Chapters 9-11, 13, 14, & 17-21 Chemical Reactions

Addition Reactions of Alkenes Summary Common Reactants/Solvents

Hydrohalogentation
Markovnikov/anti-Markovnikov
addition
H, X 1. Chirality centers
2. Carbocation
rearrangements
HI, HCl, or HBr/ *ROOR
(* = if added, then anti-Markovnikov is favored for
HBr only.)
Acid-catalyzed Hydration
Markovnikov addition
H, OH 1. Chirality centers Dilute H3O
+
Oxymercuration-
Demercuration
Markovnikov addition
H, OH
or
H, Nuc:
1. No carbocation
rearrangements
1) Hg(OAc)2, Nuc-H, ROH, RNH2, or H2O
2) NaBH4
Hydroboration-oxidation
anti-Markovnikov addition
H, OH 1. Chirality centers
2. Syn addition
1) BH3 THF
2) H2O2, NaOH
Catalytic Hydrogenation H, H 1. Chirality centers
2. Syn addition
3. Meso compounds
H2 or D2 (deuterium)/ Pd, Pt, Ni, or
*Wilkinsons catalyst [* = Rh(PPh)3Cl]
Halogenation X, X 1. Chirality centers
2. Anti addition
3. Meso compounds
Br2 or Cl2
Halohydrin Formation
Markovnikov addition
cis or trans substituents remain
cis or trans in the epoxide
X, OH 1. Chirality centers
2. Anti addition
1) Br2 or Cl2
2) H2O, ROH, or RNH2
Anti Dihydroxylation
cis or trans substituents remain
in the epoxide
OH, OH 1. Chirality centers
2. Anti addition
3. Meso compounds
1) RCO3H or MCPBA (epoxide formation only)
2) H3O
+

Syn Dihydroxylation OH, OH 1. Chirality centers
2. Syn addition
3. Meso compounds
1) OsO4 or cold KMnO4, NaOH
2) Na2SO3/ H2O or NaHSO3/ H2O
*Co-oxidants: NMO with OsO4 or
(CH3)3COOH, NaOH with OsO4
(* = regenerate OsO4 as it is consumed during the
reaction)
Oxidative Cleavage O, O
None
1) O3
2) DMS or Zn/H2O (both are reducing agents)

Elimination & Addition Reactions of Alkynes Summary Common Reactants/Solvents
Preparation of Alkynes
Equilibrium favors the formation of the weaker acid and weaker base
Used for the preparation of terminal alkynes
1) xs NaNH2/ NH3 (l)
2) H2O
Catalytic Hydrogenation
syn addition
cis alkene is formed only
H, H H2/ *Lindlars catalyst or Ni2B
(* = Quinoline, Pd/BaSO4, CH3OH)
Dissolving Metal Reduction
anti addition
trans alkene is formed only
H, H Na/ NH3 (l)
Hydrohalogenation
Markovnikov addition
H, X xs HI, HCl, or HBr/ *ROOR
(* = if added, then anti-Markovnikov is favored
for HBr only and E and Z isomers are produced
for a terminal alkyne)
Acid-Catalyzed Tautomerization (Hydration)
Markovnikov addition
Unsymmetrical alkynes produce a mixture of ketones
Symmetrical alkynes produce only one ketone
H, OH H2SO4, H2O, *HgSO4
(* = increases the rate of hydration)
Hydroboration-Oxidation/
Base-Catalyzed Tautomerization (Hydration)
anti-Markovnikov addition
An aldehyde is formed at the terminal end of an alkyne
H, OH 1) Disiamylborane, 9-BBN, or R2BH
2) H2O2, NaOH
Halogenation
anti addition
E isomer is the major product
X, X xs Br2/ CCl4 or xs Cl2/ CCl4
Oxidative Cleavage
A carboxylic acid is formed at the carbon before the triple bond
CO2 is also produced for a terminal alkyne only
OH, OH 1) O3
2) H2O
Alkylation of Terminal Alkynes
Methyl or primary alkyl halides only
R1, R2 1) NaNH2
2) RX
Radical Reactions Summary Common Reactants/Solvents
Halogenation of Alkanes
Involves radical, not ionic intermediates
O2 inhibits the reaction
1. No rearrangements X2, light, heat, or added ROOR

Allylic Bromination

1. Chirality centers 1) *NBS (N-bromosuccinimide)
2) light (hv)
(* = used as a reagent instead of Br2 to favor allylic
bromination instead of ionic addition of Br2)

Reactions of Alcohols and Phenols Summary Common Reactants/Solvents
Deprotonation of an Alcohol
Equilibrium favors the formation of the weaker acid and weaker base
Forms an alkoxide ion and hydrogen gas
RO

NaH or Li, Na, or K
or
NaOH (for phenols only)
Reduction of a Ketone (or Aldehyde) to an Alcohol
NaBH4 doesnt react with a carboxylic acid or an ester

C=O
to
ROH
H2 or D2 (deuterium)/ Pd, Pt, or Ni
or
NaBH4/ EtOH, MeOH, or H2O
or
1) LAH
2) H2O
Grignard Reagent and a Ketone or Aldehyde
Reacts with esters and produces two R groups.
Does not react with the C=O group of a carboxylic acid, but deprotonates it
RMgX 1) RMgX
2) H2O
SN1 & SN2 Reactions with Alcohols
The reaction between SOCl2 and an alcohol also produce SO2 and X

The reaction between PBr3 and an alcohol produce HOPBr2
RXR 1 & 2 alcohol: SOCl2/ py, PBr3,
HCl/ ZnCl2, or
1) TsCl, py
2) NaX
1 & 3 alcohol: HBr
E1 & E2 Reactions with Alcohols = H2SO4/ heat ()
Oxidation Reactions of Alcohols
A secondary alcohol can be oxidized with chromic acid or with PCC
ROH
to
HC=O or
COOH
Na2Cr2O7/ H2SO4, H2O (H2CrO4)
(carboxylic acid as product)
or
CrO3, H3O
+
, acetone (H2CrO4)
(carboxylic acid as product)
or
PCC/ CH2Cl2
(aldehyde as product)

Reactions of Ethers, Epoxides, Thiols, and Sulfides Summary Common Reactants/Solvents
Williamson Ether Synthesis
Produces unsymmetrical ethers
ROH
to
ROR
1) NaH
2) RX

Alkoxymercuration-Demercuration
Markovnikov addition
RO, H

1) Hg(OAc)2, ROH
2) NaBH4
Acidic Cleavage of an Ether
HF does not cause acidic cleavage of ethers
A phenol ether is not further converted into a halide
2 RX 1) xs HI, HBr, or *HCl/ heat ()
(* = less efficient)
Epoxide Formation from Halohydrins
The alkoxide ion functions as a nucleophile in an intramolecular
SN2-like process
None NaOH
Epoxide Ring Opening with a Strong Nucleophile
The nucleophile attacks at the less substituted (less hindered)
position
An inversion of configuration is observed at a chirality center
None 1) NaOR, NaCN, NaSH, RMgBr, or LAH
2) H2O
or
NaOH/ H2O
Acid-Catalyzed Ring Opening of an Epoxide
The second step can be a nucleophilic attack (SN2) by a halide,
water, or an alcohol
The nucleophile attacks at the most substituted (more hindered)
position
None [H2SO4] or HX/ H2O or ROH
([ ] = functions as a catalyst)
Preparation of Thiols
An SN2 reaction between NaSH and an alkyl halide
RSH NaSH
Oxidation of Thiols to Disulfides

RSSR NaOH/ H2O, Br2

Reactions of Ethers, Epoxides, Thiols, and Sulfides Summary (cont.) Common Reactants/Solvents
Reduction of Disulfides to Thiols

2 RSH 1) HCl/ Zn
Preparation of Sulfides from Thiols
An SN2 with methyl and primary and secondary alkyl halides, but
not for tertiary alkyl halides
The sulfur analog to the Williamson ether synthesis
RSH
to
RSR
1) NaOH
2) RX
or
RS

(thiolate ion)
Oxidation of Sulfides to Sulfoxides RSR
to
RSOR
NaIO4 (sodium meta-periodiate)
Oxidation of Sulfoxides to Sulfones RSOR
to
RSO2R
2 eq. H2O2

Aromatic Compound Reactions Summary Common Reactants/Solvents
Catalytic Hydrogenation of Benzene

None 3 eq. H2/ Pd, Pt, or Ni, 100 atm, 150 C
Oxidation of AlkylBenzenes
The alkyl group is entirely excised, leaving only the
benzylic carbon atom behind
The product is benzoic acid, regardless of the identity of
the alkyl group
The benzylic position must have at least one proton
ArCOOH Na2Cr2O7/ H2SO4, H2O (H2CrO4)
or
1) KMnO4/ H2O or NaOH, heat ()
2) H3O
+

Free-Radical Allylic Bromination
Bromination occurs primarily at the benzylic position
The reaction is highly regioselective due to resonance
stabilization of the intermediate benzylic radical
1. Chirality centers *NBS/ heat ()
(* = used as a reagent instead of Br2 to favor allylic
bromination instead of ionic addition of Br2)
Birch Reduction None Na, CH3OH, NH3 (l)

Aromatic Substitution Reactions Summary Common Reactants/Solvents
Bromination of Benzene
Iron tribromide or aluminum tribromide and hydrochloric
acid is produced with the product
ArBr Br2/ FeBr3 or AlBr3
Chlorination of Benzene
Aluminum trichloride and hydrochloric acid is produced with the product
ArCl Cl2/ AlCl3
Sulfonation of Benzene
Fuming sulfuric acid is a mixture of H2SO4 and SO3 gas
The reaction is reversible with dilute H2SO4
ArSO3H Concentrated fuming H2SO4
Nitration of Benzene ArNO2 HNO3/ H2SO4
Reduction of Nitrobenzene to Aniline ArNO2
to
ArNH2
Fe or Zn/ HCl
Friedel-Crafts Alkylation
Secondary and tertiary halides are converted into carbocations in the
presence of AlCl3
Primary alkyl halides are not converted into carbocations
Aluminum trichloride and hydrochloric acid is produced with the product
ArR RX/ AlCl3
Friedel-Crafts Acylation
The product is an aryl ketone
Ar(C=O)R Cl(C=O)R/ AlCl3
Clemmensen Reduction
The carbonyl group is reduced and replaced with two hydrogen atoms
No carbocation rearrangements
Polyacylation is not observed, because the introduction of an acyl group deactivates
the ring toward further acylation
None
*Zn [Hg]/ HCl, heat ()
(* = zinc amalgam)
Nucleophilic Aromatic Substitution
The ring must contain a powerful electron-withdrawing group (typically a nitro group)
The ring must contain a leaving group (usually a halide)
The leaving group must be either ortho or para to the electron-withdrawing group
ArOH 1) NaOH, 70 C
2) *H3O
+
(* = protonates the phenolate ion)
Elimination-Addition


ArOH 1) NaOH, 350 C
2) *H3O
+

(* = protonates the phenolate ion)
When other substituents are present on the ring, a benzyne intermediate is formed, and
two products are obtained
ArNH2 1) NaNH2, NH3 (l)
2) H3O
+


Aldehydes and Ketones Reactions Summary Common Reactants/Solvents
Base-Catalyzed Hydration
The rate of reaction is slow under neutral conditions but is enhanced in the presence
of a base
R2C(OH)2 NaOH
Acid-Catalyzed Hydration
The rate of reaction is slow under neutral conditions but is enhanced in the presence
of an acid
R2C(OH)2 [H
+
], H2O

Acetal Formation
Common acids include para-toluenesulfonic acid (TsOH) and sulfuric acid
A compound containing two OH groups can be used, forming a cyclic acetal
The cyclic acetal can be removed using H3O
+

Produces an intermediate called a hemiacetal
R2C(OR)2 [H
+
], 2 ROH
or
[H
+
], OHCH2CH2OH
Imine Formation
In mildly acidic conditions, an aldehyde or ketone will react with a primary amine
Produces an intermediate called a carbinolamine
R=NR [H
+
], RNH2
Enamine Formation
In acidic conditions, an aldehyde or ketone will react with a secondary amine
Produces an intermediate called a carbinolamine
=RNR2 [H
+
], R2NH
Oxime Formation
The mechanism is directly analogous to the mechanism of imine formation
Produces an intermediate called a carbinolamine
R=NOH [H
+
], NH2OH
Hydrazone Formation
The mechanism is directly analogous to the mechanism of imine formation
Produces an intermediate called a carbinolamine
R=NNH2 [H
+
], NH2NH2
Wolff-Kishner Reduction
Hydrazones are readily reduced under strongly basic conditions
alkane KOH or NaOH/H2O, heat
Cannizzaro Reduction None 1) NaOH
2) H3O
+
Reduction of a Ketone (or Aldehyde) to an Alcohol
NaBH4 doesnt react with a carboxylic acid or an ester to produce an alcohol, but
LAH will
NaBH4 functions as a nucleophile or a delivery agent of nucleophilic H:
-

LAH functions as a nucleophile or a delivery agent of nucleophilic H:
=
C=O
to
ROH
NaBH4/ EtOH, MeOH, or H2O
or
1) LAH
2) H2O
Grignard Reagent and a Ketone or Aldehyde
Reacts with esters and produces two R groups.
Does not react with the C=O group of a carboxylic acid, but deprotonates it
RMgX 1) RMgX
2) H2O
Cyanohydrin Formation

R(C=O)R
to
OHCR2CN
KCN, HCN
or
KCN, HCl
Reduction of a Cyano Group

CN
to
NH2
1) LAH
2) H2O
CN
to
COOH
1) H3O
+
, heat
Wittig Reaction
Converts a ketone into an alkene by forming a new C-C bond at the location of the
carbonyl moiety
C=O
to
C=C
H2C=PPh3 (phosphorane)
Preparation of Wittig Reagent (Phosphorane)
Primary alkyl halides will react more readily than secondary alkyl halides, and
tertiary alkyl halides cannot be used
Useful for the preparing mono-, di, or trisubstituted alkenes
None 1) RX
2) *BuLi
(* = CH3CH2CH2CH2: Li
+
)
Baeyer-Villiger Oxidation
The migration of an R group produces an ester
The treatment of a cyclic ketone with peroxy acid yields a cyclic ester or lactone
When an unsymmetrical ketone is treated with a peroxy acid, formation of the ester is
regioselective
R(C=O)R
to
RCOOR
RCO3H or MCPBA







Carboxylic Acids and Their Derivatives Reactions Summary Common Reactants/Solvents
Hydrolysis of Nitriles
The resulting nitrile is then hydrolyzed to yield a carboxylic acid that has one
more carbon atom than the original alkyl halide
RCOOH H3O
+
, heat
Carboxylation of Grignard Reagents
Converts an alkyl (or vinyl or aryl) halide to a carboxylic acid
Does not react with the C=O group of a carboxylic acid, but deprotonates it
RCOOH 1) CO2
2) H3O
+

Preparation of Carboxylic Acids (from alkyl halides)

RX
to
RCOOH
1) Mg
2) CO2
3) H3O
+

or
1) NaCN (via SN2)
2) H3O
+
, heat
Reduction of a Carboxylic Acid to an Alcohol
Borane reacts selectively with a carboxylic acid moiety in the presence of
another carbonyl group
LAH is not a powerful nucleophile, but it can function as a strong base,
forming a carboxylate ion
RCOOH
to
ROH
1) xs LAH
2) H3O
+
or
BH3 THF

Nucleophilic Acyl Substitution
In acidic conditions, avoid formation of a negative charge and avoid an
intermediate with two positive charges
In alkaline conditions (strongly basic conditions), avoid formation of a
positive charge and avoid an intermediate with two negative charges
R(C=O)X
to
R(C=O)Nuc
Nuc:
Preparation of Acid Chlorides (from carboxylic acids)
HCl as a by-product can produce undesired reaction with other functional
groups that might present, so pyridine is used to remove the HCl as it is being
produced
RCOOH
to
R(C=O)Cl
*SOCl2, pyridine
(* = thionyl chloride)

Hydrolysis of Acid Chlorides
HCl as a by-product can produce undesired reaction with other functional
groups that might present, so pyridine is used to remove the HCl as it is being
produced
R(C=O)Cl
to
RCOOH
H2O, pyridine
Alcoholysis of Acid Chlorides
Pyridine is used to remove the HCl as it is being produced
Acylation of an OH group is sensitive to steric effects and will selectively
acylate a primary alcohol in the presence of a secondary (more hindered)
alcohol
R(C=O)Cl
to
RCOOR

ROH, pyridine
Aminolysis of Acid Chlorides
Pyridine is not used in this reaction, because ammonia is a strong base to
neutralize the HCl as it is produced

R(C=O)Cl
to
R(C=O)NH2
or
R(C=O)NHR
or
R(C=O)NR2
2 eq. NH3, RNH2, or R2NH
Reduction of an Acid Chloride (with LAH)

R(C=O)Cl
to
ROH
1) xs LAH
2) H2O or H3O
+

Reduction of an Acid Chloride [with LiAl(OR)3H]
The hydride-reducing agent will react with acid chlorides more rapidly than
aldehydes, but will produce an aldehyde
R(C=O)Cl
to
R(C=O)H
1) *LiAl(OR)3H
2) H2O
[* = lithium tri(t-butoxy) aluminum hydride]
Reaction between Acid Chlorides and
Organometallic Reagents
The reaction between an acid chloride and a Grignard reagent cannot be used
to produce a ketone
R(C=O)Cl
to
R(R)2OH
1) xs RMgBr
2) H2O
(an alcohol with two alkyl groups)

The reaction between an acid chloride and a Gilman reagent can be used to
produce a ketone
R(C=O)R *R2CuLi
[* = lithium dialkyl cuprate (Gilman reagent)]
Preparation of Acid Anhydrides (from acid chloride)
This method can be used to prepare symmetrical or unsymmetrical
anhydrides
R(C=O)Cl
to
R(C=O)O(C=O)R
*RCOO
-
Na
+
(* = carboxylate ion)

Preparation of Acid Anhydrides (from carboxylic acids) RCOOH
to
R(C=O)O(C=O)R
1) NaOH
2) CH3COCl
Saponification of Esters



RCOOR
to
RCOOH
1) NaOH
2) H3O
+

Carboxylic Acids and Their Derivatives Reactions Summary (cont.) Common Reactants/Solvents
Preparation of Esters
The Fisher esterification process is reversible
RCOOH
to
RCOOR
1) NaOH
2) RX (via SN2)
or
ROH, [H
+
], -H2O (via Fisher esterification)
Acid-Catalyzed Hydrolysis of Esters
This process is the reverse of a Fisher esterification
RCOOR
to
RCOOH
H3O
+
Aminolysis of Esters RCOOR
to
R(C=O)NH2
NH3
Reduction of Esters (via Hydride-Reducing Agents) RCOOR
to
ROH
1) xs LAH
2) H2O

One equivalent of DIBAH reduces the ester to an aldehyde
The reaction is performed at low temperature to prevent further reduction
of the aldehyde
RCOOR
to
R(C=O)H
1) *DIBAH
2) H2O
(* = Diisobutylaluminium hydride)
Reaction between an Ester and a Grignard Reagent
Esters are reduced to yield alcohols with the introduction of two alkyl groups
The process is directly analogous to the reaction between a Grignard reagent
and an acid chloride
RCOOR
to
ROH
1) xs RMgBr
2) H2O
Acid-Catalyzed Hydrolysis of Amides
An ammonium ion is formed as the by-product
The equilibrium favors formation of products, rendering the process
irreversible
R(C=O)NH2
to
RCOOH
H3O
+
, heat
Base-Catalyzed Hydrolysis of Amides
The formation of the carboxylate ion drives the reaction to completion and
renders the process irreversible
R(C=O)NH2
to
RCOOH
1) NaOH, heat
2) H3O
+
Reduction of Amides
The carbonyl group is completely removed
R(C=O)NH2
to
RNH2
1) xs LAH
2) H2O
Preparation of Nitriles
Tertiary alkyl halides cannot be used
RX
to
RCN
NaCN (via SN2)

Preparation of Nitriles from Amides
Useful for preparing tertiary nitriles, which cannot be prepared via an SN2
process
R(C=O)NH2
to
RCN
*SOCl2
(* = thionyl chloride)

Hydrolysis of Nitriles to Carboxylic Acids RCN
to
RCOOH
H3O
+
, heat
or
1) NaOH, H2O
2) H3O
+
Reaction between a Nitrile and a Grignard Reagent
A ketone is obtained when the imine is hydrolyzed under acidic conditions
RCN
to
R(C=O)R
1) RMgBr
2) H3O
+
or H2O
Reduction of Nitriles to Amines RCN
to
RNH2
1) xs LAH
2) H2O













Alpha Carbon Chemistry: Enols and Enolates Reaction Summary Common Reactants/Solvents
Alpha Halogenation in Acidic Conditions
Reaction is observed for chlorine, bromine, and iodine, but not for
fluorine
Enol formation represents the rate-determining step for the process
Alpha halogenation on unsymmetrical ketones occurs primarily at
the more substituted product
R(C=O)R
to
R(C=O)BrR
[H3O
+
], Br2, Cl2, or I2

,-Unsaturation Formation in a Ketone
(via elimination)
C=C 1) [H3O
+
], Br2, Cl2, or I2
2) Pyridine, Li2CO3, or *K
+

-
OC(CH3)3
(* = potassium tert-butoxide)
Alpha Halogenation in Basic Conditions: The
Haloform Reaction
When there is more than one proton present, it is difficult to
achieve monobromination in basic conditions
The presence of the halogen renders the position more acidic, and
the second halogenation step occurs more rapidly
The negative charge on carbon is stabilized by the electron-
withdrawing effects of the three halogen atoms, rendering CX3
-
a
suitable leaving group
X
(X = halogen)
NaOH, Br2, Cl2, or I2
or
1) NaOH, Br2, Cl2, or I2
2) *H3O
+
(* = used to recover the carboxylic acid)

Aldol Addition & Retro-Aldol Reaction
For most simple aldehydes, the position of equilibrium favors the
adol product
For most ketones, the aldol product is not favored, and poor yields
are common
R(C=O)H or
R(C=O)
to
-hydroxy aldehyde
or ketone
NaOH, H2O
Adol Condensation (via elimination of H2O)
A small water molecule of water is lost
The position is deprotonated to form an enolate prior to the
ejection of an hydroxide ion to afford the product
The product with the least steric hindrance is the major product in
cases where two steresisomeric bonds can be formed
At a low temperature (10 C) the aldol addition product is obtained
At a high temperature (100 C) the aldol condensation product is
obtained
R(C=O)H or
R(C=O)
to
,-unsaturated
aldehyde or ketone
1) NaOH, H2O (aldol addition)
2) [H3O
+
] or [OH
-
], heat

Crossed Aldol Reactions
If one of the aldehydes lacks an proton and possess an unhindered
carbonyl group, then one product dominates
If aromatic aldehydes are present, then equilibrium favors the
condensation product
Crossed adol reactions can be performed using LDA as a base
(directed aldol addition)
Four (4) possible
products:
2 symmetrical
2 crossed
R(C=O)R or R(C=O)R
R(C=O)R or R(C=O)H
R(C=O)H or R(C=O)H
Intramolecular Aldol Reactions
Smaller rings are possible but are not observed
A cyclic five- or six-
membered ring
(cyclic enone)
NaOH, heat
Clasien Condensation
Deprotonation at the end of the mechanism provides a driving force
that causes the equilibrium to favor condensation
The starting ester must have two protons. If it has only one
proton, then the driving force for condensation is absent
Hydroxide cannot be used as the base for a Claisen condensation
because it can cause hydrolysis of the starting ester
The alkoxide used must be the same OR group that is present in the
starting ester in order to avoid transesterification
EtO(C=O)R
to
-keto ester
1) NaOEt
2) H3O
+
Crossed Claisen Reactions
If one ester has no protons and cannot form an enolate, then the
number of products is reduced
A directed Claisen condensation can be performed in which LDA is
used as a base to irreversibly form an ester enolate, which is then
treated with a different ester
EtO(C=O)R
and
EtO(C=O)R
to
-keto ester
EtO(C=O)R, EtO(C=O)R
Intramolecular Claisen Condensations:
The Dieckmann Cyclization
A cyclic five- or six-
membered ring
(cyclic, -keto ester)
1) NaOEt
2) H3O
+

Alkylation via Enolate Ions
The enolate ion functions as a nucleophile and attacks the alkyl halide
in an SN2 reaction (methyl or primary halide)
With a secondary or tertiary alkyl halide, the enolate functions as a
base instead of a nucleophile, and the alkyl halide undergoes
elimination rather than substitution
With an unsymmetrical ketone, two possible enolates can be formed
R
(R = alkyl halide)
1) LDA, -78 C (kinetic enolate)
2) RX
or
1) NaH, 25 C (thermodynamic enolate)
2) RX

Alpha Carbon Chemistry: Enols and Enolates Reaction Summary (cont.) Common Reactants/Solvents
The Malonic Ester Synthesis
Diethyl malonate can be dialkylated to produce carboxylic
acids

RX
to
COOH
(1,3-dicarboxylic acid)
1) *EtO(C=O)CH2(C=O)OEt, NaOEt, EtOH
2) RX
3) H3O
+
, **heat
or
1) *EtO(C=O)CH2(C=O)OEt, NaOEt, EtOH
2) NaOEt, EtOH
3) RX
4) NaOEt
5) RX
6) H3O
+
, **heat
(* = diethyl malonate)
(** = If present, then decarboxylation occurs
to produce a monosubsituted acetic acid and CO2)
The Acetoacetic Ester Synthesis
Ethyl acetoacetate can be dialkylated to produce carboxylic
acids

RX
to
RCH2(C=O)R
1) *EtO(C=O)CH2(C=O)CH3, NaOEt, EtOH
2) RX
3) H3O
+
, **heat
or
1) *EtO(C=O)CH2(C=O)CH3, NaOEt, EtOH
2) NaOEt, EtOH
3) RX
4) NaOEt
5) RX
6) H3O
+
, **heat
(* = ethyl acetoacetate)
(** = If present, then decarboxylation occurs
to produce a ketone and CO2)
Michael Reactions
Enolates are less reactive than Grignard reagents but more
reactive than lithium dialkyl cuprates, therefore both
1,2-addition and 1,4-additon products are observed
Doubly stabilized enolates are stabilized to produce
1,4 conjugate addition exclusively
1,4- conjugate addition

1) KOH, Michael donor
2) Michael acceptor
3) H3O
+

The Stork Enamine Synthesis
Enolates are not stable enough to function as Michael
donors, therefore a stabilized enolate, or some species that
will behave like a stabilized enolate is required
A ketone is converted into an enamine by the treatment
with a secondary amine
Enamines do not possess a net negative charge, as enolates
do, and therefore, enamines are less reactive than enolates
The transformation requires that the group to be installed
at the position of the starting material
R(C=O)R
to
=RNR2
1) [H
+
], R2NH
2) Michael acceptor
3) *H3O
+
[* = when treated with aqueous acid, both groups
(iminium ion and an enolate ion) are converted into
carbonyl groups]
The Robinson Annulation Synthesis
Two-step method for forming a ring, in which a Michael
addition is followed by an intramolecular aldol
condensation
Polycyclic compounds Michael donor, Michael acceptor,
NaOH, heat