{"id":25338,"date":"2022-08-12T05:56:48","date_gmt":"2022-08-12T04:56:48","guid":{"rendered":"https:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=25338"},"modified":"2022-08-14T07:36:54","modified_gmt":"2022-08-14T06:36:54","slug":"unexpected-isomerization-of-oxetane-carboxylic-acids-a-viable-mechanism","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=25338","title":{"rendered":"Unexpected Isomerization of Oxetane-Carboxylic Acids \u2013 a viable mechanism"},"content":{"rendered":"
\n

In the previous post<\/a>, I looked at the intramolecular rearrangement of the oxetane carboxylic acid to a lactone, finding the barrier to the Sn2 reaction with retention was unfeasibly high. Here I explore alternatives.<\/p>\n

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

    \n
  1. This first attempt uses a second molecule of a carboxylic acid (modelled as formic acid for simplicity) to see if it can catalyse the reaction. All FAIR data at 10.14469\/hpc\/10820<\/a>
    \n    \"\"<\/a>
    \nThe reaction still occurs with retention at the Sn2 centre, and the free energy barrier is 47.9 kcal\/mol (\u03c9B97XD\/Def2-TZVPP), very little different from the unimolecular reaction without additional acid (49.9 kcal\/mol).
    \n\"\"<\/li>\n
  2. How about inversion at the Sn2 centre? The energy profile now looks quite wrong, because the additional acid is too small to simultaneously straddle the entire molecule from the point of proton removal to the point of reprotonation, if inversion occurs at the Sn2 centre. The reaction ends up (or starts, depending on your point of view) with a proton in the wrong place!
    \n    \"\"
    \n\"\"<\/a><\/li>\n
  3. So the need to make the proton transfer agent larger, by now including TWO additional carboxylic acids.
    \n    \"\"<\/a>
    \n    \"\"<\/a>
    \n\"\"
    \nThere are now three proton transfers, one at each end of the oxetane-carboxylate and the product lactone and one between the two transfer acids. Watch the animation carefully to note the sequence in which they occur. The free energy barrier is now 27.0 kcal\/mol for a standard state of 1 atm (ωB97XD\/Def2-TZVPP). This could be reduced (3.2 kcal\/mol or more) for the higher effective molar concentrations in the liquid or solid state of the pure oxetane.<\/li>\n
  4. The structure of this transition state (click image below to view 3D model) shows one interesting point of CH…O interaction between transfer catalyst and substrate.
    \"\"<\/li>\n<\/ol>\n

    The next steps will be to explore the impact of making substitutions in the oxetane ring; there now seems to be a viable model to use for this purpose.<\/p>\n

    \n

    DOI 10.14469\/hpc\/10848 and 10.14469\/hpc\/10862<\/a><\/p>\n

    \n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    In the previous post, I looked at the intramolecular rearrangement of the oxetane carboxylic acid to a lactone, finding the barrier to the Sn2 reaction with retention was unfeasibly high. Here I explore alternatives. This first attempt uses a second molecule of a carboxylic acid (modelled as formic acid for simplicity) to see if it […]<\/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":[],"tags":[],"ppma_author":[2661],"class_list":["post-25338","post","type-post","status-publish","format-standard","hentry"],"yoast_head":"\nUnexpected Isomerization of Oxetane-Carboxylic Acids \u2013 a viable mechanism - 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=25338\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Unexpected Isomerization of Oxetane-Carboxylic Acids \u2013 a viable mechanism - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"In the previous post, I looked at the intramolecular rearrangement of the oxetane carboxylic acid to a lactone, finding the barrier to the Sn2 reaction with retention was unfeasibly high. Here I explore alternatives. This first attempt uses a second molecule of a carboxylic acid (modelled as formic acid for simplicity) to see if it […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=25338\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2022-08-12T04:56:48+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2022-08-14T06:36:54+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2022\/08\/oxetane.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=\"2 minutes\" \/>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Unexpected Isomerization of Oxetane-Carboxylic Acids \u2013 a viable mechanism - 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=25338","og_locale":"en_GB","og_type":"article","og_title":"Unexpected Isomerization of Oxetane-Carboxylic Acids \u2013 a viable mechanism - Henry Rzepa's Blog","og_description":"In the previous post, I looked at the intramolecular rearrangement of the oxetane carboxylic acid to a lactone, finding the barrier to the Sn2 reaction with retention was unfeasibly high. 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We are now\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":25313,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=25313","url_meta":{"origin":25338,"position":1},"title":"Unexpected Isomerization of Oxetane-Carboxylic Acids – a first look at the mechanism","author":"Henry Rzepa","date":"August 7, 2022","format":false,"excerpt":"Derek Lowe's blog has a recent post entitled A Downside to Oxetane Acids which picks up on a recent article describing how these acids are unexpectedly unstable, isomerising to a lactone at a significant rate without the apparent need for any catalyst. This is important because these types of compound\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":25439,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=25439","url_meta":{"origin":25338,"position":2},"title":"Unexpected Isomerization of Oxetane-Carboxylic Acids \u2013 an alternative autocatalytic mechanism evaluated.","author":"Henry Rzepa","date":"August 17, 2022","format":false,"excerpt":"Previously, I looked at autocatalytic mechanisms where the carboxyl group of an oxetane-carboxylic acid could catalyse its transformation to a lactone, finding that a chain of two such groups were required to achieve the result. Here I look at an alternative mode where the oxetane-carboxylate itself acts as the transfer\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":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2022\/08\/saddle.gif?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":25415,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=25415","url_meta":{"origin":25338,"position":3},"title":"Unexpected Isomerization of Oxetane-Carboxylic Acids \u2013 substrate design.","author":"Henry Rzepa","date":"August 14, 2022","format":false,"excerpt":"Having established a viable model for the unexpected isomerism of oxetane carboxylic acids to lactones, and taken a look at a variation in the proton transfer catalyst needed to accomplish the transformation, I now investigate the substrate itself. R' is set to have three values, R'=H (the original substituent), R'=\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":18091,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=18091","url_meta":{"origin":25338,"position":4},"title":"The conformation of carboxylic acids revealed.","author":"Henry Rzepa","date":"April 11, 2017","format":false,"excerpt":"Following my conformational exploration of enols, here is one about a much more common molecule, a carboxylic acid. The components of the search are shown as four queries below, which will be combined in various Boolean senses (DOI:\u00a010.14469\/hpc\/2462). Query one defines the carboxylic acid, with 3-coordinate carbon specified at 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":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2017\/04\/051-1024x676.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":5114,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=5114","url_meta":{"origin":25338,"position":5},"title":"Mechanism of the reduction of a carboxylic acid by borane: revisited and revised.","author":"Henry Rzepa","date":"October 16, 2011","format":false,"excerpt":"I asked a while back\u00a0whether blogs could be considered a serious form of scholarly scientific communication (and so has Peter Murray-Rust more recently). A case for doing so might be my post of about a year ago, addressing why borane reduces a carboxylic acid, but not its ester, where I\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":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2011\/10\/acyloxy1-page001.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\/25338","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=25338"}],"version-history":[{"count":23,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/25338\/revisions"}],"predecessor-version":[{"id":25435,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/25338\/revisions\/25435"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=25338"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=25338"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=25338"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=25338"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}