alcohol and aldehyde

7/29/2019 alcohol and aldehyde

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1CHEM 4113 ORGANIC CHEMISTRY II LECTURE NOTESCHAPTER 21

1 . Introduction

Carboxylic acid derivatives are compounds that can be hydrolyzed (under either acidic or basicconditions) to give a related carboxylic acid . All of them can be conceptually derived by replacing a

small part of the carboxylic acid structure with other groups.

Carboxylic acid derivatives share close similarities in their chemistry. With the exception ofnitriles, all derivatives share a carbonyl group. Like the aldehydes and ketones, the chemistry of theacid derivatives is determined by initial attack of a nucleophile on the electron defficient carbon of thecarbonyl group. Unlike the aldehydes and ketones, the acid derivatives have a relatively good leavinggroup on the carbonyl, which can then affect the ultimate outcome of the carbonyl addition process.

R

O

O

H

R

X

O

R

O

O

R

O

O

R'

R

NH2

O

R

O

R C N

Amide

CarboxylicAcid

AcidHalide

AcidAnhdride

EsterNitrile

Carboxylic Acid Derivatives

2 . Nomenclature

All acid derivatives are named from their parent carboxylic acid. Usually the -ic acid (or -oicacid) suffix is dropped and a new suffix, indicative of the specific derivative, is employed. Thefollowing are general rules of nomenclature

a. Acyl (Acid) HalidesChange the name of the alkanoic acid from which they are derived to alkanoyl halide.

b. Acid AnhydridesAdd the term anhydride to the acid name ( or names, in case of mixed anhydride) fromwhich it derives, i.e.. alkanoic anhydride

c. EstersName the group attached to the oxygen first. Change the name of the acid from which theyare derived from alkanoic acid to alkanoate, i.e. alkyl alkanoate

d. Amides


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2Change the name of the acid from which they are derived form alkanoic acid to alkanamide.Name any group attached to the nitrogen first, preceded by the prefix N- , i.e. N-alkylalkanamide

R CO

XC Br

O

C

O

X

R C

O

O C

O

R'

H3C O CH3

O O

H3C O CH2CH3

O O

R C

O

O R' OC

O CH2Ph

C

O

OR

C

O

O CH2CH3

R C

O

NY

Z

C

O

NH2 C

O

N

H

CH3

C

O

OR

CN(CH3)2

O

C

O

NH2

C

O

Cl

acylgroup

Acyl (Acid) Halides

halide

Drop -ic acid from name ofcarboxylic acid, add suffix-yl followed by name of thespecific halide.

12

34

5

4-phenyl pentanoyl bromide

When the acyl group is ona ring, replace the -carboxylicacid ending with -carbonylfollowed by name of thespecific halide cyclopentanecarbonyl chloride

Acid Anhydrides

Use acid name(s) that makeup the anhydride followedby the word anhydride

fromaceticacid

fromaceticacid

acetic anhydride

fromaceticacid

frompropionicacid

acetic propionic anhydride

Esters

fromacid

fromalcohol

First name the group attached tothe oxygen followed by a space,then the part derived from acid

changing -ic to -ate.

12

34 5

1'2'

3'

2-methylpropyl 3-benzylpentanoate

When the ester group is ona ring, replace the -carboxylicacid ending with -carboxylate

ethyl 2-cyclopentenecarboxylate

123

Amides

Y,Z = H Primary amideY=H, Z= Alkyl Secondary amideY,Z = Alkyl Tertiary amide

Replace -ic acid or -oic acid with

-amide. Position of alkyl groups

in 2 and 3 anides indicated by

N- prefix benzamide N-methyl benzamide

N,N-dimethyl4-methylhexanamide

When the amide group is ona ring, replace the -carboxylicacid ending with carboxamide. 1

234 2,4-cyclohexadienecarboxamide

IUPAC Nomenclature


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3

3. React ivity of the Carboxylic Acid Derivat ives.

The chemistry of the different acid derivatives is dominated by a single reaction type:Nucleophilic Acyl Substitution. Mechanistically these reactions take place by the initial addition

of a nucleophile to the polar carbonyl group of the acid derivative, forming a tetrahedral intermediate.This step is mechanistically similar to the nucleophilic acyl addition reactions of aldehydes andketones. The difference, however, lies in the presence of good leaving groups in the acid derivatives.In these compounds, subsequent elimination of the leaving group from the tetrahedral intermediate,regenerates a new carbonyl and results in a new substitution product. This substitution process on acarbonyl takes place much more rapidly than at a saturated carbon (SN2, for example). Thecarboxylic acid derivatives react with water, organometallic compounds and hydride reducing agentsby this process.

RC

Y

O

C

O

RNuc

Y

C

OH

R

Nuc

Y

RC

Y

Nuc

RC

Y

O

C

O

RNuc

Y RC

Nuc

O

Nucleophilic Acyl Addition

Y is a poor leavinggroup such as H or R

Nuc

TetrahedralIntermediate

H+

-H2O

Nucleophilic Acyl Substitution

Y is a good leavinggroup such as OH or Cl

Nuc


-Y-

Acyl Addition vs Acyl Substitution

The relative reactivity of the substrates follows a consistent order:Acid Halides > Anhydrides >> Esters >> Amides

This relative order depends on several factors. The first being the extent by which lone pair electronson the leaving group Y delocalize onto the carbonyl carbon, as well as the inductive effect of Y on the

carbonyl carbon (i.e. Electronic Effects). The second factor is the stability of the :Y- anion which islost ( i.e. leaving group ability of Y).

i. Electronic Effects

Acid halides have an extremely electronegative halogen atom which is a poor electron pairdonor. This was the reason that in halobenzenes, the halogen is a deactivating substituent. Thus inacid halides the inductive electron-withdrawing effect of the halogen predominates. This effectincreases the positive charge at the carbonyl carbon making nucleophilic attack at this site more likely.


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4Esters achieve a balance between the inductive electron-withdrawing nature of the oxygenand the donor ability of the oxygen lone-pairs. The carbonyl carbon is not greatly affected.

Amides contain a nitrogen atom which is much less electronegative then either oxygen or ahalogen. The lone-pair electrons on the nitrogen of amides are even more available for resonanceoverlap than the lone-pair electrons of an ester oxygen. Amides involve active neutralization of the

positive charge on the carbonyl carbon. Thus amides are much less reactive toward nucleophiles.The donation of lone-pair electrons into the carbonyl group does make amides more basic at thecarbonyl oxygen than the other acid derivatives.

RC

X

O

RC

OCOR

O

RC

OR

O

RC

NH2

O

R

C

Y

O

RC

O

RC

NH2

O

CH3C

Y

O

CHC

Y

O

CC

Y

O

YC

C

O

AcidAnhydride

Amide

R

R R

Nuc

R

R

+

Compare: Acid Chloride(most reactive) vs Amide (least reactive)

Steric Factors influencethe reactivity of the carboxylicacid derivatives

CH2C

Y

OR

Nuc

AcidHalide

R

RR

Ester

X

Decreasing Reactivity resulting fromincreasing steric henderance aboutthe carbonyl carbon

Relative Reactivities of Acid Derivatives

Decreasing Reactivity resulting fromDecreasing + on carbonyl carbon

Electronic Factors influencethe reactivity of the carboxylicacid derivatives

Electronegative halogenatom increases the +on carbonyl carbon byinduction

Lone-pair electrons onnitrogen will reduce +on carbonyl carbon byresonance

The reactivity of the acid derivative is also afunction of the leaving group ability of Y

CR

OCl

Nuc RC

Nuc

O+ Cl CR

ONH2

Nuc RC

Nuc

O+ NH2

good leaving group poor leaving group

ii. Leaving Groups Effects.

Since nucleophilic acyl substitution is a two step process, the overall rate of reaction will also

be affected by the second step, or elimination of the leaving group :Y-. The more stable the leavinggroup the faster the overall rate of the reaction. One way to determine the relative stability of an


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5anion :Y- is to compare the pKa's of the conjugate acids of these anions, i.e. H-Y. The strongeracid is an indication of a more stable conjugate base. A comparison of the acidity of HCl (pKa = -

3.7) with that of NH3 (pKa = 35), shows that Cl - is a much more stable anion than is NH2-, and is a

much better leaving group.

Consideration of both electronic and leaving group effects, taken alone or together, result inthe acid halide being most reactive and the amide being least reactive among the acid derivatives.

RC

NH2O

RC

Nuc

O

RC

Cl

O

RC

Y

O

C

O

RY

NucENERGY

G1 G2

GDifference

+ Nuc + Y

The rate of nucleophilic acyl substitution reactions depend on the size of the activation barrier

G. The electron-withdrawing ability of the chloride in the acid chloride, raises the energy

of the carbonyl group (because of the increased +). Whereas, the electron-donating ability of

the amide -NH2 group lowers the energy of the carbonyl ( because of the decreased +). he

acid chloride has a lower activation barrier and is more reactive.

Carbonyl Stability and Nucleophilic Acyl Substitution

An important consequence of the reactivity order is that it is possible to convert a more reactive acidderivative into a less reactive one, but one cannot easily go in the opposite direction. This allows usto develop a reactivity manifold which is a way to keep track of a large number of reactions


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6

R

O

O

H

R

X

O

R

O

O

R

O

O

R'

R

NH2

O

R

O

R C NAmide

CarboxylicAcid

AcidHalide

Acid

Anhdride

Ester

Nitrile

Acid Derivative Reactivity Manifold

4. Synthes is of Acid Derivatives from Carboxylic Acids

The -OH functionality of carboxylic acids can be transformed into a variety of other groups,giving rise to the carboxylic acid derivatives.

a. Acid Chlorides and Acid Anhydrides

The hydroxy substituent is a poor leaving group, not only in SN2 reactions, but also innucleophilic acyl substitutions. In alcohols, we converted it into a better leaving group either viaprotonation or by conversion to an inorganic ester using SOCl2 or POCL3. A similar approach isused in carboxylic acids, where SOCl2 or P2O5 are used to convert the -OH group into a betterleaving group. The so-modified acid can then undergo an addition-elimination process leading to anacid halide or anhydride.

R

O

O

H

R

O

OCl

SCl

O

R

O

O

S

O

Cl

RO

O

S

O

ClCl

R

Cl

O

H+

+- Cl

-

Cl

HCl + SO2 +

ACID

ACIDCHLORIDE

NetReaction

Synthesis of Acid Halides


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7

RC

OH

O

RC

OC

R

O O

P O PO

O

O

ORC

OH

O

RC

O

O

P O P

O O

OHO

RC

OC

R

O

RC

OP

OH

O OR

CO

OHO

H

HOP

O

O

RC

OC

R

O O

2

P2O5

Dehydration with P2O5

+PO3 + H2PO3

+ +

-PO3goodleaving group

Mechanism

Anhydrides via Acid Dehydration

b. Ester Synthesis

Esters can be prepared from acids by two complimentary processes. By the alkylation ofcarboxylate anions using alkyl halides and diazomethane, and by the esterification of an acid with analcohol. The first process involves a simple nucleophilic substitution on a saturated carbon (SN2reaction), while the second process arises from a nucleophilic acyl substitution reaction.

i. Esterification by alkylationWhen a carboxylic acid is treated with diazomethane in ether solution, it is rapidly converted

into a methyl ester. Diazomethane is a base and rapidly converts the acid into its carboxylate anion(which is a good nucleophile). The diazomethane itself is converted into the methyldiazonium ion.

This ion has the ultimate leaving group, molecular nitrogen (N2 ) . An SN2 reaction of thecarboxylate anion and the methyldiazonium ion results in the displacement of N2 and the formation ofan ester .

Carboxylate ions are less basic than alkoxide anions and they will give substitution processeson primary and unhindered secondary alkyl halides. The will give E2 processes when reacting withtertiary alkyl halides however.


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8

R C

O

O

H

H2C N N H2C N N

R C

O

O

CH3

R C

O

O

H

H2C N N R C

O

OH3C N N

R C

O

O

CH3

R C

O

O

H

R C

O

OR Br R C

O

O

R

Basic carbon

Mechanism

CH2N2

Et2O

+

Good

LeavingGroup

-N2

Alkylation of carboxylic acids by diazomethane

NaOH + -Br-

Diazomethane CH2N2 Neutral, Dipolar Base and Nucleophile

Diazomethaneacts as a base S

N

2

Methyl estersonly

Alkylation of carboxylate anion with alkyl halides

SN2

Primary and unhindered secondary

alkyl groups onlySynthesis of Esters by Alkylation of Carboxylate Anions

ii. Acid Catalyzed EsterificationWhen a carboxylic acid and alcohol are mixed together, no reaction takes place. However on

addition of catalytic amounts of mineral acid such as HCl or H2SO4, the two combine to give an esterand water. The reaction is not very exothermic and the equilibrium constant is about one, leading toequilibrium concentrations of about 50% acid and 50% ester. The equilibrium may be shifted byadding excess alcohol and removing either ester or water from the mixture.

The mechanism of esterification can be followed by labeling the alcohol oxygen with the 18Oisotope. This label allows differentiation between two mechanistic possibilities. The mechanismwhich involves initial protonation of the acid carbonyl, rather than protonation of the alcohol oxygenpredicts that the labeled oxygen will end up in the ester. This is what happens in the actual case. Inthe experimentally verified mechanism, initial protonation of the carbonyl results in an electron poorcarbonyl carbon which is then attacked by the weakly nucleophilic alcohol oxygen. The -OH groupof the acid is eventually lost as water.


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9

R

O

O

H

R

O

O

H

H

Et

OH

R

OH

O

HO

Et

H

R

OH

O

HO

Et

H

R

O

O Et

H

R

O

O

Et

Et

OH

Et

OH H RO

O

H

RO

O

H

Et

OHH

RO

O

Et

-H+

H+ProtonTransfer -H2O

Mechanism A - Carbonyl Protonation - Nucleophilic Acyl Substitution

*

*

* *

*

In the carbonyl protonation mechanism theradioisotopically labeled oxygen atom (O*)of the alcohol should end up incorporated asthe ester oxygen.

Mechanism B - Alcohol Protonation - SN2

*H+

*

*+

-H+ In the alcohol protonation mechanismthe radioisotopically labeled oxygenatom (O*) of the alcohol should end upin the lost H2O rather than the ester.

Two mechanisms were proposed for the acid esterification reaction. Which is correct?

The actual experiment with radiolabeled alcohol (18O isotope) had all the

isotopic alcohol oxygen atoms incorporated in the ester, none in the water.

Mechanism A must be correct.

Acid Esterification Mechanism - Experimental Evidence

R

O

O

H

R

O

O

R'

R

O

O

H

R

O

O

H

H

R

O

O

H

HEt

OH

R

OH

OHO

Et

H

R

OH

OHO

Et

H

R

O

O Et

H

R

O

O Et

H

R

O

O

Et

H+

H+(cat)

+ R'OH

Equilibrium is shifted to the right by employing large X.S of R'OH

+ HOH

+

Protonated intermediate activated towardnucelophilic attack on carbonyl carbon Tetrahedral Intermediate

ProtonTransfer

-H2O-H+

Resonance stabilized cation

protonated ester

ACID

ESTER

NetReaction

Acid Catalyzed Esterification of a Carboxylic Acid


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10c. Amide Synthesis

Because nitrogen is less electronegative than oxygen, amines are both more basic and morenucleophilic than alcohols. Depending on reaction conditions, they will react in either mode withcarboxylic acids. Initially, reaction of the basic amine with the carboxylic acid leads to formation ofammonium carboxylate salts by an acid-base reaction. On heating this process is reversed, and theslower but more stable addition-elimination process to form the amide takes place.

RC

OH

OR

CO

O

RC

NH2

O+ NH3

+ NH4

+ H2O

At room temperature the top reactionis favored, but on heating salt formationis reversed and a slower but more favoredthermodynamic process forming amidetakes over.150C

NetReaction

Amides from Acids

4 . Reactions of Acid Derivativesa. Acid Halides

Acid halides undergo nucleophilic acyl substitution reactions with nucleophiles. The stronglyelectronegative halide inductively withdraws electron density from the carbonyl resulting in a large +on the carbon. Even weak nucleophiles such as water and alcohols will rapidly react with acidhalides.


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11

RC

Cl

O

HO

H

O

CR ClO

HH

RC

O

O H

H

RC

O

O

H

RC

Cl

O

RO

H

O

CR ClO

R

HR

CO

OH

R

RC

O

O

R

RC

Cl

O

H

NH

O

CR ClN

H HR

CN

OH

H

RC

N

O

H

H

HH

H

RC

Cl

O

Hydrolysis

- Cl

Addition


Elimination

-H

ACID

Alcoholysis

- Cl

Addition Elimination

-H

ESTERAminolysis

- Cl


-H

AMIDE

+

Acid chlorides have a highly electron defficient carbonyl carbonand are susceptible to nucleophilic attack by even weak nucleophiles.The presence of a good leaving group such as the chloride ion leadsto a rapid nucleophilic acyl substitution process.

Acyl Halide Reactions


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12

PhC

Cl

O

C

O- MgBr+

PhCl

MePh

CMe

O

C

O- MgBr+

PhMe

Me

C

OH

PhMe

Me

PhC

Cl

O

- Cl-

C

O- Li+

PhCl

Me

MeMgBrether

H3O+

Ester KetoneFAST

PhC

Me

O

Net Reaction: Addition of two equivalents of Grignardreagent to the acyl halide.

R2CuLiether

Alcohol

Addition of Grignard reagents to acyl halides

MeMgBrether

VERYFAST

- Cl-

R2CuLiether

Ester Ketone

Addition of lithium dialkylcuprate to acyl halides

Organocuprates are organometallic reagents that are less nucleophilic thanorganolithium or Grignard reagents. They will react with the acid chloridebecause of the greater electrophilic nature of its carbonyl carbon. However,they will not add to the much less reactive ketone carbonyl.

NO FURTHERREACTION

FAST

Reaction of Acid Halides with Organometallic Reagents


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13

RC

O

RC

H

O

RC

HH

OH

RC

OCH3 RC

H

O

AlO O

H

ReadilyReduced toAldehyde

ReadilyReduced toAlcohol

NET REACTION: Additionof two hydrides results information of alcoholMOST

REACTIVE

SLIGHTLY

LESS REACTIVE

LiAlH4 LiAlH4 H3O+

REDUCE THE ACID HALIDE USING A LESS POWERFUL AND THUSMORE "SELECTIVE"ALUMINIUM HYDRIDE REDUCING AGENT:

Lithium tri-t-butoxyaluminium Hydride LiAlH(O-t-Bu)3

Cl

O

C

CH3

CH3

CH3

CCH3

CH3

CH3

C

CH3

CH3

CH3

The electronegative oxygen atomslower the charge density on thealuminum hydride making it much lessnucleophilic.Thus it will deliver a hydrideonly tothe extremely reactive acid halidecarbonyl arbon

O 1) Li AlH(OtBu)3

2) H3O+

Reductions of Acid Halides

b. Esters

Esters are significantly less reactive than acid chlorides or anhydrides, but they have an

extensive chemistry nonetheless. In contrast to the more reactive acid derivatives, esters do not reactwith water or alcohols unless a catalyst is present.

i. Acid catalyzed hydrolysisBecause the esteri ficatio n of an acid with an alcohol is a reversible process,

esters can be hydrolyzed to acids in the presence of strong mineral acids. Thus hydrolysis andesterification are flip sides of the same coin . In most cases hydrolysis is slow and theposition of equilibrium must be shifted by employing a large excess of water. As in other acid-catalyzed reactions at the carbonyl, protonation makes the carbonyl carbon more electrophilic.Protonation of the leaving oxygen converts it into a much better leaving group.


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14

R

O

O

R'

R

O

O

H

R

O

O

R'

R

O

O

R'

H

R

O

O

R'

HH

OH

R

OH

O

'RO

H

H

R

OH

O

'RO

H

H

R

O

O H

H

R

O

O H

H

R

O

O

H

H+

H+(cat)

+ H2O

For the above chemical reaction the Keq = 1. That means that normally the yield of eitherhydrolysis or esterification is 50%. Equilibrium is shifted to the right by employing a largeexcess of H2O; equilibrium is shifted to the left by using a large excess of R'OH.

+ R'OH

+


ProtonTransfer

- R'OH-H+


protonated acid

ESTER

NetReaction

Acid Catalyzed Hydrolysis of an Ester

Hydrolysis

Esterification

Acid catalyzed hydrolysisand esterification are theopposite direction of thesame chemical equation.

ACID

Mechanism

ii. TransesterificationEsters react with alcohols in an acid-catalyzed process called transesterification. It allows for

the direct conversion of one ester into another without proceeding through the free acid.Transesterification is an equilibrium reaction; to shift the equilibrium a large excess of the alcohol isusually employed. The mechanism of acid catalyzed esterification is a straightforward permutation ofthe corresponding hydrolysis of an ester to a carboxylic acid.


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15

R

O

O

R''

R

O

O

R'

R

O

O

R''

R

O

O

R''

H

R

O

O

R''

HR'

OH

R

OH

O

R''O

R'

H

R

OH

O

R''O

R'

H

R

O

O R'

H

R

O

O R'

H

R

O

O

R'

H+

H+(cat)

+ R'OH

For the above chemical reaction the Keq = 1. That means that normally the yield of eitherester is 50%. Equilibrium is shifted to the right by employing a large excess of R'OH;equilibrium is shifted to the left by using a large excess of R''OH.

+ R''OH

+


ProtonTransfer

- R''OH-H+


protonated acid

ESTER A

NetReaction

Acid Catalyzed Transesterification of an Ester

Esterification

Transesterification allowsthe ester oxygen alkyl groupto be changed by refluxingwith another alcohol under acidconditions.

Mechanism

Esterification

ESTER B

iii. Amides from estersEsters react with amines, which are more nucleophilic than water or alcohols, to form

amides; no catalyst is needed. The mechanism of this reaction, too, is nucleophilic acylsubstitution involving addition-elimination.

RC

OCH3

O

NH2 CH3 C

O

ROCH3

N HHCH3

RC

NHCH3

O

H

RC

NHCH3

O

+ OCH3

+ CH3OH

very goodnucleophile

Aminolysis of Esters

iv. Ester ReductionThe reduction of esters to alcohols is carried out by lithium aluminum hydride as mentioned in

chapter 17. A milder reducing agent allows the reaction to be stopped at the aldehyde oxidation stage.


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16With DIBAH the reaction proceeds only to the initial addition step. Aqueous acidic work-upfurnishes the hemiacetal of the aldehyde which rapidly decomposes to the aldehyde product.

RC

O

RC

H

O

RC

HH

OH

RC

OCH3

O

RC

H

O

Al(CH3)2CHCH2 CH2CH(CH3)2DIBAH =

H

1)DIBAH

2)H3O+

ReadilyReduced toAldehyde

ReadilyReduced toAlcohol NET REACTION: Additionof two hydrides results in

formation of alcoholMOSTREACTIVE

SLIGHTLYLESS REACTIVE

LiAlH4 LiAlH4 H3O+

REDUCE THE ESTER USING A LESS POWERFUL ANDTHUS MORE "SELECTIVE"ALUMINIUM HYDRIDEREDUCING AGENT: DIISOBUTYLALUMINUM HYDRIDE

ONLY REACTSWITHESTERS

Reduction of Esters

OCH3

c. Reactions of Amides

Amides are the least reactive of the carboxylic acid intermediates. The active donation of thenitrogen lone-pair electrons into the carbonyl lowers the +d on the carbonyl carbon making itmuch less susceptible to nucleophilic attack. Nucleophilic addition-elimination reactions on amides

require catalysts and the use of harsh conditions such as strongly acidic or basic solutions andprolonged heating.

i. Hydrolysis of amides

Amides are hydrolyzed in water using either H+ or OH- as catalyst. Acid hydrolysis liberatesthe amine in the form of the corresponding ammonium salt, whereas base hydrolysis initially gives thecarboxylate anion and the amine. Acidic work-up then produces the amine.


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17

R

NHR

O

R

O

O

H

RNHR

O

RNHR

O H

H

OH

R

OH

ORHN

H

H

R

O

O H

H

R

O

O H

H

R

O

O

H

H+

H+(cat)

+ H2O + NH3R

Protonated intermediate activated towardnucelophilic attack on carbonyl carbon

ProtonTransfer

-H+


R

OH

OHRHN

H

Mechanism

- :NH2R

AMIDE

ACID

Net Reaction

Acid Hydrolysis of Amides

R

NHR

O

R

O

O

R

NHR

O OH

R

O

OHRHN

R

O

O

H

+ H2O + NH2R

-H+

Mechanism

AMIDE

ACID

Net Reaction

Base Hydrolysis of Amides

- OH cat


R

O

O

H

+ NHR

R

O

O

+ NH2R

ii. Amide ReductionsIn contrast to the reactions of carboxylic acids and other derivatives such as acid halides,

anhydrides and esters, treatment of amides with LiAlH4 does not produce alcohols. On

treatment with lithium aluminum hydride amides are converted into the corresponding amine in highyield. The mechanism of addition is thought to include hydride addition followed by aluminateelimination. This difference is due to the relatively poor leaving group ability of the amine anion ascompared to the aluminate anion and the high stability of the iminium cation formed in this process.


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18

R

NHR

O

R

NHR

O

Mechanism

AMIDE

1) LiAlH4, ether

2) H3O+ R CH2 NHR

Al

H

H

H

H Li

R CO

NHRH

Al

H

H H

R CO

NHRH

AlH2

HydrideAddition

AluminateElimination

-AlOH2

AluminateFormation

C N R

H

R

H

Al

H

H

H

HLi

HydrideAddition

R CH2 NHR

NetReaction

AMINE

LiAlH4 Reduction of Amides

Modified hydride reducing agents such as DIBAH allow the reduction of amides to be stopped at thealdehyde oxidation state. Such reactions work best with N,N-dialkylated amides.

R

NR2

O1) DIBAH, ether

2) H3O+ R

H

O

5 . Chemistry of Nitriles

Nitriles, R-CN, are considered derivatives of carboxylic acids because the nitrile carbon is in

the same oxidation state as the carbonyl carbon of an acid, and nitriles can be readily hydrolyzed tocarboxylic acids on treatment with water and a suitable catalyst. Nitriles are less reactive tha n theother acid derivatives .

a. Nomenclature

There are two acceptable methods for naming nitriles:

1. For simple unsubstituted nitrile, take the alkane name of the same number of carbonsand add the suffix -nitrile, i.e. alkanenitrile

2. For more complex nitriles, drop the -ic acidor -oic acid from the name of the acid with thesame number of carbons and add the suffic -onitrile, i.e. alkanonitrile


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R C

C

C NC

Drop -ic acid or -oic acid fromname of carboxylic acid, addsuffix -onitrile

12

345

When the cyano group is ona ring, replace the -carboxylicacid ending with -carbonitrle

cyclopentanecarbonitrile

N

N

N

R C N

4-phenylpentanonitrile

cyano

group

simple alkyl group

complex alkyl

Add suffix -nitrile to alkanename with same number ofcarbons

C N1

2

3

4

5

6

hexanenitrile

Nitrile Nomenclature

b. Preparation of N itriles

The best and most general route to nitriles is by dehydration (loss of H2O) of a primary amide .Thionyl chloride (SOCl2), POCL3 and P2O5 have all been used in this process.

RC

NH2

O

RC

NH2

OS

Cl

Cl

O

RC

N

OS

H

H

O

Cl

RC

N

OS

H

O

Cl

R C N HR C N

+ Cl - HCl

The amide oxygen is basicand nucleophilic due tonitrogen lone-pair donation

+ SO2 + Cl- HCl

Nitriles via Amide Dehydration with SOCl2

Nitriles can also be prepared by the cyanohydrin reaction on aldehydes and ketones as well as

the conjugate addition of-CN to ,-unsaturated aldehydes and ketones. The simplest method of

nitrile preparation is the SN2 substitution reaction of a cyanide anion (-CN) on a primary orunhindered secondary alkyl halide.


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RC

H

O

C

OH

RH

C N

CH

CH

O

CH2

CH

CH

O

CHNC

R X R C N

Nitrile Synthesis

Cyanohydrin Reaction

NaCN

NaHSO4

Conjugate Addition of-CN

NaCN

NaHSO4

Nucleophilic addition at carbonylcarbon, followed by protonationof tetrahedral intermediate

SN2 Substitution

Nucleophilic addition at -carbon,followed by protonation and enolrearrangement to keto form..

NaCNThe SN2 reaction of-CN, like all

SN2 reactions requires a primary or

unhindered secondary alkyl substrate

c. Hydrolysis of Nitriles

Nitriles are very difficult to hydrolyze . Under acidic conditions initial protonation on nitrogenfollowed by nucleophilic attack by water forms a primary amide, which then continues to undergohydrolysis to afford a carboxylic acid. Nitriles are slower to hydrolyze than amides because theequilibrium involving protonation on the nitrogen (the activation step) is very unfavorable. Thus,once the more reactive amide forms it is quickly hydrolyzed under these harsh conditions.

R C N R C NH R C NH R C NH

OHH

R C NH2

OH

R C

NH2

OR C

OH

O

H+

OH2

SLOWProtontransfer

- H+H+/H2O

FAST

AMIDEACID

NITRILE

Net Reaction

Acid Hydrolysis of Nitriles

d. Reductions of Nitriles by Hydride Reagents

Nucleophilic addition to the nitrile carbon may be carried out by hydride reagents. Treatmentof nitriles with storng hydride reagents like LiAlH4 give double hydride addition and thecorresponding amine is obtained on dilute acid work-up. If a less strong reagent such as DIBAH isused, the second addition of hydride does not occur. The imine intermediate is hydrolyzed to analdehyde


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R C N

H Al

H

H

H

R C N

H

R C N

H

H

R C NH2

H

H

R C N R C N

H

R C NH R C

H

OH Al[CH2CH(CH3)2]2

Li

Hydride adds

Again

LiAlH4 -2 H3O+

DIBAH deliversonly one hydride

H3O+ H3O

+

Reduction with LiAlH4

Reduction with DIBAH

Metal Hydride Reductions of Nitriles

ALDEHYDE

AMINE

H

imine

e. Grignard Addition to Nitriles

Strongly nucleophilic organometallic reagents suchas Grignards and alkyllithiums will addonce to the nitrile carbon to give anionic imine salts. Acidic work-up gives the neutral imine, which israpidly hydrolyzed to the ketone.

R C N R C N

CH3R C NH R C

CH3

OH3O

+ H3O+

KETONE

CH3

imine

H3C MgX+ NH3

General Ketone Synthesis via Nitriles

alcohol and aldehyde

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