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⁺X^1- 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. K_b of the amine. Larger K_b (smaller pK_b) means a stronger base.
2. K_a of the conjugate acid of the amine (ammonium ion)

A stronger base has an ammonium ion with a small K_a (larger pK_a), and a weaker base has an ammonium ion with a large K_a (small pK_a). The more acidic the ammonium ion (larger K_a or smaller pK_a), 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 pK_a for ammonium ion.
Stronger base: Larger pK_a 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 -----> 1^o amine
RCONHR -----> 2^o amine
RCONR₂ -----> 3^o 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.  S_N2 Rxns of Alkyl Halides (alkylation of ammonia or alkylamine)
Ammonia and other alkylamines are good nucleophiles in S_N2 reactions.
                                                                        NaOH
Ammonia NH₃ + RX -------> RNH₃¹⁺X^1- --------> RNH₂ Primary
Primary RNH₂ + RX ------> R₂NH₂¹⁺X^1- --------> R₂NH Secondary
Secondary R₂NH + RX -----> R₃NH¹⁺X^1- ---------> R₃N Tertiary
Tertiary R₃N + RX ----------> R₄N¹⁺X^1- 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, N₃^1-, 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 --> 1^o amine
RCOR’ + 1^o amine --> reduction --> 2^o amine
RCOR’ + 2^o amine --> reduction --> 3^o 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
1^o Amine RNH₂ + RX ----> R₂NH₂¹⁺X^1- ----> R₂NH Secondary
2^o Amine R₂NH + RX ----> R₃NH¹⁺X^1- ----> R₃N Tertiary
3^o Amine R₃N + RX ----> R₄N¹⁺X^1- 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