Enol/Enolate Alkylations. Enolization: ROH2C!+ !-R' You should remember this picture from previous notes. The slight positive charge which develops on the carbonyl carbon does more than make it a good electrophile - it also “acidifies” the protons 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 an elimination): OHHRH!+!-OHOHHR+ H2O The product of this reaction is an enolate. Enols can form under acidic conditions, but because the carbonyl form is more thermodynamically stable, the enol is only present in tiny amounts: OHHRHH+OHHRHHOHHOHHHR Enolates are stabilized by a mechanism similar to that of carboxylates - the negative charge is stabilized over two different atoms – in this case, both a carbon and an oxygen atom. This method of stabilization is present in both enols and enolates: OHHROHHROHHHROHHHR In the presence of good electrophiles, a nucleophilic attack occurs, leading to substitution of 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 (or enolates) 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 Ketones Our 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 not take place! OHH HH+ / Br2OHHH HHOHOHHHBrBrOHH BrHH2OHOHOHH Br OH2O / Br2 / HBrOBrH2O / Br2 / HBrONO REACTION!!! Because the various enols possible are under equilibrating conditions, usually the MOST STABLE enol 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 one is the most stable, and thus predominates:OH2O / Br2 / HBrOHOHmore stableless stableOBr There are two major uses for these bromo-ketones and aldehydes. The first is elimination to form conjugated carbonyl compounds. This is a classic (and simple) method for preparing such compounds: OHH Brwarm pyridineOH With cyclic ketones, these halogenated compounds can undergo what is called the Favorskii reaction. This is in essence a ring-contracting reaction, and usually proceeds in good yield. Time permitting, we will discuss this mechanism in class: OBr1) KOHOOH2) H3O+ The Hell-Volhard-Zelinskii Reaction As stated above, the acid-promoted alpha halogenation only works with aldehydes and ketones. What if you need to brominate a carboxylic acid? That’s where the HVZ reaction comes in. The reaction basically takes a difficult-to-enolize carboxylic acid, and first turns it into a much more enolizable acid bromide. This reaction produces HBr, which then assists in the alpha bromination of this acid bromide. Aqueous workup returns the acid bromide to the carboxylic acid state. 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 an ester 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+ BH However, we must generally be careful with our choice of bases – if the base is also a good nucleophile, then attack at the carbonyl carbon becomes a more likely pathway. The most common bases used to form enolate ions are sodium hydride (very basic, non-nucleophilic) and Lithium Diisopropylamide (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 allyl anion and the carboxylate anion). The form where the charge is localized on the oxygen predominates (because of the electronegativity of oxygen), but the form with the charge localized on carbon is more nucleophilic, and is thus the form that typically reacts with electrophiles: OOEOE There are a few exceptions to this rule; generally acyl and silyl halides (TMS-Cl or CH3COCl) will react 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 look at is a method for the destruction of a carbon-carbon bond. Essentially, the haloform reaction takes a methyl ketone (or a molecule which can be oxidized to a methyl ketone), and turns it into a carboxylic acid with one less carbon: ORI2 / NaOHOR O+ HCI3 How does it work? As you probably expect, the enolate is formed, and is then halogenated. The protons on the halogenated compound are even more acidic, thus facilitating further enolization and halogenation. When the compound is fully halogenated (in this case, forming a CI3 group), there are 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):OROR OOR CHOHHHI IOR CIHHOR CIIINo more acidicprotons...HOR CIIIHO OH+CI3 Alkylation of Enolates: Normal enolates formed by the action of LDA or NaH can generally be alkylated with alkyl iodides, bromides or tosylates, or benzylic or allylic halides. However, these reactions can sometimes be difficult to perform in high yield. A few methods do exist which allow enolate alkylations in high yield, and both take advantage of highly stabilized enolate anions: The Malonic Ester 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 the highly stabilized enolate (note sodium