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Transcript of chapter24 amine
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Chapter 24. Aminesand Heterocycles
Based on McMurrys Organic Chemistry, 7th edition
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Amines Organic Nitrogen
Compounds Organic derivatives of ammonia, NH3,
Nitrogen atom with a lone pair of electrons, makingamines both basic and nucleophilic
Occur in plants and animals
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Why this Chapter?
Amines and carbonyl compounds are the
most abundant and have rich chemistry
In addition to proteins and nucleic acids, a
majority of pharmaceutical agents contain
amine functional groups
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24.1 Naming Amines
Alkyl-substituted (alkylamines) or aryl-substituted(arylamines)
Classified: 1 (RNH2), methyl (CH3NH2), 2 (R2NH),3 (R3N)
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Quaternary Ammonium Ions
A nitrogen atom with four attached groups is
positively charged
Compounds are quaternary ammonium salts
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IUPAC Names Simple Amines
For simple amines, the suffix -amine is added to the
name of the alkyl substituent
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IUPAC Names -amine Suffix
The suffix -amine can be used in place of the final -e
in the name of the parent compound
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IUPAC Names Amines With More
Than One Functional Group
Consider the NH2 as an amino substituent on the
parent molecule
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IUPAC Names Multiple Alkyl
Groups
Symmetrical secondary and tertiary amines are
named by adding the prefix di- ortri- to the alkyl
group
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IUPAC Names Multiple, Different
Alkyl Groups
Named as N-substituted primary amines
Largest alkyl group is the parent name, and otheralkyl groups are considered N-substituents
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Common Names of Heterocyclic
Amines
If the nitrogen atom occurs as part of a ring, thecompound is designated as being heterocyclic
Each ring system has its own parent name
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24.2 Properties of Amines
Bonding to N is similar to that in ammonia
N is sp3-hybridized
CNC bond angles are close to 109 tetrahedral
value
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Chirality Is Possible (But Not
Observed) An amine with three different substituents on nitrogen
is chiral (in principle but not in practice): the lone pairof electrons is the fourth substituent
Most amines that have 3 different substituents on N
are not resolved because the molecules interconvertbypyramidal inversion
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Amines Form H-Bonds
Amines with fewer than five carbons are water-
soluble
Primary and secondary amines form hydrogen
bonds, increasing their boiling points
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24.3 Basicity of Amines
The lone pair of electrons on nitrogen makes aminesbasic and nucleophilic
They react with acids to form acidbase salts andthey react with electrophiles
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Relative Basicity
Amines are stronger bases than alcohols, ethers, orwater
Amines establish an equilibrium with water in whichthe amine becomes protonated and hydroxide is
produced The most convenient way to measure the basicity of
an amine (RNH2) is to look at the acidity of thecorresponding ammonium ion (RNH3
+)
High pKa weaker acid and stronger conjugatebase.
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General Patterns of Basicity
Table 24.1: pKa values of ammonium ions
Most simple alkylammmonium ions have pKa's of 10
to 11
Arylamines and heterocyclic aromatic amines areconsiderably less basic than alkylamines (conjugate
acid pKa 5 or less)
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Amides
Amides (RCONH2) in general are not proton acceptors except invery strong acid
The C=O group is strongly electron-withdrawing, making the N avery weak base
Addition of a proton occurs on O but this destroys the double
bond character of C=O as a requirement of stabilization by N
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24.4 Basicity of Substituted
Arylamines
The N lone-pair electrons in arylamines aredelocalized by interaction with the aromatic ring Telectron system and are less able to accept H+ thanare alkylamines
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Substituted Arylamines
Can be more basic or less basic than aniline
Electron-donating substituents (such as CH3,NH2, OCH3) increase the basicity of thecorresponding arylamine
Electron-withdrawing substituents (such as Cl,NO2, CN) decrease arylamine basicity
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24.5 Biological Amines and the
Henderson-Hasselbalch Equation What form do amines exist at physiological pH insidecells
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24.6 Synthesis of Amines
Arylamines are prepared from nitration of an aromaticcompound and reduction of the nitro group
Reduction by catalytic hydrogenation over platinum issuitable if no other groups can be reduced
Iron, zinc, tin, and tin(II) chloride are effective inacidic solution
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SN2 Reactions of Alkyl Halides
Ammonia and other amines are good nucleophiles
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Uncontrolled Multiple Alkylation
Primary, secondary, and tertiary amines all have
similar reactivity, the initially formed monoalkylated
substance undergoes further reaction to yield a
mixture of products
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Selective Preparation of Primary Amines:
the Azide Synthesis
Azide ion, N3 displaces a halide ion from a primary
or secondary alkyl halide to give an alkyl azide, RN3 Alkyl azides are not nucleophilic (but they are
explosive)
Reduction gives the primary amine
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Gabriel Synthesis of Primary
Amines
Aphthalimide alkylation for preparing a primary
amine from an alkyl halide
The N-H in imides (CONHCO) can be removed
by KOH followed by alkylation and hydrolysis
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Reductive Amination of Aldehydes
and Ketones
Treatment of an aldehyde or ketone with ammonia or
an amine in the presence of a reducing agent
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Reductive Amination Is
Versatile Ammonia, primary amines, and secondary aminesyield primary, secondary, and tertiary amines,
respectively
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Mechanism of Reductive Amination
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Reducing Step
Sodium cyanoborohydride, NaBH3CN, reduces C=Nbut not C=O
Stable in water
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Hofmann and Curtius
Rearrangements
Carboxylic acid derivatives can be converted intoprimary amines with loss of one carbon atom by boththe Hofmann rearrangement and the Curtiusrearrangement
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Hofmann Rearrangement
RCONH2 reacts with Br2 and base
Gives high yields of arylamines and alkylamines
Figure 24.5 See Mechanism
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Curtius Rearrangement
Heating an acyl azide prepared from an acid chloride
Migration ofR from C=O to the neighboring
nitrogen with simultaneous loss of a leaving group
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24.7 Reactions of Amines
Alkylation and acylation have already been presented
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Hofmann Elimination
Converts amines into alkenes
NH2 is very a poor leaving group so it converted to
an alkylammonium ion, which is a good leaving group
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Silver Oxide Is Used for the
Elimination Step
Exchanges hydroxide ion for iodide ion in the
quaternary ammonium salt, thus providing the base
necessary to cause elimination
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Orientation in Hofmann Elimination
We would expect that the more highly substitutedalkene product predominates in the E2 reaction of analkyl halide (Zaitsev's rule)
However, the less highly substituted alkene
predominates in the Hofmann elimination due to thelarge size of the trialkylamine leaving group
The base must abstract a hydrogen from the moststerically accessible, least hindered position
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Steric Effects Control the
Orientation
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24.8 Reactions of Arylamines
Amino substituents are strongly activating, ortho- and
para-directing groups in electrophilic aromatic
substitution reactions
Reactions are controlled by conversion to amide
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Arylamines Are Not Useful for
Friedel-Crafts Reactions
The amino group forms a Lewis acidbase complex
with the AlCl3 catalyst, preventing further reaction
Therefore we use the corresponding amide
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Diazonium Salts: The Sandmeyer
Reaction
Primary arylamines react with HNO2, yielding stable
arenediazonium salts
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Uses of Arenediazonium Salts
The N2 group can be replaced by a nucleophile
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Preparation of Aryl Halides
Reaction of an arenediazonium salt with CuCl orCuBr gives aryl halides (Sandmeyer Reaction)
Aryl iodides form from reaction with NaI without acopper(I) salt
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Aryl Nitriles and Carboxylic
Acids An arenediazonium salt and CuCN yield the nitrile,
ArCN, which can be hydrolyzed to ArCOOH
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Formation of Phenols (ArOH)
From reaction of the arenediazonium salt with
copper(I) oxide in an aqueous solution of copper(II)
nitrate
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Reduction to a Hydrocarbon
By treatment of a diazonium salt with
hypophosphorous acid, H3PO2
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Mechanism of Diazonium
Replacement
Through radical (rather than polar or ionic) pathways
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Diazonium Coupling Reactions
Arenediazonium salts undergo a coupling reactionwith activated aromatic rings, such as phenols andarylamines, to yield brightly colored azo compounds,
ArN=NArd
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How Diazonium Coupling Occurs
The electrophilic diazonium ion reacts with theelectron-rich ring of a phenol or arylamine
Usually occurs at the para position but goes ortho ifpara is blocked
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Azo Dyes
Azo-coupled products have extended T conjugationthat lead to low energy electronic transitions thatoccur in visible light (dyes)
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24.9 Heterocycles
A heterocycle is a cyclic compound that
contains atoms of two or more elements in its
ring, usually C along with N, O, or S
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Pyrole and Imidazole
Pyrole is an amine and a conjugated diene,
however its chemical properties are not
consistent with either of structural features
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Chemistry of Pyrole
Electrophilicsubstitutionreactions occur atC2 b/c it is position
next to the N
A more stableintermediate cationhaving 3 resonance
forms At C3, only 2
resonance forms
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Polycyclic Heterocycles
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24.10 Spectroscopy of Amines -
Infrared
Characteristic NH stretching absorptions 3300 to
3500 cm1
Amine absorption bands are sharper and less intense
than hydroxyl bands
Protonated amines show an ammonium band in
the range 2200 to 3000 cm1
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Examples of Infrared Spectra
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Nuclear Magnetic Resonance
Spectroscopy
NH hydrogens appear as broad signals without
clear-cut coupling to neighboring CH hydrogens
In D2O exchange of ND for NH occurs, and the N
H signal disappears
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Chemical Shift Effects
Hydrogens on C next to N and absorb at lower fieldthan alkane hydrogens
N-CH3 gives a sharp three-H singlet at H 2.2 to H 2.6
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13C NMR
Carbons next to amine N are slightly deshielded -about 20 ppm downfield from where they wouldabsorb in an alkane
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Mass Spectrometry
A compound with an odd number of nitrogen atomshas an odd-numbered molecular weight and acorresponding parent ion
Alkylamines cleave at the CC bond nearest thenitrogen to yield an alkyl radical and a nitrogen-containing cation
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Mass Spectrum of N-
Ethylpropylamine
The two modes of a cleavage give fragment ions atm/z= 58 and m/z= 72.