{"id":10145,"date":"2013-04-04T15:05:11","date_gmt":"2013-04-04T14:05:11","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=10145"},"modified":"2013-04-05T07:10:04","modified_gmt":"2013-04-05T06:10:04","slug":"feists-acid-stereochemistry-galore","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=10145","title":{"rendered":"Feist’s acid. Stereochemistry galore."},"content":{"rendered":"
\n

Back in the days (1893) when few compounds were known, new ones could end up being named after the discoverer. Thus Feist is known for the compound bearing his name; the 2,3 carboxylic acid of methylenecyclopropane (1<\/strong>, with Me replaced by CO2<\/sub>H). Compound 1<\/strong> itself nowadays is used to calibrate chiroptical calculations<\/a>[1]<\/a><\/span>, which is what brought it to my attention. But about four decades ago, and now largely forgotten, both 1<\/strong> and the dicarboxylic acid were famous for the following rearrangement that gives a mixture of 2<\/strong> and 3<\/strong>[2]<\/a><\/span>. I thought I might here unpick some of the wonderfully subtle stereochemical analysis that this little molecule became subjected to.
\"methylene-cyclopropane\"<\/p>\n

Feist’s acid and its derivatives have attracted constant attention a long while. The rearrangement shown above was identified in 1932, and by 1960 it was shown that 1<\/strong>\u00a0as a pure enantiomer gave products 2<\/strong> and 3<\/strong>\u00a0that retained optical activity (read about all of this here[3]<\/a><\/span>).\u00a0By 1970 attention had shifted to the absolute configurations of the molecules involved and the mechanism of the reaction. Why? Woodward and Hoffmann had just put pericyclic reactions on the map[4]<\/a><\/span>, and one of the examples they cited was this one. They identified the reaction as a [1,3]sigmatropic rearrangement (the red bond<\/span> breaks and the blue bond<\/span> forms) and their new theory required the configuration at carbon 1<\/strong> to be inverted by the reaction, from (R) to (S) as shown above. In order to verify this, von Doering (who had been a student of Woodward’s) subjected Feist’s ester and its rearrangement products to a series of chemical transformations[4]<\/a><\/span> in order to relate its absolute stereochemistry to that of known compounds. Gajewski[5]<\/a><\/span> took over and with four further chemical transformations, was able to assert that the (S,S)-dimethyl enantiomer of\u00a01<\/strong> has an optical rotation of -59.4\u00b0.\u2021<\/sup> The molecules 2<\/strong> and 3<\/strong> were subjected to a similar stereochemical analysis, which finally revealed them to have\u00a0(S) configuration at the carbon labelled 1<\/strong>, thus confirming the inversion of configuration<\/strong><\/em> so confidently predicted by Woodward and Hoffmann. I imagine Feist never imagined the molecule which came to bear his name would be used as a confirmation of one\u00a0of the pivotal 20th century stereochemical theories of organic chemistry.<\/p>\n

So what of the mechanism for this rearrangement? Well, a\u00a0\u03c9B97XD\/6-311G(d,p) calculation reveals the transition state as shown below. The two dashed lines represent the red and blue bonds shown schematically above, and these bond either break or form to the same face of the three-carbon allyl fragment (suprafacially), but that carbon 1<\/strong> (pointed to by the blue arrow below) suffers an Sn2-like inversion of configuration (= antarafacial) as proven by all that hard chemical synthesis noted above.\u00a0\"methylene-cyclopropane\"<\/p>\n

The reaction is concerted, with a predicted barrier of around 50 kcal\/mol. This is a little higher than the measured value of ~41 kcal\/mol[6]<\/a><\/span>. This is taken to indicate that the wavefunction has a contribution from an open-shell biradical configuration (indeed it is unstable at the transition state, having a lower energy triplet state) which would lower the barrier by 10-15 kcal\/mol. The observation that the product has NOT lost optical activity suggests that the mechanism cannot simply be that of an achiral biradical, and that a “memory” of the starting stereochemical configuration must be retained throughout the dynamic reaction trajectory. Modelling such a process requires more sophisticated (multi-configuration) techniques than the one I have illustrated here, and quite probably a smattering of reaction dynamics thrown in. It goes to show that quite innocent looking molecules can be devils to model (both for their reaction dynamics and<\/strong> their optical activity!).\u00a0<\/p>\n\n\n\n
\"methylenecyclopropane\"–[7]<\/a><\/span><\/td>\n\"methylenecyclopropane\"<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Feist’s acid itself reveals a profile for the computed rearrangement IRC (\u03c9B97XD\/6-311G(d,p)\/SCRF=water) that I have never seen as prominently before, a veritable table top<\/a> of a mountain! This feature (and its reflection in the gradient norm) is a nice example of a “hidden intermediate”. In this case, it is a species which may be either biradical or zwitterionic, and which sits atop the mountain plateau. It can drop (bifurcate) off the mountain to form either compound 2<\/strong> or 3<\/strong>, a process which must likely be best studied by dynamics rather than purely as an intrinsic reaction coordinates.<\/p>\n\n\n\n\n
\n
\"feist1\"

Click for 3D<\/p><\/div>
\n
[8]<\/a><\/span><\/td>\n

\"feiste\"<\/td>\n<\/tr>\n
\u00a0\"feistg\"<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

\n

\u2021<\/sup>See comment here<\/a>.<\/p>\n

References<\/h2>\n
  1. E.D. Hedeg\u00e5rd, F. Jensen, and J. Kongsted, \"Basis Set Recommendations for DFT Calculations of Gas-Phase Optical Rotation at Different Wavelengths\", Journal of Chemical Theory and Computation<\/i>, vol. 8, pp. 4425-4433, 2012. https:\/\/doi.org\/10.1021\/ct300359s<\/a>\n\n<\/li>\n
  2. J.J. Gajewski, \"Hydrocarbon thermal degenerate rearrangements. IV. Stereochemistry of the methylenecyclopropane self-interconversion. Chiral and achiral intermediates\", Journal of the American Chemical Society<\/i>, vol. 93, pp. 4450-4458, 1971. https:\/\/doi.org\/10.1021\/ja00747a019<\/a>\n\n<\/li>\n
  3. W. von E. Doering, and H. Roth, \"Stereochemistry of the methylenecyclopropane rearrangement\", Tetrahedron<\/i>, vol. 26, pp. 2825-2835, 1970. https:\/\/doi.org\/10.1016\/s0040-4020(01)92859-5<\/a>\n\n<\/li>\n
  4. R.B. Woodward, and R. Hoffmann, \"The Conservation of Orbital Symmetry\", Angewandte Chemie International Edition in English<\/i>, vol. 8, pp. 781-853, 1969. https:\/\/doi.org\/10.1002\/anie.196907811<\/a>\n\n<\/li>\n
  5. https:\/\/doi.org\/<\/a>\n\n<\/li>\n
  6. J.P. Chesick, \"<b>Kinetics of the Thermal Interconversion of 2-Methylmethylenecyclopropane and Ethylidenecyclopropane<\/b>\", Journal of the American Chemical Society<\/i>, vol. 85, pp. 2720-2723, 1963. https:\/\/doi.org\/10.1021\/ja00901a009<\/a>\n\n<\/li>\n
  7. H.S. Rzepa, \"Gaussian Job Archive for C6H10\", 2013. https:\/\/doi.org\/10.6084\/m9.figshare.670632<\/a>\n\n<\/li>\n
  8. H.S. Rzepa, \"Gaussian Job Archive for C6H6O4\", 2013. https:\/\/doi.org\/10.6084\/m9.figshare.674600<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    Back in the days (1893) when few compounds were known, new ones could end up being named after the discoverer. Thus Feist is known for the compound bearing his name; the 2,3 carboxylic acid of methylenecyclopropane (1, with Me replaced by CO2H). Compound 1 itself nowadays is used to calibrate chiroptical calculations, which is what […]<\/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":[4],"tags":[824,1040,1038,843,1039,373],"ppma_author":[2661],"class_list":["post-10145","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry","tag-chemical-synthesis","tag-chemical-transformations","tag-lower-energy-triplet-state","tag-reaction-mechanism","tag-rearrangement-products","tag-tutorial-material"],"yoast_head":"\nFeist's acid. 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Some benzidine rearrangements are indeed thought to go through the [3,3] route. The topic has been reviewed here.\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":"NCI surface. Click for 3D.","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/01\/benzidinenci.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":26997,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=26997","url_meta":{"origin":10145,"position":2},"title":"Exploring Methanetriol – “the Formation of an Impossible Molecule”","author":"Henry Rzepa","date":"May 16, 2024","format":false,"excerpt":"What constitutes an \"impossible molecule\"? Well, here are two, the first being the topic of a recent article. The second is a favourite of organic chemistry tutors, to see if their students recognise it as an unusual (= impossible) form of a much better known molecule. Perhaps we could define\u2026","rel":"","context":"With 2 comments","block_context":{"text":"With 2 comments","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=26997#comments"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2024\/05\/COLRUT.gif?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":14944,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=14944","url_meta":{"origin":10145,"position":3},"title":"A tutorial problem in stereoelectronic control. A Grob alternative to the Tiffeneau-Demjanov rearrangement?","author":"Henry Rzepa","date":"November 28, 2015","format":false,"excerpt":"In answering tutorial problems, students often need skills in deciding how much time to spend on explaining what does not happen, as well as what does. Here I explore alternatives to the mechanism outlined in the previous post to see what computation\u00a0has to say about what does (or might) not\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":"Alt1","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2015\/11\/Alt1.gif?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":16441,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=16441","url_meta":{"origin":10145,"position":4},"title":"An alternative mechanism for nucleophilic substitution at silicon using a tetra-alkyl ammonium fluoride.","author":"Henry Rzepa","date":"May 27, 2016","format":false,"excerpt":"In the previous post, I explored the mechanism for nucleophilic substitution at a silicon centre proceeding via retention of configuration involving a Berry-like pseudorotation.\u00a0Here\u00a0I probe an alternative route involving inversion of configuration at the Si centre. Both stereochemical modes are known to occur, depending on the leaving group, solvent and\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":9135,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=9135","url_meta":{"origin":10145,"position":5},"title":"Why is N,O-diphenyl hydroxylamine (PhNHOPh) unknown?","author":"Henry Rzepa","date":"January 16, 2013","format":false,"excerpt":"If you search e.g. Scifinder for N,O-diphenyl hydroxylamine (RN\u00a024928-98-1) there is just one literature citation, to a 1962 patent. Nothing else; not even a calculation (an increasing proportion of the molecules reported in Chemical Abstracts have now only ever been subjected to calculation, not synthesis).\u00a0A search of Reaxys also offers\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":[]}],"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\/10145","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=10145"}],"version-history":[{"count":25,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/10145\/revisions"}],"predecessor-version":[{"id":10175,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/10145\/revisions\/10175"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=10145"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=10145"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=10145"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=10145"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}