{"id":21982,"date":"2020-03-25T07:27:52","date_gmt":"2020-03-25T07:27:52","guid":{"rendered":"https:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=21982"},"modified":"2020-05-03T11:48:19","modified_gmt":"2020-05-03T10:48:19","slug":"the-mechanism-of-michael-14-nucleophilic-addition-a-computationally-derived-reaction-pathway","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21982","title":{"rendered":"The mechanism of Michael 1,4-Nucleophilic addition: a computationally derived reaction pathway."},"content":{"rendered":"
\n

In 2013, I created an iTunesU library of 115\u00a0mechanistic types in organic and organometallic chemistry, illustrated using video animations of the intrinsic reaction coordinate (IRC) computed using a high level quantum mechanical procedure. Many of those examples first derived from posts here. That collection\u00a0 is still available<\/a> and is viewable \u00a0in the iTunesU app on an iPhone or an iPad. The realisation struck me now\u2021<\/sup> that one of the types not described in that library was Michael-type 1,4-nucleophilic addition to an activated alkene, as described at\u00a0Wikipedia<\/a>. So here is that addition.<\/p>\n

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

The base used will be NH3<\/sub> and the activating groups R will all be formyl. The DFT computational method will be\u00a0\u03c9B97XD\/Def2-TZVPP\/SCRF=water and the FAIR data will collect at DOI: 10.14469\/hpc\/7027<\/a><\/p>\n

The full reaction mechanism can be represented as below \"\"<\/a><\/p>\n\n\n\n\n\n\n\n\n\n\n\n
Species<\/th>\n\u0394\u0394G298<\/sub>, kcal\/mol<\/th>\nFAIR Data DOI<\/th>\n<\/tr>\n
Reactant<\/td>\n0.0<\/td>\n7028<\/a><\/td>\n<\/tr>\n
TS1<\/td>\n6.7<\/td>\n7029<\/a><\/td>\n<\/tr>\n
Int1<\/td>\n-7.7<\/td>\n7036<\/a><\/td>\n<\/tr>\n
TS2<\/td>\n16.3<\/td>\n7031<\/a><\/td>\n<\/tr>\n
Int2<\/td>\n-8.7<\/td>\n7033<\/a><\/td>\n<\/tr>\n
Int3<\/td>\n-8.7<\/td>\n7035<\/a><\/td>\n<\/tr>\n
TS3<\/td>\n9.6<\/td>\n7030<\/a><\/td>\n<\/tr>\n
Product<\/td>\n-13.2<\/td>\n7034<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

The rate-limiting step of C-C bond formation is coupled with almost synchronous protonation on the remote oxygen. It is driven by reducing the dipole moment of the zwitterion Int1<\/strong>, as shown below.\"\"<\/a><\/p>\n

Attempts to find an analogous route with carbon protonation leading directly to the product did not succeed.<\/p>\n

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

By varying parameters such as the nature of the R groups or the base, one might be able to control the choreography of the C-C bond formation relative to the accompanying proton transfer to oxygen in TS2 (in the manner that was possible for e.g.<\/em> peracid epoxidation[1]<\/a><\/span>). These changes could then be subjected to e.g.<\/em> the measurement of kinetic isotope effects and comparison with values calculated from the computational mechanism.<\/p>\n

\n

\u2021<\/sup>With Coronavirus now changing our lives and our work patterns, and having done my allowed quota of one exercise walk for the day at 06.30 (to avoid social contact, although in fact the park we went to<\/a> had lots of other people exercising, even at that time) I settled down to think about what else could be done. The Michael reaction suddenly appeared! Locating transition states is one of those things that gives me considerable pleasure, and I have not reported any for a few posts now.<\/p>\n

References<\/h2>\n
  1. J.E.M.N. Klein, G. Knizia, and H.S. Rzepa, \"Epoxidation of Alkenes by Peracids: From Textbook Mechanisms to a Quantum Mechanically Derived Curly\u2010Arrow Depiction\", ChemistryOpen<\/i>, vol. 8, pp. 1244-1250, 2019. https:\/\/doi.org\/10.1002\/open.201900099<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    In 2013, I created an iTunesU library of 115\u00a0mechanistic types in organic and organometallic chemistry, illustrated using video animations of the intrinsic reaction coordinate (IRC) computed using a high level quantum mechanical procedure. Many of those examples first derived from posts here. That collection\u00a0 is still available and is viewable \u00a0in the iTunesU app on […]<\/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_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":[],"ppma_author":[2661],"class_list":["post-21982","post","type-post","status-publish","format-standard","hentry","category-reaction-mechanism-2"],"yoast_head":"\nThe mechanism of Michael 1,4-Nucleophilic addition: a computationally derived reaction pathway. - 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=21982\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"The mechanism of Michael 1,4-Nucleophilic addition: a computationally derived reaction pathway. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"In 2013, I created an iTunesU library of 115\u00a0mechanistic types in organic and organometallic chemistry, illustrated using video animations of the intrinsic reaction coordinate (IRC) computed using a high level quantum mechanical procedure. 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That collection\u00a0 is still available and is viewable \u00a0in the iTunesU app on […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21982\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2020-03-25T07:27:52+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2020-05-03T10:48:19+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2020\/03\/michael1.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":"The mechanism of Michael 1,4-Nucleophilic addition: a computationally derived reaction pathway. - 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=21982","og_locale":"en_GB","og_type":"article","og_title":"The mechanism of Michael 1,4-Nucleophilic addition: a computationally derived reaction pathway. - Henry Rzepa's Blog","og_description":"In 2013, I created an iTunesU library of 115\u00a0mechanistic types in organic and organometallic chemistry, illustrated using video animations of the intrinsic reaction coordinate (IRC) computed using a high level quantum mechanical procedure. 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The model nucleophile was malonaldehyde after deprotonation and the model electrophile was acrolein (prop-2-enal), with the rate determining transition state being carbon-carbon bond formation between the two, accompanied by proton transfer\u2026","rel":"","context":"In "Curly arrows"","block_context":{"text":"Curly arrows","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2327"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":26523,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=26523","url_meta":{"origin":21982,"position":1},"title":"More examples of “double-headed” curly arrows: S and C Nucleophiles attacking acetyl chloride","author":"Henry Rzepa","date":"October 12, 2023","format":false,"excerpt":"In an earlier post on this topic,\u2021 I described how the curly-arrows describing the mechanism of a nucleophilic addition at a carbonyl group choreograph in two distinct ways, as seen in red or blue below. The arrows in red can be described as firstly addition to the carbonyl group to\u2026","rel":"","context":"In \"Interesting chemistry\"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?tag=interesting-chemistry"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":11995,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11995","url_meta":{"origin":21982,"position":2},"title":"The wrong trousers: the anti-Markovnikov addition of borane to 2-methylpropene.","author":"Henry Rzepa","date":"March 2, 2014","format":false,"excerpt":"A staple of introductory undergraduate teaching in organic chemistry is Markovnikov's rule, which states: \"the addition of a protic acid HX to an alkene results in the acid hydrogen (H) becoming attached to the carbon with fewer alkyl substituents and the halide (X) group to the carbon with more alkyl\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.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2014\/03\/borane%2Bbutene.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":10184,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10184","url_meta":{"origin":21982,"position":3},"title":"Intermediates in oxime formation from hydroxylamine and propanone: now you see them, now you don’t.","author":"Henry Rzepa","date":"April 14, 2013","format":false,"excerpt":"A recent theme here has been to subject to scrutiny well-known mechanisms supposedly involving intermediates. 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