{"id":9459,"date":"2013-02-10T17:38:48","date_gmt":"2013-02-10T17:38:48","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=9459"},"modified":"2023-09-16T19:44:38","modified_gmt":"2023-09-16T18:44:38","slug":"the-conformational-preference-of-s-cis-amides","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=9459","title":{"rendered":"The conformational preference of s-cis amides."},"content":{"rendered":"
\n

\n\tAmides with an H-N group are a component of the peptide linkage<\/a> (O=C-NH). Here I ask what the conformation (it could also be called a configuration) about the C-N bond is. A search of the following type can be defined:\n<\/p>\n

\n\t\"cis-amide\"<\/a>\n<\/p>\n

\n\tThe dihedral shown is for H-N-C=O (but this is equivalent to the C-C-N-C dihedral, which is also often called the dihedral angle<\/a> associated with the peptide group). I have also added a distance, from a C-H to the carbonyl oxygen. Other search constraints include T ≤ 175K, R < 0.05, no disorder, no errors, that neither N-C bonds are part of a ring and that the two carbons marked T4 both have four connected bonds<\/strong>. The search results in 619 hits (January 2013 version of the CCDC database), and these are displayed below.\n<\/p>\n

\n\t\"cis-amide-search-heat\"<\/a>\n<\/p>\n

\n\tThe horizontal axis reveals the highest concentration (red) at ~2.4Å due to a syn-co-planar alignment of the C-H bond with the plane of the C=O bond in the s-cis conformer (the significantly smaller hot-spot at ~3.9A may be due to an anti-co-planar alignment of this C-H bond).\n<\/p>\n

\n\t\"s-cis-amide\"\n<\/p>\n

\n\tThe vertical axis shows a clear preference for a dihedral of 179° (in fact no hits with a dihedral of less than 14o° were found) and this can only arise from the s-cis<\/em><\/strong> conformation in which the H-N bond is oriented antiperiplanar to the axis of the C=O bond. This preference can be rationalised by filled\/empty NBO-orbital interactions, which include:\n<\/p>\n

    \n
  1. \n\t\tAntiperiplanar interaction between the N-H as donor and the C=O as a σ-acceptor (E(2) = 4.1 kcal\/mol)<\/span>\n\t<\/li>\n
  2. \n\t\tAntiperiplanar interaction between the N-H as acceptor and C-H as donor (E(2) = 4.7 kcal\/mol)\n\t<\/li>\n<\/ol>\n
    \"Click

    H-N\/C=O. Click for 3D<\/p><\/div>\n

    \"Click

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

    \n\tThis latter overlap conspires to bring the C-H hydrogen close to the oxygen (~2.35Å, DIST1 in the diagram above). So one might be entitled to ask: is this a hydrogen bond? There are (at least) two ways of testing this.\n<\/p>\n

      \n
    1. \n\t\tThe NBO E(2) interaction energy between the oxygen in-plane lone pair and the H-C as acceptor is 0.8 kcal\/mol. For hydrogen bonds, such E(2) energies more or less resemble the actual H-bond strengths, i.e.<\/em> a strong H-bond has an E(2) energy of ~ 8 kcal\/mol; and a medium O…H-C hydrogen bond weighs in at around 3 kcal\/mol.  So this one is very weak. This is due to poor overlap resulting from the small ring size<\/a> (5).\n\t<\/li>\n
    2. \n\t\tThe NCI (non-covalent-interaction) surface does reveal a feature in the CH…O region, but the colour coding (which indicates how attractive\/repulsive this is) is both pale blue (attractive) and yellow (repulsive). Again this is only consistent with a very weak overall H-bond.\n\t<\/li>\n<\/ol>\n
      \"NCI

      NCI surface. Click for 3D.<\/p><\/div>\n

      \n\tI end by reminding that the s-cis H-N-C=O conformation is a very common feature in peptides <\/a>(the CCDC database comprises mostly small molecules, not larger peptides and proteins) arising from really quite subtle orbital interactions.\n<\/p>\n

      \n

      Acknowledgments<\/h4>\n

      This post has been cross-posted in PDF format at Authorea<\/a>.<\/p>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

      Amides with an H-N group are a component of the peptide linkage (O=C-NH). Here I ask what the conformation (it could also be called a configuration) about the C-N bond is. A search of the following type can be defined: The dihedral shown is for H-N-C=O (but this is equivalent to the C-C-N-C dihedral, which is […]<\/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":[1745,4],"tags":[17,24,41,1380,997,996,373],"ppma_author":[2661],"class_list":["post-9459","post","type-post","status-publish","format-standard","hentry","category-crystal_structure_mining","category-interesting-chemistry","tag-conformational-analysis","tag-energy","tag-interaction-energy","tag-peptide","tag-search-constraints","tag-search-results","tag-tutorial-material"],"yoast_head":"\nThe conformational preference of s-cis amides. - 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=9459\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"The conformational preference of s-cis amides. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"Amides with an H-N group are a component of the peptide linkage (O=C-NH). Here I ask what the conformation (it could also be called a configuration) about the C-N bond is. A search of the following type can be defined: The dihedral shown is for H-N-C=O (but this is equivalent to the C-C-N-C dihedral, which is […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=9459\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2013-02-10T17:38:48+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2023-09-16T18:44:38+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/02\/cis-amide.jpg\" \/>\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":"The conformational preference of s-cis amides. - 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=9459","og_locale":"en_GB","og_type":"article","og_title":"The conformational preference of s-cis amides. - Henry Rzepa's Blog","og_description":"Amides with an H-N group are a component of the peptide linkage (O=C-NH). Here I ask what the conformation (it could also be called a configuration) about the C-N bond is. 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Here I explore some geometric properties of amides related to the C-N bond and the torsions about it. The key aspect of amides is that a lone pair of electrons on the nitrogen can conjugate\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":"","width":0,"height":0},"classes":[]},{"id":9500,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=9500","url_meta":{"origin":9459,"position":2},"title":"The conformational preference of s-cis amides. Ramachandran plots.","author":"Henry Rzepa","date":"February 11, 2013","format":false,"excerpt":"This is really just a postscript to the previous post. There I showed how a search of the (small molecule) crystal database revealed the s-cis conformation about the N-C amide bond (the one with partial double bond character that prevents rotation) and how this conformation means that a C-H approaches\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":12678,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=12678","url_meta":{"origin":9459,"position":3},"title":"Amides and inverting the electronics of the B\u00fcrgi\u2013Dunitz trajectory.","author":"Henry Rzepa","date":"June 26, 2014","format":false,"excerpt":"The B\u00fcrgi\u2013Dunitz angle describes the trajectory of an approaching nucleophile towards the carbon atom of a carbonyl group. A colleague recently came to my office to ask about the inverse, that is what angle would an electrophile approach (an amide)? Thus it might approach either syn or\u00a0anti\u00a0with respect to the\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":22595,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=22595","url_meta":{"origin":9459,"position":4},"title":"The Willgerodt-Kindler Reaction: mechanistic reality check 3. A peek under the hood for transition state location.","author":"Henry Rzepa","date":"August 27, 2020","format":false,"excerpt":"The two previous surveys of the potential energy surface for this, it has to be said, rather obscure reaction led to energy barriers that were rather to high to be entirely convincing.\u00a0So here is a third possibility. The red section corresponds to the previous exploration, in which a 3-membered sulfur\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":21128,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21128","url_meta":{"origin":9459,"position":5},"title":"A Non-nitrogen Containing Morpholine Isostere; an application of FAIR data principles.","author":"Henry Rzepa","date":"August 4, 2019","format":false,"excerpt":"In the pipeline reports on an intriguing new ring system acting as an isostere for morpholine. I was interested in how the conformation of this ring system might be rationalised electronically and so I delved into the article. Here I recount what I found. The basis for the isosteric claim\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.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2019\/08\/jm-2019-00348p_0004-2.gif?resize=350%2C200&ssl=1","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\/9459","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=9459"}],"version-history":[{"count":26,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/9459\/revisions"}],"predecessor-version":[{"id":26479,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/9459\/revisions\/26479"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=9459"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=9459"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=9459"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=9459"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}