CHAPTER 18: FUNCTIONAL DERIVATIVES OF CARBOXYLIC ACIDS
Esters are considered to be functional derivatives of carboxylic acids in which the acidic proton has been replaced by an organic group. The synthesis of esters by the acid catalyzed condensation of a carboxylic acid and an alcohol was considered at the end of the previous chapter. We can also consider the conjugate base of a carboxylic acid, a carboxylate anion, as a functional derivative of the carboxylic acid. Two additional functional group derivatives will be considered in this chapter, viz., amides and acid chlorides. Together, these five classes of organic compounds can also be considered as acyl compounds, since they all contain the acyl group (RC=O). Aldehydes and ketones, referred to jointly as carbonyl compounds, are not considered to be acyl derivatives. The acyl compounds as a group all contain a carbon atom (the acyl carbon) in the +3 oxidation state, so that their interconversions, which are the special emphasis of this chapter, are not redox reactions. Carbonyl compounds have the +2 oxidation state of the carbonyl carbon atom.
q As noted previously, the carboxylate anion has two equivalent resonance structures and has the largest resonance stabilization of these acyl compounds.
q We have also noted extensively that the resonance stabilizations of the carboxylic acid and ester functionalities are virtually identical and both very considerable, but less than for the carboxylate anion.
We now want to consider the amide and acid chloride functionalities. First, the amide function.
q We note that the nitrogen atom of an amide has an unshared electron pair which can be shared with the electron deficient carbonyl group (see the third structure, below). The unshared pair on nitrogen is less tightly held than that on the corresponding oxygen atom of a carboxylic acid or ester, because of electronegativity considerations, so that placing a positive charge on nitrogen is less unfavorable than on oxygen. Consequently, the third resonance structure for an amide function is a more major contributor than the third canonical structure for an ester or carboxylic acid. But of course the amide does not have two equivalent resonance structures, so it is less highly resonance stabilized than the carboxylate anion. We can therefore place the amide function in between the carboxylate anion and the carboxylic acid/ester groups.
q We should also note that the nitrogen atom of an amide is sp2 hybridized, unlike the nitrogen atom of ammonia or organic derivatives of ammonia (called amines), where the nitrogen prefers the sp3 hybridization state. The reason for the sudden change in hybridization is that the sp2 hybridization state places the unshared electron pair in a 2p AO, so that the pi bonding indicated in structure three above is optimum. Otherwise the electron pair would be in an sp3 AO on nitrogen. Overlap of this type of orbital with the 2p AO on the carbonyl carbon would be much less efficient (recall that pi bonding is most efficient between p type orbitals).
q As a consequence, the nitrogen atom of amides is planar, not pyramidal as in amines or ammonia. Because of the very strong pi bonding between the nitrogen atom and the carbonyl carbon in amides, the trigonal plane of nitrogen atom is required to be coincident with the trigonal plane of the carbonyl carbon atom (also, of course, sp2 hybridized). As a result no less than six atoms are required to be coplanar, i.e., all of the atoms directly connected to the carbonyl carbon and also to the amide nitrogen atom. Specifically, these are the carbonyl carbon, its attached oxygen, the atom (R) attached to the carbonyl carbon, the nitrogen and the two atoms (R’,R’’) attached to nitrogen.
q In the case of acid chlorides, the third resonance structure is the least favorable of all of the acyl compounds, placing a positive charge on the highly electronegative chlorine atom. Also, the 3p orbital of chlorine is too large to overlap very efficiently with the much smaller 2p AO on the carbonyl carbon. Consequently, acid chlorides have the least resonance stabilization and the highest reactivity of all of the acyl derivatives.
q Recall that the esterification of a carboxylic acid is completely reversible, so that when the starting material is an ester, it can be converted to the carboxylic acid by hydrolysis in aqueous, acidic media. The overall reaction is shown below:
q Also, recall that the equilibrium constant is approximately K = 1, so that the reaction only goes to completion because a large excess of water, used as the solvent, drives it essentially to completion.
q The reaction mechanism is essentially the reverse of that written for esterification, except that the catalyst is now hydronium ion and the solvent is water (in esterification, the catalyst is the conjugate acid of the alcohol, which is often used as the solvent). The mechanism of acid catalyzed hydrolysis of an ester is written below:
BASE-PROMOTED ESTER HYDROLYSIS (SAPONIFICATION)
q If you recall, esterification of a carboxylic acid with an alcohol was not possible, because the base (presumably one would use the conjugate base of the alcohol, i.e., an alkoxide ion) reacts with the acidic proton of the carboxylic acid to yield the highly resonance stabilized, negatively charged carboxylate anion, while also neutralizing the reactive base. Even if one were to use a large exces of the alkoxide anion, it would be unable to add to this functionality at an appreciable rate.
q In contrast, an ester does not have the relatively acidic proton, so that the base (hydroxide ion) adds to the carbonyl group, leading to efficient hydrolysis of the ester.
q It should be noted that the hydroxide ion is consumed in the final step of the reaction, so that the reaction is not base-catalyzed, but rather requires a stoichiometric amount of the base. The reaction is described as base-promoted.
q Although the unavoidable consumption of the base requires that we use a mole for mole amount of sodium or potassium hydroxide, there is also a favorable aspect of this final, neturalization, step. As noted previously, the equilibrium between a carboxylic acid and an ester is not highly favorable to either ( K = ca. 1). However, the final step results in the formation of the highly resonance stabilized carboxylate anion, providing the thermodynamic driving force for driving the reaction to completion.
q The mechanism of the base-promoted ester hydrolysis is illustrated below. Note in particular that the step in which the carbonyl pi bond is broken is the “slow” step. Also that the reaction is not a direct displacement as in the case of an SN1 or SN2 reaction, but a stepwise addition/elimination process.
Amides can be hydrolyzed to carboxylic acids by either acid-promoted or base-promoted processes. We will consider in detail only the more common acid-catalyzed mechanism. As background for the acid catalyzed hydrolysis of amides, let’s consider the basicity of amides.
q As in the case of esters or carboxylic acids, there are two basic sites in an amide function which could potentially be protonated, namely the carbonyl oxygen and the amide nitrogen. Interestingly, and somewhat surprisingly, protonation of amides occurs preferentially on the carbonyl oxygen. Surprisingly, because the electron pair on trivalent nitrogen is typically much less strongly held to the nucleus than are electron pairs on neutral, divalent oxygen. An example would be the relatively high basicity of amines such as RNH2, which are very much more basic than alcohols, ketones, esters, etc.
q What is responsible for this dramatic inversion of the relative ease of protonation of oxygen and nitrogen? The same factor which caused esters and carboxylic acids to be preferentially protonated on the carbonyl oxygen, rather than the R’O type oxygen, viz., the carbonyl oxygen-protonated conjugate acid is highly resonance stabilized (see three resonance structures, including one in which the unshared pair on nitrogen is used to stabilize the cation).
q In contrast, the nitrogen-protonated conjugate acid has no resonance stabilization at all (there is only one valid resonance structure). The positive charge is also localized on an atom (N) which is directly attached to a highly electron deficient carbonyl carbon (electrostatic repulsion).
q Finally, note that because of the third resonance structure of the oxygen-protonated conjugate acid of the amide, amides are substantially more basic than carboxylate esters or carboxylic acids. This third structure has positive charge on nitrogen (ammonium character), which is much more favorable than positive charge on oxygen (oxonium character)
MECHANISM OF ACID-CATALYZED HYDROLYSIS OF AMIDES.
q NOTE: To this point, the conversion is from an amide to a carboxylic acid. Since the amide is far more resonance-stabilized than the carboxylic acid, by the end of step 5 the equilibrium lies well to the left, i.e., on the side of the starting amide.
q However, there is a sixth step which is highly exergonic and drives the equilibrium to completion. That step (see below) involves the neutralization of the hydronium ion regenerated in step 5 by the basic amine formed in step 4. Step 6 is thus an essential part of the mechanism.
q This also reveals why the reaction is not catalytic, but acid-promoted, i.e., the hydronium ion formed in step 5 is neutralized by the amine, in step 6.
BASE-PROMOTED AMIDE HYDROLYSIS.
q We will not consider the specifics of this mechanism, but we should understand that the reaction is base-promoted (not catalyzed), and that the reaction only goes to completion because of a final, neutralization step which is highly exergonic.
q This is the neutralization of the carboxylic acid by the hydroxide anion (just as in the case of base-promoted ester hydrolysis).
q The overall reaction, starting from the amide, goes to completion because the carboxylate anion has greater resonance stabilization than the amide.
q Note that the hydroxide anion is consumed quantitatively in the reaction. It must be used in an equimolar amount.
q Another practical consequence of this neutralization is that in order to obtain the carboxylic acid, one must do an acidic, aqueous workup in order to protonate the carboxylate anion, which is the primary product of the reaction.
Interestingly, although the formation of an amide functionality from a carboxylic acid is strongly exergonic and therefore thermodynamically favorable, there is no simple and effective Bronsted acid or base catalyzed or promoted mechanism for this reaction. Why not?
q Bronsted acid catalysis/promotion is frustrated by a rapid neutralization reaction between the strong acid and the basic amine required for amide formation. The use of excess acid is to no avail, because the amine has been fully converted to the conjugate acid, which is not nucleophilic at all.
q Base catalysis/promotion is also precluded by the neutralization of the carboxylic acid by the base, giving the unreactive carboxylate anion. This same result would obtain whether hydroxide ion or any other strong base (such as the conjugate base of the amine) were used.
q Thermal condensation of a carboxylic acid with an amine.
q The carboxylic acid is a weak acid, but at higher temperatures (150 – 200 oC), it can act as an acid catalyst.
q In order to use this method, the compounds (amine and carboxylic acid, as well as the product amide) must be thermally stable.
q The reaction can be accelerated toward completion by removal of water.
q Reaction of an Acid Chloride With An Amine.
o Since acid chlorides are much less thermodynamically stable than carboxylic acids, or any of the other acyl derivatives, their reactions with nucleophiles can proceed rapidly, at much lower temperatures (room temperature) and without the need for catalysis.
o This is a convenient laboratory means for preparing either amides or esters.
q Condensation of a Carboxylic Acid with An Amine via Carbodiimide Catalysis
o Many compounds (carboxylic acids or amines) are not thermally stable enough to survive the elevated temperatures required for thermal condensation between carboxylic acids and amide. They may also be too sensitive chemically to the conditions necessary for the formation of an acid chloride (see below).
o A chemically and thermally mild method for amide formation would therefore be extremely useful. Such a method is the room temperature condensation between carboxylic acids and amines catalyzed by dicyclohexylcarbodimide (R’’’ = cyclohexyl).
o This method is extensively used to prepare peptides from amino acids.
o Incidentally, the diimide is neither strongly basic nor acidic. It is, however, basic enough to be protonated on one of the imide nitrogens by the carboxylic acid. We will not write out the detailed mechanism for this powerful method for the catalysis of amidification. However, please note that the water produced in the formation of the amide link is effectively removed by combination with the diimide to yield a derivative of the very thermodynamically stable molecule urea.
q Nitriles are organic cyanides. They are often prepared by SN2 reactions of the powerfully nucleophilic cyanide anion with an organic halide.
q Note that the nitrile carbon is in the +3 oxidation state, so that although it is not an acyl derivative, it is at the same oxidation level as the other acyl derivatives.
q Therefore, nitriles can be hydrolyzed to carboxylic acids or esters by either acidic or basic hydrolysis.