CHAPTER 19:ENOLATE ANIONS:NOTES
THIS UNIT DEALS WITH BOTH
ENOLS AND ENOLATES. THE
DISCUSSION OF ENOLS IS IN YOUR
TEXT IN CH. 16 ON PP.577-582.
WE HAVE SEEN THAT THE REACTIVITY OF CARBONYLCOMPOUNDS (ALDEHYDES AND KETONES) OFTEN FOCUSES UPON ADDITION TO THE CARBONYL GROUP.HOWEVER, THE PRESENCE OF THIS CARBONYL GROUP CAN ALSO HIGHLY ACTIVATE NEARBY CARBON-HYDROGEN BONDS (CALLED ALPHA HYDROGENS) TO UNDERGO VARIOUS SUBSTITUTION REACTIONS. THESE ARE THE REACTIONS WHICH WE WILL FOCUS ON INTHIS UNIT.
ENOLS ARE ISOMERS OF ALDEHYDES OR KETONES IN WHICH ONE ALPHA HYDROGEN HAS BEEN REMOVED AND PLACED ON THE OXYGEN ATOM OF THE CARBONYL GROUP. THE MOLECULE HAS A C=C AND AN -OH GROUP, SO IT IS CALLED AN ENE/OL, I.E., AN ENOL.ENOLS CAN BE FORMED ONLY FROM CARBONYL COMPOUNDS WHICH HAVE ALPHA HYDROGENS. THEY CAN BE FORMED BY ACID OR BASE CATALYSIS, AND ONCE FORMED ARE HIGHLY REACTIVE TOWARD ELECTROPHILES, LIKE BROMINE.
MECHANISM OF ACID CATALYZED ENOLIZATION . The process of enol formation is called "enolization". It requires either acid or base catalysis. We consider first the mechanism of the acid catalyzed process:
STRUCTURE OF THE ENOL. The C=C of an enol is very electron rich, because of the hydroxyl substituent, which can donate an electron pair via the resonance structure shown below. It is therefore quite nucleophilic, even more so than the typical C=C. It therefore reacts very rapidly with electrophiles, such as bromine, to result in overall substitution of Br for H at the alpha carbon atom. The mechanism for acid catalyzed bromination is given below:
DL/PC Structure of the Enol
RELATIVE STABILITY OF THE ENOL AND KETO TAUTOMERS. Isomers which differ only in shifting a hydrogen from one atom to another are often called tautomers. Enols and their corresponding keto isomers are tautomers. The keto tautomer is typically much more stable than the enol form, with K's of about 10 to the -5th power. You should know that this is essentially because the C=O double bond is much more stable than the C=C double bond.
FORMATION OF BOTH THE ENOL AND ENOLATE UNDER BASIC CONDITIONS. The formation of an enol under base catalysis involves the intermediate formation of an enolate, the conjugate base of the carbonyl compound. So we will first consider the formation of an enolate, beginning with the dissociation of a carbonyl compound in aqueous solution to give its conjugate base (that is, we consider the acidity of the carbonyl compound).
Acidity of Carbonyl Compounds.
In aqueous solution, an aldehyde or ketone which has an alpha type hydrogen can lose it to water, giving hydronium ion and the conjugate base of the carbonyl compound, which is called an enolate. This C-H bond is significantly less acidic than the O-H bond of an alcohol and much less acidic than the O-H bond of a carboxylic acid. The pK's are typically about 19-20. Nevertheless, they are outstandingly acidic for H's bond to carbon. The reason for this is the strong resonance stabilization of the enolate, which has both carbanion and alkoxide character (see the resonance structures above). Both resonance structures are comparably stable, so that the resonance stabilization is large. Although the C=C double bond of the alkoxide structure is less stable than the C=O of the carbanion structure, the former has negative charge on oxygen, which is better than having the negative charge on carbon.
Base Catalyzed Enolate Formation.
The mechanism for enolate formation in aqueous base is shown above: This reaction is fast, but the equilibrium is somewhat unfavorable (the pKa of water is ca. 16, while that of the ketone is ca.19-20. However, there is easily enough enolate present to observe efficient reactions since it (the enolate) is a powerful nucleophile.
The Equilibrium between Ketone and Enolate in Aqueous Base: How to calculate the position of the equilibrium using a qualitative criterion and a quantitative criterion; Quantitative generation of the enolate.(Important)
Further, stronger bases can be used to drive the equilibrium to completion. such as base would be an amide base (LDA, lithium diisopropylamide, the conjugate base of an amine (pK 38, i.e., about same as ammonia) . Amide ion (NH2 anion) is basic enough, but it is also nucleophilic enough to add to the carbonyl carbon, irreversibly. Instead, the more hindered amide base LDA is used preferentially.
Base Catalyzed Formation of the Enol. When the enolate is formed, it can abstract a proton at either oxygen or carbon, both being positions of partial negative charge. Protonation at oxygen gives the enol, which protonation of carbon yields back the keto form. Thus, the enolate is the conjugate base of both the keto and enol forms. any time the enolate is formed in water or a hydroxylic solvent, it will be in equilibrium with both the enol and the ketone.
Relative Amounts of Enolate and Enol.
Both the enolate and enol are minor components in equilibrium with the ketone or aldehyde at netural pH. Since the K for enol formation is larger, there is much more enol than enolate (see the K values for acid dissociation vs. enol formation). However, in the presence of strong base, the enol equilibrium is unaffected, but the amount of enolate increases. So the amount of enolate may easily exceed that of the enol in basic solutions. In acidic solutions, there will be very little enolate (it will be protonated to give the enol and keto forms, the neutral forms).
Bromination of the Enol (Acid Catalyzed Bromination). Both the enol and the enolate provide an opportunity to effect substitution reactions at the carbon alpha to (attached to) the carbonyl carbon, assuming that at least one hydrogen atom is attached to this carbon (an alpha hydrogen), thus permitting enol and enolate formation. In acidic solution, essentially only the enol is present. Nevertheless, the C=C of the enol is nucleophilic and reactive toward electrophiles, especially reactive electrophiles like bromine.The mechanism of this reaction is shown below. Note that the "carbocation" intermediate, which is involved in this electrophilic reaction is actually the conjugate acid of the product, which is an alpha bromoketone or aldehyde. That is, there are two major resonance structures, and the ion has both carbocation character and oxonium character.The mechanism shown below assumes that the enol has been formed by the acid catalyzed mechanism already discussed.
Mechanism of the Reaction of Bromine with an Enol
In Acidic Solution, Enol Formation is Rate Determining! The subsequent reaction of the enol with bromine is very fast, so that the enol is prevented from returning to the keto form.
Details of the Mechanism of Acid Catalyzed Bromination of Carbonyl Compounds.
Mechanism of Base Promoted Bromination of Carbonyl Compounds.
THE ALDOL ADDITION REACTION.
The overall reaction and its mechanism are illustrated for the simplest aldehyde which undergoes the reaction, ethanal (acetaldehyde). [Incidentally, why does methanal note undergo the reaction?] The special importance of the reaction is that it forms a new C-C bond. It does this, in basic solution,by using the enolate as a nucleophile which adds to the electrophilic carbonyl carbon. The slow step is the addition to the carbonyl group, as usual. The product is both an aldehyde and an alcohol (-ol), therefore it was called an "aldol". The IUPAC name in this particular case is 3-hydroxybutanal.Incidentally, the reaction also proceeds in acidic solution, using the enol as the nucleophile and the conjugate acid of the aldehyde as a stronger electrophile.
Mechanism of the aldol addition:
RELATIVE REACTIVITIES OF THE ENOLATE, ENOL, AND A SIMPLE ALKENE. Recall that even simple alkenes are relatively nucleophilic (they react with electrophiles via the pi bond). The enol is more so because the -OH substituent donates electrons to the pi bond (see resonance structures for the enol, above). In other words, the enol has some carbanion character at the carbon beta to the hydroxyl group. The enolate, being negatively charged , is even more nucleophilic than the enol (please see scheme 18.7). In terms of resonance structures, the second resonance structure of the enol has charge separation and is a relatively minor contributor. In the enolate, neither structure has charge separation and both structures are relatively close together in energy. One structure has the stronger C=O bond, but the other has negative charge on oxygen rather than carbon.
THE ALDOL ADDITION MORE GENERALLY. It is important to note that an unbranched aldehyde, even a simple one like propanal, gives a branched aldol, because the enolate or enol always is formed at the alpha position to the carbonyl group. The branching therefore occurs alpha to the aldehyde functional group, not alpha to the hydroxyl group of the aldol. You should be able to predict the structure of an aldol product from any aldehyde or ketone. As you would expect, the aldol reaction works better with aldehydes than with ketones, because the equilibrium is less favorable for ketones (recall the greater thermodynamic stability of the ketone carbonyl). We will see how this problem can be resolved.
THE ALDOL CONDENSATION REACTION. The somewhat greater difficulty with which ketones are converted to their corresponding aldol products can be partially circumvented by carrying out the reaction as an aldol condensation reaction. In this reaction, in which the conditions are essentially the same as for the aldol addition, except that the reaction is warmed to RT or above, the initially formed aldol product is dehydrated to give an alpha,beta unsaturated carbonyl compound.
Mechanism of the Aldol Condensation
RESONANCE STRUCTURES FOR THE ENONE
THE INTRAMOLECULAR ALDOL CONDENSATION. If two carbonyl groups are present in the same molecule, the aldol condensation can be carried out intramolecularly, one carbonyl group providing the source of the enolate and the other providing the carbonyl function. In most cases only the more stable 5 and 6 memebered rings are formed. See the Scheme below for one example.
Sketch of the Intramolecular aldol mechanism:
THE CROSSED ALDOL REACTION.
For a reaction of broader scope, it would be nice to be able to use two different carbonyl compounds in the aldol, since two different roles (enolate and carbonyl) are involved. However, if one does this in the most naieve way, as shown below, four different compounds can result, and generally will if both compounds have the ability to fulfill both roles. The Four Products from a crossed aldol reaction between ethanal and propanal
There are two requirements for this procedure to be effective:
THE DIRECTED ALDOL REACTION: A MORE GENERAL SOLUTION TO THE PROBLEMS OF THE NARROW SCOPE OF THE CROSSED ALDOL REACTION IS THE DIRECTED ALDOL.