Chapter 19: Enols and Enolates of Carbonyl Compounds and Their Reactions

 

 

         We have seen that the carbonyl group of aldehydes and ketones is highly reactive, and that additions to this functionality are common. In the present chapter we will see that not only is the carbonyl functionality reactive per se, but that it also activates nearby carbon-hydrogen bonds (specifically alpha hydrogens) to undergo a variety of substitution reactions.

 

ENOLS.

 

q      Enols are isomers of aldehydes or ketones in which one alpha hydrogen has been removed and replaced on the oxygen atom of the carbonyl group. The resulting molecule has both a C=C (-ene) and an –OH (-ol) group, so it is referred to as an enol. Strictly speaking, to be an enol the –OH and the C=C must be directly attached to one another, i.e., in conjugation with each other, as shown below.

 

 

q      We shall see that enols can be formed either by acid or base catalysis and that, once formed, they are highly reactive toward electrophiles (i.e., they are pretty strong nucleophiles). We shall also see that not all carbonyl compounds can form enols, but only those which have hydrogens of the alpha type. The carbon of an aldehyde or the two carbons of a ketone which are directly attached to the carbonyl carbon are designated as alpha carbons, and any hydrogens directly attached to these carbon atoms are termed alpha hydrogens. There can be more than one type of alpha hydrogen, or there may be no alpha hydrogens in a given carbonyl compound.

 

 

 

q      We should not be surprised at all that  in the equilibrium between a carbonyl compound and its corresponding enol, the equilibrium lies well to the carbonyl side, i.e., usually only small amounts of enol are present in the equilibrium. The preference for the carbonyl form over the enol form derives from the well-known circumstance that the C=O function is imuch more stable than the C=C function.

 

Mechanism of Acid-Catalyzed Enolization

 

q      Enol formation is called “enolization”. The mechanism whereby enols are formed in acidic solution is a simple, two step process, as indicated below:

 

q      Step 1 is simply the protonation of the carbonyl oxygen to form the conjugate acid of the carbonyl compound. Remember that proton transfers from oxygen to oxygen are virtually always extremely fast. The equilibrium of the first step is established very quickly.

 

q      The second step is the removal of an alpha proton from the conjugate acid by water acting as the base. Although both steps are relatively fast, this is the slower of the two steps. The transfer of a proton from carbon is not as fast as that from oxygen, in general.

 

 

q      The overall result is addition of a proton to the carbonyl oxygen and removal of a proton from the alpha carbon, in that order.

 

 

q      We should also note that the reverse of the second step, the protonation of the enol form,  occurs at the carbon which we call the beta carbon of the enol (the same carbon which was called the alpha carbon in the context of carbonyl chemistry) to go back to the same conjugate acid as was formed by the protonation of the carbonyl form.  A key point here is that this conjugate acid is the common conjugate acid of both the carbonyl compound and its enol form. It is the intermediate which allows them to be rapidly equilibrated. By considering the resonance structures for this conjugate acid, shown below, you can see how they relate in structure to both the carbonyl form (the oxonium structure) and the enol form (the carbocation structure).

 

 

q      When this conjugate acid loses a proton from the oxygen atom, it goes to the carbonyl compound. When it loses a proton from the alpha carbon, it goes to the enol form. Depending on whether the proton is lost from oxygen or carbon, this conjugate acid can deliver either the carbonyl form or the enol form.

 

Structure and Resonance Stabilization of the Enol.

 

 

q      Since the unshared pair of electrons on  the hydroxyl oxygen and the pi electrons of the alkene double bond are directly connected so as to be in conjugation, the two groups interact, resulting in delocalization of the electrons and resonance stabilization.

 

q      Note that the second resonance structure has charge separation, so it is not as low in energy as the first. As a result, the resonance stabilization is only modest..

 

q      The pi bond of an alkene is already nucleophilic, but that of an enol becomes even more electron-rich because of the carbanion character generated at the beta carbon. Enols therefore react extremely rapidly with electrophiles. We have already discussed their protonation. We will see that other electrophiles like bromine also react rapidly and at the beta carbon in particular.

 

Relative Stabilities of the Carbonyl and Enol Isomers

 

         In a typical carbonyl/enol equilibrium, the equilibrium constant is about 10-5 , i.e., there is only about .001% of the enol. As briefly mentioned previously, this reflects the greater stability of the C=O double bond than the C=C double bond.

 

Mechanism for Base-Catalyzed Enolization

 

q      As noted before, the enol can be generated by either an acid- or a base-catalyzed mechanism. Incidentally, at pH 7 enolization is very slow, so that either acid or base is required for enolization.

 

 

q      As in acid-catalyzed enolization, the slower step is the removal of the alpha proton.

 

q      It is important to note that the enolate is the conjugate base of both the carbonyl compound and the enol form. If the enolate is protonated on oxygen, it generates the enol (step 2 of the above mechanism), but if it protonates on carbon (see the reverse of step 1), it generates the carbonyl compound. Since there is partial negative charge on both of these, protonation can occur readily on either one.

 

 

q      Also important is the fact that this alpha proton is acidic enough to be removed rapidly by the strong base, hydroxide ion. The pKa of a carbonyl compound which has an alpha hydrogen is typically about 19, only about three powers of ten less than the pKa of water (17.7). Note that the equilibrium lies on the side of the weaker acid (the carbonyl compound; water being the stronger acid), but the K value is ca. 10-3.

 

q      Why is this proton so acidic, when C-H bond protons of alkanes typically have pKa’s of 50? Recall that anion stability is usually the controlling factor in determining relative acidities. The anion formed in this case is an enolate anion which is highly resonance stabilized, as shown above.

 

q      Recall that the rules of resonance specify that large resonance stabilizations result when there are 2 or more structures of equal energy. Usually, this happens when, as in the case of carboxylate anions, the two structures are equivalent. However, equal or near equal energies can result even when two canonical structures are not symmetry-equivalent. This is the case with an enolate anion.

 

q      In one structure, there is carbanion character and in the other oxyanion character. The latter, is of course, substantially more favorable energetically. However, the structure which has carbanion character has a carbonyl group, which is more favorable than the alkene double bond present in structure having oxyanion character. Each structure has one favorable and one unfavorable character, leading to an approximate equality in energy for the two structures. Consequently, the resonance energy is relatively large.

 

 

 

Relative Amounts of the Enolate, Enol, and Carbonyl Compound.

 

 

q      We have already seen that the enol is a minor (but mechanistically important) component of the carbonyl/enol equilibrium. The position of this equilibrium is, of course, unaffected by the pH, since it depends only upon the relative free energies of the carbonyl and enol components. On the other hand, since the pKa of carbonyl compounds having alpha type hydrogens is only ca. 10-19, there is a negligible amount of enolate present in aqueous solution at neutral pH:

 

 

q      However, the base hydroxide ion is much more powerful than the base water, so that the equilibrium --- in this case---is much more favorable, although still lying somewhat on the carbonyl side.

 

 

q      However, it will be useful for us to know that a still stronger base than hydroxide ion, e.g., the amide ion, can quantitatively convert the carbonyl compound to its enolate.

 

 

q      In contrast, at acidic pH’s, the enolate concentration is too miniscule to warrant consideration.

 

q      As a result of these considerations we can see that at neutral or acidic pH’s, there is more enol than enolate. For example, at neutral pH, the K for enolization (10-5) is much larger than the K for acid dissociation (10-19). But in the presence of hydroxide anion, there is more enolate than enol, because the equilibrium constant for conversion of an carbonyl compound to its corresponding enolate (10-3) is larger than the K for enolization (10-5).

 

Acid-Catalyzed Bromination

 

         We have seen that the enol can be generated by acid or base-catalyzed mechanisms. Also, we have seen that the enol contains an  electron-rich alkene functionality, which should be highly reactive toward electrophiles. Bromine is a very reactive electrophile, even toward simple alkenes. It should be and is enormously reactive toward enols. The net result is the substitution of a bromine atom for one of the alpha hydrogens of the carbonyl compound. Note also that carbonyl compounds without alpha hydrogens do not react with bromine at all.

 

Mechanism of Acid-Catalyzed Bromination

 

q      The first two steps are essentially identical to those in acid-catalyzed enolization. It is the enol, not the carbonyl compound, which is reactive toward bromine. The sole difference is that in the case of bromination, the second step is actually rate-determining (rather than just “slow”). This is because the enol is so reactive toward bromine that it never has a chance to reverse step 2, i.e., it is not protonated by hydronium ion to give back the conjugate acid of the carbonyl compound. So bromine reacts much more rapidly than does hydronium ion with the intermediate enol. Once formed, the enol always goes on to brominated product. The rate of enol formation is exactly equal to the rate of formation of the brominated product.

 

q       An interesting and important consequence of the fact that bromine does not take part in the reaction until after the rds is that the reaction rate (the rate of consumption of the carbonyl compound or the rate of formation of the brominated carbonyl compound) is independent of the concentration of bromine. If we double the concentration of bromine, the rate remains exactly the same or if we cut the concentration in half, the rate is not diminished at all. This is because the formation of the enol is rate-determining.

 

q      Even further, if we use chlorine rather than bromine, the rate is still the same as for bromination. The rate is not only independent of the concentration of the halogen but also of the nature of the halogen. Even though bromine is more reactive than chlorine, in general, in electrophilic additions, chlorination and bromination both occur at exactly the same rate.

 

Base-Promoted Bromination

 

         As we have noted, when hydroxide ion is present, both the enol and enolate are typically present in equilibrium with the carbonyl component. We have also seen that under these basic conditions the enolate is the predominant form. However, the enolate is also the more reactive form toward electrophiles. For both of these reasons the enolate is the reactive species of interest in basic solutions. Please keep in mind also that the carbonyl component, which is present in great excess over both the enol and enolate, is essentially unreactive toward bromine and many other electrophiles ( excluding, of course, hydronium ion).

 

Mechanism:

 

 

q      Again, as with acid-catalyzed bromination, bromine does not appear in the reaction until after the rds. The enolate reacts much more rapidly with bromine (step 2) than with water (reverse of step 1). So step 1 is never reversed, and the enolate once formed always goes on and goes on rapidly to the product.

 

q      Note that the canonical structure of the enolate which gives it carbanion character is not a charge-separated structure, as it is in the case of the enol. So the enolate has much more carbanion character than the enol, and is much more reactive towards electrophiles.

 

THE ALDOL REACTION

 

         We have seen that the enol form of a carbonyl compound, though only a minor constituent in the equilibrium mixture, is vitally important in the reaction with electrophiles. The same is true of the enolate in basic solutions. We have also seen that the enolate is a more potent nucleophile than the enol. Since the carbonyl group of the carbonyl form is strongly electrophilic and reacts with a variety of nucleophiles, it would be reasonable to expect the strongly nucleophilic enolate to be able to add to the carbonyl group of the carbonyl component (which is the major component in the equilibrium).

 

Mechanism of the Aldol Addition Reaction.

 

 

q      The “slow” step is the addition of the highly nucleophilic enolate to the electrophilic carbonyl carbon of the relatively strong carbonyl pi bond. As with most carbonyl additions, this reaction is reversible, so it is not rate determining.

 

q      Note that the aldol product is so-called because it has both an aldehyde and an alcohol moiety. It is specifically called an aldol addition because it works better with aldehydes than ketones (recall that the carbonyl pi bond of ketones is thermodynamically more stable than that of aldehydes).

 

 

q      The special importance of the reaction, is that it can be used to construct new carbon-carbon bonds, the most essential aspect of organic synthesis.

 

q      Since carbonyl compounds which do not have alpha hydrogens can not form an enolate, they cannot undergo the aldol reaction. Therefore the simplest aldehyde, methanal (formaldehyde) cannot undergo the aldol reaction.

 

The simplest case: Aldol Addition of Ethanal (Acetaldehyde)

 

 

 

q      Note that the hydroxyl group is always formed at the 3-position of the aldol product.

 

q      Also, please remember that there are two distinct “roles” in the aldol reaction for the aldehyde. These are: (1) the enolate role and (2) the carbonyl role. In viewing a given aldol product, you can see which portion of the product arose from the enolate and which from the carbonyl component.

 

 

Predicting the Structure of Aldol Addition Products

 

q      When an aldehyde more complex than ethanal is used, the structure of the aldol addition product is slightly more difficult to predict, since it will typically have one or more branches in the chain. Consider the product of the aldol reaction of propanal.

 

 

q      The branch, incidentally, always occurs on the enolate side of the aldol product. It is there because only the alpha hydrogen can be removed to form the enolate, leaving any other more remote carbons of the aldehyde as a branch.

 

 

q      You should be able to :(1) Write the detailed mechanism for the aldol addition reaction of any specified aldehyde  (2) Draw the structure of the appropriate aldol product from any specified aldehyde without having to write out the mechanism (3) Indicate, for any aldol product, which part is derived from the enolate and which from the carbonyl component .

 

The Crossed Aldol

 

q      It has been noted that in the aldol addition reaction, there are two distinct roles, that of the enolate and that of the carbonyl compound. But in this reaction, a single carbonyl compound is used as the source of both the enolate and the carbonyl components. Consequently many structures which might be desirable are not accessible because they would require two different components. Consider the hydroxyaldehyde given below:

 

 

q      If one attempted an aldol reaction between ethanal and propanal, this aldol would indeed be one of the products, but it would only be one of four different products (there are two enolates and two carbonyl components, resulting in four possible combinations, all of which are realized. Consequently, the crossed aldol is not a generally feasible reaction.

 

 

q      However, it has been noted that a number of carbonyl compounds, those which lack alpha hydrogens, are not able to form enolates at all. In many cases it is possible to perform crossed aldol reactions between one of these non-enolizable carbonyl compounds and a general aldehyde. In the examples below, benzaldehyde, pivaldehyde, and methanal are the non-enolizable carbonyl compounds.

 

 

 

q      You may notice that there are still two possible aldols since, although there is only one enolate, there are still two possible carbonyl components. That is, we can get the crossed aldol shown, but we can also get the normal aldol of the enolizable component.

 

q      In order to minimize the formation of the normal aldol product and maximize the yield of the crossed aldol product, the non-enolizable carbonyl component is kept in excess by adding the enolizable componet in a dropwise fashion to the basic solution of the non-enolizable component. Thus, when the enolate is formed, it always has a greater opportunity to react with the non-enolizable carbonyl component.

 

 

The Aldol Condensation Reaction

 

         A condensation reaction is one in which water or another small molecule, such as methanol, is formed in a reaction between two organic molecules. The aldol condensation reaction is a reaction which starts just like the aldol addition, but then subsequently the aldol adduct undergoes a further reaction, the elimination of water to generate a C=C bond in place of the alcohol function. The simplest aldol condensation reaction is illustrated below:

 

 

q      In an overall sense, the carbonyl oxygen of one molecule and two alpha hydrogens of another are eliminated as water. The reaction proceeds first to give the aldol addition product, by exactly the same mechanism as indicated previously, but because of the higher temperature employed, this aldol adduct undergoes dehydration to yield the aldol condensation product.

 

 

q      The formation of the enolate in base is expected, but the elimination of hydroxide anion is, perhaps, a little surprising, and indeed it is the slow step. The mild surprise might be that hydroxide ion is considered to be a rather poor leaving group, and it is. However, in the context of an intramolecular reaction in which the negative charge is in the same molecule as the hydroxyl group, it often occurs.

 

The Claisen Ester Condensation

 

         The carbonyl group of an ester functionality also activates any alpha hydrogens which may be present. But, since the ester group has additional resonance stabilization beyond that of a carbonyl (ester resonance), it does not activate these hydrogens quite as much as does an aldehyde or ketone. This can be seen in the pKa values of esters which have alpha hydrogens (ca. 21). Nevertheless, the enolate of an ester can be formed in small but sufficient quantities for the purposes of many reactions simply by treating the ester with a strong base such as ethoxide anion.

 

 

q      In a manner very similar to the aldol condensation of aldehydes and ketones, the enolate of an ester can add to the carbonyl group of another ester molecule. The overall result of this reaction, which is called the Claisen ester condensation, is the formation of a beta ketoester (as compared to a beta hydroxyester in the aldol addition reaction).

 

 

q      There are several new features to this mechanism, but the first two steps are essentially the same as for the aldol reaction. In the third step, however, an ethoxide anion is eliminated, resulting in the formation of a ketone function. Essentially, this step is the reverse of hemiacetal formation from a ketone function and ethoxide anion, and we know that this equilibrium is favorable to the ketone side of the equation.

 

q      Another new, and exceedingly  important, feature of this mechanism is found in the fourth and final step. An alpha type proton is abstracted by the ethoxide ion in a reaction which (please note) goes to completion. This particular hydrogen is alpha to two carbonyl groups, an ester carbonyl and a ketone carbonyl. As such it is especially highly acidic, so that the equilibrium goes to completion.

 

q      The pKa’s of protons which are alpha to two carbonyl groups is typically ca. 10. Since the acid on the right hand side of  equation 4 (ethanol) has a pKa of 16, this latter acid is the weaker acid, and the equilibrium proceeds far to the right. In fact the K value is ca. 106 (remember how to calculate K’s from the Ka’s of the reactant and product acids?).

 

q      The reason for the especially high acidity of the beta keto ester, as we have often seen, lies in anion stability. The conjugate base of this substrate is highly resonance stabilized, having three relatively good resonance structures (recall that a ketone enolate only has two).

 

q      It is important to note that without this highly favorable (exergonic) neutralization reaction, the Claisen ester condensation would not work at all. This reason for this is as follows: The net result of steps 1-3 of the mechanism is the conversion of one ester function to a ketone function, thus forfeiting the substantial ester resonance. However, the final exergonic step drives the reaction to completion.

 

q      As we have seen in other instances before, this means that the reaction is not catalytic, but promoted, which means that we have to use a stoichiometric amount of ethoxide anion, in contrast to the aldol condensation, which is catalytic in base. Finally, To obtain the ultimate product, the beta keto ester, we have to acidify the solution with strong acid in the aqueous workup. [Why wouldn’t just a neutral aqueous workup do the job?].

 

 

 

 

The Dieckmann Condensation: An Intramolecular Version of the Claisen Ester Condensation.

 

         When a difunctional ester is used, if the ester groups are positioned so that there are 4 or 5 carbon atoms between them, an intramolecular version of the Claisen condensation can occur and is especially useful in the construction of five and six-membered rings.

 

 

q      Although the extended (all anti) conformation of such a diester is the conformational minimum, other conformations are possible, and are substantially populated by facile rotations around the carbon-carbon single bonds, in which the alpha carbon of one ester function is very proximate to the carbonyl group of the other ester function (as shown in the first equilibrium above). This can lead to a cyclization reaction between the ester enolate and the other ester function present in the same molecule, affording a 5 or 6 membered ring.

 

q      The mechanism of the reaction is the same as for the standard Claisen condensation and is shown below:

 

 

q      This works efficiently because the enolate, once formed, reacts more rapidly with the carbethoxy group in the same molecule (i.e., intramolecularly) than with a carbethoxy group of another molecule (intermolecularly).

 

q      In effect, when the second ester function is present in the same molecule as the enolate, the effective concentration of the ester function is much higher than in the bulk solution.

 

q      This kind of reaction is an excellent way to synthesize relatively unstrained five and six membered rings. The following ester would yield a six-membered ring.