Organic Chemistry
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Transcript Organic Chemistry
Carboxyl Derivatives
Classes shown, formally, via dehydration.
O
RCCl
A n acid
chloride
-H2 O
O
RC-OH H-Cl
O O
RCOCR'
An acid
anhydride
-H2 O
O
O
RC-OH H-OCR'
O
RCOR'
An ester
-H2 O
O
RC-OH H-OR'
O
RCNH2
An amide
-H2 O
O
RC-OH H-NH2
RC N
A nitrile
-H2 O
HO H
RC=N
Th e enol of
an amide
18-1
Structure: Acid Chlorides
The
functional group of an acid halide is an acyl
group bonded to a halogen.
• The most common are the acid chlorides.
• To name, change the suffix -oic acid to -oyl halide.
O
O
RCAn acyl
group
O
CH3 CCl
O
Cl
Ethan oyl ch loride Benzoyl chloride
(Acetyl ch loride)
Cl
Cl
O
Hexan edioyl ch loride
(Adip oyl chloride)
18-2
Related: Sulfonyl Chlorides
• Replacement of -OH in a sulfonic acid by -Cl gives a
sulfonyl chloride.
O
CH3 SOH
O
Methanes ulfon ic
acid
O
CH3 SCl
O
Methanes ulfonyl ch loride
(Mesyl ch loride, MsCl)
O
H3 C
SOH
O
p-Toluen esulfon ic
acid
O
H3 C
SCl
O
p-Toluen esulfon yl chloride
(Tosyl chlorid e, TsCl)
18-3
Structure: Acid Anhydrides
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.
O O
O O
CH3 COCCH3
COC
Acetic anhydride
Benzoic anhydride
18-4
Acid Anhydrides
Cyclic
anhydrides are named from the
dicarboxylic acids from which they are derived.
O
O
O
S u cci n ic
an h ydride
O
O
O
Male i c
an h ydride
O
O
O
Ph th al ic
an h ydride
18-5
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.
O
O
O
O
O
Ethyl ethan oate
(Ethyl acetate)
Is op ropyl
ben zoate
EtO
OEt
O
D iethyl butaned ioate
(D ieth yl s uccin ate)
18-7
Esters; Lactones
Lactone:
A cyclic ester.
• name the parent carboxylic acid, drop the suffix -ic
acid and add -olactone.
2
3
H3 C
O
O
1
O
3-Bu tanolactone
-Butyrolactone)
1
2
O
3 4
4-Bu tanolactone
-Bu tyrolacton e)
3
4
2
O
1
O
5 6
6-Hexan olacton e
-Cap rolactone)
18-8
Amides
The
functional group of an amide is an acyl
group bonded to a nitrogen atom.
• drop -oic acid from the name of the parent acid and
add -amide. (For the common acid name, drop -ic of
the acid name and add -amide.)
• an alkyl or aryl group bonded to the N: name the group
and show its location on nitrogen by N-.
O
CH3 CNH2
A cetamide
(a 1° amide)
ethanamide
O H
CH3 C-N
CH3
O CH3
H-C-N
CH3
N-Methylacetamide N ,N-D imethyl(a 2° amid e)
formamid e (DMF)
(a 3° amide)
18-10
Amides: resonance
18-11
Amides; Characteristics
18-12
Amides; Lactams
Lactams:
A cyclic amides are called lactams.
• Name the parent carboxylic acid, drop the suffix -ic
acid and add -lactam.
2
3
H3 C
O
1
NH
3-Bu tanol actam
-Butyrol actam)
3
4
O
2
1
NH
5
6-He xan olactam
-C aprolactam)
6
Indicates where the N is located.
18-13
Imides
The
functional group of an imide is two acyl
groups bonded to nitrogen.
• Both succinimide and phthalimide are cyclic imides.
O
NH
O
Succinimide
O
NH
O
Phthalimide
18-14
Related: Nitriles
The
functional group of a nitrile is a cyano group
• IUPAC names: name as an alkanenitrile.
• common names: drop the -ic acid and add -onitrile.
CH3 C N
Ethanen itrile
(A cetonitrile)
C N
Benzon itrile
CH2 C N
Phenylethan enitrile
(Phenylacetonitrile)
18-15
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.
O
CH3 CNH2
Acetamide
pKa 15-17
O
SNH2
O
NH
O
NH
O
O
O
Ben zenesu lfonamide Succinimide Phth alimide
pK a 10
p Ka 9.7
p Ka 8.3
18-16
Acidity of N-H bonds
Effect
of neighboring carbonyl groups.
1.0
18-17
Acidity of N-H
• Imides such as phthalimide readily dissolve in
aqueous NaOH as water-soluble salts.
O
NH +
O
pK a 8.3
(stron ge r
aci d)
O
N aOH
-
N Na
+
+
H2 O
O
(stron ge r
base )
(weak e r
base )
pK a 15.7
(weak e r
aci d)
18-18
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. More resonance delocalization of the negative charge.
O
N
O
O
N
O
A resonance-stabilized an ion
O
N
O
18-19
Lab related: Sulfonamides (Hinsberg)
Experimental test to distinguish primary, secondary and
tertiary amines.
1
soluble
insoluble
2
insoluble
3
soluble
In base
In acid
Reaction replaces one H with the sulfonyl group. In
18-20
an H remains it is soluble in base.
Characteristic Reactions: Ketones & Aldehydes
Nucleophilic
acyl Addition:
Protonation makes carbonyl better electrophile. Ok with
poor nucleophile.
Carbonyl weaker electrophile.
Need good nucleophile.
18-21
Characteristic Reactions: Derivatives
Nucleophilic
acyl substitution: An additionelimination sequence resulting in substitution of
one nucleophile for another.
O
O
R
C
+
Y
:Nu
R
O
C
Nu
R
C
+
Nu
:Y
Y
Te trah edral carbon yl S u bstitu tion
addi tion i n te rme diate
produ ct
Dominant for derivatives due to good leaving group (Y),
uncommon for ketones or aldehydes.
18-22
Characteristic Reactions
Poor bases make good leaving groups.
O
R2 N-
RO-
RCO-
X-
Increasing leaving ability
Increasing basicity
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.
18-23
Water and Acid Chlorides
• Low-molecular-weight acid chlorides react rapidly with
water.
• Higher molecular-weight acid chlorides are less
soluble in water and react less readily.
O
CH3 CCl + H2 O
Acetyl chlorid e
O
CH3 COH + HCl
18-24
Water and Anhydrides
• Low-molecular-weight anhydrides react readily with
water to give two molecules of carboxylic acid.
• Higher-molecular-weight anhydrides also react with
water, but less readily.
O O
CH3 COCCH3 + H2 O
Acetic an hydrid e
O
O
CH3 COH + HOCCH3
18-25
Mechanism- Anhydrides
• Step 1: Addition of H2O to give a TCAI. (Addition)
H +
O
CH3 -C- O-C- CH 3
O-H
H
H
O
O
CH3 -C- O-C- CH 3
+
O H
H
O-H
H
H
O
O
+
CH3 -C- O-C- CH 3 + H- O-H
O
H
H
Te trah edral carbon yl
addi tion i n te rme diate
Acid makes carbonyl better electrophile.
18-26
Mechanism- Anhydrides
• Step 2: Protonation and collapse of the TCAI. (Elimination)
H
H
+O
H
H
H
O
H
O
O
O
CH3 -C-O-C-CH3
O
H
H
H
+O
H
+ H
O
CH3 C O C CH3
H
H
H
O
CH3
O
O
C + O C
O
CH3
H
Acid sets up better leaving group.
18-27
Water and 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.
• acid catalyst protonates the carbonyl oxygen and
increases its electrophilic character toward attack by
water (a weak nucleophile) to form a tetrahedral
carbonyl addition intermediate.
• Collapse of this intermediate gives the carboxylic acid
and alcohol.
18-28
Mechanism: Acid/H2O - Esters (1o and 2o alkoxy)
Acid-catalyzed
R
O
C
ester hydrolysis.
OH
C
+
+
OCH3
Acid makes
carbonyl
Better
electrophile.
H2 O
H
R
H
+
OH
R
O
C
+
OH
CH3 OH
OCH3
Tetrahed ral carbonyl
ad dition intermed iate
Acid sets up
leaving group.
18-29
Mechanism: Reaction with Acid/H2O – Esters (3o alkoxy)
But wait!!!!!!!
water
alcohol
18-30
Reaction with Base/H2O - Esters
Saponification:
The hydrolysis of an esters in
aqueous base.
• Each mole of ester hydrolyzed requires 1 mole of base
• For this reason, ester hydrolysis in aqueous base is
said to be base promoted.
O
RCOCH3 + NaOH
H2 O
O
-
RCO Na
+
+ CH3 OH
18-31
Mechanism of Reaction with Base/H2O – Esters
• Step 1: Attack of hydroxide ion (a nucleophile) on the
carbonyl carbon (an electrophile). (Addition)
• Step 2: Collapse of the TCAI. (Elimination)
• Step 3: Proton transfer to the alkoxide ion; this step is
irreversible and drives saponification to completion.
O
O
O
(1)
(2)
R- C +
R- C-OCH3+ OH
R- C OCH3
O
OH
H
O
OCH3 (3) R- C + HOCH3
O
18-32
Acidic Reaction with H2O - Amides
Hydrolysis
of an amide in aqueous acid requires
one mole of acid per mole of amide.
• Reaction is driven to completion by the acid-base
reaction between the amine or ammonia and the acid.
O
O
N H2 + H2 O + HCl
Ph
2-Ph e n ylbu tan am ide
H2 O
heat
OH + N H4
+
Cl
-
Ph
2-Ph e n ylbu tan oi c aci d
18-33
Basic Reaction with H2O - Amides
Hydrolysis
of an amide in aqueous base requires
one mole of base per mole of amide.
• Reaction is driven to completion by the irreversible
formation of the carboxylate salt.
O
CH3 CNH
N-Phen yleth anamide
(N-Phen ylacetamid e,
Acetan ilide)
+ NaOH
H2 O
heat
O
CH3 CO- Na+ + H2 N
Sodiu m
acetate
A niline
18-34
Mechanism: Acidic H2O - Amides
• Step1: Protonation of the carbonyl oxygen gives a
resonance-stabilized cation intermediate.
O
+
R C NH2 + H O H
H
+H
O
R C NH2
H
H
O
R C
+
O
NH2
R C
+
NH2
+ H2 O
Reso nance-stabil ized catio n i ntermed iate
18-35
Acidic H2O - Amides
• Step 2: Addition of water (a nucleophile) to the carbonyl carbon
(an electrophile) followed by proton transfer gives a TCAI.
OH
+
R C NH2 +
OH
O H
H
R C NH2
O+
H
H
proton
transfe r from
O to N
OH
R C NH3 +
H
O
• Step 3: Collapse of the TCAI and proton transfer. (Elimination)
H
R C NH3 +
OH
H
+
O
R
O
C
+
NH3
R
O
C
+
OH + NH4
OH
18-36
Mechanism: Reaction with Basic H2O - Amides
Amide
hydroxide ion
Dianion!
18-37
Acidic H2O and Nitriles
The
cyano group is hydrolyzed in aqueous acid
to a carboxyl group and ammonium ion.
Ph CH2 C N + 2 H2 O + H2 SO4
Phenylacetonitrile
H2 O
heat
O
+
Ph CH2 COH + NH4 HSO4
Ph enylacetic
Ammoniu m
acid
hydrogen s ulfate
• Protonation of the cyano nitrogen gives a cation that
reacts with water to give an imidic acid.
• Keto-enol tautomerism gives the amide.
Acid
OH
O
+
+
H
+
H
O
R-C N
R-C NH
R-C-NH 2
2
Ammonium
A n imidic acid
An amide
ion
(en ol of an amide)
18-38
Basic H2O and Nitriles
• Hydrolysis of a cyano group in aqueous base gives a
carboxylic anion and ammonia; acidification converts
the carboxylic anion to the carboxylic acid.
CH3 ( CH2 ) 9 C N
Un decan enitrile
NaOH, H2 O
h eat
O
+
CH3 ( CH2 ) 9 CO Na + NH3
S od ium und ecanoate
HCl H2 O
O
CH3 ( CH2 ) 9 COH + NaCl + NH4 Cl
Und ecanoic acid
18-39
Synthesis: Reaction with H2O - Nitriles
• Hydrolysis of nitriles is a valuable route to carboxylic
acids.
CH 3 ( CH2 ) 8 CH2 Cl KCN
ethanol,
1-C hlorode cane
water
CH3 ( CH2 ) 9 C N
Unde cane nitril e
OH
H2 SO4 , H2 O
heat
O
CH3 ( CH2 ) 9 COH
Unde canoic aci d
OH
CHO HCN , KCN
CN H2 SO 4 , H2 O
COOH
e th an ol,
heat
wate r
Be n z al de hyde
Be n z al de h yde cyan oh ydrin 2-H ydroxyph e n ylacetic aci d
(Man de l on itri le )
(Man de l ic acid)
(racemic)
(racemic)
18-40
Synthesis: Grignards + Nitriles ->ketone 1
NMgX
RC
N
R'MgX
RCR'
NH
H2O
RCR'
diethyl
ether
Grignard
reagents add to carbon-nitrogen triple
bonds in the same way that they add to carbonoxygen double bonds.
The product of the reaction is an imine.
18-41
Synthesis: Grignards + Nitriles ->ketone 2
NMgX
RC
N
R'MgX
RCR'
NH
H2O
RCR'
diethyl
ether
H3O+
Imines hydrolyzed to ketones.
O
RCR'
18-42
Reaction of Alcohols and Acid Halides
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.
O
O
Cl + HO
Butanoyl
chloride
Cyclohexan ol
O
+ HCl
Cyclohexyl butan oate
18-43
Reaction with Alcohols, Sulfonic Esters
• Sulfonic acid esters are prepared by the reaction of an
alkane- or arenesulfonyl chloride with an alcohol or
phenol.
• The key point here is that OH- (a poor leaving group) is
transformed into a sulfonic ester (a good leaving
group) with retention of configuration at the chiral
center.
OT s
OH
+
(R)-2-Octanol
T sCl
pyridine
p-Toluenesulfonyl
chloride
(Tosyl chloride)
(R)-2-Octyl p-t oluenesulfonate
[(R)-2-Octyl tosylate]
18-44
Reaction of Alcohols and Acid Anhydrides
Acid
anhydrides react with alcohols to give one
mole of ester and one mole of a carboxylic acid.
O O
CH3 COCCH3 + HOCH2 CH 3
Ace ti c an h ydride Eth an ol
O
O
CH3 COCH2 CH3 + CH3 COH
Ace ti c aci d
Eth yl ace tate
• Cyclic anhydrides react with alcohols to give one ester
group and one carboxyl group.
O
O
O
O
Phth alic
anh yd rid e
+
O
OH
HO
O
2-Butan ol
(sec-Butyl alcohol)
(s ec-Bu tyl h yd rogen
phth alate
18-45
Reaction of Alcohols and Esters
Esters
react with alcohols in the presence of an
acid catalyst in an equilibrium reaction called
transesterification.
O
+
OCH3
Me th yl prope n oate
(Me th yl acrylate)
(bp 81°C )
HO
1-Bu tan ol
(bp 117°C )
HCl
O
O
+ CH3 OH
Bu tyl prope n oate
Me th an ol
(Bu tyl acrylate)
(bp 65°C )
(bp 147°C )
18-46
Reaction of Ammonia, etc. and Acid Halides
Acid
halides react with ammonia, 1° amines, and
2° amines to form amides.
• Two moles of the amine are required per mole of acid
chloride.
O
O
Cl + 2 NH3
Hexanoyl
chloride
Ammon ia
+
-
NH2 + NH4 Cl
Hexan amid e
Ammon ium
chloride
18-47
Reaction of Ammonia, etc. and Anhydrides.
Acid
anhydrides react with ammonia, and 1° and
2° amines to form amides.
• Two moles of ammonia or amine are required.
O O
CH3 COCCH3 + 2 NH3
Acetic
Ammon ia
anh yd rid e
O
O
+
+
CH
CO
NH
CH3 CNH2
3
4
Acetamid e Ammon ium
acetate
18-48
Ammonia, etc. and Esters
Esters
react with ammonia and with 1° and 2°
amines to form amides.
• Esters are less reactive than either acid halides or acid
anhydrides.
O
Ph
O
OEt + NH3
Ethyl p henylacetate
Ph
NH2 +
Phenylacetamide
Et OH
Ethanol
Amides
do not react with ammonia or with 1° or
2° amines.
18-49
Acid Chlorides with Salts
Acid
chlorides react with salts of carboxylic
acids to give anhydrides.
• Most commonly used are sodium or potassium salts.
O
O
+
CH3 CCl + N a - OC
Ace tyl
ch loride
S odiu m
be n zoate
O O
CH3 COC
+
N a+ Cl
-
Ace ti c be n z oic
an h ydride
18-50
Interconversions of Acid Derivatives
18-51
Grignard and an Ester.
Look for two kinds of reactions.
O
OMgX
O
O
R-Mg-X
R-Mg-X
R'
R'
Any
alcohol
will do
here.
OEt
OEt
R'
R
R'
R
R
R
Substitution
EtOH
R'COCl
But where does an ester
come from?
OH
Acid
chloride
R'
SOCl2
R'CO2H
R
R
Perhaps this carboxylic
acid comes from the
oxidation of a primary
alcohol or reaction of a
Grignard with CO2.
Addition
18-52
Grignard Reagents and Formic Esters
• Treating a formic ester with two moles of Grignard
reagent followed by hydrolysis in aqueous acid gives a
2° alcohol.
O
HCOCH3 + 2RMgX
An ester of
formic acid
OH
magnesium H O, HCl
2
alkoxide
HC-R + CH3 OH
salt
R
A 2° alcohol
18-53
Reactions with RLi
Organolithium
compounds are even more
powerful nucleophiles than Grignard reagents.
O
RCOCH3
1 . 2 R' Li
2 . H2 O, HCl
OH
R- C-R' + CH3 OH
R'
18-54
Gilman Reagents
Acid
chlorides at -78°C react with Gilman
reagents to give ketones.
O
O
1 . ( CH3 ) 2 CuLi, eth er, -78°C
Cl 2 . H O
2
Pe n tan oyl ch l ori de
2-H exan on e
Gilman Reagents do not react with acid
anhydrides, esters, amides or nitriles under these
conditions. Selective reaction.
18-55
Synthesis: Reduction - Esters by LiAlH4
Most
reductions of carbonyl compounds use
hydride reducing agents.
• Esters are reduced by LiAlH4 to two alcohols.
• The alcohol derived from the carbonyl group is
primary.
O
Ph
OCH3
Me th yl 2-ph en yl propan oate
(race mic)
1 . LiA lH4 , e t he r
2 . H2 O, HCl
Ph
OH + CH3 OH
2-Ph e n yl-1propan ol
(race mic)
Me th an ol
18-56
Mechanism: Reduction - Esters by LiAlH4
Reduction
occurs in three steps plus workup:
• Steps 1 and 2 reduce the ester to an aldehyde.
O
R C OR' +
H
(1)
O
R C OR'
(2)
O
R C
H
+
OR'
H
A tetrahedral carbonyl
addition intermediate
• Step 3: Work-up gives a 1° alcohol derived from the
carbonyl group.
O
R C
H
+ H
(3)
O
R C H
H
OH
(4)
R C H
H
A 1° alcohol
18-57
Synthesis: Selective Reduction by NaBH4
NaBH4
reduces aldehydes and ketones. It does
not normally reduce esters. LiAlH4 reduces all.
Selective reduction is often possible by the
proper choice of reducing agents and
experimental conditions.
O
O
OEt
NaBH4
OH O
EtOH
OEt
(racemic)
18-58
Synthesis: Reduction - Esters by DIBAlH -> Aldehyde
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.
O
1 . DIBALH , toluen e, -78°C
OCH3
2 . H2 O, HCl
Me th yl h e xan oate
O
H + CH3 OH
He xan al
18-59
Synthesis: Reduction - Amides by LiAlH4
LiAlH4
reduction of an amide gives a 1°, 2°, or 3°
amine, depending on the degree of substitution
of the amide.
O
1 . LiAlH4
NH2 2 . H O
2
Octanamide
NH2
1-Octanamine
O
NMe2 1 . LiAlH4
2 . H2 O
N,N -D imethylben zamide
NMe2
N ,N-D imeth ylb enzylamine
18-60
Synthesis: Reduction - Nitriles by LiAlH4
The
cyano group of a nitrile is reduced by LiAlH4
to a 1° amine.
1 . LiA lH4
CH3 CH= CH( CH 2 ) 4 C N
2 . H2 O
6-O cte n en i tri le
CH3 CH= CH ( CH2 ) 4 CH2 N H2
6-O cte n -1-am in e
Can use catalytic hydrogenation also.
18-61
Interconversions
Problem: Show reagents and experimental conditions to
bring about each reaction.
O
Ph
Cl
(a)
(b )
O
Ph
OH
Ph enylacetic
acid
O
O
(d )
Ph
(c)
(e)
Ph
OMe
(g)
(f)
Ph
OH
NH2
(h )
Ph
NH2
18-62