CARBANIONS

Carbanions are units that contain a negative charge on a carbon atom. The negativecharge gives good nucleophilic properties to the unit that can be used in the formation ofnew carbon carbon bonds. Carbanions thus act as nucleophiles in substitution reactions, incarbonyl addition and substitution reactions, and in 1,4- addition (Michael) reactions.

C RR

R

a carbanion

Carbanions bear many substituents that can affect the structure and reactivity of thecarbanion, and can affect the acidity of a parent C-H precursor. Halogens stabilizecarbanions in the order of Br > Cl > F. A prominent I-π repulsion between the F andCarbanionic center causes some destabilization in alpha-fluorinated carbanions. Themagnitude of the destabilization depends on the carbanion structure. The destabiziationmaximizes as the carbanion structure approaces a planar configuration. Thus, fluorinatedcarbanions possess pyramidal structues with high barriers to inversion.

Carbanion StructureCarbanions are trivalent with sp3 hybridization. The lone pare of electrons occupies

one of the sp3 orbitals. The geometery is thus tetrahedral. The tetrahedron can undergoinversion or retain its stereochemistry depending on the attached substitutents. A methycarbanion has a barrier to inversion of about 2 kcal/ mole. The trifluoromethyl carbanionhas a barrier of 120 kcal/mole. A fluorine atom is however more stabilizing than ahydrogen atom because of the fluorine electronegativity.

CR R

R

tetrahedral carbanion

CR

R

Rinversion

R = H; barrier = 2 kcal/moleR = F; barrier = 120 kcal/mole

The rate of inversion in hydrocarbon system is slowed by incorporation of thecarbanion into a three membered ring.

SO2Ph

17 kcal 5.8 kcal

NSO2Ph

10 kcal

NH3

Experiments involving the use of chiral substrates aids the study of carbanionstereochemistry as inversion causes loss of optical activity. Cleavage of the methyl ketonebelow with amide ion give a carbanion with a slow rate of inversion. The carbanionabstracts a proton to give an optically active product. Carbanions that contain fluorineatoms often show a slow rate of inversion.

F

BrClH3C

O

F

BrCl

F

BrCl

H

NH2-

H2O

optically active optically active

When the rate of deuterium exchange at a chiral center is not equal to the rate ofracemization it shows that an intermediate is involved as an ion pair. Carbanion ion-pairsare show to be present through labeling at a chiral center. The rate of d exchange isdifferent from the rate of inversion, indicating that the ion pair is encumbered with the cationor the solvent.

H3C

DN(CH3)2

O

k D-exchangek racemization

= 148

Ph

DNCEt

= 0.5

Carbanions containing beta fluorine atoms are strongly stabilized. Electronegativityof the fluorine atom is the main reason but some consideration must be given to "Negativehyperconjugation", as has been found from the crystal structure of the compound below.Negative hyperconjugation is possible because fluorine atoms have a very low energy sigma* orbital to accept the electron. In the structures below the fluorine atom position is identicalin each structure.

CF3

F3C

F

F

F

F

CF2

F3C

F

F

F

F

F

The formation of carbanion intermediates in the elimination of HF fromfluorcarbons often occurs (E1Cb) as shown below.

Ph

OF

B+Ph

OF

+ BH

Ph

OF

Ph

O

+ F

k1k-1

k2

Acidity

The conversion of carboxylic acids and phenols to carboxylate or phenolate ions iscommon because the proton is acidic, thus the proton is easily removed to form the anion inweakly basic medium. Most organic compounds are much less acidic than carboxylic acids,and thus need stronger basic medium to ionize a carbon-hydrogen bond. Because of thehigh electronegativity of a fluorine atom, fluorinated compounds are always more acidicthan non-fluorinated compounds. Fluorination alpha to an anionic site can sometimes bedestabilizing depending on the geometry of the anion. Thus the p-π backbonding fromfluorine is maximized in planar carbanions. But fluorinated carbanions tend not to beplanar. Beta fluorination increases acidity dramatically, and trifluoromethyl groups verymuch increase acidity.

In the planar fluroene systems shown below the decreasing acidity effect of thefluorine by p-π interaction of the non-bonding fluorine atoms with the occupied p orbital isevident, as the rate of C-D exchange in the fluorinated compound is the slowest of all thecompounds. The mechanism for exchange involves a carbanion intermediate which in thiscase is planar.

R DR = HR = F

R = ClR = Br

8.71.0

34806090

The equilibrium expression below how the pKa is related to the basic medium whereH- is the base constant. Thus for compounds of weak acid strength (high pKa) a large baseconstant is needed to form the carbanion.

R-H + base R- + base-H

[R-][base-H]

[R-H][base]Ka =

pKa -log[R-][base-H]

[R-H][base}=

H- log RH/R-+pKa =

The pKa values of some common organic compounds are shown below.Hydrocarbons which have pKa of about 48 are almost non-acidic, but with special structuralfeatures such as added benzene rings or adjacent carbony groups, the pKa values approacesthat of weak organic acids.

pKa

PhCH2-H 41

CH3COO-H 4.8 C6H5-OH 10

Ph2CH-H 33

Ph3C-H 31 H 49

HH

23 18 H

O

H

16

26

O

O

O O

OEtEtO

O O

OEtH3C

O O

CH3H3C

13

16

14

11

C6F5-OH 5.5

CF3

CF3

CF3

F3C

F3C

-2

F

F

F

F

F

14

O O

OEtPh

10.7 O O

OEtPhF

8.5

CF3COO-H 0.5(CH3)3C-OH 19

(CF3)3C-OH 5.4

OH Compounds

HydrocarbonsCH3CH2-H 48

Several basicity constants are show below. When a system has a basicity constanthigher that the pKa of an acid then a reaction will occur to form a carbanion. Thus anumber of bases are now known that can be used for the generation of carbanions that arethen used in some synthetic process.

H-

RLi 50

6M KOH 16

10 M KOH 17-18

0.01 M NaOCH3 in DMSO/MeOH 15

NH Cs+N

Li+

40 40Solvents and Bases

The formation of carbanions can occur in several solvent systems. Very strongbases cannot be formed in protic solvents because they abstract a hydrogen atom from thesolvent to form a hydrocarbon.

Commonly Used Solvents

Ether, THF, Hexane--covalent aprotic

Water, Alcohols---polar protic

DMSO, DMF, HMPA---polar, aprotic

The strongest bases are obtained from the reaction of metal with organohalogencompounds to give reagents known as Grignard reagents or organolithium reagents.

BasesOrganolithium reagents

n-BuLi, PhLi, MeLi commercially available

t-BuLi > sec-BuLi> n-BuLi in base strength

Bu-Br + 2 Li Bu-Li + LiBrcold

ether or hexane

The organolithium reagents tent to exist as tetramers because of the covalent natureof lithium to carbon bonds. The tetramers are still very strong bases and stongnucleophiles, and can be converted to even stronger bases on coordination withtetramethylethylenediamine as shown.

Li

LiLiLi

R

R

R

Rtetramer

(H3C)2N N(CH3)2

(H3C)2N N(CH3)2

N(CH3)2(H3C)2N

Li

Li

R

R

Postassium tert-butoxide, commercially available, and lithium diisopropamide(LDA), easily prepared in the lab, are frequently used for reaction with the alpha hydrogenof carbonyl compounds to produce enolates.

NH N Lin-BuLi strong base

poor nucleophile

t-BuO K Potassium tert-butoxide

Stabilization of Carbanions

The negative charge on a carbanion is stabilized by neighboring electronwithdrawing groups (WEG) such as carbonyl, nitro, and sulfone.

EWG = C=O , NO2 , CN , SO2

The stabilizing dispersal of the electrons into the EWG is shown in the examplesbelow. Carbonyl functions are very effective in stabilizing adjacent negative charge andwhen two carbonyl groups are present (as in diethyl malonate or acetylacetone) a veryuseful carbanionic intermediate is produced. The intermediate is called an enolate. Thedithane system is capable of stablizing the carbanion by dispersal of the charge into the dorbitals of the sulfur atoms.

C CC

O

C

O

C C

O

C

O

C C

O

C

O

CC

O

C

O

CH3C-CH3

O Obase

CH2C-CH3ketone enolate

CH2=C-CH3

O

Whan carbanions are formed in unsymmetrical ketones, two carbanions is possible.One , the more substituted carbanion and more stable, is called the thermodynamic anion;while the least substituted and first formed anions is called the kinteic anion. LDA is a baseof choice for formation of kinetic products while hydroxide and alkoxides give thethermodynamic anion.

O O O

kinetic thermodynamic

and/or

LDAt-BuOK

71 29

20 80O O O

and/or

99 1

12 88O O O

99 1

26 74

LDAt-BuOK

LDAt-BuOK

and/or

Fluorine atoms alpha to a carbonyl group oppose the normal polarization of thecarbonyl which contains positive charge on the carbon and negative charge on the oxygen.Thus fluorinated aldehydes and ketones show higher enol content than the hydrogencounterparts.

Synthetic Applications of EnolatesProcesses in organic chemistry used for synthesis generaly include functional group

changes and formation of new carbon-carbon bonds. Carbanions are very usefulintermediates for the formation of new carbon-carbon bonds. Thus carbanionsparticipate in 1) SN2 alkylation reactions, 2) in 1,2 additions to carbonylfunctions, and 3) in 1,4-additions such as Michael Reactions. Fluorinated carbanionsare very common useful intermediates for the synthesis of new fluorinated materials. Asalready noted, the fluorine atom will act in a stabilizing manner to with draw electrons fromthe carbanion when the carbanion has a pyrimadial shape. Fluorine backbonding would bejust the opposite in donating electrons to the carbanion center, and thus be destabilizing.The overall result is that fluorinated carbanions are pyramidal and therefor stabilized by thefluorine. There appears to be little difference between fluorinated and non-fluorinatedcarbanions in synthetic procedures.

Enolate Reactions with Carbonyl GroupsAldol CondensationAn aldehyde or ketone that has a hydrogen next to the carbonyl group, an a-

hydrogen, can form an enolate in basic solution, and the enolate can react by nucleophilicaddition at the carbonyl group of another molecule. This process is a very importantsynthetic procedure and is known as the Aldol Condensation. The final product fromaliphatic aldehydes or ketones contains both a carbonyl and an alcohol group. Theproduct is called an aldol.

CH3CH=O CH2CH=O CH2=CH-OOH

CH3CH=O

CH2CH=O

CH3CH-O

CH2CH=O

H2OCH3CH-OH

CH2CH=Oan aldol

Some examples of the aldol condensation from aldehydes and ketones are shownbelow.

CH3CH2CH=O CH3CHCH=OCH3CH2CH-OH

CH3CHCH=O

OHH2O

Aldehyde

OOH

O O

secondmolecule

+

OH2O

Ketone

OH

The aldol products react readily with acid to undergo dehydration and give α,β-unsaturated carbonyl compounds that are also very useful in synthetic organic andbiological chemistry.

H O+O

OHIntramolecular aldol condensations are useful in the formation of cyclic α,β-

unsaturated ketones.O

O

O

O

O2) H+

OH

OOH

H3C CH3

Crossed-Aldol CondensationThe main aldol condensation involves reaction between two aldehydes or

ketones of the same structure. But, the procedure can be modified so that the enolate canreact with another aldehyde of different structure. The requirement is that the otheraldehyde has to be more reactive than the first and it contains no a-hydrogens.Formaldehyde, CH2C=O, and benzaldehyde, PhCH=O, both meet these requirements andare useful in this procedure called the crossed-aldol condensation. All three of the α-hydrogens in acetaldehyde can react in a crossed-aldol condensation with formaldehyde.

CH3CH=O CH2CH=OOH CH2=O

-CHCH=OHOCH2H2O

CH3CH=O CH2=O+ 3

HOCH2HOCH2

HOCH2

CCH=OOH

Aromatic ketones bearing α-hydrogens give aldol reaction products readily, but inthis case the aldol product spontaneously loses water to form the unsaturated ketone.When benzaldehyde is used in the crossed-aldol condensation the final product is theunsaturated aldehyde or ketone. Conjugation of the double bond with the aromatic ring isthe reason for the spontaneous dehydration.

CH3CH=OCH3-C-CH3O

OHPhCHOPhCH=CHCH=O PhCH=CH-C-CH3

O

OH

Fluoroacetonitrile condenses with carbon disulfide in an interesting aldol-typereaction as shown below.

FCH2CNCS2 CH3I

LiHMDS(CH3S)2C=CCN

F

94 %

The carbanion for ethyl fluoroacetate reacts readily with benzaledhyde in a cross-aldol reaction to give the fluorinated alcohol. Alpha fluorinated carbonyl compounds areoften very toxic materials because biologically they are converted to fluoroacetate which istoxic to the Krebs cycle. Thus extreme care is needed when using these compounds.

FOEt

O LDA

PhCHO

FOEt

O

HO PhEsters

Claisen CondensationEsters, like aldehydes and ketones, give an aldol-type reaction. The a-hydrogen of

the ester is removed by base to give the enolate. The enolate reacts with another molecule ofthe ester in an addition-elimination reaction characteristic of esters, which appears asdisplacement of the alkoxide. The resulting product is a β-ketoester. The reaction is knownas the Claisen condensation.

O OO

O

CH2C-OC2H5CH3C-OC2H5CH3C-OC2H5

CH2C-OC2H5 CH2C-OC2H5CH3C

C2H5O

CH3C-O

OC2H5

O O

The α-hydrogens in the product β-ketoester are more acidic than the α-hydrogensin the starting ester. Thus a new enolate is formed that is more stable than the first enolate,thus helping the reaction go to completion.

O O O

O

CH3C-CH2-CO2C2H5 CH3C-CH-CO2C2H5 CH3C=CH-CO2C2H5C2H5O

HCH3C-CH2-CO2C2H5

+

Crossed-Claisen condensation occurs when a highly reactive ester with no α-hydrogens reacts with the enolate derived from another ester. Ethyl benzoate and ethylformate are two frequently used esters that have no α-hydrogens.

O OO

O

R

RCHC-OC2H5HC-OC2H5

RCH2C-OC2H5

CHC-OC2H5

C2H5O

H+CH3CH2O-C

O

H

O

RCHC-OC2H5CH

O

Claisen condensation of ethyl benzoate with ethyl acetate affords ethylbenzoylacetate in the crossed-Claisen method.

O CH2CH3

OCH3C-OCH2CH3

O

CH3CH2O Na+O

CH2CH3O O

Intramolecular Claisen condensations go by the name of Dieckmann condensationsand are useful for the preparation of five and six-membered rings.

Ethyl fluoroacetate reacts readily in a crossed-Claisen reaction with diethylcarbonate to give diethyl fluoromalonate. Diethyl fluoromalonate can be used syntheticallyjust as diethyl malonate.

FOEt

O

EtO OEt

O O

EtO OEtF

OO

+OEt

_

90 %

C2H5O

Dieckmann condensation

CH3OCO

O OCH3CH3OC

O

O

Enolate Anion Alkylation ReactionsGeneral ReactionWhen strong anhydrous bases such as sodium hydride, sodamide or lithium

diethylamide LiN(C2H5)2, are used to prepare the enolate anions at low temperatures, theresulting enolate reacts very slowly with carbonyl groups and can be used as nucleophiles inthe SN2 reaction with primary alkyl halides. In the resonance stabilized enolate, a negativecharge exists on both a carbon and an oxygen. Both sites are possible nucleophiles in thereaction but the carbon nucleophile predominates because it is a stronger nucleophile, butminor products from O-alkylation are found.

ON(CH2CH3)2Li

O O

CH3IO O

CH3

CH3

+

major minor

Alkylation of simple fluoroketones seems to be little studied, but alkylation of thecyclohexylimine of fluoroactone show temperature dependent regioselectivity. Mixtures areformed but the major isomer shown is produced in about 90 % yield. Imines are usedbecause there is no competition for Aldol type additions.

NF

1) LiHMDS

2) CH3I1) LiHMDS

2) CH3I -30o -80o

NF

NF

The fluorinated oxazine below is alkylated easily with benzyl bromide. Afterreduction and hydrolysis a fluoro aldehyde is obtained. This is a fluoro modification of theMeyers synthesis.

N

OF

1) n-BuLi, THF, -78o

2) PhCH2BrN

OF

Ph

N

OF

Ph

1) NaBH4

2) H3O+ H

OF

Ph

76 %

51%

Alkylation of Ethyl Acetoacetate and Diethyl Malonateβ-Keto esters have earned a special place in organic chemistry for their value as

compounds used in the synthesis of new carbon-carbon bonds. The general method fortheir use involves a) formation of the enolate between the carbonyl groups, b) reaction ofthe enolate in an SN2 reaction with an alkyl halide, and c) removal of one of the carbonylgroups by decarboxylation. The result is the formation of methyl ketones or acetic acidderivatives.

CH3C-CH2-C-OCH2CH3

O O

CH3CH2O-C-CH2-C-OCH2CH3

O O

Ethyl Acetoacetate

Diethyl Malonate

CH3C-CH-C-OCH2CH3

O O

CH3CH2O-C-CH-C-OCH2CH3

O O

base

base

Ethyl AcetoacetateThe a-hydrogens of ethyl acetoacetate are acidic enough (pKa =11) to be removed

by a variety of bases. The enolate anion can be used to displace a halogen in an alkylhalide. Hydrolysis of the product gives a β-ketoacid which loses CO2 on mild heating. Aderivative of acetone is the final product.

O O

R

OR-X

CH3CCHCO2C2H5 CH3CCHCO2C2H5 CH3CCHCO2C2H5C2H5O

H3O+ O

RCH3CCHCO2H

heat

- CO2

O

RCH3CCH2

substituted acetone

The decarboxylation occurs readily because it proceeds through a favorable cyclictransition state as shown below.

CH3

OO

OH

CH3OH

RR

CH3O

R

CO2

Double alkylation of ethyl acetoacetate in sequential steps can provide a synthesisof highly branched derivatives of acetone after the hydrolysis and decarboxylation steps.

O O

C2H5

O

O

C2H5

CH3CCHCO2C2H5 CH3CCHCO2C2H5CH3CCH2CO2C2H5

C2H5O H3O+

heatCH3CCHCH3

C2H5-Br

2) CH3Br

1)

C2H5O

O

C2H5

CH3CCCO2C2H5

CH3

Diethyl malonate Diethyl malonate also possess acidic α-hydrogens and may be used instead of

ethyl acetoacetate in the above sequence. The difference is found in the final product thatcontains an acetic acid structural unit instead of an acetone structural unit.

O O O OC2H5OCCHCOC2H5C2H5OCCH2COC2H5

C2H5O

O O

R R

C2H5OCCHCOC2H5H3Oheat-CO2

RBr CH2COOH

substitutedacetic acid

+

The Michael ReactionEnolate AdditionEnolates may also be alkylated with α,β-unsaturated carbonyl substrates. The

enolate adds in the 1,4 fashion to give a unit extended by three carbon atoms in a processknown as the Michael reaction. Many α,β-unsaturated carbonyl systems may be preparedby the dehydration of aldol products. Examples of the Michael reaction using methyl vinylketone and acrylonitrile, two common units in the reaction, are shown below.

O OC2H5OCCHCOC2H5

CH3

O1)

2) H+

O OC2H5OCCHCOC2H5

CH2CH2CCH3O

O OCH3CCHCO2C2H5

CH2=CHCNCH3CCHCO2C2H5

CH2CH2CNH2O2)

1)

Michael Reaction

Enamine AdditionsEnamines, the products of the acid-catalyzed addition of secondary amines to

aldehydes or ketones, can be viewed as weakly nucleophilic enolate anions. Enamines willreact with a,b-unsaturated carbonyl systems in the Michael reaction in method that permitsintroduction of new carbon-carbon bonds adjacent to the carbonyl group.

NHO

H+N N

+

enamine

Enamine Addition

N CH2=CHCN

O

CN

H3O+

N+

CN

Robinson Ring-forming ReactionA unique reaction that produces a new ring containing an a,b-unsaturated ketone is

the Robinson reaction. When an enolate derived from a ketone reacts with methyl vinylketone, the enolate adds in the Michael reaction, then a second enolate in the ketone productis formed that cyclizes in an Aldol condensation to give the final product.

O

2) H+

CH3

OOH O CH3

O

O CH2

O

Oaldol

Michael

Robinson Reaction

The dithane system is capable of stablizing the carbanion by dispersal of the chargeinto the d orbitals of the sulfur atoms. When the dithiane carbanion is used as anucleophile, the dithiane unit can be hydrolyzed to a carbonyl group. This the dithanefunctions as a masked aldehyde.

S S S S SS

S SCH3CH2Br

S SHg2+, H2O CH3CH2CHO

OrganometallicsOrganometallic reagents are well-know in organic chemistry. The Grignard reagent

(RMgX), organo lithium reagents and organozinc reagents are used as nucleophiles in theaddition to carbonyl groups , in SN2 reaction and in Michael reactions. A few examples oftheir counterparts in organofluorine chemistry are shown here.

The trifluormethyl anion is prepared from by reaction of trifluoromethyltrimethylsilane with fluoride ion. The strong affinity of fluoride for silane drives thisreaction toward the trifluoromethy anion. The anion behaves like a good nucleophile inmany reaction. Addition to a carbonyl group is shown here.

CF3SiMe3 FSiMe3 + CF3-+ F-

O CF3-OH

CF3

Trifluormethyl copper shows good ability as a coupling reagent with arylaromatics.

CF3Br + Cu [CF3Cu]

ArI [CF3Cu]+ ArCF3Trifluorovinyl lithium is produced from chlorotrifluoroethene and butyl lithium.

The lithium reagent adds easily to carbonyl groups.CF2=CFCl

n-BuLi CF2=CFLi

PhCHOCF2=CFLi PhCH(OH)CF=CF2

CF3CH2Fn-BuLi

Reformatsky ReactionInstead of forming the enolate from an α-hydrogen, an α-bromine atom can also be

used. Zinc reacts with ethyl α-bromoacetate to form a zinc enolate that reacts at thecarbonyl function of aldehydes and ketones to produce α,β-hydroxyester. The method ismade easier by addition of the bromoester to a mixture of zinc and the carbonyl compound.

H3C CH3

O

H3C CH3

BrZnO CH2CO2C2H5

H3C CH3

HO CH2CO2C2H5

ether BrZn CH2CO2C2H5ZnBrCH2CO2C2H5

BrZn CH2CO2C2H5

H3O

Reformatsky Reaction

Ethyl bromodifluoroacetate is used frequently in Reformatsky procedures to givehigh yields of alcohol products.

etherZnBrCF2CO2C2H5

O

O

CHO O

O

CO2C2H5

FF

OH

Keto-Enol Equilibrium

Ketones can exist as two equilibrated molecules. One molecule is the often writtenketone structure while the other structure is a tautomer known as an enol. In some cases theenol contribution can be large. When fluorine atoms are present in the ring, the electronwithdrawl by fluorine around the carbonyl increases the positive charge at the carbonyl.The molecule responds by forming the enol.

O OH

O OH

O O O OH

OO OHO

O O O OH

O OH

OHO

10-7

10-4

20

>50

0

infinity

10-7

O

OOH

t-Bu

t-Bu

CH3

Rearrangements of Carbanions

Homoallylic rearrangements

The structures below represent allylic, homoallylic and homobenzylic. The “homo” meansthat there is one additional carbon atom. Some interesting rearrangements occur with thehomoallylic systems.

allylic homoallylic homobenzylic

The examples below show a homobenzylic rearrangement where the carbanion interactswith the aromatic ring. The carbanion appears to insert between the ring and the carboncontaining the two methyl groups. The mechanism of the rearrangement is proven byisolation of the cyclopropane structure when a para phenyl group is present.

H3C

CH3

H3C

CH3

H3C

CH3

1) CO2

2) H+COOH

CH3H3C

H3C

CH3

H3C

CH3

Ph PhCOOH

The examples below represent some well known reactions.

Ph-CH2-O-CH3

n-BuLiPh-CH-O

CH3

Ph-CH-O-CH3

PhCH2-S-CHPh

CH3

PhCH2-CHPh

SCH3

Stevens

Wittig

CH2-N(CH3)2

CH2 CH2-N(CH3)2

CH3Sommelet-Hauser

O2S Br

O2S

- SO2 Ramburg-Backland