{"id":21472,"date":"2019-11-26T07:38:11","date_gmt":"2019-11-26T07:38:11","guid":{"rendered":"https:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=21472"},"modified":"2019-12-01T08:23:04","modified_gmt":"2019-12-01T08:23:04","slug":"the-structure-of-tetrodotoxin-as-a-free-base-with-a-better-solvation-model","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21472","title":{"rendered":"The Structure of Tetrodotoxin as a free base – with a better solvation model."},"content":{"rendered":"
\n

In the previous post<\/a>, I discussed the structure of the free base form of tetrodotoxin, often represented as originally suggested by Woodward[1]<\/a><\/span> below in an ionic form:<\/p>\n

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

Quantum calculations suggested that this form was higher in energy than neutral forms devoid of the zwitterionic charge separation in a relatively non polar solvent such as chloroform. For this, a so-called continuum solvation model was used. But even chloroform is capable of forming rather strong O…H-C hydrogen bonds<\/a>, and these specific isotropic interactions are not well modelled using a continuum solvent; you need to include the specific hydrogen bonds to do that. So here are two better models, the first including one or two chloroform molecules (in continuum chloroform) and the second three water molecules (in continuum water). The (FAIR) data for these results are available at\u00a0DOI: 10.14469\/hpc\/6278<\/a> and you can view the 3D models by clicking on the images below.<\/p>\n\n\n\n\n\n
System<\/th>\n\u0394\u0394G298<\/sub>, + 1CHCl3<\/sub><\/th>\n\u0394\u0394G298<\/sub>, + 2CHCl3<\/sub><\/th>\n\u0394\u0394G298<\/sub>, + 3H2<\/sub>O<\/th>\n<\/tr>\n
Ionic form<\/td>\n0.0<\/td>\n0.0<\/td>\n0.0<\/td>\n<\/tr>\n
non-ionic form<\/td>\n-7.1<\/td>\n-4.9<\/td>\n+1.5<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Adding additional solvent molecules in a “non-stochastic” manner is clearly an approximation. For example, three water molecules added to the neutral (non-zwitterionic) form could take up residency in many different ways, given the number of oxygen atoms present in tetrodotoxin. The energies reported above are for the lowest energy forms of the two that I located; I did not investigate more possibilities. However, the ionic form, with the water molecules directly hydrogen bonding with the ionic oxygen are more certain.
\n

\"\"

Ionic form: Click image to view 3D model<\/p><\/div>

\"\"

Neutral form: Click image to view 3D model<\/p><\/div><\/p>\n

So we now see that Woodward’s original proposal for a charge-separated ionic form for the free base of tetrodotoxin may indeed be accurate, but only for polar solutions such as water. In rather less polar solutions such as chloroform it is probably not ionic. Clearly the stability also depends on the number of solvent molecules included in the model. The rather large chloroform molecule is less likely to accumulate around the ionic oxygen in numbers >>2 (and including more makes the calculation much slower), but already with just three water molecules the ionic form becomes the more stable. Also, e.g.<\/i> two chloroforms or merely three waters are insufficient to form any sort of stabilizing “bridge” connecting the two ionic centres. So these results must be treated with a little caution. <\/p>\n

It is always rather risky to bet against Woodward’s chemical intuitions and insights (as for example Robinson found when debating the structure of strychnine[2]<\/a><\/span> with him). He may well have been correct with the ionic structure of tetrodotoxin as well (at least in aqueous solutions)!<\/p>\n

References<\/h2>\n
  1. R.B. Woodward, \"The structure of tetrodotoxin\", Pure and Applied Chemistry<\/i>, vol. 9, pp. 49-74, 1964. https:\/\/doi.org\/10.1351\/pac196409010049<\/a>\n\n<\/li>\n
  2. R.B. Woodward, M.P. Cava, W.D. Ollis, A. Hunger, H.U. Daeniker, and K. Schenker, \"THE TOTAL SYNTHESIS OF STRYCHNINE\", Journal of the American Chemical Society<\/i>, vol. 76, pp. 4749-4751, 1954. https:\/\/doi.org\/10.1021\/ja01647a088<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    In the previous post, I discussed the structure of the free base form of tetrodotoxin, often represented as originally suggested by Woodward below in an ionic form: Quantum calculations suggested that this form was higher in energy than neutral forms devoid of the zwitterionic charge separation in a relatively non polar solvent such as chloroform. […]<\/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,"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}},"categories":[4],"tags":[],"ppma_author":[2661],"class_list":["post-21472","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry"],"yoast_head":"\nThe Structure of Tetrodotoxin as a free base - with a better solvation model. - 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=21472\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"The Structure of Tetrodotoxin as a free base - with a better solvation model. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"In the previous post, I discussed the structure of the free base form of tetrodotoxin, often represented as originally suggested by Woodward below in an ionic form: Quantum calculations suggested that this form was higher in energy than neutral forms devoid of the zwitterionic charge separation in a relatively non polar solvent such as chloroform. […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21472\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2019-11-26T07:38:11+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2019-12-01T08:23:04+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2019\/11\/tetrodo.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 Structure of Tetrodotoxin as a free base - with a better solvation model. - 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=21472","og_locale":"en_GB","og_type":"article","og_title":"The Structure of Tetrodotoxin as a free base - with a better solvation model. - Henry Rzepa's Blog","og_description":"In the previous post, I discussed the structure of the free base form of tetrodotoxin, often represented as originally suggested by Woodward below in an ionic form: Quantum calculations suggested that this form was higher in energy than neutral forms devoid of the zwitterionic charge separation in a relatively non polar solvent such as chloroform. […]","og_url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21472","og_site_name":"Henry Rzepa's Blog","article_published_time":"2019-11-26T07:38:11+00:00","article_modified_time":"2019-12-01T08:23:04+00:00","og_image":[{"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2019\/11\/tetrodo.svg","type":"","width":"","height":""}],"author":"Henry Rzepa","twitter_card":"summary_large_image","twitter_misc":{"Written by":"Henry Rzepa","Estimated reading time":"2 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21472#article","isPartOf":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21472"},"author":{"name":"Henry Rzepa","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281"},"headline":"The Structure of Tetrodotoxin as a free base – with a better solvation model.","datePublished":"2019-11-26T07:38:11+00:00","dateModified":"2019-12-01T08:23:04+00:00","mainEntityOfPage":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21472"},"wordCount":473,"commentCount":0,"image":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21472#primaryimage"},"thumbnailUrl":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2019\/11\/tetrodo.svg","articleSection":["Interesting chemistry"],"inLanguage":"en-GB","potentialAction":[{"@type":"CommentAction","name":"Comment","target":["https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21472#respond"]}]},{"@type":"WebPage","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21472","url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21472","name":"The Structure of Tetrodotoxin as a free base - 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This post was inspired by reading Steve Bachrach's post, itself alluding to this aspect in the title \"Computationally handling ion pairs\". It references this recent article on the topic in which\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":17089,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=17089","url_meta":{"origin":21472,"position":1},"title":"Hydrogen bonding to chloroform.","author":"Henry Rzepa","date":"November 14, 2016","format":false,"excerpt":"Chloroform, often in the deuterated form CDCl3, is a very common solvent for NMR and other types of spectroscopy. Quantum mechanics\u00a0is increasingly used to calculate such spectra to aid assignment and the solvent is here normally simulated as a continuum rather than by explicit inclusion of one or more chloroform\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":"","width":0,"height":0},"classes":[]},{"id":20886,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=20886","url_meta":{"origin":21472,"position":2},"title":"An Ambimodal Trispericyclic Transition State: the effect of solvation?","author":"Henry Rzepa","date":"May 2, 2019","format":false,"excerpt":"Ken Houk's group has recently published this study of cycloaddition reactions, using a combination of classical transition state location followed by molecular dynamics trajectory calculations, and to which Steve Bachrach's blog alerted me. The reaction struck me as being quite polar (with cyano groups) and so I took a look\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":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2019\/04\/Screenshot-32-1024x662.jpg?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":25043,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=25043","url_meta":{"origin":21472,"position":3},"title":"Geometries of proton transfers: modelled using total energy or free energy?","author":"Henry Rzepa","date":"April 18, 2022","format":false,"excerpt":"Proton transfers are amongst the most common of all chemical reactions. They are often thought of as \"trivial\" and even may not feature in many mechanistic schemes, other than perhaps the notation \"PT\".\u00a0The types with the lowest energy barriers for transfer often involve heteroatoms such as N and O, and\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\/2022\/04\/plot-1024x734.png?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":21436,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21436","url_meta":{"origin":21472,"position":4},"title":"The Structure of Tetrodotoxin as a free base.","author":"Henry Rzepa","date":"November 9, 2019","format":false,"excerpt":"The notorious neurotoxin Tetrodotoxin is often chemically represented as a zwitterion, shown below as 1. This idea seems to originate from a famous article written in 1964 by the legendary organic chemist, Robert Burns Woodward. This structure has propagated on to Wikipedia and is found in many other sources. 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":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2019\/11\/MEP-1024x749.jpg?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":1135,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=1135","url_meta":{"origin":21472,"position":5},"title":"The SN1 Reaction- revisited","author":"Henry Rzepa","date":"November 11, 2009","format":false,"excerpt":"In an earlier post I wrote about the iconic SN1 solvolysis reaction, and presented a model for the transition state involving 13 water molecules. Here, I follow this up with an improved molecule containing 16 water molecules, and how the barrier for this model compares with experiment. This latter is\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":"Transition state for Sn1 solvolysis of tert-butyl chloride","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/11\/sn1.jpg?resize=350%2C200","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\/21472","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=21472"}],"version-history":[{"count":10,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/21472\/revisions"}],"predecessor-version":[{"id":21536,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/21472\/revisions\/21536"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=21472"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=21472"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=21472"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=21472"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}