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Nucleophilic addition – reaction of aldehydes and ketones
• C of C=O is delta positive (the most electrophilic centre).
• R groups are inductively donating and reduce delta positive charge on C of
C=O. Ketones have two R groups and so are less reactive with nucleophiles
than aldehydes.
• Nucleophiles react with carbonyls as shown below – they attack at delta
positive C of C=O breaking pi bond and generating intermediate alkoxide.
• Resulting intermediate is typically protonated to give product.
http://www.mhhe.com/physsci/chemistry/carey/student/olc/ch17nucleophilicaddition.html
Reaction with a hydride – reduction to alcohol
• Lithium aluminium hydride (LiAlH4) and sodium borohydride (NaBH4)
reduce aldehydes and ketones to alcohols.
• Both species can be simplified as H- which is the nucleophile that adds
to the carbonyl.
• Attack at the electron poor C of the C=O gives an alkoxide:
• On work-up the alkoxide is protonated by the aqueous media:
http://www.chemguide.co.uk/mechanisms/nucadd/reduce.html
Reaction with a nitrile
• Cyanide addition to carbonyls occurs in exactly the same manner.
• Initial attack by nucleophilic cyanide results in breakage of pi bond to give
intermediate alkoxide which is quenched out on protons present in the
reaction.
• Note that the difference here from reaction with LiAlH4 or NaBH4 is that
reaction occurs in presence of acid/aqueous media (hydride sources would
react with protic media to give hydrogen).
http://osxs.ch.liv.ac.uk/java/A%20Level%20Nucleophilic%20substitution%20at%20the%20carbonyl%20group%20-%20Cyanohydrin%20formation.html
Imine formation
• Imine formation is also a nucleophilic addition.
• There is a different end result here, though as elimination of water occurs.
• The initial reaction is attack of the amine on the carbonyl to give the alkoxide
intermediate as normal.
• Following protonation of the alkoxide and loss of the proton on the amino moiety,
an aminol is generated.
• The presence of acid in the media is key for the next step as the hydroxyl group is
protonated becoming a good leaving group (reaction occurs very slowly in
absence of acid).
• Loss of water generates the imine.
http://usefulchem.wikispaces.com/Chapter+4+-+Imine+Synthesis
Nucleophilic addition/elimination
• For addition/elimination mechanism, the initial step is the same as we have seen
previously. Attack on the carbonyl carbon generates an alkoxide intermediate (the
tetrahedral intermediate).
• The difference here is that there is a group capable of leaving the tetrahedral
intermediate to regenerate a carbonyl species.
http://chemwiki.ucdavis.edu/Textbook_Maps/Map%3A_Bruice_6ed_Organic_Chemistry/17%3A_Carbonyl_Compounds_I%3A_Reactions_of_Carbo
xylic_Acids_and_Carboxylic_Derivatives/17.7____General_Mechanism_for_Nucleophilic_Addition-Elimination_Reactions
Reaction of acid chlorides
• A good example of this mechanism is reaction of acid chlorides with amines or
alcohols – the first step is as we have seen previously.
• However, the chloride is a good leaving group and the alkoxide can regenerate the
carbonyl ejecting the chloride:
• Removal of the proton of the amine by chloride (or by an amine molecule) gives an
amide:
http://www.chemguide.co.uk/mechanisms/addelim/amines.html
Why is the mechanism different than for aldehydes/ketones?
• The tetrahedral intermediate generated with aldehydes or ketones would need to
eject the high energy H- or R- to regenerate a carbonyl.
• We say that these are poor leaving groups unlike Cl- which is a low energy stable
anion.
• Acid intermediates can be ranked in order of reactivity as shown below:
http://chemwiki.ucdavis.edu/Textbook_Maps/Map%3A_Bruice_6ed_Organic_Chemistry/17%3A_Carbonyl_Compounds_I%3A_Reactions_of_Carboxylic_Acids_and_Carb
oxylic_Derivatives/17.7____General_Mechanism_for_Nucleophilic_Addition-Elimination_Reactions
A very important addition/elimination reaction
• Aspirin is made by an addition/elimination reaction.
• The phenol attack the acid anhydride (slightly less reactive than acid chloride
but still very reactive).
• As usual a tetrahedral intermediate is generated.
• This intermediate can regenerate the carbonyl by ejection of CH3CO2(ethanoate) as a leaving group – this give an ester.
• The whole mechanism can be drawn in one step with a double-headed arrow
on the carbonyl as shown below:
• Even though we have not seen this reactivity before we can predict it from
the previous slides…
http://alevelchem.com/aqa_a_level_chemistry/unit3.4/s3405/03.htm