{"id":764,"date":"2018-11-29T22:50:19","date_gmt":"2018-11-29T22:50:19","guid":{"rendered":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/?post_type=chapter&#038;p=764"},"modified":"2022-05-31T13:39:43","modified_gmt":"2022-05-31T13:39:43","slug":"17-2-reactions-involving-arenediazonium-salts","status":"publish","type":"chapter","link":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/17-2-reactions-involving-arenediazonium-salts\/","title":{"raw":"17.3. Reactions involving arenediazonium salts","rendered":"17.3. Reactions involving arenediazonium salts"},"content":{"raw":"<header class=\"elm-header\">\r\n<div class=\"elm-header-custom\"><\/div>\r\n<\/header><article id=\"elm-main-content\" class=\"elm-content-container\"><section class=\"mt-content-container\">\r\n<div id=\"s91036\" class=\"mt-include\">\r\n<div>\r\n<div class=\"textbox shaded\">\r\n<h3 class=\"boxtitle\">Key Terms<\/h3>\r\nMake certain that you can define, and use in context, the key terms below.\r\n<ul>\r\n \t<li>arenediazonium salt<\/li>\r\n \t<li>Sandmeyer reaction<\/li>\r\n<\/ul>\r\n<\/div>\r\n<\/div>\r\n<div id=\"note\">\r\n<div class=\"textbox key-takeaways\">\r\n<h3>Study Notes<\/h3>\r\n<div id=\"note\">\r\n\r\nAn \u201carenediazonium salt\u201d is formed by the reaction of an aromatic amine with nitrous acid at 0\u20135\u00b0C, and has the structure shown below.\r\n<p class=\"max-66\"><img class=\"internal aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165144\/24-8f.png\" alt=\"general structure for a arenediazonium salt\" \/><\/p>\r\nAlkanediazonium salts are very unstable; therefore, arenediazonium salts are often simply referred to as diazonium salts.\r\n\r\nAs is mentioned in the textbook, arenediazonium salts are very useful intermediates from which a wide variety of aromatic compounds can be prepared. You should be thoroughly familiar with the use of diazonium salts to prepare each of the classes of compounds. In addition, you should be aware that fluoroarenes can also be prepared from diazonium salts, as follows:\r\n<p class=\"max-66\"><img class=\"internal aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165146\/24-8g.png\" alt=\"decomposition reaction of diazonium tetrafluoroborate\" \/><\/p>\r\nIn this case the diazonium salt is prepared using fluoroboric acid, HBF<sub>4<\/sub>, and sodium nitrite. The thermal decomposition of the salt, called the Balz-Schiemann reaction, can be quite hazardous.\r\n\r\nHypophosphorous acid has the structure shown below:\r\n<p class=\"max-66\"><img class=\"internal aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165149\/24-8h.png\" alt=\"hypophosphorous acid\" \/><\/p>\r\nThe presence of the letters \u201cazo\u201d in a compound\u2019s name usually implies that a nitrogen\u2011nitrogen double bond is present in its structure. Azo compounds in which two aryl groups are joined by an\u00a0$\\ce{-}$N$\\ce{=}$N$\\ce{-}$ linkage \u00a0are usually very colorful.\r\n\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<div id=\"section_4\" class=\"mt-section\">\r\n<h2 id=\"Diazonium_Salts:_The_Sandmeyer_Reaction-91036\">Overview of diazonium salt chemistry<\/h2>\r\n<\/div>\r\n<div id=\"bodyContent\" class=\"mw-body-content\">\r\n<div id=\"mw-content-text\" class=\"mw-content-ltr\" dir=\"ltr\" xml:lang=\"en\">\r\n<dl>\r\n \t<dd><\/dd>\r\n<\/dl>\r\n<div id=\"section_4\" class=\"mt-section\">\r\n<h3>Making the aromatic ring available for attack by nucleophiles<\/h3>\r\n<p id=\"Diazonium_Salts:_The_Sandmeyer_Reaction-91036\">Most preparations of aromatic compounds we have seen (such as <a href=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/14-1-electrophilic-aromatic-substitution-reactions\/\">electrophilic aromatic substitution<\/a>, as well as the <a href=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/17-2-palladium-catalyzed-couplings\/\">Suzuki reaction<\/a> covered in the previous section) involve the aromatic ring as nucleophile, reacting with an electrophilic reagent.\u00a0 <a href=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/17-1-nucleophilic-aromatic-substitution\/\">Nucleophilic aromatic substitution<\/a> (in 17.1.) involves nucleophilic reagents, but it is limited to rings with strong electron-withdrawing groups <em>ortho<\/em> or <em>para<\/em> to a leaving group.\u00a0 The most versatile way to make aromatic rings available for nucleophilic attack is to prepare arenediazonium salts, containing the ArN<sub>2<\/sub><sup>+<\/sup> ion.\u00a0 The diagram below shows the variety of reactions possible with arenediazonium salts.<\/p>\r\n<img class=\"size-full wp-image-3141 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/15053119\/AreneDiazoniumSaltReactions.png\" alt=\"Chart showing the preparation of arenediazonium salts from anilines, and reactions to produce halides, nitriles, phenols, free arenes and azo compounds\" width=\"676\" height=\"362\" \/>\r\n\r\nArenediazonium salts are easily prepared from arylamines (anilines) using a process called diazotization.\u00a0 The process involves dissolving the amine in a suitable acid, cooling in an ice bath to 0-5 <sup>o<\/sup>C, then adding sodium nitrite (NaNO<sub>2<\/sub>) solution.\u00a0 The acid reacts with the NaNO<sub>2<\/sub> to form nitrous acid (HNO<sub>2<\/sub>), which then reacts with the arylamine to form the arenediazonium salt. The most common salt to use for these reactions is the chloride (made using HCl as the acid), which are fairly soluble but decompose rapidly at room temperature.\u00a0 However, in some reactions (such as phenol formation) the chloride ion may interfere and substitute a Cl, so in those cases the sulfate (made using H<sub>2<\/sub>SO<sub>4<\/sub>) is used.\u00a0 Diazonium sulfates are a little more stable than chlorides, but they are also generally less soluble and thus more awkward to use.\u00a0 Diazonium tetrafluoroborates are made from chlorides by adding HBF<sub>4<\/sub>; they are usually completely insoluble, which allows them to be filtered off, then dried for decomposition without water present to introduce a fluorine onto the ring.\u00a0 This method for introducing fluorine onto an aromatic ring is called the <a href=\"https:\/\/en.wikipedia.org\/wiki\/Balz%E2%80%93Schiemann_reaction\">Balz-Schiemann reaction<\/a>.\r\n\r\nArenediazonium salts are useful intermediates, and they easily lose nitrogen react with a variety of nucleophiles, as shown in the diagram above.\u00a0 Since nitrogen is very stable, and is lost as a gas, this provides a powerful driving force for these reactions to occur.\u00a0 In the case of water or iodide ion, the nucleophile reacts without need for any catalysis.\u00a0 However, many reactions of diazonium salts are catalyzed by copper(I), in which case the reaction is referred to as a <strong>Sandmeyer reaction<\/strong>.\r\n\r\nOne reaction that retains the two nitrogens involves coupling to another (electron-rich) aromatic ring, as shown on the left part of the reaction scheme.\u00a0 This is very important in the artificial dye industry, which was mainly established using the production of these \"azo dyes\" after the discovery of <a href=\"https:\/\/en.wikipedia.org\/wiki\/Mauveine\">Perkin's mauve<\/a> in 1856.\r\n<h2>Use in synthesis<\/h2>\r\nDiazonium salt chemistry, being based on nucleophilic reagents used with an electrophilic aromatic ring, is complementary to electrophilic aromatic substitution (EAS, which uses electrophilic reagents).\u00a0 Diazonium salts are easily prepared from aromatics via a three step synthesis:\r\n\r\n<img class=\"wp-image-3158 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26053408\/DiazoniumSaltFullSynthesis.png\" alt=\"Benzene is nitrated to nitrobenzene, which is reduced to aniline, which is then diazotized to form a diazonium salt\" width=\"741\" height=\"106\" \/>\r\n\r\nIf other substituents are needed, these can be introduced during the synthesis.\u00a0 If a meta substituent is needed, the substituent is introduced at or before the nitro stage; for ortho\/para substituents, this can be done at the NH<sub>2<\/sub> stage.\u00a0 The amino group in an arylamine (aniline) is a very powerful activator, so many EAS reactions of arylamines rapidly introduce 2 or 3 substituents unless the NH<sub>2<\/sub> group's reactivity is moderated by formation of an amide - recall this method for <a href=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/16-2-preparation-of-alkylbenzenes\/\">protection of amines via acetylation, from chapter 16<\/a>.\u00a0 In some cases, the new substituent may also be reduced during the reduction of the nitro group, as in this synthesis of meta-propylbenzenediazonium chloride from benzene:\r\n\r\n<img class=\"wp-image-3159 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26062455\/MetaPropylBenzeneDiazoniumSynthesis.png\" alt=\"Benzene is acetylated then nitrated, then reduced and diazotized\" width=\"805\" height=\"155\" \/>\r\n\r\nFor the synthesis of the para isomer, the arylamine is acetylated before the Friedel-Crafts reaction, then deacetylated by heating with excess aq. HCl right before diazotization.\r\n\r\n<img class=\"wp-image-3160 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26062912\/ParaPropylBenzeneDiazoniumSynthesis.png\" alt=\"Benzene is nitrated, then the NO2 is reduced and acetylated to give acetanilide. This is then acylated via Friedel-Crafts, reduced, deacetylated and diazotized\" width=\"718\" height=\"307\" \/>\r\n\r\nThis para isomer synthesis shows the use of the acetyl group to control the reactivity of the amino group.\u00a0 (An alternative synthesis could avoid this by introducing the propyl group first, before nitration.)\u00a0 Although these syntheses appear to be long, they involve synthetic steps that are reliable and reproducible, and they follow a standard pattern.\u00a0 Also, the fact that different substituents can be introduced at selected positions along the way makes this approach a very valuable synthetic sequence.\r\n\r\n<\/div>\r\n<h2 id=\"firstHeading\" class=\"firstHeading\" xml:lang=\"en\">Sandmeyer reaction<\/h2>\r\n<p class=\"firstHeading\" xml:lang=\"en\">The <b>Sandmeyer reaction<\/b> is a subset of these reactions of diazonium salts, in cases where a copper(I) salt is used as a catalyst. It is an example of a <a title=\"Radical-nucleophilic aromatic substitution\" href=\"https:\/\/en.wikipedia.org\/wiki\/Radical-nucleophilic_aromatic_substitution\">radical-nucleophilic aromatic substitution<\/a>. The Sandmeyer reaction provides a method through which one can perform unique transformations on benzene, such as halogenation, <a href=\"https:\/\/en.wikipedia.org\/wiki\/Cyanation\">cyanation<\/a>, <a title=\"Trifluoromethylation\" href=\"https:\/\/en.wikipedia.org\/wiki\/Trifluoromethylation\">trifluoromethylation<\/a>.<\/p>\r\nThe reaction was discovered in 1884 by Swiss chemist <a title=\"Traugott Sandmeyer\" href=\"https:\/\/en.wikipedia.org\/wiki\/Traugott_Sandmeyer\">Traugott Sandmeyer<\/a>, when he synthesized phenylacetylene from benzenediazonium chloride and copper(I) acetylide. The reaction is a method for substitution of an aromatic amino group via preparation of its diazonium salt followed by its displacement with a nucleophile, catalyzed by copper(I) salts. The nucleophile can include <a title=\"Halide\" href=\"\/wiki\/Halide\">halide<\/a> anions, <a title=\"Cyanide\" href=\"\/wiki\/Cyanide\">cyanide<\/a>, <a title=\"Thiol\" href=\"\/wiki\/Thiol\">thiols<\/a>, water, and others. The reaction does not proceed well with the fluoride anion, but fluorination can be carried out using tetrafluoroborate anions (see below).\r\n<h2><span id=\"Reaction_mechanism\" class=\"mw-headline\">Reaction mechanism<\/span><\/h2>\r\nThe <a title=\"Nitrous acid\" href=\"\/wiki\/Nitrous_acid\">nitrous acid<\/a> is typically prepared <i>in situ<\/i> from <a title=\"Sodium nitrite\" href=\"\/wiki\/Sodium_nitrite\">sodium nitrite<\/a> and acid. Following two <a title=\"Protonation\" href=\"\/wiki\/Protonation\">protonation<\/a> steps, one equivalent of water is lost to form the <a class=\"mw-redirect\" title=\"Nitrosonium ion\" href=\"\/wiki\/Nitrosonium_ion\">nitrosonium ion<\/a>. The nitrosonium ion then acts as an <a title=\"Electrophile\" href=\"\/wiki\/Electrophile\">electrophile<\/a> in a reaction with an <a class=\"mw-redirect\" title=\"Aromatic\" href=\"\/wiki\/Aromatic\">aromatic<\/a> (or <a class=\"mw-redirect\" title=\"Heterocyclic\" href=\"\/wiki\/Heterocyclic\">heterocyclic<\/a>) amine, such as <a title=\"Aniline\" href=\"\/wiki\/Aniline\">aniline<\/a>, to form a diazonium salt, proceeding through a <a title=\"Nitrosamine\" href=\"\/wiki\/Nitrosamine\">nitrosamine<\/a> intermediate.<sup id=\"cite_ref-Zerong_2010_4-1\" class=\"reference\"><a href=\"#cite_note-Zerong_2010-4\">[4]<\/a><\/sup> The substitution of the aromatic diazo group with a halogen or <a title=\"Pseudohalogen\" href=\"\/wiki\/Pseudohalogen\">pseudohalogen<\/a> is initiated by a one-electron transfer mechanism catalyzed by copper(I) to form an <a title=\"Aryl radical\" href=\"\/wiki\/Aryl_radical\">aryl radical<\/a> with loss of nitrogen gas.<sup id=\"cite_ref-Kochi_1956_5-0\" class=\"reference\"><a href=\"#cite_note-Kochi_1956-5\">[5]<\/a><\/sup><sup id=\"cite_ref-Hodgson_1947_6-0\" class=\"reference\"><a href=\"#cite_note-Hodgson_1947-6\">[6]<\/a><\/sup><sup id=\"cite_ref-7\" class=\"reference\"><a href=\"#cite_note-7\">[7]<\/a><\/sup><sup id=\"cite_ref-Galli_1988_8-0\" class=\"reference\"><a href=\"#cite_note-Galli_1988-8\">[8]<\/a><\/sup> The substituted <a class=\"mw-redirect\" title=\"Arene\" href=\"\/wiki\/Arene\">arene<\/a> is formed through a radical mechanism with regeneration of the copper(I) catalyst. This reaction is known as the Sandmeyer reaction and is an example of a <a title=\"Radical-nucleophilic aromatic substitution\" href=\"\/wiki\/Radical-nucleophilic_aromatic_substitution\">radical-nucleophilic aromatic substitution<\/a>. The radical mechanism of the Sandmeyer reaction was resolved through the detection of <a class=\"mw-redirect\" title=\"Biaryl\" href=\"\/wiki\/Biaryl\">biaryl<\/a> byproducts.<sup id=\"cite_ref-Galli_1988_8-1\" class=\"reference\"><a href=\"#cite_note-Galli_1988-8\">[8]<\/a><\/sup> It proceeds through the following mechanism.\r\n<h3><span id=\"Formation_of_the_nitrosonium_ion\" class=\"mw-headline\">Formation of the nitrosonium ion<\/span><\/h3>\r\nThe nitrosonium ion (NO<sup>+<\/sup>) is formed from nitrous acid (HNO<sub>2<\/sub>) by a mechanism analogous to formation of NO2+ from HNO<sub>3<\/sub>, which we saw in <a href=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/14-3-the-general-mechanism-chemistry-libretexts\/\">section 14.2<\/a>. The mechanism here can occur in water, because HNO<sub>2<\/sub> is more easily protonated (the first step) than is HNO<sub>3<\/sub>.\r\n\r\n<img class=\"wp-image-3144 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/17054534\/NitrosylIonFormation.png\" alt=\"HNO2 is protonated, then loses H2O to form NO+\" width=\"541\" height=\"111\" \/>\r\n<dl>\r\n \t<dd><\/dd>\r\n<\/dl>\r\n<h3><span id=\"Formation_of_the_benzenediazonium_ion\" class=\"mw-headline\">Formation of the benzenediazonium ion<\/span><\/h3>\r\nThe mechanism for formation of the benzenediazonium is beyond the scope of this class, but the reaction can be regarded overall as a dehydration:\r\n\r\nArNH<sub>2<\/sub> + NO<sup>+<\/sup>\u00a0 ----&gt;\u00a0 ArN<sub>2<\/sub>+\u00a0 +\u00a0 H<sub>2<\/sub>O\r\n<dl>\r\n \t<dd><\/dd>\r\n<\/dl>\r\n<h2 class=\"mw-parser-output\">Specific reactions of diazonium salts<\/h2>\r\n<h3>Halogenation<\/h3>\r\n<div class=\"mw-parser-output\">\r\n\r\nAryl iodides can be prepared simply by treating the diazonium salt (chloride or sulfate) with iodide ion, usually as a solution of sodium or potassium iodide.\u00a0 A copper(I) catalyst is not essential, though it is sometimes used.\r\n\r\n<img class=\"wp-image-3163 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/04060418\/DiazoniumIodination.png\" alt=\"Aniline is diazotized then treated with KI to form iodobenzene\" width=\"319\" height=\"89\" \/>\r\n\r\nFor preparation of aryl bromides and chlorides, the Sandmeyer reaction is used, since the reaction is sluggish without copper(I) catalysis.\u00a0 The corresponding copper halide is used - CuBr for Br, and CuCl for Cl, for example[footnote]Example taken from Organic Syntheses, 1923, 3, 79, http:\/\/www.orgsyn.org\/demo.aspx?prep=CV1P0162[\/footnote]:\r\n\r\n<img class=\"wp-image-3147 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/22083531\/SandmeyerCuCl.png\" alt=\"m-nitroaniline reacts with NaNO2 and HCl, then CuCl, to make m-chloronitrobenzene\" width=\"433\" height=\"82\" \/>\r\n<dl>\r\n \t<dd><\/dd>\r\n<\/dl>\r\nThe <a title=\"Balz\u2013Schiemann reaction\" href=\"\/wiki\/Balz%E2%80%93Schiemann_reaction\">Balz\u2013Schiemann reaction<\/a> uses <a title=\"Tetrafluoroborate\" href=\"\/wiki\/Tetrafluoroborate\">tetrafluoroborate<\/a> ion and delivers the halide-substituted product, <a title=\"Fluorobenzene\" href=\"\/wiki\/Fluorobenzene\">fluorobenzene<\/a>, which is not obtained by the use of <a title=\"Copper fluoride\" href=\"\/wiki\/Copper_fluoride\">copper fluorides<\/a>.\r\n\r\n<img class=\"wp-image-3154 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/25173613\/DiazoniumFluoridation.png\" alt=\"3-bromoaniline is diazotized, then treated with HBF4, dried, then heated to produce 3-bromofluorobenzene\" width=\"399\" height=\"104\" \/>\r\n<h3><span id=\"Cyanation\" class=\"mw-headline\">Cyanation<\/span><\/h3>\r\nAnother use of the Sandmeyer reaction is for <a title=\"Cyanation\" href=\"\/wiki\/Cyanation\">cyanation<\/a> which allows for the formation of <a title=\"Benzonitrile\" href=\"\/wiki\/Benzonitrile\">benzonitriles<\/a>, an important class of organic compounds. <img class=\"wp-image-3152 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/25160131\/DiazotizationCyanationExample.png\" alt=\"Sandmeyer reaction example. 2-Methylaniline (o-toluidine) is diazotized then treated with CuCN, forming 2-methylbenzonitrile (o-tolunitrile)\" width=\"351\" height=\"107\" \/>\r\n\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<div id=\"footer\" role=\"contentinfo\"><article id=\"elm-main-content\" class=\"elm-content-container\"><section class=\"mt-content-container\">\r\n<div id=\"section_1\" class=\"mt-section\">\r\n<h3>Replacement of nitrogen with hydrogen (reduction)<\/h3>\r\nThe amino functional group can in effect be removed by diazotization followed by reduction.\u00a0 The most common reagent is hypophosphorous acid (H<sub>3<\/sub>PO<sub>2<\/sub>), but NaBH<sub>4<\/sub> also works.\u00a0 Ethanol can also effect the reduction, and this is commoner in the older literature.\r\n\r\nRemoval of the NH<sub>2<\/sub> in this way can be useful in synthesis, because the amino group is a powerful activator and ortho-para director.\u00a0 For example, the NH<sub>2<\/sub> can be used to introduce three bromines rapidly ortho\/para to itself, then the NH<sub>2<\/sub> can be removed to leave the bromines intact.\u00a0 A compound such as 2,4,6-tribromobenzoic acid can be easily prepared in this way.\r\n\r\n<\/div>\r\n<\/section><\/article><img class=\"alignnone wp-image-3156\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/25183821\/DiazoniumDeamination.png\" alt=\"3-amino-2,4,6-tribromobenzoic acid is diazotized then treated with H3PO2. This replaces the diazonium group with a simple H, giving 2,4,6-tribromobenzoic acid\" width=\"395\" height=\"131\" \/>\r\n\r\n<article id=\"elm-main-content\" class=\"elm-content-container\"><section class=\"mt-content-container\">\r\n<div id=\"section_2\" class=\"mt-section\">\r\n<h3 class=\"editable\">Substitution by an -OH group<\/h3>\r\nThe NH<sub>2<\/sub> can be replaced by OH simply by warming the acidic solution of the benzenediazonium salt, and water acts as the incoming nucleophile.\u00a0 Since chloride ion can act as a competing nucleophile at higher temperatures, we avoid a halogenation side reaction by using a non-nucleophilic anion such as hydrogen sulfate, HSO<sub>4<\/sub>\u00af.\u00a0 The diazonium hydrogen sulfate salt is prepared simply using NaNO<sub>2<\/sub> in cold dilute sulfuric acid, and then warmed to produce the phenol.\u00a0 In some cases, the entire reaction is done in warm aqueous H<sub>2<\/sub>SO<sub>4<\/sub>.\r\n\r\n<img class=\"wp-image-3150 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/25153706\/DiazotizationPhenolExample.png\" alt=\"2-Bromo-4-methylaniline is diazotized then treated with CuCN to form 2-bromo-4-methylphenol\" width=\"450\" height=\"109\" \/>\r\n\r\n<\/div>\r\n<div id=\"section_2\" class=\"mt-section\">\r\n\r\nSince there is no easy way to introduce an OH group directly onto an aromatic ring via electrophilic aromatic substitution, this reaction is the most commonly used way to prepare phenols in synthesis.\u00a0 Given the importance of the hydroxyl group in organic chemistry - many phenols are found in nature, for example - means that this reaction is widely used.\r\n\r\n<\/div>\r\n<div id=\"section_9\" class=\"mt-section\">\r\n<h2 id=\"Diazonium_Coupling_Reactions-91036\">Diazonium coupling reactions<\/h2>\r\nAlthough most reactions of diazonium salts involve loss of nitrogen, there are some useful reactions where the nitrogen is retained.\u00a0 The most important of these is where the diazonium salt acts as an electrophile in an electrophilic aromatic substitution (EAS), forming an \"azo compound\".\u00a0 The reaction only occurs where the aromatic nucleophile is highly activated, and the azo group is attached at the most activated position(s) - usually ortho or para to a hydroxy or amino group.\u00a0 The resultant azo compounds are brightly colored and used very widely used as dyes, since they provide a conjugated system involving both aromatic rings.\u00a0 Some common azo dyes are shown in the table,\r\n<table style=\"border-collapse: collapse; width: 100%;\" border=\"1\">\r\n<tbody>\r\n<tr>\r\n<td style=\"width: 25%;\">Methyl Red<\/td>\r\n<td style=\"width: 25%;\">Azobenzene<\/td>\r\n<td style=\"width: 25%;\">Evans' Blue<\/td>\r\n<td style=\"width: 25%;\">Para Red<\/td>\r\n<\/tr>\r\n<tr>\r\n<td style=\"width: 25%;\"><\/td>\r\n<td style=\"width: 25%;\"><\/td>\r\n<td style=\"width: 25%;\"><\/td>\r\n<td style=\"width: 25%;\"><\/td>\r\n<\/tr>\r\n<tr>\r\n<td style=\"width: 25%;\"><img class=\"alignnone size-full wp-image-3172\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/07024424\/MethylRed.png\" alt=\"A sample of Methyl Red dye\" width=\"1016\" height=\"861\" \/><\/td>\r\n<td style=\"width: 25%;\"><img class=\"transparent\" src=\"https:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/0\/0f\/Azobenzene_structure.svg\/630px-Azobenzene_structure.svg.png\" alt=\"https:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/0\/0f\/Azobenzene_structure.svg\/630px-Azobenzene_structure.svg.png\" \/><\/td>\r\n<td style=\"width: 25%;\"><\/td>\r\n<td style=\"width: 25%;\"><\/td>\r\n<\/tr>\r\n<\/tbody>\r\n<\/table>\r\nThe EAS mechanism is shown here, in this synthesis of the dye Methyl Red from 2-aminobenzoic acid and <em>N<\/em>,<em>N<\/em>-dimethylaniline:\r\n\r\n<img class=\"alignnone wp-image-3167\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/06210108\/MethylRedMechanism.png\" alt=\"The diazonium salt from 2-aminobenzoic acid is attacked by the para position of N,N-dimethylaniline, and after loss of H+ forms Methyl Red.\" width=\"837\" height=\"140\" \/>\r\n\r\nIn another example, Para Red is synthesized from 2-naphthol and 4-nitrobenzenediazonium hydrogen sulfate:\r\n\r\n<img class=\"alignnone wp-image-3169\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/06210352\/ParaRedSynthesis.png\" alt=\"4-nitroaniline is diazotized, then reacted with 2-naphthol to form Para Red\" width=\"789\" height=\"131\" \/>\r\n<h3 class=\"editable\">Contributors<\/h3>\r\nMartin A. Walker\r\n\r\nJim Clark (<a class=\"external\" title=\"http:\/\/www.chemguide.co.uk\" href=\"http:\/\/www.chemguide.co.uk\" target=\"_blank\" rel=\"external nofollow noopener\">Chemguide.co.uk<\/a>)\r\n<div id=\"section_4\" class=\"mt-section\">\r\n<h2>Practice problems<\/h2>\r\nThe following examples illustrate some combined applications of these options to specific cases. You should try to conceive a plausible reaction sequence for each. Once you have done so, you may check suggested answers below.\r\n\r\n<a title=\"ardiazpb.gif\" href=\"https:\/\/chem.libretexts.org\/@api\/deki\/files\/1477\/ardiazpb.gif?revision=1\" rel=\"internal\"><img class=\"internal default aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165155\/ardiazpb.gif\" alt=\"ardiazpb.gif\" \/><\/a>\r\n<dl>\r\n \t<dt>[reveal-answer q=\"534781\"]Answer 1:[\/reveal-answer]\r\n[hidden-answer a=\"534781\"]\r\n<dl>\r\n \t<dd>It should be clear that the methyl substituent will eventually be oxidized to a carboxylic acid function. The timing is important, since a methyl substituent is ortho\/para-directing and the carboxyl substituent is meta-directing. The cyano group will be introduced by a diazonium intermediate, so a nitration followed by reduction to an amine must precede this step.\r\n\r\n<img class=\"internal default aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165158\/ardizpb1.gif\" alt=\"ardizpb1.gif\" \/><\/dd>\r\n<\/dl>\r\n<strong>[\/hidden-answer]<\/strong><\/dt>\r\n<\/dl>\r\n<dl>\r\n \t<dt>[reveal-answer q=\"33282\"]Answer 2:[\/reveal-answer]\r\n[hidden-answer a=\"33282\"]\r\n<dl>\r\n \t<dd>The hydroxyl group is a strong activating substituent and would direct aromatic ring chlorination to locations ortho &amp; para to itself, leading to the wrong product. As an alternative, the nitro group is not only meta-directing, it can be converted to a hydroxyl group by way of a diazonium intermediate. The resulting strategy is self evident.\r\n\r\n<img class=\"internal default\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165201\/ardizpb2.gif\" alt=\"ardizpb2.gif\" \/><\/dd>\r\n<\/dl>\r\n[\/hidden-answer]<\/dt>\r\n<\/dl>\r\n<dl>\r\n \t<dt>[reveal-answer q=\"995704\"]Answer 3:[\/reveal-answer]\r\n[hidden-answer a=\"995704\"]\r\n<dl>\r\n \t<dd>Selective introduction of a fluorine is best achieved by treating a diazonium intermediate with tetrafluoroborate anion. To get the necessary intermediate we need to make p-nitroaniline. Since the nitro substituent on the starting material would direct a new substituent to a meta-location, we must first reduce it to an ortho\/para-directing amino group. Amino groups are powerful activating substituents, so we deactivate it by acetylation before nitration. The acetyl substituent also protects the initial amine function from reaction with nitrous acid later on. It is removed in the last step.\r\n\r\n<img class=\"internal default\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165204\/ardizpb3.gif\" alt=\"ardizpb3.gif\" \/><\/dd>\r\n<\/dl>\r\n[\/hidden-answer]<\/dt>\r\n \t<dt>[reveal-answer q=\"75519\"]Answer 4:[\/reveal-answer]\r\n[hidden-answer a=\"75519\"]\r\n<dl>\r\n \t<dd>Polybromination of benzene would lead to ortho\/para substitution. In order to achieve the mutual meta-relationship of three bromines, it is necessary to introduce a powerful ortho\/para-directing prior to bromination, and then remove it following the tribromination. An amino group is ideal for this purpose. Reductive removal of the diazonium group may be accomplished in several ways (three are shown).\r\n\r\n<img class=\"internal default\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165207\/ardizpb4.gif\" alt=\"ardizpb4.gif\" \/><\/dd>\r\n<\/dl>\r\n[\/hidden-answer]<\/dt>\r\n<\/dl>\r\n<dl>\r\n \t<dt><strong>\r\n[reveal-answer q=\"70476\"]Answer 5:[\/reveal-answer]\r\n[hidden-answer a=\"70476\"]<\/strong>\r\n<dl>\r\n \t<dd>The propyl substituent is best introduced by Friedel-Crafts acylation followed by reduction, and this cannot be carried out in the presence of a nitro substituent. Since an acyl substituent is a meta-director, it is logical to use this property to locate the nitro and chloro groups before reducing the carbonyl moiety. The same reduction method can be used to reduce both the nitro group (to an amine) and the carbonyl group to propyl. We have already seen the use of diazonium intermediates as precursors to phenols.\r\n\r\n<img class=\"internal default\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165210\/ardizpb5.gif\" alt=\"ardizpb5.gif\" \/><\/dd>\r\n<\/dl>\r\n<strong>[\/hidden-answer]<\/strong><\/dt>\r\n<\/dl>\r\n<\/div>\r\n<div id=\"section_5\" class=\"mt-section\">\r\n\r\n<strong>[reveal-answer q=\"17300\"]Answer 6:[\/reveal-answer]<\/strong>\r\n<strong>[hidden-answer a=\"17300\"]<\/strong>\r\n<div id=\"section_4\" class=\"mt-section\">\r\n<dl>\r\n \t<dd>Aromatic iodination can only be accomplished directly on highly activated benzene compounds, such as aniline, or indirectly by way of a diazonium intermediate. Once again, a deactivated amino group is the precursor of p-nitroaniline (prb.#3). This aniline derivative requires the more electrophilic iodine chloride (ICl) for ortho-iodination because of the presence of a deactivating nitro substituent. Finally, the third iodine is introduced by the diazonium ion procedure.\r\n\r\n<img class=\"internal default\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165212\/ardizpb6.gif\" alt=\"ardizpb6.gif\" \/><\/dd>\r\n<\/dl>\r\n<\/div>\r\n<strong>[\/hidden-answer]<\/strong>\r\n<div id=\"section_5\" class=\"mt-section\">\r\n<p id=\"Diazonium_Coupling_Reactions-91036\"><strong>Propose a synthesis for each of the following compounds from benzene.<\/strong><\/p>\r\n\r\n<\/div>\r\n<div id=\"section_6\" class=\"mt-section\">\r\n<div class=\"textbox exercises\">\r\n<div id=\"s61707\" class=\"mt-include\">\r\n<div id=\"section_17\" class=\"mt-section\">\r\n\r\n(a) <em>N,<\/em><em>N<\/em>-Diethylaniline\r\n\r\n(b) <em>p<\/em>-Bromoaniline\r\n\r\n(c) <em>m<\/em>-Bromoaniline\r\n\r\n(d) 2,4-Diethylaniline\r\n\r\n&nbsp;\r\n\r\n<strong>Q24.8.3<\/strong>\r\n\r\nPropose a synthesis for each of the following molecules from benzene via the diazonium ion.\r\n\r\n(a) <em>p<\/em>-Chlorobenzoic acid\r\n\r\n(b) <em>m<\/em>-Chlorobenzoic acid\r\n\r\n(c) <em>m<\/em>-Dichlorobenzene\r\n\r\n(d) <em>p<\/em>-Ethylbenzoic acid\r\n\r\n(e) 1,2,4-Trichlorobenzene\r\n\r\n<\/div>\r\n<div id=\"section_18\" class=\"mt-section\">\r\n\r\n&nbsp;\r\n<h3>Solutions<\/h3>\r\n<div id=\"section_6\" class=\"mt-section\">\r\n<div id=\"s61707\" class=\"mt-include\">\r\n<div id=\"section_18\" class=\"mt-section\">\r\n\r\n<strong>(S24.8.1 <\/strong>Removed)\r\n\r\n<strong>S24.8.2<\/strong>\r\n\r\n(a) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Zn(Hg), HCl; 3. EtBr\r\n\r\n(b) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Zn(Hg), HCl; 3. (CH<sub>3<\/sub>CO)O<sub>2<\/sub>; 4. Br<sub>2<\/sub>, FeBr<sub>3<\/sub>; 5. H<sub>2<\/sub>O, NaOH\r\n\r\n(c) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Br<sub>2<\/sub>, FeBr<sub>3<\/sub>; 3. Zn(Hg), HCl\r\n\r\n(d) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Zn(Hg), HCl; 3. (CH<sub>3<\/sub>CO)O<sub>2<\/sub>; 4. EtCl, AlCl<sub>3<\/sub>; 5. H<sub>2<\/sub>O, NaOH\r\n\r\n&nbsp;\r\n\r\n<strong>S24.8.3<\/strong>\r\n\r\n(a) 1. CH<sub>3<\/sub>CH<sub>2<\/sub>Cl, AlCl<sub>3<\/sub>; 2. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 3. SnCl<sub>2<\/sub>; 4. NaNO<sub>2<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 5. CuBr; 6. KMnO<sub>4<\/sub>, H<sub>2<\/sub>O\r\n\r\n(b) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Cl<sub>2<\/sub>, FeCl<sub>3<\/sub>; 3. SnCl<sub>2<\/sub>, H<sub>3<\/sub>O<sup>+<\/sup>; 4. NaNO<sub>2<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 5. CuCN; 6. H<sub>3<\/sub>O<sup>+<\/sup>\r\n\r\n(c) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Cl<sub>2<\/sub>, FeCl<sub>3<\/sub>; 3. SnCl<sub>2<\/sub>; 4. NaNO<sub>2<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 5. CuCl\r\n\r\n(d) 1.\u00a0CH<sub>3<\/sub>CH<sub>2<\/sub>Cl, AlCl<sub>3:<\/sub> 2. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 3. SnCl<sub>2<\/sub>; 4. NaNO<sub>2<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 5. CuCN; 6. H<sub>3<\/sub>O<sup>+<\/sup>\r\n\r\n(e) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. H<sub>2<\/sub>\/PtO<sub>2<\/sub>; 3. (CH<sub>3<\/sub>CO)<sub>2<\/sub>O; 4. 2 Cl<sub>2<\/sub>; 5. H<sub>2<\/sub>O, NaOH; 6. NaNO<sub>2<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 7. CuCl\r\n\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<div id=\"section_7\" class=\"mt-section\">\r\n<h3 id=\"Contributors-91036\">Contributors<\/h3>\r\n<ul>\r\n \t<li><a class=\"external\" title=\"http:\/\/science.athabascau.ca\/staff-pages\/dietmark\" href=\"http:\/\/science.athabascau.ca\/staff-pages\/dietmark\" target=\"_blank\" rel=\"external nofollow noopener\">Dr. Dietmar Kennepohl<\/a> FCIC (Professor of Chemistry, <a class=\"external\" title=\"http:\/\/www.athabascau.ca\/\" href=\"http:\/\/www.athabascau.ca\/\" target=\"_blank\" rel=\"external nofollow noopener\">Athabasca University<\/a>)<\/li>\r\n \t<li>Prof. Steven Farmer (<a class=\"external\" title=\"http:\/\/www.sonoma.edu\" href=\"http:\/\/www.sonoma.edu\" target=\"_blank\" rel=\"external nofollow noopener\">Sonoma State University<\/a>)<\/li>\r\n \t<li>William Reusch, Professor Emeritus (<a class=\"external\" title=\"http:\/\/www.msu.edu\/\" href=\"http:\/\/www.msu.edu\/\" target=\"_blank\" rel=\"external nofollow noopener\">Michigan State U.<\/a>), <a class=\"external\" title=\"Template:ContribReusch\" href=\"https:\/\/www2.chemistry.msu.edu\/faculty\/reusch\/VirtTxtJml\/intro1.htm\" target=\"_blank\" rel=\"external nofollow noopener\">Virtual Textbook of\u00a0Organic\u00a0Chemistry<\/a><\/li>\r\n<\/ul>\r\n<\/div>\r\n<\/div>\r\n<h3>Video<\/h3>\r\n<img class=\"alignleft wp-image-2879 size-thumbnail\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/07190718\/frame-26-150x150.png\" alt=\"\" width=\"150\" height=\"150\" \/>\r\n\r\n<\/div>\r\n<\/section><\/article><\/div>\r\n<\/div>\r\n<\/section><\/article>","rendered":"<header class=\"elm-header\">\n<div class=\"elm-header-custom\"><\/div>\n<\/header>\n<article id=\"elm-main-content\" class=\"elm-content-container\">\n<section class=\"mt-content-container\">\n<div id=\"s91036\" class=\"mt-include\">\n<div>\n<div class=\"textbox shaded\">\n<h3 class=\"boxtitle\">Key Terms<\/h3>\n<p>Make certain that you can define, and use in context, the key terms below.<\/p>\n<ul>\n<li>arenediazonium salt<\/li>\n<li>Sandmeyer reaction<\/li>\n<\/ul>\n<\/div>\n<\/div>\n<div id=\"note\">\n<div class=\"textbox key-takeaways\">\n<h3>Study Notes<\/h3>\n<div id=\"note\">\n<p>An \u201carenediazonium salt\u201d is formed by the reaction of an aromatic amine with nitrous acid at 0\u20135\u00b0C, and has the structure shown below.<\/p>\n<p class=\"max-66\"><img decoding=\"async\" class=\"internal aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165144\/24-8f.png\" alt=\"general structure for a arenediazonium salt\" \/><\/p>\n<p>Alkanediazonium salts are very unstable; therefore, arenediazonium salts are often simply referred to as diazonium salts.<\/p>\n<p>As is mentioned in the textbook, arenediazonium salts are very useful intermediates from which a wide variety of aromatic compounds can be prepared. You should be thoroughly familiar with the use of diazonium salts to prepare each of the classes of compounds. In addition, you should be aware that fluoroarenes can also be prepared from diazonium salts, as follows:<\/p>\n<p class=\"max-66\"><img decoding=\"async\" class=\"internal aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165146\/24-8g.png\" alt=\"decomposition reaction of diazonium tetrafluoroborate\" \/><\/p>\n<p>In this case the diazonium salt is prepared using fluoroboric acid, HBF<sub>4<\/sub>, and sodium nitrite. The thermal decomposition of the salt, called the Balz-Schiemann reaction, can be quite hazardous.<\/p>\n<p>Hypophosphorous acid has the structure shown below:<\/p>\n<p class=\"max-66\"><img decoding=\"async\" class=\"internal aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165149\/24-8h.png\" alt=\"hypophosphorous acid\" \/><\/p>\n<p>The presence of the letters \u201cazo\u201d in a compound\u2019s name usually implies that a nitrogen\u2011nitrogen double bond is present in its structure. Azo compounds in which two aryl groups are joined by an\u00a0$\\ce{-}$N$\\ce{=}$N$\\ce{-}$ linkage \u00a0are usually very colorful.<\/p>\n<\/div>\n<\/div>\n<\/div>\n<div id=\"section_4\" class=\"mt-section\">\n<h2 id=\"Diazonium_Salts:_The_Sandmeyer_Reaction-91036\">Overview of diazonium salt chemistry<\/h2>\n<\/div>\n<div id=\"bodyContent\" class=\"mw-body-content\">\n<div id=\"mw-content-text\" class=\"mw-content-ltr\" dir=\"ltr\" xml:lang=\"en\">\n<dl>\n<dd><\/dd>\n<\/dl>\n<div id=\"section_4\" class=\"mt-section\">\n<h3>Making the aromatic ring available for attack by nucleophiles<\/h3>\n<p id=\"Diazonium_Salts:_The_Sandmeyer_Reaction-91036\">Most preparations of aromatic compounds we have seen (such as <a href=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/14-1-electrophilic-aromatic-substitution-reactions\/\">electrophilic aromatic substitution<\/a>, as well as the <a href=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/17-2-palladium-catalyzed-couplings\/\">Suzuki reaction<\/a> covered in the previous section) involve the aromatic ring as nucleophile, reacting with an electrophilic reagent.\u00a0 <a href=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/17-1-nucleophilic-aromatic-substitution\/\">Nucleophilic aromatic substitution<\/a> (in 17.1.) involves nucleophilic reagents, but it is limited to rings with strong electron-withdrawing groups <em>ortho<\/em> or <em>para<\/em> to a leaving group.\u00a0 The most versatile way to make aromatic rings available for nucleophilic attack is to prepare arenediazonium salts, containing the ArN<sub>2<\/sub><sup>+<\/sup> ion.\u00a0 The diagram below shows the variety of reactions possible with arenediazonium salts.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"size-full wp-image-3141 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/15053119\/AreneDiazoniumSaltReactions.png\" alt=\"Chart showing the preparation of arenediazonium salts from anilines, and reactions to produce halides, nitriles, phenols, free arenes and azo compounds\" width=\"676\" height=\"362\" \/><\/p>\n<p>Arenediazonium salts are easily prepared from arylamines (anilines) using a process called diazotization.\u00a0 The process involves dissolving the amine in a suitable acid, cooling in an ice bath to 0-5 <sup>o<\/sup>C, then adding sodium nitrite (NaNO<sub>2<\/sub>) solution.\u00a0 The acid reacts with the NaNO<sub>2<\/sub> to form nitrous acid (HNO<sub>2<\/sub>), which then reacts with the arylamine to form the arenediazonium salt. The most common salt to use for these reactions is the chloride (made using HCl as the acid), which are fairly soluble but decompose rapidly at room temperature.\u00a0 However, in some reactions (such as phenol formation) the chloride ion may interfere and substitute a Cl, so in those cases the sulfate (made using H<sub>2<\/sub>SO<sub>4<\/sub>) is used.\u00a0 Diazonium sulfates are a little more stable than chlorides, but they are also generally less soluble and thus more awkward to use.\u00a0 Diazonium tetrafluoroborates are made from chlorides by adding HBF<sub>4<\/sub>; they are usually completely insoluble, which allows them to be filtered off, then dried for decomposition without water present to introduce a fluorine onto the ring.\u00a0 This method for introducing fluorine onto an aromatic ring is called the <a href=\"https:\/\/en.wikipedia.org\/wiki\/Balz%E2%80%93Schiemann_reaction\">Balz-Schiemann reaction<\/a>.<\/p>\n<p>Arenediazonium salts are useful intermediates, and they easily lose nitrogen react with a variety of nucleophiles, as shown in the diagram above.\u00a0 Since nitrogen is very stable, and is lost as a gas, this provides a powerful driving force for these reactions to occur.\u00a0 In the case of water or iodide ion, the nucleophile reacts without need for any catalysis.\u00a0 However, many reactions of diazonium salts are catalyzed by copper(I), in which case the reaction is referred to as a <strong>Sandmeyer reaction<\/strong>.<\/p>\n<p>One reaction that retains the two nitrogens involves coupling to another (electron-rich) aromatic ring, as shown on the left part of the reaction scheme.\u00a0 This is very important in the artificial dye industry, which was mainly established using the production of these &#8220;azo dyes&#8221; after the discovery of <a href=\"https:\/\/en.wikipedia.org\/wiki\/Mauveine\">Perkin&#8217;s mauve<\/a> in 1856.<\/p>\n<h2>Use in synthesis<\/h2>\n<p>Diazonium salt chemistry, being based on nucleophilic reagents used with an electrophilic aromatic ring, is complementary to electrophilic aromatic substitution (EAS, which uses electrophilic reagents).\u00a0 Diazonium salts are easily prepared from aromatics via a three step synthesis:<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-3158 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26053408\/DiazoniumSaltFullSynthesis.png\" alt=\"Benzene is nitrated to nitrobenzene, which is reduced to aniline, which is then diazotized to form a diazonium salt\" width=\"741\" height=\"106\" \/><\/p>\n<p>If other substituents are needed, these can be introduced during the synthesis.\u00a0 If a meta substituent is needed, the substituent is introduced at or before the nitro stage; for ortho\/para substituents, this can be done at the NH<sub>2<\/sub> stage.\u00a0 The amino group in an arylamine (aniline) is a very powerful activator, so many EAS reactions of arylamines rapidly introduce 2 or 3 substituents unless the NH<sub>2<\/sub> group&#8217;s reactivity is moderated by formation of an amide &#8211; recall this method for <a href=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/16-2-preparation-of-alkylbenzenes\/\">protection of amines via acetylation, from chapter 16<\/a>.\u00a0 In some cases, the new substituent may also be reduced during the reduction of the nitro group, as in this synthesis of meta-propylbenzenediazonium chloride from benzene:<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-3159 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26062455\/MetaPropylBenzeneDiazoniumSynthesis.png\" alt=\"Benzene is acetylated then nitrated, then reduced and diazotized\" width=\"805\" height=\"155\" \/><\/p>\n<p>For the synthesis of the para isomer, the arylamine is acetylated before the Friedel-Crafts reaction, then deacetylated by heating with excess aq. HCl right before diazotization.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-3160 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26062912\/ParaPropylBenzeneDiazoniumSynthesis.png\" alt=\"Benzene is nitrated, then the NO2 is reduced and acetylated to give acetanilide. This is then acylated via Friedel-Crafts, reduced, deacetylated and diazotized\" width=\"718\" height=\"307\" \/><\/p>\n<p>This para isomer synthesis shows the use of the acetyl group to control the reactivity of the amino group.\u00a0 (An alternative synthesis could avoid this by introducing the propyl group first, before nitration.)\u00a0 Although these syntheses appear to be long, they involve synthetic steps that are reliable and reproducible, and they follow a standard pattern.\u00a0 Also, the fact that different substituents can be introduced at selected positions along the way makes this approach a very valuable synthetic sequence.<\/p>\n<\/div>\n<h2 id=\"firstHeading\" class=\"firstHeading\" xml:lang=\"en\">Sandmeyer reaction<\/h2>\n<p class=\"firstHeading\" xml:lang=\"en\">The <b>Sandmeyer reaction<\/b> is a subset of these reactions of diazonium salts, in cases where a copper(I) salt is used as a catalyst. It is an example of a <a title=\"Radical-nucleophilic aromatic substitution\" href=\"https:\/\/en.wikipedia.org\/wiki\/Radical-nucleophilic_aromatic_substitution\">radical-nucleophilic aromatic substitution<\/a>. The Sandmeyer reaction provides a method through which one can perform unique transformations on benzene, such as halogenation, <a href=\"https:\/\/en.wikipedia.org\/wiki\/Cyanation\">cyanation<\/a>, <a title=\"Trifluoromethylation\" href=\"https:\/\/en.wikipedia.org\/wiki\/Trifluoromethylation\">trifluoromethylation<\/a>.<\/p>\n<p>The reaction was discovered in 1884 by Swiss chemist <a title=\"Traugott Sandmeyer\" href=\"https:\/\/en.wikipedia.org\/wiki\/Traugott_Sandmeyer\">Traugott Sandmeyer<\/a>, when he synthesized phenylacetylene from benzenediazonium chloride and copper(I) acetylide. The reaction is a method for substitution of an aromatic amino group via preparation of its diazonium salt followed by its displacement with a nucleophile, catalyzed by copper(I) salts. The nucleophile can include <a title=\"Halide\" href=\"\/wiki\/Halide\">halide<\/a> anions, <a title=\"Cyanide\" href=\"\/wiki\/Cyanide\">cyanide<\/a>, <a title=\"Thiol\" href=\"\/wiki\/Thiol\">thiols<\/a>, water, and others. The reaction does not proceed well with the fluoride anion, but fluorination can be carried out using tetrafluoroborate anions (see below).<\/p>\n<h2><span id=\"Reaction_mechanism\" class=\"mw-headline\">Reaction mechanism<\/span><\/h2>\n<p>The <a title=\"Nitrous acid\" href=\"\/wiki\/Nitrous_acid\">nitrous acid<\/a> is typically prepared <i>in situ<\/i> from <a title=\"Sodium nitrite\" href=\"\/wiki\/Sodium_nitrite\">sodium nitrite<\/a> and acid. Following two <a title=\"Protonation\" href=\"\/wiki\/Protonation\">protonation<\/a> steps, one equivalent of water is lost to form the <a class=\"mw-redirect\" title=\"Nitrosonium ion\" href=\"\/wiki\/Nitrosonium_ion\">nitrosonium ion<\/a>. The nitrosonium ion then acts as an <a title=\"Electrophile\" href=\"\/wiki\/Electrophile\">electrophile<\/a> in a reaction with an <a class=\"mw-redirect\" title=\"Aromatic\" href=\"\/wiki\/Aromatic\">aromatic<\/a> (or <a class=\"mw-redirect\" title=\"Heterocyclic\" href=\"\/wiki\/Heterocyclic\">heterocyclic<\/a>) amine, such as <a title=\"Aniline\" href=\"\/wiki\/Aniline\">aniline<\/a>, to form a diazonium salt, proceeding through a <a title=\"Nitrosamine\" href=\"\/wiki\/Nitrosamine\">nitrosamine<\/a> intermediate.<sup id=\"cite_ref-Zerong_2010_4-1\" class=\"reference\"><a href=\"#cite_note-Zerong_2010-4\">[4]<\/a><\/sup> The substitution of the aromatic diazo group with a halogen or <a title=\"Pseudohalogen\" href=\"\/wiki\/Pseudohalogen\">pseudohalogen<\/a> is initiated by a one-electron transfer mechanism catalyzed by copper(I) to form an <a title=\"Aryl radical\" href=\"\/wiki\/Aryl_radical\">aryl radical<\/a> with loss of nitrogen gas.<sup id=\"cite_ref-Kochi_1956_5-0\" class=\"reference\"><a href=\"#cite_note-Kochi_1956-5\">[5]<\/a><\/sup><sup id=\"cite_ref-Hodgson_1947_6-0\" class=\"reference\"><a href=\"#cite_note-Hodgson_1947-6\">[6]<\/a><\/sup><sup id=\"cite_ref-7\" class=\"reference\"><a href=\"#cite_note-7\">[7]<\/a><\/sup><sup id=\"cite_ref-Galli_1988_8-0\" class=\"reference\"><a href=\"#cite_note-Galli_1988-8\">[8]<\/a><\/sup> The substituted <a class=\"mw-redirect\" title=\"Arene\" href=\"\/wiki\/Arene\">arene<\/a> is formed through a radical mechanism with regeneration of the copper(I) catalyst. This reaction is known as the Sandmeyer reaction and is an example of a <a title=\"Radical-nucleophilic aromatic substitution\" href=\"\/wiki\/Radical-nucleophilic_aromatic_substitution\">radical-nucleophilic aromatic substitution<\/a>. The radical mechanism of the Sandmeyer reaction was resolved through the detection of <a class=\"mw-redirect\" title=\"Biaryl\" href=\"\/wiki\/Biaryl\">biaryl<\/a> byproducts.<sup id=\"cite_ref-Galli_1988_8-1\" class=\"reference\"><a href=\"#cite_note-Galli_1988-8\">[8]<\/a><\/sup> It proceeds through the following mechanism.<\/p>\n<h3><span id=\"Formation_of_the_nitrosonium_ion\" class=\"mw-headline\">Formation of the nitrosonium ion<\/span><\/h3>\n<p>The nitrosonium ion (NO<sup>+<\/sup>) is formed from nitrous acid (HNO<sub>2<\/sub>) by a mechanism analogous to formation of NO2+ from HNO<sub>3<\/sub>, which we saw in <a href=\"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/14-3-the-general-mechanism-chemistry-libretexts\/\">section 14.2<\/a>. The mechanism here can occur in water, because HNO<sub>2<\/sub> is more easily protonated (the first step) than is HNO<sub>3<\/sub>.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-3144 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/17054534\/NitrosylIonFormation.png\" alt=\"HNO2 is protonated, then loses H2O to form NO+\" width=\"541\" height=\"111\" \/><\/p>\n<dl>\n<dd><\/dd>\n<\/dl>\n<h3><span id=\"Formation_of_the_benzenediazonium_ion\" class=\"mw-headline\">Formation of the benzenediazonium ion<\/span><\/h3>\n<p>The mechanism for formation of the benzenediazonium is beyond the scope of this class, but the reaction can be regarded overall as a dehydration:<\/p>\n<p>ArNH<sub>2<\/sub> + NO<sup>+<\/sup>\u00a0 &#8212;-&gt;\u00a0 ArN<sub>2<\/sub>+\u00a0 +\u00a0 H<sub>2<\/sub>O<\/p>\n<dl>\n<dd><\/dd>\n<\/dl>\n<h2 class=\"mw-parser-output\">Specific reactions of diazonium salts<\/h2>\n<h3>Halogenation<\/h3>\n<div class=\"mw-parser-output\">\n<p>Aryl iodides can be prepared simply by treating the diazonium salt (chloride or sulfate) with iodide ion, usually as a solution of sodium or potassium iodide.\u00a0 A copper(I) catalyst is not essential, though it is sometimes used.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-3163 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/04060418\/DiazoniumIodination.png\" alt=\"Aniline is diazotized then treated with KI to form iodobenzene\" width=\"319\" height=\"89\" \/><\/p>\n<p>For preparation of aryl bromides and chlorides, the Sandmeyer reaction is used, since the reaction is sluggish without copper(I) catalysis.\u00a0 The corresponding copper halide is used &#8211; CuBr for Br, and CuCl for Cl, for example<a class=\"footnote\" title=\"Example taken from Organic Syntheses, 1923, 3, 79, http:\/\/www.orgsyn.org\/demo.aspx?prep=CV1P0162\" id=\"return-footnote-764-1\" href=\"#footnote-764-1\" aria-label=\"Footnote 1\"><sup class=\"footnote\">[1]<\/sup><\/a>:<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-3147 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/22083531\/SandmeyerCuCl.png\" alt=\"m-nitroaniline reacts with NaNO2 and HCl, then CuCl, to make m-chloronitrobenzene\" width=\"433\" height=\"82\" \/><\/p>\n<dl>\n<dd><\/dd>\n<\/dl>\n<p>The <a title=\"Balz\u2013Schiemann reaction\" href=\"\/wiki\/Balz%E2%80%93Schiemann_reaction\">Balz\u2013Schiemann reaction<\/a> uses <a title=\"Tetrafluoroborate\" href=\"\/wiki\/Tetrafluoroborate\">tetrafluoroborate<\/a> ion and delivers the halide-substituted product, <a title=\"Fluorobenzene\" href=\"\/wiki\/Fluorobenzene\">fluorobenzene<\/a>, which is not obtained by the use of <a title=\"Copper fluoride\" href=\"\/wiki\/Copper_fluoride\">copper fluorides<\/a>.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-3154 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/25173613\/DiazoniumFluoridation.png\" alt=\"3-bromoaniline is diazotized, then treated with HBF4, dried, then heated to produce 3-bromofluorobenzene\" width=\"399\" height=\"104\" \/><\/p>\n<h3><span id=\"Cyanation\" class=\"mw-headline\">Cyanation<\/span><\/h3>\n<p>Another use of the Sandmeyer reaction is for <a title=\"Cyanation\" href=\"\/wiki\/Cyanation\">cyanation<\/a> which allows for the formation of <a title=\"Benzonitrile\" href=\"\/wiki\/Benzonitrile\">benzonitriles<\/a>, an important class of organic compounds. <img loading=\"lazy\" decoding=\"async\" class=\"wp-image-3152 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/25160131\/DiazotizationCyanationExample.png\" alt=\"Sandmeyer reaction example. 2-Methylaniline (o-toluidine) is diazotized then treated with CuCN, forming 2-methylbenzonitrile (o-tolunitrile)\" width=\"351\" height=\"107\" \/><\/p>\n<\/div>\n<\/div>\n<\/div>\n<div id=\"footer\" role=\"contentinfo\">\n<article id=\"elm-main-content\" class=\"elm-content-container\">\n<section class=\"mt-content-container\">\n<div id=\"section_1\" class=\"mt-section\">\n<h3>Replacement of nitrogen with hydrogen (reduction)<\/h3>\n<p>The amino functional group can in effect be removed by diazotization followed by reduction.\u00a0 The most common reagent is hypophosphorous acid (H<sub>3<\/sub>PO<sub>2<\/sub>), but NaBH<sub>4<\/sub> also works.\u00a0 Ethanol can also effect the reduction, and this is commoner in the older literature.<\/p>\n<p>Removal of the NH<sub>2<\/sub> in this way can be useful in synthesis, because the amino group is a powerful activator and ortho-para director.\u00a0 For example, the NH<sub>2<\/sub> can be used to introduce three bromines rapidly ortho\/para to itself, then the NH<sub>2<\/sub> can be removed to leave the bromines intact.\u00a0 A compound such as 2,4,6-tribromobenzoic acid can be easily prepared in this way.<\/p>\n<\/div>\n<\/section>\n<\/article>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-3156\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/25183821\/DiazoniumDeamination.png\" alt=\"3-amino-2,4,6-tribromobenzoic acid is diazotized then treated with H3PO2. This replaces the diazonium group with a simple H, giving 2,4,6-tribromobenzoic acid\" width=\"395\" height=\"131\" \/><\/p>\n<article id=\"elm-main-content\" class=\"elm-content-container\">\n<section class=\"mt-content-container\">\n<div id=\"section_2\" class=\"mt-section\">\n<h3 class=\"editable\">Substitution by an -OH group<\/h3>\n<p>The NH<sub>2<\/sub> can be replaced by OH simply by warming the acidic solution of the benzenediazonium salt, and water acts as the incoming nucleophile.\u00a0 Since chloride ion can act as a competing nucleophile at higher temperatures, we avoid a halogenation side reaction by using a non-nucleophilic anion such as hydrogen sulfate, HSO<sub>4<\/sub>\u00af.\u00a0 The diazonium hydrogen sulfate salt is prepared simply using NaNO<sub>2<\/sub> in cold dilute sulfuric acid, and then warmed to produce the phenol.\u00a0 In some cases, the entire reaction is done in warm aqueous H<sub>2<\/sub>SO<sub>4<\/sub>.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-3150 aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/25153706\/DiazotizationPhenolExample.png\" alt=\"2-Bromo-4-methylaniline is diazotized then treated with CuCN to form 2-bromo-4-methylphenol\" width=\"450\" height=\"109\" \/><\/p>\n<\/div>\n<div id=\"section_2\" class=\"mt-section\">\n<p>Since there is no easy way to introduce an OH group directly onto an aromatic ring via electrophilic aromatic substitution, this reaction is the most commonly used way to prepare phenols in synthesis.\u00a0 Given the importance of the hydroxyl group in organic chemistry &#8211; many phenols are found in nature, for example &#8211; means that this reaction is widely used.<\/p>\n<\/div>\n<div id=\"section_9\" class=\"mt-section\">\n<h2 id=\"Diazonium_Coupling_Reactions-91036\">Diazonium coupling reactions<\/h2>\n<p>Although most reactions of diazonium salts involve loss of nitrogen, there are some useful reactions where the nitrogen is retained.\u00a0 The most important of these is where the diazonium salt acts as an electrophile in an electrophilic aromatic substitution (EAS), forming an &#8220;azo compound&#8221;.\u00a0 The reaction only occurs where the aromatic nucleophile is highly activated, and the azo group is attached at the most activated position(s) &#8211; usually ortho or para to a hydroxy or amino group.\u00a0 The resultant azo compounds are brightly colored and used very widely used as dyes, since they provide a conjugated system involving both aromatic rings.\u00a0 Some common azo dyes are shown in the table,<\/p>\n<table style=\"border-collapse: collapse; width: 100%;\">\n<tbody>\n<tr>\n<td style=\"width: 25%;\">Methyl Red<\/td>\n<td style=\"width: 25%;\">Azobenzene<\/td>\n<td style=\"width: 25%;\">Evans&#8217; Blue<\/td>\n<td style=\"width: 25%;\">Para Red<\/td>\n<\/tr>\n<tr>\n<td style=\"width: 25%;\"><\/td>\n<td style=\"width: 25%;\"><\/td>\n<td style=\"width: 25%;\"><\/td>\n<td style=\"width: 25%;\"><\/td>\n<\/tr>\n<tr>\n<td style=\"width: 25%;\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-3172\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/07024424\/MethylRed.png\" alt=\"A sample of Methyl Red dye\" width=\"1016\" height=\"861\" \/><\/td>\n<td style=\"width: 25%;\"><img decoding=\"async\" class=\"transparent\" src=\"https:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/0\/0f\/Azobenzene_structure.svg\/630px-Azobenzene_structure.svg.png\" alt=\"https:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/0\/0f\/Azobenzene_structure.svg\/630px-Azobenzene_structure.svg.png\" \/><\/td>\n<td style=\"width: 25%;\"><\/td>\n<td style=\"width: 25%;\"><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>The EAS mechanism is shown here, in this synthesis of the dye Methyl Red from 2-aminobenzoic acid and <em>N<\/em>,<em>N<\/em>-dimethylaniline:<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-3167\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/06210108\/MethylRedMechanism.png\" alt=\"The diazonium salt from 2-aminobenzoic acid is attacked by the para position of N,N-dimethylaniline, and after loss of H+ forms Methyl Red.\" width=\"837\" height=\"140\" \/><\/p>\n<p>In another example, Para Red is synthesized from 2-naphthol and 4-nitrobenzenediazonium hydrogen sulfate:<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-3169\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/06210352\/ParaRedSynthesis.png\" alt=\"4-nitroaniline is diazotized, then reacted with 2-naphthol to form Para Red\" width=\"789\" height=\"131\" \/><\/p>\n<h3 class=\"editable\">Contributors<\/h3>\n<p>Martin A. Walker<\/p>\n<p>Jim Clark (<a class=\"external\" title=\"http:\/\/www.chemguide.co.uk\" href=\"http:\/\/www.chemguide.co.uk\" target=\"_blank\" rel=\"external nofollow noopener\">Chemguide.co.uk<\/a>)<\/p>\n<div id=\"section_4\" class=\"mt-section\">\n<h2>Practice problems<\/h2>\n<p>The following examples illustrate some combined applications of these options to specific cases. You should try to conceive a plausible reaction sequence for each. Once you have done so, you may check suggested answers below.<\/p>\n<p><a title=\"ardiazpb.gif\" href=\"https:\/\/chem.libretexts.org\/@api\/deki\/files\/1477\/ardiazpb.gif?revision=1\" rel=\"internal\"><img decoding=\"async\" class=\"internal default aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165155\/ardiazpb.gif\" alt=\"ardiazpb.gif\" \/><\/a><\/p>\n<dl>\n<dt>\n<div class=\"qa-wrapper\" style=\"display: block\"><span class=\"show-answer collapsed\" style=\"cursor: pointer\" data-target=\"q534781\">Answer 1:<\/span><\/p>\n<div id=\"q534781\" class=\"hidden-answer\" style=\"display: none\">\n<\/dt>\n<dd>It should be clear that the methyl substituent will eventually be oxidized to a carboxylic acid function. The timing is important, since a methyl substituent is ortho\/para-directing and the carboxyl substituent is meta-directing. The cyano group will be introduced by a diazonium intermediate, so a nitration followed by reduction to an amine must precede this step.<\/p>\n<p><img decoding=\"async\" class=\"internal default aligncenter\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165158\/ardizpb1.gif\" alt=\"ardizpb1.gif\" \/><\/dd>\n<\/dl>\n<p><strong><\/div>\n<\/div>\n<p><\/strong><\/p>\n<dl>\n<dt>\n<div class=\"qa-wrapper\" style=\"display: block\"><span class=\"show-answer collapsed\" style=\"cursor: pointer\" data-target=\"q33282\">Answer 2:<\/span><\/p>\n<div id=\"q33282\" class=\"hidden-answer\" style=\"display: none\">\n<\/dt>\n<dd>The hydroxyl group is a strong activating substituent and would direct aromatic ring chlorination to locations ortho &amp; para to itself, leading to the wrong product. As an alternative, the nitro group is not only meta-directing, it can be converted to a hydroxyl group by way of a diazonium intermediate. The resulting strategy is self evident.<\/p>\n<p><img decoding=\"async\" class=\"internal default\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165201\/ardizpb2.gif\" alt=\"ardizpb2.gif\" \/><\/dd>\n<\/dl>\n<\/div>\n<\/div>\n<dl>\n<dt>\n<div class=\"qa-wrapper\" style=\"display: block\"><span class=\"show-answer collapsed\" style=\"cursor: pointer\" data-target=\"q995704\">Answer 3:<\/span><\/p>\n<div id=\"q995704\" class=\"hidden-answer\" style=\"display: none\">\n<\/dt>\n<dd>Selective introduction of a fluorine is best achieved by treating a diazonium intermediate with tetrafluoroborate anion. To get the necessary intermediate we need to make p-nitroaniline. Since the nitro substituent on the starting material would direct a new substituent to a meta-location, we must first reduce it to an ortho\/para-directing amino group. Amino groups are powerful activating substituents, so we deactivate it by acetylation before nitration. The acetyl substituent also protects the initial amine function from reaction with nitrous acid later on. It is removed in the last step.<\/p>\n<p><img decoding=\"async\" class=\"internal default\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165204\/ardizpb3.gif\" alt=\"ardizpb3.gif\" \/><\/dd>\n<\/dl>\n<\/div>\n<\/div>\n<div class=\"qa-wrapper\" style=\"display: block\"><span class=\"show-answer collapsed\" style=\"cursor: pointer\" data-target=\"q75519\">Answer 4:<\/span><\/p>\n<div id=\"q75519\" class=\"hidden-answer\" style=\"display: none\">\n<dl>\n<dd>Polybromination of benzene would lead to ortho\/para substitution. In order to achieve the mutual meta-relationship of three bromines, it is necessary to introduce a powerful ortho\/para-directing prior to bromination, and then remove it following the tribromination. An amino group is ideal for this purpose. Reductive removal of the diazonium group may be accomplished in several ways (three are shown).<\/p>\n<p><img decoding=\"async\" class=\"internal default\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165207\/ardizpb4.gif\" alt=\"ardizpb4.gif\" \/><\/dd>\n<\/dl>\n<\/div>\n<\/div>\n<dl>\n<dt><strong><\/p>\n<div class=\"qa-wrapper\" style=\"display: block\"><span class=\"show-answer collapsed\" style=\"cursor: pointer\" data-target=\"q70476\">Answer 5:<\/span><\/p>\n<div id=\"q70476\" class=\"hidden-answer\" style=\"display: none\"><\/strong>\n<\/dt>\n<dd>The propyl substituent is best introduced by Friedel-Crafts acylation followed by reduction, and this cannot be carried out in the presence of a nitro substituent. Since an acyl substituent is a meta-director, it is logical to use this property to locate the nitro and chloro groups before reducing the carbonyl moiety. The same reduction method can be used to reduce both the nitro group (to an amine) and the carbonyl group to propyl. We have already seen the use of diazonium intermediates as precursors to phenols.<\/p>\n<p><img decoding=\"async\" class=\"internal default\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165210\/ardizpb5.gif\" alt=\"ardizpb5.gif\" \/><\/dd>\n<\/dl>\n<p><strong><\/div>\n<\/div>\n<p><\/strong><\/p>\n<\/div>\n<div id=\"section_5\" class=\"mt-section\">\n<p><strong><\/p>\n<div class=\"qa-wrapper\" style=\"display: block\"><span class=\"show-answer collapsed\" style=\"cursor: pointer\" data-target=\"q17300\">Answer 6:<\/span><\/strong><br \/>\n<strong><\/p>\n<div id=\"q17300\" class=\"hidden-answer\" style=\"display: none\"><\/strong><\/p>\n<div id=\"section_4\" class=\"mt-section\">\n<dl>\n<dd>Aromatic iodination can only be accomplished directly on highly activated benzene compounds, such as aniline, or indirectly by way of a diazonium intermediate. Once again, a deactivated amino group is the precursor of p-nitroaniline (prb.#3). This aniline derivative requires the more electrophilic iodine chloride (ICl) for ortho-iodination because of the presence of a deactivating nitro substituent. Finally, the third iodine is introduced by the diazonium ion procedure.<\/p>\n<p><img decoding=\"async\" class=\"internal default\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/26165212\/ardizpb6.gif\" alt=\"ardizpb6.gif\" \/><\/dd>\n<\/dl>\n<\/div>\n<p><strong><\/div>\n<\/div>\n<p><\/strong><\/p>\n<div id=\"section_5\" class=\"mt-section\">\n<p id=\"Diazonium_Coupling_Reactions-91036\"><strong>Propose a synthesis for each of the following compounds from benzene.<\/strong><\/p>\n<\/div>\n<div id=\"section_6\" class=\"mt-section\">\n<div class=\"textbox exercises\">\n<div id=\"s61707\" class=\"mt-include\">\n<div id=\"section_17\" class=\"mt-section\">\n<p>(a) <em>N,<\/em><em>N<\/em>-Diethylaniline<\/p>\n<p>(b) <em>p<\/em>-Bromoaniline<\/p>\n<p>(c) <em>m<\/em>-Bromoaniline<\/p>\n<p>(d) 2,4-Diethylaniline<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Q24.8.3<\/strong><\/p>\n<p>Propose a synthesis for each of the following molecules from benzene via the diazonium ion.<\/p>\n<p>(a) <em>p<\/em>-Chlorobenzoic acid<\/p>\n<p>(b) <em>m<\/em>-Chlorobenzoic acid<\/p>\n<p>(c) <em>m<\/em>-Dichlorobenzene<\/p>\n<p>(d) <em>p<\/em>-Ethylbenzoic acid<\/p>\n<p>(e) 1,2,4-Trichlorobenzene<\/p>\n<\/div>\n<div id=\"section_18\" class=\"mt-section\">\n<p>&nbsp;<\/p>\n<h3>Solutions<\/h3>\n<div id=\"section_6\" class=\"mt-section\">\n<div id=\"s61707\" class=\"mt-include\">\n<div id=\"section_18\" class=\"mt-section\">\n<p><strong>(S24.8.1 <\/strong>Removed)<\/p>\n<p><strong>S24.8.2<\/strong><\/p>\n<p>(a) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Zn(Hg), HCl; 3. EtBr<\/p>\n<p>(b) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Zn(Hg), HCl; 3. (CH<sub>3<\/sub>CO)O<sub>2<\/sub>; 4. Br<sub>2<\/sub>, FeBr<sub>3<\/sub>; 5. H<sub>2<\/sub>O, NaOH<\/p>\n<p>(c) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Br<sub>2<\/sub>, FeBr<sub>3<\/sub>; 3. Zn(Hg), HCl<\/p>\n<p>(d) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Zn(Hg), HCl; 3. (CH<sub>3<\/sub>CO)O<sub>2<\/sub>; 4. EtCl, AlCl<sub>3<\/sub>; 5. H<sub>2<\/sub>O, NaOH<\/p>\n<p>&nbsp;<\/p>\n<p><strong>S24.8.3<\/strong><\/p>\n<p>(a) 1. CH<sub>3<\/sub>CH<sub>2<\/sub>Cl, AlCl<sub>3<\/sub>; 2. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 3. SnCl<sub>2<\/sub>; 4. NaNO<sub>2<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 5. CuBr; 6. KMnO<sub>4<\/sub>, H<sub>2<\/sub>O<\/p>\n<p>(b) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Cl<sub>2<\/sub>, FeCl<sub>3<\/sub>; 3. SnCl<sub>2<\/sub>, H<sub>3<\/sub>O<sup>+<\/sup>; 4. NaNO<sub>2<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 5. CuCN; 6. H<sub>3<\/sub>O<sup>+<\/sup><\/p>\n<p>(c) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. Cl<sub>2<\/sub>, FeCl<sub>3<\/sub>; 3. SnCl<sub>2<\/sub>; 4. NaNO<sub>2<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 5. CuCl<\/p>\n<p>(d) 1.\u00a0CH<sub>3<\/sub>CH<sub>2<\/sub>Cl, AlCl<sub>3:<\/sub> 2. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 3. SnCl<sub>2<\/sub>; 4. NaNO<sub>2<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 5. CuCN; 6. H<sub>3<\/sub>O<sup>+<\/sup><\/p>\n<p>(e) 1. HNO<sub>3<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 2. H<sub>2<\/sub>\/PtO<sub>2<\/sub>; 3. (CH<sub>3<\/sub>CO)<sub>2<\/sub>O; 4. 2 Cl<sub>2<\/sub>; 5. H<sub>2<\/sub>O, NaOH; 6. NaNO<sub>2<\/sub>, H<sub>2<\/sub>SO<sub>4<\/sub>; 7. CuCl<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<div id=\"section_7\" class=\"mt-section\">\n<h3 id=\"Contributors-91036\">Contributors<\/h3>\n<ul>\n<li><a class=\"external\" title=\"http:\/\/science.athabascau.ca\/staff-pages\/dietmark\" href=\"http:\/\/science.athabascau.ca\/staff-pages\/dietmark\" target=\"_blank\" rel=\"external nofollow noopener\">Dr. Dietmar Kennepohl<\/a> FCIC (Professor of Chemistry, <a class=\"external\" title=\"http:\/\/www.athabascau.ca\/\" href=\"http:\/\/www.athabascau.ca\/\" target=\"_blank\" rel=\"external nofollow noopener\">Athabasca University<\/a>)<\/li>\n<li>Prof. Steven Farmer (<a class=\"external\" title=\"http:\/\/www.sonoma.edu\" href=\"http:\/\/www.sonoma.edu\" target=\"_blank\" rel=\"external nofollow noopener\">Sonoma State University<\/a>)<\/li>\n<li>William Reusch, Professor Emeritus (<a class=\"external\" title=\"http:\/\/www.msu.edu\/\" href=\"http:\/\/www.msu.edu\/\" target=\"_blank\" rel=\"external nofollow noopener\">Michigan State U.<\/a>), <a class=\"external\" title=\"Template:ContribReusch\" href=\"https:\/\/www2.chemistry.msu.edu\/faculty\/reusch\/VirtTxtJml\/intro1.htm\" target=\"_blank\" rel=\"external nofollow noopener\">Virtual Textbook of\u00a0Organic\u00a0Chemistry<\/a><\/li>\n<\/ul>\n<\/div>\n<\/div>\n<h3>Video<\/h3>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignleft wp-image-2879 size-thumbnail\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/3773\/2018\/11\/07190718\/frame-26-150x150.png\" alt=\"\" width=\"150\" height=\"150\" \/><\/p>\n<\/div>\n<\/section>\n<\/article>\n<\/div>\n<\/div>\n<\/section>\n<\/article>\n\n\t\t\t <section class=\"citations-section\" role=\"contentinfo\">\n\t\t\t <h3>Candela Citations<\/h3>\n\t\t\t\t\t <div>\n\t\t\t\t\t\t <div id=\"citation-list-764\">\n\t\t\t\t\t\t\t <div class=\"licensing\"><div class=\"license-attribution-dropdown-subheading\">CC licensed content, Shared previously<\/div><ul class=\"citation-list\"><li>22.10: Arenediazonium Salts. <strong>Authored by<\/strong>: Dr. Dietmar Kennepohl FCIC; Prof. Steven Farmer; William Reusch, professor Emeritus. <strong>Provided by<\/strong>: Athabasca University; Sonoma State University, Michigan State U. <strong>Located at<\/strong>: <a target=\"_blank\" href=\"https:\/\/chem.libretexts.org\/Textbook_Maps\/Organic_Chemistry\/Map%3A_Organic_Chemistry_(Vollhardt_and_Schore)\/22%3A_Chemistry_of_the_Benzene_Substituents%3A_Alkylbenzenes%2C_Phenols%2C_and_Benzenamines\/22.10%3A_Arenediazonium_Salts\">https:\/\/chem.libretexts.org\/Textbook_Maps\/Organic_Chemistry\/Map%3A_Organic_Chemistry_(Vollhardt_and_Schore)\/22%3A_Chemistry_of_the_Benzene_Substituents%3A_Alkylbenzenes%2C_Phenols%2C_and_Benzenamines\/22.10%3A_Arenediazonium_Salts<\/a>. <strong>Project<\/strong>: Chemistry LibreTexts . <strong>License<\/strong>: <em><a target=\"_blank\" rel=\"license\" href=\"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/\">CC BY-NC-SA: Attribution-NonCommercial-ShareAlike<\/a><\/em><\/li><li>Sandmeyer reaction. <strong>Authored by<\/strong>: Wikipedia. <strong>Provided by<\/strong>: Wikipedia. <strong>Located at<\/strong>: <a target=\"_blank\" href=\"https:\/\/en.wikipedia.org\/wiki\/Sandmeyer_reaction\">https:\/\/en.wikipedia.org\/wiki\/Sandmeyer_reaction<\/a>. <strong>Project<\/strong>: Wikipedia. <strong>License<\/strong>: <em><a target=\"_blank\" rel=\"license\" href=\"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/\">CC BY-NC-SA: Attribution-NonCommercial-ShareAlike<\/a><\/em><\/li><li>Reactions of Diazonium Salts. <strong>Authored by<\/strong>: Jim Clark. <strong>Located at<\/strong>: <a target=\"_blank\" href=\"https:\/\/chem.libretexts.org\/Textbook_Maps\/Organic_Chemistry\/Supplemental_Modules_(Organic_Chemistry)\/Phenylamine_and_Diazonium_Compounds\/Reactions_of_Diazonium_Salts\">https:\/\/chem.libretexts.org\/Textbook_Maps\/Organic_Chemistry\/Supplemental_Modules_(Organic_Chemistry)\/Phenylamine_and_Diazonium_Compounds\/Reactions_of_Diazonium_Salts<\/a>. <strong>Project<\/strong>: Chemistry LibreTexts. <strong>License<\/strong>: <em><a target=\"_blank\" rel=\"license\" href=\"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/\">CC BY-NC-SA: Attribution-NonCommercial-ShareAlike<\/a><\/em><\/li><\/ul><\/div>\n\t\t\t\t\t\t <\/div>\n\t\t\t\t\t <\/div>\n\t\t\t <\/section><hr class=\"before-footnotes clear\" \/><div class=\"footnotes\"><ol><li id=\"footnote-764-1\">Example taken from Organic Syntheses, 1923, 3, 79, http:\/\/www.orgsyn.org\/demo.aspx?prep=CV1P0162 <a href=\"#return-footnote-764-1\" class=\"return-footnote\" aria-label=\"Return to footnote 1\">&crarr;<\/a><\/li><\/ol><\/div>","protected":false},"author":311,"menu_order":3,"template":"","meta":{"_candela_citation":"[{\"type\":\"cc\",\"description\":\"22.10: Arenediazonium Salts\",\"author\":\"Dr. Dietmar Kennepohl FCIC; Prof. Steven Farmer; William Reusch, professor Emeritus\",\"organization\":\"Athabasca University; Sonoma State University, Michigan State U\",\"url\":\"https:\/\/chem.libretexts.org\/Textbook_Maps\/Organic_Chemistry\/Map%3A_Organic_Chemistry_(Vollhardt_and_Schore)\/22%3A_Chemistry_of_the_Benzene_Substituents%3A_Alkylbenzenes%2C_Phenols%2C_and_Benzenamines\/22.10%3A_Arenediazonium_Salts\",\"project\":\"Chemistry LibreTexts \",\"license\":\"cc-by-nc-sa\",\"license_terms\":\"\"},{\"type\":\"cc\",\"description\":\"Sandmeyer reaction\",\"author\":\"Wikipedia\",\"organization\":\"Wikipedia\",\"url\":\"https:\/\/en.wikipedia.org\/wiki\/Sandmeyer_reaction\",\"project\":\"Wikipedia\",\"license\":\"cc-by-nc-sa\",\"license_terms\":\"\"},{\"type\":\"cc\",\"description\":\"Reactions of Diazonium Salts\",\"author\":\"Jim Clark\",\"organization\":\"\",\"url\":\"https:\/\/chem.libretexts.org\/Textbook_Maps\/Organic_Chemistry\/Supplemental_Modules_(Organic_Chemistry)\/Phenylamine_and_Diazonium_Compounds\/Reactions_of_Diazonium_Salts\",\"project\":\"Chemistry LibreTexts\",\"license\":\"cc-by-nc-sa\",\"license_terms\":\"\"}]","CANDELA_OUTCOMES_GUID":"","pb_show_title":"on","pb_short_title":"","pb_subtitle":"","pb_authors":[],"pb_section_license":""},"chapter-type":[],"contributor":[],"license":[],"class_list":["post-764","chapter","type-chapter","status-publish","hentry"],"part":636,"_links":{"self":[{"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/pressbooks\/v2\/chapters\/764","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/pressbooks\/v2\/chapters"}],"about":[{"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/wp\/v2\/types\/chapter"}],"author":[{"embeddable":true,"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/wp\/v2\/users\/311"}],"version-history":[{"count":47,"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/pressbooks\/v2\/chapters\/764\/revisions"}],"predecessor-version":[{"id":3253,"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/pressbooks\/v2\/chapters\/764\/revisions\/3253"}],"part":[{"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/pressbooks\/v2\/parts\/636"}],"metadata":[{"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/pressbooks\/v2\/chapters\/764\/metadata\/"}],"wp:attachment":[{"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/wp\/v2\/media?parent=764"}],"wp:term":[{"taxonomy":"chapter-type","embeddable":true,"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/pressbooks\/v2\/chapter-type?post=764"},{"taxonomy":"contributor","embeddable":true,"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/wp\/v2\/contributor?post=764"},{"taxonomy":"license","embeddable":true,"href":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/wp-json\/wp\/v2\/license?post=764"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}