Reactions at α-position

Transcription

1 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 NUC NUC Another reaction that can occur with carbonyl compounds, however, is to react an electrophile with the carbonyl E C 2 E The electrophile adds to the α-position and allows the synthesis of a variety of substituted carbonyl compounds by reacting different electrophiles

2 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 keto C 2 enol Br Br C 2 Br 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

3 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 base C 2 C 2 E C 2 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

4 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 E E C 2 E Reaction at carbon C 2 C 2 C 2 Reaction at oxygen In order to make this prediction, it is important to recognize which orbital is reacting As in all nucleophilic reactions, the M of the nucleophile is reacting with the LUM of the electrophile Consider the M for the enolate nucleophile: The charge in the M 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 M of enolate Therefore the enolate reacts preferentially at the carbon site

5 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 S N 2 versus E2 reactions) A base/nucleophile used could react either by reaction at carbonyl carbon or by abstracting the hydrogen on the α-carbon base/nucleophile C 2 NUC Formation of enolate Reaction at carbonyl Which pathway is preferred depends on the choice of base/nucleophile used

6 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) N BuLi N Li 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 LDA C 2

7 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 C 2 C 2 C 2 () 2 N C 2 N RC C N Aldehydes are typically lower pka than ketones Esters and amides are less acidic 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 Na LDA C 2 C 2

8 Reactions at α-position The keto/enol equilibrium is also affected by the structure of the carbonyl compound K C 2 C 2 Both ketones and aldehydes highly favor keto form, but aldehyde have relatively more enol form present 3 β-dicarbonyl compounds have a much higher concentration of enol form due to intramolecular hydrogen bond Enol form is highly favored with phenol due to aromatic stabilization

9 Reactions at α-position The amount of enol present is increased in either acidic or basic conditions + 2 C 2 Na 2 C 2 C 2 Formation of enol allows hydrogens on α-carbon to be exchanged NaD, D 2 D+, D 2 D 3 C CD 3 D 3 C CD 3

10 Racemization of Enols and Enolates A consequence of the formation of enols or enolates is the α-carbon goes from sp 3 (and potentially chiral) to sp 2 (and therefore planar and achiral) hybridization + + or α-carbon is chiral α-carbon is planar 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

11 alogenation When enols are generated in the presence of dihalogen compounds, an electrophilic reaction occurs which places a halogen on the α-carbon + 2 C 2 Br Br Br C 2 In acidic conditions the halogenation is stopped at one addition because the protonated carbonyl compound is less stable after a halogen has been added Br C 2 Br C 2 Positive charge is less stable with adjacent C-Br bond

12 alogenation In basic conditions, however, an enolate is generated instead of an enol Na C 2 Br Br Br C 2 The enolate is more stable with an attached halogen and therefore under basic conditions the α-position is polyhalogenated Br C 2 Na C Br Br Br CBr 2 More stable anion Reaction will continue until all α-hydrogens are replaced with halogen Br 2 R Na R CBr 3

13 aloform Reaction When the α-carbon is a methyl group, the basic halogenation places three halogens on carbon Br 2 R Na R CBr 3 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 R CBr 3 Na R CBr 3 R CBr 3 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)

14 alogenation of Carboxylic Acids Carboxylic acids can also be halogenated in the α-position, but the acid halide needs to be formed first PBr 3 Br 2 Br Br Br 2 Br Br The acid halide can easily be converted back into the acid with water work-up Br Br 2 Br N 3! N 2 alanine These α-bromo acids are very convenient compounds to prepare α-amino acids with reaction with ammonia

15 Alkylation of Enolates Enolates are very useful to form new C-C bonds by reacting the enolate with alkyl halides LDA Br C 2 C 2 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 C 2 LDA 2 C C 2 or C Br Br The conditions used to form the enolate determines which is favored 2 C C 2 C

16 Alkylation of Enolates Differences in enolate formation control preferential pathway LDA C 2 2 C C 2 2 C C 2 C C ydrogen is easier to abstract, therefore this is the kinetic enolate 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) Br C 2 2 C C 2 1) LDA, 40 C 2) Br C 2 C

17 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 ther types of carbonyl compounds can also be alkylated using these conditions Esters: 1) LDA 2) Br C 2 C Acids: With esters there is only one α-position and therefore alkylation occurs at this site Na LDA Br C 2 C 2 C C With carboxylic acids, first need to deprotonate the acidic hydrogen before deprotonating at α-position, alkylation will then occur at the α-position

18 Alkylation of Enolates Aldehydes: LDA C 2 C 2 C 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 RN 2 N R LDA N R 1) Br 2) 2 C 2 C 2 C C The imine anion can react with the alkyl halide and then the α-alkylated imine can be hydrolyzed back to the aldehyde with water

19 Alkylation of Enolates β-dicarbonyl: Na Br 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 Na! 2 C C 2 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)

20 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 N N C 2 The enamine can then react with an alkyl halide to alkylate the compound N Br N 2 C 2 C 2 C 2 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

21 Aldol Reaction As mentioned when forming enolates with aldehydes a potential problem is an aldol reaction Na C 2 C 2 C 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 Alexander Borodin ( ) Borodin is more famous today as a composer, but coinvented the aldol reaction and this could just as easily been called the Borodin reaction

22 Aldol Reaction The β-hydroxy ketone compounds obtained after an aldol reaction can also be dehydrated + 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 1) Na 2) + C

23 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 Na 2 nce 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 Na 2 2 C 5-membered rings are more stable than 7-membered, typically intramolecular aldol reactions are favored in forming either 5- or 6-membered rings

24 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 Na C 2 C 2 C C C 2 2 C C 2 C C 3 3 C 2 C C 2 C 2 If the two carbonyls are both present, then the enolate could form on either nce 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

25 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 Na 2 C 2 nly 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

26 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 LDA 3C2C 2 C C 2 2 C C 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 LDA C 2 2 C C 2 C 2 C 2

27 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 Na C 2 C 2 C C C 2 2 C C 2 C C 3 3 C 2 C C 2 C 2 All obtained in ~equal yield To synthesize only one, which enolate is required can be determined from the structure 1) LDA 2) 2 C C 2 nly product C 2 C 2

28 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 Na Difference in ketone and ester pka allows ketone enolate to be formed C 2 Na β-diketone formed has an acidic methylene (pka ~10) that is deprotonated in these basic conditions

29 Claisen Condensation Claisen condensation can also occur with only an ester present Na 2 C 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 Na Rainer Ludwig Claisen ( ) Will generate a β-keto ester after acidifying the solution

30 Dieckmann Condensation An intramolecular Claisen condensation is called a Dieckmann condensation Na 2 C Ketone is more acidic than ester (6-membered ring more stable than 4) Walter Dieckmann ( ) 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 Na +, 2! The β-keto ester can then be hydrolyzed to acid and decarboxylated

31 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 N Due to the more acidic β-dicarbonyl compound, the enolate can be formed with amine base 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 ( )

32 Michael Reaction Michael reactions, or sometimes called Michael additions, can occur when the electrophile has an α,β unsaturation NUC NUC NUC NUC 1,2 addition 1,4 addition (Michael) E 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 ( ) r 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

33 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 MgBr Grignard reagents and hydride delivery agents (LA) favor 1,2 addition Stabilized nucleophiles, however, favor 1,4 addition ( ) 2 CuLi Cuprates favor 1,4 addition ther stabilized nucleophiles favoring Michael addition are β-dicarbonyl enolates and enamines

34 Michael Reaction Michael addition using β-dicarbonyl enolates Na If a β-diester is used, then the ester can be hydrolyzed and decarboxylated Michael addition using an enamine 1) +, 2 2)! N N +, 2 The imminium salts generated initially can be hydrolyzed to the ketone

35 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 1) N 2) +, 2 An advantage for the Stork reaction is that an enolate of a ketone generally reacts in a 1,2 addition Gilbert Stork (b 1921) By forming the enamine first, a Michael addition can occur instead

36 Michael Reaction We observed an example of a Michael reaction when discussing radical reactions in an earlier chapter Calicheamicin γ 1 S NC 2 Michael addition S NC 2 binding group binding group DNA Bergman cyclization S binding group C 2 N DNA diradical DNA cleavage 2 S binding group C 2 N

37 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) Na A small amount of enolate is formed by reacting a ketone with an alkoxide base 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 Na Robert Robinson ( ) Upon work-up this aldol dehydrates to form π bond C 2

38 Robinson Annulation Robinson annulation is a convenient method to synthesize polycyclic ring junctions The two α-carbons have different acidities and thus reaction occurs selectively at more acidic position Na Allows synthesis of fused polycyclic structures in high yield For example, this fused ring system is similar to steroid ring structures