Nucleophilic Substitution at the Carbonyl Carbon

Topics: Carboxylic acid, Alcohol, Ester Pages: 4 (322 words) Published: September 25, 2014
*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


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 =...
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