{"id":10743,"date":"2013-06-26T13:14:02","date_gmt":"2013-06-26T12:14:02","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=10743"},"modified":"2013-06-27T06:58:42","modified_gmt":"2013-06-27T05:58:42","slug":"mechanism-of-the-boekelheide-rearrangement","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10743","title":{"rendered":"Mechanism of the Boekelheide rearrangement"},"content":{"rendered":"
\n

A reader asked me about the mechanism of\u00a0the reaction of 2-picoline N-oxide with acetic anhydride to give 2-acetoxymethylpyridine (the\u00a0Boekelheide Rearrangement[1]<\/a><\/span>). He wrote ”\u00a0I don’t understand why the system should prefer to go via<\/em> fragmentation-recombination<\/span> (… the evidence being that\u00a0oxygen labelling shows scrambling)\u00a0when there is an easy concerted pathway available (… a [3,3]sigmatropic shift). Furthermore, is it possible for two pathways to co-exist?” Here is how computation might enlighten us.<\/p>\n

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

The first model I built discards the apparently extraneous product in the first reaction, ethanoic acid. A transition state is located (\u03c9B97XD\/6-311G(d,p)\/SCRF=dichloromethane) and its intrinsic reaction coordinate is shown below.[2]<\/a><\/span><\/p>\n

\"Boek1\"<\/p>\n\n\n\n
\"Boek1\"<\/td>\n\"Boek1G\"<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n
    \n
  1. One first notes that the reaction is concerted, with no intermediates along the route.<\/span><\/li>\n
  2. The reaction barrier (~21 kcal\/mol) is quite reasonable for a [3,3] sigmatropic reaction.<\/li>\n
  3. There is an almost undiscernible blip (inflexion) in the gradient norm at about +1 and a more obvious one at IRC +8. The latter is a hidden intermediate<\/em> corresponding to a conformational rotation about the newly formed C-O bond. The former is more significant, since it is providing the faintest of hints that a hidden intermediate<\/em>[3]<\/a><\/span> corresponding to an ion-pair (in red in the scheme above) might be attempting to form. But it is only a hint, no more.<\/li>\n<\/ol>\n

    So\u00a0an easy concerted pathway is indeed available. But the solvent model (dichloromethane) is not really very polar. How about water, which should better stabilise any ion-pair intermediate? That tiny blip in the gradient norm of the IRC (@~1) becomes a bit more prominent, but the reaction is computed as resolutely concerted.<\/p>\n

    \"Boek2G\"<\/p>\n

    So to explain why oxygen label scrambling is possible, we have to adopt a better model. That ethanoic acid discarded from our first attempt is re-instated. It serves the purpose of potentially stabilising any ion-pair which might form via<\/em> explicit hydrogen bonds.[4]<\/a><\/span><\/p>\n

    \"Click

    Click for 3D.<\/p><\/div>\n

    The IRC[5]<\/a><\/span> for this variation does indeed show a change; at IRC +3, there is now a very prominent hidden intermediate<\/em> feature, showing that the additional molecule of ethanoic acid formed in the first step is stabilizing the ion-pair. It also serves to reduce the barrier to the reaction (by ~4 kcal\/mol).\u2021<\/sup><\/p>\n\n\n\n\n
    \"Boek4\"<\/td>\n<\/tr>\n
    \"Boek4\"<\/td>\n\u00a0\"Boek4G\"<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

    Although the\u00a0Boekelheide rearrangement sounds like a rather obscure reaction that few have heard of, discussing it actually introduces an important concept common to many reactions. That is that they can proceed via<\/em> either relatively neutral or highly ionic pathways, and that the balance between these two may be both subtle and influenced by external factors. In this case, the formation of a hydrogen bond stabilising the transition state for the reaction. This of course is also how many an enzyme achieves its action! For the\u00a0Boekelheide rearrangement,\u00a0a single hydrogen bonded ethanoic acid promotes, but does not fully establish the ion-pair mechanism over the neutral [3,3] pericyclic rearrangement. However, one might imagine that adding perhaps a second explicit stabilising H-bond might swing the balance over from merely a hidden intermediate to a real (ion-pair) intermediate. It is also possible that changing the acidity of this component (by replacing e.g.<\/em> CH3<\/sub>CO2<\/sub>H by e.g. CF3<\/sub>CO2<\/sub>H) might achieve the same result.<\/p>\n

    As to whether “it is\u00a0possible for two pathways to co-exist”,\u00a0a nice example of this in my experience comes from the enantiomerisation of isobornyl chloride in cresol,[6]<\/a><\/span> which has been shown by extensive isotope labelling to proceed by two concurrent but very different pathways. It is probably more common than we realise.<\/p>\n

    \n

    \u2021<\/sup> It is worth noting that the [3,3] sigmatropic reaction is unimolecular, whereas the ethanoic-assisted variation is bimolecular. Apart from taking into account the entropic requirements of the latter, it is also necessary to redefine the standard state for the free energy from 1 atm to a more reasonable 1M, which reduces the free energy barrier by about 1.9 kcal\/mol, and a correction which reduces the free energy of a bimolecular reaction a further 2.6 kcal\/mol can be applied as a solvent correction.[7]<\/a><\/span>. These two corrections mean that bimolecular solution reactions are often not so unfavourable compared to unimolecular equivalents as is often made out.<\/p>\n

    References<\/h2>\n
    1. A. Massaro, A. Mordini, A. Mingardi, J. Klein, and D. Andreotti, \"A New Sequential Intramolecular Cyclization Based on the Boekelheide Rearrangement\", European Journal of Organic Chemistry<\/i>, vol. 2011, pp. 271-279, 2010. https:\/\/doi.org\/10.1002\/ejoc.201000936<\/a>\n\n<\/li>\n
    2. H.S. Rzepa, \"Gaussian Job Archive for C8H9NO2\", 2013. https:\/\/doi.org\/10.6084\/m9.figshare.730627<\/a>\n\n<\/li>\n
    3. E. Kraka, and D. Cremer, \"Computational Analysis of the Mechanism of Chemical Reactions in Terms of Reaction Phases: Hidden Intermediates and Hidden Transition States\", Accounts of Chemical Research<\/i>, vol. 43, pp. 591-601, 2010. https:\/\/doi.org\/10.1021\/ar900013p<\/a>\n\n<\/li>\n
    4. H.S. Rzepa, \"Gaussian Job Archive for C10H13NO4\", 2013. https:\/\/doi.org\/10.6084\/m9.figshare.730621<\/a>\n\n<\/li>\n
    5. H.S. Rzepa, \"Gaussian Job Archive for C10H13NO4\", 2013. https:\/\/doi.org\/10.6084\/m9.figshare.731688<\/a>\n\n<\/li>\n
    6. J. Kong, P.V.R. Schleyer, and H.S. Rzepa, \"Successful Computational Modeling of Isobornyl Chloride Ion-Pair Mechanisms\", The Journal of Organic Chemistry<\/i>, vol. 75, pp. 5164-5169, 2010. https:\/\/doi.org\/10.1021\/jo100920e<\/a>\n\n<\/li>\n
    7. J.R. Alvarez-Idaboy, L. Reyes, and J. Cruz, \"A New Specific Mechanism for the Acid Catalysis of the Addition Step in the Baeyer\u2212Villiger Rearrangement\", Organic Letters<\/i>, vol. 8, pp. 1763-1765, 2006. https:\/\/doi.org\/10.1021\/ol060261z<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

      A reader asked me about the mechanism of\u00a0the reaction of 2-picoline N-oxide with acetic anhydride to give 2-acetoxymethylpyridine (the\u00a0Boekelheide Rearrangement). He wrote ”\u00a0I don’t understand why the system should prefer to go via fragmentation-recombination (… the evidence being that\u00a0oxygen labelling shows scrambling)\u00a0when there is an easy concerted pathway available (… a [3,3]sigmatropic shift). Furthermore, is […]<\/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,"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":[4,559,1086],"tags":[943,1050,1094,1092,40,206,1093],"ppma_author":[2661],"class_list":["post-10743","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry","category-pericyclic","category-reaction-mechanism-2","tag-atm","tag-cf-3-co","tag-ch-3-co","tag-extraneous-product","tag-free-energy","tag-free-energy-barrier","tag-recombination"],"yoast_head":"\nMechanism of the Boekelheide rearrangement - 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=10743\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Mechanism of the Boekelheide rearrangement - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"A reader asked me about the mechanism of\u00a0the reaction of 2-picoline N-oxide with acetic anhydride to give 2-acetoxymethylpyridine (the\u00a0Boekelheide Rearrangement). He wrote ”\u00a0I don’t understand why the system should prefer to go via fragmentation-recombination (… the evidence being that\u00a0oxygen labelling shows scrambling)\u00a0when there is an easy concerted pathway available (… a [3,3]sigmatropic shift). Furthermore, is […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10743\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2013-06-26T12:14:02+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2013-06-27T05:58:42+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/06\/boeckelheide.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=\"4 minutes\" \/>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Mechanism of the Boekelheide rearrangement - 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=10743","og_locale":"en_GB","og_type":"article","og_title":"Mechanism of the Boekelheide rearrangement - Henry Rzepa's Blog","og_description":"A reader asked me about the mechanism of\u00a0the reaction of 2-picoline N-oxide with acetic anhydride to give 2-acetoxymethylpyridine (the\u00a0Boekelheide Rearrangement). He wrote ”\u00a0I don’t understand why the system should prefer to go via fragmentation-recombination (… the evidence being that\u00a0oxygen labelling shows scrambling)\u00a0when there is an easy concerted pathway available (… a [3,3]sigmatropic shift). 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Stereochemistry galore.","author":"Henry Rzepa","date":"April 4, 2013","format":false,"excerpt":"Back in the days (1893) when few compounds were known, new ones could end up being named after the discoverer. Thus Feist is known for the compound bearing his name; the 2,3 carboxylic acid of methylenecyclopropane (1, with Me replaced by CO2H). Compound 1 itself nowadays is used to calibrate\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":"methylene-cyclopropane","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/04\/methylene-cyclopropane.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":9105,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=9105","url_meta":{"origin":10743,"position":1},"title":"The Benzidine rearrangement. Computed kinetic isotope effects.","author":"Henry Rzepa","date":"January 11, 2013","format":false,"excerpt":"Kinetic isotope effects have become something of a lost art when it comes to exploring reaction mechanisms. But in their heyday they were absolutely critical for establishing the mechanism of the benzidine rearrangement. This classic mechanism proceeds via bisprotonation of diphenyl hydrazine, but what happens next was the crux. Does\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":16441,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=16441","url_meta":{"origin":10743,"position":2},"title":"An alternative mechanism for nucleophilic substitution at silicon using a tetra-alkyl ammonium fluoride.","author":"Henry Rzepa","date":"May 27, 2016","format":false,"excerpt":"In the previous post, I explored the mechanism for nucleophilic substitution at a silicon centre proceeding via retention of configuration involving a Berry-like pseudorotation.\u00a0Here\u00a0I probe an alternative route involving inversion of configuration at the Si centre. Both stereochemical modes are known to occur, depending on the leaving group, solvent and\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":8961,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8961","url_meta":{"origin":10743,"position":3},"title":"The mechanism of the Benzidine rearrangement.","author":"Henry Rzepa","date":"January 6, 2013","format":false,"excerpt":"The benzidine rearrangement is claimed to be an example of the quite rare\u00a0[5,5] sigmatropic migration, which is a ten-electron homologation of the very common [3,3] sigmatropic reaction (e.g. the Cope or Claisen). Some benzidine rearrangements are indeed thought to go through the [3,3] route. The topic has been reviewed here.\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":"NCI surface. Click for 3D.","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/01\/benzidinenci.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":14944,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=14944","url_meta":{"origin":10743,"position":4},"title":"A tutorial problem in stereoelectronic control. A Grob alternative to the Tiffeneau-Demjanov rearrangement?","author":"Henry Rzepa","date":"November 28, 2015","format":false,"excerpt":"In answering tutorial problems, students often need skills in deciding how much time to spend on explaining what does not happen, as well as what does. Here I explore alternatives to the mechanism outlined in the previous post to see what computation\u00a0has to say about what does (or might) not\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":"Alt1","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2015\/11\/Alt1.gif?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":6618,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=6618","url_meta":{"origin":10743,"position":5},"title":"The mechanism of the Baeyer-Villiger rearrangement.","author":"Henry Rzepa","date":"May 7, 2012","format":false,"excerpt":"The Baeyer-Villiger rearrangement was named after its discoverers, who in\u00a01899\u00a0described the transformation of menthone into the corresponding lactone using Caro's acid (peroxysulfuric acid). The mechanism is described in all text books of organic chemistry as involving an alkyl migration. Here I take a look at the scheme described by\u00a0Alvarez-Idaboy, Reyes\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":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/05\/bv1.svg","width":350,"height":200},"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\/10743","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=10743"}],"version-history":[{"count":26,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/10743\/revisions"}],"predecessor-version":[{"id":11077,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/10743\/revisions\/11077"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=10743"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=10743"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=10743"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=10743"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}