-1-
ORGANOELEMENTS NOTES
NITROGEN
C-N σ-bonds are almost as strong as a typical C-C bond, so they are generally hard
to break (usually need to be charged). They are, however, slightly polarised due to
the electronegativity difference.
Much of the organic chemistry is driven by the lone pair on N. It also allows N to form
tetravalent (positively charged species), which are common. Hence it is basic.
Amines
pKa of ammonia is 9.26. Substituting alkyl groups for H’s increases the pKa (i.e. are
more basic). Electron-donating groups stabilise the positive charge, reducing Ka and
therefore raising the pKa.
Obviously, they are also nucleophiles. Amines react with alkyl halides via an SN2
mechanism. We expect to see multiple nucleophilic substitutions as the amine gets
more nucleophilic (alkyls e-donate to the N) such that we end up with tertiary amines
or ammonium salts. Generally, secondary amines are the best nucleophiles
(electrostatics) followed by primary (kinetics), with tertiary amines the worst
nucleophiles (sterically hindered).
Amines also react with carbonyls, forming imines and enamines, and with nitrous
acid (HNO2) – see later.
Synthesis of Amines
As has been mentioned earlier, forming amines by nucleophilic substitution with alkyl
halides etc. is unlikely to be useful, as further substitutions are likely to occur. Most
methods now use “monophilic” ammonia-based compounds.
Some examples:
The Gabriel Method
Note that a modified version of this with malonic esters allows the synthesis of simple
amino acids.
CF3CONH2/NaH, then OH-(aq)
Same type of reaction as the Gabriel method, but milder conditions.
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -2-
NaN3 then H2/Pd-C
This gives good yields. Azide is a good nucleophile that will only react once, and it is
then reduced.
(PhCH2)2NH then H2/Pd-C
Based on the removal of the benzyl group by hydrogenation.
KCN, then reduction
Another nucleophile that reacts only once. The product gains an extra carbon atom,
as the C is the nucleophilic part of the cyanide.
Amines via Reduction Reactions
Reagent LiAlH4 NaBH4 H2/catalyst
Imines 3 3 3
Amides 3 2 2
Nitro Groups 3 2 3
Nitriles 3 2 3
Imines
R1R2C=N-R3
• Susceptible to nucleophilic attack on carbon.
• Easily protonated to produce iminium ions.
• Prepared by reacting an amine with an aldehyde or ketone (requires water
removal to prevent equilibrium lying on amine + carbonyl side).
Reactions of Imines
It is always worth bearing in mind that imines and iminium ions are very easily
hydrolysed, which can lead to useful workup, or require specific conditions to avoid it.
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -3-
Imines are usually attacked by carbon nucleophiles, such as enolates and Grignards.
For most nucleophiles, the imine is not trapped in situ. However, in the Mannich-type
Reactions and also the Strecker Reaction it is.
Strecker Reaction:
Synthesis of amino acids.
Mannich Reactions:
Can trap iminium ions intermolecularly or intramolecularly.
e.g.
These reactions are successful because of the unhindered nature of the iminium ion,
and also that it holds a full positive charge and is thus very reactive.
Intramolecular versions happen very readily, and often lead to cyclisations, e.g.
This reaction is common in biosynthesis of many alkaloids.
Vilsmeyer Reaction:
Extension of the Mannich Reaction:
Good for forming aldehydes.
Reduction of Imines
This is a simple process that yields amines. Typical reducing agents are catalytic
hydrogenation or NaBH4.
Enamines
Using a secondary amine to attack a ketone instead of a primary amine often leads
to the formation of enamines instead of imines, like so:
This occurs because of the lack of the second proton on the nitrogen that can be lost.
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -4-
They almost always react as β-carbon nucleophiles (not at nitrogen), like enols. They
are more reactive than enols due to the positive charge, but less reactive than
negatively charged enolates.
Formation of Enamines
The formation is acid catalysed (slow otherwise), and requires the removal of water
(prevents hydrolysis, as for imines).
Unsymmetrical ketones can form two possible regioisomers. In practice, the more
substituted double bond is strongly favoured:
In general, enamines are formed under reversible conditions (thermodynamic
control), and the most stable alkene results (least sterically crowded):
Reactions of Enamines with Electrophiles
They react with alkyl halides, aldehydes, ketones, conjugated ketones and acid
chlorides, i.e. anything normally attacked by enols/enolates.
Hydrolysis of Enamines
This proceeds via the imine:
Enamine chemistry is often not used for substitution at the β-carbon, however. This is
because of the recent advances in enolate chemistry that allow greater control over
the products. Enamine chemistry is widely used for initiating intramolecular reactions,
however:
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
ORGANOELEMENTS NOTES
NITROGEN
C-N σ-bonds are almost as strong as a typical C-C bond, so they are generally hard
to break (usually need to be charged). They are, however, slightly polarised due to
the electronegativity difference.
Much of the organic chemistry is driven by the lone pair on N. It also allows N to form
tetravalent (positively charged species), which are common. Hence it is basic.
Amines
pKa of ammonia is 9.26. Substituting alkyl groups for H’s increases the pKa (i.e. are
more basic). Electron-donating groups stabilise the positive charge, reducing Ka and
therefore raising the pKa.
Obviously, they are also nucleophiles. Amines react with alkyl halides via an SN2
mechanism. We expect to see multiple nucleophilic substitutions as the amine gets
more nucleophilic (alkyls e-donate to the N) such that we end up with tertiary amines
or ammonium salts. Generally, secondary amines are the best nucleophiles
(electrostatics) followed by primary (kinetics), with tertiary amines the worst
nucleophiles (sterically hindered).
Amines also react with carbonyls, forming imines and enamines, and with nitrous
acid (HNO2) – see later.
Synthesis of Amines
As has been mentioned earlier, forming amines by nucleophilic substitution with alkyl
halides etc. is unlikely to be useful, as further substitutions are likely to occur. Most
methods now use “monophilic” ammonia-based compounds.
Some examples:
The Gabriel Method
Note that a modified version of this with malonic esters allows the synthesis of simple
amino acids.
CF3CONH2/NaH, then OH-(aq)
Same type of reaction as the Gabriel method, but milder conditions.
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -2-
NaN3 then H2/Pd-C
This gives good yields. Azide is a good nucleophile that will only react once, and it is
then reduced.
(PhCH2)2NH then H2/Pd-C
Based on the removal of the benzyl group by hydrogenation.
KCN, then reduction
Another nucleophile that reacts only once. The product gains an extra carbon atom,
as the C is the nucleophilic part of the cyanide.
Amines via Reduction Reactions
Reagent LiAlH4 NaBH4 H2/catalyst
Imines 3 3 3
Amides 3 2 2
Nitro Groups 3 2 3
Nitriles 3 2 3
Imines
R1R2C=N-R3
• Susceptible to nucleophilic attack on carbon.
• Easily protonated to produce iminium ions.
• Prepared by reacting an amine with an aldehyde or ketone (requires water
removal to prevent equilibrium lying on amine + carbonyl side).
Reactions of Imines
It is always worth bearing in mind that imines and iminium ions are very easily
hydrolysed, which can lead to useful workup, or require specific conditions to avoid it.
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -3-
Imines are usually attacked by carbon nucleophiles, such as enolates and Grignards.
For most nucleophiles, the imine is not trapped in situ. However, in the Mannich-type
Reactions and also the Strecker Reaction it is.
Strecker Reaction:
Synthesis of amino acids.
Mannich Reactions:
Can trap iminium ions intermolecularly or intramolecularly.
e.g.
These reactions are successful because of the unhindered nature of the iminium ion,
and also that it holds a full positive charge and is thus very reactive.
Intramolecular versions happen very readily, and often lead to cyclisations, e.g.
This reaction is common in biosynthesis of many alkaloids.
Vilsmeyer Reaction:
Extension of the Mannich Reaction:
Good for forming aldehydes.
Reduction of Imines
This is a simple process that yields amines. Typical reducing agents are catalytic
hydrogenation or NaBH4.
Enamines
Using a secondary amine to attack a ketone instead of a primary amine often leads
to the formation of enamines instead of imines, like so:
This occurs because of the lack of the second proton on the nitrogen that can be lost.
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -4-
They almost always react as β-carbon nucleophiles (not at nitrogen), like enols. They
are more reactive than enols due to the positive charge, but less reactive than
negatively charged enolates.
Formation of Enamines
The formation is acid catalysed (slow otherwise), and requires the removal of water
(prevents hydrolysis, as for imines).
Unsymmetrical ketones can form two possible regioisomers. In practice, the more
substituted double bond is strongly favoured:
In general, enamines are formed under reversible conditions (thermodynamic
control), and the most stable alkene results (least sterically crowded):
Reactions of Enamines with Electrophiles
They react with alkyl halides, aldehydes, ketones, conjugated ketones and acid
chlorides, i.e. anything normally attacked by enols/enolates.
Hydrolysis of Enamines
This proceeds via the imine:
Enamine chemistry is often not used for substitution at the β-carbon, however. This is
because of the recent advances in enolate chemistry that allow greater control over
the products. Enamine chemistry is widely used for initiating intramolecular reactions,
however:
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
