from "Master Organic Chemistry"

Identifying the Patterns in Carbonyl Reaction Mechanisms masterorganicchemistry.com

2019 Version, Copyright 2019 James A. Ashenhurst
james@masterorganicchemistry.com

O Reactions of neutral NR 2 NR 2
HO R nucleophiles with
Grignard Reaction A P R X SN2 D
R–MgX alkyl halides R R R
R R R R

Reactions of HO RO
O anionic nucleophiles R X R OR R OH R CN SN2
HO CN
Cyanohydrin NaCN A P with alkyl halides CN
formation R R R R
O O
O Enolate alkylation R X base
Ketone or aldehyde HO H D SN2
NaBH 4 (ketones or esters) R CH2R R R
reduction A P
or LiAlH4 R R R R R

O O O OH O
base HO H
Base-catalyzed aldol P
D A P Reduction of esters LiAlH4 A E A
reaction R CH2R H R R R R OR R H
R

Addition of neutral O O
nucleophiles to acid RNH 2 Grignard Reaction O HO R
A E D + acid chloride, A E A P
halides or anhydrides RMgX
R Cl R NHR ester, or anhydride R Cl R R
(e.g.amines, alcohols, water)

O O O O R
O acid N
Addition of anionic nucleophiles HO RO
A E Imine formation RNH 2 P A PT E D
to acid halides or anhydrides R Cl R OH R OR R NH 2 R R R R
H 2N
(e.g.RO , H 2N , HO )

O O O O O acid O
base PT D
Claisen condensation D A E Fischer esterification ROH P A E
*note 1 R OH R OR
R CH2R R OR R R
R
O O
O O acid
1,4 addition of Gilman R 2CuLi Amide hydrolysis H 2O P A PT E D
14A P R NR 2 R OH
reagent R R

R
O O O O O acid RO OR
base E D
Formation of acetals ROH P A PT A
Michael reaction D 14A P R R R R
R CH2R R R R
R

O O RO OR acid O
Hydrolysis of acetals H 2O P E A PT E D
RNH 2 14A PT R R R R
1,4 addition of R R
neutral nucleophiles
RHN
O O acid O
Acid catalyzed aldol P T A PT T 14E D
R CH2R H R R R
R
*note 1 - There is actually a fourth step; base removes a proton from the
acidic alpha-carbon, rendering the reaction irreversible. Acidic workup gives
the final product. The Nine Mechanistic Components (with examples)

Addition to carbonyl [1,2-addition] Elimination [1,2-elimination] SN2 Deprotonation Proton Transfer

O O O O O
O Nu O Intramolecular acid-base reaction
A O Nu E SN2 R H R D base PT
R H 3C R H 2C R example:
X R X R X R Nu R
Cα X H
Nu Removal of a proton from substrate H
HO OR H 2O OR

[1,4] addition Protonation R R R R

[1,4] elimination Keto-Enol Tautomerization
O O O O This can either be drawn as
OH H acid
O O OH P an intramolecular reaction (one step)
14A Nu 14E T or as a deprotonation (D)followed by
R R H H 2C R H 3C R
R R H 3C R R a protonation (P)
Nu H Addition of a proton to substrate
Nu X β