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D riv ivD riv iv

1

Reference: Organic Chemistry, Seventh Edit ion, Francis A. Carey, 2008, McGraw Hill

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Greater AcidityGreater Acidity of Carboxylic Acids is Attributedof Carboxylic Acids is Attributed

a za on oa za on o ar oxy a ear oxy a e on yon y

RCRC RCRC

2OO

OO

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Substituent Effects on Acidity

Electronegative substituents withdraw.

3

,equilibrium constant for its formation.

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4Effect ofelectronegative substituent decreases as number ofbonds between it and carboxyl group increases

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Preparation and Hydrolysis of Nitriles

OOCC NN HH33OO++ ++

SSNN22 heatheat

44

Converts an alkyl halide to a carboxylic acid

havin one more carbon atom than thestarting halide

5

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Exam le

NaNaCNCN

CHCH22ClCl CHCH22CNCNDMSODMSO (92%)(92%)

HH22OO

22 44

heatheatOO

CHCH22COHCOH

6(77%)(77%)

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Exam le

OO OHOH1.1. NaNaCNCN

CHCH33CCHCCH22CHCH22CHCH33 CHCH33CCHCCH22CHCH22CHCH332. H2. H++

CNCN

HH22OO

,,

CCOO HH

7

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Synthesis offenoprofen (a nonsteroidal anti-inflammatory drug)

marketed under the trade name Nalfon

8

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Carboxylation of Grignard Reagents

Grignard reagents react with dry CO2 to yield a metalcar oxyate

The organomagnesium halide adds to C=O ofcarbon dioxide Protonation by addition ofaqueous HCl in a separate step gives

the free carboxylic acid

9

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Preparation of phenylacetic acid

from benzyl bromide

10

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Acid-catalyzed Esterification

(also called(also called FischerFischer esterificationesterification))

OO

++ CHCH33OOHHCOHCOH

OO

++ HH22OOCCOOCHCH33

Important fact: the oxygen of the alcohol

11is incorporated into the ester as shown.

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Mechanism of

12

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NucleophilicNucleophilic AcylAcyl SubstitutionSubstitution

Carboxylic acid derivatives have an acyl group bonded to an

as their characteristic reaction.

13

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General Mechanism for

14

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MostMost LeastLeast

Reactivity Carbonyl groupOO

reactivereactive stabilizedstabilizedRCClRCCl

''

OO

RCOR'RCOR'

''

OO

LeastLeast MostMost

22

OO

reactivereactive stabilizedstabilizedRCORCO15

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OO

OO

CCRR

CCRR

Acyl chlorides have the least stabilized carbonyl group.

Delocalization of lone pair of Cl into C=O group is

16

.

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OO OO OOOO

RR OO

RR RR OO

RR

Lone pair donation from oxygen stabilizes thecarbonyl group of an acid anhydride.

Both carbonyl groups are competing for the same

17

. ,

is stabilized is reduced.

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OOOO

++CCRR OR'OR'

CCRR OR'OR'

one pa r ona on rom oxygen s a zes ecarbonyl group of an ester.

Stabilization reater than com arable stabilization

18of an anhydride.

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OOOO

RR NR'NR'22

RR NR'NR'22

Lone pair donation from nitrogen stabilizes the.

N is less electronegative than O; therefore,amides are stabilized more than esters and

19

.

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OOOO

RR NR'NR'22

RR NR'NR'22

Amide resonance imparts significant double-bond.

normal single-bond distance of147 pmin amines.

20

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OO OO

RR

OO

RR

OO

Very efficient electron delocalization and dispersalo nega ve c arge

Maximum stabilization

21

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In general:In general:

OO

OO

CCRR XX

CCRR YY

carbonyl is converted to a more stabilized onemore reactive to less reactive

22

more reactive to less reactive .

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most reactive

OO

OO OORCClRCCl

OO

RCOR'RCOR' OOA carboxylic acidA carboxylic acidderivative can bederivative can be

RCNR'RCNR'22OO

convertedconverted byby

nucleo hilicnucleo hilic ac lac lRCORCOsubstitution to any othersubstitution to any other

23least reactive

this table.this table.

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Preparation of Acyl Chlorides

FromFromcarbox lic acidscarbox lic acids andand thion lthion l chloride (SOClchloride (SOCl ))

(CH(CH )) CHCOHCHCOHSOClSOCl22

(CH(CH )) CHCCHCClCl ++ SOSO ++ HClHCleaea

(90%)(90%)

On treatment with the appropriate nucleophile, anacyl chloride may be converted to an acidanhydride, an ester, an amide, or a carboxylic acid.

24

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Reactions of Acyl Chlorides

AcylAcyl chlorideschlorides react withreact with carboxylic acidscarboxylic acids to giveto give

OO OO

CHCH33(CH(CH22))55CCClCl ++ CHCH33(CH(CH22))55COHCOH

pyridinepyridine

OO OO

CHCH33(CH(CH22))55COC(CHCOC(CH22))55CHCH33

25(78(78--83%)83%)

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OO

ridineridine

OO

66 55 33 33

(80%)(80%)66 55 33 33

26

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AcylAcyl chlorideschlorides react withreact with ammoniaammonia oror aminesaminesto iveto ive amides:amides:

OOOO

RCRCClCl ++ RCNR'RCNR'22 ++ HH22OOR'R'22NHNH ++ HOHO ++ ClCl

Synthesis of the sedative ( ) trimetozine in the presence ofone equivalent of NaOH

27

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carboxylic acidscarboxylic acids (carboxylate ion in base):(carboxylate ion in base):

OO OO

RCRCClCl ++ RCOHRCOH ++ HClHClHH22OO

OO OORCRCClCl ++ RCORCO ++ ClCl2HO2HO

28

++ HH22OO

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Reactions of Acid Anhydrides

Carboxylic acid anhydridesCarboxylic acid anhydrides react withreact with alcoholsalcohols

to giveto give esters:esters:

OOOO OO OO

++ RCOR'RCOR' ++R'OHR'OHRCOCRRCOCR RCOHRCOH

Reaction can be carried out in presence ofpyridine (a base) or it can be catalyzed by acids.

29

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Esterification by treating with an acid anhydride

in the presence ofpyridine

All -OH groups react

30

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Catalyzed by acids

Water and othernucleophiles add to a

protonated carbonylgroup (step 2) much

a neutral one.

31

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Acid anhydridesAcid anhydrides react withreact with ammoniaammonia oror aminesamines

Acetaminophen (Paracetamol) (), a drug used inover- e-coun er pa n ers.

3232

f

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Acid anhydridesAcid anhydrides react withreact with waterwater to giveto give

22

OOOO OO

++ 2RCO2RCO ++2HO2HO HH22OORCOCRRCOCR

33

R ti f E t

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Reactions of Esters

Acid-Catalyzed Ester Hydrolysis

++ ''RCOR'RCOR' ++ HH OOHH++

EquilibriumEquilibriumisis closely balancedclosely balanced because carbonyl group ofbecause carbonyl group of

ester and of carboxylic acid areester and of carboxylic acid are comparably stabilized.comparably stabilized.Maximize conversion to esterby removing water.

34

ax m ze ester hydrolysis by having large excess of water.

M h i f

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Mechanism of

-

ester hydrolysis

35

Reactions of Esters

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Reactions of Esters

Ester Hydrolysis in Aqueous Base

OOOO

RCORCO ++ R'OHR'OHRCOR'RCOR' ++ HOHO

Is called saponification

Is irreversible, because of strong stabilization of carboxylate ion

,by a separate acidification step (simply a pH adjustment)

36

Mechanism of

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Mechanism of

base-induced

ester hydrolysis(saponification)

37

Reactions of Esters

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Reactions of Esters

EstersEsters react withreact with ammoniaammonia oror aminesamines

to giveto give amides:amides:

38

R ti f A id

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Reactions of Amides

Hydrolysis of amides isHydrolysis of amides is irreversible.irreversible.

give an ammonium salt.give an ammonium salt.

OOOO

++ R'R'NNHH33++

RCOHRCOHRCRCNNHR'HR' ++ HH22OO HH++++

39

Reactions of Amides

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Reactions of Amides

InIn basicbasic solution thesolution the carboxylic acid productcarboxylic acid product

isis de rotonatedde rotonated to ive ato ive a carbox late ion.carbox late ion.

'' ''

40

Documents

org 13.pdf