{"id":21363,"date":"2019-10-09T13:12:57","date_gmt":"2019-10-09T12:12:57","guid":{"rendered":"https:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=21363"},"modified":"2019-10-10T16:01:46","modified_gmt":"2019-10-10T15:01:46","slug":"catalytic-mitsunobo-reaction","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21363","title":{"rendered":"Catalytic Mitsunobu reaction."},"content":{"rendered":"
\n

If, as a synthetic chemist, you want to invert the configuration of an alcohol in which the OH group is at a chiral centre, then the Mitsunobu reaction has been a stalwart for many years. Now a catalytic version has been published, [1]<\/a><\/span> along with a proposed mechanism. Here I apply computation as a reality check to see what the energetics of this mechanism might be.<\/p>\n

The chosen computational procedure was B3LYP+GD3BJ dispersion, Def2-TZVPP basis and SCRF=toluene as solvent and for the alcohol, R1<\/sub>=R2<\/sub>=Me.\u00a0Data is at DOI: 10.14469\/hpc\/6186<\/a><\/p>\n

\"\"<\/a><\/p>\n\n\n\n\n\n\n\n\n
Molecule<\/th>\n\u0394\u0394G, kcal\/mol<\/th>\n<\/tr>\n
1<\/td>\n0.0<\/td>\n<\/tr>\n
2<\/td>\n25.4<\/td>\n<\/tr>\n
3<\/td>\n15.0<\/td>\n<\/tr>\n
TS<\/td>\n36.8<\/td>\n<\/tr>\n
4<\/td>\n+4.5<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

In the mechanism above, the proton transfers have not been included in the modelling, with the presumption that the step involving the inversion at carbon is rate limiting.<\/p>\n

\"\"<\/a>Overall, the reaction is slightly endoenergic, and this is supported by the need to azeotropically remove water from the reaction. The activation barrier for TS<\/strong> from species 1<\/strong> however is perhaps somewhat high for a reaction occuring in refluxing toluene. Annoyingly so, since high barriers are sometimes indicative that the mechanism modelled is missing some key aspect. So there must be (a small?) possibility that a more complex mechanism might operate in this catalytic cycle, or that a systemic error in the \u00a0DFT (density functional theory) approach might be present.<\/p>\n

References<\/h2>\n
  1. R.H. Beddoe, K.G. Andrews, V. Magn\u00e9, J.D. Cuthbertson, J. Saska, A.L. Shannon-Little, S.E. Shanahan, H.F. Sneddon, and R.M. Denton, \"Redox-neutral organocatalytic Mitsunobu reactions\", Science<\/i>, vol. 365, pp. 910-914, 2019. https:\/\/doi.org\/10.1126\/science.aax3353<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    If, as a synthetic chemist, you want to invert the configuration of an alcohol in which the OH group is at a chiral centre, then the Mitsunobu reaction has been a stalwart for many years. Now a catalytic version has been published, along with a proposed mechanism. Here I apply computation as a reality check […]<\/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":[1086],"tags":[],"ppma_author":[2661],"class_list":["post-21363","post","type-post","status-publish","format-standard","hentry","category-reaction-mechanism-2"],"yoast_head":"\nCatalytic Mitsunobu reaction. - 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=21363\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Catalytic Mitsunobu reaction. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"If, as a synthetic chemist, you want to invert the configuration of an alcohol in which the OH group is at a chiral centre, then the Mitsunobu reaction has been a stalwart for many years. Now a catalytic version has been published, along with a proposed mechanism. Here I apply computation as a reality check […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21363\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2019-10-09T12:12:57+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2019-10-10T15:01:46+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2019\/10\/mitsunobo.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":"Catalytic Mitsunobu reaction. - 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=21363","og_locale":"en_GB","og_type":"article","og_title":"Catalytic Mitsunobu reaction. - Henry Rzepa's Blog","og_description":"If, as a synthetic chemist, you want to invert the configuration of an alcohol in which the OH group is at a chiral centre, then the Mitsunobu reaction has been a stalwart for many years. 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Each achieves its chiral magic by control of the geometry at the transition state for\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":8776,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8776","url_meta":{"origin":21363,"position":3},"title":"How to tame an oxidant: the mysteries of “tpap” (tetra-n-propylammonium perruthenate).","author":"Henry Rzepa","date":"December 24, 2012","format":false,"excerpt":"tpap, as it is affectionately known, is a ruthenium-based oxidant of primary alcohols to aldehydes discovered by Griffith and Ley. Whereas ruthenium tetroxide (RuO4) is a voracious oxidant, its radical anion countered by a tetra-propylammonium cation is considered a more moderate animal. 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A common question asked by\u2026","rel":"","context":"In "Curly arrows"","block_context":{"text":"Curly arrows","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2327"},"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":21363,"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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