Amines (McM chapt 24)
(R: alkyl, aryl)
R
R
NH
R'
Secondary amine
R-NH2
Primary amine
R
N R''
R'
Tertiary amine
R'
N
R'''
X
R''
Quartenary ammonium salts
Basic compounds
R
R' N
R''
H-OH
(R: H, alkyl, aryl)
R
R' N H
R''
+ OH
pKa Alkylamines: ca 9-11
Arylamines: ca 4-5
(anilines)
Known react. from KJM10xx
Synthesis
Alkylation (ammonia or amine, phtalimide)
H
H
R-X
N
H
N R
H
H
R
H N
H
Base
H
X
R-X
(R: H, alkyl, aryl)
O
O
N-H
Base
O
O
CO2H
OH
R-X
N
+
N R
O
H2N R
CO2H
O
Acidity
c.f. 1,3-dicarbonyls
Reductive amination
O
Aldehyde
ketone
R
H N
H
NR
sec amine
H
R
NH
- H2O
ammonia
prim amine
R
H N
R
[red]
- H2O
Imine
R
N
R
Iminium
ion
H2 / Ni
NaCNBH3
etc
[red]
H
R
N
R
Reductions
•Nitriles
•Azides
•Amides
R N N N
R C N
LiAlH4
Nitrile
H H
R C N
H H
LiAlH4
H H
R C N
H H
R N N N
O
R
N
R'
R''
LiAlH4
Amide
R, R', R'': H, alkyl, aryl
Azide
CN
N3
R-X
•Aromatic nitro compounds
[red]
Ar-NO2
Ar-NH2
Red: H2 / cat
SnCl2, H+
H R''
R C N
H R'
Synthesis: “New” reactions
O
R
Hofmann rearrangement
NaOH, Br2
NH2
R-NH2 + CO2
H2O
prim amide
O
R
O
OH
R
NH2
O
O
Br-Br
N
H
R
N
H
Br
OH
R
R N C O
Isocyanate
O
O
R
OH2
N
Br
R
N
H
Br
N
Br
Acid / base properties amides
R
R
NH2
R
NH
NH2
R
NH2
O
R
R
NH3
No resonance stab.
NH
+
H
R
H
H2N R
pKa ca 17
- CO2
O
N
H
R
carbamic acid
instable
O
OH
OH
O
O
O
O
NH2
+
H
pKa ca -0.5
O
Curtius rearrangement
R
N3
R-NH2 + CO2
H2O, heat
+ N2
acyl azide
acyl azide
O
R
O
N3
R
Cl
OH2
N
N
acyl halide
R N C O
N
Isocyanate
R-NH2
- CO2
O
R
N
N
N
Mechanistic. related to Hofmann rearrang.
O
O
R
NH2
R
N
Br
O
R
N
Br
OH2
R N C O
Isocyanate
- CO2
R-NH2
Reactions of amines (Alkylamines)
Alkylamines:
•Alkylation
•Acylation / synth of amide
•Hofmann elimination (≠ Hofmann rearrangement)
E2 elimination to form alkene
E2: mechanism
B
H
R'
R
R
R'
X
R'
R'
R
R
+ BH + X
CH3I (excess)
Base
H
R
NH2
X= halogen, (OH)
X ≠ NR2 Strong base / bad leaving group
R
CH3I (excess)
Base
H
R
Removal of less sterically hindered H
Not necessarily most stable alkene formed
R
NH2
CH3I (excess)
H
H
R
H
Ag20
R
R
R
H20
NH2
I
N CH
3
H3C
CH3
H3C
N CH
3
CH3
OH
+
AgI
H3C
Morphine
N
CH3
N
CH3
H3C
Base
HO
O
OH
H3C
O
O
N
N
CH3
Ph
N CH
3
CH3
CH3
Codeine
OH
OH
O
H3C O
Much better
leaving group
than R2N
OH
CH3-I
OH
pKa=10.0
OH
N
CH2
N CH
CH3
CH3-I
pKa ca 17
H3C O
O
OH
H3C O
O
I
3
OH
CH3
N
CH3
Hoffman
elim
H3C O
O
OH
Reactions of Arylamines (aniline derivatives)
NH2
NH2
NH2
NH2
•Weak base (pKa ca 4.6)
•Highly Activated for E-fil Ar Subst (o/p)
•Protect. as amide: Less activated, still o/p
O
R
N
O
R'
NR3
Aniline
o/p directing
m-directing
Nucleophilic Aromatic Substitution - Mechanisms
•SNAr √
X
Nu
•SN1
•Benzyne √
•SRN1: Involves radicals
•(VNS: Vicarious Nucl. Subst.)
X
X
Nu
X
Nu
Nu
Nu
Formation of Diazonium Salts and the Sandmeyer Reaction
R
R N N
X
R
N N
Diazonium salt
R N N N
N N
R'
R N N N
R'
Azide
Diazo compound
H2SO4 / HNO2
R
R N N
R-NH2
+ N2
Synthetically seldom useful
very unstable
prim alkylamine
Nu
N
N
NH2
Substitution
Nu
H2SO4 / HNO2
Y
N
Aryl amine
Relatively stable
N
Diazo couplng
Y
Y: OH, NH2
Diazotation of primary amine
Ar NH2
2
H N O
O N O N O
nitrous acid
(salpetersyrling)
Ar
+ H2O
- NO2
dinitrogen trioxide
H
N N O
H
taut
Ar
-H
N N O
H
Ar
N N OH
Nitrosoamine
H
Ar N N
Sec amine gives nitroso compound
Ar NH
R
Ar
N N O
R
Nitrosoamine
Amines with acidic a-H may give diazo compounds
R'
RO2C
H
R'
NH2
RO2C
H
R
N
N N
N
-H
RO2C
+ H2O
Toxicity nitroso compounds (not in McM) - Alkylation of biomolecules
endoplasmatic
reticulum
NO2 / NO3
OH
H3C
CYP450 enzyme
CH2O +´
N N O
H3C
N N O
H3C
H
N N O
H3C
H3C
NH
H3C
OH
CH3
sec alkylamine
H3C N N
N N
H3C
CH3
S
O
HN
H2N
N
CH3
N
N
N-7 alkylation of guanine in DNA
N
H
O
S-methylated cysteine in
a peptide/protein
I
CN
NaI or KI
Br
CuCN
OH
N
N
H+ / H2O
or
Cu2O / Cu(NO3)2
H2O
H
N2 as leaving group
CuBr
Cl
CuCl
HBF4
H3PO4
F
SN1 like mechanism or radical mechanism
Nu
N N
Nu
CuX
N N
- N2
Cu2+
X
X
Cu+
Cu-salt mediated react.
Sandmeyer react.
(radical mech.)
Diazo coupling
+
Y
Phenol
Aniline der
(Reactive Nu)
N N
N
N
H
Electrophilic
Aromatic subst.
Electrophile
Y
N
Y
Base
Azo dyes
Bayer etc
Late 1800-century, ex.
HO3S
N
N
N
Metylorange
HO
O2N
Pararødt
N
N
Metylorange
HO3S
N
N
O3S
N
N
N
pH < 3.1
pH >4.4
OH
N
N
Azo dyes
Bayer etc
Late 1800-century, ex.
HO3S
N
N
N
Metylorange
Screening of dyes as antibacterials
HO
O2N
Pararødt
N
N
1932: Prontocil active against Streptoccocces infection
no activity on bacterial cultures
O
H2N S
O
H2N
N
N
NH2
1935: Prontocil metabilized (azoreductase) to Sulfanilamid in vivo
O
H2N S
O
Antibacterial sulfonamides
NH2
Modern sulfa drugsr
O
H
R N S
O
NH2
R: Aryl or hetroaryl
(rel. toxisk)
Heterocycles (McM chapt 24)
•Monocyclic or fused rings
•Cont. one ore more ring atom ≠ C (normally O; N; S)
•Aromatic, partly saturated or saturated ring(s)
5-Membered rings (Heteroatom N, O, S)
S
N
H
Pyrrole
Thiophene
O
Thiophene
Other examples
N
N
N
H
Imidazole
Thiazole
R
H2N
NH2
N
N
N
H
S
N
N
H
Adenine
(purine der.)
H2N
N
N
H
R=CO2H: Histidine
R=H: Histamine
H3C
HO
N
S
Thiamin
(Vit B1)
Indole
R'
N
N
CH3
NHR
R''
N
H
R=H
R'=H
R'''=OH
R=H
R'=CO2H
R'''=H
R=Ac
Serotonin R'=H
R'''=OCH3
Tryptophane
Melatonin
Criteria for Aromaticity (Hückel)
(Monocyclic) ring
Planar
No of π-electrons in conjugation 4n+2 (n: 0, 1, 2,....)
Cyclopentadienyl anion
S
S
X
X
X
Thiophene
X
X
X
X: S, Se
e- in d-orb.
Benzene
Energy
6 π electrons
Cyclobutadiene
4 π electrons
Diradical
Cyclopentadienyl anion
6 π−electrons
Thiophene
6 π−electrons
S
All π electrons in
the bonding MO
5-membered rings - electron rich on C - reactive i E-fil. Ar subst.
X
X
X
X
X
X
X: S, Se
e- in d-orb.
X
+ E
E
H
X
E
X
+ E
X
E
X
H
E
H
X
E
H
H
X
X
E
React. in α-position generally preferred
Selectivity not always good
React.: Pyrrole > thiophene > furan
X
E
H
H
6-Membered rings (Heteroatom N)
N
N
H
Pyridine
H
H
Other examples
N
N
N
N
Quinoline
Pyrimidine
N
Pyrazine
N
N
Pyridazine
Rare in nature
HO
NH2
N
H3CO
N
Quinine
O
N
H2NHN
N
N
H
Cytosine
Ant pheremone
N
N
Hydralazine
Antihypertensive drug
Pyridine as a base
N
H
+
H
N
H
H
H
H
H
N
H
pKa: 5.2
N
H
H
H
sp2 N less basic than sp3
H
H
N
N
H
pKa 0.4
N
H
pKa 11.3
N
H
pKa 7.1
(≈amidine)
N
S
pKa 2.5
Electrophilic Reaction on Carbon: E-phil. Ar. Subs.
6-membered rings - electron deficient on C - ↓ reactivity
N
H
N
N
N
E
E
N
+ res. forms
N
•Both C and N may react
•3/5 pos. most reactive C
+ E
•Diazines less reactive
N
•Sulfonation, Nitration, halogenatil
N
E
•Not FC react.
N
Nucleophilic Aromatic Substitution
•SNAr
X
X
Nu
X
Nu
X
Nu
Nu
•SN1: Via arylic cation
•Benzyne
•SRN1: Involves radicals
•VNS: Vicarious nucl. Subst.
6-membered rings - electron deficient - reactive in Nu-fil. Ar subst.
OMe
N
Cl
OMe
N Cl
N
OMe
+ res. form
2 / 4 Pos. reactive; electron def. C, neg. charge partly on N in intermed
3 / 5-Pos. much less reactive (benzenoid pos.)
Nu