Materials preparation to the practical classes

Materials preparation to the practical classes

for the students of pharmaceutical faculty

LESSON № 13

Theme 1. Mono- and dicarboxylic acids.

Theme 2. Functional derivates of the carboxylic acids.

 

Carboxylic acids

Carboxylic acids are а compound whose characteristic functional group is the carboxyl group, example: 

  

             

 

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).

Carboxylic acids are distinguished by the functional grouping CO₂H. Four ways of writing this grouping, referred to as the carboxyl group, are shown.

                                     

lewis structure                 kekule structure            condensed structures

Countless natural products are carboxylic acids or are derived from them. Some carboxylic acids, such as acetic acid, have been known for centuries. Others, such as the prostaglandins, which are powerful regulators of numerous biological processes, remained unknown until relatively recently. Still others, aspirin for example, are the products of chemical synthesis. The therapeutic effects of aspirin, welcomed long before the discovery of prostaglandins, are now understood to result from aspirin’s ability to inhibit the biosynthesis of prostaglandins.

The chemistry of carboxylic acids is the central theme of this chapter. The importance of carboxylic acids is magnified when we realize that they are the parent compounds of a large group of derivatives that includes acyl chlorides, acid anhydrides, esters and amides. These classes of compounds will be discussed in the chapter following this one. Together, this chapter and the next tell the story about some of the most fundamental structural types and functional group transformations in organic and biological chemistry.

Either an organic group or а hydrogen may be attached to the carboxy group. The carbon atom in а carboxy group uses three hybrid orbitals to bond to the oxygen of the ОН group, the carboxy oxygen, and to hydrogen or an organic radical. These three orbitals are approximately spa hybrids that lie in one plane. The remaining p orbital on the carbon forms а m bond to а р orbital on the carboxy oxygen. There are two distinct С-O bond distances, corresponding to C=O and С-О. The bond angles and bond lengths formic acid determined by microwave spectroscopy. Note that the bond angles around the carboxy carbon are only approximately those expected for sp²-hybridization. The array НСОО is planar and the hydroxy hydrogen lies outside of this plane.

In the solid and liquid phases, as well as in the vapour phase at moderately high pressure, carboxylic acids exist largely in the dimeric form depicted:

Nomenclature:  There are two systems of nomenclature currently in use for carboxylic acids, and the student should be acquainted with both. Since many of the simpler acids are naturally occurring and were discovered early in the history of organic chemistry, they have well-entrenched “common” names. Now here in organic chemistry are commoames used more often than with the carboxylic acids. Many carboxylic acids are better known by commoames than by their systematic names, and the framers of the IUPAC nomenclature rules have taken a liberal view toward accepting these commoames as permissible alternatives to the systematic ones. Table 1 lists both the common and the systematic names of a number of important carboxylic acids. Systematic names for carboxylic acids are derived by counting the number of carbons in the longest continuous chain that includes the carboxyl group and replacing the -e ending of the corresponding alkane by –oic acid. The first three acids in the table, methanoic (1 carbon), ethanoic (2 carbons), and octadecanoic acid (18 carbons), illustrate this point. When substituents are present, their locations are identified by number; numbering of the carbon chain always begins at the carboxyl group. This is illustrated in entries 4 and 5 in the table.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 1. Systematic and commoames of some carboxylic acids

 

      

Notice that compounds 4 and 5 are named as hydroxy derivatives of carboxylic acids, rather than as carboxyl derivatives of alcohols. We have seen earlier that hydroxyl groups take precedence over double bonds, and double bonds take precedence over halogens and alkyl groups, iaming compounds. Carboxylic acids outrank all the common groups we have encountered to this point. Double bonds in the main chain are signaled by the ending –enoic acid, and their position is designated by a numerical prefix. Entries 6 and 7 are representative carboxylic acids that contain double bonds. Double-bond stereochemistry is specified by using either the cis–trans or the E–Z notation. When a carboxyl group is attached to a ring, the parent ring is named (retaining the final -e) and the suffix -carboxylic acid is added, as shown in entries 8 and 9. Compounds with two carboxyl groups, as illustrated by entries 10 through 12, are distinguished by the suffix –dioic acid or –dicarboxylic acid as appropriate. The final –e in the base name of the alkane is retained.

 

At the 1892 IUPAC Congress, it was agreed to derive the name of а carboxylic acid:

1.     Select as the parent carbon chain the longest carbon chain that includes the carbon atom of the carboxyl group.

2.     Name the parent chain by changing the -е ending of the corresponding alkane to –oic acid.

3.     Number the parent chain by assigning the number 1 to the carboxyl carbon atom.

4.     Determine the identity and location of any substituents ш the usual manner and append this information to the front of the parent chaiame.

 2-hydroxy-6-methylheptanoic acid

When using commoames, the chain is labeled a, b ,g, d, and so on, beginning wit the carbon adjacent to the carboxy carbon.

  d–phenylvaleric acid or 5- phenylpentanoic acid (not s-phenylpentanoic acid)

Structure and bonding of carbocylic acids

The structural features of the carboxyl group are most apparent in formic acid. Formic acid is planar, with one of its carbon–oxygen bonds shorter than the other, and with bond angles at carbon close to 120°.

        Bond distances                Bond angles

         C=O    120 pm                 H-C=O      124°

        C-O     134 pm                  H-C-O        111°

                                                  O-C=O       125°

         This suggests sp² hybridization at carbon, and a σ+π carbon–oxygen double bond analogous to that of aldehydes and ketones.

Additionally, sp² hybridization of the hydroxyl oxygen allows one of its unshared electron pairs to be delocalized by orbital overlap with the π system of the carbonyl group. In resonance terms, this electron delocalization is represented as:

Lone-pair donation from the hydroxyl oxygen makes the carbonyl group less electrophilic than that of an aldehyde or ketone. The graphic that opened this chapter is an electrostatic potential map of formic acid that shows the most electron-rich site to be the oxygen of the carbonyl group and the most electron-poor one to be, as expected, the OH proton.

Classification of Carboxylic Acids

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

a) Saturated acid is acid, which has only simple bonds in molecule. (example: acetic acid, formic acid, butanoic acid).

For example:

    

acetic acid                               propionic acid

b) Unsaturated acid is acid, which has both as simple and double bounds in molecule (example: palmitoleic acid,, oleic acid linoleic acid, linolenic acid, arahidonic acid).

For example:

       

acrylic acid                                       oleic acid

c) aromatic acid is acid, which contains aromatic ring (example: benzoic acid).

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

a)    mocarboxylic acids are acids group in molecule (example: acetic acid, formic acid, butanoic acid).

For example:

                

acetic acid                                                      butanoic acid

b)    dicarboxylic acids are acids which has two carboxylic groups in molecule (example: oxalic acid, malonic acid).

For example:

    

c)    polycarboxylic 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.

The melting points and boiling points of carboxylic acids are higher than those of hydrocarbons and oxygen-containing organic compounds of comparable size and shape and indicate strong intermolecular attractive forces.

The hydroxyl group of one carboxylic acid molecule acts as a proton donor toward the carbonyl oxygen of a second. In a reciprocal fashion, the hydroxyl proton of the second carboxyl function interacts with the carbonyl oxygen of the first. The result is that the two carboxylic acid molecules are held together by two hydrogen bonds. So efficient is this hydrogen bonding that some carboxylic acids exist as hydrogen-bonded dimers even in the gas phase. In the pure liquid a mixture of hydrogen-bonded dimers and higher aggregates is present. In aqueous solution intermolecular association between carboxylic acid molecules is replaced by hydrogen bonding to water. The solubility properties of carboxylic acids are similar to those of alcohols. Carboxylic acids of four carbon atoms or fewer are miscible with water in all proportions.

The boiling points of carboxylic acids are higher than expected for their molecular weights because of hydrogen bonding. The lower molecular weight acids are liquids at room temperature. The first four acids are fully miscible with water in all proportions. As the chain length is increased, the water solubility steadily decreases.

Acidity of carboxylic acids.

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

Compounds containing the functional group-COOH are weakly acidic; in fact it is this property from which the class derives its name. When acetic acid is dissolved in the water, the equilibrium in equation:

 

 

Values of pKa for common alkyl carboxylic acids are around 5 (Ka ~ 10-5).

E.g. ethanoic acid has pKa = 4.74, (alcohols have pKa ~ 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.

The equilibrium constant for this reaction, is called as “acid dissociation constant”

Carboxylic acids are the most acidic class of compounds that contain only carbon, hydrogen, and oxygen. With ionization constants Ka on the order of 105 (pKa~5), they are much stronger acids than water and alcohols. The case should not be overstated, however. Carboxylic acids are weak acids; a 0.1 M solution of acetic acid in water, for example, is only 1.3% ionized. To understand the greater acidity of carboxylic acids compared with water and alcohols, compare the structural changes that accompany the ionization of a representative alcohol (ethanol) and a representative carboxylic acid (acetic acid). The equilibrium that define Ka are

The large difference in the free energies of ionization of ethanol and acetic acid reflects a greater stabilization of acetate ion relative to ethoxide ion. Ionization of ethanol yields an alkoxide ion in which the negative charge is localized on oxygen. Solvation forces are the chief means by which ethoxide ion is stabilized. Acetate ion is also stabilized by solvation, but has two additional mechanisms for dispersing its negative charge that are not available to ethoxide ion:

Inductive effects.

The carbonyl group of acetate ion is electron-withdrawing, and by attracting electrons away from the negatively charged oxygen, acetate anion is stabilized. This is an inductive effect, arising in the polarization of the electron distribution in the σ bond between the carbonyl carbon and the negatively charged oxygen.

Electronegative groups whose bonds to carbon are highly polar have important effects on the acidity of acids, that this effect could be interpreted in terms of the electrostatic interaction of а bond dipole with the anionic negative charge. The вате behavior is manifest by substituent groups in carboxylic acids. Because of the higher acidity and ease of measurement of carboxylic acids, а wealth of quantitative acidity data is available. Atoms that have high electronegativity tend to withdraw electron density from carbon and have а marked acid-strengthening effect. Chloroacetic acid is 1.9 рK_a, units more acidic than acetic acid. The С – Cl bond dipole is oriented in such а way that the positive end is closer to the negative charge on the carboxy group than is the negative end. Electrostatic attraction exceeds the repulsion and the negative charge of the anion в тоге stabilized.

Carbon-carbon double and triple bonds have а significant еlectron-attracting effect that is reflected in the enhanced acidity of vinylacetic and ethynylacetic acids. The sp²– hybridized carbon obital with its greater s character is effectively more electronegative than an sp³ orbital. The higher alkanoic acids are  somewhat less acidic than acetic acid. Alkyl groups manifest a small but  significant electron-donatin inductive effect in appropriate systems in solution. The indinductive effect of remote substituents falls off dramatically with increased distance from the charged center.

The resonance effect of the carbonyl group.

Electron delocalization, expressed by resonance between the following Lewis structures, causes the negative charge in acetate to be shared equally by both oxygens. Electron delocalization of this type is not available to ethoxide ion.

The acid-strengthening effect of electronegative atoms or groups is easily seen as an inductive effect of the substituent transmitted through the σ bonds of the molecule. According to this model, the σ electrons in the carbon–chlorine bond of chloroacetate ion are drawn toward chlorine, leaving the σ– carbon atom with a slight positive charge. The  carbon, because of this positive character, attracts electrons from the negatively charged carboxylate, thus dispersing of the charge and stabilizing of the anion. The more stable anion, the greater equilibrium constant for its formation.

Methods of carboxylic acids receiving

1.    Side-chain oxidation of alkylbenzenes.

A primary or secondary alkyl side chain on an aromatic ring is converted to a carboxyl group by reaction with a strong oxidizing agent such as potassium permanganate or chromic acid.

2. Oxidation of primary alcohols.

Potassium permanganate and chromic acid convert primary alcohols to carboxylic acids by way of the corresponding aldehyde.

3. Oxidation of aldehydes.

Aldehydes are particularly sensitive to oxidation and are converted to carboxylic acids by a number of oxidizing agents, including potassium permanganate and chromic acid.

4. Synthesis of carboxylic acids by the carboxylation of Grinyar reagents.

We’ve seen how Grinyar reagents add to the carbonyl group of aldehydes, ketones, and esters. Grinyar reagents react in much the same way with carbon dioxide to yield magnesium salts of carboxylic acids. Acidification converts these magnesium salts to the desired carboxylic acids.

 

Overall, the carboxylation of Grinyar reagents transforms an alkyl or aryl halide to a carboxylic acid in which the carbon skeleton has been extended by one carbon atom.

5. Synthesis of carboxylic acids by the preparation and hydrolysis of nitriles.

Primary and secondary alkyl halides may be converted to the next higher carboxylic acid by a two-step synthetic sequence involving the preparation and hydrolysis of nitriles. Nitriles, also known as alkyl cyanides, are prepared by nucleophilic substitution.

 

Aryl and vinyl halides do not react. Dimethyl sulfoxide is the preferred solvent for this reaction, but alcohols and water–alcohol mixtures have also been used. Once the cyano group has been introduced, the nitrile is subjected to hydrolysis. Usually this is carried out in aqueous acid at reflux.

 

6. Dicarboxylic acids have been prepared from dihalides by the following method:

7. Maleic acid is obtained by dehydration of malic acid at a temperature of 250°C

 

 

 

 

 

8. Hydrocarboxylation of alkenes.

Alkenes with carbon (II) oxide and hydrogen in a presence of acid catalyst under the heating and pressure form the carboxylic acids:

CH2=CH2 + CO+ H2O = CH3-CH2-COOH

                                               propionic acid

9. Hydrocarboxylation of alkynes.

In the presence of carbonyl metals, alkyne interact with oxide carbon (II) in water with the formation of α, β-unsaturated acids

C2H2 + CO+ H2O   =   CH2=CH-COOH

10. The industry production of phthalic acid is oxidation of naphthalene in the presence of air oxygen as catalyst:

11. Hydrolysis of esters

Hydrolysis of esters with mineral acids or alkalines gives carboxylic acids

Chemical propertis

Reactions: The chemistry of carboxylic acids may be divided mechanistically into four categories: (а) reactions involving the acidic O-Н bond, (b) reactions occurring in the hydrocarbon side chain, (с) reactions occurring at the carboxy carbon atom, and (d) one-carbon degradations.

1) Reactions involving the ОН-bond

a) Important reaction of carboxylic acids involving the ОН bond – the reaction with bases to give salts: 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.

 

b) Another important reaction involving this bond is the reaction of carboxylic acids with diazomethane. The products of this reaction are the methyl ester and nitrogen.

2) Reactions involving the hydrocarbon side chain

a) Carboxylic acids undergo the normal reactions of alkanes, as modified by the presence of the carboxy group, in the hydrocarbon chain of the molecule. For example, butyric acid undergoes combustion and free-radical chlorination.

Since these reactions are not selective for any particular position along the chain, they generally have по preparative utility.

b) One reaction of the aliphatic chain that does have utility is the reaction of carboxylic actds with phosphorus tribromide and bromine. This reaction is sometimes known as the Hell-Volhard–Zelinsky reaction, after its discoverers.

c) Note that the reaction is positional selective – only the hydrogen on С-2 is replaced. This is not а free-radical halogenation reaction. The overall result, a–bromination, is accomplished by а sequence of steps. The key step involves the reaction of bromine with the enol form of the corresponding acyl bromide. Phosphorus tribromide facilitates the reaction by reacting with the carboxylic acid to yield the acyl bromide (bromoanhydride), which undergoes enolization much more readily than the acid itself.

 

3) Reactions Occurring at the Carbonyl Carbon

a) The formation of amides. The most common reaction of this type is the reaction of carboxylic acids with ammonia or amines to give amides. Carboxylic acids react with ammonia to give ammonium salt which on further heating at high temperature give amides. When ammonia is bubbled through butyric acid at 185⁰, butyramide is obtained in 85% yield. The reaction involves two stages. At room temperature, or even below, butyric acid reacts with the weak base ammonia to give the salt ammonium butyrate. This salt is perfectly stable at normal temperatures. However, pyrolysis of the salt results in the elimination of water and formation of the amide.                                      

 

b) esterification: Carboxylic acids react readily with alcohols in the presence of catalytic amounts of mineral acids to yield compounds called esters. The process is called esterification.

Unlike most of the reactions we have encountered, this one has an equilibrium constant of relatively low magnitude. The experimental equilibrium constant for the reaction of acetic acid with ethanol is:

c) reaction with halo-compounds

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

Carboxylic acids react with thionyl chloride, phosphorus pentachloride, and phosphorus tribromide in the same way that alcohols do. The products are acyl halides:

d) reaction formation of anhydrides.

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

e) Lithium aluminum hydride reduction. Carboxylic acids are reduced to primary alcohols by the powerful reducing agent lithium aluminum hydride.

Dicarboxylic acids

Dicarboxylic acid is a compound that contains two carboxylic groups of a carbon chain. Saturation acids of this type are named by appending the suffix –dioic acid to the corresponding alkane name.

                 

Oxalic acid                           malonic 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 eveumber.

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

 

Decarboxylation reaction:

 

Dicarboxylic acid has the same properties as monocarboxylic.

Reactions by carboxylic group:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Reactions by hydrocarbon chain:

Carboxylic acid functional derivatives

 

These classes of compounds are classified as carboxylic acid functional derivatives. All may be converted to carboxylic acids by hydrolysis.

 

The hydrolysis of a carboxylic acid derivative is but one example of a nucleophilic acyl substitution. Nucleophilic acyl substitutions connect the various classes of carboxylic acid derivatives, with a reaction of one class often serving as preparation of another. These reactions provide the basis for a large number of functional group transformations both in synthetic organic chemistry and in biological chemistry. Also included in this chapter is a discussion of the chemistry of nitriles, compounds of the type RCPN. Nitriles may be hydrolyzed to carboxylic acids or to amides and, so, are indirectly related to the other functional groups presented here.

Nomenclature of carboxylic acid functional derivatives

With the exception of nitriles , all carboxylic acid derivatives consist of an acyl groupattached to an electronegative atom. Acyl groups are named by replacing the –ic acid ending of the corresponding carboxylic acid by –yl. Acyl halides are named by placing the name of the appropriate halide after that of the acyl group.

Although acyl fluorides, bromides, and iodides are all known classes of organic compounds, they are encountered far less frequently than are acyl chlorides. Acyl chlorides will be the only acyl halides discussed in this chapter.

Iaming carboxylic acid anhydrides in which both acyl groups are the same, we simply specify the acyl group and add the word “anhydride.” When the acyl groups are different, they are cited in alphabetical order.

The alkyl group and the acyl group of an ester are specified independently. Esters are named as alkyl alkanoates. The alkyl group R′ of is cited first, followed by the acyl portion . The acyl portion is named by substituting the suffix -ate for the –ic ending of the corresponding acid.

Aryl esters, that is, compounds of the type , are named in an analogous way. The names of amides of the type are derived from carboxylic acids by replacing the suffix –oic acid or –ic acid by -amide.

 

We name compounds of the typeand  as N-alkyl- and N,N–dialkylsubstituted derivatives of a parent amide.

Substitutive IUPAC names for nitriles add the suffix –nitrile to the name of the parent hydrocarbon chain that includes the carbon of the cyano group. Nitriles may also be named by replacing the –ic acid or –oic acid ending of the corresponding carboxylic acid with –onitrile. Alternatively, they are sometimes given functional class IUPAC names as alkyl cyanides.

Methods of preparation and chemical properties

Method of preparation of acyl chlorides.

Chemical properties of acyl chlorides.

1. Reaction with carboxylic acids. Acyl chlorides react with carboxylic acids to yield acid anhydrides. When this reaction is used for preparative purposes, a weak organic base such as pyridine is normally added. Pyridine is a catalyst for the reaction and also acts as a base to neutralize the hydrogen chloride that is formed.

Reaction with alcohols. Acyl chlorides react with alcohols to form esters. The reaction is typically carried out in the presence of pyridine.

Reaction with ammonia and amines. Acyl chlorides react with ammonia and amines to form amides. A base such as sodium hydroxide is normally added to react with the hydrogen chloride produced.

Hydrolysis. Acyl chlorides react with water to yield carboxylic acids. In base, the acid is converted to its carboxylate salt. The reaction has little preparative value because the acyl chloride is nearly always prepared from the carboxylic acid rather than vice versa.

 

Preparation of carboxylic acid anhydrides

After acyl halides, acid anhydrides are the most reactive carboxylic acid derivatives. Three of them, acetic anhydride, phthalic anhydride, and maleic anhydride, are industrial chemicals and are encountered far more often than others. Phthalic anhydride and maleic anhydride have their anhydride function incorporated into a ring and are referred to as cyclic anhydrides.

 

The customary method for the laboratory synthesis of acid anhydrides is the reaction of acyl chlorides with carboxylic acids:

Cyclic anhydrides in which the ring is five- or six-membered are sometimes prepared by heating the corresponding dicarboxylic acids in an inert solvent:

Chemical properties of carboxylic acid anhydrides

1. Friedel–Crafts acylation

2. Reaction with alcohols . Acid anhydrides react with alcohols to form esters. The reaction may be carried out in the presence of pyridine or it may be catalyzed by acids. In the example shown, only one acetyl group of acetic anhydride becomes incorporated into the ester; the other becomes the acetyl group of an acetic acid molecule.

3. Reaction with ammonia and amines. Acid anhydrides react with ammonia and amines to form amides. Two molar equivalents of amine are required. In the example shown, only one acetyl group of acetic anhydride becomes incorporated into the amide; the other becomes the acetyl group of the amine salt of acetic acid.

4. Hydrolysis. Acid anhydrides react with water to yield two carboxylic acid functions. Cyclic anhydrides yield dicarboxylic acids.

Preparation of carboxylic acids esters

1. From carboxylic acids. In the presence of an acid catalyst, alcohols and carboxylic acids react to form an ester and water. This is the Fischer esterification.

2. From acyl chlorides. Alcohols react with acyl chlorides by nucleophilic acyl substitution to yield esters. These reactions are typically performed in the presence of a weak base such as pyridine.

3. From carboxylic acid anhydrides Acyl transfer from an acid anhydride to an alcohol is a standard method for the preparation of esters. The reaction is subject to catalysis by either acids (H2SO4) or bases (pyridine).

4. Baeyer–Villiger oxidation of ketones. Ketones are converted to esters on treatment with peroxy acids. The reaction proceeds by migration of the group R from carbon to oxygen. It is the more highly substituted group that migrates. Methyl ketones give acetate esters.

Chemical properties of carboxylic acids esters

1. Reaction with Grinyar reagents. Esters react with two equivalents of a Grinyar reagent to produce tertiary alcohols. Two of the groups bonded to the carbon that bears the hydroxyl group in the tertiary alcohol are derived from the Grinyar reagent.

2. Reduction with lithium aluminum hydride. Lithium aluminum hydride cleaves esters to yield two alcohols.

3. Reaction with ammonia and amines. Esters react with ammonia and amines to form amides. Methyl and ethyl esters are the most reactive.

4. Hydrolysis. Ester hydrolysis may be catalyzed either by acids or by bases. Acid-catalyzed hydrolysis is an equilibrium-controlled process, the reverse of the Fischer esterification. Hydrolysis in base is irreversible and is the method usually chosen for preparative purposes.

Carboxamides.

Two molar equivalents of amine are required in the reaction with acyl chlorides and acid anhydrides; one molecule of amine acts as a nucleophile, the second as a Bronsted base.

Amides are sometimes prepared directly from carboxylic acids and amines by a two-step process. The first step is an acid–base reaction in which the acid and the amine combine to form an ammonium carboxylate salt. At the heating, the ammonium carboxylate salt loses water to form an amide.

Imides of carboxylic acid derivatives

Compounds that have two acyl groups bonded to single nitrogen are known as imides. The most common imides are cyclic ones:

Cyclic imides can be prepared by heating the ammonium salts of dicarboxylic acids:

Only nucleophilic acyl substitution reaction that amides undergo is hydrolysis. Amides are fairly stable in water, but the amide bond is cleaved on heating in the presence of strong acids or bases. Nominally, this cleavage produces an amine and a carboxylic acid.

On treatment with bromine in basic solution, amides of the type undergo an interesting reaction that leads to amines. This reaction was discovered by the nineteenth century German chemist August W. Hofmann and is called the Hofmann rearrangement.

Nitriles of carboxylic acid derivatives

Nitriles are organic compounds that contain the functional group. We have already discussed the two main procedures by which they are prepared, namely, the nucleophilic substitution of alkyl halides by cyanide and the conversion of aldehydes and ketones to cyanohydrins.

1. Nucleophilic substitution by cyanide ion Cyanide ion is a good nucleophile and reacts with alkyl halides to give alkyl nitriles. The reaction is of the SN2 type and is limited to primary and secondary alkyl halides. Tertiary alkyl halides undergo elimination; aryl and vinyl halides do not react.

2.    Cyanohydrin formation. Hydrogen cyanide adds to the carbonyl group of aldehydes and ketones.

 

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