{"id":25662,"date":"2022-10-08T08:31:01","date_gmt":"2022-10-08T07:31:01","guid":{"rendered":"https:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=25662"},"modified":"2022-10-08T19:14:12","modified_gmt":"2022-10-08T18:14:12","slug":"nitroaryls-a-less-toxic-alternative-reagent-for-ozonolysis-modelling-the-final-step-to-form-carbonyls","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=25662","title":{"rendered":"Nitroaryls- A less-toxic alternative reagent for ozonolysis: modelling the final step to form carbonyls."},"content":{"rendered":"
\n

Sometimes you come across a reaction which is so simple in concept that you wonder why it took so long to be accomplished in practice. In this case, replacing toxic ozone O3<\/sub>\u00a0as used to fragment an alkene into two carbonyl\u00a0compounds (“ozonolysis”) by a relatively non-toxic simple nitro-group based reagent, ArNO2 <\/sub>in which the central atom of ozone is substituted by an N-aryl group.\u00a0As reported by Derek Lowe<\/a>, two groups have published[1]<\/a><\/span>, [2]<\/a><\/span> details of such a reaction (Ar = 4-cyano or 3-CF3<\/sub>,5-NO2<\/sub>). But there are (at least) two tricks; the first is to use photo-excitation using purple LEDs (390nm light) to activate the nitro group. The second is to establish the best aryl substituents to use for achieving maximum yields of the carbonyl compounds and the best conditions for achieving the cyclo-reversion reaction, shown below as TS1<\/strong>.\u00a0That step requires heating the cyclo-adduct up to ~80\u00b0 in (aqueous) acetonitrile for anywhere between 1-48 hours. Here I take a computational look at that last step, the premise being that if such a model is available for this mechanism, it could in principle be\u00a0used to optimise the conditions for the process.<\/p>\n

The proposed mechanism for the workup in aqueous acetonitrile[2]<\/a><\/span> is shown below, involving\u00a0TS1<\/strong> (a thermal pericyclic cycloreversion reaction),\u00a0TS2<\/strong> and TS3<\/strong> involving intervention of either two or three water molecules to produce the carbonyl compounds and \u00a0an aryl hydroxylamine (which might of itself be a valuable product).\u00a0It was also mooted[2]<\/a><\/span> that an alternative mechanism might involve extrusion of an aryl nitrene instead of a cycloreversion (shown as\u00a0TS4<\/strong>). The calculations use the following method: (U)\u03c9B97XD\/Def2-TZVPP\/SCRF=acetonitrile. The FAIR data DOI for them is\u00a010.14469\/hpc\/11269<\/a>.<\/p>\n

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

Since the workup occurs at up to ~80\u00b0 in aqueous acetonitrile,[2]<\/a><\/span> the activation free energy that would allow this must be <~25 kcal\/mol.<\/p>\n

    \n
  1. The first model is a simple closed shell cyclo-reversion, solvated only by the model continuum, giving a barrier (for ethene as substrate) which is a little on the high side for a relatively facile thermal reaction.<\/li>\n
  2. At this level, the nitrene extrusion reaction identifies as a second order saddle-point with a very high energy, eliminating it from possibility for the mechanism.<\/li>\n
  3. Allowing the wavefunction to have some biradical character (TS1<\/strong> has <S2<\/sup>> before annihilation 0.5534, after 0.0858;\u00a0a pure biradical for which singlet and triplet states are equal in energy would have a value of 1.00) lowers the energy by a modest 2.5 kcal\/mol in this model, but producing a somewhat more realistic free energy barrier.<\/li>\n
  4. Adding 2H2<\/sub>O to the model allows TS2<\/strong> and \u00a0TS3<\/strong> to be directly compared to\u00a0TS1<\/strong>.\u00a0The barrier drops a further 3.0 or 4.3 kcal\/mol respectively for 2 or 3 waters, and also clearly indicates that\u00a0TS1<\/strong> is the rate-limiting step. The barrier corresponds to a reaction which is reasonably fast at ambient or slightly elevated temperatures.<\/li>\n<\/ol>\n\n\n\n\n\n\n\n\n\n\n
    Model<\/th>\nΔG‡<\/sup> TS1<\/th>\nΔG‡<\/sup> TS2<\/th>\nΔG‡<\/sup> TS3<\/th>\n<\/tr>\n
    Reactants<\/td>\n0<\/td>\n<\/tr>\n
    Closed shell ionic<\/td>\n30.0<\/a><\/td>\n–<\/td>\n<\/tr>\n
    “TS4”<\/td>\n73.9<\/a><\/td>\n–<\/td>\n<\/tr>\n
    +biradical<\/td>\n27.5<\/a><\/td>\n–<\/td>\n<\/tr>\n
    +biradical + 2H2O<\/td>\n24.5<\/a><\/td>\n13.7<\/a><\/td>\n9.2<\/a><\/td>\n<\/tr>\n
    +biradical + 3H2O<\/td>\n23.2<\/a><\/td>\n12.6<\/a><\/td>\n-1.5<\/a><\/td>\n<\/tr>\n
    Products + 3H2O<\/td>\n-20.4<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

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

    The results here could be used for e.g.<\/i> computational exploration of how variation in the aromatic group might affect the barrier for cycloreversion.‡<\/sup> Ideally, a version of this reaction which might operate at much lower temperatures would enhance this alternative to using ozone.<\/p>\n

    \n

    ‡<\/sup> The ΔG‡<\/sup>value for p-CN.3H2<\/sub>O is lower (22.1 kcal\/mol vs 23.3 kcal\/mol) suggesting it proceeds rather more quickly than the m-CF3<\/sub>,NO2<\/sub> version. This post has DOI: 10.14469\/hpc\/11319<\/p>\n

    References<\/h2>\n
    1. D.E. Wise, E.S. Gogarnoiu, A.D. Duke, J.M. Paolillo, T.L. Vacala, W.A. Hussain, and M. Parasram, \"Photoinduced Oxygen Transfer Using Nitroarenes for the Anaerobic Cleavage of Alkenes\", Journal of the American Chemical Society<\/i>, vol. 144, pp. 15437-15442, 2022. https:\/\/doi.org\/10.1021\/jacs.2c05648<\/a>\n\n<\/li>\n
    2. A. Ruffoni, C. Hampton, M. Simonetti, and D. Leonori, \"Photoexcited nitroarenes for the oxidative cleavage of alkenes\", Nature<\/i>, vol. 610, pp. 81-86, 2022. https:\/\/doi.org\/10.1038\/s41586-022-05211-0<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

      Sometimes you come across a reaction which is so simple in concept that you wonder why it took so long to be accomplished in practice. In this case, replacing toxic ozone O3\u00a0as used to fragment an alkene into two carbonyl\u00a0compounds (“ozonolysis”) by a relatively non-toxic simple nitro-group based reagent, ArNO2 in which the central atom […]<\/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":[2648],"ppma_author":[2661],"class_list":["post-25662","post","type-post","status-publish","format-standard","hentry","category-reaction-mechanism-2","tag-interesting-chemistry"],"yoast_head":"\nNitroaryls- A less-toxic alternative reagent for ozonolysis: modelling the final step to form carbonyls. - 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=25662\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Nitroaryls- A less-toxic alternative reagent for ozonolysis: modelling the final step to form carbonyls. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"Sometimes you come across a reaction which is so simple in concept that you wonder why it took so long to be accomplished in practice. 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One of the many wonderful talks presented was by Tobias Ritter and entitled \"Late-stage fluorination for PET imaging\" and this resonated for me. The challenge is how to produce C-F bonds under\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.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2018\/09\/fluoridation.gif?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":1183,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=1183","url_meta":{"origin":25662,"position":1},"title":"Multi-centre bonding in the Grignard Reagent","author":"Henry Rzepa","date":"December 1, 2009","format":false,"excerpt":"The Grignard reaction is encountered early on in most chemistry courses, and most labs include the preparation of this reagent, typically by the following reaction: 2PhBr + 2Mg \u2192 2PhMgBr\u00a0\u2194 MgBr2 + Ph2Mg The reagent itself exists as part of an equilibrium, named after Schlenk, in which a significant concentration\u2026","rel":"","context":"In "Hypervalency"","block_context":{"text":"Hypervalency","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=7"},"img":{"alt_text":"The crystal structure of a di-aryl magnesium. Click to view 3D","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/12\/udaqiz.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":25662,"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. The standard explanation is that the\u2026","rel":"","context":"In \"metal\"","block_context":{"text":"metal","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?tag=metal"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/11\/4.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":11110,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11110","url_meta":{"origin":25662,"position":3},"title":"Coarctate reactions as a third fundamental organic-mechanistic type.","author":"Henry Rzepa","date":"September 4, 2013","format":false,"excerpt":"According to Herges, the mechanism of single-step (concerted) reactions can be divided into three basic types; linear (e.g. substitution, elimination etc), pericyclic (e.g. Diels Alder) and a third much rarer, and hence very often overlooked type that was named coarctate. This is based on the topology of\u00a0bond redistribution patterns, an\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":"Click for 3D","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/09\/coarctate-ts.jpeg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":9917,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=9917","url_meta":{"origin":25662,"position":4},"title":"Concerted vs stepwise (Meisenheimer) mechanisms for aromatic nucleophilic substitution.","author":"Henry Rzepa","date":"March 25, 2013","format":false,"excerpt":"My two previous explorations of aromatic substitutions have involved an electrophile (NO+ or Li+). Time now to look at a nucleophile, representing nucleophilic aromatic substitution. The mechanism of this is thought to pass through an intermediate analogous to the Wheland for an electrophile, this time known as the Meisenheimer complex.\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\/03\/trinitro.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":16942,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=16942","url_meta":{"origin":25662,"position":5},"title":"\u03c3 or \u03c0 nucleophilic reactivity of imines? 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":[]}],"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","author_category":"1","first_name":"Henry","last_name":"Rzepa","user_url":"https:\/\/orcid.org\/0000-0002-8635-8390","job_title":"","description":"Henry Rzepa is Emeritus Professor of Computational Chemistry at Imperial College London."}],"_links":{"self":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/25662","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=25662"}],"version-history":[{"count":54,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/25662\/revisions"}],"predecessor-version":[{"id":25725,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/25662\/revisions\/25725"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=25662"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=25662"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=25662"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=25662"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}