{"id":22541,"date":"2020-07-21T09:35:19","date_gmt":"2020-07-21T08:35:19","guid":{"rendered":"https:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=22541"},"modified":"2020-07-21T09:35:19","modified_gmt":"2020-07-21T08:35:19","slug":"the-willgerodt-kindler-reaction-mechanistic-reality-check-1","status":"publish","type":"post","link":"https:\/\/www.rzepa.net\/blog\/?p=22541","title":{"rendered":"The Willgerodt-Kindler Reaction: mechanistic reality check 1."},"content":{"rendered":"
\n

The Willgerodt reaction[1]<\/a><\/span>, discovered in 1887 and shown below, represents a transformation with a once famously obscure mechanism. A major step in the elucidation of that mechanism came[2]<\/a><\/span> using the then new technique of 14<\/sup>C radio-labelling, shortly after the atom bomb projects during WWII made 14<\/sup>CO2<\/sub> readily available to researchers. Here I am going to start the process of applying the far more recent technique of quantitative quantum mechanical modelling to see if some of the proposed mechanisms stand up to its scrutiny.<\/p>\n

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

In the classic experiment, it was shown that if acetophenone labelled on the carbonyl group with 14<\/sup>C was subjected to Willgerodt conditions, almost 100% of the label ended up in the benzylic carbon(red dot).[2]<\/a><\/span> Why was this considered remarkable? Because it was effectively the oxygen of the carbonyl (via<\/em> the proxy of the N in the intermediate enamine) that appeared to be migrating along the C2<\/sub> carbon chain, rather than the phenyl group which is a known very effective migrator! The rather harsh conditions of the Willgerodt reaction were replaced in 1923 by the somewhat milder Kindler modification,[3]<\/a><\/span> using morpholine + S8<\/sub> as the catalyst\u00a0instead of ammonia + S8<\/sub>. The mechanism below is adapted from a typical source of named organic reactions<\/a>; the Wikipedia page<\/a> is a rather more elaborate version of this. In essence these mechanisms suggest that the aziridine species labelled Int2<\/strong> below is an undetected intermediate accounting for the radio-labelling experiment.<\/p>\n

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

The computational reality check can be undertaken by calculating the relative free energies of the species labelled above, setting that of the reactant to\u00a0\u0394\u0394G = 0.0. The model used is B3LYP+GD3+BJ\/Def2-TZVPP\/SCRF=water (FAIR data DOI: 10.14469\/hpc\/7294<\/a>). For the reaction to be reasonably fast at 403K, the highest species on this pathway should be no higher than ~30 kcal\/mol above the reactant. The calculations reveal that TS3<\/strong> is around 42.6 kcal\/mol above the reactant, with a very flat potential energy surface in the region of the transition state, in which C-N cleavage preceeds 1,2-hydrogen migration.<\/p>\n

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

\"\"<\/a>\"\"<\/a>The value of this barrier height suggests an alarm bell ringing. Protonating the species (via<\/em> tosic acid) does not help. So we conclude that the mechanism needs \u00a0“optimising” to try to find a lower energy pathway to product.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n
Species<\/th>\n\u0394\u0394G<\/th>\n<\/tr>\n
Reactant<\/td>\n0.0<\/td>\n<\/tr>\n
TS1<\/td>\n27.9 (44.4)a<\/sup><\/td>\n<\/tr>\n
Int1<\/td>\n5.8 (13.0)a<\/sup><\/td>\n<\/tr>\n
TS2<\/td>\n16.9 (22.4)a<\/sup><\/td>\n<\/tr>\n
Int2<\/td>\n14.7<\/td>\n<\/tr>\n
TS3<\/td>\n42.6<\/span><\/td>\n<\/tr>\n
Product<\/td>\n-21.2<\/td>\n<\/tr>\n
Int3<\/td>\n-0.4<\/td>\n<\/tr>\n
a<\/sup>Protonated on S<\/small><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

A hint of how this might be done comes from the energy of the species labelled Int3<\/strong>, which is a thiirane rather than an aziridine intermediate. \u00a0Such thiiranes will be explored in part two of this theme. It may also be that explicit base catalysis of TS3 via<\/em> proton abstraction may be more facile than a direct [1,2] hydrogen shift. Much like organic syntheses, where reaction yields have to be optimised by often long and arduous explorations, so too on occasion do reaction mechanisms!<\/p>\n

References<\/h2>\n
  1. C. Willgerodt, \"Ueber die Einwirkung von gelbem Schwefelammonium auf Ketone und Chinone\", Berichte der deutschen chemischen Gesellschaft<\/i>, vol. 20, pp. 2467-2470, 1887. https:\/\/doi.org\/10.1002\/cber.18870200278<\/a>\n\n<\/li>\n
  2. W.G. Dauben, J.C. Reid, P.E. Yankwich, and M. Calvin, \"The Mechanism of the Willgerodt Reaction<sup>1<\/sup>\", Journal of the American Chemical Society<\/i>, vol. 72, pp. 121-124, 1950. https:\/\/doi.org\/10.1021\/ja01157a034<\/a>\n\n<\/li>\n
  3. K. Kindler, \"Studien \u00fcber den Mechanismus chemischer Reaktionen. Erste Abhandlung. Reduktion von Amiden und Oxydation von Aminen\", Justus Liebigs Annalen der Chemie<\/i>, vol. 431, pp. 187-230, 1923. https:\/\/doi.org\/10.1002\/jlac.19234310111<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    The Willgerodt reaction, discovered in 1887 and shown below, represents a transformation with a once famously obscure mechanism. 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. Here I am going to […]<\/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,"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":[1085],"tags":[],"class_list":["post-22541","post","type-post","status-publish","format-standard","hentry","category-reaction-mechanism-2"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/p1gPyz-5Rz","jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts\/22541","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=22541"}],"version-history":[{"count":0,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts\/22541\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=22541"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=22541"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=22541"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}