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Amines and Heterocycles
McMurry: Chapter 24
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Introduction to Amines and Heterocycles
Amines and heterocycles (cyclic amines) are ammonia derivatives many of which are found widely in living organisms:
Introduction to Amines and Heterocycles
derivatives, many of which are found widely in living organisms:
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Colourful Amines and Heterocycles
Nature has inspired chemists to duplicate natural dyes and create new synthetic ones to introduce colour to our world:
Colourful Amines and Heterocycles
create new synthetic ones to introduce colour to our world:
King George VI
N
O HN Br
- purpura molluscs
NHBr
O
purpura molluscs
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Heterocyclic Amines
Heterocycles are cyclic compounds containing at least one h
ete ocyc c es
heteroatom:
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Heterocyclic Amines
Heterocycles are found in many natural products that exhibit useful biological activity and in widely used pharmaceuticals:
ete ocyc c es
useful biological activity and in widely used pharmaceuticals:
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Amine Nomenclature
Amines are named by added the suffix –amine, but in more l d h i b i b icomplex compounds, the amine can be an amino substituent
or an aniline derivative:
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2
Complex compounds are treated as alkanamines with simpler alkyl groups on the amine identified with the locant “N”:alkyl groups on the amine identified with the locant N :
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Take‐Home: Nomenclature
Draw the following compounds:
a e o e: o e c atu e
• 4‐bromo‐N‐isopropyl‐3‐methylaniline
• (R,E)‐oct‐6‐en‐3‐amine
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Amine Structure and Propertiesp
Alkyl amines have an sp3‐N with approximately tetrahedral Th N H i i i h d b digeometry. The N‐H groups participate in hydrogen bonding:
Small amines have a bad odor resembling fi h/d i t i lfish/decaying material:
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Basicity of Alkyl Aminesy y
Amines have a lone pair of electrons on the nitrogen that make h b h b i d l hili ithem both basic and nucleophilic in nature:
Nucleophilic amine:Nucleophilic amine:
Basic amine:ammonium salt
ammonium salt
The relative base strengths of amines are calculated
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gusing the pKa of the ammonium salt!
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Basicity of Aminesy
ammonium salt
( d)k j b (NR ) Low pKa (strong acid)weak conjugate base (NR3) …
High pKa (weak acid)strong conjugate base (NR3) … g p a ( )g j g ( 3)
stronger base weaker basestronger base weaker base10
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Explaining Relative Basicity of Aminesp g yAmides are non‐basic and non‐nucleophilic due to resonance with the carbonyl:with the carbonyl:
Aryl amines are less basic than alkyl amines due to electron delocalization into the aromatic ring:
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Basicity of Aryl Aminesy ySubstituents on the aromatic ring varies the amine basicity:Electron donors: increase basicityElectron donors: increase basicity
‐ adds electron density to nitrogenElectron withdrawing: decrease basicityElectron withdrawing: decrease basicity
‐ withdraws electron density from nitrogen
strong base weak basestrong base weak base12
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IR Spectroscopy of AminesN‐H stretch: 3500‐3300 cm‐1
R NH h 1 b d hil RNH h 2 b d
Spect oscopy o es
• R2NH have 1 band while RNH2 have 2 bands • sharper and less intense than O‐H stretch
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NMR Spectroscopy of AminesNMR Spectroscopy of Amines13C NMR:
• Carbons attached to amines are deshielded and are found between 30‐65 ppm.
1H NMR: • RNH: variable chemical shift (1.0‐4.0 ppm, broad singlet)• R2CHNH: deshielded and found in the 2.0‐3.0 ppm range
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Amine Synthesis: SN2 ReactionsAmines are good nucleophiles, so they readily participate in SN2 reactions with alkyl halides:
y N
SN2 reactions with alkyl halides:
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Amine Synthesis: SN2 Reactions
How can SN2 reactivity be limited? U l f i i i lk l i
y N
Use a large excess of amine to maximize monoalkylation:
H th i S 2 ti it b d d tili d?How can the excessive SN2 reactivity be made and utilized? If the quaternary salt is desired, use excess alkylating reagent:
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Alkyl Amine Reactivity: Hofmann EliminationAmines (like alcohols) can be eliminated to give alkenes. Just like H2O is a better leaving group than –OH the amide ion (–NH2)
y e eact ty: o a at o
H2O is a better leaving group than OH, the amide ion ( NH2) must be converted to a better LG for elimination to occur:
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Alkyl Amine Reactivity: Hofmann EliminationElimination of the ammonium salt is promoted by silver oxide, which exchanges the iodide ion for a hydroxide ion Then an E2
y e eact ty: o a at o
which exchanges the iodide ion for a hydroxide ion. Then, an E2 reaction occurs to give the less substituted alkene due to sterics:
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Synthesis Problems*
Predict the products of the following Hofmann elimination reactions:
2 2
2 2
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Amine Synthesis: Azidesy
Azide ions (‐N3) are useful alternatives to NH3 since they only d S 2 i i d b d d 1° iundergo SN2 reactivity once and can be reduced to 1° amines:
4 22
2
3
NNalkyl azide
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Amine Synthesis: Gabriel Synthesisy y
The Gabriel synthesis of 1° amines utilizes phthalimide lk l i d i id h d l ialkylation and imide hydrolysis steps:
N
phthalimide
2
2
2
2
2
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Take‐Home Mechanism ProblemDraw the imide hydrolysis mechanism:*Hint: an imide is just like 2 amide functional groups!
a e o e ec a s ob e
j f g p
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Amine Synthesis: Reductive AminationyReductive amination is another common amine synthesis which involves converting an aldehyde or ketone to an iminewhich involves converting an aldehyde or ketone to an imine and then reduced it with sodium cyanoborohydride:
HN
O NaBH3CN OH
HCNB H Na
H
O 3
very slow
NH NaBH3CN NH2
H very fast23
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Synthesis ProblemsSy t es s ob e s
Complete the following Gabriel synthesis:
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Take‐Home Synthesis Problemsa e o e Sy t es s ob e sPredict the starting material or product in the following reactions:
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Aryl Amine Reactivity: Diazonium SaltsWhen aryl amines are treated with nitrous acid (made in situ), the reaction produces very useful and reactive intermediates
y e eact ty: a o u Sa ts
the reaction produces very useful and reactive intermediates called diazonium salts:
l f lk l b d h26
Diazonium salts from alkyl amines cannot be used since they spontaneously decompose!
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Diazonium Salts in Sandmeyer Reactions
Diazonium salts are useful because they can be replaced with a
a o u Sa ts Sa d eye eact o s
variety of substituents including halides in Sandmeyer reactions:
The mechanism is believed to occur via radical intermediates.
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Diazonium Salts in SEAr Reactions
Diazonium salts also couple with phenols and anilines in an S Ar reaction to give azo compounds:
a o u Sa ts SE eact o s
SEAr reaction to give azo compounds:
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Chemistry ConnectionsyAzo Compounds: Keeping Things Colourful!
Azo compounds have extended conjugation so theyAzo compounds have extended conjugation so they absorb in the visible region, which we perceive as colour:
•Small structural changes to the azo compound allows a variety of colours to be made.•These compounds are used widely as dyes (called azo p y y (dyes) for textiles, paint, food, cosmetics, and indicators.
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In‐Class Synthesis Problem
Predict the products of the following reactions:
C ass Sy t es s ob e
2
2 2
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Take‐Home Synthesis Problem*
Propose a synthesis for the following compounds using benzene
a e o e Sy t es s ob e
and phenol as your starting materials:
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