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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.

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Organic chemistry

Organic

Chemistry

William H. Brown &

Christopher S. Foote


Organic chemistry

Carboxyl

Derivatives


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 derivatives1

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

Structure: Acid Chlorides

  • The functional group of an acid halide is an acyl group bonded to a halogen

    • to name, change the suffix -ic acidto -yl halide


Acid chlorides

Acid Chlorides

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


Acid anhydrides

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 anhydrides1

Acid Anhydrides

  • Cyclic anhydrides are named from the dicarboxylic acids from which they are derived


Acid anhydrides2

Acid Anhydrides

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


Esters

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


Esters1

Esters

  • Cyclic esters are called lactones

    • name the parent carboxylic acid, drop the suffix -ic acid, and add -olactone


Amides

Amides

  • The functional group of an amide is an acyl group bonded to a nitrogen atom

    • IUPAC: drop -oic acidfrom 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-


Amides1

Amides

  • Cyclic amides are called lactams

  • Name the parent carboxylic acid, drop the suffix -ic acid and add -lactam


Penicillins

Penicillins

  • The penicillins are a family of -lactam antibiotics


Penicillins1

Penicillins

  • Amoxicillin


Cephalosporins

Cephalosporins

  • The cephalosporins are also -lactam antibiotics


Cefetamet

Cefetamet


Nitriles

Nitriles

  • The functional group of a nitrile is a cyano group

  • IUPAC: name as an alkanenitrile

  • Common: drop the -ic acidand add -onitrile


Acidity of n h bonds

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 bonds1

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

Acidity of N-H

  • imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts


Ir spectroscopy

IR Spectroscopy


Nmr spectroscopy

NMR Spectroscopy

  • 1H-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

Characteristic Reactions

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


Characteristic reactions1

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 reactions2

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 h 2 o rcocl

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 h 2 o rco 2 or

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 h 2 o esters

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 h 2 o esters1

Rexn with H2O - Esters

  • Acid-catalyzed ester hydrolysis


Rexn with h 2 o esters2

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 h 2 o amides

Rexn with H2O - Amides

  • Hydrolysis of an amide in aqueous acid requires 1 mole of acid per mole of amide


Rexn with h 2 o amides1

Rexn with H2O - Amides

  • Hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide


Rexn with h 2 o nitriles

Rexn with H2O - Nitriles

  • The cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion


Rexn with h 2 o nitriles1

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 h 2 o nitriles2

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 h 2 o nitriles3

Rexn with H2O - Nitriles

  • Hydrolysis of nitriles is a valuable route to carboxylic acids


Rexn with alcohols

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 alcohols1

Rexn with Alcohols

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


Rexn with alcohols2

Rexn with Alcohols

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


Rexn with alcohols3

Rexn with Alcohols

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


Rexn with alcohols4

Rexn with Alcohols

  • aspirin is synthesized by treatment of salicylic acid with acetic anhydride


Rexn with alcohols5

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

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 etc1

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 etc2

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

Interconversions


Acid chlorides with salts

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

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

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 grignards1

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

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

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

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 reagents1

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 lialh 4

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 lialh 41

Redn - Esters by LiAlH4

  • Reduction occurs in three steps plus workup


Redn esters by lialh 42

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

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 lialh 4

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 lialh 41

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 lialh 42

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 lialh 4

Redn - Nitriles by LiAlH4

  • The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine


Interconversions1

Interconversions

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


Hofmann rearrangement

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 rearrangement1

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 rearrangement2

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

Prob 18.19

Propose a structural formula for each compound.


Prob 18 19 cont d

Prob 18.19 (cont’d)

Propose a structural formula for each compound.


Prob 18 20

Prob 18.20

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


Prob 18 26

Prob 18.26

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


Prob 18 28

Prob 18.28

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


Prob 18 31

Prob 18.31

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


Prob 18 32

Prob 18.32

Complete these reactions.


Prob 18 35

Prob 18.35

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


Prob 18 36

Prob 18.36

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


Prob 18 37

Prob 18.37

Propose a mechanism for each step in this sequence.


Prob 18 38

Prob 18.38

Propose a mechanism for each step in this sequence.


Prob 18 39

Prob 18.39

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


Prob 18 40

Prob 18.40

Show how to prepare isoniazid from 4-pyridinecarboxylic acid.


Prob 18 41

Prob 18.41

Show how to bring about this conversion.


Prob 18 42

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

Prob 18.43

Propose a mechanism for this reaction.


Prob 18 44

Prob 18.44

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


Prob 18 45

Prob 18.45

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


Prob 18 46

Prob 18.46

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


Prob 18 47

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

Prob 18.48

Propose a mechanism for this reaction.


Prob 18 49

Prob 18.49

Propose a mechanism for this reaction.


Prob 18 50

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

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

Prob 18.52

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


Prob 18 53

Prob 18.53

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


Organic chemistry

Derivatives of

Carboxylic Acids

End Chapter 18


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