Beta-Keto Carboxylic Acids: Properties and Synthesis

Introduction

Beta-keto carboxylic acids are organic compounds characterized by a carbonyl group (keto group) located on the beta-carbon atom relative to a carboxylic acid group. These compounds are valuable intermediates in organic synthesis due to the unique reactivity conferred by the adjacent carbonyl and carboxyl functionalities. This article aims to comprehensively explore the properties, synthesis, and applications of beta-keto carboxylic acids.

Properties of Beta-Keto Carboxylic Acids

Acidity

The α-hydrogens in β-dicarbonyl compounds, including beta-keto carboxylic acids, exhibit significant acidity. This is due to the stabilization of the enolate formed upon deprotonation by resonance across both carbonyl groups. This acidity allows for the easy generation of enolates by treating a β-dicarbonyl compound with a base, such as an alkoxide (RO-).

Decarboxylation

Decarboxylation is a reaction where a carboxylic acid loses a CO2 molecule. Most carboxylic acids do not readily undergo decarboxylation. However, β-keto acids readily decarboxylate due to the carbonyl group at the β-position, which helps to form a six-membered cyclic transition state. This transition state facilitates the removal of the CO2 molecule and the generation of an enol.

Reactivity

The presence of both a ketone and a carboxylic acid group in the same molecule leads to versatile reactivity. Beta-keto carboxylic acids can undergo reactions characteristic of both ketones and carboxylic acids. They are also useful in the synthesis of more complex organic molecules.

Synthesis of Beta-Keto Carboxylic Acids

Claisen Condensation

Claisen condensation is a fundamental method for synthesizing β-keto esters, which can then be hydrolyzed to β-keto acids. In this reaction, two esters react in the presence of a strong base, such as sodium ethoxide, to form a β-keto ester and an alcohol. The reaction is typically conducted under anhydrous conditions to prevent hydrolysis of the reactants.

Read also: Explore Properties of Beta-Keto Aldehydes

Depending on the structures of the reactants, different products could be generated in Claisen condensation, for example, β-keto ester, 1,3-diester, or 1,3-diketone, and they could all be generally categorized as β-dicarbonyl compounds.

Alkylation and Decarboxylation

Alkylation and decarboxylation are commonly used as sequential steps in synthesizing target products with specific structures from β-dicarbonyl compounds.

1. Enolate Formation: An enolate is generated by treating a β-dicarbonyl compound with a base, such as an alkoxide (RO-). The resulting enolate is a nucleophile.
2. Alkylation: The enolate undergoes alkylation with an alkyl halide in an SN2 reaction. After introducing the first alkyl group, a second alkylation can be carried out if desired.
3. Hydrolysis: All of these Claisen condensation reactions produce a difunctional compound in which a carbonyl group is located on the beta position of an ester. There is a useful reaction that can be carried out if the ester is hydrolyzed to the corresponding acid. The (\beta)-ketoester here is known as acetoacetic ester
4. Decarboxylation: Following alkylation, hydrolysis and decarboxylation occur, leading to the formation of a ketone.

Ethyl Acetoacetate Synthesis

One specific compound with a very common application in synthesis is ethyl acetoacetate. Upon alkylation, followed by hydrolysis and decarboxylation, ethyl acetoacetate is a useful reactant for the preparation of substituted methyl ketones. Based on the structure of the target methyl ketone, i.e., the specific structure of R1 and R2, the corresponding alkyl halide can be employed either once or twice. All the steps can be put together on the reaction arrows.

Malonic Ester Synthesis

Another important method is the malonic ester synthesis, which involves the alkylation of a malonic ester derivative followed by hydrolysis and decarboxylation to yield a substituted acetic acid.

Other Synthetic Methods

Other methods for the synthesis of carboxylic acids have already been mentioned, including the haloform reaction, and the Cannizzaro reaction.

Read also: Benefits of Beta-Alanine

Reactions of Carboxylic Acids

Because many carboxylic acids can be obtained from natural sources, they are frequently used as starting materials for other types of compounds.

Conversion to Acid Derivatives

Treatment of a carboxylic acid with thionyl chloride, SOCl2 (often in the presence of an amine such as pyridine, C5H5N), converts the carboxyl group to the corresponding acyl chloride (RCOOH → RCOCl). Several other reagents (e.g., PCl3, PCl5) can also be used, but thionyl chloride is usually the most convenient because the other products of the reaction, hydrogen chloride (HCl) and sulfur dioxide (SO2), are gases, making isolation of the acyl chloride simple. This is an important reaction because several types of acid derivatives (mainly carboxylic esters and amides) are more easily made from the acyl chloride than from the carboxylic acid.

Esterification

Esters can be prepared by treatment of a carboxylic acid with an alcohol in the presence of an acid catalyst, most commonly sulfuric acid or hydrochloric acid, in a reaction known as Fischer esterification. Treatment of 4-aminobenzoic acid with ethanol (ethyl alcohol) in the presence of an acid catalyst, for example, gives the topical (surface) anesthetic benzocaine. Fischer esterification has the disadvantage that it is an equilibrium reaction (as shown by the equilibrium arrows ⇌), meaning that the reaction stops before completion, with substantial amounts of carboxylic acid and alcohol still present. However, there are several ways to drive such reactions to completion, including the removal of the water by distillation and the use of a large excess of one of the reactants. Therefore, this reaction is frequently used to synthesize carboxylic esters, although the use of acyl chlorides is often more convenient.

Conversion to Amides and Anhydrides

Conversion of carboxylic acids directly to amides or anhydrides is generally not feasible; acyl chlorides are commonly used for these purposes. Treatment of a carboxylic acid with ammonia (NH3) or an amine (RNH2) does not give an amide but yields instead the salt (RCOOH + NH3→ RCOO−NH4+). There are certain compounds that can be added to produce an amide, the most important being dicyclohexylcarbodiimide (DCC): Diimides of this type, however, are expensive and are generally used only when small quantities are involved and very high yields are important. (Yields in the acyl chloride method are usually somewhat lower.) The DCC method is most commonly employed in the synthesis of proteins. Heating a carboxylic acid does not produce an anhydride, except for those dicarboxylic acids that yield five- or six-membered cyclic anhydrides

Applications in Organic Synthesis

Synthesis of Methyl Ketones

Upon alkylation, followed by hydrolysis and decarboxylation, ethyl acetoacetate is a useful reactant for the preparation of substituted methyl ketones. Based on the structure of the target methyl ketone, i.e., the specific structure of R1 and R2, the corresponding alkyl halide can be employed either once or twice.

Read also: Easy Low-Carb Cheese Crackers

Construction of Complex Molecules

The synthesis of β-keto acids via Claisen condensation significantly impacts organic synthesis by providing versatile intermediates that can be transformed into various functional groups and complex molecules. The ability to form carbon-carbon bonds through this method expands the toolkit for chemists, facilitating the construction of larger frameworks necessary for pharmaceuticals and other organic materials.

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).

Nomenclature of Carboxylic Acids

1. 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.

   • HCO2Hformic acidants (L.
   • CH3CO2Hacetic acid vinegar (L.
   • CH3CH2CO2Hpropionic acidmilk (Gk.
   • CH3(CH2)2CO2H butyric acidbutter (L.
   • CH3(CH2)4CO2H caproic acidgoats (L.
   • CH3(CH2)5CO2H enanthic acidvines (Gk.
   • CH3(CH2)6CO2H caprylic acidgoats (L.
   • CH3(CH2)8CO2H capric acidgoats (L.

2. 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.

   (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. Larry & Moe Perform Silly Antics" (note that the names of the three stooges are in alphabetical order).

Occurrence and Examples

1. 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. 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 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.
2. 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. 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.

Physical Properties of Carboxylic Acids

1. 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). 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.
2. The pKa '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 (pKa = 16) and 2-methyl-2-propanol (pKa = 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. 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 pKa , 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 pKa 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). Compounds in which an enolic hydroxyl group is conjugated with a carbonyl group also show enhanced acidity. 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 pKa'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 (row #1), and shows how inductive electron withdrawal may also increase the acidity of carboxylic acids (rows #2 & 3). 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.

Synthesis 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. 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 SN2 reaction, in which cyanide anion is a nucleophilic precursor of the carboxyl group. In the second procedure the electrophilic halide is first transformed into a strongly nucleophilic metal derivative, and this adds to carbon dioxide (an electrophile). An existing carboxylic acid may be elongated by one methylene group, using a homologation procedure called the Arndt-Eistert reaction.

Principal Reactions of Carboxylic Acids

1. 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. 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.
2. This reaction class could be termed electrophilic substitution at oxygen, and is defined as follows (E is an electrophile). 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 SN2 reactions, as in equations 2 & 3, has been described elsewhere. 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.
3. 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. The amide and anhydride formations shown in equations #2 & 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. 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 th…

tags: #beta-keto #carboxylic #acid #properties #and #synthesis