Chapter 19 Study Guide
1) Enolates can react in a variety of ways.
O
R
1) LDA
2) RX
1) LDA
2) pentanal
3) H3O+
O
O
OH
O
O
1) LDA
2) Propanoyl chloride
2) β-dicarbonyl compounds are much more acidic than monocarbonyls
O
O
O
MOST ACIDIC PROTONS ON EITHER MOLECULE
3) Self “Aldol” reaction with esters—Claisen Condensation. In Chapter 17 we
learned that 2 equivalents of an aldehyde or ketone will self-condense in what
we know as an aldol reaction. Esters can also do this. You need to use a
stronger base. The base must match the ester’s alkyl group. You must have 2
α-protons available next to ester.
O
O
NaOEt
OEt
OEt
O
4) The mechanism is as follows:
O
O
OEt
H
OEt
H
H
NaOEt
EtO
O
NaOEt
O
O
H
H 2O
OEt
Final
Product
OEt
O
O
5) Dieckmann condensation is a intramolecular claisen reaction. It involves a
dicarbonyl cyclizing on itself. It preferentially makes 5 and 6 member rings.
O
O
O
O
O
O
O
6) Crossed claisens are useful as long as one of the molecules has no α-protons
otherwise self-condensation is possible.
EtO
O
O
O
+
OEt
EtO
O
7) Acylation reactions. You can use carbanions generated from ketones to create
1,3 diketones. Or you can use an ester with ONLY one α-proton to create a βketo ester.
O
O
1) LDA
2) ethyl pentanoate
O
1,3-diketone
O
O
O
H3 C
O
1) Sodium triphenylmethanide
2) propanoyl chloride
O
H
1 α-proton
8) Substituted ketones can be made from acetoacetic acid. In this case the ester
almost serves as a protective activating group, since in the end it is removed.
Allows for substituted acetones to be made under non-harsh conditions. It acts
as a substitute for ketones in synthesis when using a ketone is not applicable.
O
O
1) NaOEt
2) RX
O
O
O
O
RX can be 1 o, allylic, benzyllic
or sometimes 2o
acetoacetic ester
1) dilute NaOH/Δ
2) Η3Ο+
3) Heat
WHY DO YOU USE DILUTE NAOH?
O
R
OR
1) Potassium tert
butoxide
2) R' X
O
O
R
O
'
R
R
1) dilute NaOH/Δ
2) Η3Ο+
3) Heat
WHY DO YOU USE POTASSIUM TERT BUTOXIDE?
O
R
R
9) The above is known as the acetoacetic ester synthesis. It can be done with
halo-esters or halo-ketones instead of RX to create γ-keto acids and γdiketones.
O
O
1) NaOEt
O
2) Br
C2 H5
O
O
O
O
O
acetoacetic ester
O
1) dilute NaOH/Δ
2) Η3Ο+
3) Heat
O
OEt
OEt
O
γ-ketoester
O
WHY DID
THIS ESTER
DISAPPEAR?
O
O
1) NaOEt
2) Br
O
O
O
O
acetoacetic ester
O
1) dilute NaOH/Δ
2) Η3Ο+
3) Heat
O
LDA
O
γ-diketone
?
10) Acetoacetic esters can react with acid chlorides and acid anhydrides to give
the same type of claisen condensations. However you need to use an aprotic
solvent(DMSO or DMF) since acid chlorides/anhydrides react with protic
solvents and you need to use a suitable base(NaH).
O
O
O
1) LDA
2) ethyl pentanoate
1,3-diketone
O
O
1) NaOEt/DMSO
2) Cl
C2 H5
O
O
1) NaOEt/DMSO
O
O
2)
C2 H5
O
O
O
3) dilute NaOH/Δ
4) Η3Ο+
5) Heat
O
O
1,3-diketone
O
O
O
3) dilute NaOH/Δ
4) Η3Ο+
5) Heat
1,3-diketone
11) To add a benzene to the carbon between two carbonyls requires the following
special conditions.
O
O
C2 H5
O
Bromobenzene
2 eq. NaNH2
in liquid NH3
O
O
C2 H5
O
12) Acetoacetic esters can also be used to add groups to the terminal carbon
through use of a dianion.
O
O
O
O
2 eq. KNH2
in liquid NH 3
O
The terminal anion always reacts first.
The internal anion can react with a second equivalent
of electrophile or just protonate with water.
1) RX
2) H 2O
C2 H5
O
C2 H5
O
O
R
C2 H5
O
13) Diesters can be used very similiarly to the above synthesis(#8) to create
substituted acids.
O
O
O
1) NaOEt
2) RX
EtO
OEt
O
EtO
OEt
o
Diethyl malonate
RX can be 1 , allylic, benzyllic
or sometimes 2o
1) dilute NaOH/Δ
2) Η3Ο+
3) Heat
R
OR
O
1) Potassium tert
butoxide
2) R' X
O
O
R
HO
EtO
OEt
R'
R
1) dilute NaOH/Δ
2) Η3Ο+
3) Heat
What is the difference
mechanistically between this and
the acetoacetic ester mechanism?
O
R
HO
R
14) Diethyl malonate can also be used to create diacids and α-cyclic acids. 3, 4, 5,
and 6 membered rings are possible.
O
O
EtO
2
O
OEt
O
CH2
1) NaOEt
2) CH 2I2
EtO
EtO
OEt
OEt
Diethyl malonate
O
O
1) HCl(aq)
2) heat
O
HO
Which 2 esters are
decarboxylated?
O
OH
O
O
O
EtO
1) NaOEt + 1, 2-dibromoethane
2) HCl(aq)
HO
3) heat
OEt
Diethyl malonate
O
O
O
EtO
1) NaOEt + 1, 3-dibromopropane
2) HCl(aq)
HO
3) heat
OEt
Diethyl malonate
O
O
O
EtO
1) NaOEt + 1, 4-dibromobutane
2) HCl(aq)
HO
3) heat
OEt
Diethyl malonate
O
O
O
EtO
Diethyl malonate
1) NaOEt +1, 5-dibromopentane
2) HCl(aq)
HO
3) heat
OEt
15) Electron withdrawing groups can serve to do most of these reactions since
they have acidic protons. Ketones, aldehydes, esters, amides, nitriles, nitros,
sulfoxides, sulfonates, sulfonate esters and sulfonamides all can form enolates
that can react with RX.
16) Esters and nitriles can undergo direct alkylation instead of claisen and nitrile
condensations if a strong bulkybase is used such as LDA.
With a weak base esters undergo self-condensation. I.E. the Claisen condensation
O
O
NaOEt
OEt
OEt
O
With a stong, bulky base esters undergo direct alkylation reactions.
O
1) LDA
2) RX
O
OEt
OEt
R
With a weak base nitriles undergo self-condensation.
CN
NaOEt
CN
With a stong, bulky base nitriles undergo direct alkylation reactions.
1) LDA
2) RX
CN
R
CN
17) Aldehydes are extremely electrophilic. However the nature of the aldehyde
can be changed. The hydrogen of the aldehyde is not acidic; however, by
protecting the aldehyde and a thioacetal, we not only reverse the polarity we
allow addition to occur directly at the carbonyl. The term for reversing the
polarity is umpolung. The reaction is known as the Corey-Seebach reaction.
O
O
H
R
HOWEVER USING THE THIOACETAL...
O
1,3-propanethiol/H3O
+
S
This proton is
now acidic!!!
It requires a
strong base to
deprotonate.
S
H
H
1) Butyl Lithium
2) RCH2X
O
HgCl2 , Methanol, water
R
S
S
R
Raney Ni
?
18) Knoevenagel Condensation is when compounds like acetoacetic esters
condense with aldehydes and ketones. Just a fancy name for another aldoltype reaction.
19) Activated compounds(α-dicarbonyls) also can do Michael additions(1,4) to
α, β-unsaturated carbonyls. Activated compounds can do Michael additions to
acetylenic esters and α, β-unsaturated nitriles.
O
O
1) NaOEt
O
2)
O
O
O
O
O
O
O
O
1) NaOEt
O
2)
O
O
O
O
1) NaOEt
2)
CN
O
O
O
O
CN
20) Enolates react with formaldehyde and primary(or secondary) amines to form
Mannich bases.
O
Formaldehyde, diethylamine
HCl
O
N(CH2CH 3) 2
21) Aldehydes and Ketones can be “protected” as enamines which react just like
the aldehyde or ketone would. Then the iminium ion is then deprotected to the
alcohol. Enamines react with methyl, primary, allylic and benzylic halides.
They also react with acyl chlorides and acid anhydrides as well as halo esters.
O
H
N
O
1) RX
2) H2O
N
R
p-TsOH
O
O
O
R
O
O
1) RX
2) H2O
(or anhydride)
1)
Cl
2) H2O
HOW DOES THIS
HAPPEN?
Cl
1)
2) H2O
O
O
1)
N
2) H2O
O
Br
O
OEt
OEt
O
22) The mechanism for the Stork enamine synthesis is as follows:
O
H
p-TsOH
HO
N
NH
H2 O
H
H
N
B-
N
O
N
N
H2O
O
Cl
O
O
23) Also know the synthesis of barbiturates.
O
O
H
N
OEt
+
UREA
O
OEt
O
N
H
O
CHAPTER 19
O
O
O
+
EtO
OEt
EtO
O
If removing a H from a substituted carbon you must use stronger base
O
O
O
O
O K
1 )
E t
E t
O
O
2 ) P r o p y l C h lo r id e
1 ) d ilu te N a O H
+
2 ) H 3O
3 ) h e at
O
O
O
O
1 )
E t
E t
E t
O
O
O
O K
E t
O
O
2 ) P ro p y l C h lo rid e
1 ) d i l u te N a O H
2 ) H 3O
3 ) heat
O
H O
O
O
Et
1 ) S o d i u m tr ip h e n y l m e t h a n id e
O
2 ) P r o p y l c h l o r id e
Et
O
+
The acetoacetic ester synthesis can be used to make all sorts of ketone, diketones,
Ketoesters…if the ketone is on the second carbon it comes from a standard acetoacetic ester
reaction. If the diketone is a 1,3 diketone the reagent used was an acid chloride, anhydride,
ester…if it is 1,4 diketone…1,5,..1,6…then it was either a bromo or a Michael addition as below.
1) N aO M e
O
O
O
2) Prop yl c hloride
3) d ilute Na OH 4) H 3 O + 5 ) he at
Et
O
O
1) N aO M e
2) Prop anol y c hloride
O
Et
O
O
3) d ilute Na OH 4) H 3 O + 5 ) he at
O
O
1 ) Na OM e
2)
O
O
O
O
Br
Et
O
3 ) dilu te NaO H 4) H 3 O + 5) hea t
O
1 ) Na OM e
O
O
2)
O
O
O
O
Et
O
3 ) dilu te NaO H 4) H 3 O + 5) hea t
1) Na OM e
O
O
O
2)
Et
O
3) dilute N aOH 4) H 3 O + 5) h eat
1) N aOM e
O
O
O
2)
Br
Et
O
O
3) di lute Na OH 4) H 3 O + 5) he at
O
If the ketone is not on the second carbon then you must use a special reagent to extend the chain
in both directions or if you have a benzene next to the ketone you need to use a special reagent.
1) 2 eq. KNH 2/NH3
O
O
2) Propyl chloride
3) Butyl chloride
Et
+
O
4) dilute NaOH 5) H3 O 6) heat
O
1) 2 eq. KNH 2/NH 3
2) Propyl chloride
O
O
3) Butanoyl chloride
+
Et
4) dilute NaOH 5) H3 O 6) heat
O
O
O
1) 2 eq. KNH2/NH3
2) hexyl chloride
O
3)
O
Et
O
Br
O
+
4) dilute NaOH 5) H 3O 6) heat
O
O
C2 H5
O
Bromobenzene
2 eq. NaNH2
in liquid NH 3
O
O
O
O
C 2H5
O
Everything done with acetoacetic ester can be done with diethyl malonate, the final product will
be an acid instead of a ketone.
O
1) NaOMe
2) Propyl chloride
3) dilute NaOH 4) H3O+ 5) heat
O
Et
EtO
O
HO
O
1) NaOMe
O
O
Et
EtO
O
HO
O
O
1) NaOMe
2)
O
O
O
O
Br
Et
EtO
O
2) Propanoly chloride
3) dilute NaOH 4) H3O+ 5) heat
HO
O
3) dilute NaOH 4) H3O+ 5) heat
O
1) NaOMe
O
2)
O
O
O
O
O
Et
EtO
HO
O
3) dilute NaOH 4) H3O+ 5) heat
1) NaOMe
O
O
O
2)
Et
EtO
HO
O
+
3) dilute NaOH 4) H3O 5) heat
O
1) NaOMe
2)
O
O
Br
Et
EtO
HO
O
O
3) dilute NaOH 4) H3O + 5) heat
O
O
O
H
R
HOWEVER USING THE THIOACETAL...
O
1,3-propanethiol/H 3O
+
S
This proton is
now acidic!!!
It requires a
strong base to
deprotonate.
S
H
H
1) Butyl Lithium
2) RCH 2X
O
HgCl 2 , Methanol, water
R
S
S
R
Raney Ni
?
O
H
N
O
1) RX
2) H2O
N
R
p-TsOH
O
O
O
R
O
O
(or anhydride)
1) RX
2) H2O
1)
Cl
2) H2O
HOW DOES THIS
HAPPEN?
Cl
1)
2) H2O
O
O
1)
N
2) H2O
O
Br
O
OEt
OEt
O
O
H
p-TsOH
HO
N
NH
H2 O
H
H
N
B-
N
O
N
N
H 2O
O
Cl
O
O
O
O
O
EtO
1) NaOEt + 1, 2-dibromoethane
2) HCl(aq)
3) heat
HO
OEt
Diethyl malonate
O
O
O
EtO
1) NaOEt + 1, 3-dibromopropane
2) HCl(aq)
HO
3) heat
OEt
Diethyl malonate
O
O
O
EtO
1) NaOEt + 1, 4-dibromobutane
2) HCl(aq)
HO
3) heat
OEt
Diethyl malonate
O
O
O
EtO
1) NaOEt +1, 5-dibromopentane
2) HCl(aq)
3) heat
HO
OEt
Diethyl malonate
O
O
O
O
O
O
O
I. Give the Product of the following Reactions
Acetoacetic ester reactions.
1) N aOE t/E tha nol
2) B enzyl C hloride
3) D ilute N aO H/hea t
O
4) H 3O
5) heat
O
+
O Et
1) N aO Et/E thanol
2) H exyl chloride
Diethyl malonate reactions.
O
E tO
1)
2)
3)
4)
O
N a O E t/ Et h a n o l
P ro p y l C h lo r id e
H C l (a q )
heat
OEt
1 ) N a O E t/ Et h a n o l
2 ) C H 2 I2
II. Give the Reagents needed for the following.
O
O
O
Et
O
O
O
O
O
Et
O
O
O
O
Et
Et
O
HO
O
III. Which one of the two compounds below will self-condense. Explain.
O
O
OEt
OEt
Br
Br
A
B
KEY
I. Give the Product of the following Reactions
A Acetoacetic ester reactions.
O
1) NaOEt/Ethanol
2) Benzyl Chloride
3) Dilute NaOH/heat
4) H 3O +
5) Heat
O
O
O
OEt
O
1) NaOEt/Ethanol
2) Hexyl Chloride
OEt
.
B. Diethyl malonate reactions.
1) NaOEt/Ethanol
2) Propyl Chloride
3) HCl(aq)
4) Heat
O
EtO
O
HO
O
O
O
OEt
1) NaOEt/Ethanol
2) CH2I 2
EtO
OEt
EtO
OEt
O
O
II. Give the Reagents needed for the following.
O
1) NaOEt/Ethanol
2) Propyl Chloride
3) Potassium tert-butoxide
4) Methyl Iodide
5) Dilute NaOH/heat
6) H+
7) Heat
O
Et
O
O
1) NaOEt/Ethanol
2)
O
Cl
O
O
O
Et
O
3) Dilute NaOH/heat
4) H+
5) Heat
1) NaOEt/Ethanol
2) Hexyl chloride
O
O
Et
Et
O
O
3) Dilute NaOH/Heat
4) H+
5) Heat
O
HO
O
III. Which one of the two compounds below will self-condense. Explain your
answer.
O
O
OEt
OEt
Br
Br
A
B
PRODUCT A WILL SELF-CONDENSE. B WILL NOT. THE REASON
IS THAT A HAS 2 ALPHA PROTONS AND B HAS ONLY ONE ALPHA
PROTON. THERE MUST BE 2 ALPHA PROTONS TO DRIVE THE
SELF-CONDENSATION REACTION.
I. COMPLETE AND SHOW MECHANISM FOR THE FOLLOWING:
O
O
NaOMe
Methanol
H
N
1) p-TsOH +
O
2) benzyl bromide
3) H2O
Br
II. OUTLINE A SYNTHESIS OF THE FOLLOWING STARTING WITH
AN ESTER:
O
A
B
C
O
O
OEt
O
O
Br
OEt
O
OEt
O
D
OET
III. SYNTHESIZE THE FOLLOWING FROM ACETOACETIC ACID:
O
O
OEt
ACETOACETIC ACID
O
O
O
O
O
O
OEt
O
BR
IV. SYNTHESIZE THE FOLLOWING FROM DIETHYL MALONATE
O
EtO
O
OEt
DIETHYLMALONATE
O
O
HO
HO
O
O
HO
O
HO
O
OH
V. SYNTHESIZE THE FOLLOWING USING CH. 19 REACTIONS:
O
O
S
O
O
O
O
O
OEt
OEt
O
O
O
O
N(CH3) 2
ANSWER KEY
I. COMPLETE AND SHOW MECHANISM FOR THE FOLLOWING:
O
O
OMe
H
OMe
H
NaOMe
NaOMe
H
O
H
OMe
OMe
O
O
H3O
+
O
OMe
O
H
O
HO
p-TsOH
N
Br
Br
H
N
H2 O
NH
H
N
N
Br
Br
B-
Br
N
Br
Br
H2O
O
Br
II. OUTLINE A SYNTHESIS OF THE FOLLOWING STARTING WITH
AN ESTER:
O
A
O
1) Sodium triphenyl methanide
2) 2-methyl hexanoyl chloride
OEt
OEt
O
1) NaOEt/Ethanol
B
O
O
O
O
OEt
2)
OEt
OEt
C
Br
EtO
OEt
O
O
Br
NaOEt
OEt
Ethanol
O
O
O
1) LDA
2) Propyl chloride
OEt
D
O
OET
III. SYNTHESIZE THE FOLLOWING FROM ACETOACETIC ACID:
O
1) NaOEt
2) Butyl chloride
3) dilute NaOH/Δ
4) Η3Ο+
5) Heat
O
OEt
O
ACETOACETIC ESTER
O
O
OEt
1) NaOEt
2) Butyl chloride
3) Potassium tert butoxide
4) Methyl iodidi
5) dilute NaOH/Δ
6) Η3Ο+
7) Heat
O
ACETOACETIC ESTER
O
O
O
O
1) 2 eq. KNH2 /NH3
2) 2 eq. Ethyl Chloride
OEt
OEt
ACETOACETIC ESTER
O
1) NaOEt
2)1,4-dibromo-2-ketoheptane
3) dilute NaOH/Δ
4) Η3Ο+
5) Heat
O
OEt
O
ACETOACETIC ESTER
O
O
1) NaOEt
2) 1-bromo-2-keto-3-methypentant
3) dilute NaOH/Δ
4) Η3Ο+
5) Heat
6) LDA
7) H3O+
O
OEt
ACETOACETIC ESTER
8) heat
Br
O
IV. SYNTHESIZE THE FOLLOWING FROM DIETHYL MALONATE
O
O
EtO
OEt
DIETHYLMALONATE
O
O
HO
O
EtO
OEt
DIETHYLMALONATE
O
1) NaOEt
2) Hexyl chloride
3) dilute NaOH/Δ
4) Η3Ο+
5) Heat
1) NaOEt
2) CH2I2
3) HCl(aq)
4) Heat
O
HO
O
OEt
1) NaOEt + 1,5-dibromopentane
2) HCl(aq)
3) Heat
DIETHYLMALONATE
EtO
OH
O
EtO
O
O
1) NaOEt
2) Heptyl chloride
1) Potassium tertbutoxide/DMSO O
2) Ethanoyl Chloride
3) dilute NaOH/Δ
4) Η3Ο+
HO
5) Heat
O
OEt
DIETHYLMALONATE
O
HO
V. SYNTHESIZE THE FOLLOWING USING CH. 19 REACTIONS:
O
O
O
OEt
ACETOACETIC ESTER
1) 2 eq. KNH2 /NH3
2) Butyl Chloride
3) Propyl Chloride
4) dilute NaOH/Δ
5) Η 3Ο+
6) Heat
O
S
1) LDA
2) Ethyl Chloride
N(CH3) 2
O
O
S
N(CH3) 2
O
O
1) NaOEt
2)
O
OEt
O
O
O
OEt
ACETOACETIC ESTER
O
1) NaOEt/DMSO
2)
O
O
O
OH
O
OEt
OEt
3) SOCl2
4) Propanoic Acid
ACETOACETIC ESTER
O
O
O
O
O
O
O
O
O
OEt
O
O
O
O
OH
HO
O
O
HO
O
EtO
OEt
O
O
EtO
HO
O
OEt
O
O
1)
2)
3)
4)
5)
6)
O
2 eq. KNH2/NH3
Butyl Chloride
Ethyl Chloride
NaOH
H3O+
Heat
O
OEt
1)
2)
3)
4)
5)
NaOEt/Ethanol
Br
NaOH O
H3O+
Heat
1)
2)
3)
4)
5)
6)
7)
O
NaOEt/Ethanol
1-bromo-3-ketopentane
NaOH
H3O+
Heat
LDA
H3O+/heat
1) NaOEt/DMSO
O
2)
Cl
3) NaOH
4) H3O+
5) Heat
O
O
O
O
1) NaOEt/Ethanol
OEt
2)
O
1)
2)
3)
4)
O
EtO
OEt
1) NaOEt/Ethanol
2) bromocyclopentane
O
2 eq. NaNH2/NH3
Bromobenzene
HCl(aq)
Heat
1)
2)
3)
4)
5)
6)
HO
NaOEt/Ethanol
Propyl chloride
Potassium tert butoxide
Propyl Chloride
HCl(aq)
Heat
O
HO
O
EtO
O
OEt
OH
HO
3) HCl(aq) O
4) Heat
O