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D riv ivD riv iv
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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.
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,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
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Converts an alkyl halide to a carboxylic acid
havin one more carbon atom than thestarting halide
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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
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Synthesis offenoprofen (a nonsteroidal anti-inflammatory drug)
marketed under the trade name Nalfon
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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
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Preparation of phenylacetic acid
from benzyl bromide
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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
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NucleophilicNucleophilic AcylAcyl SubstitutionSubstitution
Carboxylic acid derivatives have an acyl group bonded to an
as their characteristic reaction.
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General Mechanism for
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MostMost LeastLeast
Reactivity Carbonyl groupOO
reactivereactive stabilizedstabilizedRCClRCCl
''
OO
RCOR'RCOR'
''
OO
LeastLeast MostMost
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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
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.
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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
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. ,
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
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.
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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.
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OO OO
RR
OO
RR
OO
Very efficient electron delocalization and dispersalo nega ve c arge
Maximum stabilization
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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
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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.
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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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Reactions of Acyl Chlorides
OO
ridineridine
OO
66 55 33 33
(80%)(80%)66 55 33 33
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Reactions of Acyl Chlorides
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
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Reactions of Acyl Chlorides
carboxylic acidscarboxylic acids (carboxylate ion in base):(carboxylate ion in base):
OO OO
RCRCClCl ++ RCOHRCOH ++ HClHClHH22OO
OO OORCRCClCl ++ RCORCO ++ ClCl2HO2HO
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++ 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.
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Esterification by treating with an acid anhydride
in the presence ofpyridine
All -OH groups react
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Catalyzed by acids
Water and othernucleophiles add to a
protonated carbonylgroup (step 2) much
a neutral one.
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Reactions of Acid Anhydrides
Acid anhydridesAcid anhydrides react withreact with ammoniaammonia oror aminesamines
Acetaminophen (Paracetamol) (), a drug used inover- e-coun er pa n ers.
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f
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Reactions of Acid Anhydrides
Acid anhydridesAcid anhydrides react withreact with waterwater to giveto give
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OOOO OO
++ 2RCO2RCO ++2HO2HO HH22OORCOCRRCOCR
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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.
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ax m ze ester hydrolysis by having large excess of water.
M h i f
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Mechanism of
-
ester hydrolysis
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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)
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Mechanism of
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Mechanism of
base-induced
ester hydrolysis(saponification)
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Reactions of Esters
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Reactions of Esters
EstersEsters react withreact with ammoniaammonia oror aminesamines
to giveto give amides:amides:
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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++++
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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.
'' ''
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