Chemistry of amines
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This document discusses the structure, classification, naming, physical properties, preparation, and reactions of amines. It begins by describing amines as derivatives of ammonia with hydrogens and/or alkyl groups attached to the nitrogen atom. Amines can be classified as primary, secondary, or tertiary based on the number of alkyl groups. Common methods for preparing amines include SN2 reactions with alkyl halides, reduction of nitro compounds, and reductive amination of aldehydes and ketones. The document notes that amines act as bases and undergo nucleophilic substitution, electrophilic aromatic substitution, and other reactions similar to ammonia. It provides examples of biologically active amines that function as neurotransmitters, hormones
![b) relative base strength
RNH2 > NH3 > ArNH2
Kb ionization of the base in water
:Base + H2O H:Base+ + OH-
Kb = [ H:Base+ ] [ OH- ] / [ :Base ]
Kb
aliphatic amines 10-3 – 10-4
ammonia 1.8 x 10-5
anilines 10-9 or less](https://image.slidesharecdn.com/chemistryofamines-141218045550-conversion-gate01/85/Chemistry-of-amines-21-320.jpg)
Chemistry of amines
- 2. Amines
- 3. Structure and Classification of Amines • Amines are derivatives of ammonia, the same way that alcohols are derivatives of water • Amines have a nitrogen, with hydrogens and/or alkyl groups attached • The shape around the nitrogen is pyramidal and there is a lone pair of electrons on the nitrogen • Amines can be classified as 1º, 2º or 3º, just like carbons, based on how many alkyl groups are attached to the nitrogen NH2 H N N H N H H Ammonia Primary Amine Secondary Amine Tertiary Amine
- 4. Naming Amines • Most simple amines are named by their common names (which are accepted by IUPAC) • For common names, the alkyl groups attached to the N are named alphabetically, and amine is added to the end • IUPAC rules are more often used for more complicated amines - find the longest chain bonded to N, and replace -e in alkane name with amine - number at end nearest N and give number for position of N - the prefixes di, tri etc. are used for multiple amines - when amines are with other functional groups they are called amino groups N H N NH2 H ONH2 H2N NH2 trimethylamine ethylmethylamine 2-butanamine 3-aminobutanal 1,2-ethanediamine
- 5. Naming Aromatic Amines • Aromatic amines are named as anilines • When alkyl groups are attached to the aromatic N, they are written as N-alkyl at the beginning of the name • As substituents on the ring they are named as amino groups NH2 CH3 NH2 NO2 NH2 3-Methylaniline (m-Toluidine) Aniline 4-Nitroaniline (p-Nitroaniline) CH3 CHCH3 NH2 NH2 H2 N NH2 1,6-HexanediamineCyclohexanamine2-Propanamine
- 6. – when four atoms or groups of atoms are bonded to a nitrogen atom, as for example CH3NH3 +, nitrogen bears a positive charge and is associated with an anion as a salt – name the compound as a salt of the corresponding amine – replace the ending -amine or aniline by -ammonium or anilinium and add the name of the anion ( CH3 CH2 )3 NH + Cl - Triethylammonium chloride Amine salts
- 7. Physical Properties of Amines • Primary and secondary amines can H-bond with themselves, so have relatively high boiling points • However, because the N-H bond is less polar than the O-H bond, amines have lower boiling points than alcohols • Primary and secondary amines have boiling points similar to aldehydes and ketones • Tertiary amines can’t H-bond with themselves, and so have boiling points near those of ethers and hydrocarbons • Smaller amines (less than 5 carbons) are soluble in water - primary and secondary amines are more soluble than tertiary because they have more H-bonding with water
- 9. •an N-H---N hydrogen bond is weaker than an O-H---O hydrogen bond because the difference in electronegativity between N and H (3.0 - 2.1 = 0.9) is less than that between O and H (3.5 - 2.1 = 1.4)
- 11. 1. SN2 Reactions of Alkyl Halides Ammonia and other alkylamines are good nucleophiles and react with 1° and 2° alkyl halides via an SN 2 reaction yielding alkyl amines. Any amine formed by nucleophilic substitution still has a nonbonded electron pair, making it a nucleophile as well. It will react with remaining alkyl halide to form a more substituted amine, resulting in a mixture of 10, 20, and 30 amine products. Consequently, the reaction is most useful in preparing 10 amines by using a large excess of NH3, and for preparing quaternary ammonium salts by alkylating any nitrogen nucleophile with one or more equivalents of alkyl halide.
- 12. 2. Selective Preparation of Primary Amines: the Azide Synthesis • Azide ion, N3 displaces a halide ion from a primary or secondary alkyl halide to give an alkyl azide, RN3 • Alkyl azides are not nucleophilic (but they are explosive) • Reduction gives the primary amine RH2C X N N N+ RH2C N N N RH2C NH2 SN 2 1° amine then H2O LiAlH4, ether
- 13. 3. Reduction of Nitro compound • Arylamines are prepared from nitration of an aromatic compound and reduction of the nitro group • Reduction by catalytic hydrogenation over platinum is suitable if no other groups can be reduced R HNO3 H2SO4 R NO2 H2, Pd/C 1° arylamine R NH2 -or- Fe, HCl
- 14. 4. Gabriel Synthesis of Primary Amines • A phthalimide alkylation for preparing a primary amine from an alkyl halide • The N-H in imides (CONHCO) can be removed by KOH followed by alkylation and hydrolysis
- 15. 5. Reductive Amination of Aldehydes and Ketones • Treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent
- 16. 6. Reduction of nitriles and amides LiAlH4 reduces nitriles to 1° amines RH2C X + RH2C C N RH2C-H2C NH2 SN 2 1° amine then H2O LiAlH4, ether C N LiAlH4 reduces amides to 1°, 2° or 3° amines R1CO2H R1 Cl C O R1 N C O NR1H2C R2 N H R3 R2 R3 R3 R2 then H2O LiAlH4, ether
- 17. Amines, reactions Amines are similar to ammonia in their reactions. Like ammonia, amines are basic. Like ammonia, amines are nucleophilic and react with alkyl halides, acid chlorides, and carbonyl compounds. The aromatic amines are highly reactive in electrophilic aromatic substitution.
- 18. Amine, reactions: 1. As bases 2. Alkylation 3. Reductive amination 4. Conversion into amides 5. Reactions with nitrous acid 6. EAS
- 19. 1.As bases a) with acids b) relative base strength c) Kb d) effect of groups on base strength
- 20. a) with acids NH2 + HCl NH3 + Cl- (CH3CH2)2NH + CH3COOH (CH3CH2)2NH2 + , - OOCCH3 anilinium chloride diethylammonium acetate
- 21. b) relative base strength RNH2 > NH3 > ArNH2 Kb ionization of the base in water :Base + H2O H:Base+ + OH- Kb = [ H:Base+ ] [ OH- ] / [ :Base ] Kb aliphatic amines 10-3 – 10-4 ammonia 1.8 x 10-5 anilines 10-9 or less
- 22. Why are aliphatic amines more basic than ammonia? NH3 + H2O NH4 + + OH- R-NH2 + H2O R-NH3 + + OH- The alkyl group, -R, is an electron donating group. The donation of electrons helps to stabilize the ammonium ion by decreasing the positive charge, lowering the ΔH, shifting the ionization farther to the right and increasing the basicity.
- 23. Why are aromatic amines less basic than aliphatic amines? R-NH2 + H2O R-NH3 + + OH- NH2 + H2O NH3 + OH NH2 NH2 NH3 NH3 NH2 NH2 NH2 resonance stabilization of the free base, increases the ΔH, shifts the ionization to the left, decreasing base strength.
- 24. d) Effect of substituent groups on base strength: NH2 + H2O NH3 + OH G G Electron donating groups will stabilize the anilinium ion, decreasing the ΔH, shifting the ionization farther to the right and making the compound a stronger base. Electron withdrawing groups destabilize the anilinium ion, increasing the ΔH, shifting the ionization towards the reactants, making the compound a weaker base.
- 25. Common substituent groups: -NH2, -NHR, -NR2 -OH -OR -NHCOCH3 electron donating groups -C6H5 -R -H -X -CHO, -COR -SO3H electron withdrawing groups -COOH, -COOR -CN -NR3 + -NO2
- 26. Number the following in decreasing order of base strength (let #1 = most basic, etc. NH3 NH2 NH2 NH2 NH2 NO2 OCH3 4 1 5 3 2
- 27. 2. Alkylation (ammonolysis of alkyl halides)
- 29. 4. Conversion into amides R-NH2 + RCOCl RCONHR + HCl 1o N-subst. amide R2NH + RCOCl RCONR2 + HCl 2o N,N-disubst. amide R3N + RCOCl NR 3o
- 30. 5. Reactions with nitrous acid NH2 + HONO N N diazonium salt R-NH2 + HONO N2 + mixture of alchols & alkenes primary amines secondary amines H N R + HONO N R N O N-nitrosamine tertiary amines N R R + HONO N R R N O p-nitrosocompound
- 31. 6. EAS -NH2, -NHR, -NR2 are powerful activating groups and ortho/para directors a) nitration b) sulfonation c) halogenation d) Friedel-Crafts alkylation e) Friedel-Crafts acylation
- 32. a) Nitration
- 33. b) Sulfonation NH2 + H2SO4 NH3 SO3 cold H2SO4 NH3 HSO4
- 34. c) Halogenation NH2 + Br2, aq. NH2 Br Br Br no catalyst needed use polar solvent Br2,Fe Br HNO3 H2SO4 Br NO2 + ortho- H2/Ni Br NH2 polyhalogenation!
- 35. d) Friedel-Crafts alkylation NR with –NH2, -NHR, -NR2 NH2 CH3 + CH3CH2Br, AlCl3 NR Do not confuse the above with the alkylation reaction: NH2 CH3 + CH3CH2Br NHCH2CH3 CH3
- 36. e) Friedel-Crafts acylation NR with –NH2, -NHR, -NR2 NH2 CH3 + NR Do not confuse the above with the formation of amides: NH2 CH3 NHCCH3 CH3 H3C C O Cl AlCl3 + H3C C O Cl O
- 37. Example of biologically active amines H2NCH2CH2CH2CH2NH2 putrescine H2NCH2CH2CH2CH2CH2NH2 cadaverine H2NCH2CH2CH2CH2NCH2CH2CH2CH2NH2 spermidineH H2N(CH2)N(CH2)4N(CH2)3NH2 spermineH H NHCH3 OHH HO HO epinephrine (adrenaline) NH2 OHH HO HO norepinephrine (noradrenaline) NH2HO HO dopamine
- 38. • A large number of physiologically active compounds are derived from 2-phenethylamine (C6H5CH2CH2NH2). These compounds include adrenaline, noradrenaline, methamphetamine, and mescaline. Each contains a benzene ring bonded to a two-carbon unit with a nitrogen atom (shown in red).
- 40. More biologically active amines… NH2 CH3H amphetamine (benzadrine) N CH2CH2NH2 HO H NHCH3 CH3H methamphetamine (speed) serotonin mescaline NH2CH3O CH3O OCH3 N CO2H nicotinic acid (niacin) NN CH2CH2NH2 H histamine
- 41. • Histamine, a rather simple triamine that is present in many tissues, is responsible for a wide variety of physiological effects. • Understanding the physiological properties of histamine has helped chemists design drugs to counteract some of its undesirable effects. Antihistamines bind to the same active site as histamine in the cell, but they evoke a different response. Examples are brompheniramine and cimetidine.
- 42. H2N C OCH2CH3 O benzocaine (a topical anesthetic) Cl N N H O O diazepam (Valium) N N O N N CH3 CH2CH2CH3 H SO O N N CH3 CH3CH2O Sildenafil (Viagra)
- 43. R'O O RO NCH3 codeine (R = CH3, R' = H) morphine (R and R' = H) heroin (R and R' = COCH3) mepiridine (Demerol) N N N N O O CH3 H3C CH3 caffeine N N CH3 H nicotine N H3C C O H O C O H OCH3 cocaine NCH3C O CH3CH2O Methadone C6H5 NCH3C O CH3CH2 CH3 CH3
- 44. • Cocaine, amphetamines, and several other addicting drugs increase the level of dopamine in the brain, which results in a pleasurable “high.” With time, the brain adapts to increased dopamine levels, so more drug is required to produce the same sensation. • Understanding the neurochemistry of these compounds has led to the synthesis and availability of several useful drugs. Examples are fentanyl and sumatripan.
- 46. N HO H N H H quinine N O N O H H strychnine N N H C O (CH3CH2)2N CH3 lysergic acid diethylamide (LSD) N H CH2CH2CH3 H coniin (the poison from hemlock used to kill Socrates)