Download An Overview of Carbonyl Compound Chemistry

An Overview of Carbonyl Compound Chemistry
Dr. Yuming Zhao
Department of Chemistry; email: [email protected]
February 17, 2008
2
Contents
1 Carboxylic Acid Derivatives
5
1.1
Reactions involving carbon nucleophiles and hydride ions . . . . . . . . . . . . . . .
7
1.2
Understanding the roles of acid and base . . . . . . . . . . . . . . . . . . . . . . . . .
9
1.3
A bit more about amides and nitriles . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.4
Resonance effects in esters and amides . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.5
Retrosynthetic strategies for carboxylic acid derivatives . . . . . . . . . . . . . . . . 12
2 Regarding Ketones and Aldehydes
15
2.1
H -Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.2
C -Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.3
O-Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.4
S -Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.5
N -Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.6
Conjugate addition on α, β-unsaturated carbonyl compounds . . . . . . . . . . . . . 22
2.7
Retrosynthetic analyses for ketones and aldehydes . . . . . . . . . . . . . . . . . . . 23
3 Substitutions at the α-Carbons
3.1
25
Synthetic uses of malonic esters and acetoacetic esters . . . . . . . . . . . . . . . . . 27
4 Carbonyl Condensation Reactions
31
4.1
Aldol reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
4.2
Claisen and Dieckmann condensations . . . . . . . . . . . . . . . . . . . . . . . . . . 33
4.3
Robinson annulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3
4
CONTENTS
Chapter 1
Carboxylic Acid Derivatives
Carboxylic acid derivatives (categorized as Carbonyl Compounds I in the textbook) have a common
structural feature, that is a heteroatom (O, N, Cl, or Br) is immediately connected to the carbon
atom of a carbonyl group, except for the structure of nitriles (see below).
O
O
R
R
Cl
O
O
O
R'
O
R
R
acyl halides
Br
O
R
R'
O
OH
acid anhydride
carboxylic acid
carboxylic ester
O
R
R C N
NR'2
nitrile (dehydrated primary amide)
amide
Varieties of carboxylic acid derivatives
The heteroatom substituents in above structures serve as leaving groups (good, moderate or
poor sometimes) in the reactions termed Nucleophilic Acyl Substitution Reactions. The general
mechanism for such reactions is illustrated below. The different natures (i.e. leaving group ability)
of the substituents adjacent to the C=O group play a critical role in the reactivities of various
carboxylic acid derivatives.
O
O
O
+ LG
R
LG
R
LG
Nu
Nu
5
R
Nu
6
CHAPTER 1. CARBOXYLIC ACID DERIVATIVES
Notice that the above mechanism comprises two basic steps: (i) nucleophilic addition, and (ii)α-
elimination. In a general sense, if the nucleophile (Nu− ) is a stronger base than the leaving anion
(LG− ), the reaction can readily occur to afford the substitution product. If the nucleophile is a
weaker base than the leaving anion, then the reaction simply does not occur. However, sometimes
it is difficult to compare the basicities of the nucleophile and the leaving anion. A better way of
making judgement is to evaluate the acidities of their conjugate acids. A weak acid (e.g. MeOH)
should always correspond to a strong conjugate base (e.g. MeO− ), and vice versa.
The general ranking of the reactivities for carboxylic acid derivatives is summarized below, from
which you can easily observe an increasing trend of reactivity with the acidity of the conjugate acid
of the leaving group anion (H-LG).
O
O
most reactive
R
R
Br
O
R
O
O
O
HO
R
R
is a relatively strong acid (pKa ~3-5)
O
O
R
HCl and HBr are strong acids (pKa ~ -6-7)
Cl
OH
R
OR
H2O and HOR are weak acids (pKa ~ 16-18)
O
least reactive
R
HNR2 is an extremely weak acid (pKa ~ 38)
NR2
Ranking of reactivities for class I carbonyl compounds
It is also obvious from the above ranking chart that acyl halides are suitable starting reagents
for synthesizing other less reactive carboxylic acid derivatives such as acid anhydrides, esters, and
amides. However, the high reactivities of acyl halides usually make them very unstable and difficult
to be stored for a long period of time in the laboratory. To avert this practical difficulty, acyl halides
are usually generated fresh from corresponding carboxylic acids in the presence of thinoyl chloride
or PBr3 before use. This step is called ”activation” of carboxylic acid.
O
R
O
R
O
SOCl2
OH
R
O
O
R'COOH
R'
O
R'OH
R'
Cl
O
R
O
R'NH2
R'
R
N
H
1.1. REACTIONS INVOLVING CARBON NUCLEOPHILES AND HYDRIDE IONS
7
Although the general mechanism for reactions involving carboxylic acid derivatives (i.e. nucleophilic acyl substitution) is kind of straightforward, the detailed mechanism for a particular reaction
tends to be slightly different depending on the reagents and conditions being used. For this reason,
you need to be a bit careful and judicious in proposing mechanistic steps and intermediates for a
particular reaction. In the following section, we will examine a few different cases.
1.1
Reactions involving carbon nucleophiles and hydride ions
Carbanions and hydrides are strongly nucleophilic in nature and they are generally “very poor”
leaving groups to be expelled once attached to the carbonyl carbon. Therefore, they can quickly displace the leaving group in a carboxylic acid derivative, resulting in ketone or aldehyde intermediates
at the first stage (see the scheme below).
O
R
O
O
Cl
R
H 3C
H3C MgBr
R
Cl
CH3
H3C MgBr
O
OH
p.t.
R
H3 C
CH3
R
H 3C
CH3
The ketones and aldehydes, once they are formed, are also very reactive toward the carbon nucleophiles; as a result, a second nucleophilic attack can quickly happen, eventually producing alcohols
as the final products. For example, when organometallic compounds, Grignard or organolithium
reagents, are used as the carbanion species, they can react with the ketone or aldehyde intermediates very rapidly to form a second tetrahedral intermediate, in which no good leaving groups
are present. Overall, the reaction cannot stop at the stage of ketones and aldehydes. Rather,
secondary or tertiary alcohols will be yielded as the final products. One thing you should be well
aware is that carboxylic acids are not suitable for reactions with organometallic reagents, because
their acidic protons will induce very fast acid-base reaction instead of nucleophilic addition. As a
result, carboxylate ions will be formed. Notice that a carboxylate ion is not an electrophile any
more; it is a good nucleophile. Therefore, the reaction will simply yield a magnesium carboxylate
salt as shown in the following example.
8
CHAPTER 1. CARBOXYLIC ACID DERIVATIVES
O
R
O
O
H
R
O
+ CH4
MgBr
H3C MgBr
If a strong metal hydride, such as LiAlH4 , is added to a carboxylic acid, acid-base reaction
will take place at first. However, the resulting carboxylate, once associated with Al to form a
Lewis complex, can be reduced readily by hydride anions and eventually lead to the formation of
a primary alcohol.
O
R
H
O
O
H
O
AlH2
- H2
R
AlH2
O
R
O
H
H AlH3 Li
OH
O
LAH
R
R
H
Basically, lithium aluminium hydride (LAH) can reduce most carbonyl compounds into alcohols
or amines (in the case of reduction of amides or nitriles). A weak metal hydride, such as NaBH4 ,
can only be useful for reducing acyl chorides, ketones and aldehydes in alcohol solvents, and it is
quite inert to esters and amides. The reactivity of diisobutyl aluminium hydride (DIBAL) has a
reactivity between LAH and NaBH4 . A prominent usage of DIBAL is to reduce an ester into an
aldehyde at low temperature (-78 ◦ C).
O
R
Cl
R
R
R
O
1) DIBAL, -78 oC
O
OR'
2) H2O, H+, then
warm up
NaBH4
O
OH
NaBH4
R
OR'
O
H
R
X
no rxn
O
R'2CuLi
Cl
R
R'
Another mild reagent worthy of remarking is lithium diorganocuprates (R2 CuLi), i.e. the
Gilmann reagents. As can be seen in the last example of the above scheme, the Gilmann reagent
only leads to the displacement of the halogen group with an alkyl group, but no further addition
can occur on the resulting ketone. Synthetically, this provides a simple way to make ketones from
carboxylic acids.
1.2. UNDERSTANDING THE ROLES OF ACID AND BASE
1.2
9
Understanding the roles of acid and base
Generally speaking, if a regular acid (e.g. HCl, H2 SO4 , or HOAc) or a base (e.g. NaOH, KOH)
is applied to a reaction involving a carboxylic acid derivative, it will be most likely functioning
as a catalyst. In acidic conditions, the C=O group will be protonated at first to make it more
electrophilic, while in basic conditions, deprotonation will occur at first to make a nucleophile more
nucleophilic. For very reactive species, like acyl halides, there is no need to add an acid or a
base as the catalyst. In most cases for esters or derivatives less reactive than esters, for example,
hydrolysis of esters, amides, and nitriles, either acids or bases would be added to accelerate the
rates of reactions. Also be aware that under these conditions proton transfer(s) can easily occur on
the intermediate(s) involved in each mechanistic step. However, you should be very careful with
proposing reactive intermediates under different conditions. For instance, under basic conditions
any cationic intermediates exist in very low concentrations and thus should not be proposed as
key intermediates in relevant mechanistic steps. On the contrary, under acidic conditions, anionic
intermediates would play quite insignificant roles in mechanism and should be generally avoided.
Whatever the structures of reactants are, tetrahedral intermediates should be involved in the mechanisms. There is only one exception that does not involve the tetrahedral intermediate in mechanism
among the reactions we have learned so far — the hydrolysis of t-butly esters. The very stable
tert-butyl carbocation (by hyperconjugative effect) makes an SN 1 pathway much more favorable
than the typical addition-elimination mechanism.
H+
O
R
O
CH3
R
O
O
O
CH3
CH3
R
p.t.
CH3
R
O
H O
O
H
H
H
H
O
O
HO
H
H
H
H
O
R
O
p.t.
OH
R
+ CH3OH
OH
H+
H
O
H
O
H2O
O
+
R
O
R
O
R
HO
O
Mechanisms for acid-catalyzed ester hydrolysis reactions
10
CHAPTER 1. CARBOXYLIC ACID DERIVATIVES
Recall that under acidic conditions, each mechanistic step in the hydrolysis of an ester is re-
versible. Therefore, to achieve high yield, the equilibrium is usually broken by removal of the
byproduct, alcohol, through distillation or by adding a large excess of water. Under basic conditions, however, the hydrolysis (or saponification) turns out to be an irreversible process, because
of the formation of carboxylate ion. Check your textbook to see the detailed explanation. One
thing should be noticed is that when an ester is treated with a base, say NaOH or NaOEt, under
non-aqueous conditions, Claisen condesation rather than hydrolysis will happen (see below). So,
you must carefully read the conditions given in the exam to decide what type of reaction is to take
place.
O
1) NaOH, H2O
OEt
2) H2O, H
+
O
O
OH
vs
O
1) NaOEt
OEt
2) H2O, H
+
O
OEt
To be Claisen or to be hydrolysis, this is a question!
1.3
A bit more about amides and nitriles
Amides and nitriles are located at the bottom of the reactivity ranking chart for carbonyl compounds I. Therefore, to make them react, much harsher conditions need to be enlisted. Generally,
an acid or a base catalyst plus heating can be used to accelerate the hydrolysis of amides or nitriles.
The products are simply carboxylic acids and different types of amines (primary or secondary) depending on the starting materials. Besides hydrolysis, amides and nitriles can also be reduced by
LAH to form amines. This reaction can be useful in the synthesis of amino-containing compounds
using carboxylic acids as starting materials. If a primary amine is desired, you should choose to
reduce a primary amide or a nitrile with LAH. In addition to this reductive amination approach,
another useful method, called Gabriel synthesis, can be employed as well to make various alkylsubstituted primary amine. Again, it is time to check your textbook if you don’t know the Gabriel
synthesis.
1.4. RESONANCE EFFECTS IN ESTERS AND AMIDES
11
H+
OH
H
O
O
N
H
CH3
CH3
N
H
CH3
N
H
O
H
H
O
H
H
p.t.
OH
H
O
O
H
N
OH
OH
CH3
H
HO
+ H2NCH3
O
O
O
N
H
H
CH3
OH
N
H
O
H
CH3
OH
+ H2NCH3
OH-
OH
O
O
OH
quenched with
O
H3O+
1.4
Resonance effects in esters and amides
Both amides and esters show resonance effects at the carbonyl group. However, in an amide the
resonance effect is much stronger than in an ester. So the charge-separated resonance structure
contributes to a significant degree to the properties of an amide. In an ester, however, the resonance
effect is less significant because of the strong electronegativity of oxygen atom. In fact, the oxygen
atom next the carbonyl induces a dominating inductive effect that counteracts the resonance effect.
O
O
O
N
N
significant
O
O
O
insignificant
The interplay between resonance and inductive effects in an amide and an ester leads to different
outcomes. In an amide, the resonance effect wins. As a result, an amide shows a much stronger
diople moment, and the diople-diople interactions account well for the relatively high melting points
for amides. The winning resonance effect also makes the stretch of C=O in an amide shifts to a lower
frequency than a typical ketone C=O. In an ester, the inductive effect is the winner. Therefore, an
ester usually has a fairly low melting point and, in the IR spectrum, its C=O stretching frequency
is much higher than a typical C=O bond as in ketones or aldehydes.
12
CHAPTER 1. CARBOXYLIC ACID DERIVATIVES
1.5
Retrosynthetic strategies for carboxylic acid derivatives
Knowing that carboxylic acid derivatives can occur a common reaction, nucleophilic acyl substitution, you may find that bond disconnection at the carbonyl carbon and heteroatom bond ((O=C)–
X) is indeed a very good starting point for numerous syntheses of carboxylic acid derivatives.
However, this does not mean that you should always perform this operation in the beginning of
retrosynthesis. Other operations such as functional group interconversion (FGI) or functional group
addition (FGA) can also be good choices depending on the exact structures of target compounds.
Let’s take a look at a few examples to better understand this.
The first example is to synthesize an aromatic compound containing both an amide and an
ester groups.
H
N
H3C
O
O
O
target
Retrosynthesis
Route 1
H3C
H
N
O
O
O
NH2
BD
H3C
+
O
Cl
O
O
???
Route 2
H
N
H3C
O
CH3OH +
O
O
O
H3C
Cl
FGI
H
N
H
N
BD
+
O
Cl
O
O
NH2
H3C
H
N
H
N
BD
O
FGI
O
HO
Retro-oxd.
O
O
If you start the retrosynthesis with bond disconnection at the amide group (route 1), you will
get two precursors, a para-substituted aniline and an acyl chloride. It seems plausible by the first
glance. But you can quickly find a problem with one of the synthons–the aniline precursor. Notice
that it has both an amino group as the nucleophile and an ester group as the electrophile within
the same molecule, the molecule can readily follow an intermolecular aminolysis pathway to form
polyamides. So, route 1 reachs a dead end.
1.5. RETROSYNTHETIC STRATEGIES FOR CARBOXYLIC ACID DERIVATIVES
13
However, if a bond disconnection begins at the ester group, no such problems will happen
because the amide group is relatively stable. Following a sequence of FGI and BD, a reasonable
synthetic plan can be easily formulated as suggested by route 2.
Synthesis
O
O
O
KMnO4
Cl
H3 C
H3 C
NH2
NH
HOOC
NH
SOCl2
O
O
O
CH3OH
NH
H3CO
O
NH
Cl
It should also be noted that making an amide from aniline is a very good way to protect the
amino group. Recall that aniline cannot occur Friedel-Crafts reactions directly. Over the past few
years, I have seen such a mistake be made by a lot of students. So you certainly do not want to
repeat this common mistake in your exams. Remember the amino group needs to be protected at
first, and transforming it into an amide is a very good choice.
Now, let’s try another synthesis example.
O
HO
O
O
O
HO
OH
OH
Retrosynthesis
O
HO
O
FGI
OH
N
C
C
O
HO
FGI
N
O
FGI
Br
Br
HO
OH
+ CN-
OH
Just by looking at the starting material and the product, you may be puzzled a bit as to how
to elongate the carbon chain between the two carboxyl groups by two carbon atoms. Obviously
bond disconnection won’t work in the retrosynthesis. However, after performing a number of FGIs,
the clue becomes clearer and clearer. The key step in this retrosynthesis is to take advantage of
nitrile hydrolysis reaction. Recall that a nitrile group can be hydrolyzed into an amide, which can
be further hydrolyzed into a carboxylic acid. Therefore, adding a nitrile group via an SN 2 attack
will not only install a precursor to a carboxyl group, but also increase the number of carbons in the
molecule by one. From the above retrosynthesis, it is very easily to propose a synthesis of glutaric
acid from malonic acid.
14
CHAPTER 1. CARBOXYLIC ACID DERIVATIVES
Synthesis
O
HO
O
LAH
PBr3
HO
OH
NaCN
OH
Br
NC
Br
CN
H3O+
heat
O
O
HO
OH
Exercise. Identify compounds A-M in the following scheme.
Br
H3O+
NaCN
A
(1) (CH3)2CuLi
SOCl2
B
(2) H2O
heat
(1) LAH
(2) H2O
CH3OH, H+
F
C
(1) DIBAL, -78 oC
(2) H2O
(i) CH3Li
H
G
(2) H2O
(1) LAH
(2) H2O
(CH3O)2O
I
E
D
J
PBr3
K
NaCN
L
(1) CH3MgBr
(2) H2O
M
Chapter 2
Regarding Ketones and Aldehydes
If you truly understand the meaning of the resonance structures of a carbonyl group shown below,
you will have no problem with understanding the reactions at the carbonyl group of a ketone or an
aldehyde.
O
O
O
O
O
O
Nu
H
Nu:
B:
The resonance structure on the right hand side tells that the carbonyl carbon possesses partly
carbon cation character. Like a typical carbon cation, two possible reactions can occur around
the carbonyl carbon. The first is simply an addition reaction in which a nucleophile is added to
the carbonyl to form a new covalent bond (termed AdN , addition nucleophilic). The second is
a β-elimination in the presence of a base instead of a nucleophile. This reaction, which kind of
resembles the E1 reaction, leads to the formation of an enolate, and the enolate forms the very
basis for many complex condensation and annulation reactions in Chapter 18 of the textbook.
For direct carbonyl addition reactions, there are two conditions can be used–acidic and basic.
In acidic conditions, the C=O bond becomes more polar after protonation, which in turn makes
the carbonyl carbon more electrophilic. By this means, the incoming nucleophile can be added to
C=O at a much faster rate.
15
16
CHAPTER 2. REGARDING KETONES AND ALDEHYDES
H+
H
H
O
O
O
However, you should be well aware that acidic conditions may not favor the addition reaction
of nucleophilic species that show strong basicity. For instance, the addition of an amine can be
significantly slowed down if strong acidity (pH < 3) is applied. The reason is that the nucleophilicity
of an amine will be considerably reduced after being protonated, even though the C=O group shows
improved electrophilicity under acidic conditions. For this reason, the reaction between a ketone
and an amine occur the fastest at an optimized pH value (ca. 5). A detailed explanation for this
phenomenon is given in the context of Chapter 17 (p. 808).
Notice that, under basic conditions, the electrophilicity of the C=O group is barely changed.
It is virtually the increased nucleophilicity of the nucleophile that speeds up the addition step.
Nucleophiles with acidic protons (e.g. H2 O, ROH) can occur rapid proton transfer under basic
conditions to form corresponding anionic conjugate bases (e.g.
− OH, − OR)
which are far better
nucleophiles than their neutral forms. For example,
Neutral
O
O
very slow
O
R
R OH
Basic
O
fast
H
O
O
R
R O
Basic condition is commonly used in Carbonyl I reactions. However, in AdN reactions of ketones
and aldehydes, it is rarely used. Why? It is because the addition of an oxygen nucleophile is a
reversible process, and the good leaving ability of the nucleophilic group, e.g. OR, makes tetrahedral
product unstable in basic conditions. Therefore, it will reform the more stable ketone quickly. In a
sense, both the forward and reverse reactions are accelerated by a base catalyst, but the equilibrium
favors the left (backward) direction.
What makes base-catalyzed carbonyl addition really meaningful and useful are actually the enolate involved reactions, e.g. aldol reaction, Claisen reaction, Robinson annulation. These reactions
all contain an irreversible step in their mechanisms, so that the reactions can be carried on to the
right (forward) direction. We shall go through them soon in the subsequent sections.
2.1. H-NUCLEOPHILES
17
Moreover, steric factors are also crucial to the reaction rate of carbonyl addition reaction (AdN ).
Basically, aldehydes are more reactive than ketones because there is less steric hinderance at the
carbonyl of an aldehyde. Recall that a nucleophile approaches towards the C=O via the so called
Bürgi-Dunitz trajectory.
Nu
107o
O
π*
For various carbonyl involved AdN reactions, they are better to summarized based on the types
of nucleophiles.
2.1
H -Nucleophiles
Because the carbonyl carbon exhibits partial carbon cation character, it is much susceptible to
nucleophilic attacks by various nucleophiles. Metal hydrides, such as NaBH4 , DIBAL, and LAH,
can easily attack a C=O group to reduce it into an alcohol. Notice that the reduction is irreversible
because the added H is an extremely poor leaving group. If an aldehydes is to be reduced, the
product will be a primary alcohol. Ketones will only lead to secondary alcohols through metal
hydride reduction, and there is no way to produce a tertiary alcohol by directly reduction on a
carbonyl compound.
O
O
H
H+
OH
H
H
H
H
H
H B H
H
O
O
H
H
H Al H
H
H+
OH
H
18
CHAPTER 2. REGARDING KETONES AND ALDEHYDES
2.2
C -Nucleophiles
A tertiary alcohol however can be easily produced by adding a carbanion into a ketone. Organometallic compounds such as Grignard reagents and alkyllithium compounds can be regarded as equivalents to carbanions, with the reaction mechanism similar to hydride reduction.
O
O
H
OH
H+
H
CH3
H3C MgBr
O
O
H3 C
OH
H+
Li
Notice that the addition of organometallics to C=O is also irreversible, and normally a quenching
step is required by the end of the reaction to dissociate the complexation between the alkoxide and
the metal ion to release a neutral alcohol product.
In addition to organometallics, enolates, Wittig reagents, and cyanides are also very good C nucleophiles for C=O addition. The enolate reactions will be elaborated shortly, while at this
moment let’s focus on the cyanide addition. Recall that an cyanide ion can be reversibly added
into C=O to form cyanohydrins. Because of the reversibility of the reaction, careful control over the
pH value is critical. In general, acidic condition is required to ensure the formation of cyanohydrin
(see the discussion on p. 805 in the textbook). In basic conditions, however, a cyanohydrin will be
immediately reverted a ketone and a cyanide ion.
H
O
CN
OH
O
NC
NC
CN
cyanohydrin
OHO
H
O
O
+ CN-
NC
NC
A good LG in
basic conditions
2.3. O-NUCLEOPHILES
2.3
19
O-Nucleophiles
Oxygen-Nucleophiles (usually H2 O and alcohols) prefer to attack the C=O group in aldehydes
or ketones under acidic conditions, because of the reasons mentioned previously. Water reacts
with aldehydes or ketones to form hydrates, the stability of which are dependent on steric effects.
Alcohols react with adehydes or ketones to form hemiacetals and acetals. Synthetically, this kind
of addition reactions provide a very useful strategy for protecting the C=O group, as acetals can
be readily reverted back to ketones or aldehydes under suitable conditions.
H+, 2 equiv ROH
Dean-Stark
O
RO OR
H+, H2O
Protection and deprotection of a C=O group
Notice that the reaction between an O-nucleophile and C=O is normally reversible. In order
to obtain the desired product, different conditions should be used accordingly. To get acetal, the
reaction needs to be performed in acidic, non-aqueous solution and a Dean-Stark trap is commonly
used to remove the byproduct–water–from the system. In hydrolysis of acetals, however, excess
water should be added so that to shift the equilibrium of the reaction in favor of the formation of
carbonyl products. The mechanisms of the formation or removal of acetals are rather lengthy and
complex. However, you should be well aware of one key step as shown below. Never try a direct
SN 2 mechanism, albeit it looks simple and tempting.
H
O
H+
O
OH
CH3OH
O CH3
p.t.
OH2
O
CH3
OCH3
O CH3
H
O CH3
H
CH3OH
p.t.
OH2
OCH3
O CH3
OCH3
CH3OH
NEVER propose this SN2 mechanism
An example demonstrating the synthetic use of such protection/deprotection strategy is given
below.
20
CHAPTER 2. REGARDING KETONES AND ALDEHYDES
O
O
O
OH
O
Synthesis
OH
O
O
, H+
O
O
O
O
O
O
OH
O
H+, H2O
O
LAH
OH
OH
Dean-Stark
2.4
S -Nucleophiles
S -Nucleophiles behave in a similar manner to O-nucleophiles in reactions with carbonyl groups. A
thioacetal is formed when two thiol molecules react with one molecule of ketone or aldehyde in the
presence of a Lewis acid catalyst, e.g. BF3 , under non-aqueous conditions. In general a dithiol is
used as a common protecting reagent for C=O. Again, the Dean-Stark trap is preferred to be used
in the synthesis in order to remove the byproduct, H2 O.
SH
O
O
O
SH
, BF3
S
S
O
O
LAH
O
S
S
H+, H2O
OH
OH
HgCl2
Dean-Stark
Raney Ni
OH
The resulting thioacetal is capable of protecting a C=O group as is an acetal. However, sometimes thioacetals can find other synthetic usages instead of merely C=O protection. A notable
transformation is the desulfurization reaction shown above. This reaction provides an alternative
means to remove C=O group in addition to the well known Clemensen and Wolff-Kishner reactions.
2.5
N -Nucleophiles
Ketone and aldehydes can react smoothly with primary or secondary amines under moderately
acidic conditions. The mechanism involves two essential steps, addition and elimination.
For primary amines, the elimination step yields imines as the products, whereas for secondary
amines iminium ions are formed.
2.5. N-NUCLEOPHILES
21
H+
H
OH
O
O
OH2
p.t.
p.t.
N
N
NH2
R
NH
R
H
R
R
R NH2
H
H+
H
OH
O
O
OH2
p.t.
N
N
HN
R
R
R
N
R
R NH
R
R
R
R
R
Reactions between amines and ketones or aldehydes are called condensation reactions; that
is, one molecule of water is lost during the reaction. For condensation reactions involving primary
amines and carbonyl compounds, the two hydrogens on the amino group (NH2 ) are both eliminated
during dehydration to yield an imine (C=N) product and H2 O. As for secondary amines, the
dehydration reaction removes one hydrogen from the amino group and another hydrogen from the
nearby α-hydrogen(s), forming an enamine (C=C-NR) rather than an imine after dehydration.
Both imines and enamines can be hydrolyzed into ketones or aldehydes in the presence of excess
water and acid.
Enamines are analogous carbon nucleophiles to enols or enlates. Synthetically, they show several advantages over enolates. The major synthetic uses of an enamine include direct alkylation
and acylation of the α-carbon of a ketone. Notice that the enamine reactions show much better
regioselectivity than the enolate reactions in general; the less substituted α-carbon is preferred to
be alkylated or acylated due to steric argument.
O
N
H
O
N
N
H3O+
CH3CH2Br
heat
H+
O
Cl
N
O
O
H3 O +
heat
O
22
CHAPTER 2. REGARDING KETONES AND ALDEHYDES
2.6
Conjugate addition on α, β-unsaturated carbonyl compounds
α, β-Unsaturated carbonyl compounds can occur both direct addition at C=O and 1,4-addition
(also called conjugate addition), in which a nucleophilic group is added to the β-carbon of C=O.
Commonly used substrates for 1,4-addition are:
O
O
H(R)
O
OR
CN
NR2
The mechanism for 1,4-addition is shown in the following scheme. Practically, 1,4-addition
offers a direct route to functionalize the β-carbon of a carbonyl compound.
O
O
O
A
R
H
R
R
Nu
Nu
Nu:
In synthesis if a target compound requires functionalization at the β-carbon, 1,4-addition could
be a very good choice. An example is shown below.
O
O
COOH
Retrosynthesis
O
α
COOH
β
FGR
FGA
retro-conjugate
CN addition
[+ HBr]
H
O
O
O
O
FGI
Br BD
Synthesis
O
Br2, H
Br
t-BuOK
O
O
O
O
+
H+, H2O
NaCN
heat
CN
COOH
Moreover, α, β-unsaturated ketones or aldehydes can be readily converted into diverse products
such as ketones or alcohols through different reduction approaches. Pay particular attention to the
following examples.
2.7. RETROSYNTHETIC ANALYSES FOR KETONES AND ALDEHYDES
O
OH
23
O
H2 (xs)
H2 (1 equv)
Pd/C, heat
Pd/C
NaBH4
CeCl3
OH
2.7
Retrosynthetic analyses for ketones and aldehydes
If the target compound or intermediate(s) in a synthesis is a ketone or aldehyde, you should consider
using the reactions we have just gone through in the previous sections. The following lists some
examples of how to perform reasonable retrosynthetic analysis for ketones and aldehydes.
Example 1. Synthesis of a ketone from an aldehyde.
O
O
H
Retrosynthesis
O
OH
O
BD
FGI
+ BrMg
H
Synthesis
O
O
OH
(1) BrMg
PCC
H
(2) H2O
Example 2. Synthesis of an alkene from a ketone.
O
Retrosynthesis
O
HO
BD
FGA
+ CH3Li
[+ H2O]
Synthesis
O
(1) CH3Li
(2) H2O
HO
H2SO4
heat
24
CHAPTER 2. REGARDING KETONES AND ALDEHYDES
Example 3. Two approaches to make C=C bonds from ketones.
O
Retrosynthesis 1
FGA
OH
BD
O + BrMg
[+ H2O]
H
Synthesis 1
O
(1)
BrMg
H2SO4
OH
heat
(2) H2O
Retrosynthesis 2
O
PPh3
+
Wittig reagent
Synthesis 2
PPh3
NaH
PPh3
PPh3 Br
Br
O
In making a C=C bond
from a ketone or an
aldehyde, you can also
use the Wittig reaction.
Exercise. Propose reasonable routes for the following transformations starting from cyclohexanol.
OH
Br
O
OH
OH
Chapter 3
Substitutions at the α-Carbons
Reactions of carbonyl compounds (ketones, aldehydes, esters and alike) at their α-carbons always
involve the formation of enols or enolates in the initial step(s). To reasonably propose their mechanisms, you should keep the pKa values for a number of compounds in mind.
R
H
H
R
R'
O
R'
R
H
H
H
pKa ~ 17-18
O
O
O
O
R
pKa ~ 20
pKa ~ 25
O
O
N
H
R'
pKa ~ 30
R'
R
H
pKa ~ 10-11
Enols are normally generated in equilibrium with aldehydes or ketones under aqueous acidic
conditions. The mechanism is shown below. In the first step, the C=O group is protonated by an
acid. The protonation makes the α-hydrogen far more acidic than its neutral form. As a result of
the increased acidity at the α-hydrogen, a rapid proton transfer step can quickly follow up to form
the enol product. In the second step, the solvent, e.g. H2 O, acts as a weak base to eliminate the
α-hydrogen, and both steps are reversible.
H
H
H+
O
O
R
OH
R
H
R
O
R
H
enol is a good nucleophile
H 2O
Notice that an enol is an electron-rich alkene as suggested by its resonance contributor. The
α-carbon is electron-rich in nature, and it functions as the nucleophile in numerous polar reactions.
One point needs to be clarified at the moment is that enoalization (also called tautomerization) is
quite different in concept from resonance. Recall that resonance structures, no matter more or less,
25
26
CHAPTER 3. SUBSTITUTIONS AT THE α-CARBONS
are different facets or portraits for a single compound. Resonance is not a chemical transformation!
In drawing resonance structures, only the positions of valence electrons and lone pair electrons are
changeable, whereas the positions of all nuclei of the molecule should remain the same. In contrast,
enolization or tautomerization is a unique chemical transformation where only one acidic hydrogen
atom of the molecule changes its position.
H
H
O
H
O
O
O
H
Resonance
Enolization or tautomerization
Unlike enols, enolates are produced in basic conditions. Depending on the strength of the base,
the enolate ions formed in a reaction can be either in equilibrium with its carbonyl precursor or
exclusively produced. Generally speaking, − OH or − OR ions can only partially deprotonate typical
carbonyl compounds, such as aldehydes, ketones, and esters, to form enolates in equilibration.
Much stronger bases, e.g. LDA, NaH, and BuLi, however, can completely transform these carbonyl
compounds into their enolate forms. The two different outcomes of enolate formation should be
carefully considered and evaluated in various enolate involved reactions.
Enolates are more electron-rich than enols because of their negatively charged characteristics.
Hence, they tend to be more reactive towards electropohiles. One significant example is the haloform
reaction. In basic conditions, excess iodine can completely replace the α-hydrogens of a methyl
ketone. The resulting -CI3 serves a good leaving group in a subsequent nucleophilic acyl substitution
reaction. Distinctive observation of iodoform (CHI3 )–a yellow precipitate–makes this reaction useful
in identification of various methyl ketones.
O
I2
R
CH3
O
O
O
R
R
CI3
OH-
R
O
CI3
H
:CI3
HO
HO:
O
R
O
+ CHI3
yellow precipitate
Besides halogenation reactions, enolates can also occur alkylations with a variety of alkyl halides.
For unsymmetric ketones, regioselectivity needs to be considered. If a strong base LDA and low
temperatures are applied, deprotonation usually favors the less substituted (i.e. less hindered) αcarbons. The resulting enolates are called kinetic enolates, because they are formed at much faster
3.1. SYNTHETIC USES OF MALONIC ESTERS AND ACETOACETIC ESTERS
27
reaction rates. If the reaction is carried out at room temperature in the presence of a relatively weak
base, e.g. alkoxide ions, deprotonation occurs preferentially at the more substituted α-carbons. The
enolates formed under these conditions are called thermodynamic enolates.
O
O
Li
O
CH3CH2Br
LDA
-78 oC
kinetic enolate
O
O
Na
NaOEt
O
CH3CH2Br
EtOH
25 oC
thermodynamic
enolate
To achieve better regioselectivity at the less substituted α-carbons, a method of using N,N dimethylhydrozone derivatives has been devised. The reason for the high selectivity rests on the
steric effects illustrated below. Read the detailed explanations in the textbook.
CH3
O
H 2N N
CH3
N
CH3
CH3
N
N CH3
CH3
N
CH3
N CH3
N
Li
Li
LDA
CH3
favored
disfavored
You may recall that enamine reactions also serve a good approach to selectively functionalize
substituted α-carbons of ketones (see previous section). The rationalization is based on sterics as
well.
3.1
Synthetic uses of malonic esters and acetoacetic esters
As mentioned in the beginning of this section, 1,3-dicarbonyl compounds have unusually acidic
α-hydrogens (pKa = 10–11). The reason for this is because their enolates are highly delocalized
(in resonance with two carbonyl groups). The relatively high acidity of 1,3-dicarbonyl compounds
makes them very useful in synthesis.
Malonic esters are handy precursors to various α-substituted carboxylic acids. For instance, a
decarboxylation reaction occurs in the following synthesis, which produces a mono-carboxylic acid
as the final product.
28
CHAPTER 3. SUBSTITUTIONS AT THE α-CARBONS
O
O
O
R
EtO
OH
OEt
R'
Example
O
O
O
NaOH (1 equiv)
(1) NaOH (1 equiv)
EtO
EtO
O
O
OEt
(2) Br
(1 equiv)
OEt
EtO
OEt
Br
Br
Br
O
O
OH
O
decarboxylation
O
HO
O
OH
- CO2
O
H+, H2O
heat
EtO
OEt
H
O
O
O
HO
OH
+ CO2
O
Mechanism of decarboxylation
Acetoacetic esters are suitable precursors to methyl ketones. A synthetic example is given
below.
O
O
O
R
CH3
OEt
R'
Example
O
O
O
O
O
O
NaOH (1 equiv)
(1) NaOH (1 equiv)
OEt
OEt
OEt
(2) Br
(1 equiv)
Br
Br
Br
O
O
O
H+, H2O
decarboxylation
OH
- CO2
heat
O
O
OEt
H
O
O
O
O
+ CO2
Mechanism of decarboxylation
It is rather straightforward to comprehend the steps in a synthesis using malonic esters and
acetoacetic acids as starting materials. However, in retrosynthesis the clues can be sometimes
3.1. SYNTHETIC USES OF MALONIC ESTERS AND ACETOACETIC ESTERS
29
obscure, particularly when the molecular structure becomes complex. A useful trick is to locate
the α-carbon in a carboxylic acid or a methyl ketone at first, and then add a carboxyl group on it.
The following two examples show how to perform reasonable retrosynthetic analysis for the cases
where malonic esters or acetoacetic esters are to be used.
O
O
COOH
EtO
OEt
Step 2: Add a carboxyl group on this α-carbon
Step 1: Find the α-carbon
O
O
OH
OH
α
OH
O
Step 3: Perform retrosynthesis
O
O
OH
O
O
HO
OH
FGA
O
EtO
O
OEt
BD
FGI
O
EtO
OEt
Br
+
Br
[+ CO2]
O
O
O
CH3
OEt
Step 2: Add a carboxyl group on this α-carbon
Step 1: Find the α-carbon
O
O
CH3
CH3
α
OH
O
Step 3: Perform retrosynthesis
O
O
CH3
HO
FGA
O
O
CH3
EtO
FGI
O
O
CH3
BD
EtO
Br
[+ CO2]
O
CH3
+
Br
30
CHAPTER 3. SUBSTITUTIONS AT THE α-CARBONS
Exercise. Propose reasonable syntheses for the following compounds using diethyl malonate or
acetoacetate as the starting material.
OH
COOH
COOH
O
O
OH
Chapter 4
Carbonyl Condensation Reactions
Three important carbonyl condensation reactions–aldol condensation, Claisen (Dieckmann) condensation, and Robinson annulation (Michael addition plus aldol condensation)–have been discussed
in the lectures, which are very useful in making a variety of organic compounds.
4.1
Aldol reactions
Aldol reactions include aldol addition and aldol condensation. Their mechanisms are straightforward. As illustrated in the following example, the first step is an aldol addition, where an enolate is
added to an aldehyde. The common bases used for aldol addition are NaOH, NaOMe, and NaOEt.
The aldol adduct is a β-hydroxyl aldehyde, which is usually unstable. Upon further treatment
with concentrated base or acid together with heat, dehydration will occur immediately to yield
a stable product, α, β-unsaturated aldehyde. In basic conditions, the elimination of water takes
place through a conjugate base elimination mechanism, termed E1cb, while in acidic conditions the
simple E2 mechanism is operating.
O
O
O
O
NaOH
E1cb
NaOH
H
H
H
heat
OH
OH
β-hydroxy aldehyde
H+, heat
H
E2
O
H
OH2
31
H
32
CHAPTER 4. CARBONYL CONDENSATION REACTIONS
Synthetically, aldol condensation provides an effective way of direct C-C bond formation. The
following is an example demonstrating the power of the aldol reactions.
O
Retrosynthetic analysis
O
O
BD
FGA
The synthesis
seems requires
the formation of
this C-C bond
An α,β-unsaturated
ketone is a product
of aldol condensation
So, let's add two
functional groups
Synthesis
O
O
O
-
H2, Pd/C
NaOH
H2NNH2, OH
Wolff-Kishner
heat
Exercise. Propose synthesis using aldol reactions.
OH
H
OH O
O
Ph
Ph
O
H
Cross-aldol reactions normally produce more than one products. Therefore, they are not very
useful in synthesis. However, when a highly enolizable carbonyl compound and a carbonyl compound without α-hydrogens are mixed together in the presence of a base, only one major aldol
product can be formed. An example of cross-aldol synthesis is given below.
O
O
O
O
O
H
NaOEt
EtO
OEt
EtOH
EtO
O
EtO
OEt
O
OEt
OH
NaOEt
O
O
EtO
E1cb
OEt
Also notice that intramolecular aldol condensation be used to make five- or six-membered cyclic
ketones effectively.
O
O
O
HO
NaOEt
E1cb
NaOEt
EtOH
O
O
O
O
O
4.2. CLAISEN AND DIECKMANN CONDENSATIONS
4.2
33
Claisen and Dieckmann condensations
When an ester with α-hydrogens is added into a non-aqueous basic solution, condensation instead
of base-catalyzed hydrolysis will happen. These reactions are called Claisen condensations, if the
reactions occur intermolecularly. If the reactions are intramolecular, they are then called Dieckmann
condensations. Such condensations are typically performed under the conditions of NaOMe-MeOH
(for methyl esters) or NaOEt-EtOH (for ethyl esters) dependent on the types of esters being used.
Generally, Claisen and Dieckmann reactions are carried out through two steps, (i) base treatment and (ii) acidic quenching.
In basic conditions
O
OEt
H
OEt
OEt
OEt
OEt
OEt
O
O
O
O
H
O
OEt
O
:OEt
O
O
EtO:
It is this irreversible deprotonation step that
drives the reaction to completion.
The first three steps are reversible.
In acidic quenching step
O
O
H + , H 2O
OEt
OEt
O
O
Like the intramolecular aldol condensation, the Dieckmann reaction is also a very useful reaction
to make five- or six-membered cyclic ketones. Forming smaller-sized rings, such as three or fourmembered, are however highly disfavored because of the significant ring strains encountered.
O
O
O
OEt
EtO
(1) NaOEt, EtOH
O
+
(2) H , H2O
O
O
O
O
Small rings cannot be
formed in Diekmann
condensation.
4.3
Robinson annulation
Among all the methods you have learned to make six-membered rings in this course, Robinson
annulation is probably the most versatile and efficient one, since it generates three new covalent
bonds in one reaction. The starting materials for a Robinson annulation include a vinyl ketone
34
CHAPTER 4. CARBONYL CONDENSATION REACTIONS
and a regular ketone with α-hydrogens. The reactions are usually carried out under the catalysis
of bases like NaOH, NaOMe, or NaOEt.
Mechanistically, the Robinson annulation consists of a typical Michael addition and an aldol
condensation. You should know how to draw this mechanism correctly, at least for the sake of final
examination! Review the mechanism very carefully from your lecture notes and textbook.
Robinson annulation
NaOH
+
O
O
O
A six-membered ring bearing a conjugated vinyl ketone moiety can be cut into two pieces in
its retrosynthesis. The trick here is to first locate the α-carbon that is on a C=C bond and the
β-carbon on the other side of the cyclic ketone. Next, perform bond disconnections at the α-double
bond and the β–γ single bond. Finally, make a C=C double bond at α–β position and install a =O
group onto the carbon that previously belongs to the C=C bond as shown in the following scheme.
By following these three steps, one can easily come up with the two starting materials for a desired
Robinson annulation. Examine the following retrosynthetic analysis carefully to make sure truly
understand how to perform synthesis using Robinson annulation reactions.
Make this bicyclic compound through Robinson annulation
Retrosynthesis
β
β
BD
FGA
O
O
α
Add a ketone and a C=C group at
first. Then mark the α- and β-carbons
α
O
Cut the molecule into two pieces at
the marked two joints, and add a
new C=C bond and a new C=O
group at the right places.
Synthesis
O
O
H2
NaOH
+
Pd/C
O
Zn, HCl
Clemensen
O
Exercise. Propose syntheses for the following compounds using Robinson annulation reactions.
O
O
O