nucleophilic acyl substitution reaction among the most ... · hydrolysis most nucleophilic acyl...
Embed Size (px)
TRANSCRIPT
SCH 206
Dr. Solomon Derese
Carboxylic acid derivatives
57
Nucleophilic acyl substitution reactionAmong the most important reactions of carboxylicacids are those that convert the carboxyl group intoother acid derivatives by a nucleophilic acylsubstitution reaction.
R O
OH
R O
OR'
R O
OCl
R O
O
R'
O
R N
OR1
R2
SCH 206
Dr. Solomon Derese
Acyl chloride
58
Preparation of acyl chloridesAcid chlorides can not be prepared by reaction betweencarboxylic acid and HCl. This is because the carbonylcarbon is not electrophilic enough to be attacked bychloride and also the fact that the hydroxyl group is abad leaving group.
We use PCl5 (an acid chloride of phosphoric acid), PCl3(an acid chloride of phosphorous acid), SOCl2 (Thionylchloride), an acid chloride of sulfurous acid, or oxalylchloride, an acid chloride of oxalic acid.
X
SCH 206
Dr. Solomon Derese 59
PCl3
PCl5
Cl
O
Cl
O
SCH 206
Dr. Solomon Derese 60
Very reactiveGoodLeavingGroup
Good electrophile
SCH 206
Dr. Solomon Derese
Reaction of acyl chloridesAcyl chlorides are the most reactive of acyl compoundstowards nucleophiles. Lower molecular weight saturatedacyl chlorides react explosively with water, and evenmore rapidly with stronger nucleophiles.
61
Because of their reactivity and the ease with which theycan be prepared from carboxlylic acids, acyl chloridesare the most commonly used starting materials for thesynthesis of carboxylic acid derivatives in general.
SCH 206
Dr. Solomon Derese 62
O
R ClAcid
chloride
[H]H2O
NR1R2HR'OH
O
R OH
SOCl2
O
R OHHydrolysis
Most nucleophilic acyl substitution reactions of acylchlorides are irreversible.
SCH 206
Dr. Solomon Derese
Acyl chlorides are hydrolyzed by water to give thecorresponding carboxylic acid.
Hydrolysis: Conversion into acids
63
N
H2O
O
OH
Pyridine scavenges the HCl
SCH 206
Dr. Solomon Derese
Alcoholysis: Ester formation
In most cases this reaction is carried out in thepresence of a base such as triethylamine, pyridinewhich will scavenge the acid (HCl).
64
SCH 206
Dr. Solomon Derese
Ammonlysis: Conversion into amides
The reaction is carried out using an excess of the amine,which serves to remove the acid (HCl) as a salt.
65
Example
DEET, the active ingredient in the most widely usedinsect repellents, is effective against mosquitoes, fleas,and ticks.
SCH 206
Dr. Solomon Derese 66
Ammonolysis reactions carried with NaOH aresometimes referred to as Schotten – Baumannreaction.
Trimetozine (Opalene, Trimolide, Trioxazine) isa sedative that has been marketed in Europe since1959. It also has mild tranquilizing effects and hasbeen used in the treatment of anxiety.
SCH 206
Dr. Solomon Derese 67
The search for a synthetic fiber with properties similar to silkled to the discovery of nylon a polyamide. There are severaldifferent kinds of nylon, but the most well known is callednylon 6,6. It can be synthesized from two six-carbonmonomers (hence its name)—adipoyl chloride (ClOC-(CH2)4-COCl) and hexamethylenediamine (H2N(CH2)6NH2).
Application: Nylon 6,6
SCH 206
Dr. Solomon Derese
Example
68
The aldehyde intermediate can be isolated if the lesspowerful reducing agent, LiAlH (Ot-Bu)3.
Example
Reduction: Conversion into alcohols
SCH 206
Dr. Solomon Derese
Reaction with aromatic compoundsThe Friedel Crafts acylation
69
R Cl
O
R
O
Acyl benzene
R' R'AlCl3
Reaction with Organometallic reagentsGrignard reagent
Organolithiums react similarly to give tertiary alcohols.
SCH 206
Dr. Solomon Derese 70
Less reactive than Grignard/organolithium reagent and yieldketones rather than tertiary alcohols.
Organocopper (R2CuLi) (Gilman) reagents
Example
The ester functional group is not affected.
SCH 206
Dr. Solomon Derese 71
R
O
Cl
O
R
R
OH
H
R
O
H
H
1. LiAlH4
2. H2O
R'2CuLiR
O
R'
1. R'M
gBr
R'Li
2. H2O
orR
OH
R"R'
H2OR
O
OH
R'OHPyridine
Pyridine
R
O
OR'
R
O
NR1R2
NHR
1R2
(exc
ess)
AlCl3LiAlH(OtBu)3
Summary of the reactions of acid chlorides
SCH 206
Dr. Solomon Derese 72
Assignment 21I. How do you achieve the following transformation?
II. Qiana, a polyamide fiber with a silky texture, has thefollowing structure. What are the monomer units usedin the synthesis of Qiana?
SCH 206
Dr. Solomon Derese
Acid anhydrides
The 2nd most reactive carboxylic acid derivatives.
73
Preparation of acetic anhydridesFrom acid chlorides
Most commonly used bases are pyridine andtriethylamine.
SCH 206
Dr. Solomon Derese
Example
74
MechanismO
O
Cl
O
O
O O
SCH 206
Dr. Solomon Derese
The chemistry of anhydrides is similar to that of acidchlorides except that anhydrides react more slowly, but thekind of reactions the two groups undergo are the same.
Reactions of acid anhydrides
75
SCH 206
Dr. Solomon Derese
Examples
76
SCH 206
Dr. Solomon Derese
Esters
Many simple low molecular weight esters arepleasant smelling liquids that are responsible for thefragrant odors of fruits and flowers.
77
R O
O
R'
Acid component Alcohol component
SCH 206
Dr. Solomon Derese 78
O
O
Methyl 3-methylbutanoate
O
O
Propyl propionate
O
O
Butyl acetate
O
O
3-Methylbutyl acetate
O
O
Methyl octanoate
O
O
Benzyl butanoate
Commercial applications of estersThe characteristics fruity smell of esters lead to their use inartificial fruit essences.
SCH 206
Dr. Solomon Derese
Preparation of esters Fisher esterification General reaction
Catalyzed by conc. H2SO4 or HCl.
a) Use of excess of acid or alcoholb) Removing water from the reaction mixtures
as it is formed.
Equilibrium reaction and yield can be increased by:
79
SCH 206
Dr. Solomon Derese 80
R O
O
H
H
OHR1
Mechanism
SCH 206
Dr. Solomon Derese
Carboxylic acids whose molecules have a hydroxyl group ona g- or d- carbon undergo intramolecular esterification togive cyclic esters (Lactones) known as g- or d- lactones.
81
RO
H
OH
OHydroxy acid
O
O
R-Lactone
H3O
Example
SCH 206
Dr. Solomon Derese
From acid chlorides/acid anhydride/carboxylic acid salts
Williamson ester synthesis
General reaction
82
SCH 206
Dr. Solomon Derese
Diazomethane esterification
83
R O
O
H H2C N N
Example
Diazomethane, CH2N2, which is best drawn as a hybrid oftwo contributing structures, can be used to synthesize estersfrom carboxylic acid.
N
H
H
N
SCH 206
Dr. Solomon Derese
Reactions of Esters
84
SCH 206
Dr. Solomon Derese
Hydrolysis of Esters
Examples
85
Reversible, Why?
Irreversible, Why?
SCH 206
Dr. Solomon Derese 86
All soaps are salts of fatty acids. The main differencebetween soaps is the addition of other ingredientsthat do not alter their cleaning properties: dyes forcolor, scents for a pleasing odor, and oils forlubrication. Soaps that float are aerated so that theyare less dense than water.
Soaps Saponification
Ester hydrolysis in base
SCH 206
Dr. Solomon Derese
Transesterification is the conversion of an ester intoanother ester by heating it with an excess of eitheran alcohol or a carboxylic acid in the presence of anacid or a base catalyst.
Transesterification
87
In an equilibrium reaction, either the alcohol or theacid portion of the original ester is removed.
SCH 206
Dr. Solomon Derese 88
The equilibrium is shifted to the right by allowing thelow boiling alcohol to distil from the reactionmixture.
Example
SCH 206
Dr. Solomon Derese 89
Biodiesel
Biodiesel is produced from renewablesources such as vegetable oils andanimal fats and is a cleanerreplacement for petroleum. It isnontoxic and biodegradable. It hasphysical properties similar to those ofpetroleum diesel.
SCH 206
Dr. Solomon Derese 90
Assignment 22
Draw a stepwise mechanism for each reaction.
SCH 206
Dr. Solomon Derese 91
I. The following reactivity order has been found for thesaponification of p-substituted methyl benzoates:
Y = NO2 > Br > H > CH3 > OCH3
How can you explain this reactivity order? Where wouldyou expect Y = CHO and Y = NH2 to be in the reactivity list?
Assignment 23
II. When ethyl benzoate is heated in methanol containing asmall amount of HCl, methyl benzoate is formed.Propose a mechanism for the reaction.
SCH 206
Dr. Solomon Derese 92
The aldehyde intermediate can be isolated if 1equivalent of the less reactive reducing agentdiisobutylaluminum hydride (DIBAH) is used insteadof LiAlH4. The reaction is carried out at -78°C to avoidfurther reduction to the alcohol.
Reduction of Esters
SCH 206
Dr. Solomon Derese 93
SCH 206
Dr. Solomon Derese 94
I. Predict the major product(s) for each of the following reactions:Assignment 24
II. Explain why ester A is more reactive than ester B in nucleophilicsubstitution.
SCH 206
Dr. Solomon Derese 95
Amides
From acid chlorides
Preparation of amidesNo free rotation across the C-N bond
SCH 206
Dr. Solomon Derese 96
From acid anhydrides
From esters
SCH 206
Dr. Solomon Derese 97
Carboxylic acids react with aqueous ammonia toform ammonium salts:
From carboxylic acids
Because of the low reactivity of the carboxylate iontoward nucleophilic substitution reaction, furtherreaction does not usually take place in aqueoussolution.
An ammoniumcarboxylate
SCH 206
Dr. Solomon Derese 98
Amides are of great importance in life. The linkages that joinindividual amino acids together to form proteins areprimarily amide linkages. Proteins/peptides are formed byreacting the carboxyl group of one amino acid with theamino group another amino acid.
As a consequence, much research has been done to findconvenient and mild ways for amide synthesis.Dialkylcarbodiimides (R-N=C=N=R), for exampledicyclohexylcarbodiimide (DCC), are especially usefulreagents for amide synthesis.
amide linkages
SCH 206
Dr. Solomon Derese 99
R O
OH N
C
N
Diclohexylcarbodiimide(DCC)
HN
C
N
OR
O
The carbonyl carbon is now moreelectrophilic than the carboxyl andthe bad leaving group –OH isreplaced by a good leaving group.
SCH 206
Dr. Solomon Derese 100
R N
O
HR1
R2
HN
C
N
O
+
R N
O
R1
R2 +
HN
C
N
OH
SCH 206
Dr. Solomon Derese 101
The following reaction will not happen as shown.
a. Show what would happen instead.b. How could you obtain the desired product?
Show the reagents to be used and the structures of any intermediates.
Assignment 25
SCH 206
Dr. Solomon Derese
Reactions of amides
HydrolysisAmides are hydrolyzed in either acidic or alkalinesolution. In either case, the acid or base is a reactant,not a catalyst, and must be used in a 1.1 molar ratio orin excess.
102
This property is at most important in biological systemsfor the stability of proteins. If the amide could hydrolyzeeasily we wont even be able to touch water.
SCH 206
Dr. Solomon Derese 103
Reduction
Mechanism
SCH 206
Dr. Solomon Derese 104
I. Predict the major product(s) for each of the following reactions:
Assignment 26
II. Propose a mechanism for each of the following transformations:
SCH 206
Dr. Solomon Derese
Preparation of nitriles
I. From dehydration of amides
105
Nitriles
SCH 206
Dr. Solomon Derese 106
O
H2N
RS
O
ClCl
ON
R
HS
Cl O
Mechanism
Example
SCH 206
Dr. Solomon Derese
SN2 reaction of cyanide ion with primary alkyl halides
107
Example
SCH 206
Dr. Solomon Derese
Reactions of nitriles
108
Hydrolysis of nitrites
Reduction of nitriles
R C N
NH2
RH
H
1. LiAlH4 2. H2O
orH2 / Pd/C
SCH 206
Dr. Solomon Derese 109
Mechanism
Example
R C N Al
H
HH
H
RCN
H
H
H
SCH 206
Dr. Solomon Derese
Reaction with organometalic reagents
110
An alternative to Friedel-Crafts acylation
SCH 206
Dr. Solomon Derese 111
CN R
R'
H
HH2O
R R'
OH
NH3
R R'
O
+ NH4
SCH 206
Dr. Solomon Derese 112
I. Predict the major product(s) for each of thefollowing reactions:
Assignment 27
CN
b)a) CN Br1. LiAlH4
2. H2O 2. MeMgBr
1. NaCN
3. H3O
c) 1. EtMgBr
4. H3O
2. H2O
3. LiAlH4
SCH 206
Dr. Solomon Derese 113
II. Propose a mechanism for the followingtransformation:
III. Propose an efficient synthesis for each of thefollowing transformations:
SCH 206
Dr. Solomon Derese 114
IV. Identify compounds A-M in the following reactionsequence.
SCH 206
Dr. Solomon Derese
Reduction of carboxylic acid
General reaction
115
SCH 206
Dr. Solomon Derese
Example
116
BH3 / THFO
HO
Selectively reduces carboxylicacids in the presence ofaldhydes/ketones and esters
SCH 206
Dr. Solomon Derese
Decarboxylation of β-keto acids and β- diacidsAcids whose molecules have a carbonyl group onecarbon removed from the carboxyl group, called β-keto acids, decarboxylate readily when they areheated to 100-150°C.
117
R O
O O
H
- KetoacidH H
SCH 206
Dr. Solomon Derese
There are two reasons for this ease of decarboxylation.1) When the carboxylate ion decarboxylate, it forms a
resonance stabilized enolate anion:
Resonance stabilized anion 118
R O
O O
H
- KetoacidH H
R
O
H
H
R
O
H
H
SCH 206
Dr. Solomon Derese
II. The decarboxylation takes place though a stable six -membered cyclic transition state.
b-Keto carboxylic acid
119
OH
O
O
R
ROH
R
R
Example
SCH 206
Dr. Solomon Derese 120
Write the organic product(s) and reaction mechanism of thefollowing reaction:
Assignment 28