{"id":17032,"date":"2016-10-09T17:35:50","date_gmt":"2016-10-09T16:35:50","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=16942"},"modified":"2016-10-09T17:35:50","modified_gmt":"2016-10-09T16:35:50","slug":"%cf%83-or-%cf%80-nucleophilic-reactivity-of-imines-a-mechanistic-reality-check-using-substituents","status":"publish","type":"post","link":"https:\/\/www.rzepa.net\/blog\/?p=17032","title":{"rendered":"\u03c3 or \u03c0 nucleophilic reactivity of imines? A mechanistic reality check using substituents."},"content":{"rendered":"
\n

Previously<\/a>, a mechanistic twist to the oxidation of imines using peracid had emerged. Time to see how substituents respond to this mechanism.<\/p>\n

\"azir-x\"<\/a><\/p>\n

With\u00a0X = NO2<\/sub> 100% oxaziridine and no nitrone is obtained experimentally; with\u00a0X =\u00a0NMe2\u00a0<\/sub>, the population is inverted with nitrone as the dominant product at\u00a078%.[1]<\/a><\/span> Calculations (\u03c9B97XD\/Def2-TZVPP\/SCRF=dichloromethane), data collection \u00a0DOI: 10.14469\/hpc\/1743<\/a>[2]<\/a><\/span> are summarised in the table.\u00a0The initial model employs the simpler peracetic acid as oxidant (R=Me) and we see here a computed\u00a0preference of 4.2\u00a0kcal\/mol for oxiziridine when the aryl substituent\u00a0X = NO2\u00a0<\/sub>(a ratio of\u00a01024:1 in its favour) but reduced to 1.4 kcal\/mol when \u00a0X =\u00a0NMe2<\/sub>. \u00a0This hardly changes when the acid is changed from ethanoic\u00a0to mCPBA (meta-chloroperbenzoic acid), the oxidant actually used in the experiments.<\/p>\n\n\n\n\n\n\n\n
Substituents<\/th>\n\u03c0<\/th>\n\u03c3<\/th>\n<\/tr>\n
R=Me, X=NO2<\/sub><\/td>\n-4.2<\/td>\n0.0\u00a0<\/td>\n<\/tr>\n
R=Me, X=NMe2<\/sub><\/td>\n-1.4<\/td>\n0.0<\/td>\n<\/tr>\n
R=m-Cl-phenyl, X=NO2<\/sub><\/td>\n-4.1<\/td>\n0.0\u00a0<\/td>\n<\/tr>\n
R=m-Cl-phenyl, X=NMe2<\/sub><\/td>\n-1.3<\/td>\n0.0<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

You can see from the transition state structures that\u00a0\u03c0 attack is helped by stacking between the aryl face of the m-chloroperbenzoic acid and the aryl group on the imine, whereas\u00a0\u03c3 is not.\u00a0<\/p>\n

\"4\"\"3\"<\/p>\n

These results show that our proposed mechanism can reproduce the selectivity for formation of oxaziridine when the aryl group bears\u00a0X=NO2\u00a0<\/sub> but misses the mark of predicting nitrone formation when\u00a0X=NMe2<\/sub>. Experimentally nitrone is favoured by \u0394\u0394G298<\/sub> 0.75 kcal\/mol, whereas the calculation disfavours this by -1.3 kcal\/mol. Is this discrepancy enough to sink this mechanistic model? \u00a0Or might yet another variation on the mechanism, such shifting the proton from peracid to the\u00a0X=NMe2\u00a0<\/sub>do the trick?\u00a0<\/p>\n

What \u00a0I have tried to show here is how one can iterate towards a realistic mechanism by gradually refining the models so that more and more experimental observations are correctly predicted. \u00a0Sometimes of course, it might be the experiment itself that has to be repeated and refined, although we have not quite reached that point yet with this example.<\/p>\n

 <\/p>\n

References<\/h2>\n
  1. D.R. Boyd, P.B. Coulter, N.D. Sharma, W. Jennings, and V.E. Wilson, \"Normal, abnormal and pseudo-abnormal reaction pathways for the imine-peroxyacid reaction\", Tetrahedron Letters<\/i>, vol. 26, pp. 1673-1676, 1985. https:\/\/doi.org\/10.1016\/s0040-4039(00)98582-4<\/a>\n\n<\/li>\n
  2. H. Rzepa, \"\u00cf\u0083 or \u00cf\u0080 nucleophilic reactivity of imines\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1743<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    Previously, a mechanistic twist to the oxidation of imines using peracid had emerged. Time to see how substituents respond to this mechanism. With\u00a0X = NO2 100% oxaziridine and no nitrone is obtained experimentally; with\u00a0X =\u00a0NMe2\u00a0, the population is inverted with nitrone as the dominant product at\u00a078%. Calculations (\u03c9B97XD\/Def2-TZVPP\/SCRF=dichloromethane), data collection \u00a0DOI: 10.14469\/hpc\/1743 are summarised in […]<\/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":[1453,1874,1883,1884,1891],"class_list":["post-17032","post","type-post","status-publish","format-standard","hentry","category-reaction-mechanism-2","tag-functional-groups","tag-imine","tag-nitrone","tag-nme2","tag-oxaziridine"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/p1gPyz-4qI","jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts\/17032","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=17032"}],"version-history":[{"count":0,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts\/17032\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=17032"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=17032"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=17032"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}