{"id":6762,"date":"2012-11-30T12:44:13","date_gmt":"2012-11-30T17:44:13","guid":{"rendered":"https:\/\/www.masterorganicchemistry.com\/?p=6762"},"modified":"2025-05-07T19:21:26","modified_gmt":"2025-05-08T00:21:26","slug":"deciding-sn1sn2e1e2-2-the-nucleophilebase","status":"publish","type":"post","link":"https:\/\/www.masterorganicchemistry.com\/2012\/11\/30\/deciding-sn1sn2e1e2-2-the-nucleophilebase\/","title":{"rendered":"Deciding SN1\/SN2\/E1\/E2 (2) &#8211; The Nucleophile\/Base"},"content":{"rendered":"<p><strong>S<sub>N<\/sub>1 \/ S<sub>N<\/sub>2 \/ E1 \/ E2 The Nucleophile \/ Base<\/strong><\/p>\n<ul>\n<li>This article assumes you understand the mechanisms of the S<sub>N<\/sub>1\/S<sub>N<\/sub>2\/E1 and E2 reactions. For review, see here [<a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/07\/13\/the-sn1-mechanism\/\">S<sub>N<\/sub>1<\/a>] [<a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/07\/04\/the-sn2-mechanism\/\">S<sub>N<\/sub>2<\/a>] [<a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/09\/19\/the-e1-reaction\/\">E1<\/a>] [<a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/09\/27\/the-e2-mechanism\/\">E2<\/a>]<\/li>\n<li>S<sub>N<\/sub>1\/S<sub>N<\/sub>2\/E1\/E2 reactions tend to happen on <strong>alkyl<\/strong> halides [<em>see <a href=\"https:\/\/www.masterorganicchemistry.com\/2023\/01\/18\/where-will-substitution-elimination-reactions-occur\/\">Identifying Where Substitution and Elimination Reactions Happen<\/a><\/em>]<\/li>\n<li>Determining whether the alkyl halide is primary, secondary, tertiary (or methyl) helps to narrow down the possibilities\u00a0 [<em><span style=\"color: #993366;\">See <a style=\"color: #993366;\" href=\"https:\/\/www.masterorganicchemistry.com\/2012\/11\/21\/deciding-sn1sn2e1e2-1-the-substrate\/\">SN1\/SN2\/E1\/E2 &#8211; The Substrate<\/a><\/span>]<\/em><\/li>\n<li><strong>Primary<\/strong> alkyl halides tend to go through <strong>S<sub>N<\/sub>2<\/strong> reactions. <strong>Tertiary<\/strong> alkyl halides <strong>never<\/strong> go S<sub>N<\/sub>2.<\/li>\n<li>Identifying the substrate alone often isn&#8217;t enough to narrow down the available possibilities, so the next step is to examine the <strong>nucleophile \/ base.\u00a0<\/strong>That&#8217;s the purpose of this article!<\/li>\n<li>For our purposes, &#8220;<strong>strong<\/strong>&#8221; nucleophiles\/bases are <strong>negatively <\/strong>charged and &#8220;<strong>weak&#8221;<\/strong> nucleophiles\/bases are <strong>neutral<\/strong><\/li>\n<li>A good rule of thumb is to expect <strong>S<sub>N<\/sub>2<\/strong><strong>\/E2<\/strong> with &#8220;<strong>strong<\/strong>&#8216; (i.e. negatively charged) nucleophiles\/bases and expect <strong>S<sub>N<\/sub>1\/E1<\/strong> with <strong>neutral<\/strong> nucleophiles\/bases<\/li>\n<li>So the main focus of this article is in<strong> distinguishing S<sub>N<\/sub>1\/E1 from S<sub>N<\/sub>2\/E2<\/strong>, although this article will also discuss some ways of distinguishing S<sub>N<\/sub>2 from E2 based on basicity.<\/li>\n<li>Many quizzes and examples below, including exceptions.<\/li>\n<\/ul>\n<p><img fetchpriority=\"high\" decoding=\"async\" class=\"alignnone wp-image-34959\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2023\/05\/0-sn1-sn2-e1-e2-summary-identity-of-the-nucleophile-summary.gif\" alt=\"sn1-sn2-e1-e2-summary-identity of the nucleophile summary\" width=\"640\" height=\"760\" \/><\/a><\/p>\n<p><strong>Table of Contents<\/strong><\/p>\n<ol>\n<li style=\"list-style-type: none;\">\n<ol>\n<li><a href=\"#one\">Identifying the Nucleophile \/ Base<\/a><\/li>\n<li><a href=\"#two\">&#8220;Strong&#8221; (Negatively charged) Versus &#8220;Weak&#8221; (Neutral) Acids and Bases<\/a><\/li>\n<li><a href=\"#three\">The Six Major Cases, Based On Substrate + Nucleophile\/Base<\/a><\/li>\n<li><a href=\"#four\">Secondary Alkyl Halides: The Importance of Base Strength<\/a><\/li>\n<li><a href=\"#five\">More On The &#8220;S<sub>N<\/sub>1 vs E1&#8243; and &#8220;S<sub>N<\/sub>2 vs E2&#8243; Cases<\/a><\/li>\n<li><a href=\"#six\">Do Acid-Base Reactions First<\/a><\/li>\n<li><a href=\"#seven\">Because You Can Never Have Enough Practice With Intramolecular Examples<\/a><\/li>\n<li><a href=\"#eight\">The Substrate Always Has The Final Say<\/a><\/li>\n<li><a href=\"#nine\">Summary<\/a><\/li>\n<li><a href=\"#notes\">Notes<\/a><\/li>\n<li><a href=\"#quiz\">Quiz Yourself!<\/a><\/li>\n<li><a href=\"#references\">(Advanced) References and Further Reading<\/a><\/li>\n<\/ol>\n<\/li>\n<\/ol>\n<hr \/>\n<h2><a id=\"one\"><\/a>1. Identifying the Nucleophile \/ Base<\/h2>\n<p>In previous articles were able to identify <strong>substrates<\/strong> as primary, secondary or tertiary. [<em><span style=\"color: #993366;\">See articles<\/span> &#8211;<a href=\"https:\/\/www.masterorganicchemistry.com\/2023\/01\/18\/where-will-substitution-elimination-reactions-occur\/\"> Identifying Where Substitution and Elimination Reactions Happen<\/a>, <span style=\"color: #993366;\">and<\/span> <a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/11\/21\/deciding-sn1sn2e1e2-1-the-substrate\/\">S<sub>N<\/sub>1\/S<sub>N<\/sub>2\/E1\/E2 &#8211; The Substrate<\/a>]<\/em><\/p>\n<p>This was helpful in being able to quickly rule out certain reactions.<\/p>\n<ul>\n<li>For example, if a substrate is\u00a0<strong>primary<\/strong>, you can generally rule out the S<sub>N<\/sub>1 or E1 reactions since they go through a carbocation intermediate and primary carbocations are unstable. With few exceptions (<span style=\"color: #993366;\"><em>bulky bases<\/em><\/span>) primary substrates will generally go through S<sub>N<\/sub>2.<\/li>\n<li>If a substrate is <strong>tertiary<\/strong>, you can rule out S<sub>N<\/sub>2 since backside attack will be too slow due to steric hindrance impeding the nucleophile&#8217;s approach to the C-LG sigma* orbital<\/li>\n<\/ul>\n<p>Once you have done this analysis, you&#8217;ll likely still have several possibilities. How can you narrow them down even further?<\/p>\n<p>The next step in the deductive process is to examine the\u00a0<strong>nucleophile<\/strong> or\u00a0<strong>base<\/strong>. (<span style=\"color: #993366;\"><em>Remember, a &#8220;nucleophile&#8221; is just what we call a base when it&#8217;s attacking an atom other than hydrogen, such as carbon<\/em><\/span>.)<\/p>\n<p>See if you can identify the nucleophile or base in these reactions below. When there are multiple potential nucleophiles\/bases present, choose the <strong>strongest\u00a0<\/strong>one. (<span style=\"color: #993366;\"><em>More on that in a second<\/em><\/span>).<\/p>\n<div class=\"wq-quiz-wrapper\" data-id=\"34736\"><style type=\"text\/css\" id=\"wq-flip-custom-css\">.wq-quiz-wrapper[data-id=\"34736\"] {\n--wq-question-width: 100%;\n--wq-question-color: #009cff;\n--wq-question-height: auto;\n--wq-font-color: #444;\n}\n\n\t\t\t.wq-quiz-wrapper[data-id=\"34736\"] {\n\t\t\t\t--wq-question-width: 600px;\n\t\t\t}\n\n\t\t\t@media screen and (max-width: 600px) {\n\t\t\t\t.wq-quiz-wrapper[data-id=\"34736\"] .wq_singleQuestionWrapper { width:100% !important; height:auto !important; }\n\t\t\t}\n\t\t<\/style><!-- wp quiz -->\n<div id=\"wp-quiz-34736\" class=\"wq_quizCtr single flip_quiz wq-quiz wq-quiz-34736 wq-quiz-flip wq-layout-single wq-skin-traditional wq-should-show-correct-answer\" data-quiz-id=\"34736\">\n<div class=\"wq-questions wq_questionsCtr\">\n\t<div class=\"wq-question wq_singleQuestionWrapper wq-question-5eq4h\" data-id=\"5eq4h\">\n\n\t\n\t<div class=\"item_top\">\n\t\t<div class=\"title_container\">\n\t\t\t<div class=\"wq_questionTextCtr\">\n\t\t\t\t<h4 class=\"wq-question-title\"><\/h4>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n\n\t<div class=\"card \">\n\t\t<div class=\"front\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2489-Front.gif\" \/>\n\t\t\n\t\t\n\t\n\t\n\t\t\t<span class=\"top-desc\">Click to Flip<\/span>\n\t<\/div>\n\t\t<div class=\"back\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2489-Reverse.gif\" \/>\n\t\t\n\t\t\n\t\n\t<\/div>\n\t<\/div>\n\n\t\n<\/div>\n<\/div>\n<\/div>\n<!-- \/\/ wp quiz-->\n<\/div><!-- End .wq-quiz-wrapper -->\n<p>The substrate will react the <strong>fastest<\/strong> with the <strong>strongest<\/strong> nucleophile\/base that is present.<\/p>\n<p>The conjugate base is always a better nucleophile [<span style=\"color: #993366;\"><em>See article &#8211; <a style=\"color: #993366;\" href=\"https:\/\/www.masterorganicchemistry.com\/2012\/06\/18\/what-makes-a-good-nucleophile\/\">What Makes A Good Nucleophile?<\/a><\/em><\/span>], and the conjugate base is always a stronger base [<span style=\"color: #993366;\"><em>See article &#8211;\u00a0 <a style=\"color: #993366;\" href=\"https:\/\/www.masterorganicchemistry.com\/2010\/09\/29\/how-to-use-a-pka-table\/\">How To Use A pK<sub>a<\/sub> Table<\/a><\/em><\/span>].<\/p>\n<p>So if you see NaOCH<sub>2<\/sub>CH<sub>3<\/sub> in the presence of CH<sub>3<\/sub>CH<sub>2<\/sub>OH or\u00a0<em>t<\/em>BuO(-) in the presence of<em>\u00a0t-<\/em>BuOH<em>, <\/em>the negatively charged species will be the active one.<\/p>\n<p><img decoding=\"async\" class=\"alignnone wp-image-34553\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2023\/05\/2-The-conjugate-base-is-a-stronger-base-and-a-better-nucleophile.gif\" alt=\"The conjugate base is a stronger base and a better nucleophile\" width=\"640\" height=\"430\" \/><\/a><\/p>\n<p>Another tip:\u00a0 don&#8217;t fall into the common trap of assuming that the nucleophile will always be listed on the top of the arrow. Sometimes it&#8217;s actually the <strong>nucleophile<\/strong> that is drawn as the reactant and the <strong>substrate<\/strong> is over the arrow!<\/p>\n<p>It&#8217;s better to try understand what&#8217;s going on than to try to memorize simplistic (<em><span style=\"color: #993366;\">and often faulty!<\/span> <\/em>) rules like &#8220;the nucleophile will always be the first thing above the arrow&#8221;.<\/p>\n<p>OK. Let&#8217;s look at another, slightly more complex set of questions.<\/p>\n<div class=\"wq-quiz-wrapper\" data-id=\"34737\"><style type=\"text\/css\" id=\"wq-flip-custom-css\">.wq-quiz-wrapper[data-id=\"34737\"] {\n--wq-question-width: 100%;\n--wq-question-color: #009cff;\n--wq-question-height: auto;\n--wq-font-color: #444;\n}\n\n\t\t\t.wq-quiz-wrapper[data-id=\"34737\"] {\n\t\t\t\t--wq-question-width: 600px;\n\t\t\t}\n\n\t\t\t@media screen and (max-width: 600px) {\n\t\t\t\t.wq-quiz-wrapper[data-id=\"34737\"] .wq_singleQuestionWrapper { width:100% !important; height:auto !important; }\n\t\t\t}\n\t\t<\/style><!-- wp quiz -->\n<div id=\"wp-quiz-34737\" class=\"wq_quizCtr single flip_quiz wq-quiz wq-quiz-34737 wq-quiz-flip wq-layout-single wq-skin-traditional wq-should-show-correct-answer\" data-quiz-id=\"34737\">\n<div class=\"wq-questions wq_questionsCtr\">\n\t<div class=\"wq-question wq_singleQuestionWrapper wq-question-t0hxb\" data-id=\"t0hxb\">\n\n\t\n\t<div class=\"item_top\">\n\t\t<div class=\"title_container\">\n\t\t\t<div class=\"wq_questionTextCtr\">\n\t\t\t\t<h4 class=\"wq-question-title\"><\/h4>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n\n\t<div class=\"card \">\n\t\t<div class=\"front\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2490-Front.gif\" \/>\n\t\t\n\t\t\n\t\n\t\n\t\t\t<span class=\"top-desc\">Click to Flip<\/span>\n\t<\/div>\n\t\t<div class=\"back\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2490-Reverse.gif\" \/>\n\t\t\n\t\t\n\t\n\t<\/div>\n\t<\/div>\n\n\t\n<\/div>\n<\/div>\n<\/div>\n<!-- \/\/ wp quiz-->\n<\/div><!-- End .wq-quiz-wrapper -->\n<p>Another point which often trips students up is in failing to distinguish potential nucleophiles from various aprotic <strong>solvents\u00a0<\/strong>which find use in, but do not participate in, these reactions.<\/p>\n<p><strong>Polar aprotic solvents<\/strong> are often chosen when substitution (usually S<sub>N<\/sub>2) is desired, since they are polar enough to dissolve charged nucleophiles, but cannot hydrogen-bond to them. The result is that nucleophiles in a polar aprotic solvent are relatively &#8220;free&#8221; and react faster with electrophiles, relative to their rates in polar protic solvents. [<em>See article &#8211; <a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/04\/27\/polar-protic-polar-aprotic-nonpolar-all-about-solvents\/\">Polar Protic? Polar Aprotic? All About Solvents<\/a><\/em>]<\/p>\n<p>Here are some common solvents to be aware of in substitution and elimination reactions. Note that they can be depicted in several different ways! (<span style=\"color: #993366;\"><em>Acetonitrile, for example,\u00a0 can be written as CH<sub>3<\/sub>CN, MeCN or just &#8220;acetonitrile&#8221;<\/em><\/span>.)<\/p>\n<p>At the bottom are various polar\u00a0<strong>protic<\/strong> solvents such as water, alcohols, carboxylic acids and even ammonia. These solvents\u00a0<strong>are<\/strong> capable of participating in substitution\/elimination reactions.<\/p>\n<p><img decoding=\"async\" class=\"alignnone wp-image-34554\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2023\/05\/4-common-solvents-used-in-substitution-and-elimination-reactions-dmso-dmf-acetnitrile-etc.gif\" alt=\"common solvents used in substitution and elimination reactions dmso dmf acetnitrile etc\" width=\"640\" height=\"644\" \/><\/a><\/p>\n<ul>\n<li>Polar\u00a0<strong>protic\u00a0<\/strong>solvents such as water, alcohols, and even NH<sub>3<\/sub> <strong>can<\/strong> potentially act as nucleophiles\/bases in reactions.<\/li>\n<li>However, for our purposes, polar <strong>aprotic<\/strong> solvents will never be nucleophiles in S<sub>N<\/sub>1\/S<sub>N<\/sub>2\/E1\/E2 reactions. [<a href=\"#noteone\"><span style=\"color: #ff0000;\">Note 1<\/span><\/a>]<\/li>\n<\/ul>\n<p>Note that the choice of solvent [polar protic vs polar aprotic] can have a strong influence on whether a reaction favors E2 or S<sub>N<\/sub>2. We&#8217;ll cover this in a subsequent article. [<span style=\"color: #993366;\"><em>See article &#8211;<span style=\"color: #993366;\"><a style=\"color: #993366;\" href=\"https:\/\/www.masterorganicchemistry.com\/2012\/12\/04\/deciding-sn1sn2e1e2-the-solvent\/\"> Deciding S<sub>N<\/sub>1\/S<sub>N<\/sub>2\/E1\/E2 &#8211; Solvent<\/a><\/span><\/em><\/span>]<\/p>\n<p>Here&#8217;s another set of more challenging cases:<\/p>\n<div class=\"wq-quiz-wrapper\" data-id=\"34738\"><style type=\"text\/css\" id=\"wq-flip-custom-css\">.wq-quiz-wrapper[data-id=\"34738\"] {\n--wq-question-width: 100%;\n--wq-question-color: #009cff;\n--wq-question-height: auto;\n--wq-font-color: #444;\n}\n\n\t\t\t.wq-quiz-wrapper[data-id=\"34738\"] {\n\t\t\t\t--wq-question-width: 600px;\n\t\t\t}\n\n\t\t\t@media screen and (max-width: 600px) {\n\t\t\t\t.wq-quiz-wrapper[data-id=\"34738\"] .wq_singleQuestionWrapper { width:100% !important; height:auto !important; }\n\t\t\t}\n\t\t<\/style><!-- wp quiz -->\n<div id=\"wp-quiz-34738\" class=\"wq_quizCtr single flip_quiz wq-quiz wq-quiz-34738 wq-quiz-flip wq-layout-single wq-skin-traditional wq-should-show-correct-answer\" data-quiz-id=\"34738\">\n<div class=\"wq-questions wq_questionsCtr\">\n\t<div class=\"wq-question wq_singleQuestionWrapper wq-question-jet9o\" data-id=\"jet9o\">\n\n\t\n\t<div class=\"item_top\">\n\t\t<div class=\"title_container\">\n\t\t\t<div class=\"wq_questionTextCtr\">\n\t\t\t\t<h4 class=\"wq-question-title\"><\/h4>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n\n\t<div class=\"card \">\n\t\t<div class=\"front\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2491-Front.gif\" \/>\n\t\t\n\t\t\n\t\n\t\n\t\t\t<span class=\"top-desc\">Click to Flip<\/span>\n\t<\/div>\n\t\t<div class=\"back\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2491-Reverse.gif\" \/>\n\t\t\n\t\t\n\t\n\t<\/div>\n\t<\/div>\n\n\t\n<\/div>\n<\/div>\n<\/div>\n<!-- \/\/ wp quiz-->\n<\/div><!-- End .wq-quiz-wrapper -->\n<p>To summarize this section:<\/p>\n<ul>\n<li>There are no hard and fast rules about whether the nucleophile appears above or below the reaction arrow<\/li>\n<li>Look for negatively charged species to be your &#8220;best&#8221; nucleophiles\/bases<\/li>\n<li>Know how to identify potential solvents &#8211; they will not participate in substitution or elimination, but they <strong>can<\/strong> influence the ratio of substitution vs. elimination products<\/li>\n<li>Sometimes the nucleophile \/ base is present on the substrate itself! These are examples of &#8220;intramolecular&#8221; reactions [<a href=\"#seven\">More below<\/a>]<\/li>\n<\/ul>\n<h2><a id=\"two\"><\/a>2. &#8220;Strong&#8221; vs. &#8220;Weak&#8221; Nucleophiles \/ Bases<\/h2>\n<p>Now that we have had some practice in identifying the likely nucleophile,\u00a0 I am going to suggest a somewhat rough but very helpful classification that will help in distinguishing S<sub>N<\/sub>1\/E1 reactions from S<sub>N<\/sub>2\/E2 reactions.<\/p>\n<p>Let&#8217;s call negatively charged nucleophiles &#8220;<strong>strong&#8221;<\/strong> and call neutral nucleophiles &#8220;<strong>weak<\/strong>&#8220;. [<a href=\"#notetwo\"><span style=\"color: #ff0000;\">Note<\/span> <span style=\"color: #ff0000;\">2<\/span><\/a>]<\/p>\n<ul>\n<li><strong>S<sub>N<\/sub>2\/E2<\/strong> reactions tend to occur with\u00a0<strong>strong\u00a0<\/strong>nucleophiles\/bases.<\/li>\n<li><strong>S<sub>N<\/sub>1\/E1<\/strong> reactions tend to occur with <strong>weak <\/strong>nucleophiles\/bases.<\/li>\n<\/ul>\n<p>The rate determining step in S<sub>N<\/sub>1\/E1 reactions is formation of a carbocation, which is generally only possible with secondary and tertiary substrates in highly polar, ionizing solvents like water, alcohols, carboxylic acids <span style=\"color: #000000;\">and mixtures thereof<\/span>. Carbocations have an empty p-orbital and will readily combine even with weak Lewis bases such as water and alcohols since the carbon on the resulting product will have a full octet.<\/p>\n<p>The rate determining step in S<sub>N<\/sub>2\/E2 requires that the nucleophile\/base displace a\u00a0<strong>leaving group\u00a0<\/strong>from a carbon that already has a full octet. Generally these reactions work best when the nucleophile\/base is a stronger base than the leaving group.<\/p>\n<p>Since alcohols, water, and carboxylic acids are relatively poor bases, many S<sub>N<\/sub>2\/E2 reactions with them as nucleophiles\/bases are disfavored from an acid-base standpoint. [<span style=\"color: #993366;\"><em>See article:\u00a0 <span style=\"color: #993366;\"><a style=\"color: #993366;\" href=\"https:\/\/www.masterorganicchemistry.com\/2011\/04\/12\/what-makes-a-good-leaving-group\/\">What Makes A Good Leaving Group<\/a><\/span><\/em><\/span>]\u00a0 [<a href=\"#notethree\"><span style=\"color: #ff0000;\">Note 3<span style=\"color: #000000;\">]<\/span><\/span><\/a><\/p>\n<p>With that in mind, classify the nucleophiles below as &#8220;strong&#8221; or &#8220;weak&#8221; (there are some land mines buried in this question!)<\/p>\n<div class=\"wq-quiz-wrapper\" data-id=\"34739\"><style type=\"text\/css\" id=\"wq-flip-custom-css\">.wq-quiz-wrapper[data-id=\"34739\"] {\n--wq-question-width: 100%;\n--wq-question-color: #009cff;\n--wq-question-height: auto;\n--wq-font-color: #444;\n}\n\n\t\t\t.wq-quiz-wrapper[data-id=\"34739\"] {\n\t\t\t\t--wq-question-width: 600px;\n\t\t\t}\n\n\t\t\t@media screen and (max-width: 600px) {\n\t\t\t\t.wq-quiz-wrapper[data-id=\"34739\"] .wq_singleQuestionWrapper { width:100% !important; height:auto !important; }\n\t\t\t}\n\t\t<\/style><!-- wp quiz -->\n<div id=\"wp-quiz-34739\" class=\"wq_quizCtr single flip_quiz wq-quiz wq-quiz-34739 wq-quiz-flip wq-layout-single wq-skin-traditional wq-should-show-correct-answer\" data-quiz-id=\"34739\">\n<div class=\"wq-questions wq_questionsCtr\">\n\t<div class=\"wq-question wq_singleQuestionWrapper wq-question-trhz1\" data-id=\"trhz1\">\n\n\t\n\t<div class=\"item_top\">\n\t\t<div class=\"title_container\">\n\t\t\t<div class=\"wq_questionTextCtr\">\n\t\t\t\t<h4 class=\"wq-question-title\"><\/h4>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n\n\t<div class=\"card \">\n\t\t<div class=\"front\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2492-Front.gif\" \/>\n\t\t\n\t\t\n\t\n\t\n\t\t\t<span class=\"top-desc\">Click to Flip<\/span>\n\t<\/div>\n\t\t<div class=\"back\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2492-Reverse.gif\" \/>\n\t\t\n\t\t\n\t\n\t<\/div>\n\t<\/div>\n\n\t\n<\/div>\n<\/div>\n<\/div>\n<!-- \/\/ wp quiz-->\n<\/div><!-- End .wq-quiz-wrapper -->\n<h2><a id=\"three\"><\/a>3. The Six Major Cases, Based On Substrate + Nucleophile<\/h2>\n<p>You have already learned how to identify substrate as primary, secondary, tertiary.<\/p>\n<p>Having identified the best nucleophile, and classifying it as strong or weak, we&#8217;re now ready to start applying this to some reactions. See how you do:<\/p>\n<div class=\"wq-quiz-wrapper\" data-id=\"34740\"><style type=\"text\/css\" id=\"wq-flip-custom-css\">.wq-quiz-wrapper[data-id=\"34740\"] {\n--wq-question-width: 100%;\n--wq-question-color: #009cff;\n--wq-question-height: auto;\n--wq-font-color: #444;\n}\n\n\t\t\t.wq-quiz-wrapper[data-id=\"34740\"] {\n\t\t\t\t--wq-question-width: 600px;\n\t\t\t}\n\n\t\t\t@media screen and (max-width: 600px) {\n\t\t\t\t.wq-quiz-wrapper[data-id=\"34740\"] .wq_singleQuestionWrapper { width:100% !important; height:auto !important; }\n\t\t\t}\n\t\t<\/style><!-- wp quiz -->\n<div id=\"wp-quiz-34740\" class=\"wq_quizCtr single flip_quiz wq-quiz wq-quiz-34740 wq-quiz-flip wq-layout-single wq-skin-traditional wq-should-show-correct-answer\" data-quiz-id=\"34740\">\n<div class=\"wq-questions wq_questionsCtr\">\n\t<div class=\"wq-question wq_singleQuestionWrapper wq-question-o7hae\" data-id=\"o7hae\">\n\n\t\n\t<div class=\"item_top\">\n\t\t<div class=\"title_container\">\n\t\t\t<div class=\"wq_questionTextCtr\">\n\t\t\t\t<h4 class=\"wq-question-title\"><\/h4>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n\n\t<div class=\"card \">\n\t\t<div class=\"front\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2493-Front.gif\" \/>\n\t\t\n\t\t\n\t\n\t\n\t\t\t<span class=\"top-desc\">Click to Flip<\/span>\n\t<\/div>\n\t\t<div class=\"back\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2493-Reverse.gif\" \/>\n\t\t\n\t\t\n\t\n\t<\/div>\n\t<\/div>\n\n\t\n<\/div>\n<\/div>\n<\/div>\n<!-- \/\/ wp quiz-->\n<\/div><!-- End .wq-quiz-wrapper -->\n<p>Since there are really only six major cases (not counting methyl) it might be helpful to draw up a grid like this:<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-34555\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2023\/05\/8-narrowing-down-sn2-and-e2-versus-sn1-and-sn1-depends-on-the-nucleophile-or-base.gif\" alt=\"narrowing down sn2 and e2 versus sn1 and sn1 depends on the nucleophile or base\" width=\"640\" height=\"488\" \/><\/a><\/p>\n<p>The six general cases are:<\/p>\n<ul>\n<li><strong>Primary \/ strong<\/strong> and\u00a0 <strong>primary \/ weak\u00a0<\/strong> . With rare exceptions (bulky bases like KOt-Bu) these will be S<sub>N<\/sub>2.<\/li>\n<li><strong>Secondary \/ strong<\/strong> will be S<sub>N<\/sub>2 <em>or<\/em> E2<\/li>\n<li><strong>Secondary \/ weak<\/strong> will be S<sub>N<\/sub>1 <em>or<\/em> E1<\/li>\n<li><strong>Tertiary \/ strong<\/strong> will be E2 with only rare exceptions [<span style=\"color: #ff0000;\"><a style=\"color: #ff0000;\" href=\"#notefour\">Note 4<\/a><\/span>]<\/li>\n<li><strong>Tertiary \/ weak<\/strong> will be S<sub>N<\/sub>1\/E1 [Note]<\/li>\n<\/ul>\n<p>Here is some more practice:<\/p>\n<div class=\"wq-quiz-wrapper\" data-id=\"34741\"><style type=\"text\/css\" id=\"wq-flip-custom-css\">.wq-quiz-wrapper[data-id=\"34741\"] {\n--wq-question-width: 100%;\n--wq-question-color: #009cff;\n--wq-question-height: auto;\n--wq-font-color: #444;\n}\n\n\t\t\t.wq-quiz-wrapper[data-id=\"34741\"] {\n\t\t\t\t--wq-question-width: 600px;\n\t\t\t}\n\n\t\t\t@media screen and (max-width: 600px) {\n\t\t\t\t.wq-quiz-wrapper[data-id=\"34741\"] .wq_singleQuestionWrapper { width:100% !important; height:auto !important; }\n\t\t\t}\n\t\t<\/style><!-- wp quiz -->\n<div id=\"wp-quiz-34741\" class=\"wq_quizCtr single flip_quiz wq-quiz wq-quiz-34741 wq-quiz-flip wq-layout-single wq-skin-traditional wq-should-show-correct-answer\" data-quiz-id=\"34741\">\n<div class=\"wq-questions wq_questionsCtr\">\n\t<div class=\"wq-question wq_singleQuestionWrapper wq-question-636vz\" data-id=\"636vz\">\n\n\t\n\t<div class=\"item_top\">\n\t\t<div class=\"title_container\">\n\t\t\t<div class=\"wq_questionTextCtr\">\n\t\t\t\t<h4 class=\"wq-question-title\"><\/h4>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n\n\t<div class=\"card \">\n\t\t<div class=\"front\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2494-Front.gif\" \/>\n\t\t\n\t\t\n\t\n\t\n\t\t\t<span class=\"top-desc\">Click to Flip<\/span>\n\t<\/div>\n\t\t<div class=\"back\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2494-Reverse.gif\" \/>\n\t\t\n\t\t\n\t\n\t<\/div>\n\t<\/div>\n\n\t\n<\/div>\n<\/div>\n<\/div>\n<!-- \/\/ wp quiz-->\n<\/div><!-- End .wq-quiz-wrapper -->\n<p>You might find it annoying that after all this work of analyzing the substrate and the nucleophile we still have multiple situations where we still can&#8217;t really nail down the dominant pathway.<\/p>\n<p>Helpfully, analyzing the\u00a0<strong>basicity<\/strong> of some strong nucleophiles\/bases will help us make some clearer distinctions.<\/p>\n<h2><a id=\"four\"><\/a>4. Secondary Alkyl Halides: The Importance of Base Strength<\/h2>\n<p>The E2 reaction generally requires a strong base. Negatively charged species that are weak bases such as halides, carboxylates, cyanide, azide, or thiolates [RS(-)] generally won&#8217;t perform E2 reactions. [<a href=\"#notefive\"><span style=\"color: #ff0000;\">Note 5<\/span><\/a>]<\/p>\n<p>Strong bases such as hydroxide ion HO (-),\u00a0 alkoxides RO(-), and species more basic than them (e.g. acetylides, amide bases, hydride) are fully capable of performing E2 reactions, however.<\/p>\n<p>So a reasonably good dividing line for &#8220;E2-capable&#8221; bases is around a pK<sub>a<\/sub> of 12 for the conjugate acid. More basic than thiolates, in other words.<\/p>\n<p>This chart might help. Note that this is specific for\u00a0<strong>secondary\u00a0<\/strong>alkyl halides.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-34556\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2023\/05\/10-classifying-nucleophiles-based-on-how-basic-they-are-will-determine-whether-they-can-do-E2-or-SN2.gif\" alt=\"classifying nucleophiles based on how basic they are will determine whether they can do E2 or SN2\" width=\"640\" height=\"503\" \/><\/a><\/p>\n<p>For secondary alkyl halides with weakly basic nucleophiles, expect S<sub>N<\/sub>2 for everything up to thiolates, and elimination for everything more basic than alkoxides. Amide bases (e.g. NH<sub>2<\/sub>(-), R<sub>2<\/sub>N(-), NaH, and acetylides will primarily give E2 products. (<span style=\"color: #993366;\"><em>Acetylides are fine nucleophiles with primary alkyl halides, but will perform E2 reactions on secondary alkyl halides<\/em><\/span>).<\/p>\n<p>Depending on conditions, hydroxide and alkoxides themselves can go either way with secondary alkyl halides,\u00a0 We&#8217;ll cover this in more detail in a subsequent article. [<span style=\"color: #993366;\"><em>See article &#8211; <a style=\"color: #993366;\" href=\"https:\/\/www.masterorganicchemistry.com\/2012\/12\/04\/deciding-sn1sn2e1e2-the-solvent\/\">Deciding SN1\/S<sub>N<\/sub>2\/E1\/E2 &#8211; The Solvent<\/a><\/em><\/span>]<\/p>\n<div class=\"wq-quiz-wrapper\" data-id=\"34742\"><style type=\"text\/css\" id=\"wq-flip-custom-css\">.wq-quiz-wrapper[data-id=\"34742\"] {\n--wq-question-width: 100%;\n--wq-question-color: #009cff;\n--wq-question-height: auto;\n--wq-font-color: #444;\n}\n\n\t\t\t.wq-quiz-wrapper[data-id=\"34742\"] {\n\t\t\t\t--wq-question-width: 600px;\n\t\t\t}\n\n\t\t\t@media screen and (max-width: 600px) {\n\t\t\t\t.wq-quiz-wrapper[data-id=\"34742\"] .wq_singleQuestionWrapper { width:100% !important; height:auto !important; }\n\t\t\t}\n\t\t<\/style><!-- wp quiz -->\n<div id=\"wp-quiz-34742\" class=\"wq_quizCtr single flip_quiz wq-quiz wq-quiz-34742 wq-quiz-flip wq-layout-single wq-skin-traditional wq-should-show-correct-answer\" data-quiz-id=\"34742\">\n<div class=\"wq-questions wq_questionsCtr\">\n\t<div class=\"wq-question wq_singleQuestionWrapper wq-question-igmsp\" data-id=\"igmsp\">\n\n\t\n\t<div class=\"item_top\">\n\t\t<div class=\"title_container\">\n\t\t\t<div class=\"wq_questionTextCtr\">\n\t\t\t\t<h4 class=\"wq-question-title\"><\/h4>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n\n\t<div class=\"card \">\n\t\t<div class=\"front\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2495-Front.gif\" \/>\n\t\t\n\t\t\n\t\n\t\n\t\t\t<span class=\"top-desc\">Click to Flip<\/span>\n\t<\/div>\n\t\t<div class=\"back\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2495-Reverse.gif\" \/>\n\t\t\n\t\t\n\t\n\t<\/div>\n\t<\/div>\n\n\t\n<\/div>\n<\/div>\n<\/div>\n<!-- \/\/ wp quiz-->\n<\/div><!-- End .wq-quiz-wrapper -->\n<p>The E2 reaction on tertiary alkyl halides also requires a reasonably strong base such as hydroxide, alkoxides, or species more basic than that. (<span style=\"color: #993366;\"><em>One exception &#8211;\u00a0 neutral nitrogen bases such as triethylamine or <a href=\"https:\/\/en.wikipedia.org\/wiki\/1,8-Diazabicyclo(5.4.0)undec-7-ene\">DBU<\/a> will also perform E2 reactions<\/em><\/span>)<\/p>\n<div class=\"wq-quiz-wrapper\" data-id=\"34743\"><style type=\"text\/css\" id=\"wq-flip-custom-css\">.wq-quiz-wrapper[data-id=\"34743\"] {\n--wq-question-width: 100%;\n--wq-question-color: #009cff;\n--wq-question-height: auto;\n--wq-font-color: #444;\n}\n\n\t\t\t.wq-quiz-wrapper[data-id=\"34743\"] {\n\t\t\t\t--wq-question-width: 600px;\n\t\t\t}\n\n\t\t\t@media screen and (max-width: 600px) {\n\t\t\t\t.wq-quiz-wrapper[data-id=\"34743\"] .wq_singleQuestionWrapper { width:100% !important; height:auto !important; }\n\t\t\t}\n\t\t<\/style><!-- wp quiz -->\n<div id=\"wp-quiz-34743\" class=\"wq_quizCtr single flip_quiz wq-quiz wq-quiz-34743 wq-quiz-flip wq-layout-single wq-skin-traditional wq-should-show-correct-answer\" data-quiz-id=\"34743\">\n<div class=\"wq-questions wq_questionsCtr\">\n\t<div class=\"wq-question wq_singleQuestionWrapper wq-question-58s1d\" data-id=\"58s1d\">\n\n\t\n\t<div class=\"item_top\">\n\t\t<div class=\"title_container\">\n\t\t\t<div class=\"wq_questionTextCtr\">\n\t\t\t\t<h4 class=\"wq-question-title\"><\/h4>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n\n\t<div class=\"card \">\n\t\t<div class=\"front\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2496-Front.gif\" \/>\n\t\t\n\t\t\n\t\n\t\n\t\t\t<span class=\"top-desc\">Click to Flip<\/span>\n\t<\/div>\n\t\t<div class=\"back\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2496-Reverse.gif\" \/>\n\t\t\n\t\t\n\t\n\t<\/div>\n\t<\/div>\n\n\t\n<\/div>\n<\/div>\n<\/div>\n<!-- \/\/ wp quiz-->\n<\/div><!-- End .wq-quiz-wrapper -->\n<p>S<sub>N<\/sub>1 reactions are sometimes observed when\u00a0 &#8220;strong&#8221; , weakly basic nucleophiles such as (-)CN or N<sub>3<\/sub>(-) are in solution with a tertiary alkyl halide under conditions that favor carbocation formation. These species are such excellent nucleophiles that they can out-compete the solvent.\u00a0\u00a0[<span style=\"color: #ff0000;\">Ref <\/span>]<\/p>\n<h2><a id=\"five\"><\/a>5. More on the &#8220;SN1 vs E1&#8221; and &#8220;S<sub>N<\/sub>2 vs E2&#8243; Cases<\/h2>\n<p>At this point we have shown how to identify alkyl halides as primary, secondary, or tertiary, then how to identify nucleophiles as &#8220;strong&#8221; or &#8220;weak&#8221;, and then how to further narrow down negatively charged nucleophiles so as to identify which would be more likely to perform S<sub>N<\/sub>2 or E2.<\/p>\n<p>The two problems that remain for a comprehensive assignment of S<sub>N<\/sub>1\/S<sub>N<\/sub>2\/E1\/E2 are:<\/p>\n<ul>\n<li>distinguishing S<sub>N<\/sub>1 from E1 (<span style=\"color: #993366;\"><em>the short answer is that heat favors elimination, more on that in a subsequent article &#8211; see <span style=\"color: #993366;\"><a style=\"color: #993366;\" href=\"https:\/\/www.masterorganicchemistry.com\/2012\/12\/19\/deciding-sn1sn2e1e2-4-the-temperature\/\">Deciding S<sub>N<\/sub>1\/S<sub>N<\/sub>2\/E1\/E2 &#8211; The Temperature<\/a><\/span><\/em><\/span>).<\/li>\n<li>distinguishing S<sub>N<\/sub>2 from E2 for <strong>secondary<\/strong> alkyl halides with <strong>strong<\/strong> nucleophiles\/bases in the &#8220;borderline&#8221; region [hydroxide and alkoxides].\u00a0 (<span style=\"color: #993366;\"><em>My short answer here &#8211; besides &#8220;ask your instructor, because many disagree&#8221; &#8211;\u00a0 is that polar aprotic solvents will favor substitution, but more in <span style=\"color: #993366;\"><a style=\"color: #993366;\" href=\"https:\/\/www.masterorganicchemistry.com\/2012\/12\/04\/deciding-sn1sn2e1e2-the-solvent\/\">Deciding SN1\/S<sub>N<\/sub>2\/E1\/E2 &#8211; The Solvent<\/a><\/span><\/em><\/span>).<\/li>\n<\/ul>\n<p>We will deal with these in subsequent articles.<\/p>\n<p>Other than that, are there any other loose ends and exceptions to tie up? Yes!<\/p>\n<p>Let&#8217;s finish up by dealing with <strong>acid-base<\/strong> reactions, intramolecular examples, and a final word from your substrate.<\/p>\n<h2><a id=\"six\"><\/a>6. A Reminder To Do Acid-Base Reactions First<\/h2>\n<p>In our rush to cover the basics of strong and weak nucleophiles, above, we only considered that a nucleophile\/base would either do substitution or elimination.<\/p>\n<p>There is actually a third possibility (<span style=\"color: #800080;\"><em>a fourth, if you count &#8220;no reaction&#8221;<\/em><\/span>).<\/p>\n<p>The nucleophile\/base can also perform an\u00a0<strong>acid-base reaction<\/strong> on the substrate.<\/p>\n<p>This is most likely when reasonably acidic substrates such as alcohols, thiols, terminal acetylenes and carboxylic acids are treated with\u00a0<strong>strong bases<\/strong>.<\/p>\n<p>Acid-base reactions tend to be\u00a0<strong>fast<\/strong>, relative to substitution and elimination reactions [<span style=\"color: #993366;\"><em>See article &#8211; <span style=\"color: #993366;\"><a style=\"color: #993366;\" href=\"https:\/\/www.masterorganicchemistry.com\/2012\/05\/21\/acid-base-reactions-are-fast\/\">Acid-Base Reactions Are Fast<\/a><\/span><\/em><\/span>]. So it makes sense to apply them <strong>first<\/strong>.<\/p>\n<p>The resulting\u00a0<strong>conjugate base<\/strong> will be, as we discussed above, a superior nucleophile\/base relative to its conjugate acid.<\/p>\n<p>These reactions show examples of a deprotonation step followed by a substitution step. See if you can draw the products.<\/p>\n<div class=\"wq-quiz-wrapper\" data-id=\"34744\"><style type=\"text\/css\" id=\"wq-flip-custom-css\">.wq-quiz-wrapper[data-id=\"34744\"] {\n--wq-question-width: 100%;\n--wq-question-color: #009cff;\n--wq-question-height: auto;\n--wq-font-color: #444;\n}\n\n\t\t\t.wq-quiz-wrapper[data-id=\"34744\"] {\n\t\t\t\t--wq-question-width: 600px;\n\t\t\t}\n\n\t\t\t@media screen and (max-width: 600px) {\n\t\t\t\t.wq-quiz-wrapper[data-id=\"34744\"] .wq_singleQuestionWrapper { width:100% !important; height:auto !important; }\n\t\t\t}\n\t\t<\/style><!-- wp quiz -->\n<div id=\"wp-quiz-34744\" class=\"wq_quizCtr single flip_quiz wq-quiz wq-quiz-34744 wq-quiz-flip wq-layout-single wq-skin-traditional wq-should-show-correct-answer\" data-quiz-id=\"34744\">\n<div class=\"wq-questions wq_questionsCtr\">\n\t<div class=\"wq-question wq_singleQuestionWrapper wq-question-ai4ay\" data-id=\"ai4ay\">\n\n\t\n\t<div class=\"item_top\">\n\t\t<div class=\"title_container\">\n\t\t\t<div class=\"wq_questionTextCtr\">\n\t\t\t\t<h4 class=\"wq-question-title\"><\/h4>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n\n\t<div class=\"card \">\n\t\t<div class=\"front\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2497-Front.gif\" \/>\n\t\t\n\t\t\n\t\n\t\n\t\t\t<span class=\"top-desc\">Click to Flip<\/span>\n\t<\/div>\n\t\t<div class=\"back\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2497-Reverse.gif\" \/>\n\t\t\n\t\t\n\t\n\t<\/div>\n\t<\/div>\n\n\t\n<\/div>\n<\/div>\n<\/div>\n<!-- \/\/ wp quiz-->\n<\/div><!-- End .wq-quiz-wrapper -->\n<p>The corollary to &#8220;the conjugate base is a better nucleophile&#8221; is &#8220;the conjugate acid is a better leaving group&#8221;.<\/p>\n<p>Addition of acids (including Lewis acids) will help turn poor leaving groups into better leaving groups.<\/p>\n<p>This is most often seen with\u00a0<strong>alcohols<\/strong>, where addition of H+ converts the poor -OH leaving group into the (much better) \u00a0leaving group H<sub>2<\/sub>O.<\/p>\n<div class=\"wq-quiz-wrapper\" data-id=\"34745\"><style type=\"text\/css\" id=\"wq-flip-custom-css\">.wq-quiz-wrapper[data-id=\"34745\"] {\n--wq-question-width: 100%;\n--wq-question-color: #009cff;\n--wq-question-height: auto;\n--wq-font-color: #444;\n}\n\n\t\t\t.wq-quiz-wrapper[data-id=\"34745\"] {\n\t\t\t\t--wq-question-width: 600px;\n\t\t\t}\n\n\t\t\t@media screen and (max-width: 600px) {\n\t\t\t\t.wq-quiz-wrapper[data-id=\"34745\"] .wq_singleQuestionWrapper { width:100% !important; height:auto !important; }\n\t\t\t}\n\t\t<\/style><!-- wp quiz -->\n<div id=\"wp-quiz-34745\" class=\"wq_quizCtr single flip_quiz wq-quiz wq-quiz-34745 wq-quiz-flip wq-layout-single wq-skin-traditional wq-should-show-correct-answer\" data-quiz-id=\"34745\">\n<div class=\"wq-questions wq_questionsCtr\">\n\t<div class=\"wq-question wq_singleQuestionWrapper wq-question-0ptqc\" data-id=\"0ptqc\">\n\n\t\n\t<div class=\"item_top\">\n\t\t<div class=\"title_container\">\n\t\t\t<div class=\"wq_questionTextCtr\">\n\t\t\t\t<h4 class=\"wq-question-title\"><\/h4>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n\n\t<div class=\"card \">\n\t\t<div class=\"front\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2498-Front.gif\" \/>\n\t\t\n\t\t\n\t\n\t\n\t\t\t<span class=\"top-desc\">Click to Flip<\/span>\n\t<\/div>\n\t\t<div class=\"back\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2498-Reverse.gif\" \/>\n\t\t\n\t\t\n\t\n\t<\/div>\n\t<\/div>\n\n\t\n<\/div>\n<\/div>\n<\/div>\n<!-- \/\/ wp quiz-->\n<\/div><!-- End .wq-quiz-wrapper -->\n<p>Halides can be made into better leaving groups through addition of silver salts, which irreversibly precipitate the halides out of solution.<\/p>\n<h2><a id=\"seven\"><\/a>7. Intramolecular Reactions<\/h2>\n<p>It always pays to look at the\u00a0<strong>intramolecular\u00a0<\/strong>variant of every new reaction you learn, since they are a perennial favorite of exam-writers everywhere.<\/p>\n<p>In an intramolecular S<sub>N<\/sub>2 reaction, the nucleophile and substrate are on the same molecule. Their combination will result in a new ring.<\/p>\n<div class=\"wq-quiz-wrapper\" data-id=\"34746\"><style type=\"text\/css\" id=\"wq-flip-custom-css\">.wq-quiz-wrapper[data-id=\"34746\"] {\n--wq-question-width: 100%;\n--wq-question-color: #009cff;\n--wq-question-height: auto;\n--wq-font-color: #444;\n}\n\n\t\t\t.wq-quiz-wrapper[data-id=\"34746\"] {\n\t\t\t\t--wq-question-width: 600px;\n\t\t\t}\n\n\t\t\t@media screen and (max-width: 600px) {\n\t\t\t\t.wq-quiz-wrapper[data-id=\"34746\"] .wq_singleQuestionWrapper { width:100% !important; height:auto !important; }\n\t\t\t}\n\t\t<\/style><!-- wp quiz -->\n<div id=\"wp-quiz-34746\" class=\"wq_quizCtr single flip_quiz wq-quiz wq-quiz-34746 wq-quiz-flip wq-layout-single wq-skin-traditional wq-should-show-correct-answer\" data-quiz-id=\"34746\">\n<div class=\"wq-questions wq_questionsCtr\">\n\t<div class=\"wq-question wq_singleQuestionWrapper wq-question-jbz5s\" data-id=\"jbz5s\">\n\n\t\n\t<div class=\"item_top\">\n\t\t<div class=\"title_container\">\n\t\t\t<div class=\"wq_questionTextCtr\">\n\t\t\t\t<h4 class=\"wq-question-title\"><\/h4>\n\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n\n\t<div class=\"card \">\n\t\t<div class=\"front\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2499-Front.gif\" \/>\n\t\t\n\t\t\n\t\n\t\n\t\t\t<span class=\"top-desc\">Click to Flip<\/span>\n\t<\/div>\n\t\t<div class=\"back\" >\n\t\n\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-images\/2499-Reverse.gif\" \/>\n\t\t\n\t\t\n\t\n\t<\/div>\n\t<\/div>\n\n\t\n<\/div>\n<\/div>\n<\/div>\n<!-- \/\/ wp quiz-->\n<\/div><!-- End .wq-quiz-wrapper -->\n<p>You can never have enough practice with intramolecular reactions.<\/p>\n<h2><a id=\"eight\"><\/a>8. The Substrate Always Has The Final Say<\/h2>\n<p>I know this is a lot to learn. Substrates, nucleophiles, reactions. That&#8217;s one of many reasons why students find organic chemistry difficult.<\/p>\n<p>Rules of thumb, checklists, and flowcharts can be very helpful for making sense of all the information you&#8217;re asked to process.<\/p>\n<p>You&#8217;re probably not going to like that there is one last thing, but there is one last thing.<\/p>\n<p>At the end of the analysis process you will still have to apply the appropriate bond-forming\/breaking pattern to your substrate in order to be able to draw the correct product.<\/p>\n<p>And sometimes&#8230; even though you have run through all the checklists&#8230; your substrate might still have (or lack) a crucial feature that results in a specific reaction being unworkable.<\/p>\n<p>Here are some examples.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-34590\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2023\/05\/16-in-substitution-and-elimination-reactions-the-substrate-has-the-final-say-neopentyl-bridgehead-etc.gif\" alt=\"in substitution and elimination reactions the substrate has the final say - neopentyl bridgehead etc\" width=\"640\" height=\"479\" \/><\/a><\/p>\n<p>So by all means use flowcharts and rules of thumb, but don&#8217;t get so &#8220;locked in&#8221; on following a flowchart that you forget to actually look at the molecule itself and decide whether or not that reaction is even <strong>possible<\/strong>.<\/p>\n<p>Your substrate always has a veto.<\/p>\n<h2><a id=\"nine\"><\/a>9. Summary<\/h2>\n<p>In the process of trying to decide if a reaction is S<sub>N<\/sub>1\/S<sub>N<\/sub>2\/E1\/E2, there are five general steps. This article is the third of five.<\/p>\n<p>We&#8217;ve previously covered <strong>Step 1<\/strong> (look for alkyl halides [<a href=\"https:\/\/www.masterorganicchemistry.com\/2023\/01\/18\/where-will-substitution-elimination-reactions-occur\/\">link<\/a>]) and <strong>Step 2<\/strong> (determine if the alkyl halide is primary, secondary or tertiary [<a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/11\/21\/deciding-sn1sn2e1e2-1-the-substrate\/\">link<\/a>]).\u00a0<strong>Step 4\u00a0<\/strong>(solvent [<a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/12\/04\/deciding-sn1sn2e1e2-the-solvent\/\">link<\/a>]) and <strong>Step 5<\/strong> (temperature [<a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/12\/19\/deciding-sn1sn2e1e2-4-the-temperature\/\">link<\/a>]) are next.<\/p>\n<p>In this article, we first looked at various reactions and looked for the strongest <strong>nucleophile\/base <\/strong>present in each case. (<span style=\"color: #800080;\"><em>A nucleophile is our name for a base when it&#8217;s forming a bond with any atom other than hydrogen<\/em><\/span>).<\/p>\n<ul>\n<li>We then made a rule of thumb in defining nucleophiles\/bases bearing a negative charge as &#8220;strong&#8221;, and neutral nucleophiles\/bases as &#8220;weak&#8221;.<\/li>\n<li>This gives us six key cases to analyze (primary, secondary, tertiary with strong\/weak).<\/li>\n<li>Primary alkyl halides tend to undergo S<sub>N<\/sub>2 reactions regardless of whether or not the nucleophile is strong or weak.<\/li>\n<li>E2 reactions generally require reasonably strong bases (as strong as hydroxide or alkoxides, or stronger).<\/li>\n<li>For secondary alkyl halides, strong nucleophiles\/bases tend to perform S<sub>N<\/sub>2\/E2 reactions, and weak nucleophiles\/bases tend to perform S<sub>N<\/sub>1\/E1 reactions.<\/li>\n<li>With <strong>secondary<\/strong> substrates, negatively charged nucleophiles that are weaker bases than hydroxide tend to do S<sub>N<\/sub>2 exclusively, and negatively charged nucleophiles that are stronger bases than hydroxides\/alkoxides tend to do E2 exclusively.<\/li>\n<li>\u00a0Hydroxide\/alkoxide ions with secondary alkyl halides is a borderline area and may go either S<sub>N<\/sub>2 or E2. [More on that next]<\/li>\n<li>For tertiary alkyl halides, strong bases tend to perform E2 reactions, and weak nucleophiles\/bases give S<sub>N<\/sub>1\/E1 products.<\/li>\n<li>When acids\/bases are added to the substrate, perform the acid-base reactions first.<\/li>\n<li>By all means apply rules of thumb \/ flowcharts, but still be alert for substrates where an S<sub>N<\/sub>1\/S<sub>N<\/sub>2\/E1\/E2 reaction might not work due to the presence or absence of certain structural features (like the lack of a beta carbon with a C-H bond making E2 impossible for instance).<\/li>\n<\/ul>\n<hr \/>\n<h2><strong><a id=\"notes\"><\/a>Notes<\/strong><\/h2>\n<div class=\"related-articles\"><p><strong>Related Articles<\/strong><\/p><ul><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/12\/04\/deciding-sn1sn2e1e2-the-solvent\/\" class=\"\"><span>Deciding SN1\/SN2\/E1\/E2 (3) \u2013 The Solvent<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/11\/21\/deciding-sn1sn2e1e2-1-the-substrate\/\" class=\"\"><span>Deciding SN1\/SN2\/E1\/E2 (1) \u2013 The Substrate<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/12\/19\/deciding-sn1sn2e1e2-4-the-temperature\/\" class=\"\"><span>Deciding SN1\/SN2\/E1\/E2 (4) \u2013 The Temperature<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2013\/01\/18\/wrapup-the-quick-n-dirty-guide-to-sn1sn2e1e2\/\" class=\"\"><span>Wrapup: The Quick N\u2019 Dirty Guide To SN1\/SN2\/E1\/E2<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/organic-chemistry-practice-problems\/sn1-sn2-e1-e2-practice-problems\/\" class=\"\"><span>SN1 SN2 E1 E2 Practice Problems (MOC Membership)<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/08\/08\/comparing-the-sn1-and-sn2-reactions\/\" class=\"\"><span>Comparing the SN1 and SN2 Reactions<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2012\/11\/08\/comparing-the-e1-and-sn1-reactions\/\" class=\"\"><span>Comparing the E1 vs SN1 Reactions<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2010\/06\/16\/1-2-3-4\/\" class=\"\"><span>Primary, Secondary, Tertiary, Quaternary In Organic Chemistry<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2023\/01\/18\/where-will-substitution-elimination-reactions-occur\/\" class=\"\"><span>Identifying Where Substitution and Elimination Reactions Happen<\/span><\/a><\/li><\/ul><\/div>\n<p><strong><a id=\"one\"><\/a>Note 1.\u00a0 <\/strong>The lone pair on acetonitrile (and other nitriles) will react with carbocations in a reaction known as the <a href=\"\" class=\"custom-tooltip\" data-image=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2023\/05\/Supp-1-Example-of-the-Ritter-Reaction-between-carbocations-and-nitrile-nitrogens.gif\" data-link=\"\" data-title=\"\" data-text=\"\">Ritter reaction <\/a> but that&#8217;s beyond the scope of what we&#8217;ll cover here. [<a href=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2023\/05\/Supp-1-Example-of-the-Ritter-Reaction-between-carbocations-and-nitrile-nitrogens.gif\">link<\/a>]<\/p>\n<p><strong><a id=\"two\"><\/a>Note 2.\u00a0<\/strong>The biggest quibble I have about this &#8220;strong&#8221; and &#8220;weak&#8221; designation is that neutral amines such as triethylamine are perfectly capable of performing E2 reactions.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-34964\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2023\/05\/F1-example-of-NEt3-as-base-for-E2-elimination-on-secondary-alkyl-halides.gif\" alt=\"example of NEt3 as base for E2 elimination on secondary alkyl halides\" width=\"640\" height=\"191\" \/><\/a><\/p>\n<p>Other nitrogenous bases such as DBU and DBN will perform elimination reactions as well.<\/p>\n<p>Secondly, neutral PPh<sub>3<\/sub> is perfectly capable of performing S<sub>N<\/sub>2 on some secondary alkyl halides.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-34965\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2023\/05\/F2-example-of-PPh3-reacting-as-a-nucleophile-with-a-secondary-alkyl-halide.gif\" alt=\"example of PPh3 reacting as a nucleophile with a secondary alkyl halide\" width=\"640\" height=\"215\" \/><\/a><\/p>\n<p><strong><a id=\"three\"><\/a>Note 3.\u00a0<\/strong>You won&#8217;t go too wrong if you think of substitution reactions as being a fancy class of acid-base reaction, which tend to be successful when reaction of a stronger base with a substrate results in a weaker base (the leaving group).<\/p>\n<p>One key difference is that substitution and elimination reactions tend to be irreversible and acid-base reactions are reversible.<\/p>\n<p><strong><a id=\"four\"><\/a>Note 4.\u00a0<\/strong>One example of a &#8220;strong&#8221; nucleophile\/base reacting with a tertiary alkyl halide can be found in this example of an azide ion &#8220;intercepting&#8221; the carbocation formed from Ph<sub>3<\/sub>CCl in water.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-34967\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2023\/05\/F3-intercepting-carbocations-formed-under-sn1-conditions-with-external-nucleophiles-such-as-nan3.gif\" alt=\"intercepting-carbocations-formed-under-sn1-conditions-with-external-nucleophiles-such-as-nan3\" width=\"640\" height=\"264\" \/><\/a><\/p>\n<p><strong><a id=\"five\"><\/a>Note 5.\u00a0<\/strong>Triethylamine and other neutral basic nitrogenous compounds are the main exception.<\/p>\n<p>&nbsp;<\/p>\n<hr \/>\n<h2><strong><a id=\"quiz\"><\/a>Quiz Yourself!<\/strong><\/h2>\n\n<p class=\"p1\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-26714\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-previews\/3221-Front-Image-Only.png\" alt=\"\" width=\"640\" height=\"616\" \/><\/p>\n<p><a href=\"https:\/\/www.masterorganicchemistry.com\/moc-membership\/\"><strong>Become a\u00a0 MOC member<\/strong><\/a> to see the clickable quiz with answers on the back. <br \/>\n<\/p>\n<p class=\"p1\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-26714\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-previews\/3222-Front-Image-Only.png\" alt=\"\" width=\"640\" height=\"616\" \/><\/p>\n<p><a href=\"https:\/\/www.masterorganicchemistry.com\/moc-membership\/\"><strong>Become a\u00a0 MOC member<\/strong><\/a> to see the clickable quiz with answers on the back. <br \/>\n<\/p>\n<p class=\"p1\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-26714\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-previews\/3223-Front-Image-Only.png\" alt=\"\" width=\"640\" height=\"616\" \/><\/p>\n<p><a href=\"https:\/\/www.masterorganicchemistry.com\/moc-membership\/\"><strong>Become a\u00a0 MOC member<\/strong><\/a> to see the clickable quiz with answers on the back.  <\/p>\n\n<p class=\"p1\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-26714\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-previews\/3224-Front-Image-Only.png\" alt=\"\" width=\"640\" height=\"616\" \/><\/p>\n<p><a href=\"https:\/\/www.masterorganicchemistry.com\/moc-membership\/\"><strong>Become a\u00a0 MOC member<\/strong><\/a> to see the clickable quiz with answers on the back.  <\/p>\n\n<p class=\"p1\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-26714\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-previews\/3225-Front-Image-Only.png\" alt=\"\" width=\"640\" height=\"616\" \/><\/p>\n<p><a href=\"https:\/\/www.masterorganicchemistry.com\/moc-membership\/\"><strong>Become a\u00a0 MOC member<\/strong><\/a> to see the clickable quiz with answers on the back.  <\/p>\n\n<p class=\"p1\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-26714\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/quiz-previews\/3226-Front-Image-Only.png\" alt=\"\" width=\"640\" height=\"616\" \/><\/p>\n<p><a href=\"https:\/\/www.masterorganicchemistry.com\/moc-membership\/\"><strong>Become a\u00a0 MOC member<\/strong><\/a> to see the clickable quiz with answers on the back.  <\/p>\n<hr \/>\n<h2><strong><a id=\"references\"><\/a>(Advanced) References and Further Reading<\/strong><\/h2>\n<p>[literature]<\/p>\n<p><em>Reference. <a id=\"refone\"><\/a>J. Am. Chem. Soc.<\/em> <strong>1953<\/strong>,\u00a0<em>75<\/em>, 136.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>SN1 \/ SN2 \/ E1 \/ E2 The Nucleophile \/ Base This article assumes you understand the mechanisms of the SN1\/SN2\/E1 and E2 reactions. For <\/p>\n","protected":false},"author":1,"featured_media":34959,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[1417],"tags":[624,472,473,201,841,825,502,271,279],"post_folder":[],"class_list":["post-6762","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-sn1sn2e1e2","tag-bulky-base","tag-e1","tag-e2","tag-elimination","tag-leaving-group","tag-nucleophile","tag-sn1","tag-sn2","tag-substitution"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.7 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Deciding SN1\/SN2\/E1\/E2 (2) - The Nucleophile\/Base<\/title>\n<meta name=\"description\" content=\"Deciding SN1\/SN2\/E1\/E2, Part 2: The Nucleophile\/Base. Once we&#039;ve analyzed the substrate, the next step is to analyze the nucleophile base. 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