{"id":16902,"date":"2016-09-28T08:37:55","date_gmt":"2016-09-28T07:37:55","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=16902"},"modified":"2016-10-03T09:58:00","modified_gmt":"2016-10-03T08:58:00","slug":"%cf%83-or-%cf%80-nucleophilic-reactivity-of-imines-a-mechanistic-twist-emerges","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=16902","title":{"rendered":"\u03c3 or \u03c0 nucleophilic reactivity of imines? A mechanistic twist emerges."},"content":{"rendered":"
\n

The story so far<\/a>. Imines react with a peracid to form either a nitrone (\u03c3-nucleophile) or an oxaziridine (\u03c0-nucleophile).[1]<\/a><\/span> The balance between the two is on an experimental\u00a0knife-edge, being strongly influenced by substituents on the imine. Modelling these reactions using the “normal” mechanism for peracid oxidation did not reproduce this knife-edge, with \u0394\u0394G (\u03c0-\u03c3) 16.2 kcal\/mol being rather too far from a fine balance.<\/p>\n

There are two general reasons why computational modelling using quantum mechanics\u00a0may\u00a0not match experimental outcome. Until perhaps 10 or so years ago, the culprits may often have been the approximations necessary to apply the theory, as bounded by the limitations of the CPU power of the then available computers to evaluate the associated equations. Nowadays, an equally likely explanation is that the molecular model for which these equations are solved is either wrong or maybe just incomplete. For an organic reaction, these models are initially set out by “arrow pushing” a possible mechanistic pathway. Such speculations have been a\u00a0common feature of most new articles reporting the outcome of reaction experiments for perhaps 60 years now. It is now more common (but by no means universal) to\u00a0augment this with a computational reality check. So previously<\/a>, when I applied a reality check on the “standard” epoxidation mechanism, it did not pass the test.<\/p>\n

So time to revise the mechanism, as per below. The difference is that the model includes an extra water molecule to facilitate proton transfers, with the imine now being protonated by the peracid to form a zwitterion, which\u00a0collapses to an addition product and it is this species that rearranges to the final oxaziridine. Free energies relative to the reactant 1<\/strong> are shown in red below.\u2021<\/sup><\/p>\n

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

The IRC for 2 (TS) is shown below, being\u00a0a proton transfer mediated by the transfer agent (water in this case, but it could be also peracid or eventually the product acid) to form a ion-pair.<\/p>\n

\"2ts-irc1\"<\/p>\n

4 (TS) shows the collapse of the ion-pair to form an addition product across the imine.<\/p>\n

\"4ts-irc1\"<\/p>\n

6 (TS, below) is the most interesting and also the high point on the free-energy pathway (i.e.<\/em> the rate determining step). The addition product cyclises to an oxaziridine as induced by the nitrogen lone pair helping to evict the acetate anion. This is followed at IRC ~7 by a transfer of the N-H proton back to the carboxylic acid, again using water as a transfer agent with the whole being part of a concerted but asynchronous mechanistic step.<\/p>\n

\"6ts-irc1\"<\/p>\n

\"6g\"<\/a><\/p>\n

Crucially, 6 (TS) is 23.4 kcal\/mol below the oxaziridination transition state modelled without a prior proton transfer[2]<\/a><\/span>,[3]<\/a><\/span> and even 7.6 kcal\/mol below the transition state for nitrone formation.[4]<\/a><\/span>,[5]<\/a><\/span><\/p>\n

So the original mechanism is now replaced by an alternative, which really only differs in the timing of how the acidic proton attached to the peracid responds to the process. By getting actively involved prior to the crucial reaction with the nitrogen lone pair of the imine, this proton enables a lower energy route to be established. We are now ready for the next “reality check” on these mechanisms, which are the effects of substituents on the imine. If these can be replicated, we can then really start to claim that computation has put the mechanism of this reaction onto a firmer footing than that based just on “arrow-pushing”.<\/p>\n

\n

\u2021<\/sup>Calculations (\u03c9B97XD\/Def2-TZVPP\/SCRF=dichloromethane) for the species above are archived as a collection at DOI: 10.14469\/hpc\/1704<\/a>[6]<\/a><\/span> and individually at\u00a01[7]<\/a><\/span>, 2 (TS)[8]<\/a><\/span>, 3[9]<\/a><\/span>, 4 (TS)[10]<\/a><\/span>, [11]<\/a><\/span>, 5[12]<\/a><\/span>, 6 (TS)[13]<\/a><\/span>,[14]<\/a><\/span>, 7[15]<\/a><\/span>.<\/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, \"Imine + peracetic acid, \u00cf\u0080 attack + H2O, TS.\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1698<\/a>\n\n<\/li>\n
  3. H. Rzepa, \"Imine + peracetic acid, pi attack + H2O, TS. IRC\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1701<\/a>\n\n<\/li>\n
  4. H. Rzepa, \"Imine + peracetic acid,N attack + H2O, TS\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1697<\/a>\n\n<\/li>\n
  5. H. Rzepa, \"Imine + peracetic acid,N attack + H2O, TS IRC\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1702<\/a>\n\n<\/li>\n
  6. H. Rzepa, \"Imine + peracetic acid, pi attack zwitterion + H2O reactant\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1695<\/a>\n\n<\/li>\n
  7. H. Rzepa, \"Imine + peracetic acid, \u00cf\u0080 attack zwitterion + H2O\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1703<\/a>\n\n<\/li>\n
  8. H. Rzepa, \"Imine + peracetic acid, \u00cf\u0080 attack zwitterion + H2O intermediate\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1696<\/a>\n\n<\/li>\n
  9. H. Rzepa, \"Imine + peracetic acid, pi attack zwitterion + H2O IRC => C-O formation TS\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1692<\/a>\n\n<\/li>\n
  10. H. Rzepa, \"Imine + peracetic acid, pi attack zwitterion + H2O IRC => C-O formation TS IRC\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1700<\/a>\n\n<\/li>\n
  11. H. Rzepa, \"Imine + peracetic acid, pi attack zwitterion + H2O TS IRC, addition int\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1690<\/a>\n\n<\/li>\n
  12. H. Rzepa, \"Imine + peracetic acid, pi attack zwitterion + H2O TS\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1694<\/a>\n\n<\/li>\n
  13. H. Rzepa, \"Imine + peracetic acid, \u00cf\u0080 attack zwitterion + H2O TS IRC\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1693<\/a>\n\n<\/li>\n
  14. H. Rzepa, \"Imine + peracetic acid, pi attack zwitterion + H2O TS IRC, oxaziridine product\", 2016. https:\/\/doi.org\/10.14469\/hpc\/1691<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    The story so far. Imines react with a peracid to form either a nitrone (\u03c3-nucleophile) or an oxaziridine (\u03c0-nucleophile). The balance between the two is on an experimental\u00a0knife-edge, being strongly influenced by substituents on the imine. Modelling these reactions using the “normal” mechanism for peracid oxidation did not reproduce this knife-edge, with \u0394\u0394G (\u03c0-\u03c3) 16.2 […]<\/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":true,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_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}},"categories":[1086],"tags":[1891,1890,1412,1888,1889,1794,1410,1887],"ppma_author":[2661],"class_list":["post-16902","post","type-post","status-publish","format-standard","hentry","category-reaction-mechanism-2","tag-addition-product","tag-free-energy-pathway","tag-functional-groups","tag-imine","tag-nitrone","tag-nucleophile","tag-organic-chemistry","tag-oxaziridine"],"yoast_head":"\n\u03c3 or \u03c0 nucleophilic reactivity of imines? A mechanistic twist emerges. - 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=16902\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"\u03c3 or \u03c0 nucleophilic reactivity of imines? A mechanistic twist emerges. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"The story so far. Imines react with a peracid to form either a nitrone (\u03c3-nucleophile) or an oxaziridine (\u03c0-nucleophile). The balance between the two is on an experimental\u00a0knife-edge, being strongly influenced by substituents on the imine. 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A mechanistic twist emerges. - 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=16902","og_locale":"en_GB","og_type":"article","og_title":"\u03c3 or \u03c0 nucleophilic reactivity of imines? A mechanistic twist emerges. - Henry Rzepa's Blog","og_description":"The story so far. Imines react with a peracid to form either a nitrone (\u03c3-nucleophile) or an oxaziridine (\u03c0-nucleophile). The balance between the two is on an experimental\u00a0knife-edge, being strongly influenced by substituents on the imine. 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A mechanistic reality check using substituents.","author":"Henry Rzepa","date":"October 9, 2016","format":false,"excerpt":"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\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":"","src":"","width":0,"height":0},"classes":[]},{"id":16844,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=16844","url_meta":{"origin":16902,"position":1},"title":"\u03c3 or \u03c0? 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I previously discussed how for this example, the\u2026","rel":"","context":"In "crystal_structure_mining"","block_context":{"text":"crystal_structure_mining","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=1745"},"img":{"alt_text":"imine2","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2016\/09\/imine2.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":8216,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8216","url_meta":{"origin":16902,"position":2},"title":"Secrets revealed for conjugate addition to cyclohexenone using a Cu-alkyl reagent.","author":"Henry Rzepa","date":"November 4, 2012","format":false,"excerpt":"The text books say that cyclohexenone A will react with a Grignard reagent by delivery of an alkyl (anion) to the carbon of the carbonyl (1,2-addition) but if dimethyl lithium cuprate is used, a conjugate 1,4-addition proceeds, to give the product B shown below. 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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":[]},{"id":22011,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22011","url_meta":{"origin":16902,"position":4},"title":"Substituent effects on the mechanism of Michael 1,4-Nucleophilic addition.","author":"Henry Rzepa","date":"March 29, 2020","format":false,"excerpt":"In the previous post, I looked at the mechanism for 1,4-nucleophilic addition to an activated alkene (the Michael reaction). The model nucleophile was malonaldehyde after deprotonation and the model electrophile was acrolein (prop-2-enal), with the rate determining transition state being carbon-carbon bond formation between the two, accompanied by proton transfer\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":10237,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10237","url_meta":{"origin":16902,"position":5},"title":"How to predict the regioselectivity of epoxide ring opening.","author":"Henry Rzepa","date":"April 28, 2013","format":false,"excerpt":"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%\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":[]}],"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","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/16902","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=16902"}],"version-history":[{"count":32,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/16902\/revisions"}],"predecessor-version":[{"id":16960,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/16902\/revisions\/16960"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=16902"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=16902"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=16902"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=16902"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}