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<!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Transitional//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-transitional.dtd"> <html xmlns="http://www.w3.org/1999/xhtml"> <head profile="http://gmpg.org/xfn/1"> <title>Computational Organic Chemistry » 2016 » March</title> <meta name="google-site-verification" content="g1Myv4tUVAmqRbwZeBi7IPuSZpP64RWjVJ6itIoouCo"> <meta http-equiv="Content-Type" content="text/html; charset=UTF-8"> <style type="text/css" media="screen">@import url( /blog/wp-content/themes/comporg/style.css);</style> <link rel="stylesheet" id="wp-block-library-css" href="/blog/wp-includes/css/dist/block-library/style.min.css?ver=5.6.1" type="text/css" media="all"> <script type="text/javascript">  </script> </head> <body> <div id="header"> <div id="header_img"></div> </div> <div id="link_section"> <div style="float:left"> <a href="/blog/about">About this Blog</a> | <a href="/">Book Homepage</a> | <a href="http://www.wiley.com/WileyCDA/WileyTitle/productCd-0471713422.html">Purchase the Book</a> </div> </div> <div id="after_links"></div> <div id="content"> <div id="main"> <h2 class="post-title">Archive for March, 2016</h2> <div class="box"> <h2><a href="/blog/archives/3730" rel="bookmark" title="Permanent Link: 1,3,5-Trifluorenylcyclohexane">1,3,5-Trifluorenylcyclohexane</a></h2> <div class="post-content"> <p>Reid, Rathore and colleagues report on the attempted preparation of the interesting molecule 1,3,5-trifluorenylcyclohexane (TFC) <b>1</b>.<a href="#TFC"><sup>1</sup></a> They had hoped to prepare it by subjecting the precursor <b>2</b> to acid, which might then undergo a Friedel-Crafts reaction to prepare the last fluorenyl group, and subsequent loss of a proton would give <b>1</b>. Unfortunately, they could not get this step to occur, even at high temperature and for long reaction times. What made it particularly frustrating was that they could get <b>3</b> to react under these conditions to give 1,4-difluorenylcyclohexane (14-DFC) <b>4</b>, and convert <b>5</b> into 1,4-difluorenylcyclohexane (13-DFC) <b>6</b>.</p> <table align="center" border="0" cellspacing="0" cellpadding="3"> <tr align="center"> <td> <p><img src="/blog/wp-content/TFCrxn1.png"></p> </td> </tr> <tr align="center"> <td> <p><img src="/blog/wp-content/TFCrxn2.png"></p> </td> </tr> <tr align="center"> <td> <p><img src="/blog/wp-content/TFCrxn3.png"></p> </td> </tr> </table> <p>To get at why <b>1</b> could not be formed they utilized PCM(CH<sub>2</sub>Cl<sub>2</sub>)/M06-2X/6-31G(d) calculations. The lowest energy conformations of <b>1</b> and <b>4</b> are shown in Figure 1. While <b>4</b> is in a chair conformation, <b>1</b> is not in a chair conformation since this would bring the three fluorenyl groups into very close contact. Instead, the cyclohexyl ring of <b>1</b> adopts a twist-boat conformation, with a much flattened ring. They estimate that <b>1</b> is strained by about 17 kcal mol<sup>-1</sup>, with 10 kcal mol<sup>-1</sup> coming from strain in the twist-boat conformation and another 7 kcal mol<sup>-1</sup> of strain due to steric crowding of the fluorenyl groups.</p> <p>They next optimized the structures of the intermediates and transition states on the path taking <b>2</b> into <b>1</b> and <b>3</b> into <b>4</b>. The transition states of the Friedel-Crafts reaction are the highest points on these paths, and their geometries are shown in Figure 1. The barrier through the TS for the Friedel-Crafts step forming <b>1</b> is about 17 kcal mol<sup>-1</sup> higher than for the barrier to form <b>4</b>. This very large increase in activation barrier, due to the strains imposed by that third fluorenyl group, explains the lack of reaction. Furthermore, since the reaction <b>2</b> → <b>1</b> is 2.0 kcal mol<sup>-1</sup> endothermic, at high temperature the reaction is likely to be reversible and favors <b>2</b>.</p> <table align="center" border="0" cellspacing="0" cellpadding="5"> <tr align="center" valign="bottom"> <td> <p></p> <div class="jmol" id="TFC"> <a onclick="return false"><br> <img src="/blog/wp-content/TFC.jpg" onclick="insertJmol('TFC',320,320,'TFC.xyz')"></a> </div> <p><b>1</b></p> </td> <td> <p></p> <div class="jmol" id="DFC"> <a onclick="return false"><br> <img src="/blog/wp-content/DFC.jpg" onclick="insertJmol('DFC',320,320,'DFC.xyz')"></a> </div> <p><b>4</b></p> </td> </tr> <tr align="center" valign="bottom"> <td> <p></p> <div class="jmol" id="TFCts"> <a onclick="return false"><br> <img src="/blog/wp-content/TFCts.jpg" onclick="insertJmol('TFCts',320,320,'TFCts.xyz')"></a> </div> <p><b>TS to 1</b></p> </td> <td> <p></p> <div class="jmol" id="DFCts"> <a onclick="return false"><br> <img src="/blog/wp-content/DFCts.jpg" onclick="insertJmol('DFCts',320,320,'DFCts.xyz')"></a> </div> <p><b>TS to 4</b></p> </td> </tr> </table> <p align="center"><b>Figure 1</b>. PCM(CH<sub>2</sub>Cl<sub>2</sub>)/M06-2X/6-31G(d) optimized geometries.</p> <h3>References</h3> <p><a href="#TFC"></a></p> <p>(1) Talipov, M. R.; Abdelwahed, S. H.; Thakur, K.; Reid, S. A.; Rathore, R. "From Wires to Cables: Attempted Synthesis of 1,3,5-Trifluorenylcyclohexane as a Platform for Molecular Cables," <i>J. Org. Chem.</i> <b>2016</b>, DOI: <a href="http://dx.doi.org/10.1021/acs.joc.5b02792">10.1021/acs.joc.5b02792</a>. </p> <h3>InChIs</h3> <p><b>1 (TFC)</b>: InChI=1S/C42H30/c1-7-19-34-28(13-1)29-14-2-8-20-35(29)40(34)25-41(36-21-9-3-15-30(36)31-16-4-10-22-37(31)41)27-42(26-40)38-23-11-5-17-32(38)33-18-6-12-24-39(33)42/h1-24H,25-27H2<br>InChIKey=CXXRVQFQMRJLAI-UHFFFAOYSA-N</p> <p><b>4 (14-DFC)</b>: InChI=1S/C30H24/c1-5-13-25-21(9-1)22-10-2-6-14-26(22)29(25)17-19-30(20-18-29)27-15-7-3-11-23(27)24-12-4-8-16-28(24)30/h1-16H,17-20H2<br>InChIkey=ZZTDGVHNROVFMK-UHFFFAOYSA-N</p> <p><b>6</b> <b>(13-DFC):</b>InChI=1S/C30H24/c1-2-11-22(12-3-1)24-14-4-5-15-25(24)23-13-10-20-30(21-23)28-18-8-6-16-26(28)27-17-7-9-19-29(27)30/h1-9,11-19H,10,20-21H2<br>InChIKey=TTZIUDUAWUTKAI-UHFFFAOYSA-N</p>  </div> <p class="bottom"> <span class="cat"><a href="/blog/archives/category/uncategorized" rel="category tag">Uncategorized</a></span> <span class="user">Steven Bachrach</span> <span class="date">28 Mar 2016</span> <span class="comments"><a href="/blog/archives/3730#respond">No Comments</a></span> </p> </div> <div class="box"> <h2><a href="/blog/archives/3762" rel="bookmark" title="Permanent Link: FEP study">FEP study</a></h2> <div class="post-content"> <p>The ACS National Meeting this week in San Diego had <i>computers in chemistry</i> as its theme. A number of sessions featured computer-aided drug design, and the paper that garnered a lot of attention in many of these sessions was one I missed from last year. The work, done by the Schrödinger company, presents the application of some improved techniques for performing free energy perturbation (FEP) computations.<a href="#FEP_1"><sup>1</sup></a> FEP involves changing a small number of atoms from one type to another and determining the free energy change with this perturbation. Since so much of the system is left unaffected, the idea is that errors in the non-perturbed parts of the system will cancel, allowing for accurate determination of the free energy change due to the perturbation.</p> <p>This study features a number of new technologies that have enabled much more accurate predictions. First, they have employed a new force field, OPLS2.1, which appears to provide much improved energies. Second, they have improved sampling of configuration space using the Desmond program and replica exchange with solute tempering (REST). Third, these have been implemented on GPUs that results in dramatically improved throughput. And fourth, they developed a workflow to automate the selection of ligands, created by the perturbations with the protein of interest. They examined up to 10 atom perturbations within the initial ligand.</p> <p>In a validation study of 8 proteins involving 330 ligands, the RMS error in the free energy of binding was about 1 kcal mol<sup>-1</sup>. Case studies of different types of perturbations leading to gain or loss of hydrophobic or electrostatic interactions, loss of a binding water and exposure to solvent are detailed. Lastly, in a study of two new proteins, they report a high success in predicting both strong binders and weak binders, with very few false positives.</p> <h3>References</h3> <p><a name="FEP_1"></a></p> <p>(1) Wang, L.; Wu, Y.; Deng, Y.; Kim, B.; Pierce, L.; Krilov, G.; Lupyan, D.; Robinson, S.; Dahlgren, M. K.; Greenwood, J.; Romero, D. L.; Masse, C.; Knight, J. L.; Steinbrecher, T.; Beuming, T.; Damm, W.; Harder, E.; Sherman, W.; Brewer, M.; Wester, R.; Murcko, M.; Frye, L.; Farid, R.; Lin, T.; Mobley, D. L.; Jorgensen, W. L.; Berne, B. J.; Friesner, R. A.; Abel, R. "Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field," <i>J. Am. Chem. Soc.</i> <b>2015</b>, <i>137</i>, 2695-2703, DOI: <a href="http://dx.doi.org/10.1021/ja512751q">10.1021/ja512751q</a>.</p>  </div> <p class="bottom"> <span class="cat"><a href="/blog/archives/category/fep" rel="category tag">FEP</a></span> <span class="user">Steven Bachrach</span> <span class="date">21 Mar 2016</span> <span class="comments"><a href="/blog/archives/3762#respond">No Comments</a></span> </p> </div> <div class="box"> <h2><a href="/blog/archives/3722" rel="bookmark" title="Permanent Link: Mechanism of organocatalysis by Cinchona alkaloids">Mechanism of organocatalysis by Cinchona alkaloids</a></h2> <div class="post-content"> <p>Cinchona alkaloids cat catalyze reactions, such as shown in Reaction 1. Wynberg<a href="#cinchona1"><sup>1</sup></a> proposed a model to explain the reaction, shown in Scheme 1, based on NMR. Grayson and Houk have now used DFT computations to show that the mechanism actually reverses the arrangements of the substrates.<a href="#cinchona2"><sup>2</sup></a></p> <table align="center" border="0" cellspacing="0" cellpadding="4"> <tr align="center" valign="middle"> <td> <img src="/blog/wp-content/cinchonaRxn1.png"> </td> <td> <p>Reaction 1</p> </td> </tr> </table> <p align="center"><b>Scheme 1</b>.</p> <table align="center" border="0" cellspacing="0" cellpadding="4"> <tr align="center"> <td> <p><img src="/blog/wp-content/cinchonaMode1.png"><br>Wynberg Model</p> </td> <td> <p><img src="/blog/wp-content/cinchonaMode2.png"><br>Grayson and Houk Model</p> </td> </tr> </table> <p>M06-2X/def2-TZVPP−IEFPCM(benzene)//M06-2X/6-31G(d)−IEFPCM(benzene) computations show that the precomplex of catalyst <b>3</b> with nucleophile <b>1</b> and Michael acceptor <b>2</b> is consistent with Wynberg鈥檚 model. The alternate precomplex is 5.6 kcal mol<sup>-1</sup> higher in energy. These precomplexes are shown in Figure 1.</p> <table align="center" border="0" cellspacing="0" cellpadding="3"> <tr align="center"> <td> <p></p> <div class="jmol" id="cinchonaC1"> <a onclick="return false"><br> <img src="/blog/wp-content/cinchonaComplex1.jpg" onclick="insertJmol('cinchonaC1',300,300,'cinchonaComplex1.xyz')"></a> </div> <p>Wynberg precomplex</p> </td> <td> <p></p> <div class="jmol" id="cinchonaC2"> <a onclick="return false"><br> <img src="/blog/wp-content/cinchonaComplex2.jpg" onclick="insertJmol('cinchonaC2',300,300,'cinchonaComplex2.xyz')"></a> </div> <p>Grayson/Houk precomplex</p> </td> </tr> </table> <p align="center"><b>Figure 1</b>. Precomplexes structures</p> <p>However, the lowest energy transition state takes the Grayson/Houk pathway and leads to the major isomer observed in the reaction. The Grayson/Houk TS that leads to the minor product has a barrier that is 3 kcal mol<sup>-1</sup> higher in energy. The lowest energy TS following the Wynberg path leads to the minor product, and is 2.2 kcal mol<sup>-1</sup> higher than the Grayson/Houk path. These transition states are shown in Figure 2. The upshot is that complex formation is not necessarily indicative of the transition state structure.</p> <table align="center" border="0" cellspacing="0" cellpadding="3"> <tr align="center"> <td> <p></p> <div class="jmol" id="cinchonaAmaj"> <a onclick="return false"><br> <img src="/blog/wp-content/modeAtsMajor.jpg" onclick="insertJmol('cinchonaAmaj',300,300,'modeAtsMajor.xyz')"></a> </div> <p>Wynberg TS (major)<br>Rel Δ<i>G</i> = 5.3</p> </td> <td> <p></p> <div class="jmol" id="cinchonaAmin"> <a onclick="return false"><br> <img src="/blog/wp-content/modeAtsMinor.jpg" onclick="insertJmol('cinchonaAmin',300,300,'modeAtsMinor.xyz')"></a> </div> <p>Wynberg TS (minor)<br>Rel Δ<i>G</i> = 2.2</p> </td> </tr> <tr align="center"> <td> <p></p> <div class="jmol" id="cinchonaBmaj"> <a onclick="return false"><br> <img src="/blog/wp-content/modeBtsMajor.jpg" onclick="insertJmol('cinchonaBmaj',300,300,'modeBtsMajor.xyz')"></a> </div> <p>Grayson/Houk TS (major)<br>Rel Δ<i>G</i> = 0.0</p> </td> <td> <p></p> <div class="jmol" id="cinchonaBmin"> <a onclick="return false"><br> <img src="/blog/wp-content/modeBtsMinor.jpg" onclick="insertJmol('cinchonaBmin',300,300,'modeBtsMinor.xyz')"></a> </div> <p>Grayson/Houk TS (minor)<br>Rel Δ<i>G</i> = 3.0</p> </td> </tr> </table> <p align="center"><b>Figure 2</b>. TS structures and relative free energies (kcal mol<sup>-1</sup>).</p> <h3>References</h3> <p><a name="cinchona1"></a></p> <p>(1) Hiemstra, H.; Wynberg, H. "Addition of aromatic thiols to conjugated cycloalkenones, catalyzed by chiral .beta.-hydroxy amines. A mechanistic study of homogeneous catalytic asymmetric synthesis," <i>J. Am. Chem. Soc.</i> <b>1981</b>, <i>103</i>, 417-430, DOI: <a href="http://dx.doi.org/10.1021/ja00392a029">10.1021/ja00392a029</a>.</p> <p><a name="cinchona2"></a></p> <p>(2) Grayson, M. N.; Houk, K. N. "Cinchona Alkaloid-Catalyzed Asymmetric Conjugate Additions: The Bifunctional Br酶nsted Acid鈥揌ydrogen Bonding Model," <i>J. Am. Chem. Soc.</i> <b>2016</b>, <i>138</i>, 1170-1173, DOI: <a href="http://dx.doi.org/10.1021/jacs.5b13275">10.1021/jacs.5b13275</a>.</p> <h3>InChIs</h3> <p><b>1</b>: InChI=1S/C10H14S/c1-10(2,3)8-4-6-9(11)7-5-8/h4-7,11H,1-3H3<br>InChIKey=GNXBFFHXJDZGEK-UHFFFAOYSA-N</p> <p><b>2</b>: InChI=1S/C8H12O/c1-8(2)5-3-4-7(9)6-8/h3-4H,5-6H2,1-2H3<br>InChIKey=CDDGRARTNILYAB-UHFFFAOYSA-N</p> <p><b>3</b>: InChI=1S/C18H22N2O/c1-12-11-20-9-7-13(12)10-17(20)18(21)15-6-8-19-16-5-3-2-4-14(15)16/h2-6,8,12-13,17-18,21H,7,9-11H2,1H3/t12?,13?,17?,18-/m1/s1<br>InChIKey=ZOZLJWFJLBUKKL-NKHWWFDVSA-N</p> <p><b>4</b>: InChI=1S/C18H26OS/c1-17(2,3)13-6-8-15(9-7-13)20-16-10-14(19)11-18(4,5)12-16/h6-9,16H,10-12H2,1-5H3/t16-/m0/s1<br>InChIKey=XUTYYZOSKLYWLW-INIZCTEOSA-N</p>  </div> <p class="bottom"> <span class="cat"><a href="/blog/archives/category/authors/houk" rel="category tag">Houk</a> &<a href="/blog/archives/category/reactions/michael-addition" rel="category tag">Michael addition</a> &<a href="/blog/archives/category/stereoinduction" rel="category tag">stereoinduction</a></span> <span class="user">Steven Bachrach</span> <span class="date">03 Mar 2016</span> <span class="comments"><a href="/blog/archives/3722#respond">No Comments</a></span> </p> </div> <p align="center"></p> </div> <div id="sidebar"> <ul> <li class="box"> <h2> Categories </h2> <ul> <li class="cat-item cat-item-25"> <a href="/blog/archives/category/acidity">Acidity</a> (12) </li> <li class="cat-item cat-item-3"> <a href="/blog/archives/category/aromaticity">Aromaticity</a> (91) </li> <li class="cat-item cat-item-53"> <a href="/blog/archives/category/authors">Authors</a> (153) <ul class="children"> <li class="cat-item cat-item-42"> <a href="/blog/archives/category/authors/borden">Borden</a> (12) </li> <li class="cat-item cat-item-12"> <a href="/blog/archives/category/authors/cramer">Cramer</a> (11) </li> <li class="cat-item cat-item-83"> <a href="/blog/archives/category/authors/grimme">Grimme</a> (17) 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href="/blog/archives/category/molecules/fulvalenes">fulvalenes</a> (1) </li> <li class="cat-item cat-item-21"> <a href="/blog/archives/category/molecules/hexacyclinol">hexacyclinol</a> (2) </li> <li class="cat-item cat-item-78"> <a href="/blog/archives/category/molecules/nanohoops">nanohoops</a> (4) </li> <li class="cat-item cat-item-41"> <a href="/blog/archives/category/molecules/non-classical">non-classical</a> (4) </li> <li class="cat-item cat-item-34"> <a href="/blog/archives/category/molecules/norbornyl-cation">norbornyl cation</a> (2) </li> <li class="cat-item cat-item-49"> <a href="/blog/archives/category/molecules/nucleic-acids">nucleic acids</a> (4) </li> <li class="cat-item cat-item-36"> <a href="/blog/archives/category/molecules/oximes">oximes</a> (1) </li> <li class="cat-item cat-item-75"> <a href="/blog/archives/category/molecules/phenyloxenium">phenyloxenium</a> (1) </li> <li class="cat-item cat-item-8"> <a href="/blog/archives/category/molecules/polycyclic-aromatics">polycyclic aromatics</a> (7) </li> <li class="cat-item cat-item-50"> <a href="/blog/archives/category/molecules/propellane">propellane</a> (2) </li> <li class="cat-item cat-item-79"> <a href="/blog/archives/category/molecules/stilbene">stilbene</a> (1) </li> <li class="cat-item cat-item-80"> <a href="/blog/archives/category/molecules/sugars">sugars</a> (5) </li> <li class="cat-item cat-item-85"> <a href="/blog/archives/category/molecules/terpenes">terpenes</a> (2) </li> <li class="cat-item cat-item-89"> <a href="/blog/archives/category/molecules/twistane">twistane</a> (1) </li> </ul> </li> <li class="cat-item cat-item-22"> <a href="/blog/archives/category/nmr">NMR</a> (40) </li> <li class="cat-item cat-item-31"> <a href="/blog/archives/category/optical-rotation">Optical Rotation</a> (16) </li> <li class="cat-item cat-item-28"> <a href="/blog/archives/category/qm-method">QM Method</a> (96) <ul class="children"> <li class="cat-item cat-item-20"> <a href="/blog/archives/category/qm-method/caspt2">CASPT2</a> (1) </li> <li class="cat-item cat-item-7"> <a href="/blog/archives/category/qm-method/dft">DFT</a> (71) </li> <li class="cat-item cat-item-45"> <a href="/blog/archives/category/qm-method/focal-point">focal point</a> (7) </li> <li class="cat-item cat-item-14"> <a href="/blog/archives/category/qm-method/g3">G3</a> (3) </li> <li class="cat-item cat-item-60"> <a href="/blog/archives/category/qm-method/mp">MP</a> (11) </li> </ul> </li> <li class="cat-item cat-item-56"> <a href="/blog/archives/category/reactions">Reactions</a> (83) <ul class="children"> <li class="cat-item cat-item-13"> <a href="/blog/archives/category/reactions/12-addition">1,2-addition</a> (1) </li> <li class="cat-item cat-item-35"> <a href="/blog/archives/category/reactions/aldol">aldol</a> (4) </li> <li class="cat-item cat-item-32"> <a href="/blog/archives/category/reactions/bergman-cyclization">Bergman cyclization</a> (6) </li> <li class="cat-item cat-item-44"> <a href="/blog/archives/category/reactions/claisen-rearrangement">Claisen rearrangement</a> (2) </li> <li class="cat-item cat-item-10"> <a href="/blog/archives/category/reactions/cope-rearrangement">Cope Rearrangement</a> (5) </li> <li class="cat-item cat-item-69"> <a href="/blog/archives/category/reactions/cycloadditions">cycloadditions</a> (12) </li> <li class="cat-item cat-item-23"> <a href="/blog/archives/category/reactions/diels-alder">Diels-Alder</a> (26) </li> <li class="cat-item cat-item-47"> <a href="/blog/archives/category/reactions/electrocyclization">electrocyclization</a> (11) </li> <li class="cat-item cat-item-76"> <a href="/blog/archives/category/reactions/electrophilic-aromatic-substitution">electrophilic aromatic substitution</a> (1) </li> <li class="cat-item cat-item-5"> <a href="/blog/archives/category/reactions/ene-reaction">ene reaction</a> (1) </li> <li class="cat-item cat-item-52"> <a href="/blog/archives/category/reactions/hajos-parrish-reaction">Hajos-Parrish Reaction</a> (1) </li> <li class="cat-item cat-item-61"> <a href="/blog/archives/category/reactions/mannich">Mannich</a> (2) </li> <li class="cat-item cat-item-64"> <a href="/blog/archives/category/reactions/michael-addition">Michael addition</a> (5) </li> <li class="cat-item cat-item-40"> <a href="/blog/archives/category/reactions/ozonolysis">ozonolysis</a> (1) </li> <li class="cat-item cat-item-43"> <a href="/blog/archives/category/reactions/proton-transfer">proton transfer</a> (1) </li> <li class="cat-item cat-item-38"> <a href="/blog/archives/category/reactions/pseudopericyclic">pseudopericyclic</a> (4) </li> <li class="cat-item cat-item-63"> <a href="/blog/archives/category/reactions/strecker">Strecker</a> (1) </li> <li class="cat-item cat-item-24"> <a href="/blog/archives/category/reactions/substitution">Substitution</a> (6) </li> <li class="cat-item cat-item-93"> <a href="/blog/archives/category/reactions/wittig">Wittig</a> (1) </li> </ul> </li> <li class="cat-item cat-item-87"> <a href="/blog/archives/category/second-edition">Second Edition</a> (3) </li> <li class="cat-item cat-item-11"> <a href="/blog/archives/category/solvation">Solvation</a> (17) </li> <li class="cat-item cat-item-77"> <a href="/blog/archives/category/stereochemistry">Stereochemistry</a> (2) </li> <li class="cat-item cat-item-68"> <a href="/blog/archives/category/stereoinduction">stereoinduction</a> (4) </li> <li class="cat-item cat-item-71"> <a href="/blog/archives/category/tunneling">Tunneling</a> (26) </li> <li class="cat-item cat-item-1"> <a href="/blog/archives/category/uncategorized">Uncategorized</a> (57) </li> <li class="cat-item cat-item-82"> <a href="/blog/archives/category/vibrational-frequencies">vibrational frequencies</a> (3) </li> </ul> </li> <li class="box"> <h2> Monthly </h2> <ul> <li><a href="/blog/archives/date/2019/06">June 2019</a></li> <li><a href="/blog/archives/date/2019/04">April 2019</a></li> <li><a href="/blog/archives/date/2019/03">March 2019</a></li> <li><a href="/blog/archives/date/2019/02">February 2019</a></li> <li><a href="/blog/archives/date/2019/01">January 2019</a></li> <li><a href="/blog/archives/date/2018/12">December 2018</a></li> <li><a href="/blog/archives/date/2018/11">November 2018</a></li> <li><a href="/blog/archives/date/2018/10">October 2018</a></li> <li><a href="/blog/archives/date/2018/09">September 2018</a></li> <li><a href="/blog/archives/date/2018/08">August 2018</a></li> <li><a href="/blog/archives/date/2018/07">July 2018</a></li> <li><a href="/blog/archives/date/2018/06">June 2018</a></li> <li><a href="/blog/archives/date/2018/05">May 2018</a></li> <li><a href="/blog/archives/date/2018/04">April 2018</a></li> <li><a href="/blog/archives/date/2018/03">March 2018</a></li> <li><a href="/blog/archives/date/2018/02">February 2018</a></li> <li><a href="/blog/archives/date/2018/01">January 2018</a></li> <li><a href="/blog/archives/date/2017/12">December 2017</a></li> <li><a href="/blog/archives/date/2017/11">November 2017</a></li> <li><a href="/blog/archives/date/2017/10">October 2017</a></li> <li><a href="/blog/archives/date/2017/09">September 2017</a></li> <li><a href="/blog/archives/date/2017/08">August 2017</a></li> <li><a href="/blog/archives/date/2017/07">July 2017</a></li> <li><a href="/blog/archives/date/2017/06">June 2017</a></li> <li><a href="/blog/archives/date/2017/05">May 2017</a></li> <li><a href="/blog/archives/date/2017/04">April 2017</a></li> <li><a href="/blog/archives/date/2017/03">March 2017</a></li> <li><a href="/blog/archives/date/2017/02">February 2017</a></li> <li><a href="/blog/archives/date/2017/01">January 2017</a></li> <li><a href="/blog/archives/date/2016/12">December 2016</a></li> <li><a href="/blog/archives/date/2016/11">November 2016</a></li> <li><a href="/blog/archives/date/2016/10">October 2016</a></li> <li><a href="/blog/archives/date/2016/09">September 2016</a></li> <li><a href="/blog/archives/date/2016/08">August 2016</a></li> <li><a href="/blog/archives/date/2016/07">July 2016</a></li> <li><a href="/blog/archives/date/2016/06">June 2016</a></li> <li><a href="/blog/archives/date/2016/05">May 2016</a></li> <li><a href="/blog/archives/date/2016/04">April 2016</a></li> <li><a href="/blog/archives/date/2016/03" aria-current="page">March 2016</a></li> <li><a href="/blog/archives/date/2016/02">February 2016</a></li> <li><a href="/blog/archives/date/2016/01">January 2016</a></li> <li><a href="/blog/archives/date/2015/12">December 2015</a></li> <li><a href="/blog/archives/date/2015/11">November 2015</a></li> <li><a href="/blog/archives/date/2015/10">October 2015</a></li> <li><a href="/blog/archives/date/2015/09">September 2015</a></li> <li><a href="/blog/archives/date/2015/08">August 2015</a></li> <li><a href="/blog/archives/date/2015/07">July 2015</a></li> <li><a href="/blog/archives/date/2015/06">June 2015</a></li> <li><a href="/blog/archives/date/2015/05">May 2015</a></li> <li><a href="/blog/archives/date/2015/04">April 2015</a></li> <li><a href="/blog/archives/date/2015/03">March 2015</a></li> <li><a href="/blog/archives/date/2015/02">February 2015</a></li> <li><a href="/blog/archives/date/2015/01">January 2015</a></li> <li><a href="/blog/archives/date/2014/12">December 2014</a></li> <li><a href="/blog/archives/date/2014/11">November 2014</a></li> <li><a href="/blog/archives/date/2014/10">October 2014</a></li> <li><a href="/blog/archives/date/2014/09">September 2014</a></li> <li><a href="/blog/archives/date/2014/08">August 2014</a></li> <li><a href="/blog/archives/date/2014/07">July 2014</a></li> <li><a href="/blog/archives/date/2014/06">June 2014</a></li> <li><a href="/blog/archives/date/2014/05">May 2014</a></li> <li><a href="/blog/archives/date/2014/04">April 2014</a></li> <li><a href="/blog/archives/date/2014/03">March 2014</a></li> <li><a href="/blog/archives/date/2014/02">February 2014</a></li> <li><a href="/blog/archives/date/2014/01">January 2014</a></li> <li><a href="/blog/archives/date/2013/12">December 2013</a></li> <li><a href="/blog/archives/date/2013/11">November 2013</a></li> <li><a href="/blog/archives/date/2013/10">October 2013</a></li> <li><a href="/blog/archives/date/2013/09">September 2013</a></li> <li><a href="/blog/archives/date/2013/08">August 2013</a></li> <li><a href="/blog/archives/date/2013/07">July 2013</a></li> <li><a href="/blog/archives/date/2013/06">June 2013</a></li> <li><a href="/blog/archives/date/2013/05">May 2013</a></li> <li><a href="/blog/archives/date/2013/04">April 2013</a></li> <li><a href="/blog/archives/date/2013/03">March 2013</a></li> <li><a href="/blog/archives/date/2013/02">February 2013</a></li> <li><a href="/blog/archives/date/2013/01">January 2013</a></li> <li><a href="/blog/archives/date/2012/12">December 2012</a></li> <li><a href="/blog/archives/date/2012/11">November 2012</a></li> <li><a href="/blog/archives/date/2012/10">October 2012</a></li> <li><a href="/blog/archives/date/2012/09">September 2012</a></li> <li><a href="/blog/archives/date/2012/08">August 2012</a></li> <li><a href="/blog/archives/date/2012/07">July 2012</a></li> <li><a href="/blog/archives/date/2012/06">June 2012</a></li> <li><a href="/blog/archives/date/2012/05">May 2012</a></li> <li><a href="/blog/archives/date/2012/04">April 2012</a></li> <li><a href="/blog/archives/date/2012/03">March 2012</a></li> <li><a href="/blog/archives/date/2012/02">February 2012</a></li> <li><a href="/blog/archives/date/2012/01">January 2012</a></li> <li><a href="/blog/archives/date/2011/12">December 2011</a></li> <li><a href="/blog/archives/date/2011/11">November 2011</a></li> <li><a href="/blog/archives/date/2011/10">October 2011</a></li> <li><a href="/blog/archives/date/2011/09">September 2011</a></li> <li><a href="/blog/archives/date/2011/08">August 2011</a></li> <li><a href="/blog/archives/date/2011/07">July 2011</a></li> <li><a href="/blog/archives/date/2011/06">June 2011</a></li> <li><a href="/blog/archives/date/2011/05">May 2011</a></li> <li><a href="/blog/archives/date/2011/04">April 2011</a></li> <li><a href="/blog/archives/date/2011/03">March 2011</a></li> <li><a href="/blog/archives/date/2011/02">February 2011</a></li> <li><a href="/blog/archives/date/2011/01">January 2011</a></li> <li><a href="/blog/archives/date/2010/12">December 2010</a></li> <li><a href="/blog/archives/date/2010/11">November 2010</a></li> <li><a href="/blog/archives/date/2010/10">October 2010</a></li> <li><a href="/blog/archives/date/2010/09">September 2010</a></li> <li><a href="/blog/archives/date/2010/08">August 2010</a></li> <li><a href="/blog/archives/date/2010/07">July 2010</a></li> <li><a href="/blog/archives/date/2010/06">June 2010</a></li> <li><a href="/blog/archives/date/2010/05">May 2010</a></li> <li><a href="/blog/archives/date/2010/04">April 2010</a></li> <li><a href="/blog/archives/date/2010/03">March 2010</a></li> <li><a href="/blog/archives/date/2010/02">February 2010</a></li> <li><a href="/blog/archives/date/2010/01">January 2010</a></li> <li><a href="/blog/archives/date/2009/12">December 2009</a></li> <li><a href="/blog/archives/date/2009/11">November 2009</a></li> <li><a href="/blog/archives/date/2009/10">October 2009</a></li> <li><a href="/blog/archives/date/2009/09">September 2009</a></li> <li><a href="/blog/archives/date/2009/08">August 2009</a></li> <li><a href="/blog/archives/date/2009/07">July 2009</a></li> <li><a href="/blog/archives/date/2009/06">June 2009</a></li> <li><a href="/blog/archives/date/2009/05">May 2009</a></li> <li><a href="/blog/archives/date/2009/04">April 2009</a></li> <li><a href="/blog/archives/date/2009/03">March 2009</a></li> <li><a href="/blog/archives/date/2009/02">February 2009</a></li> <li><a href="/blog/archives/date/2009/01">January 2009</a></li> <li><a href="/blog/archives/date/2008/12">December 2008</a></li> <li><a href="/blog/archives/date/2008/11">November 2008</a></li> <li><a href="/blog/archives/date/2008/10">October 2008</a></li> <li><a href="/blog/archives/date/2008/09">September 2008</a></li> <li><a href="/blog/archives/date/2008/08">August 2008</a></li> <li><a href="/blog/archives/date/2008/07">July 2008</a></li> <li><a href="/blog/archives/date/2008/06">June 2008</a></li> <li><a href="/blog/archives/date/2008/05">May 2008</a></li> <li><a href="/blog/archives/date/2008/04">April 2008</a></li> <li><a href="/blog/archives/date/2008/03">March 2008</a></li> <li><a href="/blog/archives/date/2008/02">February 2008</a></li> <li><a href="/blog/archives/date/2008/01">January 2008</a></li> <li><a href="/blog/archives/date/2007/12">December 2007</a></li> <li><a href="/blog/archives/date/2007/11">November 2007</a></li> <li><a href="/blog/archives/date/2007/10">October 2007</a></li> <li><a href="/blog/archives/date/2007/09">September 2007</a></li> <li><a href="/blog/archives/date/2007/08">August 2007</a></li> <li><a href="/blog/archives/date/2007/07">July 2007</a></li> </ul> </li> </ul> <a rel="license" href="https://creativecommons.org/licenses/by-nd/3.0/"> <img alt="Creative Commons License" style="border-width:0" src="https://i.creativecommons.org/l/by-nd/3.0/88x31.png"> </a> <br>This work is licensed under a <a rel="license" href="https://creativecommons.org/licenses/by-nd/3.0/">Creative Commons Attribution-No Derivative Works 3.0 Unported License</a>. </div>  <div class="clear"></div> </div>  <div id="footer"> <p>Copyright © 2021 <strong>Computational Organic Chemistry</strong>. </p> </div> </body> </html>