{"id":16402,"date":"2016-05-25T10:44:00","date_gmt":"2016-05-25T09:44:00","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=16402"},"modified":"2016-06-26T08:23:10","modified_gmt":"2016-06-26T07:23:10","slug":"the-mechanism-of-silylether-deprotection-using-a-tetra-alkyl-ammonium-fluoride","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=16402","title":{"rendered":"The mechanism of silylether deprotection using a tetra-alkyl ammonium fluoride."},"content":{"rendered":"
\n

\n\tThe substitution of a nucleofuge<\/a> (a good leaving group) by a nucleophile at a carbon centre occurs with inversion of configuration at the carbon, the mechanism being known by the term SN<\/sub>2 (a story I have also told in this post<\/a>). Such displacement at silicon famously proceeds by a quite different mechanism, which I here quantify with some calculations.\n<\/p>\n

\n\t\"\"\n<\/p>\n

\n\tTrialkylsilyl is often used to protect OH groups, and as shown in the diagram above is specifically used to enforce the enol form of a ketone by replacing the OH with OTMS. The TMS can then be removed when required by utilising nucleophilic addition of e.g.<\/em> fluoride anion from tetra-alkyl ammonium fluoride to form a 5-coordinate silicon intermediate, followed by collapse of this intermediate with expulsion of the oxygen to form an enolate anion. Before starting the calculations, I searched the crystal structure database for examples of R3<\/sub>SIF(OR), as in the search query below.\n<\/p>\n

\n\t\"\"\n<\/p>\n

\n\tThere were 55 instances of such species, and show below are their geometric characteristics. In all cases, the two electronegative substituents occupy the axial positions of a trigonal bipyramidal<\/strong> geometry. This of course is the orientation adopted by the two electronegative substituents in the SN<\/sub>2 mechanism for carbon, but with silicon this carbon "transition state" can be replaced by a stable (and as we see often crystalline) intermediate!\n<\/p>\n

\n\t\"\"\n<\/p>\n

\n\tTurning to calculations (ωB97XD\/6-31+G(d)\/SCRF=thf), one can locate three<\/strong> transition states for the silicon process (there is only one for the SN<\/sub>2 reaction with carbon).\n<\/p>\n

    \n
  1. \n\t\tTS1 represents attack of fluoride anion along the axial position of the forming 5-coordinate silicon.[1]<\/a><\/span>,[2]<\/a><\/span> The oxygen in this instance occupies an equatorial position, and this close proximity between the incoming F(-) and the about to depart OR groups represents a retention of configuration <\/em><\/span>at the Si. Note that the reaction is endo-energic. (c.f.<\/em> [3]<\/a><\/span>).
    \n\t\t\"\"
    \n\t\t\"\"
    \n\t\t\"\"\n\t<\/li>\n
  2. \n\t\tThe next step, TS2[4]<\/a><\/span>,[5]<\/a><\/span>  is to move the F ligand to an equatorial position and the OR group from equatorial to its own axial position so that it can depart in the manner the F adopted to arrive. This requires what is called a Berry pseudorotation<\/span>, an essentially isoenergic process.
    \n\t\t\"\"
    \n\t\t\"\"
    \n\t\t\"\"
    \n\t\tYou might note a "hidden intermediate" at IRC ~-7 (the "bump" in the energy profile). This is caused by re-organisation of the ion-pair geometry, with the tetra-alkyl ammonium cation moving its orientation.
    \n\t\t\"\"\n\t<\/li>\n
  3. \n\t\tTS3[6]<\/a><\/span>,[7]<\/a><\/span> now eliminates the –<\/sup>OR group to complete the deprotection.
    \n\t\t\"\"
    \n\t\t\"\"
    \n\t\t\"\"\n\t<\/li>\n<\/ol>\n

    \n\tThe free energies are summarised below. Key points include:\n<\/p>\n

      \n
    1. \n\t\tThe overall free energy of deprotection is appropriately exo-energic.\n\t<\/li>\n
    2. \n\t\tThe highest energy barrier is actually for pseudo-rotation! This suggests that tuning the deprotection with alternative alkyl or aryl groups on the silicon may be a matter of controlling the Berry pseudorotation process.\n\t<\/li>\n
    3. \n\t\tTS1-3 proceed with the attacking and leaving groups in close proximity (the angle between an axial and an equatorial group is ~90° of course, whereas for a di-axial relationship (the inversion of the SN<\/sub>2 mechanism) it is instead 180°. This close proximity of nucleophile and nucleofuge minimises the required reorganisation of the ammonium counter-ion in the ion-pairs, and possibly also the dipole moments induced by the reactions, the changes of which for the three reactions are shown below:
      \n\t\t\"\"
      \n\t\t\"\"
      \n\t\t\"\"\n\t<\/li>\n
    4. \n\t\tThe 5-coordinate intermediate where both F and O are axial is in fact significantly lower in energy (a cooperative effect) than when only one of them is axial, which matches the orientations identified above in the 55 crystal structures. For a substitution to occur, the cooperative strengthening of the Si-O and Si-F bonds must be removed; hence the retention of configuration<\/em><\/span>.\n\t<\/li>\n<\/ol>\n\n\n\n\n\n\n\n\n\n\n\n
      \n\t\t\t\tSystem\n\t\t\t<\/th>\n\n\t\t\t\tRelative free energy\n\t\t\t<\/th>\n\n\t\t\t\tDataDOI\n\t\t\t<\/th>\n<\/tr>\n
      \n\t\t\t\tReactants\n\t\t\t<\/td>\n\n\t\t\t\t0.0\n\t\t\t<\/td>\n\n\t\t\t\t[8]<\/a><\/span>\n\t\t\t<\/td>\n<\/tr>\n
      \n\t\t\t\tTS1\n\t\t\t<\/td>\n\n\t\t\t\t7.9\n\t\t\t<\/td>\n\n\t\t\t\t[1]<\/a><\/span>\n\t\t\t<\/td>\n<\/tr>\n
      \n\t\t\t\tInt F(ax), O(eq)\n\t\t\t<\/td>\n\n\t\t\t\t5.1\n\t\t\t<\/td>\n\n\t\t\t\t[9]<\/a><\/span>\n\t\t\t<\/td>\n<\/tr>\n
      \n\t\t\t\tTS2\n\t\t\t<\/td>\n\n\t\t\t\t10.2 (9.2)*\n\t\t\t<\/td>\n\n\t\t\t\t[4]<\/a><\/span>\n\t\t\t<\/td>\n<\/tr>\n
      \n\t\t\t\tInt F(eq), O(ax)\n\t\t\t<\/td>\n\n\t\t\t\t5.1\n\t\t\t<\/td>\n\n\t\t\t\t[10]<\/a><\/span>\n\t\t\t<\/td>\n<\/tr>\n
      \n\t\t\t\tTS3\n\t\t\t<\/td>\n\n\t\t\t\t5.2\n\t\t\t<\/td>\n\n\t\t\t\t[6]<\/a><\/span>\n\t\t\t<\/td>\n<\/tr>\n
      \n\t\t\t\tProducts\n\t\t\t<\/td>\n\n\t\t\t\t-4.0\n\t\t\t<\/td>\n\n\t\t\t\t[11]<\/a><\/span>\n\t\t\t<\/td>\n<\/tr>\n
      \n\t\t\t\tInt F,O(ax)\n\t\t\t<\/td>\n\n\t\t\t\t-2.5\n\t\t\t<\/td>\n\n\t\t\t\t[12]<\/a><\/span>\n\t\t\t<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

      \n\t*A lower energy orientation of the ion-pair has subsequently been found.[13]<\/a><\/span>\n<\/p>\n

      \n\tThis analysis shows just how different the carbon and the silicon substitution reactions are and how it is the pseudorotation interconverting two 5-coordinate intermediates that appears to be a key step. But questions remain unanswered. What is the energy of the pseudorotation interconverting an intermediate with ax\/eq<\/strong> electronegative groups to one with di-axial<\/strong> electronegative groups? Are there transition states starting from the diaxial intermediate and resulting in elimination, and if so what are their relative energies? I leave answers to a follow up post. <\/p>\n

      References<\/h2>\n
      1. H. Rzepa, \"trimethyl silyl enol + Me4N(+).F(-) 5-coordinate intermediate F axial TS\", 2016. https:\/\/doi.org\/10.14469\/hpc\/554<\/a>\n\n<\/li>\n
      2. H. Rzepa, \"trimethyl silyl enol + Me4N(+).F(-) 5-coordinate intermediate F axial TS IRC\", 2016. https:\/\/doi.org\/10.14469\/hpc\/564<\/a>\n\n<\/li>\n
      3. L. Wozniak, M. Cypryk, J. Chojnowski, and G. Lanneau, \"Optically active silyl esters of phosphorus. II. Stereochemistry of reactions with nucleophiles\", Tetrahedron<\/i>, vol. 45, pp. 4403-4414, 1989. https:\/\/doi.org\/10.1016\/s0040-4020(01)89077-3<\/a>\n\n<\/li>\n
      4. H. Rzepa, \"trimethyl silyl enol + Me4N(+).F(-) 5-coordinate intermediate Berry pseudorotation TS\", 2016. https:\/\/doi.org\/10.14469\/hpc\/551<\/a>\n\n<\/li>\n
      5. H. Rzepa, \"trimethyl silyl enol + Me4N(+).F(-) 5-coordinate intermediate Berry pseudorotation TS IRC\", 2016. https:\/\/doi.org\/10.14469\/hpc\/553<\/a>\n\n<\/li>\n
      6. H. Rzepa, \"trimethyl silyl enol + Me4N(+).F(-) TS\", 2016. https:\/\/doi.org\/10.14469\/hpc\/539<\/a>\n\n<\/li>\n
      7. H. Rzepa, \"trimethyl silyl enol + Me4N(+).F(-) TS IRC\", 2016. https:\/\/doi.org\/10.14469\/hpc\/552<\/a>\n\n<\/li>\n
      8. H. Rzepa, \"enol + Me4N(+).F(-) Reactant\", 2016. https:\/\/doi.org\/10.14469\/hpc\/565<\/a>\n\n<\/li>\n
      9. H. Rzepa, \"enol + Me4N(+).F(-) 5-coordinate intermediate F axial\", 2016. https:\/\/doi.org\/10.14469\/hpc\/555<\/a>\n\n<\/li>\n
      10. H. Rzepa, \"trimethyl silyl enol + Me4N(+).F(-) 5-coordinate intermediate\", 2016. https:\/\/doi.org\/10.14469\/hpc\/540<\/a>\n\n<\/li>\n
      11. H. Rzepa, \"enol + Me4N(+).F(-) Product\", 2016. https:\/\/doi.org\/10.14469\/hpc\/563<\/a>\n\n<\/li>\n
      12. H. Rzepa, \"trimethyl silyl enol + Me4N(+).F(-) 5-coordinate intermediate F\/O axial\", 2016. https:\/\/doi.org\/10.14469\/hpc\/550<\/a>\n\n<\/li>\n
      13. H. Rzepa, \"5-coordinate intermediate Berry pseudorotation TS2 New conf?\", 2016. https:\/\/doi.org\/10.14469\/hpc\/577<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

        The substitution of a nucleofuge (a good leaving group) by a nucleophile at a carbon centre occurs with inversion of configuration at the carbon, the mechanism being known by the term SN2 (a story I have also told in this post). Such displacement at silicon famously proceeds by a quite different mechanism, which I here quantify with some calculations. Trialkylsilyl is often […]<\/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":[1086],"tags":[1784,1787,24,939,931,40,1779,1788,1630,1785,151,1780,734,1786,1560,1775],"ppma_author":[2661],"class_list":["post-16402","post","type-post","status-publish","format-standard","hentry","category-reaction-mechanism-2","tag-berry-mechanism","tag-elimination-reaction","tag-energy","tag-energy-barrier","tag-energy-profile","tag-free-energy","tag-leaving-group","tag-lower-energy-orientation","tag-molecular-geometry","tag-organic-reactions","tag-overall-free-energy","tag-pseudorotation","tag-search-query","tag-sn2-reaction","tag-stereochemistry","tag-trigonal-bipyramidal-molecular-geometry"],"yoast_head":"\nThe mechanism of silylether deprotection using a tetra-alkyl ammonium fluoride. - 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=16402\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"The mechanism of silylether deprotection using a tetra-alkyl ammonium fluoride. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"The substitution of a nucleofuge (a good leaving group) by a nucleophile at a carbon centre occurs with inversion of configuration at the carbon, the mechanism being known by the term SN2 (a story I have also told in this post). 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Matthias Bickelhaupt had suggested that the Sn2 reaction involving displacement at a carbon atom was an anomaly; the true behaviour was in fact exhibited by the next element down in the series, silicon. 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":"","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/09\/sn2-Na1.gif?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":4002,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=4002","url_meta":{"origin":16402,"position":1},"title":"The Sn1…Sn2 mechanistic continuum. The special case of neopentyl bromide","author":"Henry Rzepa","date":"May 9, 2011","format":false,"excerpt":"Introductory organic chemistry invariably features the mechanism of haloalkane solvolysis, and introduces both the Sn1 two-step mechanism, and the Sn2 one step mechanism to students. They are taught to balance electronic effects (the stabilization of carbocations) against steric effects in order to predict which mechanism prevails. It was whilst preparing\u2026","rel":"","context":"In \"free energy\"","block_context":{"text":"free energy","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?tag=free-energy"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2011\/05\/neopentyl-ts.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":25313,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=25313","url_meta":{"origin":16402,"position":2},"title":"Unexpected Isomerization of Oxetane-Carboxylic Acids – a first look at the mechanism","author":"Henry Rzepa","date":"August 7, 2022","format":false,"excerpt":"Derek Lowe's blog has a recent post entitled A Downside to Oxetane Acids which picks up on a recent article describing how these acids are unexpectedly unstable, isomerising to a lactone at a significant rate without the apparent need for any catalyst. This is important because these types of compound\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":20464,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=20464","url_meta":{"origin":16402,"position":3},"title":"The Graham reaction: Deciding upon a reasonable mechanism and curly arrow representation.","author":"Henry Rzepa","date":"February 18, 2019","format":false,"excerpt":"Students learning organic chemistry are often asked in examinations and tutorials to devise the mechanisms (as represented by curly arrows) for the core corpus of important reactions, with the purpose of learning skills that allow them to go on to improvise mechanisms for new reactions. A common question asked by\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":"","width":0,"height":0},"classes":[]},{"id":20560,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=20560","url_meta":{"origin":16402,"position":4},"title":"Smoke and mirrors. All is not what it seems with this Sn2 reaction!","author":"Henry Rzepa","date":"April 4, 2019","format":false,"excerpt":"Previously, I explored the Graham reaction to form a diazirine. The second phase of the reaction involved an Sn2' displacement of N-Cl forming C-Cl. Here I ask how facile the simpler displacement of C-Cl by another chlorine might be and whether the mechanism is Sn2 or the alternative Sn1. 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":"","src":"","width":0,"height":0},"classes":[]},{"id":8540,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8540","url_meta":{"origin":16402,"position":5},"title":"The mechanism of the Birch reduction. Part 3: reduction of benzene","author":"Henry Rzepa","date":"December 4, 2012","format":false,"excerpt":"Birch reduction of benzene itself results in 1,4-cyclohexadiene rather than the more stable (conjugated) 1,3-cyclohexadiene. Why is this? The mechanism, as elaborated in the previous two posts, involves a one-electron transfer from a sodium atom to form the radical anion, which is then protonated in a second step, and this\u2026","rel":"","context":"In \"Birch reduction\"","block_context":{"text":"Birch reduction","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?tag=birch-reduction"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/12\/birch-ip.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\/16402","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=16402"}],"version-history":[{"count":38,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/16402\/revisions"}],"predecessor-version":[{"id":16461,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/16402\/revisions\/16461"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=16402"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=16402"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=16402"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=16402"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}