{"id":6998,"date":"2012-07-05T11:30:51","date_gmt":"2012-07-05T10:30:51","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=6998"},"modified":"2012-07-24T10:42:21","modified_gmt":"2012-07-24T09:42:21","slug":"connections-in-chemistry-anti-malaria-drug-%e2%86%94-organocatalysis","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=6998","title":{"rendered":"Connections in chemistry. Anti-malaria drug \u2194 organocatalysis."},"content":{"rendered":"
\n

Back in 1994, we published the crystal structure of the molecule below (X=H), a putative anti-malarial drug called halofantrine<\/strong>. Little did we realise that a whole area of organo catalysis based on a thiourea catalyst with a similar motif would emerge a little later. Here is how the two are connected.<\/p>\n

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

In our original article<\/a>\u00a0we described how our interest was sparked by observing the following chiral HPLC behaviour. The two enantiomers of compound 2<\/strong>\u00a0(X=Y=Cl) separated nicely on the column. So did the compound where X=Cl, Y=H (4<\/strong>). However, when X=H,Y=Cl specifically (3<\/strong>), all chiral recognition on the column vanished! What was the reason?<\/p>\n

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

As it happens, we had recently acquired our stereoscopic CAChe system<\/a>, and the structure was loaded into this. After a little while, we noticed that the compound formed a complementary dimer, glued together by C-H…O hydrogen bonds (magenta arrows below). When the H is replaced by Cl, this edge-on dimeric structure is completely destroyed, and is replaced by \u03c0-\u03c0 stacking instead.\u00a0<\/p>\n

\"\"

The dimeric structure of Halofantrine. Click for 3D<\/p><\/div>\n

The significance is that the hydrogen atom specifically antiperiplanar to the electron withdrawing CF3<\/sub> group was the one forming the C-H…O hydrogen bond (quite a short one as it happens, see 3D above). This despite 7-bonds separating the H-C from the CF3<\/sub> group. In the article,we speculated on how this effect of acidifying the hydrogen to encourage it to form a hydrogen bond might even be augmented. On historical note, we had made the article available<\/a> using the then newly accessible World-Wide Web, providing MPEG diagrams<\/a> corresponding to the structure above. It would be reasonable to claim that this is the very first article in chemistry to have been made so available, dating from mid 1994! If anyone can find an earlier example, do let me know! You might also note the difference between the MPEG movie and the presentation now available above.\u00a0<\/p>\n

In another part of the world a few years later, Peter Schreiner and his group were exploring organocatalysts based on thiourea (see\u00a010.1021\/jo201864e<\/a> for a recent article) and in 2003 they had discovered<\/a> remarkable catalytic properties for the system below.<\/p>\n

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

As with us, they speculated that in addition to hydrogen bonds formed to substrates from the N-H groups, these could be augmented by rather weaker secondary interactions to the adjacent C-H bonds; certainly the presence of the CF3<\/sub> groups was the secret of these catalysts (now quite a family). It is tempting to conclude that both sets of observations are related by the same phenomenon!<\/p>\n

I end here by showing a QTAIM analysis<\/a> of our halofantrine system (see similar analysis<\/a> for the Pirkle reagent). The key region indicated with magenta arrows above does indeed contain bond critical points (BCPs), with values of\u00a0\u03c1(r) ~ 0.045, which is near the top of the range experienced for hydrogen bonds of this type.<\/p>\n

\"\"

QTAIM analysis, showing three bond critical points. Click for 3D.<\/p><\/div>\n

Connections like this probably permeate chemistry, and all too few of them are actually spotted.<\/p>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

Back in 1994, we published the crystal structure of the molecule below (X=H), a putative anti-malarial drug called halofantrine. Little did we realise that a whole area of organo catalysis based on a thiourea catalyst with a similar motif would emerge a little later. Here is how the two are connected. In our original article\u00a0we […]<\/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":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[2,4],"tags":[2651,857,856,894],"ppma_author":[2661],"class_list":["post-6998","post","type-post","status-publish","format-standard","hentry","category-chemical-it","category-interesting-chemistry","tag-historical","tag-mpeg","tag-peter-schreiner","tag-skolnik"],"yoast_head":"\nConnections in chemistry. Anti-malaria drug \u2194 organocatalysis. - 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=6998\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Connections in chemistry. Anti-malaria drug \u2194 organocatalysis. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"Back in 1994, we published the crystal structure of the molecule below (X=H), a putative anti-malarial drug called halofantrine. Little did we realise that a whole area of organo catalysis based on a thiourea catalyst with a similar motif would emerge a little later. Here is how the two are connected. In our original article\u00a0we […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=6998\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2012-07-05T10:30:51+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2012-07-24T09:42:21+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/07\/halofantrine.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":"Connections in chemistry. 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Let me explain the connection, but also to follow-up further\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":"FSSCl","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/09\/FSSCl.gif?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":4647,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=4647","url_meta":{"origin":6998,"position":1},"title":"Computers 1967-2011: a personal perspective. Part 3. 1990-1994.","author":"Henry Rzepa","date":"July 12, 2011","format":false,"excerpt":"In 1986 or so, molecular modelling came of age. Richard Counts, who ran an organisation called QCPE (here I had already submitted several of the program codes I had worked on) had a few years before contacted me to ask for my help with his Roadshow. He had started these\u2026","rel":"","context":"In "Chemical IT"","block_context":{"text":"Chemical IT","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2011\/07\/halofantrine.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":19569,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19569","url_meta":{"origin":6998,"position":2},"title":"Aromaticity-induced basicity.","author":"Henry Rzepa","date":"April 18, 2018","format":false,"excerpt":"The molecules below were discussed in the previous post as examples of highly polar but formally neutral molecules, a property induced by aromatisation of up to three rings. Since e.g. compound 3 is known only in its protonated phenolic form, here I take a look at the basicity of the\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":221,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=221","url_meta":{"origin":6998,"position":3},"title":"How do molecules interact with each other?","author":"Henry Rzepa","date":"April 12, 2009","format":false,"excerpt":"Understanding how molecules interact (bind) with each other when in close proximity is essential in all areas of chemistry. One specific example of this need is for the molecule shown below. 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His point is that orally taken drugs have to survive acid (green below) encountered in the stomach,\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","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\/6998","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=6998"}],"version-history":[{"count":20,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/6998\/revisions"}],"predecessor-version":[{"id":7378,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/6998\/revisions\/7378"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=6998"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=6998"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=6998"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=6998"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}