{"id":15415,"date":"2016-01-07T14:15:43","date_gmt":"2016-01-07T14:15:43","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=15415"},"modified":"2023-09-17T07:11:21","modified_gmt":"2023-09-17T06:11:21","slug":"ive-started-so-ill-finish-the-ionisation-mechanism-and-kinetic-isotope-effects-for-13-dimethylindolin-2-one","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=15415","title":{"rendered":"I\u2019ve started so I\u2019ll finish. The ionisation mechanism and kinetic isotope effects for 1,3-dimethylindolin-2 one"},"content":{"rendered":"
\n

This is the third and final study deriving from my Ph.D.[1]<\/a><\/span>. The first two topics dealt with the mechanism of heteroaromatic electrophilic attack using either a diazonium cation or a proton as electrophile, followed by either proton abstraction or carbon dioxide loss from the resulting Wheland intermediate. This final study inverts this sequence by starting with the proton abstraction from an indolinone by a base to create\/aromatize to a indole-2-enolate intermediate, which only then is followed by electrophilic attack (by iodine).  Here I explore what light quantum chemical modelling might cast on the mechanism.<\/p>\n

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

The concentration of I3<\/sub><\/strong>–<\/strong> <\/sup>is used to follow the reaction, given by the expression:  [I3<\/sub>–<\/sup>] = k1<\/sub>[B][indolinone]t –<\/em> k-1<\/sub>\/k2*<\/sup><\/span><\/sub>ln[I3<\/sub>–<\/sup><\/strong>] + const, <\/span>where  k2<\/sub>*<\/span> = k2<\/sub>\/715[I–<\/sup><\/strong>] + k2<\/sub>' <\/span>, the latter being the rate coefficient for the reaction between the enolate intermediate and I3<\/sub>–<\/sup>. With appropriate least squares analysis of this rate equation,‡<\/sup> a value for k1<\/sub> using either 1<\/sup>H or 2<\/sup>H (≡ D) isotopes can be extracted and this gives an isotope effect k1<\/sub>H<\/sup>\/k1<\/sub>D<\/sup> of 6.3 ± 0.6. Note that this value does NOT depend on [B]. Here, I am going to try to see if I can construct a quantum mechanical model which reproduces this value.<\/p>\n

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

    \n
  1. \n Model 1<\/strong> uses just three water molecules as a proton relay (B3LYP+D3\/Def2-TZVP\/SCRF=water).\n <\/li>\n
  2. \n Model 2<\/strong> uses 2H2<\/sub>O.NaOH solvated by two extra passive water molecules. Since under these conditions, the NaOH is largely ionic, [B] ≡ [OH–<\/sup>]\n <\/li>\n<\/ol>\n\n\n\n\n\n
    \n Model\n <\/th>\n\n ΔG‡<\/sup>298<\/sub> (ΔH‡<\/sup>298<\/sub>)\n <\/th>\n\n kH<\/sup>\/kD<\/sup> (298K)\n <\/th>\n\n DataDOIs\n <\/th>\n<\/tr>\n
    \n 1\n <\/td>\n\n 28.0 (22.9)\n <\/td>\n\n 10.3\n <\/td>\n\n [2]<\/a><\/span>,[3]<\/a><\/span>,[4]<\/a><\/span>\n <\/td>\n<\/tr>\n
    \n 2\n <\/td>\n\n 2.5 (2.8)\n <\/td>\n\n 4.4\n <\/td>\n\n [5]<\/a><\/span>,[6]<\/a><\/span>,[7]<\/a><\/span>\n <\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

    The plot of rate vs [B] shows[1]<\/a><\/span> that the uncatalysed (water) rate is very slow (intercept passes more or less through zero) and the calculated free energy barrier (28.0 kcal\/mol) confirms a slow rate at ambient temperatures. Note in the final (aromatized) product, there is a noticeable hydrogen bond between the 3-carbon and a water molecule (2.14Å). The calculated kinetic isotope effect[8]<\/a><\/span> is substantially larger than observed experimentally for the base catalysed contribution.<\/p>\n

    \"Indolineone<\/p>\n

    In the presence of NaOH (standard state = 1 atm = 0.044M), the enthalpy barrier drops very substantially to 2.8 kcal\/mol and the free energy to 2.5 kcal\/mol. Similar behaviour was noted previously on this blog for the hydrolysis of thalidomide<\/a>. Although the magnitude of the reduction in barrier in fact implies an extremely fast reaction, recollect that [B]=[OH–<\/sup>] appears in the rate equation  and since its value is very much less than 0.044M, the observed rate is relatively slow.<\/p>\n

    \"Indolineone<\/p>\n

    The calculated KIE for the hydroxide catalysed mechanism is much smaller that for the water route, but also smaller than is observed. This is a value uncorrected for tunnelling, which given the small barrier might be significant. <\/p>\n

    These calculations show how a model for ionization of indolinone can be constructed, and used to e.g.<\/em> probe the sensitivity of KIE to perturbations induced by ring substituents, which may form the basis of a future post.<\/p>\n

    \n

    ‡<\/sup>This is a non-linear equation with kinetics that straddle zero and first order behaviour. In 1972, it was not easily possible to graph such functions in a manner where the slope of a linear plot would yield the rate constant. It was only computers and languages such as Fortran which allowed such non-linear least squares analysis of the rate. In the event, it turned out that the presence of 50% methanol in the mixed aqueous solutions was the cause; in other solvents the kinetics approximated zero order behavour very well.<\/p>\n

    \n

    Acknowledgments<\/h4>\n

    This post has been cross-posted in PDF format at Authorea<\/a>.<\/p>\n

    References<\/h2>\n
    1. B.C. Challis, and H.S. Rzepa, \"Heteroaromatic hydrogen exchange reactions. Part VIII. The ionisation of 1,3-dimethylindolin-2-one\", Journal of the Chemical Society, Perkin Transactions 2<\/i>, pp. 1822, 1975. https:\/\/doi.org\/10.1039\/p29750001822<\/a>\n\n<\/li>\n
    2. H.S. Rzepa, \"C 10 H 17 N 1 O 4\", 2016. https:\/\/doi.org\/10.14469\/ch\/191786<\/a>\n\n<\/li>\n
    3. H.S. Rzepa, \"C 10 H 17 N 1 O 4\", 2016. https:\/\/doi.org\/10.14469\/ch\/191765<\/a>\n\n<\/li>\n
    4. H.S. Rzepa, \"C10H17NO4\", 2016. https:\/\/doi.org\/10.14469\/ch\/191784<\/a>\n\n<\/li>\n
    5. H.S. Rzepa, \"C 10 H 20 N 1 Na 1 O 6\", 2016. https:\/\/doi.org\/10.14469\/ch\/191787<\/a>\n\n<\/li>\n
    6. H.S. Rzepa, \"C 10 H 20 N 1 Na 1 O 6\", 2016. https:\/\/doi.org\/10.14469\/ch\/191782<\/a>\n\n<\/li>\n
    7. H.S. Rzepa, \"C10H20NNaO6\", 2016. https:\/\/doi.org\/10.14469\/ch\/191785<\/a>\n\n<\/li>\n
    8. H. Rzepa, \"Mechanisms and kinetic isotope effects for the base catalysed ionisation of 1,3-dimethyl indolinone.\", 2016. https:\/\/doi.org\/10.14469\/hpc\/202<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

      This is the third and final study deriving from my Ph.D.. The first two topics dealt with the mechanism of heteroaromatic electrophilic attack using either a diazonium cation or a proton as electrophile, followed by either proton abstraction or carbon dioxide loss from the resulting Wheland intermediate. 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Subversive thoughts for electrophilic substitution of Indole.","author":"Henry Rzepa","date":"March 10, 2013","format":false,"excerpt":"I mentioned in the last post that one can try to predict the outcome of electrophilic aromatic substitution by approximating the properties of the transition state from those of either the reactant or the (presumed Wheland) intermediate by invoking Hammond's postulate. A third option is readily available nowadays; calculate 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":"Click for 3D.","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/03\/3-NO-indole-ESP.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":12056,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=12056","url_meta":{"origin":15415,"position":1},"title":"The mechanism of diazo coupling: more hidden mechanistic intermediates.","author":"Henry Rzepa","date":"March 8, 2014","format":false,"excerpt":"The diazo-coupling reaction dates back to the 1850s (and a close association with Imperial College via the first professor of chemistry there, August von Hofmann) and its mechanism was much studied in the heyday of physical organic chemistry. Nick Greeves, purveyor of the excellent ChemTube3D site, contacted me about the\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":"cis-diazo","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2014\/03\/cis-diazo.gif?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":12115,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=12115","url_meta":{"origin":15415,"position":2},"title":"Aromatic electrophilic substitution. A different light on the bromination of benzene.","author":"Henry Rzepa","date":"March 12, 2014","format":false,"excerpt":"My previous post related to the aromatic electrophilic substitution of benzene using as electrophile phenyl diazonium chloride. Another prototypical reaction, and again one where benzene is too inactive for the reaction to occur easily, is the catalyst-free bromination of benzene to give bromobenzene and HBr.\u00a0 The \"text-book\" mechanism involves nucleophilic\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":"br2+benzene","src":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2014\/03\/br2+benzene.svg","width":350,"height":200},"classes":[]},{"id":15048,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=15048","url_meta":{"origin":15415,"position":3},"title":"I’ve started so I’ll finish. The mechanism of diazo coupling to indoles – forty (three) years on!","author":"Henry Rzepa","date":"December 24, 2015","format":false,"excerpt":"The BBC TV quiz series Mastermind\u00a0was first broadcast in the UK in 1972,\u00a0the same time\u00a0I was starting to investigate\u00a0the mechanism of diazocoupling to substituted indoles as part of my Ph.D. researches. The BBC program became known\u00a0for the\u00a0catch phrase\u00a0I've started so I'll finish;\u00a0here I will try to follow this precept with\u2026","rel":"","context":"In "Historical"","block_context":{"text":"Historical","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=565"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":9659,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=9659","url_meta":{"origin":15415,"position":4},"title":"Understanding the electrophilic aromatic substitution of indole.","author":"Henry Rzepa","date":"March 3, 2013","format":false,"excerpt":"The electrophilic substitution of indoles is a staple of any course on organic chemistry. Indoles also hold a soft-spot for me, since I synthesized not a few as part of my Ph.D. studies., The preference for substitution in the 3-position is normally explained using the arrows shown below (position 3=green,2=blue,1=red).\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":"Molecular electrostatic potential. Click for 3D.","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2013\/03\/indole-mep.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":7344,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=7344","url_meta":{"origin":15415,"position":5},"title":"The first curly arrows. The d\u00e9nouement.","author":"Henry Rzepa","date":"July 23, 2012","format":false,"excerpt":"Recollect, Robinson was trying to explain why the nitroso group appears to be an o\/p director of aromatic electrophilic substitution. Using \u03c3\/\u03c0 orthogonality, I suggested that the (first ever) curly arrows as he drew them could not be the complete story, and that a transition state analysis would be needed.\u2026","rel":"","context":"In "Curly arrows"","block_context":{"text":"Curly arrows","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2327"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/07\/p-wheland.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\/15415","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=15415"}],"version-history":[{"count":40,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/15415\/revisions"}],"predecessor-version":[{"id":26488,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/15415\/revisions\/26488"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=15415"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=15415"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=15415"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=15415"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}