{"id":111,"date":"2009-04-04T15:02:28","date_gmt":"2009-04-04T14:02:28","guid":{"rendered":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111"},"modified":"2011-06-12T09:17:29","modified_gmt":"2011-06-12T09:17:29","slug":"aromatic-electrophilic-substitution-a-different-way-of-predicting-regiospecificity","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111","title":{"rendered":"Aromatic electrophilic substitution: a different way of predicting regiospecificity"},"content":{"rendered":"<div class=\"kcite-section\" kcite-section-id=\"111\">\n<p><script src=\"..\/Jmol\/Jmol.js\" type=\"text\/javascript\"><\/script><br \/>\nEvery introductory course or text on aromatic electrophilic substitution contains an explanation along the lines of the resonance diagram shown below. With an <em>o<\/em>\/<em>p<\/em> directing group such as NH<sub>2<\/sub>, it is argued that negative charge accumulates in those positions as a result of the resonance structures shown.<\/p>\n<p><div id=\"attachment_112\" style=\"width: 250px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-112\" class=\"aligncenter size-full wp-image-112\" title=\"groups1\" onclick=\"jmolInitialize('..\/Jmol\/');jmolSetAppletColor('yellow');jmolApplet([450,450],'load &quot;wp-content\/uploads\/2009\/04\/ph-nh2.jvxl&quot;;isosurface &quot;&quot;;zoom 150;color isosurface blue;');\" src=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/groups1.jpg\" alt=\"groups1\" width=\"240\" height=\"267\" \/><p id=\"caption-attachment-112\" class=\"wp-caption-text\">MEP for PhNH2. Click for 3D.<\/p><\/div>The opposite occurs for electron withdrawing groups. Shown below is a group such as BR<sub>2<\/sub>, a somewhat unusual choice it has to be said (and indeed rather un-represented in the literature as well).<\/p>\n<div id=\"attachment_113\" style=\"width: 282px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-113\" class=\"aligncenter size-full wp-image-113\" title=\"groups2\" onclick=\"jmolInitialize('..\/Jmol\/');jmolSetAppletColor('yellow');jmolApplet([450,450],'load &quot;wp-content\/uploads\/2009\/04\/ph-bh2.jvxl&quot;;isosurface &quot;&quot;;zoom 150;color isosurface blue;');\" src=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/groups2.jpg\" alt=\"groups2\" width=\"272\" height=\"254\" \/><p id=\"caption-attachment-113\" class=\"wp-caption-text\">MEP for PhBH2. Click for 3D.<\/p><\/div>\n<p>But stick with me for a little while on this one, since we are now going to pose the question: what the result of combining both groups onto the same aryl ring, as below?<\/p>\n<div id=\"attachment_116\" style=\"width: 275px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-116\" class=\"aligncenter size-full wp-image-116\" title=\"mixed2\" onclick=\"jmolInitialize('..\/Jmol\/');jmolSetAppletColor('yellow');jmolApplet([450,450],'load &quot;wp-content\/uploads\/2009\/04\/phbh2nh2a.jvxl&quot;;isosurface &quot;&quot;;zoom 150;color isosurface blue;');\" src=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/mixed2.jpg\" alt=\"mixed2\" width=\"265\" height=\"172\" \/><p id=\"caption-attachment-116\" class=\"wp-caption-text\">MEP for PhBH2NH2. Click for 3D.<\/p><\/div>\n<p>The conventional outcome, based on the resonance forms shown in the first two diagrams, is that the two positions annotated with red text are disfavoured, and the two positions labelled with green or orange text are both favoured. Thus far, we are still in &#8220;exam question territory&#8221;. Reality however intrudes. When a similar combination of electron withdrawing and donating groups is tried out in the lab, only the green outcome is observed, and not the orange. So finally, the point of this blog. Is there any other tool we can use to (correctly) predict the outcome of this particular reaction?<\/p>\n<p>One way of mapping where charge in a molecule accumulates or decreases is a property known as the <strong>molecular electrostatic potential <\/strong>(see 1<a href=\"http:\/\/dx.doi.org\/10.1021\/ja973105j\" target=\"_blank\">0.1021\/ja973105j <\/a>and references cited there for details). Put simply, it measures how attractive (blue) or repulsive (red) any region of the molecule is to a proton placed at any point surrounding the molecule. Mapping these regions produces so-called iso-surfaces, where the measure of repulsion or attraction is the same everywhere on this surface.<\/p>\n<p>So now, if you click on the first diagram, you will see this <a href=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/talks\/madrid\/groups1.html\" target=\"new\">MEP<\/a>. Notice how it is blue close to the <em>o<\/em> or <em>p<\/em> positions, and does its best to avoid the <em>m<\/em> position.<\/p>\n<div id=\"attachment_151\" style=\"width: 281px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-151\" class=\"size-full wp-image-151\" title=\"groups11\" src=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/groups11.jpg\" alt=\"Molecular electrostatic potential\" width=\"271\" height=\"212\" \/><p id=\"caption-attachment-151\" class=\"wp-caption-text\">Molecular electrostatic potential<\/p><\/div>\n<p>Clicking on the second diagram will reveal the opposite.<\/p>\n<div id=\"attachment_154\" style=\"width: 234px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-154\" class=\"size-full wp-image-154\" title=\"groups21\" src=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/groups21.jpg\" alt=\"Molecular electrostatic potential\" width=\"224\" height=\"140\" \/><p id=\"caption-attachment-154\" class=\"wp-caption-text\">Molecular electrostatic potential<\/p><\/div>\n<p>Thus far this simple picture is in perfect accord with the simple resonance diagrams we started with. But the advantage of this MEP method is that the effects of two (or indeed more) substituents can be properly combined to give an overall effect. Thus in the <a href=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/talks\/madrid\/multiple2.html\" target=\"new\">third diagram<\/a>, you can now see that the blue accumulates only over the green-text region, and not at all over the orange-text region!<\/p>\n<div id=\"attachment_156\" style=\"width: 182px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-156\" class=\"size-full wp-image-156\" title=\"groups3\" src=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/groups3.jpg\" alt=\"Molecular electrostatic potential\" width=\"172\" height=\"220\" \/><p id=\"caption-attachment-156\" class=\"wp-caption-text\">Molecular electrostatic potential<\/p><\/div>\n<p>OK, one can derive a resonance structure in 5 seconds in an exam. One can hardly compute a MEP under such conditions. But what this example shows is that sometimes, quantum mechanics produces results which cannot be simply reduced to memorable rules, but must be applied natively to get the correct result.<\/p>\n<!-- kcite active, but no citations found -->\n<\/div> <!-- kcite-section 111 -->","protected":false},"excerpt":{"rendered":"<p>Every introductory course or text on aromatic electrophilic substitution contains an explanation along the lines of the resonance diagram shown below. With an o\/p directing group such as NH2, it is argued that negative charge accumulates in those positions as a result of the resonance structures shown. The opposite occurs for electron withdrawing groups. Shown [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"activitypub_content_warning":"","activitypub_content_visibility":"","activitypub_max_image_attachments":5,"activitypub_interaction_policy_quote":"anyone","activitypub_status":"","footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[4],"tags":[190,2651,2648,191],"ppma_author":[2661],"class_list":["post-111","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry","tag-aromatic","tag-historical","tag-interesting-chemistry","tag-mep"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Aromatic electrophilic substitution: a different way of predicting regiospecificity - Henry Rzepa&#039;s Blog<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Aromatic electrophilic substitution: a different way of predicting regiospecificity - Henry Rzepa&#039;s Blog\" \/>\n<meta property=\"og:description\" content=\"Every introductory course or text on aromatic electrophilic substitution contains an explanation along the lines of the resonance diagram shown below. With an o\/p directing group such as NH2, it is argued that negative charge accumulates in those positions as a result of the resonance structures shown. The opposite occurs for electron withdrawing groups. Shown [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa&#039;s Blog\" \/>\n<meta property=\"article:published_time\" content=\"2009-04-04T14:02:28+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2011-06-12T09:17:29+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/groups1.jpg\" \/>\n<meta name=\"author\" content=\"Henry Rzepa\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Henry Rzepa\" \/>\n\t<meta name=\"twitter:label2\" content=\"Estimated reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"3 minutes\" \/>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Aromatic electrophilic substitution: a different way of predicting regiospecificity - Henry Rzepa&#039;s Blog","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111","og_locale":"en_GB","og_type":"article","og_title":"Aromatic electrophilic substitution: a different way of predicting regiospecificity - Henry Rzepa&#039;s Blog","og_description":"Every introductory course or text on aromatic electrophilic substitution contains an explanation along the lines of the resonance diagram shown below. With an o\/p directing group such as NH2, it is argued that negative charge accumulates in those positions as a result of the resonance structures shown. The opposite occurs for electron withdrawing groups. Shown [&hellip;]","og_url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111","og_site_name":"Henry Rzepa&#039;s Blog","article_published_time":"2009-04-04T14:02:28+00:00","article_modified_time":"2011-06-12T09:17:29+00:00","og_image":[{"url":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/groups1.jpg","type":"","width":"","height":""}],"author":"Henry Rzepa","twitter_card":"summary_large_image","twitter_misc":{"Written by":"Henry Rzepa","Estimated reading time":"3 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111#article","isPartOf":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111"},"author":{"name":"Henry Rzepa","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281"},"headline":"Aromatic electrophilic substitution: a different way of predicting regiospecificity","datePublished":"2009-04-04T14:02:28+00:00","dateModified":"2011-06-12T09:17:29+00:00","mainEntityOfPage":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111"},"wordCount":540,"commentCount":0,"image":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111#primaryimage"},"thumbnailUrl":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/groups1.jpg","keywords":["aromatic","Historical","Interesting chemistry","MEP"],"articleSection":["Interesting chemistry"],"inLanguage":"en-GB","potentialAction":[{"@type":"CommentAction","name":"Comment","target":["https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111#respond"]}]},{"@type":"WebPage","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111","url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111","name":"Aromatic electrophilic substitution: a different way of predicting regiospecificity - Henry Rzepa&#039;s Blog","isPartOf":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#website"},"primaryImageOfPage":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111#primaryimage"},"image":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111#primaryimage"},"thumbnailUrl":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/groups1.jpg","datePublished":"2009-04-04T14:02:28+00:00","dateModified":"2011-06-12T09:17:29+00:00","author":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281"},"breadcrumb":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111#breadcrumb"},"inLanguage":"en-GB","potentialAction":[{"@type":"ReadAction","target":["https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111"]}]},{"@type":"ImageObject","inLanguage":"en-GB","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111#primaryimage","url":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/groups1.jpg","contentUrl":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/groups1.jpg"},{"@type":"BreadcrumbList","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=111#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog"},{"@type":"ListItem","position":2,"name":"Aromatic electrophilic substitution: a different way of predicting regiospecificity"}]},{"@type":"WebSite","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#website","url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/","name":"Henry Rzepa&#039;s Blog","description":"Chemistry with a twist","potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-GB"},{"@type":"Person","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281","name":"Henry Rzepa","image":{"@type":"ImageObject","inLanguage":"en-GB","@id":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g370be3a7397865e4fd161aefeb0a5a85","url":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","contentUrl":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","caption":"Henry Rzepa"},"description":"Henry Rzepa is Emeritus Professor of Computational Chemistry at Imperial College London.","sameAs":["https:\/\/orcid.org\/0000-0002-8635-8390"],"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?author=1"}]}},"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/pDef7-1N","jetpack-related-posts":[],"jetpack_likes_enabled":false,"authors":[{"term_id":2661,"user_id":1,"is_guest":0,"slug":"admin","display_name":"Henry Rzepa","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/111","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=111"}],"version-history":[{"count":0,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/111\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=111"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=111"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=111"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=111"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}