Prof. Dr.

Burkhard König, Institut für Organische Chemie, Uni Regensburg 1

Enolate Chemistry
1. Some Basics

In most cases the equilibrium lies almost completely on the side of the ketone.

The ketone tautomer is electrophilic and reacts with nucleophiles:

The enol tautomer is nucleophilic and reacts with electrophiles. There are two possible
products - enols are ambident nucleophiles:

The nucleophilic enol tautomer (and especially the enolate variant) is one of the most
important reactive species for C-C bond formation.

Treat a ketone with an appropriate base and can get deprotonation at the α-position to form an
enolate:

Enolates are synthetically much more useful than enols (although they react analogously).

Imine anions and eneamines are synthetic equivalents of enolate anions.

Li N
N

H H

Imine anion eneamine

By knowing the pKa values of the relevant acidic protons it is possible to predict suitable
bases for forming the corresponding enolates.
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 2

Some Important pKa Values

- -
- O
H2C N +
O
H3C NO2 H2C N +

pKa ~ 10
O O -

Enolates are nucleophiles and ketones are electrophiles - therefore there is always the
potential problem for self condensation.

If this is desirable we need to use a base which does not completely deprotonate the carbonyl
compound i.e. set up an equilibrium. This is best achieved when the pKa of the carbonyl
group and conjugate acid (of the base) are similar:
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 3

pKa (tBuOH) ~ 18. A stronger base. pKa difference of 2. Ratio of ketone to enolate will be of
the order 100:1 i.e. there will be about 1% enolate in solution.

The greater is the difference in pKa's the more heavily shifted is the equilibrium (to
either left or right).

When it is desirable to generate the enolate in small quantities, an alkoxide base is ideal (at
least with standard ketones).

NOTE: All bases are potential nucleophiles. Alkoxide addition to the carbonyl group is
reversible in the case of ketones and is therefore usually not a problem. Ideally we want to use
non-nucleophilic bases to avoid potential chemoselectivity problems. Most non-nucleophilic
bases have the nucleophilic centre surrounded by sterically very demanding substituents.

How can we avoid self-condensation? Use a very strong base to shift the equilibrium
completely over to the right.

Important 'Strong' Bases for Forming Enolates from Ketones:

So for LDA the pKa difference between acetone (20) and diisopropylamine (38) is 18 (very
large). Consequently treatment of a ketone with 1 equivalent of LDA causes essentially
complete deprotonation to form the corresponding lithium enolate.

Butyl Lithium (BuLi) is an excellent base and even stronger than any lithium amide, but is
only very rarely used to form enolates from ketones. BuLi is a strong nucleophile with little
steric hindrance.

2. Regioselective Enolate Formation

Kinetic versus Thermodynamic Control

Consider the following unsymmetrically substituted ketone. There are two sites of proton
abstraction leading to two different product enolates. It is clearly important to be able to
control the site of enolate formation - ideally we should have two sets of reaction conditions
for accessing selectively either enolate.
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 4

Although the pKa difference between the two sites is only 1-2 units, this difference, when
combined with the steric accessibility of the α-protons, is usually enough to be able to
selectively form the kinetic enolate.

NOTE: The more substituted enolate is not always the thermodynamically more stable
enolate; in some cases steric hindrance can destabilise the more substituted enolate; thus in
these cases the kinetic and thermodynamic enolate are the same product.

Enolate formation is essentially just an acid-base reaction. The position of the equilibrium is
controlled by a variety of factors: solvent, base, cation, temperature.

factors favouring the kinetic factors favouring the

enolate thermodynamic enolate
protic solvents e.g. ROH which
have slightly more acidic protons
aprotic solvents e.g. THF, Et2O
than the enolate and favour
(no acidic proton to encourage
formation of the enol and
the reverse reaction)
tautomerisation to the ketone
(i.e. the reverse reaction)
strong bases e.g. LDA (which
generate a weak conjugate acid
weaker bases which provide a
(e.g. iPr2NH) specifically one
relatively strong conjugate acid.
which is less acidic than the
enolate product).

oxophilic cations e.g. Li+

low temperature (e.g. < -78 C) higher temperature

short reaction times long reaction times

All these conditions suppress

All these conditions encourage
equilibration and ensure the
the reverse reaction
reaction is irreversible.
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 5

Formation of the Kinetic Enolate

Formation of the Thermodynamic Enolate

Other Methods of Regioselective Enolate Formation

It is not always necessary to rely on kinetic or thermodynamic control for forming enolates. In
many cases chemical modification of pre-existing functionality (especially α,β-unsaturated
ketones) can be used to regioselectively introduce the enolate:

Example 1. Enone reduction

Example 2. From α-bromo ketones

Example 3. Conjugate addition of soft nucleophiles such as cuprates to enones.

Example 4. Hydrosilylation of enones.

 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 6

Example 5. Direct deprotonation of enones.

3. Stereoselective Enolate Formation - Control of E / Z Enolate

Geometry
We will see that the geometry of a substituted enolate (E or Z) can be very important in
determining the stereochemical outcome of aldol reactions. In many cases the aldol reaction is
stereospecific; thus if we can access either enolate geometry at will it should be possible to
control the stereochemistry in the aldol products. This is crucial for stereoselective synthesis.

Reminder: You must know how to assign stereochemical descriptors (E/Z) to enolates.

Consider the formation of lithium enolates using a variety of bases (kinetic control).

General observations:
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 7

1. LHMDS generally provides the (Z)-enolate as the major product

2. LTMP (very bulky) affords the (E)-enolate as the major product
3. LDA gives intermediate results.
4. Use of HMPA as a strongly Lewis basic donor-co-solvent can reverse selectivity.

Ireland has provided a rationale (there is NO physical evidence to show that the model is an
accurate representation of the deprotonation reaction) using chair-like transition states:

Two interactions are deemed important for determining the stereochemical outcome of the
reaction.

1. when R1 is NOT sterically demanding or when H <-> R2 << Me <-> R2 then the (E)-
stereoisomer is favoured.
2. when R1 is large (tBu is especially good) then Me <-> R1 >> H <-> R1 and this
overrides the Me <-> R2 interaction and favours the formation of the (Z)-stereoisomer.

The use of strongly coordinating solvents such as HMPA disrupts the transition state and the
system is more complicated.

Cautionary note: the T.S. described invokes a monomeric organolithium species. In reality
organolithium molecules exist as oligomers (tetramers, hexamers etc). The Ireland model
while fairly useful, is a oversimplification of the real situation.

Esters and amides also form enolates on treatment with a strong base (α-proton is less acidic
in both cases than in a ketone).

In the case of esters, the (E)-enolate is favoured with LDA in THF. Addition of HMPA leads
to a preferential formation of the (Z)-enolate, which is explained by the strong solvation of the
lithum ion by the HMPA leading to a loose, perhaps acyclic transition state. Tertiary amides
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 8

tend to form (Z)-enolates due to the steric hindrance of nitrogen substituents with the double
bond substituent.

O OLi OLi
LDA, THF
O O O
-78oC

(E) (Z)
95 : 5

O OLi
LDA, HMPA
O O
-78oC

(Z)

OLi
OLi
O
LDA, THF N
N
N -78oC
(E)
(Z)
> 97 : < 3

4. Reactions of Enolates
• Enolates are ambident nucleophiles and can react at either oxygen or carbon terminus.
• SOFT electrophiles (e.g. most carbon electrophiles) tend to react at Carbon (soft
centre).
• HARD electrophiles tend to react at Oxygen (hard centre).

4.1. Silyl Enol Ethers

• Readily formed by trapping a lithium enolate with TMSCl.

• The strong Si-O bond is responsible for O-alkylation being the major product.

• Less nucleophilic than metal enolates (lithium, zinc, boron etc).

• BUT they are easily prepared and readily manipulated.

Alkylation with Alkyl Halides

• Reaction is most efficient in the presence of a Lewis acid which complexes to the
halogen making it a better leaving group.
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 9

• Tertiary alkyl halides, allylic and benzylic systems are the best - all these systems are
capable of stabilising positive charge which implies the reaction is proceeding via an
SN1-type pathway.

Alkylation with Acetals

Reaction with Enones

• Reaction proceeds in a conjugate (Michael or 1,4-) fashion.

Oxidation of Silyl Enol Ethers

1.

2.

Oxidative Cleavage

Rearrangement of Silyl Enol Ethers

 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 10

Claisen Rearrangement (an example of a [3,3]-sigmatropic shift)

This is an important example of STRATEGIC PATTERN RECOGNITION

4.2 The Crossed Aldol Reaction

• One of the most important methods for C-C bond formation.

• Very widely used in organic synthesis.

All the issues previously discussed (1-3) and more (4-6) now become very important:

1. regioselective enolate formation (kinetic and thermodynamic enolates)

2. complete or partial enolisation (self vs. cross condensation)
3. stereochemistry of the enolate (E or Z)
4. simple diastereoselection - (syn and anti aldol products)
5. diastereofacial selectivity (this becomes important when chiral aldehydes react with
achiral enolates and when achiral aldehydes react with chiral enolates)
6. double diastereodifferentiation (reaction of chiral aldehydes with chiral enolates) -
matched and mismatched pairs.

In the crossed aldol reaction, the enolate of one carbonyl group reacts with the carbonyl group
(usually an aldehyde) of another. To avoid self condensation, the enolate component is
formed beforehand.
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 11

We will consider the reaction of three types of enolate:

• lithium enolates (see above)

• boron enolates
• silyl enol ethers

Lithium Enolates in the Aldol Reaction

Simple Diastereoselection

Let us consider the reaction of achiral enolates (derived from ethyl ketones) with achiral
aldehydes. There are two possible products termed syn and anti. Consider the reaction of
various lithium enolates with benzaldehyde PhCHO:

(Z) : (E) ratio of lithium syn : anti ratio of aldol

R(1)
enolate product
Et 30 : 70 64 : 36
iPr 0 : 100 45 : 55
iPr >98 : <2 90 : 10
tBu >98 : <2 >98 : <2
mesityl (2,4,6,-
8 : 92 8 : 92
trimethylphenyl)

Observations:

• The reaction is sometimes highly stereoselective (stereospecific too).

• Stereospecificity is observed when R(1) is large (tBu or mesityl).
• Reaction is not always completely stereospecific in these cases in that the (E / Z)
stereochemistry of the enolate is not transferred directly to a similar ratio of syn:anti
products. This suggests some equilibration or isomerisation processes are also
occurring.
• (Z)-enolates are more stereoselective than (E)-enolates.
• When the reaction is stereospecific, (Z)-enolates give the syn products and (E)-
enolates afford the anti product.
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 12

Reaction through a chair-like Zimmerman-Traxler T.S. can rationalize the stereochemistry.

However the requirement for 1) a bulky group α-to the enolate and 2) a good method for
stereoselective formation of lithium enolates has restricted the synthetic utility of these
species. The search for increased stereocontrol has led to the development of boron enolates.

Boron Enolates in Aldol Reactions

• Usually much more stereoselective than lithium enolates.

• Reaction is highly stereospecific (Z)-boron enolate gives the syn aldol product and
(E)-boron enolate provides the anti aldol product.
• The stereospecificity can be readily rationalised by invoking chair-like Zimmerman-
Traxler T.S.'s (see above).
• The shorter B-O bond - compared with Li-O - leads to a tighter T.S. and accounts for
the improved stereoselectivity.

Preparation of Boron Enolates

Usually formed from a dialkylboron halide or triflate and a sterically hindered tertiary amine
base such as triethylamine or Hünig's base (iPr2NEt).

Example

• Under most conditions, (Z)-boron enolates are formed with high stereoselectivity.
• (E)-boron enolates can be formed under carefully chosen reaction conditions (e.g.
(cyclohexyl)2BCl / Et3N in Et2O):
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 13

Note that water is not sufficient to cleave the O-B bond in the aldol product. Oxidative
cleavage with alkaline peroxide is the standard method of work-up.

Silyl Enol Ethers in Aldol Reactions (Mukaiyama Aldol Reaction)

Preparation of TMS enol ethers

1) basic conditions - trap lithium enolate

2) Lewis acidic conditions - TMSOTf or TMSCl in the presence of a tertiary amine (requires
temperatures >0 C).

Mukaiyama Aldol Reaction

• TMS enol ethers are much less nucleophilic than boron or lithium enolates and do not
react directly with aldehydes.
• Lewis acid complexation increases the electrophilicity of aldehydes and this is
sufficient to allow reaction.
• The reaction mechanism is quite different to that of lithium or boron enolates
described above. Internal coordination and reaction through a 6-membered T.S. is not
possible with silicon since the silicon atom is not Lewis acidic.
• Reaction proceeds through an open T.S.

Stereoselectivity of the reaction is usually low.

 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 14

Examples:

The Lewis acid activation conditions allows the use of acetals as masked aldehydes:

The use of chiral Lewis acids in sub-stoichiometric quantities provides one important method
for controlling the stereoselectivity of this reaction and is rapidly becoming a very useful
method. One example developed by Carreira will serve to illustrate the idea:

S.V.Ley and L. R. Cox, Chemtracts: Org. Chem., 1997, 10, 853-857.

 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 15

Diastereofacial Selectivity

So far we have discussed three types of enolates which sometimes give high levels of simple
diastereoselectivity (syn or anti product). In most cases the relative stereocontrol is
determined by the geometry of the enolate (cyclic T.S. with boron or lithium enolates).

To control the absolute stereochemistry of the reaction requires facial selectivity of the
prochiral carbonyl group. There are three methods to do this:

1. substrate control in which stereochemical information in the substrate(s) directs the

stereochemical outcome of the reaction.
2. auxiliary control involves the use of a temporary directing group usually attached to
the enolate
3. reagent control in which chiral ligands on the metal enolate or a chiral Lewis acid
provides stereocontrol.

Substrate Control

Models for 1,2- induction

1,2-induction in a α-chiral carbonyl compound

Cram-chelate model (L = OR´, NHR´etc)

Cram model
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 16

Felkin-Ahn model

O. Reiser, A. Mengel Chem. Rev. 1999, 99, 1191.

Chiral Aldehyde and Achiral Enolate

• Aldehydes which possess an α-stereogenic centre often react with high levels of
stereocontrol.
• The nature of the groups attached to the stereogenic centre as well as the precise
reaction conditions will determine which type of T.S. is important.

Example1.

Example 2.

Aldol reaction of α-chiral aldehyde and Z-enolate

 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 17

1,3-syn-pentane interaction gauche interaction

Anti-Felkin transition state

Minimizes both unfavorable
interactions

Example 3.

Aldol reaction of α-chiral aldehyde and E-enolate

leads to Felkin product gauche interaction unfavorable

 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 18

The (E)-enolate should provide the anti aldol product (cyclic T.S.) i.e. B and D. The α-
stereogenic centre in the aldehyde favours product B (Felkin-Anh T.S.)

Chiral Enolate and Achiral Aldehyde

The presence of a stereogenic centre α-to the enolate can sometimes provide a good method
for controlling diastereofacial selectivity.

Double Diastereodifferentiation

The problem is complicated when both aldehyde and enolate substrates are chiral and possess
controlling stereogenic centres (usually α).

This is a common problem in complex natural product synthesis.

In this case each substrate has an inherent facial bias. When both substrates have the same
bias, they reinforce the facial selectivity leading to improved stereoselectivity (reinforced
stereoselection). Matched case.

When the inherent facial bias in each substrate opposes one another, stereoselectivity is
reduced. Mismatched case.
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 19

One substrate usually has a stronger facial bias than the other and can completely override the
facial preference of its partner. In this case one substrate controls the stereochemical outcome
entirely.

Auxiliary Control

• Many successful chiral auxiliaries have been developed for controlling the
stereochemical outcome of the aldol reaction.
• Only one example will be discussed - chiral oxazolidinones developed by Evans.

• Lithium, boron and titanium enolates allow stereocontrol of enolate alkylation or aldol
reactions
• Metal cations form chelates
• (Z)-enolates are invariably formed and reaction proceeds through a cyclic T.S. to
provide the syn products (almost exclusively).
• The substituent(s) on the oxazolidinone controls the facial selectivity. The
norephedrine-derived auxiliary provides one product and the phenylalanine- and
valine-derived auxiliaries give the opposite facial selectivity.
• These auxiliaries are so powerful in their facial directing ability that they usually
override the inherent facial bias of chiral aldehydes and even the mismatched pair can
provide high levels of stereoselectivity.
 Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg 20

Reagent Control

• Use of chiral ligands at the metal centre provides an alternative and powerful approach
to controlling the stereochemical outcome of reactions.
• The most widely used system is to prepare the boron enolate from diisopinocamphenyl
boron triflate or chloride. Other systems are derived from menthone.
• This system is usually used to reinforce or overturn the inherent stereochemical bias of
a chiral ketone or aldehyde and is particularly useful at later stages of synthesis.

Example: