Tutorial 7 – Carbonyl Chemistry 2
Suggested Reading:
Lecture Course – Dr Jenkinson – Hilary Term weeks 5-7
Jones; Core Carbonyl Chemistry (OUP primer series)
Warren; Chemistry of the Carbonyl Group
Clayden, Green, Warren and Wothers; Organic Chemistry
Nucleophilic attack at carbonyl compounds was covered in a previous tutorial. This tutorial aims to cover
another major function of carbonyl compounds: enolisation and subsequent reaction as a nucleophile. A
proton α to a carbonyl centre is acidic (we can delocalise the charge on to the electronegative oxygen) and
so this C-H can be deprotonated and then further functionalised by reaction with an electrophile.
N.B. There are a lot of reactions that you need to know in this tutorial most of which involve
enolisation of carbonyl groups, again as for the last tutorial, you should concentrate on
understanding the basic principles of these reactions and how to apply them and use the names
only as a memory aid if that is helpful for you.
Make sure you cover the following topics:
1. Keto - Enol tautomerism: structural effects on enol content. Base and acid catalysis. Factors
contributing to the choice of which bases are used for particular reactions; reactivity of enols and
enolates.
2. Simple reactions involving enols and enolates: Halogenation (base and acid catalysed, the haloform
reaction), deuteration, racemisation; enol ethers (compare with acetals) and enol esters.
3. Alkylation: stabilised and non-stablised enolates; pKa of substrate and choice of base. Simple ketone
enolates. C versus O alkylation. Regioselectivity, formation of specific enolates, intramolecular alkylation
leading to cyclisation.
4. Carbonyl condensations: enolisation followed by attack at C=O; Aldol condensation and its reverse,
α,β-unsaturated carbonyls, ester condensation both acyclic and cyclic (Claisen and Dieckmann). Crossed
condensations, such as Aldol and Claisen type.
5. α,β-Unsaturated carbonyl compounds: Michael-type additions; 1,2 versus 1,4 addition. Hard versus.
soft arguments. Use of lithium/magnesium/copper reagents for 1,2 or 1,4 addition, etc.
6. Reactions of compounds without α-protons: Benzoin condensation, other reactions of carbonyl
compounds with bases: Benzilic acid rearrangement.
The Claisen Condensation
The Claisen condensation is reversible and depends on the deprotonation of the product to drive the
reaction. The uses of the β-ketoesters formed in the Claisen reaction are summarised in the diagram
below. The acidity of the proton between the two carbonyl groups is the key to the utility of these
reagents in synthesis.
O
O
R
R
H3O+
R
O
i) base
ii) 1/2 eq
I(CH2)nI
iii) H3O+
O
OEt
R R
(CH2)n
R
O
base;
then RI
COMe
O
O
H3O+
OEt
n-1
H3O+
R
MeOC
CO2Et
n-1
R
O
RI
O
1/2 eq
I(CH2)nI
O
OEt
(CH2)n
MeCOCl
H3O+
I2
O
O
O
COMe
OEt
OEt
OEt
H3O+ O
O
OEt
COMe
I(CH2)nI
MeCOCHCO2Et
O
O
O
O
O
H3O+
(CH2)n
KOH
EtOH
O
OH
OH
O
O
O
O
The preparation of ketones relies on the hydrolysis of an ester followed by easy decarboxylation (loss of
CO2) of the β-ketoacids, R.CO.CH2.CO2H. Decarboxylation, RCOOH → RH, involves the substitution of
CO2H by H. This is clearly easiest when the anion left behind (RCOO- → R-) is stabilised in some way
and can occur under acidic, basic or neutral conditions; make sure you can draw mechanisms for each of
these reactions. The preparation of carboxylic acids relies on the reversibility of the Claisen condensation.
Questions:
1. a) Draw the mechanism for the synthesis of ethyl acetoacetate (EAA) from ethyl acetate
O
O
NaOEt
O
OEt
OEt
Ethyl acetate
Ethyl acetoacetate
and then comment on the following:
i) Why is sodium ethoxide, not sodium hydroxide, the most suitable base catalyst for this reaction.
ii) The importance of the relative pKa’s of EAA (~9), EtOH (~16) and MeCO2Et (~20).
iii) Why does Me2CHCO2Et not do an analogous reaction unless a very strong base is used.
b) Diethyl adipate, EtO2C(CH2)4CO2Et, does an analogous reaction intramolecularly (the Dieckman
cyclisation); draw the product. What are the two possible products from the cyclisation of
EtO2C(CH2)3CHMeCO2Et? Which would you expect to be formed during the reaction?
c) Draw the mechanisms of decarboxylation from RCOCH2CO2H in i) acidic, ii) basic and iii) neutral
conditions. Give the product(s) of decarboxylation of CCl3CO2Na, ClCH2CO2Na and 1.
1
HO2C
O
d) Draw a mechanism for the formation of EtCH2COOH from the reaction of MeCOCH(Et)COOEt with
NaOH in EtOH.
e) Suggest a mechanism for the following reaction and explain the driving force for the reaction:
O
Me
CO2Et
O
i) NaOEt/EtOH
ii) H+
Me
CO2Et
2. Suggest mechanistic pathways for the following reactions. Explain the difference in orientation of
addition observed.
b)
Ph
OHO
PhCHO + MeCOCH2Me
H+
Ph
O
3. Suggest mechanistic pathways for the following transformations:
OH-/H2O
a)
CH3CHO + excess CH2O
b)
Me2CO + CH2O + Me2NH2Cl-
C(CH2OH)4
MeCOCH2CH2NHMe2
PhSNa
heat
O
c)
PhCH2COCH3
NaNO2, H3O+
Ph
MeCOCH2CH2SPh
O
Me
H3O+
Ph
NOH
Me
O
O
d)
PhCHO + 2 MeCOCH2COOEt
NaHCO3, H2O
EtO2C
O
H+
Ph
Me
CO2Et
Ph
Me
3. Predict what would happen when the following compounds are treated with strong aqueous base,
propose mechanisms for the reactions
a)
PhCOCCl3
c)
MeCOCH2CH2COMe
e)
b)
Me2C(OH)CH2COMe
d)
MeCOCH2COMe
h)
Me3CCHO
O
O
4. Suggest products and mechanisms for the following reactions
O
a)
i)
NH
, H+cat, reflux
?
ii) CH3CH2I, then H3-O+
O
b)
NaOH, Br2
Ph
O
O
Me
c)
CO2Et
O
O
EtO
NaOEt
i) NaOEt, I2 (0.5eq.)
d)
OEt
?
ii) H3O+, heat
?
?