Professional Documents
Culture Documents
Aim of Course
• To build upon elements of Dr E.H. Smith’s and Dr. D.C. Braddocks’s course.
• To introduce the chemistry of the carbonyl functional groups.
Course Objectives
At the end of this course you should be able to:
Recommended Texts
• We begin our study of carbonyl compounds with the study of aldehydes and
ketones (the aldehyde/ketone oxidation level).
– Carbonyl compounds are molecules containing the carbonyl group, C=O.
These include:
Carboxylic acid derivatives:
O
O
• Esters C
• Aldehydes C R OR'
R H
O O
O
• Anhydrides C
• Ketones C R O R'
R R'
O
O
O
• Amides R
C
NH2
• Carboxylic acids R
C
OH
2
Nomenclature of Aldehydes and Ketones
• Common names are used for the simplest aldehydes and ketones:
O O
O
C C H
C H
H H CH3 CH2 CH2
O O O
C C CH3 C
H3 C CH3
• Traditional names are used for a great many aldehydes and ketones which
were recognized as substances long before systems of nomenclature were
developed:
H
O H
O H2 C CH C O
C H
O
• Three of the four bases which comprise DNA contain carbonyl groups (and all
four bases are nitrogen heterocycles, which we will discuss later):
O O NH2
H3 C
N NH N
NH
N N O N O
N NH2 H H
H
• Aldehydes and ketones are polar molecules because the C=O bond has a
dipole moment: For acetone: dipole moment = 2.7 D
b oiling piint = 56.5 ºC
O For propene: dipole moment = 0.4 D
b oiling point = -47.4 ºC
C For i-propanol: dipole moment = 1.7 D
b oiling point = 82.3 ºC
• Their polarity makes aldehydes and ketones have higher boiling points than
alkenes of similar molecular weight.
• Aldehydes and ketones are not hydrogen bond donors (they can’t donate a
proton); therefore, they have lower boiling points than alcohols of similar
molecular weight.
• Aldehydes and ketones are hydrogen bond acceptors; this makes them have
considerable solubilities in water.
O
O H Ketones such as acetone are good solvents
H H
H O because they dissolve both aqueous and organic
compounds
C
R R' Recall that acetone is a polar, aprotic solvent.
6
Reactions of Aldehydes and Ketones
• The reactions of aldehydes and ketones can be divided into two main
categories:
+
O O E
C +
E C
O +
+ O H
H H
C H O
C + O
H H
8
Carbonyl Group Reactions
• Addition Reactions
– Carbonyl groups in aldehydes and ketones undergo addition reactions.
– This is one of the most important reactions of the carbonyl group.
O O E
+
C E Y C
Y
O O
oxidation
C C
H OH
H O
OH O
H3 C C OH H3 C C OH
H3 C C CH3 H3 C C CH3
H H
alcohol to aldehyde: two electron oxidation alcohol to carboxylic acid: four electron oxidation
O O
aldehyde to carboxylic acid:
two electron oxidation H3 C C H H3 C C OH
10
Basicity of Aldehydes and Ketones
11
+ R R
O O
C C
H3 C CH3 H3 C + CH3
C
…more stable than:
C
H3 C + CH3
+ H H
O O
C C
H3 C CH3 H3 C + CH3
• The polar effect of the oxygen in the carbon-oxygen bond attracts electrons.
• But… electron-attracting groups adjacent to carbocations are destabilizing
• However, the resonance stabilization outweighs this destabilization
12
Stability of Protonated Aldehydes/Ketones
overall reaction: OH OH
H2SO 4
CH3 O
H3 C C C CH3 H3 C C C CH3 + H2O
mechanism:
H+
+
OH OH OH2 OH OH CH3 OH
+
H3 C C C CH3 H3 C C C CH3 H3 C C C CH3 H3 C C C CH3
+
CH3 CH3 CH3 CH3 CH3 CH3 CH3
+ H2 O
H #-hydroxy carbocation
O H
CH3 O H
H3 C C C CH3
rearrangement occurs
+ because tertiary
CH3
carbocation is more stable
#-hydroxy carbocation 13
• Compare pKa values of the conjugate acids of aldehyde/ketones with those for
the conjugate acids of alcohols:
+
O H
Protonated alcohols are
H
less acidic; therefore
O
R R' R + H
alcohols are more basic
than ketones
pKa: -7 -2.5
14
Reversible Additions to Aldehydes and Ketones
O OH
+ H2 O H3 C C H
H3 C H OH
H2 O
+
H2 O H OH2
+ + H + H
H OH2 O H O OH
OH OH
ketone: O
+
O H
16
Addition Under Basic Conditions
H O
! H
! C O HO C O !
OH HO C OH + OH
• Note that regioselectivity of addition is the same for acid or base catalyzed
nucleophilic addition
17
• The sp2 hybridization of the carbonyl compound means that attack of the
nucleophile on the carbonyl carbon may occur from either face.
• The resulting addition product is sp3-hybridized.
Nu
Nu:$
O OH R C R'
Keq Keq = Nu
+ H-Nu: R C R'
R R' O
Nu . H-Nu:
R R'
• Reactant Stability:
– Recall that alkyl groups stabilize double bonds (more highly substituted
alkenes are more stable than less substituted alkenes)
– This works for C=O double bonds, too
– Ketones are more stable than aldehydes
– Therefore, the addition to ketones is less favored than addition to aldehydes
• Product Stability:
– The four groups in the product are closer together than the three groups
attached to the carbonyl carbon in the reactant.
– Alkyl groups cause more steric destabilization in the tetrahedral addition
product than does hydrogen
– Therefore, the ketone addition product is less favored than the aldehyde
addition product 20
Equilibria in Carbonyl Addition Reactions
• Conjugation with the carbonyl group makes addition less favorable (smaller
(Keq).
• Larger size of groups attached to the carbonyl carbon makes addition less
favorable (smaller Keq).
21
OH
O acid or base Note: this bond to carbon
+ R OH C indicates that it may be either to
C an alkyl group or to hydrogen.
OR
hemiacetal
• Hemiacetals react further with alcohols under acidic conditions to form acetals.
OH OR
O acid or base R OH
+ R OH C C + H2 O
C
OR OR
aldehyde
or ketone hemiacetal acetal
23
H R H R
H O + + R
O + H O H O O
+ H2 O
C C C C
+
OR OR
+ ROH
R
OR R
O R OR H O
H O C + H
C + R C
+ O R O
H OR
H
24
Acetals as Protecting Groups
• The reversibility of acetal formation along with the relative inertness of the
RO-C-OR linkage make acetals useful as protecting groups.
• Protecting groups are functional groups which may be introduced in a molecule
by converting another functional group in a reversible reaction.
• If the protecting group is more inert than the original functional group, then
other reactions may be carried out with this molecule without worrying about
altering or destroying the protecting group.
• When the other desired reactions are completed, the original group may be
restored by carrying out the reverse of the reaction which introduced the
protecting group.
OR OR H3 O+ O
O
+ ROH C C C
C
OR OR
Cyclic Hemiacetals
• Cyclic hemiacetals containing five and six atoms in the ring can form
spontaneously from hydroxyaldehydes:
HO H
H
HO O
CH3
H
3 acid O O
H3 C O
H3 C O CH3
O
O acid
HO OH + O + H2 O
27
O
H
N acid
+ N O + H2 O
• Aldehydes and ketones also undergo addition reactions which are essentially
irreversible.
• These reactions use organometallic reagents to add alkyl groups to the
carbonyl carbon atom.
• These reactions are nucleophilic additions; this means that the organic group
added is acting as a nucleophile in the reaction.
We’re accustomed to electrophilic behavior of alkyl groups (I.e., carbocations), but
how does an alkyl group act as a nucleophile?
Organometallic Reagents
O
Grignard reagent Grignard reagents are highly
prepared in diethyl ether R Mg X polar compounds and are very
strong Lewis bases.
O
Step 1: Addition of the nucleophilic alkyl group to the carbonyl carbon, aided
by Lewis acid interaction between MgX+ and the carbonyl oxygen. The
product of this step is a halomagnesium alkoxide (see previous slide).
Step 2.
33
H H3O +
C +
MgBr + Mg2+ Br! + H2O
C
O step 1 step 2
OH
• The net effect of the reaction of a Grignard reagent with an aldehyde or ketone
in the addition of the components R and H across the C=O double bond.
• Compare to nucleophilic addition of HCN:
O O H
O H H CN
O 1. R MgBr
C C CN
C R
C
+
2. H / H2O
• Other metal-based reagents also add components across the C=O bond in an
analogous way:
– Metal hydrides add H- and H+ across the C=O double bond.
– When we add H-H to a double bond, we call the reaction a reduction.
36
Metal Hydrides
+ ! + !
+ Li Li O H
O Li
O O AlH3 H3O +
!
! C C H C O Al 4 C H
C H AlH3 AlH3
H H 4
+ Li+ , Al3+ salts
• The hydride ion in LiAlH4 is more basic than the hydride ion in NaBH4, and
therefore it is more reactive.
• Some functional groups which may be reduced by LiAlH4 are unreactive with
NaBH4 (e.g., alkyl halides R-X, nitro groups -NO2)
– Therefore NaBH4 may be used to reduce C=O bonds in the presence of
such groups.
37
Carboxylic Acids
Lewis basicity
(greater at this oxygen) • reactions at the
chemistry at #
carbonyl group
-hydrogens Lewis basicity
O (lesser at this oxygen) • reactions at the
H carboxylate oxygen
C
C O H
• reactions involving
Bronsted acidity #-hydrogens
Lewis acidity
38
Nomenclature of Carboxylic Acids
• Carboxylic acids may also contain two carboxy groups. These compounds are
called dicarboxylic acids.
O
O O O
OH
OH
HO OH HO OH
O
O
• Compare bond lengths and angles to other C=O and C-O containing
compounds:
sp2
-sp3 single bond is shorter than sp3
-sp3 bond
O H O R
R O H O
• Carboxylic acids have high boiling points
due to their ability to act as both donors and Carboxylic acids can exist
acceptors in hydrogen bonding. as dimers in solution
40
Acidity of Carboxylic Acids
conjugate base:
! !
O O O
! !
R O R O R + O !
O O
R OH R + OH
+ O H
O O H O H
+ + H2 O
+ H3 O
R OH R OH R + OH R OH
+
• Why does protonation occur only at the carbonyl oxygen, and not at the
carboxylate oxygen?
carbonyl carbon:
+
O O E
• Another important reaction + E Y
O E
+
is the reaction of the R OH R OH R OH
carbonyl oxygen with an !
+ Y
electrophile:
!
O O O
• Reaction at the carboxylate + H2 O
!
oxygen results in ionization: R OH R O R O
+
+ H3 O
43
O O
C H2 SO4 C
OH H3CO H OCH3 + H2O
+
excess
+
H
H3CO
+ H
OH OH
O H O
+ H3CO H R OH R OH
+
R OH R OH CH3 O CH3 O
protonation addition H
+
H
H3 CO
H3 CO H
H
• This reaction differs from addition to deprotonation
aldehydes and ketones in the next
step -- in what happens to the
tetrahedral intermediate.
45
OH + + OH
H OH + OH OH
OCH3
R OH +
H R OH2 R R R
CH3 O
CH3 O CH3 O CH3 O CH3 O
+
+ H2 O
+ O
H +
O H carbonyl C=O double bond is
R H3CO H + OCH3 retained in the substitution
CH3 O R OCH3 H product
46
Substitution vs. Addition
Esterification by Alkylation
• Another route to esterification of carboxylic acids involves one of the other
types of reactions we outlined at the beginning of the discussion of carboxylic
acids.
reactivity at the carboxylate oxygen
mechanism:
O ! + O
H2 C N N O
+
R O H + H3 C N N + N2
! R O CH3
R O
both steps involve the carboxylate oxygen and not the carbonyl oxygen
48
Synthesis of Acid Chlorides from Carboxylic Acids
• Acid chlorides are prepared from carboxylic acids using either thionyl chloride
(SOCl2) or phosphorus pentachloride (PCl5).
O O O
+ + HCl +SO2
S
R OH Cl Cl R Cl
• This reaction fits the pattern of substitution at the carbonyl group; however, the
mechanism proceeds slightly differently from that of Fischer esterification.
• The first step involves attack of the sulfur of thionyl chloride by the carbonyl
oxygen acting as a Lewis base.
O
O O S
S
O Cl ! The sulfur is very electrophilic; why?
Cl Cl Cl
R O H
R O H
+
49
• Carbonyl oxygen acts as a Lewis base to attack the electrophilic sulfur atom
instead of attacking a proton.
– Or, the Cl- anion can undergo nucleophilic attack on the carbonyl carbon
(because this species is so electrophilic, even a weak nucleophile like Cl-
can undergo this reaction).
O O O O
S S S S
O Cl O Cl O Cl O Cl
R O H R O R O H R OH
+ +
! Cl
!
Cl HCl Cl
50
Preparation of Acid Chlorides
• The last step is the elimination of the thionyl chloride group as SO2 and HCl.
This step is irreversible because SO2 is a gas.
H
O O O
+ HCl +SO2
S R Cl
R O Cl
Cl
O
O
Redraw two of the intermediates in this mechanism: S
S O Cl
O Cl
Drawn this way, it makes it look like a simple
R OH
substitution at the carboxylate oxygen. R O Cl
R OH 51
O O H
R O H R O
….however, when the reaction takes place, it does so via attack by the more
Lewis basic carbonyl oxygen (whichever one that happens to be at that instant
in time), and not via the less basic carboxylate oxygen.
O O
S
R O Cl
The oxygen that is a carbonyl in this intermediate was a carboxylate when the
reaction started.
52
Preparation of Acid Chlorides
• Another interesting point about the mechanism of acid chloride formation is the
role of the thionyl intermediate.
• If the minor species is too reactive, a high concentration might make it subject
to unwanted side reactions.
• The concentration of the minor species is kept low by virtue of its reversible
reaction to form the more stable major species.
• This “reservoir” meters the concentration of the minor species so that it reacts
immediately to products and can’t build up in concentration.
Products
54
Preparation of Acid Anhydrides
• Anhydrides may be formed by reaction between an acid chloride and the conjugate base
of a carboxylic acid.
O
O O H3 C Cl O O
+ H2 O !
Cl
! H O CH3
H O H H O
• Cyclic anhydrides may be formed by treating a dicarboxylic acid with another anhydride.
O O
O O
OH + CH3 COOH
+ O
OH H O CH3
O 55
O
O O
-OH is replaced by L
R L R OH
esters, L = OR’
R OR'
O
O O
acid anhydrides, L = OCOR’
R O R'
• Not only are the structures of these compounds related, but their chemistries
are related also.
• One of the most important types of reactions these compounds undergo are
nucleophilic addition-elimination reactions resulting in the replacement of L with
another nucleophile.
!
O O O
!
R + L
R L R L Nu
Nu
!
Nu
• Compare the C-O bond lengths of acyl compounds with their related single-
bonded compounds:
O O O
R OCH3 R NH2 R Cl
! !
O O O
Esters + +
R OR' R OR' R OR
! !
O O O
Acid +
chlorides R Cl R
+
Cl R Cl
• Let’s take a look at one of the high energy resonance forms and compare them
for the different acyl compounds.
! ! ! !
O O O O O
+ + + +
R NH2 R OR R O &+ R' R &+ Cl
!
O O O
!
+ Nu TS TS R + L
1 2
R L R L Nu
Nu
!G1 !G2
The height of the first transition The height of the second transition
state will depend on the state will depend on the
stability of the starting acyl proficiency of L as a leaving group
compound
61
Case (a): transition states Case (b): reactant is more Case (c): reactant is
for formation and stable relative to transition destabilized compared to
breakdown of tetrahedral state 1 and L is a worse Case (a), and L:- is a better
intermediate are similar in leaving group compared to leaving group in this case.
energy (Nuc:- and L:- are Case (a).
similar).
62
Reactivity in Nucleophilic Acyl Substitution
• The trends for reactant stability and leaving group ability tend to work
together (both contributing to make the compound more reactive or both
contributing to make the compound less reactive)
O O O O O
INCREASING REACTIVITY
63
• Acid chlorides are the most reactive of the acyl substituted carboxylic acid
derivatives, and they readily undergo a variety of nucleophilic addition-
elimination reactions.
O
React with water to form
carboxylic acids (hydrolysis).
R OH
NaOH
React with O
alcohols to form
O O
esters. O O R O
!
R Cl R O R'
R OR' R'OH
• Acid chlorides react with NH3, primary and secondary amines to give amides.
H
O
! O
H
Notice that two moles
O N of the amine are
"R R'
R Cl N
+
R' required to complete
R
R Cl N + ! the reaction: one to act
R"
"R H
Cl as the nucleophile
H
R' which substitutes for Cl,
N and one to act as a
"R R' O
H + H base to deprotonate the
R' N
ammonium ion.
R N "R R'
R"
• Other methods for carrying out the proton transfer step have been developed
for cases where the amine is too costly to waste in the final proton transfer step.
– Add a tertiary amine to carry out the final proton transfer step (why tertiary?)
– Run a two-phase reaction with a strong base (OH-) preent in the aqueous
layer. 65
• Tertiary amines such as pyridine or triethylamine can carry out the proton
transfer step:
H+
O N
O
H N
R' +
+
N R' R N
R +
R" R"
O
O H H + H NaOH
H
+ + + H2 O + NaCl
R' N N
N
R N "R ! R' "R R'
R Cl "R R'
Cl
R"
66
Reaction of Acid Chlorides
• Esters are formed from the nucleophilic substitution of acid chlorides with
alcohols.
– Hydrochloric acid is a by-product of this reaction. In practice, tertiary
amines are often added to neutralize the HCl.
N
O O H+ !
N Cl
H3C
+
H3 C OH + Cl
H3 C
• Anhydrides are formed from acid chlorides and salts of carboxylic acids.
– This provides a way to prepare mixed anhydrides (R and R’ may be
different groups).
O O O
O ether
+ NaCl
+
!
H2 CH3 C Cl H3 C O H2 CH3 C O CH3
67
amines amides
anhydrides
alcohols esters
O O
!
OCH3 O
! + CH3 OH
+ OH
NO2 NO2
69
!
O O
O !
+ OCH3
R O CH3
R OCH3 R OH
OH
!
OH
This alkoxide leaving group
reacts with the acid -- why?
O O
H CH3 OH
N !
H3 C + OH H3 C O! + CH3 NH2
H2 O
CH3
71
Chemistry of Nitriles
C !
KOH / H2 O O K+ + NH3
72
Hydrolysis of Nitriles
• Hydrolysis of nitriles under both acidic and basic conditions involves the
formation of an amide, which is then hydrolyzed to a carboxylic acid as we
have already discussed.
73
74
Reduction of Carboxylic Acid and Acid Derivatives
+
!
Li O Li + Li
+
O ! O
R Cl !
H AlH2 H AlH2
C C
R H H R Cl
75
• We have learned that the oxygen of a carbonyl group can act as a Bronsted or
a Lewis base by attacking protons or other electrophiles.
• We have shown how the carbon of a carbonyl group can act as a Lewis acid
resulting in addition of a nucleophile.
• Now we will explore chemistry at the carbon atom adjacent to the carbonyl
carbon (#-carbon).
76
Bronsted Acidity of Aldehydes and Ketones
O O !
! O
B
C ! C C
H C R C R C R
pKa = 16 + B H
• Compare to the ionization of an proton further removed from the C=O bond:
not acidic H O
H H
H C C
Hydrogens on carbon atoms not C C R
adjacent to the carbonyl carbon can’t H
form resonance-stabilized conjugate H H
#-hydrogen
bases acidic
77
pKa = 16 + B H
pKa = 42 + B H
!
• It’s oxygen’s electronegativity that O O
makes the difference. ! C
C
• Delocalizing charge onto a more C R C R
electronegative atom adds stability to
the enolate anion
!
• The polar effect of the C=O dipole CH2 CH2
also stabilizes the enolate anion: ! C
C
C R C R
O
!
C C
R favorable charge-dipole interaction
79
!
O H O
C C + B H C C + B!
R R
!
• Enolate ions are O O
O O
!
Lewis bases C C C
C C
(nucleophiles). C
R
R
!
C O
! O
O
C O C
C C C
R
R
80
Molecular Orbitals of Enolate Ions
• The two highest occupied molecular orbitals of the enolate ion are shown below.
C C
!
O
This higher energy orbital is
where the electrons come from
when the enolate ion acts as a
Lewis base.
There are three M.O.’s of the enolate ion, derived from the three 2p orbitals involved in the
overlap; the third (not shown) is an unoccupied antibonding orbital. 81
• How do we know whether the attack of the enolate ion will occur at the #-
carbon or at oxygen?
• The molecular orbital picture tells us that:
– The enolate electrons which will participate in a nucleophilic attack reside
predominantly on the oxygen.
– The orbital which participates in the nucleophilic attack is distorted toward
the # -carbon.
• Reactions which are dominated by charges and electrostatic interactions occur
at the oxygen.
• Reactions which are dominated by orbital interactions occur at the #-carbon.
82
Reactions of Enolate Ions
• Remember that resonance structures are not separate entities, but that the
molecule is some weighted average of these structures.
• We can write the curved arrow mechanism using either resonance structure.
– Example: attack of the enolate carbanion on a carbonyl carbon:
!
O O
O O
!
C C + C C C
C
R
R
! !
O O O
O
C C C C C
+
R C
R
83
• When the enolate ion acts as a Bronsted base, it may use either the #-carbon
or the oxygen to attack a proton.
– When enolate ions attack protons, either a C-H bond or an O-H bond
may be formed.
O H H O
R C C + B! R C C + B!
B H B H
aldehyde !
O O enol
or !
ketone C C C C
R R
84
Formation of Enols
O H H O
R C C R C C
ketone enol
• For most simple aldehydes and ketones, the equilibrium concentration lies far
on the side of the ketone.
• The reaction is catalyzed by both acids and bases.
• The mechanisms for acid- and base-catalyzed enolization are different.
85
Stability of Enols
O Keq" 10-20 OH
Esters are even less favored to form enols.
H3 C OC2 H5 H2 C OC2 H5
ethyl acetate
Keq" 10 H
O O O O '-dicarbonyl compounds form relatively stable
H enols due to resonance stabilized conjugation
H3 C CH3 H3 C CH3 and the opportunity for hydrogen bonding.
H H
O OH
H
Keq" 1014 Phenol is the “ultimate enol”. Its aromaticity
H makes it significantly more stable than its keto
phenol form.
86
Mechanisms of Enolization
starting O !
O CH 3
both enantiomers C
! CH3 H
compound C C C C
are formed: Ph C
! OH CH3
H Ph Ph
Ph Ph O
O
O C
C H CH3
Ph C
H
H chiral Ph C
H
Ph
CH3 information is Ph
H H
lost here
+
O H O H H O CH3
H +
+ C C CH3 C C CH3 C C
O H
H +
H Ph Ph Ph Ph Ph O
Ph H
H
O
H 88
H
Aldol Addition and Aldol Condensation Reactions
• Aldehydes and ketones undergo a reaction called the aldol addition to form "-
hydroxy aldehydes and ketones:
O O OH- OH O
+
H3 C H H3 C H H2 O H3 C CH2 H
• Under more severe basic conditions, or under acidic conditions, the reaction
proceeds further.
• Dehydration to form an #,'-unsaturated carbonyl compound is called the
aldol condensation:
O O concentrated OH O O
base
+ + H2 O
heat H3 C H
H3 C H H3 C H H3 C CH2 H
• These reactions are addition-elimination reactions which proceed via acid and
base-mediated mechanisms which should be familiar to us by now.
89
O
H O
+ O formation of the
H C
H
!
H H enolate ion
H CH2
H
OH!
addition of the
O O O O
!
enolate ion to the
H carbonyl carbon of
!
the second aldehyde
H CH2 H3 C H H CH2 CH3 molecule
! O
O O H H O OH protonation of the
H + OH!
H addition product
H CH2 CH3 H CH2 CH3
90
Mechanisms of the Aldol Reaction
+
H OH2
+ H
O O
+ O protonation of
H H the aldehyde
H CH3 H CH3
+ H O
O OH
H H deprotonation to
H form the enol
H C H CH2
H
H
91
+ O
O H OH H H O OH
H H
H CH2 CH3 H CH2 CH3
+ H3 O+
• Under acidic conditions, the aldol addition product is not stable; it undergoes
acid-catalyzed dehydration to form the aldol condensation product:
O OH O
H 3 O+
H + H2 O
H CH2 CH3 H CH3
O OH O OH
H OH! H H2 O
H
H C CH3 H CH CH3
!
H
O OH O !
H + OH
H CH CH3 H CH3
!
• What happens if an aldol addition reaction is carried out with two different
carbonyl compounds?
O O
+
CH3
H CH3 H C
H2
O OH O OH O OH
O OH
H H
H H
H C2 H5 H CH3 H C2 H5
H CH3
CH3 CH3
• If only one of the two carbonyl compounds has #-hydrogens, only one can form
an enolate ion.
– So now we’re down to a maximum of two possible products.
– Can we be even more selective? What reaction product(s) do we expect
from this reaction?
O O
+
?????
H3 C CH3 H
95
Claisen-Schmidt Condensation
• This reaction gives only one product, the “cross” condensation product:
O
O O H
+ H3 C
H3 C CH3 H H Ph
condensation
can’t form an enolate cross product
O O
97
• With what we know about the mechanism of the aldol condensation, we should
be able to deconvolute the origins of any aldol condensation product.
– Identify the carbonyl compound which was the enolate or enol compound.
– Identify the carbonyl compound which was attacked by the enolate or enol.
– Then ask the question: is this a feasible reaction? How complex will the
product mixture be?
O
R4
This portion is attacked R1 This portion forms
by the enolate or enol the enolate or enol
R3 R2
O O
R2
R4 R3 R1 CH2
98
Synthesis With the Aldol Condensation
• We can also identify the '-hydroxy aldehyde or ketone which was formed from
our starting materials as the first step before the aldol condensation.
O
R4
This portion is attacked R1 This portion forms
by the enolate or enol the enolate or enol
R3 R2
OH O
R4
R1
R3
R2
O O
R2
R4 R3 R1 CH2
99
!
EtO
O
O
!
H Et + EtOH
Et H2 C O
C O
H2
ester enolate ion
pKa ! 25
(#-proton is less acidic than #
-protons in aldehydes/ketones)
!
O O O tetrahedral
O
Et ! H3 C C C C O Et intermediate
Et H2
H3 C O H2 C O OEt
O O O O
!
EtO !
! Et Et EtO
+ EtOH
H3 C CH O H3 C C O
H2
"-keto ester
pKa = 10.7
We can drive the reaction to completion
by using one equivalent of the "-keto esters are much less stable
ethoxide base instead of a catalytic than the ester starting material.
amount
101
Claisen Condensation
• We can use the acidic hydrogen adjacent to the two carbonyl groups to form
the salt.
• We acidify the solution afterwards to regenerate the unionized '-keto ester.
O O
O O H3 O+
! Et H2 O
Et
H3 C C O
H3 C CH O H2
This means that we need to have at least two #-hydrogens on our ester;
• one to form the original enolate ion to form the C-C bond.
• one to form the ionized '-keto ester product.
(the starting ester in this example actually had three !-hydrogens)
102
Claisen Condensation: Summary
– one to form the original enolate ion to form the C-C bond.
– one to form the ionized '-keto ester product.
103
• There is also a crossed Claisen condensation, which works best if one ester
has no #-hydrogens or if one ester is especially reactive.
O
O
O
Na O
O Et + H Et
O Et
Et H O EtOH AcOH
O
O O O
(two separate steps)
Et
104
Summary of the Claisen Condensation
O O O
2 EtONa H 3 O+ H + EtO H
Et Et
H3 C O EtOH H3 C C O
EtO ( H
O
O
Et
Et H C O
H3 C O H2
H ( OEt
O O
H Et Et
H3 C CH2 O O
O O
R3
R1 Et Work backwards from the product
CH C O
R2 H
1 2
1 2
O
O
R1 R3
enolate component: R3 Et CH C
H2 C O H2
R2
O O
acceptor carbonyl R1 Et Et Et
CH O O
compound: O
R2
108
Alkylation of Enolate Ions
!
+ O O
N Li H NH
Et ! Et
H2 C O H2 C O
• The enolate ion that is formed may be used in a subsequent (separate) step as
a nucleophile to attack alkyl halides in an SN2 reaction.
O O
! Et + H3 C Br Et + LiBr
H2 C O H3 C O
• Why doesn’t the strong base attack the Lewis acidic carbonyl carbon?
X
X
!
+ O
N Li
Et
H3 C O
The bulky alkyl groups on LDA experience severe van der Waals repulsions with
groups on the carbonyl compound, retarding the rate of reaction at the carbonyl C
compared to reaction at the #-hydrogen.
The ester is totally consumed before (enolate+ester) have time to react together 110
Enolate Formation and Reactivity
• When bases such as ethoxide attack esters to form ester enolate ions, the reaction is
never complete (it’s driven to the left).
– This means that the solution will consist of a mixture of the starting ester and a small fraction of
its enolate anion.
– This allows the Claisen condensation to take place.
O EtO- O
H
Et
ester and enolate
!
C O Et + EtOH both exist in solution
H2 H2 C O
• When much stronger bases such as LDA are used, enolate formation is rapid
and complete (it’s driven to the right).
– This means that the solution will consist solely of the enolate anion.
– This allows us to carry out alkylation without Claisen condensation as a side reaction.
!
+
N Li
O
O enolate only
Et
! Et exists in solution
H3 C O H2 C O
111
• Dicarbonyl compounds like diethyl malonate (malonic ester) have especially acidic
#-hydrogens.
– Such compounds can form enolate ions completely with weaker bases than LDA.
O O
O O
Et Et EtO- Et
!
Et + EtOH
O C O
H2 O C O
H
• The enolate may be alkylated with alkyl halides as we have just shown.
• A second alkylation may also be carried out using a different alkyl halide (in a
separate step!).
– This provides flexibility in synthesis, creating two C-C bonds in the same molecule.
O O O O
1) enolate formation 1) enolate formation R1
Et Et Et Et
O C O O C O
H2 2) alkylation with R1 X 2) alkylation with R2 X
R2
112
Malonic Ester Synthesis
• Malonic acids and their derivatives decarboxylate (lose CO2) upon heating.
The mechanism involves formation of an enol-like intermediate:
H
H O
O O OH
O O R2
! CO2 R2
HO CH
HO C O HO C
HO C O
R1
R1 R2 R1
R1 R2
113
• Ketones may be formed from '-keto esters like ethyl acetoacetate via a series
of reactions that proceeds via formation of an enolate ester anion.
B:- RX
'-keto ester enolate alkylated '-keto ester
O O O O O O
!
Et Et Et
H 3C CH2 O H 3C CH O H 3C CH O
OH-/H2O (saponification)
ketone
O
decarboxylation H3O+/H2O O O
!
H3 C CH O
H 3C CH2 (protonation)
R
R
114
Conjugate Addition Reactions
• We learned that '-hydroxy aldehydes and ketones undergo dehydration to form #,'-
unsaturated carbonyl compounds.
– These compounds undergo further reactions at the C=C bond which are not found in the
reactions of simple alkene compounds.
• Nucleophilic addition to the C=C bond can occur: why?
– A resonance-stabilized enolate intermediate is formed.
– The overall observed reaction is the net addition to the double bond.
H H
O + Nu + !
O Nu O
R1 R2 R1 R2 R1 R2
!
Nu H
H
Nu O Nu O
R1 CH R2
R1 R2
H 115
• We know that nucleophiles can attack the Lewis acidic carbonyl carbon atom.
• Thus it seems reasonable that the conjugate addition reaction we’ve just
described may compete with nucleophilic attack at the carbonyl carbon.
• How can we tell which reaction will dominate?
Nu H
116
#,'-Unsaturated Carbonyl Compounds
Nu O OH
R1 R2 R1 R2
Nu
+
Nu O When carbonyl additions
Nu H
are reversible, conjugate
slower but R1 R2 addition wins out.
irreversible
R1 R2
Nu O
+ Nu H
slower and
R1 R2
irreversible
119
faster and O
irreversible Nu = OH-
O R1 Nu
R1 OR
Nu O
+ Nu H
slower and
irreversible R1 OR
120
Competition between C=C and C=O Reactions
• Summary:
– Conjugate addition occurs with nucleophiles that are relatively weak bases.
– Irreversible carbonyl reactions (addition or acyl substitution) occur with
stronger bases.
O
+ Nu H
R1 X
R1 R2 R1 Nu R1 R2
Nu
H
acyl substitution carbonyl addition
121
122
Michael Additions
O
O O OR3
O
O !
!
CH CH CH R2
R3 O C OR3 R1 CH R2 CH
H C
R3 O
R1 O
ester #,'-unsaturated
enolate ion carbonyl compound enolate ion 123
Michael Additions
• The enolate ion that is formed from the addition reaction then goes on to
deprotonate another molecule of the original ester.
– This forms the neutral addition product and regenerates an ester enolate anion.
• Thus, this reaction is catalytic in base: only a small amount of base is required
(compare to Claisen condensation, which requires one equivalent of base)
– once the original base forms some ester enolate anion, the reaction proceeds
without further need of the base.
O O
O O
!
R3 O CH OR3 C another ester
R3 O C OR3 enolate anion is
H H
O formed
OR3
! O O
O
CH CH R2 OR3 Michael addition
CH C R3 O HC CH2 R2 product is formed
R3 O CH
R1 O C
R1 O
124
Synthesis With Michael Additions
• Working backwards from the Michael addition product, we can envision two
ways of putting the molecule together. O
O
CH
OR 3 C
Which combination of starting R1 CH3 R2
materials should we choose?
O OR3
O
forms the enolate
OR3
O
enolate ion formed here
CH CH2 R2
CH C
R3 O
R1 O
enolate ion formed here
Choose the enolate ion which is less
O basic (to avoid competition from carbonyl
O O addition)
CH
C R1 CH R2
OR 3 CH2 OR3 Choose the enolate that is less likely to
undergo self-condensation.
forms the enolate choose this
125