Carboxylic Acids.

The carboxyl functional group that characterizes the carboxylic acids is unusual in that it is composed of two functional groups described earlier in this text. As may be seen in the formula on the right, the carboxyl group is made up of a hydroxyl group bonded to a carbonyl group. It is often written in condensed form as –CO₂H or –COOH. Other combinations of functional groups were described previously, and significant changes in chemical behavior as a result of group interactions were described (e.g. phenol & aniline). In this case, the change in chemical and physical properties resulting from the interaction of the hydroxyl and carbonyl group are so profound that the combination is customarily treated as a distinct and different functional group.

The carboxylic group is the functional group of the carboxylic acids. It is kind of a combined carbonyl and hydroxyl group. The carbon atom in the group has sp² hybridization. The carbon atom has a double bond to one oxygen atom a single bond to the other. This other oxygen atom is also bonded to a hydrogen atom. It is this hydrogen atom that gives these compounds their acidic properties and the “acid” part of their names

In carboxylic acids, the bonds to the carboxyl carbon lie in one plane and are separated by about 120°. The carboxylic carbon is less electrophilic than carbonyl carbon because of the possible resonance structure shown below:

Structure of the Carboxyl Group

The most stable conformation of formic acid is an almost planar arrangement of the molecule.

The carbon is sp² hybridized , and the O-H bond lies in the plane described by the sp² carbon, eclipsing the C=O double bond.

This unexpected geometric arrangement can be explained by resonance (or conjugation).

Classification of Carboxylic Acids

I. Considering the hydrocarbonate radicals nature in the molecule, organic acid are being classified in:

a) Saturated acid is acid, which has only simple bonds in molecule.

For example:

acetic acid propionic acid

b) Unsaturated acid is acid, which has both as simple and double bounds in molecule.

For example:

acrylic acid oleic acid

c) aromatic acid is acid, which contain aromatic ring.

II. Considering the number of carboxyl groups in the molecule, acids can be classified in:

a) mocarboxylic acids are acids group in molecule.

For example:

acetic acid butanoic acid

b) dicarboxylic acids are acids which has two carboxylic groups in molecule.

For example:

c) policarboxylic acids are acids which has more than two carboxylic groups in molecule.

For example:

tricarboxylic acid - Citric acid

Physical Properties

The first three members are colourless liquids and have pungent smell. The next six members are oily liquids with a faint unpleasant odour. Still higher acids are colourless waxy solids.

They have higher boiling points than the corresponding alcohols of comparable molecular masses. Carboxylic acids have higher boiling points due to the presence of intramolecular hydrogen bonding. Due to the hydrogen bonding, carboxylic acids exist as dimers. The first four members of aliphatic carboxylic acids are very soluble in water. The solubility in water decreases gradually with rise in molecular mass. All are soluble in alcohol or ether. Benzoic acid is sparingly soluble in cold water but is soluble in hot water, alcohol and ether.

1. Nomenclature of Carboxylic Acids

As with aldehydes, the carboxyl group must be located at the end of a carbon chain. In the IUPAC system of nomenclature the carboxyl carbon is designated #1, and other substituents are located and named accordingly. The characteristic IUPAC suffix for a carboxyl group is "oic acid", and care must be taken not to confuse this systematic nomenclature with the similar common system. These two nomenclatures are illustrated in the following table, along with their melting and boiling points.

Formula	Common Name	Source	IUPAC Name	Melting Point	Boiling Point
HCO2H	formic acid	ants (L. formica)	methanoic acid	8.4 ºC	101 ºC
CH3CO2H	acetic acid	vinegar (L. acetum)	ethanoic acid	16.6 ºC	118 ºC
CH3CH2CO2H	propionic acid	milk (Gk. protus prion)	propanoic acid	-20.8 ºC	141 ºC
CH3(CH2)2CO2H	butyric acid	butter (L. butyrum)	butanoic acid	-5.5 ºC	164 ºC
CH3(CH2)3CO2H	valeric acid	valerian root	pentanoic acid	-34.5 ºC	186 ºC
CH3(CH2)4CO2H	caproic acid	goats (L. caper)	hexanoic acid	-4.0 ºC	205 ºC
CH3(CH2)5CO2H	enanthic acid	vines (Gk. oenanthe)	heptanoic acid	-7.5 ºC	223 ºC
CH3(CH2)6CO2H	caprylic acid	goats (L. caper)	octanoic acid	16.3 ºC	239 ºC
CH3(CH2)7CO2H	pelargonic acid	pelargonium (an herb)	nonanoic acid	12.0 ºC	253 ºC
CH3(CH2)8CO2H	capric acid	goats (L. caper)	decanoic acid	31.0 ºC	219 ºC

Substituted carboxylic acids are named either by the IUPAC system or by common names. If you are uncertain about the IUPAC rules for nomenclature you should review them now. Some common names, the amino acid threonine for example, do not have any systematic origin and must simply be memorized. In other cases, common names make use of the Greek letter notation for carbon atoms near the carboxyl group. Some examples of both nomenclatures are provided below.

Simple dicarboxylic acids having the general formula HO₂C–(CH₂)_n–CO₂H (where n = 0 to 5) are known by the common names: Oxalic (n=0), Malonic (n=1), Succinic (n=2), Glutaric (n=3), Adipic (n=4) and Pimelic (n=5) Acids. Common names, such as these can be troublesome to remember, so mnemonic aids, which take the form of a catchy phrase, have been devised. For this group of compounds one such phrase is: "Oh My Such Good Apple Pie".

2. Carboxylic Acid Natural Products

Carboxylic acids are widespread in nature, often combined with other functional groups. Simple alkyl carboxylic acids, composed of four to ten carbon atoms, are liquids or low melting solids having very unpleasant odors. The fatty acids are important components of the biomolecules known as lipids, especially fats and oils. As shown in the following table, these long-chain carboxylic acids are usually referred to by their common names, which in most cases reflect their sources. A mnemonic phrase for the C₁₀ to C₂₀ natural fatty acids capric, lauric, myristic, palmitic, stearic and arachidic is: "Curly, Larry & Moe Perform Silly Antics" (note that the names of the three stooges are in alphabetical order).
Interestingly, the molecules of most natural fatty acids have an even number of carbon atoms. Analogous compounds composed of odd numbers of carbon atoms are perfectly stable and have been made synthetically. Since nature makes these long-chain acids by linking together acetate units, it is not surprising that the carbon atoms composing the natural products are multiples of two. The double bonds in the unsaturated compounds listed on the right are all cis (or Z).

FATTY ACIDS

Saturated
Formula	Common Name	Melting Point
CH3(CH2)10CO2H	lauric acid	45 ºC
CH3(CH2)12CO2H	myristic acid	55 ºC
CH3(CH2)14CO2H	palmitic acid	63 ºC
CH3(CH2)16CO2H	stearic acid	69 ºC
CH3(CH2)18CO2H	arachidic acid	76 ºC

Unsaturated
Formula	Common Name	Melting Point
CH3(CH2)5CH=CH(CH2)7CO2H	palmitoleic acid	0 ºC
CH3(CH2)7CH=CH(CH2)7CO2H	oleic acid	13 ºC
CH3(CH2)4CH=CHCH2CH=CH(CH2)7CO2H	linoleic acid	-5 ºC
CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7CO2H	linolenic acid	-11 ºC
CH3(CH2)4(CH=CHCH2)4(CH2)2CO2H	arachidonic acid	-49 ºC

The following formulas are examples of other naturally occurring carboxylic acids. The molecular structures range from simple to complex, often incorporate a variety of other functional groups, and many are chiral.

3. Related Carbonyl Derivatives

Other functional group combinations with the carbonyl group can be prepared from carboxylic acids, and are usually treated as related derivatives. Five common classes of these carboxylic acid derivatives are listed in the following table. Although nitriles do not have a carbonyl group, they are included here because the functional carbon atoms all have the same oxidation state. The top row (yellow shaded) shows the general formula for each class, and the bottom row (light blue) gives a specific example of each. As in the case of amines, amides are classified as 1º, 2º or 3º, depending on the number of alkyl groups bonded to the nitrogen.

Functional groups of this kind are found in many kinds of natural products. Some examples are shown below with the functional group colored red. Most of the functions are amides or esters, cantharidin being a rare example of a natural anhydride. Cyclic esters are called lactones, and cyclic amides are referred to as lactams. Penicillin G has two amide functions, one of which is a β-lactam. The Greek letter locates the nitrogen relative to the carbonyl group of the amide.

Properties of Carboxylic Acids

1. Physical Properties of Carboxylic Acids

The table at the beginning of this page gave the melting and boiling points for a homologous group of carboxylic acids having from one to ten carbon atoms. The boiling points increased with size in a regular manner, but the melting points did not. Unbranched acids made up of an even number of carbon atoms have melting points higher than the odd numbered homologs having one more or one less carbon. This reflects differences in intermolecular attractive forces in the crystalline state. In the table of fatty acids we see that the presence of a cis-double bond significantly lowers the melting point of a compound. Thus, palmitoleic acid melts over 60º lower than palmitic acid, and similar decreases occur for the C₁₈ and C₂₀ compounds. Again, changes in crystal packing and intermolecular forces are responsible.

The factors that influence the relative boiling points and water solubilities of various types of compounds were discussed earlier. In general, dipolar attractive forces between molecules act to increase the boiling point of a given compound, with hydrogen bonds being an extreme example. Hydrogen bonding is also a major factor in the water solubility of covalent compounds To refresh your understanding of these principles Click Here. The following table lists a few examples of these properties for some similar sized polar compounds (the non-polar hydrocarbon hexane is provided for comparison).

Physical Properties of Some Organic Compounds
Formula	IUPAC Name	Molecular Weight	Boiling Point	Water Solubility
CH3(CH2)2CO2H	butanoic acid	88	164 ºC	very soluble
CH3(CH2)4OH	1-pentanol	88	138 ºC	slightly soluble
CH3(CH2)3CHO	pentanal	86	103 ºC	slightly soluble
CH3CO2C2H5	ethyl ethanoate	88	77 ºC	moderately soluble
CH3CH2CO2CH3	methyl propanoate	88	80 ºC	slightly soluble
CH3(CH2)2CONH2	butanamide	87	216 ºC	soluble
CH3CON(CH3)2	N,N-dimethylethanamide	87	165 ºC	very soluble
CH3(CH2)4NH2	1-aminobutane	87	103 ºC	very soluble
CH3(CH2)3CN	pentanenitrile	83	140 ºC	slightly soluble
CH3(CH2)4CH3	hexane	86	69 ºC	insoluble

The first five entries all have oxygen functional groups, and the relatively high boiling points of the first two is clearly due to hydrogen bonding. Carboxylic acids have exceptionally high boiling points, due in large part to dimeric associations involving two hydrogen bonds. A structural formula for the dimer of acetic acid is shown here. When the mouse pointer passes over the drawing, an electron cloud diagram will appear. The high boiling points of the amides and nitriles are due in large part to strong dipole attractions, supplemented in some cases by hydrogen bonding.

2. Acidity of Carboxylic Acids

The pK_a 's of some typical carboxylic acids are listed in the following table. When we compare these values with those of comparable alcohols, such as ethanol (pK_a = 16) and 2-methyl-2-propanol (pK_a = 19), it is clear that carboxylic acids are stronger acids by over ten powers of ten! Furthermore, electronegative substituents near the carboxyl group act to increase the acidity.

Compound	pKa	Compound	pKa
HCO2H	3.75	CH3CH2CH2CO2H	4.82
CH3CO2H	4.74	ClCH2CH2CH2CO2H	4.53
FCH2CO2H	2.65	CH3CHClCH2CO2H	4.05
ClCH2CO2H	2.85	CH3CH2CHClCO2H	2.89
BrCH2CO2H	2.90	C6H5CO2H	4.20
ICH2CO2H	3.10	p-O2NC6H4CO2H	3.45
Cl3CCO2H	0.77	p-CH3OC6H4CO2H	4.45

Why should the presence of a carbonyl group adjacent to a hydroxyl group have such a profound effect on the acidity of the hydroxyl proton? To answer this question we must return to the nature of acid-base equilibria and the definition of pK_a , illustrated by the general equations given below. These relationships were described in an previous section of this text.

We know that an equilibrium favors the thermodynamically more stable side, and that the magnitude of the equilibrium constant reflects the energy difference between the components of each side. In an acid base equilibrium the equilibrium always favors the weaker acid and base (these are the more stable components). Water is the standard base used for pK_a measurements; consequently, anything that stabilizes the conjugate base (A:^(–)) of an acid will necessarily make that acid (H–A) stronger and shift the equilibrium to the right. Both the carboxyl group and the carboxylate anion are stabilized by resonance, but the stabilization of the anion is much greater than that of the neutral function, as shown in the following diagram. In the carboxylate anion the two contributing structures have equal weight in the hybrid, and the C–O bonds are of equal length (between a double and a single bond). This stabilization leads to a markedly increased acidity, as illustrated by the energy diagram displayed by clicking the "Toggle Display" button.

The resonance effect described here is undoubtedly the major contributor to the exceptional acidity of carboxylic acids. However, inductive effects also play a role. For example, alcohols have pK_a's of 16 or greater but their acidity is increased by electron withdrawing substituents on the alkyl group. The following diagram illustrates this factor for several simple inorganic and organic compounds, and shows how inductive electron withdrawal may also increase the acidity of carboxylic acids. The acidic hydrogen is colored red in all examples.

Water is less acidic than hydrogen peroxide because hydrogen is less electronegative than oxygen, and the covalent bond joining these atoms is polarized in the manner shown. Alcohols are slightly less acidic than water, due to the poor electronegativity of carbon, but chloral hydrate, Cl₃CCH(OH)₂, and 2,2,2,-trifluoroethanol are significantly more acidic than water, due to inductive electron withdrawal by the electronegative halogens (and the second oxygen in chloral hydrate). In the case of carboxylic acids, if the electrophilic character of the carbonyl carbon is decreased the acidity of the carboxylic acid will also decrease. Similarly, an increase in its electrophilicity will increase the acidity of the acid. Acetic acid is ten times weaker an acid than formic acid (first two entries in the second row), confirming the electron donating character of an alkyl group relative to hydrogen, as noted earlier in a discussion of carbocation stability. Electronegative substituents increase acidity by inductive electron withdrawal. As expected, the higher the electronegativity of the substituent the greater the increase in acidity (F > Cl > Br > I), and the closer the substituent is to the carboxyl group the greater is its effect (isomers in the 3rd row). Substituents also influence the acidity of benzoic acid derivatives, but resonance effects compete with inductive effects. The methoxy group is electron donating and the nitro group is electron withdrawing (last three entries in the table of pK_a values).

Formation

1. Oxidation of Primary Alcohols and Aldehydes

Carboxylic acids can also be formed by the oxidation of primary alcohols Mild oxidation changes the alcohol into an aldehyde and strong oxidation takes it all the way to carboxylic acid.

2. Hydrolysis of esters

Hydrolysis of esters with mineral acids or alkalines gives carboxylic acids

3. Hydrolysis of nitriles

The nitriles are hydrolysed in dilute aqueous acidic or alkaline medium

Reactions

Carboxylic acids can dissociate in aqueous solution into carboxylate ions and protons. The equilibrium constant for this process is K_a, and more frequently we talk in terms of pK_a.

Values of pK_a for common alkyl carboxylic acids are around 5 (K_a ~ 10^-5).

E.g. ethanoic acid has pK_a = 4.74, (alcohols have pK_a ~ 18, so carboxylic acids are about 10¹³ times more acidic than alcohols).

The reason why carboxylic acids are much more acidic than alcohols is because the carboxylate anion is much more stable than the alkoxide anion.

Both alcohols are carboxylic acids are acidic since their respective O-H bonds can be broken heterolytically, giving a proton and an oxygen anion.

The difference lies in the fact that the carboxylate anion has the negative charge spread out over two oxygen atoms, whereas the alcohol has the negative charge localized on a single oxygen atom.

The carboxylate anion can be viewed as a resonance hybrid of the two anionic structures, or as a conjugated system of three interacting p orbitals containing four electrons (like the allylic anion system).

The C and two oxygens are all sp² hybridized, and the remaining p orbitals create the p MO system giving rise to the half p bond between each C and O, and the half negative charge on the end oxygens.

 1. The acidity of carboxylic acid

Carboxylic acids are weak acids that ionized to form carboxylate ion and hydronium ion in water:

 Carboxylic acids are weaker acids than the strong acids (HCl, H₂SO₄, HNO₃), but stronger acids than phenols and much stronger than alcohols

2. With metals and metal hydroxides

The carboxylic acids evolve hydrogen with electropositive metals and form salts with alkalies. They react with weaker bases such as carbonates and hydrogencarbonates to evolve carbon dioxide. This reaction is used to detect the presence of carboxyl group in an organic compound.

3. Esterification

Esterification is the reaction of a carboxylic acid and alcohol in the presence of an acid catalyst to produce an ester. The main chain of an ester comes from the carboxylic acid, while the alkyl group in an ester comes from the alcohol.

4. Formation of anhydride

Carboxylic acids on heating with mineral acids such as H₂SO₄ or with P₂O₅ give corresponding anhydride.

5. Formation of acid chlorides

The hydroxyl group of carboxylic acids, behaves like that of alcohols and is easily replaced by chlorine atom on treating with PCl₅ or PCl₃.

6. Reaction with ammonia

Carboxylic acids react with ammonia to give ammonium salt which on further heating at high temperature give amides. For example:

7. Reduction

Carboxylic acids are reduced to primary alcohols by lithium aluminium hydride.

Dicarboxylic acids

Dicarboxylic acids are organic compounds that are substituted with two functional carboxylic acid groups. In molecular formula for dicarboxylic acids, these groups are often written as , where R may be carbohydrate chain.

Examples:

Saturated dicarboxylic acids

Oxalic acid (ethanedioic acid)

Malonic acid (propanedioic acid)

Succinic acid (butanedioic acid)

Unsaturated dicarboxylic acids

Saturated dicarboxylic acids are crystalline substances. Water solubility decreases proportionally with the substances molecular mass. Acids with an odd number of carbon atoms are more soluble in comparison with those with an even number.

Due to the existence of two carboxyl groups in the molecule, those acids are stronger than saturated monocarboxylic acids.

Chemical properties

In general, dicarboxylic acids show the same chemical behavior and reactivity as monocarboxylic acids.

Specific reactions

1. Oxalic acid when boiled at over 200°C, decomposes in carbon dioxide and formic acid that can be divided in carbon monoxide an water (in the presence of sulphuric acid).

2. Malonic acid, when boiled at 120-150°C loses carbon dioxide and passes in acetic acid.

Urea

Urea (also known as carbamide) is a waste product of many living organisms, and is the major organic component of human urine. This is because it is at the end of chain of reactions which break down the amino acids that make up proteins. An adult typically excretes about 25 grams of urea per day.

Urea (NH2CONH2) is of great importance to the agriculture industry as a nitrogen-rich fertilizer. Urea is made from ammonia and carbon dioxide.

Aqueous solutions of urea decompose to form CO₂ and NH₃.

Biuret is the result of condensation of two molecules of urea.

The "Biuret Test" is a chemical test used for detecting the presence of peptide bonds, for diagnosis of hyperproteinuria for example. The biuret test is a chemical test used for detecting the presence of peptide bonds. In a positive test, a copper(II) ion is reduced to copper(I), which forms a complex with the nitrogens and carbons of the peptide bonds in an alkaline solution. A violet color indicates the presence of proteins.

Biuret reagent is so-named, not because it contains biuret, but because of its reaction to the peptide-like bonds in the biuret molecule.

Preparation of Carboxylic Acids

The carbon atom of a carboxyl group has a high oxidation state. It is not surprising, therefore, that many of the chemical reactions used for their preparation are oxidations. Such reactions have been discussed in previous sections of this text, and the following diagram summarizes most of these. To review the previous discussion of any of these reaction classes simply click on the number (1 to 4) or descriptive heading for the group.

Two other useful procedures for preparing carboxylic acids involve hydrolysis of nitriles and carboxylation of organometallic intermediates. As shown in the following diagram, both methods begin with an organic halogen compound and the carboxyl group eventually replaces the halogen. Both methods require two steps, but are complementary in that the nitrile intermediate in the first procedure is generated by a S_N2 reaction, in which cyanide anion is a nucleophilic precursor of the carboxyl group. The hydrolysis may be either acid or base-catalyzed, but the latter give a carboxylate salt as the initial product.

In the second procedure the electrophilic halide is first transformed into a strongly nucleophilic metal derivative, and this adds to carbon dioxide (an electrophile). The initial product is a salt of the carboxylic acid, which must then be released by treatment with strong aqueous acid.

Reactions of Carboxylic Acids

1. Salt Formation

Because of their enhanced acidity, carboxylic acids react with bases to form ionic salts, as shown in the following equations. In the case of alkali metal hydroxides and simple amines (or ammonia) the resulting salts have pronounced ionic character and are usually soluble in water. Heavy metals such as silver, mercury and lead form salts having more covalent character (3rd example), and the water solubility is reduced, especially for acids composed of four or more carbon atoms.

RCO2H	+	NaHCO3	→	RCO2^(–) Na^(+)   +   CO2   +   H2O
RCO2H	+	(CH3)3N:	→	RCO2^(–) (CH3)3NH^(+)
RCO2H	+	AgOH	→	RCO2^δ(-) Ag^δ^(+)   +   H2O

Carboxylic acids and salts having alkyl chains longer than six carbons exhibit unusual behavior in water due to the presence of both hydrophilic (CO₂) and hydrophobic (alkyl) regions in the same molecule. Such molecules are termed amphiphilic (Gk. amphi = both) or amphipathic. Depending on the nature of the hydrophilic portion these compounds may form monolayers on the water surface or sphere-like clusters, called micelles, in solution.

2. Substitution of the Hydroxyl Hydrogen

This reaction class could be termed electrophilic substitution at oxygen, and is defined as follows (E is an electrophile). Some examples of this substitution are provided in equations (1) through (4).

RCO2–H   +   E^(+)

RCO2–E  +  H^(+)

If E is a strong electrophile, as in the first equation, it will attack the nucleophilic oxygen of the carboxylic acid directly, giving a positively charged intermediate which then loses a proton. If E is a weak electrophile, such as an alkyl halide, it is necessary to convert the carboxylic acid to the more nucleophilic carboxylate anion to facilitate the substitution. This is the procedure used in reactions 2 and 3. Equation 4 illustrates the use of the reagent diazomethane (CH₂N₂) for the preparation of methyl esters. This toxic and explosive gas is always used as an ether solution (bright yellow in color). The reaction is easily followed by the evolution of nitrogen gas and the disappearance of the reagent's color. This reaction is believed to proceed by the rapid bonding of a strong electrophile to a carboxylate anion. The nature of S_N2 reactions, as in equations 2 & 3, has been described elsewhere. The mechanisms of reactions 1 & 4 will be displayed by clicking the "Toggle Mechanism" button below the diagram.

Alkynes may also serve as electrophiles in substitution reactions of this kind, as illustrated by the synthesis of vinyl acetate from acetylene. Intramolecular carboxyl group additions to alkenes generate cyclic esters known as lactones. Five-membered (gamma) and six-membered (delta) lactones are most commonly formed. Electrophilic species such as acids or halogens are necessary initiators of lactonizations. Even the weak electrophile iodine initiates iodolactonization of γ,δ- and δ,ε-unsaturated acids. Examples of these reactions will be displayed by clicking the "Other Examples" button.

3. Substitution of the Hydroxyl Group

Reactions in which the hydroxyl group of a carboxylic acid is replaced by another nucleophilic group are important for preparing functional derivatives of carboxylic acids. The alcohols provide a useful reference chemistry against which this class of transformations may be evaluated. In general, the hydroxyl group proved to be a poor leaving group, and virtually all alcohol reactions in which it was lost involved a prior conversion of –OH to a better leaving group. This has proven to be true for the carboxylic acids as well. Four examples of these hydroxyl substitution reactions are presented by the following equations. In each example, the new bond to the carbonyl group is colored magenta and the nucleophilic atom that has replaced the hydroxyl oxygen is colored green. The hydroxyl moiety is often lost as water, but in reaction #1 the hydrogen is lost as HCl and the oxygen as SO₂. This reaction parallels a similar transformation of alcohols to alkyl chlorides, although its mechanism is different.

Reactions of Carboxylic Acid Derivatives

1. Acyl Group Substitution

This is probably the single most important reaction of carboxylic acid derivatives. The overall transformation is defined by the following equation, and may be classified either as nucleophilic substitution at an acyl group or as acylation of a nucleophile. For certain nucleophilic reagents the reaction may assume other names as well. If Nuc-H is water the reaction is often called hydrolysis, if Nuc–H is an alcohol the reaction is called alcoholysis, and for ammonia and amines it is called aminolysis.

Different carboxylic acid derivatives have very different reactivities, acyl chlorides and bromides being the most reactive and amides the least reactive, as noted in the following qualitatively ordered list. The change in reactivity is dramatic. In homogeneous solvent systems, reaction of acyl chlorides with water occurs rapidly, and does not require heating or catalysts. Amides, on the other hand, react with water only in the presence of strong acid or base catalysts and external heating.

Reactivity:   acyl halides > anhydrides >> esters ≈ acids >> amides

Because of these differences, the conversion of one type of acid derivative into another is generally restricted to those outlined in the following diagram. Methods for converting carboxylic acids into these derivatives were shown in a previous section, but the amide and anhydride preparations were not general and required strong heating. A better and more general anhydride synthesis can be achieved from acyl chlorides, and amides are easily made from any of the more reactive derivatives. Specific examples of these conversions will be displayed by clicking on the product formula. The carboxylic acids themselves are not an essential part of this diagram, although all the derivatives shown can be hydrolyzed to the carboxylic acid state (light blue formulas and reaction arrows). Base catalyzed hydrolysis produces carboxylate salts.

Before proceeding further, it is important to review the general mechanism by means of which all these acyl transfer or acylation reactions take place. Indeed, an alert reader may well be puzzled by the facility of these nucleophilic substitution reactions. After all, it was previously noted that halogens bonded to sp² or sp hybridized carbon atoms do not usually undergo substitution reactions with nucleophilic reagents. Furthermore, such substitution reactions of alcohols and ethers are rare, except in the presence of strong mineral acids. Clearly, the mechanism by which acylation reactions occur must be different from the S_N1 and S_N2 procedures described earlier. In any substitution reaction two things must happen. The bond from the substrate to the leaving group must be broken, and a bond to the replacement group must be formed. The timing of these events may vary with the reacting system. In nucleophilic substitution reactions of alkyl compounds examples of bond-breaking preceding bond-making (the S_N1 mechanism), and of bond-breaking and bond-making occurring simultaneously (the S_N2 mechanism) were observed. On the other hand, for most cases of electrophilic aromatic substitution bond-making preceded bond-breaking.

As illustrated in the following diagram, acylation reactions generally take place by an addition-elimination process in which a nucleophilic reactant bonds to the electrophilic carbonyl carbon atom to create a tetrahedral intermediate. This tetrahedral intermediate then undergoes an elimination to yield the products. In this two-stage mechanism bond formation occurs before bond cleavage, and the carbonyl carbon atom undergoes a hybridization change from sp² to sp³ and back again. The facility with which nucleophilic reagents add to a carbonyl group was noted earlier for aldehydes and ketones.

Other reagents that produce a similar conversion to acyl halides are PCl₅ and SOBr₂. The amide and anhydride formations shown in equations 3 require strong heating, and milder procedures that accomplish these transformations will be described in the next chapter.

Reaction 4 is called esterification, since it is commonly used to convert carboxylic acids to their ester derivatives. Esters may be prepared in many different ways; indeed, equations #1 and #4 in the previous diagram illustrate the formation of tert-butyl and methyl esters respectively. The acid-catalyzed formation of ethyl acetate from acetic acid and ethanol shown here is reversible, with an equilibrium constant near 2. The reaction can be forced to completion by removing the water as it is formed. This type of esterification is often referred to as Fischer esterification. As expected, the reverse reaction, acid-catalyzed ester hydrolysis, can be carried out by adding excess water. A thoughtful examination of this reaction (4) leads one to question why it is classified as a hydroxyl substitution rather than a hydrogen substitution. The following equations, in which the hydroxyl oxygen atom of the carboxylic acid is colored red and that of the alcohol is colored blue, illustrate this distinction (note that the starting compounds are in the center).

H2O  +   CH3CO-OCH2CH3

H-substitution

CH3CO-OH  +   CH3CH2-OH

HO-substitution

CH3CO-OCH2CH3  +   H2O

In order to classify this reaction correctly and establish a plausible mechanism, the oxygen atom of the alcohol was isotopically labeled as ¹⁸O (colored blue in our equation). Since this oxygen is found in the ester product and not the water, the hydroxyl group of the acid must have been replaced in the substitution. A mechanism for this general esterification reaction will be displayed on clicking the "Esterification Mechanism" button; also, once the mechanism diagram is displayed, a reaction coordinate for it can be seen by clicking the head of the green "energy diagram" arrow. Addition-elimination mechanisms of this kind proceed by way of tetrahedral intermediates (such as A and B in the mechanism diagram) and are common in acyl substitution reactions. Acid catalysis is necessary to increase the electrophilic character of the carboxyl carbon atom, so it will bond more rapidly to the nucleophilic oxygen of the alcohol. Base catalysis is not useful because base converts the acid to its carboxylate anion conjugate base, a species in which the electrophilic character of the carbon is reduced.
Since a tetrahedral intermediate occupies more space than a planar carbonyl group, we would expect the rate of this reaction to be retarded when bulky reactants are used. To test this prediction the esterification of acetic acid was compared with that of 2,2-dimethylpropanoic acid, (CH₃)₃CO₂H. Here the relatively small methyl group of acetic acid is replaced by a larger tert-butyl group, and the bulkier acid reacted fifty times slower than acetic acid. Increasing the bulk of the alcohol reactant results in a similar rate reduction.

Reductions Oxidations of Carboxylic Acids

1. Reduction

The carbon atom of a carboxyl group is in a relatively high oxidation state. Reduction to a 1º-alcohol takes place rapidly on treatment with the powerful metal hydride reagent, lithium aluminum hydride, as shown by the following equation. One third of the hydride is lost as hydrogen gas, and the initial product consists of metal salts which must be hydrolyzed to generate the alcohol. These reductions take place by the addition of hydride to the carbonyl carbon, in the same manner noted earlier for aldehydes and ketones. The resulting salt of a carbonyl hydrate then breaks down to an aldehyde that undergoes further reduction.

4 RCO2H   +   3 LiAlH4

ether

4 H2  +   4 RCH2OM   +   metal oxides

H2O

4 RCH2OH   +   metal hydroxides

Diborane, B₂H₆, reduces the carboxyl group in a similar fashion. Sodium borohydride, NaBH₄, does not reduce carboxylic acids; however, hydrogen gas is liberated and salts of the acid are formed. Partial reduction of carboxylic acids directly to aldehydes is not possible, but such conversions have been achieved in two steps by way of certain carboxyl derivatives. These will be described later.

2. Oxidation

Because it is already in a high oxidation state, further oxidation removes the carboxyl carbon as carbon dioxide. Depending on the reaction conditions, the oxidation state of the remaining organic structure may be higher, lower or unchanged. The following reactions are all examples of decarboxylation (loss of CO₂). In the first, bromine replaces the carboxyl group, so both the carboxyl carbon atom and the remaining organic moiety are oxidized. Silver salts have also been used to initiate this transformation, which is known as the Hunsdiecker reaction. The second reaction is an interesting bis-decarboxylation, in which the atoms of the organic residue retain their original oxidation states. Lead tetraacetate will also oxidize mono-carboxylic acids in a manner similar to reaction #1. Finally, the third example illustrates the general decarboxylation of β-keto acids, which leaves the organic residue in a reduced state (note that the CO₂ carbon has increased its oxidation state.).

Three additional examples of the Hunsdiecker reaction and a proposed mechanism for the transformation will be shown above by clicking on the diagram. Note that the meta- dihalobenzene formed in reaction 4 could not be made by direct halogenation reactions, since chlorine and bromine are ortho/para-directing substituents. Also, various iodide derivatives may be prepared directly from the corresponding carboxylic acids. A heavy metal carboxylate salt is transformed into an acyl hypohalide by the action of a halogen. The weak oxygen-halogen bond in this intermediate cleaves homolytically when heated or exposed to light, and the resulting carboxy radical decarboxylates to an alkyl or aryl radical. A chain reaction then repeats these events. Since acyl hypohalites are a source of electrophilic halogen, this reaction takes a different course when double bonds and reactive benzene derivatives are present. In this respect remember the addition of hypohalous reagents to double bonds and the facile bromination of anisole.

Carboxylation of Grignard Reagents

(R = alkyl, aryl or vinyl)

Reaction type:  Oxidative Insertion then Nucleophilic Addition

Summary:

· Magnesium can insert into C-X bonds (X = Br, I)  in ether or THF to give Grignard reagents.

· Grignard reagents react with CO₂ (which can be viewed as a C=O compound) to give the carboxylic acid after acid work-up.

· Note that the carbon skeleton is extended by 1 C atom during this reaction.

· Remember that Grignard reagents also react with -OH, -NH, -SH and C=O groups.

Preparation of Carboxylic Acid Derivatives

Reaction type:  Nucleophilic Acyl Substitution

Overview

· In principle, all carboxylic acids derivatives can be made from the parent carboxylic acid see above.

· In practice, there may be better methods, e.g. amides are more readily prepared from the more reactive acyl chlorides.

· However, appreciating the relationship between these groups is important and useful.

Study Tip: Disconnect carboxylic acids derivatives back to the parent acid plus the related component.

Preparation of Acyl Chlorides

Reaction type:  Nucleophilic Acyl Substiution

· Acyl chlorides are prepared by treating the carboxylic acid with thionyl chloride, SOCl₂, in the presence of a base.

· Acyl chlorides are by far the most commonly encountered of the acyl halides.

Preparation of Acid Anhydrides

Reaction type:  Nucleophilic Acyl Substitution

· Symmetrical anhydrides can be are prepared by heating the carboxylic acid

· Symmetrical anhydrides are by far the most commonly encountered, e.g. acetic anhydride.

· This reaction will be discussed in more detail in Chapter 20.

Preparation of Esters

Reaction type:  Nucleophilic Acyl Substitution

· This reaction is also known as the Fischer esterification.

· Esters are obtained by refluxing the parent carboxylic acid with the appropriate alcohol with an acid catalyst.

· The equilibrium can be driven to completion by using an excess of either the alcohol or the carboxylic acid, or by removing the water as it forms.

· Alcohol reactivity order :  CH₃OH > 1^o > 2^o > 3^o (steric effects)

· Esters can also be made from other carboxylic acid derivatives, especially acyl halides and anhydrides, by reacting them with the appropriate alcohol in the presence of a weak base (see chapter 20)

· If a compound contains both hydroxy- and carboxylic acid groups, then cyclic esters or lactones can form via an intramolecular reaction. Reactions that form 5- or 6-membered rings are particularly favorable.

Study Tip: The carboxylic acid and alcohol combination used to prepare an ester are reflected by the name of the ester, e.g. ethyl acetate (or ethyl ethanoate), CH₃CO₂CH₂CH₃  can be made from CH₃CO₂H, acetic acid (or ethanoic acid) and HOCH₂CH₃ (ethanol). This general "disconnection" is shown below:

MECHANISM FOR REACTION FOR ACID catalyzed ESTERIFICATION
Step 1: An acid/base reaction. Protonation of the carbonyl makes it more electrophilic.
Step 2: The alcohol O functions as the nucleophile attacking the electrophilic C in the C=O, with the electrons moving towards the oxonium ion, creating the tetrahedral intermediate.
Step 3: An acid/base reaction. Deprotonate the alcoholic oxygen.
Step 4: An acid/base reaction. Need to make an -OH leave, it doesn't matter which one, so convert it into a good leaving group by protonation.
Step 5: Use the electrons of an adjacent oxygen to help "push out" the leaving group, a neutral water molecule.
Step 6: An acid/base reaction. Deprotonation of the oxonium ion reveals the carbonyl in the ester product.

Preparation of Amides

Reaction type:  Nucleophilic Acyl Substiution

· In general, it is not easy to prepare amides directly from the parent carboxylic acid.

· The acid will protonate the amine preventing further reaction since the carboxylate is a poor electrophile and the ammonium ion is not nucleophilic.

· It is much easier to convert the carboxylic acid to the more reactive acyl chloride first.

Study Tip: Even though "acid + amine" is not a good synthetic method, it at least puts you on the right track.

Related Reactions

· Preparation of Acyl Chlorides

· Preparation of Esters

Reduction of Carboxylic Acids

Reaction usually in Et₂O or THF followed by H₃O⁺ work-ups

Reaction type:  Nucleophilic Acyl Substitution then Nucleophilic Addition

· Carboxylic acids are less reactive to reduction by hydride than aldehydes, ketones or esters.

· Carboxylic acids are reduced to primary alcohols.

· As a result of their low reactivity, carboxylic acids can only be reduced by LiAlH₄ and NOT by the less reactive  NaBH₄

Related Reactions

· Reaction of RLi and RMgX with esters

· Reaction of RLi and RMgX with carbon dioxide

· Reduction of Aldehydes and Ketones

· Reduction of Esters

a-Halogenation (Hell-Volhard-Zelinsky reaction)

Reaction type: Substitution

· Reagents most commonly : Br₂ and either PCl₃, PBr₃ or red phosphorous in catalytic amounts.

· Carboxylic acids can be halogenated at the C adjacent to the carboxyl group.

· This reaction depends on the enol type character of carbonyl compounds.

· The product of the reaction, an a-bromocarboxylic acid can be converted via substitution reactions to a-hydroxy- or a-amino carboxylic acids.

Related Reactions

· a-Halogenation of Aldehydes and Ketones

Decarboxylation

Reaction type: Elimination

· Loss of carbon dioxide is called decarboxylation.

· Simple carboxylic acids rarely undergo decarboxylation.

· Carboxylic acids with a carbonyl group at the 3- (or b-) position readily undergo thermal decarboxylation, e.g. derivatives of malonic acid.

· The reaction proceeds via a cyclic transition state giving an enol intermediate that tautomerizes to the carbonyl.

DECARBOXYLATION
Step 1: Remember curly arrows flow.... Start at the protonation of the carbonyl, break the O-H bond and form the p bond, break the C-C and make the C=C. Note the concerted nature of this reaction and the cyclic transition state.
Step 2: Tautomerization of the enol of the carboxylic acid leads to the acid product (not shown here).

Reactions at the α-Carbon

Many aldehydes and ketones were found to undergo electrophilic substitution at an alpha carbon. These reactions, which included halogenation, isotope exchange and the aldol reaction, take place by way of enol tautomer or enolate anion intermediates, a characteristic that requires at least one hydrogen on the α-carbon atom. In this section similar reactions of carboxylic acid derivatives will be examined. Formulas for the corresponding enol and enolate anion species that may be generated from these derivatives are drawn in the following diagram.

Acid-catalyzed alpha-chlorination and bromination reactions proceed more slowly with carboxylic acids, esters and nitriles than with ketones. This may reflect the smaller equilibrium enol concentrations found in these carboxylic acid derivatives. Nevertheless, acid and base catalyzed isotope exchange occurs as expected; some examples are shown in equations 1 and 2 below. The chiral alpha-carbon in equation 2 is racemized in the course of this exchange, and a small amount of nitrile is hydrolyzed to the corresponding carboxylic acid.

Acyl halides and anhydrides are more easily halogenated than esters and nitriles, probably because of their higher enol concentration. This difference may be used to facilitate the alpha-halogenation of carboxylic acids. Thus, conversion of the acid to its acyl chloride derivative is followed by alpha-bromination or chlorination, and the resulting halogenated acyl chloride is then hydrolyzed to the carboxylic acid product. This three-step sequence can be reduced to a single step by using a catalytic amount of phosphorus tribromide or phosphorus trichloride, as shown in equation #3. This simple modification works well because carboxylic acids and acyl chlorides exchange functionality as the reaction progresses. The final product is the alpha-halogenated acid, accompanied by a trace of the acyl halide. This halogenation procedure is called the Hell-Volhardt-Zelinski reaction.

To see a mechanism for the acyl halide-carboxylic acid exchange click the "Show Mechanism" button.

In a similar fashion, acetic anhydride serves as a halogenation catalyst for acetic acid (first equation below). Carboxylic acids that have a higher equilibrium enol concentration do not need to be activated for alpha-halogenation to occur, as demonstrated by the substituted malonic acid compound in the second equation below. The enol concentration of malonic acid (about 0.01%) is roughly ten thousand times greater than that of acetic acid. This influence of a second activating carbonyl function on equilibrium enol concentrations had been noted earlier in the case of 2,4-pentanedione.

(I)

CH3-CO2H   +   Br2  + (CH3CO)2O catalyst

heat →

BrCH2CO2H   +   HBr

(II)

RCH(CO2H)2   +   Br2

→

RCBr(CO2H)2   +   HBr

1. Enolate Intermediates

Many of the most useful alpha-substitution reactions of ketones proceeded by way of enolate anion conjugate bases. Since simple ketones are weaker acids than water, their enolate anions are necessarily prepared by reaction with exceptionally strong bases in non-hydroxylic solvents. Esters and nitriles are even weaker alpha-carbon acids than ketones (by over ten thousand times), nevertheless their enolate anions may be prepared and used in a similar fashion. The presence of additional activating carbonyl functions increases the acidity of the alpha-hydrogens substantially, so that less stringent conditions may be used for enolate anion formation. The influence of various carbonyl and related functional groups on the equilibrium acidity of alpha-hydrogen atoms (colored red) is summarized in the following table. For common reference, these acidity values have all been extrapolated to water solution, even though the conjugate bases of those compounds having pK_as greater than 18 will not have a significant concentration in water solution.

Acidity of α-Hydrogens in Mono- and Di-Activated Compounds
Mono-Activation	Compound	RCH2–NO2	RCH2–COR	RCH2–CO2CH3	RCH2–C≡N	RCH2–SO2R	RCH2–CON(CH3)2
	pKa	9	20	25	25	25	28
Di-Activation	Compound	CH2(NO2)2	(CH3CO)2CH2	CH3COCH2CO2C2H5	CH2(C≡N)2	CH2(CO2C2H5)2	CH2(SO2CH3)2
	pKa	4	9	11	11	13	13

To illustrate the general nucleophilic reactivity of di-activated enolate anions, two examples of S_N2 alkylation reactions are shown below. Malonic acid esters and acetoacetic acid esters are commonly used starting materials, and their usefulness in synthesis will be demonstrated later in this chapter. Note that each of these compounds has two acidic alpha-hydrogen atoms (colored red). In the equations written here only one of these hydrogens is substituted; however, the second is also acidic and a second alkyl substitution may be carried out in a similar fashion.

2. Claisen Condensation

The aldol reaction, is a remarkable and useful reaction of aldehydes and ketones in which the carbonyl group serves both as an electrophilic reactant and the source of a nucleophilic enol species. Esters undergo a similar transformation called the Claisen Condensation. Four examples of this base-induced reaction, which usually forms beta-ketoester products, are shown in the following diagram. Greek letter assignments for the ester products are given in blue. Equation 1 presents the synthesis of the important reagent ethyl acetoacetate, and 2 illustrates the general form of the Claisen condensation. Intramolecular reactions, such as #3, lead to rings (usually five or six-membered) and are referred to as Dieckmann Condensations. The last equation shows a mixed condensation between two esters, one of which has no alpha-hydrogens. The product in this case is a phenyl substituted malonic ester rather than a ketoester.

By clicking the "Structural Analysis" button below the diagram, a display showing the nucleophilic enolic donor molecule and the electrophilic acceptor molecule together with the newly formed carbon-carbon bond will be displayed. A stepwise mechanism for the reaction will be shown by clicking the "Reaction Mechanism" button. In a similar mode to the aldol reaction, the fundamental event in the Claisen condensation is a dimerization of two esters by an alpha C–H addition of one reactant to the carbonyl group of a second reactant. This bonding is followed by alcohol elimination from the resulting hemiacetal. The eventual formation of a resonance stabilized beta-ketoester enolate anion, as shown on the third row of the mechanism, provides a thermodynamic driving force for the condensation. Note that this stabilization is only possible if the donor has two reactive alpha-hydrogens.

The Claisen condensation differs from the aldol reaction in several important ways.

(I) The aldol reaction may be catalyzed by acid or base, but most Claisen condensations require base.

(II) In contrast to the catalytic base used for aldol reactions, a full equivalent of base (or more) must be used for the Claisen condensation. The extra base is needed because beta-ketoesters having acidic hydrogens at the alpha-carbon are stronger acids (by about 5 powers of ten) than the alcohol co-product. Consequently, the alkoxide base released after carbon-carbon bond formation (upper right structure in the mechanism diagram) immediately removes an alpha proton from the beta-ketoester product. As noted above, formation of this doubly-stabilized enolate anion provides a thermodynamic driving force for the condensation.

(III) The aldol reaction may be catalyzed by hydroxide ion, but the Claisen condensation requires that alkoxide bases be used, in order to avoid ester hydrolysis. The specific alkoxide base used should match the alcohol component of the ester to avoid ester exchange reactions. Very strong bases such as LDA may also be used in this reaction.

(IV) The stabilized enolate product must be neutralized by aqueous acid in order to obtain the beta-ketoester product.

Transformations similar to the Claisen condensation may be effected with mixed carbonyl reactants, which may include ketones and nitriles as well as esters. Esters usually serve as the electrophilic acceptor component of the condensation. Acyl chlorides and anhydrides would also be good electrophilic acceptors, but they are more expensive than esters and do not tolerate the alcohol solvents often used for Claisen condensations.

In the case of mixed condensations, complex product mixtures are commonly avoided by using an acceptor ester that has no alpha-hydrogens. Examples of such reactants are: ethyl formate (HCO₂C₂H₅), diethyl carbonate (C₂H₅OCO₂C₂H₅), ethyl benzoate (C₆H₅CO₂C₂H₅) and diethyl oxalate (C₂H₅O₂C-CO₂C₂H₅). Equations 2, 3 , 4 below illustrate the use of such acceptors with ester, ketone and nitrile donor compounds. The nucleophilic enol species from the nitrile in 4 may be written as: C₆H₅CH=C=N^(–). The 2-formylcyclohexanone product from reaction 3 exists predominantly as its hydrogen-bonded enol. Most beta-ketoesters have significant enol concentrations, but the formyl group has an exceptional bias for this tautomer.

Equation 1 shows a condensation in which both reactants might serve either as donors or acceptors. The selective formation of one of the four possible condensation products is due to the reversibility of these reactions and the driving force provided by resonance stabilization of the enolate anion of 2,4-pentanedione (pK_a=9). Protonation of this anion gives the product. The last equation (5) presents an interesting example of selectivity. There are three ester functions, each of which has at least one alpha-hydrogen. Only one of these, that on the left, has two alpha-hydrogens and will yield an enolizable beta-ketoester by functioning as the donor in a Dieckmann cyclization. Strained four-membered rings are not favored by reversible condensation reactions, so ring closure to the ester drawn below the horizontal chain does not occur. The only reasonable product is the five-membered cyclic ketoester.

Although many Claisen condensations are carried out with a full equivalent of the alkoxide base, an effective alternative procedure, used in reaction 5, uses sodium hydride (NaH) together with a catalytic amount of alcohol. The catalytic alcohol reacts with NaH to produce alkoxide, this initiates a condensation reaction and the product alcohol then reacts with more NaH to give alkoxide.

Condensation Reactions in Synthesis

Applications of Condensation Reactions to Synthesis

The construction of complex molecules by a series of suitable reactions carried out from simple starting compounds is called synthesis. Synthesis is not only of immense practical importance (aspirin and nylon are two examples of commercially valuable synthetic compounds), but it also allows us to prepare novel molecules with which to test our understanding of structure and reactivity. Three challenges must be met in devising a synthesis for a specific compound:

1. The carbon atom framework or skeleton that is found in the desired compound (the target) must be assembled.

2. The functional groups that characterize the target compound must be introduced or transformed from other groups at appropriate locations.

3. If centers of stereoisomerism are present, they must be fixed in a proper manner.

Recognition of these tasks does not imply that they are independent of each other, or should be approached and solved separately. A successful plan or strategy for a synthesis must correlate each step with all these goals, so that an efficient and practical solution to making the target molecule is achieved. Nevertheless, it is useful to classify the various reactions we have studied with respect to their ability to (I) enlarge or expand a given structure, (II) transform or relocate existing functional groups, and (III) do both of these in a stereoselective fashion. The organization of this text by functional group behavior partially satisfies the second point, and the following discussion focuses on the first.

1. Carbon-Carbon Bond Formation

A useful assortment of carbon-carbon bond forming reactions have been described in this and earlier chapters. These include:

(1) Friedel-Crafts alkylation and acylation.

(2) Diels-Alder cycloaddition.

(3) addition of organometallic reagents to aldehydes, ketones carboxylic acid derivatives.

(4) alkylation of acetylide anions.

(5) alkylation of enolate anions.

(6) Claisen and aldol condensations.

With the exception of Friedel-Crafts alkylation these reactions all give products having one or more functional groups at or adjacent to the bonding sites. As a result, subsequent functional group introduction or modification may be carried out in a relatively straightforward manner. This will be illustrated for aldol and Claisen condensations in the following section.

2. Modification of Condensation Products

A. Reactions of Aldol Products

The aldol reaction produces beta-hydroxyaldehydes or ketones, and a number of subsequent reactions may be carried out with these products. As shown in the following diagram, they may be (I) reduced to 1,3-diols, (II) a 2є-hydroxyl group may be oxidized to a carbonyl group, (III) acid or base catalyzed beta-dehydration may produce an unsaturated aldehyde or ketone, and (IV) organometallic reagents may be added to the carbonyl group (assuming the hydroxyl group is protected as an ether or a second equivalent of reagent is used).

B. Reactions of Claisen Products

The Claisen condensation produces beta-ketoesters. These products may then be modified or enhanced by further reactions. Among these, the following diagram illustrates (I) partial reduction of the ketone with NaBH₄, (II) complete reduction to a 1,3-diol by LiAlH₄, (III) enolate anion alkylation, and (IV) ester hydrolysis followed by thermal decarboxylation of the resulting beta-ketoacid.

C. Synthesis Examples

To illustrate how the reaction sequences described above may be used to prepare a variety of different compounds, five examples are provided here. The first is a typical aldol reaction followed by reduction to a 1,3-diol (2-ethyl-1,3-hexanediol). In the second example, the absence of alpha-hydrogens on the aldehyde favors the mixed condensation, and conjugation of the double bond facilitates dehydration. The doubly-activated methylene group of malonic and acetoacetic acids or esters makes them good donors in any condensation, as is demonstrated by the third aldol-like reaction. A concerted dehydrative-decarboxylation (shown by the magenta arrows) leads to the unsaturated carboxylic acid product. Amine bases are often used as catalysts for aldol reactions, as in equations 2 , 3.

The fourth reaction demonstrates that the conjugate base of the beta-ketoester products from Claisen or Dieckmann condensation may be alkylated directly. Thermal decarboxylation of the resulting beta-ketoacid gives a mono-alkylated cyclic ketone. Finally, both acidic methylene hydrogens in malonic ester or ethyl acetoacetate may be substituted, and the irreversible nature of such alkylations permits strained rings to be formed. In this case thermal decarboxylation of a substituted malonic acid generates a carboxylic acid. In all these examples the remaining functional groups could be used for additional synthetic operations.

Some Exercises

If you understand the previous discussion of reactions useful in synthesis you should try the following problems. Some of them are complex so don't be concerned if you don't solve them all immediately. Analyze each problem carefully, and try to learn from it. The solutions will be displayed by clicking the answer button under the diagram.

The following problems ask you to devise a synthesis for a given target molecule. The first two problems make use of the common starting materials, diethyl malonate and ethyl acetoacetate. The third problem leaves the choice of materials open. The nature of the target molecule suggests that an aldol condensation might be useful. The fourth problem must be solved by using diethyl succinate as the only reagent. Finally, other reactants composed of no more than five carbon atoms may be used in the last problem.

Reactions with Organolithium Compounds and Metal Hydrides

Carboxylic acids are both Brønsted acids and Lewis acids. Their Lewis acid qualities may be attributed not only to the acidic proton, but also to the electrophilic carbonyl carbon, as they are both able to act as an electron acceptor. However, if a carboxylic acid is treated with an organolithium compound, an acid-base reaction first takes place. In such a reaction, the acidic proton is abstracted by the organolithium compound's alkyl or aryl anion, as alkyl and aryl anions are extremely strong bases. Nevertheless, alkyl and aryl anions are also efficient nucleophiles. As a result, the carbonyl carbon of the carboxylate anion which is formed in the first reaction step is nucleophilically attacked by an additional alkyl or aryl anion. The result of a subsequent hydrolysis is the protonation of the dianion. This yields a geminal diol and lithium hydroxide. The geminal diol represents a ketone's hydrate. Thus, it spontaneously eliminates water to yield the ketone. The reaction may be carried out with primary, secondary, and tertiary alkyllithium compounds, as well as with aryllithium compounds. In order to obtain a ketone in this reaction, two equivalents of the organolithium compound to one equivalent of carboxylic acid must be applied, as the first equivalent is consumed by the acid-base reaction which cannot be prevented.

Due to the negative charge of the carboxylate anion, the electrophilicity of a ketone's carbonyl carbon is comparatively higher. Nevertheless, the ketone does not react with the organolithium compound, as it is not formed until the workup with water through which the remaining organolithium compound is also hydrolyzed.

In contrast with lithium aluminum hydride, carboxylic acids are reduced to the corresponding primary alcohol.

The mechanism of carboxylic acids' reduction with lithium aluminum hydride is as follows: first of all, an acid-base reaction takes place in which a carboxylate anion is generated, very similar to the reaction with organolithium compounds. The carboxylate anion's carbonyl carbon is then nucleophilically attacked by a hydride that is supplied by the aluminum hydride, while the carbonyl oxygen is complexed by the remaining aluminum species. The following elimination of an oxoaluminum hydride anion yields the aldehyde.

The aldehyde's carbonyl carbon is still electrophilic. Thus, it is nucleophilically attacked by a further hydride anion that is supplied by lithium aluminum hydride. Subsequent hydrolysis finally yields the primary alcohol.

Reactions of Carboxylic Acids

Carbonic acid (H2CO3 or HO(C=O)OH) is in itself not stable. It decomposes easily into water and carbon dioxide through decarboxylation. However, the salts of carbonic acid - hydrogen carbonates and carbonates - are, in fact, stable and isolable. Sodium hydrogen carbonate (NaHCO3) and sodium carbonate (soda, Na₂CO₃) are popular examples of carbonic acid's salts.

Carbonic acid (unstable)	Sodium hydrogencarbonate (stable)	Sodium carbonate (stable)

Monoesters of carbonic acids are also unstable and easily decarboxylate. Decarboxylation is irreversible, as the gaseous carbon dioxide escapes. However, diesters of carbonic acid are stable.

Carbamic acid (amidocarbonic acid, aminoformic acid) is unstable	Urea (stable)	Methyl carbamate (stable)

Carboxylic acids that, in contrast to β-keto acids and 1,3-dicarboxylic acids, do not easily decarboxylate may be decarboxylated by an electrochemical reaction, which is known as the Kolbe electrolysis reaction. In Hermann Kolbe's electrolysis, carboxylate anions are electrochemically oxidized. The resulting carboxyl radicals spontaneously decarboxylate and the two remaining alkyl radicals subsequently combine, thus yielding a new hydrocarbon.

Reaction scheme

An example

Hunsdiecker Reaction

Analogous to the Kolbe electrolysis reaction, the Hunsdiecker reaction (after Heinz Hunsdiecker, born in 1904) is a decarboxylation with a radical intermediate. However, it is not an electrochemical reaction.

The Hunsdiecker reaction takes place when a silver carboxylate is heated in CCl4 in the presence of bromine. In the initial step of the Hunsdiecker reaction, the silver carboxylate is converted into an acyl hypobromite through the action of bromine. The main driving force of this reaction step is the precipitation of the extremely poorly soluble and stable silver bromide. Subsequently, a radical chain reaction occurs. The chain initiation is the homolytic cleavage of the relatively weak oxygen-bromine bond. This yields a carboxyl radical and a bromine atom. Similar to the Kolbe electrolysis reaction, the carboxyl radical decarboxylates spontaneously. This is the first propagation step of the chain reaction. The resulting alkyl radical, or hydrocarbon radical, abstracts a bromine atom from a further acyl hypobromite molecule. In this second propagation step, an alkyl bromide - the product - is formed and a carboxyl radical is recovered, which then once again acts as a starting product of the first propagation step. Silver carboxylates, required as starting products for the Hunsdiecker reaction, may be obtained through conversion of the corresponding carboxylic acid with silver oxide.

There are several variations of the Hunsdiecker reaction that are known, in which silver(I) carboxylate is, for instance, exchanged for thallium(I) carboxylate, or in which the carboxylic acid is directly treated with a combination of lead tetraacetate and halide ions (chloride, bromide, or iodide). Through the application of these reagents carboxylic acids are converted into alkyl chlorides and alkyl iodides, as well.

Alkylation of Carboxylic Acids in α Position

Similar to carbonyl compounds, the α carbon of carboxylic acids may be deprotonated. The resulting carbanions are good nucleophiles which are utilized in many syntheses, for example in the α alkylation of carboxylic acids.

Due to the higher acidity of the carboxyl hydrogen, two equivalents of a base are required in generating the α carbanion of a carboxylic acid. The base must be considerably strong in order to abstract the α hydrogen. However, the nucleophilicity of the base at the same time be must be as low as possible in order to prevent a nucleophilic attack on the carboxyl carbon. A sufficient base for this reaction is, for instance, lithium diisopropylamide (LDA). LDA is a strong base whose nucleophilicity is relatively low, due to steric reasons.

If a carboxylic acid is treated with LDA, a lithium carboxylate is initially formed. The second equivalent of LDA abstracts the α hydrogen, thus yielding a dianion.

The dianion is a good nucleophile. The most nucleophilic position is the α carbanionic position. The dianion may consecutively nucleophilically attack an electrophile. If the electrophile is a bromine, for instance, α bromination is obtained. Alkylation in α position occurs if an alkyl halide, instead of bromine, is applied. In alkylations, primary alkyl halides offer good results, while with secondary and tertiary alkyl halides, eliminations may occur as side reactions or even as main reactions.

Hell-Volhard-Zelinskii Reaction

The treatment of carboxylic acids with bromine and phosphorus tribromide (PBr3) or a mixture of bromine and phosphorus, yields the α-bromocarboxylic acid. Phosphorus tribromide is often applied only as a catalyst. Thus, if chlorine and PBr3 are applied, chlorination occurs instead of bromination.

The reaction is known as the Hell-Volhard-Zelinskii reaction (after J. Volhard, C.M. Hell, and N.D. Zelinskii). In the frist reaction step, PBr3 converts the carboxylic acid into the corresponding acyl bromide. The acyl bromide is in equlibrium with the corresponding enol. A nucleophilic attack of the enol π bond on a bromine molecule yields HBr and an α-bromoacyl bromide, which may be isolated.

Analogous to acyl halides, α-bromoacyl halides may be converted into α-bromoesters, α-bromocarboxamides, and "back" to the α-bromocarboxylic acid. However, their α bromine atom may also be exchanged for another nucleophile in an SN2 reaction. The α-cyanocarboxylic acids and α-aminocarboxylic acids are, for example, available in this way.

If catalytic amounts of PBr3 are applied, the intermediate α-bromoacyl bromide is attacked by another carboxylic acid molecule, yielding the corresponding anhydride. The bromide that is released during anhydride formation, then cleaves the anhydride into an α-bromocarboxylic acid - the product - and an acyl bromide. The acyl bromide reenters the reaction cycle.