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1、22.7Reactions of Amines:A Review and a Preview,Preparation of Amines,Two questions to answer: 1) How is the CN bond to be formed? 2) How do we obtain the correct oxidation state of nitrogen (and carbon)?,Methods for CN Bond Formation,Nucleophilic substitution by azide ion (N3) (Section 8.1, 8.13) Ni
2、tration of arenes (Section 12.3) Nucleophilic ring opening of epoxides by ammonia (Section 16.12) Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11) Nucleophilic substitution by ammonia on a-halo acids (Section 19.16) Nucleophilic acyl substitution (Sections 20.3, 20.5,
3、 and 20.11) Hofmann rearrangement (Section 20.17),22.8Preparation of Aminesby Alkylation of Ammonia,Alkylation of Ammonia,Desired reaction is:,2 NH3,+,RX,RNH2,+,NH4X,Alkylation of Ammonia,Desired reaction is:,2 NH3,+,RX,RNH2,+,NH4X,via:,+,+,then:,+,+,Alkylation of Ammonia,But the method doesnt work
4、well in practice.Usually gives a mixture of primary, secondary,and tertiary amines, plus the quaternary salt.,NH3,RX,RNH2,RX,R2NH,RX,R3N,RX,Example,CH3(CH2)6CH2Br,NH3,CH3(CH2)6CH2NH2,As octylamine is formed, it competes with ammonia for the remaining 1-bromooctane. Reaction of octylamine with 1-brom
5、ooctane gives N,N-dioctylamine.,Example,CH3(CH2)6CH2Br,NH3,CH3(CH2)6CH2NH2,(45%),+,CH3(CH2)6CH2NHCH2(CH2)6CH3,(43%),As octylamine is formed, it competes with ammonia for the remaining 1-bromooctane. Reaction of octylamine with 1-bromooctane gives N,N-dioctylamine.,22.9The Gabriel Synthesis of Primar
6、y Alkylamines,gives primary amines without formation ofsecondary, etc. amines as byproducts uses an SN2 reaction on an alkyl halide to formthe CN bond the nitrogen-containing nucleophileis N-potassiophthalimide,Gabriel Synthesis,gives primary amines without formation ofsecondary, etc. amines as bypr
7、oducts uses an SN2 reaction on an alkyl halide to formthe CN bond the nitrogen-containing nucleophileis N-potassiophthalimide,Gabriel Synthesis,the pKa of phthalimide is 8.3 N-potassiophthalimide is easily prepared bythe reaction of phthalimide with KOH,N-Potassiophthalimide,O,O,KOH,N-Potassiophthal
8、imide as a nucleophile,O,O,N,+,SN2,Cleavage of Alkylated Phthalimide,+,acid or base,imide hydrolysis is nucleophilic acyl substitution,Cleavage of Alkylated Phthalimide,hydrazinolysis is an alternative method of releasing the amine from its phthalimide derivative,+,Example,+,C6H5CH2Cl,DMF,Example,+,
9、C6H5CH2Cl,DMF,(74%),Example,+,C6H5CH2NH2,H2NNH2,(97%),22.10Preparation of Amines by Reduction,almost any nitrogen-containing compound canbe reduced to an amine, including: azidesnitrilesnitro-substituted benzene derivativesamides,Preparation of Amines by Reduction,SN2 reaction, followed by reduction
10、, gives a primary alkylamine.,Synthesis of Amines via Azides,NaN3,(74%),(89%),1. LiAlH4,2. H2O,SN2 reaction, followed by reduction, gives a primary alkylamine.,Synthesis of Amines via Azides,NaN3,(74%),(89%),1. LiAlH4,2. H2O,azides may also bereduced by catalytichydrogenation,SN2 reaction, followed
11、by reduction, gives a primary alkylamine.,Synthesis of Amines via Nitriles,CH3CH2CH2CH2Br,NaCN,(69%),CH3CH2CH2CH2CH2NH2,(56%),CH3CH2CH2CH2CN,H2 (100 atm), Ni,SN2 reaction, followed by reduction, gives a primary alkylamine.,Synthesis of Amines via Nitriles,CH3CH2CH2CH2Br,NaCN,(69%),CH3CH2CH2CH2CH2NH2
12、,(56%),CH3CH2CH2CH2CN,H2 (100 atm), Ni,nitriles may also bereduced by lithiumaluminum hydride,SN2 reaction, followed by reduction, gives a primary alkylamine.,Synthesis of Amines via Nitriles,CH3CH2CH2CH2Br,NaCN,(69%),CH3CH2CH2CH2CH2NH2,(56%),CH3CH2CH2CH2CN,H2 (100 atm), Ni,the reduction alsoworks w
13、ith cyanohydrins,Synthesis of Amines via Nitroarenes,HNO3,(88-95%),(95%),1. Fe, HCl,2. NaOH,Cl,H2SO4,Synthesis of Amines via Nitroarenes,HNO3,(88-95%),(95%),1. Fe, HCl,2. NaOH,Cl,H2SO4,nitro groups may alsobe reduced with tin (Sn)+ HCl or by catalytichydrogenation,Synthesis of Amines via Amides,(86-
14、89%),(88%),1. LiAlH4,2. H2O,1. SOCl2,2. (CH3)2NH,CH2N(CH3)2,Synthesis of Amines via Amides,(86-89%),(88%),1. LiAlH4,2. H2O,1. SOCl2,2. (CH3)2NH,CH2N(CH3)2,only LiAlH4 is anappropriate reducingagent for this reaction,22.11Reductive Amination,The aldehyde or ketone equilibrates with theimine faster th
15、an hydrogenation occurs.,Synthesis of Amines via Reductive Amination,+,NH3,fast,+,H2O,In reductive amination, an aldehyde or ketoneis subjected to catalytic hydrogenation in thepresence of ammonia or an amine.,Synthesis of Amines via Reductive Amination,H2, Ni,+,NH3,fast,+,H2O,The imine undergoes hy
16、drogenation fasterthan the aldehyde or ketone. An amine is the product.,Example: Ammonia gives a primary amine.,+,NH3,H2, Ni,ethanol,(80%),via:,Example: Primary amines give secondary amines,H2, Ni,ethanol,(65%),Example: Primary amines give secondary amines,H2, Ni,ethanol,(65%),via:,Example: Secondary amines give tertiary amines,H2, Ni, ethanol,(93%),+,Example: Secondary amines give tertiary amines,possible intermediates include:,
