MCAT Organic Chemistry Review: For MCAT 2015 (Graduate School Test Preparation) - P.J. Alaimo, Ph.D. 2015

Carbonyl Chemistry

6.1 ALDEHYDES AND KETONES

Two very important classes of oxygen-containing organic compounds are aldehydes and ketones. We begin the discussion of these functional groups by looking at a common way carbonyls are formed—the oxidation of an alcohol:

Note: Since the oxidizing agent removes a hydrogen from the carbon, tertiary alcohols are not able to react to form carbonyls since they have no hydrogen at the reactive site.

Oxidizing agents are able to absorb electrons (and be reduced). Below are some common oxidizing agents that appear on the MCAT. Note that only the anhydrous oxidant (PCC) will NOT overoxidize the primary alcohol to the carboxylic acid (we’ll talk more about this functional group later). All oxidizing agents shown can be used to form ketones from secondary alcohols.

Now that we understand how aldehydes and ketones are formed, let’s look at their reactivities. The key to understanding the chemistry of aldehydes and ketones is to understand the electronic structure and properties of the carbonyl group. The C=O double bond is very polarized because oxygen is much more electronegative than carbon, and so it is able to pull the π electrons of the C=O double bond toward itself and away from carbon. This is illustrated by the following resonance structures:

So overall, carbonyls react like

This bond polarization renders the carbon atom electrophilic (δ⁺) and accounts for two kinds of reactions of aldehydes and ketones. First, these molecules have acidic protons α to (i.e., next to) the carbonyl group.

An α-proton is acidic because the electrons left behind upon deprotonation can delocalize into the π system of the carbonyl. Second, the electrophilic carbon of the carbonyl group makes aldehydes and ketones susceptible to nucleophilic attack. In the aldol condensation, which we will study in some detail, both of these types of reactivity are involved in a single reaction.

Acidity and Enolization

The first type of reaction that is commonly observed with aldehydes and ketones is the result of the relative acidity of protons that are α to the carbonyl group. These α-protons are sufficiently acidic that they can be removed by a strong base [such as hydroxide ion (OH⁻) or an alkoxide ion (OR⁻)] to yield a carbanion. This carbanion can be easily formed because the electrons that are left behind on the carbon can be delocalized into the carbonyl π system. In this way, the negative charge can be delocalized onto the electronegative oxygen atom. A resonance-stabilized carbanion of this type is referred to as an enolate ion. An enolate ion is negatively charged and nucleophilic. The nucleophilic character of an enolate ion lies predominantly at the carbon at which the proton was abstracted, not the oxygen atom of the carbonyl. This is why the α-carbon of enolates is the nucleophile in most common enolate reactions.

An example that demonstrates the acidity of α-protons is the exchange reaction that occurs between the α-proton of Compound I (below) and deuterium from D₂O. Compound I has a single α-proton that is α to two carbonyl groups in comparison to the six other α-protons in the molecule that are α to only one carbonyl group. It is this lone α-proton that exchanges with a deuterium of D₂O over the course of a couple of days, even in the absence of base. Being next to two carbonyl groups greatly enhances the acidity of this α-proton and allows it to exchange (although slowly) with a deuterium from D₂O. The mechanism of this exchange, which essentially consists of protonation of the intermediate enolate ion, is shown in the following figure:

Example 6-1: As a review of acidity, for each of the following pairs of compounds, identify the one with the more acidic proton.

(a)

(b)

(c)

(d)

(e)

(f)

(g)

Solution:

(a)

(b)

(c)

(d)

(e)

(f)

(g)

Keto-Enol Tautomerism

A ketone is converted into an enol by deprotonation of an α-carbon atom and subsequent protonation of the carbonyl oxygen. These two forms of the molecule are very similar to one another and differ only by the position of a proton and a double bond. This is referred to as keto-enol tautomerism. Two molecules are tautomers if they are readily interconvertible constitutional isomers in equilibrium with one another.

Tautomerization has consequences for molecules with chiral α-carbons. Imagine an alcohol with a chiral center adjacent to the hydroxyl group (as shown below). If this stereochemically-defined alcohol were oxidized, the corresponding ketone would have racemic stereochemistry.

Because the α-carbon of the compound is sp² hybridized and planar in the enol tautomer, protonation to form the keto tautomer can occur from both the top and bottom faces of the double bond. This loss of defined stereochemistry, which results in a mixture of R and S configurations at the once chiral α-carbon, is termed racemization.

Nucleophilic Addition Reactions to Aldehydes and Ketones

Because of the polarized nature of the C=O double bond in aldehydes and ketones, the carbon of the carbonyl group is very electrophilic. This means that it will attract nucleophiles and can readily be reduced. The attack of a nucleophile upon the carbon of a carbonyl group, called a nucleophilic addition reaction, is shown below with a generic nucleophile (Nu:).

Nucleophilic addition reactions are defined by the bonding changes that occur over the course of the reaction. In these reactions, a π bond in the starting material is broken, and two σ bonds in the product result. This very general reaction allows for the conversion of aldehydes or ketones into a variety of other functional groups, such as alcohols, via hydride reduction:

Note: Sodium borohydride (NaBH₄) and lithium aluminum hydride (LiAlH₄) are common reducing agents seen on the MCAT. In general, strong reducing agents easily lose electrons by adding hydride (a hydrogen atom and a pair of electrons) to the carbonyl. Reducing agents often have many hydrogens attached to other elements with low electronegativity.

Organometallic Reagents

Organometallic reagents are commonly used to perform nucleophilic addition to a carbonyl carbon. The basic structure of an organometallic reagent is R⁻ M⁺. They act as electron rich, or anionic carbon atoms and therefore function as either strong bases or nucleophiles. Grignard and lithium reagents are the most common organometallic reagents.

Grignard reagents are generally made via the action of an alkyl or acyl halide on magnesium metal, as depicted below.

To avoid unwanted protonation of the very basic Grignard reagent, the reaction is carried out in an aprotic solvent such as diethyl ether.

The carbonyl containing compounds are then added to the Grignard reagents to yield alcohol products. In the reaction below, the methyl magnesium bromide acts as a nucleophile and adds to the electrophilic carbonyl carbon. An intermediate alkoxide ion is formed that is rapidly protonated to produce the alcohol during an aqueous acidic workup step.

In addition to using an aprotic solvent, care must also be taken to avoid the presence of any other acidic hydrogens in the substrate molecule bearing the carbonyl. This means that alcohol groups or carboxylic acid groups must be absent, or else first be protected, before the Grignard reagent can be added to the carbonyl compound.

Mesylates and Tosylates

Two commonly used strategies for the protection of alcohols are their transformation into mesylates and tosylates. By adding a mesyl (methanesulfonyl, CH₃−SO₃⁻) or tosyl group (toluenesulfonyl, CH₃C₆H₄−SO₃⁻) in the place of hydroxyl, the reactive nature of the protic, and potentially nucleophilic −OH group is removed, allowing the molecule to participate in reactions the presence of the hydroxyl may have prevented.

The formation of mesylates and tosylates from alcohols are shown below. Reaction of a sulfonyl chloride, either mesyl chloride or tosyl chloride, with an alcohol in the presence of a base (generally triethylamine or pyridine) leads to nucleophilic attack at the sulfur, followed by expulsion of the chloride.

The base in each reaction is required to neutralize the HCl (consisting of the hydroxyl proton and the chloride from the sulfonyl group) and pull it out of solution as an ammonium or pyridinium chloride salt.

These groups, particularly the tosyl group, may be similarly utilized in the protection of amino (−NH₂) groups. In either case, hydroxyl or amino, the protected functionality is rendered sufficiently inert for the purposes of the subsequent reaction steps. Once the protection is no longer required, the protecting group may be removed and the hydroxyl or amine functionality regenerated, generally under reductive conditions.

In addition to their use as protecting groups, both mesylates and tosylates are good leaving groups in reactions featuring nucleophilic attack. Whereas hydroxyl is a poor leaving group requiring a very strong nucleophile for displacement, conversion of a hydroxyl into a mesylate or tosylate makes attack and displacement facile.

Acetals and Hemiacetals

Acetals and hemiacetals, which are of fundamental importance in biochemical reactions that occur in living organisms, can be synthesized from nucleophilic addition reactions to aldehydes or ketones. There are many examples of these molecules in common biochemical pathways. Before we learn the chemistry of these groups, we must be able to identify acetals and hemiacetals.

Note: The terms ketal and hemiketal once referred to acetals and hemiacetals made from ketones, but this nomenclature has been abandoned by IUPAC.

General Formulas

Some Specific Examples

Example 6-2: For each of the following compounds, identify whether it’s an acetal, hemiacetal, or neither:

(a)

(b)

(c)

(d)

(e)

(f)

(g)

Solution:

(a) hemiacetal

(b) neither

(c) neither

(d) acetal

(e) hemiacetal

(f) acetal

(g) acetal

Acetals are formed when aldehydes or ketones react with alcohols in the presence of acid. This occurs by a nucleophilic addition mechanism. It is easy to predict the product of an acetal formation reaction. Notice that hydrogens or carbons attached to the carbonyl carbon of the aldehyde or ketone remain attached in the acetal product with the subsequent addition of two −OR groups from the alcohol. Also, note that an intermediate hemiacetal results from the addition of one −OR group to an aldehyde or ketone with subsequent protonation of the carbonyl oxygen. The aldehyde or ketone, the hemiacetal, and the acetal are all in equilibrium with one another. In order for the hemiacetal to form the acetal, a molecule of water must be lost.

Acetal Formation

The mechanism of this important reaction is shown below. In the first step, the carbonyl oxygen is protonated, making the carbonyl carbon even more susceptible to nucleophilic attack by the oxygen of the attacking alcohol molecule. Following nucleophilic attack, the oxygen of the alcohol nucleophile is positively charged. This positive charge is unfavorable, and neutrality is achieved by loss of a proton, which yields the intermediate hemiacetal. Remember that the reaction mixture is acidic so that a lone pair of electrons on the hemiacetal −OH can be protonated, thereby converting a poor leaving group into a good leaving group. Once again, this increases the electrophilicity of the carbon and makes it more susceptible to a second nucleophilic attack by an alcohol molecule. All that remains is for the positively charged oxygen from the attacking alcohol to lose a proton to yield the acetal product.

The Mechanism

The Overall Reaction

Example 6-3: Predict the acetal product from the following reactions:

(a)

(b)

(c)

(d)

Solution:

(a)

(b)

(c)

(d)

Cyanohydrin Formation

Whereas the nucleophilic attack of an alcohol or alkoxide on a ketone or aldehyde leads to the formation of a tetrahedral hemiacetal, attack by cyanide (^‒C≡N) results in the formation of a cyanohydrin. The mechanism, shown below, is very similar to the one at work in the formation of hemiacetals. While cyanohydrin formation can be technically envisioned as an equilibrium process, much like the formation of hemiacetals, the equilibrium heavily favors the products and can practically be envisioned as a one-way reaction.

Amines

Before looking at the next few examples of nucleophilic addition reactions, we should first briefly discuss the nucleophile used in the reactions—namely amines. Organic compounds that contain nitrogen are of fundamental importance in biological systems. The most common class of nitrogen-containing compounds are referred to as amines and have the general structure of R−NH₂. Amines can be further classified as either alkyl amines or aryl amines. Alkyl amines are compounds in which nitrogen is bound to an sp³-hybridized carbon, while aryl amines are compounds in which nitrogen is bonded to an sp²-hybridized carbon of an aromatic ring.

Below are a few examples of common amines.

Amines can be further categorized as primary amines, secondary amines, tertiary amines, and quaternary ammonium ions.

In the simple methyl amine, CH₃NH₂, notice that the nitrogen has three σ bonds and one lone electron pair. Its hybridization is therefore sp³ with approximately 109° bond angles. The molecular geometry of an alkyl amine is pyramidal.

Most importantly, because of the lone pair of electrons on the N, amines behave as either Brønsted-Lowry bases or as nucleophiles. Let’s now look at a few reactions in which the nucleophile is an amine.

Imine Formation

A class of reactions that closely resembles acetal formation are the reactions of aldehydes or ketones with amines. These reactions are often catalyzed under weakly acidic conditions (pH about 4-5). When an aldehyde or ketone reacts with a primary amine (RNH₂), an imine will form.

As in the acetal formation reaction, whatever R groups are originally attached to the carbonyl carbon stay attached in the product, and a molecule of water is liberated as a byproduct. A brief examination of the reaction mechanism will help illustrate these common features.

Mechanism

In the first step of this reaction, a lone pair of electrons on the carbonyl oxygen is protonated by the acidic medium. As in acetal formation, protonation of the carbonyl oxygen makes the carbonyl carbon more electrophilic and therefore more susceptible to nucleophilic attack. This time, the nucleophile is a primary amine, but attack by the nucleophilic nitrogen on the electrophilic carbon results in a similar tetrahedral intermediate. This intermediate is then deprotonated at the nitrogen and protonated at the oxygen, thereby converting a poor leaving group (−OH) into a good one (−OH₂⁺). Next, the oxygen departs as a neutral water molecule, leaving behind a carbocation that is resonance-stabilized by the lone pair of electrons on nitrogen, reminiscent of the stabilization by the incoming oxygen during acetal formation. (Note: Only the more stable resonance form is shown in the mechanism above.) The similarities to acetal formation end here, as the final step of imine production is the deprotonation of the iminium ion to regenerate the acid catalyst.

Enamine Formation

While imines are derived from primary amines, if a secondary amine (R₂NH) is used under similar reaction conditions, the result is a functional group called an enamine. The overall reaction of a typical enamine synthesis is shown below. Note that this is another reversible reaction, and that enamines can be hydrolyzed to the carbonyl compound under aqueous acidic conditions.

The mechanism of enamine formation is identical to imine formation until the final step. Since the incoming amine is secondary rather than primary, the iminium ion cannot be deprotonated as in the imine mechanism. Instead, deprotonation of a hydrogen α to the double bond, now substantially more acidic on account of the positive charge on nitrogen, yields the enamine.

Enamines are a class of organic molecules resembling enols, in which the enol-oxygen of the aldehyde or ketone is replaced by a secondary amine. The chemistry of enamines is similar to enol chemistry in that it is largely governed by the resonance between the enamine and iminium structures. The partial double-bond character in the C—N bond, implied by the iminium resonance structure, results in the sp²−hybridization of the enamine nitrogen and hindered rotation around the C—N bond (and the C—C_α bond in acyclic compounds).

As the iminium resonance form above suggests, the α-carbon of the enamine is nucleophilic and will readily react with electrophiles. The increased donor ability of nitrogen, as compared to oxygen, results in enamines being more nucleophilic than neutral enols, but less nucleophilic than charged enolates (as we’ll see shortly). As shown below, attack by the nucleophilic α-carbon on the polarized carbon of an alkyl halide results in the expulsion of the halide leaving group. This generates an iminium ion, which, as mentioned above, will reform the carbonyl under acidic, aqueous workup conditions.

Example 6-4: Predict the major organic product of each of the following reactions:

(a)

(b)

(c)

(d)

Solution:

(a)

(b)

(c)

(d)

Aldol Condensation

A classic reaction in which the enolate anion of one carbonyl compound reacts with the carbonyl group of another carbonyl compound is called the aldol condensation. This reaction combines the two types of aldehyde/ketone reactivities: the acidity of the α-proton, and the electrophilicity of the carbonyl carbon, and forms a β-hydroxycarbonyl compound as the product.

As the mechanism below shows, in the first step of this reaction, a strong base removes an α-proton from the aldehyde or ketone, resulting in the formation of a resonance-stabilized enolate anion. (Remember, the enolate anion is nucleophilic and usually reacts at the carbon atom that was deprotonated.) Next, the α-carbon of the enolate anion attacks the carbonyl carbon of another aldehyde molecule, thereby generating an alkoxide ion that is subsequently protonated by a molecule of water. This results in the formation of a general class of molecules referred to as β-hydroxy carbonyl compounds.

The Mechanism

There are three important points to note about this reaction. First, it requires a strong base (typically hydroxide, OH⁻ or an alkoxide ion RO⁻) to remove an α-proton adjacent to the carbonyl group. Second, one of the aldehydes or ketones must act as a source for the enolate ions while the other aldehyde or ketone will come under nucleophilic attack by the enolate carbanion. Third, the aldol condensation does not require the two carbonyl groups that participate in the reaction to be the same. When they are different, it is called a crossed aldol condensation reaction. In order to avoid obtaining a complex mixture of products in a crossed aldol condensation, it is often the case that one of the carbonyl compounds is chosen such that it does not have any acidic α-protons, and therefore cannot act as the nucleophile (enolate ion), it must be the electrophile.

Kinetic vs. Thermodynamic Control of the Aldol Reaction

When asymmetric ketones with more than one set of α-protons are treated with base, two different enolates are possible. When these ketones are used to perform aldol reactions, different products are formed depending on which enolate is used. Regiochemical control of such a reaction can be achieved through the choice of base and the reaction conditions, as depicted below.

The upper-pathway, run at room temperature with an unencumbered base, is said to be under thermodynamic control. In general, double bonds with more carbon-substituents (fewer vinyl-hydrogens) are more thermodynamically stable than less-substituted alkenes. In the absence of other constraints, the enolate formed by removing protons from the more sterically crowded α-carbon will be favored.

Formation of the less-substituted enolate (the lower-pathway) may be achieved by denying the base access to the more sterically hindered α-carbon. Two ways to do this include using a bulky base that cannot fit into the area required to remove the sterically-shielded proton (in this case, lithium diisopropyl amide, or LDA), or by doing the reaction at very low temperature. At a reduced temperature, there is not enough energy to overcome the activation barrier associated with the base approaching the more crowded α-carbon. Through use of these constraints, the base will deprotonate the less hindered, more kinetically accessible α-carbon. These reactions are said to be under kinetic control.

Retro-Aldol Reaction and Dehydration

Though stabilized by an intramolecular hydrogen bond between the hydroxyl and carbonyl groups, and hence generally thermodynamically stable at moderate temperatures and pH levels, β-hydroxy aldehydes and ketones are not immune to further transformations. When treated with strong bases, deprotonation of the free hydroxyl group may induce the reverse of the initial aldol condensation in a reaction known as a retro-aldol reaction. It is useful to note that the constitutive pieces of any β-hydroxy aldehyde or ketone synthesized via an aldol reaction may be determined by working through the mechanism of the retro-aldol.

If the β-hydroxyaldehyde or ketone products are heated, they will undergo an elimination reaction (dehydration) to form an α,β-unsaturated carbonyl compound. Notice that the newly formed carbon-carbon π bond is in conjugation with the carbonyl group; this stabilizes the molecule.

Example 6-5: Predict the condensation products of each of the following reactions. Show both the β-hydroxy carbonyl product and the elimination product.

(a)

(b)

(c)

(d)

Solution:

(a)

(b)

(c)

(d)

6.2 CARBOXYLIC ACIDS

Carboxylic acids are of fundamental importance in many biological systems. Fatty acids, for example, are long chain carboxylic acids that play important roles in both cellular structure and metabolism (as we’ll see in Section 7.4). In the following sections, we’ll explore the basic physical properties and common chemical reactions of carboxylic acids and their derivatives.

Hydrogen Bonding

Carboxylic acids form strong hydrogen bonds because the carboxylate group contains both a hydrogen bond donor and a hydrogen bond acceptor. This can be seen in the intermolecular hydrogen bonding of acetic acid. Notice that the acidic proton is the hydrogen bond donor and a lone pair of electrons on the carbonyl oxygen is the hydrogen bond acceptor. For this reason, carboxylic acids can form stable hydrogen bonded dimers, giving them high melting and boiling points.

Reduction of Carboxylic Acids

Earlier in the chapter we discussed the use of boron and aluminum hydrides in the reduction of ketones and aldehydes to their respective alcohols. Carboxylic acids can similarly be reduced to primary alcohols, with one important difference: LiAlH₄ is effective, but NaBH₄ is not.

As aluminum is slightly more electropositive than boron, the Al—H bond is more highly polarized, more reductive, and ultimately capable of performing these more challenging reductions.

Decarboxylation Reactions of β-Keto Acids

Carboxylic acids that have carbonyl groups β to the carboxylate are unstable because they are subject to decarboxylation. The reaction proceeds through a cyclic transition state and results in the loss of carbon dioxide from the β-keto acid.

6.3 CARBOXYLIC ACID DERIVATIVES

Carboxylic acid derivatives include acid chlorides, acid anhydrides, esters, and amides. The general chemical structures for these acid derivatives are:

As you might expect, the derivatives of carboxylic acids react similarly to aldehydes because they are also electrophilic at the carbonyl carbon atom. However, unlike reactions with aldehydes and ketones, nucleophilic additions to carboxylic acid derivatives are usually followed by elimination. (Note that additions and eliminations are opposites—while you can recognize an addition reaction because a π bond is broken and replaced by two new σ bonds, eliminations are the reverse. A new π bond is formed while two σ bonds break.) This is because the tetrahedral intermediate formed upon attack of the nucleophile on the carbonyl carbon has both a negatively charged oxygen atom (the former carbonyl oxygen), and a good leaving group (the eN-group of the carboxylic acid derivative). This elimination by the electrons on the oxygen atom regenerates the carbonyl, thereby displacing the leaving group (eN⁻). This is called a nucleophilic addition-elimination reaction, and is sometimes referred to as an acyl substitution.

Esterification Reactions

An esterification reaction occurs when a carboxylic acid reacts with an alcohol in the presence of a catalytic amount of acid.

Esterification

The following mechanism shows that protonation of the carbonyl oxygen makes the carbonyl carbon more electrophilic, and nucleophilic attack by the oxygen of the alcohol results in a tetrahedral intermediate that is neutralized by deprotonation. An −OH group of the tetrahedral intermediate is then protonated, converting a poor leaving group (−OH) into a good one (−OH₂⁺). As a result, a water molecule departs, leaving behind the protonated form of the ester. Deprotonation of the carbonyl oxygen yields the ester product and regenerates the acid catalyst.

The Acid-Catalyzed Mechanism

Acidic and Basic Hydrolysis of Esters

Let’s now examine both the acidic and basic hydrolysis of the ester methyl benzoate to form the carboxylic acid and alcohol. First, we look at the acid-catalyzed reaction:

In the first step of this reaction, the carbonyl oxygen is protonated. As before, the protonation of the carbonyl oxygen makes the carbon more electrophilic. Nucleophilic attack by a water molecule, followed by deprotonation, leads to the formation of a tetrahedral intermediate. In any nucleophilic addition-elimination reaction of an acid derivative, there will always be a tetrahedral intermediate.

Acid-Catalyzed Ester Hydrolysis Mechanism

Next, the leaving group of the tetrahedral intermediate is protonated under the acidic reaction conditions. Notice that protonation of the hydroxyl oxygens can also occur. This leads to the reverse reaction. Protonation of the leaving group converts a poor leaving group (RO⁻, an alkoxide ion) into a good one (ROH, a neutral alcohol molecule). The alcohol leaves and yields a protonated acid that only has to undergo a deprotonation to give the carboxylic acid product.

Acid-Catalyzed Mechanism, Continued

Transesterification

Not only can esters be hydrolyzed to carboxylic acids, but treatment of esters with alcohols, generally with acid catalysis, results in a process known as transesterification. Following an equivalent mechanism as shown above for hydrolysis, the nucleophilic attack by an alcohol on the electrophilic carbonyl-carbon of the ester results in the replacement of the original −OR (below depicted as EtO−) with the incoming alcohol (depicted below as isobutanol).

Like the esterification/hydrolysis reactions, the two esters exist in equilibrium, but there are a number of ways to favor the formation of the desired ester. One way is to employ conditions that remove by-products of the reaction from solution. For example, since ethanol is more volatile than isobutanol, mildly heating the reaction on the previous page will drive ethanol into the vapor phase and push the reaction to the right via Le Chatelier’s principle. Similarly, using a large excess of the alcohol constituting the desired −OR in the product serves to shift the equilibrium in the desired direction. Such conditions are indicated as in the equation below.

Placing isobutanol above or below the arrow denotes that it is used as the solvent, and is therefore in great excess. As a result, the equilibrium is essentially halted and the reaction is driven completely to the right. The reverse reaction is, of course, still possible if the isobutanol solvent is removed and replaced with ethanol.

Base-Mediated Ester Hydrolysis Mechanism

We now consider the corresponding base-mediated hydrolysis of methyl benzoate. In the first step of the reaction, the strongly nucleophilic hydroxide ion directly attacks the electrophilic carbonyl carbon. The nucleophilic attack results in the formation of a tetrahedral intermediate.

The tetrahedral intermediate then undergoes an elimination reaction, reforming the carbonyl when a pair of electrons on the negatively charged oxygen regenerates the carbon-oxygen π bond. This eliminates the alkoxide ion as a leaving group. However, since the reaction is carried out under basic conditions and the alkoxide ion is a strong enough base to deprotonate the newly formed carboxylic acid, the final step of the mechanism is the acid-base reaction shown on the previous page. In order to recover the carboxylic acid from this process, the reaction must have a final aqueous acidic workup.

In summary, these two reactions, the acid-catalyzed hydrolysis of an ester and the base-mediated hydrolysis of an ester, display the most common reactivities of all of the carboxylic acid derivatives. Both of these reactions give the same products, but by different mechanisms. Most importantly, both of the mechanisms proceed through nucleophilic addition and elimination steps. A good understanding of these two reaction mechanisms leads to a solid understanding of all of the reactions of carboxylic acids and their derivatives.

Saponification: An Example of a Base-Mediated Ester Hydrolysis Reaction

The hydrolysis of fats and glycerides is a chemical reaction that has been practiced for many centuries in the process of making soap. Typically, large vats of animal fat are treated with lye (NaOH or KOH) and stirred over a roaring fire. This bubbling cauldron liberates free fatty acids from the animal fat, which then can be utilized as soap.

Upon inspection, it is clear that this ancient method is simply the basic hydrolysis of a triacylglyceride to yield a molecule of glycerol and three fatty acids. This is the reaction mechanism we just reviewed.

The three electrophilic carbonyl carbons of the triacylglyceride sequentially undergo nucleophilic attack by hydroxide ions to produce an oxy-anion tetrahedral intermediate. Then the tetrahedral intermediate eliminates the −OR portion of the ester as an alkoxide ion which is then protonated to form the alcohol. This happens three times to ultimately yield glycerol and three molecules of fatty acid.

Fatty acids are amphipathic molecules, because they contain a negatively charged carboxylate group that is hydrophilic and a long hydrocarbon tail that’s hydrophobic. As a result, these amphipathic fatty acid molecules form micelles in water in which the hydrophobic tails associate with one another to exclude water, while the charged carboxylate groups are localized on the exterior of the micelles. Greases and fats are adsorbed by the fatty portion of these micelles and the whole micelle is “washed” away by water. This is the physical basis of soap. We will discuss this further in Chapter 7.

Synthesis of the Carboxylic Acid Derivatives

Now that we understand how the electronic structure of the carboxylic acid derivatives relates to their reactivity, the synthesis of carboxylic acid derivatives should be straightforward. For the most part, we shall only be concerned with the interconversion of one derivative to another.

Acid Halides

Carboxylic acid halides are made from the corresponding carboxylic acid and either SOCl₂ or PX₃ (X = Cl, Br).

Acid Anhydrides

As their name implies, anhydrides (meaning “without water”) can be prepared by the condensation of two carboxylic acids with the loss of water.

Acid anhydrides are also prepared from addition of the corresponding carboxylic acid (or carboxylate ion) to the corresponding acid halide.

Esters

Esters are most easily synthesized from the corresponding carboxylic acid and an alcohol, as we saw earlier. This reaction is referred to as esterification. Esters can also be prepared from an acid halide, an anhydride, or another ester and a corresponding alcohol.

Amides

Amides can be prepared from the corresponding acid halide, anhydride, or ester with the desired amine. They cannot be prepared from the carboxylic acid directly. This is because amines are very basic, and carboxylic acids are very acidic; an acid-base reaction occurs much faster than the desired addition-elimination reaction.

Carboxylic acids can be prepared from any of the derivatives merely by heating the derivative in acidic aqueous solutions.

Relative Reactivity of Carboxylic Acid Derivatives

Now that we are familiar with the general reactivity of carboxylic acid derivatives, we will examine how chemical structure affects the relative chemical reactivity of common acid derivatives. The order of reactivity in nucleophilic addition-elimination reactions for acid derivatives is:

If we examine the leaving groups of these acid derivatives, it is clear that the reactivity of acid derivatives in nucleophilic addition-elimination reactions decreases with increasing basicity of the leaving group.

Acid Derivative Reactivity

While acid chlorides and anhydrides are readily hydrolyzed in water, esters and amides are much more stable. Esters require either acidic or basic conditions and elevated temperatures in order to effect hydrolysis, and amides are generally only hydrolyzed under acidic conditions, high temperatures, and long reaction times.

Chapter 6 Summary

• The C=O bond is very polarized due to the high electronegativity of oxygen, resulting in the carbon of the carbonyl group being electrophilic.

• Protons α to a carbonyl are acidic and can be removed by a strong base to yield a nucleophilic carbanion, or enolate.

• Keto-enol tautomerism is the rapid equilibration of the more stable keto form of a carbonyl and the less stable enol form where the α-proton shifts to the carbonyl oxygen.

• Nucleophilic additions involve the attack of a nucleophile on the carbon of an aldehyde or ketone; these reactions break one π bond to form two σ bonds.

• Hydride reduction, a type of nucleophilic addition, can convert ketones or aldehydes into alcohols; alcohols can be converted back to carbonyl compounds using oxidizing agents.

• An aldol condensation is a C—C bond forming reaction where the carbonyl carbon of one molecule is the electrophile, while the α-carbon of another carbonyl compound is the nucleophile.

• The formation of a specific enolate from an asymmetrical ketone can be controlled by carefully manipulating reaction conditions. The less substituted (kinetic) enolate is formed at low temperatures with bulky bases, while the more substituted (thermodynamic) enolate is formed at higher temperatures with small bases.

• The reactivity of carboxylic acid derivatives decreases as follows: acid halide > acid anhydride > ester > amide

• Nucleophilic addition to the carbonyl carbon in a carboxylic acid derivative is usually followed by elimination due to the presence of a good electronegative leaving group.

CHAPTER 6 FREESTANDING PRACTICE QUESTIONS

1. Rank the protons from least acidic to most acidic.

A) H^a < H^b = H^d < H^c

B) H^c < H^d < H^b < H^a

C) H^c < H^b = H^d < H^a

D) H^c < H^b < H^d < H^a

2. Predict a possible product of the following reaction:

A)

B)

C)

D)

3. The enol and keto tautomers of 3-pentanone (shown below) are best described as:

A) resonance structures.

B) geometric isomers.

C) constitutional isomers.

D) diastereomers.

4. Which of the following carbonyl compounds cannot undergo a self aldol condensation?

A) 2,2,4,4-tetramethylpentan-3-one

B) 1,2,2-triphenylethanone

C) 3,3-dimethylbutan-2-one

D) pentan-2-one

5. Which of the following would increase the rate of the reaction shown below?

I. Addition of acid

II. Addition of base

III. Increased concentration of EtOH

A) I only

B) I and II only

C) I and III only

D) I, II, and III

CHAPTER 6 PRACTICE PASSAGE

Carboxylic acids play a large role in many biological pathways, including the synthesis of amino acids. Carboxylic acids and their derivatives are unlike aldehydes and ketones because they undergo addition-elimination reactions rather than simple additions. This is due to the fact that carboxylic acids and their derivatives contain a leaving group. The leaving group, in large part, determines the reactivity of the molecule. The better the leaving group is, the more reactive the molecule will be.

Carboxylic acids can be used to synthesize carboxylic acid derivatives. For example, one way to form an amide is shown in Figure 1.

Figure 1 Amide Synthesis

As their name implies, carboxylic acids have acidic properties. The first step in the reaction shown above is, in fact, an acid-base reaction that forms a salt. However, by using an excess of the amine, high temperatures, and long reaction times, the salt can be converted to the amide product. This method of amide formation is not regularly used since amides are more easily produced by reacting an amine with another carboxylic acid derivative.

1. Rank the following reagents in order of decreasing reactivity with methylamine to form a new amide product.

A) IV > II > I > III

B) II > IV > III > I

C) II > IV > I > III

D) IV > I > III > II

2. Which of the following carboxylic acids is most acidic?

A)

B)

C)

D)

3. In Figure 1 the amine acts as the:

A) electrophile.

B) leaving group.

C) catalyst.

D) nucleophile.

4. Why do carboxylic acids have a higher boiling point than esters?

A) Carboxylic acids have electronegative oxygen atoms.

B) Carboxylic acids have intermolecular hydrogen bonding.

C) Carboxylic acids are larger in size.

D) Esters have significantly larger dipole moments than do carboxylic acids.

5. Predict the product of the following reaction:

A)

B)

C)

D)

SOLUTIONS TO CHAPTER 6 FREESTANDING PRACTICE QUESTIONS

1. C Because H^a is bound to a carbon that is adjacent to two carbonyl groups, it is the easiest proton for a base to abstract since the conjugate base has the most resonance structures. Therefore, you can eliminate choice A. Because this molecule has a mirror plane, H^b and H^d are equivalent, so you can eliminate choices B and D, which leaves choice C as the correct choice. H^c is on a carbon that is not adjacent to any electron withdrawing groups or pi electrons, so it is the least acidic.

2. B This is an addition reaction involving a ketone and a Grignard reagent (RMgX). The R-group in the Grignard reagent, in this case the phenyl, adds on to the carbonyl carbon, and the acid workup step is used to protonate the carbonyl oxygen into an alcohol. This gives the product shown in choice B. Choice A can be eliminated as ketones cannot undergo substitution reactions with Grignard reagents due to lack of an appropriate leaving group. Choices C and D can be eliminated since the halogen is not the nucleophilic atom in a Grignard reagent.

3. C Tautomers do not have the same connectivity of atoms; they are constitutional isomers which are in equilibrium with one another. Choices A, B, and D all have the same connectivity of atoms.

4. A A self aldol condensation occurs between two molecules of the same compound. In order for an aldol condensation to occur, at least one of the carbonyl compounds must be able to form an enolate through deprotonation of an α-carbon. Since 2,2,4,4-tetramethylpentan-3-one contains no α-hydrogens, it cannot form an enolate, and therefore cannot undergo a self-condensation reaction. All of the other molecules listed have at least one α-hydrogen, and therefore can undergo self-condensation reactions.

5. A Although hemiacetal formation is catalyzed by both acid and base, conversion of the hemiacetal to the acetal requires a catalytic amount of acid to protonate the hemiacetal OH group so it can leave as water. The presence of base would prevent this from occurring, and slow acetal formation. Therefore, choices B and D can be eliminated, and Item I is true; it catalyzes both hemiacetal and acetal formation. Although hemiacetal formation occurs through nucleophilic addition, a bimolecular mechanism that involves both the carbonyl compound and the nucleophile (in this case, EtOH), the rate limiting step of this reaction is the conversion of the hemiacetal to the acetal. This conversion requires formation of a high-energy carbocation intermediate. Therefore, the kinetics of the rate limiting step are independent of the concentration of EtOH, and increasing its concentration would not increase the rate of the reaction.

SOLUTIONS TO CHAPTER 6 PRACTICE PASSAGE

1. C The passage mentions that acid derivatives can be combined with amines to form amides, and that the reactivity of carboxylic acid derivatives is largely determined by the leaving group. The halides are the best leaving groups due to their low basicity, and anionic stability. Therefore, Item II is the most reactive (choices A and D can be eliminated). Item I has a leaving group that contains an oxide, while Item III has a leaving group that contains a nitride. Oxide is less basic than a nitride, which makes it a better leaving group. Therefore Item III would be the least reactive, so choice B can be eliminated.

2. D The carboxylic acids in question differ in the placement of the fluorine atom on the molecule. As we know, inductive effects can dramatically affect the acidity of a compound. In this case, fluorine is highly electronegative, so it will pull electron density toward itself and weaken the O—H bond. The strongest effect will occur when the fluorine is on the carbon next to the carbonyl carbon so choices A and B can be eliminated. The difference between choices C and D is the presence of the methyl group on compound C. Since methyl groups are electron donating, they will mitigate the effect of the fluorine atom and make the acid weaker, so choice C can be eliminated.

3. D Glancing at Figure 1, we see that the amine ends up in the product. Therefore, choice C can be eliminated because catalysts are never consumed in a reaction. Choice B can be eliminated because the leaving group cannot contain nitrogen since the starting material is a carboxylic acid. Finally, choice A can be eliminated because an electrophile is an electron pair acceptor. The amine has a lone pair, which it donates.

4. B Recall that boiling point increases with overall size and increasing strength of intermolecular interactions. Choice A can be eliminated since both carboxylic acids and esters have electronegative oxygen atoms. Choice C can be eliminated because no size is specified. If choice D were true, esters would have the higher boiling points. Carboxylic acids can hydrogen bond with one another; esters cannot. Therefore, choice B is the best answer.

5. A This question tests your knowledge of the addition-elimination reaction referred to in the passage. The conditions shown will make an ester instead of an amide. The nucleophile attacks the carbonyl group and replaces the methoxy leaving group, giving us choice A. Choice B can be eliminated because in addition to the transesterification, it shows the formation of an ether via a substitution reaction, which is unlikely under these conditions. Choice C can be eliminated as it is suggestive of acetal formation, when a functional group is formed from the acid catalyzed reaction of alcohols with aldehydes or ketones. Choice D can be eliminated because it shows intramolecular esterification, which is highly unlikely because of the strain associated with a four-membered ring.