{"id":9778,"date":"2013-03-16T10:56:53","date_gmt":"2013-03-16T10:56:53","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=9778"},"modified":"2014-01-17T07:38:36","modified_gmt":"2014-01-17T07:38:36","slug":"lithiation-of-heteroaromatic-rings-analogy-to-electrophilic-substitution","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=9778","title":{"rendered":"Lithiation of heteroaromatic rings: analogy to electrophilic substitution?"},"content":{"rendered":"
\n

Functionalisation of a (hetero)aromatic ring by selectively (directedly) removing protons using the metal lithium is a relative mechanistic newcomer, compared to the pantheon of knowledge on\u00a0aromatic electrophilic substitution<\/a>. Investigating the mechanism using quantum calculations poses some interesting challenges, ones I have not previously discussed on this blog.<\/p>\n

\"Li\"<\/p>\n

My model will be the system above, based on the pyridine ring, and also carrying a directing group (R=Me, DG = O–<\/sup>). The reagent used to remove the hydrogen and to substitute it (with a carbon-metal bond) is an alkyl lithium. The arrow pushing I have shown is speculative, since at this stage we have no idea if it really is such a pericyclic process. Indeed things are about to get complicated when we find out that the structure of the electron deficient lithium alkyls is much more complex than one might imagine.<\/p>\n

Fortunately, crystal structures are available. Let me start with n-butyl lithium, a very commonly used reagent[1]<\/a><\/span>. This forms a complex cluster of six lithiums, in which each metal is surrounded by three CH2<\/sub>–<\/sup> terminii of the n-butyl anion, and vice-versa<\/em>, each\u00a0\u00a0CH2<\/sub>–<\/sup>\u00a0group is in contact with three lithium atoms (making the carbanionic carbon in effect hexa-coordinate<\/a>).<\/p>\n

\"SUHBEC.

SUHBEC. CLICK FOR 3D.<\/p><\/div>\n

Another frequently used lithium alkyl is the t-butyl derivative, which has a different\u00a0tetrameric motif, again with each\u00a0Me3<\/sub>C–<\/sup>\u00a0coordinated to three Li atoms (making this carbon again hexa-coordinate).<\/p>\n

\"SUHBIG.

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

The interesting issue now is whether these metal alkyls react in these oligomeric forms or whether they are in equilibrium with a reduced monomeric form that constitutes the reactive species. With n-butyl lithium, it is possible to try to achieve this chemically by adding tetramethylethylenediamine. As you can see from the structure below, this strategy can be only partially successful; in this instance the\u00a0\u00a0CH2<\/sub>–<\/sup>\u00a0 coordination is reduced from three Li atoms to two[2]<\/a><\/span>. With t-butyl lithium, this strategy reduces the structure to a true monomer[3]<\/a><\/span>, the Me3<\/sub>C–<\/sup>\u00a0now being just 4-coordinate.<\/p>\n\n\n\n
\n
\"WAFJAO.

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

\n
\"LOKTAH.

LOKTAH. Click for 3D.<\/p><\/div>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

These systems are all pretty large to investigate using modelling, and so I will start the process by reducing the alkyl lithium model down to just a monomeric CH3<\/sub>Li molecule, placing it and pyridine-N-oxide into a continuum solvent cavity (\u03c9B97XD\/6-311G(d,p)\/SCRF=benzene) and seeing what happens[4]<\/a><\/span>. You can see it is both facile and a concerted process, corresponding pretty much to the arrow pushing illustrated at the top of this post.<\/p>\n\n\n\n
\"Li1a\"<\/td>\n\u00a0\"Li1a\"<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

But wait, where have we seen an aromatic substitution reaction which does exactly this in a single concerted step, first remove a proton and then replace it with an electrophile? This was in fact revealed in the IRC for electrophilic substitution of indole in the 1-position<\/a>! Of course, there is a difference. With indole, we had pseudo-inversion at the nitrogen centre (a pseudo-Sn2 reaction if you will), whereas here it is pseudo-retention at the 2-carbon.<\/p>\n

Is this model robust? Let us try a dimeric (MeLi)2<\/sub> model coordinated to one pyridine-N-oxide. The IRC[5]<\/a><\/span> is very similar, but the initial barrier to proton transfer is lower.<\/p>\n\n\n\n
\"Li2\"<\/td>\n\"Li2\"<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Next, we have a\u00a0model\u00a0in which two molecules of pyridine-N-oxide (PNO) aggregate around two molecules of MeLi. This model is starting to resemble the\u00a0tetramethylethylenediamine partially de-aggregated n-butyl lithium structure shown as\u00a0WAFJAO above. The basic features[6]<\/a><\/span> of the process remain intact, including the small barrier.<\/p>\n\n\n\n
\"Li2d\"<\/td>\n\"Li2d\"<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Finally, I go back to the simple model, but with the directing group (DG) removed to give just pyridine. The profile[7]<\/a><\/span> is the same, but the barrier is much larger. So perhaps both aggregation and coordination to a directing group help accelerate the reaction?<\/p>\n\n\n\n
\"Li0a\"<\/td>\n\"Li0a\"<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

So two reaction types, not normally associated with each other, turn out to have some intriguing similarities and an interesting difference.<\/p>\n

References<\/h2>\n
  1. T. Kottke, and D. Stalke, \"Structures of Classical Reagents in Chemical Synthesis: (<i>n<\/i>BuLi)<sub>6<\/sub>, (<i>t<\/i>BuLi)<sub>4<\/sub>, and the Metastable (<i>t<\/i>BuLi \u00b7 Et<sub>2<\/sub>O)<sub>2<\/sub>\", Angewandte Chemie International Edition in English<\/i>, vol. 32, pp. 580-582, 1993. https:\/\/doi.org\/10.1002\/anie.199305801<\/a>\n\n<\/li>\n
  2. M.A. Nichols, and P.G. Williard, \"Solid-state structures of n-butyllithium-TMEDA, -THF, and -DME complexes\", Journal of the American Chemical Society<\/i>, vol. 115, pp. 1568-1572, 1993. https:\/\/doi.org\/10.1021\/ja00057a050<\/a>\n\n<\/li>\n
  3. V.H. Gessner, and C. Strohmann, \"Lithiation of TMEDA and its Higher Homologous TEEDA: Understanding Observed \u03b1- and \u03b2-Deprotonation\", Journal of the American Chemical Society<\/i>, vol. 130, pp. 14412-14413, 2008. https:\/\/doi.org\/10.1021\/ja8058205<\/a>\n\n<\/li>\n
  4. H.S. Rzepa, \"Gaussian Job Archive for C6H8LiNO\", 2013. https:\/\/doi.org\/10.6084\/m9.figshare.651068<\/a>\n\n<\/li>\n
  5. H.S. Rzepa, \"Gaussian Job Archive for C7H11Li2NO\", figshare<\/i>, 2013. https:\/\/doi.org\/10.6084\/m9.figshare.651764<\/a>\n\n<\/li>\n
  6. H.S. Rzepa, \"Gaussian Job Archive for C6H8LiN\", 2013. https:\/\/doi.org\/10.6084\/m9.figshare.653672<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    Functionalisation of a (hetero)aromatic ring by selectively (directedly) removing protons using the metal lithium is a relative mechanistic newcomer, compared to the pantheon of knowledge on\u00a0aromatic electrophilic substitution. Investigating the mechanism using quantum calculations poses some interesting challenges, ones I have not previously discussed on this blog. 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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":[]},{"id":15415,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=15415","url_meta":{"origin":9778,"position":1},"title":"I\u2019ve started so I\u2019ll finish. The ionisation mechanism and kinetic isotope effects for 1,3-dimethylindolin-2 one","author":"Henry Rzepa","date":"January 7, 2016","format":false,"excerpt":"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. This final study\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":9706,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=9706","url_meta":{"origin":9778,"position":2},"title":"Kinetic vs Thermodynamic control. 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":12115,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=12115","url_meta":{"origin":9778,"position":3},"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":11450,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11450","url_meta":{"origin":9778,"position":4},"title":"The NMR spectra of methano[10]annulene and its dianion. The diatropic\/paratropic inversion.","author":"Henry Rzepa","date":"October 26, 2013","format":false,"excerpt":"The 1H NMR spectrum of an aromatic molecule such as benzene is iconic; one learns that the unusual chemical shift of the protons (~\u03b4 7-8 ppm) is due to their deshielding by a diatropic ring current resulting from the circulation of six aromatic \u03c0-electrons following the H\u00fcckel 4n+2 rule. But\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\/10\/dianion.jpeg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":9917,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=9917","url_meta":{"origin":9778,"position":5},"title":"Concerted vs stepwise (Meisenheimer) mechanisms for aromatic nucleophilic substitution.","author":"Henry Rzepa","date":"March 25, 2013","format":false,"excerpt":"My two previous explorations of aromatic substitutions have involved an electrophile (NO+ or Li+). Time now to look at a nucleophile, representing nucleophilic aromatic substitution. The mechanism of this is thought to pass through an intermediate analogous to the Wheland for an electrophile, this time known as the Meisenheimer complex.\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\/trinitro.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","author_category":"1","first_name":"Henry","last_name":"Rzepa","user_url":"https:\/\/orcid.org\/0000-0002-8635-8390","job_title":"","description":"Henry Rzepa is Emeritus Professor of Computational Chemistry at Imperial College London."}],"_links":{"self":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/9778","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=9778"}],"version-history":[{"count":47,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/9778\/revisions"}],"predecessor-version":[{"id":11927,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/9778\/revisions\/11927"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=9778"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=9778"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=9778"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=9778"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}