Unit-II

Aromatic nucleophilic substitution Reaction and Addition to carbon-carbon multiple bonds

and carbon - oxygen double bond

Aromatic nucleophilic substitution reaction: Unimolecular, Bimolecular and Benzyne

mechanisms - Reactivity, effect of substrate, leaving group and attacking nucleophile - typical
reaction as oxygen and sulphur as nucleophile - Bucherer and Rosenmund reaction - Smiles
rearrangement.

Catalytic hydrogenation - Birch reduction - Dieckmann condensation - Mannich reaction - Wittig

reaction - Sharpless asymmetric epoxidation - addition of hydrogen halides to carbon - carbon
double bond - addition of boranes, Michael addition (1,2 and 1,4).

Addition of dialkyl groups to triple bonds. Addition of hydrides – LiAlH4 and NaBH4.

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Nucleophilic aromatic substitution

A nucleophilic aromatic substitution is a substitution reaction in organic chemistry in

which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring.
There are 6 nucleophilic substitution mechanisms encountered with aromatic systems is,

 SNAr (addition-elimination) mechanism

 Aromatic SN1 mechanism encountered with diazonium salts

 Benzyne mechanism (E1cb-AdN)

 Radical-nucleophilic aromatic substitution

Radical-nucleophilic aromatic substitution in organic chemistry is a type of substitution

reaction in which a certain substituent on an aromatic compound is replaced by a nucleophile
through an intermediary free radical species.

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  ANRORC mechanism (Addition of the Nucleophile, Ring Opening, and Ring Closure in
nucleophilic attack on ring systems)

 Vicarious nucleophilic substitution

In organic chemistry, the vicarious nucleophilic substitution is a special type of

nucleophilic aromatic substitution in which a nucleophile replaces a hydrogen atom on the
aromatic ring and not leaving groups such as halogen substituents which are ordinarily
encountered in SNAr.

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 The typical SN1 and SN2 mechanisms are not feasible in aromatic systems, because the p-
electrons in aromatic systems are in conjugation. Moreover, back side attack (as in SN2) and
inversion is prohibited by the geometry of the ring. On the other hand, SN1 type of substitution
would require formation of the phenyl cation which is less stable than a primary carbocation.

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Unimolecular

Unimolecular nucleophilic substitution reactions proceed by a two-stage mechanism in

which heterolysis precedes reaction with the nucleophile. The following equation is a typical
example:

The symbols (δ+) and delta minus (δ−) are indicating the partial positive and negative
charges. In this reaction mechanism, the bromide ion separate to give a carbonium ion. This step
is the rate-determining step. In the second step, the carbonium ion interacts with the nucleophile
to give the products. The unimolecular reaction is a first order kinetics reaction (i.e., the rate
depends only on the concentration of the substrate and not the nucleophile).

Bimolecular

In bimolecular nucleophilic substitution reactions, the substrate is attacked at a saturated

carbon atom, the starting material has a tetrahedral structure and the transition state has a trigonal
bipyramidal structure. A typical bimolecular substitution reaction is,

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 The chemical symbols represent atoms of the elements as above (with N the symbol for
any nucleophilic agent). The mechanism of this reaction is characterized by entry of the
nucleophilic reagent from one side of the substrate molecule and departure of the bromide ion
from the other side. It is bimolecular in that one molecule each of substrate and nucleophile are
involved in the transition state. This bimolecular reaction is second order kinetics (i.e., the rate
depends on the concentrations of both the substrate and the nucleophilic reagent). The transition
state is highly crowded, so that effects of steric hindrance are large.

The aryl halides are very low reactivity toward the nucleophilic reagents like OH–, OR–,
NH3 and CN– that play an important role in chemistry of the alkyl halides.

The chlorobenzene is converted into phenol by aqueous sodium hydroxide at 300oC. The
presence of a nitro group ortho or para to the chlorine greatly increases its reactivity: o- or p-

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chloronitrobenzene is converted into the nitrophenol by treatment with aqueous sodium
hydroxide at 160oC. A nitro group meta- to the chlorine, has practically no effect on reactivity.
As the number of ortho- and para-nitro groups on the ring is increased, the reactivity increases,
the phenol is obtained from 2,4-dinitrochlorobenzene by treatment with hot aqueous sodium
carbonate, and from 2,4,6-trinitrochlorobenzene by simple treatment with water.

Benzyne mechanisms

Aryl halides have no activating groups to progress the reactions with strong base to give
benzyne intermediate which undergoes reaction with nucleophile to give a mixture of
regioisomers.

The substituted halobenzenes on treatment with strong bases under harsh conditions lead
to products formed by nucleophilic aromatic substitution reaction.

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 These reactions cannot be explained by addition-elimination mechanism. After several
studies, it was proposed that these reactions involve initial elimination of HX by the strong base.
The intermediate thus formed contains a triple bond within the benzene and is called benzyne.
This is a very unstable intermediate and radical undergoes addition of nucleophile (base) in a
second step. This addition can take place at either end of the triple bond and after subsequent
protonation, lead to mixture of products are obtained.

In the addition-elimination reaction, the order of halogen reactivity is I > Br > Cl > F.
The evidence for this mechanism is, reaction of 2,6-dimethylchlorobenzene with sodium amide
in liquid ammonia. No substitution is observed in this reaction because there is no beta-hydrogen
atom in this compound.

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 Further support was obtained by trapping the benzyne intermediate in a Diels-Alder
reaction.

The reaction conditions, the use of strong bases could also act as nucleophiles and add to
benzyne forming substitution products. One can generate benzynes without the strong bases; the
non-basic nucleophile is used to generate the intermediate benzyne. Example, the thermal
decomposition of diazonium salt derived from anthranilic acid leads to the formation of benzyne,
which undergoes addition of methanol to form anisole. In this reaction amyl nitrite is used to
prepare the diazonium slat.

Typical reaction as nucleophile

Halides

The reactivity of halide increases with increase in number of electron withdrawing groups
(Scheme 1). For examples, the reactivity of chlorobenzene having nitro groups towards aqueous

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NaHCO3 follows,

However, m-nitrochlorobenzene does not undergo similar reaction:

Mechanism

Oxyanions

Aryl ethers bearing EWG in ortho and para positions proceed hydrolysis to afford
phenols.

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Sulfite Ion

Aryl sulphonic acid can be converted to phenols, by alkali fusion. In spite of the extreme
conditions, the reaction gives fairly good yields, except when the substrate contains other groups
that are attacked by the alkali. Milder conditions can be used when the substrate contains
activating groups, but the presence of deactivating groups hinders the reaction. The mechanism
is hidden but the benzyne intermediate has been ruled out by the finding that the cine
substitution does not occur. For example, sodium p-toluenesulfonate with fused sodium
hydroxide gives p- cresol at 250-300oC.

Nitrogen Anions

Nitrite ion could be displaced if other nitro groups are present to activate the aromatic
nucleus.

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Substitution via Benzynes

Halobenzenes (except fluorobenzene) directly react with strong base such as sodamide to
give benzyne that can be reacted with any nucleophile present the reaction medium. For example,
the addition of malonic ester to liquid ammonia having amide ion afford the corresponding
enolate that reacts with benzyne as it is produced.

Furthermore, ortho substituted benzenes can generated two stable molecules by

elimination afford benzynes on thermolysis.

If the nucleophile is not present in the reaction medium, benzyne dimerizes to give
biphenylene.

Bucherer reaction

Bucherer reaction is the reversible conversion of a naphthol to a naphthylamine in the

presence of ammonia and sodium bisulfate.

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 C10H7-2-OH + NH3 ⇌ C10H7-2-NH2 + H2O

The reaction is used to convert 1,7-dihydroxynaphthalene into 7-amino-1-naphthol and 1-

aminonaphthalene-4-sulfonic acid into 1-hydroxynaphthalene-4-sulfonic acid. It is also useful for
transamination reactions of 2-aminonaphthalenes.

Mechanism

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 In the first step, a proton adds to a carbon atom with high electron density therefore by
preference to C2 or C4 of naphthol. This leads to resonance stabilized adducts 1a-1e. De-
aromatization of the first ring of the naphthalene system occurs. In the next step a bisulfite anion
adds to C3 through 1e. This results in the formation of 3a which tautomerizes to the more stable
3b to the sulfonic acid of tetralone. A nucleophilic addition follows of the amine with formation
of 4a and its tautomer 4b loses water to form the resonance stabilized cation 5a. This compound
is deprotonated to the imine 5b or the enamine 5c but equilibrium exists between both species.
The enamine eliminates sodium bisulfite with formation of naphthylamine 6.

It is important that this is a reversible reaction. The reaction is summarized as follows,

Rosenmund reduction

The Rosenmund reduction is a hydrogenation process in which an acyl chloride is

selectively reduced to an aldehyde.

The hydrogenolysis is catalysed by palladium on barium sulfate, which is sometimes

called the Rosenmund catalyst.

Mechanism

Initially, hydrogen gas is passed through acid chloride in the presence of Pd/BaSO4. So
that, aldehyde and the hydrochloric acid is formed. The formed aldehyde reacts again with
Pd/BaSO4 to form alcohol and it further generates alkanes.

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Smiles rearrangement

The Smiles rearrangement is a type of intramolecular nucleophilic aromatic substitution.

where X in the arene compound can be a sulfone, a sulfide, a ether or any substituent
capable of removing from the arene carrying a negative charge. The terminal functional group Y
is able to act as a strong nucleophile for instance an alcohol, amine or thiol.

In the other nucleophilic aromatic substitutions, the arene requires activation by an

electron-withdrawing group preferably in the aromatic ortho position.

In the modified Truce-Smiles rearrangement, the incoming nucleophile is sufficiently

strong so the arene does not require the additional activation, when the organolithium is a
nucleophile. This reaction is exemplified by the conversion of an aryl sulfone into a sulfinic acid
by action of n-butyllithium,

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Catalytic Hydrogenation

Hydrogenation meaning, to treat with hydrogen is a chemical reaction between molecular

hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as
nickel, palladium or platinum. So if hydrogenation means, adding hydrogen to a double or triple
bond, catalytic hydrogenation means using a catalyst to add hydrogen.

Hydrocarbons are one of the most common examples of organic compounds. They are
mainly composed of carbon and hydrogen atoms. There are mainly two types of hydrocarbons;
aliphatic and aromatic hydrocarbons. Aliphatic hydrocarbons are open chain compounds means
they have straight carbon parent chain with single, double or triple covalent bonds.

Aromatic compounds are cyclic unsaturated compound which are stabilized with
delocalization of pi-electrons. Therefore they show unique chemical and physical properties
which are not resemble with other unsaturated aliphatic hydrocarbons like alkenes or alkynes.
The extra stability of aromatic compounds is due to resonance energy.

The presence of multiple bonds (double or triple covalent bonds) makes the molecule
unsaturated and more reactive compare to saturated hydrocarbons; alkanes. These unsaturated
hydrocarbons readily give addition reactions and tend to convert into saturated hydrocarbons.
Some common examples of addition reactions of unsaturated hydrocarbons are hydrogenation,
ozonolysis, halogenation, hydration etc. All these addition reactions involve the cleavage of pi-

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bond of double or triple covalent bond and form saturated stable products. For example,
hydrohalogenation involves the addition of H−X over double or triple covalent bond and form
alkyl halide.

Catalytic Hydrogenation of Alkenes

The hydrogenation of alkene in the presence of metal catalyst is called as catalytic

hydrogenation. For example, reaction of ethene with hydrogen gas in the presence of finely
divided nickel catalyst at a 150∘C temperature forms ethane.

CH2=CH2 + H2 + Catalyst → CH3−CH3

The reaction of alkene with hydrogen is an electrophilic addition reaction, which occurs
at the metal surface. Different metal catalyst like Pt, Pd, Ni or Rh can be used for this
hydrogenation reaction. The reaction involves cleavage of C-C pi bond and H-H sigma bond. At
the same time two C-H sigma bonds are formed during reaction. The reaction follows the
mechanism of heterogenous catalysis.

In the step-1, hydrogen atoms and alkenes absorb on the metal surface. On metal surface
only, hydrogen atom is transferred to alkene and form alkane with the formation of two new C-H
sigma bonds.

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Catalytic Hydrogenation of Alkynes

Alkenes, alkynes also have multiple covalent bonds. They have triple covalent bond
between carbon atoms. We know that a triple covalent bond is formed by one sigma and two pi-
bonds therefore alkynes are more unsaturated compare to alkenes. Like alkenes, complete
hydrogenation of alkynes also forms alkanes. Metal catalyst can be used for catalytic
hydrogenation of alkyens. This is also an electrophilic addition reaction.

Lindlar's catalyst (Pd / CaCO3 / quinoline) reduces alkynes to cis-alkenes whereas Na in

NH3 preferentially gives trans-alkene. Metal catalyst usually shows complete hydrogenation and
forms alkanes as final product.

Catalytic Hydrogenation of Esters

Esters are organic compounds with general formula RCOOR. It contains one >C=O
(carbonyl group) and one –OR (alkoxide group) close to each other.

Compare to other carbonyl compounds, esters show more resistance towards reduction.
The catalytic reduction of esters results the formation of alcohols. Metal catalyst like copper
chromite can be used for this reduction process,

RCOOR′ + 2H2 → RCH2OH + R′OH

Bouveault-Blanc reduction is more common for hydrogenation of esters which is a

reduction process in the presence of sodium and ethanol,

Homogeneous Catalytic Hydrogenation

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 On the basis of phase of catalyst, they can be classified as homogenous and
heterogeneous catalysis. In homogenous catalysis, the phase of catalyst and reactants are same
whereas in case of heterogeneous catalysis, reactants and catalyst are in different phase.
Homogenous catalytic hydrogenation is usually carried out in the presence of some
organometallic catalyst such a Wilkinson’s catalyst.

Catalytic Hydrogenation of Alkenes Stereochemistry

The catalytic hydrogenation of alkenes results the formation of alkanes with formation of
two new C−H sigma bonds and cleavage of one pi bond between two carbon atoms. For example
the hydrogenation of 1,2-dimethylcyclohexene in the presence of metal catalyst forms 1,2-
dimethylcyclohexane with syn addition of hydrogen atoms. No anti-addition takes place in this
case. It is an example of heterogeneous catalysis.

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Birch reduction

Birch reduction is an organic reaction which is converts aromatic compounds into a 1,4-
cyclohexadienes in liquid ammonia with sodium, lithium or potassium and an alcohol, such as
ethanol and tert-butanol.

Mechanism

The Birch reduction invokes protonation of a radical anion that was meta- to the ring
methoxy and alkyl groups. Birch's original mechanism was based on the radical anion's electron
density, resulting from the addition of an electron to an electron donor (such as methoxy or
methyl).

Dieckmann condensation

The Dieckmann condensation is the intramolecular chemical reaction of diesters with

base to give β-keto esters.

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Mechanism

Deprotonation of an ester at the α-position generates an enolate ion which then undergoes
a 5-exo-trig nucleophilic attack to give a cyclic enol. Protonation with an acid, re-forms the β-
keto ester.

Due to the steric stability of five- and six-membered rings structures are formed. 1,6
diesters will form five-membered cyclic β-keto esters, while 1,7 diesters will form six-membered
β-keto esters.

Mannich reaction

Mannich reaction is consists of an amino alkylation of an acidic proton placed next to a

carbonyl functional group by formaldehyde and a primary or secondary amine or ammonia. The
final product is a β-amino-carbonyl compound also known as a Mannich base.

The Mannich reaction is an example of nucleophilic addition of an amine to a carbonyl

group followed by dehydration to the Schiff base. In the Mannich reaction, primary or secondary
amines or ammonia are employed for the activation of formaldehyde.

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Mechanism

The mechanism starts with the formation of an iminium ion from the amine and the
formaldehyde.

The compound with the carbonyl functional group (in this case a ketone) can tautomerize
to the enol form, after which it can attack the iminium ion.

Wittig reaction

The Wittig reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone

with a triphenyl phosphonium ylide (often called a Wittig reagent) to give an alkene and
triphenylphosphine oxide.

Mechanism

The steric bulk of the ylide 1 influences the stereochemical outcome of nucleophilic
addition to give the betaine 3. Note that for betaine 3 both R1 and R2 as well as PPh3+ and O− are
positioned anti to one another. Carbon-carbon bond rotation gives the betaine 4, which then

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forms the oxaphosphetane 5. Elimination gives the desired Z-alkene 7 and triphenylphosphine
oxide 6.

With simple Wittig reagents, the first step occurs easily with both aldehydes and ketones,
and the decomposition of the betaine (to form 5) is the rate-determining step. However, with
stabilized ylides the first step is the slowest step, so the overall rate of alkene formation
decreases and a bigger proportion of the alkene product is the E-isomer.

Sharpless asymmetric epoxidation

Sharpless epoxidation is an enantioselective chemical reaction to prepare 2,3-

epoxyalcohols from primary and secondary allylic alcohols.

Catalyst structure

The structure of the catalyst is uncertain. Regardless, all studies have concluded that the
catalyst is a dimer of [Ti(tartrate)(OR)2].

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 The Sharpless epoxidation can also give kinetic resolution of a racemic mixture of
secondary 2,3-epoxyalcohols.

Synthetic utility

Sharpless epoxidation is possible with a large range of primary and secondary olefinic
alcohols.

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 The synthetic utility of Sharpless Epoxidation, the Sharpless group created synthetic
intermediates of various natural products: methymycin, erythromycin, leukotriene C-1, and (+)-
disparlure.

Epoxidation of allylic alcohols

Allylic alcohols give facial selectivity when using m-CPBA as an oxidant. This
selectivity was reversed when the allylic alcohol was acetylated.

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Addition of hydrogen halides to carbon - carbon double bond

Due to the nature of the π bond, π bonds can act like a nucleophile and undergo addition
of electrophiles. The π electrons have a high electron density in the π electron cloud which can
be easily polarized and can act like a nucleophile.

In a reaction with a polar molecule such as hydrogen chloride (HCl), for example, the π
bond of an alkene reacts as a nucleophile. Thus, the partially positively charged hydrogen atom
of HCl acts as an electrophile protonating the double bond of the alkene. Hydrogen halides
provide both an electrophile (proton) and a nucleophile (halide). By adding a proton of a strong
acid to a double bond a carbocation ion is formed.

The carbocation ion is formed by protonation of an alkene by HCl, is subsequently

attacked by the chloride anion resulting in a mono-halogenated alkane. The reaction type is A +
B → C, an addition reaction. Since the first step in this addition reaction is the interaction of a
double bond with an electrophile, the reaction, therefore, is called an electrophilic addition. The
rate-determining step is formation of the carbocation.

Addition to symmetrical alkenes

All alkenes undergo addition reactions with the hydrogen halides. A hydrogen atom joins
to one of the carbon atoms originally in the double bond, and a halogen atom to the other. For
example, ethane reacts with hydrogen chloride to get chloroethane.

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With but-2-ene you get 2-chlorobutane

Addition to unsymmetrical alkenes

If HCl adds to an unsymmetrical alkene like propene, there are two possible ways it could
add and only one as major product.

Electrophilic addition reactions involving hydrogen bromide

Alkenes react with hydrogen bromide in the cold. The double bond breaks and a
hydrogen atom end up attached to one of the carbons and a bromine atom to the other. In the case
of ethene, bromoethane is formed.

CH2=CH2 + HBr → CH3CH2Br

With cyclohexene you get bromocyclohexane

Mechanism

The reactions are examples of electrophilic addition. With ethene and HBr,

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and with cyclohexene,

Electrophilic addition reactions involving the other hydrogen halides

Hydrogen chloride and the other hydrogen halides add on in exactly the same way. For
example, hydrogen chloride adds to ethene to make chloroethane,

CH2=CH2 + HCl → CH3CH2Cl

The only difference is in how fast the reactions happen with the different hydrogen
halides. The rate of reaction increases as you go from HF to HCl to HBr to HI.

HF > HCl > HBr > HI

Mechanism

The reactions are still examples of electrophilic addition. With ethene and HCl, for
example,

All the other mechanisms for symmetrical alkenes and the hydrogen halides would be
done in the same way.

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Addition of an H-B bond to C-C double bonds (Hydroboration of Alkenes)

Hydroboration-oxidation transforms alkenes into alcohols. It performs the net addition of

water across an alkene.

Mechanism

The reaction begins with the syn addition of B and H across the double bond, with the
boron adding to the less substituted carbon (Step 1, arrows A and B). In the second step,
hydrogen peroxide and a base such as NaOH are added. The NaOH deprotonate the hydrogen
peroxide (Step 2, arrows C and D), which makes the conjugate base of hydrogen peroxide (a
better nucleophile than H2O2 itself).

The resulting NaOOH then attacks the boron (Step 3, arrow E).

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 This sets up the key migration step, where the carbon-boron bond migrates to the oxygen
bound to boron, breaking the weak oxygen-oxygen bond (Step 4, arrows F and G). The OH
expelled then comes back to form a bond on the boron (Step 5, arrows H and I) resulting in the
deprotonated alcohol (alkoxide). The alkoxide is then protonated by water or some other
comparably acidic species (Step 6, arrows J and K).

Michael addition

Enolates of carbonyl compounds will add to an α,β-unsaturated carbonyl compounds to

give 1,5-dicarbonyl compounds. This is called the Michael reaction.

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Mechanism

Removal of a proton from the ketone with strong base (Step 1, arrows A and B) results in
an enolate, which then performs a 1,4-addition on the α,β-unsaturated carbonyl compound (Step
2, arrows C and D), which is then protonated (Step 3, arrows E and F).

Basic reaction of 1,2 addition

Here the nucleophile adds to the carbon which is in the one position. The hydrogen adds
to the oxygen which is in the two positions.

Basic reaction of 1,4 addition

Nucleophiles which add 1,4 to α, β unsaturated carbonyls

Water

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Alcohols

Thiols

1o Amines

2o Amines

HBr

Cyanides

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Nucleophiles which add 1,2 to α, β unsaturated carbonyls

Metal Hydrides

Grignard Reagents

Organolithium Reagents

Addition of hydrides

The most common sources of the hydride Nucleophile are lithium aluminum hydride
(LiAlH4) and sodium borohydride (NaBH4). The hydride anion is not present during this
reaction; rather, these reagents serve as a source of hydride due to the presence of a polar metal-
hydrogen bond. Because aluminum is less electronegative than boron, the Al-H bond in LiAlH4
is more polar, thereby, making LiAlH4 a stronger reducing agent.

Addition of a hydride anion (H:-) to an aldehyde or ketone gives an alkoxide anion, which
on protonation yields the corresponding alcohol. Aldehydes produce 1º alcohols and ketones
produce 2º alcohols.

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 In the sodium borohydride reduction, the methanol solvent completes this hydrolysis
automatically. In the lithium aluminum hydride reduction, water is usually added in a second
step. The lithium, sodium, boron and aluminum end up as soluble inorganic salts at the end of
either reaction. LiAlH4 and NaBH4 are both capable of reducing aldehydes and ketones to the
corresponding alcohol.

Mechanism

This mechanism is for a LiAlH4 reduction. The mechanism for a NaBH4 reduction is the
same except methanol is the proton source used in the second step.

1. Nucleopilic attack by the hydride anion

2. The alkoxide is protonated

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