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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 H3C O NUC CH3 H3C CH3 NUC Another reaction that can occur with carbonyl compounds, however, is to react an electrophile with the carbonyl O H3C O E CH3 H3 C 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 K 5 x 10-9 O H3C OH CH3 keto H3C O Br Br CH2 H3 C 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 CH2 Br 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 H3C CH3 O O base H3C CH2 H3C CH2 E O H3 C 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 O H3 C O E CH2 E H3C O CH2 Reaction at carbon H3C O E CH2 H3C E CH2 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) Enolate structure HOMO of enolate Therefore the enolate reacts 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 H3C O base/nucleophile CH3 H3C O CH2 Formation of enolate H3C CH3 NUC Reaction 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 N BuLi 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 H3C O LDA 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 O O O O O H CH2 H3 C CH2 H3CO Aldehydes are typically lower pKa than ketones CH2 (H3C)2N Esters and amides are less acidic CH2 HN 24 CH3 RHC C N Amidate is more 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 H3 C O NaOH CH2 H3C O LDA CH3 H3 C CH2 Reactions at α-Position The keto/enol equilibrium is also affected by the structure of the carbonyl compound K O 10-9 H3C OH CH3 H3 C O 10-7 H O 3 H3C Both ketones and aldehydes highly favor keto form, but aldehyde have relatively more enol form present OH H CH3 O O CH3 O 1013 CH2 H3C CH2 H O β-dicarbonyl compounds have a much higher concentration of enol form due to intramolecular hydrogen bond CH3 OH Enol form is highly favored with phenol due to aromatic stabilization Reactions at α-Position The amount of enol present is increased in either acidic or basic conditions O H3C H+ CH3 O H3C O H3C H3 C OH H2O CH3 O NaOH CH3 H H3C OH H2 O CH2 CH2 H3C CH2 Formation of enol allows hydrogens on α-carbon to be exchanged O D3C O NaOD, D2O CD3 H3C O D+, D2O 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 O OH H+ H3C CH3 CH3 α-carbon is chiral H3 C CH3 CH3 H+ or CH3 O CH3 α-carbon is planar H3 C 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 O H3C O H+ CH3 H3C H CH3 H2 O OH H3C O Br Br CH2 H3 C C H2 Br In acidic conditions the halogenation is stopped at one addition because the protonated carbonyl compound is less stable after a halogen has been added O H3C H CH3 O H3C H CH3 O H3C H C H2 O Br H3C H C H2 Positive charge is less stable with adjacent C-Br bond Br Halogenation In basic conditions, however, an enolate is generated instead of an enol O H3C O NaOH H3 C CH3 O Br Br CH2 H3 C C H2 Br The enolate is more stable with an attached halogen and therefore under basic conditions the α-position is polyhalogenated O H3 C C H2 Br O NaOH H3 C C H O Br Br Br H3C CHBr2 More stable anion Reaction will continue until all α-hydrogens are replaced with halogen O R O Br2 CH3 NaOH R CBr3 Haloform Reaction When the α-carbon is a methyl group, the basic halogenation places three halogens on carbon O R O Br2 NaOH 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 R CBr3 O O NaOH R CBr3 OH R CHBr3 O 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 H3C PBr3 OH Br2 H H OH O H3 C H3C Br H H Br2 Br O H3 C H Br H The acid halide can easily be converted back into the acid with water work-up O H3 C H2O Br H Br O H3C H Br NH3 OH ! O H3C OH H NH2 alanine These α-bromo acids are very convenient compounds to prepare α-amino acids with reaction with ammonia Br Alkylation of Enolates Enolates are very useful to form new C-C bonds by reacting the enolate with alkyl halides LDA O H3C CH3Br O H3C CH3 O 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 H3C CH2CH3 O O LDA or H2C CH2CH3 H3C CHCH3 CH3Br The conditions used to form the enolate determines which is favored CH3Br O O H3CH2C CH2CH3 H3C CHCH3 CH3 Alkylation of Enolates Differences in enolate formation control preferential pathway O H3C O LDA CH2CH3 H2C CH2CH3 H2 C O O O CH2CH3 Hydrogen is easier to abstract, therefore this is the kinetic enolate H3C CHCH3 H3C CHCH3 Double bond of enolate is more stable, therefore this is 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 2) CH3Br O H3C CH2CH3 H3CH2C 1) LDA, 40˚C 2) CH3Br O H3C O CH2CH3 CH2CH3 O 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 2) CH3Br O H3CO O CH2CH3 H3CO CHCH3 CH3 With esters there is only one α-position and therefore alkylation occurs at this site Acids: O HO O NaH CH2CH3 O O LDA CH2CH3 O O CH3Br 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 H O LDA H CH2CH3 H CH2CH3 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 H N RNH2 O CH2CH3 H R CH2CH3 N LDA H R CHCH3 1) CH3Br 2) H2O O 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 H3CO H3CO O O 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 NaOH O H3CH2C HO H3CO CH3 O ! CH2CH3 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 N O H3C H3 C CH3 CH2 The enamine can then react with an alkyl halide to alkylate the compound CH3Br N H3 C CH2 H2O N H3 C CH2CH3 O H3 C 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 H O CH3ONa CH2CH3 H H CHCH3 O CH2CH3 OH CH3 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 βhydroxy (ol) functionality, a characteristic of an aldol reaction is the formation of a β-hydroxy carbonyl Alexander Borodin (1833-1887) Borodin is more famous today as a composer, but coinvented the aldol reaction and this could 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 CH3 H O H+ CH3 H 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 Aldol reactions can occur with either aldehydes or ketones O CH3 1) NaOH 2) H+ O CH3 C 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 H3 C NaOH CH3 O CH3 OH CH3 H2 O 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 CH3 H3 C O CH3 O NaOH H2 O O O CH3 H3C CH3 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 H3 C O O CH3 H3 C CH2 OH CH3 CH3 H3 C NaOH H2 O O H3CH2C CH2CH3 O O H3CH2C CHCH3 O CH3 CH2CH3 CH2CH3 H3 C OH H3CH2C OH CH3 CH3 H3CH2C O OH CH3 CH2CH3 CH2CH3 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 O H3 C H O CH3 H H2 O O O NaOH H3 C CH2 H3C 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 H3CH2C O LDA H3CH2C CH2CH3 H3C CHCH3 O CH3 OH H3CH2C CH3 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 H3C O LDA CH3 H3 C H3CH2C CH2 O CH2CH3 H3 C OH CH2CH3 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 H3 C O O CH3 H3 C OH CH3 CH3 H3 C CH2 NaOH H2 O O H3CH2C CH2CH3 O O H3CH2C CHCH3 O CH3 CH2CH3 CH2CH3 H3 C OH H3CH2C OH O CH3 CH3 H3CH2C OH CH3 CH2CH3 CH2CH3 All obtained in ~equal yield To synthesize only one, which enolate is required can be determined from the structure O H3C O 1) LDA CH3 H3 C O 2) H3CH2C CH2CH3 OH CH2CH3 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 H3C O CH3 H3C NaOCH3 OCH3 H3C Difference in ketone and ester pKa allows ketone enolate to be formed O H3 C H3C O CH2 OCH3 O CH3 CH3 OCH3 H3C NaOCH3 O O H3 C O O 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 NaOCH3 O H3C OCH3 O H2C H3C OCH3 OCH3 O O CH3 OCH3 H3CO The enolate is harder to form due to the less acidic ester, but if it is the only carbonyl present it can still form Want to use same alkoxide as ester used, otherwise a transesterification will occur O O H3CO CH3 NaOCH3 O Rainer Ludwig Claisen (1851-1930) H3CO O CH3 Will generate a β-keto ester after acidifying the solution Dieckmann Condensation An intramolecular Claisen condensation is called a “Dieckmann” condensation O H3 C NaOCH3 O O H2C OCH3 O O O OCH3 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 OCH3 H3CO O O NaOCH3 H3CO O H+, H2O 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 N O H3CO O O O OCH3 H3CO O H O H3CO OCH3 Due to the more acidic β-dicarbonyl compound, the enolate can be formed with amine base OCH3 H If generated in presence of ketone or 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 NUC H O NUC O O CH3 NUC CH3 1,2 addition NUC 1,4 addition (Michael) E O NUC 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 (1853-1942) Or the enolate can be reacted with a different 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 CH3MgBr O OH CH3 CH3 CH3 Grignard reagents and hydride delivery agents (LAH) favor 1,2 addition Stabilized nucleophiles, however, favor 1,4 addition O O (CH3)2CuLi CH3 Cuprates favor 1,4 addition H3C Other stabilized nucleophiles favoring Michael addition are β-dicarbonyl enolates and enamines Michael Reaction Michael addition using β-dicarbonyl enolates O O H3CO NaOCH3 O OCH3 O H3CO O O CH3 O H3CO OCH3 H3CO If a β-diester is used, then the ester can be hydrolyzed and decarboxylated O 1) H+, H2O 2) ! O O HO Michael addition using an enamine O N H3 C CH3 N H3 C H+, H2O O CH3 O H3C The imminium salts generated initially can be hydrolyzed to the ketone O CH3 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) CH3 2) H+, H2O N O O 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 H3 C H3C O Gilbert Stork (b 1921) By forming the enamine first, a Michael addition can occur instead Michael Reaction We observed an example of a Michael reaction when discussing radical reactions in an earlier chapter Calicheamicin γ1 HO O S NHCO2CH3 HO Michael addition O NHCO2CH3 S binding group O binding group O Bergman cyclization DNA HO O CO2CH3 NH DNA diradical O2 S binding group HO O DNA cleavage O CO2CH3 NH • S binding group O • 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 NaOCH3 A small amount of enolate is formed by reacting a ketone with an alkoxide base O CH3 CH3 Eventually the Michael addition will occur The Michael product under these conditions can equilibrate to place enolate at other α-carbon By placing enolate at this position, an intramolecular aldol reaction can occur that generates a 6-membered ring Robert Robinson (1886-1975) O Upon work-up this aldol dehydrates to form π bond CH3OH O CH3 NaOCH3 O O O O O CH2 Robinson Annulation Robinson annulation is a convenient method to synthesize polycyclic ring junctions OCH3 O The two α-carbons have different acidities and thus reaction occurs selectively at more acidic position OCH3 O NaOCH3 CH3OH O Allows synthesis of fused polycyclic structures in high yield For example, this fused ring system is similar to steroid ring structures