Topic 12: Carbonyls: Reactions of Carboxylic Acid Derivatives Flashcards
Why are the leaving groups of an acid anhydride (CF3COO^-)/CH3COO^-) good leaving groups + which is better
Lowers the pKa of conjugate acid
Stabilises negative charge of carboxylate leaving group
CF3COO^- is better (-0.25 pKa) compared with 4.76
is OMe a good leaving group?
Middle leaving group
pKa 15.5
is NMe2 a good leaving group
No
pKa 38
Rank the following in order of reactivity
Acid Anhydride
Ester
Carboxylate
Acid Chloride
Amide
What factors influence this order?
Acid Chloride
Acid Anhydride
Ester
Amide
Carboxylate
The delta + charge on a carbonyl group is influenced by the pi resonance and inductive effects
The higher the delta +, the more electronegative and reactive towards nucleophilic addition
Inductive effect of the leaving group on the delta + carbon
Operate through … framework
Substituents withdraw electron density from carbonyl carbon
sigma
Resonance effect of the leaving group on the delta + carbon
Operate through … framework
If leaving group is halogen, O, N + sp2 hybridised, the pAO contains a lone pair of electrons. Overlap of this pAO with pi-MO f carbonyl group pushes electron density towards carbonyl carbon, decreasing electrophilicity. Mesomerically donating
pi
Reaction of acid chloride and amine makes a … and … which can … the amine to make a … . This means the … on the amine isn’t available so it’s no longer … so can’t react with the acid chloride
The reaction goes to … . To avoid this you can add … as it’s a … and acts as a scavenger to form …
amide
HCl
protonate
salt
lone pair
nucleophilic
50%
triethylamine (NEt3)
non-nucleophilic base
Cl^-HNEt3^+
An ester reacts with 1 equivalent of … to form a … or 2 to form a …
DIBAL
aldehyde
alcohol
You can reduce an amide using … under the conditions … to form a … . Or, a carboxylic acid can react under these conditions to form a … . The … would be too weak to react with these
LiAlH4
heat, reflux
amine
alcohol
NaBH4
An ester can react with … to form a … via a … . But … are more … than the esters so the … will react with the … instead of the ester starting material to form a … . To avoid this, use … instead as the … is more stable so no … is formed. When you carry out a … work up, it will … the … and the … and quenches the … first. So, there is now a good … to form a … . The best amide for this is the …
a Grinard reagent
ketone
tetrahedral intermediate
ketones
electrophilic
nucleophile
ketone
tetrahedral intermediate
amides
tetrahedral intermediate
ketone
acidic
protonate
intermediate
amine
Grinard
leaving group
ketone
Weinreb amide
Hydrolysis of Esters and Amides
The parent carboxylic acid can be obtained from all its derivatives through reaction with H2O (…). Unlike acid chlorides, which are … and react readily with … such as … .Esters are not … and do not react with … at pH 7 at any appreciable rate.
However, the rate of … can be increased substantially by performing the reaction under … or … conditions. The most common approach is to use a … or … to form a … charged intermediate with … and form a … carboxylic acid then a carboxylic acid with the leaving group … . The system is completely under … . Excess … pushes the … to the … while excess … pushes it to the …
hydrolysis
strong electrophiles
mild nucleophiles
water
particularly electrophilic
water
ester hydrolysis
acidic
basic
Lewis acid
Brønsted acid
positively
increased electrophilicity
protonated
methanol
equilibrium
water
equilibrium
right
methanol
left
You can increase the rate of ester hydrolysis by increasing the reactivity of the … .Negatively charged species are more … than their neutral conjugate acids . Hydroxide is a better … than water. The loss of … from the …, the … is a … . … now functions as a … and … the … – the large difference in pKa values
between an alcohol (~15) and a carboxylic acid (~5) ensures that this is essentially complete.
The carboxylate product is no longer … and so the reverse reaction is effectively completely suppressed.
The base-mediated hydrolysis of esters is a … efficient method for forming … than the … . This is often called the …
nucleophile
nucleophilic
nucleophile
methoxide
tetrahedral intermediate,
carbonyl-containing product
carboxylic acid
Methoxide
base
deprotonates
carboxylic acid
electrophilic
more
carboxylic acids
acid-catalysed process
Sapnification
Amides can be successfully … using both … although the lower … of this functionality makes the reaction harder to perform so this is not a way of making …
hydrolysed
acid and base hydrolysis
reactivity
amides
