BIFUNCTIONAL CHEMISTRY Organic Chemistry, J. Clayden, N. Greeves, S. Warren and P. Wothers, Oxford University Press.

ress. Mainly Chapters 21, 26, 27, 28, 10, 29. Background / revision: Chapters 6, 12, 14 (reactions of aldehydes, ketones and esters lectures from year 1) Similar chapters will be found in all Organic Chemistry texts, e.g. T. Solomons & C. Fryhle, F. Carey etc. Also recommended is Chemisty Of The Carbonyl Group, A Programmed Approach To Organic Reaction Mechanisms, S. Warren (Wiley, 1974) - but only one copy in the library and now out of print! Bifunctional Compounds, RS Ward, OP (Oxford Primer No. 17): useful in parts CONTENTS OVERVIEW Tautomers Reactions of enols: C-Hal and C-N=O bond formation Reactions of enols and enolates with aldehydes and ketones Reactions of enolates with acylating agents Reactions of enolates with alkylating agents Reactions of enamines Conjugate addition reactions 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. Tautomers and evidence for tautomerism Carbonyl group tautomers Factors affecting tautomeric stability Stable enols and other tautomers Reactions implicating tautomers Acid and base catalysis of enolisation Implications of tautomersisation: racemisation and C=C isomerisation Stable enol equivalents Halogenation of enols and enolates Nitrosation of enols Base and acid catalysed aldol reactions Dehydration of -hydroxy carbonyl compounds Crossed condensations: Knoevenagel condensation The Henry (nitroaldol) reaction The Claisen and Dieckmann condensations Decarboxylation reactions Problems with crossed condensations and alkylations Lithium enolates Malonate and -keto esters (1,3-dicarbonyls) Alkylation of nitriles and nitronates Conjugate addition reactions The Michael reaction conjugate addition reactions with enolates Conjugate additions reactions with enamines, nitronates and nitrile anions The Robinson annulation Acylation and alkylation of enamines

How can a "pure" compound be a mixture of two (or more) molecules?

O acetyl acetone (pentan-2,4-dione) H3C C C H2

O C CH3

H-C= acidic OH -CH-

CH3-

O H3C 14.5 H O O CH3 2.24 H3C C C H 5.50 C CH3 2.05 C

O C CH3 H

C H

O H3C 2.24 C C H2 3.60

O C

O H3C C

O C CH3

C H

16% "keto" form

84% "enol" form

These molecules exist in a dynamic equilibrium. Neither can be isolated on its own. These molecules are referred to as tautomers

(NB for the life of me I cannot get this picture to paste in properly. You have the picture in the lecture handouts!)

1H-NMR spectroscopy using D2O as co-solvent

NMR using CDCl3 as solvent 5.5 H O

8.2 OH

3.5

2.2 acidic OH 1.1

2.2 1.0

2.6

D2O

add D2O shake sample tube, wait.... re-reun NMR spectrum O

D OD O

CH2 to two C=O

For the C-H to be acidic enough to be lost easily it must be to ("next door") a carbonyl group. If it is to two different carbonyl groups it will be even more acidic.

Tautomers
Compounds whose structures differ markedly in arrangement of atoms, but which exist in equilibrium are called TAUTOMERS. This is not to be confused with resonance which refers to movement of electrons only. The atoms that 'move' are always protons. A variety of factors will determine the stability of each tautomer and therefore the relative abundance of each. Consideration of acid-base reactions can be useful for simple examples. C H pKa1 Ka1 C H O H Ka2 H O

pKa2

Keto-enol tautomerism O H H C H C CH3 H C H enol form - stronger acid OH C CH3

keto form - weaker acid Unsymmetrical ketones O H3C H C H C CH2 H

OH H3C C H more substituted C=C C CH3

OH

> ~

H3C H

C H

CH2

less substituted C=C

keto form still more stable than both enols Energy (kJ/mol) Ea reflects rate of interconversion between tautomers Ea H keto enol reflects difference in energy between tautomers

the keto tautomer for a simple ketone is ~85 kJmole-1 more stable than its enol (can be thought of as reflecting difference in sum of bond energies).

Evidence for the existence of tautomers

The tautomeric mixture may be affected by solvent. A hydrogen bond can be worth 20-30 kJmol-1 Effect of solvent O H3C C C H2 O C CH3 H3C O C H O C CH3 conjugation H2C H H-bonding

O C

O C CH3

C H

C H2

Solvent
polar protic water acetonitrile polar aprotic (neat liquid)

% Enol
15% 58% 76%

Observations
Multiple H-bonding opportunities between ketone tautomer and solvent

nonpolar

hexane

92%

Solvent forms a non-polar cage around the molecule. Stabilization from intramolecular H-bonding only.

H3C O H3C C H O C CH3 base H3 C O C C H O C CH3 H3C ACAC anion Cu(II)

C O

H C

CH3

C H

O Cu2+ O O C C H C CH3

acidic H easily removed by a weak base

The ACAC anion is a good bidentate ligand for making metal complexes

Carbonyl group tautomers

Carbonyl compound
O H2C H O H2 C H O EtO C CH H O H O H O O OEt H O C OEt

% Enol form

pKa

Tautomer
O H

OEt

~0

23-5
(typical ester)

H2C

OEt H

O CH3

10-6

18-20
(acyclic ketone)

H2C

CH3

10-2

13

EtO

CH

17
H

O CH H

O C OEt

'
H3C

10
OEt

11
H3 C

CH

O H3C

O CH H

'

75
CH3

9
H3C

O C

O C CH3

CH

General trend is the more acidic a molecule is the greater the (total) amount of enol present. The acidic Hs are always next door (-) to at least one C=O group.

Tautomeric Stability
Carbonyl compound
N C C H2 O C OEt HN C C H H

Tautomer
O C OEt

Notes
double bonds brought into conjugation

O H3C IR C C H2

O C OEt H3C

O C

O C H-bonding and conjugation OEt

C H O O

1720cm-1 1740cm-1

unsaturated ester = 1640cm-1

O H3C C

O C CH3

C H

H-bonding and conjugation O H3C C C H2 O C CH3 H3 C O C H O C CH3

C H H

O H3 C C

O C CH2 H-bonding but no conjugation = less stable enol

C H2

Stable enols
Some molecules exist entirely in their enol form. Phenol OH H O Loss of aromatic stabilization in keto form - a big energy penalty. (the keto form is however implied as important intermediates in some reactions - see Yr 3)

Vitamin C (ascorbic acid) - antioxidant protects body from stray reactive oxygen species HO H O H HO OH HO H HO H O N C in vivo O CH3 p-CF3C6H4 H N O N C p-CF3C6H4 H N H O O CH3 hydrogen is - to three C-X multiple bonds - very acidic OH CH3 A77-1726 the active drug species O O OH O OH H OH O HO [oxidation] H O O O O OH O O

HO

keto forms OH

reduced form

oxidised form

A77-1726 - the active metabolite of arthritis drug leflunomide (AravaTM) H N H N p-CF3C6H4 O

Leflunomide (AravaTM)

More Tautomers
plus relative stability for simple examples
Imine-enamine tautomerism N H H C H C R1 H N C R1 very similar to keto-enol tautomerisation R

>
stability

C H

R = H, aldimine R = alkyl, ketimine Nitro-acid tautomerism O H H C H nitro Amide-iminol tautomerism O H H C H C R N H N O

enamine

H in the nitro form the O is resonance delocalized between two oxygens (rather than O and C) so is more stable that the aci tautomer.

>
stability

C H

aci

OH

OH R N

>>

H H

C H

>

C H

R N H

stability amide this is very stable as the nitrogen lone pair is delocalised (resonance) into the carbonyl group (without H moving of course) O H H C H C R N H X Y Z

iminol

enol

The NH is more acidic than the CH as nitrogen is more electronegative than carbon.

GENERAL CASE H X Y X,Y,Z = C, N, O, S, P.....

Z H COMPOUNDS MUST BE IN EQUILIBRIUM TO BE CONSIDERED AS TAUTOMERS

Hydrolysis of nitriles and alkynes

Many reactions involve mechanisms in which a tautomeric conversion is required to explain the final product isolated. Hydration of nitriles can be achieved with aqueous acid H+
n n n

Bu

N H2 O

Bu O

NH

Bu H -H+

C O H

NH

H
n

H C O amide NH2
n

Bu

Bu H

C O

NH iminol

Hydration of alkynes Alkynes are isoelectronic with nitriles, but much less polar, if not apolar (when symmetrical). This reaction needs a mercury catalyst, but Hg+can be treated in this mechanism as if it was just like a proton in the reaction above. cf. bromonium ion 1o carbocation (AcO)Hg Hg(OAc) Hg (OAc) Hg(OAc)2 C C n C C Bu H C C H2 O n Bu H n H Bu
n n

Bu C C

Hg (OAc)

Bu C C

Hg (OAc)

-H

Bu C C

Hg (OAc) 2o carbocation H

O H

H2 O

Bu C O C

Hg (OAc) H H keto

Bu C C

H H enol

Bu C O keto CH3

- Hg(OAc) HO

H+

Chemistry of Enols and Enolates

Energy (kJ/mol)

The rate of interconversion between keto and enol tautomers can be increased by acid or base catalysis (lowers Ea), however the position of the equilibrium does not change. The enol tautomeric form (or more reactive enolate) is often implicated in organic reactions and used extensively in reaction mechanisms. Acid catalysis H O CH3 H H C H C

Ea
keto

enol

O H H C H C

H CH3 H C H

O C

H CH3

Base catalysis O H H HO C H C CH3 H H C O C CH3 H C H O C

OH O H H CH3

CH3

C H

ENOLATE - more reactive than the enol due to its charge. Unsymmetrical ketones O O H3C C C C H H H OH O H3C H C C H CH2 H3C C O C CH2 H3C C O C H H3C H C H C H CH3 H3C C H H CH2 O C H more CH3 substituted

H H

more less substituted

generation of on less substituted carbon preferred as no +I Me group.

H H fastest formed (kinetic) enolate

H H less substituted

Neither enol is formed 100% exclusively under all conditions. It is a question of which is favoured and to what extent.

Implications of enolisation
Racemisation if the -carbon is a sterogenic centre, then enolisation can result in complete racemisation H3C Base catalysed H3C Ph O H OMe CH3 NaOMe Ph O H OMe H3C Ph Acid catalysed AcHN R O H OH H+ source
heating in AcOH

H OMe O + H OMe O

OMe

Ph

NHAc Ph OH OH Ph

NHAc OH O

during recrystallization

Isomerisation of double bonds As well as the normal acid-catalysed migration of double bonds (middle example), isomerisation can be achieved via the enol (acidic conditions) or enolate (basic conditions). OH H H H H O H O H

H OH2 O H H H O H H O H

H O OH H O

H O H H

HO

R2

Enol ethers and Enamines

R1

C R4

R3

X = O, R1 = H, X = NH or NR

Enol ethers and enamines are stable, "protected" forms of aldehydes and ketones. They are reactive towards acid and water, which returns the starting carbonyl compound. Enol ethers - "protection" of aldehydes and ketones O H+ H EtOH H H OEt
remember H+/ROH/RCHO > acetal H+/H2O/RCH(OR)2 > aldehyde

OH EtOH

OH OEt H OEt OEt

+ H+ -H+

OH2 OEt

HOEt OEt

+H

OEt DIETHYL ACETAL

-H+

-EtOH - remove by distillation OEt ENOL ETHER

Enamines -can be made by reaction of aldehydes/ketones with a secondary amine. Enamines are useful compounds for a wide range of transformations. They can be used in place of enols and enolates as will be illusrated later on in the course O HN H+ catalyst OH HN HO HN

N H -H2O
(removed by Dean Stark trap to drive eqbm. to product)

H2O

ENAMINE

IMINIUM ION

Acid-catalysed Halogenation of Enols

Tautomerisation with a Bronsted acid catalysis produces the more substituted enol. Further iodination is hampered by steric hindrance of the corresponding iodo-enol. H O O O I H 2 R C C C C CH3 RCH CH3 RCH2 CH3 AcOH H I I I Halogenation with Lewis acid catalysis. Under these conditions the enol is more reactive than the benzene ring towards electrophilic subsitution. O Ph 0.75 eq. AlCl3 Br2 Ph Br Br O AlCl3 O Ph Br

The Hell-Volhard Zelinsky reaction is a useful way to derivatise carboxylic acids via an enol. made in situ or added Br2, P Br Br Br PBr3 H3PO3 OH Br Br R R R R O Br2, P (cat.) -H3PO3 Br R O Br overall process O R O PBr3 Br R O Br R O H O OH

Br

O OH bromide exchange with unreacted acid

Bromination of silyl enol ethers can be acheived with just bromine Me3SiO Br Br Br Me3SiO Br Me3Si O Br -Me3SiBr O Br

(NB Markovnikov-like: addition to give more stable cation)

Base-catalysed halogenation of Enolates

The base catalysed halogenation of ketones occurs through the more reactive enolate (i.e. not the enol). In unsymmetrical ketones the less hindered, more acidic proton is removed preferentially. O CH3CH2 C CH3 O CH3CH2 enolate more reactive than enol due to charge CH3CH2 C enolate CH3CH2 Br Br reaction also possible with iodine O C = faster Br CH2

OH

CH2

OH C

enol

CH2

The product -bromo ketone possesses an -CH more acidic than in the starting material due to the presence of the electron withdrawing bromine. This means the product is more easily converted to the enolate. Despite steric hindrance, polyhalogenation can occur (it is impossible to isolate the mono bromo product in good yield) and this is the basis for the iodoform test. The Iodoform Reaction (a visual test for methyl ketones) O R C CH3 aq. NaOH excess I2 mech. as above R O C > H H I repeat x 2 R C I HO C I I

O C

-I halogen increases acidity of remaining -Hs

O R C O R

O C OH R

O C OH

CI3

CHI3
soluble carboxylate salt plus preciptate of yellow iodoform

CI3

Nitrosation of enols
Nitroso-oxime tautomerism N H H C H nitroso C O H R OH {c.f. aldimine/ketimine: can have aldoximes (R=H) and ketoximes (R=alkyl/aryl)}

<

H H

H oxime

Nitrosation of enols can be achived using conditions that generate NO (cf diazonium salt formation) O H O O HCl CO2Et C CO2Et C H3C C C CO2Et H3C C H3C C NaNO2 H N H2 H + NO NaNO2, HCl O N H2 O N HO O H+ O -H2O N O O note the extended conjugation H3C C C N O C OH OEt

Synthesis of 1,2-diketones by oxime hydrolysis O HCl NaNO2 O H N O O OH N HCl H2O, heat (oxime hydrolysis gives a ketone) Synthesis of -amino acids by oxime reduction O EtO C C H2 O C HCl OEt NaNO2 EtO O C C N O EtO C CH O C H O C OEt OEt EtO O C C O C OEt O O

N HO Hg-Al -orsodium dithionite (oxime reduction)

NH2

The aldol reaction

The aldol reaction is a base- or acid-catalyzed reaction between two aldehydes or ketones. In simple cases the two reacting partners are the same molecule - i.e. a dimerization. Base-catalyzed aldol reaction: It is important to remember that the aldehyde hydrogen is not acidic! O Et H H H O OH H Et H Et O H Et H O H OH H O H Et Et H O H Et

H HO

hydroxyaldehyde

Another example of the base-catalyzed aldol reaction (tBu- = Me3C-) O

t

O OH CH3 O
t

O CH2
t

O
t

Bu

Bu

Bu H3C
t

Bu H3C HO

H3C H3C C

CH3 no -H here

H3C O

Bu

Bu H OH

Bu

CH3

hydroxyaldehyde

Base-catalyzed aldol reaction: what happens with more than one type of acidic hydrogen? O Me C H2 C OH CH3 Me C H O C minor CH3 + Me C H2 O C major CH2

O O O

OH

OH

The Aldol Reaction: acid catalysis

The acid catalyzed aldol reaction uses the less reactive enol (as opposed to enolate), but the aldehyde group can be "activated" (made more reactive) by protonation. O H3C C CH3 +H H3C protonated ketone more reactive electrophile C OH -H CH3 H3C C OH CH3 less reactive than enolate O H C H H3C C H CH3 H H C OH CH3 O C CH3

Acid-catalyzed reaction with a dialdehyde: an intramolecular reaction results in cyclisation. O OHC-(CH2)4-CHO It does not matter which aldehyde enolises as the molecule is symmetrical O OH H O O OH

An unsymmetrical aldehyde will produce two enols and therefore two possible products.
1

O
2 5

O O H+
2 3 1 4 6 5

OH
7
+

OH O
7 6

R
3 4

R
3 4

7 6

2 5

OH
2 3 1 4 6 5

O
7

H
1

O OH
7 6

R
3 4

2 5

The Aldol Reaction: synthesis of ,unsaturated carbonyl compounds

Dehydration of an aldol product may follow the condensation reaction to produce ,unsaturated carbonyl compounds. This is normally inevitable and rapid with acid catalysis but will depend on the substrate and conditions in base catalysed reactions. Loss of water is (essentially) irreversible. Acid-catalyzed dehydration O H OH OH H O O

O -H2O

OH2

Base-catalysed elimination: This follows the E1cb mechanism as OH is a poor leaving group. "cb" stands for conjugate base and the reaction rate is proportional to [OH]x[ketone]. In some texts this process is incorrectly shown as a concerted process with proton abstraction and hydroxide leaving in a concerted fashion. O O O OH H H CH H 3 CH3 H H CH3 O O H O H -H2O slower CH3 OH H H faster CH3 OH E2 (or E1) elimination not likely with poor leaving group H H OH

O H CH3

OH

The aldol reaction: crossed condensations

Order of Reactivity: due to steric and inductive effects, different carbonyl groups will show differing levels of reactivity towards enolates, i.e. they will have different electrophilicity. O H C + H > R O C + H > R O C + R

increasing steric hindrance at electrophilic carbon decreasing + due to inductive effects of R

For successful crossed condensations only one carbonyl reactant must be "enolizable" and the other reactant must be a more reactive electrophile than the one which enolizes. O C O 2N Ar O HC CH Ar C Ph -H2O E1cb H2C Ar C OH O C H Ph O H + H3C C Ph Ar C O H2 C Ar C O H O C H H OH Ph H2 C O C Ph

Reactions with formaldehyde (methanal) are often tricky as it is so reactive. Double aldol reactions can result. O H HO CH2O K2CO3 O H H O H OH OH HO H H O O H

faster addition than HO elimination

More aldol reactions and crossed condensations

Intramolecular aldol reaction: ring size may control which product forms. Here a five membered ring forms faster than a three membered ring. If the three membered aldol product does form it is unlikely to eliminate to form the strained cyclopropene, but can be converted back to the enolate through a retro aldol reaction. major minor O H aq. KOH O O O H + O
ring strain means retro aldol is more likely than elimination to cyclopropene

O H

-H2O E1cb

O O O

"Double" aldol reactions O aq. KOH 2 mol. eq. PhCHO Ph

(c.f. dibenzylidene acetone experiment in lab) O acidic -H Ph O Ph

no -Hs

The Knoevenagel condensation is a reaction of malonic acid ester with an aldehyde. The Doebner modification uses malonic acid and results in a decarboxylated product (see later and in organic labs). O EtO H H O OEt
N H

O EtO H

O OEt
N

O EtO H H O

O OEt R
N H

R O O EtO R O -H2O OEt E1cb EtO HO R O O OEt

O EtO HO

OEt R

The nitro aldol reaction: The Henry reaction

The nitro tautomer is thermodynamically more stable than the aci form, but the Ea for interconversion is relatively large (compared to keto-enol). The acid isomer thefore takes time to convert back to the equilibrium position (it is "kinetically semi-stable").
Energy (kJ/mol)

Nitro-aci tautomerism The pKa of nitroethane (R = Me) is ~9 O O HO N R C H O

CH2

The hydrogen atoms - to a nitro group are very acidic as C-H groups go, and much more so than simple ketones or aldehydes. Organo nitro compounds can therefore undergo a reaction analogous to the aldol reaction. Also, the nitro group is not electrophilic under these reaction conditions and so no self condensation takes place.

Ea
nitro aci

Generation of a nitronate (cf. enolate) anion O O O H OH

O N O

CH2 O

O H OH

H2C

O N nitroalkene

O -H2O

O N O

OH

CHO H3C

O N O

O NaOH, MeOH N O

nitrostyrene

The Claisen Condensation

The Claisen condensation is similar to the aldol reaction except that it is a reaction between esters and not aldehydes or ketones. The Claisen reaction has can be considered to be the acylation of an enolate General reaction O R H pKa = 25 C H OEt NB O R R C O aq. HCl work up O R R C CH C O OEt C C OEt R R C O C O C H R OEt OEt R O C C C OEt H R C O C OEt
R C

O R C H
OEt

OEt

EtOH

pKa = 16

O C H OEt OEt

+
EtOH

pKa = 11

Due to the acidity of the product a whole molar equivalent of NaOEt is needed. When equilbrium is reached the ethanol is removed by distillation to shift the equilibrium towards the side of the salt, whereupon aqueous acid is added to liberate the product.

Specific example O Ph H EtO O Ph Ph C CH C O aq. HCl OEt work up Ph Ph C O stable enolate C C H C OEt
Ph C

O O Ph C H
OEt

EtO-H OEt Ph

Ph C O

C H OEt

OEt

O C Ph OEt C C O

O C H OEt OEt

Ph

EtOH

The intramolecular Claisen condensation: The Dieckmann cyclisation

The Claisen condensation is between two different molecules of an ester O NaOEt OEt H EtO EtO O OEt O OEt O O EtOH

intramolecular cyclisation of a diester is useful for making 5,6 or 7-membered rings O O MeO OMe H H OMe O 5 MeO
3 2 1 4

O OMe
3 2 1 4 5

O OMe

OMe

O OMe

aq. HCl work up

O OMe O

MeO

O OMe

O O NaOEt OEt no CH O
4 5 6 2 3

OEt

O
1

OEt

OEt O

OEt O aq. HCl work up OEt O H O

OEt O O

Problems with reactions of enolates

Crossed condensations when both reactants have enolizable hydrogens H O O OEt NaOEt OEt OH O O OEt

This reaction will not work as the aldehyde has -Hs more acidic than the ester, and it is also a more reactive electrophile - an aldol will take place. The ester enolate concentration is very low. Reaction of enolates: use of non-carbonyl electrophiles X O X O Br R X R O

X = OEt or alkyl/aryl

This reaction will not work as the ketone / ester electrophiles are more reactive than the alkyl halide. An aldol (or Claisen) reaction will take place in preference to the alkylation. The problems alluded to above are due to the fact that the enolate is being generated in equilibrium with the parent acid (carbonyl compound) using a weak base. If a stronger base is used then complete deprotonation can be effected and the problems of competing reactions is much reduced. Li N Li N Si lithium tetramethylpiperidide (LiTMP) 37 Li N

Si

lithium diisopropylamide (LDA) 36

lithium hexamethyldisilazide (LiHMDS) 30

pKa of amine

pKa of amine

The lithium salts of deprotonated secondary amines make useful non-nucleophilic strong bases. R EtO + O pKa 20 R N + O -78 C
o

R O + EtOH pKa 16 an equilibrium

THF

R + O HN pKa 36 essentially a one way reaction

note use of low T conditions and Li-coordinating solvent tetrahydrofuran (THF)

Lithium enolates
Deprotonation is initited by coordination of the lithium ion to the carbonyl oxygen. Li H unsymmetrical ketone O Me THF -78 oC kinetic enolate OLi Me

N H

Li

O R

THF -78 oC

OLi R

Steric factors mean that unsymmetrical ketones may produce one enolate faster (kinetic enolate) even if it is not the most stable enolate (thermodynamic enolate). However generation of Li enolates from aldehydes suffer from some problems: OLi R N LDA -78 oC R O H LDA -78 oC fast addition product Reaction of Li enolates with aldehydes O LDA -78 oC O O Li O Ph H Li O Et H -78 to 0oC EtCHO Ph O Li O Et PhCHO O R R O Li H+ Ph H+ Ph O Li -78 oC O R H OLi

H fast too! R H

aldol product

OH Ph OH Et

O Ph

Ph two geometric isomers

two diastereoisomers

Reaction of Li enolates with alkyl halides O LDA, THF -78 oC OEt O OtBu LDA, THF -78 oC OLi OtBu OEt n-BuI -78 to 0oC OLi MeI -78 to 0oC O

OEt O OtBu

-Dicarbonyl compounds: properties and decarboxylation

H3C O O OEt MeO O O
O MeO OMe

OMe

Ethyl acetoacetate ethyl 3-oxobutanoate made in the Claisen condensation of ethyl acetate

Dimethyl malonate (diester of malonic acid)

made in the crossed condensation of methyl acetate and dimethyl carbonate

The presence of a -carbonyl group increases the acidity of an hydrogen pKa ~ 20 H H3C O EtO H H3C O EtOH pKa ~ 16 CH2 H3C O O OEt MeO O EtOH pKa ~ 16 CH2 MeO O EtOH O CH2 H3C O O pKa ~ 11 H H OEt pKa ~ 25 H MeO O EtO H OMe CH2 MeO O O pKa ~ 13 H H OMe

EtOH

-Keto acids undergo facile decarboxylation. 1,3-Dicarboxylic acids will also lose CO2 if pushed a bit harder. H R O O H OEt NaOH ester hydrolysis H R O O H O Na H HCl (aq) R O H O H O

T oC T = RT-100 oC for R = alkyl or aryl T = >150 o C for R = OH H R O H H H R H OH enol O C O

In conclusion, the -carboxylic ester: 1) can be used to control and direct deprotonation; 2) can be used to produce an enolate in "quantitative yield" (though not isolated); 3) can be removed by the process of ester hydrolysis followed by decarboxylation.

Alkylation of dimethyl malonate

Malonate derivatives (1,3-diesters in general) can be easily mono-alkylated and dialkylated favourable O MeO O MeO H R1 O OMe O OMe Br R
1

cannot self condense O MeO H O OMe if R1 = R2 use 2 eq. NaOEt and RBr in a one pot reaction O O MeO R1 i) NaOH (aq), ii) HCl(aq) + heating O HO R1 + CO2 R2 OMe

NaOMe

repeat

NaOMe R2CH2Br

i) NaOH (aq), ii) HCl(aq) + heating O + CO2

HO

R2 alkylation of a malonate ester followed by decarboxylation produces the same net result as alkylation of a simple enolate. "Meldrum's acid" is a cyclic malonate ester. Both malonate and Meldrum's acid can also be acylated using acid chlorides or anhydrides. Can be used to make -keto esters. O O O O Cl O OEt R Cl H O O R O H O O O O O O -Cl O R O -CO2 O OH R O O Et R O C O O O Et R O O O H O O Et H transfer
+

O R O

O O O H Et EtOH R

O O O keto

OH

stable enol O

Alkylation of ethyl acetoacetate

-keto esters can be easily alkylated in the same fashion as malonate esters. O H3C H H OEt O H3C CH2R1 H3C OH -CO2 H3C CH2R1 H O R1 O OEt NaOEt H3C R1 O O OEt Br O H O H3C H NaOH (aq) HCl(aq) heating O H3C H O ONa O O OEt R1

R1 not normally isolated

A second alkylation can be achieved regiospecifically between the two C=O groups. R1 and R2 can be added sequentially (R1=R2) or in one go using 2 moles of base and halide (for R1=R2). O H3C H H O OEt R1 Br H3C R2 Br R1 R2 O O OEt i, NaOH (aq) ii, HCl(aq) heating H3C R1 O R2

mechanism via sequential deprotonation/alkylation even if 2 eq. of base / RBr used Dieckmann products (cyclic -keto esters) can be alkylated just as easily. OEt O O i, Dieckmann OEt ii, NaOEt NaOH (aq) O OH -CO2 O H O O HCl(aq) heating O O O O O OEt Br O OEt O

Alkylation of other stablized anions

Organonitriles and organonitro compounds can also easily be alkylated H Ph H C N H Ph C N H Ph C N H Ph C N

OH

Br

The CN bond is less electrophilic than the C=O group so competing aldol-like or Claisen-like reactions are avoided.

Br

C H H

OH heat

Br H

+ Br

good for making 3-7 membered rings; deprotonation of the nitrile is faster than OH SN2 Organonitro compounds are relatively acidic (pKa ~10) so deprotonation can even be acheived with weak bases such as triethylamine or potassium carbonate. Nitronate anions do not condense with themsleves (nitro compounds) so they can effectively alkylated with alkyl halides. NO2 Me C Me H Cl O2 N O Me Bu4NOH H2O-benzene Me NO2 C Me Me Ar N C O Me intramolecular faster than NO2 intermolecular Cl O2N Me NO2

Br H

NO2 H

K2CO3 CO32-

Br

NO2

Cannot use an amine base here, will react with alkyl halide in an SN2 process. Also good for a range of ring sizes (as above)

Conjugate addition reactions

,-Unsaturated carbonyl compounds may react at the carbonyl carbon OR at the -carbon depending on the choice of nucleophile and / or conditions. Me OH 1. MeMgBr 2. H2O O 1. MeMgBr 1% Cu(I)Cl 2. H2O O

Me

NC OH

NaCN HCN 5-10 oC

O +

NaCN HCN 80 oC

O CN 1,4- or 'conjugate' addition product

1,2- or 'direct' addition product

In the case of CN the direct addition product is formed reversibly, so at high temps the more stable 1,4-addition product is formed. Direct addition gives the kinetic product (fastest formed), but conjugate addition gives the thermodynamic product (more stable). Factors favouring direct addition Kinetic control (faster formed product) in reversible reactions, lower T and shorter reaction times More reactive carbonyl compounds (aldehydes, acid chlorides) Substituted -carbon atom (more steric hindrance) Hard nucleophiles which prefer to react with the hard electrophilic C= carbon. HARD NUCLEOPHILES OH, ROH, RMgBr (early row elements) High charge density on nucleophilic atom. Property dominated by electrostatics Factors favouring conjugate addition Thermodynamic control (forming the more stable product) in reversible reactions, higher T and longer reaction times Less reactive or unreactive carbonyl compounds (esters, amides) Unsubstituted -carbon atom (less steric hindrance) Soft nucleophiles which prefer to react with the soft electrophilic -carbon.

SOFT NUCLEOPHILES I, RS, RSH, (later row elements) also stable enolates Polarizable nucleophilic atom. Property dominated by orbital effects

Conjugate addition with enolates: the Michael Reaction

Cl O DECREASING REACTIVITY OF CARBONYL GROUP H R OR O O O NR2 O

INCREASING PREFERENCE FOR CONJUGATE ADDITION R R R O O DECREASING STERIC HINDRANCE AT THE BETA CARBON O RO O R2 O R2 R1 R1 O H O 1,4O R2 R1 1,2O R2 R1 O O

OR

Even though the 1,2 addition is the faster process (kinetic) it is reversible, so ultimately the 1,4addition product forms.

O R2 R1 OH OR

Stable enolates, such as those from malonates and -keto esters, make excellent nucleophiles for conjugate addition reactions. They are soft nucleophiles and their stable enolate favours the retro aldol step in reaction shown above. O MeO MeO O MeONa MeO MeO2C O OMe O MeO2C O MeO2C "H " = MeOH or * O Ph RT O Ph O CH3OC CH3OC Ph "H " Ph CH3OC O CH3OC Ph O Ph "H " OMe MeO2C O OMe

MeOH, MeO2C

*
O H3C H3C O KOH cat. H3C H3C

As the final enolate is more basic than methoxide or hydroxide, this can be used to deprotonate the starting 1,3-dicarbonyl compound* and the reactions can be run with a catalytic amount of added base.

Conjugate addition of enolate-like nucleophiles

Enamines H O N heat OH N H OH OH N O OH

Nitroalkanes are excellent for conjugate addition reactions OEt O N O OH O N O O EtOH, O O O H3C N H O OH CH3 O H3C N C O O O CH3 EtOH,
R=H, CH3

OEt O2N EtO H O O2 N O H OEt O

CH3

CH2

OEt O

NO2

NO2

Organontrile compounds: the nitrile is not as reactive to direct attack in comparison to carbonyl compounds so unsaturated nitriles such as acrylonitrile are amongst the best known Michael acceptors. N O C Ph H OH N O C Ph O C Ph "cyanoethylation" C N CH3 H OH CH3 C N N O C Ph C N CH3

Michael reactions can be followed by cyclization

Michael reactions can produce compounds that are eminently suitable for subsequent aldol or Claisen cyclisation reactions. O Michael then aldol - the "Robinson annulation" O H O CO2Me MeO CO2Me O O H CO2Me OMe

MeO O

O aldol CO2Me O HO E1cb - H2O CO2Me O

O K2CO3 MeOH heat O

CO2Me O

CO2Me

There are three possible enolates of this molecule. Can you work out why the other two do not lead to a product?

CO2Me

Michael then Claisen - synthesis of dimedone O MeO CO2Me MeO MeO O CO2Me O
heat 2h

O MeO CO2Me

OMe

MeO H O

O CO2Me MeO

O CO2Me MeO MeOH MeO

O CO2Me

O O CO2Me H3O+ O

There are three possible enolates of this molecule. Can you work out why the other two do not lead to a product?

H3 O + CO2Me heat -CO2 -MeOH O

dimedone

Reactions of Enamines
Acylation reactions are Claisen-like, as the electrophile (anhydride or acid chloride) is in the same oxidation state as an ester. This reaction in effect enables ketones or aldehydes as nucleophiles (as enamines) to cross react with anhydrides or acid chlorides. C-acylation of enamines is straightforward as N-acylation is reversible.

O Ph O2CCH3

O O O Ph

N O

O O Ph

O Ph H

CH3CO2

Enamines also react at carbon with active alkyl halides (allylic, benzylic, -haloketones) with heating. Less reactive halides on the other hand can also react on nitrogen forming an ammonium salt. This reaction is irreversible and causes problems with by-product formation. Br N N heat MeCN several h. Br N H -H N

The enamine is described as an ambident nucleophile as it can react at either the N or C end. Enamines can be hydrolysed in aqueous acid back to the corresponding carbonyl compound.

N N Ph H H2O O Ph
+

O H+

+ H+ Ph

H+ H2O O O - H2O

H2O

H N - H+ Ph
+

H Ph

N O

+H

OH2

Reactions of Enamines
Alkylation of enamines is particularly useful when applied aldehydes. Remember that enolates of aldehydes, even if generated with LDA, are very sensitive to aldol-like reactions. morpholine O H O NH cat H O N heat MeCN several h. O N H+ O H Br O N H O H

O NH

+ H

H3O heat

H+

transfer

Enamines can also be useful nucleophiles for cyclisation reactions which involve a conjugate addition reaction followed by an aldol-like condensation. 4o centre: cannot form enamine RT, 4 h + O overall 8M HCl O O H NR2 H O NR2 H+ NR2 HO NR2 O NR2

NR2