A! Aalto university School of Chemical Technology © Ari Koskinen KE-4.4120 Organic Synthesis 15....

A!Aalto universitySchool of Chemical Technology

KE-4.4120 Organic Synthesis15. Chemistry of the Double Bond:

Reactions at -Center (Enolate Chemistry)

Prof. Ari KoskinenLaboratory of Organic Chemistry

Chemistry of the Double Bond1. Reactions of the Carbonyl Group1.1 At Carbonyl1.1.1 Reduction (hydride

addition)1.1.2 Alkylation1.1.3 Allylation/Propargylation1.2 At -Center (Enolate

Chemistry)1.2.1 Alkylation1.2.2 Aldol Reaction1.3 At -Carbon of Enone1.3.1 Michael (1,4-) Addition2. Reactions of Olefins2.1 Oxidation2.1.1 Epoxidation2.1.2 Dihydroxylation2.1.3 Aminohydroxylation2.2 Reduction

Reactions of the Carbonyl Group

• Protons on the a-carbon are, in principle, acidic, and a non-nucleophilic base can deprotonate the carbon.

• A prerequisite for deprotonation is a correct conformation!

CH3CHO

O-Li+Me

Enolisation

Addition to carbonyl

Acidity of carbonyl compounds

acetaldehydepKa 13.5

acetonepKa 20

ethyl acetatepKa 25

propandialpKa ca. 5

ethyl acetoacetatepKa 10.6

diethyl malonatepKa 12.9

Acidity of keto and enol tautomers

pK = 8.22

enolateenol

pK = 10.94O

(1) + (2) = (3)O

pK = 19.16O

enolate

Compare with the pKa of phenol (9.95)

Simple carbonyls prefer keto form

Bond strengths (kJ/mol)

s bond p bonde Sum

keto form (C-H) 440 (C=O) 720 1160

enol form (O-H) 500 (C=C) 620 1120

The enol form is usually less stable than the keto form. However, even small quantities of the enol form can be important!

keto form enol f orm

enolG°inc r

e as i

Carbonyl enolization in water

Carbonylcompound

Kenol/keto

5x10-6

Carbonylcompound

Kenol/keto

Catalytic enolization in water: base

enolateanion

enol formof aldehyde

loss ofH f rom carbon

protonationon oxygen

Catalytic enolization in water: acid

In both acid- and base-catalyzed enolizations, two things need to happen: 1) loss of proton from carbon and 2) protonation on oxygen.

In the base-catalyzed enolization, these events take place in this order. In the acid-catalyzed enolization, the carbonyl is activated towards enolization by protonation at oxygen. A weak base (e.g. water) is then enough to pull off the proton.

enol formof aldehyde

loss ofH f rom carbon

protonationon oxygen

The enolate anion

The enolate ion is quite nucleophilic and comparable to the allyl anion in its reactivity. The oxygen has more of the overall negative charge, but the carbonhas more of the HOMO.

bonding

nonbonding

antibonding O LUMO

nucleophilic at both ends

Reactivity of the enolate anion

enolate anionreacts through oxygen

SiH3C CH3

O base OSi

CH3CH3

silyl enol ether(or enol silane)

enolate anionreacts through

carbonI

O base

pentan-2-one(alkylated enolate)

Silylation

Alkylation

Reactivity of the enolate ion

In the enolate ion

• the oxygen atom has more of the overall negative charge• the carbon atom has more of the HOMO

• Hard electrophiles (charged, polar electrophiles, RCOCl, R3SiCl, H+) react preferably at the oxygen end

• Soft electrophiles (maximal orbital overlap; R-halides, I2) react preferably at the carbon end

Enolate Chemistry – The Beginning

NaOH, EtOH

Schmidt, J.G. Ber. Dtsch. Chem. Ges. 1880, 13, 2341; 1881, 14, 1459.Claisen, L.; Claparède, A. Ber. Dtsch. Chem. Ges.1881, 14, 349.

Claisen, L. Ber. Dtsch. Chem. Ges. 1887, 20, 655.Claisen, L. Justus Liebigs Ann. Chem. 1899, 306, 322.

CO2Et1. NaH, Et2O

2. H3O+

Geuther, A. Arch. Pharm. (Weinheim) 1863, 106, 97.Claisen, L.; Claparède, A. Ber. Dtsch. Chem. Ges. 1881, 14, 2460.

Claisen, L.; Lowman, O. Ber. Dtsch. Chem. Ges. 1887, 20, 651.

CLAISEN-SCHMIDT CONDENSATION

ACETOACETIC ESTER CONDENSATION

Enolate Chemistry – The Beginning

O Zn, Me2CO

Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210.J. Russ. Phys. Chem. Soc. 1890, 22, 44.

Perkin, W.H. J. Chem. Soc. 1868, 21, 53, 181; 1877, 31, 388.

REFORMATSKY REACTION

PERKIN REACTION

benzeneClOEt

ONa O O

Enolates

• The term enolate first appeared in 1907, when Hans Stobbe discussed the FeCl3 color test for enols in terms of ‘das violette Eisenenolat’. The term was first applied to describe C=C-O- species in 1920, when Scheibler and Vo described the preparation of several ester enolates. The first explicit formulation of a delocalized enolate was by Ingold, Shoppee and Thorpe in 1926, who represented base-catalyzed tautomerisms as shown below. The authors did not, however, use the term ‘enolate’, not even thirty years later!

• The ambident nucleophilic nature of enolates was established by 1937, when Hauser accurately described the base-promoted enolisation in the mechanism of acetoacetic ester condensation.

• In the early days, the enolates were generated in the presence of the electrophile. It was only in the ‘50’s that Hauser first reported the use of a preformed enolate to obtain cross-coupling products of esters and aldehydes.

LiNH2, NH3

H C C O H C C O H C C OHB B

Enolates• The first important base of reduced nucleophilicity was BMDA (bromomagnesium

di-isopropylamide), which was first used by Hauser in 1949 as a catalyst for acetoacetic ester condensation. The first useful, nowadays perhaps the most popular base, was LDA (lithium di-isopropylamide), used originally by Levine for the same purpose in 1950 Hamell, M.; Levine, R. J. Org. Chem. 1950, 15, 162; Levine, R. Chem. Rev. 1954, 54, 467. However, it took another decade until Wittig employed LDA for the deprotonation of aldimines in the ‘Wittig directed aldol condensation’.

Hauser, 1950 47 %

LDA, ether25 ºC, 15 min

N N O NH

PhPh Ph

Wittig, 1963

LDA, THFH3O+

Ph2C=O

Methods for Enolate Generation

Metallo-Enolates and

Enol Derivatives

Acid/BaseChemistry

Reduction of-Halocarbonyls

1,4-Reduction1,4-Addition

A Vast Number ofTransformations

Isomerization ofAllylic Alkoxides

Isomerizationof Epoxides

Addition toKetenes

Catalytic Cycloreductions, Cycloadditions and Cycloisomerizations: Enones as Latent Enolates in Catalysis

Michael J. Krische, Univeristy of Texas at Austin

Deprotonation-Derivatization of Unmodified Carbonyl Compounds

Hauser (1951): First Use of Preformed Enolates (LiNH2/NH3).

Wittig (1963): First Use of LDA for Preformation of Aldimine Anion.

Rathke (1970): First Use of LHMDS for Ester Enolate Preformation.

Posner (1972): First Use of LDA for Ester Enolate Preformation.

Metallo-Enolates and Related Enol Derivatives

Stoichiometric Enolate Preformation

Enolates from Carbonyls

O Lewis Acid(MLn)

Regioselective enolisation of ketones

•Thermodynamic enolates:

• more substituted• more stable• favored by excess ketone, high temperature, long reaction time•less than stoichiometric amount of base•weak, sterically non-hindered base•protic solvents

•Kinetic enolates:

• less substituted• less stable• favored by strong, hindered bases, low temperature, short reaction time•at least stoichiometric amount of base•strong, bulky base•polar aprotic solvents

base baseO

thermodynamicenolate

kineticenolate

House J. Org. Chem. 1971, 36, 2361.Stork J. Org. Chem. 1974, 39, 3459.

Regioselective enolizationO LDA

(Z) + (E)THF, -78 °C

71 : 29

(Z) + (E)THF, -78 °C

14 : 86

THF, -78 °C+

99 : 1

THF, -78 °C+

90 : 10

Kinetic and thermodynamic control

• A tetrasubstituted alkene A is more stable• If A and B can equilibrate, and [A] > [B]

– A is the thermodynamic enolate• If equilibration is not possible (e.g. large, strong

base, which only ‘sees’ the methyl group), a kinetically controlled product mixture is formed;– B is the kinetic enolate

CHH3C Me

3 H 1 H

Kinetic vs. thermodynamic control

Thermodynamically favoredMore stable

Kinetically favoredForms faster

Regioselective Enolate Formation

THERMODYNAMIC ENOLATE FORMATION:• less than stoichiometric amount of base• weak, sterically non-hindered base• protic solvents

KINETIC ENOLATE FORMATION:• at least stoichiometric amount of base• strong, bulky base• polar aprotic solvents

House J. Org. Chem. 1971, 36, 2361.Stork J. Org. Chem. 1974, 39, 3459.

Ph3CLiequil.

equil.

789922

Ph3CLiequil.

Ketone

Enolate

Thermodynamic Kinetic

Enolates• Hydrophobic strong bases (triphenylmethylsodium, -potassium, and -lithium) were

developed in the ‘50’s and ‘60’s as reagents soluble in most common organic solvents and basic enough to deprotonate ketones and esters. Furthermore, they are highly colored, and can thus serve as indicators - this is their principal use nowadays. Early examples of stoichiometric enolisation from normal ketones originated from the laboratories of Herbert O. House.

O OLi OLi

LDA, DME-78 ºC

1 %99 %

LDA, DME-78 ºC

House, H.O.; Sayer, T.S.B.; Yau, C.-C. J. Org. Chem. 1978, 3, 2153.

tBuOKtBuOH,

86-94%

LDA, THF,

hexane, -72oC 65oC

77-84%

House, H. J. Org. Chem. 1979, 44, 2400.

MeI MeO

Ainoa tuote!

Aksiaalinen

Enolates, enol equivalents and metalloenamines

NR1 R2

metal enolatesilyl enol ether(enol equivalent)

enamine(enol equivalent)

metalloenamine(enol equivalent)

reactivity increases predicted by electronegativity:

- enamines more reactive than enols (O vs. N)

- metal enolates more reactive than enols (M vs. C; more e-density to oxygen)

- the same applies to metalloenamines vs. enamines

Reviews: Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66 (reactivity) Arya, P.; Qin.; H. Tetrahedron 2000, 56, 917 (asymmetric synthesis via enolates) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1-200 (boron enolate aldols)

increasing reactivity

Reactivity scale for neutral enol equivalents

OMe3Si

Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66

increasing reactivity

OMe3Si

log k = s(N + E) s = nucleophile-specif ic parameter (typically between 0.7 and 1)N = nucleophilicity parameterE = electrophilicity parameter

Regioselective Enolate Formation1. Use of Activating Groups

Baisted, J. Chem. Soc. 1965, 2340.Johnson, J. Am. Chem. Soc. 1960, 82, 614.

Coates, Tetrahedron Lett. 1974, 1955.

overall

HCO2EtNaOEt

Acid or base

2. Use of Blocking Groups

Woodward J. Chem. Soc. 1957, 1131.

HCO2EtNaOEt

TsS STs

Removal: Ra-Ni

3. Use of Enamines

Augustine Org. Synth Coll Vol V 1973, 869.

Erel = 1.6 kcal/molErel = 0

+ R'2NHH+ cat.

4. Use of Enamines - Robinson type

Augustine Org. Synth Coll Vol V 1973, 869.

- R'2NH

Use of enol equivalents: enamines

The overall process achieves an alkylation of a ketone but strong basesare avoided altogether so there is no danger of uncontrolled addition reactions.

cat. H+

N 1. R—X

2. H2O, H+

enamine

enamineiminiumion

hydrolysis

Alkylation of enamines

Enamines can be used only with the most reactive alkylating agents:• allylic and benzylic halides• a-halo carbonyl compounds• methyl iodide

2. H2O, 82 °C

O R2NH

cat. H+

NR2 BrPh

2. H2O

Alkylation of aldehydes via enamines

cat. H+i-Bu2N

2. H2O

cat. H+

2. H2O

5. Enones as Enolate Precursors

Li, NH3

t-BuOH LiO

Boeckman JACS 1974, 96, 6179Stork JACS 1974, 96, 6181

Boeckman JACS 1973, 95, 6867

Me2CuLi

Enones as Latent Enolates in Catalysis

99 01 LiN(i-Pr)2, THF, -78oC1

22 78 Me3SiCl, TEA, DMF, 80oC1

03 97 BrMgN(i-Pr)2, HMPA, 25oC, then Me3SiCl, TEA2

CH3 H3C

Favored

Disfavored

CH3H3C

3-Enolate

2-Enolate

7,8-UnsaturationInverts Regiochemical

Preference!(Toromanof f !)

Na/NH3

Then R-X

Rh(I)Ln

Silane

Rovis Tetrahedron Lett. 1987, 28, 4809.Morken J. Am. Chem. Soc. 2000, 122, 4528.

Corey J. Am. Chem. Soc. 1955, 77, 2505.Djerassi J. Chem. Soc. 1962, 1323.

Sondheimer J. Am. Chem. Soc. 1958, 80, 6296.

1House J. Org. Chem. 1969, 34, 2324.2Holton Tetrahedron Lett. 1983, 24, 1345.

Stork J. Am. Chem. Soc. 1961, 83, 2965.

Problem: Regioselectivity in Enolisation

Catalytic: Reductive Generation of Enolates

6. Enol Derivativesa) Enol acetates

House J. Org. Chem. 1965, 30, 1341, 2502.

Erel = 2.3 kcal/mol

Erel = 0

Me- Me2CO

Favored

6. Enol Derivativesb) Silyl enolates

Stork, G. J. Am. Chem. Soc. 1968, 90, 4462.House, H.O. J. Org. Chem. 1969, 34, 2324.

Stork, G. J. Am. Chem. Soc. 1974, 96, 7114.

O TMSO TMSO+

TMS-Cl, Et3N, DMF 9 : 91 (88%)

LDA, then TMS-Cl 99 : 1 (74%)

O TMSO

1) Li/NH3

2) TMS-Cl

TMSO -O O

1) Me2CuLi

2) TMS-Cl> 90%

MeLi etc.

Boeckman J. Am. Chem. Soc. 1974, 96, 6179.

Stork, G. J. Am. Chem. Soc. 1973, 95, 6152.

LOBA: Bulky base

n-BuLi[conditionsunknown]

97% 3%

97.5% 2.5%

THF, TMS-Cl

-78 oC

Corey, S.J.; Gross, A.E. Tetrahedron Lett. 1984, 25, 495.Corey, S.J.; Gross, A.E. Org. Synth. 1987, 65, 166.

Regioselective Enolization

Denniff, P.; Whiting, D.A. J. Chem. Soc., Chem. Commun. 1976, 712.Denniff, P.;Macleod, I.; Whiting, D.A. J. Chem. Soc. Perkin I 1981, 82.

1. LDA, DME, -78oC (92:8 selectiviy in enolisation*)

2. hexanal

3. H2O, HCl

(rac)-[6]-gingerol (57%)

* LiHMDS in place of LDA gave only 75:25 selectivity in enolisation

Lee, R.A.; McAndrews, C.; Patel, K.M.; Reusch, W. Tetrahedron Lett 1973, 965.Ringold, J.; Malhotra, S.K. Tetrahedron Lett 1972, 669.

kinetic enolate

thermodynamic enolate

LICA, THF

t-BuOK,t-BuOH,

LICA =Lithium i-propylcyclohexylamide

1. LDA, THF

1. LiAlH42. H2O

Stork, G.; Danheiser, R.L. J. Org. Chem. 1973, 38, 1775.

LDATHF, HMPA

1. MeLi2. H3O+Cl

-vetivone

Stork, G.; Danheiser, R.L.; Ganem, B. J. Am. Chem. Soc. 1973, 95, 3414.

Vetiver oil (originally cous-cous, from Indian perennial grass of Poaceae family) contains vetivones and khusimone, used in nearly 90% of western fragrances. Annual production of Lavania ca 250 tonnes.

Stork, G.; d’Angelo, J. J. Am. Chem. Soc. 1974, 06, 7114.

1. Li, NH3, t-BuOH

2. CH2O, Et2O, -78oC

1. Li, NH3, PhNH2

2. CH2O, Et2O, -78oC

Gelin, S.; Gelin, R. Bull. Chim. Soc. Fr. 1970, 340-341.

R2 OEt

X COOHX C

H2C COOEt

HC (COOEt)2

H2C CH

% enol % enolka 105

CCl4CCl4

Synthesis of PGE2 Intermediate

Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1985, 107, 3348.

OTBSOTBS

Ph3SnO

I CO2Me

1. CuI, Ph3P, THF2. compound 13. HMPA, Ph3SnCl

PGE2 f amily

Enolates: Regioselectivity

Krafft, M.E.; Holton, R.A. J. Org. Chem. 1984, 49, 3669.Kharasch reagent: Krafft, M.E.; Holton, R.A. J. Am. Chem. Soc. 1984, 106, 7619.

LDA, TMSCl

Fe(0)/TMSCl/TEA

Fe(0)/MeMgBr/TMSCl/TEA

The ene reaction

the Diels-Alder reaction the Alder ene reaction

Frontier orbital explanation:

HOMO of ene

LUMO of anhydride

bonding

Normally we simply treat the p orbital of an alkene as an independent unit, without considering

combinations with other orbitals. Here we need to do this to form the molecular HOMO.

Review: Conia J.M. Synthesis 1975, 1–19.

Pd catalyzed alkylation

PdCl2(MeCN)2

2 Et3NCO2MeR'

O CO2MeR'

then add H2

THF, -60 oC to rt

pKa ~10-17

Hegedus, L. J. Am. Chem. Soc. 1977, 99, 7093–7094.J. Am. Chem. Soc. 1980, 102, 4973–4979.

Greener alkylation?

R[Rh(coe)2Cl]2 (2.5 mol%)

IMes (5 mol%), TsOH.H2O (10 mol%)

(25 mol%)

PhMe (0.2 M), 130 oC, 48 h

MeMe Me

Mo, F.; Dong, G. Science 2014, 345, 68–72.

Explanation

Mo, F.; Dong, G. Science 2014, 345, 68–72.

A! Aalto university School of Chemical Technology © Ari Koskinen KE-4.4120 Organic Synthesis 15....

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