Reactions at α-Position

In preceding chapters on carbonyl chemistry, a common reaction mechanism observed was a nucleophile reacting at the electrophilic carbonyl carbon site

O NUC O

H C CH H C CH3 3 3 3 NUC

Another reaction that can occur with carbonyl compounds, however, is to react an electrophile with the carbonyl

O E O

H3C CH3 H3C CH2 E

The electrophile adds to the α-position and allows the synthesis of a variety of substituted carbonyl compounds by reacting different electrophiles Reactions at α-Position

In order to react with electrophiles at the α-position, the carbonyl compound needs to be nucleophilic at the α-position

There are two general methods to become nucleophilic at α-position:

1) React through the enol form

O OH O K Br Br -9 5 x 10 H3C CH3 H3C CH2 H3C CH2 Br keto enol

A carbonyl compound is in equilibrium with an enol

Typically the equilibrium for a ketone though lies heavily in the keto form

The enol form, however, is more reactive than an alkene and can undergo similar reactions as observed with reactions with π bonds Reactions at α-Position

2) To make a carbonyl compound even more nucleophilic at the α-position, a base can be added to form an enolate

O base O O

H3C CH3 H3C CH2 H3C CH2

E

O

H3C CH2 E

The α-position of a ketone is relatively acidic (pKa ~19) because the anion is stabilized by resonance with the carbonyl oxygen

The negatively charged enolate anion can react with an electrophile to form a new bond between the α-carbon and the electrophilic atom Reactions at α-Position Since the enolate anion resonates between two atoms, it is important to recognize which atom will react preferentially with an electrophile E O E O O E O

H3C CH2 H3C CH2 H3C CH2 H3C CH2 E Reaction at carbon Reaction at oxygen In order to make this prediction, it is important to recognize which orbital is reacting As in all nucleophilic reactions, the HOMO of the nucleophile is reacting with the LUMO of the electrophile Consider the HOMO for the enolate nucleophile: The charge in the HOMO for the unsymmetrical enolate is far greater on the carbon than the oxygen (this is offset by a greater electron density in the lowest occupied orbital)

Therefore the enolate reacts Enolate structure HOMO of enolate preferentially at the carbon site Reactions at α-Position

To form an enolate therefore a base can be reacted with a carbonyl compound to deprotonate the hydrogen on the α-carbon

Realize, however, that most strong bases are also strong nucleophiles

(remember factors in SN2 versus E2 reactions)

A base/nucleophile used could react either by reaction at carbonyl carbon or by abstracting the hydrogen on the α-carbon

O base/nucleophile O O

H C CH H C CH H C CH3 3 3 3 2 3 NUC

Formation Reaction of enolate at carbonyl

Which pathway is preferred depends on the choice of base/nucleophile used Reactions at α-Position

To generate enolate need to use a base that will not act as a nucleophile

Common choice is to use lithium diisopropylamide (LDA)

Li H N BuLi N

LDA

LDA is a strong base (pKa of conjugate is in high 30’s), while it is very bulky so it will not react as nucleophile on carbonyl

LDA will therefore quantitatively deprotonate α-carbon without reacting at carbonyl carbon

O LDA O

H3C CH3 H3C CH2 Reactions at α-Position

The type of carbonyl compound will also affect the enolate formation

Due to the resonance stabilization of some of the carboxylic acid derivatives, the pKa values vary amongst different carbonyl compounds

pKa of conjugate 16.7 19.3 24 25 18 24

O O O O O

H CH2 H3C CH2 H3CO CH2 (H3C)2N CH2 HN CH3 RHC C N

Aldehydes are typically Esters and amides are Amidate is more acidic lower pKa than ketones less acidic than α-carbon

Therefore while LDA will quantitatively deprotonate the α-carbon, hydroxide or alkoxide bases (pKa ~ 16) will only deprotonate a small fraction of molecules

O O O NaOH LDA

H3C CH2 H3C CH3 H3C CH2 Reactions at α-Position

The keto/enol equilibrium is also affected by the structure of the carbonyl compound

K O OH 10-9 H3C CH3 H3C CH2 Both ketones and aldehydes highly favor keto form, but aldehyde have relatively O OH more enol form present 10-7 H CH3 H CH2

H β-dicarbonyl compounds have a much O O O O 3 higher concentration of enol form due to H3C CH3 H3C CH3 intramolecular hydrogen bond

O OH Enol form is highly favored with phenol 1013 due to aromatic stabilization Reactions at α-Position

The amount of enol present is increased in either acidic or basic conditions

H O H+ O H2O OH

H3C CH3 H3C CH3 H3C CH2

O O OH NaOH H2O

H3C CH3 H3C CH2 H3C CH2

Formation of enol allows hydrogens on α-carbon to be exchanged

O NaOD, D2O O D+, D2O O

D3C CD3 H3C CH3 D3C CD3 Racemization of Enols and Enolates

A consequence of the formation of enols or enolates is the α-carbon goes from sp3 (and potentially chiral) to sp2 (and therefore planar and achiral) hybridization

O

H3C CH3 O OH CH3 H+ H+ or H3C CH3 H3C CH3 CH3 CH3 O

α-carbon is chiral α-carbon is planar H3C CH3 CH3

racemic

When the keto form is regenerated, the chirality at the α-carbon is lost

The α-position therefore becomes racemic if there is an α-hydrogen present Halogenation

When enols are generated in the presence of dihalogen compounds, an electrophilic reaction occurs which places a halogen on the α-carbon

H O H+ O H2O OH Br Br O Br H3C CH3 H3C CH3 H3C CH2 H3C C H2

In acidic conditions the halogenation is stopped at one addition because the protonated carbonyl compound is less stable after a halogen has been added

H H H H O O O O Br Br H3C CH3 H3C CH3 H3C C H3C C H2 H2

Positive charge is less stable with adjacent C-Br bond Halogenation

In basic conditions, however, an enolate is generated instead of an enol

O O O NaOH Br Br Br H3C CH3 H3C CH2 H3C C H2

The enolate is more stable with an attached halogen and therefore under basic conditions the α-position is polyhalogenated

O O O NaOH Br Br Br Br H3C C H3C C H3C CHBr2 H2 H More stable anion

Reaction will continue until all α-hydrogens are replaced with halogen

O Br2 O NaOH R CH3 R CBr3 Haloform Reaction

When the α-carbon is a methyl group, the basic halogenation places three halogens on carbon

O Br2 O NaOH R CH3 R CBr3

Under the basic conditions of the reaction, however, the three halogens convert the methyl group into a good leaving group and thus the hydroxide can react at carbonyl carbon

O O NaOH O CHBr3 R CBr R CBr3 R O 3 OH bromoform

The reaction thus will convert a methyl ketone into a carboxylic acid

Called a “haloform” reaction because the common name for a trihalogen substituted carbon is a haloform (chloroform, bromoform or iodoform) Halogenation of Carboxylic Acids

Carboxylic acids can also be halogenated in the α-position, but the acid halide needs to be formed first

O O OH O PBr3 Br H C H C H C 2 H C 3 OH 3 Br 3 Br 3 Br Br2 H H H H H H Br

The acid halide can easily be converted back into the acid with water work-up

O O O H2O NH3 H3C H3C H3C Br OH ! OH H Br H Br H NH2 alanine

These α-bromo acids are very convenient compounds to prepare α-amino acids with reaction with ammonia Alkylation of Enolates

Enolates are very useful to form new C-C bonds by reacting the enolate with alkyl halides

O LDA O CH3Br O

H3C CH3 H3C CH2 H3C CH2CH3

Allows formation of new C-C bond at the α-position, works best with methyl or 1˚ halides as more sterically hindered alkyl halides react through E2 mechanism

When using symmetrical ketones, alkylation at either α-position generates the same product, but when using unsymmetrical ketones two different products can be obtained

O LDA O O or H3C CH2CH3 H2C CH2CH3 H3C CHCH3

CH3Br CH3Br

The conditions used to form O O the enolate determines which is favored H3CH2C CH2CH3 H3C CHCH3 CH3 Alkylation of Enolates

Differences in enolate formation control preferential pathway

O LDA O O O O

H3C CH2CH3 H2C CH2CH3 H2C CH2CH3 H3C CHCH3 H3C CHCH3

Hydrogen is easier to abstract, Double bond of enolate is therefore this is the more stable, therefore this is kinetic enolate the thermodynamic enolate

When trying to control kinetic versus thermodynamic, typically the temperature can be used as the lower temperature favors kinetic and the higher temperature favors thermodynamic

1) LDA, -78˚C O O 2) CH3Br

H3C CH2CH3 H3CH2C CH2CH3

1) LDA, 40˚C O O 2) CH3Br

H3C CH2CH3 H3C CHCH3 CH3 Alkylation of Enolates

Alkylation of ketones is therefore relatively straightforward, add one equivalent of LDA at either low temperature for kinetic enolate and high temperature for thermodynamic enolate and then add the required alkyl halide

Other types of carbonyl compounds can also be alkylated using these conditions

Esters: 1) LDA O 2) CH3Br O

H3CO CH2CH3 H3CO CHCH3 CH3

With esters there is only one α-position and therefore alkylation occurs at this site

Acids:

O NaH O LDA O CH3Br O

HO CH2CH3 O CH2CH3 O CHCH3 O CHCH3 CH3

With carboxylic acids, first need to deprotonate the acidic hydrogen before deprotonating at α-position, alkylation will then occur at the α-position Alkylation of Enolates

Aldehydes: O O O LDA H CH2CH3

H CH2CH3 H CHCH3

Alkylation of aldehydes can sometimes be problematic because the aldehyde carbonyl is more reactive than a ketone, therefore the enolate formed can react with the carbonyl (called an aldol reaction to be seen shortly)

A way to circumvent this potential problem, the aldehyde can be converted to an imine

R R 1) CH3Br O RNH2 N LDA N 2) H2O O

H CH2CH3 H CH2CH3 H CHCH3 H CHCH3 CH3

The imine anion can react with the alkyl halide and then the α-alkylated imine can be hydrolyzed back to the aldehyde with water Alkylation of Enolates

β-dicarbonyl:

O O CH3ONa O O CH3Br O O

H3CO H3CO H3CO CH3 A distinct advantage with β-dicarbonyl compounds is the α-hydrogen is more acidic and can be quantitatively deprotonated with alkoxide base

When discussing carboxylic acid derivatives, also observed that when a β-keto ester is hydrolyzed to the acid form a decarboxylation readily occurs

O O O O O NaOH !

H3CO HO H3CH2C CH2CH3 CH3 CH3

Thus this allows a much easier method to alkylate a ketone without needing to use LDA nor controlling kinetic versus thermodynamic (only obtain anion α to both carbonyls) Alkylation of Enolates

Another option to alkylate a ketone instead of needing to form an enolate is to react the ketone with a secondary amine to form an enamine

H N O N

H3C CH3 H3C CH2

The enamine can then react with an alkyl halide to alkylate the compound

N CH3Br N H2O O

H3C CH2 H3C CH2CH3 H3C CH2CH3

The imminium ion that forms after alkylation is easily hydrolyzed with water to the ketone

The enamine is less reactive than an enolate, but more reactive than an enol Aldol Reaction

As mentioned when forming enolates with aldehydes a potential problem is an aldol reaction O

O CH3ONa O H CH2CH3 O OH CH3 H CH2CH3 H CHCH3 H CH3 Aldol product Instead of merely being a potential side product, the aldol reaction can be favored by forming the enolate with alkoxide bases While the enolate is only formed in small concentration due to the differences in pKa, each enolate that is generated is in the presence of an excess of aldehyde After work-up the product will contain an aldehyde (ald) and a β- hydroxy (ol) functionality, a characteristic of an aldol reaction is the formation of a β-hydroxy carbonyl

Borodin is more famous today as a composer, Alexander Borodin but coinvented the aldol reaction and this could (1833-1887) just as easily been called the “Borodin” reaction Aldol Reaction

The β-hydroxy ketone compounds obtained after an aldol reaction can also be dehydrated

O OH O H+ CH CH H 3 H 3

CH3 CH3

The dehydration can occur under either acidic or basic conditions, although the dehydration is typically much easier under acidic conditions

The dehydration is favored compared to other alcohols dehydrating to alkenes due to the conjugation of the obtained α,β-unsaturated alkene with the carbonyl

As the conjugation increases, sometimes it is difficult to isolate the β-hydroxy carbonyl and only the α,β-unsaturated carbonyl is obtained

O O CH Aldol reactions can 1) NaOH 3 2) H+ occur with either CH3 C aldehydes or ketones H Aldol Reaction

If a compound contains both an enolizable position and a different carbonyl, then an intramolecular aldol reaction can occur to form a new ring

O O CH3 O CH3 NaOH CH3 OH H3C H2O CH3 O CH3

Once formed the β-hydroxy ketone can also dehydrate to form the α,β-unsaturated ketone When there are multiple enolizable positions, must consider the different types of possible products O O

CH3 H2C O CH NaOH O 3 CH3 H3C H2O O O CH3 O CH3 H3C CH3 O 5-membered rings are more stable than 7-membered, typically intramolecular aldol reactions are favored in forming either 5- or 6-membered rings Crossed Aldol Reaction

In addition to considering different enolizable positions in an intramolecular aldol reaction, when two different carbonyls are reacted in an aldol a variety of products are obtained

O O O OH O OH

H C CH H C CH H C CH3 H C CH2CH3 3 3 3 2 3 CH 3 CH CH NaOH 3 2 3

O H2O O O OH O OH

CH3 CH CH H3CH2C CH2CH3 H3CH2C CHCH3 H3CH2C H3CH2C 2 3 CH3 CH2CH3 CH3 CH3

If the two carbonyls are both present, then the enolate could form on either

Once formed, each enolate could react with either carbonyl that is present to yield 4 different products (assuming the compounds don’t dehydrate to yield potentially more products)

All four products will be obtained in similar amounts as the reactivity difference between different ketones is minimal

This is called a “crossed aldol” or “mixed aldol” Crossed Aldol Reaction

While reacting two different ketones with alkoxide base is impractical due to the variety of products obtained, the desired product would only be obtained in low yield after a difficult separation, there are methods to react two different carbonyls in an aldol reaction efficiently

A simple solution is if one of the two carbonyls does not have an enolizable position O

H O O O NaOH O H H C H2O 3 H3C CH3 H3C CH2

Only enolate possible

The enolate formed could still react with either carbonyl to generate two different products, but since an aldehyde is more reactive than a ketone benzaldehyde will react preferentially

Due to the extra conjugation, more than likely only the dehydrated product will be obtained Crossed Aldol Reaction The vast majority of time, however, there will be two carbonyls that either both have enolizable positions or the reactivity of the two carbonyls are similar, in these cases more than one product will be obtained if using alkoxide bases

A solution for these cases is to quantitatively form the enolate rather than having an equilibrium between the enolate and keto forms with weak base

O

O LDA O H3C CH3 O OH CH H3CH2C CH2CH3 H3CH2C CHCH3 H3CH2C 3 CH3 CH3 First, quantitatively form the enolate from the desired ketone Then in a second step add the appropriate electrophilic carbonyl to react and only one product will be obtained

By controlling the order of steps, any of the desired aldol products can be obtained O O O O OH LDA H3CH2C CH2CH3 CH CH H3C CH3 H3C CH2 H3C 2 3 CH2CH3 Crossed Aldol Reaction The main difference is that the weak base only forms a small amount of enolate and thus once this enolate is generated it is in the presence of the ketone form to react Therefore both carbonyls would need to be present at the same time and thus a variety of products are obtained O O O OH O OH

H C CH H C CH H C CH3 H C CH2CH3 3 3 3 2 3 CH 3 CH CH NaOH 3 2 3

O H2O O O OH O OH

CH3 CH CH H3CH2C CH2CH3 H3CH2C CHCH3 H3CH2C H3CH2C 2 3 CH3 CH2CH3 CH3 CH3 All obtained in ~equal yield

To synthesize only one, which enolate is required can be determined from the structure

O 1) LDA O OH

H C CH O H C CH2CH3 3 3 3 CH CH 2) 2 3 H3CH2C CH2CH3 Only product Claisen Condensation

An aldol reaction refers to any reaction between an enolate nucleophile and a carbonyl electrophile

When using ketone or aldehyde carbonyls, the reaction is equilibrium controlled

When the electrophilic carbonyl is an ester, however, an irreversible last step occurs to drive the reaction to completion

These aldol reactions with an ester are called “Claisen condensations”

O

O O NaOCH3 O H3C OCH3 O O CH H3C CH3 H3C OCH3 H3C CH2 H3C 3 OCH3 Difference in ketone and ester pKa allows ketone enolate to be formed O O NaOCH3 O O

H3C CH3 H3C CH3

β-diketone formed has an acidic methylene (pKa ~10) that is deprotonated in these basic conditions Claisen Condensation

Claisen condensation can also occur with only an ester present

O

O NaOCH3 O H3C OCH3 O O CH H3C OCH3 H2C OCH3 H3CO 3 OCH3 The enolate is harder to form due to the less acidic ester, but if it is the only carbonyl present it can still form O O Want to use same alkoxide as ester used,

otherwise a transesterification will occur H3CO CH3

NaOCH3

O O

Rainer Ludwig Claisen H3CO CH3 (1851-1930) Will generate a β-keto ester after acidifying the solution Dieckmann Condensation

An intramolecular Claisen condensation is called a “Dieckmann” condensation

O O O NaOCH3 O O O OCH3 H3C OCH3 H2C OCH3

Ketone is more acidic than ester (6-membered ring more stable than 4) Walter Dieckmann (1869-1925) O O In presence of alkoxide base, diketone will be deprotonated to drive reaction

Dieckmann condensation can also occur with diester compounds to generate β-keto ester

O O O O NaOCH3 H+, H O OCH3 2 H3CO H3CO O !

The β-keto ester can then be hydrolyzed to acid and decarboxylated Knoevenagel Reaction

Another variant of the aldol condensation involves the formation of an enolate from an acidic position, usually a β-dicarbonyl, using an amine base O H O O N H O O O O H3CO OCH3

H3CO OCH3 H3CO OCH3 H

Due to the more acidic β-dicarbonyl compound, If generated in presence of ketone or the enolate can be formed with amine base aldehyde, an aldol reaction occurs which typically readily dehydrates

A key factor in a Knoevenagel reaction is the extra stability of the formed enolate, allows formation exlusively at more acidic position even in presence of the less acidic ketone or aldehyde and thus can be formed even with weaker bases (typically amines) Emil Knoevenagel (1865-1921) Michael Reaction

Michael reactions, or sometimes called Michael additions, can occur when the electrophile has an α,β unsaturation O

H NUC O NUC O O

CH CH3 E 3 NUC NUC O 1,2 addition 1,4 addition NUC (Michael) E

When reacting with a nucleophile, the nucleophile can react in two different ways: 1) React directly on the carbonyl carbon (called a 1,2 addition) 2) React instead at the β-position (called a 1,4 addition)

In a 1,4 addition, initially an enolate is formed which can be neutralized in work-up to reobtain the carbonyl

Arthur Michael Or the enolate can be reacted with a different (1853-1942) electrophile in a second step to create a product that has substitution at both the α and β positions Michael Reaction

Whether a reaction proceeds with 1,2 addition or 1,4 addition (Michael) is often dependent upon the type of nucleophile being used

Strong nucleophiles often favor 1,2 addition

O CH3MgBr OH Grignard reagents CH and hydride delivery agents (LAH) CH3 3 CH3 favor 1,2 addition

Stabilized nucleophiles, however, favor 1,4 addition

O (CH ) CuLi O 3 2 Cuprates favor 1,4 addition CH3 H3C

Other stabilized nucleophiles favoring Michael addition are β-dicarbonyl enolates and enamines Michael Reaction

Michael addition using β-dicarbonyl enolates O O O NaOCH O O O O 3 CH3

H3CO OCH3 H3CO OCH3 H3CO

H3CO O

If a β-diester is used, 1) H+, H2O then the ester can be hydrolyzed and decarboxylated 2) ! O O

HO Michael addition using an enamine O

H+, H O N CH3 N O 2 O O

H3C H3C CH3 H3C CH3

The imminium salts generated initially can be hydrolyzed to the ketone Michael Reaction

When an enamine is used as the Michael donor with an α,β unsaturated carbonyl as the Michael acceptor, the reaction is called a “Stork” reaction after its inventor

The Stork reaction allows the formation of a 1,5 dicarbonyl compound

O 1) CH N 3 O O 2) H+, H2O CH3

An advantage for the Stork reaction is that an enolate of a ketone generally reacts in a 1,2 addition O O O CH3 CH3 H3C

H3C O Gilbert Stork By forming the enamine first, a Michael addition can occur instead (b 1921) Michael Reaction

We observed an example of a Michael reaction when discussing radical reactions in an earlier chapter

Calicheamicin γ1

HO O Michael HO O S NHCO2CH3 addition NHCO2CH3 S

O O binding group binding group Bergman cyclization DNA

O O HO CO2CH3 HO CO2CH3 DNA NH NH diradical • O S 2 S

DNA O O binding group • binding group cleavage Robinson Annulation

Many of these reactions can be used in combination to create interesting structures, one combination is to do a Michael reaction followed by an intramolecular aldol reaction (called a Robinson annulation) O O O O O

NaOCH3 CH3 CH3

Eventually the Michael addition A small amount of enolate is CH3OH formed by reacting a ketone will occur with an alkoxide base O O The Michael product under these

conditions can equilibrate to place CH3 enolate at other α-carbon

By placing enolate at this NaOCH3 position, an intramolecular O aldol reaction can occur that O O generates a 6-membered ring O CH Upon work-up this aldol 2 Robert Robinson dehydrates to form π bond (1886-1975) Robinson Annulation

Robinson annulation is a convenient method to synthesize polycyclic ring junctions

OCH3 O OCH3

NaOCH O 3 CH3OH O The two α-carbons have different acidities and thus reaction occurs selectively at more acidic position

Allows synthesis of fused polycyclic structures in high yield

For example, this fused ring system is similar to steroid ring structures