Chapter 19: Amines. Introduction

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1 Chapter 19: Amines Chap 19 HW: (be able to name amines); 37, 39, 41, 42, 44, 46, 47, 48, 53-55, 57, 58 Introduction Organic derivatives of ammonia. Many are biologically active. Chap 19: Amines Slide

2 Biological Activity Neurotransmitters: dopamine Bioregulators: epinephrine Vitamins: niacin, B 6 Alkaloids: nicotine, morphine, cocaine Amino acids Chap 19: Amines Slide 19-3 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. Chap 19: Amines Slide

3 Classify: N CH 3 CH 3 N H CH 3 CH 3 C NH 2 CH 3 CH 3 CH 2 _ Br + N CH 2 CH 3 CH 3 Chap 19: Amines Slide 19-5 Common Names Name the alkyl or aryl groups bonded to nitrogen, then add suffix -amine. diethylmethylamine cyclohexyldimethylamine diphenylamine Chap 19: Amines Slide

4 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 Chap 19: Amines Slide 19-7 Aromatic Amines Amino group is bonded to a benzene ring. Parent compound is called aniline. Chap 19: Amines Slide

5 Heterocyclic Amines The nitrogen is assigned the number 1. Chap 19: Amines Slide 19-9 IUPAC Names Name is based on longest carbon chain. -e of alkane is replaced with -amine. Substituents on nitrogen have N- prefix. Br NH 2 CH 2 CH 2 CHCH 2 CH 3 3-bromo-1-pentanamine N(CH 3 ) 2 CH 3 CH 2 CHCH 2 CH 2 CH 3 N,N-dimethyl-3-hexanamine Chap 19: Amines Slide

6 Structure of Amines Nitrogen is sp 3 hybridized with a lone pair of electrons in an sp 3 orbital. Chap 19: Amines Slide Chirality of Amines Nitrogen may have 3 different groups and a lone pair, but enantiomers cannot be isolated due to inversion around N. Chap 19: Amines Slide

7 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. Chap 19: Amines Slide Boiling Points N-H less polar than O-H. Weaker hydrogen bonding. Tertiary amines cannot hydrogen bond. Chap 19: Amines Slide

8 Solubility and Odor Small amines (<6 C) soluble in water. All amines accept hydrogen bonds from water and alcohol. Branching increases solubility. 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 Chap 19: Amines Slide 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. Chap 19: Amines Slide

9 Energy Diagram Alkyl groups are electron-donating and stabilize the cation. Chap 19: Amines Slide Resonance Effects Any delocalization of the electron pair weakens the base. Chap 19: Amines Slide

10 Hybridization Effects Electrons are held more tightly in orbitals with more s character, so those compounds are weaker bases. Chap 19: Amines Slide Amine Salts Ionic solids with high melting points Soluble in water No fishy odor Chap 19: Amines Slide

11 Purifying an Amine Chap 19: Amines Slide Phase Transfer Catalysts Chap 19: Amines Slide

12 IR Spectroscopy N-H stretch between cm-1. Two peaks for 1 amine, one for 2. Chap 19: Amines Slide NMR Spectrum Chap 19: Amines Slide

13 Mass Spectrum Chap 19: Amines Slide Reactions with C=O Ammonia and primary amines react with carbonyls to give an imine (Schiff base). Chap 19: Amines Slide

14 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 meta-allowing deactivator. Attempt to nitrate aniline may explode. Chap 19: Amines Slide Aniline Substitution Chap 19: Amines Slide

15 Electrophilic Substitution of Pyridine Strongly deactivated by electronegative N. Substitutes in the 3-position. Electrons on N can react with electrophile. Chap 19: Amines Slide Mechanism for Electrophilic Substitution Attack at the 3-position (observed) Attack at the 2-position (not observed) Chap 19: Amines Slide

16 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. Chap 19: Amines Slide Mechanism for Nucleophilic Substitution Attack at the 2-position (observed) Nucleophilic Attack at the 3-position (not observed) Chap 19: Amines Slide

17 Alkylation of Amines Amines react with 1 alkyl halides via the S N 2 mechanism. Mixtures of the mono-, di-, and tri-alkylated products are obtained. Chap 19: Amines Slide Useful Alkylations Exhaustive alkylation to form the tetraalkylammonium salt. NH 2 CH 3 CH 2 CHCH 2 CH 2 CH 3 3 CH 3 I NaHCO 3 + _ N(CH 3 ) 3 I CH 3 CH 2 CHCH 2 CH 2 CH 3 Reaction with large excess of NH 3 to form the primary amine. CH 3 CH 2 CH 2 Br NH 3 (xs) CH 3 CH 2 CH 2 NH 2 + NH 4 Br Chap 19: Amines Slide

18 Acylation of Amines by Acid Chlorides Amine attacks C=O, chloride ion leaves. Product is amide, neutral, not basic. Useful for decreasing activity of aniline toward electrophilic aromatic substitution. O NH 2 O CH 3 C Cl N H C CH 3 to remove HCl N Chap 19: Amines Slide Formation of Sulfonamides Primary or secondary amines react with sulfonyl chloride. O O + R NH 2 R' S Cl R' S NH R O O H _ Cl base O R' S NH R O Sulfa drugs are sulfonamides that are antibacterial agents. Chap 19: Amines Slide

19 Hofmann Elimination A quaternary ammonium salt has a good leaving group - a neutral amine. Heating the hydroxide salt produces the least substituted alkene. + _ N(CH 3 ) 3 I CH 3 CHCH 2 CH 2 CH 3 Ag 2 O H 2 O + _ N(CH 3 ) 3 OH CH 3 CHCH 2 CH 2 CH 3 heat CH 2 CHCH 2 CH 2 CH 3 Chap 19: Amines Slide E2 Mechanism Chap 19: Amines Slide

20 Oxidation of Amines Amines are easily oxidized, even in air. Common oxidizing agents: H 2 O 2, MCPBA. 2 Amines oxidize to hydroxylamine (-NOH). 3 Amines oxidize to amine oxide (-N + -O - ). Chap 19: Amines Slide Cope Elimination Amine oxides undergo elimination to form the least substituted alkene under milder conditions than the Hofmann reaction. _ O + H N(CH 3 ) 2 CH 2 CHCH 2 CH 2 CH 3 O HO H N(CH 3 ) 2 N(CH 3 ) 2 CH 2 CHCH 2 CH 2 CH 3 CH 2 CHCH 2 CH 2 CH 3 Chap 19: Amines Slide

21 Nitrous Acid Reagent Nitrous acid is produced in situ by mixing sodium nitrite with HCl. The nitrous acid is protonated, loses water to form the nitrosonium ion. Chap 19: Amines Slide Reaction with Nitrous Acid 1 Amines form diazonium salts, R-N + N. Alkyldiazonium salts are unstable, but arenediazonium salts are widely used for synthesis. 2 Amines form N-nitrosoamines, R 2 N-N=O, found to cause cancer in laboratory animals. Chap 19: Amines Slide

22 Arenediazonium Salts Stable in solution at 0 10 C. The - + N N group is easily replaced by many different groups. Nitrogen gas, N 2, is a by-product. Chap 19: Amines Slide Synthesis by Reductive Amination To produce a 1 amine, react an aldehyde or ketone with hydroxylamine, then reduce the oxime. To produce a 2 amine, react an aldehyde or ketone with a 1 amine, then reduce the imine. To produce a 3 amine, react an aldehyde or ketone with a 2 amine, then reduce the imine salt. Chap 19: Amines Slide

23 Examples primary amine secondary amine C O H HN(CH 3 ) 2 H + H 3 C CH 3 N + C H Na(CH 3 COO) 3 BH CH 3 COOH H 3 C CH 3 N C H H tertiary amine Chap 19: Amines Slide Acylation-Reduction An acid chloride reacts with ammonia or a 1 amine or a 2 amine to form an amide. The C=O of the amide is reduced to CH 2 with lithium aluminum hydride. Ammonia yields a 1 amine. A 1 amine yields a 2 amine. A 2 amine yields a 3 amine. Chap 19: Amines Slide

24 Examples primary amine tertiary amine Chap 19: Amines Slide Direct Alkylation (1 ) Use a large excess (10:1) of ammonia with a primary alkyl halide or tosylate. Reaction mechanism is S N 2. CH 3 CH 2 CH 2 Br NH 3 CH 3 CH 2 CH 2 NH 2 + NH 4 Br Chap 19: Amines Slide

25 Gabriel Synthesis (1 ) Use the phthalimide anion as a form of ammonia that can only alkylate once. React the anion with a good S N 2 substrate, then heat with hydrazine. Chap 19: Amines Slide Azide Reduction (1 ) Azide ion, N 3-, is a good nucleophile. React azide with unhindered 1 or 2 halide or tosylate (S N 2). Alkyl azides are explosive! Do not isolate. Chap 19: Amines Slide

26 Nitrile Reduction (1 ) Nitrile, -C N, is a good S N 2 nucleophile. Reduction with H 2 or LiAlH 4 adds -CH 2 NH 2. Br NaCN CN 1) LiAlH 4 2) H 2 O CH 2 NH 2 Chap 19: Amines Slide Reduction of Nitro Compounds (1 ) -NO 2 is reduced to -NH 2 by catalytic hydrogenation, or active metal with acid. Commonly used to synthesize anilines. Chap 19: Amines Slide

27 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 Chap 19: Amines Slide Hofmann Mechanism (1) N-H protons of amide are abstracted. Rearrangement forms an isocyanate. Chap 19: Amines Slide

28 Hofmann Mechanism (2) Isocyanate reacts with water to form carbamic acid, which loses CO 2. Chap 19: Amines Slide End of Chapter 19 Chap 19: Amines Slide

Amines. Introduction Organic derivatives of ammonia. Many are biologically active.

Amines. Introduction Organic derivatives of ammonia. Many are biologically active. Amines Introduction Organic derivatives of ammonia. Many are biologically active. 1 Biological Activity Neurotransmitters: dopamine Bioregulators: epinephrine Vitamins: niacin, B 6 Alkaloids: nicotine,