UK CHE 232 - Chapter 22: Enol/Enolate Alkylations.

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Chapter 22: Enol/Enolate Alkylations.Suggested Problems: All of them!Enolization:ROH2C∂+ ∂-R'You should remember this picture from Chapter 19. The slight positive charge whichdevelops on the carbonyl carbon does more than make it a good electrophile - it also “acidifies” theprotons on the carbon next to it. In essence, it turns the pair of electrons in the π-bond into a good“leaving group” – even moderately weak bases can effect this transformation (sort of like anelimination):OHHRH∂+∂-OHOHHR+ H2OThe product of this reaction is an enolate. Enols can form under acidic conditions, but because thecarbonyl form is more thermodynamically stable, the enol is only present in tiny amounts:OHHRHH+OHHRHHOHHOHHHREnolates are stabilized by a mechanism similar to that of carboxylates - the negative chargeis stabilized over two different atoms – in this case, both a carbon and an oxygen atom. Thismethod of stabilization is present in both enols and enolates:OHHROHHROHHHROHHHRIn the presence of good electrophiles, a nucleophilic attack occurs, leading to substitutionof the alpha carbon (the carbon next to the carbonyl group).OHHROHHRE+EThe addition of electrophiles to the alpha carbon via the acid or base-induced formation of enols (orenolates) forms the bulk of the material of this chapter. Let’s begin with our first example.Reactions of Enols (i.e. Acidic conditions)Acid-Catalyzed Halogenation of Aldehydes and KetonesOur first example works under mild acidic conditions. Aldehydes can easily be mono-halogenated at the alpha position by simply mixing the aldehyde with a halogen (usually Br2 or I2)and a trace of acid. IMPORTANT NOTE - if there are no alpha hydrogens, this reaction will nottake place!OHHHH+ / Br2OHHHHHOHOHHHBrBrOHHBrHH2OHOHOHHBrOH2O / Br2 / HBrOBrH2O / Br2 / HBrONO REACTION!!!Because the various enols possible are under equilibrating conditions, usually the MOST STABLEenol is the one formed in the highest consentration - and thus the one which reacts with the halide.For example, methyl cyclohexanone can form two different enols - the more highly substituted oneis the most stable, and thus predominates:OH2O / Br2 / HBrOHOHmore stableless stableOBrThere are two major uses for these bromo-ketones and aldehydes. The first is eliminationto form conjugated carbonyl compounds. This is a classic (and simple) method for preparing suchcompounds:OHHBrwarm pyridineOHWith cyclic ketones, these halogenated compounds can undergo what is called theFavorskii reaction. This is in essence a ring-contracting reaction, and usually proceeds in goodyield. Time permitting, we will discuss this mechanism in class:OBr1) KOHOOH2) H3O+The Hell-Volhard-Zelinskii ReactionAs stated above, the acid-promoted alpha halogenation only works with aldehydes andketones. What if you need to brominate a carboxylic acid? That’s where the HVZ reaction comesin. The reaction basically takes a difficult-to-enolize carboxylic acid, and first turns it into a muchmore enolizable acid bromide. This reaction produces HBr, which then assists in the alphabromination of this acid bromide. Aqueous workup returns the acid bromide to the carboxylic acidstate. Workup with an alcohol would, of course, produce the ester.OOH1) PBr3 / Br22) H2O (or R'OH)ROOHRBr(or OR')Please remember that while this reaction can be used to form and ester, it cannot be used with anester as starting material – you must start with the carboxylic acid!OOH1) PBr3 / Br22) MeOHOOMeBrHot PyridineOOMeReactions of Enolates (i.e. basic conditions)Under sufficiently basic conditions, an enolate ion can be formed:OCB:HHHO+ BHHowever, we must generally be careful with our choice of bases – if the base is also a goodnucleophile, then attack at the carbonyl carbon becomes a more likely pathway. The most commonbases used to form enolate ions are sodium hydride (very basic, non-nucleophilic) and LithiumDiisopropylamide (LDA, very bulky, thus non nucleophilic). Occasionally, hydroxide ion is used,but this is usually for very specific reactions (e.g. the haloform reaction).The enolate ion has two nonequivalent resonance forms (compare this with both the allylanion and the carboxylate anion). The form where the charge is localized on the oxygenpredominates (because of the electronegativity of oxygen), but the form with the charge localizedon carbon is more nucleophilic, and is thus the form that typically reacts with electrophiles:OOEOEThere are a few exceptions to this rule; generally acyl and silyl halides (TMS-Cl or CH3COCl) willreact with the oxygen anion, to give silyl enol ethers and enol acetates, respectively.As you can see, alkylation of an enolate is a powerful tool for the formation of carbon-carbon bonds under relatively mild conditions. Let’s explore this reaction a bit further.The Haloform Reaction:While enolates are great for forming new carbon-carbon bonds, the first reaction we’ll lookat is a method for the destruction of a carbon-carbon bond. Essentially, the haloform reaction takesa methyl ketone (or a molecule which can be oxidized to a methyl ketone), and turns it into acarboxylic acid with one less carbon:ORI2 / NaOHORO+ HCI3How does it work? As you probably expect, the enolate is formed, and is then halogenated. Theprotons on the halogenated compound are even more acidic, thus facilitating further enolization andhalogenation. When the compound is fully halogenated (in this case, forming a CI3 group), thereare no more acidic protons, so we look for the next possible mechanistic route: nucleophilic attack.Addition-elimination as shown leads to the carboxylate anion and a haloform (in this case,iodoform):OROROORCHOHHHIIORCIHHORCIIINo more acidicprotons...HORCIIIHO OH+CI3Alkylation of Enolates:Normal enolates formed by the action of LDA or NaH can generally be alkylated with alkyliodides, bromides or tosylates, or benzylic or allylic halides. However, these reactions cansometimes be difficult to perform in high yield. A few methods do exist which allow enolatealkylations in high yield, and both take advantage of highly stabilized enolate anions: The MalonicEster synthesis, and the Acetoacetic Ester synthesis. We’ll look at each of these in detail.The Malonic Ester Synthesis.Esters of malonic acid (in this case, diethyl malonate) are easily deprotonated to form thehighly stabilized enolate (note sodium ethoxide is used as base – why not NaOMe?):OEtO OEtONaOEtOEtO OEtOOEtO OEtOOEtO


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UK CHE 232 - Chapter 22: Enol/Enolate Alkylations.

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