Nucleophilic substitution at carbonyl Flashcards
What can esters be formed from?
Acid chlorides
Acid anhydrides
How can acid anhydrides be made from acid chlorides?
If carboxylate is the nucleophile
What nucleophile is required for the formation of amides?
Amine
What does the stability of the tetrahedral intermediate depend on?
How good a leaving group X- is
What makes a good leaving group?
Most electronegative is the most stable as a negative charge
What can the leaving group ability of X- be judged by?
How strong an acid HX is
How does acid strength affect leaving group ability?
Strong acids HX readily dissociate to give X-, so X- must be relatively stable and a good leaving group
How does pKaH relate to leaving group ability?
The lower the pKaH, the better the leaving group
What tends to be the best leaving group?
Cl-
pKaH = -7
How does pKaH relate to the strength of the molecule as a nucleophile?
The higher the pKaH, the better the nucleophile
What is the most electrophilic carboxylic acid derivative and why?
Acid chloride
Most electronegative Cl- makes C=O more delta positive
What is the least electrophilic carboxylic acid derivative and why?
Amide
Inductive electron withdrawal is less as nitrogen is less electronegative
What effect does protonation of the C=O have?
Makes the carbon more delta positive
What effect does protonation of the leaving group have?
Lowers pKaH and makes it a better leaving group
What type of reaction is acid catalysed ester hydrolysis?
Reversible
REMEMBER arrows
What type of reaction is base mediated ester hydrolysis ?Why?
Irreversible as the CO2- is very stable
What harsh conditions are required for amide hydrolysis under acidic conditions?
Strong acid, eg. H2SO4
High temperatures eg. 100 degrees
What harsh conditions are required for amide hydrolysis under basic conditions?
Strong base eg. NaOH, 100 degrees
Why are harsh conditions required for amide hydrolysis?
The amide is very stable due to conjugation
What electrophile can be used to make acid chlorides from carboxylic acids?
SOCl2
Is the mechanism for the formation of acid chloride form a carboxylic acid reversible or irreversible and why?
Gases HCl and SO2 are lost
Making the reaction irreversible
What conditions are needed for the formation of acid chloride from carboxylic acid?
SOCl2
80 degrees
6 hours
What reagents are needed to form a ketone from an ester?
- Organometallic (R-Li) or Grignard reagent (r-MgBr) / THF
2. HCl, H2O
Why is it difficult to form a ketone from an ester?
A ketone is more electrophilic than the ester so it will be attacked again by the Grignard reagent to form a tertiary alcohol
How can the problem of not being able to form a ketone be rectified?
Using a much poorer leaving group than OMe and getting rid of all the reagent so there is none to react when the ketone is formed
