Amines and Reactions
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The document provides an extensive overview of amines, categorizing them by their nitrogen class, nomenclature, physical properties, and methods of synthesis. Various reactions involving amines, such as their roles as bases, alkylation, and amide formations, are also described, along with specific techniques for identifying and characterizing different types of amines. Comprehensive synthesis pathways for producing amines from various organic compounds are detailed, including reduction, ammonolysis, and reductive amination.
![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
24](https://image.slidesharecdn.com/aminesmrh-171229121124/85/Amines-and-Reactions-24-320.jpg)
Amines and Reactions
- 1. 1 Amines Md. Saiful Islam Dept. of Pharmaceutical Sciences North South University Facebook Group: Pharmacy Universe
- 2. Amines (organic ammonia) :NH3 :NH2R or RNH2 1o amine (R may be Ar) :NHR2 or R2NH 2o amine :NR3 or R3N 3o amine NR4 + 4o ammonium salt 2
- 3. NB amines are classified by the class of the nitrogen, primary amines have one carbon bonded to N, secondary amines have two carbons attached directly to the N, etc. Nomenclature. Common aliphatic amines are named as “alkylamines” CH3NH2 methylamine 1o (CH3)2NH dimethylamine 2o (CH3)3N trimethylamine 3o CH3CH2NHCH3 ethylmethylamine 2o CH3CH2CHCH3 NH2 sec-butylamine 1o CH3CCH3 CH3 NH2 tert-butylamine 1o 3
- 4. NH2 cyclohexylamine 1o Complex amines are named by prefixing "amino"-" ( or N-methylamino, N,N-dimethyl amino-, etc.) to the parent chain: CH3CH2CHCH2CH2CH3 NH2 3-aminohexane CH3NHCH2CH2OH 2-(N-methylamino)ethanol CH2NH2 benzylamine 4
- 5. NH2 NH2 NH2 NH2 CH3 CH3 CH3 aniline o-toluidine m-toluidine p-toluidine N CH3H3C N,N-dimethylaniline H N diphenylamine 5
- 6. Salts of amines: change amine ammonium + anion change aniline anilinium + anion CH3CH2CH2NH3 + Cl- n-propylammonium chloride (C6H5NH3)2SO4 anilinium sulfate 6
- 7. Amines, physical properties: Nitrogen is sp3 hybridized, amines are polar and can hydrogen bond. mp/bp are relatively high for covalent substances amines are basic and will turn litmus blue insoluble in water (except for four-carbons or less) soluble in 5% HCl “fishy” smell N 7
- 8. RNH2 + HCl RNH3 + + Cl- water water insoluble soluble RNH3 + + OH- RNH2 + H2O water water soluble insoluble 1. test for amines 2. can be used to separate amines from neutral or acidic organic compounds 8
- 9. Amines, syntheses: 1. Reduction of nitro compounds Ar-NO2 + H2,Ni Ar-NH2 2. Ammonolysis of 1o or methyl halides R-X + NH3 R-NH2 3. Reductive amination R2C=O + NH3, H2, Ni R2CHNH2 4. Reduction of nitriles R-C≡N + 2 H2, Ni RCH2NH2 5. Hofmann degradation of amides RCONH2 + KOBr RNH2 9
- 10. 1. Reduction of nitro compounds: 10
- 12. 2. Ammonolysis of 1o or methyl halides. R-X NH3 RNH2 R-X R2NH R-X R3N R-X R4N+X- 1o 2o 3o 4o salt R-X must be 1o or CH3 CH3CH2CH2CH2Br NH3 CH3CH2CH2CH2NH2 n-butylamine 12
- 13. CH3CH2CH2NH2 CH3Cl CH3CH2CH2NHCH3 n-propylamine methyl-n-propylamine NH2 2 CH3CH2Br N Et Et aniline N,N-diethylaniline H2 C NH2 benzylamine (xs) CH3I H2 C N CH3 CH3 CH3 I benzyltrimethylammonium iodide 13
- 14. 3. Reductive amination: O H2, Ni or NaBH3CN CH NH2+ NH3 O H2, Ni or NaBH3CN CH NHR+ RNH2 O H2, Ni or NaBH3CN CH NR2+ R2NH 1o amine 3o amine 2o amine 14
- 15. C O NH3 C OH NH2 C NH - H2O H2, Ni C H NH2 imine H2,Ni Reductive amination via the imine. 15
- 16. H3C C O CH3 acetone NH3, H2/Ni CH3CHCH3 NH2 isopropylamine CCH2CH3 O propiophenone + CH3CH2NH2 NaBH3CN CHCH2CH3 NH CH2CH3 1-(N-ethylamino)-1-phenylpropane O cyclohexanone NH3, H2/Ni NH2 cyclohexylamine 16
- 17. 4. Reduction of nitriles R-C≡N + 2 H2, catalyst R-CH2NH2 1o amine R-X + NaCN R-CN RCH2NH2 primary amine with one additional carbon (R must be 1o or methyl) CH2Br NaCN CH2C N 2 H2, Ni CH2CH2NH2 benzyl bromide 1-amino-2-phenylethane 17
- 18. 5. Hofmann degradation of amides R C NH2 O KOBr R-NH2 Removes one carbon! 2,2-dimethylpropanamide OBr CH3C CH3 CH3 NH2 tert-butylamine CH3C CH3 CH3 C O NH2 18
- 19. Outline possible laboratory syntheses for each of the following amines, starting with toluene. Use a different method for each compound. NH2 CH2CH2NH2 CH2NH2 CHCH3 NH2 H3C H3C NH2 aniline p-toluidine 1-amino-2-phenylethane benzylamine 1-amino-1-(p-tolyl)ethane 19
- 20. NH2 CH2CH2NH2 CH2NH2 CHCH3 NH2 H3C H3C NH2 CH3 HNO3 H2SO4 H3C NO2 H2, Ni Br2,hv CH2Br NH3 (CH3CO)2O AlCl3 H3C CCH3 O NH3 H2,Ni CH2Br NaCN CH2CN 2 H2 Pt COOH PCl3 COCl NH3 CONH2 OBr- KMnO4,heat Br2,hv 20
- 21. Amine, reactions: 1. As bases 2. Alkylation 3. Reductive amination 4. Conversion into amides 5. EAS 6. Hofmann elimination from quarternary ammonium salts 7. Reactions with nitrous acid 21
- 22. 1. As bases a) with acids b) relative base strength c) Kb d) effect of groups on base strength 22
- 23. with acids NH2 + HCl NH3 +Cl- (CH3CH2)2NH + CH3COOH (CH3CH2)2NH2 + , - OOCCH3 anilinium chloride diethylammonium acetate 23
- 24. 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 24
- 25. 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. 25
- 26. 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. 26
- 27. 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. 27
- 28. Common substituent groups: -NH2, -NHR, -NR2 -OH -OR -NHCOCH3 electron donating -C6H5 groups -R -H -X -CHO, -COR -SO3H electron withdrawing -COOH, -COOR groups -CN -NR3 + -NO2 28
- 29. 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 29
- 30. 2. Alkylation (ammonolysis of alkyl halides) RNH2 R-X R2NH R-X R3N R-X R4N+X- 1o 2o 3o 4o salt SN2: R-X must be 1o or CH3 CH3CH2CH2CH2Br NH3 CH3CH2CH2CH2NH2 n-butylamine 30
- 31. CH3CH2CH2NH2 CH3Cl CH3CH2CH2NHCH3 n-propylamine methyl-n-propylamine NH2 2 CH3CH2Br N Et Et aniline N,N-diethylaniline H2 C NH2 benzylamine (xs) CH3I H2 C N CH3 CH3 CH3 I benzyltrimethylammonium iodide 31
- 32. 3. Reductive amination C O H2, Ni or NaBH3CN CH NHR+ RNH2 C O H2, Ni or NaBH3CN CH NR2+ R2NH 3o amine 2o amine 32
- 33. CCH2CH3 O propiophenone + CH3CH2NH2 NaBH3CN CHCH2CH3 NH CH2CH3 1-(N-ethylamino)-1-phenylpropane O cyclohexanone CH3NH2, H2/Ni NHCH3 cyclohexylmethylamine 33
- 34. 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 34
- 35. 35
- 36. Conversion into sulfonamides R-NH2 + ArSO2Cl ArSO2NHR + HCl 1o N-subst.sulfonamide R2NH + ArSO2Cl ArSO2NR2 + HCl 2o N,N-disubst.sufonamide R3N + ArSO2Cl NR 36
- 37. Schotten-Baumann technique: reactions of aromatic acid chlorides are sped up by the addition of base. R-NH2 + ArSO2Cl + KOH ArSO2NHR 1o acidic ArSO2NR water soluble salt R2NH + ArSO2Cl + KOH ArSO2NR2 + HCl 2o N,N-disubst.sufonamide water insoluble 37
- 38. Hinsberg Test: unknown amine + benzenesulfonyl chloride, KOH (aq) Reacts to produce a clear solution and then gives a ppt upon acidification primary amine. Reacts to produce a ppt secondary amine. Doesn’t react tertiary amine. 38
- 39. NH2 N N CH3 CH3 + SO2Cl S O O KOH (CH3CH2)2NH SO2Cl KOH + SO2Cl KOH + S O O N CH2CH3 CH2CH3 NR water sol. ppt 39
- 40. 5. 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 f) coupling with diazonium salts g) nitrosation 40
- 41. a) nitration 41
- 42. b) sulfonation NH2 + H2SO4 NH3 SO3 cold H2SO4 NH3 HSO4 42
- 43. 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! 43
- 44. e) 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 44
- 45. f) 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 45
- 46. g) nitrosation N H3C CH3 NaNO2, HCl N H3C CH3 N O The ring is sufficiently activated towards EAS to react with the weak electrophile NO+ 46
- 47. h) coupling with diazonium salts azo dyes NH2 CH3 + N2 Cl benzenediazonium chloride CH3 NH2 N N an azo dye 47
- 48. 6. Hofmann elimination from quarternary hydroxides step 1, exhaustive methylation 4o salt step 2, reaction with Ag2O 4o hydroxide + AgX step 3, heat to eliminate alkene(s) + R3N CH3CH2CH2CH2 (xs) CH3I CH3CH2CH2CH2NH2 N CH3 CH3 CH3 I- CH3CH2CH2CH2 N CH3 CH3 CH3 I- Ag2O CH3CH2CH2CH2 N CH3 CH3 CH3 OH- + AgI CH3CH2CH2CH2 N CH3 CH3 CH3 OH ∆ CH3CH2CH=CH2 + (CH3)3N 48
- 49. 49
- 50. 7. 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 50