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Carboxylic Acids

The Importance of Carboxylic Acids (RCO2H) Starting materials for acyl derivatives (esters, amides,

and acid chlorides) Abundant in nature from oxidation of aldehydes and

alcohols in metabolism Acetic acid, CH3CO2H, - vinegar Butanoic acid, CH3CH2CH2CO2H (rancid butter) Long-chain aliphatic acids from the breakdown of fats

Carboxylic acids present in many industrial processes and most biological processes

They are the starting materials from which other acyl derivatives are made

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Naming Carboxylic Acids Carboxylic Acids, RCO2H If derived from open-chain alkanes, replace the

terminal -e of the alkane name with -oic acid The carboxyl carbon atom is C1

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Alternative Names

Compounds with CO2H bonded to a ring are named using the suffix -carboxylic acid

The CO2H carbon is not itself numbered in this system

Use common names for formic acid (HCOOH) and acetic acid (CH3COOH) – see Table 20.1

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Structure and Properties of Carboxylic Acids Carboxyl carbon sp2 hybridized: carboxylic acid

groups are planar with C–C=O and O=C–O bond angles of approximately 120°

Carboxylic acids form hydrogen bonds, existing as cyclic dimers held together by two hydrogen bonds

Strong hydrogen bonding causes much higher boiling points than the corresponding alcohols

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Dissociation of Carboxylic Acids Carboxylic acids are proton donors toward weak and

strong bases, producing metal carboxylate salts, RCO2

+M Carboxylic acids with more than six carbons are only

slightly soluble in water, but their conjugate base salts are water-soluble

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Acidity Constant and pKa

Carboxylic acids transfer a proton to water to give H3O+ and carboxylate anions, RCO2

, but H3O+ is a much stronger acid

The acidity constant, Ka,, is about 10-5 for a typical carboxylic acid (pKa ~ 5)

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Substituent Effects on Acidity

Electronegative substituents promote formation of the carboxylate ion

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Inductive Effects on Acidity

Fluoroacetic, chloroacetic, bromoacetic, and iodoacetic acids are stronger acids than acetic acid

Multiple electronegative substituents have synergistic effects on acidity

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Preparation of Carboxylic Acids

Oxidation of a substituted alkylbenzene with KMnO4or Na2Cr2O7 gives a substituted benzoic acid (see Section 16.9)

1° and 2° alkyl groups can be oxidized, but tertiary groups are not

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From Alkenes

Oxidative cleavage of an alkene with KMnO4 gives a carboxylic acid if the alkene has at least one vinylic hydrogen (see Section 7.9)

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From Alcohols

Oxidation of a primary alcohol or an aldehyde with CrO3 in aqueous acid

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Reactions of Carboxylic Acids: An Overview Carboxylic acids transfer a proton to a base to give

anions, which are good nucleophiles in SN2 reactions Like ketones, carboxylic acids undergo addition of

nucleophiles to the carbonyl group In addition, carboxylic acids undergo other reactions

characteristic of neither alcohols nor ketones

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Carboxylic Acid Derivatives:

Nucleophilic Acyl Substitution Reactions

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Carboxylic Compounds Acyl group bonded to X, an electronegative atom or

leaving group Includes: X = halide (acid halides), acyloxy

(anhydrides), alkoxy (esters), amine (amides)

Nucleophilic acyl substitution

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Naming Carboxylic Acid Derivatives

Acid Halides, RCOX Derived from the carboxylic acid name by replacing the

-ic acid ending with -yl or the -carboxylic acid ending with –carbonyl and specifying the halide

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Naming Acid Anhydrides, RCO2COR'

If symmetrical replace “acid” with “anhydride” based on the related carboxylic acid

From substituted monocarboxylic acids: use bis-ahead of the acid name

Unsymmetrical anhydrides— cite the two acids alphabetically

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Naming Amides, RCONH2

With unsubstituted NH2 group. replace -oic acid or -ic acid with -amide, or by replacing the -carboxylic acid ending with –carboxamide

If the N is further substituted, identify the substituent groups (preceded by “N”) and then the parent amide

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Naming Esters, RCO2R’

Name R’ and then, after a space, the carboxylic acid (RCOOH), with the “-ic acid” ending replaced by “-ate”

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Nucleophilic Acyl Substitution

Carboxylic acid derivatives have an acyl carbon bonded to a group Y that can leave

A tetrahedral intermediate is formed and the leaving group is expelled to generate a new carbonyl compound, leading to substitution

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Relative Reactivity of Carboxylic Acid Derivatives Nucleophiles react

more readily with unhindered carbonyl groups

More electrophilic carbonyl groups are more reactive to addition (acyl halides are most reactive, amides are least)

The intermediate with the best leaving group decomposes fastest

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General Reactions of Carboxylic Acid Derivatives water ˝ carboxylic

acid alcohols ̋ esters ammonia or an

amine ˝ an amide hydride source ˝

an aldehyde or an alcohol

Grignard reagent ˝ a ketone or an alcohol

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Conversion of Carboxylic Acids into Acid Chlorides Reaction with thionyl chloride, SOCl2

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Conversion of Carboxylic Acids into Acid Anhydrides Acid anhydrides can be derived from two molecules of

carboxylic acid by strong heating to remove water

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Conversion of Carboxylic Acids into Esters Methods include reaction of a carboxylate anion with

a primary alkyl halide

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Fischer Esterification

Heating a carboxylic acid in an alcohol solvent containing a small amount of strong acid produces an ester from the alcohol and acid

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Chemistry of Acid Halides Acid chlorides are prepared from carboxylic acids by

reaction with SOCl2 Reaction of a carboxylic acid with PBr3 yields the acid

bromide

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Hydrolysis: Conversion of Acid Halides into Acids Acid chlorides react with water to yield carboxylic

acids HCl is generated during the hydrolysis: a base is

added to remove the HCl

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Conversion of Acid Halides to Esters Esters are produced in the reaction of acid chlorides

with alcohols in the presence of pyridine or NaOH. This is called Alcoholysis

The reaction is better with less steric bulk

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Aminolysis: Conversion of Acid Halides into Amides Amides result from the reaction of acid chlorides with

NH3, primary (RNH2) and secondary amines (R2NH) The reaction with tertiary amines (R3N) gives an

unstable species that cannot be isolated HCl is neutralized by the amine or an added base

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Reaction of Acid Chlorides with Organometallic Reagents Grignard reagents react with acid chlorides to yield

tertiary alcohols in which two of the substituents are the same

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Formation of Ketones from Acid Chlorides Reaction of an acid chloride with a lithium

diorganocopper (Gilman) reagent, Li+ R2Cu

Addition produces an acyl diorganocopper intermediate, followed by loss of RCu and formation of the ketone

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Chemistry of Acid Anhydrides

Prepared by nucleophilic acyl substitution of a carboxylate with an acid chloride

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Reactions of Acid Anhydrides

Similar to acid chlorides in reactivity

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Acetylation

Acetic anhydride forms acetate esters from alcohols and N-substituted acetamides from amines

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Chemistry of Esters Many esters are pleasant-smelling liquids: fragrant

odors of fruits and flowers Also present in fats and vegetable oils

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Preparation of Esters

Esters are usually prepared from carboxylic acids

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Reactions of Esters

Less reactive toward nucleophiles than are acid chlorides or anhydrides

Cyclic esters are called lactones and react similarly to acyclic esters

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Hydrolysis: Conversion of Esters into Carboxylic Acids An ester is hydrolyzed by aqueous base or aqueous

acid to yield a carboxylic acid plus an alcohol

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Reduction: Conversion of Esters into Alcohols Reaction with LiAlH4 yields primary alcohols

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Reaction of Esters with Grignard Reagents React with 2 equivalents of a Grignard reagent to

yield a tertiary alcohol

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21.7 Chemistry of Amides

Amides are abundant in all living organisms…proteins, nucleic acids, and other pharmaceuticals have amid functional groups

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Preparation of Amides Prepared by reaction of an acid chloride with

ammonia, monosubstituted amines, or disubstituted amines

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Reduction: Conversion of Amides into Amines Reduced by LiAlH4 to an amine rather than an

alcohol Converts C=O CH2

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Nitriles, RCN

Closely related to carboxylic acids named by adding -nitrile as a suffix to the alkane name, with the nitrile carbon numbered C1

Complex nitriles are named as derivatives of carboxylic acids. Replace -ic acid or -oic acid ending with -onitrile

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Chemistry of Nitriles

Nitriles and carboxylic acids both have a carbon atom with three bonds to an electronegative atom, and contain a bond

Both both are electrophiles

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Reactions of Nitriles

RCN is strongly polarized and with an electrophilic carbon atom

Attacked by nucleophiles to yield sp2-hybridized imine anions

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Hydrolysis: Conversion of Nitriles into Carboxylic Acids Hydrolyzed in with acid or base catalysis to a

carboxylic acid and ammonia or an amine

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Hydrolysis of Nitriles Hot acid or base yields carboxylic acids Conversion of an alkyl halide to a nitrile (with cyanide

ion) followed by hydrolysis produces a carboxylic acid with one more carbon (RBr RCN RCO2H)

Best with primary halides because elimination reactions occur with secondary or tertiary alkyl halides

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Reduction: Conversion of Nitriles into Amines

Reduction of a nitrile with LiAlH4 gives a primary amine

Nucleophilic addition of hydride ion to the polar CN bond, yieldis an imine anion

The C=N bond undergoes a second nucleophilic addition of hydride to give a dianion, which is protonated by water

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Reaction of Nitriles with Organometallic Reagents Grignard reagents add to give an intermediate imine anion that

is hydrolyzed by addition of water to yield a ketone

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Amines

Organic Bases

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Amines – Organic Nitrogen Compounds Organic derivatives of ammonia, NH3, Nitrogen atom with a lone pair of electrons, making

amines both basic and nucleophilic Occur in plants and animals

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Naming Amines Alkyl-substituted (alkylamines) or aryl-substituted (arylamines) Classified: 1° (RNH2), methyl (CH3NH2), 2° (R2NH), 3° (R3N)

Quaternary Ammonium Ions: A nitrogen atom with four attached groups is positively charged.

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Simple Amines For simple amines, the suffix -amine is added to the name of the

alkyl substituent

The suffix -amine can be used in place of the final -e in the name of the parent compound

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Amines With More Than One Functional Group Consider the NH2 as an amino substituent on the parent

molecule

Multiple Alkyl Groups: Symmetrical secondary and tertiary amines are named by adding the prefix di- or tri- to the alkyl group

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Multiple, Different Alkyl Groups

Named as N-substituted primary amines Largest alkyl group is the parent name, and other alkyl groups are

considered N-substituents

If the nitrogen atom occurs as part of a ring, the compound is designated as being heterocyclic amines.

Each ring system has its own parent name.

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Amines Form H-Bonds Amines with fewer than five carbons are water-soluble Primary and secondary amines form hydrogen bonds,

increasing their boiling points

Basicity of Amines: The lone pair of electrons on nitrogen makes amines basic and nucleophilic

They react with acids to form acid–base salts and they react with electrophiles

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SN2 Reactions of Alkyl Halides

Ammonia and other amines are good nucleophiles

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Uncontrolled Multiple Alkylation

Primary, secondary, and tertiary amines all have similar reactivity, the initially formed monoalkylated substance undergoes further reaction to yield a mixture of products

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Reductive Amination of Aldehydes and Ketones Treatment of an aldehyde or ketone with ammonia or

an amine in the presence of a reducing agent

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Reductive Amination Is Versatile Ammonia, primary amines, and secondary

amines yield primary, secondary, and tertiary amines, respectively

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Hofmann Rearrangements

Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement rearrangement

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Hofmann Elimination Converts amines into alkenes NH2

is very a poor leaving group so it converted to an alkylammonium ion, which is a good leaving group

Silver Oxide Is Used for the Elimination Step: Exchanges hydroxide ionfor iodide ion in the quaternary ammonium salt, thus providing the basenecessary to cause elimination

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Diazonium Salts: The Sandmeyer Reaction Primary arylamines react with HNO2, yielding stable

arenediazonium salts

The N2 group can be replaced by a nucleophile

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Diazonium Coupling Reactions Arenediazonium salts undergo a coupling reaction

with activated aromatic rings, such as phenols and arylamines, to yield brightly colored azo compounds, ArN=NAr

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Azo Dyes Azo-coupled products have extended conjugation

that lead to low energy electronic transitions that occur in visible light (dyes)

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