Organic Chemistry William H. Brown & Christopher S. Foote

Carboxyl Derivatives

Carboxyl Derivatives In this chapter, we study five classes of organic compounds under the structural formula of each is a drawing to help you see its relationship to the carboxyl group

Carboxyl Derivatives an amide is formally related to a carboxyl group by loss of -OH from the carboxyl and -H from ammonia loss of -OH and -H from an amide gives a nitrile

Structure: Acid Chlorides The functional group of an acid halide is an acyl group bonded to a halogen to name, change the suffix -ic acid to -yl halide

Acid Chlorides replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride

Acid Anhydrides The functional group of an acid anhydride is two acyl groups bonded to an oxygen atom the anhydride may be symmetrical (two identical acyl groups) or mixed (two different acyl groups) to name, replace acid of the parent acid by anhydride

Acid Anhydrides Cyclic anhydrides are named from the dicarboxylic acids from which they are derived

Acid Anhydrides A phosphoric acid anhydride contains two phosphoryl groups bonded to an oxygen atom

Esters The functional group of an ester is an acyl group bonded to -OR or -OAr name the alkyl or aryl group bonded to oxygen followed by the name of the acid change the suffix -ic acid to -ate

Esters Cyclic esters are called lactones name the parent carboxylic acid, drop the suffix -ic acid, and add -olactone

Amides The functional group of an amide is an acyl group bonded to a nitrogen atom IUPAC: drop -oic acid from the name of the parent acid and add -amide if the amide nitrogen is bonded to an alkyl or aryl group, name the group and show its location on nitrogen by N-

Amides Cyclic amides are called lactams Name the parent carboxylic acid, drop the suffix -ic acid and add -lactam

Penicillins The penicillins are a family of -lactam antibiotics

Penicillins Amoxicillin

Cephalosporins The cephalosporins are also -lactam antibiotics

Cefetamet

Nitriles The functional group of a nitrile is a cyano group IUPAC: name as an alkanenitrile Common: drop the -ic acid and add -onitrile

Acidity of N-H bonds Amides are comparable in acidity to alcohols water-insoluble amides do not react with NaOH or other alkali metal hydroxides to form water soluble salts Sulfonamides and imides are more acidic than amides

Acidity of N-H bonds Imides are more acidic than amides because 1. the electron-withdrawing inductive of the two adjacent C=O groups weakens the N-H bond, and 2. the imide anion is stabilized by resonance delocalization of the negative charge

Acidity of N-H imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts

IR Spectroscopy

NMR Spectroscopy 1H-NMR 13C-NMR H on the -carbon to a C=O group are slightly deshielded and come into resonance at  2.1-2.6 H on the carbon of the ester oxygen are more strongly deshielded and come into resonance at  3.7-4.7 13C-NMR the carbonyl carbons of esters show characteristic resonance at  160-180

Characteristic Reactions Nucleophilic acyl substitution: an addition-elimination sequence resulting in substitution of one nucleophile for another

Characteristic Reactions in this general reaction, we have shown the leaving group as an anion to illustrate an important point about them: the weaker the base, the better the leaving group

Characteristic Reactions halide ion is the weakest base and the best leaving group; acid halides are the most reactive toward nucleophilic acyl substitution amide ion is the strongest base and the poorest leaving group; amides are the least reactive toward nucleophilic acyl substitution

Rexn with H2O - RCOCl low-molecular-weight acid chlorides react rapidly with water higher molecular-weight acid chlorides are less soluble in water and react less readily

Rexn with H2O - RCO2OR low-molecular-weight acid anhydrides react readily with water to give two molecules of carboxylic acid higher-molecular-weight acid anhydrides also react with water, but less readily

Rexn with H2O - Esters Esters are hydrolyzed only slowly, even in boiling water Hydrolysis becomes more rapid if they are heated with either aqueous acid or base Hydrolysis in aqueous acid is the reverse of Fischer esterification the role of the acid catalyst is to protonate the carbonyl oxygen and increase its electrophilic character toward attack by water to form a tetrahedral carbonyl addition intermediate collapse of this intermediate gives the carboxylic acid and alcohol

Rexn with H2O - Esters Acid-catalyzed ester hydrolysis

Rexn with H2O - Esters Hydrolysis of an esters in aqueous base is often called saponification each mole of ester hydrolyzed requires 1 mole of base; for this reason, ester hydrolysis in aqueous base is said to be base promoted hydrolysis of an ester in aqueous base involves formation of a tetrahedral carbonyl addition intermediate followed by its collapse and proton transfer

Rexn with H2O - Amides Hydrolysis of an amide in aqueous acid requires 1 mole of acid per mole of amide

Rexn with H2O - Amides Hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide

Rexn with H2O - Nitriles The cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion

Rexn with H2O - Nitriles protonation of the cyano nitrogen gives a cation that reacts with water to give an imidic acid keto-enol tautomerism of the imidic acid gives the amide

Rexn with H2O - Nitriles hydrolysis of a cyano group in aqueous base gives a carboxylic anion and ammonia; acidification converts the carboxylic anion to the carboxylic acid

Rexn with H2O - Nitriles Hydrolysis of nitriles is a valuable route to carboxylic acids

Rexn with Alcohols Acid halides react with alcohols to give esters acid halides are so reactive toward even weak nucleophiles such as alcohols that no catalyst is necessary where the alcohol or resulting ester is sensitive to HCl, reaction is carried out in the presence of a 3° amine to neutralize the acid

Rexn with Alcohols sulfonic acid esters are prepared by the reaction of an alkane- or arenesulfonyl chloride with an alcohol or phenol

Rexn with Alcohols Acid anhydrides react with alcohols to give one mole of ester and one mole of carboxylic acid

Rexn with Alcohols cyclic anhydrides react with alcohols to give one ester group and one carboxyl group

Rexn with Alcohols aspirin is synthesized by treatment of salicylic acid with acetic anhydride

Rexn with Alcohols Esters react with alcohols in the presence of an acid catalyst in a reaction called transesterification, an equilibrium reaction

Rexn with Ammonia, etc. Acid halides react with ammonia, 1° amines, and 2° amines to form amides 2 moles of the amine are required per mole of acid chloride

Rexn with Ammonia, etc. Acid anhydrides react with ammonia, and 1° and 2° amines to form amides. 2 moles of ammonia or amine are required

Rexn with Ammonia, etc. Esters react with ammonia, and 1° and 2° amines to form amides esters are less reactive than either acid halides or acid anhydrides Amides do not react with ammonia, or 1° or 2° amines

Interconversions

Acid Chlorides with Salts Acid chlorides react with salts of carboxylic acids to give anhydrides most commonly used are sodium or potassium salts

Rexns with Grignards treatment of a formic ester with 2 moles of Grignard reagent followed by hydrolysis with aqueous acid gives a 2° alcohol

Rexn with Grignards treatment of an ester other than formic with a Grignard reagent followed by hydrolysis in aqueous acid gives a 3° alcohol

Rexns with Grignards 1. addition of 1 mole of RMgX to the carbonyl carbon gives a TCAI 2. collapse of the TCAI gives a ketone (an aldehyde from a formic ester)

Reaction with Grignards 3. reaction of the ketone with a 2nd mole of RMgX gives a second TCAI 4. treatment with aqueous acid gives the alcohol

Rexns with RLi Organolithium compounds are even more powerful nucleophiles than Grignard reagents they react with esters to give the same types of 2° and 3° alcohols as do Grignard reagents and often in higher yields

Gilman Reagents Acid chlorides at -78°C react with Gilman reagents to give ketones. under these conditions, the TCAI is stable, and it is not until acid hydrolysis that the ketone is liberated

Gilman Reagents Gilman reagents react only with acid chlorides they do not react with acid anhydrides, esters, amides, or nitriles under the conditions described

Redn - Esters by LiAlH4 Most reductions of carbonyl compounds now use hydride reducing agents esters are reduced by LiAlH4 to two alcohols the alcohol derived from the carbonyl group is primary

Redn - Esters by LiAlH4 Reduction occurs in three steps plus workup

Redn - Esters by LiAlH4 NaBH4 does not normally reduce esters, but it does reduce aldehydes and ketones Selective reduction is often possible by the proper choice of reducing agents and experimental conditions

Redn - Esters by DIBAlH Diisobutylaluminum hydride (DIBAlH) at -78°C selectively reduces an ester to an aldehyde at -78°C, the TCAI does not collapse and it is not until hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated

Redn - Amides by LiAlH4 LiAlH4 reduction of an amide gives a 1°, 2°, or 3° amine, depending on the degree of substitution of the amide

Redn - Amides by LiAlH4 The mechanism is divided into 4 steps Step 1: transfer of a hydride ion to the carbonyl carbon Step 2: formation of an oxygen-aluminum bond

Redn - Amides by LiAlH4 Step 3: redistribution of electrons gives an iminium ion Step 4: transfer of a second hydride ion completes the reduction to the amine

Redn - Nitriles by LiAlH4 The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine

Interconversions Problem: show reagents and experimental conditions to bring about each reaction

Hofmann Rearrangement When a 1° amide is treated with bromine or chlorine in aqueous NaOH or KOH, the carbonyl carbon is lost as carbonate ion, and the amide is converted to an amine of one fewer carbon atoms

Hofmann Rearrangement Stage 1: acid-base reaction gives an amide anion, which reacts as a nucleophile with Br2 Stage 2: a 2nd acid-base reaction followed by elimination of Br- gives a nitrene, an electron-deficient species, that rearranges to an isocyanate

Hofmann Rearrangement Stage 3: reaction of the isocyanate with water gives a carbamic acid Stage 4: decarboxylation of the carbamic acid gives the primary amine

Prob 18.19 Propose a structural formula for each compound.

Prob 18.19 (cont’d) Propose a structural formula for each compound.

Prob 18.20 Draw a structural formula for the product formed on treatment of benzoyl chloride with each reagent.

Prob 18.26 Draw a structural formula for the product of treating this a,b-unsaturated ketone with each reagent.

Prob 18.28 Draw a structural formula for the product of treating this anhydride with each reagent.

Prob 18.31 Show how to bring about each step in this conversion of nicotinic acid to nicotinamide.

Prob 18.32 Complete these reactions.

Prob 18.35 Draw structural formulas for the products of complete hydrolysis of each compound in hot aqueous acid.

Prob 18.36 Show reagents to bring about each step in this synthesis of anthranilic acid.

Prob 18.37 Propose a mechanism for each step in this sequence.

Prob 18.38 Propose a mechanism for each step in this sequence.

Prob 18.39 Show how to prepare the insect repellent DEET from 3-methyltoluic acid.

Prob 18.40 Show how to prepare isoniazid from 4-pyridinecarboxylic acid.

Prob 18.41 Show how to bring about this conversion.

Prob 18.42 Propose a mechanism for the formation of this bromolactone, and account for the observed stereochemistry of each substituent on the cyclohexane ring.

Prob 18.43 Propose a mechanism for this reaction.

Prob 18.44 Propose a synthesis of this b-chloroamine from anthranilic acid.

Prob 18.45 Show reagents for the synthesis of 5-nonanone from 1-bromobutane as the only organic starting material.

Prob 18.46 Describe a synthesis of procaine from the three named starting materials.

Prob 18.47 The following sequence converts (R)-2-octanol to (S)-2-octanol. Propose structural formulas for A and B, and specify the configuration of each.

Prob 18.48 Propose a mechanism for this reaction.

Prob 18.49 Propose a mechanism for this reaction.

Prob 18.50 Show how each hypoglycemic drug can be synthesized by converting an appropriate amine to a carbamate ester, and then treating its sodium salt with a substituted benzenesufonamide.

Prob 18.51 Propose a mechanism for Step 1, and reagents for Step 2 in the synthesis of the antiviral agent amantadine.

Prob 18.52 Propose structural formulas for intermediates A-F and for the configuration of the bromoepoxide.

Prob 18.53 Show reagents for the synthesis of (S)-Metolachlor from the named starting materials

Derivatives of Carboxylic Acids End Chapter 18