{"id":22694,"date":"2020-09-07T10:14:50","date_gmt":"2020-09-07T09:14:50","guid":{"rendered":"https:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=22694"},"modified":"2020-09-10T06:58:51","modified_gmt":"2020-09-10T05:58:51","slug":"the-willgerodt-kindler-reaction-completing-the-box-set","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22694","title":{"rendered":"The Willgerodt-Kindler reaction. Completing the Box set."},"content":{"rendered":"
\n

These four posts (the box set) set out to try to define the energetics for a reasonable reaction path for the Willgerodt-Kindler reaction. The rate of this reaction corresponds approximately to a free energy barrier of ~30 kcal\/mol. Any pathway found to be >10 kcal\/mol at its highest point above this barrier was deemed less probable. The first three efforts at defining such pathways all gave such a result. Here I try a fourth pathway in search of the hitherto elusive appropriately low energy barrier.<\/p>\n

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

The previously explored<\/a> pathway invoked an aziridinium cation as an intermediate (Int4<\/strong>). The challenge now is to define a route into this intermediate and another out of it to lead to the eventual product. I previously explored the energy of forming Int4<\/strong> by first using the lone pair of electrons on the nitrogen to form the ring, resulting in a carbanionic ylid which only then gained a proton to form Int4<\/strong>. This time I will try reversing this sequence, by protonation first to form Int5<\/strong> via<\/em> TS4<\/strong>,\u00a0forming a cation resonance stabilized via<\/em> sulfur. Only then does the nitrogen lone pair come into play to form the ring via TS8<\/strong>.\u00a0The free energy barriers for both these species are now within a reasonable range, being within 10 kcal\/mol of the estimated rate barrier (FAIR data for this pathway collected at DOI:\u00a010.14469\/hpc\/7385<\/a>).\u00a0It is also important to note that this is only an exploratory model, which has not yet been “optimized”. Thus to reduce the computer time needed, ammonia is used as a model base. The full model would use morpholine, which as a better base might be expected to eg<\/em> reduce the barrier for TS4<\/strong>. Also, these are bimolecular reactions computed for a standard state of ~0.04M. More concentrated solutions would also reduce the barrier. The anion present along the entire reaction pathway is not included in this model; doing so might also alter slightly the barriers.<\/p>\n

\"\"<\/a>

TS4<\/strong>.<\/p><\/div>

\"\"<\/a>

TS5<\/strong><\/p><\/div><\/p>\n

Having found a reasonable route to Int4<\/strong>, it now has to be converted in the first instance to \u00a0Int6,\u00a0<\/strong>which is then easily protonated to the initial product, leading eventually to the thioamide outcome of this reaction. After much exploration, a good route was found to unexpectedly involve\u00a0Int7<\/strong>. This is formed by ring opening of Int4<\/strong> via<\/em> TS9<\/strong>, with the sulfur migrating along the carbon chain in preference to forming the rather less resonance stabilized benzylic cation. Int7<\/strong> then reverses this migration, with the base removing a proton and the sulfur migrating back to the carbon atom it had started from in Int4<\/strong>\u00a0via<\/em> TS10. <\/strong>Both these barriers are also <10 kcal\/mol of the barrier inferred from the reaction rate.<\/p>\n

\"\"

TS9<\/strong><\/p><\/div>\n

\"\"<\/p>\n

\"\"

TS10<\/strong><\/p><\/div>\n

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

We thus finally have a model which is in accord with the kinetics of this reaction. As noted above, the model can always be refined further by eg<\/em> improving the base, searching for lower energy conformers of the various transition states etc. Such optimisation can often reduce barriers further by perhaps 3-4 kcal\/mol, along with the aforementioned reduction of a bimolecular reaction by increasing concentrations.<\/p>\n

I hope this “box set” of mechanistic investigations gives some insight into how a reaction can be explored using calculations. In this instance we also have the benefit that our final mechanism does lead to an interesting prediction. Thus Int7<\/strong> is predicted to be almost as stable as the final product. Perhaps its presence might be detectable if searched for. Identifying some\u00a0Int7<\/strong> in the reaction products would certainly provide good supporting evidence for our conclusions.<\/p>\n

\n

The DOI for this post is 10.14469\/hpc\/7387<\/a><\/p>\n

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

These four posts (the box set) set out to try to define the energetics for a reasonable reaction path for the Willgerodt-Kindler reaction. The rate of this reaction corresponds approximately to a free energy barrier of ~30 kcal\/mol. Any pathway found to be >10 kcal\/mol at its highest point above this barrier was deemed less […]<\/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":[1086],"tags":[],"ppma_author":[2661],"class_list":["post-22694","post","type-post","status-publish","format-standard","hentry","category-reaction-mechanism-2"],"yoast_head":"\nThe Willgerodt-Kindler reaction. Completing the Box set. - 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=22694\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"The Willgerodt-Kindler reaction. Completing the Box set. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"These four posts (the box set) set out to try to define the energetics for a reasonable reaction path for the Willgerodt-Kindler reaction. The rate of this reaction corresponds approximately to a free energy barrier of ~30 kcal\/mol. Any pathway found to be >10 kcal\/mol at its highest point above this barrier was deemed less […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22694\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2020-09-07T09:14:50+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2020-09-10T05:58:51+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2020\/09\/Willgerodt-4.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=\"3 minutes\" \/>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"The Willgerodt-Kindler reaction. 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A major step in the elucidation of that mechanism came using the then new technique of 14C radio-labelling, shortly after the atom bomb projects during WWII made 14CO2 readily available to researchers.\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\/2020\/07\/TS3m.gif?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":22578,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22578","url_meta":{"origin":22694,"position":1},"title":"The Willgerodt-Kindler Reaction: mechanistic reality check 2.","author":"Henry Rzepa","date":"August 14, 2020","format":false,"excerpt":"Continuing an exploration of the mechanism of this reaction, an alternative new mechanism was suggested in 1989 (having been first submitted to the journal ten years earlier!). Here the key intermediate proposed is a thiirenium cation (labelled 8 in the article) and labelled\u00a0Int3 below. The model chosen is the same\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":10743,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10743","url_meta":{"origin":22694,"position":2},"title":"Mechanism of the Boekelheide rearrangement","author":"Henry Rzepa","date":"June 26, 2013","format":false,"excerpt":"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 (...\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":"Boek1","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/06\/Boek1.gif?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":10408,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10408","url_meta":{"origin":22694,"position":3},"title":"Concerted 1,4-addition of thioacetic acid: a (requested) reality check.","author":"Henry Rzepa","date":"May 11, 2013","format":false,"excerpt":"Lukas, who occasionally comments on this blog, sent me the following challenge. In a recent article he had proposed that the stereochemical outcome (Z) of reaction between a butenal and thioacetic acid as shown below arose by an unusual concerted cycloaddtion involving an S-H bond. He wrote in the article\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":8246,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8246","url_meta":{"origin":22694,"position":4},"title":"Thalidomide. The role of water in the mechanism of its aqueous racemisation.","author":"Henry Rzepa","date":"November 10, 2012","format":false,"excerpt":"Thalidomide is a chiral molecule, which was sold in the 1960s as a sedative in its (S,R)-racemic form. The tragedy was that the (S)-isomer was tetragenic, and only the (R) enantiomer acts as a sedative. What was not appreciated at the time is that interconversion of the (S)- and (R)\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.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/11\/thal1.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":7964,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=7964","url_meta":{"origin":22694,"position":5},"title":"Text-books and the bromination of ethene.","author":"Henry Rzepa","date":"October 14, 2012","format":false,"excerpt":"There is often a disconnect between how a text-book (schematically) represents a reaction and a more quantitive \"reality\" revealed by quantum mechanics. Is the bromination of ethene to give 1,2-dibromoethane one such example? Text-books will show how ethene interacts with bromine to form a cyclic bromonium cation, which with the\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.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/10\/Br2b2.gif?resize=350%2C200","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\/22694","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=22694"}],"version-history":[{"count":29,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/22694\/revisions"}],"predecessor-version":[{"id":22745,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/22694\/revisions\/22745"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=22694"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=22694"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=22694"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=22694"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}