{"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_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":[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. 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Here I ask what the conformation (it could also be called a configuration) about the C-N bond is. 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