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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
TetrahedralIntermediate
-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
TetrahedralIntermediate
Elimination
-H
ACID
Alcoholysis
- Cl
Addition Elimination
-H
ESTERAminolysis
- Cl
Addition Elimination
-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
+
Protonated intermediate activated towardnucelophilic attack on carbonyl carbon Tetrahedral Intermediate
ProtonTransfer
- R'OH-H+
Resonance stabilized cation
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
+
Protonated intermediate activated towardnucelophilic attack on carbonyl carbon Tetrahedral Intermediate
ProtonTransfer
- R''OH-H+
Resonance stabilized cation
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+
Resonance stabilized cation
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
Addition Elimination
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