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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