Carboxylic acids and their derivatives Synthesis of acids Properties of acids Nomenclature of acids Reactions of acids Acid derivatives and their properties Nomenclature of acid derivatives Reactions of acid derivatives

Carboxylic acids The carboxylic acid functional group consist of a carbonyl group that has a hydroxyl group attached to the carbonyl carbon. Carboxylic acid groups are generally written as R-COOH or R-CO2H Carboxylic acids are generally weak acids that are only partially ionized. [ ]

Properties of carboxylic acids Boiling Points Higher boiling points than similar alcohols, due to dimer formation. Acetic acid, b.p. 118C Melting Points Aliphatic acids with more than 8 carbons are solids at room temperature. Double bonds (especially cis) lower the melting point. Note these 18-C acids: Stearic acid (saturated): 72C Oleic acid (one cis double bond): 16C Linoleic acid (two cis double bonds): -5 (cis,cis-9,12-octadecadienoic acid)

Properties of carboxylic acids Solubility Water solubility decreases with the length of the carbon chain. Up to 4 carbons, acid is miscible in water. More soluble in alcohol. Also soluble in relatively nonpolar solvents like chloroform because it dissolves as a dimer.

Acidity

Structure of Carboxyl Carbon is sp2 hybridized. Bond angles are close to 120. O-H eclipsed with C=O, to get overlap of  orbital with orbital of lone pair on oxygen.

Substituent Effects on Acidity Acid + Base salt + “water”

Naming Carboxylic acids Historical names are commonly used for many carboxylic acids. Positions of substituents on the chain are labeled with Greek letters.

Common Carboxylic acid Names formic acid acetic acid propionic acid butyric acid Benzoic acid phthalic acid

Common Carboxylic acid Names oxalic acid malonic acid succinic acid adipic acid IUPAC: hexanedioic acid

Naming Carboxylic acids IUPAC Names Remove -e from alkane (or alkene) name, add -oic acid. The carboxylic acid group has priority over all over groups. The carbon of the carboxyl group is #1. 2-chlorobutanoic acid trans-3-phenyl-2-propenoic acid (cinnamic acid)

o-hydroxybenzoic acid Naming Cyclic Acids When the -CO2H is bonded to a cycloalkane ring the compound is named as a cycloalkanecarboxylic acids. Aromatic acids are named based on benzoic acids. o-hydroxybenzoic acid (salicylic acid) 2-isopropylcyclopentanecarboxylic acid

Dicarboxylic Acids Aliphatic diacids are usually called by their common names (to be memorized). For IUPAC name, number the chain from the end closest to a substituent. Two carboxyl groups on a benzene ring indicate a phthalic acid. 3-bromohexanedioic acid -bromoadipic acid 1,3-benzenedicarboxylic acid m-phthalic acid

Common Carboxylic acid Names Long chain carboxylic acids are called fatty acid. Fatty acids are generally found as ester in nature. Fat - a triglyceride - three fatty acids esterified to glycerol (propane-1,2,3-triol) - that is solid at room temperature. Generally animal source. Fatty acid chains are generally saturated. Oil - a triglyceride that is liquid at room temperature. Generally plant source. Fatty acid chains are generally unsaturated. See handout for the composition of different fats and oils.

Common Carboxylic acid Names For fatty acids containing double bonds, the location of the double bond is sometimes specified relative to the last carbon in the chain - the omega () carbon. Linoleic acid (an -6 fatty acid) Alpha-linolenic acid (an -3 fatty acid)

Common Carboxylic acid Names A deprotonated acid is a carboxylate ion. The -oic acid becomes -oate in the deprotonated form. The name of the metal counterion comes first in the compound name. Acetic acid Sodium acetate Sodium benzoate benzoic acid

Acidity of Carboxylic acids [RCOO][H+] Ka = [RCOOH] The larger the Ka values the stronger the acid. Since most carboxylic acids have small Ka values (104 and lower), acid strength is often expressed using pKa values.

Strong acids have small pKas Acidity of Carboxylic acids pKa = log Ka pKa and acid strength are inversely related Strong acids have small pKas Most carboxylic acids have pKa vales in the 4.0 to 5.0 range. HCOOH pKa = 3.75 CH3COOH pKa = 4.74 Benzoic acid pKa = 4.19

Acidity of Carboxylic acids Which to the stronger acid? pKa 4.19 4.46 3.41

Acidity of Carboxylic acids The proximity of electron withdrawing groups has an effect. pKa = 2.86 pKa = 4.52

Acid-Base reaction

spectroscopy of carboxylic acids C=O of COOH 1710 cm1 (conjugation lowers ) -O-H stretch of carboxylic acid 2500 - 3500 cm1 -O-H stretch of alcohol 3300 cm1 (2800 - 3200 cm1)

Proton NMR 10-12 ppm 1.0 1.6 2.4 13C-NMR 34 31 181 ppm 22 25 14

Synthesis of acids

Synthesis of acids

Synthesis of acids

Synthesis of acids

Synthesis of acids Nitriles can undergo either acid or base catalyzed hydrolysis to form carboxylic acids or carboxylates. Nitriles can easily be prepared from the corresponding halides.

Synthesis of acids Malonic ester synthesis: Diethyl malonate This second step is a decarboxylation reaction.

Synthesis of acids

Synthesis of acids Commercial sources Many carboxylic acids are derived commercially from natural sources. Straight chain acid with 6 to 18 are readily obtained from fats and oil. Fats and oils are composed of triesters of glycerol (triglyceride). The acid is obtained by either acid or base hydrolysis of the ester groups. The base hydrolysis is called saponification (the making of soap) produces the carboxylate salt. Acid hydrolysis gives the free acid.

Synthesis of acids Commercial sources Acetic acid is produced via both fermentation and catalytic processes. Other acids such as benzoic acid, phthalic acid and adipic acid are produced via oxidation of an appropriate substrate.

Reactions of acids The reactivity of these acid derivatives is dependent on the basicity of the leaving group. (List the leaving groups in order of increasing basicity.)

Synthesis of acid chlorides

Synthesis of esters from acids Ester synthesis

Esterification under acid conditions (Fischer esterification)

Esterification using diazomethane Yields of the methyl ester are very good. However, diazomethane is a toxic, explosive gas. The reagent is generated just before it is used. Ether solutions of this reagent are relatively safe to work with.

Ester from acid Chlorides What is the mechanism for this reaction?

Synthesis of amide from acids The initial formation of the ammonium carboxylate salt is an exothermic reaction. The reaction mixture is then typically heated to 125-150°C to convert the salt to the amide with loss of water.

Synthesis of amide from acid chlorides The HCl that is generated by this reaction must be neutralized or scavenged from the reaction mixture to prevent the protonating of unreacted amine. This is often done with pyridine, NaOH or Na2CO3. The reaction must be kept dry since acid chloride will react with water to give the acid.

Synthesis of acid anhydrides Acid anhydrides react similarly to acid chlorides to form esters and amides.

Reduction of Acids Note that esters undergo an analogous reaction with LAH.

Reduction of Acid Chlorides

Nomenclature and reactions of acid derivatives

Naming Esters Esters are named as alkyl carboxylates. Alkyl from the alcohol, carboxylate from the carboxylic acid precursor.

Cyclic Esters Reaction of -OH and -COOH on same molecule produces a cyclic ester, lactone. To name, add word lactone to the IUPAC acid name or replace the -ic acid of common name with -olactone. 4-hydroxybutanoic acid lactone γ -hydroxybutyrolactone 4-hydroxybutanoic acid γ-hydroxybutyric acid

Reactions of Esters transesterification saponificaton

Amides Product of the reaction of a carboxylic acid and ammonia or an amine. Not basic because the lone pair on nitrogen is delocalized by resonance.

Classes of Amides 1 amide has one C-N bond (two N-H). 2 amide or N-substituted amide has two C-N bonds (one N-H). 3 amide or N,N-disubstituted amide has three C-N bonds (no N-H).

Classes of Amides DMF is a common polar and aprotic solvent that is often used in the laboratory. Because of the very strong hydrogen bonding in 1° and 2° amides they have very high melting and boiling points.

Naming Amides For 1 amide, drop -ic or -oic acid from the carboxylic acid name, add -amide. For 2 and 3 amides, the alkyl groups bonded to nitrogen are named with N- to indicate their position. N-ethyl-N,2-dimethylpropanamide N-ethyl-N-methylisobutyramide

4-aminobutanoic acid lactam Cyclic Amides Reaction of -NH2 and -COOH on same molecule produces a cyclic amide, lactam. To name, add word lactam to the IUPAC acid name or replace the -ic acid of common name with -olactam. 4-aminobutanoic acid lactam -butyrolactam

Reactions of Amides (only work with 1 amides)

Naming Nitriles For IUPAC names, add -nitrile to the alkane name. Common names come from the carboxylic acid. Replace -ic acid with -onitrile. 5-bromohexanenitrile -bromocapronitrile Cyclohexanecarbonitrile

Nitriles synthesis Unlike other acid derivatives nitriles do not contain a carbonyl. Nitriles can be prepared by treating an amide with POCl3 or at high temperature over an alumina catalyst.

Reactions of Nitriles (Note: shorter periods of hydrolysis can yield an intermediate amide)

Acid Halides Named by replacing -ic acid with -yl halide. 3-bromobutanoyl bromide -bromobutyryl bromide benzoyl chloride

Acid Halides (Pyridine or NaHCO3(aq) is used to help control acidity since protonating the N stops the reaction.

To name an anhydride drop the word acid and replace with anhydride. Acid Anhydrides Two molecules of acid combine with the loss of water to form the anhydride. A carboxylate ion is the leaving group in nucleophilic acyl substitution reactions. To name an anhydride drop the word acid and replace with anhydride. R C O H

1,2-benzenedicarboxylic anhydride Acid Anhydrides ethanoic anhydride acetic anhydride 1,2-benzenedicarboxylic anhydride phthalic anhydride

Acid Anhydrides (Note: The benzene ring cannot be strongly deactivated.)

Multifunctional Compounds The functional group with the highest priority determines the parent name. Acid > ester > amide > nitrile > aldehyde > ketone > alcohol > amine > alkene > alkyne. ethyl o-cyanobenzoate

Solubility Acid chlorides and anhydrides are too reactive to be used with water or alcohol. Esters, 3 amides, and nitriles are good polar aprotic solvents. Solvents commonly used in organic reactions: Ethyl acetate Dimethylformamide (DMF) Acetonitrile

1H NMR Spectroscopy

13C NMR Spectroscopy

Acid Chloride to Anhydride Acid or carboxylate ion attacks the C=O. Tetrahedral intermediate forms. Chloride ion leaves, C=O is restored, H+ is abstracted.

Acid Chloride to Ester Alcohol attacks the C=O. Tetrahedral intermediate forms. Chloride ion leaves, C=O is restored, H+ is abstracted.

Acid Chloride to Amide Ammonia yields a 1 amide A 1 amine yields a 2 amide A 2 amine yields a 3 amide

Anhydride to Ester Alcohol attacks one C=O of anhydride. Tetrahedral intermediate forms. Carboxylate ion leaves, C=O is restored, H+ is abstracted.

Anhydride to Amide Ammonia yields a 1 amide A 1 amine yields a 2 amide A 2 amine yields a 3 amide

Ester to Amide Nucleophile must be NH3 or 1 amine. Prolonged heating required.

Transesterification One alkoxy group can be replaced by another with acid or base catalyst. Use large excess of preferred alcohol.