amines. nitrogen-based functional groups amines as pharmaceutical agents
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Amines
Nitrogen-Based Functional Groups
Amines as Pharmaceutical Agents
22.1Amine Nomenclature
The Naming of Parts
Alkylamines
Nitrogen atom isattached to alkyl group:
Arylamines
Nitrogen atom isattached to aryl group:
Nomenclature of Primary Alkylamines (RNH2)
Two IUPAC styles
1) analogous to alcohols: replace -e ending by -anamine
2) name alkyl group and attach -amine as a suffix
Nomenclature of Primary Alkylamines
n-propylamineor
propanamine
cyclopropylamineor
cyclopetanamine
2-bromo-3-chlorobutylamine
Nomenclature of Arylamines (ArNH2)
aniline
2,4-dibromoaniline
4-bromo-2-ethylaniline
These compounds are named as derivatives of aniline
Amino Groups have Lower Priority than Alcohols
aminoethanol
p-aminobenzoic acid
With regards to nomenclature, amines rank lower than alcohols and are named as substituents:
Secondary and Tertiary Amines
N,N-diisopropylethylamine(a.k.a. Hünig’s base)
4-bromo-N,N-dimethyl-2-methylaniline
Name as N-substituted derivatives of parent primary amine. The longest chain takes the root name.
Ammonium Salts (R4-nHnN+ X-)
Nitrogen atoms are positively charged when bonded to four substituents. The root name in this case is the ammonium ion (NH4
+). Remember to name as a salt - two words.
methylammonium acetate
N-ethyl-N-methylbenzylammonium chloride
Quaternary Ammonium Salts (R4N+ X-)
Nitrogen atoms are positively charged when bonded to four
substituents: when all of these substituents are carbon, the
molecule is referred to as a quaternary ammonium ion.
tetrabutylammonium fluoride(TBAF)
benzyltrimethylammonium hydroxide
Quaternary ammonium salts are relatively soluble in organic solvents and consequently are used as phase transfer catalysts
22.2Structure and Bonding
of Amines
147 pm147 pm
106°106°112°112°
Structure of Alkylamines
Note the high electron density on the nitrogen atom. The
chemistry of amines is dominated by reactivity of the lone
pair on this atom. Amines behave as nucleophiles and
Bronsted bases.
Alkylamines - Distribution of Electron Density
The hybridization adopted by nitrogen depends upon the nature of the N-substituents.Compare methylamine and formamide:
Alkylamines - Hydridization at Nitrogen
the hybridization adopted by nitrogen depends upon the nature of the N-substituents - compare methylamine and formamide.
Amines & Amides - Geometry at Nitrogen
Angle that the C—N bond makes with bisector ofH—N—H angle is a measure of the pyramidalization at nitrogen.
spsp33 spsp22
~125°~125°180°180°
142.5°142.5°
Amines - Geometry at Nitrogen
Angle that the C—N bond makes with bisector ofH—N—H angle is a measure of the pyramidalization at nitrogen.
142.5°142.5°
Amines - Geometry at Nitrogen
Geometry at the nitrogen atom in aniline is pyramidal; closer tomethylamine than to formamide.
142.5°142.5°
The hybridization of the nitrogen atom in aniline lies between sp2 and sp3
1) Delocalization of the nitrogen lone pair into the aromatic ring is most effective if the nitrogen atom is sp2-hybridized and planar.
2) A planar nitrogen atom increases repulsion between filled lone pair orbital and -system of aromatic ring - sp3 hybridization reduces this “bad” interaction.
Geometry of Aniline
Aniline - Distribution of Electron Density
Enforce a non-planar geometry (sp3-like) at the nitrogen center
- highest negative potential is on nitrogen.
Enforce a planar geometry (sp2-like) at the nitrogen center
- negative potential is shared by both nitrogen and ring.
22.3Physical Properties of
Amines
Amines - Physical Properties
Amines are more polar and have higher boiling points than alkanes; but are less polar andhave lower boiling points than alcohols.
CH3CH2CH3 CH3CH2NH2 CH3CH2OH
dipolemoment ():
boiling point:
0 D 1.2 D 1.7 D
-42°C 17°C 78°C
Amines - Physical Properties
Boiling points of isomeric amines decrease ingoing from primary to secondary to tertiary amines.
Primary amines have two hydrogens on nitrogen capable of being involved in intermolecular hydrogen bonding. Secondary amines have one. Tertiary amines cannot be involved in intermolecular hydrogen bonds.
CH3CH2NHCH3CH3CH2CH2NH2 (CH3)3N
boilingpoint:
50°C 34°C 3°C
22.4Basicity of Amines
Amines are Brønstead Bases and Nucleophiles
Brønstead Basicity of Amines
Basicity of Amines in Aqueous Solution
The Relationship between pKa and Basicity
The Relationship Between Basicity and Structure
Basicity of Amines in Aqueous Solution
The Relationship Between Basicity and Structure
Basicity of Amines in Aqueous Solution
Arylamines are Relatively Weak Brønstead Bases
Anilinium Ion
Arylamines are Relatively Weak Brønstead Bases
Increasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine.
Arylamines - Effect of Substituents on Basicity
1. Alkyl groups on the ring increase basicity by only one 1 pK unit.
2. Electron withdrawing groups, especially orthoand/or para to amine group, decrease basicityand can have a large effect.
Arylamines - Effect of Substituents on Basicity
Basicity of Arylamines - p-Nitroaniline
Lone pair on amine nitrogen is conjugated with p-nitro group—more delocalized than in aniline itself. This delocalization is lost upon protonation.
Electron Withdrawing Effects are Cumulative
Electron Withdrawing Effects are Cumulative
piperidine pyridinepyridinepKa of conjugate acid:
11.2
pKa of conjugate acid:
5.2
(an alkylamine)(an alkylamine)(resembles an(resembles anarylamine inarylamine in
basicity)basicity)
Heterocyclic Amines
imidazole pyridinepKa of conjugate acid:
7.0
pKa of conjugate acid:
5.2
Heterocyclic Amines
q. Which nitrogen is protonated in imidazole?
Protonation of Imidazole
Protonation in the direction shown gives a stabilized ion.
Protonation of Imidazole - Resonance Picture
The Term ‘Alkaloid’
The Term ‘Alkaloid’
The Term ‘Alkaloid’
Amines as Natural Products - Alkaloids
Conium maculatum Hemlock contains the alkaloid
coniine, among other compounds
The Toxic Alkaloids of Conium maculatum
Reduction of Nitroarenes - Example
Aromatic nitro compounds are easy to prepare and are readily Aromatic nitro compounds are easy to prepare and are readily reduced to the corresponding anilines under a wide range of reduced to the corresponding anilines under a wide range of conditions.conditions.
Reduction of Nitroarenes - Example
18.918.9
The Aldol CondensationThe Aldol Condensation
Aldol CondensationAldol Condensation
Aldol Condensation of ButanalAldol Condensation of Butanal
dehydration of dehydration of -hydroxy aldehyde can be-hydroxy aldehyde can be
catalyzed by either acids or basescatalyzed by either acids or bases
Dehydration of Aldol Addition ProductDehydration of Aldol Addition Product
CC OO
CC
CCOHOH
HHCC OO
CC
CC
in base, the enolate is formed in base, the enolate is formed
Dehydration of Aldol Addition ProductDehydration of Aldol Addition Product
OHOH
HHCC OO
CC
CC
NaOHNaOH
OHOH
CC OO
CC
CC
••••––
the enolate loses hydroxide to form the the enolate loses hydroxide to form the
,,-unsaturated aldehyde-unsaturated aldehyde
Dehydration of Aldol Addition ProductDehydration of Aldol Addition Product
OHOH
HHCC OO
CC
CC
NaOHNaOH
OHOH
CC OO
CC
CC
••••––
Aldol reactions of ketonesAldol reactions of ketones
the equilibrium constant for aldol addition the equilibrium constant for aldol addition reactions of ketones is usually unfavorablereactions of ketones is usually unfavorable
Termite Self-Defense!
Diethyl Zinc and Deacidification of Brittle BooksDiethyl Zinc and Deacidification of Brittle Books
14.1314.13Carbenes and Carbenes and
CarbenoidsCarbenoids
CarbeneCarbene
name to give to species that contains aname to give to species that contains adivalent carbon (carbon with two bondsdivalent carbon (carbon with two bondsand six electrons)and six electrons)
CC••••
BrBr BrBr
dibromocarbenedibromocarbene
Carbenes are very reactive; normally cannot be Carbenes are very reactive; normally cannot be isolated and stored.isolated and stored.Are intermediates in certain reactions.Are intermediates in certain reactions.
Generation of DibromocarbeneGeneration of Dibromocarbene
CC
BrBr
BrBr
BrBr
HH ++ OC(CHOC(CH33))33
––
••••
••••••••
HH++ OC(CHOC(CH33))33••••
••••CC
BrBr
BrBr
BrBr
––••••
Generation of DibromocarbeneGeneration of Dibromocarbene
++
CC
BrBr
BrBr
BrBr
––••••
CC••••
BrBr BrBr BrBr––
Carbenes react with alkenesCarbenes react with alkenesto give cyclopropanesto give cyclopropanes
+ CH+ CHBrBr33
BrBr
BrBr
(75%)(75%)CBrCBr22 is a highly reactive is a highly reactive (shortlived) intermediate(shortlived) intermediate
KOC(CHKOC(CH33))33
(CH(CH33))33COHCOH
Why the synthesis ofWhy the synthesis ofcyclopropanes is important?cyclopropanes is important?
Chrysanthemum cinerariaefolium
Why the synthesis ofWhy the synthesis ofcyclopropanes is important?cyclopropanes is important?
20.720.7Sources of EstersSources of Esters
3-methylbutyl acetate
also called "isopentyl acetate" and "isoamyl also called "isopentyl acetate" and "isoamyl acetate"acetate"
contributes to characteristic odor of bananascontributes to characteristic odor of bananas
Esters are Commonly Found in Natural Products
R, R', and R" can be the same or differentR, R', and R" can be the same or different
called "triacylglycerols," "glyceryl triesters," or called "triacylglycerols," "glyceryl triesters," or "triglycerides""triglycerides"
fats and oils are mixtures of glyceryl triestersfats and oils are mixtures of glyceryl triesters
Esters of Glycerol
Tristearin: found in manyanimal and vegetable fats
Fat & Oil are Mixtures of Glyceryl Triesters
(Z)-5-Tetradecen-4-olide(Z)-5-Tetradecen-4-olide(sex pheromone of female Japanese beetle)(sex pheromone of female Japanese beetle)
OOOO
HH
HH
CHCH22(CH(CH22))66CHCH33
Lactones are Cyclic Esters
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