{"id":221,"date":"2009-04-12T09:21:00","date_gmt":"2009-04-12T08:21:00","guid":{"rendered":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=221"},"modified":"2009-08-31T10:06:48","modified_gmt":"2009-08-31T09:06:48","slug":"how-do-molecules-interact-with-each-other","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=221","title":{"rendered":"How do molecules interact with each other?"},"content":{"rendered":"
\n

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.<\/p>\n

\"The

The Pirkle reagent<\/p><\/div>\n

This is the so-called Pirkle Reagent<\/strong> and is much used to help resolve the two enantiomers of a racemic mixture, particularly drug molecules. The reagent binds to each enantiomer of a racemic drug differently, and this difference can be exploited by using e.g. column chromatography to separate the two forms. The conventional wisdom is that such chiral recognition<\/em> occurs via a three-point binding model. In other words, at least three different interactions must occur between the Pirkle reagent and the drug to allow such chiral recognition.<\/p>\n

So how do we identify where these bindings might occur? A good place to start is to look at the self-binding of the Pirkle reagent, in other words, how does it interact with itself in the crystal state? An X-ray structure of the pure enantiomer of the Pirkle reagent shows that it binds with itself to form a loose dimer. We are now in a position to analyze exactly how this binding occurs. To do this, we are going to invoke a technique known as Atoms-in-molecules<\/strong> or AIM<\/strong>. This effectively looks at the curvature of the electron density in the dimer, and from the characteristics of this curvature, identifies a series of so called critical points<\/strong>, or regions where the first derivative of the electron density (referred to as \u03c1(r) ) with respect to the geometry is zero. These critical points come in four varieties only;<\/p>\n

    \n
  1. A nuclear critical point, which almost exactly corresponds to where the nuclei are<\/li>\n
  2. A bond critical point, which is the key to understanding not only where actual bonds<\/strong> are in the molecule, but also a range of weaker interactions which are conventionally not graced with the term bond, but which nevertheless can be essential in understanding how to molecules interact weakly with each other.<\/li>\n
  3. The remaining two types of critical point relate to rings and cages, and we will not be concerned further with them here.<\/li>\n<\/ol>\n

    The electron density required for this analysis could in principle come from the X-ray measurements themselves, but it is not easy to acquire this to the required accuracy (although it can be done). In this case, it is easier (and probably no less accurate) to calculate the density from a DFT-based quantum mechanical calculation. The result of this is shown below.
    \n

    \"Pirkle

    Pirkle dimer. Click for 3D.<\/p><\/div>
    \nThe light blue spheres show the position of selected bond critical points<\/strong> or BCPs in the AIM analysis. So what do they tell us about how two molecules of Pirkle molecule interact with each other? Three different points labelled 1-3 are highlighted for discussion.<\/p>\n

      \n
    1. Points 1 connect the hydrogen of the OH group with the carbons of the \u03c0-face of the anthracene ring (the left ring of the molecule as shown above). This is an unusual type of interaction<\/em> known as a \u03c0-facial hydrogen bond, and it has only been recognized as such in the last 30 years. Note that this interaction is not restricted to occur just between a pair of atoms, but can involve more (in this case almost a whole benzene ring). By finding the value of the electron density \u03c1(r) at this BCP, one can estimate the energy of interaction resulting from its formation. In this case, \u03c1(r) ~ 0.014 au, and comparison with other types of hydrogen bond suggests that this value corresponds to an interaction energy of around 2.5 kcal\/mol. This is a little weaker than a conventional OH…O hydrogen bond, but is still quite significant. Two of these interactions occur in this Pirkle dimer.<\/li>\n
    2. Points 2 are equally unexpected. They connect the oxygen of the same OH group involved in the previous interaction, and one of the ring C-H groups. Again, that C-H…O groups can interact has only been recognized relatively recently. The value of \u03c1(r) of ~ 0.018 indicates a hydrogen bond strength of ~3 kcal\/mol, again hardly insignificant.<\/li>\n
    3. There are four specific interactions of the final type 3. These occur in the region of overlap of the two anthracene rings, and these are referred to as \u03c0-\u03c0 stacking interactions. Again, the \u03c1(r) of ~ 0.005, calibrated against known systems, suggests that each is individually worth around 1 kcal\/mol.<\/li>\n<\/ol>\n

      So adding up all eight interactions indicates that the two molecules of the Pirkle reagent have an interaction energy of around 15 kcal\/mol resulting just from these weak bonds<\/i> (there are other types of interactions between two molecules known as dispersion forces, which also contribute), and which together provide more than enough free energy to overcome the entropy required to bring the two molecules together.<\/p>\n

      Armed with tools such as AIM, one can now be more confident in analyzing the various terms that contribute to two molecules interacting with each other, and in the case of chiral molecules, how these interactions may result in chiral recognitions.<\/p>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

      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. This is the so-called Pirkle Reagent and is much used to help resolve the two enantiomers of a racemic mixture, particularly drug molecules. The […]<\/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":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2},"jetpack_post_was_ever_published":false},"categories":[4],"tags":[24,40,41,2648,42],"ppma_author":[2661],"class_list":["post-221","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry","tag-energy","tag-free-energy","tag-interaction-energy","tag-interesting-chemistry","tag-x-ray"],"yoast_head":"\nHow do molecules interact with each other? - 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=221\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"How do molecules interact with each other? - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"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. This is the so-called Pirkle Reagent and is much used to help resolve the two enantiomers of a racemic mixture, particularly drug molecules. 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Published recently by Johnson, Keinan, Mori-Snchez, Contreras-Garca, Cohen and Yang, it came to my attention at a conference to celebrate the 20th birthday of ELF when Julia Contreras-Garcia talked about the procedure. It is one\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":"The Pirkle reagent","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/pirkle.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":17579,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=17579","url_meta":{"origin":221,"position":1},"title":"Ammonium tetraphenylborate and the mystery of its \u03c0-facial hydrogen bonding.","author":"Henry Rzepa","date":"March 10, 2017","format":false,"excerpt":"A few years back, I did a post about the Pirkle reagent and the unusual \u03c0-facial hydrogen bonding structure it exhibits. For the Pirkle reagent, this bonding manifests as a close contact between the acidic OH hydrogen and the edge of a phenyl ring; the hydrogen bond is off-centre from\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":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2017\/03\/142-1024x770.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":20354,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=20354","url_meta":{"origin":221,"position":2},"title":"Epoxidation of ethene: a new substituent twist.","author":"Henry Rzepa","date":"December 21, 2018","format":false,"excerpt":"Five years back,\u00a0I speculated about the mechanism of the epoxidation of ethene by a peracid, concluding that kinetic isotope effects provided interesting evidence that this mechanism is highly asynchronous and involves a so-called \"hidden intermediate\". Here I revisit this reaction in which a small change is applied to the atoms\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\/2018\/12\/imine2.gif?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":4224,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=4224","url_meta":{"origin":221,"position":3},"title":"D\u00e9j\u00e0 vu all over again. Are H…H interactions attractive or repulsive?","author":"Henry Rzepa","date":"May 31, 2011","format":false,"excerpt":"The Pirkle reagent is a 9-anthranyl derivative (X=OH, Y=CF3). The previous post on the topic had highlighted DIST1, the separation of the two hydrogen atoms shown below. The next question to ask is how general this feature is. Here we take a look at the distribution of lengths found in\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.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2011\/05\/9-anthranyl1.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":6998,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=6998","url_meta":{"origin":221,"position":4},"title":"Connections in chemistry. Anti-malaria drug \u2194 organocatalysis.","author":"Henry Rzepa","date":"July 5, 2012","format":false,"excerpt":"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\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":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/07\/halofantrine.svg","width":350,"height":200},"classes":[]},{"id":363,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=363","url_meta":{"origin":221,"position":5},"title":"The chirality of M\u00f6bius annulenes","author":"Henry Rzepa","date":"April 22, 2009","format":false,"excerpt":"Much like climbing Mt. Everest because its there, \u00a0some hypothetical molecules are just too tantalizing for chemists to resist attempting a synthesis. Thus in 1964, Edgar Heilbronner \u00a0speculated on whether a conjugated annulene ring might be twistable into a \u00a0M\u00f6bius strip. It was essentially a fun thing to try to\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":"The 16-annulene synthesized by Herges and his team.","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/herges.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\/221","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=221"}],"version-history":[{"count":0,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/221\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=221"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=221"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=221"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=221"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}