Amines Introduction Organic derivatives of ammonia. Many are biologically active. 1
Biological Activity Neurotransmitters: dopamine Bioregulators: epinephrine Vitamins: niacin, B 6 Alkaloids: nicotine, morphine, cocaine Amino acids Amine Reagents 2
Classes of Amines Primary (1 ): one C-N bond, 2 N-H bonds. Secondary (2 ): two C-N bonds, 1 N-H bond. Tertiary (3 ): three C-N bonds, no N-H bond. Quaternary (4 ): four C-N bonds, nitrogen has a + formal charge. Common Names Name the alkyl or aryl groups bonded to nitrogen, then add suffix -amine. diethylmethylamine cyclohexyldimethylamine diphenylamine 3
Amine as Substituent On a molecule with a higher priority functional group, the amine is named as a substituent. NH 2 CH 2 CH 2 CH 2 COOH OH γ-aminobutyric acid or 4-aminobutanoic acid NHCH 3 2-methylaminophenol 4
Aromatic Amines Amino group is bonded to a benzene ring. Parent compound is called aniline. Heterocyclic Amines The nitrogen is assigned the number 1. 5
Structure of Amines Nitrogen is sp 3 hybridized with a lone pair of electrons in an sp 3 orbital. Chirality of Amines Nitrogen may have 3 different groups and a lone pair, but often enantiomers cannot be isolated due to inversion around N. 6
Chiral Amines Amines with chiral carbon: 2-butanamine. Quaternary ammonium salts with four different groups bonded to nitrogen. Amines in which the nitrogen is restricted in rotation so it cannot interconvert. 7
Boiling Points N-H less polar than O-H. Weaker hydrogen bonding. Tertiary amines cannot hydrogen bond. Compound CH 3 CH 3 CH 3 OH CH 3 NH 2 CH 3 CH 2 CH 3 CH 3 CH 2 OH CH 3 CH 2 NH 2 Mol.Wt. 30 32 31 44 46 45 Boiling Point ºC -88.6º 65º -6.0º -42º 78.5º 16.6º 8
Compo und Butane Propanol Metil-etilamine Propilamine terbutane Isopropanol Isopropilamine trimetil amine Mol.Wt. 58 60 59 59 58 60 59 59 Boiling Point ºC -0.5º 97º 48º 37º -12º 82º 34º 3º Solubility and Odor Small amines (<6 C) soluble in water. All amines accept hydrogen bonds from water and alcohol. Most amines smell like rotting fish. NH 2 CH 2 CH 2 CH 2 CH 2 CH 2 NH 2 1,5-pentanediamine or cadaverine 9
Basicity of Amines Lone pair of electrons on nitrogen can accept a proton from an acid Aqueous solutions are basic to litmus. Ammonia pk b = 4.74 Alkyl amines are usually stronger bases than ammonia. Increasing the number of alkyl groups decreases solvation of ion, so 2 and 3 amines are similar to 1 amines in basicity. pka + pkb = 14 the higher the pka the stronger the base Compound NH 3 CH 3 C N pk a 11.0 10.7 10.7 9.3 5.2 4.6 1.0 0.0-1.0-10.0 10
Energy Diagram Alkyl groups are electron-donating and stabilize the cation. Resonance Effects Any delocalization of the electron pair weakens the base. 11
Hybridization Effects Electrons are held more tightly in orbitals with more s character, so those compounds are weaker bases. influence of substituents 12
Acidity of Amines NH 3 + H 2 O > NH 2 ( ) + H 2 O-H (+) C 6 H 5 SO 2 NH 2 + KOH C 6 H 5 SO 2 NH ( ) K (+) + H 2 O a sulfonamide base (CH 3 ) 3 COH + NaH (CH 3 ) 3 CO ( ) Na (+) + H 2 (C 2 H 5 ) 2 NH + C 4 H 9 Li (C 2 H 5 ) 2 N ( ) Li (+) + C 4 H 10 an amide base an alkoxide base Compound PhSO 2 NH 2 pk a 33 27 19 15 10 9.6 Amine Salts Ionic solids with high melting points Soluble in water No fishy odor 13
Purifying an Amine Phase Transfer Catalysts 14
IR Spectroscopy N-H stretch between 3200-3500 cm -1. Two peaks for 1 amine, one for 2. NMR Spectrum 15
Mass Spectrum Electrophilic Substitution at Nitrogen 2 R 2 NH + E (+) R 2 NHE (+) R 2 NE + H (+) Electrophile RCH 2 X RCH 2 OSO 2 R R 2 C=O R(C=O)X RSO 2 Cl HO N=O Name Alkyl Halide Alkyl Sulfonate Aldehyde or Ketone Acid Halide or Anhydride Sulfonyl Chloride Nitrous Acid 16
Synthesis: RNH 2 Nitrogen Reactant Carbon Reactant 1 st Reaction Type Initial Product 2 nd Reaction Conditions 2 nd Reaction Type Final Product 1. N 3 ( ) RCH 2 -X or R 2 CH-X S N 2 RCH 2 -N 3 or R 2 CH-N 3 LiAlH 4 or 4 H 2 & Pd Hydrogenolysis RCH 2 -NH 2 or R 2 CH-NH 2 2. C 6 H 5 SO 2 NH ( ) RCH 2 -X or R 2 CH-X S N 2 RCH 2 -NHSO 2 Ph or R 2 CH-NHSO 2 Ph Na in NH 3 (liq) Hydrogenolysis RCH 2 -NH 2 or R 2 CH-NH 2 3. CN ( ) RCH 2 -X or R 2 CH-X S N 2 RCH 2 -CN Or R 2 CH-CN LiAlH 4 Reduction RCH 2 -CH 2 NH 2 or R 2 CH-CH 2 NH 2 4. NH 3 RCH=O or R 2 C=O Addition/ Elimination RCH=NH or R 2 C=NH H 2 & Ni or NaBH 3 CN Reduction RCH 2 -NH 2 or R 2 CH-NH 2 5. NH 3 RCOX Addition /Elimination RCO-NH 2 LiAlH 4 Reduction RCH 2 -NH 2 6. NH 2 CONH 2 R 3 C (+) S N 1 R 3 C-NHCONH 2 NaOH soln. Hydrolysis R 3 C-NH 2 Synthesis: RNH 2 17
Synthesis: RNH 2 Reductive Amination 18
Synthesis: R 2 NH Synthesis: R 2 NH, R 3 N 19
Synthesis: R 2 NH, R 4 N + Hofmann and Curtius Rearrangements 20
Hofmann Rearrangement of Amides (1 ) In the presence of a strong base, primary amides react with chlorine or bromine to form amines with one less C. O C NH 2 Br 2, OH _ NH 2 H 2 O Hofmann Mechanism (1) N-H protons of amide are abstracted. Rearrangement forms an isocyanate. 21
Hofmann Mechanism (2) Isocyanate reacts with water to form carbamic acid, which loses CO 2. Curtius Rearrangement substitution an acid chloride Migration of R from C=O to the neighboring nitrogen with simultaneous loss of a leaving group Heating an acyl azide prepared from 22
Reactions with C=O Ammonia and primary amines react with carbonyls to give an imine (Schiff base). Electrophilic Substitution of Aniline -NH 2 is strong activator, o-,p-directing. May trisubstitute with excess reagent. H + changes -NH 2 to -NH 3+, a metaallowing deactivator. Attempt to nitrate aniline may explode. 23
Aniline Substitution Electrophilic Substitution of Pyridine Strongly deactivated by electronegative N. Substitutes in the 3-position. Electrons on N can react with electrophile. 24
Mechanism for Electrophilic Substitution Attack at the 3-position (observed) Attack at the 2-position (not observed) Nucleophilic Substitution of Pyridine Deactivated toward electrophilic attack. Activated toward nucleophilic attack. Nucleophile will replace a good leaving group in the 2- or 4-position. 25
Mechanism for Nucleophilic Substitution Attack at the 2-position (observed) Nucleophilic Attack at the 3-position (not observed) Adapted from: Organic Chemistry, 6th Edition; Chapter 19, Amines L. G. Wade, Jr. Chapter 19 52 26
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