{"id":16563,"date":"2016-06-21T08:35:02","date_gmt":"2016-06-21T07:35:02","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=16563"},"modified":"2016-06-26T08:18:46","modified_gmt":"2016-06-26T07:18:46","slug":"exploring-the-electrophilic-directing-influence-of-heteroaromatic-rings-using-crystal-structure-data-mining","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=16563","title":{"rendered":"Exploring the electrophilic directing influence of heteroaromatic rings using crystal structure data mining."},"content":{"rendered":"
\n

\n\tThis is a follow-up to the post on exploring the directing influence of (electron donating) substituents on benzene<\/a>[1]<\/a><\/span> with the focus on heteroaromatic rings such indoles<\/a>, pyrroles and group 16 analogues (furans, thiophenes etc).\n<\/p>\n

\n\t\"s-cis-ester1\"\n<\/p>\n

\n\tThe search query is shown above (and is available here[2]<\/a><\/span>). As before, the distance is compared from an electrophile, modelled as the hydrogen atom of an OH group, to both the carbon next to the heteroatom (C2) and the C3 carbon. The torsion is defined so as to ensure that the OH group is approaching the π-face of the ring. The other constraints are R < 0.1, no disorder and no errors and normalised H positions.\n<\/p>\n

\n\tFirstly, indoles (as above). There are only a few hits, but even so one can see that they all cluster in the top left triangle, where the distance to C2 is always longer than to C3. Indeed, this is the known position for electrophilic substitution of indoles.\n<\/p>\n

\n\t\"s-cis-ester1\"\n<\/p>\n

\n\tThe search can be extended by removing the benzo group so as to also include pyrroles. More hits are obtained, and again most of them collect in the top left triangle. The hot spot indicates that the difference in lengths is ~0.3Å in favour of the 3-position, a very similar discrimination to that previously found for benzene groups with an electron donating substituent.\n<\/p>\n

\n\t\"s-cis-ester1\"\n<\/p>\n

\n\tNext, the N atom is replaced by any atom from group 16 of the periodic table (i.e. <\/em>O, S, etc). The scatter is now in both top left and bottom right triangles, which suggest much weaker discrimination between C2 and C3;  if anything in favour of C2 (often the observed regiospecificities for such compounds).\n<\/p>\n

\n\t\"s-cis-ester1\"\n<\/p>\n

\n\tFinally, pyridines. Only a slight bias towards the C2 position. With pyridines of course, the electrophile in fact first interacts with the nitrogen lone pair in the plane of the molecule, which perturbs the eventual outcome. So this crystallographic method is perhaps a better intrinsic probe than kinetic reactivity.\n<\/p>\n

\n\t\"s-cis-ester1\"<\/p>\n

References<\/h2>\n
  1. H.S. Rzepa, \"Discovering More Chemical Concepts from 3D Chemical Information Searches of Crystal Structure Databases\", Journal of Chemical Education<\/i>, vol. 93, pp. 550-554, 2015. https:\/\/doi.org\/10.1021\/acs.jchemed.5b00346<\/a>\n\n<\/li>\n
  2. H. Rzepa, \"Search for HO interactions to indoles, pyrroles, furans, and thiophenes\", 2016. https:\/\/doi.org\/10.14469\/hpc\/665<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    This is a follow-up to the post on exploring the directing influence of (electron donating) substituents on benzene with the focus on heteroaromatic rings such indoles, pyrroles and group 16 analogues (furans, thiophenes etc). The search query is shown above (and is available here). As before, the distance is compared from an electrophile, modelled as the hydrogen atom of […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_feature_clip_id":0,"_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":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2},"jetpack_post_was_ever_published":false},"categories":[1745],"tags":[1754,387,1006,1444,1750,1608,1747,1753,734,1619,1752,1751],"ppma_author":[2661],"class_list":["post-16563","post","type-post","status-publish","format-standard","hentry","category-crystal_structure_mining","tag-asymmetric-hydrogenation","tag-benzene","tag-benzo","tag-electrophile","tag-furan","tag-indole","tag-pyridine","tag-pyrrole","tag-search-query","tag-simple-aromatic-rings","tag-substitution-reaction","tag-thiophene"],"yoast_head":"\nExploring the electrophilic directing influence of heteroaromatic rings using crystal structure data mining. - Henry Rzepa'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=16563\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Exploring the electrophilic directing influence of heteroaromatic rings using crystal structure data mining. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"This is a follow-up to the post on exploring the directing influence of (electron donating) substituents on benzene with the focus on heteroaromatic rings such indoles, pyrroles and group 16 analogues (furans, thiophenes etc). 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As before, the distance is compared from an electrophile, modelled as the hydrogen atom of […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=16563\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2016-06-21T07:35:02+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2016-06-26T07:18:46+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2016\/06\/hetero-sq.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=\"2 minutes\" \/>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Exploring the electrophilic directing influence of heteroaromatic rings using crystal structure data mining. - Henry Rzepa'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=16563","og_locale":"en_GB","og_type":"article","og_title":"Exploring the electrophilic directing influence of heteroaromatic rings using crystal structure data mining. - Henry Rzepa's Blog","og_description":"This is a follow-up to the post on exploring the directing influence of (electron donating) substituents on benzene with the focus on heteroaromatic rings such indoles, pyrroles and group 16 analogues (furans, thiophenes etc). 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Here\u00a0I explore, quite literally, a different angle to the hydrogen bonding interactions between a benzene ring and\u00a0OH or NH groups. 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Introductory organic chemistry tells us that electron donating substituents promote the ortho and para positions over the meta. Here I try to\u2026","rel":"","context":"In "Chemical IT"","block_context":{"text":"Chemical IT","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":9778,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=9778","url_meta":{"origin":16563,"position":2},"title":"Lithiation of heteroaromatic rings: analogy to electrophilic substitution?","author":"Henry Rzepa","date":"March 16, 2013","format":false,"excerpt":"Functionalisation of a (hetero)aromatic ring by selectively (directedly) removing protons using the metal lithium is a relative mechanistic newcomer, compared to the pantheon of knowledge on\u00a0aromatic electrophilic substitution. Investigating the mechanism using quantum calculations poses some interesting challenges, ones I have not previously discussed on this blog. My model will\u2026","rel":"","context":"In "Hypervalency"","block_context":{"text":"Hypervalency","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=7"},"img":{"alt_text":"SUHBEC. CLICK FOR 3D.","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/03\/SUHBEC.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":30548,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=30548","url_meta":{"origin":16563,"position":3},"title":"Molecules of the year 2025: Benzene-busting inverted sandwich.","author":"Henry Rzepa","date":"January 1, 2026","format":false,"excerpt":"Sandwich compounds are the colloquial term used for molecules where a metal atom such as an iron dication is \"sandwiched\" between two carbon-based rings as ligands, most commonly cyclopentadienyl anion (the \"bread\") as in e.g. Ferrocene - a molecule first discovered in 1951. An \"inverted\" sandwich is where the carbon\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":15415,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=15415","url_meta":{"origin":16563,"position":4},"title":"I\u2019ve started so I\u2019ll finish. The ionisation mechanism and kinetic isotope effects for 1,3-dimethylindolin-2 one","author":"Henry Rzepa","date":"January 7, 2016","format":false,"excerpt":"This is the third and final study deriving from my Ph.D.. The first two topics dealt with the mechanism of heteroaromatic electrophilic attack using either a diazonium cation or a proton as electrophile, followed by either proton abstraction or carbon dioxide loss from the resulting Wheland intermediate. This final study\u2026","rel":"","context":"In "Historical"","block_context":{"text":"Historical","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=565"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":16361,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=16361","url_meta":{"origin":16563,"position":5},"title":"What is the approach trajectory of enhanced (super?) nucleophiles towards a carbonyl group?","author":"Henry Rzepa","date":"May 11, 2016","format":false,"excerpt":"I have previously commented on the B\u00fcrgi\u2013Dunitz angle, this being the preferred approach trajectory of a nucleophile towards the electrophilic carbon of a carbonyl group. Some special types of nucleophile such as hydrazines (R2N-NR2) are supposed to have enhanced reactivity due to what might be described as\u00a0buttressing of adjacent lone\u2026","rel":"","context":"In "Chemical IT"","block_context":{"text":"Chemical IT","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]}],"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","author_category":"1","first_name":"Henry","last_name":"Rzepa","user_url":"https:\/\/orcid.org\/0000-0002-8635-8390","job_title":"","description":"Henry Rzepa is Emeritus Professor of Computational Chemistry at Imperial College London."}],"_links":{"self":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/16563","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=16563"}],"version-history":[{"count":9,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/16563\/revisions"}],"predecessor-version":[{"id":16572,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/16563\/revisions\/16572"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=16563"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=16563"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=16563"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=16563"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}