22.7 Reactions of Amines: A Review and a Preview 3

Two questions to answer: 1) How is the C—N bond to be formed? Preparation of Amines Two questions to answer: 1) How is the C—N bond to be formed? 2) How do we obtain the correct oxidation state of nitrogen (and carbon)? 6

Methods for C—N Bond Formation Nucleophilic substitution by azide ion (N3–) (Section 8.1, 8.13) Nitration 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, and 20.11) Hofmann rearrangement (Section 20.17) 6

22.8 Preparation of Amines by Alkylation of Ammonia 3

Alkylation of Ammonia Desired reaction is: 2 NH3 + R—X R—NH2 + NH4X 3

Alkylation of Ammonia Desired reaction is: 2 NH3 + R—X R—NH2 + NH4X via: •• • • R X H3N R + •• • • X – H3N • • + + H N R + N H R • • then: H3N H + + H3N • • + 3

Alkylation of Ammonia But the method doesn't work well in practice. Usually gives a mixture of primary, secondary, and tertiary amines, plus the quaternary salt. RX RX NH3 RNH2 R2NH RX RX R4N + X – R3N 3

Example NH3 CH3(CH2)6CH2Br CH3(CH2)6CH2NH2 As octylamine is formed, it competes with ammonia for the remaining 1-bromooctane. Reaction of octylamine with 1-bromooctane gives N,N-dioctylamine. 4

Example NH3 CH3(CH2)6CH2Br 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. 4

22.9 The Gabriel Synthesis of Primary Alkylamines 3

uses an SN2 reaction on an alkyl halide to form the C—N bond Gabriel Synthesis gives primary amines without formation of secondary, etc. amines as byproducts uses an SN2 reaction on an alkyl halide to form the C—N bond the nitrogen-containing nucleophile is N-potassiophthalimide 6

uses an SN2 reaction on an alkyl halide to form the C—N bond Gabriel Synthesis gives primary amines without formation of secondary, etc. amines as byproducts uses an SN2 reaction on an alkyl halide to form the C—N bond the nitrogen-containing nucleophile is N-potassiophthalimide O N • • – K + 6

N-Potassiophthalimide the pKa of phthalimide is 8.3 N-potassiophthalimide is easily prepared by the reaction of phthalimide with KOH O O N • • – K + NH KOH • • O 7

N-Potassiophthalimide as a nucleophile R • • SN2 – •• • • R X N + • • • • O + •• • • X – 7

Cleavage of Alkylated Phthalimide N R • • + H2O imide hydrolysis is nucleophilic acyl substitution acid or base CO2H + H2N R 7

Cleavage of Alkylated Phthalimide hydrazinolysis is an alternative method of releasing the amine from its phthalimide derivative O N R • • O NH H2NNH2 + H2N R 7

Example O N • • – K + + C6H5CH2Cl DMF 4

Example O N • • – K + + C6H5CH2Cl DMF O N CH2C6H5 • • (74%) 4

Example O NH + C6H5CH2NH2 (97%) H2NNH2 O N CH2C6H5 • • 4

22.10 Preparation of Amines by Reduction 3

Preparation of Amines by Reduction almost any nitrogen-containing compound can be reduced to an amine, including: azides nitriles nitro-substituted benzene derivatives amides 6

Synthesis of Amines via Azides SN2 reaction, followed by reduction, gives a primary alkylamine. CH2CH2Br NaN3 CH2CH2N3 (74%) 1. LiAlH4 2. H2O CH2CH2NH2 (89%) 12

Synthesis of Amines via Azides SN2 reaction, followed by reduction, gives a primary alkylamine. CH2CH2Br NaN3 CH2CH2N3 (74%) azides may also be reduced by catalytic hydrogenation 1. LiAlH4 2. H2O CH2CH2NH2 (89%) 12

Synthesis of Amines via Nitriles SN2 reaction, followed by reduction, gives a primary alkylamine. NaCN CH3CH2CH2CH2Br CH3CH2CH2CH2CN (69%) H2 (100 atm), Ni CH3CH2CH2CH2CH2NH2 (56%) 12

Synthesis of Amines via Nitriles SN2 reaction, followed by reduction, gives a primary alkylamine. NaCN CH3CH2CH2CH2Br CH3CH2CH2CH2CN (69%) nitriles may also be reduced by lithium aluminum hydride H2 (100 atm), Ni CH3CH2CH2CH2CH2NH2 (56%) 12

Synthesis of Amines via Nitriles SN2 reaction, followed by reduction, gives a primary alkylamine. NaCN CH3CH2CH2CH2Br CH3CH2CH2CH2CN (69%) the reduction also works with cyanohydrins H2 (100 atm), Ni CH3CH2CH2CH2CH2NH2 (56%) 12

Synthesis of Amines via Nitroarenes Cl NO2 HNO3 Cl H2SO4 (88-95%) 1. Fe, HCl 2. NaOH Cl NH2 (95%) 12

Synthesis of Amines via Nitroarenes Cl NO2 HNO3 Cl H2SO4 nitro groups may also be reduced with tin (Sn) + HCl or by catalytic hydrogenation (88-95%) 1. Fe, HCl 2. NaOH Cl NH2 (95%) 12

Synthesis of Amines via Amides COH O CN(CH3)2 O 1. SOCl2 2. (CH3)2NH (86-89%) 1. LiAlH4 2. H2O CH2N(CH3)2 (88%) 12

Synthesis of Amines via Amides COH O CN(CH3)2 O 1. SOCl2 2. (CH3)2NH (86-89%) only LiAlH4 is an appropriate reducing agent for this reaction 1. LiAlH4 2. H2O CH2N(CH3)2 (88%) 12

22.11 Reductive Amination 3

Synthesis of Amines via Reductive Amination In reductive amination, an aldehyde or ketone is subjected to catalytic hydrogenation in the presence of ammonia or an amine. O C R R' fast NH C R R' + NH3 + H2O The aldehyde or ketone equilibrates with the imine faster than hydrogenation occurs. 12

Synthesis of Amines via Reductive Amination The imine undergoes hydrogenation faster than the aldehyde or ketone. An amine is the product. O C R R' fast NH C R R' + NH3 + H2O NH2 R R' C H H2, Ni 12

Example: Ammonia gives a primary amine. H2, Ni O H NH2 + NH3 ethanol (80%) NH via: 18

Example: Primary amines give secondary amines CH3(CH2)5CH O + H2N H2, Ni ethanol CH3(CH2)5CH2NH (65%) 18

Example: Primary amines give secondary amines CH3(CH2)5CH O + H2N H2, Ni ethanol CH3(CH2)5CH2NH (65%) N CH3(CH2)5CH via: 18

Example: Secondary amines give tertiary amines H CH3CH2CH2CH O + H2, Ni, ethanol N CH2CH2CH2CH3 (93%) 18

Example: Secondary amines give tertiary amines possible intermediates include: CHCH2CH2CH3 N HO CHCH2CH2CH3 N + N CH CHCH2CH3 18