Summary Sheet #7 - Identifying the Patterns in Carbonyl Reaction Mechanisms

from "Master Organic Chemistry" masterorganicchemistry.com Version 1.1 Apr 2011, copyright 2010 James A. Ashenhurst comments/corrections/suggestions? james@writechem.com NR2

O Grignard Reaction RMgX R O Cyanohydrin formation Ketone or aldehyde reduction NaCN R O NaBH4 or LiAlH4 O R CH2R H R R O R R R

HO R HO R HO R base R O

R R CN R H R OH R R

12A

Reactions of neutral nucleophiles with alkyl halides Reactions of anionic nucleophiles with alkyl halides Enolate alkylation (ketones or esters)

NR2 R HO CN O R CH2R R X base R RO R X R X R R

SN2 R

OR

OH

CN

12A

SN2

O R R D SN2

12A

Base-catalyzed aldol reaction

O D 12A P Reduction of esters LiAlH4 R OR

HO R

H H

12A

12E

12A

Addition of neutral nucleophiles to acid halides or anhydrides (e.g.amines, alcohols, water)

O R Cl

RNH2 R

O NHR 12A 12E D

Grignard Reaction + acid chloride, ester, or anhydride

O RMgX R Cl

HO R R R acid OH R O R O

R R

12A

12E

12A

Addition of anionic nucleophiles to acid halides or anhydrides (e.g.RO , H2N , HO ) O Claisen condensation R

O R Cl

HO H2N

RO R

O OH R

O OR R

O NH2 12A 12E Imine formation RNH2 R

O R O

acid

N P R 12A

PT

12E

O CH2R R O OR

base R

O R R O R 14A P Amide hydrolysis D 12A 12E Fischer esterification ROH R

OR

12A

PT

12E

1,4 addition of Gilman reagent

R2CuLi R R

O H2O R NR2

acid

OH

12A

PT

12E

O Michael reaction R CH2R

O R

base R

O R R D 14A P

O Formation of acetals ROH R R

acid

RO R

OR R

12A

PT

12E

12A

O 1,4 addition of neutral nucleophiles RNH2 R RHN

O R 14A PT

Hydrolysis of acetals

H2O

RO R

OR R O

acid R acid

O P R O R R R P T 12A PT T 14E D 12E 12A PT 12E D

O Acid catalyzed aldol R CH2R H

The Nine Mechanistic Components (with examples)

[1,2] addition O 12A C X Nu O R Nu X 12E O R [1,2] elimination Nu X R O SN2 Nu R H X H SN2 O R O R R D H3C Deprotonation O R base H2C O R PT Proton Transfer Intramolecular acid-base reaction example: H HO OR R O H3C R R H2O OR R R

Removal of a proton from substrate Protonation O P H2C R acid

[1,4] addition O 14A Nu R Nu Nu O R 14E X

[1,4] elimination OH R O H T R H3C

Keto-Enol Tautomerization O R H H OH R

Addition of a proton to substrate