DECARBOXYLATION OF

CARBOXYLIC ACIDS
INTRODUCTION
Decarboxylation is a chemical reaction that releases CO2. Usually,
decarboxylation refers to a reaction of carboxylic acids, removing a
carbon atom from a carbon chain. The reverse process, which is the first
chemical step in photosynthesis, is called carbonation, the addition of
CO2 to a compound.
Useful in Synthetic and Bio-Organic Chemistry.

There are basically 2 types of Decarboxylation.

1) -carbonyl Carboxylic acids(non radical conditions)

2) Simple Carboxylic acids (Radical Conditions)

-CARBONYL CARBOXYLIC ACIDS
General Reaction

The type of reaction followed is First Hydrolysis then Elimination of CO2

It plays a key role in Aceto-acetic Ester synthesis and Malonic ester

synthesis.
MECHANISM
Step 1 =>
Start at the protonation of the carbonyl, break the O-H bond and form
The p bond, break the C-C and make the C=C. Note the concerted
Nature of this reaction and the cyclic transition state.
Step 2 =>
Tautomerization of the enol of the ketone leads to the more
Favorable enolic form
EXAMPLE
AcetoAcetic Ester Synthesis

Malonic Ester Synthesis

SIMPLE CARBOXYLIC ACIDS
General Reaction

Reaction type is Elimination then addition of H+

It plays a role in Ruff Degradation of Sugars and Initiation of Radical Polymers.

MECHANISM
EXAMPLE
RUFF DEGRADATION of SUGARS
IMPORTANT POINTS TO REMEMBER
Decarboxylation is used to reduce the carbon chain in a
compound.
It is used as a method of preparation of alkanes
If there is a beta-keto group Decarboxylation occurs
upon Simple heating.
The most common reactants used for Decarboxylation
are (NaOH + CaO)
 Dieckmann
condensation
Examples
 The Diels-Alder
Reaction
The DielsAlder reaction is an organic chemical
reaction (specifically, a cycloaddition) between a
conjugated diene and a substituted alkene, commonly
termed the dienophile, to form a substituted cyclohexene
system.
The Mechanism of
Diels-Alder
Reaction
 six-electron cyclic
reaction
The dienophile can be considered as simultaneously a nucleophile
and electrophile
The driving force is the conversion of two bonds into two
bonds
The reaction will not happen without a Hckel number of electrons
dienes are electron-rich
dienophiles are electron-poor
 Typical dienophiles have
electron-poor double bonds
 Regiochemistry of
the Diels-Alder Reaction

With asymmetric diene and dienophile, there are two possible

regiochemical orientations
The diene must be in the proper conformation for the reaction to
occur

This conformation is called s-cis because the sigma bond must be

rotated into a pseudo-cis conformation
 The Diels-Alder reaction is
stereospecific in the dienophile
The Diels-Alder reaction form
asymmetric carbon atoms
EXAMPLES
 An elimination reaction is a type of organic reaction in
which two substituents are removed from a molecule in
either a one or two-step mechanism.[2] The one-step
mechanism is known as the E2 reaction, and the two-step
mechanism is known as the E1 reaction. The numbers do
not have to do with the number of steps in the mechanism,
but rather the kinetics of the reaction, bimolecular and
unimolecular respectively.
In most organic elimination reactions, at least one hydrogen
is lost to form the double bond: the unsaturation of the
molecule increases. It is also possible that a molecule
undergoes reductive elimination, by which the valence of an
atom in the molecule decreases by two. An important class
of elimination reactions are those involving alkyl halides,
with good leaving groups, reacting with a Lewis base to form
an alkene. Elimination may be considered the reverse of an
addition reaction. When the substrate is asymmetric,
regioselectivity is determined by Zaitsev's rule.
 E1 is a model to explain a particular type of chemical
elimination reaction. E1 stands for unimolecular elimination
and has the following specificities.
E1 typically takes place with tertiary alkyl halides, but is
possible with some secondary alkyl halides.
The reaction rate is influenced only by the concentration of the
alkyl halide because carbocation formation is the slowest step
aka rate-determining step. Therefore first-order kinetics apply
(unimolecular).
Reaction usually occurs in complete absence of base or
presence of only a weak base (acidic conditions and high
temperature).
E1 reactions are in competition with SN1 reactions because
they share a common carbocationic intermediate.
A secondary deuterium isotope effect of slightly larger than 1
(commonly 1 - 1.5) is observed.
No antiperiplanar requirement. An example is the pyrolysis of a
certain sulfonate ester of menthol:
An example in scheme 2 is the reaction of tert-butylbromide with potassium
ethoxide in ethanol.
 E2 is a one-step process of elimination with a single transition
state.
Typically undergone by primary or secondary substituted alkyl
halides
The reaction rate, influenced by both the alkyl halide and the base
(bimolecular), is second order.
Because E2 mechanism results in formation of a pi bond, the two
leaving groups (often a hydrogen and a halogen) need to be
coplanar. An antiperiplanar transition state has staggered
conformation with lower energy than a synperiplanar transition
state which is in eclipsed conformation with higher energy. The
reaction mechanism involving staggered conformation is more
favorable for E2 reactions (unlike E1 reactions).
E2 typically uses a strong base, It needs a chemical strong enough
to pull off a weakly acidic hydrogen.
In order for the pi bond to be created, the hybridization of carbons
need to be lowered from sp3 to sp2.
The C-H bond is weakened in the rate determining step and
therefore a primary deuterium isotope effect much larger than 1
(commonly 2-6) is observed.
E2 is very similar to the SN2 reaction mechanism.
An example of this type of reaction in scheme 1 is the reaction of
isobutylbromide with potassium ethoxide in ethanol. The reaction
products are isobutylene, ethanol and potassium bromide.
The E1cB elimination reaction is a special type of elimination
reaction in organic chemistry. This reaction mechanism explains the
formation of alkenes from (mostly) alkyl halides through a carbanion
intermediate given specified reaction conditions and specified
substrates. The abbreviation stands for Elimination Unimolecular
conjugate Base. The reaction takes place around a sp3 - sp3 carbon
to carbon covalent bond with an -acidic hydrogen atom substituent
and a -leaving group. This leaving group can be a halide or a
sulfonic acid ester such as a tosyl group. A strong base abstracts
the proton generating a carbanion. The electron pair then expels
the leaving group and the double bond is formed. When the first
step to the carbanion is slow and the second step fast the reaction
is irreversible and named (E1cB)i. When the first step is fast and the
leaving group is expelled reversibly then the reaction mechanism is
(E1cB)r. In the (E1cB)anion variation the carbanion is especially
stable with a rapid first step and a slow second step.
The terms SN1 and E1 mean "substitution, nucleophilic,
unimolecular" and "elimination, unimolecular," respectively.
These two reaction types are being considered together for two
reasons:
1.They often occur simultaneously and competitively with one
another, under the same reaction conditions.
2.They each involve the formation of a carbocation as the
crucial intermediate in the rate-determining step; these reactions
exhibit unimolecular (or "first-order") kinetics, because only one
molecule -- the immediate precursor of the carbocation -- is
involved in the rate-determining step.
The generalized mechanism for each of these reaction types
has been depicted below, using tert-butyl chloride as the starting
material:
Notice that the product of an SN1 substitution reaction has simply replaced
the chlorine atom with the new substituent, "Nu" in this case. The alkyl group
(t -butyl) present in the starting material is still intact, and the hybridization of
the substituent-bearing carbon has not changed (it's still sp3). Conversely,
the product of the elimination reaction is an alkene: the starting material has
lost the elements of HCl, and the hybridization of the carbon originally
bearing the chlorine atom has changed from sp3 to sp2

Note also that the nucleophile in an SN1 reaction does not have to bear a
negative charge. In fact, these reactions are typically performed under
"solvolysis" conditions, i.e., simply heating the starting material in a protic
solvent (an alcohol or carboxylic acid) that can also act as a nucleophile. In
these cases, of course, the product of carbocation capture by the solvent
will bear a "+" charge, and it will have to lose H+ in order to form a neutral
product. Similarly, the base in an E1 reaction does not have to be strong.
In fact, the base must not be strong, otherwise the E2 mechanism will be
followed. It is common for the solvent to act as the base in an E1 reaction,
just as it acted as the nucleophile in an SN1 process
Self-test question #1
The following products are formed when tert-butyl
bromide is heated in ethanol:

What three (organic) products would you expect to

be formed if t -pentyl bromide were heated in
ethanol? Which of these products is (are) formed by
substitution and which is (are) formed by elimination
pathways?
Self-test question #2
Can you explain why heating either enantiomer
of 2-bromo-2-phenylbutane in ethanol leads to
the same substitution product, i.e., a racemic
mixture of 2-ethoxy-2-phenylbutane?
 The reaction rate is influenced by halogen's reactivity; iodide and
bromide being favored. Fluoride is not a good leaving group. There is
a certain level of competition between elimination reaction and
nucleophilic substitution. More precisely, there are competitions
between E2 and SN2 and also between E1 and SN1. Substitution
generally predominates and elimination occurs only during precise
circumstances. Generally, elimination is favored over substitution
when
In one study [4] the kinetic isotope effect (KIE) was determined for the
gas phase reaction of several alkyl halides with the chlorate ion. In
accordance with a E2 elimination the reaction with t-butyl chloride
results in a KIE of 2.3. The methyl chloride reaction (only SN2
possible) on the other hand has a KIE of 0.85 consistent with a SN2
reaction because in this reaction type the C-H bonds tighten in the
transition state. The KIE's for the ethyl (0.99) and isopropyl (1.72)
analogues suggest competition between the two reaction modes
 Summary of SN1, SN2, E1, and E2 Reactivity
The following chart and table summarize the expected modes of
reactivity es, although the reader should recall the alcohols, under
acidic conditions, can react in the same ways (except for E2, which
requires base). Note that these charts do not include substrates that
could ionize to produce carbocations that would be stabilized by
resonance effects. In those cases, SN1 and E1 reactions could be
expected to compete more effectively than their bimolecular
counterparts.
Summary of SN1, SN2, E1, and E2 Reactivity
(as a function of RX Structure)

In general, substrates react in the following way:

RCH2X Mostly SN2 substitution
(primary)

R2CHX SN2 substitution with nonbasic nucleophiles

(primary)
E2 elimination with strong bases
Mostly E2 elimination
R3CX (SN1 substitution and E1 eliminationin nonbasic
(primary)

solvents
Correlation of Structure and Reactivity for Substitution and Elimination Reactions

Hali
de SN1 SN2 E1 E2
Type

Occurs
RCH2 Does not Highly Does not when
X occur favored occur strong
(primary)
bases
are used
Can Can
Occurs
occur occur Favored
in
R2CH with with when
competiti
X benzylic benzylic strong
on
(secondary)
and and bases
with E2
allylic allylic are used
reaction
halides halides
Occurs
Favored Favored
in
in Does not when
R3CX competiti
hydroxyli occur bases
(tertiary)
on
c are
with SN2
solvents used
reaction
 Self-test question #5
Although it is difficult for most beginning students to predict which of the four
modes of reactivity -- SN1, SN2, E1, and/or E2 -- will be followed for a
particular set of conditions, one should certainly be able to say which mode
of reactivity was followed if shown the reactants, conditions, and products of a
particular reaction. For each of the products of the reactions shown below,
indicate which of the four mechanisms was involved in its formation. Use the
"structure/reactivity correlation chart"shown above if you need help:
 FriedelCrafts alkylation involves the alkylation of
an aromatic ring with an alkyl halide using a
strong Lewis acid catalyst. With anhydrous ferric
chloride as a catalyst, the alkyl group attaches at
the former site of the chloride ion.
 FriedelCrafts alkylation is a reversible reaction
This reaction has one big disadvantage, namely that
the product is more electrophilic than the reactant due
to the electron donating alkyl-chain.
Steric hindrance can be exploited to limit the number of
alkylations, as in the t-butylation of 1,4-dimethoxybenzene
 Alkylations are not limited to alkyl halides:
FriedelCrafts reactions are possible with
any carbocationic intermediate such as
those derived from alkenes and a protic
acid, Lewis acid, enones, and epoxides.

An example is the synthesis of neophyl

chloride from benzene and methallyl
chloride
H2C=C(CH3)CH2Cl + C6H6
C6H5C(CH3)2CH2Cl
 FriedelCrafts acylation is the acylation of aromatic
rings with an acyl chloride using a strong Lewis
acid catalyst. FriedelCrafts acylation is also
possible with acid anhydrides
 Due to the electron-withdrawing effect of
the carbonylgroup, the ketone product is always
less reactive than the original molecule, so multiple
acylations do not occur.
Also, there are no carbocation rearrangements, as
the carbonium ion is stabilized by a resonance
structure in which the positive charge is on the
oxygen.
 FRIES
REARRANGEMENT
 It is a rearrangement reaction of a phenyl ester to
a hydroxy aryl ketone by catalysis of Lewis acids. he
reaction is ortho and para selective and one of the
two products can be favoured by changing reaction
conditions, such as temperature and solvent.
MECHANISM
The orientation of the substitution
reaction is temperature dependent.
A low reaction temperature
favors para substitution and with
high temperatures
the ortho product prevails.
Formation of the ortho product is
also favoured in non-polar
solvents; as the solvent polarity
increases, the ratio of the para
product also increases.
Phenols react to esters but do not
react to hydroxyarylketones with
acylhalogen compounds
under Friedel-Crafts
acylation reaction conditions and
therefore this reaction is of
industrial importance for the
synthesis of hydroxyarylketones
which are important intermediates
for several pharmaceutics such
as paracetamol and salbutamol.
EXAMPLES
--Abuturab mohammadi
 Gabriels phthalimide systhesis converts
R-X and NH3 into 1amine
First step is the conversion of phthalic
anhydride into phthalamide
Phthalic acid is reused as anhydride and thus is the carrier of the
reaction[DMF is polar aprotic solvent and is an excellent medium for
SN2]

The alkyl halide undergoes nucleophilic displacement by phthalimide

anion(sn2)to form N-substituted phthalimide the latter is then
hydrolysed either by acid or by alkali
 Instead of using acid or base hydrolysis
hydrazine can also be used if hydrolysis is
difficult
 Gabriels sysnthesis is useful for the
synthesis of complex compund because
phthalimide group is fairly unreactive & is
easily separated at the end of hydrolysis

It is the best method of preparation of

1amines
Which of the above cannot be prepared by the method?
GATTERMANN
REACTION
This method synthetizes phenolic
aldehydes by treatment of an
aromatic compound
with hydrogen chloride
and metallic cyanide as zinc
cyanide in the presence of Lewis
acid
catalysts via ELECTROPHILIC
AROMATIC SUBSTITUTION.
MECHANISM
EXAMPLES
Gomberg-Bachmann reaction- Named for the
Ukrainian-American chemist Moses Gomberg
and the American chemist Werner Emmanuel
Bachmann

It is a base-promoted radical coupling between

an aryl diazonium salt and an arene to form a
diaryl compound. An aryl-aryl coupling
reaction via a diazonium salt.
Type of Reaction: Aryl-aryl coupling reaction via a diazonium salt.
Reagent: NaOh (basic medium)

The arene compound 1 (here benzene) is coupled with

base with the diazonium salt 2 to the biaryl 3 through
an intermediate aryl radical. For example, p-
bromobiphenyl may be prepared from 4-bromoaniline
and benzene:

BrC6H4NH2 + C6H6 BrC6H4C6H5

BrC6H4NH2 + C6H6 BrC6H4C6H5
Q)

BrC6H4NH2 + C6H6 BrC6H4C6H5

HELL-VOLHARD ZELINSKY
The Hell VolhardZelinsky
halogenation reaction halogenatess
carboxylic acids at the carbon

It is a REDUCTION reaction
Reaction
 Mechanism
PBr3 replaces the carboxylic OH with a bromide, resulting in a carboxylic acid
bromide. The acyl bromide can then tautomerize to an enol, which will readily
react with the Br2 to brominate a second time at the position.
In neutral to slightly acidic aqueous solution, hydrolysis of the -bromo acyl
bromide occurs spontaneously, yielding the -bromo carboxylic acid in an example
of a nucleophilic acyl substitution. If an aqueous solution is desirable, a full molar
equivalent of PBr3 must be used as the catalytic chain is disrupted.
If little nucleophilic solvent is present, reaction of the -bromo acyl bromide with
the carboxylic acid yields the -bromo carboxylic acid product and regenerates the
acyl bromide intermediate. In practice a molar equivalent of PBr3 is often used
anyway to overcome the slow reaction kinetics.
The mechanism for the exchange between an alkanoyl bromide and a carboxylic
acid is at below. The -bromoalkanoyl bromide has a strongly electrophilic
carbonyl carbon because of the electron-withdrawing effects of the two bromides.
The carboxylic acid will act as a nucleophile that the carbonyl oxygen of the
carboxylic acid has a partial negative charge
.

Mechanism *(continued)
 Function of Reagent
Another use for PBr3 is as a catalyst for the -
bromination of carboxylic acids. Although acyl
bromides are rarely made in comparison
with acyl chlorides, they are used as
intermediates in Hell-Volhard-Zelinsky
halogenation.[4] Initially PBr3 reacts with the
carboxylic acid to form the acyl bromide,
which is more reactive towards bromination.
 Function of Reagent
overall process can be represented as
 Extra Info
Unlike other halogenation reactions, this
reaction takes place in the absence of a
halogen carrier. The reaction is initiated by
addition of a catalytic amount of PBr3, after
which one molar equivalent of Br2 is added.
It is a nucleophilic substitution reaction.
Examples
Hoffman maritus rearrangement
The HofmannMartius
rearrangement in organic chemistry is
a rearrangement reaction converting an
N-alkylated aniline to the
corresponding ortho and / or paraaryl-
alkylated aniline. The reaction requires
heat and the catalyst is an acid
like hydrochloric acid [1][2]
The reaction is also known to work
for aryl ethers and two
conceptually related reactions are
the Fries rearrangement and
the FischerHepp rearrangement.
Itsreaction mechanism centers
around dissociation of the reactant
with the positively charged organic
residue R attacking the aniline ring
in a FriedelCrafts alkylation.
In one study this rearrangement is
applied to a 3-N(CH3)(C6H5)-2-
oxindole
HOFFMANN BROMAMIDE
DEGRADATION
 Preliminary information

The Hofmann rearrangement is the organic reaction of a

primary amide to a primary amine with one
fewer carbon atom

The reaction is named after its discoverer: August Wilhelm

von Hofmann. This reaction is also sometimes called
the Hofmann degradation or the H.armon Process
 MECHANISM

The reaction of bromine with sodium

hydroxide forms sodium hypobromite in situ,
which transforms the primary amide into an
intermediate isocyanate. The intermediate
isocyanate is hydrolyzed to a primary amine,
giving off carbon dioxide.
Mechanism Continued
BY THIS METHOD THE AMIDE (CONH2) GROUP IS CONVERTED INTO
PRIMARY AMINE ( NH2) GROUP.

R - CO - NH2 + BR2 + 4KOH R - NH2 + 2KBR + K2CO3 + 2H2O

(AMIDE) (PRIMARY-AMINE )

THIS IS THE MOST CONVENIENT METHOD FOR PREPARING PRIMARY

AMINES.

THIS METHOD GIVES AN AMINE CONTAINING ONE CARBON ATOM LESS

THAN AMIDE.
PROBLEMS
Example 1: Acetamide changes into
methylamine by
(a) Hofmann bromamide reaction
(b) Hofmann reaction
(c) Friedel-Craft's reaction
(d) Hinsberg reaction

Ans: a

Example 2: Hofmann's hypobromite reaction is

a method of
(a) Preparing a tertiary amine
(b) Preparing a mixture of amines
(c) Stepping down a series
(d) Stepping up a series

Ans: b,c
 Variation
Several reagents can substitute for bromine. N-
Bromosuccinimide and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) can effect a Hofmann rearrangement. In the following
example, the intermediate isocyanate is trapped by methanol,
forming a carbamate.[4]
 HOFMANNS
ELIMINATION REACTION
THE MECHANISM
 THE DEFINITION
When a quaternary salt obtained by the
exhaustive methylation of an amine is treated
with moist silver oxide, corresponding
quaternary hydroxide is obtained which, on
heating at 400K, undergoes an elimination
reaction to yield an alkene, trimethylamine
and water. This reaction is called Hofmanns
Elimination Reaction
 Simplifying the definition
Quaternary means a group of four. In this
case, four alkyl groups surrounding one
nitrogen atom denotes the quaternary salt.
 So, simply put, this reaction deals with a salt
derived from an amine.
It is treated with moist silver oxide, forming a
hydroxide.
Finally, due to heating, it loses a water molecule
to produce an alkene and a trimethylamine.
 Hoffmans Rule
It states that the loss of the -hydrogen occurs preferably from the
most unhindered position in the quaternary hydroxide. The
product alkene with fewer substituents will predominate.
This rule is followed in the reaction while determining the major
product.

C-2 from the right is the lesser substituted carbon. Hence elimination occurs there and
The corresponding alkene is formed. Steric hindrance of C-4 inhibits elimination.
THE MECHANISM
 THE MAJOR PRODUCT
According to Hofmanns
rule, these are the major
compound. Unlikely compounds
Hell-Volhard Zelinsky

Reaction
 In this reaction the alpha-H is replaced by a halogen atom on
reaction of the carboxylic group with red phosphorus and Cl2 or
Br2

Br
Br2,red P Br2,red P
RCH2COOH RCHCOOH RCCOOH

Br
Br
Unlike any other halogenation, this reaction takes place in the
absence of a halogen carrier. PBr3 replaces the carboxylic OH
with a bromide,resulting in a carboxylic acid bromide. The acyl
bromide then tautomerises to form an enol which readily
reacts with Br2 to brominate a second time at the alpha
position. tautomerises
PBr3
RCH2COOH RCHCOOH RCH=CBr

Br OH

-HBr
+
RCHCOBr Br2

Br
 SN1 reaction takes place between carboxylic acid bromide and
carboxylic acid to yield alpha bromo carboxylic acid and acyl bromide
intermediate. The alpha bromoalkanoylbromide acts as a strong
electrophile due to the -I effect of the two bromide groups. While the
carbonyl oxygen of the carboxylic acid acts as a neuclophile due to its
lone pair.

R =O .. Br R
R
Br RCH2COOH
Br O-
+
= O+ Br
Br
RCHCOOH Br R
OH
+ R Br R
RCH2C=O
=O
R O =O
Br H =O+
O Br-
Hydroboration
Oxidation
What Is It?

addition of OH group in alkenes (when added to

alkynes, tautomerism occurs to make carbonyl
compounds) at less substituted carbon atom.
Alkenes are converted to Alcohols And
Alkynes are converted to
Aldehydes/ketones (an addition reaction)
Reagents are:
In Step 1--- BH3 in tetrahydrofuran (THF)
(Hydroboration)
In Step 2--- H2O2 in basic medium
(oxidation)
Mechanism
 Important points

THF/ diglyme is used as solvent so that

diborane exists as a monomer
Undergoes syn addition of OH- and H+ group
The H+ comes from BH3 and OH- comes from
H2O2 (Important when BD3 or D2O2 is used)
Anti-Markovnikoff addition occurs
Examples