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Carboxylic Acid Derivatives
Compounds that can be hydrolyzed to a carboxylic acid in acidic water are called carboxylic acid derivative compounds
H+, H2O
O
H3C
O
OH H3C
Acid
O
Cl H3C
Acid
chloride
O
O
O
CH3 H3C
Anhydride
O
OCH3 H3C
Ester
O
H3C !+ LG
NH2
Amide
H2 C C O
Ketene
H3C C N
Nitrile
!+
!+
H2C C O H3C C N
While most of these compounds have an acyl structure with a leaving group attached to the
carbonyl, some have two double bonds from one carbon (ketenes) and some are nitriles
In all cases, however, the carbonyl carbon or the carbon attached to nitrogen are electrophilic
Likewise carboxylic acid can be converted into any of the derivative compounds either in a
single step, or through a couple of steps, thus making all derivatives interconvertible
Carboxylic Acid Derivatives
Carboxylic acid derivatives will react similar to ketones and aldehydes in that the first step is
reaction of the nucleophile with the electrophilic carbonyl carbon
O
H
H3 C
O
H3C
O
NUC
H3C
H3C
H3C
LG
NUC
H
NUC
O
O
NUC
LG
H
NUC
OH
H+
H3 C
NUC
LG
A ketone or aldehyde does not have a suitable leaving group with the initial alkoxide
intermediate, thus it can only be protonated on work-up to the alcohol
The leaving group present with carboxylic acid derivatives, however, allows the compound to reform a carbonyl and expel the leaving group
Thus carboxylic acid derivatives typically react through an addition/elimination mechanism
Carboxylic Acid Derivatives
All of the carboxylic acid derivatives with an acyl structure can react with a nucleophile to generate the same carbonyl product – the difference is the leaving group
Identical product
O
H3C
O
H3C
H3 C
O
O
CH3
H3C
H3 C
OCH3
~4-5
NUC
H3 C
H3C
O
NUC
CH3O
16
O
NUC
NH2
O
O
NUC
O
NUC
-7
Cl
O
NUC
O
H3C
O
NUC
Cl
pKa of conjugate for leaving group
H3 C
NUC
NH2
35
The stability of the leaving group affects the reactivity pattern for the acid derivatives
Carboxylic Acid Derivatives
Reactivity of the carbonyl carbon in derivatives is also affected by the C=O bond strength
As seen in IR, substituents on the carbonyl carbon can affect the C=O bond in two ways: Inductive effect
Resonance effect
O
O
R
R !+ Y !-
O
Y
R
Y
More electronegative Y pulls electron density Lone pair of electrons on Y atom can resonate
from carbon, thus making the carbonyl
to create a C=Y double bond and a C-O single
carbon more electrophilic (δ+)
bond, making carbonyl more stable
Generally the greater difference in electronegativity between C and Y causes inductive effect to become dominant
3p
2p
Y group also affects the stability amongst the resonance forms
!+ !- !+
O
Cl
O
O
O
Poor orbital overlap More inductive
in acid chloride
effect than ester
O
OR
O
OR
Positive charge on
electronegative oxygen
Resonance stability
O
NH2
O
NH2
Positive charge on less
electronegative nitrogen
Carboxylic Acid Derivatives
These differences in relative effects of induction and resonance with carbonyl compounds,
and the relative stability of the various resonance forms for the acyl derivatives are indicated directly in the differences in carbonyl stretching frequency in the IR
O
H3C
O
Cl
H3C
O
O
O
CH3
H3C
O
OCH3
H3C
NH2
Acid chlorides
Anhydrides
Esters
Amides
Strong induction, weak
Presence of second Placing positive charge Placing positive charge
resonance stabilization carbonyl affects partial
on electronegative
on less electronegative
due to electronegative
charges, also causes
oxygen destabilizes
nitrogen atom makes
Cl and poor overlap
two carbonyl stretching
resonance form
this the most stable
peaks in IR
resonance form
ν ~ 1810 cm-1
ν ~ 1760 + 1830 cm-1
O
H3C
ν ~ 1750 cm-1
O
O
O
CH3
Symmetrical stretch
H3C
ν ~ 1650-1680 cm-1
O
O
CH3
Unsymmetrical stretch
Always obtain 2 stretching peaks for coupled vibrations (need vibrating bonds to be
connected by a common atom for coupling to occur) characteristic of anhydrides
Acid Chlorides
Acid chlorides are named by replacing the final –ic acid in the name for the corresponding
carboxylic acid and replacing it with –yl halide
O
O
OH
Cl
Butanoic acid
Butanoyl chloride
By far the most common acid halides that are used are the acid chlorides (instead of acid bromides or iodides) and thus most discussion will be with acid chlorides
Some common names for small acid chlorides:
O
O
Cl
Acetyl chloride
(ethanoyl chloride)
H
O
Cl
Formyl chloride
(methanoyl chloride)
Cl
Cl
Phosgene
Acid Chlorides
Remember carboxylic acids can be converted into acid chlorides by reaction with thionyl chloride
O
H3C
O
SOCl2
OH
H3C
Cl
The acid chloride can also be converted back to the carboxylic acid by reaction with water
(in either acidic or basic conditions)
O
H3C
O
H2O
H3C
Cl
OH
Characteristic for all
carboxylic acid
derivatives
This reaction follows the general scheme for acyl derivatives by reacting through an addition/elimination route
O
H3C
Cl
O
O
OH
H3C
Cl
OH
H3C
OH
Cl
Acid Chlorides
The acid chlorides can also be converted directly into any of the other acyl derivatives
through the same addition/elimination mechanism
O
O
H3C
H3 C
Cl
O
H3C
H3C
Cl
O
H3C
CH3
OCH3
O
NH3
Cl
O
O
CH3OH
O
H3C
O
OH
H3C
NH2
Since the acid chloride is more reactive than the anhydride, ester or amide, the acid chloride can be converted directly to any of these acyl derivatives
Acid Chlorides
As seen in discussion of carbonyl reactions, addition of one equivalent of Grignard reagent to an acid chloride (or ester) will generate a tetrahedral intermediate
O
H3C
RMgBr
Cl
O
O
H3C
Cl
H3C
Cl
R
R
Unlike when reacting a Grignard with a ketone or aldehyde, however, this tetrahedral intermediate has a good leaving group attached (the chlorine)
The alkoxide will reform a carbonyl (strong bond) with the good leaving group present
Since this ketone is formed in the presence of the Grignard reagent, a second addition occurs
O
H3C
O
R
RMgBr
H3 C
R
R
OH
H+
H3 C
R
R
Thus when either an acid chloride or ester react with a Grignard, two equivalents of Grignard are required and a 3˚ alcohol is obtained
Acid Chlorides
In order to stop at the ketone stage, a weaker nucleophile than a Grignard reagent is required
A solution is to use organocuprates
CuI
2
Li
2 CuLi
LiI
Organocuprates react with acid chlorides but they are not reactive enough to add to ketones
O
H3C
O
2 CuLi
Cl
H3C
Acid Chlorides
Likewise, acid chlorides will react twice with LAH to obtain tertiary alcohols the initial aldehyde after first addition will react a second time
O
H3C
OH
LAH
H3 C
Cl
H
H
There have been two solutions developed to stop reduction at aldehyde stage
First is to use a less reactive, bulky aluminum hydride reagent
CH3
Li
O
H3C
Cl
H Al O
CH3
CH3
O
3
(lithium aluminum tri-t-butoxy hydride)
H
H3 C
Bulky hydride
agent does not
reduce aldehyde
Second is called the “Rosenmund” reduction
H2, BaSO4, Pd
O
H3C
Cl
quinoline, !
O
H3 C
Poisoned catalyst
stops at aldehyde
H
stage
Anhydrides
Symmetrical anhydrides are named from the corresponding carboxylic acid name and then replace –acid in name with -anhydride
O
H3C
O
OH
Acetic acid
(ethanoic acid)
H3C
O
O
CH3
Acetic anhydride
(ethanoic anhydride)
Unsymmetrical anhydrides have both constituent acids named, listed alphabetically and then followed with -anhydride
O
H3C
O
O
Butanoic ethanoic anhydride
O
O
O
Benzoic propanoic anhydride
Anhydrides
Amongst the acyl derivatives, anhydrides can be converted directly into any of the less reactive carbonyl types
O
H3C
O
O
O
H3C
CH3O
O
H3 C
H3C
O
NH2
O
O
CH3
H3 C
CH3NH2
CH3
O
O
O
H3C
CH3
O
O
O
H3 C
O
O
CH3
O
O
O
CH3
H3 C
CH3
N
H
CH3
HO
The anhydride is less reactive than an acid chloride
Lose one carbonyl as a leaving group
(therefore with acetic anhydride shown lose acetic acid as leaving group) CH3
Anhydrides
Cyclic anhydrides can be formed from dicarboxylic acids
O
O
HO
O
H+
OH
O
O
-H2O
When cyclic anhydrides react with either an alcohol or amine, difunctional unsymmetrical carbonyl compounds are obtained
O
O
O
O
CH3NH2
HO
O
NHCH3
Both carbonyls are part of the product, an atom efficient way to create unsymmetrical compounds
Esters
Esters are named according to the parent carboxylic acid and the –ic acid is replaced with an
–ate suffix, the alkyl ester substituent is named as a separate alkyl group with the name in
front of the alkanoate name
O
O
OH
2-methylpentanoic acid
OCH3
Methyl 2-methylpentanoate
Cyclic esters are called “lactones”
Possible naming:
O
O
γ-Lactone
(indicate position of oxygen with Greek letter)
O
!
O
"
2-oxocyclopentanone
(place oxo indicating where oxygen substituted in cycloalkanone)
#
4-hydroxybutanoic acid lactone
(name parent hydroxy acid if ester is cleaved, place lactone at end)
Esters
Esters can react under either acidic or basic conditions to be hydrolyzed to the acid
O
H3C
O
H+
H3C
OR
H
O
H2 O
OR
H
OH2
OR
H3C
-H+
O
H3C
O
-ROH
OH
H3C
H
O
H+
OH
OR
H
H3C
This mechanism is the exact reverse of a Fischer esterification
Fischer esterification
O
H3C
O
H+, ROH
OH
H+, H2O
Ester hydrolysis
H3C
OR
H
OH
OR
Esters
Instead of hydrolyzing the ester with water, the same mechanism can be used to convert one ester into another ester
Called “Transesterification”
O
H3 C
O
EtONa
O
H3 C
O
H+, EtOH
OCH3
H3 C
O
As with ester hydrolysis, reaction can occur under either acidic or basic conditions
Important consideration when running reactions with esters, always use the alkoxide of the ester (ethoxide with ethyl ester for example) otherwise in addition to whatever other reaction is occurring (will see base catalyzed
reactions with esters in later chapters) a transesterification of the product will also occur
Esters
Similar to acid chlorides, when esters react with Grignard reagents two additions occur to generate 3˚ alcohols
O
H3 C
CH3CH2MgBr
OCH3
CH3CH2MgBr
O
H3C
OH
H3C
CH2CH3
Two of the R groups
on 3˚ alcohol must
be identical
Same mechanism occurs with LAH as two hydrides are delivered to generate 1˚ alcohol
O
H3 C
LAH
OH
OCH3
To stop at one addition, diisobutyl aluminum hydride (DIBAL-H) has been developed to reduce an ester to an aldehyde
C(CH3)2
H Al
O
H3 C
O
C(CH3)2
OCH3
(DIBAL-H)
-70˚C
H3C
H
Need to run reaction
at low temperature to
prevent second
addition
Amides
Amides are named by dropping the –oic acid from the parent carboxylic acid and writing –amide as the suffix
O
H3 C
O
OH
Acetic acid
(ethanoic acid)
H3C
CH2CH3
N
CH3
Substituents on amide
nitrogen are labeled as Nalkyl in alphabetical order
N-ethyl-N-methyl acetamide
(N-ethyl-N-methylethanamide)
Cyclic amides are called “lactams”, similar to cyclic esters called “lactones”
O
2-azacyclohexanone
δ-lactam
$ 5-aminopentanoic acid lactam
!
Nitrogen analogs of anhydrides
are called “imides”
NH
"
O
H
N
O
#
Succinimide
(imide version from succinic acid)
Amides
Like all carboxylic acid derivatives, amides can be hydrolyzed to the carboxylic acid form
under either acidic or basic conditions
O
O
NaOH
H3 C
OH
!
H3C
CH2CH3
N
CH3
O
H+, H2O
!
H3 C
OH
Due to the lower reactivity of amides compared to the other carboxylic acid derivative
compounds, higher temperature is required to allow this transformation to occur
Also due to the nature of the leaving group, for amide hydrolysis the acidic conditions are much easier than the basic
The amides cannot be converted directly to any of the other acyl carboxylic acid derivatives due to the lower reactivity
To change the amide to an ester, for example, first need to hydrolyze the amide to the acid
and then convert the acid to the desired ester compound
Carboxylic Acid Derivatives
O
H3C
Reactivity
Cl
O
H3C
O
H3C
O
O
CH3
OH
O
H3C
OCH3
Amongst the derivatives,
however, only the more reactive
can be converted to the less
reactive directly (cannot synthesize a more reactive
derivative directly from a less
reactive)
O
H3C
NH2
All carboxylic acid derivatives can be converted to the acid under either acidic or basic hydrolysis
Also the carboxylic acid can be converted directly to each of the derivatives
Amides
While amides cannot be changed directly to the acyl carboxylic acid derivatives, it can react with hydride delivery agents
O
H3 C
H3 C
O
CH2CH3
N
CH3
N
LAH
H3 C
H3 C
N
H3C
CH2CH3
H
H
H3C
O
CH2CH3
H
O
CH2CH3
H
H3 C
LAH
N
CH3
AlH2
H3 C
H
CH2CH3
N
CH3
The amide (negative charged nitrogen)
is too unstable to allow
reaction to occur
CH2CH3
N
H
Instead alkoxide coordinates to
CH3
aluminum to make a leaving group
and formation of imminium ion
The imminium ion will be reduced with
LAH to form an amine, overall amide was thus reduced to amine
Amides
Another convenient reaction is that nitriles are the “dehydrated” forms of amides
O
-H2O
NH2
H3C
H3C
N
Can cause this interconversion with strong dehydrating agents
(e.g. POCl3 or P2O5 are common)
O
NH2
POCl3
N
Obviously would need a primary amide to allow reaction to occur
(need two hydrogens on amide nitrogen for dehydration)
One of two common ways to synthesize nitriles
(other is SN2 reaction of cyanide with alkyl halides)
Amides
A type of amide that is used biologically are β-lactams
β refers to nitrogen of amide attached to the second carbon from carbonyl (hence β-carbon)
H
N
R
O
H
S
N
O
CO2H
Penicillin
Unlike normal amides or lactams, β-lactams are more reactive due to the strain of the 4-membered ring
Amides
Therefore nucleophiles will react with the amide carbonyl of the ring to open the ring and release the ring strain
O
H
N
R
O
H
S
N
O
H
N
H
O
NUC
N
R
O
HN
S
NUC
R
S
O
HN
CO2H
NUC
The other amide is unreactive because it does not have ring strain, reacts like other amides discussed earlier
CO2H
Amides
β-Lactams as antibacterial agents
Bacterial cells survive many conditions that mammalian cells do not due to a
rigid cell wall composed of carbohydrates linked together by peptide bonds
O
H2 N
enzyme
OH
Polymer chain of
cell wall
O
HN
Penicillin interferes
with enzyme With the β-lactam penicillin present, the cell walls of the bacterial are disrupted because the
enzyme that forms the cell walls is turned off by undergoing a nucleophilic reaction with
penicillin and thus the bacterial cells eventually die
Penicillin does not disrupt mammalian cells since they are surrounded by a lipid bilayer and not a peptide linked cell wall
Nitriles
Nitriles are named as alkanenitriles
Find longest carbon chain containing nitrile to determine the root name
O
HO
N
CH2CH2CH3
Butanoic acid
CH2CH2CH3
Butanenitrile
(include nitrile carbon in root)
If nitrile is not the highest priority group, then name group as a cyano prefix
O
CN
4-cyano-2-pentanone
Have already seen that the most common methods to synthesize a nitrile are either
dehydration of a primary amide (usually with P2O5 or POCl3) or SN2 reaction with cyanide
Nitriles
Obviously nitriles are not acyl derivatives as the other carboxylic acids observed, but they are still considered a type of carboxylic acid derivatives because the nitrile can be
hydrolyzed to a carboxylic acid and the acid can be converted to a nitrile through an amide R C N
H+
R C N H
N
H2 O
R
H
N
-H+
OH2
R
H
OH
H+
OH
R
O
NH2
H+, H2O
R
O
NH2
-H+
R
OH
H
R
N
H
OH
Hydrolysis can occur under either acidic or basic mechanism, although reaction under basic
conditions can lead to other types of reactions so acidic hydrolysis is preferred
Nitriles
The electrophilic carbon of nitriles can also react with strong nucleophiles
When reacting nitriles with Grignard reagents, a ketone is obtained after hydrolysis
N
CH3MgBr
R C N
R
N
H+
R
CH3
Cannot react a second
equivalent due to negative
charge on nitrogen (would generate a -2 charge if
reacted again)
H
O
H+, H2O
R
CH3
CH3
Imines hydrolyze to ketones
with acidic water
Allows synthesize of ketones with Grignard reagents, when either acid chlorides or esters
reacted with Grignard a tertiary alcohol was obtained
O
H3 C
CH3CH2MgBr
OCH3
CH3CH2MgBr
O
H3C
CH2CH3
OH
H3C
Nitriles
When nitriles are reduced with LAH, both π bonds are reduced to obtain an amine
R C N
1) LAH
2) H2O
R CH2NH2
Nitriles can also be reduced to amines with catalytic hydrogenation
CN
H2
Pd
CH2NH2
Nitriles
The LAH reduction of nitriles to primary amines is a convenient way to synthesize primary amines as the nitriles can also be easily synthesized from alkyl halides
Br
NaCN
CN
1) LAH
2) H2O
NH2
Another functional group that can be reduced to primary amines is an azide, likewise an azide can also be easily synthesized from alkyl halides
Br
NaN3
N3
1) LAH
2) H2O
NH2
(realize that when a nitrile is reduced one extra carbon is included due to the carbon from the
nitrile, therefore these two routes synthesize primary amines with a different number of carbons)
Amines
Remember also that it is difficult to synthesize primary amines by reacting ammonia directly
with the alkyl halide as polyalkylation often occurs to generate the quaternary product
NH3
Br
NH2
10.9%
N
H
N
N
17.9%
19.1%
<1%
When the alkyl halide and ammonia are reacted in a 1:1 ratio, a low yield of the primary
amine is obtained because the primary amine is also nucleophilic and can react again
If the ammonia is used in excess, majority of product is 1˚ amine while if alkyl halide is used in excess, the majority of product is quaternary amine
Another way to avoid this problem is instead of reacting ammonia, use the phthalimide anion
O
O
NH
KOH
O
Called the “Gabriel”
synthesis
N
O
O
Br
N
O
CO2H
NaOH
NH2
CO2H
Due to carbonyls, only
In base, phthalimide
one addition occurs
hydrolyzes to amine and acid
Ketenes
Ketenes are compounds that contain a ketone functionality and the carbonyl carbon also has a double bond attached to another carbon
The IUPAC naming for these compounds involve naming as alkene-substituted ketones, the common naming however names the functional group as ketene and then list the alkyl
substituents to the ketene alphabetically
H
H3 C
C C O
H3CH2C
C C O
H
Ethenone
(ketene)
2-methyl-1-buten-1-one
(ethylmethylketene)
Ketenes are synthesized by elimination reactions of acid chlorides using tertiary amines
O
Cl
H
Et3N
H3 C
C C O
H3CH2C
Ketenes
The carbonyl carbon of ketenes is very electrophilic and will react with weak nucleophiles
H
C C O
O
NUC
H2C
H
H2 C
NUC
O
OH
H+
H3C
NUC
NUC
Upon initial reaction of nucleophile, an enolate is formed which upon protonation
equilibrates to a carbonyl structure
Ketenes can thus react to form carboxylic acids or derivatives like esters or amides
H
C C O
H3C
H
H
C C O
C C O
H
OH
O
CH3OH
H3C
H
H
O
H2 O
OCH3
O
CH3NH2
H3C
NHCH3
Reduction of Carbonyl Compounds
O
Reducing H C
3
reagent
O
CH3 H3C
O
O
OH
H3C
Cl
H3 C
OH
H3 C
OH H3C
O
OCH3 H3C
NH2 H3C
H3 C
NH2 H3C
N
C
OH
LAH
H3 C
CH3 H3C
OH
NH2
OH
NaBH4
H3 C
CH3
LiAlH(OtBu)3
slow at
RT
(bulky)
NR
NR
slow
(NR at RT)
O
NR
H3 C
H
CH3 H3C
OH
H3 C
H
H3 C
RMgBr
H3C
CH3 H3C
O
H3C
R
H
H3 C
H
H3 C
(0˚C)
O
O
O
OH H3C
R OH
R
O
(-78˚C)
H
(-78˚C)
R OH
O
(-78˚C)
OH
H3 C
NR
O
(-78˚C)
DIBAL
NR
R OH
H3 C
R
H3C
H
(-78˚C)
Poor
reaction
H
H3C
(-78˚C)
O
H3C
R
Oxidation to Synthesize Carbonyl Compounds
Similar to there being a variety of reducing agents to selective reduce carbonyl compounds,
there are also a variety of oxidizing conditions to synthesize carbonyl compounds
Alkenes oxidized, if H present obtain aldehyde
O
O
HO
H
HO
H
OH
O
O
OH
OH
OH
MnO2
HO
O
Cr(VI), acidic
HO
H
Only allylic
alcohols oxidized
Consider this diol
starting material
Swern
-78˚C
O
OH
1) O3, 2) H2O2
1) O3, 2) Zn
O
Alkenes oxidized, if H present obtain acid
HO
Cr(VI), basic
(PDC or PCC)
O
H
1˚ alcohols oxidized to
aldehyde, no metal
O
O
1˚ alcohols
oxidized to acid
O
H
1˚ alcohols oxidized
to aldehyde
Baeyer-Villiger
There are some reactions that allow conversion of a ketone to a carboxylic acid derivative
(have already seen that organolithiums can convert a carboxylic acid to a ketone)
A Baeyer-Villiger reaction allows conversion of ketone to ester
O
O
RCO3H
R
R
R
O
R
Mechanism of oxygen insertion?
O
O
R
H
R
O
R
O
O
O
R
H
O
R
O
R
O
H
O
O
R
O
R
HO R
R
R
O
R
O
O
Weak oxygen-oxygen
single bond
Mechanism is not an insertion, but rather a reaction at carbonyl followed by a migration
Baeyer-Villiger
Migration with unsymmetrical carbonyls
If the two alkyl components of the ketone are different, which one migrates?
O
R1
O
RCO3H
R2
R1
O
O
R2
or
R2
O
R1
There is a distinct preference for one group to migrate selectively
H
>
3˚ alkyl >
2˚ alkyl ~ phenyl >
1˚ alkyl >
In general, a hydrogen migrates first, but then a more substituted alkyl group migrates preferentially
methyl
Baeyer-Villiger
Examples
O
RCO3H
O
More substituted substituent migrates preferentially
O
O
O
O
RCO3H
O
O
RCO3H
Another way to oxidize aldehyde to carboxylic acid
HO
H
Cyclic ester (lactone)
O
H
H
O
H
RCO3H
H
O
Migration occurs with retention of configuration for migrating group
Beckmann Rearrangement
While the Baeyer-Villiger oxidation converts a ketone to an ester, the Beckmann rearrangement converts a ketone to an amide
1) NH2OH, H+
2) H2SO4
O
H3 C
O
CH3
H3C
NHCH3
The Beckmann rearrangement also involves a migration of one of the alkyl substituents of
the ketone, but has a water leaving group rather than breaking a O-O single bond
O
H3 C
N
NH2OH
CH3
H+
H3C
OH
N
H2SO4
CH3
H3C
OH2
O
NH
CH3
N
CH3
CH3
Oxime formation
H3 C
H3 C
H2 O
H3C
HO
H3C
N
-H+
CH3
H2 O
N
CH3
Hofmann Rearrangement
Converts primary amides to amines with loss of the carbonyl carbon
The main advantage of this method is to generate amines on 3˚ carbons,
realize that with SN2 methods cannot place amine on 3˚ carbon
Hofmann rearrangement starts with primary amide
that can be generated from the acid chloride
Upon introduction of basic halide solution (Br2 or Cl2) an amine is obtained
O
Br2, NaOH
NH2
NH2
-CO2
The reaction is driven by loss of carbon dioxide
Hofmann Rearrangement
The mechanism of the Hofmann rearrangement involves a migration of the alkyl group to form an isocyanate
O
Br2, NaOH
O
NH2
N
H
NH2
-CO2
Br
O
NaOH
O
N
H
N
O
Br
NaOH
N
N
C
O
Carbamic acid
isocyanate
Br
O
Nomenclature
The compounds with one carbonyl are named according to the rules presented earlier
Compounds with multiple functional groups, however, need a priority for naming
Remember that carboxylic acid derivatives outrank all other substituents
Amongst carbonyl compounds the following priorities apply:
Acid > ester > amide > nitrile > aldehyde > ketone
Carboxylic Acid Derivatives
Example of carboxylic acid derivative chemistry in biology
Why do humans take aspirin?
O
O
OH
aspirin
O
Found naturally in willow bark and myrtle leaves
In the fifth century BC, Hippocrates wrote about the curative powers of willow bark
In the nineteenth century, the compound was synthesized for the first time from salicylic acid and acetic anhydride
Carboxylic Acid Derivatives
Biological targets
Arachidonic acid is converted into PGH2 by an enzymatic pathway called prostaglandin synthase
CO2H
Prostaglandin
synthase
CO2H
OH
Arachidonic acid
PGH2
Carboxylic Acid Derivatives
PGH2 is converted into prostaglandins and thromboxanes biologically
HO
CO2H
HO
OH
O
CO2H
Prostaglandins
Amongst other things,
stimulate inflammation
and induce fever
CO2H
HO
OH
OH
CO2H
O
O
PGH2
OH
Thromboxanes
Stimulate platelet
aggregration
OH
CO2H
HO
O
OH
Carboxylic Acid Derivatives
Aspirin interacts directly with the enzyme cyclooxygenase
(which is the initial part of the prostaglandin synthase enzyme)
Part of the cyclooxygenase enzyme has a primary hydroxy group (CH2OH) attached to a serine amino acid, thus called a serine hydroxy group
O
CH3
O
O
HOH2C
OH
H3 C
OH2C
CO2
CO2
Active enzyme
Inactive enzyme
Aspirin will transesterify this serine hydroxy group (through a carboxylic acid derivative chemistry) and thus inactivating the enzyme
Thus both prostaglandins and thromboxanes will not be produced
Carboxylic Acid Derivatives
How aspirin therefore affects health
Aspirin turns off the cyclooxygenase enzyme
This enzyme is part of the prostaglandin synthase enzyme which converts arachidonic acid into PGH2
(which in turn is converted into prostaglandins and thromboxanes)
Aspirin will therefore prevent inflammation and reduce fever (effects of prostaglandins) and also will lower platelet aggregation (effect of thromboxanes)
Presumably the prevention of thromboxanes is why aspirin has been reported
to reduce the incidence of strokes and heart attacks
Also reason why aspirin should not be taken in the days before surgery, do not want anticoagulants in the body during surgery