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<li><a href="#abstract">Abstract</a></li>
<li><a href="#intro">Introduction</a></li>
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<p class="art-type" id="articleinfo">Research Article</p>
<p class="art-title">NMR <sup>1</sup>H Spectra of the [1,2]Diazepino[4,5-b]Indole Derivatives: Experimental versus GIAO calculated Data</p>
<p class="art-author"><?php $authors="A V Muratov<sup>1</sup>, Yu V Berestneva<sup>2</sup>, S Yu Zinchenko<sup>1</sup>, D I Matveyeva<sup>1</sup>, V Yu Popov<sup>1</sup>, A A Voitash<sup>1</sup>, Elena Vladimirovna Raksha<sup>2*</sup> and Alexander Borisovich Eresko<sup>1*</sup>"; echo (stristr($authors,$coauthor))?str_replace($coauthor,"<a href='".$extpath."authors/".$courl."' target='_blank'>".$coauthor."</a>",$authors):$authors; ?></p>
<p class="art-affl"><sup>1</sup>Department of the Biologically Active Compounds Chemistry, L.M. Litvinenko Institute of Physical Organic and Coal Chemistry R. Luxemburg str. 70, Donetsk, 283114, Ukraine<br/><sup>2</sup>Supramolecular Chemistry Depertment, L.M. Litvinenko Institute of Physical Organic and Coal Chemistry R. Luxemburg str. 70, Donetsk, 283114, Ukraine</p>
<p class="art-aff"><b>*Corresponding author: <?php $corresponding_author="Alexander Borisovich Eresko"; echo ($coauthor!="" && $coauthor==$corresponding_author)?"<a href='".$extpath."authors/".$courl."' target='_blank'>".$coauthor."</a>":$corresponding_author;?></b>, Senior Research Fellow, L.M. Litvinenko Institute of Physical Organic Chemistry and Coal Chemistry, Donetsk, Ukraine, E-mail: <a href="mailto:a_eresko77@mail.ru">a_eresko77@mail.ru</a><br/> <b>Elena Vladimirovna Raksha</b>, Research Fellow, L.M. Litvinenko Institute of Physical Organic Chemistry and Coal Chemistry, Donetsk, Ukraine, E-mail: <a href="mailto:elenaraksha411@gmail.com">elenaraksha411@gmail.com</a></p>
<p class="art-aff"><b>Received</b>: December 25, 2018 <b>Accepted</b>: January 18, 2019 <b>Published</b>: January 28, 2019</p>
<p class="art-aff"><b>Citation</b>: Muratov AV, Berestneva YV, Zinchenko SY, et al. NMR <sup>1</sup>H Spectra of the [1,2]Diazepino[4,5-b]Indole Derivatives: Experimental versus GIAO calculated Data. <i>Int J Chem Res</i>. 2018; 1(1): 9-12. doi: <a href="https://doi.org/10.18689/ijcr-1000102">10.18689/ijcr-1000102</a></p>
<p class="art-aff"><b>Copyright</b>: &copy; 2019 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p>
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<p class="art-subhead" id="abstract">Abstract</p>
<p class="art-para">A comprehensive study of new [1,2]diazepino[4,5-b]indole derivatives molecular geometry as well as their NMR <sup>1</sup>H spectra by DFT method was performed. GIAO-calculated NMR <sup>1</sup>H chemical shifts as obtained at B3LYP/6-31G (d,p)/PCM computational level are reported for the 1,2-diazepine compounds.</p>
<p class="art-para"><b>Keywords:</b> [1,2]Diazepino[4,5-b]indoles; B3LYP; GIAO; NMR <sup>1</sup>H spectra; Chemical shift.</p>
<p class="art-subhead" id="intro">Introduction</p>
<p class="art-para">The biological activity of compounds containing in their structure the 1-aryl-2,3-benzodiazepine skeleton is best demonstrated by the example of tofisopam, a wellknown anxiolytic drug, or talampanel <a href="#1" id="ref1">[1</a>,<a href="#2" id="ref2">2]</a>. Related condensed heterocyclic systems, such as indolo-1,2-diazepines, can be considered as potentially useful structures for drug design. It is known that indole-condensed azacycles are structural components of many natural and synthetic biologically active compounds <a href="#3" id="ref3">[3</a>,<a href="#4" id="ref4">4]</a>. Investigations on the synthesis of indolo[1,2]diazepines are few <a href="#5" id="ref5">[5</a>-<a href="#8" id="ref8">8]</a> and limited to derivatives containing alkyl substituent&#8217;s in the diazepine ring. Synthesis and structural modification of arylcontaining indolodiazepines have been demonstrated recently <a href="#9" id="ref9">[9]</a>. As a continuation of our research on the synthesis and reactivity of heterocyclic systems based on 1,2-diazepine <a href="#8" id="ref8">[8</a>,<a href="#10" id="ref10">10</a>-<a href="#12" id="ref12">12]</a>, this paper presents the results of molecular modeling of the structure and NMR <sup>1</sup>H spectra of some new indolo[1,2]diazepines.</p>
<p class="art-subhead">Experimental Part</p>
<p class="art-para">NMR <sup>1</sup>H spectra were recorded in DMSO-d<sub>6</sub> on 400/100 MHz NMR spectrometer (Bruker Avance II 400) and chemical shifts values (&#948;) are given in parts per million relative to tetramethylsilane (TMS). The melting points were determined on a Boetius hot stage. The CHN elemental analysis was performed using a Varian MICRO Cube analyzer. The mass spectra were recorded on an Agilent 1100 LC/MSD VL instrument (atmospheric pressure chemical ionization; Zorbax SBC18 column, 50 &#215; 4.6 mm; eluent acetonitrile-water (95:5) containing 0.1% of trifluoroacetic acid, flow rate 3.0 mL/min, gradient elution).</p>
<p class="art-para">For detailed information on the synthesis of [1,2]diazepino[4,5-b]indoles 1-3 as well as their precursors, see our recent article <a href="#9" id="ref9">[9]</a>.</p>
<p class="art-para"><b>1-(4-methylphenyl)-5,10-dihydro[1,2]diazepino[4,5-<i>b</i>]indol-4(3H)-one (1).</b></p>
<p class="art-para">Yield 45%, M.p. 281-282&#176;&#1057;. NMR <sup>1</sup>H (DMSO-d<sub>6</sub>), <b>&#948;</b>, ppm: 2.42 s (3&#1053;, 4&#8242;-&#1057;&#1053;<sub>3</sub>), 3.59 s (2&#1053;, &#1057;&#1053;<sub>2</sub>), 7.06 t (1&#1053;, &#1053;-7, <i>J</i> 8.0 Hz), 7.18 t (1&#1053;, &#1053;-8, <i>J</i> 8.0 Hz), 7.24 d (2&#1053;, &#1053;-3&#8242;,5&#8242;, <i>J</i> 8.0 Hz), 7.38 d (1&#1053;, &#1053;-9, <i>J</i> 8.0 Hz), 7.65 d (3&#1053;, H-6,2&#8242;,6&#8242;, <i>J</i> 8.0 Hz), 10.64 s (1&#1053;, CONH), 11.08 s (1&#1053;, NH). Mass-spectrum: <i>m/z</i> 290.2 [<i>M</i> + 1]+. Found, %: &#1057; 74.70; &#1053; 5.25; N 14.51. Anal. Calcd. for C<sub>18</sub>H<sub>15</sub>N<sub>3</sub>O, %: &#1057; 74.72; &#1053; 5.23; N 14.52. <i>M</i> 289.33.</p>
<p class="art-para"><b>1-(4-methylphenyl)-5,10-dihydro[1,2]diazepino[4,5-<i>b</i>]indole-4(3<i>H</i>)-thione (2).</b></p>
<p class="art-para">Yield 82%, M.p. 200-202&#176;&#1057;. NMR <sup>1</sup>H (DMSO-d<sub>6</sub>), <b>&#948;</b>, ppm: 2.44 s (3&#1053;, 4&#8242;-&#1057;&#1053;<sub>3</sub>), 4.01 s (2&#1053;, &#1057;&#1053;<sub>2</sub>), 7.13 t (1&#1053;, H-7, <i>J</i> 8.0 Hz), 7.26 t (1&#1053;, H-8, <i>J</i> 8.0 Hz), 7.32 d (2&#1053;, H-3&#8242;,5&#8242;, <i>J</i> 8.0 Hz), 7.42 d (1&#1053;, H-9, <i>J</i> 8.0 Hz), 7.66 d (2&#1053;, H-2&#8242;,6&#8242;, <i>J</i> 8.0 Hz), 7.73 d (1&#1053;, H-6, <i>J</i> 8.0 Hz), 11.41 s (1&#1053;, NH), 12.51 s (1&#1053;, CSNH). Mass-spectrum: <i>m/z</i> 306 [<i>M</i> + 1]+. Found, %: &#1057; 71.02; &#1053; 4.57; N 14.13. Anal. Calcd. for C<sub>18</sub>H<sub>15</sub>N<sub>3</sub>S, %: &#1057; 70.79; H 4.95; N 13.76. <i>M</i> 305.40.</p>
<p class="art-para"><b>1-(4-methylphenyl)-4-(pyrrolidin-1-yl)-5,10-dihydro[1,2]diazepino[4,5-<i>b</i>]indole (3a)</b></p>
<p class="art-para">Yield 72%, M.p. 273-275&#176;&#1057; (with decomposition). NMR <sup>1</sup>H (DMSO-d<sub>6</sub>), <b>&#948;</b>, ppm: 1.90 s (4&#1053;, N&#1057;&#1053;<sub>2</sub><u>&#1057;&#1053;</u><sub>2 pyrrolidine</sub>), 2.42 s (3&#1053;, 4&#8242;-&#1057;&#1053;<sub>3</sub>), 3.00 br.s (1&#1053;, &#1057;&#1053;<sub>2</sub>), 3.51 br.s (5&#1053;, N<u>&#1057;&#1053;</u><sub>2</sub>&#1057;&#1053;<sub>2 pyrrolidine</sub>, &#1057;&#1053;<sub>2</sub>), 7.03 t (1&#1053;, H-7, <i>J</i> 8.0 Hz), 7.14 t (1&#1053;, H-8, <i>J</i> 8.0 Hz), 7.23 d (2&#1053;, H-3&#8242;,5&#8242;, <i>J</i> 8.0 Hz), 7.38 d (1&#1053;, H-9, <i>J</i> 8.0 Hz), 7.65 d (1&#1053;, H-6, <i>J</i> 8.0 Hz), 7.68 d (2&#1053;, H-2&#8242;,6&#8242;, <i>J</i> 8.0 Hz), 11.09 s (1&#1053;, NH). Mass-spectrum: <i>m/z</i> 343 [<i>M</i> + 1]+. Found, %: &#1057; 77.28; &#1053; 6.31; N 16.47. Anal. Calcd. for C<sub>22</sub>H<sub>22</sub>N<sub>4</sub>, %: C 77.16; H 6.48; N 16.36. <i>M</i> 342.44.</p>
<p class="art-para"><b>1-(4-methylphenyl)-4-(morpholin-1-yl)-5,10-dihydro[1,2]diazepino[4,5-<i>b</i>]indole (3b)</b></p>
<p class="art-para">Yield 62%, M.p. 221-223&#176;&#1057;. NMR <sup>1</sup>H (DMSO-d<sub>6</sub>), <b>&#948;</b>, ppm: 2.43 s (3&#1053;, 4&#8242;-&#1057;&#1053;<sub>3</sub>), 2.98 br. s (1&#1053;, &#1057;&#1053;<sub>2</sub>), 3.38 br. s (4&#1053;, N&#1057;&#1053;<sub>2 morpholine</sub>), 3.61 br. s (4&#1053;, O-&#1057;&#1053;<sub>2 morpholine</sub>),4.30 s (1&#1053;, &#1057;&#1053;<sub>2</sub>), 7.04 t (1&#1053;, H-7, <i>J</i> 8.0 Hz), 7.17 t (1&#1053;, H-8, <i>J</i> 8.0 Hz), 7.24 d (2&#1053;, H-3&#8242;,5&#8242;, <i>J</i> 8.0 Hz), 7.39 d (1&#1053;, H-9, <i>J</i> 8.0 Hz), 7.70 d (3&#1053;, H-6, H-2&#8242;,6&#8242;, <i>J</i> 8.0 Hz), 11.16 s (1&#1053;, NH). Mass-spectrum: <i>m/z</i> 359 [<i>M</i>+1]+. Found, %: &#1057; 73.89; &#1053; 5.97; N 15.84. Anal. Calcd. for C<sub>22</sub>H<sub>22</sub>N<sub>4</sub>O., %: C 73.72; H 6.19; N 15.63. <i>M</i> 358.43.</p>
<p class="art-subhead">Theoretical Methods and Computational Details</p>
<p class="art-para">Initial molecular geometries of the [1,2]diazepino[4,5-b]indoles 1-3 for molecular modeling were generated using the algorithm of complete inclusion of possible geometric and steric factors implemented in the Conformer plug-in of the Marvin software package <a href="#13" id="ref13">[13]</a>. This algorithm enables generation of molecular structures with complete analysis of the carbon skeleton, functional groups and heteroatom&#8217;s, geometric isomers, and asymmetric centers.</p>
<p class="art-para">Molecular geometry and electronic structure parameters, thermodynamic characteristics of the [1,2]diazepino[4,5-b]indoles 1-3 conformers were calculated using the Gaussian 09 <a href="#14" id="ref14">[14]</a> software package. Geometric parameters, harmonic vibrational frequencies, and the vibrational contribution to the zero-point vibrational energy were determined after full geometry optimization in the framework of B3LYP/6-31G (d,p) density functional calculations. The solvent (DMSO) effect was considered in the PCM approximation <a href="#15" id="ref15">[15]</a>. The optimized geometric parameters were used for total electronic energy calculations. The 6-31G (d,p) basis set was used in this work because it has a low computational cost. Only the lowest energy conformers of the [1,2]diazepino[4,5-b]indoles 1-3 were used for further consideration.</p>
<p class="art-para">The magnetic shielding tensors (&#967;, ppm) for <sup>1</sup>H nuclei of the [1,2]diazepino[4,5-b]indoles 1-3 were calculated with the B3LYP/6-31G(d,p)/PCM optimized geometries by standard GIAO (Gauge-Independent Atomic Orbital) approach <a href="#16" id="ref16">[16]</a>. The calculated magnetic isotropic shielding tensors, &#967;<sub>i</sub>, were transformed to chemical shifts relative to TMS, &#948;<sub>i</sub>, by &#948;<sub>i</sub>=&#967;<sub>ref</sub>-&#967;<sub>i</sub>, where both, &#967;<sub>ref</sub> and &#967;<sub>i</sub>, were taken from calculations at the same computational level. &#967; Values for magnetically equivalent nuclei were averaged.</p>
<p class="art-subhead" id="discussion">Results and Discussion</p>
<p class="art-para">The main method of a 1,2-diazepine ring condensed with a heterocyclic fragment formation is the condensation of 1,5-dicarbonyl compounds with hydrazine <a href="#8" id="ref8">[8</a>,<a href="#10" id="ref10">10</a>-<a href="#12" id="ref12">12]</a>. Our approach to obtaining [1,2]diazepino[4,5-b]indoles 1-3 involves the synthesis of the starting 1,2-diazepine 1 and its subsequent structural modification to obtain compounds 2-3 (<a href="#f001">Figure 1</a>).</p>
<div class="art-img" id="f001">
<img src="<?php echo $imgpath;?>images/ijcr-102-f001.gif" class="img-responsive center-block"/></div>
<div class="text-center"><b>Figure 1</b>. Synthesis of [1,2]diazepino[4,5-b]indoles 1-3.</div>
<p class="art-para">The starting [1,2]diazepino[4,5-b]indol-4-one 1 was obtained by cyclization of ethyl [2-(4-methylbenzoyl)-1H-indole-3-yl] acetic acid with hydrazine in the presence of a catalytic amount acetic acid. Then [1,2]diazepino[4,5-b]indol-4-one 1 was transformed to the corresponding thion 2 by reaction with Lawesson&#8217;s reagent. Diazepin-4-thion 2 interacts with corresponded amine when heated in propanol-2 with the formation of compounds 3a,b. The structure of the obtained new compounds 1-3 was confirmed by NMR spectroscopy.</p>
<p class="art-para">The peculiarity of the NMR <sup>1</sup>H spectrum of N-substituted [1,2]diazepino[4,5-b]indol-4-ones 3a,b compared with the corresponding 1,2-diazepin-4-one 1 and 1,2-diazepin-4-thion 2 is the appearing of the methylene group protons as two broadened singlets with chemical shifts of 3.00 and 3.51 ppm (compound 3a) as well as 2.98 and 4.30 ppm (compound 3b), which indicates a non-planar configuration of the diazepine ring. It is obvious that the presence of two large substituent&#8217;s in the diazepine ring reduces its conformational mobility, thus in the NMR <sup>1</sup>H spectrum of compound 3, separate signals correspond to the equatorial and axial protons of the methylene group.</p>
<p class="art-para">For the studied [1,2]diazepino[4,5-b]indoles 1-3, molecular geometry optimization was performed in the B3LYP/6-31G(d,p)/PCM approximation (solvent is dimethyl sulfoxide). The parameters of their molecular geometry and electronic structure were estimated. Some of the characteristics obtained are listed in <a href="#t001">table 1</a>. For all the 1,2-diazepins mentioned, only conformers with the lowest total energy were considered. Structural models of 1,2-diazepines 1-3 with the numbering of atoms used in the discussion of the calculated chemical shifts, are shown on <a href="#f002">figure 2</a>.</p>
<div class="text-center"><b>Table 1</b>. Parameters of the molecular geometry and electron structure of studied 1,2-diazepino[4,5-b]indoles 1-3 obtained by B3LYP/6-31G(d,p) method within PCM approximation (solvent - DMSO).</div>
<div class="art-img" id="t001">
<img src="<?php echo $imgpath;?>images/ijcr-102-t001.gif" class="img-responsive center-block"/></div><br/>
<div class="art-img" id="f002">
<img src="<?php echo $imgpath;?>images/ijcr-102-f002.gif" class="img-responsive center-block"/></div>
<div class="text-center"><b>Figure 2</b>. Structural models of the [1,2]diazepino[4,5-b]indoles 1-3(B3LYP/6-31G(d,p)/PCM level) with atom labels used for calculated NMR <sup>1</sup>H chemical shifts presenting for studied compounds.</div>
<p class="art-para">For the most stable conformers of the studied 1,2-diazepines molecules, the NMR <sup>1</sup>H chemical shifts were estimated. To calculate the magnetic shielding constants using the standard GIAO method, the equilibrium configurations of compounds 1-3, obtained by B3LYP/6-31G(d,p) method with PCM approximation were used. The obtained chemical shifts for the compounds 1-3 are given in <a href="#t002">table 2</a>. The NMR <sup>1</sup>H parameters of the studied 1,2-diazepines are correctly reproduced at this theoretical level except for NH protons. It should be noted that taking into account non-specific solvation within PCM model is not sufficient for the correct reproduction of these protons, and the formation of hydrogen bonds with the solvent molecules should be considered. Thus chemical shifts of NH protons were not considered in further discussion. Linear relationships between the experimental chemical shifts and the calculated ones have been obtained for all studied diazepines molecules (<a href="#f003">Figure 3</a>). The correlation coefficients (R) corresponding to obtained dependences are within 0.993&#8211;0.999. Equations, obtained for the individual compounds and the total one:</p>
<p class="art-para">1. &#948;<sub>exp</sub>=(0.952 &#177; 0.009)&#183;&#948;<sub>calc</sub>+(0.14 &#177; 0.06), R=0,99946;<br/>2. &#948;<sub>exp</sub>=(0.953 &#177; 0.007)&#183;&#948;<sub>calc</sub>+(0.15 &#177; 0.05), R=0,99966;<br/>3a. &#948;exp=(0.952 &#177; 0.037)&#183;&#948;calc+(0.09 &#177; 0.22), R=0,99317;<br/>3b. &#948;<sub>exp</sub>=(0.945 &#177; 0.015)&#183;&#948;<sub>calc</sub>+(0.18 &#177; 0.05), R=0,99735;<br/>Total: &#948;<sub>exp</sub>=(0.945 &#177; 0.013)&#183;&#948;<sub>calc</sub>+(0.18 &#177; 0.08), R=0,99628.</p>
<div class="text-center"><b>Table 2</b>. Experimental (in DMSO-d<sub>6</sub> solution) and calculated (B3LYP/6-31G(d,p)/PCM) NMR <sup>1</sup>H chemical shifts of the [1,2]diazepino[4,5-b]indoles 1-3.</div>
<div class="art-img" id="t002">
<img src="<?php echo $imgpath;?>images/ijcr-102-t002.gif" class="img-responsive center-block"/></div><br/>
<div class="art-img" id="f003">
<img src="<?php echo $imgpath;?>images/ijcr-102-f003.gif" class="img-responsive center-block"/></div>
<div class="text-center"><b>Figure 3</b>. Total linear correlation between the theoretical (GIAO, B3LYP/6-31G(d,p)/PCM level) and experimental (DMSO-d<sub>6</sub> solution) proton chemical shifts of [1,2]diazepino[4,5-<i>b</i>]indoles 1-3. (Chemical shifts of NH protons were not considered).</div>
<p class="art-para">For N-substituted [1,2]diazepino[4,5-b]indoles 3a and 3b difference between calculated chemical shifts for non-equivalent methylene group protons exceeds the experimental value. This is due to the fast dynamics of the diazepine ring in the NMR time scale. With an increase in the temperature of the NMR experiment, one can expect higher conformation exchange rates, and, as a consequence, an even greater closing-in of these protons signals up to their coalescence. We observed such pattern for the 1,4-biaryl derivatives of benzofuro[2,3-d] [1,2]-diazepines experimental NMR <sup>1</sup>H spectra <a href="#17" id="ref17">[17]</a>. Thus, a comprehensive study of the 1,2-diazepine core dynamics of condensed diazepines by dynamic NMR spectroscopy as well as DFT method will be the next stage of our work.</p>
<p class="art-subhead">Conclusion</p>
<p class="art-para">A comprehensive study of the [1,2]diazepino[4,5-b]indole derivatives by experimental NMR 1H spectroscopy and molecular modeling methods was performed. Structural parameters of the studied diazepines compounds were obtained by B3LYP method. GIAO-calculated NMR <sup>1</sup>H chemical shifts as obtained at B3LYP/6-31G (d,p)/PCM computational level are reported for the [1,2]diazepino[4,5-b]indoles. For NMR <sup>1</sup>H spectra of the diazepines in DMSO-d<sub>6</sub> this method approximation allows to obtain the correct spectral pattern. Linear correlations between the calculated and experimental values of the 1H chemical shifts for the studied molecules were obtained.</p>
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