Amines | Organic Chemistry 3

Amines are studied in this chapter: nomenclature and properties of amines, preparation of amine by substitution reactions, reductive amination, and reductions, reactivity of amines, Hofmann elimination, reactions of amines with nitrous acid, Mannich reaction.

Nomenclature of Amines

Amines:

Derivatives of ammonia NH3, in which one or more hydrogen atoms have been replaced by alkyl or aryl groups. Amines are classified as primary, secondary, or tertiary depending on the number of groups attached to the nitrogen atom.

 

 

Nomenclature of primary amines:

The IUPAC nomenclature allows 2 different ways of naming primary amines, which can be used in most cases:

  • Common name: If the alkyl group is rather simple, the compound is generally named as an alkylamine.
    1. Name the alkyl group attached to the nitrogen atom.
    2. Add the suffix -amine.
  • Systematic name: Amines containing more complex alkyl groups are generally named as alkanamines.
    1. Find the longest continuous carbon chain attached to the amine nitrogen.
    2. Change the -e ending of the corresponding alkane to -amine.
    3. Then, using the usual rules of nomenclature, number the chain and name the substituents.

The amine functional group has the lowest order of priority of all functional groups except alkene, alkyne and halogens. The prefix amino- is used when the amine is a substituent.
 



Nomenclature of secondary and tertiary amines:

Again, the IUPAC nomenclature allows 2 different ways to name secondary and tertiary amines:

  • Common name: when all alkyl groups are rather simple.
    1. Name the alkyl group attached to the nitrogen atom and list them in alphabetical order.
    2. Add the prefixes di- and tri- if the same alkyl group appears more than once.
    3. Add the suffix -amine.
  • Systematic name: If one of the alkyl groups is complex, the compound is usually named as an alkanamine.
    1. Find the most complex alkyl group ⇒ this group is treated as the parent chain, while the simpler alkyl groups are treated as substituents.
    2. Change the -ane ending of the corresponding alkane to -amine.
    3. Then, using the usual rules of nomenclature, number the chain and name the substituents. Use the locant N- to indicate that a group is connected to the nitrogen atom.

 

 


Nomenclature of aromatic amines:

Aromatic amines are generally named as derivatives of aniline. The numbering of the aromatic ring begins at the carbon attached to the amino group and continues in the direction that gives the lower number to the first point of difference. When the name is assembled, all substituents are listed alphabetically.

 

 

Properties of Amines

Physical properties:

Amines have properties similar to alcohols, but nitrogen is less electronegative than oxygen and therefore has weaker hydrogen bonding.

  • Polarity: Nitrogen is more electronegative than carbon or hydrogen, making C-N and N-H bonds polar ⇒ significant dipole moment.
  • Solubility: Amines are soluble in organic solvents. Molecules with less than 6 carbons are soluble in water, favored by the formation of hydrogen bonds.
  • Boiling points: Higher than analogous alkanes, but lower than analogous alcohols. The boiling point of amines increases as a function of their ability to form hydrogen bonds: bp (RNH2) > bp (R2NH) > bp (R3N).

 

Geometry and orbitals:

  • The nitrogen of an amine is sp3 hybridized (the lone pair occupying an sp3 hybridized orbital) ⇒ trigonal pyramidal geometry.
  • Amines containing 3 different alkyl groups are chiral compounds: the nitrogen atom has 4 different groups (3 alkyl groups and a lone pair). However, amines are not optically active at room temperature because pyramidal inversion occurs rapidly, producing a racemic mixture of enantiomers.

 Alkanamine is tetrahedral

 

Absorption spectroscopy:

  • 1H NMR: δ ~ 1.0-5.0 ppm (broad signal).
  • IR spectroscopy: ~ 3350-3500 cm-1 (N-H stretching, less intense band than O-H signals)
    Primary amines give 2 peaks (symmetric and asymmetric stretching), while secondary amines give only 1 peak.

Preparation of Amines via Substitution Reactions

Alkylation of ammonia:
 

Mechanism:

Ammonia is a good nucleophile and can attack alkyl halide in an SN2 process.

  1. Nucleophilic attack of the ammonia on the alkyl halide to form an ammonium salt.


     
  2. Deprotonation of the ammonium salt to form a primary amine.


     
  3. Further alkylations to form secondary amine, tertiary amine, and finally quaternary ammonium salt.

 

Limitations: each alkylation makes the nitrogen atom more nucleophilic ⇒ polyalkylation is generally unavoidable, alkylation of ammonia is not efficient for synthesis of primary amines.

 

Synthesis of amines from azides:
 


Conversion of an alkyl azide into a primary amine via SN2 process and reduction reaction.

Mechanism:

  1. Nucleophilic attack of the azide ion on the alkyl halide to form an alkyl azide.
  2. Nucleophilic attack of a hydride ion from LiAlH4 on the alkyl azide.
  3. Loss of a leaving group, nitrogen gas N2, to form an amide ion.
  4. Protonation of the amide ion to form a primary amine.


     

Azide synthesis is a better method for preparing primary amines than alkylation of ammonia because it avoids polyalkylation (formation of secondary and tertiary amines).

 

Synthesis of amines from nitriles:
 


Conversion of a nitrile into a primary amine via SN2 process and reduction reaction.

Mechanism:

  1. Nucleophilic attack of the cyanide ion on the alkyl halide to form a nitrile.
  2. Nucleophilic attack of a hydride ion on the cyano group to form an anion which complexes with the AlH3.
  3. Second nucleophilic attack of a hydride ion on the carbon of the former cyano group to form a dianion which complexes with the AlH3.
  4. Hydrolysis with water to protonate the dianion and form a primary amine.

This method avoids polyalkylation and results in the introduction of an additional carbon atom (from the cyano group).

 

Gabriel Synthesis:


Conversion of an alkyl halide into a primary amine.

Mechanism:

  1. Deprotonation of the phthalimide (pKa = 8.3) to form potassium phthalimide.
  2. Nucleophilic attack of the potassium phthalimide on the alkyl halide to form an alkylated imide.
  3. Nucleophilic acyl substitution reactions with hydrazine (NH2NH2) to release the primary amine.


     


This method avoids overalkylation and allows the synthesis of primary amines.

Acid- or base-catalyzed hydrolysis can also be used to release the amine by a mechanism analogous to the hydrolysis of amides, but this approach is slow.
 


Gabriel synthesis works well with primary and many secondary alkyl halides, but not with tertiary alkyl halides.

Preparation of Amines via Reductive Amination

Synthesis of amines from aldehydes and ketones (reductive amination):
 


Conversion of an aldehyde or ketone into a 1o, 2o, or 3o amine.

Mechanism:

  1. Nucleophilic attack of NH3 (or other amines) on the carbonyl group to form an imine.
  2. Reduction of the imine with sodium cyanoborohydride (NaBH3CN) to form an amine.


     


Sodium cyanoborohydride (NaBH3CN) is used as the reducing agent in the reductive amination because it is more selective than NaBH4 ⇒ NaBH4 would reduce the starting ketone or aldehyde, while NaBH3CN would only reduce the intermediate protonated imine (not the carbonyl groups).

Reductive amination is widely used for the selective preparation of primary, secondary and tertiary amines.

 

Synthesis of amines from carboxylic acid:
 


Conversion of a carboxylic acid into 1o, 2o, or 3o amine by reduction of amides.

Mechanism:

  1. Conversion of a carboxylic acid into an acid chloride and then into an amide.
  2. Reduction of the amide to form the desired amine.

Reactivity of Amines

Reactivity of amines:

The nitrogen atom of an amine has a lone pair ⇒ The reactivity of amines is dominated by this nonbonded pair on the nitrogen atom:

  • Amines can be used as bases (pKa of alkyl amines is ~10-11):

 

  • Amines can be used as nucleophiles:

 

Amines as nucleophiles (review):

  •  Reactions with aldehydes and ketones:
     


Conversion of an aldehyde or ketone into an imine (with 1o amine) or an enamine (with 2o amine).

Mechanism:

  1. Nucleophilic addition of the amine to the carbonyl group to form a carbinolamine.
  2. Loss of water to form an imine or an enamine.

 

  • Reaction with acid chlorides and acid anhydrides:
     


Conversion of an acid chloride or acid anhydride into an amide.

Mechanism:

  1. Nucleophilic attack of the amine on the carbonyl group to form a tetrahedral intermediate.
  2. Loss of the leaving group, Cl- or RCOO-, to re-form the carbonyl and yield an amide.

Hofmann Elimination

Ammonium salt as a good leaving group:

Hofmann elimination is an E2 process and requires the conversion of the amino group into a better leaving group. This is done by converting the amino group into a quaternary ammonium salt via exhaustive alkylation in the presence of excess methyl iodide.


 

Hofmann elimination:
 


Conversion of an amine into an alkene via an E2 process.

Mechanism:

  1. Nucleophilic attack of the amine on the methyl iodide (CH3I) to form a quaternary ammonium salt.
  2. Conversion of the ammonium salt into another ammonium salt by exchange of the iodide ion for a hydroxide ion.
  3. Upon heating, deprotonation of a proton from the β carbon atom and loss of the leaving group, a tertiary amine, to form an alkene.

 

Regioselectivity of the Hofmann elimination:

In an Hofmann elimination, the major product is the less substituted alkene.

This regioselectivity is in opposite from other E2 eliminations, which form the more substituted alkene (Zaitsev rule). This result can be explained by the steric hindrance of the leaving group (a tertiary amine) ⇒ the base will deprotonate the proton from the less substituted, more accessible β carbon atom.

 

Reactions of Amines with Nitrous Acid

Formation of nitrous acid and nitrosonium ions:
 

Mechanism:

  1. Protonation of nitrite ion to form nitrous acid.
  2. Protonation of nitrous acid to form an oxonium ion.
  3. Loss of the leaving group, a molecule of water, to form a nitrosonium ion.


     


Reactions of primary amines and nitrous acid (diazotization):
 


Conversion of a 1o amine into a diazonium ion.

Mechanism:

Part 1 - Formation of an N-nitrosamine

  1. Formation of a nitrosonium salt from sodium nitrite (NaNO2) and HCl.
  2. Nucleophilic attack of a primary amine on the nitrosonium ion to form an ammonium ion.
  3. Deprotonation of the ammonium ion to form an N-nitrosamine.


     

Part 2 - Loss of H2O to form a diazonium ion

  1. Protonation of the oxygen atom.
  2. Deprotonation of the second proton of the starting amine to form a double bond between the nitrogen atoms.
  3. Protonation of the oxygen atom to form a good leaving group.
  4. Loss of the leaving group, H2O, to form a diazonium ion.


     

 

Stability of diazonium ions:

  • Alkyldiazonium salt is highly unstable and is too reactive to be isolated ⇒ it can spontaneously release nitrogen gas N2 to form a carbocation, which then reacts in a variety of ways to form a mixture of substitution, elimination, and rearrangement products.
     

 

  • Aryldiazonium salt is stable enough to be isolated ⇒ it does not release nitrogen gas because this would involve the formation of a high-energy aryl cation. Aryldiazonium salt are useful synthetic intermediates.
     


Aryldiazonium ions are stabilized by resonance:
 

 


Reactions of secondary amines and nitrous acid:
 


Conversion of a 2o amine into an N-nitrosamine.

Mechanism:

  1. Formation of a nitrosonium ion.
  2. Nucleophilic attack of the amine on the nitrosonium ion to form an ammonium salt.
  3. Deprotonation of the ammonium salt to form an N-nitrosamine.

Mannich Reaction

Mannich reaction:


Conversion of an aldehyde or ketone into a β-aminoalkyl carbonyl compound.

Mechanism:

  1. Nucleophilic addition of the amine to the carbonyl group to form an iminium ion.


     
  2. Enolization.


     
  3. Nucleophilic attack of the enol on the iminium ion to form a carbon-carbon bond.
  4. Proton transfer to form an ammonium salt.
  5. Deprotonation of the ammonium to form a β-aminoalkyl carbonyl compound.


     


The Mannich reaction can be thought of as a variation of the aldol condensation where a carbonyl is replaced by an imminium ion. It works well with primary and secondary aliphatic amines, but not with aromatic amines.