Organic Chemistry

Organic Chemistry

Amines 23-1 Structure & Classification Amines are classified as: 1, 2, or , 3 amines: Amines in which there are 1, 2, or 3 alkyl or aryl groups. : : CH3 -NH2 CH3 -NH CH3 CH3 CH3 -N: CH3 MethylamineDimethylamineTrimethylamine (a 1 amine) (a 2 amine) (a 3 amine) 23-2 Structure & Classification Amines are further divided into aliphatic,

aromatic, and heterocyclic amines: Aliphatic amine: An amine in which nitrogen is bonded only to alkyl groups. Aromatic amine: An amine in which nitrogen is bonded to one or more aryl groups. : CH3 CH2 -N-CH3 : N-H : NH2 CH3 Aniline N-Methylaniline Benzyldimethylamine (a 1 aromatic amine) (a 2 aromatic amine) (a 3 aliphatic amine) 23-3 Structure & Classification Heterocyclic amine: An amine in which nitrogen is one of the atoms of a ring. N

N H H Pyrrolidine Piperidine (heterocyclic aliphatic amines) N N H Pyrrole Pyridine (heterocyclic aromatic amines) 23-4 Nomenclature Aliphatic amines: replace the suffix -e of the parent alkane by -amine. amine NH2 H2 N NH2 2-Propanamine (S)-1-Phenylethanamine NH2

1,6-Hexanediamine 23-5 Nomenclature The IUPAC system retains the name aniline. NH2 NH2 NH2 NH2 OCH3 NO2 CH3 Aniline 4-Nitroaniline4-Methylaniline 3-Methoxyaniline (p-Nitroaniline)(p-Toluidine) (m-Anisidine) 23-6 Nomenclature Among the various functional groups, -NH2 is one of the lowest in order of precedence.

H2 N OH 2-Aminoethanol OH NH2 (S)-2-Amino-3-methyl1-butanol Amine vs alcohol H2 N COOH 4-Aminobenzoic acid Amine vs acid 23-7 Nomenclature Common names for most aliphatic amines are derived by listing the alkyl groups bonded to nitrogen in one word ending with the suffix -amine. amine

CH3 NH2 H NH2 N Et3 N Methylamine tert-Butylamine Dicyclopentylamine Triethylamine 23-8 Nomenclature When four groups are bonded to nitrogen, the compound is named as a salt of the corresponding amine. 1-ethyl-1-methylpiperidinium chloride Cl N N Cl N Cl

tetramethylammonium chloride 1-ethylpyridinium chlride 23-9 Chirality of Amines Consider the unshared pair of electrons on nitrogen as a fourth group, then the arrangement of groups around N is approximately tetrahedral. An amine with three different groups bonded to N is chiral and exists as a pair of enantiomers and, in principle, can be resolved. 23-10 Chirality of Amines In practice, however, they cannot be resolved because they undergo inversion, which converts one enantiomer to the other. 23-11 Chirality of Amines Pyramidal inversion is not possible with quaternary ammonium ions, and their salts can be resolved. ClN Et Me S Enantiomer -

Cl N Et Me R Enantiomer 23-12 Physical Properties Amines are polar compounds, and both 1 and 2 amines form intermolecular hydrogen bonds. N-H- - -N hydrogen bonds are weaker than O-H- - -O hydrogen bonds 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). Using bp as an indication of H bonding CH3 CH3 MW (g/mol) 30.1 bp (C) -88.6 CH3 NH2 CH3 OH 31.1 -6.3 32.0

Increasing strength 65.0 23-13 Basicity All amines are weak bases, and aqueous solutions of amines are basic. H + CH3 -N-H O-H H CH3 -N + H-O-H H Methylamine H Methylammonium hydroxide It is common to discuss their basicity by reference to the acid ionization constant of the conjugate acid. CH3NH3 + CH3 NH2 + H3 O+ + H2 O

+ Ka = [CH3NH2][H3 O ] + [CH3 NH3 ] = 2.29 x 10-11 pKa = 10.64 23-14 Basicity Using values of pKa, we can compare the acidities of amine conjugate acids with other acids. CH3NH2 + CH3 COOH pKa 4.76 (stronger acid) + - CH3NH3 + CH3COO pKa 10.64 (weaker acid) pKeq =-5.88

Keq = 7.6 x 105 23-15 Basicity-Aliphatic Amines Aliphatic Amines note that pKa + pKb = 14 Amine Structure Ammonia NH3 Primary Amines methylamine CH3 NH2 ethylamine CH3 CH2 NH2 cyclohexylamine C6 H1 1 NH2 pKa pKb 9.26 4.74 10.64 3.36 10.81 3.19 10.66 3.34 Stronger bases

Secondary Amines (CH3 ) 2 NH dimethylamine 10.73 3.27 diethylamine (CH3 CH2 ) 2 NH 10.98 3.02 Tertiary Amines trimethylamine 9.81 4.19 (CH3 ) 3 N triethylamine (CH3 CH2 ) 3 N 10.75 3.25 23-16 Basicity-Aromatic Amines Amine Structure pKa of Conjugate Acid Aromatic Amines Aniline 4-Methylaniline 4.63 NH2 NH2 CH3

4-Chloroaniline Cl 4-Nitroaniline O2N NH2 NH2 5.08 Weaker bases 4.15 1.0 Heterocyclic Aromatic Amines Pyridine Imidazole N 5.25 Intermediate N 6.95 N

H 23-17 Basicity-Aromatic Amines Aromatic amines are considerably weaker bases than aliphatic amines. NH2 + H2 O Cyclohexylamine NH2 + H2 O Aniline + - pKa =10.66 - pKa =4.63 NH3 OH Cyclohexylammonium hydroxide + NH3 OH Aniliniumhydroxide

23-18 Basicity-Aromatic Amines Aromatic amines are weaker bases than aliphatic amines because of two factors: Resonance stabilization of the free base, which is lost on protonation. H N H . H . H . H . H+ H N H+H N H unhybridized 2p orbital of N ..

. . N H H +H N H H nitrogen is sp2 hybridized 23-19 Basicity-Aromatic Amines The greater electron-withdrawing inductive effect of the sp2-hybridized carbon of an aromatic amine compared with that of the sp3-hybridized carbon of an aliphatic amine. And note the effect of substituents Electron-releasing groups, such as alkyl groups, increase the basicity of aromatic amines. Electron-withdrawing groups, such as halogens, the nitro group, and a carbonyl group decrease the basicity of aromatic amines by a combination of resonance and inductive effects.

23-20 Example: Basicity-Aromatic Amines 3-nitroaniline is a stronger base than 4-Nitroaniline. O2 N NH2 O2 N 4-Nitroaniline pKa 1.0 delocalization of the nitrogen lone pair onto the oxygen atoms of the nitro group 3-Nitroaniline pKa 2.47 - O +N - O NH2 NH2 O +N

NH2 + -O Cannot do this kind of resonance in 3 nitroaniline 23-21 Basicity-Aromatic Amines Heterocyclic aromatic amines are weaker bases than heterocyclic aliphatic amines. N N H Piperidine pKa 10.75 N Pyridine pKa 5.25 N H Imidazole pKa 6.95 23-22

Basicity-Aromatic Amines In pyridine, the unshared pair of electrons on N is not part of the aromatic sextet. . H . . H H . . H . N H : an sp2 hybrid orbital; the electron pair in this orbital is not a part of the aromatic sextet nitrogen is sp2 hybridized Pyridine is a weaker base than heterocyclic aliphatic

amines because the free electron pair on N lies in an sp2 hybrid orbital (33% s character) and is held more tightly to the nucleus than the free electron pair on N in an sp3 hybrid orbital (25% s character). 23-23 Basicity-Aromatic Amines Imidazole Which N lone pair is protonated? The one which is not part of the aromatic system. This electron pair Aromaticity is is not a part of the maintained when aromatic sextet imidazole is protonated : : : This electron N + H2 O pair is a part of the aromatic N sextet H Imidazole H N+

+ OH- N H Imidazolium ion 23-24 Basicity-Guanidine Guanidine is the strongest base among neutral organic compounds. NH H2 N C NH2 Guanidine + NH2 + H2 O H2 N C NH2 - + OH

Guanidinium ion pKa =13.6 Its basicity is due to the delocalization of the positive charge over the three nitrogen atoms. H2 N C NH2 NH2 : NH2 NH2 : C : : H2 N +

: NH2 : + H2 N C + NH2 Three equivalent contributing structures 23-25 Reaction with Acids All amines, whether soluble or insoluble in water, react quantitatively with strong acids to form water-soluble salts. OH HO OH NH2

+ HCl HO (R)-Norepinephrine (only slightly soluble in water) H2 O HO NH3 + Cl- HO (R)-Norepinephrine hydrochloride (a water-soluble salt) 23-26 Reaction with acids Separation and purification of an amine and a neutral compound. 23-27 Preparation We have already covered these methods nucleophilic ring opening of epoxides by ammonia and amines.

addition of nitrogen nucleophiles to aldehydes and ketones to form imines reduction of imines to amines reduction of amides to amines by LiAlH4 reduction of nitriles to a 1 amine nitration of arenes followed by reduction of the NO 2 group to a 1 amine 23-28 Preparation Alkylation of ammonia and amines by SN2 substitution. SN2 + NH CH3 Br 3 CH3 NH3 + BrMethylammonium bromide Unfortunately, such alkylations give mixtures of products through a series of proton transfer and nucleophilic substitution reactions. CH3Br + NH3 + -

+ - + - + - CH3NH3 Br + (CH3) 2NH2 Br + (CH3) 3NH Br + (CH3) 4N Br polyalkylations 23-29 Preparation via Azides Alkylation of azide ion. + Ph CH2 Cl Benzyl chloride - R :

RN3 Azide ion (a good nucleophile) K N3 + N N N: - : + N N N: : -: : N3 - An alkyl azide 1. LiAlH4 Ph CH2 N3 2. H2O Benzyl azide

Ph CH2 NH2 Benzylamine Overall Alkyl Halide Alkyl amine 23-30 Example: Preparation via Azides Alkylation of azide ion. ArCO3 H Cyclohexene + O 1. K N3 - 2. H2 O 1,2-Epoxycyclohexane OH 1. LiAlH4 2. H2 O N3 trans2-Azidocyclohexanol (racemic)

OH NH2 trans2-Aminocyclohexanol (racemic) Note retention of configuration, trans trans 23-31 Reaction with HNO2 Nitrous acid, a weak acid, is most commonly prepared by treating NaNO2 with aqueous H2SO4 or HCl. HNO2 + H2O H3O+ + NO2 - pKa =3.37 In its reactions with amines, nitrous acid: Participates in proton-transfer reactions. A source of the nitrosyl cation, NO+, a weak electrophile. 23-32 Reaction with HNO2

NO+ is formed in the following way. Step 1: Protonation of HONO. Step 2: Loss of H2O. + H + H O N O (1) + H O N O (2) H + H O + N O H + N O The nitrosyl cation We study the reactions of HNO2 with 1, 2, and 3 aliphatic and aromatic amines. 23-33

Tertiary Amines with HNO2 3 Aliphatic amines, whether water-soluble or waterinsoluble, are protonated to form water-soluble salts. 3 Aromatic amines: NO+ is a weak electrophile and participates in Electrophilic Aromatic Substitution. Me2 N 1. NaNO2 , HCl, 0-5C 2. NaOH, H2O N,N-Dimethylaniline Me2 N N=O N,N-Dimethyl-4-nitrosoaniline 23-34 Secondary Amines with HNO2 2 Aliphatic and aromatic amines react with NO+ to give N-nitrosamines. carcinogens N-N=O + H2 O N-H + HNO2 N-Nitrosopiperidine Piperidine

Mechanism: N (1) N=O N=O N H + + H O H H

H O H + N (2) H + + N O 23-35

RNH2 with HNO2 1 aliphatic amines give a mixture of unrearranged and rearranged substitution and elimination products, all of which are produced by way of a diazonium ion and its loss of N2 to give a carbocation. Diazonium ion: An RN2+ or ArN2+ ion 23-36 1 RNH2 with HNO2 Formation of a diazonium ion. Step 1: Reaction of a 1 amine with the nitrosyl cation. keto-enol tautomerism R-N=N-O-H A diazotic acid An N-nitrosamine : : : : +

R-NH 2 + :N O : A 1 aliphatic amine : : : : H R-N-N=O : : Step 2: Protonation followed by loss of water. : : : : + H R-N=N-O-H A diazotic acid H + -H2 O R-N N O-H + N N

A diazonium ionA carbocation + R R + N N 23-37 1 RNH2 with HNO2 (Aliphatic) Aliphatic diazonium ions are unstable and lose N2 to give a carbocation which may: 1. Lose a proton to give an alkene. 2. React with a nucleophile to give a substitution product. 3. Rearrange and then react by Steps 1 and/or 2. Cl (5.2%)

NH2 NaNO2 , HCl 0-5oC OH + (25%) (13.2%) (25.9%) OH + (10.6%) 23-38 1 RNH2 with HNO2 Tiffeneau-Demjanov reaction: Treatment of a aminoalcohol with HNO2 gives a ketone and N2. OH CH2 NH2 + HNO2 A-aminoalcohol O + H2 O + N2 Cycloheptanone

23-39 Mechanism of Tiffeneau-Demjanov Reaction with NO+ gives a diazonium ion. Concerted loss of N2 and rearrangement followed by proton transfer gives the ketone. : : : OH CH2NH2 HNO 2 :O-H CH2 + N N: -N2 (A diazonium ion) + O H + CH2 CH2

proton transfer to2H O A resonance-stabilized cation : : : :O H O Cycloheptanone Similar to pinacol rearrangement 23-40 1 Primary Amines with HNO2 (Aromatic) The -N2+ group of an arenediazonium salt can be replaced in a regioselective manner by these groups. H2O Ar-NH2

HNO2 0-5C Ar-N2 + (-N2) Ar-OH HBF4 Ar-F HCl, CuCl Ar-Cl HBr, CuBr Ar-Br KCN, CuCN Ar-CN KI Ar-I H3PO2 Ar-H Schiemann reaction Sandmeyer reaction

23-41 1 ArNH2 with HNO2 A 1 aromatic amine converted to a phenol. NH2 OH Br Br 1. HNO2 2. H2O, heat CH3 2-Bromo-4methylaniline CH3 2-Bromo-4methylphenol 23-42 1 ArNH2 with HNO2 Problem: What reagents and experimental conditions will bring about this conversion? CH3 CH3 (1)

COOH (2) NO2 COOH (3) NO2 COOH (4) NH2 OH 23-43 1 ArNH2 with HNO2 Problem: Show how to bring about each conversion. CH3 Cl (5) CH3 CH3

NH2 (6) (8) Cl C N CH3 CH3 (7) NH2 Cl CH2 NH2 CH3 (9) Cl Cl 23-44

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