1 Reactions at -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. H3C CH3 H3C CH3. NUC. Another reaction that can occur with carbonyl compounds, however, is to react an electrophile with the carbonyl O E O. H3C CH3 H3 C CH2. E. The electrophile adds to the -position and allows the synthesis of a variety of substituted carbonyl compounds by reacting different electrophiles Reactions at -Position In order to react with electrophiles at the -position, the carbonyl compound needs to be nucleophilic at the -position There are two general methods to become nucleophilic at -position: 1) React through the enol form O OH O. K Br Br 5 x 10-9 H3C CH3 H3C CH2 H3 C 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 bonds Reactions at -Position 2) To make a carbonyl compound even more nucleophilic at the -position, a base can be added to form an enolate O base O O.
2 H3C CH3 H3C CH2 H3C CH2. E. O. H3 C CH2. E. The -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 -carbon and the electrophilic atom Reactions at -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. H3 C 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 -Position To form an enolate therefore a base can be reacted with a carbonyl compound to deprotonate the hydrogen on the -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 -carbon O base/nucleophile O O.
3 H3C CH3 H3C CH2 H3C CH3. NUC. Formation Reaction of enolate at carbonyl Which pathway is preferred depends on the choice of base/nucleophile used Reactions at -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 -carbon without reacting at carbonyl carbon O LDA O. H3C CH3 H3C CH2. Reactions at -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 24 25 18 24 O O O O O. H CH2 H3 C CH2 H3CO CH2 (H3C)2N CH2 HN CH3 RHC C N.
4 Aldehydes are typically Esters and amides are Amidate is more acidic lower pKa than ketones less acidic than -carbon Therefore while LDA will quantitatively deprotonate the -carbon, hydroxide or alkoxide bases (pKa ~ 16) will only deprotonate a small fraction of molecules O NaOH O O. LDA. H3 C CH2 H3C CH3 H3 C CH2. Reactions at -Position The keto/enol equilibrium is also affected by the structure of the carbonyl compound K O OH. 10-9 H3C CH3 H3 C 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 -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 -Position The amount of enol present is increased in either acidic or basic conditions H.
5 O H+ O H2O OH. H3C CH3 H3C CH3 H3C CH2. O O H2 O OH. NaOH. H3C CH3 H3 C CH2 H3C CH2. Formation of enol allows hydrogens on -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 -carbon goes from sp3 (and potentially chiral) to sp2 (and therefore planar and achiral) hybridization O. H3C CH3. O OH CH3. H+ H+. H3C CH3 H3 C CH3. or CH3 CH3 O. -carbon is chiral -carbon is planar H3 C CH3. CH3. racemic When the keto form is regenerated, the chirality at the -carbon is lost The -position therefore becomes racemic if there is an -hydrogen present Halogenation When enols are generated in the presence of dihalogen compounds, an electrophilic reaction occurs which places a halogen on the -carbon H. O H+ O H2 O OH Br Br O. Br H3C CH3 H3C CH3 H3C CH2 H3 C C.
6 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 NaOH O O. Br Br Br H3C CH3 H3 C CH2 H3 C C. H2. The enolate is more stable with an attached halogen and therefore under basic conditions the -position is polyhalogenated O O O. NaOH Br Br Br Br H3 C C H3 C C H3C CHBr2. H2 H. More stable anion Reaction will continue until all -hydrogens are replaced with halogen O Br2 O. R CH3 NaOH R CBr3. Haloform Reaction When the -carbon is a methyl group, the basic halogenation places three halogens on carbon O Br2 O. R CH3 NaOH 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 O.
7 NaOH. CHBr3. R CBr3 R CBr3 R O. 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 -position, but the acid halide needs to be formed first O O OH O. PBr3 Br2. H3C H3 C H3C H3 C. OH Br2 Br Br Br 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. H3 C H3C H3C. Br OH ! OH. H Br H Br H NH2. alanine These -bromo acids are very convenient compounds to prepare -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.
8 Allows formation of new C-C bond at the -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 -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 H2 C 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.
9 O O. 2) CH3Br H3C CH2CH3 H3CH2C CH2CH3. 1) LDA, 40 C. O 2) CH3Br O. 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 -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 -position, alkylation will then occur at the -position Alkylation of Enolates Aldehydes: O. O LDA O H CH2CH3. H CH2CH3 H CHCH3.
10 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 -alkylated imine can be hydrolyzed back to the aldehyde with water Alkylation of Enolates -dicarbonyl: O O CH3 ONa O O CH3Br O O. H3CO H3CO H3CO. CH3. A distinct advantage with -dicarbonyl compounds is the -hydrogen is more acidic and can be quantitatively deprotonated with alkoxide base When discussing carboxylic acid derivatives , also observed that when a -keto ester is hydrolyzed to the acid form a decarboxylation readily occurs O O O O O.