{"id":18351,"date":"2017-06-01T11:34:34","date_gmt":"2017-06-01T10:34:34","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=18351"},"modified":"2022-04-10T08:04:46","modified_gmt":"2022-04-10T07:04:46","slug":"tautomeric-polymorphism","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=18351","title":{"rendered":"Tautomeric polymorphism."},"content":{"rendered":"
\n

Conformational polymorphism occurs when a compound crystallises in two polymorphs differing only in the relative orientations of flexible groups (e.g.<\/strong> Ritonavir<\/a>).[1]<\/a><\/span> At the Beilstein conference<\/a>, Ian Bruno mentioned another type; \u00a0tautomeric polymorphism<\/strong>, where a compound can crystallise in two forms differing in the position of acidic protons. Here I explore three such examples.<\/p>\n

The term occurs in the title of this article,[2]<\/a><\/span> for a compound known as\u00a0Omeprazole<\/a>.<\/p>\n

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

When the bottom structure (the 6-methoxy) is used to search the CSD, two separate series are found. The first of these is\u00a0UDAVIF (DOI:\u00a0\u00a010.5517\/ccp82qq<\/a>,\u00a0\u00a06-Methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl)-1H-benzimidazole). There is no information regarding the absolute configuration of the chiral S-centre. Although the downloaded coordinates show it as\u00a0R<\/strong> it is probably\u00a0a racemic mixture.\u00a0A\u00a0note added to the structure declares disorder: “Omeprazole exists as solid solutions of the two tautomers. The structure is mixed 5-methoxy\/6-methoxy with occupancies 0.078:0.922<\/em>“, which indicates 7.8% is present as in the upper structure above.\u00a0<\/p>\n

\"\"<\/p>\n

The second hit\u00a0is VAYXOI (DOI: 10.5517\/ccp82pp<\/a>,\u00a0rac-6-Methoxy-2-(((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-1H-benzimidazole) which now contains no disorder; the contaminating 5-methoxy tautomer is no longer present. Perhaps not quite a true tautomeric polymorph, since the 5-methoxy tautomer is never observed in pure form.<\/p>\n

This does occur with a second example. DEBFAR[3]<\/a><\/span> represents the keto form on the right which crystallises from methanol, whilst YUYDOL as the enol form on the left crystallises from n-hexane.\u00a0<\/p>\n

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

Calculations shed some light on this behaviour. DEBFAR has a computed (DOI: 10.14469\/hpc\/2591<\/a>)\u00a0\u00a0dipole moment of 11D, whereas YUYDOL (DOI: 10.14469\/hpc\/2590<\/a>) is 2.5D. In chloroform solutions (~half way between the two solvent polarities), the keto form is ~6.1 kcal\/mol lower in\u00a0\u0394G than the enol. The crystal packing for the two forms is very different and the differences in this packing must clearly amount to >6.1 kcal\/mol to over-ride the lesser stability of DEBFAR in solution.<\/p>\n

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

The final example [4]<\/a><\/span> is illustrated using scheme 2 from that article, one\u00a0entitled tautomeric species of 4-hydroxynicotinic acid:<\/em><\/p>\n

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

The original diagram has two\u00a0unfortunate bond errors which are NOT reproduced above\u00a0(and which perhaps are a good topic for discussion in tutorials with students), along with an unusual interpretation of the term tautomerism<\/strong>. The blue arrows above are mine and I suggest the isomerism between the connected species is resonance isomerism<\/strong>, and not tautomerism. So three possible different true tautomers then. Five crystal structures are reported which I list below.<\/p>\n

    \n
  1. 10.5517\/cctswjz<\/a>\u00a0(KUXPUP, 4-oxo-1,4-dihydropyridine-3-carboxylic acid, no H2<\/sub>O),\u00a0\u00a010.5517\/ccdc.csd.cc1kfyxv<\/a>\u00a0(KUXPUP01 no H2<\/sub>O) and\u00a010.5517\/ccdc.csd.cc1kfyzx<\/a>\u00a0(KUXPUP02 no H2<\/sub>O)<\/li>\n
  2. 10.5517\/ccx59s4<\/a>\u00a0(AVEMUK, 4-Oxo-1,4-dihydropyridine-3-carboxylic acid hemihydrate) and\u00a0\u00a010.5517\/ccdc.csd.cc1kfz21<\/a>\u00a0(AVEMUK01)<\/li>\n
  3. 10.5517\/ccdc.csd.cc1kfz54<\/a>\u00a0(AKIHIN,\u00a04-hydroxypyridin-1-ium-3-carboxylate monohydrate)\u00a0<\/li>\n
  4. 10.5517\/ccdc.csd.cc1kfz10<\/a>\u00a0(AKIHAF,\u00a04-hydroxypyridin-1-ium-3-carboxylate)<\/li>\n<\/ol>\n

    KUXPUP and AVEMUK differ only in the presence of one solvent water molecule and both represent tautomer\u00a02<\/strong>\u00a0above. AKIHIN and AKIHAF similarly represent tautomer 3<\/strong> above; both are represented as 3a<\/strong> in the CSD and not as\u00a03b<\/strong>. There are no examples of tautomer 1<\/strong> in the crystal structure database; it may only exist in the gas phase. So the equilibrium 2<\/strong>\u00a0\u21cc 3<\/strong>\u00a0is another genuine example of tautomeric polymorphism, with the keto form favoured by more polar solvents, as was noted for the previous example.<\/p>\n

    With this last article,[4]<\/a><\/span> comprehensive calculations at a good level were reported, including modelling the periodic cell using the Crystal<\/strong> program and including corrections such as BSSE (basis set superposition error) and dispersion terms. I was hopeful that this might lead me to something as simple as the computed dipole moments of the (isolated) species (as I reported above for the previous system), but these were not mentioned in the text of the article. Unfortunately, the supporting information also had no details of any such calculations, which left me frustrated again at how difficult it can be in (it has to be said) the vast majority of articles which report calculations to get details of such calculations.\u00a0<\/p>\n

    Tautomeric polymorphism remains a very rare phenomenon. SciFinder for example only has 19 references citing it (2 of which are to conference talks). Perhaps the most intriguing[5]<\/a><\/span> claims that 2-thiobarbituric acid has the richest collection of tautomeric polymorphs with five. Since no calculations are reported there, I might try these out and report back here.<\/p>\n

    Postscript: \u00a0<\/strong>Here is some analysis of\u00a02-thiobarbituric.<\/p>\n

      \n
    1. THBARB (DOI 10.5517\/cctbxcd<\/a>,\u00a010.5517\/cctbxfg<\/a>\u00a0 and\u00a010.5517\/cctbxgh<\/a>) are three polymorphs of\u00a0\u00a0the keto tautomer, the isolated molecule\u00a0having a small calculated dipole moment (DOI:\u00a010.14469\/hpc\/2632<\/a>).\"\"<\/li>\n
    2. PABNAJ (DOI:\u00a010.5517\/cctbxbc<\/a>) is a polymorph in the enol form, with a much larger calculated dipole moment (DOI:\u00a010.14469\/hpc\/2633<\/a>)\"\"<\/li>\n
    3. PABNIR (DOI:\u00a010.5517\/cctbxdf<\/a>) is a mixed polymorph with one enol paired with one keto form.\u00a0\"\"<\/li>\n<\/ol>\n

      The relative free-energies of the isolated molecules are 0.0 (keto) and 9.0 (enol). The keto-enol pair is 0.4 kcal\/mol more stable than the isolated components. This again shows the effect that crystal packing can have on the relative energies and also shows that a \u00a0simple inspection of the dipole moment may cast light on the polymorphism.<\/p>\n

       <\/p>\n

      <\/p>\n

      References<\/h2>\n
      1. G.J.O. Beran, I.J. Sugden, C. Greenwell, D.H. Bowskill, C.C. Pantelides, and C.S. Adjiman, \"How many more polymorphs of ROY remain undiscovered\", Chemical Science<\/i>, vol. 13, pp. 1288-1297, 2022. https:\/\/doi.org\/10.1039\/d1sc06074k<\/a>\n\n<\/li>\n
      2. P.M. Bhatt, and G.R. Desiraju, \"Tautomeric polymorphism in omeprazole\", Chemical Communications<\/i>, pp. 2057, 2007. https:\/\/doi.org\/10.1039\/b700506g<\/a>\n\n<\/li>\n
      3. Y. Akama, M. Shiro, T. Ueda, and M. Kajitani, \"Keto and Enol Tautomers of 4-Benzoyl-3-methyl-1-phenyl-5(2H)-pyrazolone\", Acta Crystallographica Section C Crystal Structure Communications<\/i>, vol. 51, pp. 1310-1314, 1995. https:\/\/doi.org\/10.1107\/s0108270194007389<\/a>\n\n<\/li>\n
      4. S. Long, M. Zhang, P. Zhou, F. Yu, S. Parkin, and T. Li, \"Tautomeric Polymorphism of 4-Hydroxynicotinic Acid\", Crystal Growth & Design<\/i>, vol. 16, pp. 2573-2580, 2016. https:\/\/doi.org\/10.1021\/acs.cgd.5b01639<\/a>\n\n<\/li>\n
      5. M. Chierotti, L. Ferrero, N. Garino, R. Gobetto, L. Pellegrino, D. Braga, F. Grepioni, and L. Maini, \"The Richest Collection of Tautomeric Polymorphs: The Case of 2\u2010Thiobarbituric Acid\", Chemistry \u2013 A European Journal<\/i>, vol. 16, pp. 4347-4358, 2010. https:\/\/doi.org\/10.1002\/chem.200902485<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

        Conformational polymorphism occurs when a compound crystallises in two polymorphs differing only in the relative orientations of flexible groups (e.g. Ritonavir). At the Beilstein conference, Ian Bruno mentioned another type; \u00a0tautomeric polymorphism, where a compound can crystallise in two forms differing in the position of acidic protons. Here I explore three such examples. The term […]<\/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":[2,1745],"tags":[1395,2218,2119,2128,1014,145,2167,1665,1978,1976,2217,2216],"ppma_author":[2661],"class_list":["post-18351","post","type-post","status-publish","format-standard","hentry","category-chemical-it","category-crystal_structure_mining","tag-chemistry","tag-chloroform-solutions","tag-conformational-isomerism","tag-crystal","tag-crystallography","tag-gas-phase","tag-ian-bruno","tag-isomerism","tag-polymorphism","tag-ritonavir","tag-s-centre","tag-tautomer"],"yoast_head":"\nTautomeric polymorphism. - 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=18351\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Tautomeric polymorphism. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"Conformational polymorphism occurs when a compound crystallises in two polymorphs differing only in the relative orientations of flexible groups (e.g. Ritonavir). 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Did this idea first surface 100 years ago?","author":"Henry Rzepa","date":"February 9, 2016","format":false,"excerpt":"The phenomenon of bond stretch isomerism, two isomers of a compound differing predominantly in just one bond length, is one of those chemical concepts that wax and occasionally\u00a0wane. Here I explore such isomerism for the elements Ge, Sn and Pb. In one earlier post, I noted a form of\u00a0bond stretch\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":"lewis1","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2016\/02\/lewis1-1-1024x421.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":23434,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=23434","url_meta":{"origin":18351,"position":2},"title":"Deltamethrin – a polymorphed insecticide.","author":"Henry Rzepa","date":"March 24, 2021","format":false,"excerpt":"Deltamethin is a pyrethroid insecticide for control of malaria which has been used for a little while. Perhaps inevitably, mosquitoes are developing resistance to it. So what could be done about countering this? Well, perhaps surprisingly, form a polymorph!\u00a0These crystal structure isomers are often highly undesirable; thus\u00a0Ritonavir, which changed its\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\/2021\/03\/Screenshot-643-1024x716.jpg?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":13353,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=13353","url_meta":{"origin":18351,"position":3},"title":"Chiroptical spectroscopy of the natural product Steganone.","author":"Henry Rzepa","date":"February 10, 2015","format":false,"excerpt":"Steganone is an unusual natural product, known for about 40 years now. The assignment of its absolute configurations makes for an interesting, on occasion rather confusing, and perhaps not entirely atypical story. I will start with the modern accepted stereochemical structure of this molecule, which comes in the form of\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":[]},{"id":26962,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=26962","url_meta":{"origin":18351,"position":4},"title":"Detecting anomeric effects in tetrahedral boron bearing four oxygen substituents.","author":"Henry Rzepa","date":"April 30, 2024","format":false,"excerpt":"In an earlier post, I discussed a phenomenon known as the \"anomeric effect\" exhibited by tetrahedral carbon compounds with four C-O bonds. Each oxygen itself bears two bonds and has two lone pairs, and either of these can align with one of three other C-O bonds to generate an anomeric\u2026","rel":"","context":"Similar post","block_context":{"text":"Similar post","link":""},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2024\/04\/Screenshot-304.jpg?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2024\/04\/Screenshot-304.jpg?resize=350%2C200&ssl=1 1x, https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2024\/04\/Screenshot-304.jpg?resize=525%2C300&ssl=1 1.5x, https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2024\/04\/Screenshot-304.jpg?resize=700%2C400&ssl=1 2x"},"classes":[]},{"id":17063,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=17063","url_meta":{"origin":18351,"position":5},"title":"The largest C-C-C angle?","author":"Henry Rzepa","date":"November 1, 2016","format":false,"excerpt":"I am now inverting the previous question by asking what is the largest angle subtended at a chain of three connected 4-coordinate carbon atoms? Let's see if further interesting chemistry can be unearthed. Specifying only angles > 130\u00b0, the following distribution is obtained. Note the maximum at ~138\u00b0. This is\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":"vajhap","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2016\/10\/VAJHAP.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\/18351","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=18351"}],"version-history":[{"count":43,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/18351\/revisions"}],"predecessor-version":[{"id":25042,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/18351\/revisions\/25042"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=18351"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=18351"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=18351"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=18351"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}