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Amines
23-1
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
CH 3 - N H 2 Methylamine (a 1 amine) CH 3 - N H C H3 Dimethylamine (a 2 amine) CH 3 CH 3 - N : CH 3 Trimethylamine (a 3 amine) : :
23-2
:
NH2
23-3
23-4
N (S)-N icotine
Caffein
Morphine
Heroin
23-5
1,6-Hexanediamine
23-6
Nomenclature
The
23-7
Nomenclature
Among
the various functional groups discussed in the text, -NH2 is one of the lowest in order of precedence
H2 N OH OH NH2 (S)-2-Amino-3-methyl1-butanol H2 N COOH
2-Aminoethanol
4-Aminobenzoic acid
23-8
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 CH3 NH2 NH2 N Et 3 N
23-9
Nomenclature
When
four groups are bonded to nitrogen, the compound is named as a salt of the corresponding amine
Me4 N Cl
+ -
Cl
Tetramethy Tetrad ecylpyrid inium ch loride ammonium (Cetylp yridin ium chloride) chloride
23-10
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
the u nsh ared electron pair in the fourth sp 3 hybrid orbital H H Et Et Me Me (S)-Ethylmethylamin e (R )-Ethylmethylamin e N N
23-11
Chirality of Amines
in practice, however, they cannot be resolved because they undergo pyramidal inversion, which converts one enantiomer to the other
Un hy bri di z e d 2p orbi tal sp 3 N H Me N sp 2 Et N sp 3 The trans i ti on state has a p l ane o f s ym m e try ; i t i s ac hi ral
H Et Me S Enan ti om e r
R Enan ti om e r
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Chirality of Amines
pyramidal inversion is not possible with quaternary ammonium ions, and their salts can be resolved
Cl
N Et Me S Enan tiomer
23-13
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)
CH3 CH3 MW (g/mol) bp (C) 30.1 -88.6 CH3 NH2 31.1 -6.3 CH3 OH 32.0 65.0
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Basicity
All
amines are weak bases, and aqueous solutions of amines are basic
H CH3 -N + H-O-H H Methylamine H + - O-H CH3 -N-H H Methylammoniu m h yd roxide
it is common to discuss their basicity by reference to the acid ionization constant of the conjugate acid
CH3 NH3 Ka =
+
+ H2 O
+ +
pK a = 10.64
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Basicity
using values of pKa, we can compare the acidities of amine conjugate acids with other acids
CH3 NH2 + CH3 COOH pK a 4.76 (s tronger acid) CH3 NH3 + CH3 COO pK a 10.64 (w eak er acid )
+ -
pK eq = -5.88 Ke q = 7.6 x 10
5
23-16
Basicity-Aliphatic Amines
Aliphatic
Amines
Structure NH3 CH3 NH2 CH3 CH2 NH2 C6 H1 1 NH2 p Ka 9.26 10.64 10.81 10.66 pK b 4.74 3.36 3.34 3.19
Amine Ammon ia Primary Amines methylamin e ethylamine cyclohexylamine Secon dary A min es dimethylamine dieth ylamine Tertiary Amines trimeth ylamine triethylamin e
(CH3 ) 2 NH 10.73 (CH3 CH2 ) 2 NH 10.98 (CH3 ) 3 N (CH3 CH2 ) 3 N 9.81 10.75
23-17
Basicity-Aromatic Amines
Amine Aromatic A min es An iline 4-Methylanilin e 4-Ch loroaniline 4-N itroanilin e CH3 Cl O2 N NH2 NH2 NH2 NH2 4.63 5.08 4.15 1.0 Structure pK a of Conju gate A cid
23-18
Basicity-Aromatic Amines
aromatic amines are considerably weaker bases than aliphatic amines
NH2 + H2 O Cycloh exylamine NH3 OH Cyclohexylammonium hydroxid e NH3 + OHA niliniu m h yd roxide pK a = 4.63
+ -
pK a = 10.66
NH2 + H2 O A niline
23-19
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 N H + H N H + H N
H
.
. .
H
. ..
H . H
N H
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
23-21
Basicity-Aromatic Amines
4-nitroaniline is a weaker base than 3-nitroaniline
O2 N NH2 3-N itroanilin e pK a 2.47 O2 N NH2
O +N O NH2
O +N NH2 +
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Basicity-Aromatic Amines
Heterocyclic
23-23
Basicity-Aromatic Amines
in pyridine, the unshared pair of electrons on N is not part of the aromatic sextet
.
. .
. .
H H
N H
an sp 2 h yb rid orbital; th e electron p air in this orbital is n ot a p art of the aromatic s extet nitrogen is sp 2 h yb rid ized
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)
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Basicity-Aromatic Amines
Imidazole
This ele ctron pair is not a part of the aromatic s extet Aromaticity is maintained when imidazole is protonate d H
+ H2 O
:
N
N+
+ OH-
H Imidazole
:
N
H Imidazoliu m ion
:
N
23-25
Basicity-Guanidine
Guanidine
NH2 H2 O
+
+
H2 N C NH2
p Ka = 13.6
its basicity is due to the delocalization of the positive charge over the three nitrogen atoms
+
H2 N
N H2
N H2
H2 N
N H2
N H2
N H2
H2 N
N H2
23-26
amines, whether soluble or insoluble in water, react quantitatively with strong acids to form water-soluble salts
OH HO NH2 + HCl H2 O HO HO (R)-N orepinep hrine h yd roch loride (a w ater-s olu ble salt) OH NH3 + Cl-
23-27
Preparation
We
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 arene2 followed by reduction of the NO2 group to 1 amines (22.1B)
23-28
Preparation
Alkylation
CH3 Br + N H3
unfortunately, such alkylations give mixtures of products through a series of proton transfer and nucleophilic substitution reactions
CH3 Br + NH3 CH3 NH3 Br + (CH3 ) 2 NH2 Br
+
+ (CH3 ) 3 NH Br + (CH3 ) 4 N Br
23-29
of azide ion
N + N N :RN 3 R N + N
-:
N:
An alk yl azide
-
K N3
1. LiAlH4
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23-31
acid, a weak acid, is most commonly prepared by treating NaNO2 with aqueous H2SO4 or HCl
HNO2 + H2O H3O + NO2
+ -
pK a = 3.37
In
participates in proton-transfer reactions is a source of the nitrosyl cation, NO+, a weak electrophile
23-32
(1)
H O N O + H
+ H O N O H H O + H +
(2)
N O
+ N O
we study the reactions of HNO2 with 1, 2, and 3 aliphatic and aromatic amines
23-33
2 . NaOH, H2 O N ,N-Dimethylaniline
N,N-D imethyl-4-nitrosoaniline
23-34
Step 1: reaction of the 2 amine (a nucleophile) with the nitrosyl cation (an electrophile) Step 2: proton transfer
+ N O
(1) H
N H H O H
+ N
(2)
N=O
+ + H O H H
N=O
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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
of a diazonium ion
H : : : keto-enol tautomerism
R -N - N = O : A n N-nitrosamine
R-N + N
N N
H + O-H
-H2 O R
+
: : : :
A diazoniu m ion
A carbocation
23-37
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
Cl
(5.2%)
OH
N H 2 N a N O2 , H Cl + OH
0-5oC
(13.2%)
+
(25%)
(25.9%)
(10.6%)
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23-39
: OH
CH2NH 2 HNO2
: :O H + CH2 :
: O-H
CH2 N N:
-N2
(A diazonium ion)
:
+ O H
CH2
A resonance-stabilized cation
proton transfer to H 2O
Cycloheptanone
23-40
-N2+ group of an arenediazonium salt can be replaced in a regioselective manner by these groups
H2 O HBF4 HCl, CuCl HNO2 0-5C
+ (-N ) 2
Ar-OH Ar-F Ar-Cl Ar-Br Ar-CN Ar-I Ar-H San dmeyer reaction Sch ieman n reaction
Ar-NH2
Ar-N2
23-41
23-42
COOH
OH
23-43
CH3
Cl
Cl
Cl
23-44
Hofmann Elimination
Hofmann
H2 O
CH3 (Cyclohexylmethyl)trimethyl- Silver oxide ammonium iodide CH3 OH+ CH2 - N - CH 3 + AgI
23-45
Hofmann Elimination
Step 2: thermal decomposition of the 4 ammonium hydroxide
CH 3 OH+ CH 2 -N - CH 3 CH 3 (Cyclohexylme thyl)trimethylammonium hydroxide CH2 + Methyle necyclohexane ( CH 3 ) 3 N + H2 O 160
Trime thylamine
23-46
Hofmann Elimination
Hofmann
heat
-
N(CH3 ) 3 OH
CH2 + (CH3 ) 3 N + H2 O
Hofmanns
rule: any -elimination that occurs preferentially to give the least substituted alkene as the major product is said to follow Hofmanns rule
23-47
Hofmann Elimination
HO H C H CH3 CH 2 C H H + N ( CH3 ) 3 HOH
H CH3 CH 2
H C C H N ( CH3 ) 3
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 haloalkanes
23-48
Cope Elimination
Cope
Step 2: if the amine oxide has at least one -hydrogen, it undergoes thermal decomposition to give an alkene
H + 100-150C CH2 N-CH3 CH3 O
-
Cope Elimination
Cope elimination shows syn stereoselectivity but little or no regioselectivity mechanism: a cyclic flow of electrons in a sixmembered transition state
C H
-
C N+ :O
C CH3 CH3
:
N O
Transition s tate
23-50
Amines
End Chapter 23
23-51