{"id":3287,"date":"2018-07-04T13:23:23","date_gmt":"2018-07-04T13:23:23","guid":{"rendered":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/?post_type=chapter&#038;p=3287"},"modified":"2024-01-16T04:31:04","modified_gmt":"2024-01-16T04:31:04","slug":"9-7-enolate-alkylation","status":"publish","type":"chapter","link":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/chapter\/9-7-enolate-alkylation\/","title":{"raw":"9.7. Enolate alkylation","rendered":"9.7. Enolate alkylation"},"content":{"raw":"<section class=\"mt-content-container\">The anions from ketones, called enolates, can act as a nucleophile in S<sub>N<\/sub>2 type reactions.\u00a0 Overall an \u03b1 hydrogen is replaced with an alkyl group and a new carbon-carbon bond is formed.\u00a0 These alkylations are affected by the same limitations as S<sub>N<\/sub>2 reactions previously discussed.\u00a0 A good leaving group, chloride, bromide, iodide or tosylate, should be used.\u00a0 Also, secondary and tertiary leaving groups should not be used because of poor reactivity and possible competition with elimination reactions.\u00a0 Lastly, it is important to use a strong base, such as LDA, for preparing the enolate from the ketone.\u00a0 Using a weaker base such as hydroxide or an alkoxide leaves the possibility of multiple alkylations occurring, and competing S<sub>N<\/sub>2 reactions with the base.<img class=\"size-full wp-image-4873 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152013\/EnolateAlkylation1Ruesch1.png\" alt=\"\" width=\"394\" height=\"108\" \/>\r\n<table class=\"Example\">\r\n<tbody>\r\n<tr>\r\n<th>Example 1: Alpha Alkylation<\/th>\r\n<\/tr>\r\n<tr>\r\n<td><img class=\"size-full wp-image-4879 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152523\/alphaAlkylation1Ruesch1.jpg\" alt=\"\" width=\"624\" height=\"102\" \/><\/td>\r\n<\/tr>\r\n<\/tbody>\r\n<\/table>\r\n<div id=\"section_1\" class=\"mt-section\">\r\n<h3 class=\"editable\">Mechanism<\/h3>\r\n1) Formation of the enolate via an acid-base reaction:\r\n\r\n<img class=\"alignnone  wp-image-5172\" src=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism1.png\" alt=\"Formation of an enolate by deprotonation of a ketone with LDA\" width=\"816\" height=\"120\" \/>\r\n\r\n2) S<sub>N<\/sub>2 reaction of the enolate (as nucleophile) with a primary or secondary alkyl halide.\r\n\r\n<img class=\"alignnone  wp-image-5173\" src=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism2.png\" alt=\"Mechanism of the SN2 reaction of an enolate with an alkyl halide\" width=\"751\" height=\"116\" \/>\r\n\r\n<\/div>\r\n<div id=\"section_2\" class=\"mt-section\">\r\n<h3 class=\"editable\">Alkylation of Unsymmetrical Ketones<\/h3>\r\nUnsymmetrical ketones can be regioselctively alkylated to form one major product depending on the reagents.\r\n\r\nTreatment with LDA in THF at -78<sup>o<\/sup>C tends to form the less substituted kinetic enolate.\r\n\r\n<img class=\"alignnone wp-image-4876\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152313\/EnolateAlkylationLDA1.png\" alt=\"\" width=\"536\" height=\"140\" \/>\r\n\r\nUsing sodium ethoxide in ethanol at room temperature forms the more substituted thermodynamic enolate, though yields of alkylation product are likely to be poorer because of the side reactions mentioned above.\r\n\r\n<\/div>\r\n<div id=\"section_3\" class=\"mt-section\">\r\n\r\n<img class=\"alignnone wp-image-4877\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152359\/EnolateAlkylationNaOEt1.png\" alt=\"\" width=\"553\" height=\"153\" \/>\r\n<h3 class=\"editable\">Problems<\/h3>\r\n1) Please write the structure of the product for the following reactions.\r\n\r\n<img class=\"alignnone wp-image-4880\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152609\/EnolateAlkylationProblems1.jpg\" alt=\"\" width=\"276\" height=\"199\" \/>\r\n\r\nAnswers\r\n\r\n1)\r\n\r\n<img class=\"alignnone wp-image-4881\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152648\/EnolateAlkylationAnswers1.jpg\" alt=\"\" width=\"274\" height=\"138\" \/>\r\n\r\n<\/div>\r\n<div id=\"section_4\" class=\"mt-section\">\r\n<h3 class=\"editable\">Contributors<\/h3>\r\n<ul>\r\n \t<li>William Reusch, Professor Emeritus (<a class=\"external\" title=\"http:\/\/www.msu.edu\/\" href=\"http:\/\/www.msu.edu\/\" target=\"_blank\" rel=\"external nofollow noopener\">Michigan State U.<\/a>), <a href=\"https:\/\/www2.chemistry.msu.edu\/faculty\/reusch\/VirtTxtJml\/intro1.htm\">Virtual Textbook of\u00a0Organic\u00a0Chemistry<\/a><\/li>\r\n \t<li>Prof. Steven Farmer (<a class=\"external\" title=\"http:\/\/www.sonoma.edu\" href=\"http:\/\/www.sonoma.edu\" target=\"_blank\" rel=\"external nofollow noopener\">Sonoma State University<\/a>)<\/li>\r\n<\/ul>\r\n<\/div>\r\n<footer class=\"mt-content-footer\"><\/footer><\/section>","rendered":"<section class=\"mt-content-container\">The anions from ketones, called enolates, can act as a nucleophile in S<sub>N<\/sub>2 type reactions.\u00a0 Overall an \u03b1 hydrogen is replaced with an alkyl group and a new carbon-carbon bond is formed.\u00a0 These alkylations are affected by the same limitations as S<sub>N<\/sub>2 reactions previously discussed.\u00a0 A good leaving group, chloride, bromide, iodide or tosylate, should be used.\u00a0 Also, secondary and tertiary leaving groups should not be used because of poor reactivity and possible competition with elimination reactions.\u00a0 Lastly, it is important to use a strong base, such as LDA, for preparing the enolate from the ketone.\u00a0 Using a weaker base such as hydroxide or an alkoxide leaves the possibility of multiple alkylations occurring, and competing S<sub>N<\/sub>2 reactions with the base.<img loading=\"lazy\" decoding=\"async\" class=\"size-full wp-image-4873 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152013\/EnolateAlkylation1Ruesch1.png\" alt=\"\" width=\"394\" height=\"108\" \/><\/p>\n<table class=\"Example\">\n<tbody>\n<tr>\n<th>Example 1: Alpha Alkylation<\/th>\n<\/tr>\n<tr>\n<td><img loading=\"lazy\" decoding=\"async\" class=\"size-full wp-image-4879 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152523\/alphaAlkylation1Ruesch1.jpg\" alt=\"\" width=\"624\" height=\"102\" \/><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<div id=\"section_1\" class=\"mt-section\">\n<h3 class=\"editable\">Mechanism<\/h3>\n<p>1) Formation of the enolate via an acid-base reaction:<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone  wp-image-5172\" src=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism1.png\" alt=\"Formation of an enolate by deprotonation of a ketone with LDA\" width=\"816\" height=\"120\" srcset=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism1.png 1305w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism1-300x44.png 300w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism1-768x113.png 768w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism1-1024x151.png 1024w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism1-65x10.png 65w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism1-225x33.png 225w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism1-350x51.png 350w\" sizes=\"auto, (max-width: 816px) 100vw, 816px\" \/><\/p>\n<p>2) S<sub>N<\/sub>2 reaction of the enolate (as nucleophile) with a primary or secondary alkyl halide.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone  wp-image-5173\" src=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism2.png\" alt=\"Mechanism of the SN2 reaction of an enolate with an alkyl halide\" width=\"751\" height=\"116\" srcset=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism2.png 1160w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism2-300x46.png 300w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism2-768x119.png 768w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism2-1024x158.png 1024w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism2-65x10.png 65w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism2-225x35.png 225w, https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/wp-content\/uploads\/sites\/3369\/2018\/07\/Enolate-alkylation-mechanism2-350x54.png 350w\" sizes=\"auto, (max-width: 751px) 100vw, 751px\" \/><\/p>\n<\/div>\n<div id=\"section_2\" class=\"mt-section\">\n<h3 class=\"editable\">Alkylation of Unsymmetrical Ketones<\/h3>\n<p>Unsymmetrical ketones can be regioselctively alkylated to form one major product depending on the reagents.<\/p>\n<p>Treatment with LDA in THF at -78<sup>o<\/sup>C tends to form the less substituted kinetic enolate.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-4876\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152313\/EnolateAlkylationLDA1.png\" alt=\"\" width=\"536\" height=\"140\" \/><\/p>\n<p>Using sodium ethoxide in ethanol at room temperature forms the more substituted thermodynamic enolate, though yields of alkylation product are likely to be poorer because of the side reactions mentioned above.<\/p>\n<\/div>\n<div id=\"section_3\" class=\"mt-section\">\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-4877\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152359\/EnolateAlkylationNaOEt1.png\" alt=\"\" width=\"553\" height=\"153\" \/><\/p>\n<h3 class=\"editable\">Problems<\/h3>\n<p>1) Please write the structure of the product for the following reactions.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-4880\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152609\/EnolateAlkylationProblems1.jpg\" alt=\"\" width=\"276\" height=\"199\" \/><\/p>\n<p>Answers<\/p>\n<p>1)<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-4881\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3369\/2018\/07\/06152648\/EnolateAlkylationAnswers1.jpg\" alt=\"\" width=\"274\" height=\"138\" \/><\/p>\n<\/div>\n<div id=\"section_4\" class=\"mt-section\">\n<h3 class=\"editable\">Contributors<\/h3>\n<ul>\n<li>William Reusch, Professor Emeritus (<a class=\"external\" title=\"http:\/\/www.msu.edu\/\" href=\"http:\/\/www.msu.edu\/\" target=\"_blank\" rel=\"external nofollow noopener\">Michigan State U.<\/a>), <a href=\"https:\/\/www2.chemistry.msu.edu\/faculty\/reusch\/VirtTxtJml\/intro1.htm\">Virtual Textbook of\u00a0Organic\u00a0Chemistry<\/a><\/li>\n<li>Prof. Steven Farmer (<a class=\"external\" title=\"http:\/\/www.sonoma.edu\" href=\"http:\/\/www.sonoma.edu\" target=\"_blank\" rel=\"external nofollow noopener\">Sonoma State University<\/a>)<\/li>\n<\/ul>\n<\/div>\n<footer class=\"mt-content-footer\"><\/footer>\n<\/section>\n\n\t\t\t <section class=\"citations-section\" role=\"contentinfo\">\n\t\t\t <h3>Candela Citations<\/h3>\n\t\t\t\t\t <div>\n\t\t\t\t\t\t <div id=\"citation-list-3287\">\n\t\t\t\t\t\t\t <div class=\"licensing\"><div class=\"license-attribution-dropdown-subheading\">CC licensed content, Shared previously<\/div><ul class=\"citation-list\"><li>23.8: Direct Enolate Alkylation. <strong>Authored by<\/strong>: William Reusch,  Prof. Steven Farmer. <strong>Located at<\/strong>: <a target=\"_blank\" href=\"https:\/\/chem.libretexts.org\/Textbook_Maps\/Organic_Chemistry\/Map%3A_Organic_Chemistry_(Smith)\/Chapter_23%3A_Substitution_Reactions_of_Carbonyl_Compounds_at_the_Alpha_Carbon\/23.8%3A_Direct_Enolate_Alkylation\">https:\/\/chem.libretexts.org\/Textbook_Maps\/Organic_Chemistry\/Map%3A_Organic_Chemistry_(Smith)\/Chapter_23%3A_Substitution_Reactions_of_Carbonyl_Compounds_at_the_Alpha_Carbon\/23.8%3A_Direct_Enolate_Alkylation<\/a>. <strong>Project<\/strong>: Chemistry LibreTexts. <strong>License<\/strong>: <em><a target=\"_blank\" rel=\"license\" href=\"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/\">CC BY-NC-SA: Attribution-NonCommercial-ShareAlike<\/a><\/em><\/li><\/ul><\/div>\n\t\t\t\t\t\t <\/div>\n\t\t\t\t\t <\/div>\n\t\t\t <\/section>","protected":false},"author":311,"menu_order":7,"template":"","meta":{"_candela_citation":"[{\"type\":\"cc\",\"description\":\"23.8: Direct Enolate Alkylation\",\"author\":\"William Reusch,  Prof. Steven Farmer\",\"organization\":\"\",\"url\":\"https:\/\/chem.libretexts.org\/Textbook_Maps\/Organic_Chemistry\/Map%3A_Organic_Chemistry_(Smith)\/Chapter_23%3A_Substitution_Reactions_of_Carbonyl_Compounds_at_the_Alpha_Carbon\/23.8%3A_Direct_Enolate_Alkylation\",\"project\":\"Chemistry 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