{"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":"2013-03-16T10:56:53","modified_gmt":"2013-03-16T10:56:53","slug":"lithiation-of-heteroaromatic-rings-analogy-to-electrophilic-substitution","status":"publish","type":"post","link":"https:\/\/www.rzepa.net\/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. \"C12H16Li2N2O2\", 2013. http:\/\/doi.org\/10042\/24399<\/a>\n\n<\/li>\n
  7. 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. My model will be the system above, based […]<\/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,"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":[5,6],"tags":[1016,1003,246,1028,1029,1529,1530,1527],"class_list":["post-9778","post","type-post","status-publish","format-standard","hentry","category-hypervalency","category-interesting-chemistry","tag-carbon-metal-bond","tag-lithiation","tag-metal","tag-metal-alkyls","tag-metal-lithium","tag-pericyclic","tag-reaction-mechanism","tag-tutorial-material"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/p1gPyz-2xI","jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts\/9778","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=9778"}],"version-history":[{"count":0,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts\/9778\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=9778"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=9778"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=9778"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}