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Copyright 2012 James Ashenhurst masterorganicchemistry.

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R–MgX Grignard

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O M OR Ester enolate OH R O OR R

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O M R Ketone enolate OH O R R

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NR2 R Enamine OH NR2 R RO R RO O

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O M R

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R–NH2 amine (primary amine) N R R R H R

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M–CN Cyanide OH H CN

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R–OH/ R–OM alcohol/ alkoxide RO R OR H

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H2O/ M–OH water/ hydroxide HO R OH H R

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NaBH4 Sodium borohydride OH H H R

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LiAlH4 Lithium aluminum hydride OH H H

β−keto ester enolate
O O

O

OH H R R

A

R

Aldehyde

2° alcohol

Aldol Reaction

Aldol Reaction

heating under basic conditions will lead to elimination of OH - Aldol condensation also note that reaction can be reversible under basic conditions : Retro-aldol reaction O OH Cl R 3° alcohol R R R O O OR R O O R R O NR2 R

Knoevenagel Condensation

Imine (aldimine)

Cyanohydrin

Acetal Requires acid catalysis to form

Hydrate (usu. thermodynaically disfavored, except for electron poor aldehydes) If aldehyde is enolizable, hydroxide can form enolate. O

1° alcohol

1° alcohol

O RO O

OH R R R

O NHR R

O CN R

O OR R

OH OH H 2° alcohol R H R

OH H H 2° alcohol

B

R

Acyl chloride

β−keto ester

Amide (Schotten-Bauman reaction) O R R NHR

Acid nitrile

Ester

Carboxylic acid

O

O O R'

OH R R R 3° alcohol OH R

O

O OR R

O

O R R

O

NR2 R RO

O

O

O R CN R

O OR R

O OH Borderline R

OH H H

C

R

Anhydride O

O OH R R' O OR R OH R' O R R OH R NR2 R RO R O

R O OR R

Amide N R R R'

Acid nitrile OH R CN R' Cyanohydrin

Ester RO R OR R'

Carboxylic Acid HO R OH R R OH R' H

1° alcohol OH R R' H

D

R

R'

R

R'

R

Ketone

3° alcohol

Aldol Reaction

Aldol Reaction

Note: best when ketones are identical or when only one can enolize (to avoid scrambling) O O R O OR R O O R R O NR2 R RO O OH R

Imine (ketimine)

Acetal Requires acid catalysis

Hydrate see above: even less favored than with aldehydes due to sterics O

2° alcohol

2° alcohol

E

R α, β unsaturated ketone (enone) O

Varies with conditions: 1,2 adduct is kinetic pdt.

O R RHN NC

O R RO

O R RO

R

Varies with conditions: 1,2 adduct is kinetic product, 1,4 adduct is thermodynamic.

Michael Reaction

Michael Reaction O R

Note: in both cases, very prone to the reverse reaction (elimination) O O NHR NR R OR'

Note: Easily reversible O R OH NR R OH H H

OH OR R R R R

O

O OR R

O

O R Borderline Borderline R

F

R

Ester O

3° alcohol

β−keto ester: Claisen Condensation

1,3 diketone: Claisen Condensation

Amide

G

O OH Deprotonation Deprotonation Deprotonation NR Deprotonation R NHR NR

R

Transesterification Saponification Can be done under basic (basic conditions) or acidic conditions. Can also hydrolyze with aqueous acid O R OR' ––– NR

1° alcohol OH H H 1° alcohol R

Carboxylic acid

Usually requires dehydration agent (e.g. DCC) 1° and 2° amides: deprotonation 3°amides: NR 1° and 2° amides: deprotonation 3°amides: NR NR

Fischer esterification (requires acid, heat) Borderline reaction: requires strong acid, alcohol as solvent, heat O R OH NR

O

H R NH2 H Amine

H

R

NH2

Deprotonation

NR

NR

NR

Amide O O OR Enolate Alkylation R R R NR2 R RO R Alkyl halide Enolate Alkylation Stork enamine reaction note: capable of alkylating a second time Amine caution! product is a good nucleophile; can obtain multiple alkylations Williamson Ether Synthesis requires basic conditions O O R R NHR R CN R OR

Amide Hydrolysis Requires strong conc. acid, heat R OH NR

I

R

X

Mix of addition /deprotonation

R

R

H

requires basic conditions

Alkane