gory, 119991 Moscow, Russian Federation.
of 5b,c from 10–20% to 80–90%. Moreover, in the case of 5b
and 6b,d
,
the reaction time was considerably reduced
compared to the standard technique.12 However, under these
reaction conditions 1,4-diazepinodicarbonitrile 5a was only
obtained in trace amounts. TLC indicated that the formation of
† Electronic Supplementary Information (ESI) available: ESI mass spectra, 1H NMR,
13C NMR, IR, and fluorescence spectra of synthesized compounds; 1H-13C HSQC and
1H-13
C HMBC spectra of 6d; thermogravimetric analysis of 5b,c and 6d; full
computational details. See DOI: 10.1039/x0xx00000x
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DOI: 10.1039/C5OB02098K
NC
NC
NH2
NH2
R
R
R
N
N
NC
NC
NC
NC
O
O
a
b
c
d
N
O
N
N
1
5a-c
3
Br
O
Br
nPr
R
NC
NC
NH2
NH2
R =
R
N
N
NC
NC
NC
NC
O
O
O
Bn
C3H7
C3H7
C3H7
N
O
N
2
6b,d
4
R
Scheme 1 Synthesis of 5,7-bis(2'-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles.
desired product 5a starts within the first 20 minutes in boiling close to ambient temperature.6 In the case of 6-propyl-
toluene; however, after 2.5 h, an insignificant change in its substituted dinitriles and 6b,d, the presence of a propyl
4
amount along with an accumulation of side products was group at the C6 atom in the 1,4-diazepine heterocycle
observed. An attempt to accelerate the target reaction by significantly increases the energy barrier of cycle inversion.
increasing the temperature to 144°C (o-xylene medium) failed. This leads to the existence of
4 and 6b,d as a mixture of two
Apparently, a further increase in temperature does not isomers with equatorial and axial positions of the propyl
substantially affect the condensation rate, but promotes side radical, which is reflected by the appearance of two sets of
1
reactions such as polymerization of 313 and the Cannizzaro signals in the H NMR spectra (Scheme 2 and Figs. 1, S8, S16,
reaction of pyridine-4-carbonitrile.14 Bearing in mind that the S18, and S23). Integration of the signals in the NMR spectrum
mechanism of condensation is similar to that of the for compound
4 (Fig. S8) gave an approximate ratio of 1:70 for
Knoevenagel reaction, in which the limiting step is the attack the axial to equatorial isomers, that is, the axial isomer content
of C nucleophiles at the carbonyl group, we decided to is less than 5%. At the same time, products 6b and 6d form
increase the rate of condensation by increasing the almost equimolar isomeric mixtures (see Figs. 1, S16, S18, and
concentration of the ionic form of
using a higher content of the organic base (piperidine). An application of two-dimensional Н-1Н COSY, H-13C HSQC, and
equimolar ratio of piperidine to
and a reaction time of 2.5 h 1H-13С HMBC NMR spectroscopy (Figs. 1 and S20–S23 as well
in toluene medium were found to be optimal reaction as Table S1).
3, which can be reached by S23). Full assignment of the NMR signals was achieved by the
1
1
3
conditions, giving 5а in a 30% yield.
Furthermore, the presence of an alkyl substituent at C6
led, not only to the inversion isomers (axial and equatorial),
but also to different rotational isomers with either type A or B
NMR study
In the 1H NMR spectra, equatorial and axial diastereotopic configuration of the arylalkenyl substituent, resulting from
protons of the diazepine CH2 group show signals at 5.2–5.4 hindered rotation of the latter around the С5–С8 and С7–C9
and 2.1–2.3 ppm in the case of 5a–с and 5.12–5.09 and 1.65– bond axes15 (Scheme 2). Having applied a combination of two-
1.57 ppm in the case of 6b,d (see Figs. S8, S10, S12, S14, S16, dimensional NOESY experiments and quantum chemical
and S18), proving that all of the obtained dinitriles exist in the calculations, we managed to distinguish between these
6H tautomeric form (Scheme 2).
rotational isomers. For both inversion isomers of 6b and 6d,
Broadened signals for the 6-H protons in the NMR spectra 1H-1H NOESY spectra show through-space correlation between
of 5a–c indicate that the coalescence temperature, resulting the ethenyl protons of the alkene moiety and the equatorial
from the inversion of 1,4-diazepine ring in these compounds, is protons located in the immediate vicinity (up to 3 Å), as shown
R
A
R
R1
H
R1
6
H
R
B
R
R
R
5
7
8
9
N
N
N 4
3
1 NH
2
R1
rotational
isomerization
imine–enamine
tautomerization
N
N
NC
CN
NC
CN
NC
CN
Scheme 2 Possible isomers of 5,7-bis(2'-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles.
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Fig. 2 1H-1H NOESY NMR spectrum of 6d in CDCl3.
Fig. 1 1H-1H COSY NMR spectrum of 6d in CDCl3.
of theory showed that the difference between the Gibbs
energies of the inversion isomers is 5 kJ mol-1 for
4 and 2 and 1
in Figure 2. In the case of the equatorial isomer, the observed
correlation between the CH2** protons of the propyl radical
kJ mol-1 for 6b and 6d, respectively (Table 1). Thus, the results
α
of the calculations suggest that the substitution of methyl
and 1'-H** ethenyl protons of the alkene moiety clearly
indicates that it exists only in the type B configuration (Figs. 2
and S24 as well as Tables S14 and S22). For the axial isomer,
the equatorial 6-H* proton in the 1H-1H NOESY spectra
correlates with both 1'-H* and 2'-H* ethenyl protons, showing
that its alkenyl fragments adopt both A and B configuration
types (Figs. 2 and S24 as well as Tables S24, S26, and S28).
It is worth noting that the inversion isomers have different
spin–spin coupling constants 3J for alkenyl -CH=CH- protons.
groups in
between the Gibbs energies of the corresponding inversion
isomers, resulting in 6b being obtained as a statistical
4 for arylalkenyl groups decreases the difference
,d
mixture of axial and equatorial isomers.
The data could be explained as follows: for both isomers,
the n-alkyl group experiences steric tensions with either the
1,4-diazepine ring or the alkenyl substituents in the case of the
axial and equatorial isomers, respectively. Thus, the presence
3
Thus, J = 15.3 and 15.9 Hz for axial and equatorial isomers,
Table 1. Relative Gibbs energies of DFT-optimized structures§
respectively. This difference is a result of H-C=C bond angle
distortions, owing to steric effects of the substituents, which
are associated with both 1,4-diazepine cycle inversion and the
rotation of the arylalkenyl fragment in these isomers.
Grel, kJ mol-1
Rotational conformers
Axial isomer
Equatorial isomer
4
6b
6d
5
2
1
0
0
0
B+B
B+B
DFT study and conformational analysis
Quantum-chemical calculations at the B3LYP/6-31G(d,p) level
§For details, see the Supporting Information.
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Fig. 3 Theoretical analysis of rotation of the arylalkenyl substituents in 5,7-bis(2'-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles.
of two arylalkenyl substituents in 6b,d leads to an additional conformational states to those of the transition states (Fig. 3
steric tension between the n-alkyl and arylalkenyl groups and and Tables S18-S22 and S24-S28), one can see that the
causes alignment of the energies of the axial and equatorial existence of equatorial isomer of 6d with type A configuration
isomers, unlike compound
previously reported that the products of 6-n-alkyl substitution and this state is comparable in energy to the transition state
in compound form stable equatorial isomers; therefore, (Fig. 3, A+A conformer). In the case of the axial isomer, the
4
. In contrast, Horiguchi et al.16 of the arylalkenyl substituents is most sterically unfavorable,
3
further aldol condensation with aryl aldehydes at one of the steric hindrance between the n-alkyl and arylalkenyl groups is
methyl groups gives exclusively equatorial isomers. The absent and 6d may exist as conformers with both A and B
discrepancy between Horiguchi's results and the data reported configuration types of the arylalkenyl substituents, which
herein can be explained, firstly, by the presence of two differ slightly in their energies (Fig. 3). The analysis of the
arylalkenyl substituents in our case, and, secondly, by the fact hindered rotation of the arylalkenyl fragments revealed the
that the authors16 based on the X-ray data to obtain the presence of transition states, and the activation energies of
information about the most stable conformers. It is clear that this rotation for both isomers (axial and equatorial) have
the physical state of the substance may have a significant similar values (Fig. 3). At the same time the difference
impact on its conformational state; thus, our study of the between the activation barriers of inversion for both rotational
conformational states of 5,7-bis(2'-arylethenyl)-6H-1,4- isomers (B+B and A+A conformers) is more than twice larger
diazepine-2,3-dicarbonitriles was carried out in solution.
than that of rotation (Table 2). Hence, the transition states for
As noted in the previous section, the rotation of arylalkenyl rotation are less influenced than the transition states for cycle
substituents around the С5–С8 and С7–C9 bond axes are inversion by the steric effect of the interaction between the 6-
observed, in addition to cycle inversion (Scheme 2). Comparing n-propyl group and the arylalkenyl moiety. There is a slight
the energies of the inversion isomers in different difference (3 kJ mol-1) between the Gibbs energies of
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Table 2. Relative Gibbs energies for inversion isomers of 6d§
1,4-diazepine heterocycles provides ways of controlling the
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properties of the compounds based on tDhOemI: 1,0w.10h3ic9h/C,5iOnBt0u2r0n9,8iKs
important for biochemical research.
Rotational
conformers
A+A
Grel, kJ mol-1
Axial isomer
Ts
127
109
92
Equatorial isomer
6
4
1
33
16
0
UV/Vis, TD-DFT and NBO analyses
B+A
B+B
Quantum-chemical calculations using the TD-DFT method at
the CAM-B3LYP/6-31G(d,p) level of theory showed that the
HOMO–LUMO transition makes the largest contribution to the
long wavelength absorption (more than 90%), as shown in
Tables S3, S6, S9, S11, S13, S15, S17, S23, and S29. The
theoretical spectra are in good agreement with experimental
data (Fig. 4).
NBO analysis revealed that the alkenyl substituents in the
studied dinitriles exhibit an electron-donating effect towards
the 1,4-diazepine heterocycle (Table S33).
The energy diagram of the frontier molecular orbitals
(MOs) demonstrates that the molecules are highly sensitive to
the nature of aromatic moiety in the 2’-arylethenyl substituent
(Fig. 5). Changing the substituent on the phenyl ring, when
going from 5b to 5c, results in an appreciable increase in the
HOMO and LUMO energy levels, indicating a strengthening of
the electron donor effect of the substituent. Such sensitivity of
the frontier MOs to impact of an aryl moiety provides evidence
of effective conjugation between the 1,4-diazepine ring and
the arylalkenyl substituent. This is supported by intermediate
С–С bond lengths (1.45–1.36 Å) in the alkenyl moieties, as well
as by the arrangement of the alkenyl moiety, N=C bond of the
diazepine heterocycle, and the aryl ring in one plane with a
deviation of less than 5°. Thus, by introducing various aryl
moieties, we can effectively tune the physicochemical
properties of the resulting 5,7-alkenyl-substituted 1,4-
diazepine-2,3-dicarbonitriles. For example, when going from
5a, with pyridyl ethenyl groups, to 5c, with more electron-
donating substituent, a bathochromic shift in the UV/Vis bands
of about 50 nm is observed (Fig. 4). In the case of the inversion
§For details, see the Supporting Information.
conformers with either A or B type configuration of the
arylalkenyl fragments for compounds with a C6-unsubstituted
1,4-diazepine heterocycle using 5a as the example, which also
indicates the existence of these compounds in solution as a
mixture of rotational isomers.
Thus, the calculations performed at the B3LYP/6-31G(d,p)
level of theory are in good agreement with 2D NMR
spectroscopic data (see above), indicating that the
simultaneous presence of substituents at the C5, C6, and C7
positions of the 1,4-diazepine heterocycle results in effective
intramolecular steric interactions, which, in turn, significantly
affects the stability of the conformational state of the
molecule. Elucidating the structural and steric regularities of
Fig. 5 Energy levels of frontier MO’s and their contour plots obtained from DFT
B3LYP/6-31G(d,p) calculations.
Fig. 4 Experimental (I) and TD-DFT calculated (II) UV/Vis spectra of 4, 5a-c, 6b,d.
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isomers, theoretical calculations showed a slight bathochromic S34). Furthermore, in the cases of 5c and 6b,d, no distinct
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shift of the absorption bands in simulated spectra of the axial effects appear in the DSC curves (Figs. D6O, IS: 3103.,10a3n9d/C5SO3B40).20T9h8iKs
isomers, owing to LUMO stabilization, which has previously can be explained by the influence of additional effects caused
been observed.16
by conformational changes of 1,4-diazepine heterocycles with
bulky substituents on the crystallinity of the specimens.
DSC curves of 5,7-arylethenylsubstituted 1,4-diazepine-2,3-
Fluorescence
The fluorescence of 1,4-diazepine heterocycles is known to be dicarbonitriles 5a–c exhibit an exothermic effect in the range
quenched by ring inversion and, therefore, depends on the of 240–280 °C with an accompanying mass loss associated with
+
temperature, owing to the hindrance of ring inversion with the CH2 moiety and the detection of the C2H3 ion in the mass
decreasing temperature.17 All of the investigated 5,7-bis(2'- spectrum (Figs. 6, S32, and S33). We suppose that, owing to
arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles showed weak the recyclization of the diazepine heterocycle into pyrazine,18
fluorescence in solution at room temperature (Fig. S31). It is highly reactive :CH2 moiety evolves, followed by the formation
+
worth noting that a hindrance effect on the inversion of 1,4- of C2H4, which then produces C2H3 molecular ion with m/z =
diazepine ring in n-alkyl substituted derivatives 6b,d did not 27 (Fig. 6). n-Propyl substitution at the C6 position reduces the
noticeably influence the fluorescence, which can be explained thermal stability of the 1,4-diazepine cycle, however, the
by the availability of additional pathways for fluorescence mechanism of thermal degradation is changed, and the
quenching resulting from the conformational rotation of characteristic signs of recyclization of 1,4-diazepine
arylalkenyl fragments at room temperature.
heterocycle into pyrazine are no longer observed. This can be
explained by the steric effects of bulky substituents at C6 on
the mechanism of destruction.
Thermogravimetric studies
STA clearly demonstrates the effect of hindered
conformational states on the physicochemical properties of
Conclusions
the obtained compounds. Thus, compound
4, existing
predominantly (over 95%) as the equatorial isomer, melts
without decomposition at 120 °C, which results in an apparent
endothermic peak in the DSC curve (Fig. 6). Compounds 5a–c
and 6b,d decompose while melting, so the heats of these
processes overlap and cannot be resolved (Figs. 6 and S32–
A
series of 5,7-bis(2'-arylethenyl)-6H-1,4-diazepine-2,3-
dicarbonitriles, including derivatives substituted with propyl at
C6 position, has been prepared. According to STA data, all of
the compounds obtained showed sufficient thermal stability to
be used as precursors for template macrocyclization. 2D
NOESY NMR spectroscopy combined with quantum-chemical
calculations at the B3LYP/6-31G(d,p) level of theory
demonstrated that steric effects play a key role in the
conformational behavior of n-alkyl-substituted 1,4-
diazepinodicarbonitriles
4 and 6b,d in solution. UV/Vis
spectroscopy, TD-DFT, and NBO analysis showed strong
influence of the arylalkenyl substituent on the 1,4-diazepine
heterocycle. Thus, analysis of the experimental and theoretical
data on the intramolecular, steric, and electronic interactions
in 5,7-bis(2'-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles
indicates effective ways to control the physicochemical
properties of both 1,4-diazepinodicarbonitriles, and the
macrocycles based on them, by changing the nature of the
substituents introduced into the 1,4-diazepine heterocycle.
The latter is particularly promising for applied research, as the
introduction of various substituents is the basic technique
used in synthetic chemistry to find the optimal properties of
synthesized compounds.
Experimental section
General Information
UV/Vis and fluorescence spectra were recorded on a Hitachi U-
2900 spectrophotometer using quartz cuvettes (10×10 mm)
with the samples dissolved in MeOH, unless otherwise
1
specified. H and 13C NMR spectra were recorded on Bruker
Avance 500 (500 and 125 MHz, respectively) and Bruker AM-
200 (200 and 50 MHz, respectively) instruments with the
Fig. 6 TG-DSC-MS curves for 4(I), 6b(II) and 5a(III).
6 | J. Name., 2012, 00, 1-3
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samples dissolved in CDCl3 or DMSO-d6. Chemical shifts are order to evaluate the solvent effect on the geometries, Gibbs
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given in parts per million (ppm) relative to TMS. Signals of energies, and electronic spectra of the DmOoI:le10c.u10le3s9/iCn5OqBu0e2s0t9io8nK
protons belonging to the keto and enol tautomers are marked geometry optimizations were done for the following three
†
‡
with and , respectively. Proton signals of conformers with cases: the gas phase, chloroform solution, and methanol one,
either axial or equatorial position of the 6-propyl group are while TD-DFT calculations were performed for the first and the
designated as * and **, respectively. IR spectra were recorded last case. Specifically, the well-established conductor-like
on a Bruker IFS 113v spectrometer using KBr pellets. Melting Polarizable Continuum Model (C-PCM)25 was used to model
points were determined using a Kofler apparatus. ESI mass solvent effects, using which the geometries of all the
spectra were obtained using a Shimadzu LCMS 2020. Column structures in the above mentioned solutions were found to be
chromatography was carried out on silica gel 60 (Merck). almost identical to the corresponding gas-phase ones and the
Preparative TLC was performed using Merck Silica Gel 60 F254 same could be said about Gibbs energies that differ by at most
flexible plates. All other reagents and solvents were obtained 2 kJ/mol. The calculated spectra in MeOH solution were
or distilled according to standard procedures. All reactions virtually identical to that in the gas phase.
were controlled by TLC and UV/Vis until complete Natural bond orbital (NBO) method 6.026 was used to evaluate
disappearance of the starting reagents, if not otherwise the electronic effects of substituents at 5,7-positions.
specified.
Thermoanalytical investigations were carried out using a STA
Quantum-chemical calculations were performed at the DFT 409 PC Luxx (Netzsch) simultaneous thermal analyzer coupled
level using the hybrid functional B3LYP19 with 6-31G(d,p) with a QMS 403C Aëolos mass spectrometer. Measurements
basis20, as provided by the most recent 2014 R1 version of the were performed in an alumina crucible with a temperature
GAMESS package21. The search for different conformers was range of 40–600°C and a heating rate of 10°С min-1 under an
performed using the ''torsion-driving'' approach, which air atmosphere.
consists of the following steps:
1) Starting from some initial molecular geometry, rotatable
Synthesis
bonds are identified.
2) Then, by systematically changing the values of the the described synthetic route27 with a modified isolation
corresponding dihedral angles, a set of input geometries is procedure. Acetylacetone (15.0 g, 150 mmol) was dissolved
generated. in dry acetone (100 mL) and anhydrous K2CO3 (19.3 g, 140
3-n-Propyl-2,4-pentanedione (2) was synthesized according to
1
3) Finally, by optimizing the structures obtained in the mmol) was added. The resulting mixture was stirred vigorously
previous step, a set of conformers can be obtained. Values of at ambient temperature for 15 minutes; then, 1-
the dihedral angles from the second step were increased bromopropane (17.8 g, 145 mmol) was added in small portions
sequentially from 0 to 360° by a step of 30°, as it is hard to over a period of 10 minutes. The mixture was refluxed under
encounter a situation in which an angle between substituents vigorous stirring for 24 h, controlling the reaction by TLC. Upon
around a rotatable bond in two conformers differs by less than completion of the reaction, diethyl ether (150 mL) was added
30°, which reflects the widely used Klyne–Prelog system for to the reaction mixture. The resulting solution was filtered to
naming conformations about a single bond.22
remove any inorganic salts and the filtrate was concentrated in
The starting geometry for every transition state structure was vacuo. Then, the high-boiling residue was subjected to vacuum
obtained by the relaxed potential energy surface (PES) scan in fractional distillation; the fraction at 100–120°C (50 mm Hg)
the directions of the corresponding hypothesized reaction was collected. As a result, compound
2 was obtained as a
coordinate. Intrinsic reaction coordinate (IRC) calculations colorless, oily substance (16.0 g, yield 81%). 1H NMR (200 MHz,
were performed for all the resulting transition state structures CDCl3) δ ppm: 16.68 (0.2 H, s, OH‡), 3.64 (0.8 H, t, J = 7.2 Hz,
3
†
,
‡
to verify the connections on the PES. Geometry optimizations CH†), 2.23–1.99 (6.4 H, m, CH3 ‡; αCH2 ), 1.77 (1.6 H, q, 3J = 7.5
†
†,
were performed using tighter than default convergence Hz, αCH2 ), 1.39–1.16 (2 H, m, βCH2 ‡), 0.93–0.83 (3 H, m,
†
,
gradient criteria, namely, the largest component of the PrCH3 ‡).
gradient was required to be less than 0.00001 Hartree/Bohr. 5,7-Dimethyl-6H-1,4-diazepine-2,3-dicarbonitrile
(3
)
was
The tight grid having 99 radial and 590 angular points was used prepared according to the published procedure11. Colorless
to achieve the desired accuracy in nuclear gradients; the same crystals. Mp 199–201 °C.
grid was used later for TD-DFT calculations which were 5,7-Dimethyl-6-propyl-6H-1,4-diazepine-2,3-dicarbonitrile
performed using the CAM-B3LYP23 functional in the Tamm- was synthesized by putting diaminomaleonitrile (3.04 g, 0.028
Dancoff approximation24. For all the structures corresponding mol), diketone
(4.00 g, 0.028 mol), oxalic acid (0.07 g) and
(4)
2
to stationary points on the PES geometry optimization was benzene (50 mL) into a flask equipped with a Dean–Stark trap,
followed by analytic harmonic vibrational frequency reflux condenser, and stirring bar. The mixture was refluxed
calculations to not only verify the nature of stationary points for 9 h, controlling the reaction by TLC. Upon completion of
(zero imaginary frequencies and exactly one for minima and the reaction, the solvent was evaporated under reduced
transitions states respectively) but also to obtain the pressure. The resulting dry residue was dissolved in CHCl3 (100
thermodynamical quantities of interest.
mL), filtered, and evaporated to 10 mL. The product was
As mentioned above, NMR and UV-Vis studies were done in isolated by column chromatography (SiO2, CHCl3/MeOH 100/1)
1
chloroform and methanol solutions, respectively. Thus, in as a white solid (2.8 g, yield 47%). Mp 123–124 °C. H NMR
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 9
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(200 MHz, CDCl3) δ ppm: 2.30–2.13 (8H, m, 5,7-CH3; αCH2), 136.5, 130.4, 128.9, 128.5, 128.0, 127.7, 122.4, 122.2, 116.2,
View Article Online
1.49 (2H, m, βCH2), 1.36 (1H, t, 3J = 7.2 Hz, 6-H), 1.07 (3H, t, 3J = 115.5, 69.4. IR (KBr), ν cm-1: 3033w, 2D0O21I:m10,.1013599/8Cs5,OB10526079m8K,
7.2 Hz, PrCH3). 13C NMR (50 MHz, CDCl3) δ ppm: 153.7, 121.4, 1517s, 1453m, 1424w, 1300w, 1256s, 1169s, 1024m, 967m,
114.4, 58.4, 28.9, 21.7, 21.3, 13.9. IR (KBr), ν cm-1: 3010w, 822m, 729m, 693m, 513w. UV/Vis (DMSO), λmax (lgε) nm: 355
2966m, 2935m, 2879w, 2229s, 1675w, 1571s, 1468w, 1418m, (4.86), 430 (4.43). MS (ESI): m/z 559 [M
–
H]–.
1378m, 1333m, 1233s, 1202w, 1189m, 1106m, 1003m, 976w, C37H28N4O2×0.79H2O (574.88): calcd. C 77.30, H 5.19, N 9.75;
749w, 712w, 637m, 588w, 529w, 424w. MS (ESI): m/z 213 [M – found C 77.58, H 5.25, N 9.35.
H]–. C12H14N4 (214.27): calcd. C 67.27, H 6.59, N 26.15; found C 5,7-Bis[2'-(4-bromophenyl)ethenyl]-6-propyl-6H-1,4-
67.03, H 6.63, N 26.17.
diazepine-2,3-dicarbonitrile (6b): Yield 0.4 g (31%). Vinous
5,7-Bis(2'-arylethenyl)-6H-1,4-diazepine-2,3-dicarbonitriles
solid. Mp 101–106 °C. 1H NMR (500 MHz, CDCl3) δ ppm: 7.67
5a–c and 6b
procedure. 1,4-Diazepine-2,3-dicarbonitrile
corresponding aldehyde (4.66 mmol), piperidine (0.023 mmol; ArH)**, 6.82 (1H, d, J = 16 Hz, 1'-H)**, 6.62 (1H, d, J = 15.3
,d
were synthesized by following a general (1H, d, 3J = 15.4 Hz, 2'-H)*, 7.55–7.52 (5H, m, 2'-H**; o-Ar*,**),
3
3
3
or 4 (2.33 mmol), 7.42 (2H, d, J = 8.3 Hz, m-ArH)*, 7.39 (2H, d, J = 8.4 Hz, o-
3
3
3
3
2.33 mmol for 5a), and toluene (50 mL), were put into a flask Hz, 1'-H)*, 5.11 (0.5H, t, J = 7.5 Hz, 6-H)*, 2.50 (1H, q, J = 7.7
equipped with a Dean–Stark trap, reflux condenser, and Hz, αCH2)**, 1.65–1.58 (1.5H, m, CH2; 6-H)**, 1.36 (1H, m,
β
stirring bar. The reaction mixture was refluxed under vigorous βCH2)*, 1.13 (1.5H, t, J = 7.3 Hz, PrCH3)**, 1.06 (1H, q, J = 7.5
3
3
stirring for 2.5 h (5a), 3 h (5b), 5 h (5c), or 7 h (6b,d
), Hz, αCH2)*, 0.94 (1.5H, t, 3J = 7.3 Hz, PrCH3)*. 13C NMR (50 MHz,
controlling the reaction by TLC. Upon completion of the CDCl3) δ ppm: 150.9, 147.2, 146.9, 143.1, 133.4, 133.2, 132.4,
reaction, the solvent was evaporated under reduced pressure. 132.3, 129.6, 126.3, 125.6, 125.4, 121.9, 121.7, 117.7, 115.3,
The resulting dry residue was dissolved in ethyl acetate (5a), 115.3, 56.2, 53.2, 29.7, 28.5, 23.5, 21.1, 14.1, 13.8. IR (KBr), ν
acetone (5b
evaporated to 2–5 mL. The product was isolated by column 1486s, 1401m, 1308m, 1779m, 1069s, 1017s, 970m, 808s,
,c), or chloroform (6b,d
) (100 mL), filtered, and cm-1: 3052w, 2923m, 2852w, 2223m, 1617s, 1584m, 1515s,
chromatography on silica gel, using
acetate/chloroform 3/2 (5a), chloroform/acetone 7/3 (5b
or chloroform/acetone 19/1 (6b ) as the eluent.
5,7-Bis[2'-(pyridine-4-yl)ethenyl]-6H-1,4-diazepine-2,3-
dicarbonitrile
a
mixture of 718w, 494m. UV/Vis (DMSO), λmax (lgε) nm: 341 (4.58), 405
,c
), (4.28). MS (ESI): m/z 548 [M]–. C26H20Br2N4 (548.27): calcd. C
56.96, H 3.68, N 10.22; found C 56.80, H 3.98, N 9.79.
,d
5,7-Bis[2'-(4-methoxyphenyl)ethenyl]-6-propyl-6H-1,4-
(
5a): Yield 0.24 g (30%). Yellow solid. Mp > diazepine-2,3-dicarbonitrile (6d): Yield 0.6 g (57%). Orange
200 °C (decomp.). H NMR (200 MHz, DMSO-d6) δ ppm: 8.63 solid. Mp 174–175 °C. 1H NMR (500 MHz, CDCl3) δ ppm: 7.69
1
(4H, d, 3J = 8.6 Hz, α-Py), 8.06 (2H, d, 3J = 16.4 Hz, 2'-H), 7.69 (1H, d, J = 15.3 Hz, 2'-H)**, 7.56 (1H, d, J = 15.9 Hz, 2'-H)*,
3
3
(4H, d, 3J = 5.3 Hz, β-Py), 7.36 (2H, t, 3J = 16.4 Hz, 1'-H), 5.41 7.51 (2H, d, 3J = 8.8 Hz, o-Ar)*, 7.48 (2H, d, 3J = 8.8 Hz, o-Ar)**,
(1H, br s, ax 6-H), 2.16 (1H, br s, eq 6-H). 13C NMR (50 MHz, 6.93–6.90 (4H, m, m-Ar)*,**, 6.73 (1H, d, J = 15.9 Hz, 1'-H)*,
3
3
3
DMSO-d6) δ ppm: 151.0, 150.6, 142.0, 141.6, 128.8, 123.3, 6.49 (1H, d, J = 15.3 Hz, 1'-H)**, 5.11 (0.5H, t, J = 7.5 Hz, 6-
122.0, 115.6. IR (KBr), ν cm-1: 3028w, 2225m, 1627m, 1592s, H)*, 3.84 (3H, s, -OMe), 3.85 (3H, s, -OMe), 2.48 (1H, q, 3J = 7.7
1528s, 1409s, 1347m, 1312m, 1291s, 1235m, 1208m, 1196m, Hz, αCH2)**, 1.65–1.57 (1.5H, m, CH2; 6-H)**, 1.35 (1H, m,
β
1175m, 1117m, 1057w, 857w, 810s, 781w, 716w, 640w, 610w, βCH2)*, 1.12 (1.5H, t, J = 7.3 Hz, PrCH3)**, 1.05 (1H, q, J = 7.7
550w, 505m, 455m. UV/Vis (DMSO), λmax (lgε) nm: 304 (4.7), Hz, αCH2)*, 0.94 (1.5H, t, 3J = 7.4 Hz, PrCH3)*. 13C NMR (50 MHz,
328 (4.24). MS (ESI): m/z 349 [M – H]–. C21H14N6 (350.38): CDCl3) δ ppm: 162.1, 162.0, 151.9, 148.2, 147.8, 143.8, 130.2,
calcd. C 71.99, H 4.03, N 23.99; found C 72.05, H 4.31, N 23.83. 127.6, 127.3, 123.7, 121.6, 121.5, 115.8, 115.7, 114.9, 114.6,
3
3
5,7-Bis[2'-(4-bromophenyl)ethenyl]-6H-1,4-diazepine-2,3-
114.5, 56.2, 55.5, 52.5, 28.7, 23.7, 21.2, 21.1, 14.2, 13.8. IR
dicarbonitrile (5b): Yield 1.01 g (86%). Yellow solid. Mp 254– (KBr), ν cm-1: 2960m, 2835w, 2221m, 1601s, 1571m, 1511s,
1
256 °C. H NMR (200 MHz, DMSO-d6) δ ppm: 8.02 (2H, d, 3J = 1424m, 1293m, 1256s, 1173s, 1088w, 1024m, 974m, 824m,
16.4 Hz, 2'-H), 7.68 (4H, d, 3J = 8.6 Hz, ArH), 7.59 (4H, d, 3J = 8.3 712w, 544w, 515. UV/Vis (DMSO), λmax (lgε) nm: 364 (4.74),
Hz, ArH), 7.13 (2H, d, 3J = 16.3 Hz, 1'-H), 5.53 (1H, br s, ax 6-H), 440 (4.42). MS (ESI): m/z 450 [M – H]–. C28H26N4O2×0.71H2O
2.10 (1H, br s, eq 6-H). 13C NMR (50 MHz, DMSO-d6) δ ppm: (463.32): calcd. C 72.58, H 5.97, N 12.09; found: C 72.94, H
151.6, 143.5, 134.0, 132.2, 130.3, 125.3, 124.5, 122.9, 115.8. IR 5.92, N 11.71.
(KBr), ν cm-1: 3062w, 2221m, 1617s, 1582m, 1559w, 1515s,
1486m, 1457w, 1403w, 1331w, 1300m, 1204w, 1175m,
1133w, 1073m, 1005m, 970m, 812m, 716w, 640w, 490m,
Acknowledgements
463w. UV/Vis (DMSO), λmax (lgε) nm: 333 (4.85), 402 (4.36). MS
(ESI): m/z 505 [M – H]–. C23H14Br2N4 (506.19): calcd. C 54.57, H
2.79, N 11.07; found C 55.04, H 3.23, N 10.70.
The research was supported by the Russian Foundation for
Basic Research (Grant Nos. 14-03-32031, 15-33-21012, 15-03-
05890). The thermoanalytical investigations were performed
at the User Facilities Center of M.V. Lomonosov Moscow State
University under financial support of the Ministry of Education
and Science of Russian Federation (Contract N16.552.11.7081).
The authors acknowledge partial support from the M.V.
Lomonosov Moscow State University Program of
Development. The authors also thank Joined Supercomputer
5,7-Bis[2'-(4-benzyloxyphenyl)ethenyl]-6H-1,4-diazepine-2,3-
dicarbonitrile (5c): Yield 1.10 g (84%). Orange solid. Mp 205–
1
208 °C. H NMR (200 MHz, DMSO-d6) δ ppm: 8.03 (2H, d, 3J =
16.2 Hz, 2'-H), 7.73 (4H, d, 3J = 8.1 Hz, o-Ar), 7.41–7.35 (10H, m,
o,m,p-Ph), 7.09–6.94 (6H, m, m-Ar; 1'-H), 5.15 (4H, s, -CH2-Ph).
13C NMR (50 MHz, DMSO-d6) δ ppm: 160.8, 152.3, 144.6,
8 | J. Name., 2012, 00, 1-3
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Center of the Russian Academy of Sciences (www.jscc.ru) for
providing computing resources.
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