How Long Is Rxn Of Nucleophile?

*substitution (of a carboxylic/acid derivative) = addition + elimination

- substitution at the tetrahedral intermediate from the addition of an organometallic to an aldehyde/ketone will not (usually) work as R- (i.e. H- or CH3-) is a bad leaving group
- addition of a Grignard reagent to an aldehyde/ketone = stable tetrahedral intermediate (alkoxide)
- addition of an alcohol to a carbonyl group in the presence of a base = unstable intermediate (hemiacetal/hydrate) - nucleophiles with good leaving groups (anions i.e. Cl-, RO-, RCO2-) = unstable - starting carbonyl compound with good leaving group = unstable (makes a Tetrahedral intermediate then collapses to form the starting carbonyl group) i.e. Grignard reagent added to an ester
Factors Determining the Successful (Forward) RXN of Nucleophilic Substitution at C=O
1.
Stability: is RCOX electrophilic enough?
2. Nucleophilicity: good enough nucleophile?
3. Leaving Group Ability: X- (usually a halogen – on the acid) > Nu-

1. Carboxylic/Acid Derivative Stability
* C=O electrophilicity is increased by protonation (addition of acid)
2. & 3. Nucleophilicity & Leaving Group Ability
- Nu trends don’t necessarily apply for substitution at sp3 – carbon
- nucleophilicity increases by deprotonation
- leaving group ability increases by protonation
REVISION:

ANSWERS (in white):
- forward
- reverse
- reverse

Reduction of Esters by LiAlH4
- makes alcohol NOT aldehyde - does not stop at aldehyde because more electrophilic

Acid Chlorides & Acid Anhydrides React With Alcohols to Form Esters

Carboxylic Acids React with Alcohol and Conc. H2SO4 to form Esters

Problem: Making Ketones from Esters
- ester + organometallic reagent = tertiary alcohol (excess organometallic reagent = very good method)
- makes alcohol NOT ketone
- does stop at the ketone because it would be more electrophilic than the starting material
- 1 equivalent mixtures of organometallic reagent = tertiary alcohol + starting ester

Solution: Making Ketones from Esters
- start with a more reactive (electrophilic) carboxylic acid derivative i.e. acyl chloride
- (…from esters/any carboxylic acid derivatives) use an organocupurate (i.e. CuCN) instead of a transmettalation (i.e. BrMgMe)
- make the 1st tetrahedral intermediate more stable - from lithium carboxylates

- from Weinreb amides

- from nitriles