{"id":6750,"date":"2012-05-19T21:58:05","date_gmt":"2012-05-19T20:58:05","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=6750"},"modified":"2012-05-19T22:05:18","modified_gmt":"2012-05-19T21:05:18","slug":"mechanism-of-the-diazomethane-alkylation-of-a-carboxylic-acid","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=6750","title":{"rendered":"Mechanism of the diazomethane alkylation of a carboxylic acid."},"content":{"rendered":"
\n

Many reaction mechanisms involve a combination of bond formation\/cleavage between two non-hydrogen atoms and those involving reorganisation of proximate hydrogens. The Baeyer-Villiger discussed previously<\/a> illustrated a complex dance between the two types. Here I take a look at another such mechanism, the methylation of a carboxylic acid by diazomethane.<\/p>\n

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

Text-books (or e-books<\/a>) invariably show path (a). But the Baeyer-Villiger showed us that involvement of an additional acid as a proton transfer agent via<\/em> a cyclic (7 or 11-membered) transition state was possible. So how about path (b, R=H), calculated <\/a>using wB97XD\/6-311G(d,p)\/SCRF=dichloromethane?<\/p>\n

\"\"

Path (b) in the diazomethane alkylation of a carboxylic acid. Click for 3D animation.<\/p><\/div>\n

The IRC (intrinsic reaction coordinate) shows us the more detailed steps in the mechanistic dance. This tells us that the transition state shown above corresponds to the final stage of the reaction, path (c) in fact. The requisite reorganisation of the protons has already happened, and the reaction is happening from the zwitterionic intermediate shown in (c), with a barrier of only ~ 4 kcal\/mol from that species.<\/p>\n\n\n\n
\"\"<\/a><\/td>\n\"\"<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

The transition state<\/a> for the formation of the zwitterionic intermediate is itself shown below. One proton is clearly moving (to the carbon), but is the other? Again, an IRC is needed to tell us.\u00a0<\/p>\n\n\n\n\n
\n
\"\"

Transitions state for proton transfer, path (c). Click for 3D animation.<\/p><\/div><\/td>\n

\"\"<\/a><\/td>\n<\/tr>\n
\"\"<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

It seems that the two acid molecules do not co-operate with each other. The mechanism really does simply involve a protonation of the diazomethane by a molecule of acid to form a zwitterionic intermediate, following by attack by the anion of the acid on the diazonium cation to displace the nitrogen, path (a).\u00a0<\/p>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

Many reaction mechanisms involve a combination of bond formation\/cleavage between two non-hydrogen atoms and those involving reorganisation of proximate hydrogens. The Baeyer-Villiger discussed previously illustrated a complex dance between the two types. Here I take a look at another such mechanism, the methylation of a carboxylic acid by diazomethane. Text-books (or e-books) invariably show path […]<\/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_feature_clip_id":0,"_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":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2},"jetpack_post_was_ever_published":false},"categories":[1],"tags":[521,373],"ppma_author":[2661],"class_list":["post-6750","post","type-post","status-publish","format-standard","hentry","category-general","tag-e-books","tag-tutorial-material"],"yoast_head":"\nMechanism of the diazomethane alkylation of a carboxylic acid. - 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=6750\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Mechanism of the diazomethane alkylation of a carboxylic acid. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"Many reaction mechanisms involve a combination of bond formation\/cleavage between two non-hydrogen atoms and those involving reorganisation of proximate hydrogens. The Baeyer-Villiger discussed previously illustrated a complex dance between the two types. Here I take a look at another such mechanism, the methylation of a carboxylic acid by diazomethane. Text-books (or e-books) invariably show path […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=6750\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2012-05-19T20:58:05+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2012-05-19T21:05:18+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/05\/diazomethane2.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":"Mechanism of the diazomethane alkylation of a carboxylic acid. - 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=6750","og_locale":"en_GB","og_type":"article","og_title":"Mechanism of the diazomethane alkylation of a carboxylic acid. - Henry Rzepa's Blog","og_description":"Many reaction mechanisms involve a combination of bond formation\/cleavage between two non-hydrogen atoms and those involving reorganisation of proximate hydrogens. The Baeyer-Villiger discussed previously illustrated a complex dance between the two types. Here I take a look at another such mechanism, the methylation of a carboxylic acid by diazomethane. 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The mechanism is described in all text books of organic chemistry as involving an alkyl migration. Here I take a look at the scheme described by\u00a0Alvarez-Idaboy, Reyes\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":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/05\/bv1.svg","width":350,"height":200},"classes":[]},{"id":8246,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8246","url_meta":{"origin":6750,"position":1},"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":14161,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=14161","url_meta":{"origin":6750,"position":2},"title":"The formation of tetrahedral intermediates.","author":"Henry Rzepa","date":"June 12, 2015","format":false,"excerpt":"In the preceding post, I discussed\u00a0the reaction between mCPBA (meta-chloroperbenzoic acid) and cyclohexanone, resulting in Baeyer-Villiger oxidation via a tetrahedral intermediate (TI). Dan Singleton, in whose group the original KIE (kinetic isotope measurements) were made, has kindly\u00a0pointed out\u00a0on this blog that his was a mixed-phase reaction, and that mechanistic comparison\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":25391,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=25391","url_meta":{"origin":6750,"position":3},"title":"Unexpected Isomerization of Oxetane-Carboxylic Acids \u2013 catalyst design.","author":"Henry Rzepa","date":"August 13, 2022","format":false,"excerpt":"Previously, a mechanism with a reasonable predicted energy was modelled for the isomerisation of an oxetane carboxylic acid to a lactone by using two further molecules of acid to transfer the proton and in the process encouraging an Sn2 reaction with inversion to open the oxetane ring. 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":6708,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=6708","url_meta":{"origin":6750,"position":4},"title":"Reductive ozonolysis: the interesting step.","author":"Henry Rzepa","date":"May 7, 2012","format":false,"excerpt":"The mechanism of the reaction of alkenes known as ozonolysis was first set out in its modern form by Criegee. The crucial steps, (a), (b) and (d), are all pericyclic cycloaddition\/eliminations. The last step (e) is known as reductive ozonolysis, and this step is often treated as an afterthought, part\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\/2012\/05\/ozonolysis.svg","width":350,"height":200},"classes":[]},{"id":14112,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=14112","url_meta":{"origin":6750,"position":5},"title":"Natural abundance kinetic isotope effects: mechanism of the Baeyer-Villiger reaction.","author":"Henry Rzepa","date":"June 10, 2015","format":false,"excerpt":"I have blogged before about the mechanism of this classical oxidation reaction. Here I further explore computed models, and whether they match the observed kinetic isotope effects (KIE) obtained using the natural-abundance method described in the previous post. There is much previous study of this rearrangement, and the issue can\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":[]}],"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","author_category":"1","first_name":"Henry","last_name":"Rzepa","user_url":"https:\/\/orcid.org\/0000-0002-8635-8390","job_title":"","description":"Henry Rzepa is Emeritus Professor of Computational Chemistry at Imperial College London."}],"_links":{"self":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/6750","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=6750"}],"version-history":[{"count":27,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/6750\/revisions"}],"predecessor-version":[{"id":6788,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/6750\/revisions\/6788"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=6750"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=6750"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=6750"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=6750"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}