Organic Chemistry II Chapter 21 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions

Carboxylic Acids and Their Derivatives—Nucleophilic Acyl Substitution Carboxylic Acid Derivatives:

Types of anhydrides: Types of amides:

Cyclic esters and amides: Nitriles:

Carboxylic Acid Derivatives Carboxylic Acids Derivatives Carboxylic Acid Derivatives Acid Chloride Ester Amide Acid anhydride The derivatives of carboxylic acids are compounds in which the -OH of carboxylic acid is replaced by nucleopile (-X for acid halide, -OR for ester, -NH2, -NHR, -NR2 for amids, -OOCR for anhydride). Carboxylic acids derivatives can converted to carboxylic acids by simple acidic or basic hydrolysis.

Carboxylic Acids And Their Derivatives 1-Nomenclature Of Acid Chlorides Replace the -ic acid ending in the name of the parent acid by –yl chloride. IUPAC: Ethanoyl chloride Benzoylchloride Propanoyl chloride Common : Acetyl chloride

Carboxylic Acids And Their Derivatives 2- Nomenclature of esters The alkyl group (R’) is written first followed by the name of the parent acid with replacing of the ending –ic acid by –ate : (IUPAC) Ethyl ethanoate Methyl benzoate (common) Ethyl acetate (IUPAC) Methyl propanoate Isopropyl-4-hydroxy-5-methyl-5- hexenoate 9

Carboxylic Acids And Their Derivatives 3- Nomenclature of amide Replace the ending oic acid of the parent acid’s by the word amide If there is R group on the nitrogen atom, it is listed first and designated with –N. (IUPAC) Ethanamide Benzamide N-Methylpropanamide (common) Acetamide N-Methylpropionamide (IUPAC) N,N-Dimethylmethanamide N-Ethyl-N-methylbenzamide (Common) N,N-Dimethylformamide 10

Carboxylic Acids And Their Derivatives 4- Nomenclature of anhydride An anhydride is named by replacing the word acid in the corresponding acid by the word anhydride. (IUPAC) Ethanoic anhydride Benzoic anhydride Butandioic anhydride (Common) Acetic anhydride Succinic anhydride

Nomenclature

Spectroscopy of CADs: IR Absorption at 1650-1820 cm-1 for C=O

Spectroscopy of CADs: NMR 13C-NMR: Carbonyl carbon slightly upfield from aldehydes and ketones 1H-NMR: H adjacent to C=O around d2, but doesn’t always help you determine functional group Look for OH (CA), NH (amide), or OR (ester)

Nomenclature For acyclic acid chlorides: change the suffix –ic acid of the parent carboxylic acid to the suffix –yl chloride; or When the –COCl group is bonded to a ring: change the suffix –carboxylic acid to –carbonyl chloride.

Compound that containing carbonyl groups –called carbonyl compound. An acyl group consists of a carbonyl group attached to an alkyl group ( R) or an aryl group (Ar)

Carbonyl Compounds

Acyl Halides Acyl halides have a Cl or Br in place of OH. Acyl halides are named by replacing “ic acid” with the “yl chloride”

Acid Anhydrides Symmetrical anhydride when R1 the same as R2 Mixed (unsymmetrical anhydride) when R1 the not the same as R2

Esters The name of the group (R) attached to the carboxyl group is start 1st , followed by the name of the acid, with “ic acid” replaced by “ate”

Amides An amide has an NH2, NHR, or NR2 group in place of OH group. Amides are named by replacing “oic acid”, “ic acid” or “ylic acid” of the acid name with “amide”

Hydrolysis of Amides (Basis of peptide hydrolysis and protein digestion) Acid-catalyzed: Base-catalyzed:

Some Important Amides “bullet proof” vests Tylenol Penicillin Imodium (an opiod) Capsaicin LSD Kevlar (Nomex is the meta isomer) “bullet proof” vests

Nucleophilic Acyl Substitution Reactions

Addition-elimination is catalyzed by acid or base. Acid catalysis of an addition-elimination reaction proceeds by initial protonation of the carbonyl group and subsequent protonation of the leaving group.

Base catalysis proceeds by deprotonating the nucleophile.

Nucleophilic Acyl Substitution Carboxylic Acids → Carboxylic Acids Derivatives reactions Also used to make Carboxylic Acids from Carboxylic Acid Derivatives and convert between Carboxylic Acids Derivatives Z is leaving group Compare to nucleophilic addition (aldehydes/ketones)

Nucleophilic Acyl Substitution Mechanism Acid or base catalyst typically needed Acid makes electrophile more electrophilic Base makes nucleophile more nucleophilic

Nucleophilic Acyl Substitution Reactivity: Less substituted molecules are more reactive

Nucleophilic Acyl Substitution Reactivity: Molecules with better leaving groups are more reactive Less reactive compounds need heat or catalyst to react and are limited in the number of reactions they will undergo Example: amides only undergo hydrolysis and reduction

Nucleophilic Acyl Substitution Reactivity: More reactive compounds can be converted to less reactive compounds Can an ester be converted into an amide? Can an amide be converted into an ester?

Introduction to Nucleophilic Acyl Substitution Nucleophilic acyl substitutions is the characteristic reaction of carboxylic acid derivatives. This reaction occurs with both negatively charged nucleophiles and neutral nucleophiles.

Other nucleophiles that participate in this reaction include:

To draw any nucleophilic acyl product: [1] Find the sp2 hybridized carbon with the leaving group. [2] Identify the nucleophile. [3] Substitute the nucleophile for the leaving group. With a neutral nucleophile, the proton must be lost to obtain a neutral substitution product.

Based on this order of reactivity, more reactive compounds can be converted into less reactive ones. The reverse is not usually true.

Reactions of Acid Chlorides Acid chlorides react readily with nucleophiles to form nucleophilic substitution products. HCl is usually formed as a by-product. A weak base like pyridine is added to the reaction mixture to remove the strong acid (HCl), forming an ammonium salt.

Acid chlorides react with oxygen nucleophiles to form anhydrides, carboxylic acids and esters.

Acid chlorides also react with ammonia and 1° and 2° amines to form 1°, 2° and 3° amides respectively. Two equivalents of NH3 or amine are used. One equivalent acts as the nucleophile to replace Cl, while the other reacts as a base with the HCl by-product to form an ammonium salt.

As an example, reaction of an acid chloride with diethylamine forms the 30 amide N,N-diethyl-m-toluamide, popularly known as DEET. DEET is the active ingredient in the most widely used insect repellents, and is effective against mosquitoes, fleas and ticks.

Reactions of Anhydrides Nucleophilic attack occurs at one carbonyl group, while the second carbonyl becomes part of the leaving group.

Besides the usual steps for nucleophilic addition and elimination of the leaving group, the mechanism involves an additional proton transfer.

Reactions of Carboxylic Acids Nucleophiles that are also strong bases react with carboxylic acids by removing a proton first, before any nucleophilic substitution reaction can take place.

Figure 22.2 Nucleophilic acyl substitution reactions of carboxylic acids

Treatment of a carboxylic acid with thionyl chloride (SOCl2) affords an acid chloride. This is possible because thionyl chloride converts the OH group of the acid into a better leaving group, and because it provides the nucleophile (Cl¯) to displace the leaving group.

Although carboxylic acids cannot readily be converted into anhydrides, dicarboxylic acids can be converted to cyclic anhydrides by heating to high temperatures. This is a dehydration reaction because a water molecule is lost from the diacid.

Treatment of a carboxylic acid with an alcohol in the presence of an acid catalyst forms an ester. This reaction is called a Fischer esterification. The reaction is an equilibrium, so it is driven to the right by using excess alcohol or by removing water as it is formed.

Esterification of a carboxylic acid occurs in the presence of acid but not in the presence of base. Base removes a proton from the carboxylic acid, forming the carboxylate anion, which does not react with an electron-rich nucleophile.

Intramolecular esterification of - and -hydroxyl carboxylic acids forms five- and six-membered lactones.

Carboxylic acids cannot be converted into amides by reaction with NH3 or an amine because amines are bases, and undergo an acid-base reaction to form an ammonium salt before nucleophilic substitution occurs. However, heating the ammonium salt at high temperature (>100°C) dehydrates the resulting ammonium salt of the carboxylate anion to form an amide, although the yield can be low.

The overall conversion of RCOOH to RCONH2 requires two steps: [1] Acid-base reaction of RCOOH with NH3 to form an ammonium salt. [2] Dehydration at high temperature (>100°C).

A carboxylic acid and an amine readily react to form an amide in the presence of an additional reagent, dicyclohexylcarbodimide (DCC), which is converted to the by-product dicyclohexylurea in the course of the reaction.

DCC is a dehydrating agent. The dicyclohexylurea by-product is formed by adding the elements of H2O to DCC. DCC promotes amide formation by converting the carboxy group OH group into a better leaving group.

Reactions of Esters Esters are hydrolyzed with water in the presence of either acid or base to form carboxylic acids or carboxylate anions respectively. Esters react with NH3 and amines to form 1°, 2°, or 3° amides.

Basic hydrolysis of an ester is also called saponification. Hydrolysis is base promoted, not base catalyzed, because the base (OH–) is the nucleophile that adds to the ester and forms part of the product. It participates in the reaction and is not regenerated later.

The carboxylate anion is resonance stabilized, and this drives the equilibrium in its favor. Once the reaction is complete and the anion is formed, it can be protonated with strong acid to form the neutral carboxylic acid.

Reactions of Amides Amides are the least reactive of the carboxylic acid derivatives. Amides are hydrolyzed in acid or base to form carboxylic acids or carboxylate anions. In acid, the amine by-product is protonated as an ammonium ion, whereas in base, a neutral amine forms.

The mechanism of amide hydrolysis in acid is exactly the same as the mechanism of ester hydrolysis in acid. The mechanism of amide hydrolysis in base has the usual two steps in the general mechanism for nucleophilic acyl substitution, plus an additional proton transfer.

Summary of Nucleophilic Acyl Substitution Reactions

Nitriles Nitriles have the general structural formula RCN. Two useful biologically active nitriles are letrozole and anastrozole. Nitriles are prepared by SN2 reactions of unhindered methyl and 1° alkyl halides with ¯CN.

Reactions of Nitriles—Hydrolysis Nitriles are hydrolyzed with water in the presence of acid or base to yield carboxylic acids or carboxylate anions. In this reaction, the three C—N bonds are replaced by three C—O bonds.

The mechanism of this reaction involves formation of an amide tautomer The mechanism of this reaction involves formation of an amide tautomer. Two tautomers can be drawn for any carbonyl compound, and those for a 1° amide are as follows:

The imidic acid and amide tautomers are interconverted by treatment with acid or base, analogous to keto-enol tautomers of other carbonyl compounds.

Nucleophilic Acyl Substitution Types of reactions

Nucleophilic Acyl Substitution Types of reactions: Reaction Nucleophile Product Special Notes Hydrolysis H2O Carboxylic acid Alcoholysis ROH Ester Aminolysis NH3 1° amine 2° amine 1° amide 2° amide 3° amide With acid chlorides, 2 eq. of amine are needed: the nucleophile neutralizes HCl byproduct Reduction Hydride from LAH CA → 1° ROH Ester → 1° ROH Anhydride → 1° ROH Acid chloride → 1° ROH Amides → amines Hydride from DIBALH aldehyde Ester only Grignard RMgX 3° alcohol Ester and acid halide only

Nucleophilic Acyl Substitution Summary of reactions: acid halide Also Grignard Anhydride formation:

Nucleophilic Acyl Substitution Summary of reactions: anhydrides Example: commercial preparation of aspirin

Nucleophilic Acyl Substitution Summary of reactions: esters Hydrolysis Alcoholysis Aminolysis Reduction (to 1° alcohols and aldehydes) Grignard Alcoholysis of esters = transesterification

Nucleophilic Acyl Substitution Summary of reactions: amides Hydrolysis Acid or base catalyst Heat Reduction

Nucleophilic Acyl Substitution Summary of reactions: nitriles Hydrolysis Acid or base catalyst Heat Reduction

Nucleophilic Acyl Substitution Complete the chart with the functional group that will form from the following reactions.   H2O ROH NH3 LAH Grignard Carboxylic acid Acid halide Acid anhydride Ester Amide Nitrile

Nucleophilic Acyl Substitution Complete the chart with the functional group that will form from the following reactions.   H2O ROH NH3 LAH Grignard Carboxylic acid -COOH  -COOR -CONH2 -CH2OH R-H Acid halide -COOH ESTER AMIDE ALCOHOL KETONE Acid anhydride  KETONE Ester NO RXN Amide Nitrile

Interconversion of Carboxylic Acid Derivatives You should know the ones in red ! Ask yourself what interconversions are possible, indicating the reagent required and then a reaction mechanism.

Nucleophilic Acyl Substitution Specific reactions: Saponification (soap-making) Hydrolysis of ester in base Irreversible reaction

Nucleophilic Acyl Substitution Condensation polymerization A step-growth reaction Example: polyamide What is a polyester? How could a polyester be synthesized?

Nucleophilic Acyl Substitution Step-growth polymerization Compare Fischer esterification… …to polymerization

Nucleophilic Acyl Substitution Step-growth polymerization Biodegradable polymers

What is the order of decreasing activity (most reactive = 1, least reactive = 4) toward nucleophilic acyl substitution for the following carboxylic acid derivatives?

Draw the products of these reactions.

Synthesis Propose a synthesis for ethyl acetate from ethanol.

Provide reagents to complete the reaction scheme

Provide reagents for the following reactions:

Some Examples

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