{"id":22011,"date":"2020-03-29T06:25:55","date_gmt":"2020-03-29T05:25:55","guid":{"rendered":"https:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=22011"},"modified":"2020-04-04T06:01:10","modified_gmt":"2020-04-04T05:01:10","slug":"substituent-effects-on-the-mechanism-of-michael-14-nucleophilic-addition","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22011","title":{"rendered":"Substituent effects on the mechanism of Michael 1,4-Nucleophilic addition."},"content":{"rendered":"
\n

In the previous post<\/a>, I looked at the mechanism for 1,4-nucleophilic addition to an activated alkene (the Michael reaction). 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 to the oxygen of the acrolein.<\/p>\n

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

Here I look at the effect of changing one<\/strong> of the aldehyde groups on the malonaldehyde to a variety of others and in particular how this might affect the relative timing of the C-C formation and the accompanying proton transfer to oxygen. Will this vary with substituents?<\/p>\n

The activation free energies for TS2 are shown below, showing that as the acidity of the proton on the incipient nucleophile decreases along the series R=NO2<\/sub> to R=H, the free energy barrier goes up.\u00a0<\/p>\n\n\n\n\n\n\n\n\n
Substituent<\/th>\n\u0394\u0394G298<\/sub>\u2021<\/sup><\/a> (TS2)<\/th>\nAngle of approach<\/th>\n<\/tr>\n
\n

NO2<\/p>\n<\/td>\n

11.5<\/td>\n110.8<\/td>\n<\/tr>\n
\n

CHO<\/p>\n<\/td>\n

16.3<\/td>\n118.2<\/td>\n<\/tr>\n
\n

CN<\/p>\n<\/td>\n

16.7<\/td>\n111.2<\/td>\n<\/tr>\n
\n

OMe<\/p>\n<\/td>\n

31.9<\/td>\n121.8<\/td>\n<\/tr>\n
\n

H<\/p>\n<\/td>\n

35.8<\/td>\n116.7<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

The asynchrony of the C-C formation and the PT is clearly shown for R=NO2<\/sub>. This can be seen most clearly when the gradient norm along the reaction path is plotted. This has TWO maxima at IRC 0.5 and 1.4, with a hidden (zwitterionic) intermediate in-between.<\/p>\n

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

\"\"<\/a> \"\"<\/a> For R=H the gradient norm peaks are at IRC 0.8 and 2.1; the reaction is equally asynchronous. If you are wondering why the barrier looks smaller for R=H than for R=NO2<\/sub> it is because Int1<\/strong> is a lot less stable for R=H (= more reactive) than for nitro. \"\"<\/a>\"\"<\/a><\/p>\n

So this was a surprise in the end. Unlike substituent effects on electrophilic peracid epoxidation of an alkene,[1]<\/a><\/span> nucleophilic addition to an alkene does not seem to exhibit a large substituent effect on its choreography.<\/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 the previous post, I looked at the mechanism for 1,4-nucleophilic addition to an activated alkene (the Michael reaction). 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 to the oxygen of the […]<\/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":[2327,1086],"tags":[],"ppma_author":[2661],"class_list":["post-22011","post","type-post","status-publish","format-standard","hentry","category-curl-arrows","category-reaction-mechanism-2"],"yoast_head":"\nSubstituent effects on the mechanism of Michael 1,4-Nucleophilic addition. - 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=22011\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Substituent effects on the mechanism of Michael 1,4-Nucleophilic addition. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"In the previous post, I looked at the mechanism for 1,4-nucleophilic addition to an activated alkene (the Michael reaction). 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 to the oxygen of the […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22011\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2020-03-29T05:25:55+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2020-04-04T05:01:10+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2020\/03\/michael2.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=\"1 minute\" \/>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Substituent effects on the mechanism of Michael 1,4-Nucleophilic addition. - 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=22011","og_locale":"en_GB","og_type":"article","og_title":"Substituent effects on the mechanism of Michael 1,4-Nucleophilic addition. - Henry Rzepa's Blog","og_description":"In the previous post, I looked at the mechanism for 1,4-nucleophilic addition to an activated alkene (the Michael reaction). 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 to the oxygen of the […]","og_url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22011","og_site_name":"Henry Rzepa's Blog","article_published_time":"2020-03-29T05:25:55+00:00","article_modified_time":"2020-04-04T05:01:10+00:00","og_image":[{"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2020\/03\/michael2.svg","type":"","width":"","height":""}],"author":"Henry Rzepa","twitter_card":"summary_large_image","twitter_misc":{"Written by":"Henry Rzepa","Estimated reading time":"1 minute"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22011#article","isPartOf":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22011"},"author":{"name":"Henry Rzepa","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281"},"headline":"Substituent effects on the mechanism of Michael 1,4-Nucleophilic addition.","datePublished":"2020-03-29T05:25:55+00:00","dateModified":"2020-04-04T05:01:10+00:00","mainEntityOfPage":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22011"},"wordCount":291,"commentCount":0,"image":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22011#primaryimage"},"thumbnailUrl":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2020\/03\/michael2.svg","articleSection":["Curly arrows","reaction mechanism"],"inLanguage":"en-GB","potentialAction":[{"@type":"CommentAction","name":"Comment","target":["https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22011#respond"]}]},{"@type":"WebPage","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22011","url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22011","name":"Substituent effects on the mechanism of Michael 1,4-Nucleophilic addition. - 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Many of those examples first derived from posts here. That collection\u00a0 is still available and is viewable\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":22153,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22153","url_meta":{"origin":22011,"position":1},"title":"Choreographing a chemical ballet: a story of the mechanism of 1,4-Michael addition.","author":"Henry Rzepa","date":"April 13, 2020","format":false,"excerpt":"A reaction can be thought of as molecular dancers performing moves. A choreographer is needed to organise the performance into the ballet that is a reaction mechanism. Here I explore another facet of the Michael addition of a nucleophile to a conjugated carbonyl compound. The performers this time are p-toluene\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\/2020\/04\/SC.jpg?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":7779,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=7779","url_meta":{"origin":22011,"position":2},"title":"Oxime formation from hydroxylamine and ketone: a (computational) reality check on stage one of the mechanism.","author":"Henry Rzepa","date":"September 23, 2012","format":false,"excerpt":"The mechanism of forming an oxime from nucleophilic addition of a hydroxylamine to a ketone is taught early on in most courses of organic chemistry. Here I subject the first step of this reaction to form a tetrahedral intermediate to quantum mechanical scrutiny. The first decision is to decide which\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\/09\/hydroxylamine%2Bacetone-O-1H2O-6-ring_small.gif?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":10184,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10184","url_meta":{"origin":22011,"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. These transients can often involve the creation\/annihilation of charge separation resulting from \u00a0proton transfers, something that a cyclic mechanism can avoid. Here I revisit the formation of an oxime from hydroxylamine and propanone, but with\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":"N-pre","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/04\/N-pre.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":3576,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=3576","url_meta":{"origin":22011,"position":4},"title":"The formation of cyanohydrins: re-writing the text books. ! or ?","author":"Henry Rzepa","date":"March 4, 2011","format":false,"excerpt":"Nucleophilic addition of cyanide to a ketone or aldehyde is a standard reaction for introductory organic chemistry. But is all as it seems? The reaction is often represented as below, and this seems simple enough. But attention to detail suggests that, HCN being a weak acid, there will be only\u2026","rel":"","context":"In \"acidic solutions\"","block_context":{"text":"acidic solutions","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?tag=acidic-solutions"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2011\/03\/cyano1.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":6921,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=6921","url_meta":{"origin":22011,"position":5},"title":"Transition state models for Baldwin dig(onal) ring closures.","author":"Henry Rzepa","date":"June 10, 2012","format":false,"excerpt":"This is a continuation of the previous post exploring the transition state geometries of various types of ring closure as predicted by \u00a0Baldwin's rules. I had dealt with bond formation to a trigonal (sp2) carbon; now I add a digonal (sp) example (see an interesting literature variation).\u00a0 As before, I\u2026","rel":"","context":"In \"Baldwins rules\"","block_context":{"text":"Baldwins rules","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?tag=baldwins-rules"},"img":{"alt_text":"","src":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/06\/baldwin-dig.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\/22011","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=22011"}],"version-history":[{"count":21,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/22011\/revisions"}],"predecessor-version":[{"id":22042,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/22011\/revisions\/22042"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=22011"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=22011"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=22011"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=22011"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}