{"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":"2019-10-09T13:12:57","modified_gmt":"2019-10-09T12:12:57","slug":"catalytic-mitsunobo-reaction","status":"publish","type":"post","link":"https:\/\/www.rzepa.net\/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_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,"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}},"categories":[1085],"tags":[],"class_list":["post-21363","post","type-post","status-publish","format-standard","hentry","category-reaction-mechanism-2"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/p1gPyz-5yz","jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts\/21363","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=21363"}],"version-history":[{"count":0,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts\/21363\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=21363"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=21363"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=21363"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}