Introduction
The discussion of carboxylic acids, introduced the members of the carboxylic acid family; carboxylic acids, esters, amides, anhydrides, and acyl halides. This topic looks at the latter four members of this family, with an emphasis on the formation of esters and amides.
Nucleophilic Acyl Substitution Reactions
Consider for a moment, the reactions outlined in Equations 1 and 2.
In our discussion of nucleophilic aliphatic substitution reactions we considered the experimental evidence that led to the formulation of the mechanism for reaction 1. Figure 1 reiterates that mechanism using iodide ion as both the nucleophile and the leaving group.
Figure 1
The Sn2 Mechanism
At first glance it seems reasonable to assume that reaction 2 proceeds by this same mechanism. However, the experimental results of the isotopic labeling study shown in Figure 2 show clearly that this assumption is false.
Figure 2
An Isotopic Exchange Experiment
If the reaction outlined in Figure 2 involved direct displacement of a (protonated) OH group by an isotopically labeled water molecule, then all of the label should end up in the acyl oxygen. Mass spectral analysis indicates that half of the label ends up in the acyl oxygen, while the other half is found in the carbonyl oxygen. This 50/50 distribution suggests that a symmetrical intermediate is involved in this reaction. Scheme 1 indicates how such an intermediate might be formed.
Scheme 1
Rationalizing Results
According to this scheme, the benzoic acid is activated toward nucleophilic attack by protonation of the carbonyl oxygen. This preliminary equilibrium generates oxonium ion A. In the second step, addition of a labeled water molecule to the carbonyl carbon produces the tetrahedral intermediate B. A series of proton transfers, steps 3 and 4, scrambles the label between all three oxygen atoms. Note that intermediates B, C, and D are identical except for the isotopic label. Loss of a molecule of water, step 5, produces an intermediate, resonance-stabilized, carbocation, E, in which the two OH groups are indistinguishable except for the label. In step 6, loss of a proton from either OH group, followed by reformation of the C-O double bond regenerates the benzoic acid. Since the probability of losing Ha is identical to that of losing Hb, the 18O label is evenly distributed between the two oxygen atoms of the equilibrated benzoic acid.
Exercise 1 Draw resonance structures for intermediate E in Scheme 1.
Exercise 2 How many valid resonance structures are there for intermediate E?
A key feature of the reactions shown in Scheme 1 and of nucleophilic acyl substitution reactions in general is the formation of a tetrahedral intermediate by addition of a nucleophile to the carbonyl carbon. This step is the rate determining step in all nucleophilic acyl substitution reactions. It is analogous to the first step in the nucleophilic addition reactions of aldehydes and ketones. We will consider the alternative fates of the tetrahedral intermediates involved in these two pathways shortly. First however, let's take a look at a nucleophilic acyl substitution reaction of major biological importance, namely saponification of esters.
Saponification of Esters
When methyl benzoate is refluxed with a concentrated solution of sodium hydroxide, the initially heterogeneous mixture slowly becomes homogeneous. Work-up of the reaction mixture by acidification with strong acid yields a white precipitate of benzoic acid in high yield. Equation 3 illustrates the overall reaction, while Scheme 2 outlines the sequence of transformations step-by-step.
Scheme 2
Saponification of an Ester
The reaction begins with addition of a hydroxide ion to the carbonyl carbon of the ester. This generates tetrahedral intermediate A. Regeneration of the carbonyl group in Step 2 leads to the expulsion of either the OH group that bonded to the carbonyl carbon originally (Step 2a) or to expulsion of the methoxy group (Step 2b). The former event regenerates the starting materials, while the latter produces a molecule of benzoic acid, which, in the strongly basic solution is immediately deprotonated (Step 3). The resulting sodium benzoate, being ionic, is soluble in the aqueous solution. However, protonation of the benzoate ion yields benzoic acid which is much less soluble and which precipitates from the reaction mixture.
The mechanism outlined in Scheme 2 is quite general. Esters, amides, acid halides, and anhydrides all undergo nucleophilic acyl substitution reactions by this mechanism. Consider the reactions shown in Equations 4-6.
In each case, the reaction begins with the addition of hydroxide ion to the acyl group, which produces a tetrahedral intermediate. Regeneration of the carbonyl group is accompanied by expulsion of the leaving group, either chloride ion, amide ion, or benzoate ion. The relative stabilities of these leaving groups determines the relative rates at which the starting materials react. The relative stabilities of the leaving groups is easily assessed by comparing the pKa values of their conjugate acids, which, in the case of reactions 3-6 are CH3OH (pKa=16), HCl (pKa = -7), NH3 (pKa = 38), and C6H5CO2H (pKa = 5). This means that chloride ion is the best leaving group, while amide ion is the worst. In other words, acid halides are more reactive than anhydrides, which are more reactive than esters, which are more reactive than amides towards nucleophilic aliphatic substitution. We can push the use of pKa values a bit further and say that acid chlorides are approximately 1012 times as reactive as anhydrides; anhydrides are around 1011 times more reactive than esters; esters are about 1012 times as reactive as amides. What this means is that running reaction 4 is a risky proposition; the reaction would be extremely exothermic, perhaps even causing the reactants to boil out of the flask. On the other hand, you should expect reaction 5 to require an extended period of heating before all of the benzamide reacts.
As mentioned earlier, acid halides and anhydrides are generally not synthetic targets. Rather they are used to prepare esters and amides. Equations 7-10 offer some typical examples.
In this reaction a buffer of acetic acid and sodium acetate keeps the pH high enough to insure that the 4-aminophenol is not completely protonated by the acetic acid that is formed as a side product. If the buffer were omitted, the acetic acid generated in the reaction could protonate unreacted 4-aminophenol, rendering it non-nucleophilic.
The reaction of the diacid chloride, sebacoyl chloride, with the diamine, hexmethylenediamine, results in nucleophilic acyl substitution at both ends of both molecules. The product is the well known polyamide nylon[6,6], where the symbol [6,6] indicates the number of carbons in the diacid chloride and the diamine. Nylons with different repeat units are easily prepared by variations on the reaction shown in Equation 9.
In this reaction the NaOH acts as an acid trap, neutralizing the HCl that is formed as a side product. The product of the reaction, trimetozine, is sometimes used as a sedative.
Note that in all of these reactions the nucleophilic may be described as ROH, RNH2, or R2NH. Whenever the nucleophile is electrically neutral, the nucleophilic atom must have an H attached to it in order for the substitution to be productive. Ultimately that H ends up combined with the leaving group as HCl or HOAc, etc. Thus, while ethers, ROR, and tertiary amines, R3N, both contain nucleophilic atoms, they do not react in a productive manner.
While it is possible to prepare esters from acid halides or anhydrides, the more common approach involves the direct, acid catalysed reaction of carboxylic acids with alcohols. A specific example is the esterification of salicylic acid with methanol to produce methyl salicylate, one of the major components in oil of wintergreen, as shown in Equation 11.
Many esters are fragrant compounds. For example, isoamyl acetate, which may be synthesized by the reaction of acetic acid with isoamyl alcohol as outlined in Equation 12, smells like bananas. It is also a component of the alarm pheromone of honeybees.
An interesting question involving esterification reactions like 11 and 12 involves the identities of the oxygen atoms in the reactants and products. In other words, does the OH group of the water come from the alcohol or from the carboxylic acid? The experiment outlined in Figure 3 provided the answer to this question.
Figure 3
Another Isotopic Exchange Experiment
Here the benzoic acid was mixed with isotopically labeled methanol. If methanol acts as the nucleophile, displacing (protonated) OH from the carbonyl group the first alternative should be observed. If the acyl oxygen atom acts as a nucleophile, displacing (protonated) OH from the methyl group, then the second outcome should obtain. Analysis of the methyl benzoate and water formed in the reaction revealed that all of the 18O was present in the methyl benzoate and none of it was in the water.
Although they involve an acid catalyst, esterification reactions like 11 and 12 are still nucleophilic acyl substitution reactions. The mechanism of acid catalysed esterification is similar to that outlined in Scheme 2 except that the process begins with protonation of a carbonyl oxygen atom. Scheme 3 summarizes the steps required to transform the reactants to products.
Scheme 3
Acid Catalysed Esterification
Extensions
Carboxylic acids are not the only kinds of acids that react with alcohols to produce esters. Phosphoric acid and sulfonic acids behave similarly to produce phosphate esters and sulfonate esters. Figure 4 compares the structures of these three types of acids.
Figure 4
A Comparison of Different Types of Acids
Esterification is not limited to carboxylic acids. Alcohols react with phosphoric acid to produce phosphate esters, which are important components of nucleic acids. Adensosine monophospahte (AMP) is an important phosphate ester in biological systems.
Adenosine monophosphate
Sulfonate esters are useful intermediates in organic synthesis. Figure 5 illustrates a key step in one of the first total syntheses of (-)-taxol, a natural product that is used in the treatment of ovarian cancer. The reaction involves an intramolecular nucleophilic substitution in which a primary alcohol displaces a sulfonate ester of p-toluenesulfonic acid. The tosylate group was introduced into the molecule by esterification of an alcohol in an earlier step in the synthesis.
Figure 5
The Use of a Sulfonate Ester in Organic Synthesis
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