Strategy VIII: Introduction to Carbonyl

Condensations

The next 10 chapters are about the synthesis of carbon skeletons with two functional groups.
Compounds such as 1-3 will all be treated as l ,3-difunctionalised compounds since the important
thing is not the type of functional group but the relationship between them. Our logic is that all
FGs can be derived from alcohols, ketones (or aldehydes) or acids by substitution and that those

w
three can be interconverted by oxidation or reduction.

OH

�OH
o o
1 3

Analysis will be by FGI to reveal the oxygen-based functionality at the right oxidation level
and then by C-C disconnection using the relationship between the FGs as our guide. So we shall
be using two-group disconnections throughout. The carbon synthons used will be the same as
those we used for two-group C-X disconnections in chapter 6. Most of the chemistry revolves
around the carbonyl group and we need to think first how that group affects the behaviour of
molecules.
The carbonyl group is the most important functional group in organic synthesis because it can
be naturally electrophilic or nucleophilic at carbon. lt hardly needs saying that carbonyl com­
pounds are naturally electrophilic, 4 or 5, at the carbonyl carbon and so react with nucleophiles
at that atom 6. If there is a leaving group X, the tetrahedral intermediate pushes it out 7 to
regenerate the carbonyl group. The result 8 is acylation of the carbon nucleophile.

º:?
0�11-
R � O

R �X �X --+-�R
4 5 6 7 8

The corresponding disconnection is of the newly formed C-C bond 8a. The synthons are the
acyl cation and a nucleophilic carbon species that rnight be a metal derivative RM (chapter 13)
but will generally be an enolate in the next 10 chapters. And that is how carbonyl compounds
are nucleophilic.
130 18 Strategy VIII: lntroduction to Carbonyl Condensations

o synthons O reagents

)y'R
===> 0
R
===> )lX
R-M
8a 9 4

Carbonyl compounds such as acetone 10 exist predominantly in the keto form 10 but are in
equilibrium with the enol form 11. We shall be more interested in the formation of the enolate
anion 13 with base 12 and its reactions at the <1-carbon with carbon electrophiles.

o OH o
)� A �R

10; ketone 11; enol 12 13; enolate 14

The disconnection is of the newly formed C-C bond 14a and is not the same as Sa. Toe
synthons are represented by the enolate anion and a carbon electrophile. We saw alkyl halides
in this role in chapter 13 but in the next 1 O chapters we shall be mostly interested in combining
enol(ate)s with carbonyl compounds.

synthons reagents
o o 0
o
¾R ===> Áe ===> A
0 R-Hal
R

14a 15 16

Nucleophilic and Electrophilic Synthons

The synthons 9 and 15 have natural polarity and it will be helpful in the next 1 O chapters if
you recognise whether synthons such as these and 17 have natural polarity. We have discussed
9 and 15 above and 17 in chapters 6 and 13 where we used <1,�-unsaturated compounds 18 as
electrophiles. You may find it helpful to use the labels suggested by Seebach.1 The letters a
and d are used for acceptor (electrophilic) and donor (nucleophilic) synthons and a superscript
number shows which atom is meant. The carbonyl group is always atom number 1. So the enolate
becomes a d2 synthon and 9 and 17 are a 1 and a3 synthons. If you don't like these labels, ignore
them, they are entirely optional.

o o o o o o o
�� Áe �0� y� �20 �3
11 .. 0

9 15 17 18 an a 1 synthon a d2 synthon an a3 synthon

So if we wish to make a compound like 19 we can disconnect a C-C bond to reveal two
synthons, 20, a d2 synthon easily recognised as the enolate of ketone 22, and an a1 synthon 21
realised in the aldehyde 23. We have rediscovered the aldol reaction.

synthons reagents
O OH O OH o o
e-e i1 el R2 �
R1�R2 ====> R1 � 0
------,.,
R1
�
H
A
R2
19 20 21 22 23
Two-Group C-C Disconnections 11:
1,3-Difunctionalised Compounds

This chapter deals with target molecules of two main types: hydroxyketones 1 and 1,3-
or �-diketones 4. Both have a 1,3-relationship between the two functionalised carbons. Both can
be disconnected at one of the C-C bonds between the functional groups to reveal the enolate 2
of one carbonyl compound reacting with either an aldehyde 3 or acid derivative 5 such as an
ester.

O OH o o o
1.....- c "'
U b 1, 3 -diO 11 1U c l� 1, 3 -diO
R1 � R2 ====;> R1� R1 R2 ====;>
2 0 2
.,,-"--X
1 2 3 4

We shall need to understand the formation of enol(ate)s from aldehydes, ketones and esters
and it is worthwhile establishing now that these three types of compounds form a graded series
of electrophiles whilst their enolates form a graded series of nucleophiles in the reverse direction.
Any of these enolates can react with any of the carbonyl compounds.

more reactive

most electro- most stable

o o o
philic carbonyl R R�R R carbonyl
compounds JH JOMe compounds
aldehydes ketones esters

most stable most nucleo-

o0 o0 o0
enols or R R�R R� philic enols
enolates �H - OMe or enolates

more reactive

�-Hydroxy Carbonyl Compounds: The Aldol Reaction

With compounds of type 1, only one of the two C-C bonds is worth disconnecting: the one next
to the hydroxyl carbon. A simple example without any selectivity is ketone 6 which disconnects
to the enolate 7 and the ketone 8. It is easy to see that 7 is the enolate of 8 so this is a
Strategy IX: Control in Carbonyl
Condensations

The last chapter introduced sorne good disconnections based on carbonyl compounds as both
nucleophiles and electrophiles but avoided all questions of chemo- or regioselectivity. These
reactions are so important that you need to understand how to control these issues. All the chief
difficulties crop up in the synthesis of the conjugated enone l.

o a,�-unsaturated o o
carbonyl compound
Ph� Ph� + H�
2 3

This all looks very sound and we met examples in the last chapter. We want the ketone 2 to
form an enolate and to combine 4 with the aldehyde 3 to give the anion of an aldol that would
almost certainly dehydrate to the target molecule l.

0
o o o
base �
Ph� Ph ? � Ph� � 1
)
2 4 5

But will any of this happen? We want the ketone 2 to form the enolate, but won't the aldehyde
3 form an enolate more easily? We want the enolate to form on the less substituted side of the
ketone, but won't the conjugated enolate be more stable? We want the enolate to attack the
aldehyde, but might it not ínstead attack another molecule of 2 in a self-condensation? We want
a cross-condensation between two different carbonyl compounds. To be satisfied with our plan
we need answers to these three questions:

The Three Key Questions for Successful Cross-Condensations

1. Which compound will enolise/form an enolate?
2. If it is an unsymmetrical ketone: on which side will it form an enol(ate)?
3. Which compound will act as the electrophile?