{"id":11785,"date":"2018-08-20T06:00:47","date_gmt":"2018-08-20T10:00:47","guid":{"rendered":"https:\/\/www.masterorganicchemistry.com\/?p=11785"},"modified":"2026-04-18T06:41:41","modified_gmt":"2026-04-18T11:41:41","slug":"nucleophilic-aromatic-substitution-nas","status":"publish","type":"post","link":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/","title":{"rendered":"Nucleophilic Aromatic Substitution (NAS)"},"content":{"rendered":"<p><strong>Nucleophilic Aromatic Substitution (NAS)<\/strong><\/p>\n<p>In many ways, nucleophilic aromatic substitution is the mirror opposite of electrophilic aromatic substitution.<\/p>\n<ul>\n<li>In Nucleophilic Aromatic Substitution, an\u00a0<strong>electron-poor<\/strong> aromatic ring is attacked by a\u00a0<strong>nucleophile<\/strong>, resulting in a\u00a0<strong>substitution reaction<\/strong><\/li>\n<li>The reaction proceeds through a <strong>negatively charged<\/strong> (carbanion) <strong>intermediate<\/strong><\/li>\n<li>The reaction is accelerated by the presence of <strong>electron-withdrawing groups<\/strong> on the aromatic ring<\/li>\n<li>The placement of electron withdrawing groups <em>ortho-<\/em> or <em>para-<\/em> to the leaving group results in faster reactions than does the placement of electron withdrawing groups\u00a0<em>meta-<\/em> to the leaving group<\/li>\n<li>Fluorine can act as a leaving group (!) in nucleophilic aromatic substitution reactions, since it is quite electron-withdrawing and C-F bond breakage is not the rate-limiting step.<\/li>\n<\/ul>\n<p><img fetchpriority=\"high\" decoding=\"async\" class=\"alignnone wp-image-15957\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/0-summary-of-nucleophilic-aromatic-substitution-meisenheimer-intermediate.gif\" alt=\"summary of nucleophilic aromatic substitution meisenheimer intermediate\" width=\"600\" height=\"408\" \/><\/p>\n<p><strong>Table of Contents<\/strong><\/p>\n<ol>\n<li><a href=\"#one\">Probably Not The Aromatic Substitution Reaction You Were Expecting<\/a><\/li>\n<li><a href=\"#two\">Introducing&#8230;.Nucleophilic Aromatic Substitution<\/a><\/li>\n<li><a href=\"#three\">The Effect Of Substituents On The Ring<\/a><\/li>\n<li><a href=\"#four\">The Effect Of The Leaving Group<\/a><\/li>\n<li><a href=\"#five\">The Effect Of Substitution Pattern<\/a><\/li>\n<li><a href=\"#six\">The &#8220;Meisenheimer&#8221; Intermediate Provides A Clue To The Mechanism of Nucleophilic Aromatic Substitution<\/a><\/li>\n<li><a href=\"#seven\">The Mechanism of Nucleophilic Aromatic Substitution<\/a><\/li>\n<li><a href=\"#eight\">Why Is The <i>para-<\/i> Isomer Faster Than The <i>meta-<\/i> Isomer ? It&#8217;s All About Stabilizing Negative Charge<\/a><\/li>\n<li><a href=\"#nine\">The Reaction Energy Diagram Of SNAr<\/a><\/li>\n<li><a href=\"#ten\">A Few Examples<\/a><\/li>\n<li><a href=\"#eleven\">Summary: Nucleophilic Aromatic Substitution<\/a><\/li>\n<li><a href=\"#notes\">Notes<\/a><\/li>\n<li><a href=\"#quiz\"><strong>Quiz Yourself!<\/strong><\/a><\/li>\n<li><a href=\"#references\">(Advanced) References and Further Reading<\/a><\/li>\n<\/ol>\n<hr \/>\n<h2><strong><a id=\"one\"><\/a>1. Probably Not The Aromatic Substitution Reaction You Were Expecting<\/strong><\/h2>\n<p>Let&#8217;s review electrophilic aromatic substitution (EAS). What have we learned?<\/p>\n<ul>\n<li>The <strong>aromatic ring acts as a nucleophile<\/strong>, and attacks an added electrophile E<\/li>\n<li>An <strong>electron-deficient carbocation intermediate is formed<\/strong> (the rate-determining step) which is then deprotonated to restore aromaticity<\/li>\n<li><strong>electron-donating groups on the aromatic ring<\/strong> (such as OH, OCH<sub>3<\/sub>, and alkyl) <strong>make the reaction faster<\/strong>, since they help to stabilize the electron-poor carbocation intermediate<\/li>\n<li><strong>Lewis acids can make electrophiles even more electron-poor<\/strong> (reactive), increasing the reaction rate. For example\u00a0 FeBr<sub>3<\/sub> \/ Br<sub>2<\/sub> allows bromination to occur at a useful rate on benzene, whereas Br<sub>2<\/sub> by itself is slow).<\/li>\n<\/ul>\n<p>Everything we&#8217;ve learned so far about substitution on aromatic rings would teach us that it proceeds much faster with methoxybenzene than with nitrobenzene, and much faster with an electrophile like Cl<sub>2<\/sub> than with, say, an electron-rich nucleophile like NaOCH<sub>3<\/sub>.<\/p>\n<p>Which brings us to the reaction below. The aromatic ring\u00a0 is electron-poor and we&#8217;re adding an electron-rich nucleophile.<\/p>\n<p>What could happen here?\u00a0<em>Nothing<\/em>, right?<\/p>\n<p><img decoding=\"async\" class=\"alignnone wp-image-15958\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/1-question-how-likely-is-this-electrophilic-aromatic-substitution-reaction-with-methoxide.gif\" alt=\"question how likely is this electrophilic aromatic substitution reaction with methoxide\" width=\"600\" height=\"254\" \/><\/p>\n<p>&#8220;Nothing&#8221; is a good guess! Certainly,\u00a0thinking of this as an\u00a0<strong>electrophilic<\/strong> aromatic substitution, you&#8217;d be right in thinking that the answer to &#8220;what happens here?&#8221; is &#8220;jack squat&#8221;.<\/p>\n<h2><strong><a id=\"two\"><\/a>2. Introducing&#8230;.Nucleophilic Aromatic Substitution<\/strong><\/h2>\n<p>In fact, a substitution reaction\u00a0<em>does<\/em> occur! (But, as you may suspect, this isn&#8217;t an electrophilic aromatic substitution reaction.)<\/p>\n<p>In this substitution reaction the C-Cl bond breaks, and a C-O bond forms on the same carbon.<\/p>\n<p><img decoding=\"async\" class=\"alignnone wp-image-15959\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/2-example-of-nucleophilic-aromatic-substitution-with-methoxide-and-p-chloronitrobenzene.gif\" alt=\"xample of nucleophilic aromatic substitution with methoxide and p chloronitrobenzene\" width=\"600\" height=\"260\" \/><\/p>\n<p>So while it <em>is<\/em> a substitution reaction, it has a few important differences:<\/p>\n<ul>\n<li>The species that attacks the ring is a nucleophile, not an electrophile<\/li>\n<li>The aromatic ring is electron-poor (electrophilic), not electron rich (nucleophilic)<\/li>\n<li>The &#8220;leaving group&#8221; is chlorine, not H+<\/li>\n<li>The position where the nucleophile attacks is determined by where the leaving group is,\u00a0<span style=\"text-decoration: underline;\">not<\/span> by electronic and steric factors (<em>i.e. <\/em>no mix of <em>ortho<\/em>&#8211; and\u00a0<em>para-\u00a0<\/em>products as with electrophilic aromatic substitution).<\/li>\n<\/ul>\n<p>In short, <strong>the roles of the aromatic ring and attacking species are reversed<\/strong>!<\/p>\n<p>The attacking species (CH<sub>3<\/sub>O<sup>\u2013<\/sup>) is the nucleophile, and the ring is the electrophile.<\/p>\n<p>Since the nucleophile is the attacking species, this type of reaction has come to be known as\u00a0<strong>nucleophilic aromatic substitution.\u00a0<\/strong><\/p>\n<h2><strong><a id=\"three\"><\/a>3. The Effect Of Substituents On The Ring\u00a0<\/strong><\/h2>\n<p>In nucleophilic aromatic substitution (NAS), all the trends you learned in electrophilic aromatic substitution operate, but <em>in reverse.<\/em><\/p>\n<p>The first trend to understand is that <strong>electron withdrawing groups\u00a0<\/strong>(EWG&#8217;s) dramatically\u00a0<strong>increase<\/strong> the rate of reaction, not decrease it.<\/p>\n<p>From this, it follows that the more EWG&#8217;s there are, the faster the reaction.<\/p>\n<p>For example, the rate of NAS for 2,4-dinitrophenyl chloride is about 10<sup>5<\/sup>\u00a0times faster than for <em>p-<\/em>nitrophenyl chloride. [<a href=\"#noteone\">Note 1<\/a>]<\/p>\n<p>(I don&#8217;t have a rate constant for 2,4,6-trinitrophenyl chloride readily available, but it is orders of magnitude faster still).<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-15960\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/3-electron-withdrawing-groups-in-nucleophilic-aromatic-substitution-two-ewgs-accelerate-rate-by-about-100000.gif\" alt=\"electron withdrawing groups in nucleophilic aromatic substitution two ewgs accelerate rate by about 100000\" width=\"600\" height=\"292\" \/><\/p>\n<h2><strong><a id=\"four\"><\/a>4. The Effect Of The Leaving Group<\/strong><\/h2>\n<p>One of the most eye-opening aspects of nucleophilic aromatic substitution is noting that\u00a0<strong>fluorine is often used as a leaving group.\u00a0<\/strong>This is seen in <strong>Sanger&#8217;s reage<\/strong>nt for sequencing peptides, to take one example (<em>more on that below<\/em>).<\/p>\n<p>After all, given the stern tones we instructors use in Org 1 on this subject, the words\u00a0 &#8220;FLUORINE IS NEVER A LEAVING GROUP IN S<sub>N<\/sub>2 AND S<sub>N<\/sub>1 REACTIONS&#8221; may as well have been carved on one of the stone tablets handed down to Moses on Mt. Sinai.<\/p>\n<p>Here&#8217;s a thought: if even a &#8220;bad&#8221; leaving group like fluorine works in nucleophilic aromatic substitution, then surely a &#8220;better&#8221; leaving group like bromine or iodine would work even better. Right?<\/p>\n<p>This is a good hunch.\u00a0 It is also wrong &#8211; which <em>does not make it a dumb idea<\/em>,\u00a0 only that organic chemistry is deep.<\/p>\n<p>For one reaction studied [<a href=\"#notethree\">Note 3<\/a>], F as the leaving group\u00a0 was observed to be 3300 times faster than iodine !<\/p>\n<p>And between chlorine, bromine, and iodine, the difference was only by a factor of about 3.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-15961\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/4-nucleophilic-aromatic-substitution-fluorine-is-best-leaving-group-rate-accelerating-electron-withdrawing-character.gif\" alt=\"nucleophilic aromatic substitution fluorine is best leaving group rate accelerating electron withdrawing character\" width=\"600\" height=\"281\" \/><\/p>\n<p>So what could be different about nucleophilic aromatic substitution that makes the rate of reaction much less sensitive to the identity of the leaving group than the S<sub>N<\/sub>1 and S<sub>N<\/sub>2 reactions?<\/p>\n<p>Well, for one thing, this would suggest that, unlike the S<sub>N<\/sub>1 and S<sub>N<\/sub>2 reactions, C-F bond cleavage does not occur in the rate-determining step. This information is helpful in coming up with a mechanism for the reaction.<\/p>\n<h2><strong><a id=\"five\"><\/a>5. The Effect Of Substitution Pattern<\/strong><\/h2>\n<p>Unlike in electrophilic aromatic substitution, there are no &#8220;<em>ortho-,para-<\/em>&#8221; or &#8220;<em>meta-<\/em>&#8221; directors. The position of substitution is controlled by the placement of the leaving group.<\/p>\n<p>However that isn&#8217;t to say that the rate of the reaction isn&#8217;t affected by the relative position of the leaving group and the electron-withdrawing group.<\/p>\n<p>For example, nucleophilic aromatic substitution of\u00a0<em>p<\/em>-nitrophenyl fluoride is orders of magnitude faster than\u00a0<em>m<\/em>-nitrophenyl fluoride, even though the NO<sub>2<\/sub> is closer to the leaving group and should presumably exert more of an inductive effect.<\/p>\n<p>The <em>ortho\u00a0<\/em>isomer is also faster than the\u00a0<em>meta<\/em> by a large margin.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-15962\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/5-nucleophilic-aromatic-subsittution-rate-pattern-para-is-faster-than-meta-why.gif\" alt=\"nucleophilic aromatic subsittution rate pattern para is faster than meta why\" width=\"600\" height=\"326\" \/><\/p>\n<p><em>What&#8217;s going on?\u00a0<\/em><\/p>\n<h2><strong><a id=\"six\"><\/a>6. The &#8220;Meisenheimer&#8221; Intermediate Provides A Clue To The Mechanism of Nucleophilic Aromatic Substitution<\/strong><\/h2>\n<p>In the course of adding nucleophiles to various electron-poor aromatic molecules with a leaving group, intermediates have been isolated. One of the first was isolated in 1902 by Jacob Meisenheimer, and the general name &#8220;Meisenheimer complex&#8221; is given to these intermediates.<\/p>\n<p>The intermediate is the (non-aromatic) addition product between the aromatic ring and the nucleophile. In the case below, the negative charge is delocalized to an oxygen on one of the nitro groups:<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-15963\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/6-nucleophilic-aromatic-substitution-showing-meisenheimer-intermediate-salt-can-be-isolated-clear-evidence-for-mechanism.gif\" alt=\"nucleophilic aromatic substitution showing meisenheimer intermediate salt can be isolated clear evidence for mechanism\" width=\"630\" height=\"401\" \/><\/p>\n<p>Meisenheimer intermediates can be isolated and characterized. However, if heated, the compound goes on to form the final nucleophilic aromatic substitution product.<\/p>\n<p>This is very\u00a0<em>suggestive,\u00a0<\/em>to say the least.<\/p>\n<h2><strong><a id=\"seven\"><\/a>7. The<\/strong>\u00a0<strong>Mechanism of Nucleophilic Aromatic Substitution<\/strong><\/h2>\n<p>Taking all of these observations into account we can now propose a mechanism for this reaction.<\/p>\n<p>The first step is<strong> attack of the nucleophile on the electron-poor ring to generate a negatively charged intermediate<\/strong> <em>(e.g.<\/em> the &#8220;Meisenheimer&#8221; intermediate, above)<\/p>\n<p>Since this disrupts the aromaticity of the ring, it&#8217;s also the rate-limiting step:<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-15964\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/7-mechanism-for-nucleophilic-aromatic-substitution-step-1-attack-of-nucleophile-on-aromatic-ring.gif\" alt=\"mechanism for nucleophilic aromatic substitution step 1 attack of nucleophile on aromatic ring\" width=\"600\" height=\"255\" \/><\/p>\n<p>In electrophilic aromatic substitution (EAS) we saw that electron-rich substituents stabilized the electron-poor intermediate.<\/p>\n<p>But in nucleophilic aromatic substitution (NAS) the tables are turned!\u00a0 Instead, the <strong>intermediate is electron-rich<\/strong>, and is stabilized by electron-withdrawing substituents, such as NO<sub>2<\/sub>.<\/p>\n<p>The second step in nucleophilic aromatic substitution is expulsion of the leaving group:<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-15965\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/8-nucleophilic-aromatic-substitution-step-2-mechanism-elimination-fluoride.gif\" alt=\"nucleophilic aromatic substitution step 2 mechanism elimination fluoride\" width=\"600\" height=\"286\" \/><\/p>\n<h2><a id=\"eight\"><\/a>8. Why Is The <em>para-<\/em> Isomer Faster Than The <em>meta-<\/em> Isomer ? It&#8217;s All About Stabilizing Negative Charge<\/h2>\n<p>This two-step mechanism where addition is the rate-determining step helps to explain our earlier puzzle of why the\u00a0reaction with <em>para-<\/em>nitro is faster than the\u00a0<em>meta- <\/em>isomer.<\/p>\n<ul>\n<li>Note how the <strong>anion<\/strong> in the <em>para-<\/em>\u00a0intermediate can be <strong>delocalized to the oxygen<\/strong> on the nitro group, putting a negative charge on (more electronegative) oxygen.<\/li>\n<li>In the <em>meta-<\/em>\u00a0intermediate,<strong> the negative charge cannot be delocalized to the nitro group<\/strong>, and is stuck on (less electronegative) carbon.<\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-15966\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/9-stability-of-para-versus-ortho-intermediate-in-nucleophilic-aromatic-substitution-rationale.gif\" alt=\"stability of para versus ortho intermediate in nucleophilic aromatic substitution rationale\" width=\"600\" height=\"520\" \/><\/p>\n<p>(This also explains why addition is fast for the\u00a0<em>ortho<\/em>&#8211; isomer).<\/p>\n<p>It also helps to explain why fluorine substituents increase the rate of nucleophilic aromatic substitution: <strong>the rate determining step is attack on the aromatic ring, not breaking the very strong C-F bond.<\/strong> The highly electronegative fluorine pulls electron density out of the ring, activating it towards attack.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-15967\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/10-in-nucleophilic-aromatic-substitution-fluorine-helps-activate-ring-towards-attack.gif\" alt=\"in nucleophilic aromatic substitution fluorine helps activate ring towards attack\" width=\"600\" height=\"227\" \/><\/p>\n<p>So even though breaking a C-F bond is generally not energetically favorable, this is compensated by the fact that it restores aromaticity.<\/p>\n<p><span style=\"color: #993366;\"><em>[<strong>UPDATE<\/strong>: In the comments,\u00a0\u00a0Matt brings up a very interesting\u00a0\u00a0recent study that suggests that some nucleophilic aromatic substitution reactions that don&#8217;t have F as a leaving group may proceed through a concerted mechanism.\u00a0 I would agree in considering this more advanced material is unlikely to be covered in most introductory courses, (except maybe Eugene&#8217;s) but very worthy of interest.]<\/em><\/span><\/p>\n<h2><strong><a id=\"nine\"><\/a>9. The Reaction Energy Diagram Of SNAr<\/strong><\/h2>\n<p>Putting it all together, we can sketch out a reaction-energy diagram for this mechanism that would look something like this:<\/p>\n<p><span style=\"color: #993366;\">(<em>remember: transitition states are &#8220;peaks&#8221;, and intermediates are &#8220;valleys&#8221;. Intermediates can (at least theoretically) be isolated; transition states have partial bonds, only last a femtosecond, and can&#8217;t be isolated<\/em>).<\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-15968\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/11-reaction-energy-diagram-sketch-of-nucleophilic-aromaticx-substitution-showing-fast-and-slow-step.gif\" alt=\"reaction energy diagram sketch of nucleophilic aromaticx substitution showing fast and slow step\" width=\"600\" height=\"418\" \/><\/p>\n<p>The nucleophile adds to the aromatic ring through transition state A (the rate limiting step) to give the negatively charged intermediate B, with a further input of energy (Ea) ascends to transition state C (loss of the leaving group, the fast step) and from there, the final product.<\/p>\n<h2><strong><a id=\"ten\"><\/a>10. A Few Examples<\/strong><\/h2>\n<p>Here&#8217;s three representative examples:<\/p>\n<ul>\n<li>The first is a straightforward nucleophilic aromatic substitution using an amine as a nucleophile.<\/li>\n<li>The second uses a stronger base (NaOH) to make a weaker base (the conjugate base of phenol) which attacks the electron-poor ring.<span style=\"color: #993366;\"> <em>(A variation of this reaction was used in a synthesis of the antibiotic vancomycin)<\/em><\/span><\/li>\n<li>The third example shows the <em>N<\/em>-terminus of a peptide reacting with\u00a02,4-dinitrophenyl fluoride in a nucleophilic aromatic substitution reaction. Fred Sanger used this reagent to label the terminal residues in insulin, which led (after a <em>lot<\/em> of detective work <a href=\"#notetwo\">Note 2<\/a>],\u00a0to the first reported sequence of a protein (and a Nobel Prize in chemistry in 1958).<\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-15969\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/12-examples-of-nucleophilic-aromatic-substitution-showing-products-sangers-reagent.gif\" alt=\"examples of nucleophilic aromatic substitution showing products sangers reagent\" width=\"600\" height=\"655\" \/><\/p>\n<h2><a id=\"eleven\"><\/a>11. Summary: Nucleophilic Aromatic Substitution<\/h2>\n<p>Well, now you&#8217;ve seen something we once said was impossible: fluorine as a leaving group. While we&#8217;re here, what other commandments from Org 1 can we possibly break?<\/p>\n<p>How about putting a triple bond on an aromatic ring?<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-15970\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/13-drawing-of-benzyne.gif\" alt=\"drawing of benzyne\" width=\"600\" height=\"104\" \/><\/p>\n<p>That&#8217;s next!<\/p>\n<p>In the next post, we&#8217;ll cover a reaction that also qualifies as &#8220;nucleophilic aromatic substitution&#8221; although it goes through a completely different mechanism, involving this &#8220;triple bond&#8221;, above.<\/p>\n<p><strong>Next Post: <a href=\"https:\/\/www.masterorganicchemistry.com\/2018\/09\/17\/nucleophilic-aromatic-substitution-2-arynes\/\">Nucleophilic Aromatic Substitution (2): Arynes<\/a><\/strong><\/p>\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\/2018\/09\/17\/nucleophilic-aromatic-substitution-2-benzyne\/\" class=\"\"><span>Nucleophilic Aromatic Substitution (2) \u2013 The Benzyne Mechanism<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2018\/06\/13\/reactions-on-the-benzylic-carbon-bromination-and-oxidation\/\" class=\"\"><span>Reactions on the \u201cBenzylic\u201d Carbon: Bromination And Oxidation<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2011\/05\/06\/nucleophilic-acyl-substitution\/\" class=\"\"><span>Nucleophilic Acyl Substitution (With Negatively Charged Nucleophiles)<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2013\/01\/18\/wrapup-the-quick-n-dirty-guide-to-sn1sn2e1e2\/\" class=\"\"><span>Nucleophilic Aromatic Substitution (SNAr) (MOC Membership)<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2018\/01\/29\/ortho-para-and-meta-directors-in-electrophilic-aromatic-substitution\/\" class=\"\"><span>Ortho-, Para- and Meta- Directors in Electrophilic Aromatic Substitution<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/2018\/02\/02\/understanding-ortho-para-meta-directors\/\" class=\"\"><span>Understanding Ortho, Para, and Meta Directors<\/span><\/a><\/li><li><a href=\"https:\/\/www.masterorganicchemistry.com\/organic-chemistry-practice-problems\/electrophilic-aromatic-substitution-practice-problems\/\" class=\"\"><span>Electrophilic Aromatic Substitution Practice Problems (MOC Membership)<\/span><\/a><\/li><\/ul><\/div>\n<p><a id=\"noteone\"><\/a><strong>Note 1<\/strong>. This is for the reaction below:<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-39010\" src=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2025\/02\/F1-example-of-placing-second-nitro-group-upon-aromatic-ring-accelerates-reaction-by-about-100000-revised.gif\" alt=\"example of placing second nitro group upon aromatic ring accelerates reaction by about 100000-revised\" width=\"600\" height=\"414\" \/><\/a><\/p>\n<p><strong><a id=\"notetwo\"><\/a>Note 2<\/strong>. Sanger&#8217;s detective work is detailed <a href=\"http:\/\/www.genetics.org\/content\/162\/2\/527\">here<\/a>.<\/p>\n<p><strong><a id=\"notethree\"><\/a>Note 3.\u00a0<\/strong>Link to the study is <a href=\"https:\/\/pubs.acs.org\/doi\/10.1021\/ja01559a040\">here<\/a>.<\/p>\n<hr \/>\n<h2><a id=\"quiz\"><\/a>Quiz Yourself!<\/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\/0542-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\/0543-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\/0544-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\/3062-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\/3063-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>This is on nucleophilic aromatic substitution, specifically the addition-elimination reaction.<\/p>\n<ol>\n<li><strong>Ueber Reactionen aromatischer Nitrok\u00f6rper<br \/>\n<\/strong>Jakob Meisenheimer<br \/>\n<em> Liebig. Ann. Chem. <\/em><strong>1902<\/strong>, <em>323<\/em> (2), 205-246<br \/>\n<strong>DOI:<\/strong> <a href=\"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jlac.19023230205\">10.1002\/jlac.19023230205<\/a><br \/>\nThe addition intermediates from SNAr reactions can frequently be detected or isolated, and are called Meisenheimer complexes, after Jakob Meisenheimer, who first demonstrated their formation.<\/li>\n<li><strong>The S<sub>N<\/sub> mechanism in aromatic compounds. Part VII<\/strong><br \/>\nPeter Briner, Joseph Miller, M. Liveris, and (Miss)P. G. Lutz<br \/>\n<em>J. Chem. Soc.,<\/em> <strong>1954<\/strong>, 1265-1266<br \/>\n<strong>DOI<\/strong>: <a href=\"https:\/\/pubs.rsc.org\/en\/content\/articlelanding\/1954\/jr\/jr9540001265#!divAbstract\">10.1039\/JR9540001265<\/a><\/li>\n<li><strong>The \u201cElement Effect\u201d as a Criterion of Mechanism in Activated Aromatic Nucleophilic Substitution Reactions<\/strong><br \/>\nF. Bunnett, Edgar W. Garbisch Jr., and Kenneth M. Pruitt<br \/>\n<em>Journal of the American Chemical Society<\/em> <strong>1957,<\/strong> <em>79<\/em> (2), 385-391<br \/>\n<strong>DOI<\/strong>: <a href=\"https:\/\/pubs.acs.org\/doi\/10.1021\/ja01559a040\">10.1021\/ja01559a040<\/a><\/li>\n<li><strong>Nucleophilic substitution. Linear free energy relations between reactivity and physical properties of leaving groups and substrates<\/strong><br \/>\nGiuseppe Bartoli and Paolo Edgardo Todesco<br \/>\n<em>Accounts of Chemical Research<\/em> <strong>1977,<\/strong> <em>10<\/em> (4), 125-132<br \/>\n<strong>DOI<\/strong>: <a href=\"https:\/\/pubs.acs.org\/doi\/10.1021\/ar50112a004\">10.1021\/ar50112a004<\/a><br \/>\nThese are mechanistic studies on the reaction, demonstrating that the order of reactivity is F &gt; Cl &gt; Br &gt; I. In nucleophilic aromatic substitution, the formation of the addition intermediate is usually the rate-determining step so the ease of C-X bond breaking does not affect the rate.<\/li>\n<li><strong>NUCLEOPHILIC AROMATIC SUBSTITUTION OF ARYL FLUORIDES BY SECONDARY NITRILES: PREPARATION OF 2-(2-METHOXYPHENYL)-2-METHYLPROPIONITRILE<\/strong><br \/>\nSt\u00e9phane Caron, Jill M. Wojcik, and Enrique Vazquez<br \/>\n<em>Org. Synth.<\/em> <strong>2002<\/strong>, <em>79<\/em>, 209<br \/>\n<strong>DOI<\/strong>: <a href=\"http:\/\/www.orgsyn.org\/demo.aspx?prep=V79P0209\">10.15227\/orgsyn.079.0209<\/a><br \/>\nA procedure in <em>Organic Syntheses<\/em> for an S<sub>N<\/sub>Ar reaction, featuring nucleophilic displacement of an aryl fluoride.<\/li>\n<li><strong>The terminal peptides of insulin<\/strong><br \/>\nFrederick Sanger<br \/>\n<em>Biochemical Journal<\/em> (1 January 1949) 45 (5): 563\u2013574<br \/>\n<strong>DOI<\/strong>: <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC1275055\/pdf\/biochemj00933-0062.pdf\">10.1042\/bj0450563<\/a><br \/>\nOne of this historically most significant examples of aromatic nucleophilic substitution is the reaction of amines with 2,4-dinitrofluorobenzene. This reaction was used by Frederick Sanger (who won 2 <em>unshared<\/em> Nobel Prizes in Chemistry) to develop a method for identification of the N-terminal amino acid in proteins.<\/li>\n<li><strong>Concerted nucleophilic aromatic substitutions<\/strong><br \/>\nEugene E. Kwan, Yuwen Zeng, Harrison A. Besser &amp; Eric N. Jacobsen<br \/>\n<em>Nature Chemistry<\/em> volume 10, pages 917\u2013923 (<strong>2018<\/strong>)<br \/>\n<strong>DOI<\/strong>: <a href=\"https:\/\/www.nature.com\/articles\/s41557-018-0079-7\">10.1038\/s41557-018-0079-7<\/a><br \/>\nThis is at the cutting edge of chemistry \u2013 the authors use interesting NMR experiments to assert that S<sub>N<\/sub>Ar reactions proceed through concerted rather than stepwise mechanism.<\/li>\n<\/ol>\n<p>&#8216;,&#8217;Nucleophilic Aromatic Substitution (NAS)<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Nucleophilic Aromatic Substitution (NAS) In many ways, nucleophilic aromatic substitution is the mirror opposite of electrophilic aromatic substitution. In Nucleophilic Aromatic Substitution, an\u00a0electron-poor aromatic ring <\/p>\n","protected":false},"author":1,"featured_media":15957,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[1297],"tags":[1352,1351,1350,488,1353],"post_folder":[],"class_list":["post-11785","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-aromatic-reactions","tag-meisenheimer","tag-nas","tag-nucleophilic-aromatic-substitution","tag-reaction-coordinate","tag-sangers-reagent"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.7 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Nucleophilic Aromatic Substitution: Introduction and Mechanism<\/title>\n<meta name=\"description\" content=\"What is Nucleophilic Aromatic Substitution and how does it differ from Electrophilic Aromatic Substitution? Let&#039;s look at some examples of both.\" \/>\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.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Nucleophilic Aromatic Substitution: Introduction and Mechanism\" \/>\n<meta property=\"og:description\" content=\"What is Nucleophilic Aromatic Substitution and how does it differ from Electrophilic Aromatic Substitution? Let&#039;s look at some examples of both.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/\" \/>\n<meta property=\"og:site_name\" content=\"Master Organic Chemistry\" \/>\n<meta property=\"article:publisher\" content=\"https:\/\/www.facebook.com\/Master-Organic-Chemistry-242610599108055\/\" \/>\n<meta property=\"article:published_time\" content=\"2018-08-20T10:00:47+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2026-04-18T11:41:41+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/0-summary-of-nucleophilic-aromatic-substitution-meisenheimer-intermediate.gif\" \/>\n\t<meta property=\"og:image:width\" content=\"876\" \/>\n\t<meta property=\"og:image:height\" content=\"596\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/gif\" \/>\n<meta name=\"author\" content=\"James Ashenhurst\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"James Ashenhurst\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"15 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/#article\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/\"},\"author\":{\"name\":\"James Ashenhurst\",\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/#\\\/schema\\\/person\\\/78d83ec7d02b4b7365bade2cedaef80c\"},\"headline\":\"Nucleophilic Aromatic Substitution (NAS)\",\"datePublished\":\"2018-08-20T10:00:47+00:00\",\"dateModified\":\"2026-04-18T11:41:41+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/\"},\"wordCount\":2292,\"commentCount\":22,\"publisher\":{\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/#organization\"},\"image\":{\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/#primaryimage\"},\"thumbnailUrl\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/wp-content\\\/uploads\\\/2019\\\/12\\\/0-summary-of-nucleophilic-aromatic-substitution-meisenheimer-intermediate.gif\",\"keywords\":[\"meisenheimer\",\"nas\",\"nucleophilic aromatic substitution\",\"reaction coordinate\",\"sanger's reagent\"],\"articleSection\":[\"Reactions of Aromatic Molecules\"],\"inLanguage\":\"en-US\",\"potentialAction\":[{\"@type\":\"CommentAction\",\"name\":\"Comment\",\"target\":[\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/#respond\"]}]},{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/\",\"url\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/\",\"name\":\"Nucleophilic Aromatic Substitution: Introduction and Mechanism\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/#website\"},\"primaryImageOfPage\":{\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/#primaryimage\"},\"image\":{\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/#primaryimage\"},\"thumbnailUrl\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/wp-content\\\/uploads\\\/2019\\\/12\\\/0-summary-of-nucleophilic-aromatic-substitution-meisenheimer-intermediate.gif\",\"datePublished\":\"2018-08-20T10:00:47+00:00\",\"dateModified\":\"2026-04-18T11:41:41+00:00\",\"description\":\"What is Nucleophilic Aromatic Substitution and how does it differ from Electrophilic Aromatic Substitution? Let's look at some examples of both.\",\"breadcrumb\":{\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/#breadcrumb\"},\"inLanguage\":\"en-US\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/\"]}]},{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/#primaryimage\",\"url\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/wp-content\\\/uploads\\\/2019\\\/12\\\/0-summary-of-nucleophilic-aromatic-substitution-meisenheimer-intermediate.gif\",\"contentUrl\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/wp-content\\\/uploads\\\/2019\\\/12\\\/0-summary-of-nucleophilic-aromatic-substitution-meisenheimer-intermediate.gif\",\"width\":876,\"height\":596,\"caption\":\"summary of nucleophilic aromatic substitution meisenheimer intermediate\"},{\"@type\":\"BreadcrumbList\",\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/2018\\\/08\\\/20\\\/nucleophilic-aromatic-substitution-nas\\\/#breadcrumb\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"Nucleophilic Aromatic Substitution (NAS)\"}]},{\"@type\":\"WebSite\",\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/#website\",\"url\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/\",\"name\":\"Master Organic Chemistry\",\"description\":\"\",\"publisher\":{\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/#organization\"},\"potentialAction\":[{\"@type\":\"SearchAction\",\"target\":{\"@type\":\"EntryPoint\",\"urlTemplate\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/?s={search_term_string}\"},\"query-input\":{\"@type\":\"PropertyValueSpecification\",\"valueRequired\":true,\"valueName\":\"search_term_string\"}}],\"inLanguage\":\"en-US\"},{\"@type\":\"Organization\",\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/#organization\",\"name\":\"Master Organic Chemistry\",\"url\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/\",\"logo\":{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/#\\\/schema\\\/logo\\\/image\\\/\",\"url\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/wp-content\\\/uploads\\\/2019\\\/04\\\/cutmypic.png\",\"contentUrl\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/wp-content\\\/uploads\\\/2019\\\/04\\\/cutmypic.png\",\"width\":225,\"height\":225,\"caption\":\"Master Organic Chemistry\"},\"image\":{\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/#\\\/schema\\\/logo\\\/image\\\/\"},\"sameAs\":[\"https:\\\/\\\/www.facebook.com\\\/Master-Organic-Chemistry-242610599108055\\\/\"]},{\"@type\":\"Person\",\"@id\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/#\\\/schema\\\/person\\\/78d83ec7d02b4b7365bade2cedaef80c\",\"name\":\"James Ashenhurst\",\"image\":{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\\\/\\\/secure.gravatar.com\\\/avatar\\\/f9e9df435875e5e6b0bdff6b8522a7279d5717644b3efa7299da22c837bf9fcf?s=96&d=retro&r=g\",\"url\":\"https:\\\/\\\/secure.gravatar.com\\\/avatar\\\/f9e9df435875e5e6b0bdff6b8522a7279d5717644b3efa7299da22c837bf9fcf?s=96&d=retro&r=g\",\"contentUrl\":\"https:\\\/\\\/secure.gravatar.com\\\/avatar\\\/f9e9df435875e5e6b0bdff6b8522a7279d5717644b3efa7299da22c837bf9fcf?s=96&d=retro&r=g\",\"caption\":\"James Ashenhurst\"},\"description\":\"Ph.D. 2006, McGill University (James L. Gleason). Postdoctoral Associate, 2008-2010, Massachusetts Institute of Technology (M. Movassaghi). Founder, Master Organic Chemistry, 2010-present.\",\"sameAs\":[\"https:\\\/\\\/www.masterorganicchemistry.com\\\/about\\\/\"],\"url\":\"https:\\\/\\\/www.masterorganicchemistry.com\\\/author\\\/james\\\/\"}]}<\/script>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Nucleophilic Aromatic Substitution: Introduction and Mechanism","description":"What is Nucleophilic Aromatic Substitution and how does it differ from Electrophilic Aromatic Substitution? Let's look at some examples of both.","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/","og_locale":"en_US","og_type":"article","og_title":"Nucleophilic Aromatic Substitution: Introduction and Mechanism","og_description":"What is Nucleophilic Aromatic Substitution and how does it differ from Electrophilic Aromatic Substitution? Let's look at some examples of both.","og_url":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/","og_site_name":"Master Organic Chemistry","article_publisher":"https:\/\/www.facebook.com\/Master-Organic-Chemistry-242610599108055\/","article_published_time":"2018-08-20T10:00:47+00:00","article_modified_time":"2026-04-18T11:41:41+00:00","og_image":[{"width":876,"height":596,"url":"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/0-summary-of-nucleophilic-aromatic-substitution-meisenheimer-intermediate.gif","type":"image\/gif"}],"author":"James Ashenhurst","twitter_card":"summary_large_image","twitter_misc":{"Written by":"James Ashenhurst","Est. reading time":"15 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/#article","isPartOf":{"@id":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/"},"author":{"name":"James Ashenhurst","@id":"https:\/\/www.masterorganicchemistry.com\/#\/schema\/person\/78d83ec7d02b4b7365bade2cedaef80c"},"headline":"Nucleophilic Aromatic Substitution (NAS)","datePublished":"2018-08-20T10:00:47+00:00","dateModified":"2026-04-18T11:41:41+00:00","mainEntityOfPage":{"@id":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/"},"wordCount":2292,"commentCount":22,"publisher":{"@id":"https:\/\/www.masterorganicchemistry.com\/#organization"},"image":{"@id":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/#primaryimage"},"thumbnailUrl":"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/0-summary-of-nucleophilic-aromatic-substitution-meisenheimer-intermediate.gif","keywords":["meisenheimer","nas","nucleophilic aromatic substitution","reaction coordinate","sanger's reagent"],"articleSection":["Reactions of Aromatic Molecules"],"inLanguage":"en-US","potentialAction":[{"@type":"CommentAction","name":"Comment","target":["https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/#respond"]}]},{"@type":"WebPage","@id":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/","url":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/","name":"Nucleophilic Aromatic Substitution: Introduction and Mechanism","isPartOf":{"@id":"https:\/\/www.masterorganicchemistry.com\/#website"},"primaryImageOfPage":{"@id":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/#primaryimage"},"image":{"@id":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/#primaryimage"},"thumbnailUrl":"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/0-summary-of-nucleophilic-aromatic-substitution-meisenheimer-intermediate.gif","datePublished":"2018-08-20T10:00:47+00:00","dateModified":"2026-04-18T11:41:41+00:00","description":"What is Nucleophilic Aromatic Substitution and how does it differ from Electrophilic Aromatic Substitution? Let's look at some examples of both.","breadcrumb":{"@id":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/#breadcrumb"},"inLanguage":"en-US","potentialAction":[{"@type":"ReadAction","target":["https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/"]}]},{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/#primaryimage","url":"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/0-summary-of-nucleophilic-aromatic-substitution-meisenheimer-intermediate.gif","contentUrl":"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/12\/0-summary-of-nucleophilic-aromatic-substitution-meisenheimer-intermediate.gif","width":876,"height":596,"caption":"summary of nucleophilic aromatic substitution meisenheimer intermediate"},{"@type":"BreadcrumbList","@id":"https:\/\/www.masterorganicchemistry.com\/2018\/08\/20\/nucleophilic-aromatic-substitution-nas\/#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/www.masterorganicchemistry.com\/"},{"@type":"ListItem","position":2,"name":"Nucleophilic Aromatic Substitution (NAS)"}]},{"@type":"WebSite","@id":"https:\/\/www.masterorganicchemistry.com\/#website","url":"https:\/\/www.masterorganicchemistry.com\/","name":"Master Organic Chemistry","description":"","publisher":{"@id":"https:\/\/www.masterorganicchemistry.com\/#organization"},"potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/www.masterorganicchemistry.com\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-US"},{"@type":"Organization","@id":"https:\/\/www.masterorganicchemistry.com\/#organization","name":"Master Organic Chemistry","url":"https:\/\/www.masterorganicchemistry.com\/","logo":{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/www.masterorganicchemistry.com\/#\/schema\/logo\/image\/","url":"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/04\/cutmypic.png","contentUrl":"https:\/\/www.masterorganicchemistry.com\/wp-content\/uploads\/2019\/04\/cutmypic.png","width":225,"height":225,"caption":"Master Organic Chemistry"},"image":{"@id":"https:\/\/www.masterorganicchemistry.com\/#\/schema\/logo\/image\/"},"sameAs":["https:\/\/www.facebook.com\/Master-Organic-Chemistry-242610599108055\/"]},{"@type":"Person","@id":"https:\/\/www.masterorganicchemistry.com\/#\/schema\/person\/78d83ec7d02b4b7365bade2cedaef80c","name":"James Ashenhurst","image":{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/secure.gravatar.com\/avatar\/f9e9df435875e5e6b0bdff6b8522a7279d5717644b3efa7299da22c837bf9fcf?s=96&d=retro&r=g","url":"https:\/\/secure.gravatar.com\/avatar\/f9e9df435875e5e6b0bdff6b8522a7279d5717644b3efa7299da22c837bf9fcf?s=96&d=retro&r=g","contentUrl":"https:\/\/secure.gravatar.com\/avatar\/f9e9df435875e5e6b0bdff6b8522a7279d5717644b3efa7299da22c837bf9fcf?s=96&d=retro&r=g","caption":"James Ashenhurst"},"description":"Ph.D. 2006, McGill University (James L. Gleason). Postdoctoral Associate, 2008-2010, Massachusetts Institute of Technology (M. Movassaghi). Founder, Master Organic Chemistry, 2010-present.","sameAs":["https:\/\/www.masterorganicchemistry.com\/about\/"],"url":"https:\/\/www.masterorganicchemistry.com\/author\/james\/"}]}},"_links":{"self":[{"href":"https:\/\/www.masterorganicchemistry.com\/wp-json\/wp\/v2\/posts\/11785","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.masterorganicchemistry.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.masterorganicchemistry.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.masterorganicchemistry.com\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.masterorganicchemistry.com\/wp-json\/wp\/v2\/comments?post=11785"}],"version-history":[{"count":0,"href":"https:\/\/www.masterorganicchemistry.com\/wp-json\/wp\/v2\/posts\/11785\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.masterorganicchemistry.com\/wp-json\/wp\/v2\/media\/15957"}],"wp:attachment":[{"href":"https:\/\/www.masterorganicchemistry.com\/wp-json\/wp\/v2\/media?parent=11785"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.masterorganicchemistry.com\/wp-json\/wp\/v2\/categories?post=11785"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.masterorganicchemistry.com\/wp-json\/wp\/v2\/tags?post=11785"},{"taxonomy":"post_folder","embeddable":true,"href":"https:\/\/www.masterorganicchemistry.com\/wp-json\/wp\/v2\/post_folder?post=11785"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}