![Basicity:Basicity:
KKbb ==
[RNH[RNH33] [HO ]] [HO ]
[RNH[RNH22]]
++ --
~~ 1010-4-4
Ammonium ion
ppKKbb ~ 4~ 4
Recall:Recall:
ppKKaa + p+ pKKbb = 14= 14
Thus, pThus, pKKaa of protonated amine ~of protonated amine ~ 1010](https://image.slidesharecdn.com/chapter21-140331234703-phpapp01-180125094743/85/Chapter21-140331234703-phpapp01-18-320.jpg)
Chapter21 140331234703-phpapp01
- 1. Chapter 21: Amines andChapter 21: Amines and Their DerivativesTheir Derivatives Medicines, amino acids, peptides,Medicines, amino acids, peptides, proteins, alkaloids, industrial materialsproteins, alkaloids, industrial materials FluoxetinFluoxetin (Prozac)(Prozac) O F F F PolypeptidePolypeptide
- 2. AmphetamineAmphetamine MescalineMescalineEpinephrineEpinephrine (Adrenaline)(Adrenaline) Alkaloids (natural amines)Alkaloids (natural amines) HO OH HO H NHCH3 H2C H2N H CH3 H3CO OCH3 OCH3 NH2
- 3. Amines in Industry: Nylon Nylon 6,6Nylon 6,6 Hosiery, gears, textile fiber,.......
- 4. Primary aminesPrimary amines Secondary aminesSecondary amines TertiaryTertiary aminesamines Naming:Naming: AlkanaminesAlkanamines NN--alkylalkyl, as, as in amidesin amides
- 5. Substituent name:Substituent name: Amino-Amino- Common names:Common names: AlkylamineAlkylamine 4-(2-4-(2-AminoAminoethylethyl)benzoic acid)benzoic acid HOOC NH2
- 6. Physical PropertiesPhysical Properties 1.1. Tetrahedral structureTetrahedral structure BasicBasic EEaa = 5-7 kcal mol= 5-7 kcal mol-1-1 InversionInversion
- 7. 3. Basicity-Nucleophilicity3. Basicity-Nucleophilicity RNHRNH22 :: HHClCl RNHRNH33 ++ ClCl --++ Primary ammonium chloridePrimary ammonium chloride :::: :: :: RNHRNH22 :: CHCH33II RNHRNH22CHCH33 ++ II ++ :::: :: :: -- Secondary ammonium chlorideSecondary ammonium chloride 2. Chiral amines racemize2. Chiral amines racemize
- 8. Ammonium salts are configurationally stableAmmonium salts are configurationally stable N H3C C6H5 CH2CH3 N H3C C6H5 CH2CH3 CH2Cl N H3C C6H5 CH2CH3 H2C N H3C C6H5 CH2CH3 H2C + Cl: : :: - Cl: : :: - + + + + Can be resolved, e.g, byCan be resolved, e.g, by fractional crystallization of afractional crystallization of a salt with optically active anionsalt with optically active anion
- 9. 4. Weaker hydrogen bonds than OH4. Weaker hydrogen bonds than OH NR H H NH H R : : Only primary and secondary amines can functionOnly primary and secondary amines can function as proton donorsas proton donors Less electronegativeLess electronegative than oxygenthan oxygen
- 11. SpectroscopySpectroscopy InfraredInfrared spectrum of cyclohexanaminespectrum of cyclohexanamine N-H IR stretch:N-H IR stretch: 3300–35003300–3500 cmcm-1-1
- 12. 11 H NMRH NMR spectrum of azacyclohexanespectrum of azacyclohexane NH usually broad, variable, like OH
- 13. 13 C Chemical Shifts (ppm) N isN is lessless deshielding than Odeshielding than O
- 14. Mass spectrumMass spectrum ofof NN,,NN -diethylethanamine-diethylethanamine Odd molecular weight
- 15. •C : Mass 12 and tetravalent,C : Mass 12 and tetravalent, e.g. CHe.g. CH44, results in, results in eveneven MM++ • N: Mass 14 and trivalent,N: Mass 14 and trivalent, e.g. NHe.g. NH33, results in odd, results in odd MM++ for N = 1,3,5...for N = 1,3,5... • Preferred fragmentationPreferred fragmentation αα––ββ bondbond cleavage (even fragments)cleavage (even fragments)
- 16. Acidity and BasicityAcidity and Basicity Acidity:Acidity:
- 17. • Preparation of Sodium Amide:Preparation of Sodium Amide: • Preparation of LDA:Preparation of LDA: Needs strong base 2Na + 2NH3 2NaNH2 + H2 Catalytic Fe3+
- 18. Basicity:Basicity: KKbb == [RNH[RNH33] [HO ]] [HO ] [RNH[RNH22]] ++ -- ~~ 1010-4-4 Ammonium ion ppKKbb ~ 4~ 4 Recall:Recall: ppKKaa + p+ pKKbb = 14= 14 Thus, pThus, pKKaa of protonated amine ~of protonated amine ~ 1010
- 19. Better (to compare with otherBetter (to compare with other ppKKaa values):values): O H H R + ppKKaa == -3-3
- 20. SynthesisSynthesis 1.1. AlkylationAlkylation of NHof NH33, primary, and, primary, and secondary aminessecondary amines Problem:Problem: • OveralkylationOveralkylation: Even though amine gets more: Even though amine gets more hindered, it also gets more nucleophilichindered, it also gets more nucleophilic One solution is to haveOne solution is to have excessexcess of RNHof RNH22 andand use RX as limiting reagentuse RX as limiting reagent
- 21. 2. Via2. Via nitrilesnitriles 3. Arenamine via3. Arenamine via nitroarenenitroarene 1,3-Benzenediamine1,3-Benzenediamine HNO3,H2SO4 NO2 HNO3,H2SO4 NO2 NO2 H2,Ni CF3CO3H NH2 NH2
- 22. 4.4. GabrielGabriel Synthesis ( RSynthesis ( RXX →→ RNHRNH22)) Solves problem of overalkylation
- 23. 5.5. ReductiveReductive AminationAmination Primary aminePrimary amine Secondary amineSecondary amine Tertiary amineTertiary amine Goes through iminium ion Goes through iminium ion
- 24. Formaldehyde and a secondary amine:Formaldehyde and a secondary amine: Use of formaldehydeUse of formaldehyde effectseffects monomethylationmonomethylation of an amine.of an amine. RedAminRedAmin
- 25. 6. Reduction of6. Reduction of amidesamides RCNHR’RCNHR’ LiAlHLiAlH44 OO RCHRCH22NHR’NHR’ Recall:Recall: 7.7. HofmannHofmann RearrangementRearrangement RCClRCCl OO AmideAmide andand RCNHR’RCNHR’ OO RCNR’’R’RCNR’’R’ OO August Wilhelm von Hofmann 1818-1892
- 26. Reactions of AminesReactions of Amines 1.1. Hofmann EliminationHofmann Elimination Recall:Recall: :::: Oxonium ionOxonium ion Analogous (but attenuated) behavior inAnalogous (but attenuated) behavior in quaternary ammonium ions. Works for E2quaternary ammonium ions. Works for E2 ROH H+ R−OH2 +
- 27. Hofmann eliminations are often used to breakHofmann eliminations are often used to break down larger amines, e.g., alkaloids, into smallerdown larger amines, e.g., alkaloids, into smaller fragments.fragments. Procedure: First, methylate exhaustively to theProcedure: First, methylate exhaustively to the quaternary ammonium salt; second, treat withquaternary ammonium salt; second, treat with base.base.
- 28. Degradation of a simple alkaloidDegradation of a simple alkaloid HH HH
- 29. 2.2. Mannich ReactionMannich Reaction Alkylation of Enols by Iminium Ions The enol is derived from an enolizable ketone/aldehyde and the iminium ion is formed in situ by condensation of a second, more reactive carbonyl component with an amine. The outcome is a β- aminocarbonyl product. Form iminium ionForm iminium ion Form iminium ionForm iminium ion Carl Ulrich Franz Mannich 1877-19471877-1947
- 30. Net:Net: αα–Amino-–Amino- methylation ofmethylation of enolizable alde-enolizable alde- hydehyde MannichMannich
- 31. 3. Reaction with nitrous acid3. Reaction with nitrous acid • Nitrosyl cation: likeNitrosyl cation: like C OC O , but more electrophilic, but more electrophilic (charged) and gets attacked by amines(charged) and gets attacked by amines :::: TertiaryTertiary amineamine (stable)(stable) SecondarySecondary amineamine NN –Nitrosamines are–Nitrosamines are implicated in theimplicated in the carcinogenicity ofcarcinogenicity of cured meatscured meats
- 32. PrimaryPrimary NN -nitrosamines-nitrosamines decomposedecompose R = AlkylR = Alkyl mess, R = Arenemess, R = Arene stable (Chapter 22)stable (Chapter 22)
- 33. 4. Diazomethane CH4. Diazomethane CH22 N NN N Amides are also subject toAmides are also subject to NN -Nitrosation-Nitrosation N-Methyl-N-nitrosourea is a precursor to diazomethane ――――――――
- 34. Step 1: Hydroxide AdditionStep 1: Hydroxide Addition C O NH2H3CN N O OH C O NH2H3CN N O OH :: :::: :::: :: :::: :: :: :: :: :: :: :: :: :: -- :: :: :: -- Mechanism:Mechanism: Step 2: EliminationStep 2: Elimination C O NH2H3CN N O OH CH3N N O C HO NH2 O HOH CH3N NOH OH CO2 HNH2 -- :: :: :::: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :::: :: :::: :: :: :: :::: -- ++ ++ ++
- 35. CH2N NOH OH -H2O H2C N N OH H2C N N H2C N NH Step 3: DehydrationStep 3: Dehydration :: :: :: :: :: :: :::: :::: :: :: :: :: :::: :: :: - OH- OH -- -- -- ++ -- :: Diazomethane has two applications as aDiazomethane has two applications as a reagent: In esterifications and as a source ofreagent: In esterifications and as a source of carbene CHcarbene CH22..
- 36. H2C N NC O OR H C O OR H3C N N N N C O OCH3R • Formation of EstersFormation of Esters • Generation of CarbeneGeneration of Carbene • CyclopropanationCyclopropanation H2C N N ++ -- :: H2C N N C H H ::::++ -- hhνν or Cu oror Cu or ∆∆ :: ++ :: :: -- ++:: :: :: ++ :::: :: :: --