Chapter 24 Amines Naming Amines
Chapter 24 Amines
Naming Amines - amines are classified as primary (RNH2), secondary (R2NH), or tertiary (R3N), depending upon the number of substituents attached to the nitrogen CH3 H3C
C
CH3
OH
H3C
CH3
N CH3
trimethylamine (a tertiary amine)
tert-butyl alcohol (a tertiary alcohol)
CH3 H3C
C
NH2
CH3
tert-butylamine (a primary amine)
- nitrogen atoms with four groups make up quaternary ammonium salts, the nitrogen atom being a formal +1 charge CH3 H3C
N
R
X
quaternary ammonium salt
CH3
- two naming schemes are used for primary amines: - primary amines are named by adding the suffix -amine to either the name of the alkyl substituent or the parent compound
NH2
cyclohexylamine
H2NCH2CH2CH2CH2NH2
1,4-butanediamine
H3C
NH2
H 3C
4,4-dimethylcyclohexanamine
- when more than one functional group is present, the -NH2 group is referred to as an amino substituent COOH NH2
NH2
CH3CH2CHCOOH
2-aminobutanoic acid
O H2NCH2CH2CCH3
4-amino-butanone NH2
2,4-diaminobenzoic acid
1
- symmetrical secondary and tertiary amines are named by adding the prefix di- or tri- to the alkyl group H CH3CH2
N
N
CH2CH3
CH2CH3
triethylamine diphenylamine
- unsymmetrically substituted secondary and tertiary amines are named as N-substituted primary amines CH3
N
H3C
CH3
CH2CH3
N
CH2CH2CH3
N,N-dimethylpropylamine N-ethyl-N-methylcyclohexylamine
Common Names NH2
NH2 CH3
aniline
o-toluidine
N
pyrimidine
quinoline
N
N N
N
pyridine
N
N
N
H
H
H
pyrrole
imidazole
pyrrolidine
N
N
H
H
piperidine
indole
Structure and Bonding Amines - the nitrogen atom is sp3-hybridized, with the three substituents occupying three corners of a tetrahedron and the lone pair of electrons occupying the fourth corner
N H3C CH3 H3C
sp3-hybridized
- C-N-C angles are close to 109o (C-N-C value is 108o in triethyl amine, C-N bond 147 pm)
2
Chiral Amines - an amine with three different substituents on nitrogen is chiral - placement of the substituents and lone pair of electrons within the amine is analogous to a chiral alkane
X
W
W
N
N
Y
Z
Z
Y
W X
chiral amine
X
C Y
Z
chiral alkane
- most chiral amines cannot be resolved because the two enantiomeric forms rapidly interconvert by a pyramidal inversion - spectroscopic studies have shown that the barrier to nitrogen inversion is about 25 kJ/mol (6 kcal/mol) (twice as large as the barrier to rotation about a C-C single bond)
Properties and Sources of Amines - alkyl amines have minor applications for the preparation of insecticides and pharmaceuticals O CH2CH CH2
OH CH2CHCH2NHCH(CH3)2
CH3 CH2CHNH2
propranolol (heart stimulant)
- methylated amines are prepared by reaction of ammonia with methanol in the presence of an alumina catalyst; products are easy to separate by way of distillation NH3
+
CH3OH
Al2O3 450oC
H
CH3NH2
CH3
+ CH3NCH3 + CH3NCH3
3
- alkyl amines with fewer than five carbon atoms are generally watersoluble, associating by way of hydrogen bonds R
R
R' N
H
H
N
N R'
R
R' N
H
H
H
hydrogen bond structure
N R'
R
R'
R
- as a result, amines generally have higher boiling points than alkanes H CH3CH2NCH2CH3
CH3CH2CH2CH2CH3
diethylamine, MW = 71.1 g/mol bp = 56.3oC
pentane, MW = 72.1 g/mol bp = 56.3oC
- low-molecular-weight amines also have a characteristic fish odor
Basicity of Amines - chemistry of amines is dominated by the lone pair of electrons on the nitrogen, which makes amines both acidic and nucleophilic
+ H
N
N
A
H
amine
+
A
salt
- amines are considerably more basic than alcohols, ethers, or water RNH2
+
H2O
RNH3+
[RNH3+][OH-]
Kb =
[RNH2]
+
OH-
pKb = -logKb
- the most convenient way to measure the basicity of an amine is to look at the acidity of the corresponding ammonium ion RNH3+
Ka =
+
H2O
[RNH2][H3O+] [RNH3+]
RNH2
+
H3O+
pKa = -logKa = 14 - pKb
- the more acidic the ammonium ion (i.e. larger Ka or smaller pKa), the weaker the base Weaker base:
Smaller pKa for ammonium ion
Stronger base: Larger pKa for ammonium ion
4
Low Basicity of Pyridine, Pyrrole, and Amides - the low basicity of pyridine is due to the fact that the lone pair of electrons on the nitrogen are in a sp2-hybridized orbital, while those in an alkyl are in a sp3-hybridized orbital
sp3-orbital H3C
N CH3
CH3
- electrons in an orbital with more s character are held more closely to the nucleus and are less available for bonding (sp2-hybridized orbital, 33% s character, sp3-hybridized orbital, 25% s character)
- in pyrrole, the lone pair electrons are part of an aromatic sextet - the aromatic stability would have to be disrupted for bonding
- amides are nonbasic since the amide is stabilized by delocalization of lone pair electrons through overlap with the carbonyl group O C
O N
C
H
N
H
H
H
- primary and secondary amines can also act as very weak acids because an N-H proton can be removed with a strong base
CH(CH3)2
C4H9Li butyllithium
+
H
N CH(CH3)2
diisopropylamine
THF
CH(CH3)2
Li+
+
N
C4H10
CH(CH3)2
lithium diisopropylamine (LDA)
- such dialkylamine anions are used in organic chemistry to generate enolate ions
5
Basicity of Substituted Arylamines - arylamines are generally less basic than alkylamines because the nitrogen lone pair electrons are delocalized by interaction with the aromatic ring π system, making them less available for bonding to H+ NH2
NH2
NH2
NH2
NH2
- resonance stabilization is lost upon protonation NH3
NH3
- substituted arylamines are either more basic or less basic than aniline, depending on the substituent Electron-donating groups increase the basicity e.g. -CH3, -NH2, -OCH3 Electron-withdrawing groups decrease the basicity e.g. -Cl, -NO2, -CN
Synthesis of Amines Reduction of Nitiles, Amides, and Nitro Compounds - amines can be prepared by reduction of amides and nitriles with LiAlH4
RX
NaCN
1) LiAlH4, ether
RCN
2) H2O
alkyl halide O R
C
OH
carboxylic acid
1) SOCl2 2) NH3
O R
C
NH2
RCH2NH2 1o amine
1) LiAlH4, ether 2) H2O
RCH2NH2 1o amine
6
- arylamines are usually prepared by nitration of an aromatic starting material, followed by reduction of the nitro group - the reduction can be carried out in a number of ways: CH3 H3C
NO2
C CH3
1) LiAlH4, ether 2) H2O
CH3 H3C
NH2
C CH3
p-tert-butylnitrobenzene
p-tert-butylaniline (100%)
NO2
NH2 1) SnCl2, H3O+ 2) NaOH, H2O CHO
CHO
m-nitrobenzaldehyde
m-aminobenzaldehyde (90%)
- catalytic reduction over Pt is sensitive to other reducible groups
SN2 Reactions of Alkyl Halides - the simplest method of alkylamine synthesis is by SN2 alkylation of ammonia or an alkylamine with an alkyl halide NH3
+
RNH2 +
R R
X
RNH3 X R2NH2 X
X
R2NH +
R
X
R3NH X
+
R
X
R4N X
R3 N
NaOH NaOH NaOH
NaOH
RNH2
primary
R2NH
secondary
R3N
tertiary
quaternary salt
- these reactions, however, do not cleanly stop after the first alkylation, since primary, secondary, and tertiary amines have similar reactivities
- for example, four products form in the reaction between 1-bromooctane and ammonia CH3(CH2)6CH2NH2
+
CH3(CH2)6CH2Br
1-bromooctane
[CH3(CH2)6CH2]2NH
dioctylamine (43%)
octylamine (45%) NH3 [CH3(CH2)6CH2]3N
trace
+
[CH3(CH2)6CH2]4N
trace
7
- a better method for preparing primary amines is to use the azide synthesis where the azide ion, N3-, is used for SN2 displacement of the halide ion to give an alkyl azide, RN3
CH2CH2N
CH2CH2Br
N
CH2CH2NH2
N
NaN3
1) LiAlH4, ether
ethanol
2) H2O
1-bromo-2phenylethane
2-phenylethyl azide
2-phenylethyl amine (89%)
- reduction gives the primary amine - caution! Azides are also explosive
- an alternative to the azide synthesis is the Gabriel amine synthesis, which uses a phthalimide alkylation for preparing the primary amine from an alkyl halide O
O
O
KOH N
H
N
ethanol O
RX
N
DMF
O
O
phthalimide
R
-OH/H O 2
potassium phthalimide
CO2
RNH2 +
O
CH2Br
1)
CO2
N
CH2NH2 O
2) -OH/H2O
benzyl bromide
benzyl amine (81%)
Reductive Amination of Aldehydes and Ketones - treatment of an aldehyde or a ketone with ammonia or an amine in the presence of a reducing agent produces an amine in a single step in a process known as reductive amination
O CH2CCH3
NH2
NH3
CH2CHCH3
H2/Ni
phenyl-2-propanone
+
H2O
amphetamine
- ammonia, primary amines, and secondary amines can be used in a reductive elimination reaction, giving primary, secondary, and tertiary amines, respectively
8
Mechanism
O R
C
NH3 H2/cat.
H C
R
R' R’’NH2 H2/cat.
R’’NH2 H2/cat.
H
NH2
H
R'
R
primary amine
NHR'' C
R
NR''2 R'
R'
tertiary amine
secondary amine H3C
O
+
C
N
CH3
NaBH3CN
HN(CH3)2
CH3OH
cyclohexanone
N,N-dimethylcyclohexylamine (85%)
Hofmann and Curtius Rearrangements - carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and the Curtis rearrangement O
Hofmann R
C
NaOH, Br2
NH2
H2O
RNH2
+
CO2
amide
O
Curtis R
C
H2O
N
N
N
heat
RNH2
+
CO2
+
N2
acyl azide
- both involve similar mechanisms
9
Mechanism
- despite being complex, the Hofmann rearrangement often gives high yields of both aryl- and alkylamines
CH3 CH2 C
CH3
-OH, Cl
2
CONH2
CH2 C
H2O
CH3
NH2
CH3
phentermine “fen-fen”
2,2-dimethyl-3-phenylpropanamide
- the Curtis rearrangement also involves migration of an -R group from the C=O carbon atom to the nitrogen and simultaneous loss of a leaving group O R
C
Cl
acid chloride
NaN3
O R
C
N
N
acyl azide
N
heat
O
C
N
R
+ N2
isocyanate H2O R
NH2
amine
10
- Curtis rearrangement has also been used commercially
COCl H
H
NH2 H
H
1) NaN3 2) Heat 3) H2O
tranylcypromine (anti-depressant)
trans-2-phenylcyclopropanecarbonyl chloride
Reactions of Amines Alkylation and Acylation O
O R
C
Cl
+
NH3
pyridine solvent
R
C
H
N
+ HCl
H O
O R
C
+ Cl
R’NH2
C
solvent
R
C
R'
N
+ HCl
H O
O R
pyridine
+ Cl
R’2NH
pyridine solvent
R
C
R'
N
+ HCl
R'
Hofmann Elimination - amines can be converted into alkenes by an elimination reaction - since an amide ion, NH2- is a poor leaving group, it must be converted into a better leaving group, which can be achieved using an alkyl halide CH3CH2CH2CH2CH2CH2NH2 hexylamine
CH3I excess
+ CH3CH2CH2CH2CH2CH2N(CH3)3Ihexyltrimethylammonium iodide Ag2O H2O, heat
CH3CH2CH2CH2CH
CH2
+ N(CH3)3
1-hexene (60%)
11
- the silver oxide functions by exchanging hydroxide ion for iodide ion in the quaternary salt, providing the base for the elimination
HO
H C
E2 reaction
C
C
C
+ H2O + N(CH3)3
N(CH3)3
- the Hofmann elimination gives products different than most E2 elimination reactions
- the less highly substituted alkene, in contrast to Zaitsev’s rule, forms during a Hofmann elimination CH3 OHH3 C
N
CH3CH2CH2CH
CH3
more hindered
CH2
+ CH3CH2CH
CHCH3
2-pentene
1-pentene
CH3CH2CH2CHCH3 less hindered
94:6 ratio
(1-methylbutyl)trimethylammonium hydroxide
- the reason is attributed to sterics, since it is most likely that the base must abstract a hydrogen atom from the most sterically accessible location
Reactions of Arylamines Electrophilic Aromatic Substitution - amino substituents are strongly activating, being ortho- and para- directing groups - the strong activating nature of amines means that it can be difficult to attach substituents on a benzene ring since polysubstitution is likely; amines also interfere with Friedel-Crafts reactions NH2
NH2
Br
Br
HNO2 H2SO4
aniline
Br
2,4,6-tribromoaniline (100%)
- one way to avoid polysubstitution is to use aromatics with amides as substituents
12
- amido substituents are less strong activating and less basic than amino groups because their nitrogen lone-pair electrons are delocalized by the carbonyl group O H
NH2
N
C
O H
CH3
(CH3CO)2O
N
C
Br2
NH2
CH3
Br
NaOH
Br
H2O
pyridine
CH3
CH3
CH3
CH3
p-toluidine
2-bromo-4-methylaniline (79%)
O O H
NH2
N
C
(CH3CO)2O
H CH3
N
C
C5H5COCl
pyridine
NaOH H2 O
AlCl3
aniline
NH2
CH3
O
O
C
C
4-aminobenzophenone (80%) O
O O H
N
C
H
N
C
H CH3
CH3
N
C
NH2 CH3
NH3
HOSO2Cl
NaOH
H2 O O
acetanilide
S
O
Cl
H2 O O
S
O
O
S
O
NH2
NH2
sulfanilamide (sulfa drug)
Diazonium Salts - primary arylamines react with nitrous acid, HNO2, to yield arenediazonium salts - to diazotization is tolerant to a wide variety of substituents NH 2
N
N
+ HNO2 + H2SO4
HSO4- + 2H2O
- the resulting arenediazonium salts are very useful synthetically
N
N
HSO4- + :Nu-
Nu
+ N2
13
Sandmeyer Reaction - preparation of aryl chlorides and bromides by reaction of an arenediazonium salt with a cuprous halide
NH2 H3C
N HSO4
N
HNO2 H2SO4
H3C
p-methylaniline
NH2
Br
HBr CuBr
H3C
p-bromotoluene (73%)
N HSO4-
N HNO2 H2SO4
I NaI
H3C
iodobenzene (67%)
aniline
- the Sandmeyer reaction can be expanded to cyanide and hydroxide ions for the synthesis of nitriles and phenols, respectively NH2
N CH3
N HSO4
CH3
HNO2 H2SO4
o-methylaniline
C
NH2
N HNO2
CH3
H3O+
o-methylbenzonitrile
o-methylbenzoic acid OH
N HSO4Cu2O Cu(NO3)2, H2O
H2SO4
p-methylaniline
CH3
CuCN
o-methylbenzenediazonium bisulfate
CH3
COOH
N
KCN
CH3
CH3
p-cresol (93%)
14
- a diazonium salt can also be reduced to give an arene; this process is extremely useful for temporarily introducing an amino group on an aromatic ring to take advantage of its directing effect NH2
NH2
N
Br
2 Br2
Br
HNO2
N HSO4
Br
Br
Br
Br
H3PO2
H2SO4 CH3
CH3
CH3
CH3
3,5-dibromobenzene
p-methylaniline Br
2 Br2 FeBr3 CH3
Br CH3
toluene
2,4-dibromotoluene
Diazonium Coupling Reactions - arenediazonium salts undergo a coupling reaction with activated aromatic rings to give brightly colored azo compounds
N
Y
N HSO4-
Y N
+
N
Y = -OH or -NR2
- reaction has widespread application in the design of dyes
Mechanism HSO4-
N
O OH
N
N
+ benzenediazonium bisulfate
N
H
H
OH2
phenol
OH N
N
p-hydroxyazobenzene
15
Coloring Agent HSO4-
N
N
N
+ benzenediazonium bisulfate
CH3
CH3
N
CH3
N
N,N-dimethylaniline
CH3
N
p-(dimethylamino)azobenzene
Phase-Transfer Catalysis CHCl3, 50% NaOH in H2O
no reaction
H Cl
CHCl3, 50% NaOH in H2O + C6H5CH2N(CH2CH3)3Cl-
Cl H
- the benzyltriethylammonium cation facilitates transfer of the OH- ion into the organic solvent, where the anion reacts with the alkene
- many different reactions are subject to phase transfer catalysis (e.g. oxidations, reductions, alkylations, SN2 reactions) - very often, inorganic nucleophiles display improved reactivity in the organic medium, as compared to the aqueous phase
CH3(CH2)6Br + 1-bromooctane
NaCN
CHCl3, 50% NaOH in H2O + C6H5CH2N(CH2CH3)3Cl-
CH3(CH2)6CN + NaBr nonanenitrile (92%)
16
Spectroscopy of Amines Infrared Spectroscopy - characteristic N-H stretching band in the 3300 - 3500 cm-1 range - amines are generally sharper and less intense than alcohols - primary amines: pair of bands at 3350 and 3450 cm-1 - secondary amines: single band at 3350 cm-1 - addition of HCl produces a broad and strong absorption at 2200 - 3000 cm-1 caused by an ammonium band, R3N-H
Infrared Spectrum of Cyclohexylamine
17
Infrared Spectrum of Diisopropylamine
Infrared Spectrum of Trimethylammonium Chloride
NMR Spectroscopy - N-H resonances can appear over a broad range and are exchangeable by adding a small amount of D2O N
N
H
D
+ HDO
- hydrogen on the carbons next to the nitrogen atom are somewhat deshielded because of the electron-withdrawing effect of the nitrogen, being located at a lower field than an alkane H
25.2 26.5
33.3
N
33.4 CH3
58.7
- corresponding carbon atoms are deshielded in the 13C spectrum
18
1H
NMR Spectrum of N-methylcyclohexylamine
Mass Spectrometry - nitrogen rule: a compound with an odd number of nitrogen atoms has an odd-numbered molecular weight - the rule is realized by considering the fact that nitrogen is trivalent, and thus requires an odd number of hydrogen atoms (i.e. 3n) - aliphatic amines undergo a characteristic α cleavage, similar to alcohols +• R' RCH2
CH2
α
N R
alpha cleavage
R' RCH2
+
CH2
N R
19
Naming Amines - amines are classified as primary (RNH2), secondary (R2NH), or tertiary (R3N), depending upon the number of substituents attached to the nitrogen CH3 H3C
C
CH3
OH
H3C
CH3
N CH3
trimethylamine (a tertiary amine)
tert-butyl alcohol (a tertiary alcohol)
CH3 H3C
C
NH2
CH3
tert-butylamine (a primary amine)
- nitrogen atoms with four groups make up quaternary ammonium salts, the nitrogen atom being a formal +1 charge CH3 H3C
N
R
X
quaternary ammonium salt
CH3
- two naming schemes are used for primary amines: - primary amines are named by adding the suffix -amine to either the name of the alkyl substituent or the parent compound
NH2
cyclohexylamine
H2NCH2CH2CH2CH2NH2
1,4-butanediamine
H3C
NH2
H 3C
4,4-dimethylcyclohexanamine
- when more than one functional group is present, the -NH2 group is referred to as an amino substituent COOH NH2
NH2
CH3CH2CHCOOH
2-aminobutanoic acid
O H2NCH2CH2CCH3
4-amino-butanone NH2
2,4-diaminobenzoic acid
1
- symmetrical secondary and tertiary amines are named by adding the prefix di- or tri- to the alkyl group H CH3CH2
N
N
CH2CH3
CH2CH3
triethylamine diphenylamine
- unsymmetrically substituted secondary and tertiary amines are named as N-substituted primary amines CH3
N
H3C
CH3
CH2CH3
N
CH2CH2CH3
N,N-dimethylpropylamine N-ethyl-N-methylcyclohexylamine
Common Names NH2
NH2 CH3
aniline
o-toluidine
N
pyrimidine
quinoline
N
N N
N
pyridine
N
N
N
H
H
H
pyrrole
imidazole
pyrrolidine
N
N
H
H
piperidine
indole
Structure and Bonding Amines - the nitrogen atom is sp3-hybridized, with the three substituents occupying three corners of a tetrahedron and the lone pair of electrons occupying the fourth corner
N H3C CH3 H3C
sp3-hybridized
- C-N-C angles are close to 109o (C-N-C value is 108o in triethyl amine, C-N bond 147 pm)
2
Chiral Amines - an amine with three different substituents on nitrogen is chiral - placement of the substituents and lone pair of electrons within the amine is analogous to a chiral alkane
X
W
W
N
N
Y
Z
Z
Y
W X
chiral amine
X
C Y
Z
chiral alkane
- most chiral amines cannot be resolved because the two enantiomeric forms rapidly interconvert by a pyramidal inversion - spectroscopic studies have shown that the barrier to nitrogen inversion is about 25 kJ/mol (6 kcal/mol) (twice as large as the barrier to rotation about a C-C single bond)
Properties and Sources of Amines - alkyl amines have minor applications for the preparation of insecticides and pharmaceuticals O CH2CH CH2
OH CH2CHCH2NHCH(CH3)2
CH3 CH2CHNH2
propranolol (heart stimulant)
- methylated amines are prepared by reaction of ammonia with methanol in the presence of an alumina catalyst; products are easy to separate by way of distillation NH3
+
CH3OH
Al2O3 450oC
H
CH3NH2
CH3
+ CH3NCH3 + CH3NCH3
3
- alkyl amines with fewer than five carbon atoms are generally watersoluble, associating by way of hydrogen bonds R
R
R' N
H
H
N
N R'
R
R' N
H
H
H
hydrogen bond structure
N R'
R
R'
R
- as a result, amines generally have higher boiling points than alkanes H CH3CH2NCH2CH3
CH3CH2CH2CH2CH3
diethylamine, MW = 71.1 g/mol bp = 56.3oC
pentane, MW = 72.1 g/mol bp = 56.3oC
- low-molecular-weight amines also have a characteristic fish odor
Basicity of Amines - chemistry of amines is dominated by the lone pair of electrons on the nitrogen, which makes amines both acidic and nucleophilic
+ H
N
N
A
H
amine
+
A
salt
- amines are considerably more basic than alcohols, ethers, or water RNH2
+
H2O
RNH3+
[RNH3+][OH-]
Kb =
[RNH2]
+
OH-
pKb = -logKb
- the most convenient way to measure the basicity of an amine is to look at the acidity of the corresponding ammonium ion RNH3+
Ka =
+
H2O
[RNH2][H3O+] [RNH3+]
RNH2
+
H3O+
pKa = -logKa = 14 - pKb
- the more acidic the ammonium ion (i.e. larger Ka or smaller pKa), the weaker the base Weaker base:
Smaller pKa for ammonium ion
Stronger base: Larger pKa for ammonium ion
4
Low Basicity of Pyridine, Pyrrole, and Amides - the low basicity of pyridine is due to the fact that the lone pair of electrons on the nitrogen are in a sp2-hybridized orbital, while those in an alkyl are in a sp3-hybridized orbital
sp3-orbital H3C
N CH3
CH3
- electrons in an orbital with more s character are held more closely to the nucleus and are less available for bonding (sp2-hybridized orbital, 33% s character, sp3-hybridized orbital, 25% s character)
- in pyrrole, the lone pair electrons are part of an aromatic sextet - the aromatic stability would have to be disrupted for bonding
- amides are nonbasic since the amide is stabilized by delocalization of lone pair electrons through overlap with the carbonyl group O C
O N
C
H
N
H
H
H
- primary and secondary amines can also act as very weak acids because an N-H proton can be removed with a strong base
CH(CH3)2
C4H9Li butyllithium
+
H
N CH(CH3)2
diisopropylamine
THF
CH(CH3)2
Li+
+
N
C4H10
CH(CH3)2
lithium diisopropylamine (LDA)
- such dialkylamine anions are used in organic chemistry to generate enolate ions
5
Basicity of Substituted Arylamines - arylamines are generally less basic than alkylamines because the nitrogen lone pair electrons are delocalized by interaction with the aromatic ring π system, making them less available for bonding to H+ NH2
NH2
NH2
NH2
NH2
- resonance stabilization is lost upon protonation NH3
NH3
- substituted arylamines are either more basic or less basic than aniline, depending on the substituent Electron-donating groups increase the basicity e.g. -CH3, -NH2, -OCH3 Electron-withdrawing groups decrease the basicity e.g. -Cl, -NO2, -CN
Synthesis of Amines Reduction of Nitiles, Amides, and Nitro Compounds - amines can be prepared by reduction of amides and nitriles with LiAlH4
RX
NaCN
1) LiAlH4, ether
RCN
2) H2O
alkyl halide O R
C
OH
carboxylic acid
1) SOCl2 2) NH3
O R
C
NH2
RCH2NH2 1o amine
1) LiAlH4, ether 2) H2O
RCH2NH2 1o amine
6
- arylamines are usually prepared by nitration of an aromatic starting material, followed by reduction of the nitro group - the reduction can be carried out in a number of ways: CH3 H3C
NO2
C CH3
1) LiAlH4, ether 2) H2O
CH3 H3C
NH2
C CH3
p-tert-butylnitrobenzene
p-tert-butylaniline (100%)
NO2
NH2 1) SnCl2, H3O+ 2) NaOH, H2O CHO
CHO
m-nitrobenzaldehyde
m-aminobenzaldehyde (90%)
- catalytic reduction over Pt is sensitive to other reducible groups
SN2 Reactions of Alkyl Halides - the simplest method of alkylamine synthesis is by SN2 alkylation of ammonia or an alkylamine with an alkyl halide NH3
+
RNH2 +
R R
X
RNH3 X R2NH2 X
X
R2NH +
R
X
R3NH X
+
R
X
R4N X
R3 N
NaOH NaOH NaOH
NaOH
RNH2
primary
R2NH
secondary
R3N
tertiary
quaternary salt
- these reactions, however, do not cleanly stop after the first alkylation, since primary, secondary, and tertiary amines have similar reactivities
- for example, four products form in the reaction between 1-bromooctane and ammonia CH3(CH2)6CH2NH2
+
CH3(CH2)6CH2Br
1-bromooctane
[CH3(CH2)6CH2]2NH
dioctylamine (43%)
octylamine (45%) NH3 [CH3(CH2)6CH2]3N
trace
+
[CH3(CH2)6CH2]4N
trace
7
- a better method for preparing primary amines is to use the azide synthesis where the azide ion, N3-, is used for SN2 displacement of the halide ion to give an alkyl azide, RN3
CH2CH2N
CH2CH2Br
N
CH2CH2NH2
N
NaN3
1) LiAlH4, ether
ethanol
2) H2O
1-bromo-2phenylethane
2-phenylethyl azide
2-phenylethyl amine (89%)
- reduction gives the primary amine - caution! Azides are also explosive
- an alternative to the azide synthesis is the Gabriel amine synthesis, which uses a phthalimide alkylation for preparing the primary amine from an alkyl halide O
O
O
KOH N
H
N
ethanol O
RX
N
DMF
O
O
phthalimide
R
-OH/H O 2
potassium phthalimide
CO2
RNH2 +
O
CH2Br
1)
CO2
N
CH2NH2 O
2) -OH/H2O
benzyl bromide
benzyl amine (81%)
Reductive Amination of Aldehydes and Ketones - treatment of an aldehyde or a ketone with ammonia or an amine in the presence of a reducing agent produces an amine in a single step in a process known as reductive amination
O CH2CCH3
NH2
NH3
CH2CHCH3
H2/Ni
phenyl-2-propanone
+
H2O
amphetamine
- ammonia, primary amines, and secondary amines can be used in a reductive elimination reaction, giving primary, secondary, and tertiary amines, respectively
8
Mechanism
O R
C
NH3 H2/cat.
H C
R
R' R’’NH2 H2/cat.
R’’NH2 H2/cat.
H
NH2
H
R'
R
primary amine
NHR'' C
R
NR''2 R'
R'
tertiary amine
secondary amine H3C
O
+
C
N
CH3
NaBH3CN
HN(CH3)2
CH3OH
cyclohexanone
N,N-dimethylcyclohexylamine (85%)
Hofmann and Curtius Rearrangements - carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and the Curtis rearrangement O
Hofmann R
C
NaOH, Br2
NH2
H2O
RNH2
+
CO2
amide
O
Curtis R
C
H2O
N
N
N
heat
RNH2
+
CO2
+
N2
acyl azide
- both involve similar mechanisms
9
Mechanism
- despite being complex, the Hofmann rearrangement often gives high yields of both aryl- and alkylamines
CH3 CH2 C
CH3
-OH, Cl
2
CONH2
CH2 C
H2O
CH3
NH2
CH3
phentermine “fen-fen”
2,2-dimethyl-3-phenylpropanamide
- the Curtis rearrangement also involves migration of an -R group from the C=O carbon atom to the nitrogen and simultaneous loss of a leaving group O R
C
Cl
acid chloride
NaN3
O R
C
N
N
acyl azide
N
heat
O
C
N
R
+ N2
isocyanate H2O R
NH2
amine
10
- Curtis rearrangement has also been used commercially
COCl H
H
NH2 H
H
1) NaN3 2) Heat 3) H2O
tranylcypromine (anti-depressant)
trans-2-phenylcyclopropanecarbonyl chloride
Reactions of Amines Alkylation and Acylation O
O R
C
Cl
+
NH3
pyridine solvent
R
C
H
N
+ HCl
H O
O R
C
+ Cl
R’NH2
C
solvent
R
C
R'
N
+ HCl
H O
O R
pyridine
+ Cl
R’2NH
pyridine solvent
R
C
R'
N
+ HCl
R'
Hofmann Elimination - amines can be converted into alkenes by an elimination reaction - since an amide ion, NH2- is a poor leaving group, it must be converted into a better leaving group, which can be achieved using an alkyl halide CH3CH2CH2CH2CH2CH2NH2 hexylamine
CH3I excess
+ CH3CH2CH2CH2CH2CH2N(CH3)3Ihexyltrimethylammonium iodide Ag2O H2O, heat
CH3CH2CH2CH2CH
CH2
+ N(CH3)3
1-hexene (60%)
11
- the silver oxide functions by exchanging hydroxide ion for iodide ion in the quaternary salt, providing the base for the elimination
HO
H C
E2 reaction
C
C
C
+ H2O + N(CH3)3
N(CH3)3
- the Hofmann elimination gives products different than most E2 elimination reactions
- the less highly substituted alkene, in contrast to Zaitsev’s rule, forms during a Hofmann elimination CH3 OHH3 C
N
CH3CH2CH2CH
CH3
more hindered
CH2
+ CH3CH2CH
CHCH3
2-pentene
1-pentene
CH3CH2CH2CHCH3 less hindered
94:6 ratio
(1-methylbutyl)trimethylammonium hydroxide
- the reason is attributed to sterics, since it is most likely that the base must abstract a hydrogen atom from the most sterically accessible location
Reactions of Arylamines Electrophilic Aromatic Substitution - amino substituents are strongly activating, being ortho- and para- directing groups - the strong activating nature of amines means that it can be difficult to attach substituents on a benzene ring since polysubstitution is likely; amines also interfere with Friedel-Crafts reactions NH2
NH2
Br
Br
HNO2 H2SO4
aniline
Br
2,4,6-tribromoaniline (100%)
- one way to avoid polysubstitution is to use aromatics with amides as substituents
12
- amido substituents are less strong activating and less basic than amino groups because their nitrogen lone-pair electrons are delocalized by the carbonyl group O H
NH2
N
C
O H
CH3
(CH3CO)2O
N
C
Br2
NH2
CH3
Br
NaOH
Br
H2O
pyridine
CH3
CH3
CH3
CH3
p-toluidine
2-bromo-4-methylaniline (79%)
O O H
NH2
N
C
(CH3CO)2O
H CH3
N
C
C5H5COCl
pyridine
NaOH H2 O
AlCl3
aniline
NH2
CH3
O
O
C
C
4-aminobenzophenone (80%) O
O O H
N
C
H
N
C
H CH3
CH3
N
C
NH2 CH3
NH3
HOSO2Cl
NaOH
H2 O O
acetanilide
S
O
Cl
H2 O O
S
O
O
S
O
NH2
NH2
sulfanilamide (sulfa drug)
Diazonium Salts - primary arylamines react with nitrous acid, HNO2, to yield arenediazonium salts - to diazotization is tolerant to a wide variety of substituents NH 2
N
N
+ HNO2 + H2SO4
HSO4- + 2H2O
- the resulting arenediazonium salts are very useful synthetically
N
N
HSO4- + :Nu-
Nu
+ N2
13
Sandmeyer Reaction - preparation of aryl chlorides and bromides by reaction of an arenediazonium salt with a cuprous halide
NH2 H3C
N HSO4
N
HNO2 H2SO4
H3C
p-methylaniline
NH2
Br
HBr CuBr
H3C
p-bromotoluene (73%)
N HSO4-
N HNO2 H2SO4
I NaI
H3C
iodobenzene (67%)
aniline
- the Sandmeyer reaction can be expanded to cyanide and hydroxide ions for the synthesis of nitriles and phenols, respectively NH2
N CH3
N HSO4
CH3
HNO2 H2SO4
o-methylaniline
C
NH2
N HNO2
CH3
H3O+
o-methylbenzonitrile
o-methylbenzoic acid OH
N HSO4Cu2O Cu(NO3)2, H2O
H2SO4
p-methylaniline
CH3
CuCN
o-methylbenzenediazonium bisulfate
CH3
COOH
N
KCN
CH3
CH3
p-cresol (93%)
14
- a diazonium salt can also be reduced to give an arene; this process is extremely useful for temporarily introducing an amino group on an aromatic ring to take advantage of its directing effect NH2
NH2
N
Br
2 Br2
Br
HNO2
N HSO4
Br
Br
Br
Br
H3PO2
H2SO4 CH3
CH3
CH3
CH3
3,5-dibromobenzene
p-methylaniline Br
2 Br2 FeBr3 CH3
Br CH3
toluene
2,4-dibromotoluene
Diazonium Coupling Reactions - arenediazonium salts undergo a coupling reaction with activated aromatic rings to give brightly colored azo compounds
N
Y
N HSO4-
Y N
+
N
Y = -OH or -NR2
- reaction has widespread application in the design of dyes
Mechanism HSO4-
N
O OH
N
N
+ benzenediazonium bisulfate
N
H
H
OH2
phenol
OH N
N
p-hydroxyazobenzene
15
Coloring Agent HSO4-
N
N
N
+ benzenediazonium bisulfate
CH3
CH3
N
CH3
N
N,N-dimethylaniline
CH3
N
p-(dimethylamino)azobenzene
Phase-Transfer Catalysis CHCl3, 50% NaOH in H2O
no reaction
H Cl
CHCl3, 50% NaOH in H2O + C6H5CH2N(CH2CH3)3Cl-
Cl H
- the benzyltriethylammonium cation facilitates transfer of the OH- ion into the organic solvent, where the anion reacts with the alkene
- many different reactions are subject to phase transfer catalysis (e.g. oxidations, reductions, alkylations, SN2 reactions) - very often, inorganic nucleophiles display improved reactivity in the organic medium, as compared to the aqueous phase
CH3(CH2)6Br + 1-bromooctane
NaCN
CHCl3, 50% NaOH in H2O + C6H5CH2N(CH2CH3)3Cl-
CH3(CH2)6CN + NaBr nonanenitrile (92%)
16
Spectroscopy of Amines Infrared Spectroscopy - characteristic N-H stretching band in the 3300 - 3500 cm-1 range - amines are generally sharper and less intense than alcohols - primary amines: pair of bands at 3350 and 3450 cm-1 - secondary amines: single band at 3350 cm-1 - addition of HCl produces a broad and strong absorption at 2200 - 3000 cm-1 caused by an ammonium band, R3N-H
Infrared Spectrum of Cyclohexylamine
17
Infrared Spectrum of Diisopropylamine
Infrared Spectrum of Trimethylammonium Chloride
NMR Spectroscopy - N-H resonances can appear over a broad range and are exchangeable by adding a small amount of D2O N
N
H
D
+ HDO
- hydrogen on the carbons next to the nitrogen atom are somewhat deshielded because of the electron-withdrawing effect of the nitrogen, being located at a lower field than an alkane H
25.2 26.5
33.3
N
33.4 CH3
58.7
- corresponding carbon atoms are deshielded in the 13C spectrum
18
1H
NMR Spectrum of N-methylcyclohexylamine
Mass Spectrometry - nitrogen rule: a compound with an odd number of nitrogen atoms has an odd-numbered molecular weight - the rule is realized by considering the fact that nitrogen is trivalent, and thus requires an odd number of hydrogen atoms (i.e. 3n) - aliphatic amines undergo a characteristic α cleavage, similar to alcohols +• R' RCH2
CH2
α
N R
alpha cleavage
R' RCH2
+
CH2
N R
19
