1 Substitution reactions of carbonyl com pounds at the α-position Carbonyl compounds are acidic at α-C (e.g. CHR2COR ); this is because of the electrophilic nature of carbonyl C=O bond. The pKa values of simple carbonyl compounds are generally in between 15-20; loss of an α hydrogen is stabilized by the C=O dipole. Thus under basic conditions, bases immediately deprotonate carbonyl compounds to give an enolate. HROH H-:BHROHHROHresonance-stabilized enolate How important is the electronegative oxygen atom to the stabilization of the enolate? pKa of an α hydrogen of CH3CH=CH2 = 43 pKa of an α hydrogen of CH3CH=O = 16.7 Under acidic conditions, carbonyl compounds are protonated on O first, then weak base deprotonates at the α-C to give enol. HROHH HHROHHHROHHresonance-stabilized enolHROH HH3O+/H2OHROHH H In base or in acid, carbonyl compounds that have α-hydrogens are in equilibrium with their enolate or enol forms. So, where does the equilibrium lie between the carbonyl compound and its enol form, and how does it depend on structure? OHOH Simple aldehydes and ketones are predominantly in their carbonyl forms; e.g. acetaldehyde and acetone have less than 1% of the enol tautomer present at equilibrium – the C=O bond is stronger than the C=C bond and dominates (see section 23.2 in your textbook).2 More complex carbonyl compounds can be much more enolized; for example, 1,3-dicarbonyls (β-dicarbonyls) exist primarily in their enol forms O OO OH HHOOHHH76% enol tautomerspKa = 9 See Table 23.2 for typical pKa values for carbonyl compounds and nitriles. Reactions of Enols and Enolates Both enolate and enol are nucleophilic at C (and O). For example, enolates react in the presence of good electrophiles by undergoing substitution of the alpha carbon. The addition of electrophiles to the alpha carbon via the acid- or base-induced formation of enols or enolates is quite common. 1. Reaction under acidic conditions (i.e. reaction of enols): 1a. Acid-Catalyzed Halogenation of Aldehydes and Ketones 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! when various possible enols are formed under equilibrating conditions, usually the MOST STABLE enol is the one formed in the highest concentration and thus, is the one that reacts with the halide. For example, methyl cyclohexanone can3 form two different enols - the more highly substituted one is the most stable, and thus predominates: 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: 1b. The Hell-Volhard-Zelinskii Reaction 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. Aqueous workup returns the acid bromide to the carboxylic acid state. Workup with an alcohol would, of course, produce the ester. the first step is formation of the acid bromide, which is in equilibrium with its enol form. Bromination of the enol form gives an isolable α-bromo acid bromide. OHROHHBrROHHBrROHHBrROBrHPBr3Br2acid bromideenol form The latter reacts like an acid chloride and can be used to generate α-bromo acid, ester, and amide.4 BrROBrHHORORROBrHNH2ROBrHNH3H2OOHROBrH Please remember that while this reaction can be used to form an ester, it cannot be used with an ester as starting material – you must start with the carboxylic acid! 2. Reaction under basic conditions (i.e. Reaction of enolates) Under sufficiently basic conditions, an enolate ion can be formed: 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). Discuss Table 23.3 – HO- and RO- bases are more useful for forming enolates from 1,3-dicarbonyl compounds or in reactions that involve both the enolate and carbonyl starting material. 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: 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 enol5 acetates, respectively. As you might expect, alkylation of an enolate is a powerful tool for the formation of carbon-carbon bonds under relatively mild conditions. 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: 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): 2b. 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