Chapter 21: Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
The acyl group and the five families of carboxylic acid derivatives
The compounds of this chapter share one structural feature: an acyl group, RC=O, bonded to a substituent Y that is electronegative and capable of leaving as a stable anion. That leaving group is the whole difference from Chapter 19: a nucleophile still attacks the carbonyl carbon, but the tetrahedral intermediate can now expel Y, so addition becomes substitution. The identity of Y defines the family. Chlorine gives an acid halide, a carboxylate gives an acid anhydride, an alkoxy group gives an ester, and nitrogen gives an amide. A nitrile is included with these families by convention because…
One mechanism for the whole chapter: addition, then elimination
All of the reactions in this chapter follow one mechanism, and the reason substitution at an acyl carbon is mechanistically different from substitution at an sp³ carbon lies in the geometry and the available orbitals. An sp³ carbon bearing a leaving group is attacked from the side opposite that group in a single concerted step, because there is no way to accommodate a fifth pair of electrons at carbon. An acyl carbon offers an alternative: the carbonyl π orbital accepts the incoming electron pair, and the electrons displaced from the π bond are stored on the electronegative oxygen as an…
Why the reactivity order is acid halide > anhydride > ester > amide
The rate at which a derivative undergoes nucleophilic acyl substitution spans many orders of magnitude across the four families, and the order acid halide > anhydride > ester > amide follows from two contributions that reinforce one another. The first contribution appears in the elimination step. Expelling the leaving group from the tetrahedral intermediate is easier when that group is a weak base. Chloride is the conjugate base of a strong acid and is expelled readily. A carboxylate is stabilized by its own resonance and is also a good leaving group, though not as good as chloride. An…
Acid halides: preparation and conversion to every other derivative
Acid chlorides occupy the top of the reactivity ladder and are consequently prepared from the carboxylic acid rather than from another derivative. Thionyl chloride is the usual reagent; the acid attacks sulfur, and the resulting chlorosulfite is displaced by chloride. Both by-products leave as gases, which removes them from the equilibrium and drives the reaction to completion. Oxalyl chloride serves the same purpose under milder conditions. With heteroatom nucleophiles the pattern is uniform. Hydrolysis regenerates the carboxylic acid. An alcohol gives an ester, an amine gives an amide, and…
Anhydrides: a milder acylating agent that sacrifices half of itself
An anhydride is formally two carboxylic acid units sharing one oxygen, and its chemistry follows from the fact that one of those units is an excellent leaving group. Nucleophilic addition to either carbonyl carbon gives a tetrahedral intermediate that can expel a carboxylate, a resonance-stabilized and therefore weakly basic anion. The result is that anhydrides acylate alcohols to esters and amines to amides at rates approaching those of acid chlorides, while water simply returns two equivalents of the carboxylic acid. The atom economy is poor by design. Only one of the two acyl groups…
Ester hydrolysis: saponification and its acid-catalyzed counterpart
Esters undergo hydrolysis under either basic or acidic conditions, and the two routes differ in a way that matters both mechanistically and practically. Under basic conditions, hydroxide adds directly to the carbonyl carbon to give a tetrahedral alkoxide intermediate. Collapse of that intermediate requires expelling either hydroxide, which regenerates the ester, or alkoxide, which gives the carboxylic acid. Alkoxide is the more basic group and its expulsion is intrinsically less favorable, but the reaction does not stop there: the alkoxide immediately removes the acidic proton of the…
Esters with alcohols, amines, hydride, and Grignard reagents
Beyond hydrolysis, esters undergo four transformations that recur constantly in synthesis, and three of them illustrate the same principle about intermediate reactivity. Transesterification exchanges one alkoxy group for another and is catalyzed by acid or by an alkoxide. Because the leaving alkoxide and the incoming alkoxide are of similar basicity, neither direction is intrinsically favored, and the reaction is controlled entirely by Le Châtelier's principle: the incoming alcohol is used in large excess, usually as solvent, or the displaced alcohol is removed by distillation when it is the…
Amides: delocalized nitrogen, forcing hydrolysis, and reduction to an amine
The distinctive chemistry of amides follows from a single structural fact: the nitrogen lone pair is delocalized into the carbonyl group, giving the carbon–nitrogen bond substantial double-bond character. The nitrogen is therefore planar, the carbon–nitrogen bond is about 1.34 Å rather than the 1.47 Å expected of a single bond, and rotation about it is hindered by a barrier close to 20 kcal/mol — high enough that the two methyl groups of N,N-dimethylformamide give separate NMR signals at room temperature and coalesce only on warming. The same delocalization explains why an amide nitrogen is…
Thioesters and acyl phosphates: how biology activates an acyl group
The reactivity ladder of the laboratory is unusable in a cell. Acid chlorides and anhydrides hydrolyze far too quickly in water, and ordinary esters and amides are too unreactive to transfer an acyl group at a useful rate under physiological conditions. Two intermediate activated forms occupy the gap. The thioester is the more common. Replacing the ester oxygen with sulfur changes the electronic situation in a specific way: sulfur's valence lone pair occupies a 3p orbital, which is larger and more diffuse than the carbon 2p orbital it must overlap with, so π donation into the carbonyl group…
Polyamides and polyesters from difunctional monomers
Nothing new is required to explain polymer formation from the chemistry already developed in this chapter; the only change is that each monomer carries two reactive groups instead of one. A molecule with two carboxylic acid groups, or a more reactive derivative of one, reacts at one end with a diamine, and the product still has a carboxylic acid at one end and an amine at the other. Both ends remain reactive, so condensation continues, and the result is a polyamide. Substituting a diol for the diamine gives a polyester by the same argument. Two commercial materials illustrate the pattern.…
Reading the carbonyl stretch: which derivative is it?
Infrared spectroscopy distinguishes the derivative families more cleanly than any of Chapter 12's other routine tools, and the reason is the same electronic effect that sets their reactivity. A carbonyl stretching frequency reflects the force constant of the carbon–oxygen bond. Donation of a lone pair from the attached heteroatom into the carbonyl π system adds single-bond character, weakens the bond, and lowers the frequency. Nitrogen donates most strongly, so amides absorb lowest, in the region of 1660 cm⁻¹. Oxygen donates less, and esters absorb near 1735 cm⁻¹ — slightly higher than the…
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