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CHEM 2222 Chapter 21 Notes

by: annafen

CHEM 2222 Chapter 21 Notes Chem 212 - Organic Chemistry II

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Organic Chemistry (Carey) Chapter 21
Organic Chemistry II
Dr. Alissa Hare
Class Notes
amines, Organic Chemistry
25 ?




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This 32 page Class Notes was uploaded by annafen on Sunday May 29, 2016. The Class Notes belongs to Chem 212 - Organic Chemistry II at Vanderbilt University taught by Dr. Alissa Hare in Spring 2016. Since its upload, it has received 5 views. For similar materials see Organic Chemistry II in Chemistry at Vanderbilt University.


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Date Created: 05/29/16
21 1 Amine Nomenclature Amines • Amines are classified by the degree of substitution at N • Amines are named as alkylamines or as alkanamines 1 Amine Nomenclature • Amines as substituents are called an amino substituent • Substituents on the amine have N as locant 2 21.2 Structure and Bonding Structure • In alkylamines, nitrogen and carbon are both • In arylamines, like aniline the pyramidal nitrogen is flattened suggesting hybridization • In amides, the nitrogen is planar and Methylamine Aniline Formamide 3 Pyramidal Inversion • An amine with three different substituents on the nitrogen is chiral with the lone pair of electrons being the fourth substituent • Amines undergo pyramidal inversion which racemizes the chirality center • 4 21 4 Basicity of Amines Basicity of Amines • Amines are not very acidic, but the protonated amine (ammonium) is acidic + - • Alkyl ammonium ions, R NH X , have pKa val3es in the range of 10-11 (ammonium ion, H N X , has a pK = 9.3) 4 a • The ammonium ions of aryl amines and heterocyclic aromatic amines are more acidic than alkyl amines (pK < 5). a 5 Basicity of Amines • The lone pair of electrons on the nitrogen of aniline are conjugated with the π-electrons of the aromatic ring and are therefore less available for acid-base chemistry • Protonation removes the ability of the lone pair to be in conjugation • Substituents can greatly influence the basicity of the aniline 6 Basicity of Amines • Electron-donating substituents (-CH , -OH, -OCH ) make the substitut3d 3 aniline more basic than aniline • Electron-withdrawing substituents (-Cl, -NO ) make the substituted 2 aniline less basic than aniline 7 21.6 Reactions That Lead to Amines Preparation of Amines • Nucleophilic substitution • Nitration of arenes • Nucleophilic ring opening of epoxides 8 Preparation of Amines • Reaction of amines with ketones and aldehydes • Nucleophilic substitution of α-halo acids • Nucleophilic acyl substitution 9 21.7 Preparation of Amines by Alkylation of Ammonia Preparation of Amines • Ammonia and other alkylamines are good nucleophiles and react with 1º and 2º alkyl halides or tosylates via an S N 2 reaction yielding alkyl amines • 1º, 2º, and 3º amines all have similar reactivity in SN2 reactions • The initially formed monoalkylation product can undergo further reaction to yield a mixture of alkylated products 10 21.8 The Gabriel Synthesis of Primary Alkylamines The Gabriel Synthesis • This is the general method for synthesis of primary alkylamines • SN2 reaction with potassium phthalimide with alkyl halides or tosylates • Hydrazine then acidic or basic workup can be used to hydrolyze the N- substituted phthalimide 11 21 9 Preparation of Amines by Reduction Reduction Reactions • LiAlH reduce4 azides to 1º amines • LiAlH reduce4 nitriles to 1º amines • H + Ni2or Pd/C reduces nitro groups • LiAlH reduce4 amides 12 21 10 Reductive Amination Reductive Amination • Imines formed by condensation of amines and ketones and then are reduced to an amine 13 Reductive Amination • Sodium cyanoborohydride is a weak hydride source and will react with the iminium ion • This reaction can be done all at once because the NaBH CN reacts very 3 slowly with the ketone or aldehyde starting material 14 21.11 Reactions of Amines: A Review and a Preview Reactions of Amines • Reaction of ammonia and 1º amines with aldehyde and ketones to yield imines • Reaction of 2º amines with aldehyde and ketones with an α-proton to yield an enamine • Reaction of ammonia, 1º, and 2º amines with acid chloride, anhydrides and esters to make amides 15 21 12 Reaction of Amines with Alkyl Halides Reaction with Alkyl Halides • Just like with ammonia, amines and alkyl halides reaction via SN2 • Over-alkylation yields quaternary ammonium salts 16 21 13 The Hofmann Elimination The Hofmann Elimination • Elimination reaction (E2) with an quaternary ammonium as the leaving group • The elimination gives the least substituted alkene 17 The Hofmann Elimination • Steric effects control the elimination step to yield the anti-Zaitsev product = Hofmann product 18 21.14 Electrophilic Aromatic Substitution in Arylamines Reactions of Aniline • The aniline is often protected using acetic anhydride or acyl chloride to avoid cross-reactivity • Specifically for the Friedel-Crafts alkylation or acylation because the amine will complex with the AlCl 3 • The amide is also an ortho/para substituent but is less activating – Can be used to avoid over-halogenation 19 21 15 Nitrosation of Alkylamines Nitrosation of Alkylamines • Reaction of nitrous acid with amines yields the diazonium cation • The diazonium cation is a great leaving group and for secondary and tertiary amines, the carbocation is formed 20 Mechanism Continued 21 21 16 Nitrosation of Arylamines Nitrosation of Arylamines • Anilines react with nitrous acid HONO to yield diazonium salts • The aryl diazonium salt reacts with nucleophiles in substitution reactions • N is a 2reat leaving group Sandmeyer reaction: promoted by Cu(I) salts 22 Value of Aryl Diazonium Cations 1. Introduces substituents that are not available through other synthetic means - fluoro, iodo, cyano, and hydroxy 2. Allows the preparation of compounds with substitution patterns that are otherwise inaccessible 23 21 17 Synthetic Transformations of Aryl Diazonium Salts Formation of Phenols and Aryl Halides • Diazonium cations are hydrolyzed to phenols • Diazonium cations react with potassium iodide to form aryl iodides • Diazonium cations formed with the HBF to make aryl fluorides. This is 4 called Schiemann reaction 24 Sandmeyer Reaction • Diazonium cations react with copper(I) bromide and copper(I) chloride to form the corresponding aryl bromide or chloride • If CuCN is used, then the nitrile is made 25 Reduction of Aryl Diazonium Cations • Diazonium cations are reduced by with hypophosphorous acid (H PO ) 3 2 • This removes the amine group and can be used as a removable directing group 26 21 18 Azo Coupling Azo Coupling • Aryl diazonium cations are weak electrophiles that can be attacked by activated aromatics 27 21 19 Spectroscopic Analysis of Amines Infra Red Spectroscopy • Primary alkyl- and arylamines exhibit two peaks in the range 3000–3500 −1 cm • Secondary amines have one peak there • This is the same range as OH, but is less intense H 3(H C) 2 C-N4 2 2 -O-H H C3H C) H2C-O3 2 28 1 H NMRSpectroscopy • Nitrogen is less electronegative than oxygen and so shields neighboring nuclei to a greater extent • Hydrogens on carbons adjacent to the amine are usually in the δ 2.2 - 3.0 range • The chemical shifts and splittings of amino group protons are variable and are sensitive to solvent, concentration, and temperature 2H, s 3H, t 5H, m Ph-CH 2-N- -CH 2-CH 3 C 6H 5 2H, q -N-CH -2H 3 1H, s -N- H 29 13 C NMRand UV-vis Spectroscopy 13 • C NMR- Carbons that are bonded to nitrogen are more shielded than those bonded to oxygen but are more deshielded relative to an alkane 128.3 128.0 43.7 54.0 15.3 126.8 140.6 30 Mass Spectrometry • Nitrogen Rule: • The molecular ion of compounds with an odd number of nitrogens is odd • An even number of nitrogens give an even molecular weight. 31


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