Aliphatic N Aromatic Sub

Dr.
Muhammed Basheer Ummathur 2021
Unit 1: Aliphatic and Aromatic Substitutions

Syllabus (9 hrs):
Nucleophilic Aliphatic Substitution: Mechanism and Stereochemistry of SN2 and SN1 reactions. Ion-pair mechanism.
The effect of substrate structure, reaction medium, nature of leaving group and nucleophile on S N2 and SN1 reactions.
SNi and neighboring group mechanism. SET mechanism. Allylic and benzylic substitutions. Ambident nucleophiles
and substrates regioselectivity.
Electrophilic Aliphatic Substitution: Mechanism and stereochemistry of SE1, SE2 (front), SE2 (back) and SEi reactions.
The effect of substrate structure, leaving group and reaction medium on SE1 and SE2 reactions.
Electrophilic Aromatic Substitution: Arenium ion mechanism, substituent effect on reactivity in mono and
disubstituted benzene rings, ortho/para ratio, Ipso substitution. Relationship between reactivity and selectivity.
Nucleophilic Aromatic substitution: Addition‐ elimination (SNAr) mechanism, elimination-addition (benzyne)
mechanism, cine substitution, SN1 and SRN1 mechanism. The effect of substrate structure, nucleophile and leaving
group on aromatic nucleophilic substitution.
Substitution reactions are the reactions in which an atom, group or ion is replaced by
another atom, group or ion. They include nucleophilic substitution reactions, electrophilic
substitution reactions and free radical substitution reactions.
Nucleophilic Aliphatic Substitution

Alkyl halides undergo nucleophilic
substitution reactions due to the polarity of C-X
bond. Nucleophiles always attack at the electron
deficient α-carbon.
By the SN reaction of alkyl halides a large number of organic compounds can be synthesized.
Sl. No. Reagent Nucleophile Product Homologous Series
-
1 KOH, AgOH OH ROH Alcohol
2 KI I- RI Alkyl iodide
-
3 KCN C≡N RCN Nitrile (cyanide)
4 AgCN Ag-C≡N RNC Isocyanide (carbylamine)
5 KNO2 O=N-O- RONO Alkyl nitrite
6 AgNO2 Ag-O-N=O RNO2 Nitroalkane
-
7 NaSH SH RSH Thioalcohol (Thiol, Mercaptan)
8 NaOR R-O- ROR Ether (Williamson’s synthesis)
9 NaSR, Na2S R-S- RSR Thioether (dialkyl sulphide)
10 RCOOAg R-COO- RCOOR Ester
11 LiAlH4 H- RH Hydrocarbon
12 RC≡CNa RC≡C- RC≡CR Higher alkyne
13 NH3 NH3 RNH2 1o Amine
14 RNH2 RNH- R2NH 2o Amine
15 R2NH R2N- R3N 3o Amine
16 R-M+ R- RR Alkane
1 KAHM Unity Women’s College, Manjeri

Dr. Muhammed Basheer Ummathur 2021
Cyanide and nitrite ions possess two donor atoms and are called ambident nucleophiles.
KCN is ionic and provides cyanide ions. Although both carbon and nitrogen atoms are in a
position to donate electron pairs, the attack takes place mainly through carbon atom since C—C
bond is more stable than C—N bond (C-C bond energy is comparatively high). However, AgCN
is mainly covalent in nature and nitrogen is free to donate electron pair forming isocyanide as the
main product.
KNO2 is ionic and provides nitrite ions. Although
both oxygen and nitrogen atoms are in a position to donate
electron pairs, the attack takes place mainly through oxygen
because it carries a negative charge.
AgNO2 is mainly covalent in nature and nitrogen is donate electron pair preferentially
(since nitrogen is less electronegative tan oxygen) forming nitroalkane as the main product.
The SN reactions take place generally by two mechanisms; SN1 and SN2.
SN2 (Substitution, Nucleophilic, Bimolecular)
CH3-Cl + OH- -----> CH3-OH + Cl-
Rate = K[substrate][nucleophile]; Order = 2
When the rate of SN reaction depends both on the concentration of the substrate and the
nucleophile the reaction will be second order and is called SN2.
Mechanism:
In SN2 reaction the nucleophile always attacks from the backside because the front side attack
is prevented by the negative charge of the leaving of group. The energy released during the
formation of C-O bond is used for breaking C-X bond. The reaction takes place in a single step
without the formation of an intermediate and proceeds through a transition state. In the transition
state, the C-O bond is partially formed the C-X bond is partially broken. Carbon and three
hydrogen atoms are lying in the same plane while –OH group and -Cl atom are lying in a plane
perpendicular to it with a trigonal bipyramidal geometry. The transition state is highly unstable
because the valency of carbon is apparently 5 and negative charge is spread all over.. So, it is
transformed into the product in a fast step.
Characteristics:
(1) Kinetics: SN2 reaction follow 2nd order kinetics.

(2) Effect of the substrate: Rate of SN2 reaction decrease in the order CH3>10>20>30 because the
transition state becomes more and more sterically hindered.
The rate of the reaction depends not only on the number of alkyl groups attached to the α-
carbon, but also on their size. Eg: Ethyl bromide is more reactive than propyl bromide because
bulkier propyl group provides more steric hindrance to back-side attack. Also, although neopentyl
bromide is a primary alkyl halide, it undergoes SN2 reactions very slowly because its single alkyl
group is unusually bulky.
(3) Effect of the nucleophile: The rate of SN2 reaction increases with increase in concentration
and nucleophilicity of the nucleophile because the rate-determining step involves the nucleophile.
(a) Negatively charged nucleophiles are
stronger than their neutral counter parts.
(b) Molecules/ions with attacking atoms of approximately the same size (same period) have
nuclophilicity α basicity.
Acidity: NH3 < H2O < HF Basicity: NH2 - > OH- > F- Nucleophilicity: NH2- > OH- > F-
(c) Molecules/ions with attacking atoms of different size the nucleophilicity depends on the
polarizability of the atom. Because the electrons are farther away in the larger atom, they are not
held as tightly and can move more freely toward a positive charge.
In gas phase nuclophilicity α basicity. If the reaction is carried out in a protic solvent
(solvent molecules have hydrogen bonded to oxygen or to nitrogen) the relationship between
basicity and nucleophilicity becomes inverted. The largest atom is the best nucleophile even
though it is the weakest base. Therefore, iodide ion is the best nucleophile of the halide ions in a
protic solvent (For explanation, refer effect of the solvent).
(d) A bulky nucleophile cannot approach the back side of a carbon easily due to steric hindrance.
Thus, the bulky tert-butoxide ion is a poorer nucleophile than ethoxide ion even though tert-
butoxide ion is a stronger base.
(4) Effect of the leaving group: Weakly basic and highly polarisable groups increase the rate of
SN2 because they are powerful leaving groups.
Acidity: HF < HCl < HBr < HI; Basicity: F- > Cl- > Br- > I- Leaving tendency: F- < Cl- < Br -< I-

Therefore, alkyl iodides are the most reactive of the alkyl halides, and alkyl fluorides are
the least reactive. In fact, the fluoride ion is such a strong base that alkyl fluorides essentially do
not undergo SN2 reactions.
(5) Effect of the solvent: In protic solvents, the smaller nucleophiles are more solvated than
larger nucleophiles (solvation energy α charge/size). The solvent molecules arrange themselves so
that their partially positively charged hydrogens point toward the nucleophile (ion–dipole
interaction). Because the solvent shields the nucleophile, at least one of the ion–dipole
interactions must be broken before the nucleophile can participate in an S N2 reaction.
Weak bases interact weakly with protic
solvents, whereas strong bases interact more strongly
because they are better at sharing their electrons.
Hence it is easier to break the ion–dipole interactions
between an iodide ion (a weak base) and the solvent
than between a fluoride ion (a stronger base) and the
solvent. As a result, iodide ion is a better nucleophile
than fluoride ion in a protic solvent.
Due to the absence of ion–dipole interactions, fluoride ion is a better nucleophile in a non-
polar solvent than in a polar solvent. Ionic compounds are insoluble in most non-polar solvents,
but soluble in aprotic polar solvents like DMF or DMSO. The molecules of an aprotic polar
solvent have a partial negative charge on their surface that can solvate cations, but the partial
positive charge is on the inside of the molecule, which makes it less accessible. The relatively
“naked” anion can be a powerful nucleophile in an aprotic polar solvent. Fluoride ion, therefore,
is a better nucleophile in DMSO than it is in water.
Increasing the polarity of a solvent will have a strong stabilizing effect on the negatively
charged nucleophile. The transition state also has a negative charge, but the charge is dispersed
over two atoms. Consequently, the interactions between the solvent and the transition state are not
as strong as the interactions between the solvent and the fully charged nucleophile. Therefore, a
polar solvent stabilizes the nucleophile more than it stabilizes the transition state, so increasing the
polarity of the solvent will decrease the rate of S N2 reaction.
If the nucleophile is neutral, the charge on the transition state will be larger than the charge
on the neutral reactants. So increasing the polarity of the solvent will increase the rate of the S N2
reaction.

A negatively charged nucleophile generally will not dissolve in a non-polar solvent. So an

aprotic polar solvent is used. As aprotic polar solvents are not hydrogen bond donors, they are less
effective than polar protic solvents in solvating negative charges. Thus, the rate of S N2 reaction
involving a negatively charged nucleophile will be greater in an aprotic polar solvent than in a
protic polar solvent. Consequently, an aprotic polar solvent is the solvent of choice for S N2
reaction in which the nucleophile is negatively charged, whereas a protic polar solvent is used if
the nucleophile is a neutral molecule.
(6) Effect of configuration: If SN2 reaction is performed on a chiral substrate, the product will
have a configuration that is inverted relative to that of the reactant (just as an umbrella has a
tendency to invert in a windstorm). This is called Walden inversion.
(7) Rearrangement: SN2 reaction not accompanied by rearrangement because the attack of
nucleophile and removal of leaving group takes place simultaneously.
(8) Energy Profile Diagram: The reaction coordinate diagrams for the reactions of unhindered
methyl bromide and a sterically hindered alkyl bromide show that steric hindrance raises the
energy of the transition state, slowing the reaction.
SN1 (Substitution, Nucleophilic, Unimolecular)

(CH3)3C-Br + OH- -----> (CH3)3C-OH + Cl- Rate = K[substrate] Order = 1
When rate of nucleophilic substitution reaction depends only on the concentration of the
substrate and is independent of the concentration of the nucleophile, the reaction will be first
order and is called SN1.
Mechanism: SN1 reaction takes place in 2 steps.

Step 1: Slow heterolysis of the substrate to form the carbocation.
(CH3)3C-Br -----> (CH3)3C+ + Cl-
Step 2: Fast attack of the nucleophile to form the product.
(CH3)3C+ + OH------> (CH3)3C-OH
Characteristics:
(1) Kinetics: SN1 reaction follows first order kinetics.
(2) Effect of the substrate: Rate of SN1 reaction increase in the order CH3-<10<20<30 due to
increase in the stability of the carbocations ions in the same order.
Primary carbocations and methyl cations are so unstable that primary alkyl halides and
methyl halides do not undergo SN1 reactions.
(3) Effect of the nucleophile: The rate of SN1 reaction is independent of the concentration and
nucleophilicity of the nucleophile because the rate-determining step does not involve the
nucleophile.
(4) Effect of the leaving group: Weakly basic and highly polarisable groups increase the rate of
SN1 because they are powerful leaving groups. F- < Cl- < Br -< I- (Refer SN2).
(5) Effect of the solvent: Polar solvents favour SN1 because they give sufficient solvation energy
for initial heterolysis.
The alkyl halide is the only reactant in the rate-determining step of an SN1 reaction. It is a
neutral molecule with a small dipole moment. The rate determining transition state has a greater
charge because as the carbon–halogen bond breaks, the carbon becomes more positive and the
halogen becomes more negative. Since the charge on the transition state is greater than the charge
on the reactant increasing the polarity of the solvent will increase the rate of the reaction.
If the compound undergoing an SN1 reaction is charged, increasing the polarity of the
solvent will decrease the rate of the reaction because the more polar solvent will stabilize the full
charge on the reactant to a greater extent than it will stabilize the dispersed charge on the
transition state.
(6) Effect of configuration: If SN1 reaction is performed on an optically active substrate, partial
recemisation takes place and the inverted product predominates. This is because the attack of the
nucleophile takes place before the leaving group has left completely from the vicinity of the
carbocation. So the negative charge of the leaving group will prevent the front side attack for a

while. During this time backside attack takes place (inversion). After the leaving group has left
completely from the vicinity, there is equal probability for both front (retention) and back
(inversion) side attacks. During this time racemisation takes place.
The reaction of (S)-2-bromobutane forms two substitution products—one with the same
relative configuration as the reactant and the other with the inverted configuration. If the
nucleophile attacks the carbocation from a side the bromide ion left, the product will have the
same relative configuration as the reactant. If it attacks the opposite side, the product will have the
inverted configuration.
When cis-1-bromo-4-methylcyclohexane undergoes an SN2 reaction, only the trans

product is obtained because the carbon bonded to the leaving group is attacked by the nucleophile
only on its back side.
However, when cis-1-bromo-4-methylcyclohexane undergoes an SN1 reaction, both the cis

and the trans products are formed because the nucleophile can approach the carbocation
intermediate from either side.
(7) Rearrangement: SN1 reaction may be accompanied by rearrangement because of the formation
of the intermediate carbonium ion.

(8) Energy Profile Diagram: Because the rate of an SN1 reaction depends only on the
concentration of the alkyl halide, the first step must be the slow and rate-determining step.
SN Reactions in Benzylic and Allylic Halides

Benzylic and allylic halides readily undergo SN2 reactions unless they are tertiary. Tertiary
benzylic and tertiary allylic halides, like other tertiary halides, are unreactive in S N2 reactions
because of steric hindrance.
Benzylic and allylic halides (primary also) readily undergo SN1 reactions because they
form relatively stable carbocations.

If the resonance contributors of the allylic carbocation intermediate have different groups
bonded to their sp2 carbons, two substitution products will be obtained.
SN Reactions in Vinylic and Aryl Halides

Vinylic and aryl halides do not undergo
SN1 or SN2 reactions. They do not undergo SN2
reactions because, as the nucleophile approaches
the back side of the sp2 carbon, it is repelled by
the π electron cloud of the double bond or the
aromatic ring.
There are two reasons that vinylic halides and aryl halides do not undergo SN1 reactions.
1. Vinylic and aryl cations are unstable than primary carbocations because the positive
charge is on an sp carbon. Since sp carbons are more electronegative they are more
resistant to becoming positively charged.
2. Since sp2 carbons form stronger bonds than sp3 carbons it is harder to break the carbon–
halogen bond when the halogen is bonded to an sp2 carbon.
3. The C-X bond in both vinyl and aryl halides have a partial double bond character due to
resonance.
The SNi (Substitution, Nucleophilic, Internal) Mechanism

In the SNi mechanism, part of the leaving group attack the substrate, detaching itself from
the rest of the leaving group in the process.
The first step is same as SN1 mechanism, dissociation into an intimate ion pair. But in the
second step part of the leaving group attacks, from the front since it is unable to get to the rear,
which results in retention of configuration.

Alcohols which possess an aromatic substituent react with thionyl chloride to give the
corresponding chlorides with retention of the configuration of the hydroxyl-bearing carbon atom.
Reaction occurs through the chlorosulfite which collapses, with the elimination of sulfur
dioxide, to give an ion-pair and thence the chloride.
The role of the aromatic substituent is probably to stabilize the cationic part of the ion-pair
by delocalizing the positive charge.
The reaction is second order, but the decomposition by simple heating of ROSOCl is first
order.
In the presence of pyridine inversion of configuration occurs because the pyridine removes
a proton from the hydrogen chloride generated in the first step and the resulting chloride then
reacts with the chlorosulfite in the SN2 manner.
The Neighboring-Group Mechanism

Neighboring-group mechanism consists of two SN2 substitutions, each causing an
inversion so the net result is retention of configuration.
In the first step, the neighboring group acts as a nucleophile, pushing out the leaving
group but still retaining attachment to the molecule. In the second step, the external nucleophile
displaces the neighboring group by a backside attack.
The neighboring group Z is said to be lending anchimeric assistance. The reaction follow first
order kinetics, Y does not take part in the rate-determining step because attack by Z is faster than
that by Y, since Z is more available.

In some cases, substitution and rearrangement products are often produced together.
Another possibility is that the intermediate may be stable or may find some other way to
stabilize itself. In such cases, Y never attacks at all and the product is cyclic. These are simple
internal SN2 reactions. Two examples are formation of epoxides and lactones.
Acetolysis of both 4-methoxy-1-pentyl brosylate (24) and 5-methoxy-2-pentyl brosylate

(25) gave the same mixture of products is further evidence for participation by a neighboring
group. In this case, the intermediate 26 is common to both substrates.
Important neighboring groups include COO-, COOR, COAr, OCOR, OR, OH, O, NH2,
NHR, NR2, NHCOR, SH, SR, S, SO2Ph, I, Br, and Cl. The effectiveness of halogens as
neighboring groups decreases in the order I > Br > Cl. The Cl is a very weak neighboring group
and can be shown to act in this way only when the solvent does not interfere. For example, when
5-chloro-2-hexyl tosylate is solvolyzed in acetic acid, there is little participation by the Cl, but
when the solvent is changed to trifluoroacetic acid, which is much less nucleophilic, neighboring-
group participation by the Cl becomes the major reaction pathway. Thus, Cl acts as a neighboring
group only when there is need for it.
SET (Single Electron Transfer) Mechanism
In certain nucleophilic substitutions there is evidence that radicals and/or radical ions are
involved.

The first step in such a process is transfer of an electron from the nucleophile to the
substrate to form a radical anion.
Once formed, the radical ion cleaves.
The radicals formed in this way can go on to product by reacting with the Y . produced in
Step 1 or with the original nucleophilic ion Y -, in which case an additional step is necessary.
or
One type of evidence for an SET mechanism is the finding of some racemization. A totally
free radical would result in a completely racemized product RY, but it has been suggested that
inversion can also take place in some SET processes. The suggestion is that in Step 1 the Y- still
approaches from the back side, even although an ordinary SN2 mechanism will not follow, and
that the radical R., once formed, remains in a solvent cage with Y. still opposite X, so that steps 1,
2, and 3 can lead to inversion.
Reactions with SET mechanisms typically show predominant, although not 100%, inversion.
Other evidence cited for SET mechanisms is the detection of radical or radical ion
intermediates by esr. Reactions can take place at 1-norbornyl bridgeheads; and the formation of
cyclic side products when the substrate has a double bond in the 5,6 position (such substrates are
called radical probes). Free radicals with double bonds in this position are known to cyclize
readily. The SET mechanism is chiefly found, where X = I or NO2.
Ambident (Bidentant) Nucleophiles: Regioselectivity

Ambident nucleophiles contain lone pair of electrons on more than one atom and hence
can attack at the substrates in different manner giving rise to different products. Mixtures are
often obtained, although this is not always the case. When a reaction can potentially give rise to
two or more structural isomers (e.g., RCN or RNC), but actually produces only one, the reaction
is said to be regioselective.
1. Ions derived by the removal of a proton from malonic esters, β-keto esters, β-diketones, and so
on, are resonance hybrids.

They can thus attack a saturated carbon with their carbon atoms (C-alkylation) or with
their oxygen atoms (O-alkylation).
With unsymmetrical ions, three products are possible, since either oxygen can attack.
2. Compounds of the Type CH3COCH2CO can give up two protons, if treated with 2 equivalents
of a strong enough base, to give dicarbanions:
They have two possible attacking carbon atoms, aside from the oxygens. In such cases, the
attack is always by the more basic carbon. Since the hydrogen of a carbon bonded to two carbonyl
groups is more acidic than that of a carbon bonded to just one, the CH group is less basic than the
CH2 group, so the latter attacks the substrate. For example, ethyl acetoacetate can be alkylated at
either the methyl or the methylene group.
3. The CN- ion: This nucleophile can give nitriles RCN or isocyanides RNC.
4. The Nitrite ion: This ion can give nitrite esters RON=O or nitro compounds RNO2.
5. Phenoxide ions (which are analogous to enolate anions) can undergo C-alkylation or O-
alkylation:
6. Removal of a proton from an aliphatic nitro compound gives a carbanion that can be alkylated
at oxygen or carbon. O-Alkylation gives nitronic esters, which are generally unstable to heat but
break down to give an oxime and an aldehyde or ketone.
Nucleophilicity in general depends on the polarizability (hard–soft character) of the

nucleophile and solvation effects.

1. In an SN1 mechanism, the nucleophile attacks a carbocation, which is a hard acid. In an S N2

mechanism, the nucleophile attacks the carbon atom of a molecule, which is a softer acid. The
more electronegative atom of an ambident nucleophile is a harder base than the less
electronegative atom.
As the character of a given reaction changes from S N1 to SN2 an ambident nucleophile
becomes more likely to attack with its less electronegative atom. Therefore, changing from SN1
to SN2 conditions should favor C attack by CN, N attack by NO2, C attack by enolate or
phenoxide ions, etc.
Primary alkyl halides are attacked (in protic solvents) by the carbon atom of the anion of
CH3COCH2COOEt, while α-chloro ethers, which react by the SN1 mechanism, are attacked by
the oxygen atom. However, this does not mean that attack is by the less electronegative atom in
all SN2 reactions and by the more electronegative atom in all S N1 reactions. The position of
attack also depends on the nature of the nucleophile, the solvent, the leaving group, and other
conditions.
2. All negatively charged nucleophiles have a positive counter ion. If this ion is Ag+ (or some
other ion that specifically helps in removing the leaving group), rather than the more usual Na+
or K+, then the transition state is more SN1-like. Therefore the use of Ag+ promotes attack at the
more electronegative atom. For example, alkyl halides treated with NaCN generally give
mostly RCN, but the use of AgCN increases the yield of isocyanides RNC.
3. In many cases, the solvent influences the position of attack. The freer the nucleophile it attack
with its more electronegative atom, but the more this atom is encumbered by either solvent
molecules or positive counterions, it attack by the less electronegative atom.
In protic solvents, the more electronegative atom is better solvated by hydrogen bonds than
the less electronegative atom. In polar aprotic solvents, neither atom of the nucleophile is
greatly solvated, but these solvents are very effective in solvating cations. Thus in a polar
aprotic solvent the more electronegative end of the nucleophile is freer from entanglement by
both the solvent and the cation, so that a change from a protic to a polar aprotic solvent often
increases the extent of attack by the more electronegative atom.
An example is attack by sodium β-naphthoxide on benzyl bromide, which resulted in 95% O-
alkylation in dimethyl sulfoxide and 85% C-alkylation in 2,2,2-trifluoroethanol. Changing the
cation from Li+ to Na+ to K+ (in non-polar solvents) also favors O- over C-alkylation for
similar reasons (K+ leaves the nucleophile much freer than Li+), as does the use of crown
ethers, which are good at solvating cations. Alkylation of the enolate anion of cyclohexanone
in the gas phase, where the nucleophile is completely free, showed only O-alkylation and no C-
alkylation.
4. In extreme cases, steric effects can govern the regioselectivity.
Ambident Substrates
The substrates that can be attacked by the nucleophile at two or more positions are called
ambident substrates.e.g., 1,3-dichlorobutane.
There are two kinds of substrates that are inherently ambident (unless symmetrical); the allylic
type, and the epoxy substrate.

Substitution of the free epoxide in neutral or basic solution usually involves an S N2 mechanism.
Hence unsymmetrical epoxides are attacked at the less highly substituted carbon with inversion at
that carbon. Under acidic conditions protonated epoxide undergoes the reaction. Under these
conditions the mechanism can be either SN1 or SN2. In SN1 mechanisms attack would be at the
more highly substituted carbon, due to stability of the carbocation. However, even when
protonated epoxides react by the SN2 mechanism, attack is usually at the more highly substituted
position. Thus, it is often possible to change the direction of ring opening by changing the
conditions from basic to acidic or vice versa. In the ring opening of 2,3-epoxy alcohols, the
presence of Ti(O-iPr)4 increases both the rate and the regioselectivity, favoring attack at C-3
rather than C-2. When an epoxide ring is fused to a cyclohexane ring, S N2 ring opening invariably
gives diaxial rather than diequatorial ring opening.
Cyclic sulfates, prepared from 1,2-diols, react in the same manner as epoxides, but usually
more rapidly.
Electrophilic Aliphatic Substitution

Electrophilic substitutions can be carried out, by the removal of a proton, at acidic positions
like α-carbon of a carbonyl group or at first carbon of a 1-alkyne (RC≡CH). Since metallic ions
are easily able to bear positive charges organometallic compounds are susceptible to electrophilic
substitution.
Anionic cleavage, involves the breaking of C–C bonds with carbon leaving groups producing a
carbanon. So is the subject of very weak acids and very strong bases because the weakest acids
are those in which the hydrogen is bonded to carbon.
There are four possible major mechanisms; which we call SE1, SE2 (front), SE2 (back), and
SEi. The SE1 is unimolecular and others are bimolecular. To describe the steric course of an
aliphatic substitution reaction, the suffixes ‘‘ret’’ and ‘‘inv’’ were proposed, referring to retention
and inversion of configuration, respectively.
Bimolecular Mechanisms: SE2 and SEi
When the nucleophilic species attacks (donates electrons to) an electrophile, which brings to
the substrate only a vacant orbital, we can imagine two main possibilities: delivery of the
electrophile to the front; SE2 (front), and delivery of the electrophile to the rear; SE2 (back).
The former reaction result in retention of configuration and the latter in inversion.
When the electrophile reacts from the front, there is a third
possibility. A portion of the electrophile may assist in the
removal of the leaving group, forming a bond with it at the
same time that the new C–Y bond is formed.

This mechanism is called SEi mechanism, which also results in retention of configuration.
Plainly, where a second order mechanism involves this kind of internal assistance, backside attack
is impossible.
When cis-1 was treated with labeled mercuric chloride, the 2 produced was 100% cis. The
bond between the mercury and the ring must have been broken (as well as the other Hg–C bond),
since each of the products contained about half of the labeled mercury.
Another indication of front side attack is that SE2 reactions proceed very easily at bridgehead
carbons. Neopentyl systems undergo electrophilic substitution only slightly more slowly than
ethyl is further evidence for front side attack.
Another proof is given below.
The compound di-sec-butylmercury was prepared

with one sec-butyl group optically active and the
other racemic. This was accomplished by treatment
of optically active sec-butylmercuric bromide with
racemic sec-butylmagnesium bromide. The di-sec-
butyl compound was then treated with mercuric
bromide to give 2 eqiuivalents of sec-butylmercuric
bromide. The steric course of the reaction could then
be predicted by the following analysis, assuming that
the bonds between the mercury and each carbon have
a 50% chance of breaking.
The original activity referred to is the activity of the optically active sec-butylmercuric
bromide used to make the dialkyl compound. The actual result was that, under several different
sets of conditions, the product had one-half of the original activity, demonstrating retention of
configuration.
The SE1 Mechanism
The SE1 mechanism is analogous to the SN1. It involves two steps: a slow ionization and a
fast combination.

First-order kinetics is predicted and many such examples have been found. Other evidence
for the SE1 mechanism was obtained in a study of base-catalyzed tautomerization.
In the reaction, the rate of deuterium exchange was the same as the rate of racemization and
there was an isotope effect.
The SN1 reactions do not proceed at strained bridgehead carbons (e.g., in [2.2.1] bicyclic
systems) because planar carbocations cannot form at these carbons. However, carbanions not
stabilized by resonance are not planar, and SE1 reactions readily occur with this type of substrate.
Thus, the carbanion structure is intimately tied into the problem of the stereochemistry of the S E1
reaction.
If a carbanion is planar, racemization should occur. If it is pyramidal and can hold its
structure, the result should be retention of configuration. Unfortunately, the only carbanions that
can be studied easily are those stabilized by resonance, which makes them planar, as expected.
For simple alkyl carbanions, the main approach to determining structure has been to study the
stereochemistry of SE1 reactions. Racemization is almost always observed, but whether this is
caused by planar carbanions or by oscillating pyramidal carbanions is not known. In either, case
racemization occurs whenever a carbanion is completely free or is symmetrically solvated.
However, even planar carbanions need not give racemization. Cram found that retention and
even inversion can occur in the alkoxide cleavage reaction.
It is a first-order SE1 reaction involving resonance-stabilized planar carbanions. By changing

the solvent Cram was able to produce products ranging from 99% retention to 60% inversion and
including complete racemization. These results are explained by a carbanion that is not
completely free but is solvated. In non-dissociating, non-polar solvents, such as benzene or
dioxane, the alkoxide ion exists as an ion pair, solvated by the solvent BH.
In the course of the cleavage, the proton of the solvent moves in to solvate the newly forming
carbanion. This solvation is asymmetrical since the solvent molecule is already on the front side
of the carbanion. When the carbanion bonds with the proton, the result is retention of the original
configuration. In protic solvents, such as diethylene glycol, a good deal of inversion is found. In
these solvents, the leaving group solvates the carbanion, so the solvent can solvate it only from
the opposite side.

When C–H bond formation occurs, the result is inversion. Racemization results in polar
aprotic solvents, such as DMSO. In these solvents, the carbanions are relatively long lived
(because the solvent has no proton to donate) and symmetrically solvated.
Similar behavior was found for carbanions generated by base-catalyzed hydrogen exchange.
In this case, information was obtained from measurement of the ratio of ke (rate constant for
isotopic exchange) to ka (rate constant for racemization). A ke/ka ratio >1 means retention of
configuration, since many individual isotopic exchanges are not producing a change in
configuration. A ke/ka ratio of ~1 indicates racemization and a ratio of 1/2 corresponds to
inversion.
All three types of steric behavior were found, depending on R, the base, and the solvent. As
with the alkoxide cleavage reaction, retention was found in solvents of low dielectric constant,
racemization in polar aprotic solvents, and inversion in protic solvents. However, in the proton-
exchange reactions, a fourth type of behavior was encountered. In aprotic solvents, with aprotic
bases like tertiary amines, the ke/ka ratio was found to be less than 0.5, indicating that
racemization took place faster than isotopic exchange (this process is known as isoracemization).
Under these conditions, the conjugate acid of the amine remains associated with the carbanion as
an ion pair. Occasionally, the ion pair dissociates long enough for the carbanion to turn over and
recapture the proton.
Thus, inversion (and hence racemization, which is produced by repeated acts of inversion)
occurs without exchange. A single act of inversion without exchange is called isoinversion.
The isoinversion process can take place by a pathway in which a positive species migrates in
a stepwise fashion around a molecule from one nucleophilic position to another. For example, in
the exchange reaction of 3-carboxamido-9-methylfluorene (4) with Pr3N in t-BuOH, it has been
proposed that the amine removes a proton from the 9 position and conducts the proton out to the
C=O oxygen around the molecule, and back to C-9 on the opposite face of the anion. Collapse of
7 gives the inverted product 8. Of course, 6 could also go back to 4, but a molecule that undergoes
the total process 4 → 5 → 6 → 7 → 8 has experienced an inversion without an exchange.

Evidence for this pathway, called the conducted tour mechanism, is that the 12-carboxamido
isomer of 4 does not give isoracemization. In this case, the negative charge on the oxygen atom in
the anion corresponding to 6 is less, because a canonical form in which oxygen acquires a full
negative charge (9) results in disruption of the aromatic sextet in both benzene rings. Whether the
isoracemization process takes place by the conducted tour mechanism or a simple non-structured
contact ion-pair mechanism depends on the nature of the substrate (e.g., a proper functional group
is necessary for the conducted tour mechanism) and of the base.
Vinylic carbanions can maintain configuration, so that SE1 mechanisms should produce
retention there. For example, trans-2-bromo-2-butene was converted to 64–74% angelic acid.
Only 5% of the cis isomer, tiglic acid, was produced. In addition, certain carbanions in which the
negative charge is stabilized by d-orbital overlap can maintain configuration and S E1 reactions
involving them proceed with retention of configuration.
The Effect of Substrate Structure

For SE1 reactions electron-donating groups decrease rates and electron-withdrawing groups
increase them. This is because the rate-determining step is analogous to the cleavage of a proton
from an acid. For the SE2 (back) mechanism, the reactivity of alkyl groups is similar to that for the
SN2 mechanism (i.e., Me > Et > Pr > iPr > neopentyl), since both involve backside attack and both
are equally affected by steric hindrance. For S E2 reactions α branching increased the rates, while β
branching decreased them. The decreased rates are due to steric hindrance, although attack here
was definitely frontside, and the increased rates to the electron-donating effect of the alkyl groups,
which stabilized the electron-deficient transition state. The rates of certain second-order
substitutions of organotin compounds have been found to increase with increasing electron
withdrawal by substituents. This behavior has been ascribed to an S E2 mechanism involving ion
pairs. Solvolysis of 2-bromo-1,1,1-trifluoro-2-(p-methoxyphenyl)ethane in water proceeds via a
free carbocation intermediate, but ion pairing influences the reaction in the presence of bromide
ion.
The Effect of Leaving Group
For both SE1 and second-order mechanisms, the more polar the C–X bond, the easier it is for
the electrofuge to cleave. For metallic leaving groups in which the metal has a valence >1, the
nature of the other group or groups attached to the metal thus has an effect on the reaction. For
example, consider a series of organomercurials RHgW. Because a more electronegative W
decreases the polarity of the C–Hg bond and furthermore results in a less stable HgW+, the

electrofugal ability of HgW decreases with increasing electronegativity of W. Thus, HgR’ (from
RHgR’) is a better leaving group than HgCl (from RHgCl). Also in accord with this is the
leaving-group order Hg-t-Bu > Hg-iPr > HgEt > HgMe, reported for acetolysis of R2Hg, since the
more highly branched alkyl groups better help to spread the positive charge. It might be expected
that, when metals are the leaving groups, SE1 mechanisms would be favored, while with carbon
leaving groups, second-order mechanisms would be found. However, the results so far reported
have been just about the reverse of this. For carbon leaving groups the mechanism is usually SE1,
while for metallic leaving groups the mechanism is almost always S E2 or SEi. A number of reports
of SE1 reactions with metallic leaving groups have appeared, but the mechanism is not easy to
prove and many of these reports have been challenged. In such reactions a nucleophile (which
may be the solvent) must assist in the removal of the electrofuge and refer to such processes as
SE1(N) reactions.
The Effect of Solvent
In addition to the solvent effects on certain S E1 reactions, mentioned earlier, solvents can
influence the mechanism that is preferred. As with nucleophilic substitution an increase in solvent
polarity increases the possibility of an ionizing mechanism, in this case S E1, in comparison with
the second-order mechanisms, which do not involve ions. The solvent can also exert an influence
between the SE2 (front or back) and SEi mechanisms in that the rates of SE2 mechanisms should
be increased by an increase in solvent polarity, while S Ei mechanisms are much less affected.
Electrophilic Aromatic Substitution

Due to the presence of π electron density above and below the plane of its ring, benzene
behaves as a nucleophile and hence is attacked by electrophiles. Whether the electrophilic attack
in a benzene ring leads to addition or substitution can be explained by considering the relative
stabilities of the products formed from their energy profile diagram.
In both electrophilic addition and electrophilic substitution the rate determining step is the
attack of the electrophile to form a carbocation. If the carbocation is attacked by the nucleophile,
an addition product is formed. If the carbocation loses a proton, substitution product is formed. In
benzene only substitution product is formed because substitution retains the aromaticity (stability
by resonance) while addition destroys the aromaticity.

The reaction coordinate

diagram shows that the
reaction of benzene to form
substituted benzene has a ΔGo
close to zero. The reaction of
benzene to form the much less
stable nonaromatic addition
product would have been a
highly endergonic reaction.
Consequently, benzene undergoes electrophilic substitution reactions that preserve

aromaticity, rather than electrophilic addition reactions, which would destroy aromaticity.
In aromatic electrophilic substitution reactions, the
H+ ion from the benzene ring will be replaced by an
electrophile.
The reactions include halogenation, nitration, sulphonation, Friedal-Craft’s alkylation
and Friedal-Craft’s acylation.
All these reactions proceed though a general two step mechanism. In the first step,
benzene reacts with an electrophile forming a carbocation intermediate (arenium ion or a sigma
complex) which has three resonance forms. In the second step, a base in the reaction mixture pulls
off a proton from the carbocation intermediate, and the electrons that held the proton move into
the ring to reestablish its aromaticity (deprotonation and aromatization). The proton is always
removed from the carbon that has formed the new bond with the electrophile.
The first step is relatively slow and endergonic (rate determining step) because an
aromatic compound is being converted into a much less stable non-aromatic intermediate. The
second step is fast and strongly exergonic because this step restores the stability enhancing
aromaticity.
Halogenation of Benzene
When benzene is treated with halogen in the
absence of sunlight and in presence of a halogen
carrier (any Lewis acid like BF3, AlCl3, FeCl3, FeBr3
etc) halobenzene is formed.
Chlorobenzene and bromobenzene can be prepared
by this method.
Bromine is not sufficiently electrophilic to react with benzene, and the formation of Br+
(bromonium ion) is difficult. Lewis acid FeBr3 catalyzes the reaction by forming a complex with
Br2 that reacts like Br+. Bromine donates a pair of electrons to FeBr3 forming a stronger
electrophile with a weakened Br-Br bond and a partial positive charge on one of the bromine
atoms. Attack by benzene forms the sigma complex. Bromide ion from FeBr4 - acts as a weak base
to remove a proton from the sigma complex, giving the aromatic product and HBr, and
regenerating the catalyst.
Chlorination of
benzene works much like
bromination, except that
AlCl3 is most often used
as the Lewis acid
catalyst.
FeBr3 and FeCl3 react readily with moisture in the air during handling, which inactivates
them as catalysts. Therefore, instead of using the actual salt, FeBr 3 or FeCl3 is generated in situ by
adding iron filings and bromine or chlorine to the reaction mixture. Therefore, the halogen in the
Lewis acid is the same as the reagent halogen.
Unlike the reaction of benzene with Br2 or Cl2 the reaction of an alkene does not require a
Lewis acid. An alkene is more reactive than benzene because an alkene has smaller activation
energy, since carbocation formation is not accompanied by a loss of aromaticity. As a result, the
Br-Br or Cl-Cl bond does not have to be weakened to form a better electrophile.
Iodobenzene cannot be prepared by the direct iodination of benzene because HI, formed as
a byproduct, being a powerful reducing agent will reduce iodobenzene back into benzene.
Therefore, iodination is carried out in presence of an oxidizing agent like HNO 3 or HIO3.

Iodination involves iodine cation

as the electrophile which is generated by
oxidation of iodine by nitric acid.
Once the electrophile is formed,
iodination occurs by the same
mechanism as bromination and
chlorination.
Nitration of Benzene
When benzene is treated with nitrating mixture, nitrobenzene is formed. Nitrating mixture
is a mixture of fuming HNO3 and conc. H2SO4. Fuming nitric acid is conc. HNO3 containing
dissolved NO2.
The electrophile during nitration is nitronium ion ( +NO2). The function of conc. H2SO4
(catalyst) is the generation of nitronium ion.
In the nitrating mixture nitric acid behaves as the base. Sulfuric acid protonates the
hydroxyl group of nitric acid, allowing it to leave as water and form a nitronium ion. The
nitronium ion reacts with benzene to form a sigma complex in the rate determining step. Loss of a
proton from the sigma complex by any base present in the reaction mixture (H2O, HSO4- or
solvent) gives nitrobenzene.

Sulphonation of Benzene
When benzene is treated with
fuming H2SO4, benzene sulphonic acid is
formed. Fuming H2SO4 (pyrosulphuric acid
or oleum) is conc. H2SO4 containing
dissolved SO3. Sulphonation is a reversible reaction.
The electrophile during sulphonation is SO3. Although it is uncharged, SO3 is a strong
electrophile, with three sulfonyl bonds (S=O) drawing electron density away from the sulfur atom.
Benzene attacks at the sulphur of SO3, forming a sigma complex. Loss of a proton on the
tetrahedral carbon and reprotonation on oxygen gives benzenesulphonic acid.
Sulphonation is reversible, and a sulphonic acid group may be removed from an aromatic
ring by heating in dilute sulphuric acid. In practice, steam is often used as a source of both water
and heat for desulfonation.

As the following mechanism show, a substantial amount of electrophilic SO3 is generated

when concentrated H2SO4 is heated, as a result of the electrophile +SO3H losing a proton.
Friedel–Crafts Alkylation of Benzene

When benzene is treated with an alkyl halide in presence of anhydrous AlCl3 alkyl
benzene or higher homologues of benzene are formed.
The electrophile during alkylation is carbocation. The function of Lewis acid is the
generation of carbocation.
The electrophile in a Friedel–Crafts alkylation is formed by the complexation of the Lewis
acid AlCl3 with the halogen of an alkyl halide in same way as in the bromination of benzene with
FeBr3 and Br2. If the alkyl halide is secondary or tertiary, this complex can further react to form
carbocation intermediates.
Either the alkyl halide–Lewis acid complex, or the carbocation derived from it, can serve
as the electrophile in a Friedel–Crafts alkylation. The sigma complex thus produced undergoes
deprotonation by the base followed by aromatization. The catalyst is also regenerated.
Alkyl fluorides, alkyl chlorides, alkyl bromides, and alkyl iodides can all be used. Vinyl
halides and aryl halides cannot be used because their carbocations are too unstable to be formed.

With primary alkyl halides, the free primary carbocation is too unstable. The actual
electrophile is a complex of aluminum chloride with the alkyl halide. In this complex, the carbon–
halogen bond is weakened and there is considerable positive charge on the carbon atom.
Friedel–Crafts Alkylation using other carbocation sources: Two common methods of

producing carbocations are protonation of alkenes and treatment of alcohols with dilute mineral
acids or Lewis acids.

Alkenes are protonated by HF to give carbocations. Fluoride ion is a weak nucleophile and
does not immediately attack the carbocation. If benzene (or an activated benzene derivative) is
present, electrophilic substitution occurs. The protonation step follows Markovnikov’s rule,
forming the more stable carbocation, which alkylates the aromatic ring.
Alcohols commonly form carbocations when treated with Lewis acids such as boron
trifluoride.
Limitations of the Friedel–Crafts Alkylation: Although the Friedel–Crafts alkylation looks

good in principle, it has three major limitations that severely restrict its use.
1. The reaction fails with compounds containing strongly deactivating groups like
nitrobenzene, benzoic acid, benzenesulfonic acid, and phenyl ketones (Nitrobenzene is used as a
solvent in Friedal-Craft’s reaction). Aniline, even though contains an activating group, do not give
the reaction because the catalyst is deactivated by Lewis acid-base reaction.
2. Since the electrophile is a carbocation, sometimes the reaction may be accompanied by
rearrangement.

3. Because alkyl groups are activating substituents, the product of the Friedel–Crafts alkylation is
more reactive than the starting material and multiple alkylations take place.
If we need to make ethylbenzene, we might try adding some to a mixture of 1 mole of

ethyl chloride and 1 mole of benzene. As some ethylbenzene is formed, however, it is activated,
reacting even faster than benzene itself. The product is a mixture of some (ortho and para)
diethylbenzenes, some triethylbenzenes, a small amount of ethylbenzene, and some leftover
benzene.
The problem of overalkylation can be minimized by using a large excess of benzene. For
example, if 1 mole of ethyl chloride is used with 50 moles of benzene, the concentration of
ethylbenzene is always low, and the electrophile is more likely to react with benzene than with
ethylbenzene. Distillation separates the product from excess benzene. This is a common industrial
approach, since a continuous distillation can recycle the unreacted benzene.
In the laboratory, we must often alkylate aromatic compounds that are more expensive
than benzene. Because we cannot afford to use a large excess of the starting material, a more
selective method is needed.
Friedel–Crafts Acylation of Benzene

When benzene is treated with an acid chloride or an acid anhydride in presence of

anhydrous AlCl3, acyl group is introduced into the benzene ring and aromatic ketones
(acylbenzenes) are formed.
The electrophile during Friedel-Crafts acylation is acylonium ion. The function of

anhydrous AlCl3 is the generation of acylonium ion. Anhydrous AlCl3, being a Lewis acid,
polarize the C-Cl bond in acid chlorides and C-O bond in acid anhydrides producing the
acylonium ion, which being an electrophile, is attacked by the benzene ring to form the sigma
complex in the rate determining step. The sigma complex thus produced undergoes deprotonation
by the base followed by aromatization. The catalyst is also regenerated.
Because the product contains a carbonyl group that can complex with AlCl3, the reaction
must be carried out with more than one equivalent of AlCl3. When the reaction is over, water is
added to the reaction mixture to liberate the product from the complex.

The acylbenzene has a carbonyl group (a deactivating group) bonded to

the aromatic ring. Since Friedel–Crafts reactions do not occur on strongly
deactivated rings, the acylation stops after one substitution.
Thus, Friedel–Crafts acylation overcomes two of the three limitations of the alkylation:
The acylium ion is resonance-stabilized, so that no rearrangements occur; and the acylbenzene
product is deactivated, so that no further reaction occurs. Like the alkylation, however, the
acylation fails with strongly deactivated aromatic rings.
Both Friedel–Crafts alkylation and acylation reactions can occur intramolecularly when
the product contains a five- or six-membered ring (proximity effect).
The synthesis of benzaldehyde from benzene poses a problem because formyl chloride, the
acyl halide required for the reaction, is unstable and cannot be purchased or stored. Formyl
chloride can be prepared by means of the Gatterman–Koch formylation reaction. This reaction
uses a high-pressure mixture of carbon monoxide and HCl to generate formyl chloride, along with
an aluminum chloride–cuprous chloride catalyst to carry out the acylation reaction.
Alkylbenzenes can be best synthesised by first converting benzene into acyl benzene by
acylation followed by Clemmenson reduction.

Wolff-Kishner reduction is employed if we

have to protect an alcoholic group in the reactant.
Alkylbenzenes with straight-chain alkyl groups can
also be prepared by Corey-House synthesis.
ORIENTATION OF AROMATIC SUBSTITUTION

The slow step of an electrophilic aromatic substitution reaction is the addition of an
electrophile to the nucleophilic aromatic ring to form a carbocation intermediate.
Substituents that are capable of donating electrons into the benzene ring will stabilize both
the carbocation intermediate and the transition state leading to its formation, thereby increasing
the rate of electrophilic aromatic substitution.
In contrast, substituents that withdraw electrons from the benzene ring will destabilize the
carbocation intermediate and the transition state leading to its formation, thereby decreasing the
rate of electrophilic aromatic substitution.
Electron donating and electron withdrawing groups:

Alkyl substituents (+I group) donate electrons inductively compared with hydrogen due to
the slight polarity of C-H bond, since carbon is slightly more electronegative than hydrogen.
Alkyl groups with α-hydrgen are electron donating because of hyperconjugation also.
If the atom attached to the
benzene ring is more electronegative than
carbon and hydrogen, or carries a positive
charge (-I group) that substituent
withdraws electron density inductively.
If a substituent has a lone pair on the atom that is directly attached to the benzene ring
(+M group), the lone pair can be delocalized into the ring; these substituents donate electrons by
resonance. Eg: -OH, -OR, and -Cl. These substituents also withdraw electrons inductively (-I
group) because the atom attached to the benzene ring is more electronegative than a hydrogen.
If a substituent is attached to the benzene ring by an atom that is multiply bonded to a

more electronegative atom, the electrons of the ring can be delocalized onto the substituent; these
substituents withdraw electrons by resonance (-M group). Eg: C=O, C≡N, -NO2 etc. These

substituents also withdraw electrons inductively (-I group) because the atom attached to the
benzene ring has a full or partial positive change and, therefore, is more electronegative than a
hydrogen.
Relative Reactivity of Substituted Benzenes:

Electron donating groups activate the benzene ring for electrophilic substitution by increasing
the electron density inside the benzene ring. Such groups are called activating groups. Activating
substituents donate electrons into the ring by resonance (+M effect) and withdraw electrons from
the ring by -I effect. Electron donation into the ring by resonance is more significant than
inductive electron withdrawal from the ring.
Electron withdrawing groups deactivate the benzene ring for electrophilic substitution by
decreasing the electron density inside the benzene ring. Such groups are called deactivating
groups. Deactivating substituents withdraw electrons from the ring by both resonance (-M effect)
and -I effects.
The alkyl groups containing α-hydrogen activate the benzene ring via both inductive effect
and hyperconjugation. Thus the methyl group of toluene activates the benzene ring for
electrophilic substitution.
In halobenzene the –I effect of halogen atom is more predominant than its +M effect. So,
the electron density in the benzene ring of halobenzene is less than in benzene. Hence –X is a
deactivating +M group.
Moderately activating substituents are less effective at donating electrons into the ring by
resonance because they can donate electrons by resonance in two competing directions: into the
ring and away from the ring. Overall they donate electrons by resonance into the ring more
strongly.
Electron withdrawal by the carbonyl

group will make the nitrogen of the anilide a
poorer electron donar compared to the –NH2
group of aniline.

Alkyl, aryl, and alkenyl groups are weakly activating substituents. Alkyl groups are
electron donating due to +I effect and hyperconjugation. Aryl and alkenyl groups can donate
electrons into the ring by resonance and can withdraw electrons from the ring by resonance. The
fact that they are weak activators indicates that they are slightly more electron donating than they
are electron withdrawing.
The halogens are weakly deactivating substituents;
they donate electrons into the ring by resonance and
withdraw electrons from the ring inductively. Overall they
withdraw electrons inductively more strongly than they
donate electrons by resonance.
The moderately deactivating
substituents have carbonyl groups
directly attached to the benzene ring.
Carbonyl groups withdraw electrons
both inductively and by resonance.
The strongly deactivating substituents are
powerful electron withdrawers. Except for the
ammonium ions (+NH3, +NH2R, +NHR2 and +NR3),
these substituents withdraw electrons both
inductively and by resonance. The ammonium ions
have no resonance effect, but the positive charge on
the nitrogen atom causes them to strongly withdraw electrons inductively.
Effect of substituents on orientation:
When a monosubstituted
benzene ring undergoes further
substitution, the new entrant can
occupy either ortho, meta or para
positions.
A group already present

in the benzene ring will decide
the position of incoming group
and is called the orientation
effect of the substituent.
All activating groups
and weakly deactivating
halogens are ortho para
directing because they increase
the electron density at both
ortho and para positions.
All deactivating groups
are meta directing because they
decrease the electron density at
both ortho and para positions.

The preferential attack of the electrophile at ortho, meta or para positions can be
explained by comparing the relative stability of the carbocation intermediates (sigma complex)
produced in the reaction, as this step is the rate determining step.
If a substituent donates electrons inductively, the indicated resonance forms are most
stable because the substituent attached directly to the positively charged carbon stabilizes the
carbocation by inductive electron donation. These relatively stable resonance forms are obtained
only when the incoming group is directed to an ortho or para position. Therefore, the most stable
carbocation is obtained by directing the incoming group to the ortho and para positions. Thus,
any substituent that donates electrons inductively is an ortho–para director.
If a substituent donates electrons by resonance, the carbocations formed by putting the

incoming electrophile on the ortho and para positions have a fourth resonance contributor. This is
an especially stable resonance contributor because all atoms (except for hydrogen) have complete
octets. Therefore, all substituents that donate electrons by resonance are ortho–para directors.

Substituents with a positive charge or a partial positive charge on the atom attached to the
benzene ring, withdraw electrons inductively and by resonance. For all such substituents, the
indicated resonance forms are the least stable because they have a positive charge on each of two
adjacent atoms, so the most stable carbocation is formed when the incoming electrophile is
directed to the meta position. Thus, all substituents that withdraw electrons (except for the
halogens, which are ortho–para directors because they donate electrons by resonance) are meta
directors.
The only deactivating substituents that are ortho–para directors are the halogens, which
are the weakest of the deactivators. They are deactivators because they inductively withdraw
electrons from the ring more strongly than they donate electrons by resonance. The halogens
nevertheless are ortho–para directors because of their ability to donate electrons by resonance;
they can stabilize the transition states leading to reaction at the ortho and para positions by
resonance electron donation.
All +M groups are ortho-para directing and all -M groups are meta directing. Alkyl
groups with α-hydrogen are ortho-para directing due to hyperconjugation. Aryl and vinyl groups
are ortho-para directing due to the presence of conjugated π bond with the benzene ring. If the
substituent does not exert resonance effect (as in anilinium cation and benzotrichloride), the
groups are found to be meta directors since the corresponding sigma complex is more stable.
Some more substituent effects:
The activating and deactivating effects of the substituent determine the conditions needed
to carry out a reaction.
-NH2 and –OH groups are so
strongly activating that halogenation is
carried out without the Lewis acid
catalyst and a tribromo derivative is
formed in a polar solvent like water or
glacial acetic acid.

If a methoxy group is present a

monobromo derivative is formed because
the methyl substituent sterically hinders the
+M effect of oxygen lone pair.
To get a monobromoderivative from aniline the –NH2 group is first protected by

acetylation. Electron withdrawal by the carbonyl group will make the nitrogen of the anilide a
poorer electron donar compared to the –NH2 group of aniline.
Aniline cannot be nitrated because nitric acid is an oxidizing agent and primary amines are
easily oxidized (Nitric acid and aniline can be an explosive combination). Hence to introduce –
NO2 group into the benzene ring of aniline, -NH2 group is first protected by acylation.
Tertiary aromatic amines, however, can be nitrated. Because the tertiary amino group is a
strong activator, nitration is carried out with nitric acid in acetic acid, a milder combination than
nitric acid in sulfuric acid. About twice as much para isomer is formed as ortho isomer.
All Friedel–Crafts reactions require the Lewis acid catalyst. However, if there is a
deactivating group in the ring, it will be too unreactive to undergo either Friedel–Crafts acylation
or Friedel–Crafts alkylation.
Aniline and N-substituted anilines also do not

undergo Friedel–Crafts reactions. The lone pair on the
amino group will complex with the Lewis acid that is
needed to carry out the reaction, converting the substituent
into a deactivating meta director.

Phenol and anisole undergo Friedel–Crafts reactions—orienting ortho and para—because

oxygen, being a weaker base than nitrogen, does not complex with the Lewis acid.
Orientation in Benzene Rings with More Than One Substituent
In many cases, the groups already on the ring reinforce each other. Thus, 1,3-
dimethylbenzene is substituted at the 4 position (ortho to one group and para to the other), but not
at the 5 position (meta to both). Likewise, the incoming group in p-chlorobenzoic acid goes to the
position ortho to the chloro and meta to the carboxyl group.
When the groups oppose each other, predictions may be more
difficult. In a case such as where two groups of about equal directing
ability are in competing positions, all four products can be expected, and it
is not easy to predict the proportions, except that steric hindrance should
probably reduce the yield of substitution ortho to the acetamido group,
especially for large electrophiles.
Mixtures of about equal proportions are frequent in such cases. Nevertheless, even when
groups on a ring oppose each other, there are some regularities.
1. If a strong activating group competes with a weaker one or with a deactivating group, the
former controls. Thus o-cresol gives substitution mainly ortho and para to the hydroxyl
group and not to the methyl. For this purpose groups are arranged in the following order:
NH2, OH, NR2, O > OR, OCOR, NHCOR > R, Ar > halogen > meta-directing groups.
2. All other things being equal, a third group is least likely to enter between two groups in
the meta relationship. This is the result of steric hindrance and increases in importance
with the size of the groups on the ring and with the size of the attacking species.
3. When a meta-directing group is meta to an ortho–para-directing group, the incoming
group primarily goes ortho to the meta-directing group rather than para. For example,
chlorination of 18 gives mostly 19.
The importance of this effect is underscored by the fact that 20, which is in violation of the
preceding rule, is formed in smaller amounts, but 21 is not formed at all. This is called the ortho
effect. Another is the nitration of p-bromotoluene, which gives 2,3-dinitro-4-bromotoluene. In this
case, once the first nitro group came in, the second was directed ortho to it rather than para, even
though this means that the group has to come in between two groups in the meta position. There is
no good explanation yet for the ortho effect, though possibly there is intramolecular assistance
from the meta-directing group.
It is interesting that chlorination of 18 illustrates all three rules. Of the four positions open to
the electrophile, the 5 position violates rule 1, the 2 position rule 2, and the 4 position rule 3. The
principal attachment is therefore at position 6.
The Ortho/Para Ratio

An aromatic substitution reaction of a benzene derivative bearing an ortho, para-directing
group would give twice as much ortho as para product if substitution were completely random,
because there are two ortho positions and only one para position available for substitution.
On a purely statistical basis there would be 67% ortho and 33% para.
However, the phenonium ion which arises from protonation of benzene,
has the approximate charge distribution shown.
If we accept this as a model for the arenium ion in aromatic
substitution, a para substituent would have a greater stabilizing effect on
the adjacent carbon than an ortho substituent.
If other effects are absent, this would mean that >33% para and <67% ortho substitution
would be found.
For example, nitration of toluene gives twice as much o-nitrotoluene as p-nitrotoluene.
This result occurs because the nitration of toluene at either the ortho or para position is so
fast that it occurs on every encounter of the reagents; that is, the energy barrier for the reaction is
insignificant. Hence, the product distribution corresponds simply to the relative probability of the
reactions. Because the ratio of ortho and para positions is 2 : 1, the product distribution is 2 : 1. In
fact, the ready availability of o-nitrotoluene makes it a good starting material for certain other
ortho-substituted benzene derivatives.
Another important factor is the steric effect. If either the group on the attacking ring or the
group on the electrophile is large, steric hindrance inhibits formation of the ortho product and
increases the amount of the para isomer. For example, Friedel–Crafts acylation of toluene gives
essentially all para substitution product and almost no ortho product. The following nitration
reactions illustrate the decrease in the ortho–para ratio with an increase in the size of the alkyl
substituent.
To make the reaction synthetically useful the separation shall be made easier. Usually,
syntheses that give mixtures of isomers are avoided because, in many cases, isomers are difficult
to separate. However, the ortho and para isomers obtained in many electrophilic aromatic
substitution reactions have sufficiently different physical properties that they are readily
separated. For example, the boiling points of o- and p-nitrotoluene, 2200C and 2380C,
respectively, and these isomers can be separated by careful fractional distillation. The melting
points of o- and p-chloronitrobenzene, 340C and 840C, respectively, are so different that the para
isomer can be selectively crystallized. The para isomer has the higher melting point.

When the ortho–para-directing group is one with an unshared pair,

the predominance of the para isomer can be explained by comparing
the relative stabilities of the arenium ions. C is a canonical form with
an ortho-quinoid structure, while D has a para-quinoid structure.
Since para-quinones are more stable than the ortho isomers, D is
more stable than C, and therefore contributes more to the hybrid and
increases its stability compared to the ortho intermediate.
Ipso Attack
The position bearing the substituent in a mono substituted arene is called the ipso position.
Ipso attack has mostly been studied for nitration. When attack of +NO2 leads to incorporation at
the ipso position there are at least five possible fates for the resulting arenium ion.
Path a: The arenium ion can lose +NO2 and revert to the starting compounds. This results in no
net reaction and is often undetectable.
Path b: The arenium ion can lose Z+, in which case this is simply aromatic substitution with a
leaving group other than H.
Path c: The electrophilic group (+NO2) can undergo a 1,2-migration, followed by loss of the
proton. The product in this case is the same as that obtained by direct attachment of +NO2 at the
ortho position of PhZ. It is not always easy to tell how much of the ortho product in any
individual case arises from this pathway, though there is evidence that it can be a considerable
proportion. Because of this possibility, many of the reported conclusions about the relataive
reactivity of the ortho, meta, and para positions are cast into doubt, since some of the product
may have arisen not from direct attachment at the ortho position, but from attachment at the ipso
position followed by rearrangement.
Path d: The ipso substituent (Z) can undergo 1,2-migration, which also produces the ortho
product. The evidence is that this pathway is very minor, at least when the electrophile is +NO2.
Path e: Attack of a nucleophile on 17. In some cases, the products of such an attack
(cyclohexadienes) have been isolated (this is 1,4-addition to the aromatic ring), but further
reactions are also possible.

Relationship between Reactivity and Selectivity

Not all electrophiles are equally powerful. The nitronium ion attacks not only benzene but
also aromatic rings that contain a strongly deactivating group. On the other hand, diazonium ions
couple only with rings containing a powerful activating group. Attempts have been made to
correlate the influence of substituents with the power of the attacking group. The most obvious
way to do this is with the Hammett equation.
For aromatic substitution, k0 is divided by 6 and, for meta substitution, k is divided by 2, so

that comparisons are made for only one position (consequently, k = k0 for the methyl group at a
para position is identical to the partial rate factor pfMe). It was soon found that, while this
approach worked fairly well for electron withdrawing groups, it failed for those that are electron
donating. However, if the equation is modified by the insertion of the Brown σ+ values instead of
the Hammett σ values (because a positive charge develops during the transition state), more
satisfactory correlations can be made, even for electron-donating groups.
Groups with a negative value of σp+ or σm+ are activating for that position; groups with a
positive value are deactivating. The ρ values correspond to the susceptibility of the reaction to
stabilization or destabilization by the Z group and to the reactivity of the electrophile. The ρ
values vary not only with the electrophile, but also with conditions. A large negative value of ρ
means an electrophile of relatively low reactivity. This approach is completely useless for ortho
substitution, since the Hammett equation does not apply there.
A modification of the Hammett approach, suggested by Brown, called the selectivity
relationship, is based on the principle that reactivity of a species varies inversely with selectivity.
Electrophiles can be arranged in order of selectivity as measured by two indexes: (1) their
selectivity in attacking toluene rather than benzene, and (2) their selectivity between the meta and
para positions in toluene. An electrophile more selective in one respect is also more selective in
the other. In many cases, electrophiles known to be more stable (hence less reactive) than others
shows a higher selectivity. For example, the tert-butyl cation is more stable and more selective
than the isopropyl, and Br2 is more selective than Br+. However, deviations from the relationship
are known. Selectivity depends not only on the nature of the electrophile but also on the
temperature. As expected, it normally decreases with increasing temperature.
Nucleophilic Aromatic Substitution

Aryl halides are less reactive towards nucleophilic substitution reactions than alkyl
halides due to three reasons.
(a) Polarity of C-X bond: C-X bond of aryl halides are less polar than in alkyl halides because in
aryl halides the dipole moments due to –I and +M effects of halogens oppose each other. So lesser
+ve charge will be available in the α carbon of aryl halides making the attack of nucleophile
difficult.
(b) Resonance stabilization: As a result of resonance the C-X bond of aryl halides acquire a
partial double bond character and hence its cleavage will be relatively difficult.

(c) % of s-character of α carbon:
In alkylhalides α carbon is sp3 hybridized while in aryl halides it is sp2 hybridized. Since sp2
carbon is more electronegative than sp3 C, lesser +ve charge will be available in α carbon of aryl
halide making the attack of nucleophile difficult.
Aryl halides do not react with nucleophiles under standard reaction conditions because the π
electron clouds repel the approach of a nucleophile. If the aryl halide has one or more electron
withdrawing substituents at ortho or para to the halogen, nucleophilic aromatic substitution
reactions can occur without using extreme conditions. The greater the number of electron-
withdrawing substituents, the easier it is to carry out the nucleophilic aromatic substitution
reaction. Eg: Chlorobenzene to phenol (Dow’s process).
Aromatic nucleophilic substitution reactions generally take place by two mechanisms.

1. Addition-elimination mechanism.
2. Elimination-addition mechanism.
Addition-Elimination (SNAr) Mechanism
It proceeds by a two-step reaction known as an SNAr reaction (substitution nucleophilic
aromatic).
In the first step, the nucleophile attacks the carbon bearing the leaving group from a trajectory
perpendicular to the aromatic ring (slow step), hence is bimolecular. Nucleophilic attack forms a
resonance-stabilized carbanion intermediate called a Meisenheimer complex. In the second step,
the leaving group departs, reestablishing the aromaticity of the ring.

In a nucleophilic aromatic substitution reaction, the incoming nucleophile must be a stronger

base than the substituent that is being replaced, because the weaker of the two bases will be the
one eliminated from the intermediate.
The electron-withdrawing substituent must be ortho or para to the site of nucleophilic attack
because the electrons of the attacking nucleophile can be delocalized onto the substituent only if
the substituent is in one of those positions.
A variety of substituents can be placed on a benzene ring by means of nucleophilic aromatic

substitution reactions. The only requirement is that the incoming group be a stronger base than the
group that is being replaced.
The most convincing evidence was the isolation of the intermediate in the reaction between
2,4,6-trinitrophenetole and methoxide ion.
If the mechanism were similar to SN1 or SN2, the Ar–X bond would be broken in the rate-
determining step. In the SNAr mechanism, this bond is broken after the rate-determining step.
If the SNAr mechanism is operating, a change in leaving group should not have much effect on
the reaction rate. Consider the reaction of dinitro compound with piperidine,
When X was Cl, Br, I, SOPh, SO2Ph, or p-nitrophenoxy, the rates differed only by a factor of
105. The rates are not identical because the nature of X affects the rate at which Y attacks. An
increase in the electronegativity of X causes a decrease in the electron density at the ipso carbon,
resulting in a faster attack by a nucleophile. Hence when X = F, the relative rate was 3300
(compared with I = 1). The fact that fluoro is the best leaving group among the halogens in most
aromatic nucleophilic substitutions is good evidence that the mechanism is different from S N1 and
SN2, where fluoro is by far the poorest leaving group of the halogens.
Step 1 of the SNAr mechanism has been studied for the reaction between picryl chloride and
OH- ions, and spectral evidence has been reported for two intermediates, one a π complex, and the
other a radical ion–radical pair.
Elimination-Addition Mechanism (Benzyne Mechanism)

An aryl halide such as chlorobenzene can undergo a nucleophilic substitution reaction in the
presence of a very strong base such as amide ion. There are two surprising features about this
reaction.
1. The aryl halide does not have to contain an electronwithdrawing group
2. The incoming substituent does not always end up on the carbon vacated by the leaving
group.
For example, when chlorobenzene with the carbon to which the chlorine is attached
isotopically labeled with 14C is treated with amide ion in liquid ammonia, aniline is obtained as
the product. Half of the product has the amino group attached to the isotopically labeled carbon
(denoted by the asterisk) as expected, but the other half has the amino group attached to the
carbon adjacent to the labeled carbon.
Hence the reaction takes place by a mechanism that forms an intermediate in which the two
carbons to which the amino group is attached in the product are equivalent. The mechanism
involves the formation of a benzyne intermediate. Benzyne has a triple bond between two
adjacent carbon atoms of benzene. In the first step of the mechanism, the strong base removes a
proton from the position ortho to the halogen. The resulting anion expels the halide ion forming
benzyne.
The incoming nucleophile can attack either of the carbons of the “triple bond” of benzyne.
Protonation of the resulting anion forms the substitution product. The overall reaction is an
elimination–addition reaction: Benzyne is formed in an elimination reaction and immediately
undergoes an addition reaction.

Substitution at the carbon that was attached to the leaving group is called direct substitution.
Substitution at the adjacent carbon is called cine substitution. In the following reaction, o-
toluidine is the direct-substitution product; m-toluidine is the cine-substitution product.
Although benzyne is too unstable to be isolated, evidence that it is formed can be obtained by a
trapping experiment. When furan is added to a reaction that forms a benzyne intermediate, furan
traps the benzyne intermediate by reacting with it in a Diels–Alder reaction. The product of the
Diels–Alder reaction can be isolated.
Evidence for the benzyne mechanism are the following.

1. If the aryl halide contains two ortho substituents, the reaction should not be able to occur.
2. A synthesis employing a benzyne intermediate is a good way to prepare meta-amino substituted
aryl ethers. The amide ion preferentially attacks the meta position because there is less steric
hindrance at this position and the resulting negative charge can be stabilized by the adjacent
electron-withdrawing oxygen atom.
3. The fact that the order of halide reactivity is Br > I > Cl > F (when the reaction is performed
with KNH2 in liquid NH3) shows that the SNAr mechanism is not operating here.
Structure of benzyne: As the base (amide
ion) pulls off a proton from the β-carbon a
filled sp2 orbital result on the β-carbon.
The lone pair of electron in carbanion is in
an sp2 orbital in the plane of the ring. The C–

Br bond is in the plane of the sp2 orbital. As

the halide ion leaves from the α-carbon with
its bonding electron pair an empty sp2 orbital
is formed on the α-carbon.
The new C-C π bond is formed by the lateral overlapping

between filled sp2 orbital on the β-carbon with the empty sp 2
orbital of the α-carbon. The new C-C π bond is abnormal and is
formed by overlap of two sp2 orbitals outside the ring. This
external π bond is very weak and benzyne is a very unstable
intermediate.
The SN1 Mechanism
For aryl halides and sulfonates, even active ones, S N1 mechanism is very rare. It has observed
only for aryl triflates in which both ortho positions contain bulky groups (tert-butyl or SiR3).
Mechanism is important in reactions with diazonium salts.
The following are the evidences of the mechanism.

1. The reaction rate is first order in diazonium salt and independent of the concentration of Y.
2. When high concentrations of halide salts are added, the product is an aryl halide but the rate is
independent of the concentration of the added salts.
3. The effects of ring substituents on the rate are consistent with a unimolecular rate-determining
cleavage.
4. When reactions were run with substrate deuterated in the ortho position, isotope effects of
~1.22 were obtained. It is difficult to account for such high secondary isotope effects in any
other way except that an incipient phenyl cation is stabilized by hyperconjugation, which is
reduced when hydrogen is replaced by deuterium.
5. That the first step is reversible cleavage was demonstrated by the observation that when
Ar15NH≡N was the reaction species, recovered starting material contained not only
Ar15NH≡N, but also ArNH≡N15. This could arise only if the nitrogen breaks away from the
ring and then returns. Additional evidence was obtained by treating ArNH≡N15 with unlabeled
N2 at various pressures. At 300 atm, the recovered product had lost 3% of the labeled nitrogen,
indicating that PhN2+ was exchanging with atmospheric N2.
There is kinetic evidence that step 1 is more complicated and involves two steps, both
reversible. Intermediate [Ar+N2] has been trapped with carbon monoxide.

The SRN1 Mechanism

When 5-iodo-1,2,4-trimethylbenzene was treated with KNH2 in NH3, (A) and (B) were formed
in the ratio 0.63:1.
A B
But 6-iodo-1,2,4-trimethylbenzene with KNH2 in NH3, yield (A) and (B) in the ratio 5.9:1. The
chloro and bromo analogs did give the same ratio, 1.46:1, showing that the benzyne mechanism
may be taking place there.
To explain the iodo result, besides the benzyne mechanism, this free-radical mechanism is
proposed. This is called the SRN1 mechanism.
Last step of the mechanism produces ArI . radical ions, so the process is a chain mechanism.
Solvated electrons from KNH2 in NH3 initiate the reaction. Evidence was that the addition of
potassium metal (a good producer of solvated electrons in ammonia) completely suppressed the
cine substitution. Further evidence for the S RN1 mechanism was that addition of radical
scavengers (which would suppress a freeradical mechanism) led to 9:10 ratios much closer to
1.46:1. Further evidence for the SRN1 mechanism in the case above was that some 1,2,4-
trimethylbenzene was found among the products. This could easily be formed by abstraction by
Ar. of H from the solvent NH3. Besides initiation by solvated electrons SRN1 reactions have been
initiated photochemically, electrochemically, and even thermally.
Effect of the Substrate Structure
SNAr mechanism
These substitutions are accelerated by electron-withdrawing groups, especially in positions
ortho and para to the leaving group and hindered by electron-attracting groups.
The most highly activating group, N2+, is seldom deliberately used to activate a reaction. In the
diazotization of a compound, such as p-nitroaniline or p-chloroaniline, the group para to the
diazonium group is replaced by OH from the solvent or by X from ArN 2+X. By far, the most
common activating group is the nitro group and the most common substrates are 2,4-dinitrophenyl
halides and 2,4,6-trinitrophenyl halides (also called picryl halides). Polyfluorobenzenes (e.g.,
C6F6), also undergo aromatic nucleophilic substitution quite well. Activating groups, by
withdrawing electron density, are able to stabilize the intermediates and the transition states
leading to them. Reactions taking place by the S NAr mechanism are also accelerated when the
aromatic ring is coordinated with a transition metal.
Benzyne mechanism
Two factors affect the position of the incoming group, the first being the direction in which the
aryne forms. When there are groups ortho or para to the leaving group, there is no choice.

But when a meta group is present, the aryne can form in two different ways:
In such cases, the more acidic hydrogen is removed. Since acidity is related to the field effect
of Z, an electron-attracting Z favors removal of the ortho hydrogen while an electron-donating Z
favors removal of the para hydrogen. The second factor is that the aryne, once formed, can be
attacked at two positions. The favored position for nucleophilic attack is the one that leads to the
more stable carbanion intermediate, and this in turn also depends on the field effect of Z. For -I
groups, the more stable carbanion is the one in which the negative charge is closer to the
substituent.
The Effect of the Leaving Group

The common leaving groups in aliphatic nucleophilic substitution (halide, sulfate, sulfonate,
NR3+, etc.) are also common leaving groups in aromatic nucleophilic substitutions, but the groups
NO2, OR, OAr, SO2R, and SR, which are not generally lost in aliphatic systems, are leaving
groups when attached to aromatic rings.
Surprisingly, NO2 is a particularly good leaving group. An approximate order of leaving-group
ability is F > NO2 > OTs > SOPh > Cl, Br, I > N3 > NR3+ > OAr, OR, SR, NH2. However, this
depends greatly on the nature of the nucleophile, as illustrated by the fact that C 6Cl5OCH3 treated
with NH2 gives mostly C6Cl5NH2; that is, one methoxy group is replaced in preference to five
chlorines.

As usual, OH can be a leaving group if it is converted to an inorganic ester. Among the

halogens, fluoro is generally a much better leaving group than the other halogens, which have
reactivities fairly close together. The order is usually Cl > Br > I, but not always. The leaving-
group order is quite different from that for the S N1 or SN2 mechanisms. The most likely
explanation is that the first step of the S NAr mechanism is usually rate determining, and this step
is promoted by groups with strong –I effects. This would explain why fluoro and nitro are such
good leaving groups when this mechanism is operating. Fluoro is the poorest leaving group of the
halogens when the second step of the SNAr mechanism is rate determining or when the benzyne
mechanism is operating. The four halogens, as well as SPh, NMe3+, and OPO(OEt)2, have been
shown to be leaving groups in the SRN1 mechanism. The only important leaving group in the S N1
mechanism is N2+.
Effect of the Attacking Nucleophile
It is not possible to construct an invariant nucleophilicity order because different substrates and
different conditions lead to different orders of nucleophilicity. But an overall approximate order is
NH2 > Ph3C > PhNH (aryne mechanism) > ArS - > RO- > R2NH- > ArO- > OH- > ArNH2 > NH3 >
I- > Br- > Cl- > H2O > ROH. As with aliphatic nucleophilic substitution, nucleophilicity is
generally dependent on base strength and nucleophilicity increases as the attacking atom moves
down a column of the periodic table, but there are some surprising exceptions. Fr example, OH-, a
stronger base than ArO-, is a poorer nucleophile. In a series of similar nucleophiles, such as
substituted anilines, nucleophilicity is correlated with base strength. Oddly, the cyanide ion is not
a nucleophile for aromatic systems, except in some special cases.

Aliphatic N Aromatic Sub

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Aliphatic N Aromatic Sub

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Dr.

Muhammed Basheer Ummathur 2021

Unit 1: Aliphatic and Aromatic Substitutions

Nucleophilic Aliphatic Substitution

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A negatively charged nucleophile generally will not dissolve in a non-polar solvent. So an

SN1 (Substitution, Nucleophilic, Unimolecular)

Mechanism: SN1 reaction takes place in 2 steps.

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When cis-1-bromo-4-methylcyclohexane undergoes an SN2 reaction, only the trans

However, when cis-1-bromo-4-methylcyclohexane undergoes an SN1 reaction, both the cis

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SN Reactions in Benzylic and Allylic Halides

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SN Reactions in Vinylic and Aryl Halides

The SNi (Substitution, Nucleophilic, Internal) Mechanism

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The Neighboring-Group Mechanism

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Acetolysis of both 4-methoxy-1-pentyl brosylate (24) and 5-methoxy-2-pentyl brosylate

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Once formed, the radical ion cleaves.

Ambident (Bidentant) Nucleophiles: Regioselectivity

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Nucleophilicity in general depends on the polarizability (hard–soft character) of the

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1. In an SN1 mechanism, the nucleophile attacks a carbocation, which is a hard acid. In an S N2

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Electrophilic Aliphatic Substitution

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The compound di-sec-butylmercury was prepared

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It is a first-order SE1 reaction involving resonance-stabilized planar carbanions. By changing

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The Effect of Substrate Structure

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Electrophilic Aromatic Substitution

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The reaction coordinate

Consequently, benzene undergoes electrophilic substitution reactions that preserve

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Iodination involves iodine cation

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As the following mechanism show, a substantial amount of electrophilic SO3 is generated

Friedel–Crafts Alkylation of Benzene

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Friedel–Crafts Alkylation using other carbocation sources: Two common methods of

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Limitations of the Friedel–Crafts Alkylation: Although the Friedel–Crafts alkylation looks

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If we need to make ethylbenzene, we might try adding some to a mixture of 1 mole of

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When benzene is treated with an acid chloride or an acid anhydride in presence of

The electrophile during Friedel-Crafts acylation is acylonium ion. The function of

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The acylbenzene has a carbonyl group (a deactivating group) bonded to

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