The Aldol Rxn
The Aldol Rxn is a carbonyl
condensation involving aldehydes and/or ketones to yield a-hydroxy
carbonyl compound which can be dehydrated.
Dehydration of Aldol Products: Synthesis of Enones
a-hydroxy
aldehydes and a-hydroxy
ketones (Aldol rxn products) can be easily dehydrated to yield conjugated
enones.
Mixed Aldol Rxns
In general, a mixed aldol reaction between two similar
ketone or aldehyde components leads to a mixture of four possible products.
Acetaldehyde + Propanal --> Four possible products (A, B, C, D)
(A) CH3CHOHCH2CHO Symmetrical cond. {Acetaldehyde donor / Acetaldehyde acceptor = AA}
(B) CH3CH2CHOHCH2(CH3)CHO Symmetrical cond. {Propanal donor / Propanal acceptor = PP}
(C) CH3CH2CHOHCH2CHO Mixed cond. {Acetaldehyde donor / Propanal acceptor = AP}
(D) CH3CHOHCH2(CH3)CHO Mixed cond. {Propanal donor / Acetaldehyde acceptor = PA}
The Claisen Condensation Reaction
Condensation of esters with
a
hydrogens to yield b-keto
esters.
1. NaOEt/EtOH
2 Ethyl acetate ---------------------> Ethyl acetoacetate
+ EtOH
2. H3O+
Mixed Claisen Condensations
Mixed Claisen condensations
are generally successful only when one of the two ester components has
no a hydrogens
and thus can't form an enolate ion.
Intramolecular Claisen Cond.: The Dieckmann Cyclization
The Dieckmann Cyclization is an intramolecular
Claisen condensation of diesters which yields cyclic b-keto
esters.
The Michael Reaction
The Michael Reaction is
a conjugate addition which occurs when a nucleophilic enolate ion reacts
with an a,b-unsaturated
carbonyl compound to give a conjugate addition product rather than the
direct addition product.
The Stork Enamine Reaction
The Stork Enamine Reaction
is a Michael-type process whereby an enamine adds to an a,b-unsaturated
carbonyl acceptor. The initial product is then hydrolyzed to yield a 1,5-dicarbonyl
compound.
Carbonyl Condensation Reactions in Synthesis: The Robinson
Annulation Reaction
The Robinson annulation is a two-step process that combines
a Michael reaction with an internal aldol reaction.
It takes place between a nucleophilic
donor, such as a b-keto
ester or b-diketone,
and an a,b-unsaturated
ketone acceptor such as 3-buten-2-one. The product is a substituted
2-cyclohexanone.
Amine Classification
Amines are classified according to the degree of substitution
at nitrogen (based on the number of organic substituents on nitrogen).
This is analogous to carbon but the atom of reference is now nitrogen.
Primary amine (one substituent) CH3NH2
Methylamine
Secondary amine (two substituents) (CH3)2NH
Dimethylamine
Tertiary amine (three substituents) (CH3)3N
Trimethylamine
Quaternary ammonium salts (four substituents) (CH3)4N1+X1-
Tetramethylammonium iodide
Amine Nomenclature
IUPAC allows two methods for simple primary amines:
1. Name as alkyl amines. Add the suffix -amine to the
name of the alkyl substituent.
2. Name systematically. Add suffix –amine to the name
of the chain or ring.
Amines with more than one functional group are named
by considering the -NH2 as an amino substituent on the parent
molecule. Symmetrical secondary and tertiary amines are named by
adding the prefix di- or tri- to the alkyl group. Unsymmetrical substituted
secondary and tertiary amines are named as N-substituted primary amines.
The largest alkyl group is chosen as the parent name, and the other alkyl
groups are considered N-substituents on the parent. Heterocyclic amines
incorporate nitrogen atom as part of a ring. Each ring has its own parent
name with the nitrogen as the number 1 position.
Properties of Amines
Similar to ammonia. Nitrogen is sp3 hybridized
with three substituents occupying three corners of a tetrahedron and the
fourth occupied by the lone pair. Bond angles close to 1090.
Amines with fewer than 5 carbons are water soluble.
Primary and secondary form hydrogen bonds.
Low-molecular-weight amines have fish-like odors.
Amine Basicity
Amine chemistry is dominated by lone pair.
Because of the lone pair, amines are both basic and nucleophilic.
Amines turn red litmus paper blue.
Amines are more basic than alcohols, ethers, or water.
Basicity: Hydroxide, Alkoxide, Carbanions >> Amines > Water
Two conventions to measure base strength of amines:
1. Kb of the amine. Larger Kb (smaller
pKb) means a stronger base.
2. Ka of the conjugate acid of the amine (ammonium
ion)
A stronger base has an ammonium ion with a small Ka (larger pKa), and a weaker base has an ammonium ion with a large Ka (small pKa). The more acidic the ammonium ion (larger Ka or smaller pKa), the weaker the base.
Amides are completely nonbasic.
Base strength of arylamines is generally lower than that of aliphatic amines.
Amine Base Rxns
Acid + Base ------> Salt + Water
HCl + NaOH ----> NaCl + H2O
HCl + NH3 ----> NH4Cl
(N with 3 bonds/1 lone pair = neutral)
(N with 4 bonds/0 lone pair = positive)
(N with 2 bonds/2 lone pair = negative)
HCl + RNH2 ----> RNH3Cl
HCl + CH3NH2 ----> CH3NH3Cl
HCl + R2NH ----> R2NHCl
HCl + R3N ----> R3NHCl
Acidity of the Ammonium Cation
NH4Cl + NaOH ----> NaCl + H2O +
NH3
RNH3Cl + NaOH ----> NaCl + H2O + RNH2
Weaker base: Smaller pKa for ammonium ion.
Stronger base: Larger pKa for ammonium ion.
Synthesis of Amines
A. Nitrile Reduction. Outcome is a
primary alkyl halide is converted into a primary amine having one more
carbon atom than the alkyl halide.
NaCN
1. LiAlH4, Et2O
1 o Alkyl halide ----------------> RCN --------------------->
1 o Amine
DMF
2. H2O
NaCN
1. LiAlH4, Et2O
Ethylbromide -------------> CH3-CH2-CN
-----------------------> CH3-CH2-CH2-NH2
DMF
2. H2O
B. Amide Reduction
RCONH2 -----> 1o amine
RCONHR -----> 2o amine
RCONR2 -----> 3o amine
1. SOCl2
2. CH3-CH2-CH2-NH2
Propanoic acid -----------------------------> (CH3-CH2-CH2-)2NH
3. LiAlH4, Et2O
4. H2O
C. Arylamine Preparation
Aryl amines are most often prepared by nitration of an
aromatic starting material, followed by reduction of the nitro group.
The reduction step can be:
1. Catalytic hydrogenation over Pt, but is often incompatible
with the presence elsewhere in the molecule of other reducible groups,
such as C=C or carbonyl groups.
Nitro compd + H2/Pt/EtOH
--> arylamine
2. Fe, Zn, Sn, and stannous chloride (SnCl2)
are effective in acidic aqueous solution. Stannous chloride is particularly
mild and is often used when other reducible functional groups are present.
Nitro compd + (1)Fe/HCl (2)NaOH/H2O
--> arylamine
Nitro compd + (1)SnCl2/H3O1+
(2)NaOH/H2O --> arylamine
EXAMPLE
1. SnCl2, H3O1+
2,4-dinitrotoluene --------------------> 2,4-diaminotoluene
2. NaOH, H2O
D. SN2 Rxns of Alkyl Halides (alkylation
of ammonia or alkylamine)
Ammonia and other alkylamines are good nucleophiles in
SN2 reactions.
NaOH
Ammonia NH3 + RX -------> RNH31+X1-
--------> RNH2 Primary
Primary RNH2 + RX ------> R2NH21+X1-
--------> R2NH Secondary
Secondary R2NH + RX -----> R3NH1+X1-
---------> R3N Tertiary
Tertiary R3N + RX ----------> R4N1+X1-
Quaternary ammonium salt
Reaction does not stop after single alkylation. Primary, secondary, and tertiary amines all have similar reactivity so the initially formed monoalkylated compound often undergoes further alkylation to yield a mixture of products.
E. Azide Synthesis
1. Azide ion, N31-, is used to
displace halide ion from primary or secondary halides to give an
alkyl azide, RN3. Overalkylation cannot occur.
2. Reduction by catalytic hydrogenation over a palladium catalyst or by reaction with LiAlH4 leads to the desired primary amine.
EXAMPLE
1-Bromo-2-phenylethane + NaN3/EtOH --> Ph-CH2-CH2-N=N=N
(2-Phenylethyl azide)
2-Phenylethyl azide + (1) LiAlH4 (2) H2O
--> 2-Phenylethylamine
F. Gabriel Amine Synthesis
1. Phthalimide alkylation of alkyl halide to prepare
primary amines.
2. Imides (-CONHCO-) are similar to ethyl acetoacetate
in that the N-H hydrogen is flanked by two carbonyl groups. Thus, imides
are deprotonated and the resultant anions are readily alkylated in a reaction
similar to the acetoacetic ester synthesis.
3. Basic hydrolysis of the N-alkylated imide then yields
a primary amine.
1. KOH / EtOH
2. Ph-CH2-Cl / DMF
Phthalimide ---------------------------> benzylamine
3. NaOH / H2O
G. Reductive Amination of Ketones and Aldehydes
1 o, 2 o, or 3 o amines
can be prepared.
Reducing Agents: H2 / Ni or
Sodium cyanoborohydride, NaBH3CN / MeOH
NaBH3CN / MeOH
Cyclohexanone + Dimethylamine ---------------------------->N,N-Dimethylcyclohexylamine
Ammonia, primary amines, and secondary amines can all be used in the reductive amination reaction to yield primary, secondary, and tertiary amines, respectively.
RCOR’ + Ammonia --> reduction --> 1o amine
RCOR’ + 1o amine --> reduction --> 2o
amine
RCOR’ + 2o amine --> reduction --> 3o
amine
H. Rearrangements: Hofmann and Curtius
Rearrangements
Carboxylic acid derivatives converted into primary amines
with the loss of one carbon atom.
H1. Hofmann Rearrangement
Involves A Primary Amide.
RCONH2 + NaOH / Br2 / H2O ---> RNH2
+ CO2
H2. Curtius
Rearrangement Involves An Acyl Azide.
RCON=N=N + Heat / H2O ---> RNH2 + CO2
+ N2
Reactions of Amines
A. Alkylation
1o Amine RNH2 + RX ----> R2NH21+X1-
----> R2NH Secondary
2o Amine R2NH + RX ----> R3NH1+X1-
----> R3N Tertiary
3o Amine R3N + RX ----> R4N1+X1-
Quaternary ammonium salt
B. Acylation
Ammonia or amine + acid chloride ---> amide
NH3 + ROCl (Pyridine/ether) --> RCONH2
+ HCl
RNH2 + ROCl (Pyridine/ether) --> RCONHR +
HCl
R2NH + ROCl (Pyridine/ether) --> RCONR2
+ HCl
C. Hofmann Elimination
Amines converted to alkenes by an elimination.
XS CH3I
Ag2O / H2O / Heat
Hexylamine -------------> Hexyltrimethylammonium iodide
-----------------------> 1-Hexene + Trimethylamine
Hofmann elimination gives products different from most E2 reactions. The more highly substituted alkene predominates in E2 reaction of an alkyl halide (Zaitsev's rule = "Poor get poorer.").
Amine Synthesis and Reaction Review Problems
1. CH3NH2
1. Acetone --------------------> ?
2. NaBH3CN
1. NaCN / DMF
2. Ph-CH2-Cl ----------------------> ?
2. LiAlH4, Et2O
3. H2O
NaOH, Br2
3. CH3-CONH2 -------------------->
?
H2O
1. HNO3 / H2SO4
4. Benzene -------------------------> ?
2. SnCl2, H3O1+
3. NaOH(aq)
5. Cyclohexylamine + HCl ----> ?
1. NaN3 / EtOH
6. Ph-CH(Cl)-CH3 ----------------------> ?
2. LiAlH4, Et2O
3. H2O
1. SOCl2
2. CH3NH2
7. Benzoic acid ----------------------> ?
3. LiAlH4, Et2O
4. H2O
1. NaCN / DMF
8. Cl-CH2-CH2-CH2-Cl
---------------------> ?
2. LiAlH4, Et2O
3. H2O
NaOH
9. NH3 + CH3-CH2-Cl
-----------> ?
1. KOH / EtOH
2. CH3-CH2-Cl / DMF
10. Phthalimide ---------------------------> ?
3. NaOH / H2O
11. How could you prepare butylamine?
12. What carbonyl compound and what amine would be required to prepare N,N-diethylbenzylamine?
13. Using reductive amination of a carbonyl compound, show all precursors for the production of N-ethylisopropylamine.
Pyridine
14. Acetyl chloride + Ph-CH2-NH2
--------------> ?
15. Show both products expected from the Hofmann elimination reaction of 2-aminobutane.
16. Starting with any alkyl halide and any carboxylic acid, show how you would prepare triethylamine.
Reactions of Arylamines
A. Electrophilic Aromatic Substitution
Amino substituents are strongly activating, ortho- and para-directing groups in EAS rxns (Sec. 16.5).
EXAMPLE:
1. arylamine + acetic anhydride/pyridine --> aromatic
amide
2. amide + Br2 ---> ortho-substituted bromo
amide
3. ortho-substituted bromo amide + NaOH/H2O
--> o-bromo aniline
EXAMPLE: Friedel-Crafts
1. Aniline + acetic anhydride/pyridine --> Amide
2. Amide + benzoyl chloride/AlCl3 --> p-acylated
amide
3. p-acylated amide + NaOH/H2O --> p-acylated
arylamine
B. Diazonium Salts: The Sandmeyer Reaction
Primary amines react with nitrous acid, HNO2,
to yield stable arenediazonium salts, Ar-N=N+X-.
EXAMPLE of the Sandmeyer Rxn
o-Methylaniline + HNO2/H2SO4
---> o-methylbenzenediazonium bisulfate
o-methylbenzenediazonium bisulfate + KCN /CuCN ---->
o-Methylbenzonitrile
o-Methylbenzonitrile + H3O1+ --->
o-Methylbenzoic acid
C. Diazonium Coupling Rxns
Arenediazonium salts undergo a coupling reaction with
activated aromatic rings to yield brightly colored azo compounds,
Ar-N=N-Ar'. Substituent on ring could be -OH or -NH2.
Suggested problems for Chapter 24 Amines
24.23; 24.24; 24.25; 24.27; 24.29; 24.30; 24.31; 24.34; 24.35