Organic

1

• Organic
• Chemistry

William H. Brown Christopher S. Foote
2

• Amines

Chapter 22
3
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

4
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

5
Structure Classification

• heterocyclic amine an amine in which nitrogen is
  one of the atoms of a ring

6
Structure Classification

• Example classify each amino group by type

7
Structure Classification

• Aliphatic amines replace the suffix -e of the
  parent alkane by -amine

8
Nomenclature

• The IUPAC system retains the name aniline

9
Nomenclature

• Among the various functional groups discussed in
  the text, -NH2 is one of the lowest in order of
  precedence

10
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

11
Nomenclature

• When four groups are bonded to nitrogen, the
  compound is named as a salt of the corresponding
  amine

12
Chirality of Amines

• if we 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 3 different groups bonded to N is
  chiral and exists as a pair of enantiomers and,
  in principle, can be resolved

13
Chirality of Amines

• in practice, however, they cannot be resolved
  because they undergo pyramidal inversion, which
  converts one enantiomer to the other

14
Chirality of Amines

• pyramidal inversion is not possible with
  quaternary ammonium ions, and their salts can be
  resolved

15
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)

16
NMR Spectroscopy

• 1H-NMR
• the chemical shift of amine hydrogens is
  variable, and may be found in the region ? 0.5 to
  5.0 depending on the solvent, concentration, and
  temperature
• they generally appear as singlets
• 13C-NMR
• carbons bonded to nitrogen are generally shifted
  approximately 20 ppm downfield relative to their
  signal in an alkane of comparable structure

17
IR Spectroscopy

• 1 and 2 amines show N-H stretching absorption
  in the region 3300 - 3500 cm-1
• 1 amines show two bands in this region
• 2 amines show only one band in this region

18
Basicity

• All amines are weak bases, and aqueous solutions
  of amines are basic

19
Basicity

• it is more common to discuss the basicity of
  amines by reference to the acid ionization
  constant of the corresponding conjugate acid
• for any acid-conjugate base pair

20
Basicity

• using values of pKa, we can compare the acidities
  of amine conjugate acids with other acids

21
Basicity-Aliphatic Amines

• Aliphatic Amines

22
Basicity-Aromatic Amines

• Aromatic amines

23
Basicity-Aromatic Amines

• aromatic amines are considerably weaker bases
  than aliphatic amines

24
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

25
Basicity-Aromatic Amines

• resonance delocalization of the electron pair on
  nitrogen by interaction with the pi system of the
  aromatic ring decreases basicity

26
Basicity-Aromatic Amines

• the greater electron-withdrawing inductive effect
  of the sp2 carbon of an aromatic amine compared
  with the sp3 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

27
Basicity-Aromatic Amines

• 4-nitroaniline is a weaker base than
  3-nitroaniline

28
Basicity-Aromatic Amines

• Heterocyclic aromatic amines are weaker bases
  than heterocyclic aliphatic amines

29
Basicity-Aromatic Amines

• in pyridine, the unshared pair of electrons on N
  is not part of the aromatic sextet
• 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)

30
Basicity-Aromatic Amines

• Imidazole

31
Basicity-Guanidine

• Guanidine is the strongest base among neutral
  organic compounds
• its basicity is due to the delocalization of the
  positive charge over the three nitrogen atoms

32
Reaction with Acids

• All amines, whether soluble or insoluble in
  water, react quantitatively with strong acids to
  form water-soluble salts

33
Preparation

• We have already covered these methods
• nucleophilic ring opening of an epoxide by
  ammonia and amines (11.9B)
• addition of ammonia and 1 and 2 amines to
  aldehydes and ketones to give an imine followed
  by reduction of the imine to an amine (16.10)
• reduction of an amide by LiAlH4 (18.11B)
• reduction of a nitrile to a 1 amine (18.11C)
• Hofmann rearrangement of a 1 amide (18.12)
• nitration of an arene followed by reduction of
  the NO2 group to a 1 amine (21.1B)

34
Preparation

• Alkylation of ammonia and amines by SN2
• unfortunately, such alkylations give mixtures of
  products through a series of proton transfer and
  nucleophilic substitution reactions

35
Preparation via Azides

• Alkylation of azide ion

36
Preparation via Azides

• alkylation of azide ion

37
Reaction with HNO2

• Nitrous acid is a weak acid, most commonly
  prepared by treating aqueous NaNO2 aqueous H2SO4
  or HCl
• In its reactions with amines, it
• participates in proton-transfer reactions
• is a source of the nitrosyl cation, NO, a weak
  electrophile

38
Reaction with HNO2

• NO is formed in the following way
• we study the reactions of HNO2 with 1, 2, and
  3 aliphatic and aromatic amines

39
Amines with HNO2

• 3 aliphatic amines, whether water-soluble or
  water-insoluble, are protonated to form
  water-soluble salts
• 3 aromatic amines NO is a weak electrophile
  and, as such, participates in EAS
• 2 aliphatic and aromatic amines react with NO
  to give N-nitrosoamines

40
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

41
1 RNH2 with HNO2

• Formation of a diazonium ion
• Step 1 reaction of a 1 amine with the nitrosyl
  cation
• Step 2 protonation followed by loss of water

42
1 RNH2 with HNO2

• 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 1 and/or 2

43
1 RNH2 with HNO2

• Tiffeneau-Demjanov reaction treatment of a
  ?-aminoalcohol with HNO2 gives a ketone and N2

44
1 RNH2 with HNO2

• reaction with NO gives a diazonium ion
• concerted loss of N2 and rearrangement followed
  by proton transfer gives the ketone

45
1 ArNH2 with HNO2

• The -N2 group of an arenediazonium salt can be
  replaced in a regioselective manner by these
  groups

46
1 ArNH2 with HNO2

• A 1 aromatic amine can be converted to a phenol

47
1 ArNH2 with HNO2

• Problem what reagents and experimental
  conditions will bring about this conversion?

48
1 ArNH2 with HNO2

• Problem Show how to bring about each conversion

49
Hofmann Elimination

• Hofmann elimination thermal decomposition of a
  quaternary ammonium hydroxide to give an alkene
• Step 1 formation of a 4 ammonium hydroxide

50
Hofmann Elimination

• Step 2 thermal decomposition of the 4 ammonium
  hydroxide

51
Hofmann Elimination

• Hofmann elimination is regioselective - the major
  product is the least substituted alkene
• Hofmanns rule any ?-elimination that occurs
  preferentially to give the least substituted
  alkene as the major product is said to follow
  Hofmanns rule

52
Hofmann Elimination

• the regioselectivity of Hofmann elimination is
  determined largely by steric factors, namely the
  bulk of the -NR3 group
• hydroxide ion preferentially approaches and
  removes the least hindered hydrogen and, thus,
  gives the least substituted alkene
• bulky bases such as (CH3) 3CO-K give largely
  Hofmann elimination with alkyl halides

53
Cope Elimination

• Cope elimination thermal decomposition of an
  amine oxide
• Step 1 oxidation of a 3 amine gives an amine
  oxide
• Step 2 if the amine oxide has at least one
  ?-hydrogen, it undergoes thermal decomposition to
  give an alkene

54
Cope Elimination

• Cope elimination shows syn stereoselectivity but
  little or no regioselectivity
• mechanism a cyclic flow of electrons in a
  six-membered transition state

55
Prob 22.24

• From each pair, select the stronger base.

56
Prob 22.25

• Calculate the ratio of morpholine to its
  conjugate acid at pH 7.0. At what pH are the
  concentrations of morpholine and its conjugate
  acid equal?

57
Prob 22.26

• Which of the nitrogens of pyridoxamine is the
  stronger base? Explain.

58
Prob 22.27

• Which of the nitrogens in epibatidine is the
  stronger base? How many stereocenters are present
  in epibatidine?

59
Prob 22.29

• Complete each acid-base reaction and predict
  whether equilibrium lies to the left or right.

60
Prob 22.29 (contd)

• Complete each acid-base reaction and predict
  whether equilibrium lies to the left or right.

61
Prob 22.29 (contd)

• Complete each acid-base reaction and predict
  whether equilibrium lies to the left or right.

62
Prob 22.30

• Provide an explanation for fact that
  quinuclidine is a considerably stronger base than
  triethylamine.

63
Prob 22.31

• Devise a chemical procedure to separate a
  mixture of these three compounds and recover each
  in pure form.

64
Prob 22.33

• Show how to convert each compound to benzylamine.

65
Prob 22.34

• Propose a structural formula for acetylcholine
  chloride.

66
Prob 22.35

• Show how the hydroxylated compound can be
  transformed into an alkyldiazonium ion, an active
  carcinogen, in the presence of an acid catalyst.

67
Prob 22.36

• Analyze the mechanism of each rearrangement, and
  list their similarities and differences.

68
Prob 22.37

• Propose a mechanism for this conversion. Account
  for the stereospecificity of the reaction.

69
Prob 22.38

• Propose structural formulas for compound A and B.

70
Prob 22.39

• Propose a structural formula for C10H16.

71
Prob 22.41

• Propose a mechanism for pyrolysis of this ester.

72
Prob 22.43

• Show how propranil can be synthesized from
  benzene and propanoic acid.

73
Prob 22.44

• Show to bring about each step in this synthesis.

74
Prob 22.45

• Show how to bring about this synthesis.

75
Prob 22.46

• Show how to bring about the conversion of phenol
  to 4-methoxybenzylamine.

76
Prob 22.47

• Show how to prepare methylparaben from toluene.

77
Prob 22.48

• Show how to synthesize this 3 amine from benzene.

78
Prob 22.49

• Show how to prepare N-methylmorpholine from the
  named starting materials.

79
Prob 22.50

• Given this retrosynthetic analysis, propose a
  synthesis for tridemorph, a systemic agricultural
  fungicide.

80
Prob 22.51

• Propose a mechanism for this example of a Ritter
  reaction. What would be the product of a Ritter
  reaction using acetonitrile?

81
Prob 22.52

• Show how each of these diamines can be prepared
  from acetonitrile.

82
Prob 22.53

• Given this retrosynthetic analysis, propose a
  synthesis for the intravenous anesthetic propofol.

83
Prob 22.54

• Given this retrosynthetic analysis, propose a
  synthesis for propoxyphene.

84
Amines
End Chapter 22