Davey 1

Mechanisms 1-10: CHEM 725

1. Acetoacetic Ester Synthesis: This reaction involves the substitution of an alkyl group (commonly designated as "R")
for an acidic -hydrogen of acetoacetic ester via an SN2 pathway (typical limitations apply). The product of this reaction,
after it undergoes decarboxylation, is said to produce a three carbon longer methyl ketone (in reference to the "R" group,
it becomes three carbons longer and contains a methyl ketone). Other products may be formed by manipulation of the
reacton conditions.1
Reaction equation:
3a. 3b.
O O O O O
1. NaH, Ethanol
2. CH3I H + H + CO2 (g)
O O O
R H 3a. Conc. KOH; H+ R R
or
3b. Dilute KOH; H+
Reaction mechanism:
3
O O O O O O
2 Ethanol 2. H3C I
Na
O Na H O O
R H H R CH3
+ NaI
(Acetoacetic ester moiety)

O O O O O O
3a. Conc. K OH R K
H +
O O K O O
HO
R R

H
O O H3O X O X O
R + K R +
(Hydrolysis now occurs) H
O O O O

H2O
H H
O O X O
H + + HX
R O R O O OH
H O H O H R
H
X
or:
H
O O O O O O Decarboxylation (-CO2)
3b. Dilute K OH K
+ O
O O O K (Retro-ene mechanism
R R OH R shown5)
-Ketoacid intermediate4)

H
O O
Tautomerization

R R
(enol intermediate6)

Ogawa K, Sasaki M, Nozaki T. Appl Radiat Isot. 1997; 48: 623–630.

1. Very basic conditions support the formation of a carbanion whereas mildly basic conditions do

not.

2. The base used to deprotonate acetoacetic ester cannot be NaOH because acetoacetic ester

would undergo hydrolysis to the corresponding carboxylate anion which would halt the overall

reaction because deprotonation of the carboxylic acid happens preferentially to deprotonation

of the -hydrogen(s). NaOEt could be used because it would yield the same ester (NaOMe could

not, etc.).

3. A monosubstituted dicarbonyl can be deprotonated again to yield a disubstituted product via

the previous mechanism.

4. Decarboxylation is a typical reaction of -ketoacids.

5. There is another way to show decarboxylation. It begins with the protonation of the ketone

oxygen and then conjugate base attacks the carboxylic acid proton which leads to the

generation of CO2 gas and the enol. This enol then undergoes tautomerization to yield the

corresponding carbonyl.

6. Enols typically undergo tautomerization to their corresponding carbonyl compound because of

the stability of the C=O bond. Tautomerization can also be shown by the C=C double bond

attacking an acidic proton and then undergoing formation of the C=O via a conjugate base.
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2. Aldol Condensation: This reaction involves the joining of aldehydes and ketones to synthesize an aldol (a -
hydroxycarbonyl compound). This reaction is useful because it is a method of making C-C bonds. There are three
variations of the aldol condenstion: between two identical ketones or aldehydes the reaction is called an aldol
condensation, betwen two different carbonyl compounds the reaction is called a crossed aldol condensation, and when
the carbonyl groups are located within the same molecule the reaction is called an intramolecular aldol condensation.
Aldol condensations can be acid- or base-catalyzed1.

Reaction equation:
OH O
O O
+ LDA, solvent
-72°C, 15-20 min C6H5 R
C6H5 H R

Reaction mechanism:
Li
Li
O N O O (The enolate compound is generally
prepared separately from the
R R R electrophilic carbonyl compound to
H H avoid unwanted by-products.)
Li

2
O O O O OH O
H+ from solvent
Li
R C6H5 H R C6H5 C6H5 R
Li

Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.;

1. An acid-catalyzed mechanism can be found on pg. 137 of Grossman's “The Art of Writing

Reasonable Organic Reaction Mechanisms.”

2. The product can be converted into an -unsaturated carbonyl by dehydration via acid catalysis

or E1cb.
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3. Arndt-Eistert Reaction: This reaction uses two common reactions to convert a carboxylic acid into its carboxylic acid
homologue (meaning that it contains addtional carbon atoms but retains the same functional group). The first reaction
uses thionyl chloride (or similar reagents) to synthesize an acid chloride which undergoes nucleophilic substitution and
Wolff rearrangement with diazomethane acting as the nucleophile. This reaction is commonly used in the synthesis of
amino acids.2

Reaction equation: O
1
Pg OH 1. Et3N/ClCO2Et Pg Ag2O, H2O Pg
N N N2 N OH + N2 (g)
H 2. CH2N2 H H
O O

Reaction mechanism:

H
O
Pg OH Pg O Et3N Pg O Pg O
N 1. N N N
H Cl O H H H
O O O O
Cl Cl
O O O O
O O
Et3NH
Cl Et3NH
Cl
Pg O Pg O
N Et3NH N
H H + Et3NH O + CO2
O Cl

O O

Cl Pg
Pg O 2. H2C N N Pg O Pg O - N2(g)
N N N O N
H H H H
Cl N N N N

Cl
O O
Pg H2O, Ag2O Pg H H2O Pg
O N N O N OH
H H H H

Seebach, D.; Overhand, M.; Kuhnle, F. N. M.; Martinoni, B.;

1. Protecting group

2. cite
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4. Baeyer-Villiger Reaction: This reaction uses RCO3H (commonly m-CPBA, although many reagents can be used,
including non-RCO3H reagents) to convert a cylic ketone into a cylic ester (a lactone). This reaction can be acid- or
base-catalyzed.

Reaction equation:
O O O
F F F
m-CPBA O O
acid catalyst +

Reaction mechanism:
H A
O O A O H H
F H+ F O Cl O O
O F
+ Cl O
O H

(m-CPBA)

A
H A
O H H
O O O
Cl O O F
O F F Cl H
O + O O + HA

Kaneda, K.; Yamashita, T. Tetrahedron Lett. 1996, 37, 4555-4558.

5. Benzilic Acid Rearrangement: This reaction involves the base-catalyzed rearrangement of a phenyl group of benzilic
acid which results in the synthesis of a carboxylic acid.

Reaction equation:
O O
1. Conc. KOH Ph
Ph HO
Ph O H
2. H+
O Ph

Reaction mechanism:

O O O O
K K Ph K
Ph 1. Conc. K OH Ph Ph 2. H+
Ph Ph H O O
O OH O O H
O Ph Ph

O
Ph
HO
O H
Ph

H Kwart and I M Sarasohn. J Am. Chem. See, 1961, 83, 909.

6. Benzoin Condesation: This reaction is characterized by the joining of two aldehydes to make a C-C bond from the
carbonyl carbon one of aldehyde to the carbonyl carbon of another aldehyde. More importantly, this reaction can occur
without -hydrogen atoms thus synthesizing compounds which could not be via aldol condensation.

Reaction equation:
O
O 1. Cat. KCN, aprotic solvent
(2 moles)
H HO

Reaction mechanism:
1
K
O H O Tautomerization O H O
1. Cat. K CN
+
K
H CN CN H

2 K
H O
O O K O OH
+ KCN
CN CN HO

cite

1. The presence of two highly EWGs (a phenyl group and a nitrile) facilitate this tautomerization.

Also, note that this is why an aprotic solvent is required; if the reaction occurred in the presence

of a protic solvent the carbanion would be quenched by deprotonation of the solvent.

2. The presence of the nitrile group (a very good leaving group) allows the formation of a ketone

(in the next step) which facilitates this intramolecular proton transfer.