{"id":8761,"date":"2012-12-20T11:28:35","date_gmt":"2012-12-20T11:28:35","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=8761"},"modified":"2021-01-20T08:04:29","modified_gmt":"2021-01-20T08:04:29","slug":"vitamin-b12-and-the-genesis-of-a-new-theory-of-chemistry","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761","title":{"rendered":"Vitamin B12 and the genesis of a new theory of chemistry."},"content":{"rendered":"
\n

I have written earlier about dihydrocostunolide<\/a>, and how in 1963 Corey missed spotting the electronic origins of a key step in its synthesis.[1]<\/a><\/span>. A nice juxtaposition to this failed opportunity relates to Woodward’s project at around the same time to synthesize vitamin B12. The step in the synthesis that caused him to ponder is shown below.<\/p>\n

\"p2\"<\/p>\n

In the 1950s, Linus Pauling was the shining example in the use of model building in chemistry, and the so-called CPK<\/a> (Corey, Pauling and Koltun) model was being adopted by most synthetic chemists as a part of the design of their syntheses (I have argued <\/a>that the progenitor of the CPK model was in fact created by Loschmidt, in 1860). These were physical models, and it is quite likely that Woodward would have used one to ponder the conversion shown above as G\u00a0\u21d2 J or H. As you can read from the quote above (taken from\u00a0\u00a0Chem. Soc. Special Publications (Aromaticity)<\/i>,\u00a01967<\/b>,\u00a021<\/i>, 217, a document not available online), he had concluded that\u00a0G\u00a0\u21d2 J was more likely than\u00a0G\u00a0\u21d2 H, and so was considerably surprised when the reaction actually proceeded to give the latter and not the former. In fact, photolysis of (the undesired) H gave I, which then did give (the desired) J upon heating, so he got what he wanted in the end (he usually did!). Of course, we now know that this electrocyclisation proceeds under what is sometimes called orbital control (as explained by Woodward and Hoffmann[2]<\/a><\/span>) and what can also be taught as a manifestation of transition state aromaticity[3]<\/a><\/span>.<\/p>\n

For this blog, I do not want to investigate the transition states, but just to update Woodward’s use of physical (possibly CPK) models to predict the outcome of reactions. CPK models are characterised by their use of van der Waals radii for the atom spheres, the so-called space-filling representation, and as such they are in effect looking at the repulsive steric interactions (the 12 of the 6-12 potential). What they do not do is measure the attractive dispersion contributions to the model. I had suggested<\/a> that differential dispersion contributions may be a (dominant?) factor in explaining why Sharpless epoxidation goes enantioselectively. With this in mind, I optimized the geometry of species H<\/a> and J<\/a> above at a dispersion and solvent-corrected level of theory (\u03c9B97XD\/6-311G(d,p)\/SCRF=dichloromethane) to see if the relative stabilities of the products might agree with Woodward’s prediction that J should have formed.<\/p>\n\n\n\n\n
\u0394G 0.0 kcal\/mol<\/td>\n\u0394G +1.0 kcal\/mol<\/td>\n<\/tr>\n
\n
\"H.

H. Click for 3D<\/p><\/div>\n<\/td>\n

\n
\"J.

J. Click for 3D.<\/p><\/div>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

This computation shows that H is the lower in free energy by 1.0 kcal\/mol, and by 0.8 kcal\/mol in dispersion energy. So Woodward’s hypothesis that J was the more likely to form on steric grounds is not supported by this modern equivalent of a CPK model. I should add that a CPK model may only take an hour or so to build (but possibly weeks to order the components) whereas this quantum model took around 9 hours to compute.\u00a0<\/p>\n

References<\/h2>\n
  1. E.J. Corey, and A.G. Hortmann, \"The Total Synthesis of Dihydrocostunolide\", Journal of the American Chemical Society<\/i>, vol. 87, pp. 5736-5742, 1965. https:\/\/doi.org\/10.1021\/ja00952a037<\/a>\n\n<\/li>\n
  2. R.B. Woodward, and R. Hoffmann, \"Stereochemistry of Electrocyclic Reactions\", Journal of the American Chemical Society<\/i>, vol. 87, pp. 395-397, 1965. https:\/\/doi.org\/10.1021\/ja01080a054<\/a>\n\n<\/li>\n
  3. H.S. Rzepa, \"The Aromaticity of Pericyclic Reaction Transition States\", Journal of Chemical Education<\/i>, vol. 84, pp. 1535, 2007. https:\/\/doi.org\/10.1021\/ed084p1535<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    I have written earlier about dihydrocostunolide, and how in 1963 Corey missed spotting the electronic origins of a key step in its synthesis.. A nice juxtaposition to this failed opportunity relates to Woodward’s project at around the same time to synthesize vitamin B12. The step in the synthesis that caused him to ponder is shown […]<\/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":[4,559,1086],"tags":[391,40,2651,2650],"ppma_author":[2661],"class_list":["post-8761","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry","category-pericyclic","category-reaction-mechanism-2","tag-dispersion-energy","tag-free-energy","tag-historical","tag-pericyclic"],"yoast_head":"\nVitamin B12 and the genesis of a new theory of chemistry. - 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=8761\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Vitamin B12 and the genesis of a new theory of chemistry. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"I have written earlier about dihydrocostunolide, and how in 1963 Corey missed spotting the electronic origins of a key step in its synthesis.. A nice juxtaposition to this failed opportunity relates to Woodward’s project at around the same time to synthesize vitamin B12. The step in the synthesis that caused him to ponder is shown […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2012-12-20T11:28:35+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2021-01-20T08:04:29+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/12\/p2.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":"Vitamin B12 and the genesis of a new theory of chemistry. - 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=8761","og_locale":"en_GB","og_type":"article","og_title":"Vitamin B12 and the genesis of a new theory of chemistry. - Henry Rzepa's Blog","og_description":"I have written earlier about dihydrocostunolide, and how in 1963 Corey missed spotting the electronic origins of a key step in its synthesis.. A nice juxtaposition to this failed opportunity relates to Woodward’s project at around the same time to synthesize vitamin B12. The step in the synthesis that caused him to ponder is shown […]","og_url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761","og_site_name":"Henry Rzepa's Blog","article_published_time":"2012-12-20T11:28:35+00:00","article_modified_time":"2021-01-20T08:04:29+00:00","og_image":[{"url":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/12\/p2.svg","type":"","width":"","height":""}],"author":"Henry Rzepa","twitter_card":"summary_large_image","twitter_misc":{"Written by":"Henry Rzepa","Estimated reading time":"3 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761#article","isPartOf":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761"},"author":{"name":"Henry Rzepa","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281"},"headline":"Vitamin B12 and the genesis of a new theory of chemistry.","datePublished":"2012-12-20T11:28:35+00:00","dateModified":"2021-01-20T08:04:29+00:00","mainEntityOfPage":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761"},"wordCount":537,"commentCount":0,"image":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761#primaryimage"},"thumbnailUrl":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/12\/p2.svg","keywords":["dispersion energy","free energy","Historical","pericyclic"],"articleSection":["Interesting chemistry","pericyclic","reaction mechanism"],"inLanguage":"en-GB","potentialAction":[{"@type":"CommentAction","name":"Comment","target":["https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761#respond"]}]},{"@type":"WebPage","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761","url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761","name":"Vitamin B12 and the genesis of a new theory of chemistry. - Henry Rzepa's Blog","isPartOf":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#website"},"primaryImageOfPage":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761#primaryimage"},"image":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761#primaryimage"},"thumbnailUrl":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/12\/p2.svg","datePublished":"2012-12-20T11:28:35+00:00","dateModified":"2021-01-20T08:04:29+00:00","author":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281"},"breadcrumb":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761#breadcrumb"},"inLanguage":"en-GB","potentialAction":[{"@type":"ReadAction","target":["https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761"]}]},{"@type":"ImageObject","inLanguage":"en-GB","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761#primaryimage","url":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/12\/p2.svg","contentUrl":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/12\/p2.svg"},{"@type":"BreadcrumbList","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8761#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog"},{"@type":"ListItem","position":2,"name":"Vitamin B12 and the genesis of a new theory of chemistry."}]},{"@type":"WebSite","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#website","url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/","name":"Henry Rzepa's Blog","description":"Chemistry with a twist","potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-GB"},{"@type":"Person","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281","name":"Henry Rzepa","image":{"@type":"ImageObject","inLanguage":"en-GB","@id":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g370be3a7397865e4fd161aefeb0a5a85","url":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","contentUrl":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","caption":"Henry Rzepa"},"description":"Henry Rzepa is Emeritus Professor of Computational Chemistry at Imperial College London.","sameAs":["https:\/\/orcid.org\/0000-0002-8635-8390"],"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?author=1"}]}},"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/pDef7-2hj","jetpack-related-posts":[{"id":5763,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=5763","url_meta":{"origin":8761,"position":0},"title":"So near and yet so far. The story of the electrocyclic ring opening of a cyclohexadiene.","author":"Henry Rzepa","date":"December 6, 2011","format":false,"excerpt":"My previous three posts set out my take on three principle categories of pericyclic reaction. Here I tell a prequel to the understanding of these reactions. In 1965, Woodward and Hoffmann in their theoretical analysis (submitted Nov 30, 1964) for which the Nobel prize (to Hoffmann only of the pair,\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\/2011\/12\/ht.gif?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":23319,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=23319","url_meta":{"origin":8761,"position":1},"title":"The thermal reactions \u2026 took precisely the opposite stereochemical course to that which we had predicted. A non-covalent-interaction view of the model.","author":"Henry Rzepa","date":"February 3, 2021","format":false,"excerpt":"Another foray into one of the more famous anecdotal chemistry \"models\", the analysis of which led directly to the formulation of the WoodWard-Hoffmann (stereochemical) rules for pericyclic reactions. Previously, I tried to produce a modern computer model of what Woodward might have had to hand when discovering that the stereochemical\u2026","rel":"","context":"In "Historical"","block_context":{"text":"Historical","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=565"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2021\/02\/yes.jpg?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":23281,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=23281","url_meta":{"origin":8761,"position":2},"title":"The Stevens rearrangement: how history gives us new insights.","author":"Henry Rzepa","date":"January 29, 2021","format":false,"excerpt":"In a recent post, I told the story of how in the early 1960s, Robert Woodward had encountered an unexpected stereochemical outcome to the reaction of a hexatriene, part of his grand synthesis of vitamin B12. He had constructed a model of the reaction he wanted to undertake, perhaps with\u2026","rel":"","context":"In "Historical"","block_context":{"text":"Historical","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=565"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2021\/01\/sden.jpg?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":23203,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=23203","url_meta":{"origin":8761,"position":3},"title":"The thermal reactions … took precisely the opposite stereochemical course to that which we had predicted","author":"Henry Rzepa","date":"January 20, 2021","format":false,"excerpt":"The quote of the post title comes from R. B. Woodward explaining the genesis of the discovery of what are now known as the Woodward-Hoffmann rules for pericyclic reactions. I first wrote about this in 2012, noting that \"for (that) blog, I do not want to investigate the transition states\".\u00a0Here\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\/2021\/01\/Screenshot-515-300x215.jpg?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":3802,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=3802","url_meta":{"origin":8761,"position":4},"title":"Why are \u03b1-helices in proteins mostly right handed?","author":"Henry Rzepa","date":"April 9, 2011","format":false,"excerpt":"Understanding why and how proteins fold continues to be a grand challenge in science. I have described how Wrinch in 1936 made a bold proposal for the mechanism, which however flew in the face of much of then known chemistry. Linus Pauling took most of the credit (and a Nobel\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\/2011\/04\/left-n.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":31375,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=31375","url_meta":{"origin":8761,"position":5},"title":"A breakthrough in Molecular Solar Thermal (MOST) energy storage – Dewar Pyrimidone.","author":"Henry Rzepa","date":"May 14, 2026","format":false,"excerpt":"MOST is a chemical method of converting photonic or light energy into storable thermal energy which can be released on demand. A recent breakthrough in such methods has been reported in which a pyrimidone molecule is efficiently converted by 310nm light into the isomeric Dewar pyrimidone. This molecule is thermally\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":[]}],"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\/8761","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=8761"}],"version-history":[{"count":15,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/8761\/revisions"}],"predecessor-version":[{"id":23208,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/8761\/revisions\/23208"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=8761"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=8761"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=8761"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=8761"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}