{"id":2244,"date":"2018-11-30T16:30:12","date_gmt":"2018-11-30T16:30:12","guid":{"rendered":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/?post_type=chapter&p=2244"},"modified":"2019-01-09T12:50:49","modified_gmt":"2019-01-09T12:50:49","slug":"23-2-preparation-of-amines","status":"publish","type":"chapter","link":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/23-2-preparation-of-amines\/","title":{"raw":"23.2. Preparation of Amines","rendered":"23.2. Preparation of Amines"},"content":{"raw":"
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Nucleophilic substitution of haloalkanes<\/span><\/h2>\r\nThis was discussed earlier in section 9.4<\/a>.\r\n\r\n\"\"\r\n\r\nPrimary amines can be synthesized by alkylation of ammonia. A large excess of ammonia is used if the primary amine is the desired product.\u00a0 Haloalkanes react with amines to give a corresponding alkyl-substituted amine, with the release of a halogen acid. Such reactions, which are most useful for alkyl iodides and bromides, are rarely employed because the degree of alkylation is difficult to control. If the reacting amine is tertiary, a quaternary ammonium cation results. Many quaternary ammonium salts can be prepared by this route with diverse R groups and many halide and pseudohalide anions.\r\n\r\nWhen primary amines are heated with halogenoalkanes,\u00a0a complicated series of reactions occurs, giving a mixture of products - probably one of the most confusing sets of reactions you will meet at this level. The products of the reactions include secondary and tertiary amines and their salts, and quaternary ammonium salts.<\/span>\r\n
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Making secondary amines and their salts<\/h3>\r\nIn the first stage of the reaction, you get the salt of a secondary amine formed. For example if you started with ethylamine and bromoethane, you would get diethylammonium bromide<\/span>\r\n\r\n\"\"<\/span>\r\n\r\nIn the presence of excess ethylamine in the mixture, there is the possibility of a reversible reaction. The ethylamine removes a hydrogen from the diethylammonium ion to give free diethylamine - a secondary amine.<\/span>\r\n\r\n\"\"<\/span>\r\n\r\n<\/div>\r\n
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Making tertiary amines and their salts<\/h3>\r\nBut it doesn't stop here! The diethylamine also reacts with bromoethane - in the same two stages as before. This is where the reaction would start if you reacted a secondary amine with a halogenoalkane.<\/span>\r\n\r\nIn the first stage, you get triethylammonium bromide.<\/span>\r\n\r\n\"\"<\/span>\r\n\r\nThere is again the possibility of a reversible reaction between this salt and excess ethylamine in the mixture.<\/span>\r\n\r\n\"\"<\/span>\r\n\r\nThe ethylamine removes a hydrogen ion from the triethylammonium ion to leave a tertiary amine - triethylamine.<\/span>\r\n\r\n<\/div>\r\n
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Making a quaternary ammonium salt<\/h3>\r\nThe final stage! The triethylamine reacts with bromoethane to give tetraethylammonium bromide - a quaternary ammonium salt (one in which all four hydrogens have been replaced by alkyl groups).<\/span>\r\n\r\n\"\"<\/span>\r\n\r\nThis time there isn't any hydrogen left on the nitrogen to be removed. The reaction stops here.<\/span>\r\n\r\n<\/div>\r\n
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Preparation of Primary Amines<\/h3>\r\nAlthough direct alkylation of ammonia (large excess) by alkyl halides leads to 1\u00ba-amines, alternative procedures are preferred in many cases. These methods require two steps, but they provide pure product, usually in good yield. The general strategy is to first form a carbon-nitrogen bond by reacting a nitrogen nucleophile with a carbon electrophile. The following table lists several general examples of this strategy in the rough order of decreasing nucleophilicity of the nitrogen reagent. In the second step, extraneous nitrogen substituents that may have facilitated this bonding are removed to give the amine product.\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n\r\n
Nitrogen\r\nReactant<\/strong><\/th>\r\nCarbon\r\nReactant<\/strong><\/th>\r\n1st Reaction\r\nType<\/strong><\/th>\r\nInitial Product<\/strong><\/th>\r\n2nd Reaction\r\nConditions<\/strong><\/th>\r\n2nd Reaction\r\nType<\/strong><\/th>\r\nFinal Product<\/strong><\/th>\r\n<\/tr>\r\n<\/thead>\r\n
N3<\/sub>(\u2013)<\/sup><\/td>\r\nRCH2<\/sub>-X or\r\nR2<\/sub>CH-X<\/td>\r\nSN<\/sub>2<\/td>\r\nRCH2<\/sub>-N3<\/sub> or\r\nR2<\/sub>CH-N3<\/sub><\/td>\r\nLiAlH4<\/sub> or\r\n4 H2<\/sub> & Pd<\/td>\r\nHydrogenolysis<\/td>\r\nRCH2<\/sub>-NH2<\/sub> or\r\nR2<\/sub>CH-NH2<\/sub><\/td>\r\n<\/tr>\r\n
C6<\/sub>H5<\/sub>SO2<\/sub>NH(\u2013)<\/sup><\/td>\r\nRCH2<\/sub>-X or\r\nR2<\/sub>CH-X<\/td>\r\nSN<\/sub>2<\/td>\r\nRCH2<\/sub>-NHSO2<\/sub>C6<\/sub>H5<\/sub> or\r\nR2<\/sub>CH-NHSO2<\/sub>C6<\/sub>H5<\/sub><\/td>\r\nNa in NH3<\/sub> (liq)<\/td>\r\nHydrogenolysis<\/td>\r\nRCH2<\/sub>-NH2<\/sub> or\r\nR2<\/sub>CH-NH2<\/sub><\/td>\r\n<\/tr>\r\n
CN(\u2013)<\/sup><\/td>\r\nRCH2<\/sub>-X or\r\nR2<\/sub>CH-X<\/td>\r\nSN<\/sub>2<\/td>\r\nRCH2<\/sub>-CN or\r\nR2<\/sub>CH-CN<\/td>\r\nLiAlH4<\/sub><\/td>\r\nReduction<\/td>\r\nRCH2<\/sub>-CH2<\/sub>NH2<\/sub> or\r\nR2<\/sub>CH-CH2<\/sub>NH2<\/sub><\/td>\r\n<\/tr>\r\n
NH3<\/sub><\/td>\r\nRCH=O or\r\nR2<\/sub>C=O<\/td>\r\nAddition \/\r\nElimination<\/td>\r\nRCH=NH or\r\nR2<\/sub>C=NH<\/td>\r\nH2<\/sub> & Ni\r\nor NaBH3<\/sub>CN<\/td>\r\nReduction<\/td>\r\nRCH2<\/sub>-NH2<\/sub> or\r\nR2<\/sub>CH-NH2<\/sub><\/td>\r\n<\/tr>\r\n
NH3<\/sub><\/td>\r\nRCOX<\/td>\r\nAddition \/\r\nElimination<\/td>\r\nRCO-NH2<\/sub><\/td>\r\nLiAlH4<\/sub><\/td>\r\nReduction<\/td>\r\nRCH2<\/sub>-NH2<\/sub><\/td>\r\n<\/tr>\r\n
NH2<\/sub>CONH2<\/sub>\r\n(urea)<\/td>\r\nR3<\/sub>C(+)<\/sup><\/td>\r\nSN<\/sub>1<\/td>\r\nR3<\/sub>C-NHCONH2<\/sub><\/td>\r\nNaOH soln.<\/td>\r\nHydrolysis<\/td>\r\nR3<\/sub>C-NH2<\/sub><\/td>\r\n<\/tr>\r\n<\/tbody>\r\n<\/table>\r\nA specific example of each general class is provided in the diagram below. In the first two, an anionic nitrogen species undergoes an SN<\/sub>2 reaction with a modestly electrophilic alkyl halide reactant. For example #2 an acidic phthalimide derivative of ammonia has been substituted for the sulfonamide analog listed in the table. The principle is the same for the two cases, as will be noted later. Example #3 is similar in nature, but extends the carbon system by a methylene group (CH2<\/sub>). In all three of these methods 3\u00ba-alkyl halides cannot be used because the major reaction path is an E2 elimination.\r\n\r\n\"aminerx1.gif\"<\/a>\r\n\r\nThe methods illustrated by examples #4 and #5 proceed by attack of ammonia, or equivalent nitrogen nucleophiles, at the electrophilic carbon of a carbonyl group. A full discussion of carbonyl chemistry is presented later, but for present purposes it is sufficient to recognize that the C=O double bond is polarized so that the carbon atom is electrophilic. Nucleophile addition to aldehydes and ketones is often catalyzed by acids. Acid halides and anhydrides are even more electrophilic, and do not normally require catalysts to react with nucleophiles. The reaction of ammonia with aldehydes or ketones occurs by a reversible addition-elimination pathway to give imines<\/strong> (compounds having a C=N function). These intermediates are not usually isolated, but are reduced as they are formed (i.e. in situ<\/em>). Acid chlorides react with ammonia to give amides, also by an addition-elimination path, and these are reduced to amines by LiAlH4<\/sub>.\r\n\r\nThe 6th example is a specialized procedure for bonding an amino group to a 3\u00ba-alkyl group (none of the previous methods accomplishes this). Since a carbocation is the electrophilic species, rather poorly nucleophilic nitrogen reactants can be used. Urea, the diamide of carbonic acid, fits this requirement nicely. The resulting 3\u00ba-alkyl-substituted urea is then hydrolyzed to give the amine. One important method of preparing 1\u00ba-amines, especially aryl amines, uses a reverse strategy. Here a strongly electrophilic nitrogen species (NO2<\/sub>(+)<\/sup>) bonds to a nucleophilic carbon compound. This nitration reaction gives a nitro group that can be reduced to a 1\u00ba-amine by any of several reduction procedures.\r\n\r\nThe Hofmann rearrangement <\/a>of 1\u00ba-amides provides an additional synthesis of 1\u00ba-amines.\r\n\r\n<\/div>\r\n
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Reduction of Other Functional Groups that Contain Nitrogen<\/h3>\r\n<\/div>\r\n
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Reduction of Nitro Groups<\/h3>\r\n
\r\n\r\nSeveral\u00a0 methods for reducing nitro groups to amines are known, and some of these were discussed at the end of section 14.2<\/a>. These include catalytic hydrogenation (H2<\/sub> + Pd\/C), zinc or tin in dilute HCl, and sodium sulfide in ammonium hydroxide solution.\r\n
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Nitriles can be converted to 1\u00b0 amines by reaction with LiAlH4<\/sub><\/h3>\r\nDuring this reaction the hydride nucleophile attacks the electrophilic carbon in the nitrile to form an imine anion. Once stabilized by a Lewis acid-base complexation the imine salt can accept a second hydride to form a dianion. The dianion can then be converted to an amine by addition of water.\r\n\r\n<\/div>\r\n
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\"1.jpg\"<\/h3>\r\n<\/div>\r\n
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Amides can be converted to 1\u00b0, 2\u00b0 or 3\u00b0 amines using LiAlH4<\/sub><\/h3>\r\n<\/div>\r\n<\/div>\r\n
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\"1.jpg\"<\/h3>\r\n<\/div>\r\n
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Reductive amination<\/h3>\r\nAldehydes and ketones can be converted into 1o<\/sup>, 2o<\/sup> and 3o<\/sup> amines using reductive amination.\u00a0 The reaction takes place in two parts.\u00a0 The first step is the nucleophiic addition of the carbonyl group to form an imine.\u00a0 The second step is the reduction of the imine to an amine using an reducing agent. A reducing agent commonly used for this reaction is sodium cyanoborohydride (NaBH3<\/sub>CN).\r\n\r\n\"\"\r\n\r\n\"\"\r\n\r\n\"\"\r\n\r\n<\/div>\r\n
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Hofmann rearrangement<\/h3>\r\nHofmann rearrangement, also known as Hofmann degradation and not to be confused with Hofmann elimination<\/a>, is the reaction of a primary amide with a halogen (chlorine or bromine) in strongly basic (sodium or potassium hydroxide) aqueous medium, which converts the amide to a primary amine. For example:\r\n\r\n\"\"\r\n\r\nMechanism:\r\n\r\n\"\"\r\n\r\n<\/div>\r\n
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Curtius Rearrangement<\/h3>\r\nThe Curtius rearrangement involves an acyl azide.\r\n\r\n\"\"The mechanism of the Curtius rearrangement involves the migration of an -R group form the carbonyl carbon to the the neighboring nitrogen.\r\n\r\n\"\"\r\nContributors<\/span>\r\n\r\n<\/div>\r\n
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