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_Carboxylic_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_Carboxylic_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