{"id":12705,"date":"2014-07-05T09:42:47","date_gmt":"2014-07-05T08:42:47","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=12705"},"modified":"2014-07-06T07:47:07","modified_gmt":"2014-07-06T06:47:07","slug":"the-5%cf%83-confidence-level-how-much-chemistry-achieves-this","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=12705","title":{"rendered":"The 5\u03c3-confidence level: how much chemistry achieves this?"},"content":{"rendered":"
\n

I was lucky enough to attend the announcement made in 2012 of the discovery of the Higgs Boson. It consisted of a hour-long talk mostly about statistics, and how the particle physics community can only claim a discovery when their data has\u00a0achieved a 5\u03c3 confidence level<\/a>. This represents a 1 in 3.5 million probability of the result occurring by chance. I started thinking: how much chemistry is asserted at that level of confidence? Today, I read Steve Bachrach’s post on the structure of Citrinalin B<\/a>\u00a0and how “use of Goodman\u2019s DP4 method indicates a 100% probability that the structure of citrinalin B is (the structure below)”.<\/em>\u00a0Wow, that is even higher than the physicists. Of course, 100% has been obtained by rounding 99.7 (3\u03c3 is 99.73%<\/a>) or whatever (this is one number that should never be so rounded!). \"pc\" But there was one aspect of this that I did want to have a confidence level for; the absolute configuration<\/strong> of citrinalin B. Reading the article Steve quotes[1]<\/a><\/span>,\u00a0one sees this aspect is attributed to ref 5[2]<\/a><\/span>, dating from 2005. There the configuration was assigned on the basis of “comparison of the electronic circular dichroism (ECD) spectra for 1 and 2 with those of known spirooxiindole alkaloids<\/i>“. However, this method can fail[3]<\/a><\/span>. Also, one finds “comparison of the vibrational circular dichroism (VCD) spectra of 1 with those of model compounds<\/i>“[2]<\/a><\/span>. Nowadays, one would say that there is no need for model compounds, why not measure and compute the VCD of the actual compound? Even a determination using the Flack crystallographic method can occasionally be wrong![4]<\/a><\/span>. Which leads to asking what typical confidence levels might be for these three techniques, and indeed whether improving instrumentation means that the confidence level gets higher with time. OK, I am going to guess these.<\/p>\n

    \n
  1. I think the confidence level for assigning absolute configurations on the basis of ECD analogy with other compounds is the lowest of all the methods. Around 1\u03c3 or 68.3% (and this mostly from additional information such as the chemical transforms performed from starting materials of known absolute configuration).<\/li>\n
  2. VCD is higher. If performed on the actual compound, I think it can be as high as 2-3\u03c3 or 95.5-99.7%. It is difficult to know how much of this certainty is lost by using only model compounds.<\/li>\n
  3. Flack analysis (of anomalous X-ray)[5]<\/a><\/span> is probably also at\u00a02-3\u03c3; I suggest however that a fair bit of uncertainly not included in the 2-3\u03c3 probably arises from analysing a tiny crystal (1 \u00b5g) arising from a solution perhaps 10,000 times larger in weight of sample.<\/li>\n
  4. And of course combining the uncertainties from multiple experiments reduces it overall.<\/li>\n<\/ol>\n

    I am not casting any doubts on an assigned absolute configuration on which that of citrinalin B is based, as done in 2005. I have no grounds to think it is wrongly assigned. I am merely suggesting that in 2014, one\u00a0should be able to\u00a0achieve an even greater confidence level. And do what the physicists do, try to estimate the confidence level attained. I wonder how much chemistry would match the physicists\u00a05\u03c3-confidence level (99.99994%)<\/span>?<\/p>\n

    References<\/h2>\n
    1. E.V. Mercado-Marin, P. Garcia-Reynaga, S. Romminger, E.F. Pimenta, D.K. Romney, M.W. Lodewyk, D.E. Williams, R.J. Andersen, S.J. Miller, D.J. Tantillo, R.G.S. Berlinck, and R. Sarpong, \"Total synthesis and isolation of citrinalin and cyclopiamine congeners\", Nature<\/i>, vol. 509, pp. 318-324, 2014. https:\/\/doi.org\/10.1038\/nature13273<\/a>\n\n<\/li>\n
    2. T. Mugishima, M. Tsuda, Y. Kasai, H. Ishiyama, E. Fukushi, J. Kawabata, M. Watanabe, K. Akao, and J. Kobayashi, \"Absolute Stereochemistry of Citrinadins A and B from Marine-Derived Fungus\", The Journal of Organic Chemistry<\/i>, vol. 70, pp. 9430-9435, 2005. https:\/\/doi.org\/10.1021\/jo051499o<\/a>\n\n<\/li>\n
    3. F. Cherblanc, Y. Lo, E. De\u2005Gussem, L. Alcazar\u2010Fuoli, E. Bignell, Y. He, N. Chapman\u2010Rothe, P. Bultinck, W.A. Herrebout, R. Brown, H.S. Rzepa, and M.J. Fuchter, \"On the Determination of the Stereochemistry of Semisynthetic Natural Product Analogues using Chiroptical Spectroscopy: Desulfurization of Epidithiodioxopiperazine Fungal Metabolites\", Chemistry \u2013 A European Journal<\/i>, vol. 17, pp. 11868-11875, 2011. https:\/\/doi.org\/10.1002\/chem.201101129<\/a>\n\n<\/li>\n
    4. F.L. Cherblanc, Y. Lo, W.A. Herrebout, P. Bultinck, H.S. Rzepa, and M.J. Fuchter, \"Mechanistic and Chiroptical Studies on the Desulfurization of Epidithiodioxopiperazines Reveal Universal Retention of Configuration at the Bridgehead Carbon Atoms\", The Journal of Organic Chemistry<\/i>, vol. 78, pp. 11646-11655, 2013. https:\/\/doi.org\/10.1021\/jo401316a<\/a>\n\n<\/li>\n
    5. H.D. Flack, and G. Bernardinelli, \"The use of X\u2010ray crystallography to determine absolute configuration\", Chirality<\/i>, vol. 20, pp. 681-690, 2007. https:\/\/doi.org\/10.1002\/chir.20473<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

      I was lucky enough to attend the announcement made in 2012 of the discovery of the Higgs Boson. It consisted of a hour-long talk mostly about statistics, and how the particle physics community can only claim a discovery when their data has\u00a0achieved a 5\u03c3 confidence level. This represents a 1 in 3.5 million probability of […]<\/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":[1],"tags":[27,1242,20,42],"ppma_author":[2661],"class_list":["post-12705","post","type-post","status-publish","format-standard","hentry","category-general","tag-chemical","tag-reading","tag-steve-bachrach","tag-x-ray"],"yoast_head":"\nThe 5\u03c3-confidence level: how much chemistry achieves this? - 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=12705\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"The 5\u03c3-confidence level: how much chemistry achieves this? - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"I was lucky enough to attend the announcement made in 2012 of the discovery of the Higgs Boson. 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