{"id":10237,"date":"2013-04-28T13:52:36","date_gmt":"2013-04-28T12:52:36","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=10237"},"modified":"2014-01-17T07:43:34","modified_gmt":"2014-01-17T07:43:34","slug":"how-to-predict-the-regioselectivity-of-epoxide-ring-opening","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10237","title":{"rendered":"How to predict the regioselectivity of epoxide ring opening."},"content":{"rendered":"
\n

I recently got an email from a student asking about the best way of rationalising epoxide ring opening using some form of molecule orbitals. This reminded me of the famous experiment involving propene epoxide.[1]<\/a><\/span><\/p>\n

\"propenoxide\"<\/p>\n

In the presence of 0.3% NaOH, propene epoxide reacts with ethanol at the unsubstituted carbon (~82% compared with 56% in pure water, with retention of configuration at the other carbon) but in 1.3% H2<\/sub>SO4<\/sub>, the predominant product involves attack of ethanol at the more substituted carbon (presumably with inversion of configuration at that carbon). There are many ways of modelling this, but here I choose a simple one; inspecting the energy of the lowest unoccupied orbital (the one that will interact with the lone pair orbital on the incoming nucleophile). The issue is what kind of orbital that should be? The best to choose in this sort of situation is a localized orbital<\/strong>, an NBO in fact.<\/p>\n\n\n\n\n\n
NaOH<\/td>\nH2<\/sub>SO4<\/sub><\/td>\n<\/tr>\n
\n
\"Energy\"

Energy 0.353 au<\/p><\/div>\n<\/td>\n

\n
\"Energy\"

Energy -0.004 au<\/p><\/div><\/p>\n

 <\/p>\n<\/td>\n<\/tr>\n

\n
\"Energy\"

Energy 0.347 au<\/p><\/div>\n<\/td>\n

\u00a0
\n
\"Energy\"

Energy -0.061 au<\/p><\/div>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

In NaOH solutions (where protonation of the epoxide oxygen is suppressed), the lowest energy unoccupied NBO is the O-C\u00a0 \u03c3* orbital involving the unsubstituted carbon, but where the oxygen is protonated, it now becomes the O-C \u03c3* orbital involving the substituted carbon.<\/p>\n

One can also teach a simpler heuristic, namely that protonation of the epoxide encourages the early formation of a carbocation, and that the most substituted such cation is the most stable. In the absence of protonation, some (small) contribution from an incipient alkoxy anion favours the alkoxide formed on the more stable carbon.<\/p>\n

References<\/h2>\n
  1. H.C. Chitwood, and B.T. Freure, \"The Reaction of Propylene Oxide with Alcohols\", Journal of the American Chemical Society<\/i>, vol. 68, pp. 680-683, 1946. https:\/\/doi.org\/10.1021\/ja01208a047<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    I recently got an email from a student asking about the best way of rationalising epoxide ring opening using some form of molecule orbitals. This reminded me of the famous experiment involving propene epoxide. In the presence of 0.3% NaOH, propene epoxide reacts with ethanol at the unsubstituted carbon (~82% compared with 56% in pure […]<\/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":[4],"tags":[905,24,1043,1044,843,373],"ppma_author":[2661],"class_list":["post-10237","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry","tag-10-1021","tag-energy","tag-lowest-energy","tag-predominant-product","tag-reaction-mechanism","tag-tutorial-material"],"yoast_head":"\nHow to predict the regioselectivity of epoxide ring opening. - 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=10237\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"How to predict the regioselectivity of epoxide ring opening. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"I recently got an email from a student asking about the best way of rationalising epoxide ring opening using some form of molecule orbitals. 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In the presence of 0.3% NaOH, propene epoxide reacts with ethanol at the unsubstituted carbon (~82% compared with 56% in pure […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10237\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2013-04-28T12:52:36+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2014-01-17T07:43:34+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/04\/propenoxide.svg\" \/>\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=\"1 minute\" \/>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"How to predict the regioselectivity of epoxide ring opening. - 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=10237","og_locale":"en_GB","og_type":"article","og_title":"How to predict the regioselectivity of epoxide ring opening. - Henry Rzepa's Blog","og_description":"I recently got an email from a student asking about the best way of rationalising epoxide ring opening using some form of molecule orbitals. This reminded me of the famous experiment involving propene epoxide. In the presence of 0.3% NaOH, propene epoxide reacts with ethanol at the unsubstituted carbon (~82% compared with 56% in pure […]","og_url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10237","og_site_name":"Henry Rzepa's Blog","article_published_time":"2013-04-28T12:52:36+00:00","article_modified_time":"2014-01-17T07:43:34+00:00","og_image":[{"url":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/04\/propenoxide.svg","type":"","width":"","height":""}],"author":"Henry Rzepa","twitter_card":"summary_large_image","twitter_misc":{"Written by":"Henry Rzepa","Estimated reading time":"1 minute"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10237#article","isPartOf":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10237"},"author":{"name":"Henry Rzepa","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281"},"headline":"How to predict the regioselectivity of epoxide ring opening.","datePublished":"2013-04-28T12:52:36+00:00","dateModified":"2014-01-17T07:43:34+00:00","mainEntityOfPage":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10237"},"wordCount":296,"commentCount":0,"image":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10237#primaryimage"},"thumbnailUrl":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/04\/propenoxide.svg","keywords":["10.1021","energy","lowest energy","predominant product","Reaction Mechanism","Tutorial material"],"articleSection":["Interesting chemistry"],"inLanguage":"en-GB","potentialAction":[{"@type":"CommentAction","name":"Comment","target":["https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10237#respond"]}]},{"@type":"WebPage","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10237","url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10237","name":"How to predict the regioselectivity of epoxide ring opening. - 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This is an application of Hammond's postulate[ in extrapolating the properties of a\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":"Click for 3D.","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/05\/hidden-intermediate-1.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":8588,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8588","url_meta":{"origin":10237,"position":1},"title":"Why is the Sharpless epoxidation enantioselective? Part 1: a simple model.","author":"Henry Rzepa","date":"December 9, 2012","format":false,"excerpt":"Sharpless epoxidation converts a prochiral allylic alcohol into the corresponding chiral epoxide with > 90% enantiomeric excess,. Here is the first step in trying to explain how this magic is achieved. The scheme above shows how (achiral) prop-2-enol is converted using the asymmetric catalyst\u00a0(R,R)-diethyl tartrate \u00a0and t-butyl hydroperoxide as oxidant\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":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/12\/sharpless.gif?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":10367,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10367","url_meta":{"origin":10237,"position":2},"title":"Transition states for the (base) catalysed ring opening of propene epoxide.","author":"Henry Rzepa","date":"May 8, 2013","format":false,"excerpt":"The previous post described how the acid catalysed ring opening of propene epoxide by an alcohol (methanol) is preceded by pre-protonation of the epoxide oxygen to form a \"hidden intermediate\" on the concerted intrinsic reaction pathway to ring opening. Here I take a look at the mechanism where a strong\u2026","rel":"","context":"In \"Reaction Mechanism\"","block_context":{"text":"Reaction Mechanism","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?tag=reaction-mechanism"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":16721,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=16721","url_meta":{"origin":10237,"position":3},"title":"Molecule orbitals as indicators of reactivity: bromoallene.","author":"Henry Rzepa","date":"September 1, 2016","format":false,"excerpt":"Bromoallene is a pretty simple molecule, with two non-equivalent double bonds. How might it react with an electrophile, say dimethyldioxirane (DMDO) to form an epoxide? Here I explore the difference between two different and very simple approaches to predicting its reactivity. Both approaches rely on the properties of the reactant\u2026","rel":"","context":"In "reaction mechanism"","block_context":{"text":"reaction mechanism","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=1086"},"img":{"alt_text":"KS1","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2016\/08\/KS1.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":12308,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=12308","url_meta":{"origin":10237,"position":4},"title":"Enantioselective epoxidation of alkenes using the Shi Fructose-based catalyst. An undergraduate experiment.","author":"Henry Rzepa","date":"April 15, 2014","format":false,"excerpt":"The journal of chemical education can be a fertile source of ideas for undergraduate student experiments. Take this procedure for asymmetric epoxidation of an alkene. When I first spotted it, I thought not only would it be interesting to do in the lab, but could be extended by incorporating some\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":8658,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8658","url_meta":{"origin":10237,"position":5},"title":"Why the Sharpless epoxidation is enantioselective!","author":"Henry Rzepa","date":"December 17, 2012","format":false,"excerpt":"Part one\u00a0on this topic showed how a quantum mechanical model employing just one titanium centre was not successful in predicting the stereochemical outcome of the Sharpless asymmetric epoxidation. Here in part 2, I investigate whether a binuclear model might have more success.\u00a0The new model is constructed using two units of\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":"WAWBUR. 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