Organic Lecture Series AminesAmines Epinephrine (adrenaline) Chapter 23 1 Organic Lecture Series Structure & Classification • Amines are classified as – 1°, 2°, or , 3° amines: amines in which 1, 2, or 3 hydrogens of NH3 are replaced by alkyl or aryl groups 2 o o 2 Structure & ClassificationOrganic Lecture Series • 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 CH CH : 3 3 NH 2 N-H: CH2 -N-CH: 3 Aniline N-Methylaniline Benzyldimethylamine (a 1° aromatic amine) (a 2° aromatic amine) (a 3° aliphatic amine) 3 Organic Lecture Series Structure & Classification – heterocyclic amine: an amine in which nitrogen is one of the atoms of a ring N N N N H H H PyrrolidinePiperidine Pyrrole Pyridine (heterocyclic aliphatic amines) (heterocyclic aromatic amines) 4 Organic Lecture Series Structure & Classification CH3 N H H COOCH3 (a) (b) N (c) N CH OCH H N 3 6 5 (S)-Coniine (S)-Nicotine Co cain e O Coniine is a poisonous alkaloid found in poison hemlock and the Yellow Pitcher Plant, and contributes to hemlock's fetid smell. It is a neurotoxin which disrupts the peripheral nervous system. Caffeine 5 Organic Lecture Series Nomenclature • Aliphatic amines: replace the suffix -eofe the parent alkane by -amine NH2 NH2 H2 N NH2 2-Propanamine (S)-1-Phenyl- 1,6-Hexanediamine ethanamine 6 Organic Lecture Series Nomenclature • The IUPAC system retains the name aniline: NH2 NH2 NH2 NH2 OCH3 NO2 CH3 Aniline 4-Nitroaniline 4-Methylaniline 3-Methoxyaniline (p-Nitroaniline) (p-Toluidine) (m-Anisidine) 7 Organic Lecture Series Nomenclature • Among the various functional groups discussed in the text, -NH2 is one of the lowest in order of precedence OH OH H2 N H2 N COOH NH2 2-Aminoethanol (S)-2-Amino-3-methyl- 4-Aminobenzoic acid 1-butanol 8 Organic Lecture Series 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 H CH NH 3 2 NH2 N Et 3 N Methylamine tert-Butylamine Dicyclopentylamine Triethylamine 9 Organic Lecture Series Nomenclature • When four groups are bonded to nitrogen, the compound is named as a salt of the corresponding amine - Cl + - + Me 4 N Cl NCH2 (CH2 )12CH3 - Ph CH2 NMe3 OH Tetramethy Tetradecylpyridinium chloride Benzyltrimethyl- ammonium (Cetylp yridin ium chloride) ammonium chloride hydroxide 10 Organic Lecture Series 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) CH 3 CH 3 CH 3 NH 2 CH 3 OH MW (g/mol) 30.1 31.1 32.0 bp (°C)-88.6 -6.3 65.0 11 Organic Lecture Series Basicity • All amines are weak bases, and aqueous solutions of amines are basic H H + - CH 3 -N + H- O- H CH 3 -N-H O-H H H Methylamine Methylammonium hydroxide 12 Organic Lecture Series Basicity – it is common to discuss their basicity by reference to the acid ionization constant of the conjugate acid: + + CH 3 NH3 + H2 O CH3 NH2 + H3 O + [CH NH ][H O ] 3 2 3 -1 1 Ka = + = 2.29 x 10 pKa = 10.64 [CH3 NH3 ] 13 Organic Lecture Series Basicity – using values of pKa, comparisons of the acidities of amine conjugate acids with other acids can be made: + - CH 3 NH2 + CH3 COOH CH3 NH3 + CH 3 COO pKeq = -5.88 5 pKa 4.76 pKa 10.64 Keq = 7.6 x 10 (stronger (weaker acid) acid) : + + R—NH2 + H RNH3 conjugate acid 14 Basicity-Aliphatic Amines Organic Lecture Series Amine Structure pKa pKb Ammonia NH3 9.26 4.74 Primary Amines methylamine CH3 NH2 10.64 3.36 ethylamine CH3 CH2 NH2 10.81 3.19 cyclohexy lam ine C6 H11NH2 10.66 3.34 Secondary A min es dimethylamine (CH3 ) 2 NH 10.73 3.27 diethylamine (CH3 CH2 )2 NH 10.98 3.02 Tertiary Amines trimethylamine (CH3 ) 3 N 9.81 4.19 triethylamine (CH3 CH2 )3 N 10.75 3.25 : + + R—NH2 + H RNH3 conjugate acid 15 Organic Lecture Series Basicity-Aromatic Amines Amine Structure pKa of Conjugate Acid Aromatic Amines Aniline NH2 4.63 4-Methylaniline Note the effect of CH NH 5.08 3 2 Ar-X on the acidity: 4-Chloroaniline Cl NH2 4.15 The stronger the - 4-Nitroaniline O2 N NH2 1.0 e withdrawing effect, the weaker Heterocyclic Aromatic Amines the base & Pyrid ine N 5.25 stronger the conj N acid. Im idazo le 6.95 N H 16 Organic Lecture Series Basicity-Aromatic Amines – aromatic amines are considerably weaker bases than aliphatic amines + - NH2 + H2 O NH3 OH pKa = 10.66 Cyclohexylamine Cyclohexylammonium hydroxide + - NH2 + H2 O NH3 OH pKa = 4.63 Aniline Anilinium hydroxide 17 Organic Lecture Series 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 HH+ H + H H + H NNNHN . H . H unhybridized 2p orbital of N . .. H H . N H nitrogen is sp2 hybridized H H 18 Organic Lecture Series Basicity-Aromatic Amines – the greater electron-withdrawing inductive effect of the sp2-hybridized carbon of an aromatic amine compared with the sp3- hybridized carbon of an aliphatic amine also decreases basicity • Electron-releasing, 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 19 Organic Lecture Series Basicity-Aromatic Amines 4-nitroaniline is a weaker base than 3-nitroaniline O2 N NH2 O2 N NH2 3-Nitroaniline 4-Nitroaniline pKa 2.47 pKa 1.0 delocalization of the nitrogen lone pair onto the oxygen atoms of the nitro group - O O + + NNH2 + N NH2 O - - O 20 Organic Lecture Series Basicity-Aromatic Amines • Heterocyclic aromatic amines are weaker bases than heterocyclic aliphatic amines N N N N H H PiperidinePyridine Imidazole pK 6.95 pKa 10.75 pKa 5.25 a 21 Basicity-Aromatic Amines Organic Lecture Series – in pyridine, the unshared pair of electrons on N is not part of the aromatic sextet . an sp2 hybrid orbital; the electron H H . pair in this orbital is not a part of the aromatic sextet H . N : 2 H H nitrogen is sp 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) 22 Organic Lecture Series Reaction with Acids • All amines, whether soluble or insoluble in water, react quantitatively with strong acids to form water-soluble salts OH OH HO NH HO NH + Cl- 2 H O 3 + HCl 2 HO HO (R)-Norepinephrine (R)-Norepinephrine hydrochloride (only slightly soluble in water) (a water-soluble salt) 23 Organic Lecture Series Preparation • A summary of synthetic methods: – nucleophilic ring opening of epoxides by ammonia and amines (11.9B) – addition of nitrogen nucleophiles to aldehydes and ketones to form imines (Section 16.8) – reduction of imines to amines (16.8A) – reduction of amides by LiAlH4 (18.10B) – reduction of nitriles to a 1° amine (18.10C) – nitration of arenes followed by reduction of the NO2 group to 1° amines (22.1B) 24 Preparation Organic Lecture Series • Alkylation of ammonia and amines by SN2 SN2 + - CH3 Br + NH3 CH3 NH3 Br Methylammonium bromide – unfortunately, such alkylations give mixtures of products through a series of proton transfer and nucleophilic substitution reactions CH3 Br+ NH3 + - + - + - + - CH 3 NH3 Br +++(CH3 ) 2 NH2 Br (CH3 ) 3 NH Br (CH3 ) 4 N Br These arise from N-polyalkylation 25 Organic Lecture Series Preparation via Azides - • Alkylation of azide ion, N3 : : - - : ++: - - N 3 ::NNNN: RN 3 R NN Azide ion An alkyl azide (a good nucleophile) + - K N3 1. LiAlH4 Ph CH 2 Cl Ph CH2 N3 Ph CH2 NH2 2. H O Benzyl ch loride Ben zyl azid e2 Benzylamin e 26 Organic Lecture Series Preparation via Azides – alkylation of azide ion + ArCO H 1. K N - 3 O 3 2. H2 O Cy clo hexen e 1,2-Epoxy- cyclohexane (chiral) OH OH 1. LiAlH4 2. H2 O N3 NH2 trans-2-Azido- trans-2-Amino- cyclohexan ol cyclohexanol (racemic) (racemic) 27 Organic Lecture Series Reaction with HNO2 • Nitrous acid, a weak acid, is most commonly prepared by treating NaNO2 with aqueous H2SO4 or HCl HNO + H OHO+ - 2 2 3 + NO2 pKa = 3.37 • In its reactions with amines, nitrous acid – participates in proton-transfer reactions – is a source of the nitrosyl cation, NO+, a weak electrophile 28 Organic Lecture Series Reaction with HNO2 • NO+ is formed in the following way: (1) + (2) H OON + H+ HNOO H + + H O + NO NO H The nitrosyl cation – Focus upon reactions of HNO2 with 1° aliphatic and aromatic amines 29 Organic Lecture Series 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 30 Organic Lecture Series 1° RNH2 with HNO2 • Formation of a diazonium ion Step 1: reaction of a 1° amine with the nitrosyl cation keto-enol H : : : : + : : : tautomerism : : : : : R-NH2 + NR-N-N=OO R-N=N-O-H A 1° aliphatic An N-nitrosamine A diazotic acid amine Step 2: protonation followed by loss of water H + : : : H •• •• + -H2 O R-N=N-O-H: R-N N O- H •• A diazotic acid + • • + • • • R NN R + NN A diazonium ion A carbo- cation 31 NOT responsible for mechanism Organic Lecture Series 1° RNH2 with HNO2 • Aliphatic diazonium ions are unstable and lose N2 to give a carbocation which may 1.