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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 » 2017 » July</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 July, 2017</h2> <div class="box"> <h2><a href="/blog/archives/4037" rel="bookmark" title="Permanent Link: A few review articles">A few review articles</a></h2> <div class="post-content"> <p>A few nice review/opinion pieces have been piling up in my folder of papers of interest for this Blog. So, this post provides a short summary of a number of review articles that computationally-oriented chemists may find of interest.</p> <h3>Holy Grails in computational chemistry</h3> <p>Houk and Liu present a short list of “Holy Grails” in computationally chemistry.<a href="#RevSum_1"><sup>1</sup></a> They begin by pointing out a few technical innovations that must occur for the Grails to be found: development of a universal density functional; an accurate, generic force field; improved sampling for MD; and dealing with the combinatorial explosion with regards to conformations and configurations. Their list of Grails includes predicting crystal structures and structure of amorphous materials, catalyst design, reaction design, and device design. These Grails overlap with the challenges I laid out in my similarly-themed article in 2014.<a href="#RevSum_2"><sup>2</sup></a></p> <h3>Post-transition state bifurcations and dynamics</h3> <p>Hare and Tantillo review the current understanding of post-transition state bifurcations (PTSB).<a href="#RevSum_3"><sup>3</sup></a> This type of potential energy surface has been the subject of much of Chapter 8 of my book and <a href="/blog/archives/category/dynamics">many of my blog posts</a>. What is becoming clear is the possibility of a transition state followed by a valley-ridge inflection leads to reaction dynamics where trajectories cross a single transition state but lead to two different products. This new review updates the state-of-the-art from Houk’s review<a href="#RevSum_4"><sup>4</sup></a> of 2008 (see <a href="/blog/archives/89">this post</a>). Mentioned are a number of studies that I have included in this Blog, along with reactions involving metals, and biochemical systems (many of these examples come from the Tantillo lab). They close with the hope that their review might “inspire future studies aimed at <i>controlling</i> selectivity for reactions with PTSBs” (italics theirs). I might offer that controlling selectivity in these types of dynamical systems is another chemical Grail!</p> <p>The Hase group has a long review of direct dynamics simulations.<a href="#RevSum_5"><sup>5</sup></a> They describe a number of important dynamics studies that provide important new insight to reaction mechanism, such as bimolecular S<sub>N</sub>2 reactions (including the <a href="/blog/archives/56">roundabout mechanism</a>) and unimolecular dissociation. They write a long section on post-transition state bifurcations, and other dynamic effects that cannot be interpreted using transition state theory or RRKM. This section is a nice complement to the Tantillo review.</p> <h3>Benchmarking quantum chemical methods</h3> <p>Mata and Suhm look at our process of benchmarking computational methods.<a href="#RevSum_6"><sup>6</sup></a> They point out the growing use of high-level quantum computations as the reference for benchmarking new methods, often with no mention of any comparison to experiment. In defense of theoreticians, they do note the paucity of useful experimental data that may exist for making suitable comparisons. They detail a long list of better practices that both experimentalists and theoreticians can take to bolster both efforts, leading to stronger computational tools that are more robust at helping to understand and discriminate difficult experimental findings.</p> <h3>References</h3> <p><a name="RevSum_1"></a></p> <p>1) Houk, K. N.; Liu, F., "Holy Grails for Computational Organic Chemistry and Biochemistry." <i>Acc. Chem. Res.</i> <b>2017,</b> <i>50</i> (3), 539-543, DOI: <a href="http://dx.doi.org/10.1021/acs.accounts.6b00532">10.1021/acs.accounts.6b00532</a>.</p> <p><a name="RevSum_2"></a></p> <p>2) Bachrach, S. M., "Challenges in computational organic chemistry." <i>WIRES: Comput. Mol. Sci.</i> <b>2014,</b> <i>4</i>, 482-487, DOI: <a href="http://dx.doi.org/10.1002/wcms.1185">10.1002/wcms.1185</a>.</p> <p><a name="RevSum_3"></a></p> <p>3) Hare, S. R.; Tantillo, D. J., "Post-transition state bifurcations gain momentum – current state of the field." <i>Pure Appl. Chem.</i> <b>2017,</b> <i>89</i>, 679-698, DOI: <a href="http://dx.doi.org/10.1515/pac-2017-0104">0.1515/pac-2017-0104</a>.</p> <p><a name="RevSum_4"></a></p> <p>4) Ess, D. H.; Wheeler, S. E.; Iafe, R. G.; Xu, L.; Çelebi-Ölçüm, N.; Houk, K. N., "Bifurcations on Potential Energy Surfaces of Organic Reactions." <i>Angew. Chem. Int. Ed.</i> <b>2008,</b> <i>47</i>, 7592-7601, DOI: <a href="http://dx.doi.org/10.1002/anie.200800918">10.1002/anie.200800918</a> </p> <p><a name="RevSum_5"></a></p> <p>5) Pratihar, S.; Ma, X.; Homayoon, Z.; Barnes, G. L.; Hase, W. L., "Direct Chemical Dynamics Simulations." <i>J. Am. Chem. Soc.</i> <b>2017,</b> <i>139</i>, 3570-3590, DOI: <a href="http://dx.doi.org/10.1021/jacs.6b12017">10.1021/jacs.6b12017</a>.</p> <p><a name="RevSum_6"></a></p> <p>6) Mata, R. A.; Suhm, M. A., "Benchmarking Quantum Chemical Methods: Are We Heading in the Right Direction?" <i>Angew. Chem. Int. Ed.</i> <b>2017</b>, ASAP, DOI: <a href="http://dx.doi.org/10.1002/anie.201611308">10.1002/anie.201611308</a>.</p>  </div> <p class="bottom"> <span class="cat"><a href="/blog/archives/category/dynamics" rel="category tag">Dynamics</a> &<a href="/blog/archives/category/authors/houk" rel="category tag">Houk</a></span> <span class="user">Steven Bachrach</span> <span class="date">25 Jul 2017</span> <span class="comments"><a href="/blog/archives/4037#respond">No Comments</a></span> </p> </div> <div class="box"> <h2><a href="/blog/archives/4010" rel="bookmark" title="Permanent Link: Structure of GlyGly">Structure of GlyGly</a></h2> <div class="post-content"> <p>Continuing their application of laser ablation molecular beam Fourier transform microwave (LA-MB-FTMW) spectroscopy and computational chemistry to biochemical molecules (see <a href="/blog/?s=alonso">these previous posts</a>), the Alonso group reports on the structure of the glycine-glycine dipeptide <b>1</b>.<a href="#GlyGly"><sup>1</sup></a> The microwave spectrum shows three different conformers. MP2/6-311++G(d,p) computations, the same method they have previously utilized for predicting geometries, revealed a number of different conformations. By matching the spectroscopic parameters obtained from the spectrum with those of the computed structures, they proposed the three conformations <b>1a</b>, <b>1b</b>, and <b>1c</b>, shown in Figure 1.</p> <table align="center" border="0" cellspacing="0" cellpadding="4"> <tr align="center"> <td> <p></p> <div class="jmol" id="GlyGly1a"> <a onclick="return false"><br> <img src="/blog/wp-content/GlyGly1a.png" onclick="insertJmol('GlyGly1a',300,300,'GlyGly1a.xyz')"></a> </div> <p><b>1a</b></p> </td> </tr> <tr align="center"> <td> <p></p> <div class="jmol" id="GlyGly1b"> <a onclick="return false"><br> <img src="/blog/wp-content/GlyGly1b.png" onclick="insertJmol('GlyGly1b',300,300,'GlyGly1b.xyz')"></a> </div> <p><b>1b</b></p> </td> </tr> <tr align="center"> <td> <p></p> <div class="jmol" id="GlyGly1c"> <a onclick="return false"><br> <img src="/blog/wp-content/GlyGly1c.png" onclick="insertJmol('GlyGly1c',300,300,'GlyGly1c.xyz')"></a> </div> <p><b>1c</b></p> </td> </tr> </table> <p align="center"><b>Figure 1</b>. ωb97xd/6-31G(d) optimized structures of the three conformers of <b>1</b>.<br><i>Note that the authors did not report their structures in their supporting materials(!) so I have optimized them.</i></p> <p>The structures of conformers <b>1a</b> and <b>1b</b> are nearly planar. MP2 predicts a non-planar rotomer of <b>1a</b>, which brings the carboxyl group out of plane, to be the lowest conformation in terms of electronic energy. With the M06-2x functional, this non-planar rotomer is about isoenergetic with <b>1a</b>. With all computational levels <b>1a</b> is the lowest in free energy. The barrier for rotation between the non-planar rotomer and <b>1a</b> is very small, and this explains why it is not observed in the supersonic expansion.</p> <h3>References</h3> <p><a name="GlyGly"></a></p> <p>1) Cabezas, C.; Varela, M.; Alonso, J. L., "The Structure of the Elusive Simplest Dipeptide Gly-Gly." <i>Angew. Chem. Int. Ed. </i><b>2017,</b> <i>56</i>, 6420-6425, DOI: <a href="http://dx.doi.org/10.1002/anie.201702425">10.1002/anie.201702425</a>.</p> <h3>InChIs</h3> <p><b>1</b>: InChI=1S/C4H8N2O3/c5-1-3(7)6-2-4(8)9/h1-2,5H2,(H,6,7)(H,8,9)<br>InChIKey=YMAWOPBAYDPSLA-UHFFFAOYSA-N</p>  </div> <p class="bottom"> <span class="cat"><a href="/blog/archives/category/molecules/amino-acids" rel="category tag">amino acids</a></span> <span class="user">Steven Bachrach</span> <span class="date">17 Jul 2017</span> <span class="comments"><a href="/blog/archives/4010#comments">1 Comment</a></span> </p> </div> <div class="box"> <h2><a href="/blog/archives/3997" rel="bookmark" title="Permanent Link: Another procedure for computing NMR chemical shifts">Another procedure for computing NMR chemical shifts</a></h2> <div class="post-content"> <p>Here’s another take on automating a procedure for using computer <sup>13</sup>C chemical shifts to assess chemical structure.<a href="#NMR_nevir1"><sup>1</sup></a> (Have a look at <a href="/blog/archives/category/nmr">these previous posts</a> for some alternative methods and applications.) The approach here is to benchmark a few computational methods against a conformationally flexible drug-like molecule, in this case <b>1</b>. A variety of conformations were optimized using the different computational methods, and <sup>13</sup>C chemical shifts evaluated from a Boltzmann-weighted distribution. While the best agreement with the experimental chemical shifts (based on the root-mean-squared deviation) is with ωB97XD/cc-pVDZ, the authors opt for B3LYP/cc-pVDZ for its computational efficiency with only slightly poorer performance. (It should be note that WC04/cc-pVDZ, <a href="/blog/archives/23">a functional designed</a> for computing <sup>13</sup> chemical shifts,<a href="#NMR_nevir2"><sup>2</sup></a> is almost as good as ωB97XD/cc-pVDZ. Also, not mentioned in the article is the dramatically poorer performance of the pcS-2 basis set, despite the fact that it was parametrized<a href="#NMR_nevir3"><sup>3</sup></a> for NMR computation!)</p> <p align="center"><img src="/blog/wp-content/NMR_nevirImg1.png"></p> <p>They apply the procedure to a number of test cases. For example, the HIV-1 reverse transcriptase inhibitor nevirapine hydrolyzes to a compound whose structure has been difficult to identify. The four proposed structures <b>2a-d</b> were subjected to the computational method, and the <sup>13</sup>C chemical shift RMSD for <b>2d</b> is only 2.3ppm, significantly smaller than for the other 3 structures. Compound <b>2d</b> was then synthesized and its NMR matches that of the nevirapine hydrolysis product.</p> <p align="center"><img src="/blog/wp-content/NMR_nevirImg2.png"></p> <h3>References</h3> <p><a name="NMR_nevir1"></a></p> <p>1) Xin, D.; Sader, C. A.; Chaudhary, O.; Jones, P.-J.; Wagner, K.; Tautermann, C. S.; Yang, Z.; Busacca, C. A.; Saraceno, R. A.; Fandrick, K. R.; Gonnella, N. C.; Horspool, K.; Hansen, G.; Senanayake, C. H., "Development of a 13C NMR Chemical Shift Prediction Procedure Using B3LYP/cc-pVDZ and Empirically Derived Systematic Error Correction Terms: A Computational Small Molecule Structure Elucidation Method." <i>J. Org. Chem.</i> <b>2017</b>, ASAP, DOI: <a href="http://dx.doi.org/10.1021/acs.joc.7b00321">10.1021/acs.joc.7b00321</a>.</p> <p><a name="NMR_nevir3"></a></p> <p>2) Wiitala, K. W.; Hoye, T. R.; Cramer, C. J., “Hybrid Density Functional Methods Empirically Optimized for the Computation of <sup>13</sup>C and <sup>1</sup>H Chemical Shifts in Chloroform Solution,” <i>J. Chem. Theory Comput.</i> <b>2006</b>, <i>2</i>, 1085-1092, DOI: <a href="http://dx.doi.org/10.1021/ct6001016">10.1021/ct6001016</a>.<br> <a name="NMR_nevir2"></a></p> <p>3) Jensen, F., “Basis Set Convergence of Nuclear Magnetic Shielding Constants Calculated by Density Functional Methods,” <i>J. Chem. Theory Comput.</i>, <b>2008</b>, <i>4</i>, 719-727, DOI: <a href="http://dx.doi.org/10.1021/ct800013z">10.1021/ct800013z</a>.</p> <h3>InChIs</h3> <p><b>1</b>: InChI=1S/C24H26F4N2O4S/c1-4-35(33,34)18-7-8-20-15(10-18)9-17(30-20)13-23(32,24(26,27)28)22(2,3)12-14-5-6-16(25)11-19(14)21(29)31/h5-11,30,32H,4,12-13H2,1-3H3,(H2,29,31)/t23-/m0/s1<br>InChIKey=ILKZCEOVIFOUBJ-QHCPKHFHSA-N</p> <p><b>2d</b>: InChI=1S/C15H16N4O2/c1-9-6-8-17-14(18-10-4-5-10)12(9)19-13-11(15(20)21)3-2-7-16-13/h2-3,6-8,10H,4-5H2,1H3,(H,16,19)(H,17,18)(H,20,21)<br>InChIKey=ZLFOGBWAZNUXAD-UHFFFAOYSA-N</p>  </div> <p class="bottom"> <span class="cat"><a href="/blog/archives/category/nmr" rel="category tag">NMR</a></span> <span class="user">Steven Bachrach</span> <span class="date">10 Jul 2017</span> <span class="comments"><a href="/blog/archives/3997#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"> 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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" aria-current="page">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">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" 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