Under acidic conditions, carbonyl compounds are protonated on O first, then weak base deprotonates at the α-c to give enol.

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1 Substitution reactions of carbonyl compounds at the α-position Carbonyl compounds are acidic at α-c (e.g. C 2 C ); this is because of the electrophilic nature of carbonyl C= bond. The pka values of simple carbonyl compounds are generally in between 15-20; loss of an α hydrogen is stabilized by the C= dipole. Thus under basic conditions, bases immediately deprotonate carbonyl compounds to give an enolate. - :B resonance-stabilized enolate ow important is the electronegative oxygen atom to the stabilization of the enolate? pka of an α hydrogen of C 3 C=C 2 = 43 pka of an α hydrogen of C 3 C= = 16.7 Under acidic conditions, carbonyl compounds are protonated on first, then weak base deprotonates at the α-c to give enol. 3 + / 2 resonance-stabilized enol 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? 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= bond is stronger than the C=C bond and dominates (see section 23.2 in your textbook). 1

2 More complex carbonyl compounds can be much more enolized; for example, 1,3-dicarbonyls (β-dicarbonyls) exist primarily in their enol forms pka = 9 76% enol tautomers See Table 23.2 for typical pka values for carbonyl compounds and nitriles. eactions of Enols and Enolates Both enolate and enol are nucleophilic at C (and ). 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. eaction under acidic conditions (i.e. reaction of enols): 1a. Acid-Catalyzed alogenation of Aldehydes and Ketones Aldehydes can easily be mono-halogenated at the alpha position by simply mixing the aldehyde with a halogen (usually 2 or I 2 ) and a trace of acid. IMPTANT NTE - if there are no alpha hydrogens, this reaction will not take place! when various possible enols are formed under equilibrating conditions, usually the MST STABLE enol is the one formed in the highest concentration and thus, is the one that reacts with the halide. For example, methyl cyclohexanone can 2

3 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 ell-volhard-zelinskii eaction The acid-promoted alpha halogenation only works with aldehydes and ketones. What if you need to brominate a carboxylic acid? That s where the VZ 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. omination of the enol form gives an isolable α-bromo acid bromide. P 3 2 enol form acid bromide The latter reacts like an acid chloride and can be used to generate α-bromo acid, ester, and amide. 3

4 2 N 3 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! N 2 2. eaction under basic conditions (i.e. eaction of enolates) Under sufficiently basic conditions, an enolate ion can be formed: owever, 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). ccasionally, hydroxide ion is used, but this is usually for very specific reactions (e.g. the haloform reaction). Discuss Table and - 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 C 3 CCl) will react with the oxygen anion, to give silyl enol ethers and enol 4

5 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 aloform eaction: 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: ow 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 CI 3 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 Na can generally be alkylated with alkyl iodides, bromides or tosylates, or benzylic or allylic halides. owever, 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 ethoxide is used as base why not NaMe?): 5

6 As you can see, the negative charge is delocalized over one carbon and two oxygens a very stable anion! The only significantly nucleophilic form is the one with the negative charge on the carbon, and this is the form that gets alkylated. You should note that there are two acidic protons on a malonic ester - thus it can be alkylated twice if desired. If an alkyl compound with two halogens is added, cyclic compounds can be formed. But the really cool thing about malonic esters (and acetoacetic esters, which we ll see in a minute) is a reaction called decarboxylation. nce a malonic ester is hydrolyzed, then treated with acid, the two carbonyl groups interact, and through a 6-membered ring transition state (remember how organic molecules love to react through 6-membered ring - e.g. think of the Diels Alder reaction!), one of the carbonyl groups is blown off as C 2 : Note that this is not a common reaction, and only happens with 1,3-dicarbonyl groups!!!!! Thus, malonic ester chemistry is an ideal way to make substituted acetic acids (which can then be converted to acid chlorides). Let s look at an example: Acetoacetic Ester Synthesis The acetoacetic ester synthesis is almost exactly like the malonic ester synthesis invloves a 1,3-dicarbonyl compound that is easily alkylated, and which also decarboxylates. But instead of making substituted acetic acid derivatives, this reaction makes substituted acetones. Just like in the malonic ester synthesis, the protons between the carbonyl groups are particularly acidic. They can be deprotonated with alkoxide (e.g. 6

7 NaEt), or sodium hydride, to yield the stabilized anion. Alkylation is also straightforward. The only difference comes in the decarboxylation step, where the only carboxyl group is lost to leave a methyl ketone Some things to note for both the acetoacetic ester and malonic ester synthesis (all of which are noted for the scheme below): 1) These are highly stabilized anions, and will thus add to conjugated carbonyl compounds in a 1,4 fashion. Decarboxylation leads to the vinyl-substituted compound. 2) Saponiofication and decarboxylation can occur in one step - provided the temperature is high enough (usually, C will do it). 3) Note that all esters in the molecule are saponified, but only the 1,3- dicarbonyl compounds can undergo decarboxylation. 4) As you ll see in lecture, many different electron withdrawing groups can stabilize enolate charges, and lead to a large variety of different compounds. owever, you ll only get decarboxylation if you have at least one group that can be hydrolyzed to an acid, which is separated from another carbonyl group by one carbon. For example: f course, this same ketone could be alkylated directly: The product is the same, and there are fewer steps, but the reaction conditions are much more harsh. Furthermore, if we were not working with a symmetrical ketone, a mixture of products would result. Sometimes taking a few extra steps is worth it... 7

8 With simple esters and ketones, however, direct alkylation of the enolate is usually the way to go: Notes: 1) These non-stabilized enolated are very basic - alkylation generally won t happen with anything other than primary, allylic or benzylic halides. Secondary and tertiary halides will give elimination products... 2) Again, if there is more than one way to form the enolate, you ll get a mixture of products... 8